Small Animal Critical Care Medicine [3 ed.] 032376469X, 9780323764698

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REFERENCE RANGES FOR SELECT LABORATORY VALUES All readers are urged to use reference values specific for the laboratory or instrumentation device used when interpreting values for individual patients. Reference intervals depend on the region of the world/country, the type of sample (whole blood vs. plasma or serum), and the type of instrument that is being used.

Coagulation Test Reference Ranges (note: point-of-care machines may have markedly different ranges) PT (sec)

Arterial and Venous Blood Gas Values for Normal Cats (at 37°C)a Arterial

Venous

Canine

Feline

pH

7.46 (7.44-7.47)

7.39 (7.38-7.4)

6-11

6-12

PCO2 (mm Hg)

30 (28-32)

37.5 (36-39)

aPTT (sec)

10-25

10-25

Bicarbonate (mmol/L)

21 (20 – 22)

22 (21-24)

FDP (mcg/ml)

,10

,10

97 (94-100)

35 (33-37)

d-dimer

,250

,250

PO2 (mm Hg) (sea level)

(ng/dl)

ACT (sec)

60-125

,165

BMBT (min)

1.7-4.2

1.4-2.4

Fibrinogen (mg/dl)

150-400

150-400

Herbert DA, Mitchell RA. Blood gas tensions and acid-base balance in awake cats. J Appl Physiol 1971;30(3):434-436; Bachmann K, Kutter APN, Schefer RJ, et. al. Determination of reference intervals and comparison of venous blood parameters using standard and non-standard collection methods in 24 cats. J Feline Med Surg 2017;19(8):831-840 a

PT, prothrombin time; aPTT, activated partial thromboplastin time; FDP, fibrinogen degradation products; ACT, activated clotting time; BMBT, buccal mucosal bleeding time.

Normal Adrenal Function Test Values Canine and Feline

Arterial and Venous Blood Gas Values for Normal Dogs (temperature corrected for dog)

Resting cortisol (mcg/dl)

2-6

Arterial

Post-ACTH cortisol (mcg/dl)

6-18

ACTH, adrenocorticotropic hormone.

Venous

pH

7.361 – 7.444

7.345 – 7.433

PCO2 (mm Hg)

27 - 39

40 - 46

Base deficit (mmol/L)

27 to 21.6

–6 to 0.4

Bicarbonate (mmol/L)

17 - 23

19 - 26

Total CO2 (mmol/L)

18 - 24

20 - 27

PO2 (mm Hg) (sea level)

83 - 120

32 - 64

Vanova-Uhrikova I, Rauserova-Lexmaulova L, Rehakova K, et. al. Determination of reference intervals of acid-base parameters in clinically healthy dogs. J Vet Emerg Crit Care 2017;27(3):325-332.

Liver Function Tests Reference Values

Urinalysis Reference Values Canine

Feline

Canine

Feline

Ammonia (mcg/dl)

45-120

30-100

Specific gravity

NH3 post ATT (mcg/dl)

Minimal change from normal

No change from normal

Minimum

1.001

1.001

Maximum

1.060

1.080

Bile acids—fasting (µM)

,10

,2

Usual limits

1.018-1.050

1.018-1.050

Bile acids—2-hour postprandial (µM)

,15.5

,10

Volume (ml/kg/day)

24-41

22-30

Osmolality (mOsm/kg)

369-2416

366-2178

Protein/creatinine ratio

,0.5 5 normal 0.5-1.0 5 gray zone .1.0 5 abnormal

NH3, ammonia; ATT, ammonia tolerance test.

Normal Urinary Fractional Electrolyte Clearance Values (%) Canine

Feline

Sodium

,1

,1

Chloride

,1

,1.3

Potassium

,20

,20

Phosphate

,40

,73

Cerebrospinal Fluid Analysis Reference for Dogs and Cats Value Color

Colorless

Clarity

Transparent, clear

Refractive index

1.3347-1.3350

Protein concentration

Cisternal: ,25 mg/dl Lumbar: ,40 mg/dl

Total cell count

RBC: 0/µl WBC: ,3/µl cisternal ,5/µl lumbar

WBC differential count

Mononuclear cells Small mononuclear cells: 60%-70% Large mononuclear cells: 30%-40% Polymorphonuclear cells Neutrophils: ,1% Eosinophils: ,1% Others Ependymal lining cells: rare Nucleated RBC: rare in lumbar taps

Glucose (mg/dl)

61-116

RBC, Red blood cells; WBC, white blood cells.

Categories of Effusions in Dogs and Cats Transudate

Modified Transudate

Exudate

Hemorrhagic

Chylous*

Specific gravity

,1.017

1.017-1.025

.1.025

N/A

N/A

Total protein (g/dl)

,2.5

2.5-5.0

.3.0

. 2.5

.2.5 Refractometer may be inaccurate

Nucleated cell count (per µl) or PCV

,1000

500-10,000

.5,000

PCV 10% Variable with peripheral PCV

Variable . 3,000

Predominant cell type

Mononuclear Mesothelial

Lymphocytes Monocytes Mesothelial RBCs Neutrophils

Neutrophils Mononuclear cells RBCs

RBCs Neutrophils Lymphocytes Monocytes (no platelets, non-clotting unless actively bleeding)

Small lymphocytes

*Triglycerides .100mg/dl or 1.7mmol/L also supportive of chylous effusion.

Resting Energy Requirement (kcal/24h) and Daily Maintenance Fluid Volume in mL BW0.75 3 70 (BW5body weight in kg) Body Weight (kg)

Daily Maintenance Fluid Volume (ml) and Resting Energy Requirement (kcal/24 hr)

Body Weight (kg)

Daily Maintenance Fluid Volume (ml) and Resting Energy Requirement (kcal/24 hr)

1

70

26

806

2

118

27

829

3

160

28

852

4

198

29

875

5

234

30

897

6

268

31

920

7

301

32

942

8

333

33

964

9

364

34

986

10

394

35

1007

11

423

36

1029

12

451

37

1050

13

479

38

1071

14

507

39

1092

15

534

40

1113

16

560

41

1134

17

586

42

1154

18

612

43

1175

19

637

44

1196

20

662

45

1216

21

687

46

1236

22

711

47

1257

23

735

48

1277

24

759

49

1296

25

783

50

1316

THIRD EDITION

SMALL ANIMAL

Critical Care Medicine Deborah C. Silverstein, DVM, DACVECC Professor of Small Animal Critical Care Medicine Department of Clinical Sciences and Advanced Medicine School of Veterinary Medicine University of Pennsylvania Philadelphia, PA

Kate Hopper, BVSc, PhD, DACVECC Professor of Small Animal Emergency and Critical Care University of California, Davis Department of Surgery and Radiological Sciences School of Veterinary Medicine Davis, CA United States

3251 Riverport Lane St. Louis, Missouri 63043

SMALL ANIMAL CRITICAL CARE MEDICINE, THIRD EDITION

ISBN: 978-0-323-76469-8

Copyright © 2023 by Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notice Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Previous editions copyrighted 2015 and 2009.

Content Strategist: Jennifer Catando Content Development Specialist: Shweta Pant Publishing Services Manager: Deepthi Unni Project Manager: Thoufiq Mohammed Design Direction: Margaret Reid

Printed in India. Last digit is the print number:  9  8  7  6  5  4  3  2  1

D E D I C AT I O N As the saying goes, “Three’s a charm!” Despite the extended pandemic timeline for completion, this third edition of the Small Animal Critical Care Medicine Textbook is by far the best one yet. However, it would not have been possible without the support of so many wonderful people. I want to dedicate this book to my incredible coeditor, Dr. Kate Hopper, and everyone who contributed their writings despite the most challenging of times. The need for cutting-edge, high-quality veterinary critical care medicine has never been greater, and it is exhilarating to be a part of this exciting specialty. The connection between people, animals, and doctors for all species has never felt stronger, and our ability to push the envelope toward new heights of critical care medicine is at our fingertips. I would also like to dedicate this book to my nearest and dearest humans in this world: my husband, Stefan, and my sons, Maxwell and Henry, who keep me grounded, balanced, and fulfilled and have given me never-ending support and unlimited patience as I pursue crazy book editing endeavors. I love you to the moon and back. And lastly, thank you to my dad who was and will always be my greatest inspiration to be the best you can be. Your memory will most definitely always be a blessing. So much to be grateful for. Thank you to all who have made this dream a reality! - Deb I dedicate this book to my family, both Australian and American. In particular, to the next generation of my family, Levi, Jack H, Jack B, Zara, Lucy, and Alex. You bring me so much love and fun and I feel incredibly lucky to have you all in my life. And to my veterinary friends the world over who have enriched my life and have made this career such a wonderful experience. I first met my coeditor, Dr. Deb Silverstein, as a resident mate and she has become the best friend and collaborator one could wish for. Thank you! -Kate

v

CONTRIBUTORS Sophie Adamantos, BVSc, CertVA, DACVECC, DECVECC, MRCVS, FHEA

Dominic Barfield, BSc, BVSc, MVetMed, DECVECC, DACVECC

Clinical Director Paragon Referrals Wakefield, England United Kingdom

Senior Lecturer Royal Veterinary College, London Clinical Science and Services Hertfordshire, England United Kingdom

Ashley E. Allen-Durrance, DVM, DACVECC Clinical Assistant Professor University of Florida Department of Small Animal Clinical Sciences College of Veterinary Medicine Gainesville, FL United States

Ciara A. Barr, VMD, DACVAA

Lillian Ruth Aronson, VMD, DACVS Professor of Surgery University of Pennsylvania Clinical Sciences and Advanced Medicine School of Veterinary Medicine Philadelphia, PA United States

Associate Professor Emergency and Critical Care University of Melbourne, Melbourne Victoria Australia

Manuel Boller, Dr med vet, MTR, DACVECC

Assistant Professor of Clinical Anesthesiology University of Pennsylvania Clinical Sciences and Advanced Medicine School of Veterinary Medicine Philadelphia, PA United States

Specialist Central Victoria Veterinary Hospital Victoria, BC Canada

Linda S. Barter, BVSc, PhD, DACVAA

Senior Lecturer in Emergency and Critical Care Murdoch University School of Veterinary and Biomedical Sciences Murdoch, Western Australia Australia

Robert A. Armentano, DVM, DACVIM Internal Medicine Specialist Veterinary Specialty Center Buffalo grove, IL United States

Elise Mittleman Boller, DVM, DACVECC

Professor University of California, Davis Department of Surgical and Radiological Sciences School of Veterinary Medicine Davis, CA United States

Anthony Barthélemy, DMV, MS, PhD Doctor in ICU & ER Center Hospitalier Vétérinaire HOPia, Guyancourt, France

Corrin Boyd, BSc, BVMS (Hons), GradDipEd, MVetClinStud, MANZCVS, DACVECC

Søren R. Boysen, DVM, DACVECC Associate Professor University of Calgary Veterinary Clinical and Diagnostic Services Calgary, Alberta Canada

Amanda Arrowood, BS, CVT, VTS (ECC) Veterinary Nurse University of Pennsylvania Intensive Care Unit School of Veterinary Medicine Philadelphia, PA United States

Kari Santoro Beer, DVM, DACVECC Emergency and Critical Care Specialist Oakland Veterinary Referral Services Bloomfield Hills, MI United States

Allyson Berent, DVM, DACVIM Anusha Balakrishnan, BVSc, DACVECC Staff Criticalist Cornell University Veterinary Specialists Stamford, CT United States Adjunct Assistant Clinical Professor of Emergency-Critical Care Cornell University College of Veterinary Medicine Ithaca, NY United States

Ingrid M. Balsa, MEd, DVM, DACVS-SA Assistant Clinical Professor University of California, Davis Department of Surgical and Radiological Sciences School of Veterinary Medicine Davis, CA United States

vi

Staff Veterinarian; Director Interventional Endoscopy Services The Animal Medical Center Interventional Radiology/Endoscopy New York, NY United States

Rachael Birkbeck, DVM, PGCert, MVetMed, DACVECC, MRCVS Specialist Dick White Referrals Cambridge, England United Kingdom

Amanda K. Boag, MA, VetMB, DECVECC, DACVECC, DACVIM, FHEA, FRCVS Chief Medical Officer IVC Evidensia Keynsham, Bristol United Kingdom

Benjamin M. Brainard, VMD, DACVAA, DACVECC Edward H Gunst Professor of Small Animal Critical Care University of Georgia Small Animal Medicine and Surgery College of Veterinary Medicine Athens, GA United States

Sara R. Brethel, DVM Cardiology University of Florida College of Veterinary Medicine Gainesville, FL United States

Gareth J. Buckley, MA, VetMB, MRCVS, DACVECC, DECVECC Clinical Associate Professor, Emergency & Critical Care University of Florida Small Animal Clinical Sciences College of Veterinary Medicine Gainesville, FL United States

CONTRIBUTORS

Yekaterina Buriko, DVM, DACVECC

Dana L. Clarke, VMD, DACVECC

Meredith L. Daly, VMD, DACVECC

Assistant Professor - Critical Care University of Pennsylvania Department of Clinical Sciences and Advanced Medicine School of Veterinary Medicine Philadelphia, PA United States

Assistant Professor of Interventional Radiology & Critical Care University of Pennsylvania Department of Clinical Sciences & Advanced Medicine School of Veterinary Medicine Philadelphia, PA United States

Head of Medical Quality Medical Operations Bond Vet New York, NY United States

Jenna H. Burton, DVM, MS, Dip ACVIM (Oncology) Associate Professor, Medical Oncology Colorado State University Clinical Sciences College of Veterinary Medicine Fort Collins, CO United States

Alessia Cenani, DVM, MS, DACVAA Assistant Professor of Clinical Anesthesia University of California, Davis School of Veterinary Medicine Davis, CA United States

Steven J. Centola, BVMS, MRCVS, DACVECC Emergency and Critical Care University of Pennsylvania School of Veterinary Medicine Philadelphia, PA United States

Daniel L. Chan, DVM, DACVECC, DECVECC, DACVIM(Nutrition), FHEA, MRCVS Professor in Emergency and Critical Care The Royal Veterinary College Clinical Sciences and Service Hertfordshire, England United Kingdom

Peter S. Chapman, BVetMed, DECVIMCA, DACVIM, MRCVS Medical Director Internal Medicine Veterinary Specialty and Emergency Center Levittown, PA United States

Dennis J. Chew, DVM, Dipl ACVIM (Internal Medicine) Professor Emeritus The Ohio State University Veterinary Clinical Sciences College of Veterinary Medicine Columbus, OH United States

Melissa A. Claus, DVM, DACVECC Head of Department Emergency and Critical Care Perth Veterinary Specialists, Perth Australia Adjunct Senior Lecturer School of Veterinary Medicine Murdoch University, Perth Australia

vii

Harold Davis, BA, RVT, VTS (ECC) (Anesthesia & Analgesia) Clinical Educational Consultant West Sacramento California United States Former Manager University of California, Davis Small Animal Emergency and Critical Care Service School of Veterinary Medicine Davis, CA United States

Leah A. Cohn, DVM, PhD, DACVIM (SAIM)

Armelle de Laforcade, DVM, DACVECC

Professor, Small Animal Internal Medicine University of Missouri Department of Veterinary Medicine and Surgery College of Veterinary Medicine Columbia, MO United States

Associate Professor Tufts University Clinical Sciences Cummings School of Veterinary Medicine North Grafton, MA United States

Stephen Cole, VMD, MS, DACVM (Bacteriology/Mycology, Immunology)

Sage M. De Rosa, DVM, DACVECC

Assistant Professor of Microbiology University of Pennsylvania School of Veterinary Medicine Philadelphia, PA United States

Assistant Professor University of Pennsylvania Department of Clinical Sciences and Advanced Medicine School of Veterinary Medicine Philadelphia, PA United States

Edward S. Cooper, VMD, MS, DACVECC Professor—Clinical The Ohio State University Veterinary Clinical Sciences School of Veterinary Medicine Columbus, OH United States

Jamie M. Burkitt Creedon, DVM, DACVECC Assistant Professor of Clinical Small Animal Emergency and Critical Care University of California Department of Surgical and Radiological Sciences School of Veterinary Medicine Davis, CA United States

Teresa C. DeFrancesco, DVM, DACVIM, DACVECC Professor of Cardiology and Critical Care North Carolina State University Department of Clinical Sciences College of Veterinary Medicine Raleigh, NC United States

Amy Dixon-Jimenez, DVM, MS, DACVIM Cardiologist Wheat Ridge Animal Hospital Petcardia Wheat Ridge, CO United States

viii

CONTRIBUTORS

Kenneth J. Drobatz, DVM, MSCE, DACVIM, DACVECC Professor and Chief, Section of Critical Care Director, Emergency Service University of Pennsylvania Department of Clinical Studies School of Veterinary Medicine Philadelphia, PA United States

Justin Duval, BSc, DVM, DACVECC Diplomate of the American College of Veterinary Emergency and Critical Care Emergency and Critical Care Veterinary Specialty Center of Seattle Lynnwood, WA United States

Daniel J. Fletcher, PhD, DVM, DACVECC

Giacomo Gianotti, DVM, DVSc, DACVAA

Associate Professor, Emergency and Critical Care Cornell University Department of Clinical Sciences College of Veterinary Medicine Ithaca NY United States

Associate Professor—Anesthesia University of Pennsylvania Department of Clinical Sciences and Advanced Medicine School of Veterinary Medicine Philadelphia, PA United States

Thierry Francey, Dr med vet, Dipl ACVIM (SAIM), Dipl ECVIM-CA

Erin A. Gibson, BS, DVM

Head, Nephrology Group (Small Animal Internal Medicine) University of Bern Department of Clinical Veterinary Medicine Vetsuisse Faculty Bern Switzerland

Adam E. Eatroff, DVM, DACVIM (SAIM) Staff Internist and Nephrologist ACCESS Specialty Animal Hospitals Los Angeles, CA United States

Steven E. Epstein, DVM, DACVECC Professor of Clinical Emergency and Critical Care University of California, Davis Department of Surgical and Radiological Sciences School of Veterinary Medicine Davis, CA United States

Kate S. Farrell, DVM, DACVECC Assistant Professor of Clinical Small Animal Emergency and Critical Care University of California, Davis Department of Surgical and Radiological Sciences School of Veterinary Medicine Davis, CA United States

Christiana Fischer, BS, VMD, DACVECC Criticalist Emergency and Critical Care Metropolitan Veterinary Associates, Norristown, PA United States

Molly J. Flaherty, DVM, CCRP, CVA, CVPP Rehabilitation Medicine Clinician University of Pennsylvania Department of Clinical Sciences School of Veterinary Medicine Philadelphia, PA United States

Fellow, Minimally Invasive Procedures University of California, Davis Department of Surgical and Radiological Sciences School of Veterinary Medicine Davis, CA United States

Massimo Giunti, DVM, PhD, DECVECC Mack Fudge, DVM, MPVM, DACVECC Colonel (ret) Veterinary Corps US Army Retired, Helotes Texas United States Director of Medical Research Surgery Hill Country Animal League, Boerne Texas United States

Joao Felipe de Brito Galvao, MV, MS, DACVIM (SAIM) Internal Medicine Specialist VCA Arboretum View Animal Hospital Downers Grove, IL United States

Caroline K. Garzotto, VMD, DACVS, CCRT Surgeon, Department Head Mount Laurel Animal Hospital Mount Laurel, NJ United States

Anna R.M. Gelzer, DMV, PhD, DACVIM (Cardiology), DECVIM-CA (Cardiology) Professor of Cardiology University of Pennsylvania Department of Clinical Sciences and Advanced Medicine School of Veterinary Medicine Philadelphia, PA United States

Katherine K. Gerken, DVM, MS, DACVECC Assistant Clinical Professor Auburn University Department of Clinical Sciences College of Veterinary Medicine Auburn, AL United States

Associate Professor Alma Mater Studiorum - University of Bologna Department of Veterinary Medical Sciences Bologna Italy

Kris Gommeren, DMV, MSc, PhD, DECVIM-CA, DECVECC Assistant Professor Liege University Small Animal Department Liege Belgium

Jennifer M. Good, DVM, DACVECC, CVA Clinical Assistant Professor of Emergency and Critical Care University of Georgia Small Animal Medicine and Surgery Athens, GA United States

Thomas D. Greensmith, BVetMed, MVetMed, DACVECC, DECVECC, FHEA, MRCVS Lecturer in Emergency and Critical Care Royal Veterinary College Clinical Science and Services Hertfordshire, England United Kingdom

Tamara Grubb, DVM, PhD, DACVAA Adjunct Professor Washington State University Veterinary Clinical Sciences Pullman, WA United States

CONTRIBUTORS

Julien Guillaumin, Docteur Veterinaire, DACVECC, DECVECC Associate Professor Colorado State University Department of Clinical Sciences Fort Collins, CO United States

Rebecka S. Hess, DVM, MSCE, DACVIM Professor University of Pennsylvania Department of Clinical Sciences & Advanced Medicine School of Veterinary Medicine Philadelphia, PA United States

Timothy B. Hackett, DVM, MS, DACVECC Chair, Department of Clinical Sciences Professor, Emergency and Critical Care Medicine Cornell University Department of Clinical Sciences College of Veterinary Medicine Ithaca, NY United States

Guillaume Laurent Hoareau, DVM, PhD, Diplomate ACVECC, Diplomate ECVECC

Emergency and Critical Care Clinician Vets Now Manchester Manchester, England United Kingdom

Assistant Professor University of Utah Health Emergency Medicine Division Salt Lake City, UT United States Investigator Nora Eccles-Harrison Cardiovascular Research and Training Institute University of Utah Health, Salt Lake City, UT United States

Bernie Hansen, DVM, MS, DACVECC, DACVIM (Internal Medicine)

Sabrina N. Hoehne, Dr med vet, DACVECC, DECVECC

Associate Professor North Carolina State University Clinical Sciences Raleigh, NC United States

Assistant Professor of Emergency and Critical Care Medicine Department of Veterinary Clinical Sciences Washington State University, Pullman WA United States

Simon P. Hagley, BVSc, DACVECC

Samantha Hart, BVMS (Hons), MS, DACVS, DACVECC ER Veterinarian Veterinary Emergency Group, Edgewater, CO United States

Ralph C. Harvey, DVM, MS, Diplomate ACVAA

Marie K. Holowaychuk, DVM, DACVECC Veterinary Wellbeing Advocate and Small Animal Emergency and Critical Care Specialist Calgary, Alberta Canada

Chair - Veterinary Advisory Board BioTraceIT Corporation Charlottetown, Prince Edward Island Canada Associate Professor, Retired University of Tennessee Small Animal Clinical Sciences Knoxville, TN United States

Kate Hopper, BVSc, PhD, DACVECC

Galina Hayes, BVSc, PhD, DACVECC, DACVS

Dez Hughes, BVSc (Hons), DACVECC

Assistant Professor Cornell University Small Animal Surgery Ithaca, NY United States

Professor of Small Animal Emergency & Critical Care University of California, Davis Department of Surgical & Radiological Sciences School of Veterinary Medicine Davis, CA United States

Associate Professor and Section Head, Emergency and Critical Care University of Melbourne Faculty of Veterinary and Agricultural Science Werribee, Victoria Australia

ix

Daniel Z. Hume, DVM, DACVIM, DACVECC Medical Director - Critical Care WestVet Boise, ID United States

Karen Humm, MA, VetMB, MSc, CertVA, DACVECC, FHEA, MRCVS Associate Professor in Transfusion Medicine and Emergency and Critical Care The Royal Veterinary College Clinical Sciences and Services London, England United Kingdom

Karl E. Jandrey, DVM, MAS, DACVECC Professor of Clinical Small Animal Emergency & Critical Care Associated Dean of Admissions and Student Programs University of California, Davis School of Veterinary Medicine Davis, CA United States

Tania Perez Jimenez, DVM, MS, PhD, DACVAA Program in Individualized Medicine, Pharmacogenomics Laboratory, Department of Veterinary Clinical Sciences College of Veterinary Medicine, Washington State University Washington United States

Lynelle R. Johnson, DVM, MS, PhD, Dipl ACVIM (SAIM) Professor University of California, Davis Department of Medicine & Epidemiology School of Veterinary Medicine Davis, CA United States

Andrea N. Johnston, DVM, PhD Assistant Professor Louisiana State University Veterinary Clnical Sciences School of Veterinary Medicine Baton Rouge, LA United States

Joanna L. Kaplan, DVM Cardiology Resident University of California, Davis Department of Medicine & Epidemiology School of Veterinary Medicine Davis, CA United States

x

CONTRIBUTORS

Iain Keir, BVMS, DACVECC, DECVECC Head of Critical Care Medicine Small Animal Specialist Hospital Sydney, New South Wales Australia

Marie E. Kerl, DVM, MPH, DACVIM (SAIM), DACVECC Chief Medical Officer VCA Animal Hospitals Inc. Medical Operations Los Angeles, CA United States

Marguerite F. Knipe, BA, DVM, DACVIM (Neurology) Health Sciences Clinical Professor University of California, Davis Department of Surgical & Radiological Sciences School of Veterinary Medicine Davis, CA United States

Kathryn Good, DVM, DACVO Associate Clinical Professor of Veterinary Ophthalmology University of California, Davis Department of Surgical & Radiological Sciences School of Veterinary Medicine Davis, CA United States

Amie Koenig, DVM, DACVIM (SAIM), DACVECC Professor, Emergency and Critical Care University of Georgia Department of Small Animal Medicine and Surgery College of Veterinary Medicine Athens, GA United States

Lucy Kopecny, BVSc (Hons) DACVIM (SAIM) Small Animal Internal Medicine Specialist Small Animal Specialist Hospital Sydney, New South Wales Australia

Marc S. Kraus, DVM, Dipl ACVIM (Internal Medicine, Cardiology), DECVIM -CA (Cardiology) Professor University of Pennsylvania Department of Clinical Sciences & Advanced Medicine School of Veterinary Medicine Philadelphia, PA United States

Catherine E. Langston, DVM, DACVIM Professor - Small Animal Internal Medicine The Ohio State University Columbus, OH United States

Jennifer A. Larsen, DVM, MS, PhD, DACVN Professor of Clinical Nutrition University of California, Davis Department of Molecular Biosciences School of Veterinary Medicine Davis, CA United States

Chai-Fei Li, DVM, DACVIM (Neurology) Assistant Professor University of California, Davis Department of Surgical & Radiological Sciences School of Veterinary Medicine Davis, CA United States

Ronald H. L. Li, DVM, MVetMed, PhD, DACVECC Associate Professor of Small Animal Emergency and Critical Care University of California, Davis Department of Surgical & Radiological Sciences School of Veterinary Medicine Davis, CA United States

Ta-Ying Debra Liu, DVM, DACVECC Veterinary Criticalist VCA Orange County Veterinary Specialists Tustin, CA United States

Natalie Kovak, DVM, DACVECC Criticalist Small Animal Emergency and Critical Care Metropolitan Veterinary Associates, Norristown, PA United States

Alex Lynch, BVSc (Hons), DACVECC, MRCVS Assistant Professor North Carolina State University Department of Clinical Sciences College of Veterinary Medicine Raleigh, NC United States

Bridget M. Lyons, VMD, DACVECC Service Head Department of Emergency and Critical Care Cornell University Veterinary Specialists, Stamford, CT United States

Kristin A. MacDonald, DVM, PhD, DACVIM (Cardiology) Veterinary Cardiologist VCA Animal Care Center of Sonoma County Rohnert Park, CA United States

Deborah C. Mandell, VMD, DACVECC Professor, Emergency and Critical Care University of Pennsylvania Department of Clinical Sciences & Advanced Medicine School of Veterinary Medicine Philadelphia, PA United States

Linda G. Martin, DVM, MS, DACVECC Associate Professor, Emergency and Critical Care Medicine Washington State University Veterinary Clinical Sciences Pullman, WA United States

Karol Mathews, DVM, DVSc, DACVECC Professor Emerita University of Guelph Clinical Studies Ontario Veterinary College Guelph, Ontario Canada

Katie D. Mauro, DVM, DACVECC Assistant Professor of Emergency and Critical Care Medicine Small Animal Clinical Sciences Michigan State University East Lansing, MI, United States

Elisa M. Mazzaferro, MS, DVM, PhD, DACVECC Staff Criticalist Cornell University Veterinary Specialists Department of Emergency & Critical Care Stamford, CT United States Adjunct Associate Clinical Professor Emergency and Critical Care Cornell University Ithaca, NY United States

CONTRIBUTORS

xi

Duana McBride, BVSc, DACVECC, MVMedSc, FHEA, MRCVS

Adam Moeser, DVM, DACVIM (neurology)

Mark A. Oyama, DVM, MSCE, DACVIM-Cardiology

Veterinary Criticalist Southfields Veterinary Specialist Essex, England United Kingdom

Veterinary Neurologist MedVet Commerce, MI United States

Megan E. McClosky, DVM, DACVIM

Bea Monteiro, DVM, PhD, PgDip

Assistant Professor Clinical Medicine and Extracorporeal Therapies University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA United States

Research Advisor Universite de Montreal Department of Clinical Sciences Saint-Hyacinthe, Quebec Canada

Charlotte Newton Sheppard Endowed Chair of Medicine and Professor of Cardiology University of Pennsylvania Department of Clinical Sciences and Advanced Medicine Philadelphia, PA United States

Maureen A. McMichael, DVM, M.Ed., DACVECC Professor Auburn University Department of Clinical Sciences College of Veterinary Medicine Auburn, AL United States Professor Carle-Illinois College of Medicine Department of Biomedical & Translational Science Urbana, IL United States

Margo Mehl, DVM, DACVS Veterinary Surgeon San Franciso Animal Medical Center San Francisco, CA United States

Matthew S. Mellema, DVM, PhD, DACVECC Vice-President for Product Development Applaud Medical Inc. San Francisco, CA United States

Julie M. Menard, DVM, DACVECC Assistant Professor University of Calgary Department of Veterinary Clinical and Diagnostic Services Calgary, Alberta Canada

Vishal D. Murthy, DVM, DACVIM (Neurology) Assistant Professor Washington State University Department of Veterinary Clinical Sciences College of Veterinary Medicine Pullman, WA United States

Sarah E. Musulin, DVM, DACVECC Clinical Associate Professor, Emergency and Critical Care North Carolina State University Molecular Biomedical Sciences Raleigh, NC United States Director of Emergency Services Blood Bank Director NC State Veterinary Hospital

Adesola Odunayo, DVM, MS, DACVECC Clinical Associate Professor of Emergency and Critical Care University of Florida Department of Small Animal Clinical Sciences College of Veterinary Medicine Gainesville, FL United States

Maureen S. Oldach, DVM, DACVIM (Cardiology) Resident, Cardiology University of California, Davis Department of Medicine and Epidemiology School of Veterinary Medicine Davis, CA United States

Laura Osborne, BVSc Hons, DACVECC Carrie J. Miller, DVM, DACVIM Director of Internal Medicine Virginia Veterinary Specialists Charlottesville, VA United States

Criticalist Western Veterinary Specialist and Emergency Centre Calgary, Alberta Canada

James B. Miller, DVM, MS, DACVIM

Katie E. Osekavage, DVM, DACVECC

Retired Stratford Prince Edward Island Canada

Criticalist Upstate Veterinary Specialists Greenville, SC United States

Carrie A. Palm DVM, MAS, DACVIM (Internal Medicine) Professor University of California, Davis Department of Medicine and Epidemiology School of Veterinary Medicine Davis, CA United States

Romain Pariaut, DVM, DACVIM, DECVIM-CA Associate Professor of Cardiology Cornell University Department of Clinical Sciences College of Veterinary Medicine Ithaca, NY United States

Medora Pashmakova, DVM, DACVECC Staff Criticalist BluePearl Veterinary Partners Clearwater, FL United States

Simon Platt, BVM&S, FRCVS, Dipl ACVIM (Neurology), Dipl ECVN Professor of Neurology University of Georgia Department of Small Animal Medicine and Surgery College of Veterinary Medicine Athens, GA United States

Céline Pouzot-Nevoret, DVM, MS, PhD, DECVECC Associate Professor, Head of the ICU (SA-ICU) SIAMU® VetAgro Sup Campus Vétérinaire, Marcy l’Etoile Rhône France

Lisa Leigh Powell, DVM, DACVECC Associate Emergency and Critical Care Clinician Blue Pearl Veterinary Partners Eden Prairie, Minnesota United States

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CONTRIBUTORS

Bruno H. Pypendop, DrMedVet, DrVetSci, DACVAA Professor Department of Surgical and Radiological Sciences School of Veterinary Medicine, University of California, Davis, Davis California United States

Jane Quandt, BS, DVM, MS, DACVAA, DACVECC Professor Department of Small Animal Medicine & Surgery University of Georgia, Athens Georgia United States

Jessica M. Quimby, DVM, PhD, DACVIM Associate Professor of Internal Medicine Department of Veterinary Clinical Sciences The Ohio State University, Columbus Ohio United States

Louisa J. Rahilly, DVM, DACVECC Medical Director Cape Cod Veterinary Specialists, Bourne Massachusetts United States

Alan G. Ralph, DVM, DACVECC Staff Criticalist MedVet, Metairie Louisiana United States

Kaitlyn Rank, DVM Resident, Emergency and Critical Care Department of Clinical Sciences Small Animal Emergency & Critical Care North Carolina State College of Veterinary Medicine, Raleigh North Carolina United States

Alan H. Rebar, DVM, PhD, DACVP

Tommaso Rosati, DVM, DACVECC

Emeritus Dean & Emeritus Professor of Veterinary Clinical Pathology College of Veterinary Medicine Purdue University, West Lafayette Indiana United States Former Vice Chancellor for Research and Innovation University Administration North Carolina State University, Raleigh North Carolina United States

Senior Clinician Department of Small Animals University of Zurich Zurich Switzerland

Erica L. Reineke, VMD, DACVECC

Elizabeth Rozanski, DVM, DACVIM (SA-IM), DACVECC

Associate Professor Emergency and Critical Care Medicine Department of Clinical Studies and Advanced Medicine University of Pennsylvania, Philadelphia Pennsylvania United States

Patricia G. Rosenstein, DVM, DACVECC Criticalist Emergency and Critical Care Animal Referral Hospital, Sydney New South Wales Australia

Associate Professor Department of Clinical Sciences Tufts Cummings School of Veterinary Medicine, North Grafton Massachusetts United States

Christin L. Reminga, DVM, DACVECC

Elke Rudloff, DVM, DACVECC, cVMA

Critical Care Specialist, DVM Manager Emergency and Critical Care DoveLewis Animal Emergency and Specialty Hospital, Portland Oregon United States

Staff Criticalist Emergency and Critical Care BluePearl Specialty + Emergency Pet Hospital, Glendale Wisconsin United States

Joris H. Robben, DVM, PhD, Dipl ECVECC, Dipl ECVIM-CA

Jonathan Schaefer, MSc, DVM, DACVECC

Associate Professor, Emergency and Critical Care Medicine Department of Clinical Sciences Faculty of Veterinary Medicine, Utrecht University, Utrecht Netherlands

Narda G. Robinson, DO, DVM, MS, FAAMA

Assistant Teaching Professor Small Animal Emergency and Critical Care University of Missouri College of Veterinary Medicine, Columbia Missouri United States

Michael Schaer, DVM, DACVIM, DACVECC

Founder and CEO Medical Education CuraCore VET, Fort Collins Colorado United States

Emeritus Professor; Adjunct Professor Emergency Medicine and Critical Care Department of Small Animal Clinical Sciences University of Florida, Gainesville Florida United States

Mark P. Rondeau, DVM, DACVIM (SAIM)

Gretchen L. Schoeffler, DVM, DACVECC

Professor of Clinical Medicine Department of Clinical Sciences and Advanced Medicine University of Pennsylvania School of Veterinary Medicine, Philadelphia Pennsylvania United States

Clinical Professor Department of Clinical Sciences Cornell University College of Veterinary Medicine, Ithaca New York United States

Shelley C. Rankin, BSc (Hons), PhD Emeritus Professor of Microbiology School of Veterinary Medicine Department of Pathobiology University of Pennsylvania, Philadelphia Pennsylvania United States

CONTRIBUTORS

Sergi Serrano, LV, DVM, DACVECC

Kimberly Slensky, DVM, DACVECC

Staff Criticalist Emergency and Critical Care Veterinary Medical Center or Long Island, West Islip New York United States Chief Operating Officer ECCVET LLC, Norwalk Connecticut United States

Assistant Professor of Clinical Emergency and Critical Care Department of Clinical Sciences and Advanced Medicine University of Pennsylvania School of Veterinary Medicine, Philadelphia Pennsylvania United States

Claire R. Sharp, BSc, BVMS, MS, DACVECC Associate Professor School of Veterinary Medicine Murdoch University, Murdoch Western Australia Australia

Ashley N. Sharpe, DVM Cardiology Resident Department of Medicine and Epidemiology University of California, Davis, Davis California United States

Sean D. Smarick, VMD, DACVECC

Rebecca S. Syring, DVM, DACVECC

Adjunct Associate Professor College of Science, Health, Engineering and Education Murdoch University, Murdoch Western Australia Australia Criticalist Small Animal Specialist Hospital, Tuggerah New South Wales Australia

Critical Care Specialist Veterinary Specialty and Emergency Center, Levittown Pennsylvania United States

Nadja E. Sigrist, Dr med vet, FVH, DACVECC, DECVECC

Paulo V. Steagall, MV, MSc, PhD, DACVAA

Meg M. Sleeper, VMD, DACVIM Clinical Professor of Cardiology Department of Small Animal Clinical Sciences University of Florida College of Veterinary Medicine, Gainesville Florida United States

Jane E. Sykes, BVSc (Hons), PhD, MBA, DACVIM

Lisa Smart, BVSc, DACVECC, PhD

Florence Soares-Dabalos, MS, LMFT

Professor of Small Animal Critical Care Medicine Department of Clinical Sciences and Advanced Medicine University of Pennsylvania School of Veterinary Medicine, Philadelphia Pennsylvania United States

Doctor Department of Radiological & Surgical Sciences University of California Davis, Davis California United States

Professor Department of Medicine & Epidemiology University of California, Davis, Davis California United States

Assistant Professor, Small Animal Internal Medicine Department of Clinical Sciences Colorado State University, Fort Collins Colorado United States

Deborah C. Silverstein, DVM, DACVECC

Beverly K. Sturges, DVM, MS, MaS, DACVIM (Neurology)

Consultant North Huntingdon Pennsylvania United States

Sarah B. Shropshire, DVM, PhD, DACVIM

CEO and Owner Veterinary Emergency and Critical Care Consulting and Education Affoltern am Albis, Switzerland

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Client Support & Wellness Professional Veterinary Medical Teaching Hospital University of California, Davis, Davis California United States

Associate Professor of Veterinary Anesthesia and Pain Management Department of Clinical Sciences Faculty of Veterinary Medicine, Université de Montréal, Saint-Hyacinthe Quebec Canada

Joshua A. Stern, DVM, PhD, DACVIM (Cardiology) Professor of Cardiology & Associate Dean for Veterinary Medical Center Operations Department of Medicine and Epidemiology School of Veterinary Medicine, University of California Davis, Davis California United States

Kelly Tart, BA, DVM, DACVECC Professor Department of Veterinary Clinical Sciences University of Minnesota, College of Veterinary Medicine, Shoreview Minnesota United States

Vincent J. Thawley, VMD, DACVECC Clinical Asst Professor—Emergency and Critical Care Medicine Department of Clinical Sciences and Advanced Medicine School of Veterinary Medicine, University of Pennsylvania, Philadelphia Pennsylvania United States

Isabelle Goy-Thollot, DVM, MS, PhD, DECVECC Project Manager VetAgro Sup Agriculture and Food Ministry, Marcy l’Étoile France

Elizabeth J. Thomovsky, DVM, MS, DACVECC Clinical Associate Professor Department of Veterinary Clinical Sciences Purdue University, West Lafayette Indiana United States

Randolph H. Stewart, DVM, PhD, DACVIM

Jeffrey Michael Todd, DVM, DACVECC

Clinical Professor Department of Veterinary Physiology & Pharmacology Texas A&M University, College Station Texas United States

Associate Professor Department of Veterinary Clinical Sciences University of Minnesota, College of Veterinary Medicine, St. Paul Minnesota United States

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CONTRIBUTORS

Carissa W. Tong, BVM&S, DACVECC Staff Criticalist VCA Canada CARE Centre Calgary Alberta Canada

Roberta Troia, DVM, PhD, DECVECC Research Fellow Department of Veterinary Sciences University of Bologna, Ozzano dell’Emilia, Bologna Italy

Yu Ueda, DVM, PhD, DACVECC Clinical Assistant Professor Department of Clinical Sciences North Carolina State University, Raleigh North Carolina United States

Kelley M. Varner, DVM, DACVAA Assistant Clinical Professor of Anesthesia Molecular Biomedical Science North Carolina State University, Raleigh, NC United States

Karen M. Vernau, DVM, MAS, DACVIM (Neurology) Clinical Professor of Neurology/ Neurosurgery Department of Surgical and Radiological Sciences University of California Davis, Davis California United States

Cecilia Villaverde, BVSc, PhD, DACVN, DECVCN Consultant Clinical Nutrition Expert Pet Nutrition, Fermoy Cork Ireland

Lance C. Visser, DVM, MS, DACVIM (Cardiology) Associate Professor of Cardiology Department of Medicine & Epidemiology University of California, Davis, Davis California United States

Lori S. Waddell, DVM, DACVECC Clinical Professor, Critical Care Department of Clinical Sciences and Advanced Medicine University of Pennsylvania School of Veterinary Medicine, Philadelphia Pennsylvania United States

Orla Mahoney-Wages, MVB, DACVIM, DECVIM Clinical Assistant Professor Department of Clinical Sciences Tufts University, Cummings School of Veterinary Medicine, N. Grafton Massachusetts United States

Jake Wolf, DVM, DACVECC Clinical Assistant Professor Department of Small Animal Clinical Sciences University of Florida, Gainesville, FL United States

Bonnie Wright, DVM, DACVAA Ashley L. Walker, DVM Cardiology Resident Department of Medicine and Epidemiology School of Veterinary Medicine, University of California, Davis, Davis California United States

Cynthia R. Ward, VMD, PhD, DACVIM Meigs Distinguished Teaching Professor Emerita Department of Small Animal Medicine and Surgery University of Georgia College of Veterinary Medicine, Athens Georgia United States

Wendy A. Ware, DVM, MS, DACVIM (Cardiology) Professor Emerita Departments of Veterinary Clinical Sciences and Biomedical Sciences Iowa State University, Ames Iowa United States

Samantha Wigglesworth, VMD, DACVECC Criticalist Red River Animal Emergency Hospital, Fargo, ND United States

Michael D. Willard, DVM, MS, DACVIM Professor Emeritus Department of Small Animal Clinical Sciences Texas A&M University, College Station Texas United States

Kevin Winkler, DVM, DACVS Surgeon BluePearl Veterinary Partners, Atlanta Georgia United States Medical Director BluePearl Veterinary Partners, Atlanta Georgia United States

Associate Colorado Canine Orthopedics and Rehab, Colorado Springs Colorado United States Affiliate Faculty Veterinary Medicine and Biomedical Sciences Colorado State University, Fort Collins Colorado United States CEO Mistral Vet, Johnstown Colorado United States

Kathy N. Wright, DVM, DACVIM (Cardiology and Internal Medicine) Veterinary Cardiologist Cardiology and Small Animal Internal Medicine MedVet Medical and Cancer Centers for Pets, Fairfax, OH United States

Todd A. Green, DVM, MS, DACVIM (Internal Medicine) Internist VCA West Coast Specialty and Emergency Animal Hospital Los Angeles, CA United States

F O R E WO R D It is my great pleasure to introduce you to the third edition of Small Animal Critical Care Medicine. The first two editions established the text as a go-to information source for veterinarians caring for critically ill dogs and cats. This edition will further cement its reputation as a definitive resource for those who strive to improve their understanding of the pathophysiology of critical illness and how to monitor and treat it. The last three decades have witnessed remarkable growth in our capacity to provide intensive care for our sickest patients. Not that long ago, there were only a handful of people doing this, and even in teaching hospitals we sometimes struggled to convince medical and surgical colleagues of the value of collaborating with a specialist in critical care. We often “made do” with used equipment and practiced in relative isolation, relying on a knowledge of physiology and extrapolating from the young specialty in human medicine. Drs. Silverstein and Hopper were trained and mentored by one of the “founding fathers” who brought purpose and credibility to the specialty, Dr. Steve Haskins. Like Steve, they are intellectually curious, clinically gifted, professionally meticulous, and incredibly productive, as evidenced in the pages that follow. They are among the vanguard of a “second wave” of Diplomates in the American College of Veterinary Emergency and Critical Care, and their skill as researchers, teachers, and leaders in the specialty had a positive impact on the entire profession even before the inception of the first edition of this book. As early as the 1990s, many members of the American College of Veterinary Emergency and Critical Care were keen to collaborate to

publish a text that would serve as a guide and resource for the care of critically ill dogs and cats. The challenges and obstacles to success were formidable, and progress faltered. Drs. Silverstein and Hopper took it upon themselves to pick up the slack and, with characteristic efficiency and fortitude, got the job done. Thirteen years on, they prevailed yet again when, barely a year into the creation of this edition, the COVID-19 pandemic landed upon us. Despite the chaos imposed on everyone involved, they successfully guided the project to completion. Deb and Kate not only wrote much (and edited all) of the material in this book, but they also recruited a Who’s Who of experts to author the text and shepherded us through the arduous process of writing the two hundred and twelve (!) chapters contained herein. The result of this hard work is the marvelous resource you see before you. If you are new to the field of critical care (welcome!), this book will provide a very readable in-depth introduction to the pathophysiology of severe illness and how it is monitored and treated. If you are already immersed in emergency and critical care medicine, you will find this edition to be an updated, irreplaceable resource that you’ll come back to time and time again for factual support and expert advice. Bernie Hansen, DVM, MS, DACVECC, DACVIM Raleigh, North Carolina

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CONTENTS Contributors, vi Foreword, xv

PART I  Key Critical Care Concepts 1 Evaluation and Triage of the Critically Ill Patient, 1 Erica L. Reineke

2 Physical Examination and Daily Assessment of the Critically Ill Patient, 9 Timothy B. Hackett

3 Hemostasis, 15 Ronald H. L. Li

4 Cardiopulmonary Resuscitation, 22 Daniel J. Fletcher, Manuel Boller

5 Postcardiac Arrest Care, 30

24 Pneumonia, 138 Amanda K. Boag, Gretchen L. Schoeffler

25 Acute Respiratory Distress Syndrome, 149 Laura Osborne, Kate Hopper

26 Pulmonary Contusions and Hemorrhage, 154 Sergi Serrano

27 Pulmonary Thromboembolism, 161 Vincent J. Thawley

28 Chest Wall Disease, 166 Christiana Fischer, Deborah C. Silverstein

29 Pleural Space Disease, 170 Bridget M. Lyons

30 Respiratory Distress Look-Alikes, 177 Sage M. De Rosa, Deborah C. Silverstein

Manuel Boller, Daniel J. Fletcher

PART III  Advanced Respiratory Support

Armelle de Laforcade, Deborah C. Silverstein

31 High Flow Nasal Oxygen, 181

Kaitlyn Rank, Bernie Hansen

32 Mechanical Ventilation—Core Concepts, 185

Duana McBride

33 Mechanical Ventilation—Advanced Concepts, 193

Lisa Smart, Deborah C. Silverstein

34 Jet Ventilation, 198

James B. Miller

35 Ventilator Waveforms, 201

Randolph H. Stewart

36 Anesthesia and Monitoring of the Ventilator Patient, 212

Matthew S. Mellema

37 Nursing Care of the Ventilator Patient, 219

Galina Hayes, Karol Mathews

38 Discontinuing Mechanical Ventilation, 223

6 Classification and Initial Management of Shock States, 37 7 SIRS, MODS, and Sepsis, 42 8 Oxygen Toxicity, 49

9 The Endothelial Surface Layer, 55 10 Hyperthermia and Fever, 61 11 Interstitial Edema, 67 12 Patient Suffering in the Intensive Care Unit, 72 13 Predictive Scoring Systems in Veterinary Medicine, 75

Iain Keir

Kate Hopper

Kimberly Slensky, Deborah C. Silverstein Bruno H. Pypendop

Matthew S. Mellema

Kimberly Slensky, Ciara A. Barr

Simon P. Hagley, Steven E. Epstein Kate Hopper

PART II  Respiratory Disorders

39 Ventilator-induced Lung Injury, 227

14 Control of Breathing, 80

40 Ventilator-Associated Pneumonia, 232

Kate S. Farrell

15 Oxygen Therapy, 85

Steven E. Epstein

Elisa M. Mazzaferro

Part IV  Cardiovascular Disorders

Steve C. Haskins, Deborah C. Silverstein

41 Mechanisms of Heart Failure, 238

Meredith L. Daly

42 Ventricular Failure and Myocardial Infarction, 243

Dana L. Clarke

43 Feline Cardiomyopathy, 246

16 Hypoxemia, 89

17 Hypoventilation, 95

18 Upper Airway Disease, 101 19 Tracheal Collapse: Management & Indications for Tracheal Stents, 113 Dana L. Clarke

20 Feline Bronchopulmonary Disease, 119 Elizabeth Rozanski, Gareth J. Buckley

21 Lower Airway Disease in Dogs, 122 Lynelle R. Johnson

22 Pulmonary Hypertension, 127 Lance C. Visser, Yu Ueda

23 Pulmonary Edema, 132 Sophie Adamantos, Dez Hughes

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Lisa Smart, Kate Hopper

Mark A. Oyama

Sara R. Brethel, Meg M. Sleeper

Joshua A. Stern, Maureen S. Oldach

44 Canine Cardiomyopathy, 255 Joanna L. Kaplan, Joshua A. Stern

45 Canine Myxomatous Mitral Valve Disease, 260 Ashley N. Sharpe, Lance C. Visser

46 Blunt Cardiac Injury, 266 Maureen S. Oldach

47 Pericardial Diseases, 271 Wendy A. Ware

48 Bradyarrhythmias and Conduction Disturbances, 279 Romain Pariaut

CONTENTS

49 Supraventricular Tachyarrhythmias, 283 Teresa C. DeFrancesco

50 Ventricular Tachyarrhythmias, 291 Romain Pariaut

51 Myocarditis, 296 Sara R. Brethel, Meg M. Sleeper

52 Cardiac Biomarkers, 300 Mark A. Oyama

53 Systemic Hypertension, 304

73 Diabetic Ketoacidosis, 432 Sabrina N. Hoehne

74 Hyperglycemic Hyperosmolar Syndrome, 438 Amie Koenig

75 Hypoglycemia, 444 Amie Koenig

76 Diabetes Insipidus, 451 Melissa A. Claus

Edward S. Cooper

77 Syndrome of Inappropriate Antidiuretic Hormone Secretion, 454

Thomas D. Greensmith, Dominic Barfield

78 Thyroid Storm, 457

54 Cardiopulmonary Bypass, 309

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Kate Hopper

Cynthia R. Ward

PART V  Electrolyte and Acid-Base Disturbances

79 Hypothyroid Crisis in the Dog, 461

55 Sodium Disorders, 316

80 Pheochromocytoma, 465

Jamie M. Burkitt Creedon

56 Potassium Disorders, 326 Samantha Wigglesworth, Michael Schaer

57 Calcium Disorders, 333

Joao Felipe de Brito Galvao, Dennis J. Chew, Todd A. Green

58 Magnesium and Phosphate Disorders, 342

Rebecka S. Hess

Kari Santoro Beer

81 Critical Illness-Related Corticosteroid Insufficiency, 470 Jamie M. Burkitt Creedon

82 Hypoadrenocorticism, 475 Jamie M. Burkitt Creedon

Linda G. Martin, Ashley E. Allen-Durrance

PART VIII  Neurologic Disorders

Kate Hopper

83 Neurological Evaluation of the ICU Patient, 480

Kate Hopper

84 Seizures and Status Epilepticus, 489

Patricia G. Rosenstein, Dez Hughes

85 Intracranial Hypertension, 494

Justin Duval, Kate Hopper

86 Tetanus, 502

59 Traditional Acid-Base Analysis, 350 60 Nontraditional Acid-Base Analysis, 357 61 Hyperlactatemia, 362 62 Urine Osmolality and Electrolytes, 369

Marguerite F. Knipe

Chai-Fei Li, Karen M. Vernau

Chai-Fei Li, Beverly K. Sturges Simon Platt

PART VI  Fluid Therapy 63 Assessment of Hydration, 373

87 Hepatic Encephalopathy, 506 Alex Lynch

Elke Rudloff

Part IX  Infectious Disorders

Søren R. Boysen, Kris Gommeren

88 Hospital-Associated Infections and Zoonoses, 510

64 Assessment of Intravascular Volume, 378 65 Crystalloids and Hemoglobin-Based Oxygen-Carrying Solutions, 386 Ta-Ying Debra Liu, Deborah C. Silverstein

66 Colloid Solutions, 391

Steven J. Centola, Deborah C. Silverstein

67 Daily Intravenous Fluid Therapy, 396 Natalie Kovak, Deborah C. Silverstein

68 Shock Fluids and Fluid Challenge, 402 Anusha Balakrishnan, Deborah C. Silverstein

69 Transfusion Medicine, 409 Sarah E. Musulin

70 Blood Types, Pretransfusion Compatibility, and Transfusion Reactions, 416

Shelley C. Rankin

89 Febrile Neutropenia, 513 Melissa A. Claus

90 Sepsis and Septic Shock, 519 Elise Mittleman Boller, Deborah C. Silverstein

91 Bacterial Infections, 527 Stephen Cole

92 Fungal Infections, 532 Elizabeth J. Thomovsky

93 Viral Infections, 538 Jane E. Sykes

94 Canine Parvovirus Infection, 544 Rachael Birkbeck, Karen Humm

Sarah E. Musulin

95 Infective Endocarditis, 549

Corrin Boyd, Lisa Smart

96 Urosepsis, 557

71 Hemorrhagic Shock, 422

Kristin A. MacDonald, Steven E. Epstein Lillian Ruth Aronson

PART VII  Endocrine Disorders

97 Necrotizing Soft Tissue Infections, 564

72 The Diabetic Patient in the ICU, 429

98 Catheter-Related Bloodstream Infections, 569

Elizabeth Rozanski, Orla Mahoney-Wages

Elke Rudloff, Kevin Winkler Christin L. Reminga

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CONTENTS

  99 Multidrug-Resistant Infections, 576 Steven E. Epstein

100 Infectious Disease Control in the ICU, 580 Timothy B. Hackett

PART X  Hematologic Disorders 101 Hypercoagulable States, 584 Alan G. Ralph, Benjamin M. Brainard

102 Feline Aortic Thromboembolism, 595 Julien Guillaumin

103 Platelet Disorders, 599 Ronald H.L. Li

104 Coagulopathy in the ICU, 608 Alex Lynch

105 Management of the Bleeding Patient in the ICU, 615 Yekaterina Buriko

106 Anemia in the ICU, 619 Alex Lynch

107 Dyshemoglobinemias, 624

PART XIII  Nutrition 124 Nutritional Assessment, 729 Cecilia Villaverde, Jennifer A. Larsen

125 Nutritional Modulation of Critical Illness, 735 Daniel L. Chan

126 Enteral Nutrition, 740 Daniel L. Chan

127 Parenteral Nutrition, 746 Daniel L. Chan

PART XIV  Trauma 128 Traumatic Brain Injury, 751 Rebecca S. Syring, Daniel J. Fletcher

129 Wound Management, 756 Caroline K. Garzotto

130 Thermal Burn Injury, 765 Caroline K. Garzotto

Louisa J. Rahilly, Deborah C. Mandell

PART XV  Anesthesia and Pain Management

Leah A. Cohn

131 Pain Assessment, 770

108 Acute Hemolytic Disorders, 632

Alessia Cenani, Linda S. Barter

PART XI  Intraabdominal Disorders

132 Sedation of the Critically Ill Patient, 776

109 Acute Abdominal Pain, 640

133 Anesthesia in the Critically Ill Patient, 778

Kenneth J. Drobatz

110 Acute Pancreatitis, 644 Jennifer M. Good

111 Acute Cholecystitis, 651 Mark P. Rondeau

112 Hepatitis and Cholangiohepatitis, 655 Mark P. Rondeau

113 Hepatic Failure, 660

Giacomo Gianotti Jane Quandt

134 Analgesia and Constant Rate Infusions, 787 Jane Quandt

135 Physical Rehabilitation for the Critical Care Patient, 795 Molly J. Flaherty

136 Integrative Veterinary Medicine for the Intensive Care Unit Patient, 800 Narda G. Robinson

Allyson Berent

114 Portal Hypertension, 668 Andrea N. Johnston

115 Portosystemic Shunt Management, 675 Margo Mehl

116 Acute Gastroenteritis, 680 Adesola Odunayo

117 Gastrointestinal Hemorrhage, 685 Søren R. Boysen

118 Regurgitation and Vomiting, 691 Peter S. Chapman

119 Diarrhea, 696 Daniel Z. Hume

120 Peritonitis, 701 Kelly Tart

PART XVI  Environmental Emergencies 137 Smoke Inhalation, 804 Tommaso Rosati, Kate Hopper

138 Hypothermia, 810 Jeffrey Michael Todd

139 Heat Stroke, 817 Kenneth J. Drobatz

140 Drowning and Submersion Injury, 822 Lisa Leigh Powell

PART XVII  Miscellaneous Disorders 141 Anaphylaxis, 826 Medora Pashmakova

PART XII  Urogenital Disorders

142 Gas Embolism, 831

121 Acute Kidney Injury, 706

143 Subcutaneous Emphysema, 835

Catherine E. Langston, Adam E. Eatroff

122 Chronic Kidney Disease, 713

Catherine E. Langston, Adam E. Eatroff

123 Kidney Transplantation, 721 Lillian Ruth Aronson

Bonnie Wright

Carissa W. Tong, Anusha Balakrishnan

144 Ocular Disease in the Intensive Care Unit, 840 Kathryn Good

145 Critically Ill Neonatal and Pediatric Patients, 845 Maureen A. McMichael, Katherine K. Gerken

146 Critically Ill Geriatric Patients, 851

Maureen A. McMichael, Katherine K. Gerken

CONTENTS

PART XVIII  Pharmacology

175 Fluoroquinolones, 1001

147 Catecholamines, 855

176 Antifungal Therapy, 1007

Samantha Hart, Deborah C. Silverstein

148 Vasopressin, 861

Deborah C. Silverstein, Samantha Hart

149 Antihypertensives, 867

Jonathan Schaefer, Deborah C. Silverstein Marie E. Kerl

177 Miscellaneous Antibiotics, 1011 Julie M. Menard

Edward S. Cooper

PART XX  Extracorporeal Therapy

Joshua A. Stern, Ashley L. Walker

178 Renal Replacement Therapies, 1017

Thierry Francey

179 Apheresis, 1022

Jessica M. Quimby

180  Extracorporeal Therapies for Blood Purification, 1026

150 Pimobendan, 872 151 Diuretics, 877

152 Appetite Stimulants, 882 153 Gastrointestinal Protectants, 886 Michael D. Willard

154 Antiemetics and Prokinetics, 890

Carrie A. Palm, Lucy Kopecny Carrie A. Palm, Lucy Kopecny

Katie D. Mauro, Megan E. McClosky

Michael D. Willard, Ralph C. Harvey

Part XXI  Monitoring

Ralph C. Harvey

181 Hemodynamic Monitoring, 1030

Ralph C. Harvey

182 Cardiac Output Monitoring, 1037

Bruno H. Pypendop

183 Electrocardiogram Evaluation, 1043

Bea Monteiro, Paulo V. Steagall

184 Oximetry Monitoring, 1049

Tamara Grubb

185 Colloid Osmotic Pressure and Osmolality, 1054

Tania Perez Jimenez

186 Coagulation and Platelet Monitoring, 1059

Ciara A. Barr, Kelley M. Varner

187 Viscoelastic Monitoring, 1064

155 Opioid Agonists and Antagonists, 895 156 Benzodiazepines, 902 157 a2-Agonists and Antagonists, 905 158 Nonsteroidal Antiinflammatory Drugs, 911 159 Gabapentin, 919 160 Tramadol, 922 161 Trazodone, 925

162 Cannabinoid Medicine in Intensive Care Unit Patients, 928 Narda G. Robinson

163 Anticonvulsants, 932 Adam Moeser

164 Antiplatelet Drugs, 937 Benjamin M. Brainard, Sarah B. Shropshire

165 Anticoagulants, 943

Benjamin M. Brainard, Amy Dixon-Jimenez

166 Thrombolytic Agents, 951 Julien Guillaumin

Lori S. Waddell

Edward S. Cooper

Marc S. Kraus, Anna R.M. Gelzer Kate S. Farrell

Lori S. Waddell Claire R. Sharp

Anthony Barthélemy, Céline Pouzot-Nevoret, Isabelle Goy-Thollot

188 Intraabdominal Pressure Monitoring, 1071 Guillaume Laurent Hoareau

189 Point-of-Care Ultrasound in the ICU, 1076 Kris Gommeren, Søren R. Boysen

190 Capnography, 1093 Bruno H. Pypendop

191 Intracranial Pressure Monitoring, 1097 Beverly K. Sturges

192 Urine Output, 1103 Sean D. Smarick

167 Hemostatic Drugs, 956 Katie E. Osekavage, Benjamin M. Brainard

PART XXII  Procedures

Kathy N. Wright

193 Peripheral Venous Catheterization, 1107

Carrie J. Miller

194 Intraosseous Catheterization, 1112

Jenna H. Burton

195 Central Venous Catheterization, 1117

Robert A. Armentano, Michael Schaer

196 Blood Film Evaluation, 1125

168 Antiarrhythmic Agents, 961 169 Inhaled Medications, 967

170 Complications of Chemotherapy Agents, 972 171 Antitoxins and Antivenoms, 978

Harold Davis

Massimo Giunti, Roberta Troia Harold Davis

Alan H. Rebar

PART XIX  Antimicrobial Therapy

197 Endotracheal Intubation and Tracheostomy, 1131

172 Antimicrobial Use in the Critical Care Patient, 983

198 Thoracocentesis, 1137

Steven E. Epstein

173 b-Lactam Antimicrobials, 991 Steven E. Epstein

174 Aminoglycosides, 995 Julie M. Menard

Mack Fudge

Nadja E. Sigrist

199 Thoracostomy Tube Placement and Drainage, 1141 Nadja E. Sigrist

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CONTENTS

Karl E. Jandrey

PART XXIII Intensive Care Unit Design and Management

Elisa M. Mazzaferro

209 Intensive Care Unit Facility Design, 1187

Jake Wolf, Deborah C. Silverstein

210 Management of the Intensive Care Unit, 1196

Teresa C. DeFrancesco

211 Client Communication, Grief, and Veterinary Wellness, 1200

200 Abdominocentesis, 1146 201 Arterial Catheterization, 1149 202 Blood Gas Sampling, 1153 203 Temporary Cardiac Pacing, 1157 204 Cardioversion, 1163 Romain Pariaut

205 Defibrillation, 1166 Gareth J. Buckley

206 Cerebrospinal Fluid Sampling and Interpretation, 1169 Vishal D. Murthy, Beverly K. Sturges

207 Urinary Catheterization, 1175 Sean D. Smarick

208 Urinary Diversion Techniques, 1181 Erin A. Gibson, Ingrid M. Balsa

Joris H. Robben

Amanda Arrowood, Lori S. Waddell Florence Soares-Dabalos

212 Prevention of Compassion Fatigue and Burnout, 1205 Marie K. Holowaychuk

Appendices, 1212 Index, 1218

VIDEO TO C Video 28-1: This video illustrates flail chest in a dog. Video 28-2: This video illustrates Polyradiculoneuritis in a dog with abdominal breathing. Video 83-1: This video illustrates and explains differences between some acute postures seen in patients with neurological injury Video 83-2: This video demonstrates the cranial nerve exam and illustrates related anatomy for interpretation Video 86-1: This video illustrates a 7yr old male neutered mix breed dog with an ‘exercise intolerance’ causing tetraparesis with limited activity. Video 95-1: This video illustrates mitral valve endocarditis in a dog.

Video 95-2: This video illustrates concurrent mitral and aortic infective endocarditis in a dog. Video 135-1: This video illustrates passive range of motion (PROM) forelimb. Video 135-2: This video illustrates passive range of motion (PROM) hindlimb. Video 198-1: This video illustrates over-the-needle thoracocentesis in a cat. Video 206-1: This video shows the patient positioning and collection of a cerebellomedullary cisternal CSF sample. Video 206-2: This video shows the patient positioning and collection of a lumbar cistern CSF sample.

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PART I   Key Critical Care Concepts

1 Evaluation and Triage of the Critically Ill Patient Erica L. Reineke, VMD, DACVECC KEY POINTS • Critically ill or hospitalized animals may deteriorate suddenly due to several disease complications or progression of disease. • A systematic approach to a deteriorating critically ill patient includes an initial evaluation of the respiratory, cardiovascular, and neurologic systems to guide immediate stabilizing interventions

followed by a more complete physical examination and medical record review. • Point-of-care blood testing and ultrasound are used alongside the physical examination to determine the cause of the patient’s deterioration and direct additional therapies and diagnostic testing.

INTRODUCTION

animal is assessed. Nurses may also play a vital role in this step by notifying veterinarians of a deteriorating patient, thereby helping to identify and prioritize which critically ill animals may need immediate intervention. The decision regarding which animal should be addressed first is typically based on the recognition of a change in vital signs such as tachypnea, increased respiratory effort, tachycardia, hypotension, change in mentation, or metabolic disturbances such as hypoglycemia or acidemia. Table 1.1 and Table 1.2 illustrate physical examination and diagnostic findings that may be identified in deteriorating patients.

Critical illness, secondary to diseases such as trauma, sepsis, pancreatitis, immune mediated disease, neoplasia and pneumonia, can cause significant metabolic derangements that require intensive care to sustain life or enhance metabolic stability.1 These conditions may result in tissue hypoperfusion and hypoxia, ultimately triggering a cascade of events including severe systemic inflammation that could result in multiple organ dysfunction and death.2 Organ dysfunction that may occur in critically ill animals includes respiratory dysfunction such as acute respiratory distress syndrome and pulmonary thromboembolism; cardiovascular dysfunction such as left ventricular dysfunction, arrhythmias and vasopressor dependent hypotension; gastrointestinal tract dysfunction such as gastric stasis and ileus, hemorrhagic diarrhea and bacterial translocation, hepatic dysfunction, and acute kidney injury; and coagulation abnormalities such as disseminated intravascular coagulation resulting in thrombosis and bleeding.3 As a result of organ dysfunction, progression of underlying disease, or complications of treatment, all hospitalized critically ill animals are at risk for sudden deterioration. A systematic approach to an acutely deteriorating critically ill patient is essential in order to quickly recognize and institute life-saving therapies. This approach consists of a primary survey followed by a more thorough secondary survey (i.e., complete physical examination), which includes a review of available medical records. Point-ofcare ultrasound, blood tests, and other cage side diagnostics are used alongside the primary survey to direct therapeutic interventions and guide additional diagnostic testing. If multiple critically ill patients require evaluation at the same time, as often occurs in a busy intensive care unit, the animal with the most life-threatening abnormalities (e.g., those with impending respiratory failure, hypotension, or severe cardiac arrhythmias) should be assessed first and life-saving interventions initiated (i.e., administration of an intravenous fluid bolus for hypotension or supplementation oxygen administration) before the next

PRIMARY SURVEY The primary survey is a rapid assessment of the animal’s respiratory, cardiovascular, and neurologic systems.4 While this assessment is being performed, a brief patient medical and surgical history, medications, and current nursing concerns can be relayed to the veterinarian.

Respiratory System Evaluation Evaluation of the respiratory system is focused on determining the presence or absence of hypoxemia or hypoventilation. In patients with an increased respiratory rate and effort, the airway should be assessed first followed by thoracic auscultation and evaluation of the chest wall and diaphragm. During the patient evaluation, oxygen supplementation typically via mask or flow-by should be provided until more objective assessments for hypoxemia are made. Although tachypnea can indicate the presence of hypoxemia, it can also be associated with concurrent hypovolemia, metabolic acidosis, pain, and abdominal distension, and other nonrespiratory disease. Therefore, a complete evaluation of the animal, including point-of-care bloodwork and ultrasound (see below), should be performed. If the patient is not breathing, immediate endotracheal intubation should be performed, and positive pressure ventilation should be initiated. A patient with respiratory arrest should also be evaluated for

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PART I  Key Critical Care Concepts

TABLE 1.1  Diagnostic Findings that May

Signal the Deterioration of a Critically Ill Patient

SpO2 ,95% or PaO2 ,80 mm Hg PaCO2 .50 mm Hg SBP ,90 mm Hg Lactate .2.5 mmol/L pH ,7.35 Base deficit ,24 mmol/L (dog) or ,25 mmol/L (cat) BG ,60 mg/dl or .180 mg/dl Na .160 mEq/L or ,130 mEq/L K .6.0 mEq/L or ,3 mEq/L iCa ,0.8 mmol/L Creatinine .2 mg/dl or rise in creatinine by 0.3 mg/dl from baseline or suspected oliguria or anuria Cardiac arrhythmias White blood cell count (3 103) ,6 or .16; .3% bands Thrombocytopenia PT or PTT prolongation of .25%

TABLE 1.2  Physical Examination Findings That May Signal Deterioration During Critical Illness Mentation Mucous membranes Capillary refill time Heart rate

Respiratory rate Temperature Pulse quality

Obtunded, Stuporous, Comatose, or Sudden Change in Mentation Pale pink, white, injected/dark pink or red .2 s or ,1 s Cats: .220 bpm, ,160 bpm Small-breed dogs: .160 bpm Large-breed dogs: .100 bpm .20 breaths/min (dog), .40 breaths/min (cat) Stridor/stertor ,100.58F (38.18C) or .102.58F (39.28C) Absent or weak femoral or pedal pulses Narrow or wide pulse pressure

cardiac arrest and chest compressions initiated depending on the resuscitation status of the patient (i.e., do not resuscitate versus cardiopulmonary resuscitation). The presence of stertor or stridor, along with an increased inspiratory effort, indicates upper airway obstruction.5 Airway obstruction is more likely to occur in brachycephalic dogs, dogs with a history of coughing and diagnosed or suspected to have tracheal or mainstem bronchial collapse, or in dogs with underlying laryngeal dysfunction. Additionally, airway obstruction may also occur in animals that have traumatic injuries to the neck or skull or secondary to orofacial surgery as a result of hemorrhage and/or progressive swelling. Stabilizing interventions for patients with upper airway obstruction may include administration of sedatives, cooling measures if hyperthermic, and antiinflammatory medications. If airway obstruction is severe, endotracheal intubation and tracheostomy may be needed depending on the underlying disease. Next, auscultation of the trachea and thorax should be performed along with an evaluation of the mucous membrane color. It is important to note that cyanotic mucous membranes are a late and severe sign of hypoxemia. Dull lung sounds on thoracic auscultation are most commonly associated with pleural space disease; however, severe consolidation of lung parenchyma can also contribute to dull lung

sounds.5 Pleural effusion may develop in critically ill patients secondary to the systemic inflammatory response syndrome and endothelial damage resulting in leakage of fluid, severe hypoalbuminemia, massive pulmonary thromboembolism and right-sided heart failure, fluid overload in cats, and following thoracic surgery, for example. A pneumothorax may develop spontaneously due to ruptured pulmonary bulla in dogs, secondary to severe asthma in cats, following blunt or penetrating thoracic trauma, postthoracic or diaphragmatic surgery, as a complication of needle thoracocentesis, or due to barotrauma from anesthesia or mechanical ventilation. If pleural space disease is suspected, point-of-care ultrasound and needle thoracocentesis should be performed, if indicated, as soon as possible. Additional diagnostic evaluation, including thoracic radiography, echocardiography, and/or computed tomography could be considered on a case-by-case basis (see Chapter 29, Pleural Space Disease). On thoracic auscultation, increased breath sounds and pulmonary crackles or wheezes are associated with the development of pulmonary parenchymal disease.5 Animals with gastrointestinal dysfunction and neurologic disease and those needing aggressive pain management (especially opioid medications) are at high risk for regurgitation, vomiting, and the development of aspiration pneumonia, which may cause acute respiratory distress. It is not uncommon for regurgitation and aspiration events to be unwitnessed. Other causes of pulmonary parenchymal disease in critically ill patients include acute lung injury and acute respiratory distress syndrome, fluid overload and congestive heart failure, and pulmonary thromboembolism. Identified risk factors in veterinary patients for the development of acute lung injury and acute respiratory distress syndrome include systemic inflammatory response syndrome, sepsis, infection, smoke inhalation, near drowning, and severe trauma.6,7 Point-of-care lung ultrasound at the cage side may help to confirm the presence of parenchymal disease (see Chapter 189, Point of Care Ultrasound in the ICU), but ultimately thoracic radiography will be the first step in diagnosing the underlying cause. Additionally, echocardiography and/or computed tomography may also be necessary. During the respiratory assessment, a noninvasive assessment of oxygenation via pulse oximetry should be obtained. A pulse oximetry reading of at least 95% is normal; values less than 95% (corresponding to a partial pressure of oxygen [PaO2] of less than 80 mm Hg) indicate hypoxemia.8 Arterial blood gas analysis, although more invasive than pulse oximetry, can also be performed to determine if hypoxemia and/or hypoventilation is present. Hypoxemia is defined as a PaO2 ,80 mm Hg when breathing room air whereas hypoventilation is defined as a partial pressure of carbon dioxide (PaCO2) .50 mm Hg (see Chapter 16, Hypoxemia).9 A PaO2 to fraction of inspired oxygen (FiO2) ratio can be calculated in animals receiving oxygen supplementation with ratios of ,300 suggesting acute lung injury and ,200 suggestive of acute respiratory distress syndrome.6 When arterial blood gas analysis cannot be performed, an oxygen saturation (SpO2) to FiO2 ratio can be calculated on spontaneously breathing dogs as a surrogate assessment of hypoxemia.10 Hypoventilation may occur in patients in the immediate postoperative period secondary to anesthesia or in those treated with opioids, benzodiazepines, or other respiratory depressant medications, in patients with cervical myelopathy, thoracic trauma or pain, secondary to intoxications, neuromuscular disease, or central nervous system pathology. If hypoxemia is suspected or confirmed, supplemental oxygen therapy (either by mask, flow-by or cage) should be instituted immediately, if not already provided, and the clinical response to treatment should be evaluated. Supplemental oxygen should be administered to all animals with tachypnea and increased respiratory effort to try and decrease the work of breathing, even if the pulse oximetry reading

CHAPTER 1  Evaluation and Triage of the Critically Ill Patient (.95%) is normal. Additional therapeutics such as administration of a diuretic, bronchodilator, and antibiotics should be made on a caseby-case basis depending on the underlying disease process suspected or confirmed via additional diagnostic evaluation. For patients with hypoventilation, the specific underlying cause should be addressed, e.g., reversal of respiratory depressant medication or administration of analgesic medications to patients with thoracic injury.

Cardiovascular System Evaluation The evaluation of the cardiovascular system is performed to identify poor tissue perfusion resulting in decreased tissue oxygen delivery. Conditions that may develop in critically ill patients and result in poor tissue perfusion include hypovolemia secondary to gastrointestinal dysfunction with fluid and electrolyte losses from vomiting/regurgitation and diarrhea, third space losses of fluid due to systemic endothelial damage and vascular leak, massive urinary losses of fluid (e.g., postobstructive diuresis), hemorrhage, severe hypoalbuminemia, cardiac disease and ventricular dysfunction, cardiac arrhythmias, cardiac tamponade, and vasodilatory states such as sepsis or systemic inflammatory response syndrome (SIRS). Animals identified as having poor tissue perfusion should receive rapid therapy and the underlying cause for the shock identified as soon as possible. Physical examination findings consistent with poor tissue perfusion include pale mucous membranes, prolonged capillary refill time, tachycardia (or bradycardia in cats), tall and narrow pulse profile, and poor or absent peripheral pulses. In vasodilatory states such as sepsis and SIRS, the mucous membranes may be red (primarily in dogs) with a shortened capillary refill time and peripheral pulses may be widened due to a lower diastolic pressure. The absence of peripheral pulses is a specific indicator of hypotension (systolic blood pressure ,90 mm Hg); however the presence of palpable pulses does not rule out hypotension and a blood pressure measurement should be obtained.11,12 Additionally, animals with alterations in systemic perfusion frequently have a dull mentation, heart sounds may be quiet, the body temperature may be low, and the extremities are often cool to the touch (see Table 1.2).13 A rectal-interdigital (temperature taken between the third and fourth digit in the pelvic limb) temperature gradient can be performed; a gradient of 211.6°F is suggestive of shock in dogs.14 It is important for the veterinarian to recognize that animals in the early stages of compensatory shock may only have mild changes in their cardiovascular parameters (i.e., heart rate and pulse quality). It may not be until the late stages of shock (or decompensated shock) that marked changes (i.e., tachycardia, weak pulses) in these cardiovascular parameters are recognized (see Chapter 6, Classification and Initial Management of Shock States). Animals that are assessed in the early stages of shock may initially appear stable and treatment thereby delayed; this could result in patient deterioration and subsequently a worse outcome. Therefore, careful evaluation of the cardiovascular parameters in conjunction with the patient’s clinical history and comparisons to previous measurements should be performed to determine if shock might be present. If there is concern during the primary survey that the patient may be in shock, more objective measurements of the cardiovascular system should be performed and/or therapy should be instituted (such as administration of an intravenous fluid bolus) while the patient’s response to treatment is assessed. Objective assessments of the cardiovascular system during the cardiovascular evaluation may include an electrocardiographic tracing to evaluate for cardiac arrhythmias (both tachycardias and bradyarrhythmias) that may be affecting cardiac output and a noninvasive blood pressure measurement. Cardiac arrhythmias may develop secondary to abnormalities such as hyperkalemia, cardiac ischemia, intraabdominal disease, underlying cardiac disease, and central nervous system disease.

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A Doppler blood pressure measurement less than 90 mm Hg is considered low and may represent shock in both cats and dogs. Once a blood pressure measurement has been obtained, a shock index (heart rate divided by blood pressure) can be calculated with shock index .1.0 (dogs) or .1.6 (cats) identifying the possible presence of shock. This may be especially useful in patients with early compensatory shock where vital signs and systemic perfusion are not significantly different from normal.15-18 A blood lactate measurement is another useful diagnostic test that can aid in assessing for the presence of poor perfusion to the tissues. Under conditions of hypoxia, cells switch to anerobic metabolism and lactate will be produced. A blood lactate concentration .2.5 mmol/L may be indicative of systemic hypoperfusion, although other conditions such as sepsis may lead to elevated lactate levels (see Chapter 61, Hyperlactatemia).19-21 It is important to note that no single variable, whether subjective or objective, can provide an accurate and consistent estimate of the adequacy of global tissue perfusion, and all variables mentioned to determine the adequacy of systemic perfusion should be assessed within the clinical context of the patient.

Neurologic System Evaluation Evaluation of the animal’s neurologic system should include an evaluation of mentation (level of consciousness), brainstem reflexes (pupil size, pupillary light responses and physiologic nystagmus), and motor ability (see Chapter 83, Neurologic Evaluation of the ICU Patient). A modified Glasgow Coma Scale score can be calculated serially in critically ill patients with neurologic disease allowing for comparison over time.22 Problems affecting the neurologic system that require immediate stabilizing interventions include seizures and altered mental state such as stupor or coma. Patients with known or suspected intracranial disease, such as traumatic brain injury, meningoencephalitis or neoplasia, may develop seizures during hospitalization. In critically ill patients without primary intracranial disease, new onset seizures may occur secondary to a variety of extracranial causes, including rapid decreases in blood glucose causing cerebral edema which may occur in a diabetic patient receiving insulin, secondary to neuroglycopenia (a blood glucose ,60 mg/dl), rapid decreases in blood sodium concentration causing cerebral edema, brain hemorrhage or thrombosis, secondary to hepatic encephalopathy, following congenital portosystemic shunt ligation, or secondary to medication administration such as enrofloxacin or dobutamine. Seizures should be treated immediately since prolonged seizure activity can result in hyperthermia, cerebral edema and irreversible brain injury, regardless of the underlying cause of the seizures (see Chapter 84, Seizures and Status Epilepticus).23 A patient that experiences new onset seizures during hospitalization should have blood glucose and blood electrolytes assessed immediately in addition to a medical chart evaluation to rule out drug-induced seizures. Increased intracranial pressure, which may occur secondary to intracranial disease such as traumatic brain injury, neoplasia, or inflammatory brain diseases or due to extracranial causes such as hepatic encephalopathy, should be suspected in any animal with a severely altered mental status (see Section VIII, Neurologic Disorders). Additionally, disequilibrium syndrome has been documented in animals following hemodialysis or relief of urinary tract obstruction due to rapid changes in plasma osmolality that result in cerebral edema and elevations in intracranial pressure.24,25 On cardiovascular examination, animals with elevations in intracranial pressure may exhibit the Cushing reflex characterized by bradycardia and hypertension. Prolonged elevations in intracranial pressure can lead to ischemia of the brain and herniation through the foramen magnum.23 Therefore, animals with altered mental status should have stabilizing therapies initiated

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PART I  Key Critical Care Concepts

immediately, such as administration of hyperosmotic agents (i.e., mannitol or hypertonic saline) and placement on a slant board to elevate the head and neck 15 to 30 degrees to decrease cerebral blood volume through increased venous drainage. Additionally, as changes in mentation may precede the onset of seizures, point-of-care blood work should be obtained, including an evaluation of blood glucose, electrolytes, and a blood ammonia in animals with suspected hepatic encephalopathy. A blood pressure measurement should be obtained to evaluate for both hypotension and hypertension, which can lead to altered mentation in addition to other neurologic signs. Severely altered mental status can be seen in patients with severe hypotension and impending cardiopulmonary arrest due to cerebral hypoxia, whereas changes in mentation due to systemic hypertension may occur secondary to cerebral hemorrhage, infarction, and edema.26-29 In animals in which acute brain herniation is suspected, such as those with decerebrate rigidity characterized by stupor or coma and extended front and pelvic limbs, tracheal intubation and mechanical ventilation should be instituted to temporarily lower arterial blood carbon dioxide levels in addition to the aforementioned treatment strategies. This will result in cerebral vasoconstriction, thereby lowering intracranial pressure, and could be considered for short-term management of marked elevations in intracranial pressure. Once the initial assessment of the cardiovascular, respiratory, and neurologic systems has been performed and stabilizing therapies instituted, a more thorough secondary assessment of the animal should be undertaken. This more thorough assessment should include a review of the patient history including past medical problems and chart review including medications administered. A more formal and complete physical examination of all body systems should be performed, including but not limited to abdominal palpation to assess for acute abdominal pain and investigation of urine output to assess for the development of oligoanuria or anuria.

SUPPORTING DIAGNOSTICS Point-of-Care Bloodwork In addition to the physical examination, point-of-care blood testing such as a packed cell volume, total solids via refractometry, blood glucose, blood gas analysis, lactate, electrolytes, and creatinine are important parameters for evaluating the acutely deteriorating critically ill animal. Most benchtop venous blood gas analyzers are able to provide this information rapidly and use minimal amounts of blood. These blood values provide useful diagnostic information about the animal and may help guide emergent therapeutic interventions. Additionally, tracking changes in these values may indicate a need to adjust interventions, progression of illness, or the development of complications. For example, a postoperative patient that has a deteriorating cardiovascular status with a new onset fever and hypoglycemia could indicate sepsis; possible sites of infection should be investigated (including surgical and catheter sites), blood cultures obtained, and initiation or adjustments to the antimicrobial therapy should be considered. The packed cell volume can be measured to assess for hemorrhage or severe anemia. Hemorrhage, reflected by a decreasing packed cell volume and total solids, may occur as a complication of major thoracic or abdominal surgery, secondary to disseminated intravascular coagulation, or gastrointestinal hemorrhage resulting from gastrointestinal dysfunction and/or ulceration (see Chapter 71, Hemorrhagic Shock). Gastrointestinal ulceration and hemorrhage are seen most commonly in critically ill patients as a complication of hypoperfusion, in patients administered steroids, secondary to hepatic failure, underlying gastrointestinal tract disease (i.e., severe inflammatory bowel disease or lymphoma), or as a complication of gastrointestinal tract surgery or

portosystemic shunt ligation due to portal hypertension. A decrease in total solids via refractometer, reflecting hypoalbuminemia, may also suggest hemorrhage, losses of albumin from the gastrointestinal tract or urinary system, or decreased albumin production due to hepatic dysfunction. Patients with severe hypoalbuminemia can develop hypovolemia from transvascular fluid movement into the thoracic or abdominal cavity. This is commonly identified on point-of-care ultrasound (see below). Patients with intravascular volume deficits secondary to severe hypoalbuminemia may respond to resuscitation with either canine or human albumin (dogs) and/or plasma products (fresh frozen, frozen, or cryopoor plasma) in addition to intravascular volume resuscitation with isotonic crystalloids or synthetic colloids. The administration of synthetic colloids, such as hydroxyethyl starches, may interfere with refractometer measurements of total solids, and values should be interpreted cautiously in these patients.30,31 Ideally, either a measurement of colloid osmotic pressure or serum albumin in patients receiving synthetic colloids should be performed. A blood glucose measurement should be done to assess for hypo- or hyperglycemia, both of which occur commonly in critically ill patients. Decreasing blood glucose levels and hypoglycemia, in addition to changes in vital signs, may indicate the development of sepsis (see Chapter 75, Hypoglycemia). Sepsis may occur postoperatively in patients that have had major surgery due to leakage of gastrointestinal contents during surgery or dehiscence, due to the development of incisional or surgical site infections, or as a result of aspiration pneumonia, for example. In patients with gastrointestinal tract disease or dysfunction, sepsis may occur as a result of bacterial translocation. Other causes of hypoglycemia include toy breed hypoglycemia, insulinoma or insulin overdose, hepatic failure, and xylitol toxicity. Patients with hypoglycemia (blood glucose ,60 mg/dl) should be treated with a bolus of 0.25–0.5 g/kg of 50% dextrose diluted at least 1:3 with sterile water or isotonic crystalloids for injection and intravenous fluids should be supplemented with 2.5%–5% dextrose. Hyperglycemia (blood glucose .180 mg/dl) is commonly seen in nondiabetic critically ill animals and likely results from a combination of low or normal insulin concentrations, increased counterregulatory hormone secretion, peripheral tissue insulin resistance, and deranged hepatic autoregulatory mechanisms.32 Additionally, hyperglycemia may result from the administration of medications, such as catecholamines and steroids, or from parenteral nutrition. Acute hyperglycemia (blood glucose levels may be over .300 mg/dl) can be seen in patients with severe cardiovascular and/or respiratory dysfunction and may indicate severe impairment in tissue oxygen delivery and impending cardiopulmonary arrest. Generally, mild and acute elevations in blood glucose do not cause acute clinical signs and the underlying disease or identification of complications should be investigated and treated. The acid-base status of a deteriorating patients is an important part of the evaluation. A metabolic acidosis (defined as a pH ,7.34, base deficit ,24 mmol/L [dogs] ,25 mmol/L [cats]) is common in critically ill dogs and cats and often associated with hyperlactatemia (lactate .2.5 mmol/L) due to altered tissue perfusion.33 Normalization of lactate (i.e., serial evaluations of lactate) in response to therapeutic interventions should be assessed in patients with hyperlactatemia; failure to normalize lactate has been associated with a worse outcome in canine studies (see Chapter 61, Hyperlactatemia).34,35 Other common causes of metabolic acidosis in critically ill patients include diabetic ketoacidosis, renal failure, renal tubular acidosis, and loss of bicarbonate from the gastrointestinal tract (typically secondary to diarrhea). Severe metabolic acidosis (pH ,7.2) may affect the cardiovascular system by causing myocardial dysfunction, vasodilation, hypotension, and decreased responsiveness to catecholamines.36 Metabolic alkalosis (pH .7.45) is most commonly seen in hospitalized

CHAPTER 1  Evaluation and Triage of the Critically Ill Patient critically ill patients following furosemide therapy, animals with gastrointestinal tract obstruction, gastric stasis, and/or regurgitation, or secondary to nasogastric tube suctioning due to loss of chloride from the gastrointestinal tract.37 This can be addressed through the administration of 0.9% NaCl, correction of underlying hypokalemia, and administration of prokinetic medications such as metoclopramide. Blood electrolytes, including sodium, potassium and ionized calcium, should also be rapidly evaluated. Rapid increases in sodium (and chloride) may occur in critically ill patients due to hypotonic fluid losses from the respiratory (i.e., secondary to panting) or gastrointestinal systems, skin, or urinary tract. A syndrome of inappropriate antidiuretic hormone (SIADH) secretion leading to hyponatremia may be identified secondary to pneumonia, neoplasia, babesiosis, intracranial disease, or medication administration.38-42 In general, the change in sodium seen with SIADH is slowly progressive, but rapid changes are possible. Marked changes in blood sodium, either increasing rapidly or decreasing rapidly, can be associated with the onset of neurologic signs and seizures as noted above. In addition to managing acute cerebral edema secondary to rapid decreases in sodium concentration, hypernatremia should be addressed through parenteral administration of hypotonic fluids (5% dextrose in water or 0.45% NaCl) or via orally or enterally administered water. Careful monitoring must follow to ensure a safe lowering of blood sodium levels (maximum 0.5–1 mEq/hr) in animals with chronic hypernatremia. Similarly, changes in blood potassium may occur in a critically ill patient. Hyperkalemia may occur secondary to renal failure, urinary tract obstruction, rupture, or urine leakage following urogenital surgery, hypoadrenocorticism, ischemia reperfusion injury (i.e., resolving aortic thromboembolism), or iatrogenically due to oversupplementation of potassium chloride in intravenous fluids. Patients with an elevated blood potassium (.6 mEq/L) on point-of-care blood work should have an electrocardiogram performed (if not already done during the cardiovascular assessment) to assess for cardiac arrhythmias such as bradycardia, tented T-waves, widened QRS, and atrial standstill.43 When cardiac arrhythmias are identified, treatment with intravenous calcium gluconate (50–100 mg/kg IV over 5 minutes)44 is used to stabilize the heart rhythm and additional medications such as treatment with regular insulin (0.2 units/kg IV) and 2.5% dextrose or terbutaline sulfate intravenously (0.01 mg/kg)45 may be considered. The specific underlying cause for the hyperkalemia should be investigated and treated. Hypokalemia (potassium ,3.0 mEq/L) results most commonly from treatment with potassium deficient intravenous fluids and inadequate oral intake. However, a number of conditions are also associated with severe hypokalemia including diabetic ketoacidosis, renal failure, albuterol intoxication, and hyperaldosteronism for example. Blood potassium concentrations between 2.0 mEq/L and 3.0 mEq/L are unlikely to cause severe clinical signs; however, blood potassium concentration falling below 2.0 mEq/L can cause severe muscular weakness leading to hypoventilation and cardiac arrhythmias. Finally, patients receiving massive transfusions should be evaluated for hypocalcemia and hypomagnesemia, which may result from citrate toxicity. In summary, when electrolyte abnormalities are present, veterinarians should diagnose and manage the underlying disease, institute treatments (i.e., potassium supplementation for hypokalemia) to correct these abnormalities or consider altering the current treatment strategies (i.e., discontinuing 0.9% NaCl in a patient that becomes hypernatremic or hyperchloremic). Serial evaluations of creatinine in the critically ill patient may indicate the presence of acute kidney injury indicated by a change of creatinine of 10.3 mg/dl from baseline.46 Along with evaluation of creatinine, an assessment of urine output should be done in patients with a low urine output (,0.5–1 ml/kg/hr). Evaluation of creatinine

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and urine output should be made in light of the intravascular volume status of the patient; for example, in patients with an intravascular volume deficit, urine output may decrease due to a decrease in the glomerular filtration rate. High urine output that exceeds the rate of intravenous fluid therapy rate of administration may be seen in animals following relief of a urinary tract obstruction due to a postobstructive diuresis or recovery from an acute kidney injury.47,48 This can cause hypovolemia if intravenous fluid therapy and/or oral water intake are not adjusted accordingly. A urine specific gravity can be helpful when investigating kidney function at the cage side but should be interpreted cautiously in a patient already treated with fluids; this can lead to medullary washout and inadequate urine concentration (urine specific gravity may be in the isosthenuric or hyposthenuric range) even in conditions of hypoperfusion. Administration of synthetic colloids will artificially increase the urine specific gravity and therefore urine specific gravity in these patients cannot be reliably interpreted.49 However, isosthenuric or hyposthenuric urine, urine specific gravity ,1.008–1.012, may indicate nephrogenic (i.e., secondary to pyelonephritis, pyometra, hypokalemia or hyperkalemia for example) or central diabetes insipidus, liver failure, or secondary to medication administration such as diuretic therapy. In addition to point-of-care blood testing, additional blood should be obtained for a complete blood count, chemistry screen, urinalysis, and coagulation testing depending on the clinical situation. These tests should be performed initially to diagnose the underlying disease process, but serial evaluations, especially in a hospitalized patient that acutely deteriorates, should be performed to diagnose infection and organ failure, which may complicate critical illness. In one study of septic dogs, multiple organ dysfunction including coagulation, renal, and hepatic dysfunction was identified in approximately 50% of dogs.3

Point-of-Care Ultrasound (see also Chapter 189, Point-of-Care Ultrasound in the ICU) A point-of-care ultrasound evaluation, including a thoracic and abdominal focused assessment with sonography, to assess for free abdominal, pleural, and pericardial fluid should be performed following the primary survey in patients with tissue hypoperfusion, respiratory distress, acute abdominal distension, or abdominal pain.50-52 This can be done quickly at the cage side, generally taking less than 5 minutes to perform. The information gained may help guide therapeutic interventions and identify causes for the patient’s deterioration. In patients with suspected pleural effusion, point-of-care thoracic ultrasound can be used to confirm the presence of fluid and guide needle thoracocentesis. This should be performed immediately to relieve respiratory distress and diagnose the underlying cause. The pleural effusion should be evaluated microscopically for bacteria, and a total solids via refractometry can be done to characterize the type of effusion present (i.e., transudate versus exudate). A packed cell volume of the effusion should be evaluated if on visual inspection it appears to be hemorrhagic. Similarly, in patients that are identified to have abdominal effusion or increasing abdominal effusion on point-of-care ultrasound, diagnostic sampling of the effusion should be performed. The fluid should be evaluated visually (i.e., hemorrhagic effusion, serosanguineous or sanguineous effusion) and microscopically for the presence of bacteria or other abnormalities. An evaluation of packed cell volume and refractometer total solid, measurement can be done on hemorrhagic effusions. Septic effusions are characterized by suppurative inflammation with intracellular bacteria (see Chapter 120, Peritonitis). A lactate and glucose measurement in the effusion can be compared with a lactate and glucose in the peripheral blood if septic peritonitis is suspected but intracellular bacteria are not identified. A lactate difference of .2 mmol/L and glucose difference of ,20 mg/dl of the effusion compared with blood may indicate septic

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peritonitis.53 However, a glucose and lactate comparison of the effusion to blood should not be used to assess for the development of septic peritonitis in dogs following a laparotomy; analysis of intraabdominal drain fluid was found to not reliably detect septic peritonitis.54 In addition to septic peritonitis and hemorrhage, abdominal effusion may occur secondary to a uroperitoneum (i.e., leakage of urine following urinary tract surgery or trauma), bile peritonitis (secondary to biliary mucocele rupture or blunt trauma), pancreatitis, or neoplasia, or may occur secondary to third spacing of fluid as a result of severe hypoalbuminemia. Additional evaluations of the effusion may include an evaluation of the effusion creatinine and potassium as compared with blood for uroperitoneum (effusion creatinine to blood .2:1 or effusion potassium to blood .1.4 [dogs] or 1.9 [cats]: 1)55,56 and total bilirubin levels of effusion compared with blood (effusion total bilirubin to blood .2:1)57. Bile pigments (free green or yellow brown material) or acellular mucinous fibrillar material may be seen microscopically in patients with bile peritonitis.57-60 In addition to the identification of free fluid, thoracic and lung ultrasonography should also be performed in patients with respiratory distress to aid in identifying pneumothorax, diaphragmatic hernia, and interstitial-alveolar disease.51,61 A pneumothorax may be suspected in patients with dull lung sounds on respiratory evaluation and indicated by the absence of a glide sign on lung ultrasound. Once a pneumothorax is diagnosed, immediate needle thoracocentesis should be performed. Thoracostomy tubes may be needed if the patient cannot be managed with intermittent needle thoracocentesis or the air removed via needle thoracocentesis does not stop or decrease. Interstitial-alveolar disease is indicated by the presence of .3 B-lines in more than one lung field on point-of-care lung ultrasound.61 This can be seen secondary to congestive heart failure, fluid overload, and other conditions affecting the lung parenchyma (e.g., pneumonia, non-cardiogenic edema, and acute respiratory distress syndrome). A focused cardiac ultrasound evaluation should be performed next in a patient noted to have B-lines on lung ultrasound to differentiate between cardiac and noncardiac causes of interstitial-alveolar disease. A patient with congestive heart failure or fluid overload should have evidence of left atrial enlargement with a left atrial to aortic diameter of at least 1.5 to 1.62-64 Additionally, an evaluation of cardiac contractility can be done to investigate for left ventricular dysfunction, which may be seen in patients with dilated cardiomyopathy or as a complication of critical illness.1 If fluid overload and/or congestive heart failure is suspected as the cause of respiratory distress based on the results of point-of-care ultrasound, furosemide should be administered, and any intravenous fluids should be discontinued. It is important to note that dogs with mitral valve disease and hospitalized for other conditions may have underlying left atrial enlargement but noncardiac causes of interstitial-alveolar disease. Therefore, point-of-care ultrasound should not replace thoracic radiography and echocardiography, and point-ofcare ultrasound findings should always be confirmed when possible. Differentiating between other cause of interstitial-alveolar edema, such as pneumonia and acute respiratory distress syndrome for example, can only be diagnosed via thoracic radiography or computed tomography and results of additional diagnostic testing such as an endotracheal wash cytology with culture and susceptibility testing results.

SUMMARY Critically ill patients may deteriorate suddenly due to a variety of reasons, and changes in vital signs or metabolic status typically herald the development of complications. Therefore, a systematic approach to a patient with recognized changes to the cardiovascular, respiratory, and neurologic systems should be performed to identify and

address the underlying cause. Point-of-care blood testing and ultrasound should be evaluated alongside the physical examination to help guide acute stabilizing interventions. With this type of approach, organ dysfunction and complications of critical illness can be addressed rapidly, and ultimately disease progression and patient death may be prevented.

SELECTED REFERENCES Kenney EM, Rozanski EA, Rush JE, et al: Association between outcome and organ system dysfunction in dogs with sepsis: 114 cases (2003-2007), J Am Vet Med Assoc 29:1303-1310, 2010. A retrospective study provides criteria for the diagnosis of multiple organ dysfunction and evaluates association of organ dysfunction and outcome in dogs with sepsis. Boiron L, Hopper K, Borchers A: Risk factors, characteristics and outcomes of acute respiratory distress syndrome in dogs and cats: 54 cases, J Vet Emerg Crit Care 29(2):173-179, 2019. A retrospective study that identifies risk factors for the development of ARDS including sepsis, SIRS and shock. A grave outcome was identified with a case fatality rate of 84% in dogs and 100% in cats. Thoen ME, Kerl ME: Characterization of acute kidney injury in hospitalized dogs and evaluation of a veterinary acute kidney injury staging system, J Vet Emerg Crit Care 21(6):648-657, 2011. A veterinary acute kidney injury staging system was retrospectively applied to 164 critically ill dogs. Dogs that developed acute kidney injury during hospitalization were less likely to survive to hospital discharge. McMurray J, Boysen S, Chalhoub S: Focused assessment with sonography in nontraumatized dogs and cats in the emergency and critical care setting, J Vet Emerg Crit Care 26(1):64-73, 2016. A prospective study describing the use of focused assessment with sonography to identify thoracic and abdominal effusion in non-traumatized dogs and cats. Free fluid was identified in 75% of cardiovascularly unstable or dyspneic patients compared to only 9% of stable patients.

REFERENCES 1. Nelson OL, Thompson PA: Cardiovascular dysfunction in dogs associated with critical illness, J Am Anim Hosp Assoc 42:344-349, 2006. 2. Aldrich J: Shock fluids and fluid challenge. In Silverstein DC, Hopper K, editors: Small animal critical care medicine, St. Louis, 2009, Saunders Elsevier, pp 276-280. 3. Kenney EM, Rozanski EA, Rush JE, et al: Association between outcome and organ system dysfunction in dogs with sepsis: 114 cases (2003-2007), J Am Vet Med Assoc 29:1303-1310, 2010. 4. Aldrich J: Global assessment of the emergency patient, Vet Clinic Small Anim 35:281-305, 2005. 5. Sigrist NE, Adamik KN, Doherr MG, et al: Evaluation of respiratory parameters at presentation as clinical indicators of respiratory localization in dogs and cats with respiratory disease, J Vet Emerg Crit Care 21(1): 13-23, 2011. 6. Wilkins PA, Otto CM, Baumgardner JE, et al: Acute lung injury and acute respiratory distress syndromes in veterinary medicine consensus definitions: the Dorothy Russell Havemeyer Working Group on ALI and ARDS in Veterinary Medicine, J Vet Emerg Crit Care 17(4):333-339, 2007. 7. Boiron L, Hopper K, Borchers A: Risk factors, characteristics and outcomes of acute respiratory distress syndrome in dogs and cats: 54 cases, J Vet Emerg Crit Care 29(2):173-179, 2019. 8. Reeves RB, Park JS, Lapennas GN, Olszowka JA: Oxygen affinity and Bohr coefficients of dog blood, J Appl Physiol 53(1):87-95, 1982. 9. Tobin MJ, editor: Indications for mechanical ventilation, 2nd ed, New York, 2006, McGraw-Hill, pp 129-162. 10. Calabro JM, Prittie JE, Palma DA: Preliminary evaluation of the utility of comparing SpO2/FiO2 and PaO2/FiO2 ratios in dogs, J Vet Emerg Crit Care 23(3)280-285, 2013.

CHAPTER 1  Evaluation and Triage of the Critically Ill Patient 11. Ateca LB, Reineke EL, Drobatz KJ: Evaluation of the relationship between peripheral pulse palpation and Doppler systolic blood pressure in dogs presenting to an emergency service, J Vet Emerg Crit Care 28(3):226-231, 2018. 12. Reineke EL, Rees C, Drobatz KJ: Prediction of systolic blood pressure using peripheral pulse palpation in cats, J Vet Emerg Crit Care 26(1): 52-57, 2016. 13. Boag AK, Hughes D: Assessment and treatment of perfusion abnormalities in the emergency patient, Vet Clin Small Anim 35:319-342, 2005. 14. Schaefer JD, Reminga C, Drobatz KJ: Evaluation of the rectal-interdigital temperature gradient as a diagnostic marker of shock in dogs presenting with undifferentiated shock, J Vet Emerg Crit Care 27(S1):S9, 2017. 15. Porter AE, Rozanski EA, Sharp CR, et al: Evaluation of the shock index in dogs presenting as emergencies, J Vet Emerg Crit Care 23(5):538-544, 2013. 16. Peterson KL, Hardy BT, Hall K: Assessment of shock index in healthy dogs and dogs in hemorrhagic shock, J Vet Emerg Crit Care 23(5):545-550, 2013. 17. McGowan EE, Marryott K, Drobatz KJ, Reineke EL: Evaluation of the use of shock index in identifying acute blood loss in healthy blood donor dogs, J Vet Emerg Crit Care 27(5):524-531, 2017. 18. Kenton R, Adamantos S: An evaluation of the shock index in cats with hypoperfusion; a novel, pilot study (abstract), BSAVA Conference Proceedings, 2016. 19. Hughes D, Rozanski ER, Shofer FS, et al: Effect of sampling site, repeated sampling, pH and pCO2 on plasma lactate concentration in healthy dogs, Am J Vet Res 60:521-524, 1999. 20. Redavid LA, Sharp CR, Mitchell MA, Beckel NF: Plasma lactate measurements in healthy cats, J Vet Emerg Crit Care 22(5):580-587, 2012. 21. Reineke EL, Rees C, Drobat KJ: Association of blood lactate concentration with physical perfusion variables, blood pressure and outcome for cats treated at an emergency service, J Am Vet Med Assoc 247:79-84, 2015. 22. Platt SR, Radaelli ST, McDonnell JJ: The prognostic value of the modified Glasgow Coma Scale in head trauma in dogs, J Vet Intern Med 16(6): 581-584, 2001. 23. Syring RS: Assessment and treatment of central nervous system abnormalities in the emergency patient, Vet Clin Small Anim 35:343-358, 2005. 24. Shi ZW, Wang ZG: Acute cerebral and pulmonary edema induced by hemodialysis, Chin Med J 121(11):1003-1009, 2008. 25. Ostroski CJ, Cooper ES: Development of dialysis disequilibrium-like clinical signs during postobstructive management of feline urethral obstruction, J Vet Emerg Crit Care 24(4):444-449, 2014. 26. Oppenheimer BS, Fishbery AM: Hypertensive encephalopathy, Arch Intern Med 41(2):264-278, 1928. 27. Lowrie M, De Risio L, Dennis R, et al: Concurrent medical conditions and long-term outcome in dogs with nontraumatic intracranial hemorrhage, Vet Radiol Ultrasound 53:381-388, 2012. 28. Littman MP: Spontaneous systemic hypertension in 24 cats, J Vet Intern Med 8:79-86, 1994. 29. Kyles AE, Gregory CR, Wooldridge JD, et al: Management of hypertension controls postoperative neurologic disorders after renal transplantation in cats, Vet Surg 28:436-441, 1999. 30. Bumpus SE, Haskins SC, Kass PH: Effect of synthetic colloids on refractometric readings of total solids, J Vet Emerg Crit Care 8(1):21-26, 1998. 31. Yam E, Hosgood G, Rossi G, Smart L: Synthetic colloid fluids (6% hydroxyethyl starch 130/0.4 and 4% succinylated gelatin) interfere with total plasma protein measurements in vitro, Vet Clin Pathol 47(4):575-581, 2019. 32. Mizock BA: Alterations in fuel metabolism in critical illness: hyperglycemia, Best Pract Res Clin Endocrinol Metab 15(4):533-551, 2001. 33. Kohen CJ, Hopper K, Kass PH, Epstein SE: Retrospective evaluation of the prognostic utility of plasma lactate concentration, base deficit, pH and anion gap in canine and feline emergency patients, J Vet Emerg Crit Care 28(1):54-61, 2018. 34. Zollo AM, Ayoob AL, Prittie JE, et al: Utility of admission lactate, lactate variables and show index in outcome assessment in dogs diagnosed with shock, J Vet Emerg Crit Care 29(5):505-513, 2019. 35. Cortellini S, Seth M, Kellett-Gregory LM: Plasma lactate concentrations in septic peritonitis: a retrospective study of 83 dogs (2007-2012), J Vet Emerg Crit Care 25(3):388-395, 2014.

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36. Kimmoun A, Novy E, Auchet T, et al: Hemodynamic consequences of severe lactic acidosis in shock states: from bench to bedside, Crit Care 19(1):175, 2015. 37. Ha YS, Hopper K, Epstein SE: Incidence, nature, and etiology of metabolic alkalosis in dogs and cats, J Vet Intern Med 27(4):847-853, 2013. 38. Kokko H, Hall PD, Afrin LB: Fentanyl-associated syndrome of inappropriate antidiuretic hormone secretion, Pharmacotherapy 22(9):1188-1192, 2002. 39. Barrot AC, Bedard A, Dunn M: Syndrome of inappropriate antidiuretic hormone secretion in a dog with a histiocytic sarcoma, Can Vet J 58(7): 713-715, 2017. 40. Martinez R, Torrente C: Syndrome of inappropriate antidiuretic hormone secretion in a mini-breed puppy associated with aspiration pneumonia, Top Companion Anim Med 32(4):146-150, 2017. 41. Zygner G, Bartosik J, Gorski P, Zygner W: Hyponatremia and syndrome of inappropriate antidiuretic hormone secretion in non-azotaemic dogs with babesiosis associated with decreased arterial blood pressure, J Vet Res 63(3):339-344, 2019. 42. De Monaco SM, Koch MW, Southward TL: Syndrome of inappropriate antidiuretic hormone secretion in a cat with a putative Rathke’s cleft cyst, J Feline Med Surg 16(12):1010-1015, 2014. 43. Tag TL, Day TK: Electrocardiographic assessment of hyperkalemia in dogs and cats, J Vet Emerg Crit Care 18(1):61-67, 2008. 44. Calcium gluconate. In Plumb DC, editor: Veterinary drug handbook, 4th ed, Ames, Iowa, 2002, Iowa State Press. 45. Terbutaline Sulfate. In Plumb DC, editor: Veterinary drug handbook, 4th ed, Ames, Iowa, 2002, Iowa State Press. 46. Thoen ME, Kerl ME: Characterization of acute kidney injury in hospitalized dogs and evaluation of a veterinary acute kidney injury staging system, J Vet Emerg Crit Care 21(6):648-657, 2011. 47. Francis BJ, Wells RJ, Rao S, Hackett TB: Retrospective study to characterize post-obstructive diuresis in cats with urethral obstruction, J Feline Med Surg 12(8):606-608, 2010. 48. Frohlich L, Hartmann K, Louis-Sautter C, Dorsch R: Postobstructive diuresis in cats with naturally occurring lower urinary tract obstruction: incidence, severity and association with laboratory parameters on admission, J Feline Med Surg 18(10):809-817, 2016. 49. Smart L, Hopper K, Aldrich J, et al: The effect of hetastarch (670/0.75) on the urine specific gravity and osmolality in the dog, J Vet Intern Med 23(2):388-391, 2009. 50. Boysen SR, Rozanski EA, Tidwell AS, et al: Evaluation of a focused assessment with sonography for trauma protocol to detect free abdominal fluid in dogs involved in motor vehicle accidents, J Am Vet Med Assoc 225(8): 1198-1204, 2004. 51. Lisciandro GR, Lagutchik MS, Mann KA, et al: Evaluation of a thoracic focused assessment with sonography for trauma (TFAST) protocol to detect pneumothorax and concurrent thoracic injury in 145 traumatized dogs, J Vet Emerg Crit Care 18(3):258-269, 2008. 52. McMurray J, Boysen S, Chalhoub S: Focused assessment with sonography in nontraumatized dogs and cats in the emergency and critical care setting, J Vet Emerg Crit Care 26(1):64-73, 2016. 53. Bonczynski JJ, Ludwig LL, Baron LJ, et al: Comparison of peritoneal fluid and peripheral blood pH, bicarbonate, glucose and lactate concentration as a diagnostic tool for septic peritonitis in dogs and cats, Vet Surg 32(2):161-166, 2003. 54. Guieu LS, Bersenas AM, Brisson BA: Evaluation of peripheral blood and abdominal fluid variables as predictors of intestinal surgical site failure in dogs with septic peritonitis following celiotomy and the placement of closed-suction abdominal drains, J Am Vet Med Assoc 249(5):515-525, 2016. 55. Schmiedt C, Tobias KM, Otto CM: Evaluation of abdominal fluid: peripheral blood creatinine and potassium ratios for diagnosis of uroperitoneum in dogs, J Vet Emerg Crit Care 11(4):275-280, 2001. 56. Aumann M, Worth LT, Drobat KJ: Uroperitoneum in cats: 26 cases (1986-1995), J Am Anim Hosp Assoc 34:315-324, 1998. 57. Ludwig LL, McLoughlin MA, Graves TK, Crisp MS: The surgical treatment of bile peritonitis in 24 dogs and 2 cats: a retrospective study (1987-1994), Vet Surg 26:90-98, 1997.

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58. Parchman MB, Flanders JA: Extrahepatic biliary tract rupture: evaluation of the relationship between the site of rupture and the cause of rupture in 15 dogs, Cornell Vet 80:267-272, 1990. 59. Elsheikh TM, Silverman JF, Sturgis TM, Geisinger KR: Cytologic diagnosis of bile peritonitis, Diagn Cytopathol 14:56-59, 1996. 60. Owens SD, Gossett R, McElhaney R, Christopher MM, Shelly SM: Three cases of canine bile peritonitis with mucinous material in the abdominal fluid as the prominent cytologic finding, Vet Clin Pathol 32(3):114-120, 2003. 61. Ward JL, Lisciandro GR, Keen BW, et al: Accuracy of point-of-care lung ultrasonography for the diagnosis of cardiogenic pulmonary edema in dogs and cats with acute dyspnea, J Am Vet Med Assoc 250:666-675, 2017.

62. Ward JL, Lisciandro GR, Ware WA, et al: Evaluation of point-of-care thoracic ultrasound and NT-proBNP for the diagnosis of congestive heart failure in cats with respiratory distress, J Vet Intern Med 32(5):1530-1540, 2018. 63. Ostroski C, Hezzell M, Oyama M, Drobatz K, Reineke EL: Focused cardiac ultrasound and point-of-care NT-proBNP assay in the emergency room improves the differentiation of respiratory and cardiac causes of dyspnea in cats (abstract), J Vet Emerg Crit Care 26:S9, 2016. 64. Hezzell M, Ostroski C, Oyama M, Drobatz K, Reineke EL: Focused cardiac ultrasound in the emergency room improves the differentiation of respiratory and cardiac causes of dyspnea in dogs (abstract), J Vet Intern Med 31:206, 2017.

2 Physical Examination and Daily Assessment of the Critically Ill Patient Timothy B. Hackett, DVM, MS, DACVECC

KEY POINTS • Physical examination of critical patients is essential to detect lifethreatening changes in their condition. • Thorough, efficient physical examination should precede blood tests, electrodiagnostics, or imaging. • Physiologic variables related to oxygen delivery take precedence in evaluating the critical patient. • Veterinarians and support staff should note and record both subjective and objective physical examination parameters as often as

necessary while taking into consideration the patient’s current problems and anticipated complications. • Algorithms and checklists can enhance patient care through targeted, problem-oriented, rapid assessment of key variables. • The ideal monitoring plan allows for early detection of metabolic or physiologic derangements with minimal risks for iatrogenic insult, unnecessary expense to the client, and inappropriate use of intensive care unit resources.

Assessment of the critical patient begins with a thoughtful, historyguided physical examination. The frequency of exams will be guided by patient condition and patient familiarity of the medical team. Thorough exams should be conducted at least daily along with a review of the medical record and the results of recent diagnostics. Thorough physical examinations are the key to detecting subtle changes and establishing a baseline; they are especially important for new veterinarians and support staff to perform at shift changes following patient rounds and repeatedly during each shift. The goal of serial physical examination is to detect problems with organ function in time for targeted interventions that prevent organ failure. Monitoring and record keeping are important, but not as important as the interpretation of the physical examination findings and diagnostics that lead to timely changes in treatment. A monitored variable is useful only if changes in that variable are linked to an intervention or therapy that affects outcome.1 While more frequent, focused examinations may be useful for known problems, the dynamic, multiorgan nature of critical illness demands frequent checks of the whole patient. Available technology helps in the identification of life-threatening problems. Arterial and venous blood gas analysis, oscillometric blood pressure monitors, pulse oximetry, point-of-care ultrasonography, computed tomography, coagulation analysis and other point-of-care tests are some the technologies that have found their way into 24-hour emergency and critical care practice.

better able to measure adequacy of perfusion or degree of hydration than the physical examination. For example, parameters like heart rate and blood pressure provide valuable information, but only when interpreted in conjunction with the physical examination. When a veterinarian reaches for an ultrasound probe or electrocardiogram before looking at and touching the patient with eyes, hands, and stethoscope, readily available information can be left on the table. The physical examination should be both planned and focused for unplanned and emergent changes in patient condition.2 The physical examination of the critically ill patient is approached much the same as the triage and primary survey of the emergency patient. With focus on the efficacy of oxygen delivery, the priority is assessment of the respiratory and cardiac systems. The ABCs (airway, breathing, and circulation) of resuscitation provide a simple systematic approach to the primary survey in both the ICU and emergency room (see Chapter 1, Evaluation and Triage of the Critically Ill Patient).3

PHYSICAL EXAMINATION Serial physical examination is core to the practice of critical care medicine. Physical examination interfaces with, and adds context to, medical technology. Both are necessary. Their appropriate use has improved our ability to provide the best care to our patients. The additional data can be overwhelming, and with reliance on technology, the importance of the practiced and repeated physical examination may be minimized. There is still no readily available technology that is

Airway and Breathing Patients adopt respiration positions and patterns to minimize the work of breathing. Recognition of altered or adaptive breathing patterns is a feature of a complete physical examination. A very slow or apneustic respiratory pattern may be indicative of impending respiratory arrest, and the patient should be rapidly assessed and stabilized as necessary (see Part II: Respiratory Disorders). Similarly, an increase in respiratory rate or effort indicates the need for rapid assessment. Animals with upper airway obstruction, dynamic airway collapse, bronchitis, or other obstructions to airflow will often breathe slower and more deeply to minimize airway resistance. With laryngeal disease or extrathoracic tracheal collapse/obstruction, increased effort will be noted on inspiration. With obstructions or collapse of the intrathoracic airways, there is greater effort on expiration. When there is physical obstruction such as a mass or foreign body, the abnormal effort can be noticed on both inspiration and expiration. Auscultating the entire respiratory tract and finding the point of maximal intensity can help identify the location of the obstruction (see Chapter 18, Upper Airway Disease).

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Animals with pulmonary parenchymal disease or pulmonary fibrosis may adopt a restrictive breathing pattern to overcome increased elastic forces of the pulmonary parenchyma. By minimizing the change in volume and increasing the respiratory rate, they can attempt to maintain alveolar minute ventilation despite decreased pulmonary compliance (see Chapters 20–26). Respiratory failure is not only a failure of gas exchange and hypoxemia but also of ventilation (see Chapters 16 and 17, Hypoxemia and Hypoventilation, respectively). Hypoventilation is an important cause of hypoxemia and a treatable cause of acidosis. When assessing respiratory rate and pattern, adequacy of ventilation should be estimated. Noting shallow breathing at normal or decreased respiratory rates should be followed by definitive diagnostics. Monitoring of pH and carbon dioxide (CO2) directly through blood gas analysis or indirectly with end-tidal CO2 are the most objective ways to follow trends (see Chapters 59, 60, and 190, Traditional Acid-Base Analysis, NonTraditional Acid-Base Analysis, and Capnography, respectively).

Circulation Alveolar ventilation is the first step in providing oxygen to the tissues. A normal cardiovascular system is then necessary to carry oxygenated blood from the lungs to the body. Physical assessment of the circulatory system relies on palpation of the arterial pulse (for synchrony, quality, and pulse rate), evaluation of venous distention, assessment of mentation and mucous membrane color and capillary refill time, and auscultation of the heart and lungs. Inadequate global perfusion is considered an indicator of circulatory shock and is a clinical diagnosis that can be made from physical examination alone (see Chapter 6, Classification and Initial Management of Shock).4

Heart Rate A normal heart rate indicates that at least one component of cardiac output is normal. A heart rate of 70 to 120 beats/min is considered normal in small dogs, 60 to 120 beats/min in large dogs, and 140 to 200 beats/min in cats. Bradycardia can result in decreased cardiac output and subsequent poor perfusion (see Chapter 48, Bradyarrhythmias and Conduction Disturbances). Cats often develop bradycardia (,120 beats/min) in shock, and this can be associated with imminent cardiac arrest. Bradycardia is an unusual finding in a critically ill patient and can result from electrolyte imbalances (hyperkalemia), neurologic disease (increased intracranial pressure), or conduction disturbances (atrioventricular block, sick sinus syndrome), or can be a side effect of analgesic or anesthetic drugs. An electrocardiogram (ECG) is indicated for full assessment of bradycardia. Sinus tachycardia (dogs .180 beats/min, cats .220 beats/min) is the body’s response to decreased blood volume, pain, anxiety, hypoxemia, and systemic inflammation (see Chapter 49, Supraventricular Tachyarrhythmias). Increasing heart rate will temporarily increase cardiac output and oxygen delivery. However, there are some physiologic limitations to this response. When the heart rate becomes too fast, diastolic filling is compromised and stroke volume is inadequate. Sinus tachycardia often results from circulatory shock or pain. Tachycardia that is irregular or associated with pulse deficits usually indicates an arrhythmia, and an ECG is indicated (see Chapter 50, Ventricular Tachyarrhythmias).

Mucous Membrane Evaluation of mucous membrane color is subjective but can give important information about peripheral capillary perfusion. Pale or white mucous membranes can be indicative of anemia or a vasoconstrictive response to shock. Red mucous membranes suggest vasodilation and

are observed in systemic inflammatory states and hyperthermia. Cyanotic gums indicate severe hypoxemia in the face of a normal packed cell volume because cyanosis will not be clinically evident without adequate hemoglobin levels. A yellow hue (icterus) indicates increased serum bilirubin resulting from hepatic disease, posthepatic disease, or hemolysis. A brown discoloration of the mucous membranes is observed with methemoglobinemia, and a “cherry red” may be observed with carbon monoxide poisoning (see Chapter 107, Dyshemoglobinemia). During examination of the gums, petechiation or bleeding should be noted because petechiae and bruising are clinical signs of platelet deficiency or dysfunction, and thrombocytopenia is an early finding in disseminated intravascular coagulation.

Capillary Refill Time Evaluation of capillary refill time (CRT) provides further information on peripheral perfusion. Used in conjunction with pulse quality, respiratory effort, heart rate, and mucous membrane color, the CRT can help assess a patient’s blood volume and peripheral perfusion and provide information on shock etiology. Normal CRT is 1 to 2 seconds. This is consistent with a normal blood volume and perfusion. A CRT longer than 2 seconds suggests poor perfusion due to peripheral vasoconstriction.5 Peripheral vasoconstriction is an appropriate response to low circulating blood volume and reduced oxygen delivery to vital tissues. Patients with hypovolemic and cardiogenic shock should be expected to have peripheral vasoconstriction. Peripheral vasoconstriction is also commonly associated with cool extremities, assessed by palpation of the distal limbs. Significant hypothermia will also cause vasoconstriction. A CRT of less than 1 second is suggestive of a hyperdynamic state and vasodilation. Hyperdynamic states can be associated with systemic inflammation, distributive shock, and heat stroke or hyperthermia.

Venous Distention Venous distention can be a sign of volume overload, right-sided congestive heart failure, or increased right-sided filling pressure. Palpation of the jugular vein may demonstrate distention, although it may be easier to visualize by clipping hair over the lateral saphenous vein. The patient is positioned in lateral recumbency; if the lateral saphenous vein in the upper limb appears distended, the limb is slowly raised above the level of the heart. If the vein remains distended, it may suggest an elevated central venous pressure. Potential causes of an elevated central venous pressure include volume overload, pericardial effusions, or right-sided congestive heart failure. A patient with pale mucous membranes and a prolonged CRT from vasoconstriction in response to hypovolemia would not be expected to have venous distention. In comparison, cardiogenic shock with biventricular failure is more likely to cause pale mucous membranes, prolonged CRT, and increased venous distention.

Pulse Quality The femoral pulse should be palpated while listening to the heart or palpating the cardiac apex beat. A strong pulse that is synchronous with each heartbeat is normal and consistent with adequate blood volume and cardiac output. Digital palpation of pulse quality is largely a reflection of pulse pressure. Pulse pressure equals the difference between the systolic and diastolic arterial blood pressures. A normal pulse pressure may be felt despite abnormal systolic and diastolic pressures. Global markers of anaerobic metabolism like base deficit and lactate, along with low mixed venous oxygen saturation, are more sensitive indicators of perfusion than blood pressure or physical examination parameters. If other indicators suggest inadequate perfusion, the patient should be evaluated for pathologic hyperdynamic conditions

CHAPTER 2  Physical Examination and Daily Assessment of the Critically Ill Patient such as sepsis or causes of a low diastolic pressure. For example, the presence of a holosystolic murmur with normal to increased pulse pressure can indicate diastolic runoff through a patent ductus arteriosus. Both the femoral and dorsal pedal pulses should be palpated. At least one study suggests a palpable dorsal pedal arterial pulse indicates a systolic blood pressure less than 90 mm Hg,6 although experienced clinicians will find they are able to feel these pulses in hypotensive patients. An irregular pulse or one that is asynchronous with cardiac auscultation is a sign of a significant cardiac arrhythmia. An ECG can confirm the arrhythmia and help determine the best treatment. Weak pulses are a common finding in the critically ill and can be due to decreased cardiac output as a result of either low stroke volume or decreased contractility, peripheral vasoconstriction, or decreased pulse pressure. The simultaneous evaluation of pulse pressure and response to intravenous fluid therapy will help distinguish the common causes of shock.

Auscultation Cardiac and pulmonary auscultation is an essential part of the physical examination. Clinicians and critical care technicians should perform serial auscultation throughout a patient’s hospitalization. Patient care staff and clinicians should auscultate the heart and pulmonary sounds at least twice during a shift. Subtle changes in respiratory noise may identify potential fluid overload or early pulmonary dysfunction. The respiratory system should be evaluated from the nasal cavity, larynx, and trachea to all lung fields. Stertor and wheezes in the upper airways and quiet crackles in the lungs may be an early sign of fluid overload.7 Inspiratory stridor can be heard with laryngeal paralysis, whereas expiratory wheezes suggest small airway collapse and bronchitis. Crackles can be heard with pneumonia, pulmonary edema, pulmonary hemorrhage, and small airway disease. Aspiration pneumonia often affects the cranioventral lung fields, with normal breath sounds giving way to adventitious sounds in these areas. Pulmonary edema may begin in the perihilar lung fields. Decreased lung sounds may be heard with pulmonary consolidation, pneumothorax, and pleural effusion. With pleural effusion, a fluid line may be detected by auscultating the patient’s chest while the patient is standing or held in sternal recumbency. Changes in lung sounds may be an indication for further examination by thoracic radiography or ultrasound (see Chapter 29, Pleural Space Disease). Critically ill patients with evidence of pulmonary dysfunction should have their oxygenating ability evaluated with pulse oximetry or arterial blood gas measurement. Any change in respiratory character or sounds should prompt immediate reevaluation of oxygenation status (see Chapter 16, Hypoxemia). Cardiac auscultation should be repeated at least once daily. As mentioned with pulse quality, the pulse should be palpated while listening to the heart. New murmurs or asynchronous pulses should be noted and investigated. Cardiac arrhythmias in the critically ill are an early sign of cardiac dysfunction. As with the failure of any organ system, these abnormalities should be investigated and underlying metabolic or oxygen delivery abnormalities corrected.

Level of Consciousness The patient’s level of consciousness and response to surroundings should be assessed frequently (see Chapter 83, Neurological Evaluation of the ICU Patient). If the patient appears normal, alert, and responsive, overall neurologic and metabolic status is likely normal. Patients that are obtunded or less responsive to visual and tactile stimuli may be suffering from a variety of complications and illnesses. Patients with stupor can be aroused only with painful stimuli. Stupor is a sign of severe neurologic or metabolic derangements. Coma and seizures are signs of abnormal cerebral electrical activity from either

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primary neurologic disease or severe metabolic derangements such as hepatic encephalopathy. One of the most concerning issues in the critically ill patient is any decrease in the gag reflex. This may be a result of a general decrease in the level of consciousness or a primary neurologic deficit. A decrease in the gag reflex places the animal at high risk of aspiration pneumonia, a potentially fatal complication. Oral intake should be withheld in animals with a compromised gag reflex, and if the gag reflex is absent, immediate endotracheal intubation to protect the airway is indicated.

Temperature Body temperature should be monitored frequently, if not continuously, in the critically ill patient. Environmental hyperthermia should be differentiated from primary hyperthermia. Hospitalized animals may develop hyperthermia from cage heat or heating pads. Primary hyperthermia or true fever should be investigated quickly because systemic inflammation and infectious complications are common sequalae of critical illness. Hypothermia is also common in critically ill animals. Many have difficulty maintaining their body temperature and require external heat supplementation. Passive warming with a dry blanket is safer than active warming with external heat sources. Active warming should take care to prevent burns and iatrogenic hyperthermia. Circulating hot air systems are an excellent source for active rewarming. Heat may be supplied by circulating hot water blankets or by placing warm water-filled gloves or bottles in towels next to the animal. A warming waterbed can be made by placing a thick plastic bag over an appropriate-size container filled with warm water. A towel placed under the animal will prevent the patient’s nails from perforating the plastic. Blankets placed on top of the animal will prevent heat from escaping. Heating pads should be used with caution, using both a low temperature setting and insulating the animal with a blanket or fleece pad. Heat lamps should be used from a distance of more than 30 inches to prevent burns. Electric cage dryers or handheld blow dryers are useful if the animal is wet. Intravenous fluids warmed to body temperature can be beneficial when rapid administration rates are used but are not effective at maintenance fluid rates.8 To prevent overwarming, body temperature should be monitored at regular intervals and warming measures discontinued when the body temperature reaches 100°F. Animals should be monitored carefully to prevent iatrogenic hyperthermia or thermal burns.

Hydration Whereas perfusion parameters such as mucous membrane color, CRT, and heart rate are measures of intravascular volume, hydration status is a subjective measure of interstitial fluid content. It is important to assess intravascular and interstitial fluid compartments separately and individualize fluid plans according to needs in both spaces. Day-to-day changes in body weight reflect fluid balance; therefore, daily body weight is the most objective way to monitor hydration. A dehydrated patient should gain weight as fluid volumes are restored. Overhydration is associated with progressive increases in body weight. Evaluating skin turgor or skin elasticity is used to assess hydration. With dehydration, skin turgor is decreased and skin tenting becomes prolonged. With overhydration, skin turgor increases and the subcutaneous tissues gain a “jelly-like” consistency. Serous nasal discharge, peripheral edema, and chemosis are additional supporting signs of overhydration. Peripheral edema can also indicate vasculitis or decreased oncotic pressure such as that seen with hypoproteinemia. Skin turgor is affected by the amount of subcutaneous fat, making it difficult to assess in cachectic and obese animals. Clinicians should be wary of third-space fluid accumulation. Third-space fluid loss is fluid collection within a body cavity that does

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not contribute to circulation. Pleural and abdominal effusions can lead to increases in body weight or maintenance of body weight in a patient that is becoming hypovolemic. Daily, or more often when appropriate, assessment of fluid balance is essential in critically ill animals. This requires accurate measurement of all fluid intake and output to include food and water consumption, urine, vomit, and any drain fluid production. Discrepancies in the volume of intake versus output require reevaluation of the patient and alteration of the fluid plan.

Abdominal Palpation and Gastrointestinal Assessment The abdominal examination is necessary due to the hidden nature of many important organ systems and their association with many infectious complications. Serial, gentle abdominal palpation can help localize tenderness. Measurement of the abdominal circumference at the last rib can provide objective serial data for the early detection of abdominal distension. The gastrointestinal (GI) tract may be difficult to evaluate on physical examination but is very important as GI problems are often seen with circulatory shock and critical illness. Thorough abdominal palpation is an important part of a complete physical examination. Clinicians and technicians should evaluate the patient’s abdomen for effusion, organ size, and location and localize any discomfort. Contents of the intestinal tract can be evaluated by both gentle palpation and digital rectal examination. The frequency, character, and volume of GI losses should be monitored. If fresh or digested blood is observed, GI protectants and antibiotics may be indicated.

POINT-OF-CARE ULTRASOUND It has been over 15 years since the introduction of a focused assessment with sonography for trauma protocol in canine patients following motor vehicle accidents.9 Since then, point-of-care ultrasound (POCUS) has seen expanded application and has been the focus of intense study. The availability of compact, high-resolution ultrasound units has made the technology available across all aspects of veterinary medicine. Used in conjunction with physical examination and previously described monitoring parameters, POCUS has found acceptance in many aspects of acute and critical care. Detailed discussion on the utility of POCUS in augmenting emergency and serial assessment, its limitations, and responsible training can be found in Chapter 189, Point-of-Care Ultrasound in the ICU.

MONITORING AND LABORATORY DATA The use of checklists has been promoted to enhance care for critically ill patients.10 By combining aspects of the physical examination with the most essential diagnostic tests, patient status is reviewed in a systematic manner, minimizing the chance of missing significant changes in condition. Kirby’s Rule of 20, a list of monitoring parameters for septic small animal patients, predates much of the current human literature on the use of checklists.11 Box 2.1 lists these 20 parameters and provides an excellent initial approach to monitoring most critically ill animals. This work provided the groundwork for critical care monitoring of the septic patient and has been adapted for most critical veterinary patients. Optimal care is provided when information collected by physical examination and clinical observation is integrated with the results of ancillary tests and technologically derived data. Fluid balance; oxygenation; mentation; perfusion and blood pressure; heart rate, rhythm, and contractility; GI motility; mucosal integrity; and nursing care have all been discussed in the physical examination section of this chapter. The remainder of this checklist makes up the daily monitoring and laboratory assessment recommended for most critical patients.

BOX 2.1  Kirby’s Rule of 20 for Monitoring

the Critically Ill Patient8

• Fluid balance • Oncotic pull • Glucose • Electrolyte and acid-base balance • Oxygenation and ventilation • Mentation • Perfusion and blood pressure • Heart rate, rhythm, and contractility • Albumin levels • Coagulation • Red blood cell and hemoglobin concentration • Renal function • Immune status, antibiotic dosage and selection, and WBC count • GI motility and mucosal integrity • Drug dosages and metabolism • Nutrition • Pain control • Nursing care and patient mobilization • Wound care and bandage change • Tender loving care GI, gastrointestinal; WBC, white blood cell count.

Oncotic Pull, Total Protein, and Albumin Hypoproteinemia is a common finding in critically ill patients. Total protein should be monitored at least daily, and serum albumin should be monitored every 24 to 48 hours. Hypoalbuminemic animals may require support with synthetic or natural colloids. Although albumin levels less than 2 mg/dl have been associated with increased mortality in human patients, albumin transfusions to increase serum levels have not resulted in increased survival.12 Colloid osmotic pressure (COP), the osmotic pressure exerted by large molecules, serves to hold fluid within the vascular space. It is normally the role of plasma proteins, primarily albumin, that stay within the vasculature. Inadequate COP can contribute to vascular volume loss and peripheral edema. The COP can be measured directly with a colloid osmometer; however, it is not commonly available, so most clinicians will base assessment of oncotic pressure on serum total protein (see Chapter 185, Colloid Osmotic Pressure and Osmolality). The limitation to the use of serum total protein is that the correlation between the refractive index of infused synthetic colloids and COP is not reliable.13

Glucose Hyper and hypoglycemia can occur rapidly in critically ill patients. Blood glucose concentration should be monitored routinely. The frequency of measurement will depend on the severity of illness and the nature of the underlying disease. The development of hypoglycemia in a critically ill adult patient should prompt the consideration of sepsis. Studies of human ICU patients have also demonstrated increased morbidity and mortality associated with hyperglycemia.14 The 2016 Surviving Sepsis guidelines recommend targeted treatment for hyperglycemia in patients with an upper blood glucose level of 180 mg/dl.15 A veterinary study of 660 dogs presenting to an emergency room with a blood glucose concentration measured within 6 hours of presentation found hyperglycemia (.120 mg/dl) in 40.1% of dogs. Hypoglycemia was detected in 9.0%, and the mortality rates were significantly higher in hyper- and hypoglycemic patients (33.3% and 44.6%, respectively), compared with those with normoglycemia (24.9%).16

CHAPTER 2  Physical Examination and Daily Assessment of the Critically Ill Patient

Electrolyte and Acid-Base Balance Abnormalities in serum electrolytes are common in critically ill patients. Serum sodium, chloride, potassium, phosphorous, magnesium, and calcium should be monitored and maintained within the normal ranges through appropriate supplementation and crystalloid fluid choices. Measurement of acid-base status has become routine, and both arterial and venous samples can be evaluated. Interpretation of acidbase abnormalities can be aided by the measurement of lactate and electrolyte concentrations (see Chapters 59–61, Traditional and NonTraditional Acid-Base Analysis and Hyperlactatemia, respectively).

Oxygenation and Ventilation In addition to the physical examination described for the respiratory system, additional monitoring is recommended to objectively assess respiratory function. Respiratory failure can be a failure of oxygenation, resulting in hypoxemia, or a failure of ventilation, resulting in hypercapnia (see Chapters 16 and 17, Hypoxemia and Hypoventilation, respectively). Pulse oximetry, end-tidal CO2 measurement, and arterial and venous blood gases can all be used to assess oxygenation and ventilation.

Red Blood Cell and Hemoglobin Concentrations The oxygen content of arterial blood is mostly bound to hemoglobin, making anemia an easily identified cause of reduced arterial oxygen content. Daily assessment of hemoglobin concentration is one important variable in a clinician’s understanding of a patient’s oxygen delivery. Human and canine studies have attempted to establish an optimal hematocrit value, or transfusion trigger, for oxygen transport with reported values ranging from 30% to 60%.17 With many interfering factors and adaptive mechanisms, it becomes more important to assess daily changes in patient hematocrit along with other individual variables affecting oxygen delivery in order to determine the need for transfusions of whole blood, packed red blood cells, or hemoglobincontaining solutions.

Blood Pressure Blood pressure can be measured indirectly by Doppler or oscillometric techniques or directly via an indwelling arterial catheter. Blood pressure should be measured at least daily in critically ill patients. Continuous blood pressure monitoring may be indicated for hemodynamically unstable patients (see Chapter 181, Hemodynamic Monitoring).

Coagulation Coagulation abnormalities often occur in critically ill patients. They can result from primary diseases such as vitamin K antagonist intoxication or hepatic disease, a coexisting problem such as von Willebrand disease, or nonsteroidal antiinflammatory drug administration, or because of an acquired problem such as dilutional coagulopathy or disseminated intravascular coagulation. The choice of coagulation test will depend on the patient’s history, primary disease process, and available tests. Practices should be able to evaluate platelet number, function, and clotting factor function (see Chapters 104 and 186, Coagulopathy in the ICU and Coagulation and Platelet Monitoring, respectively).

13

disease are at risk of acute kidney injury. Critical patients often receive potentially nephrotoxic drugs. Normal urine output in a well-perfused, normally hydrated patient is 1 to 2 ml/kg/hr. In both oliguric and polyuric patients, measurement of fluid intake and GI and urinary losses can be used to facilitate fluid therapy. Indwelling urinary catheters are often used in the critically ill patient to maintain normal bladder size and prevent urine scald. Because they allow for frequent checks of urine output, indwelling urinary catheters should also be considered a simple monitoring technique. With careful attention to cleanliness, these can be very effective tools without significant risk of ascending urinary tract infection.18 Serum creatinine and blood urea nitrogen levels should be monitored daily during a crisis period. Urine should be evaluated daily for evidence of renal tubular casts or glucosuria.

Immune Status, Antibiotic Dosage and Selection, and White Blood Cell Count Bacterial infection is a common complication in ICU admissions (see Part IX: Infectious Disorders). Empiric broad-spectrum, parenteral antibiotic therapy is often initiated based on knowledge of common pathogens and results of Gram staining of appropriate specimens. Culture and sensitivity results should be reviewed when available and empiric antibiotic choices adjusted accordingly. White blood cell count and differential should be monitored frequently for evidence of new or nonresponsive infections.

DRUG DOSAGES AND METABOLISM Drug dosages should be reviewed daily. Animals with renal and hepatic dysfunction or neonatal patients may have altered metabolism and/or distribution, and dosages may need to be adjusted. Interactions among drugs should be considered in animals receiving multiple therapies.

NUTRITION GI dysfunction can present in many ways, from nausea, changes in appetite, and anorexia to more the serious loss of intestinal mucosal integrity, hemorrhagic diarrhea, enteric bacterial translocation, septicemia, and death. Attention to total food intake, nausea behaviors, stomach size and GI motility via POCUS, and digital rectal examination for GI bleeding and stool character are all points to assess regularly. Symptomatic treatment of the GI complications associated with critical illness can be an important consideration in these patients. Examples of these treatments include antiemetics, antiulcer strategies, motility modifying drugs, and antibiotics. Once a patient is hemodynamically stable, caloric intake becomes an important monitoring variable and treatment goal (see Chapter 124, Nutritional Assessment). Nutrition is an essential yet commonly overlooked component of successful management of the critical patient. Patients that develop a negative energy and protein balance may develop a loss of host defenses, loss of muscle strength, visceral organ atrophy and dysfunction, GI barrier breakdown, pneumonia, sepsis, and death. Enteral malnutrition is a predisposing factor in bacterial translocation and secondary sepsis, making enteral feeding the preferred route when possible (see Chapters 126 and 127, Enteral and Parenteral Nutrition, respectively).

Renal Function and Urine Output

NURSING CARE

Urine output should be monitored in critically ill patients (see Chapter 192, Urine Output). Decreased urine output can reflect inadequate renal perfusion or acute renal failure. Patients who have experienced hypotension during anesthesia or secondary to their underlying

Recumbent patients require attentive nursing care to prevent secondary complications. Patients should be turned every 4 to 6 hours through both laterals and sternal recumbency and encouraged to take deep breaths to prevent pulmonary atelectasis. The skin should be

14

PART I  Key Critical Care Concepts

assessed often. Pressure points over bony protuberances should be evaluated regularly to prevent decubitus ulcers. Moisture from urine, feces, or other draining fluids should be identified early to prevent scalding of the skin. Urine output and bladder size should be monitored frequently. This is especially true in animals at risk for renal failure or in patients with neurologic disease that prevents normal micturition. Frequent assessment of patient comfort is subjective but important (see Chapter 131, Pain Assessment). Appropriate pain control should always be provided (see Chapter 134, Analgesia and Constant Rate Infusions). Hands-on contact with the patient is invaluable in highquality clinical assessment and monitoring. Mental health is as important as physical health. Comfortable, dry bedding, gentle handling by staff members, and visits from owners are important. If possible, normal circadian rhythms should be maintained, with lights out or dimmed at night. Owner visits may improve the attitude of the patient and provide insights that may not be appreciated with the physical examination alone.

REFERENCES 1. Prittie J: Optimal endpoints of resuscitation and early goal-directed therapy, J Vet Emerg Crit Care 16:329, 2006. 2. Illuzzi E, Gillespie M. Physical Examination in the ICU. In: Oropello JM, Pastores SM, Kvetan V. eds. Critical Care. McGraw Hill. Accessed June 29, 2022. https://accessmedicine-mhmedical-com.proxy.library.upenn.edu/ content.aspx?bookid=1944§ionid=143515966 3. Aldrich J: Global assessment of the emergency patient, Vet Clin North Am Small Anim Pract 35:281, 2005. 4. Kittleson MD: Signalment, history and physical examination. In Kittleson MD, Kienle RD, editors: Small animal cardiovascular medicine, St. Louis, 1998, Mosby. 5. Chalifoux N, Spielvogel CF, Stefanovski D, Silverstein DC: Standardization and reliability of capillary refill time in hospitalized dogs, J Vet Emerg Crit Care 31(5):545-674, 2021.

6. Ateca LB, Reineke EL, Drobatz KJ: Evaluation of the relationship between peripheral pulse palpation and Doppler systolic blood pressure in dogs presenting to an emergency service, J Vet Emerg Crit Care (San Antonio) 28(3):226-231, 2018. doi:10.1111/vec.12718. 7. Kotlikoff MI, Gillespie JR: Lung sounds in veterinary medicine. Part I. Terminology and mechanisms of sound production, Comp Cont Educ Pract Vet 5:634, 1984. 8. Chiang V, Hopper K, Mellema MS: In vitro evaluation of the efficacy of a veterinary dry heat fluid warmer, J Vet Emerg Crit Care 21(6):639-647, 2011. 9. Boysen SR, Rozanski EA, Tidwell AS, et al: Evaluation of a focused assessment with sonography for trauma protocol to detect free abdominal fluid in dogs involved in motor vehicle accidents, J Am Vet Med Assoc 225(8):1198-1204, 2004. 10. Winters BD, Gurses AP, Lehmann H, Sexton CJ, Pronovost PJ: Clinical review: checklists—translating evidence into practice, Crit Care 13:1, 2009. 11. Kirby R: Septic shock. In Bonagura JD, editor: Current veterinary therapy XII, Philadelphia, 1995, Saunders, pp 139-146. 12. Mazzaferro EM, Rudloff E, Kirby R: The role of albumin replacement in the critically ill veterinary patient, J Vet Emerg Crit Care 12:113, 2002. 13. Bumpus SE, Haskins SC, Kass PH: Effect of synthetic colloids on refractometric readings of total solids, J Vet Emerg Crit Care 8:21-26, 1998. 14. Krinsley JS: Effect of an intensive glucose management protocol on the mortality of critically ill adult patient, Mayo Clin Proc 79:992, 2004. 15. Rhodes A, Evans LE, Alhazzani W, et al: Surviving Sepsis campaign: international guidelines for management of sepsis and septic shock: 2016, Intensive Care Med 43:304-377, 2013. 16. Hagley SP, Hopper K, Epstein SE: Etiology and prognosis for dogs with abnormal blood glucose concentrations evaluated in an emergency room, J Vet Emerg Crit Care 30(5):567-573, 2020. doi:10.1111/vec.12996. 17. Winfield WE: The transfusion trigger. In Wingfield WE, Raffe MR, editors: The veterinary ICU book, Jackson Hole, WY, 2002, Teton NewMedia. 18. Smarick SD, Haskins SC, Aldrich J, et al: Incidence of catheter-associated urinary tract infection among dogs in a small animal intensive care unit, J Am Vet Med Assoc 224:1936, 2004.

3 Hemostasis Ronald H. L. Li, DVM, MVetMed, PhD, DACVECC

KEY POINTS • The initial interactions between platelets and the injured endothelium play a key role in initiating thrombus formation. • Elaborate connections between coagulation factors, the cell surface, and the immune system occur in vivo, which can be explained by the cell-based model of coagulation. • Dysregulation of the negative feedback mechanisms for controlling thrombin generation can lead to excessive fibrin deposition and spontaneous clot formation.

• Appropriate fibrinolysis has an essential role in hemostasis, while excessive fibrinolysis can lead to bleeding, and inadequate fibrinolysis promotes thrombosis. • Immunothrombosis is an important component of innate immunity mediated by the formation of neutrophil extracellular traps.

The hemostatic system, which comprises circulating blood, endothelium, and subendothelial matrixes, is necessary to maintain blood flow to organs and tissues in the face of dynamic pathophysiologic conditions. Under normal physiologic conditions, a delicate balance between antithrombotic and prothrombotic properties is constantly maintained. In response to damage to the vasculature, the hemostatic system rapidly responds to limit excess blood loss and tissue destruction. However, many critically ill animals have underlying disease processes that disrupt the dynamic balance of hemostasis, clinically manifested by either bleeding or thrombosis. This chapter focuses on the fundamental concepts in the physiology of hemostasis, including platelet physiology, their interactions with the humoral coagulation network, and many of the feedback mechanisms that regulate the hemostatic system.

per platelet. The seven-transmembrane receptor family is the major agonist receptor family that includes thrombin receptors (protease activation receptors [PAR]), ADP receptors (P2Y1 and P2Y12), thromboxane receptors, and prostacyclin (PGI2)/prostaglandin (PGE2) receptors. Lastly, platelets contain unique membrane-bound granules within the cytoplasm. a-Granules are unique to platelets and contain a variety of membrane/soluble proteins that are integral to hemostasis/ thrombosis, inflammation, angiogenesis, host defense, and mitogenesis. Platelet dense granules, a subtype of lysosome-related organelle, contain high concentrations of cations, polyphosphates, adenosine nucleotides, and bioactive amines like serotonin and histamine. Granular contents are released following platelet activation.

OVERVIEW OF PLATELET STRUCTURE AND FUNCTION Platelets, which are anuclear, discoid-shaped, subcellular fragments of megakaryocytes, are the primary effector cells of hemostasis. The peripheral zone of a platelet consists of the plasma membrane, receptors, integrins, surface-connected open canalicular system, and dense tubular system. The open canalicular system consists of membrane-lined invaginations that extend deep within the cytoplasm, providing passages for secretory products as well as uptake or transfer of products from plasma. The platelet plasma membrane, with its asymmetrical composition, plays a significant role in cell signaling and thrombin generation. Lipid rafts, a subdomain of the phospholipid bilayer consisting of high concentrations of cholesterol and glycosphingolipids, carry signaling molecules such as integrins and glycoproteins along the plasma membrane to initiate signal transduction.1 Abrupt disturbance of these lipid rafts can lead to unnecessary cell signaling and platelet activation. Platelet integrins are heterodimeric receptors consisting of transmembrane a and b subunits that mediate cell–cell interaction and cell–matrix interactions. Integrins must undergo conformational changes from their low-affinity to high-affinity states, leading to firm adhesion to extracellular matrix or fibrinogen and, subsequently, robust cell signaling and activation (outside-in signaling).2 Of these, aIIbb3 is the most abundant integrin with 80,000 to 100,000 copies

PRIMARY HEMOSTASIS AND THE THREE-STAGE MODEL OF PLATELET ACTIVATION Primary hemostasis comprises the endothelium, the inner lining of blood vessels, platelets, and extracellular matrix components of the endothelium. The initial interactions between platelets and the injured blood vessels play a key role in initiating thrombus formation. The end goal of primary hemostasis is the formation of platelet aggregates that facilitate thrombus growth and stabilization. In pathological conditions, dysregulation of these interactions results in hemorrhage or thrombotic vascular occlusion. The initial platelet plug formation in flowing blood, commonly described as the three-stage model of platelet activation, is summarized in Fig. 3.1.

1. Initiation: Vascular injury leads to exposure of subendothelial collagen complexes, fibronectin, laminin, and von Willebrand factor (vWF), a multimeric glycoprotein.3 Of these, vWF and collagen play a key role in platelet adhesion. vWF, stored within the Weibel–Palade bodies of endothelial cells and the platelet a-granules, is also secreted into plasma upon activation of endothelial cells and platelets, respectively. The pathological level of shear stress results in conformational changes of vWF and its receptor, glycoprotein GP1ba (subunit of GP1b-IX-V), thus increasing their binding affinity to each other.4 Plasma vWF, once cleaved and immobilized on collagen, forms multimers that capture

15

16

PART I  Key Critical Care Concepts

Fig. 3.1  A schematic diagram summarizing the three-stage model of platelet activation demonstrating initiation, extension, and stabilization of the initial platelet plug formation in flowing blood.

platelets at vascular lesions. The initial binding of vWF and platelet glycoprotein (GP1ba) results in tethering and rolling of platelets along the endothelium.5 As the velocity of rolling decreases, bonds between vWF and GP1ba increase and strengthen, leading to adhesion and formation of a platelet monolayer. The binding of platelets to collagen and vWF triggers platelet activation (Fig. 3.1).6

2. Extension: Extension of the adhered platelet monolayer on injured vessels undergoes further activation resulting in secretion, shape change, formation of the procoagulant membrane, and integrin activation.7 Local accumulation of thrombin and secretion of agonists such as thromboxane A2 and ADP act as autocrine and paracrine factors to recruit and

CHAPTER 3  Hemostasis activate nearby platelets. Agonists then trigger inside-out signaling, which activates integrins, of which the most essential is the binding of fibrinogen to aIIbb3, to initiate platelet aggregation. The activation of integrin, as a result of inside-out signaling, facilitates conformational changes from a low-affinity to high-affinity state.2 (Fig. 3.1).

Stabilization: Firm adhesion to fibrinogen via platelet integrins results in outside-in signaling, a cascade of events that occur downstream of integrins, and leads to the clustering of the platelet integrin within the lipid rafts and protein complexes that are linked to the actin/myosin filaments.2 Mechanical forces generated by contraction of actin/myosin filaments in platelet further strengthen platelet-to-platelet interactions by narrowing the gap between platelets and preventing the diffusion of activators away from the platelets, hence fostering a local procoagulant microenvironment. This also causes clot retraction when fibrin is deposited, thereby further stabilizing the platelet plug while minimizing premature disaggregation (Fig. 3.1).

SECONDARY HEMOSTASIS The end goal of secondary hemostasis is the formation of a stable fibrin clot. A series of enzymatic reactions activates thrombin (factor II). The coagulation cascade, which is initiated by two distinct pathways (extrinsic and intrinsic), leads to activation of the common pathway (factors X, V, prothrombin, and fibrinogen) (Fig. 3.2). The theory that secondary hemostasis exists as three arbitrary pathways remains conceptually important to this day as it is helpful for clinicians to interpret results of coagulation assays such as prothrombin time or activated partial thromboplastin time for the screening of clotting factors deficiencies. It is important to note, however, that this model of the coagulation cascade does not occur in vivo as it neglects the elaborate connections between coagulation factors, the cell surface, and the immune system.8

Cell-based Model of Coagulation In vivo, secondary hemostasis takes place on phospholipids on the external leaflet of intact cells, including fibroblasts, platelets, leukocytes and microparticles, which are subcellular membrane-bound particles. Phospholipids provide docking sites for the assembly of coagulation complexes to form. For this to occur, two important events must take place: 1. Disruption of membrane asymmetry and exposure of negatively charged phospholipids. Phosphatidylserine (PS) plays a key role in coagulation complex formations during secondary hemostasis. The localization of PS is dynamic, capable of moving between the cytoplasmic and exoplasmic (outer) leaflets of the cell membrane. This is mediated by the coordinated actions of the transmembrane enzymes flippase, floppase and scramblase. 9 During homeostasis, PS is largely maintained in the cytoplastic membrane leaflets of the cell membrane by flippase. Increased activity of scramblase in apoptotic cells and activated platelets facilitates the exposure of PS on the cell surface, providing necessary docking sites for the assembly of tenase (factors IXa-VIIIa) and prothrombinase complexes (factors Xa-Va) on cells.10 A good example of the importance of membrane topology in hemostasis is the congenital disorder Scott syndrome, which is caused by a mutation of the gene affecting scramblase function and production. Despite normal platelet function and clotting factors, dogs with Scott syndrome have bleeding diathesis that resembles the phenotypes of hemophilia (see Chapter 103, Platelet Disorders).11 2. Gamma-carboxylation of glutamic acid of clotting factors. Clotting factors must first undergo posttranslational modification enabling

17

them to interact with negatively charged phospholipids. The process of g-carboxylation is carried out by vitamin K-dependent carboxylase, which facilitates the addition of an extra negative charge on glutamic acid on clotting factors X, IX, VII, II, protein C, and protein S; hence the name “vitamin K-dependent coagulation factors.” This allows clotting factors to bind to calcium, resulting in a conformational change that enables them to interact with PS on the cell surface (Fig. 3.2). The drug warfarin disrupts the vitamin K cycle to stop g-carboxylation of glutamic acid on clotting factors to achieve its anticoagulant property. The cell-based model of coagulation comprises four phases (initiation, amplification, propagation, and termination) and not only emphasizes the contribution of the cell membrane to thrombin generation but also highlights the feedback mechanisms that amplify the coagulation cascade while preventing excessive fibrin formation. Fig. 3.3 summarizes the cell-based model of coagulation.

Initiation: Factor VII and tissue factor (TF) are considered the main initiator of secondary hemostasis. Factor VII, produced by the liver as a zymogen, is converted to a serine protease, factor VIIa, by minor proteolysis in the blood. Factor VIIa (FVIIa) has little enzymatic activity in the absence of TF, a transmembrane glycoprotein, which is mainly synthesized in adventitial fibroblasts. Upon vascular injury, the exposure of TF-bound fibroblasts to FVIIa facilitates the assembly of the FVIIa-TF complex, which activates small amounts of factors IX and X. Activated factor X (FXa) activates FV to form the prothrombinase complex (FXa-FVa) converting small amounts of prothrombin (FII) to thrombin (FIIa).12,13 This is essential for the continuation to the next phase, amplification. It is believed that the initiation phase is continuously occurring outside the blood vessels in the absence of vascular injury.

Amplification: Upon vascular injury, platelets, which play a dominant role in primary hemostasis, leave the vasculature and bind to extracellular matrixes such as collagen to form the initial platelet plug, where it provides procoagulant membrane surfaces for clotting factors to bind to. In addition, activated platelets also release partially activated factor V. The small amount of thrombin generated during the initial phase has several important functions. First, thrombin, as a potent platelet agonist, maximizes platelet aggregation and formation of procoagulant membrane. Second, thrombin activates factors XI, V, and VIII, which become dissociated from vWF (Fig. 3.3B).14 Factors attached on the surface of platelets lead to the propagation phase.

Propagation: This phase is characterized by the production of a substantial amount of thrombin via formations of the tenase (FIXa-FVIIIa) and prothrombinase complexes (FXa-FVa) on activated platelets (Fig. 3.3C).14 In addition to the FIXa generated during the initiation phase, more FIXa is generated by FXIa bound on platelets. The formation of tenase complex facilitates the generation of large amounts of FXa, which results in prothrombinase complex formation leading to activation of large amounts of FIIa (thrombin). Thrombin is responsible for cleaving fibrinogen into fibrin monomers that eventually polymerize to form a fibrin clot. Factor XIII, which is activated by thrombin, is responsible for the crosslinking of fibrin monomers to further stabilize fibrin clots.

Termination: An essential feature of the coagulation system is its ability to regulate fibrin formation so that a stable clot is formed without excessive thrombosis within the vasculature. In general, there are several negative

18

PART I  Key Critical Care Concepts

Fig. 3.2  Traditional model of the coagulation cascade divided into extrinsic, intrinsic/contact, and common pathways. Vitamin K-dependent coagulation factors FVII, FX, FIX, and FII undergo g-carboxylation, which facilitates the binding of calcium and complex formations on phospholipids, and are outlined in red here. Prothrombin time (PT) is sensitive to the deficiencies in coagulation factors in the extrinsic and common pathway (excluding tissue factor) while activated partial thromboplastin time (APTT) and activated clotting time (ACT) allow assessment of deficiencies of clotting factors in the intrinsic and common pathways. HMWK, high molecular weight kininogen.

feedback mechanisms for controlling thrombin generation. First, the endothelium produces and secretes tissue factor pathway inhibitor (TFPI), which regulates coagulation through inhibition of a quaternary complex of TPFI, FVIIa, FXa, and TF. The natural anticoagulant antithrombin (AT), which is produced by the liver, inhibits thrombin generation by forming molar complexes with thrombin, FIXa, FXa, FXIa, and FXIIa and is facilitated by the glycosaminoglycans, heparin, and heparin sulfate by inducing conformational changes to AT. Animals deficient in AT due to protein-losing nephropathy or enteropathy are at increased risk for thrombosis.15 Protein C and protein S are vitamin K-dependent natural anticoagulants that play an essential role in controlling excessive coagulation. Protein C is activated by thrombin bound to thrombomodulin (TM), which is a transmembrane protein expressed on endothelial cells. This process can be further augmented by endothelial cell protein C receptor, which is another endothelial transmembrane protein. Activated protein C, once bound with its cofactor, protein S, inhibits coagulation by causing proteolysis of factors Va and VIIIa (Fig. 3.3D).16

OVERVIEW OF FIBRINOLYSIS Following healing of the vascular lesion, the fibrin clot must be dissolved to allow the reestablishment of blood flow. This process, termed

fibrinolysis, is a highly regulated system maintained by a dynamic equilibrium between proteolytic and inhibitory proteins; excessive breakdown of fibrin results in bleeding, whereas inadequate fibrinolytic activity may exacerbate the extension of thrombus formation. Fig. 3.4 summarizes the intricate balance of fibrinolysis.

Activators of Fibrinolysis Plasminogen, a zymogen form of plasmin that is predominantly produced by the liver and is present in tissues such as kidneys and brain, plays a key role in fibrinolysis. Fibrinolysis occurs when plasminogen is cleaved to plasmin by two physiologic activators, tissue-type plasminogen activator (tPA) and urinary-type plasminogen activator (uPA), to generate a two-chain molecule linked by disulfide bonds. tPA is constituently expressed in the endothelium and is also stored in vesicles of various cell types such as neuroendocrine and adrenal chromaffin cells. tPA is rapidly released into the circulation upon stimulation by agonists from the coagulation cascade such as thrombin and FXa, and beta-adrenergic agents, histamine, and bradykinin. Plasminogen is only readily activated by tPA in the presence of fibrin via the formation of a tertiary complex (Fig. 3.4).17 The amino acid lysine on fibrin binds to the lysine-binding sites on plasminogen. These lysine residues are crucial for facilitating tPA-catalyzed plasminogen activation.18 In fact, the antifibrinolytic drugs tranexamic acid and

CHAPTER 3  Hemostasis

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Fig. 3.3  A summary of the cell-based model of coagulation. A, Initiation: Tissue factor (TF)-bearing cells come into contact with FVIIa, which facilitates the formation of small amounts of thrombin (FIIa). B, Amplification: Thrombin activates platelets to degranulate and externalize phosphatidylserine, which facilitates their adhesion to subendothelial matrixes and activates other factors (FXI, V and VIII). C, Propagation: Formation of tenase (FIXa-FVIIIa) and prothrombinase complexes (FXa-FVa) on activated platelets propagates massive formation of thrombin. D, Termination: Thrombin generation is countered by endogenous anticoagulants including tissue factor pathway inhibitor (TFPI), protein C (PC), protein S (PS), and antithrombin.

aminocaproic acid are synthetic derivatives of lysine, which irreversibly binds to the lysine-binding sites on plasminogen, thereby preventing its interaction with fibrin and its activation to plasmin.19 uPA, also known as urokinase, is activated from single-chain urinary plasminogen activator by plasmin and does not require fibrin as a cofactor. Instead, it binds to the specific uPA receptor on certain cell types, which enhances the activation of cell-bound plasminogen.

Inhibitors of Fibrinolysis The two most important inhibitors of fibrinolysis are plasminogen activator inhibitor 1 (PAI-1) and alpha-2 antiplasmin. Platelets are the main source of circulating PAI-1, although it is produced in many other cell types such as endothelial and smooth muscle cells, cardiac myocytes, hepatocytes, and adipocytes.20 PAI-1 inhibits fibrinolysis by formation of non-covalent complexes with tPA and uPA.17 Alpha-2 antiplasmin, produced by the liver, inhibits fibrinolysis by either binding noncovalently to plasminogen or crosslinking to fibrin, thus preventing plasmin and tPA from binding to fibrin (Fig. 3.4). Thrombin-activatable fibrinolysis inhibitor (TAFI), also produced by the liver, is a zymogen that is activated by the thrombin/TM complex and plasmin. Once activated, TAFI removes the lysine residues, which are crucial for the binding of plasminogen to fibrin and

fibrinolysis. Alpha-2 macroglobulin, C1-inhibitor, and lipoprotein(a) are other minor inhibitors of fibrinolysis.

IMMUNOTHROMBOSIS The innate immune system functions as an active initiator of thrombosis through the activation of neutrophils, monocytes, and dendritic cells to propagate clot formation and activate platelets. For example, inflammatory cytokines such as tissue necrosis factor and interleukins can upregulate TF expression on endothelial cells and macrophages. On the other hand, coagulation factors can also bind to protease-activated receptors on immune cells to facilitate the release of cytokines.21 Increased fibrin formation within the vasculature in the face of pathogen invasion is an important first line of defense as it prevents systemic dissemination of pathogens via the circulation. This protective mechanism known as immunothrombosis can become dysregulated in diseases resulting in excessive clot formation or consumptive coagulopathy. Neutrophil extracellular traps (NETs), which are web-like scaffolds of cell-free DNA (cfDNA) decorated with neutrophil granular proteins, are key players in the genesis of immunothrombosis. Recently, NETs have been found to be structural components of human and feline arterial thrombi, highlighting the multifaceted abilities of NETs to stimulate thrombus generation.22,23 First, cell-free double-stranded

20

PART I  Key Critical Care Concepts

Fig. 3.4  The primary initiators of fibrinolysis are tissue plasminogen activator (tPA) and urinary-type plasminogen activator (uPA). The formation of a tertiary complex, tPA, in the presence of fibrin converts plasminogen to plasmin, which cleaves fibrin to fibrin degradation products (FDPs). Fibrinolysis is mainly inhibited by plasminogen activator inhibitor-1 (PAI-1), which inhibits tPA and uPA, and alpha2-antiplasmin (a2-AT). Once activated by the thrombin-thrombomodulin (T-TM) complex, thrombin activable fibrinolysis inhibitor (TAFI) inhibits fibrinolysis by removing the lysine residues on fibrin.

DNA, which forms the architectural structure of NETs, facilitates binding of factor XII and other contact activation factors such as high- molecular weight kininogen to activate the contact pathway of coagulation. The web-like structure of cfDNA also fortifies clots by binding to circulating erythrocytes, platelets, and clotting factors, including TF and fibrin.24 Moreover, histones on NETs can activate platelets and increase thrombin generation.25 Histones exhibit further prothrombotic effects by modulating the activation of the natural anticoagulant protein C. NETs can also impede fibrinolysis by the formation of ternary complex of DNA, plasmin, and fibrin.23

SUMMARY Hemostasis is a complex and balanced process facilitated by a network of zymogens, proteins, phospholipids, platelets, immune cells, and the endothelium. It is also meticulously regulated via intricate negative feedback mechanisms. There are numerous interactions between innate immunity and the coagulation system. Excessive innate immune response seen in sepsis or systemic inflammation can lead to dysregulation of hemostasis, causing thrombotic or consumptive coagulopathy via NETs production or an extensive crosstalk between inflammation and coagulation.

REFERENCES 1. Komatsuya K, Kaneko K, Kasahara K: Function of platelet glycosphingolipid microdomains/lipid rafts, Int J Mol Sci 21:5539, 2020. 2. Durrant TN, van den Bosch MT, Hers I: Integrin IIb3 outside-in signaling, Blood 130:1607-1619, 2017. 3. Nagy M, Heemskerk JWM, Swieringa F: Use of microfluidics to assess the platelet-based control of coagulation, Platelets 28:441-448, 2017. 4. Kim J, Zhang CZ, Zhang X, et al: A mechanically stabilized receptor- ligand flex-bond important in the vasculature, Nature 466:992-995, 2010. 5. Dopheide SM, Maxwell MJ, Jackson SP: Shear-dependent tether formation during platelet translocation on von Willebrand factor, Blood 99: 159-167, 2002. 6. Ruggeri ZM, Orje JN, Habermann R, et al: Activation-independent platelet adhesion and aggregation under elevated shear stress, Blood 108: 1903-1910, 2006. 7. Goggs R, Poole AW: Platelet signaling-a primer, J Vet Emerg Crit Care (San Antonio) 22:5-29, 2012. 8. Hoffman M: A cell-based model of coagulation and the role of factor VIIa, Blood Rev 17(Suppl 1):S1-S5, 2003. 9. Suzuki J, Umeda M, Sims PJ, et al: Calcium-dependent phospholipid scrambling by TMEM16F, Nature 468:834-838, 2010. 10. Tzima E, Walker JH: Platelet annexin V: the ins and outs, Platelets 11: 245-251, 2000.

CHAPTER 3  Hemostasis 11. Jandrey KE, Norris JW, Tucker M, et al: Clinical characterization of canine platelet procoagulant deficiency (Scott syndrome), J Vet Intern Med 26:1402-1407, 2012. 12. Bouchama A, Al-Mohanna F, Assad L, et al: Tissue factor/factor VIIa pathway mediates coagulation activation in induced-heat stroke in the baboon, Crit Care Med 40:1229-1236, 2012. 13. Butenas S, van ‘t Veer C, Mann KG: Evaluation of the initiation phase of blood coagulation using ultrasensitive assays for serine proteases, J Biol Chem 272:21527-21533, 1997. 14. Negrier C, Shima M, Hoffman M: The central role of thrombin in bleeding disorders, Blood Rev 38:100582, 2019. 15. Jacinto AML, Ridyard AE, Aroch I, et al: Thromboembolism in dogs with protein-losing enteropathy with non-neoplastic chronic small intestinal disease, J Am Anim Hosp Assoc 53:185-192, 2017. 16. Esmon CT: The protein C pathway, Chest 124:26S-32S, 2003. 17. Thelwell C, Longstaff C: The regulation by fibrinogen and fibrin of tissue plasminogen activator kinetics and inhibition by plasminogen activator inhibitor 1, J Thromb Haemost 5:804-811, 2007. 18. Voskuilen M, Vermond A, Veeneman GH, et al: Fibrinogen lysine residue A alpha 157 plays a crucial role in the fibrin-induced acceleration of

21

plasminogen activation, catalyzed by tissue-type plasminogen activator, J Biol Chem 262:5944-5946, 1987. 19. McCormack PL: Tranexamic acid: a review of its use in the treatment of hyperfibrinolysis, Drugs 72:585-617, 2012. 20. Brogren H, Karlsson L, Andersson M, et al: Platelets synthesize large amounts of active plasminogen activator inhibitor 1, Blood 104:3943-3948, 2004. 21. Kranzhofer R, Clinton SK, Ishii K, et al: Thrombin potently stimulates cytokine production in human vascular smooth muscle cells but not in mononuclear phagocytes, Circ Res 79:286-294, 1996. 22. Duler L, Nguyen N, Ontiveros E, et al: Identification of neutrophil extracellular traps in paraffin-embedded feline arterial thrombi using immunofluorescence microscopy, J Vis Exp (157), 2020. 23. Ducroux C, Di Meglio L, Loyau S, et al: Thrombus neutrophil extracellular traps content impair tPA-induced thrombolysis in acute ischemic stroke, Stroke 49:754-757, 2018. 24. Martinod K, Wagner DD: Thrombosis: tangled up in NETs, Blood 123:2768-2776, 2014. 25. Semeraro F, Ammollo CT, Morrissey JH, et al: Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4, Blood 118:1952-1961, 2011.

4 Cardiopulmonary Resuscitation Daniel J. Fletcher, PhD, DVM, DACVECC, Manuel Boller, Dr med vet, MTR, DACVECC

KEY POINTS • Early recognition of cardiopulmonary arrest (CPA) and rapid initiation of cardiopulmonary resuscitation (CPR) are crucial for patient survival. • Basic life support, consisting of high-quality chest compressions at a rate of 100–120 per minute, a depth of one-third to one-half the width of the chest, and delivered in uninterrupted cycles of 2 minutes, as well as ventilation at a rate of 10 breaths per minute, is arguably the most important aspect of CPR. • Monitoring priorities during CPR include electrocardiography to obtain a rhythm diagnosis and end-tidal carbon dioxide monitoring

to evaluate the effectiveness of chest compressions and as an early indicator of return of spontaneous circulation. • Advanced life support interventions for asystole and pulseless electrical activity include vasopressor therapy and parasympatholytic therapy, especially in cases of bradycardic arrest due to high vagal tone. • The most effective advanced life support therapy for ventricular fibrillation is electrical defibrillation. Only a single shock should be delivered initially, followed by a full 2-minute cycle of basic life support before administering an additional shock in refractory ventricular fibrillation.

Cardiopulmonary arrest (CPA) in cats and dogs is a highly lethal condition, with rates of survival to discharge of only 6%–7%.1 Widespread training targeted to standardized cardiopulmonary resuscitation (CPR) guidelines in human medicine has led to substantial improvements in outcome after in-hospital CPA from 13.7% in 2000 to 22.3% in 2009.2 An exhaustive literature review completed by the Reassessment Campaign on Veterinary Resuscitation (RECOVER) initiative in 2012 generated the first evidence-based, consensus veterinary CPR guidelines.3 The evidence evaluation and guidelines were distributed among five domains: preparedness and prevention,4 basic life support (BLS),5 advanced life support,6 monitoring,7 and postcardiac arrest care.8 The goal of this chapter is to summarize the most important treatment recommendations from the first four domains. Chapter 5 discusses the postcardiac arrest care guidelines.

patient. In nonanesthetized patients, a diagnosis of CPA should be highly suspected in any unconscious patient that is not breathing. A brief assessment lasting no more than 10–15 seconds based on evaluation of airway, breathing, and circulation (ABC) will efficiently identify CPA. If CPA cannot be definitively ruled out, CPR should be initiated immediately rather than pursuing further diagnostic assessment. The rationale for this aggressive approach includes: (1) pulse palpation is an insensitive test for CPA in people, and this may also be the case in dogs and cats; (2) even short delays in starting CPR in pulseless patients reduce survival rates; and (3) starting CPR on a patient not in CPA carries minimal risks.18,19 Therefore, there should be no delay in starting CPR in any patient in which there is a suspicion of CPA.

PREPAREDNESS AND PREVENTION

BLS includes chest compressions to restore blood flow to the tissues and the pulmonary circulation and ventilation to provide oxygenation of the arterial blood and removal of carbon dioxide from the venous blood. BLS should be initiated as quickly as possible once a diagnosis of CPA has been made using the treatment mnemonic CAB (circulation, airway, breathing). More than any other CPR intervention, highquality BLS focused first on chest compressions followed by ventilation likely has the most significant impact on outcome.18 However, given the higher incidence of primary respiratory arrest in dogs and cats than in people, early airway management and ventilation are strongly recommended. In multiple rescuer CPR, an airway should be established simultaneously with the initiation of chest compressions.

It has been long understood that early recognition of and response to CPA are critical if survival rates are to be improved. Both didactic training targeted at establishing a baseline CPR knowledge base and hands-on practice for psychomotor skill development in training programs improve CPR performance and outcomes.9,10 Once baseline training has been completed, refresher training at least every 6 months is recommended for personnel likely to be involved in CPR attempts to reduce decline of skills and knowledge.11,12 A centrally located, routinely audited crash cart containing all necessary drugs and equipment should be maintained in the practice. Readily available cognitive aids, such as algorithm and dosing charts, improve adherence to guidelines as well as individual performance during CPR.13–15 Staff should be trained on the use of these aids regularly. Short post-event debriefing sessions where team performance is discussed and critically evaluated can help improve future performance and serve as refresher training at the same time.16,17 A standardized assessment leading to early recognition of CPA is crucial and should be applied immediately to any acutely unresponsive

22

BASIC LIFE SUPPORT

Circulation — Chest Compressions Tissue hypoxia and ischemic injury occur rapidly in patients with untreated CPA, an immediate consequence of which is the exhaustion of cellular energy stores. Altered cellular membrane potentials and organ dysfunction follow rapidly, and longer duration of ischemia primes the system for more severe reperfusion injury when tissue blood flow resumes. Administration of high-quality chest compressions can provide

CHAPTER 4  Cardiopulmonary Resuscitation vital blood flow to tissues, decreasing ischemic injury and blunting the reperfusion injury set in motion with return of spontaneous circulation (ROSC). Chest compressions are targeted at two main goals: (1) restoration of pulmonary CO2 elimination and oxygen uptake by providing pulmonary blood flow; and (2) delivery of oxygen to tissues to restore organ function and metabolism by providing systemic arterial blood flow. Even well-executed chest compressions produce only approximately 30% of normal cardiac output; therefore, meticulous attention to chest compression technique is essential. Any delay in starting high-quality chest compressions or excessive pauses in compressions reduce the likelihood of ROSC and survival to discharge. During ventricular systole in the spontaneously beating heart, coronary blood flow is negligible and at times may be retrograde; several mechanisms have been proposed to explain this finding, including backward pressure waves, the intramyocardial pump theory, coronary systolic flow impediment, and cardiac compression.20,21 This same phenomenon has been described during CPR using external chest compressions.22,23 Therefore, it is important to consider that the majority of myocardial perfusion during CPR occurs during the decompression phase of chest compressions and is predominantly determined by coronary perfusion pressure (CPP, also known as myocardial perfusion pressure), which is defined as the difference between aortic diastolic pressure (ADP) and right atrial diastolic pressure (RADP) (CPP 5 ADP – RADP). There is strong evidence that higher CPP during CPR is associated with better success in both humans and dogs, leading to the use of CPP as a primary marker of CPR quality.24,25 Unfortunately, little experimental or clinical data are available to guide chest compression technique in dogs and cats, but anatomical principles suggest that chest compressions may be delivered with the patient in either left or right lateral recumbency,26 with a compression depth of one-third to one-half the width of the chest and at a rate of 100–120 compressions per minute regardless of animal size or species. An experimental study in dogs showed that higher compression rates lead to higher CPP and coronary blood flow velocity, but because anterograde flow occurred only during chest decompression, net coronary blood flow decreased at compression rates above 120 per minute, so faster rates should be avoided.27 To ensure the correct compression frequency, the use of cues such as a metronome or a song with the correct tempo (e.g., the Bee Gees’ “Staying Alive”) is recommended. Leaning on the chest between compressions will reduce filling of the heart by preventing full elastic recoil of the chest and must be avoided. Compressions should be delivered without interruption in cycles of 2 minutes to optimize development of adequate CPP, as it takes approximately 60 seconds of continuous chest compressions before CPP reaches its maximum.28 CPP is the primary determinant of myocardial blood flow, and higher CPP is associated with a higher likelihood of ROSC. Electrocardiogram analysis to diagnose the arrest rhythm and pulse palpation to identify ROSC require pauses in chest compressions, and should be accomplished during a brief cessation (2–5 seconds) of compressions at the end of each 2-minute BLS cycle. To minimize compressor fatigue, a new team member should take over chest compressions during this planned pause. The generation of blood flow to the tissues during CPR occurs in fundamentally different ways than in a patient with a spontaneously beating heart. There are two models explaining the mechanisms of forward flow during external chest compressions, and based upon these models, it is likely that the most effective technique for chest compressions will depend upon patient size and chest geometry. The cardiac pump theory proposes that direct compression of the left and right ventricles increases ventricular pressure, opening the pulmonic and aortic valves and allowing blood flow to the lungs and the tissues respectively.29 Thoracic elastic properties allow the chest to recoil

23

between compressions, creating a subatmospheric intrathoracic pressure that draws venous blood into the ventricles prior to the subsequent compression. In contrast, an increase in overall intrathoracic pressure during a chest compression forcing blood from the thorax into the systemic circulation is proposed in the thoracic pump theory. Rather than as a pump, the heart acts simply as a conduit for blood flow.30 Taking these two theories into account and which is more likely to be most exploitable given an individual patient’s thoracic shape and size, recommendations can be made for rescuer hand position during chest compressions. Table 4.1 specifies the recommended approach to chest compressions in dogs and cats based upon size and thoracic conformation. It should be noted that although animals of the same breed tend to have similar chest conformations, each individual should be evaluated independently and the most appropriate technique applied regardless of breed. Medium to large dogs with round chest conformations (lateral width similar to dorsal-ventral height) are likely best compressed in lateral recumbency using the thoracic pump theory by placing the hands over the widest portion of the chest (the highest point when laying in lateral recumbency). In contrast, similarly sized dogs with deeper, keel-chested conformations (lateral width significantly smaller than dorsal-ventral height) are likely to be more effectively compressed using a cardiac pump approach, with the hands placed directly over the heart. In markedly flat-chested dogs (such as many English Bulldogs) with dorsoventrally compressed chests similar to humans (lateral width significantly larger than dorsal-ventral depth), the cardiac pump theory may be maximally employed by positioning the hands over the sternum with the patient in dorsal recumbency. In medium to large dogs with low chest compliance, considerable compression force is necessary for CPR to be effective. The compressor’s posture has a significant impact on efficacy; the compressor should lock the elbows with one hand on top of the other and position the shoulders directly above the hands. Engaging the core muscles rather than the biceps and triceps by using this posture will allow the compressor to maintain optimal compression force and reduce fatigue. The use of a step stool is recommended if the patient is on a table and the elbows cannot be locked. Alternatively, the compressor can kneel over the patient by climbing onto the table or placing the patient on the floor. Chest compressions should be done directly over the heart in most cats and small dogs. These patients tend to have highly compliant, predominantly keel-shaped chests that favor the cardiac pump mechanism. Either the same two-handed technique as described above for large dogs or a single-handed technique with the hand wrapped around the sternum and compressions achieved by squeezing the chest can be used. Circumferential compressions of the chest using both hands may also be considered.

Airway and Breathing — Ventilation Dogs and cats in CPA should be ventilated as soon as possible after chest compressions are started. Patients should be intubated immediately if the equipment is available. Intubation should occur in lateral recumbency without interrupting chest compressions. In intubated patients, chest compressions and ventilation are done simultaneously. The inflated endotracheal tube cuff prevents gastric insufflation with air, allows pulmonary inflation during chest compressions, and minimizes interruptions in chest compressions. The following ventilation targets should be used during CPR: ventilation rate of 10 breaths per minute, a short inspiratory time of approximately 1 second, and a tidal volume of approximately 10 ml/kg. This low minute ventilation is adequate during CPR because pulmonary blood flow is reduced. Because low arterial CO2 tension causes cerebral vasoconstriction leading to decreased cerebral blood flow and oxygen delivery, hyperventilation

24

PART I  Key Critical Care Concepts

TABLE 4.1  Chest Compression Approaches Conformation

Breed Examples

Predominant Theory

Technique

Medium and large breed round-chested dogs

• Labrador Retriever • Golden Retriever • Rottweiler • German Shepherd • American Pitbull Terrier

Thoracic pump

Lateral recumbency, two-hand technique, hands over the widest part of the chest (highest point in lateral recumbency)

Medium and large breed keel-chested dogs

• Greyhound • Doberman Pinscher

Cardiac pump

Lateral recumbency, two-hand technique, hands directly over the heart

Flat-chested dogs

• English Bulldog • French Bulldog

Cardiac pump

Dorsal recumbency, two-hand technique, hands directly over the sternum

Cats and small dogs in average body condition • All cats • Chihuahua • Yorkshire Terrier • Maltese • Shih Tzu

Cardiac pump

Lateral recumbency, (a) one-hand technique, hand wrapped around sternum over heart (2) twohand technique, hands directly over the heart, take care not to over-compress the chest

Obese cats and small dogs

Cardiac pump

Lateral recumbency, two-hand technique, hands over the heart (if chest is keel-shaped) or the widest part of the chest (if chest if roundshaped)

or Thoracic pump

must be avoided. In addition, increased intrathoracic pressure due to positive pressure ventilation will impede venous return to the chest, reducing effectiveness of chest compressions and reducing CPP. Therefore, limiting the ventilation rate to reduce the mean intrathoracic pressure will improve cardiac output. Mouth-to-snout ventilation is an alternative breathing strategy and will provide sufficient oxygenation and CO2 removal but should only be used if endotracheal intubation is not possible. Firmly close the animal’s mouth with one hand while extending the neck to align the snout with the spine. The rescuer should then make a seal over the patient’s nares with his/her mouth and inflate the lungs by blowing firmly into the nares while visually inspecting the chest during the procedure, continuing the breath until a normal chest excursion is accomplished. An inspiratory time of approximately 1 second should be targeted. Because ventilation cannot be accomplished simultaneously with chest compressions in nonintubated patients, rounds of 30 chest compressions should be delivered, immediately followed by two short breaths. Compressions and mouth-to-snout breaths at a ratio of 30:2 should be continued for 2-minute cycles, and the rescuers rotated every cycle to prevent fatigue. This technique necessitates pauses in chest compressions and should only be employed when endotracheal intubation is impossible due to lack of equipment or trained personnel.

MONITORING Because of motion artifact and the lack of adequate pulse quality during CPR, many monitoring devices are of limited use, including pulse oximeter and indirect blood pressure monitors such as Doppler and oscillometric devices. However, electrocardiography (ECG) and capnography are two useful monitoring modalities during CPR and their use is recommended.

to minimize pauses in chest compressions, the only time the ECG should be evaluated is between 2-minute cycles of BLS while compressors are being rotated. The team leader should clearly announce the rhythm diagnosis and invite other team members to express agreement or dissent to minimize misdiagnosis. In the event of differing opinions on the rhythm diagnosis, chest compressions should be resumed immediately, and discussion should proceed into the next cycle. The three most common arrest rhythms leading to CPA in dogs and cats are: asystole, pulseless electrical activity (PEA), or ventricular fibrillation (VF).1,31,32

Capnography End-tidal CO2 (ETCO2) monitoring is safe and feasible during CPR, and is resistant to motion artifact regardless of technology.33,34 Detection of measurable ETCO2 suggests (but is not definitive for) correct endotracheal tube placement, especially in the CPA patient with poor pulmonary blood flow.35 ETCO2 can also be used as an indicator of chest compression efficacy because when minute ventilation is held constant, ETCO2 is proportional to pulmonary blood flow. A very low ETCO2 value during CPR (e.g., ,10–15 mm Hg) has been associated with a reduced likelihood of ROSC in dogs and humans.1,36 ETCO2 substantially increases upon ROSC and therefore is a valuable early indicator of ROSC during CPR.

ADVANCED LIFE SUPPORT ALS, including drug therapy and electrical defibrillation, is initiated once BLS procedures have been started. It should be emphasized that in the absence of high-quality BLS interventions, ALS procedures are unlikely to be successful; therefore, all ALS interventions should be implemented so as to minimize any impact on BLS quality.

Electrocardiography

Drug Therapy

Many important decisions about advanced life support (ALS) therapy are dependent upon the ECG rhythm diagnosis. However, it is important to note that the ECG is highly susceptible to motion artifact and cannot be interpreted during ongoing chest compressions; therefore,

During CPR, drug therapy should preferentially be administered by the intravenous or intraosseous route, and early placement of a peripheral venous, central venous, or intraosseous catheter is recommended. Cutdown procedures to obtain peripheral venous access are

CHAPTER 4  Cardiopulmonary Resuscitation commonly required. Note that BLS should not be paused during vascular access procedures. Vasopressors, parasympatholytics, and/or antiarrhythmics may be indicated in dogs and cats with CPA, depending on the underlying arrest rhythm. Depending on the type of arrest, the duration, and predisposing factors, other potentially useful ALS therapies may include reversal agents, intravenous fluids, and alkalinizing drugs. Table 4.2 summarizes the doses of drugs that may be of use during CPR. As part of preparedness for CPR, a drug dose chart should be in plain view in the ready area of the hospital. CPR algorithms and drug dose charts produced as part of the RECOVER initiative are available at http://www.veccs.org.

Vasopressors Because cardiac output during CPR is generally 30% or less of normal, increasing peripheral vascular resistance to redirect blood flow from the periphery to the core can be useful regardless of the arrest rhythm. The best-studied vasopressor during CPR is epinephrine, a catecholamine that causes peripheral vasoconstriction via stimulation of a1 receptors but also acts on b1 and b2 receptors. The a1 effects have been shown to be the most beneficial during CPR,37 and these vasoconstrictive effects predominate in the periphery, while sparing the coronary and cerebral vasculature and preserving blood flow to these core organs.38 A meta-analysis showed that low-dose epinephrine (0.01 mg/kg IV/IO every other cycle of CPR) was associated with

25

higher rates of survival to discharge in people than high-dose epinephrine (0.1 mg/kg IV/IO every other cycle of CPR).39 A metaanalysis of human clinical trials confirmed that the use of epinephrine was associated with increased rates of survival to discharge and with increased rates of poor neurologic outcome, possibly due to increased survival rates among more severely ill patients in the epinephrine groups.40 However, a more recent large scale, placebo-controlled clinical trial in humans showed improved survival to 30 days in the group receiving epinephrine with no difference in functional neurologic outcome.41 Therefore, early in CPR, low-dose epinephrine is recommended. However, after prolonged CPR, a higher dose (0.1 mg/ kg IV/IO every other cycle of CPR) may be considered due to evidence that this dose is associated with a higher rate of ROSC, but only with the understanding that the use of high-dose epinephrine may lead to a lower likelihood of survival to discharge, and should be avoided in patients with acute, reversible causes of CPA. Intratracheal (IT) administration of epinephrine is also possible (0.02 mg/kg low dose; 0.2 mg/kg high dose) and should be accomplished by feeding a long catheter through the tube and diluting the epinephrine 1:1 with isotonic saline or sterile water.42 Although still considered a mainstay of therapy for asystole and PEA, there is controversy regarding the utility of epinephrine during CPR. Despite evidence of increased ROSC rates with its use, no consistent long-term survival or functional outcome effect has been demonstrated.43

TABLE 4.2  CPR Drugs and Doses Arrest

Drug

Common Concentration Dose / Route

Comments

Epinephrine (low dose)

1 mg/ml (1:1000)

0.01 mg/kg IV/IO 0.02–0.1 mg/kg IT

Every other basic life support cycle for asystole/pulseless electrical activity Increase dose 2–103 and dilute for IT administration

Epinephrine (high dose)

1 mg/ml (1:1000)

0.1 mg/kg IV/IO/IT

Consider for prolonged (.10 minutes) cardiopulmonary resuscitation

Vasopressin

20 U/ml

0.8 U/kg IV/IO 1.2 U/kg IT

Every other basic life support cycle Increase dose for IT use

Atropine

0.4 mg/ml

0.04 mg/kg IV/IO

Every other basic life support cycle during cardiopulmonary resuscitation Recommended for bradycardic arrests / known or suspected high vagal tone Increase dose for IT use

0.15–0.2 mg/kg IT

Antiarrhythmic

Reversals

Defibrillation (may increase dose once by 50%–100% for refractory VF/pulseless VT)

Bicarbonate

1 mEq/ml

1 mEq/kg IV/IO

For prolonged cardiopulmonary resuscitation/ PCA phase when pH ,7.0 Do not use if hypoventilating

Amiodarone

50 mg/ml and 1.8 mg/ml

5 mg/kg IV/IO

For refractory ventricular fibrillation/pulseless ventricular tachycardia Associated with anaphylaxis in dogs

Lidocaine

20 mg/ml

2 mg/kg slow IV/IO push (1–2 minutes)

For refractory ventricular fibrillation/pulseless ventricular tachycardia only if amiodarone is not available

Naloxone

0.4 mg/ml

0.04 mg/kg IV/IO

To reverse opioids

Flumazenil

0.1 mg/ml

0.01 mg/kg IV/IO

To reverse benzodiazepines

Atipamezole

5 mg/ml

100 mg/kg IV/IO

To reverse a2 agonists

Monophasic External

4–6 J/kg

Monophasic Internal

0.5–1 J/kg

Biphasic External

2–4 J/kg

Biphasic Internal

0.2–0.4 J/kg

IT, intratracheal; PCA, post cardiac arrest

26

PART I  Key Critical Care Concepts

An alternative to epinephrine is vasopressin (0.8 U/kg IV/IO every other cycle of CPR), a vasopressor that acts via activation of peripheral V1 receptors. It may be used interchangeably or in combination with epinephrine during CPR. Unlike epinephrine, it is efficacious in acidic environments in which a1 receptors may become unresponsive to epinephrine. It also lacks the inotropic and chronotropic b1 effects that may worsen myocardial ischemia in patients that achieve ROSC.44 Like epinephrine, vasopressin may be administered endotracheally as described above. See Chapter 148, Vasopressin.

Parasympatholytics Atropine is a parasympatholytic drug and has been extensively studied in CPR.45–47 Its administration may be considered during CPR in all dogs and cats (0.04 mg/kg IV/IO every other cycle of CPR), and it may be especially useful in patients with asystole or PEA associated with increased vagal tone, such as occurs with chronic or severe, acute gastrointestinal, respiratory, or ocular disease. Endotracheal administration is also possible (0.08 mg/kg).48 Although the guidelines state that it may be repeated every 3–5 minutes during CPR, given its long halflife, it may be judicious to repeat only once or twice.

Antiarrhythmic Drugs Patients with VF refractory to electrical defibrillation (discussed in the next section) may benefit from treatment with the antiarrhythmic drug amiodarone at a dose of 2.5–5 mg/kg IV/IO.49 There are reports of anaphylactic reactions in dogs, so close monitoring for signs of anaphylaxis is warranted once ROSC is achieved, and if noted, they should be treated appropriately (see Chapter 141, Anaphylaxis). Lidocaine (2 mg/kg slow IV/IO push) is a less effective alternative to amiodarone for patients with refractory VF. Although lidocaine has been shown to increase the energy required for successful electrical defibrillation in dogs in one study, others have shown that this drug is beneficial.50,51

Reversal Agents If any reversible sedative drugs were administered to the patient before CPA, reversal agents may be beneficial and are unlikely to cause harm. Commonly available reversal agents include naloxone (0.04 mg/kg IV/ IO) for opioids, flumazenil (0.01 mg/kg IV/IO) for benzodiazepines, and atipamezole (0.1 mg/kg IV/IO) or yohimbine (0.1 mg/kg IV/IO) for a2 agonists.

Intravenous Fluids Administration of IV fluid boluses during CPR may be harmful to euvolemic or hypervolemic patients because they tend to increase central venous (and hence right atrial) pressure rather than arterial blood pressure in patients in CPA. This elevation in right atrial pressure can compromise perfusion of the brain and heart by decreasing CPP and cerebral perfusion pressure. Conversely, patients with documented or suspected hypovolemia will likely benefit from IV fluids, which will help to restore adequate preload, and may increase the efficacy of chest compressions and improve arterial systolic and diastolic pressures, leading to increased cerebral perfusion pressure and CPP.

Corticosteroids Most studies have shown no definitive evidence of benefit or harm from corticosteroid administration during CPR, although most were confounded by coadministration of other drugs.52,53 One prospective observational study in dogs and cats showed an increased rate of ROSC in dogs and cats, but the type and dose of steroids administered were highly variable, and a causative effect could not be inferred due to the study design.1 It is well known that significant gastrointestinal ulceration can develop from a single high dose of corticosteroids.54–56

In addition, immunosuppression and reduced renal perfusion due to decreased renal prostaglandin production are known side effects. Because of this nonadvantageous risk:benefit ratio, the routine use of corticosteroids is not recommended during CPR.

Alkalinizing Agents Severe metabolic acidosis can develop with prolonged CPA (greater than 10–15 minutes), leading to inhibition of normal enzymatic and metabolic activity as well as severe vasodilation. Administration of sodium bicarbonate (1 mEq/kg, once, diluted IV) may be considered in these patients. It should be remembered that these metabolic disturbances may resolve rapidly after ROSC; therefore, bicarbonate therapy in patients with prolonged CPA should be reserved for those with severe acidemia (pH ,7.0) of metabolic origin.

Electrical Defibrillation Electrical defibrillation is the cornerstone of therapy for VF and pulseless ventricular tachycardia (VT). Guidelines for the approach to electrical defibrillation during CPR have recently been modified due to data suggesting a three-phase model of ischemia during VF in the absence of CPR. The initial electrical phase during the first 4 minutes is characterized by minimal ischemia and continued availability of cellular energy stores to maintain metabolic processes. The subsequent 6 minutes, constituting the circulatory phase, are characterized by reversible ischemic injury due to depletion of cellular ATP stores. After 10 minutes, the metabolic phase begins, and potentially irreversible ischemic damage begins to occur. Based on this model, if the duration of VF is known or suspected to be of duration of 4 minutes or less, chest compressions should be continued only until the defibrillator is charged and the patient should then be defibrillated immediately. However, one full cycle of CPR should be done before defibrillating if the patient has been in VF for more than 4 minutes. This allows for blood flow and oxygen delivery to the myocardial cells, which can then generate ATP and restore normal membrane potentials, making the cells more likely to respond favorably to electrical defibrillation.57 Two types of defibrillators are available. Monophasic defibrillators deliver current in one direction between the paddles and across the patient’s chest, while biphasic defibrillators deliver current in one direction before reversing polarity and delivering a current in the opposing direction. Biphasic defibrillators have been shown to successfully defibrillate patients at a lower energy output, leading to less myocardial damage, and are therefore recommended over monophasic devices. Dosing for monophasic defibrillators begins at 4–6 J/kg, while biphasic defibrillation dosing starts at 2–4 J/kg. The second dose may be increased by 50%, but subsequent doses should not be further increased (see Chapter 205, Defibrillation). Regardless of the technology used, ALS algorithms no longer recommend three stacked shocks. Instead, chest compressions should be resumed immediately after a single defibrillation attempt without a pause for rhythm analysis. A full 2-minute cycle of BLS should then be administered before reassessing the ECG. If the patient is still in VF, defibrillation should be repeated at the end of this cycle of BLS.58,59

OPEN-CHEST CPR The International Liaison Committee on Resuscitation consensus on science does not currently provide any recommendations on openchest CPR (OCCPR) due to the lack of controlled clinical trials.60 However, there are a number of experimental studies in dogs and clinical studies in people showing improvements in hemodynamic variables, CPP and cerebral perfusion pressure, and outcome when

CHAPTER 4  Cardiopulmonary Resuscitation comparing OCCPR with closed-chest CPR.61,62 There is also evidence that delays in starting OCCPR lead to poorer outcomes, and that after 20 minutes of closed-chest CPR in dogs, OCCPR is unlikely to be effective.63 Although significantly more invasive and costly than closedchest CPR, the prevailing evidence suggests that improved outcomes from CPA are likely with OCCPR compared with closed-chest CPR, and in cases in which owner consent has been obtained and no underlying diseases that would be contraindications to OCCPR are present (such as thrombocytopenia or coagulopathy), the procedure should be employed as soon as possible after diagnosis of CPA. To perform OCCPR, a left lateral thoracotomy in the fourth to fifth intercostal space is performed with the animal in right lateral recumbency, and Finochietto retractors are used to open the chest for access to the heart. The pericardium may be removed in all cases to facilitate compressions but should always be removed in patients with pericardial effusion or other pericardial disease. The ventricles can then be directly compressed using either a two-hand technique with the right ventricle cupped in the left hand and the fingers of the right hand placed over the left ventricle or a one-hand technique with the fingers of the right hand placed over the left ventricle and the heart compressed against the sternum.64 Care should be taken to compress the ventricles from apex to base to maximize forward blood flow. If ROSC is achieved, intensive postcardiac arrest care will be required after the thoracotomy is closed and a chest tube placed to reduce the risk of pneumothorax. Although OCCPR may be employed in any patient in CPA, for some conditions leading to CPA, it is likely the only viable option. Conditions making external chest compressions futile include pleural space disease, pericardial effusion, and penetrating thoracic injuries. In addition, it is likely that closed-chest CPR will be ineffective in giant breed dogs with round or flat-chested conformation, and OCCPR is preferable. Finally, patients already in surgery that experience CPA should likely have OCCPR rather than closed-chest CPR. In patients undergoing abdominal surgery, the heart is easily accessible via an incision in the diaphragm, so thoracotomy is not required. A recent experimental study found that a transdiaphragmatic approach to OCCPR took the same time for initiation of cardiac compressions as a lateral thoracotomy in a nonsurgical scenario, suggesting it is a possible alternative beyond the abdominal surgery setting.65

PROGNOSIS There are limited data on prognosis in dogs and cats after CPA. It is likely, however, that the cause of the arrest is an important prognostic indicator, as evidenced by several retrospective studies of dogs and cats with CPA. In one, the authors found that of 15 dogs and 3 cats that survived to hospital discharge, only 3/18 had significant underlying chronic disease, whereas all other patients had acute disease leading to CPA.31 It is likely that patients experiencing CPA as a consequence of severe, untreatable, or progressive chronic diseases are less likely to survive to hospital discharge, even though these outcomes are confounded by euthanasia. Patients that arrest in the perianesthetic period have a markedly better prognosis, as high as 47% survival to discharge in one prospective observational veterinary study, than patients that arrest due to other etiologies.1 A more recent prospective, observational study of 172 dogs and 47 cats that underwent CPR at a tertiary referral facility showed that cats had a 19% survival to discharge rate and were almost five times as likely to survive than dogs, and that animals that experienced CPA under the care of the anesthesia service were almost 15 times as likely to survive as animals that arrested in other parts of the hospital.66,67 CPR efforts in the population of cats and dogs with acute, treatable disease, especially when incited by an anesthetic event, are warranted, and should be aggressive and persistent if the owner consents.

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REFERENCES 1. Hofmeister EH, Brainard BM, Egger CM, Kang S: Prognostic indicators for dogs and cats with cardiopulmonary arrest treated by cardiopulmonary cerebral resuscitation at a university teaching hospital, J Am Vet Med Assoc 235(1):50-57, 2009. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/19566454. 2. Girotra S, Nallamothu BK, Spertus JA, et al: Trends in survival after inhospital cardiac arrest, N Engl J Med 367(20):1912-1920, 2012. Available at: http://www.nejm.org/doi/abs/10.1056/NEJMoa1109148. 3. Fletcher DJ, Boller M, Brainard BM, et al: RECOVER evidence and knowledge gap analysis on veterinary CPR. Part 7: Clinical guidelines, J Vet Emerg Crit Care (San Antonio) 22(Suppl 1):S102-S131, 2012. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22676281. 4. McMichael M, Herring J, Fletcher DJ, Boller M: RECOVER evidence and knowledge gap analysis on veterinary CPR. Part 2: Preparedness and prevention, J Vet Emerg Crit Care (San Antonio) 22(Suppl 1):S13-S25, 2012. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22676282. 5. Hopper K, Epstein SE, Fletcher DJ, Boller M: RECOVER evidence and knowledge gap analysis on veterinary CPR. Part 3: Basic life support, J Vet Emerg Crit Care (San Antonio) 22(Suppl 1):S26-S43, 2012. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22676283. 6. Rozanski EA, Rush JE, Buckley GJ, Fletcher DJ, Boller M: RECOVER evidence and knowledge gap analysis on veterinary CPR. Part 4: Advanced life support, J Vet Emerg Crit Care (San Antonio) 22(Suppl 1):S44-S64, 2012. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22676286. 7. Brainard BM, Boller M, Fletcher DJ: RECOVER evidence and knowledge gap analysis on veterinary CPR. Part 5: Monitoring, J Vet Emerg Crit Care (San Antonio) 22(Suppl 1):S65-S84, 2012. Available at: http://www.ncbi. nlm.nih.gov/pubmed/22676287. 8. Smarick SD, Haskins SC, Boller M, Fletcher DJ: RECOVER evidence and knowledge gap analysis on veterinary CPR. Part 6: Post-cardiac arrest care, J Vet Emerg Crit Care (San Antonio) 22(Suppl 1):S85-S101, 2012. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22676288. 9. Noordergraaf GJ, Van Gelder JM, Van Kesteren RG, Diets RF, Savelkoul TJ. Learning cardiopulmonary resuscitation skills: does the type of mannequin make a difference? Eur J Emerg Med 4(4):204-209, 1997. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9444504. 10. Cimrin AH, Topacoglu H, Karcioglu O, Ozsarac M, Ayrik C: A model of standardized training in basic life support skills of emergency medicine residents, Adv Ther 22(1):10-18, 2005. Available at: http://www.ncbi.nlm. nih.gov/pubmed/15943217. 11. Isbye DL, Meyhoff CS, Lippert FK, Rasmussen LS: Skill retention in adults and in children 3 months after basic life support training using a simple personal resuscitation manikin, Resuscitation 74(2):296-302, 2007. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17376582. 12. Mpotos N, Lemoyne S, Wyler B, et al: Training to deeper compression depth reduces shallow compressions after six months in a manikin model, Resuscitation 82(10):1323-1327, 2011. Available at: http://www.ncbi.nlm. nih.gov/pubmed/21723028. 13. Royse AG: New resuscitation trolley: stages in development, Aust Clin Rev 9(3-4):107-114, 1989. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/2486036. 14. Schade J: An evaluation framework for code 99, QRB Qual Rev Bull 9(10):306-309, 1983. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/6417586. 15. Dyson E, Smith GB: Common faults in resuscitation equipment—guidelines for checking equipment and drugs used in adult cardiopulmonary resuscitation, Resuscitation 55(2):137-149, 2002. Available at: http://www. ncbi.nlm.nih.gov/pubmed/12413751. 16. Edelson DP, Litzinger B, Arora V, et al: Improving in-hospital cardiac arrest process and outcomes with performance debriefing, Arch Intern Med 168(10):1063-1069, 2008. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/18504334. 17. Dine CJ, Gersh RE, Leary M, Riegel BJ, Bellini LM, Abella BS: Improving cardiopulmonary resuscitation quality and resuscitation training by combining audiovisual feedback and debriefing, Crit Care Med 36(10):2817-2822, 2008. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18766092.

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PART I  Key Critical Care Concepts

18. Rittenberger JC, Menegazzi JJ, Callaway CW: Association of delay to first intervention with return of spontaneous circulation in a swine model of cardiac arrest, Resuscitation 73(1):154-160, 2007. Available at: http://www. ncbi.nlm.nih.gov/pubmed/17223246. 19. Dick WF, Eberle B, Wisser G, Schneider T: The carotid pulse check revisited: what if there is no pulse? Crit Care Med 28(11 Suppl):N183-N185, 2000. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11098941. 20. Tyberg JV: Late-systolic retrograde coronary flow: an old observation finally explained by a novel mechanism, J Appl Physiol 108(3):479-480, 2010. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20075268. 21. Khouri EM, Gregg DE, Rayford CR: Effect of exercise on cardiac output, left coronary flow and myocardial metabolism in the unanesthetized dog, Circ Res 17(5):427-437, 1965. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/5843879. 22. Kern KB, Hilwig R, Ewy GA: Retrograde coronary blood flow during cardiopulmonary resuscitation in swine: intracoronary Doppler evaluation, Am Heart J 128(3):490-499, 1994. Available at: http://www.ncbi.nlm.nih. gov/pubmed/8074010. 23. Andreka P, Frenneaux MP: Haemodynamics of cardiac arrest and resuscitation, Curr Opin Crit Care 12(3):198-203, 2006. Available at: http://www. ncbi.nlm.nih.gov/pubmed/17241498. 24. Kern KB, Ewy GA, Voorhees WD, Babbs CF, Tacker WA: Myocardial perfusion pressure: a predictor of 24-hour survival during prolonged cardiac arrest in dogs, Resuscitation 16(4):241-250, 1988. Available at: http:// www.ncbi.nlm.nih.gov/pubmed/2849790. 25. Paradis NA, Martin GB, Rivers EP, et al: Coronary perfusion pressure and the return of spontaneous circulation in human cardiopulmonary resuscitation, JAMA 263(8):1106-1113, 1990. Available at: http://www.ncbi.nlm. nih.gov/pubmed/2386557. 26. Maier GW, Tyson GS, Olsen CO, et al: The physiology of external cardiac massage: high-impulse cardiopulmonary resuscitation, Circulation 70(1):86-101, 1984. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/6723014. 27. Wolfe JA, Maier GW, Newton JR, et al: Physiologic determinants of coronary blood flow during external cardiac massage, J Thorac Cardiovasc Surg 95(3):523-532, 1988. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/3343860. 28. Kern K, Hilwig R, Berg R, Sanders A: Importance of continuous chest compressions during cardiopulmonary resuscitation, Circulation 105(5):645-649, 2002. Available at: http://circ.ahajournals.org/content/105/5/645.short. 29. Kouwenhoven WB, Jude JR, Knickerbocker GG: Closed-chest cardiac massage, JAMA 173:1064-1067, 1960. Available at: http://www.ncbi.nlm.nih. gov/pubmed/14411374. 30. Niemann JT, Rosborough J, Hausknecht M, Ung S, Criley JM: Blood flow without cardiac compression during closed chest CPR, Crit Care Med 9(5):380-381, 1981. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/7214963. 31. Waldrop JE, Rozanski EA, Swanke ED, O’Toole TE, Rush JE: Causes of cardiopulmonary arrest, resuscitation management, and functional outcome in dogs and cats surviving cardiopulmonary arrest, J Vet Emerg Crit Care 14(1):22-29, 2004. Available at: http://doi.wiley. com/10.1111/j.1534-6935.2004.04006.x. 32. Plunkett SJ, McMichael M: Cardiopulmonary resuscitation in small animal medicine: an update, J Vet Intern Med 22(1):9-25, 2008. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18289284. 33. Grmec S, Klemen P: Does the end-tidal carbon dioxide (EtCO2) concentration have prognostic value during out-of-hospital cardiac arrest? Eur J Emerg Med 8(4):263-269, 2001. Available at: http://www.ncbi.nlm.nih. gov/pubmed/11785591. 34. Pokorná M, Necas E, Kratochvíl J, Skripský R, Andrlík M, Franek O: A sudden increase in partial pressure end-tidal carbon dioxide (P(ET)CO(2)) at the moment of return of spontaneous circulation, J Emerg Med 38(5): 614-621, 2010. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19570645. 35. Li J. Capnography alone is imperfect for endotracheal tube placement confirmation during emergency intubation, J Emerg Med 20(3):223-229, 2001. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11267809.

36. Kolar M, Krizmaric M, Klemen P, Grmec S: Partial pressure of end-tidal carbon dioxide successful predicts cardiopulmonary resuscitation in the field: a prospective observational study, Crit Care 2008 12(5):R115. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid525927 43&tool5pmcentrez&rendertype5abstract. 37. Bassiakou E, Xanthos T, Papadimitriou L: The potential beneficial effects of beta adrenergic blockade in the treatment of ventricular fibrillation, Eur J Pharmacol 616(1-3):1-6, 2009. Available at: http://www.ncbi.nlm. nih.gov/pubmed/19555681. 38. Koehler RC, Michael JR, Guerci AD, et al: Beneficial effect of epinephrine infusion on cerebral and myocardial blood flows during CPR, Ann Emerg Med 14(8):744-749, 1985. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/4025969. 39. Vandycke C, Martens P: High dose versus standard dose epinephrine in cardiac arrest - a meta-analysis, Resuscitation 45(3):161-166, 2000. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10959014. 40. Loomba RS, Nijhawan K, Aggarwal S, Arora RR: Increased return of spontaneous circulation at the expense of neurologic outcomes: is prehospital epinephrine for out-of-hospital cardiac arrest really worth it? J Crit Care 30(6):1376-1381, 2015. 41. Perkins GD, Ji C, Deakin CD, et al: A randomized trial of epinephrine in out-of-hospital cardiac arrest, N Engl J Med 379(8):711-721, 2018. 42. Manisterski Y, Vaknin Z, Ben-Abraham R, et al: Endotracheal epinephrine: a call for larger doses, Anesth Analg 95(4):1037-1041, 2002. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12351290. 43. Callaway CW: Epinephrine for cardiac arrest, Curr Opin Cardiol 28(1): 36-42, 2013. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23196774. 44. Biondi-Zoccai GGL, Abbate A, Parisi Q, et al: Is vasopressin superior to adrenaline or placebo in the management of cardiac arrest? A meta- analysis, Resuscitation 59(2):221-224, 2003. Available at: http://linkinghub.elsevier.com/retrieve/pii/S030095720300234X. 45. Blecic S, Chaskis C, Vincent JL: Atropine administration in experimental electromechanical dissociation, Am J Emerg Med 10(6):515-518, 1992. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1388375. 46. DeBehnke DJ, Swart GL, Spreng D, Aufderheide TP: Standard and higher doses of atropine in a canine model of pulseless electrical activity, Acad Emerg Med 2(12):1034-1041, 1995. Available at: http://www.ncbi.nlm.nih. gov/pubmed/8597913. 47. Coon GA, Clinton JE, Ruiz E: Use of atropine for brady-asystolic prehospital cardiac arrest, Ann Emerg Med 10(9):462-467, 1981. Available at: http://www.annemergmed.com/article/S0196-0644(81)80277-6/abstract. 48. Paret G, Mazkereth R, Sella R, et al: Atropine pharmacokinetics and pharmacodynamics following endotracheal versus endobronchial administration in dogs, Resuscitation 41(1):57-62, 1999. Available at: http://www. ncbi.nlm.nih.gov/pubmed/10459593. 49. Anastasiou-Nana MI, Nanas JN, Nanas SN, et al: Effects of amiodarone on refractory ventricular fibrillation in acute myocardial infarction: experimental study, J Am Coll Cardiol 23(1):253-258, 1994. Available at: http:// www.ncbi.nlm.nih.gov/pubmed/8277089. 50. Dorian P, Cass D, Schwartz B, Cooper R, Gelaznikas R, Barr A: Amiodarone as compared with lidocaine for shock-resistant ventricular fibrillation, N Engl J Med 346(12):884-890, 2002. Available at: http://www.ncbi. nlm.nih.gov/pubmed/11907287. 51. Dorian P, Fain ES, Davy JM, Winkle RA: Lidocaine causes a reversible, concentration-dependent increase in defibrillation energy requirements, J Am Coll Cardiol 8(2):327-332, 1986. Available at: http://linkinghub.elsevier.com/retrieve/pii/S073510978680047X. 52. Mentzelopoulos SD, Zakynthinos SG, Tzoufi M, et al: Vasopressin, epinephrine, and corticosteroids for in-hospital cardiac arrest, Arch Intern Med 169(1):15-24, 2009. Available at: http://archinte.ama-assn.org/cgi/ content/abstract/169/1/15. 53. Smithline H, Rivers E, Appleton T, Nowak R: Corticosteroid supplementation during cardiac arrest in rats, Resuscitation 25(3):257-264, 1993. Available at: http://www.sciencedirect.com/science/article/pii/03009572 93901238. 54. Levine JM, Levine GJ, Boozer L, et al: Adverse effects and outcome associated with dexamethasone administration in dogs with acute thoracolumbar

CHAPTER 4  Cardiopulmonary Resuscitation intervertebral disk herniation: 161 cases (2000-2006), J Am Vet Med Assoc 232(3):411-417, 2008. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/18241109. 55. Dillon AR, Sorjonen DC, Powers RD, Spano S: Effects of dexamethasone and surgical hypotension on hepatic morphologic features and enzymes of dogs, Am J Vet Res 44(11):1996-1999, 1983. Available at: http://www. ncbi.nlm.nih.gov/pubmed/6650953. 56. Rohrer CR, Hill RC, Fischer A, et al: Gastric hemorrhage in dogs given high doses of methylprednisolone sodium succinate, Am J Vet Res 60(8):977-981, 1999. 57. Weisfeldt ML, Becker LB: Resuscitation after cardiac arrest a 3-phase time-sensitive model, J Am Med Assoc 288(23):3035-3038, 2002. 58. Cammarata G, Weil MH, Csapoczi P, Sun S, Tang W: Challenging the rationale of three sequential shocks for defibrillation, Resuscitation 69(1):23-27, 2006. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/16517041. 59. Tang W, Snyder D, Wang J, et al: One-shock versus three-shock defibrillation protocol significantly improves outcome in a porcine model of prolonged ventricular fibrillation cardiac arrest, Circulation 113(23):26832689, 2006. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16754801. 60. Shuster M, Lim SH, Deakin CD, et al: Part 7: CPR techniques and devices: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with treatment recommendations, Circulation 122(16 Suppl 2):S338-S344, 2010. Available at: http:// www.ncbi.nlm.nih.gov/pubmed/20956255.

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61. Alzaga-Fernandez AG, Varon J: Open-chest cardiopulmonary resuscitation: past, present and future, Resuscitation 64(2):149-156, 2005. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15680522. 62. Benson DM, O’Neil B, Kakish E, et al: Open-chest CPR improves survival and neurologic outcome following cardiac arrest, Resuscitation 64(2):209-217, 2005. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15680532. 63. Kern KB, Sanders AB, Ewy GA: Open-chest cardiac massage after closedchest compression in a canine model: when to intervene, Resuscitation 15(1):51-57, 1987. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/3035670. 64. Barnett WM, Alifimoff JK, Paris PM, Stewart RD, Safar P: Comparison of open-chest cardiac massage techniques in dogs, Ann Emerg Med 15(4):408-411, 1986. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/3954173. 65. Jack MW, Wierenga JR, Bridges JP, et. al: Feasibility of open-chest cardiopulmonary resuscitation through a transdiaphragmatic approach in dogs, Vet Surg 48:1042-1049, 2019. 66. Hoehne SN, Hopper K, Epstein SE: Prospective evaluation of cardiopulmonary resuscitation performed in dogs and cats according to the RECOVER guidelines. Part 2: patient outcomes and CPR practice since guideline implementation, Front Vet Sci 6:1-11, 2019. 67. Hoehne SN, Epstein SE, Hopper K: Prospective evaluation of cardiopulmonary resuscitation performed in dogs and cats according to the RECOVER guidelines. Part 1: prognostic factors according to Utstein-style reporting, Front Vet Sci 6:1-10, 2019.

5 Postcardiac Arrest Care Manuel Boller, Dr med vet, MTR, DACVECC, Daniel J. Fletcher, PhD, DVM, DACVECC

KEY POINTS • The systemic response to ischemia and reperfusion, anoxic brain injury, postresuscitation myocardial dysfunction, and persistent precipitating pathologic conditions define post-cardiac arrest care measures needed for each individual patient. • Immediate post-cardiac arrest care focuses on prevention of rearrest by ensuring optimal ventilation, oxygenation, and tissue perfusion, as well as identifying and correcting reversible causes of cardiopulmonary arrest. • Early hypoxemia and hyperoxemia after return of spontaneous circulation (ROSC) should be prevented by controlled reoxygenation with a target SaO2/SpO2 of 94% to 98% or a PaO2 of 80 to 100 mm Hg.

• Hemodynamic optimization measures after ROSC include administration of intravenous fluids, pressors, inotropes, and blood products to reach a mean arterial pressure (MAP) of 80 mm Hg or higher, an ScvO2 of 70% or more, and a lactate of less than 2.5 mmol/L. • Targeted temperature management (32°C to 36°C) for 24 to 48 hours is recommended in patients that remain comatose after ROSC and if advanced critical care capability is available. • Additional neuroprotective strategies include permissive hypothermia, slow rewarming (0.25°C to 0.5°C/hr), osmotic therapy, and seizure prophylaxis. • Critically ill survivors should be referred to veterinary critical care centers for post-cardiac arrest care.

Ahead of his time, the Russian resuscitation scientist and physician Vladimir Negovsky stated in 1972 that “after the first step in resuscitation when heart function and respiration have been restored, the second step in resuscitation arises—the more complicated problems of treating the after-effects of a general hypoxia.”1 Since then, postcardiac arrest (PCA) care has been increasingly emphasized as a critical part of cardiopulmonary resuscitation (CPR). Current CPR guidelines in both human and veterinary medicine devote entire sections to the care of those patients that achieved return of spontaneous circulation (ROSC) after cardiopulmonary arrest (CPA).2,3 The rationale behind this is twofold. First, epidemiologic studies in people show that twothirds of in-hospital cardiac arrest (IHCA) patients who achieve stable ROSC do not survive to hospital discharge.4 In veterinary medicine, 79% of dogs or cats with any ROSC are euthanized or die before hospital discharge.5 Thus optimization of PCA care has the potential to save many lives. Second, new effective PCA therapies have been discovered. Foremost, strong evidence of the neuroprotective potential of controlled postresuscitation hypothermia boosted the field of PCA care. Human epidemiologic data suggest that recent improvement in outcomes achieved after IHCA is in part due to increased postresuscitation survival.6 PCA arrest care is now considered the final essential link of a comprehensive treatment strategy to improve outcomes from CPA. There are two paradigms of care during the PCA phase. One targets the pathophysiologic processes that occur in the postresuscitation phase, namely (1) ischemia and reperfusion (IR) injury, (2) PCA brain injury, (3) PCA myocardial dysfunction, and (4) persistent precipitating pathologic conditions (Fig. 5.1). The second paradigm of care responds to a shift in treatment prioritization with time. Immediately after ROSC, the focus is on preventing the recurrence of cardiac arrest

and limitation of organ injury. Later care emphasizes treatment of the underlying disease processes, prognostication, and rehabilitation.

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PROPAGATING SUSTAINED ROSC The majority of dogs and cats that are initially successfully resuscitated die within the first few hours because of rearrest.7 In a recent observational study, 41% of the animals achieved any ROSC, and 15% of these animals rearrested within 20 minutes (Fig. 5.1).5 In people, 24% of patients with sustained ROSC (i.e., ROSC 20 minutes) rearrested after a median duration of 5.4 h.8 The goal immediately after ROSC is to sustain spontaneous circulation and perfusion of vital organs, such as the brain and the myocardium, attenuating further injury and preventing rearrest. Although patient monitoring options are limited during CPA (see Chapter 4), common monitoring such as noninvasive blood pressure measurement and pulse oximetry provide useful information after ROSC. Identification of any reversible cause of CPA needs to be proactively pursued. If not already addressed during advanced life support, it is important to assess for abnormalities in electrolytes, glucose, acid-base status, hematocrit, arterial oxygenation, and ventilation soon after ROSC. Abnormalities such as hypoxemia, severe anemia, hypotension, and hyperkalemia or hypocalcemia must be corrected. The incidence of rearrest rhythms has not been systematically reported in veterinary patients, but in people, one study (n5381) reported that the majority (76%) of first identified rhythms were nonshockable.8 If ventricular tachycardia persists, treatment with lidocaine (2 mg/kg intravenous [IV] bolus, followed by a 30 to 50 µg/kg/min continuous rate infusion [CRI]) is recommended. Shortly after ROSC, epinephrine [0.1 to 0.5 µg/kg/min CRI]) may be necessary to maintain vascular tone and adequate blood pressure, as adrenal function may be

CHAPTER 5  Postcardiac Arrest Care

31

Post–cardiac arrest syndrome

Systemic ischemiareperfusion response

Post–cardiac arrest brain injury

Post–cardiac arrest myocardial dysfunction

• SIRS

Pathophysiology

• Impaired vasoregulation • Increased coagulation • Adrenal suppression • Impaired tissue oxygen delivery and utilization

• Impaired cerebrovascular autoregulation • Cerebral edema (limited) • Postischemic neurodegeneration

• Right and left ventricular dysfunction (myocardial stunning)

Potential treatments

Clinical manifestations

• Impaired resistance to infection

• Ongoing tissue hypoxia– ischemia

• Delirium, stupor, coma

• Hypotension

• Seizures

• Hypotension

• Pyrexia (fever)

• Myoclonus

• Arrhythmias

• Hyperglycemia

• Cognitive dysfunction

• Multiorgan failure

• Cortical blindness

• Ongoing tissue hypoxiaischemia

• Infection

• Brain death

• Early hemodynamic optimization

• Targeted temperature management

• Intravenous fluids

• Early hemodynamic optimization

• Early hemodynamic optimization

• Airway protection and mechanical ventilation

• Inotropes

• Seizure control

• Targeted temperature management

• Vasopressors • Temperature control • Glucose control • Antibiotics for documented infection

• Controlled reoxygenation (SaO2 94% to 98%)

Persistent precipitating pathology

• Infection (sepsis, pneumonia) • Upper airway obstruction • Cardiovascular disease (cardiomyopathy) • Pulmonary disease (CHF, ARDS) • Thromboembolic disease (PTE) • CNS disease • Toxicological (overdose, poisoning) • Hypovolemia (hemorrhage, dehydration) • MODS

• Reduced cardiac output • Specific to cause • Complicated by concomitant PCA syndrome

• Disease-specific • Guided by patient condition and concomitant PCA syndrome

• Supportive care

Fig. 5.1  Flowchart summarizing pathophysiology, clinical manifestations, and potential treatments for the four major components of post-cardiac arrest syndrome. ARDS, Acute respiratory distress syndrome; CHF, congestive heart failure; CNS, central nervous system; MODS, multiorgan dysfunction syndrome; PCA, post-cardiac arrest; PTE, pulmonary thromboembolism; SIRS, systemic inflammatory response syndrome. (Modified with permission from Boller M, Boller EM, Oodegard S, et al: Small animal cardiopulmonary resuscitation requires a continuum of care: proposal for a chain of survival for veterinary patients, J Am Vet Med Assoc 240[5]:540-554, 2012.)

insufficient after ROSC.9 This can then be replaced with more targeted catecholamine use (e.g., norepinephrine for vasodilation; dobutamine for left ventricular dysfunction) once a more refined understanding of the patient’s physiology is acquired. Positive inotropic support (i.e., dobutamine, 5–10 µg/kg/min CRI) can mitigate postischemic left

ventricular systolic dysfunction, and response to treatment can be assessed with repeat cardiovascular point-of-care ultrasound. Ventilatory assistance is commonly required during the immediate PCA phase and may be provided by either manual or mechanical ventilation with a target PaCO2 of 32 to 43 mm Hg in dogs and 26 to 36 mm Hg

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PART I  Key Critical Care Concepts

in cats.10 Once sustained ROSC has been achieved for 20 to 40 minutes, the priorities are the mitigation of further organ injury that arises as a consequence of IR and the titration of supportive care adapted to the needs of the patient.

SYSTEMIC RESPONSE TO ISCHEMIA AND REPERFUSION: SEPSIS-LIKE SYNDROME ROSC after the global ischemic event of CPA leads to a whole-body IR syndrome that Negovsky characterized as “postresuscitation disease” nearly 50 years ago.1 The syndrome shares many characteristics with severe sepsis, specifically in regard to inflammation, coagulation, and endothelial injury. After observing neutrophil and endothelial activation paired with high concentrations of circulating cytokines (tumor necrosis factor a [TNF-a], interleukin 6 [IL-6], IL-9, IL-10) in the PCA phase in humans, Adrie et al. coined the term sepsis-like syndrome to describe the phenotype of post-cardiac arrest abnormalities.11 Thus the PCA patient may demonstrate characteristics that are similar to sepsis and multiorgan dysfunction syndrome. With that in mind, therapeutic concepts involving (1) early hemodynamic optimization, (2) glycemic control, and (3) critical illness-related corticosteroid insufficiency (CIRCI) are being examined in human medicine and may have relevance to veterinary PCA care. Naturally, treatment is highly individualized, with each element of care titrated to the patient’s needs.

Hemodynamic Optimization Early goal-directed therapy (EGDT) was studied by Rivers et al. 20 years ago as a strategy for hemodynamic optimization in patients with severe sepsis and septic shock.12 EGDT uses an algorithm in which single interventions are started or discontinued based on the achievement of predefined physiologic endpoints with an emphasis on early resuscitation. In human medicine, the EGDT approach has been implemented for PCA care as an early hemodynamic optimization protocol.13 Included interventions are those used to optimize tissue oxygen delivery (fluid administration, vasopressors/inotropes, red blood cell transfusion, oxygen supplementation) and decrease tissue oxygen demand (sedation, mechanical ventilation, neuromuscular blockade, temperature control). A veterinary PCA hemodynamic optimization algorithm has been published by the RECOVER initiative.10 Resuscitation endpoints are a high-normal mean arterial pressure (MAP) (80 to 120 mm Hg) and perfusion parameters (central venous oxygen saturation [ScvO2] .70 %; lactate ,2.5 mmol/L). The blood pressure target is higher than in septic patients, as cerebrovascular autoregulation can be absent, and perivascular edema and intravascular clot formation can compromise PCA cerebral blood flow. Markers of vasodilation, such as injected mucous membranes or shortened capillary refill time, pulse quality, and echocardiographic determination of left ventricular function should also be included in a comprehensive hemodynamic assessment. Such monitoring will guide effective yet safe treatment with fluids, vasopressors, and inotropes (see Chapters 8 and 183).

Glycemic Control Hyperglycemia commonly occurs after cardiac arrest in humans, dogs, and cats and has been associated with worse outcomes.5,14 Mild to moderate hyperglycemia combined with a total plasma insulin decrease of 60% was observed in experimental research in dogs early after ROSC.15 In dogs, hyperglycemia after ROSC worsens ischemic brain injury.16 In humans, iatrogenic hypoglycemia occurred in 18% of PCA patients treated with tight glycemic control (4.4 to 6.1 mmol/L; 80 to 110 mg/dl). There is no evidence that strict glucose control provides additional benefits over a less stringent target, and no specific

target range is currently recommended in humans.2 Insulin administration to control severe hyperglycemia while avoiding iatrogenic hypoglycemia is reasonable in dogs and cats. Implementation of glycemic control with intravenous insulin administration follows the recommendation for patients with severe sepsis (see Chapter 6).

Adrenal Dysfunction Steroids are essential to the physiologic response to severe stress and are important for the regulation of vascular tone and endothelial permeability. CIRCI, or relative adrenal insufficiency, after ROSC was identified in several human clinical studies and has been associated with increased mortality.17 Low-dose steroid administration for septic shock remains controversial, and direct evidence supporting corticosteroid administration during PCA care is lacking. Because of this and the risk for infection and peptic ulcer and the exacerbation of postischemic neurologic injury associated with corticosteroid administration, routine administration of corticosteroids during PCA care is not recommended.10 However, administration of low-dose hydrocortisone (1 mg/kg IV followed by either 1 mg/kg IV q6h or an intravenous infusion of 0.15 mg/kg/hr) in dogs and cats with vasopressor-dependent shock after CPA, with or without documented CIRCI, may be considered.10

POST-CARDIAC ARREST BRAIN INJURY In humans, cerebral dysfunction after cardiac arrest is the single greatest concern and the most common single cause of death. In one study, neurologic injury was the cause of death in two-thirds of patients after out-of-hospital cardiac arrest (OHCA) and one-fifth after IHCA.18 In small animals, PCA brain injury has been described in experimental and clinical reports, but little is known about its epidemiology. PCA brain injury results from global cerebral IR.19 Although the process is complex and not understood in its entirety, some aspects of cerebral IR injury are clear: 1. Most of the injury is sustained during reperfusion and not during ischemia, affording the clinician the opportunity to intervene after ROSC is achieved. 2. Cytosolic and mitochondrial calcium overload leads to the activation of proteases that may lead to neuronal death and production of reactive oxygen species (ROS). 3. A burst of ROS occurs during reperfusion, leading to oxidative alterations of lipids, proteins, and nucleic acids, propagating injury of neuronal cell components and limiting the cells’ protective and repair mechanisms. 4. Hypothermia after ROSC is proven to reduce PCA cerebral dysfunction.20

Brain Injury Sustained During Ischemia Versus During Reperfusion Much of the injury sustained after CPA evolves during reperfusion rather than ischemia. By optimizing the reperfusion process, extended durations of ischemia can be tolerated. Nevertheless, IR is a continuum that is initiated during cellular ischemia. A sudden decline in oxygen delivery occurs upon onset of CPA. Glycolysis allows for limited continued energy production, but cerebral adenosine triphosphate (ATP) stores are depleted within 2 to 4 minutes. In contrast, 20 to 40 minutes are required for the same event to occur in the intestines and the myocardium. Once ATP is depleted, cellular membrane potentials are rapidly lost. Clinically, any cardiac electrical activity as detected by electrocardiogram (ECG) provides evidence that the global myocardial membrane potential has not yet subsided or has been reestablished during reperfusion. Large amounts of sodium, chloride, and

CHAPTER 5  Postcardiac Arrest Care calcium enter the cells, followed by cellular edema and membrane disruption. It is believed that the combined influences of increased exposure to calcium, oxidative stress, and energy depletion lead to mitochondrial injury, finally leading to more ROS production upon reperfusion and to apoptosis and necrosis. Therefore, protective reperfusion strategies (e.g., reperfusion with cardiopulmonary bypass) include tolerance of mild hypocalcemia and avoidance of hyperoxemia.21,22 Experimental studies in swine have demonstrated neurologically intact survival using these strategies even after 30 minutes of warm cerebral ischemia.23

Controlled Reoxygenation Large amounts of ROS are generated after ROSC. Becker and Neumar summarized in detail the pathobiology of ROS produced by IR in the PCA period.24,25 Excessive production of ROS in the presence of exhausted protective mechanisms results in elaboration of highly reactive free radicals, namely hydroxyl radicals (•OH) and peroxynitrite (ONOO•), which in turn cause cell membrane damage, lipid peroxidation, DNA damage, and protein alterations. Rapid reoxygenation following prolonged global ischemia is an implied goal of CPR and essential for saving lives after cardiac arrest. However, the absolute requirement of reintroducing oxygen conflicts with the toxic potential of oxygen as substrate for ROS. Much evidence suggests that arterial hyperoxemia soon after ROSC increases oxidative brain injury, increases neurodegeneration, worsens functional neurologic outcome, and negatively affects overall survival. Retrospective clinical studies in humans demonstrated an association between post-ROSC hyperoxemia and in-hospital mortality and documented a linear relationship between the degree of hyperoxemia and nonsurvival.26 In a canine experimental study, titration of oxygen supplementation to an SpO2 of 94% to 96% compared with a consistent FiO2 of 1 led to superior functional neurologic outcomes and a reduction in neuronal degeneration in vulnerable brain regions.27 The inspired oxygen concentration, especially early after ROSC, should therefore be titrated to normoxemia (PaO2 80 to 100 mm Hg; SpO2 94% to 98%), avoiding both hypoxemia and hyperoxemia.10

Targeted Temperature Management Targeted temperature management (TTM), an intervention originally known as mild therapeutic hypothermia, describes the therapeutic control of the core body temperature in the range of 32–36°C (89.6°F– 96.8°F).28 Mechanistically, the protective effect of hypothermia from global IR injury is well established and has been shown to occur via many pathways, including mitochondrial protection, decreased cerebral metabolism, impediment of cellular calcium influx, reduced neuronal excitotoxicity, reduced elaboration of ROS, attenuated apoptosis, and control of seizure activity.20 Unlike other interventions that target just a single pathway of injury, the combined effects of these mechanisms may be responsible for the robust benefit observed in a large number of experimental animal studies across species and models. Taking all animal data together, we can surmise that (1) mild hypothermia reduces anoxic brain injury; (2) hypothermia during arrest has the most profound and long-lasting effect; (3) after reperfusion, any delay in hypothermia reduces the beneficial effect; (4) long duration of hypothermia improves the protective effect, and (5) long duration of hypothermia can “rescue” the loss of effect due to delayed onset of cooling. The first human PCA guidelines recommending hypothermia in 2005 reflected the findings of the two pivotal randomized controlled studies and recommended that adult unconscious patients with ROSC after OHCA should be cooled (32°C–34°C) for 12–24 hours, if the initial rhythm was ventricular fibrillation.29-31 With more clinical data,

33

the 2015 American Heart Association guidelines include a more liberal temperature target (33°C–36°C) for patients after OHCA and IHCA and irrespective of the arrest rhythm but emphasize the importance of constant temperature maintenance within that target range for at least 24 hours.2 The 2012 RECOVER guidelines suggest that in dogs or cats that remain comatose after CPA, hypothermia to a core temperature of 32°C–34°C should be instituted as quickly as possible and be maintained for 24–48 hours.10 It is possible that a less stringent temperature window will be recommended in the upcoming revision to the RECOVER guidelines, with an emphasis on avoiding rapid rewarming and hyperthermia. A rewarming rate of 0.25°C to 0.5°C (0.45°F to 0.9°F) per hour should be targeted. In reality, most small-animal PCA patients will be hypothermic when they achieve ROSC, and prevention of rapid rewarming rather than induction of hypothermia is the goal. As the TTM target refers to core temperature, the use of an esophageal thermocouple is preferred over a rectal probe, especially in cases with active surface cooling as a significant temperature differential between rectal and core temperature may be present. Patient management and monitoring efforts may be considerable during TTM and are likely similar to that needed for mechanical ventilation. Clinical application of TTM requires managing the side effects. Cooling induces increased muscle tone and shivering, which in turn leads to increased oxygen consumption, metabolic rate, and respiratory and heart rates and requires sedation, endotracheal intubation, and ventilation. Cooling without sedation may abolish the protective effect of TTM.20 Other physiologic disturbances can occur, including changes in metabolism, acid-base status, electrolytes, ECG, drug elimination, coagulation, and immune function, and the clinician should be familiar with those alterations when using PCA cooling. However, adverse effects associated with PCA hypothermia in humans with OHCA were found to be on par with normothermic care and did not affect mortality.32 Nevertheless, the side effect profile may be different in other species such as dogs and cats and after IHCA, where sepsis and coagulopathy are more common. If either of these conditions is present, the benefit of TTM must be carefully weighed against the risk, and a higher (e.g., 35°C) as opposed to lower (e.g., 33°C) temperature target may be indicated. Many small animals are spontaneously hypothermic after CPA. Allowing these patients to remain hypothermic and slowly rewarming them to normal core temperature over many hours after ROSC (i.e., permissive hypothermia) offers an alternative to TTM. Even though the entire potential of TTM may not be realized with this approach, it may attenuate the well-documented harmful effects of a rapid increase in brain temperature after ischemia. It is reasonable to target a rewarming rate of 0.25°C to 0.5°C (0.45°F to 0.9°F) per hour.10 In addition, it is important to prevent fever or hyperthermia after CPA as this may worsen neurologic outcome.2

Other Neuroprotective Treatment Strategies Although epidemiologic data are lacking, clinical experience suggests that PCA seizures can occur in dogs and cats. In humans, the occurrence of seizures during the first 3 days after CPA is associated with worse outcome. Nonconvulsive status epilepticus (i.e., only identified by electroencephalography) commonly occurs in humans who remain comatose after ROSC.33 Seizure activity leads to a drastic increase in cerebral metabolism and oxygen demand, possibly outstripping oxygen supply. Thus, patients should be monitored for seizures and treated accordingly if they occur (see Chapter 84). Prophylactic administration of anticonvulsants may also be considered.10 This is particularly relevant in animals that remain comatose or are sedated because nonconvulsive seizure activity may be present and difficult to diagnose.

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PART I  Key Critical Care Concepts

Cytotoxic and vasogenic cerebral edema have been described after CPA and are associated with poor neurologic outcome in people. In contrast, intracranial hypertension (ICH) does not commonly occur, but if it does it can compromise cerebral perfusion pressure and thus cerebral blood flow. In dogs, hypertonic fluid administration after 14 minutes of anoxic brain injury decreased cerebral edema but did not affect survival or functional neurologic outcome.34 In general, the use of hypertonic solutions such as mannitol or hypertonic saline for the reduction of cerebral edema after cardiac arrest has not been well examined, and the few studies available demonstrate neither benefit nor harm.3 Thus the use of mannitol or hypertonic saline can be considered if the presence of cerebral edema is suggested by clinical signs, such as coma, stupor, or decerebrate posture.10 Unfortunately, the clinical signs of ICH overlap with the neurologic deficits caused by brain ischemia during CPA. Induction of supranormal cerebral perfusion pressure during the PCA phase is beneficial, indicating that a clinically relevant increase of intracranial pressure or resistance to blood flow exists. In dogs after 12.5 minutes of untreated ventricular fibrillation, more than 50% of the brain remained below baseline blood flow 1 to 4 hours after resuscitation but not in animals with hypertensive hemodilution with a hematocrit of 20% and a MAP of 140 mm Hg.35 Similar results were found in other animal studies of optimized brain perfusion after prolonged cardiac arrest. In addition to increased intracranial pressure, perivascular edema, intravascular coagulation, and a loss of blood flow, autoregulation may also be responsible for the beneficial effect of supranormal cerebral perfusion pressures after prolonged cardiac arrest. It is likely that these mechanisms are of less importance during shorter durations of CPA, and thus a less aggressive perfusion pressure goal may be sufficient in most clinical veterinary cases.10 Experimental evidence suggests that the CO2 responsiveness of cerebral arteries is disturbed for the first several hours after prolonged ischemia such that arterial vasodilation in response to increasing PaCO2 is abolished.36 In contrast, with shorter durations of cerebral ischemia or later after reperfusion, CO2 responsiveness was maintained or restored such that hyperventilation after ROSC reduced cerebral blood flow and worsened neurologic outcomes compared with normoventilation. Similarly, the decreased tissue pH associated with hypoventilation could be harmful. It is therefore reasonable to avoid both hypoventilation and hyperventilation after ROSC and to control ventilation such that normocapnia is achieved (dog: PaCO2 32 to 42 mm Hg; cat: PaCO2 26 to 36 mm Hg).10

NEUROLOGIC ASSESSMENT AND PROGNOSTICATION Assessing the patient’s PCA neurologic status is relevant for treatment decisions and prognostication. Complete neurologic examinations should be undertaken directly after ROSC and initially every 2 to 4 hours. Care should be taken to interpret the findings in light of factors that confound the neurologic examination, such as sedation, neuromuscular blockade, seizures, and postictal status. Neurologic deficit scoring systems that include metrics of consciousness, motor and sensory function, and behavior have been used in clinical and experimental studies in dogs.37,38 Alternatively, the Modified Glasgow Coma Scale (MGCS), originally developed for dogs with traumatic brain injury, can be used to systematically assess and track the patient’s overall PCA neurologic status, although it has not been validated for this indication. The MGCS assesses function of the brainstem (cranial nerve reflexes) and cerebral cortex (motor response and level of consciousness). In principle, any signs of normal neurological function early after ROSC (e.g., spontaneous ventilation, gag reflex, pupillary light reflex

[PLR]) likely support a favorable prognosis despite the lack of evidence in the veterinary literature. Predicting neurologic futility is more complicated. Studies of unconscious human CPA survivors (i.e., those that remain comatose shortly after ROSC) substantiate that clinical neurological examination alone is a poor predictor of functional outcome during the first 72 hours after ROSC.2 Some of the delay is due to therapeutic hypothermia and the sedation required for the duration of TTM. A prognostication algorithm has been devised by the European Resuscitation Council that describes the integrated use of a series of examination modalities.39 The algorithm first prescribes up to 48 hours of TTM followed by slow rewarming as recommended for all unconscious survivors from CPA. No conclusive prognostic assessment is made until 72 hours after ROSC, by which time sedation (for TTM) is expected to be weaned without any residual effects. Findings from five modes of examination are then assessed: (1) clinical examination, (2) electroencephalography (EEG), (3) somatosensory evoked potential (SSEP), (4) imaging, and (5) circulating markers. Poor neurologic outcome is predicted if a clinical examination after 72 hours shows the absence of response to a noxious stimulus and bilaterally absent PLRs and corneal reflexes. The absence of SSEP in an unconscious patient is likewise highly predictive of a poor outcome. If neither of these highly sensitive indicators of poor prognosis (PLR or SSEP) are available, a set of less sensitive signs should be considered, but not until another 24 hours after the 72-hour assessment. These include (1) high levels of circulating neurospecificity enolase, a commonly used biomarker of neuronal injury after CPA; (2) diffuse anoxic injury on brain computed tomography/magnetic resonance imaging; (3) unreactive burst-suppression or status epilepticus on EEG, or (4) status myoclonus. The presence of at least two of these less reliable factors suggests that a poor outcome is highly likely. In the absence of these poor prognostic indicators, treatment should continue, and the patient be reevaluated in regular intervals. It is likely that adult animals and humans with CPA-related anoxic brain injury recover along a similar timeline. Thus, allowing 24–72 hours after ROSC before making a euthanasia decision is reasonable unless financial constraints are a factor. Depending on comorbidities, this may require costly PCA care before a definitive poor neurologic outcome can be established. Clinical assessment of unconsciousness (i.e., absence of response to painful stimulus), PLR and corneal reflexes may be useful as they are in humans. Experimental and limited clinical evidence in dogs and cats demonstrates the significant potential for neurological recovery, provided adequate supportive care is provided.40 Waldrop et al. (2004) documented that neurologic abnormalities after ROSC (i.e., dullness, ataxia, circling, seizures, and blindness) resolved in 90% of CPA survivors before hospital discharge.40 Unfortunately, veterinary data are sparse, and more evidence is needed to determine the specifics of PCA prognostication in dogs and cats.

MYOCARDIAL DYSFUNCTION Myocardial dysfunction (MD) is well described after cardiac arrest in experimental studies and in humans and has been the subject of one veterinary case report.41,42 MD occurs even in cases free of coronary artery disease and, like brain injury, is attenuated by hypothermia. The mechanisms of injury are not fully understood and are multifactorial. Myocyte dysfunction results from cellular processes associated with cellular IR comparable to those evolving in the nervous system. Thus, the severity of MD depends on the duration and extent of myocardial ischemia as well as the conditions under which reperfusion occurs (e.g., presence or absence of hypothermia and hyperoxia). Second, a lack of capillary blood flow during PCA (myocardial no-reflow) may occur. Microvascular obstruction or plugging may occur subsequent to

CHAPTER 5  Postcardiac Arrest Care endothelial cell activation and swelling, neutrophil–endothelial cell interactions, activation of coagulation, and platelet aggregation.43 Pericapillary edema will further impede microvascular blood flow. With alterations in capillary permeability, the subsequent increase in microvascular hematocrit and total protein and the associated rheologic properties can impair tissue blood flow. Moreover, postischemic red blood cells may have reduced deformability and have a tendency toward endothelial cell adhesion and formation of erythrocyte plugs. Third, factors associated with worse MD include intraarrest administration of epinephrine and high energy and monophasic waveform defibrillation.44 Clinically, PCA MD is characterized by increased central venous and pulmonary capillary wedge pressure, reduced left- and right-sided systolic and diastolic ventricular function with increased end-diastolic and end-systolic volume, and reduced left ventricular ejection fraction and cardiac output. These changes may be further complicated by ventricular tachyarrhythmia and lead to cardiogenic shock in severe cases. MD is reversible and typically resolves within 48 hours. This reversibility in the absence of cell necrosis is the basis for the term myocardial stunning. Diagnosis and monitoring of progression and resolution of MD during the PCA phase are best accomplished noninvasively via serial echocardiography. Dobutamine administration at typical clinical doses used in dogs and cats was shown to effectively improve left ventricular function and cardiac output in humans and swine.41 Cardiac arrhythmias should be addressed commensurate to their significance (see the Cardiac Disorders section).

PERSISTENT PRECIPITATING PATHOLOGY IHCA, the most common CPA scenario confronting the small-animal clinician, may be triggered by preexisting disease processes, such as severe sepsis, trauma, or respiratory failure. These pathologic conditions will likely persist after ROSC. They will affect the specific PCA care provided and influence the prognosis. Precipitating processes and preexisting comorbidities add considerable variability to the PCA patient population. Limited information is available about what these precipitating factors are in small-animal patients. In one veterinary study in a tertiary referral facility including 204 dogs and cats, causes of CPA were identified as hypoxemia (36%), shock (18%), anemia (13%), arrhythmia (8%), multiple organ dysfunction syndrome (MODS) (6%), traumatic brain injury (5%), anaphylaxis (1%), or other causes (21%).7 Another study suggests that trauma is a more common clinical feature in cats compared with dogs with CPA.45 It should be noted that in many veterinary general practice settings, CPA is likely most commonly associated with anesthesia, and multiple veterinary studies have documented significantly better rates of ROSC and survival to discharge in these patients.5,7 Meaney et al. evaluated the causes of CPA in 51,919 human patients with IHCA and found the following: hypotension (39%), acute respiratory failure (37%), acute myocardial infarction (10%), and metabolic/electrolyte disturbances (10%).46 A validated prognostic tool used in early human survivors from IHCA found that age, initial arrest rhythm, prearrest neurologic function, and duration of CPR were predictors of CPA, as well as the presence of preexisting disease, including mechanical ventilation, renal and hepatic insufficiency, sepsis, malignancy, and hypotension.47 Accordingly, the cause of death in adults with sustained ROSC after IHCA was comorbid withdrawal of care (36%), refractory hemodynamic shock (25%) and sudden cardiac arrest (11%).48 Neurologic withdrawal of care occurred in only 27% of people after IHCA, while the same was true in 73% of OHCA cases. A larger veterinary data set is required to acquire similar information in dogs and cats.49 The PCA population encountered after IHCA is influenced by a plethora of preexisting conditions. These demand an individualized

35

patient approach using critical care principles to support oxygenation, ventilation, circulation, and metabolism in order to realize the animal’s potential for a positive, meaningful outcome.

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21. Allen BS, Castella M, Buckberg GD, Tan Z: Conditioned blood reperfusion markedly enhances neurologic recovery after prolonged cerebral ischemia, J Thorac Cardiovasc Surg 126(6):1851-1858, 2003. 22. Hazelton JL, Balan I, Elmer GI, et al: Hyperoxic reperfusion after global cerebral ischemia promotes inflammation and long-term hippocampal neuronal death, J Neurotrauma 27(4):753-762, 2010. 23. Allen BS, Ko Y, Buckberg GD, Tan Z: Studies of isolated global brain ischaemia: II. Controlled reperfusion provides complete neurologic recovery following 30 min of warm ischaemia - the importance of perfusion pressure, Eur J Cardiothor Surg 41(5):1147-1154, 2012. 24. Neumar RW: Optimal oxygenation during and after cardiopulmonary resuscitation, Curr Opin Crit Care 17(3):236-240, 2011. 25. Becker LB: New concepts in reactive oxygen species and cardiovascular reperfusion physiology, Cardiovasc Res 61(3):461-470, 2004. 26. Kilgannon JH, Jones AE, Parrillo JE, et al: Relationship between supranormal oxygen tension and outcome after resuscitation from cardiac arrest, Circulation 123(23):2717-2722, 2011. 27. Balan IS, Fiskum G, Hazelton J, et al: Oximetry-guided reoxygenation improves neurological outcome after experimental cardiac arrest, Stroke 37(12):3008-3013, 2006. 28. Brodeur A, Wright A, Cortes Y: Hypothermia and targeted temperature management in cats and dogs, J Vet Emerg Crit Care 27(2):151-163, 2017. 29. American Heart Association. Guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 7.5: postresuscitation support, Circulation 112(suppl 24):IV-84-88, 2005. 30. Bernard SA, Gray TW, Buist MD, et al: Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia, N Engl J Med 346(8):557-563, 2002. 31. Hypothermia after Cardiac Arrest Study Group: Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest, N Engl J Med 346(8):549-556, 2002. 32. Nielsen N, Sunde K, Hovdenes J, et al: Adverse events and their relation to mortality in out-of-hospital cardiac arrest patients treated with therapeutic hypothermia, Crit Care Med 39(1):57-64, 2011. 33. Rittenberger JC, Popescu A, Brenner RP, et al: Frequency and timing of nonconvulsive status epilepticus in comatose post-cardiac arrest subjects treated with hypothermia, Neurocrit Care 16(1):114-122, 2012. 34. Kaupp HA Jr, Lazarus RE, Wetzel N, Starzl TE: The role of cerebral edema in ischemic cerebral neuropathy after cardiac arrest in dogs and monkeys and its treatment with hypertonic urea, Surgery 48(2):404-410, 1960.

35. Leonov Y, Sterz F, Safar P, et al: Hypertension with hemodilution prevents multifocal cerebral hypoperfusion after cardiac arrest in dogs, Stroke 23(1):45-53, 1992. 36. Nemoto EM, Snyder JV, Carroll RG, Morita H: Global ischemia in dogs: cerebrovascular CO2 reactivity and autoregulation, Stroke 6(4): 425-431, 1975. 37. Buckley GJ, Rozanski EA, Rush JE: Randomized, blinded comparison of epinephrine and vasopressin for treatment of naturally occurring cardiopulmonary arrest in dogs, J Vet Intern Med 25(6):1334-40, 2011. 38. Safar P, Xiao F, Radovsky A, et al: Improved cerebral resuscitation from cardiac arrest in dogs with mild hypothermia plus blood flow promotion, Stroke 27(1):105-113, 1996. 39. Cronberg T: Assessing brain injury after cardiac arrest, towards a quantitative approach, Curr Opin Crit Care 25(3):211-217, 2019. 40. Waldrop JE, Rozanski EA, Swanke ED, et al: Causes of cardiopulmonary arrest, resuscitation management, and functional outcome in dogs and cats surviving cardiopulmonary arrest, J Vet Emerg Crit Care 14(1): 22-29, 2004. 41. Bougouin W, Cariou A: Management of postcardiac arrest myocardial dysfunction, Curr Opin Crit Care 19(3):195-201, 2013. 42. Nakamura RK, Zuckerman IC, Yuhas DL, et al: Postresuscitation myocardial dysfunction in a dog, J Vet Emerg Crit Care 22(6):710-715, 2012. 43. Niccoli G, Burzotta F, Galiuto L, Crea F: Myocardial no-reflow in humans, J Am Coll Cardiol 54(4):281-292, 2009. 44. Kern KB: Postresuscitation myocardial dysfunction, Cardiol Clin 20(1): 89-101, 2002. 45. Kass PH, Haskins SC: Survival following cardiopulmonary resuscitation in dogs and cats, J Vet Emerg Crit Care 2(2):57-65, 1992. 46. Meaney PA, Nadkarni VM, Kern KB, et al: Rhythms and outcomes of adult in-hospital cardiac arrest, Crit Care Med 38(1):101-108, 2010. 47. Chan PS, Spertus JA, Krumholz HM, et al: A validated prediction tool for initial survivors of in-hospital cardiac arrest, Arch Intern Med 172(12):947-953, 2012. 48. Witten L, Gardner R, Holmberg MJ, et al: Reasons for death in patients successfully resuscitated from out-of-hospital and in-hospital cardiac arrest, Resuscitation 136:93-99, 2019. 49. Boller M, Fletcher DJ, Brainard BM, et al: Utstein-style guidelines on uniform reporting of in-hospital cardiopulmonary resuscitation in dogs and cats. A RECOVER statement, J Vet Emerg Crit Care 26(1): 11-34, 2016.

6 Classification and Initial Management of Shock States Armelle de Laforcade, DVM, DACVECC, Deborah C. Silverstein, DVM, DACVECC

KEY POINTS • Shock is defined as inadequate cellular energy production and most commonly occurs secondary to poor tissue perfusion from low or unevenly distributed blood flow. This leads to a critical decrease in oxygen delivery (DO2) to the tissues. • There are numerous ways to classify shock, and many patients suffer from more than one type of shock simultaneously. A common classification scheme includes hypovolemic, distributive, cardiogenic, and obstructive, although metabolic and hypoxic causes of shock are also well recognized.

• For most forms of shock, the mainstay of therapy involves rapid vascular access and administration of isotonic crystalloid fluids. Studies have not shown a clear benefit of one type of fluid over another; however, failure to administer an appropriate volume of fluids may contribute significantly to mortality. • Endpoints of resuscitation such as normalization of heart rate and blood pressure, improved pulse quality and mentation, and resolution of lactic acidosis are necessary to tailor therapy to the individual patient.

Shock is defined as a severe imbalance between oxygen supply and demand, leading to inadequate cellular energy production, cellular death, and multiorgan failure. It most commonly occurs secondary to poor tissue perfusion from low or unevenly distributed blood flow that causes a critical decrease in oxygen delivery (DO2) relative to oxygen consumption (V˙O2). Although metabolic disturbances (e.g., cytopathic hypoxia, hypoglycemia, toxic exposures) and decreased arterial oxygen content (e.g., severe anemia, pulmonary dysfunction, methemoglobinemia/carbon monoxide poisoning) can lead to shock, it more commonly results from a reduction in DO2 secondary to one of four major mechanisms: loss of intravascular volume (hypovolemic shock), maldistribution of vascular volume (distributive shock), obstruction to diastolic filling (obstructive shock), or failure of the cardiac pump (cardiogenic shock). Box 6.1 lists all the functional classes of shock. There are numerous ways to classify shock and no gold standard exists; variations merely reflect the various ways of categorizing the different mechanisms and treatments. Multiple forms of shock can and often do occur concurrently. Early recognition of shock based on a combination of physical examination findings and point-of-care testing are all that is necessary to initiate therapy. Rapid, aggressive therapy and appropriate monitoring, along with the removal of any underlying causes, are necessary to optimize the chance for a successful outcome.

primary mechanisms of circulatory shock (e.g., hypovolemic, distributive, cardiogenic, and obstructive), although other types of shock do exist (metabolic, hypoxic) and further details can be found elsewhere (see Chapters 16, 75, 106, and 107; Hypoxemia, Hypoglycemia, Anemia in the ICU, and Dyshemoglobinemias, respectively).

PATHOPHYSIOLOGY Inadequate cellular energy production leads to cell membrane ion pump dysfunction (e.g., Na-K ATPase), intracellular edema, leakage of intracellular contents extracellularly, and the inability to regulate intracellular pH. This ultimately leads to systemic acidemia, endothelial dysfunction, and activation of inflammatory and antiinflammatory cascades. Therefore, rapid recognition and appropriate treatment of patients in shock are key to prevent irreversible organ damage and possible death. The information below focuses on the

Hypovolemic Shock Hypovolemic shock occurs secondary to a loss of intravascular fluid volume causing inadequate organ perfusion. Insufficient oxygen delivery causes a shift from aerobic to anaerobic metabolism with accumulation of lactate, hydrogen ions, and oxygen free radicals. Damage associated molecular patterns (DAMPs) consisting of mitochondrial DNA, histones, heat shock proteins, and other mediators rise in response to damaged or dying cells. DAMPs activate the innate immune system by interacting with pattern recognition receptors and triggering a pathologic systemic inflammatory response.1,2 Prolonged oxygen deprivation at the cellular level ultimately causes cellular necrosis and apoptosis, followed by end-organ damage and multiple organ dysfunction. Compensatory mechanisms aimed at preserving intravascular volume begin within minutes of an acute drop in venous return and cardiac output. Baroreceptors function to keep arterial blood pressure constant by communicating with the brain via the glossopharyngeal nerve and vagus nerve to the nucleus of the solitary tract in the brainstem. There is a decrease in impulse firing to the medulla oblongata in response to low pressure or stretch in the carotid sinuses or aortic arch; this enables (disinhibits) sympathetic activation while inhibiting parasympathetic activation. The resultant response to shock-induced hypotension includes increased arteriolar and venous tone, cardiac contractility, and heart rate. Peripheral chemoreceptors are located in the aortic and carotid bodies and respond to changes in CO2, hydrogen ions (decreased pH), and to a lesser extent, the partial pressure of O2. Stimulation of these chemoreceptors causes both vasoconstriction and increased minute ventilation. Central chemoreceptors in the respiratory

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PART I  Key Critical Care Concepts

BOX 6.1  Functional Classifications and

Examples of Shock

Inadequate Oxygen Delivery Hypovolemic: Decrease in Circulating Blood Volume Hemorrhage Severe dehydration Trauma Distributive: Marked Decrease or Increase in Systemic Vascular Resistance or Maldistribution of Blood Sepsis Anaphylaxis Catecholamine excess (pheochromocytoma, extreme fear) Cardiogenic: Decrease in Forward Flow from the Heart Congestive heart failure Cardiac arrhythmia Drug overdose (e.g., anesthetics, b-blockers, calcium channel blockers) Obstructive: Reduced Diastolic Filling and Preload Gastric dilatation–volvulus Obstruction of the vena cava or aorta Tension pneumothorax Pericardial tamponade High positive end-expiratory pressure mechanical ventilation Hypoxic: Decreased Oxygen Content in Arterial Blood Anemia Severe pulmonary disease Carbon monoxide toxicity Methemoglobinemia Inappropriate Use of Oxygen by Tissues Metabolic: Deranged Cellular Metabolic Machinery Hypoglycemia Cyanide toxicity Mitochondrial dysfunction Cytopathic hypoxia of sepsis

tissue injury resulting in worsened microvascular dysfunction, endothelial injury, and vasomotor tone derangements. Gastrointestinal bleeding, coagulopathies, and vascular erosion are examples of nontraumatic causes of hemorrhagic shock. Traumatic hypovolemic shock (without hemorrhage) can occur following large surface burns and deep skin lesions. Hypovolemic shock without hemorrhage results from a severe imbalance between fluid intake and fluid loss and can occur secondary to severe vomiting and diarrhea, uncompensated renal losses, or large volume fluid sequestration.

Distributive Shock Distributive shock refers to a state of relative hypovolemia due to the pathologic redistribution of fluid caused by changes in vascular tone or increased vascular permeability. Subcategories of distributive shock include septic, anaphylactic, and neurogenic shock. Sepsis is defined as life-threatening organ dysfunction in response to infection, and persistent hypotension requiring vasopressor therapy indicates septic shock (see Chapter 90, Sepsis and Septic Shock). Central to the pathophysiology of sepsis is cytokine-mediated endothelial dysfunction, which causes both increased endothelial permeability and vasodilation. The result is both a relative decrease in vascular filling and a shift of volume from the intravascular to the interstitial space. Histamine-induced vasodilation characterizes anaphylaxis (see Chapter 141, Anaphylaxis). Vasodilation seen in neurogenic shock (typically traumatic brain or spinal cord injury) results from abnormally low sympathetic tone and unopposed parasympathetic stimulation of vascular smooth muscle.

Cardiogenic Shock Unlike hypovolemic or distributive shock, cardiogenic shock is characterized by systolic or diastolic cardiac dysfunction resulting in hemodynamic abnormalities that include increased heart rate, decreased stroke volume, decreased cardiac output, decreased blood pressure, increased peripheral vascular resistance, and increased right atrial, pulmonary arterial, and pulmonary capillary wedge pressures (see Chapter 41, Mechanisms of Heart Failure). These pathologic changes result in diminished tissue perfusion and increased pulmonary venous pressures, resulting in pulmonary edema and increased respiratory effort.

Obstructive Shock center of the medulla oblongata sense an increase in CO2 or decrease in pH of the cerebrospinal fluid and cause an increase in respiratory rate and tidal volume. Other changes associated with severe hypotension include an increase in circulating catecholamines and b endorphin release, which reduces perception to pain. Over a period of hours, reduced capillary pressure results in a net shift in fluid from the interstitial to the intravascular compartment, although the significance of this shift has been questioned (see Chapter 11, Interstitial Edema). Other factors, such as the osmotic effect of hyperglycemia, may also contribute to intravascular volume replacement during shock. Reduced renal blood flow activates the renin-angiotensin-aldosterone system, which leads to an increase in norepinephrine and angiotensin II-mediated vasoconstriction as well as sodium and water retention via the release of both aldosterone and antidiuretic hormone, respectively. Subclassifications of hypovolemic shock have been proposed to account for slight differences in pathophysiology and include hemorrhagic shock, traumatic hemorrhagic shock, hypovolemic shock without hemorrhage, and traumatic hypovolemic (nonhemorrhagic) shock. Both hemorrhagic shock and traumatic hemorrhagic shock are characterized by an acute drop in circulating red blood cells causing tissue hypoxia; however, traumatic hemorrhagic shock is further complicated by the inflammatory response that accompanies severe soft

Compression of the heart or a great vessel compromises venous return, diastolic filling, and cardiac preload and is referred to as obstructive shock. Causes include severe gastric dilation (with or without volvulus) decreasing preload and tension pneumothorax or cardiac tamponade, reducing diastolic filling. High positive end-expiratory pressure ventilation can also negatively affect venous return and cardiac output. As with other forms of shock, reduced cardiac output results in reduced perfusion and oxygen delivery, ultimately resulting in tissue hypoxia and organ failure.

CLINICAL PRESENTATION OF CIRCULATORY SHOCK Compensatory responses increase tissue perfusion and intravascular volume such that the clinical signs of shock maybe initially subtle. Animals with compensated shock commonly exhibit mild to moderate mental depression, tachycardia, normal or prolonged capillary refill time, cool extremities, fair to moderate pulse quality, tachypnea, and a normal blood pressure (see Chapter 64, Assessment of Intravascular Volume). With ongoing compromise of systemic perfusion, compensatory mechanisms are no longer adequate and often begin to fail. Pale mucous membranes, poor peripheral pulse quality, depressed mentation, and a drop in blood pressure become apparent as the animal

CHAPTER 6  Classification and Initial Management of Shock States progresses to decompensated shock. Ultimately, if left untreated, reduced organ perfusion results in end-organ failure (e.g., oliguria) and ultimately death. Dogs with sepsis or systemic inflammatory response syndrome (SIRS) may show clinical signs of hyperdynamic or hypodynamic shock (see Chapters 7 and 90, SIRS, MODS, and Sepsis and Sepsis and Septic Shock, respectively). The initial hyperdynamic phase of sepsis or SIRS is characterized by tachycardia, fever, bounding peripheral pulse quality, and hyperemic mucous membranes secondary to cytokinemediated peripheral vasodilation (e.g., nitric oxide). This is often referred to as vasodilatory shock. If septic shock or SIRS progresses unchecked, a decreased cardiac output and signs of hypoperfusion often ensue secondary to cytokine effects on the myocardium or myocardial ischemia. Clinical changes may then include tachycardia, pale (and possibly icteric) mucous membranes with a prolonged capillary refill time, hypothermia, poor pulse quality, and a dull mentation. Hypodynamic septic shock is the decompensatory stage of sepsis and without intervention will result in organ damage and death (see Chapter 7, SIRS, MODS, and Sepsis). Lastly, the gastrointestinal tract is the shock organ in dogs, so shock often leads to ileus, diarrhea, hematochezia, and melena. The hyperdynamic phase of shock is rarely recognized in cats. Also, in contrast to dogs, changes in heart rate in cats with shock are unpredictable; they may exhibit tachycardia or bradycardia. In general, cats typically present with pale mucous membranes (and possibly icterus), weak pulses, cool extremities, hypothermia, and generalized weakness or collapse. In cats, the lungs are vulnerable to damage during shock or sepsis, and signs of respiratory dysfunction are common in this species.3-5 Although the classifications of shock are useful in understanding the underlying mechanism of cardiovascular instability, different forms of shock can occur simultaneously in the same patient. A dog with gastric dilatation–volvulus, for example, will often have a component of hypovolemic shock secondary to fluid pooling in the stomach and blood loss associated with rupture of the short gastric vessels, in addition to obstructive shock with compromised cardiac output from great vessel compression. Dogs with septic peritonitis may experience tissue hypoxia as a result of cytokine-mediated mitochondrial dysfunction (metabolic shock), cytokine-mediated cardiac dysfunction (cardiogenic shock), and vasodilation (distributive shock) and a relative hypovolemia, and absolute hypovolemia as well if severe cavitary effusions or protracted vomiting/diarrhea are present.

DIAGNOSTICS AND MONITORING Some basic diagnostic tests should be completed for all patients in shock to assess the extent of organ injury and identify the etiology of the shock state. A venous or arterial blood gas with lactate measurement, a complete blood cell count, blood chemistry panel, coagulation panel, blood typing, urinalysis, and point-of-care ultrasound should be performed (see Chapters 202 and 189, Blood Gas Sampling and Point-of-Care Ultrasound in the ICU, respectively). Thoracic and abdominal radiographs, abdominal ultrasound, and echocardiography may be indicated once the patient is stabilized. Additional monitoring techniques that are essential in the diagnosis and treatment of the shock patient include continuous electrocardiographic monitoring, blood pressure measurement, and pulse oximetry (see Monitoring section below and Chapter 181, Hemodynamic Monitoring). Gradual resolution of tachycardia (and hypotension), as well as mental alertness, often signals successful return of cardiovascular stability, whereas persistent tachycardia and mental depression indicate ongoing cardiovascular instability. It is important to note that

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the best form of monitoring is a thorough physical examination, and frequent patient assessment will also provide important clues regarding response to therapy.

Monitoring Tissue Perfusion and Oxygen Delivery The magnitude of the oxygen deficit is a key predictor of outcome in shock patients. Therefore, optimizing oxygen delivery and tissue perfusion is the goal of treatment, and sufficient monitoring tools are necessary to achieve this objective. A well-perfused patient possesses the following characteristics: central venous pressure between 0 and 6 cm H2O; urine production of at least 1 ml/kg/hr; mean arterial pressure between 70 and 100 mm Hg; normal body temperature, heart rate, heart rhythm, and respiratory rate; and moist, pink mucous membranes with a capillary refill time of less than 2 seconds. Monitoring these parameters is the tenet of patient assessment. Additional monitoring tools that may prove beneficial include the measurement of blood lactate, indices of systemic oxygenation transport, and mixed venous oxygen saturation, as discussed below.

Blood Lactate Levels Critically ill patients with inadequate oxygen delivery, oxygen uptake, or tissue perfusion often develop hyperlactatemia and acidemia that are reflective of the severity of cellular hypoxia. A lactic acidosis in human patients carries a greater risk for developing multiple organ failure, and these people demonstrate a higher mortality rate than those without an elevated lactate concentration.6 High blood lactate levels may also aid in predicting mortality in dogs.7-9 The normal lactate concentration in adult dogs and cats is less than 2.5 mmol/L; lactate concentrations greater than 7 mmol/L are severely elevated.7 However, normal neonatal and pediatric patients may have higher lactate concentrations.10 In addition, sample collection and handling procedures can affect lactate concentration.11 Serial lactate measurements taken during the resuscitation period help to gauge response to treatment and evaluate resuscitation end points; the changes in lactate concentrations are a better predictor of survival than single measurements (see Chapter 61, Hyperlactatemia).

Cardiac Output Monitoring and Indices of Oxygen Transport The measurement of indices of systemic oxygen transport is a direct method of assessing the progress of resuscitation in shock patients, although it is rarely utilized in clinical patients due to its invasive nature, potential risks, and questionable benefit. A right-sided cardiac catheter or pulmonary artery catheter (PAC, also termed Swan-Ganz catheter or balloon-directed thermodilution catheter) is typically used to monitor these parameters (see Chapters 182 and 184, Cardiac Output Monitoring and Oximetry Monitoring, respectively). The PAC enables the measurement of central venous and pulmonary arterial pressure, mixed venous blood oxygen parameters (PvO2 and SvO2), pulmonary capillary wedge pressure, and cardiac output. With this information, further parameters of circulatory and respiratory function can be derived (i.e., stroke volume, end-diastolic volume, systemic vascular resistance index, pulmonary vascular resistance index, arterial oxygen content, mixed venous oxygen content, DO2 index, V˙O2 index, and oxygen extraction ratio). Although cardiac output is typically determined using thermodilution methods, other less invasive techniques are available (see Chapter 182, Cardiac Output Monitoring).

Mixed Venous Oxygen Saturation and Central Venous Oxygen Saturation Changes in the global tissue oxygenation (oxygen supply to demand) can be assessed using mixed venous oxygen saturation

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PART I  Key Critical Care Concepts

(SvO2) measurements. Assuming V˙ O2 is constant, SvO2 is determined by cardiac output, hemoglobin concentration, and SaO2. SvO2 is decreased if DO2 decreases (i.e., low CO, hypoxemia, severe anemia) or if V˙O2 increases (i.e., fever, seizure activity). With conditions such as the hyperdynamic stages of sepsis and cytotoxic tissue hypoxia (e.g., cyanide poisoning), SvO2 is increased. A reduction in SvO2 may be an early indicator that the patient’s clinical condition is deteriorating. In addition, SvO2 may be an alternative to measuring cardiac index during resuscitative efforts. Ideally, venous oxygen saturation is measured in a blood sample from the pulmonary artery. However, in animals that do not have a PAC, venous oxygen saturation can be measured from the central circulation, using a central venous catheter in the cranial or proximal caudal vena cava. This is termed central venous oxygen saturation (ScvO2). Although the ScvO2 values are generally higher than SvO2 in critically ill patients with circulatory failure, the two measurements closely parallel each other in patients with less severe disease. Therefore, a pathologically low ScvO2 likely indicates an even lower SvO2. A prospective, randomized study comparing two algorithms for early goal-directed therapy in human patients with severe sepsis and septic shock showed that maintenance of a continuously measured ScvO2 above 70% (in addition to maintaining central venous pressure above 8 to 12 mm Hg, mean arterial pressure above 65 mm Hg and urine output above 0.5 ml/kg/hr) resulted in a 15% absolute reduction in mortality compared with the same treatment without ScvO2 monitoring.12 A study of dogs with severe sepsis and or septic shock evaluated changes in tissue perfusion parameters in response to goal-directed hemodynamic resuscitation.13 In this study, resuscitation was aimed at restoring parameters related to tissue perfusion, including capillary refill time, central venous pressure, blood pressure, lactate, base deficit, and ScvO2. A higher ScvO2 was associated with a lower risk of death, highlighting the importance of microcirculatory and macrocirculatory dysfunction in severe sepsis and septic shock.14 Similarly, in a prospective study of dogs with pyometra-induced sepsis or septic shock, ScvO2 and base deficit had prognostic value, with a higher ScvO2 and a lower abnormal base deficit at admission to the ICU associated with a lower risk of death.15 Until these parameters are more extensively studied in naturally occurring shock in dogs, early recognition of shock followed by aggressive goal-driven resuscitation is likely crucial to a successful outcome.

TREATMENT Treatment of circulatory shock hinges on early recognition of the condition and rapid restoration of the cardiovascular system so that DO2 to the tissues is normalized as soon as possible. The mainstay of therapy for all forms of circulatory shock except cardiogenic shock is based on rapid administration of intravenous fluids to restore an effective circulating volume and tissue perfusion.16 Vascular access is essential for successful treatment of shock but can be difficult as a result of poor vascular filling and a collapsed cardiovascular state; short, large-bore catheters should be placed in a central or peripheral vein for initial resuscitation. When intravenous access is difficult or delayed because of cardiovascular collapse, a cutdown approach or intraosseous catheterization may be necessary (see Chapters 194 and 195, Intraosseous and Central Venous Catheterization, respectively). The type of fluid selected for the treatment of shock may vary (see Chapter 68, Shock Fluid Therapy). Replacement isotonic crystalloids such as lactated Ringer’s solution, 0.9% sodium chloride, or Normosol R are the mainstay of therapy for shock, administered rapidly and titrated to effect with total doses up to one blood volume (90 ml/kg for the dog, 50 ml/kg for the cat). The administered fluid rapidly spreads

into the extracellular fluid compartment so that only approximately 25% of the delivered volume remains in the intravascular space 30 minutes after infusion;17 some animals will therefore require additional resuscitation at this time point. Hypotensive resuscitation (to a mean arterial pressure of approximately 60 mm Hg) may prove beneficial in treatment of hemorrhagic shock since aggressive fluid therapy prior to definitive control may worsen bleeding and outcome (see Chapter 71, Hemorrhagic Shock).18 The “shock doses” of crystalloids serve as useful guidelines for fluid resuscitation of the shock patient; however, the actual volume administered should be titrated according to the patient’s clinical response in order to prevent volume overload, endothelial damage, and interstitial edema (see Chapter 11, Interstitial Edema). Additional fluid therapy options in patients with complicated shock states include synthetic colloid solutions, hypertonic saline, blood products, and hemoglobin-based oxygen carrying solutions (see Chapters 66 and 68, Colloid Solutions and Shock Fluid Therapy, respectively). Concerns regarding potential adverse effects of synthetic colloids have limited their use in human patients, although similar research in dogs and cats remains limited.19-22 The use of human albumin for treatment of circulatory shock is commonly used in people, but a risk:benefit analysis should be performed in dogs due to potential immune reactions.18,23-25 Lyophilized canine albumin may provide a less antigenic natural colloid alternative.26-27 The use of 7% to 7.5% sodium chloride (hypertonic saline) can be lifesaving in the emergency setting (see Chapter 65, Crystalloid Solutions). Combinations of hypertonic saline and synthetic colloid solutions may provide more rapid improvement in hemodynamic status and with lower overall crystalloid requirements than when crystalloids are used alone.19,20 Blood component therapy is often used during resuscitation of the shock patient with severe hemorrhage (see Chapters 69 and 71, Transfusion Medicine and Hemorrhagic Shock, respectively). Shock patients that remain hypotensive despite intravascular volume resuscitation often require vasopressor or inotrope therapy. There is increasing evidence in people to suggest that early vasopressor use may decrease fluid overload and improve outcome, especially with septic shock.30 Because oxygen delivery to the tissue is dependent on both cardiac output and systemic vascular resistance, therapy for hypotensive patients includes maximizing cardiac output with fluid therapy, as discussed earlier, and inotropic drugs or modifying vascular tone with vasopressor agents (see Chapters 6, 147, and 148, Pathophysiology and Mechanisms of Shock, Catecholamines, and Vasopressin, respectively). Commonly used vasopressors include catecholamines (epinephrine, norepinephrine, dopamine), positive inotropic agents, and the sympathomimetic drug phenylephrine. In addition, vasopressin, corticosteroids, and glucagon have been used as adjunctive pressor agents. Unlike hypovolemic or distributive shock, patients with cardiogenic shock experience a combination of cardiovascular changes that result in diminished tissue perfusion and increased pulmonary venous pressures, resulting in pulmonary edema and dyspnea. Supplemental oxygen therapy and minimal handling are extremely important to avoid further decompensation in patients with cardiogenic shock. A brief physical examination combined with point-of-care ultrasound may be very helpful in differentiating heart failure from other causes of dyspnea (see Chapter 189, Point-of-Care Ultrasound in the ICU). The diuretic furosemide administered intravenously or intramuscularly is the mainstay of therapy for congestive heart failure (see Part IV, Cardiovascular Disorders). Animals that fail to show clinical signs of improvement after repeated doses of diuretics may require more specific therapy targeting the underlying cardiac abnormality (e.g., systolic dysfunction, diastolic failure, arrhythmias). Ultimately, the dyspneic

CHAPTER 6  Classification and Initial Management of Shock States patient in cardiogenic shock that fails to respond to therapy should either be treated with high flow nasal oxygen or be anesthetized, intubated, and positive pressure ventilated with 100% oxygen to stabilize the animal and allow the clinician to perform a thorough physical examination and pursue further diagnostics such as thoracic radiographs and echocardiography. Early recognition and initiation of therapy are essential for successful treatment of the shock patient. Therapy for the shock patient is complicated by the need for rapid decision making in the absence of a complete medical history or diagnostic tests. In all forms of shock other than cardiogenic shock, intravenous fluid administration is the mainstay of therapy. Although under-resuscitation or delayed onset of therapy could clearly contribute to a negative outcome, excessive or overaggressive resuscitation may also have undesirable consequences, including a dilutional coagulopathy and pulmonary edema. The combination of breed, signalment, and physical examination findings will help the emergency clinician identify the type of shock present, and serial evaluation with clearly defined endpoints of resuscitation is essential for successful management of the shock patient.

REFERENCES 1. Chen GY, Nunez G: Sterile inflammation: sensing and reacting to damage, Nat Rev Immunol 10(12):826-837, 2010. 2. Nakahira K, Hisata S, Choi AMK: The roles of mitochondrial damage-associated molecular patterns in diseases, Antioxid Redox Signal 23(17):1329-1350, 2015. 3. Schutzer KM, Larsson A, Risberg B, et al: Lung protein leakage in feline septic shock, Am Rev Respir Dis 147:1380, 1993. 4. Brady CA, Otto CM, Van Winkle TJ, et al: Severe sepsis in cats: 29 cases (1986-1998), J Am Vet Med Assoc 217:531, 2000. 5. Costello MF, Drobatz KJ, Aronson LR, et al: Underlying cause, pathophysiologic abnormalities, and response to treatment in cats with septic peritonitis: 51 cases (1990-2001), J Am Vet Med Assoc 225:897, 2004. 6. Nguyen HB, Rivers EP, Knoblich BP, et al: Early lactate clearance is associated with improved outcome in severe sepsis and septic shock, Crit Care Med 32:1637, 2004. 7. Boag A, Hughes D: Assessment and treatment of perfusion abnormalities in the emergency patient, Vet Clin North Am Small Anim Pract 35:319, 2005. 8. dePapp E, Drobatz KJ, Hughes D, et al: Plasma lactate concentration as a predictor of gastric necrosis and survival among dogs with gastric volvulus: 102 cases (1995-1998), J Am Vet Med Assoc 215:49, 1999. 9. Nel M, Lobetti RG, Keller N, et al: Prognostic value of blood lactate, blood glucose and hematocrit in canine babesiosis, J Vet Intern Med 18:471, 2004. 10. McMichael MA, Lees GE, Hennessey J, et al: Serial plasma lactate concentration in 68 puppies aged 4 to 80 days, J Vet Emerg Crit Care 15:17, 2005. 11. Hughes D, Rozanski ER, Shofer FS, et al: Effect of sampling site, repeated sampling, pH, and PCO2 on plasma lactate concentration in healthy dogs, Am J Vet Res 60:521, 1999. 12. Rivers E, Nguyen B, Havstad S, et al: Early goal-directed therapy in the treatment of severe sepsis and septic shock, N Engl J Med 345:1368, 2001.

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13. Conti-Patara A, de Araujo Caldeira J, de Mattos-Junior E, et al: Changes in tissue perfusion parameters in dogs with severe sepsis/septic shock in response to goal-directed hemodynamic optimization at admission to ICU and the relation to outcome, J Vet Emerg Crit Care 22(4):409-418, 2012. 14. Trzeciak S, McCoy JV, Dellinger RP, et al: Early increases in microcirculatory perfusion during protocol-directed resuscitation are associated with reduced multi-organ failure at 24 h in patients with sepsis, Intensive Care Med 34(12):2210-2217, 2008. 15. Conti-Patara A, de Araujo Caldeira J, de Mattos-Junior E: Changes in tissue perfusion parameters in dogs with severe sepsis/septic shock in response to goal-directed hemodynamic optimization at admission to ICU and the relation to outcome, J Vet Emerg Crit Care 22(4):409-418, 2012. 16. Silverstein DC, Kleiner J, Drobatz KJ: Effectiveness of intravenous fluid resuscitation in the emergency room for treatment of hypotension in dogs: 35 cases (2000-2010), J Vet Emerg Crit Care 22(6):666-673, 2012. 17. Silverstein DC, Aldrich J, Haskins SC, et al: Assessment of changes in blood volume in response to resuscitative fluid administration in dog, J Vet Emerg Crit Care 15:185, 2005. 18. Stern SA, Wang S, Mertz M, et al: Under-resuscitation of near-lethal uncontrolled hemorrhage: effects on mortality and end-organ function at 72 hours, Shock 15:16, 2001. 19. Martin GS, Bassett P: Crystalloids vs. colloids in the intensive care unit: a systematic review, J Crit Care 50:144-154, 2019. 20. Sigrist NE, Kalin N, Dreyfus A: Changes in serum creatinine concentration and acute kidney injury (AKI) grade in dogs treated with hydroxyethyl starch 130/0.4 from 2013 to 2015, J Vet Intern Med 31(2):434-441, 2017. 21. Sigrist NE, Kalin N, Dreyfus A: Effects of hydroxyethylstarch 130/0.4 on serum creatinine concentration and development of acute kidney injury in nonazotemic cats, J Vet Intern Med 31(6):1749-1756, 2017. 22. Hayes G, Benedicenti L, Mathews K: Retrospective cohort study on the incidence of acute kidney injury and death following hydroxyethyl starch (HES 10% 250/0.5/5:1) administration in dogs (2007-2010), J Vet Emerg Crit Care 26(1):35-40, 2016. 23. Cohn LA, Kerl ME, Dodam JR, et al: Clinical response to human albumin administration in healthy dogs, Am J Vet Res 68:657, 2007. 24. Francis AH, Martin LG, Haldorson GJ, et al: Adverse reactions suggestive of Type III hypersensitivity in six healthy dogs given human albumin, J Am Vet Med Assoc 230(6):873-879, 2007. 25. Martin LG, Luther TY, Alperin DC, et al: Serum antibodies against human albumin in critically ill and healthy dogs, J Am Vet Med Assoc 232(7):1004-1009, 2008. 26. Craft EM, Powell LL: The use of canine-specific albumin in dogs with septic peritonitis, J Vet Emerg Crit Care 22(6):631-639, 2012. 27. Enders B, Musulin S, Holowaychuk M, et al: Repeated infusion of lyophilized canine albumin safely and effectively increases serum albumin and colloid osmotic pressure in healthy dogs, J Vet Emerg Crit Care 28(S1):S5, 2018. 28. Shertel ER, Allen DA, Muir WW, et al: Evaluation of a hypertonic sodium chloride/dextran solution for treatment of traumatic shock in dogs, J Am Vet Med Assoc 208:366, 1996. 29. Fantoni DT, Auler JO Jr, Futema F, et al: Intravenous administration of hypertonic sodium chloride solution with dextran or isotonic sodium chloride solution for treatment of septic shock secondary to pyometra in dogs, J Am Vet Med Assoc 215:1283, 1999. 30. Ospina-Tascón GA, Hernandez G, Alvarez I: Effects of very early start of norepinephrine in patients with septic shock: a propensity score-based analysis, Crit Care 24(1):52, 2020.

7 SIRS, MODS, and Sepsis Kaitlyn Rank, DVM, Bernie Hansen, DVM, MS, DACVECC, DACVIM (Internal Medicine)

BACKGROUND The term systemic inflammatory response syndrome (SIRS) was coined in 1992 by participants of the joint American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference and published in a concerted effort to standardize the terminology used to describe the clinical syndromes of systemic inflammation, sepsis, and septic shock.1,2 Their goal was to create a conceptual framework characterizing sepsis (and the inflammatory response that accompanies it) in order to both improve individual patient management and to better define illness severity in patients enrolled in clinical research. Conference participants created a working definition of SIRS that required the presence of any two of the four clinical findings of hyper/hypothermia, tachycardia, tachypnea (or hyperventilation), and leukocyte count abnormalities in the absence of other known causes such as exercise or chemotherapy (Table 7.1). They also recommended specific definitions for sepsis, severe sepsis, septic shock, and multiple organ dysfunction syndrome (MODS). MODS was defined as the presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention, and sepsis was defined as SIRS caused by an infectious agent. The consensus conference recommendations were a milestone in the history of medicine, encouraging clinicians to abandon meaningless terms like “septicemia” and creating a mechanism to stratify patients with infectious disease within a continuum that was anchored by infection without systemic illness on one end, and septic shock on the other. Sepsis became, by definition, infection accompanied by two or more of the four SIRS criteria. Adoption of the consensus definitions of SIRS and sepsis as screening tools for sick companion animals was proposed separately by Purvis3 in 1994 and Hardie4 in 1995, using rectal temperature and heart rate criteria that were empirically modified for dogs and cats. The diagnostic utility of using these criteria to identify bacterial sepsis (defined as SIRS due to infection) was first tested by Hauptman in 1997, who applied institution-specific normal range cutoffs (Table 7.1) prospectively to 350 hospitalized dogs and required at least two of the four criteria to be abnormal for a diagnosis of sepsis.5 The sensitivity of this SIRS schema to identify sepsis in dogs with confirmed infection and “systemic illness” (n 5 30) was 97%, but over one-third of the 320 dogs without infection met the “2 of 4” criteria and were erroneously classified as septic. Because their goal was to evaluate the SIRS criteria as a screening test for sepsis, the authors did not consider the utility of the criteria as a diagnostic or prognostic tool. A similar approach was retrospectively applied by Brady et al. to cats with severe sepsis confirmed at necropsy. Clinical findings obtained within 12 hours of death were used to generate feline-specific cutoff values for these criteria in 29 cats that were ill enough to

42

die or be euthanized in response to a poor prognosis.6 In that study, severe sepsis was defined as postmortem evidence of multiorgan involvement with bacterial thrombi or multifocal necrosis in cats that had clinical features of grave illness. All 15 cats that had a complete blood count (CBC) performed fulfilled three of the four SIRS criteria, prompting the authors to recommend “3 of 4” as the threshold for a clinical diagnosis of SIRS in cats. These two studies served as the basis for classification of animals as SIRS-positive or SIRS-negative in several subsequent investigations. More recently, Alves et al. applied SIRS criteria (using cutoffs only slightly different from Hauptman’s) to dogs with laboratory-confirmed canine parvovirus infection to establish the accuracy of SIRS criteria to classify dogs with this viral infection, a disorder frequently complicated by bacterial sepsis.7 Results of that study suggested improved accuracy when the “2-of-4” criteria approach was combined with assessment for abnormalities of the mucous membranes (Table 7.1). The association of MODS with mortality in critically ill dogs was formally described in 2010 by Kenney et al. in a retrospective study of 114 dogs undergoing surgery for septic peritonitis.8 The authors included cases of confirmed abdominal sepsis that had sufficient laboratory data to evaluate renal, cardiovascular, respiratory, hepatic, and coagulation function. Arbitrary thresholds, based on direct extrapolation from the human Sequential Organ Failure Assessment (SOFA) score (see below) and Multiple Organ System Dysfunction Score, were used to determine the presence or absence of organ dysfunction.9 The thresholds included hypotension requiring pressor support (cardiovascular), oxygen supplementation (respiratory), an increase in serum creatinine of 0.5 mg/dl from preoperative values (renal), a serum bilirubin concentration 0.5 mg/dl (hepatic), and a prothrombin time or activated partial thromboplastin time 25% higher than reference range or a platelet count #100,000/µl (coagulation). Each category was treated as binary (present or absent) with no weighted scores applied to indicate severity, and MODS was diagnosed if there were two or more organ systems affected. Although there was no effort to quantify the severity of dysfunction of any organ, the mere presence of any organ system dysfunction had a significant association with outcome. When compared with dogs with no organ system dysfunction, the odds ratio of death in dogs with organ dysfunction ranged from 6.73 (one organ) to 18.7 (four or five organs involved).

EVOLUTION OF DEFINITIONS With time, several limitations to the 1992 consensus definitions became apparent. First and foremost were the lack of specificity of SIRS criteria for infection in hospitalized patients and the lack of sensitivity of SIRS criteria to predict severity of illness and prognosis. These observations reinforced the evidence accumulating from

TABLE 7.1  Examples of SIRS Schemes Proposed for Companion Animals. The Four Clinical Characteristics that Comprise the SIRS Criteria are Numbered at the Top 4 Leukocyte Abnormalities Leukocytosis Leukopenia Bandemia (%) (3 103/mm3) (3 103/mm3)

Criteria

.38°C (100.4°F) ,36°C (96.8°F)

.90

.20

,32

.12

,4

.10

Any 2 of 4

Opinion

.39.7°C (103.5°F) ,37.8°C (100°F)

.160 (dog) .250 (cat)

.20

,32

.12

,4

.10

Any 2 of 4

Dog/cat

Opinion

.40°C (104°F) ,38°C (100.4°F)

.120 (dog) .140 (cat)

.20

,30 (dog) ,28 (cat)

.18

,5

.5

Any 2 of 4

1997

Dog

Observational study

.39°C (102.2°F) ,38°C (100.4°F)

.120

.20

3

.16

,6

.3

Any 2 of 4

Brady6

2000

Cat

Retrospective study

.39.7°C (103.5°F) ,37.8°C (100°F)

.225 or ,140

.40

3

.19.5

,5

.5

Any 3 of 4

Alves7

2020

Dog

Observational study

.39.4°C (102.9°F) ,37.8°C (100°F)

.140

.30

,32

.16

,6

.3

Any 2 of 4, 1 prolonged CRT or abnormal MM color

1 Temperature

ACCP/SCCM1

1992

Human

Consensus

Purvis3

1994

Dog/cat

Hardie4

1995

Hauptman5

CHAPTER 7  SIRS, MODS, and Sepsis

2 Heart Rate (BPM) 3 Respiration Respiratory pCO2 (mm Hg) rate (BrPM)

First author Year Species Method

43

44

PART I  Key Critical Care Concepts

experimental and clinical research that progression of critical illnesses, especially sepsis, has more to do with dysregulated host responses and organ dysfunction than it does with the presence of inflammation alone.10-13 An attempt to address this at the 2001 Sepsis-2 conference led to the recommendation to adopt the PIRO scheme (Predisposition, Insult/infection, Response, Organ dysfunction) to try to better incorporate the clinical features of organ dysfunction in an approach that was modelled on the TMN classification scheme used for staging many cancers.14 With time, scoring systems based on the PIRO concept were developed, but the approach remained tethered to the requirement for some SIRS criteria of inflammation, and a rigorous scoring system remained elusive for well over a decade.15 Growing awareness of the limitations, imposed by defining sepsis in terms of SIRS ultimately led to the revisions drafted by the third sepsis consensus conference (Sepsis-3) published in 2016, defining sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection.13 The specific phrase multiple organ dysfunction syndrome was not reviewed or redefined in the conference proceedings, but the participants emphasized progressive organ dysfunction as a keystone event in the development of critical illness. Organ dysfunction, rather than clinical features of inflammation, was recognized as a hallmark feature of sepsis syndrome, and it can be characterized clinically by various scoring systems. The SOFA score and the quick SOFA (qSOFA) score were identified as the most clinically useful methods.

ASSESSMENT OF MODS SEVERITY The SOFA score was developed in the 1990s as an evaluation tool for organ dysfunction in any ICU patient (septic or not), but was revalidated as an assessment tool for septic patients in conjunction with the work of the Sepsis-3 conference task force.16 The score is based on the combined clinical assessment of cardiopulmonary (blood pressure, P/F ratio), neurologic (Glasgow Coma Score), renal (serum creatinine), hepatic (serum bilirubin), and coagulation (platelet count) system functions, with deviations from normal scored on a 5-point scale (Fig. 7.1). The score (from 0 to 4) assigned to a patient is the value of the highest subscore in the schema. Patients are assumed to have a baseline score of 0 unless there is known preexisting disease. A score of 2 is accompanied by at least a 10% mortality risk in humans hospitalized with infection, and a score of 2 or an increase in the score by a value of 2 in infected patients has defined human sepsis since the Sepsis-3 conference.17 Application of the SOFA score to a small group of hospitalized dogs was described by Ripanti in 2012.18 The authors slightly modified the human SOFA score and used it to prospectively evaluate a convenience sample of 45 dogs admitted to the ICU for three consecutive days. Forty dogs survived to complete data collection; all dogs

met two of the four SIRS criteria using cutoffs only slightly different from Hauptman’s. As might be expected, 19/20 of the dogs whose SOFA scores increased during those three days died, and 19/20 dogs with stable or decreasing SOFA scores survived. Half of the dogs had confirmed infection and were therefore classified as septic based on the combination of meeting SIRS criteria and infection. There was no difference in survival or time to discharge between septic and nonseptic dogs, suggesting that it was the severity and progression of organ dysfunction, not the presence of infection, that had the greatest impact on survival. The same Sepsis-3 study that evaluated the predictive value of the SOFA score examined the simplified qSOFA.16 This scoring system uses three elements (altered mentation, systolic blood pressure #100 mm Hg, respiratory rate of 22) to create a scale of 0–3, with each abnormality assigned 1 point. Because there is good agreement between qSOFA and SOFA and because qSOFA does not require laboratory tests and may be quickly and repeatedly applied, the Sepsis-3 conference recommendations include using this as a screening tool for sepsis outside of the ICU. A qSOFA score 2 increases the likelihood of a poor outcome and warrants further investigation to rule out sepsis. As of this writing, there are only two published studies of the utility of the qSOFA score in dogs. As reported in 2021,19 Ortolani and Bellis retrospectively applied the unedited human criteria to 267 dogs hospitalized in an ICU with a variety of diseases, including sepsis, to determine whether there was an association with mortality. Using those human scoring parameters patient qSOFA scores were not associated with survival. Adding blood lactate concentration to the assessment improved the sensitivity of the instrument to predict mortality, but this was not superior to measurement of lactate alone. Possible explanations for this apparent lack of utility are that the blood pressure and respiratory rate cutoffs appropriate for humans do not work for dogs, and identifying significant change in mentation in this species may be more difficult. Similarly, the second study retrospectively applied the same human criteria to dogs with sepsis. Sepsis was defined by finding at least two of the four SIRS criteria and a documented site of infection requiring surgical source control.20 When applied to dogs with sepsis, a qSOFA score of 2 was associated with a sevenfold higher risk of death and an increased duration of both postoperative complications and length of hospitalization. Thus, the qSOFA tool may have more value for animals with sepsis as opposed to other causes of severe illness, but accurate assessment of the tool’s utility to identify either will require prospective trials.

THE APPLE SCORE To date, the most comprehensive validated illness severity scoring system to characterize organ dysfunction and risk of death in dogs and cats is the Acute Patient Physiologic and Laboratory Evaluation

Fig. 7.1  The Sequential Organ Failure Assessment (SOFA) score. Adapted from reference 17.

CHAPTER 7  SIRS, MODS, and Sepsis (APPLE) score developed by Hayes et al. and reported in 201021 (dogs) and 201122 (cats). Both instruments were developed via analysis of physiological data acquired within 24 hours of hospital admission using the LOWESS approach23 to parse continuous physiological data into discrete categories. Each categorized variable was then screened via univariate logistic regression, and suitable candidate variables were assessed using a multivariate logistic regression model to identify the association between each variable and mortality outcome. Out of 55 preliminary variables evaluated for dogs and 41 for cats, the models were reduced to 10 (APPLEfull) or 5 (APPLEfast) variables in dogs (Fig. 7.2) and 8 or 5 variables in cats (Fig. 7.3). The individually weighted scores add up to a maximum possible score of 80 (APPLEfull) or 50 (APPLEfast). When applied to a cohort of ICU patients with high mortality rates (18.4% in dogs and 25.8% in cats), the accuracy of the APPLEfull score to predict survival in the authors’ validation groups was strong, with an area under the receiver operator curve (AUROC) value of .91 for dogs and .88 for cats. The APPLEfast scores performed nearly as well when predicting survival, with AUROC values of .85 in dogs and .76 in cats. Multiple investigators have subsequently used the APPLE score instruments to categorize animals for studies of critical illness from sepsis, trauma, and other disorders. Summers et al. retrospectively applied APPLEfull, APPLEfast, and an older classification system (Survival Prediction Index) to 37 dogs with septic shock and a very high

45

(81.1%) mortality rate. Of the three classification schema, only the APPLEfull had good predictive value, with an AUROC value of 0.8 across the range of calculated scores.24 In an overlapping retrospective study using some of the same subjects, higher APPLEfull scores were found in septic dogs treated with hydrocortisone for suspected relative adrenal insufficiency, consistent with clinical assessment that those dogs were sicker than dogs not treated with hydrocortisone. In critically ill dogs meeting SIRS criteria, APPLE scores were generally higher in nonsurvivors across several studies.25-28 Higher APPLEfull scores also predict mortality following traumatic injury in both cats29 and dogs;30: in the canine study, an APPLEfull score of 31 was 90% sensitive and 84.6% specific for nonsurvival with an AUROC of 0.912. Although some of the predictive variables in the APPLE scheme (age, body cavity fluid, temperature, and blood glucose) do not directly represent organ dysfunction, most of the included variables are directly related to the neurologic, cardiopulmonary, hepatic, renal, and hemostatic systems and thus provide an assessment for multiple organ dysfunction. As with other scoring systems, the weights assigned to different categorical variables do not necessarily correlate with clinical severity. For example, in the canine APPLEfull model, hyperglycemia (blood glucose concentration .273 mg/dl) is weighted at 0 and a normal blood glucose concentration (84-102) is weighted with a score of 8 (Fig. 7.2). Similarly, both the APPLEfull and APPLEfast instruments

Fig. 7.2  The canine APPLEfull and APPLEfast score.21

46

PART I  Key Critical Care Concepts

assign an item score of 0 for marked anemia (packed cell volume (PCV) ,11% or ,16%, respectively) and a score of 14 or 9, respectively, to cats with an admission PCV of 40% (Fig. 7.3). Such counterintuitive score assignments are likely due to a combination of multivariate effects in the model plus the nature of underlying disease in animals used for instrument development. For example, cats with marked anemia and dogs with marked hyperglycemia may have survived to discharge following transfusion or treatment with insulin.

ASSESSMENT OF ANIMALS WITH SIRS OR MODS Although the 2016 redefinition of sepsis was stripped of its original association with SIRS, the clinical identification of systemic inflammation remains a foundational screening tool for severe illness due to infectious and noninfectious disease in humans, dogs, and cats. Hyper/hypothermia, unexplained sinus tachy- or bradycardia, and tachypnea are significant features of critical illness in companion animals, particularly when accompanied by other physical examination findings such as depressed mentation or abnormal mucus membrane color, skin temperature, and femoral pulse quality. Discovery of physical evidence of SIRS criteria should trigger immediate investigation to localize the cause additional testing such as hematology (necessary to complete the SIRS evaluation), serum biochemistry panel, blood lactate, arterial blood pressure, pulse oximetry, cytology, bacteriological culture, and diagnostic imaging. The low specificity of SIRS criteria for predicting outcome means that a prognosis should not be offered based on the presence of the syndrome alone. Additionally, a majority of animals meeting SIRS criteria may ultimately have no evidence of an infectious cause, as these criteria are not specific for sepsis. However, if an infectious cause is suspected, the appropriate steps for diagnosing (collecting blood, urine, and/or site-specific cultures) and treatment (starting broad spectrum antibiotics) should be

initiated. When the source of suspected infection is not immediately apparent, ancillary testing should include point-of-care or comprehensive ultrasound examination of the thorax and abdomen, with aspirates of any body cavity fluid or abnormal masses for cytology and bacterial culture and susceptibility testing. The urogenital system should be examined for evidence of pyelonephritis, pyometra, or prostatitis and a urine sample collected aseptically for analysis and microbial culture with susceptibility testing. Thoracic radiographs should be obtained to rule out pneumonia or pulmonary masses; if heavy lung infiltrate suggests severe pneumonia, an airway wash to collect a respiratory fluid sample for culture may be warranted. A CBC may reveal changes supportive of infection, such as leukocytosis, leukopenia, or a left shift, and examination of a blood smear may reveal neutrophil toxic change or evidence of intracellular or extracellular organisms. Serologic testing may be indicated for agents such as Rickettsia ricketsii or other causes of systemic illness. If no localized source of infection is evident, or if bacterial endocarditis is suspected, blood cultures (including Bartonella alphaproteobacteria growth medium culture) should be obtained. Additional testing is patientspecific, and could include diagnostics such as an echocardiogram if a new murmur is auscultated, arthrocentesis if joints are effusive or painful, cerebrospinal fluid tap and/or spinal radiographs if evidence of neck or back pain. Empiric therapy with antimicrobials should be based on clinical suspicion and informed by local experience, organ involvement, apparent virulence, and when available, cytology and Gram stain results. Treatment of suspected bacterial sepsis should utilize intravenous antibiotics administered at the upper end of the therapeutic dosage range, adhering to principles of time- or concentrationdependent drug administration. Time-dependent antibiotics may best be administered as a loading dose followed by a continuous rate intravenous infusion to maintain tissue concentrations above the

Fig. 7.3  The feline APPLEfull and APPLEfast score.22

CHAPTER 7  SIRS, MODS, and Sepsis minimal inhibitory concentration for the target organism. Although many drugs in widespread use may be effective in animals with no recent antibiotic exposure (e.g., fluoroquinolones for Escherichia coli infection), animals recently treated with antibiotics for other illnesses likely are at a higher risk of multidrug resistant infections and may need escalated therapy at the onset of treatment. In contrast to SIRS criteria, comprehensive screening for multiple organ dysfunction is more complex because its quantification requires more than just a physical examination combined with a CBC. At present, there is no reliable cage-side prediction tool that adequately characterizes multiple organ dysfunction or estimates mortality risk in animals as well as the qSOFA score does in humans. The APPLEfast and APPLEfull scores are the best validated of the companion animal illness severity assessments, and in cats the APPLEfast score can be estimated rather quickly with a combination of physical examination and pointof-care testing (see Chapter 13, Predictive Scoring Systems in Veterinary Medicine). However, both of the canine APPLE scores and the feline APPLEfull score require a biochemistry profile in addition to an ultrasound examination of both body cavities, and therefore may be more useful as an objective tool to characterize illness severity and predict prognosis rather than a triage screening instrument. It is important to recognize that mortality estimates provided by the APPLE scores are based on data obtained from one hospital between 2007 and 2009, and treatment strategies that affect mortality may be very different now. Therefore, the APPLE score should be folded into the overall clinical assessment of the patient, and not mistaken for an objective way to quantify absolute mortality risk for any individual patient. An interactive APPLE score calculator is available for download31 this point-and-click template simplifies the computation of either APPLE score.

SUMMARY The systemic inflammatory response is a common reaction to both sepsis and noninfectious critical illness. Its presence should alert the clinician to the likelihood that something serious is going on. SIRS criteria and other features of inflammation such as altered skin temperature, changes to mucous membrane color and/or capillary refill time, and abnormal behavior may be quickly identified via physical examination and basic hematology. Possible causes such as trauma, burns, or cellulitis may be obvious during initial examination. However, when the cause is not quickly apparent, identifying SIRS criteria in a dog or cat should prompt diagnostic testing to rule out bacterial sepsis, viral, protozoal, or rickettsial infections, pancreatitis, immunemediated disease, or neoplasia. In conjunction with additional diagnostic testing and application of scoring indices such as APPLE, the identification of MODS carries more important and accurate implications for outcome. However, treatment decisions and prognosis for each patient are clinically complex and should never be based solely on any illness severity index.

REFERENCES 1. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis, Crit Care Med 20(6):864-874, 1992. 2. Bone RC, Balk RA, Cerra FB, et al: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis, Chest 101(6):1644-1655, 1992. 3. Purvis D, Kirby R: Systemic inflammatory response syndrome: septic shock, Vet Clin North Am Small Anim Pract 24(6):1225-1247, 1994.

47

4. Hardie EM: Life-threatening bacterial infection, Compend Contin Educ Pract Vet 17(6):763-778, 1995. 5. Hauptman JG, Walshaw R, Olivier NB: Evaluation of the sensitivity and specificity of diagnostic criteria for sepsis in dogs, Vet Surg 26(5):393-397, 1997. 6. Brady CA, Otto CM, Van Winkle TJ, et al: Severe sepsis in cats: 29 cases (1986-1998), J Am Vet Med Assoc 217(4):531-535, 2000. 7. Alves F, Prata S, Nunes T, et al: Canine parvovirus: a predicting canine model for sepsis, BMC Vet Res 16(1):199, 2020. 8. Kenney EM, Rozanski EA, Rush JE, et al: Association between outcome and organ system dysfunction in dogs with sepsis: 114 cases (2003-2007), J Am Vet Med Assoc 236(1):83-87, 2010. 9. Marshall JC, Cook DJ, Christou NV, et al: Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome, Crit Care Med 23(10):1638-1652, 1995. 10. Kaukonen KM, Bailey M, Pilcher D, et al: Systemic inflammatory response syndrome criteria in defining severe sepsis, N Engl J Med 372(17): 1629-1638, 2015. 11. Fernando SM, Tran A, Taljaard M, et al: Prognostic accuracy of the quick sequential organ failure assessment for mortality in patients with suspected infection: a systematic review and meta-analysis, Ann Intern Med 168(4):266-275, 2018. 12. Ghnewa YG, Fish M, Jennings A, et al: Goodbye SIRS? Innate, trained and adaptive immunity and pathogenesis of organ dysfunction, Med Klin Intensivmed Notfmed 115(Suppl 1):10-14, 2020. 13. Singer M, Deutschman CS, Seymour CW, et al: The third international consensus definitions for sepsis and septic shock (Sepsis-3), J Am Med Assoc 315(8):801-810, 2016. 14. Levy MM, Fink MP, Marshall JC, et al: 2001 SCCM/ESICM/ACCP/ATS/ SIS international sepsis definitions conference, Crit Care Med 31(4): 1250-1256, 2003. 15. Marshall JC: The PIRO (predisposition, insult, response, organ dysfunction) model: toward a staging system for acute illness, Virulence 5(1): 27-35, 2014. 16. Seymour CW, Liu VX, Iwashyna TJ, et al: Assessment of clinical criteria for sepsis: for the third international consensus definitions for sepsis and septic shock (Sepsis-3), J Am Med Assoc 315(8):762-774, 2016. 17. Lambden S, Laterre PF, Levy MM, et al: The SOFA score-development, utility and challenges of accurate assessment in clinical trials, Crit Care 23(1):374, 2019. 18. Ripanti D, Dino G, Piovano G, et al: Application of the sequential organ failure assessment score to predict outcome in critically ill dogs: preliminary results, Schweiz Arch Tierheilkd 154(8):325-330, 2012. 19. Ortolani JM, Bellis TJ: Evaluation of the quick sequential organ failure assessment score plus lactate in critically ill dogs, J Small Anim Pract 62(10):874-880, 2021. 20. Stastny T, Koenigshof AM, Brado GE, et al: Retrospective evaluation of the prognostic utility of quick sequential organ failure assessment scores in dogs with surgically treated sepsis (2011-2018): 204 cases, J Vet Emerg Crit Care 32(1):68-74, 2022. 21. Hayes G, Mathews K, Doig G, et al: The acute patient physiologic and laboratory evaluation (APPLE) score: a severity of illness stratification system for hospitalized dogs, J Vet Intern Med 24(5):1034-1047, 2010. 22. Hayes G, Mathews K, Doig G, et al: The Feline Acute Patient Physiologic and Laboratory Evaluation (Feline APPLE) Score: a severity of illness stratification system for hospitalized cats, J Vet Intern Med 25(1):26-38, 2011. 23. Cleveland WS: Robust locally weighted regression and smoothing scatterplots, J Am Stat Assoc 74(368):829-836, 1979. 24. Summers AM, Vezzi N, Gravelyn T, et al: Clinical features and outcome of septic shock in dogs: 37 cases (2008-2015), J Vet Emerg Crit Care 31(3):360-370, 2021. 25. Langhorn R, Oyama MA, King LG, et al: Prognostic importance of myocardial injury in critically ill dogs with systemic inflammation, J Vet Intern Med 27(4):895-903, 2013. 26. Giunti M, Troia R, Bergamini PF, et al: Prospective evaluation of the acute patient physiologic and laboratory evaluation score and an extended clinicopathological profile in dogs with systemic inflammatory response syndrome, J Vet Emerg Crit Care 25(2):226-233, 2015.

48

PART I  Key Critical Care Concepts

27. Heilmann RM, Grutzner N, Thames BE, et al: Serum alpha1-proteinase inhibitor concentrations in dogs with systemic inflammatory response syndrome or sepsis, J Vet Emerg Crit Care 27(6):674-683, 2017. 28. Köster LS, Fosgate GT, Suchodolski J, et al: Comparison of biomarkers adiponectin, leptin, c-reactive protein, s100a12, and the Acute Patient Physiologic and Laboratory Evaluation (APPLE) score as mortality predictors in critically ill dogs, J Vet Emerg Crit Care 29(2):154-160, 2019.

29. Murgia E, Troia R, Bulgarelli C, et al: Prognostic significance of organ dysfunction in cats with polytrauma, Front Vet Sci 6:189, 2019. 30. Goggs R, Letendre JA: High mobility group box-1 and pro-inflammatory cytokines are increased in dogs after trauma but do not predict survival, Front Vet Sci 5:179, 2018. 31. https://docs.google.com/spreadsheets/d/1bQ_iaUHeILWn3NpGxFi1 Ewvbp8zEiwKAn0SvsOc0VRI/copy

8 Oxygen Toxicity Duana McBride, BVSc, DACVECC, MVMedSc, FHEA, MRCVS KEY POINTS • Oxygen is a stable molecule that is metabolized to water during a three-stage reduction. Hyperoxia or pathological states can result in the incomplete reduction of oxygen, producing reactive oxygen and nitrogen species (RONS). • RONS cause oxidative injury by inducing damage to lipids (via lipid peroxidation), nucleic acids, and proteins, resulting in cellular injury. • Hyperoxia can result in cellular injury that predominantly affects the respiratory, central nervous, and cardiovascular systems.

• Hyperoxia is associated with worse outcome in critically ill people, including patients with sepsis, those receiving mechanical ventilation, and postcardiac arrest patients. • Antioxidants are endogenous or exogenous compounds that can delay or prevent the oxidation of substrates into RONS, which are important mechanisms in protecting cells against oxidative injury.

PATHOPHYSIOLOGY The oxygen molecule (O2) consists of a pair of oxygen atoms bound together with two unpaired electrons in the outer shell (known as a biradical [Box 8.1]). Unpaired electrons are considered free radicals and are typically highly reactive.1 However, oxygen is unique in that the unpaired electrons orbit around the oxygen atom in parallel, and therefore it is not highly reactive. Reactive oxygen and nitrogen species (RONS) are natural byproducts of the normal metabolism of oxygen and have important roles in cell signaling and homeostasis.1,2 Excess accumulation of RONS is limited by the body’s capacity to convert RONS into stable molecules via antioxidants. When oxidative injury occurs due to endogenous or exogenous sources (Box 8.2), the body’s capability to metabolize RONS becomes exhausted, resulting in dangerous levels of RONS production (Fig. 8.1).

Three-stage Reduction of Oxygen The three-stage reduction of oxygen involves the reduction of 90%– 95% of oxygen to water when there are no pathological stresses on the body.1,2 The remaining 5% of oxygen only partially undergoes reduction, and the intermediate products leak into the cytosol and outside the cell and cause oxidative injury. Initially, oxygen is reduced to the superoxide anion (• O22), which is a precursor of most other reactive oxygen species (ROS). The superoxide anion is one of the most reactive ROS; however, it is rapidly metabolized due to the presence of superoxide dismutase and glutathione peroxidase. Dismutation of • O22 produces hydrogen peroxide (H2O2), which is not a free radical as it has no unpaired electrons, but it is highly toxic. Hydrogen peroxide is then reduced to water through a reaction catalyzed by catalase (Fig. 8.1).

Fenton/Haber–Weiss Reaction The Fenton reaction, also known as the Haber–Weiss reaction, is the most cytotoxic of all oxidative pathways. The reaction is dependent on the availability of H2O2, iron, and copper.1,2 The products of this

BOX 8.1  Definitions Oxygen molecule: A pair of oxygen atoms bound together with two unpaired electrons in the outer shell. Hyperoxia: An excess of oxygen supply in tissues or organs.2,3 Hyperoxemia: Partial pressure of oxygen in arterial blood (PaO2) above normal values.2,3 Free radical: Reactive atom or group of atoms that has one or more unpaired electrons.1,2 Reactive oxygen and nitrogen species (RONS): Chemically reactive species containing oxygen or nitrogen.1,2 Antioxidant: Compound that inhibits oxidation.1,2 Oxygen toxicity/oxidative injury: Where excessive tissue oxygen or pathological states can result in the transformation of a stable oxygen molecule to highly toxic substances, causing damage to nucleic acids, proteins, and lipids.2,3

BOX 8.2  Sources of Oxygen Toxicity Endogenous

Exogenous

Aerobic respiration Excessive oxygen in the tissues compared with antioxidant defence mechanisms Free electron production from NADPH in neutrophils and macrophages during phagocytosis Ischemic reperfusion injury Iron Copper Oxidation of hemoglobin to methemoglobin

Ionizing radiation Environmental background radiation Ultraviolet radiation Pollution Paraquat toxicity Bleomycin toxicity

NADPH, nicotinamide adenine dinucleotide phosphate.

49

50

PART I  Key Critical Care Concepts

•HO + OH– + 1O2 Cu/Fe2+ 2e– 2O2

2H+ 2•O2–

Fenton/Haber-Weiss reaction 2e– 2H+

O2

Superoxide dismutase/ glutathione peroxidase

H2O2

O2

Catalase

Three-stage reduction of oxygen

2H2O

2HOCI Myeloperoxidase reaction 2CI–

2NO•

2ONO2– Reactive nitrogen species Fe2+

Fe3+

Fig. 8.1.  ​Three-stage reduction of oxygen and reactive oxygen/nitrogen species production. 1O2, singlet oxygen molecule; Cl, chloride; Cu, copper; e2, electron; Fe, iron; H2O, water; H2O2, hydrogen peroxide; HOCl, hypochlorous acid; O2, dioxygen; • O22, superoxide anion; OH2, hydroxyl anion; • OH, hydroxyl free radical; ONO22, peroxynitrite. R (PUFA)

reaction are the hydroxyl free radical (• OH), which is one of the most toxic ROS; the hydroxyl anion (OH2); and the singlet oxygen molecule (1O2). The 1O2 is a free radical and ROS formed by internal rearrangement of unpaired electrons from the dioxide oxygen molecule (O2) (Fig. 8.1).

–

ONO

or •HO H2O •R (lipid radical)

Myeloperoxidase Reaction

O2

Hydrogen peroxide can react with chloride to form hypochlorous acid (HOCl), which occurs in the phagocytic vesicles of neutrophils and is important in killing bacteria (Fig. 8.1).1,2 Hypochlorous acid is not a free radical. It is a ROS and a precursor to free radicals.

R (PUFA) + •RO2 (peroxyl radical)

ROOH (lipid peroxide)

Reactive Nitrogen Species Nitric oxide (NO •) is a potent endogenous vasodilator, cell messenger, and platelet inhibitor and can have cytotoxic effects in large quantities (e.g., during ischemia-reperfusion injury [IRI]).1,2 Nitric oxide can react with O• 22 to produce peroxynitrite (ONO22), which is a reactive nitrogen species that can initiate lipid peroxidation (Fig. 8.1). Peroxynitrite can also rearrange itself into nonreactive molecules and has a role as an antioxidant.

2

Fe2+ •RO (ocoxyl radical)

Fig. 8.2.  ​Lipid peroxidation. • HO, hydroxyl free radical; ONO22, peroxynitrite; PUFA, polyunsaturated fatty acid.

CELLULAR EFFECT OF OXIDATIVE INJURY

backbone. There are endogenous DNA repair mechanisms that prevent mutagenesis; however, DNA and RNA mutations can result if these repair mechanisms are overwhelmed.4

Lipid Peroxidation

Proteins

Lipids are the most susceptible to oxidative injury due to their relatively unstable double bonds and high prevalence in cell membranes. Lipid peroxidation is a major source of cellular injury, resulting in increased cell membrane permeability; inhibition of normal cellular enzyme processes; damage to proteins, intracellular membranes, capillaries, and alveoli; and inactivation of lung surfactant. The two main free radicals that can initiate lipid peroxidation are • OH and ONO22, although many other free radicals and RONS can also initiate lipid peroxidation. Polyunsaturated fatty acid is the major target of lipid peroxidation, and injury to polyunsaturated fatty acids results in a chain reaction of the generation of other ROS (Fig. 8.2).

Proteins are affected during oxidative stress due to decreased production secondary to inhibition of ribosomal translation, and direct reversible and irreversible oxidative injury. The most susceptible amino acid residues are cysteine and methionine; oxidation of the sulfhydryl groups results in the formation of disulphide bridges, which can inactivate a range of proteins. As a result, impairment of cellular signaling and metabolism can occur.

Nucleic Acids Oxidative stress can cause DNA and RNA damage, including mutations, and is therefore one of the contributing factors in mutagenesis, carcinogenesis, and aging. Hydroxyl radicals can react with DNA molecules, damaging purine and pyrimidine bases and the deoxyribose

Role of Inflammation During Oxidative Injury In addition to necrosis and apoptosis, oxidative injury can result in release of damage-associated molecular pattern molecules (DAMPS).2 DAMPS are recognized by pattern recognition receptors of the innate immune system and activate polymorphonuclear neutrophils (PMNs), thus contributing to the release of cytokines and the recruitment of monocytes and additional neutrophils. PMNs stimulate the inflammatory response and contribute to further RONS production, which in turn causes a vicious cycle of oxidative injury.2

CHAPTER 8  Oxygen Toxicity

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CLINICAL EFFECTS OF HYPEROXIA

ISCHEMIA-REPERFUSION INJURY IRI can be a source of oxidative injury in critically ill patients. It has been associated with myocardial infarction, thrombolytic therapy, aortic cross-clamping, cardiac bypass surgery, and organ transplantation in people.5 In veterinary medicine, IRI has been documented to occur in dogs with gastric dilation and volvulus, in dogs with myocardial injury, and in cats with arterial thromboembolism.6-8 During ischemia, anaerobic metabolism occurs, leading to the accumulation of intracellular lactate and hydrogen ions. There is decreased ATP available for ATP-dependent cell membrane pumps, resulting in a net efflux of potassium, and an influx of sodium, calcium, and chloride, leading to cell swelling. The high intracellular calcium concentration plays a large part in early IRI, causing cell apoptosis and necrosis, and contributes to the activation of the xanthine oxidoreductase system (Fig. 8.3). Activation of nuclear factor-kB occurs, increasing inflammatory mediators, resulting in leukocyte adhesion at the site of ischemia and during the reperfusion process. As oxygen is required for NO•  production, ischemia results in NO•  depletion and subsequent vasoconstriction, decreased perfusion, and cellular injury. During reperfusion, there is an increase in NO•  production, which is cytotoxic and causes severe nonresponsive vasodilation. Concurrently, there is release of ROS, which can inactivate NO •. In addition, NO •  and • O22 combine to produce ONO22 and cause further cellular injury. One of the most significant causes of cellular injury during IRI is the xanthine oxidoreductase system (Fig. 8.3). During ischemia, ATP is degraded to adenosine diphosphate, then to adenosine followed by inosin, and finally to hypoxanthine. In addition, the increased intracellular calcium catalyzes the metabolism of xanthine dehydrogenase to xanthine oxidase, which initiates the xanthine oxidoreductase system when reperfusion occurs. Upon reperfusion, there is a sudden increase in oxygen delivery, and in combination with oxidized nicotinamide adenine dinucleotide (NAD1), causes xanthine and uric acid production. This process occurs 10–30 seconds after the onset of reperfusion. During this process, NAD1 is reduced to NADH, and H2O2 and • O22 production occurs. The endothelium and gastrointestinal mucosa have the greatest amount of xanthine oxidase and, as a result, are highly susceptible to IRI. The most common clinical signs associated with IRI are hyperkalemia, acidemia, and associated cardiac arrhythmias; the “no reflow” phenomenon (where despite the occlusion being resolved, there is decreased perfusion due to leukocyte adhesions, platelet–leukocyte aggregation, and decreased endothelium-dependent vasorelaxation); myocardial stunning; central nervous system changes; gastrointestinal signs; and multiple organ dysfunction syndrome.

Hyperoxia and the Lungs The lungs are the organ most affected by hyperoxia due to high exposure levels compared with other tissues. Despite protective mechanisms (e.g., high antioxidant activity), hyperoxia can result in apoptosis and necrosis of pulmonary parenchymal cells, inflammation, noncardiogenic pulmonary edema, impaired gas exchange, and fibrosis, for which the underlying causes are multifactorial.1 The NO•  pathway plays a key role in the lungs, with the increased production of NO•  resulting in ONO22 formation in epithelial and endothelial cells.1 Vacuolation and thinning of the pulmonary capillary endothelium can result in increased permeability and pulmonary interstitial edema. Release of DAMPs and activation of PMNs result in inflammation, which leads to systemic inflammatory response syndrome, pulmonary inflammation, and a subsequent increase in alveolar–capillary permeability.9 Eventually, type I pneumocytes of the alveolar epithelium are lost and replaced by type II, which are surfactant-secreting pneumocytes that are relatively resistant to oxygen and also contribute to a thicker alveolar/capillary membrane, leading to diffusion impairment and eventually pulmonary fibrosis. Hyperoxia can lead to alveolar collapse by multiple mechanisms. First, nitrogen, an important molecule in preventing pulmonary atelectasis, is displaced by administration of 100% oxygen, thus resulting in absorptive atelectasis.9 Increased alveolar oxygen concentration results in a marked alveolar to arterial oxygen gradient, resulting in rapid diffusion of oxygen from the alveoli to the pulmonary circulation, also contributing to atelectasis.1 In addition, hyperoxia can induce surfactant impairment due to the downregulation of surfactant-associated proteins.9 Overall, atelectasis results in decreased alveolar capacity, decreased tidal volume, and ventilationperfusion mismatch; these affect both oxygenation and ventilation.1 Hyperoxia decreases mucociliary clearance and alters the pulmonary microbial flora and immune function, causing a predisposition to secondary infections.1,10,11 The duration of hyperoxia in people ranges from as little as 3 hours of 100% oxygen delivery to cause decreased mucociliary clearance and up to 30 hours to result in a decrease in vital capacity and gas diffusion. However, the effects of hyperoxia on the lungs are species-specific, with no available data in dogs or cats, and confounding illness factors must be taken into account in the clinical setting.

Hyperoxia and the Cardiovascular System Hyperoxia results in increased systemic vascular resistance and vasoconstriction secondary to decreased NO • bioavailability. ROS, most notably • O22, inhibits NO • via multiple mechanisms by reducing12,13

Inosine Hypoxanthine NAD+ + O2 Xanthine oxidase H2O2 NADH + O2– SOD Protease Xanthine Xanthine Ca2+ + dehydrogenase NAD + O2 Xanthine oxidase H2O2 NADH + O2– SOD Uric acid Fig. 8.3.  ​Xanthine oxidoreductase system. Ca21, calcium; H2O2, hydrogen peroxide; NAD1, oxidized nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; O2, oxygen; O22, superoxide anion; SOD, superoxide dismutase.

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PART I  Key Critical Care Concepts

1) L-arginine levels (a precursor of NO •); 2) nitric oxide synthase, which catalyzes the reaction of L-arginine to NO •; and 3) the offloading of NO • from the hemoglobin molecule.13 Other proposed mechanisms of hyperoxia-induced vasoconstriction include a reduction in other vasodilators, including prostaglandin, alterations in ATP secretion (which can alter NO • production), and alterations in the morphology of erythrocytes that modulate vasomotor tone.13 In addition, NO•  is released in response to a decrease in oxyhemoglobin saturation; hence, hyperoxia may counteract this response.12 Because of the vasoconstrictive effects, baroreceptors respond by decreasing the heart rate with no change in stroke volume, resulting in a decrease in cardiac output. Additionally, the difference between arterial and venous oxygen content of blood is also reduced due to reduced oxygen consumption.1,2 Therefore, despite hyperoxia, oxygen delivery to cells is actually unchanged.1,2 Deleterious effects of hyperoxia on the cardiovascular system result from the vasoconstrictive effects that lead to decreased perfusion to vital organs, predominantly the myocardium and brain,12 as well as skeletal muscle, retina, and skin.13 Hyperoxic vasoconstriction has some beneficial effects, including its ability to reduce intracranial pressure; counterbalance the vasodilatory effects of septic shock; preserve perfusion to the sublingual, hepato-splanchnic, pulmonary systems; and improve renal circulation in experimental studies.3,2,12,14

Hyperoxia and the Central Nervous System Hyperoxia can result in decreased cerebral blood flow secondary to hypoxic vasoconstriction, though this same vasoconstrictive effect also decreases intracranial pressure.3 Hyperoxia may also lead to increased cerebral excitotoxicity, thus attenuating secondary brain injury.15

HYPEROXIA IN THE CRITICALLY ILL Although oxygen supplementation is often prescribed in the critically ill, hyperoxia has been associated with worse outcomes in critically ill people.1,16-18 Subgroup analysis in various meta-analyses has shown that hyperoxia in postcardiac arrest patients, those that require extracorporeal membrane oxygenation, or those that suffer from ischemic stroke or traumatic brain injury (TBI) is associated with a higher mortality rate.16,17,19

Oxygen Targets in the Mechanically Ventilated Although there is evidence that there is a time- and dose-dependent association of hyperoxia with mortality,20 there is conflicting evidence regarding the outcome when comparing liberal versus conservative (SpO2 targets of 98% vs. 88%) oxygen treatment strategies in the critically ill.18,21,20,22-24 The current recommendation for patients requiring mechanical ventilation is to target a SpO2 of 88%–92% or a PaO2 of 55–80 mm Hg.9

Hyperoxia in Sepsis Hyperoxia in the presence of sepsis can exacerbate the vicious cycle of hyperoxia and inflammation.3 Subgroup analysis of patients with sepsis exposed to hyperoxia in a meta-analysis showed no difference in mortality.17,25 However, one recent randomized controlled trial was terminated upon finding that patients exposed to hyperoxia had a higher risk of mortality and serious adverse events.26

Hyperoxia Following Cardiac Arrest Cardiopulmonary arrest can result in severe hypoxemia and reperfusion injury after return of spontaneous circulation (ROSC).1 Several studies found an association between hyperoxia after ROSC and mortality and worse neurological outcomes, although some studies have

conflicting results.1 The current recommendation is to minimize hyperoxia in postcardiac arrest care.

Hyperoxia in Traumatic Brain Injury Subgroup analysis from a meta-analysis found an increased mortality rate with hyperoxia in people with TBI.16,17,19 However one study demonstrated improved outcome with a combined use of hyperbaric oxygen therapy (HBOT) and normobaric oxygen therapy in patients with TBI.27 At the time of this publication, there has been no clear benefit of hyperbaric or normobaric oxygen therapy for treatment of TBI.

HYPERBARIC OXYGEN THERAPY HBOT is the therapeutic use of pressurized 100% oxygen, above 1.5– 3.0 atmosphere absolute in a closed chamber.28-30 This therapy increases the oxygen content in the blood by increasing PaO2 beyond the saturable oxygen capacity of the hemoglobin molecule. The principle of HBOT is based on the gas laws described in Box 8.3. Dalton’s Law states that in a mixed gas, each element exerts a pressure proportional to its partial pressure.28,29 Boyle’s Law states that the volume of gas decreases as pressure increases. Therefore, as the partial pressure of oxygen in alveoli (PAO2) increases, gas volume decreases, thus allowing more oxygen to enter the alveoli.29 Based on Henry’s Law and Fick’s Law, diffusion of gas occurs from a high to low concentration gradient. Therefore, increasing the PAO2 causes a greater pressure gradient between the alveoli and pulmonary capillary bed, increasing the rate of diffusion.28,29 As hemoglobin becomes completely saturated with oxygen, further diffusion of oxygen into the circulation will increase PaO2. Oxygen unbound to hemoglobin diffuses much more readily into tissues and can provide oxygen in areas that are not accessible to hemoglobin.28,29 Boyle’s Law plays another important role in reducing unwanted volumes of gas in blood and tissues (i.e., treatment of decompression sickness and air embolism).29 HBOT can also have potential antimicrobial, immunomodulatory, angiogenic, and vasoconstrictive effects.29,30 Indications for the use of HBOT in people include treatment of gas embolization, decompression sickness, carbon monoxide toxicity, cyanide toxicity, ischemic or burn injuries, severe crush injuries, gas gangrene, diabetic wounds, radiation injuries, and compartment syndrome.13 Although HBOT has been used for TBI and ischemic brain injury, there is no strong evidence for its use. Complications associated with HBOT include barotrauma, decompression sickness, pulmonary oxygen toxicity, and seizures. Seizures occur secondary to decreased cerebral metabolism, leading to decreased levels of g-aminobutyric acid, an inhibitory neurotransmitter. Another proposed mechanism is the denaturation of DNA secondary to RONS. A recent prospective clinical trial in 230 hyperbaric oxygen treatments in dogs and cats found no major adverse effects and

BOX 8.3  Gas Laws Involved in Hyperbaric

Oxygen Therapy

Dalton’s Law PTotal 5 P1 1 P2 Boyle’s Law P1V1 5 P2V2 Henry’s Law Conc 5 P(sol) Fick’s Law Vgas 5 A/T • D(P1 – P2) D 5 sol/MW A, area; Conc, concentration; D, diffusion constant; MW, molecular weight; P, pressure; sol, solubility; T, thickness; V, volume.

CHAPTER 8  Oxygen Toxicity 76 minor adverse effects of no clinical significance.30 HBOT is contraindicated in patients with pneumothorax; it should be avoided or used with extreme caution in patients with bulla, pulmonary lesions, history of thoracic or ear surgery, pyrexia, pregnancy, or upper respiratory tract infections.

ANTIOXIDANTS Antioxidants include any compound that can delay or prevent the oxidation of a substrate, thus helping to protect cells against oxidative injury.1 They are important in minimizing oxidative injury, DNA mutations, malignant transformation, and cell damage.1 Antioxidant depletion can occur with chronic kidney disease,31 cardiac disease,1,32 hepatic disease,33 diabetes mellitus, neoplasia, and in the critically ill.1 Antioxidants can be classified into three categories: endogenous antioxidant enzymes (superoxide dismutase [SOD], glutathione peroxidase, catalase), endogenous nonenzymatic antioxidant compounds (glutathione, albumin, ferritin, transferrin, ceruloplasmin, haptoglobin, bilirubin, uric acid, coenzyme Q, lipoic acid, vitamin C, vitamin E, glutathione, selenium, lycopene, melatonin), and exogenous antioxidants (vitamin C, vitamin E, beta-carotene, phenolics, acetylcysteine, selenium, zinc).1 The endogenous antioxidant enzymes play an important role in preventing oxidative injury by catalyzing the pathways of oxygen metabolism, therefore minimizing production of intermediate ROS products. SOD production is stimulated by hyperoxia and by inflammatory cytokines such as interferons, tumor necrosis factor, interleukins, and lipopolysaccharides. There are three forms of SOD: extracellular SOD, cytoplasmic SOD containing manganese, and mitochondrial SOD containing copper and zinc. SOD has a very short half-life and is relatively unstable in circulation due to rapid renal excretion. Therefore, therapeutic use has been limited, although there have been recent advances in SOD mimetics. Catalase catalyzes the decomposition of H2O2 to water and oxygen. As with SOD, catalase is found in the extracellular space, cytoplasm, and mitochondria, with particularly high concentrations in the liver and erythrocytes. Glutathione peroxidase contains selenium and scavenges ROS and reactive species formed during lipid peroxidation.1

PREVENTION AND TREATMENT OF OXYGEN TOXICITY It is important to prevent oxygen toxicity by titrating oxygen supplementation to the desired levels of oxygenation, although this value is still debatable. Mild to moderate hypoxemia (PaO2 of 60–80 mm Hg or SpO2 of 90%–95%) may be well tolerated in some patients. When deciding on minimally acceptable oxygen levels, the overall clinical condition of the patient should be considered while considering all determinants of oxygen delivery to the tissues, including cardiac output and hemoglobin concentration of the patient. As antioxidant depletion has been described in some critically ill conditions, it is logical to consider the use of exogenous antioxidant supplementation in critically ill patients at risk of oxidative injury. These supplements include ascorbic acid, vitamin E, N-acetylcysteine, silymarin, and S-adenosylmethionine.1 However, if the balance is reversed to reduce RONS, the vital roles of RONS (i.e., cell signaling) may be inhibited. In addition, exogenous antioxidants may not have the same effects as endogenous antioxidants.2 Currently, there is no evidence for the use of antioxidants in the critically ill. Investigative therapies that might decrease oxidative stress include modulation of protein kinases and transcription factors, as well as

53

manipulation of chemokines, cytokines, growth factors, receptors, and DAMPs, although clinical applications have not yet been described.2 Future advances are likely to change the recommended treatment strategies for the modulation of the inflammatory system.

REFERENCES 1. Pisoschi AM, Pop A: The role of antioxidants in the chemistry of oxidative stress: a review, Eur J Med Chem 97:55-74, 2015. 2. Damiani E, Donati A, Girardis M: Oxygen in the critically ill: friend or foe? Curr Opin Anaesthesiol 31:129-135, 2018. 3. Helmerhorst HJF, Schultz MJ, van der Voort PHJ, et al: Bench-to bedside review: the effects of hyperoxia during critical illness, Crit Care 19: 284-296, 2015. 4. Poff AM, Kernagis D, D’Agostino DP: Hyperbaric environment: oxygen and cellular damage versus protection, Compr Physiol 7:213-234, 2017. 5. McMichael M, Moore R: Ischemia-reperfusion injury pathophysiology, part I, J Vet Emerg Crit Care 14(4):231-241, 2014. 6. Vajdovich P: Free radicals and antioxidants in inflammatory processes and ischemia-reperfusion injury, Vet Clin North Am Small Anim Pract 38:31-123, 2008. 7. Guillaumin J, Gibson RMB, Goy-Thollot I, Bonagura JD: Thrombolysis with tissue plasminogen activator (TPA) in feline acute aortic thromboembolism: a retrospective study of 16 cases, J Feline Med Surg 21(4): 340-346, 2019. 8. Welch KM, Rozanski EA, Freeman LM, Rush JE: Prospective evaluation of tissue plasminogen activator in 11 cats with arterial thromboembolism, J Feline Med Surg 12:122-128, 2010. 9. Pannu SR: Too much oxygen: hyperoxia and oxygen management in mechanically ventilated patients, Semin Respir Crit Care Med 37:16-22, 2016. 10. Patel VS, Sitapara RA, Gore A, et al: High Mobility Group Box-1 mediates hyperoxia-induced impairment of Pseudomonas aeruginosa clearance and inflammatory lung injury in mice, Am J Respir Cell Mol Biol 48(3):269-270, 2013. 11. Kennedy TP, Nelson S: Hyperoxia, HMGB1, and ventilator-associated pneumonia: reducing risk by practicing what we teach, Am J Respir Cell Mol Biol 48(3):269-270, 2013. 12. Brugniaux JV, Coombs GB, Barak OF, et al: Highs and lows of hyperoxia: physiological, performance, and clinical aspects, Am J Physiol Regul Integr Comp Physiol 315:R1-R27, 2018. 13. Sjoberg F, Singer M: The medical use of oxygen: a time for critical reappraisal, J Intern Med 274:505-528, 2013. 14. He X, Su F, Xie K, et al: Should hyperoxia be avoided during sepsis? An experimental study in ovine peritonitis, Crit Care Med 45:e1060-e1067, 2017. 15. Quintard H, Patet C, Suys T, et al: Normobaric hyperoxia is associated with increased cerebral excitotoxicity after severe traumatic brain injury, Neurocrit Care 22:243-250, 2015. 16. Damiani E, Adrario E, Girardis M, et al: Arterial hyperoxia and mortality in critically ill patients: a systematic review and meta-analysis, Crit Care 18:711, 2014. 17. You J, Fan X, Bi X, et al: Association between arterial hyperoxia and mortality in critically ill patients: a systematic review and meta-analysis, J Crit Care 47:260-268, 2018. 18. Helmerhorst HJF, Schultz MJ, van der Voort PH, et al: Effectiveness and clinical outcomes of a two-step implementation of conservative oxygenation targets in critically ill patients: a before and after trial, Crit Care Med 44:554-563, 2016. 19. Ni YN, Wang YM, Liang BM, Liang ZA: The effect of hyperoxia on mortality in critically ill patients: a systematic review and meta analysis, BMC 19:53-66, 2019. 20. Barbateskovic M, Schjorring OL, Krauss SR, et al: Higher versus lower fraction of inspired oxygen or targets of arterial oxygenation for adults admitted to the intensive care unit, Cochrane Database Syst Rev 2019(11):CD012631, 2019.

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21. Girardis M, Busani S, Damiani E, et al: Effect of conservative vs conventional oxygen therapy on mortality among patients in an intensive care unit. The oxygen-ICU randomized clinical trial, JAMA 316(15): 1583-1589, 2016. 22. Suzuki S, Eastwood GM, Goodwin MD, et al: Atelectasis and mechanical ventilation mode during conservative oxygen therapy: a before-and-after study, J Crit Care 30:1232-1237, 2015. 23. Panwar R, Hardie M, Bellomo R, et al: Conservative versus liberal oxygen targets for mechanically ventilated patients – a pilot multicentre randomized controlled trial, Am J Respir Crit Care Med 193:43-51, 2016. 24. Mackle D, Bellomo R, Bailey M, et al: Conservative oxygen therapy during mechanical ventilation in the ICU, N Engl J Med 382:989-998, 2020. 25. Helmerhorst HJF, Arts D, Schultz MJ, et al: Metrics of arterial hyperoxia and associated outcomes in critical care, Crit Care Med 45:187-195, 2017. 26. Asfar P, Schortgen F, Boisrame-Helms J, et al: Hyperoxia and hypertonic saline in patients with septic shock (HYPERS2S): a two-by-two factorial, multicentre, randomised clinical trial, Lancet Respir Med 15:180-190, 2017. 27. Rockswold SB, Rockswold GL, Zaun DA, Liu J: A prospective, randomized Phase II clinical trial to evaluate the effect of combined hyperbaric and

normobaric hyperoxia on cerebral metabolism, intracranial pressure, oxygen toxicity, and clinical outcome in severe traumatic brain injury, J Neurosurg 118:1317-1328, 2013. 28. Poff AM, Kernagis D, D’Agostino DM: Hyperbaric environment: oxygen and cellular damage versus protection, Compr Physiol 7:213-234, 2017. 29. Braswell C, Crowe T: Hyperbaric oxygen therapy, Compend Contin Educ Vet 34(3):E1-5, 2012. 30. Birnie GL, Fry DR, Best MP: Safety and tolerability of hyperbaric oxygen therapy in cats and dogs, J Am Anim Hosp Assoc 54(4):188-194, 2018. 31. Daenen K, Andries A, Mekahli D, et al: Oxidative stress in chronic kidney disease, Pediatr Nephrol 34:975-991, 2019. 32. Genga J, Qiana J, Weijun S, et al: The clinical benefits of perioperative antioxidant vitamin therapy in patients undergoing cardiac surgery: a meta-analysis, Interact Cardiovasc Thorac Surg 25(6):966-974, 2017. 33. Vandeweerd J, Cambier C, Gustin P: Nutraceuticals for canine liver disease: assessing the evidence, Vet Clin Nort Am Small Anim Pract 43: 1171-1179, 2013.

9 The Endothelial Surface Layer Lisa Smart, BVSc, DACVECC, PhD, Deborah C. Silverstein, DVM, DACVECC

KEY POINTS • The endothelial surface layer plays many important roles that are vital to the blood-to-vessel and vessel-to-interstitium interfaces. • Damage or modification of the endothelial surface layer affects vascular permeability, vasomotor tone, inflammation, and coagulation. • Animals with critical illness are at increased risk for endothelial surface layer damage and shedding; organ dysfunction may result from this damage.

• Measurement of circulating endothelial glycocalyx biomarkers and videomicroscopic estimation of the perfused boundary region are commonly used to detect and monitor this damage. • Therapeutic restoration of the endothelial surface layer and repair of the glycocalyx are areas of active investigation.

INTRODUCTION

in the coming years that may alter interventions used in veterinary critical care medicine.

The endothelial surface layer (ESL) on the luminal side of blood vessels comprises a gel-like glycocalyx with an immobile plasma layer. The ESL plays many important roles in the blood-to-blood vessel and vessel-to-interstitium interfaces, for example, modulating inflammation, coagulation, vasomotor tone, and vessel wall permeability. There has been a large amount of research in this area in the last 10 to 15 years, most of which cannot be covered in detail in this chapter. Instead, this chapter reviews broad concepts of the ESL, with references to detailed, or focused, reviews or key studies provided as examples. Two terms are frequently used throughout this chapter: ESL and the endothelial glycocalyx (EG). The ESL refers to the entire endothelial layer itself, whereas the EG refers to only the glycocalyx structure within the ESL. This difference is subtle but important to distinguish.

THE IMPORTANCE OF THE ESL IN CRITICAL ILLNESS Damage or modification of the ESL affects vascular permeability, vasomotor tone, inflammation, and coagulation. A better understanding of the barrier role of the ESL has led to modification of the traditional Starling hypothesis for fluid movement. This has had a particular impact on our understanding of fluid distribution and fueled the debate on ideal fluid types for fluid resuscitation. It is well established that critical illness, especially illness involving a systemic inflammatory response or ischemia, causes shedding of the ESL. This may increase the risk of interstitial edema, propagation of inflammation, and thrombosis and decrease vasomotor function. Interventions common in the intensive care unit have also been shown to modify the ESL, such as rapid intravenous fluid administration. It is not yet known if protecting the ESL by modifying our treatment approaches, or using interventions specifically to repair the ESL, affects clinical outcome. However, it is prudent to be aware of the pathophysiological consequences of endothelial damage and dysfunction. This is a burgeoning area of research in critical care medicine, and new therapies are likely to emerge

STRUCTURE AND FUNCTION The ESL has been an elusive structure that is hard to visualize or preserve. Traditional preparation of the endothelium for high-resolution microscopy reveals only bare luminal surfaces. More recent methods for preserving this delicate structure of the ESL in situ have revealed a furry or fuzzy layer of varying thickness (Fig. 9.1).1 Further developments in real-time in vivo microscopy techniques have revealed two areas of the intravascular space: a central column of traveling red blood cells, white blood cells, and an immobile perimeter of cell-free plasma (Fig. 9.2). This outer perimeter is the domain of the ESL. At a systemic level, the volume of plasma residing in this cell-free space has been estimated to be 15% of circulating plasma volume.2 The measured thickness of the ESL varies with location and imaging technique. Our understanding of the structures within the ESL has developed over time. Most methods for discovery have relied on first culturing endothelial cells in vitro, then labeling certain molecules to detect their presence or absence. This has revealed a forest-like structure of proteoglycans and attached glycosaminoglycan chains (Fig. 9.3). These individual elements of the ESL have been reviewed in detail elsewhere.3-5 Briefly, the proteoglycans include syndecans and glypican-1, with sulfated glycosaminoglycan chains extending from their intraluminal segments, or ectodomains. The sulfated glycosaminoglycans include heparan, chondroitin, and dermatan sulfate; the first of these is the most abundant. Hyaluronan, a long glycosaminoglycan chain, weaves its way along the forest floor directly attached to the endothelium or associated with chondroitin sulfate. Moving within this basic structure are proteins such as albumin, uromucoids and anticoagulants, and phospholipids, such as sphingosine-1 phosphate. The presence of these additional molecules within the EG structure is thought to be important for maintaining ESL thickness and barrier function. The ESL provides a barrier to the interstitial tissues through the physical nature of the gel-like layer (preventing adhesion, rolling or

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Fig. 9.1  ​The endothelial glycocalyx stained with Alcian blue 8GX and visualized with electron microscopy. The Alcian blue stains the glycosaminoglycans since they are acidic polysaccharides.1

A

B

Median RBC column width

PBR

PBR

Perturbed ESL

PBR

Healthy ESL

PBR

56

Median RBC column width

Fig. 9.2  ​Sidestream darkfield (SDF) imaging to measure the perfused boundary region (PBR) in the sublingual capillary bed. A, Recordings from the sublingual capillary bed made with the SDF camera (left). Capillaries are automatically recognized and analyzed after various quality checks (right). Based on the shift in red blood cell (RBC) column width in time, the PBR can be calculated. B, Model of a blood vessel showing the PBR in a healthy situation (left). The endothelial glycocalyx (EG) prevents the RBC from approaching the endothelial cell; thus, a small PBR is measured. In a disease situation (right) or after enzymatic EG breakdown in an animal model, the damaged EG allows the RBCs to approach the endothelium more often. This results in a higher variation in RBC column width reflected by a high PBR.1 ESL, endothelial surface layer.

CHAPTER 9  The Endothelial Surface Layer

57

Endothelial surface layer

Flowing plasma

Immobile plasma

Endothelial cell

Interstitium KEY Syndecan

Glypican-1

CD44 (green) and hyaluronan (orange)

Heparan sulfate

Chondroitin sulfate

Albumin

Fig. 9.3  ​Basic structure of the endothelial surface layer. The scaffold of the endothelial glycocalyx, within the endothelial surface layer, is provided by proteoglycans: syndecans (four subtypes) and glypican-1. Glycosaminoglycans are attached to proteoglycans (e.g., heparan sulfate) or the endothelial surface (hyaluronan). Molecules suspended in the plasma of the endothelial surface layer include proteins such as albumin. These proteins create a protein-poor subglycocalyx area that is important for transvascular colloid osmotic pressure balance. For simplicity, structures within the interendothelial cleft are not represented. (Reproduced with permission from Smart L, Hughes D: The effects of resuscitative fluid therapy on the endothelial surface layer, Front Vet Sci 8:661660, 2021. doi: 10.3389/fvets.2021.661660)

migration of large cells such as white blood cells), maintaining an electrostatic charge (repelling positively charged ions), and having a relatively protein-free fluid space (thereby creating an oncotic pressure gradient favoring intravascular fluid retention) between the clefts of the endothelial cells.6 It also contains anticoagulants, such as antithrombin and tissue factor pathway inhibitor, discouraging thrombosis of the endothelium.3,7 Other roles include detection of changes in shear stress and modulation vasomotor tone. For example, removal of glycosaminoglycans leads to loss of shear-induced nitric oxide production, which would normally cause compensatory vasodilation.5

FLUID MOVEMENT ACROSS THE ENDOTHELIUM One of the pivotal roles of the ESL that is currently under investigation is its influence on transvascular fluid flux (see also Chapter 11, Interstitial Edema). Recent developments in this area have led to some researchers challenging the traditional Starling principle for fluid movement (see Chapter 185, Colloid Osmotic Pressure and Osmolality Monitoring).8,9 The original concept was that the direction of fluid movement was determined by the balance of hydrostatic pressure and colloid osmotic pressure (COP) between the vascular space and interstitium.10 Added factors

include the reflection coefficient and permeability of the blood vessel concerned. In the revised Starling principle, based on controlled benchtop experiments, the opposing forces of COP belong to the intravascular space and the protein-poor subglycocalyx space.8,9,11 This means that interstitial proteins have little influence on transvascular fluid movement, as previously described in the classic Starling principle. The revised theory states that fluid is never reabsorbed into capillaries except during an acute, large decrease in intravascular hydrostatic pressure, and that this reversal is very brief before net filtration of fluid is reestablished. The period of fluid resorption is brief as proteins back diffuse into the subglycocalyx space, increasing the subglycocalyx COP, and reducing the influence of the COP gradient between the capillary and the subglycocalyx space. This new principle challenges the concept that fluid can be reabsorbed, including after infusion of hyperoncotic fluids, except for this brief deviation during extreme hypotension. However, some authors have challenged this new Starling principle, as the “no absorption rule” is not consistent with clinical experience.12 There is still much to be elucidated for in vivo fluid dynamics, including transvascular fluid flux in the presence of a denuded, ESL-free endothelium. This question is highly relevant to patients with critical illness that likely experience shedding or modification of the ESL.

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SHEDDING OF THE ESL The ESL is shed, modified, or compacted by many factors relevant to critical care, which includes tissue trauma, inflammation, hyperglycemia, hemodilution, and hypervolemia.13,14 Inflammatory cytokines have a direct shedding effect on the ESL, which allows for exposure of adhesion receptors and margination of leukocytes into tissue.15 This is an adaptive response to local inflammation but can become, presumably, maladaptive in critical illness. Inflammatory cytokines also upregulate components of the EG within the ESL, which may lead to increased turnover and, subsequently, increased circulating concentrations of these molecules.16-18 Increased turnover becomes relevant when interpreting EG biomarker concentrations in clinical studies (discussed further below). Shedding of the ESL by mechanisms other than inflammation can also stimulate inflammation. For example, enzymatic removal of the EG leads to increased leucocyte adhesion and inflammatory cytokine production,19-21 and some components of the EG that are released into circulation, such as soluble heparan sulfate and low molecular weight hyaluronan, can also stimulate inflammation.22,23 Other conditions related to severe inflammation, such as ischemia– reperfusion injury and oxidative stress, can also cause shedding of the EG.24,25 Also relevant to any severe inflammatory process is the effect of coagulation proteins on the EG. Both thrombin and plasmin, which are increased in severe inflammation, have been shown to cleave syndecan ectodomains from endothelial cells.26 Relevant to sepsis, or any process that causes bacteremia, is the effect of bacterial fragments on the ESL. Lipopolysaccharide, contained within the wall of Gramnegative bacteria, not only accelerates shedding of syndecans but also upregulates their expression on endothelium.27,28 Another example is the bacterial peptide formylmethionyl-leucyl-phenylalanine, which has been shown to shed glycosaminoglycans from the EG.25 Mild hyperglycemia due to critical illness, or stress hyperglycemia, is another common condition in the small animal intensive care unit.29 Given the evidence of ESL thinning in people with diabetes mellitus, several studies have investigated the direct impact of glucose on the shedding of the ESL. In healthy human volunteers who had hyperglycemia induced to ∼288 mg/dl (16 mmol/L), there was reduced estimated ESL volume, increased plasma hyaluronan concentration, and decreased flow-mediated dilation, a measurement of endothelial function.30 Shedding of the EG after the addition of glucose has also been shown in an endothelial cell culture model, which mimicked clinically relevant hyperglycemic conditions of 200 mg/dl (11 mmol/L).31 Therefore, the presence of hyperglycemia in critically ill animals, especially those with diabetes mellitus, may contribute to ESL shedding, and subsequently a proinflammatory and procoagulative state. Resuscitation fluid therapy can cause ESL shedding by several proposed mechanisms, including dilution of plasma proteins and secretion of natriuretic peptides. These proposed mechanisms have been reviewed in detail elsewhere.32 Plasma proteins have a stabilizing effect on the ESL, therefore dilution of plasma proteins with crystalloid fluid likely causes ESL shedding. Rodent models have shown that infusion of albumin solution or plasma maintains the ESL better than infusion of a clear fluid, such as a crystalloid.33,34 Rapid infusion of large volumes of crystalloid fluid may also lead to natriuretic peptide release, due to the stretch of cardiac chambers. Natriuretic peptides have a direct shedding effect on the ESL35 and have been shown to rise in concert with biomarkers of EG shedding after fluid administration in people.36,37 A canine hemorrhagic shock model was unable to demonstrate this relationship; however, small sample size or assay sensitivity may have precluded being able to detect significant changes in atrial natriuretic peptide.38

The consequences of ESL shedding may include worsening inflammation, promotion of coagulation, an increase in endothelial permeability, and interference with the normal regulation of vasomotor tone. It may also contribute to microcirculatory dysfunction or lack of hemodynamic coherence, whereby improvement of macrohemodynamics does not improve microcirculatory flow.39 This family of problems is well recognized in patients with a systemic inflammatory response, especially in those with sepsis, and is likely on the pathophysiological continuum to multiple organ dysfunction. Measures of ESL shedding in critically ill people, such as those with sepsis or severe traumatic injury, have been associated with increased severity of illness and worse clinical outcome. Other illnesses relevant to critical care that have been associated with increased EG biomarkers are reviewed in detail elsewhere.13 There has been a bevy of research in this area in the last decade identifying these biomarkers, investigating their prognostic ability, and using these biomarkers to assess the effect of interventions on the ESL.

METHODS FOR DETECTION OF ESL SHEDDING The two most frequently used methods for detecting ESL shedding in clinical studies are measurement of circulating EG biomarkers and videomicroscopic estimation of the perfused boundary region (PBR). Shedding of the ESL releases both glycosaminoglycans (e.g., hyaluronan) and proteoglycan ectodomains (e.g., syndecan-1) into circulation, which can be measured in the plasma or serum by a range of laboratory techniques. There are some limitations to the use of EG biomarkers for quantifying ESL shedding. The first limitation is that there may be other sources of these biomarkers in critical illness.14 The elements are not unique to the EG; they are present on all cells in the body to varying degrees. Some of these molecules are also present throughout the interstitium, especially hyaluronan, which may be flushed into circulation via lymphatic flow after intravenous fluid therapy. Second, it is known that some EG biomarkers are upregulated on the surface of the endothelium in response to changes within the blood, such as inflammation. Third, measurement of these biomarkers relies on research-grade assays that may have varying sensitivity and reproducibility. Finally, there is a limitation of validated commercial assays for measurement of these biomarkers in dogs and cats, with hyaluronan currently being the only known exception. The direct relationship between increased biomarkers of ESL shedding, thinning of the ESL, and endothelial dysfunction in the clinical setting requires further research. The second potential method used for detection of ESL damage is measurement of the PBR using sidestream darkfield imaging (SDF) with specialized software for bedside evaluation. This technique uses videomicroscopy to determine lateral red blood cell movement within the vessels (the PBR) of the microcirculation (diameter 5–25 µm). The PBR is normally regulated by the ESL barrier to maintain separation from the RBCs (Fig. 9.2).39 When the ESL is damaged or thinned, the RBCs penetrate more deeply towards the endothelium and the PBR increases. Studies in people have found that critical illness results in a thinner ESL, as measured by SDF microscopy.40 Experimental animal models have also used this technique to quantify the effect of certain diseases and therapeutic interventions on ESL thickness.41 Use of SDF microscopy for estimation of the ESL in dogs and cats is still in the early stages; however, reference values for healthy dogs and cats have been published in abstract form42,43 and continued research is underway. These studies have laid the groundwork for an additional study evaluating the jejunal microvasculature of healthy dogs44 and another study in healthy cats examining the effect of a single bolus of isotonic crystalloids

CHAPTER 9  The Endothelial Surface Layer or synthetic colloids on the PBR; there were no significant differences compared with controls (abstract only).45 Further studies in critically ill animals are warranted, although the need for general anesthesia limits the clinical application of this technology.

ESL SHEDDING IN DOGS AND CATS Two studies in dogs comparing fluid therapy strategies have measured hyaluronan concentration as a marker of ESL shedding. In an atraumatic hemorrhagic shock model, dogs received either 80 ml/kg of balanced isotonic crystalloid, or 20 ml/kg of either fresh whole blood, 4% succinylated gelatin or low molecular weight hydroxyethyl starch (n 5 6 per group), given intravenously over 20 minutes.38 Although hyaluronan concentration increased at various time points in all four groups after fluid resuscitation, the most marked changes were after crystalloid or gelatin fluid. The group that received crystalloid fluid also had significantly greater inflammatory biomarker concentrations after fluid resuscitation. In a study comparing healthy dogs that received an intraoperative infusion of 5 ml/kg/hr or 10 ml/kg/hr of lactated Ringer’s solution (n 5 19 per group), there was a significant rise in plasma hyaluronan concentration at the end of fluid therapy, compared with at induction of anesthesia, for both groups.46 However, there was no significant difference between groups. Several abstracts have been published assessing markers of ESL shedding in critically ill small animals: three in dogs, one in cats. In dogs with sepsis and multiple organ dysfunction (n 5 18), serum hyaluronan concentration was significantly higher than healthy controls (n 5 20), as were concentrations of other endothelial activation biomarkers.47 In 8 dogs with septic peritonitis, serum hyaluronan concentration was associated with serum interleukin-6 concentration and daily intravenous fluid volume.48 In 27 dogs meeting systemic inflammatory response syndrome (SIRS) criteria, only 5 had detectable serum concentrations of canine syndecan-1, compared with none of the 20 healthy dogs.49 A human syndecan-1 kit was also trialed with a subset of these dogs, and higher concentrations in dogs with SIRS than healthy dogs were found. There was no significant difference in serum hyaluronan concentration between dogs with SIRS and healthy dogs. Finally, PBR was estimated in 30 cats that received 10 ml/kg of either lactated Ringer’s solution or hydroxyethyl starch, or no fluid, under propofol anesthesia.45 No significant difference was detected either between groups or over time.

PROTECTION OF THE ESL IN DISEASE Therapeutic restoration of the ESL and repair of the glycocalyx are areas of active investigation. Numerous potential agents have been shown to ameliorate vascular leak, decrease markers of glycocalyx degradation, and improve survival in experimental animal models of disease. In addition to albumin and plasma administration as mentioned above, additional promising future treatments include disintegrin and metalloprotease 17 inhibitor,50 sphingosine-1 phosphate,51 heparin,52 intravenous hyaluronan, chondroitin sulfate, and sulodexide,53 among others. Changes to fluid therapy strategies, such as limiting crystalloid fluid volume and slowing down fluid administration, may also be useful for mitigating ESL shedding;32 however, this needs further investigation.

CONCLUSION There is strong evidence from benchtop and laboratory animal research that conditions of critical illness cause shedding of the ESL, which in turn has pathophysiological consequences that likely contribute to organ dysfunction. Clinical evidence from human critical care

59

has demonstrated a relationship between biomarkers of EG shedding and severity of illness; however, this research is still in the early stages and causal relationships have not been confirmed. There are still several limitations of the ability to assess ESL shedding in veterinary medicine. As research progresses in this field, changes to critical care interventions to provide better protection or repair of the ESL are likely to emerge.

REFERENCES 1. Dane MJ, van den Berg BM, Lee DH, et al: A microscopic view on the renal endothelial glycocalyx, Am J Physiol Renal Physiol 308:F956-F966, 2015. 2. Hahn RG: Water content of the endothelial glycocalyx layer estimated by volume kinetic analysis, Intensive Care Med Exp 8:29, 2020. 3. Reitsma S, Slaaf DW, Vink H, van Zandvoort MA, oude Egbrink MG: The endothelial glycocalyx: composition, functions, and visualization, Pflugers Arch 454:345-359, 2007. 4. Zeng Y, Zhang XF, Fu BM, Tarbell JM: The role of endothelial surface glycocalyx in mechanosensing and transduction, Adv Exp Med Biol 1097:1-27, 2018. 5. Tarbell JM, Simon SI, Curry FR: Mechanosensing at the vascular interface, Annu Rev Biomed Eng 16:505-532, 2014. 6. Becker BF, Chappell D, Jacob M: Endothelial glycocalyx and coronary vascular permeability: the fringe benefit, Basic Res Cardiol 105:687-701, 2010. 7. Bashandy GM: Implications of recent accumulating knowledge about endothelial glycocalyx on anesthetic management, J Anesth 29:269-278, 2015. 8. Levick JR, Michel CC: Microvascular fluid exchange and the revised Starling principle, Cardiovas Res 87:198-210, 2010. 9. Woodcock TE, Woodcock TM: Revised Starling equation and the glycocalyx model of transvascular fluid exchange: an improved paradigm for prescribing intravenous fluid therapy, Br J Anaesth 108:384-394, 2012. 10. Starling EH: On the absorption of fluids from the connective tissue spaces, J Physiol 19:312-326, 1896. 11. Weinbaum S, Cancel LM, Fu BM, Tarbell JM: The glycocalyx and its role in vascular physiology and vascular related diseases, Cardiovasc Eng Technol 12(1):37-71, 2021. 12. Hahn RG, Dull RO, Zdolsek J: The Extended Starling principle needs clinical validation, Acta Anaesthesiol Scand 64:884-887, 2020. 13. Gaudette S, Hughes D, Boller M: The endothelial glycocalyx: structure and function in health and critical illness, J Vet Emerg Crit Care 30:117-134, 2020. 14. Smart L: Endothelial glycocalyx biomarkers in sepsis and trauma: associations with inflammation, organ failure and fluid bolus therapy, Dissertation, 2020, University of Western Australia. 15. Lipowsky HH: The endothelial glycocalyx as a barrier to leukocyte adhesion and its mediation by extracellular proteases, Ann Biomed Eng 40: 840-848, 2012. 16. Ramnath R, Foster RR, Qiu Y, et al: Matrix metalloproteinase 9-mediated shedding of syndecan 4 in response to tumor necrosis factor alpha: a contributor to endothelial cell glycocalyx dysfunction, FASEB J 28:4686-4699, 2014. 17. Rops AL, van den Hoven MJ, Baselmans MM, et al: Heparan sulfate domains on cultured activated glomerular endothelial cells mediate leukocyte trafficking, Kidney Int 73:52-62, 2008. 18. Klein NJ, Shennan GI, Heyderman RS, Levin M: Alteration in glycosaminoglycan metabolism and surface charge on human umbilical vein endothelial cells induced by cytokines, endotoxin and neutrophils, J Cell Sci 102(Pt 4):821-832, 1992. 19. McDonald KK, Cooper S, Danielzak L, Leask RL: Glycocalyx degradation induces a proinflammatory phenotype and increased leukocyte adhesion in cultured endothelial cells under flow, PLoS One 11:e0167576, 2016. 20. Lygizos MI, Yang Y, Altmann CJ, et al: Heparanase mediates renal dysfunction during early sepsis in mice, Physiol Rep 1:e00153, 2013.

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21. Constantinescu AA, Vink H, Spaan JA: Endothelial cell glycocalyx modulates immobilization of leukocytes at the endothelial surface, Arterioscler Thromb Vasc Biol 23:1541-1547, 2003. 22. Wrenshall LE, Stevens RB, Cerra FB, Platt JL: Modulation of macrophage and B cell function by glycosaminoglycans, J Leuk Biol 66:391-400, 1999. 23. Scheibner KA, Lutz MA, Boodoo S, Fenton MJ, Powell JD, Horton MR: Hyaluronan fragments act as an endogenous danger signal by engaging TLR2, J Immunol 177:1272-1281, 2006. 24. Kurzelewski M, Czarnowska E, Beresewicz A: Superoxide- and nitric oxidederived species mediate endothelial dysfunction, endothelial glycocalyx disruption, and enhanced neutrophil adhesion in the post-ischemic guinea-pig heart, J Physiol Pharmacol 56:163-178, 2005. 25. Mulivor AW, Lipowsky HH: Inflammation- and ischemia-induced shedding of venular glycocalyx, Am J Physiol Heart Circ Physiol 286:H1672H1680, 2004. 26. Schmidt A, Echtermeyer F, Alozie A, Brands K, Buddecke E: Plasmin- and thrombin-accelerated shedding of syndecan-4 ectodomain generates cleavage sites at Lys(114)-Arg(115) and Lys(129)-Val(130) bonds, J Biol Chem 280:34441-34446, 2005. 27. Strand ME, Aronsen JM, Braathen B, et al: Shedding of syndecan-4 promotes immune cell recruitment and mitigates cardiac dysfunction after lipopolysaccharide challenge in mice, J Mol Cell Cardiol 88:133-144, 2015. 28. Strand ME, Herum KM, Rana ZA, et al: Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan-4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure-overloaded heart, FEBS J 280:2228-2247, 2013. 29. Torre DM, deLaforcade AM, Chan DL: Incidence and clinical relevance of hyperglycemia in critically ill dogs, J Vet Intern Med 21:971-975, 2007. 30. Nieuwdorp M, van Haeften TW, Gouverneur MC, et al: Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo, Diabetes 55:480-486, 2006. 31. Diebel LN, Diebel ME, Martin JV, Liberati DM: Acute hyperglycemia exacerbates trauma-induced endothelial and glycocalyx injury: an in vitro model, J Trauma Acute Care Surg 85:960-967, 2018. 32. Smart L, Hughes D: The effects of resuscitative fluid therapy on the endothelial surface layer, Front Vet Sci 8:661660, 2021. Available at: https://doi. org/10.3389/fvets.2021.661660. 33. Torres LN, Sondeen JL, Dubick MA, Filho IT: Systemic and microvascular effects of resuscitation with blood products after severe hemorrhage in rats, J Trauma Acute Care Surg 77:716-723, 2014. 34. Torres Filho IP, Torres LN, Salgado C, Dubick MA: Plasma syndecan-1 and heparan sulfate correlate with microvascular glycocalyx degradation in hemorrhaged rats after different resuscitation fluids, Am J Physiol Heart Circ Physiol 310:H1468-H1478, 2016. 35. Jacob M, Saller T, Chappell D, Rehm M, Welsch U, Becker BF: Physiological levels of A-, B- and C-type natriuretic peptide shed the endothelial glycocalyx and enhance vascular permeability, Basic Res Cardiol 108:347, 2013. 36. Chappell D, Bruegger D, Potzel J, et al: Hypervolemia increases release of atrial natriuretic peptide and shedding of the endothelial glycocalyx, Crit Care 18:538, 2014.

37. Belavic´ M, Sotošek Tokmadžic´ V, Fišic´ E, et al: The effect of various doses of infusion solutions on the endothelial glycocalyx layer in laparoscopic cholecystectomy patients, Minerva Anestesiol 84:1032-1043, 2018. 38. Smart L, Boyd CJ, Claus MA, Bosio E, Hosgood G, Raisis A: Large-volume crystalloid fluid is associated with increased hyaluronan shedding and inflammation in a canine hemorrhagic shock model, Inflammation 41:1515-1523, 2018. 39. Lee DH, Dane MJ, van den Berg BM, et al: Deeper penetration of erythrocytes into the endothelial glycocalyx is associated with impaired microvascular perfusion, PLoS One 9:e96477, 2014. 40. Donati A, Damiani E, Domizi R, et al: Alteration of the sublingual microvascular glycocalyx in critically ill patients, Microvasc Res 90:86-89, 2013. 41. Cui N, Wang H, Long Y, Su L, Liu D: Dexamethasone suppressed LPSinduced matrix metalloproteinase and its effect on endothelial glycocalyx shedding, Mediators Inflamm 2015:912726, 2015. 42. Londono L, Bowen CM, Buckley GJ: Evaluation of the endothelial glycocalyx in healthy anesthetized dogs using rapid, patient-side GlycoCheck analysis software, J Vet Emerg Crit Care 28:S7, 2018. 43. Millar KK, Yozova Y, Londono L, Monday JS, Thomson N, Sano H: Evaluation of the endothelial glycocalyx in healthy anesthetized cats using rapid, patient-side GlycoCheck analysis software, J Vet Emerg Crit Care 29:S11, 2019. 44. Mullen KM, Regier PJ, Londono L, Millar KK, Groover J: Evaluation of jejunal microvasculature of healthy anaesthetized dogs with sidestream dark field video microscopy, Am J Vet Res 81:888-893, 2020. 45. Yozova ID, Londono L, Sano H, Thomson N, Munday J, Cave N: Assessment of the endothelial glycocalyx after a fluid bolus in healthy anesthetized cats using rapid, patient-side GlycoCheck analysis software, J Vet Emerg Crit Care 30:S27, 2020. 46. Beiseigel M, Simon BT, Michalak C, Stickney MJ, Jeffery U: Effect of perioperative crystalloid fluid rate on circulating hyaluronan in healthy dogs: a pilot study, Vet J 267:105578, 2021. 47. Gaudette S, Smart L, Hughes D, et al: Biomarkers of endothelial activation are increased in dogs with severe sepsis, J Vet Emerg Crit Care 28:S14, 2018. 48. Shaw K, Bersenas A, Bateman S, Blois S, Guieu LV, Wood R: Evaluation of hyaluronic acid as a marker of glycocalyx degradation in dogs with septic peritonitis, J Vet Emerg Crit Care 30:S33, 2020. 49. Briganti A, Di Franco C, Meucci V: Endovascular shedding markers in critically ill patients, J Vet Emerg Crit Care 29:S36, 2019. 50. Palau V, Riera M, Soler MJ: ADAM17 inhibition may exert a protective effect on COVID-19, Nephrol Dial Transplant 35:1071-1072, 2020. 51. Zeng Y, Adamson RH, Curry FR, Tarbell JM: Sphingosine-1-phosphate protects endothelial glycocalyx by inhibiting syndecan-1 shedding, Am J Physiol Heart Circ Physiol 306:H363-H372, 2014. 52. Yini S, Heng Z, Xin A, Xiaochun M: Effect of unfractionated heparin on endothelial glycocalyx in a septic shock model, Acta Anaesthesiol Scand 59:160-169, 2015. 53. Song JW, Zullo JA, Liveris D, Dragovich M, Zhang XF, Goligorsky MS: Therapeutic restoration of endothelial glycocalyx in sepsis, J Pharmacol Exp Ther 361(1):115-121, 2017.

10 Hyperthermia and Fever James B. Miller, DVM, MS, DACVIM KEY POINTS • Thermoregulation is controlled by the preoptic region of the hypothalamus. It responds to thermoreceptors in the brain and peripheral nervous system to maintain a narrow range of body temperature by increasing or decreasing heat production or loss. • Hyperthermia describes any elevation in core body temperature above accepted normal values. • A true fever is the body’s normal response to infection, inflammation, or injury and is part of the acute-phase response. It is controlled by the thermoregulatory center in the hypothalamus. • Other forms of hyperthermia are a result of an imbalance between heat production and heat loss. Nonfebrile hyperthermic patients are approached differently from those with a fever, both diagnostically and therapeutically. • A fever may be beneficial to the host by decreasing bacterial growth and inhibiting viral replication. Most fevers and other forms of hyperthermia are not a threat to life unless body temperature exceeds 107°F (41.6°C).

• A fever will increase water and caloric requirements, and this must be considered when treating the febrile patient. • In most cases an accurate diagnosis should be obtained before initiating nonspecific therapy for a fever unless the fever exceeds 107°F (41.6°C). • Nonsteroidal antiinflammatory drugs and glucocorticoids will reduce a fever, but the latter will also block the acute-phase inflammatory response. • Total body cooling may be counterproductive and is usually reserved for afebrile hyperthermia or when fevers approach 107°F (41.6°C). • Antimicrobial therapy should not be used empirically for fever management unless there is a documented or strongly suspected indication of infection. Treatment should be based on culture and susceptibility testing, as indicated.

Obtaining a body temperature measurement is important in the evaluation of all patients, especially the critically ill patient. A rectal temperature higher than 102.5°F (39.2°C) is considered elevated in the unstressed dog or cat. The method of measurement must also be taken into account because ear, axillary, or toe web measurements will be lower than rectal temperatures. An intravascular thermistor is considered the most accurate but is usually impractical in the clinical setting. It is tempting for the veterinarian to associate any elevation in body temperature with true fever. The assumption is often made that the fever is caused by an infectious agent, even if there is no obvious cause. If the patient’s fever resolves after antimicrobials are administered, the assumption is made that it was caused by a bacterial infection. A normal body temperature is often assumed to indicate the absence of infectious disease. This approach to fever, hyperthermia, or normothermia can be misleading and result in inaccurate diagnoses and inappropriate, or even lack of, therapy. In one French study, almost half the 50 febrile dogs that were retrospectively examined had a noninfectious cause for the increased body temperature.1 This is less than human ICU patients where up to 70% are due to sepsis.2

Changes in ambient and core body temperatures are sensed by the peripheral and central thermoreceptors, and information is conveyed to the AH via the nervous system. The thermoreceptors sense that the body is below or above its normal temperature (set point) and subsequently cause the AH to stimulate the body to increase heat production and reduce heat loss through conservation if the body is too cold or to dissipate heat if the body is too warm (Fig. 10.1). Through these mechanisms, the dog and cat can maintain a narrow core body temperature range in a wide variety of environmental conditions and activity levels. With normal ambient temperatures, most body heat is produced by muscular activity, even while at rest. Cachectic or anesthetized patients, or those with severe neurologic impairment, may not be able to maintain a normal set point or generate a normal response to changes in core body temperature. Neonatal dogs and cats have a poorly developed thermoregulatory center and lack significant muscle mass. They require higher ambient temperatures to maintain normal body temperature.

THERMOREGULATION

Hyperthermia is the term used to describe any elevation in core body temperature above the accepted normal range for that species. When heat is produced or stored in the body at a rate greater than it is lost, hyperthermia results.4 The term fever is reserved for those hyperthermic animals in whom the set point in the AH has been reset to a higher temperature. In hyperthermic states other than fever, temperature elevation is not a result of the body attempting to raise its temperature

Thermoregulation is the balance between heat loss and heat production. Metabolic, physiologic, and behavioral mechanisms are used by homeotherms to regulate heat loss and production. The thermoregulatory control center for the body is located in the central nervous system in the preoptic area of the anterior hypothalamus (AH).3

HYPERTHERMIA

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Anterior hypothalamic area of the brain

Monoamines

Cutaneous and deep receptors

Heat gain mechanisms

Increased production Decreased loss Catecholamines Vasoconstriction Thyroxine Piloerection Shivering Postural changes Seeking warm environment

Heat loss mechanisms Panting Vasodilation Postural changes Seeking cool environment Perspiration Grooming (cat)

Fig. 10.1  Schematic representation of normal thermoregulation. (From Miller JB: Hyperthermia and fever of unknown origin. In Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal medicine, ed 7, St Louis, 2010, Saunders.)

but is due to the physiologic, pathologic, or pharmacologic changes that cause heat gain to exceed heat loss. Box 10.1 outlines the various classifications of hyperthermia.

TRUE FEVER True fever is the normal response of the body to invasion or injury and is part of the acute-phase response.5 Other parts of the acute-phase response include increased neutrophil numbers and phagocytic ability, enhanced T and B lymphocyte activity, increased acute-phase protein production by the liver, increased fibroblast activity, and increased sleep. Fever and other parts of the acute-phase response are initiated by exogenous pyrogens that lead to the release of endogenous pyrogens (Fig. 10.2).6

Exogenous Pyrogens True fever may be initiated by a variety of substances, including infectious agents or their products, immune complex formation, tissue inflammation or necrosis, and several pharmacologic agents. Collectively, these substances are called exogenous pyrogens. Their ability to directly affect the thermoregulatory center is probably minimal and they primarily cause the release of endogenous pyrogens by the host. Box 10.2 lists some of the more important known exogenous pyrogens.

Endogenous Pyrogens In response to stimulation by an exogenous pyrogen, proteins (cytokines) released from cells of the immune system trigger the febrile response. Macrophages are the primary immune cells involved, although T and B lymphocytes and other leukocytes may play significant roles. The proteins produced are called endogenous pyrogens or fever-producing cytokines. Although interleukin 1, interleukin 6, and tumor necrosis factor-a are considered the most important fever-producing cytokines, at least 11 cytokines are capable of initiating a febrile response (Table 10.1). Some neoplastic cells are also capable of producing cytokines that lead to a febrile response. The cytokines travel via the bloodstream to the AH, where they bind to the vascular endothelial cells within the AH

BOX 10.1  Classification of Hyperthermia True Fever Production of endogenous pyrogens Inadequate Heat Dissipation Heat stroke Hyperpyrexic syndromes Exercise-Induced Hyperthermia Normal exercise Hypocalcemic tetany (eclampsia) Seizure disorders Pathologic or Pharmacologic Origin Lesions in or around the anterior hypothalamus Malignant hyperthermia Hypermetabolic disorders Monoamine metabolism disturbances From Miller JB: Hyperthermia and fever of unknown origin. In Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal medicine, ed 7, St Louis, 2010, Saunders.

and stimulate the release of prostaglandins (PGs), primarily PGE2 and possibly PGF2a.7,8 The set point is raised, and the core body temperature rises through increased heat production and conservation. The body also produces cytokines in response to insult or injury that are cytoprotective with increased body temperature. They are called heat shock proteins and provide protection against a variety of insults, including heat.2

INADEQUATE HEAT DISSIPATION Heat Stroke Heat stroke is a common result of inadequate heat dissipation (see Chapter 139, Heat Stroke). Exposure to high ambient temperatures

CHAPTER 10  Hyperthermia and Fever

63

Fever Increased “set point” Anterior hypothalamus (Chemical mediators−−prostaglandins) Circulation Neoplastic cell

Endogenous pyrogen (IL-1, others) Activated immune cell

Exogenous pyrogen

Immune cell (macrophage, lymphocytes)

Fig. 10.2  Schematic representation of the pathophysiology of fever. IL-1, interleukin 1.  (From Miller JB: Hyperthermia and fever of unknown origin. In Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal medicine, ed 10, St Louis, 2010, Saunders.)

BOX 10.2  Exogenous Pyrogens Infectious Agents Bacteria (Live and Killed) Gram positive Gram negative Bacterial Products Lipopolysaccharides Streptococcal exotoxin Staphylococcal enterotoxin Staphylococcal proteins Fungi (Live and Killed) Fungal products Cryptococcal polysaccharide Cryptococcal proteins

Nonmicrobial Agents Soluble Antigen-Antibody Complexes Bile Acids Pharmacologic Agents Bleomycin Colchicine Tetracycline Hydromorphone (cats) Levamisole (cats) Tissue Inflammation and Necrosis

Viruses Rickettsial disease Protozoa From Miller JB: Hyperthermia and fever of unknown origin. In Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal medicine, ed 7, St Louis, 2010, Saunders.

may increase heat load at a faster rate than it can be dissipated from the body. This is especially true in large breed dogs and obese or brachycephalic animals. Heat stroke may occur rapidly, especially in closed environments with poor ventilation (e.g., inside a car with the windows closed on a moderately hot day). Environmental temperatures inside a closed car exposed to direct sun may exceed 120°F (48°C) in less than 20 minutes, even when the outside temperature is only 75°F (24°C). Death may occur in less than an hour, especially in the predisposed animal types described earlier. Severely affected animals may have peripheral blood nucleated red blood cells; these dogs have a 50% mortality rate despite aggressive therapy.9 A prospective study in 83 human heat stroke patients during a heat wave in France found a death rate of 52% at 28 days and 71% at 2 years.10

TABLE 10.1  Proteins with Pyrogenic Activity Endogenous Pyrogen

Principal Source

Cachectin (TNF-a) Lymphotoxin (TNF-b) IL-1a IL-1b Interferon a

Macrophages Lymphocytes (T and B) Macrophages and many other cell types Macrophages and many other cell types Leukocytes (especially monocytes/ macrophages) Fibroblasts T lymphocytes Many cell types Macrophages

Interferon b Interferon g IL-6 Macrophage inflammatory protein 1 a Macrophage inflammatory protein 1 b IL-8

Macrophages Macrophages

IL, interleukin; TNF, tumor necrosis factor. From Miller JB: Hyperthermia and fever of unknown origin. In Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal medicine, ed 7, St Louis, 2010, Saunders. Adapted from Beutler B, Beutler SM: The pathogenesis of fever. In Bennett JC, Plum F, editors: Cecil textbook of medicine, ed 20, Philadelphia, 1996, Saunders.

Heat stroke will not respond to antipyretics used for the management of a true fever. The severely hyperthermic patient must undergo immediate total body cooling to prevent organ damage or death. Mechanisms of heat loss from the body include the following: radiation (electromagnetic or heat exchange between objects in the environment), conduction (between the body and environmental objects that are in direct contact with the skin, as determined by the relative temperatures and gradients), convection (the movement of fluid, air, or water over the surface of the body), and evaporation (disruption of heat by the energy required to convert the material from a liquid to a gas, as with panting). There are numerous strategies for cooling the

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BOX 10.3  Cooling Options for the

Hyperthermic Patient

Oxygen and Intravenous Isotonic Fluid Therapy Surface Cooling Techniques Clip fur if indicated Tepid water applied to skin or whole body (manually or via bath) Fan Ice packs over areas with large vessels (neck, axilla, inguinal region) Combination of above techniques Internal Cooling Techniques Rectal administration of cool isotonic fluids Gastric lavage Open body cavity Peritoneal dialysis Extracorporeal Techniques Antipyretic Drugs Antiprostaglandins Dantrolene Dipyrone Aminopyrine COX-2 inhibitors Glucocorticoids Additional NSAIDs COX-2, cyclooxygenase-2; NSAIDs, nonsteroidal antiinflammatory drugs.

hyperthermic patient (Box 10.3), and the techniques chosen should be based on the severity of the animal’s condition, temperature, and response to therapy. In most veterinary patients, total body cooling is best accomplished by administering intravenous fluids (see Chapter 68, Shock Fluid Therapy), providing water baths and rinses using tepid water, and placing a fan near the animal. If the water applied to the animal is too cold, there is a tendency for peripheral vasoconstriction that will inhibit radiant heat loss and slow the cooling process. Cooling should be discontinued when body temperature approaches normal (approximately 103°F [39.4°C]) to prevent iatrogenic hypothermia.

Hyperpyrexic Syndrome Hyperpyrexic syndrome is associated with moderate to severe exercise in hot and humid climates. This syndrome may be more common in hunting dogs or dogs that “jog” with their owners. In humid environments, evaporative cooling via panting is minimal. In addition, heavy exercise may lead to vasodilation to increase blood flow to skeletal muscles but simultaneous vasoconstriction of cutaneous vessels, thus compromising peripheral heat loss. Many hunting dogs and dogs that run with their owners will continue to work or run until they become weak, stagger, and collapse. In suspected cases of hyperpyrexic syndrome, owners should measure the dog’s rectal temperature if the dog shows any signs of becoming weak or not wanting to continue. Owners should be instructed that rectal temperatures above 106°F (41°C) require immediate total body cooling and temperatures above 107°F (41.6°C) may lead to permanent organ damage or death.

Exercise-Induced Hyperthermia The body temperature will rise with sustained exercise of even moderate intensity because of heat production associated with muscular

activity. Even when extreme heat and humidity are not factors, dogs will occasionally reach temperatures that require total body cooling. This is especially true in dogs that do not exercise frequently, have thick undercoats, are overweight, or have respiratory disease. Eclampsia results in extreme muscular activity that can lead to significant heat production and result in severe hyperthermia. Total body cooling should be initiated if the patient is hyperthermic, in conjunction with therapy for the eclampsia. Seizure disorders from organic, metabolic, or idiopathic causes are encountered often in small animals (see Chapter 84, Seizures and Status Epilepticus). Hyperthermia associated with increased muscular activity can result, especially if the seizures are prolonged or occur in clusters. The first treatment priority should be to stop the seizures, but when significant hyperthermia is present, total body cooling is also recommended as soon as possible.

Pathologic and Pharmacologic Hyperthermia The pathologic and pharmacologic causes of hyperthermia encompass several disorders that will impair the heat balance equation. Hypothalamic lesions may obliterate the thermoregulatory center, leading to impaired responses to both hot and cold environments. Malignant hyperthermia has been reported in dogs and cats. It leads to a myopathy and subsequent metabolic heat production secondary to disturbed calcium metabolism that is initiated by pharmacologic agents such as inhalation anesthetics (especially halothane) and muscle relaxants (e.g., succinylcholine). Extreme muscle rigidity may or may not be present. Removal of the offending causative agent and total body cooling may prevent death. Dantrolene sodium, a muscle relaxant, is a specific and effective therapy for malignant hyperthermia and acts by binding to the ryanodine receptor to depress excitation-contraction coupling in skeletal muscle. It is dosed at 1 to 3 mg/kg IV or 1 to 5 mg/kg PO. Hypermetabolic disorders may also lead to hyperthermic states. Endocrine disorders such as hyperthyroidism and pheochromocytoma can lead to an increased metabolic rate or vasoconstriction, resulting in excess heat production, decreased ability to dissipate heat, or both. These conditions rarely lead to severe hyperthermia that requires total body cooling. Recent evidence suggests that thyroid hormone may also act directly on the hypothalamic set point resulting in a true fever as part of the hyperthermia.2 The use of opioids, especially as a preanesthetic, may lead to hyperthermia. Both retrospective and prospective studies have been done in cats using opioids as a preanesthetic.11,12 In both studies, most cats had significant elevations (.40°C) in body temperature between 1 and 5 hours after recovery from anesthesia. The highest temperature was 42.5°C (108.5°F). Studies in guinea pigs with opioid-induced hyperthermia showed that the hyperthermia was centrally mediated. It did not appear to be related to prostaglandins since it was not responsive to nonsteroidal antiinflammatory drugs (NSAIDs) but could be reversed with naloxone.13 Cats given opioids as a preanesthetic should be monitored following recovery for hyperthermia and treated with naloxone or total body cooling, if indicated.

BENEFITS AND DETRIMENTS OF FEVER Benefits Fever is part of the acute-phase response and is a normal response of the body. Even poikilotherms such as fish and reptiles will respond to a pyrogen by seeking higher environmental temperatures to raise their body temperatures.14 It is logical to think that a true fever is beneficial to the host. Most studies have shown that a fever will reduce the duration of morbidity and decrease mortality from many infectious diseases. A fever decreases the ability of many bacteria to use iron, which

CHAPTER 10  Hyperthermia and Fever is necessary for them to live and replicate.14 Use of NSAIDs to block fever in rabbits with Pasteurella infections significantly increases mortality rates. Many viruses are heat sensitive and cannot replicate in high temperatures. Raising the body temperature in neonatal dogs with herpesvirus infections significantly reduces the mortality rate. Most studies in human ICU patients with infection found that the prognosis is better when fever is present. In contrast, fever in patients with noninfectious diseases such as traumatic brain injury may carry a worse prognosis.2

Detriments Hyperthermia increases tissue metabolism and oxygen consumption, thus raising both caloric and water requirements by approximately 7% for each degree Fahrenheit (0.6°C) above accepted normal values. In addition, hyperthermia leads to suppression of the appetite center in the hypothalamus; the thirst center usually remains unaffected. Animals that have sustained head trauma or a cerebrovascular accident may suffer more severe brain damage if coexisting hyperthermia is present; total body cooling may therefore be beneficial in these patients. Body temperatures above 107°F (41.6°C) often lead to increases in cellular oxygen consumption that exceed oxygen delivery, resulting in the deterioration of cellular function and integrity. This may lead to disseminated intravascular coagulation (DIC) (see Chapters 101 and 105, Hypercoagulable States and Management of the Bleeding Patient in the ICU, respectively), with thrombosis and bleeding, or cause serious damage to organ systems, including the brain (cerebral edema and subsequent confusion, delirium, obtundation, seizures, coma); heart (arrhythmias); liver (hypoglycemia, hyperbilirubinemia); gastrointestinal tract (epithelial desquamation, endotoxin absorption, bleeding); and kidneys (acute kidney injury). Additional abnormalities might include hypoxemia, hyperkalemia, skeletal muscle cytolysis, tachypnea, metabolic acidosis, tachycardia, tachypnea, and hyperventilation. Exertional heat stroke and malignant hyperthermia may lead to severe rhabdomyolysis, hyperkalemia, hypocalcemia, myoglobinemia, myoglobinuria, and elevated levels of creatine phosphokinase. Fortunately, true fevers rarely lead to body temperatures of this magnitude and are usually a result of other causes of hyperthermia that should be managed as medical emergencies.

CLINICAL APPROACH TO THE HYPERTHERMIC PATIENT The evaluation of the hyperthermic patient should be approached in a logical manner to avoid making erroneous conclusions.4 A complete history and physical examination should be performed unless the patient is unstable or severely hyperthermic (temperature higher than 106°F [41°C]). In such cases, stabilization and immediate total body cooling should be initiated. In stable patients, a thorough physical examination and specific questions concerning previous injuries or infections, exposure to other animals, disease in other household pets, previous geographic environment, and recent or current drug therapy may be beneficial. This approach enables the clinician to decide if the elevated body temperature is a true fever. Temperatures less than 106°F (41°C), unless prolonged, are usually not life threatening, and antipyretic therapy should not be administered before performing a proper clinical evaluation.

NONSPECIFIC THERAPY FOR FEBRILE PATIENTS Mild to moderate elevations in body temperature (,107°F) are rarely fatal and may be beneficial to the body. As stated before, hyperthermia

65

may inhibit viral replication, increase leukocyte function, and decrease the uptake of iron by microbes (which is often necessary for their growth and replication). If a fever exceeds 107°F (41.6°C), there is a significant risk of permanent organ damage and DIC. The benefits of nonspecific therapy versus its potential negative effects should be considered before initiating such management. As stated earlier, fever associated with traumatic brain injury should be addressed to improve outcome. Nonspecific therapy for true fever usually involves inhibitors of prostaglandin synthesis. The compounds most commonly used are the NSAIDs (see Chapter 158, Nonsteroidal Antiinflammatory Drugs). These products inhibit the chemical mediators of fever production and allow normal thermoregulation. They do not block the production of endogenous pyrogens.4 These drugs are relatively safe in stable animals, although acetylsalicylic acid is potentially toxic to the cat (cyclooxygenase-2 [COX-2] inhibitors are relatively safe) and animals with gastrointestinal ulceration or renal disease should not receive these drugs. Consensus guidelines have been published on the use of NSAIDS in cats.15 Dipyrone, an injectable NSAID sometimes used in cats, may lead to bone marrow suppression, especially with prolonged use. Total body cooling with water, fans, or both in a febrile patient will reduce body temperature; however, the thermoregulatory center in the hypothalamus will still be directing the body to increase the body temperature. This may result in a further increase in metabolic rate, oxygen consumption, and subsequent water and caloric requirements. Unless a fever is life threatening, this type of nonspecific therapy is counterproductive. Glucocorticoids block the acute-phase response, fever, and most other parts of this (adaptive) response. In general, their use should be reserved for those patients in whom the cause of the fever is known to be noninfectious and blocking the rest of the acute-phase response will not be detrimental (and may prove beneficial). The most common indications include some immune-mediated diseases in which fever plays a significant role and glucocorticoid therapy is often part of the chemotherapeutic protocol (e.g., immune-mediated hemolytic anemia, immune-mediated polyarthritis). Phenothiazines can be effective in alleviating a true fever by depressing normal thermoregulation and causing peripheral vasodilation. The sedative qualities of the phenothiazines and their potential for hypotension should be considered before administration to the febrile patient.

THE FEBRILE INTENSIVE CARE PATIENT Fever is a common problem in critically ill veterinary patients. The clinician must attempt to exclude noninfectious causes and then determine the infection site and likely pathogens (see Chapter 7, SIRS, MODS and Sepsis). Intensive care patients often have both infectious and noninfectious causes of fever, necessitating a systematic and comprehensive diagnostic approach. Altered immune function, indwelling catheter devices, and more invasive monitoring and treatment approaches put these patients at high risk for inflammation and nosocomial infections. Noninfectious causes of fever in intensive care patients commonly include phlebitis or thrombophlebitis, postoperative inflammation, posttransfusion reactions, post trauma, pancreatitis, hepatitis, cholecystitis, aspiration pneumonitis, acute respiratory distress syndrome, and neoplastic processes. Nosocomial infection in critically ill patients is an important cause of new-onset fevers. Although incidence studies have not been performed in veterinary patients, the reported range in people is 3%

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to 31%. Commonly implicated sources include the lungs (aspiration or ventilator-associated pneumonia), the bloodstream, catheters, incisions, and the urinary tract (see Chapter 98, Catheter-Related Bloodstream Infection). An initial diagnostic evaluation might include a complete blood cell count, thoracic and abdominal imaging, and close inspection of all catheter sites or incisions. Additional diagnostic tests that might be indicated include culture and susceptibility testing of blood, urine, airway fluid, pleural or peritoneal effusions, postoperative incisions, cerebrospinal fluid, joint fluid, nasal discharge, and diarrhea. Antimicrobial therapy is indicated for the febrile patient only when a specific pathogen is known or strongly suspected.4 The use of antimicrobials in these patients without knowledge that a microbial agent is causing the fever can lead to bacterial resistance (see Chapter 172, Antimicrobial Use in the Critical Care Patient). Dogs with evidence of a systemic inflammatory response syndrome have a higher mortality rate,16 and the source should be rapidly identified and treated. However, if an infectious cause is not suspected and the patient is not deteriorating or neutropenic, antimicrobial additions or changes should be delayed until more definitive information is obtained.

REFERENCES 1. Chervier C, Chabanne L, Godde M, et al: Causes, diagnostic signs, and the utility of investigations of fever in dogs: 50 cases, Can Vet J 53(5):525, 2012. 2. Walter E, Hanna-Jumma S, Forni L: The pathophysiological basis and consequences of fever, Critical Care 20(1):200, 2016. 3. Cunningham JG: Textbook of veterinary physiology, ed 2, St Louis, 1997, Saunders.

4. Mackowiac PA: Approach to the febrile patient. In Humes HD, editor: Kelley’s textbook of internal medicine, ed 4, Philadelphia, 2000, Lippincott Williams & Wilkins. 5. Dinarella CA: The acute phase response. In Bennet JC, Plum F, editors: Cecil textbook of medicine, ed 20, Philadelphia, 1996, Saunders. 6. Beutler B, Buetler SM: The pathogenesis of fever. In Bennet JC, Plum F, editors: Cecil textbook of medicine, ed 20, Philadelphia, 1996, Saunders. 7. Steiner AA, Ivanov AI, Serrats J, et al: Cellular and molecular bases of the initiation of fever, PLoS Biol 4(9):E284, 2006. 8. Esikilsson A, Matsuwaki T, Shionoya K, et al: Immune-induced fever is dependent on local but not generalized Prostaglandin E2 synthesis in the brain, J Neurosci 37(19):5035-5044, 2017. 9. Bruchim Y, Horowitz M, Aroch I: Pathophysiology of heatstroke in dogs – revisited, Temperature (Austin) 4(4):356-370, 2017. 10. Argaud L, Tristan F, Le QH, et al: Short- and long-term outcomes of heatstroke following the 2003 heat wave in Lyon, France, Arch Intern Med 167(20):2177-2183, 2007. 11. Niedfeldt RL, Robertson SA: Postanesthetic hyperthermia in cats: a retrospective comparison between hydromorphone and buprenorphine, Vet Anaesth Analg 33(6):384-389, 2006. 12. Posner LP, Pavuk AA, Rokshar JL, et al: Effects of opioids and anesthetic drugs on body temperature in cats, Vet Anaesth Analg 37(1)35-43, 2010. 13. Kandasamy SB, Williams BA: Hyperthermic responses to central injections of some peptide and non-peptide opioids in the guinea-pig, Neuropharmacology 22(5):321-328, 1983. 14. Berlin MT, Abeche AM: Evolutionary approach to medicine, South Med J 94:26, 2001. 15. Sparkes AH, Heiene R, Lascelles BD, et al: ISFM and AAFP consensus guidelines, long-term use of NSAIDs in cats, J Feline Med Surg 12(7):521, 2010. 16. DeClue AE: Biomarkers for sepsis in small animals. In Proceedings of the annual meeting of the ACVP/ASVCP, Seattle, WA, December 2012.

11 Interstitial Edema Randolph H. Stewart, DVM, PhD, DACVIM KEY POINTS • Interstitial fluid is formed by filtration of fluid out of microvessels and removed via the lymphatic system or transudation across the serosal surface of the organ. • Interstitial edema, or increased interstitial fluid volume, commonly forms in response to increased microvascular pressure, hypoproteinemia, increased microvascular permeability, and inflammatory or immune-mediated changes in mechanical relationships within the interstitial space.

• Interstitial edema impairs tissue function by impeding oxygen diffusion to cells and altering the mechanical properties of the affected tissue (e.g., pulmonary compliance or intestinal motility). • Management of interstitial edema requires an understanding of the forces and tissue properties involved in interstitial fluid volume regulation.

Interstitial edema formation, or an increase in interstitial fluid volume, is a common clinical condition observed in conjunction with heart failure, venous thrombosis, protein-losing disorders, excessive crystalloid administration, anaphylaxis, burns, and inflammatory disease/ systemic inflammatory response syndrome. Interstitial edema can negatively affect many organ systems, such as the skin, lung, intestine, brain, skeletal muscle, kidney, and heart. The presence of edema in these organs impairs proper oxygen delivery and cellular function in addition to altering the mechanical properties of the tissue (e.g., pulmonary compliance). Because each organ system possesses a unique set of tissue properties, the specific manner in which individual organs respond to an edemagenic challenge is necessarily organ-specific. However, a common set of principles and mechanisms govern interstitial volume, pressure, and flow in all organs. Interstitial fluid volume is determined by the balance between filtration of fluid out of capillaries and venules into the interstitial space and lymphatic removal of that interstitial fluid. In organs located within body cavities—the heart, lungs, liver, and intestines—transudation of interstitial fluid across the organ’s serosal surface into the surrounding space provides an additional avenue for interstitial fluid removal. The variable primarily responsible for mediating the balance between microvascular filtration and the two interstitial outflows is the interstitial fluid pressure.1 An increase in interstitial pressure acts to inhibit filtration and simultaneously promote lymph flow and serosal transudation. The interstitial fluid volume depends on interstitial fluid pressure and the current interstitial pressure–volume relationship.

microvessels and interstitial space, respectively; sd is the osmotic reflection coefficient; and Pp and Pint are the colloid osmotic pressures exerted by plasma and interstitial fluid, respectively.2 A revised view of the Starling-Landis principle has been proposed based on two related ideas: (1) the endothelial glycocalyx is the primary barrier to microvascular filtration and (2) the colloid osmotic pressure of the fluid on the interstitial side of the glycocalyx and within the endothelial clefts, termed Pg, has a more direct effect on filtration than that of bulk interstitial fluid (Pint). The glycocalyx is a complex of glycoproteins, proteoglycans, and glycosaminoglycans that form a layer attached to the luminal surface of vascular endothelial cells.2 Because of the combined effects of protein sieving by the glycocalyx and the convective flow of filtered fluid through the clefts, the colloid osmotic pressure of this filtered fluid can be lower than that of bulk interstitial fluid.2 The Starling-Landis equation shows that the direction of microvascular filtration depends on the sum of the hydrostatic and colloid osmotic pressure gradients, whereas the magnitude of filtration is the product of the hydraulic conductivity, surface area, and net pressure gradient. Pmv in most organs is between 7 and 17 mm Hg. That pressure is opposed by Pint, which, in many tissues, such as subcutaneous tissue, lung, and resting skeletal muscle, is subatmospheric because of the active removal of interstitial fluid by the lymphatic system. This establishes a hydrostatic pressure gradient (Pmv 2 Pint) favoring filtration out of the microvessels into the interstitial space. The colloid osmotic pressure gradient, however, opposes filtration and favors retention of fluid within the microvasculature. Colloid osmotic pressure of plasma and interstitial fluid is a consequence of the concentration of proteins, particularly albumin, as well as the redistribution of permeable ions induced by the presence of charges on those proteins. The colloid osmotic pressure of plasma is predictably higher than that of interstitial fluid; however, the interstitial fluid protein concentration and colloid osmotic pressure are not as low as commonly reported. Using lymph albumin concentration as an indicator of interstitial fluid albumin concentration, values of the lymph-to-plasma albumin concentration ratio have been reported to be 0.86 (dog heart), 0.90 (sheep lung), 0.81 (dog lung) and 0.92 (dog intestine).3-6 However, according to the revised Starling-Landis principle described above, the effective

MICROVASCULAR FILTRATION The microvascular filtration rate is determined by forces and tissue properties modeled in the Starling-Landis equation: JV 5 LpA [(Pmv 2 Pint) 2 sd(Pp 2 Pint)]

Equation 1

where JV is the microvascular filtration rate; Lp is the hydraulic conductivity (a measure of water permeability); A is the filtration surface area; Pmv and Pint are the hydrostatic pressures within the

67

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colloid osmotic pressure of the interstitial fluid may be much lower than that drained by the lymphatic system. This effect is hypothesized to be the result of protein passing from plasma to the interstitial space directly through endothelial cells via vesicular transport, thus bypassing the endothelial clefts.2 The colloid osmotic pressure gradient in Equation 1, Pp 2 Pint, is modified by sd. This coefficient is a function of the protein permeability of the microvascular barrier and possesses a value between 0 (indicating a membrane that is freely permeable to protein) and 1 (for a membrane that is impermeable to protein). The fraction of the colloid osmotic pressure gradient that is expressed across the microvascular barrier is represented by sd. Its value is close to 1 for the blood–brain barrier, and it approaches 0 for the sinusoids of the liver. In most microvascular beds, there is a small net pressure gradient favoring filtration. The commonly reported view that filtration occurs at the arteriolar end of the capillary and reabsorption occurs at the venular end is not supported by experimental or theoretical analysis. Current evidence indicates that all the microvascular filtrate is removed by lymphatic drainage or trans-serosal flow, and little or no microvascular reabsorption occurs under normal conditions in most tissues.2 Relevant studies have demonstrated that as Pmv decreases, filtration into the interstitial space (JV) decreases, but, at steady state, JV does not reverse to absorb fluid, even at very low microvascular pressures.2,7 Reduction in the rate of microvascular filtration as seen with decreasing capillary pressures is accompanied by two changes that limit continued decreases in JV. First, a decrease in JV is accompanied by an increase in protein concentration of the filtered fluid in the endothelial clefts and, thus, Pg.2 Second, at normal interstitial volumes, the interstitial compliance in most tissues is low; therefore, small decreases in interstitial volume are accompanied by large decreases in interstitial hydrostatic pressure (Pint).8 The increase in Pg and decrease in Pint both act to maintain filtration out of the capillary despite the fall in capillary hydrostatic pressure.

strength and frequency of lymphatic contractions, while increased lymph flow results in a shear-mediated relaxation.10,11 This shearmediated response has a beneficial but counterintuitive effect. Following edema-induced elevations in lymph flow, the reduction in lymphatic pumping caused by increased lymph flow and shear stress further enhances flow because when lymphatic inlet pressure exceeds outlet pressure, passive flow can exceed the pumping capacity of the vessel.12 Pleural fluid and peritoneal fluid are removed by lymphatic drainage and returned to the venous circulation. These fluids exit these cavities through direct connections called lymphatic stomata into lymphatic vessels within the diaphragm and body wall.13 The lymphatic system drains into the great veins of the neck; therefore, systemic venous pressure is the downstream pressure against which lymph must flow (see Equation 2). Because of this arrangement, elevations in venous pressure can diminish lymph flow and thereby contribute to edema formation. This effect, however, is usually modest in unanesthetized animals. The lymphatic circulation is normally more sensitive to changes in the interstitial pressure upstream than it is to changes in the systemic venous pressure downstream. In other words, although lymph flow generally increases markedly in response to interstitial edema formation, it does not usually decrease markedly in response to venous hypertension. This is because lymphatic vessels respond to increased outflow pressure by increasing pumping activity via increases in the strength and frequency of contractions. However, in the presence of interstitial edema caused by increased microvascular filtration, increased venous pressure in the neck may significantly impede lymph flows and, thereby, exacerbate edema formation.14 In addition, many anesthetic agents significantly reduce lymphatic pumping and thus increase lymphatic sensitivity to venous hypertension. This means that the sensitivity to edemagenic challenges such as intravenous crystalloid administration is exaggerated in anesthetized patients.

LYMPHATIC DRAINAGE

SEROSAL TRANSUDATION

The lymphatic system removes interstitial fluid and returns it to the venous blood. This system begins with terminal lymphatic vessels within the interstitial space, converges to progressively larger vessels through lymph nodes, and eventually terminates in the venous system. The determinants of lymph flow have been modeled on a modification of Ohm’s law as given here:

In organs suspended within potential spaces, such as the heart, lung, liver, and intestine, interstitial fluid may be removed, in part, via transudation across the serosal surface into the surrounding space. This process is driven by hydrostatic and colloid osmotic pressure gradients like those seen in Equation 1. Edema-induced increases in interstitial hydrostatic pressure will increase the rate of transudation and may result in effusion within the surrounding cavity.15

QL 5 (Pint 1 Ppump – Psv)/RL

Equation 2

where QL is lymph flow, Pint is the interstitial hydrostatic pressure, Ppump is the effective driving pressure generated by the cyclic intrinsic contraction and extrinsic compression of the lymphatic vessels working in concert with one-way valves, Psv is systemic venous pressure, and RL is the effective resistance to lymph flow.9 Most lymphatic vessels possess intramural smooth muscle and contain one-way valves at regular intervals. Spontaneous phasic contraction and extrinsic compression of these vessels propel lymph antegrade. Lymphatic pumping explains why lymph is able to flow from an interstitial space with subatmospheric pressure to the systemic venous blood where the pressure is 2 to 5 mm Hg. In addition, lymphatic pumping is the prime reason that interstitial hydrostatic pressure can be maintained below atmospheric pressure. Lymph flow is regulated by multiple factors. The strength and frequency of lymphatic contractions are modified by numerous vasoactive mediators, including prostaglandins, thromboxane, nitric oxide, epinephrine, acetylcholine, substance P, and bradykinin. In addition, increased stretch of lymphatic vessels stimulates increased

ANTIEDEMA MECHANISMS When confronted with an edemagenic insult, interstitial edema formation is moderated by a set of antiedema mechanisms. These intrinsic interdependent mechanisms include (1) increased interstitial hydrostatic pressure, (2) increased lymph flow, (3) decreased interstitial colloid osmotic pressure, and (4) increased trans-serosal flow in organs within potential spaces. Increased interstitial pressure opposes microvascular filtration and promotes lymph flow and trans-serosal flow. In response to increased microvascular pressure and subsequent interstitial fluid accumulation, lymph flow can increase tenfold in many tissues. Increased microvascular filtration is characterized by an increase in water filtration that exceeds the increase in protein filtration. The resulting decrease in the protein concentration of the filtrate results in a decrease in colloid osmotic pressure within the endothelial clefts, which acts to lessen microvascular filtration.2,7 In addition, serosal transudation is enhanced by the combined effects of increased Pint and decreased Pint.

CHAPTER 11  Interstitial Edema

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These self-regulating mechanisms are efficient because they incur little energy cost and are effective because they respond rapidly to edema formation; however, their effectiveness diminishes in the presence of continued challenge. Therefore, a patient that has responded to an edemagenic stress, such as hypoproteinemia, is at increased risk of edema development in response to additional challenge, such as crystalloid infusion.

challenges. However, because the protective mechanisms are already engaged, even moderate hypoproteinemia can make the patient particularly susceptible to further edemagenic challenge (e.g., crystalloid infusion). In an experimental canine study, a 55% decrease in total plasma protein over 3 hours resulted in myocardial interstitial edema formation of sufficient magnitude to impair left ventricular function.17

MECHANISMS OF EDEMA FORMATION The pathophysiology of interstitial edema formation involves changes in the factors responsible for interstitial fluid formation and removal (Table 11.1). However, edemagenic diseases commonly result in perturbations of more than one of these factors. In addition, therapeutic measures, such as intravenous fluid administration, may exacerbate these perturbations. In fact, because the pathogenesis of edemagenic diseases may be quite complex, it is perhaps more beneficial clinically to emphasize the degree to which the sensitivity of the fluid balance system has been changed rather than the specific effects of changes in microvascular pressure, permeability, etc. The degree to which the sensitivity of the system to edemagenic challenge, termed edemagenic gain, can be changed has been illustrated for histamine and endotoxin.16 Five basic edemagenic conditions are discussed next and shown in Table 11.1. It should be noted that, although clinical assessment of interstitial edema is often limited to the lungs and subcutaneous tissue, other organs, such as the heart, liver, kidney and intestines, may also be significantly affected.

According to Equation 1, apparent changes in microvascular permeability may involve changes in water permeability (Lp), microvascular surface area (A), and protein permeability (sd). Experimentally, it is very difficult to differentiate between changes in Lp and changes in A. If Lp or A increase, the microvascular filtration rate will be greater for any given transmembrane pressure gradient. If protein permeability increases, the microvascular filtration rate increases because the effectiveness with which the plasma-to-interstitium colloid osmotic pressure gradient restrains fluid filtration is diminished. This increase in protein permeability also impairs the effectiveness of the decrease in interstitial colloid osmotic pressure to serve as an antiedema mechanism. There is growing evidence that a contributing factor leading to increased microvascular permeability in disease states involves damage to the endothelial glycocalyx layer (see Chapter 9, Endothelial Glycocalyx). In experimental preparations of mesenteric (rat and frog) and coronary (pig) microvessels, enzyme-induced damage to the glycocalyx resulted in increased permeability to water and protein.18-20 Preclinical and clinical studies implicate glycocalyx degradation in the pathogenesis of both sepsis and hemorrhagic shock.21,22

Venous Hypertension

Impaired Lymph Flow

Elevations in venous pressure seen with heart failure and venous obstruction (e.g., thrombosis or mass effect) reliably cause regional increases in microvascular hydrostatic pressure. The resulting increase in microvascular filtration (Equation 1) expands interstitial fluid volume in the tissues drained by the affected veins. The severity of the edema is directly proportional to the magnitude of the venous pressure increase. In addition, hypertension of the central veins can retard lymph flow, particularly in anesthetized patients, because it increases lymphatic outflow pressure.

In the short term, lymphatic obstruction or functional impairment generally results in only mild edema formation caused by the diminished interstitial fluid removal. However, the combination of impaired lymph flow with any additional edemagenic challenge can result in profound edema. This is true not only because increased lymph flow is a very important antiedema mechanism but because the effectiveness of the other antiedema mechanisms—decreased interstitial colloid osmotic pressure and increased trans-serosal flow—is dependent on adequate lymph flow. Recall that the inhibitory effect of systemic venous hypertension on lymph flow is increased in anesthetized patients and patients with preexisting interstitial edema.

Hypoproteinemia An acute decrease in plasma colloid osmotic pressure resulting from hypoproteinemia, particularly hypoalbuminemia, results in increased microvascular filtration (see Equation 1). The relationship between the degree of hypoproteinemia and the resulting edema formation is nonlinear such that mild to moderate protein deficits cause little edema formation. This nonlinearity is likely caused by the engagement of antiedema mechanisms that readily compensate for mild to moderate

Increased Microvascular Permeability

Inflammatory Edema Inflammation is characterized by the elaboration of numerous proinflammatory substances mediated, in part, by neutrophils.23-25 This process impacts interstitial fluid balance by increasing microvascular pressure and surface area via vasodilation, increasing microvascular permeability to fluid and protein, and altering

TABLE 11.1  Edemagenic Conditions with Related Mechanisms and Example Disease Processes Condition Venous hypertension

Mechanism Increased microvascular pressure and filtration

Relevant Disease Process Examples Heart disease, venous thrombosis

Hypoproteinemia

Decreased plasma colloid osmotic pressure, increased filtration

Protein-losing enteropathy and nephropathy

Increased microvascular permeability

Increased filtration, diminished influence of plasma-interstitial fluid colloid osmotic pressure gradient

Inflammation, infection

Impaired lymph flow

Vessel obstruction or damage, pharmacologic impairment of pump mechanism

Trauma, surgical damage, systemic venous hypertension, anesthesia

Increased negativity of interstitial fluid pressure

Shift in interstitial pressure–volume relationship, decreased interstitial pressure

Inflammation, anaphylaxis, burn injury, frostbite

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PART I  Key Critical Care Concepts

Interstitial pressure

lymphatic function.4,26-30 The net effect of these changes is to increase the edemagenic gain, that is, the volume of interstitial edema that forms in response to a 1-mm Hg increase in microvascular pressure. In experimental sheep studies, histamine and endotoxin increased edemagenic gain in the lung approximately twofold and sixfold, respectively.16 This change in sensitivity to microvascular pressure in affected patients makes them much more susceptible to further edemagenic challenges such as intravenous fluid administration. An additional mechanism of edema formation identified in skin and tracheal mucosa involves changes in the interstitial pressure–volume relationship that manifest as increased negativity of interstitial fluid pressure. This phenomenon has been reviewed by the investigators primarily responsible for its elucidation.31-33 Under normal conditions, interstitial pressure increases predictably with increases in interstitial volume. However, in response to inflammation, this mechanical relationship can shift markedly in a short period.31-33 A consequence of this shift is a sudden fall in interstitial pressure and a consequent rapid increase in microvascular filtration and interstitial volume (Fig. 11.1). This edema formation can occur with no significant changes in microvascular pressure or permeability. This phenomenon appears to be the result of a structural rearrangement of the extracellular matrix modulated by alterations in the attachment of cells, particularly fibroblasts, to collagen fibers. Collagen fibers in the interstitial space act to restrain or compress interstitial volume. This effect is actuated by fibroblasts exerting tension on multiple collagen fibers via integrin-mediated connections, thus contracting the extracellular matrix.31,32 Inflammation and immunemediated phenomena appear to disrupt this fibroblast-collagen bond. This change in the interstitial pressure–volume relationship has been reported in skin and tracheal mucosa in select experimental models of inflammation, direct tissue damage of burns and freezing, ischemia-reperfusion, neurogenic inflammation induced by vagal nerve stimulation, and anaphylaxis.31-34 This condition has been experimentally created by induction of mast cell degranulation, exposure to lipopolysaccharides, complement activation, and antigen

0 A

C

B Interstitial volume Fig. 11.1  ​A proposed mechanism of inflammatory change in the interstitial pressure–volume relationship. Baseline interstitial pressure and volume values (A) lie along the normal pressure–volume relationship (solid line). With the induction of inflammatory or immune-mediated disease, this relationship may change rapidly (dashed line). In experimental preparations in which microvascular filtration is hindered, interstitial pressure drops (B). More commonly, the fall in interstitial pressure promotes microvascular filtration resulting in marked interstitial edema formation (C).

exposure as well as by introduction of inflammatory mediators, including tumor necrosis factor a (TNF-a), platelet activating factor, interleukin-1b (IL-1b), IL-6, and prostaglandins E1, E2, and I2.31,32 Several agents have been shown experimentally to prevent or reverse the fall in interstitial pressure, including prostaglandin F2a, corticotropin releasing factor, a-trinositol, platelet-derived growth factor BB, insulin, and vitamin C.31,32

CHRONIC EDEMAGENIC CONDITIONS When evaluating chronic disease states, a difficulty arises when trying to ascribe the magnitude, persistence, or absence of edema to the mechanisms described earlier. Assessment of the mechanisms responsible for acute edema depends on parameters having relatively constant values (e.g., Lp and sd in Equation 1, Ppump and RL in Equation 2) and variables with values that can change readily (e.g., Pmv, Pint, Pp). However, the interstitial fluid balance system is not only complex but also adaptive. Chronic increases in interstitial volume, pressure, or flow induce adaptive changes in the values of those previously “constant” parameters.35-38 These might include changes in microvascular permeability to water and protein, interstitial compliance, lymphatic contractile function, and serosal permeability as well as lymphangiogenesis, the growth of new lymphatic vessels. In addition, interstitial edema affecting the heart or lung lasting for more than a few days induces development of interstitial fibrosis.37,39,40 To add to the complexity, an adaptive change in one dimension, such as microvascular permeability, alters the signal for change in another dimension, such as lymphatic pumping. These multiple interdependent responses have the effect of changing both the magnitude of interstitial volume at equilibrium and the edemagenic gain, the sensitivity of the system to edemagenic challenge. These adaptive changes in fluid balance parameters make it difficult to predict the occurrence and severity of interstitial edema in chronic conditions.

CONCLUSION Disease conditions characterized by interstitial edema development can best be understood via changes in the factors responsible for interstitial fluid balance—increased venous and microvascular pressures, decreased plasma colloid osmotic pressure, increased microvascular permeability, impaired lymphatic function, and altered interstitial compliance. However, these cases can often be difficult to manage for two reasons. First, more than one mechanism of edema formation is often involved. For example, inflammatory disease may alter lymphatic pumping, microvascular permeability to water and protein, and the interstitial pressure–volume relationship simultaneously. Second, disease conditions that last for more than 1 to 2 days can induce adaptive responses in the interstitial fluid balance system that diminish clinical predictive accuracy. Preliminary evidence exists for several therapeutic interventions specific to the treatment of interstitial edema. In a rodent model of intestinal edema induced by mesenteric venous hypertension and crystalloid infusion, hypertonic saline treatment significantly reduced interstitial edema formation.41 This effect appeared to be the result of fluid redistribution leading to increased urine production, intestinal luminal fluid volume, and peritoneal fluid volume.41 In a model of anaphylaxis in albumin-sensitized rats, a-trinositol, an isomer of the intracellular messenger inositol trisphosphate, abolished the fall in tracheal interstitial fluid pressure induced by albumin administration, whereas hydrocortisone had no effect.42 a-Trinositol also successfully prevented edema formation and the decrease in interstitial pressure when used as a pretreatment in

CHAPTER 11  Interstitial Edema experimentally induced ischemia-reperfusion.34 Perhaps more promising, platelet-derived growth factor with 2 subunits (BB) was shown to be effective after treatment to speed resolution of the anaphylaxisinduced drop in dermal interstitial pressure.43,44 Clinical trials demonstrating the effectiveness of these and related therapies remain to be performed.

REFERENCES 1. Dongaonkar RM, Laine GA, Stewart RH, Quick CM: Balance point characterization of interstitial fluid volume regulation, Am J Physiol Regul Integr Comp Physiol 297(1):R6-R16, 2009. doi:10.1152/ajpregu.00097.2009. 2. Levick JR, Michel CC: Microvascular fluid exchange and the revised Starling principle, Cardiovasc Res 87(2):198-210, 2010. doi:10.1093/cvr/cvq062. 3. Stewart RH, Geissler HJ, Allen SJ, Laine GA: Protein washdown as a defense mechanism against myocardial edema, Am J Physiol Heart Circ Physiol 279(4):H1864-H1868, 2000. 4. Brigham KL, Woolverton WC, Blake LH, Staub NC: Increased sheep lung vascular permeability caused by pseudomonas bacteremia, J Clin Invest 54(4):792-804, 1974. 5. Parker JC, Falgout HJ, Grimbert FA, Taylor AE: The effect of increased vascular pressure on albumin-excluded volume and lymph flow in the dog lung, Circ Res 47:866-875, 1980. 6. Laine GA, Granger HJ: Permeability of intestinal microvessels in chronic arterial hypertension, Hypertension 5:722-727, 1983. 7. Michel CC, Phillips ME: Steady state fluid filtration at different capillary pressures in perfused frog mesenteric capillaries, J Physiol 388:421-435, 1987. 8. Aukland K, Reed RK: Interstitial-lymphatic mechanisms in the control of extracellular fluid volume, Physiol Rev 73(1):1-78, 1993. 9. Drake RE, Laine GA, Allen SJ, Katz J, Gabel JC: A model of the lung interstitial-lymphatic system, Microvasc Res 34(1):96-107, 1987. 10. Shirasawa Y, Benoit JN: Stretch-induced calcium sensitization of rat lymphatic smooth muscle, Am J Physiol Heart Circ Physiol 285(6): H2573-H2577, 2003. 11. Gashev AA, Davis MJ, Zawieja DC: Inhibition of the active lymph pump by flow in rat mesenteric lymphatics and thoracic duct, J Physiol 540 (Pt 3):1023-1037, 2002. 12. Quick CM, Venugopal AM, Gashev AA, Zawieja DC, Stewart RH: Intrinsic pump-conduit behavior of lymphangions, Am J Physiol Regul Integr Comp Physiol 292(4):R1510-R1518, 2007. 13. Wang ZB, Li M, Li JC: Recent advances in the research of lymphatic stomata, Anat Rec 293(5):754-761, 2010. 14. Drake RE, Abbott RD: Effect of increased neck vein pressure on intestinal lymphatic pressure in awake sheep, Am J Physiol Regul Integr Comp Physiol 262(5 Pt 2):R892-R894, 1992. 15. Stewart RH, Rohn DA, Allen SJ, Laine GA: Basic determinants of epicardial transudation, Am J Physiol Heart Circ Physiol 273(3 Pt 2): H1408-H1414, 1997. 16. Dongaonkar RM, Quick CM, Stewart RH, et al: Edemagenic gain and interstitial fluid volume regulation, Am J Physiol Regul Integr Comp Physiol 294(2):R651-R659, 2008. 17. Miyamoto M, McClure DE, Schertel ER, et al: Effects of hypoproteinemiainduced myocardial edema on left ventricular function, Am J Physiol Heart Circ Physiol 274(3):H937-H944, 1998. 18. Adamson RH: Permeability of frog mesenteric capillaries after partial pronase digestion of the endothelial glycocalyx, J Physiol 428(1):1-13, 1990. 19. Huxley VH, Williams DA: Role of a glycocalyx on coronary arteriole permeability to proteins; evidence from enzyme treatments, Am J Physiol Heart Circ Physiol 278(4):H1177-H1185, 2000. 20. Betteridge KB, Arkill KP, Neal CR, et al: Sialic acids regulate microvessel permeability, revealed by novel in vivo studies of endothelial glycocalyx structure and function, J Physiol 595(15):5015-5035, 2017. 21. Uchimido R, Schmidt EP, Shapiro NI: The glycocalyx: a novel diagnostic and therapeutic target in sepsis, Critical Care 23(1):16, 2019. doi:10.1186/ s13054-018-2292-6.

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22. Halbgebauer R, Braun CK, Denk S, et al: Hemorrhagic shock drives glycocalyx, barrier and organ dysfunction early after polytrauma, J Crit Care 44:229-237, 2018. 23. Aziz M, Jacob A, Yang W, Matsuda A, Wang P: Current trends in inflammatory and immunomodulatory mediators in sepsis, J Leukoc Biol 93:329-342, 2013. 24. Lord JM, Midwinter MJ, Chen Y, et al: The systemic immune response to trauma: an overview of pathophysiology and treatment, Lancet 384: 1455-1465, 2014. 25. Ma Y, Yang X, Chatterjee V, et al: Role of neutrophil extracellular traps and vesicles in regulating vascular endothelial permeability, Front Immunol 10:1037, 2019. doi:10.3389/fimmu.2019.01037. 26. Drake RE, Gabel JC: Effect of histamine and alloxan on canine pulmonary vascular permeability, Am J Physiol Heart Circ Physiol 239(8):H96-H100, 1980. 27. Gabel JC, Hansen TN, Drake RE: Effect of endotoxin on lung fluid balance in unanesthetized sheep, J Appl Physiol 56(2):489-494, 1984. 28. Korthuis RJ, Wang CY, Spielman WS: Transient effects of histamine on the capillary filtration coefficient, Microvasc Res 28:322-344, 1984. 29. Johnston MG, Gordon JL: Regulation of lymphatic contractility by arachidonate metabolites, Nature 293(5830):294-297, 1981. 30. Ferguson MK, Shahinian HK, Michelassi F: Lymphatic smooth muscle responses to leukotrienes, histamine and platelet activating factor, J Surg Res 44:172-177, 1988. 31. Reed RK, Liden A, Rubin K: Edema and fluid dynamics in connective tissue remodeling, J Mol Cell Cardiol 48(3):518-523, 2010. doi:10.1016/j. yjmcc.2009.06.023. 32. Reed RK, Rubin K: Transcapillary exchange: role and importance of the interstitial fluid pressure and the extracellular matrix, Cardiovasc Res 87(2):211-217, 2010. doi:10.1093/cvr/cvq143. 33. Wiig H, Rubin K, Reed RK: New and active role of the interstitium in control of interstitial fluid pressure: potential therapeutic consequences, Acta Anaesthesiol Scand 47(2):111-121, 2003. 34. Nedrebø T, Reed RK, Berg A: Effect of alpha-trinositol on interstitial fluid pressure, edema generation, and albumin extravasation after ischemia- reperfusion injury in rat hind limb, Shock 20(2):149-153, 2003. 35. Laine GA: Microvascular changes in the heart during chronic arterial hypertension, Circ Res 62(5):953-960, 1988. 36. Gashev AA, Delp MD, Zawieja DC: Inhibition of active lymph pump by simulated microgravity, Am J Physiol Heart Circ Physiol 290(6): H2295-H2308, 2006. 37. Desai KV, Laine GA, Stewart RH, et al: Mechanics of the left ventricular myocardial interstitium: effects of acute and chronic myocardial edema, Am J Physiol Heart Circ Physiol 294(6):H2428-H2434, 2008. doi:10.1152/ ajpheart.00860.2007. 38. Dongaonkar RM, Nguyen TL, Quick CM, et al: Adaptation of mesenteric lymphatic vessels to prolonged changes in transmural pressure, Am J Physiol Heart Circ Physiol 305(2):H203-H210, 2013. doi:10.1152/ajpheart. 00677.2012. 39. Davis KL, Laine GA, Geissler HJ, et al: Effects of myocardial edema on the development of myocardial interstitial fibrosis, Microcirculation 7(4):269-280, 2000. 40. Drake RE, Doursout MF: Pulmonary edema and elevated left atrial pressure: four hours and beyond, News Physiol Sci 17:223-226, 2002. 41. Radhakrishnan RS, Shah SK, Lance SH, et al: Hypertonic saline alters hydraulic conductivity and up-regulates mucosal/submucosal aquaporin 4 in resuscitation-induced intestinal edema, Crit Care Med 37(11):2946-2952, 2009. doi:10.1097/CCM.0b013e3181ab878b. 42. Woie K, Westerberg E, Reed RK: Lowering of interstitial fluid pressure will enhance edema in trachea of albumin-sensitized rats, Am J Respir Crit Care Med 153(4 Pt 1):1347-1352, 1996. 43. Rodt S, Åhlén K, Berg A, Rubin K, Reed RK: A novel physiologic function for platelet-derived growth factor-BB in rat dermis, J Physiol 495(Pt 1): 193-200, 1996. 44. Lidén Å, Berg A, Nedrebø T, Reed RK, Rubin K: Platelet-derived growth factor BB-mediated normalization of dermal interstitial fluid pressure after mast cell degranulation depends on b3 but not b1 integrins, Circ Res 98(5):635-641, 2006.

12 Patient Suffering in the Intensive Care Unit Matthew S. Mellema, DVM, PhD, DACVECC KEY POINTS • Suffering is “an experience of unpleasantness and aversion associated with the perception of harm or threat of harm in an individual.” • Pain is far from the only unpleasant sensation critically ill animals are likely to experience.

• Relief of as many forms of patient suffering as possible is likely to lead to improved outcomes.

Patient suffering is a difficult topic to discuss in the clinical setting. A common perception is that the topic of animal suffering has been coopted (some might say hijacked) by animal welfare advocates, including those perceived as extremist in their viewpoints. This perception seems to have led to a reactive pushback and reluctance to address the topic by many small animal clinicians. If this is the case, then it is unfortunate and also incompatible with the veterinarian’s oath, which includes a mandate to use our training in “the prevention and relief of animal suffering.” Another factor that may limit clinician consideration of patient suffering is the perception that if there are larger, more acutely life-threatening aspects of critical illness that require our attention, then patient suffering is a minor issue in the grander scheme of things and can be underevaluated or undertreated. Suffering in animals is challenging to define because of the inability of the patients to verbalize their perception of their sense of well- being. One definition of suffering is that it is “the state of undergoing pain, distress, or hardship;” however, this definition is overly focused on pain and provides little guidance to clinicians. A more useful definition might be that suffering is “an experience of unpleasantness and aversion associated with the perception of harm or threat of harm in an individual.” The author prefers this definition because it can more easily be tied to the physiology of homeostasis in vertebrates. It captures the key concept that suffering is linked to the perception of both genuine harm and potential harm. It also offers the flexibility of treating harm as a multidimensional parameter rather than equating it to a single unpleasant sensation (e.g., pain). This definition allows for the consideration of the different forms of suffering that may be either physical or mental in nature and that there is a continuous range in the intensity of suffering rather than just a binary state (e.g., mild, moderate, severe versus a present/absent model). If one adopts the authors’ preferred definition of suffering, then it can be put into a larger physiologic context that has relevance to critical illness and patient assessment. By focusing on patient perception of real or potential harm, one is led directly to the consideration of how animals monitor their body systems for harm and how their behavior changes in response to harm surveillance signals. Vertebrates have a range of what some have called “primal alert signals” that appear to be highly conserved across species. These signals are linked to the fundamental needs required by animals to maintain homeostasis. Further, these signaling systems are designed to alert the animal to threats to

these needs being met and drive both aversive and adaptive behaviors. The responses to these alarm signals can occur at the cortical and subcortical levels. The best understood of these primal alert signals is pain. Pain is the alert signal tied to tissue integrity surveillance. Real or perceived threats to tissue integrity will be monitored by nociceptive fibers, conveyed by associated transmission pathways, and processed at brainstem and cortical centers. Activation of these receptors will lead to both aversive and adaptive behavioral responses. For example, if a child places his or her finger into a flame, then nociception will result in the reflex withdrawal of the finger (aversive response) and then the child will know not to repeat the process in the future based on the pain perception (adaptive behavior). Although pain is an important alarm signal with great relevance to both animal suffering and clinical practice, there are several others and some evidence to suggest that pain is not the most unpleasant among them.

72

MASLOW’S HIERARCHY OF NEEDS AND PRIMAL ALERT SIGNALS A consideration of animal suffering is inextricably linked to the consideration of their behavior. Indeed, ill animals have such a consistent clustering of disease manifestations when they are ill that the term sickness behavior has arisen to describe the four most common clinical signs associated with illness (i.e., fever, lethargy, anorexia, cachexia).1 Psychologists have long sought to develop an understanding of what drives human behavior. One widely influential model was proposed by Abraham Maslow in 1934 and has come to be known as Maslow’s hierarchy of needs model.2 In Maslow’s framework, much of human (and perhaps animal) behavior is attributed to the perpetual drive to meet specific needs. These drives are akin to instincts. What was unique about Maslow’s work was that he explicitly described a hierarchy and a continuum of dependencies. That is to say, Maslow considered that not all needs are of equal importance and proposed that humans will not exhibit behaviors designed to meet higher order needs (e.g., personal achievement) unless basic needs (e.g., food, water, shelter) are first adequately met. Maslow arranged the needs that may drive human behavior into a pyramid with the most important or essential needs at the bottom (Fig. 12.1). The needs were arranged into several tiers (physiologic, safety, love/belonging, esteem, and self-actualization). Physiologic needs were assigned preeminence.

73

CHAPTER 12  Patient Suffering in the Intensive Care Unit Physiologic need

Sleep

Selfactualization Morality, creativity, spontaneity, acceptance, experience purpose, meaning and inner potential

Nutrient intake

Water balance

Self-esteem Confidence, achievement, respect of others, the need to be a unique individual

Toxin avoidance/clearance

Love and belonging Friendship, family, intimacy, sense of connection

Tissue integrity preservation

Safety and security Health, employment, property, family and social stability

Air; alveolar ventilation

Physiologic needs Breathing, food, water, shelter, clothing, sleep Fig. 12.1  Maslow’s original hierarchy of human needs. Highest priority needs are at the bottom of the pyramid. These needs must be met for needs in a tier lying above them to receive priority. Few would dispute that most of the highest priority needs are shared between humans and animals (excluding clothing, which in some cases may actually lead to patient suffering via humiliation; see also “dogs in sweaters”).

Although sociology and psychology have moved on to embrace attachment theory as an alternative explanation of human behaviors, Maslow’s hierarchy of needs remains better suited to application in veterinary clinical practice. Each of the physiologic needs may be linked to a primal alert signal that provides input regarding whether that need is being met or is under potential threat. Pain may be considered the alert signal linked to threats to tissue integrity. Dyspnea is considered the signal linked to alveolar ventilation adequacy. Thirst and hunger herald threats to water and nutrient balance, respectively. Hunger may be a more nuanced signal that can be altered to drive behaviors geared toward meeting fairly specific nutrient requirements (e.g., cravings, pica). Nausea is likely tied to toxic threats or waste excretion and drives both aversive behaviors (vomiting) and adaptive behaviors (food aversion). Not all the primal alert signals are clearly evident as distinct or unique sensations, yet behavioral changes are still evident. Sleep is a fundamental need of vertebrate species and yet to date no specific, unique sensation linked to sleep inadequacy has been described. Feelings of drowsiness are nonspecific and may be elicited in subjects that have little or no sleep debt under some conditions (e.g., postprandial somnolence). Because primal alert signals linked to procreation have little or no relevance to critical care, the authors have elected to exclude them from this chapter. Some researchers have expanded Maslow’s hierarchy into subhierarchies. For example, physiologic needs are not all given equal priority (Fig. 12.2). The available evidence indicates that the need for air is assigned the top priority. This proposed relationship comes from the finding in human hospice patients with both pain and dyspnea where these patients report that dyspnea is the more unpleasant sensation of

Primal alert signal

Drowsiness

Hunger

Thirst

Nausea

Pain

Dyspnea

Fig. 12.2  A second subhierarchy of the basic physiologic needs and the primal alert signals used to herald real or perceived threats to meeting those needs.

the two.3 In laboratory-induced models of pain and dyspnea, one finds that concurrent dyspnea makes pain less noticeable, whereas the converse is not true (i.e., pain does not make dyspnea less unpleasant). Animal studies have compared how unpleasant dyspnea is versus hunger and find that in most species animals will remain starved rather than seek out food that is made available in an environment that will result in sensations of dyspnea (e.g., argon-filled chamber). Consideration of some, but perhaps not all, of these primal alert signals is a routine part of critically ill patient assessment. In the present era, it would be assumed by the authors that clinicians are frequently monitoring patients for evidence of pain. Signs of respiratory distress are often equated with sensations of dyspnea in veterinary practice. Periodic assessment of hunger, thirst, and nausea may also be performed. Patients may be considered to have a significant sleep debt when microsleeps become apparent. Microsleeps are brief (1- to 60-second) periods of involuntary sleep that occur regardless of what the patient is doing (e.g., briefly falling asleep while sitting upright). Increases in the delta state effectively shut down the brain for a brief period in response to a large sleep debt. Surveillance for the evidence of activation of these primal alert signals is a routine part of clinical practice whether it is done with a recognition of this conceptual framework or not. One entire specialty of medical practice (i.e., palliative care) is devoted to the recognition and alleviation of these symptoms/clinical signs, but all clinicians share a responsibility to monitor for these signs of basic needs not being met in their patients. As described earlier, pain research has dominated the field of patient suffering research. This has clearly been to the patients’ benefit, but much work remains to be done in expanding our understanding of other unpleasant sensations and how they may be alleviated. A growing body of evidence from human intensive care medicine suggests that even at the finest institutions symptom relief is far from optimal. In a study by Denise Li and colleagues out of the University of California at San Francisco, the prevalence of unaddressed symptoms (i.e., unpleasant sensations interfering with a sense of well-being) was 100%.4 All patients reported some degree of dyspnea (i.e., shortness of

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PART I  Key Critical Care Concepts

r  0.74 Tiredness

Generalized discomfort r  0.52

r  0.79

Thirst

r  0.79 r  0.54 Anxiety

r  0.58

Dyspnea

r  0.52 Feelings of depression

Hunger Fig. 12.3  Correlation between symptoms in critically ill human patients.4

breath). Prevalence rates were also quite high for most of the other symptoms that were evaluated (thirst, tiredness, anxiety, hunger, generalized discomfort, pain, dyspnea, depressed feelings, and nausea). Interestingly, this study found that there was a high degree of correlation between some symptoms and others (Fig. 12.3). These associations may be of use in veterinary intensive care. For example, in Fig. 12.3 one finds a high correlation among thirst, tiredness, general discomfort, and anxiety. This suggests that in patients that appear anxious and uncomfortable, providing greater opportunity for rest and meeting water intake needs may have a crossover benefit that translates to less sedative and analgesic need. A similar study by Nelson et al., which focused on cancer patients in the ICU setting, identified prevalence rates of greater than 50% for six different symptoms (all at a moderate to severe level).5 The six symptoms that had these high prevalence rates were discomfort, unsatisfied thirst, difficulty sleeping, anxiety, pain, and unsatisfied hunger. Depression and dyspnea were also identified in 34% to 39% of patients at moderate to severe levels. These same authors also investigated symptom burden in a population of chronically critically ill human patients, and in this group prevalence rates of greater than 50% were identified for all 16 symptoms assessed (weight loss, lack of energy, inappetence, pain, dry mouth, hunger, drowsiness, dyspnea in two settings, insomnia, nausea, difficulty communicating, thirst, worried, sad, and nervous).6 Clearly, some but not all of these symptoms may be relevant to small animal patients. For example, although human patients expressed distress over weight loss, it strains credibility to think that dogs are overly concerned with body image. However, this study does raise some interesting points. Human patients appeared to find dry mouth distressing and unpleasant. Although mucous membrane hydration is frequently assessed in small animal patients, the authors’ impression is that little or no effort is made to maintain membrane moisture as a therapeutic goal.

Impact of Symptom Relief Data would suggest that clinicians are far more likely to consider palliative relief as an important goal in and of itself when such measures can be tied to clinical outcomes. There is evidence that failure to address symptoms in humans and animal models can be linked to both outcomes and physiologic derangements. The ICU can be a noisy environment, and sleep patterns may be frequently disrupted by the chaos and commotion that can occur at unpredictable intervals. Studies in dogs in which their sleep was frequently disrupted by an alarm sounding have demonstrated that such sleep fragmentation leads to systemic hypertension. Considering the number of equipment alarms

(e.g., ventilators, fluid pumps, syringe pumps) that may go off on a typical overnight shift in a busy veterinary ICU, it is not implausible to consider that this noise burden may contribute to cardiovascular instability in some cases. An industry-academia summit was convened recently to address “alarm fatigue” in the human ICU setting.7 Addressing the human toll of alarm signals and hospital noise was the major focus of this meeting. Moreover, it has been shown that symptom experience is an independent predictor of important outcomes in human critically ill patients. Symptom distress has also been associated with unfavorable outcomes including higher mortality rates. Conversely, reduction of symptom burden may promote favorable outcomes such as physiologic stability and reduced resource expenditures. Taken together, the available evidence suggests that greater attention to relief of clinical signs may yield improved outcomes even when clinicians don’t consider palliative measures to be their own reward.

Palliative Measures Some aspects of palliative care may appear self-evident and represent current standard of care, whereas others might require a revision of patient care protocols. Addressing thirst, hunger, and pain in a proactive manner can be easily justified. Consideration should be given to offering small amounts of oral liquids to maintain membrane moisture (even when oral intake should be limited) and increase patient comfort. Providing adequate opportunity for uninterrupted sleep should also be a primary goal. Clustering treatments to minimize patient awakenings is advised. Providing quiet periods with reduced lighting overnight is recommended whenever feasible. Greater vigilance for signs of nausea and earlier intervention may be warranted based on the human ICU experience. Serial monitoring using validated pain scoring systems is advised as well. Nebulized furosemide may provide symptomatic relief from dyspnea, as may opioid administration. It is advised to encourage owner visitations and to make efforts to get patients outside for a portion of each day whenever such measures would not represent an undue risk. Providing opportunities for patients to express normal behaviors may enhance comfort and reduce anxiety. In summary, pain is far from the only unpleasant sensation critically ill animals are likely to experience. The application of a broader definition of animal suffering in the hospital environment may lead to more comprehensive palliative care being provided and to improved outcomes. Increased patient comfort is likely to also lead to improved workplace safety and reduction in negative patient–caregiver interactions as patient tolerance of handling is enhanced.

REFERENCES 1. Tizard I: Sickness behavior, its mechanisms and significance, Anim Health Res Rev 9(1):87, 2008. 2. Zalenski RJ, Raspa R: Maslow’s hierarchy of needs: a framework for achieving human potential in hospice, J Palliat Med 9(5):1120, 2006. 3. Banzett RB, Gracely RH, Lansing RW: When it’s hard to breathe, maybe pain doesn’t matter, J Neurophysiol 97:959, 2007. 4. Li DT, Puntillo K: A pilot study on coexisting symptoms in intensive care patients, Appl Nurs Res 19(4):216, 2006. 5. Nelson JE, Meier DE, Oei EJ, et al: Self-reported symptom experience of critically ill cancer patients receiving intensive care, Crit Care Med 29(2):277, 2001. 6. Nelson JE, Meier DE, Litke A, et al: The symptom burden of chronic critical illness, Crit Care Med 32(7):1527, 2004. 7. Improving clinical alarms: fall summit aims to develop action plan, Biomed Instrum Technol (Suppl 7), 2011.

13 Predictive Scoring Systems in Veterinary Medicine Galina Hayes, BVSc, PhD, DACVECC, DACVS, Karol Mathews, DVM, DVSc, DACVECC

KEY POINTS • Scoring systems objectively quantify an individual patient’s risk of experiencing a defined medical event. • Scoring systems can be used to triage, assist medical decision making, and trend patient progression over time. • In clinical research, scoring systems can facilitate analytic control when observational study associations are confounded by illness

severity and can also be used to demonstrate equivalence of treatment groups. • It is important to assess the predictive accuracy of any score in a patient population distinct from that which was used to derive the score weightings.

DEFINITION

negatively impact a patient. For example, a risk probability should not be used, at least in isolation, to justify withdrawal of care. In general terms, the utility of severity scores is lower when applied to individual patients compared with clinical research populations. However, severity scores can provide an objective measure to assist prognostication and supplement clinical judgment. This may help ensure that owner consent is appropriately informed and that expectations are realistic. Daily score calculation has been used to facilitate objective patient trending1 and decide on the appropriate location of care, such as inpatient versus outpatient.2 Scores indicating high risk can be used to prompt modification of interventions (i.e., high American Society of Anesthesiologists physical status classifications may prompt different drug selections and monitoring protocols for animals undergoing anesthesia). Some examples of veterinary clinical scoring systems and their modeled outcomes are shown in Table 13.1. In general terms, however, at the individual patient level, the utility of any score is an adjunct to, rather than replacement for, the clinical judgment of the primary clinician. This acknowledges the ability of an individual patient to confound any algorithm, no matter how sophisticated.

A scoring system is an algorithm applied to a patient’s characteristics that generates a numeric value. This value reflects the probability of the modeled diagnosis or outcome. Similar to the flow of any clinical assessment, scoring systems typically assign various weights to combinations of clinical signs, components of the medical history, and diagnostic test results to generate a prognosis or guide a treatment decision. However, unlike an individual clinician’s assessment, the risk prediction generated by a scoring system is repeatable both within and between patients and clinicians, is uncolored by recent experience, and is generated from clinical components that have been identified to be statistically associated with outcome in large numbers of patients. In the ideal approach, a clinician synthesizes an individual patient’s plan by integrating probabilistic information generated by a score with their own medical knowledge and acumen.

OUTCOME PROBABILITY VS. CLINICAL DECISION AID TOOLS Scoring systems typically generate a risk probability for a specific modeled outcome, such as death, survival duration, need for a specific intervention, or final diagnosis. Although it may be tempting to employ score cut-offs to prompt specific interventions, such as increased monitoring for dogs at higher risk of complications after airway surgery, the desired reduction in risk resulting from this type of change in practice cannot be assumed to occur until demonstrated in appropriately designed clinical trials.

APPLICATIONS IN CLINICAL PRACTICE Severity scores can provide an objective tool that can be used to assist baseline patient assessment at admission or some other defined time point. However, the confidence interval that surrounds a risk probability for an individual is inherently substantially wider than that generated for a population risk probability. For this reason, it is considered inappropriate to use a severity score as a sole measure to prompt an intervention that might

APPLICATIONS IN HOSPITAL MANAGEMENT Quantification of unit workload may be necessary to appropriately manage staffing, equipment, and workspace needs. Case numbers alone can lack sophistication as a surrogate measure of workload, particularly when cases are complex. Workload may be more accurately quantified as the sum of the total illness severity burden. Similarly, when comparing care unit treatment outcomes, allowance should be made for the average illness severity of the cases managed by that unit. Outcomes will always be better when illness severity is lower, and case illness severity should not be assumed to be homogenous between treatment centers.

APPLICATIONS IN RESEARCH Descriptive Studies Reporting a score that has a known and previously validated association with illness severity provides important contextual information in purely

75

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PART I  Key Critical Care Concepts

TABLE 13.1  Select Veterinary Clinical Scoring Systems and their Modeled Outcomes Score

Patient Group

Modeled Outcome

Score Range

Publication Reference

American Society of Anesthesiologists Physical Status Score (ASA PS) Canine Acute Patient Physiologic and Laboratory Evaluations (APPLE) score Feline Acute Patient Physiologic and Laboratory Evaluations (APPLE) score Animal Trauma Triage (ATT) score

Dogs and cats undergoing general anesthesia Dogs admitted to ICU

Perianesthetic death

I to V 1/2 E

Death or euthanasia over the period of hospitalization

0–80 (APPLEfull)

Bille, Auvigne, Libermann, Vet Anesth Analg 2012; 39:59-68 Hayes, Mathews, Doig, J Vet Intern Med 2010; 24:1034-1047

Death or euthanasia over the period of hospitalization

0–80 (APPLEfull)

Survival 7 days post trauma

0–18

Death or disease associated euthanasia at 30 d post admission Survival 48 hr later

0–18

3–18

Platt SR, Radaelli ST, McDonnell JJ. The prognostic value of the modified Glasgow Coma Scale in head trauma in dogs. J Vet Intern Med. 2001 Nov-Dec;15(6):581-4. doi: 10.1892/ 0891-6640(2001)0152.3.co;2. PMID: 11817064.

Composite of need for postoperative oxygen support for .48 hr, need for a postoperative tracheostomy, or death Survival at 24 hr after birth

0–10

Tarricone, Hayes, Singh, Vet Surg 2019; 48(7):1253-1261

0–10

Survival to discharge and dialysis free at 30 d post discharge Hemangiosarcoma diagnosis

1.11–42.15

Veronesi, Panzani, Faustini, Theriogenology 2009; 72:401-407 Segev, Kass, Francey, J Vet Intern Med 2008; 22:301-308

Diagnosis of hypoadrenocorticism

Probability of diagnosis

Cats admitted to ICU

Canine Acute Pancreatitis Severity (CAPS) score

Dogs and cats following trauma Dogs with acute pancreatitis

Modified Glasgow Coma Scale (mGCS)

Dogs admitted after acute head trauma

Brachycephalic Risk (BRisk) score

Brachycephalic dogs undergoing airway surgery

Apgar score

Puppies at 5 min after birth Dogs with AKI undergoing hemodialysis

Hemodialysis outcome score (model B) Hemangiosarcoma Likelihood Prediction (HeLP) score Hypoadrenocorticism prediction model

Dogs with spontaneous hemoabdomen Dogs with suspect hypoadrenocorticism based on clinical signs

0-50 (APPLEfast)

0-50 (APPLEfast)

0–100

Hayes, Mathews, Doig, J Vet Intern Med 2011; 25:26-38 Rockar, Drobatz, Shofer, J Vet Emerg Crit Care 1994; 4(2):77-83 Fabres, Dossin, Reif, J Vet Intern Med 2019; 33:499-507

Schick, Hayes, Singh, J Vet Emerg Crit Care 2019; 29:239-245 Borin-Crivellenti, Garabed, Moreno-Torres, Am J Vet Res 2017; 78:1171-1181

AKI, acute kidney injury.

descriptive studies such as case reports or case series, giving observations greater interpretability and external validity.3 High external validity allows study findings to be better generalized to the wider population.

Observational Studies The ability to select the most efficacious treatment, or form an accurate prognosis, may be impeded in the absence of well-designed observational studies or randomized controlled trials. Case series and retrospective observational studies make up a substantial proportion of the veterinary literature. These often rely on case accrual over several years and are subject to many pitfalls including lack of case homogeneity and lack of defined control groups. The findings of observational studies may be hampered by confounders, defined as the presence of an extraneous factor distorting the relationship between the outcome and the variable under study.4 Control of confounders minimizes erroneous conclusions about the relationships between exposure and outcome. A common confounder of the relationship between treatment and outcome is illness severity; a clinician-induced selection bias occurs when a treatment is applied with greater frequency in the more severely ill, and this bias may create an inappropriate association between the treatment and mortality that is a result of confounding by illness severity. Objective quantification of illness

severity facilitates analytical control of this variable and can improve the quality of observational studies. In one approach, a minimum or maximum illness score can be set as a predefined criterion for study entry. Alternatively, illness severity can be entered as a covariable with treatment in a regression analysis of treatment effect on outcome. This approach will allow the effect of treatment on outcome to be estimated, while controlling for illness severity. It may also be useful to demonstrate equivalent illness severity among treatment or exposure groups, despite lack of formal randomization. With the increasing availability of appropriately validated scores in veterinary medicine, research use is likely to increase.

DEMONSTRATION OF EFFECTIVE OR INEFFECTIVE RANDOMIZATION IN RANDOMIZED CONTROLLED TRIALS The process of randomization in controlled trials is intended to equally distribute potential confounding factors such as age or degree of illness severity among treatment groups and thus eliminate the effects of confounding. However, when case numbers are small or confounding factors are numerous or variable, randomization may

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CHAPTER 13  Predictive Scoring Systems in Veterinary Medicine not be successful in achieving this goal, and inaccurate estimates of a treatment effect can result. Delineating the severity of illness of animals assigned to treatment and control groups allows for both documentation and analytical control of ineffective randomization, decreasing the risk of an important treatment effect being missed or wrongly assessed.5

basis can be challenging due to the lack of practicality or appropriateness of in-depth owner questioning at a time of emotional stress. Clinician subjectivity and clinician misconceptions can also be sources of error.9 Handling of euthanized patients in veterinary models varies from complete exclusion10 through exclusion of some subsets11 to complete inclusion.12

REDUCTION OF REQUIRED SAMPLE SIZES

CRITICAL APPRAISAL

Illness severity scores are an effective tool by which to improve power and decrease the sample size required to detect a significant difference between treatment or exposure groups in clinical research. Stratifying patients by severity of illness to ensure patient group homogeneity can decrease the sample size required to measure an effect.6 Multivariable regression can be thought of conceptually as the ultimate form of stratified analysis. In this context, the overall sample size required to identify a statistically significant measure of effect between a variable and outcome is decreased when an additional variable that explains a significant degree of the data variation is introduced.7

The key test of any prediction system is not how it performs in the training data set from which it was derived but whether it retains its predictive value in another test data set. While many studies report score performance characteristics only on the training data, these estimates of accuracy must be viewed with caution.13 The theoretically ideal score will hold its predictive utility when applied to a noncontemporary population at a different treatment center. It is up to the potential score user to critically assess the test and validation populations for similarity or otherwise. A number of statistical techniques are available to summarize predictive accuracy. Score discrimination is assessed using the area under the receiver operator characteristic (AUROC). This is a plot of the sensitivity versus the specificity of the score for predicting the outcome of interest in the population being assessed. Typically, a score probability of .0.5 is set as the threshold for predicting the outcome to occur, although this can be adjusted to prioritize sensitivity over specificity and vice versa. Predicted positive and negative outcomes are assessed against true positive and negative outcomes. The ideal discriminator will have a curve which touches the upper left-hand corner of the graph, and the area under the curve would be 1.0 (see Fig. 13.1). In comparison, a discriminator no better than chance alone will have a diagonal line running from bottom left to top right, and an AUROC of 0.5. An example of interpretation for a mortality outcome score with an AUROC of 0.8 would be that for two animals, one of which survived, and one did not, the score had an 80% likelihood of identifying the animal at higher risk. One caveat to be aware of when assessing a

0.

85

=

0.

95

1.0

A

75

0.8

0.

50

0.6

0.

Development of a scoring system has been well described8 but typically begins with defining the outcome of interest (e.g., intraoperative death) and then collecting patient data on a number of variables that might reasonably be hypothesized to be associated with that outcome (e.g., intraoperative hemorrhage). In the ideal situation, patient data are collected from two groups with the same selection criteria but that are receiving treatment at two independent centers or groups of centers. Once data collection is complete, the variables most strongly associated with outcome are identified, and data from one center is used to provide the weightings for score calculation. The accuracy of the score at predicting the outcome is then tested against the data from the second center. While the process of deriving the weightings (typically from a regression analysis) requires some statistical skill, the calculation of the score is generally straightforward requiring only adding or subtracting, together with looking up a reference table or graph. When constructing a score of this type, several key points are worth emphasizing. First, the variable weightings have to be “trained” on a reasonable number of outcomes to perform robustly; as a general rule at least 10 of the outcomes of interest (i.e., at least 10 deaths, if deaths are being modeled) are needed per variable in the score, and the more the better. Too many variables and too few outcomes risk overfitting the model and poor prospective performance. Second, variable selection needs to be pragmatic; if very few centers have the ability to measure the variable being used, then score uptake is likely to be poor. Thirdly, many medical parameters have a biologically nonlinear association with risk outcomes. For example, both very high and very low heart rates may be associated with increased mortality risk, and this needs to be accounted for in the modeling process. Finally, if mortality is used as the modeled outcome, then the way in which euthanized animals are to be handled needs to be considered. The performance and timing of euthanasia reflects multiple factors, including severity of patient illness, owner financial and emotional status, diagnosis of a disease anticipated to be terminal at some future point, subjective assessments of degree of suffering, and individual clinician perspective. If all euthanized patients are excluded from the model development data set, available patient data may be limited and biased. If all patients are included regardless of euthanasia status, the significance of a particular variable as a risk factor for death may be masked by patients euthanized for financial reasons. Attempting to determine the exact reason for euthanasia and discriminate among patient subsets on that

True-positive proportion

CONSTRUCTION OF SCORING SYSTEMS

0.4

0.2

0 0

0.2

0.4

0.6

0.8

False-positive proportion Fig. 13.1  Area under the receiver operator characteristic curve.

1.0

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PART I  Key Critical Care Concepts

40

.6

0

0

.2

20

.4

No dogs

Negative outcome risk

60

.8

1

78

0

2

4

6 BRisk score

Predicted negative outcome risk

8

10

Measured negative outcome risk per BRisk category

No. dogs per BRisk score category Fig. 13.2  Relationship between the number of dogs in each BRisk score group in the study population (n 5 283), the measured negative outcome risk for each of those groups, and the outcome predicted using the BRisk score. BRisk, brachycephalic risk. From Tarricone J, Hayes G, Singh A, Davis G: Development and validation of a brachycephalic risk (BRisk) score to predict the risk of complications in dogs undergoing surgical treatment of brachycephalic obstructive airway syndrome, Vet Surg 48(7):1253-1261, 2019.

score performance by an AUROC value alone is that when the outcome event is rare, the proportion of false positives, and thus specificity, will drive accuracy. For example, in an ICU with a mortality risk of 5%, a score that predicted 100% survival for every patient would have an AUROC of 0.95, and yet it clearly has no utility as a classifier. AUROC generates excessively optimistic estimates of discriminative performance when the frequency of nonevents greatly exceeds the frequency of events.14 A complementary, and often more informative, measure of score performance is calibration. In a perfectly calibrated model, 8 of 10 animals with an 80% predicted probability of mortality would die, and 2 of 10 would survive. Conversely, 99 of 100 animals with a 1% risk would survive. Well-calibrated models estimate individual event probabilities that reflect the true distribution of risk in the population. A useful graphic (see Fig. 13.2) for examining this capacity of a score is a plot of predicted risk outcomes versus observed risk outcomes over the range of the score; a superimposed histogram showing the number of test animals contributing to each risk category can also be helpful in giving the reader a sense of the stability of the risk estimates. This score characteristic can be tested formally in the context of a logistic regression model using the Hosmer–Lemeshow test.15

CONCLUSION In conclusion, predictive scoring systems can be used to complement the clinician’s clinical judgment, provide objective trends of patient progression, and assist in the triage of patients to different levels of care or intervention. In the research setting, they can enable analytic

control of disease severity and demonstrate the effectiveness of randomization for achieving treatment group equivalence at baseline. Critical appraisal of scores is important before choosing to employ them routinely in clinical practice, and seeking evidence of external validation of the score is an important component of this.

REFERENCES 1. Ferreira FL, Bota DP, Bross A, Melot C, Vincent JL: Serial evaluation of the SOFA score to predict outcome in critically ill patients, J Am Med Assoc 286(14):1754-1758, 2001. 2. Meneghini RM, Ziemba-Davis M, Ishmael MK, Kuzma AL, Caccavallo P: Safe selection of outpatient joint arthroplasty patients with medical risk stratification: the Outpatient Arthroplasty Risk Assessment Score, J Arthroplasty 32(8):2325-2331, 2017. 3. Le Gall JR: The use of severity scores in the intensive care unit, Intensive Care Med 31:1618-1623, 2005. 4. Dohoo I, Martin W, Stryhn H: Confounder bias: analytic control and matching. In McPike M, editor: Veterinary epidemiologic research, Charlottetown, PEI, Canada, 2007, VER Inc., pp 235-270. 5. Higgins TL: Severity of illness indices and outcome prediction. In Fink MP, Abraham E, Vincent JL, Kochanek PM, editors: Textbook of critical care, Philadelphia, 2005, Elsevier Saunders, pp 2195-2206. 6. Higgins TL: Quantifying risk and benchmarking performance in the adult intensive care unit, J Intensive Care Med 22:141-156, 2007. 7. Greenland S: Introduction to regression models. In Rothman KJ, Greenland S, Lash TL, editors: Modern epidemiology, Philadelphia, 2008, Lippincott Williams, pp 381-417.

CHAPTER 13  Predictive Scoring Systems in Veterinary Medicine 8. Zhang Z, Zhang H, Khanal MK: Development of scoring systems for risk stratification in clinical medicine: a step by step tutorial, Ann Transl Med 5(21):436, 2017. 9. Rockar RA, Drobatz KS: Development of a scoring system for the veterinary trauma patient, J Vet Emerg Crit Care 4:77-82, 1994. 10. Brewer BD, Koterba AM: Development of a scoring system for the early diagnosis of equine neonatal sepsis, Equine Vet J 20:18-22, 1988. 11. Segev G, Kass PH, Francey T, Cowgill LD: A novel clinical scoring system for outcome prediction in dogs with acute kidney injury managed by hemodialysis, J Vet Intern Med 22:301-308, 2008.

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12. Rohrbach BW, Buchanan BR, Drake JM, et al: Use of a multivariable model to estimate the probability of discharge in hospitalised foals that are seven days of age or less, J Am Vet Med Assoc 228:1748-1756, 2006. 13. Seymour DG, Green M, Vaz FG: Making better decisions: construction of clinical scoring systems by the Spiegelhalter-Knill-Jones approach, Br Med J 300:223-226, 1990. 14. Leisma D: Rare events in the ICU: an emerging challenge in classification and prediction, Crit Care Med 46:418-424, 2018. 15. Hosmer DW, Lemeshow S: Assessing the fit of the model. In Shewhart WA, Wilks SS, Hosmer DW, Lemeshow S, editors: Applied logistic regression, New York, 2000, Wiley and Sons, pp 143-202.

PART II  Respiratory Disorders

14 Control of Breathing Kate S. Farrell, DVM, DACVECC KEY POINTS • The medulla is considered the respiratory center, and it is the site responsible for the generation of the respiratory pattern and coordination of voluntary and involuntary input that can alter breathing activity. • Within the medulla is a collection of neurons known as the central pattern generator, which acts as a group pacemaker system that produces the basic rhythm of breathing. • Other areas of the central nervous system, including the pontine respiratory group, the cortex, and other higher centers, can alter the respiratory pattern.

Breathing is automatically initiated by the central nervous system (CNS) and occurs largely without conscious awareness. The respiratory center in the fetal brainstem develops early in pregnancy and continues throughout life to generate spontaneous cycles of inspiration and exhalation.1,2 While neurons in the medulla initiate and coordinate control of breathing without conscious input, the automatic cycle of inspiration and exhalation can be altered or interrupted by commands from higher centers of the brain (such as the cortex and hypothalamus), by involuntary actions (such as swallowing, coughing, or sneezing), and by feedback from multiple sensors, including central chemoreceptors, peripheral chemoreceptors, and receptors in the lung parenchyma and airways. Ultimately, this neuronal network controls activity of the motor neurons that innervate the respiratory muscles, resulting in changes in ventilation. In this regard, there can be finetuning of gas exchange in the lungs to meet metabolic demands of the body, allowing O2 and CO2 to be maintained within a narrow range in the normal patient.

CENTRAL CONTROL OF BREATHING The respiratory center of the brain resides in the medulla, where complex collections of neurons form a group pacemaker system known as the central pattern generator (CPG). While the medullary respiratory center is considered essential for generation of the basic rhythm of breathing, influences from other regions of the CNS, including the pontine respiratory group, the cortex, and other higher centers, can alter this pattern. Each of these regions is discussed in more detail below.

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• Central chemoreceptors sense changes in carbon dioxide and pH, while peripheral chemoreceptors also sense changes in oxygenation, and the combined input from these receptors can alter the respiratory pattern to help return blood gases to normal. • Carbon dioxide has a major influence on breathing in health, whereas the partial pressure of oxygen must generally fall to less than 50–60 mm Hg to induce large changes in ventilation. • Receptors in the lungs and airways and other sensory receptors are also involved in reflex mechanisms that can modify the respiratory pattern.

Respiratory Central Pattern Generator To produce a spontaneous respiratory rhythm, collections of associated neurons within the medulla generate intrinsic recurring bursts of neuronal activity. This complex network of neurons acts as a group pacemaker system and is known as the CPG. While neurons involved in this group pacemaker activity are spread throughout the medulla, they are concentrated in a region known as the pre-Bötzinger complex (discussed below). Multiple groups of neurons with intrinsic firing patterns are recognized to contribute to this pacemaker activity, and they can be classified into categories based on shape (augmenting, decrementing, or constant/plateau) and phase of respiration.1,3-5 The resulting respiratory cycle consists of three phases.1,4,5 The first is the inspiratory phase, characterized by a sudden onset of activity of early inspiratory neurons and a ramp increase in inspiratory augmenting neurons, resulting in motor discharge to inspiratory muscles and airway dilators. The next phase is the postinspiratory phase or expiratory phase I, characterized by declining motor discharge to inspiratory muscles and passive exhalation. Expiratory decrementing neurons decrease in activity, resulting in a decline in laryngeal adductor muscle tone that functions as a mechanical brake to expiratory flow. In the final stage, expiratory or expiratory phase II, there is no inspiratory muscle activity. During quiet normal breathing, exhalation is almost entirely passive. During active exhalation, such as during exercise, voluntary forced exhalation, or high minute volumes, expiratory augmenting neurons support expiratory muscle activity. This CPG functions automatically and generates periodic firing to produce respiratory rhythmogenesis. The spontaneous activity

CHAPTER 14  Control of Breathing exhibited by these respiratory neurons is dependent on intrinsic membrane properties and neurotransmitters required for excitatory and inhibitory feedback mechanisms. Similar to cardiac pacemaker cells, multiple types of sodium, potassium, and calcium ion channels are required for the generation of intrinsic membrane activity.4,5 Key neurotransmitters involved in synaptic interactions in the CPG include glutamate (typically excitatory), and GABA and glycine (inhibitory). Additionally, acetylcholine, monoamines, and various neuropeptides act as neuromodulators that, while not essential to rhythmogenesis, can exert significant influence on the CPG.5

Medullary Respiratory Center Located within the brainstem, the medulla is considered the respiratory center and is the region responsible for the generation of the respiratory pattern and coordination of respiratory activity. There are many neuronal connections into and out of the medulla. Neurons related to respiratory function are mostly clustered in two anatomic locations known as the dorsal and ventral respiratory groups. Dorsal respiratory group. The function of the dorsal respiratory group (DRG) is primarily timing of the respiratory cycle.1 The DRG is composed of mostly inspiratory neurons that project to the contralateral spinal cord. These neurons initiate activity in the phrenic nerves, which innervate the diaphragm. Positioned bilaterally in the medulla, the DRG lies in close relation to the nucleus tractus solitarius at the termination of visceral afferents from cranial nerves IX (glossopharyngeal) and X (vagus).1 These nerves carry sensory information that may influence control of breathing, including pH and arterial partial pressures of O2 and CO2 (from carotid and aortic chemoreceptors) and systemic arterial blood pressure (from carotid and aortic baroreceptors).6 The vagus nerve also transmits information from stretch receptors and other sensors in the lungs. Given the location of the DRG, it may serve as a site for the integration of cardiopulmonary reflexes that can alter the pattern of breathing.6 Ventral respiratory group. The ventral respiratory group (VRG) consists of inspiratory and expiratory neurons located in four main collections: the caudal ventral respiratory group (including the nucleus retroambigualis and nucleus paraambigualis), the rostral ventral respiratory group (mostly comprised of the nucleus ambiguus), the pre-Bötzinger complex, and the Bötzinger complex (within the nucleus retrofacialis).1 The caudal respiratory group has expiratory function and governs the force of contraction of inspiratory muscles; the rostral ventral respiratory group controls airway dilator functions of the larynx, pharynx, and tongue; and the Bötzinger complex has extensive expiratory functions. As discussed above, the pre-Bötzinger complex is thought to be essential for pacemaker activity that is responsible for central pattern generation.

Pontine Respiratory Group The pontine respiratory group (PRG) is a collection of neurons located in the pons that functions to fine-tune the breathing pattern via multisynaptic connections to the medullary respiratory center.1 This region corresponds to what was formerly called the “pneumotaxic center”.1,3,6 While the PRG is no longer considered essential for respiratory rhythm generation, the activity of its neurons does act to influence the timing of the respiratory phases, stabilize the breathing pattern, and alter the respiratory rhythm.3 In particular, increased activity of neurons in this region can promote termination of inspiration, and experimental lesions in the PRG have been shown to cause an increase in the duration of inspiration.3 There are many central afferent pathways that connect with the PRG, including those from the cortex, hypothalamus, and nucleus tractus solitarius, suggesting that the pons

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serves as a coordinating center for input from the CNS, peripheral sensors, and cardiovascular reflexes.1 The “apneustic center” is a region located in the caudal pons that has also classically been described in animals and is involved in coordination of speed of inspiration and exhalation. Excitatory impulses from this center to the inspiratory area of the medulla tend to prolong inspiration.7 Experimental lesions in animals disconnecting this region from the PRG, along with vagal transection, result in an abnormal pattern of breathing called apneusis, which is characterized by prolonged gasping inspiratory efforts punctuated by brief inefficient expiratory efforts.3,6 The exact role that this region plays in normal breathing has not been fully elucidated.

Cortex and Other Higher Centers Breathing can occur under voluntary control with input from the cerebral cortex and other suprapontine structures, though interruptions and alterations to the breathing pattern are limited primarily by changes in arterial blood gases. Neuronal input from the cerebral cortex can override impulses from the brainstem or may completely bypass the respiratory center to directly innervate respiratory muscle lower motor neurons.1 In addition to voluntary changes in the respiratory pattern, numerous involuntary suprapontine reflexes alter breathing during actions such as vocalization, sneezing, coughing, swallowing, mastication, vomiting, and hiccupping. There is also experimental and clinical evidence from disease states that other suprapontine structures, such as the hypothalamus and amygdala, can exert strong modulating influence on the normal respiratory pattern generated in the brainstem.8,9 These higher centers can influence respiratory responses during hypoxia, hypercapnia, exercise, thermal changes, pain, and responses to other stressors (e.g., fear, anxiety, defense response).8,9

DESCENDING PATHWAYS Ultimately, axons originating in the brainstem, cerebral cortex, and other suprapontine structures descend along pathways in the white matter of the spinal cord to directly affect lower motor neurons to different groups of respiratory muscles. The respiratory muscles primarily involved in inspiration include the diaphragm, chest wall muscles, and some neck muscles. Active exhalation requires muscles of the abdominal and chest walls. Muscles of the pharynx and larynx also help control upper airway resistance.10

CHEMORECEPTORS AND RESPONSE TO BLOOD GASES While the medulla is the center for initiating and coordinating breathing, regulation of the respiratory pattern is a complex process that involves feedback loops from multiple types of sensors in the body (Fig. 14.1). A chemoreceptor is a type of sensory receptor that responds to alterations in the chemical composition of blood or fluid in which it is immersed. Afferent information from central chemoreceptors (located primarily in the medulla) and peripheral chemoreceptors (located in the aortic and carotid bodies) is transmitted to the respiratory center and provides input that affects automatic regulation of breathing. Central chemoreceptors are responsible for the majority of the response to changes in CO2 and pH, whereas peripheral chemoreceptors exclusively respond to hypoxemia and are also influenced by CO2 and pH. Ultimately, changes in the body’s partial pressure of CO2 (PCO2), pH, and partial pressure of O2 (PO2) trigger alterations in alveolar ventilation that return these variables to their target values.

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PART II  Respiratory Disorders

Medullary respiratory center

Higher brain centers (+⁄–)

Pontine respiratory center (+⁄–)

Central chemoreceptors (+) CO2, H+

Carotid body peripheral chemoreceptors (+) O2, CO2, H+

Aortic arch peripheral chemoreceptors (+) O2, CO2, H+

Pain, temperature, and touch receptors (+)

Muscle and joint receptors (+)

Respiratory muscles

Pulmonary stretch receptors (–) Irritant receptors (+) J receptors (+)

+ : Stimulus increases rate/depth of breathing – : Stimulus decreases rate/depth of breathing

Fig. 14.1  The medulla is considered the center for control of breathing and is the location for the generation of the respiratory rhythm. The medullary respiratory center receives input from other centers in the brain, the central and peripheral chemoreceptors, and multiple other types of receptors in the body that can alter the central respiratory pattern and affect neuronal output to the respiratory muscles. (Illustration by Chrisoula Toupadakis Skouritakis, PhD.)

Central Chemoreceptors Central chemoreceptors are primarily located on the ventrolateral surface of the medulla, close to the origins of the glossopharyngeal and vagus nerves. Many other areas of the CNS, including locations within the brainstem, cerebellum, hypothalamus, and midbrain, show increased neural activity with CO2 stimulation and are proposed as additional central chemosensitive areas; however, their contribution to respiratory control remains unclear.11 Central chemoreceptors are sensitive to changes in brain interstitial fluid pH, which mainly results from changes in PCO2 but is influenced to some degree by cerebral blood flow and brain metabolism.11 Central chemoreceptors do not respond to changes in PO2. While it was historically believed that the respiratory center itself reacted to changes in CO2, it is now recognized that central chemoreceptors are anatomically separate from respiratory neurons of the medulla. Neurons in the

region of the central chemoreceptors have connections to the nearby CPG and thereby function to modify ventilation.1 The PCO2 of blood ultimately helps to regulate ventilation by affecting the pH of the extracellular fluid surrounding central chemoreceptors. Because this interstitial fluid in the brain is in contact with cerebrospinal fluid (CSF), changes in the pH of the brain interstitial fluid and CSF affect ventilation. When arterial PCO2 rises, it causes a concurrent elevation in the PCO2 of venous blood, brain interstitial fluid, and CSF, which are typically 5–10 mm Hg higher than arterial PCO2.1,6 While the blood brain barrier is relatively impermeable to hydrogen and bicarbonate ions, CO2 molecules diffuse freely across this barrier. CO2 that diffuses into the CSF and brain interstitium becomes hydrated and forms carbonic acid, which rapidly dissociates to H1 and HCO3- ions. As the brain interstitium and CSF lack much of the buffering capability of blood due to considerably lower protein

CHAPTER 14  Control of Breathing levels, an elevation in arterial PCO2 results in a significant rise in H1 concentration (and therefore decrease in pH) of the brain extracellular fluid and CSF.7 Furthermore, an increase in arterial PCO2 is accompanied by cerebral vasodilation, and this enhances the diffusion of CO2 into the brain interstitium. This change in pH as a result of altered CO2 levels is believed to affect central chemoreceptors, though the exact mechanism by which this occurs remains disputed.1,11 Following a rise in arterial PCO2 and subsequent decline in brain interstitial pH, respiratory rate and depth are altered to allow return of PCO2 to normal. After several hours, if PCO2 remains elevated, the pH of extracellular fluid in the brain is partially corrected by compensatory changes in bicarbonate concentration, which ultimately restores ventilation to normal, blunting the response to CO2 over time.1

Peripheral Chemoreceptors Peripheral chemoreceptors lie within the carotid bodies close to the bifurcation of the common carotid arteries and within the aortic bodies located along the aortic arch. It is almost exclusively the carotid bodies that are responsible for the respiratory response, whereas the aortic bodies have a greater influence on circulation.1 Peripheral chemoreceptors respond rapidly, within 1–3 seconds, to a decline in PaO2, a rise in PaCO2, an increase in H1 concentration, or hypoperfusion.1 It has been suggested that stimulation of peripheral chemoreceptors is related to decreased PaO2 rather than decreased oxygen content, resulting in little stimulation due to anemia or dyshemoglobinemias.1 However, controversy remains on this subject, and there is some evidence to suggest direct peripheral chemoreceptor stimulation secondary to anemia.12 While the response to PCO2 is more rapid in peripheral chemoreceptors, the change is quantitatively less than that produced on the central chemoreceptors. An increase in blood temperature can also stimulate peripheral chemoreceptors and enhances the ventilatory responses to changes in O2 and CO2. Other drugs and chemical stimulants are known to affect peripheral chemoreceptors as well. Oxygen sensing occurs in specialized cells called type I (glomus) cells that compose the highly vascularized chemoreceptors. Potassium channels in these cells are inhibited either directly by hypoxia or by hypoxia-induced molecules such as reactive oxygen species, carbon monoxide, or hydrogen sulfide.1 This results in modulation of neurotransmitter release from glomus cells. Afferent information from these cells is transmitted to the respiratory center via the carotid sinus nerves (branches of the glossopharyngeal nerve from the carotid bodies) and vagus nerve (from the aortic bodies), resulting in increased rate and depth of breathing. In addition to these effects, stimulation of peripheral chemoreceptors can also result in other consequences, including bradycardia, hypertension, increased bronchiolar tone, and adrenal secretion of catecholamines.1

Integration of Responses to O2, CO2, and pH Through input from central and peripheral chemoreceptors that is assimilated in the respiratory center, alterations in PCO2, pH, and PO2 result in changes to the respiratory pattern that return these variables to their normal values. In the healthy individual, PCO2 is the most important factor affecting control of breathing. Central chemoreceptors have been attributed to account for approximately 60%–80% of the response to CO2, as compared to peripheral chemoreceptors.1,13 One study in awake dogs demonstrated that central chemoreceptors accounted for 63% of the steady-state response to increases in arterial PCO2, though there was significant dog-to-dog variability.14 Because central chemoreceptors appear to rely on extracellular pH within the brain, they are considered

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monitors of steady-state arterial PCO2 and cerebral tissue perfusion, while peripheral chemoreceptors detect and react to rapid and shortterm changes in arterial PCO2, though the response to peripheral chemoreceptors results in less profound changes in ventilation.1 Overall, an increase in PaCO2 results in a nearly linear increase in alveolar ventilation.1,6 This increase in ventilation is amplified by hypoxemia and metabolic acidosis. As opposed to PCO2, variations in oxygenation play a minimal role in health, and progressive hypoxemia results in a hyperbolic increase in ventilation. Hypoxemia causes changes in ventilation primarily through the stimulation of peripheral chemoreceptors, but it has no effect on central chemoreceptors; hypoxemia may also cause changes in ventilation at higher integrating sites. When PaO2 is near the normal range, a decrease in its value to less than 100 mm Hg results in a small increase in alveolar ventilation, whereas a large change in alveolar ventilation does not occur until PaO2 falls below 50–60 mm Hg.1,6,7 Conversely, if there is concurrent elevation of PCO2, changes in ventilation occur with only minimal decreases in PaO2. Exercise and metabolic acidosis also enhance the ventilatory response to hypoxemia, even without elevations in PCO2. In patients with chronic respiratory diseases resulting in hypercapnia, the response to elevated PCO2 is diminished, and hypoxemia becomes the principal stimulus for ventilation. While rare in veterinary medicine, administration of oxygen to these patients can result in a reduced ventilatory drive and severe hypercapnia.15 This is most classically seen in human patients with chronic obstructive pulmonary disease.

OTHER SENSORY RECEPTORS In addition to afferent input from chemoreceptors, information is transmitted from many receptors located in the lungs, airways, cardiovascular system, muscles, tendons, joints, skin, and viscera, all of which can generate reflexes that contribute to control of breathing (Fig. 14.1).

Lung and Airway Receptors Multiple receptors in the lungs and airways contribute to feedback loops that can alter respiratory rate and tidal volume, and some of these are discussed below. Pulmonary stretch receptors. Pulmonary stretch receptors, also known as slowly adapting pulmonary stretch receptors, are present in the smooth muscles of the airways. These receptors are activated in response to excessive and sustained distention of the lung and transmit information to the respiratory center (inspiratory area in the medulla and apneustic center of the pons) via large myelinated vagal fibers. Stimulation of these receptors causes inhibition of inspiratory discharge and slowing of the respiratory rate, resulting in the protective feedback loop known as the Hering–Breuer inflation reflex.1,6,7 An opposite response, known as the deflation reflex, initiates inspiratory activity with deflation of the lungs. Irritant receptors. Located in the epithelium of the nasal mucosa, upper airways, tracheobronchial tree, and possibly the alveoli, irritant receptors are activated by noxious gases, inhaled dust, cold air, and other mechanical and chemical stimuli.1,6,7 The receptors in the larger airways respond to stretch as well and are also referred to as rapidly adapting pulmonary stretch receptors. Irritant receptors transmit information largely via myelinated vagal afferent fibers, and their activation can result in bronchoconstriction, cough, laryngeal spasm, mucus secretion, and increased rate, and depth of breathing. Afferent pathways from receptors in the nasal mucosa send impulses via the trigeminal and olfactory tracts and can result in sneezing.6 J receptors. J receptors, or juxtacapillary receptors, are located in the pulmonary interstitium in close proximity to the pulmonary

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capillaries. These receptors are stimulated by pulmonary capillary distension, interstitial edema, and chemicals in the pulmonary circulation. Information is transmitted to the respiratory center via slowly conducting nonmyelinated C fibers of the vagus nerve, leading to a rapid, shallow breathing pattern or even apnea in extreme circumstances. J receptors are thought to result in the sensation of dyspnea in patients with diseases such as left-sided congestive heart failure and interstitial lung disease.

activates peripheral chemoreceptors and stimulates the medullary respiratory center. Additional respiratory stimulants include aminophylline/theophylline, caffeine, and progesterone. In addition to iatrogenic causes, intrinsic diseases can result in abnormalities in breathing. Causes of hypoventilation (see Chapter 17) and abnormal respiratory patterns witnessed with brain injury and intracranial hypertension (see Chapter 86) are discussed elsewhere.

Other Sensory Receptors

REFERENCES

In addition to those located within the respiratory system, receptors located in other regions of the body can help to adjust breathing patterns under certain circumstances. Arterial baroreceptors. The arterial baroreceptors are predominantly involved in regulation of the cardiovascular system, but they can also mediate ventilatory changes that occur with significant fluctuations in blood pressure.16 A marked decrease in arterial blood pressure sensed by the aortic and carotid sinus baroreceptors can result in reflex hyperventilation, while a substantial increase in blood pressure can cause hypoventilation. Muscle, tendon, and joint receptors. Somatic receptors located in muscles, tendons, and joints can also influence ventilation.6 For instance, receptors in muscles of respiration and rib joints respond to changes in length and tension of respiratory muscles and provide feedback regarding lung volume and work of breathing. Afferent fibers from the musculoskeletal system also likely play a large role in the hyperventilation induced by exercise. Pain and temperature. Receptors that detect pain, temperature, touch, and proprioception send information along ascending pathways of the spinal cord and can influence breathing. Painful stimuli detected by nociceptors can cause initial apnea followed by hyperventilation. An increase in temperature detected on the skin can also induce hyperventilation.

ABNORMALITIES IN THE CONTROL OF BREATHING The complex system that controls breathing is exquisitely fine-tuned and allows for moment-to-moment adjustments in ventilation to meet the metabolic demands of the body. However, drugs and diseases that affect the central and peripheral mechanisms that control respiration can have substantial effects on ventilation and the ability to maintain blood gases. Any drug that causes CNS depression may also result in respiratory depression, and almost all general anesthetic agents produce a dose-related decrease in ventilation. Opioids and benzodiazepines have been well documented to cause dose-dependent respiratory depression and impaired ventilatory response to hypoxemia and hypercapnia.1 Doxapram, on the other hand, is a CNS stimulant that

1. Lumb AB, editor: Control of breathing. In Nunn’s applied respiratory physiology, ed 8, Edinburgh, 2017, Elsevier, pp 51-72. 2. Blanco CE: Maturation of fetal breathing activity, Biol Neonate 65 (3–4):182-188, 1994. 3. Nogués MA, Roncoroni AJ, Benarroch E: Breathing control in neurologic diseases, Clin Auton Res 12(6):440-449, 2002. 4. Richter DW, Smith JC: Respiratory rhythm generation in vivo, Physiol 29(1):58-71, 2014. 5. Bianchi AL, Denavit-Saubie M, Champagnat J: Central control of breathing in mammals: neuronal circuitry, membrane properties, and neurotransmitters, Physiol Rev 75(1):1-45, 1995. 6. Levitsky MG, editor: Control of breathing. In Pulmonary physiology, ed 9, New York, 2018, McGraw Hill, pp 206-233. 7. West JB, Luks AM, editor: Gas transport by the blood. In West’s respiratory physiology: the essentials, ed 10, Philadelphia, 2016, Wolters Kluwer, pp 87-107. 8. Horn EM, Waldrop TG: Suprapontine control of respiration, Respir Physiol 114(3):201-211, 1998. 9. Kinkead R, Tenorio L, Drolet G, Bretzner F, Gargaglioni L: Respiratory manifestations of panic disorder in animals and humans: a unique opportunity to understand how supramedullary structures regulate breathing, Respir Physiol Neurobiol 204:3-13, 2014. 10. Lumb AB, editor: Pulmonary ventilation. In Nunn’s applied respiratory physiology, ed 8, Edinburgh, 2017, Elsevier, pp 73-88. 11. Nattie E, Li A: Central chemoreceptors: locations and functions, Compr Physiol 2(1):221-254, 2012. 12. Hatcher JD, Chiu LK, Jennings DB: Anemia as a stimulus to aortic and carotid chemoreceptors in the cat, J Appl Physiol 44(5):696-702, 1978. 13. Cloutier MM, Thrall RS: Control of respiration. In Koeppen BM, Stanton BA, editors: Berne & Levy physiology, ed 7, Philadelphia, 2018, Elsevier, pp 489-497. 14. Smith CA, Rodman JR, Chenuel BJA, Henderson KS, Dempsey JA: Response time and sensitivity of the ventilatory response to CO2 in unanesthetized intact dogs: central vs. peripheral chemoreceptors, J Appl Physiol 100(1):13-19, 2006. 15. Lumb AB, editor: Airway disease. In Lumb AB, editor: Nunn’s applied respiratory physiology, ed 8, Edinburgh, 2017, Elsevier, pp 389-405. 16. McMullan S, Pilowsky PM: The effects of baroreceptor stimulation on central respiratory drive: a review, Respir Physiol Neurobiol 174(1-2): 37-42, 2010.

15 Oxygen Therapy Elisa M. Mazzaferro, MS, DVM, PhD, DACVECC

KEY POINTS • Tissue hypoxia occurs in a variety of critical illnesses. Oxygen supplementation can improve oxygen delivery and decrease the incidence of lactic acidosis. • Supplemental oxygen administration should be provided whenever a patient’s PaO2 is less than 70 mm Hg or their oxygen saturation (SpO2) is less than 93% on room air. • Noninvasive means of oxygen supplementation, including flow-by, mask, hood, high-flow nasal cannula and oxygen cages, are simple ways to provide an oxygen-enriched environment to a critical patient.

• High-flow nasal oxygen cannula and machines are available from human medical supply sources for use in veterinary patients and can improve oxygenation in severely hypoxemic animals. • Tracheal oxygen supplementation provides a higher FiO2 than nasal or noninvasive means of oxygen therapy, but it is technically slightly more difficult and has greater inherent risks to the patient.

In clinical medicine the term hypoxia is defined as a decrease in the level of oxygen supply to the tissues, whereas hypoxemia strictly refers to inadequate oxygenation of arterial blood and is defined as a PaO2 less than 80 mm Hg (at sea level) (see Chapter 16, Hypoxemia). Because hypoxemia reduces the oxygen content of the arterial blood (CaO2), it may result in tissue hypoxia. Oxygen delivery to the tissues (DO2) is dependent on the product of cardiac output and CaO2 (Box 15.1); as such, increases in cardiac output can prevent tissue hypoxia in hypoxemic patients. Hypoxemia can occur as a result of hypoventilation, ventilation– perfusion mismatch, diffusion impairment, decreased oxygen content of inspired air, and intrapulmonary shunt (see Chapter 16, Hypoxemia). Global oxygen delivery is often reduced in systemic illnesses such as sepsis, systemic inflammatory response syndrome, anemia, and acid-base imbalances.

indicated in patients with a PaO2 less than 70 mm Hg or SaO2 less than 93% on room air or if the patient’s effort at breathing is increased and at risk of respiratory fatigue.1 Oxygen supplementation is also indicated in patients with other causes of low DO2 such as cardiovascular instability or anemia in an effort to prevent tissue hypoxia. Oxygen therapy can be divided into noninvasive and somewhat invasive administration techniques. The type of oxygen supplementation method of delivery is largely dependent on each patient’s individual needs and tolerance, patient size, the degree of hypoxemia, the level of fraction of inspired oxygen (FiO2) desired, the anticipated length of oxygen supplementation required, clinical experience and skill, and equipment and monitoring available.2

ARTERIAL OXYGEN CONTENT

A variety of methods for oxygen supplementation exist. Ideally, all methods include some kind of humidification source in order to avoid drying and irritation of the nasal mucosa and airways if long-term oxygen therapy is required. The administration of nonhumidified oxygen for more than several hours will result in drying and dehydration of the nasal mucosa, respiratory epithelial degeneration, impaired mucociliary clearance, and increased risk of infection.2 A supplemental oxygen source can easily be humidified by bubbling the delivered oxygen through a bottle of sterile saline or water.2 As oxygen is bubbled through the liquid, it becomes humidified and accumulates above the surface of the solution. The gas that collects can then be delivered through a length of oxygen tubing to the patient’s oxygen source, whether it is a mask or tube into some component of the respiratory tract. Commercial bubble humidifiers are readily available and can be a convenient way to provide humidified oxygen; however, they may result in inadequate humidification at high flow rates.3,4 Highflow oxygen delivery systems provide a heat source to air-oxygen

Arterial oxygen content depends on the concentration of hemoglobin and the binding affinity or degree of oxygen saturation (SaO2) of the hemoglobin present. The majority of arterial oxygen is delivered to tissues while bound to hemoglobin. A small fraction is delivered as dissolved (or unbound [0.003 3 PaO2]) in plasma (see Box 15.1). Provision of supplemental oxygen by increasing the fraction of inspired oxygen over 21% is an effective means of increasing both bound and unbound oxygen in arterial blood, provided that a pulmonary parenchymal shunt is not present.1

INDICATIONS FOR OXYGEN THERAPY Oxygen supplementation aims to increase CaO2, which is of particular benefit to the hypoxemic animal but is considered of benefit to all patients at risk of tissue hypoxia. Supplemental oxygen administration is

METHODS OF OXYGEN ADMINISTRATION Humidification

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BOX 15.1  Equation of Oxygen Delivery (DO2) DO2 5 Q 3 CaO2 Where Q 5 cardiac output and CaO2 5 arterial oxygen content and is calculated as: CaO2 5 [1.34(ml O2/g) 3 SaO2 (%) 3 Hemoglobin (g/dl)] 1 [PaO2(mm Hg) 3 0.003 (ml O2/dl/mm Hg)]

admixtures and improve humidification of oxygen delivered to the patient5 without the adverse effects of desiccating the nasal mucosa.

Noninvasive Methods Flow-by Oxygen Flow-by oxygen supplementation is one of the simplest techniques to utilize in an emergent patient. Flow-by oxygen provides an increased concentration of oxygen to the patient when a length of oxygen tubing (ideally connected to a humidified oxygen source although not essential for short-term therapy) is held adjacent to or within 2 cm of a patient’s nostril.6 An oxygen flow rate of 2 to 3 L/min generally provides an FiO2 of 25% to 40%.7 An advantage of this technique is that it is generally well tolerated by most patients and can be used while initial triage and assessment are being performed. Because this technique also delivers a large quantity of oxygen to the surrounding environment, it is thus wasteful and not appropriate or economical for long-term use.

Face Mask Short-term oxygen supplementation can be administered by placing a face mask over a patient’s muzzle, then delivering humidified oxygen or tank oxygen in a circle rebreathing or a nonrebreathing circuit. With a tight-fitting face mask, flow rates of 8 to 12 L/min can provide an FiO2 of up to 50% to 60%.6,7 With loose-fitting face masks, higher flow rates of 2 to 5 L/min are recommended, depending on the size of the patient and degree of hypoxemia. With a tight-fitting face mask, rebreathing of CO2 can occur. The face mask should be vented periodically or changed to a looser face mask or alternate means of oxygen supplementation as soon as possible. Awake and coherent patients often do not tolerate oxygen delivered by face mask for long periods. An attendant must be present to ensure that the mask does not become detached and that the patient does not struggle or damage its eyes with the edge of the mask.6,7 Advantages of this technique are that minimal equipment is required and that the patient can be simultaneously treated and evaluated in emergent situations.

Oxygen Hood Several varieties of oxygen hoods are available from commercial manufacturers or can be easily made in hospital with cling film (e.g., Saran Wrap), tape, and a rigid Elizabethan collar. To create an oxygen hood, the front of a rigid Elizabethan collar is covered with lengths of cling film taped in place. A small portion of the front is left open to room air to allow the hood to vent. The collar is then placed over the patient’s neck and secured snugly. A length of oxygen tubing is placed through the back of the collar and taped to the side of the collar so that it doesn’t become dislodged with patient movement. Once the oxygen hood has been flooded with oxygen (1 to 2 L/min), oxygen flow rates of 0.5 to 1 L/min typically will deliver an FiO2 of 30% to 40%,8,9 depending on the size of the patient and how tightly fitted the collar is around the patient’s neck. With extremely small patients, such as toy breeds or neonates, the entire patient can be placed into the collar for a homemade oxygen tent or mini-cage. Some patients will not tolerate the collar and can become hyperthermic. If left unvented, CO2 and

moisture can accumulate within the hood and contribute to patient distress. Overall, an oxygen hood is an economical and practical means of supplemental oxygen administration and is generally well tolerated by most patients.

Oxygen Cage Supplemental oxygen can be delivered into a Plexiglas box to administer higher FiO2 concentrations than nasal, hood, or flow-by oxygen.8,9 Oxygen cages that control oxygen concentration, humidity, and temperature are available from commercial sources. The cages are also vented to decrease buildup of expired CO2. Oxygen cages can be manufactured from human pediatric incubator units into which humidified oxygen is supplied through a length of oxygen tubing. FiO2 levels can reach up to 60% or higher, depending on the size of cage and patient and oxygen flow rate, but typically are maintained at 40% to 50%.2,8,9 Oxygen cages are very useful, but they are an expensive means of administering supplemental oxygen because oxygen within the cage is let out into the external environment whenever the cage is opened. In some patients, hyperthermia can develop if the temperature within the cage is not maintained at 70°F (22°C).8,9 Ice packs can be placed within an oxygen cage to decrease ambient temperature, but they should not be placed directly on the patient because peripheral vasoconstriction can potentially exacerbate hyperthermia. Although many authors describe lack of direct patient access as a disadvantage of this oxygen supplementation technique, the use of continuous monitoring of pulse oximetry, blood pressure, and electrocardiogram allow patient monitoring through the Plexiglas cage doors.8,9

Invasive Methods Nasal Prongs Human nasal prongs can be used in medium and large dogs. They are easy to place, relatively inexpensive, and well tolerated by most dogs. The disadvantages include the ease with which the animal can dislodge the nasal prongs and the unknown FiO2 they supply. It is likely that nasal prongs would provide an FiO2 similar to or possibly higher than flow-by oxygen but less than that provided with a nasal oxygen catheter.

Nasal and Nasopharyngeal Oxygen If supplemental oxygen is going to be required for more than 24 hours, placement of a nasal or nasopharyngeal oxygen catheter should be considered. Nasal oxygen catheters are fairly simple to place, require minimal equipment, and are generally well tolerated by most patients.9 Oxygen insufflation catheters can be placed into the nasal cavity or directly into the nasopharyngeal region by a similar technique. To place a nasal oxygen catheter, the patient’s nasal passage should be anesthetized first with topical 2% lidocaine or proparacaine. Next, the tip of a 5- to 10-French (depending on patient size) red rubber or polypropylene catheter should be premeasured. To approximate the distance to advance a nasal oxygen catheter, it should be premeasured from the nose to the level of the lateral canthus of the eye and the distance marked on the tube using a permanent marker. The tip of the tube is lubricated, and the tube is gently inserted into the ventral nasal meatus to the level of the mark on the tube. To enter the ventral meatus, it may be necessary to angle the tube ventromedially when inserted. The tube can be secured adjacent to the nostril with suture or staples. The length of tube can then be secured to the lateral maxilla or between the patient’s eyes with suture or staples. To help prevent patient intolerance of the tube, be sure to avoid securing the tube to the patient’s whiskers. Oxygen should be provided from a humidified oxygen source to avoid drying and irritation of the nasal mucosa. A large range of FiO2 can be provided by nasal catheters, depending on the size

CHAPTER 15  Oxygen Therapy of the animal, respiratory rate, and panting or mouth breathing.8-11 Flow rates of 50 to 150 ml/kg/min can provide 30% to 70% FiO22,10,11 (Table 15.1). Higher flow rates can be irritating to the patient and cause sneezing. Total oxygen flow rates provide similar tracheal FiO2 when provided through one catheter or divided between two nasal catheters.8-11 Sneezing and patient intolerance can be alleviated in most cases with reapplication of a topical anesthetic or advancement of the nasal catheter into the nasopharyngeal region. The method to place a nasopharyngeal catheter is almost identical to the placement of a catheter into the nasal meatus, with the exception of the anatomic landmark of where to premeasure the tube. After application of the topical anesthetic, the tip of the catheter is placed at the ramus of the mandible and marked at the tip of the nose (Fig. 15.1). The lubricated tube is then placed ventromedially into the ventral nasal meatus. To facilitate passage of the tube ventrally and medially to the turbinates, the lateral aspect of the nostril should be pushed medially, and the patient’s nasal philtrum pushed dorsally as the tube is passed. Once the tube has been passed to the level of the mark on the tube, it can be secured to the patient’s face in an identical manner as the nasal oxygen catheter. Overzealous pressure as either tube is placed can result in epistaxis. After placement of a nasal or nasopharyngeal catheter, an Elizabethan collar should be placed to help avoid iatrogenic tube dislodgement by the patient. A length of oxygen tubing attached to a humidified oxygen source can be attached to the proximal end of the nasal tube with a cut 1-ml syringe or Christmas tree adapter.

TABLE 15.1  Nasal Oxygen Flow Rates and

Associated Tracheal FiO27

Total Oxygen Flow Rate (ml/kg/min) 50

Tracheal FiO2 (%) 29.8 6 5.6

100

37.3 6 5.7

200*

57.9 6 12.7

400*

77.3 6 13.5

Note: The 400 ml/kg/min flow rate was achieved by bilateral nasal oxygen catheters each at 200 ml/kg/min. *Patient discomfort is often noted with flow rates above 100 ml/kg/ min.

Fig. 15.1  Measurement of a red rubber catheter to the ramus of the mandible in preparation for placement of a nasopharyngeal oxygen catheter.

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High-Flow Nasal Oxygen High-flow oxygen devices12 are available from human medical sources and have been used with success in small animal patients.3,5,13 The high-flow oxygen system mixes medical grade air with an oxygen source and then heats it with a water source to provide humidification. The heated, humidified air-oxygen admixture is then passed through a membrane prior to delivery with various sized nasal prongs and circuit tubing, depending on patient size. Manufacturer recommendations suggest that nasal prong size should be no larger than 50% of the diameter of the patient’s nares, to allow for adequate removal of exhaled gases.3 With high-flow oxygenation methods, FiO2 and flow rates can be adjusted from 21%–100% and 25–60 L/min, respectively.13 The recommended starting flow rate for use in clinical patients is 0.4–2.0 L/kg/min for optimal tolerance.13 High-flow nasal oxygen has the ability to provide a higher FiO2 than other nasal oxygen administration techniques as well as the potential to provide continuous positive airway pressure. See Chapter 31, High Flow Nasal Oxygen for more details on this technique.

Transtracheal Oxygen Placement of a catheter directly into the trachea is an effective means of administering increased FiO2 to patients that are intolerant of nasal or hood oxygen, are panting or displaying open-mouthed breathing, or have an upper airway obstruction. Although this technique is more labor intensive and requires a higher degree of skill than placement of a nasal catheter, higher FiO2 with a degree of continuous airway pressure is provided14 and can be beneficial for patients who require a higher degree of supplemental oxygen than that provided with a nasal catheter but who do not require mechanical ventilation, such as animals with severe bronchopneumonia. The use of these techniques in patients with upper airway obstruction should be performed with caution as the animal may not be able to exhale adequately and pulmonary overdistension can occur. It is generally used as a very short term, lifesaving intervention while a patent airway is secured in these patients. Two methods of tracheal oxygen supplementation have been described. The first method uses a through the needle large-bore catheter placed percutaneously through the skin and underlying tissues directly into the trachea.8,14 The patient’s ventral cervical region should be clipped from just proximal to the larynx to the thoracic inlet and laterally off of midline. To avoid iatrogenic introduction of bacteria and debris into the tracheal lumen, aseptic technique must be followed at all times. The clipped area should be aseptically scrubbed. A small bleb of 2% lidocaine should be placed at the level of the third through fifth tracheal ring, infiltrating the subcutaneous tissues and skin as the needle is backed out. The area is aseptically scrubbed again. Wearing sterile gloves, the patient’s trachea is gently palpated, then grasped in the operator’s fingers for stabilization. A small nick incision can be made through the skin with a #11 scalpel blade to decrease tissue drag as the catheter is inserted. The needle of the catheter is then inserted through the skin (with or without the nick incision), through the subcutaneous tissue and sternohyoideus muscle, and into the trachea. A pop will be felt as the needle enters the trachea. Once in place, the catheter with stylette is inserted through the needle into the tracheal lumen. The needle is then removed from the trachea once the catheter has been inserted to its hub. Depending on the size of the animal, the distal end of the catheter may run to the level of the carina. The catheter can be connected to a humidified oxygen source with a cut 1-ml syringe or Christmas tree adapter and oxygen run at a flow rate of 50 to 150 ml/kg/min.14 The catheter should be secured to the neck with lengths of white tape. Caution must be exercised to monitor the patient carefully because ventral flexion of the neck or excessive skin

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folds can cause kinking of the catheter and catheter occlusion. Excessive skin folds can be pulled dorsally and secured on dorsal cervical midline with several horizontal mattress sutures until the catheter is no longer required. The second method of intratracheal oxygen supplementation is more invasive and requires heavy sedation or the administration of a short-acting anesthetic agent such as propofol or fentanyl/diazepam (see Chapters 132 and 133). The patient’s ventral cervical region should be clipped and aseptically scrubbed in an identical manner as listed earlier. The area should be aseptically draped with sterile field towels and infiltrated with a local anesthetic (2% lidocaine, 1 to 2 mg/kg). A vertical skin incision should be made over the third through fifth tracheal rings. The subcutaneous tissues and sternohyoid muscle should be bluntly dissected with a curved hemostat or tips of a Metzenbaum scissors until the trachea is visible. A small incision is then made in between the fourth and fifth tracheal rings with a #11 scalpel blade, taking care to avoid cutting more than 50% circumference of the trachea. A curved hemostat is used to open the hole between tracheal rings, and a grooved director (from a spay pack) is inserted into the tracheal lumen. A large-bore multifenestrated catheter with a stylette is then inserted into the tracheal lumen along the grooved director. Once the catheter is inserted, the grooved director and catheter stylette can be removed and the catheter secured in place. A 4 3 4 square of sterile gauze with antimicrobial ointment should be placed over the incision and the catheter secured with lengths of white tape. The cranial and caudal edges of large skin incisions should be sutured with nonabsorbable suture. The benefit of this technique is that larger catheters can be inserted and administer continuous airway pressure at higher oxygen flow rates than other methods of oxygen supplementation. Oxygen flow rates of 50 ml/kg/min are required to achieve 40% to 60% FiO2.14 This technique is well tolerated by many patients and is economical but has the inherent risks associated with sedation, general anesthesia, and introduction of bacteria directly into the tracheal lumen. Jet lesions and damage to the trachea with tracheitis can occur with this technique.8

Hyperbaric Oxygen Hyperbaric oxygen administers 100% oxygen under supraatmospheric pressures (.760 mm Hg) to increase the percent of dissolved oxygen in the patient’s bloodstream by 10% to 20%.1,15 Dissolved oxygen can diffuse readily into tissues that are damaged and may not have adequate circulation. Hyperbaric oxygen has been recommended for the treatment of severe soft tissue lesions, including burns, shearing injuries, infection, and osteomyelitis. Ruptured tympanum and pneumothorax have been associated with the use of hyperbaric oxygen therapy. Hyperbaric oxygen is rarely used in veterinary medicine, given the expense of the equipment and space required for a specialized “dive chamber” in which to place the patients during treatment. An additional disadvantage is that once the dive chamber has been pressurized to supraatmospheric levels, the chamber cannot be opened to gain patient access should complications occur.

COMPLICATIONS OF OXYGEN THERAPY The administration of supplemental oxygen is not an innocuous treatment. Hypercapnia is the primary stimulus for respiration in normal patients. In patients with chronic respiratory disease and hypercapnia, however, hypercapnic respiratory drive can be diminished or lost and the patient becomes largely dependent on hypoxia as a respiratory

stimulant. The administration of supplemental oxygen to a chronically hypercapnic patient depresses the hypoxic respiratory drive and can result in severe hypoventilation and respiratory failure. Mechanical ventilation may be necessary to treat the severe hypercapnia and hypoxia that develop.1 This “blue bloater” syndrome is an uncommon occurrence in small animal medicine and is best described in human chronic obstructive pulmonary disease patients.

Oxygen Toxicity Oxygen therapy can be directly toxic to the pulmonary epithelium, and it is important to avoid prolonged exposure to high FiO2 levels. As a general rule, an FiO2 level of more than 50% should not be administered for longer than 24 to 72 hours to avoid pulmonary oxygen toxicity.16,17 See Chapter 8, Oxygen Toxicity for a more detailed discussion of this topic.

REFERENCES 1. Tseng LW, Drobatz KJ: Oxygen supplementation and humidification. In King LG, editor: Textbook of respiratory disease in dogs and cats, St Louis, 2004, Elsevier, pp 205-213. 2. Camps-Palau MA, Marks SL, Cornick JL: Small animal oxygen therapy, Comp Contin Educ Pract Vet 21(7):587, 2000. 3. Daly JL, Guenther CL, Haggerty JM, et al: Evaluation of oxygen administration with a high-flow nasal cannula to clinically normal dogs, Am J Vet Res 78(5):624, 2017. 4. Darin J, Broadwell J, MacDonnell R: An evaluation of water-vapor output from four brands of unheated, prefilled bubble humidifiers, Respir Care 27(1):41, 1982. 5. Keir I, Daly J, Haggerty J, Guenther C: Retrospective evaluation of the effect of high flow oxygen therapy delivered by nasal cannula on PaO2 in dogs with moderate-to-severe hypoxemia, J Vet Emerg Crit Care 26(4):598, 2016. 6. Wong AM, Uquillas E, Hall E, et al: Comparison of the effect of oxygen supplementation using flow-by or a face mask on the partial pressure of arterial oxygen in sedated dogs, N Z Vet J 67(1):36, 2019. 7. Loukopoulos P, Reynolds WW: Comparative evaluation of oxygen therapy techniques in anaesthetized dogs: face-mask and flow-by techniques, Aust Vet Practit 27(1):34, 1997. 8. Drobatz KJ, Hackner S, Powell S: Oxygen supplementation. In Bonagura JD, Kirk RW, editors: Current veterinary therapy XII: small animal practice, Philadelphia, 1995, WB Saunders, pp 175-179. 9. Loukopoulos P, Reynolds W: Comparative evaluation of oxygen therapy techniques in anaesthetized dogs: intranasal catheter and Elizabethan collar canopy, Aust Vet Practit 26(4):199, 1996. 10. Marks SL: Nasal oxygen insufflation, JAAHA 35(5):366, 1999. 11. Dunphy ED, Mann FA, Dodam JR, et al: Comparison of unilateral versus bilateral catheters for oxygen administration in dogs, J Vet Emerg Crit Care 12(4):245, 2002. 12. Matthay MA: Saving lives with high-flow nasal oxygen, N Engl J Med 372(23):2225, 2015. 13. Jagodich TA, Bersenas AME, Bateman SW, et al: Comparison of high flow nasal cannula oxygen administration to traditional nasal cannula oxygen therapy in healthy dogs, J Vet Emerg Crit Care 29:246, 2019. 14. Mann FA, Wagner-Mann C, Allert JA, Smith J: Comparison of intranasal and intratracheal oxygen administration in healthy awake dogs, Am J Vet Res 53(5):856, 1992. 15. Braswell C, Crowe DT: Hyperbaric oxygen therapy, Compend Contin Educ Vet 34:E1–E5, 2012. 16. Jackson RM: Pulmonary oxygen toxicity, Chest 86(6):900, 1985. 17. Mensack S, Murtaugh R: Oxygen toxicity, Compend Contin Educ Vet 21(4):341, 1999.

16 Hypoxemia Steve C. Haskins, DVM, MS, DACVAA, DACVECC, Deborah C. Silverstein, DVM, DACVECC

†

KEY POINTS • Hypoxemia is defined as a partial pressure of oxygen of less than 80 mm Hg or arterial blood hemoglobin saturation of less than 95%. • When cyanosis is manifested as a sign of hypoxemia, it is always a late sign of severe hypoxemia. • There are three causes of hypoxemia: low inspired oxygen concentration, hypoventilation, and venous admixture. • There are four causes of venous admixture: low ventilationperfusion regions, small airway and alveolar collapse or infiltration

(no ventilation-perfusion regions), diffusion defects, and anatomic right-to-left shunts. • There are several methods to assess the severity of hypoxemia, including the physical examination, alveolar to arterial oxygen gradient, PaO2:FiO2 ratio, SaO2:FiO2 ratio, oxygenation index, and oxygen saturation index.

Hypoxemia is generally defined as an arterial partial pressure of oxygen (PaO2) of less than 80 mm Hg or an arterial blood hemoglobin saturation (SaO2 or SpO2) of less than 95%. Serious, potentially lifethreatening hypoxemia is generally defined as a PaO2 less than 60 mm Hg or an SaO2 or SpO2 of less than 90%. Atmospheric oxygen is normally ventilated into the alveoli; it then diffuses across the respiratory membrane along partial pressure gradients into the plasma. Anything that interferes with one or more of these processes will decrease the plasma PO2. Oxygen diffuses from the plasma into the red blood cell and binds to hemoglobin. Both the PaO2 and SaO2 are affected by the same pulmonary processes, and SaO2 or SpO2 is often used as a surrogate marker of PaO2. Blood oxygen can also be expressed as a concentration or content (milliliters of oxygen per 100 ml of whole blood), but this parameter is primarily determined by hemoglobin concentration and is not considered to be a marker of hypoxemia per se.

RECOGNITION OF HYPOXEMIA

COLLECTION OF BLOOD SAMPLES FOR IN VITRO MEASUREMENT Arterial blood should be used for an assessment of pulmonary function. Venous blood comes from the tissues and is more a reflection of tissue function than lung function. The details of blood sampling and storage before analysis have been detailed elsewhere, and further details can be found in Chapter 202, Blood Gas Sampling).1-3 The blood sample must be taken as anaerobically as possible (exposure to air will change the partial pressures of both O2 and CO2) and analyzed as soon as possible. (In vitro metabolism and diffusion of gases into and through the plastic of the syringe will change the partial pressures of both O2 and CO2.4) Excessive dilution with anticoagulant should be avoided.5

†

Author in memoriam

PaO2 The PaO2 is the partial pressure (the vapor pressure) of oxygen dissolved in solution in the plasma of arterial blood and is measured with a blood gas analyzer, usually with a silver anode/platinum cathode system in an electrolyte solution (polarography) separated from the unknown solution (the blood) by a semipermeable (to oxygen) membrane. The arterial PO2 (PaO2) is a measure of the ability of the lungs to move oxygen from the atmosphere to the blood. The normal PaO2 at sea level ranges between 80 and 110 mm Hg.

SpO2 Hemoglobin saturation with oxygen (SaO2) is the inevitable consequence of the increase in PaO2 during the arterialization of venous blood as it traverses the lung; PaO2 and SaO2 are directionally (though not linearly) related. Hemoglobin saturation with oxygen can be measured with a benchtop oximeter (SaO2) using many wavelengths of red to infrared light. Pulse oximeters use only two wavelengths (660 nm and 940 nm) and are designed to measure only oxygenated hemoglobin (SpO2) (see Chapter 184, Oximetry Monitoring).6,7 SpO2 is directionally, but not linearly, associated with PaO2 (Fig. 16.1) and therefore can be used as a surrogate marker of PaO2 (Table 16.1). The SO2/PO2 relationship is described by a sigmoid curve, the oxygen-hemoglobin dissociation curve (Fig. 16.1 and Table 16.1). There are several important clinical implications of this relationship. Most importantly, the difference between normoxemia and hypoxemia is only a few saturation percentage points (Table 16.1), and severe hypoxemia is only a few saturation percentage points below that. Small changes in SpO2 represent large changes in PaO2 in this region of the oxyhemoglobin dissociation curve. Second, severe hypoxemia is defined at a level when the hemoglobin is still 90% saturated. This may not seem fair, but it is the partial pressure of oxygen in the plasma, not hemoglobin saturation, that drives oxygen diffusion down to the mitochondria. PO2 is the driving force; SO2 (more specifically oxygen

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Hemoglobin saturation (%)

Oxyhemoglobin dissociation curves of different species

content) is the reservoir that prevents the rapid decrease in PO2 that would otherwise occur when oxygen diffuses out of the blood. Third, saturation measurements cannot detect the difference between a PaO2 of 100 and 500. This difference is important when monitoring and tracking the progress of animals breathing an enriched oxygen mixture. With these, and a few additional caveats, pulse oximeters noninvasively, continuously, and automatically monitor very well the parameter they were designed to measure—hypoxemia. Pulse oximeter readings are prone to error, and suspected hypoxemia should be corroborated with other clinical signs and an arterial blood gas analysis if necessary.

Cyanosis

Partial pressure of oxygen (PO2) Horse P5023.8

Dog P5028.7

Man

Cat

P5026.8

P5034.1

Fig. 16.1  Oxyhemoglobin dissociation curves for the horse, human, dog, and cat.8-11

TABLE 16.1  Correlation Between PaO2

and SaO2*

Hyperoxemia Normoxemia Hypoxemia Severe hypoxemia Life-threatening Hypoxemia

Grayish to bluish discoloration of mucous membranes commonly signals the presence of deoxygenated hemoglobin in the observed tissues. The observation of cyanosis is dependent on the visual acuity of the observer (some individuals can see it earlier than others), lighting (it is more readily detected in a well-lit room than in the shadows of a cage), and the type of lighting used (it is more readily detectable with incandescent as opposed to fluorescent lighting).12 In general, it requires an absolute concentration of deoxygenated hemoglobin to manifest sufficient cyanosis that everyone agrees to its existence; 5 gm/dl (arterial blood) is the commonly cited figure.13 This is important for two reasons. First, if a dog had a hemoglobin concentration of 15 gm/dl, cyanosis would manifest when the arterial blood saturation decreased to 67% (equivalent to a PaO2 of about 37 mm Hg (Fig. 16.1). When cyanosis is manifested as a sign of hypoxemia, it is always a late sign of severe hypoxemia. Second, if an animal is anemic—for instance, having a hemoglobin concentration of 5 gm/dl—it would die of hypoxemia and the resultant tissue hypoxia long before manifesting cyanosis.

MECHANISMS OF HYPOXEMIA

PaO2 mm Hg .125 80–125 ,80 ,60

SaO2% 100 95–99 ,95 ,90

,30

,40

*This chart represents rounded approximations of the relationship between PaO2 and SaO2 in people and dogs. Cats have a right-shifted curve with an average P50 of 34, in comparison, and the corresponding SaO2 values are lower (see Fig. 16.1).

There are three causes of hypoxemia: low inspired oxygen concentration, hypoventilation, and venous admixture (Fig. 16.2; Table 16.2 and Table 16.3). A fourth cause of hypoxemia can be a reduced venous oxygen content14-18 secondary to low cardiac output or sluggish peripheral blood flow (shock) or high oxygen extraction by the tissues (e.g., seizures). When venous oxygen content is very low, it takes more oxygen and more time for the capillary blood to be arterialized. This lowers alveolar PO2 (PAO2) and therefore PaO2 will be lowered. In practice, the impact of low venous oxygen and blood flow is often offset by a decrease in shunt fraction, which offsets the decrease in PaO2.14,19 Low venous oxygen is verified by measuring central or mixed venous oxygen.

Hypoxemia

Decreased efficiency of transport of oxygen from the alveoli to the pulmonary capillaries

Low alveolar oxygen due to reduced delivery of oxygen to the alveoli

Low V/Q regions Low inspired oxygen

Zero V/Q regions

Hypoventilation Diffusion impairment

Right-to-left A-V shunt

Fig. 16.2  Categorical causes of hypoxemia.

Low alveolar oxygen due to increased extraction of oxygen from the alveoli (see text)

Low venous oxygen content

CHAPTER 16  Hypoxemia

TABLE 16.2  Primary Physiologic Causes

of Hypoxemia Causes of Hypoxemia

Recognition and Examples

Low inspired oxygen

Inspection of the apparatus Improper functioning apparatus to which the animal is attached Depleted oxygen supply; altitude Global Elevated PaCO2, end-tidal hypoventilation CO2, or PvCO2 Neuromuscular dysfunction; airway obstruction, abdominal distention, chest wall dysfunction, pleural space filling defect Venous See Table 16.3 admixture

Treatment Oxygen supplementation if at altitude Disconnect patient from mechanical apparatus and repair/replace apparatus Oxygen supplementation, positive pressure ventilation, remove/bypass obstruction, decompress abdomen, close or stabilize chest wall, perform thoracocentesis See Table 16.3

CO2, carbon dioxide; PvCO2, venous PCO2.

TABLE 16.3  Venous Admixture Mechanisms of Venous Admixture Low V/Q regions

Atelectasis (no V/Q regions) Diffusion defects

Right-to-left shunts

Causes Moderate to severe diffuse lung disease (edema, pneumonia, hemorrhage) Severe to very severe diffuse lung disease (edema, pneumonia, hemorrhage) Moderate to severe, diffuse lung disease (oxygen toxicity, smoke inhalation, ARDS) Right-to-left PDA and VSD; intrapulmonary A-V anatomic shunts

Notes Common; responsive to oxygen therapy Common; not responsive to oxygen but responsive to PPV Uncommon; partially responsive to oxygen

Uncommon; not responsive to oxygen or PPV; surgery possible

A-V, arterial to venous; ARDS, acute respiratory distress syndrome; low V/Q ratio, low ventilation compared with blood flow because of either low regional ventilation or high regional perfusion; PDA, patent ductus arteriosus; PPV, positive pressure ventilation; Q, perfusion; V, ventilation; VSD, ventricular septal defect.

Low Inspired Oxygen Low inspired oxygen must be considered any time an animal is attached to mechanical apparatus such as a face mask, anesthetic circuit, or ventilator or is in an enclosed environment such as an oxygen cage. Inspired or ambient oxygen concentration can be measured with a variety of commercially available oxygen meters. The problem can often be identified by inspection and verification of the improper operation of the mechanical device and remedied by replacing the device with one that is operating properly. The decrease in inspired oxygen concentration decreases the alveolar oxygen concentration and subsequently arterial blood oxygenation.

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High altitude is another cause of low inspired oxygen. Atmospheric oxygen concentration is 21% at any altitude, but as altitude increases, barometric pressure decreases and the partial pressure of oxygen in the atmosphere (PatmO2) represented by 21% also decreases. Normal individuals living at higher altitudes have lower PaO2 values and compensate to some extent by hyperventilating.

Hypoventilation Hypoventilation is defined by an elevated PaCO 2 (45 mm Hg) or one of its surrogate markers: end-tidal CO 2 (usually about 5 mm Hg lower than PaCO2) or central venous PCO2 (usually about 5 mm Hg higher than PaCO2). See Chapter 17 for further discussion of this topic. Alveolar oxygen is the balance between the amount of oxygen being delivered to the alveoli (inspired oxygen concentration and alveolar minute ventilation) and the amount of oxygen being removed from the alveoli by the arterialization of venous blood (ultimately, tissue metabolism). A decrease in alveolar minute ventilation (hypoventilation) decreases the delivery of oxygen to the alveoli and subsequently to the blood leading to hypoxemia. Increasing the inspired oxygen concentration is very effective in preventing hypoxemia secondary to hypoventilation. There are only four gases of note in alveoli: O2, CO2, water vapor, and nitrogen. The partial pressure of alveolar oxygen (PAO2) can be determined by the alveolar air equation (see below). The normal alveolar composition of gases when breathing room air at sea level is water vapor 50 mm Hg (fixed; alveolar gases are always 100% saturated at body temperature), CO2 ,40 mm Hg (regulated by the brainstem respiratory control center; varies between species), O2 105 mm Hg, and nitrogen 560 mm Hg.19 If an animal were to hypoventilate to a PaCO2 of 80 mm Hg, the water vapor pressure and nitrogen levels would remain unchanged, but the oxygen would fall to about 65 mm Hg and the patient would become hypoxemic. When breathing 100% oxygen for a time to allow the elimination of nitrogen from the readily mobilized stores (alveoli, blood, and vessel-rich tissues), the alveolar water vapor and CO2 levels would not change but nitrogen would decrease to near 0 and oxygen would increase to near 665. If an animal were to severely hypoventilate while breathing 100% oxygen, the alveolar CO2 could theoretically rise to about 550 mm Hg before the alveolar oxygen decreased to a level that would lead to hypoxemia (PaO2 ,80 mm Hg). Hence, hypoventilation is a cause of hypoxemia in patients breathing room air but not in patients breathing enriched oxygen mixtures. Further hypoxemia as a result of hypoventilation is readily resolved with oxygen therapy.

Venous Admixture Venous admixture is all the ways in which venous blood can get from the right side to the left side of the circulation without being properly oxygenated. Blood flowing through some regions of the lung may be suboptimally oxygenated or may not be oxygenated at all. When this “venous” blood admixes with optimally arterialized blood flowing from the more normally functioning regions of the lung, the net oxygen content and PaO2 are reduced. There is typically a small amount of venous admixture in the normal lung (,5%).20 There are four causes of venous admixture (see Table 16.2): (1) low ventilation-perfusion regions of the lung, (2) small airway and alveolar collapse (atelectasis or zero ventilation but perfused lung units), (3) diffusion defects, and (4) anatomic right-to-left shunts. Most diffuse lung disease will have a variable combination of several of these mechanisms; however, one often predominates. These mechanisms have important therapeutic implications. It is also inappropriate to use the term ventilation-perfusion (V/Q) mismatch as a cause of hypoxemia

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without some adjective (i.e., “high” or “low”) because not all types of V/Q mismatch contribute to hypoxemia.

Regions of Low Ventilation-Perfusion (V/Q) Ratio Alveoli with a low ventilation-perfusion (V/Q) ratio occur secondary to small airway narrowing or alveolar fluid accumulation which impairs ventilation, but some gas exchanged is maintained. Because it is a ratio, a low V/Q could also be caused by an increased Q, such as that which occurs in pulmonary thromboembolism. Small airway narrowing may be caused by bronchospasm, fluid accumulation along the walls of the lower airways, or epithelial edema. Like global hypoventilation, regional hypoventilation results in the reduced delivery of oxygen to alveoli (compared with that removed by the circulation) and a reduction in alveolar and arterial PO2. Poorly oxygenated blood from these capillary beds admixes with blood from more normally functioning regions of the lung, diluting and reducing the net oxygen concentration. This is a common mechanism of hypoxemia in moderate pulmonary disease. Like global hypoventilation, regional hypoventilation is very responsive to oxygen therapy.

2 µm BM FB

Ep

RBC

Alv IS

Diffusion Impairment Diffusion impairment as a result of a thickened respiratory membrane is an uncommon cause of hypoxemia. Capillaries meander through the interstitial septae, between alveoli, bulging first into one alveolus and then into the adjacent alveolus (Fig. 16.3). The interstitium between the endothelium and the epithelium on the “bulge side” or “active side” of the capillary (encompassing two-thirds to three-fourths of the circumference of the capillary) is either nonexistent (the endothelial and epithelial basement membranes are one and the same) or is functionally nonexistent, and no fluid accumulates here (Fig. 16.3). This “active side” of the septa constitutes the gas exchange surface. Transcapillary fluid leaks occur on the thick (“service”) side of the capillary but do not accumulate here either. Fluid is forced (by the low compliance of the interstitial tissues and lymphatics) upward toward the loose interstitial tissues surrounding the medium-sized arterioles, venules, and bronchioles toward the hilus of the lung.21 Eventually, these interstitial fluids build up enough pressure that they break into the airways and distribute along the airway surfaces, causing first airway narrowing and increased alveolar surface tension (low V/Q units) and then causes small airway and alveolar collapse (zero V/Q units), as discussed earlier and without a diffusion defect per se. In order for a diffusion defect to occur, the flat type I alveolar pneumocytes have to be damaged by inhalation or inflammatory injury. In the healing process, the thick, cuboidal type

Alv

EN

Regions of Zero V/Q Small airway and alveolar collapse (regions of zero V/Q) occurs in diseases associated with the accumulation of airway fluids (transudate, exudates, or blood). Small airway and alveolar collapse is common in the dependent regions of the lung if animals are recumbent for prolonged periods of time (e.g., general anesthesia or coma) in the absence of an occasional deep (sigh) breath. Blood flowing through these areas will not be arterialized. This condition has been referred to as “physiologic shunt” (blood flowing past nonfunctional alveoli) to differentiate it from a “true or anatomic shunt,” where blood completely bypasses all alveoli (whether they’re functional or not). Hypoxemia due to zero V/Q regions is not responsive to oxygen therapy because oxygen cannot get to the gas exchange surface. Collapsed small airways and alveoli can only be “reactivated” by increasing airway or transpulmonary pressure, by taking a deep spontaneous breath, or by augmentation of airway pressure. This is a common mechanism of hypoxemia in severe pulmonary disease as proven by the fact that positive pressure ventilation and positive end-expiratory pressure can be very effective at improving lung oxygenating efficiency.

End

Fig. 16.3  Electron micrograph of alveolar septum. Details of the interstitial space, the capillary endothelium, and alveolar epithelium. Thickening of the interstitial space is confined to the left of the capillary (the service side), whereas the total alveolar/capillary membrane remains thin on the right (the active side) except where it is thickened by the endothelial nucleus. Alv, alveolus; BM, basement membrane; EN, endothelial nucleus; End, endothelium; Ep, epithelium; FB, fibroblast process; IS, interstitial space; RBC, red blood cell. (From Lumb AB, Thomas CR: Nunn and Lumb’s applied respiratory physiology, ed 9, Oxford, 2021, Elsevier. Fig 1.8.)

II alveolar pneumocytes proliferate across the surface of the gas exchange surface. This can occur with oxygen toxicity or during progression of the acute respiratory distress syndrome.22 Such thickening of the gas exchange membrane represents a substantial diffusion defect until such time as the type II pneumocytes mature to type I pneumocytes. Diffusion defects are partially responsive to oxygen therapy.

Anatomic Shunts Anatomic shunts that cause hypoxemia are vascular abnormalities where the blood flows from the right side to the left side of the circulation, bypassing all alveoli in the process. This is not a common mechanism of hypoxemia and is most commonly found in young animals with congenital defects. This cause of hypoxemia is not responsive to either oxygen therapy or positive pressure ventilation. Some are amenable to surgical intervention.

ESTIMATING THE MAGNITUDE OF THE VENOUS ADMIXTURE In pulmonary parenchymal disease, lungs often fail to effectively oxygenate arterial blood before their ability to get CO2 out fails. This is apparent from the rather common cooccurrence of hypocapnia and hypoxemia and is attributed to the fact that alveolar-capillary units that are working relatively well can easily compensate for those that are working relatively poorly with respect to CO2 elimination but not for oxygen intake. It is for this reason that it is important to evaluate PaCO2 and PaO2 separately. PaCO2 defines alveolar minute ventilation; PaO2 defines blood oxygenation. Given the specifics of the situation,

CHAPTER 16  Hypoxemia any combination of ventilation (normo-, hypo-, or hyperventilation) and oxygenation (normo-, hypo-, or hyperoxygenation) can coexist in a patient at a given time, and different combinations mandate different therapeutic strategies. Although PaO2 defines the status of blood oxygenation, the clinical significance of the measurement (the status of lung function; the magnitude of the venous admixture) can only be fully appreciated when PaO2 is referenced to the PaCO2 and the inspired oxygen at the time of measurement.

Alveolar-Arterial PO2 Gradient The alveolar-arterial PO2 gradient (A-a gradient) is the difference between the calculated PAO2 and the measured arterial PaO2. The A-a gradient is useful in assessing the oxygenation ability of the lungs while removing the effects of changes in minute ventilation (PaCO2). In order to calculate the PAO2, the alveolar air equation is used (Box 16.1). At sea level, breathing 21%, the alveolar air equation can be shortened to: PAO2 5 150 2 PaCO2 At different altitudes and inspired oxygen concentrations, the complete formula must be used. Once PAO2 has been calculated, the A-a gradient is calculated by subtracting the measured PaO2 from the calculated PAO2. When breathing room air, the usual A-a gradient is less than 10 mm Hg; values above 20 mm Hg are considered to represent decreased oxygenating efficiency (venous admixture). Unfortunately, the normal A-a gradient increases at higher inspired oxygen concentrations and may be as high as 100 to 150 mm Hg at an inspired oxygen concentration of 100%. As a result, the A-a gradient is of most value when assessing room air blood gases. The A-a gradient evaluates the magnitude of venous admixture; although hypoventilation will cause hypoxemia when breathing room air, it will not cause an abnormal A-a gradient.

PaCO2 1 PaO2 Added Value (“The 120 Rule”) When breathing 21% oxygen at sea level, the PaCO2 1 PaO2 added value calculation can identify the presence of venous admixture, in a manner similar to the A-a gradient. A normal PaCO2 of 40 mm Hg and a minimum PaO2 value for normoxemia of 80 mm Hg add to 120. An added value of less than 120 mm Hg suggests the presence of venous admixture, and the greater the discrepancy, the worse the lung function. If PaCO2 increases from 40 mm Hg to 60 mm Hg by hypoventilation, the PaO2 should decrease from 80 mm Hg to about 60 mm Hg if the animal does not have lung disease, and the addition of the two values will still equal 120. The conclusion is that the cause of the hypoxemia in this situation was purely hypoventilation. If instead the animal has a PaCO2 of 60 mm Hg and a PaO2 of 40 mm Hg, the added value is 100 (less than 120), and it can be concluded that the animal has lung dysfunction in addition to hypoventilation. This added value rule or “120 rule” can only be used when the patient is breathing 21% oxygen at near-sea level conditions. At altitude, atmospheric and alveolar and arterial PO2 and the “added value rule” need to be proportionately decreased.

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PaO2/FiO2 Ratio Many approaches have been suggested that could be used to compensate for the variation in A-a gradient associated with variation in inspired oxygen. The PaO2/fraction of inspired oxygen (FiO2) (or P/F) ratio is the easiest to calculate. The P/F ratio is calculated by dividing the measured PaO2 by the corresponding FiO2 as a decimal value. A normal P/F ratio is approximately 500 (PaO2 5 100 mm Hg, FiO2 5 0.21). If a patient is on 100% O2, their expected PaO2 would be 500 mm Hg. The P/F ratio can be very misleading when used at 21% inspired oxygen concentrations if PaCO2 values are elevated. PaCO2 values have been ignored in this calculation, but when breathing room air, changes in PaCO2 can have a significant impact on PaO2. It is recommended to use the “120 rule” or A-a gradient when evaluating room air blood gases and to use the P/F ratio if evaluating arterial blood gases from patients on supplemental oxygen.

SpO2/FiO2 Ratio The SpO2/FiO2 ratio (S/F) has been studied in dogs as a surrogate for the P/F ratio since it is faster, less invasive, can be measured continuously, and is associated with fewer complications than obtaining an arterial blood sample. S/F values in dogs recovering from surgery with or without supplemental oxygen or those with mild to moderate hypoxemia were moderately to well-correlated with the P/F ratio.23,24 However, it is important to consider the limitations of pulse oximetry stated above. The S/F ratio has been widely studied in several human patient populations with favorable results. In one large human study, an S/F ,315 corresponds with a P/F ,300 and an S/F ,235 with a P/F ,200.25

Oxygenation Index and Oxygen Saturation Index The oxygenation index (OI) is another means of evaluating oxygenation in ventilated patients. This technique takes into account the mean airway pressure (MAP) as a means of comparing patients with different degrees of ventilatory support by performing the following calculation: OI 5 MAP 3 FiO2 3 100/PaO2 A lower number indicates better lung function, and cutoffs have been developed in human medicine (e.g., OI .40 is an indication for extracorporeal membrane oxygenation).26 The OI may also be used for predicting outcome in human neonates.27 The oxygenation saturation index (OSI) replaces the PaO2 with SpO2 in the OI equation and is therefore less invasive and allows continuous measurement of oxygenation: OSI 5 MAP 3 FiO2 3 100/SpO2. It has been studied primarily in neonates with hypoxemic respiratory failure.28

Venous Admixture (Shunt) Calculation If a mixed venous blood sample (pulmonary artery) can be obtained, then venous admixture can be calculated as: Qs  / QT 5 (CcO2 2 CaO2) / (CcO2 2 C2 v O2)

BOX 16.1  Alveolar Air Equation PAO2 5 (PB-PH2O)*FiO2 – (PaCO2/RQ) PB 5 atmospheric pressure PH2O 5 partial pressure of water FiO2 5 concentration of oxygen in inspired air RQ 5 respiratory quotient (,0.8) n the ratio of CO2 produced to O2 consumed by the body PaCO2 5 measured value from the patient

Where QS is shunt fraction, QT is the cardiac output, QS/QT is the venous admixture expressed as a percent of cardiac output, CcO2 is the oxygen content of end-capillary blood, CaO2 is the oxygen content of arterial blood, and CvO2 is the oxygen content of mixed venous blood. Jugular venous blood is sometimes used as a surrogate for pulmonary arterial blood. Arterial and mixed venous PO2 is measured and oxygen content (ml/dl) is calculated as (1.34 3 Hb 3 SO2) 1 (0.003 3 PO2)

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where SO2 is percent hemoglobin saturation with oxygen. Capillary PO2 is assumed to be equal to calculated PAO2 and is used to calculate capillary oxygen content. PO2 is measured and SO2 is either measured (accuracy mandates a benchtop oximeter) or extrapolated from a standard oxyhemoglobin dissociation curve (which is the value reported on the printout from some blood gas analyzers), or can be derived by hand from an oxyhemoglobin dissociation curve such as in Fig. 16.1. Venous admixture is normally less than 5%.20 Values greater than 10% are considered to be increased and may increase to more than 50% in severe, diffuse lung disease. Although the equation shown earlier seems like a lot of math, it is considered to be the most accurate way to estimate venous admixture.29 If blood samples are taken while the patient is breathing room air, all the previously discussed categorical mechanisms of venous admixture are assessed. If blood samples are taken while the patient is breathing 100% oxygen, the low V/Q mechanism of hypoxemia is eliminated from the assessment and diffusion defects are minimized. In this usage, the formula is referred to as the “shunt” formula because it assesses the magnitude of the remaining two causes of venous admixture: “physiologic” shunts secondary to atelectasis and true “anatomic” shunts. Intermediate inspired oxygen concentrations and particularly changes in inspired oxygen concentration will change the venous admixture calculated by this formula by virtue of the impact of the FiO2 on the low V/Q regions.30-32 Like the P/F ratio, venous admixture will also be impacted by changes in MAP by virtue of its impact on the open/closed status of alveoli. It is usually recommended to determine the venous admixture at the current inspired oxygen and ventilator settings, whatever they might be, depending on the needs of the patient.30

REFERENCES 1. Haskins SC: Sampling and storage of blood for pH and blood gas analysis, J Am Vet Med Assoc 170:429-433, 1977. 2. Gray S, Powell LL: Blood gas analysis. In Burkitt-Creedon JM, Davis H, editors: Advance monitoring and procedures for small animal emergency and critical care, Oxford, UK, 2012, John Wiley & Sons, pp 286-292. 3. Kennedy SA, Constable PD, Sen I, Couetil L: Effects of syringe type and storage conditions on results of equine blood gas and acid-base analysis, Am J Vet Res 73:979-987, 2012. 4. Rezende ML, Haskins SC, Hopper K: The effects of ice-water storage on blood gas and acid-base measurements, J Vet Emerg Crit Care 17:67-71, 2006. 5. Hopper K, Rezende ML, Haskins SC: Assessment of the effect of dilution of blood samples with sodium heparin on blood gas, electrolyte, and lactate measurements in dogs, Am J Vet Res 65:656-660, 2005. 6. Biebuyck JF: Pulse oximetry, Anesthesiology 70:98-108, 1989. 7. Ayres DA: Pulse oximetry and CO-oximetry. In Burkitt-Creedon JM, Davis H, editors: Advanced monitoring and procedures for small animal emergency and critical care, Oxford, UK, 2012, John Wiley & Sons, pp 274-285. 8. Smale K, Anderson LS, Butler PJ: An algorithm to describe the oxygen equilibrium curve for the Thoroughbred racehorse, Equine Vet J 26: 500-502, 1994. 9. Kelman GR: Digital computer subroutine for the conversion of oxygen tension into saturation, J Appl Physiol 21:1375-1376, 1966.

10. Cambier C, Wierinckx M, Clerbaux T, et al: Haemoglobin oxygen affinity and regulating factors of the blood oxygen transport in canine and feline blood, Res Vet Sci 77:83-88, 2004. 11. Clerbaux T, Gustin P, Detry B, Cao ML, Frans A: Comparative study of the oxyhaemoglobin dissociation curve of four mammals: man, dog, horse, and cattle, Comp Biochem Physiol 106:687-694, 1993. 12. Kelman GR, Nunn JF: Clinical recognition of hypoxaemia under fluorescent lamps, Lancet 1:1400-1403, 1966. 13. Martin L, Khalil H: How much reduced hemoglobin is necessary to generate central cyanosis? Chest 87:182-185, 1990. 14. Bishop MJ, Cheney FW: Effects of pulmonary blood flow and mixed venous O2 tension on gas exchange in dogs, Anesthesiology 58:130-135, 1983. 15. Giovannini I, Boldrini G, Sganga G, et al: Quantification of the determinants of arterial hypoxemia in critically ill patients, Crit Care Med 11: 644-645, 1983. 16. Huttemeier PC, Ringsted C, Eliasen K, Mogensen T: Ventilation-perfusion inequality during endotoxin-induced pulmonary vasoconstriction in conscious sheep: mechanisms of hypoxia, Clin Physiol 8:351-358, 1988. 17. Santolicandro A, Prediletto R, Formai E, et al: Mechanisms of hypoxemia and hypocapnia in pulmonary embolism, Am J Respir Crit Care Med 152:336-347, 1995. 18. Cooper CB, Celli B: Venous admixture in COPD: pathophysiology and therapeutic approaches, COPD 5:376-381, 2008. 19. Lumb AB: Nunn’s applied respiratory physiology, ed 6, Oxford, 2005, Butterworth Heinemann. 20. Haskins SC, Pascoe PJ, Ilkiw JE, et al: Reference cardiopulmonary values in normal dogs, Comp Med 55:158-163, 2005. 21. Staub NC: The pathogenesis of pulmonary edema, Prog Cardiovasc Dis 23:53-80, 1980. 22. Ware LB, Matthay MA: The acute respiratory distress syndrome, N Engl J Med 342:1334-1349, 2000. 23. Calabro JM, Prittie JE, Palma DA: Preliminary evaluation of the utility of comparing SpO2/FiO2 and PaO2/FiO2 ratios in dogs, J Vet Emerg Crit Care 23(3):280-285, 2013. 24. Carver A, Bragg R, Sullivan L: Evaluation of PaO2/FiO2 and SaO2/FiO2 ratios in postoperative dogs recovering on room air or nasal oxygen insufflation, J Vet Emerg Crit Care 26(3):437-445, 2016. 25. Rice TW, Wheeler AP, Bernard GR, Hayden DL, Schoenfeld DA, Ware LB: Comparison of the SpO2/FIO2 ratio and the PaO2/FIO2 ratio in patients with acute lung injury or ARDS, Chest 132(2):410-417, 2007. 26. Fletcher K, Chapman R, Keene S: An overview of medical ECMO for neonates, Semin Perinatol 42(2):68-79, 2018. 27. Kumar D, Super DM, Fajardo RA, Stork EE, Moore JJ, Saker FA: Predicting outcome in neonatal hypoxic respiratory failure with the Score for Neonatal Acute Physiology (SNAP) and Highest Oxygen Index (OI) in the first 24 hours of admission, J Perinatol 24(6):376-381, 2004. 28. Rawat M, Chandrasekharan PK, Williams A, et al: Oxygen saturation index and severity of hypoxic respiratory failure, Neonatology 107(3): 161-166, 2015. 29. Wandrup JH: Quantifying pulmonary oxygen transfer deficits in critically ill patients, Acta Anaesthesiol Scand 107:37-44, 1996. 30. Gowda MS, Klocke RA: Variability of indices of hypoxemia in adult respiratory distress syndrome, Crit Care Med 25:41-45, 1997. 31. Whiteley JP, Gavaghan DJ, Hahn DEW: Variation of venous admixture, SF6 shunt, PaO2, and the PaO2/FIO2 ratio with FIO2, Br J Anaesth 88:771-778, 2002. 32. Oliven A, Abinader E, Bursztein S: Influence of varying inspired oxygen tensions on the pulmonary venous admixture (shunt) of mechanically ventilated patients, Crit Care Med 8:99-101, 1980.

17 Hypoventilation Meredith L. Daly, VMD, DACVECC

KEY POINTS • Minute ventilation (V E) is determined by respiratory rate (RR) and tidal volume (VT) (V E 5 RR 3 VT). • Dead space (VD) is the portion of VT that does not participate in gas exchange. • Hypercapnia results when alveolar ventilation is insufficient at removing carbon dioxide produced in the body by aerobic metabolism. • The gold standard for assessment of arterial carbon dioxide (PaCO2) levels is arterial blood gas analysis. • Hyperventilation is generally defined as a PaCO2 less than 30 to 35 mm Hg. Slight species-specific differences exist.

Carbon dioxide (CO2) is the product of aerobic metabolism. It is produced primarily in the mitochondria and subsequently diffuses via a series of sequential partial pressure gradients into the cytoplasm, the extracellular space the intravascular space, and the pulmonary capillaries. Upon reaching the pulmonary capillaries, CO2 diffuses into the alveoli, where a balance between CO2 production and alveolar ventilation determines its concentration. Therefore, in a patient with relatively constant CO2 production, arterial CO2 concentration serves as a surrogate for alveolar ventilation. Conditions that increase CO2 production (e.g., fever), reduce minute ventilation, and/or increase dead space may result in increased arterial CO2 concentrations. The most common cause of hypercapnia in clinical patients is hypoventilation secondary to decreased minute ventilation.

DEFINITIONS AND MEASUREMENT Minute ventilation (V E) is the total volume of gas exhaled per minute. It is equal to the product of tidal volume (VT) and respiratory rate (RR) (V E 5 VT 3 RR). The volume of inhaled air is slightly greater than the exhaled volume because more oxygen is inhaled than CO2 is exhaled; this difference is usually less than 1% of the VT in health. VT is composed of dead space volume (VD), or the portion of VT that does not actively participate in gas exchange, and the volume of fresh gas entering the alveoli that participates in gas exchange (VA).1 Alveolar ventilation (V A) is the volume of fresh air (non-dead space gas) available for gas exchange that enters the alveoli per minute, equivalent to the total amount of gas exhaled per minute (V E) minus the air contained in the dead space per minute (V D). Alveolar ventilation, like minute ventilation is measured during exhalation; inhaled and exhaled volumes are also similar in health. V A can be derived from the following equations: 

VT  VD  V A

(equation 1)

• Hypoventilation is defined as a PaCO2 greater than 40 to 45 mm Hg. Slight species-specific differences exist. • Clinical signs associated with hypoventilation may be the result of the systemic effects of hypercapnia, uncompensated respiratory acidosis, or the disease process causing the hypoventilation. • Hypoventilation is treated by increasing alveolar ventilation through the treatment of the underlying disease, chemical stimulation of breathing, or manual/mechanical ventilation.

multiplying by respiratory rate,

VE  VD VA

(equation 2)

which can be rearranged as

VA  VE  VD

(equation 3)

where V E is the expired minute ventilation and (V D) is the dead space ventilation.1 Dead space ventilation is the portion of VT per minute that does not actively participate in gas exchange. Dead space can be subdivided into anatomic, alveolar, physiologic, and apparatus dead space. The volume of gas filling the upper airway, trachea, and lower airways to the level of the terminal bronchioles does not participate in gas exchange and therefore is considered anatomic dead space. Alveolar dead space is defined as the portion of inspired gas that passes through the anatomic dead space and mixes with gas in the alveoli but does not participate in gas exchange with the pulmonary capillaries.1 Physiologic dead space is comprised of anatomic and alveolar dead space and is the sum of all portions of the VT that do not participate in gas exchange. Physiologic dead space is approximately the same as anatomic dead space in health. However, in the presence of ventilation– perfusion inequality (i.e., when a portion of VT ventilates alveoli that are not perfused), physiologic dead space is increased due to increased alveolar dead space. Lastly, when patients are connected to a breathing device, the circuit may contribute to dead space if a portion of the VT is rebreathed without fresh gas flow replacement. This is known as apparatus dead space and is most important in patients that are small or have decreased ability to generate an effective VT. Dead space ventilation can be measured in several different ways; two of the most common include Fowler’s method and Bohr’s method. Fowler’s method involves measuring the concentration of an exhaled tracer gas, typically nitrogen, over time following a single breath with

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100% oxygen. Nitrogen concentration in the expired gas rises as dead space gas is washed out by alveolar gas over time. The nitrogen concentration is then displayed graphically against the volume of gas exhaled. The anatomic dead space volume is subsequently derived from this graph; it is a function of the geometry of the airways.2 Bohr’s method is different from Fowler’s method; it measures the volume of lung that does not eliminate CO2. Therefore, this method involves measurement of physiologic dead space rather than simply anatomic dead space. Bohr’s method uses the principle that all of the CO2 in the exhaled gas (FE) originates from the alveolus (FA). The CO2 concentration in the exhaled gas (FE) is composed of alveolar CO2 (FA) that has been diluted by the CO2-free gas in the conducting airways and in the airways that are poorly perfused.2 VT  FE  V A  FA

(equation 4)

which can be rearranged knowing that VA 5 VT – VD to VD  V T  (FA  FE) / FA

(equation 5)

The partial pressure of any gas is proportional to its concentration, therefore (equation 6, VD  VT  (PACO 2  PECO 2) / PACO 2 Bohr equation) Assuming alveolar and arterial oxygen PCO2 are equal, then VD  VT  (PaCO 2  PECO 2) / PaCO 2

(equation 7)

Once the corresponding dead space volume is determined, alveolar ventilation can be calculated by subtracting dead space ventilation from the total ventilation measured via spirometry. Alveolar ventilation is reduced by an increase in dead space ventilation, regardless of whether the dead space is of anatomic, alveolar, or apparatus origin. The corresponding changes in alveolar gas tensions are identical to those produced by a decreased V E due to a different cause, such as a decreased RR. Another way of measuring alveolar ventilation is to use the alveolar ventilation equation. The equation states that alveolar PCO2 (PACO2) is directly proportional to the amount of CO2 produced by metabolism (V CO2) and delivered to the lungs and inversely proportional to the alveolar ventilation (V A).1 PACO2  (VCO 2  VA ) k

(equation 8)

Although the derivation of the equation is for alveolar PCO2, its clinical usefulness stems from the fact that alveolar and arterial PCO2 can be assumed to be equal in patients with normal lungs because of the highly diffusible nature of CO2. Therefore,

VA  (VCO 2  PaCO 2) k

(equation 9)

The constant k 5 0.863 is necessary to equate dissimilar units for V CO2 (ml CO2/min), and (V A) (L/min) to PaCO2 pressure units (mm Hg).1 This means, for example, if the alveolar ventilation is halved, the PaCO2 is doubled as long as CO2 production remains unchanged. Even when alveolar and arterial PCO2 are not equal (as in states of severe ventilation–perfusion mismatch), the relationship expressed by the equation (PCO2 ∝V CO2 /V A) remains valid because of the high solubility of CO2 in the circulation. From the alveolar ventilation equation, it can be concluded that the only physiologic reason for increased PaCO2 is a level of alveolar ventilation that is inadequate for the amount of CO2 produced by aerobic metabolism and subsequently delivered to the lungs.1

Arterial PCO2 is therefore a measure of the ventilatory status of a patient. Normal values vary depending upon the analyzer used but generally fall within the range of 30 to 42 mm Hg in the dog and 25 to 36 mm Hg in the cat.3 A PaCO2 less than 30 to 35 mm Hg generally indicates hyperventilation (lower in felines), and a PaCO2 greater than 40 to 45 mm Hg indicates hypoventilation. Venous CO2 values reflect a combination of arterial PCO2, tissue metabolism, and blood flow. Venous CO2 values are typically 3 to 6 mm Hg higher than the corresponding arterial values during steady state (33 to 42 mm Hg canine, 32 to 44 mm Hg feline) but can diverge significantly in disease states, particularly those associated with decreased tissue perfusion and pulmonary circulation.3

MECHANISMS AND ETIOLOGIES OF HYPERCAPNIA Hypercapnia results when alveolar ventilation is inadequate to restore PaCO2 to the normal range. It is the result of increased inspired CO2, increased CO2 production with a fixed V E, or impaired CO2 excretion. CO2 excretion is decreased when V E is decreased secondary to a decreased RR, decreased tidal volume (VT) decreases in both RR and VT, or increases in the dead space fraction of the tidal volume (VD/VT).

Increased Inspired CO2 Under general anesthesia, faulty breathing circuits, excess apparatus dead space, or inadequate fresh gas flows can lead to an increase in the inspired CO2 as a result of rebreathing.5 Exhausted absorbent agents, faulty unidirectional valves, and increased apparatus dead space in smaller patients are common causes of CO2 rebreathing in veterinary patients.18

Increased CO2 Production with a Fixed Minute Ventilation (VE)

If V E is fixed, increased CO2 production secondary to thyrotoxicosis, fever, sepsis, malignant hyperthermia, overfeeding, or exercise will result in hypercapnia. However, these are uncommon causes of hypercapnia in spontaneously breathing patients because compensatory increases in V E typically restore PaCO2 values to the normal range. Though not technically the result of increased CO2 production, systemic absorption of CO2 gas used for peritoneal cavity insufflation during laparoscopy may also contribute to hypercapnia in the presence of a fixed V E.19

Impaired CO2 Excretion Due to Global Hypoventilation or Increased Dead Space

Total minute ventilation (V E) is determined by RR and VT (VD 1 VA), both of which are controlled by central and peripheral factors (see Chapter 14, Control of Breathing). Hypercapnia can be caused by any process interfering with the ability to initiate or generate a normal tidal breath. General categories include central neurologic disease affecting the respiratory control center, peripheral or central chemoreceptor dysfunction, upper or lower motor neuron disease, spinal cord disease, neuromuscular disease, abnormal respiratory mechanics, or increased airway resistance. Specific disease processes causing hypoventilation within each of these categories are listed in Box 17.1. The pathophysiology of hypoventilation associated with each condition is discussed in greater detail in relevant chapters (see Part II, Respiratory Disorders and Chapter 83, Neurological Evaluation of the ICU Patient) which address these disease processes individually. Select conditions are reviewed below to illustrate, more specifically, the impact of disease on total V E, RR, VT, and dead space ventilation. Reduction in either the central respiratory drive or peripheral muscle, nerve, or thoracic cage function will result in global hypoventilation,

CHAPTER 17  Hypoventilation

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BOX 17.114  Differential Diagnosis of Hypoventilation/Hypercapnia Decreased Minute Ventilation 1. Central neurological disease (medulla, cerebrum, pons) a. Sedative overdose (e.g., narcotics or benzodiazepines, anesthetics) b. Encephalitis c. Trauma d. Neoplasia e. Vascular f. Cerebral edema g. Severe metabolic disturbances h. Severe hypothermia (80°F) 2. Cervical spinal cord disease a. Trauma I. Spinal cord hemorrhage II. Fracture b. Neoplasia c. Infection d. Intervertebral disk disease e. Inflammatory f. Anterior horn cell disease 3. Lower motor neuron disease/neuromuscular disease a. Myasthenia gravis b. Neuromuscular blockade c. Botulism d. Tick paralysis e. Demyelination f. Polyradiculoneuritis g. Infection 4. Chemoreceptor abnormalities a. Drugs/anesthetic agents b. Metabolic alkalosis c. Cerebrospinal fluid acidosis 5. Abnormal respiratory mechanics a. Pulmonary fibrosis b. Respiratory fatigue from increased work of breathing c. Pickwickian syndrome d. Pleural space disease I. Pneumothorax II. Hemothorax III. Chylothorax IV. Hydrothorax V. Malignant effusion VI. Space-occupying mass VII. Diaphragmatic hernia e. Loss of elasticity of chest wall/lungs I. Extrathoracic compression II. Fibrosis

normal minute ventilation (VE) with increased VD/VT, or both. The central respiratory center receives inputs from central and peripheral chemoreceptors and baroreceptors, thermal and mechanical receptors in the upper airway and lungs, and cognitive inputs from the cortex, among others. These signals are integrated into a combined output to the muscles of respiration which determinesV E. Central chemoreceptors, located in multiple areas of the brainstem, are thought to be responsible for more than 50% of the hypercapnic ventilatory response.4,14 Any anatomic, physiologic, or pharmacological process that impacts the central respiratory center can cause diminished respiratory drive and hypercapnia as a result of decreased RR or VT. Common causes in veterinary patients include sedative overdose, traumatic brain injury, and neoplasia.

f. Loss of structural integrity of chest wall I. Flail chest II. Chest wound g. Decreased functional residual capacity I. Anesthetic agents II. Patient positioning (especially dorsal recumbency) 6. Increased airway resistance a. Upper airway obstruction I. Mucus plugs II. Neoplasia III. Foreign body IV. Recurrent laryngeal nerve damage V. Laryngeal edema VI. Inflammatory laryngitis VII. Polyp b. Increased breathing circuit resistance under general anesthesia c. Tracheal or mainstem bronchus collapse d. Brachycephalic obstructive airway syndrome e. Bronchoconstriction I. Feline asthma II. Chronic bronchitis Increased Dead Space Ventilation a. Increased physiologic dead space (High V/Q) I. Low cardiac output II. Shock III. Pulmonary embolus IV. Pulmonary hypotension V. Pulmonary bulla b. Increased apparatus dead space I. Excessive dead space in ventilator/anesthesia breathing circuit II. Excessively long endotracheal tube Increased Carbon Dioxide Production with a Fixed Tidal Volume a. Malignant hyperthermia b. Reperfusion injury c. Excessive nutritional support in a ventilated patient d. Fever e. Iatrogenic hyperthermia f. Thyrotoxicosis Increased Inspired Carbon Dioxide a. Expired or old soda lime b. Faulty unidirectional valves c. Increased apparatus dead space

Patients with neuromuscular disease most commonly develop hypoventilation due to a decrease in VT. In health, the muscles of respiration affect VE by altering respiratory rate and the depth and duration of inspiration (VT). In the presence of muscle weakness, patients may adopt a shallower breathing pattern in which tidal volumes are reduced. Given that anatomical dead space volume remains fairly constant in a given patient, a greater proportion of the tidal breath is allocated to the anatomical dead space in a smaller VT breath than in a breath with a normal VT (increased VD/VT). Minute ventilation (V E) may decrease in these patients due to a decreased VT, or it may remain normal as a result of compensatory increases in RR. However even if V E remains normal as a result of increased RR, alveolar ventilation

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will be decreased in patients with shallower breathing due to greater VD/VT, resulting in hypercapnia. Patients with decreased chest wall compliance or function and pleural space disease may develop a decrease in VT due to decreased lung expansion. Minute ventilation (V E) may initially remain normal secondary to increases in RR; however, hypercapnia secondary to decreased alveolar ventilation may be present as a result of lower tidal volumes and greater VD/VT. Additionally, the RR will decrease in these patients due to respiratory muscle fatigue and increased work of breathing over time if the primary condition is not treated. Occasionally, hypercapnia may be seen in patients exhibiting increased V E with normal or increased tidal volumes, and an increase in the arterial to end-expiratory PCO2 gradient. This is the result of decreased alveolar ventilation secondary to increased alveolar dead space, or ventilation to areas of poorly perfused lung, and increased VD/VT. In clinical patients this may be seen in the presence of significant pulmonary thromboembolic disease, pulmonary capillary compression secondary to pulmonary overinflation, and cardiovascular shock.

CLINICAL SIGNS Clinical signs associated with hypoventilation may be the result of the systemic effects of hypercapnia, uncompensated respiratory acidosis, or the disease process causing hypoventilation. Patients with a decreased V E may present with shallow, rapid breathing or deep, slow breathing; increased respiratory effort may or may not be present, depending upon the underlying condition. For example, patients with impaired central respiratory drive often do not appear to have difficulty breathing. However, in patients with acute mechanical failure of the respiratory system, such as a complete upper airway obstruction, an increased breathing effort is readily apparent. In these situations, hypoxemia, rather than hypercapnia, is most often the immediate threat to life. In patients with more chronic respiratory acidosis, clinical signs may be more subtle. Although less common, patients may be hypercapnic despite an increased V E as a result of hypoperfusion of ventilated alveoli, which leads to increased physiologic dead space. Hypercapnia and the accompanying respiratory acidosis can cause diffuse systemic effects; alterations in autonomic, cardiorespiratory, neurologic, and metabolic functions are common. Acute respiratory acidosis has variable effects on the cardiovascular system. Hypercapnia and acidosis directly decrease myocardial contractility and systemic vascular resistance.4 However, these effects are typically offset by increased sympathetic nervous system activation and catecholamine release which occur secondary to acute hypercapnia, leading to increases in heart rate and systemic blood pressure. Tachyarrhythmias are commonly seen, and prolongation of the QT interval has been reported rarely.6 Hypercapnia causes vasoconstriction in the pulmonary circulation.27 Additionally, high PCO2 levels can lead to bronchodilation and decreased diaphragmatic contractility.26 Neurologic sequelae depend upon the magnitude and the duration of the hypercapnia, as well as the degree of concurrent hypoxemia. In general, cerebral blood flow is increased in response to increases in PCO2 as a result of vasodilation of cerebral vasculature and increased systemic blood pressure. This increase in cerebral blood flow leads to increased intracranial pressure. Clinical manifestations are variable and include deteriorating level of consciousness, altered brainstem reflexes, seizures, and altered postural and motor responses. CO2 narcosis, seen when PCO2 is greater than 90 mm Hg, is likely the result of alterations in intracellular pH and changes in cellular metabolism.4,1 Hypercapnia may also impact metabolic and endocrine function. At high levels of PCO2, constriction of the renal afferent arteriole may

result in acute kidney injury and decreased urine output. Hypercapnia may cause increased sodium and water retention, as well as hyperkalemia.27 The anterior pituitary may be stimulated by increased CO2, leading to increased adrenocorticotropic hormone secretion.4 Hypercapnia produces a respiratory acidosis. This acidosis may result in several clinical effects including cardiovascular instability, altered mentation, and electrolyte abnormalities. In addition, hypercapnia (and acidosis) will cause a rightward shift of the oxyhemoglobin dissociation curve, which increases release of oxygen to the tissues.1,2

DIAGNOSIS The gold standard for assessment of arterial PaCO2 levels is arterial blood gas analysis (see Chapter 202, Blood Gas Sampling). Arterial blood samples can be collected via percutaneous puncture of the femoral, dorsal pedal, coccygeal, sublingual, and dorsal auricular arteries in dogs. Obtaining an arterial sample in cats can be more difficult; the most accessible sites are the femoral and coccygeal arteries. If arterial blood cannot be obtained, a venous blood gas sample can be used. Central venous samples obtained from the jugular vein or vena cava or mixed venous samples obtained from a pulmonary arterial catheter provide the most accurate venous results. If these are not available, peripheral venous samples can be used; however, caution should be exercised when interpreting venous PCO2 values in states of reduced blood flow. In normal animals, the venous partial pressure of CO2 is usually about 3 to 6 mm Hg higher than the arterial PaCO2. This normal venous–arterial gradient occurs because CO2 is removed from tissues and transported in venous blood back to the lungs as dissolved CO2 in plasma (about 10%) and buffered within red blood cells as bicarbonate (about 90%).1,4 However, the venous–arterial PCO2 gradient (Pv-aCO2) can increase significantly in states of decreased tissue perfusion. Venous CO2 (PVCO2) is a reflection of arterial CO2 inflow, de novo local tissue CO2 production, and tissue blood flow. PaCO2, as previously discussed, is most dependent on alveolar ventilation. During tissue hypoxia, tissue CO2 production is increased as a result of increased hydrogen ion production secondary to lactate formation and hydrolysis of ATP.7 These protons are buffered by HCO3–, which subsequently leads to increased CO2 production. In addition, CO2 accumulates in tissues if decreased blood flow is present. The net result is increased PvCO2. The difference between venous and arterial PCO2 (Pv-aCO2) has been used to identify patients suffering from decreased tissue blood flow in a variety of disease states. Increased Pv-aCO2 has been correlated with decreased cardiac output in human and canine models of hemorrhagic and septic shock8,9 and decreased Pv-aCO2 has been correlated with return of spontaneous circulation in animal models of cardiopulmonary arrest.10 Therefore, although useful, venous CO2 values should be interpreted in conjunction with measures of oxygen content and tissue perfusion in clinical patients. Direct measurement of PaCO2 remains the gold standard for patient monitoring; however, blood gas analysis provides only a single measurement of what is often a rapidly changing clinical picture. In addition, arterial samples may be difficult to obtain or painful to the patient; a means of continuously monitoring PaCO2 without the need for repeat blood gas analysis is desirable. Invasive continuous arterial blood gas monitoring systems are available in human medicine; however, they are costly and subject to technical difficulties related to the maintenance of arterial blood flow and motion artifact. These difficulties would likely restrict the use of these monitors in veterinary patients to those under general anesthesia or mechanical ventilation. Methods for the continuous noninvasive monitoring of PaCO2 include end-tidal and transcutaneous devices.

CHAPTER 17  Hypoventilation End-tidal capnography is a readily available, noninvasive surrogate for PaCO2 (see Chapter 190, Capnography). Capnography analyzes the CO2 concentration of the expiratory air stream, plotting CO2 concentration against either time or exhaled volume. After anatomic dead space has been cleared, the CO2 rises progressively to its maximal value at end exhalation, a number that reflects the CO2 tension of mixed alveolar gas. When ventilation and perfusion are distributed evenly, as they are in healthy subjects, end-tidal PCO2 (PETCO2) closely approximates PaCO2. Normally PETCO2 underestimates PaCO2 by 2 to 6 mm Hg; this gradient is a function of dead space ventilation and cardiac output and has been shown to change in pathologic conditions that affect these physiologic variables.4 In portions of the lung that are hypoperfused, either because of decreased cardiac output or pulmonary embolism, less CO2 is delivered to the lungs for elimination; this translates to a low PETCO2 and an increased PaCO2-PETCO2 gradient. The PaCO2-PETCO2 difference is minimized when perfused alveoli are recruited maximally. Transcutaneous CO2 (TC-CO2) monitors provide another means of noninvasively monitoring PaCO2. These monitors use heated electrodes to measure CO2 in capillary beds. TC-CO2 monitoring is accurate in human patients with normal respiratory function and more accurate than PETCO2 in patients with ventilation–perfusion mismatching.11 In addition, TC-CO2 monitoring can be applied in situations that impact the accuracy of end-tidal CO2 values, such as highfrequency oscillatory ventilation and oxygen supplementation. TC-CO2 measurement has been used to monitor acid-base balance in human patients with diabetic ketoacidosis and more recently, to assess the adequacy of tissue perfusion in critical illness and shock.11,26 Transcutaneous CO2 monitors have been evaluated in veterinary patients.12,20 To date, studies have found that TC-CO2 values are not a reliable surrogate for PaCO2 in dogs and cats. In addition to blood gas analysis and noninvasive CO2 measurement, tests should be performed to help identify the underlying cause of hypoventilation. A baseline complete blood count, chemistry panel, and urinalysis are recommended. Additional tests include, but are not limited to, chest radiography, thoracic and abdominal ultrasound, cervical radiography, testing for infectious and neuromuscular disease, computed tomography or magnetic resonance imaging, electromyography, nerve conduction velocity testing, cerebrospinal fluid analysis, endocrine and pulmonary function testing, and nerve and muscle biopsies. Test selection should be dictated by the clinical status of the patient and the suspected disease process(es).

TREATMENT Definitive treatment of hypercapnia is achieved through prompt diagnosis and elimination or the management of the underlying cause. In the emergent setting, airway patency should be confirmed immediately, and supplemental oxygen administered as relief of airway obstruction, tracheostomy tube placement, or endotracheal intubation is performed, if indicated. Once an airway has been secured and manual ventilation has been provided, if indicated, hemodynamic stability should be optimized to ensure hypercapnia secondary to poor pulmonary perfusion is not confounding interpretation. Provision of supplemental oxygen to the hypoventilating patient is controversial. Patients with significant hypoxemia require oxygen therapy to prevent life-threatening complications of hypoxemia (see Chapter 16, Hypoxemia). However, hypercapnia secondary to oxygen therapy may be observed in patients with chronic hypoventilation and acute hypoxemia. Patients with chronically increased CO2 levels have a diminished central and peripheral response to CO2; arterial hypoxemia becomes the principal stimulus for ventilation in these patients. In this

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setting, sudden correction of arterial hypoxemia causes further hypercapnia through a combination of three mechanisms: (1) depression of hypoxia-driven chemoreceptors, (2) relief of hypoxic pulmonary vasoconstriction in poorly ventilated lung regions as local perfusion increases without concomitant increase in ventilation, and (3) significant correction of hypoxemia causes better saturation of hemoglobin so that previously buffered protons on deoxyhemoglobin are released with subsequent generation of new CO2 from stores (Haldane effect).13 In human medicine, slow titration of low-flow oxygen (1–2 L/min increased in increments of 1 L/min) to achieve a target arterial PO2 of 60–70 mm Hg and pulse oximetry values of 90%–93% is recommended.25 Close monitoring of PaO2 and PCO2 is recommended during titration to ensure improvement in oxygenation and to prevent oxygen-induced hypercapnia. Additional therapies should be directed at treatment of the underlying cause of the hypercapnia. For example, patients receiving opioids, sedatives, or neuromuscular blockade should receive reversal medications if indicated. Manual/mechanical ventilation may be needed until the medications have been reversed or metabolized. For patients under general anesthesia, the anesthetic circuit and the anesthetic gas adsorbent should be evaluated and changed, if indicated, to address hypercapnia. Patients with pleural space disease should undergo thoracocentesis as soon as possible. In human medicine, the use of respiratory stimulant medications has fallen out of favor in most conditions due to lack of evidence demonstrating improvement in hypercapnia or clinical outcomes with their use.25 Respiratory stimulant medications include doxapram, aminophylline/theophylline, caffeine, and progesterone, among others. Studies evaluating the impact of these medications on hypercapnia and respiratory function in small animal clinical patients are lacking; therefore, careful evaluation of the risks and benefits of these medications in individual patients is advised prior to use. Doxapram stimulates respiration via activation of peripheral chemoreceptors; at higher doses, the medullary respiratory center is stimulated, causing an increase in VT and RR. Side effects of doxapram result from systemic catecholamine release and central nervous system stimulation. In addition, this drug may increase the work of breathing, which can lead to increased oxygen consumption and CO2 production.14 Methylxanthine drugs, including aminophylline, theophylline, and caffeine, have been shown to improve ventilation in experimental both dogs and cats. Methylxanthines have several beneficial respiratory effects including bronchodilation, central respiratory center stimulation, improved skeletal muscle and diaphragmatic contractility, and enhanced mucociliary clearance, among others.15,16 Use has been shown to prevent diaphragmatic fatigue in adult humans.15,16 Aminophylline has been shown to significantly increase V E, VT, RR, and diaphragmatic and intercostal contractility in dogs.23,24 Specific effects appear to vary to some degree between methylxanthines. For example, caffeine is considered to be more effective in stimulating the central nervous and respiratory systems and appears to penetrate the cerebrospinal fluid more readily than theophylline.17 Theophylline is considered a more potent cardiac stimulant and has greater diuretic and bronchodilator effects but is associated with a higher incidence of tachycardia.17 Caffeine citrate has been used in the management of apnea of prematurity because of its more predictable pharmacokinetics and decreased side effect profile in comparison to theophylline. Use has been associated with a decreased apnea frequency and improvement in both short and long-term clinical outcomes in preterm infants.27 Studies evaluating safety and efficacy of caffeine citrate in clinical veterinary patients or neonates are warranted before this medication can be routinely recommended.

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Sodium bicarbonate administration is not indicated for the correction of acidemia secondary to respiratory acidosis. Hypercapnia may worsen after administration due to increased production of CO2 from bicarbonate. Acetazolamide is a diuretic that induces a metabolic acidosis via bicarbonate ion excretion. This acidosis may stimulate ventilation; however, caution should be exercised when using this drug in patients with a preexisting respiratory acidosis; severe systemic complications of acidemia may result. The most effective treatment for hypoventilation is mechanical ventilation (see Chapters 32 and 33, Mechanical Ventilation Core Concepts and Advanced Concepts, respectively). Many patients with central nervous system disease, neuromuscular disease, or altered respiratory mechanics leading to hypoventilation may require this therapeutic modality. Ventilated patients require referral for 24-hour monitoring in an intensive care facility. Mechanical ventilation is lifesaving for patients with reversible causes of hypoventilation and should be strongly considered in these patients when other therapeutic options are unsuccessful.

REFERENCES 1. Lumb AJ: Distribution of pulmonary ventilation and perfusion. In Lumb AJ, editor: Nunn’s applied respiratory physiology, ed 6, Philadelphia, 2005, Elsevier. 2. West JB: Ventilation, control of ventilation. In West JB, editor: Respiratory physiology: the essentials, ed 6, Baltimore, 2000, Lippincott Williams & Wilkins. 3. Hopper K, Haskins SC: A case-based review of a simplified quantitative approach to acid-base analysis, J Vet Emerg Crit Care 18(5):467, 2008. 4. Lumb AJ: Control of breathing. In Lumb AJ, editor: Nunn’s applied respiratory physiology, ed 6, Philadelphia, 2005, Elsevier. 5. Mattson S, Kerr C, Dyson D: Anesthetic equipment fault leading to hypercapnia in a cat, Vet Anaes Analg 31:231, 2004. 6. Johnson RA, Autran de Morais H: Respiratory acid-base disorders. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders in small animal practice, ed 3, St Louis, 2006, Elsevier. 7. Boller MB: CO2 in Low blood flow states. In Multidisciplinary systems review, 17th International VECC Symposium, 2011. 8. Bakker J, Vincent JL, Gris P, et al: Veno-arterial carbon dioxide gradient in human septic shock, Chest 101(2):509, 1992. 9. Van der Linden P, Rausin I, Deltell A, et al: Detection of tissue hypoxia by arteriovenous gradient for PCO2 and pH in anesthetized dogs during progressive hemorrhage, Anesth Analg 80(2):269, 1995.

10. Grundler W, Weil MH, Rackow EC: Arterio-venous carbon dioxide and pH gradients during cardiac arrest, Circulation 74:1071, 1986. 11. Tobias JD: Transcutaneous carbon dioxide monitoring in infants and children, Paediatr Anaesth 19(5):434, 2009. 12. Vogt R, Rohling R, Kästner S: Evaluation of a combined transcutaneous carbon dioxide pressure and pulse oximetry sensor in adult sheep and dogs, Am J Vet Res 68(3):265, 2007. 13. McConville JF, Soloway J: Disorders of ventilation. In Longo DL, Fauci AS, Kasper DL, et al, editors: Harrison’s principles of internal medicine, ed 18, New York, 2011, McGraw-Hill Professional. 14. Campbell VL, Perkowski S: Hypoventilation. In King LK, editor: Textbook of respiratory diseases in dogs and cats, St Louis, 2004, Elsevier. 15. Bhatia J: Current options in the management of apnea of prematurity, Clin Pediatr 39:327, 2000. 16. Randa JV, Gorman W, Bergsteinsson H, et al: Efficacy of caffeine in treatment of apnea in the low-birth-weight infant, J Pediatr 90:467, 1977. 17. Kriter KE, Blanchard J: Management of apnea in infants, Clin Pharmacy 8:577, 1989. 18. Riou B: Case scenario: increased end tidal carbon dioxide, Anesthesiology 112:440, 2010. 19. Fukushima F, Malm C, Andrade MEJ, et al: Cardiorespiratory and blood gas alterations during laparoscopic surgery for intrauterine artificial insemination in dogs, Can Vet J 52:77, 2011. 20. Holowaychuk M, Fujita H, Bersenas A: Evaluation of a transcutaneous blood gas monitoring system in critically ill dogs, J Vet Emerg Crit Care 24:545, 2014. 21. Bar S, Fischer MO: Regional capnometry to evaluate the adequacy of tissue perfusion, J Thorac Dis 11(Suppl 11):S1568, 2019. 22. Dobson NR, Patel RM: The role of caffeine in noninvasive respiratory support, Clin Perinat 43:773, 2016. 23. Jagers JG, Hawes HG, Easton PA: Aminophylline increases ventilation and diaphragm contractility in awake canines, Respir Physiol Neurobiol 167:273, 2009. 24. Suneby J, Ji M, Rothwell B, et al: Aminophylline increases parasternal muscle action in awake canines, Pulm Pharm Ther 56:1, 2019. 25. Feller Kopman D, Schwartzstein RM: The evaluation, diagnosis, and treatment of the adult patient with acute hypercapnic respiratory failure, Available at https://www.uptodate.com/contents/the-evaluation-diagnosisand-treatment-of-the-adult-patient-with-acute-hypercapnic-respiratoryfailure. Accessed 2 Dec, 2019. 26. Domino KB, Emery MJ, Swenson ER, et al: Ventilation heterogeneity is increased in hypocapnic dogs but not pigs, Respir Physiol 111:89, 1998. 27. Lumb AJ: Hypercapnia in clinical practice. In Lumb AJ, editor: Nunn’s applied respiratory physiology, ed 6, Philadelphia, 2005, Elsevier.

18 Upper Airway Disease Dana L. Clarke, VMD, DACVECC

KEY POINTS • Upper airway obstruction is a common cause of respiratory distress in small animals and requires immediate recognition and treatment. • Common diseases leading to upper airway obstruction in dogs include laryngeal paralysis, tracheal collapse, and brachycephalic obstructive airway syndrome. • Upper airway obstruction is less common in cats, and can be secondary to nasal disease, inflammatory laryngeal disease, and tracheal and laryngeal neoplasia.

• Patient stabilization, including oxygen, sedation, and anxiety control, should be a priority over diagnostics to avoid further patient distress. • Complications of upper airway obstruction are common, including hyperthermia, aspiration pneumonia, and noncardiogenic pulmonary edema.

In veterinary medicine, upper airway disease causing airway obstruction and secondary respiratory distress is a common reason for emergency patient evaluation. Regardless of the cause, patients in distress often have exhausted their physiologic compensatory reserves for ventilation and oxygenation, and even small stresses such as restraint for examination can result in rapid decompensation. Prompt treatment with oxygen, anxiolytics, and for some patients, intubation or tracheostomy, may be necessary before the definitive cause is determined or diagnostics performed.

low-pitched snoring such as inspiratory and/or expiratory noise. Obstructive diseases of the larynx or trachea can result in coughing, gagging (particularly with eating or drinking), and respiratory stridor, which is a highpitched noise associated with inspiration. Laryngeal and pharyngeal disease can lead to changes in vocalization (dysphonia).1-4 Coughing is a common clinical sign in animals with tracheal, mainstem bronchus, and laryngeal disease. Since it also commonly is associated with lower airway, pulmonary parenchymal, and cardiac disease, it is important to rule out other causes for coughing. Coughing that results from upper airway disease tends to be dry and nonproductive, whereas coughing of a lower airway or pulmonary parenchymal origin tends to result in a moist, productive cough.5,6 However, many owners have difficulty appropriately determining the productivity of a cough because patients may quickly swallow sputum, or the cough may be associated with terminal, productive retching of gastrointestinal origin.

HISTORY AND CLINICAL SIGNS Clinical signs noted by owners of patients with upper airway disease depend on the location, severity, chronicity, and species. Since cats breathe predominantly through their noses and only open-mouth breathe or pant with severe respiratory compromise, owners may not immediately recognize changes in respiratory comfort. The more sedentary lifestyle of cats can also delay diagnosis of respiratory disease because exercise intolerance is likely to be noticed only as a late change in cats. Dogs with upper airway disease often pant in response to respiratory difficulty. Because panting in dogs may not be recognized as abnormal, respiratory changes may not be obvious when panting is the only clinical sign. The upper airway consists of the nasal passages and choanae, nasopharynx and oropharynx, larynx, and trachea to the thoracic inlet. Clinical signs associated with disease along the upper respiratory tract can by dynamic or static. Dynamic signs occur during inspiration or expiration, depending on the location of the obstruction, or with stress, anxiety, and activity that alter airflow dynamics and precipitate obstruction. Static signs occur with fixed intraluminal or extraluminal obstruction or compression. Disease in the rostral regions of the upper airway (nasal passages, choanae, and nasopharynx) can result in nasal discharge, sneezing, reverse sneezing, snoring, stertorous breathing, and an inability to breathe comfortably when not panting. Stertorous respiration is characterized by

PATIENT EVALUATION Hospitalized patients can develop upper airway obstruction with stress, excessive panting and anxiety, after intubation and recovery from general anesthesia, and after vomiting and regurgitation. Recognition of patients at risk for developing upper respiratory complications, such as those with brachycephalic airway disease, laryngeal dysfunction, and tracheal collapse, is important in order to plan for controlled anesthetic recovery, prepare for reintubation or tracheostomy, and aggressively manage nausea and choose drugs less likely to induce vomiting and regurgitation. Laryngeal, tracheal, and thoracic auscultation often reveals loud, referred upper airway noise, which often can be localized to the point of maximal intensity with thorough auscultation of the entire respiratory tract. Patients with upper airway disease tend to have loud, noisy breathing and increased inspiratory time. Inspiratory noise and distress result from the collapse or obstruction of the upper airway rostral to the thoracic inlet trachea due to the creation of negative intrathoracic

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TABLE 18.1  Commonly Used Medications

for the Management of Patients with Upper Airway Obstruction in the ICU

Fig. 18.1  Bulldog in respiratory distress, demonstrating excessive panting, hypersalivation and orthopnea secondary to upper airway obstruction from brachycephalic obstructive airway syndrome.

pressure upon inspiration that results in a negative transmural pressure and tendency to collapse. This collapse prolongs the inspiratory phase and creates noise from air and tissue reverberation in the lumen. Increased (positive) intrapleural pressure upon expiration collapses the airway caudal to the thoracic inlet (intrathoracic trachea and mainstem bronchi) and results in prolonged expiration, expiratory dyspnea, and lower airway sounds (e.g., wheezes) on auscultation. In a retrospective evaluation of dogs and cats presenting for emergency evaluation of respiratory distress, inspiratory dyspnea in dogs and inspiratory noise in dogs and cats were significantly associated with disease localization to the upper airway. Too few cats in that study had disease isolated to the upper airway to fully characterize the nature of inspiratory dyspnea seen with upper airway disease.7 The degree of upper airway noise often worsens with the severity of the obstruction.1 Thorough auscultation of the pulmonary parenchyma can be difficult in the face of loud referred upper noise but is imperative because of parenchymal complications of upper airway obstruction such as noncardiogenic pulmonary edema and aspiration pneumonia. Panting and subsequent evaporative cooling are major methods of thermoregulation, especially in dogs. Intolerance of warm and humid conditions is often seen in patients with upper airway disease resulting from a decreased ability to efficiently increase minute ventilation to enhance heat dissipation and is a described risk factor for heat stroke.8-11 Hyperthermia and heat stroke can also result from failure to effectively eliminate heat secondary to upper airway obstruction; these are common findings in patients with laryngeal paralysis and brachycephalic airway syndrome. Prompt recognition and treatment of hyperthermia (see Chapter 10, Hyperthermia and Fever) are essential to prevent secondary consequences such as renal, neurologic, cardiovascular, and coagulation disorders.9-11 Since aspiration pneumonia is also a complication of upper airway obstruction, fever should be considered as a source of increased rectal temperature as well (see Chapter 10, Hyperthermia and Fever). In addition to loud respiratory noise, marked respiratory distress, and hyperthermia, other clinical signs that can be recognized with severe upper airway obstruction include extension of the head and neck (orthopnea), cyanosis of the tongue and mucous membranes, and collapse (Fig. 18.1). In such severe cases, immediate intubation or emergency tracheostomy (see Chapter 197, Endotracheal Intubation and Tracheostomy) may be necessary life-saving interventions.

Medication

Dose

Indication/Considerations

Acepromazine

0.005 to 0.02 mg/ kg IV and 0.01 to 0.05 mg/kg IM

Anxiolytic Takes 15 min to reach full effect (IV)12 Caution in cardiovascularly unstable patients

Butorphanol

0.1 to 0.5 mg/kg IM or IV

Sedative, cough suppressant, analgesic

trazodone

2–5 mg/kg PO q8-12

Anxiolytic Oral formulation only

Dexamethasone sodium phosphate

0.05 to 0.2 mg/kg IM, IV, SC

Antiinflammatory glucocorticoid Caution with poor perfusion and suspected airway neoplasia (may impede diagnosis)

STABILIZATION OF PATIENTS WITH UPPER AIRWAY OBSTRUCTION The work of breathing against an upper airway obstruction can precipitate the cycle of edema and inflammation, patient distress, and progressive obstruction, so supplemental oxygen and techniques to minimize patient stress are universally recommended treatment strategies, regardless of the origin of the obstruction. For some patients, the restraint necessary for intravenous catheter placement, venipuncture, and other diagnostics may exacerbate stress and oxygen demands, leading to further respiratory compromise or respiratory arrest. Therefore IM administration of medications is necessary when catheter placement is not safe or feasible. Oxygen therapy can be provided in several different manners; the method selected depends on availability and patient tolerance (see Chapter 15, Oxygen Therapy). An oxygen cage is one of the best ways to provide high levels of inspired oxygen while minimizing patient stress and handling. However, enclosure within an oxygen cage prevents the clinicians and nurses from hearing upper airway noises that can indicate worsening obstruction, which can be dangerous in patients with upper airway disease. Control of anxiety and discomfort is essential for patients with upper airway obstruction and respiratory distress. Treatment of secondary inflammation may also be needed (see Chapter 132, Sedation of the Critical Patient) (Table 18.1). When sedation and anxiety control do not relieve respiratory distress, or for patients at risk of imminent respiratory arrest, rapid induction for endotracheal intubation or tracheostomy is necessary (see Chapters 133 and 197, Anesthesia of the Critical Patient and Endotracheal Intubation and Tracheostomy, respectively). If a challenging intubation is anticipated, as with laryngeal collapse or paralysis, upper airway foreign bodies, or neoplasia, a Cook Airway Exchange Catheter (Cook Medical LLC, Bloomington, IN) can be very helpful to provide initial oxygen insufflation and serve as rigid stylet to facilitate intubation.

DIAGNOSTICS While signalment and physical examination findings are crucial in the evaluation of the upper airway obstruction patient, diagnostics are needed to confirm the etiology, evaluate severity and secondary consequences, and assist in therapeutic decision making. Blood gas analysis is helpful in patients with upper airway obstruction to assess the

CHAPTER 18  Upper Airway Disease degree of ventilatory dysfunction and/or hypoxemia. Arterial blood gas analysis is the standard for assessing oxygenation and ventilation, though collection of an arterial sample is often not possible in patients with respiratory distress (see Chapters 16 and 17, Hypoxemia and Hypoventilation, respectively) (Table 18.2). Diagnostics imaging is an important part of the work-up in all patients with respiratory disease but must not be obtained at the risk of patient safety (Table 18.2). Heavy sedation or general anesthesia often is required for computed tomography (CT) and skull radiography, so these diagnostics often are performed as second-tier diagnostics. Dynamic disease processes such as nasopharyngeal, laryngeal, and tracheal collapse may not be seen on sedated or anesthetized CT examinations. Studies evaluating a clear plastic patient positioning device (VetMousetrap) that contains the animal and restricts movement have shown promising

TABLE 18.2  Diagnostics Commonly Utilized

in the Patient with Upper Airway Obstruction

Diagnostic Testing Findings with Upper Airway Obstruction Arterial or venous blood gas

Increased partial pressure of carbon dioxide (PaCO2/PvCO2) 6 metabolic compensation

Arterial blood gas

Alveolar-arterial (A-a) gradient to rule out hypoventilation as a contributor to hypoxemia

Thoracic radiographs

Noncardiogenic pulmonary edema Bronchopneumonia (aspiration or infectious), Intrathoracic tracheal collapse Mainstem bronchial collapse Airway or pulmonary neoplasia

Cervical radiographs

Laryngeal and pharyngeal masses Extrathoracic tracheal collapse Radioopaque foreign bodies

Upper airway fluoroscopy

Dynamic assessment of nasopharyngeal, tracheal, and bronchial collapse Lung lobe herniation

Computed tomography

Nasal passage/nasopharynx imaging Bulla Tracheal neoplasia Pulmonary metastasis Radiation planning

Sedated laryngeal examination

Tonsillar eversion, hyperemia, masses Laryngeal structure and function Laryngeal saccular eversion, edema Inflammatory or proliferative laryngeal changes Epiglottic retroversion Soft palate length, thickness, irregularity

Rigid and flexible endoscopy

Nasal turbinate proliferation, inflammation, plaques associated with fungal diseases and nasal masses Nasopharyngeal stenosis, masses, turbinates, foreign bodies Nasopharyngeal collapse Tracheal and mainstem bronchial collapse Tracheal foreign bodies, granulation tissue Tracheal and bronchial neoplasia

Airway sampling (transtracheal, endotracheal, bronchoalveolar lavage)

Airway cytology Aerobic culture and susceptibility testing Mycoplasma culture and PCR

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results for dynamic CT evaluation of upper airway obstruction secondary to laryngeal, tracheal, and bronchial disease without the need for anesthesia or sedation.13 Awake CT examination for cats with upper airway obstruction also has proven effective for diagnosing disease processes such as intramural airway masses, laryngeal paralysis, and laryngotracheitis.14 Sedated laryngeal examination is indicated in all patients with upper airway disease, even if laryngeal disease or dysfunction is not considered the primary pathology. Sedation protocols proven to have minimal influence on laryngeal exam include intravenous propofol slowly titrated to effect, with or without the use of concurrent doxapram (1.1 to 2.2 mg/kg IV), or premedication with acepromazine (0.2 mg/kg IM) and butorphanol (0.4 mg/kg IM) 20 minutes before mask induction with isoflurane.15-19 High-dose intramuscular acepromazine was recommended based on the results from normal dogs that did not permit mask induction when lower doses were used early in the trial, but caution is advised when using higher doses to avoid adverse effects.17 Critically ill or compromised patients require lower doses of intramuscular acepromazine, and titration to effect starting with lower doses (0.01 to 0.05 mg/kg) should be considered for clinical patients (see Chapter 132, Sedation of the Critical Patient). A standard laryngoscope with blade and light source is used most commonly for direct visualization of the larynx and oropharynx, although rostral pulling of the tongue and pressure of the blade on the epiglottis may distort laryngeal and oropharyngeal examination. To avoid distortion and for image archival, transoral rigid or flexible endoscopy is extremely helpful and is advised, whenever possible.15,20,21During laryngeal function assessment, it is important to have an assistant indicating the phases of respiration during laryngeal exam to confirm appropriate laryngeal motion and rule out paradoxical laryngeal motion, which can be confused as laryngeal function in dogs with laryngeal paralysis. Paradoxical laryngeal motion is defined as inward movement of the arytenoids secondary to negative pressure generated upon inspiration. Epiglottic retroversion, or caudal displacement of the epiglottis into the rima glottis, should also be ruled out as an uncommon cause of upper airway obstruction and respiratory distress22 (Fig. 18.2). The length and appearance of the soft palate should be assessed, as should the epiglottis. The caudal aspect of the soft palate should contact the epiglottis or extend no more than a few millimeters past it.23 Bronchopneumonia, whether secondary to aspiration, mucociliary dysfunction, or underlying chronic lower airway disease, is a common secondary complication to upper airway disease and obstruction (see Chapter 24, Pneumonia). Sampling from the airway for cytology and culture is helpful to guide antimicrobial therapy, especially in patients with repeated episodes of pneumonia. However, in animals with severe respiratory distress, airway sampling may not be safe and a delay in antimicrobial therapy could hinder pulmonary parenchymal recovery. Therefore, empiric antimicrobial therapy may be necessary. For patients stable enough to undergo airway sampling, transtracheal, endotracheal, and bronchoalveolar lavage can be considered for airway cytology and aerobic bacterial and Mycoplasma cultures.

DISEASES OF THE UPPER AIRWAY Brachycephalic Airway Syndrome Brachycephalic airway syndrome (BAS), brachycephalic syndrome, and brachycephalic obstructive airway syndrome are synonymous terms used to describe the cluster of anatomic abnormalities seen in brachycephalic breeds, such as English Bulldogs, Pugs, French Bulldogs, and Boston Terriers, that contribute to dysfunction of the upper airway. The classic primary anatomic components of BAS include stenotic nares and an elongated soft palate, although other commonly

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A

B Fig. 18.2  Rigid endoscopic examination from a Yorkshire Terrier demonstrating epiglottic retroversion where the tip of the epiglottis becomes entrapped over the caudal edge of the soft palate.

recognized components include tracheal hypoplasia and nasopharyngeal turbinates. Secondary complications from chronic increased resistance to airflow on inspiration include everted laryngeal saccules, tonsillar eversion, laryngeal collapse, tracheal collapse, chronic gastrointestinal signs, and even syncope.24-30 Approximately 80% of the resistance to airflow during inspiration is from the nose in normal dogs.1,25,27,31,32 This is exaggerated in brachycephalic animals with stenotic nares, excessive pharyngeal tissues, elongated soft palate, and/or tracheal hypoplasia, which lead to turbulent airflow, edema, and increased inspiratory noise.1,2,25,27 In addition to increased respiratory noise, other clinical signs seen in BAS patients include snoring, stertor, stridor, heat and exercise intolerance, hypersalivation, vomiting, and regurgitation.24,25,28,29 It is most common in young adult dogs (2 to 3 years), although English Bulldogs have been reported to present at younger ages (i.e., 1 year).33-35 Diagnosis of BAS is made based on signalment, clinical signs, and examination of the nares, oropharynx, and larynx during a sedated oral examination using a laryngoscope or endoscope (flexible or rigid). Oral examination should include assessment of the soft palate length, size and shape of the rima glottis, and the presence or absence of laryngeal saccule eversion and laryngeal collapse. Thoracic radiographs can be helpful to evaluate for tracheal hypoplasia, tracheal collapse, hiatal hernia, and pneumonia, although caution must be exercised when diagnosing tracheal hypoplasia when bronchopneumonia is present because inflammation and

edema of the trachea during an active airway infection may be deceiving.36,37 Fluoroscopy can be helpful to evaluate for dynamic nasopharyngeal collapse, which has been described in brachycephalic dogs.38 Blood gas analysis may show signs of hypoxemia and/or hypoventilation, and brachycephalic breeds often have higher carbon dioxide levels and lower oxygen pressures than mesocephalic or dolichocephalic dogs.39 Retroflexed endoscopy of the nasopharynx may show nasopharyngeal inflammation, collapse, or the presence of nasal turbinates protruding in the nasopharynx, which has been documented in approximately 20% of dogs symptomatic for BAS, with 80% of affected dogs being Pugs in one study.26 Bronchoscopic evaluation of dogs with BAS presenting for surgery showed that 87% of dogs had some degree of bronchoscopically detectable collapse or stenosis and that a worsened degree of bronchial collapse was associated with laryngeal collapse.40 Upper gastrointestinal flexible endoscopy is helpful to evaluate for esophagitis, gastritis, reflux, hiatal hernia, and pyloric stenosis, which have been found in up to 80% of BAS patients, with worsened gastrointestinal signs correlated with worsened respiratory clinical signs.29,30 Biomarker evaluation may show increased cardiac troponin I (cTnI), which may be secondary to myocardial injury from chronic hypoxemia. However, C-reactive protein and haptoglobin levels have not been shown to be increased in dogs with upper airway obstruction secondary to BAS, indicating that there may be minimal systemic inflammation.41 First-line management of BAS includes weight loss, control of excitement and activity triggers, medical treatment for gastrointestinal signs, and treatment of underlying pulmonary parenchymal disease. However, surgical correction of BAS anatomic abnormalities often is required for successful management of most animals with clinical signs of upper airway obstruction due to the structural nature of the disease pathology. Since the nasal passage creates the most resistance to airflow, widening the nares is considered the most important aspect of surgery for BAS, especially because many of the other airway changes are considered secondary to stenotic nares. Widening of the nares at a young age is recommended and shown to provide significant improvement in dogs postoperatively, regardless of the multiple techniques available.* Correction of other components of BAS, including soft palate resection, resection of everted laryngeal saccules, and tonsillectomy also may be needed and can be helpful even in advanced BAS cases with laryngeal collapse.33,40,46 Tracheal hypoplasia and bronchial collapse has not been associated with outcome in dogs undergoing surgical intervention for BAS.34,40 Cricoarytenoid lateralization combined with thyroarytenoid caudolateralization (arytenoid laryngoplasty) has been described in patients with advanced laryngeal collapse, a disease for which permanent tracheostomy was previously considered the only viable surgical intervention.47

Nasopharyngeal Polyps Nasopharyngeal polyps are a common cause of upper airway obstruction in cats, accounting for 28% of cats with nasopharyngeal disease.48 They also have been implicated in moderate to life-threatening upper airway obstruction in three dogs.49-51 Nasopharyngeal polyps are benign inflammatory lesions that arise from the mucosa of the auditory tube or middle ear and grow into the nasopharynx or external ear canal. The exact cause is not known, and attempts to isolate and amplify feline herpes virus, feline calicivirus, Mycoplasma species, Bartonella species, and Chlamydophila felis DNA or RNA from feline aural and nasopharyngeal polyps has been unsuccessful.48,52-58 Clinical signs commonly seen in cats with nasopharyngeal polyps include respiratory noise or stertor, sneezing, nasal discharge, and dysphagia, which may contribute to weight loss.52,53,55,57 Progression of the polyp can * References 27, 30, 34, 40, 42-46.

CHAPTER 18  Upper Airway Disease lead to apparent dyspnea and signs consistent with upper airway obstruction. Diagnosis is usually made based on historical information, oropharyngeal examination with palpation of the soft palate, otoscopy, retroflexed rhinoscopy, radiographs, CT, and/or magnetic resonance imaging52,53,56,59 (Fig. 18.3A). Medical management is generally unrewarding; therefore, surgical intervention is recommended. Tractionavulsion is the simplest method of removal but can be associated with a 40% to 50% chance of recurrence, especially if removed from the auditory canal53,56,60,61 (Fig. 18.3B). For this reason, ventral bulla osteotomy (VBO) is recommended, especially for those patients with polyps in the auditory tube or evidence of middle ear disease.53,57,61 VBO is associated with a higher incidence of postoperative Horner syndrome (43% of cats treated with traction and 57% of cats treated with VBO), vestibular dysfunction, and facial and hypoglossal nerve paralysis.53,57,61 In most cats, Horner syndrome resolves postoperatively, although it can take up to 4 weeks.60-62 Preoperative hearing deficits were not reversed in cats with polyps that had VBO performed.63 Prolonged antimicrobial therapy is indicated for bacterial otitis media or interna; however, the role of postoperative steroids for treatment of nasopharyngeal polyps is unclear. However, one study showed decreased incidence of recurrence when prednisolone was administered postoperatively.61 In general, the prognosis for cats treated surgically for inflammatory nasopharyngeal polyps is good.

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Nasopharyngeal Stenosis Nasopharyngeal stenosis (NPS) is reported uncommonly in dogs and cats.64-68 Nasopharyngeal stenosis occurs when there is partial or complete narrowing of the nasopharynx by a membrane caudal to the choanae and rostral to the caudal aspect of the soft palate. It can overlie the hard or soft palate and may cover both if the membrane is thick enough. NPS can be a congenital lesion, or secondary to chronic inflammatory diseases such as rhinitis (infectious or aspiration), trauma, and neoplastic obstructions. Clinical signs, which often persist for months before diagnosis, include chronic nasal discharge, stertor, stridor, exercise intolerance, gagging, and in severe cases, dyspnea.67-72 Diagnosis is generally made through CT and retroflexed rhinoscopy, although barium contrast rhinography also has been described.69 Surgical correction of the stenosis via surgical access through a midline incision in the soft palate has been described in cats.73,74 When retroflexed flexible endoscopy is used to confirm or diagnose NPS, balloon dilation can be performed simultaneously to open the obstruction using minimally invasive techniques. An angioplasty balloon can be passed normograde through the ventral meatus of the nasal passage, or advanced retrograde through the oral cavity over a wire within a cut red rubber catheter that has been passed retrograde through the nose.67,69-71 Balloon dilation is performed under constant retroflexed visualization, with or without concurrent fluoroscopy, once the balloon is positioned across the stenosis and confirming the balloon is not within the choanae. Restenosis over time is common, and repeated balloon dilations may be necessary depending on how clinically affected the patient is and the extent of restenosis.67,68,70,71 In patients in whom balloon dilation has failed to resolve the NPS sufficiently, stent placement may be considered via surgical placement or using combined fluoroscopy and retroflexed rhinoscopy.68,72 All animals had improvement in their respiratory signs poststent placement. Complications include dysphagia and hair entrapment, tissue in-growth, and prolonged nasal discharge.68 Stent erosion through the soft palate in two dogs (4 and 20 months after placement of covered nasopharyngeal stents) has been described. It is a serious complication that should be considered before placement of nasopharyngeal stents, particularly over the soft palate.75

Congenital Choanal Atresia Congenital choanal atresia also has been reported rarely in cats and in one dog and can cause similar clinical signs to NPS, including nasal discharge, stertor, exercise intolerance, and open-mouth breathing.66,76-78 It results from abnormal bone or soft tissue obstructing the caudal nasal passage just rostral to the common nasopharynx and can be unilateral or bilateral. CT and retroflexed rhinoscopy can be used to make a diagnosis of choanal atresia. Treatment options include transnasal puncture with temporary stenting and surgical approach to the nasopharynx.66,76-78

Nasopharyngeal Foreign Bodies and Infection

B Fig. 18.3  A, Retroflexed rhinoscopy of the caudal nasopharynx in an 11-year-old Shih Tzu showing the presence of a dorsal soft tissue mass. B, Appearance of the nasopharynx of the same dog after endoscopic electrocautery snare mass removal. Histopathology confirmed the mass was a benign inflammatory polyp.

Nasopharyngeal foreign bodies and infections occur infrequently in dogs and cats but can result in upper airway obstructive signs. Nasopharyngeal cryptococcosis, blastomycosis, and extensive bacterial infection and bony proliferation of the bulla are documented to result in nasopharyngeal obstruction.79-81 Nasopharyngeal foreign bodies tend to cause acute-onset upper respiratory signs and also may result in sneezing. With chronicity, nasal discharge and halitosis can develop. Foreign bodies are presumed to become lodged in the nasopharynx secondary to inhalation, reflux during vomiting or regurgitation, or ingestion and secondary penetration through the soft palate. Foreign bodies can be removed via transoral removal via traction on the soft palate, retroflexed rhinoscopic basket retrieval, nasal flushing,

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and surgical excision via access through the soft palate. Nasopharyngeal foreign bodies found in dogs and cats include bones, foam, a premolar, a trichobezoar, plant material, a stone, sewing needles, and a pet fish.82-88

Laryngeal Paralysis Laryngeal paralysis is the result of recurrent laryngeal nerve dysfunction that impairs arytenoid cartilage abduction during inspiration, leading to respiratory stridor and distress.15,89-91 It is a common form of upper airway obstruction generally recognized in middle-age to older large and giant breed dogs.91,92 Some studies suggest that Labrador Retrievers are overrepresented.91-94 Congenital and acquired laryngeal paralysis have been described in dogs. The disease process also is recognized in cats, although not nearly as commonly. In normal dogs, the larynx accounts for only 6% of resistance to airflow during nasal breathing because contraction of the dorsal cricoarytenoideus muscle, which is innervated by the recurrent laryngeal nerve, abducts the arytenoid cartilages and widens the glottis.89 In cases of dysfunction of the recurrent laryngeal nerve, atrophy of one or both of the paired dorsal cricoarytenoideus muscles results, impairing abduction of the arytenoid cartilages and vocal folds. The net effect is narrowing of the glottis upon inspiration, causing increased velocity and turbulence of airflow, increased muscular effort for inspiration, dynamic collapse of the larynx, and ultimately, upper airway obstruction.89 The cause of recurrent laryngeal nerve dysfunction can be congenital denervation, traumatic, iatrogenic, idiopathic, neoplastic, and associated with diffuse neuromuscular disease.15,89,90 Congenital laryngeal paralysis has been described in Bouvier des Flandres, Rottweilers, Dalmatians, Siberian Huskies, and Husky mixed breeds, Bull Terriers, Pyrenean Mountain Dogs, and Leonbergers. Affected dogs were less than 1 year of age in all breeds except the Leonbergers.95-101 Injury to the recurrent laryngeal nerve secondary to accidental cervical trauma, cervical, mediastinal or thoracic neoplasia, and iatrogenic injury during thyroidectomy and extraluminal tracheal ring prosthesis placement can result in acquired laryngeal paralysis.15,89-91,102,103 Myasthenia gravis and hypothyroidism have also been implicated in cases of laryngeal paralysis, although the exact relationship is not understood completely.91,102,103,105 However, an underlying cause is not confirmed for most cases of acquired laryngeal paralysis, resulting in many cases being labeled idiopathic, although evidence is growing that laryngeal paralysis is one component of generalized peripheral polyneuropathy.91-94,103,106 Clinical signs recognized in dogs with laryngeal paralysis depend on the severity of airway obstruction and can include inspiratory stridor, change in bark, exercise intolerance, coughing, and gagging. Most dogs do not develop significant clinical signs until bilateral laryngeal paralysis has developed.91 Hypersalivation and vomiting or regurgitation may be seen in patients with laryngeal paralysis; however, the absence of gastrointestinal signs does not exclude the possibility of esophageal dysmotility.91 In more severely affected animals, respiratory distress, cyanosis, and collapse can result. Clinical signs can be exacerbated by exercise, stress, anxiety, and increased ambient temperature or humidity. Animals with profound airway obstruction and laryngeal edema may require emergency intubation or tracheostomy. Before anesthesia for laryngeal examination or definitive surgery, thoracic radiographs are imperative to assess for evidence of pneumonia because resolving or subclinical aspiration pneumonia is common.91,102 Other pulmonary pathology, such as noncardiogenic pulmonary edema, cardiomegaly, and intrathoracic or mediastinal neoplasia affecting the recurrent laryngeal nerve, hiatal hernia, and metastatic neoplasia should also be ruled out prior to anesthesia if feasible. Assessment of esophageal motility may be considered because

dogs with esophageal dysmotility are at higher risk of aspiration pneumonia. Liquid-phase esophagram may better predict postoperative aspiration pneumonia compared with neurologic status.92 Laryngeal paralysis usually is confirmed via sedated, direct laryngeal examination or laryngoscopy. Care must be taken not to distort the oropharynx or larynx if a laryngoscope is used and to ensure paradoxical movement of the arytenoids during examination is not confused with proper, active arytenoid abduction.15,21,22 Transoral flexible video endoscopy can be useful because it provides magnification and allows laryngeal examination without the need for manipulation of the tongue or epiglottis.22 Transnasal flexible endoscopy for evaluation of the larynx also has been described in dogs weighing more than 20 kg and can be performed with lower doses of premedication and induction agents, especially if intranasal lidocaine is applied before the procedure.107 Laryngeal ultrasound (echolaryngography) and CT have also been used successfully for diagnosing unilateral and bilateral laryngeal paralysis.13,108 In dogs that are mildly affected by laryngeal paralysis, symptomatic medical care, including weight loss, avoidance of stressors, heat, and humidity, anxiolytic therapy, and medications for gastrointestinal supportive care (antacid therapy, promotility agents, antiemetic drugs) may ameliorate some clinical signs. Treatment of underlying disorders such as hypothyroidism and myasthenia gravis also may be beneficial. However, in more clinically affected dogs, especially those with upper airway obstruction, surgical intervention is needed to improve or resolve upper airway signs. Multiple surgical techniques are described, and the decision to perform unilateral or bilateral repair is debated in dogs that have bilateral laryngeal paralysis. The goal of surgical intervention is to widen the glottis to relieve the airway obstruction without deforming the laryngeal anatomy to preserve the airway protective function of the larynx.15,89 Surgical techniques are characterized into three main procedural outcome goal categories: widen the dorsal glottis (unilateral and bilateral arytenoid lateralization), widen the ventral glottis (vocal fold resection, partial laryngectomy, modified castellated laryngofissure), and widen the dorsal and ventral glottis (castellated laryngofissure combined with bilateral arytenoid lateralization).89 Unilateral arytenoid lateralization (tie-back) is performed more commonly than bilateral lateralization, even in patients with bilateral laryngeal paralysis.15,91,92,109,110 Bilateral arytenoid lateralization is associated with increased mortality and postoperative complications, including aspiration pneumonia and acute respiratory distress compared with unilateral lateralization and partial laryngectomy.91 The most common postoperative complication is aspiration pneumonia, which is seen in 8% to 33% of patients.91,109,111 Other reported complications include coughing and gagging, return of clinical signs, seroma formation, respiratory distress, and sudden death.15,91,109,111 Despite complications, most animals (90%) experience improvement in their respiratory status and stridor postoperativ­ ely.91,92,109 Arytenoid lateralization also has been described for small breed, nonbrachycephalic dogs with combined laryngeal paralysis and laryngeal collapse as a viable technique to improve upper airway obstructive symptoms.111 Laryngeal paralysis is uncommon in cats, but the clinical signs are often similar to dogs.113-115 Affected cats tend to be older, with median or mean ages reported from 8 to 16 years depending on the study.113-115 Suspected congenital laryngeal paralysis also has been reported sporadically in young cats less than 2 years of age.113,115 No clear guidelines exist regarding whether surgical intervention should be performed in cats with unilateral disease. Postoperative complications include transient Horner syndrome, dyspnea, pulmonary edema, laryngeal edema, and obstructive laryngeal stenosis.113-115 Immediate postoperative aspiration pneumonia has been described in only two cats.113

CHAPTER 18  Upper Airway Disease Laryngeal Collapse While laryngeal collapse is most commonly seen as a secondary complication of BAS, it can also occur with other forms of airway obstruction, such as laryngeal paralysis, tracheal collapse, and as a component of Norwich Terrier upper airway syndrome.116-120 In obstructive diseases, chronically increased negative intraluminal airway pressures lead to weakening of the cartilages, loss of rima glottic diameter, increased work of breathing, inflammation, and airway obstruction. When laryngeal collapse is diagnosed in dogs with tracheal collapse, it is possible that the pathologic chondromalacia affecting the tracheal cartilages could also be affecting the laryngeal cartilages, predisposing them to collapse and exacerbated by the increased respiratory effort associated with tracheal collapse. Additional investigation into these two concurrent disease processes is needed to prove this association. In Norwich Terriers, a unique disease syndrome characterized by narrowed infraglottic lumen, varying degrees of laryngeal collapse, partially or fully obliterated piriform recess, redundant laryngeal mucosa, and redundant dorsal pharyngeal wall has been described through extensive work evaluating the airways of dogs with varying degrees of clinical airway signs and pedigrees.118-120 Work evaluating the genetic basis of the disease and detailed grading system for all laryngeal abnormalities seen in Norwich Terriers is underway.120 Laryngeal collapse is graded on a scale of 1–3, with grade 1 defined by eversion of the laryngeal saccules, grade 2 is medial positioning of the cuneiform processes and aryepiglottic collapse, and grade 3 is collapse of the corniculate cartilages. Clinical signs of laryngeal collapse are similar to those observed with other forms of laryngeal disease, including noisy respiration, gagging, intolerance of heat, stress, or excitement, stridor, and respiratory distress. Initial management strategies with weight loss, stress and anxiety control, and antiinflammatory medications (corticosteroids or nonsteroidal antiinflammatory drugs) may improve respiratory comfort in some patients, especially those that are less severely affected. For more severely affected patients, or those that fail to respond to medical therapy, surgical intervention may be indicated. A variety of techniques have been described to address specific aspects of the complex disease, include sacculectomy, unilateral arytenoid lateralization, unilateral arytenoid laryngoplasty, and ventral laryngotomy.118-120 For advanced cases, or those that fail other surgical attempts, permanent tracheostomy is often performed.121

Inflammatory Laryngeal Disease Upper airway obstruction resulting from inflammatory or granulomatous laryngeal disease is uncommon in veterinary medicine and has been reported only sporadically in cats and dogs.55,122-128 Little is known about the underlying cause, but potential causes include feline respiratory viruses, secondary bacterial infection, endotracheal intubation, previous foreign body, and secondary to laryngeal surgery.122-124,127,128 Cervical radiography may show increased soft tissue opacity or laryngeal narrowing.122,124-128 Sedated laryngeal examination reveals thickening and erythema of the larynx and vocal folds.122,125 Nodules or mass-like lesions may also be seen on the arytenoid cartilages or within the rima glottis.122,124-126 Since the gross appearance cannot differentiate inflammatory or granulomatous laryngitis from neoplasia, fine-needle aspirate, or preferably, biopsy and histopathology must be performed. Depending on the severity of clinical signs, temporary tracheostomy may be necessary, especially if significant inflammation develops secondary to manipulation or biopsy.122,1123 Clinical outcome depends on response to treatment with corticosteroids, antibiotics, and surgical intervention, such as debulking of polypoid or mass-like inflammatory lesions.55,122-125,127,128 Permanent tracheostomy may be necessary for refractory or nonresponsive cases.122,124

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Tracheal Stenosis/Stricture Tracheal injury secondary to intraluminal trauma, as with endotracheal intubation, and extraluminal trauma, which is seen with bite wounds and vehicular trauma, is not commonly reported in dogs and cats.129-133 Injury and tearing of the dorsal tracheal membrane generally result from overinflation of the endotracheal tube cuff or repositioning of the head and neck during anesthesia without disconnecting the endotracheal tube from the anesthetic circuit. Acute injury generally results in pneumomediastinum, pneumothorax, subcutaneous emphysema, and respiratory distress.131 Less severe, full-thickness tracheal tears can result in circumferential tracheal stricture and ultimately tracheal narrowing, which, if severe enough, can result in upper airway obstruction. Tracheal stenosis also can be the result of scarring from prior surgery or tracheal avulsion.129,130,134 Thoracic radiographs, CT, and tracheoscopy can be used to confirm a diagnosis of tracheal stricture. Treatment options include surgical tracheal resection and anastomosis, bronchoscopic debridement of necrotic tissue, and intraluminal tracheal stenting (see Chapter 19, Tracheal Stents: Indications and Management).129,130,132,134,135 Tracheal narrowing leading to upper airway obstruction also has been reported secondary to intraluminal tracheal hemorrhage resulting from anticoagulant rodenticide toxicity and a tracheal hematoma in dogs136-138 (Fig. 18.4).

Tracheal Foreign Bodies Aspiration of foreign material into the trachea can cause coughing, gagging, head and neck extension, and respiratory distress. The duration of clinical signs can vary depending on the type and extent of airway obstruction and the degree of associated inflammation. Retrieved tracheal materials in dogs and cats include grass awns, plant material, plastic material, stones and gravel, an owl tooth, and Cuterebra spp. in cats.139-143 Cervical and thoracic radiographs can be helpful in the diagnosis of tracheal foreign material. Tracheoscopy allows for direct visualization and can be used for the removal of the foreign body using grasping forceps or an endoscopic snare passed through the working channel of the bronchoscope (Fig. 18.5).139,141,142 One study reports an 86% success rate for bronchoscope-assisted foreign body retrieval in dogs and 40% success in cats.139 When bronchoscopic removal is not feasible or fails, surgical excision can be considered.139,142,143 Retrieval using grasping forceps and fluoroscopic guidance has been described as a successful technique for tracheal foreign body removal in cats.141 Novel retrieval techniques using the inflated balloon from a Foley catheter or fluoroscopic guided over-the-wire balloon angioplasty catheters have also been described.140,144

Fig. 18.4  Lateral radiograph showing diffuse tracheal narrowing secondary to hemorrhage into the dorsal tracheal membrane secondary to anticoagulant rodenticide intoxication.

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Fig. 18.5  Endoscopic retrieval of a cherry pit from the trachea of a French Bulldog.

Upper Airway Neoplasia Nasal and nasopharyngeal neoplasia are uncommon causes of upper airway obstructive signs, unless there is complete obstruction to nasal airflow, which can cause nasal discharge, inspiratory dyspnea, openmouth breathing (cats), and inability to sleep (dogs). Canine nasal neoplasias are generally carcinomas (adenocarcinoma, squamous cell carcinoma, and undifferentiated carcinoma) or sarcomas (fibrosarcoma, osteosarcoma, and chondrosarcoma).145 In cats, nasal lymphoma is most common, but sarcomas (fibrosarcoma, osteosarcoma, chondrosarcoma, and hemangiosarcoma), carcinomas (adenocarcinoma, undifferentiated carcinoma), and olfactory neuroblastomas are also reported.145-147 Since achieving surgical margins is extremely difficult in the nasal passage, treatment usually involves systemic chemotherapy and radiation therapy. Intraarterial chemotherapy delivery has also been described as an adjunct treatment modality for nasal neoplasia. Nasopharyngeal neoplasias reported in dogs include lymphoma, mast cell tumor, squamous cell carcinoma, undifferentiated carcinoma, adenocarcinoma, fibrosarcoma, osteosarcoma, and spindle cell tumor.82 Nasopharyngeal neoplasias are less commonly reported in cats and include lymphoma and adenocarcinoma.14,48,82,147 Surgical treatment may be possible for small or well-circumscribed nasopharyngeal neoplasias, although chemotherapy and radiation are more likely to be beneficial. Primary laryngeal neoplasia is uncommon in dogs and cats and requires histopathology to differentiate from inflammatory/granulomatous laryngitis and benign lesions because they can have similar appearance on direct visual examination.55,122,125 In general, animals with laryngeal tumors are older (median age of 8 years) and tend to have a history of coughing, choking, dyspnea, and voice change.148 Most patients have significant disease progression by the time of presentation. In cats, laryngeal neoplasias include lymphoma, squamous cell carcinoma, poorly differentiated round cell tumor, carcinoma, and adenocarcinoma.55,125,126,148,149 In dogs, confirmed laryngeal neoplasias include chondrosarcoma, extramedullary plasmacytoma, rhabdomyoma, carcinoma, mast cell tumor, squamous cell carcinoma, lymphoma, adenocarcinoma, melanoma, granular cell tumor, and chondroma.148,150-153 Benign laryngeal lipomas and rhabdomyomas also are rarely seen in dogs.148,149,154,155 Surgical resection is difficult and may require total laryngectomy and permanent tracheostomy for

long-term management but can be successful for small or benign lesi­ ons.148,154,155 Overall, prognosis for laryngeal tumors is guarded and depends on type, invasiveness, metastatic spread, resectability, and response to chemotherapy or radiation.149 Primary tracheal neoplasia is also uncommon in dogs and cats, and one study suggests it is less common than primary laryngeal neoplasia.148 The most common tracheal tumor reported in dogs is osteochondroma; however, other reported types include chondrosarcoma, chondroma, adenocarcinoma, carcinoma, mast cell tumor, leiomyoma, extramedullary plasmacytoma, and osteosarcoma.148,156 Lymphoma is the most common feline tracheal tumor; however, carcinoma, adenocarcinoma, adenoma, squamous cell carcinoma, neuroendocrine carcinoma, and basal cell carcinoma also have been reported.126,149,153,156-159 The median age of dogs and cats with tracheal tumors is 9 years except for dogs with osteochondroma and enchondroma, which tend to be less than 2 years of age.148,156 Coughing, wheezing, dyspnea, and stridor are common clinical signs in patients with tracheal tumors.148,156 Cervical and thoracic radiographs can be helpful in the diagnosis of an intraluminal tracheal mass, which can be located at any point in the trachea from caudal to the larynx to the level of the carina. CT, which can be performed in the awake, nonintubated patient, is helpful to more precisely determine the extent of the mass and degree of luminal occlusion.14 Tracheoscopy is valuable for direct visualization of the mass as well as obtaining biopsy or brush cytology samples but often requires extubation in small patients, which can be dangerous with obstructive lesions. Options for the management of tracheal masses include surgical resection, endoscopic snaring, cryotherapy, radiation, chemotherapy, and palliative intraluminal stenting.125,156,157,134 The prognosis varies and depends on the extent of disease, mass type, and treatment response.

Complications of Upper Airway Obstruction In addition to the respiratory distress, hypoxemia, and hypercarbia that can be associated with upper airway obstruction, there are numerous potential secondary complications that can result from obstructive upper airway disease, including hyperthermia (see Chapter 10, Hyperthermia and Fever), noncardiogenic pulmonary edema (see Chapter 23, Pulmonary Edema), and aspiration pneumonia (see Chapter 24, Pneumonia). Temperature should be monitored closely in all patients with upper airway disease, especially if there is concern for obstruction and failure to appropriately dissipate heat. Failure to actively cool a severely hyperthermic patient can result in respiratory, cardiovascular, neurologic, renal, and coagulation derangements that can progress to multiorgan dysfunction syndrome, multiorgan failure, and disseminated intravascular coagulation (see Chapter 7, SIRS, MODS and Sepsis). Identification of pulmonary pathology consistent with noncardiogenic edema (caudodorsal interstitial to alveolar infiltrates) and aspiration pneumonia (cranioventral interstitial to alveolar infiltrates) is important before any anesthetic procedure, and in the case of aspiration pneumonia, warrants consideration for airway sampling for cytology, culture and susceptibility testing at anesthetic induction, and institution of appropriate antimicrobial therapy. Treatment for noncardiogenic pulmonary edema is supportive and should include oxygen therapy and judicious crystalloid and colloid fluid therapy (see Chapter 23, Pulmonary Edema). The use of diuretics and b-agonists in noncardiogenic pulmonary edema is controversial because increased clearance of alveolar fluid has not been proven.160-162

Additional Upper Airway Management Strategies In addition to the specific treatment strategies to manage the underlying cause of upper airway obstruction, additional patient support

CHAPTER 18  Upper Airway Disease strategies may be necessary to provide relief of respiratory distress and improve oxygenation, ventilation and patient comfort. High-flow nasal canula (HFNC) oxygen therapy not only provides high-flow oxygen therapy and continuous positive airway pressure (CPAP), but it also warms and humidifies the air, and is generally well tolerated compared with traditional nasal prongs (see Chapter 31, High Flow Nasal Oxygen). HFNC has proven useful in acutely hypoxic dogs that failed to respond to traditional oxygen supplementation as a method to avoid mechanical ventilation.163 HFNC has also been shown to support hypoxic brachycephalic dogs and improve their dyspnea scores upon recovery from general anesthesia, though impairment in ventilation and aerophagia were noted.164 Another device to deliver CPAP that has been shown to be helpful in acutely hypoxic dogs is a pediatric CPAP helmet or hood.165 In this group of hypoxic dogs with primary pulmonary dysfunction, PaO2, A-a gradient, SpO2, and PaO2:FiO2 were improved and the helmet was well tolerated in 15/17 dogs within an hour of CPAP therapy.165 The V-gel supraglottic airway device was originally designed for blind intubation in pediatric patients anticipated to be difficult to intubate and has documented utility for pediatric intubation by less experienced physicians.166 In healthy cats, the device was found to be useful for mechanical ventilation pressure maintenance up to 16 cm H2O and had less leaking than endotracheal intubation. The device can be placed blindly and with direct visualization in veterinary patients and may help avoid the laryngeal and tracheal irritation associated with endotracheal intubation.167 In another study of healthy cats, less postintubation stridor was associated with V-gel use.168

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40. De Lorenzi D, Bertoncello D, Drigo M: Bronchial abnormalities found in a consecutive series of 40 brachycephalic dogs, J Am Vet Med Assoc 235(7):835-840, 2009. 41. Planellas M, Cuenca R, Tabar MD, et al: Evaluation of C-reactive protein, haptoglobin and cardiac troponin 1 levels in brachycephalic dogs with upper airway obstructive syndrome, BMC Vet Res 8:152-159, 2012. 43. Harvey CE: Stenotic nares surgery in brachycephalic dogs, J Am Anim Hosp Assoc 18:535-537, 1982. 43. Ellison GW: Alapexy: an alternative technique for repair of stenotic nares in dogs, J Am Anim Hosp Assoc 40:484-489, 2004. 44. Huck JL, Stanley BJ, Hauptman JG: Technique and outcome of nares amputation (Trader’s technique) in immature shih tzus, J Am Anim Hosp Assoc 44(2):82-85, 2008. 45. Lodato DL, Hedlund CS: Brachycephalic airway syndrome: management, Compendium 34(8):E4-E7, 2012. 46. Pink JJ, Doyle RS, Hughes JML, et al: Laryngeal collapse in seven brachycephalic puppies, J Small Anim Pract 47(3):131-135, 2006. 47. White RN: Surgical management of laryngeal collapse associated with brachycephalic airway obstruction syndrome in dogs, J Small Anim Pract 28;53(1):44-50, 2011. 48. Allen HS, Broussard J, Noone K: Nasopharyngeal diseases in cats: a retrospective study of 53 cases (1991-1998), J Am Anim Hosp Assoc 35(6): 457-461, 1999. 49. Smart L, Jandrey KE: Upper airway obstruction caused by a nasopharyngeal polyp and brachycephalic airway syndrome in a Chinese Shar-Pei puppy, J Vet Emer Crit 18(4):393-398, 2008. 50. Fingland RB, Gratzek A, Vorhies MW, et al: Nasopharyngeal polyp in a dog, J Am Anim Hosp Assoc 29:311-314, 1993. 51. Pollock S: Nasopharyngeal polyp in a dog, a case study, Vet Med Small Anim Clin 66(7):705-706, 1971. 52. Holt DE: Nasopharyngeal polyps. In King LG, editor: Textbook of respiratory disease in dogs and cats, St. Louis, 2004, Saunders, pp 328-332. 53. Reed N, Gunn-Moore D: Nasopharyngeal disease in cats: 1. Diagnostic investigation, J Feline Med Surg 14(5):306-315, 2012. 54. Kudnig ST: Nasopharyngeal polyps in cats, Clin Tech Small Anim Pract 17(4):174-177, 2002. 55. Griffon DJ: Upper airway obstruction in cats: diagnosis and treatment, Compendium 22(10):897-909, 2000. 56. Muilenburg RK, Fry TR: Feline nasopharyngeal polyps, Vet Clin Small Anim Pract 32(4):839-849, 2002. 57. Tillson DM, Donnelly KE: Feline inflammatory polyps and ventral bulla osteotomy, Compendium 26(6):1-5, 2004. 58. Klose TC, MacPhail CM, Schultheiss PC, et al: Prevalence of select infectious agents in inflammatory aural and nasopharyngeal polyps from client-owned cats, J Feline Med Surg 12(10):769-774, 2010. 59. Oliveira CR, O’Brien RT, Matheson JS, et al: Computed tomographic features of feline nasopharyngeal polyps, Vet Radiol Ultrasound 53(4): 406-411, 2012. 60. Kapatin AS, Mattheisen DT, Noone KE, et al: Results of surgery and long term follow up in 31 cats with nasopharyngeal polyps, J Am Anim Hosp Assoc 26:387-392, 1990. 61. Anderson DM, Robinson RK, White RA: Management of inflammatory polyps in 37 cats, Vet Rec 147(24):684-687, 2000. 62. Trevor PB, Martin RA: Tympanic bulla osteotomy for treatment of middle-ear disease in cats: 19 cases (1984-1991), J Am Vet Med Assoc 202(1):123-128, 1993. 63. Anders BB, Hoelzler MG, Scavelli TD, et al: Analysis of auditory and neurologic effects associated with ventral bulla osteotomy for removal of inflammatory polyps or nasopharyngeal masses in cats, J Am Vet Med Assoc 233(4):580-585, 2008. 64. Billen F, Day MJ, Clercx C: Diagnosis of pharyngeal disorders in dogs: a retrospective study of 67 cases, J Small Anim Pract 47(3):122-129, 2006. 65. Henderson SM, Bradley K, Day MJ, et al: Investigation of nasal disease in the cat—a retrospective study of 77 cases, J Feline Med Surg 6(4):245-257, 2004. 66. Coolman BR, Marretta SM, McKiernan BC, et al: Choanal atresia and secondary nasopharyngeal stenosis in a dog, J Am Anim Hosp Assoc 34(6):497-501, 1998.

67. Berent AC, Kinns J, Weisse C: Balloon dilatation of nasopharyngeal stenosis in a dog, J Am Vet Med Assoc 229(3):385-388, 2006. 68. Berent AC, Weisse C, Todd K, et al: Use of a balloon-expandable metallic stent for treatment of nasopharyngeal stenosis in dogs and cats: six cases (2005-2007), J Am Vet Med Assoc 233(9):1432-1440, 2008. 69. Boswood A, Lamb CR, Brockman DJ, et al: Balloon dilatation of nasopharyngeal stenosis in a cat, Vet Radiol Ultrasound 44(1):53-55, 2003. 70. Glaus TM, Tomsa K, Reusch CE: Balloon dilation for the treatment of chronic recurrent nasopharyngeal stenosis in a cat, J Small Anim Pract 43(2):88-90, 2002. 71. Glaus TM, Gerber B, Tomsa K, et al: Reproducible and long-lasting success of balloon dilation of nasopharyngeal stenosis in cats, Vet Rec 157(9):257-259, 2005. 72. Novo RE, Kramek B: Surgical repair of nasopharyngeal stenosis in a cat using a stent, J Am Anim Hosp Assoc 35(3):251-256, 1999. 73. Mitten RW: Nasopharyngeal stenosis in four cats, J Small Anim Pract 29(6):341-345, 1988. 74. Griffon DJ, Tasker S: Use of a mucosal advancement flap for the treatment of nasopharyngeal stenosis in a cat, J Small Anim Pract 41(2):71-73, 2000. 75. Cook AK, Mankin KT, Saunders AB, et al: Palatal erosion and oronasal fistulation following covered nasopharyngeal stent placement in two dogs, Ir Vet J 66(1):8-14, 2013. 76. Khoo A, Marchevsky A, Barrs V, et al: Choanal atresia in a Himalayan cat—first reported case and successful treatment, J Feline Med Surg 9(4):346-349, 2007. 77. Azarpeykan S, Stickney A, Hill KE, et al: Choanal atresia in a cat, N Z Vet J 61(4):237-241, 2013. 78. Schafgans KE, Armstrong PJ, Kramek B, et al: Bilateral choanal atresia in a cat, J Feline Med Surg 14(10):759-763, 2012. 79. Wehner A, Crochik S, Howerth EW, et al: Diagnosis and treatment of blastomycosis affecting the nose and nasopharynx of a dog, J Am Vet Med Assoc 233(7):1112-1116, 2008. 80. Malik R, Martin P, Wigney DI, et al: Nasopharyngeal cryptococcosis, Aust Vet J 75(7):483-488, 1997. 81. Forster-van Hijfte MA, Groth AM, Emmerson TD: Expansile, inflammatory middle ear disease causing nasopharyngeal obstruction in a cat, J Feline Med Surg 13(6):451-453, 2011. 82. Hunt GB, Perkins MC, Foster SF, et al: Nasopharyngeal disorders of dogs and cats: a review and retrospective study, Compendium 24(3):184-203, 2002. 83. Kang MH, Lim CY, Park HM: Nasopharyngeal tooth foreign body in a dog, J Vet Dent 28(1):26-29, 2011. 84. Haynes KJ, Anderson SE, Laszlo MP: Nasopharyngeal trichobezoar foreign body in a cat, J Feline Med Surg 12(11):878-881, 2010. 85. Riley P: Nasopharyngeal grass foreign body in eight cats, J Am Vet Med Assoc 202(2):299-300, 1993. 86. Ober CP, Barber D, Troy GC: What is your diagnosis? J Am Vet Med Assoc 231(8):1207-1208, 2007. 87. Papazoglau LG, Patsikas MN: What is your diagnosis? A radiopaque foreign body located in the nasopharynx, J Small Anim Prac 36(10):425, 434, 1995. 88. Simpson AM, Harkin KR, Hoskinson JJ: Radiographic diagnosis: nasopharyngeal foreign body in a dog, Vet Radiol Ultrasound 41(4):326-328, 2000. 89. Holt DE, Brockman DJ: Laryngeal paralysis. In King LG, editor: Textbook of respiratory disease in dogs and cats, St. Louis, 2004, Saunders, pp 319-328. 90. Griffin J: Laryngeal paralysis: pathophysiology, diagnosis, and surgical repair, Compendium 7:1-13, 2005. 91. MacPhail CM, Monnet E: Outcome of and postoperative complications in dogs undergoing surgical treatment of laryngeal paralysis: 140 cases (1985-1998), J Am Vet Med Assoc 218(12):1949-1956, 2001. 92. Stanley BJ, Hauptman JG, Fritz MC, et al: Esophageal dysfunction in dogs with idiopathic laryngeal paralysis: a controlled cohort study, Vet Surg 39(2):139-149, 2010. 93. Thieman KM, Krahwinkel DJ, Shelton D, et al: Laryngeal paralysis: part of a generalized polyneuropathy syndrome in older dogs, Vet Surg 36:E26, 2007.

CHAPTER 18  Upper Airway Disease 94. Thieman KM, Krahwinkel DJ, Sims MH, et al: Histopathological confirmation of polyneuropathy in 11 dogs with laryngeal paralysis, J Am Anim Hosp Assoc 46(3):161-167, 2010. 95. Venker-van Haagen AJ, Bouw J, Hartman W: Hereditary transmission of laryngeal paralysis in Bouviers, J Am Anim Hosp Assoc 17:75-76, 1981. 96. Mahony OM, Knowles KE, Braund KG, et al: Laryngeal paralysis-polyneuropathy complex in young rottweilers, J Vet Intern Med 12:330-337, 1998. 97. Braund KG, Shores A, Cochrane S, et al: Laryngeal paralysis-polyneuropathy complex in young dalmatians, Am J Vet Res 55:534-542, 1994. 98. Polizopoulou ZS, Koutinas AF, Papadopoulos GC, et al: Juvenile laryngeal paralysis in three Siberian husky x Alaskan malamute puppies, Vet Rec 153:624-627, 2003. 99. O’Brien JA, Hendriks JC: Inherited laryngeal paralysis: analysis in the husky cross, Vet Q 8:301-302, 1986. 100. Gabriel A, Poncelet L, Van Ham L, et al: Laryngeal paralysis-polyneuropathy complex in young related Pyrenean mountain dogs, J Small Anim Pract 47(3):144-149, 2006. 101. Shelton GD, Podell M, Poncelet L, et al: Inherited polyneuropathy in Leonberger dogs: a mixed or intermediate form of Charcot-Marie-Tooth disease? Muscle Nerve 27:471-477, 2003. 102. Klein MK, Powers BE, Withrow SJ, et al: Treatment of thyroid carcinoma in dogs by surgical resection alone: 20 cases (1981-1989), J Am Vet Med Assoc 206:1007-1009, 1995. 103. White R, Williams JM: Tracheal collapse in the dog-is there really a role for surgery? A survey of 100 cases, J Small Anim Pract 35(4):191-196, 1994. 104. Jaggy A, Oliver JE, Ferguson DC, et al: Neurological manifestations of hypothyroidism: a retrospective study of 29 dogs, J Vet Intern Med 8:328-336, 1994. 105. Dewey CW, Bailey CS, Shelton GD, et al: Clinical forms of acquired myasthenia gravis in dogs: 25 cases (1988-1995), J Vet Intern Med 11:50-57, 1997. 106. Jeffery ND, Talbot CE, Smith PM, et al: Acquired idiopathic laryngeal paralysis as a prominent feature of generalised neuromuscular disease in 39 dogs, Vet Rec 158:17, 2006. 107. Radlinsky MG, Williams J, Frank PM, et al: Comparison of three clinical techniques for the diagnosis of laryngeal paralysis in dogs, Vet Surg 38(4):434-438, 2009. 108. Rudorf H, Barr FJ, Lane JG: The role of ultrasound in the assessment of laryngeal paralysis in the dog, Vet Radiol Ultrasound 42(4):338-343, 2001. 109. Hammel SP, Hottinger HA, Novo RE: Postoperative results of unilateral arytenoid lateralization for treatment of idiopathic laryngeal paralysis in dogs: 39 cases (1996-2002), J Am Vet Med Assoc 228(8):1215-1220, 2006. 110. Snelling SR, Edwards GA: A retrospective study of unilateral arytenoid lateralisation in the treatment of laryngeal paralysis in 100 dogs (19922000), Aust Vet J 81(8):464-468, 2003. 111. Greenberg MJ, Reems MR, Monnet E: Use of perioperative metoclopramide in dogs undergoing surgical treatment of laryngeal paralysis: 43 cases, Vet Surg 36:E11, 2007. 112. Nelissen P, White RAS: Arytenoid lateralization for management of combined laryngeal paralysis and laryngeal collapse in small dogs, Vet Surg 21:261-265, 2011. 113. Hardie RJ, Gunby J, Bjorling DE: Arytenoid lateralization for treatment of laryngeal paralysis in 10 cats, Vet Surgery 38(4):445-451, 2009. 114. Thunberg B, Lantz GC: Evaluation of unilateral arytenoid lateralization for the treatment of laryngeal paralysis in 14 cats, J Am Anim Hosp Assoc 46(6):418-424, 2010. 115. Schachter S, Norris CR: Laryngeal paralysis in cats: 16 cases (1990-1999), J Am Vet Med Assoc 216(7):1100-1103, 2005. 116. Nelissen P, White RA: Arytenoid lateralization for management of combined laryngeal paralysis and laryngeal collapse in small dogs, Vet Surg 41(2):261-265, 2012. 117. MacPhail CM: Laryngeal disease in dogs and cats: an update, Vet Clin North Am Small Anim Pract 50(2):295-310, 2020. 118. Johnson LR, Mayhew PD, Steffey MA, Hunt GB, Carr AH, McKiernan BC: Upper airway obstruction in Norwich Terriers: 16 cases, J Vet Intern Med 27(6):1409-1415, 2013.

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119. Koch DA, Rosaspina M, Wiestner T, Arnold S, Montavon PM: Comparative investigations on the upper respiratory tract in Norwich terriers, brachycephalic and mesaticephalic dogs, Schweiz Arch Tierheilkd 156(3):119-124, 2014. 120. Lai G, Stanley B, Nelson N, et al: Clinical and laryngoscopic characterization of Norwich Terrier Upper Airway Syndrome (NTUAS): preliminary results, Athens, Greece, July 4-6, 2018, European College of Veterinary Surgeons (ECVS). 121. Gobbetti M, Romussi S, Buracco P, Bronzo V, Gatti S, Cantatore M: Long-term outcome of permanent tracheostomy in 15 dogs with severe laryngeal collapse secondary to brachycephalic airway obstructive syndrome, Vet Surg 47(5):648-653, 2018. 122. Costello MF, Keith D, Hendrick M, et al: Acute upper airway obstruction due to inflammatory laryngeal disease in 5 cats, J Vet Emerg Crit Care 11(3):205-210, 2001. 123. Costello MF: Upper airway disease. In Silverstein DC, Hopper KA, editors: Small animal critical care medicine, St Louis, 2009, Elsevier, pp 67-71. 124. Tasker S, Foster DJ, Corcoran BM, et al: Obstructive inflammatory laryngeal disease in three cats, J Feline Med Surg 1(1):53-59, 1999. 125. Taylor SS, Harvey AM, Barr FJ, et al: Laryngeal disease in cats: a retrospective study of 35 cases, J Feline Med Surg 11(12):954-962, 2009. 126. Jakubiak MJ, Siedlecki CT, Zenger E, et al: Laryngeal, laryngotracheal, and tracheal masses in cats: 27 cases (1998-2003), J Am Anim Hosp Assoc 41(5):310-316, 2005. 127. Oakes MG, McCarthy RJ: What is your diagnosis? [granulomatous laryngitis], J Am Vet Med Assoc 204:1891, 1994. 128. Harvey CE, O’Brien JA: Surgical treatment of miscellaneous laryngeal conditions in dogs and cats, J Am Anim Hosp Assoc 18:557-562, 1982. 129. Roach W, Krahwinkel DJ: Obstructive lesions and traumatic injuries of the canine and feline tracheas, Compendium 31(2):86-93, 2009. 130. Holt DE: Tracheal trauma. In King LG, editor: Textbook of respiratory disease in dogs and cats, St. Louis, 2004, Saunders, pp 359-363. 131. Mitchell SL, McCarthy R, Rudloff E, et al: Tracheal rupture associated with intubation in cats: 20 cases (1996-1998), J Am Vet Med Assoc 216(10):1592-1595, 2000. 132. Alderson B, Senior JM, Dugdale AHA: Tracheal necrosis following tracheal intubation in a dog, J Small Anim Pract 47(12):754-756, 2006. 133. Jordan CJ, Halfacree ZJ, Tivers MS: Airway injury associated with cervical bite wounds in dogs and cats: 56 cases, Vet Comp Orthop Traumatol 26(2):89-93, 2013. 134. Culp WTN, Weisse C, Cole SG, et al: Intraluminal tracheal stenting for treatment of tracheal narrowing in three cats, Vet Surg 36(2):107-113, 2007. 135. White RN, Milner HR: Intrathoracic tracheal avulsion in three cats, J Amall Anim Pract 36(8):343-347, 1995. 136. Blocker TL, Roberts BK: Acute tracheal obstruction associated with anticoagulant rodenticide intoxication in a dog, J Small Anim Pract 40(12):577-580, 1999. 137. Berry CR, Gallaway A, Thrall DE, et al: Thoracic radiographic features of anticoagulant rodenticide toxicity in fourteen dogs, Vet Radiol Ultrasound 34:391-396, 1993. 138. Pink JJ: Intramural tracheal haematoma causing acute respiratory obstruction in a dog, J Small Anim Pract 47(3):161-164, 2006. 139. Tenwolde AC, Johnson LR, Hunt GB, et al: The role of bronchoscopy in foreign body removal in dogs and cats: 37 cases (2000-2008), J Vet Intern Med 24(5):1063-1068, 2010. 140. Goodnight ME, Scansen BA, Kidder AC, et al: Use of a unique method for removal of a foreign body from the trachea of a cat, J Am Vet Med Assoc 237(6):689-694, 2010. 141. Tivers MS, Moore AH: Tracheal foreign bodies in the cat and the use of fluoroscopy for removal: 12 cases, J Small Anim Pract 47(3):155-159, 2006. 142. Dvorak LD, Bay JD, Crouch DT, et al: Successful treatment of intratracheal cuterebrosis in two cats, J Am Anim Hosp Assoc 36(4):304-308, 2000. 143. Bordelon JT, Newcomb BT, Rochat MC: Surgical removal of a Cuterebra larva from the cervical trachea of a cat, J Am Anim Hosp Assoc 45(1): 52-54, 2009.

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144. Pratschke KM, Hughes JML, Guerin SR, et al: Foley catheter technique for removal of a tracheal foreign body in a cat, Vet Rec 144(7):181-182, 1999. 145. Malinowski C: Canine and feline nasal neoplasia, Clin Tech Small Anim Pract 21(2):89-94, 2006. 146. McEntee MC: Neoplasms of the nasal cavity. In King LG, editor: Textbook of respiratory disease in dogs and cats, St. Louis, 2004, Saunders, pp 293-301. 147. Little L, Patel R, Goldschmidt M: Nasal and nasopharyngeal lymphoma in cats: 50 cases (1989-2005), Vet Pathol 44(6):885-892, 2007. 148. Carlisle CH, Biery DN, Thrall DE: Tracheal and laryngeal tumors in the dog and cat: literature review and 13 additional patients, Vet Radiol Ultrasound 32(5):229-235, 1991. 149. Saik JE, Toll SL, Diters RW, et al: Canine and feline laryngeal neoplasia: a 10-year survey, J Am Anim Hosp Assoc 22:359-365, 1986. 150. Muraro L, Aprea F, White RAS: Successful management of an arytenoid chondrosarcoma in a dog, J Small Anim Pract 54:33-35, 2013. 151. Witham AI, French AF, Hill KE: Extramedullary laryngeal plasmacytoma in a dog, N Z Vet J 60(1):61-64, 2012. 152. Hayes AM, Gregory SP, Murphy S, et al: Solitary extramedullary plasmacytoma of the canine larynx, J Small Anim Pract 48(5):288-291, 2007. 153. Rossi G, Magi GE, Tarantino C, et al: Tracheobronchial neuroendocrine carcinoma in a cat, J Comp Pathol 137(2-3):165-168, 2007. 154. O’Hara AJ, McConnell M, Wyatt K, et al: Laryngeal rhabdomyoma in a dog, Aust Vet J 79(12):817-821, 2001. 155. Brunnberg M, Cinquoncie S, Burger M, et al: Infiltrative laryngeal lipoma in a Yorkshire Terrier as cause of severe dyspnoea, Tierarztl Prax Ausg K Kleintiere Heimtiere 41(1):53-56, 2013. 156. Brown MR, Rogers KS: Primary tracheal tumors in dogs and cats, Compendium 25(11):854-860, 2003. 157. Drynan EA, Moles AD, Raisis AL: Anaesthetic and surgical management of an intra-tracheal mass in a cat, J Feline Med Surg 13(6):460-462, 2011. 158. Jelinek F, Vozkova D: Carcinoma of the trachea in a cat, J Comp Pathol 147(2-3):177-180, 2012.

159. Green ML, Smith J, Fineman L, et al: Diagnosis and treatment of tracheal basal cell carcinoma in a Maine Coon and long-term outcome, J Am Anim Hosp Assoc 48(4):273-277, 2012. 160. Bachmann M, Waldrop JE: Noncardiogenic pulmonary edema, Compendium 34(11):E1-E9, 2012. 161. Hughes D: Pulmonary edema. In Silverstein DC, Hopper KA, editors: Small animal critical care medicine, St. Louis, 2009, Elsevier, pp 86-90. 162. Boothe DM: Drugs affecting the respiratory system. In King LG, editor: Textbook of respiratory disease in dogs and cats, St. Louis, 2004, Saunders, pp 229-252. 163. Jagodich TA, Bersenas AME, Bateman SW, Kerr CL: High-flow nasal cannula oxygen therapy in acute hypoxemic respiratory failure in 22 dogs requiring oxygen support escalation, J Vet Emerg Crit Care (San Antonio) 30(4):364-375, 2020. 164. Jagodich TA, Bersenas AME, Bateman SW, Kerr CL: Preliminary evaluation of the use of high-flow nasal cannula oxygen therapy during recovery from general anesthesia in dogs with obstructive upper airway breathing, J Vet Emerg Crit Care (San Antonio) 30(4):487-492, 2020. 165. Ceccherini G, Lippi I, Citi S, et al: Continuous positive airway pressure (CPAP) provision with a pediatric helmet for treatment of hypoxemic acute respiratory failure in dogs, J Vet Emerg Crit Care (San Antonio) 30(1):41-49, 2020. 166. Bielski A, Smereka J, Madziala M, Golik D, Szarpak L: Comparison of blind intubation with different supraglottic airway devices by inexperienced physicians in several airway scenarios: a manikin study, Eur J Pediatr 178(6):871-882, 2019. doi:10.1007/s00431-019-03345-4. 167. Prasse SA, Schrack J, Wenger S, Mosing M: Clinical evaluation of the vgel supraglottic airway device in comparison with a classical laryngeal mask and endotracheal intubation in cats during spontaneous and controlled mechanical ventilation, Vet Anaesth Analg 43(1):55-62, 2016. 168. van Oostrom H, Krauss MW, Sap R: A comparison between the v-gel supraglottic airway device and the cuffed endotracheal tube for airway management in spontaneously breathing cats during isoflurane anaesthesia, Vet Anaesth Analg 40(3):265-271, 2013.

19 Tracheal Collapse: Management & Indications for Tracheal Stents Dana L. Clarke, VMD, DACVECC

KEY POINTS • Tracheal collapse is a progressive, degenerative disease of the tracheal cartilages commonly seen in older toy and small breed dogs. • Signalment, history, and physical examination are used to determine if the patient is clinical for obstructive tracheal collapse, with diagnostic imaging used to support this tentative diagnosis. • Tracheal stenting is a minimally invasive intervention to restore airway patency in both acute and chronic cases of airway obstruction.

• Tracheal stents can effectively palliate dogs and cats with obstructive tracheal neoplasia. • Complications associated with tracheal stenting include stent fracture, migration, chronic infections, and granulation tissue formation. Case selection and precise sizing are imperative to reduce the risk of short- and long-term complications.

ETIOLOGY

into the histopathologic and clinical presentation differences is needed to definitively redefine the grading scheme for tracheal collapse, as well as determine if this is a congenital condition or a different form of acquired progressive airway obstruction.

Tracheal collapse is a progressive, degenerative disease of the tracheal cartilages commonly seen in older toy and small breed dogs, particularly Yorkshire Terriers.1 The disease has been reported in dogs of all ages, although the majority are middle aged. It is rarely reported in cats and miniature horses. The exact cause of tracheal collapse is unknown; however, dorsal trachealis flaccidity and loss of rigidity of the tracheal cartilages resulting from decreased glycosaminoglycan, chondroitin, and calcium content are suspected.2-6 The result is airway narrowing and collapse and an inability to withstand changing intraluminal airway pressures during respiration. The repeated mucosal contact from cyclic collapse results in chronic irritation, inflammation, and the loss of the ciliated columnar epithelial component of the mucociliary escalator. The tracheal mucosa undergoes squamous metaplasia, and coughing becomes the major mechanism of tracheobronchial clearance in the absence of a functional mucociliary escalator. Bronchomalacia is the result of similar pathology to cartilage of the bronchi and bronchioles, which can occur as an isolated disease process or in conjunction with tracheal collapse.5-9 Tracheal collapse has historically been graded as I–IV, with each grade an approximately 25% progressive reduction in tracheal diameter lumen and flattening of the tracheal cartilages and dorsal tracheal membrane. Grade IV also has the feature of inversion of the ventral tracheal cartilages.10 More recent investigation has suggested that there are two forms of tracheal collapse: traditional chondromalacia with dynamic collapse and a static form of airway obstruction.11 Dogs with the static form of airway obstruction have ventral cartilage inversion into the tracheal lumen (grade IV/“W” shape to the ventral margin of the trachea). This inversion varies from rigid and noncompressible to soft and easily displaced ventrally out of the airway lumen. This is a new concept in tracheal collapse classification, with the developing thought that what was previously called grade IV tracheal collapse is a separate disease process from traditional chondromalacia changes (grades I–III), though dogs may have both static rigid cartilage malformation and dynamic motion from the redundant tracheal membrane.11 Research

CLINICAL SIGNS Tracheal collapse can affect the trachea along its length, and the location of collapse often determines clinical signs. Patients with cervical (extrathoracic) tracheal collapse tend to have inspiratory dyspnea resulting from the inability of the tracheal cartilages to withstand the negative airway pressure created by chest wall expansion, diaphragmatic contraction, and progressively negative airway pressures. Conversely, on expiration, increased intrapleural pressure tends to collapse the diseased intrathoracic trachea. Animals with collapse of the thoracic inlet trachea can have both inspiratory and expiratory signs. Tracheal malformations tend to occur at the thoracic inlet, and depending on the rigidity of the malformation, as well as the presence or absence of concurrent chondromalacia in other regions of the trachea, they can result in static or dynamic respiratory dyspnea.11 Clinical signs vary depending on the location and severity of collapse and whether or not there is concurrent nasopharyngeal, laryngeal, bronchial, or pulmonary parenchymal disease. Classifying clinical signs and physical examination findings into two broad categories, obstructive “honkers” and nonobstructive coughers, can be very helpful to guide differentials, diagnostics, and management strategies (Table 19.1).12 This is a general classification; there are cases with signs from both categories. For these patients, it is important to determine what percentage of their clinical signs are attributable to each classification in order to best understand how much medical management and airway intervention will alleviate their symptoms and improve their quality of life. The honking sound heard during respiration and panting is characteristic of obstructive airway disease, generally with collapse of the cervical or thoracic inlet trachea. Heat, stress, activity, and excitement can worsen the severity of honking. Exercise and stress intolerance are common. Other clinical signs

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TABLE 19.1  Clinical Characteristics of

Honkers with Airway Obstruction Versus Coughers with Lower Airway Disease Honkers

Coughers

Abducted elbows

Increased respiratory effort on expiration

Prolonged inspiratory phase of respiration

Expiratory abdominal “push”

Increased respiratory effort on inspiration

Harsh expiratory lung sounds

Pectus excavatum

Herniation of cranial lung lobes

Sinus arrhythmia

Crackles on pulmonary auscultation

External rotation of the costochondral junctions creating pointed ventral ribs

Overdeveloped abdominal musculature creating a “heave line”

Extended head/neck/orthopnea

Perineal hernia

Increased or decreased sounds on cervical/thoracic inlet tracheal auscultation

Fecal incontinence from increased abdominal pressure on coughing expiration

From Clarke DL: Interventional radiology management of tracheal and bronchial collapse, Vet Clin North America 48(5):765-779, 2018.

include excessive panting, stridor, gagging after eating or drinking, and respiratory distress.1,3,10 Coughers tend to have a dry, hacking cough, which can also be high pitched, productive, and associated with a terminal retch. Coughing tends to be the result of bronchial collapse, chronic bronchitis, pulmonary parenchymal disease, and/or intrathoracic tracheal collapse.6 These dogs do not tend to have exercise intolerance or respiratory distress when mildly to moderately affected. However, with more advanced lower airway collapse or concurrent pulmonary parenchymal disease that impedes oxygenation, exercise intolerance may be present. Extensive literature and consensus are lacking regarding reclassification of tracheal collapse into traditional chondromalacia and tracheal malformations, but preliminary literature suggests that dogs with malformations tend to be younger when diagnosed with tracheal collapse.11 Clinical experience supports this finding; these dogs also often have more static respiratory signs and physical examination changes such as elbow abduction, sinus arrythmia, pectus excavatum, and palpable changes to the costochondral junctions. If there is concurrent chondromalacia, dynamic respiratory signs may also be present in addition to the static respiratory compromise. Nasopharyngeal collapse has been documented in dogs with tracheal collapse and is believed to contribute to upper airway noise, snoring, and possibly sleep apnea.13 The exact etiology and cause for this disease process are not known, nor is the timing for the development of nasopharyngeal collapse development in relation to onset of signs of tracheal collapse. It is suspected that nasopharyngeal collapse may occur secondary to chronic inspiratory airway obstruction and work of breathing; however, more research into nasopharyngeal collapse and its association with airway disease is needed.

DIAGNOSTIC EVALUATION Thoracic radiographs alone are of modest benefit for diagnosing tracheal collapse because they rely on static images to document a dynamic process.10 Paired inspiratory and expiratory thoracic radiographs improve their utility but can still underestimate severity and extent of disease.14 Radiographs misdiagnosed the location of tracheal

Fig. 19.1  Lateral radiograph of a dog with a thoracic inlet tracheal malformation/grade 4 collapse showing an intraluminal soft tissue opacity arising from the ventral border of the trachea.

collapse in 44% of dogs and failed to diagnose tracheal collapse in 8% of dogs when compared with fluoroscopy.14 However, thoracic radiographs are essential to assess for chest wall conformation changes, cardiomegaly, lower airway disease, bronchiectasis, interstitial lung disease, and pulmonary parenchymal infiltrates such as pneumonia or pulmonary edema.1,10,15 Radiographs are also very important for tracheal malformation assessment. Malformations tend to occur at the thoracic inlet and appear as a soft tissue opacity or irregular tracheal margin arising from the ventral aspect of the tracheal border (Fig. 19.1). Fluoroscopy provides dynamic assessment of the tracheal diameter changes along the length during the entire breath cycle and when coughing and allows for evaluation of lung lobe herniation.16 Assessment of nasopharyngeal and mainstem bronchial collapse also can be performed during fluoroscopy, which is important since both disease processes have been documented to occur concurrently with tracheal collapse.13 Tracheal ultrasound and computed tomography (CT) have been shown to have adjunctive diagnostic benefit in tracheal collapse patients, improve tracheal diameter measurements under positive pressure ventilation, and further characterize severity and extent of tracheal malformations.17-20 When a patient positioning device (VetMousetrap[TM] Universal Medical Systems, Solon, Ohio) is used to reduce patient movement, CT can also be used for dynamic airway assessment in awake or lightly sedated patients.17 Primary pulmonary hypertension can exacerbate coughing and secondary pulmonary hypertension can be seen with chronic lower airway and pulmonary parenchymal disease. Echocardiography is warranted in dogs with coughing as their primary clinical sign, as treatment for pulmonary hypertension may improve coughing and respiratory effort. Tracheobronchoscopy is the gold standard for grading the severity of tracheal collapse, though endoscopic collapse grade does not necessarily correspond with clinical signs.6,10,19,21 It is also helpful to rule out tracheal masses, evaluate for bronchial collapse, and assess for the presence of a tracheal malformation (Fig. 19.2).11 Concurrent bronchial collapse has been documented in 83% of dogs with cervical tracheal collapse.6,10 Since general anesthesia is required for tracheobronchoscopy, recovery from this procedure can be challenging in patients with tracheal collapse and upper airway obstruction without intervention. Therefore, it is often delayed until definitive treatment for airway obstruction is planned. If anesthesia is performed in patients with tracheal collapse, a systematic laryngeal examination is imperative, as laryngeal dysfunction has been documented in up to 30% of patients with tracheal collapse.10,22 Laryngeal collapse has also been documented in dogs undergoing tracheal stenting (Fig. 19.3).

CHAPTER 19  Tracheal Collapse: Management & Indications for Tracheal Stents

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determination of oxygenation, especially if underlying lung disease is present. Dogs with severe tracheal obstruction can have impaired ventilation and respiratory acidosis, characterized by increased PaCO2/ PvCO2, which should be reevaluated upon resolution of the upper airway obstruction.

MEDICAL MANAGEMENT

Fig. 19.2  Endoscopic image obtained during tracheobronchoscopy demonstrating the ventral tracheal cartilage inversion noted in grade 4 tracheal collapse/tracheal malformations.

Fig. 19.3  Endoscopic image of grade 2/3 laryngeal collapse in a dog undergoing tracheal stenting.

Airway sampling via endotracheal wash or bronchoalveolar lavage for cytology and aerobic culture and susceptibility testing also should be performed in all dogs with tracheal collapse to rule out active tracheal infection prior to placement of a permanent implant and the postoperative use of antiinflammatory doses of steroids and cough suppression. In normal dogs, the trachea is not sterile, therefore cytologic evidence of infection or inflammation is important to correlate with concurrent positive culture results. In dogs with tracheobronchial collapse diagnosed via endoscopy, as well as those undergoing tracheal stent placement, commonly reported bacterial isolates cultured include Pseudomonas, Pasteurella, Escherichia coli, Staphylococci and Enterobacter aerogenes.23-26 Mycoplasma culture and PCR should also be considered, though the exact role of this pathogen in tracheobronchial collapse is not fully understood. Complete blood count and serum chemistry evaluation should be performed in patients with tracheal collapse to look for inflammatory leukogram changes consistent with infection and evidence of liver injury and dysfunction (elevated alanine aminotransferase and bile acids), which has been documented in dogs with tracheal collapse and is suspected to be secondary to hypoxemia.27 If possible, pulse oximetry and arterial blood gas analysis should be performed for objective

Medical management is the mainstay of tracheobronchial collapse management. However, medications can only control the clinical signs of coughing and inflammation; they do not directly address the physiology of airway collapse or obstruction. If possible, efforts should be made to institute medical therapies before surgical or interventional options are pursued, since up to 71% of dogs can be effectively managed with medications for more than 12 months.1 Oftentimes, breaking the cycle of dyspnea, distress, and anxiety with sedation (see Chapter 132, Sedation of the Critically Ill Patient), anxiolytics, oxygen supplementation (see Chapter 15, Oxygen Therapy), cough suppression (0.25–0.5 mg/kg hydrocodone PO q4-8, 0.1–0.3 mg/kg butorphanol PO q6-12), and tapering antiinflammatory doses of corticosteroids (if indicated) can relieve the airway obstruction crisis well enough to facilitate discharge with continued medical management. The benefit of inhaled over systemic steroids in dogs with tracheal collapse has not yet been determined. The role of bronchodilators in tracheal collapse alone is controversial, though they may be indicated in patients with bronchial collapse and/or chronic bronchitis, for whom coughing is their primary concern. In one study evaluating theophylline as a first-line therapy for dogs with tracheal collapse, coughing did improve with the use of theophylline, though the final dose was associated with degree of intrathoracic tracheal collapse. Less than five dogs in the retrospective study had signs of dyspnea, and instead their primary clinical sign was coughing, with many dogs having evidence of collapse of the carina. These findings likely support that the dogs in this study were more clinically affected by coughing, and not honking and airway obstruction, supporting the possibility that theophylline may provide more of a benefit with coughing than airway obstruction.28 Use of a harness (rather than a collar around the neck), weight loss, and control of exacerbating factors, such as heat, stress, and excitement, are also essential elements of medical management. When medical management fails to control clinical signs, the patient’s quality of life is declining, or respiratory distress and compromise cannot be relieved with medical therapies, surgical or interventional options to address tracheal collapse should be considered.

TRACHEAL RINGS In dogs with cervical tracheal and/or proximal thoracic inlet collapse that have failed medical therapy or are in too severe of respiratory distress to allow time for medical therapy to be effective, prosthetic extraluminal tracheal rings can be considered. Commercially made rings are available in four sizes from New Generation Devices (http:// ngdvet.com). Extraluminal rings can also be made from sterilized polypropylene syringes or syringe cases. Caution must be exercised during tracheal dissection and ring placement to avoid damaging the segmental tracheal blood supply and the recurrent laryngeal nerve. The success rate for prosthetic rings is reported to be 75% to 85%.10,29 Postoperative complications include infection, laryngeal paralysis (10% to 21%), tracheal necrosis, and progressive tracheal collapse.1,4,10,29,30 Patients typically are hospitalized for several days of intensive monitoring after ring placement. In dogs with cervical tracheal collapse treated with prosthetic ring placement, no survival difference was found between dogs with cervical collapse alone and those with concurrent intrathoracic tracheal collapse, indicating that even dogs with intrathoracic

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disease may benefit from ring placement if inspiratory dyspnea is severe enough to warrant intervention.30

TRACHEAL STENTING In dogs with tracheal collapse at any point along the trachea, including diffuse collapse, or those deemed to be poor surgical candidates for ring placement (laryngeal dysfunction, impaired healing concerns, concerns for prolonged anesthesia), endoluminal tracheal stenting can be considered.1,29,31-38 Tracheal stents have also been beneficial in dogs with tracheal collapse that present in respiratory crisis that are nonresponsive to medical stabilization and animals with airway obstruction secondary to nonresectable tracheal masses or strictures.34,35,39 Management of expectations and an understanding of what can and cannot be accomplished with tracheal stenting is important prior to proceeding with stent placement. For dogs with airway obstruction and respiratory distress secondary to tracheal collapse, tracheal stenting is a life-saving procedure to alleviate the obstruction and improve respiratory comfort. For dogs in whom the majority of their clinical signs are associated with coughing and not airway obstruction, tracheal stenting is unlikely to provide significant relief. Most dogs for whom tracheal stents are placed will require lifelong cough suppression, even those that did not cough prior to stent placement. It is imperative that clients understand ongoing medical therapy will likely be needed. Initial experience with tracheal stenting using biliary wall stents or balloon expandable stents was met with significant complications, such as foreshortening, migration, fracture, and excessive airway irritation.31-33,36,40-43 Negative experience and outcomes led to tracheal stenting being considered a salvage procedure, which was likely a function of stent type(s) placed, lack of experience, and patient selection. Tracheal stents made for dogs (http://infinitimedical.com) have gone through multiple design iterations and engineering adjustments, including the development of a tapered stent to optimally fit the nonuniform tracheal diameter. These design enhancements have improved their sizing and placement predictability, patient tolerance, and risk for fracture.11,37,44,45 Measurements to determine tracheal stent size are made under general anesthesia, with stent placement immediately following ideal size determination. The use of radiographs, fluoroscopy, and CT have been described to measure anesthetized maximal tracheal diameters, which are used to select stent size.20,46 Currently, there is no method to predict the appropriate stent size in the awake patient. Therefore, a variety of stent lengths and diameters need to be readily available prior to anesthesia, especially in critical patients for whom recovery without definitive intervention for their airway obstruction would not be possible. In addition, since most tracheal stent complications result from sizing issues, every effort to size the stent as ideally as possible is imperative for good patient outcomes.11,46 Once under anesthesia, the patient is placed in right lateral recumbency, and a marker catheter is positioned in the esophagus to calibrate the digital radiography or fluoroscopy unit used for precise tracheal diameter measurements (Fig. 19.4). The boundaries of the trachea, the caudal aspect of the cricoid cartilage and cranial aspect of the carina, must be visualized to prevent malposition of the stent into the larynx or bronchi. Maximal tracheal diameter measurements are made along the length of the trachea, using positive pressure breath holds at 20 cm H2O and the inflated endotracheal tube cuff to maintain airway pressure. Using the maximal tracheal diameter determined, a stent diameter 10%–20% larger than this value is chosen so that there is constant outward force of the stent on the tracheal mucosa to maintain positioning. Once the diameter determination has been made, the length is

Fig. 19.4  Fluoroscopic image of an esophageal marker catheter used for measurement calibration during tracheal stent sizing.

chosen to span the entire length of the trachea aside from 1 cm caudal to the cricoid cartilage and 1 cm cranial to the carina. 19-Fluoroscopy is used traditionally for stent placement, but bronchoscopic guidance has also been described.38 Tracheal stents are placed through an endotracheal tube with a bronchoscope adapter attached so that oxygen can be provided during stent positioning and deployment. Constant fluoroscopic visualization during deployment is preferred to ensure appropriate positioning and adequate expansion and to avoid inadvertent deployment within the endotracheal tube, carina, or larynx. Most tracheal stents are reconstrainable and can be recaptured into the delivery sheath until approximately 75% of the stent is deployed. Once the stent position is confirmed to be appropriate, it is fully deployed, and the delivery system removed from the endotracheal tube. Immediately after stent placement, tracheoscopy is repeated to confirm positioning and apposition of the stent with the tracheal mucosa. Gaps in contact between the stent and mucosa contribute to poor mucosalization, which may precipitate mucous accumulation, recurrent chronic tracheal infections, and granulation tissue formation (Fig. 19.5). Since these areas of poor contact/gapping, mucus accumulation, and chronic infection do not become clinically apparent for several months, the time delay to diagnosis precludes stent removal. For this reason, repeat tracheoscopy immediately after stent placement has become an invaluable aspect of successful case management. Areas of poor contact are of particular concern when stenting cases of tracheal malformations since the circular stent may not conform the W shape of the tracheal lumen. If the stent fails to expand in the region

Fig. 19.5  Endoscopic image of a tracheal stent with focal areas of poor stent contact with the tracheal mucosa, creating a “gutter” for mucus accumulation and chronic infection.

CHAPTER 19  Tracheal Collapse: Management & Indications for Tracheal Stents of the malformation or has poor contact with the tracheal mucosa because of the malformation, balloon dilation of the stent with the endotracheal tube cuff balloon under fluoroscopy may help expand the stent and engage the mucosa. If this is ineffective at resolving regions of poor contact (“gutters”), stent removal and placement of a larger diameter stent or placement of a second stent within the first may be indicated. However, tracheal stents are strongest when fully expanded to their nominal diameter, and weaker with progressive constraint to a smaller diameter. Therefore, placing a larger diameter stent into an area that physically cannot be expanded by the rigid nature of the malformation may result in a weaker stent that is more predisposed to fracture. If there is imperfect contact that has not improved with focal balloon dilation, but the sizing of the stent diameter based on the rest of the tracheal measurements is appropriate, placement of second stent may be the best method to achieve increased outward forces to displace the malformation.

POST-STENTING MANAGEMENT CONSIDERATIONS Most patients are discharged the day after stent placement, unless concurrent diseases such as pneumonia necessitate ongoing hospital care. Patients are discharged with antibiotics pending airway culture results, a 2–3 week tapering course of steroids, and regular (q6-8h) cough suppression. A short, dry, self-limiting cough is to be expected for 6–8 weeks post-stent placement while the stent is becoming incorporated into the tracheal mucosa. It is important that clients are advised of this expected postoperative clinical sign, as many clients are very nervous and stressed about coughing being an indication of possible stent complication while adjusting to the new normal life with their stented dogs. Long-term, thoracic radiographs are monitored every 3–4 months for the first year after placement, then every 6 months thereafter. If at any point post-stent placement the patient develops a change in their cough or respiratory comfort, thoracic radiographs should be taken to evaluate for stent complications such as fracture, migration, granulation tissue, and pneumonia. Since granulation tissue can be challenging to diagnose radiographically, tracheoscopy and endotracheal wash may be needed to determine the etiology of the change in the nature of the cough.

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stent/mucosal contact, long-term diligent monitoring for changes to the nature or frequency of coughing is essential. When tracheal infections are documented early, they can often be managed with cultureguided antibiotic therapy and steroids after confirming infection via endotracheal wash, culture, and tracheoscopy. These dogs may require intermittent (1–2 times per year) treatment for chronic infections, which can be expensive and intensive, but they may mitigate the need for placement of a second stent if obstructive granulation tissue development can be prevented through effective infection management.

STENTING FOR TRACHEAL NEOPLASIA Tracheal stents can be considered for palliation nonresectable obstructive tracheal neoplasia, after regrowth of previously resected tracheal masses, and restoration of luminal patency secondary to tracheal strictures.47 They can also be used to improve patient stability in preparation for palliative radiation therapy when surgery is not possible or desired (Fig. 19.6). Preoperative imaging, including thoracic radiographs, CT, and tracheoscopy are valuable for assessing for mass extent and proximity to the larynx or carina, checking for metastasis, radiation planning, and endoscopic biopsy collection. Stent sizing and the placement procedure are similar to stenting for tracheal collapse. Case reports and clinical experience for tracheal stenting for neoplasia describe the use of uncovered tracheal stents, though covered stents may also be considered in cases of tracheal strictures to prevent ingrowth of the stricture into the stent.47

TRACHEAL STENT COMPLICATIONS Historically, tracheal stent fractures were thought to be a catastrophic complication of tracheal stents. However, with improved patient selection, sizing technique, stent design, including tapered stents that avoid oversizing of the intrathoracic trachea, and experience with placement of a second stent within the fractured stent, this complication is infrequent and readily manageable.11,40-42,45 Tracheal stent migration is uncommon when appropriately (10%–20%) oversized stents are selected based on anesthetized maximal tracheal diameter measurements. Since migration tends to be an early complication, if promptly recognized, these stents can be removed and a larger diameter stent placed. Inflammatory (granulation) tissue formation in dogs with tracheal stents is thought to occur in patients with areas of poor mucosal ingrowth into the stent, resulting in mucus accumulation in the tracheal gutters and chronic infection. Management of nonobstructive granulation tissue has anecdotally shown promising response to immunosuppressive steroid therapy and airway culture-guided antibiotic therapy. For cases in which granulation tissue progresses to airway obstruction, early experience with repeated tracheal stenting, steroids, and antimicrobials has shown success. In dogs with areas of imperfect

A

B Fig. 19.6  Radiographic image of an obstructive, nonresectable tracheal mass in a dog (A) and use of tracheal stent to restore luminal patency and palliate the obstruction in preparation for radiation therapy (B).

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REFERENCES 1. White R, Williams JM: Tracheal collapse in the dog-is there really a role for surgery? A survey of 100 cases, J Small Anim Pract 35(4):191-196, 1994. 2. Dallman MJ, McClure RC, Brown EM: Histochemical study of normal and collapsed tracheas in dogs, Am J Vet Res 49(12):2117-2125, 1988. 3. Mason RA, Johnson LR: Tracheal collapse. In King LG, editor: Textbook of respiratory disease in dogs and cats, St. Louis, 2004, Saunders, pp 346-355. 4. Payne JD, Mehler SJ, Weisse C: Tracheal collapse, Compendium 28(5): 373-383, 2006. 5. Done SH, Drew RA: Observations on the pathology of tracheal collapse in dogs, J Small Anim Pract 17(12):783-791, 1976. 6. Johnson LR, Pollard RE: Tracheal collapse and bronchomalacia in dogs: 58 cases (7/2001-1/2008), J Vet Intern Med 24(2):298-305, 2010. 7. Adamama-Moraitou KK, Pardali D, Dai MJ, et al: Canine bronchomalacia: a clinicopathological study of 18 cases diagnosed by endoscopy, Vet J 191(2):261-266, 2012. 8. Bottero E, Bellino C, De Lorenzi D, et al: Clinical evaluation and endoscopic classification of bronchomalacia in dogs, J Vet Intern Med 27(4):840-846, 2013. 9. Maggiore AD: Tracheal and airway collapse in dogs, Vet Clin North Am Small Anim Pract 14(1):117-127, 2014. 10. Tanger CH, Hobson H: A retrospective study of 20 surgically managed cases of collapsed trachea, Vet Surg 11(4):146-149, 1982. 11. Weisse C, Berent A, Violette N, et al: Short-, intermediate-, and long-term results for endoluminal stent placement in dogs with tracheal collapse, J Am Vet Med Assoc 254(3):380-391, 2019. 12. Clarke DL: Interventional radiology management of tracheal and bronchial collapse, Vet Clin North Am Small Anim Pract 48(5):765-779, 2018. 13. Rubin JA, Holt DE, Reetz JA, Clarke DL: Signalment, clinical presentation, concurrent diseases, and diagnostic findings in 28 dogs with dynamic pharyngeal collapse, J Vet Intern Med 29(3):815-821, 2015. 14. Macready DM, Johnson LR, Pollard RE: Fluoroscopic and radiographic evaluation of tracheal collapse in dogs: 62 cases (2001–2006), J Am Vet Med Assoc 230(12):1870-1876, 2007. 15. Marolf A, Blaik M, Specht A: A retrospective study of the relationship between tracheal collapse and bronchiectasis in dogs, Vet Radiol Ultrasound 48(3):199-203, 2007. 16. Nafe LA, Robertson ID, Hawkins EC: Cervical lung lobe herniation in dogs identified by fluoroscopy, Can Vet J 54(10):955-959, 2013. 17. Stadler K, Hartman S, Matheson J, et al: Computed tomography imaging of dogs with primary laryngeal or tracheal airway obstruction, Vet Radiol Ultrasound 52(4):377-384, 2011. 18. Eom K, Moon K, Seong Y, et al: Ultrasonographic evaluation of tracheal collapse in dogs, J Vet Sci 9(4):401-405, 2008. 19. Heyer CM, Nuesslein TG, Jung D, et al: Tracheobronchial anomalies and stenoses: detection with low-dose multidetector CT with virtual tracheobronchoscopy-comparison with flexible tracheobronchoscopy, Radiology 242(2):542-549, 2007. 20. Scansen BA: Tracheal diameter and area: computed tomography versus fluoroscopy for stent sizing in 12 dogs with tracheal collapse, J Vet Intern Med 28(4):1364, 2014. 21. Bottero E, Bellino C, De Lorenzi D, et al: Clinical evaluation and endoscopic classification of bronchomalacia in dogs, J Vet Intern Med 27(4):840-846, 2013. 22. Johnson LR: Laryngeal structure and function in dogs with cough, J Am Vet Med Assoc 249(2):195-201, 2016. 23. McKiernan BC, Smith AR, Kissil M: Bacterial isolates from the lower trachea of clinically healthy dogs, J Am Anim Hosp Assoc 20:139-142, 1984. 24. Johnson LR, Fales WH: Clinical and microbiologic findings in dogs with bronchoscopically diagnosed tracheal collapse: 37 cases (1990-1995), J Am Vet Med Assoc 219(9):1247-1250, 2001.

25. Clarke DL, Luskin A, Brown D: Endotracheal wash cytology and microbiologic results in dogs undergoing tracheal stenting: 34 cases (2011-2014), J Vet Emerg Crit Care 25(S1):S1-S34, 2015. 26. Lesnikowski S, Weisse C, Berent A, et al: Bacterial infection before and after stent placement in dogs with tracheal collapse syndrome, J Vet Intern Med 34:725-733, 2020. 27. Bauer NB, Schneider MA, Neiger R, et al: Liver disease in dogs with tracheal collapse, J Vet Intern Med 20(4):845-849, 2006. 28. Jeung SY, Sohn SJ, An JH, et al: A retrospective study of theophyllinebased therapy with tracheal collapse in small-breed dogs: 47 cases (20132017) [published correction appears in J Vet Sci. 2019 Nov;20(6):e66], J Vet Sci 20(5):e57, 2019. doi:10.4142/jvs.2019.20.e57. 29. Buback JL, Boothe HW, Hobson HP: Surgical treatment of tracheal collapse in dogs: 90 cases, J Am Vet Med Assoc 208:380-384, 1996. 30. Becker WM, Beal M, Stanley BJ, et al: Survival after surgery for tracheal collapse and the effect of intrathoracic collapse on survival, Vet Surg 41(4):501-506, 2012. 31. Sura PA, Krahwinkel DJ: Self-expanding nitinol stents for the treatment of tracheal collapse in dogs: 12 cases (2001-2004), J Am Vet Med Assoc 232(2):228-236, 2008. 32. Moritz A, Schneider M, Bauer N: Management of advanced tracheal collapse in dogs using intraluminal self-expanding biliary wallstents, J Vet Intern Med 18(1):31-42, 2004. 33. Sun F, Usón J, Ezquerra J, et al: Endotracheal stenting therapy in dogs with tracheal collapse, Vet J 175(2):186-193, 2008. 34. McGuire L, Winters C, Beal MW: Emergency tracheal stent placement for the relief of life-threatening airway obstruction in dogs with tracheal collapse, J Vet Emerg Crit Care 23(S1):S9, 2013. 35. Beal MW: Tracheal stent placement for the emergency management of tracheal collapse in dogs, Top Comp Anim Med 28(3):106-111, 2013. 36. Gellasch KL, Gomez TDC, McAnulty JF, et al: Use of intraluminal nitinol stents in the treatment of tracheal collapse in a dog, J Am Vet Med Assoc 221(12):1719-1723, 2002. 37. Kim JY, Han HJ, Yun HY, et al: The safety and efficacy of a new self-expandable intratracheal nitinol stent for the tracheal collapse in dogs, J Vet Sci 9(1):91-93, 2008. 38. Durant AM, Sura P, Rohrbach B, et al: Use of nitinol stents for end-stage tracheal collapse in dogs, Vet Surg 41(7):807-817, 2012. 39. Culp WT, Weisse C, Cole SG, et al: Intraluminal tracheal stenting for treatment of tracheal narrowing in three cats, Vet Surg 36(2):107-113, 2007. 40. Radlinsky MG, Fossum TW, Walker MA, et al: Evaluation of the Palmaz stent in the trachea and mainstem bronchi of normal dogs, Vet Surg 26(2):99-107, 1997. 41. Mittleman E, Weisse C, Mehler SJ, Lee JA: Fracture of an endoluminal nitinol stent used in the treatment of tracheal collapse in a dog, J Am Vet Med Assoc 225(8):1217-1221, 2004. 42. Ouellet M, Dunn ME, Lussier B, Chailleux N, Hélie P: Noninvasive correction of a fractured endoluminal nitinol tracheal stent in a dog, J Am Anim Hosp Assoc 42(6):467-471, 2006. 43. Woo HM, Kim MJ, Lee SG, et al: Intraluminal tracheal stent fracture in a Yorkshire terrier, Can Vet J 48:1063-1066, 2007. 44. Clarke DL, Tappin S, de Madron E, et al: Evaluation of a novel tracheal stent for the treatment of tracheal collapse in dogs, J Vet Intern Med (4):1364, 2014. 45. Violette NP, Weisse CW, Berent AC, et al: Correlations among tracheal dimensions, tracheal stent dimensions, and major complications after endoluminal stenting of tracheal collapse syndrome in dogs, J Vet Intern Med 33:2209-2216, 2019. 46. Weisse CW: Intraluminal tracheal stenting. In Weisse CW, Berent AC, editors: Veterinary image guided interventions, Ames, Iowa, 2015, Wiley Blackwell, pp 73-82. 47. Culp WT, Weisse C, Cole SG, Solomon JA: Intraluminal tracheal stenting for treatment of tracheal narrowing in three cats, Vet Surg 36(2):107-113, 2007.

20 Feline Bronchopulmonary Disease Elizabeth Rozanski, DVM, DACVIM (SA-IM), DACVECC, Gareth J. Buckley, MA, VetMB, MRCVS, DACVECC, DECVECC KEY POINTS • Airway disease typically affects young to middle-aged cats. • Bronchopulmonary disease is a spectrum of diseases, ranging from true asthma to bronchiectasis. • Expiratory distress is a common clinical sign, with historical cough frequently mistaken for hairballs.

• Glucocorticoids, either inhaled or orally administered, are the mainstay of treatment. • Parasitic infections and hypersensitivity disorders should be excluded.

Respiratory distress in cats is a true emergency. It is commonly caused by airway disease, but other frequent etiologies include congestive heart failure, pleural space disease, and neoplasia. It is essential to attempt to accurately determine the cause of the distress in order to have the best chance of a successful outcome. Feline bronchopulmonary disease is an umbrella term encompassing a spectrum of airway disease in cats and may be referred to as feline asthma.1 Airway diseases in cats may include upper airway disease as well, and the concept of the “unified airway” has been applied to allergic airway diseases affecting people and should likely be considered in cats as well.2 While the focus of this chapter is bronchopulmonary disease, other diseases should be excluded, if possible, before treatment for bronchopulmonary disease is initiated. Mammalian airways can respond to stimuli in a limited number of ways, including airway smooth muscle hypertrophy, excessive mucus production, and bronchoconstriction. These changes result in the clinical signs of difficulty breathing and cough.1 Airway disease or bronchopulmonary disease in cats may be divided into asthma and chronic bronchitis. Feline asthma is defined as hyperreactive airways with reversible bronchoconstriction, while chronic bronchitis is characterized by thickening of the airways and excessive mucus production. Feline asthma is considered to be a type I hypersensitivity reaction following sensitization to aeroallergens. The actual allergen is uncommonly identified. Some cats may have signs of both chronic cough and episodic bronchoconstriction leading to increased end-expiratory lung volume, increased work of breathing, and ultimately respiratory fatigue.3 The stimulus for the development of airway disease remains unknown in most cats. A similar syndrome can be mimicked in the laboratory by sensitizing cats to an aeroallergen, such as Bermuda grass.2,5 It is assumed but not proven that cats with airway disease have an allergy to some environmental trigger. A recent study documented increased serum IgE levels in some cats with eosinophilic airway disease.6 It is also possible to have intrinsic asthma, where a specific trigger is not detected. In children, viral infections early in life predispose them to asthma; viral upper respiratory infections are very common in cats, but the relationship to the subsequent development of asthma in cats is also unknown. Parasitic infection may produce similar respiratory signs.

HISTORY AND PHYSICAL EXAMINATION Most cats are young adult to middle-aged at the first development of clinical signs of airway disease. Siamese cats were overrepresented in one report, but overall the vast majority of cats are of mixed heritage. Young cats (,1 year) typically have infectious causes of respiratory distress (viral or parasitic) or occasionally, nasopharyngeal polyps. Older cats more commonly have neoplastic processes, including laryngeal masses, which may cause audible wheezes. Bronchopulmonary disease is typically lifelong, so older cats may be affected, but clinical signs usually appear at an earlier age. While uncommonly used in cats, potassium bromide has been associated with cough and respiratory disease, and its use should be discontinued in any cat with respiratory disease. Physical examination typically shows a well-conditioned cat with respiratory distress and/or cough. Weight loss, unkempt coats, or muscle wasting are rare to nonexistent. Cats may present only with intermittent cough, which may be mistaken for hairballs, or may present with respiratory distress. Cats with airway disease severe enough to require admission to the ICU will have expiratory distress due to airtrapping and bronchoconstriction; however, this can be occasionally hard to detect due to tachypnea with resulting short inspiratory and expiratory time. Cats may also have crackles and wheezes, which represent fluid/mucus in the airways causing them to collapse and reopen with each breath. A murmur may also be present due to concurrent heart disease or simply a flow murmur. In contrast to cats with active congestive heart failure, cats with bronchopulmonary disease will have normal rectal temperatures. Imaging The classical imaging modality used for identification of airway disease is thoracic radiographs. Bronchial or bronchointerstitial patterns are the most frequently observed, with occasional collapse of the right middle lung lobe due to mucus plug formation (Fig. 20.1). Hyperinflation caused by air-trapping is also common due to expiratory flow limitation. Bronchiectasis may also be present. Completely normal thoracic radiographs should prompt consideration for another disease process, such as a laryngeal mass or paralysis, particularly in a geriatric cat that has no prior history of cough or wheeze.

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Fig. 20.1  A lateral thoracic radiograph from a cat with airway disease demonstrating right middle lung lobe collapse. Also note the hyperinflation and bronchial pattern.

Fig. 20.2  A computed tomography scan showing severe bronchiectasis in a cat with chronic bronchopulmonary disease. Note the dilated, mucus-filled airway in the left caudal lung field.

Point-of-care ultrasound (POCUS) may be used to demonstrate the lack of B-lines (see Chapter 189, Point-of-Care Ultrasound in the ICU), but despite widespread use in the diagnosis of pulmonary parenchymal diseases, POCUS has not been evaluated in cats with airway disease. In children with asthma, POCUS is useful for excluding other conditions such as pneumonia.6 Echocardiography or N-terminal pro-brain natriuretic peptide (NT-pro-BNP) testing is useful to exclude clinically significant heart disease. Pulmonary hypertension due to airway disease has not been reported in cats to the authors’ knowledge, although it has been described in horses with experimental asthma.8 Other imaging modalities, such as computed tomography (CT) scanning, are rarely used in cats with airway disease, unless the diagnosis is unclear or if there is concern for other comorbidities (see Fig. 20.2 demonstrating severe bronchiectasis; this CT was performed due to poor response to steroids and recognition of an abnormality on thoracic radiographs).

PFT determinations with airway sampling.8 Arterial blood gases might document hypercarbia or hypoxemia but are practically very challenging to perform in cats with respiratory distress. A venous blood gas can document severe hypercarbia if present. Awake pulse oximetry and end-tidal CO2 analysis are unreliable in cats. The 6-minute walk test has not been attempted in cats.

LABORATORY TESTING Complete blood count and chemistry profile are typically within references ranges. Some cats have circulating eosinophilia, although absence of this does not rule out airway disease. Cats should be tested for heartworm disease if they live within endemic areas and a Baermann fecal sedimentation should be performed for diagnosis of potential lung worm infection. Serum allergy testing may be pursed in cats with severe signs; hyposensitization was found to be useful in research cats, but testing in naturally affected cats has not been evaluated.5

LUNG FUNCTION TESTING While pulmonary function testing (PFT) is widely used in people, due to challenges in cooperation, PFT is far less widely used in cats. However, in an intubated patient hooked up to a critical care ventilator, static and dynamic compliance, as well as airway resistance, may be easily calculated.9,10 In the authors’ practice, it is simple to combine

AIRWAY SAMPLING An endotracheal wash or bronchoalveolar lavage may be performed for confirmation of the diagnosis or when looking for evidence of infectious or parasite disease. Cytological changes consistent with allergic airway disease most commonly include the presence of eosinophilia, although in cases of chronic bronchitis, a neutrophilic infiltrate may be detected. Larva may be detected with lungworms, and bacteria may be observed with infection. The degree of normal airway eosinophilia in cats has been debated with some studies suggesting as much as 17%.9,10 A more recent study concluded that greater than 5% eosinophil percentage was abnormal.11 An upper airway examination prior to intubation may be indicated. Pretreatment with albuterol or terbutaline is suggested prior to sampling to minimize reflex bronchoconstriction which can be severe. Most cats (.95%) tolerate airway wash with only transient desaturation, but this technique should be performed with caution in cats with moderate or severe respiratory distress.12 Airway sampling may be combined with tracheobronchoscopy if desired.

TREATMENT The mainstay therapy for cats with bronchopulmonary disease is to remove any potential allergens (e.g., air fresheners, cigarette smoke, dust exposure) and treat the airway inflammation. The two most common mistakes that clinicians make in treating bronchopulmonary disease in cats are trying to stop steroids and prescribing daily bronchodilators. Unless a specific underlying cause can be identified and eliminated, glucocorticoids are the mainstay of

CHAPTER 20  Feline Bronchopulmonary Disease therapy. Glucocorticoids may be administered as an oral tablet/ liquid, most commonly as prednisolone. A typical dose would be 5 mg per cat twice daily until remission occurs, then once daily and then tapered but not stopped to 2.5 mg twice a week. Glucocorticoids may also be administered via a metered dose inhaler, most commonly as fluticasone. Inhalant medication requires the use of a chamber and face mask. Using inhalant medications over orally administered glucocorticoids have been shown to be effective in treatment of feline bronchopulmonary disease; they reduce but do not entirely eliminate systemic glucocorticoid effects in cats.9 Fluticasone is dosed at 110–220 mcg twice daily, with rare cats requiring a lower dose. Almost all cats can be trained to accept the mask. In rare cases where oral or inhaled medication administration is not possible or practical, glucocorticoids may be administered via a reposital preparation, such as methylprednisolone (DepoMedrol) at a dose of 10–20 mg/cat every 2–6 weeks. Bronchodilators should only be administered if there are signs of bronchoconstriction; daily use may lead to tachyphylaxis as well as signs of restlessness or anxiety. In an acute crisis, albuterol by aerosol (1–2 puffs/cat) or terbutaline (0.01 mg/kg IV, SQ or IM) are useful for promoting bronchodilation. Theophylline, which has been historically used, is hard to find outside of compounding pharmacies, and more importantly, appears to have limited efficacy in cats and has tricky pharmacokinetics.13 Other therapies that may be considered include antimicrobials if there is evidence of neutrophilic inflammation or a septic process, or potentially a secondary infection (e.g., Mycoplasma or Bordetella bronchiseptica). Cats should be dewormed if there is evidence of parasitic infection or potential for lung worms such as Aelurostrongylus abstrusus (fenbendazole, 50 mg/kg PO 3 14 days).

PROGNOSIS The prognosis for most cats with bronchopulmonary disease is excellent, although in a small subgroup of cats, severe recurrent airway obstruction associated with bronchoconstriction or mucus plugging can be fatal. In an ICU setting, cats should be “better by morning” if typical feline bronchopulmonary disease is present. However, owners should understand that bronchopulmonary disease is not cured, but rather chronic environmental and medical management are typically

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necessary. Failure to improve with emergent treatment should cause the clinician to reassess the diagnosis. Disclosures: One of the authors (ER) has received research support from Trudell Medical, the makers of the Aerokat chamber.

REFERENCES 1. Trzil JE, Reinero CR: Update on feline asthma, Vet Clin North Am Small Anim Pract 44(1):91-105, 2014. 2. Stachler RJ: Comorbidities of asthma and the unified airway, Int Forum Allergy Rhinol 5(Suppl 1):S17-S22, 2015. 3. O’Donnell DE, Laveneziana P: Physiology and consequences of lung hyperinflation in COPD, Eur Respir Rev 15(100):61-67, 2006. 4. Reinero CR, Byerly JR, Berghaus RD, et al: Rush immunotherapy in an experimental model of feline allergic asthma, Vet Immunol Immunopathol 110(1-2):141-153, 2006. 5. Buller MC, Johnson LR, Outerbridge CA, et al: Serum immunoglobulin E responses to aeroallergens in cats with naturally occurring airway eosinophilia compared to unaffected control cats, J Vet Intern Med 34(6):26712676, 2020. 6. Dankoff S, Li P, Shapiro AJ, Varshney T, Dubrovsky AS: Point of care lung ultrasound of children with acute asthma exacerbations in the pediatric ED, Am J Emerg Med 35(4):615-622, 2017. 7. Decloedt A, Borowicz H, Slowikowska M, Chiers K, van Loon G, Niedzwiedz A: Right ventricular function during acute exacerbation of severe equine asthma, Equine Vet J 49(5):603-608, 2017. 8. Vershoor-Kirss M, Rozanski EA, Sharp CR, et al: Treatment of naturally occurring asthma with inhaled fluticasone or oral prednisolone: a randomized pilot trial, Can J Vet Res 85(1):61-67, 2021. 9. Bernhard C, Masseau I, Dodam J, et al: Effects of positive end-expiratory pressure and 30% inspired oxygen on pulmonary mechanics and atelectasis in cats undergoing non-bronchoscopic bronchoalveolar lavage, J Feline Med Surg 19(6):665-671, 2017. 10. Shibly S, Klang A, Galler A, et al: Architecture and inflammatory cell composition of the feline lung with special consideration of eosinophil counts, J Comp Pathol 150:408-415, 2014. 11. Johnson LR, Drazenovich TL: Flexible bronchoscopy and bronchoalveolar lavage in 68 cats (2001-2006), J Vet Intern Med 21(2):219-225, 2007. 12. Guenther-Yenke CL, McKiernan BC, Papich MG, et al: Pharmacokinetics of an extended-release theophylline product in cats, J Am Vet Med Assoc 15;231(6):900-906, 2007.

21 Lower Airway Disease in Dogs Lynelle R. Johnson, DVM, MS, PhD, Dipl ACVIM (SAIM)

KEY POINTS • Most airway diseases (bronchitis, bronchomalacia, eosinophilic lung disease, and bronchiectasis) are common in both small and large dogs, but tracheal collapse is almost exclusively a disease of small breed dogs. • Identification of complicating conditions that exacerbate airway collapse such as infection, inflammation, obesity, aspiration injury, and cardiac disease can provide avenues for interventions that will improve quality of life.

• Treatment of airway collapse relies on conservative measures to reduce the stressors that trigger cough and airway irritation. • Anxiety or overexcitement can be limited by judicious use of anxiolytics (e.g., trazodone) in conjunction with avoidance measures. • Narcotic cough suppressants are often required for management of cough associated with airway collapse after infection and inflammation have been resolved.

INTRODUCTION

crackles. Both conditions can also be associated with an abnormal pattern of breathing; an expiratory push or exaggerated abdominal effort is common and appears to be more severe in dogs with bronchomalacia. Definitive diagnosis of respiratory conditions requires a combination of laboratory testing, diagnostic imaging, laryngeal examination, and airway sampling. Documentation of airway collapse is particularly challenging. The presence of bronchiectasis suggests more substantial inflammation, and established bronchiectasis that can be visualized on radiographs is typically irreversible. Computed tomography has proven useful in early detection of the more subtle changes and is characterized by a pulmonary arterial to bronchial lumen ratio that exceeds 2.0.4 Dynamic changes in airway diameter can be visualized better when multiple views are obtained (e.g., right and left lateral images along with cervical radiographs). Where available, fluoroscopy is valuable for real-time assessment of dynamic airway collapse (Fig. 21.1). It can also document tracheal kinking and cranial lung herniation, the latter of which occurs in up to 70% of dogs with airway collapse.5 In some practices, bronchoscopy will have been utilized to detect tracheobronchomalacia (Fig. 21.2). Bronchomalacia is characterized by .50% collapse of airway luminal diameter. It can be static or dynamic and affect a single bronchus or multiple airways. Bronchiectasis can also be visualized during bronchoscopy by thinning of airway bifurcations and increased luminal space, with or without accumulation of secretions. While this procedure requires anesthesia, it also allows for a comprehensive laryngeal examination, as well as collection of airway samples to determine the type of inflammation present and to perform culture and susceptibility testing. Bronchoalveolar lavage fluid normally comprises 70%–75% macrophages and 5%–8% neutrophils, eosinophils, and lymphocytes. Alterations in cell percentages are used to characterize inflammatory airway disease, and neutrophils are scrutinized for intracellular bacteria to document infection, bearing in mind that up to 25% of dogs with infection might lack evidence of airway sepsis.6 Aerobic and Mycoplasma cultures are warranted in dogs that have airway samples collected for evaluation of cough, and anaerobic cultures are also recommended in dogs with bronchiectasis or suppurative pneumonia.

The most common disorders affecting the lower airways of dogs are related to structural disease (tracheal and bronchial collapse or bronchiectasis), airway infection, and airway inflammation, including eosinophilic lung disease, lymphocytic inflammation, or chronic bronchitis characterized by nonseptic suppurative inflammation. Many dogs will suffer from multiple disorders concurrently1-3 requiring extensive work-up beyond that performed in the ICU setting.

DIAGNOSIS OF UNDERLYING CONDITIONS Dogs with airway disease are typically presented for evaluation of a cough that has finally exceeded the tolerance of the owner. Signalment can be helpful in prioritizing the type of airway disease present because younger animals are more likely to have infectious disease (canine infectious respiratory disease complex) and cervical tracheal collapse while older dogs tend to be affected by bronchomalacia, with or without tracheal collapse, and chronic bronchitis. Bronchiectasis can be found in a young dog with ciliary dyskinesia or eosinophilic lung disease but is more commonly encountered in older dogs with chronic inflammatory or infectious disease or in older dogs with chronic aspiration injury. Tracheal collapse is almost exclusively a disease of small breed dogs; however, all other airway diseases (bronchitis, bronchomalacia, eosinophilic lung disease, and bronchiectasis) are common in both small and large dogs. Physical examination reveals tracheal sensitivity in most dogs with cough, regardless of etiology because irritant receptors between epithelial cells can be activated by infection, inflammation, or airway compression. Detection of abnormal lung sounds is variable, and increased breath sounds (rather than adventitious sounds) might be the only abnormality detected. Bronchomalacia can result in inspiratory and/or expiratory crackles when airways dynamically open and close during the respiratory cycle. Bronchitis is occasionally associated with an expiratory wheeze as air flows from the alveolar region to the glottis through narrowed airways, but this can also result in expiratory

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CHAPTER 21  Lower Airway Disease in Dogs

A

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B

Fig. 21.1  An inspiratory lateral image captured from a fluoroscopic study (A) reveals attenuation of the luminal diameter of the trachea as it traverses the thoracic inlet, consistent with cervical tracheal collapse. During expiration (B), the intrathoracic trachea is almost completely collapsed, as are the cranial and caudal lobar bronchi.

and while uncommon, secondary infection can develop from immunosuppression in some dogs, necessitating repeated diagnostic testing.

DISEASE EXACERBATION Cranial Caudal

Exacerbations of disease can be reflected by worsening cough, acute onset of respiratory distress, or by the development of systemic signs of illness such as anorexia, exercise intolerance, or collapse. Any of these features can result in presentation to the emergency room and hospitalization in the ICU, with varying degrees of urgency in reaching a diagnosis and establishing a treatment plan.

Infection

Fig. 21.2  Bronchoscopic view of the left cranial and caudal lobar bronchi of a dog with severe bronchial collapse.

STANDARD TREATMENT Treatment of airway collapse relies on conservative measures to reduce the stressors that trigger cough and airway irritation. Anxiety or overexcitement can be limited by judicious use of anxiolytics (e.g., trazodone) in conjunction with avoidance measures. Exercise should be discouraged in hot or humid environments, and a harness should be used in place of a collar. While controversial, extended-release theophylline appears to be clinically beneficial in reducing cough and respiratory effort by improving expiratory airflow.7 Caution is warranted when using this drug because vomiting and agitation are recognized side effects, which could trigger exacerbation of disease. Currently, extended-release theophylline is available only from compounding pharmacies, and little data are available on these medications, although one formulation has been demonstrated to have good bioavailability.8 Steroids are typically indicated for management of bronchitis and eosinophilic lung disease; however, in the absence of airway sampling, it is important to recognize that not all cases of bronchomalacia have inflammation, and steroids can actually aggravate clinical signs in some dogs by induction of panting, weight gain, and worsening of preexisting infections. Disease can worsen as drug dosages are tapered downward,

The most common sources of infection in client-owned dogs are exposure to organisms in the canine infectious respiratory disease complex (viruses and bacteria) or via aspiration (see below). Dogs receiving corticosteroids should be considered particularly at risk for infection at any time, and a quick history should be obtained to assess exposure history to a potentially infected dog while triaging the patient. Also, dogs with airway collapse that come into contact with infected dogs seem to be more likely to trap certain organisms in the lower airways and display worsening or refractory disease. Pronounced coughing is likely the most common presenting complaint in affected dogs. When an infectious organism is considered likely to contribute to disease exacerbation, infection is typically local and complete blood count changes are not seen. Similarly, radiographic changes are not expected, although they are typically performed at an emergency visit to rule out other conditions. When the dog appears healthy and physical examination is relatively unremarkable apart from tracheal sensitivity, treatment is predicated on the knowledge of the characteristics of organisms involved. The decision to collect a lower airway sample is clinically based. Oropharyngeal swab cultures should not be considered suitable substitutes for a bronchial sample in most cases.9 Current guidelines for the management of acute respiratory infection presumed related to Mycoplasma, Bordetella, and other respiratory pathogens recommend the use of doxycycline (3–5 mg/kg PO BID).10 Owners should be advised to deliver water or food after administration of the drug to reduce the risk of esophageal stricture formation. Follow-up clinical assessment should be obtained if the condition worsens or cough does not resolve within 7–10 days.

Intubation A dog with tracheal or airway collapse can present to the ICU for worsened cough after anesthesia and intubation for diagnostic testing or completion of an elective procedure. Airway irritation from the endotracheal tube can initiate an unrelenting cough in an affected dog typically results within 1–2 days of the procedure. This seems to occur most commonly in small breed dogs, which are frequently affected by

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lower airway disease and also dental disease that requires treatment under general anesthesia. Any animal suspected of having purely tracheal irritation from intubation should be screened for possible aspiration of gastric contents or dental material with a complete blood count and thoracic radiographs. It is rare that cases of intubation injury require tracheoscopy to assess the severity of injury, especially given the potential risk of pneumothorax. Even when subcutaneous edema or pneumomediastinum raise concern for tracheal rupture, it is uncommon to be able to visualize the area of tracheal injury and therefore the potential benefit may not be worth the risk. Dogs with intubation irritation alone are typically managed with sedation (e.g., gabapentin, trazodone or acepromazine) and cough suppression (e.g., butorphanol or hydrocodone). Home treatment with neuroleptanalgesia is advised along with continued monitoring over the course of 10–14 days for worsened or persistent cough, as well as for development of signs consistent with a tracheal tear.

Cardiac Enlargement or Congestive Heart Failure Controversy exists over the role of left atrial enlargement or cardiomegaly in the generation or exacerbation of cough, and this is particularly challenging to define in dogs with airway collapse. Due to the positioning of the heart within the thorax in relation to several of the large lobar bronchi (left cranial, right middle, and accessory), enlargement of the heart could theoretically lead to compression of the airways between other thoracic structures. However, the commonality of left mainstem bronchial compression in brachycephalic breeds11 might argue for a more complex role of anatomical considerations other than simple cardiomegaly. Many small breed dogs are affected by combinations of mitral valve disease, bronchomalacia, and chronic bronchitis, making it difficult to assess the contribution of various diseases to the generation of cough (Fig. 21.3). One study failed to find a difference in the location or severity of airway collapse between a group of dogs with left atrial enlargement due to myxomatous mitral valve disease and a control group of dogs lacking cardiomegaly.12 In dogs evaluated in that study, most had evidence of inflammatory airway disease in conjunction with airway collapse, suggesting that airway disease was the primary cause of cough.

Fig. 21.3  Right lateral radiograph showing marked left atrial enlargement but no evidence of congestive heart failure. The pulmonary veins are equal in size to the pulmonary arteries, and no pulmonary infiltrates are present. The cardiac silhouette appears enlarged although this is likely related to pulmonary hypoinflation. The diagnosis in this dog was diffuse bronchomalacia.

Findings of tachypnea and tachycardia in a dog with heart murmur would support the likelihood of congestive failure because pulmonary edema initially fills the interstitium and induces tachypnea (see Chapter 41, Mechanisms of Heart Failure).13 Cardiomegaly is virtually always present when left-sided congestive heart failure develops, with left atrial and left ventricular enlargement, pulmonary venous enlargement, and interstitial to alveolar infiltrates in the hilar or caudal lung region (Fig. 21.4). In such a case, a trial on furosemide (1–4 mg/kg IV) would be advised. Follow-up thoracic radiographs obtained 24–48 hours after a furosemide trial that confirm clearing of infiltrates would support a diagnosis of congestive heart failure (see Part IV, Cardiovascular Disorders).

Pulmonary Hypertension (see Chapter 22, Pulmonary Hypertension) Virtually any chronic pulmonary disease can result in the complication of increased pulmonary vascular pressure, likely due to increased pulmonary vascular resistance associated with obstructive or obliterative diseases of the vasculature or from chronic and global hypoxic vasoconstriction. Pulmonary hypertension has been described in association with a variety of congenital and acquired cardiopulmonary conditions, including pneumonia in young dogs, brachycephalic syndrome, chronic tracheobronchial disease (bronchitis or airway collapse), embolic disease, and suspected interstitial lung disease.14 Syncope appears to be a relatively common finding, and recent onset of collapse in a respiratory patient should prompt consideration of pulmonary hypertension. Stabilization in oxygen should be performed with subsequent referral to a cardiologist.

Obesity Although not typically considered a cause for ICU admission, weight gain can have disastrous consequences for the dog with respiratory disease, and owners might be unaware of how the situation has progressed until the dog develops acute worsening of cough or respiratory difficulty. Excessive fat on the thoracic cage compromises respiration by reducing chest wall compliance, decreasing diaphragmatic excursion through fat deposition in the abdomen, and enhancing airway compression.15 These features are most deleterious for animals with lower respiratory tract disease including airway collapse and inflammatory airway disease, but they are also important for brachycephalic dogs and dogs with laryngeal paralysis.

Fig. 21.4  Right lateral radiographs displaying moderate to severe interstitial to alveolar infiltrates in conjunction with left atrial enlargement, consistent with heart failure.

CHAPTER 21  Lower Airway Disease in Dogs Although somewhat uncommon, dogs with lower airway disease can become tolerant of gradual carbon dioxide retention, causing chemoreceptors to lose the ventilatory response to hypercapnia. When placed into an oxygen-enriched environment, these dogs can decompensate, as evidenced by increased work of breathing and worsened respiratory distress. This rare occurrence usually responds to withdrawal of exogenous oxygen supplementation. Dogs should subsequently be referred to their local veterinarian for a comprehensive work-up of medical conditions that can contribute to weight gain and the development of a weight-loss plan that relies on calculation of calories based on body condition scoring.

Aspiration Injury (see Chapter 24, Pneumonia) Risk factors for aspiration pneumonia include swallowing disorders (megaesophagus or esophagitis), vomiting, decreased level of consciousness (postanesthesia, postictus, head trauma), and laryngeal dysfunction or surgery. Acid injury is primarily responsible for the ventilatory abnormalities seen in animals with aspiration pneumonia, although some dogs have a substantial bacterial component to their disease. Physical examination in dogs with acute and moderate to severe aspiration injury is characteristic of pneumonia, with a rapid shallow breathing pattern and cough. Special attention should be paid to identifying any physical examination factors that relate to risk factors for aspiration, with careful auscultation over the larynx to detect stridor on inspiration, suggesting laryngeal paralysis as a predisposing feature. Laboratory testing is beneficial for assessing the severity of inflammation and for following the response to therapy. A complete blood count often reveals leukocytosis, although the severity and the presence of a band response are variable. A biochemical panel can provide early detection of systemic changes that might accompany multiorgan failure. Pulse oximetry is a worthwhile screening tool to determine whether an arterial blood gas analysis should be obtained, when available. An oxygen saturation (SpO2) below 95% correlates with a partial pressure of oxygen (PaO2) ,80 mm Hg and indicates that a blood gas analysis should be considered. Although the pulse oximeter provides only a crude estimate of arterial oxygenation, it can be useful in conjunction with a physical examination and lung auscultation for quantifying trends in clinical improvement or worsening of pneumonia. Thoracic radiographs in patients with aspiration pneumonia typically show cranioventral alveolar infiltrates or middle lung lobe disease; however, the position of the animal at the time of aspiration will affect the radiographic distribution. Also, the time that has elapsed since aspiration will determine whether an interstitial or alveolar infiltrate is identified. Conflicting results have been obtained in studies that compared the severity of radiographic changes with outcome;16,17 therefore, caution is warranted in offering prognosis based on radiographs alone. If the aspiration event has been witnessed or if an inert substance such as mineral oil has been aspirated, immediate bronchoscopic suction of the material can be beneficial; however, this is rarely clinically possible. If bronchoscopy is performed, excessive fluid lavage should be avoided because this can force particulate matter deeper into the parenchyma and result in airway obstruction or deep-seated inflammation or infection. General treatment of pneumonia is implemented in the animal that has aspirated, including antimicrobial therapy directed at gastrointestinal and oropharyngeal bacteria, anaerobes, and Mycoplasma (see Chapter 172, Antimicrobial Use in the Intensive Care Patient). In hospitalized patients, parenteral administration of a penicillin and fluoroquinolone is typically advised.10 Intravenous fluid support is usually indicated for supportive care, and airway nebulization can be performed to liquefy secretions. Coupage should not be performed if

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the animal is vomiting or regurgitating. Terbutaline administration (0.01 mg/kg SQ, IM, or IV BID to TID) can be considered in the first 24–48 hours to combat acid-induced bronchoconstriction. If hypoxemia is severe, the animal displays clinical evidence of poor tissue oxygenation, or if exaggerated work of breathing is noted, exogenous oxygen supplementation should be provided. High inspiratory oxygen and long periods of oxygen supplementation should be avoided to limit oxygen-induced lung injury through generation of free radicals and toxic oxygen species (see Chapter 8, Oxygen Toxicity).18 Aspiration pneumonia can progress to acute respiratory distress syndrome, and ventilatory support is required in animals that display severe derangements in gas exchange and/or excessive work of breathing. Importantly, the underlying condition that resulted in aspiration must be identified and aggressively managed in order to avoid further episodes of aspiration and recurrent lung damage. Fortunately, overall survival can approach 75% despite the presence of multiple risk factors for aspiration.19

CONCLUSION Chronic respiratory conditions can be worsened by a variety of events, some easily recognized and others that are more challenging to define. Immediate stabilization of the patient with oxygen and sedation is often the best strategy, followed by investigation of the underlying inciting event with laboratory testing and thoracic radiographs.

REFERENCES 1. Johnson LR, Pollard RE: Tracheal collapse and bronchomalacia in dogs: 58 cases (2001-2008), J Vet Intern Med 24:298-305, 2010. 2. Johnson LR, Vernau W: Bronchoalveolar lavage lymphocytosis in 104 dogs (2006-2016), J Vet Intern Med 33(3):1315-1321, 2019. 3. Johnson LR, Johnson EG, Hulsebosch SE, Dear JD, Vernau W: Eosinophilic lung disease in 76 dogs (2006-2016), J Vet Intern Med 33:2217-2226, 2019. 4. Cannon MS, Johnson LR, Pesavento PA, Kass PH, Wisner ER: Quantitative and qualitative computed tomographic characteristics of bronchiectasis in 12 dogs, Vet Radiol Ultrasound 54:351-357, 2013. 5. Nafe L, Robertson ID, Hawkins EC: Cervical lung lobe herniation in dogs identified by fluoroscopy, Can Vet J 54:955-959, 2013. 6. Johnson LR, Queen EV, Vernau W, Sykes JE, Byrne BA: Microbiologic and cytologic assessment of bronchoalveolar lavage fluid in dogs with lower respiratory tract infection, J Vet Intern Med 27:259-267, 2013. 7. Jeung SY, Sohn SJ, An JH, et al: A retrospective study of theophyllinebased therapy with tracheal collapse in small-breed dogs: 47 cases (2013-2017), J Vet Sci 20(5):e57, 2019. doi:10.4142/jvs.2019.20.e57. 8. Cavett CL, Li Z, McKiernan BC, Reinhart JM: Pharmacokinetics of a modified, compounded theophylline product in dogs, J Vet Pharmacol Ther 42:593-601, 2019. doi:10.1111/jvp.12813. 9. Sumner CM, Rozanski EA, Sharp CR, Shaw SP: The use of deep oral swabs as a surrogate for transoral tracheal wash to obtain bacterial cultures in dogs with pneumonia, J Vet Emerg Crit Care 21:515-520, 2011. 10. Lappin MR, Blondeau J, Boothe D, et al: Antimicrobial use guidelines for treatment of respiratory tract disease in dogs and cats: antimicrobial guidelines working group of the International Society for Companion Animal Infectious Diseases, J Vet Intern Med 31(2):279-295, 2017. 11. De Lorenzi D, Bertoncello D, Drigo M: Bronchial abnormalities found in a consecutive series of 40 brachycephalic dogs, J Am Vet Med Assoc 235:835-840, 2009. https://doi.org/10.2460/javma.235.7.835. 12. Singh MK, Johnson LR, Kittleson MD, Pollard RE: Bronchomalacia in dogs with myxomatous mitral valve degeneration, J Vet Intern Med 26:312-319, 2012. 13. Ferasin L, Crews L, Biller DS, Lamb KE, Borgarelli M: Risk factors for coughing in dogs with naturally acquired myxomatous mitral valve disease, J Vet Intern Med 27:286-292, 2013.

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14. Johnson LR, Stern JA: Clinical features and outcome in 25 dogs with respiratory-associated pulmonary hypertension treated with sildenafil, J Vet Intern Med 34:65-73, 2020. 15. Bach JF, Rozanski EA, Bedenice D, et al: Association of expiratory airway dysfunction with marked obesity in healthy adult dogs, Am J Vet Res 68:670-675, 2007. 16. Kogan DA, Johnson LR, Jandrey KE, Pollard RE: Clinicopathologic and radiographic findings in dogs with aspiration pneumonia: 88 cases (2004-2006), J Am Vet Med Assoc 233:1642-1747, 2008. 17. Tart KM, Babski DM, Lee JA: Potential risks, prognostic indicators, and diagnostic and treatment modalities affecting survival in dogs with

presumptive aspiration pneumonia: 125 cases (2005-2008), J Vet Emerg Crit Care 20:319-329, 2010. 18. Knight PR, Kurek C, Davidson BA, et al: Acid aspiration increases sensitivity to increased ambient oxygen concentrations, Am J Physiol Lung Cell Mol Physiol 278:L1240-L1247, 2000. 19. Kogan DA, Johnson LR, Sturges BK, Jandrey KE, Pollard RE: Etiology and clinical outcome in dogs with aspiration pneumonia: 88 cases (2004-2006), J Am Vet Med Assoc 233:1748-1755, 2008.

22 Pulmonary Hypertension Lance C. Visser, DVM, MS, DACVIM (Cardiology), Yu Ueda, DVM, PhD, DACVECC

KEY POINTS • Pulmonary hypertension (PH) is caused by increased pulmonary blood flow, increased pulmonary vascular resistance, increased pulmonary venous pressure, or a combination thereof. It represents an abnormal hemodynamic condition and not a disease in and of itself. • PH can exacerbate clinical signs and worsen the prognosis of certain diseases, ultimately leading to right heart failure. • Echocardiography performed by a skilled and knowledgeable operator represents a key clinical tool to diagnose PH. • PH is classified into groups of similar diseases/conditions, which includes PH secondary to 1) pulmonary arterial hypertension,

2) left-sided heart disease, 3) respiratory disease/hypoxia, 4) pulmonary thrombi/thromboemboli, 5) parasitic diseases (heartworm or Angiostrongylus infection), or 6) multifactorial or unclear mechanisms. • Optimal management of clinically significant PH is best accomplished by determining and treating the underlying disease, and, in most cases, a PH-specific treatment such as a phosphodiesterase5 inhibitor (sildenafil or tadalafil). • Phosphodiesterase-5 inhibitors are not first-line therapy for dogs with PH secondary to left heart disease/failure (e.g., myxomatous mitral valve disease).

DEFINITIONS AND TERMINOLOGY

vascular disease, or both. In several diseases this is the primary cause of (precapillary) PH. However, increased pulmonary blood flow (e.g., from a left-to-right cardiac shunt) or, as previously described, chronically increased pulmonary venous pressure (from left-sided heart disease) can also lead to increases in PVR. This is thought to occur secondary to reactive vasoconstriction, pulmonary vascular disease (wall stiffening, endothelial dysfunction, vascular inflammation & thrombosis, and fibrosis), or both.2-4 Increased PVR results in increased RV afterload. This triggers RV hypertrophy, which is typically a mixed hypertrophy (wall thickening and chamber dilation). Over time, sustained increases in PAP can cause RV dysfunction/failure largely because the RV is not well suited to sustained pressure overloads. Clinically, this manifests as right-sided heart failure, i.e., increased systemic venous pressures and subsequent pleural and/or abdominal effusions.

Pulmonary hypertension (PH) is not a defining characteristic of a specific disease. It represents a hemodynamic and pathophysiologic state that might be present in and contribute to the morbidity and mortality in a broad spectrum of diseases. It is defined by abnormally increased pressure within the pulmonary vasculature. In humans, PH has been defined by a mean pulmonary arterial pressure (PAP) $25 mm Hg at rest measured invasively by right heart catheterization.1 PH can be caused by 1) increased pulmonary blood flow (cardiac output), 2) increased pulmonary vascular resistance (PVR), 3) increased pulmonary venous pressure or some combination thereof (Table 22.1). PH caused by increased PVR in the absence of increased pulmonary venous pressure is called precapillary PH. This is typically the result of vasoconstriction, structural pulmonary arterial changes due to pulmonary vascular disease, or both. PH associated with increased pulmonary venous pressure is called postcapillary PH (also called pulmonary venous hypertension). Postcapillary PH occurs secondary to left-sided heart disease and increased left atrial (LA) pressure. Increased LA pressure and subsequently increased pulmonary venous pressure ultimately increases the load the right ventricle (RV) has to pump through the pulmonary circulation. Chronic postcapillary PH (typically from severe left heart disease or failure) can lead to pulmonary arterial vasoconstriction and pulmonary vascular disease, which increases PVR. Therefore, postcapillary PH can occur in isolation (isolated postcapillary PH, also called “passive PH”) or can be paired with increased PVR (combined postcapillary and precapillary PH, also called “reactive PH”) as a result of chronic, severe left-sided heart disease.

PATHOPHYSIOLOGY Sustained increases in PAP result from increases in PVR due to pulmonary artery (arteriolar) vasoconstriction, pulmonary arterial remodeling/

ASSESSMENT OF PH The gold standard method for the assessment of PH is right heart catheterization with direct assessment of PAP and pulmonary artery wedge pressure (surrogate of LA pressure), where cardiac output can be measured and PVR can be calculated. This is rarely performed in clinical patients. Thus, veterinarians rely heavily on echocardiography and other supportive clinical findings for the noninvasive assessment of PH. Because echocardiography does not provide a definitive diagnosis, it should be viewed as a clinical tool to help assess the probability that a patient has PH (versus a definitive diagnosis of PH).5-7 The American College of Veterinary Internal Medicine (ACVIM) consensus guidelines on PH provide criteria to help assess the probability (low, intermediate, or high) that a patient has clinically significant PH using echocardiography.7 Details of echocardiographic assessment of PH are beyond the scope of this chapter but the criteria involve two key components:

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TABLE 22.1  Mechanisms for the

Development of Pulmonary Hypertension (PH) Mechanisms of PH*

Examples of Causes

Increased pulmonary blood flow

Left-to-right shunt due to intra- or extracardiac defects (e.g., patent ductus arteriosus, ventricular septal defect, atrial septal defect) Pulmonary arterial (arteriolar) vasoconstriction Pulmonary arterial thrombosis Pulmonary endothelial dysfunction Pulmonary vascular remodeling Perivascular inflammation Pulmonary vascular luminal obstruction Increased blood viscosity Pulmonary arterial wall stiffening Pulmonary parenchymal destruction Left heart disease (e.g., myxomatous mitral valve disease) Compression or stenosis of a large pulmonary vein(s)

Increased pulmonary vascular resistance

Increased pulmonary venous pressure

*Combinations of the mechanisms of PH are possible. Dogs with chronic and progressive left heart disease and increased pulmonary venous pressure can develop increased pulmonary vascular resistance (combined postcapillary and precapillary PH). Dogs with leftto-right shunts can also develop increased pulmonary vascular resistance.

1) characteristic cardiac changes that occur secondary to PH (so-called echocardiographic signs of PH) and 2) estimates of systolic PAP using Doppler echocardiography. Echocardiographic changes commonly seen with PH include structural or functional changes of the ventricles (e.g., RV hypertrophy and systolic dysfunction, left ventricular underfilling, flattening of the interventricular septum), pulmonary artery (e.g., dilation and altered blood flow profile), and right atrium (RA)/caudal vena cava (i.e., enlargement). In the absence of a RV outflow tract obstruction, estimating systolic PAP using echocardiography largely involves quantifying peak tricuspid regurgitation velocity (TRV). This can be converted to a pressure gradient (between the RA and RV in systole) using the simplified Bernoulli equation: pressure gradient 5 4 3 velocity [m/s]2 This pressure gradient has been conventionally used to quantify the degree of PH as mild (30–50 mm Hg), moderate (50–75 mm Hg), and severe (.75 mm Hg). However, the ACVIM consensus guidelines point out these cutoffs are arbitrary and potentially inaccurate and misleading.7 Severity of clinical signs, degree of structural and functional changes identified by echocardiography, and the TRV are likely more accurate to determine the severity of PH. Clinically significant PH is unlikely unless clinical signs are apparent (Table 22.2) and at least an intermediate probability of PH is present as determined by echocardiographic examination by a skilled sonographer.7 This involves a TRV cutoff of .3.4 m/s (pressure gradient .46 mm Hg). The proposed criteria set forth by the ACVIM consensus guidelines are intended to avoid a misdiagnosis and inappropriate treatment of PH that might have a lasting impact or, in some cases, cause harm. It should also be recognized that echocardiography represents one, albeit important, aspect of the assessment of PH. Echocardiographic findings should always be interpreted within the clinical context and in light of other diagnostic tests.

TABLE 22.2  Clinical Signs/Findings

that Might be Associated with Clinically Significant Pulmonary Hypertension (PH)* Strongly Suggestive of PH

Possibly Suggestive of PH

Syncope (especially with exertion or excitement) Respiratory distress at rest Activity/exercise terminating in respiratory distress Right heart failure (cardiogenic ascites)

Tachypnea at rest Increased respiratory effort at rest Prolonged postexercise/activity tachypnea

*None of these clinical signs/findings are specific to PH and should be interpreted within the clinical context. Adapted from the American College of Veterinary Internal Medicine consensus guidelines.7

CLASSIFICATION OF PH In addition to the hemodynamic classification (i.e., precapillary PH, postcapillary PH), the ACVIM consensus guidelines have proposed a clinical classification scheme for PH in dogs that consists of six groups: PH secondary to 1) pulmonary arterial hypertension (PAH), 2) leftsided heart disease (LHD), 3) respiratory disease/hypoxia, 4) pulmonary thrombotic or thromboembolic disease (PT/PTE), 5) parasitic disease (heartworm or Angiostrongylus), and 6) multifactorial or unclear mechanisms (Table 22.3). These groups are modeled after the classification scheme used in humans8 and are grouped based on similarities in the causes of PH, including clinical presentation, hemodynamic characteristics, pathophysiology, and treatment. A summary of the terminology, hemodynamic definitions, and echocardiographic findings with the corresponding clinical classification is presented in Table 22.4. Due to the high prevalence of subclinical myxomatous mitral valve disease (MMVD) in middle-aged to older dogs, one specific classification warrants brief discussion. For PH to be considered secondary to LHD (e.g., MMVD), two criteria must be met via echocardiography: 1) documentation of LHD, and, importantly, 2) documentation of unequivocal LA enlargement.7 Documentation of LA enlargement serves as a surrogate, albeit crude, marker for chronically increased LA pressure (postcapillary PH). In other words, it should be considered very unlikely for PH to be secondary to LHD/MMVD unless unequivocal LA enlargement is identified. In the authors’ experience, PH secondary to PAH (group 1) or respiratory disease/hypoxia (group 3) are frequently encountered in dogs with incidentally detected subclinical MMVD without LA enlargement. These dogs should be considered to have PH secondary to PAH (group 1) and respiratory disease/hypoxia (group 3), respectively, and not LHD (group 2).

CLINICAL FINDINGS Clinical findings of animals affected with PH are variable and largely reflect the underlying cause of PH. The severity of clinical signs generally relates to the severity of PH. Clinical findings commonly seen in animals with PH are presented in Table 22.2. Syncope (especially following exertion), respiratory difficulty, and exercise intolerance are among the most common clinical signs reported that are suggestive of PH in dogs.9-11 Physical examination might reveal abnormal respiratory sounds, tachypnea, apparent dyspnea, cyanotic or pale mucous

CHAPTER 22  Pulmonary Hypertension

TABLE 22.3  Classification of Pulmonary

Hypertension (PH) in Dogs Proposed by the American College of Veterinary Internal Medicine Consensus Guidelines7 Classification and examples of diseases/conditions in each group Group 1. Pulmonary arterial hypertension (PAH) 1a. Idiopathic (IPAH) 1b. Heritable 1c. Drugs and toxins induced 1d. Associated with (APAH) 1d1. Congenital cardiac shunts 1d2. Pulmonary vasculitis 1d3. Pulmonary vascular amyloid deposition 1e. Pulmonary vasoocclusive disease or pulmonary capillary hemangiomatosis Group 2. PH secondary to left heart disease 2a. Left ventricular dysfunction 2a1. Canine dilated cardiomyopathy 2a2. Myocarditis 2b. Valvular disease 2b1. Acquired 2b1a. Myxomatous mitral valve disease 2b1b. Valvular endocarditis 2c. Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies 2c1. Mitral valve dysplasia 2c2. Mitral valve stenosis 2c3. Aortic stenosis Group 3. PH secondary to respiratory disease, hypoxia or both 3a. Chronic obstructive airway disorders 3a1. Tracheal or mainstem bronchial collapse 3a2. Bronchomalacia 3b. Primary pulmonary parenchymal disease 3b1. Interstitial lung disease 3b1a. Fibrotic lung disease 3b1b. Cryptogenic organizing pneumonia/secondary organizing pneumonia 3b1c. Pulmonary alveolar proteinosis 3b1d. Unclassified interstitial lung disease 3b1e. Eosinophilic pneumonia/eosinophilic bronchopneumopathy 3b2. Infectious pneumonia, pneumocystis 3b3. Diffuse pulmonary neoplasia 3c. Obstructive sleep apnea/sleep disordered breathing, brachycephalic obstructive airway syndrome 3d. Chronic exposure to high altitude 3e. Developmental lung disease 3f. Miscellaneous: bronchiolar disorders, bronchiectasis, emphysema, postpneumonectomy Group 4. PH secondary to pulmonary thrombus/thromboembolism (PT/PTE) 4a. Acute PT/PTE 4b. Chronic PT/PTE Group 5. PH secondary to parasitic disease (Dirofilaria, Angiostrongylus infection) Group 6. PH with multifactorial or unclear etiologies 6a. Disorders having clear evidence of two or more underlying Groups 1–5 pathologies contributing to PH 6b. Masses compressing the pulmonary arteries (e.g., neoplasia, fungal granuloma) 6c. Other disorders with unclear mechanisms

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membranes, jugular venous distension or pulsation, and/or ascites from right heart failure. Cardiac auscultation might yield a loud or split second heart sound. Systolic heart murmurs over the mitral (secondary to concurrent MMVD) and/or tricuspid valve are common. Loud murmurs over the tricuspid valve region are highly suggestive of PH in dogs with MMVD.12

DIAGNOSTIC EVALUATION From a critical care perspective, veterinarians should know when to request an echocardiographic examination for assessment of PH, i.e., when the aforementioned clinical findings (Table 22.2), physical examination, baseline bloodwork, and thoracic imaging are present without another clear etiology. A common clinical scenario when assessment for PH may be warranted is a dog that has experienced syncope that is not associated with a brady- or tachyarrhythmia, severe heart disease/failure, neurologic disease, or severe metabolic/hematologic derangements. Unexplained abdominal effusion (modified transudates) coupled with a dilated caudal vena cava should also warrant an echocardiographic examination to assess the probability of PH. Right heart failure secondary to PH is a more likely explanation in this scenario. The ACVIM consensus guidelines provide other clinical scenarios and should be reviewed for additional guidance.7 These guidelines also provide suggested diagnostic evaluations for dogs with an intermediate or high probability of PH. Determining the underlying cause of PH is highly recommended because it is of key importance for optimal clinical management of PH.

CLINICAL MANAGEMENT Clinical management of PH centers around treatment of the underlying disease(s)/factors contributing to the PH in addition to PHspecific treatment. General recommendations such as oxygen supplementation (as indicated and at least in the short term), heartworm prevention, exercise restriction, and avoiding air travel and high altitude (without oxygen supplementation) also seem prudent. A discussion of specific treatments of the underlying disease(s) contributing to PH are beyond the scope of this chapter; some recommendations are provided elsewhere7 and in other chapters. A consultation with a specialist may be beneficial. The most common PH-specific treatment used in dogs is phosphodiesterase-5 inhibitors (PDE5i), which cause accumulation of cyclic guanosine monophosphate (cGMP) in pulmonary vascular smooth muscle cells by inhibiting cGMP catabolism. Accumulation of cGMP results in relaxation of vascular smooth muscle and inhibition of pulmonary arterial smooth muscle cell hypertrophy. PDE5i drugs are generally effective at lowering PVR and potentially delaying adverse remodeling of pulmonary arteries, both of which represent the primary therapeutic target for patients with precapillary PH. PDE5i’s are also thought to increase the cGMP concentration in the myocardium and augment myocardial function and limit cardiac hypertrophy.13 Sildenafil (1–3 mg/kg PO q8h) is a highly selective PDE5i, and several studies have suggested a clinical benefit (improved clinical signs, quality of life, and exercise capacity) in dogs with PH.10,14-16 However, a PDE5A gene polymorphism has been identified,17 and one study has suggested that the polymorphism can blunt the effectiveness of sildenafil in dogs with PH.14 Sildenafil is ideally administered every 8 hours given its short half-life.18 Another PDE5i medication with a longer half-life, tadalafil, appears to be a reasonable alternative. Tadalafil can be administered every 24 hours (2 mg/kg PO q24h). In a randomized double-blinded pilot study comparing sildenafil and tadalafil, tadalafil

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did not cause any significant differences in improvements in clinical signs, quality of life, or outcome.19 Additional PH-specific therapies have been proposed for use in dogs and include phosphodiesterase 3 inhibitors (pimobendan, milrinone), tyrosine kinase inhibitors (toceranib, imatinib), and L-arginine. These therapies are not routinely recommended. The reader is referred elsewhere for further discussion of these therapies.7 The decision to start PDE5i therapy should be made based on an echocardiographic examination performed by a skilled and knowledgeable sonographer (cardiology specialist in most cases). In general, a PDE5i is only recommended in dogs with clinical signs/findings suggestive of PH and an intermediate or high echocardiographic probability of PH (precapillary PH), i.e., when significant right heart remodeling has been demonstrated (in the absence of other causes), TRV is .3.4 m/s, or both.7 Provided these conditions are met, treatment with a PDE5i can be considered for dogs with PH classified in groups 1 and 3–5. Use of PDE5i in dogs in group 2 are discussed below. PH-specific treatment in dogs in group 6 are made on a caseby-case basis. Empirical use of PDE5i therapy is discouraged and PDE5i treatment should be used with caution in dogs with PH secondary to LHD since treatment could induce pulmonary edema in these patients. In dogs with PH secondary to LHD, increased PVR may (combined postcapillary and precapillary PH) or may not (isolated postcapillary PH) be present (Table 22.4). Thus, first-line therapy is centered around decreasing LA pressure (e.g., furosemide and pimobendan in dogs with MMVD) and management of heart failure, if present. First-line therapy should not include a PDE5i because administering a PDE5i to a dog without increased PVR or with increased PVR but with especially responsive pulmonary arterioles will likely acutely increase right heart cardiac output and venous return to the LA. This will increase LA, pulmonary venous, and pulmonary capillary pressure, potentially culminating in iatrogenic pulmonary edema. As previously described, some dogs with PH secondary to LHD develop combined postcapillary and precapillary PH and predicting vascular responsiveness to a PDE5i in this situation is difficult. Thus, PDE5i should only be considered (typically starting with conservative doses e.g., sildenafil 0.5 mg/kg PO q8h) if dogs remain symptomatic following strategies to lower LA pressure and if left heart failure is well controlled (if initially present) or if right heart failure is present.7 Close monitoring of breathing rate and effort is advised.

Critical Care Management of PH Animals with PH may require critical care management due to acute decompensation of hemodynamic and oxygenation status as a result of PH progression or because of triggering factors (e.g., PTE, arrhythmia, sepsis, and fluid overload). These animals may present with right heart failure and systemic hypotension with low cardiac output and/or respiratory distress and hypoxemia. The initial management should focus on addressing any potential triggering factors and reducing the RV afterload by administering PDE5i.20,21 In addition, respiratory and hemodynamic resuscitation should be attempted as soon as possible. Providing oxygen therapy and meticulous fluid volume management to optimize the preload are important, as hypervolemia can have detrimental effects. In some cases, diuretics are often indicated to optimize blood volume and RV preload. In cases of severe decompensation (impaired cardiac output due to severe RV systolic dysfunction) positive inotropic therapy should be considered. In humans, low-dose dobutamine is often utilized as a first-line inotrope; however, dobutamine might worsen systemic hypotension because of its vasodilatory effect. In case of persistent systemic hypotension, norepinephrine could also be considered because it increases systemic vascular resistance and RV contractility (see Chapter 147, Catecholamines).21

PROGNOSIS AND MONITORING The prognosis for dogs with PH is variable and linked to the cause and severity of the underlying disease(s) causing the PH. PH might be reversible in some cases but is likely to worsen survival in most diseases when compared with dogs affected with the same disease that do not suffer from PH. Studies have shown that PH worsens the prognosis of dogs affected with MMVD22 and respiratory disease/hypoxia.23,24 Clinical experience suggests that dogs with right heart failure secondary to PH have a worse prognosis. Monitoring response to PH-specific therapy is advised. This should largely be tailored to the individual patient. Clinical response to therapy is the most important and typically involves reassessment of clinical signs or adverse clinical findings. The utility of performing repeat echocardiographic examinations for all cases of PH is debatable but unlikely to be necessary. Improvement in echocardiographic variables (e.g., TRV and estimated PAP) is not always documented following administration of PDE5i. However, this should not dissuade the use of PH-specific therapy or trigger dose adjustments if clinical response is otherwise positive.

TABLE 22.4  Summary of the Terminology, Hemodynamic Classification, Key Echocardiographic

Findings, and Clinical Classification Groups Related to Pulmonary Hypertension (PH) Hemodynamic Classification

Key Echocardiographic Findings

Clinical Classification Group

Precapillary PH • Increased PVR • LA pressure not increased

• No LA enlargement • Structural or functional changes of the RV, pulmonary artery, or RA/caudal vena cava are expected

Postcapillary PH • Isolated postcapillary PH • Increased LA pressure • PVR not increased • Combined postcapillary and precapillary PH • Increased LA pressure • Increased PVR

• Unequivocal LA enlargement • No/minimal structural or functional changes of the RV, pulmonary artery, or RA/caudal vena cava

Group 1. Pulmonary arterial hypertension* Group 3. Respiratory disease/hypoxia Group 4. Thrombi/thromboemboli Group 5. Parasitic disease Group 6. Multifactorial/unclear mechanisms Group 2. Left heart disease

• Unequivocal LA enlargement • Structural or functional changes of the RV, pulmonary artery, or RA/caudal vena cava are expected

Group 2. Left heart disease Group 6. Multifactorial/unclear mechanisms

LA, left atrial; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; RA, right atrial; RV, right ventricle. *With shunting lesions, the primary abnormality might be increased right heart cardiac output and not solely increased pulmonary vascular resistance. Adapted from the American College of Veterinary Internal Medicine consensus guidelines.7

CHAPTER 22  Pulmonary Hypertension

REFERENCES 1. Hoeper MM, Bogaard HJ, Condliffe R, et al: Definitions and diagnosis of pulmonary hypertension, J Am Coll Cardiol 62(Suppl 25):D42-D50, 2013. 2. Thenappan T, Ormiston ML, Ryan JJ, Archer SL: Pulmonary arterial hypertension: pathogenesis and clinical management, BMJ 360:j5492, 2018. 3. Guazzi M, Arena R: Pulmonary hypertension with left-sided heart disease, Nat Rev Cardiol 7(11):648-659, 2010. 4. Guazzi M, Naeije R: Pulmonary hypertension in heart failure: pathophysiology, pathobiology, and emerging clinical perspectives, J Am Coll Cardiol 69(13):1718-1734, 2017. 5. Augustine DX, Coates-Bradshaw LD, Willis J, et al: Echocardiographic assessment of pulmonary hypertension: a guideline protocol from the British Society of Echocardiography, Echo Res Pract 5(3):G11-G24, 2018. 6. Galiè N, Humbert M, Vachiery JL, et al: 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT), Eur Heart J 37(1):67-119, 2016. 7. Reinero C, Visser LC, Kellihan HB, et al: ACVIM consensus statement guidelines for the diagnosis, classification, treatment, and monitoring of pulmonary hypertension in dogs, J Vet Intern Med 34(2):549-573, 2020. 8. Simonneau G, Gatzoulis MA, Adatia I, et al: Updated clinical classification of pulmonary hypertension, J Am Coll Cardiol 62(Suppl 25):D34-D41, 2013. 9. Campbell FE: Cardiac effects of pulmonary disease, Vet Clin North Am Small Anim Pract 37(5):949-962, vii, 2007. 10. Kellum HB, Stepien RL: Sildenafil citrate therapy in 22 dogs with pulmonary hypertension, J Vet Intern Med 21(6):1258-1264, 2007. 11. Kellihan HB, Stepien RL: Pulmonary hypertension in dogs: diagnosis and therapy, Vet Clin North Am Small Anim Pract 40(4):623-641, 2010. 12. Ohad DG, Lenchner I, Bdolah-Abram T, Segev G: A loud right-apical systolic murmur is associated with the diagnosis of secondary pulmonary arterial hypertension: retrospective analysis of data from 201 consecutive client-owned dogs (2006-2007), Vet J 198(3):690-695, 2013. 13. Schwartz BG, Levine LA, Comstock G, Stecher VJ, Kloner RA: Cardiac uses of phosphodiesterase-5 inhibitors, J Am Coll Cardiol 59(1):9-15, 2012.

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14. Ueda Y, Johnson LR, Ontiveros ES, Visser LC, Gunther-Harrington CT, Stern JA: Effect of a phosphodiesterase-5A (PDE5A) gene polymorphism on response to sildenafil therapy in canine pulmonary hypertension, Sci Rep 9(1):6899, 2019. 15. Brown AJ, Davison E, Sleeper MM: Clinical efficacy of sildenafil in treatment of pulmonary arterial hypertension in dogs, J Vet Intern Med 24(4):850-854, 2010. 16. Bach JF, Rozanski EA, MacGregor J, Betkowski JM, Rush JE: Retrospective evaluation of sildenafil citrate as a therapy for pulmonary hypertension in dogs, J Vet Intern Med 20(5):1132-1135, 2006. 17. Stern JA, Reina-Doreste Y, Chdid L, Meurs KM: Identification of PDE5A:E90K: a polymorphism in the canine phosphodiesterase 5A gene affecting basal cGMP concentrations of healthy dogs, J Vet Intern Med 28(1):78-83, 2014. 18. Akabane R, Sato T, Sakatani A, Miyagawa Y, Tazaki H, Takemura N: Pharmacokinetics of single-dose sildenafil administered orally in clinically healthy dogs: effect of feeding and dose proportionality, J Vet Pharmacol Ther 41(3):457-462, 2018. 19. Jaffey JA, Leach SB, Kong LR, Wiggen KE, Bender SB, Reinero CR: Clinical efficacy of tadalafil compared to sildenafil in treatment of moderate to severe canine pulmonary hypertension: a pilot study, J Vet Cardiol 24: 7-19, 2019. 20. Savale L, Weatherald J, Jaïs X, et al: Acute decompensated pulmonary hypertension, Eur Respir Rev 26(146), 2017. 21. Hoeper MM, Granton J: Intensive care unit management of patients with severe pulmonary hypertension and right heart failure, Am J Respir Crit Care Med 184(10):1114-1124, 2011. 22. Borgarelli M, Abbott J, Braz-Ruivo L, et al: Prevalence and prognostic importance of pulmonary hypertension in dogs with myxomatous mitral valve disease, J Vet Intern Med 29(2):569-574, 2015. 23. Johnson LR, Stern JA: Clinical features and outcome in 25 dogs with respiratory-associated pulmonary hypertension treated with sildenafil, J Vet Intern Med 34(1):65-73, 2020. 24. Jaffey JA, Wiggen K, Leach SB, Masseau I, Girens RE, Reinero CR: Pulmonary hypertension secondary to respiratory disease and/or hypoxia in dogs: clinical features, diagnostic testing and survival, Vet J 251:105347, 2019.

23 Pulmonary Edema Sophie Adamantos, BVSc, CertVA, DACVECC, DECVECC, MRCVS, FHEA, Dez Hughes, BVSc (Hons), DACVECC

KEY POINTS • Pulmonary edema is a common cause of dyspnea in dogs and cats. • Two main pathophysiologic forms exist: high hydrostatic pressure edema and increased permeability edema. • The most common cause of pulmonary edema in dogs and cats is cardiogenic edema. • The prognosis for animals with pulmonary edema and the response to therapy depends on the underlying cause.

• Cardiogenic pulmonary edema usually responds well to loop diuretic therapy, whereas noncardiogenic pulmonary edema responds less readily to treatment. • Fluid therapy should be administered with caution in all patients with pulmonary edema.

Pulmonary edema is the accumulation of extravascular fluid within the pulmonary parenchyma or alveoli. The two main pathophysiologic forms are high hydrostatic pressure edema (due to increased pulmonary capillary hydrostatic pressure) and increased permeability edema (due to damage of the microvascular barrier and alveolar epithelium in more severe cases). Pulmonary edema is a relatively common disease process in veterinary patients that can quickly become life threatening. The diagnostic approach to pulmonary edema is to rapidly determine whether it is cardiogenic (i.e., caused by left-sided cardiac failure) or noncardiogenic edema (all the causes other than failure of the left side of the heart). Recent advances in knowledge and skill set in point-of-care ultrasound allow rapid identification of pulmonary edema and the presence of cardiac disease.

Pulmonary edema occurs when the rate of interstitial fluid formation overwhelms the protective fluid clearance mechanisms. Hydrostatic pressure is the main determinant of fluid extravasation and edema formation in the lungs,6 providing the rationale for using hydrostatic pressure modulators in the treatment of all forms of pulmonary edema. The pulmonary ultrastructure is designed to protect gaseous diffusion. Most interstitial fluid flow is on the side of the capillary opposite to that where gas exchange occurs (see Fig. 16.3), and the distensibility of the lung interstitium increases toward the peribronchovascular region. This results in initial fluid accumulation in areas not used for gas exchange.7 High hydrostatic pressure edema forms as a result of increasing pulmonary capillary pressure leading to fluid extravasation that eventually overwhelms the lymphatic removal capacity. Fluid initially flows toward the peribronchovascular interstitium, then distends all parts of the pulmonary interstitium and eventually spills into the airspaces at the junction of the alveolar and airway epithelia.6 In many animals with cardiogenic edema, the increase in pressure occurs gradually and overt edema may develop over a period of months; however, if there are acute increases in hydrostatic pressure (e.g., chordae tendineae rupture) then edema will form rapidly. Increased permeability edema occurs secondary to injury to the microvascular barrier and alveolar epithelium, resulting in extravasation of fluid with a high protein content.6 Any protective fall in COP is thereby diminished, so the hydrostatic pressure becomes the main determinant of edema formation. Interstitial fluid accumulation can then occur at even lower hydrostatic pressures and relatively small rises in pressure can result in greater edema formation. In more severe cases in which the alveolar epithelium is also damaged, a direct conduit may form between the intravascular space and the alveoli, and interstitial edema progresses rapidly to alveolar flooding. This explains the greater severity and fulminant course of increased permeability edema compared with hydrostatic edema. Although the lymphatic system plays a major role in limiting interstitial fluid accumulation, it has only a minor role in the clearance of

PATHOPHYSIOLOGY In normal tissues, transvascular fluid fluxes are determined by the capillary hydrostatic pressure, interstitial hydrostatic pressure, capillary colloid osmotic pressure (COP), the COP beneath the endothelial glycocalyx, and the reflection and filtration coefficients for the tissues.1 The filtration coefficient is a measure of fluid efflux from the vasculature of specific tissues and is dependent on the capillary surface area and hydraulic conductivity. The reflection coefficient indicates the relative permeability of the membrane to protein. In tissues with a nondistensible interstitium, such as the lung, increased interstitial hydrostatic pressures and increased driving pressure for lymphatic flow (which can increase up to 10 times normal) protect the lung against edema. The pulmonary capillary microvascular barrier is relatively permeable to protein compared with other tissues,2 so this increased lymphatic flow is largely responsible for protecting the lung against edema.3 The reduced role of the COP gradient also helps explain why hypoproteinemia per se rarely results in pulmonary edema. Some studies have demonstrated that the pulmonary glycocalyx is thicker than in other tissues,4,5 and is lost during endotoxemia,5 but the understanding of the role of the pulmonary glycocalyx in transvascular fluid flux is still in its infancy.

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CHAPTER 23  Pulmonary Edema pulmonary edema. Most fluid is cleared via the bronchial circulation, probably because most fluid tends to accumulate in the peribronchovascular areas.8 The rate of resolution depends on the fluid type, with pure water being reabsorbed much more rapidly than fluid containing macromolecules (including artificial colloids) and cells.

CLINICAL PRESENTATION Pulmonary edema results in reduced oxygenation (usually as a result of ventilation–perfusion mismatching) so most animals have signs of respiratory distress usually with tachypnea. Oxygen should be given to all patients with respiratory distress and the benefits of giving an animal time to recover in a quiet, oxygen-enriched environment cannot be overemphasized. As in all animals presenting with respiratory distress, careful evaluation of the patient is necessary to prioritize problems and identify likely differentials. Historical information that should alert the clinician to possible cardiogenic pulmonary edema includes cardiac disease or a murmur/ gallop sound, or previous congestive heart failure. Noncardiogenic pulmonary edema may be associated with environmental exposure to smoke inhalation, near strangulation, electric shock, head trauma or seizures. In some cases, pulmonary edema is a feature of a disease, with patients presenting with clinical signs referable to the primary condition (e.g., sepsis). Physical examination of animals with pulmonary edema will include tachypnea and/or dyspnea. There is controversy regarding whether cough is a major feature of pulmonary edema specifically, rather than a feature of the primary disease process or coexistent diseases.9 Lung sounds will generally be increased in animals with pulmonary edema and careful auscultation will usually reveal the presence of pulmonary crackles or louder and coarser lung sounds. These may be difficult to hear in dogs and cats with low tidal volumes or high respiratory rates. Careful auscultation may allow the abnormal lung sounds to be localized to one region and this may aid in the diagnosis, such as a cranioventral distribution with aspiration pneumonia and a perihilar distribution with cardiogenic pulmonary edema in the dog.

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congestion, which in its most life-threatening form is pulmonary edema. As a result of chronic increases in blood volume, the capillary pressure at which edema forms is higher than in the normal dog or cat. In severe cases, blood vessel rupture may occur, leading to a serosanguineous appearance of secretions, as evidenced by pink frothy sputum. There are a few common diseases that cause cardiogenic pulmonary edema, and signalment can be extremely useful in narrow diagnoses. Middle-aged, large breed dogs tend to have dilated cardiomyopathy, whereas the smaller breeds tend to have mitral valve disease. Cats are more prone to myocardial disease, with hypertrophic and restrictive cardiomyopathies seen most commonly.11,12

Fluid Therapy Fluid therapy is an uncommon cause of pulmonary edema without preexisting heart or lung disease, due to the effective safety mechanisms within the lung. However, fluid therapy may cause rapid increases in hydrostatic pressure in animals with preexisting (although asymptomatic) heart disease, leading to pulmonary edema. Experimental studies have demonstrated that dogs are able to cope with large volumes: dosages of 360 ml/kg of crystalloid over 1 hour were given before severe fluid overload was seen.13 Clinically, it appears that cats are more likely to develop respiratory signs associated with fluid overload than dogs, although this and the relative incidence of pulmonary edema versus pleural effusion are poorly documented in the literature. One retrospective case series demonstrated that cats with urethral obstruction that developed volume overload developed respiratory signs. Cats were more likely to develop signs of fluid overload if they received a fluid bolus or developed a murmur or gallop during treatment. Most of the cats that were assessed with echocardiogram had evidence of underlying heart disease.14 Other reasons for this might include relative overdosing of fluid therapy as cats have a lower blood volume than dogs and a reduced capacity to cope with extra intravascular volume.15 When there are other risk factors, such as systemic inflammation and pulmonary parenchymal disease, fluid therapy may more easily lead to pulmonary edema.

High Hydrostatic Pressure Edema

Increased Permeability Edema

Cardiogenic Edema

An increase in permeability is caused by direct injury to the microvascular barrier, alveolar epithelium, or both. Increased permeability edema is synonymous with acute respiratory distress syndrome (ARDS). ARDS (see Chapter 25, Acute Respiratory Distress Syndrome) is the most severe form of increased permeability edema and is extremely difficult to manage. Other causes of increased permeability edema include pneumonia, pulmonary thromboembolism, and ventilator-associated lung injury.

Cardiogenic pulmonary edema is probably the most common form of high-pressure edema. It occurs as a result of left-sided congestive heart failure. Cardiac disease is often chronic, and in dogs there is usually a history of clinical signs consistent with heart disease: cough, orthopnea, exercise intolerance, and usually, a heart murmur. An acute onset of signs may be seen, particularly if there has been a precipitating event such as stress. Cardiac disease is the most common cause of dyspnea in cats,10 and approximately half of cats with left-sided congestive heart failure will have pulmonary edema. Owners may not report premonitory clinical signs prior to the onset of dyspnea in cats, although there may be a precipitating stressful event. Over half of cats presenting with heart failure will have reduced appetite, and weight loss is present in about a third. In contrast to dogs, a significant proportion of cats will not have auscultatable cardiac abnormalities detected, with one study reporting about 20% of cats with left-sided heart failure having no auscultatory abnormalities,11 and a more recent study reported murmurs in 23% cats and a gallop in 23% of cats with heart failure. Gallop sounds are more specifically associated with the presence of heart failure than murmurs.10 Due to the chronic progression of heart disease, compensatory mechanisms result in fluid retention to maintain cardiac output and, although beneficial in the short term, this eventually leads to signs of

Mixed Cause Edema There are a number of other causes of pulmonary edema in which the pathophysiology is incompletely understood that are probably due to a combination of hydrostatic and increased permeability edema. Neurogenic pulmonary edema (NPE) and negative pressure pulmonary edema (NPPE) are probably the most common forms and have been discussed and described synonymously in the veterinary literature. However, it is worth separating these conditions to improve clarity and understanding. NPE is seen following an acute neurological event, such as head trauma or seizures. The proposed mechanism is that there is a surge in intracranial pressure that results in a catecholamine surge. This increases systemic vascular resistance and results in alveolar capillary leakage. A number of mechanisms have been proposed to cause the pulmonary edema. These include direct myocardial injury, altered

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ventricular compliance secondary to the increased systemic and pulmonary pressures, acute transient rise in capillary pressure inducing barotrauma and damage to the capillary alveolar membrane (known as Blast theory16,17), and direct damage to the pulmonary vascular bed due to pulmonary venular adrenergic hypersensitivity. The clinical course of NPE is variable. The edema can form up to 24 hours after the initial insult and is believed to resolve within 48 hours. Radiographic features of NPE in dogs and cats have been reported to be less severe than NPPE18 but are highly variable.19 NPPE is seen following upper airway obstruction.18,19 In some cases the obstruction can appear relatively mild (e.g., a sharp pull on a lead). In these cases, negative intrathoracic pressure is thought to cause the pathophysiological cascade resulting in pulmonary edema. The amount of negative intrathoracic pressure generated is particularly high in young people, and this may be why younger animals seem to be more easily affected by NPPE than older animals. In NPPE the negative intrathoracic pressure increases venous return to the right side of the heart, leading to increased pulmonary venous pressures and decreased perivascular interstitial hydrostatic pressure; there is also increased left ventricular afterload due to transmural pressure across the cardiac wall. This results in the movement of fluid from the pulmonary capillaries into the interstitium and alveoli. Hypoxia causes cardiac dysfunction. Sympathetic stimulation increases venous return secondary to venoconstriction and increased systemic vascular resistance. The end result of these cardiovascular changes is that there is formation of pulmonary edema. NPPE has been documented in both dogs and cats and tends to be acute in onset and resolve within 48 hours. Other forms of edema include reexpansion edema, which has been reported in dogs and cats after acute reexpansion of chronically collapsed lung lobes. Suggested mechanisms include trauma, decreased surfactant levels in collapsed lung tissue, negative interstitial pressure, and oxygen free radical formation and reperfusion injury.

DIAGNOSTIC TESTS Conventionally, thoracic radiographs have been the most widely used diagnostic test for the identification of pulmonary edema; however, they can be highly stressful and should be avoided in the most severely dyspneic patient until initial stabilization with empiric therapy has been attempted. Equipment should be made ready in advance and oxygen supplementation should be available before attempting to radiograph these patients. The distribution of the alveolar pattern can be helpful in discriminating between cardiogenic (Fig. 23.1) and noncardiogenic edema, but nearly all causes of edema can cause a diffuse alveolar pattern. Mild cardiogenic edema in dogs is typically seen in the perihilar region. In cats, however, there tends to be an interstitial-alveolar pattern that can be patchy and almost nodular (Fig. 43.1). Pulmonary veins that are more distended than the pulmonary arteries may also be seen in some cases of left-sided heart failure. A brief echocardiogram may reveal an enlarged left atrium, which raises the likelihood of congestive heart failure; however, dyspneic patients should not be stressed excessively to obtain an echocardiogram. A dorsocaudal alveolar pattern suggests noncardiogenic pulmonary edema; however, a recent case series has described highly variable radiographs in this condition.19 In dyspneic patients, positioning to obtain diagnostic quality radiographs maybe challenging and risky. Because of the challenges obtaining diagnostic radiographs in dyspneic dogs and cats, there has been an increase in the use of point- of-care ultrasound. Pulmonary edema can be suspected based on the presence of increased numbers of B-lines within the lung tissue.

A

B Fig. 23.1  A, Lateral thoracic radiograph of a dog (Doberman Pinscher) showing marked perihilar alveolar infiltrates, an enlarged cardiac silhouette, and left atrial enlargement. This dog had severe congestive heart failure secondary to dilated cardiomyopathy. B, Lateral radiograph of the same dog 3 days later after intensive diuretic, positive inotropic, and vasodilator therapy (furosemide, dobutamine, pimobendan, and nitroprusside). There is marked improvement in the alveolar pattern, although mild perihilar infiltrates are still present.

Although other lung conditions may be associated with B-lines (e.g., other interstitial or alveolar diseases), the presence of B-lines in the acutely dyspneic patient should alert the clinician to the presence of pulmonary edema.20 Supportive evidence such as increased left atrial to aortic ratio may increase suspicion of cardiogenic pulmonary edema, particularly in cats. Ultrasonography in experienced hands is likely more sensitive for the identification of pulmonary edema than radiography. Arterial blood gas analysis or pulse oximetry may be used to provide objective evidence of hypoxemia; however, these tests are not essential for stabilization and can cause too much stress to be worthwhile in many animals. Pulse oximeters can be unreliable, especially in conscious patients that are moving or have darkly pigmented skin, although new technology is increasing reliability. Pulse oximeters with plethysmography indexes can allow assessment of the quality of the saturation readings as this is a noninvasive indicator of peripheral perfusion. Blood gas analyzers are becoming increasingly available,

CHAPTER 23  Pulmonary Edema and with practice, arterial blood sampling is a relatively easy technique to master. Arterial blood gas analysis also allows calculation of the alveolar-arterial gradient and the partial pressure of arterial oxygen: fraction of inspired oxygen ratio (PaO2:FiO2), which can be used to potentially assess the efficacy of therapy (see Chapters 16, Hypoxemia and 184, Oximetry Monitoring).

TREATMENT Oxygen Therapy Treatment of pulmonary edema depends on the underlying cause. No therapy is uniformly effective. Oxygen supplementation should be provided by the least stressful means to increase arterial oxygen content and tissue oxygen delivery. Patients should be subjected to minimal stress and movement or struggling should be limited to prevent increases in oxygen demand. Dyspneic animals should never be forcibly restrained. A purpose-built oxygen cage is ideal for cats or small dogs following initial evaluation, but these are expensive and require maintenance and large oxygen supplies. Administration by mask, flowby, or nasal cannula can be considered if a cage is unsuitable or not available, but these techniques are of limited use in cats. High flow oxygen therapy is increasingly available in veterinary hospitals and provides a noninvasive way of providing oxygen supplementation; however, sedation is required to improve tolerance in some patients.21 If noninvasive methods for oxygen supplementation fail, invasive methods may be required. Continuous positive airway pressure (CPAP) ventilation is less invasive than traditional intermittent positive pressure ventilation (PPV). Both require deep sedation or, more commonly, anesthesia and maintenance of an airway either via a laryngeal mask or endotracheal tube. CPAP is sometimes possible via nasal cannulae, but this is limited by equipment design. PPV is indicated in patients that cannot maintain a hemoglobin saturation above 90% or a PaO2 over 60 mm Hg with noninvasive methods of oxygen supplementation or those with evidence of hypoventilation (PaCO2 .55 to 60 mm Hg). If impending respiratory fatigue is a concern, PPV should be considered before there is significant deterioration. There is contradictory evidence in the literature regarding the effects of PPV on the resolution of pulmonary edema; PPV may help to resolve pulmonary edema in some situations, but slow it in others.22,23 There can be significant morbidity associated with PPV, so careful case-by-case consideration should be made before commencing ventilation. PPV is of particular benefit in patients where there are reversible causes of pulmonary edema such as cardiogenic mechanisms. Body position can also be important. Sternal recumbency aids with gas exchange, probably by reducing atelectasis. In animals with unilateral disease, it is preferable initially to place the patient with the affected lung lobe down if the animal will not tolerate sternal recumbency. In some patients placing the more severely affected lung uppermost can precipitate severe hypoxemia and respiratory arrest.

Medical Therapy The key to managing cardiogenic pulmonary edema is the reduction of pulmonary capillary pressures by reducing preload. Promotion of left-sided forward flow is also important in patients with large regurgitant fractions. The drugs used can be split into two groups: diuretics and vasodilators. Furosemide is the most frequently used diuretic and is particularly useful because of its rapid onset of action (Chapter 151, Diuretics). Excessive use and lack of close monitoring could result in hypovolemia as a result of an excessive reduction in preload. For acute congestive heart failure in dogs, furosemide should be administered at 1–2 mg/kg hourly until the respiratory status is stabilized of a maximum dose of 8 mg/kg has been reached and evidence of pulmonary

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congestion is improved. In life-threatening pulmonary edema, constant rate infusion (CRI) administration alongside bolus is recommended.24 The frequency and dosage are subsequently reduced. The dose in cats should be moderate as cats are more sensitive to the effects of furosemide than dogs. There is evidence that furosemide acts as a pulmonary vasodilator and bronchodilator and causes an increase in COP secondary to hemoconcentration. These changes, in combination with the resultant reduction in pulmonary hydrostatic capillary pressure, may assist with alveolar fluid reabsorption.25,26 Concerns have been expressed about reduced mucociliary clearance due to excessive dehydration of secretions, but in life-threatening situations this is not an immediate concern. Bolus injection of furosemide in people has been associated with excessive volume contraction, and as a result, CRIs have been suggested as an alternative with fewer complications. CRIs are more effective in promoting fluid excretion than intermittent boluses in people with congestive heart failure, and experimental studies in healthy greyhounds have shown better diuresis with a CRI than with bolus injection.27 Human studies have shown bolus injection and CRIs to be equally effective for management of heart failure using endpoints other than diuresis, and so there is limited evidence to suggest one over the other.28 CRIs are associated with greater diuresis and should be used in cats with caution. Because hydrostatic pressure influences edema due to increased permeability edema and increased hydrostatic pressure, capillary pressure modification can be considered in all cases of pulmonary edema. Most patients with increased permeability edema do not respond as well as those with cardiogenic edema to medical interventions to decrease hydrostatic pressure. In noncardiogenic pulmonary edema, there is limited clinical evidence for a beneficial effect with furosemide, but most experimental data support therapies that modulate hydrostatic pressure. When there is any concern of hypoperfusion the use of any diuretic may still be logical, but there should be careful risk– benefit analysis. Notably, diuresis is not recommended in any form of noncardiogenic pulmonary edema in people. In the absence of heart disease, therefore, if in risk–benefit analysis, use of a diuretic is considered appropriate, then lower doses of furosemide should be used for diuresis and monitored for effect in order to prevent unwanted hypoperfusion. Care should be taken if this approach is used. Vasodilators are less commonly used but can prove beneficial. A number of drugs are available, but in acute situations the most useful group are the nitric oxide donors, which include nitroprusside, isosorbide dinitrate, and glycerol trinitrate (nitroglycerin). Nitroprusside causes dilation of arteries and veins, whereas nitroglycerine is mainly a venodilator. Nitroprusside may cause hypotension due to arteriolar dilation. It has a short half-life and is therefore administered intravenously as a CRI. Nitroprusside should be used with extreme caution in hypotensive patients because the general goal with therapy is to only reduce the mean arterial pressure (or systolic blood pressure) by 10 to 15 mm Hg from the baseline pressure. In hypotensive patients, nitroprusside should not be used without a positive inotrope; however, there is evidence to suggest that even in patients with severe left ventricular dysfunction, nitroprusside is associated with beneficial cardiopulmonary effects.29 Animals should be monitored carefully for clinical signs of hypotension, ideally with invasive blood pressure monitoring, although this may not be possible in all cases. In addition to its hypotensive effects, nitroprusside may cause a reduction in hypoxic pulmonary vasoconstriction, thereby increasing ventilation– perfusion mismatch. A reflex tachycardia can also be observed. Nitroprusside is difficult to obtain in many countries and can be expensive, but its use is included in the ACVIM consensus guidelines for the diagnosis and treatment of myxomatous mitral valve disease in dogs.24

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Nitroglycerin is mainly a venodilator, and minimal hypotension or tachycardia is seen with this drug, making it safe in most cases. Nitroglycerin is available in some countries as a paste, which is applied to hairless areas such as the axilla or ear flap, or as a spray that can be applied to mucous membranes. Empiric doses are recommended. Tachyphylaxis occurs rapidly, and the drug may have reduced efficacy after as little as 24 hours. There is limited evidence of efficacy in dogs and cats, and its use is no longer recommended.30 a-Adrenergic antagonists have been used experimentally and clinically in cases of NPE and have been associated in limited cases with rapid improvement.17,31 There is no evidence of use in veterinary patients, but this therapy may prove useful in some cases. Other drugs that have been of benefit in experimental models of noncardiogenic pulmonary edema include b2-agonists, such as terbutaline.32,33 These act via cyclic adenosine monophosphate (cAMP)32 to increase fluid reabsorption from the alveolar space. Use of intravenous and inhaled salbutamol in people with respiratory failure and ARDS revealed worse outcome including death and ventilator free days, possibly due to increased cardiac output. Because of these unwanted side effects, the use of b-2-agonists cannot be routinely recommended, and they should only be used, if at all, with extreme caution.34,35 Phosphodiesterase inhibitors such as pimobendan increase cAMP levels, and these drugs may also prove useful in the management of pulmonary edema. Intravenous administration of pimobendan in healthy dogs rapidly increases blood pressure and reduces left ventricular end diastolic pressure36, and may be of particular benefit in dogs with forward and congestive failure.

Fluid Therapy Because the hydrostatic pressure gradient is so important in the pathogenesis of pulmonary edema, it seems prudent to restrict fluid administration to these patients. In all cases, the decision to restrict intravenous fluid administration should be balanced against the risks of compromised renal function and multiple organ failure although hypovolemia would have to be severe and persistent to cause such severe effects. The pulmonary, microvascular barrier is relatively permeable to protein,2 and therefore natural or synthetic colloids such as albumin or hetastarch, respectively, may equilibrate rapidly across the endothelial space. If there is increased permeability such that more than half of the number of colloid molecules extravasate, colloid therapy may worsen pulmonary edema. Furthermore, macromolecular clearance from the alveoli is slow compared to isotonic electrolyte solutions and water. Because there is no way yet of clinically determining vascular, interstitial, and epithelial permeability, one has to rely on response to therapy. Given the lack of a supportive evidence base for the use of artificial colloids for many conditions, it could be argued that their use in animals with pulmonary edema fails a risk–benefit analysis and so should be avoided.

PROGNOSIS Because of the diversity of causes of pulmonary edema, general statements about prognosis cannot be made. Usually when there is no serious underlying disease, the prognosis for resolution is relatively good. In contrast, when there is evidence of multisystemic disease and severe increased permeability edema, the prognosis is guarded at best. The prognosis for cardiogenic edema is related to the severity of the underlying disease; some dogs with mitral valve disease may survive for 2 or 3 years after initial diagnosis of left-sided heart failure, with a median of 276 days,37 whereas the prognosis for dogs in forward failure with dilated cardiomyopathy may be poorer.38 In cats, the prognosis with congestive heart failure seems less favorable and few of these animals

live beyond 1 to 1½ years from the time of diagnosis, with a median of 194 days.11 The outcome in animals with pulmonary edema severe enough to warrant PPV is generally poor, although financial concerns are often involved in many of these decisions.39,40

REFERENCES 1. Starling EH: On the absorption of fluid from connective tissue spaces, J Physiol 19:312, 1896. 2. Taylor AE: The lymphatic safety factor: the role of edema-dependent lymphatic factors (EDLF), Lymphology 23:111, 1990. 3. Zarins CK, Rice CL, Smith DE, et al: Role of lymphatics in preventing hypooncotic pulmonary edema, Surg Forum 27:257, 1976. 4. Yang Y, Schmidt EP: The endothelial glycocalyx, Tissue Barriers 1 (1):e23494, 2013. doi:10.4161/tisb.23494. 5. Schmidt EP, Yang Y, Janssen WJ, et al: The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis, Nat Med 18:1217-1223, 2012. http://dx.doi.org/10.1038/ nm.2843. 6. Demling RH, LaLonde C, Ikegami K: Pulmonary edema: pathophysiology, methods of measurement, and clinical importance in acute respiratory failure, New Horiz 1:371, 1993. 7. Conhaim ROL, Lai-Fook SJ, Staub NC: Sequence of perivascular liquid accumulation in liquid-inflated dog lung lobes, J Appl Physiol 60:513, 1986. 8. Fukue M, Serikov VB, Jerome EH: Bronchial vascular reabsorption of low protein interstitial edema liquid perfused in sheep lungs, J Appl Physiol 81:810, 1996. 9. Ferasin L and Linney C: Coughing in dogs: what is the evidence for and against a cardiac cough? J Small Anim Pract 60:139-145, 2019. doi:10.1111/jsap.12976. 10. Dickson D, Little CJL, Harris J, et al: Rapid assessment with physical examination in dyspnoeic cats: the RAPID CAT study, J Small Anim Pract 59:75-84, 2018. doi:10.1111/jsap.12732. 11. Payne J, Luis Fuentes V, Boswood A, et al: Population characteristics and survival in 127 referred cats with hypertrophic cardiomyopathy (1997 to 2005), J Small Anim Pract 51:540, 2010. 12. Ferasin L: Feline myocardial disease 1: classification, pathophysiology and clinical presentation, J Feline Med Surg 11:3, 2009. 13. Cornelius LM, Finco DR, Culver DH: Physiologic effects of rapid infusion of Ringers lactate solution into dogs, Am J Vet Res 39:1185, 1978. 14. Ostroski CJ, Drobat, KJ, Reineke EL: Retrospective evaluation of and risk factor analysis for presumed fluid overload in cats with urethral obstruction: 11 cases (2002–2012), J Vet Emerg Crit Care (San Antonio) 27:561-568, 2017. doi:10.1111/vec.12631. 15. Paige CF, Abbott JA, Elvinger F, et al: Prevalence of cardiomyopathy in apparently healthy cats, J Am Vet Med Assoc 234:1398, 2009. 16. Robin TJ: Speculations on neurogenic pulmonary edema (NPE), Am Rev Respir Dis 113:405, 1976. 17. Davison DL, Terek M, Chawla LS: Neurogenic pulmonary edema, Crit Care 16:212, 2012. 18. Drobatz KJ, Saunders HM, Pugh CR, et al: Noncardiogenic pulmonary edema in dogs and cats: 26 cases (1987-1993), J Am Vet Med Assoc 206(11):1732-1736, 1995. 19. Bouyssou S, Specchi S, Desquilbet L, et al: Radiographic appearance of presumed noncardiogenic pulmonary edema and correlation with underlying cause in dogs and cats, Vet Radiol Ultrasound 58:259-265, 2017. doi:10.1111/vru.12468. 20. Ward JL, Lisciandro GR, Keene BW, et al: Accuracy of point-of-care lung ultrasonography for the diagnosis of cardiogenic pulmonary edema in dogs and cats with acute dyspnea, J Am Vet Med Assoc 250(6):666-675, 2017. 21. Pouzot-Nevoret C, Hocine L, Nègre J, et al: Prospective pilot study for evaluation of high-flow oxygen therapy in dyspnoeic dogs: the HOT-DOG study, J Small Anim Pract 60:656-662, 2019. doi:10.1111/jsap.13058.

CHAPTER 23  Pulmonary Edema 22. Colmenero-Ruiz M, Fernandez-Mondejar E, Fernandez-Sacristan MA, et al: PEEP and low-tidal volume ventilation reduce lung water in porcine pulmonary edema, Am J Respir Crit Care Med 155:964, 1997. 23. Blomqvist H, Wickerts CJ, Berg B, et al: Does PEEP facilitate the resolution of extravascular lung water after experimental hydrostatic pulmonary oedema? Eur Respir J 4:1053, 1991. 24. Keene BW, Atkins CE, Bonagura JD, et al: ACVIM consensus guidelines for the diagnosis and treatment of myxomatous mitral valve disease in dogs, J Vet Intern Med 33:1127-1140, 2019. https://doi.org/10.1111/ jvim.15488. 25. Schuster CJ, Weil MH, Besso J, et al: Blood volume following diuresis induced by furosemide, Am J Med 76:585, 1984. 26. Ali J, Chernicki W, Wood LDH: Effect of furosemide in canine low-pressure edema, J Clin Invest 64:1494, 1979. 27. Adin DB, Taylor AW, Hill RC, et al: Intermittent bolus injection versus continuous infusion of furosemide in normal adult greyhound dogs, J Vet Intern Med 17:632, 2003. 28. Felker GM, Lee KL, Bull DA, et al: Diuretic strategies in patients with acute decompensated heart failure, N Engl J Med 364:797, 2011. 29. Khot UN, Novaro GM, Popovicc ZB, et al: Nitroprusside in critically ill patients with left ventricular dysfunction and aortic stenosis, N Engl J Med 348:1756, 2003. 30. Stillion JR, Boysen SR: Does adding transdermal nitroglycerine to other therapies used for management of left-sided congestive heart failure in dogs speed the resolution of clinical signs? Vet Evid 2(4), 2017. https://doi. org/10.18849/ve.v2i4.115. 31. Wohns RN, Tamas L, Pierce KR, Howe JF: Chlorpromazine treatment for neurogenic pulmonary edema, Crit Care Med 13:210, 1985.

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32. McAuley DF, Frank JA, Fang X, et al: Clinically relevant concentrations of b2-adrenergic agonists stimulate maximal cyclic adenosine monophosphate-dependent airspace fluid clearance and decrease pulmonary edema in experimental acid-induced lung injury, Crit Care Med 32:1470, 2004. 33. Sakuma T, Okaniwa G, Nakada T, et al: Alveolar fluid clearance in the resected human lung, Am J Respir Crit Care Med 150:305, 1994. 34. Matthay MA, Brower RG, Carson S, The Acute Respiratory Distress Syndrome Network et al: Randomized, placebo-controlled clinical trial of an aerosolized beta-2 agonist for treatment of acute lung injury, Am J Respir Crit Care Med 342:1301, 2011. 35. Smith FG, Perkins GD, Gates S, et al., for the BALTI-2 study investigators: Effect of intravenous b-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial, Lancet 379:229, 2012. 36. Hori Y, Taira H, Nakajima Y, et al: Inotropic effects of a single intravenous recommended dose of pimobendan in healthy dogs, J Vet Med Sci 81(1):22-25, 2019. doi:10.1292/jvms.18-0185. 37. Häggström J, Boswood A, O’Grady M, et al: Effect of pimobendan or benazepril hydrochloride on survival times in dogs with congestive heart failure caused by naturally occurring myxomatous mitral valve disease: the QUEST study, J Vet Intern Med 22:1124, 2008. 38. O’Grady MR, Minors SL, O’Sullivan ML, Horne R: Effect of pimobendan on case fatality rate in Doberman Pinschers with congestive heart failure caused by dilated cardiomyopathy, J Vet Intern Med 22:897, 2008. 39. King LG, Hendricks JC: Use of positive-pressure ventilation in dogs and cats: 41 cases (1990-1992), J Am Vet Med Assoc 204:1045, 1994. 40. Lee JA, Drobatz KJ, Koch MW, King LJ: Indications for and outcome of positive-pressure ventilation in cats: 53 cases (1993-2002), J Am Vet Med Assoc 226:924, 2005.

24 Pneumonia Amanda K. Boag, MA, VetMB, DECVECC, DACVECC, DACVIM, FHEA, FRCVS, Gretchen L. Schoeffler, DVM, DACVECC

KEY POINTS • Pneumonia is an infection of the lung; bacteria are the most common causative agent, although other infectious organisms (viral, parasitic, mycotic) may be involved. • In dogs and cats with pneumonia, an underlying cause is almost always present and must be identified and treated to minimize persistence and recurrence of disease. • Diagnosis is usually based on history, physical examination, and radiography. The severity of respiratory compromise is best assessed and monitored by arterial blood gas analysis. • Antimicrobial drug therapy should be directed by cytologic evaluation, Gram stain, and bacterial culture and susceptibility testing of biologic samples.

• Bacterial culture and susceptibility testing with prompt deescalation to targeted antimicrobial therapy can reduce antibiotic resistance and adverse drug reactions. • The optimal duration of antimicrobial therapy and timing of clinical and radiographic follow-up to assess for treatment failure are not known. Factors to consider include choice of antimicrobials, severity of disease and presence of comorbidities, and the patient’s initial response to treatment.

PATHOLOGY

associated with viral pneumonia typically starts in the interstitium and in severe cases extends into the alveolar spaces.

The pathologic process common to all pneumonias is infection and inflammation of the distal pulmonary parenchyma.1, 2 Infections are primarily caused by bacteria and viruses and less commonly by fungi and parasites. Aspiration pneumonia, an important cause of pneumonia in dogs and cats, results when bacterial infection develops in patients following aspiration and subsequent pneumonitis. Pneumonia is characterized by the infiltration of polymorphonuclear leukocytes, edema fluid, erythrocytes, mononuclear cells, and fibrin into the lung. Individual types of pneumonia may differ by the route of infection and mode of spread. Anatomically, three different distribution patterns can differentiate pneumonias that follow a lobar pattern, from those that behave more like a bronchopneumonia, and those with the pattern of an interstitial pneumonia. These anatomical distributions are reflected in radiographic changes. Lobar pneumonia describes a pattern that characteristically encompasses an entire lung lobe. Spread of lobar pneumonia is believed to occur from alveolus to alveolus and from acinus to acinus through interalveolar pores. Bronchopneumonia is characterized by distal airway inflammation and alveolar disease, and the inflammatory process is thought to spread through airways rather than through adjacent alveoli and acini. Bronchopneumonias have a patchy distribution, whereas lobar pneumonias appear as dense consolidations involving a portion or the entire lobe. With interstitial pneumonia, the inflammatory process initially occurs within the interstitium rather than alveolar spaces. Individual patients with pneumonia may have a mixture of each of the three patterns in varying proportions. For example, the inflammatory process

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PATHOPHYSIOLOGY Infectious pneumonia results when the patient’s protective upper airway mechanisms and humoral and cell-mediated immunity become overwhelmed. The upper and lower airways provide a first line of defense against inhaled pathogens and contaminated particulate matter. They protect the lung through a variety of defenses including anatomical barriers, cough reflex, the mucociliary apparatus with its associated enzymes and secretory immunoglobulin (IgA), and phagocytic dendritic cells within the basal layer of the respiratory mucosa. Particles smaller than 3 µm may bypass the upper respiratory tract defenses and get deposited in the alveoli.1 The bronchoalveolar junction is a major site of small particle (0.5 to 3 µm) deposition and is especially vulnerable to damage. Surfactant and alveolar macrophages are quickly overwhelmed when considerable numbers of organisms or those with high virulence are deposited. Complex interactions between the cell-mediated and humoral immune systems and elevated levels of cytokines and chemokines induce an inflammatory response to clear the offending agents. Infection and inflammation of the distal pulmonary parenchyma may lead to hypoxemia via ventilation–perfusion (V/Q) mismatch, intrapulmonary shunting, and impaired diffusion resulting in an increased alveolar-arterial gradient and, in some cases, limited oxygen responsiveness. Hypercapnia is less common3 and suggests respiratory muscle fatigue, bronchoconstriction, or the presence of severe pulmonary parenchymal disease (see Chapter 17, Hypoventilation).

CHAPTER 24  Pneumonia

SPECIFIC TYPES OF PNEUMONIA Bacterial Pneumonia Other than some specific primary bacterial pathogens (e.g., Bordetella bronchiseptica and Mycoplasma cynos), most dogs and cats with bacterial pneumonia have an underlying predisposition to lung disease that should be investigated as part of their evaluation. Predisposing factors and disorders associated with pneumonia are listed in Table 24.1. Bacteria may gain entry to the pulmonary parenchyma through a variety of routes including inhalation, aspiration, direct extension from the pleural space and other intrathoracic structures, and via hematogenous spread. The most common bacteria isolated from tracheal wash samples collected from dogs with pneumonia include the Gramnegative bacilli Pasteurella spp. (22% to 28% of dogs with bacterial pneumonia) and Enterobacteriaceae such as Escherichia coli (17% to 46%), and Gram-positive cocci such as Staphylococcus spp. (10% to

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16%) and Streptococcus spp. (14% to 21%).3-5 In puppies with pneumonia, Bordetella bronchiseptica is most common (49%).6 Anaerobic bacteria are isolated in 10% to 21% of cases,3,4 and their presence warrants suspicion for pulmonary abscess formation. Mycoplasma spp. are commonly detected, either as sole organisms (8%) or as coinfections with other bacteria in a large proportion of dogs with bacterial pneumonia (62%).5,7 Often, bacterial cultures from small animal patients with pneumonia reveal multiple species of bacteria (e.g., 43%,4 47%,3 and 74% [including Mycoplasma]8 of dogs and 38% of cats).9

Aspiration Pneumonia Aspiration pneumonia can result from bacterial colonization of the lung after aspiration of acid or gastrointestinal material that is contaminated with oropharyngeal bacteria. Studies suggest that the magnitude of lung injury after gastric aspiration depends on the pH, volume, osmolality, and presence of particulate matter in the aspirate.10,11 Severe

TABLE 24.1  Factors Predisposing to or Associated with Pneumonia in Dogs and Cats Factor

Comment

Impaired Patient Mobility Unconsciousness (natural or via general anesthesia)*

Attenuation, loss of reflexes (gag, cough)

Mechanical ventilation

Intubation bypass normal defense mechanisms of the upper airway; normal movement and coughing prevented Regurgitation or aspiration of oropharyngeal bacteria may contribute

Weakness, paresis, paralysis* Upper Airway Disorders Laryngeal mass or foreign body*

— Successful laryngeal examination possible in many/most unsedated dogs using only a bright light source (Finnoff transilluminator), especially in dogs with marked dyspnea from upper airway obstruction

Laryngeal paralysis* Laryngeal or pharyngeal dysfunction or surgery*

Regurgitation Syndromes Esophageal motility disorder*

Aspiration pneumonia (without overt clinical signs)—a common postoperative complication in animals with laryngeal paralysis (see Chapter 18, Upper Airway Disease) Dynamic esophagram (barium swallow) required for diagnosis Important if other tests do not identify an underlying cause for pneumonia

Esophageal obstruction*

Foreign body sometimes visible on thoracic radiographs Caution necessary with barium swallow procedures (barium aspiration risk); endoscopy may be preferable

Megaesophagus*

Often identifiable on plain thoracic radiographs

Other Factors Bronchoesophageal fistula

Usually acquired via trauma (e.g., perforating esophageal foreign body)

Cleft palate

Aspiration of ingesta from nasal cavity

Crowded or unclean housing

Increased concentration and persistence of infectious organisms in the environment

Forceful bottle feeding*

Aspiration possible when care provider squeezes the nursing bottle during suckling or if hole in nipple is too large

Gastric intubation*

—

Immune compromise

Specific conditions: anticancer or immunosuppressive chemotherapy; concurrent illness, including feline leukemia, feline infectious peritonitis, diabetes mellitus, or hyperadrenocorticism; primary ciliary dyskinesia; immunoglobulin or leukocyte defects or deficiencies

Inadequate vaccination

Viral, bacterial, or parasitic infection with secondary opportunistic bacterial pneumonia

Induced vomiting*

—

Seizures*

Must differentiate pneumonia radiographically from noncardiogenic pulmonary edema

Tracheostomy*

—

*Indicates predisposition to aspiration pneumonia.

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histologic damage is caused by aspirates with a pH less than 1.5, but minimal damage is caused by aspirates with pH greater than 2.4 unless they also contain particulate matter.12,13 Inhaled particulate matter may cause small airway obstruction, prolong the inflammatory response, and act as a source of, and nidus for, bacterial infection.14 Combination acid-particulate aspirates induce greater injury than either component alone.15 The development of pneumonia after gastric aspiration is a risk factor for subsequent development of both acute respiratory distress syndrome (ARDS)16 and sepsis,17,18 which substantially increase the risk of mortality. Bacteria that are commonly cultured from companion animals with aspiration pneumonia include enteric bacteria such as Escherichia coli, Klebsiella spp., and Enterococcus spp.; oropharyngeal Mycoplasma spp.; primary respiratory pathogens, including Pasteurella spp., Pseudomonas spp., and Streptococcus spp.; and commensals such as Staphylococcus spp.19,20 Gastrointestinal disorders (.60%) are the most common risk factor, and megaesophagus is the leading cause (26%) of aspiration pneumonia in dogs.17,19 Other important predisposing disorders include neurologic (18%) and laryngeal (13%) dysfunction.17,19 Like people, many dogs have multiple risk factors, including recent anesthesia.21

Pneumonia Associated with Canine Infectious Respiratory Disease Pneumonia can be a serious complication of canine infectious respiratory disease (CIRD) complex. CIRD is an endemic, worldwide syndrome in which multiple viral and bacterial pathogens sequentially or synergistically coinfect dogs. Organisms associated with this complex are ubiquitous in densely populated settings, and development of illness likely depends on a combination of both host and environmental factors. Naive and immunocompromised dogs that are exposed to novel pathogens in new, overcrowded environments are at highest risk.22 Viral pathogens implicated in CIRD include canine adenovirus type-2, canine parainfluenza, canine distemper virus, canine respiratory coronavirus, canine influenza virus, canine pneumovirus, and canine herpesvirus.23-29 Infection with either canine adenovirus type-2 or canine parainfluenza virus typically results in mild, self-limiting respiratory signs but infection with these viruses can be more serious when complicated by coinfection or immunosuppression.29,30 In contrast, infection with canine distemper virus leads to severe systemic disease. The canine distemper virus initially replicates in the lymphoid cells of the respiratory tract before spreading to the epithelial cells of other organ systems, including the central nervous system. Clinical signs may include ocular and nasal discharge, respiratory distress, vomiting, diarrhea, hyperkeratosis of the foot pads, and progressive neurological dysfunction.29-31 Canine respiratory coronavirus infection contributes to decreased mucociliary clearance and facilitates secondary infection.29 Two influenza subtypes, H3N8 and H3N2, are important in dogs. Both strains are unique in that they can be transmitted horizontally between dogs and when complicated by bacterial coinfection, can result in hemorrhagic bronchopneumonia with mortality rates as high as 80%. While infections in canines with other subtypes have been reported (H5N1, H1N1, and H3N1), they have only rarely been associated with clinical disease.29,32 Canine pneumovirus has only recently been isolated from dogs with respiratory disease and little is known about its pathogenesis. Infection with canine herpes virus commonly leads to death in immunologically naive fetuses and puppies less than 2 weeks of age; however, clinical signs in older puppies and adults are uncommon.29 Younger dogs and dogs with a higher number of coinfections are more likely to develop secondary bacterial pneumonia and have more severe clinical signs associated with CIRD.22 It is probable that an initial pathogen alters the patient’s pulmonary defense mechanisms

thereby allowing additional organisms to infect the respiratory tissues. The most common bacterial pathogens identified in CIRD patients are Bordetella bronchiseptica, Streptococcus equi subspecies zooepidemicus, and Mycoplasma cynos.23, 27, 29, 33-35 B. bronchiseptica is a Gram-negative, aerobic coccobacillus that can act as a primary pathogen or cause CIRD concurrently with other bacteria and viruses. Affected animals develop a dry, paroxysmal cough with nasal discharge, and in severe cases, infection with B. bronchiseptica can lead to pneumonia and death.29 In shelters, Streptococcus equi subspecies zooepidemicus, a Gram-positive, beta hemolytic coccus, belonging to the Lancefield group C, has been associated with a syndrome of acute, hemorrhagic, fatal pneumonia in dogs, suggesting that contagion may play an important role.36-38 Mycoplasma spp. lack a cell wall and are fastidious and difficult to grow in culture and as a result may frequently be underdiagnosed. Though Mycoplasma spp. can be normal commensal organisms, Mycoplasma cynos has been implicated as an important, primary pathogen in the lower respiratory tract of dogs and cats.

Foreign Body Pneumonia Grass awns and other foreign materials contaminated with bacteria and fungi can be inhaled, lodge in a bronchus, and may ultimately lead to lobar pneumonia and other complications such as pneumo- and pyothorax. The organisms most frequently cultured from patients with foreign body pneumonia include Pasteurella spp., Streptococcus spp., Nocardia spp., Actinomyces spp., and various anaerobic bacteria.39-41 Many of these patients are young, sporting breed dogs from geographic regions with exposure opportunities for specific types of grass awns and other risky plant materials. These patients frequently have a history of recurrent clinical and radiographic signs as well as cutaneous and visceral foreign body migrations.

Parasitic Pneumonia Parasitic pneumonia may result when nematodes and trematodes migrate through the lung. Dogs and cats may be asymptomatic, or they may have variable, nonspecific clinical signs (e.g., cough). Clinical suspicion is based on the pet’s geographic location, lifestyle, immunocompetency, and radiographic findings. Both dogs and cats can be infected with Eucoleus (Capillaria) aerophilus and Paragonimus kellicotti, and cats can be infected with Aelurostrongylus abstrusus. Dogs can be infected with Filaroides hirthi, Crenosoma vulpis, and Oslerus (Filaroides) osleri. Additionally, canine neonates with severe diarrhea that are seriously infected with Strongyloides stercoralis may develop life-threatening bronchopneumonia and pulmonary hemorrhage. Lastly, while the lifethreatening effects of Angiostrongylus vasorum infection are most often associated with bleeding tendencies, respiratory signs can be severe.

Mycotic Pneumonia Infection with fungal agents is a relatively uncommon and geographically restricted cause of pneumonia in dogs and cats. Some fungal agents such as Blastomyces dermatitidis and Histoplasma capsulatam typically cause insidious onset systemic disease with lower respiratory tract signs as an important, but not the only, symptom. Pneumocystis carinii, which was previously classified as a protozoon, is another fungal agent that can cause severe pneumonia and is seen most in certain small breed dogs (notably Miniature Dachshunds and Cavalier King Charles Spaniels).42 As it is a ubiquitous saprophyte with low virulence, it is thought these breeds’ susceptibility may be due to localized pulmonary immunodeficiency.

Ventilator-Associated Pneumonia Ventilator-associated pneumonia is an iatrogenic cause of pneumonia associated with the use of mechanical ventilation for intensive respiratory

CHAPTER 24  Pneumonia

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support. It will not be covered in this chapter as it is addressed separately and in more detail in Chapter 40, Ventilator-Associated Pneumonia.

CLINICAL FEATURES Patients with pneumonia can present with a wide range of clinical signs. Critically ill animals with pneumonia require rapid identification and treatment because deterioration may occur quickly. Nonspecific signs of inappetence and lethargy, mild tachypnea, increased respiratory effort, and a soft cough may be the earliest signs in some dogs and cats. Additionally, patients with pneumonia may show no respiratory signs (e.g., 36% of cats),9 with the diagnosis being made incidentally on thoracic radiographs. Pneumonia may become a consideration at one of at least three points in the evolution of a case: when clinical signs are noted by the owner, veterinarian, or both; when predisposing causes are identified; or when characteristic findings are apparent on thoracic radiographs.

History A full clinical history from the primary caregiver is important in making a diagnosis of pneumonia. Elements of a patient’s history that should raise the clinician’s index of suspicion are numerous. Broadly, historical clues include recent vomiting, regurgitation or anesthesia, respiratory signs (cough, increased respiratory effort, purulent nasal discharge), systemic signs including lethargy and inappetence, and signs associated with predisposing or underlying causes. Approximately 36% to 57% of dogs with pneumonia are found to have a concurrent predisposing disorder (Table 24.1).4, 6 With aspiration pneumonia, an index of suspicion must be maintained even in the absence of a clear history of aspiration because aspiration episodes are rarely witnessed. Hospitalized patients perceived as “at risk” should have frequent respiratory system assessments and aspiration should be suspected if respiratory distress develops acutely. Vaccination history may raise or lower the likelihood of specific infectious etiologies (e.g., canine distemper in puppies), and geographic location and travel history may reveal important details to consider in patients suspected of having fungal or parasitic disease.

Physical Examination Physical abnormalities in patients with pneumonia are often nonspecific.1,6 Demeanor may be normal, with some patients showing a bright and alert disposition, or abnormal, with lethargy or even obtundation predominating. Fever is a highly variable finding in both dogs and cats, and pneumonia can be neither confirmed nor ruled out based on body temperature. Mucous membrane color is frequently pink, but hyperemic or cyanotic membranes may be observed. Mucopurulent nasal discharge may or may not be present in either species. Respiratory pattern, rate, rhythm, effort, and depth should be noted, though respiratory abnormalities are rarely sensitive or specific. For example, respiratory distress may occur with moderate or severe pneumonia but is usually absent in mild cases; 78% of puppies with pneumonia are tachypneic and 72% have an increased respiratory effort.6 Cats with infectious pneumonia rarely cough (8%)9 in contrast to dogs (47%).8 The cough of a patient with pneumonia may be moist or dry and may be elicited with tracheal pressure in some patients and not in others. Auscultation of adventitious lung sounds are nonspecific and do not allow differentiation from other respiratory diseases (pulmonary edema, pulmonary hemorrhage); however, most dogs with pneumonia (.90%) have abnormally loud breath sounds, crackles, or wheezes on pulmonary auscultation.8 It is particularly important to consider whether the lung sounds are appropriate for the patient’s respiratory rate and effort.43 Rarely, lung sounds may be

Fig. 24.1  The “chessboard” analogy, wherein the lung fields are subdivided into smaller areas to enhance sensitivity of auscultation and to enable more accurate localization of abnormal lung sounds.

significantly decreased if a large bronchus becomes filled with exudates and cellular debris preventing the passage of air. Subdivision of the lung fields for auscultation may aid in lesion localization and improve detection rates (Fig. 24.1). Patients that aspirate typically have an acute change in respiratory pattern accompanied by weakness or collapse, cough, and abnormal lung sounds.19,44 Fine crackles may be heard during inspiration, with the location suggesting the cause (e.g., predominantly cranioventral following aspiration if patient is standing or sternal). In addition, patients that aspirate frequently display additional clinical signs such as nausea, vomiting, and regurgitation. Animals with fungal, viral, parasitic, or protozoal pneumonia may have multisystem involvement (e.g., bone, intestinal tract, lymph nodes). These patients frequently have other associated physical examination findings related to the underlying etiology (ocular involvement, draining tracts, evidence of coagulopathy).

DIAGNOSTIC APPROACH Pneumonia is suspected in an animal when one or more compatible signs are noted in the history and physical examination, especially in a patient with a predisposing condition (see Table 24.1). Evaluation of patients suspected of having pneumonia is centered on diagnostic imaging and sampling of respiratory secretions.

Radiography Thoracic radiography remains the routine imaging test of choice for patients with pneumonia. Three-view thoracic radiography (a dorsoventral or ventrodorsal projection and both lateral projections) is recommended in all pneumonia suspects to minimize the effects of positional atelectasis and false-negative results. When the patient is in left lateral recumbency, the right lung is better aerated and radiographically visualized and when the patient is in right lateral recumbency, the left lung is better aerated and radiographically visualized. Early radiographic evidence of pneumonia may appear as a focal, multifocal, or diffuse interstitial pattern that over time progresses to an alveolar pattern. Patients who have aspirated typically develop an alveolar lung pattern as a result of displacement of air from alveoli by fluid accumulation and cellular infiltration, although an interstitial pattern may also be seen.44 In the dog and cat, aspiration pneumonia typically affects the right middle lung lobe (which may silhouette with the heart in lateral radiograph projections) and ventral parts of the other lobes (Fig. 24.2A–B); however, lesion distribution may be affected by patient position at the time of aspiration.45 Radiographic signs of aspiration pneumonia may lag hours behind the onset of respiratory

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PART II  Respiratory Disorders Viral, bacterial, and fungal pneumonias are more likely to be distributed caudodorsally and diffusely. Inhaled foreign bodies frequently enter the accessory and right and left caudal lung bronchi and are commonly associated with a more caudodorsal, focal or lobar, recurrent alveolar pattern.46 These patients may also have radiographic evidence of pneumo- or pyothorax. Parasitic pneumonia that results from infection with A. vasorum is uniquely associated with a peripheral alveolar pattern radiographically.47 Mycotic pneumonia might show focal airspace disease or a more diffuse, reticulonodular “snowstorm” radiographic pattern.48

Computed Tomography Computed tomography (CT) may be beneficial in animals with complicated pulmonary disease or those suspected of having foreign body–associated pneumonia; the results commonly assist in planning further surgical strategies or diagnostic techniques. Typical CT findings in patients with aspiration pneumonia have been described,45 and there is evidence to suggest CT may provide important additional information in select cases.49 However, thoracic CT has not been widely used for evaluation of veterinary patients with aspiration pneumonia partly because of the accuracy of plain radiography. Animal patients commonly need sedation or general anesthesia and intubation to facilitate control of breathing to optimize the scan. The potential risks associated with sedation and or anesthesia of a patient, combined with the radiation and contrast burden, and the higher costs associated with CT are all factors that should be taken into consideration.

A

Point-of-Care Lung Ultrasound (see also Chapter 189, Point-of-Care Ultrasound in the ICU)

B Fig. 24.2  Thoracic radiographs (A, right lateral projection; B, dorsoventral projection) from a dog taken because of new-onset severe dyspnea, fever, ataxia, and obtundation during anesthetic recovery. There is severe alveolar opacification of most of the left lung, consistent with pneumonia. Infiltrates are especially prominent over the cardiac silhouette in A, a finding that may be missed with a cursory evaluation of the radiographs. The peracute postoperative onset suggests the cause was aspiration of refluxed gastroesophageal contents; atelectasis caused by the patient’s prolonged left-sided recumbency is less likely because the mediastinum has not shifted from midline.

Recently, point-of-care ultrasound techniques have become increasingly used as a noninvasive way of assessing for disease. In early or mild pneumonia, patchy areas of fluid-filled alveoli surrounded by aerated lung result in corresponding areas where numerous B-lines can be visualized. B-lines arise from the pleural line. They are hyperechoic and narrow, spanning across the entire ultrasound image without fading, and they move with lung sliding. B-lines are indicative of “wet lung” and are not specific for pneumonia. As the pneumonia progresses and portions of the lung become consolidated, the echotexture begins to resemble liver; this is referred to as hepatization and can be difficult to distinguish ultrasonographically from atelectasis. Consolidation can be further analyzed by looking for evidence of air bronchograms and the shred sign. Air bronchograms are visualized when air-filled bronchi, surrounded by consolidated tissue, reflect the ultrasound beam, and appear as bright, hyperechoic lines. The shred sign is noted when an irregular (not sharp) interface between an area of consolidated lung and an area of aerated lung is imaged. The visualization of both air bronchograms and the shred sign are suggestive of pneumonia.50

Tracheal Wash distress, change markedly over time, and persist for several days despite clinical improvement. Correlations between radiographic severity and clinical signs, hypoxemia, and prognosis are generally poor, although involvement of multiple lobes has been associated with reduced survival.19 Radiography is also useful for identifying disorders that predispose to aspiration. While megaesophagus is identified readily on plain thoracic radiographs, contrast studies are often needed to identify other pharyngeal and esophageal motility disorders. Contrast studies should be performed with caution since contrast media may be easily aspirated by these patients.

Tracheal wash (TW) is a minimally invasive diagnostic test used in both dogs and cats to obtain airway samples for cytologic analysis, bacterial and fungal culture and susceptibility, and other assays to look for viral and parasitic organisms. TW can be performed via transtracheal wash (TTW) or endotracheal wash (ETW) techniques, depending on the size and stability of the patient. Both techniques are suitable for investigation of suspected pneumonia, with ETW typically being preferred in brachycephalic and smaller patients. In dogs, TTW may be as sensitive as transbronchial biopsy, lung aspirates, and bronchoalveolar lavage (BAL) for diagnosis of pneumonia,51 although it may be less specific than other techniques. The use of TTW to diagnosis bacterial pneumonia has a sensitivity rate of 45% to 70%.19,52,53

CHAPTER 24  Pneumonia

Bronchoscopy and Bronchoalveolar Lavage Bronchoscopy allows visualization of the luminal surface of the respiratory tract (typically to the level of the tertiary bronchi), assessment of airway injury, and collection of lavage samples. BAL retrieves fluid directly from visibly affected areas and may provide greater sensitivity, specificity, and increased diagnostic yield. Guidelines for human adults recommend BAL for obtaining quantitative bacterial cultures and to differentiate pneumonitis from pneumonia.54 In dogs and cats this distinction is less clear, however, and the procedure is not without risk in patients suffering from respiratory compromise. BAL necessitates general anesthesia, is a more invasive diagnostic sampling technique than TW, and may cause bronchospasm and transient, but potentially significant, decreases in lung function. A blind BAL technique is described in which the sampling tube is inserted through the ET tube and advanced until resistance is met before the lavage fluid is injected. The technique is a valuable option in children,55 and clinical experience suggests it is also useful in veterinary patients.

Transcutaneous Fine-Needle Lung Aspirate Transcutaneous fine-needle aspiration of lung in suspected cases of infectious pneumonia may be a low-yield, high-risk procedure, especially in dogs with diffuse pulmonary disease; a lower risk is expected if the patient is kept in lateral recumbency, aspirated side down, for 30 to 60 minutes after the procedure (15 to 20 minutes if anesthetized).7 In cats with unexplained pulmonary parenchymal disease, fine-needle aspiration may provide a better yield than ETW.56

Complete Blood Cell Count and Serum Biochemistry Blood samples for complete blood cell count (CBC) and serum biochemistry values are indicated in all patients suspected of having pneumonia. Although many animals with pneumonia have unremarkable CBC results, abnormalities can include leukocytosis characterized by neutrophilia, left shift, lymphopenia, and monocytosis.8,19,44 Animals that are severely affected may be leukopenic, and dogs with idiopathic eosinophilic pneumonia may have a peripheral eosinophilia. Serum biochemistry changes such as hypoalbuminemia are nonspecific and reflect the degree of inflammatory response. Both CBC and serum biochemistry analysis are useful for identifying and investigating comorbidities.

Ancillary Laboratory Tests A coagulation profile often is helpful in assessing critically ill patients that may have a bleeding disorder or pulmonary hemorrhage. Testing for hypercoagulability (e.g., d-dimer, fibrin degradation products, antithrombin levels, and thromboelastography) may be indicated in some patients, particularly if pulmonary thromboembolism is suspected. Additional diagnostic tests that may also be indicated include fungal titers, serologic titers for heartworm disease and toxoplasmosis, viral testing, and fecal examination (flotation, Baermann sedimentation).

Biomarkers The use of biomarkers in critical illness is an area of active investigation both to help diagnose and track progress of disease, and pneumonia is no exception. Single biomarkers such as procalcitonin, Creactive protein (CRP), and interleukin-6 have all been evaluated in human community-acquired pneumonia.57 None are considered to be ideal markers, although procalcitonin may provide prognostic information.58 CRP is a nonspecific marker of the acute phase response in dogs; in dogs with respiratory disease it may be a useful additional tool in distinguishing between bacterial pneumonia and other causes.59 Cytokine profiles in BAL fluid correlate well with type and duration of injury but are yet to be validated in human studies.60 As

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evaluation of cytokines is becoming more common, developments in this area may improve the clinician’s diagnostic and prognostic accuracy in the future.

THERAPEUTIC APPROACH In veterinary patients, where the distinction between pneumonitis and pneumonia is often unclear, the principle aims of therapy are to (1) support respiratory function through airway management, oxygen supplementation, and mechanical ventilation, if necessary; (2) treat infections with appropriate antimicrobial therapy; and (3) manage underlying and predisposing conditions. In addition to managing the patient’s respiratory dysfunction, the emergency and critical care specialist must also work to prevent the emergence of systemic complications (e.g., multiple organ dysfunction), and the spread of contagion.

Airway Management After a witnessed aspiration event, foreign material obstructing the airway must be removed and airway patency ensured. Though aspirated liquid disperses quickly, suctioning of the pharynx may reduce further aspiration and will facilitate intubation, when necessary. When suctioning the airway, care should be taken to avoid mucosal damage. Therapeutic bronchoscopy is only indicated for atelectasis caused by mucous plugs, which are uncommon in animals after aspiration, and large-volume lavage of the affected areas is not recommended. Experimental work suggests that instillation of exogenous surfactant might be beneficial in canines with aspiration pneumonitis.61 Although recent large-scale trials in human ALI/ARDS were not successful,62 subgroup analyses suggested that patients with aspiration pneumonia might benefit.63 Unfortunately, a large-scale human trial investigating this treatment failed to confirm benefit, and the future of surfactant therapy following aspiration is uncertain.64

Oxygen Therapy Patients with pneumonia may have severe hypoxemia because of V/Q mismatch, intrapulmonary shunting, and hypoventilation. Oxygen therapy is indicated in animals with respiratory distress, hypoxemia, or inadequate hemoglobin saturation. Numerous minimally invasive techniques are described, including nasal flow-by or high flow oxygen, masks, insufflation via nasopharyngeal catheters, oxygen hoods, and oxygen cages (see Chapter 15, Oxygen Therapy). Supplemental oxygen should be humidified and whenever possible, a sensor used to monitor the inspired oxygen concentration. Oxygen administration should be sufficient to ensure adequate arterial partial pressure of oxygen (PaO2) and alleviate respiratory distress. Standard, low-flow intranasal oxygen should be delivered at a flow rate of 50 to 100 ml/kg/min/nare but never at a rate that causes discomfort or triggers the patient to actively close the nasopharynx (see Chapter 15, Oxygen Therapy). There is increasing interest in the use of high flow nasal oxygen delivery systems to provide additional respiratory support without requiring intubation and its associated risks (see Chapter 31, High Flow Nasal Oxygen). There is recent evidence to indicate that it is not only feasible but is also beneficial in some canine patients with respiratory compromise.65-67 Oxygen toxicity has not been reported in the clinical veterinary literature, but experimental studies suggest prolonged, high inspired oxygen concentrations may have detrimental effects, including increased lung permeability, protein extravasation, and impaired compliance.68 Over-supplementation should therefore be avoided.

Mechanical Ventilation Ventilatory support may be required in patients with progressive ventilatory failure (hypercarbia), or failure of pulmonary oxygen delivery

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PART II  Respiratory Disorders

and exchange (hypoxemia), and when less invasive methods of oxygen support are inadequate (see Chapter 32, Mechanical Ventilation: Core Concepts). The decision to mechanically ventilate is most often based on serial arterial blood gas analyses and patient assessment. Patients ventilated for pulmonary parenchymal diseases (hypoxemic failure) generally have a poorer prognosis than those ventilated for neuromuscular disease (ventilatory failure). This is likely because patients with pulmonary parenchymal disease have a much higher risk of complications of ventilation, including alveolar rupture, pneumothorax, capillary endothelial damage, impairment of venous return, and ventilatorassociated pneumonia, compared with patients with hypercapnia and primary ventilatory failure. Use of lung-protective strategies has significantly improved survival rates in human with ARDS (see Chapter 33, Mechanical Ventilation–Advanced Concepts).69 When possible, ventilation of these patients may be worthwhile because up to 30% are successfully discharged from the hospital.70

Antimicrobial Therapy Empiric antimicrobial therapy is often appropriate in the initial stages of managing patients with suspected pneumonia. Collection of appropriate samples (e.g., ETW or TTW fluid, sputum, blood, urine) for bacterial culture and susceptibility testing before initiating treatment (Table 24.2) is preferred; however, results will not be available for a minimum of 2–3 days and sample acquisition will not be possible in

all patients. Pending culture and susceptibility results, antimicrobial choices should be guided by cytologic and Gram stain analysis of airway samples. Empirical antimicrobial therapy should be chosen with consideration of local resistance profiles and should be deescalated or withdrawn if bacterial cultures are negative. Regardless of whether therapy is empirical or based on culture, it must be regularly reevaluated based on clinical response; if patients are worsening, alternative therapy and repeated airway sampling and culture should be considered. In patients with worsening respiratory signs or failure, research suggests that the bacterial isolates may have different resistance profiles from those infecting patients with less severe disease.71 Patients with pneumonia should be reevaluated no later than 10–14 days after instituting antimicrobial therapy and the decision on whether to continue antimicrobial therapy should be based on clinical, hematological, and radiographic findings.72 Long-term oral therapy may be necessary, but the exact duration of treatment must be adjusted to each patient because outcome depends on underlying cause, local immunity, nature of pathogenic organisms, and client factors. The pharmacokinetics of antimicrobial agents should be considered during product selection (see Chapter 172, Antimicrobial Use in the Critical Care Patient). Antimicrobial drugs that penetrate lung tissue and reach therapeutic levels in bronchial secretions are preferable (such as chloramphenicol, doxycycline, enrofloxacin, trimethoprim-sulfamethoxazole, and clindamycin). Polar drugs such as the cephalosporins

TABLE 24.2  Common Medications Used to Treat Pneumonia Drug

Effect or Spectrum

Dosage

Antibacterial Agents: Injectable Amikacin (Amiglyde-V)

G2

15 mg/kg (dog), 10 mg/kg (cat) IV q24h provided renal function and hydration are sufficient

Ampicillin (many names)

G1, some G2 (certain E. coli and Klebsiella strains), some anaerobes (Clostridia)

22 mg/kg IV q6-8h

Azithromycin

G1, G2, Mycoplasma

5–10 mg/kg IV q24h

Cefoxitin (Mefoxin)

Some G1, some anaerobes

30 mg/kg IV q6-8h

Clindamycin

G1, Mycoplasma, Toxoplasma, anaerobes

10 mg/kg IV q8-12h

Enrofloxacin (Baytril)

G2, Mycoplasma

5–10 mg/kg, dilute 1:1 in saline and give IV q12h or 12.5– 20 mg/kg IV q24h (dog) or maximum 5 mg/kg q24h (cat)

Gentamicin (Gentocin)

G2

10 mg/kg (dog), 6 mg/kg (cat) IV q24h provided hydration and renal function are sufficient

Metronidazole (Flagyl)

Anaerobes

10 mg/kg slow IV infusion q12h

Piperacillin-Tazobactam (Zosyn)

G1, G2, anaerobes

40–50 mg/kg slow IV infusion q6h

Trimethoprim-sulfamethoxazole

Some G1, some G2

15–30 mg/kg IV q12h

Antibacterial Agents: Oral Azithromycin (Zithromax)

G1, G2, Mycoplasma

5–10 mg/kg PO q24h

Clindamycin (Antirobe)

G1, Mycoplasma, Toxoplasma, anaerobes

10 mg/kg PO q8-12h

Metronidazole (Flagyl)

Anaerobes

10–15 mg/kg PO q12h

Trimethoprim-sulfamethoxazole (Ditrim, Tribrissen)

Some G1, some G2

15–30 mg/kg PO q12h

Additional Therapeutic Agents Aminophylline

Bronchodilator and respiratory stimulant

5 mg/kg IV q8h (dilute and give over 30 minutes; up to 10 mg/kg in dog)

Caffeine

Bronchodilator, respiratory stimulant

5–10 mg/kg IV q6-8h (dilute and give over 30 minutes)

N-Acetylcysteine

Mucolytic

70 mg/kg IV q6h (dilute and give over 30 minutes)

Terbutaline

Bronchodilator

0.01 mg/kg SC/IM/IV q4-6h

G2, Gram-negative; G1, Gram-positive; IM, intramuscularly; IV, intravenously; PO, per os; SC, subcutaneously.

CHAPTER 24  Pneumonia and penicillins are thought to penetrate poorly, although pulmonary inflammation may allow these antimicrobials to penetrate during disease states. Aminoglycosides such as amikacin and gentamicin have the advantage of rapid onset of action and bactericidal activity. They are favored for treatment of euvolemic, normotensive patients but should be used with caution in rapidly deteriorating patients with fulminant pneumonia and sepsis that are considered likely to be of Gram-negative bacterial origin, as seen in 33 of 65 puppies (51%) with bacterial pneumonia.6 Dogs and cats with moderate to severe pneumonia (based on respiratory signs, extent of pulmonary infiltrates on radiographs, appetite, and demeanor) and patients hospitalized for any reason should receive parenteral therapy.72 If a patient with pneumonia has clinical evidence of sepsis, empiric coverage should address Gram-positive, Gram-negative, and anaerobic bacteria. In many of these patients, initial therapy with either ampicillin or clindamycin combined with enrofloxacin is reasonable.72 Specifically, in patients with suspected aspiration, antimicrobial therapy is not indicated in the early stages of aspiration pneumonitis management. Early use of antimicrobials after aspiration may be more appropriate in patients with additional risk factors for pneumonia such as concurrent antacid use or gastrointestinal obstruction. If the patient is acutely but mildly affected and does not have evidence of systemic sepsis, then administration of a b-lactam antimicrobial such as ampicillin, ampicillin sulbactam, or a first-generation cephalosporin as a single agent may be sufficient. Sicker patients with aspiration pneumonia may require more broad-spectrum antimicrobials or the use of several agents with overlapping spectra, though anaerobic coverage is unlikely to be necessary.19,71 Commonly used antimicrobials include b-lactamases in combination with fluoroquinolones.17,19 Due consideration, for prudent use of antimicrobials, should be given before use of second- or third-line drugs.73 A 7–10 day course of doxycycline is a reasonable first-line antimicrobial for dogs and cats with mild pneumonia and no systemic manifestation of disease, especially those patients that may have had extensive contact with other animals and may be infected with Bordetella bronchiseptica or Mycoplasma spp. Likewise a penicillin, amoxicillin, or ampicillin may be adequate for dogs that are suspected to be infected with a strain of Streptococcus equi subspecies zooepidemicus.72

Bronchodilator Therapy The use of bronchodilators in animals with pneumonia is controversial. There is an argument that this class of drugs may be helpful in select cases by increasing airflow, improving ciliary activity, and increasing the serous nature of respiratory secretions (mucokinetic properties). Conversely, their use may suppress the cough reflex, enhance the spread of exudates within the affected lung to unaffected portions of the lung, and increase perfusion of poorly ventilated lung units thus worsening hypoxemia (V/Q mismatch). Bronchodilators may also have an impact on inflammation based on their mechanism of action. b-Agonists may have a direct antiinflammatory effect by decreasing mucosal edema and downregulating cytokine release. However, two human trials of inhaled albuterol in ALI/ARDS both suggest that this approach is unlikely to be beneficial and may worsen outcomes.74,75 Methylxanthine bronchodilators may increase mucociliary transport speed, inhibit degranulation of mast cells, and decrease microvascular permeability and leak. Additionally, aminophylline is a respiratory stimulant, and it helps increase the strength of diaphragmatic contractility to assist animals with ventilatory fatigue. Intravenous caffeine has been used in place of aminophylline, although its benefit in veterinary medicine remains unproven.

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Bronchodilator drugs such as salbutamol and terbutaline may be of use in patients with acute aspiration pneumonitis if bronchoconstriction is part of the physiologic response to acid injury. Only when bronchospasm can be identified or is strongly suspected is bronchodilator therapy rational.

Cardiovascular Support Fluid therapy should be used judiciously in patients with aspiration pneumonitis or pneumonia because any increase in pulmonary capillary hydrostatic pressure will tend to exacerbate fluid extravasation into the alveoli. The patient’s intravascular volume and hydration status should be assessed frequently, and the patient’s fluid therapy tailored to the individual, with due consideration for the degree of cardiovascular and respiratory compromise (see Chapters 63 and 67, Assessment of Hydration and Daily Intravenous Fluid Therapy, respectively). In patients with sepsis secondary to pneumonia, optimization of hemodynamic parameters through use of goal-directed therapy should be undertaken (see Chapters 7 and 90, SIRS, MODS and Sepsis and Sepsis and Septic Shock, respectively, and the Surviving Sepsis guidelines).76

Glucocorticoids Few therapies in medicine cause more contention than the use of glucocorticoids; the situation is no different in pneumonia, where recent systematic reviews fail to reach consistent and strong evidence-based conclusions.77-78 Glucocorticoids could theoretically be beneficial in suppressing the proinflammatory state that occurs in patients with aspiration pneumonitis; however, these agents suppress the immune system by decreasing levels of T-lymphocytes, inhibiting chemotaxis and phagocytosis, and antagonizing complement. In the absence of developed evidence in veterinary patients, caution is recommended and only in the specific case of vasopressor-dependent septic shock secondary to pneumonia (or patients with previously diagnosed hypoadrenocorticism) should low-dose hydrocortisone be considered.76

Nebulization Nebulizers change liquids into a mist that can be inhaled. The efficacy of nebulization treatment depends largely on the size of the droplets generated. Droplets that are between 0.5 and 5 mm are appropriate for pharmaceutical aerosols and are the size most likely to deposit in the lower airways. Very small droplets (,0.5 mm in diameter) may be exhaled and not deposit in the respiratory tract at all and particles .5–10 mm in diameter are likely to deposit in the nose, mouth, and upper airway. Vaporizers and humidifiers are not effective because the particle size generated with these methods is greater than 3 µm in diameter. Nebulization should be performed every 4 to 6 hours (or continuously) in animals with pneumonia. Nebulization using 0.9% sodium chloride is an effective means of increasing particulate saline droplets in the inhaled airstream and to liquefy thick lower airway secretions to hydrate the mucociliary system and enhance productive clearing. Mucolytic therapy is used commonly in veterinary patients, but scientific proof of its benefit is lacking. Nacetylcysteine (NAC) leads to a breakdown of the disulfide bonds in thick airway mucus and is also a precursor to glutathione, a free radical scavenger. Aerosolized NAC may irritate the airways and cause a reflex bronchoconstriction, however, and is not recommended. Dilute intravenous NAC therapy has been used in small animals, but its effects on the respiratory system via this route are unknown.

Physiotherapy Respiratory physiotherapy may be employed to support recovery in patients with pneumonia. A variety of techniques can be used with

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coupage, often following nebulization, being the most common in veterinary practice. Coupage of the chest refers to a rapid series of sharp percussions of the patient’s chest using cupped hands and closed fingers. The theory is that compression of air between the cupped hand and the chest wall creates vibrational energy that is transmitted to the underlying lungs to loosen deep secretions and consolidated areas of the lung and stimulate the cough reflex. Coupage is unnecessary in animals that are coughing spontaneously and frequently and may be contraindicated in animals that are coagulopathic, frequently regurgitating, showing signs of pain in the chest region, or are fractious. Further, no studies evaluating the impact of respiratory physiotherapy have been performed in veterinary patients. Even in human patients, the evidence base is weak and reliable conclusions about its utility cannot be made.79 Equally for recumbent patients, because atelectasis can exacerbate respiratory insufficiency, hospitalized patients with pneumonia who are recumbent should be turned every 1 to 2 hours (with exceptions made to allow for restful sleep). They should also be supported in an upright position at least every 12 hours and short walks should be encouraged.

PREVENTION Patients with severe pneumonia require intensive treatment and suffer considerable morbidity and mortality. Whenever possible, strategies to mitigate the risk of pneumonia should be implemented. For ventilator-associated pneumonia, good respiratory hygiene measures are crucial and are described in more detail in Chapters 37 and 40, Nursing Care of the Ventilator Patient and Ventilator-Associated Pneumonia, respectively. Proactive intervention can reduce the risk of perianesthetic aspiration. Guidelines on perianesthetic fasting suggest that 6 hours is appropriate to minimize gastric volumes and only 2 hours is necessary after liquid ingestion;80 however, the recommendation for perianesthetic fasting should not impede sedation or anesthesia in emergency situations. Evacuation of the stomach via suction or using a nasogastric or orogastric tube in anesthetized, high-risk patients may be appropriate.81 Enteral feeding, whether it is esophageal, gastric, or post pyloric, predisposes patients to aspiration pneumonia.82,83 Because nutritional support of critical patients is important for recovery, the aspiration risk should be minimized using safe feeding protocols. Care should be taken when recumbent patients are fed enterally, and the residual gastric volume should be ascertained before administration of food when possible. Feeding should be stopped at any sign of patient discomfort or resistance and the tube position checked.

PROGNOSIS AND OUTCOME Response to antimicrobial therapy is observed in most dogs (69% to 88%) when pneumonia is managed appropriately;5,8 acute, fulminant, hemorrhagic pneumonia of shelter dogs is an important exception.36,38 Long-term outcome depends on the ability to resolve the inciting or associated cause, with a cure expected when reversal of the trigger is possible (e.g., foreign body removal).84 In contrast, long-term management and frequent relapses can be expected when the predisposing cause lingers (e.g., idiopathic megaesophagus). Recurrent bouts of bacterial pneumonia should prompt the clinician to rule out laryngeal, pharyngeal, and esophageal disorders, bronchiectasis, the presence of an abscess or foreign body, other structural changes in the respiratory tract (e.g., ciliary dyskinesia), and inappropriate antimicrobial therapy (e.g., discontinuing therapy prematurely or antibiotic resistance).

Surgical treatment (lung lobectomy) has led to resolution of lobar pneumonia in 54% of dogs, with a higher percentage of success when a foreign body, or no bacterial isolates, were identified.84 Anecdotal reports and observations suggest that certain bacteria, specific underlying disorders, and empiric antimicrobial treatment instead of management based on culture and susceptibility are associated with a worse prognosis.5,8 Subjectively, the initial severity of clinical signs and response during treatment also offer prognostic information; however, a comprehensive assessment of specific, evidence-based prognostic parameters is lacking for small animals with bacterial pneumonia. Reported survival rates for aspiration pneumonia managed in academic referral institutions are 77% to 82%,17,19 and outcome does not appear to be dependent on the type or number of underlying disorders. Few prognostic indicators have been identified in dogs, but it should be recognized that lung injury severity after gastric aspiration represents a continuum between subclinical pneumonitis and ARDS with respiratory failure. Disease progression to ARDS and the need for ventilation heralds a lower survival rate. Fungal, viral, parasitic, and protozoal pneumonias vary in their response to management, often depending on pathogenicity of the offending organism, degree of systemic involvement, immunocompetence of the patient, and underlying risk factors.

REFERENCES 1. Brady CA: Bacterial pneumonia in dogs and cats. In King LG, editor: Textbook of respiratory disease in dogs and cats, St. Louis, 2004, Saunders, pp 412-421. 2. Cohn L: Pulmonary parenchymal diseases. In Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal medicine, ed 7, St. Louis, 2010, Elsevier, pp 1096-1119. 3. Wingfield WE, Matteson VL, Hackett T, et al: Arterial blood gases in dogs with bacterial pneumonia, J Vet Emerg Crit Care 7:75, 1997. 4. Angus JC, Jang SS, Hirsh DC: Microbiological study of transtracheal aspirates from dogs with suspected lower respiratory tract disease: 264 cases (1989-1995), J Am Vet Med Assoc 210:55, 1997. 5. Jameson PH, King LA, Lappin MR, Jones RL: Comparison of clinical signs, diagnostic findings, organisms isolated, and clinical outcome in dogs with bacterial pneumonia: 93 cases (1986-1991), J Am Vet Med Assoc 206:206, 1995. 6. Radhakrishnan A, Drobatz KJ, Culp WTN, et al: Community-acquired infectious pneumonia in puppies: 65 cases (1993-2002), J Am Vet Med Assoc 230:1493, 2007. 7. Chandler JC, Lappin MR: Mycoplasmal respiratory infections in small animals: 17 cases (1988-1999), J Am Anim Hosp Assoc 38:111, 2002. 8. Thayer GW, Robinson SK: Bacterial bronchopneumonia in the dog: a review of 42 cases, J Am Anim Hosp Assoc 20:731, 1984. 9. Macdonald ES, Norris CR, Berghaus RB, Griffey SM: Clinicopathologic and radiographic features and etiologic agents in cats with histologically confirmed infectious pneumonia: 39 cases (1991-2000), J Am Vet Med Assoc 223:1142, 2003. 10. Exarhos ND, Logan WD Jr, Abbott OA, et al: The importance of pH and volume in tracheobronchial aspiration, Dis Chest 47:167, 1965. 11. Kennedy TP, Johnson KJ, Kunkel RG, et al: Acute acid aspiration lung injury in the rat: biphasic pathogenesis, Anesth Analg 69:87, 1989. 12. Schwartz DJ, Wynne JW, Gibbs CP, et al: The pulmonary consequences of aspiration of gastric contents at pH values greater than 2.5, Am Rev Respir Dis 121:119, 1980. 13. Knight PR, Rutter T, Tait AR, et al: Pathogenesis of gastric particulate lung injury: a comparison and interaction with acidic pneumonitis, Anesth Analg 77:754, 1993. 14. Britto J, Demling RH: Aspiration lung injury, New Horiz 1:435, 1993. 15. Knight PR, Davidson BA, Nader ND, et al: Progressive, severe lung injury secondary to the interaction of insults in gastric aspiration, Exp Lung Res 30:535, 2004.

CHAPTER 24  Pneumonia 16. Wilkins PA, Otto CM, Baumgardner JE, et al: Acute lung injury and acute respiratory distress syndromes in veterinary medicine: consensus definitions: The Dorothy Russell Havemeyer Working Group on ALI and ARDS in Veterinary Medicine, J Vet Emerg Crit Care 17:333, 2007. 17. Kogan DA, Johnson LR, Sturges BK, et al: Etiology and clinical outcome in dogs with aspiration pneumonia: 88 cases (2004-2006), J Am Vet Med Assoc 233:1748, 2008. 18. Peyton JL, Burkitt JM: Critical illness-related corticosteroid insufficiency in a dog with septic shock, J Vet Emerg Crit Care 19:262, 2009. 19. Tart KM, Babski DM, Lee JA: Potential risks, prognostic indicators, and diagnostic and treatment modalities affecting survival in dogs with presumptive aspiration pneumonia: 125 cases (2005-2008), J Vet Emerg Crit Care 20:319, 2010. 20. Hoareau GL, Mellema MS, Silverstein DC: Indication, management, and outcome of brachycephalic dogs requiring mechanical ventilation, J Vet Emerg Crit Care 21:226, 2011. 21. Raghavendran K, Nemzek J, Napolitano LM, et al: Aspiration-induced lung injury, Crit Care Med 39:818, 2011. 22. Maboni G, Sequel M, Lorton A, et al: Canine infectious respiratory disease: new insights into the etiology and epidemiology of associated pathogens, PLoS One 14(4):0215817, 2019. 23. Chalker V, Brooks H, Brownlie J: The association of Streptococcus equi subsp. Zooepidemicus with canine infectious respiratory disease, Vet Microbiol 95(1-2):149, 2003. 24. Knesl O, Allan F, Shields S: The seroprevalence of canine respiratory coronavirus and canine influenza virus in dogs in New Zealand, N Z Vet J 57(5):295, 2009. 25. An D, Jeoung H, Jeong W, et al: A serological survey of canine respiratory coronavirus and canine influenza virus in Korean dogs, J Vet Med Sci 72(9):1217, 2010. 26. Kawakami K, Ogawa H, Maeda K, et al: Nosocomial outbreak of serious canine infectious tracheobronchitis (kennel cough) caused by canine herpesvirus infection, J Clin Microbiol 48(4):1176, 2010. 27. Jambhekar A, Robin E, Le Boedec K: A systematic review and meta-analysis of the association between 4 mycoplasma species and lower respiratory tract disease in dogs, J Vet Intern Med 33:1880-1891, 2019. 28. Mitchell J, Brooks H, Szladovits B, et al: Tropism and pathological findings associated with canine respiratory coronavirus (CRCoV), Vet Microbiol 162(2-4):582, 2013. 29. Day MJ, Carey S, Clercx C, et al: Aetiology of canine infectious respiratory disease complex and prevalence of its pathogens in Europe, J Comp Pathol 176:86-108, 2020. 30. Viitanen SJ, Lappalainen A, Rajamaki MM: Co-infections with respiratory viruses in dogs with bacterial pneumonia, JVIM 29(2):544-551, 2015. 31. Elia G, Camero M, Losurdo M, et al: Virological and serological findings in dogs with naturally occurring distemper, J Virol Methods 213:127-130, 2015. 32. Yoon KJ, Cooper VL, Schwartz KJ, et al: Influenza virus infection in racing greyhounds, Emerg Infect Dis 11(12):1974-1976, 2005. 33. Keil D, Fenwick B: Canine respiratory bordetellosis: keeping up with an evolving pathogen. In Carmichael LE, editor. Recent advances in canine infectious disease, Ithaca, NY, 2000, International Veterinary Information Service. Available at: http://www.ivis.org/advances/Infect_Dis_Carmichael/ keil/chapter.asp?LA51. 34. Chalker V, Owen W, Paterson C, et al: Mycoplasmas associated with canine infectious respiratory disease, Microbiology 150(10):3491, 2004. 35. Taha-Abdelaziz K, Bassel L, Harness M, et al: Cilia-associated bacteria in fatal Bordetella bronchiseptica pneumonia of dogs and cats, J Vet Diagn Invest 28(4):369, 2016. 36. Pesavento PA, Hurley KF, Bannasch MJ, et al: A clonal outbreak of acute fatal hemorrhagic pneumonia in intensively housed (shelter) dogs caused by Streptococcus equi subsp. zooepidemicus, Vet Pathol 45:51, 2008. 37. Priestnall S, Erles K: Streptococcus zooepidemicus: an emerging canine pathogen, Vet J 188(2):142, 2011. 38. Gower S, Payne R: Sudden deaths in greyhounds due to canine haemorrhagic pneumonia (letter), Vet Rec 170:630, 2012. 39. Workman H, Bailiff N, Jang S, et al: Capnocytophaga cynodegmi in a Rottweiler dog with severe bronchitis and foreign-body pneumonia, J Clin Microbiol 46(12):4099, 2008.

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40. Schultz R, Zwingenberger A: Radiographic, computed tomographic, and ultrasonographic findings with migrating intrathoracic grass awns in dogs and cats, Vet Radiol Ultrasound 49(3):249, 2008. 41. Tenwolde A, Johnson L, Hunt G, et al: The role of bronchoscopy in foreign body removal in dogs and cats: 37 cases (2000-2008), J Vet Intern Med 24(5):1063, 2010. 42. Danesi P, Ravagnan S, Johnson LR, et al: Molecular diagnosis of Pneumocystis pneumonia in dogs, Med Mycol 55(8):828-842, 2017. 43. Sigrist NE, Adamik KN, Doherr MG, et al: Evaluation of respiratory parameters at presentation as clinical indicators of the respiratory localization in dogs and cats with respiratory distress, J Vet Emerg Crit Care 21:13, 2011. 44. Kogan DA, Johnson LR, Jandrey KE, et al: Clinical, clinicopathologic, and radiographic findings in dogs with aspiration pneumonia: 88 cases (2004-2006), J Am Vet Med Assoc 233:1742, 2008. 45. Eom K, Seong Y, Park H, et al: Radiographic and computed tomographic evaluation of experimentally induced lung aspiration sites in dogs, J Vet Sci 7:397, 2006. 46. Dear JD: Bacterial pneumonia in dogs and cats: an update, Vet Clin North Am Small Anim Prac 50(2):447-465, 2020. 47. Boag AK, Lamb CR, Chapman PS, Boswood A: Radiographic findings in 16 dogs infected with Angiostrongylus vasorum, Vet Record 154(14): 426-430, 2004. 48. Crews LJ, Feeney DA, Jessen CR, Newman AB: Radiographic findings in dogs with pulmonary blastomycosis: 125 cases (1989-2006), J Am Vet Med Assoc 232:215-221, 2008. 49. Prather AB, Berry CR, Thrall DE: Use of radiography in combination with computed tomography for the assessment of noncardiac thoracic disease in the dog and cat, Vet Radiol Ultrasound 46:114, 2005. 50. Touw HRW, Tuinman PR, Gelissen HPMM, et al: Lung ultrasound: routine practice for the next generation of internists, Neth J Med 73(3): 100-107, 2015. 51. Moser KM, Maurer J, Jassy L, et al: Sensitivity, specificity, and risk of diagnostic procedures in a canine model of Streptococcus pneumoniae pneumonia, Am Rev Respir Dis 125:436, 1982. 52. Creighton SR, Wilkins RJ: Bacteriologic and cytologic evaluation of animals with lower respiratory tract disease using transtracheal aspiration biopsy, J Am Anim Hosp Assoc 10:227, 1974. 53. Angus JC, Jang SS, Hirsh DC: Microbiological study of transtracheal aspirates from dogs with suspected lower respiratory tract disease: 264 cases (1989-1995), J Am Vet Med Assoc 210:55, 1997. 54. Woodhead M, Blasi F, Ewig S, et al: Guidelines for the management of adult lower respiratory tract infections—full version, Clin Microbiol Infect 17(Suppl 6):E1, 2011. 55. Sachdev A, Chugh K, Sethi M, et al: Diagnosis of ventilator-associated pneumonia in children in resource-limited setting: a comparative study of bronchoscopic and nonbronchoscopic methods, Pediatr Crit Care Med 11:258, 2010. 56. Sauve V, Drobatz KJ, Shokek AB, et al: Clinical course, diagnostic findings, and necropsy diagnosis in dyspneic cats with primary pulmonary parenchymal disease: 15 cats (1996-2002), J Vet Emerg Crit Care 15:38, 2005. 57. Karakioulaki M, Stoltz D: Biomarkers in pneumonia: beyond calcitonin, Int J Mol Sci 20:2004, 2019. 58. Berg P, Lindhardt BO: The role of procalcitonin in adult patients with community-acquired pneumonia—a systematic review, Dan Med J 59:A4357, 2012. 59. Vitaanes SJ, Laurila HP, Lilja-Maura LI, et al: Serum C-reactive protein as a diagnostic biomarker in dogs with bacterial respiratory disease, J Vet Intern Med 28(1):84-91, 2014. 60. Jaoude PA, Knight PR, Ohtake P, et al: Biomarkers in the diagnosis of aspiration syndromes, Expert Rev Mol Diagn 10:309, 2010. 61. Zucker AR, Holm BA, Crawford GP, et al: PEEP is necessary for exogenous surfactant to reduce pulmonary edema in canine aspiration pneumonitis, J Appl Physiol 73:679, 1992. 62. Willson DF, Notter RH: The future of exogenous surfactant therapy, Respir Care 56:1369, 2011. 63. Taut FJ, Rippin G, Schenk P, et al: A Search for subgroups of patients with ARDS who may benefit from surfactant replacement therapy: a pooled

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analysis of five studies with recombinant surfactant protein-C surfactant (Venticute), Chest 134:724, 2008. 64. Spragg RG, Taut FJ, Lewis JF, et al: Recombinant surfactant protein C-based surfactant for patients with severe direct lung injury, Am J Respir Crit Care Med 183:1055, 2011. 65. Jagodich TA, Bersenas AM, Bateman SW, Kerr CL: Comparison of high flow nasal cannula oxygen administration to traditional nasal cannula oxygen therapy in healthy dogs, J Vet Emerg Crit Care 29(3):246-255, 2019. 66. Jagodich TA, Bersenas AM, Bateman SW, Kerr CL: High-flow nasal cannula oxygen therapy in acute hypoxemic respiratory failure in 22 dogs requiring oxygen support escalation, J Vet Emerg Crit Care 30(4):364-375, 2020. 67. Jagodich TA, Bersenas AM, Bateman SW, Kerr CL: Preliminary evaluation of the use of high-flow nasal cannula oxygen therapy during recovery from general anesthesia in dogs with obstructive upper airway breathing, J Vet Emerg Crit Care 30(4):487-492, 2020. 68. Nader-Djalal N, Knight PR, Davidson BA, et al: Hyperoxia exacerbates microvascular lung injury following acid aspiration, Chest 112:1607, 1997. 69. Matthay MA, Ware LB, Zimmerman GA: The acute respiratory distress syndrome, J Clin Invest 122:2731, 2012. 70. Hopper K, Haskins SC, Kass PH, et al: Indications, management, and outcome of long-term positive-pressure ventilation in dogs and cats: 148 cases (1990-2001), J Am Vet Med Assoc 230:64, 2007. 71. Epstein SE, Mellema MS, Hopper K: Airway microbial culture and susceptibility patterns in dogs and cats with respiratory disease of varying severity, J Vet Emerg Crit Care 20:587, 2010. 72. Lappin MR, Blondeau J, Boothe D, et al: Antimicrobial use guidelines for treatment of respiratory tract disease in dogs and cats: antimicrobial guidelines working group of the International Society for Companion Animal Infectious Diseases, J Vet Intern Med 31:279, 2017. 73. Morley PS, Apley MD, Besser TE, et al: Antimicrobial drug use in veterinary medicine, J Vet Intern Med 19:617, 2005.

74. Matthay MA, Brower RG, Carson S, et al: Randomized, placebo-controlled clinical trial of an aerosolized beta (2)-agonist for treatment of acute lung injury, Am J Respir Crit Care Med 184:561, 2011. 75. Gao Smith F, Perkins GD, Gates S, et al: Effect of intravenous beta-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicenter, randomized controlled trial, Lancet 379:229, 2012. 76. Dellinger RP, Levy MM, Rhodes A, et al: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012, Intensive Care Med 39:165, 2013. 77. Stern A, Skalsky K, Avni T, et al: Corticosteroids for pneumonia, Cochrane Database Syst Rev 12:CD007720, 2017. 78. Povoa P, Coelho L, Salluh J: When should we use corticosteroids in severe community acquired pneumonia? Curr Opin Infect Dis 34(2):169, 2021. 79. Chaves GSS, Freitas DA, Santino TA, et al: Chest physiotherapy for pneumonia in children, Cochrane Database Syst Rev 1:CD010277, 2019. 80. ASA: Practice guidelines for preoperative fasting and the use of pharmacologic agents to reduce the risk of pulmonary aspiration: application to healthy patients undergoing elective procedures: an updated report by the American Society of Anesthesiologists Committee on Standards and Practice Parameters, Anesthesiology 114:495, 2011 81. Jensen AG, Callesen T, Hagemo JS, et al: Scandinavian clinical practice guidelines on general anaesthesia for emergency situations, Acta Anaesthesiol Scand 54:922, 2010. 82. Kazi N, Mobarhan S: Enteral feeding associated gastroesophageal reflux and aspiration pneumonia: a review, Nutr Rev 54:324, 1996. 83. Marik PE, Zaloga GP: Gastric versus post-pyloric feeding: a systematic review, Crit Care 7:R46, 2003. 84. Murphy ST, Ellison GW, McKiernan BC, Mathews KG, Kubilis PS: Pulmonary lobectomy in the management of pneumonia in dogs: 59 cases (1972-1994), J Am Vet Med Assoc 210:235, 1997.

25 Acute Respiratory Distress Syndrome Laura Osborne, BVSc Hons, DACVECC, Kate Hopper, BVSc, PhD, DACVECC

KEY POINTS • Acute respiratory distress syndrome (ARDS) is a syndrome of increasing severity of pulmonary edema resulting from an increase in pulmonary capillary endothelial permeability in response to an underlying local or systemic inflammatory process. • ARDS is a clinical diagnosis, recognized by the development of respiratory failure as evidenced by specific criteria in a patient with a predisposing medical or surgical risk factor.

• ARDS is associated with a high mortality rate. Management strategies involve implementation of lung protective ventilatory support in addition to identification and specific treatment of the predisposing underlying clinical risk factor.

INTRODUCTION

injury (VILI) (see Chapter 39). Many of the changes seen on histopathology can be created by VILI; however, the incidence of adverse effects (e.g., diffuse alveolar damage) has declined with the widespread use of lung protective ventilation.4 This may account for some of the variability in histopathological changes noted between studies.

Acute respiratory distress syndrome (ARDS) is a form of severe hypoxemic respiratory failure with a high mortality rate that results from an inflammatory insult to the lung. It most commonly occurs secondary to an infectious process, with pneumonia, aspiration pneumonia, and sepsis accounting for more than 85% of human cases of ARDS.1 The clinical diagnosis of ARDS lacks a gold standard and relies on meeting a set of nonspecific criteria, which likely results in underdiagnosis of the disease.2 The incidence of ARDS in small animal veterinary medicine is unknown as most animals are not screened with the appropriate diagnostic tests to make a definitive diagnosis. In human medicine, the incidence of ARDS in the ICU patient population is reported to range from 2% to 19%.2 The difference likely reflects variations in diagnostic criteria for ARDS, as well as the nature of the ICU populations in these studies.

PATHOPHYSIOLOGY The major gas exchange surface of the alveolus is composed of type 1 alveolar epithelial cells in close association with the pulmonary capillary endothelium. The type 1 cells perform the crucial role of maintaining the permeability function of the alveolar membrane.3 The inciting cause of ARDS is an inflammatory insult that damages either the alveolar epithelial cells or the pulmonary capillary endothelial cells. This insult impairs the normal barrier function and results in a permeability defect that leads to flooding of the interstitium and alveoli with protein-rich fluid and inflammatory cells. This leads to surfactant dysfunction, which promotes atelectasis and altered pulmonary mechanics, as well as impaired gas exchange through both diffusion impairment and venous admixture from intrapulmonary shunting.1 The inciting inflammatory insult to the lung can be of local origin (primary pulmonary disease) or extrapulmonary origin. The progression of ARDS has been divided into phases that are described here to aid in understanding, but it is recognized that there is substantial variability and overlap between phases in clinical patients. The pathophysiology of ARDS is further confounded by the influence of ventilator-induced lung

Acute Exudative Phase The first 1 to 7 days of ARDS is typified by diffuse alveolar damage with hyaline membrane formation and neutrophil influx. Alveolar flooding with fluid, protein, leukocytes, and red blood cells occurs as a result of injury to the alveolar epithelial cell-capillary endothelial cell barrier. These changes are the result of activation of the innate immune system of the lung, causing stimulation of alveolar macrophages and recruitment of neutrophils and circulating macrophages to the lung. Immune cell activation results in widespread release of inflammatory mediators including cytokines, reactive oxygen species, and eicosanoids. These have many deleterious actions such as alveolar epithelial cell damage, protein degradation, surfactant dysfunction, increased permeability of the endothelialepithelial barrier of the alveolus, and development of local microthrombi. Neutrophils are considered to play a central role in this response, accumulating in the lung and releasing numerous injurious substances.5

Fibroproliferative Phase In the weeks following the exudative phase, there is proliferation of type II alveolar epithelial cells, interstitial fibrosis, and organization of the exudate. In human patients this phase can last for more than 3 weeks. As fibrosis progresses, there is further derangement of the architecture of the lung, resulting in significant reductions in lung compliance. Proliferation of type II alveolar epithelial cells, interstitial thickening, and obliteration of alveoli and capillary networks contribute to ongoing hypoxemia during this period. There is evidence that fibrosis can begin as early as 48 hours after onset of ARDS.6

Outcome The resolution of ARDS requires apoptosis of neutrophils, differentiation of type II alveolar epithelial cells into type I, termination of the

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fibroproliferative response, and reabsorption of alveolar edema and the provisional matrix.1 Pulmonary fibrosis following ARDS may or may not fully resolve; however, most surviving human patients recover near-normal pulmonary function within 6–12 months. Despite this, many have long-term disability and compromised quality of life.7

Ventilator-Induced Lung Injury It is now well recognized that the ventilatory strategy utilized in the management of ARDS patients may augment lung injury or impair healing. Experimental studies using animals with healthy lungs have demonstrated that ventilatory strategies using large tidal volumes or high peak airway pressures elicit clinical, physiologic, and histologic abnormalities analogous to those observed in patients with ARDS. The alveolar overdistention (volutrauma) created by these ventilatory modes is criticized as the crucial insult in the production and propagation of lung injury. Other mechanisms potentially contributing to VILI include repetitive recruitment and collapse of the distal airways and alveoli (atelectrauma), which in turn stimulates the release of proinflammatory mediators (biotrauma), as well as disruption of alveoli due to excessive pressure (barotrauma) and oxygen toxicity.8

TABLE 25.1  Reported Causes of Acute

Respiratory Distress Syndrome in Veterinary Patients12,13 COMMONLY REPORTED CAUSES ON DOGS AND CATS Direct Pulmonary Causes Aspiration pneumonia14 Pneumonia Pulmonary contusions Chest trauma Mechanical ventilation

Indirect Extrapulmonary Causes Sepsis SIRS Shock Pancreatitis15 Trauma16,17 Acute kidney injury Multiple transfusions18

Additional Causes Reported in Veterinary Medicine Bee envenomation21 Smoke inhalation19 20 Lung lobe torsion Adverse drug reactions22-24 Tracheal collapse Paraquat intoxication25

ARDS Phenotypes Two phenotypes of ARDS have been identified on the basis of clinical indices and biomarkers: hypoinflammatory and hyperinflammatory. The hyperinflammatory phenotype, which constitutes approximately 30% of patients, is associated with an increased prevalence of shock and metabolic acidosis, as well as a higher mortality rate than the hypoinflammatory phenotype.9 The two phenotypes have also been shown to have different responses to positive end expiratory pressure (PEEP) and fluid management interventions in the ALVEOLI and FACCT trials respectively, and therefore may require different management strategies. Increased awareness of the heterogeneity of ARDS and enhanced understanding of the underlying pathophysiology may improve prognostication and enable specific biological therapies in the future.10

CAUSES/RISK FACTORS ARDS represents the manifestation of an inflammatory insult to the lung from a variety of inciting causes. The inciting cause of ARDS is commonly categorized as either primary pulmonary disease (direct cause) or extrapulmonary disease (indirect cause). Direct lung injury results in local damage to the lung epithelium, whereas indirect lung injury is due to systemic inflammatory disorders that diffusely damage the vascular endothelium.11 The two retrospective studies evaluating risk factors for ARDS in veterinary medicine have noted aspiration pneumonia as a common direct inciting cause in dogs, and SIRS and sepsis as common indirect causes in both dogs and cats (Table 25.1).12,13

DIAGNOSTIC CRITERIA Diffuse alveolar damage is the pathological hallmark of ARDS. To date, there is no specific diagnostic laboratory test for the diagnosis of ARDS, and in small animals it is based on clinical criteria that have been adapted from human medicine.26 In 1994, the American European Consensus Conference (AECC) established the original diagnostic criteria for ARDS, which were clinically based and included (1) acute onset of respiratory distress, (2) bilateral infiltrates on chest radiographs, (3) hypoxemia, and (4) pulmonary artery wedge pressure ,18 mm Hg or the absence of clinical evidence of left atrial hypertension.27 The definition regarded acute lung injury (ALI) as a continuum, identifying ARDS in patients with more severe oxygenation abnormalities. The AECC definition was subsequently challenged due

to issues regarding its reliability and validity between the clinical diagnosis of ARDS and autopsy findings.28 The human medical definition was revised in 2012 to address limitations regarding the lack of standardized ventilator settings at the time of blood gas analysis, resulting in the modified Berlin definition. This removed the term ALI and categorizes ARDS as mild, moderate, or severe in patients receiving mechanical ventilation with a PEEP of 5 mm Hg (Table 25.2).29 In 2007, the Dorothy Russell Havemeyer Working Group developed diagnostic criteria for ARDS in small animals, which mirrored the original AECC definition (Table 25.2). Similarly, four criteria were required for the diagnosis of ARDS: (1) acute onset of respiratory distress (,72 hours), (2) presence of known risk factors, (3) evidence of pulmonary capillary leak without increased pulmonary capillary pressure, and (4) evidence of inefficient gas exchange. Evidence of diffuse pulmonary inflammation was included as an optional fifth criterion due to the logistical and financial constraints of performing airway sampling in critically ill animals. Using this definition, animals with mild hypoxemia (PaO2/FiO2 ratio 300) are categorized as having ALI.26 Similar to the first iteration of the human definition, the VetARDS definition has limitations and does not account for animals receiving mechanical ventilation. Thoracic imaging is a crucial diagnostic criterion and CT imaging, while not commonly performed in the veterinary respiratory distress patient, is considered the gold standard imaging modality. One human study concluded that thoracic radiographs may underestimate the occurrence of ARDS.30,31 It has also been demonstrated that even amongst trained experts there is often disagreement regarding the interpretation of the thoracic radiograph.32 In addition, none of the tests within the VetARDS criteria for evidence of pulmonary capillary leak without increased pulmonary capillary pressure are ideal methods for evaluation of left atrial pressure, as highlighted in a retrospective cohort study in which a necropsy diagnosis of CHF was made in two dogs with a clinical diagnosis of ARDS.12 Furthermore, arterial blood gas analysis is not always achievable in dogs and is generally unfeasible in cats with respiratory distress. Studies in human medicine have validated the use of the oxygen saturation/fraction of inspired oxygen (SpO2/FiO2 [S/F]) ratio for the diagnosis of ARDS.33,34 Studies in dogs have found a good correlation between the P/F and S/F ratios,35,36 and the use of the S/F ratio as a surrogate marker of hypoxemia may be an attractive alternative to aid in the diagnosis of ARDS in small animals.

CHAPTER 25  Acute Respiratory Distress Syndrome

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TABLE 25.2  Comparison of the Berlin Definition26 with the Veterinary Definition of Acute Lung

Injury and Acute Respiratory Distress Syndrome26 Criteria Timing Origin of Edema/ Diagnostics

Oxygenation*

The Berlin Definition of Acute Respiratory Distress Syndrome

Definition of Veterinary Acute Lung Injury and Acute Respiratory Distress Syndrome

Within 1 week of a known clinical insult or new or worsening respiratory symptoms • Respiratory failure not fully explained by cardiac failure or fluid overload. Need objective assessment (e.g., echocardiography) to exclude hydrostatic edema if no risk factor present • Bilateral opacities – not fully explained by effusions, lobar/lung collapse, or nodules (chest radiograph or computed tomography) Mild: 200 mm Hg ,PaO2/FiO2 #300 mm Hg with PEEP or CPAP $5 cm H2O Moderate: 100 mm Hg ,PaO2/FiO2 #200 mm Hg with PEEP $5 cm H2O Severe: PaO2/FiO2 #100 mm Hg with PEEP $5 cm H2O

• Acute onset (,72 hours) of tachypnea and labored breathing at rest • Known risk factors Evidence of pulmonary capillary leak without increased pulmonary capillary pressurea (any one of the following): a. Bilateral/diffuse infiltrates on thoracic radiographs (more than 1 quadrant/lobe) b. Bilateral dependent density on computed tomography c. Proteinaceous fluid within the conducting airways d. Increased extravascular lung water Evidence of inefficient gas exchange (any one or more of the following): a. Hypoxemia without PEEP or CPAP and known FiO2 i. PaO2/FiO2 ratio 1. #300 mm Hg for VetALI 2. #200 mm Hg for VetARDS ii. Increased alveolar–arterial oxygen gradient iii. Venous admixture (noncardiac shunt) b. Increased dead space ventilation Evidence of diffuse pulmonary inflammation a. Transtracheal wash/bronchoalveolar lavage sample neutrophilia b. Transtracheal wash/bronchoalveolar lavage biomarkers of inflammation c. Molecular imaging (PET)

Additional Criteria

*If at altitude higher than 1000 m, then a correction factor should be calculated as follows: [PaO2/FiO2 3 (barometric pressure/760)] a No evidence of cardiogenic edema (one or more of the following): PAOP ,18 mm Hg; no clinical or diagnostic evidence supporting left sided heart failure, including echocardiography. CPAP, continuous positive airway pressure; PEEP, positive end expiratory pressure; PET, positron emission tomography.

MANAGEMENT A hallmark of ARDS is refractory hypoxemia that is primarily due to venous admixture from intrapulmonary shunting.6 Severely affected patients are not responsive to oxygen therapy but may be responsive to positive pressure ventilation, which recruits alveoli and reduces the shunt fraction. Basic management strategies for patients with ARDS include provision of lung protective ventilatory support in addition to the identification and specific treatment of the predisposing underlying clinical risk factor. In one retrospective study, VetALI and VetARDS necessitated mechanical ventilation in 50% of dogs and 80% of cats,13 while a second retrospective study reported that mechanical ventilation was recommended in 86% of animals with a clinical diagnosis of ARDS.12 See Chapter 33 for more information regarding advanced mechanical ventilation of small animals; management strategies specific to ARDS patients are detailed below.

The Baby Lung Concept The baby lung concept originated from observations of CT images of ARDS patients that demonstrated two distinct lung regions: the nondependent nearly normal lung with dimensions similar to a healthy baby that was subject to harm from mechanical ventilation, and the second dependent region of consolidated and collapsed lung that was primarily responsible for the impairment in oxygenation.37 This concept is now understood to be a functional rather than anatomical division of the lung and provides physiologic reasoning to help understand VILI and the rationale for lung protective ventilation.38

The Open Lung Strategy and Lung Protective Ventilation The open lung strategy, originally proposed by Lachmann, aims to reduce atelectrauma and shear stress in heterogeneously ventilated lungs by using recruitment maneuvers to open up collapsed lung and higher PEEP to maintain alveolar stability.4 The use of recruitment maneuvers is currently controversial, with the ART trial reporting that its application was associated with increased mortality in patients with moderate to severe ARDS.39 The PHARLAP trial was subsequently abandoned due to loss of clinical equipoise following the ART trial; however, it did reveal that the intervention was associated with harmful cardiovascular consequences.40 Two recent systematic reviews of recruitment maneuvers found no improvement in mortality rate and increased rates of hemodynamic compromise despite improvement in oxygenation and reduced use of rescue therapies for hypoxemia.14,41 The open lung concept, combined with low tidal volume ventilation in line with the baby lung concept, form the foundation of lung protective ventilation. It is well established that mechanical ventilation with lower tidal volumes (4–6 ml/kg predicted body weight) and end-inspiratory plateau pressures (,30 cm H2O) reduce mortality in human patients with ARDS.42 By preventing alveolar overdistention and the associated VILI, this lung protective strategy preserves the epithelial–endothelial barrier and improves outcomes.43 PEEP is a major component of the protective ventilatory strategy; by recruiting atelectatic lung units and preventing cyclic atelectasis, it increases the functional residual capacity, decreases the shunt fraction, and allows for a reduction to a less toxic FiO2. While conventional mechanical ventilation is most commonly utilized in veterinary medicine, airway pressure release ventilation is an inverse ratio, pressure controlled,

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intermittent mandatory ventilation with unrestricted spontaneous breathing based on the open lung approach, and its use has been reported in the successful management of a canine patient with refractory hypoxemia.44

Conservative Fluid Management Due to increased endothelial permeability, fluid therapy may exacerbate alveolar edema in ARDS patients. Conservative fluid management has been shown to reduce ventilator days in people with ARDS.45

Pharmacologic Therapy Reported benefits of corticosteroids in ARDS include attenuation of proinflammatory cytokine production and prevention of progression to the fibroproliferative stage through inhibition of fibroblast proliferation and collagen deposition.46 There is currently controversy and low certainty evidence regarding the use of corticosteroids in ARDS, with studies demonstrating both increased and decreased mortality rates and no conclusive large scale trial in the period of lung protective ventilation.47 Current human guidelines suggest the use of corticosteroids in patients with early moderate to severe ARDS.48 Many other pharmacologic agents have been trialed for the treatment of ARDS with limited success, including inhaled pulmonary vasodilators, inhaled surfactants, N-acetylcysteine, statins, and beta- agonists. Inhaled nitric oxide and prostacyclins act as selective pulmonary vasodilators, resulting in improved ventilation–perfusion matching and arterial oxygenation; however, they have not shown a mortality benefit. Injury to type II alveolar epithelial cells in ARDS patients reduces the amount and function of surfactant produced, increasing alveolar surface tension and promoting atelectasis. Treatment of ARDS patients with surfactant nevertheless has not been demonstrated to alter mortality or reduce the duration of mechanical ventilation. Similarly, a benefit of antioxidant therapy with N-acetylcysteine has not been demonstrated. It has also been concluded that the antiinflammatory and immunomodulatory effects of statins probably make no difference to early mortality or duration of mechanical ventilation. Both aerosolized and intravenous beta-agonists have been trialed in ARDS to improve alveolar fluid clearance; however, they have been unsuccessful and their use is possibly associated with increased early mortality.47,48

PROGNOSIS The clinical risk factors associated with the development of ARDS appear to greatly influence the expected outcome, with the nature of the inciting insult (direct pulmonary insult vs extrapulmonary) affecting the response to ventilatory support. Recent studies evaluating lung protective ventilation strategies have demonstrated a significant reduction in mortality rate; however, current mortality rates for human ARDS patients are still higher than 40%.1,42,49 A retrospective study on long-term mechanical ventilation in dogs and cats found that ARDS was associated with a mortality rate of 92%.50 There are numerous case reports describing ARDS in dogs, with only one dog surviving without mechanical ventilation.51 There are two case reports describing ARDS in cats, with one dying and the other being euthanatized.16,52 In one retrospective cohort study, the overall case fatality rate in animals diagnosed clinically with ARDS was 84% in dogs and 100% in cats, with the majority being euthanatized within the 24 hour period following diagnosis of ARDS.12 In another retrospective evaluation of 29 cases in dogs and cats, only 10% of patients survived.13 Given the costs associated with long-term mechanical ventilation, a true understanding of the natural mortality rate of this disease in veterinary patients is clouded by elective euthanasia.

REFERENCES 1. Thompson BT, Chambers RC, Liu KD: Acute respiratory distress syndrome, N Engl J Med 377:562-572, 2017. 2. Bellani G, Laffey JG, Pham T, et al: Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries, JAMA 315:788-800, 2016. 3. Lumb A, ed: Functional anatomy of the respiratory tract. In Nunn’s applied respiratory physiology, ed 8, New York, 2017, Elsevier, pp 3-16. 4. van der Zee P, Gommers D: Recruitment maneuvers and higher PEEP, the so-called open lung concept, in patients with ARDS, Crit Care 23:73, 2019. 5. Matthay MA, Zemans RL: The acute respiratory distress syndrome: pathogenesis and treatment. In Abbas AK, Galli SJ, Howley PM, editors: Annual review of pathology: mechanisms of disease, vol 6, Palo Alto, 2011, Annual Reviews, pp 147-163. 6. Bellingan GJ: The pulmonary physician in critical care * 6: The pathogenesis of ALI/ARDS, Thorax 57:540-546, 2002. 7. Matthay MA, Zemans RL, Zimmerman GA, et al: Acute respiratory distress syndrome, Nat Rev Dis Primers 5:22, 2019. 8. Beitler JR, Malhotra A, Thompson BT: Ventilator-induced lung injury, Clin Chest Med 37:633, 2016. 9. Spadaro S, Park M, Turrini C, et al: Biomarkers for acute respiratory distress syndrome and prospects for personalised medicine, J Inflamm (London) 16:1, 2019. 10. Sinha P, Calfee CS: Phenotypes in acute respiratory distress syndrome: moving towards precision medicine, Curr Opin Crit Care 25:12-20, 2019. 11. Shaver CM, Bastarache JA: Clinical and biological heterogeneity in acute respiratory distress syndrome: direct versus indirect lung injury, Clin Chest Med 35:639-653, 2014. 12. Boiron L, Hopper K, Borchers A: Risk factors, characteristics, and outcomes of acute respiratory distress syndrome in dogs and cats: 54 cases, J Vet Emerg Crit Care 29:173-179, 2019. 13. Balakrishnan A, Drobatz KJ, Silverstein DC: Retrospective evaluation of the prevalence, risk factors, management, outcome, and necropsy findings of acute lung injury and acute respiratory distress syndrome in dogs and cats: 29 cases (2011-2013), J Vet Emerg Crit Care 27:662-673, 2017. 14. Pensier J, de Jong A, Hajjej Z, et al: Effect of lung recruitment maneuver on oxygenation, physiological parameters and mortality in acute respiratory distress syndrome patients: a systematic review and meta-analysis, Intensive Care Med 45(12):1691-1702, 2019. 15. López A, Lane IF, Hanna P: Adult respiratory distress syndrome in a dog with necrotizing pancreatitis, Can Vet J 36:240-241, 1995. 16. Katayama M, Okamura Y, Katayama R, et al: Presumptive acute lung injury following multiple surgeries in a cat, Can Vet J 54:381, 2013. 17. Kelmer E, Love LC, Declue AE, et al: Successful treatment of acute respiratory distress syndrome in 2 dogs, Can Vet J 53:167-173, 2012. 18. Thomovsky EJ, Bach J: Incidence of acute lung injury in dogs receiving transfusions, J Am Vet Med Assoc 244:170-174, 2014. 19. Guillaumin J, Hopper K: Successful outcome in a dog with neurological and respiratory signs following smoke inhalation, J Vet Emerg Crit Care 23:328-334, 2013. 20. Neath P, Brockman D, King L: Lung lobe torsion in dogs: 22 cases (1981-1999), J Am Vet Med Assoc 217:1041-1044, 2000. 21. Annane MD, Pastores AS, Rochwerg SB, et al: Guidelines for the diagnosis and management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in critically ill Patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017, Crit Care Med 45:2078-2088, 2017. 22. Hart SK, Waddell L: Suspected drug-induced infiltrative lung disease culminating in acute respiratory failure in a dog treated with cytarabine and prednisone, J Vet Emerg Crit Care 26:844-850, 2016. 23. Greensmith TD, Cortellini S: Successful treatment of canine acute respiratory distress syndrome secondary to inhalant toxin exposure, J Vet Emerg Crit Care 28:469-475, 2018. 24. Botha H, Jennings SH, Press SA, et al: Suspected acute respiratory distress syndrome associated with the use of intravenous lipid emulsion therapy in a dog: a case report, Front Vet Sci 6:225, 2019.

CHAPTER 25  Acute Respiratory Distress Syndrome 25. Kelly DF, Morgan DG, Darke PGG, et al: Pathology of acute respiratory distress in the dog associated with paraquat poisoning, J Comp Pathol 88:275-294, 1978. 26. Wilkins PA, Otto CM, Baumgardner JE, et al: Acute lung injury and acute respiratory distress syndromes in veterinary medicine: consensus definitions: The Dorothy Russell Havemeyer Working Group on ALI and ARDS in Veterinary Medicine, J Vet Emerg Crit Care 17:333-339, 2007. 27. Bernard GR, Artigas A, Brigham KL, et al: The American-European consensus conference on ARDS - definitions, mechanisms, relevant outcomes, and clinical-trial coordination, Am J Respir Crit Care Med 149:818-824, 1994. 28. Esteban A, Fernández-Segoviano P, Frutos-Vivar F, et al: Comparison of clinical criteria for the acute respiratory distress syndrome with autopsy findings, Ann Intern Med 141:440-445, 2004. 29. Ranieri VM, Rubenfeld GD, Thompson BT, et al: Acute respiratory distress syndrome: the Berlin Definition, JAMA 307:2526-2533, 2012. 30. Zompatori M, Ciccarese F, Fasano L: Overview of current lung imaging in acute respiratory distress syndrome, Eur Respir Rev 23:519-530, 2014. 31. Figueroa-Casas JB, Brunner N, Dwivedi AK, et al: Accuracy of the chest radiograph to identify bilateral pulmonary infiltrates consistent with the diagnosis of acute respiratory distress syndrome using computed tomography as reference standard, J Crit Care 28:352-357, 2013. 32. Peng JM, Qian CY, Yu XY, et al: Does training improve diagnostic accuracy and inter-rater agreement in applying the Berlin radiographic definition of acute respiratory distress syndrome? A multicenter prospective study, Crit Care (London, England) 21:12, 2017. 33. Bilan N, Dastranji A, Ghalehgolab Behbahani A: Comparison of the Spo2/ Fio2 ratio and the Pao2/Fio2 ratio in patients with acute lung injury or acute respiratory distress syndrome, J Cardiovasc Thorac Res 7:28-31, 2015. 34. Rice TW, Wheeler AP, Bernard GR, et al: Comparison of the SpO(2)/ FIO2 ratio and the Pao(2)/FIO2 ratio in patients with acute lung injury or ARDS, Chest 132:410-417, 2007. 35. Calabro JM, Prittie JE, Palma DA: Preliminary evaluation of the utility of comparing SpO2/FiO2 and PaO2/FiO2 ratios in dogs, J Vet Emerg Crit Care 23:280, 2013. 36. Carver A, Bragg R, Sullivan L: Evaluation of PaO2/FiO2 and SaO2/FiO2 ratios in postoperative dogs recovering on room air or nasal oxygen insufflation, J Vet Emerg Crit Care 26:437-445, 2016. 37. Gattinoni L, Pesenti A: The concept of “baby lung”, Intensive Care Med 31:776-784, 2005. 38. Gattinoni L, Marini J, Pesenti A, et al: The “baby lung” became an adult, Intensive Care Med 42:663-673, 2016. 39. ART Investigators Writing Group: Effect of lung recruitment and titrated positive end-expiratory pressure (PEEP) vs low PEEP on mortality in

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patients with acute respiratory distress syndrome: a randomized clinical trial, JAMA 318(14):1335-1345, 2017. 40. Hodgson CL, Cooper DJ, Arabi Y, et al: Maximal recruitment open lung ventilation in acute respiratory distress syndrome (PHARLAP). A phase II, multicenter randomized controlled clinical trial, Am J Respir Crit Care Med 200(11):1363-1372, 2019. 41. Cui Y, Cao R, Wang Y, Li G: Lung recruitment maneuvers for ARDS patients: a systematic review and meta-analysis, Respiration 99(3): 264-276, 2020. 42. Brower R, Matthay M, Morris A, et al: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome, N Engl J Med 342:1301-1308, 2000. 43. Parsons EP, Eisner DM, Thompson TB, et al: Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury, Crit Care Med 33:1-6, 2005. 44. Sabino CV, Holowaychuk M, Bateman S: Management of acute respiratory distress syndrome in a French Bulldog using airway pressure release ventilation, J Vet Emerg Crit Care 23:447-454, 2013. 45. Wiedemann HP, Wheeler AP, Bernard GR, et al: Comparison of two fluidmanagement strategies in acute lung injury. (Disease/Disorder overview), N Engl J Med 354:2564, 2006. 46. Aharon MA, Prittie JE, Buriko K: A review of associated controversies surrounding glucocorticoid use in veterinary emergency and critical care, J Vet Emerg Crit Care 27:267-277, 2017. 47. Lewis SR, Pritchard MW, Thomas CM, et al: Pharmacological agents for adults with acute respiratory distress syndrome, Cochrane Database Syst Rev 7:CD004477, 2019. 48. Buckley MS, Dzierba AL, Muir J, et al: Moderate to severe acute respiratory distress syndrome management strategies: a narrative review, J Pharm Pract 32:347-360, 2019. 49. Villar J, Blanco J, Añón J, et al: The ALIEN study: incidence and outcome of acute respiratory distress syndrome in the era of lung protective ventilation, Intensive Care Med 37:1932-1941, 2011. 50. Hopper K, Haskins SC, Kass PH, et al: Indications, management, and outcome of long-term positive-pressure ventilation in dogs and cats: 148 cases (1990-2001), J Am Vet Med Assoc 230:64-75, 2007. 51. Walker T, Tidwell AS, Rozanski EA, et al: Imaging diagnosis: acute lung injury following massive bee envenomation in a dog, Vet Radiol Ultrasound 46:300-303, 2005. 52. Evans NA, Walker JM, Manchester AC, et al: Acute respiratory distress syndrome and septic shock in a cat with disseminated toxoplasmosis, J Vet Emerg Crit Care (San Antonio, Tex: 2001) 27:472-478, 2017.

26 Pulmonary Contusions and Hemorrhage Sergi Serrano, LV, DVM, DACVECC

KEY POINTS • Pulmonary commonly occur in patients after blunt chest trauma. The contusions consist of interstitial and alveolar hemorrhage, accompanied by parenchymal destruction that starts immediately after the impact and can worsen for 24 to 48 hours after injury. • The lesions typically resolve within 3 to 10 days unless complications such as pneumonia or acute respiratory distress syndrome ensue. • Clinical signs may be acute and severe or may develop progressively over several hours after trauma. • The diagnosis of pulmonary contusions is based on a history of trauma and the presence of respiratory changes, ranging from tachypnea to severe respiratory distress, in conjunction with compatible blood gas abnormalities and characteristic changes seen on

thoracic radiographs. Thoracic ultrasound and computed tomography scanning are becoming more widely used and may have diagnostic advantages compared with radiographs. • Treatment of patients with pulmonary contusions is supportive and consists of oxygen therapy, judicious fluid administration, and analgesia for concurrent injuries. Ventilatory support may be necessary in severe cases. • Less common causes of pulmonary hemorrhage include coagulopathies, thromboembolic disease, infectious disease (viral, bacterial, and parasitic), exercise-induced hemorrhage, and neoplasia. • Treatment of atraumatic pulmonary hemorrhage is directed toward the underlying disease while providing respiratory and ventilatory support when needed.

Pulmonary contusions consist of pulmonary interstitial and alveolar hemorrhage and edema associated with blunt chest trauma, usually after a compression-decompression injury of the thoracic cage. Such injury in small animals is most commonly associated with motor vehicle trauma1 and high-rise falls2 in cats in urban areas. Thoracic bite trauma may also lead to severe contusions,3 as may other animal interactions (e.g., horse kicks), human abuse, and shock waves from explosions. Thoracic trauma has been reported in 34%,4 38.9%,5 and 57%6 of dogs and 17% of cats5 that sustain limb fractures in road traffic accidents. Pulmonary contusions may also be present in traumatized animals without limb injuries; in one study, only 32% of dogs had concurrent fractures or luxations.7 In general, pulmonary contusions are the most prevalent thoracic lesion after trauma and occur in roughly 50% of animals with thoracic injuries. They may occur as an isolated abnormality or in combination with other thoracic injuries, including pneumothorax, pleural effusion, rib fractures, diaphragmatic rupture, cardiac arrhythmias, and pericardial effusion.5,8 The clinical manifestations of pulmonary contusions can be acute and lead to immediate, severe respiratory distress or may develop progressively over several hours after the injury. Patients may display few clinical signs associated with the contusions initially; in one study, 79% of dogs with abnormal thoracic radiographic findings or low arterial partial pressure of oxygen (PaO2) had no physical examination findings that were suggestive of thoracic injury on initial examination.5 Another study found that the American Society of Anesthesiologists grade was significantly increased with the information provided by thoracic radiography.9 However, radiographic changes may also be delayed. Because aggressive fluid therapy and general anesthesia have

the potential to worsen contusions, the emergency clinician must not discount the possibility of their presence when evaluating more severe injuries, even if clinical signs of thoracic injury or respiratory distress are not apparent initially.

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PATHOPHYSIOLOGY AND PATHOLOGY Pulmonary contusions result from the release of direct or indirect energy within the lung. High-velocity missiles and blasts also lead to pulmonary contusions as shock waves pass through the parenchymal tissue and lead to bleeding into the alveolar spaces and disruption of normal lung structure and function. Several mechanisms have been postulated as potential etiologies of pulmonary contusion.10 Because of the compressible nature of the thoracic cage, acute compression and subsequent expansion lead to the transmission of mechanical forces and energy to the pulmonary parenchyma. As a result, the lung is directly injured by the increased pressure due to the spalling effect, a shearing or bursting phenomenon that occurs at gas–liquid interfaces and may disrupt the alveolus at the point of initial contact with shock waves. The inertial effect that occurs when low-density alveolar tissue is stripped from heavier hilar structures as they accelerate at different rates results in both mechanical tearing and laceration of the lungs. Finally, an implosion effect resulting from rebound or overexpansion of gas bubbles after a pressure wave passes can lead to tearing of the pulmonary parenchyma from excess distention.11,12 The parenchyma may also be injured by the displacement of fractured ribs. Subsequent hemorrhage results in bronchospasm, increased mucus production, and alveolar collapse as a result of decreased production of surfactant. In addition to hemorrhage, traumatic damage to the

CHAPTER 26  Pulmonary Contusions and Hemorrhage lung parenchyma results in the inflammatory response with increased capillary permeability and extravasation of protein-rich fluid.13 Damage to the lung leads to complex changes in respiratory function. The parenchymal damage causes ventilation-perfusion (V/Q) mismatch as the alveoli are flooded with blood and are poorly ventilated. In addition, the increase in lung water resulting from the accumulation of protein-rich edema subsequently decreases lung compliance.14 Recent experimental studies in pigs show that both true shunt and areas of low V/Q mismatch exist at both 2 and 6 hours after injury; true shunt appears to be the major cause of hypoxemia.15,16 At the expense of blood flow to areas with normal V/Q quotient, the shunt fraction and dead space ventilation increase. Both the shunt (Q) and volume of poorly aerated and nonaerated lung tissue correlate independently with PaO2.15 There is also a variable vascular reaction in response to local hypoxia (hypoxic pulmonary vasoconstriction), which may be followed by a further decrease in local perfusion secondary to vascular congestion and thrombosis. In some patients, this leads to reduced perfusion to the unventilated lung, thus minimizing an increase in the shunt fraction.17 Regardless, the patient subsequently displays apparent dyspnea from hypoxemia. Either hypocarbia or hypercarbia may be present, depending on the severity of the contusions and the effects of concurrent injuries on ventilation. In animals that survive the initial hours following injury, the respiratory derangements associated with pulmonary contusions usually resolve in 3 to 7 days, but delayed deterioration may occur; this may be secondary to complications such as bacterial pneumonia or acute respiratory distress syndrome (ARDS) due to the local or systemic inflammatory response.11 The frequency of these complications has not been well described in dogs and cats. In humans, pulmonary contusions cause severe immunodysfunction both locally and systemically, and this immunosuppression is associated with a decreased survival rate if a septic complication occurs.18 Histologic progression of pulmonary contusions has been demonstrated in a canine experimental model.19 Immediate interstitial hemorrhage is followed by interstitial edema and infiltration of monocytes and neutrophils during the first few hours. Twenty-four hours after injury, the alveoli and smaller airways are full of protein, red blood cells, and inflammatory cells. At this stage the normal architecture has been lost and edema is severe. Alveoli adjacent to the affected region remain normally perfused, but they are less compliant because of the edema and disruption of the surfactant layer. Thus they are poorly ventilated, which leads to an increase in V/Q mismatch.14,17,20,21 Furthermore, experimental studies in pigs have demonstrated that local pulmonary contusions may lead to generalized pulmonary dysfunction secondary to impaired surfactant activity and a subsequent decrease in alveolar diameter.22 Forty-eight hours after injury, healing has started and the lymphatic vessels are dilated and filled with protein. The parenchyma and affected airways contain fibrin, cellular debris, granules from type II alveolar cells, neutrophils, and macrophages.14 Another study found that within 7 to 10 days after trauma, canine lungs were almost completely healed with little scarring.20 Clinically, there is not always a clear correlation between the apparent extent of the affected lung and the clinical signs. At a mechanistic level, more recent studies on the pathophysiology of pulmonary contusions are focusing on the role of the acute inflammatory response and its impact on severity. Experimental studies highlight the potential importance of neutrophil activation, Toll-like receptors, and type II pneumocyte apoptosis in the progression of lung contusions.23 Type II pneumocyte injury leading to generalized surfactant dysfunction may also play an important role and could be a therapeutic target.24 Finally, the interactions of lung contusions with other pulmonary injuries, such as silent aspiration of gastric contents, may exacerbate permeability

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changes and the inflammatory response, potentially contributing to the more severe forms of pulmonary contusions and their progression to acute lung injury/ARDS and pneumonia.24

DIAGNOSIS Physical Examination Findings Clinically, patients usually have tachypnea or apparent dyspnea, depending on the severity of the contusions and the time between injury and arrival at the veterinary hospital. Auscultation findings may be normal, or increased breath sounds, crackles, and/or wheezes can be present and may worsen over the initial 24-hour period. These abnormalities are often asymmetric and may be truly unilateral. Lung auscultation findings can be more difficult to interpret when concurrent conditions, such as pneumothorax, are present, and frequent monitoring of respiratory rate, effort, and pulmonary auscultation is warranted. Hemoptysis (the expectoration of blood from distal to the larynx) is present in a high proportion of human patients. It appears to be an uncommon finding in small animals but is usually associated with severe pulmonary lesions. Because there is a high incidence of thoracic trauma associated with skeletal injuries and respiratory symptoms may be absent or masked initially, the clinician should maintain a high index of suspicion for contusions in any traumatized patient.

Imaging: Radiology, Computed Tomography, and Ultrasound Animals that sustain thoracic trauma may have multiple thoracic injuries, making a precise diagnosis based on the physical examination alone challenging. Imaging studies may be helpful in identifying and defining all injuries; however, as with all dyspneic patients, the riskbenefit ratio of the imaging procedure should be considered carefully, and patients should be stabilized before imaging is attempted. Thoracic ultrasound has rapidly gained acceptance as a bedside test in people and similarly in veterinary medicine because it requires minimal handling and restraining resulting in a safer option for unstable patients. Although both the presence of alveolar interstitial syndrome and peripheral parenchymal syndrome have high sensitivity and specificity for the detection of contusions,25 recent studies favor using alveolar interstitial syndrome with a cutoff of six B-lines per intercostal space.26 Lung ultrasound on admission identifies patients at risk of developing ARDS after blunt trauma in people.27 Ultrasonography has been found to be a better screening tool in the detection of pulmonary contusion than thoracic radiographs28 and is a better diagnostic test than physical examination and thoracic radiographs when evaluating patients for pulmonary contusions or pneumothorax after chest trauma.29 In veterinary medicine, point-of-care thoracic ultrasound has become widespread, and although studies are still small, findings are similar to those in people and suggest high value in the diagnosis of lesions associated to blunt chest trauma, including but not limited to pulmonary contusions.30 The accuracy of lung ultrasound, however, is more operator- and equipment-dependent than other diagnostic techniques (see Chapter 189, Point of Care Ultrasound in the ICU). Radiographic changes in patients with pulmonary contusions consist of areas of patchy or diffuse interstitial or alveolar lung infiltrates that can be either localized or generalized (Fig. 26.1). Radiographic changes may lag behind clinical signs by 12 to 24 hours, and therefore normal radiographic findings may be seen in animals with pulmonary contusions. Patients with more severe radiographic changes initially may require a longer duration of oxygen supplementation and longer hospitalization times. However, the relationship between the severity

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A

B

Fig. 26.1  Lateral (A) and dorsoventral (B) radiographs showing the characteristic appearance of pulmonary contusions. Note the diffuse alveolar pattern. It is common to see additional radiographic abnormalities such as multiple rib fractures, subcutaneous emphysema, pneumomediastinum, and pneumothorax, as seen in this case.

of the contusion based on radiographic changes and survival has not been established.7 Although computed tomography (CT) has been shown experimentally to be more sensitive for detecting initial lesions and accurately reflecting the extent of the lesion than standard radiographic techniques, lack of availability in veterinary hospitals and the need for sedation or anesthesia in a traumatized patient have so far limited its widespread use. An experimental canine model of pulmonary contusions found that a CT scan enabled detection of 100% of the pulmonary lesions, but initial thoracic radiographs only allowed identification in 37%. In addition, 21% of lesions still not visible radiographically after 6 hours. In this study, CT imaging underestimated the extent of the lesions in only 8% of the animals, whereas thoracic radiography underestimated the extent in 58% of the animals.31 In people, CT is considered the gold standard for the diagnosis of pulmonary contusions and may be predictive of progression and treatment needs. A contused volume of 20% or more is highly predictive of the need for mechanical ventilation (8% of patients with contused volume #20% compared with 40% of those patients with volumes .20%).32 The percentage of contused volume is also an independent predictive factor for the development of ARDS, with 21.5% being the best cutoff for severe pulmonary contusions.33 Furthermore, in people with blunt pulmonary contusions, the absence of a blunt pulmonary contusion volume of 20% or more, more than four fractured ribs, or a Glasgow Coma Scale score higher than 14 precluded mechanical ventilation in 100% of the cases, while the presence of all three findings together predicted the need for mechanical ventilation in 100% of the cases.34 Overall, the superior sensitivity of CT allows for the identification of injuries that would otherwise go unrecognized (occult injuries). In people, patients with occult injury and those with no injury have similar ventilator needs and requirements, while those with occult injuries remain hospitalized longer, leading to the argument that occult injuries have little to no clinical significance yet utilize increased hospital resources and cost.35

Blood Gas Analysis and Pulse Oximetry Arterial blood gas analysis is the most objective method for assessing and monitoring the physiologic effects of thoracic trauma (see Chapter 184, Oximetry Monitoring). Clinical data in dogs with pulmonary contusions reveal a high incidence of hypoxemia; however, it is usually

mild to moderate.6,7 This may be because many of the most severe cases will die before arriving at the veterinary clinic. Either hypocarbia or hypercarbia may be seen, depending on the severity of the parenchymal injury, the nature of concurrent thoracic injuries, and other factors such as pain, distress, and the effect of concurrent metabolic acid-base derangements. In humans, the arterial oxygen tension/fractional concentration of inspired oxygen ratio (PaO2/FiO2) is directly correlated with the volume of contused lung for the first 24 hours after injury, although this correlation is not consistent beyond 1 week.27 Whether this association exists in small animal patients is unknown. Although pulse oximetry has some limitations, it may be a useful quantitative assessment of oxygenation in cases in which an arterial blood gas analysis is not possible (e.g., cats). It is a less accurate indicator of impaired oxygen and does not provide a measure of ventilation, and reliable measurements can be difficult to obtain in patients that are in shock. A pulse oximeter reading of less than 95% indicates hypoxemia, and values less than 90% are consistent with severe hypoxemia (see Chapter 16, Hypoxemia).

MANAGEMENT Initial Approach Management of pulmonary contusions is supportive. Initial triage and major body system assessment should be done in any traumatized patient, and injuries should be ranked and managed based on their threat to patient life (see Chapter 1, Evaluation and Triage of the Critically Ill Patient). Prehospital management rarely occurs. However, the animal should be transported to the clinic lying in its preferred posture or kept in sternal recumbency if possible.36 Oxygen therapy, judicious fluid therapy, and adequate analgesia are essential components of patient management.

Oxygen Therapy and Ventilation Oxygen should be administered to all dyspneic patients (see Chapter 15, Oxygen Therapy). Noninvasive methods such as flow-by, nasal oxygen delivery, or oxygen cages and hoods are commonly used. More recently, high-flow nasal oxygen is being used and can prevent mechanical ventilation in some severely dyspneic patients (see Chapter 31, High Flow Nasal Oxygen). In severely affected cases, intubation and

CHAPTER 26  Pulmonary Contusions and Hemorrhage mechanical ventilation may be necessary (see Chapters 32 and 33, Mechanical Ventilation-Core and Advanced Concepts, respectively). In people, pressure-controlled ventilation with positive end-expiratory pressure is the preferred method of mechanical ventilation.37 Recent studies have shown that, contrary to previous beliefs, the presence of contusions neither increases mortality, length of stay, or pneumonia rates in severely injured human trauma patients that undergo mechanical ventilation,38 suggesting the effect of ventilation on contusions may not be as deleterious as previously thought, and ventilation should not be withheld for fear of worsening the contusions. One canine study examined 10 dogs with pulmonary contusions that required positive pressure ventilation and found that 50% of the dogs benefited from this intervention, and animals that weighed more than 25 kg were more likely to survive.39 The lack of available neonatal or pediatric ventilators may have resulted in more complications in smaller patients. Alveolar recruitment strategies and the use of low tidal volumes have been shown to increase both oxygenation and lung aeration in humans with severe chest trauma,40 although similar studies in dogs and cats are lacking. Improved ventilator strategies are being continuously evaluated. Recently the early use of high-frequency oscillatory ventilation has been deemed safe and efficacious,41 and airway pressure release ventilation is associated with a reduced risk for ventilator-associated pneumonia without changing either the need for ventilation days or the mortality rate.42 Extracorporeal membrane oxygenation has been used in people with severe pulmonary contusions and yielded good results43,44; however, this and other advanced ventilatory techniques that may prove useful such as jet ventilation, selective bronchial intubation, and dual-lung ventilation are not used routinely in the clinical setting for the management of pulmonary contusions in people or the veterinary field.

Fluid Therapy Many patients with thoracic trauma will have some degree of concurrent hypovolemic shock. The debate regarding the optimal fluid therapy strategy for use in trauma and shock patients has yet to be resolved; however, it seems that optimizing fluid therapy to maintain adequate perfusion while avoiding overzealous administration is likely to give the best results (see Chapter 68, Shock Fluid Therapy). In any patient with multiple traumatic injuries, the clinician must prioritize treatment decisions based on which major body system is most severely affected. Several fluid options are available, and the fluid type and administration strategy chosen must take into account both the cardiovascular and pulmonary changes present. Regardless of the type of fluid chosen, increases in pulmonary capillary hydrostatic pressure may lead to increased fluid extravasation into the alveoli and worsening of pulmonary function. The clinician should aim to optimize tissue perfusion while avoiding excessive fluid administration that could worsen the pulmonary edema and hemorrhage. Careful monitoring and tailoring of the fluid protocol to the patient are preferable to administering preset volumes and rates. Isotonic crystalloids are the most economical fluids and are at least as effective as colloids for resuscitation of the shock patient.45,46 Evidence for the treatment of patients with pulmonary contusions is scarce, and papers yield conflicting results. Some have shown no benefits when using hypertonic saline over isotonic solutions in experimental porcine models of pulmonary contusions,47 whereas others show less lung water retention and higher PaO2 values with the use of hypertonic saline dextran versus Ringer acetate or saline.48 Blood products and synthetic colloids may contribute to worsening pulmonary edema if they leak into the airways or interstitium.49

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Although clinical evidence is lacking, common sense dictates that although strict fluid restriction is not indicated, caution should be exercised when administering intravenous fluids to shock patients with suspected pulmonary contusions. Patients should be monitored carefully to detect any worsening of pulmonary function during fluid administration and fluid rates adjusted accordingly (see Chapters 63 and 64, Assessment of Hydration and Assessment of Intravascular Volume, respectively).

Analgesia Hypoventilation caused by pain from concurrent injuries can be severe and should be managed proactively with analgesics (see Chapter 134, Analgesia and Constant Rate Infusions). Ideally, drugs that cause minimal impairment of cardiac and respiratory functions should be used. Intercostal, intrapleural, and epidural analgesic administration can be used in conjunction with or as an alternative to systemic opioid administration. Thoracic epidural analgesia, while not widely used in veterinary medicine, has been associated with reduced mortality in people with rib fractures.50 Gabapentin has not been shown to be superior to placebo in people with rib fractures, but studies in dogs and cats are indicated.51

Antimicrobial Therapy Based on the reported low incidence of pneumonia after pulmonary contusions (1%),7 indiscriminate use of antimicrobial agents should be avoided to limit bacterial resistance. In the small number of patients that do develop bacterial pneumonia, antibiotic therapy should be based on culture and susceptibility testing results of airway cytology (see Chapter 24, Pneumonia).

Glucocorticoids There are little supportive data for glucocorticoid use in the treatment of pulmonary contusions. Although some animal studies have shown a reduction in hypoxemia and lesion size after steroid administration,52 others have shown no benefit.53 Because of their potential deleterious effects, including increased susceptibility to infection and gastrointestinal ulceration, and the lack of positive effects on outcome, these agents are not recommended for the routine management of pulmonary contusions.

Other Therapies Pulmonary contusion continues to be a significant cause of morbidity and mortality despite the standard management strategies described earlier. Ongoing research continues to identify improved treatment options. Clinically, the combined administration of vitamins C and E has been associated with improved arterial blood gas parameters and a reduction in ICU stay for people with lung contusions,54 and the use of surfactant has been proven to improve both oxygenation and compliance in patients with severe pulmonary contusions.55 Experimental studies suggest that dexmedetomidine improves hemodynamics, reduces the presence of inflammatory cells in the alveolar spaces, and modifies the inflammatory response by interfering with cytokine release.56 Melatonin has been found to cause improved histopathology from pulmonary contusions and distant organs by diminishing oxidative stress,57 and salbutamol may reduce edema, hemorrhage, leukocyte infiltration, and total lung injury score.58 The utility of these therapies in veterinary clinical patients is unknown.

PROGNOSIS AND OUTCOME Outcome is related to the severity of pulmonary contusions as well as any coexisting thoracic and extrathoracic lesions. Survival rates of 82%

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have been described,7 although the true survival rate may be lower because some of the most severely affected animals die before reaching a veterinary facility or before a diagnosis is made. Patients may require hospitalization for periods ranging from a few hours to several days, and oxygen supplementation can be required for several days to weeks. In more severely affected patients, two retrospective studies have shown that approximately 30% of dogs requiring mechanical ventilation for contusions survived to discharge.7,37 It is possible that newer lung-protective ventilatory strategies could improve outcomes. Although the long-term prognosis for animals with pulmonary contusions has not been investigated, most animals that survive to discharge do not have residual long-term sequelae. In people, even patients with severe injuries requiring ventilation show a substantial recovery, with postexercise oxygen saturations returning to normal values.59

TABLE 26.1  Etiologies of Atraumatic

ATRAUMATIC PULMONARY HEMORRHAGE

Coagulation abnormalities

Atraumatic pulmonary hemorrhage may occur secondary to a diverse range of disease conditions (Table 26.1). Although hemoptysis may occur in animals with pulmonary hemorrhage, it is an uncommon initial finding in small animals,60 and pulmonary hemorrhage cannot be ruled out based on the absence of this symptom. In a population of cats undergoing airway cytologic analysis for a variety of disease conditions, pulmonary hemorrhage was identified in 63% of cases; the incidence of hemoptysis was not reported.61

DIAGNOSTIC EVALUATION Pulmonary hemorrhage is identified by hemoptysis or hemorrhage on cytologic samples from tracheal, bronchial, or bronchoalveolar washes. The emergency clinician must be careful to distinguish true hemoptysis from hematemesis or bleeding from a source cranial to the larynx (nasal cavity, oropharynx). When using cytology specimens, acute hemorrhage is defined by the presence of red blood cells and white blood cells in proportions similar to those in peripheral blood. Platelets may be present but tend to disappear within minutes after the hemorrhagic event. Within minutes to hours, erythrophagocytosis is present within the macrophages. Considering the diverse range of differential diagnoses, a thorough and careful diagnostic evaluation, including full history, diligent physical examination, and clinicopathologic testing and imaging, may be required to reach the correct diagnosis. Historical information suggests certain diagnoses may include exposure to toxins such as rodenticides or animals living in or having traveled to areas with a high incidence of certain infectious diseases (e.g., heartworms, lungworms, leptospirosis). Location may also support exposure to envenomation (such as the eastern brown snake in Australia). The influence of any concurrent drug therapy should be considered, such as high doses of glucocorticoids, especially in patients that are at risk for pulmonary thromboembolism. Historical information may also be suggestive of chronic medical conditions and may guide and inform further testing. The patient’s signalment may suggest an increased possibility of certain coagulopathies, such as von Willebrand disease in Doberman Pinschers. The physical examination of animals with pulmonary hemorrhage may reveal clinical signs limited to the respiratory system, including hemoptysis, dyspnea, tachypnea, cough, and abnormal auscultation findings. Adventitious lung sounds are variable but may include focal or generalized harsh lung sounds progressing to crackles, focal muffled lung sounds corresponding to areas with consolidation or complete filling of the small airways, or wheezes. Heart murmurs or cardiac

Pulmonary Hemorrhage and Examples of Each Infectious

Bacterial

Leptospirosis53 Escherichia coli61 Streptococcus equi subsp. Zooepidemicus62

Fungal

—

Mycoplasmal

—

Parasitic

Heartworms (Dirofilaria spp.) Lungworms (Angiostrongylus vasorum)

Viral

—

Defects of primary hemostasis

Thrombocytopathia

Defects of secondary hemostasis

Anticoagulant rodenticide toxicity

Severe thrombocytopenia Uremia Hepatic failure

von Willebrand disease Hemophilia Thromboembolism

Cushing disease Diabetes mellitus Nephrotic syndrome Glucocorticoid therapy

Cardiac

Heart failure Pulmonary hypertension

—

Neoplasia

Primary Metastatic

—

Anatomic

Lung lobe torsion

—

Environmental

Aspiration pneumonia Foreign body

—

Miscellaneous

Exercise-induced pulmonary hemorrhage in racing Greyhounds Pulmonary-renal syndrome Postseizure67

Glomerulonephritis68

Iatrogenic

Fine-needle aspiration Percutaneous biopsy

—

Toxic

Envenomations

Eastern brown snake69

arrhythmias may also be noted and may suggest a cardiogenic cause for the pulmonary hemorrhage. However, because pulmonary hemorrhage may occur secondary to systemic disease, a full physical examination is mandatory. The presence of petechiae or ecchymoses should prompt the investigation of a bleeding disorder, whereas an elevated body temperature may suggest infectious or neoplastic disease. Some bacteria have been associated with hemorrhagic pneumonia (Escherichia coli and Streptococcus equi).62,63 Further diagnostic tests will be suggested by the patient’s history and physical examination but may include a complete blood cell count, biochemical profile, coagulogram, urinalysis, and imaging techniques. An arterial blood gas analysis will provide the best evaluation of the functional impairment of the respiratory system and may reveal hypoxemia, hypocarbia (or hypercarbia in severe cases), and an

CHAPTER 26  Pulmonary Contusions and Hemorrhage increased alveolar–arterial gradient (see Chapter 16, Hypoxemia). Animals with chronic diseases such as pulmonary neoplasia, chronic bronchitis, or pneumonia may have metabolic compensation for changes in arterial carbon dioxide tensions, whereas acutely affected animals often have uncompensated changes in acid-base status. Thoracic radiographs may reveal an interstitial, alveolar, or mixed pattern, with a focal, patchy, or diffuse distribution. A peripheral interstitial and alveolar pattern in a young to middle-aged dog is a characteristic finding in Angiostrongylus vasorum infestation.64 Caudal or generalized reticulonodular interstitial pattern with or without patchy alveolar consolidations can be associated with leptospirosis.65,66 The cardiac silhouette may be enlarged, and signs of pulmonary congestion may be evident in cases of congestive heart failure or Dirofilaria spp. infestation. If cardiac disease is suspected, echocardiography is the test of choice for characterization of the disease. Hematology findings may be unremarkable or may show changes suggestive of the underlying diagnosis, including normocytic normochromic anemia in case of chronic disease, eosinophilia with parasitic disease, and neutrophilia with or without a left shift in cases of inflammatory disease. Platelet numbers may be normal, mildly to moderately reduced (e.g., in disseminated intravascular coagulation, angiostrongylosis, and some cases of thromboembolism), or severely reduced (e.g., in immunemediated thrombocytopenia). If platelet numbers are adequate but petechiae are present, thrombocytopathia may be present, and a buccal mucosal bleeding time or platelet function testing should be performed (see Chapter 105, Management of the Bleeding Patient in the ICU). Clotting times (prothrombin time and activated partial thromboplastin time) are prolonged in animals with a coagulopathy. The prothrombin time is markedly prolonged in animals with anticoagulant rodenticide poisoning, although all clotting parameters may increase if significant bleeding has occurred. Increases in fibrin(ogen) degradation products or D-dimers may suggest pulmonary thromboembolism, although a CT scan with angiography is more definitive (see Chapter 27, Pulmonary Thromboembolism).60 In recent years, thromboelastography and viscoelastography have emerged as more comprehensive approaches to evaluate both the thrombotic and thrombolytic parts of hemostasis (see Chapter 187, Viscoelastic Monitoring). A fecal Baermann analysis should be performed if A. vasorum or other lungworm infections are suspected. Antigen or antibody detection tests for heartworm are indicated in dogs or cats living in, or traveling to, endemic areas. Testing for leptospirosis is indicated when pulmonary hemorrhage is associated with azotemia and/or liver damage in areas where the disease is prevalent. Testing for proteinuria may reveal glomerulonephritis and the presence of pulmonary-renal syndrome.

TREATMENT Treatment will ultimately need to be directed toward the underlying disease process. If the degree of respiratory compromise is marked, it may be necessary to use supportive or empiric therapy while the diagnosis is pursued. Oxygen should be administered to any patient with apparent dyspnea and in particular to those animals showing hypoxemia on arterial blood gas analysis or low pulse oximetry readings. If noninvasive oxygen supplementation does not restore adequate oxygen levels, then severe hypercarbia is present, or if the patient displays significant dyspnea with impending fatigue, then high flow nasal oxygen or positive pressure ventilation may be required (see Chapters 31 and 32, High Flow Nasal Oxygen and Mechanical Ventilation-Core Concepts, respectively). Fluid therapy should be tailored to each animal’s needs based on the cardiovascular and respiratory status, as with pulmonary contusions. Analgesia and sedation should also be used as indicated by an animal’s

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clinical status. It is often necessary to institute empiric antimicrobial or antiparasitic therapy if there is a strong clinical suspicion of an infectious etiology while diagnostic test results are pending.

PROGNOSIS AND OUTCOME Prognosis and long-term outcome will depend largely on the extent and severity of the process on admission and on the etiology of the pathology. An overall mortality rate of up to 25%60 in the 6 months after diagnosis has been reported, with patients most commonly dying as a result of the disease process or after humane euthanasia. It is difficult to predict whether any long-term impairment of function will ensue, but this likely depends on the underlying disease and its severity. Hence, owners should be given a guarded to grave prognosis until a definitive diagnosis is reached.

REFERENCES 1. Spackman C, Caywood D: Management of thoracic trauma and chest wall reconstruction, Vet Clin North Am Small Anim Pract 17:431, 1987. 2. Vnuk D, Pirkic B, Maticic D, et al: Feline high-rise syndrome: 119 cases (1998-2001), J Feline Med Surg 6:305, 2004. 3. Scheepens ET, Peeters ME, L’Eplattenier HF, Kirpensteijn J: Thoracic bite trauma in dogs: a comparison of clinical and radiological parameters with surgical results, J Small Anim Pract 47(12):721, 2006. 4. Tamas P, Paddleford R, Krahwinkel D: Thoracic trauma in dogs and cats presented for limb fractures, J Am Anim Hosp Assoc 21:161, 1985. 5. Spackman C, Caywood D, Feeney D, et al: Thoracic wall and pulmonary trauma in dogs sustaining fractures as a result of motor vehicle accidents, J Am Vet Med Assoc 185:975, 1984. 6. Selcer B, Buttrick M, Barstad R, et al: The incidence of thoracic trauma in dogs with skeletal injury, J Small Anim Pract 28:21, 1987. 7. Powell L, Rozanski E, Tidwell A, et al: A retrospective analysis of pulmonary contusion secondary to motor vehicular accidents in 143 dogs: 1994-1997, J Vet Emerg Crit Care 9:127, 1999. 8. Sigrist N, Doherr M, Spreng D: Clinical findings and diagnostic value of post-traumatic thoracic radiographs in dogs and cats with blunt trauma, J Vet Emerg Crit Care 14:259, 2004. 9. Sigrist N, Mosing M, Iff I, et al: Influence of pre-anesthetic thoracic radiographs on ASA physical status classification and anaesthetic protocols in traumatized dogs and cats, Schweiz Arch Tierheilkd 150(10):507, 2008. 10. Clemedson C: Blast injury, Physiol Rev 36(3):336, 1956. 11. Huller T, Bazini Y: Blast injuries of the chest and abdomen, Arch Surg 100:24, 1970. 12. Cohn S: Pulmonary contusions: review of the clinical entity, J Trauma 45:973, 1997. 13. Demling R, Pomfret E: Blunt chest trauma, New Horiz 1:402, 1993. 14. Oppenheimer L, Craven K, Forkert L, et al: Pathophysiology of pulmonary contusion in dogs, J Appl Physiol 47:718, 1979. 15. Batchinsky AI, Weiss WB, Jordan BS, et al: Ventilation-perfusion relationships following experimental pulmonary contusion, J Appl Physiol 103(3):895, 2007. 16. Batchinsky AI, Jordan BS, Necsiou C, et al: Dynamic changes in shunt and ventilation-perfusion mismatch following experimental pulmonary contusion, Shock 33(4):419, 2010. 17. Wagner R, Slivko B, Jamieson P, et al: Effects of lung contusion on pulmonary haemodynamics, Ann Thorac Surg 52:51, 1991. 18. Perl M, Gebhard F, Bruckner U, et al: Pulmonary contusion causes impairment of macrophage and lymphocyte immune functions and increases mortality associated with a subsequent septic challenge, Crit Care Med 2005;33:1351, 2005. 19. Fulton R, Peter E: The progressive nature of pulmonary contusion, Surgery 67:499, 1970. 20. Moseley R, Vernick J, Doty D: Response to blunt chest injury: a new experimental model, J Trauma 101:673, 1970.

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21. Hackner S: Emergency management of traumatic pulmonary contusions, Comp Cont Ed Pract Vet 17:677, 1995. 22. Hellinger A, Konerding M, Malkusch W, et al: Does lung contusion affect both the traumatized and the noninjured lung parenchyma? A morphological and morphometric study in the pig, J Trauma 39:712, 1995. 23. Raghavendran K, Notter RH, Davidson BA, et al: Lung contusion: inflammatory mechanisms and interaction with other injuries, Shock 32(2):122, 2009. 24. Raghavendran K, Davidson BA, Huebschmann JC, et al: Superimposed gastric aspiration increases the severity of inflammation and permeability injury in a rat model of lung contusion, J Surg Res 155(2):273, 2009. 25. Soldati G, Testa A, Silva FR, et al: Chest ultrasonography in lung contusion, Chest 130(2):533, 2006. 26. Abbasi S, Shaker H, Zarelee F, et al: Screening performance of ultrasonographic B-lines in detection of lung contusion following blunt trauma; a diagnostic accuracy study, Emergency 6(1):e55, 2018. 27. Leblanc D, Bouvet C, Degiovanni F, et al: Early lung ultrasonography predicts the occurrence of acute respiratory distress syndrome in blunt trauma patients, Intensive Care Med 40:1468-1474, 2014. 28. Hosseini M, Ghelichkhani P, Baikpour M, et al: Diagnostic accuracy of ultrasonography and radiography in detection of pulmonary contusion; a systematic review and meta-analysis, Emergency 3(4):127-136, 2015. 29. Hyacinthe AC, Broux C, Francony G, et al: Diagnostic accuracy of ultrasonography in the acute assessment of common thoracic lesions after trauma, Chest 141(5):1177, 2012. 30. Armenise A, Boysen RS, Rudloff E, et al: Veterinary-focused assessment with sonography for trauma-airway, breathing, circulation, disability and exposure: a prospective observational study in 64 canine trauma patients, J Small Anim Pract 60(3):173-182, 2019. 31. Schild H, Strunk H, Weber W, et al: Pulmonary contusion: CT vs plain radiogram, J Comput Assist Tomogr 13:417, 1989. 32. Hamrick MC, Duhn RD, Ochsner MG: Critical evaluation of pulmonary contusion in the early post-traumatic period: risk of assisted ventilation, Am Surg 75(11):1054, 2009. 33. Wang S, Ruan Z, Zhang J, et al: The value of pulmonary contusion volume measurements with three-dimensional computed tomography in predicting acute respiratory distress syndrome development, Ann Thorac Surg 92(6):1977, 2011. 34. de Moya MA, Manolakaki D, Chang Y: Blunt pulmonary contusion: admission computed tomography scan predicts mechanical ventilation, J Trauma 71(6):1543, 2011. 35. Kaiser M, Wheaton M, Barrios C, et al: The clinical significance of occult thoracic injury in blunt trauma patients, Am Surg 76(10):1063, 2010. 36. MacMillan MW, Whitaker KE, Hughes D, et al: Effect of body position on the arterial partial pressures of oxygen in carbon dioxide in spontaneously breathing, conscious dogs in an intensive care unit, J Vet Emerg Crit Care 19(6):564, 2009. 37. Sharma S, Mullins R, Trunkey D: Ventilatory management of pulmonary contusion patients, Am J Surg 171:529, 1996. 38. Dhar SM, Breite MD, Barnes SL, et al: Pulmonary contusions in mechanically ventilated subjects after severe trauma, Respir Care 63(8):950-954, 2018. 39. Campbell V, King L: Pulmonary function, ventilator management, and outcome of dogs with thoracic trauma and pulmonary contusions: 10 cases (1994-1998), J Am Vet Med Assoc 217:1505, 2000. 40. Schreiter D, Reske A, Stichert B, et al: Alveolar recruitment in combination with sufficient positive end-expiratory pressure increases oxygenation and lung aeration in patients with severe chest trauma, Crit Care Med 32:968, 2004. 41. Funk DJ, Lujan E, Moretti EW, et al: A brief report: the use of high- frequency oscillatory ventilation for severe pulmonary contusions, J Trauma 65(2):390, 2008. 42. Walkey AJ, Nair S, Papadopoulos S, et al: Use of airway pressure release ventilation is associated with a reduced incidence of ventilator-associated pneumonia in patients with pulmonary contusion, J Trauma 70(3):e42, 2011. 43. Yamada T, Osako T, Sakata H, et al: Successful treatment of pulmonary contusion following chest trauma using poly-2-methoxyethyl acrylate, a biocompatible polymer surface coating for extracorporeal membrane oxygenation, Acute Med Surg 1:105-108, 2014. 44. Ogawa F, Sakai T, Takahashi K, et al: A case report: veno-venous extracorporeal membrane oxygenation for severe blunt thoracic trauma, J Cardiothorac Surg 14(1):88-94, 2019.

45. Roberts I, Alderson P, Bunn F, et al: Colloids versus crystalloids for fluid resuscitation in critically ill patients (review), Cochrane Database Syst Rev (4):CD000567, 2004. 46. Finfer S, Bellomo R, Boyce N, et al: A comparison of albumin and saline for fluid resuscitation in the intensive care unit, N Engl J Med 350:2247, 2004. 47. Cohn S, Fisher B, Rosenfield A, et al: Resuscitation of pulmonary contusion: hypertonic saline is not beneficial, Shock 8:292, 1997. 48. Gryth D, Rocksen D, Drobin D, et al: Effects of fluid resuscitation with hypertonic saline dextran or Ringer’s acetate after nonhemorrhagic shock caused by pulmonary contusions, J Trauma 69(4):741, 2010. 49. Cohn S, Zieg P, Rosenfield A, et al: Resuscitation of pulmonary contusion: effects of a red cell substitute, Crit Care Med 25:484, 1997. 50. Jensen CD, Star JT, Jacobson LL, et al: Improved outcomes associated with the liberal use of thoracic epidural analgesia in patients with rib fractures, Pain Med 18(9):1787-1794, 2017. 51. Morkowith EE, Garabedian L, Hardin K, et al: A double blind, randomized controlled trial of gabapentin vs placebo for acute pain management in critically ill patients with rib fractures, Injury 49(9): 1693-1698, 2018. 52. Franz J, Richardson J, Grover F, et al: Effect of methylprednisolone sodium succinate on experimental pulmonary contusion, J Thorac Cardiovasc Surg 68:842, 1974. 53. Shepard G, Ferguson J, Forster J: Pulmonary contusion, Ann Thorac Surg 7:110, 1969. 54. Abdoulhossein D, Taheri I, Ali Saba M, et al: Effect of vitamin C and vitamin E on lung contusion: a randomized clinical trial study, Annals Med Surg 36:152-157, 2018. 55. Tsangaris I, Galiatsou E, Kostanti E, et al: The effect of exogenous surfactant in patients with lung contusions and acute lung injury, Intensive Care Med 33(5):851, 2007. 56. Wu X, Song X, Li N, et al: Protective effects of dexmedetomidine on blunt chest trauma-induced pulmonary contusions in rats, J Trauma Acute Care Surg 74(2):524, 2013. 57. Ozdinc S, Gurhan O, Cigdem O, et al: Melatonin: is it an effective antioxidant for pulmonary contusion? J Surg Res 204:445-451, 2016. 58. Demirel D, Aycicek T, Gun S, et al: Evaluation of the histopathological effects of salbutamol inhaler treatment in an experimentally induced rad model of pulmonary contusion, Turk J Med Sci 48:1285-1292, 2018. 59. Amital A, Shitrit D, Fox BD, et al: Long term pulmonary function after recovery from pulmonary contusion due to blunt chest trauma, Isr Med Assoc J 11(11):673, 2009. 60. Bailiff N, Norris C: Clinical signs, clinicopathological findings, etiology, and outcome associated with hemoptysis in dogs: 36 cases (1990-1999), J Am Anim Hosp Assoc 38:125, 2002. 61. DeHeer H, McManus P: Frequency and severity of tracheal wash hemosiderosis and association with underlying disease in 96 cats (2002-2003), Vet Clin Pathol 34:17, 2005. 62. Breitschwerdt EB, DebRoy C, Mexas AM, et al: Isolation of necrotoxigenic Escherichia coli from a dog with hemorrhagic pneumonia, J Am Vet Med Assoc 226(12):2016-2019, 2005. 63. Pesavento PA, Hurley KF, Bannash MJ, et al: A clonal outbreath of acute fatal hemorrhagic pneumonia in intensively housed (shelter) dogs caused by Streptococcus equi subsp. Zooepidemicus, Vet Pathol 45(1):51-53, 2008 64. Chapman P, Boag A, Guitian J, et al: Angiostrongylus vasorum infection in 23 dogs (1999-2002), J Small Anim Pract 45:435, 2004. 65. Kohn SM, Dubose JJ: Pulmonary contusion: an update on recent advances in clinical management, World J Surg 34:1959-1970, 2010. 66. Klopfleisch R, Kohn B, Plog S, et al: An emerging pulmonary haemorrhagic syndrome in dogs: similar to the human leptospiral pulmonary haemorrhagic syndrome? Vet Med Int 2010:928541, 2010. 67. James FE, Johnson VS, Lenarz ZM, et al: Severe haemoptysis associated with seizures in a dog, N Z Vet J 56(2):85, 2008. 68. Brown PJ, Skuse AM, Tappin SQ: Pulmonary haemorrhage and fibrillary glomerulonephritis (pulmonary-renal syndrome) in a dog, Vet Record 162(15):486-488, 2008. 69. Leong OS, Padula AM, Leister E: Severe acute haemorrhage and haemoptysis in ten dogs following Eastern Brown snake (Pseudonaja textilis) envenomation: clinical signs, treatment and outcomes, Toxicon 150: 188-194, 2018.

27 Pulmonary Thromboembolism Vincent J. Thawley, VMD, DACVECC

KEY POINTS • Pulmonary thromboembolism (PTE) occurs as a secondary complication of diseases associated with hypercoagulability, endothelial damage, and/or stasis of blood flow. • It is a challenging antemortem diagnosis and is associated with a guarded prognosis. • Clinical findings that support a diagnosis of PTE in a systemically ill patient include tachypnea, hypoxemia, echocardiographic detection of echogenic material in the pulmonary artery or evidence of acute right ventricular overload, and increased D-dimer concentration.

• Computed tomography with pulmonary angiography is increasingly used for the diagnosis of PTE. • Therapy for PTE relies primarily on treatment of the underlying disease process, support of oxygenation, anticoagulation, and potentially thrombolysis. • Thrombolysis is recommended in patients with hemodynamic instability. • Prophylaxis against thromboembolic complications should be considered in animals with serious disease syndromes that have been associated with PTE.

Pulmonary embolism can occur by obstruction of pulmonary vasculature with fat, septic emboli, metastatic neoplasia, parasites (Dirofilaria or Angiostrongylus), or thrombi. Thrombi most commonly form in the venous system or right heart and migrate to the pulmonary vasculature. The term pulmonary thromboembolism (PTE) has traditionally been used to describe this disease process, although in more recent medical literature the term pulmonary embolism is preferred. The diagnosis of PTE in human medicine is largely based on advanced computed tomography (CT) imaging, while the diagnosis of PTE in veterinary medicine is frequently limited to the recognition of clinical signs in animals with predisposing conditions and consistent findings on thoracic radiographs. Thrombi undergo 50% reduction in clot volume in the first 3 hours postmortem because of fibrinolytic dissolution; with heparin administration, clot volume is further reduced as a result of inhibition of clot formation.1 Thus necropsy confirmation of PTE can be difficult. As a result, PTE is likely underdiagnosed in the veterinary population. Clinical recognition of PTE antemortem is difficult because clinical signs and physical examination findings mimic those found in a variety of cardiopulmonary conditions. In an early report, PTE was a differential diagnosis for respiratory distress in less than 5% of dogs with PTE confirmed at necropsy.2 In a later study,3 PTE was suspected in 65% of dogs presenting with relevant respiratory signs and a recognized predisposing condition for thromboembolism, suggesting increased awareness of the condition. PTE has been associated with numerous disease states, in particular those that involve one or a combination of a hypercoagulable state, endothelial injury, and abnormalities of blood flow or blood flow stasis. In dogs, immune-mediated hemolytic anemia, sepsis, neoplasia, amyloidosis, hyperadrenocorticism, protein-losing nephropathy and enteropathy, and dilated cardiomyopathy are associated with an increased risk for PTE, whereas neoplasia, cardiomyopathy, and pancreatitis are found most often in cats with PTE.3-7 The majority of cases have comorbid conditions complicating the primary clinical disease and potentially increasing

the risk for thromboembolism. Because PTE is associated with nonspecific clinical signs such as tachypnea or respiratory distress, knowledge of predisposing conditions (Box 27.1) is important for appropriate diagnosis and treatment. Severe PTE can cause acute, life-threatening hypotension and cardiac arrest. Less severe cases can be a cause of hypoxemia and respiratory distress, while diffuse, chronic PTE is a mechanism of pulmonary hypertension, and a subset of cases in human medicine is asymptomatic.8 The overall mortality associated with PTE varies greatly depending on severity and coexisting disease processes.

PATHOPHYSIOLOGY Thromboembolism occurs in association with a hypercoagulable state. This is reviewed further in Chapter 101. The key pathophysiologic responses to PTE include alterations in hemodynamics as a result of increased pulmonary vascular resistance, abnormalities in gas exchange, altered ventilatory control, and derangements in pulmonary mechanics. Rarely, pulmonary infarction contributes to the clinical presentation. Unlike the systemic circulation, the pulmonary circulation is able to accommodate substantial changes in blood flow without increases in pulmonary vascular pressure as a result of distention and recruitment of pulmonary vessels. Vascular obstruction from embolization results in both mechanical obstruction of the vasculature and reactive vasoconstriction because of the release of vasoactive mediators, such as serotonin, thromboxane, thrombin, histamine, prostaglandins, and endothelins. The combination of these events causes a reduction in the cross-sectional area of the pulmonary circulatory bed, increases in vascular resistance, and in moderate to severe cases, increases in pulmonary arterial pressure. Subsequent gas exchange abnormalities promote hypoxic pulmonary vasoconstriction, which further increases pulmonary artery pressure. In severe cases, acute right ventricular failure resulting from increased afterload, ventricular ischemia, and impaired contractility can ultimately

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BOX 27.1  Disorders Associated with

Pulmonary Thromboembolism Immune-mediated hemolytic anemia Neoplasia Sepsis Protein-losing nephropathy/enteropathy Pancreatitis Cardiac disease Hyperadrenocorticism Corticosteroid administration Central catheter use Hemodialysis Total parenteral nutrition Hip replacement surgery (cemented) Trauma

undergone recent surgical procedures, and 10% of dogs were given blood transfusions.3 It is interesting to note that pleuritic or substernal pain is commonly reported in human patients but has not been recognized in veterinary patients.

PHYSICAL EXAMINATION Dogs with PTE typically demonstrate tachypnea or hyperpnea. Physical examination findings potentially consistent with PTE include increased respiratory rate and effort, tachycardia, right sided heart murmur, and poor perfusion. Although abnormal lung sounds maybe present, animals with PTE and no other underlying pulmonary disease may have a normal auscultation. Physical examination findings will always be impacted by any coexisting disease processes.

DIAGNOSTIC TESTING lead to right ventricular failure. This has been well documented in human patients but poorly described in veterinary patients, likely due to a lower incidence and challenges in confirming the diagnosis in an unstable patient. PTE commonly results in hypoxemia, although the impact on gas exchange is unpredictable and it has been shown that the partial pressure of oxygen (PaO2) does not correlate with the degree of embolization.9,10 Ventilation–perfusion (V/Q) mismatch is considered the major mechanism of hypoxemia following PTE, although studies in animals and human patients have shown significant variability in the V/Q alterations present both between individuals and within a single patient over time.11 Mechanisms for changes to V/Q matching include overperfusion of areas of the lung leading to low V/Q (due to high Q) areas and regions of alveolar dead space downstream from the areas of vascular occlusion. Low V/Q regions are considered the most important contribution to hypoxemia, although low PvO2 secondary to poor cardiovascular performance will worsen hypoxemia. Minor contributions to hypoxemia following PTE can include pulmonary edema (considered uncommon) and atelectasis. Atelectasis may result from reduced production of surfactant distal to the site of vascular obstruction. Hypocapnia is the most common ventilatory abnormality reported in patients with PTE, and it may be driven by hypoxemia, activation of pulmonary irritant C-fibers, and cardiovascular compromise activating peripheral chemoreceptors.11

HISTORY AND CLINICAL SIGNS Historical features consistent with PTE include labored breathing, tachypnea, lethargy, and altered neurologic status. Additional clinical signs that can be observed include cough, syncope, and hemoptysis. Altered mental state is reported in 20% of human patients with PTE and might be related to transient hypoxemia or cerebral ischemia. In a report in dogs, abnormal neurologic status was recorded in more than one-third of affected animals3 and thus might be a common finding with PTE. Importantly, obvious respiratory distress and tachypnea can be absent in some dogs or cats that have pulmonary embolization documented at necropsy. It is essential to obtain information regarding concurrent disease processes and treatment to determine the risk of embolization in hospitalized patients. In dogs with clinical syndromes associated with PTE, intravenous catheters had been placed in the majority of cases, exogenous glucocorticoid excess was reported in half, use of cytotoxic agents was found in more than one-third, 21% had

The history of a predisposing disease along with the acute onset of respiratory distress and/or cardiovascular collapse may be suggestive of PTE; however, proving the presence of embolic disease antemortem can be challenging. Given the incidence of PTE in animals appears far lower than in human patients, evaluation usually starts with ruling out more common causes of acute disease in dogs and cats. Diagnostic evaluation for PTE often includes confirming the presence of hypercoagulability, identification of indicators for pulmonary obstruction and/or abnormal coagulation, and workup for potential underlying diseases that may predispose to hypercoagulability. Viscoelastic coagulation testing such as thromboelastography (TEG) can identify hypercoagulable states and is commonly part of the diagnostic evaluation of a patient suspected of having PTE. Although two small prospective studies that included a total of 10 dogs with PTE confirmed via CT with pulmonary angiography, data from TEG alone were insufficient to diagnose PTE.12,13 In comparison to TEG, standard tests of coagulation (activated partial thromboplastin time [aPTT], prothrombin time [PT]) assess only the time required to form a clot. There is some evidence in the human literature to suggest that a shortened aPTT may be associated with an increased risk of venous thromboembolism,14 and a small retrospective veterinary study found that dogs with a shortened PT or aPTT were more likely to have suspicion of PTE compared with a control population of dogs with normal PT and aPTT. Notably however, in this study, PTE was suspected on the basis of assessment by the attending clinician and not confirmed via imaging.15 Assessment of d-dimer concentration is a routine screening test used in human medicine to help categorize the likelihood of PTE in an individual patient. d-Dimer is a degradation product of fibrin that has undergone cross-linkage, and a positive test is more specific for fibrin formation than the fibrin degradation product (FDP) test because the FDP detects both fibrin and fibrinogen breakdown products. The presence of elevated d-dimer levels is expected in patients with thromboembolic disease, and a normal level (negative d-dimer test) makes the presence of PTE unlikely.16 d-Dimer levels are nonspecific, and many diseases in veterinary medicine result in elevation of d-dimer,16 and a negative test does not exclusively rule out thromboembolism.17 A study in human medicine evaluating the accuracy of d-dimer testing versus location of embolus reported that a negative d-dimer could be used to rule out the majority (93%) of large pulmonary emboli but only half of the subsegmental emboli.18 Timing of d-dimer measurement relative to the onset of PTE may also affect the sensitivity of this test. In a study involving experimentally induced PTE in dogs, d-dimer concentration peaked within 2 hours postembolization and

CHAPTER 27  Pulmonary Thromboembolism then rapidly declined; by 48 hours the d-dimer concentration was not different from the control group.19 Cardiac troponins are markers of myocardial cell injury and may be elevated with myocardial ischemia or necrosis. In patients with PTE, cardiac troponins may be elevated due to subendocardial ischemia resulting from increased pulmonary artery pressure, systemic hypoxemia, coronary hypoperfusion, and increased right ventricular pressure leading to wall stretch and ischemia.20 In people with PTE, cardiac troponin measurement is frequently used for risk stratification, and elevated troponins have been associated with a more complicated clinical course, including a need for inotropic support or mechanical ventilation, as well as mortality.21,22 In dogs with experimentally induced PTE, cardiac troponin I (cTnI) concentration was significantly increased 2 hours following embolization, and the increase in cTnI correlated with the severity of PTE,23 although a recent prospective clinical study found a lack of correlation between cTnI concentration and PTE diagnosed via CT.12 Arterial blood gas analysis may reveal hypoxemia and hypocapnia. Thoracic radiographs may identify other causes of respiratory distress and hypoxemia, may identify underlying disease processes, and in some incidences reveal abnormalities associated with vascular obstruction (Fig. 27.1) Previously reported thoracic radiographic abnormalities associated with PTE in dogs include pleural effusion, loss of definition of the pulmonary artery, alveolar infiltrates, cardiomegaly, hyperlucent lung regions, and enlargement of the main pulmonary artery.24 Interstitial or alveolar infiltrates can represent focal or diffuse edema associated with overperfusion or atelectasis. Normal thoracic radiographs do not rule out the possibility of PTE, and normal thoracic radiographs in a patient with respiratory distress and hypoxemia should be considered highly suspicious for PTE.3 Bedside echocardiography is frequently utilized in human medicine as a means of ruling in PTE when there is a high index of suspicion.

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Echocardiographic features are variable and dependent on the degree of vascular occlusion and the effect on pulmonary vascular resistance and pulmonary artery pressure, but can include right ventricular hypokinesis, increased right ventricular end-diastolic diameter, abnormal movement of the ventricular septum, tricuspid regurgitation, and pulmonary hypertension. In some cases, thrombi are directly visualized within the pulmonary arteries or right heart. McConnell’s sign, or akinesia of the right midventricular free wall with normal contractility at the apex, is highly specific for the diagnosis of acute PTE in people.25 The use of echocardiography for detection of PTE in small animal patients is less well-defined given the comparative paucity of published data, although given that this test is relatively noninvasive it could be considered in the workup of a patient with respiratory distress and suspected PTE. It should be noted, however, that a normal echocardiogram does not exclude the possibility of PTE.25 Historically, definitive diagnosis of PTE in both human and veterinary species has required invasive techniques such as selective pulmonary angiography or ventilation/perfusion scanning. In recent years, computed tomography with pulmonary angiography (CTPA) has become the gold standard for PTE diagnosis in people and is increasingly used for small animal species. Findings on CTPA consistent with a diagnosis of pulmonary thromboembolism include intraluminal filling defects in the pulmonary arteries (Fig. 27.2), while luminal irregularities or altered arterial luminal density on the contralateral side may raise suspicion for PTE. CTPA has been shown to be feasible in awake, sedated animals, which may preclude the need for intubation to perform this test.12 Additionally, recent work has evaluated the use of the VetMousetrap device to facilitate CT in awake cats and small dogs. The VetMousetrap is a transparent plexiglass tube that patients are placed into, which allows for provision of supplemental oxygen and access to IV infusion lines during the imaging procedure.26 In a study reported in abstract form, the VetMousetrap was well tolerated in eight dyspneic dogs and allowed for good image quality, with PTE either confirmed or highly suspected in six.27

CLASSIFICATION OF ACUTE PULMONARY THROMBOEMBOLISM In the human literature, classification schemes have been developed to stratify risk of early mortality from acute PTE and to guide the use of therapeutics. The Pulmonary Embolism Severity Index (PESI) and simplified PESI (sPESI) scores, which take into account patient demographics, comorbidities, and baseline physical examination parameters, have been found to reliably predict a low risk of mortality within 30 days in patients with acute pulmonary thromboembolism.28,29 Patients with an elevated PESI or sPESI are further classified as intermediate (submassive PTE) or high risk (massive PTE), based on evidence of right ventricular dysfunction, increased cardiac troponin concentration, or hemodynamic instability (cardiac arrest, cardiogenic shock, or persistent hypotension due to PTE) (Table 27.1).30,31

TREATMENT AND PROPHYLAXIS

Fig. 27.1  Ventrodorsal thoracic radiograph of a dog with pulmonary thromboembolism. The pulmonary arteries are enlarged proximally, and the right heart is rounded with a reverse D appearance. In this case, cor pulmonale resulting from pulmonary thromboembolism and pulmonary hypertension were suspected.

Treatment of pulmonary embolism involves the identification and management of underlying comorbidities that may have contributed to thrombus formation, provision of supplemental oxygen, anticoagulation, and potentially reperfusion therapy via thrombolysis. Supplemental oxygen is indicated in hypoxemic patients and, given that most patients with PTE require ongoing oxygen therapy, this may be best provided via nasal cannula, high-flow nasal cannula, oxygen hood, or oxygen cage. Intubation and mechanical ventilation are indicated for patients with severe, refractory hypoxemia or impending respiratory

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Fig. 27.2  Transverse and parasagittal images from a computed tomography scan with pulmonary angiography in a dog with pulmonary thromboembolism (chest radiograph shown in Fig. 27.1). Intraluminal filling defects in the right and left principal pulmonary arteries (transverse image) and left caudal lobar artery (parasagittal image) are indicated by red arrows. (Courtesy Dr. Jennifer Reetz, University of Pennsylvania.)

TABLE 27.1  Risk of Early Mortality Associated with Acute Pulmonary Thromboembolism30 Early Mortality Risk High Intermediate-high Intermediate-low Low

Hemodynamic Instability 1 2 2 2

PESI Class III-V or sPESI .0 1 1 1 2

fatigue, although care should be taken to avoid high levels of PEEP and high mean airway pressures, as positive intrathoracic pressure can reduce venous return and impair cardiac output in patients with PTE and right ventricular dysfunction. Anticoagulant therapy is indicated to prevent progression of the thrombus and to reduce the likelihood of further thrombotic events. Guidelines in human medicine suggest beginning anticoagulant therapy for all patients with confirmed PTE regardless of severity, and in patients with a high probability of PTE while awaiting diagnostic results. In most instances, anticoagulant therapy is continued for a minimum of 3 months, although long-term therapy may be warranted in patients with nonreversible risk factors for thrombosis or those that have a high risk of recurrence.30 Recently published consensus guidelines on the use of antithrombotics in the veterinary setting suggest the use of either heparin (with low molecular weight heparin preferred over unfractionated heparin) or direct Xa inhibitors (e.g., rivaroxaban) rather than vitamin K antagonists or platelet inhibitors for the treatment of venous thromboembolism.32 Given the high risk for thrombosis, prophylactic antithrombotic therapy should be considered in dogs with immunemediated hemolytic anemia and protein-losing nephropathy, or when more than one risk factor for thrombosis is present.33 In people, reperfusion therapy is generally reserved for patients with massive PTE and high risk of early mortality, although it may be considered for patients at intermediate risk with evidence of myocardial injury, right ventricular dysfunction, or respiratory decline.31

Right Ventricular Elevated Cardiac Dysfunction Troponin Concentration 1 1 1 1 Only one or neither present 2 2

For these patient subsets, systemic administration of a thrombolytic is suggested, and the current human guidelines suggest the use of recombinant tissue-type plasminogen activator (rtPA) over use of first-generation thrombolytics like streptokinase and urokinase (see Chapter 166, Thrombolytic Agents).30 Surgical pulmonary embolectomy and interventional techniques using catheters to mechanically disrupt, aspirate, or deliver rtPA directly to the thrombus have also been described and may be considered if systemic thrombolytic therapy is contraindicated or has failed.30 Aside from experimental studies, the clinical use of thrombolytic therapy in small animal patients is less well described, although some case reports document the successful use of these medications. Anecdotally, at the author’s institution, catheter-directed administration of rtPA has been attempted with good outcome in some cases. Given the risk for hemorrhage, however, the use of thrombolytic medications should be weighed carefully against the potential benefit in patients with PTE.

REFERENCES 1. Moser KM, Guisan M, Bartimmo EE, et al: In vivo and post mortem dissolution rates of pulmonary emboli and venous thrombi in the dog, Circulation 48:170, 1973. 2. La Rue MG, Murtaugh RJ: Pulmonary thromboembolism in dogs: 47 cases (1986-1987), J Am Vet Med Assoc 197:1369, 1990.

CHAPTER 27  Pulmonary Thromboembolism 3. Johnson LR, Lappin MR, Baker DC: Pulmonary thromboembolism in 29 dogs: 1985-1995, J Vet Intern Med 13:338, 1999. 4. Klein MK, Dow SW, Rosychuk RAW: Pulmonary thromboembolism associated with immune-mediated hemolytic anemia in dogs: ten cases (1982-1987), J Am Vet Med Assoc 195:146, 1989. 5. Jacinto AML, Ridyard AE, Aroch I, et al: Thromboembolism in dogs with protein-losing enteropathy with non-neoplastic chronic small intestinal disease, J Am Anim Hosp Assoc 53:185, 2017. 6. Norris CR, Griffey SM, Samii VF: Pulmonary thromboembolism in cats: 29 cases (1987-1997), J Am Vet Med Assoc 215:1650, 1999. 7. Schermerhorn T, Pembleton-Corbett JR, Kornreich B: Pulmonary thromboembolism in cats, J Vet Intern Med 18:533, 2004. 8. Shteinberg M, Segal-Trabelsky M, Adir Y, et al: Clinical characteristics and outcomes of patients with clinically unsuspected pulmonary embolism versus patients with clinically suspected pulmonary embolism, Respiration 84:492-500, 2012. 9. Baird JS, Greene A, Schleien CL: Massive pulmonary embolus without hypoxemia, Pediatr Crit Care Med 6:602-603, 2005. 10. Wilson JE III, Pierce AK, Johnson RL Jr, et al: Hypoxemia in pulmonary embolism, a clinical study, J Clin Invest 50:481-491, 1971. 11. Santolicandro A, Prediletto R, Fornai E, et al: Mechanisms of hypoxemia and hypocapnia in pulmonary embolism, Am J Respir Crit Care Med 152:336-347, 1995. 12. Goggs R, Chan DL, Benigni L, et al: Comparison of computed tomography pulmonary angiography and point-of-care tests for pulmonary thromboembolism diagnosis in dogs, J Small Anim Pract 55:190, 2014. 13. Marschner CB, Kristensen AT, Rozanski EA, et al: Diagnosis of canine pulmonary thromboembolism by computed tomography and mathematical modelling using haemostatic and inflammatory variables, Vet J 229:6, 2017. 14. Tripodi A, Chantarangkul V, Martinelli I, et al: A shortened activated partial thromboplastin time is associated with the risk of venous thromboembolism, Blood 104:3631, 2004. 15. Song J, Drobatz KJ, Silverstein DC: Retrospective evaluation of shortened prothrombin time or activated partial thromboplastin time for the diagnosis of hypercoagulability in dogs: 25 cases (2006-2011), J Vet Emerg Crit Care 26:398, 2016. 16. Nelson OL, Andreason C: The utility of plasma D-dimer to identify thromboembolic disease in the dog, J Vet Intern Med 17:830, 2003. 17. Epstein SE, Hopper K, Mellema MS, et al: Diagnostic utility of D-dimers in dogs with pulmonary embolism, J Vet Intern Med 27:1646, 2013. 18. De Monyé W, Sanson B, Mac Gillavry MR, et al: Embolus location affects the sensitivity of a rapid quantitative D-dimer assay in the diagnosis of pulmonary embolism, Am J Resp Crit Care Med 165:345, 2002. 19. Ben SQ, Ni SS, Shen HH, et al: The dynamic changes of LDH isoenzyme 3 and D-dimer following pulmonary thromboembolism in canine, Thromb Res 120:575, 2007.

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20. Lippi G, Favaloro EJ, Kavsak P: Measurement of high-sensitivity cardiac troponin in pulmonary embolism: useful test or clinical distraction, Semin Thromb Hemost 45:784, 2019. 21. Aksay E, Yanturali S, Kiyan S: Can elevated troponin I levels predict complicated clinical course and inhospital mortality patients with acute pulmonary embolism? Am J Emerg Med 25:138, 2007. 22. El-Menyar A, Sathian B, Al-Thani H: Elevated serum cardiac troponin and mortality in acute pulmonary embolism: systematic review and metaanalysis, Respir Med 157:26, 2019. 23. Uzuelli JA, Dias-Junior CA, Tanus-Santos JE: Severity dependent increases in circulating cardiac troponin I and MMP-9 concentrations after experimental acute pulmonary thromboembolism, Clin Chim Acta 388:184, 2008. 24. Fluckiger MA, Gomez JA: Radiographic findings in dogs with spontaneous pulmonary thrombosis or embolism, Vet Rad 23:124, 1984. 25. Fields JM, Davis J, Girson L, et al: Transthoracic echocardiography for diagnosing pulmonary embolism: a systematic review and meta-analysis, J Am Soc Echocardiogr 30:714, 2017. 26. Oliveira CR, Ranallo FN, Pijanowski GJ, et al: The VetMousetrap: a device for computed tomographic imaging of the thorax of awake cats, Vet Radiol Ultrasound 52:41, 2011. 27. Corsi R, O’Brien RT, Mai W, et al: Prospective study of the use of the VetMousetrap device for thoracic computed tomographic imaging without anesthesia in critically ill client-owned dogs with suspected pulmonary thromboembolism: preliminary results, J Vet Emerg Crit Care 24:S4, 2014. 28. Aujesky D, Obrosky DS, Stone RA, et al: Derivation and validation of a prognostic model for pulmonary embolism, Am J Resp Crit Care Med 172:1041-1046, 2005. 29. Jiménez D, Aujesky D, Moores L, et al. Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism, Arch Intern Med 170:1383-1389, 2010. 30. Konstantinides SV, Meyer G, Becattini C, et al: 2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): the task force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC), Eur Respir J 54:1901647, 2019. 31. Jaff MR, McMurtry MS, Archer SL, et al: Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association, Circulation 123:1788-1830, 2011. 32. Goggs R, Bacek L, Bianco D, et al: Consensus on the rational use of antithrombotics in veterinary critical care (CURATIVE): domain 2 – defining rational therapeutic usage, J Vet Emerg Crit Care 29:49, 2019. 33. deLaforcade A, Bacek L, Blais MC, et al: Consensus on the rational use of antithrombotics in veterinary critical care (CURATIVE): domain 1- defining populations at risk, J Vet Emerg Crit Care 29:37, 2019.

28 Chest Wall Disease Christiana Fischer, BS, VMD, DACVECC, Deborah C. Silverstein, DVM, DACVECC

KEY POINTS • The chest wall anatomy allows for functional respiration and protection of intrathoracic structures. • There are several diseases that can affect the chest wall, including congenital abnormalities, neoplasia, neurologic disorders (cervical spinal cord disease and neuromuscular disease), and trauma. In the veterinary patient, trauma to the chest wall is the most common cause.

• Diagnosis of chest wall disease involves a thorough history and physical examination, paying close attention to chest wall shape and movement during respiration. Thoracic imaging (radiographs and/or computed tomography) may also be helpful. • Depending on the etiology of chest wall disease, medical and/or surgical interventions may be required to improve patient comfort and pulmonary function.

CHEST WALL ANATOMY AND FUNCTION

course through reticulospinal tracts to cervical nerves 5–7 as well. It is here that they synapse with interneurons that also lead to efferent signaling via the phrenic nerve.15

The chest wall anatomy is designed in a way to allow for dynamic movement during respiration but also to serve as a protective barrier for the lungs, heart, and major vessels from external forces. Dogs and cats generally have 13 pairs of ribs; 9 of these rib pairs connect to the sternum via the costal cartilages while the 4 sternal ribs are joined together to form the costal arch.1 The shape of the thorax differs between breeds of dogs ranging from a broad, barrel-shape in brachycephalic breeds to a more deep, slender, keel-chest of sighthounds. The lateral parts of the ribs are covered by thin muscle bellies of the serratus ventralis, latissimus dorsi, scalenus, and obliquus abdominis externus muscles.1 The group of pectoral muscles covers the ventral thorax; the epaxial muscles cover the dorsal thoracic vertebrae. Intercostal vessels and nerves typically run on the caudomedial aspect of each rib, and effort should be made to avoid these vessels and nerves when performing a thoracocentesis (see Chapter 198, Thoracocentesis). The diaphragm makes up the largest and most important muscle of respiration. It is innervated by the phrenic nerve, and contraction of the diaphragm during inspiration leads to expansion of the chest cavity. It is the major muscle required for inspiration; so much so that paralysis of only the external intercostal muscles does not seriously affect breathing.2 During more active respiration, such as during exercise, the accessory muscles of inspiration are engaged. These include the external intercostal muscles, the scalene, and the sternomastoids.2 Exhalation is a much more passive process. Because the lungs and chest wall have elastic properties, they tend to return to a baseline homeostatic position without muscle engagement. When more forceful expiration is required (i.e., exercise, coughing, vomiting), then the muscles of the abdominal wall are recruited to push the diaphragm cranially.2 Neuronal control of breathing relies on contraction of the muscles of respiration, as well as response to signals from the medullary respiratory center (see Chapter 14, Control of Breathing).15 The phrenic nerve, which divides into the left and right branches, courses through the thorax to innervate the diaphragm. The phrenic nerve arises from the phrenic nucleus in the cervical spinal cord and then courses through cervical nerves 4–7.15 The medullary respiratory centers

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DIAGNOSIS OF CHEST WALL DISEASE History and physical examination findings are the mainstay of diagnosing chest wall disease in veterinary patients. Animals with chest wall disease can have a variety of breathing patterns; some may breathe normally or with increased effort, while others may demonstrate abnormal patterns of respiration such as a paradoxical breathing pattern. This is manifested clinically as an inward movement of the abdomen during inspiration with concomitant decreased outward movement of the chest wall. Injury to ribs and intercostal muscles may cause exaggeration of diaphragmatic contribution, resulting in profound outward movement of the abdomen on inspiration. Flail segments will move in the opposite direction of the rest of the chest wall. Routine monitoring of carbon dioxide should be performed, especially in an animal with a suspicion of chest wall disease, as hypoventilation secondary to decreased chest wall excursions is common (see Chapter 17, Hypoventilation). Diagnostic imaging including thoracic radiographs and thoracic computed tomography may help to identify chest wall disease, including rib fractures, chest wall neoplasia, diaphragmatic tears or rupture, and congenital abnormalities.

CAUSES OF CHEST WALL DISEASE Congenital Congenital abnormalities of the chest wall and associated structures are uncommon in veterinary species. The most common congenital chest wall defect is pectus excavatum, a disease that results in dorsal deviation of the sternum and the associated costal cartilages.3 The type and degree of pectus excavatum can vary, and some animals experience drastic compression of the thorax with subsequent decrease in intrathoracic volume. Clinical severity of pectus excavatum varies, ranging from absent clinical signs to respiratory distress, cough, exercise intolerance,

CHAPTER 28  Chest Wall Disease decreased appetite, failure to gain weight, and compressive cardiac sequelae. A 2018 study found a strong positive correlation between the clinical severity score and atypical pectus excavatum in brachycephalic dog breeds,4 implying that brachycephalic breeds may be clinically more affected by this congenital abnormality. Incomplete pentalogy of Cantrell, a rare constellation of chest wall malformations comprising a sternal cleft, peritoneopericardial diaphragmatic hernia, and ventral abdominal wall hernia has been reported in veterinary medicine.5,6 Most congenital thoracic wall malformations require surgical intervention if clinical signs, such as respiratory compromise, develop.

Neoplasia Neoplasms can arise from the thoracic wall in cats and dogs but rarely cause respiratory distress. Most thoracic wall tumors are malignant; common types include chondrosarcoma, osteosarcoma, fibrosarcoma, or other spindle cell tumors. Tumors of the diaphragm have been reported, as well as intramuscular lipomas effacing the accessory muscles of respiration. Resection of diaphragmatic and thoracic wall tumors depends on clinical signs, location, and biological behavior of the tumor. Rib resection may be required for some tumors of the thoracic wall. Generally, no more than six ribs can be resected without risk of compromise to functionality of the thoracic cage.7

Trauma Animals that have sustained a significant trauma often develop injuries to their thoracic wall. Common causes of traumatic thoracic injuries include vehicular accidents, bite injury, penetrating wounds, high-rise falls, and others. These animals may also have injuries to the organs and/or vasculature within the thorax. Thoracic wall injuries may be confounded by pleural space disease, pulmonary contusions, traumatic myocarditis, and less commonly, large airway injuries, as well as extrathoracic comorbidities.

Rib Fractures Trauma is the most common cause of rib fractures in small animal veterinary patients and may contribute greatly to patient pain and apparent respiratory distress.8 In a recent study evaluating rib fractures in dogs, 56% of canine rib fractures were from vehicular accidents and 44% were caused by canine bite injuries.8 Rib fractures may contribute to hypoxemia in these patients secondary to direct lung injury from rib fragments, pain associated with generating negative pressure, and hypoventilation due to decreased effective respiratory mechanics from flail chest segments. The cough reflex may also be voluntarily suppressed, which could promote pneumonia secondary to the accumulation of respiratory secretions. Confirmation of rib fractures should be performed with thoracic radiography. Initial treatment for patients with suspected rib fractures includes oxygen supplementation and pain management (see Chapters 15 and 134, Oxygen Therapy and Analgesia and Constant Rate Infusions, respectively). The human RibScore, described by Chapman et al., is a point-based scoring system derived from radiographic evidence of rib fractures in human trauma patients.9 This human scoring system has predicted pneumonia, respiratory failure, and need for tracheostomy.9 Although not validated for veterinary patients, a recent study evaluated canine patients with traumatic rib fractures and used various scoring systems to determine outcome.8 In this study, the animal trauma triage score was a strong predictor of outcome, whereas the RibScore and a modified RibScore were not.8 Treatment of rib fractures is usually focused on pain management. Systemic analgesia can be provided with injectable opioids and/or nonsteroidal antiinflammatory drugs (see Chapters 134 and 158, Analgesia and Constant Rate Infusions and Nonsteroidal Antiinflammatory Drugs,

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respectively). Local analgesia may provide and serve as an additional modality without the adverse effects on ventilation.

Flail Chest Flail chest is a less commonly encountered thoracic injury that involves three or more rib fractures, in series, in which both the dorsal and ventral aspect of the ribs are fractured. This segment can then affect respiratory mechanics, as the flail portion will paradoxically move inward during inspiration and outward during exhalation. This is usually noticeable on initial physical examination along with crepitus in this region of the thoracic wall due to the presence of subcutaneous emphysema (see Video 28.1 for images of flail chest in a large-breed dog). Penetrating chest wall injury may tear intercostal muscles with no or few associated rib fractures, leading to some paradoxical movement of an area of chest wall that is not a full flail segment. This pseudo-flail injury has less impact on respiratory mechanics than a flail chest, although management is similar. Although the exact prevalence of flail chest in thoracic trauma is unknown in veterinary medicine, one retrospective study determined that flail chest was more common in dogs than in cats and was more common secondary to bite wounds than motor vehicle accidents.10 Pneumothorax was concurrently diagnosed in 58% of the cases in this study,10 further supporting the need for a complete physical and diagnostic evaluation in these patients. Management of flail chest is centered on pain control, as is the treatment of uncomplicated rib fractures. In addition to systemic and local pain control, placement of the patient in lateral recumbency with the flail segment down may help to stabilize the segment and prevent hypoventilation.12 This may not be possible in all patients, as some animals may experience bilateral flail chest and/or the presence of parenchymal disease may preclude lateral recumbency. A chest wrap may achieve this same goal, but care should be taken to assure the wrap does not limit the patient’s ability to ventilate. If medical management is not enough to stabilize the patient, or a thoracotomy is indicated for other injuries, then surgical correction is warranted.

Penetrating Wounds Penetrating chest wall injuries can cause serious, life-threatening injury to cats and dogs. An open pneumothorax (a sucking chest wound) may develop if the penetrating injury allows air to enter the chest. Depending on the cause of the penetrating injury, visceral damage to the lungs, heart, and other structures can occur. A recent retrospective study evaluating feline patients with surgically managed thoracic trauma found that dog bite or attack was the most common cause of penetrating chest wall trauma.12 In canine patients, common causes of penetrating thoracic trauma include dog/animal bites, gunshot wounds, and impalement injuries. Bite wounds to the chest pose an additional risk; not only can they cause penetrating injury, but also blunt injury. In a large retrospective study evaluating dog bite wounds in cats and dogs, 35% of wounds in dogs and 36% of wounds in cats were over some part of the thorax.13 Surgical exploratory thoracotomy is indicated for management of severe penetrating chest wall injury. Initial emergent treatment will often require rapid thoracocentesis (see Chapter 198, Thoracocentesis) and may require the placement of a thoracostomy tube, either through the penetrating injury or via a new site (see Chapter 199, Thoracostomy Tube Placement and Drainage). A tight chest wrap may provide an air-tight seal until surgery can be performed, although it is imperative that the pleural space remains evacuated. Additional diagnostic imaging, such as thoracic computed tomography, may be required for surgical planning, especially in cases of impalement or ballistic injury. A case report by Nolff and colleagues described the successful use of

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negative pressure wound therapy following an open thoracotomy and left lateral lung lobectomy for penetrating thoracic bite wounds in a Dachshund.14

for any animal with progressive lower motor neuron (LMN) signs presenting in an endemic region.

SPINAL CORD AND NEUROMUSCULAR DISEASE

Tick paralysis is a potentially life-threatening disease of small animals that is most commonly reported in the United States and Australia. The neurotoxin, which arises from the saliva of female ticks, acts on both motor and sensory neurons to cause inhibition of depolarization in the distal segments of motor neurons and can also block the release of acetylcholine at the neuromuscular junction.18 Various tick species have been implicated, including Dermacentor variabilis and Dermacentor andersoni in the United States and Ixodes holocyclus in Australia.18 Clinical signs usually begin 7 days after the tick attaches and start with ataxia that can progress rapidly to paresis and paralysis with autonomic signs.19 Treatment is aimed at finding and removing the tick, which usually results in cessation of clinical signs. Shaving patients to find the tick may be required, and the application of insecticides should be performed. Ventilatory support may be needed during the treatment period. Reports from Australia not only describe hypercapnia secondary to hypoventilation from tick paralysis, but also upper airway obstruction from paralysis of the laryngeal and pharyngeal muscles, and even the development of cardiogenic pulmonary edema due to the Ixodes holocyclus toxin.20 Cats and dogs that required mechanical ventilation for tick paralysis had an overall good prognosis, with 90% survival in patients that required mechanical ventilation for ventilatory failure.19 The survival rate was less (53%) for ventilated patients that had oxygenation failure secondary to tick paralysis.19

Spinal cord and neuromuscular diseases have the potential to impair normal chest wall movement, commonly referred to as respiratory paralysis. Any disease that impairs the innervation of the diaphragm or weakens inspiratory muscle function has the potential to lead to hypoventilation (see Chapter 17, Hypoventilation). As mentioned earlier, many of the important nerves that innervate the muscles of respiration arise from cervical nerve roots 4–7. Cervical disease, such as disc herniation or cervical vertebral fracture(s), in this location can result in damage to the motor axons of the phrenic nerve, resulting in hypoventilation secondary to failure of diaphragmatic contraction. Risk factors for the development of respiratory failure in dogs undergoing treatment for cervical spine disorders may include lesions in the cervical region, as well as treatment with a dorsal decompressive laminectomy.16 Treatment of spinal cord or neuromuscular diseases leading to hypoventilation includes oxygen therapy to prevent secondary hypoxemia, treatment of the primary disease and close monitoring of partial pressure of carbon dioxide. Severe hypoventilation is an indication for mechanical ventilation, which may be required for the management of many of these disease processes (see Chapter 32, Mechanical Ventilation – Core Concepts).

Elapid Snake Envenomation The Elapidae family of snakes comprises several species of coral snakes that are found most commonly in the southern United States, Australia, Central and South America, the Middle East, Asia, and Africa.26 Their venom affects cats and dogs similarly to humans, but depending on the type of elapid snake, there may be a difference in clinical syndrome seen in veterinary patients. Elapid snake venom may contain neurotoxins, hemolytic toxins, toxins that cause derangements in hemostasis and bleeding, and cytotoxins. Of these possible toxins, the neurotoxins have the potential to affect the respiratory system most dramatically. The neurotoxins in elapid venom may be either presynaptic or postsynaptic.26 The presynaptic neurotoxins are phospholipase A2 toxins and prevent release of acetylcholine, whereas the postsynaptic neurotoxins act as antagonists to the acetylcholine receptor.26 Paralysis from elapid snake envenomation may ensue rapidly and tends to occur faster in patients that are more active immediately after being bitten by these snakes. In dogs, preparalytic signs include vomiting, nausea, hypersalivation, urination and defecation, and/or collapse.27 These signs may rapidly progress (,30 minutes) to a nonpainful paralytic state, in which the most common cause of death is respiratory failure from decreased chest wall and diaphragmatic excursions.28 After envenomation in cats, a rapid and acute ascending flaccid quadriplegia with reduced nociception may ensue.28 Treatment involves antivenom administration and intubation with mechanical ventilation to treat hypoventilation. Supportive care, wound management, and blood transfusions may be required based on the effects of other toxins released from the snakebite. A retrospective evaluation of coral snake bites in cats and dogs from Florida described 14 cats and dogs with elapid bites, where four envenomated dogs required ventilator support due to hypoventilation.28 One of these ventilated dogs survived to discharge.28 One of the dogs in this study died from respiratory arrest.28 This study stresses the importance of considering envenomation as a differential

Tick Paralysis

Acute Idiopathic Polyradiculoneuritis Acute idiopathic polyradiculoneuritis (Coonhound paralysis) is an acutely progressively neurologic disease seen most commonly in hunting dogs that have exposure to raccoons.18 A substance found in raccoon saliva causes an immune-mediated syndrome of neuronal demyelination and degeneration of axons.18 Recent research in humans has indicated that coinfection with Campylobacter may be a risk factor for the development of acute polyradiculoneuritis.21 In fact, dogs with fecal positive Campylobacter infections were 9.4 times more likely to develop acute polyradiculoneuritis, which likely came from ingestion of raw chicken.21 The syndrome manifests itself 1 week after raccoon exposure or Campylobacter infection and begins with hindlimb ataxia, paresis, and hyporeflexia that quickly progresses to tetraparesis and hypotonia.18 Diagnosis is made by clinical suspicion, history and excluding other causes of LMN disease and tetraparesis (e.g., tick paralysis, botulism, and myasthenia gravis [MG]). Treatment is mainly supportive; some animals may require mechanical ventilation if the motor nerves to their respiratory muscles and/or diaphragm are affected (see Video 28.2 for images of a dog with abdominal breathing due to polyradiculoneuritis).

Botulism Botulism has been reported to cause neuromuscular disease in small animals after ingestion of preformed Clostridium botulinum toxin.18 Botulism type C toxin causes clinical disease in dogs via inhibition of acetylcholine release at the synaptic terminal by blocking presynaptic acetylcholine vesicular fusion with the terminal membrane. Clinical signs include paresis, ataxia, and even respiratory failure. Cranial nerve abnormalities may develop, which can sometimes help differentiate botulism from other LMN diseases.18 Treatment is mainly supportive, and some animals may require mechanical ventilatory support secondary to ventilatory failure or even from hypoxemia secondary to aspiration pneumonia.

CHAPTER 28  Chest Wall Disease

Myasthenia Gravis MG is another LMN disease that results from the immune-mediated destruction or blockade of acetylcholine receptors at the neuromuscular junction. The disease can either be congenital or acquired; acquired MG is one of the most common neuromuscular diseases to affect dogs but is uncommon in cats. Clinical examination may reveal a seemingly normal patient at rest, but clinical signs become more apparent as the animal is stimulated. Muscle weakness, rapid fatigue, and a shortened stride are hallmark findings in animals with MG. The most severe form of MG, the fulminant form, may result in generalized muscle weakness, megaesophagus, regurgitation, and respiratory distress.18 Presumptive diagnosis of MG is made based on clinical signs, neurologic examination, and a positive response to an edrophonium or other anticholinesterase drugs.22 Definitive diagnosis is made with detection of acetylcholine receptor antibodies in serum via immunoprecipitation radioimmunoassay.22 Therapy involves the use of anticholinesterase agents (i.e., pyridostigmine) and corticosteroids for immunosuppression, although other immunosuppressants are also described. Novel therapies, such as plasmapheresis, can also prove beneficial but are typically more successful in patients without fulminant, severe disease. In humans, 10%–20% of MG patients require mechanical ventilation secondary to either respiratory failure, aspiration pneumonia, or a combination.22 Animals with MG may present with respiratory distress for two reasons: (1) secondary to hypercapnia from decreased chest wall excursions and/or from hypoxemia related to aspiration pneumonia secondary to megaesophagus or (2) secondary to overdoses of cholinesterase inhibitors.22 Both types of scenarios may require intervention with intubation and mechanical ventilation. One retrospective veterinary study that examined outcomes of dogs requiring mechanical ventilation for LMN disease described five cases of severe MG that required mechanical ventilation. Of these five dogs, 80% had preexisting pneumonia requiring mechanical ventilation and only one dog survived to discharge.23

OBESITY Obesity in veterinary patients is common, with about 20%–40% of the canine population considered obese.24 The ventilatory deficits seen with obesity are likely a combination of variables including decreased ability for the diaphragm to move caudally into the abdomen, increased work of breathing, overall decreased chest wall compliance, and lower operating lung volumes.24 A clinical diagnosis in obese humans is obesity hypoventilation syndrome (Pickwickian-type syndrome), defined as awake arterial hypoventilation and obesity.25 Although there is no current literature about obesity hypoventilation syndrome in veterinary patients, a version of this syndrome may be seen in obese dogs and cats, particularly contributing to respiratory disease in obese brachycephalic species or following general anesthesia in any breed.

REFERENCES 1. Dyce KM: The thorax of the dog and cat. In Dyce K, editor: Textbook of veterinary anatomy, St. Louis, 2017, Saunders Elsevier, pp 420-433. 2. West JB: Mechanics of breathing. In West JB, editor: West’s respiratory physiology: the essentials, Philadelphia, 2016, Wolters Kluwer, pp 95-122. 3. Singh M, Parrah JD, Moulvi BA, Athar H, Kalim MO, Dedmari FH: A review on pectus excavatum in canines: a congenital anomaly, Iran J Vet Surg 8:59-64, 2013. 4. Hassan E, Hassan M, Torad F: Correlation between clinical severity and type and degree of pectus excavatum in twelve brachycephalic dogs, J Vet Med Sci 80(5):766-771, 2018.

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5. Eiger S, Mison M, Aronson L: Congenital sternal defect repair in an adult cat with incomplete pentalogy of Cantrell, J Am Vet Med Assoc 254(9):1099-1104, 2019. 6. Benlloch-Gonzalez M, Poncet C: Sternal cleft associated with Cantrell’s pentalogy in a German shepherd dog, J Am Anim Hosp Assoc 51(4):279-284, 2015. 7. Johnston SA: Thoracic wall. In Tobias KM, editor: Veterinary surgery: small animal, vol 2, Elsevier/Saunders, St Louis 2012, pp 2001-2019. 8. McCarthy D, Bacek L, Kyoung K, Miller G, Gaillard P, Kuo K: Use of the animal trauma triage score, RibScore, modified RibScore and other clinical features for prognositication in canine rib fractures, Vet Comp Orthop Traumatol 31:239-245, 2018. 9. Chapman BC, Herbert B, Rodil M, et al: RibScore: a novel radiographic score based on fracture pattern that predicts pneumonia, respiratory failure, and tracheostomy, J Trauma Acute Care Surg 80(1):95-101, 2016. 10. Olsen D, Renberg W, Perrett J, et al: Clinical management of flail chest in dogs and cats: a retrospective study of 24 cases (1989–1999), J Am Anim Hosp Assoc 38(4):315-320, 2002. 11. Monnet E: Chest wall disease: flail chest. In Aronson L, editor: Small animal surgical emergencies, Oxford, 2016, Wiley & Sons, Inc. 12. Lux C, Culp WTN, Mellema MS, et al: Factors associated with survival to hospital discharge for cats treated surgically for thoracic trauma, J Am Vet Med Assoc 253(5):598-605, 2018. 13. Shamir MH, Leisner S, Klement E, et al: Dog bite wounds in dogs and cats: a retrospective study of 196 cases, J Vet Med A Physiol Pathol Clin Med 49:107-112, 2002. 14. Nolff MC, Pieper K, Meyer-Lindenberg A: Treatment of a perforating thoracic bite wound in a dog with negative pressure wound therapy, J Am Vet Med Assoc 249(7):794-800, 2016. 15. Kitchell RL, Evans HE: The spinal nerves. In Evans HE, editor: Miller’s anatomy of the dog, ed 3, Philadelphia, 1993, WB Saunders, pp 840-841. 16. Beal M, Paglia DT, Griffin GM, et al: Ventilatory failure, ventilator management, and outcome in dogs with cervical spinal cord disorders: 14 cases (1991-1999), J Am Vet Med Assoc 218(10):1598-1602, 2001. 17. Kube S, Owen T, Hanson S: Severe respiratory compromise secondary to cervical disk herniation in two dogs, J Am Anim Hosp Assoc 39(6):513-517, 2003. 18. Oliver JE, Lorenz MD, Kornegay JN: Tetraparesis, hemiparesis, and ataxia. In Oliver JE, Lorenz MD, Kornegay JN, editors: Handbook of veterinary neurology, ed 3, St Louis, 1997, Saunders Elsevier. 19. Webster RA, Mills PC, Morton JM: Indications, durations and outcomes of mechanical ventilation in dogs and cats with tick paralysis caused by Ixodes holocyclus: 61 cases (2008-2011), Aust Vet J 91(6):233-239, 2013. 20. Webster RA, Haskins S, Mackay B: Management of respiratory failure from tick paralysis, Aust Vet J 91(12):499-504, 2013. 21. Martinez-Anton L, Marenda M, Firestone SM, et al: Investigation of the role of Campylobacter infection in suspected acute polyradiculoneuritis in dogs, J Vet Intern Med 32(1):352-360, 2018. 22. Khorzad R, Whelan M, Sisson A, et al: Myasthenia gravis in dogs with emphasis on treatment and critical care management, J Vet Emerg Crit Care 21(3):193-208, 2001. 23. Rutter C, Rozanski EA, Sharp CR, et al: Outcome and medical management in dogs with lower motor neuron disease undergoing mechanical ventilation: 14 cases (2003-2009), J Vet Emerg Crit Care 21(5):531-541, 2011. 24. Manens J, Bolognin M, Bernaerts F, et al: Effects of obesity on lung function and airway reactivity in healthy dogs, Vet J 193(1):217-221, 2012. 25. Murugan AT, Sharma G: Obesity and respiratory diseases, Chron Respir Dis 5(4):233-242, 2008. 26. Swindells K, Schaer M: Elapid snake envenomation: North American coral snakes and Australian Elapids (Tiger snakes, Brown snakes, Taipans, Death Adders and Black snakes). In Drobatz K, Hopper K, Rozanski L, Silverstein D, editors: Textbook of small animal emergency medicine, ed 1, Newark, 2018, John Wiley & Sons. 27. Heller J, Bosward KL, Hodgson JL, et al: Snake envenomation in dogs in New South Wales, Aust Vet J 83(5):286-292, 2005. 28. Perez M, Fox K, Schaer M: A retrospective evaluation of coral snake envenomation in dogs and cats: 20 cases (1996-2001), J Vet Emerg Crit Care 22(6):682-689, 2012.

e1 Video 28.1  Flail chest in a dog. This large-breed dog sustained trauma, resulting in a flail chest segment on the left lateral thorax. Note the paradoxical breathing pattern of the flail segment; it moves opposite to the rest of the chest wall during inhalation and exhalation.

Video 28.2  Polyradiculoneuritis in a dog with abdominal breathing. This dog was diagnosed with idiopathic polyradiculoneuritis, with innervation to the diaphragm and chest wall affected. Note that this dog fails to move its chest wall effectively and is mostly breathing with the abdominal musculature.

29 Pleural Space Disease Bridget M. Lyons, VMD, DACVECC

KEY POINTS • Abnormalities within the pleural space include pleural effusion, pneumothorax, pleural fibrosis, or space-occupying soft tissue structures such as diaphragmatic hernia or neoplasia. • Thoracocentesis may be both diagnostic and therapeutic. • Fluid analysis and cytology should always be performed on aspirates from a patient with newly diagnosed pleural effusion. • Aerobic and anaerobic culture and susceptibility testing of suppurative effusions are imperative. • Comparison of effusion and serum triglyceride and cholesterol concentrations is helpful in the diagnosis of chylothorax. • Clinical signs of cardiovascular collapse often precede dyspnea in patients with hemothorax.

• Tension pneumothorax may be rapidly fatal; therefore, immediate drainage of the pleural space must be performed and cardiovascular stability achieved prior to performing diagnostics such as thoracic radiographs. • Clinical signs of a traumatic diaphragmatic hernia may be immediate or delayed. • Point-of-care ultrasound is an invaluable initial diagnostic in the evaluation of pleural space disease. • Reexpansion pulmonary edema is an uncommon but life-threatening complication that may occur in any patient that experiences rapid reexpansion of collapsed lung, especially those with chronic lung collapse.

PLEURAL SPACE

PHYSICAL EXAMINATION

The pleura are the porous, mesenchymal, serous membranes that form the lining of the pleural space.1 The visceral pleura covers the lung and reflects on itself at the root of the lung, where it continues as the parietal pleura and covers the mediastinum, diaphragm, and thoracic wall.2 The pleural space is the potential space between the visceral and parietal pleura, i.e., the space between the lung and the thoracic wall. The mediastinum separates the hemithoraces and contains the heart, trachea, esophagus, aorta, and thymus; in dogs and cats it is often fenestrated, allowing communication between the right and left side of the thorax.2 Small amounts of fluid are continuously transuded through the pleural membrane, resulting in a small volume of fluid within the pleural space that facilitates movement of the lungs within the thoracic cavity during inhalation and exhalation.1 Fluid is removed from the pleural space via lymphatics that drain into the mediastinum, diaphragm, and the lateral surfaces of the parietal pleura.1 The pumping of fluid by the lymphatics results in a negative pressure in the pleural space that pulls the lungs against the parietal pleura, helping to counter the elastic recoil of the lungs, and there is evidence that pleural capillaries may contribute as well.1,3 Negative pleural pressure is further enhanced by the tethering of the visceral pleura to the parietal pleura, resulting in an average intrapleural pressure of 25 cm H2O.1,2,4 Although negative pleural pressure serves to balance the elastic recoil of the lungs in health, it is not necessary for normal lung function. This is demonstrated by elephants, a species that lacks a pleural space, and by patients that undergo pleurodesis without significant impairment in lung function.5 However, accumulation of large amounts of air, fluid, or soft tissue within the pleural space restricts expansion of the lungs, resulting in decreased tidal volume, total vital capacity, and functional residual capacity, as well as hypoxemia and hypoventilation.4

Clinical signs of pleural space disease may include tachypnea, openmouth breathing, cough, neck extension, elbow abduction, cyanosis, and a short, shallow breathing with increased abdominal effort. Paradoxical breathing has been strongly associated with pleural space disease in both cats and dogs.6 The degree of dyspnea is variable and depends on the volume and rate of accumulation of fluid, air, or soft tissue in the pleural space. With accumulation of fluid, breath sounds may be muffled ventrally; with air, breath sounds may be muffled dorsally. Heart sounds may also be muffled, or abnormally loud or displaced with unilateral or focal disease. Lack of a fever does not preclude infectious etiologies, as up to 50% of cats with pyothorax are normothermic or hypothermic on presentation.7 In patients with a tension pneumothorax, rapid accumulation of air in the pleural space causes increased intrathoracic pressure and decreased venous return and may result in clinical signs of cardiovascular collapse. Patients with diaphragmatic hernia may have borborygmi auscultated over the thorax, and abdominal palpation may reveal the absence of organs that are normally palpated.

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IMAGING Point-of-care ultrasound (POCUS) is an indispensable tool for expeditious identification of pleural space disease, and multiple techniques have been described (see Chapter 189, Point-of-Care Ultrasound in the ICU).8,9 Importantly, POCUS is not a replacement for a formal ultrasound or other imaging techniques; however, the rapidity of POCUS combined with a need for only minimal restraint and patient positioning makes it an ideal initial diagnostic for patients in respiratory distress. Pleural effusion will appear as hypoechoic fluid, although more cellular effusions may display echogenic swirling. Pneumothorax can

CHAPTER 29  Pleural Space Disease be identified via the absence of a glide sign, which is the motion of the visceral and parietal pleura moving past each other. Severity of pneumothorax can be evaluated by locating the lung point, which is determined by moving the probe ventrally down the thorax until the glide sign reappears.9 A curtain sign, the demarcated vertical edge separating the lung from abdominal contents, may also be abnormal with pleural space disease.10 An asynchronous curtain sign, or movement of the vertical edge in a direction opposite of abdominal contents, may be seen with pneumothorax.10 A double curtain sign, or two vertical edges seen in the same sonographic window, can be seen with pneumothorax or diaphragmatic hernia.10 Diaphragmatic hernia may also be identified by the presence of abdominal organs in the thoracic cavity (see Fig. 29.1). Thoracic radiographs are helpful in diagnosing and quantifying pleural space disease and other intrathoracic pathology. It has been shown that the horizontal beam ventrodorsal view and the standard vertical beam left lateral view have the highest detection rate for small volume pneumothorax using radiography.11 If pleural effusion is

A

C

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noted on POCUS, it is ideally removed via thoracocentesis prior to acquisition of radiographs to improve visualization of intrathoracic structures, and a dorsoventral view is preferred to ventrodorsal if using a vertical beam. Rounded, retracted lung lobes that do not expand after thoracocentesis are suggestive of fibrosing pleuritis. Computed tomography (CT) has been shown to be more sensitive for detection of pneumothorax and pleural effusion when compared with thoracic radiographs and POCUS.12,13 In addition to identification of pleural air or fluid, radiographs and CT may also reveal the presence of diaphragmatic hernia, masses, or lung lobe torsion. Radiographic signs of diaphragmatic hernia include gas-filled abdominal organs within the thorax, an incomplete diaphragmatic border, pleural effusion, or cranially displaced abdominal organs. Although CT characteristics are used to differentiate types of pleural effusion in humans, they are inconsistent in the diagnosis of effusion type in dogs and cats.14,15 Thoracoscopy allows visualization of the thoracic structures and acquisition of biopsy samples, as well as the potential for therapeutic intervention.16-18

B

D Fig. 29.1  Imaging diagnostics for pleural space disease. A, Point-of-care ultrasound of a dog with pleural effusion secondary to chylothorax. B, Thoracic radiograph of a cat with a traumatic diaphragmatic hernia. C, Thoracic radiograph of a dog with a pneumothorax, mild pleural effusion, and suspected pulmonary contusions after vehicular trauma. D, Computed tomography of a dog with a pneumothorax, hemothorax, and suspected pulmonary contusions after vehicular trauma.

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PART II  Respiratory Disorders

THORACOCENTESIS Thoracocentesis is an invaluable diagnostic and therapeutic tool for animals with pleural space disease (see Chapter 198, Thoracentesis). Indications include 1) the presence of undiagnosed pleural effusion, and 2) therapeutic thoracocentesis to relieve respiratory distress secondary to large accumulations of air or fluid. If fluid is present, ultrasound can be used to identify the optimal site of needle puncture. At a minimum, fluid samples should be submitted for cytology and fluid analysis. In patients that have a known cause of effusion and are asymptomatic, thoracocentesis can be delayed and clinical signs followed.19

PLEURAL EFFUSION Classification Traditionally, effusions are classified according to total protein concentration and cell count, and divided into transudates, modified transudates, and exudates, although there is overlap between these categories (Table 29.1). Pure transudates are characterized by a low total protein and nucleated cell count and most commonly develop secondary to hypoalbuminemia in dogs and cats.20 In the thorax, they may also occur secondary to left- or right-sided congestive heart failure in cats, right-sided congestive heart failure in dogs, or with lymphatic obstruction in cats or dogs.20,21 Modified transudates may be seen with congestive heart failure, neoplasia, lung lobe torsion, diaphragmatic hernia, and vasculitis.20,21 Transudative effusions that are long standing may also develop into modified transudates secondary to chronic irritation of the pleura, resulting in an increased total protein and nucleated cell count.21 Pleural exudates result from a local inflammatory response, hemorrhage, or lymphatic leakage.21 Inflammation results in the release of cytokines that increase mesothelial and endothelial permeability, permitting proteins and cells to leak into the exudate.20 Inflammation may be secondary to infectious causes (e.g., bacteria, fungi, viruses, protozoa, parasites), neoplasia, foreign bodies, chronic chylous effusion (or other irritating substance), or immune-complex deposition.20,21 Effusions with .70% neutrophils (degenerate or nondegenerate) are classified as neutrophilic.21 Degenerate neutrophils typically predominate with infectious etiologies.20,21 In aseptic exudates, the predominant cell type varies based on underlying etiology.

Pyothorax Pyothorax is the accumulation of septic purulent fluid within the pleural space. The underlying cause of the infection is frequently unknown, with an etiology reported in only 2%–22% of dogs and 35%–67% of cats.7 In dogs, there is regional variation in regard to common causes, and migrating foreign bodies, penetrating and blunt thoracic trauma, hematogenous and lymphatic spread, esophageal perforation, parasitic migration, discospondylitis, osteomyelitis, parapneumonic spread, ruptured lung abscesses, and iatrogenic causes have been reported.7,18,22 Evidence suggests that parapneumonic spread of aspirated oropharyngeal flora is the most common origin in cats, although penetrating

TABLE 29.1  Classification of Effusions21 Fluid Type Pure transudate Modified transudate Exudate

Total Protein ,2.5 g/dl $2.5 g/dl $2.5 g/dl

Total Nucleated Cell Count ,1000 cells/µl 1000–5000 cells/µl .5000 cells/µl

thoracic wounds, foreign body migration, and parasite migration have also been reported.7 Septic suppurative effusion is diagnosed when intracellular organisms are found on cytologic evaluation. Fluid samples suspicious for microbial infection should be submitted for aerobic and anaerobic culture and susceptibility testing. Fungal organisms are cultured less commonly than bacteria but should be investigated if cytology supports a fungal etiology. Common infectious organisms found in dogs and cats with pyothorax are listed in Box 29.1. Treatment of pyothorax consists of antimicrobial therapy and source control. Given the range of common isolates and potential for polymicrobial infection, empiric broad-spectrum intravenous antimicrobials are recommended pending culture results.7 The ideal duration of therapy is unknown and is likely to vary depending on individual patient characteristics, causative organism, and local resistance patterns. The American Association for Thoracic Surgery consensus guidelines for the management of empyema in humans recommends a minimum of 2 weeks of antimicrobial therapy, while noting that a range of 2–6 weeks is reported in the literature and that duration should be determined by the sensitivity of the organism, adequacy of source control, and response to therapy.23 Source control may include thoracostomy tube placement alone (see Chapter 199, Thoracostomy Tube Placement and Drainage) or combined with surgical exploration. The ideal duration of thoracostomy tube usage is unknown, and suggested criteria for removal include clinical improvement, a decrease in fluid production to ,2 ml/kg/day, and resolution of infection on cytology.7 Given that healthy dogs with experimentally placed thoracostomy tubes developed iatrogenic infection within 4–6 days, removal before this time frame is recommended.24 Pleural lavage has been advocated for use in veterinary medicine; however, the ideal lavage solution, fluid volume, and dwell time are unknown, and lavage is not considered standard-of-care in human empyema patients.7,25 Use of intrapleural fibrinolytics and anticoagulants have been reported but are not currently recommended for routine treatment in human or veterinary medicine.7,23,25 Repeated thoracocentesis in lieu of thoracostomy tube placement has been described but is not advised due to the higher mortality rate associated with this method of therapy.7,23 Surgery, either open thoracotomy or video-assisted thoracoscopy, is indicated in patients with loculated fluid, lung or pleural abscesses, suspected neoplasia, perforated esophagus, penetrating thoracic injury, or those that fail medical therapy.7,25 Prognosis for dogs and cats with pyothorax is variable, and mortality data are difficult to interpret as some pets are euthanized due to financial constraints or perceived poor prognosis. Overall survival is

BOX 29.1  Common Organisms Causing Pyothorax in Dogs and Cats7 • Aerobes • Nocardia spp. • Streptococcus spp. • Corynebacterium spp. • Facultative anaerobes • Escherichia coli • Pasteurella spp. • Actinomyces spp. • Staphylococcus spp. • Anaerobes • Fusobacterium spp. • Peptostreptococcus anaerobius

• Bacteroides spp. • Prevotella spp. • Porphyromonas spp. • Clostridium spp. • Fungal organisms • Cryptococcus spp. • Candida albicans • Blastomyces dermatitidis

CHAPTER 29  Pleural Space Disease 83% in dogs (range 29%–100%) and 63% in cats (range 8%–100%).25 Reported recurrence rates range from 0%–14%.7

Chylothorax Chylous effusion generally appears white or pink, depending on dietary fat content, chronicity, and concurrent hemorrhage.21 These effusions are sometimes clear or serosanguinous if the dietary fat content is low or there has been prolonged anorexia.26,27 Small lymphocytes typically predominate; however, chyle is irritating to the pleura, and over time neutrophils and macrophages may become more prominent.21,27 Effusion triglyceride concentration will be higher than in serum, and the ratio is often greater than 3:1.21 A cutoff effusion triglyceride concentration of 100 mg/dl can also be used to differentiate between chylous and nonchylous effusions.21 Effusion and serum cholesterol concentrations can also be measured, with cholesterol levels expected to be lower in chylous effusion compared to serum.27 Causes of chylothorax include congestive heart failure, pericardial disease, dirofilariasis, congenital heart disease, thoracic duct obstruction secondary to granuloma, stricture or neoplasia, traumatic thoracic duct rupture, congenital thoracic duct malformations, cranial vena cava thrombosis, lung lobe torsion, diaphragmatic hernia, and mediastinal disease.27 A predisposing cause is frequently not identified, resulting in a diagnosis of idiopathic chylothorax. Therapy should be tailored to treat any underlying disease that is identified. For patients with idiopathic chylothorax, surgery is commonly indicated. Multiple surgical interventions have been described, with the combination of thoracic duct ligation and subphrenic pericardectomy (TDL/SP) showing the most success.17,28,29 Cisterna chyli ablation has also been recommended; however, a recent retrospective study in 22 cats did not find a benefit to this procedure when combined with TDL/SP.29 Both open and video-assisted approaches have been described, and indwelling pleural access ports may be placed at the time of surgery to facilitate repeat pleural drainage.17,28-30 Success rates for TDL/SP in dogs are 60%–100% and 80% in cats.28 If surgical intervention is not successful, pleurodesis can be considered. Although medical management may be attempted with idiopathic chylothorax, the presence of chyle is irritating to the pleura and may result fibrosing pleuritis, which has a more guarded prognosis.28,31 Rutin is a benzopyrone nutraceutical that is theorized to increase lymphatic fluid uptake, reduce blood vessel permeability, and increase macrophage phagocytosis of protein in lymph and has been reported to decrease effusion accumulation in cats.28,32,33 Octreotide, a somatostatin analog used in humans with traumatic chylothorax, has not proven as effective in veterinary species.28 Although a low fat diet is frequently recommended, a study in healthy dogs found that while it reduced the lipid content of chyle, it did not reduce the volume of lymph flowing through the thoracic duct, calling into question this recommendation.28 Cases of spontaneous resolution have also been reported.34

Hemothorax Hemothorax is diagnosed when the packed cell volume of pleural effusion is at least 25% that of peripheral blood.35,36 Hemorrhage within the pleural cavity may be caused by either an acquired or intrinsic coagulopathy or noncoagulopathic etiologies. The most common cause of noncoagulopathic hemothorax in dogs is neoplasia.35 Other causes include trauma, lung lobe torsion, parasitic migration, spontaneous vascular rupture, diaphragmatic hernia, thymic hemorrhage or iatrogenic during thoracocentesis, thoracic surgery, feeding tube removal, or jugular catheter placement.35,37-40 Hypovolemic shock may precede respiratory compromise, and patients with cardiovascular compromise should be treated with intravenous fluid therapy and blood products as needed (see Chapter 69, Transfusion Medicine). Autologous blood

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transfusion should be considered in patients with large volume hemorrhage and cardiovascular instability.41 Fresh frozen plasma and vitamin K may be indicated if coagulopathy is present or anticoagulant rodenticide toxicity is suspected. Antifibrinolytics should be considered if hemorrhage cannot be controlled. Surgery is rarely indicated in animals with a traumatic hemothorax unless a penetrating injury or uncontrolled hemorrhage is present, but it may be required in other cases of noncoagulopathic hemothorax. If significant hemothorax occurs postthoracotomy, surgical reexploration should be performed emergently.

Feline Infectious Peritonitis The effusive form of feline infectious peritonitis (FIP) is a common cause of pleural effusion in cats, and may occur concurrently with peritoneal and pericardial effusion.42 The effusion is typically viscous, straw-colored, clear to cloudy, and has a high protein concentration.43 Pyogranulomas, consisting of macrophages, neutrophils, lymphocytes, and occasional plasma cells, form small aggregations around venules and are associated with the development of effusions.44 The diagnosis of FIP is rarely straightforward and should be based on cumulative information as opposed to one diagnostic test. One study found an effusion total protein concentration of .3.5 g/dl had a sensitivity of 87.1% and a specificity of 60% for FIP, and a separate study found this cut off to have a 94% positive predictive value and 100% negative predictive value for FIP.21 Total nucleated cell count is typically low (500–5000/ml), with nondegenerate neutrophils predominating, although cell type may vary.21,45 Measurement of effusion a1-acid glycoprotein concentration has also been found to be useful for differentiating FIP from non-FIP effusions.26 The Rivalta test is an inexpensive and easy test to perform cage side, with a negative result suggestive of non-FIP causes of effusion.43 Reverse transcriptase PCR for feline coronavirus may also be useful, although false positives and negatives have been reported.43 A high viral load or detection of S gene mutations is suggestive of FIP.43 Testing of effusion can be paired with PCR of the mesenteric lymph nodes, spleen, liver, and whole blood to increase sensitivity.43 Immunohistochemistry performed on biopsy samples can be used to reach a definitive diagnosis.43 Treatment of FIP is largely palliative; the disease is almost uniformly fatal, although recent advances in antiviral treatment may hold hope for the future.46

Neoplastic Effusions and Pleural Neoplasia Intrathoracic neoplasia may result in pleural effusion by causing increased vascular permeability, obstruction of pleural and pulmonary lymphatic vessels or veins, shedding of cellular debris at the pleural surface, obstruction or perforation of the thoracic duct, or hemorrhage. Pneumothorax may also result from neoplasia.47 Common primary thoracic neoplasia includes lymphoma, carcinoma, and adenocarcinoma, although mesothelioma, sarcomas, and metastatic disease may result in pleural abnormalities as well.21 Space-occupying lesions within the pleural space are frequently malignant but should be differentiated from benign lesions. Fluid analysis and cytology may be informative, but thoracic ultrasonography, CT, thoracotomy, or thoracoscopy with fine-needle aspiration or biopsy will often be necessary to obtain a definitive diagnosis. In addition to treating the underlying neoplasia, long-term and palliative management of neoplastic effusions can be achieved in some patients by placement of indwelling pleural access ports, which allow both the drainage of effusion and instillation of intracavitary chemotherapeutics if indicated.30

Bilothorax Spontaneous, traumatic, and iatrogenic bile pleuritis is a rare but reported cause of pleural effusion in dogs and cats.25,48-52 A pleural

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effusion-to-serum bilirubin concentration ratio of .1:1 is consistent with bilothorax.52 Concurrent bile peritonitis may or may not be present. Successful medical management with thoracostomy tubes has been reported in two dogs, while successful surgical management was described for three dogs and three cats.48-52 Prolonged medical management may contribute to cardiovascular instability and poor outcome.52

Urothorax Urine accumulation in the pleural space is a rare complication of trauma and has been reported in two dogs and one cat.53-55 In two cases, diaphragmatic rupture was found concurrently, but in one dog the diaphragm was intact at the time of surgery.53-55 A pleural effusionto-serum creatinine concentration ratio of .1:1 is consistent with urothorax.53 If urothorax is noted, surgical intervention is indicated.

Pleural Fibrosis Fibrosing pleuritis is a chronic condition in which the pleura becomes thickened and restricts lung expansion as a result of inflammation within the thoracic cavity and can occur secondary to any type of chronic pleural effusion. In veterinary medicine, pleural fibrosis is most commonly associated with chylous effusion, but has been reported secondary to neoplasia, FIP, pyothorax, granulomatous pleuritis, and hemothorax.31,56,57 The development of pleural fibrosis in some patients with chronic effusion but not others is unclear.58 Decortication is the only effective therapy, although pneumothorax, hemorrhage, and reexpansion pulmonary edema are potential fatal complications.31 Prognosis for diffuse disease is considered guarded, although there is scant information regarding this disease process in veterinary species.31

PNEUMOTHORAX Pneumothorax (PTX) can be classified as spontaneous, traumatic, or iatrogenic. Spontaneous PTX refers to the accumulation of air in the pleural space without a known traumatic or iatrogenic cause. Pneumothorax can also be classified as an open, closed, or tension PTX. Open PTX occurs secondary to injury to the thoracic wall, such as with penetrating thoracic trauma. Closed PTX occurs secondary to leakage of air from a lesion within the respiratory tract, esophagus, mediastinum, or diaphragm. Tension PTX occurs if the site of air leakage creates a one-way valve during inspiration and results in a rapidly increasing pleural pressure that exceeds atmospheric pressure, often leading to cardiopulmonary arrest. In dogs, spontaneous PTX is most commonly associated with rupture of pulmonary bullae or blebs; in contrast, airway disease is the most common etiology in cats.2,47 Other causes of spontaneous PTX include neoplasia, lungworms or other parasite migration, pneumonia, migrating foreign bodies, pulmonary abscesses, pulmonary thromboembolism, and tornado-induced barometric changes.2,47,59,60 Traumatic PTX is a common sequela of blunt trauma and was found concurrently in 47% of dogs following vehicular trauma and 20% of cats with high-rise syndrome.61,62 Penetrating thoracic injuries, such as those from projectiles, bite wounds, and penetrating sharp objects, are also common causes. Iatrogenic PTX may occur secondary to thoracocentesis, thoracic surgery, thoracostomy tube placement, fine-needle lung aspiration, barotrauma from positive pressure ventilation, tracheal tears, and feeding tube placement.63 Finally, an infectious PTX can be created by gas-forming bacteria within the thoracic cavity. The decision to pursue thoracocentesis and/or thoracostomy tube placement is dependent on the underlying cause of the PTX and the patient’s clinical status. A tension PTX can rapidly become life

threatening secondary to both hypoxemia and cardiovascular collapse, and immediate thoracocentesis is indicated in animals suspected to have this condition. If the PTX is not easily relieved with thoracocentesis, an emergency mini-thoracotomy or rapid placement of a thoracostomy tube with intubation and mechanical ventilation may prove lifesaving. Conversely, animals with subclinical air accumulation may not require thoracocentesis and the animal’s progression should be followed closely as the air is reabsorbed over days to weeks. Patients with a closed traumatic or iatrogenic PTX may require thoracocentesis only once or twice. A small amount of air in animals with severe concurrent pulmonary pathology may contribute significantly to respiratory distress and should be relieved if dyspnea is present. Animals should be monitored closely after thoracocentesis for return of dyspnea, as further intervention may be required. Indications for a thoracostomy tube vary according to the clinical situation, but should be placed in patients with tension PTX, PTX that develops during positive pressure ventilation, those requiring more than two thoracocenteses within 24 hours, and when negative pressure cannot be achieved (see Chapter 199, Thoracostomy Tube Placement and Drainage). If negative pressure cannot be obtained after aspiration of a thoracostomy tube, continuous negative pressure should be applied via connection of the thoracostomy tube to a three-chambered continuous suction device such as a Pleur-evac or Thora-Seal. If a continuous suction device is not available, or the patient requires transport to another facility, a Heimlich valve can be used. An exploratory thoracostomy is indicated in dogs with spontaneous PTX, as decreased recurrence and higher survival rate is associated with surgery.64 If surgery is not pursued for financial reasons, autologous blood patch pleurodesis has been successful in resolving air leakage.65 In cats, medical management of spontaneous PTX is frequently successful.47 If an open PTX is caused by a penetrating injury, the site of penetration should be covered by a sterile occlusive bandage and thoracocentesis performed immediately, and surgical intervention should not be delayed. Prognosis for PTX varies with the underlying cause but is good overall.2,64

DIAPHRAGMATIC HERNIA Congenital diaphragmatic hernias (DHs) are a result of aberrant embryogenesis and may be pleuroperitoneal, peritoneopericardial, or hiatal; discussion of these hernias is beyond the scope of this chapter.66-69 Acquired DH may result from blunt or penetrating trauma. Clinical signs frequently occur immediately after the traumatic event but may be delayed.70,71 Dyspnea varies from absent to severe according to the organs herniated, presence of pleural effusion, and concomitant thoracic injuries. The organs most often herniated are the liver, stomach, small intestine, spleen, and omentum; the large intestine, gallbladder, and pancreas are less commonly herniated.70-72 Thoracocentesis and gastrocentesis may relieve the dyspnea before surgery if there is significant effusion or the stomach is herniated. Cardiovascular stabilization prior to surgery is essential. There are conflicting reports on the timing of surgical intervention, but more recent reports indicate that the time from admission to surgery and time from trauma to surgery do not influence mortality.71,73 That said, emergent surgical intervention may be required depending on patient presentation. Indications for immediate surgical intervention include herniated stomach, strangulated bowel or other organ, inability to oxygenate properly or achieve cardiovascular stability after medical intervention, and ruptured viscera. Intra- and postoperative complications include pneumothorax, hemorrhage, aspiration pneumonia, reexpansion pulmonary edema, sepsis, arrhythmias, multiple organ failure, and death.70,71,73,74 Prognosis for full recovery is overall excellent, with

CHAPTER 29  Pleural Space Disease survival reported between 81.3%–100%.73 Negative prognostic indicators include concurrent soft tissue and orthopedic injuries, need for supplemental oxygen, and increased duration of anesthesia and surgery.73

REEXPANSION PULMONARY EDEMA Reexpansion pulmonary edema (RPE) is an uncommon but lifethreatening complication that may occur in any patient that undergoes rapid reexpansion of a collapsed lung, and has been reported in veterinary species after thoracocentesis, pectus excavatum repair, and diaphragmatic hernia repair.2,74,75 The underlying mechanism is unclear, but experimental models suggest that expansion of a chronically collapsed lung can result in an influx of inflammatory cells and oxidative injury that disrupts the capillary endothelium and results in increased permeability and noncardiogenic edema.76 The rapid lung reexpansion may also increase local lung perfusion secondary to decreased pulmonary vascular resistance and reversal of hypoxic pulmonary vasoconstriction, which may increase capillary transmural pressure and damage the basement membrane of the alveolar-capillary lining.76 Increased incidence of RPE has been associated with a longer duration of collapsed lung (72 hours).74 In humans, pleural pressure monitoring is often utilized to guide safe evacuation of the pleural space.76 If RPE develops, treatment is supportive and positive pressure ventilation may be required.

ACKNOWLEDGMENT The author would like to acknowledge and thank Valerie Sauvé, DVM, DACVECC for her original contribution as the author of the first and second editions of this chapter.

REFERENCES 1. Hall JE: Pulmonary circulation, pulmonary edema, pleural fluid. In Hall J, editor: Guyton and Hall textbook of medical physiology, ed 13, Philadelphia, 2016, Elsevier, pp 509-516. 2. Pawloski DR, Broaddus KD: Pneumothorax: a review, J Am Anim Hosp Assoc 46:385-397, 2010. 3. Casha AR, Caruana-Gauci R, Manche A, et al: Pleural pressure theory revisited: a role for capillary equilibrium, J Thorac Dis 9:979-989, 2017. 4. West JB, Luks AM: Respiratory physiology: the essentials, ed 10, Philadelphia, 2016, Wolters Kluwer. 5. Karpathiou G, Peoc’h M: Pleura revisited: from histology and pathophysiology to pathology and molecular biology, Clin Respir J 13:3-13, 2019. 6. Le Boedec K, Arnaud C, Chetboul V, et al: Relationship between paradoxical breathing and pleural diseases in dyspneic dogs and cats: 389 cases (2001-2009), J Am Vet Med Assoc 240:1095-1099, 2012. 7. Stillion JR, Letendre JA: A clinical review of the pathophysiology, diagnosis, and treatment of pyothorax in dogs and cats, J Vet Emerg Crit Care (San Antonio) 25:113-129, 2015. 8. Armenise A, Boysen RS, Rudloff E, et al: Veterinary-focused assessment with sonography for trauma-airway, breathing, circulation, disability and exposure: a prospective observational study in 64 canine trauma patients, J Small Anim Pract 60:173-182, 2019. 9. Lisciandro GR: Abdominal and thoracic focused assessment with sonography for trauma, triage, and monitoring in small animals, J Vet Emerg Crit Care (San Antonio) 21:104-122, 2011. 10. Boysen S, McMurray J, Gommeren K: Abnormal curtain signs identified with a novel lung ultrasound protocol in six dogs with pneumothorax, Front Vet Sci 6:291, 2019. 11. Lynch KC, Oliveira CR, Matheson JS, et al: Detection of pneumothorax and pleural effusion with horizontal beam radiography, Vet Radiol Ultrasound 53:38-43, 2012.

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12. Dancer SC, Le Roux C, Fosgate GT, et al: Radiography is less sensitive relative to CT for detecting thoracic radiographic changes in dogs affected by blunt trauma secondary to a motor vehicle accident, Vet Radiol Ultrasound 60:648-658, 2019. 13. Walters AM, O’Brien MA, Selmic LE, et al: Evaluation of the agreement between focused assessment with sonography for trauma (AFAST/TFAST) and computed tomography in dogs and cats with recent trauma, J Vet Emerg Crit Care (San Antonio) 28:429-435, 2018. 14. Reetz JA, Suran JN, Zwingenberger AL, et al: Nodules and masses are associated with malignant pleural effusion in dogs and cats but many other intrathoracic CT features are poor predictors of the effusion type, Vet Radiol Ultrasound 60:289-299, 2019. 15. Briola C, Zoia A, Rocchi P, et al: Computed tomography attenuation value for the characterization of pleural effusions in dogs: a cross-sectional study in 58 dogs, Res Vet Sci 124:357-365, 2019. 16. Kovak JR, Ludwig LL, Bergman PJ, et al: Use of thoracoscopy to determine the etiology of pleural effusion in dogs and cats: 18 cases (1998-2001), J Am Vet Med Assoc 221:990-994, 2002. 17. Mayhew PD, Steffey MA, Fransson BA, et al: Long-term outcome of video-assisted thoracoscopic thoracic duct ligation and pericardectomy in dogs with chylothorax: a multi-institutional study of 39 cases, Vet Surg 48:O112-O120, 2019. 18. Scott J, Singh A, Monnet E, et al: Video-assisted thoracic surgery for the management of pyothorax in dogs: 14 cases, Vet Surg 46:722-730, 2017. 19. Feller-Kopman DJ, Reddy CB, DeCamp MM, et al: Management of malignant pleural effusions. An official ATS/STS/STR clinical practice guideline, Am J Respir Crit Care Med 198:839-849, 2018. 20. Dempsey SM, Ewing PJ: A review of the pathophysiology, classification, and analysis of canine and feline cavitary effusions, J Am Anim Hosp Assoc 47:1-11, 2011. 21. Craig A, Thompson AHR: Body cavity fluids. In Raskin RE, Meyer DJ, editors: Canine and feline cytology, St Louis, MO, 2016, Elsevier. 22. Meakin LB, Salonen LK, Baines SJ, et al: Prevalence, outcome and risk factors for postoperative pyothorax in 232 dogs undergoing thoracic surgery, J Small Anim Pract 54:313-317, 2013. 23. Shen KR, Bribriesco A, Crabtree T, et al: The American Association for Thoracic Surgery consensus guidelines for the management of empyema, J Thorac Cardiovasc Surg 153:e129-e146, 2017. 24. Hung GC, Gaunt MC, Rubin JE, et al: Quantification and characterization of pleural fluid in healthy dogs with thoracostomy tubes, Am J Vet Res 77:1387-1391, 2016. 25. Epstein SE: Exudative pleural diseases in small animals, Vet Clin North Am Small Anim Pract 44:161-180, 2014. 26. Hazuchova K, Held S, Neiger R: Usefulness of acute phase proteins in differentiating between feline infectious peritonitis and other diseases in cats with body cavity effusions, J Feline Med Surg 19:809-816, 2017. 27. Singh A, Brisson B, Nykamp S: Idiopathic chylothorax: pathophysiology, diagnosis, and thoracic duct imaging, Compend Contin Educ Vet 34:E2, 2012. 28. Singh A, Brisson B, Nykamp S: Idiopathic chylothorax in dogs and cats: nonsurgical and surgical management, Compend Contin Educ Vet 34:E3, 2012. 29. Stockdale SL, Gazzola KM, Strouse JB, et al: Comparison of thoracic duct ligation plus subphrenic pericardiectomy with or without cisterna chyli ablation for treatment of idiopathic chylothorax in cats, J Am Vet Med Assoc 252:976-981, 2018. 30. Brooks AC, Hardie RJ: Use of the PleuralPort device for management of pleural effusion in six dogs and four cats, Vet Surg 40:935-941, 2011. 31. Fossum TW, Evering WN, Miller MW, et al: Severe bilateral fibrosing pleuritis associated with chronic chylothorax in five cats and two dogs, J Am Vet Med Assoc 201:317-324, 1992. 32. Kopko SH: The use of rutin in a cat with idiopathic chylothorax, Can Vet J 46:729-731, 2005. 33. Thompson MS, Cohn LA, Jordan RC: Use of rutin for medical management of idiopathic chylothorax in four cats, J Am Vet Med Assoc 215: 345-348, 339, 1999. 34. Greenberg MJ, Weisse CW: Spontaneous resolution of iatrogenic chylothorax in a cat, J Am Vet Med Assoc 226:1667-1670, 1659, 2005.

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35. Nakamura RK, Rozanski EA, Rush JE: Non-coagulopathic spontaneous hemothorax in dogs, J Vet Emerg Crit Care (San Antonio) 18:292-297, 2008. 36. Zuckerman IC, Dulake MI, Nakamura RK: What is your diagnosis? Noncoagulopathic spontaneous hemothorax, J Am Vet Med Assoc 245:885-887, 2014. 37. Sierra E, Rodriguez F, Herraez P, et al: Post-traumatic fat embolism causing haemothorax in a cat, Vet Rec 161:170-172, 2007. 38. Cohn LA, Stoll MR, Branson KR, et al: Fatal hemothorax following management of an esophageal foreign body, J Am Anim Hosp Assoc 39:251-256, 2003. 39. Uri M, Verin R, Ressel L, et al: Ehlers-Danlos syndrome associated with fatal spontaneous vascular rupture in a dog, J Comp Pathol 152:211-216, 2015. 40. Stallwood J AS, Allerton F, Adamantos S, Black V: Spontaneous haemothorax in juvenile dogs: a case series, Companion Anim 24:14-18, 2019. 41. Higgs VA, Rudloff E, Kirby R, et al: Autologous blood transfusion in dogs with thoracic or abdominal hemorrhage: 25 cases (2007-2012), J Vet Emerg Crit Care (San Antonio) 25:731-738, 2015. 42. Ruiz MD, Vessieres F, Ragetly GR, et al: Characterization of and factors associated with causes of pleural effusion in cats, J Am Vet Med Assoc 253:181-187, 2018. 43. Felten S, Hartmann K: Diagnosis of feline infectious peritonitis: a review of the current literature, Viruses 11:1068, 2019. 44. Pedersen NC: An update on feline infectious peritonitis: virology and immunopathogenesis, Vet J 201:123-132, 2014. 45. Pedersen NC: An update on feline infectious peritonitis: diagnostics and therapeutics, Vet J 201:133-141, 2014. 46. Murphy BG, Perron M, Murakami E, et al: The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies, Vet Microbiol 219:226-233, 2018. 47. Mooney ET, Rozanski EA, King RG, et al: Spontaneous pneumothorax in 35 cats (2001-2010), J Feline Med Surg 14:384-391, 2012. 48. Murgia D: A case of combined bilothorax and bile peritonitis secondary to gunshot wounds in a cat, J Feline Med Surg 15:513-516, 2013. 49. Guillaumin J, Chanoit G, Decosne-Junot C, et al: Bilothorax following cholecystectomy in a dog, J Small Anim Pract 47:733-736, 2006. 50. Bartolini F, Didier M, Iudica B, et al: What is your diagnosis? Pleural effusion in a dog with a gunshot wound, Vet Clin Pathol 44:333-334, 2015. 51. Wustefeld-Janssens BG, Loureiro JF, Dukes-McEwan J, et al: Biliothorax in a Siamese cat, J Feline Med Surg 13:984-987, 2011. 52. VanDeventer GM, Cuq BY: Spontaneous cholecystopleural fistula leading to biliothorax and sepsis in a cat, JFMS Open Rep 5:2055116919830206, 2019. 53. Tsompanidou PP, Anagnostou TL, Kazakos GM, et al: Urothorax associated with uroperitoneum in a dog without diaphragmatic disruption, J Am Anim Hosp Assoc 51:256-259, 2015. 54. Stork CK, Hamaide AJ, Schwedes C, et al: Hemiurothorax following diaphragmatic hernia and kidney prolapse in a cat, J Feline Med Surg 5:91-96, 2003. 55. Klainbart S, Merchav R, Ohad DG: Traumatic urothorax in a dog: a case report, J Small Anim Pract 52:544-546, 2011. 56. Lafond E, Weirich WE, Salisbury SK: Omentalization of the thorax for treatment of idiopathic chylothorax with constrictive pleuritis in a cat, J Am Anim Hosp Assoc 38:74-78, 2002. 57. Rehbein S, Manchi G, Gruber AD, et al: Successful treatment of pneumothorax in a dog with sterile pleural fibrosis caused by chylothorax, Front Vet Sci 6:278, 2019.

58. Huggins JT, Sahn SA: Causes and management of pleural fibrosis, Respirology 9:441-447, 2004. 59. Cichocki BN, Dugat DR, Snider TA: Traumatic lung injury attributed to tornadic activity-induced barometric pressure changes in two dogs, J Am Vet Med Assoc 248:1274-1279, 2016. 60. Sobel KE, Williams JE: Pneumothorax secondary to pulmonary thromboembolism in a dog, J Vet Emerg Crit Care (San Antonio) 19:120-126, 2009. 61. Vnuk D, Pirkic B, Maticic D, et al: Feline high-rise syndrome: 119 cases (1998-2001), J Feline Med Surg 6:305-312, 2004. 62. Simpson SA, Syring R, Otto CM: Severe blunt trauma in dogs: 235 cases (1997-2003), J Vet Emerg Crit Care (San Antonio) 19:588-602, 2009. 63. Giordano P, Kirby BM, Bennett RC, et al: Tension pneumothorax secondary to nasojejunal feeding tube misplacement in a mechanically ventilated dog, Aust Vet J 92:400-404, 2014. 64. Puerto DA, Brockman DJ, Lindquist C, et al: Surgical and nonsurgical management of and selected risk factors for spontaneous pneumothorax in dogs: 64 cases (1986-1999), J Am Vet Med Assoc 220:1670-1674, 2002. 65. Oppenheimer N, Klainbart S, Merbl Y, et al: Retrospective evaluation of the use of autologous blood-patch treatment for persistent pneumothorax in 8 dogs (2009-2012), J Vet Emerg Crit Care (San Antonio) 24:215-220, 2014. 66. Rossanese M, Pivetta M, Pereira N, et al: Congenital pleuroperitoneal hernia presenting as gastrothorax in five cavalier King Charles spaniel dogs, J Small Anim Pract 60:701-704, 2019. 67. Burns CG, Bergh MS, McLoughlin MA: Surgical and nonsurgical treatment of peritoneopericardial diaphragmatic hernia in dogs and cats: 58 cases (1999-2008), J Am Vet Med Assoc 242:643-650, 2013. 68. Phillips H, Corrie J, Engel DM, et al: Clinical findings, diagnostic test results, and treatment outcome in cats with hiatal hernia: 31 cases (1995-2018), J Vet Intern Med 33:1970-1976, 2019. 69. Morgan KRS, Singh A, Giuffrida MA, et al: Outcome after surgical and conservative treatments of canine peritoneopericardial diaphragmatic hernia: a multi-institutional study of 128 dogs, Vet Surg 49(1):138-145, 2020. 70. Minihan AC, Berg J, Evans KL: Chronic diaphragmatic hernia in 34 dogs and 16 cats, J Am Anim Hosp Assoc 40:51-63, 2004. 71. Gibson TW, Brisson BA, Sears W: Perioperative survival rates after surgery for diaphragmatic hernia in dogs and cats: 92 cases (1990-2002), J Am Vet Med Assoc 227:105-109, 2005. 72. Schmiedt CW, Tobias KM, Stevenson MA: Traumatic diaphragmatic hernia in cats: 34 cases (1991-2001), J Am Vet Med Assoc 222:1237-1240, 2003. 73. Legallet C, Thieman Mankin K, Selmic LE: Prognostic indicators for perioperative survival after diaphragmatic herniorrhaphy in cats and dogs: 96 cases (2001-2013), BMC Vet Res 13:16, 2017. 74. Stampley AR, Waldron DR: Reexpansion pulmonary edema after surgery to repair a diaphragmatic hernia in a cat, J Am Vet Med Assoc 203:1699-1701, 1993. 75. Soderstrom MJ, Gilson SD, Gulbas N: Fatal reexpansion pulmonary edema in a kitten following surgical correction of pectus excavatum, J Am Anim Hosp Assoc 31:133-136, 1995. 76. Walter JM, Matthay MA, Gillespie CT, et al: Acute hypoxemic respiratory failure after large-volume thoracentesis. Mechanisms of pleural fluid formation and reexpansion pulmonary edema, Ann Am Thorac Soc 13:438-443, 2016.

30 Respiratory Distress Look-Alikes Sage M. De Rosa, DVM, DACVECC, Deborah C. Silverstein, DVM, DACVECC

KEY POINTS • Increased respiratory rate and effort can be due to disease of the respiratory system or abnormalities of nonrespiratory tissues or organ systems. Nonrespiratory causes are also known as look-alike causes of respiratory distress. • Look-alike causes of respiratory distress have no identifiable abnormalities of the respiratory system and normal oxygenating ability. Hyperventilation may occur with some look-alike causes. • Nonrespiratory look-alikes may be caused by decreased oxygen delivery to the tissues, metabolic disease, brain disease, acidemia, hyperthermia, pain, stress or fear, and drugs.

INTRODUCTION The primary function of the respiratory system is gas exchange, specifically the removal of carbon dioxide from, and the addition of oxygen to, the blood. The respiratory system is composed of the upper and lower airways (conducting and respiratory zones), the pulmonary parenchyma, the pulmonary blood vessels, and the muscles of respiration (diaphragm, intercostals). Disease of any one of these anatomic regions can result in ineffective gas exchange and resultant hypoxemia or hypercarbia. Thus, causes of respiratory distress may involve the upper airway (nasal cavity, pharynx, larynx, trachea), lower airway (bronchi), pulmonary parenchyma, pleural space, chest wall, pulmonary arteries (pulmonary thromboembolism), or diaphragmatic impingement (i.e., due to abdominal distension). In addition to these causes, respiratory distress may arise from nonrespiratory etiologies. These so-called look-alikes can be classified as metabolic or acid/base derangements, diseases of impaired oxygen delivery, environmental factors, behavioral triggers, and drugs; they are summarized in Table 30.1.

CONTROL OF RESPIRATION Regulation of breathing is a complex phenomenon that involves the integration of the autonomic nervous system, comprising the peripheral and central sensors, brainstem control centers, and effector muscles, with voluntary control by the cerebral cortex (see Chapter 14, Control of Breathing). An appreciation for these mechanisms is essential for the understanding of pathophysiology associated with respiratory distress. Respiration is tightly controlled by the brainstem (respiratory, pneumotaxic, and apneustic centers) so that the partial pressures of oxygen (PaO2) and carbon dioxide (PaCO2) dissolved in the blood can remain in the normal range despite variable physiologic states.1 Central chemoreceptors, located in the medulla, sense changes in pH due to changes in CO2 and stimulate the inspiratory center, a

• Nonrespiratory causes of apparent increased respiratory effort may be caused by impaired oxygen delivery, such as anemia and low cardiac output states. • Diseases resulting in brain dysfunction (elevated intracranial pressure, neoplasia, trauma, vascular events) can lead to abnormal breathing patterns.

component of the respiratory center in the medulla, to increase ventilation. Peripheral chemoreceptors located in the carotid and aortic bodies respond to changes in PaO2, PaCO2 and pH; decreased PaO2 and pH and increased PaCO2 will result in an increase in respiratory rate. Furthermore, several other receptor types can affect ventilation such as mechanoreceptors in the lungs, muscles, and joints, irritant receptors in the nose and airways, J receptors in the lungs, and baroreceptors in aortic and carotid sinuses.1,2 Cumulatively, these receptors are responsible for providing the brainstem centers with the information to appropriately regulate ventilation. Despite the body’s largely involuntary ventilatory mechanisms, breathing can also be controlled by voluntary means through the cerebral cortex and by emotions such as fear or anxiety through pathways in the limbic system and hypothalamus.2

EXTRAPULMONARY CAUSES OF DECREASED OXYGEN DELIVERY Oxygen delivery is essential for aerobic respiration and the generation of energy, in the form of ATP, for the maintenance of cellular survival.3,4 For oxygen to be effectively delivered to the tissues (DO2) it must exist in the arterial blood, reflected as the arterial content of oxygen (CaO2), and it must be transported to the site of utilization via the cardiac output (CO). These relationships are outlined in Box 30.1, where DO2 is the delivery of oxygen, CaO2 is the arterial oxygen content, CO is cardiac output, SaO2 is the saturation of hemoglobin with oxygen in the arterial blood, and PaO2 is the partial pressure of oxygen dissolved in the arterial blood. The multiplier of 1.34 represents the oxygen binding capacity of hemoglobin in ml of O2/gram Hb.4 Delivery of oxygen may thus be compromised due to diseases associated primarily with the respiratory system that alter the PaO2 and thus the SaO2, anemia (reduction of [Hb]), or diseases that decrease CO. As hypoxemia is discussed elsewhere (see Chapter 16, Hypoxemia), this chapter discusses the other components.

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TABLE 30.1  Summary of Nonrespiratory Causes of Respiratory Distress and Associated

Mechanisms Cause

Examples

Mechanism

Nonrespiratory Causes of Decreased Oxygen Delivery

Anemia

1. Decreased arterial oxygen content sensed by peripheral chemoreceptors n stimulates neurons in medulla n increase respiratory rate 2. Tissue hypoxia and hyperlactatemia n decreased pH n sensed by peripheral chemoreceptors n stimulates neurons in medulla n increase in ventilatory drive

Metabolic Derangements

Drugs

Low Cardiac Output

Severely decreased stroke volume or severe arrhythmias n decreased effective circulating volume n sensed by arterial baroreceptors n transmitted to brainstem n increase ventilation

Metabolic Acidosis

Gain of acid or loss of bicarbonate n decreased blood pH/increased [H1] n sensed by peripheral chemoreceptors n increase in ventilation

Hyperthyroidism

Elevated thyroid hormone may cause tachypnea and hyperventilation

Hypoglycemia

Sympathetic stimulation and/or brain dysfunction

Bicarbonate

Increase in HCO3- n metabolized into CO2 n sensed by central and peripheral chemoreceptors n stimulates neurons in medulla n increase in ventilation

Opioids

Alter thermoregulation by directly interacting with neurons in the hypothalamus, which may lead to panting

Hyperthermia

Elevated ambient temperature or endogenous heat production n sensed by peripheral and central thermoreceptors n transmitted to thermoregulatory center in hypothalamus n tachypnea and panting n evaporative cooling

Behavioral

Pain, stress (physiologic or psychologic), fear, etc. n activation of “higher” cerebral centers n increase in heart rate, blood pressure, and ventilation

Brain Disease

Trauma, neoplasia, elevated intracranial pressure, vascular accidents n dysfunction of respiratory neurons in medulla n abnormal breathing patterns

BOX 30.1  Oxygen Delivery and Oxygen

Content Formulas

DO2 5 CaO2 3 CO CaO2 5 1.34[Hb] 3 SaO2 1 0.003(PaO2) Where DO2 is delivery of oxygen, CaO2 is the arterial oxygen content, CO is cardiac output, SaO2 is the saturation of hemoglobin with oxygen in the arterial blood, and PaO2 is the partial pressure of oxygen dissolved in the arterial blood. [Hb] is hemoglobin concentration in g/dl.

Anemia Anemic animals have a decreased hemoglobin concentration, and since more than 98% of the arterial oxygen content is bound to hemoglobin, delivery of oxygen to the tissues is impaired in anemic states. Decreased arterial oxygen content (primarily a decrease in PaO2) is sensed by the peripheral chemoreceptors (glomus type I cells) in the aortic and carotid bodies; this causes an increase in firing of the glossopharyngeal nerve, which stimulates neurons in the medulla to increase the respiratory rate.5,6 An additional mechanism by which anemia may cause an increase in the ventilatory drive is through a change in pH associated with tissue hypoxia and hyperlactatemia, which is sensed primarily by the carotid body chemoreceptors. Absolute type I hyperlactatemia (see Chapter 61, Hyperlactatemia) may result from anemia due to decreased oxygen delivery;7 this lactic acidosis is associated with a decrease in pH, which is sensed primarily by the carotid body and results in an increase in ventilation.2 This mechanism is seen particularly with severe and/or acute anemia.7 Anemia may also be accompanied by hypovolemia, such as in patients with hemorrhage. In this instance, hypovolemia will also contribute to the increase in ventilation.

Low Cardiac Output CO is one of the main determinants of oxygen delivery, and if decreased significantly, tissue hypoxia will ensue. CO is the product of stroke volume and heart rate. Stroke volume is determined by preload, afterload, and cardiac contractility. Alterations in any of these variables

may decrease CO and if severe enough, lower mean arterial pressure.8 Decreased effective circulating volume is sensed by arterial baroreceptors and transmitted to the brainstem to increase ventilation.2 Low CO due to decreased stroke volume may be caused by inadequate preload (e.g., hypovolemia, obstructions to venous return, impaired diastolic filling with cardiac tamponade or tachyarrhythmias), increased afterload (e.g., systemic hypertension), or poor contractility (e.g., dilated cardiomyopathy). Bradyarrhythmias also may result in diminished CO due to a significantly decreased heart rate. These pathophysiologic states typically must be severe to decrease CO as the body possesses compensatory mechanisms to maintain CO and oxygen delivery in the face of mild to moderate disease.9

METABOLIC DERANGEMENTS Metabolic Acidosis Hyperventilation is an expected compensatory mechanism of metabolic acidosis, the most common acid-base disturbance in small animals. It occurs within minutes and may manifest as an increased respiratory rate or effort. In humans, Kussmaul respirations, a respiratory pattern characterized by deep and labored breathing, is seen with severe acidosis. Metabolic acidosis results in an increased blood [H1] (decreased blood pH), which is sensed directly by peripheral chemoreceptors and triggers an increase in ventilation. Metabolic acidosis may be due to loss of bicarbonate ion (HCO3-), gain of acid, or decreased renal excretion of acid. Differential diagnoses for metabolic acidosis include diabetic ketoacidosis, lactic acidosis, uremic acidosis, certain intoxications (e.g., salicylates, ethylene glycol), diarrhea, renal tubular acidosis, carbonic anhydrase inhibitors, administration of chloride rich drugs or fluids, and hypoadrenocorticism (See Chapter 59, Traditional Acid-Base Analysis).10

Hypoglycemia Hypoglycemia may result in clinical signs consistent with respiratory compromise such as tachypnea or abnormal breathing patterns.11 This

CHAPTER 30  Respiratory Distress Look-Alikes may occur due to sympathetic stimulation when hypoglycemia is mild to moderate or due to brain dysfunction when neuroglycopenia results from severe hypoglycemia.12 If this is present, immediate treatment with intravenous dextrose and ventilatory support are indicated.13 Differential diagnoses for hypoglycemia include hypoadrenocorticism, sepsis, insulin overdose, severe liver dysfunction, toxicosis (e.g., xylitol), certain forms of neoplasia, juvenile hypoglycemia, starvation, pregnancy, and hunting dog hypoglycemia (see Chapter 75, Hypoglycemia).14

Hyperthyroidism High thyroid hormone levels may induce tachypnea and hyperventilation. In one study, up to 25% of cats with hyperthyroidism were noted to have panting as a clinical sign.15 Proposed mechanisms include respiratory muscle weakness, increased ventilatory drive, increased airway resistance, diminished lung compliance, and rarely tracheal compression from thyroid enlargement.16

HYPERTHERMIA Hyperthermia is a frequent exam finding in small animal patients, particularly during summer months or with increased muscle activity and subsequent heat production (see Chapter 10, Hyperthermia and Fever). One of the most common clinical signs seen in combination with hyperthermia is tachypnea or panting. Hyperthermia may result from elevated ambient temperature or from increased endogenous heat production. Changes in ambient or body temperature are sensed by peripheral and central thermoreceptors; this information is transmitted to the hypothalamus, the main center for thermoregulation.17 As core temperature increases, heat is dissipated by radiation and convection from the skin. Redistribution of blood to the periphery and vasodilation occurs to allow for cooling. As the environmental temperature approaches body temperature, or with more severe hyperthermia, evaporative cooling is employed through panting.18

BEHAVIORAL Although regulation of breathing is typically viewed as the responsibility of the brainstem, higher centers may also contribute under certain circumstances. The cerebral cortex may override the brainstem in cases of voluntary hyperventilation or breath holding; this is likely more relevant in humans than in animals. Animals that are hospitalized in the ICU are often stressed either due to their physical condition (e.g., postoperative pain, immobility) or due to anxiety/fear. Stress, which may be physiologic or psychologic, is a highly complex response that is mediated by overlapping pathways in the limbic system, hypothalamus, and brainstem. The dorsomedial/perifornical hypothalamus is one of the most important anatomic areas during stress and receives input from other hypothalamic structures as well as the amygdala; it is the main effector of the cardiorespiratory stress response and communicates with the brainstem directly. The amygdala, a part of the limbic system, is responsible for integrating conditioned or anticipatory fear with respiration by sending projections to the brainstem. The periaqueductal gray, an area surrounding the midbrain aqueduct, perceives pain and initiates autonomic responses such as increased heart rate, blood pressure, and ventilation.19

BRAIN DISEASE Brain disease, such as in the case of trauma, neoplasia, seizures, cerebral, subdural or subarachnoid hemorrhage, elevated intracranial pressure or vascular accidents, may result in altered function of the respiratory neurons in the medulla leading to abnormal breathing

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patterns (see Chapter 14, Control of Breathing).20 The mechanism by which these respiratory patterns occur has not been fully elucidated; however, interruptions of afferent or efferent neuronal pathways or processing, decreased cerebral blood flow, and/or impaired chemoresponsiveness have been suggested.21 Many different breathing patterns are possible in animals with brain disease; however, Cheyne–Stokes breathing and apneustic breathing patterns are typically associated with central nervous system disease. Cheyne–Stokes breathing is characterized by varying tidal volumes and frequencies; after an apneic period, tidal volume and frequency increase over a period of breaths and then decreases until apnea occurs again. In patients with apneustic ventilation, long periods of inspiration are separated by brief periods of exhalation.22 The abnormal breathing patterns seen with brain disease may or may not result in derangements of PaCO2 and PaO2.

DRUGS Sodium bicarbonate is occasionally administered to patients in cases of severe metabolic acidosis. As the compound bicarbonate is metabolized, CO2 is produced. This increase in CO2 is sensed by central and peripheral chemoreceptors, which triggers an increase in ventilation. Thus, in an animal with normal ventilatory abilities, the administration of sodium bicarbonate will likely cause an elevation in respiratory rate in an effort to exhale excess CO2.10 Additionally, opioid medications tend to alter thermoregulation by directly interacting with neurons in the preoptic anterior hypothalamus. It is common for dogs to pant shortly after administration.23 This effect is more commonly seen with pure mu agonists (methadone, hydromorphone, oxymorphone, morphine). Kappa and delta agonists are more likely to produce hypothermia than hyperthermia.24

SUMMARY The patient in respiratory distress may suffer from disorders of the upper or lower airways, pulmonary parenchyma, pleural space, chest well, pulmonary vessels, diaphragm, or one of the look-alike causes described above. After ruling out causes of primary respiratory system disease, one should consider decreased oxygen delivery (e.g., anemia or low CO), metabolic causes (e.g., metabolic acidosis, electrolyte derangements, hypoglycemia, hyperthyroidism), brain disease, hyperthermia, behavioral causes (e.g., pain, stress, fear), and drugs as potential causes of increased respiratory rate or effort.

REFERENCES 1. Costanzo LS, editor: Respiratory physiology. In Physiology, ed 6, Philadelphia, 2018, Elsevier, pp 189-243. 2. West JB, Luks A, editors: Control of ventilation. In West’s respiratory physiology: the essentials, Philadelphia, PA, 2016, Wolters Kluwer, pp 125-140. 3. Vincent JL, De Backer D: Oxygen transport—the oxygen delivery controversy, Intensive Care Med 30:1990-1996, 2004. 4. Castro R, Hernández G, Bakker J: Oxygen transport and tissue utilization. In Pinto Lima AA, Silva E, editors: Monitoring tissue perfusion in shock: from physiology to the bedside, Cham, 2018, Springer International Publishing, pp 15-23. 5. Pittman RN, editor: Chemical regulation of respiration. In Regulation of tissue oxygenation, San Rafael, CA, 2011, Morgan & Claypool Life Sciences. 6. Richerson GB, Boron WF: Control of ventilation. In Boron WF, Boulpaep EL, editors: Medical physiology, ed 3, Philadelphia, 2017, Elsevier, pp 700-720. 7. Rosenstein PG, Tennent Brown BS, Hughes D: Clinical use of plasma lactate concentration. Part 1: Physiology, pathophysiology, and measurement, J Vet Emerg Crit Care 28:85-105, 2018.

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8. Boulpaep EL: Regulation of arterial pressure and cardiac output. In Boron WF, Boulpaep EL, editors: Medical physiology, ed 3, Philadelphia, PA, 2017, Elsevier, pp 533-555. 9. Kovács SJ: Regulation of cardiac output. In Brown DL, editor: Cardiac intensive care, ed 3, Philadelphia, PA, 2019, Elsevier, pp 52-59. 10. DiBartola SP: Metabolic acid-base disorders. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders in small animal practice, ed 4, St Louis, 2012, W.B. Saunders, pp 253-286. 11. Barrett EJ: The endocrine pancreas. In Boron WF, Boulpaep EL, editors: Medical physiology, ed 3, Philadelphia, 2017, Elsevier, p 1035. 12. Kallem VR, Pandita A, Gupta G: Hypoglycemia: when to treat? Clin Med Insights Pediatr 11:1179556517748913, 2017. 13. Sreedharan R, Abdelmalak B: Hypoglycemia. In Fink MP, Vincent JL, Abraham E, Moore FA, Kochanek PM, editors: Textbook of critical care, ed 7, Philadelphia, 2017, Elsevier, pp 64-68. 14. Panciera DL: Chapter 20 - fluid therapy in endocrine and metabolic disorders. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders in small animal practice, ed 4, St Louis, 2012, W.B. Saunders, pp 500-513. 15. Broussard JD, Peterson ME, Fox PR: Changes in clinical and laboratory findings in cats with hyperthyroidism from 1983 to 1993, J Am Vet Med Assoc 206:302-305, 1995.

16. Mooney C: Hyperthyroidism. In Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal medicine, ed 7, St Louis, 2009, Elsevier, pp 1795-1812. 17. Hemmelgarn C, Gannon KM: Heatstroke: thermoregulation, pathophysiology, and predisposing factors, Compendium 35:E4, 2013. 18. Bruchim Y, Horowitz M, Aroch I: Pathophysiology of heatstroke in dogs revisited, Temp Austin Tex 4:356-370, 2017. 19. Kinkead R, Tenorio L, Drolet G, et al: Respiratory manifestations of panic disorder in animals and humans: a unique opportunity to understand how supramedullary structures regulate breathing, Respir Physiol Neurobiol 204:3-13, 2014. 20. Lumb AB: Ventilatory failure. In Lumb AB, Thomas CB, editors: Nunn’s applied respiratory physiology, ed 8, Philadelphia, 2017, pp 379-387. 21. Balofsky A, George J, Papadakos P: Neuropulmonology. In Wijdicks EFM, Kramer AH, editors: Handbook of clinical neurology, ed 3, Rochester, NY, 2017, Elsevier, pp 33-48. 22. Cloutier MM, editor: Control of respiration. In Respiratory physiology, ed 2, Philadelphia, 2019, pp 130-144. 23. KuKanich B, Weise A: Opioids. In Grimm KA, Lamont LA, Tranquilli WJ, Greene SA, Robertson SA, editors: Veterinary anesthesia and analgesia, ed 5, Hoboken, 2015, John Wiley & Sons. 24. Rawls SM, Benamar K: Effects of opioids, cannabinoids, and vanilloids on body temperature, Front Biosci Sch Ed 3:822-845, 2011.

PART III   Advanced Respiratory Support

31 High Flow Nasal Oxygen Iain Keir, BVMS, DACVECC, DECVECC

KEY POINTS • High flow nasal oxygen delivers oxygen flow rates of up to 60 liters/ minute with temperature and humidity control. • Higher oxygen flow rates provided by high flow nasal oxygen can match the patient’s minute volume demands. • Improved alveolar oxygen concentration is achieved through increased dead space washout and reduced atmospheric air

INTRODUCTION

dilution while producing a positive end expiratory pressure-like effect. • Adequate heating and humidification of inspired gases improves patient tolerance of high flow rates and prevents airway damage.

High flow nasal oxygen, or high flow nasal cannulae (HFNC), has been growing in popularity in recent years as a method of escalating oxygen therapy when standard nasal cannulae or oxygen cage therapy is deemed insufficient. It is important to recognize that HFNC is not simply standard nasal cannulae with high flow rates; these devices take medical grade oxygen/air and heat it to between 32oC and 42oC with a 100% relative humidity and deliver a fraction of inspired oxygen (FiO2) of 0.21–1.00 at flow rates up to 60 ml/min. The temperature, FiO2, and flow rate are set and adjusted by the clinician.

minimize complications such as airway mucosal desiccation, mucosal erosions, hemorrhage, and propensity for opportunistic infections due to impaired local immunity. In addition, when compared with dry oxygen, heated oxygen can decrease airway inflammation, maintain mucociliary function, and improve mucus clearance.1,2,3 This ability to alter the temperature of the inspired gases can improve patient tolerance of high flow rates; however, using a flow temperature that is slightly below body temperature may improve comfort. In a recent publication, an inspired gas temperature of 31°C was associated with improved patient comfort compared with a temperature of 37°C at flow rates of 30 L/min and 60 L/min.4

PHYSIOLOGICAL BENEFITS OF HIGH FLOW NASAL OXYGEN (SEE BOX 31.1)

Inspiratory Flow Demands

Heated and Humidified Gas Delivery In contrast to standard nasal oxygen that delivers cold and minimally humidified oxygen, HFNC devices actively heat and humidify the gases delivered to the patient. By heating and humidifying the inspired gases, high flow rates are better tolerated by patients and at the same time

BOX 31.1  Physiological Benefits of High Flow Nasal Oxygen Heated and humidified oxygen Inspiratory flow demands Functional reserve capacity

Lighter Oxygen dilution Washout dead space

The major direct benefit of HFNC is being able to meet the patient’s inspiratory flow demands, which is an important consideration when selecting initial flow rates. The typical recommendations for oxygen flow rates for standard nasal cannula are between 50 and 150 ml/kg/ min. However, for a 20-kg patient with acute hypoxemia that is tachypneic (respiratory rate 60 breaths/min) and has a minute volume of 18 L/min, the delivery of 150 ml/kg/min (3 L/min) may not be improving alveolar oxygen as predicted; in essence the patient will have “flow starvation.” We discuss this more when explaining oxygen dilution.

Functional Residual Capacity There is debate about how much positive end expiratory pressure (PEEP) is applied when using HFNC. In adult people it has been shown to deliver 1 mm Hg of PEEP for every 10 L/min; in healthy dogs there is evidence that HFNC can deliver some degree of PEEP.5 Daly et al. reported changes in transpulmonary pressure using the Vapotherm

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device at flow rates of 20 L/min and 30 L/min in healthy dogs.6 Jagodich et al. also found a PEEP effect of the Optiflow system set at flow rates .1 L/kg/min when used in healthy dogs.7 The application of PEEP with HFNC will increase functional residual capacity, which improves lung compliance and helps to correct some ventilation/perfusion abnormalities. There are several factors to consider when attributing the PEEP effect to the flow rate. It is likely over simplistic to apply the rule of 1 mm Hg PEEP for every 10 L/min of flow rate in veterinary patients as there are many factors that influence the amount of PEEP. These include patient size, flow rate delivered as a portion of the patient’s lung volume and minute volume, open or closed mouth breathing (pressure may escape when the mouth is open therefore reducing PEEP), and nasal cannula diameter to nares circumference ratio. In addition PEEP may have deleterious effects on the cardiovascular system, especially when used in hemodynamically unstable patients. In a sequential interval study in 10 human patients, Roca et al. demonstrated that the use of HFNC caused collapse of the inferior vena cava during inspiration compared with baseline, thus implying the potential to reduce cardiac preload.8

Lighter The nasal cannula used for HFNC is designed to fit a human face; as a result, they do not have an ideal conformation for cats and dogs. Techniques for securing the nasal cannula to veterinary patients usually include a combination of suturing techniques (finger trap) and nontoxic adhesive (Fig. 31.1). Despite these modifications they are lighter and offer improved patient comfort compared with a tight-fitting continuous positive air pressure (CPAP) mask or CPAP hood, which often require deep sedation to enable patient tolerance. The improved patient compliance will likely result in better oxygenation and reduced work in breathing.

Fig. 31.1  ​A dog with HFNO in place using white tape on the cannula tubing to lay comfortably over the bridge of the nose.

Oxygen Dilution Recommended flow rates for standard nasal cannula range from 50 to 150 ml/kg/min. In healthy dogs, Dunphy et al. demonstrated that higher flow rates resulted in a dose-dependent increase in FiO2, with a FiO2 of up to 0.8 being achieved with bilateral nasal cannula.8 This study was performed in healthy dogs with a respiratory rate of 8–12 breaths/minute. In hypoxemic patients, the respiratory rate will often exceed this value, which can have profound effects on the patient’s minute volume. This is important to understand, as the alveolar oxygen concentration will be determined by the ratio of oxygen gas flow to minute volume (assuming minimal dead space ventilation).

Mathematical Modeling of Flow Rates The Dunphy study examined dogs of uniform weight (21 kg) with a comparable respiratory rate of 9 breaths/min that were given the same dose of oxygen. If we assume these dogs had a tidal volume of 15 ml/kg given they were healthy dogs with healthy lungs, we can estimate their minute volume to be 2.84 L/min. Bilateral nasal cannula have an oxygen flow rate of 100 ml/kg/min 5 2.1 L/min. Therefore, of the 2.84 L of gas this dog inhales per minute, 2.1 L has an FiO2 of 1.0 while 0.74 L has an FiO2 of 0.21; therefore the total volume of oxygen inhaled is 2.1 L 1 (0.21 3 0.74) 5 2.26 L. With these figures, the theoretical maximum FiO2 that 100 ml/kg/min with produce in a patient breathing 9 breaths/min will be the total delivered oxygen volume divided by the patient’s minute volume, i.e., FiO2 5 (2.26/2.84 L) 3 100 5 80%. If the same dog’s respiratory rate is increased to 60 breaths/min and the tidal volume is reduced to 10 ml/kg (more representative of a dog with hypoxemia from ventilation-perfusion mismatch), this dog’s estimated minute volume is increased to 12.6 L/min [(0.01 3 21) 3 60]. If this patient is then given the same amount of oxygen supplementation (bilateral nasal cannula at 100 ml/kg/min), 2.1 L of the patient’s minute volume will be in the form of 100% oxygen while 10.5 L (total minute volume – oxygen flow rate) with be atmospheric air. Therefore, the volume of oxygen inhaled is now [2.1 L 1 (0.21 3 10.5)] 5 2.1 L 1 2.2 L54.3 L and the theoretical maximum FiO2 5 (4.3/12.6) 3 100 5 34%. If a higher nasal oxygen flow was delivered under these circumstances (respiratory rate 60, tidal volume 10 ml/kg, oxygen flow rate 200 ml/kg/min), the dog’s minute volume would remain unchanged at 12.6 L/min. The nasal cannula would provide 4.2 L/min of 100% oxygen while 8.4 L/min will be atmospheric air with 21% oxygen. The total volume of oxygen inhaled is 4.2 1 (0.21 3 8.4) 5 6.0 L. As a result, the theoretical maximum FiO2 would be (7.3/12.6) 3 100 5 58%. It is therefore apparent that providing nasal oxygen at previously recommend doses is likely to result in inadequate oxygenation, and clinicians should be cautious in assuming that nasal cannula can provide a FiO2 up to 0.8 in this set of patients. To deliver an oxygen flow rate that will effectively improve the FiO2, the oxygen flow rate should match, if not exceed, the patient’s minute ventilation to minimize oxygen dilution by atmospheric air akin to flow starvation. In the previous example (21-kg dog with a respiratory rate of 60 breaths/min), providing 100% oxygen at a flow rate of 12.6 L/min will equal the patient’s minute ventilation and theoretically achieve an alveolar oxygen concentration of close to 100%. Selecting a flow rate of 50% of the patient’s minute volume will provide an alveolar oxygen concentration of 60%, provided the oxygen flow is set at 100%. Another advantage of HFNC units is the ability to blend to oxygen with medical air. This enables the clinician to alter the inspired oxygen concentration while still meeting the inspiratory flow demands of the patient. This benefits the patient by providing some amount of PEEP

CHAPTER 31  High Flow Nasal Oxygen associated with increase gas flow rates, therefore maintaining alveolar recruitment while at the same time reducing the oxygen concentration to lowest setting to avoid oxygen toxicity (see Chapter 8, Oxygen Toxicity).

Washout Dead Space During a normal breath cycle about one-third of the previously expired tidal volume is re-breathed. This occurs because one-third of the exhaled breath remains in the upper airways; when the next inspiration occurs, this low oxygen concentration gas mixes with fresh atmospheric gas as it travels to the alveoli. This results in one-third of the newly inspired gas mixture having an oxygen concentration of 15%–16% and a CO2 of 4%–5% (compared with atmospheric air, which has an oxygen concentration of 21% and negligible CO2). Patients with acute respiratory failure have an increase in dead space ventilation as rebreathing of air in the upper airway occurs. HFNC provides a continuous flow of fresh gas at appropriately high flow rates, which results in washout of air in the patient’s nasopharyngeal and conducting airways. Thus, anatomical dead space replaces the oxygen-poor exhaled gas mixture with an oxygen-rich gas mixture. This results in each new breath containing only the oxygenrich gas mixture provided by the HFNC, which greatly improves breathing efficiency and reduces the work of breathing.

HIGH FLOW NASAL OXYGEN IN SMALL ANIMAL CRITICAL CARE The first reported use of HFNC in small animals was using the Vapotherm unit in a series of six hypoxemic dogs that were not stabilized with standard nasal oxygen therapy delivered via a bubble humidifier.9 The use of HFNC significantly improved partial pressure of oxygen (PaO2) in these hypoxemic dogs with primary lung disease that were clinically failing standard oxygen therapy. All six dogs achieved a PaO2 .100 mm Hg on HFNC with clinical resolution of the patients underlying disease occurring in 4/6 of these patients. The flow rates achieved in this group of patients ranged from 500 ml/kg/min to over 1500 ml/ kg/min. Other important information gleaned from this case series was that all patients tolerated the nasal prongs and only 1/6 required some form of sedation, and one patient had a preexisting pneumothorax, which only resolved after cessation of HFNC, suggesting some potential PEEP effect as a contributor to the ongoing air leakage. Subsequent to this, Daly et al. evaluated the effects of the same high flow oxygen device in a group of healthy, sedated dogs. Daly’s study showed that HFNC produced a PaO2 of .500 mm Hg with oxygen flow rates of 20 L/min and 30 L/min, indicating an alveolar FiO2 of 100%. Transpulmonary pressure was also measured as a surrogate marker of PEEP in these patients using an esophageal balloon catheter. The results suggested that HFNC at flow rates .20 L/min will produce some amount of positive intrathoracic pressure, although variability between individual patients exists. Jagodich et al. recently evaluated the Optiflo system in a population of healthy dogs (sedated and awake). An FiO2 of 95% was achieved at flow rates .1 L/kg/min compared to a FiO2 of 72% when low flow nasal cannulae were used with a flow rate of 400 ml/kg/min. A PEEP effect was also observed at flow rates .1 L/kg/min.

PRACTICAL GUIDANCE FOR USING HIGH FLOW NASAL OXYGEN Initial Settings The initial settings chosen for high flow nasal oxygen should be aimed at delivering the maximum amount of oxygen possible (see Box 31.2).

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BOX 31.2  Recommended Initial High Flow Nasal Oxygen Settings Flow rate 5 patient’s minute volume 5 respiratory rate 3 tidal volume (10–15 ml/kg) FiO2 5 100% Temperature 5 32 oC–37oC

This is achieved by selecting a flow rate equal to the patient’s minute volume and setting the FiO2 at 100%; the initial temperature setting should be no higher than body temperature. Typically, the patient’s respiratory rate is reduced, and oxygenation improved after 30–60 minutes of HFNC therapy. This decline in respiratory rate will reduce the patient’s minute volume; therefore it is important to recalculate the patient’s flow rate at this time.

Targeting High Flow Nasal Oxygen Therapy With the ability to exceed a patient’s minute volume, the potential for inducing hyperoxia exists with HFNC therapy. Once the treatment is started, oxygen saturation (SpO2) should be measured frequently to monitor for appropriate oxygenation. Because of the sigmoid shape of the oxygen-hemoglobin dissociation curve, an SpO2 .95% does not differentiate a normal PaO2 (80–110 mm Hg) from a supra-normal PaO2 (.110 mm Hg; see Chapter 184, Oximetry Monitoring). Therefore, oxygen toxicity can occur if targeting a SpO2 of 95%–100%. When using high flow oxygen therapy, a more conservative SpO2 target of 92%–95% is recommended to minimize the risk of hyperoxia while still preventing hypoxia. Because of the inherent difficulties in obtaining accurate pulse oximeter reading in some small animal patients, an arterial blood gas should be used as an alternative to assess oxygenation when the pulse oximeter reading is unreliable, targeting a PaO2 of 80–110 mm Hg. Altering the volume of oxygen delivered to the patients can be done by one of two ways: 1) altering the oxygen flow rate as a percentage of the patient’s minute volume while maintaining a constant set FiO2; or 2) reducing the set FiO2 while maintaining a constant gas flow rate. There is no clear advantage of one method over the other; reducing the FiO2 while the oxygen gas flow rate is unchanged will allow the PEEPlike effect of the higher flow rate to be maintained, while reducing the flow rate and maintaining a set FiO2 may aid in patient comfort and tolerance.

REFERENCES 1. Campbell EJ, Baker MD, Crites-Silver P: Subjective effects of humidification of oxygen for delivery by nasal cannula. A prospective study, Chest 93(2):289-293, 1988. 2. Dellweg D, Wenze M, Hoehn E, Bourgund O, Haidl P: Humidification of inspired oxygen is increased with pre-nasal, compared to intranasal cannula, Respir Care 58(8):1323-1328, 2013. 3. Franchini ML, Athanazio R, Amato-Lourenço LF: Oxygen with cold bubble humidification is no better than dry oxygen in preventing mucus dehydration, decreased mucociliary clearance, and decline in pulmonary function, Chest 150(2):407-414, 2016. 4. Mauri T, Galazzi A, Binda F, et al: Impact of flow and temperature on patient comfort during respiratory support by high-flow nasal cannula, Crit Care 22(1):120, 2018. 5. Groves N, Tobin A: High flow nasal oxygen generates positive airway pressure in adult volunteers, Aust Crit Care 20(4):126-131, 2007. 6. Daly JL, Guenther CL, Haggerty JM, Keir I: Evaluation of oxygen administration with a high-flow nasal cannula to clinically normal dogs, Am J Vet Res 78(5):624-630, 2017.

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7. Jagodich TA, Bersenas AME, Bateman SW, Kerr CL: Comparison of high flow nasal cannula oxygen administration to traditional nasal cannula oxygen therapy in healthy dogs, J Vet Emerg Crit Care 29(3):246-255, 2019. 8. Roca O, Pérez-Terán P, Masclans JR, et al: Patients with New York Heart Association class III heart failure may benefit with high flow nasal cannula supportive therapy: high flow nasal cannula in heart failure, J Crit Care 28(5):741-746, 2013.

9. Dunphy ED, Dodam JR, Branson KR, et al: Comparison of unilateral versus bilateral nasal catheters for oxygen administration in dogs, J Vet Emerg Crit Care 12:245-251, 2002. 10. Keir I, Daly J, Haggerty J, Guenther C: Retrospective evaluation of the effect of high flow oxygen therapy delivered by nasal cannula on PaO2 in dogs with moderate-to-severe hypoxemia, J Vet Emerg Crit Care 26(4): 598-602, 2016.

32 Mechanical Ventilation—Core Concepts Kate Hopper, BVSc, PhD, DACVECC

KEY POINTS • The main indications for mechanical ventilation are severe hypoxemia despite oxygen supplementation, severe hypoventilation despite appropriate therapy, and excessive respiratory effort. • The goal of mechanical ventilation is to maintain acceptable arterial blood gas parameters with the least aggressive ventilator settings.

• Animals with lung disease generally require more aggressive ventilator settings and may have a poorer prognosis than animals with neuromuscular disease. • The “ideal” ventilator settings for a given patient can be determined only by trial and error.

Mechanical ventilation can utilize negative or positive pressure to move gas in and out of the lungs. In clinical medicine, positive pressure ventilation (PPV) is the most common modality. This chapter provides an overview of the key concepts of PPV; the interested reader is encouraged to also read the other chapters in this text on ventilation to gain a full understanding of the clinical application of this intervention.

endotracheal tube is the source of greatest resistance present during mechanical ventilation.

PHYSIOLOGY The respiratory function of the lungs is to oxygenate the arterial blood and remove carbon dioxide from the venous blood. Oxygenation refers to the movement of oxygen from the alveoli into the pulmonary capillaries and is primarily dependent on the surface area available for gas exchange and preservation of the delicate structure of the gas exchange barrier.1,2 Ventilation refers to fresh gas movement into the alveoli and is the primary determinant of carbon dioxide elimination. When managing patients on mechanical ventilation, it is useful to think of oxygenation and ventilation as two separate processes.

Intrathoracic Pressure During spontaneous breathing, the intrathoracic or pleural pressure falls (becomes more subatmospheric) during inspiration as a result of the expansion of the chest wall and movement of the diaphragm.1 This pressure change results in the inspiratory flow of air into the lungs. In contrast, PPV utilizes positive airway pressures to generate inspiratory gas flow. The total pressure needed to generate a ventilator breath is best described by equation of motion (Box 32.1). This equation demonstrates how the inspiratory flow rate and tidal volume (VT) of a breath interacts with the compliance and resistance of the system, which includes the artificial airway, lungs, and thoracic wall.3,4

Resistance Resistance reflects the pressure required to generate a given flow and can be determined from Ohm’s law as resistance 5 driving pressure/ flow.1 Any narrowing of the airways will increase resistance including airway collapse or narrowing or diffuse bronchoconstriction. Often the

Compliance Compliance is a measure of the distensibility of the lung and is defined as the change in lung volume for a given change in pressure. It can be calculated as Dvolume/Dpressure.1,2 In ventilated patients, this translates to delivered VT/pressure required to generate the VT. The term elastance is also used in respiratory physiology and is the inverse of compliance. A lung with high compliance will accept a large increase in volume for a small pressure change, whereas low compliance would be characterized as requiring a large pressure change to create a small increase in volume. The normal, healthy lung is very compliant and, as a result, requires relatively low airway pressures during mechanical ventilation. In contrast, most pulmonary disease processes common to veterinary medicine will reduce pulmonary compliance and require higher airway pressures to adequately oxygenate and ventilate the patient.3

Dead Space Dead space is the portion of the tidal volume that does not participate in gas exchange.1,2 It can be categorized as apparatus, anatomic and alveolar in origin. In the ventilator breathing circuit, fresh gas flow is present to the level of the Y-piece. The volume of the circuit from the Y-piece to the nose of the patient comprises apparatus dead space (Fig. 32.1). The volume of the conducting airways from the nose to the level of the alveoli is the anatomic dead space, and alveoli that are ventilated but not perfused represent alveolar dead space.1

THE VENTILATOR BREATH A ventilator breath is considered to be one of two major types: mandatory or spontaneous. For a spontaneous breath the patient is responsible for both initiation and termination of inspiration. If the machine controls one or both of these factors the breath is considered mandatory. When a mandatory breath is initiated by the patient, it is classified as an assisted breath. A spontaneous breath in which inspiration is

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BOX 32.1  The Equation of Motion Pvent 1 Pmuscles 5 Elastance 3 Volume 1 Resistance 3 Flow Pvent, pressure generated by the ventilator; Pmuscles, pressure generated by inspiratory muscles Note: Elastance is the inverse of compliance.

augmented above baseline by the machine is considered a supported breath (Table 32.1).3,4

Breath Patterns Ventilator mode classification is based on three possible breath patterns. 1. Continuous mandatory ventilation (CMV): All mandatory breaths are delivered 2. Intermittent mandatory ventilation (IMV): Both mandatory and spontaneous breaths 3. Continuous spontaneous ventilation (CSV): All spontaneous breaths Most modern ventilators will allow the patient to trigger a mandatory breath allowing ventilation to be synchronized with the patient’s efforts. If all breaths delivered are mandatory this breath pattern is considered assist/control (A/C).

Phase Variables A ventilator breath can be divided into phases that help define how the ventilator determines the magnitude and nature of the breath. Fig. 32.2 depicts the phases of a ventilator breath.

Control Variable The compliance and resistance of the system are inherent to the patient and not under ventilator control. That leaves pressure, volume, and flow as the three interdependent variables that can be manipulated by the machine (as defined by the equation of motion). In any one breath the ventilator can only directly control one of these variables at a time, and the other two variables become dependent variables. Hence, a ventilator breath can be considered pressure-controlled, volumecontrolled, or flow-controlled.3 The magnitude of the remaining two dependent variables will be determined by the set value of the control

variable and the compliance and the resistance of the system. For example, in a pressure-controlled breath the machine will maintain airway pressure as determined by the operator, and inspiration ends when a preset inspiratory time is reached. The tidal volume and gas flow rate generated during the breath are dependent on the magnitude of the preset airway pressure as well as the resistance and compliance inherent to that animal. Volume-controlled and flow-controlled breaths are essentially the same; the machine will deliver the preset tidal volume over the preset inspiratory time. Airway pressure reached during these breaths is dependent on the magnitude of the preset tidal volume and subsequent flow rate, as well as the resistance and compliance of the patient’s respiratory system.

Cycle Variable This is the parameter that determines the termination of inspiratory flow. For example, time is the cycle variable for a pressure-controlled breath.5 Time is the most common cycle variable and will be determined by the preset respiratory rate and inspiration to exhalation (I:E) ratio. An inspiratory time of approximately 1 second is a common guideline, although animals with higher respiratory rates may need a shorter inspiratory time.

Trigger Variable This is the parameter that initiates inspiration; it is how the ventilator determines when to deliver a breath.5 In animals that are not making respiratory efforts on their own, time is the most common trigger variable and is determined from the set respiratory rate. If the ventilator is synchronizing the breaths with the respiratory efforts of the patient, the trigger variable may be a change in airway pressure or gas flow in the circuit indicating an inspiratory effort. Appropriate trigger sensitivity is essential to ensure ventilator breaths are synchronized with genuine respiratory efforts made by the patient. This increases patient comfort and allows the patient to increase its respiratory rate as desired. The trigger variable can be too sensitive such that nonrespiratory efforts such as patient handling may initiate breaths, and this should be avoided.

Limit Variable This is the parameter that the breath cannot exceed during inspiration, but it does not terminate the breath (in contrast with a cycle variable).5

Apparatus dead space

Endotracheal tube

ETCO2 adapter

s Fre

ow

s fl

a hg

Y-piece Breathing circuit

Fig. 32.1  ​Apparatus dead space is the volume of gas in the breathing circuit that is not fresh, carbon dioxidefree gas. In the ventilator breathing circuit, apparatus dead space includes the volume of the circuit from the Y-piece (source of fresh gas flow) to the nose of the patient, as shown in this figure. (Credit: Chrisoula Toupadakis Skouritakis, PhD.)

CHAPTER 32  Mechanical Ventilation—Core Concepts

TABLE 32.1  Ventilator Breath Types Breath Type

Initiation (Trigger)

Inspiratory Flow

Termination (Cycle)

Mandatory Assisted Spontaneous Supported

Ventilator Patient Patient Patient

Ventilator Ventilator Patient Ventilator

Ventilator Ventilator Patient Patient

This is a variable that may be found on modern ICU ventilators. For example, settings such as a volume-controlled, pressure-limited breath means that the ventilator will generate the breath by delivering a preset tidal volume, but it will not exceed the limit set for airway pressure during this delivery.

Baseline Variable This is the variable that is controlled during exhalation (also known as the expiratory control variable) and is usually a change in airway pressure.5 If airway pressure during exhalation is maintained above atmospheric pressure, it is considered positive end expiratory pressure (PEEP).

Continuous Mandatory Ventilation In this mode of ventilation, a minimum respiratory rate is set by the operator. If the trigger sensitivity is set appropriately, the patient can increase the respiratory rate, but all breaths delivered will be of a mandatory breath type. If the patient is unable to trigger breaths, it is considered controlled ventilation. More commonly, patients are allowed to trigger their own respiratory rate, which is termed A/C ventilation.

Intermittent Mandatory Ventilation In this mode a set number of mandatory breaths are delivered. Between these breaths the patient can breathe spontaneously. In modern ventilators the machine tries to synchronize the mandatory breaths with the patient’s inspiratory efforts; this is known as synchronized

intermittent mandatory ventilation (SIMV). The ventilator has a window of time in which it will deliver a mandatory breath. If the patient triggers a breath during this period, it will be assisted appropriately. If no breath is triggered by the end of this time period, a mandatory breath will be given. Between these mandatory breaths, the patient can breathe spontaneously as often or as few times as desired (Fig. 32.3). The operator can only control the minimum respiratory rate and minute ventilation; there is no control over the maximum rate or maximum minute ventilation since this is determined by the patient.3,5

Continuous Spontaneous Ventilation Every breath of CSV is triggered and cycled by the patient. The respiratory rate, inspiratory time and VT are also determined by the patient. The two most common forms of this mode are continuous positive airway pressure (CPAP) and pressure support ventilation (PSV). CPAP provides a constant level of positive pressure through out the respiratory cycle. It increases functional residual capacity and compliance, enhancing gas exchange and oxygenation.3,4 In PSV, the inspiratory flow is augmented to a preset level of inspiratory pressure. This reduces the effort required to maintain spontaneous breathing in patients with adequate respiratory drive and inadequate ventilatory strength. It can help overcome the resistance of breathing through the endotracheal tube and ventilator breathing circuit. PSV can be used alone, or to augment the spontaneous breaths during SIMV or CPAP. The cycle variable is a set reduction in inspiratory flow rate, a patientdependent variable.3,4

I:E Ratio and Respiratory Rate A normal respiratory rate (RR) of 15–20 breaths is usually selected when the patient is initially established on the machine. This can then be changed as appropriate for the patient. The ratio of the duration of inspiration to the duration of expiration (I:E ratio) may be preset by the operator or may be a default setting within the machine. Commonly, an I:E ratio of 1:2 is utilized to ensure the patient has fully exhaled prior to the onset of the next breath.3 As RRs are increased the expiratory time will be sacrificed to “squeeze” in the necessary number of breaths. When inspiratory time exceeds the expiratory time, it is known as reverse or

Inspiratory flow phase

Pause phase

Expiratory Expiratory flow pause phase phase

Peak pressure Pause (plateau) pressure

Pressure

Initiation phase

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Time Fig. 32.2  ​Pressure-time scalar showing the phases of the respiratory cycle.  (Credit: Chrisoula Toupadakis Skouritakis, PhD.)

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PART III  Advanced Respiratory Support Breath cycle

Spontaneous period

Breath cycle

Assistcontrolled breath

Controlled breath

Pressure

90%

Patient triggered

Spontaneous breaths

Time Fig. 32.3  ​This is a stylized pressure-time scalar from a patient receiving synchronized intermittent mandatory ventilation (SIMV). In this mode, a set number of mandatory breaths are delivered; between these breaths the patient can breathe spontaneously. The ventilator will attempt to synchronize the mandatory breaths with the patient efforts. For example, if the mandatory rate on SIMV was set at 10 breaths per minute, the total cycle time would be 6 seconds, and the breath cycle time (period during which a mandatory breath is guaranteed to be delivered) will be a subset of this (e.g., 3 seconds). Patients can breathe spontaneously as much or as little as they choose during the spontaneous period. If a patient’s inspiratory effort is sensed during the breath cycle time, it will trigger a full mandatory breath (assist-controlled breath). If no spontaneous effort is detected before 90% of the breath cycle time is elapsed, a controlled breath will be delivered.  (Credit: Chrisoula Toupadakis Skouritakis, PhD.)

inverse I:E ratio ventilation. This can occur as a result of the patient’s respiratory pattern, such as fast RRs. An inverse I:E ratio can result in breath stacking or intrinsic PEEP as the animal is not able to fully exhale before the start of the next inspiration. Inverse I:E ratios have also been used as a ventilation strategy to improve oxygenation.5

Positive End Expiratory Pressure PEEP is available on many ventilators. If not provided by the machine, PEEP can be added by attaching a tube to the exhalation port of the ventilator. This can then be attached to a PEEP valve, or the end of the tube can be submerged in the desired depth of water (depth in cm 5 cm H2O pressure). PEEP, as the name suggests, maintains positive pressure in the airway during exhalation that prevents the lung from emptying completely. As a result the lung is “held” at a higher volume and pressure during exhalation.1,4 PEEP can increase the oxygenating efficiency of diseased lungs by recruiting previously collapsed alveoli, preventing further alveolar collapse, and reducing ventilator-induced lung injury. The appropriate magnitude of PEEP depends on the severity of the lung disease, the clinical response of the patient, and the presence of comorbidities in the patient (e.g., hypotension and intracranial hypertension). The selection of optimal PEEP has been the focus of numerous investigations in human medicine and remains to be defined. Readers are directed to Chapter 33, Mechanical Ventilation – Advanced Concepts, for further discussion on this topic. Low levels of PEEP are commonly provided in animals with normal lung function to help prevent atelectasis. PEEP can also have detrimental effects; inspiratory pressure as delivered by the ventilator will be given at a level over and above that of the set PEEP. For example, if PEEP is set at 5 cm H2O and the ventilator is delivering 20 cm H2O during inspiration, peak airway pressure during inspiration will be 25 cm H2O. The magnitude of PEEP must be factored in when choosing the ventilator settings for a patient. PEEP maintains elevated intrathoracic pressures during exhalation and as a result may compromise venous return. Cardiovascular monitoring is recommended for all ventilator patients and is essential when high levels of PEEP and/or more aggressive ventilator settings are utilized.

VENTILATOR SETTINGS Every ventilator model has a different range of settings. The more modern and advanced the machine, the more options it will provide for the operator to manipulate the ventilator breath. It is important to note that there is no standardization of ventilator terminology; the name of specific ventilator settings may vary between manufacturers. Despite the apparent complexity of modern ventilators, a few important ventilator settings, available on almost all machines, allow the clinician to determine an effective ventilation protocol for each patient. These include RR, VT, inspiratory pressure, inspiratory time, I:E ratio, trigger sensitivity, and PEEP. The parameters that the operator can preset will depend on the type of ventilation being used. With volume-controlled ventilation the tidal volume (or minute ventilation) is preset by the operator and peak inspiratory pressure is a dependent variable. If pressure-controlled ventilation is used, the airway pressure generated during inspiration is preset and VT is a dependent variable. In some cases, the parameters can be set directly, but in others they are indirectly determined by other settings. For example, the I:E ratio can be preset directly on some ventilators, but with many machines it is the consequence of the inspiratory time and RR that is chosen by the operator.1,3 Some ventilators have a parameter called “rise time.” This is the time in which the airway pressure increases from baseline to peak pressure.3 Faster rise times are indicated in patients with rapid RRs, although caution is advised in animals with small endotracheal tubes due to increased resistance to flow. The optimal ventilator settings cannot be predicted for a given patient; the operator selects the initial settings based on the patient size, understanding of the underlying disease process and application of general guidelines. Table 32.2 provides some suggested initial ventilator settings. Following connection of the patient to the ventilator, the operator must assess the patient, review the patient data, and titrate the settings appropriately. The appropriate airway pressure and VT for a given patient will depend on the patient size and the nature of the underlying disease. The normal tidal volume for a healthy dog and cat is approximately

CHAPTER 32  Mechanical Ventilation—Core Concepts

TABLE 32.2  Suggested Initial Ventilator

Settings

Ventilator Setting Fraction of inspired oxygen Tidal volume (ml/kg) Respiratory rate (breaths/min) Pressure above PEEP (cm H2O) PEEP (cm H2O) Inspiratory flow rate (L/min) Inspiratory time (seconds) Rise time (seconds) Inspiratory-to-expiratory ratio Inspiratory trigger

Healthy Lungs

Lung Disease

100% 10 to 12 10 to 20 8 to 10 0 to 5 40 to 60 0.8 to 1 0.1 to 0.3 1:2 1 to 2 cm H2O or 1 to 2 L/min

100% 6 to 8 15 to 30 10 to 15 5 to 8 40 to 60 0.8 to 1 0.1 to 0.3 1:1–1:2 1 to 2 cm H2O or 1 to 2 L/min

PEEP, positive end expiratory pressure. Note: The optimal ventilator settings for a patient cannot be predicted and these are general guidelines only. Ventilator settings need to be titrated as appropriate, immediately after initiation of ventilation.

10–15 ml/kg. Patients with significant pulmonary disease may benefit from a lower tidal volume. For example, a tidal volume of 4–6 ml/kg predicted body weight is recommended for human patients with acute respiratory distress syndrome.6 This may not be appropriate for other species or other disease processes, but avoiding lung overdistension by minimizing tidal volume is generally considered to be beneficial. Peak airway pressure ideally is kept below 20 cm H2O, often closer to 10 cm H2O in patients with normal lungs. Animals with pulmonary disease have reduced pulmonary compliance and therefore require higher pressures in order to deliver an adequate tidal volume. As a result, airway pressures up to 30 cm H2O may be necessary in animals with severe diffuse lung disease. When using volume-controlled ventilation on an ICU ventilator, the flow rate may need to be set in addition to the tidal volume. The flow rate will determine the inspiratory time and initial flow rates are set in the range of 40 to 60 L/min.5 It can then be titrated as necessary.

VENTILATOR ALARMS Ventilator alarms provide an essential safety check for the patient and should be set with patient specific values every time you set up the ventilator and adjusted if significant changes in ventilator settings are made. Set appropriately, it is likely that ventilator alarms will sound frequently, and it is tempting to set them at extreme values to reduce the annoyance. But if set appropriately, ventilator alarms can be life saving in many situations, alerting the patient care teams to disconnections, apnea, circuit leaks, and changes in patient status, such as light anesthetic plane or reductions in pulmonary compliance. Table 32.3 provides suggested guidelines for ventilator alarm settings.

INDICATIONS FOR MECHANICAL VENTILATION There are three main indications for mechanical ventilation: (1) severe hypoxemia despite oxygen supplementation, (2) severe hypoventilation despite therapy, and (3) excessive respiratory effort with impending respiratory fatigue or failure.3,4 A fourth indication for PPV is severe hemodynamic compromise that is refractory to therapy.1,3 Mechanical ventilation can decrease oxygen consumption as well as support left heart function and may allow ongoing support of the

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TABLE 32.3  Suggested Alarm Settings

and Common Alarm Triggers5 Alarm Setting Low pressure alarm High pressure alarm

Low PEEP/CPAP Low tidal volume

Suggested Setting 5–10 cm H2O below PIP 10 cm H2O above PIP

2 cm H2O below PEEP 10%–15% below desired VT

Apnea alarm

Apnea of 20 seconds

Low minute ventilation

10%–15% below desired

Common Causes for Alarm Patient disconnect Leak Patient–ventilator dyssynchrony ET tube kink or obstruction Small size ET tube with high inspiratory flow rate VC mode: pneumothorax Leak Leak PC mode: patient–ventilator dyssynchrony, decreased compliance, pneumothorax, ET tube obstruction VC mode: patient–ventilator dyssynchrony, ET tube obstruction In spontaneous breathing modes, will need appropriate settings for mandatory rescue breaths Causes of low tidal volume Spontaneous breathing modes: low respiratory rate

CPAP, continuous positive airway pressure; ET, endotracheal; PC, pressurecontrol; PEEP, positive end expiratory pressure; PIP, peak inspiratory pressure; VC, volume-control.

patient while definitive measures to improve the hemodynamic state are made. Anesthesia is often feasible in these patients with opioid and benzodiazepine drugs alone. Severe hypoxemia is indicated by cyanosis, a partial pressure of oxygen (PaO2) of less than 60 mm Hg or an oxygen saturation (SpO2) of less than 90% (see Chapter 16, Hypoxemia for further details). It is important to note that venous values for PaO2 cannot be used to diagnose hypoxemia. When patients have severe hypoxemia despite oxygen therapy and specific treatment of the primary disease, mechanical ventilation is generally indicated. Most of these animals have primary lung disease.1 Inspired oxygen concentrations of greater than 60% for a prolonged period (24 to 48 hours) can lead to oxygen toxicity and subsequent pulmonary damage.1,4 Therefore, animals that require high concentrations of inspired oxygen for longer than 24 hours in order to achieve adequate oxygenation may also benefit from mechanical ventilation. Hypoventilation is defined as an elevation in the partial pressure of carbon dioxide (PCO2; see Chapter 17, Hypoventilation for further details). In patients that are hemodynamically stable, venous PCO2 is an accurate reflection of arterial PCO2 and can be used to evaluate hypoventilation. Severe hypoventilation is defined as a PaCO2 greater than 60 mm Hg and may be an indication for mechanical ventilation if the patient is unresponsive to therapy for the primary disease. Hypercapnia is a consequence of reduced effective alveolar ventilation.1 This may be due to increased dead space in a breathing circuit, upper airway obstruction, sedative overdose, or neurologic and/or neuromuscular diseases that impair RR or chest wall movement. Most patients with increased apparatus dead space, upper airway obstruction, or sedative overdose will respond to appropriate therapy and will not require mechanical ventilation. Patients requiring ventilation in this category have neurologic, muscular, or neuromuscular disease

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processes such as brain disease, spinal cord disease, peripheral neuropathies, neuromuscular junction abnormalities, or primary myopathies. For simplicity, this group of disease processes will be referred to as neuromuscular diseases. Animals with brain disease may not tolerate small elevations in PCO2, and mechanical ventilation may be beneficial in these patients if the PaCO2 is greater than 45 mm Hg.1 Another group of patients that may require PPV to prevent hypoventilation are those animals that require general anesthesia for reasons such as maintenance of an endotracheal tube or provision of effective analgesia. In such cases the anesthetic drugs invariably cause hypoventilation and PPV while the animal is anesthetized is ideal. Many postcardiopulmonary arrest patients will require PPV for a period of time following return of spontaneous circulation. For short durations, manual ventilation may be sufficient, but animals with apnea, inadequate or unreliable ventilatory efforts, hypercapnia, concerns for intracranial hypertension or persistent hemodynamic instability will benefit from mechanical ventilation as described in Chapter 5, Post Cardiac Arrest Care. Animals with pulmonary disease may be able to maintain adequate oxygenation and ventilation by increasing their respiratory effort. If respiratory effort is marked, patients can become exhausted and respiratory arrest may occur despite acceptable blood gas values. Intervention before the arrest and initiation of mechanical ventilation may successfully stabilize these patients. There is no definitive measure of respiratory effort and impending fatigue, and recognition of these patients requires clinical judgment.

INITIATION OF MECHANICAL VENTILATION Before initiating mechanical ventilation, appropriate machine setup and monitoring are required. If the patient is in a life-threatening state, it may be necessary to anesthetize, intubate, and provide manual PPV while ventilator setup is performed. The initial ventilator settings are based on guidelines such as those given in Table 32.2. The operator should anticipate that animals with primary lung disease will require more PEEP and higher inspired oxygen concentrations than patients with neuromuscular disease. Chapter 33, Mechanical Ventilation – Advanced Concepts, further describes detailed ventilator protocols for animals with severe lung disease. The machine should be turned on and tested with an artificial lung or rebreathing bag to ensure it is functioning properly. It is advisable to always start mechanical ventilation with 100% oxygen until appropriate ventilator function and patient stability can be confirmed. Following initial stabilization, the fraction of inspired oxygen (FiO2) can be tailored appropriately. A separate source of 100% oxygen with a means to provide manual ventilation should be available at all times in case of machine failure. Immediately after the patient is connected to the ventilator, the chest should be observed for appropriate movements. The ventilator settings should be adjusted if the chest wall movements appear excessive or inadequate. Auscultation should be performed to confirm the presence of breath sounds bilaterally. If breath sounds are not audible bilaterally, endobronchial intubation may have occurred, and the endotracheal tube should be retracted. Constant, intensive monitoring is essential for patients that are ventilated because they are completely dependent on their caregivers for survival. Patients will require general anesthesia in order to start mechanical ventilation unless they have severe neurologic deficits. Anesthesia is required to enable intubation, keep the patient immobile and allow positive pressure inflation of the lungs. A plan for anesthesia induction and maintenance should be made with consideration of the underlying disease process and patient comorbidities. See Chapter 36,

Anesthesia and Monitoring of the Ventilator Patient, for more information. Animals that are immobile and unable to fight the ventilator, such as patients with respiratory paralysis, may benefit from placement of a temporary tracheostomy tube. This will allow the reduction (or even removal) of anesthetic agents, allow for accurate neurologic evaluation and simplify patient management. Patients with normal neurologic function cannot be ventilated without general anesthesia, even with a temporary tracheostomy tube. Brachycephalic animals may benefit from the placement of a temporary tracheostomy tube for the weaning process (see Chapter 38, Discontinuing Mechanical Ventilation).7 Monitoring tools such as electrocardiography, pulse oximetry, endtidal CO2, and arterial blood pressure should then be evaluated, and significant abnormalities addressed immediately. Once the patient is considered stable, arterial blood gas evaluation is ideal to verify the accuracy of the continuous monitors as well as guide adjustment of ventilator settings. In the absence of arterial blood gases, ventilator management is based on physical examination findings, venous PCO2 levels, and pulse oximetry.

GOALS The goal of mechanical ventilation is to maintain adequate arterial blood gas levels (PaCO2 35 to 50 mm Hg, PaO2 80 to 120 mm Hg) with the least aggressive ventilator settings possible. It is always simpler to make one change at a time in the ventilator settings so that the effect of each change can be interpreted accurately. Careful recording of ventilator settings with the concurrent arterial blood gas value, endtidal carbon dioxide level, and pulse oximetry reading is essential in evaluating and modifying the ventilator protocol. The process of evaluation and titration of ventilator settings is a continuous one that is performed until the animal is liberated from the machine. The adjustment of ventilator settings based on the status of the patient, understanding of the primary disease process, and indices of oxygenation and ventilation represents the “art” of PPV and is beyond the scope of this chapter. The general concepts are provided below.

Carbon Dioxide Arterial PCO2 is directly proportional to CO2 production and is inversely proportional to alveolar minute ventilation. In most disease states, CO2 production is relatively stable, and minute-to-minute changes of PaCO2 are the result of changes in alveolar minute ventilation. Total minute ventilation is equal to the product of the RR and the VT, but a portion of this inspired gas volume does not participate in gas exchange (dead space) and as such does not contribute to the elimination of CO2. Alveolar minute ventilation is determined by RR 3 (VT – dead space volume); increases in dead space result in decreases in effective alveolar ventilation and hypercapnia.1,2 In small patients, excess tubing length between the breathing circuit Y-piece and the animal’s mouth can cause significant increases in dead space. This may be a consequence of excessive endotracheal tube length, extension pieces, or monitoring devices connected to the end of the endotracheal tube. Endotracheal tube obstruction due to kinks or the accumulation of airway secretions may also reduce the volume of effective alveolar ventilation. In the absence of these equipment issues, hypercapnia is considered to be the result of inadequate alveolar minute ventilation, and increases in RR and/or VT are made. The PCO2 concentration should be reevaluated to determine if the new ventilator protocol is adequate. Alternatively, if the PCO2 is low, minute ventilation should be decreased. If end-tidal CO2 correlates reliably with PCO2, it can be an excellent real time monitor.

CHAPTER 32  Mechanical Ventilation—Core Concepts

Oxygen Following initial stabilization on the ventilator, the first priority in titrating ventilator settings is to reduce the FiO2 to #60% as soon as possible to reduce the risk of oxygen toxicity. The magnitude of reduction in the FiO2 will be dictated by the measured PaO2. After any reduction in oxygen concentration, the PaO2 should be reevaluated. If the SpO2 correlates well with the PaO2 (or arterial blood samples are unavailable), pulse oximetry can be used as a surrogate for PaO2 to help guide changes in ventilator settings. Once the FiO2 can be reduced to #60%, reductions in the magnitude of the ventilator settings, namely PEEP and the peak inspired airway pressure, can be considered if the PaO2 is significantly higher than the targeted range. In severe cases, hypoxemia will persist despite ventilation with 100% oxygen. In these animals, changes in the ventilator settings are required. Increases in PEEP, peak inspired pressure or VT, and/or RR may help improve the oxygenating efficiency of the lung. The following chapter on advanced mechanical ventilation will discuss ventilator protocols in more detail. Prone positioning will maximize lung function in many patients, and animals with hypoxemia should be maintained in sternal recumbency until stabilized.

COMPLICATIONS Mechanical ventilation is not benign; cardiovascular compromise, ventilator-induced lung injury, ventilator-associated pneumonia, and pneumothorax are all potential complications for ventilator patients.3,4,8 Cardiovascular compromise due to impairment of intrathoracic blood flow is often an issue for patients with cardiovascular instability or when aggressive ventilator settings are necessary. Cardiovascular monitoring is recommended for all ventilator patients and is essential when high PEEP levels or more aggressive ventilator settings are used. Volutrauma and repetitive alveolar opening and collapse are believed to be the major causes of ventilator-induced lung injury and may be reduced with protective ventilation strategies (see Chapter 33, Mechanical Ventilation-Advanced Concepts). Aseptic airway procedures, intensive oral care, and reducing the incidence of gastric regurgitation are all important in preventing ventilator-associated pneumonia (see Chapter 40, Ventilator-Associated Pneumonia). Patients should be monitored continuously for evidence of a nosocomial infection and changes in pulmonary function. Routine sampling of airway fluid for cytology and culture and susceptibility testing may help to detect early ventilatorassociated pneumonia. Pneumothorax is a feared complication of PPV, but the contribution of ventilator settings in causing pneumothoraces is controversial. Pneumothorax has been shown to occur more frequently when very high airway pressures are used in human patients (plateau airway pressure .35 cm H2O).9 When more conventional ventilator settings are used, there is no correlation between airway pressure, PEEP, or other settings and the occurrence of pneumothorax.10,11 The development of a pneumothorax is more likely the result of underlying lung disease rather than the ventilator settings used. Minimizing the magnitude of ventilator settings should always be the goal of ventilator management. Pneumothorax should be a primary differential when a patient has an acute decline in oxygenating ability, elevation in PCO2, decreased chest wall movement and compliance, and patient–ventilator dyssynchrony. If not diagnosed and treated rapidly, a tension pneumothorax can prove rapidly fatal in animals receiving PPV. Unilateral or bilateral thoracostomy tubes with continuous drainage are indicated when managing these ventilated animals (see Chapter 199, Thoracostomy Tube Placement and Drainage). If an acute, life-threatening pneumothorax develops in the ventilator patient, an emergency thoracotomy

191

to create an open pneumothorax may be required to prevent cardiopulmonary arrest. Following stabilization of cardiovascular parameters, thoracostomy tube(s) are then placed as mentioned above, and the thoracotomy site is closed in a routine fashion.

TROUBLESHOOTING Patient–ventilator dyssynchrony, often called bucking the ventilator, occurs when the patient is breathing against the machine. This is a common issue; it can prevent effective ventilation and may lead to hypoxemia, hypercapnia, and hyperthermia. In addition, it increases the work of breathing and can increase patient morbidity. It is recommended to have a systematic approach to evaluation of patient–ventilator dyssynchrony. Table 32.4 provides a list of potential patient issues, many of which can be a cause of patient–ventilator dyssynchrony. If a sudden decrease in oxygenation occurs, the oxygen supply to the machine should be checked as well as confirmation that the breathing circuit is intact and the ventilator is delivering breaths as prescribed. If the patient has become hypoxemic, the FiO2 should be increased immediately to 100% and the animal placed in sternal recumbency until the condition is improved. See Table 32.4 for an outline of causes for a decrease in oxygenating ability. Sudden elevations in PCO2 can occur as a consequence of equipment faults, patient problems (e.g., pneumothorax, airway obstruction) or inappropriate ventilator settings (see Table 32.4). If no mechanical abnormalities are evident and patient disease such as pneumothorax is ruled out, the ventilator settings should then be changed to increase minute ventilation. Hypercapnia may be an acceptable consequence of some protective ventilation strategies (also known as permissive hypercapnia).

PROGNOSIS Prognosis for successful weaning from mechanical ventilation is largely dependent on the primary disease process present. Human and veterinary clinical studies have reported lower weaning rates for patients requiring ventilation for pulmonary parenchymal disease (inability to oxygenate) compared with patients with primary hypoventilation due to intracranial or neuromuscular disease processes.8,12 One veterinary study reported that approximately 30% of dogs ventilated for pulmonary parenchymal disease were successfully weaned, and about 20% left the hospital compared with a weaning rate of 50% or more for dogs with intracranial or neuromuscular disease processes with 40% surviving to hospital discharge. In contrast, a retrospective study of 58 dogs requiring mechanical ventilation reported no difference in outcome between animals with pulmonary disease versus the group with inadequate ventilation.13 It is clear that the primary disease process has a major influence on prognosis. For example, in one veterinary study, 50% of dogs with aspiration pneumonia were weaned from ventilation compared with 8% of dogs with acute respiratory distress syndrome.8 In a study of dogs and cats ventilated for tick paralysis in Australia, 64% of animals survived and a study of 16 dogs ventilated for congestive heart failure reported a 63% survival rate.14,15 Puppies (dogs #12 months of age) receiving mechanical ventilation were found to have a similar outcome as that previously reported for adult dogs.16 When compared with other breeds receiving mechanical ventilation, brachycephalic dogs do not appear to have a poorer prognosis for weaning or survival to hospital discharge.7 Overall, cats tend to have a poorer prognosis than dogs for weaning, although like dogs, it varies with the underlying disease process (see Chapter 38, Discontinuing Mechanical Ventilation).8,17

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TABLE 32.4  Troubleshooting the Ventilator Patient Problem

Causes

Potential Responses

Hypoxemia

• Loss of oxygen supply • Machine or circuit malfunction • Deterioration of the underlying pulmonary disease • Development of new pulmonary disease • Pneumothorax • Pneumonia • VILI • ARDS • Pneumothorax • Bronchoconstriction • Endotracheal tube or airway obstruction • Circuit leak • Increased apparatus dead space • Increased alveolar dead space • Alveolar overdistension • Pulmonary embolism • Inadequate ventilator settings • Low VT and/or RR Impaired natural cooling mechanisms

Increase FiO2 Sternal positioning Thoracic auscultation Verify machine function Evaluate for leaks Increases in PEEP Increases in PIP/tidal volume

Hypercapnia

Hyperthermia Inappropriate ventilator settings Full urinary bladder or colon Inadequate anesthetic depth

Patient efforts/requirements are not being met with ventilation strategy Can stimulate increased respiratory efforts, agitation Inadequate drug dosing

Evaluate patient data Thoracic auscultation Assess endotracheal tube Verify machine function Ensure adequate expiratory time Increase VT and/or RR Note: hypercapnia maybe an acceptable consequence of some ventilation strategies

Rule out fever Active cooling Titrate settings to meet patient demands Palpate abdomen or use point of care ultrasound Assess parameters of anesthetic depth

ARDS, acute respiratory distress syndrome; PEEP, positive end expiratory pressure; PIP, peak inspiratory pressure; RR, respiratory rate; VILI, ventilatorinduced lung injury; VT, tidal volume.

REFERENCES 1. Lumb AB, Thomas C. Diffusion of respiratory gases In: Lumb AB, Thomas C, editors. Nunn and Lumb’s applied respiratory physiology, ed 9, St Louis, 2021, Elsevier, pp 111-121. 2. West JB, Luks AM. Diffusion. In: West JB, Luks AM, editors. West’s respiratory physiology: the essentials, ed 10. Philadelphia, 2016 Wolters Kluwer; pp 87-107. 3. Hess DR, Kacmarek RM: Essentials of mechanical ventilation, ed 4, New York, 2019, McGraw-Hill. 4. MacIntyre NR, Branson RD: Mechanical ventilation, ed 2, Philadelphia, 2009, Saunders. 5. Cairo JM: Pilbeam’s mechanical ventilation: physiological and clinical applications, ed 7, St Louis, 2020, Elsevier. 6. Brower R, Matthay M, Morris A, et al: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome, N Engl J Med 342:1301-1308, 2000. 7. Hoareau GL, Mellema MS, Silverstein DC: Indication, management and outcome of brachycephalic dogs requiring mechanical ventilation, J Vet Emer Crit Care 21:226-235, 2011 8. Hopper K, Haskins SC, Kass PH, et al: Indications, management and outcome of long-term positive-pressure ventilation in dogs and cats (1990-2001), J Am Vet Med Assoc 230:64, 2007. 9. Boussarsar M, Thierry G, Jaber S, et al: Relationship between ventilator settings and barotrauma in the acute respiratory distress syndrome, Intensive Care Med 28:406, 2002.

10. Weg MD, Anzueto A, Balk RA, et al: The relation of pneumothorax and other air leaks to mortality in the acute respiratory distress syndrome, New Engl J Med 338:341, 1998. 11. Anzueto A, Frutos-Vivar F, Esteban A, et al: Incidence, risk factors and outcome of barotrauma in mechanically ventilated patients, Intensive Care Med 30:612, 2004. 12. Webster RA, Mills PC, Morton JM: Indications, durations and outcomes of mechanical ventilation in dogs and cats with tick paralysis caused by Ixodes holocyclus: 61 cases (2008-2011), Aust Vet J 91:233, 2013. 13. Bruchim Y, Aroch I, Sisso A, Kushnir A: A retrospective study of positive pressure ventilation in 58 dogs: indications, prognostic factors and outcome, J Sm Anim Pract 55:314-319, 2014. 14. Webster RA, Mills PC, Morton JM: Indications, durations and outcomes of mechanical ventilation in dogs and cats with tick paralysis causes by Ixodes holocyclus: 61 cases (2008-2011), Aust Vet J, 91(6):233-239, 2013. 15. Edwards TH, Coleman AE, Brainard BM, et al: Outcome of positive- pressure ventilation in dogs and cats with congestive heart failure: 16 cases (1992-2012), J Vet Emerg Crit Care 24(5):586-593, 2014. 16. Lemieux E, Buckley GJ, Chalifoux NC, et al: Indication and outcome of puppies undergoing mechanical ventilation (56 cases: 2006-2019), Abstract IVECCS, Sept 12-14, 2020, Nashville, TN. 17. Lee JA, Drobatz KJ, Koch MW, King LG: Indications for and outcome of positive-pressure ventilation in cats: 53 cases (1993-2002), J Am Vet Med Assoc 226:924, 2005.

33 Mechanical Ventilation—Advanced Concepts Kimberly Slensky, DVM, DACVECC, Deborah C. Silverstein, DVM, DACVECC

KEY POINTS • Advanced modes of ventilation can be considered to optimize oxygenation and manage hypercarbia when standard modes are insufficient. • Patient–ventilator asynchrony is a common occurrence and may be related to patient or ventilator variables. • Lung protective strategies aim to limit ventilator-induced lung injury.

• Alternate modes of ventilation, including airway pressure release ventilation, may reduce patient–ventilator dyssynchrony. • Pressure-regulated volume control may alert the clinician to realtime changes in patient lung mechanics that result in increased airway pressures and decreased tidal volumes.

INTRODUCTION

issues (endotracheal tube placement, secretions, bronchospasm, etc.) and the development of pleural space disease (i.e., pneumothorax) may also result in sudden changes in patient stability and the development of asynchrony.2 The most commonly reported patient-related factors may actually be the result of the severity of the underlying cause of the respiratory failure, including obstructive pulmonary disease and acute respiratory disease syndrome (ARDS). Ventilatorrelated factors commonly involve the selected mode and settings but may also include machine-related issues (i.e., leaks).1 PVA may lead to patient discomfort, cardiovascular instability, increased work of breathing, impaired gas exchange, ventilator-induced lung injury, and prolonged need for mechanical ventilation.1,3 It is ultimately important that the clinician monitor the patient and available waveform data to optimize the patient–ventilator interaction. See Table 32.3 for the more common causes of PVA and the associated diagnostic and therapeutic approach to each.

Mechanical ventilation is becoming more commonplace in veterinary medicine, and with the advent of more advanced ventilators, our ability to individualize patient care improves. Mechanical ventilation is certainly not without risk to the patient and requires significant financial commitment on behalf of the owners. However, newer modes of ventilation provide us with the ability to minimize risk and improve patient outcomes. An understanding of these modes as well as the anticipated effects on the patient variables are of utmost importance. This chapter provides a general overview of some of the newer modes of ventilation as well as some strategies to improve patient asynchrony–dyssynchrony and minimize lung injury.

PATIENT–VENTILATOR ASYNCHRONY Patient–ventilator asynchrony (PVA) is described as a mismatch between the needs of the patient (with regards to flow, volume, time or pressure) and the ventilator-assisted breath. Asynchrony is a common finding in mechanically ventilated veterinary and human patients, with rates reported between 10% and 85%.1 It remains difficult to identify PVA in all patients as more invasive testing (including phrenic neurogram and esophageal balloon catheter) is considered the gold standard but these approaches remain limited to select populations of patients or those involved in clinical research. Currently, most clinicians rely on waveform analysis as a noninvasive way of detecting PVA. By analyzing the waveforms (flow, volume and pressure; see Chapter 35, Ventilator Waveforms), the clinician can determine the more common types of asynchrony, which are those related to triggering, cycling, and flow.1 PVA may be as a result of both patient and ventilator variables (see Table 32.3 in previous chapter for general troubleshooting measures). Factors that increase ventilatory demand by the patient, including anxiety, fever and acidosis, will favor asynchrony as will the level of sedation and underlying disease process. Additionally, airway-related

LUNG PROTECTIVE VENTILATION Lung protective ventilation is employed as a means to limit overdistention of alveoli that may contribute to VILI (see Chapter 39, VentilatorInduced Lung Injury). This ventilation strategy involves lower tidal volumes and limited plateau airway pressures and has been most extensively studied in patients with ARDS. Positive end-expiratory pressure (PEEP) is also employed to improve oxygenation by increasing the recruitment of alveoli, reducing VILI, and decreasing shunt fraction. The potential harmful effects of higher tidal volume ventilation were recognized in the 1970s, but it was not until 1998 that Amato published a study showing mortality benefits from low tidal volume ventilation.4 This is now considered the standard of care in human mechanical ventilation and includes ventilation with tidal volumes of approximately 4–6 ml/kg. Low tidal volume ventilation reduces the incidence of volutrauma (overdistention and shearing injury), barotrauma (high airway pressures possibly leading to alveolar rupture and pneumothorax) and biotrauma (lung injury secondary to release of

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inflammatory mediators during prolonged mechanical ventilation). Low tidal volume ventilation may result in hypoventilation and a progressive rise in the partial pressure of carbon dioxide (PaCO2). As long as the pH changes are gradual and oxygenation is maintained, permissive hypercapnia may help avoid overdistention of alveoli and autoPEEP.2 However, a higher minute ventilation may be necessary for those patients adversely affected by hypercarbia, and severe hypercapnia is associated with higher mortality rates in people with ARDS.5,6 The recommended target oxygenation in people is below normal, but compatible with adequate organ oxygenation: PaO2 55–80 mm Hg or oxygen saturation (SpO2) of 88%–95% using the least aggressive settings.7 Following the work of Amato, the ARDS Network proved a clear benefit of lung protective ventilation in patients with ARDS with regards to in-hospital mortality and duration of mechanical ventilation.8 The ARDS Network group, also known as ARDSNet, created high PEEP/low fraction of inspirated oxygen (FiO2) and low PEEP/high FiO2 tables to help guide clinicians when managing ARDS patients (see Table 33.1).9 The aim is to maintain plateau pressure ,30 cm H2O when using the high/low PEEP/FiO2 tables. There have been three large trials examining higher versus lower PEEP strategies, but none revealed a clear outcome advantage.8,10,11 A meta-analysis did find that patients with moderate to severe ARDS had higher survival rates when higher PEEP was used.12 Additional evidence suggests that a wider patient population is likely to benefit from ventilation with low tidal volumes given the propensity for VILI in all mechanically ventilated patients. However, current recommendations maintain that patients with ARDS and those with risk factors for the development of ARDS are most likely to benefit from lung protective ventilation with low tidal volumes and limited peak and plateau airway pressures. Lung protective ventilation may be delivered using pressurecontrolled modes of ventilation; alternatively, volume-controlled modes may be used as long as peak airway and plateau pressures are monitored carefully. Although some studies have shown benefits of pressure-controlled modes over volume-controlled modes with regards to improved oxygenation, lower peak inspiratory pressure and reduced duration of ventilation, other studies failed to show any improvement with regards to mortality in the ARDS patient.8,13 High frequency ventilation, which includes both high frequency jet ventilation and high frequency oscillatory ventilation, has also been employed as another mode to help deliver low tidal volume breaths that allow for adequate lung volume expansion. There is some data to suggest that both modes may be associated with decreased lung inflammation as well as improved lung mechanics (including decreased peak and mean airway pressures). However, neither mode has proven superior to conventional mechanical ventilation despite wide use.14

REFRACTORY HYPOXEMIA Patients that remain hypoxemic despite mechanical ventilation with 100% oxygen and lung protective strategies are challenging to manage. In human medicine, the use of pulmonary vasodilators (e.g., inhaled nitric oxide), high frequency oscillatory ventilation, neuromuscular blocking agents (e.g., cisatracurium), corticosteroid administration, prone positioning, and extracorporeal life support are adjunctive strategies commonly employed in these patients. However, the prognosis for survival remains poor with mortality rates of ∼60%.15 Studies in small animals with refractory hypoxemia despite aggressive mechanical ventilation are scarce, and large-scale prospective studies would be beneficial. The use of recruitment maneuvers to open up (“recruit”) alveoli quickly with an increased transpulmonary pressure, followed by a high PEEP to keep them open at end expiration, has been investigated using various methods. Although recruitment maneuvers are technically simple with standard mechanical ventilators, the technique is not a “one size fits all” approach and requires deep general anesthesia 6 paralytics, and it is often difficult to determine the optimal PEEP following recruitment. Although these maneuvers have been found to decrease the need for other salvage therapies in people with recruitable lung units, there are inherent risks that must be recognized, including overdistention, volutrauma, barotrauma, and hemodynamic compromise.16-20 Effects on mortality have varied among different studies, and subsequently, its use in patients with severe pulmonary parenchymal disease and refractory hypoxemia remains controversial.16,17,21-23 Several methods for PEEP titration have been studied with mixed results. The ARDSnet PEEP tables discussed above and shown in Table 33.1 are still controversial;24 lower PEEP may increase oxygen desaturation and hypoxemia with worsening of lung injury from cyclic opening and closing of alveoli, while higher PEEP values can decrease cardiac output and cause further lung injury due to volutrauma, barotrauma, and overdistention of more normal lung regions.25-28 Optimization of PEEP can maintain recruitment of injured or collapsed alveoli and therefore reduce hypoxemia and intrapulmonary shunting, improve gas exchange, and decrease the risk for VILI.29-31 Strategies that have been studied for determining optimal PEEP include decremental PEEP trials,32 titration of PEEP up or down to find the PEEP value that is associated with the highest compliance,33,34 incremental PEEP titration using a target inspiratory plateau pressure,11 or adjusting the PEEP to achieve the best oxygenation.35-37 When increasing PEEP incrementally, a decrease in dead space and an increase in respiratory system compliance may indicate recruitment of collapsed lung units.38 Additional techniques that have been studied when titrating PEEP include monitoring of transpulmonary pressure,34 evaluation of hysteresis and aiming for a stress index of “1,” and calculation of driving pressure.29,39 The use of pressure-volume loops to determine the lower inflection point, with

TABLE 33.1  ARDSnet Protocol for PEEP Titration FiO2

0.3

0.4

0.4

0.5

0.5

Lower PEEP/higher FiO2 0.6 0.7 0.7 0.7

0.8

0.9

0.9

0.9

1.0

PEEP

5

5

8

8

10

10

14

14

16

18

18-24

FiO2

0.3

0.3

0.3

0.3

0.3

0.4

0.5-0.8

0.8

0.9

1.0

1.0

PEEP

5

8

10

12

14

14

20

22

22

22

24

10

12

14

Higher PEEP/lower FiO2 0.4 0.5 0.5 16

16

18

Note: This protocol has two different strategies with either lower PEEP and higher FiO2 or higher PEEP and lower FiO2. Stepwise changes are recommended, and the plateau pressure should remain less than 30 cm H2O.

CHAPTER 33  Mechanical Ventilation—Advanced Concepts PEEP then set above this critical closing pressure, is intuitive in theory, but challenging to utilize in the clinical setting and may not accurately represent the true alveolar closing pressure (see Fig. 35.14).4,40,41 Imaging strategies such as lung ultrasound and electrical impedance tomography are attractive monitoring tools for the assessment of lung recruitment when titrating PEEP, although ultrasound cannot assess alveolar distention and impedance tomography has not been widely studied.42,43

PRESSURE MODES OF ADVANCED MECHANICAL VENTILATION Airway Pressure Release Ventilation Airway pressure release ventilation (APRV) was first described in 1987 as a ventilation mode that utilizes sustained high levels of continuous positive airway pressure (CPAP) and only brief periods of a “release phase” that offers an opportunity for more efficient alveolar ventilation and CO2 removal.13,44 It is described as a time cycled, pressurecontrolled, intermittent mandatory ventilation mode with extreme inverse I:E ratios.45 Currently, APRV refers to a bilevel pressure control whereby two pressure levels are set, Phigh and Plow, and the ventilator alternates between both (see Fig. 33.1). This is a mandatory mode that allows for unrestricted patient breathing during Phigh and therefore may help to reduce asynchrony. The trigger for each spontaneous breath is either flow or pressure, whereas time is used as the constant to switch between high and low pressures. Ventilation is dictated by time spent at both pressures (Thigh and Tlow). Pressure and time are set by the clinician and can be manipulated to increase oxygenation (Phigh and Thigh). Thigh can also be decreased in an effort to increase the amount of time for CO2 exhalation, but excess time at Plow and Tlow must be prevented to avoid lung collapse and derecruitment.45 Table 33.2 lists suggested initial APRV settings; close monitoring of PEEP level and mean airway pressures is important. Recommendations for gradual weaning from APRV are listed in Table 33.3.

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In 2005 Habashi described “personalized APRV”, or P-APRV, which is also known as time-controlled adaptive ventilation. This method allows for more time at Phigh and less time a Plow with those times being set by analysis of the expiratory flow curve slope.44-46 By doing so, the user can tailor ventilator settings to changing lung mechanics. Approximately 80%–95% of the respiratory cycle time is spent at Phigh, with the transition to Plow set by the ratio of end-expiratory flow (EEF)/peak expiratory flow rate (PEFR). A Tlow that reaches an EEF/ PEFR of 75% has been shown to improve oxygenation and alveolar stability while decreasing alveolar shearing and microstrain.45 The goal of this method is to recruit lung segments and then allow uninhibited exhalation for only a short amount of time (avoiding complete exhalation) such that some air is trapped in the lungs creating auto-PEEP. Benefits of APRV include its lung protective strategies as well as improved hemodynamics and reduced need for sedation and neuromuscular blockade. It is important to keep in mind that this mode of ventilation supports spontaneous breathing, so neuromuscular blockade is often avoided, and titration of sedation is important so that spontaneous breathing contributes to at least 10%–30% of the total minute ventilation.47 Additionally, offering the patient the ability to spontaneously breathe may decrease the incidence of PVA. The ultimate aim is to increase alveolar surface area for gas exchange, which allows for improved ventilation–perfusion matching. APRV limits volutrauma and atelectrauma by limiting overdistention followed by collapse of alveoli, particularly in ARDS patients that suffer from significantly heterogeneic regions of lung.45 A study by Zhou et al. published in 201747 compared low tidal volume minute volume with APRV and found that early application of APRV in patients with ARDS was associated with improved oxygenation, decreased plateau pressures, and shortened length of mechanical ventilation and ICU stay, leading to the proposal that APRV should be considered a primary mode of ventilation rather than a rescue mode as most commonly employed. However, despite the potential benefits, concerns

Pressure (cmH2O)

Spontaneous breath T high P high

P low T low Time (sec) Spontaneous breath

Figure 33.1  ​Pressure-time curve for airway pressure release ventilation (APRV). Phigh is the high continuous positive airway pressure (CPAP), Plow is the low CPAP, Thigh is the duration of Phigh, and Tlow is the release period or the duration of Plow. Spontaneous breathing appears on the top of Phigh. (Reproduced from Daoud E: Airway pressure release ventilation, Ann Thorac Med 2(4):176–179, 2007.)52

TABLE 33.2  Initial Active Pressure Release

Ventilation Settings Phigh

Typically set as the plateau pressure from the previous mode (i.e., volume or pressure-controlled); maximum usually 30 cm H2O

Plow

0–5 cm H2O

Thigh

Start ~4–6 sec

Tlow

Set to approximately 40%–60% of the peak expiratory flow; start ~0.6–0.8 sec

TABLE 33.3  Weaning Strategies for

Patients in APRV

FiO2 < 50%, patient breathing spontaneously: • Decrease Phigh by 1–2 cm H2O and increase Thigh by 0.5 sec for every 1 cm H2O decrease in Phigh (“drop and stretch” method) • When Phigh is between 12 and 16 cm H2O and Thigh is between 12 and 15 sec, consider change to CPAP • Add PEEP and PS based on continued monitoring (i.e., SpO2 and EtCO2)

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remain as to the effectiveness of APRV over other lung protective modes of ventilation. In another study comparing low tidal volume ventilation with APRV in pediatric patients with moderate to severe ARDS found a twofold increase in mortality rate amongst the APRV intervention group.48 Although the authors postulate a number of reasons for this finding, the differences in adult versus pediatric findings highlight the need for additional studies, ultimately multiinstitutional studies with patient populations that vary in severity of underlying disease. Given conflicting results in relatively few studies with small sample size, the role of APRV in veterinary patients has yet to be defined.

Pressure-Regulated Volume Control Pressure-regulated volume control is also known as volume control plus (VC1) and is a mechanical ventilation mode that automatically adjusts breath to breath inspiratory pressure based on a set tidal volume and changing lung mechanics. This mode of ventilation is considered time- or patient-triggered, pressure-limited, and time cycled and can be used with patients in either assist control or simultaneous intermittent mechanical ventilation.49 The clinician sets a target tidal volume and then a series of test breaths helps to establish the pressure control necessary to achieve the target tidal volume based on the system compliance.50 A pressure limit is then set, and the ventilator will deliver a tidal volume as close to the target tidal volume without exceeding the pressure limit. The ventilator will alarm when a pressure of 5 cm H2O below the set pressure limit is required to deliver the targeted tidal volume. In this way, the ventilator is able to adjust, on a breath-by-breath basis, the amount of pressure required to deliver the set tidal volume. This also allows the ventilator to adjust to changes in lung mechanics and alert the clinician to changes that result in higher airway pressures.51 Additionally, as compliance improves, the ventilator will be able to deliver the goal tidal volume with less pressure but will not allow the pressure to fall below PEEP. The flow rate is also adjusted by the ventilator to meet the patient’s needs while maintaining a near constant minute ventilation (see Chapter 8, Essentials of Mechanical Ventilation). A potential disadvantage to this mode of ventilation is that airway pressures may increase with decreased compliance and a set tidal volume, causing alveolar overdistention. However, if pressure settings are appropriate and lung protective tidal volumes are used, this becomes less of a concern.49-51

REFERENCES 1. Holanda MA, Vasconcelos RDS, Ferreira JC, et al: Patient-ventilator asynchrony, J Bras Pneumol 44:321-333, 2018. 2. Cairo JM: Improving oxygenation and management of acute respiratory distress syndrome. In Cairo JM, editor: Pilbeam’s mechanical ventilation: physiological and clinical applications, ed 7, St. Louis, MO, 2019, Elsevier, pp 234-273. 3. Mellott KG, Grap MJ, Munro CL, et al: Patient ventilator asynchrony in critically ill adults: frequency and types, Heart Lung 43:231-243, 2014. 4. Amato MB, Barbas CS, Medeiros DM, et al: Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome, N Engl J Med 338:347-354, 1998. 5. Morales-Quinteros L, Camprubí-Rimblas M, Bringué J, et al: The role of hypercapnia in acute respiratory failure, Intensive Care Med Exp 7:39, 2019. 6. Nin N, Muriel A, Peñuelas O, et al: Severe hypercapnia and outcome of mechanically ventilated patients with moderate or severe acute respiratory distress syndrome, Intensive Care Med 43:200-208, 2017. 7. Panwar R, Hardie M, Bellomo R, et al: Conservative versus liberal oxygenation targets for mechanically ventilated patients. A pilot multicenter randomized controlled trial, Am J Respir Crit Care Med 193:43-51, 2016.

8. Brower RG, Matthay MA, Morris A, et al: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome, N Engl J Med 342:1301-1308, 2000. 9. Brower RG, Lanken PN, MacIntyre N, et al: Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome, N Engl J Med 351:327-336, 2004. 10. Mercat A, Richard JC, Vielle B, et al: Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial, JAMA 299:646-655, 2008. 11. Meade MO, Cook DJ, Guyatt GH, et al: Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial, JAMA 299:637-645, 2008. 12. Briel M, Meade M, Mercat A, et al: Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis, JAMA 303:865-873, 2010. 13. Rose L, Ed A: Advanced modes of mechanical ventilation: implications for practice, AACN Adv Crit Care 17:145-158; quiz 159-160, 2006. 14. Ethawi YH, Abou Mehrem A, Minski J, et al: High frequency jet ventilation versus high frequency oscillatory ventilation for pulmonary dysfunction in preterm infants, Cochrane Database Syst Rev 2016:Cd010548, 2016. 15. Duan EH, Adhikari NKJ, D’Aragon F, et al: Management of acute respiratory distress syndrome and refractory hypoxemia. A multicenter observational study, Ann Am Thorac Soc 14:1818-1826, 2017. 16. Fan E, Wilcox ME, Brower RG, et al: Recruitment maneuvers for acute lung injury: a systematic review, Am J Respir Crit Care Med 178:11561163, 2008. 17. Cavalcanti AB, Suzumura ÉA, Laranjeira LN, et al: Effect of lung recruitment and titrated positive end-expiratory pressure (PEEP) vs low PEEP on mortality in patients with acute respiratory distress syndrome: a randomized clinical trial, JAMA 318:1335-1345, 2017. 18. Sahetya SK, Brower RG: Lung recruitment and titrated PEEP in moderate to severe ARDS: is the door closing on the open lung? JAMA 318:13271329, 2017. 19. Goligher EC, Hodgson CL, Adhikari NKJ, et al: Lung recruitment maneuvers for adult patients with acute respiratory distress syndrome. A systematic review and meta-analysis, Ann Am Thorac Soc 14:S304-S311, 2017. 20. Xi XM, Jiang L, Zhu B: Clinical efficacy and safety of recruitment maneuver in patients with acute respiratory distress syndrome using low tidal volume ventilation: a multicenter randomized controlled clinical trial, Chin Med J (Engl) 123:3100-3105, 2010. 21. Hodgson C, Goligher EC, Young ME, et al: Recruitment manoeuvres for adults with acute respiratory distress syndrome receiving mechanical ventilation, Cochrane Database Syst Rev 11:CD006667, 2016. 22. Hodgson CL, Cooper DJ, Arabi Y, et al: Maximal recruitment open lung ventilation in acute respiratory distress syndrome (PHARLAP). A phase II, multicenter randomized controlled clinical trial, Am J Respir Crit Care Med 200:1363-1372, 2019. 23. Pensier J, de Jong A, Hajjej Z, et al: Effect of lung recruitment maneuver on oxygenation, physiological parameters and mortality in acute respiratory distress syndrome patients: a systematic review and meta-analysis, Intensive Care Med 45:1691-1702, 2019. 24. Walkey AJ, Del Sorbo L, Hodgson CL, et al: Higher PEEP versus lower PEEP strategies for patients with acute respiratory distress syndrome. A systematic review and meta-analysis, Ann Am Thorac Soc 14:S297-S303, 2017. 25. Brower RG, Lanken PN, MacIntyre N, et al: Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome, N Engl J Med 351:327-336, 2004. 26. Briel M, Meade M, Mercat A, et al: Higher vs lower positive endexpiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis, JAMA 303:865-873, 2010. 27. Guerin C: The preventive role of higher PEEP in treating severely hypoxemic ARDS, Minerva Anestesiol 77:835-845, 2011. 28. Thammanomai A, Hamakawa H, Bartolák-Suki E, et al: Combined effects of ventilation mode and positive end-expiratory pressure on mechanics,

CHAPTER 33  Mechanical Ventilation—Advanced Concepts gas exchange and the epithelium in mice with acute lung injury, PLoS One 8:e53934, 2013. 29. Marini JJ: Hysteresis as an indicator of recruitment and ventilatorinduced lung injury risk, Crit Care Med 48:1542-1543, 2020. 30. de Matos GF, Stanzani F, Passos RH, et al: How large is the lung recruitability in early acute respiratory distress syndrome: a prospective case series of patients monitored by computed tomography, Crit Care 16:R4, 2012. 31. Malbouisson LM, Muller JC, Constantin JM, et al: Computed tomography assessment of positive end-expiratory pressure-induced alveolar recruitment in patients with acute respiratory distress syndrome, Am J Respir Crit Care Med 163:1444-1450, 2001. 32. Hickling KG: Best compliance during a decremental, but not incremental, positive end-expiratory pressure trial is related to open-lung positive endexpiratory pressure: a mathematical model of acute respiratory distress syndrome lungs, Am J Respir Crit Care Med 163:69-78, 2001. 33. Pintado MC, de Pablo R, Trascasa M, et al: Individualized PEEP setting in subjects with ARDS: a randomized controlled pilot study, Respir Care 58:1416-1423, 2013. 34. Rodriguez PO, Bonelli I, Setten M, et al: Transpulmonary pressure and gas exchange during decremental PEEP titration in pulmonary ARDS patients, Respir Care 58:754-763, 2013. 35. Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial I, Cavalcanti AB, Suzumura ÉA, et al. Effect of lung recruitment and titrated positive end-expiratory pressure (PEEP) vs low PEEP on mortality in patients with acute respiratory distress syndrome: a randomized clinical trial. JAMA 2017;318:1335-1345. 36. Caramez MP, Kacmarek RM, Helmy M, et al: A comparison of methods to identify open-lung PEEP, Intensive Care Med 35:740-747, 2009. 37. Sahetya SK, Goligher EC, Brower RG: Fifty years of research in ARDS. Setting positive end-expiratory pressure in acute respiratory distress syndrome, Am J Respir Crit Care Med 195:1429-1438, 2017. 38. Gattinoni L, Caironi P, Cressoni M, et al: Lung recruitment in patients with the acute respiratory distress syndrome, N Engl J Med 354: 1775-1786, 2006. 39. Grasso S, Terragni P, Mascia L, et al: Airway pressure-time curve profile (stress index) detects tidal recruitment/hyperinflation in experimental acute lung injury, Crit Care Med 32:1018-1027, 2004.

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40. Amato MB, Barbas CS, Medeiros DM, et al: Beneficial effects of the “open lung approach” with low distending pressures in acute respiratory distress syndrome. A prospective randomized study on mechanical ventilation, Am J Respir Crit Care Med 152:1835-1846, 1995. 41. Maggiore SM, Jonson B, Richard JC, et al: Alveolar derecruitment at decremental positive end-expiratory pressure levels in acute lung injury: comparison with the lower inflection point, oxygenation, and compliance, Am J Respir Crit Care Med 164:795-801, 2001. 42. Bouhemad B, Brisson H, Le-Guen M, et al: Bedside ultrasound assessment of positive end-expiratory pressure-induced lung recruitment, Am J Respir Crit Care Med 183:341-347, 2011. 43. Costa ELV, Borges JB, Melo A, et al: Bedside estimation of recruitable alveolar collapse and hyperdistension by electrical impedance tomography, Intensive Care Med 35:1132-1137, 2009. 44. Jain SV, Kollisch-Singule M, Sadowitz B, et al: The 30-year evolution of airway pressure release ventilation (APRV), Intensive Care Med Exp 4:11, 2016. 45. Mallory P, Cheifetz I: A comprehensive review of the use and understanding of airway pressure release ventilation, Expert Rev Respir Med 14: 307-315, 2020. 46. Habashi NM: Other approaches to open-lung ventilation: airway pressure release ventilation, Crit Care Med 33:S228-S240, 2005. 47. Zhou Y, Jin X, Lv Y, et al: Early application of airway pressure release ventilation may reduce the duration of mechanical ventilation in acute respiratory distress syndrome, Intensive Care Med 43:1648-1659, 2017. 48. Lalgudi Ganesan S, Jayashree M, Chandra Singhi S, et al: Airway pressure release ventilation in pediatric acute respiratory distress syndrome. A randomized controlled trial, Am J Respir Crit Care Med 198:1199-1207, 2018. 49. Singer BD, Corbridge TC: Pressure modes of invasive mechanical ventilation, South Med J 104:701-709, 2011. 50. Hess DR, Kacmarek RM: Advanced modes of mechanical ventilation. In Essentials of mechanical ventilation, ed 3, New York, NY, 2014, McGrawHill Education, pp 72-87. 51. Cairo JM: Selecting the ventilator and the mode. In Cairo JM, editor: Pilbeam’s mechanical ventilation, ed 7, St. Louis, MO, 2019, Elsevier, pp 58-75. 52. Daoud E: Airway pressure release ventilation, Ann Thorac Med 2:176, 2007.

34 Jet Ventilation Bruno H. Pypendop, DrMedVet, DrVetSci, DACVAA

KEY POINTS • Transtracheal jet ventilation can be used for emergency ventilation; high-frequency jet ventilation can be used to ventilate patients when tracheal intubation is not possible or practical. • High-frequency ventilation can produce normoxemia and normocapnia with tidal volumes less than the volume of the dead space. • High-frequency ventilation requires the use of very high minute volumes.

• During jet ventilation, distribution of ventilation and tidal volume depend more on airway resistance than on respiratory system compliance. • Tidal volume and end-tidal carbon dioxide concentration cannot be measured accurately during jet ventilation. • The adequacy of ventilation and oxygenation should be assessed using blood gas analysis, particularly if jet ventilation is used for extended periods.

High-frequency ventilation was first explored in the 1960s in an attempt to find a positive pressure ventilation technique that would have minimal impact on circulation.1 It was assumed that insufflation of gas at a high frequency, directly in the airway, would cause a reduction in tidal volume and thereby in intrathoracic pressure. Different strategies can be used to deliver high-frequency ventilation. These include high-frequency oscillation, high-frequency jet ventilation (or jet ventilation), high-frequency flow interruption, and high-frequency positive pressure ventilation.2 This chapter focuses on jet ventilation. Jet ventilation was first used during bronchoscopy.1 A cannula was placed in an open-ended bronchoscope, and gas was delivered from a high-pressure source. Ambient air was entrained by the Venturi effect. The system was later adapted to deliver gas through a ventilating laryngoscope and through a catheter placed between the vocal cords. Percutaneous transtracheal jet ventilation was introduced during anesthesia in the early 1970s. During jet ventilation, pulses of gas are delivered at high velocity through an orifice in a T-piece connected to a tracheal tube, through a narrow tube incorporated in the tracheal tube, or through a catheter placed in the upper airway.3 Typical frequencies are in the range of 100 to 300 breaths/min.4 The major advantage of jet ventilation resides in the flexibility of the patient interface, allowing ventilation in situations where tracheal intubation is not possible. In addition to high-frequency jet ventilation, transtracheal jet ventilation can be used for emergency ventilation if a tracheal tube cannot be placed. Acceptable gas exchange can be achieved using a highpressure oxygen source, a valve, a jet injector, a catheter, and noncompliant tubing. A jet injector can be made of a cut off 1 ml syringe; the flush valve of an anesthesia machine can be used as valve.5 Ventilation is then provided at a rate of 12 to 20 breaths/min.6

into a steady and an oscillatory component. Eucapnia can then be maintained at low tidal volumes through an increase in the frequency of oscillation.7 By decreasing tidal excursion (i.e., transpulmonary pressure excursion above and below its mean), high-frequency ventilation should also limit alveolar derecruitment caused by insufficient lung volume. Interestingly, panting in dogs may be considered to represent the physiologic counterpart to mechanical high-frequency, low tidal volume ventilation and has been used as a model to study gas exchange during conditions of high-frequency ventilation.8 The volume of gas delivered to the alveoli depends on the volume of gas passing through the jet, the volume of gas entrained into the tracheal tube or airway, and the volume of the dead space.9 As frequency increases, tidal volume decreases, but dead space ventilation increases, and alveolar ventilation can therefore only be maintained with very high minute ventilation. At frequencies above 1 Hz (60 breaths/min), tidal volume is usually less than the volume of the dead space. It has been suggested that when tidal volume is less than 1.2 times the volume of the dead space, carbon dioxide elimination is greatly reduced, compared with conventional convective gas exchange, and that the length of the dead space has a larger influence than its volume on carbon dioxide elimination.9 It may therefore be beneficial to administer jet ventilation as distally as possible or practical. However, this advantage needs to be weighed with location of the tube for optimal jet delivery. It has been shown that the physical characteristics of a jet depend on the ratio of the jet diameter to tube or airway diameter, the ratio of jet diameter to tube length, the position of the jet entrance, and the driving pressure.10 Injectors can be designed to maximize flow. With distal jet ventilation, optimization of the injector is not possible, potentially resulting in decreased efficiency and flow. Although the gas volume of the jet after a single injection may not travel more than a few tracheal diameters, a continuing distal motion of previously injected gas occurs with the repetition of this jet injection, particularly at high frequencies.11 High-frequency jet ventilation results in inhomogeneous ventilation.12 Regional variation in gas concentration, air space volumes, and pressures are observed. Caudal lung lobes are usually ventilated better because of inertial factors. However,

PHYSICS AND PHYSIOLOGY High-frequency ventilation is based on the premise that transpulmonary pressure (i.e., the pressure that distends alveoli) can be divided

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CHAPTER 34  Jet Ventilation this lack of uniform ventilation is expected to have minimal impact on overall gas exchange. The volume of the jet impulse (tidal volume) is influenced by the geometry of the injector, the amount of gas entrained, the pressure of the jet, the back pressure, and the impulse duration.10 Effective injectors can entrain up to four to five times the jet flow during the early part of inspiration,4,10 although some studies suggest that this effect is minimal.13 The entrained volume, measured as a fraction of the tidal volume, is minimally affected by respiratory rate in the 12 to 200 breaths/min range.14 Entrainment is optimized by positioning the jet entrance in the proximal part of the endotracheal tube.10 Entrainment is due to the Venturi effect as a high-velocity gas stream exits the injector.14 Entrainment is limited to the early part of inspiration (first 0.08 seconds, regardless of respiratory rate), because as the lungs begin to fill, the airway pressure increases, which opposes and eventually prevents entrainment of gas. For the remainder of inspiration, some of the jet gas comes out of the airway opening without entering the lungs.14 The amount of gas lost this way (spilt volume) decreases as respiratory rate increases. During gas entrainment, there can be no spillage. As respiratory rate increases, inspiratory time decreases, but the time during which entrainment occurs remains fairly constant; therefore, the time available for spillage decreases.14 Because high frequencies are required, expiratory time is short, and end-expiratory lung volume is increased. Therefore, end-expiratory pressure is usually positive. This raises the pressure at the beginning of inspiration and may limit gas entrainment when high respiratory rates are used. Because of the high velocity of gas flow required to produce adequate ventilation at these high frequencies, changes in airway resistance will have a larger effect on tidal volume than respiratory system compliance, especially because volume changes are minimal. Similarly, distribution of ventilation will depend more on airway resistance than regional compliance, which may be beneficial in lung diseases that do not affect the airway.7

EQUIPMENT Various devices to administer jet ventilation are commercially available. They are based on a high-pressure gas source and solenoid valves to admit/interrupt gas flow. Typical settings include peak airway pressure, respiratory rate, and inspiratory time or inspiratory:expiratory time ratio (I:E ratio). Some ventilators allow the control of mean airway pressure, positive end-expiratory pressure, minute volume, and driving pressure. Rates usually range from 30 to 150 breaths/min and sometimes may be as high as 600 breaths/min.

INDICATIONS Jet ventilation is indicated in situations where mechanical ventilation is necessary or beneficial but traditional positive pressure ventilation cannot be delivered. These include laryngeal and tracheal surgery, bronchial resection, laryngoscopy, and bronchoscopy and whenever limitation of movement associated with respiration is beneficial.15 In addition, it has been suggested that jet ventilation in acute respiratory failure with circulatory shock resulted in higher cardiac output than traditional ventilation.16 Finally, jet ventilation is indicated if ventilation is required in patients with a tracheal lesion secondary to tracheostomy or prolonged intubation.15 Jet ventilation may also be used if the laryngeal opening is too small to allow intubation. It has been suggested that because of lower peak airway pressure than in traditional mechanical ventilation, jet ventilation may be preferable in airway leak situations.17 In dogs and cats, high-frequency jet ventilation has been used to maintain oxygenation and ventilation during resection and anastomosis of the intrathoracic trachea and during bronchoscopy.18,19

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Fig. 34.1  Endoscopic view showing the tip of a 13-gauge catheter used to deliver jet ventilation in a cat’s trachea.  (From McCarthy TC: Veterinary endoscopy for the small animal practitioner, St Louis, 2005, Elsevier.)

At the author’s institution, jet ventilation is primarily used to maintain oxygenation and carbon dioxide elimination during bronchoscopy in small dogs and cats. Ventilation is delivered through a 14- or 16-gauge catheter positioned in the trachea. The bronchoscope can then be passed alongside that catheter (Fig. 34.1). Transtracheal high-frequency jet ventilation can be used in emergency situations. A catheter is placed percutaneously through the cricothyroid membrane. The catheter is then secured to the neck of the patient. Migration of the catheter outside the trachea would result in severe subcutaneous emphysema.17

DISADVANTAGES Tidal volume is very difficult to measure during jet ventilation. The high velocity of the jet and entrainment of additional gas make inspiratory volume measurement very difficult; spillage of gas out of the open airway and the common addition of a bias flow make measurement of expired volume inaccurate.14 Similarly, end-tidal carbon dioxide concentration cannot be reliably measured during this mode of ventilation.3 Therefore adequacy of ventilation should be confirmed by end-tidal carbon dioxide concentration measurement during intermittent ventilation with large tidal volume or by arterial blood gas analysis. Jet ventilation may cause fluctuations in the amplitude of chest excursions and phasic changes in heart rate and systemic and pulmonary arterial pressures, resulting in fluctuations in blood flow.20 The small tidal volumes and therefore low peak airway pressure and possibly mean airway pressure during jet ventilation are expected to limit the cardiovascular effects of this mode of ventilation. However, compared with conventional mechanical ventilation, high-frequency jet ventilation may result in similar, larger, or smaller cardiovascular effects. Jet ventilation, particularly during severe bronchoconstriction or other forms of airway obstruction, may result in lung overinflation as gas accumulates because of short expiratory times. Lung hyperinflation may also result from steady alveolar pressure in excess of steady airway pressure.7 This likely is due to unequal inspiratory and expiratory impedances, distribution of oscillatory flow, and expiratory flow limitation.11,21 In addition, high-velocity gas streams as generated during high-frequency ventilation preferentially follow straight pathways. Because of the geometry of the central airway, this may result in regional differences, with an increased tendency of the lung base to be overinflated, compared with the apex.7

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Prolonged use (i.e., hours) of high-frequency jet ventilation administered in the trachea via a catheter was shown to result in endoscopic evidence of tracheal injury characterized by hypervascularity, mucus accumulation, focal hemorrhage, linear epithelial loss, and diffuse erythema and epithelial loss.22

MONITORING OF GAS EXCHANGE DURING JET VENTILATION Despite the technical difficulties limiting the ability to monitor the adequacy of ventilation during high-frequency jet ventilation, the same principles apply as for conventional mechanical ventilation.23 Arterial blood gas analysis remains the gold standard to judge the adequacy of oxygenation and ventilation and should be available if jet ventilation is used for extended periods. The same normal and abnormal partial pressure of oxygen (PaO2) and partial pressure of carbon dioxide (PaCO2) values as during conventional mechanical ventilation should be used in the interpretation of blood gas data.

VENTILATOR SETTINGS The goal of jet ventilation is to maintain adequate oxygenation and carbon dioxide elimination. However, because of the characteristics of jet ventilation, it is difficult to give guidelines for adjusting ventilatory parameters that will result in normal ventilation in different situations.4 Our clinical experience suggests that at a frequency of 180 breaths/min, tidal volumes resulting in barely detectable chest excursions usually result in adequate oxygenation and normocapnia to moderate hypocapnia. One study in dogs and cats reported that with driving pressures of 0.33 kg/cm2 and an inspiration:expiration (I:E) ratio of 1:2, cats were mildly hyperventilated at a frequency of 140 breaths/min; in dogs, a driving pressure of 1.3 to 1.8 kg/cm2 and 120 to 150 breaths/min resulted in a similar degree of hyperventilation.17

REFERENCES 1. Bohn D: The history of high-frequency ventilation, Respir Care Clin N Am 7:535, 2001. 2. Cotten M, Clark RH: The science of neonatal high-frequency ventilation, Respir Care Clin N Am 7:611, 2001. 3. Sykes MK: High frequency ventilation, Br J Anaesth 62:475, 1989.

4. Mutz N, Baum M, Benzer H, et al: Clinical experience with several types of high frequency ventilation, Acta Anaesthesiol Scand Suppl 90:140, 1989. 5. Benumof JL, Scheller MS: The importance of transtracheal jet ventilation in the management of the difficult airway, Anesthesiology 71:769, 1989. 6. Hess DR, Gillette MA: Tracheal gas insufflation and related techniques to introduce gas flow into the trachea, Respir Care 46:119, 2001. 7. Fredberg JJ, Allen J, Tsuda A, et al: Mechanics of the respiratory system during high frequency ventilation, Acta Anaesthesiol Scand Suppl 90:39, 1989. 8. Meyer M, Hahn G, Piiper J: Pulmonary gas exchange in panting dogs: a model for high frequency ventilation, Acta Anaesthesiol Scand Suppl 90:22, 1989. 9. Sykes MK: Gas exchange during high frequency ventilation, Acta Anaesthesiol Scand Suppl 90:32, 1989. 10. Baum M, Mutz N: Physical characteristics of a jet in the airways, Acta Anaesthesiol Scand Suppl 90:46, 1989. 11. Scherer PW, Muller WJ, Raub JB, et al: Convective mixing mechanisms in high frequency intermittent jet ventilation, Acta Anaesthesiol Scand Suppl 90:58, 1989. 12. Wagner PD: HFV and pulmonary physiology, Acta Anaesthesiol Scand Suppl 90:172, 1989. 13. Tamsma TJ, Spoelstra AJ: Gas flow distribution and tidal volume during distal high frequency jet ventilation in dogs, Acta Anaesthesiol Scand Suppl 90:75, 1989. 14. Young JD: Gas movement during jet ventilation, Acta Anaesthesiol Scand Suppl 90:72, 1989. 15. Rouby JJ, Viars P: Clinical use of high frequency ventilation, Acta Anaesthesiol Scand Suppl 90:134, 1989. 16. Fusciardi J, Rouby JJ, Barakat T, et al: Hemodynamic effects of high-frequency jet ventilation in patients with and without circulatory shock, Anesthesiology 65:485, 1986. 17. Haskins SC, Orima H, Yamamoto Y, et al: High-frequency jet ventilation in anesthetized, paralyzed dogs and cats via transtracheal and endotracheal tube routes, J Vet Emerg Crit Care 1:55, 1991. 18. Whitfield JB, Graves GM, Lappin MR, et al: Anesthetic and surgical management of intrathoracic segmental tracheal stenosis utilizing high-frequency jet ventilation, J Am Anim Hosp Assoc 25:443, 1989. 19. Bjorling DE, Lappin MR, Whitfield JB: High-frequency jet ventilation during bronchoscopy in a dog, J Am Vet Med Assoc 187:1373, 1985. 20. Calkins JM: Physiologic consequences of high frequency jet ventilation, Med Instrum 19:203, 1985. 21. Simon BA, Weinmann GG, Mitzner W: Mean airway pressure and alveolar pressure during high-frequency ventilation, J Appl Physiol 57:1069, 1984. 22. Haskins SC, Orima H, Yamamoto Y, et al: Clinical tolerance and bronchoscopic changes associated with transtracheal high-frequency jet ventilation in dogs and cats, J Vet Emerg Crit Care 2:6, 1992. 23. Wagner PD: Interpretation of conventional measurement of gas exchange in high frequency ventilation (HFV), Acta Anaesthesiol Scand Suppl 90:158, 1989.

35 Ventilator Waveforms Matthew S. Mellema, DVM, PhD, DACVECC

KEY POINTS • Ventilator waveform analysis can be an invaluable tool in monitoring and troubleshooting the ventilator patient. • Inspection of ventilator waveforms can be crucial in recognizing system leaks, the need for suctioning, and changes in respiratory mechanics.

• Ventilator waveforms should be inspected hourly in any patient on long-term mechanical ventilatory support. • Ventilator waveforms should be inspected immediately whenever the patient appears to be “fighting” the ventilator.

Long-term (.24 hours) intermittent positive pressure ventilation (IPPV) can be a lifesaving therapy for patients with severe respiratory compromise.1,2 It is also commonly employed as a short-term supportive measure for patients with transient respiratory dysfunction (e.g., depressed respiratory drive during anesthesia).3,4 When choosing ventilator settings the operator must first choose a mode of ventilation and then select machine settings based on general guidelines, diseasespecific guidelines, and presumed patient needs.5 These initial settings may be adjusted based on an evolving understanding of the nature of the patient’s respiratory disease and response to empiric trial. After initiation of mechanical ventilation, the ventilator settings are altered as necessary to achieve the targeted gas exchange levels. Inspection of ventilator waveforms, in combination with arterial blood gas values and inspection of the patient, often provides the most comprehensive overview of the appropriateness of the current settings, allows monitoring of disease status and ventilator troubleshooting, and may also help to identify sources of the patient–ventilator dyssynchrony (PVD).6-11 Waveform interpretation can be challenging, and this chapter is meant to serve as an introduction to the process for the interested reader.

with a rate of change that is either constant (ramp) or variable (exponential) (Fig. 35.2). Scalars are made up of a series of these waveforms plotted above and below the axis over time. Many modern ventilators can display multiple different scalars simultaneously (see Fig. 35.2). Deflections below the axis either indicate values are lower than a reference point (e.g., pressure below baseline) or can indicate directionality (e.g., flow into or out of the patient). Determining which waveform to monitor most closely depends on the machine settings and clinician need. As a rule of thumb, the scalar that represents the dependent variable will have the information that most directly reflects the patient’s respiratory mechanics. For example, if the patient is being ventilated in a pressure control mode, then the flow and volume scalars will contain useful information, whereas the pressure scalar should appear however the clinician set it to appear. This rule does not wholly apply to PVD, however, because patient effort in this setting often leads to subtle alterations in the plot of the independent variable.

WAVEFORM TYPES General Ventilator waveforms are typically divided into those wherein a single parameter is plotted over time (scalars) or two parameters are plotted simultaneously (loops). Scalar waveforms generally take on six characteristic shapes (Fig. 35.1): square, ascending ramp, descending ramp, sine, exponential rise, and exponential decay. Ramp and exponential waveforms are functionally similar enough that exponential waveforms are often lumped into the ramp category, leaving three characteristic shapes: square, ramp, and sine. Sine waveforms are characteristic of patient efforts such as are seen with spontaneous breaths in continuous positive airway pressure (CPAP) or synchronized intermittent mandatory ventilation (SIMV). Square waveforms indicate that the given parameter changes abruptly but is then held at a near constant value for a time. Ramp and exponential waveforms indicate that a parameter is changing gradually over time,

Waveforms in Different Ventilation Modes The scalar waveforms take on characteristic shapes depending on the mode of ventilation employed. Ventilator waveforms associated with commonly employed modes of ventilation are shown in Fig. 35.2 and Fig. 35.3. In Fig. 35.2, the characteristic shape of the waveforms seen with volume control modes (V-ACV, SIMV-VC) are shown.12 Two successive machine-delivered breaths are shown with no patient-triggering or spontaneous breaths. The pressure waveforms have the characteristic exponential rise shape (“shark fin”). The highlighted area denotes a period of inspiratory hold, which allows time for intrapulmonary redistribution of gas (“pendelluft”) with a resultant pressure decline from peak inspiratory pressure (PIP) to plateau pressure (Pplat).13 If the inspiratory hold was removed, then this concavity would not be present, and expiration would begin once the preset tidal volume had been achieved. Note that the flow profile in this setting is constant (square) throughout inspiration. The delivery of flow at a constant rate allows for meaningful assessment of airway resistance (Raw). However, some ventilators allow for delivery of flow during volume control modes with a descending ramp profile, which has several potential

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Square Ascending Descending Sine ramp ramp

Exponential Exponential rise decay

Time

B

B

Time

Time

C

Time

Fig. 35.3  ​A–C, The pressure, flow, and volume scalars typical of pressure control modes of ventilation are shown. An inspiratory hold may still be prescribed (encircled), and this will result in plateau of the volume scalar (C). The scalars for the second breath are typical of pressure support modes of ventilation.

Volume

C

Time

Volume

Flow

A

A

Flow

Pressure

Fig. 35.1  Characteristic shapes of ventilator waveforms. The six basic forms that make up standard ventilator scalar graphics are shown.

Pressure

202

Time

Fig. 35.2  ​A–C, The pressure, flow, and volume scalars typical of volume control modes of ventilation are shown. An inspiratory hold is in place (shaded zones), which gives the pressure scalar (A) the classic appearance of a shark fin with a bite taken out of it.

benefits. The inspiratory hold also results in a prominent plateau in the volume waveform as is shown (see Fig. 35.3). In Fig. 35.3 the characteristic shapes of the waveforms seen with pressure control modes (P-ACV, SIMV-PC) and support modes are shown. In pressure control modes the pressure waveform is now the one with the characteristic shape, whereas the flow waveform typically assumes the shape of an exponential decay.14 The volume waveform may be indistinguishable from those observed with volume control modes. The series of waveforms to the right in Fig. 35.3 show typical profiles for pressure support modes (e.g., SIMV with PSV). In this setting, inspiratory flow is not expected to reach zero before expiration begins. In these instances, the inspiratory flow is set to cycle off once a preset percentage of peak flow is achieved (e.g., 30% of peak). This point is reached within the upper dashed circle in the figure. Because the termination of inspiratory flow occurs when flow is low but not

zero, the volume waveform shows a minimal plateau (lower dashed circle). The use of SIMV as a mode of ventilation may be preferred in some clinical settings; however, it represents an additional level of complexity when it comes to ventilator waveform interpretation. In Fig. 35.4 four archetypal types of SIMV breaths are displayed for comparison.15 The vertical series labeled “a” depicts the typical waveforms associated with a mandatory breath in SIMV-VC. In this setting the shark fin pressure tracing and square wave flow tracing are evident. No inspiratory hold has been prescribed so expiration begins once the target tidal volume is achieved. Before the initiation of inspiratory flow, there is no evidence of patient effort (triggering). The second breath (vertical series “b”) is a spontaneous breath with characteristic sine wave appearance. Note that the negative portion of the pressure tracing is associated with inward flow because this is a spontaneous breath and not a positive pressure machine-delivered/assisted/supported breath. The tidal volume the patient achieves is lower than that seen with the preceding mandatory breath, which is what is typically observed (but not obligatory because it depends on patient effort and capacity). The third breath (vertical series “c”) represents a synchronized patienttriggered but machine-delivered breath. In this instance the patient’s inspiratory effort fell near to the time when the next mandatory breath was due. As such, the ventilator delivered a breath equivalent to the mandatory breath (series “c”) but did so at a time synchronous with

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c

d

Pressure

Pressure

a

a

b

A

Flow

Time

Pressure

A

c

Time

20 10 3 0

B B

Time a

Time

b

Volume

Pressure

c 1 2 3

C

Time Fig. 35.4  ​A–C, Scalar waveforms typical of SIMV breaths.

the patient’s respiratory efforts. The tidal volume is identical to that achieved with the first breath. The patient’s efforts only altered the timing of the breath, not its character. The nature of SIMV is such that there are preset periods immediately after a mandatory breath wherein the patient may breathe spontaneously and at small time intervals before a mandatory breath during which patient efforts will trigger early delivery of the next ventilator-delivered breath (thus the synchronized nature of SIMV versus IMV). The fourth breath (vertical series “d”) represents the waveforms typical of SIMV with pressure support. Here the patient’s inspiratory efforts for a spontaneous breath result in the ventilator delivering additional flow to supplement that achieved by the patient’s own efforts. This pressure support is set to cease once a predetermined level of inspiratory flow is reached (e.g., 30% of peak flow). This is reflected in the flow waveform by the fact that inspiratory flow abruptly ceases at a level above zero. The tidal volume achieved is larger than the patient achieved with a spontaneous breath (“b”) but smaller than the mandatory breaths (“a” and “c”). However, equivalent tidal volumes could be achieved by increasing the level of pressure support.

Pressure Waveform The pressure waveform typically takes on an exponential rising (volume control modes with constant flow) or square waveform (pressure control) (Fig. 35.5). In volume control modes with an exponential decay flow profile, the pressure scalar profile often appears as less square and more rounded. As mentioned earlier, when an inspiratory pause is in place the pressure waveform takes on the shape seen in Fig. 35.5A, label B. Fig. 35.5B shows that when positive end-expiratory pressure (PEEP) is being applied it is expected that pressure never returns to baseline, but rather remains at this preset level above atmospheric pressure between breaths (dashed line). Pressure decreases below this preset level indicate either patient effort, artifact, or circuit leaks.16

4

C Time Fig. 35.5  ​A–C, Pressure waveforms. Point (a) represents PIP and point (c) indicates Pplat. See text for further information.

When an inspiratory pause is in place, inspection of the pressure waveform may reveal a great deal of information regarding the patient’s lung mechanics (Fig. 35.5C). Both PIP (denoted “a” on the figure) and Pplat (denoted “c” on the figure) can be determined. These pressures can be used to calculate dynamic and static compliances, respectively. For example, tidal volume/(PIP 2 PEEP) would estimate dynamic compliance and tidal volume/(Pplat 2 PEEP) would estimate static compliance. Dynamic compliance (Cdyn) is lower than static compliance (Cs) because of the increased pressure required overcoming circuit and Raw. This pressure would be reflected by the size of the region labeled “1” in Fig. 35.5C. True static compliance can only be determined once bulk flow (gas delivery) and intrapulmonary flow (pendelluft) have ceased (point “c”). In many cases clinicians may be reluctant to design a breath with an inspiratory hold of the requisite length (,1.5 seconds) to truly measure static compliance and instead design application of a shorter inspiratory hold. In this case the pressure drops to the point labeled “b” and compliance measurements derived using these values are termed quasistatic (i.e., Cqs). In Fig. 35.5C, the determinants of mean airway pressure (MAP) can be appreciated. The major influences on MAP values are the relative height and width of four distinct pressures: (1) pressure used to overcome circuit and airway resistances, (2) pressure used to deform the lung and expand the alveoli, (3) pressure throughout the expiratory flow phase, and (4) PEEP.17 An increase in the surface area of any of these regions without an equivalent decrease in another will result in a higher MAP (Fig. 35.6). The PIP value on the pressure scalar can also be used in the estimation of Raw because resistance is equal to driving pressure divided by flow. An increase in Raw is seen as an increase in PIP without an accompanying increase in Pplat (see Fig. 35.6A). Conversely, a decrease

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Pressure

in compliance is evidenced by an increase in PIP and Pplat both with an unchanging difference between the two values (see Fig. 35.6A). Although an inspiratory hold can generate a wealth of information regarding pulmonary mechanics, an expiratory hold can also yield useful information.18 Many ventilators come equipped with an option for performing expiratory hold maneuvers. Performing this task allows

PIP Pplat

Baseline

Increased PIP Increased PIP PIP-Pplat PIP-Pplat unchanged increased Increased Static Pplat Pplat

Increased raw

Pressure

A

B

Flow Waveform

Decreased compliance

Time

Expiratory hold initiated

Intrinsic PEEP  5 cm H2O Set PEEP  5 cm H2O Total PEEP  10 cm H2O

Time

Fig. 35.6  ​A–B, Using the pressure waveform to assess changes in lung mechanics. PEEP, positive end-expiratory pressure; PIP, peak inspiratory pressure; Pplat, plateau pressure.

a

one to quantify intrinsic PEEP caused by gas trapping (auto-PEEP) as long as auto-PEEP is of a value greater than set PEEP (see Fig. 35.6B). In the example shown, set PEEP is 15 cm H2O, but auto-PEEP is present and total PEEP is actually 110 cm H2O. In these situations the auto-PEEP can have many adverse effects, including making patient triggering of the ventilator more challenging. In this instance, if the trigger value was set to –2 cm H2O below PEEP, the patient would have to drop airway pressure to –7 cm H2O instead of –2 cm H2O before a breath would be triggered because of the additional airway pressure from auto-PEEP.

The flow scalar takes on either a predictable, repeatable shape or a variable shape depending on the ventilation mode employed. In volume control modes of ventilation, the flow waveform will typically be square or descending ramp in conformation.19 Many ventilators allow the operator to choose the flow profile in this setting. In spontaneous breathing, the flow profile will be sine wave in appearance. Lastly, in pressure control modes the flow waveform typically takes on an exponential decay appearance (see Figs. 35.2 and 35.3).20 Using a constant flow pattern (square wave) does allow for certain pulmonary mechanics measurements to be made because one can assign an absolute value to flow, then measure pressure differential, and then finally calculate resistance. However, the constant flow approach does have some drawbacks. For a given tidal volume delivered, using constant flow delivery results in modestly higher PIPs than if a decelerating ramp approach is taken, as illustrated in Fig. 35.7A–B.21-25 Moreover, the use of a decelerating ramp pattern allows for fine-tuning of inspiratory time (I-time) (Figs. 35.7 and 35.8).

b

Flow

In to patient

Out from patient

A

Time

Pressure

PIP associated with constant flow pattern PIP associated with decelerating flow pattern (same tidal volume)

Flow pattern (superimposed for illustration purposes)

B

Time

Fig. 35.7  ​A–B, The pressure and flow waveformes typically seen when volume control modes of ventilation are employed. PIP, peak inspiratory pressure.

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c

Tidal volume Volume

Flow

d

b

a

Slope  Change in volume/change in time  Instantaneous flow rate

b

Time

Fig. 35.8 shows four different volume control mandatory breaths with two different flow profiles. For the breath to the far left (“a”), a constant (square) flow delivery was selected, whereas for the remaining three (“b” to “d”) a decelerating ramp flow pattern was chosen. The third breath (“c”) shows the appearance of the waveform when I-time is optimal. Flow returns all the way to zero before exhalation begins. In breath “b” the I-time is too short, and this may lead to flow asynchrony. In the case of breath “d,” the I-time is too prolonged, and there is a noticeable period of “zero-flow state” before exhalation. This zero-flow state puts the patient at risk for double triggering and other forms of PVD.26 When one looks at breath “a,” one can see that the constant flow rate option does not lend itself to the adjustment of I-time because the transition from inspiration to expiration is always abrupt when this flow pattern is selected unless an inspiratory hold is put in place. Thus, if the clinician opts for the volume control mode of ventilation, the selection of a decelerating ramp flow pattern may both allow for a lower PIP as well as allow one to optimize I-time using waveform inspection methods. The flow scalar is also a key tool in the detection of auto-PEEP without having to apply an expiratory hold. When auto-PEEP is present, the expiratory flow does not return to zero before the next breath is delivered (Fig. 35.9). That is to say, the patient is not done exhaling the last breath when the next one is applied. In this way auto-PEEP can occur even in patients without intrathoracic airway dysfunction.

Volume Waveform Of the three standard scalar waveforms (Fig. 35.10), the volume tracing typically contains the least information that would lead a clinician to alter ventilator settings. This is because most ventilators that can display graphic outputs also provide numeric outputs as well. As such, one often relies on numeric outputs of tidal volume and spends more time inspecting the other two scalars. However, there is some value to

Normal expiratory flow pattern

Flow

In to patient

Out from patient

a

A

d

Time Tidal volume

Volume

Fig. 35.8  ​The flow waveforms for four different volume control mandatory breaths with two different flow profiles are depicted.

c

Volume loss due to gas trapping or system leaks

B

Time

Fig. 35.10  ​A–B, The volume waveforms from two successive breaths are represented.

visual inspection of the volume scalar. In particular, it can provide a rapid qualitative picture of the relative size of spontaneous and mandatory breaths during SIMV or of patient effort during CPAP breathing. The volume waveform is the inextricably linked to the flow waveform. One parameter is generally derived from the other. In many modern ventilators, the circuit flow is determined (often via a flow disruptor and differential pressure transducer), and it is the flow signal over time that is used to calculate the delivered or exhaled volume. Thus, when one looks at the volume tracing one can see that the slope of the curve at any point reflects the instantaneous flow rate (ΔV/Δt), as shown in Fig. 35.10A. In this same figure, one can see that between the points labeled “a” and “b” the slope is large and positive and thus the flow scalar should have a large positive deflection at this same point. Between points “b” and “c” the slope of the volume waveform is zero; thus, volume is unchanging, and a corresponding zero-flow period is expected on the flow scalar. Lastly, between “c” and “d” one would expect to see a large negative deflection on the flow scalar to reflect the rapidly decreasing volume in the circuit. Tidal volume can also be determined from inspection of the volume scalar, as shown in this same figure. Lastly, the other major role for volume waveform inspection is in the identification of circuit leaks or gas trapping. As shown in Fig. 35.10A, a volume waveform that takes a vertical plunge straight to baseline in the mid- to late-expiratory phase indicates that more volume came in across the flow sensor than ultimately came back. This can mean that there is a leak in the circuit or that a given volume of gas has unexpectedly remained within the patient (e.g., gas trapping or unidirectional flow into the pleural cavity).

Pressure-Volume Loops Flow fails to return to baseline before the next breath begins Time

Fig. 35.9  ​The pressure tracing from two successive breaths delivered in volume control mode with descending ramp flow patterns are depicted. In this example, expiratory flow fails to return to zero before the next breath is delivered, indicating that auto-PEEP is present.

Pressure–volume loops (PV loops) are graphic representations of the dynamic interconnection between changes in circuit pressure and circuit volume. Inspection of PV loops has long been used in the assessment of lung mechanics in ventilator patients.27 In the last two decades, PV loop assessment has also come to play an important role in designing protective lung strategies for the support of acute respiratory distress syndrome patients.28 Fig. 35.11A shows a typical PV loop

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result in small patient-generated loops at other points in the tracing (e.g., the expiratory limb). The dashed vertical line and arrow indicate the PEEP value, and one can note that the patient efforts bring airway pressure below this resting value. Once the triggering threshold is reached, a machine-delivered breath proceeds. The size of the shaded area of the patient effort loop indicates the work done by the patient to trigger the breath. If the trigger sensitivity is altered, then the patient will need to do more or less work to trigger the ventilator and the size of this area will change. Changes in the orientation and area of PV loops can indicate alterations in the mechanical properties of the patient’s lungs, the circuit, or both.29 Fig. 35.12A shows two loops from the same patient. The purple loop is the initial tracing, and the blue loop shows the changes expected to occur with an increase in airway or circuit resistances. The loop bows out farther from the dynamic compliance line, indicating that relatively greater applied pressure is required to overcome resistance and reach a given volume. Note that the Cdyn (as indicated by the slope of the line) has decreased. Unlike static compliance, the value of Cdyn is altered by changes in resistance because flow is not allowed to cease entirely. Increased bowing of the PV loop should prompt the clinician to investigate whether the endotracheal tube is kinked or obstructed, heat-moisture exchanger occlusion has occurred, or airway suctioning or bronchodilator administration is needed. Compliance changes also alter the shape and position of PV loops. As shown in Fig. 35.12B, a reduction in compliance (e.g., pulmonary edema develops) causes the PV loop to rotate (labeled “A”) as if its starting point were anchored and the loop rotated toward the

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for a mandatory, machine-delivered breath in a patient on a ventilator. Because the patient is receiving IPPV, inflation of the lungs corresponds with a rise in circuit pressure (inspiratory limb). Note that in a spontaneously breathing patient (or one in a negative pressure ventilator/iron lung), the addition of volume to the circuit would be associated with a decrease in circuit pressure and thus the tracing of the loop would proceed in a clockwise fashion instead (not shown). Several features of Fig. 35.11A are noteworthy. First, the loop does not begin at a pressure value of zero. This indicates the patient is on PEEP. Next, the pressure and volume values recorded at the highest value of the loop (upper right-hand area of the plot) would correspond to PIP and tidal volume, respectively. Finally, a dashed line connecting the two points at which volume is not changing has been added. This line connects the starting and end-inspiratory points. Because no significant circuit flow is occurring at these points, the pressure value largely reflects that required to distend the lung to that volume and not the additional pressure required to overcome airway and circuit resistance. The bowing of the inspiratory limb away from this line reflects the additional pressure required to overcome these resistances. The slope of this line is a measure of pulmonary compliance. Because intrapulmonary flows have not been given enough time to cease, this form of compliance would be termed Cdyn rather than static compliance (see Fig. 35.11). Fig. 35.11B shows a patient-triggered PV loop for comparison. This figure eight type of loop is typical of patient effort.29 In this case the patient effort is triggering/initiating activity and thus the small loop lies in the lower left aspect of the tracing (shaded area). PVD may

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CHAPTER 35  Ventilator Waveforms

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Fig. 35.14  ​A–B, Upper inflection point (UIP), lower inflection point (LIP), and circuit leaks on PV loops.

x-axis. Conversely, if compliance increases (e.g., edema resolves), the loop moves as if its starting point were anchored and the loop rotated toward the y-axis (labeled “b”). The change in compliance can be appreciated by the significant alteration in the slopes of the Cdyn lines. One must keep in mind that the shape of the PV loops is not entirely independent of the ventilator settings. Providing the same tidal volume with more rapid flow rates will result in increased bowing of the loop away from the compliance line. Moreover, in pressure control modes, the latter portion of the inspiratory limb can appear nearly vertical as constant inspiratory pressure is maintained (Fig. 35.13A). Excessively large tidal volumes can lead to alveolar overdistention and “beaking” of the terminal portion of the inspiratory limb.27 Beaking reflects further increases in circuit pressure with minimal additional volume increase. This shape is assumed once the alveoli have been expanded excessively and can only accept additional volume with large pressure increases (Figs. 35.13 and 35.14). The recognition of the mechanisms underlying ventilator-induced lung injury has led to a greater role for PV loop inspection in optimizing ventilator settings. In this setting the clinician is advised to inspect the loop in search of two important inflection points (see Fig. 35.14A). The lower inflection point (LIP) reflects a point at which pulmonary compliance significantly increases. This is thought to be the point at which a number of collapsed conducting and/or gas exchange units open. The cyclic opening and closing of these areas can lead to significant pulmonary damage (atelectrauma).30 This atelectrauma can be minimized by increasing PEEP to a value greater or equal to the value

at which the LIP is observed. In contrast, the upper inflection point (UIP) reflects the point at which pulmonary compliance significantly decreases because of alveolar overdistention and risk of alveolar injury (volutrauma) is increased.31 It is generally advised to keep PIP below the pressure at which the UIP is noted. It must be noted that in small patients (,2 kg) the flow signal (and thus volume changes) may be difficult to acquire for all but the most sensitive equipment. When the monitoring equipment can’t acquire the signal, many models will continue to plot the last recorded value. The plot of a rising pressure with an absolutely constant volume will result in a sharp, narrow horizontal beak at end inspiration where flow is lowest. This signal acquisition artifact can mimic true beaking in these small patients. The clinician should remember that biologic processes rarely result in biophysical relationships that are absolutely linear in nature. A leak in the ventilator circuit can also be reflected by changes in the PV loop. Fig. 35.14B shows an open, broken, incomplete loop that is typical of a circuit leak. Monitoring for leaks is important for ensuring proper cuff inflation, ensuring delivery of targeted tidal volume, and alerting the clinician to the possibility of air leakage from the respiratory tract to the pleural space.

Flow–Volume Loops Flow–volume loops are related to the flow scalar, and the inspiratory and expiratory limbs should roughly match the shape of the flow scalar portions (IA vs. IIA; IB vs. IIB) above and below the x-axis, respectively (Fig. 35.15A–B).29 The morphology of the waveforms will not match

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pulmonary function testing, the flow–volume loops are typically presented with the expiratory limb above the x-axis and end inspiration closest to the y-axis (i.e., upside down and inverted; picture the loop in Fig. 35.16 rotated clockwise 180 degrees). In Fig. 35.16, “a” denotes the start of inspiration. Inspiration continues to point “b” then ceases. The overall shape of the inspiratory limb is square, suggesting a constant flow volume control mode is being employed in this instance. The expiratory limb begins with the transition from point “b” to point “c.” Peak expiratory flow is achieved early in exhalation and is patient effort-dependent (usually not relevant in anesthetized patients on full assist-control ventilation). After peak flow is achieved, the expiratory limb tracing progresses to the effort-independent portion of the curve (“d”). The portion of the curve labeled “d” is the most relevant to the assessment of Raw changes, although peak flow is also often altered. In the case of a significant increase in Raw, a “scooped out” appearance of the mid-to-late portion of the expiratory limb is noted with an accompanying reduction in peak expiratory flow (Fig. 35.17A).32 Such changes should prompt the clinician to investigate whether airway suctioning or bronchodilator administration is needed. Circuit leaks can also be detected on flow–volume loops (see Fig. 35.17B). In each case the key feature is that inspiratory and expiratory volumes are not equivalent. Much as was seen with the PV loop, the effect of a circuit leak on a flow–volume loop is to create a broken, incomplete appearance.29 Excessive airway secretions can also be detected via flow–volume loop inspection. Fig. 35.17C shows an example of a flow–volume loop with a saw-tooth appearance to the effort-independent portion of the expiratory limb. This finding (along with auscultation of the trachea) is considered one of the most reliable indicators of the need for tracheal suction, whereas auscultation of crackles over the thorax is less predictive of suctioning need (see Fig. 35.17).32

Peak expiratory flow

PATIENT–VENTILATOR DYSSYNCHRONY

Volume Fig. 35.16  ​Typical appearance of a flow–volume loop.

precisely because one is plotting flow against time and the other against volume, but the waveforms should be qualitatively similar. Flow–volume loops are particularly important in the assessment of excessive airway resistance and in alerting the clinician to the presence of copious airway secretions or circuit leaks. Flow asynchrony can also be detected via flow–volume loops, as is discussed in the Patient– Ventilator Dyssynchrony section later in this chapter (Figs. 35.15 and 35.16).10 In ventilator waveform presentation the flow–volume loop is typically presented with the inspiratory limb above the x-axis (see Fig. 35.16). In

PVD (also called patient–ventilator interactions or patient–ventilator asynchrony) is increasingly recognized as an important contributor to outcomes in patients requiring long-term mechanical ventilatory support.6-11 The ventilator patient’s respiratory cycle can be divided into four distinct phases (Fig. 35.18). PVD may occur during any of them, and more than one form of PVD may be detected concurrently. The first (phase 1) is the initiation of inspiration, which is also called the trigger mechanism. PVD during phase 1 is often referred to as trigger asynchrony. Trigger asynchrony has been shown to be by far the most common form of PVD in human patients.11 The predominant types of trigger asynchrony include ineffective triggering, auto-triggering, and double triggering (Fig. 35.19A, B, and C, respectively).33 Ineffective triggering involves a patient-generated decrease in airway pressure

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CHAPTER 35  Ventilator Waveforms

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with a simultaneous increase in airflow without triggering a machinedelivered breath. This form of PVD is often the result of an inappropriately set sensitivity setting on the ventilator. However, it has been shown that increasing levels of pressure support suppress respiratory drive and lead to increased frequency of ineffective triggering.33-35 Triggering delay and ineffective triggering are often easier to identify on the flow scalar than on the pressure scalar because of the larger relative change in that parameter (i.e., bigger relative change in flow than pressure with ineffective efforts to trigger inspiration). When ineffective triggering is detected, the clinician should look for evidence of an improper triggering threshold, auto-PEEP (PEEPi), significant muscle weakness/fatigue, reduced respiratory drive, or an excessively deep level of anesthesia. Not all forms of trigger asynchrony may be corrected solely by adjusting the threshold. Auto-triggering is another form of trigger asynchrony and occurs when a breath is delivered by the ventilator because of a change in airway pressure or flow not caused by patient effort. Most often autotriggering is due to an inappropriately small threshold/sensitivity setting. Alternatively, flow or pressure distortions may be due to other factors, including circuit leaks, fluid/secretions within the circuit, or cardiac oscillations. Auto-triggering is more common when there are prolonged periods of no expiratory flow between breaths. Double triggering is defined as two delivered breaths separated by an expiratory time less than half the mean expiratory time. It occurs when a patient’s inspiratory effort continues throughout the ventilator’s preset I-time and thus remains present after the I-time has been completed. This prolonged effort triggers another breath. The end result is the patient receiving a tidal volume twice the desired or preset size. This carries with it risk of overdistention and alveolar trauma. This type of trigger asynchrony may be due to exceptionally high ventilatory demand on the part of the patient, low tidal volumes, an I-time that is too short, or a flow-cycle threshold set too high (see Fig. 35.19). Flow asynchrony is the result of ventilator supply of fresh gas to the inspiratory circuit that is either too fast or too slow for the individual patient. Flow asynchrony may be recognized using ventilator waveforms during either volume control or pressure control but manifests somewhat differently in each circumstance. In volume-controlled modes with constant inspiratory flow rates, it is easiest to detect flow asynchrony by comparing passive and patient-triggered breaths on both the pressure and flow scalars. In patients with flow asynchrony the triggered breaths will often have a “scooped out,” concave appearance on the upswing of the pressure tracing (Fig. 35.20A, labeled “a”) and a saw-tooth appearance to the plateau phase of the flow tracing (see Fig. 35.20B, labeled “b”) relative to the convex mandatory breaths. Flow asynchrony may also be evident on flow volume and P-L loops and manifest as irregular concavities of the inspiratory limbs (Fig. 35.20C and 35.20D, labeled “c” and “d”). Such findings should prompt the clinician to increase inspiratory flow until the two types of breaths have similar appearing waveforms. In pressure control (with variable inspiratory flow), one should look at the pressure-time scalar. When inspiratory flow is inadequate the pressure-time scalar will assume a “scooped out” appearance during the inspiratory plateau. When inspiratory flow is excessive, one may see an early overshoot in the airway pressure waveform (Fig. 35.21C). The clinician should adjust rise time in this setting until the pressure waveforms appear nearly square, have no plateau concavity, and show no evidence of overshoot. Termination asynchrony is also termed cycling asynchrony. The two main types of termination asynchrony involve inspiration being terminated too early (premature cycling; Fig. 35.21A) or too late (delayed cycling; see Fig. 35.21B). In the first instance, the patient is continuing to make inspiratory efforts at the time the ventilator cycles off. In the latter circumstance, the patient initiates active expiratory

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efforts while the ventilator is continuing to deliver inspiratory flow. Premature cycling may be associated with double triggering (see Fig. 35.19C) if the inspiratory efforts are sufficient to trigger a second breath after the first has been terminated. On the ventilator waveforms, premature cycling may be detected by visualizing an abrupt initial reversal in the expiratory flow waveform (often with a concurrent concavity in the pressure waveform). Increasing I-time or tidal volume should address premature termination. On the ventilator waveforms, delayed termination manifests as a pressure spike on the pressure scalar during mid- to late inspiration (see Fig. 35.21B). On the flow scalar one sees an abrupt, rapid decline in inspiratory flow near end inspiration. This type of asynchrony is managed by reducing I-time or tidal volumes. It is important not to confuse the early plateau change seen with flow asynchrony and the late plateau change seen with delayed cycling because the adjustments needed to address each of these are quite different. The waveforms for each of these forms of PVD are placed together in Fig. 35.21 (B and C) to assist direct comparison. Expiratory asynchrony typically manifests as auto-PEEP (gas trapping), which has been described earlier in the section on the flow scalar (see Fig. 35.9). If auto-PEEP is detected, then a number of parameters may be adjusted, nearly all of which serve to prolong expiratory time (e.g., trigger sensitivity, peak flow, flow pattern, rise time, I-time, cycle threshold, inspiratory to expiratory ratio’ with (I:E) ratio, and respiratory rate).36 One major adverse aspect of auto-PEEP is the effect that it has on triggering (see also discussion of trigger asynchrony earlier). Auto-PEEP increases the difficulty the patient faces in reaching the triggering threshold. Increasing PEEP to account for auto-PEEP may improve triggering sensitivity and efficacy.

SUMMARY

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In closing, ventilator waveforms should be inspected hourly in any patient on long-term mechanical ventilatory support and immediately whenever the patient appears to be “fighting” the ventilator. Ventilator waveforms can be crucial in recognizing system leaks, the need for suctioning, and changes in respiratory mechanics. The waveforms can also help place blood gas values into a more meaningful context and help with disease monitoring, in addition to evaluating the response to bronchodilators. The frequency with which PVD is recognized is largely dependent on how frequently one looks for it.11 A systematic, stepwise approach evaluating all four phases can help the clinician to optimize ventilator settings and avoid overanesthetization of patients with its associated adverse effects.

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REFERENCES Delayed cycling

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1. Hopper K, Haskins SC, Kass PH, et al: Indications, management, and outcome of long-term positive-pressure ventilation in dogs and cats: 148 cases (1990-2001), J Am Vet Med Assoc 230(1):64, 2007. 2. Hopper K, Aldrich J, Haskins SC: Ivermectin toxicity in 17 collies, J Vet Intern Med 16(1):892, 2002. 3. Sedgwick CJ: Veterinary anesthesia ventilation, Mod Vet Pract 60(2):120, 1979. 4. Moens Y: Mechanical ventilation and respiratory mechanics during equine anesthesia, Vet Clin North Am Equine Pract 29(1):51, 2013. 5. ARDSnet authors: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network, N Engl J Med 342(18):1301, 2000. 6. MacIntyre NR: Patient-ventilator interactions: optimizing conventional ventilation modes, Respir Care 56(1):73, 2011.

CHAPTER 35  Ventilator Waveforms 7. Younes M, Brochard L, Grasso S, et al: A method for monitoring and improving patient: ventilator interaction, Intensive Care Med 33(8):1337, 2007. 8. Georgopoulos D, Prinianakis G, Kondili E, et al: Bedside waveforms interpretation as a tool to identify patient-ventilator asynchronies, Intensive Care Med 32(1):34, 2006. 9. Pierson DJ: Patient-ventilator interaction, Respir Care 56(2):214, 2011. 10. Nilsestuen JO, Hargett KD: Using ventilator graphics to identify patientventilator asynchrony, Respir Care 50(2):202; discussion 232-204, 2005. 11. de Wit M: Monitoring of patient-ventilator interaction at the bedside, Respir Care 56(1):61, 2011. 12. Waugh JB, Deshpande VM, Harwood RJ. Waveforms for common ventilator modes. In: Waugh JB, Deshpande VM, Harwood RJ, editors. Rapid interpretation of ventilator waveforms. Upper Saddle River NJ, 2007, Pearson Education, pp 53-76. 13. Henderson WR, Sheel AW: Pulmonary mechanics during mechanical ventilation, Respir Physiol Neurobiol 180(2-3):162, 2012. 14. Hess DR: Ventilator waveforms and the physiology of pressure support ventilation, Respir Care 50(2):166; discussion 183-166, 2005. 15. Giuliani R, Mascia L, Recchia F, et al: Patient-ventilator interaction during synchronized intermittent mandatory ventilation. Effects of flow triggering, Am J Respir Crit Care Med 151(1):1, 1995. 16. Vignaux L, Vargas F, Roeseler J, et al: Patient-ventilator asynchrony during non-invasive ventilation for acute respiratory failure: a multicenter study, Intensive Care Med 35(5):840, 2009. 17. Marini JJ, Ravenscraft SA: Mean airway pressure: physiologic determinants and clinical importance. Part 1: physiologic determinants and measurements, Crit Care Med 20(10):1461, 1992. 18. Blanch L, Bernabe F, Lucangelo U: Measurement of air trapping, intrinsic positive end-expiratory pressure, and dynamic hyperinflation in mechanically ventilated patients, Respir Care 50(1):110; discussion 123, 2005. 19. Koh SO: Mode of mechanical ventilation: volume controlled mode, Crit Care Clin 23(2):161, viii, 2007. 20. Singer BD, Corbridge TC: Pressure modes of invasive mechanical ventilation, South Med J 104(10):701, 2011. 21. Al-Saady N, Bennett ED: Decelerating inspiratory flow waveform improves lung mechanics and gas exchange in patients on intermittent positive-pressure ventilation, Intensive Care Med 11(2):68, 1985. 22. Wong PW, Nygard S, Sogoloff H, et al: The effect of varying inspiratory flow waveforms on pulmonary mechanics in critically ill patients, J Crit Care 15(4):133, 2000.

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23. Bergman NA: Effect of different pressure breathing patterns on alveolararterial gradients in dogs, J Appl Physiol 18:1049, 1963. 24. Adams AP, Economides AP, Finlay WE, et al: The effects of variations of inspiratory flow waveform on cardiorespiratory function during controlled ventilation in normo-, hypo- and hypervolaemic dogs, Br J Anaesth 42(10):818, 1970. 25. Modell HI, Cheney FW: Effects of inspiratory flow pattern on gas exchange in normal and abnormal lungs, J Appl Physiol 46(6):1103, 1979. 26. de Wit M, Pedram S, Best AM, et al: Observational study of patient-ventilator asynchrony and relationship to sedation level, J Crit Care 24(1):74, 2009. 27. Harris RS: Pressure-volume curves of the respiratory system, Respir Care 50(1):78, discussion 98-79, 2005. 28. Terragni PP, Rosboch GL, Lisi A, et al: How respiratory system mechanics may help in minimising ventilator-induced lung injury in ARDS patients, Eur Respir J Suppl 42:15s-21s, 2003. 29. Waugh JB, Deshpande VM, Harwood RJ. Pressure-volume and flow- volume loops. In: Waugh JB, Deshpande VM, Harwood RJ, editors. Rapid interpretation of ventilator waveforms. Upper Saddle River NJ, 2007, Pearson Education, pp 23-52. 30. Muscedere JG, Mullen JB, Gan K, et al: Tidal ventilation at low airway pressures can augment lung injury, Am J Respir Crit Care Med 149(5): 1327, 1994. 31. Dreyfuss D, Soler P, Basset G, et al: High inflation pressure pulmonary edema. Respective effects of high airway pressure, high tidal volume, and positive end-expiratory pressure, Am Rev Respir Dis 137(5):1159, 1988. 32. Guglielminotti J, Alzieu M, Maury E, et al: Bedside detection of retained tracheobronchial secretions in patients receiving mechanical ventilation: is it time for tracheal suctioning? Chest 118(4):1095, 2000. 33. Thille AW, Rodriguez P, Cabello B, et al: Patient-ventilator asynchrony during assisted mechanical ventilation, Intensive Care Med 32(10):1515, 2006. 34. Thille AW, Cabello B, Galia F, et al: Reduction of patient-ventilator asynchrony by reducing tidal volume during pressure-support ventilation, Intensive Care Med 34(8):1477, 2008. 35. Leung P, Jubran A, Tobin MJ: Comparison of assisted ventilator modes on triggering, patient effort, and dyspnea, Am J Respir Crit Care Med 155(6):1940, 1997. 36. Laghi F, Goyal A: Auto-PEEP in respiratory failure, Minerva Anestesiol 78(2):201, 2012.

36 Anesthesia and Monitoring of the Ventilator Patient Kimberly Slensky, DVM, DACVECC, Ciara A. Barr, VMD, DACVAA

KEY POINTS • Most veterinary patients are maintained on total intravenous anesthesia while mechanically ventilated, often on two or more simultaneous infusions. • The choice of drugs used for sedation and anesthesia in mechanically ventilated patients depends on the patient’s cardiovascular stability and level of sedation/anesthesia required for appropriate support.

• The use of adjunct agents can be useful to decrease the amount of anesthesia needed as well as to reverse any potential undesirable side effects. • Both invasive and noninvasive monitoring of the ventilated patient are utilized to optimize patient care and outcomes.

The goals of mechanical ventilation are to support the injured lung and protect the healthy lung. However, management of mechanically ventilated small animals involves an intense coordinated effort to maximize patient comfort and to monitor for any changes in the patient’s clinical status that may be a result of the ventilator circuit (dys)function, sedation/analgesia, or secondary to the underlying disease process. Sedation, analgesia and anesthesia are key components to managing mechanically ventilated patients in the veterinary ICU, so a basic understanding of drug pharmacology and the effect of prolonged sedation and anesthesia with total intravenous anesthesia (TIVA) on this population of patients is of utmost importance. Monitoring the mechanically ventilated patient includes monitoring the ventilator system (including settings, alarms and circuitry)1 as well as monitoring the patient for any changes in cardiorespiratory parameters that may indicate a change in patient status. Patient monitoring equipment should include pulse oximetry, capnography, electrocardiography, blood pressure monitoring (preferably via direct arterial blood pressure when possible), and continuous temperature readings.2

inhalants and those drugs used for TIVA, have been linked to immunosuppression, with most having a direct suppressive effect on cellular and humoral immunity.4 However, it is generally understood that TIVA has less effect on immune function than inhalants, and a recent study comparing the immunological effects of propofol versus isoflurane in dogs showed that propofol has less associated immunosuppression than isoflurane and may confer some immune-protective effects.4 Additionally, because positive pressure ventilation alone may result in alterations in elimination and metabolism of certain drugs given its effects on renal and portal blood flow,5 each anesthetic has its own risks and benefits. Therefore, the choice of anesthetic depends on the individual patient as will be discussed in detail below. Further information on anesthesia of critically ill patients can be found in Chapter 133, Anesthesia of the Critical Patient and doses are referenced in Table 133.1. When combining multiple infusions for mechanical ventilation, the lowest doses possible should be utilized to minimize cardiopulmonary compromise and prolonged recoveries.

INJECTABLE ANESTHETICS

Propofol is a short-acting anesthetic that produces its hypnotic effect via potentiation of GABA-induced chloride current via its interaction with the GABAA receptor. Propofol is supplied in a lipid emulsion without bacteriostatic agents; thus aseptic technique should be used, and it is recommended that when used as an infusion, the infusion set be discarded every 12 hours or if contamination occurs.6 A formulation of propofol containing benzyl alcohol allows for a 28-day shelf life, although no reports exist of this formulation being used for prolonged infusions lasting several days. In cats it is recommended to avoid infusions of this formulation due to the potential for accumulation of benzyl alcohol.7 While there may be a concern for lipemia due to the lipid carrier, no clinically relevant lipemia was noted in healthy dogs undergoing 24 hours of propofol sedation for mechanical ventilation.8 However, animals on propofol infusions should be evaluated for lipemia regularly, and if it develops the propofol dose should be reduced or discontinued immediately.

In order to be placed on mechanical ventilation, the patient must first be intubated. The goal of induction of anesthesia is to rapidly intubate with the least likelihood of adverse effects such as cardiovascular depression. Depending on the clinical status and needs of the patient, the induction protocol may not include the same drugs as those used for maintenance anesthesia. The mainstay of anesthesia for mechanically ventilated patients is a continuous infusion of injectable anesthetics, typically with one or two adjunct drugs such as an opioid, benzodiazepine, and/or a-2 agonists added to reduce the amount of other anesthetic drug(s) needed. Inhalant anesthesia is generally avoided, especially in patients with significant hypoxemia, as inhalants inhibit hypoxic pulmonary vasoconstriction, possibly potentiating the severity of hypoxemia.3 In addition, ICU ventilators are not set up to allow delivery of inhalant anesthetic drugs, which further limits their use. Anesthetic agents, including both

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Propofol

CHAPTER 36  Anesthesia and Monitoring of the Ventilator Patient Propofol typically results in a smooth induction, although myoclonus has been reported in unpremedicated dogs.9,10 In addition to this transitory myoclonus, there is one case report of prolonged seizurelike phenomena in a dog following TIVA with propofol that resolved with phenobarbital and levetiracetam.11 Following induction with propofol titrated to effect (typically 1–4 mg/kg), an infusion is begun at an initial rate of 0.1 mg/kg/min, IV (Table 133.1).12 This infusion rate varies depending on the individual patient as well as adjunctive agents administered. Propofol is an excellent choice for maintenance of anesthesia for mechanical ventilation as its rapid kinetics allow the clinician to titrate the depth of anesthesia as needed. While propofol does not accumulate significantly in the tissues at clinical doses, it does have an increase in context-sensitive half-time as the duration of administration increases.13 This can be seen as prolonged recoveries in dogs receiving propofol and fentanyl infusions for the maintenance of surgical anesthesia for approximately 2 hours.14 Furthermore, in cats, recovery time appears to vary depending on dose and duration of infusion.15 While administration of propofol for 24 hours for mechanical ventilation in healthy cats resulted in prolonged time to walking (18 hours), it was significantly faster than cats having received ketamine (35 hours).12 In dogs, following 24 hours of mechanical ventilation spontaneous ventilation occurred within 1 hour of discontinuation of propofol.8 Rapid recovery is especially important during weaning from mechanical ventilation as propofol causes dose and rate dependent hypoventilation and apnea.10 As the clinician is attempting to assess the patient’s ventilatory capability, it is important that the patient is not overly sedated as hypoventilation may occur due to the anesthetics used. It is also equally important that the patient not become dysphoric during this period; thus the smooth recovery quality of propofol is an added benefit during weaning from mechanical ventilation. While propofol has been used commonly as the mainstay of anesthesia for the mechanically ventilated patient, it is not without risk. Propofol causes dose-dependent vasodilation and myocardial depression resulting in hypotension.16 These effects can be particularly profound in the cardiovascularly unstable patient; thus sedatives and analgesics should be added to the protocol to reduce the dose of propofol required. Repeated studies have demonstrated that the combination of propofol with an opioid such as morphine, fentanyl, remifentanil, or alfentanil provides improved hemodynamic stability and reduces the amount of propofol needed to maintain anesthesia.17-20 A further study demonstrated that mean arterial pressure could be maintained at or above 70 mm Hg in dogs undergoing TIVA with propofol and fentanyl by a stepwise reduction in propofol infusion, with a final infusion rate of 0.05–0.43 mg/kg/ min.14 In a study examining the effects of propofol for 24 hours of mechanical ventilation in dogs a decrease in cardiac index was appreciated; however, tissue perfusion did not appear to be compromised.8 In addition to its negative cardiovascular effects, repeated daily exposure of feline red blood cells to propofol may result in Heinz body anemia.21 However, another study evaluating repeated propofol anesthesia did not find any hematologic changes,22 and in a study examining three anesthetic techniques for mechanical ventilation of healthy cats for 24 hours, anemia was not reported in patients receiving propofol infusions.12 While further study is needed, if mechanical ventilation is required in cats for longer than 24 hours, an alternative anesthetic may be selected. Propofol infusion syndrome, a rare side effect of prolonged propofol infusions, has been reported in humans in the ICU. 23 This syndrome is characterized by metabolic acidosis, arrhythmias, rhabdomyolysis and renal failure. There is one case report in a dog that appeared to show similar symptoms, including, rhabdomyolysis, myoglobinuria, cardiac arrhythmias, methemoglobinemia, and liver enzyme

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elevations.11 While this appears to be a rare complication, close monitoring is recommended and propofol should be discontinued if propofol infusion syndrome is suspected. Furthermore, the lowest infusion rate possible should be utilized in order to reduce the likelihood of occurrence.

Alfaxalone Alfaxalone is a synthetic neuroactive steroid anesthetic that binds to the GABA receptor in the central nervous system thereby providing unconsciousness and muscle relaxation. It has been characterized as providing smooth and rapid induction of anesthesia; however, undesirable events at both induction and recovery have been noted occasionally, including agitation, noise hypersensitivity, excitement, head shaking, tremoring, paddling, twitching, apnea, and cyanosis.24-27 While these events typically do not require treatment, it is important to observe patients carefully especially while weaning off alfaxalone infusions. While all patients on mechanical ventilation should be kept in a quiet environment, this may be especially important for those recovering from alfaxalone anesthesia. Alfaxalone does not appear to accumulate following repeated bolus doses in dogs and cats. It has been used for relatively short duration at infusion rates of 0.07–0.1 mg/kg/min.28,29 At clinical dose rates, alfaxalone does not appear to accumulate to a clinically relevant level in cats.30 At these doses, no changes in blood chemistry or hematologic parameters have been noted in cats.30 Unfortunately, no studies have been published regarding prolonged infusions of alfaxalone as would be needed to maintain mechanical ventilation for days. In our clinical experience, cats tend to wake with clonic muscle activity after repeated dosing or continuous infusions, although we have used this drug infrequently in mechanically ventilated patients and never as a sole agent. Similar to propofol, alfaxalone causes dose-dependent decreases in respiratory rate and minute volume. This reduction in ventilation is beneficial for the mechanically ventilated patient while trying to maintain patient–ventilator synchrony; however, it may be detrimental during the weaning period. Therefore, the lowest possible dose of alfaxalone should be utilized. Furthermore, because alfaxalone causes a dose-dependent decrease in blood pressure, dose reduction may be beneficial especially in cardiovascularly compromised patients.25,31 As an infusion, alfaxalone does not appear to cause clinically significant cardiovascular depression in healthy dogs when used at an infusion rate of 0.07 mg/kg/min.32 However, higher infusion rates (.0.1 mg/kg/ min) may be associated with lower cardiac output33 or hypotension,32 again highlighting the importance of coadministration of adjunct agents to reduce the amount of alfaxalone needed. Alfaxalone is currently supplied in a formulation containing 150 mg/ml ethanol and 0.2 mg/ml benzethonium chloride as preservatives allowing for a shelf life of 28 days. While there is theoretical concern for potential toxicity associated with ethanol in cats, this formulation has been used to maintain at least 60 minutes of anesthesia via repeated boluses of 5 mg/kg without any significant detrimental effects on clinical pathology, physiologic, or anesthetic parameters as compared to the preservative-free formulation.34 However, close monitoring should occur in patients, especially those with hepatic dysfunction, remaining on prolonged infusions of alfaxalone.

Ketamine Ketamine differs from the other anesthetics in that it is a dissociative anesthetic, functioning on the NMDA, opioid, monoaminergic, and muscarinic receptors as well as voltage-gated calcium channels.6 Antagonism at the NMDA receptor results in dissociation of the limbic and thalamocortical systems, resulting in a patient that does not appear asleep but does not respond to external stimuli.6 As the patient recovers

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from anesthesia, they are prone to abnormal behavior and emergence delirium, which may be decreased by administration of benzodiazepines, acepromazine, or dexmedetomidine.6 In cats receiving a combination of ketamine-fentanyl-midazolam for maintenance of anesthesia for 24 hours for mechanical ventilation, none of the cats exhibited emergence delirium requiring intervention.12 The authors postulated that this was due to the addition of midazolam and fentanyl to the protocol resulting in reduced excitation during recovery from ketamine. Ketamine is metabolized by the liver to inactive metabolites and renally excreted in the dog. In the cat, however, ketamine is metabolized to the active metabolite, norketamine, which is then excreted unchanged in the urine.6 In cats with renal disease this can lead to significant accumulation with prolonged anesthetic times possible.6 In healthy cats being mechanically ventilated for 24 hours, those maintained on ketamine infusions had significantly slower recoveries than those maintained on propofol or ketamine-propofol infusions.12 This potential for prolonged recoveries makes ketamine alone a less desirable anesthetic for maintenance of anesthesia for mechanical ventilation. While ketamine as the sole anesthetic may not be desirable for maintenance of anesthesia, it does have several desirable characteristics as compared with propofol. The sympathomimetic effects of ketamine resulted in fewer interventions for bradycardia or hypotension in cats maintained with ketamine as opposed to propofol.12 Additionally, ketamine causes bronchodilation, which may be beneficial in patients on mechanical ventilation.12 Ketamine’s sympathomimetic effects may lead to an increase in cerebral blood flow and intracranial pressure; thus it should be avoided in patients with elevated intracranial pressure requiring mechanical ventilation.

Etomidate Etomidate is an imidazole derivative that interacts with the GABA receptor to induce anesthesia.6 While it is an excellent choice for induction in patients with cardiovascular disease due to its minimal effects on cardiopulmonary variables,35 it is not an ideal agent for maintenance of anesthesia for prolonged periods due to its adrenocortical suppression.36 The suppression of the adrenocortical system lasts for at least 6 hours in the dog36 and 5 hours in the cat37 following a single bolus. The use of etomidate as an infusion has been associated with increased mortality in humans in the intensive care unit.38 As infusions of etomidate for long durations are not currently recommended,6 it should not be used for maintenance of patients on mechanical ventilation.

ADJUNCT AGENTS The use of adjunct agents such as opioids, benzodiazepines, and alpha-2 agonists is recommended in order to reduce the amount of anesthetic needed for mechanical ventilation. These three classes of drugs can be reversed if needed to shorten the duration of recovery or should adverse effects occur.

Opioids Opioids are useful adjunct agents for maintenance of sedation for the mechanically ventilated patient as they provide sedation and analgesia.8,39 Opioids may be administered as intermittent boluses or as continuous rate infusions with no significant difference in duration of mechanical ventilation in humans receiving either fentanyl infusions or propofol infusions with intermittent opioid boluses.40 In dogs, both morphine and fentanyl infusions have been described to facilitate mechanical ventilation in healthy dogs for 24 hours.8 Unfortunately, in this study the two protocols varied not only in the opioid chosen but the other agents used, making comparisons difficult. Ideally, one would select a short-acting opioid such as fentanyl in order allow for

more rapid adjustments in infusion rates and a faster recovery. However, after prolonged infusions of fentanyl, accumulation can occur leading to a slower recovery.14,41The use of remifentanil, an ultrashort-acting opioid, has been shown to result in rapid recoveries following discontinuation of infusion.42,43 Remifentanil may be beneficial in mechanically ventilated patients in allowing for faster extubation and decreased length of stay in the ICU.39 It is important to note, however, that remifentanil is significantly more expensive than fentanyl and may be associated with the development of hyperalgesia.39 The use of opioids, such as fentanyl, is beneficial to the maintenance of anesthesia for mechanical ventilation as they have minimal impact on blood pressure or myocardial contractility.14 Furthermore, their addition to propofol infusions can result in improved cardiovascular stability.14 It is important to note that opioids may cause dose-dependent bradycardia, which can lead to a decrease in cardiac output.8 This bradycardia is vagally mediated and can be treated with anticholinergics. While opioids have minimal impacts on cardiovascular parameters, they are not without significant side effects. Opioids decrease gastrointestinal motility, which can lead to significant ileus, especially when administered repeatedly or as an infusion.6 Opioids also depress ventilation and are anti-tussive, which may be beneficial in preventing patient–ventilator dyssynchrony and improving tolerance of the endotracheal tube.39 However, prolonged sedation and hypoventilation can be detrimental during weaning from ventilation. Furthermore, extremely large doses of fentanyl for prolonged periods have been associated with “wooden chest” syndrome in human patients where rigidity of the chest wall occurs.44 Fortunately, the side effects associated with opioids are reversible with mu antagonists such as naloxone. One must consider that reversal of opioids will also reverse their analgesic effects and can lead to profound distress; thus the smallest dose possible of reversal should be utilized in nonemergent situations.

Benzodiazepines Benzodiazepines function by enhancing the affinity of the GABA receptor for GABA, leading to hyperpolarization of postsynaptic cell membranes in the central nervous system, resulting in sedation, anxiolysis, muscle relaxation, and anticonvulsant effects.6 They may be used as an adjunct to reduce the amount of anesthetic needed for induction45 or maintenance of anesthesia.46 While midazolam and diazepam are useful as adjuncts to anesthetic agents, when used alone they are not reliable sedatives and may cause excitation in healthy dogs and cats.47,48 If excitation or dysphoria is observed during weaning, reversal with flumazenil may be considered. Benzodiazepines are useful in critically ill patients as they have minimal cardiovascular and respiratory side effects. While either midazolam or diazepam can be utilized as an adjunct to maintain anesthesia for mechanically ventilated dogs,8 midazolam may be preferred as propylene glycol toxicosis can occur with prolonged administration of diazepam. Signs of toxicosis include lactic acidosis, hyperosmolality, hemolysis, cardiac arrhythmias, seizures, and coma.49 Midazolam has been used in both cats and dogs to maintain anesthesia for mechanical ventilation for 24 hours;8,12 however, its use in human patients has been associated with longer periods of mechanical ventilation and increased delirium.50 As a result, its use is no longer recommended for routine ICU sedation in human medicine.39 The adverse effects of longer term (days to weeks) infusions of midazolam in dogs and cats have not been evaluated, and it is commonly used as part of a TIVA protocol in ventilator patients at this time.

a-2 Agonists Dexmedetomidine is the most commonly used a-2 agonist in small animals. a-2 agonists primarily cause sedation via binding to a-2

CHAPTER 36  Anesthesia and Monitoring of the Ventilator Patient adrenergic receptors in the locus coeruleus and rostroventral lateral medulla leading to decreased norepinephrine release.6 The sedation caused by dexmedetomidine may also be used to reduce the amount of induction and anesthetic maintenance agent required to maintain anesthesia.51,52 Dexmedetomidine may be administered as a bolus or infusion for maintenance of sedation and analgesia.53 As an infusion given over 24 hours, it does not appear to accumulate when administered at approximately 1 µg/kg/hr.54 This is beneficial in patients requiring prolonged sedation for mechanical ventilation where drug accumulation could be detrimental to the rapid recovery of the patient. Dexmedetomidine has minimal effect on ventilation with blood gas parameters remaining unchanged during infusions.6 Dexmedetomidine may protect lungs from ventilator-induced lung injury as was demonstrated in an experimental model.55 Furthermore, it has been shown to be superior to midazolam for sedation of humans for mechanical ventilation.50 Unfortunately, this direct comparison has not been made in cats or dogs. The use of the racemic mixture, medetomidine, has been examined for the sedation of healthy dogs for 24 hours of mechanical ventilation.8 In this study dogs were administered either medetomidine, midazolam or diazepam and morphine, or midazolam, fentanyl and propofol. This study demonstrated both protocols to be effective in sedating healthy dogs for 24 hours of mechanical ventilation with return to spontaneous ventilation within 1 hour of discontinuing infusions of either protocol.8 Dexmedetomidine use is not without risk, especially in hemodynamically compromised patients, as it has been shown to cause vasoconstriction with a reflex bradycardia leading to a decrease in cardiac output.54 However, with low-dose dexmedetomidine infusions in healthy dogs, oxygen delivery is sufficient with no increase in lactate levels observed.54 Further studies are needed to examine the effects of low-dose dexmedetomidine infusions in critically ill patients with hemodynamic instability.

Acepromazine Acepromazine is a phenothiazine that causes sedation primarily via blockade of the D2 dopamine receptors.6 It is a commonly used and reliable sedative in small animals and may be beneficial in treating dysphoria during recovery from sedation for mechanical ventilation.8 Acepromazine has minimal effects on pulmonary function with no changes in blood gas values.56 Because of its long duration of action and hemodynamic effects, it is not recommended to be administered as an infusion during sedation for mechanical ventilation. Acepromazine can cause significant hypotension via a-1 blockade leading to decreases of 20%–30% in arterial blood pressure in dogs administered large doses of 0.1 mg/kg IV.57 Low doses should be used in hemodynamically stable patients, and acepromazine should be avoided altogether in hypotensive patients.

Neuromuscular Blocking Agents The use of neuromuscular blocking agents (NMBAs) to facilitate ventilation is controversial, with some studies suggesting increased morbidity when NMBAs are used for mechanical ventilation in humans. The use of NMBAs has been associated with quadriplegic myopathy syndrome, critical illness polyneuropathy, and ventilator-induced diaphragmatic dysfunction.39 Neuromuscular blocking drugs may be beneficial in acute respiratory distress syndrome,58 especially when patient–ventilator dyssynchrony cannot be corrected with adjustment of ventilation parameters. By causing paralysis of the diaphragm, these drugs have been shown to prevent volutrauma and barotrauma associated with patient–ventilator dyssynchrony.59 While NMBAs are not commonly used in veterinary medicine for mechanical ventilation, they may be indicated for short

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periods in situations of severe acute respiratory disease syndrome patient when patient–ventilator dyssynchrony is a concern. More details on NMBA drug types, monitoring, and reversal can be found in Chapter 133, Anesthesia in the Critically Ill Patient.

MAKING AN ANESTHESIA PLAN FOR THE VENTILATOR PATIENT The anesthetic plan for each individual ventilator patient should be based on a review of the clinical status of the patient with an emphasis on the concurrent cardiovascular status. The induction protocol should be chosen accordingly, and ideally clinicians should use drugs they have some familiarity with. Prior to induction, all the necessary equipment for intubation and positive pressure ventilation should be organized. A mechanism for manual ventilation (e.g., bag-valve mask) and an oxygen source should always be on hand for ventilator patients even if the mechanical ventilator is set up and operational in case of machine malfunction. Given the critical nature of most ventilator patients, close monitoring during induction is important, ideally including continuous electrocardiogram, pulse oximetry, and the option to measure blood pressure. Having anticholinergic drugs and resuscitation drugs readily available is also recommended. Suction should also be available in the event of excessive secretions, regurgitation, or significant pulmonary edema or hemorrhage. To reduce the amount of induction agent needed, one can administer loading doses of planned adjunct infusions, such as fentanyl or midazolam, prior to administering the induction agent. As most of these patients are severely compromised, it is unlikely that an intramuscular premedication will need to be administered; however, if the patient is extremely anxious or fractious and does not have intravenous access, this can be considered. More often, fentanyl and midazolam boluses will be administered just prior to administration of propofol or alfaxalone for induction. While not routinely administered to prevent bradycardia in these patients, anticholinergics can be used to treat clinically relevant bradycardia caused by opioids or increased vagal tone. The maintenance anesthesia plan is based on an understanding of the patient’s clinical status, an estimation of the likely length of anesthesia required and potentially, the financial situation. Critically ill animals with cardiovascular compromise such as the pneumonia patient in septic shock will need very low doses (if any at all) of an anesthetic drug such as propofol or alfaxalone and can be maintained primarily on adjunct agents such as an opioid and benzodiazepine combination. In contrast, a cardiovascularly stable and relatively healthy patient will need an anesthetic drug in combination with one or more commonly two adjunct agents.

WITHDRAWAL OF ANESTHESIA FOR VENTILATOR WEANING As with induction and maintenance of anesthesia for the ventilator patient, recovery from anesthesia is dependent on the individual characteristics of the patient. The goal for weaning the patient from the ventilator is that they smoothly and rapidly recover from anesthesia to allow for return to successful spontaneous ventilation. It is important to withdraw NMBAs first as residual blockade can greatly impact ventilation, as well as pharyngeal and laryngeal function. When possible, ketamine and midazolam should also be discontinued as early as possible as these can accumulate and lead to dysphoria in the recovery period. If dysphoria from midazolam is suspected, it can be reversed with flumazenil. Dependent on the depth of sedation or anesthesia needed to tolerate intubation, the recovery process may be prolonged.

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Typically, patients with tracheostomies require less sedation than those intubated orally and may recover more quickly. These patients can also be placed back on the ventilator relatively easily without the need for re-induction of anesthesia. As the patient’s propofol or alfaxalone is discontinued, they may become distressed or dysphoric. During this period a low dose of acepromazine (0.002–0.005 mg/kg) may be helpful to reduce dysphoria. Alternatively, if the patient had been maintained on a dexmedetomidine infusion, this can be continued at a lower rate into the recovery period to prevent dysphoria. The infusion of opioids should be decreased or discontinued dependent on the patient’s anticipated analgesic requirements. If the patient is not painful and the opioid is thought to be contributing to prolonged sedation, hypoventilation, or dysphoria, it can be reversed with naloxone.

supraventricular ectopy are also common and may precipitate with given changes in volume, sympathetic and parasympathetic tone or as a result of myocardial ischemia.66 Cardiovascular instability is also a common cause of weaning failure, and standard perfusion parameters are often insensitive markers of cardiovascular dysfunction. However, changes in arterial blood pressure and/or heart rate may be early indicators of impending weaning failure and myocardial ischemia that may be precipitated by the patient’s increased work of breathing during weaning; as such, it is important to monitor heart rate, blood pressure, respiratory rate/effort, and rectal temperature for any changes that may indicate cardiorespiratory distress and impending weaning failure.66,67

MONITORING OF THE MECHANICALLY VENTILATED PATIENT

Arterial blood gas assessment is ideal in mechanically ventilated patients as it allows for evaluation of oxygenation, ventilation, and acid-base status. Venous blood gases allow monitoring of PCO2 but cannot be used to assess oxygenation. See Chapter 16, Hypoxemia, and Chapter 17, Hypoventilation, for further discussion of blood gas assessment. Blood gas assessment may be very frequent when initially stabilizing patients on the ventilator. Following stabilization, serial monitoring every 4 to 6 hours is commonly performed. When arterial blood gas analysis is not available, venous blood gas assessment with pulse oximetry is utilized.

Hemodynamic instability is commonly encountered throughout the course of mechanical ventilation, owing to altered heart–lung interactions secondary to changes in intrapleural pressure as a result of positive pressure ventilation, positive end expiratory pressure (PEEP), effects of sedatives or anesthetic agents, and the underlying disease process itself. Acute reduction in venous return is probably the most common heart– lung interaction noted with the onset of positive pressure ventilation, and may be magnified in veterinary patients requiring induction agents that inherently carry some cardiovascular depressive effects. This reduction in venous return may also be more pronounced in hypovolemic patients or those with inappropriate vasodilation secondary to sepsis.60 Decreased cardiac output secondary to positive pressure ventilation is often the result of high airway pressures (increases in mean airway pressure have a more negative effect on cardiac output than changes in peak inspired pressure), increased lung compliance, and decreased circulating volume.61 Sedatives or anesthetic agents that cause hypotensive effects via vasodilation, negative inotropy, or central mechanisms should be avoided when possible or managed with appropriate vasoactive agents and/or fluid therapy.62 Pulse pressure variation may help to identify fluid responsive patients, although this method is less accurate with low tidal volume lung-protective modes of ventilation and not useful in spontaneously breathing patients.63

Blood Pressure Continuous blood pressure monitoring via arterial catheterization is ideal and also allows for more regular blood sampling. However, frequent monitoring with noninvasive blood pressure devices (Doppler or oscillometric) is often adequate. It is important to recognize that normal blood pressure does not indicate hemodynamic stability if compensatory mechanisms remain intact. Changes in blood pressure with alterations in ventilator settings may indicate a decrease in cardiac output; conversely, it is also possible that there may be a significant drop in cardiac output with adjustments in ventilator settings with no accompanying change in blood pressure. Therefore, blood pressure may be a specific, but insensitive, indicator of changes to cardiac output.64

Electrocardiogram A continuous electrocardiogram should be placed on every patient to evaluate for rhythm disturbances. Dysrhythmias are a common complication of mechanical ventilation65 and may be compounded by the use of sedation/anesthesia or the underlying disease process and often indicate and/or lead to cardiovascular instability. Bradyarrhythmias may be the result of high vagal tone secondary to respiratory disease, manipulation of the airway or endotracheal tube, gastric distention, traumatic brain injury, or electrolyte abnormalities. Ventricular and

Blood Gases

Pulse Oximetry Pulse oximetry offers continuous, noninvasive evaluation of SaO2, which can aid in identification of arterial desaturation and allow rapid adjustments in ventilator settings, including FiO2, PEEP, tidal volumes and airway pressures.68 However, unlike an arterial blood sample, the pulse oximeter provides little indication of the patient’s acid-base or ventilatory status so changes in pH and PaCO2 may occur with little to no change in the SpO2.63 The pulse oximeter is also a relatively insensitive measure of detecting hypoxemia when the patient has a high baseline PaO2,69 so it is possible that a relatively significant drop in PaO2 may go undetected if the patient is hyperoxic at the outset. Pulse oximeters with an arterial waveform may also recognize variations in stroke volume associated with gas trapping or auto-PEEP, and the respiratory variation in the waveform amplitude may be a useful indicator of fluid responsiveness.63 It is important to keep in mind that pulse oximeters are accurate when pulse quality is good and the saturation is .80%. With progressive desaturation, movement artifact or dyshemoglobinemias, as well as changes in perfusion, including low cardiac output, vasoconstriction, and/or hypothermia, pulse oximetry becomes less reliable.63,69,70 Additionally, based on a recent study, it appears that SpO2 cannot accurately predict PaO2 in healthy dogs breathing room air, but it may provide a more accurate assessment of PaO2 in mechanically ventilated patients.70 This is in contrast to another study that showed SpO2 can accurately estimate the PaO2 in human pediatric patients with acute hypoxemic respiratory failure as long as the SpO2 remains in the linear portion of the oxyhemoglobin dissociation curve with SpO2 readings of 80%– 97%.71 Despite its limitations, pulse oximetry is considered a standard of care in critically ill patients requiring mechanical ventilation. See Chapter 184, Oximetry, for more information.

Capnography Capnography is considered an important continuous monitoring tool for patients undergoing mechanical ventilation.63 Capnography is the continuous sampling of carbon dioxide in expired respiratory gas72 with genesis of a waveform referred to as a capnogram. Sampling of carbon dioxide may be achieved by using either mainstream or side stream analyzer that is attached to the endotracheal tube. Both analyzers provide reliable estimates for PaCO2 from end-tidal carbon dioxide

CHAPTER 36  Anesthesia and Monitoring of the Ventilator Patient (ETCO2) in mechanically ventilated dogs, although they may both underestimate the degree of hypoventilation in patients with higher PaCO2.73 ETCO2 is a value obtained from the plateau of the CO2 waveform and in healthy patients is 1–5 mm Hg less that the PaCO2, making it a reliable, continuous, and noninvasive estimate of the PaCO2 in patients with normal lung function.69 The normal P(a-ET)CO2 gradient is the result of dilution of alveolar gas by gas in the physiologic dead space. In mechanically ventilated patients with abnormal lung function, there is much more variability in the P(a-ET)CO2 gradient, making the prediction of PaCO2 from ETCO2 less reliable. An increase in P(a-ET)CO2 may indicate an increase in alveolar dead space secondary to severe pulmonary parenchymal disease, decreased cardiac output, or obstruction to blood flow such as occurs with pulmonary embolism. The P(a-ET)CO2 gradient may be used to detect optimal levels of PEEP and should be the smallest when there is maximal recruitment of lung units participating in gas exchange without overdistention.73-75 Overall, changes in ETCO2 may be the result of changes in: CO2 production, CO2 delivery to the lungs or alveolar ventilation. As such, ETCO2 is considered a nonspecific indicator of cardiopulmonary homeostasis,63 and changes in ETCO2 can reliably predict a variety of clinical conditions.69 Sudden increases or decreases in ETCO2 may be associated with equipment malfunction, changes in cardiac output and obstruction of pulmonary blood flow as may occur with pulmonary thromboembolism or air embolism. An absence of ETCO2 indicates esophageal intubation or cardiac arrest. Partial obstruction of the endotracheal tube may also lead to gradual increases in exhaled CO2, despite maintaining a normal ETCO2, whereas rebreathing CO2 may increase both the inspired and expired CO2.69 A “curare cleft” may be visible on the capnogram in a patient taking spontaneous breaths during mechanical ventilation76 and may indicate inadequate sedation or patient– ventilator dyssynchrony. Capnography may also aid in decisions regarding weaning from mechanical ventilation; although divergent conclusions regarding its utility have been found in numerous studies, it seems that ETCO2 may reasonably reflect the PaCO2 in patients with and without pulmonary parenchymal disease.77 Familiarity with the normal capnogram is essential to recognition of abnormalities that may occur with mechanical ventilation and the reader is directed to Chapter 190, Capnography, for more information.

Temperature Ventilator patients, like all critically ill patients, should have all vital parameters monitored frequently with as much continuous monitoring as possible. Temperature is particularly important to monitor as hypothermia is a common consequence of anesthesia and hyperthermia will stimulate increased respiratory rate and can lead to patient– ventilator dyssynchrony.

REFERENCES 1. Price SW, Ved S: Monitoring mechanical ventilation. In Freeman BS, Berger JS, editors: Anesthesiology core review, New York, 2014, McGrawHill Education LLC, pp 1-7. 2. Clare M, Hopper K: Mechanical Ventilation: Ventilator settings, patient management, and nursing care, Compend Contin Edu Pract Vet 27(4):256-269, 2005. 3. Epstein S: Care of the ventilator patient. In Silverstein DC, Hopper K, editors: Small animal critical care medicine, ed 2, St Louis, 2015, Saunders Elsevier, pp 185-190. 4. Tomihari M, Nishihara A, Shimada T, et al: A comparison of the immunological effects of propofol and isoflurane for maintenance of anesthesia in healthy dogs, J Vet Med Sci 77(10):1227-1233, 2015. 5. Miller RD: Respiratory care. In Cucchiara RF, Miller ED, Reeves JG, et al, editors: Anesthesia, ed 5, New York, 2000, Churchill Livingstone, pp 2403-2431.

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6. Grimm KA, Lamont LA, Tranquilli WJ, Greene SA, Robertson SA, editors: Veterinary anesthesia and analgesia, ed 5, Ames, IA, 2015, Wiley Blackwell. 7. Taylor PM, Chengelis CP, Miller WR, Parker GA, Gleason TR, Cozzi E: Evaluation of propofol containing 2% benzyl alcohol preservative in cats, J Feline Med Surg 14(8):516-526, 2012. 8. Ethier MR, Mathews KA, Valverde A, et al: Evaluation of the efficacy and safety for use of two sedation and analgesia protocols to facilitate assisted ventilation of healthy dogs, Am J Vet Res 69(10):1351-1359, 2008. 9. Watney GC, Pablo LS: Median effective dosage of propofol for induction of anesthesia in dogs. Am J Vet Res, 53(12):2320-2322, 1992. 10. Muir WW, Gadawski JE: Respiratory depression and apnea induced by propofol in dogs, Am J Vet Res 59(2):157-161, 1998. 11. Mallard JM, Rieser TM, Peterson NW: Propofol infusion-like syndrome in a dog, Can Vet J 59(11):1216-1222, 2018. 12. Boudreau AE, Bersenas AME, Kerr CL, Holowaychuk MK, Johnson RJ: A comparison of 3 anesthetic protocols for 24 hours of mechanical ventilation in cats: Anesthesia for mechanical ventilation in cats, J Vet Emerg Crit Care 22(2):239-252, 2012. 13. Hughes MA, Glass PSA, Jacobs JR: Context-sensitive half-time in multicompartment: pharmacokinetic models for intravenous anesthetic drugs, Anesthesiology 76(3):334-341, 1992. 14. Andreoni V, Lynne Hughes J: Propofol and fentanyl infusions in dogs of various breeds undergoing surgery, Vet Anaesth Analg 36(6):523-531, 2009. 15. Pascoe PJ, Ilkiw JE, Frischmeyer KJ: The effect of the duration of propofol administration on recovery from anesthesia in cats, Vet Anaesth Analg 33(1):2-7, 2006. 16. Goodchild CS, Serrao JM: Cardiovascular effects of propofol in the anaesthetized dog, Br J Anaesth 63(1):87-92, 1989. 17. Hughes JM, Nolan AM: Total intravenous anesthesia in greyhounds: pharmacokinetics of propofol and fentanyl—a preliminary study, Vet Surg 28(6):513-524, 1999. 18. Joubert KE, Keller N, Du Plessis CJ: A retrospective case series of computer-controlled total intravenous anaesthesia in dogs presented for neurosurgery, J S Afr Vet Assoc 75(2):85-89, 2004. 19. Murrell JC, Wesselink van Notten R, Hellebrekers LJ: Clinical investigation of remifentanil and propofol for the total intravenous anaesthesia of dogs, Vet Rec 156(25):804-808, 2005. 20. Raisis AL, Leece EA, Platt SR, Adams VJ, Corletto F, Brearley J: Evaluation of an anaesthetic technique used in dogs undergoing craniectomy for tumour resection, Vet Anaesth Analg 34(3):171-180, 2007. 21. Andress JL, Day TK, Day DG: The effects of consecutive day propofol anesthesia on feline red blood cells, Vet Surg 24(3):277-282, 1995. 22. Bley CR, Roos M, Price J, et al: Clinical assessment of repeated propofolassociated anesthesia in cats, J Am Vet Med Assoc 231(9):1347-1353, 2007. 23. Vasile B, Rasulo F, Candiani A, Latronico N: The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome, Intensive Care Med 29(9):1417-1425, 2003. 24. Ferré PJ, Pasloske K, Whittem T, Ranasinghe MG, Li Q, Lefebvre HP: Plasma pharmacokinetics of alfaxalone in dogs after an intravenous bolus of Alfaxan-CD RTU, Vet Anaesth Analg 33(4):229-236, 2006. 25. Muir W, Lerche P, Wiese A, Nelson L, Pasloske K, Whittem T: Cardiorespiratory and anesthetic effects of clinical and supraclinical doses of alfaxalone in dogs, Vet Anaesth Analg 35(6):451-462, 2008. 26. Maddern K, Adams VJ, Hill NAT, Leece EA: Alfaxalone induction dose following administration of medetomidine and butorphanol in the dog, Vet Anaesth Analg 37(1):7-13, 2010. 27. Maney JK, Shepard MK, Braun C, Cremer J, Hofmeister EH: A comparison of cardiopulmonary and anesthetic effects of an induction dose of alfaxalone or propofol in dogs, Vet Anaesth Analg 40(3):237-244, 2013. 28. Herbert GL, Bowlt KL, Ford-Fennah V, Covey-Crump GL, Murrell JC: Alfaxalone for total intravenous anaesthesia in dogs undergoing ovariohysterectomy: a comparison of premedication with acepromazine or dexmedetomidine, Vet Anaesth Analg 40(2):124-133, 2013. 29. Suarez MA, Dzikiti BT, Stegmann FG, Hartman M: Comparison of alfaxalone and propofol administered as total intravenous anaesthesia for ovariohysterectomy in dogs, Vet Anaesth Analg 39(3):236-244, 2012. 30. Whittem T, Pasloske KS, Heit MC, Ranasinghe MG: The pharmacokinetics and pharmacodynamics of alfaxalone in cats after single and multiple

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intravenous administration of Alfaxan® at clinical and supraclinical doses, J Vet Pharmacol Ther 31(6):571-579, 2008. 31. Amengual M, Flaherty D, Auckburally A, Bell AM, Scott EM, Pawson P: An evaluation of anaesthetic induction in healthy dogs using rapid intravenous injection of propofol or alfaxalone, Vet Anaesth Analg 40(2):115-123, 2013. 32. Ambros B, Duke-Novakovski T, Pasloske KS: Comparison of the anesthetic efficacy and cardiopulmonary effects of continuous rate infusions of alfaxalone-2-hydroxypropyl-beta-cyclodextrin and propofol in dogs, Am J Vet Res 69(11):1391-1398, 2008. 33. Raisis AL, Smart L, Drynan E, Hosgood G: Cardiovascular function during maintenance of anaesthesia with isoflurane or alfaxalone infusion in greyhounds experiencing blood loss, Vet Anaesth Analg 42(2):133-141, 2015. 34. Schafer J: Freedom of information summary: supplemental new animal drug application nada 141-342 Alfaxan® Multidose (alfaxalone) Injectable Solution Cats and Dogs, 2018. Available at: https://animaldrugsatfda.fda. gov/adafda/app/search/public/document/downloadFoi/3739. 35. Pascoe PJ, Ilkiw JE, Haskins SC, Patz JD: Cardiopulmonary effects of etomidate in hypovolemic dogs, Am J Vet Res 53(11):2178-2182, 1992. 36. Dodam JR, Kruse-Elliott KT, Aucoin DP, Swanson CR: Duration of etomidate-induced adrenocortical suppression during surgery in dogs, Am J Vet Res 51(5):786-788, 1990. 37. Moon PF: Cortisol suppression in cats after induction of anesthesia with etomidate, compared with ketamine-diazepam combination, Am J Vet Res 58(8):868-871, 1997. 38. Morris C, McAllister C: Etomidate for emergency anaesthesia; mad, bad and dangerous to know? Anaesthesia 60(8):737-740, 2005. 39. Fierro MA, Bartz RR: Management of sedation and paralysis, Clin Chest Med 37(4):723-739, 2016. 40. Tedders KM, McNorton KN, Edwin SB: Efficacy and safety of analgosedation with fentanyl compared with traditional sedation with propofol, Pharmacotherapy 34(6):643-647, 2014. 41. Sano T, Nishimura R, Kanazawa H, et al: Pharmacokinetics of fentanyl after single intravenous injection and constant rate infusion in dogs, Vet Anaesth Analg 33(4):266-273, 2006. 42. Murrell JC, van Notten RW, Hellebrekers LJ: Clinical investigation of remifentanil and propofol for the total intravenous anaesthesia of dogs, Vet Rec 156(25):804-808, 2005. 43. Musk GC, Flaherty DA: Target-controlled infusion of propofol combined with variable rate infusion of remifentanil for anaesthesia of a dog with patent ductus arteriosus, Vet Anaesth Analg 34(5):359-364, 2007. 44. Vaughn RL, Bennett CR: Fentanyl chest wall rigidity syndrome—a case report, Anesth Prog 28(2):50-51, 1981. 45. Robinson R, Borer-Weir K: A dose titration study into the effects of diazepam or midazolam on the propofol dose requirements for induction of general anaesthesia in client owned dogs, premedicated with methadone and acepromazine, Vet Anaesth Analg 40(5):455-463, 2013. doi:10.1111/vaa.12052. 46. Seddighi R, Egger CM, Rohrbach BW, Cox SK, Doherty TJ: The effect of midazolam on the end-tidal concentration of isoflurane necessary to prevent movement in dogs, Vet Anaesth Analg 38(3):195-202, 2011. doi:10.1111/j.1467-2995.2011.00615.x. 47. Court MH, Greenblatt DJ: Pharmacokinetics and preliminary observations of behavioral changes following administration of midazolam to dogs, J Vet Pharmacol Ther 15(4):343-350, 1992. 48. Ilkiw JE, Suter CM, Farver TB, McNeal D, Steffey EP: The behaviour of healthy awake cats following intravenous and intramuscular administration of midazolam, J Vet Pharmacol Ther 19(3):205-216, 1996. 49. Wilson KC, Reardon C, Theodore AC, Farber HW: Propylene glycol toxicity: a severe iatrogenic illness in ICU patients receiving IV benzodiazepines: a case series and prospective, observational pilot study, Chest 128(3):1674-1681, 2005. 50. Riker RR, Shehabi Y, Bokesch PM, et al: Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial, JAMA 301(5): 489-499, 2009. 51. Escobar A, Pypendop BH, Siao KT, Stanley SD, Ilkiw JE: Effect of dexmedetomidine on the minimum alveolar concentration of isoflurane in cats, J. Vet Pharmacol Ther 35(2):163-168, 2012. 52. Pascoe PJ, Raekallio M, Kuusela E, McKusick B, Granholm M: Changes in the minimum alveolar concentration of isoflurane and some

cardiopulmonary measurements during three continuous infusion rates of dexmedetomidine in dogs, Vet Anaesth Analg 33(2):97-103, 2006. 53. Valtolina C, Robben JH, Uilenreef J, et al: Clinical evaluation of the efficacy and safety of a constant rate infusion of dexmedetomidine for postoperative pain management in dogs, Vet Anaesth Analg 36(4):369-383, 2009. 54. Lin GY, Robben JH, Murrell JC, Aspegrén J, McKusick BC, Hellebrekers LJ: Dexmedetomidine constant rate infusion for 24 hours during and after propofol or isoflurane anaesthesia in dogs, Vet Anaesth Analg 35(2): 141-153, 2008. 55. Chen C, Zhang Z, Chen K, Zhang F, Peng M, Wang Y: Dexmedetomidine regulates inflammatory molecules contributing to ventilator-induced lung injury in dogs, J Surg Res 187(1):211-218, 2014. 56. Popovic NA, Mullane JF, Yhap EO: Effects of acetylpromazine maleate on certain cardiorespiratory responses in dogs, Am J Vet Res 33(9): 1819-1824, 1972. 57. Coulter DB, Whelan SC, Wilson RC, Goetsch DD: Determination of blood pressure by indirect methods in dogs given acetylpromazine maleate, Cornell Vet 71(1):75-84, 1981. 58. Neto AS, Pereira VGM, Espósito DC, Damasceno MCT, Schultz MJ: Neuromuscular blocking agents in patients with acute respiratory distress syndrome: a summary of the current evidence from three randomized controlled trials, Ann Intensive Care 2(1):33, 2012. 59. Alhazzani W, Alshahrani M, Jaeschke R, et al: Neuromuscular blocking agents in acute respiratory distress syndrome: a systematic review and meta-analysis of randomized controlled trials, Crit Care 17(2):R43, 2013. 60. Shekerdemian L, Bohn D: Cardiovascular effects of mechanical ventilation, Arch Dis Child 80(5):475-480, 1999. 61. Vassilev E, McMichael M: An overview of positive pressure ventilation, J Vet Emerg Crit Care 14(1):15-21, 2004. 62. Pham T, Brochard LJ, Slutsky AS: Mechanical ventilation: state of the art, Mayo Clin Proc 92(9):1382-1400, 2017. 63. Hess D, Kacmarek RM: Essentials of mechanical ventilation, ed 4, New York, 2019, McGraw-Hill Education. 64. Madger S: Hemodynamic monitoring in the mechanically ventilated patient, Curr Opin Crit Care 17(1):36-42, 2011. 65. Hoareau GL, Mellema MS, Silverstein DC: Indication, management, and outcome of brachycephalic dogs requiring mechanical ventilation: brachycephalic dogs and mechanical ventilation, J Vet Emerg Crit Care 21(3):226-235, 2011. 66. Frazier SK: Cardiovascular effects of mechanical ventilation and weaning, Nurs Clin North Am 43(1):1-15, 2008. 67. Mellema MS, Haskins SC: Weaning from mechanical ventilation, Clin Tech Small Anim Pract 15(3):157-164, 2000. 68. Bekos V, Marini JJ: Monitoring the mechanically ventilated patient, Crit Care Clin 23(3):575-611, 2007. 69. Jubran A, Tobin MJ: Monitoring during mechanical ventilation, Clin Chest Med 17(3):453-473, 1996. 70. Farrell KS, Hopper K, Cagle LA, Epstein SE: Evaluation of pulse oximetry as a surrogate for PaO2 in awake dogs breathing room air and anesthetized dogs on mechanical ventilation, J Vet Emerg Crit Care 29(6): 622-629, 2019. 71. Khemani RG, Thomas NJ, Venkatachalam V, et al: Comparison of SpO2 to PaO2 based markers of lung disease severity for children with acute lung injury, Crit Care Med 40(4):1309-1316, 2012. 72. Walsh BK, Crotwell DN, Restrepo RD: Capnography/capnometry during mechanical ventilation: 2011, Respir Care 56(4):503-509, 2011. 73. Neto FJT, Carregaro AB, Mannarino R, Cruz ML, Luna SPL: Comparison of a sidestream capnograph and a mainstream capnograph in mechanically ventilated dogs, J Am Vet Med Assoc 221(11):1582-1585, 2002. 74. Marshall M: Capnography in dogs. The compendium on continuing education for the practicing veterinarian: 760-778, 2004. 75. Thompson JE, Jaffe MB: Capnographic waveforms in the mechanically ventilated patient, Respir Care 50(1):100-108, 2005. 76. Pypendop BH: Capnography. In Silverstein DC, Hopper K, editors: Small animal critical care medicine, ed 2, St Louis, 2015, Saunders, Elsevier, pp 994-997. 77. Morley TF, Giaimo J, Maroszan E, et al: Use of capnography for assessment of the adequacy of alveolar ventilation during weaning from mechanical ventilation, Am Rev Respir Dis 148(2):339-344, 1993.

37 Nursing Care of the Ventilator Patient Simon P. Hagley, BVSc, DACVECC, Steven E. Epstein, DVM, DACVECC KEY POINTS • Long-term ventilation requires specialized equipment, 24-hour one-on-one nursing care, and intensive monitoring. • Artificial airway selection, placement, and management play an important role in ventilated patient outcome. • Ventilator-associated pneumonia is a potentially fatal complication, and the risk of development can be reduced with detailed management strategies.

• Each body system should be evaluated on a daily basis to ensure that optimal care for each organ system is provided.

Mechanical ventilation, either short term (,24 hours) or long term (days to months), is becoming increasingly common in small animal practice. Much of the success or failure of this intervention is due not only to the physiological effects of positive-pressure ventilation but also the nursing care that goes along with it. Because most of these patients are anesthetized, many of the normal homeostatic functions of the body are compromised, creating potential complications for the patient. Care of the ventilator patient is aimed at minimizing these complications. With short-term ventilation, the care provided may not need to be as intense; however, long-term ventilation requires specialized care for optimal success. It has been suggested that humans requiring short-term ventilation have better outcomes than patients requiring long-term ventilation.1 Multiple complications associated with long-term ventilation have been documented, many of which relate to issues in nursing care.2 These include oral and corneal ulceration, tracheal tube occlusion or dislodgement, and gastric distention requiring decompression. The importance of nursing care for ventilator patients is emphasized in human medicine because the risk of late-onset, but not early-onset, ventilator-associated pneumonia (VAP) is affected by a lower nurse staffing level.3 Ideally each patient on the ventilator will have a dedicated veterinary technician at all times. The focus of this chapter is to review the basic concepts regarding nursing care of the ventilator patient. Creation of a checklist of topics covered in this chapter is encouraged as nursing care is multifaceted and if infrequently performed, steps may be missed.

Placement of an arterial catheter allows continuous blood pressure monitoring and arterial blood gas analysis, which should be performed every 4 to 8 hours or more frequently if indicated. For further information on monitoring please see Chapter 36. Ventilator patients may suffer from either hyper- or hypothermia. Patients that develop asynchrony with the ventilator are prone to having elevations in body temperature because of increased heat production from muscular effort. This may be treated by improving ventilator–patient synchrony, using surface cooling methods (e.g., placement of a fan or use of a cold-water spray bottle), or turning off or removing the humidification system. Removal of airway humidification should only be performed for short periods because humidification is key to airway management (see later section). Hypothermia may occur as a side effect of anesthetic agents and should be treated with circulating warm-water blankets and forced-air warming devices or by covering the patient with a blanket to reduce heat loss, depending on the degree of hypothermia.

GENERAL MONITORING Ventilator patients need intensive monitoring for optimal chances of success in liberation from mechanical ventilation. Ideal monitoring includes continuous electrocardiography, placement of a rectal thermistor for continuous temperature assessment, pulse oximetry, capnography, and serial blood pressure measurements. Auscultation of the chest and a cardiovascular physical examination should be performed at least every 4 hours to detect abnormalities as early as possible.

AIRWAY MANAGEMENT Artificial Airway Patients undergoing mechanical ventilation need intubation with either an endotracheal (ET) tube or a tracheostomy tube, with the majority of patients having intubation via the oral route (see Chapter 197). It is important to note that whenever a patient with an artificial airway is being handled, hand hygiene should be performed first, and examination gloves used; this is particularly important when the airway itself is being manipulated to reduce the risk of nosocomial infection. The intubation process should be performed with sterile gloves, ideally with a sterile ET tube. Endotracheal tube cuffs can be either high or low volume and high or low pressure; however, in veterinary medicine, size will likely restrict these options to low-volume, high-pressure or high-volume, low-pressure cuffs. The use of low-pressure cuffs is recommended because cuff pressure greater than 25 cm H2O has been shown to reduce tracheal blood flow, which can lead to necrosis, and cuff pressures greater than 30 cm H2O should be avoided.4 The use of a cuff pressure

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monitoring device (commercially available or constructed in-house), which can directly measure cuff pressure, is recommended to help prevent tracheal damage. As a precautionary measure to reduce the risk of tracheal injury, it has been suggested to deflate the cuff and reposition it every 4 hours in veterinary medicine.5 However, to help prevent VAP, the American Thoracic Society recommends that cuff pressure be maintained at more than 20 cm H2O.6 The risk of tracheal necrosis versus the risk of VAP should be weighed in each individual patient. The authors recommend the following guidelines: if a high-volume low-pressure ET tube is used and the cuff pressure can be monitored, then the cuff should not be deflated and repositioned, but the cuff pressure should be checked every 4 hours. If a low-volume high-pressure ET tube is used (e.g., for cats and small dogs) or if cuff pressure cannot be monitored, then the cuff should be deflated and repositioned every 4 hours. Before deflation and repositioning, oral care and suctioning should be performed to reduce the risk of aspiration. The ET tube should be secured with a nonporous material such as plastic intravenous tubing. Gauze exposed to oral secretions provides a growth medium for bacteria. The tie used to secure the ET tube should be retied every 4 hours to prevent damage to the lips and should be replaced every 24 hours to help prevent biofilm accumulation. The decision to change the ET tube must be made on an individual patient basis. Reintubation has been shown to increase the risk of VAP in humans, whereas ET tube occlusion has been reported to occur in up to 14% of animals.2 Patients with exudative pulmonary secretions and smaller diameter ET tubes put them at risk for occlusion and may benefit from an ET tube change every 24 to 48 hours. Patients being ventilated without significant pulmonary secretions or with relatively large diameter ET tubes may only need ET tube changes on an asneeded basis.

Humidification Patients undergoing long-term ventilation need humidification of the airways. Lack of humidification leads to increased mucus viscosity and inspissation, which can cause ET tube occlusion, tracheal inflammation, and depressed ciliary function. There are two major methods of humidification of the airways: heat and moisture exchangers (HMEs) and heated water humidifiers. Passive HMEs act as an artificial nose by trapping the heat and moisture of exhaled air in the device and then returning them on the following inspiration. HMEs increase dead space and resistance to airflow. They also have the potential to become obstructed by airway secretions and are often avoided in patients that have copious or tenacious pulmonary secretions. HMEs should not be routinely changed more frequently than every 48 hours unless they become soiled, obstructed, or mechanically fail.7 Ventilator waveforms can be evaluated for increased resistance, indicating a partially occluded HME (see Chapter 35). Heated water humidifiers were traditionally considered the gold standard. These are placed in the inspiratory limb of the breathing circuit and allow air to be humidified by passing a heated water reservoir. Potential complications include overheating and condensation of water in the inspiratory limb, which contributes to bacterial colonization of the breathing circuit. Condensation in the circuit can be largely prevented by the use of heated wire circuits. The ideal type of humidifier is unknown, with each type having benefits and complications. The decision of which type to use should be made on availability, expected level of secretions, and concerns of increased dead space and resistance to the breathing circuit.

Airway Suctioning Suctioning of the airway is of key importance to help prevent ET tube occlusion with airway secretions. In the awake patient, coughing helps

clear secretions; however, the cough reflex is blunted or absent in the anesthetized patient. Suctioning can be performed by either an open or closed-system suction method. At this time, there is no consensus as to whether suctioning should be regularly scheduled or performed on an as-needed basis; however, with smaller ET tubes suctioning may help prevent occlusion from airway secretions. The ideal catheter should be soft and flexible, have more than one distal opening, be sterile, and occlude no more than 50% of the internal diameter of the ET tube. Before suctioning, the patient should be preoxygenated with 100% oxygen for at least 5 minutes to help prevent hypoxemia during the process. With open suctioning, sterile gloves should always be worn by the person manipulating the suction catheter. A second person wearing nonsterile gloves should disconnect the breathing circuit from the ET tube to facilitate sterile insertion of the catheter, which should be inserted to the distal end of the ET tube. Insertion of the catheter farther than the distal opening of the ET tube risks tracheal inflammation, induction of coughing, or vagal-mediated bradycardia. The process should be quick, with the catheter partially occluding the lumen of the ET tube for no more than 10 to 15 seconds per suction pass. The procedure should be repeated multiple times until secretions are no longer aspirated, with the patient being reconnected to the ventilator in between each suction pass. Sterile saline should be poured into a sterile cup so the suction catheter can be cleansed between suction passes. A new cup is used each time to avoid bacterial contamination of the residual saline container. Closed-system suction catheters are kept in place between the breathing circuit and the patient when not in active use. They have the advantage that the circuit does not have to be opened for suctioning, thereby reducing the risk of contamination; however, they will increase the dead space of the circuit. If either an open or closed system is used, the suction canister and tubing should be replaced every 24 hours to minimize the chance of bacterial colonization. The addition of sterile saline to the airway to facilitate mucus recovery during suctioning remains controversial. Before suctioning, instillation of 0.1 to 0.2 ml/kg of 0.9% NaCl into the airway can be considered to help mobilize dry secretions. Concerns of saline instillation center around dislodging bacteria from the ET tube and promoting VAP as well as inducing hypoxemia. The benefit may be more effective removal of secretions, which may reduce the likelihood of VAP. If the patient has a tracheostomy tube, all of these procedures apply, with the addition of routine care as discussed in Chapter 197. Suctioning either an ET tube or tracheostomy tube carry possible risks. These include iatrogenic hypoxemia, collapse of alveoli as a result of temporary lack of positive end-expiratory pressure, tracheal irritation, bradycardia, and hypotension. The patient should have continuous pulse oximetry and electrocardiogram monitoring during the procedure. If hypoxemia or bradycardia develops, the suctioning process should be aborted and the breathing circuit reconnected.

ORAL CARE Patients anesthetized for prolonged periods can develop a significant number of complications involving the oral cavity.8 These include oral ulceration, ranula formation, and reflux of gastric contents into the oral cavity. Anesthesia inhibits the swallowing reflex, which allows for pooling of secretions in the caudal oral and pharyngeal cavities. Swallowing normally helps prevent the accumulation of bacteria within the oral cavity and prevents desiccation of oral mucous membranes. To help prevent drying of the tongue, it is usually moistened with an alternating dilute glycerin-soaked or saline-soaked gauze. Avoid wrapping the tongue circumferentially with gauze because this can lead to ranula formation. The authors prefer to not to leave the gauze indwelling and

CHAPTER 37  Nursing Care of the Ventilator Patient elect for moistening the tongue as part of fastidious oral care every 4 hours. A lack of swallowing also allows for bacteria to proliferate and pool in secretions around the endotracheal tube, increasing the risk for VAP. Meticulous oral care focusing on subglottic suctioning and selective oral decontamination has been shown to decrease the incidence of VAP and oral lesions. Whenever the oral cavity is to be handled, proper hand hygiene, including hand washing and wearing of examination gloves, is recommended. Oral care should be performed every 4 hours. The tongue should be inspected for development of a ranula. If a ranula is forming, elevating the ET tube to avoid causing pressure on the base of the tongue may be helpful. Care to avoid placement of the tongue over the teeth, as well as the use of a mouth gag, may help prevent ulceration. The entire oral cavity should be inspected for mucosal ulcerations and any identified should be recorded in both depth and size. In addition to the aforementioned assessments, oral care consists of removing the pulse oximeter probe and any mouth gag and cleaning of them with a dilute 0.12-2% chlorhexidine solution. The entire oral cavity should then be cleansed with a specifically formulated 0.12-2% chlorhexidine solution branded for such purposes. The oral cavity and caudal oropharynx should be gently suctioned, removing remaining chlorhexidine solution and oral secretions and avoiding excess stimulation, which may induce regurgitation. Brushing of the teeth twice daily can reduce the oral bacterial load and may be considered, but no beneficial effect over chlorhexidine antisepsis has been established.9 The mouth gag and pulse oximeter are then replaced in a different position to help prevent ulceration.

EYE CARE Ventilator patients are at increased risk of exposure keratopathy and microbial keratitis. Because they do not blink, the tear film cannot be spread over the cornea adequately, compromising the health of the eye. Additionally, many patients have lagophthalmos, predisposing them to exposure keratopathy. Despite eye care, up to 25% of children and 37.5% of adults on mechanical ventilation may develop ocular surface disorders.10,11 The majority of ulceration develops within the first week; however, a significant proportion can develop within 48 hours of initiation of mechanical ventilation. There are two major methods of providing lubrication to the eye: use of lubricating ointments or moisture chambers. A moisture chamber such as Doggles® or swimmer’s goggles completely seals off the eye from the environment. The advantage of this method is that the cornea is protected even if the eye is open. Repetitive lubrication involves regular cleaning of the eye with sterile saline and replacement with a hyaluronic acid-containing, petroleum-based lubricant every 2 hours (see Chapter 144). A recent meta-analysis of human eye care in the ICU showed that use of the moisture chamber was superior in preventing exposure keratopathies compared with lubricating ointments.12 Similarly, a single-centered pilot study reported limited progression of a keratopathy and improved healing with use of bandage contact lenses compared with lubricating treatments in mechanically ventilated adults.13 Although anecdotal evidence exists for the use of bandage contact lenses in ventilated veterinary patients, prospective studies are required before this can be recommended. Because of the difficulty in obtaining a good seal from a moisture chamber with the various skull structures of dogs and cats, lubricating ointment is still considered the standard of care. Eye care should be performed every 2 hours. The eye should be lavaged with sterile saline and inspected for chemosis, corneal disease, and conjunctivitis. Fluorescein staining should be performed every 24 hours to evaluate for

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ulcer formation. If no ulceration is present, a petroleum-based lubricant should be reinstilled. If ulceration is present, a broad-spectrum antibiotic ointment should be used every 4 hours. For progressive or deep ulceration, refer to Chapter 144. For some patients with lagophthalmos or exophthalmos, a temporary tarsorrhaphy may be needed. All ocular products should be used for the individual patient, rather than a communal source to reduce the chance of bacterial contamination and spread.

URINARY CARE Patients undergoing short-term ventilation should have their bladders palpated every 4 to 6 hours and expressed as needed. Voided urine can be collected in a diaper and weighed to track urinary volumes. If longterm ventilation is indicated, the patient may benefit from urinary catheterization. This avoids the repeated pressure and trauma of expressing the bladder and allows for more accurate documentation of urine volumes. Urinary catheterization can also be considered for any animal whose large size prohibits adequate bladder expression. Urinary catheterization carries the risk of development of bacteriuria either from true urinary tract infection or colonization of the catheter. In dogs the incidence of urinary tract infections associated with indwelling catheterization in nonmyelopathic conditions ranges from 10% to 20%, with length of catheterization being a risk factor.14,15 The incidence of urinary tract infections in dogs with a thoracolumbar myelopathy was not different with indwelling versus intermittent catheterization or manual expression.16 Urinary catheter care should be performed every 8 hours as long as an indwelling catheter is in place to minimize the risk of urinary tract infections (see Chapter 208).

GASTROINTESTINAL TRACT CARE Gastrointestinal complications can occur because of mechanical ventilation, including esophagitis, gastrointestinal bleeding, diarrhea, ileus, constipation, gastric distention, and regurgitation. Splanchnic hypoperfusion plays an important role in the development of many of these complications because of diminished venous return from high levels of positive end-expiratory pressure and increased levels of circulating catecholamines or proinflammatory cytokines.17 The incidence of gastrointestinal bleeding in human patients can be as high as 47%, with clinically significant bleeding in 3.3% of patients ventilated for more than 48 hours; however, this is likely lower in cats and dogs as they are less likely to have stress induced gastric ulceration. A modifiable risk factor for bleeding identified was a peak inspiratory pressure 30 cm H2O or greater.18 Using the minimal ventilator settings needed to provide adequate oxygenation and ventilation may improve gastrointestinal health. Enteric nutrition in mechanical ventilation carries both risks and benefits. It has been shown to decrease the incidence of gastrointestinal bleeding and prevent villous atrophy of the intestinal mucosa, thus potentially reducing the risk of bacterial translocation. Enteric nutrition may increase the incidence of gastroesophageal reflux and aspiration pneumonia if ileus is present. The risks versus the benefits and the estimated length of ventilation should be considered before deciding to initiate enteric feeding. Enteral feeding may be delivered via a nasogastric, gastrotomy, or jejunostomy tube. The use of an esophagostomy tube is not recommended for patients on mechanical ventilation as postesophageal feeding may be associated with a decreased risk of aspiration pneumonia. Feeding may be accomplished via continuous delivery or by intermittent bolus. The role of monitoring of gastric residual volumes in ventilated human patients is controversial. Reignier et al.19 showed that in a group of mechanically ventilated people with early enteral feeding,

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the absence of gastric residual volume monitoring did not affect the incidence of patients that developed VAP; however, there was an increased incidence of vomiting and regurgitation in that group. The role of gastric residual volume monitoring in mechanically ventilated dogs and cats is unclear at this time. Ventilated patients may develop either diarrhea or constipation. If diarrhea develops, the perianal region should be kept clean and dry. To evaluate for constipation, the colon should be palpated daily. If constipation is noted, enemas may be needed to evacuate the colon.

RECUMBENT PATIENT CARE Prolonged recumbency can induce decubital ulcers, tissue necrosis, atelectasis, muscle and ligament contracture, and regional dependent edema.5 To minimize these complications, patients should be kept on well-padded bedding at all times, and limbs should not be allowed to hang over the edge of the table. With giant breed dogs, ventilation on the floor should be considered if a large enough table is not accessible. Passive range of motion should be performed every 4 hours, including the flexion and extension of every joint in the limbs as distal as the phalanges. ICU-acquired weakness and critical illness neuromyopathy are also possible sequelae in long-term ventilation in humans but have not been documented in clinical veterinary medicine. After passive range of motion is performed, the position of recumbency should also be changed every 4 hours, alternating between sternal and each lateral position, if the patient’s oxygenation status will tolerate it. If lateral recumbency is not possible, then the patient can be kept in sternal recumbency and the hips of the patient moved from right side down to left side down every 2 to 4 hours. Special attention for ulcer formation at the elbows or for development of dermal lesions in the antebrachium is needed if the cranial half of the patient is always in sternal recumbency. For patients ventilated on a table that tilts, the ideal tilt for the table has yet to be determined. The current recommendation in human medicine is to elevate the torso 30 to 45 degrees. Ventilation with the trachea elevated above horizontal is thought to decrease gastroesophageal reflux, whereas ventilation with the trachea below horizontal may prevent aspiration of oropharyngeal secretions into the trachea. In a porcine model of sternal recumbency, all pigs with the trachea elevated 45 degrees above horizontal developed pneumonia, whereas none of the pigs with the trachea oriented 10 degrees below horizontal did.20 At this time ventilation with the trachea elevated 45 degrees cannot be recommended in veterinary medicine. It seems reasonable to keep patients in a neutral horizontal position until further research is performed.

APPARATUS CARE Part of caring for a patient on the ventilator also includes caring for the equipment. The ventilator circuit should be sterilized before use and put together wearing sterile gloves to minimize the chance of nosocomial infections. The ideal length of time for the use of a single ventilator circuit has not been established. A meta-analysis showed an increased risk of pneumonia when circuits were changed every 2 days versus every 7 days, and the absence of routine changing of the ventilator circuit did not increase the odds of VAP.21 Based on these findings, it seems safe to only change the circuit if gross contamination is noted rather than as a routine precaution. If frequent condensation occurs in the circuit due to use of a heated water humidifier, then more frequent circuit changes may be indicated.

REFERENCES 1. Feng Y, Amoateng-Adjepong Y, Kaufman D, et al: Age, duration of mechanical ventilation, and outcomes of patients who are critically ill, Chest 136(3):759, 2009. 2. Hopper K, Haskins SC, Kass PH, et al: Indication, management, and outcome of long-term positive-pressure ventilation in dogs and cats: 148 cases (1990-2001), J Am Vet Med Assoc 230:64, 2007. 3. Hugonnet S, Uckay I, Pittet D: Staffing level: a determinant of late-onset ventilator-associated pneumonia, Crit Care 11:R80, 2007. 4. Seegobin RD, van Hasselt GL: Endotracheal cuff pressure and tracheal mucosal blood flow: endoscopic study of the effects of four large volume cuffs, Br Med J 288:965, 1984. 5. Haskins SC, King LG: Positive-pressure ventilation. In King LG, editor: Textbook of respiratory disease in dogs and cats, St Louis, 2004, Saunders. 6. American Thoracic Society, Infectious Diseases Society of America: Guidelines for the management of adults with hospital-acquired, ventilator-associated and healthcare-associated pneumonia, Am J Respir Crit Care Med 171:388, 2005. 7. CDC: Guidelines for preventing health-care-associated pneumonia, Respiratory Care 49(8):926, 2004. 8. Fudge M, Anderson JG, Aldrich J, et al: Oral lesions associated with orotracheal administered mechanical ventilation in critically ill dogs, J Vet Emerg Crit Care 7:79, 1997. 9. Hua F, Xie H, Worthington HV, et al: Oral hygiene care for critically ill patients to prevent ventilator-associated pneumonia, Cochrane Database Syst Rev 10:1, 2016. 10. Dawson D: Development of a new eye care guideline for critically ill patients, Intensive Crit Care Nurs 21:119, 2005. 11. Germano EM, Mello MJG, Sena DF, et al: Incidence and risk factors for corneal epithelial defects in mechanically ventilated children, Crit Care Med 37:1097, 2009. 12. Rosenberg JB, Eisen LA: Eye care in the intensive care unit: narrative review and meta-analysis, Crit Care Med 36:3151, 2008. 13. Bendavid I, Avisar I, Serov-Volach I, et al: Prevention of exposure keratopathy in critically Ill patients: a single-center, randomized, pilot trial comparing ocular lubrication with bandage contact lenses and punctal plugs, Crit Care Med 45:1880, 2017. 14. Smarick SD, Haskins SC, Aldrich J, et al: Incidence of catheter-associated urinary tract infection among dogs in a small animal intensive care unit, J Am Vet Med Assoc 224:1936, 2004. 15. Ogeer-Gyles J, Mathews K, Weese JS, et al: Evaluation of catheter-associated urinary tract infections and multi-drug-resistant Escherichia coli isolate from the urine of dogs with indwelling urinary catheters, J Am Vet Med Assoc 229:1584, 2006. 16. Bubenik L, Hosgood G: Urinary tract infection in dogs with thoracolumbar intervertebral disc herniation and urinary bladder dysfunction managed by manual expression, indwelling catheterization or intermittent catheterization, Vet Surg 37:791, 2008. 17. Mutlu GM, Mutlu EA, Factor P: GI complications in patients receiving mechanical ventilation, Chest 119:1222, 2001. 18. Chu Y, Jiang Y, Meng M, et al: Incidence and risk factors of gastrointestinal bleeding in mechanically ventilated patients, World J Emerg Med 1:32, 2010. 19. Reignier J, Mercier E, Le Gouge A, et al: Effect of not monitoring residual gastric volume on risk of ventilator-associated pneumonia in adults receiving mechanical ventilation and early enteral feeding, J Am Med Assoc 309:249, 2013. 20. Zanella A, Cressoni M, Epp M, et al: Effects of tracheal orientation on development of ventilator-associated pneumonia: an experimental study, Intensive Care Med 38:677, 2012. 21. Han J, Liu Y: Effect of ventilator circuit changes on ventilator-associated pneumonia: a systematic review and meta-analysis, Respir Care 55:467, 2010.

38 Discontinuing Mechanical Ventilation Kate Hopper, BVSc, PhD, DACVECC

KEY POINTS • After short-term mechanical ventilation (,48 hours), an animal may be rapidly weaned without gradual reductions in ventilator settings. • Weaning of animals after longer periods of mechanical ventilation involves a process of stepwise reduction at the level of ventilator support and the use of daily spontaneous breathing trials. • Daily spontaneous breathing trials are recommended as soon as patients attain certain physiological criteria.

• Anesthetic management is a key aspect of successful weaning of the veterinary patient. Placement of a tracheostomy tube may facilitate weaning in some patients. • Intensive monitoring is necessary after discontinuing mechanical ventilation. Weaning failures require immediate action to prevent life-threatening complications and maximize future success.

Weaning or liberation from mechanical ventilation is the transition from machine support of breathing to spontaneous breathing. Evidence-based guidelines for ventilator weaning are available in human medicine, but there is little veterinary-specific information available.1 In many animals receiving short-term ventilator support that have rapidly resolving disease processes, discontinuation is simply a matter of discontinuing anesthesia and disconnecting the patient from the ventilator. Patients receiving mechanical ventilation for longer periods (greater than 2 to 3 days) and those with complex disease processes are likely to require a true weaning process. Mechanical ventilation exposes patients to numerous potential complications in addition to the associated cost of care (see Chapter 39, Ventilator Induced Lung Injury). As such, discontinuation of ventilation is a priority. Clinicians must balance potential ventilator-induced complications with the risks associated with premature removal of ventilator support, which can lead to cardiovascular collapse and/or respiratory failure. Extubation failure in human patients has been associated with increased risk of nosocomial pneumonia and a 6 to 12 times increase in mortality risk.2,3 Successful weaning has variable definitions in the human literature. An International Consensus Conference in 2007 defined it as “extubation not requiring reinstitution of ventilatory support in the 48 hours after extubation”.4 A more recent WIND classification scheme for weaning defined it as “extubation without death or reintubation within 7 days of extubation”.5 There is no consistent definition of successful weaning in the veterinary literature at this time.

Numerous coexisting factors can reduce the likelihood of successful weaning as outlined in Box 38.1. These include increased work of breathing from reduced chest wall or lung compliance and cardiovascular compromise.6 Adequate oxygen delivery is required to support effective respiratory muscle function. In addition, withdrawal of ventilator support results in increased afterload and preload to the left ventricle, which can be detrimental to animals with significant myocardial dysfunction.7 The weaning process must include the evaluation of patient readiness in addition to close monitoring during the period following discontinuation of ventilation, as there is no way to predict with certainty if weaning will be successful. It is important that patients attain certain physiologic goals before ventilator weaning is attempted. A set of criteria used in human patients to identify readiness to wean can be readily applied to veterinary patients (Box 38.2).6 The original disease process necessitating mechanical ventilation should be stable or improving. The patient needs an adequate respiratory drive and should no longer be dependent on significant ventilator support for adequate gas exchange. Adequate oxygenation, as evidenced by a partial pressure of oxygen: fraction of inspired oxygen (PaO2:FiO2) ratio of at least 150 to 200, is recommended before initiating weaning. A requirement for high inspired oxygen levels (.50%), high peak inspired airway pressures (.25 cm H2O), and high positive end-expiratory pressure levels (.5 cm H2O) to maintain oxygenation should preclude any weaning attempts. Weaning is not advised in animals that are hemodynamically unstable or have severe systemic disease such as organ dysfunction. It is recommended that patients are assessed daily for suitability for weaning (the “daily wean screen”) using these criteria.8 Patients that meet the criteria for weaning are then evaluated with a spontaneous breathing trial (SBT), discussed further below, to determine if discontinuation of ventilation can be attempted. Many human medical studies have demonstrated that the use of a weaning protocol that includes a daily standardized assessment of the readiness to wean reduces duration of ventilation compared with standard practice, which generally relies on clinician judgment to determine the time of weaning. However, there is a lack of consistency between these studies, which limits the ability to generalize the results.9

WHEN TO WEAN There are two main reasons why weaning may not be successful. The first is that the underlying disease process requiring ventilation has not improved sufficiently and the second is acquired respiratory muscle weakness that develops during controlled mechanical ventilation. Inadequate recovery from anesthetic and sedative agents and/or neuromuscular blocking agents can also be a cause of unsuccessful weaning and careful management of drug administration and anesthetic depth is an essential aspect of the weaning process.

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BOX 38.1  Common Factors Reducing the

Likelihood of Successful Ventilator Weaning Lack of resolution of primary disease process Acquired respiratory muscle weakness Inadequate recovery from anesthetic and sedative drugs and/or neuromuscular blocking agents Increased work of breathing • Increased airway resistance • Upper airway disease • Lower airway collapse • Bronchoconstriction • Decreased lung compliance • Pulmonary edema • Pulmonary fibrosis • Restrictive lung disease • Decreased chest wall compliance • Obesity • Abdominal distension • Chest wall deformity Cardiovascular instability • Myocardial dysfunction • Hypotension

BOX 38.2  Criteria for Readiness for a Spontaneous Breathing Trial6,20 • Improvement in the primary disease process • PaO2:FiO2 ratio .150–200 with FiO2 ,0.5 • PEEP #5 cm H2O • Adequate respiratory drive • Hemodynamic stability • Absence of major organ failure FiO2, fraction of inspired oxygen (0.21–1.0); PaO2, partial pressure of arterial oxygen (mm Hg); PEEP, positive end-expiratory pressure.

Acquired respiratory muscle weakness can be a cause of weaning failure in patients despite meeting the criteria. Prolonged mechanical ventilation (longer than 48 hours) can cause inspiratory muscle weakness that is proportional to the duration of ventilation.10 In addition, short-term controlled mechanical ventilation can cause decreased diaphragmatic force-generating capacity, also known as ventilator-induced diaphragmatic dysfunction.11 Ventilator strategies that include spontaneous respiratory efforts can reduce diaphragm atrophy, although some degree of diaphragmatic dysfunction is considered inevitable. Several drugs have been proposed as potential therapies for ventilator-induced diaphragmatic dysfunction, most notably theophylline, although the limited studies to date have not consistently shown a benefit.12,13 As a result, sudden discontinuation of mechanical ventilation may be poorly tolerated despite adequate gas exchange. In long-term ventilator patients, the weaning process must force the patient to assume some of the work of breathing to recondition the inspiratory muscles. Further, patients must be monitored closely following discontinuation of ventilation in case respiratory muscle fatigue develops.

ANESTHETIC CONSIDERATIONS In human patients, SBTs are usually performed in awake patients not under the influence of sedatives or anesthesia.14 This is not feasible in

most veterinary patients that require sedation or general anesthesia to maintain endotracheal intubation, control anxiety, and prevent excess mobility. This may be a limitation in translation of human ventilator weaning guidelines to veterinary patients. Having patients in a suitably light plane of anesthesia for any weaning trial is essential for success. Longer term anesthesia with injectable agents can be associated with prolonged recoveries, and modification of the anesthetic protocol in the 12 to 24 hours prior to initiation of weaning trials may aid in the weaning process. Prolonged recoveries are of particular concern in cats following intravenous anesthesia. Reversible drugs such as fentanyl and dexmedetomidine can be beneficial because they provide sedation and contribute to a balanced anesthetic protocol but may be reversed during the weaning process as necessary. See Chapter 36 for further discussion of anesthetic choices.

APPROACHES TO WEANING The longer the duration of mechanical ventilation, the longer the weaning period is likely to take. The process of weaning involves a reduction in the work of breathing performed by the machine with a proportional increase in the work performed by the patient. The actual weaning process is part of the art of mechanical ventilation. Although there are science and guidelines available, clinical judgment plays a substantial role. There are three main approaches to weaning: spontaneous breathing without ventilator support, pressure support ventilation (PSV), and synchronized intermittent mandatory ventilation (SIMV).15

Spontaneous Breathing Trials An SBT involves removing most or all ventilator support and monitoring the patient’s ability to breathe spontaneously. This can be achieved by disconnecting the animal from the machine and allowing it to breathe an enriched and humidified oxygen source (usually with an FiO2 similar to or above the level the patient was receiving while ventilated) via a breathing circuit (such as a Bain circuit) or mask. An alternative approach is to leave the patient connected to the ventilator and switch to a low level (2 to 5 cm H2O) of continuous positive airway pressure (CPAP) with or without PSV. The level of PSV support is usually limited to 5 to 8 cm H2O. The advantage of using a ventilatorbased SBT is that all monitoring and ventilator alarms can remain attached and if the patient fails the trial, ventilatory support can be reestablished rapidly. Spontaneous breathing through the circuit and machine increases the work of breathing compared with spontaneous breathing when disconnected from the circuit; a low level of CPAP or PSV is recommended to compensate for this effect and prevent unnecessary weaning failures.16 Additionally, CPAP reduces the occurrence of atelectasis, which could also reduce the possibility of successful weaning. Atelectasis is likely in sedated patients, especially those with low chest wall compliance such as the obese patient. The concept behind SBTs is to use them as training exercises once the patient is deemed sufficiently stable; there may be no expectation that the patient will be weaned with the initial trial. In human medicine it is recommended that SBTs are at least 30 minutes, but not longer than 120 minutes in duration and performed daily after the patient attains adequate physiologic goals (see Box 38.2). If at any time the patient fails the SBT, ventilation should be reinstituted. If the patient’s ability to tolerate spontaneous breathing at 120 minutes is unclear, return to mechanical ventilation is recommended. It is essential that the animal is closely monitored during the SBT, especially during the initial period as this is when respiratory muscle insufficiency is most likely to occur.17,18

CHAPTER 38  Discontinuing Mechanical Ventilation

BOX 38.3  Criteria for Failure of a

Spontaneous Breathing Trial

• Tachypnea (RR .50) • PaO2 ,60 mm Hg or SpO2 ,90% • PaCO2 .55 mm Hg or PvCO2 .60 mm Hg or ETCO2 .50 mm Hg • Tidal volume ,7 ml/kg • Tachycardia • Hypertension • Hyperthermia or increase in temperature of .1°C • Anxiety • Signs of increased respiratory effort or distress • Clinical judgment ETCO2, end-tidal carbon dioxide; PaCO2, partial pressure of arterial carbon dioxide; PaO2, partial pressure of arterial oxygen; PvCO2, partial pressure of venous carbon dioxide; RR, respiratory rate; SpO2, oxygen saturation.

Monitoring during the SBT includes respiratory rate and effort, blood pressure, heart rate, temperature, and gas exchange. Continuous monitors such as end-tidal carbon dioxide, pulse oximetry, electrocardiogram, and direct arterial blood pressure are recommended when possible. Box 38.3 lists parameters that suggest failure of a SBT and would indicate the need to return to mechanical ventilation. In human medicine, the rapid shallow breathing index (f/VT) has been shown to have some correlation with successful weaning in adults. It is calculated as the ratio of respiratory rate (f) and tidal volume (VT). Those patients who develop increased rapid shallow breathing during a SBT (marked by a higher f/VT ratio) are more likely to fail the weaning trial. A ratio of less than 100 is used in human medicine to identify patients that can be weaned.18 Although this ratio has not been a consistently reliable predictor of weaning outcome.19,20 In veterinary medicine this ratio may be difficult to adapt to our patients given the variability in normal respiratory rates, but a fast, shallow breathing pattern during an SBT should be considered a concern. When a patient fails a SBT, consideration of the factors contributing to ventilator dependence is important. Concurrent anesthetic and sedative drugs are a major confounder in veterinary medicine, and clinician judgment of their role in a SBT failure is essential. If anesthetic drug effects are suspected of impairing effective spontaneous breathing, it may be necessary to allow the animal wake up to assess it appropriately, understanding that this may result in premature extubation. Intensive monitoring and readiness to reintubate if the patient fails the attempt is essential in these situations. Animals failing a SBT should be returned to a ventilator mode that provides respiratory muscle support and ensures appropriate gas exchange. It is optimal to use a mode that allows the patient to use its respiratory muscles, but recovery from the fatigue associated with a SBT is important before trying again. If the patient continues to meet the weaning criteria, a SBT should be repeated in 24 hours. SBTs may be a superior method of weaning from mechanical ventilation compared with SIMV in human patients.21,22 The optimal approach to a SBT remains to be determined. For example, a recent human study reported higher successful extubation and weaning rates with a SBT strategy of 30 minutes of PSV when compared to 120 minutes of spontaneous breathing off the ventilator.23 In veterinary medicine, it is more common to perform an SBT when the patient is considered ready to be removed completely from ventilator support. Evidence from the human literatures suggests that daily SBTs to improve respiratory muscle strength as a prelude to successful weaning could be of benefit to many long-term ventilated small animal patients.

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Synchronized Intermittent Mandatory Ventilation SIMV is another approach to reduce ventilator support gradually. During SIMV there are both mandatory and spontaneous breaths (see Chapter 32, Mechanical Ventilation – Core Concepts). The mandatory breaths are synchronized with the patient’s inspiratory efforts, and the tidal volume of the mandatory breaths is generated totally by the ventilator (controlled ventilation). Between mandatory breaths the patient can breathe spontaneously (with or without PSV). Weaning generally is achieved by a gradual reduction in the mandatory breath rate, which demands a progressive increase in the respiratory work performed by the patient. When the patient can maintain adequate oxygenation and ventilation with minimal machine support, an SBT is performed. If the patient fails the SBT, SIMV is resumed. Patients may require a higher level of machine support than previously needed while recovering from any deleterious effects of the SBT. When first introduced, SIMV was thought to reduce patient–ventilator asynchrony, reduce respiratory muscle fatigue, and expedite weaning. There is now evidence that SIMV may worsen respiratory muscle fatigue. Two well-conducted human trials found SIMV to be the least effective method of ventilator weaning.16,22 In summary, the weaning process for patients after longer periods of mechanical ventilation is generally a process of stepwise reduction in the level of ventilator support and the initiation of daily SBTs once the animal meets the necessary criteria (see Box 38.2). Waiting to perform SBTs until the animal is ready to be completely removed from mechanical ventilation may delay successful weaning.

Noninvasive Ventilation One weaning strategy for human patients used to reduce the likelihood of reintubation following ventilator weaning is transition to noninvasive ventilation. Studies evaluating this approach have had mixed results.24,25 While some studies have demonstrated reduced length of ICU stay and decreased mortality with noninvasive ventilation, others have shown no benefit compared with conventional care. High-flow nasal oxygen therapy is a form of noninvasive ventilation that is feasible in veterinary medicine and may reduce the risk of reintubation after ventilator weaning in some patient populations (see Chapter 31, High Flow Nasal Oxygen).26

WEANING PREDICTION Many indices have been evaluated in human patients to predict the likelihood of successful ventilator weaning.27 These include single physiological parameters in addition to integrated indexes that include multiple parameters. The most studied parameter to date is the rapid shallow breathing index, which is calculated as the ratio of respiratory rate to tidal volume (f/VT). Despite earlier research supporting its use, a randomized controlled trial found use of this index prolonged weaning time.28 The many other indices that have been evaluated in human patients are beyond the scope of this discussion. Several require the patient to make spontaneous inspiratory efforts on command and are clearly not relevant to veterinary patients. Unlike awake human patients, in most circumstances dogs and cats are anesthetized prior to initiation of weaning, which further limits the relevance of many human indices. Despite the many studies on weaning prediction, no index has been found to be accurate enough to rely upon as a single predictor of weaning in human medicine at this time, and none have been evaluated in veterinary patients.27-29 The SBT remains the gold standard for the evaluation of a patient’s readiness to wean.28,29

TRACHEOSTOMY AND WEANING There is ongoing discussion in the human literature regarding the role of tracheostomy in the long-term ventilator patient. Potential benefits

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may include improved oral care, more effective airway suctioning, and improved patient comfort. Other potential advantages in human patients include less laryngeal damage (not a problem recognized in small animal patients) and reduced sedation requirements.30 However in veterinary patients, heavy sedation or anesthesia is required to keep the animal immobile and tolerant of positive pressure ventilation. As such, tracheostomy will not significantly alter the anesthetic management. One exception may be patients with neurologic or neuromuscular diseases causing immobility and respiratory paralysis; in these patients a tracheostomy tube may allow reduction or even complete withdrawal of anesthetic and sedative agents. These patients are commonly managed for the entire ventilation period with a tracheostomy tube. If not, tracheostomy will be beneficial during weaning where gradual reductions in ventilator support can be provided as the animal regains function. There is some evidence in the human literature that tracheostomy performed in the first 10 days of ventilation can reduce the duration of ventilation, although it is noteworthy that the mean ventilation period for patients in most of these studies was over 20 days.27 Given the short duration of ventilation in most veterinary patients, the relevance of this strategy may be limited. Based on preliminary research and clinical experience, the author recommends consideration of tracheostomy before weaning animals with upper airway disease (e.g., brachycephalic dogs).31 The risk/benefit ratio of tracheostomy in neurologically normal animals with pulmonary disease, but no evidence of upper airway disease, must be determined on a case by case basis. Animals with tracheostomies are prone to complications such as circuit disconnections, increased tracheal secretions, and gas distention of the stomach. The presence of a tracheostomy may delay discharge from the hospital and will increase client costs. Clinicians must consider all these factors when determining how best to manage the airway of long-term ventilator patients.

EXTUBATION Endotracheal extubation is performed subsequent to a successful SBT once adequate recovery from anesthesia has occurred and the patient is actively swallowing. In patients ventilated via a temporary tracheostomy tube, it may be prudent to leave the tube in place for 24 hours or more following disconnection from the ventilator in case the patient relapses and requires reinstitution of ventilatory support.

REFERENCES 1. Girard TD, Alhazzani W, Kress JP, et al: ATS/CHEST Ad Hoc committee on liberation from mechanical ventilation in adults. An official American Thoracic Society/American College of Chest Physicians Clinical Practice guideline: liberation from mechanical ventilation in critically ill adults: rehabilitation protocols, ventilator liberation protocols, and cuff leak tests, Am J Respir Crit Care Med 195(1):120-133, 2017. 2. Epstein SK, Ciubotaru RL, Wong JB: Effect of failed extubation on the outcome of mechanical ventilation, Chest 112(1):186-192, 1997. 3. Frutos-Vivar F, Esteban A, Apezteguía C, et al: Outcome of reintubated patients after scheduled extubation, J Crit Care 26(5):502-509, 2011. 4. Boles JM, Bion J, Connors A, et al: Weaning from mechanical ventilation, Eur Respir J 29(5):1033-1056, 2007. 5. Beduneau G, Pham T, Schortgen F, et al: Epidemiology of weaning outcome according to a new definition. The WIND study, Am J Resp Crit Care 195(6):772-783, 2017. 6. Hess DR, Kacmarek RM: Essentials of mechanical ventilation, ed 4, New York, 2019, McGraw-Hill. 7. Lemaire F, Teboul JL, Cinotti L, et al: Acute left ventricular dysfunction during unsuccessful weaning from mechanical dysfunction, Anesthesiology 69(2):171-179, 1988.

8. Ely EW, Baker AM, Evans GW, Haponik EF: The prognostic significance of passing a daily screen of weaning parameters, Intensive Care Med 25:581, 1999. 9. Blackwood B, Burns KEA, Cardwell CR, O’Halloran P: Protocolized versus non-protocolized weaning for reducing the duration of mechanical ventilation in critically ill adult patients, Cochrane Database Syst Rev 11:CD006904, 2014. 10. Chang AT, Boots RJ, Brown MG, et al: Reduced inspiratory muscle endurance following successful weaning from prolonged mechanical ventilation, Chest 128:553, 2005. 11. Kim WY, Lim CM: Ventilator-induced diaphragmatic dysfunction: diagnosis and role of pharmacological agents, Respir Care 62(11):1485-1491, 2017. 12. Yu TJ, Liu YC, Chu CM, et al: Effects of theophylline therapy on respiratory muscle strength in patients with prolonged mechanical ventilation: a retrospective cohort study, Medicine 98(2):e13982, 2019. 13. Kim WY, Park SH, Kim WY, et al: Effect of theophylline on ventilator-induced diaphragmatic dysfunction, J Crit Care 33:145-150, 2016. 14. MacIntyre NR, Cook DJ, Ely EW, et al: Evidence based guidelines for weaning and discontinuing ventilator support: a collective task force facilitated by the American College of Chest Physicians; the American Association for Respiratory Care; and the American College of Critical Care Medicine, Chest 120:375S, 2001. 15. Tobin MJ: Advances in mechanical ventilation, N Engl J Med 344:1986, 2001. 16. Brochard L, Rua F, Lorino H, et al: Inspiratory pressure support compensates for the additional work of breathing caused by the endotracheal tube, Anesthesiology 75:739, 1991. 17. Cohen C, Zagelbaum G, Gross D, Roussos C, Macklem PT: Clinical manifestations of inspiratory muscle fatigue, Am J Med 73(3):308-316, 1982. 18. Yang KL, Tobin MJ: A prospective study of indexes predicting the outcome of trials of weaning from mechanical ventilation, N Engl J Med 324:1445, 1991. 19. Epstein SK: Etiology of extubation failure and the predictive value of the rapid shallow breathing index, Am J Respir Crit Care Med 152:545, 1995. 20. Tanios MA, Nevins MI, Hendra KP, et al: A randomized controlled trial of the role of weaning predictors in clinical decision making, Crit Care Med 34:2530, 2006. 21. MacIntyre NR: Evidence-based assessments in ventilator discontinuation process, Respir Care 57:1611, 2012. 22. Esteban A, Frutos F, Tobin MJ, et al: A comparison of four methods of weaning patients from mechanical ventilation, N Engl J Med 332:345, 1995. 23. Subira C, Hernandez G, Vazquez A, et al: Effect of pressure support vs Tpiece ventilation strategies during spontaneous breathing trials on successful extubation among patients receiving mechanical ventilation: a randomized clinical trial, JAMA 321(22):2175-2182, 2019. 24. Perkins GD, Mistry D, Gates S, et al: Effect of protocolized weaning with early extubation to noninvasive ventilation vs invasive weaning on time to liberation from mechanical ventilation among patients with respiratory failure, JAMA 320(18):1881-1888, 2018. 25. Yeung J, Couper K, Ryan EG, et al: Non-invasive ventilation as a strategy for weaning from invasive mechanical ventilation: a systematic review and Bayesian meta-analysis, Intensive Care Med 44(12):2192-2204, 2018. 26. Hernandez G, Vaquero C, Gonzalez P, et al: Effect of postextubation highflow nasal cannula vs conventional oxygen therapy on reintubation in low-risk patients: a randomized clinical trial, JAMA 315(13):1354-1361, 2016. 27. Baptistella AR, Sarmento FJ, da Silva KR, et al: Predictive factors of weaning from mechanical ventilation and extubation outcome: a systematic review, Crit Care 48:56-62, 2018. 28. Tanios MA, Nevins ML, Hendra KP, et al: A randomized, controlled trial of the role of weaning predictors in clinical decision making, Crit Care Med 34(10):2530-2535, 2006. 29. Haas CF, Loik PS: Ventilator discontinuation protocols, Respir Care 57(10):1649-1662, 2012. 30. Meng L, Wang C, Li J, Zhang J: Early vs late tracheostomy in critically ill patients: a systematic review and meta-analysis, Clin Respir J 10:684-692, 2016. 31. Hoareau GL, Mellema MS, Silverstein DC: Indication, management and outcome of brachycephalic dogs requiring mechanical ventilation, J Vet Emerg Crit Care 21:226, 2011.

39 Ventilator-induced Lung Injury Lisa Smart, BVSc, DACVECC, PhD, Kate Hopper, BVSc, PhD, DACVECC

KEY POINTS • The majority of ventilator-induced lung injury in experimental models is related to high end-inspiratory volume causing stretch injury. • A second contributing factor is low end-expiratory volume, which can cause epithelial shear injury during reexpansion of the lungs.

• Ventilator-associated lung injury can be a significant contributor to morbidity and mortality in patients receiving mechanical ventilation. • Strategies to prevent ventilator-associated lung injury may decrease the duration of mechanical ventilation required and improve patient outcomes.

DEFINITIONS

pressure cannot be separated from the impact of high-volume ventilation. In terms of VILI, barotrauma is defined as extraalveolar air and is manifested clinically by pneumothorax, pneumomediastinum, or subcutaneous emphysema.2 In a study of human ARDS patients, the use of high airway pressures (peak inspiratory pressure >40 cm H2O) was associated with a higher incidence of pneumothorax than when lower airway pressures were used.3 In a separate study, when plateau pressure was maintained at less than 35 cm H2O, no relationship was found between ventilator settings and the occurrence of pneumothorax.4 Airway pressure may not accurately reflect the stress imposed on the lung parenchyma as it includes the pressure needed to expand the chest wall. The distending pressure of the lung is best reflected by the transpulmonary pressure, and this would be a better measure to use when assessing the risk of VILI.

For the purposes of this chapter, the following definitions will be used. It is important to note that there is no consensus on the definition of these terms in the current literature and they are generally considered exchangeable. Ventilator-induced lung injury (VILI): injury to the lung caused by mechanical ventilation in experimental models Ventilator-associated lung injury: worsening of pulmonary function, or presence of lesions similar to acute respiratory distress syndrome (ARDS), in clinical patients that is thought to be associated with the use of mechanical ventilation, with or without underlying lung disease Most criticalists will passionately debate whether “putting a patient on the ventilator” is a death sentence. However, it is well documented that positive pressure ventilation (PPV) can cause significant pathology in the lung and can worsen preexisting lung dysfunction. A bevy of research in the area, experimentally in animal models and clinically in people, has led to strategies designed to limit the amount of damage caused directly, or indirectly, by the ventilator. This chapter serves to review the pathophysiology and the clinical relevance of VILI and provide an introduction to preventative measures. This chapter does not review the effects of PPV on other organ systems, such as the cardiovascular system or neuroendocrine system, or other complications related to PPV, such as ventilator-associated pneumonia (see Chapter 40).

MECHANISMS OF VENTILATOR-INDUCED LUNG INJURY Potential mechanisms of VILI are summarized in Table 39.1.

Barotrauma The term barotrauma implies pressure-related injury to the lung, and experimental evidence supports that the use of higher airway pressures in healthy rats causes more lung injury than the use of lower airway pressures.1 But in such experiments, the impact of high airway

Volutrauma It is apparent that stretch injury as a result of high volume is more injurious to the lung than high pressure, without a large increase in volume.5-8 In a well-known study, rats were ventilated with either high volume/high pressure, high volume/low pressure (negative pressure ventilation), or low volume/high pressure (chest wall was restricted).7 Both high-volume strategies caused substantial lung injury while the low volume/high pressure strategy had far less evident injury. The concerns for volutrauma are supported by human clinical studies showing improved outcomes with use of low tidal volume ventilation.9,10

Atelectrauma Repetitive opening and closing of collapsed alveoli may directly traumatize epithelial cells and injure adjacent alveoli via shear stress. This is known as atelectrauma or cyclic recruitment-derecruitment injury. In healthy lungs, there are relatively few collapsed alveoli, but in injured lungs, alveoli become progressively unstable, changing shape during inflation and completely collapsing at the end of expiration.8,11 When rats are ventilated with high pressures and no positive end- expiratory pressure (PEEP), they rapidly develop severe, diffuse pulmonary edema. If they are ventilated at the same pressure with the

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TABLE 39.1  A Summary of Mechanisms of Ventilator-Induced Lung Injury and Potential

Preventative Strategies for Veterinary Patients Mechanism of Lung Injury

Description

Preventative Strategies

Barotrauma

Extraalveolar air • Pneumothorax • Pneumomediastinum • Subcutaneous emphysema

Minimize plateau airway pressure • Target ,30 cm H2O

Volutrauma

Overdistension causing stretch injury

Minimize TV • Target TV ,10 ml/kg

Atelectrauma

Cyclic recruitment – derecruitment injury

Application of PEEP

Mechanical power

Total energy transferred to the lung – includes TV, driving pressure, respiratory rate, flow rate, and PEEP

Minimize all ventilator settings – all energy transferred to the lung has the potential to cause injury

Spontaneous breathing while receiving mechanical ventilation

Alveolar distension, shear stress, atelectrauma, etc., during spontaneous breathing is equally as injurious as mechanical ventilator breaths. May promote edema formation more than positive pressure ventilation

Minimize spontaneous breathing including patient–ventilator asynchrony with appropriate sedation, optimization of ventilator settings, 6 neuromuscular blockade

Biotrauma

Release of inflammatory mediators from the injured lung leading to systemic inflammation, which may promote multiple organ dysfunction

Lung-protective ventilation strategies to limit lung injury and implement strategies to reduce microaspiration of oropharyngeal fluid

Oxygen toxicity

High oxygen concentrations may directly cause lung injury as well as contribute to absorption atelectasis

Minimizing FiO2 within 24 hours • Target FiO2 ,0.60

FIO2, fraction of inspired oxygen; PEEP, positive end-expiratory pressure; TV, tidal volume.

addition of PEEP, it is far less injurious.1 PEEP can reduce the cyclic collapse and reexpansion of alveoli and minimize atelectrauma.

Mechanical Power Gattinoni and colleagues have proposed a new way of considering the impact of PPV on the lung through the evaluation of mechanical power. The total mechanical power or energy transferred to the lung during ventilation may correlate with the likelihood for VILI. The disease characteristics of the lung are important determinants of VILI; it is therefore recommended that mechanical power is normalized to the area of ventilated lung available. This normalized value for mechanical power has been described as intensity.12 In lungs with smaller areas participating in ventilation, the value for intensity for a given degree of mechanical power would be higher. Mechanical power includes all components of a ventilator breath that can contribute to VILI: tidal volume, driving pressure, respiratory rate, flow rate, and PEEP. A novel aspect of this approach is the inclusion of respiratory rate and PEEP as potential contributors to VILI. Although PEEP can be protective of lung injury, it does increase the energy load transmitted to the lung and may contribute to VILI in some circumstances.13 Respiratory rate has long been ignored in the consideration of lung injury, and there is growing interest in its potential role.14 How the concepts of mechanical power can be applied to clinical patient management has yet to be elucidated, but it raises awareness that all settings on the ventilator are potentially relevant, and more research is needed to better understand the impact of PPV.

Spontaneous Breathing The mechanisms of VILI are a product of the dynamic stress applied to the lung during breathing efforts, and this stress can be equally injurious if breaths are generated by mechanical ventilation or spontaneous respiratory efforts.15 In addition, the decrease in pleural pressure as a result of spontaneous breathing efforts increases transvascular pressure; that is, the transmural pressure of pulmonary vessels. Consequently, there is

distension of these vessels, which can promote the formation of edema.16 These concerns are relevant to spontaneous breathing modes, in addition to animals with patient–ventilator asynchrony.17

Biotrauma VILI causes cell damage and results in an inflammatory response. The release of proinflammatory cytokines caused by VILI may promote multiple organ dysfunction, and increased inflammatory cytokines can worsen VILI in a circular fashion, which has been implicated as part of the pathophysiology of VILI.18,19 Ultimately, the morbidity and mortality associated with VILI, from any mechanism, are largely the result of the subsequent systemic inflammation known as biotrauma. Lung-protective ventilation strategies limit lung injury and have also been shown to reduce multiple organ dysfunction and improve outcomes.9,20

Oxygen Toxicity Although oxygen toxicity is a separate entity from PPV, patients receiving PPV are invariably on supra-atmospheric levels of oxygen supplementation, up to 100% inspired oxygen concentration (FiO2) (see Chapter 8, Oxygen Toxicity). This may have an additive effect to the injury caused by VILI, especially if a high oxygen concentration is delivered for an extended period. Inspired oxygen concentration of 100%, in the short term, can cause absorption atelectasis and decrease oxygen diffusion capacity.21 Beyond 24 hours, an FiO2 between 50% and 100% promotes the production of reactive oxygen and nitrogen species30,31 and causes pathologic changes similar to ARDS and VILI, including interstitial edema, hyaline membrane formation, damage to the alveolar membrane, altered mucociliary function, and fibroproliferation.10,22 The damage appears to be positively associated with the level of FiO2 and the length of time that oxygen was administered. Therefore, PPV needs to be a delicate balance among limiting volume change within the lung, applying appropriate PEEP, and limiting FiO2 to whatever level the patient can tolerate.

CHAPTER 39  Ventilator-induced Lung Injury

HISTOPATHOLOGY The histopathologic changes associated with VILI are hard to distinguish from changes associated with ARDS (see Chapter 25, Acute Respiratory Distress Syndrome). These include decreased integrity of small airway epithelial cells, destruction of type 1 alveolar epithelial cells, alveolar and airway flooding, hyaline membrane formation, interstitial edema, and infiltration of inflammatory cells.23 Lesions usually have an uneven distribution but tend to be worse in the dependent lung, likely because of worsened airway flooding and shear injury. However, experimentally in dogs this distribution of lesions disappears with prone, or sternally recumbent, positioning.24

CLINICAL RELEVANCE Because of the growing evidence from experimental studies that highvolume/low-PEEP ventilation can cause harm and worsen preexisting lung injury, focus has shifted to the question of whether or not clinically acceptable forms of PPV can also cause harm in people. In the last decade, several studies have found evidence of an association between higher tidal volumes and development of acute lung injury or respiratory failure in people.9-10 Within the same time frame, various strategies for lung-protective ventilation have been developed, centering on volume limitation and the use of PEEP. Volume limitation in patients with ALI and ARDS has shown the most dramatic results in outcome, with the landmark ARDSnet study showing a decrease in mortality when 6 ml/kg tidal volume was used versus 12 ml/kg.9 The group receiving lower tidal volumes also, incidentally, received slightly higher PEEP and inspired oxygen concentration. More recently, a meta-analysis of nine randomized trials (seven trials without high PEEP and two with high PEEP) of low volume ventilation in adult human patients with ARDS found an association with decreased mortality, although it is noteworthy that if the evaluation was restricted to the seven trials that did not include high PEEP, there was no association with decreased mortality.10 There is also evidence that low tidal volume ventilation may be of benefit in people without ARDS or acute lung injury. A meta- analysis of intraoperative ventilation concluded that low tidal volume (,10 ml/kg) ventilation decreased the frequency of pneumonia and the need for postoperative ventilatory support.25 There is little evidence in veterinary medicine that high-volume/ low-PEEP ventilation is detrimental to clinical patients, specifically dogs and cats, or that lung-protective ventilation strategies affect outcome. Further, it is unclear what may be deemed high volume in dogs and cats. Between 10 and 20 ml/kg has been estimated anecdotally for the normal tidal volume in healthy dogs and cats that are spontaneously breathing. Experimentally, in dogs, normal spontaneous tidal volume has been measured at an average of 15 ml/kg, which is consistent with anecdotal descriptions, but with considerable variation between dogs.26,27 This tidal volume of dogs is larger than the average resting tidal volume of approximately 8–9 ml/kg in conscious people.28,29 Under conditions of short-term PPV in healthy dogs, a tidal volume of 15 ml/kg improved lung performance, including a reduction in dead space ventilation, compared with 10 ml/kg.30 Another study demonstrated that 15 ml/kg with a PEEP of 5 cm H2O improved compliance and reduced atelectasis in dogs undergoing computed tomography, compared with lower tidal volume (8 ml/kg) and/or no PEEP.31 Therefore, it must be considered that human guidelines of specific tidal volumes for lung-protective ventilation may too low for dogs. In contrast, cats appear to have a smaller spontaneous tidal volume compared with dogs, measured at approximately 7–8 ml/kg.32,33

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There are some clinical observational studies reporting the use of PPV for greater than 24 hours in sick dogs and cats.34-37 The use of tidal volume greater than 10 ml/kg appears common, but the prevalence of VILI has not been captured. One study included 14 dogs with cervical spinal disorders that had relatively normal lung function before PPV and reported two dogs were euthanatized because of multiple organ dysfunction, including lung failure.36 This study reported a mean tidal volume of 18 6 5 ml/kg without a reference to PEEP. The incidence of pneumothorax, based on five different case series, varied from 0% to 28%,35-39 with the largest cohort reporting an incidence of 7%,35 which is fairly similar to the ARDSnet study.9 The highest of these (28%), a case series of cats receiving PPV, did not find an association between peak inspiratory pressure above 25 cm H2O or presence of pulmonary parenchymal disease, and pneumothorax.37 The mean tidal volume reported in this study was 23.7 6 8.6 ml/kg, but an association between tidal volume and pneumothorax was not investigated. Pneumomediastinum in cats has been reported as a complication of general anesthesia with concurrent PPV in one case series40 and secondary to PPV for aspiration pneumonia in one dog.41 It is unknown whether any of the complications reported in these observational studies, including worsening lung function and extrapulmonary gas, were associated with the ventilation strategy chosen or related to underlying pulmonary disease. However, it is likely given the evidence from experimental data and clinical evidence from human medicine that clinicians should be mindful of lung-protective strategies in order to reduce risk, where possible.

PREVENTION Conventional Mechanical Ventilation Strategies Many ventilator strategies for the prevention of VILI are part of protective lung ventilation approaches described for the management of ARDS. These are discussed further in Chapter 33, Mechanical Ventilation: Advanced Concepts.

Low Tidal Volume There is strong evidence for limiting tidal volume to less than normal in human studies, where values of 4 to 6 ml/kg have been recommended in ARDS patients.2 The optimal target for tidal volume in dogs and cats is unknown and likely varies between dog breeds due to anatomical differences. Most clinical veterinary studies on mechanical ventilation have reported the use of tidal volumes of greater than 10 ml/kg.42 It is recommended to target the lowest possible tidal volume that is needed to maintain adequate blood gases, and this is likely to be in the range of 6 to 12 ml/kg in dogs and cats. Minimizing tidal volume is of particular importance when the lungs are already compromised. Even though healthy dogs have a higher normal tidal volume than other species, the volume of functional units available for gas exchange in injured lungs may be much reduced. Inflammation in the lung causes heterogeneous changes throughout, with regions of poorer compliance and atelectasis, which causes more compliant regions to become overdistended. Because it is difficult to know in any one patient if portions of the lung are being overdistended, it is prudent to limit tidal volume as much as possible. However, using low tidal volume also increases the risk of perpetuating atelectasis and creating further shear injury; therefore, application of PEEP is vital. A common consequence of low tidal volume ventilation is hypercapnia; tolerating higher than normal PaCO2 levels rather than increasing ventilator settings is a strategy known as permissive hypercapnia. Although this approach may reduce the likelihood of VILI, there are physiological consequences of hypercapnia that may impact patient outcome.43

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Positive End-Expiratory Pressure It has been well established that some PEEP is better than no PEEP, or zero end-expiratory pressure; however, the minimum amount of PEEP needed to reduce VILI has not been established. Common levels of PEEP considered adequate in human medicine are in the range of 5 to 10 cm H2O.

Limitation of Plateau Pressure Plateau pressure best represents the pressure applied to the lung as it is not impacted by resistance of the system. It is measured during an inspiratory hold maneuver and the animal should not be making active respiratory efforts during measurement.44 The combination of high PEEP, auto-PEEP (PEEP created by increased outflow resistance during expiration, asynchrony, or incomplete expiration), and tidal volume can lead to high end-inspiratory volume, which may be indicated by high plateau pressure. Protective lung ventilation strategies in human medicine recommend targeting a plateau pressure of less than 30 cm H2O.9 Peak inspiratory pressure may be used as a surrogate for plateau pressure unless there is increased resistance in the system.

Respiratory Rate and Inspiratory Flow There is some evidence that high respiratory rates and inspiratory flow rates can promote VILI. The exact role of these parameters has yet to be defined but it is possible they could be manipulated to further improve the safety of PPV.45

Subjective Analysis of the Pressure–Volume Loop An optimal ventilator breath avoids both alveolar collapse on exhalation and overdistension on inhalation. The upper and lower inflection points of the pressure–volume loop theoretically show where these events occur, and maintaining PEEP and peak inspiratory pressure between these points could be beneficial (see Fig. 35.11). Unfortunately, determining the upper and lower inflection points is complex and not readily available at the bedside. Subjective analysis of the pressure–volume loop may be of some benefit, in particular in recognition of overdistention from the presence of “beaking” (see Fig. 35.13).

Spontaneous Breathing In severe ARDS, spontaneous breathing effort has been associated with poorer outcomes, while in less severe pulmonary disease, spontaneous breathing may actually provide benefits such as better lung recruitment and improved diaphragmatic tone.14,46,47 Studies on the use of neuromuscular blocking agents (NMBA) to abolish spontaneous breathing efforts in human ARDS patients have had contradictory results. A recent human clinical practice guideline recommended against the routine use of NMBA in patients with moderate or severe ARDS that tolerate light sedation. But in patients that require deep sedation or prone ventilation, the use of NMBA is reasonable.48

Advanced Pulmonary Support Techniques Because of the risk of VILI using conventional mechanical ventilation in people with ARDS, advanced strategies such as partial liquid ventilation, high-frequency oscillatory ventilation, extracorporeal membrane oxygenation, and carbon dioxide removal are currently being researched.

REFERENCES 1. Webb HH, Tierney DF: Experimental pulmonary edema due to intermittent positive pressure ventilation with high inflation pressures. Protection by positive end-expiratory pressure, Am Rev Respir Dis 110(5):556-565, 1974.

2. Madahar P, Beitler JR: Emerging concepts in ventilator-induced lung injury, F1000Res 9:222, 2020. 3. Miller MP, Sagy M: Pressure characteristics of mechanical ventilation and incidence of pneumothorax before and after the implementation of protective lung strategies in the management of pediatric patients with severe ARDS, Chest 134(5):969-973, 2008. 4. Boussarsar M, Thierry G, Jaber S, et al: Relationship between ventilatory settings and barotrauma in the acute respiratory distress syndrome, Intensive Care Med 28(4):406-413, 2002. 5. Carlton D, Cummings J, Scheerer R, et al: Lung overexpansion increases pulmonary microvascular protein permeability in young lambs, J Appl Physiol 69:577-583, 1990. 6. Hernandez L, Peevy K, Moise A, et al: Chest wall restriction limits high airway pressure-induced lung injury in young rabbits, J Appl Physiol 66:2364-2368, 1989. 7. Dreyfuss D, Soler P, Basset G, et al: High inflation pressure pulmonary edema. Am Rev Respir Dis 137:1159-1164, 1988. 8. Pavone L, Albert S, Carney D, et al: Injurious mechanical ventilation in the normal lung causes a progressive pathologic change in dynamic alveolar mechanics, Crit Care 11:1-9, 2007. 9. Brower RG, Matthay MA, Morris A, et al: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome, N Engl J Med 342:1301-1308, 2000. 10. Walkey AJ, Goligher EC, Del Sorbo L, et al: Low tidal volume versus nonvolume-limited strategies for patients with acute respiratory distress syndrome. A systematic review and meta-analysis, Ann Am Thorac Soc 14(Suppl 4):S271-S279, 2017. 11. Schiller H, McCann II U, Carney D, et al: Altered alveolar mechanics in the acutely injured lung, Crit Care Med 29:1049-1055, 2001. 12. Silva PL, Ball L, Rocco PRM, Pelosi P: Power to mechanical power to minimize ventilator-induced lung injury? Intensive Care Med Exp 7 (Suppl 1):38, 2019. 13. Gattinoni L, Tonetti T, Cressoni M, et al: Ventilator-related causes of lung injury: the mechanical power, Intensive Care Med 42(10):1567-1575, 2016. 14. Akoumianaki E, Vaporidi K, Georgopoulos D: The injurious effects of elevated or nonelevated respiratory rate during mechanical ventilation, Am J Respir Crit Care Med 199(2):149-157, 2019. 15. Yoshida T, Uchiyama A, Matsuura N, et al: The comparison of spontaneous breathing and muscle paralysis in two different severities of experimental lung injury, Crit Care Med 41(2):536-545, 2013. 16. Mauri T, Yoshida T, Bellani G, et al: Esophageal and transpulmonary pressure in the clinical setting: meaning usefulness and perspectives, Intensive Care Med 42(9):1360-1373, 2016. 17. Yoshida T, Fujino Y, Amato MBP, Kavanagh BP: Fifty years of research in ARDS. Spontaneous breathing during mechanical ventilation. Risks, mechanisms and management, Am J Respir Crit Care Med 195(8):985-992, 2017. 18. Curley GF, Laffey JG, Zhang H, Slutsky AS: Biotrauma and ventilator- induced lung injury: clinical implications, Chest 150(5):1109-1117, 2016. 19. Halbertsma FJ, Vaneker M, Scheffer GJ, van der Hoeven JG: Cytokines and biotrauma in ventilator-induced lung injury: a critical review of the literature, Neth J Med 63(10):382-392, 2005. 20. Parsons P, Eisner M, Thompson B, et al: Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury, Crit Care Med 33:1-6, 2005. 21. Kafer E: Pulmonary oxygen toxicity, Br J Anaesth 43:687, 1971. 22. Fisher A, Forman H, Glass M: Mechanisms of pulmonary oxygen toxicity, Lung 162:255-259, 1984. 23. Dreyfuss D, Saumon G: Ventilator-induced lung injury: lessons from experimental studies, Am J Respir Crit Care Med 157:294-323, 1998. 24. Broccard A, Shapiro R, Schmitz L, et al: Prone positioning attenuates and redistributes ventilator-induced lung injury in dogs, Crit Care Med 28:295-303, 2000. 25. Guay J, Ochroch EA, Kopp S: Intraoperative use of low volume ventilation to decrease postoperative mortality, mechanical ventilation, lengths of stay and lung injury in adults without acute lung injury, Cochrane Database Syst Rev 7(7):CD011151, 2018. 26. Gillespie DJ, Hyatt RE: Respiratory mechanics in the unanesthetized dog, J Appl Physiol 36:98-102, 1974.

CHAPTER 39  Ventilator-induced Lung Injury 27. Amis TC, Kurpershoek C: Tidal breathing flow-volume loop analysis for clinical assessment of airway obstruction in conscious dogs, Am J Vet Res 47:1002-1006, 1986. 28. Needham CD, Rogan MC, McDonald I: Normal standards for lung volumes, intrapulmonary gas-mixing, and maximum breathing capacity, Thorax 9:313-325, 1954. 29. Radford EP Jr: Ventilation standards for use in artificial respiration, J Appl Physiol 7(4).451-460, 1955. 30. Bumbacher S, Schramel JP, Mosing M: Evaluation of three tidal volumes (10, 12 and 15 mL kg-1) in dogs for controlled mechanical ventilation assessed by volumetric capnography: a randomized clinical trial, Vet Anaesth Analg 44:775-784, 2017. 31. De Monte V, Bufalari A, Grasso S, et al: Respiratory effects of low versus high tidal volume with or without positive end-expiratory pressure in anesthetized dogs with healthy lungs, Am J Vet Res 79:496-504, 2018. 32. Fordyce WE, Tenney SM: Role of the carotid bodies in ventilatory acclimation to chronic hypoxia by the awake cat, Respir Physiol 58:207-221, 1984. 33. Hoffman AM, Dhupa N, Cimetti L: Airway reactivity measured by barometric whole-body plethysmography in healthy cats, Am J Vet Res 60: 1487-1492, 1999. 34. Kelmer E, Love L, DeClue A, et al: Successful treatment of acute respiratory distress syndrome in 2 dogs, Can Vet J 53:167-173, 2012. 35. Hopper K, Haskins S, Kass P, et al: Indications, management, and outcome of long-term positive-pressure ventilation in dogs and cats: 148 cases (1990-2001), J Am Vet Med Assoc 230:64-75, 2007. 36. Beal M, Paglia D, Griffin G, et al: Ventilatory failure, ventilator management, and outcome in dogs with cervical spinal disorders: 14 cases (1991-1999), J Am Vet Med Assoc 218:1598-1602, 2001. 37. Lee J, Drobatz K, Koch M, et al: Indications for and outcome of positivepressure ventilation in cats: 53 cases (1993-2002), J Am Vet Med Assoc 226:924-931, 2005.

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38. Campbell V, King L: Pulmonary function, ventilator management, and outcome of dogs with thoracic trauma and pulmonary contusions: 10 cases (1994-1998), J Am Vet Med Assoc 217:1505-1509, 2000. 39. Rutter C, Rozanski E, Sharp C, et al: Outcome and medical management in dogs with lower motor neuron disease undergoing mechanical ventilation: 14 cases (2003-2009), J Vet Emerg Crit Care 21:531-541, 2011. 40. Thomas EK, Syring RS: Pneumomediastinum in cats: 45 cases (20002010), J Vet Emerg Crit Care (San Antonio) 23:429-435, 2013. 41. Zersen KM, Haraschak JL, Sullivan LA: Development of a tension pneumomediastinum during mechanical ventilation of a young Irish Wolfhound, J Vet Emerg Crit Care (San Antonio) 30:342-346, 2020. 42. Donati PA, Plotnikow G, Benavides G, et al: Tidal volume in mechanically ventilated dogs: can human strategies be extrapolated to veterinary patients? J Vet Sci 20(3):e21, 2019. 43. Barnes T, Zochios V, Parhar K: Re-examining permissive hypercapnia in ARDS: a narrative review, Chest 154(1):185-195, 2018. 44. Hess DR: Respiratory mechanics in mechanically ventilated patients, Respir Care 59(11):1773-1794, 2014. 45. Gattinoni L, Marini JJ, Collino F, et al: The future of mechanical ventilation: lessons from the present and the past, Crit Care 21(1):183, 2017. 46. Papazian L, Forel JM, Gacouin A, et al: Neuromuscular blockers in early acute respiratory distress syndrome, N Engl J Med 363(12):1107-1116, 2010. 47. Putensen C, Zech S, Wrigge H, et al: Long-term effects of spontaneous breathing during ventilatory support in patients with acute lung injury, Am J Respir Crit Care Med 164(1):43-49, 2001. 48. Alhazzani W, Belley-Cote E, Moller MH, et al: Neuromuscular blockade in patients with ARDS: a rapid practice guideline, Intensive Care Med 46(11): 1977-1986, 2020.

40 Ventilator-Associated Pneumonia Steven E. Epstein, DVM, DACVECC

KEY POINTS • Ventilator-associated pneumonia (VAP) is diagnosed based on the presence of systemic inflammation, worsening pulmonary function, and new or progressive pulmonary infiltrates on thoracic imaging occurring after at least 48 hours of intubation. • The main risk factor for the development of VAP is endotracheal intubation, and when VAP occurs, it is associated with high mortality rates.

• Prevention of VAP is most effective if preventative strategies are grouped in bundles and performed in every patient at risk, with education of healthcare staff being a key point. • If VAP is suspected, early diagnostics including collection of lower airway samples should be performed, and empiric therapy should started with changes to the antimicrobial therapy when culture results are available.

Ventilator-associated pneumonia (VAP) refers to pneumonia that arises more than 48 hours after endotracheal intubation and mechanical ventilation that was not present at the time of intubation.1,2 In veterinary medicine, patients may remain endotracheally intubated for prolonged periods without receiving mechanical ventilation. These patients are at risk for developing pneumonia from many of the same pathogenic factors as mechanically ventilated patients are. As such, all anesthetized dogs and cats with endotracheal intubation, regardless of mechanical ventilation status, are discussed together in this chapter. In veterinary medicine the incidence of VAP has not been reported, but in human medicine it is a common complication of mechanical ventilation. The incidence of VAP varies with study period, diagnostic criteria, and location, with current estimates of approximately 3%–10% of mechanically ventilated human patients, although some studies report a decreasing incidence.3,4 The national healthcare safety network reported rates of VAP between 0.2 and 0.8 per 1000 ventilator days in pediatric ICU in the US in 2012.5 The risk of developing VAP varies with duration of ventilation, and different risk factors have been found for early-onset vs. late-onset VAP.6 Because most animals receive mechanical ventilation for less than a week, the majority of the cases of VAP would be expected to occur in the first few days of ventilation; however, the cumulative incidence will increase as the number of days of intubation increases. Mortality rates in humans due to development of VAP remain increased despite advances in care. The development of VAP also increases the length of time mechanical ventilation is necessary, which would contribute to mortality rates in veterinary medicine. With these higher mortality rates, early diagnosis and prevention of the development of VAP are key to improving outcome.

become infected (ventilator-associated tracheobronchitis [VAT]), or if the pulmonary parenchyma becomes infected, VAP occurs. Normal respiratory defenses to colonization or infection of the lower airways include cough, mucus clearance, and humoral and cellular immune responses. These normal defenses are compromised in an anesthetized critically ill animal, as there is a reduced ability to cough due to sedation and the presence of the endotracheal tube. Inflation of a cuffed endotracheal tube depresses the mucociliary clearance rate,7 and critical illness is associated with decreased immune system function and increased susceptibility to nosocomial infection.8 In addition there is evidence for neutrophil dysfunction in VAP with a reduced phagocytic capability9 and elevation in neutrophil proteases in the alveolar space.10 With these impaired respiratory defenses, the prime risk factor for the development of VAP is the presence of an endotracheal tube. In fact, the risk for the development of VAP in patients receiving noninvasive mechanical ventilation is lower than in patients with endotracheal intubation.11 One meta-analysis found that reintubation after unsuccessful extubation is a risk factor for VAP with an odds ratio of 7.6 (95% CI 3.6%–15.8%) for the development of VAP; the study also documented differences between planned and unplanned extubation.12 Microaspiration past the cuff of the endotracheal tube and biofilm development within the endotracheal tube likely represent the two major pathologic mechanisms behind VAP. Inflation of the endotracheal cuff allows for pooling of secretions beyond the vocal folds, but above the cuff (subglottic region). When high-volume, low-pressure cuffs are used to prevent tracheal injury, the longitudinal folds that develop are associated with microaspiration or macroaspiration of subglottic fluid with subsequent translocation of bacteria to the interior of the endotracheal tube or airways. Once bacteria are present on the internal surface of the endotracheal tube, in which most are made of polyvinyl chloride, these bacteria may easily adhere and produce a complex polysaccharide matrix known as biofilm. This biofilm is inaccessible to antimicrobials unless they are aerosolized. As the bacteria proliferate within the endotracheal tube, they may be dislodged into the lower airway because of airflow, suctioning, or bronchoscopic

PATHOGENESIS One of the key factors in the pathogenesis of VAP is the introduction of a microbial pathogen into the airways. Once a pathogen gets past the cuff of the endotracheal tube there are several potential outcomes. The pathogen may be cleared by normal respiratory defenses, the lower airways may be colonized, the tracheobronchial tree may

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CHAPTER 40  Ventilator-Associated Pneumonia procedures. In a cohort of human patients with VAP, 70% had identical pathogens identified from endotracheal tube biofilm and tracheal secretions with antimicrobial susceptibility data showing greater antimicrobial resistance in the biofilm isolates.13 The bacteria associated with biofilm formation or VAP may come from either exogenous or endogenous source. Exogenous sources include contaminated respiratory equipment, the environment, or healthcare provider’s hands. (See Chapter 37 for proper hand hygiene and apparatus care.) With proper hand hygiene the primary source of colonization is likely endogenous bacteria. Normal oral flora is typically a mixed population of bacteria, whereas in critical illness aerobic Gram-negative bacteria predominate. This change in type and increased numbers of bacteria can be attributed to a lack oral hygiene seen with normal swallowing that results in the spread of saliva which contains proteases, immunoglobulins, and enzymes. Patients receiving antimicrobials may also see a change in population and an increase in resistance of oral flora because of antimicrobial pressures. Dogs and cats with respiratory failure requiring mechanical ventilation also have a shift in bacterial flora and antimicrobial resistance compared with patients with less severe respiratory disease in one study. Lower respiratory cultures from the respiratory failure group had a larger population of aerobic Gram-negative enteric bacteria and increased antimicrobial resistance rates compared with patients that did not need mechanical ventilation.14 Alternatively, the source of respiratory bacterial colonization may be gastric in origin. Critically ill patients receiving gastric antacid medications show greater rates of gastric colonization than those who do not.15 The relationship between gastric colonization and VAP is currently controversial as there is evidence for and against the relationship; however, this has led to research into the use of probiotics to help prevent VAP. Enteral feeding has been associated with the development of VAP in humans highlighting the gastrointestinal tract as a potential source.16 A variety of pathogens can be isolated with VAP, with aerobic bacteria representing the majority of cases. Anaerobic bacteria, viruses, and fungi are rarely the cause of VAP. Infections may be monomicrobial or polymicrobial in origin. Polymicrobial infections can be as common as monomicrobial infections, although mortality has not been shown to be different between groups. Initially, early-onset VAP was not thought to be associated with multidrug-resistant (MDR) bacteria; however, evidence is conflicting.17,18 It is difficult to define risk factors for the development of MDR VAP; however, previous antimicrobial use is implicated. Local epidemiologic data are important in determining the likely pathogens that may be identified with VAP.

DIAGNOSIS As tracking of VAP at a national level proved difficult because of the lack of valid and consistent definitions, in 2013 the Center for Disease Control and Prevention (CDC) introduced a new approach to surveillance that starts with tracking ventilator-associated events.19 This is a three-tiered system that starts with a ventilator-associated condition (VAC). Nested within VACs are both noninfectious and infection-related ventilator-associated conditions (IVACs). Within IVACs there can either be possible VAP or probable VAP, with each tier of diagnosis needed prior to the first.20,21 VACs are defined as at least 2 days of worsening oxygenation following at least 2 days of stability on the ventilator based on changes to the fraction of inspired oxygen or positive end-expiratory pressure. These include all forms of ventilator- induced lung injury (see Chapter 39) as well as IVACs. IVACs are diagnosed based on elevated or reduced body temperature, leukocytosis or leukopenia, and a new antimicrobial agent that is started and

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continued for 4 days. After an IVAC has been diagnosed, possible VAP can be diagnosed when purulent secretions from the lungs, bronchi, or trachea contain 25 neutrophils and #10 squamous epithelial cells per low power field or a positive culture of sputum, endotracheal aspirate, bronchoalveolar lavage, lung tissue, or protected specimen bushing is found. The culture (excluding lung tissue as a source) would exclude normal respiratory or oral flora, coagulase-negative Staphylococcus or Enterococcus spp. to count as a criterion. Probable VAP can be diagnosed when either purulent respiratory secretions are found (as stated in possible VAP) and a positive quantitative/semi-quantitative culture is found, or a positive pleural fluid culture is obtained not from an indwelling chest tube or lung histopathology. Fig. 40.1 provides a detailed modified guideline of these recommendations for veterinary use. It should be noted that in the algorithm, the suspicion for VAP does not include thoracic imaging; however, the ultimate diagnosis of it does. There is currently controversy in deciding what criteria should be used in the diagnosis of VAP in the clinical and research settings. The CDC’s National Healthcare Safety Network definition of VAP and non-VAP is listed in Box 40.1.2 There are alternative criteria for neonates, pediatrics or when specific pathogens (e.g., fungi) are present. Patients must satisfy all three criteria (imaging, systemic, and laboratory) and have a tracheostomy or endotracheal tube in place for more than 48 hours before the diagnosis of infection to receive a diagnosis of VAP. Although definitions such as these can be useful for research purposes, they may be limited for clinical decision making for individual patients as they are best performed in retrospect. VAT is an infection of the tracheobronchial tree of similar origin to VAP but does not affect the pulmonary parenchyma. VAT may produce the same clinical signs as VAP, and if a patient fulfills the clinical criteria for VAT/VAP, thoracic imaging is indicated. A new or progressive pulmonary infiltrate on thoracic imaging is required to diagnosis VAP. Thoracic radiographs may be difficult to interpret as pulmonary hemorrhage, atelectasis, or acute respiratory distress syndrome may be mistaken as pneumonic infiltrates. A recent systematic review of the use of lung ultrasound showed that small subpleural consolidations and dynamic air bronchograms were the most useful signs to diagnose VAP, and a clinical scoring system was more useful than lung ultrasound alone.22 It should be noted that none of the studies included used lung ultrasound as a screening tool. Airway sampling for microbial culture has its limitations. Endotracheal aspirates may represent colonization of the endotracheal tube rather than true infections, or if a nonbronchoscopic technique is used, fluid from a noninfected part of the lung may be sampled. Additionally, it may take up to 48 to 72 hours for culture results to return. Because of these limitations, the search for an accurate biomarker to predict VAP is underway. The proposed benefits of using biomarkers to aid in the diagnosis of VAP are that the results may return in hours instead of days and they can be noninvasively sampled by nursing staff. To date multiple biomarkers have been evaluated, and none provide the sensitivity and specificity needed to be a good diagnostic test; however, procalcitonin use has been shown to shorten antimicrobial duration without impacting survival.23

PREVENTION Because VAP is associated with high mortality rates, much study has gone into how it can be prevented. There is no one modification or treatment that is effective against the development of VAP, and preventative measures should be applied as a bundle for patients at risk. Implementation of preventative bundles has been shown to decrease the incidence of VAP in both pediatric and adult settings.24,25 A summary

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PART III  Advanced Respiratory Support

Ventilator-associated condition (VAC) If ≥2 calendar days of stable or decreasing daily minimum FiO2 or PEEP* is followed by either of the following worsening indicators of oxygenation: 1) ≥2 days increase in daily minimum FiO2 ≥0.20 over baseline period 2) ≥2 days increase in daily minimum PEEP ≥3 cm H2O over baseline period * Daily minimum FiO2 or PEEP are defined as lowest value during a calendar day maintained for ≥1 hour. PEEP values of 0–5 cm H2O are equivalent.

Infection-related ventilator-associated condition (IVAC) VAC and BOTH of the following criteria are met: 1) Canine: Body temperature of 102.6°F (39.2°C), or white blood cell count ≤6,000 cells/µl or ≥16,000 cells/µl Feline: Body temperature of 104.0°F (40.0°C), or white blood cell count ≤5,000 cells/µl or ≥19,000 cells/µl 2) A new antimicrobial agent is started and continued for ≥4 days

Possible ventilator-associated pneumonia

Probable ventilator-associated pneumonia

IVAC and ONE of the following criteria is met:

IVAC and ONE of the following criteria is met:

1) Purulent secretions from the lungs, bronchi, or trachea that contain ≥25 neutrophils (4+ or many) and ≤10 squamous epithelial cells (≤2+ or few) per low power field. 2) Positive qualitative, semi-quantitative, or quantitative culture of sputum, endotracheal aspirate, bronchoalveolar lavage, or protected specimen brush that excludes normal respiratory/oral flora or coagulasenegative Staphylococcus and Enterococcus spp. OR positive culture of any pathogen from lung tissue.

1) Purulent secretions defined in possible VAP and one of the following positive cultures: • Endotracheal aspirate with ≥105 CFU/ml* • Bronchoalveolar lavage with ≥104 CFU/ml* • Protected specimen brush with ≥103 CFU/ml* • Lung tissue with ≥104 CFU/g of any organism * with excluded organisms as in possible VAP

2) Positive pleural fluid culture not from an indwelling chest tube OR positive lung histopathology results indicating infection.

Fig. 40.1  ​Modified Centers for Disease Control and Prevention guidelines for surveillance of ventilator-associated events for veterinary use. Figure is based on reference 20 with criteria for systemic inflammation modified for dogs and cats based on Chapter 7 (SIRS, MODS, and Sepsis). CFU, colony forming units; FiO2, fraction of inspired oxygen, PEEP, positive end-expiratory pressure.

of nonpharmacologic and pharmacologic prevention strategies applicable to veterinary medicine that can minimize the occurrence of VAP are presented in Box 40.2.

Nonpharmacologic Strategies Training ICU personnel for the prevention of VAP can reduce incidence of this disease. Frequent evaluation of compliance with protocols and feedback to ICU nurses is needed to maintain a high level of care. This has been shown to decrease the incidence of VAP and increase compliance with protocols,26 with compliance increasing with lower nurse to patient ratios.27 If mechanical ventilation is not common, protocols should be reviewed at the initiation of each case to help ensure proper management. The World Health Organization and the CDC state that hand hygiene is one of the most important strategies for prevention and spread of infections. Proper hand hygiene, including alcohol-based hand rubs, can reduce the risk of VAP. Before the patient is touched, hands should

be washed or an alcohol-based hand rub should be used, then examination gloves worn. Immediately before ICU personnel touch the airway or oral cavity, proper hand hygiene should be performed. This includes performing hand hygiene before returning to the airway or oral cavity if other areas of the patient are examined. Longer duration of intubation is associated with an increased cumulative risk for VAP duration.28 When protocol-driven weaning from mechanical ventilation is used, there is evidence of shorter duration of ventilation as well as lower incidence of VAP.29 Once weaning protocols are in place, they may be nurse driven, which may decrease the duration of mechanical ventilation compared with physician-driven protocols.30 The ideal length of time for the use of a single ventilator circuit has not been established. A meta-analysis showed an increased risk of pneumonia when circuits were changed every 2 days versus every 7 days; not routinely changing the ventilator circuit did not increase the odds of VAP.31 Based on this, routine changing of the ventilator circuit should not occur unless contamination is noted.32

CHAPTER 40  Ventilator-Associated Pneumonia

BOX 40.1  Modified Centers for Disease

Control and Prevention Surveillance Definitions for Ventilator-Associated Pneumonia (PNU1)2

Imaging Test Evidence (Two or More Serial Chest Imaging Test Results With at Least One of the Following)a New and persistent or progressive and persistent Infiltrate Consolidation Cavitation Signs/Symptoms At least one of the following: Fever Leukopenia or leukocytosis And at least one of the following: New onset or change to purulent sputum or increased respiratory secretions New onset or worsening cough or respiratory distress Evidence of worsening gas exchange (e.g., oxygen desaturation, increased oxygen requirements, or increased ventilator demands) Crackles or bronchial breath sounds Laboratory At least one of the following: Organism identified from blood, pleural fluid, or lung tissue culture Positive cultureb or 5% cells with intracellular bacteria from lower respiratory tract Appropriate histopathologic evidence Patients must fulfill all three (Imaging, Signs/Symptoms, and Laboratory) criteria In patients without pulmonary or cardiac disease, one definitive chest imaging test result is acceptable. b Threshold values for cultured specimens are shown in Table 40.1. a

BOX 40.2  Preventative Measures that May Decrease the Incidence of VAP Nonpharmacologic Provide educational program for caregivers and monitoring of compliance Use of strict alcohol-based hand hygiene Minimize time of intubation with weaning protocols Do not change ventilatory circuit unless contamination occurs Aspiration of subglottic secretions Maintain endotracheal tube cuff pressure 25 cm H2O Minimize nurse to patient ratio Pharmacologic Perform oral care with dilute chlorhexidine Avoid increasing gastric pH prophylactically

As microaspiration and biofilm formation are two of the most important mechanisms in the development of VAP, much research into the ideal endotracheal tube has occurred. Research into tapered-cuff tubes and silver-coated tubes initially showed promise but have not been helpful in clinical trials.33 Other studies have investigated continuous control of cuff pressure, polyurethane cuffed tubes, and lowvolume low-pressure tubes into which further research is needed before recommendations can definitively be made. At this time in veterinary medicine, the only recommendation is to use sterile lowpressure high-volume cuffed endotracheal tubes if possible.

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There is strong evidence that suctioning of subglottic secretions can help reduce the occurrence of VAP.33 Tracheal tubes with a port that exits above the cuff for continuous suction exist, but their cost effectiveness is questionable. Intermittent suctioning of subglottic secretions is currently recommended in human medicine; however, this approach may not be practical in veterinary medicine. To help prevent microaspiration, the cuff on the endotracheal tube should be maintained with a pressure of 25 to 30 cm H2O. The ideal frequency of monitoring of this pressure has not been established. See Chapter 34 for a description of airway management to help prevent VAP.

Pharmacologic Strategies Performing oral antisepsis with chlorhexidine can reduce the incidence of VAP and is now considered a standard of care. The ideal concentration of chlorhexidine to be used has not been determined; however, favorable effects have been seen from 0.12% to 2%. The ideal frequency of oral antisepsis has not been determined; however, two to four times a day has been recommended. Brushing of teeth has been investigated as an adjunct to chlorhexidine use. In a recent systematic review, it was not shown to demonstrate a benefit over chlorhexidine use alone.34 The role of increasing gastric pH with histamine-2 receptor antagonists (H2RA) and proton pump inhibitors in mechanical ventilation is controversial in humans. The proposed benefit is to reduce stress-related mucosal disease and ulceration, whereas the proposed detriment is a higher rate of gastric colonization with bacteria. A meta-analysis comparing the use of H2RA with sucralfate showed no difference in effectiveness in the treatment of overt bleeding, but H2RA use had higher rates of gastric colonization and VAP.35 Because stress-related ulcers are rare in dogs and cats and because gastric colonization has been linked to development of VAP in humans, the routine use of gastric antacid drugs is not recommended in any species on mechanical ventilation; they should be reserved for use in cases of demonstrated gastrointestinal ulceration. Probiotics have been investigated as an alternative therapy to reduce the incidence of VAP in the hope to reduce colonization of the gastrointestinal tract with pathogenic bacteria. Some studies have shown a beneficial effect, while others have not, including a recent randomized controlled trial.36 As there is significant heterogeneity among study designs, further research is needed in this area before definitive recommendations can be made.

TREATMENT The initiation of antimicrobial therapy for VAP should commence as soon as there is clinical suspicion and airway microbiological samples have been taken and analyzed (i.e., as soon as you have reached possible VAP in the algorithm). Delays in appropriate antimicrobial administration can increase the mortality rates seen with VAP. According to the Infectious Disease Society of America (IDSA) deciding which empiric antimicrobial to be used, should be informed by the local distribution of pathogens and their antimicrobial susceptibilities.1 If local guidelines are not available, then broad-spectrum antimicrobial coverage for should be initiated. Risk factors for MDR organisms in VAP include prior antimicrobial use within 90 days, septic shock at the time of diagnosis, acute respiratory distress syndrome preceding VAP, and hospitalization for 5 days prior to occurrence of VAP. If these risk factors are present, expanding coverage for MDR organisms may be indicated (see Chapter 99). The IDSA recommends the use of an antipseudomonal antimicrobial empirically such as a fluoroquinolone, piperacillin-tazobactam, or ceftazidime for VAP due to its high prevalence in this disease. If methicillin-resistant Staphylococcus spp. are

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PART III  Advanced Respiratory Support

TABLE 40.1  Threshold Values for Cultured

Specimens Used in the Diagnosis of Pneumonia2 Collection Technique

Quantitative Threshold

Bronchoscopic bronchoalveolar lavage Blind bronchoalveolar lavage Bronchoscopic protected specimen brush Blind protected specimen brush Endotracheal aspirate Lung tissue

104 CFU/ml 104 CFU/ml 103 CFU/ml 103 CFU/ml 105 CFU/ml 104 CFU/g tissue

prevalent locally, and Gram-positive cocci are seen on respiratory fluid cytology, vancomycin may be added empirically. In a veterinary study in dogs and cats with respiratory failure and a positive lower respiratory tract culture, only amikacin and carbapenems had greater than 90% efficacy against all aerobic bacteria tested, making carbapenems a reasonable empiric option for dogs and cats when risk factors for MDR organisms are present.14 Intravenous aminoglycosides are not used as monotherapy because of their poor penetration into infected lung tissue. Choosing broad-spectrum empiric therapy mandates that, when culture and susceptibility results are available, deescalation to an antimicrobial with a narrow, more focused spectrum should occur. Aerosolized antimicrobials have the potential advantage of achieving high drug concentrations in the lungs and potentially reaching biofilms while avoiding systemic absorption and toxicities. Aminoglycosides or polymyxins are most commonly used, and both have concerns for nephrotoxicity. With mechanical ventilation, an ultrasonic or vibrating plate nebulizer should be used to maximize delivery to the site of infection. There has not been a strong association with improved mortality with routine use, and current recommendations are only to include inhaled antimicrobials when VAP is due to Gram-negative bacilli (e.g., Acinetobacter spp. or Pseudomonas aeruginosa) that are susceptible to only aminoglycosides or polymyxins.1 The majority of infections can be treated by a course of appropriate antimicrobials for a total duration of 7 days.1 Four randomized clinical trials have been performed that all agree on a short course of antimicrobials for VAP. In the largest it was demonstrated that patients treated for 8 days had no difference in mortality, recurrent infections, or ventilator-free days or length of ICU hospitalization compared with 15 days of antimicrobial therapy.37 They did document that patients with VAP caused by Gram-negative fermenting bacilli, such as Pseudomonas aeruginosa or Acinetobacter spp., had higher mortality if only 8 days of treatment were used. However, in patients with recurrent infections, MDR pathogens emerged less in the 8-day treatment group. If a fermenting Gram-negative bacillus is cultured, a 14- to 21-day course of antimicrobial therapy should be considered.

REFERENCES 1. Kalil AC, Metersky ML, Klompas M, et al: Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society, Clin Infect Dis 63(5):e61-e111, 2016. 2. National Healthcare Safety Network manual, Device-associated module: Pneumonia (Ventilator-associated [VAP] and non-ventilator-associated Pneumonia [PNEU]) Event. www.cdc.gov/nhsn/pdfs/pscmanual/6pscvapcurrent.pdf. Accessed January 2, 2020.

3. Metersky ML, Wang Y, Klompas M, Eckenrode S, Bakullari A, Eldridge N: Trend in ventilator-associated pneumonia rates between 2005 and 2013, JAMA 316(22):2427-2429, 2016. 4. Arthur LE, Kizor RS, Selim AG, van Driel ML, Seoane L: Antibiotics for ventilator-associated pneumonia, Cochrane Database Syst Rev 10:Cd004267, 2016. 5. Dudeck MA, Edwards JR, Allen-Bridson K, et al: National Healthcare Safety Network report, data summary for 2013, Device-associated Module, Am J Infect Control 43(3):206-221, 2015. 6. Giard M, Lepape A, Allaouchiche B, et al: Early- and late-onset ventilatorassociated pneumonia acquired in the intensive care unit: comparison of risk factors, J Crit Care 23(1):27-33, 2008. 7. Sackner MA, Hirsh J, Epstein S: Effect of cuffed endotracheal tubes on tracheal mucous velocity, Chest 68:774, 1975. 8. Boomer JS, To K, Chang KC, et al: Immunosuppression in patients who die of sepsis and multiple organ failure, JAMA 306:2594, 2011. 9. Conway MA, Kefala K, Wilkinson TS, et al: C5a mediates peripheral blood neutrophil dysfunction in critically ill patients, Am J Respir Crit Care Med 180:19, 2009. 10. Wilkinson TS, Morris AC, Kefala K, et al: Ventilator-associated pneumonia is characterized by excessive release of neutrophil proteases in the lung, Chest 142:1425, 2012. 11. Hess DR: Noninvasive positive-pressure ventilation and ventilator-associated pneumonia, Respir Care 50:924, 2005. 12. Gao F, Yang LH, He HR, et al. The effect of reintubation on ventilator- associated pneumonia and mortality among mechanically ventilated patients with intubation: a systematic review and meta-analysis, Heart Lung 45(4):363-371, 2016. 13. Adair CG, Gorman SP, Feron BM, et al: Implications of endotracheal tube biofilm for ventilator-associated pneumonia, Intensive Care Med 25:1072, 1999. 14. Epstein SE, Mellema MS, Hopper K: Airway microbial culture and susceptibility patterns in dogs and cats with respiratory disease of varying severity, J Vet Emerg Crit Care 20:587, 2010. 15. Kantorova I, Svoboda P, Scheer P, et al: Stress ulcer prophylaxis in critically ill patients: a randomized controlled trial, Hepatogastroenterology 51:757, 2004. 16. Mehta A, Bhagat R: Preventing ventilator-associated infections, Clin Chest Med 37(4):683-692, 2016. 17. Ibn Saied W, Souweine B, Garrouste-Orgeas M, et al: Respective impact of implementation of prevention strategies, colonization with multiresistant bacteria and antimicrobial use on the risk of early- and late-onset VAP: an analysis of the OUTCOMEREA network, PLoS One 12(11):e0187791, 2017. 18. Patro S, Sarangi G, Das P, et al: Bacteriological profile of ventilator-associated pneumonia in a tertiary care hospital, Indian J Pathol Microbiol 61(3):375-379, 2018. 19. Magill SS, Klompas M, Balk R, et al: Developing a new, national approach to surveillance for ventilator-associated events: executive summary, Clin Infect Dis 57(12):1742-1746, 2013. 20. National Healthcare Safety Network manual, Device-associated module: Ventilator-associated event protocol. https://www.cdc.gov/nhsn/PDFs/ pscManual/10-VAE_FINAL.pdf. Accessed January 2, 2020. 21. Magill SS, Rhodes B, Klompas M: Improving ventilator-associated event surveillance in the National Healthcare Safety Network and addressing knowledge gaps: update and review, Curr Opin Infect Dis 27(4):394-400, 2014. 22. Staub LJ, Biscaro RRM, Maurici R: Accuracy and applications of lung ultrasound to diagnose ventilator-associated pneumonia: a systematic review, J Intensive Care Med 33(8):447-455, 2018. 23. Dimopoulos G, Matthaiou DK: Duration of therapy of ventilator-associated pneumonia, Curr Opin Infect Dis 29(2):218-222, 2016. 24. de Neef M, Bakker L, Dijkstra S, Raymakers-Janssen P, Vileito A, Ista E: Effectiveness of a ventilator care bundle to prevent ventilator-associated pneumonia at the PICU: a systematic review and meta-analysis, Pediatr Crit Care Med 20(5):474-480, 2019. 25. Pileggi C, Mascaro V, Bianco A, Nobile CGA, Pavia M: Ventilator bundle and its effects on mortality among ICU patients: a meta-analysis, Crit Care Med 46(7):1167-1174, 2018.

CHAPTER 40  Ventilator-Associated Pneumonia 26. Mogyorodi B, Dunai E, Gal J, Ivanyi Z: Ventilator-associated pneumonia and the importance of education of ICU nurses on prevention - preliminary results, Interv Med Appl Sci 8(4):147-151, 2016. 27. Aloush SM: Does educating nurses with ventilator-associated pneumonia prevention guidelines improve their compliance? Am J Infect Control 45(9):969-973, 2017. 28. Wolkewitz M, Palomar-Martinez M, Alvarez-Lerma F, Olaechea-Astigarraga P, Schumacher M: Analyzing the impact of duration of ventilation, hospitalization, and ventilation episodes on the risk of pneumonia, Infect Control Hosp Epidemiol 40(3):301-306, 2019. 29. Dries DJ, McGonigal MD, Malian MS, et al: Protocol-driven ventilator weaning reduces use of mechanical ventilation, rate of early reintubation and ventilator-associated pneumonia, J Trauma 56:943, 2004. 30. Danckers M, Grosu H, Jean R, et al: Nurse-driven, protocol-directed weaning from mechanical ventilation improves clinical outcomes and is well accepted by intensive care unit physicians, J Crit Care 28(4):433-441, 2013. 31. Han J, Liu Y: Effect of ventilator circuit changes on ventilator-associated pneumonia: a systematic review and meta-analysis, Respir Care 55:467, 2010.

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32. Rouze A, Martin-Loeches I, Nseir S: Airway devices in ventilator-associated pneumonia pathogenesis and prevention, Clin Chest Med 39(4):775-783, 2018. 33. Rouze A, Jaillette E, Poissy J, Preau S, Nseir S: Tracheal tube design and ventilator-associated pneumonia, Respir Care 62(10):1316-1323, 2017. 34. de Camargo L, da Silva SN, Chambrone L: Efficacy of toothbrushing procedures performed in intensive care units in reducing the risk of ventilator-associated pneumonia: a systematic review, J Periodontal Res 54(6):601-611, 2019. 35. Huang J, Cao Y, Liao C, et al: Effect of histamine-2-receptor antagonists versus sucralfate on stress ulcer prophylaxis in mechanically ventilated patients: a meta-analysis of 10 randomized controlled trials, Crit Care 14:R194, 2010. 36. Mahmoodpoor A, Hamishehkar H, Asghari R, Abri R, Shadvar K, Sanaie S: Effect of a probiotic preparation on ventilator-associated pneumonia in critically ill patients admitted to the intensive care unit: a prospective double-blind randomized controlled trial, Nutr Clin Pract 34(1):156-162, 2019. 37. Chastre J, Wolff M, Fagon J, et al: Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults, JAMA 290:2588, 2003.

Part IV  Cardiovascular Disorders

41 Mechanisms of Heart Failure Mark A. Oyama, DVM, MSCE, DACVIM (cardiology) KEY POINTS • There are several mechanisms of heart failure, all of which stimulate similar neurohormonal activation and myocardial tissue hypertrophy. • The relationship between preload and cardiac performance (Frank–Starling mechanism) provides insight into the genesis of congestive heart failure.

• Staging nomenclature has been developed to help describe the clinical progression of heart disease.

Heart failure is defined as the heart’s inability to meet the metabolic needs of the peripheral tissues or instances when the heart can only do so in the presence of increased venous filling pressures.1 The specific mechanisms leading to heart failure are varied and complex, yet a basic understanding of the interplay between the heart and kidneys, as well as various neurohormonal systems such as the sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS), is needed for successful treatment of heart failure. Important mechanisms of cardiac injury also include alterations in intracellular calcium cycling, myocardial and vascular remodeling, and deficiencies in myocardial energy production, all of which perpetuate further neuroendocrine activation as part of a vicious cycle (Fig. 41.1). The clinical signs of heart failure include those relating to poor cardiac output (i.e., forward heart failure) and to congestion (i.e., backward heart failure). Typical signs of low cardiac output include weakness, activity intolerance, hypothermia, and depressed mentation. Inadequate tissue perfusion results in lactic acidosis, azotemia, and oliguria. In animals with congestive heart failure (CHF), elevated venous filling pressure causes exudation of fluid from pulmonary or systemic capillary beds, resulting in pulmonary edema, pleural effusion, and/or ascites. In reality, neither of these forms of heart failure occurs independent of the other, and dysfunction always includes some combination of reduced cardiac output along with variably detected degrees of congestion. The emergent heart failure patient requires acute manipulation of preload, afterload, contractility, atrioventricular synchrony, and heart rate so that forward cardiac output is improved and congestion alleviated. Chronic therapy for patients with heart failure concentrates on the heart as part of an integrated neuroendocrine system rather than an isolated muscular pump. Thus, with chronic therapy, targeting the neurohormonal pathways is of equal or greater importance than muscular pump function in the setting of the failing heart.

NEUROHORMONAL ASPECTS OF HEART FAILURE

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The two classic neurohormonal pathways involved in the genesis of heart failure are the RAAS and the SNS. The natriuretic peptides, endothelin, and vasopressin systems also play a role. The importance of these and other neurohormonal systems is highlighted by the fact that many of the most effective drugs in treating chronic heart failure are those that specifically target these systems.

Renin-Angiotensin-Aldosterone System The primary trigger for the activation of the RAAS is the heart’s inability to provide normal renal perfusion. Decreased renal blood flow and sodium delivery to the distal portions of the nephron induces renin release from the macula densa. Renin converts angiotensinogen to angiotensin I, which is then rapidly converted to angiotensin II by angiotensin-converting enzyme (ACE), located primarily in the pulmonary vasculature. Angiotensin II increases the production of downstream aldosterone, and both molecules are important effectors for many of the maladaptive responses that promote further cardiac injury and heart failure, including renal sodium and water retention, myocardial apoptosis, cardiac and vascular remodeling and fibrosis, increased thirst, and vasoconstriction. Activation of the RAAS in dogs with heart failure has been well described.2-4 The classic description of the RAAS involves circulating angiotensin II and aldosterone; local tissue RAAS is thought to significantly contribute to cardiac remodeling and injury. Moreover, angiotensin II can be generated from pathways independent of ACE and elevations of angiotensin II and aldosterone that can occur in spite of ACE inhibitor therapy. The end result of circulating and tissue RAAS activation is retention of fluid (which promotes development of CHF) and maladaptive myocardial and vascular remodeling (which cause further cardiac injury and depression of cardiac function).

CHAPTER 41  Mechanisms of Heart Failure

Remodeling

peptides, and increased peptide clearance or degradation. In humans with acute CHF, exogenous BNP helps alleviate the severity of dyspnea. Because of their important roles in the pathophysiology of heart failure, both ANP and BNP are forming the basis for new diagnostic, staging, and prognostic assays in dogs and cats with heart disease.

Cardiac injury

Apoptosis/necrosis Abnormal Ca2+ Energy deficiency Maladaptive responses

Heart Failure

Decreased output

ET-1 ADH RAAS SNS NP

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Fig. 41.1  The vicious cycle of heart failure. Cardiac injury leads to decreased cardiac output and tissue perfusion and subsequent neurohormonal activation. Activity of the sympathetic nervous system (SNS), renin-angiotensin-aldosterone system (RAAS), vasopressin (antidiuretic hormone [ADH]) system, and endothelin-1 system (ET-1) is upregulated and triggers a host of maladaptive responses. These responses include myocardiocyte energy depletion and deficiency, abnormal calcium ion cycling, apoptosis/necrosis, and myocardial remodeling. The maladaptive responses contribute to ongoing cardiac injury, thus completing the vicious cycle of heart failure. The natriuretic peptide (NP) system counteracts the activity of the SNS and RAAS but is not sufficiently potent to stop the cycle from continuing.

Endothelin and Vasopressin Systems Endothelin 1 is a potent vasoconstrictor produced by vascular endothelial cells in response to sheer stress, angiotensin II, and other various cytokines. Together with angiotensin II, endothelin 1 causes vasoconstriction and increased cardiac afterload. Endothelin 1 is elevated in dogs and cats with heart failure8,9 and, in addition to its vascular effects, endothelin 1 alters normal calcium cycling within muscle cells and is directly toxic to myocardiocytes. There is a potential therapeutic role for endothelin 1 antagonists in cases of pulmonary hypertension, which is a serious complication in many patients with heart disease. Arginine vasopressin or antidiuretic hormone is released following stimulation of the baroreceptors in the carotid and aortic arch secondary to decreased intravascular pressure. Subsequently, there is increased reabsorption of free water within the renal collecting duct, which contributes to development of fluid overload, CHF, and dilutional hyponatremia. Dilutional hyponatremia indicates heightened free water retention to the extent that serum sodium concentrations are decreased, despite an overall excess of body-wide sodium. In both humans and veterinary patients, dilutional hyponatremia is a marker of severe neurohormonal activation and is a poor prognostic indicator.10

MYOCARDIAL REMODELING Sympathetic Nervous System The SNS is an evolutionary response to stress. In times of danger, the SNS, through its main effector molecules, norepinephrine and epinephrine, increases heart rate, cardiac output, and increases blood flow to important stress response organs such as skeletal muscle. The SNS is, however, a short-term response and chronic activation leads to adrenergic receptor downregulation, persistent tachycardia, increased myocardial oxygen demand, and myocyte necrosis. Thus, when the acute response of the SNS becomes a chronic response, SNS activity ultimately leads to further cardiac damage. In humans with heart disease, increased norepinephrine concentrations are a significant risk factor for mortality. Increased SNS activity is likely one of the earliest systemic responses to cardiac injury. In the emergent patient with lowoutput heart failure or CHF, temporary augmentation of already heightened SNS activity is occasionally needed to treat the acute event, but long-term stimulation of the SNS is not an objective of chronic heart failure therapy.

Natriuretic Peptide System Myocardial tissue produces two main hormones that induce natriuresis, diuresis, and vasodilation. These so-called natriuretic peptides include atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), and both are produced primarily in response to the stretch or stress of myocardial tissue. The natriuretic peptide system serves as a counterregulatory system to the RAAS and SNS. Circulating concentrations of ANP and BNP are increased in dogs and cats with heart disease, roughly in proportion to disease severity.5-7 In the later stages of disease, the beneficial activity of the natriuretic peptide system is overwhelmed, resulting in the clinical manifestations of CHF. The reasons for the loss of natriuretic peptide efficacy are complex but likely involve a combination of natriuretic peptide receptor downregulation, inappropriate or inadequate production or processing of the

The pathophysiology of heart failure and its resultant morbidity and mortality are closely related to progressive alterations in cardiac structure.11 Angiotensin II, norepinephrine, aldosterone, and other related signaling molecules cause cardiac hypertrophy and alter cardiac architecture. These changes primarily consist of two different and distinct patterns of hypertrophy. Concentric hypertrophy is the response to conditions causing pressure overload (i.e., increased afterload), as in the case of systemic hypertension or subaortic stenosis. Increased afterload triggers the replication of sarcomeres in parallel, resulting in an increase in the relative thickness of the ventricular walls. Conversely, in instances of volume overload, such as mitral regurgitation or dilated cardiomyopathy, sarcomeres replicate in series, leading to the elongation of myocytes and dilation of the ventricular chamber. Cardiac hypertrophy is not without consequence, and the limitations of concentric hypertrophy include increased myocardial oxygen demand, endocardial ischemia, fibrosis, collagen disruption, and injury to small coronary vessels. The limitations of eccentric hypertrophy include increased myocardial wall stress, myocyte injury or necrosis, and myocyte slippage. The importance of myocardial remodeling in the pathophysiology of heart disease is highlighted by the fact that interventions that reduce or reverse remodeling are associated with improved survival.11

ABNORMAL CALCIUM ION HANDLING Proper cardiac contraction relies on the influx and efflux of calcium ions within the myocardial cells (Fig. 41.2). During systole, calcium ions enter the myocardial cell, which triggers the release of additional calcium ions from the main storage area of calcium, the sarcoplasmic reticulum (SR). Calcium stored in the SR flows through the ryanodine channel and then binds to troponin C located on the actin and myosin complex. The binding of calcium to troponin C begins the cascade of

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Myosin isoform switching

Impaired Ca2+ transients and ryanodine function

Ca2+

Cytoplasm

+

Myosin

Sarcoplasmic reticulum

Ryanodine receptor

Actin Troponin-C ATP

Ca2+ channels

Ca2+

ADP SERCA2a

Ca2+

– ATP

Phospholamban

Phospholamban upregulation

ADP

SERCA downregulation Energy depletion

Fig. 41.2  Myocyte calcium ion cycling in heart failure. Contraction of the actin-myosin sarcomere complex requires cytoplasmic calcium ions. These ions enter the cytoplasm partly through sarcolemmal calcium channels but mostly from intracellular calcium stores within the sarcoplasmic reticulum. Exit of calcium from the sarcoplasmic reticulum is mediated by the ryanodine receptor. Once released, the cytosolic calcium is then free to bind to troponin C located on the actin molecule. This binding initiates contraction of the sarcomere. Once contraction is complete, calcium is discharged from the troponin molecule and is taken back up into the sarcoplasmic reticulum by the ATP-dependent SERCA2a channel. Phospholamban is an intracellular calcium regulator of calcium and inhibits reuptake by SERCA2a. In animals with heart failure, numerous maladaptive changes within the calcium cycle lead to inappropriate distribution of intracellular calcium, poor sarcomeric contraction, cell injury, and apoptosis or necrosis. SERCA, sarcoplasmic/endoplasmic reticulum Ca21-ATPase.

events that results in sarcomere contraction. As soon as contraction is complete, release of calcium from troponin C initiates the relaxation cycle, and calcium ions are quickly sequestered back into the SR through the sarcoplasmic/endoplasmic reticulum Ca21-ATPase (SERCA) channel. Other effector molecules in the cytosol, such as phospholamban, help regulate the reuptake of calcium. In patients with heart disease, there are a variety of abnormalities within this system that ultimately contribute to poor global systolic and diastolic function (Fig. 41.2). Inappropriate intracellular calcium distribution can predispose the cells to electrical abnormalities, apoptosis, or necrosis.

ABNORMAL MYOCARDIAL ENERGY PRODUCTION Myocyte mitochondria provide high-energy phosphate molecules that fuel calcium and other ion pumps, sarcomere contraction and relaxation, maintenance of the resting cell membrane potential, and propagation of the cardiac action potential. In cases of severe heart disease, myocardial oxygen and substrate delivery may be decreased, resulting in ischemia and inefficient energy production via anaerobic metabolism. In dogs with myocardial disease, the oxidative phosphorylation chain located within mitochondria lack critical cytochromes and enzymes needed for energy production.12 The heart can utilize both glucose and free fatty acids as its main substrates for energy production. In cases of heart failure, the heart preferentially uses glucose, which requires less oxygen to metabolize than fatty acids.

GLOBAL CARDIAC FUNCTION The Frank–Starling Mechanism as a Key to Understanding Heart Failure The Frank–Starling mechanism describes the fundamental relationship between what is put into the heart (i.e., preload) and what comes out of the heart (i.e., cardiac output). The mechanism states that an increase in the initial volume or pressure within the ventricle increases the strength of the subsequent ventricular contraction. Thus, up to a physiologic limit, preload and contractility are positively associated. The Frank–Starling mechanism is a useful tool to describe the pathologic alterations to global cardiac function that occur in the setting of heart disease, as well as the rationale behind the use of many different cardiac medications. In health, the heart operates within a range of preload conditions that acutely affect performance. In this way, the heart self-regulates its performance based on ventricular volume and pressure. During times of increased adrenergic drive, such as when exercising, the Frank– Starling relationship is shifted up and leftward, resulting in further improvement in cardiac performance, which is needed to support the increased metabolic needs of the skeletal muscle and other organs (Fig. 41.3A). In conditions of disease, the Frank–Starling relationship is depressed downward and rightward so that despite fluid retention and increased preload, the subsequent contraction is less vigorous. Excessive amounts of preload produce CHF and its classic clinical

CHAPTER 41  Mechanisms of Heart Failure

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Exercise

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Cardiac Output Low output heart failure

Preload

Diuretics

B

Low output heart failure

C

Diseased

Preload

Preload

Cardiac Output

A

Diseased

Cardiac Output

Cardiac Output

Healthy

CHF

D

>25 mm Hg CHF develops

Mixed vasodilator Diuretics

Preload

Positive inotrope

CHF

Fig. 41.3  The Frank–Starling mechanism in health and disease. A, The Frank–Starling mechanism describes increased cardiac output in response to increased preload. During exercise, sympathetic tone present elevates the curve, whereas cardiac disease lowers the curve. In the diseased state, cardiac output at any given amount of preload is decreased. Additionally, in the diseased state, change in preload effects relatively little change in cardiac output because of the flat slope of the curve. B, Neurohormonal activation and excessive sodium and water retention lead to elevated intracardiac and venous pressure. Intravenous pressures greater than 25 mm Hg typically result in signs of congestion (triangle). Diuretics, by reducing preload, move performance leftward along the curve and to a position below the threshold for congestion (square). Because of the relatively flat slope of the curve, diuresis has relatively little detrimental effect on cardiac output. C, Cardiac injury can also result in low cardiac output (triangle). Positive inotropic drugs shift the curve upward so that cardiac output at any given amount of preload is improved. D, Patients with severe heart failure can exhibit signs of both congestion and low output (triangle). These patients require both diuretics and positive inotropes to improve function. Mixed vasodilators (those that provide both venous and arterial vasodilation) shift the curve both upward and leftward and are often used if systemic blood pressure will allow. CHF, congestive heart failure.

signs such as shortness of breath or abdominal distention. The hearts of patients with CHF operate on a point to the far right of the disease curve (Fig. 41.3B). In patients with low-output heart failure, changes in preload produce an inadequate contractile response and clinical signs such as weakness, activity intolerance, or collapse predominate (Fig. 41.3C). In the direst of circumstances, clinical signs of both forward and backward heart failure exist simultaneously (Fig. 41.3D). The Frank–Starling curve reveals why diuretics, vasodilators, and positive inotropes are used to acutely improve cardiac performance. Diuretics, by virtue of fluid loss, reduce preload and intravascular pressure, shifting the heart to the left along its curve (Fig. 41.3B). This intervention alleviates signs of congestion without markedly affecting overall cardiac performance. Excessive diuresis could result in movement farther to the left and the potential to significantly reduce cardiac output. In the clinical situation, this is unlikely to occur in the congested patient even with aggressive diuretic therapy. Positive inotropes, such as dobutamine, mid-dose dopamine, and pimobendan, improve the contractility of the heart and shift the curve upward, resulting in improved cardiac output even as preload is reduced (Fig. 41.3C). Finally, vasodilators act to either reduce afterload (arterial vasodilators) or preload (venous vasodilators). Arterial vasodilators (e.g., nitroprusside, nicardipine, clevidipine, hydralazine) improve cardiac performance by shifting the curve upward in a manner similar to a

positive inotrope, whereas venous vasodilators (e.g., low dose nitrates) reduce preload through an increase in the capacitance of the venous system and shift the curve leftward, similar to diuretics. Mixed vasodilators such as ACE inhibitors result in a combination of both upward and leftward adjustment (Fig. 41.3D).

Diastolic Heart Dysfunction Many types of heart disease primarily are due to diastolic myocardial dysfunction, as opposed to systolic dysfunction. In veterinary medicine, the classic example of diastolic heart disease is hypertrophic cardiomyopathy in cats. Diastolic heart disease can be due to primary impairments of ventricular relaxation, filling, or compliance or secondary to disease of the pericardium. In the normal heart, the ventricular chamber expands readily in diastole because of high compliance (the ability of the ventricle to accommodate blood volume at a low hydrostatic filling pressure). Ventricular compliance is affected by the thickness of the ventricular wall (concentric hypertrophy decreases compliance), changes in the cytoskeleton and extracellular matrix (fibrosis decreases compliance), and function of the pericardium (pericardial disease or effusion reduces ventricular distensibility). In the early phase of diastole, relaxation requires energy as the movement of calcium ions back into the SR operates using ATP-driven pumps (Fig. 41.2). In circumstances of myocardial ischemia and energy deficit, active relaxation is

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delayed, and early filling of the ventricle is diminished. The result of poor diastolic function is a reduction in cardiac output, which drives the same neurohormonal responses and clinical consequences that operate in systolic dysfunction. Treatment of diastolic dysfunction is targeted toward improving ventricular relaxation, increasing ventricular compliance, and alleviating any existing pericardial disease. In the absence of obvious pericardial disease, treatment focuses on increasing the time available for diastolic filling by decreasing heart rate, suppression of arrhythmias, and alleviation of congestion through the use of diuretics and vasodilators. Positive inotropes play little to no role in the management of diastolic dysfunction and might actually be deleterious.

CLINICAL STAGING AND ASSESSMENT OF HEART FAILURE Patients with heart disease are typically classified according to the presence or absence of clinical signs and whether there is evidence of cardiac remodeling. A common veterinary staging system,13 primarily developed for dogs with degenerative mitral valve disease, involves four clinical classes and can be modified to be applicable to heart disease from a variety of causes. The first class, Class A, describes overtly healthy animals that are at risk for developing heart disease. This class would contain, for instance, Cavalier King Charles Spaniels, Doberman Pinschers over the age of 4, and adult Maine Coon cats. Animals in Class A have no detectable evidence of cardiac disease but might benefit from screening programs to detect the possible onset of disease as they age. Class B describes animals with diagnostic evidence of heart disease but without clinical signs, such as asymptomatic dogs with heart murmur or asymptomatic cats with an arrhythmia. Class B is further divided into Class B1, which describes patients with little to no radiographic or echocardiographic evidence of cardiac enlargement or remodeling, and Class B2, which is the same as Class B1 but with significant radiographic or echocardiographic evidence of cardiac remodeling that indicates the potential benefit for initiating medical intervention. Class C describes animals with cardiac remodeling, as well as current or historical clinical signs of heart failure, and Class D describes patients with severe and debilitating signs of heart failure even at rest. Thus, the transition point between asymptomatic (preclinical) heart disease and symptomatic heart failure lies between Class B2 and Class C/D. It is important to note that not all animals in Class A will develop disease, nor will all animals in Class B suffer from sufficient severity of disease to cause clinical signs, and many animals will remain in Class A or B for the entirety of their life.

Clinical Manifestations of Heart Failure Low Output Versus Congestive Failure Most clinical signs of heart failure in the dog and cat involve CHF. Pulmonary venous pressures greater than 25 mm Hg and systemic venous pressures greater than 20 mm Hg are sufficient to produce congestion that manifests as pulmonary edema, pleural effusion, or ascites. Common owner complaints are increased respiratory effort and rate, coughing, activity intolerance, and abdominal distention. Peripheral edema of the limbs or subcutaneous tissues is rare in small animals with CHF. Patients with severe myocardial dysfunction have insufficient cardiac performance to provide adequate cardiac output and typically present with clinical signs of low-output heart failure. These commonly include weakness, depressed mentation, cardiogenic shock, and syncope. Diagnostic testing in these patients commonly reveals hypothermia, hypotension, azotemia, anuria or oliguria, and lactic acidosis. Patients with low-output heart failure require positive inotropes to improve contractility (see Chapters 147 and 150, Catecholamines and Pimobendan, respectively).

Left-sided Versus Right-sided Heart Failure CHF presents as predominantly left- or right-sided failure or occasionally as biventricular failure (see Chapters 42 and 45, Ventricular Failure and Myocardial Remodeling and Canine Valvular Heart Disease, respectively). Common causes of left-sided heart failure in dogs include degenerative mitral valve disease, dilated cardiomyopathy, and patent ductus arteriosus. Common causes of left-sided heart failure in cats include hypertrophic and restrictive cardiomyopathy. In both dogs and cats, pulmonary edema is exclusively a sign of left-sided heart failure. Common causes of right-sided heart failure in dogs include dilated cardiomyopathy, degenerative or congenital tricuspid valve disease, and pulmonary hypertension. In the dog, right-sided heart failure manifests as pleural effusion or ascites, whereas in the cat, pleural effusion can occur as a result of either left- or right-sided heart failure. In the author’s experience, right-sided heart failure is relatively rare in cats, and most cases of cardiogenic pleural effusion in cats are due to left-sided disease. Ascites as a sign of right-sided heart failure in cats is relatively uncommon, and most cats with ascites are afflicted with noncardiac diseases.

REFERENCES 1. Givertz MM, Colucci WS, Braunwald E: Clinical aspects of heart failure; pulmonary edema, high-output failure. In Zipes DS, Libby P, Bonow RO, et al, editors: Heart disease: a textbook of cardiovascular medicine, ed 7, Philadelphia, 2005, Elsevier Saunders. 2. Tidholm A, Haggstrom J, Hansson K: Effects of dilated cardiomyopathy on the renin-angiotensin-aldosterone system, atrial natriuretic peptide activity, and thyroid hormone concentrations in dogs, Am J Vet Res 62:961, 2001. 3. Sisson DD: Neuroendocrine evaluation of cardiac disease, Vet Clin North Am Small Anim Pract 34:1105, 2004. 4. Haggstrom J, Hansson K, Kvart C, et al: Effects of naturally acquired decompensated mitral valve regurgitation on the renin-angiotensin- aldosterone system and atrial natriuretic peptide concentration in dogs, Am J Vet Res 58:77, 1997. 5. Fox PR, Rush JE, Reynolds CA, et al: Multicenter evaluation of plasma N-terminal probrain natriuretic peptide (NT-pro BNP) as a biochemical screening test for asymptomatic (occult) cardiomyopathy in cats, J Vet Intern Med 25:1010, 2011. 6. Oyama MA, Fox PR, Rush JE, et al: Clinical utility of serum N-terminal pro-B-type natriuretic peptide concentration for identifying cardiac disease in dogs and assessing disease severity, J Am Vet Med Assoc 232:1496, 2008. 7. Connolly DJ, Magalhaes RJ, Syme HM, et al: Circulating natriuretic peptides in cats with heart disease, J Vet Intern Med 22:96, 2008. 8. O’Sullivan ML, O’Grady MR, Minors SL: Plasma big endothelin-1, atrial natriuretic peptide, aldosterone, and norepinephrine concentrations in normal Doberman Pinschers and Doberman Pinschers with dilated cardiomyopathy, J Vet Intern Med 21:92, 2007. 9. Prosek R, Sisson DD, Oyama MA, et al: Measurements of plasma endothelin immunoreactivity in healthy cats and cats with cardiomyopathy, J Vet Intern Med 18:826, 2004. 10. Brady CA, Hughes D, Drobatz KJ: Association of hyponatremia and hyperglycemia with outcome in dogs with congestive heart failure, J Vet Emerg Crit Care 14:177, 2004. 11. Cohn JN, Ferrari R, Sharpe N: Cardiac remodeling—concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Behalf of an International Forum on Cardiac Remodeling, J Am Coll Cardiol 35:569, 2000. 12. Lopes R, Solter PF, Sisson DD, et al: Characterization of canine mitochondrial protein expression in natural and induced forms of idiopathic dilated cardiomyopathy, Am J Vet Res 67:963, 2006. 13. Keene BW, Atkins CE, Bonagura JD, et al: ACVIM consensus guidelines for the diagnosis and treatment of myxomatous mitral valve disease in dogs, J Vet Intern Med 33:1127, 2019.

42 Ventricular Failure and Myocardial Infarction Sara R. Brethel, DVM, Meg M. Sleeper, VMD, DACVIM (Cardiology) KEY POINTS • Myocardial infarction is not commonly diagnosed in veterinary medicine. • A hypercoagulable state is the most common predisposing factor for myocardial infarction in dogs and cats.

• Cardiac troponins are an important diagnostic test if myocardial infarction is suspected.

Myocardial infarction causes significant morbidity and mortality in human medicine, and it is estimated by the World Health Organization that a total of 7.4 million deaths were due to coronary artery disease in 2015.1 Over the years, the antemortem recognition of myocardial infarction has evolved to incorporate electrocardiographic findings, cardiac biomarkers, in addition to clinical signs, and an appropriate clinical history. However, the role of myocardial infarction in veterinary medicine is less clear. Currently, it is believed to be an uncommon condition. Whether it goes unnoticed due to the lack of clinical suspicion or simply does not occur commonly in veterinary patients remains unclear. To date, the incidence of myocardial infarcts in veterinary species is unknown, and while case reports of this condition exist, there is much information to be learned. Pathologically, myocardial infarction is defined as myocardial cell death due to prolonged ischemia. The primary difference between predisposing factors in humans versus veterinary patients is coronary artery disease, a disease that is rare in animal species. Dogs in particular have an extensive epicardial collateral network of coronaries further reducing the risk of coronary artery disease in canines.2 While more common in humans, coronary artery disease has been described in veterinary literature. In 1986, Lui et al. identified atherosclerosis in 21 dogs over a 14year time period. Myocardial infarctions were identified within the myocardium, and diseases such as hypothyroidism, hyperlipidemia, and hypercholesterolemia were identified as risk factors.3 Common presenting clinical signs in this particular case report included gastrointestinal signs, weakness, dyspnea, anorexia, and general malaise. Another case series evaluating 37 patients with myocardial infarction had similar presenting complaints and clinical presentations.4 These vague clinical signs are one of the most likely reasons that myocardial infarction is infrequently diagnosed antemortem. Of the 37 patients with myocardial infarction, 22% (7) had primary cardiovascular disease, another 22% (7) had primary renal disease, and 16% (5) had immune-mediated hemolytic anemia and were being treated with corticosteroids. It is interesting that the majority of the patients in this case series did not even have primary cardiac disease. In contrast to human medicine, diseases that cause a hypercoagulable state appear to be the primary predisposing factor in veterinary patients leading to myocardial infarction (i.e., neoplasia, sepsis, endocrine disorders, protein losing enteropathies/nephropathies, renal disease, and glucocorticoid use).4

Normally, the endothelium contains anticoagulant factors that act to maintain normal blood flow and organ perfusion. The endothelial barrier is made up of vascular endothelial cells (ECs) and the glycocalyx, a thin and carbohydrate-rich component that localizes anticoagulant elements such as glycosaminoglycans (GAGs), proteoglycans, and glycoproteins. Heparin cofactor II and thrombomodulin (TM) are additional anticoagulants that bind the glycocalyx.5 Tissue factor pathway inhibitor (TFPI) also localizes there. The glycocalyx acts as a mechanoreceptor capable of sensing altered blood flow, and it has the ability to release nitric oxide. When activated following injury, the endothelium transitions to a prothrombotic state and the synthesis of GAG is decreased, thereby compromising the function of anticoagulants that rely on the glycocalyx.5 ECs can be activated by a plethora of factors all relating to injury of the glycocalyx. Once activated, there is release of ultra large multimers of von Willebrand factor (vWF), which can result in systemic platelet aggregation and thrombus formation. With endothelial dysfunction, procoagulant substances such as tissue factor and microparticles are released and exposed to the circulating blood. Platelets are also an important source of procoagulation. Once platelets are activated, they undergo transformation and shuffle negatively charged phospholipids to the surface, which then act as catalysts for clot formation.5 Simultaneously, there is a decrease in endogenous anticoagulants such as antithrombin, protein C, and TFPI. These primary factors of endothelial dysfunction, hypercoagulability of blood, and altered blood flow, otherwise known as Virchow’s triad, explain why patients with hypercoagulable disorders are prone to developing myocardial infarctions.

DIAGNOSIS In humans, as described, clinical signs are relatively easy to discern, but recognition of the disease can be significantly more challenging in veterinary patients. Electrocardiograms (ECGs) play an essential role in diagnosing classic changes in cases of myocardial infarctions in humans and may be an underutilized diagnostic test for this purpose in veterinary medicine. ECGs are not routinely obtained on all veterinary patients, and often ST segment changes are not identified, perhaps because 12-lead ECGs are not customarily performed and slight changes may be unnoticed on standard 6-lead electrocardiograms.

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In humans, the presence of ST elevation is suggestive of occlusion of a coronary artery and is known as ST-elevation myocardial infarction (STEMI). In order to diagnose STEMI, ST segment elevation must be greater than 0.1 mV and present in at least two contiguous or precordial leads.6 The extent and severity of the myocardial infarct and response to therapy can also be correlated to the pattern and changes in ST segment elevation. Other possible ECG abnormalities include new, pathologic Q waves and/or new conduction abnormalities such as such as bundle branch blocks or atrioventricular conduction delays. Six cases of dogs with myocardial infarction secondary to snake envenomation, sepsis, and systemic inflammatory response syndrome also had evidence of transient deep and negative T waves.7 Cardiac arrhythmias can often be observed as well: tachyarrhythmias (both ventricular and supraventricular) and bradyarrhythmias.8 There are several conditions that can mimic ECG changes suggestive of an acute myocardial infarction including early repolarization, acute pericarditis, myocarditis, left ventricular hypertrophy, hyperkalemia, bundle branch blocks (left and right), and paced rhythms.6,8 ECG changes alone are not enough to diagnose a myocardial infarct, and cardiac biomarkers play an essential role in diagnosis. Prior to the availability of cardiac troponins, other cardiac biomarkers, such as white blood cell counts and various cardiac enzymes such as creatine kinase (CK), the myocardial isoform of creatinine kinase (CK-MB), lactate dehydrogenase (LDH), the myocardial isoform of LDH (HB-DH), and aspartate aminotransferase have been utilized to identify possible myocardial damage. While useful, CK, LDH, and aspartate aminotransferase have poor specificity for cardiac damage.9 Diagnostically, cardiac troponins have proven to be superior markers of myocardial damage. However, the circulating CK-MB level will rise early with acute injury, and levels will return to baseline within 48 hours after an event.9,10 Therefore, many assays include CK-MB in addition to troponin, but their reference ranges are not standardized or established in small animal veterinary medicine due to variable immunoreactivity. Also, CK-MB can be expressed when there is damage to skeletal muscle, lungs, or the spleen.11 Troponins and tropomyosin are regulatory proteins that control thin actin filaments in striated muscle. During skeletal and cardiac muscle relaxation, tropomyosin blocks the binding sites on actin. Once intracellular calcium levels rise and ATP is present, calcium ions will bind to troponin, displacing it from tropomyosin allowing exposure of the myosin binding sites on actin.9,12 The troponin complex is made up of three distinct proteins (troponin I, T, and C).9,13,14 Each of these protein complexes have isoforms that make them more or less specific to the detection of myocardial injury. Troponin I and T play an essential role in diagnosing myocardial injury, specifically infarction. Troponin T (cTnT) is present in four isoforms, of which only one is expressed in adults, and is found in both skeletal and cardiac muscle. The other three isoforms are expressed in fetal tissue; however, there can be reexpression during times of muscle damage. Troponin I (cTnI) is present in three isoforms with only one found in cardiac muscle.14 cTnI is not expressed in fetal tissue, and there is ,50% homology with the skeletal muscle isoforms.9,15 Actomyosin ATPase is inhibited by cTnI and thereby prevents the interaction of myosin with actin binding sites. When calcium binds to troponin C, cTnI is displaced and a conformational change of tropomyosin results, allowing a muscle contraction.9 The majority of troponin is bound within the thin filaments, but a small amount remains free within the cytosol. When cardiac myocytes become damaged, the membrane integrity is compromised causing the release of troponin into the circulation. In acute phases of injury, the cytosolic pool releases an initial burst of troponin, but there is also a slower release of bound troponin, resulting in sustained elevations.9,15

Circulating cardiac troponins increase 2–4 hours after injury with peak values occurring 18–24 hours after the onset of symptoms, and elevations can last for up to 14 days.9, 12,15,16 In humans, blood samples for troponins should be drawn on presentation and then repeated 3–6 hours later.8 In order to diagnose an acute myocardial infarction in people, a rise and/or fall in troponin values with at least one value above the 99th percentile upper reference limit is required using an enzyme–linked immunosorbent assay (ELISA).8 Troponin assays are not standardized, and values between two assays cannot be compared. A plethora of institutions have established their own assay reference ranges in veterinary medicine, and no gold standard assay for troponin test exists at this time. Some assays have been specifically formulated for veterinary medicine, but human assays can be used in multiple species.9,12,14 Normal cTnI ranges for dogs are reported at ,0.03–0.07 ng/ml and for cats at ,0.03–0.16 ng/ml9,12 using the Stratus CS analyzer (Siemens Medical Solutions USA, Inc. Malvern, PA). Since troponins can detect myocardial damage, any cause of myocardial injury will result in circulating elevations. Cases of congestive heart failure or cardiomyopathy will typically result in lower steady elevations of troponin rather than a spike, as occurs with myocardial infarction. Troponins can be elevated for many other reasons as well, including renal disease, infectious diseases, inflammatory processes, trauma, extreme exercise, and sepsis to name a few.9,12-14 It is important to interpret these biomarkers in light of clinical signs and other diagnostic tests. Noninvasive imaging plays a useful role in the diagnosis of myocardial infarction, giving information pertaining to myocardial perfusion, myocyte viability, and myocardial function. In veterinary medicine, echocardiography plays an essential role in diagnosing segmental motion abnormalities and myocardial function. In order for wall motion abnormalities to be present, .20% of the myocardial wall must be affected.8 Hyperechoic foci within the myocardium has also been associated with myocardial infarction using echocardiography.17 It is important to note that these abnormalities are not specific to myocardial infarction, but when combined with elevated biomarkers and ECG abnormalities, a diagnosis can be inferred. Other more advanced imaging is often utilized in humans such as radionuclide imaging, cardiac magnetic resonance imaging, and computed tomographic angiography. While these diagnostics play an essential role in human medicine by aiding in the diagnosis, their utility in veterinary medicine is limited. With more tertiary veterinary facilities available, these tests will undoubtably become more routine.

TREATMENT Since myocardial infarction is uncommonly diagnosed, established treatments options do not exist in veterinary medicine; however, we can extrapolate therapies from human medicine. Goals of therapy include rapid reperfusion and maintaining a patent vessel. In the 1970s, thrombolytic therapy revolutionized the treatment of coronary artery infarction.18 Originally, therapy was administered in the affected coronary artery but eventually evolved to a systemic intravenous infusion. In the 1980s, balloon angioplasty became another method of treatment, and eventually the use of stents became the gold standard for nonsurgical therapy.18 It is best to administer thrombolytics within the first 6–12 hours after the onset of symptoms and ideally within the first several hours.18 The difficulty in using this approach in veterinary medicine is that often a diagnosis of myocardial infarction is not suspected; therefore, early intervention is rarely feasible. In addition to thrombolytic therapy, a 24–48-hour infusion of unfractionated heparin (UFH) or administration of low molecular weight heparin (LMWH) is recommended.19 In humans, criteria for the use of LMWH include being less than 75 years of age and having

CHAPTER 42  Ventricular Failure and Myocardial Infarction normal renal function.19 In a meta-analysis performed in 2005, therapy with LMWH decreased the occurrence of reinfarction and death by roughly one-quarter.19,20 Myocardial infarction is not routinely encountered in veterinary medicine. This can be due to decreased incidence or a low index of suspicion. Due to the high sensitivity of cardiac troponins, this test should be considered in a minimum database for cases presenting with non-specific clinical signs that could be consistent with myocardial infarction. Additionally, performing a test for troponins when patients present with significant arrhythmias can help determine the underlying cause and may affect treatment options and recommendations.

REFERENCES 1. Jayaraj JC, Davatyan K, Subramanian SS, Priya J: Epidemiology of myocardial infarction. In Pamukcu B, editor: Myocardial Infarction, London, UK, 2019, IntechoOpen. Available at: http://dx.doi.org/10.5772/intechopen.74768. 2. Fox PR, Sisson D, Moise NS: Textbook of canine and feline cardiology: principles and clinical practice, Philadelphia, PA, 1999, W.B. Saunders Company. 3. Liu SK, Tilley LP, Tappe JP, et al: Clinical and pathologic findings in dogs with atherosclerosis; 21 cases (1970-1983), J Am Vet Med Assoc 189:227, 1986. 4. Driehuys S, Van Winkle TJ, Sammarco C, et al: Myocardial infarction in dogs and cats: 37 cases (1985- 1994), J Am Vet Med Assoc 213(10):1444, 1998. 5. Macintire DK, Drobatz KJ, Haskins SC, Saxon WD: In Macintire DK, editor: Cardiac Emergencies. Manual of small animal emergency and critical care medicine, ed 2, Hoboken, NJ, 2012, John Wiley & Sons, pp 192-225. 6. Stillman AE, Oudkerk M, Blueemke D, et al: Assessment of acute myocardial infarction: current status and recommendations from North American Society for Cardiovascular Imaging and the European Society of Cardiac Radiology, Int J Cardiovasc Imaging 27:7-24, 2011. 7. Romito G, Cipone M: Transient deep and giant negative T waves in dogs with myocardial injury, J Vet Cardiol 36:131-140, 2021.

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8. Thygesen K, Alpert JS, Jaffe AS, et al: Fourth Universal Definition of Myocardial Infarction. Circulation 138:e618-e651, 2018. 9. Wells SM, Sleeper M: Cardiac troponins, J Vet Emerg Crit Care 18(3): 235-245, 2008. 10. Collinson PO: Troponin T or troponin I or CK-MB (or none?), Eur Heart J 19(Supp N):N16-N24, 1998. 11. Hyun C: Cardiac biomarkers in small animal practice – can we detect heart disease with blood samples? World Small Animal Veterinary Association World Congress Proceedings, 2011. 12. Langhorn R, Willesen JL: Cardiac troponins in dogs and cats, J Vet Intern Med 30:36-50, 2016. 13. Diniz PP, de Morais HS, Breitschwerdt EB, Schwartz DS: Serum cardiac troponin I concentration in dogs with ehrlichiosis, J Vet Intern Med 22:1136-1143, 2008. 14. Oyama MA, Sisson DD, Cardiac troponin-I concentration in dogs with cardiac disease, J Vet Intern Med 18:831-839, 2004. 15. Babuin L, Jaffe AS: Troponin: the biomarker of choice for the detection of cardiac injury, Can Med Assoc J 173(10):1191-1202, 2005. 16. Medsen LH, Christensen G, Lund T, et al: Time course of degradation of cardiac troponin I in patients with acute ST-elevation myocardial infarction: the ASSENT-2 troponin substudy, Circ Res 99:1141-1147, 2006. 17. Schneider SM, Coleman AE, Guo L, Tou S, Keene B, Kornegay J: Suspected acute myocardial infarction in a dystrophin-deficient dog, Neuromuscul Disord 26:361-366, 2016. 18. Saleh M, Ambrose JA. Understanding myocardial infarction [version 1; referees: 2 approved] F1000Res 7(F1000 Faculty Rev):1378, 2018. 19. Rubboli A: Efficacy and safety of low-molecular-weight heparins as an adjunct to thrombolysis in acute ST-elevation myocardial infarction, Curr Cardiol Rev 4(1):63-71, 2008. 20. Eikelboom JW, Quinlan DJ, Mehta SR, Turpie AG, Menown IB, Yusuf S: Unfractionated and low-molecular-weight heparin as adjuncts to thrombolysis in aspirin-treated patients with ST-elevation acute myocardial infarction. A meta-analysis of the randomized trials, Circulation 112:3855-3867, 2005.

43 Feline Cardiomyopathy Joshua A. Stern, DVM, PhD, DACVIM (Cardiology), Maureen S. Oldach, DVM, DACVIM (Cardiology)

KEY POINTS • Feline cardiomyopathy has several phenotypes and many contributing etiologies that often remain unknown; however, the current classification of feline cardiomyopathy is based on phenotype and not underlying disease etiology. • Treatment of feline cardiomyopathy aims to prevent arrhythmiainduced sudden death, congestive heart failure, and arterial thromboembolism. • Initiation of treatment in the subclinical stage is typically based on the presence of left atrial enlargement and/or significant left ventricular outflow tract obstruction.

• Clinical signs are commonly related to congestive heart failure or thromboembolism. • Management of cardiomyopathic complications in the acute setting can often be done without a cardiology specialist, although one should become involved in the evaluation and care once the patient is stable.

CLASSIFICATION AND ETIOLOGY OF FELINE CARDIOMYOPATHY

the R820W in ragdoll cats. Animals who are homozygous for these mutations have an increased risk for HCM.5,6 A myosin heavy chain 7 (MYH7) mutation has also been described in a single cat; however, the evidence for its causation of the HCM phenotype is weak.7 Although other mutations have not yet been identified, frequent observations of familial HCM support the presence of other genetic and/or epigenetic causes. There is significant overlap between phenotypes and etiologies. For example, end-stage HCM could lead to systolic dysfunction and LV chamber dilation, but with increased wall thickness, thereby classifying it as “nonspecific cardiomyopathy characterized by increased wall thickness, reduced LV systolic function, and left ventricular dilation”.2,8 However, the management of cardiomyopathies is relatively independent of the disease phenotype and involves the identification and treatment of underlying contributing diseases, monitoring for risk factors of disease complications, and treating complications that occur. The most important complications of feline cardiomyopathies are arterial thromboembolism (ATE), arrhythmias, and congestive heart failure (CHF).2 This chapter focuses primarily on the HCM phenotype, given that it is the most common phenotype, with a prevalence of 14.7% in the feline population.9 However, the diagnostic and therapeutic discussions are pertinent to all feline cardiomyopathies, unless otherwise specified. A cardiomyopathic staging system was recently developed by the ACVIM consensus statement and is outlined in Table 43.3.2

Cardiomyopathy is a disease involving abnormal myocardial function and/or structure in the absence of other cardiovascular disease sufficient to cause the observed myocardial changes.1 The term cardiomyopathy encompasses a broad range of myocardial diseases with varied phenotypes and etiologies, and the recent American College of Veterinary Internal Medicine (ACVIM) feline cardiomyopathy consensus panel developed a classification scheme based on these phenotypes and their associated clinical disease.2 Together, these cardiomyopathies represent the predominant acquired cardiac diseases of cats, that, unlike dogs, have a low risk for degenerative valve disease. Five cardiomyopathy phenotypes are recognized and described in Table 43.1.2 Despite variable contributing etiologies, patients are described as having the pertinent cardiomyopathy phenotype until any underlying diseases are diagnosed.2 For instance, a cat with systemic hypertension and left ventricular (LV) myocardial thickening would be referred to as having a “hypertrophic cardiomyopathy (HCM) phenotype with systemic hypertension”.2 Cardiomyopathies without underlying disease are presumed to be due to genetic mutations and/or epigenetic alteration of gene expression. Common underlying disease states and their associated cardiomyopathy phenotypes are described in Table 43.2. Note that some cats develop a transient HCM phenotype caused by systemic illness or stressful events, called transient myocardial thickening, which is likely due to myocarditis or myocardial edema induced by these events.3 Sarcomeric mutations involving either thick (myosin) or thin (actin) filaments causing a hypercontractile cardiac sarcomere are thought to be the underlying mechanism of genetic HCM.4 In cats, two mutations in one gene, myosin binding protein C (MYBP3), have been associated with HCM: the A31P mutation in Maine coon cats and

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PATHOPHYSIOLOGY HCM is a disease of LV hypercontractility and diastolic dysfunction. The hypercontractility leads to hypertrophy and an energy imbalance within the myocardium.10 This energy depletion and altered calcium handling along with mitochondrial dysfunction leads to myocardial fibrosis and myofiber disarray which, along with myocardial hypertrophy,

CHAPTER 43  Feline Cardiomyopathy

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TABLE 43.1  Cardiomyopathy Phenotypic Classification2 Phenotypic Classification Hypertrophic Cardiomyopathy

Characteristics • Segmental or diffusely increased left ventricular wall thickness

Possible Clinical Outcomes • Arterial thromboembolism • Congestive heart failure (pleural/pericardial effusion and/or pulmonary edema) • Ventricular arrhythmias (which may cause sudden death) • Supraventricular arrhythmias • Normal lifespan

Dilated Cardiomyopathy

• Primary reduction in left ventricular systolic function with normal or reduced LV wall thickness and eventual dilation of the LV and LA

• Arterial thromboembolism • Congestive heart failure (pleural/pericardial effusion and/or pulmonary edema) • Ventricular arrhythmias (which may cause sudden death) • Supraventricular arrhythmias • Normal lifespan is unlikely

Restrictive Cardiomyopathy (2 forms) • Endomyocardial restrictive cardiomyopathy • Myocardial restrictive cardiomyopathy

• Endomyocardial form characterized by an endocardial scar bridging the left ventricular septum and free wall with associated LA or biatrial dilation • Myocardial form characterized by left or biatrial enlargement with normal LV dimensions

• Arterial thromboembolism • Congestive heart failure (pleural/pericardial effusion and/or pulmonary edema) • Ventricular arrhythmias (which may cause sudden death) • Supraventricular arrhythmias • Normal lifespan is unlikely

Arrhythmogenic Right Ventricular Cardiomyopathy

• Severe dilation of the right heart with right ventricular systolic dysfunction and myocardial thinning

• Right-sided congestive heart failure (pleural/pericardial effusions and/or ascites) • Ventricular and supraventricular arrhythmias are common (which may cause sudden death) • Pulmonary thromboembolism

Nonspecific Cardiomyopathy (further described by defining morphologic features)

• Any phenotype not fitting the characteristics encompassed by other phenotypic definitions

• Depends on the morphology of the disease but can include any of the outcomes described above

TABLE 43.2  Underlying Diseases

Contributing to the Development of Feline Cardiomyopathy Phenotypes2 Disease State Hypertension Neoplastic myocardial infiltration Transient myocardial thickening Inflammatory myocardial infiltration Acromegaly Hyperthyroidism Taurine deficiency Chronic tachycardia

Associated Cardiomyopathy Phenotype HCM HCM HCM HCM HCM HCM, RCM, nonspecific cardiomyopathy DCM DCM

TABLE 43.3  ACVIM Consensus for Staging

Feline Cardiomyopathies2 Stage

Stage Description

A

• Cats prone to cardiomyopathy (family history or breed predilection such as Maine coon or ragdoll) • Cats with occult cardiomyopathy and at low risk for CHF, ATE • Normal or mildly enlarged LA • Cats with occult cardiomyopathy who are at higher risk for CHF, ATE • Moderate to severely enlarged LA • Overt cardiomyopathy • Has experienced CHF and/or ATE • Cats with refractory CHF

B1 B2

C D

DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; RCM, restrictive cardiomyopathy.

ATE, arterial thromboembolism; CHF, congestive heart failure; LA, left atrium.

leads to the stiffening and diastolic dysfunction of the ventricle.10,11 Additionally, LV myocardial thickening may reduce LV cavity size, impairing its capacity to fill. Diastolic dysfunction results in increased LV diastolic pressure, which translates to increased left atrial (LA) volume and pressure and eventually increased pulmonary venous pressure. When the hydrostatic pressure within the venous capillary bed exceeds the oncotic pressure holding fluid within vasculature, fluid leaks out of the capillaries, manifesting as pulmonary edema and/or pleural/pericardial effusions (CHF). HCM carries a 23.9% risk for CHF, making it the most common complication of HCM.12

Additionally, LA dilation and reduced left auricular function are associated with blood stasis and endothelial damage, which favor thrombus formation.13 Recent studies have also shown increased platelet activation in cats with HCM when compared with normal cats.14 Thus, HCM produces physiology conducive to formation of intracardiac thrombi and subsequent arterial thromboembolism (ATE), which affects approximately 11% of cats with HCM.12 Thromboembolic events most commonly involve the aortic trifurcation, causing variable degrees of paresis of the pelvic limb(s). However, embolism of the brachial artery (more commonly right) can also occur. The ischemic

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PART IV  Cardiovascular Disorders

injury that ensues is not the result of the primary arterial occlusion but of vasoactive substances released from activated platelets, such as serotonin, which cause collateral artery constriction.15 See Chapter 102, Feline Aortic Thromboembolism. The histologic changes characteristic of HCM, including cardiomyocyte disarray, arteriosclerosis and fibrosis, contribute to an arrhythmogenic substrate, which is likely an etiology for the sudden death that can be seen in some patients.12,16 Systolic function appears normal to increased, as measured by LV fractional shortening, but novel sensitive measures of cardiac systolic function show reduction in certain cardiac function measures, particularly in myocardial deformation, or strain.17 However, reduced systolic function does not likely play a significant role in disease pathogenesis until end-stage, when overt reduction of systolic function can occur; this is termed burnout or end-stage HCM.8 HCM can be further complicated by dynamic LV outflow tract obstructions (DLVOTO), which occur in 45.7%–67% of cats with HCM at some stage of their disease progression.18,19 DLVOTO can result from mid-ventricular hypertrophy or systolic anterior motion (SAM) of the mitral valve. SAM occurs when the mitral valve moves out of place during systole to make contact with the interventricular septum, impeding blood flow through the LV outflow tract. The mechanism of SAM involves anterior displacement of the anterior papillary muscle due to myocardial hypertrophy, which causes laxity of the anterior mitral chordae.20 The elongated, anteriorly displaced mitral valve leaflet is subjected to pushing and drag forces throughout systole, leading to displacement of the valve and commonly concurrent mitral regurgitation.20 The degree of SAM is labile, depending on preload, contractile state, and heart rate. Greater degrees of LV hypertrophy have been observed in cats with SAM, but it is unclear if this hypertrophy is the result of SAM or a contributor to the development of SAM.21 Although SAM is thought to play a significant role in disease pathogenesis and is a poor prognostic indicator in human HCM, it has not been shown to have negative prognostic value in cats.12 Restrictive cardiomyopathy shares pathogenic characteristics with HCM, including cardiomyocyte disarray, abnormal LV coronary arterioles, end myocardial fibrosis, and ischemia, causing diastolic dysfunction but without significant hypertrophy.22 As a result, disease outcomes are similar.22,23 Dilated cardiomyopathy involves a primary reduction in myocardial contractility, which leads to myocardial fibrosis, increased LV end diastolic volume, and LA enlargement, putting cats at risk for thromboembolism, arrhythmias, and CHF.24 Arrhythmogenic right ventricular cardiomyopathy involves cardiomyocyte death, atrophy, and subsequent right heart fibrofatty infiltration with resultant right ventricular systolic dysfunction.25 Development of right-sided CHF manifests as pleural/pericardial/abdominal effusion(s). These myocardial changes also produce an arrhythmogenic myocardial substrate, making concurrent supraventricular and/or ventricular arrhythmias common.25 This disease is also associated with intracardiac thrombi and concern for pulmonary thromboembolism.25 Nonspecific cardiomyopathy can have any combination of the above characteristics, and thus has pathogenic features of the associated cardiomyopathies.

CLINICAL PRESENTATION AND FINDINGS Patient History Clinical signs are most commonly related to development of pulmonary edema and/or pleural effusion secondary to CHF. Respiratory distress is the most common presenting complaint, but nonspecific signs such as lethargy and hiding are also common.12,23,26 Coughing is

uncommon with feline CHF and is more likely to be associated with primary respiratory disease.26 Acute pain and paresis/paralysis of the affected limb(s) is a common presentation for cats with ATE. Syncope can also occur as a result of LVOTO or arrhythmias; prolonged syncope can lead to hypoxic-anoxic seizures; thus, cardiomyopathy should be considered in patients presenting with seizure/collapse history.12

Physical Examination Subclinical Cardiomyopathy Signs of subclinical cardiomyopathy are important to recognize in all patients presenting to the emergency room, as they may affect treatment considerations, such as fluid therapy and drug choice. Although the presence of a systolic heart murmur is more common in cats with occult cardiomyopathy than normal cats, many cats without cardiac disease have murmurs secondary to dynamic right ventricular outflow tract obstruction or due to other conditions such as anemia, fever, or pregnancy.9,27 Gallop sounds are more specific for cardiac disease and are rare in normal cats.9 Similarly, arrhythmias should prompt suspicion of cardiomyopathy.28,29

Cardiomyopathy Associated with Congestive Heart Failure Tachypnea and labored breathing are common in cats with CHF, but they are also characteristic of primary respiratory compromise.23,28,30 A heart murmur is less likely to be appreciated once a cat develops CHF from cardiomyopathy than in the occult phase; however, a gallop sound and/or auscultable arrhythmia are more common in cardiomyopathic cats and cats who have developed CHF.18,26,28 Additionally, a respiratory rate of .80 breaths per minute, a rectal temperature of ,37°C (98.6°F), and a heart rate of .200 beats per minute were findings that made CHF more likely than primary respiratory disease.28 Pulmonary crackles may be present but are not a sensitive indicator of pulmonary edema in cats. Muffled heart and lung sounds, particularly along the ventral hemithorax, are expected if significant pleural effusion is present.

Feline Cardiogenic Arterial Thromboembolism Acute-presentation of ATE in cats is related to the site, causing variable degrees of paresis of one or both of the pelvic limbs and/or a thoracic limb. Patients with thromboembolism of the limbs have absent or attenuated arterial pulses, cyanosis, and often relative poikilothermia of the distal extremity when compared with unaffected limbs. The large muscle groups of the associated limbs are also often firm. Patients with ATE almost universally display signs of marked pain. Other uncommon sites of ATE include the mesenteric artery or arteries within the central nervous system.

Electrocardiography Electrocardiography should be considered for any patient with a history of collapse, seizure-like activity, or cardiac rhythm abnormality on physical examination, as ventricular and supraventricular arrhythmias and atrioventricular nodal disturbances can occur in patients with cardiomyopathy.28,29,31 Cardiac arrhythmias can be transient; if clinical signs support the presence of an arrhythmia, but in-clinic electrocardiogram (ECG) is normal, in-hospital telemetry or Holter monitoring should be considered. ECG is insensitive for the identification of LV hypertrophy and LA dilation and should not be used as a screening tool for cardiomyopathy.32 The presence of ventricular or supraventricular arrhythmias in cats should prompt clinical suspicion of cardiomyopathy and subsequent diagnostic evaluation.

Radiography Radiographs are insensitive for the identification of mild/moderate cardiomegaly. A left auricular bulge on the dorsoventral/ventrodorsal

CHAPTER 43  Feline Cardiomyopathy projection may be appreciated, and severe cardiomegaly, with a vertebral heart score .9.3 on left lateral projection, is highly suggestive of cardiomyopathy severe enough to be associated with CHF.33,34 Although the cardiac silhouette can be unremarkable in patients with cardiogenic pulmonary edema, a vertebral heart score of ,8 on a left lateral projection is unlikely to be associated with CHF.34 CHF has a varied and inconsistent appearance on thoracic radiographs. Cats may develop pulmonary edema and/or pleural effusion due to CHF. Pulmonary edema often manifests as a patchy unstructured interstitial/alveolar pattern (Fig. 43.1), sometimes with peribronchiolar infiltrates, which can have the appearance of a bronchial pattern.33 Distention of the pulmonary arteries, veins, or both is sometimes appreciable, but inconsistent.33 Although thoracic radiographs are the diagnostic test of choice for patients with respiratory distress, they should only be performed once the patient is relatively stable. They should also not be used to screen for subclinical cardiomyopathy due to their insensitivity in identifying mild disease.

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Echocardiography Echocardiography is the clinical gold standard for identifying cardiomyopathy. Ideally a complete echocardiogram is performed by a cardiology specialist in any cat with a suspicion of cardiac disease (Box 43.1).2 However, in the case of an unstable patient or if a cardiologist is unavailable, a point-of-care ultrasound (POCUS) can be completed to guide treatment decisions.2 For any cardiomyopathy, LA size is the most important measure that will guide treatment decisions. In the emergency and critical care setting, ultrasound is most useful to determine whether respiratory signs are cardiogenic or respiratory in origin or if a patient with signs of ATE has underlying cardiac disease. In both of these instances, LA size would be expected to be moderately to severely enlarged. Measurement of LA size can be performed with a POCUS (Fig. 43.2). A maximal LA dimension in long axis .16.5 mm and/or an LA:Ao .1.5 supports significant cardiac disease.26 POCUS can be used to assess for effusions and B-lines, which are suggestive of pulmonary edema.35 Greater than three B-lines present in .1 site is 78.8% sensitive and 83.3% specific for CHF.35 LV fractional shortening can be assessed with POCUS (Fig. 43.3). Normal is 40%.36 A subjective assessment of LV thickness can also be made, but it should be noted that hypovolemia can cause the appearance of thickening, termed pseudohypertrophy; however, pseudohypertrophy should never be associated with LA dilation. Fig. 43.4 shows the typical appearance of HCM on echocardiogram.

Blood Pressure Systemic hypertension can produce or exacerbate an HCM phenotype, and up to 85% of cats with systemic hypertension will have some degree of LV hypertrophy.39 Assessment of systemic blood pressure is recommended in any patient with suspected or confirmed HCM.2 Hypotension can occur with severe end-stage cardiomyopathies with reduced cardiac systolic function and may be an indicator for inotropic support.

A

BOX 43.1  Indications for Echocardiography2 History

Physical examination

B Fig. 43.1  ​Left lateral (A) and dorsoventral (B) thoracic radiographic projections of a cat with congestive heart failure. There is moderate generalized cardiomegaly, with prominent left atrial enlargement present. Pulmonary arteries and veins are both distended, and there is a severe diffuse interstitial to alveolar pulmonary pattern consistent with cardiogenic pulmonary edema.

Cats aged 9 years or older undergoing interventions that could precipitate CHF

Syncope Seizure (in the absence of other neurologic abnormalities) Family history of cardiomyopathy Weakness Exercise intolerance Intolerance to fluid therapy Pedigree cat intended for breeding Maine coon or ragdoll with MYBPC3 mutation Endocrinopathy Positive heartworm status Fever of unknown origin Abnormal cardiac auscultation (murmur, gallop sound, systolic click, arrhythmia) Tachypnea Pulmonary crackles Jugular venous distention or pulsation Ascites Hyperkinetic or hypokinetic femoral arterial pulse pressure Acute paralysis or paresis General anesthesia Fluid therapy Extended-release glucocorticoids

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PART IV  Cardiovascular Disorders

A A Fractional Shortening = ( 2.0 cm - 1.6 cm) / 2.0 cm x 100 = 19.4 %

Ao = 0.9 cm LA = 2.5 cm LA:Ao = 2.78

B Fig. 43.2.  ​Point of care cardiac ultrasound measurements of the left atrium. A, This image shows a right parasternal long axis four-chamber view indicating the measurement technique for assessing the left atrial size in long axis, which is the appropriate view for measuring the long axis maximal left atrial dimension. From the frame when the left atrium is largest (just before the mitral valve opens), the linear diameter is measured at the widest distance of the atrium, parallel to the mitral valve annulus, from the blood–tissue interface of the inner wall of the interatrial septum to the pericardial lining of the posterior left atrial wall.37 This patient’s left atrium is severely dilated, at 2.9 cm (normal ,1.65 cm), and there is left ventricular thickening secondary to HCM. B, This image shows a right parasternal short axis view at the level of the heart base, optimized for the left atrium and aortic root, which is the appropriate view for measuring the left atrium to aorta ratio (LA:Ao). At the end of systole, just before the mitral valve opens (when the left atrium is the largest), the aortic root is measured from the midpoint of the convex curvature of the wall of the right aortic sinus, extending to the point on the aortic wall where the noncoronary and left coronary cusps merge.38 The left atrium is measured by extending the aortic measurement line to the blood–tissue interface of the left atrial wall.38 This patient has severe left atrial dilation due to HCM, with an LA:Ao of 2.78.

Invasive arterial blood pressure assessment is most accurate, but Doppler blood pressure has been shown to yield acceptable estimations of invasive systolic pressure in cats, whereas oscillometric is widely variable depending on the equipment.40,41

Cardiac Biomarkers NT-ProBNP In the emergency setting, point of care (POC) NT-ProBNP assay on plasma or a 1:1 dilution of saline:pleural fluid is useful to discriminate

B Fig. 43.3  ​Point of care cardiac ultrasound assessment of left ventricular systolic function. Figures 43.3A and 43.3B show right parasternal short axis views of the heart at the level of the left ventricular papillary muscles; note this patient has pleural effusion present (*), secondary to CHF. A, Measurement of the largest diastolic dimension (LVIDd), indicated by the blue line, and B, Measurement of the smallest systolic dimension (LVIDs), indicated by the blue line. To measure fractional shortening (FS), LVIDs is subtracted from LVIDd, and this number is then divided by LVIDd and multiplied by 100 to obtain a fractional shortening percent [(LVIDd-LVIDs)/LVIDd]*100 5 LV FS. This cat’s FS is reduced at 19.4% (normal .40%).

cardiac from noncardiac etiologies of respiratory distress.42,43 The use of POC NT-ProBNP assay in the investigation of feline respiratory distress has a 93.9% sensitivity and 72.2% specificity for the diagnosis of CHF, making it more sensitive than POCUS and less dependent on the experience level of the clinician.35 In a nonemergent scenario, the quantitative NT-ProBNP test can be performed, which has better sensitivity for identifying subclinical cardiomyopathy than the POC ELISA.44

Cardiac Troponin I Although cardiac troponin I (cTnI) values have been shown to be higher in cats with CHF than in those with primary respiratory disease, overlap between groups makes it an insensitive indicator of cardiac disease.45 However an elevated cTnI (.0.7 ng/ml) has been associated with increased risk for cardiac death, independent of LA size.46

CHAPTER 43  Feline Cardiomyopathy

RV RA LV LA

251

tachypnea from pain but without pulmonary edema or pleural effusion. See Chapter 102 for further information regarding diagnostic approach to ATE. If the patient has an auscultable arrhythmia or clinical signs consistent with arrhythmia such as syncope or episodic weakness, ECG should be performed. Potential contributors to cardiomyopathy phenotypes should be investigated. These include but are not limited to serum T4 to rule out hyperthyroidism in cats .6 years of age, blood pressure assessment, plasma taurine testing if there is history of a boutique or grain-free diet, and assessment for acromegaly if the patient is diabetic or clinical signs are suggestive of the disease.

TREATMENT

A

Management of Acutely Decompensated Congestive Heart Failure

RV LV

* *

B Fig. 43.4  ​Echocardiographic appearance of hypertrophic cardiomyopathy. A, Right parasternal long axis four-chamber view showing left ventricular thickening and severe left atrial dilation. B, Right parasternal short axis view at the level of the left ventricular papillary muscles showing severe asymmetric thickening of the left ventricle and reduced left ventricular cavity size. Note the hyperechoic regions indicated by the *. These regions likely represent areas of myocardial fibrosis that are commonly seen with HCM. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

DIAGNOSTIC APPROACH In any patient presenting for respiratory distress, the most common complaint for patients with CHF, radiographs are recommended if the patient is deemed stable. However, in the unstable patient, attempts at stabilization with oxygen support and cardiac-sparing sedatives (such as opioids or benzodiazepines) and low-stress handling should be used, and if there is a high suspicion of CHF based on physical examination/history, empiric diuretics are recommended.2 In the unstable patient, POCUS can be performed in sternal recumbency while the patient receives oxygen to assess for LA dilation and presence of B-lines and effusions.42 If significant pleural effusion is present, thoracocentesis is indicated prior to pursuing thoracic radiographs. POC NT-ProBNP can also be used; negative point-of-care NT-ProBNP indicates that CHF is highly unlikely, while a positive test supports a likely diagnosis of CHF. In the nonemergent setting or once the patient is stabilized, a cardiac evaluation with complete echocardiogram by a veterinary cardiologist is recommended in all feline patients with suspected cardiac disease.2 All patients with signs of ATE should be screened for CHF; many cats with ATE have also developed CHF, but many also present for

In any patient with respiratory distress, initial stabilization includes oxygen support and administration of cardiac-sparing sedatives to minimize stress, such as opioids or benzodiazepines.2 Stress minimization is critical, as stress can exacerbate respiratory signs and can worsen CHF. If there is concern for CHF based on the presence of hypothermia, gallop sound, or arrhythmia, or if CHF is supported by POCUS or thoracic radiographs, furosemide therapy is recommended at a dose of 1–2 mg/kg administered IV, or subcutaneously or intramuscularly in the unstable or fractious patient.2 Sedation can also be of benefit during the stabilization period, and butorphanol (IV, IM or SQ) is a common choice. Furosemide should be repeated to obtain clinical improvement as an IV continuous rate infusion or intermittent boluses (q1-4 hours in the initial stabilization period, tapering down to q4-12 hours during hospitalization), while monitoring the patient’s hydration status and body weight. Loss of .10% body weight in 24 hours likely indicates excessive diuresis, and if no clinical improvement is noted, alternative diagnoses should be considered. If pleural effusion is present, thoracocentesis is indicated and will greatly improve patient stability. Intravenous fluids are contraindicated in all decompensated CHF cases. An assessment of blood chemistry renal values and electrolytes is recommended at baseline, although diuretic therapy is indicated in all acutely decompensated CHF patients, regardless of the presence of azotemia. Blood chemistry should be reassessed prior to discharge. If there are signs of low cardiac output, including hypotension, bradycardia, or reduced cardiac function, oral (or injectable where available) pimobendan should be considered, provided a loud heart murmur ( grade IV/VI) suggestive of a dynamic LVOTO is not present.2 Constant rate IV infusion of dobutamine should be considered if there is no improvement in clinical status following pimobendan or if the patient cannot tolerate oral medication.2 Oxygen supplementation should be continued to maintain patient comfort, and sedatives such as opioids or benzodiazepines and hiding boxes can be helpful to minimize stress of hospitalization. Clopidogrel at a dose of 18.75 mg PO q24h is recommended if the patient is amenable to oral medications in-hospital. Angiotensin converting enzyme blockade is not recommended in the acute setting.

Management of Chronic Heart Failure Discharge medications should include furosemide 0.5–2 mg/kg PO q8-12h; often starting at 1–2 mg/kg PO q12h and antithrombotic treatment with clopidogrel 18.75 mg PO 24 h at a minimum.2 ACE inhibition with benazepril or enalapril can be considered at a dose of 0.25-0.5 mg/kg PO q12h and is used by some cardiologists, but benazepril was shown in one randomized placebo-controlled study not to

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delay onset of recurrent CHF signs.2,47 Pimobendan can be considered in cats without clinically relevant DLVOTO.2 Pimobendan improves LA function in cats, and may improve survival in cats with CHF, but its use remains off-label.48-50 Pimobendan also has been shown to have positive lusitropic effects in dogs with dilated cardiomyopathy, but this effect has not been thoroughly investigated in cats.51 There is concern pimobendan may exacerbate DLVOTO, but this has not been shown across multiple studies and requires further investigation.48 Thus, if a significant DLVOTO is not suspected, pimobendan may be added at a dose of 0.625–1.25 mg/cat PO q12h. If a DLVOTO is suspected (i.e., based on the presence of loud murmur), consultation with a veterinary cardiologist is recommended prior to initiating pimobendan therapy. Once CHF is controlled, resting respiratory rate should remain ,30 breaths per minute, and the owner should monitor this daily.2 Reevaluation is recommended in 3–7 days to ensure resolution of pulmonary edema and/or effusions and to assess renal values and electrolytes. If the patient has not yet been evaluated by a cardiologist, this follow-up could be performed with a veterinary cardiologist.

Management of Refractory Congestive Heart Failure In stage D (refractory) CHF, furosemide may be replaced by torsemide at a dose of 0.1–0.2 mg/kg PO q24h if the patient is experiencing decompensation despite high doses of furosemide (.6 mg/kg/day PO).2 If patients have not already been started on pimobendan, this should be implemented at this time. Spironolactone 1–2 mg/kg PO q12-24h should also be considered.2 Chronic activation of the renin-angiotensin-aldosterone system in heart failure causes myocardial fibrosis, vascular remodeling, and endothelial dysfunction via mineralocorticoid receptors on myocardial, vascular, and fibroblast cells.52 These changes may exacerbate cardiac dysfunction and potentiate arrhythmias. As an aldosterone antagonist, spironolactone may block this profibrotic effect, but its clinical value has yet to be fully established in cats. Aside from rare facial excoriation, the drug seems to be well tolerated.53,54 Loss of lean body mass, referred to as cardiac cachexia, can occur in refractory CHF and is associated with shorter survival time.55 Thus, although avoiding high salt intake is also recommended; adequate calorie intake is the most important part of dietary CHF management.2

Management of Subclinical Disease (Stages B1 and B2) Cats with cardiomyopathy stage B1 are at low risk for cardiac complications.2 They may experience DLVOTO as a part of their disease, but DLVOTO is not associated with increased mortality or morbidity in cats with HCM.12 Beta blockade is the mainstay of HCM therapy in humans, and is the current recommendation of the American Heart Association.56 Theoretical benefits of beta blockers include reduced heart rate, anti-arrhythmic effects, prolongation of diastole and improved coronary perfusion, attenuation of sympathetic nervous system activity, and reduction of DLVOTO, which could mitigate signs of exercise intolerance associated with obstruction. Atenolol reduces LVOTO and ventricular ectopy in cats, but in a 5-year open-label study, atenolol was not associated with longer survival.57 DLVOTO is thought to be a significant contributor to HCM pathogenesis in humans, but DLVOTO is not associated increased morbidity and mortality in cats.12 Thus, atenolol may be considered in cats with DLVOTO.2 However, atenolol therapy should not be initiated in cats who have developed CHF, those with reduced systolic function, or those with severe LA enlargement without consultation with a veterinary cardiologist. Cats in stage B2 are at risk for ATE and CHF. Although thromboprophylaxis in cats at this stage of disease has not been studied, standard of care is to begin clopidogrel in patients with ATE risk factors

including moderate to severe LA dilation, reduced LA function as measured by fractional shortening and/or reduced auricular appendage velocity, or spontaneous echo contrast (“smoke”) within the LA.2,13,58,59 Clopidogrel is recommended, as it was shown to be superior to aspirin in preventing a second thromboembolic event in cats who have experienced an ATE.2,60 Aspirin may be considered at a dose of 81 mg PO q72h if the owner is unbale to medicate their cat daily. In the subclinical stage, benazepril had no effect on time to treatment failure in a placebo-controlled clinical trial; however, some consider cats with LA enlargement to be candidates for ACE inhibition due to the presumed upregulation of the RAAS, proposed physiological benefit, and known drug safety.47 If supraventricular or ventricular tachyarrhythmias are present, treatment with atenolol (6.25 mg/cat PO BID) or sotalol (10–20 mg/cat PO BID) should be considered.2 Atenolol therapy should not be initiated in a cat in CHF without consultation with a cardiologist. Diltiazem can be considered as an alternative for supraventricular arrhythmias, the most common of which is atrial fibrillation with rapid ventricular response rate.2 Several novel therapeutics have been under investigation for this stage of disease. Ivabradine, a “funny” channel inhibitor and negative inotrope, is less effective at reducing DLVOTO than atenolol and is not recommended.61 Small molecule sarcomere inhibitors act to reduce force generation by the hypercontractile sarcomere, which is suspected to be the primary molecular etiology of HCM.4,10 One of these drugs, MYK-461, has been shown to reduce obstruction in cats in a laboratory setting and attenuate hypertrophy in mouse models of HCM and is currently in human HCM clinical trials.62,63 These drugs may be the future of occult HCM management but are currently not available for clinical use.

REFERENCES 1. Elliott P, Andersson B, Arbustini E, et al: Classification of the cardiomyopathies: a position statement from the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases, Eur Heart J 29:270-276, 2008. 2. Luis Fuentess V, Abbott J, Chetboul V, et al: ACVIM consensus statement guidelines for the classification, diagnosis and management of feline cardiomyopathies, J Vet Intern Med 34:1062-1077, 2020. doi:10.1111/ jvim.15745. 3. Novo Matos J, Pereira N, Glaus T, et al: Transient myocardial thickening in cats associated with heart failure, J Vet Intern Med 32:48-56, 2018. 4. Cohn R, Thakar K, Lowe A, et al: A contraction stress model of hypertrophic cardiomyopathy due to sarcomere mutations, Stem Cell Reports 12:71-83, 2019. 5. Mary J, Chetboul V, Sampedrano CC, et al: Prevalence of the MYBPC3A31P mutation in a large European feline population and association with hypertrophic cardiomyopathy in the Maine Coon breed, J Vet Cardiol 12:155-161, 2010. 6. Borgeat K, Stern J, Meurs KM, Fuentes VL, Connolly DJ: The influence of clinical and genetic factors on left ventricular wall thickness in Ragdoll cats, J Vet Cardiol 17(Suppl 1):S258-S267, 2015. 7. Schipper T, Van Poucke M, Sonck L, et al: A feline orthologue of the human MYH7 c.5647G.A (p.(Glu1883Lys)) variant causes hypertrophic cardiomyopathy in a Domestic Shorthair cat, Eur J Hum Genet 27: 1724-1730, 2019. 8. Cesta MF, Baty CJ, Keene BW, Smoak IW, Malarkey DE: Pathology of endstage remodeling in a family of cats with hypertrophic cardiomyopathy, Vet Pathol 42:458-467, 2005. 9. Payne JR, Brodbelt DC, Luis Fuentes V: Cardiomyopathy prevalence in 780 apparently healthy cats in rehoming centres (the CatScan study), J Vet Cardiol 17(Suppl 1):S244-S257, 2015.

CHAPTER 43  Feline Cardiomyopathy 10. Ashrafian H, McKenna WJ, Watkins H: Disease pathways and novel therapeutic targets in hypertrophic cardiomyopathy, Circ Res 109:86-96, 2011. 11. Ueda Y, Stern JA: A one health approach to hypertrophic cardiomyopathy, Yale J Biol Med 90:433-448, 2017. 12. Fox PR, Keene BW, Lamb K, et al: International collaborative study to assess cardiovascular risk and evaluate long-term health in cats with preclinical hypertrophic cardiomyopathy and apparently healthy cats: the REVEAL study, J Vet Intern Med 32:930-943, 2018. 13. Payne JR, Borgeat K, Connolly DJ, et al: Prognostic indicators in cats with hypertrophic cardiomyopathy, J Vet Intern Med 27:1427-1436, 2013. 14. Tablin F, Schumacher T, Pombo M, et al: Platelet activation in cats with hypertrophic cardiomyopathy, J Vet Intern Med 28:411-418, 2014. 15. Butler HC: An investigation into the relationship of an aortic embolus to posterior paralysis in the cat, J Small Anim Pract 12:141-158, 1971. 16. Kittleson MD, Meurs KM, Munro MJ, et al: Familial hypertrophic cardiomyopathy in Maine coon cats: an animal model of human disease, Circulation 99:3172-3180, 1999. 17. Spalla I, Boswood A, Connolly DJ, Luis Fuentes V: Speckle tracking echocardiography in cats with preclinical hypertrophic cardiomyopathy, J Vet Intern Med 33:1232-1241, 2019. 18. Payne J, Luis Fuentes V, Boswood A, et al: Population characteristics and survival in 127 referred cats with hypertrophic cardiomyopathy (1997 to 2005), J Small Anim Pract 51:540-547, 2010. 19. Fox PR, Liu SK, Maron BJ: Echocardiographic assessment of spontaneously occurring feline hypertrophic cardiomyopathy. An animal model of human disease, Circulation 92:2645-2651, 1995. 20. Ro R, Halpern D, Sahn DJ, et al: Vector flow mapping in obstructive hypertrophic cardiomyopathy to assess the relationship of early systolic left ventricular flow and the mitral valve, J Am Coll Cardiol 64:1984-1995, 2014. 21. Schober K, Todd A: Echocardiographic assessment of left ventricular geometry and the mitral valve apparatus in cats with hypertrophic cardiomyopathy, J Vet Cardiol 12:1-16, 2010. 22. Fox PR, Basso C, Thiene G, Maron BJ: Spontaneously occurring restrictive nonhypertrophied cardiomyopathy in domestic cats: a new animal model of human disease, Cardiovasc Pathol 23:28-34, 2014. 23. Chetboul V, Passavin P, Trehiou-Sechi E, et al: Clinical, epidemiological and echocardiographic features and prognostic factors in cats with restrictive cardiomyopathy: a retrospective study of 92 cases (2001-2015), J Vet Intern Med 33:1222-1231, 2019. 24. Hambrook LE, Bennett PF: Effect of pimobendan on the clinical outcome and survival of cats with non-taurine responsive dilated cardiomyopathy, J Feline Med Surg 14:233-239, 2012. 25. Fox PR, Maron BJ, Basso C, Liu SK, Thiene G: Spontaneously occurring arrhythmogenic right ventricular cardiomyopathy in the domestic cat: a new animal model similar to the human disease, Circulation 102: 1863-1870, 2000. 26. Smith S, Dukes-McEwan J: Clinical signs and left atrial size in cats with cardiovascular disease in general practice, J Small Anim Pract 53:27-33, 2012. 27. Wagner T, Fuentes VL, Payne JR, McDermott N, Brodbelt D: Comparison of auscultatory and echocardiographic findings in healthy adult cats, J Vet Cardiol 12:171-182, 2010. 28. Dickson D, Little CJL, Harris J, Rishniw M: Rapid assessment with physical examination in dyspnoeic cats: the RAPID CAT study, J Small Anim Pract 59:75-84, 2018. 29. Bartoszuk U, Keene BW, Baron Toaldo M, et al: Holter monitoring demonstrates that ventricular arrhythmias are common in cats with decompensated and compensated hypertrophic cardiomyopathy, Vet J 243:21-25, 2019. 30. Swift S, Dukes-McEwan J, Fonfara S, Loureiro JF, Burrow R: Aetiology and outcome in 90 cats presenting with dyspnoea in a referral population, J Small Anim Pract 50:466-473, 2009. 31. Roellig DM, Ellis AE, Yabsley MJ: Oral transmission of Trypanosoma cruzi with opposing evidence for the theory of carnivory, J Parasitol 95:360-364, 2009. 32. Romito G, Guglielmini C, Mazzarella MO, et al: Diagnostic and prognostic utility of surface electrocardiography in cats with left ventricular hypertrophy, J Vet Cardiol 20:364-375, 2018.

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33. Guglielmini C, Diana A: Thoracic radiography in the cat: identification of cardiomegaly and congestive heart failure, J Vet Cardiol 17:S87-S101, 2015. 34. Sleeper MM, Roland R, Drobatz KJ: Use of the vertebral heart scale for differentiation of cardiac and noncardiac causes of respiratory distress in cats: 67 cases (2002-2003), J Am Vet Med Assoc 242:366-371, 2013. 35. Ward JL, Lisciandro GR, Ware WA, et al: Evaluation of point-of-care thoracic ultrasound and NT-proBNP for the diagnosis of congestive heart failure in cats with respiratory distress, J Vet Intern Med 32:1530-1540, 2018. 36. Häggström J, Andersson ÅO, Falk T, et al: Effect of body weight on echocardiographic measurements in 19,866 pure-bred cats with or without heart disease, J Vet Intern Med 30:1601-1611, 2016. 37. Linney CJ, Dukes-McEwan J, Stephenson HM, Lopez-Alvarez J, Fonfara S: Left atrial size, atrial function and left ventricular diastolic function in cats with hypertrophic cardiomyopathy, J Small Anim Pract 55:198-206, 2014. 38. Hansson K, Häggström J, Kvart C, Lord P: Left atrial to aortic root indices using two-dimensional and M-mode echocardiography in cavalier King Charles Spaniels with and without left atrial enlargement, Vet Radiol Ultrasound 43:568-575, 2002. 39. Chetboul V, Lefebvre HP, Pinhas C, et al: Spontaneous feline hypertension: clinical and echocardiographic abnormalities, and survival rate, J Vet Intern Med 17:89-95, 2003. 40. Cerejo SA, Teixeira-Neto FJ, Garofalo NA, et al: Effects of cuff size and position on the agreement between arterial blood pressure measured by Doppler ultrasound and through a dorsal pedal artery catheter in anesthetized cats, Vet Anaesth Analg 47:191-199, 2020. 41. Acierno MJ, Seaton D, Mitchell MA, Da Cunha A: Agreement between directly measured blood pressure and pressures obtained with three veterinary-specific oscillometric units in cats, J Am Vet Med Assoc 237:402-406, 2010. 42. Ward JL, Lisciandro GR, Ware WA, et al: Evaluation of point-of-care thoracic ultrasound and NT-proBNP for the diagnosis of congestive heart failure in cats with respiratory distress, J Vet Intern Med 32:1530-1540, 2018. 43. Wurtinger G, Henrich E, Hildebrandt N, et al: Assessment of a bedside test for N-terminal pro B-type natriuretic peptide (NT-proBNP) to differentiate cardiac from non-cardiac causes of pleural effusion in cats, BMC Vet Res 13:394, 2017. 44. Fox PR, Rush JE, Reynolds CA, et al: Multicenter evaluation of plasma N-terminal probrain natriuretic peptide (NT-pro BNP) as a biochemical screening test for asymptomatic (occult) cardiomyopathy in cats, J Vet Intern Med 25:1010-1016, 2011. 45. Connolly DJ, Brodbelt DC, Copeland H, Collins S, Fuentes VL: Assessment of the diagnostic accuracy of circulating cardiac troponin I concentration to distinguish between cats with cardiac and non-cardiac causes of respiratory distress, J Vet Cardiol 11:71-78, 2009. 46. Borgeat K, Sherwood K, Payne JR, Luis Fuentes V, Connolly DJ: Plasma cardiac troponin I concentration and cardiac death in cats with hypertrophic cardiomyopathy, J Vet Intern Med 28:1731-1737, 2014. 47. King JN, Martin M, Chetboul V, et al: Evaluation of benazepril in cats with heart disease in a prospective, randomized, blinded, placebo- controlled clinical trial, J Vet Intern Med 33:2559-2571, 2019. 48. Oldach MS, Ueda Y, Ontiveros ES, et al: Cardiac effects of a single dose of pimobendan in cats with hypertrophic cardiomyopathy; a randomized, placebo-controlled, crossover study, Front Vet Sci 6:15, 2019. 49. Baron Toaldo M, Pollesel M, Diana A: Effect of pimobendan on left atrial function: an echocardiographic pilot study in 11 healthy cats, J Vet Cardiol 28:37-47, 2020. doi:10.1016/j.jvc.2020.02.002. 50. Reina-Doreste Y, Stern JA, Keene BW, et al: Case-control study of the effects of pimobendan on survival time in cats with hypertrophic cardiomyopathy and congestive heart failure, J Am Vet Med Assoc 245:534-539, 2014. 51. Asanoi H, Ishizaka S, Kameyama T, Ishise H, Sasayama S: Disparate inotropic and lusitropic responses to pimobendan in conscious dogs with tachycardia-induced heart failure, J Cardiovasc Pharmacol 23:268-274, 1994.

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52. Jaisser F, Farman N: Emerging roles of the mineralocorticoid receptor in pathology: toward new paradigms in clinical pharmacology, Pharmacol Rev 68:49-75, 2016. 53. MacDonald KA, Kittleson MD, Kass PH: Effect of spironolactone on diastolic function and left ventricular mass in Maine coon cats with familial hypertrophic cardiomyopathy, J Vet Intern Med 22:335-341, 2008. 54. James R, Guillot E, Garelli-Paar C, et al: The SEISICAT study: a pilot study assessing efficacy and safety of spironolactone in cats with congestive heart failure secondary to cardiomyopathy, J Vet Cardiol 20:1-12, 2018. 55. Santiago SL, Freeman LM, Rush JE: Cardiac cachexia in cats with congestive heart failure: prevalence and clinical, laboratory, and survival findings, J Vet Intern Med 34:35-44, 2020. 56. Gersh BJ, Maron BJ, Bonow RO, et al: 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary, Circulation 124:2761-2796, 2011. 57. Schober KE, Zientek J, Li X, Fuentes VL, Bonagura JD: Effect of treatment with atenolol on 5-year survival in cats with preclinical (asymptomatic) hypertrophic cardiomyopathy, J Vet Cardiol 15:93-104, 2013.

58. Payne JR, Borgeat K, Brodbelt DC, Connolly DJ, Luis Fuentes V: Risk factors associated with sudden death vs. congestive heart failure or arterial thromboembolism in cats with hypertrophic cardiomyopathy, J Vet Cardiol 17(Suppl 1):S318-S328, 2015. 59. Schober KE, Maerz I: Assessment of left atrial appendage flow velocity and its relation to spontaneous echocardiographic contrast in 89 cats with myocardial disease, J Vet Intern Med 20:120-130, 2006. 60. Borenstein N, Gouni V, Behr L, et al: Surgical treatment of cor triatriatum sinister in a cat under cardiopulmonary bypass, Vet Surg 44:964-969, 2015. 61. Blass KA, Schober KE, Li X, Scansen BA, Bonagura JD: Acute effects of ivabradine on dynamic obstruction of the left ventricular outflow tract in cats with preclinical hypertrophic cardiomyopathy, J Vet Intern Med 28:838-846, 2014. 62. Stern JA, Markova S, Ueda Y, et al: A small molecule inhibitor of sarcomere contractility acutely relieves left ventricular outflow tract obstruction in feline hypertrophic cardiomyopathy, PLoS One 11:e0168407, 2016. 63. Green EM, Wakimoto H, Anderson RL, et al: Heart disease: a smallmolecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice, Science 351:617-621, 2016.

44 Canine Cardiomyopathy Joanna L. Kaplan, DVM, Joshua A. Stern, DVM, PhD, DACVIM (Cardiology)

KEY POINTS • Cardiomyopathies are among the most common cardiac diseases observed in the dog, predominantly affecting large and giant breeds. • Dilated cardiomyopathy is diagnosed by the presence of cardiac dilation and systolic dysfunction, and often leads to congestive heart failure, arrhythmias, and sudden death. • Dilated cardiomyopathy is often hereditary in the Doberman Pinscher, Great Dane, Irish Wolfhound, Manchester Terrier (juvenile), and Portuguese Water dog (juvenile). • Secondary causes such as nutritionally mediated, viral, metabolic, drugs, toxins, or tachycardia-induced dilated cardiomyopathy

should be considered in certain cases as this may alter long-term prognosis and suggest therapeutic differences. • Arrhythmogenic right ventricular cardiomyopathy is most commonly observed in the Boxers and often leads to syncope and sudden death from ventricular arrhythmias, although left-sided or biventricular congestive heart failure may be observed in more severe forms. • Treatment for congestive heart failure includes oxygen, sedation, diuretics, inotropic drugs, vasodilators, a low-stress environment, and antiarrhythmic therapy in the presence of tachyarrhythmias.

Canine cardiomyopathy can be defined as an intrinsic abnormality of the myocardium independent of any congenital or acquired cardiac diseases that lead to volume or pressure overload.1,2 Canine cardiomyopathy is one of the most common acquired heart diseases in dogs.3 Dilated cardiomyopathy (DCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) are among the most prevalent, although other types of cardiomyopathies are reported, including atrioventricular myopathy, Golden Retriever muscular dystrophy (analogous to Duchenne muscular dystrophy in human medicine), myocarditis, and hypertrophic cardiomyopathy (HCM).3-6

intervention. For example, in cases of tachycardia-induced cardiomyopathy, if the arrhythmia is appropriately treated, then the resultant cardiac remodeling is potentially reversible. This is also true for disease reversal seen with cases of nutritionally mediated DCM.

DILATED CARDIOMYOPATHY Dilated cardiomyopathy is characterized by cardiac dilation, systolic dysfunction, and often diastolic dysfunction observed on echocardiogram.1,2 DCM most commonly affects large and giant breed dogs, although all breeds have the potential to be affected.2 Causes of DCM may be primary or secondary in origin.1,3 When a cause cannot be identified, the disease is presumed to be idiopathic. At least 30%–50% of cases in humans are attributed to a genetic mutation, and similar causative mutations have been discovered in certain dog breeds as discussed below.2 Annual screening with an echocardiogram and 24-hour ambulatory electrocardiogram (ECG) are recommended in dogs used for breeding purposes within suspect breeds, such as the Doberman and Great Dane.2,7 Secondary causes of DCM include nutritionally mediated disease, myocarditis from infectious or non­ infectious inflammation, metabolic derangements such as thyroid deficiency or hypoadrenocorticism, tachycardia-induced cardiomyopathy, or certain drugs and toxins such as the irreversible myocardial damage that results from the chemotherapeutic agent doxorubicin.1,8,3 The prognosis of DCM typically depends on the underlying cause, the speed at which it progresses, and in some cases, the timing of

Clinical Signs DCM can be divided into an occult phase and clinical phase.2,8 The occult phase consists of significant structural cardiac changes and/or arrhythmias in the absence of clinical signs. Dogs are still at risk for sudden death during this phase. The clinical phase is composed of signs associated with the development of ventricular or supraventricular tachyarrhythmias, atrial fibrillation, left-sided congestive heart failure, or less commonly, right-sided or biventricular congestive heart failure. Therefore, clinical signs may consist of lethargy, inappetence, increased respiratory rate or effort, cough, weakness, exercise intolerance, presyncope or syncope, weight loss, or abdominal distension.

Physical Examination Findings Dogs with significant arrhythmias or heart failure may display obtundation, tachycardia, tachypnea, or increased respiratory effort or cough, or may have hypokinetic or absent pulses.1,8 Dogs with right-sided manifestations of congestive heart failure may have jugular venous pulsation or distension, abdominal distension, and an abdominal fluid wave from ascites. Cardiac auscultation may reveal an S3 gallop sound from systolic dysfunction, a left apical systolic murmur from mitral regurgitation, or an irregular cardiac rhythm from ventricular or atrial premature complexes or atrial fibrillation. Lung auscultation may reveal crackles consistent with cardiogenic pulmonary edema or muffled lung sounds from pleural effusion.

Diagnostics Echocardiographic findings include left ventricular dilation in systole, diastole, or both with left ventricular systolic dysfunction and often

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diastolic dysfunction.1,2,8 Left ventricular size is most commonly assessed by measuring the diameter of the left ventricle at end diastole (at its largest dimension) and end systole (at its smallest dimension) using M-mode or two-dimensional imaging. Left ventricular area and volume measurements indexed to body weight may also be used. When possible, measurements should be compared with previously established reference ranges for the particular breed of interest or size of dog. Left ventricular systolic function is most commonly assessed by measuring percent fractional shortening (%FS) (Fig. 44.1). Additional measurements of systolic function, including ejection fraction (%EF), fractional area change (%FAC), sphericity index, or E-point-to-septalseparation can be used in conjunction with %FS.2,7,9,10 Color and spectral Doppler echocardiography may be used to document mitral and tricuspid regurgitation, respectively, as well as diastolic dysfunction. Less commonly, right-sided cardiac enlargement, ascites, and pleural effusion may also be observed. A recent study suggested that dogs with DCM and concurrent atrial fibrillation more commonly show manifestations of right-sided congestive heart failure in addition to left-sided congestive heart failure.11 Arrhythmias are common, and an ECG should be performed to detect atrial or ventricular premature complexes, ventricular or supraventricular tachycardia, and atrial fibrillation.1-3,8 Arrhythmias may be noted before the development of echocardiographic changes, in which case it is important to rule out other underlying systemic diseases that may promote arrhythmogenesis. It is also important to note that many dogs with arrhythmias will also have concurrent congestive heart failure at the time of diagnosis. Chest radiographs should be performed to confirm a diagnosis of left-sided congestive heart failure if clinical suspicion is present.1,3,8 Radiographic findings include left ventricular and left atrial dilation, an interstitial to alveolar pattern most commonly observed in the caudodorsal lung lobes consistent with cardiogenic pulmonary edema, and pulmonary venous distension. Biomarker elevations, such as a cardiac troponin I (cTnI) .0.22 ng/ml (sensitivity 79.5% and specificity 84.4%) or a N-terminal pro-BNP (NTproBNP) value .550 pmol/L (sensitivity 78.6%, specificity 90.4%), have independently been established in the Doberman Pinscher to be suggestive of occult DCM.2 However, it is generally accepted that these should not be used to establish a diagnosis or make treatment

Fig. 44.1  Echocardiogram in a 3-year-old male castrated Doberman Pinscher with dilated cardiomyopathy and atrial fibrillation. The following is an M-mode image from the right parasternal short axis view at the level of the papillary muscles. The fractional shortening is severely decreased, measuring 11%.

recommendations due to their reported low sensitivities and specificities for detection of DCM. A cTnI .0.34 ng/ml may be useful to predict the risk of sudden cardiac death in Dobermans with enlarged hearts.12 An elevated cTnI may also suggest myocarditis.2 Biomarkers have their limitations as NTproBNP may be elevated in the presence of renal dysfunction, pulmonary hypertension, sepsis, systemic hypertension, or inappropriate sample handling. cTnI may be increased from systemic diseases, cardiac neoplasia, ischemia, or cardiac injury from other causes.

Dilated Cardiomyopathy in Doberman Pinschers In North America, the prevalence of DCM in Doberman Pinschers is high. Several studies with varying inclusion criteria show the prevalence is between 45% and 63% within their respective study populations.13,14 It is most commonly hereditary, with an adult age of onset of approximately 6 years.14 In North American populations, two causative genetic mutations have been identified thus far, including a splice site mutation in the gene encoding the mitochondrial protein pyruvate dehydrogenase kinase 4 and a missense variant in the titin gene.15,16 Both mutations have been described as autosomal dominant with incomplete penetrance and variable expression. Dogs that are homozygous have the potential to develop a more severe form of the disease. Genetic tests are available for both mutations at the North Carolina State University College of Veterinary Medicine. The clinical significance of these mutations in European lineages remains unknown. Clinical outcomes of DCM in the Doberman Pinscher include syncope or sudden death from ventricular arrhythmias, and left-sided or less commonly right-sided or biventricular congestive heart failure.1,2,8 Supraventricular tachyarrhythmias and atrial fibrillation are also commonly observed (Fig. 44.2). Therapeutic recommendations should be guided based on established preventative strategies or the clinical manifestation of the disease. In the occult stage when left ventricular enlargement is present, pimobendan and angiotensin converting enzyme (ACE) inhibitors have been shown to delay the onset of congestive heart failure and sudden death by up to 9 months and 3 months, respectively.9,17 Although unproven, clinicians typically extrapolate these benefits to other breeds. Despite theoretical benefits, beta blockers have not been proven to be effective in delaying the progression of disease as demonstrated in a limited study evaluating carvedilol.18 In the acute setting, ventricular arrhythmias matching the criteria of malignancy (Box 44.1) should be treated promptly. Please see Chapters 49 and 50 for further discussion regarding acute treatment of arrhythmias. Ventricular arrhythmias may be treated long-term with sotalol, a potassium channel blocker, at a dose of 1–3 mg/kg PO q12h, or mexiletine, a sodium channel blocker, at a dose of 5–8 mg/kg PO q8h. Sotalol has partial beta-blocking effects, and therefore, it may be prudent to start at the lower end of the dose to avoid the risk of further systolic dysfunction. Although the beta blocking effects of sotalol at therapeutic doses were demonstrated to be clinically insignificant in one study, caution should be exercised in cases with severe systolic dysfunction, and sotalol may be avoided altogether.19 In some cases, sotalol and mexiletine are given in combination as they work synergistically to achieve better rhythm control. Dogs in congestive heart failure should be treated with standard heart failure therapy (Chapter 41), including furosemide, pimobendan, an ACE inhibitor, and spironolactone. Oxygen therapy and sedation are often required in the acute setting. In rare cases of cardiogenic shock, dobutamine may be required. If significant ascites or pleural effusion are present, an abdominocentesis or thoracocentesis should be performed. Effusions are often consistent with a modified transudate. Fish oils at a dose of 1200 mg per 8 kg of body weight may also be administered as adjunctive therapy for both ventricular arrhythmias

CHAPTER 44  Canine Cardiomyopathy

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Fig. 44.2  Electrocardiogram displaying ventricular tachycardia (heart rate of 260 bpm) in a 7-year-old female spayed Boxer with ARVC. Ventricular ectopy is of right-sided origin. After a single intravenous bolus of lidocaine 2 mg/kg, the rhythm was cardioverted to a sinus origin. There is a single left-sided VPC (coupling interval 214 bpm) noted after termination of the ventricular arrhythmia. Lead II, 25 mm/sec, 5 mm 5 1 mV.

BOX 44.1  Criteria of Malignancy for Ventricular Arrhythmias • Frequent paroxysmal or sustained ventricular tachycardia (HR .180 bpm) • Evidence of complexity (R-on-T phenomenon, triplets, couplets, bigeminy, trigeminy) • Clinical signs of hemodynamic instability from arrhythmias • Polymorphic ventricular premature complexes are often more concerning than monomorphic because they indicate multiple regions of disease within the ventricular myocardium

and to combat cardiac cachexia that may result from congestive heart failure.20,21

Dilated Cardiomyopathy in Great Danes Dilated cardiomyopathy in the Great Dane appears to have a sexlinked mode of inheritance in some families, with a prevalence of 3.9%–11.8% and an adult age of onset.7,22,23 Dogs with the disease may have arrhythmias alone, cardiac structural changes and subsequent congestive heart failure (predominantly left sided), or both. Atrial fibrillation and ventricular arrhythmias are common and should be treated accordingly.

Dilated Cardiomyopathy in Irish Wolfhounds Irish Wolfhounds develop an adult age of onset of familial DCM.24,25 It is not uncommon to diagnose atrial fibrillation prior to the development of any cardiac structural changes or congestive heart failure. Although previously reported to have an autosomal recessive mode of inheritance, a 2019 study suggested that in the North American population, the development of atrial fibrillation appeared to have an autosomal dominant mode of inheritance.24 It is not entirely clear if cardiac chamber enlargement identified on echocardiogram is a primary change or secondary to the sustained atrial fibrillation. It is also possible that the disease manifests differently in European versus North American populations.

Other Important Breed Predilections Some families of Newfoundlands have demonstrated an autosomal dominant mode of inheritance with the development of atrial fibrillation and left-sided or biventricular congestive heart failure.1,26 A young adult-onset form of DCM has been reported in the Standard Schnauzer with development of congestive heart failure by 1.5 and 2.35 years of age in males and females, respectively.27 Pedigree analysis suggests an autosomal recessive mode of inheritance, and an associated frameshift mutation in the RNA binding motif protein 20 gene has been identified.28 Additionally, a juvenile onset form of DCM with an autosomal recessive mode of inheritance was previously demonstrated in the Portuguese Water dog.29,30 Affected puppies developed clinical

signs of congestive heart failure with rapid progression of disease and death between 2 and 32 weeks of age. Similarly, the Toy Manchester Terrier has a familial form of the disease with a juvenile age of onset.31 Affected dogs typically die at less than a year of age of sudden death without overt signs of heart disease. Golden Retriever muscular dystrophy, analogous to the human cardiomyopathy seen with Duchenne muscular dystrophy, is a degenerative neuromuscular disorder with an X-linked pattern of inheritance.6 It is caused by mutations in the cytoskeletal protein dystrophin, which is important for maintaining normal cardiac and skeletal muscle structure. Therefore, many of these dogs are at risk for developing DCM in addition to their musculoskeletal abnormalities.

Nutritionally Mediated Dilated Cardiomyopathy Nutritionally mediated causes of DCM are well described in the dog.32 While any dog breed is at risk, certain breeds appear to be more susceptible, including the Golden Retriever, American Cocker Spaniel, and Newfoundland. Taurine deficiency is documented by whole blood and plasma taurine concentrations less than or equal to 250 nmol/ml and 60 nmol/ml, respectively. Switching the diet and providing taurine and L-carnitine supplementation leads to the reversal of the disease in a large proportion of cases, including dogs with congestive heart failure. A subset of these dogs will have normal blood taurine concentrations but are still responsive to treatment. Therefore, while low taurine concentrations are meaningful, normal taurine concentrations do not rule out the disease. Taurine may be dosed at 1000 mg PO q12h in dogs that weigh greater that 25 kg and 500 mg in dogs weighing less than 25 kg. L-carnitine is typically dosed at 50 mg/kg PO q8h. Ongoing research and recent Food and Drug Administration investigations33 suggest that dogs that develop nutritionally mediated DCM are commonly fed diets that are grain-free, contain high contents of legumes and potatoes, and may be manufactured by diet manufacturing companies with less rigorous quality control standards. A recent surge in cases of nutritionally mediated DCM has warranted complete diet histories in all patients with suspected DCM. If the diet history matches the aforementioned characteristics, clinicians should employ whole blood and plasma taurine level measurement, diet change, and empiric taurine and L-carnitine supplementation. Response to therapy may be the best confirmatory test for discerning idiopathic from nutritionally mediated DCM. L-carnitine deficiency has been described in a single family of Boxers.34 Dilated cardiomyopathy in Dalmatians has been linked to low protein diets fed for the prevention of urate urolithiasis.35

ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY ARVC is most commonly reported in the Boxer and is described histopathologically by fatty or fibrofatty infiltration within the myocardium.36

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A causative mutation in the striatin gene in Boxers has been identified.22,37,38 The mutation has an autosomal dominant mode of inheritance with incomplete penetrance and variable expressivity. Dogs that are homozygous for the mutation are likely to develop a more severe form of the disease, including left ventricular dilation, systolic dysfunction, and left-sided congestive heart failure. The median age of diagnosis is 6 years.39,40 ARVC is classified into three categories.39 Type I ARVC includes dogs with subclinical ventricular arrhythmias, whereas type II includes dogs with ventricular arrhythmias and syncope, and type III includes dogs with structural cardiac changes identified on echocardiogram with a diagnosis of congestive heart failure. Ventricular arrhythmias typically originate from the right side, although structural cardiac changes often involve the left side, leading to left-sided congestive heart failure. Clinical signs include exercise intolerance, syncope, obtundation, and sudden death. Physical examination findings include those related to ventricular arrhythmias and left-sided congestive heart failure.36 An ECG predominantly reveals ventricular arrhythmias, although supraventricular arrhythmias and atrial fibrillation can also be observed36 (Fig. 44.2). A Holter monitor further characterizes the severity and frequency of ventricular ectopy to best guide antiarrhythmic therapy.40,41 It is generally accepted that a diagnosis of ARVC can be made if greater than 300 ventricular premature complexes (VPCs) are observed on a 24-hour Holter monitor.40 A total of 50–300 VPCs is considered equivocal for the disease. VPCs are typically of right ventricular origin, although VPCs of left ventricular origin may also be observed.36 Echocardiographic findings are often unremarkable.40 In more severe disease, left-sided systolic dysfunction and left cardiac enlargement is observed, making this disease a phenocopy of DCM in the severe type III form. Thoracic radiographs are typically unremarkable, but they may show cardiomegaly and left-sided congestive heart failure in more severe cases. Treatment is predominantly aimed at the clinical consequences of disease. Sotalol and mexiletine have been shown to be safe and effective at reducing the number of ventricular arrhythmias, although it is unclear whether this leads to a reduced risk of sudden death or a longer survival time.42 Nonetheless, the author prefers the use of sotalol 2–3 mg/kg PO q12h. Mexiletine (5–8 mg/kg PO q8h) may be added to achieve better control in select cases. Appropriate management of arrhythmias may help to reduce clinical signs and improve quality of life. Although dogs with ARVC have an increased risk of sudden death, median survival time compared with healthy dogs was not significantly different.40 Prognosis is poorer in dogs with type III ARVC, homozygous striatin mutation status, and left-sided congestive heart failure.

HYPERTROPHIC CARDIOMYOPATHY HCM is uncommon in the dog, and secondary causes of left ventricular hypertrophy should be considered first, such as systemic hypertension, myocarditis, cardiac neoplasia, hyperadrenocorticism or diabetes mellitus.3 An inherited form of HCM has been reported in a family of Pointer dogs.43

ATRIOVENTRICULAR MYOPATHY Atrioventricular myopathy is characterized by replacement fibrosis of the atrial myocardium with or without fatty degeneration, leading to atrial dilation and persistent atrial standstill.4 Often this disease progresses to involve the ventricular myocardium. The disease is most commonly reported in the English Springer Spaniel and Labrador Retriever, although other breeds may be affected.4,5 In some cases, atrioventricular myopathy is associated with myocarditis, nemaline

rod myopathy, and muscular dystrophy. Dogs present with clinical signs related to bradycardia, including lethargy, syncope, exercise intolerance, or congestive heart failure. Treatment often requires a permanent pacemaker. Although prognosis has previously been considered poor, a recent retrospective study reported a median survival time in dogs with persistent atrial standstill of 866 days with pacemaker implantation, with some patients living up to 8 years.

REFERENCES 1. Dukes-McEwan J, Borgarelli M, Tidholm A, et al: Proposed guidelines for the diagnosis of canine idiopathic dilated cardiomyopathy, J Vet Cardiol 5:7, 2003. 2. Wess G, Domenech O, Dukes-McEwan J, et al: European Society of Veterinary Cardiology screening guidelines for dilated cardiomyopathy in Doberman Pinschers, J Vet Cardiol 19:405, 2017. 3. Stern JA, Meurs KM: Myocardial disease: canine. In Ettinger SJ, Feldman EC, Côté E, editors: Textbook of veterinary internal medicine, ed 8, St. Louis, Missouri, 2017, Elsevier, pp 1269. 4. Schmitt KE, Lefbom BK: Long-term management of atrial myopathy in two dogs with single chamber permanent transvenous pacemaker, J Vet Cardiol 18:187, 2016. 5. Cervenec RM, Stauthammer CD, Fine DM, et al: Survival time with pacemaker implantation for dogs diagnosed with persistent atrial standstill, J Vet Cardiol 19:240, 2017. 6. Kornegay JN: The golden retriever model of Duchenne muscular dystrophy, Skelet Muscle 7:9 2017. 7. Stephenson HM, Fonfara S, López-Alvarez, et al: Screening for dilated cardiomyopathy in Great Danes in the United Kingdom, J Vet Intern Med 26:1140, 2012. 8. Tidholm A, Jönsson L: Histologic characterization of canine dilated cardiomyopathy, Vet Pathol 42:1, 2005. 9. Summerfield NJ, Boswood A, O’Grady MR, et al: Efficacy of pimobendan in the prevention of congestive heart failure or sudden death in Doberman pinschers with preclinical dilated cardiomyopathy (The PROTECT Study), J Vet Intern Med 26:1337, 2012. 10. Holler PJ, Wess G: Sphericity index and E-point-to-septal-separation (EPSS) to diagnosis dilated cardiomyopathy in Doberman Pinschers, J Vet Intern Med 28:123, 2014. 11. Ward J, Ware W, Viall A: Association between atrial fibrillation and rightsided manifestations of congestive heart failure in dogs with degenerative mitral valve disease or dilated cardiomyopathy, J Vet Cardiol 21:18, 2019. 12. Klüser L, Holler PJ, Simak J, et al: Predictors of sudden cardiac death in Doberman pinschers with dilated cardiomyopathy, J Vet Intern Med 30:722, 2016. 13. Hazlett MJ, Maxie MG, Allen DG, et al: A retrospective study of heart disease in Doberman pinscher dogs, Can Vet J 24:205, 1983. 14. Wess G, Schulze A, Butz V, et al: Prevalence of dilated cardiomyopathy in Doberman Pinschers in various age groups, J Vet Intern Med 24:533, 2010. 15. Meurs KM, Lahmers S, Keene BW, et al: A splice site mutation in a gene encoding for PDK4, a mitochondrial protein, is associated with the development of dilated cardiomyopathy in the Doberman pinscher, Hum Genet 131:1319, 2012. 16. Meurs KM, Friedenberg SG, Kolb J, et al: A missense variant in the titin gene in Doberman pinscher dogs with familial dilated cardiomyopathy and sudden cardiac death, Hum Genet 138:515, 2019. 17. O’Grady MR, O’Sullivan ML, Minors SL, et al: Efficacy of benazepril hydrochloride to delay the progression of occult dilated cardiomyopathy in Doberman pinschers, J Vet Intern Med 23:977, 2009. 18. Oyama MA, Sisson DD, Prosek R, et al: Carvedilol in dogs with dilated cardiomyopathy, J Vet Intern Med 21:1272, 2007. 19. Visser LC, Kaplan JL, Nishimura S: Acute echocardiographic effects of sotalol on ventricular systolic function in dogs with ventricular arrhythmias, J Vet Intern Med 32:1299, 2018.

CHAPTER 44  Canine Cardiomyopathy 20. Smith CE, Freeman LM, Rush JE, et al: Omega-3 fatty acids in Boxer dogs with arrhythmogenic right ventricular cardiomyopathy, J Vet Intern Med 21:265, 2007. 21. Freeman LM, Rush JE, Kehayias JJ: Nutritional alterations and the effect of fish oil supplementation in dogs with heart failure, J Vet Intern Med 12:440, 1998. 22. Meurs KM: Insights into the hereditability of canine cardiomyopathy, Vet Clin North Am Small Anim Pract 28:1449, 1998. 23. Meurs KM, Miller MW, Wright NA: Clinical features of dilated cardiomyopathy in Great Danes and results of a pedigree analysis: 17 cases (1990-2000), J Am Vet Med Assoc 218:729, 2001. 24. Fousse SL, Tyrrell WD Dentino ME, et al: Pedigree analysis of atrial fibrillation in Irish wolfhounds supports a high heritability with a dominant mode of inheritance, Canine Genet Epidemiol 6:11, 2019. 25. Vollmar AC: The prevalence of cardiomyopathy in the Irish wolfhound: a clinical study of 500 dogs, J Am Anim Hosp Assoc 36:125, 2000. 26. Tidholm A, Jönsson L: Dilated cardiomyopathy in the Newfoundland: a study of 37 cases (1983-1994), J Am Anim Hosp Assoc 32:465, 1996. 27. Harmon MW, Leach SB, Lamb KE: Dilated cardiomyopathy in standard Schnauzers: retrospective study of 15 cases, J Am Anim Hosp Assoc 53: 38, 2017. 28. Leach SB, Johnson GS, Gilliam D, et al: Dilated cardiomyopathy in standard schnauzers with a homozygous 22 bp deletion in RBM20. Proceeding of the ACVIM Forum 2014 Cardiology Research Report, Nashville, TN, 2014. 29. Dambach DM, Lannon A, Sleeper MM, et al: Familial dilated cardiomyopathy of young Portuguese water dogs, J Vet Intern Med 13:65, 1999. 30. Sleeper MM, Henthorn PS, Vijayasarathy C, et al: Dilated cardiomyopathy in juvenile Portuguese Water Dog, J Vet Intern Med 16:52, 2002. 31. Legge CH, López A, Hanna P, et al: Histological characterization of dilated cardiomyopathy in the juvenile Toy Manchester Terrier, Vet Pathol 50:1043, 2013. 32. Kaplan JL, Stern JA, Fascetti AJ, et al: Taurine deficiency and dilated cardiomyopathy in golden retrievers fed commercial diets, PLoS One 13:e0209112, 2018.

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33. Food and Drug Administration: Dilated cardiomyopathy in dogs & cats: complaints submitted to FDA-CVM January 1, 2014 – April 30, 2019, pp 1–77. 34. Keene BW, Panciera DP, Atkins CE, et al: Myocardial L-carnitine deficiency in a family of dogs with dilated cardiomyopathy, J Am Vet Med Assoc 198:647, 1991. 35. Freeman LM, Michel KE, Brown DJ, et al: Idiopathic dilated cardiomyopathy in Dalmatians: nine cases (1990-1995), J Am Vet Med Assoc 209:1592, 1996. 36. Basso C, Fox PR, Meurs KM, et al: Arrhythmogenic right ventricular cardiomyopathy causing sudden cardiac death in Boxer dogs: a new animal model of human disease, Circulation 109:1180, 2004. 37. Meurs KM, Stern JA, Sisson DD, et al: Association of dilated cardiomyopathy with the striatin mutation genotype in boxer dogs, J Vet Intern Med 27:1437, 2013. 38. Meurs KM, Mauceli E, Lahmers S, et al: Genome-wide association identifies a deletion in the 3’ untranslated region of striatin in a canine model of arrhythmogenic right ventricular cardiomyopathy, Hum Genet 128: 315, 2010. 39. Baumwart RD, Meurs KM, Atkins CE, et al: Clinical, echocardiographic, and electrocardiographic abnormalities in Boxers with cardiomyopathy and left ventricular systolic dysfunction: 48 cases (1985-2003), J Am Vet Med Assoc 226:1102, 2005. 40. Meurs KM, Stern JA, Reina-Doreste, et al: Natural history of arrhythmogenic right ventricular cardiomyopathy in the Boxer dog: a prospective study, J Vet Intern Med 28:1214, 2014. 41. Mõtsküla PF, Linney C, Palermo V, et al: Prognostic value of 24-hour ambulatory ECG (Holter) monitoring in Boxer dogs, J Vet Intern Med 27:904, 2013. 42. Meurs KM, Spier AW, Wright NA, et al: Comparison of the effects of four antiarrhythmic treatments for familial ventricular arrhythmias in Boxers, J Am Vet Med Assoc 221:522, 2002. 43. Sisson DD: Heritability of idiopathic myocardial hypertrophy and dynamic subaortic stenosis in Pointer dogs, J Vet Intern Med 9:118, 1990.

45 Canine Myxomatous Mitral Valve Disease Ashley N. Sharpe, DVM, Lance C. Visser, DVM, MS, DACVIM (Cardiology)

KEY POINTS • Myxomatous mitral valve disease (MMVD) has a long subclinical period in most dogs and is characterized by an incidental left apical systolic murmur secondary to mitral valve regurgitation. • MMVD is the most common cause of heart failure in dogs, but not all dogs with MMVD develop heart failure. • Presumptive diagnosis and empiric management of MMVD are largely guided by cardiac auscultation and thoracic radiographs, but echocardiography is recommended to confirm the diagnosis and for ideal management and prognostication. • Cough is a common clinical sign in dogs with MMVD but is not a reliable indicator of left heart failure. Dyspnea coupled with a

loud left apical systolic murmur in an older small dog are highly suggestive of left heart failure. • Pimobendan has been shown to delay the onset of heart failure in small dogs with subclinical MMVD, a loud murmur, and clinically significant cardiomegaly based on specific measurements of heart size. • Successful emergency management of heart failure involves reducing venous congestion (diuretics), optimizing cardiac output (pimobendan with or without arterial vasodilators), and improving tissue oxygenation.

INTRODUCTION

Over time (years in most cases), progressive mitral valve regurgitation (MR) can result in significantly increased left atrial (LA) pressure, left ventricular (LV) filling pressure and reduced forward stroke volume. Forward stroke volume is initially maintained, in part, by enhanced LV filling (increased preload and Frank–Starling effect) and eccentric hypertrophy (chamber dilation). Progressive chamber dilation results in displaced papillary muscles and stretch of the valve annulus, which contributes to progressive MR. Progressive increases in LA volume and declining forward stroke volume result in neurohormonal activation to attempt to compensate for reduced cardiac output and systemic arterial pressure. This includes activation of the sympathetic nervous system and renin-angiotensin-aldosterone system (RAAS), among others. This is beneficial in the short-term but ultimately leads to a vasoconstricted, fluid retentive state that further increases LA, pulmonary venous and pulmonary capillary pressures (i.e., postcapillary pulmonary hypertension). Once countermeasures are overwhelmed (e.g., natriuretic peptides, pulmonary lymphatic drainage), increased capillary hydrostatic pressure overcomes other Starling forces (interstitial hydrostatic pressure and capillary oncotic pressure) and results in cardiogenic pulmonary edema and breathing difficulty. Cardiogenic pulmonary edema coupled with clinical signs fulfills the clinical syndrome of left HF (see Chapter 41, Mechanisms of Heart Failure). Chronic neurohormonal activation including increased norepinephrine, angiotensin II, and aldosterone contributes to cardiomyocyte death and replacement fibrosis, which further contributes to pathologic hypertrophy and ultimately myocardial failure. The latter might not be apparent until the very end-stage in smaller dogs. Additional complications can arise and contribute to acute decompensation. Rupture of a major chordae leads to a flail leaflet, severe MR, and acute fulminant pulmonary edema. Rarely, weakening of the atrial wall from chronic, severe MR leads to a LA tear, which can cause an acquired left-to-right shunting atrial septal defect (minimal

Myxomatous (degenerative) mitral valve disease (MMVD) is the most common cardiac disease and cause of heart failure (HF) in dogs. The prevalence of MMVD increases with age in all breeds/somatotypes but approaches 100% in some older (.10 years) small-breed dogs (e.g., Cavalier King Charles Spaniel, Dachshund, Miniature Poodle, Yorkshire Terriers).1 Some breeds such as Cavalier King Charles Spaniels can be affected at a younger age and suffer from HF more frequently, but the rate of progression appears similar to dogs affected at an older age.2,3 Smaller dogs (,20 kg) typically experience a long but at times unpredictable subclinical period where the murmur of mitral valve regurgitation is evident for years prior to HF. Studies have shown that the median time to HF or cardiac death in untreated smaller dogs with clinically significant cardiomegaly is 2–3 years.4,5 For unknown reasons, larger dogs often exhibit overt myocardial dysfunction, progress faster, and have a more guarded prognosis.6

PATHOLOGY AND PATHOPHYSIOLOGY The etiology of MMVD is unknown, but there is evidence to support an inherited component in some breeds.7-9 The pathology of MMVD has been described in detail elsewhere.10 The valve apparatus (leaflets and chordae tendineae) undergoes variable degrees of myxomatous degeneration that is characterized by dysregulation and subsequent weakening and disorganization of the extracellular matrix. Vegetative endocarditis and significant inflammatory changes do not play a role in the development of MMVD. Variable degrees of valve thickening, irregularity, abnormal leaflet coaptation, chordae tendineae rupture, or valve prolapse become evident. These changes ultimately lead to systolic mitral valve regurgitation, a hallmark of the disease. Myxomatous degeneration can affect the other three cardiac valves, especially the tricuspid valve, but this bears little clinical relevance.

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CHAPTER 45  Canine Myxomatous Mitral Valve Disease clinical relevance in the short term) or acute pericardial effusion and cardiac tamponade. The latter is frequently associated with collapse or sudden death. Pulmonary hypertension (PH) secondary to chronic, severe MMVD is a relatively common complication of smaller dogs with MMVD (see Chapter 22, Pulmonary Hypertension).11,12 Chronic postcapillary PH (pulmonary venous hypertension) can lead to a reactive pulmonary arterial vasoconstriction and pulmonary vascular disease (combined postcapillary and precapillary PH). Syncope, right HF, or both are common sequelae. Supraventricular or ventricular tachyarrhythmias (see Chapters 49 and 50) are also not uncommon. Atrial fibrillation seems to be more common in larger dogs with MMVD and is commonly associated with biventricular or right HF.13

HISTORICAL AND PHYSICAL EXAMINATION FINDINGS An incidental left-sided systolic murmur is likely the most common clinical finding of dogs with MMVD. Murmur intensity has been shown to correlate with the severity of disease in smaller dogs with MMVD.14 However, grading murmurs is partially subjective, and murmur intensity can vary depending on the auscultator, heart rate, blood volume, and listening conditions, among other variables. Common presenting complaints of dogs with MMVD include cough, increased breathing rate or effort, exercise intolerance, syncope, or collapse. Physical examination findings of dogs with MMVD and left HF are most commonly associated with “congestive” signs, that is, pulmonary edema or cavitary effusions versus signs of reduced cardiac output and systemic hypotension. Thus, tachypnea and dyspnea are common. Orthopnea, cyanosis and abnormal lung sounds (e.g., crackles) might or might not be apparent. Physical examination findings of right HF (e.g., due to concurrent atrial fibrillation or PH) might also be apparent including abdominal distension (cardiogenic ascites), jugular venous distension, and decreased ventral lung sounds from pleural effusion. Cough is not a reliable indicator of left HF because the evidence behind pulmonary edema causing cough is suspect and because comorbidities such as tracheobronchomalacia and chronic bronchitis are common in dogs with MMVD.15-17 A sleeping or calmly resting respiratory rate (S/RRR) ,30 breaths/min essentially rules out pulmonary edema,18,19 whereas S/RRR $30 breaths/ min should heighten concern for HF in dogs with known or suspected MMVD. Tachycardia secondary to elevated sympathetic tone is nearly always present in dogs in HF; thus, dogs with normal or lower heart rates are unlikely experiencing HF. Tachyarrhythmias are invariably encountered.

CLINICOPATHOLOGIC FINDINGS AND CARDIAC BIOMARKERS Clinicopathologic findings of dogs with MMVD are nonspecific and rarely useful to aid in the diagnosis of MMVD. Changes attributable to MMVD are typically associated with severe disease and HF. The complete blood cell count may be normal or demonstrate a normochromic, normocytic nonregenerative anemia. A stress leukogram (neutrophilia, monocytosis, lymphopenia, eosinopenia) is likely in dogs with HF. The biochemical profile may demonstrate changes secondary to passive congestion of the liver (hepatopathy) or hyponatremia and hypochloridemia in chronic HF. Azotemia and signs of renal dysfunction may become apparent with concurrent HF. Conversely, the biochemical panel may be normal or demonstrate abnormalities consistent with other diseases of aged patients. Blood gas analysis may reveal varying degrees of hypoxemia with metabolic acidosis secondary to peripheral vasoconstriction and poor perfusion (lactic acidosis).

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The cardiac biomarker N-terminal pro-B-type natriuretic peptide (NT-proBNP) is released due to cardiomyocyte stretch and increases progressively with worsening MMVD and onset of HF (see Chapter 52, Cardiac Biomarkers). In general, serial NT-proBNPs within the same dog (versus comparison to a reference interval) are probably most informative due to biologic variability within individual dogs.20,21 NTproBNP can provide useful adjunct evidence for determining the cause for clinical signs (e.g., tachypnea, dyspnea, or exercise intolerance) in dogs with MMVD. This is particularly true when NT-proBNP concentration is normal or near normal in symptomatic dogs, which strongly suggests severe cardiac disease is not the cause of the clinical signs.22 There is some evidence suggesting NT-proBNP can be useful to aid treatment decisions or evaluate response to treatment, but further study would be ideal.23,24 Lastly, other factors in dogs with MMVD can increase NT-proBNP, including dogs with renal dysfunction and PH.25-27

THORACIC RADIOGRAPHIC FINDINGS Thoracic radiographs are highly recommended for all dogs with known or presumed MMVD. They help determine the clinical significance of the MMVD by assessing the magnitude of left heart enlargement, and they are essential to determine left HF status. In general, the bigger the left heart, the more severe the MMVD and the more likely a dog will benefit from therapy, that is, pimobendan to delay HF (if pulmonary edema is not present).4 The American College of Veterinary Internal Medicine (ACVIM) consensus guidelines28 support the use of objective measures of radiographic heart size, vertebral heart score (VHS)29 and vertebral left atrial size (VLAS)30 (Fig. 45.1). Subjective criteria that corroborate the objective measures for left heart enlargement from lateral projections includes straightening or loss of the dorsal caudal cardiac waist (LA enlargement) and dorsal deviation of the trachea, carina, and mainstem bronchi (LV enlargement). Left heart enlargement on the dorsoventral or ventrodorsal projection is manifested as increased soft tissue opacity between the mainstem bronchi (LA enlargement), a bulge at the 2 to 3 o’clock position (enlargement of the left auricle), and a widened cardiac silhouette (e.g., more than two-thirds of the thoracic width). Overt pulmonary venous distension may or may not be apparent. Mild or early pulmonary edema is typically seen as an increase in interstitial density in the perihilar and caudodorsal lung fields. This may involve an alveolar pattern and spread to other lung fields with severe pulmonary edema. Cardiogenic pulmonary edema has a propensity to involve the right caudal lung fields in some dogs, which is commonly apparent on the dorsoventral view. Pleural fissure lines or effusion, distension of the caudal vena cava, and loss of abdominal serosal detail from ascites may be apparent with right or biventricular HF.

CARDIAC AND THORACIC ULTRASOUND FINDINGS Although an echocardiographic examination is not essential for emergency management of most dogs with MMVD, it is highly recommended for ideal management and prognostication of cases. An echocardiographic examination by a skilled and knowledgeable operator confirms the presence of MMVD (mitral valve thickening, irregularity, and regurgitation), accurately quantifies chamber size and function, provides estimates of LV filling pressures, and identifies comorbidities or complicating factors of severe MMVD (see below). Measurements of LA and LV size have become important for staging and thus treatment recommendations prior to left HF.4,28 Echocardiographic assessment of LA size is a particularly useful skill to help corroborate clinical signs, and radiographic findings are secondary to left HF. The left atrium to aortic root

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A

Fig. 45.2  An example measurement of the left atrium to aortic root ratio (LA/Ao) at early diastole (just after aortic valve closure) acquired from a standard right parasternal short-axis basilar view in a dog with MMVD and severe left atrial enlargement.

EMERGENCY MANAGEMENT

B Fig. 45.1  Right lateral thoracic radiograph from a dog with myxomatous mitral valve disease (MMVD) demonstrating the vertebral heart score (VHS) (A) and vertebral left atrial size (VLAS) (B) measurements used to radiographically quantify heart size. VLAS is a newer measurement intended to quantify left atrial (LA) size. A line is drawn from the central and ventral border of the carina (radiolucent circular or ovoid structure within the trachea that represents the bifurcation of the left and right mainstem bronchi) to the most caudal aspect of the LA where it intersects with the dorsal border of the caudal vena cava (#). This line is then transposed to the cranial edge of the fourth thoracic vertebral body (*) and quantified in vertebral body units to the nearest 0.1 vertebra similar to VHS. A VHS $11.5 or VLAS $3.0 suggests clinically significant cardiomegaly is present in a dog with known or presumed MMVD.

ratio from the right parasternal short-axis view in early diastole (just after aortic valve closure) is the most common and convenient method to estimate LA size (Fig. 45.2). LA size represents a robust surrogate for the severity of chronic MR. In general, the bigger the LA, the worse the MR and the more likely the dog is experiencing or at risk for left HF. In other words, left HF is unlikely in dogs lacking severe LA enlargement. Point-of-care lung ultrasonography is gaining popularity as an efficient and low-stress tool to help determine the etiology of breathing difficulty or cough. Studies of dogs experiencing left HF have shown that the presence of B-line artifacts are highly suggestive of pulmonary edema.31,32 However, false positives and false negatives are possible. Because thoracic radiographs provide a more comprehensive view of the lungs, they are strongly advised to confirm findings.

Emergency management of MMVD most commonly involves management of HF. Alleviating clinical signs due to HF secondary to MMVD involves manipulating hemodynamic variables to decrease preload and venous congestion, optimize cardiac output, and improve tissue oxygenation. Consultation of the ACVIM consensus guidelines for treatment of HF secondary to MMVD is strongly encouraged.28 A summary of these recommendations follows. Diuretic therapy represents the mainstay of treatment for acute (inhospital) HF treatment because congestive signs (e.g., pulmonary edema) usually predominate. If pleural or abdominal effusion are present and contributing to discomfort or breathing difficulty, thoracocentesis or abdominocentesis are advised in addition to diuretic therapy. Diuretics reduce preload and venous congestion by reducing intravascular volume. Furosemide (2 mg/kg ideally IV, IM or SC) is most commonly used. It can be administered hourly until respiratory rate and effort improve. However, if the dog fails to show some signs of improvement within 2–4 hours, additional clinical problems or therapies should be considered. Dogs with severe dyspnea and pulmonary edema (expectoration of froth, “white-out lung,” i.e., severe and diffuse alveolar pattern on radiographs, or poor initial response within 2–4 hours) might benefit from a furosemide continuous rate infusion (CRI) with initial rates ranging from 0.5–1 mg/kg/hr. This recommendation stems from studies in humans and healthy dogs where a furosemide CRI has been shown to induce more potent diuresis compared to dose-equivalent intermittent bolus therapy.33 However, there is some evidence suggesting that a furosemide CRI might carry an increased risk for dehydration and azotemia.34 All dogs receiving diuretics should be allowed unlimited access to water. Optimization of cardiac output in dogs with acute HF secondary to MMVD involves arterial vasodilators (afterload reducers) with or without a positive inotrope, which act to reduce the amount of mitral regurgitation, thereby improving forward stroke volume. For these reasons and because of its venodilator properties, pimobendan (0.25 to 0.3 mg/kg PO q8-12h) is recommended for routine use in emergency management of

CHAPTER 45  Canine Myxomatous Mitral Valve Disease HF. In severe or refractory cases of HF secondary to MMVD, the vasodilator sodium nitroprusside (CRI rate 1 to 15 mg/kg/min for up to 48-hours) can be added. Given the cost and limited availability of nitroprusside, the parenteral dihydropyridine calcium channel blocker clevidipine (CRI rate starting at 1 mg/kg/min) can be considered. Alternatively, oral arterial vasodilators are an option (e.g., hydralazine (0.5–2.5 mg/kg PO q12h) or amlodipine (0.1–0.2 mg/kg PO q24h). These vasodilator therapies assume the dog is not hypotensive at presentation and close (ideally invasive) blood pressure monitoring can be performed. The addition of dobutamine (2.5–10 mg/kg/min; with continuous electrocardiogram monitoring) represents another means to improve cardiac output by increasing myocardial contractility. This is typically reserved for hypotensive dogs (cardiogenic shock) or dogs refractory to standard acute HF treatment (furosemide, pimobendan, and oxygen therapy). Sedatives (e.g., narcotics such as butorphanol 0.2 to 0.4 mg/kg IM/ IV with or without acepromazine 0.01–0.02 mg/kg IM/IV) and oxygen therapy should be provided to all dogs in HF with dyspnea. Oxygen therapy should be appropriately temperature and humidity controlled. Increasing the fraction of inspired oxygen coupled with the aforementioned therapies improves tissue oxygenation. Some dogs with severe HF experience respiratory failure/fatigue, which necessitates intubation and positive-pressure ventilation.35

MANAGEMENT OF COMPLICATING FACTORS Complicating factors in dogs with MMVD, usually with HF, include PH (see Chapter 22, Pulmonary Hypertension), tachyarrhythmias (see Chapters 49 and 50, Supraventricular Tachyarrhythmias and Ventricular Tachyarrhythmias), LA tear and pericardial effusion, and ruptured chordae tendineae. Dogs with PH secondary to MMVD will likely benefit from therapies intended to reduce postcapillary PH (reduce LA pressure), e.g., pimobendan and, if present, treatment for HF. Phosphodiesterase-5 inhibitors (e.g., sildenafil) are not recommended as first-line therapy. Due to the risk of inducing or worsening pulmonary edema, specific guidelines on when to use phosphodiesterase-5 inhibitors are available and should be consulted (see Chapter 22, Pulmonary Hypertension).12 Dogs in HF secondary to MMVD might also present with atrial fibrillation (particularly larger dogs). Emergency management should focus on treatment of HF. Parenteral antiarrhythmic medications (e.g., diltiazem CRI) are rarely needed for stabilization. Oral antiarrhythmics for rate control can be initiated once the dog’s HF is stabilized or ready for discharge.36 LA tear is a rare but challenging complication of MMVD. Similar to PH, therapies to lower LA pressure and, if present, treat HF are recommended. Strict rest and close monitoring during hospitalization are warranted. To avoid potentially fatal hemorrhage, pericardiocentesis should only be considered for dogs where cardiac tamponade is considered life-threatening. Rupture of a major chordae tendineae can cause acute fulminant left HF. In addition to standard management of HF, these cases are more likely to benefit from a furosemide CRI, arterial vasodilators (e.g., sodium nitroprusside), positive-pressure ventilation, or some combination thereof. Some dogs with LA tear or chordae tendineae rupture that recover and survive to hospital discharge have the potential to do surprisingly well.37,38

MONITORING Emergency management of HF requires close (hourly) monitoring of respiratory rate and effort when the dog is sedated or resting. A consistently declining hourly S/RRR or a S/RRR ,30–40 breaths/min strongly supports a significant decrease in pulmonary edema, which should prompt an adjustment of diuretic therapy. Baseline (ideally near the

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time of hospital admission) assessment of thoracic radiographs, body weight, blood pressure, volume status, acid-base status, renal function, and electrolyte concentration are strongly advised. These variables are typically reassessed every 12–24 hours or as clinically indicated throughout hospitalization. Furosemide administration will likely result in variable increases in blood urea nitrogen and creatinine concentrations and a decrease in body weight (usually by 5%–8% compared to admission) and potassium and chloride concentrations. Metabolic alkalosis is not uncommon. These findings are usually well tolerated but a significant azotemia (e.g., blood urea nitrogen .50  mg/dl, creatinine $2.5 mg/dl), usually with signs of nausea/vomiting, electrolyte disturbances, and weight loss .10% compared to admission, suggest diuretic therapy should be modified.

LONG-TERM MANAGEMENT Goals of long-term management MMVD and HF include continuing the cardiac medications initiated for emergency management of HF while adding therapies to slow the progression of disease and improve survival.28 The lowest effective dose of furosemide (2–12 mg/kg/day PO, divided twice daily) is recommended and should be titrated over time based on patient clinical condition and evidence of decompensation on thoracic radiographs. A typical starting dose of furosemide following a dog’s first episode of HF is 2 mg/kg PO q12h. Torsemide, a more potent long-acting loop diuretic, represents an alternate option.39 Dosing is typically based on 5% to 10% of the desired daily furosemide dose administered once daily or 0.1–0.3 mg/kg PO q24h. Diuretics are rarely dose-reduced post-HF provided they are well tolerated. Pimobendan (0.25–0.3 mg/kg PO q12h) should be continued. Drugs that block RAAS should be started (if not already done so) and are typically reserved for at-home administration. These include enalapril or benazepril (0.5 mg/kg PO q12h) and spironolactone (2 mg/kg/day PO). Dietary recommendations for dogs with HF secondary to MMVD should not be overlooked. Maintaining adequate calorie intake (to prevent cardiac cachexia), modest sodium restriction (helps control edema), and omega-3 fatty acid supplementation are example recommendations.28 There are numerous strategies to delay the inevitable progression of the dog’s HF. Consultation with a board-certified cardiologist regarding individual patient recommendations is highly recommended at this stage. Common approaches include up-titration of furosemide or torsemide (ceiling dose of furosemide is 12 mg/kg/day), adding a diuretic (e.g., hydrochlorothiazide), adding arterial vasodilators (e.g., amlodipine or hydralazine), or off-label up-titration of pimobendan (e.g., 0.5 mg/kg PO q12h or 0.3 mg/kg PO q8h). Long-term pharmacologic recommendations for the management of subclinical MMVD (prior to HF) are based on the degree of left heart remodeling best determined by echocardiography. Dogs with loud murmurs ($3/6), LA/Ao $1.6, and LV internal dimension normalized to body weight (kg) $1.7 (cm/kg0.294) are expected to benefit from pimobendan 0.25–0.3 mg/kg PO q12h.4,28 In the absence of echocardiography, cardiac size can be assessed radiographically. A dog with known or highly suspected MMVD and a VHS $11.5 or VLAS $3.0 is expected to benefit from pimobendan 0.25–0.3 mg/kg PO q12h.28 The evidence supporting the use of enalapril or benazepril (0.5 mg/kg PO q12h) in dogs with subclinical MMVD and cardiomegaly is unclear, but these treatments are commonly recommended and well tolerated. Lastly, surgical mitral valve repair performed at experienced centers with low complication rates can be considered in dogs with MMVD and clinically significant cardiomegaly or HF.40,41 Unfortunately, this procedure is largely limited by cost and accessibility.

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PROGNOSIS Most dogs with MMVD do not experience HF and likely die from other age-related comorbidities. This is particularly true of asymptomatic dogs without significant cardiomegaly. However, if HF occurs, it will worsen the dog’s prognosis. Prognostication of individual dogs is challenging and depends on the client’s and clinician’s perception of the disease, client dedication, client financial resources, and any complicating factors the dog might have. A reasonable expectation for most dogs with MMVD after the first onset of HF is approximately 6 to 18 months of a good quality of life. Recently, dogs with recurrent or “advanced” HF secondary to MMVD were shown to have relatively long median survival times of 9 months.42 Recurrent bouts of HF can be managed, and dogs can be returned to life at home with oral medications.

REFERENCES 1. Borgarelli M, Buchanan JW: Historical review, epidemiology and natural history of degenerative mitral valve disease, J Vet Cardiol 14(1):93-101, 2012. 2. Borgarelli M, Haggstrom J: Canine degenerative myxomatous mitral valve disease: natural history, clinical presentation and therapy, Vet Clin North Am Small Anim Pract 40(4):651-663, 2010. 3. Häggström J, Höglund K, Borgarelli M: An update on treatment and prognostic indicators in canine myxomatous mitral valve disease, J Small Anim Pract 50(s1):25-33, 2009. 4. Boswood A, Häggström J, Gordon SG, et al: Effect of pimobendan in dogs with preclinical myxomatous mitral valve disease and cardiomegaly: the EPIC study-a randomized clinical trial, J Vet Intern Med 30(6):1765-1779, 2016. 5. Borgarelli M, Ferasin L, Lamb K, et al: DELay of Appearance of sYmptoms of canine degenerative mitral valve disease treated with spironolactone and benazepril: the DELAY study, J Vet Cardiol 27:34-53, 2020. 6. Borgarelli M, Zini E, D’Agnolo G, et al: Comparison of primary mitral valve disease in German Shepherd dogs and in small breeds, J Vet Cardiol 6(2):27-34, 2004. 7. Olsen LH, Fredholm M, Pedersen HD: Epidemiology and inheritance of mitral valve prolapse in Dachshunds, J Vet Intern Med 13(5):448-456, 1999. 8. Madsen MB, Olsen LH, Häggström J, et al: Identification of 2 loci associated with development of myxomatous mitral valve disease in Cavalier King Charles Spaniels, J Hered 102(Suppl 1):S62-S67, 2011. 9. Stern JA, Hsue W, Song KH, Ontiveros ES, Luis Fuentes V, Stepien RL: Severity of mitral valve degeneration is associated with chromosome 15 loci in whippet dogs, PLoS ONE 10(10):e0141234, 2015. 10. Fox PR: Pathology of myxomatous mitral valve disease in the dog, J Vet Cardiol 14(1):103-126, 2012. 11. Borgarelli M, Abbott J, Braz-Ruivo L, et al: Prevalence and prognostic importance of pulmonary hypertension in dogs with myxomatous mitral valve disease, J Vet Intern Med 29(2):569-574, 2015. 12. Reinero C, Visser LC, Kellihan HB, et al: ACVIM consensus statement guidelines for the diagnosis, classification, treatment, and monitoring of pulmonary hypertension in dogs, J Vet Intern Med 34(2):549-573, 2020. 13. Ward J, Ware W, Viall A: Association between atrial fibrillation and rightsided manifestations of congestive heart failure in dogs with degenerative mitral valve disease or dilated cardiomyopathy, J Vet Cardiol 21:18-27, 2019. 14. Ljungvall I, Rishniw M, Porciello F, Ferasin L, Ohad DG: Murmur intensity in small-breed dogs with myxomatous mitral valve disease reflects disease severity, J Small Anim Pract 55(11):545-550, 2014. 15. Ferasin L, Crews L, Biller DS, Lamb KE, Borgarelli M: Risk factors for coughing in dogs with naturally acquired myxomatous mitral valve disease, J Vet Intern Med 27(2):286-292, 2013. 16. Ferasin L, Linney C: Coughing in dogs: what is the evidence for and against a cardiac cough? J Small Anim Pract 60(3):139-145, 2019. 17. Singh MK, Johnson LR, Kittleson MD, Pollard RE: Bronchomalacia in dogs with myxomatous mitral valve degeneration, J Vet Intern Med 26(2):312-319, 2012.

18. Ohad DG, Rishniw M, Ljungvall I, Porciello F, Häggström J: Sleeping and resting respiratory rates in dogs with subclinical heart disease, J Am Vet Med Assoc 243(6):839-843, 2013. 19. Porciello F, Rishniw M, Ljungvall I, Ferasin L, Haggstrom J, Ohad DG: Sleeping and resting respiratory rates in dogs and cats with medicallycontrolled left-sided congestive heart failure, Vet J 207:164-168, 2016. 20. Winter RL, Saunders AB, Gordon SG, Buch JS, Miller MW: Biologic variability of N-terminal pro-brain natriuretic peptide in healthy dogs and dogs with myxomatous mitral valve disease, J Vet Cardiol 19(2): 124-131, 2017. 21. Ruaux C, Scollan K, Suchodolski JS, Steiner JM, Sisson DD: Biologic variability in NT-proBNP and cardiac troponin-I in healthy dogs and dogs with mitral valve degeneration, Vet Clin Pathol 44(3):420-430, 2015. 22. Oyama MA, Fox PR, Rush JE, Rozanski EA, Lesser M: Clinical utility of serum N-terminal pro-B-type natriuretic peptide concentration for identifying cardiac disease in dogs and assessing disease severity, J Am Vet Med Assoc 232(10):1496-1503, 2008. 23. Hezzell MJ, Block CL, Laughlin DS, Oyama MA: Effect of prespecified therapy escalation on plasma NT-proBNP concentrations in dogs with stable congestive heart failure due to myxomatous mitral valve disease, J Vet Intern Med 32(5):1509-1516, 2018. 24. Wolf J, Gerlach N, Weber K, Klima A, Wess G: Lowered N-terminal proB-type natriuretic peptide levels in response to treatment predict survival in dogs with symptomatic mitral valve disease, J Vet Cardiol 14(3): 399-408, 2012. 25. Lee JA, Herndon WE, Rishniw M: The effect of noncardiac disease on plasma brain natriuretic peptide concentration in dogs, J Vet Emerg Crit Care (San Antonio) 21(1):5-12, 2011. 26. Kellihan HB, Mackie BA, Stepien RL: NT-proBNP, NT-proANP and cTnI concentrations in dogs with pre-capillary pulmonary hypertension, J Vet Cardiol 13(3):171-182, 2011. 27. Raffan E, Loureiro J, Dukes-McEwan J, et al: The cardiac biomarker NT-proBNP is increased in dogs with azotemia, J Vet Intern Med 23(6): 1184-1189, 2009. 28. Keene BW, Atkins CE, Bonagura JD, et al: ACVIM consensus guidelines for the diagnosis and treatment of myxomatous mitral valve disease in dogs, J Vet Intern Med 33(3):1127-1140, 2019. 29. Buchanan JW, Bücheler J: Vertebral scale system to measure canine heart size in radiographs, J Am Vet Med Assoc 206(2):194-199, 1995. 30. Malcolm EL, Visser LC, Phillips KL, Johnson LR: Diagnostic value of vertebral left atrial size as determined from thoracic radiographs for assessment of left atrial size in dogs with myxomatous mitral valve disease, J Am Vet Med Assoc 253(8):1038-1045, 2018. 31. Ward JL, Lisciandro GR, Keene BW, Tou SP, DeFrancesco TC: Accuracy of point-of-care lung ultrasonography for the diagnosis of cardiogenic pulmonary edema in dogs and cats with acute dyspnea, J Am Vet Med Assoc 250(6):666-675, 2017. 32. Rademacher N, Pariaut R, Pate J, Saelinger C, Kearney MT, Gaschen L: Transthoracic lung ultrasound in normal dogs and dogs with cardiogenic pulmonary edema: a pilot study, Vet Radiol Ultrasound 55(4):447-452, 2014. 33. Adin DB, Taylor AW, Hill RC, Scott KC, Martin FG: Intermittent bolus injection versus continuous infusion of furosemide in normal adult greyhound dogs, J Vet Intern Med 17(5):632-636, 2003. 34. Ohad DG, Segev Y, Kelmer E, et al: Constant rate infusion vs. intermittent bolus administration of IV furosemide in 100 pets with acute left-sided congestive heart failure: a retrospective study, Vet J 238:70-75, 2018. 35. Edwards TH, Erickson Coleman A, Brainard BM, et al: Outcome of positivepressure ventilation in dogs and cats with congestive heart failure: 16 cases (1992-2012), J Vet Emerg Crit Care (San Antonio) 24(5):586-593, 2014. 36. Pariaut R: Atrial fibrillation: current therapies, Vet Clin North Am Small Anim Pract 47(5):977-988, 2017. 37. Serres F, Chetboul V, Tissier R, et al: Chordae tendineae rupture in dogs with degenerative mitral valve disease: prevalence, survival, and prognostic factors (114 cases, 2001-2006), J Vet Intern Med 21(2):258-264, 2007. 38. Nakamura RK, Tompkins E, Russell NJ, et al: Left atrial rupture secondary to myxomatous mitral valve disease in 11 dogs, J Am Anim Hosp Assoc 50(6):405-408, 2014.

CHAPTER 45  Canine Myxomatous Mitral Valve Disease 39. Chetboul V, Pouchelon JL, Menard J, et al: Short-term efficacy and safety of torasemide and furosemide in 366 dogs with degenerative mitral valve disease: the TEST study, J Vet Intern Med 31(6):1629-1642, 2017. 40. Uechi M, Mizukoshi T, Mizuno T, et al: Mitral valve repair under cardiopulmonary bypass in small-breed dogs: 48 cases (2006-2009), J Am Vet Med Assoc 240(10):1194-1201, 2012.

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41. Mizuno T, Mizukoshi T, Uechi M: Long-term outcome in dogs undergoing mitral valve repair with suture annuloplasty and chordae tendinae replacement, J Small Anim Pract 54(2):104-107, 2013. 42. Beaumier A, Rush JE, Yang VK, Freeman LM: Clinical findings and survival time in dogs with advanced heart failure, J Vet Intern Med 32(3):944-950, 2018.

46 Blunt Cardiac Injury Maureen S. Oldach, DVM, DACVIM (Cardiology)

KEY POINTS • Blunt cardiac injury should be considered in all cases of trauma, regardless of whether there is visible trauma to the thorax. • Myocardial injury is often overlooked in trauma patients. • The most common clinical outcome of blunt cardiac injury is ventricular arrhythmias. • Most clinically significant arrhythmias occur within the first 24 hours following trauma, and resolve within 3–4 days. • Cardiac troponins, specifically cardiac troponin I (cTnI), are sensitive and specific biomarkers that can be used to evaluate for the presence of cardiac injury in dogs.

DEFINITIONS AND PATHOGENESIS Blunt cardiac injury (BCI) refers to cardiac injury that results from the impact of a body surface against a blunt surface or the impact of an object with a blunt surface against the body.1 This type of injury is commonly seen in small animal patients due to motor vehicle trauma, falls from a height, and kicks from humans or livestock.2,3,4 There is a lack of consensus on making a premortem diagnosis of BCI; therefore, the true incidence of BCI is unknown and reports vary widely, affecting 3%–76% of trauma patients in the human literature.5,6,7 There are seven described mechanisms of blunt cardiac trauma, including (1) direct impact to the chest in end diastole, during which the ventricles are at maximum capacity or at end systole during which the atria are at maximum capacity; (2) suddenly increased cardiac preload secondary to increased venous return due to impact applied to the peripheral or abdominal veins; (3) bidirectional forces that compress the heart within the thoracic cage; (4) forces of acceleration and deceleration that cause the heart to move, leading to myocardial damage/rupture and/or damage to the great vessels and/or coronary arteries; (5) blast forces leading to cardiac contusion or rupture; (6) concussive forces leading to development of arrhythmias; and (7) cardiac penetration by displaced fractures.8

Types of Blunt Cardiac Injury Through these mechanisms, a spectrum of six different cardiac injuries from BCI has been described, including myocardial rupture, pericardial rupture, septal injury, valvular injury, myocardial contusion, and commotio cordis.6 Many of these injuries are catastrophic and result in sudden cardiac death of the patient diagnosed postmortem.1,5,9 However, milder BCI injuries often accompany other injuries in polytrauma patients.2,3,9-14

Myocardial Rupture Myocardial rupture involves laceration of the atrial or ventricular walls or papillary muscles due to blunt trauma.6 Myocardial rupture is rare

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• A normal cTnI and normal ECG on admission are effective practices for ruling out clinically significant cardiac trauma. • Basic evaluation for blunt cardiac injury in a trauma patient may include electrocardiography, cTnI biomarker assessment, thoracic radiographs and ultrasonography, and echocardiography. • In small animal patients, treatment of blunt cardiac injury should be aimed at the addressing the specific complications associated with the injury.

in small animal patients and is typically associated with very highimpact trauma such as falling from a great height or high-impact motor vehicle trauma.1 The most common clinical complication of myocardial rupture is hemopericardium, which commonly leads to sudden death.1,9 If nonlethal, myocardial rupture may lead to signs of obstructive shock due to cardiac tamponade or in the case of concurrent pericardial laceration, hemothorax.6,9,15 Partial-thickness myocardial tears secondary to direct or indirect trauma to the heart can lead to the development of intracardiac thrombi, which has been reported in dogs.10

Septal Injury Septal rupture is rare and is a form of myocardial rupture that can result immediately following trauma secondary to the aforementioned traumatic forces, or can be delayed due to myocardial inflammation post trauma.6,16 Rupture of the interatrial or interventricular septum can lead to acquired intracardiac shunting lesions.11,16,17 Clinically, these acquired intracardiac shunts can result in the development of congestive heart failure. Additionally, given that the basilar interventricular septum is the location of the atrioventricular bundle, septal injury can also result in atrioventricular conduction block, which has been reported in people and dogs.11,17,18

Pericardial Laceration Pericardial laceration often occurs in addition to other cardiac trauma such as myocardial laceration, but it can also occur in isolation as a result of laceration by a bone fragment.6,9 Pericardial lacerations can be clinically silent or can result in herniations of cardiac structures, with strangulation of these structures, or may result in a hemothorax, particularly if there is a concurrent myocardial laceration.6,9,19 Alternatively, pericardial rupture can occur at the diaphragm, causing a traumatic peritoneopericardial diaphragmatic hernia, or it can occur into the pleuropericardium, which can cause herniation of the heart into the pleural space.2,6,19

CHAPTER 46  Blunt Cardiac Injury

Valve Rupture

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BCI can lead to valvular injury that results in acute valvular incompetence.6,12,13 Valves are most susceptible to injury during the time of closure: semilunar valves are most susceptible to injury in diastole, and the atrioventricular valves are most susceptible to injury in systole.6 Such trauma can cause papillary muscle, valve leaflet, or chordae tendineae rupture, leading to sudden valve regurgitation, which may lead to signs of poor cardiac output and potentially congestive heart failure.12,13 Papillary muscle rupture will result in fulminant valvular regurgitation, and likely acute congestive heart failure, but a tear of a valve leaflet or chordae tendinea may result in more insidious development of congestive heart failure over several days.

When assessing a patient for BCI, the clinical focus should be on the identification of clinical complications or risk factors for developing complications secondary to BCI, given the lack of gold standard premortem diagnostic criteria.15 It is likely that many patients with mild BCI, such as small pericardial tears or minor myocardial contusions, will have no clinical consequences from their injuries and that these injuries will heal without intervention. The clinical complications of BCI most commonly encountered that may require intervention in the clinical setting are ventricular and supraventricular tachyarrhythmias, bradyarrhythmias, hemopericardium, hemothorax, traumatic pericardial hernia, and cardiac decompensation with signs of poor cardiac output and/or congestive heart failure.2,3,6,7,9,11,13,14,24

Myocardial contusion

Physical Examination

Myocardial contusion is also known as cardiac concussion.6 Myocardial contusion is myocardial bruising that results from the previously described mechanisms of BCI but with lesser forces than those causing rupture of cardiac structures.6 Diagnosis of myocardial contusion is histopathologic, with three forms that have been described in dogs based on an experimental model of BCI.20 These forms include a hemorrhagic form, characterized by extravasation of blood without muscle fiber disruption; a necrotized form, which is characterized by coagulation necrosis and/or contraction band necrosis of the muscle fibers; and a mixed form with both hemorrhagic and necrotized forms.20 Results from a study investigating an experimental model of BCI in rabbits demonstrated that the arrhythmic effect of myocardial contusion is proportional to the kinetic energy applied to the surface of the myocardium.21 Further, this study’s findings revealed that the mechanism of arrhythmia provocation in myocardial contusion involves induction of an electrically silent region of myocardium, which leads to the initiation of a reentrant circuit around this silent region, thereby inciting development of tachyarrhythmias (most commonly ventricular in origin).21 Regional myocardial wall motion abnormalities can also occur secondary to myocardial contusion and are commonly clinically silent, but if the contusions affect large regions of the myocardium, they can potentiate cardiac decompensation and/or cardiogenic shock if the contusions are severe or if the patient has received excessive fluid resuscitation.3,6,7

Physical examination findings will vary depending on the degree and type of BCI that the patient is experiencing. Cardiac auscultation findings suggestive of BCI include premature beats, tachycardia, bradycardia, or rhythm pauses. Muffled heart sounds may indicate the presence of pericardial or pleural effusions. Jugular pulsation and distention may be appreciated in cases of pericardial effusion with cardiac tamponade, in cases of severe myocardial contusion causing right heart dysfunction, or in cases of right-sided cardiac valve rupture. New-onset heart murmurs may be indicative of valve rupture with new-onset valve insufficiency, or of septal rupture with new-onset intracardiac shunting. Displacement of the heart sounds may be recognized in cases of pleural effusion or in cases of pericardial rupture with cardiac herniation. Positional changes in blood pressure or the presence of borborygmi within the chest may be suggestive of traumatic peritoneopericardial diaphragmatic hernia.

Commotio Cordis Commotio cordis refers to sudden cardiac death from BCI without any observable pathology.6,22 This injury involves a blunt impact to the precordium during ventricular repolarization, within 15–30 milliseconds before the peak of the T wave, leading to R on T, which degenerates to ventricular fibrillation and sudden cardiac death without any histopathologic change to the myocardium.23 Commotio cordis is a common cause of sudden cardiac death in otherwise healthy human athletes and likely occurs rarely in veterinary patients, but clinical reports are lacking.22

DIAGNOSIS AND CLINICAL ASSESSMENT All patients presenting for evaluation following trauma should be evaluated for complications from BCI. It is common for patients without any overt physical examination evidence of thoracic trauma to have signs of BCI.14,24 This is likely in part due to the elastic nature of the thorax of small animals but may also be due to the fact that BCI can occur as the result of indirect trauma to the heart, including induction of a sudden increase in preload to the heart and overdistention of the cardiac chambers following impact to the extremities or abdomen or acceleration/deceleration forces applied to the extremities/head/ abdomen that are translated to the thorax indirectly.2,6,8-10

Electrocardiography A baseline electrocardiogram (ECG) is insufficient for evaluating dogs at risk for developing arrhythmias secondary to their trauma, as many arrhythmias are intermittent and may develop after initial presentation.2,24 Most clinically significant arrhythmias occur within the first 24 hours of hospitalization, so telemetry monitoring during this time should be considered.22,24 The most common and clinically relevant arrhythmias associated with BCI are ventricular tachyarrhythmias, presumably due to myocardial contusions.2,3,6,14,20,24,25 However, patients suffering from trauma can develop arrhythmias due to other conditions, such as acid-base disturbances, anemia secondary to hemorrhage, concurrent neurologic injury, electrolyte derangements, and shock.7 Therefore, the presence of ventricular arrhythmias is not diagnostic for the presence of BCI. The prevalence of ventricular arrhythmias in blunt cardiac trauma cases is high and is often underrecognized. Following trauma, 13%–17% of dogs have been reported to experience ventricular arrhythmias on admission ECG.14,24 However, a study using continuous ECG reported that 96% of dogs experienced ventricular arrhythmias following their trauma, which suggests that baseline intake ECG is inadequate to fully assess for the presence of arrhythmias following trauma.24 The prevalence of clinically significant ventricular arrhythmias that may require treatment is lower than the overall prevalence of arrhythmias in dogs following trauma, with reports of 10.6%–16% of patients presenting with trauma experiencing arrhythmias severe enough to warrant treatment.2,24 Supraventricular arrhythmias such as atrial premature complexes and supraventricular tachycardia are less common and are less likely to be hemodynamically significant but are occasionally seen secondary to BCI, presumably due to atrial contusions.7,24 Bradyarrhythmias following BCI are rare, but atrioventricular conduction block (first degree, second degree, and third degree) has been

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reported following septal rupture or contusion.3,11,17,18,20 Sinus bradycardia is often observed in trauma patients due to hypotension, increased intracranial pressure, hyperkalemia, and cervical injuries but is not directly related to BCI.7 Other ECG abnormalities including abnormal ST segment (elevation or depression), R wave alternans, increased T wave amplitude, and abnormal Q waves are often seen in trauma patients.3,20 However, ST segment change, particularly ST segment depression, has been shown to have a low specificity for cardiac contusion.3 These abnormalities do not warrant specific treatment but may further support evaluation of serum cardiac troponin I for further investigation (see below).

Cardiac Troponin Cardiac troponin monitoring is a useful tool for evaluating the clinical risk for development of arrhythmias post trauma.2 Cardiac troponins are intracellular protein components of the sarcomere, the contractile apparatus of the myocardial cell.26 These proteins exist bound to the sarcomere and free in the cytosol and are released following myocardial damage.26 Cardiac troponin I (cTnI) has been shown to be the most sensitive and specific troponin for myocardial damage in dogs.3 A recent study showed a 100% negative predictive value of a normal cTnI (0–0.11 ng/ml) and baseline ECG following trauma in dogs, which is similar to studies in humans.2,27 A reasonable approach is to screen trauma patients with ECG and cTnI on admission, with recommendations to hospitalize on telemetry if arrhythmias are noted on ECG or if cTnI is .0.11 ng/ml.2 It is important to understand that cTnI elevations are markers of myocardial damage but not specific to BCI as a cause. cTnI is commonly elevated in hospitalized patients with evidence of systemic disease.28 It should be used to help evaluate the risk for the development of clinically significant cardiac arrhythmias but not to make a definitive diagnosis of myocardial contusion or BCI.

Thoracic Ultrasound Thoracic point-of-care ultrasound assessment should be considered in all cases of trauma and can be a valuable tool for assessing for possible complications of BCI, including cardiac/pericardial rupture, which can lead to hemopericardium or hemothorax, and cardiac decompensation related to valve rupture or cardiac dysfunction secondary to myocardial contusion. The presence of pericardial effusion following trauma is highly supportive of myocardial rupture.6,9 Hemorrhagic pleural effusion may suggest myocardial and pericardial rupture but may also be secondary to pulmonary trauma.9,19 Nonhemorrhagic effusions (modified transudate) suggest cardiac decompensation, which may be related to cardiac dysfunction secondary to extensive myocardial contusion with cardiac dysfunction and/or valve rupture with new valvular insufficiency and cardiac volume overload.7

Echocardiography Echocardiography should be considered in all cases involving a newonset murmur or in patients with signs of unexplained poor cardiac output. Echocardiography is useful for identifying new-onset valve insufficiency associated with valve rupture, identification of large regional wall motion abnormalities secondary to massive contusions, identification of intracardiac shunting secondary to septal rupture, and for the identification of intracardiac thrombi.10,11,13,16

TREATMENT Treatment for BCI is targeted at the specific clinical complication that has developed in the patient. Treatment should be aimed at supporting the adequate perfusion and cardiac output of the patient. Hypoxemia,

anemia, electrolyte derangements, tissue hypoxia, and pain can all potentiate arrhythmias and cardiovascular instability, and these conditions should be corrected during the stabilization process.7

Ventricular Arrhythmias Ventricular arrhythmias should be treated based on hemodynamic significance of the arrhythmia.7,29 Single or self-limiting ventricular premature complexes in a patient who is hemodynamically stable do not require intervention unless the patient has clinical signs of syncope or collapse.7 Ventricular arrhythmias are hemodynamically significant if they are sustained for 15–30 seconds at rates .150/min in dogs and for .250/min in cats, if they exceed 180 bpm for shorter periods, if they are multiform or display R on T phenomenon, or most importantly, if they are associated with signs of hemodynamic consequence such as syncope or collapse.7,29 These arrhythmias generally warrant treatment. Vaughn Williams class I (sodium channel blocking) drugs are typically the first-line treatment, with lidocaine as the most commonly used drug for ventricular tachyarrhythmias in dogs.7,29 A bolus dose of 2 mg/kg is typically used initially, with up to an additional three doses (8 mg/kg total) IV with 3–5 minutes in between boluses to allow for clinical effect.29 Monitoring for side effects is recommended; nausea typically precedes neurologic side effects, and the dosing should be terminated if nausea or neurologic effects (such as seizure or tremors) occur.29 Following control with bolus therapy, lidocaine continuous rate infusion (CRI) should be initiated 50–100 mcg/kg/hr. Additional 1 mg/kg IV boluses may be necessary pending acquisition of steady state, which may take 5–7 hours in dogs.29 If lidocaine is not successful, assessment of magnesium and potassium status is recommended, with corrections of these derangements as needed.29 Following correction of any electrolyte derangements, procainamide is recommended with 2–8 mg/kg IV boluses over 3–5 minutes, up to 16 mg/ kg total, as this drug does carry a risk for hypotension.29 If the arrhythmias respond, CRI of procainamide is recommended at 25–40 mcg/kg/ min.29 For refractory ventricular tachycardia or in cases of loss of consciousness, amiodarone (Nexterone) at a dose of 2 mg/kg IV over 10 minutes followed by a CRI of 0.8 mg/kg/hr for 6 hours, then decreased to 0.4 mg/kg/hr for 18 hours, or electrical cardioversion can be considered.30-32 Most ventricular arrhythmias require in-hospital treatment only, as the arrhythmias typically improve within 4 days post presentation.7,24 For patients with persistent ventricular arrhythmias at the time of discharge, oral therapy, Vaughn Williams class II and III antiarrhythmic sotalol (2 mg/kg PO q12h) and/or mexiletine (5–8 mg/kg q8h), a Vaughn Williams type IB sodium channel blocker, is recommended (although it should be noted that sotalol is contraindicated in patients who received amiodarone).29 For cats with ventricular tachyarrhythmias, ventricular arrhythmias should be suppressed with sotalol at a dose of 2 mg/kg PO q12h. Lidocaine should be avoided if possible due to high risk for neurologic side effects in cats.29 If hemodynamically significant ventricular tachycardia is present and the patient is unstable, cautious lidocaine administration at 0.2–0.75 mg/kg IV slowly can be administered, repeated up to two times.29

Supraventricular Tachycardia Supraventricular tachycardia is unlikely to contribute to an increased risk of mortality in trauma patients, but very rapid rates (.220 bpm in the dog or .260 bpm in the cat) likely do exacerbate hypoperfusion and hemodynamic compromise in trauma patients, and should be addressed.7 The patient should be otherwise stabilized, and pain should be managed prior to initiating therapy specific to supraventricular tachycardia. First-line therapy for supraventricular tachycardia is diltiazem, a Vaughn Williams class IV calcium channel

CHAPTER 46  Blunt Cardiac Injury blocker.7,29 A bolus of diltiazem 0.25 mg/kg IV over 2 minutes is recommended with additional 0.25 mg/kg IV boluses every 15 minutes until conversion to a normal sinus rhythm or a maximum dose of 0.75 mg/kg is reached.7 If this is ineffective, esmolol, a Vaughn Williams class II ultra-short-acting b-blocker can be considered, but this drug is a potent negative inotrope and should not be used in patients with cardiac decompensation or concern for myocardial dysfunction.7 The recommended dose of esmolol is 0.05–0.1 mg/kg boluses every 5 minutes up to a total maximum dose of 0.5 mg/kg.7 Propranolol 0.02–0.06 mg/kg IV slowly every 8 hours can be considered as an alternative to esmolol but is less preferable due to its longer duration of action, making it more challenging to titrate to effect.7

Bradyarrhythmias Hemodynamically significant bradyarrhythmias such as third-degree atrioventricular block or high-grade second-degree atrioventricular block (.2:1 non-conducted P waves) with resultant clinical signs or hemodynamic effects require pacemaker therapy.

Pericardial Effusion If there are signs of cardiac tamponade on exam (diastolic right atrial collapse on ultrasound, hypotension, jugular pulsation and distention, hypokinetic pulses, tachycardia), fluid resuscitation and pericardiocentesis should be performed, as described elsewhere in this text.

Cardiac Dysfunction Cardiac volume overload secondary to acute valvular insufficiency from traumatic valve rupture or myocardial dysfunction secondary to massive myocardial contusion should be suspected in cases of unexplained hypotension and/or suspected congestive heart failure and should ideally be confirmed with echocardiography.6 Treatment of cardiogenic shock and congestive heart failure management is described at length elsewhere in this text, and the reader is directed to these chapters for further guidance on these topics. However, specific to cases of BCI from trauma, sedation for respiratory distress should be chosen in the context of the patient’s level of pain. Although butorphanol is used frequently in patients with congestive heart failure decompensation and respiratory compromise, this is likely inappropriate for patients with trauma; buprenorphine or a pure mu agonist 1/2 an adjunctive benzodiazepine (midazolam or diazepam) for additional sedation is likely more appropriate. Additionally, diuretic therapy should be used judiciously, as injuries from trauma may affect renal perfusion and diuretics may exacerbate renal hypoperfusion.

SUMMARY In summary, there is a large spectrum of disease that is encompassed by BCI, with a range in clinical presentation from sudden death to clinically insignificant minor myocardial contusions. In the acute setting, priority should be placed on the recognition of clinical complications associated with cardiac trauma and not on the diagnosis of the presence or specific type of cardiac trauma. Lack of gold standard diagnostic criteria for the diagnosis of BCI impedes the ability to make a premortem diagnosis, and such a diagnosis is clinically irrelevant so long as the clinical complications are recognized and addressed as indicated.

REFERENCES 1. Ressel L, Hetzel U, Ricci E: Blunt force trauma in veterinary forensic pathology, Vet Pathol 53(5):941-961, 2016.

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2. Biddick AA, Bacek LM, Fan S, Kuo KW: Association between cardiac troponin I concentrations and electrocardiographic abnormalities in dogs with blunt trauma, J Vet Emerg and Crit Care 30(2):179-186, 2020. 3. Schober KE, Kirbach B, Oechtering G: Noninvasive assessment of myocardial cell injury in dogs with suspected cardiac contusion, J Vet Cardiology 1(2):17-25, 1999. 4. Simpson SA, Syring R, Otto CM: Severe blunt trauma in dogs: 235 cases (1997-2003): retrospective study, J Vet Emerg and Crit Care 19(6): 588-602, 2009. 5. Bellister SA, Dennis BM, Guillamondegui OD: Blunt and penetrating cardiac trauma, Surg Clin North Am 97:1065-1076, 2017. 6. Huis In ‘t Veld MA, Craft CA, Hood RE: Blunt cardiac trauma review, Cardiol Clin 36(1):183-191, 2018. 7. Rush JE: Managing myocardial contusion and arrhythmias. In The 22nd Annual Walthan/OSU Symposium for the Treatment of Small Animal Diseases: Emergency Care of Trauma Patients, Vernon, 1998, Waltham USA, pp. 71-77. 8. Getz BS, Davies E, Steinberg SM, et al: Blunt cardiac trauma resulting in right atrial rupture, J Am Med Assoc 255(6):761-763, 1986. 9. Piegari G, Prisco F, De Biase D, et al: Cardiac laceration following nonpenetrating chest trauma in dog and cat, Forensic Sci Int 290:e5-e8, 2018. 10. Ballocco I, Pinna Parpaglia ML, Corda F, et al: Left atrial thrombosis secondary to blunt cardiac injury in two dogs, Vet Rec Case Rep 7(2): e000803, 2019. 11. Cunningham SM, Lindsey KJ, Rush JE: Acquired Gerbode defect and third-degree atrioventricular block secondary to vehicular trauma in a dog, J Vet Emerg and Crit Care 23(6):637-642, 2013. 12. Harpster NK, VanZwieten MJ, Bernstein M: Traumatic papillary muscle rupture in a dog, J Am Vet Med Assoc 165(12):1074-1079, 1974. 13. Miller LM, Keirstead ND, Snyder PS: Traumatic mitral valve avulsion from the annulus fibrosis producing acute left heart failure in a dog, Canadian Vet J 45(9):761-763, 2004. 14. Selcer BA, Buttrick M, Barstad R, Riedesel D: The incidence of thoracic trauma in dogs with skeletal injury, J Small Anim Pract 28(1):21-27, 1987. 15. Marcolini EG, Keegan J: Blunt cardiac injury, Emerg Med Clin North Am 33:519-527, 2015. 16. Ryan L, Skinner DL, Rodseth RN: Ventricular septal defect following blunt chest trauma, J Emerg Trauma Shock 5(2):184-187, 2012. 17. Nicholls PK, Watson PJ: Cardiac trauma and third degree AV block in a dog following a road accident, J Small Anim Pract 36(9):411-415, 1995. 18. Ali H, Furlanello F, Lupo P, et al: Clinical and electrocardiographic features of complete heart block after blunt cardiac injury: a systematic review of the literature, Heart Rhythm 14(10):1561-1569, 2017. 19. Wall MJ, Mattox KL, Wolf DA: The cardiac pendulum: blunt rupture of the pericardium with strangulation of the heart, J Trauma 59:136-141, 2005. 20. Guan DW, Zhang XG, Zhao R, et al: Diverse morphological lesions and serious arrhythmias with hemodynamic insults occur in the early myocardial contusion due to blunt impact in dogs, Forensic Sci Int 166(1):49-57, 2007. 21. Robert E, De La Coussaye JE, Aya AGM, et al: Mechanisms of ventricular arrhythmias induced by myocardial contusion: a high resolution mapping study in left ventricular rabbit heart, Anesthesiology 92(4):1132-1143, 2000. 22. Maron BJ, Estes NAM. Commotio cordis, N Engl J Med 362(10): 917-927, 2010. 23. Link MS, Wang PJ, Pandian NG, et al: An experimental model of sudden death due to low-energy chest-wall impact (commotio cordis), N Engl J Med 338(25):1805-1811, 1998. 24. Snyder P, Cooke K, Murphy S, et al: Electrocardiographic findings in dogs with motor vehicle-related trauma, J Am Anim Hosp Assoc 37(1):55-63, 2001. 25. Simpson SA, Syring R, Otto CM: Severe blunt trauma in dogs: 235 cases (1997 to 2003), J Vet Emerg and Crit Care 19(6):588-602, 2009. 26. Langhorn R, Willesen JL: Cardiac troponins in dogs and cats, J Vet Intern Med 30(1):36-50, 2016. 27. Payne EE, Roberts BK, Schroeder N, et al: Assessment of a point-of-care cardiac troponin I test to differentiate cardiac from noncardiac causes of respiratory distress in dogs, J Vet Emerg and Crit Care 21(3): 217-225, 2011. 28. Langhorn R, Thawley V, Oyama MA, et al: Prediction of long-term outcome by measurement of serum concentration of cardiac troponins in

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critically Ill dogs with systemic inflammation, J Vet Intern Med 28(5):1492-1497, 2014. 29. DeFrancesco TC: Management of cardiac emergencies in small animals, Vet Clin North Am Small Anim Pract 43:817-842, 2013. 30. Levy NA, Koenigshof AM, Sanders RA: Retrospective evaluation of intravenous premixed amiodarone use and adverse effects in dogs (17 cases: 2011-2014), J Vet Cardiol 18(1):10-14, 2016.

31. Pedro B, López-Alvarez J, Fonfara S, et al: Retrospective evaluation of the use of amiodarone in dogs with arrhythmias (from 2003 to 2010), J Small Anim Pract 53(1):19-26, 2012. 32. Prošek R: Electrical cardioversion of sustained ventricular tachycardia in three Boxers, J Am Vet Med Assoc 236(5):554-557, 2010.

47 Pericardial Diseases Wendy A. Ware, DVM, MS, DACVIM (Cardiology)

KEY POINTS • Pericardial effusion is the most common pericardial disorder. • Most pericardial effusions in dogs are hemorrhagic and of neoplastic or idiopathic origin. • Hemangiosarcoma is by far the most common neoplasm causing pericardial effusion in dogs. • Cardiac tamponade occurs when intrapericardial pressure equals or exceeds normal cardiac filling pressure.

The pericardium is a closed serosal sac that envelops the heart and is attached to the great vessels at the heart base. It provides a barrier to infection and inflammation from adjacent tissues and helps balance the output of the right and left ventricles. A small amount (approximately 0.25  ml/kg body weight) of clear, serous fluid normally serves as a lubricant between the visceral pericardium (epicardium), which is directly adhered to the heart, and the outer fibrous, parietal pericardial layer. Excess or abnormal fluid accumulation within the pericardial sac (pericardial effusion) is the most common pericardial disorder. This occurs most often in dogs and can lead to signs of severe cardiac dysfunction. Other acquired and congenital pericardial abnormalities are infrequent. Acquired pericardial disease that causes clinical signs is uncommon in cats.

PERICARDIAL EFFUSION Hemorrhagic Pericardial Effusion Most pericardial effusions in dogs are serosanguineous or sanguineous. The fluid typically appears dark red, with a packed cell volume of more than 7%, a specific gravity greater than 1.015, and a protein concentration greater than 3  g/dl. Typically, the underlying etiology is either neoplastic or idiopathic. Neoplastic effusions are more likely in dogs older than 7 years of age. Other, less common causes of intrapericardial hemorrhage include left atrial rupture secondary to severe mitral insufficiency, coagulopathy (especially from rodenticide toxicity or disseminated intravascular coagulation), and penetrating trauma.

Hemangiosarcoma Hemangiosarcoma (HSA) is by far the most common neoplasm causing hemorrhagic pericardial effusion in dogs; it is rare in cats.1 Most HSAs arise in the right atrium or right auricle, but some also infiltrate the ventricular wall.2 Occasionally, HSA occurs in the left ventricle, in the septum, or at the heart base. Metastases are common by the time of diagnosis.

• Clinical signs typically reflect poor cardiac output and systemic venous congestion. • Echocardiography is a sensitive clinical tool for identifying pericardial effusion and most cardiac masses. • Right atrial collapse is a characteristic echocardiographic feature of cardiac tamponade. • Immediate pericardiocentesis is indicated for cardiac tamponade.

Heart Base Tumors Heart base tumors are the second most common cardiac neoplasm. Chemodectoma (aortic body tumor), which arises from chemoreceptor cells at the base of the aorta, is the most common.1 Thyroid, parathyroid, lymphoid, and connective tissue neoplasms also can develop at the heart base. Heart base tumors tend to be locally invasive around the root of the aorta and surrounding structures; however, metastases to other organs can occur.2,3

Other Neoplasia Hemorrhagic pericardial effusion also can accompany pericardial mesothelioma, malignant histiocytosis, some cases of cardiac lymphoma, and metastatic carcinoma. Although pericardial mesothelioma can form mass lesions, it often has a diffuse distribution that can mimic idiopathic disease.4,5 Lymphoma involving various parts of the heart is more common in cats than in dogs (and often causes a modified transudative effusion). Other primary tumors of the heart are rare but include myxoma and various types of sarcoma.

Idiopathic (Benign) Pericardial Effusion Idiopathic pericardial effusion also is a relatively common cause of canine hemorrhagic pericardial effusion. It is reported most often in medium to large breed, middle-aged dogs. More cases have been reported in male dogs than female dogs. Its cause is still unknown; however, mild pericardial inflammation, with diffuse or perivascular fibrosis and focal hemorrhage, are common histopathologic findings.6-8

Transudative Pericardial Effusion Transudates or modified transudates occasionally accumulate in the pericardial space of both dogs and cats. A chylous effusion rarely occurs. Pure transudates are clear, with a low cell count (usually ,1000 cells/ml), specific gravity (,1.012), and protein content (,2.5  g/dl). Modified transudates may appear slightly cloudy or pink tinged. Their cellularity (approximately 1000 to 8000 cells/ml) is still low, but total protein concentration (approximately 2.5 to 5 g/dl) and specific gravity (1.015 to 1.030) are higher than those of a pure transudate.

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Transudative effusions can develop with congestive heart failure (CHF), hypoalbuminemia, congenital pericardial malformations, and systemic inflammatory disease or toxemias (including uremia) that increase vascular permeability.9 These conditions are usually associated with relatively small-volume pericardial effusion, and cardiac tamponade is rare. In cats, pericardial effusion is most commonly associated with CHF from cardiomyopathy.10 Effusion associated with cardiac lymphoma also often appears transudative.

Exudative Pericardial Effusion Exudative effusions are cloudy to opaque or serofibrinous to serosanguineous. They typically have a high nucleated cell count (usually much higher than 3000 cells/ml), protein content (often much above 3 g/dl), and specific gravity (.1.015). Cytologic findings are related to the etiology. Exudative effusions are quite uncommon in small animals. However, they have occurred from foreign body migration (e.g., plant awn or porcupine quill), extension of a pleural or mediastinal infection, and bite or other penetrating wounds. Various bacteria (aerobic and anaerobic), actinomycosis, coccidioidomycosis, aspergillosis, disseminated tuberculosis, and, rarely, systemic protozoal infections have been identified. Feline infectious peritonitis is the most important cause of symptomatic pericardial effusion in cats. Exudative effusions also have occurred with leptospirosis, canine distemper, and idiopathic pericardial effusion in dogs. Chronic uremia occasionally causes a sterile, serofibrinous, or hemorrhagic effusion.

CARDIAC TAMPONADE Clinical signs of pericardial effusion are mainly the consequence of increased intrapericardial pressure, which impedes cardiac filling. Increases in pericardial fluid volume can raise intrapericardial pressure sharply because the fibrous pericardium is relatively noncompliant. Cardiac tamponade develops when intrapericardial pressure rises to and exceeds normal cardiac diastolic pressures.11,12 This external compressive force on the heart progressively limits right ventricular filling and, with increasing severity, also reduces left ventricular filling. Systemic venous pressure increases and forward cardiac output falls. Eventually, diastolic pressures in all cardiac chambers and great veins equilibrate. The rate of pericardial fluid accumulation and the distensibility of the pericardial sac determine whether and how quickly cardiac tamponade develops. Rapid accumulation of a relatively small-volume effusion (e.g., 50 to 100 ml) can raise intrapericardial pressure markedly because pericardial tissue stretches slowly. Conversely, a slow rate of fluid accumulation might allow for enough pericardial distension to maintain low intrapericardial pressure until the effusion is quite large. A large volume of pericardial fluid implies a gradual process. As long as intrapericardial pressure is low, cardiac filling and output remain relatively normal and clinical signs are absent. Fibrosis and thickening further limit the compliance of pericardial tissue and can increase the likelihood of cardiac tamponade. Neurohormonal compensatory mechanisms are activated as cardiac output falls. These contribute to fluid retention and other clinical manifestations of tamponade. Signs of systemic venous congestion become especially prominent over time. Although pericardial effusion does not directly affect myocardial contractility, reduced coronary perfusion during tamponade can impair both systolic and diastolic function. Low cardiac output, arterial hypotension, and poor perfusion of other organs besides the heart can ultimately precipitate cardiogenic shock and death. Cardiac tamponade also causes the normally mild respiratory variation in arterial blood pressure to become exaggerated. This is known as pulsus paradoxus. In normal animals, as intrathoracic pressure decreases

during inspiration, intrapericardial and right atrial pressures also fall; this increases right heart filling and pulmonary blood flow. Simultaneously, left heart filling diminishes because more blood is held within the expanded pulmonary vasculature; the inspiratory increase in right ventricular filling also shifts the interventricular septum slightly leftward. Consequently, left ventricular output and systemic arterial pressure normally decrease slightly during inspiration. The opposite effects occur during expiration; higher intrathoracic pressure reduces right heart filling, and diminishing lung volume increases venous return to the left heart, augmenting its output. Cardiac tamponade markedly impairs right heart filling even during inspiration, leading to an exaggeration of the normal respiratory pressure fluctuation. Pulsus paradoxus is characterized by an inspiratory fall in arterial pressure of 10 mm Hg or more.11-13

CLINICAL PRESENTATION Cardiac tamponade is relatively common in dogs and rare in cats. Clinical findings reflect poor cardiac output and often systemic venous congestion. Low-output signs, including nonspecific lethargy and inappetence, can occur before obvious ascites develops, especially when pericardial fluid accumulates rapidly. However, the typical history includes exercise intolerance, abdominal enlargement, tachypnea, weakness, collapse or syncope, and sometimes, cough. Vomiting also appears to be a common historical finding, especially in dogs with elevated plasma lactate (as evidence of hypoperfusion).14 Collapse is more common in dogs with cardiac neoplasia than in those with idiopathic disease.15 Although clinical manifestations of cardiac tumors often relate to the effects of cardiac tamponade, some tumors cause intracardiac flow obstruction, arrhythmias, or myocardial dysfunction, which influences the clinical presentation. Pericardial stretch, inflammation, or neoplastic processes also might cause pain in some patients; however, these conditions have not been well studied. Animals with pericardial effusion but without cardiac tamponade might show signs of the underlying disease process or be asymptomatic.

Physical Examination Findings Jugular venous distention or a positive hepatojugular reflux (Box 47-1), hepatomegaly, ascites, labored respiration, and weakened femoral pulses are common physical findings in patients with cardiac tamponade.11,12,15 Pulsus paradoxus is occasionally detectable by femoral pulse palpation. High sympathetic tone commonly produces sinus tachycardia, pale mucous membranes, and prolonged capillary refill time. A large pericardial fluid volume causes palpably weak precordial impulses; however, acute tamponade with a small pericardial fluid volume is unlikely to substantially reduce precordial impulse strength. Likewise, heart sounds are muffled by moderate- to large-volume pericardial effusion but might seem normal with small-volume effusion. Lung sounds might be muffled ventrally in patients with pleural effusion. Pericardial effusion alone does not cause a murmur, although concurrent cardiac disease might do so. Reduced lean body mass (cachexia) is apparent in some chronic cases. Although right-sided congestive signs predominate, signs of biventricular failure can occur. Rapid pericardial fluid accumulation can cause acute tamponade, shock, and death without signs of pleural

BOX 47-1  Hepatojugular Reflex The hepatojugular reflex is assessed by applying firm pressure to the cranial abdomen while the animal stands quietly with head in a normal position. This pressure transiently increases venous return. Normally there is little to no change in jugular vein appearance. Jugular distention that persists while abdominal pressure is applied constitutes a positive (abnormal) test result.

CHAPTER 47  Pericardial Diseases

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effusion, ascites, or radiographic cardiomegaly. In such cases, jugular venous distention, hypotension, and possibly pulmonary edema could be evident.

DIAGNOSIS Cardiac tamponade often is suspected from the history and physical examination, although thoracic radiographs and especially echocardiography are important for diagnosis. The electrocardiogram (ECG) also might suggest pericardial disease, in some cases.

Thoracic Radiographs The appearance of the cardiac silhouette depends on the volume of pericardial fluid, as well as any underlying cardiomegaly.11,12,16,17 Massive pericardial effusion causes the classic globoid-shaped cardiac shadow (“basketball heart”) on both views. However, measures of vertebral heart size or cardiac sphericity are not sensitive enough to reliably differentiate pericardial effusion.16,17 Other causes of a large, rounded heart shadow include dilated cardiomyopathy and marked tricuspid (with or without mitral) insufficiency. Smaller pericardial fluid volumes allow visualization of some cardiac contours, especially those of the atria. Other radiographic findings associated with tamponade include pleural effusion, caudal vena cava distention, hepatomegaly, and ascites. Pulmonary infiltrates of edema or distended pulmonary veins are noted only occasionally. Some heart base tumors cause deviation or elevation of the trachea, a soft tissue mass effect, or both, especially just cranial to the heart. Although these findings are suggestive of a heart base mass, radiography is not very sensitive for identifying such tumors.18 Metastatic lung lesions are common in dogs with hemangiosarcoma. Advanced imaging techniques such as cardiac computed tomography (CT) and magnetic resonance imaging (MRI) can provide greater detail than plain radiographs and better reveal pulmonary metastases and other extracardiac lesions.19 However, they are not necessarily more accurate than echocardiography for identifying pericardial effusion and associated mass lesions.20 Cardiac MRI might better define anatomical structures, including the location and extent of small cardiac or pericardial masses, in cases where echocardiographic findings are inconclusive.

Echocardiography Echocardiography is highly sensitive for detecting even small-volume pericardial effusion, so it generally is the diagnostic test of choice.11,12,21 The effusion appears as an echo-free space between the bright parietal pericardium and the epicardium. Abnormal cardiac wall motion, chamber shape, and intrapericardial or intracardiac mass lesions also can be visualized. Identification of the parietal pericardium in relation to the echo-free fluid helps differentiate pleural from pericardial effusion. Evidence of collapsed lung lobes or pleural folds often can be seen within pleural effusion. Basic training in echocardiography or focused ultrasonography (thoracic/abdominal focused assessment with sonography for trauma [TFAST/AFAST]) can help the clinician identify and differentiate pericardial and pleural effusions. The diaphragmatico-hepatic view reveals most cases of pericardial effusion, although small-volume effusion might be missed.22 The pericardial view or serial examinations can increase detection sensitivity. Nevertheless, after patient stabilization, a more detailed echocardiographic examination is warranted to identify and define any mass lesions or other cardiac disease. Cardiac tamponade is characterized by diastolic (and early systolic) compression or collapse of the right atrium and sometimes the right ventricle (Fig. 47.1).11,12 In severe tamponade, the left ventricular

Fig. 47.1  Right parasternal four-chamber echocardiographic image from a 9-year-old dog with cardiac tamponade. Pericardial fluid surrounds the heart. Note the characteristic right atrial wall collapse (arrows) caused by elevated intrapericardial pressure. Electrocardiographic tracing at bottom left. LA, left atrium; LV, left ventricle; PE, pericardial effusion; RA, right atrium; RV, right ventricle.

chamber also appears small, with walls that look hypertrophied (pseudohypertrophy), because of poor cardiac filling. Visualization of heart base structures and mass lesions is usually better before pericardiocentesis is performed. It is important to carefully evaluate all portions of the heart, (especially the right atrium and auricle and right ventricle), ascending aorta, and the pericardium itself to screen for neoplasia. The full echocardiogram should entail all standard right- and left-sided views and might require some off-angle views. The left cranial long-axis view, angled to visualize the right auricle, is especially important (Fig. 47.2). Although most masses that appear to arise from the heart base are aortic body tumors (or less often, ectopic thyroid tumors), other neoplasia could have similar anatomic location and appearance, including HSA and mesothelioma.21,23 In addition, despite the fact that most right atrial masses are HSA, a variety of other histologic tumor types might arise in this location. Some mass lesions are difficult to visualize. Mesothelioma might not cause discrete masses and can therefore be indistinguishable from idiopathic pericardial effusion. Ultrasound-guided transthoracic fine needle aspiration of certain cardiac mass lesions might be possible depending on their location, which could yield cytologic diagnosis.24

Electrocardiography Although not specific for tamponade, ECG findings associated with large-volume pericardial effusion include reduced amplitude QRS complexes (less than 1 mV in dogs) and electrical alternans. The latter is an every-other-beat alteration in the size or configuration of the QRS complex (and sometimes T wave) that results from the heart swinging back and forth within the pericardium (Fig. 47.3). Electrical alternans might be more evident at heart rates between 90 and 140 beats/min or in certain body positions (e.g., standing). ST segment

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PART IV  Cardiovascular Disorders elevation, suggesting an epicardial injury current, also occurs in some cases of pericardial effusion.11 Sinus tachycardia is common with cardiac tamponade. Atrial and ventricular tachyarrhythmias occur in some cases.

Central Venous Pressure Central venous pressure (CVP) measurement can be useful in identifying tamponade, especially if sonography is not immediately available and when the jugular veins are difficult to assess. Normal CVP is in the range of 0 to 8 cm H2O. Cardiac tamponade commonly raises CVP to 10–12 cm H2O or higher.

Clinicopathologic Findings

Fig. 47.2  Left cranial long-axis echocardiographic image, optimized for right ventricular inflow tract and right auricle, from a dog with cardiac hemangiosarcoma. Pericardial effusion enhances visualization of the tumor (MASS). This view confirmed presence of the tumor and its attachment at the tip of the right auricle. PE, pericardial effusion; RA, right atrium; RAu, right auricle; RV, right ventricle.

Routine laboratory findings might reflect underlying disease or tamponade-induced prerenal azotemia or hepatic congestion, but are often otherwise nonspecific.11,21 The hemogram sometimes shows a nonregenerative or poorly regenerative anemia in dogs with neoplastic, as well as benign, effusions. HSA can be associated with a regenerative anemia, an increased number of nucleated red blood cells and schistocytes (with or without acanthocytes), leukocytosis, and thrombocytopenia. Cardiac troponin I (cTnI) can be useful in differentiating pericardial effusion caused by HSA from other etiologies, especially in cases where a mass is not obvious on echocardiogram. A cTnI concentration .0.25 ng/ml reportedly is 81% sensitive and 100% specific for identifying cardiac HSA in dogs with pericardial effusion.25 Serum or pericardial fluid can be used for the assay. Cardiac ischemia or myocardial invasion also could increase circulating cTnI concentration. Serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration is likely to be low in patients with pericardial effusion, in

Fig. 47.3  Electrocardiogram showing sinus rhythm with electrical alternans, from a dog with large-volume pericardial effusion. Note the every-other-beat change in QRS complex size and configuration in each lead. See text for further information. Leads I, II, III; 50 mm/sec, 1 cm 5 1 mV.

CHAPTER 47  Pericardial Diseases contrast to other cardiac diseases, because the heart is compressed rather than stretched.26 Pleural and peritoneal effusions that develop secondary to cardiac tamponade usually are modified transudates.

Pericardial Fluid Analysis Pericardial effusion samples (see Pericardiocentesis below) should be submitted for cytologic analysis and saved for possible bacterial (or fungal) culture. Nevertheless, reliable differentiation of sanguinous neoplastic effusions from benign hemorrhagic pericarditis usually is not possible on the basis of cytology alone.27,28 Reactive mesothelial cells within the effusion closely resemble neoplastic cells; furthermore, common tumors such as HSA and chemodectoma often do not shed cells into the effusion. Effusions associated with lymphoma typically are modified transudates, with neoplastic cells easily identified. Many neoplastic (and other noninflammatory) effusions have a pH of 7.0 or greater, whereas inflammatory effusions generally have lower pH. However, there is too much overlap for pericardial effusion pH to be a reliable discriminator.29 Yet, if cytology and pH suggest an infectious or inflammatory cause, the fluid should be cultured. Fungal titers (including for coccidioidomycosis in endemic areas) or other serologic tests could be helpful in some patients. Elevated cTnI, either in serum or pericardial fluid suggests cardiac HSA, or other cause of myocardial injury.

MANAGEMENT OF CARDIAC TAMPONADE It is important to differentiate cardiac tamponade from other causes of right-sided congestive signs because its management is unique. The compressed ventricles require high venous pressure to fill. Diuretics and vasodilators, by reducing cardiac filling pressure, further decrease cardiac output and exacerbate hypotension. Positive inotropic drugs do not improve cardiac output or ameliorate the signs of tamponade because the underlying pathophysiology is impaired cardiac filling, not poor contractility. Immediate pericardiocentesis is indicated for cardiac tamponade. This also might provide diagnostic information. Congestive signs usually resolve fairly soon after intrapericardial pressure is reduced by pericardiocentesis. Sometimes a modest dose or two of diuretic is given following pericardiocentesis to help mobilize secondary abdominal or pleural effusion. Subsequent management is guided by the underlying cause of the pericardial effusion and other clinical circumstances.

Pericardiocentesis Preparation and Positioning Pericardiocentesis is a relatively safe procedure when performed carefully. Depending on the clinical status and temperament of the animal, sedation might be helpful. ECG monitoring is recommended during the procedure; needle or catheter contact with the heart commonly induces ventricular arrhythmias. Peripheral IV catheter placement prior to pericardiocentesis is advised, to provide access for sedative, antiarrhythmic, or other drug delivery, as needed. In addition, IV fluid administered during preparations for pericardiocentesis helps support cardiac output in animals with tamponade. However, the pericardiocentesis procedure itself should not be delayed just for the purpose of giving IV fluids. Pericardiocentesis usually is approached from the right side of the chest. This minimizes the risk of trauma to the lung (by using the cardiac notch) and major coronary vessels, most of which are located on the left side. Typically, the patient is placed in left lateral recumbency to allow more stable restraint; sometimes sternal recumbency is used if the dog is cooperative. Alternatively, the author has had good success using an elevated echocardiography table with a large cutout; the animal is placed in right lateral recumbency, and the tap is performed from

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underneath. The advantage of this method is that gravity draws fluid down toward the collection site. However, if adequate space is not available for wide sterile skin preparation or for needle or catheter manipulation, this approach is not advised. Echocardiographic guidance can be used, but usually is unnecessary unless the effusion is of very small volume or appears compartmentalized. Occasionally, pericardiocentesis might be done successfully in a standing dog; however, there is increased risk of injury if the patient moves suddenly. Prior to the procedure, additional equipment should be gathered, including sterile extension tubing (except if using a butterfly needle), a three-way stopcock, a (20–60 ml) collection syringe, a 3 ml syringe, and small gauge needle for local block, lidocaine, small surgical blade (for stab incision when using a larger catheter), sterile gloves, surgical scrub, sterile ethylene diamine tetraacetic acid (EDTA) and clot (redtop) tubes for fluid samples, and a large fluid collection receptacle. Personnel to help restrain the animal and assist with fluid aspiration also are essential. Several methods can be used for pericardiocentesis. An over-theneedle catheter system (e.g., 16- to 18-gauge, 1.5 inch to 2 inches long) can be used for most cases. Larger over-the-needle catheter systems (e.g., 12- to 14-gauge, 4 to 6 inches) allow for faster fluid removal in large dogs; using sterile technique, a few extra small side holes can be cut (smoothly) near the tip of the catheter to facilitate flow, but care should be taken not to excessively weaken the catheter and risk breaking the tip off inside the patient. During initial catheter placement the extension tubing is attached to the needle stylet; after the catheter has been advanced into the pericardial space and the stylet removed, the extension tubing is attached directly to the catheter. An over-the-wire pericardial drainage catheter system or commercially available fenestrated catheter are other options, if available. In emergency situations or when an over-the-needle catheter is unavailable, an appropriately long hypodermic or spinal needle attached to extension tubing is adequate. A butterfly needle (18- to 21-gauge) or 20- to 22-gauge overthe-needle catheter can be used in tiny dogs and cats.

Pericardiocentesis Procedure The skin is shaved and surgically prepared over the right precordium, from about the third to seventh intercostal spaces and from the sternum to above the costochondral junction. Sterile gloves and aseptic technique should be used during pericardiocentesis. The drainage catheter assembly is prepared by attaching the extension tube to the catheter’s needle stylet. The three-way stopcock is then attached between the other end of the extension tubing and a collection syringe, and the stopcock turned off to air. The best puncture site is generally identified by palpating for the cardiac impulse (usually between the fourth and sixth ribs just lateral to the sternum). If no precordial impulse is felt, the location is approximated or ultrasound can be used to locate an optimal puncture site, taking care not to contaminate the skin. Local anesthesia is recommended and is essential with use of a larger catheter. Approximately 0.5–1 ml of 2% lidocaine (,2 mg/kg total dose) is infiltrated (with sterile technique) into the skin puncture site, underlying intercostal muscle and pleura. A small stab incision is made in the skin when using a larger catheter system. Carefully hand the collection syringe (attached to the drainage assembly) to an assistant. Again, verify the puncture site, which should be just cranial to a rib to avoid the intercostal vessels located caudal to each rib. It is helpful to angle the needle tip toward the point of the patient’s opposite (left) shoulder. Once the needle has penetrated the skin, the assistant should apply gentle negative pressure to the attached collection syringe (with three-way stopcock turned “off ” to air) as the operator slowly advances the needle/catheter toward the heart. In this way, any fluid will be seen in the extension tubing as soon as it is

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encountered. Pleural fluid (usually straw colored) might enter the tubing first. It is important to hold the needle/catheter assembly steady during insertion to avoid extraneous motion of the sharp tip within the chest. The pericardium increases resistance to needle advancement and might produce a subtle scratching sensation when contacted. Continued gentle pressure will advance the needle/catheter through the pericardium; a loss of resistance might be felt with needle penetration and pericardial fluid (usually dark red) will appear in the tubing. When using an over-the-needle catheter system, the needle/catheter unit must enter far enough into the pericardial space so that the catheter is not deflected by the pericardium as the catheter is advanced and the needle stylet removed. After the stylet is removed, the extension tubing is attached directly to the catheter hub. Initial pericardial fluid samples should be saved in sterile EDTA and clot tubes for evaluation; then as much fluid as possible is drained. When fluid collection becomes difficult or ceases, slight catheter position adjustment or tilting the patient a little more sternally might yield more pericardial fluid. A small back flush into the catheter also might help. A scratching or tapping sensation is usually felt if the needle or catheter contacts the heart; also, the device may move with the heartbeat and ventricular premature complexes often are provoked. If this occurs, the needle or catheter should be retracted slightly to avoid cardiac trauma. Care should be taken to minimize extraneous needle movement within the chest. If it is unclear whether pericardial fluid or intracardiac blood (from cardiac penetration) is being aspirated, a few drops can be placed on the table or into a clot tube and a sample spun in a hematocrit tube. Pericardial fluid does not clot (unless associated with very recent hemorrhage). Its packed cell volume usually is lower than that of peripheral blood, and the supernatant appears yellowtinged (xanthochromic). If ultrasound assistance is available, another method of verifying catheter location is to rapidly inject a small bolus of sterile, agitated saline through the pericardiocentesis catheter (via the three-way stopcock) to create an echocontrast (“bubble”) study. If the catheter tip is within the pericardial space, small bright microbubbles will appear within the pericardial fluid around the heart. However, if the catheter tip has penetrated into a cardiac chamber, the bubbles will appear within the heart. As pericardial fluid is drained, the patient’s ECG complexes usually increase in amplitude, tachycardia diminishes, and often the animal takes a deep breath and appears more comfortable. When no additional pericardial fluid can be aspirated, the catheter is slowly withdrawn under continued but gentle negative pressure. A quick echocardiographic recheck should verify whether any pericardial fluid remains, tamponade has been resolved, and cardiac filling is improved.

Complications of Pericardiocentesis Ventricular premature beats occur commonly from direct myocardial injury or puncture. These usually are self-limiting, resolving when the needle is withdrawn; however, IV lidocaine or other antiarrhythmic therapy might be needed in some cases. Other arrhythmias, including atrial fibrillation, have developed in some patients during or after pericardiocentesis.30 Coronary artery laceration with myocardial infarction or further bleeding into the pericardial space is uncommon, especially when pericardiocentesis is approached from the right side. Continued intrapericardial hemorrhage caused by trauma to a friable cardiac tumor (especially HSA) is a concern in some patients. Rarely, death can result from arrhythmias, coronary laceration or cardiac perforation. Lung laceration leading to pneumothorax or pulmonary hemorrhage also are potential complications of the procedure. Effective patient restraint, as well as carefully holding the needle/stylet steady and advancing slowly during placement, help prevent cardiac

and pulmonary trauma. In some cases, dissemination of infection or neoplastic cells into the pleural space is exacerbated, although this does not appear to affect survival time with HSA or mesothelioma.

Ancillary Treatment Idiopathic Pericardial Effusion Dogs with idiopathic pericardial effusion are initially treated conservatively by pericardiocentesis. After excluding an infectious cause, a glucocorticoid sometimes is used (e.g., oral prednisone, 1 mg/kg/day, tapered over 2 to 4 weeks); however, its efficacy in preventing recurrent idiopathic pericardial effusion is unknown. Some clinicians also prescribe a 7- to 14-day course of broad-spectrum antibiotic, although this should be unnecessary if sterile technique was used and the effusion shows no evidence of infection. Periodic radiographic or echocardiographic reevaluation is advised to screen for recurrence. Cardiac tamponade can recur after a variable time span (days to years). Nevertheless, extended survival times are possible in dogs with idiopathic pericardial effusion, even in those requiring more than three pericardiocenteses.15,31 However, recurrent effusion could be caused by mesothelioma or other neoplasia, which sometimes becomes evident on repeated echocardiographic examination.4,5 Recurrent effusion not responsive to repeated pericardiocenteses and antiinflammatory therapy is usually treated surgically. Subtotal pericardiectomy, with removal of the pericardium ventral to the phrenic nerves, allows pericardial fluid drainage to the larger absorptive surface of the pleural space. Less invasive thoracoscopic techniques for partial pericardiectomy and pericardiotomy (pericardial window) could also successfully manage idiopathic cases and some cases of neoplastic pericardial effusion.32-34 Biopsy samples of a mass (if identified) or even resection of a small right auricular mass also could be accomplished through thoracoscopy. A minimally invasive, transxiphoid surgical approach to the caudoventral thoracic cavity and pericardium also has been described.35 Surgical reference sources should be consulted for technical details and guidance in performing these procedures.

Neoplastic Pericardial Effusion Pericardiocentesis is repeated as needed to relieve cardiac tamponade. Attempted surgical resection (depending on tumor size and location) or surgical biopsy and trial of chemotherapy (based on biopsy or clinicopathologic findings) can be tried; or conservative therapy can be pursued until episodes of cardiac tamponade become unmanageable. Surgical resection of HSA often is not possible because of tumor size and extent, although a small mass involving only the tip of the right auricle might be successfully removed. Use of a pericardial patch graft might allow resection of larger masses.36,37 However, this alone rarely results in prolonged long-term survival. Partial pericardiectomy might prevent the recurrence of tamponade, as for idiopathic pericardial effusion (see above). Overall, the prognosis for dogs with HSA or mesothelioma especially is poor. Cardiac tumors in general are fairly unresponsive to chemotherapy, although short-term success is possible in some. Doxorubicin or carboplatin have been used, with or without surgical debulking, to provide temporary palliation in dogs with HSA.38 In regions where available, radiation therapy might provide a palliative treatment option for dogs with aortic body tumor (chemodectoma) or other masses.39 For dogs with presumptive cardiac HSA, radiation therapy appears to be well-tolerated and might reduce the frequency of pericardiocenteses needed to manage recurrent tamponade.40 Heart base tumors (e.g., chemodectoma) tend to be slow growing and locally invasive and have a low metastatic potential. Partial pericardiectomy sometimes prolongs survival for years.

CHAPTER 47  Pericardial Diseases

Infectious Pericarditis Infectious pericarditis should be treated aggressively with appropriate antimicrobial drugs, based on culture and susceptibility testing, and pericardiocentesis as needed. Infusion of an appropriate antimicrobial agent directly into the pericardium after pericardiocentesis might be helpful. If a foreign body is suspected or intermittent pericardiocentesis is ineffective, continuous drainage using an indwelling pericardial catheter or surgical debridement should be pursued. Surgical therapy allows for removal of penetrating foreign bodies, more complete flushing of exudates, and management of pericardial constrictive disease. Even with successful elimination of infection, epicardial and pericardial fibrosis can lead to constrictive pericardial disease.

CONSTRICTIVE PERICARDIAL DISEASE Constrictive pericardial disease is recognized occasionally in dogs but only rarely in cats. It occurs when scarring and thickening of the visceral or parietal pericardium restrict ventricular diastolic expansion and prevent normal cardiac filling. Typically, the entire pericardium is involved symmetrically. In some cases, fusion of the parietal and visceral pericardial layers obliterates the pericardial space. In others, the visceral layer (epicardium) alone is involved. A small amount of pericardial effusion (constrictive-effusive pericarditis) can be present. Some cases are secondary to recurrent idiopathic hemorrhagic effusion, infectious pericarditis (especially from coccidioidomycosis, but potentially other fungal or bacterial infections), pericardial foreign body, tumors, prior surgery for congenital pericardial malformation, or idiopathic osseous metaplasia or fibrosis of the pericardium.11,12 Constrictive pericardial disease essentially creates a stiff “shell” around the heart, which increases ventricular interdependence and limits filling to early or possibly mid-diastole. The compromised cardiac filling raises CVP and reduces cardiac output. Compensatory neurohormonal mechanisms lead to right-sided congestive signs, along with tachycardia and vasoconstriction.

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A CVP greater than 15 cm H2O is common. Intracardiac pressure measurements can verify the diagnosis in unclear cases. Besides high mean atrial and diastolic ventricular pressures, the atrial pressure waveform shows a prominent y descent (during ventricular relaxation), because ventricular filling pressure is low only in early diastole. This is in contrast to cardiac tamponade, where the y descent is diminished. Another classic finding with constrictive pericardial disease is an early diastolic dip in ventricular pressure, followed by a mid-diastolic plateau, but this is not present consistently. Angiocardiography could show atrial and vena caval enlargement with increased endocardial to pericardial distance, although not always. Serologic testing for Coccidioides (or other fungal agents) is advisable in endemic regions.

Treatment Therapy for constrictive pericardial disease involves surgical pericardiectomy, not just the creation of a pericardial window. Pericardiectomy is most likely to be successful when only the parietal pericardium is affected. If the visceral pericardial layer also is involved, epicardial stripping is required, which increases the surgical difficulty and associated complications. Pulmonary thrombosis reportedly is a common and potentially life-threatening postoperative complication. Tachyarrhythmias are another complication.

CONGENITAL PERICARDIAL DISEASE Peritoneopericardial diaphragmatic hernia (PPDH) is the most common pericardial malformation in dogs and cats. Other congenital pericardial defects are quite rare. With PPDH, abnormal embryonic development (probably of the septum transversum) allows persistent communication between the pericardial and peritoneal cavities at the ventral midline. Other congenital defects such as  umbilical hernia, sternal malformations, and cardiac anomalies might coexist. The pleural space is not involved. Herniation of abdominal structures into the pericardial space can lead to associated clinical signs.

Clinical Features

Clinical Features

Middle-aged, medium- to large-breed dogs are affected most often. Males might be at higher risk. Some dogs have a history of pericardial effusion. Clinical signs of right-sided CHF predominate. These signs can develop over weeks to months. Ascites and jugular venous distention are the most consistent clinical findings.

Most cases are diagnosed during the first several years of life, usually after gastrointestinal or respiratory signs develop. Vomiting, diarrhea, anorexia, weight loss, abdominal pain, cough, dyspnea, and wheezing are common signs. Physical examination findings can include muffled heart sounds on one or both sides of the chest, a weak or displaced cardiac precordial impulse, an “empty” feel on abdominal palpation (with herniation of many organs), and, rarely, signs of cardiac tamponade. However, some animals never develop clinical signs.

Diagnosis The diagnosis of constrictive pericardial disease can be challenging. Typical radiographic findings include mild to moderate cardiomegaly, pleural effusion, and caudal vena caval distention. Echocardiographic changes in dogs with constrictive pericardial disease can be subtle. Suggestive findings include abnormal diastolic septal motion (septal “bounce”), mid- and late diastolic flattening of the left ventricular free wall, and other findings secondary to the abnormal hemodynamics. Cardiac chamber dimensions can be diminished or normal. Mild pericardial effusion, without diastolic right atrial collapse, is present in some cases. The pericardium might appear thickened and intensely echogenic; however, differentiating this from normal pericardial echogenicity can be impossible. Pleural effusion and vena caval dilation (with blunted respiratory variation in diameter) can also be evident. Doppler findings illustrate the increased ventricular interdependence. Marked respiratory fluctuation occurs in peak flow velocities across the mitral and tricuspid valves, as well as into both atria. The transtricuspid early filling (E-wave) peak velocity is greatest in early inspiration, while maximum peak transmitral E-wave velocity occurs with the onset of expiration.

Diagnosis Thoracic radiographs often are diagnostic or highly suggestive of PPDH. An enlarged cardiac silhouette, dorsal tracheal displacement, overlap of the diaphragmatic and caudal heart borders, and abnormal fat or gas densities within the cardiac silhouette are characteristic findings. Echocardiography often confirms the diagnosis when radiographic findings are equivocal. Additional imaging techniques also can be used as needed, including abdominal ultrasonography, barium series, CT, and others.

Treatment Therapy involves surgical closure of the peritoneal-pericardial defect after viable abdominal structures are returned to their normal position.41 The presence of other congenital abnormalities and the animal’s clinical signs influence the decision to operate. In uncomplicated cases, prognosis is excellent; however, perioperative complications are common and, although often mild, can include death. Older animals without clinical signs might do well without surgery.

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REFERENCES 1. Ware WA, Hopper DL: Cardiac tumors in dogs: 1982-1995, J Vet Intern Med 13:95, 1999. 2. Treggiari E, Pedro B, Dukes-McEwan J, et al: A descriptive review of cardiac tumours in dogs and cats, Vet Comp Oncol 15:273-288, 2017. 3. Vicari ED, Brown DC, Holt DE, Brockman DJ: Survival times of and prognostic indicators for dogs with heart base masses: 25 cases (1986-1999), J Am Vet Med Assoc 219:485, 2001. 4. Machida N, Tanaka R, Takemura N, et al: Development of pericardial mesothelioma in Golden Retrievers with a long-term history of idiopathic haemorrhagic pericardial effusion, J Comp Path 131:166, 2004. 5. Stepien RL, Whitley NT, Dubielzig RR: Idiopathic or mesothelioma- related pericardial effusion: clinical findings and survival in 17 dogs studied retrospectively, J Small Anim Pract 41:342, 2000. 6. Day MJ, Martin MWS: Immunohistochemical characterization of the lesions of canine idiopathic pericarditis, J Small Anim Pract 43:382, 2002. 7. Martin MW, Green MJ, Stafford Johnson MJ, Day MJ: Idiopathic pericarditis in dogs: no evidence for an immune-mediated aetiology, J Small Anim Pract 47:387, 2006. 8. Zini E, Glaus TM, Bussadori C, et al: Evaluation of the presence of selected viral and bacterial nucleic acids in pericardial samples from dogs with or without idiopathic pericardial effusion, Vet J 179:225, 2009. 9. Covey HL, Connolly DJ: Pericardial effusion associated with systemic inflammatory disease in seven dogs (January 2006 - January 2012), J Vet Cardiol 20:123-128, 2018. 10. Davidson BJ, Paling AC, Lahmers SL, et al: Disease association and clinical assessment of feline pericardial effusion, J Am Anim Hosp Assoc 44:5, 2008. 11. Ware WA: Pericardial diseases and cardiac tumors. In Ware WA, Bonagura JD, editors: Cardiovascular disease in companion animals, ed 2, Boca Raton FL and Abington Oxon, 2022, CRC Press/Taylor & Francis Group, pp 705-744. 12. MacDonald K: Pericardial diseases. In Ettinger SJ, Feldman EC, Côté E, editors: Textbook of veterinary internal medicine, ed 8, St Louis, 2017, Elsevier, pp 1305-1316. 13. Savitt MA, Tyson GS, Elbeery JR, et al: Physiology of cardiac tamponade and paradoxical pulse in conscious dogs, Am J Physiol 265:H1996, 1993. 14. Fahey R, Rozanski E, Paul A, et al: Prevalence of vomiting in dogs with pericardial effusion, J Vet Emerg Crit Care (San Antonio) 27:250-252, 2017. 15. Stafford Johnson M, Martin M, Binns S, et al: A retrospective study of clinical findings, treatment and outcome in 143 dogs with pericardial effusion, J Small Anim Pract 45:546, 2004. 16. Guglielmini C, Diana A, Santarelli G, et al: Accuracy of radiographic vertebral heart score and sphericity index in the detection of pericardial effusion in dogs, J Am Vet Med Assoc 241:1048, 2012. 17. Cote E, Schwarz LA, Sithole F: Thoracic radiographic findings for dogs with cardiac tamponade attributable to pericardial effusion, J Am Vet Med Assoc 243:232-235, 2013. 18. Guglielmini C, Baron Toaldo M, Quinci M, et al: Sensitivity, specificity, and interobserver variability of survey thoracic radiography for the detection of heart base masses in dogs, J Am Vet Med Assoc 248:1391-1398, 2016. 19. Scollan KF, Bottorff B, Stieger-Vanegas S, et al: Use of multidetector computed tomography in the assessment of dogs with pericardial effusion, J Vet Intern Med 29:79-87, 2015. 20. Boddy KN, Sleeper MM, Sammarco CD, et al: Cardiac magnetic resonance in the differentiation of neoplastic and nonneoplastic pericardial effusion, J Vet Intern Med 25:1003, 2011. 21. MacDonald KA, Cagney O, Magne ML: Echocardiographic and clinicopathologic characterization of pericardial effusion in dogs: 107 cases (1985-2006), J Am Vet Med Assoc 235:1456, 2009.

22. Lisciandro GR: The use of the diaphragmatico-hepatic (DH) views of the abdominal and thoracic focused assessment with sonography for triage (AFAST/TFAST) examinations for the detection of pericardial effusion in 24 dogs (2011-2012), J Vet Emerg Crit Care (San Antonio) 26: 125-131, 2016. 23. Rajagopalan V, Jesty SA, Craig LE, et al: Comparison of presumptive echocardiographic and definitive diagnoses of cardiac tumors in dogs, J Vet Intern Med 27:1092-1096, 2013. 24. Pedro B, Linney C, Navarro-Cubas X, et al: Cytological diagnosis of cardiac masses with ultrasound guided fine needle aspirates, J Vet Cardiol 18:47-56, 2016. 25. Chun RHB, Kellihan HB, Henik RA, et al: Comparison of plasma cardiac troponin I concentrations among dogs with cardiac hemangiosarcoma, noncardiac hemangiosarcoma, other neoplasms, and pericardial effusion of nonhemangiosarcoma origin, J Am Vet Med Assoc 237:806, 2010. 26. Baumwart RD, Hanzlicek AS, Lyon SD, et al: Plasma N-terminal pro-brain natriuretic peptide concentrations before and after pericardiocentesis in dogs with cardiac tamponade secondary to spontaneous pericardial effusion, J Vet Cardiol 19:416-420, 2017. 27. De Laforcade AM, Freeman LM, Rozanski EA, et al: Biochemical analysis of pericardial fluid and whole blood in dogs with pericardial effusion, J Vet Intern Med 19:833, 2005. 28. Cagle LA, Epstein SE, Owens SD, et al: Diagnostic yield of cytologic analysis of pericardial effusion in dogs, J Vet Intern Med 28:66-71, 2014. 29. Fine DM, Tobias AH, Jacob KA: Use of pericardial fluid pH to distinguish between idiopathic and neoplastic effusions, J Vet Intern Med 17:525, 2003. 30. Humm KR, Keenaghan-Clark EA, Boag AK: Adverse events associated with pericardiocentesis in dogs: 85 cases (1999-2006), J Vet Emerg Crit Care 19:352-356, 2009. 31. Mellanby RJ, Herrtage ME: Long-term survival of 23 dogs with pericardial effusions, Vet Rec 156:568, 2005. 32. Mayhew PD, Dunn M, Berent A: Surgical views: thoracoscopy: common techniques in small animals, Compend Contin Educ Vet 35:E1, 2013. 33. Barbur LA, Rawlings CA, Radlinsky MG: Epicardial exposure provided by a novel thoracoscopic pericardectomy technique compared to standard pericardial window, Vet Surg 47:146-152, 2018. 34. Case JB: Advances in video-assisted thoracic surgery, thoracoscopy, Vet Clin North Am Small Anim Pract 46:147-169, 2016. 35. Nelson DA, Miller MW, Gordon SG, et al: Minimally invasive transxiphoid approach to the cardiac apex and caudoventral intrathoracic space, Vet Surg 41:915-917, 2012. 36. Crumbaker DM, Rooney MB, Case JB: Thoracoscopic subtotal pericardiectomy and right atrial mass resection in a dog, J Am Vet Med Assoc 237:551, 2010. 37. Morges M, Worley DR, Withrow SJ, et al: Pericardial free patch grafting as a rescue technique in surgical management of right atrial HSA, J Am Anim Hosp Assoc 47(3):224, 2011. 38. Ghaffari S, Pelio DC, Lange AJ, et al: A retrospective evaluation of doxorubicin-based chemotherapy for dogs with right atrial masses and pericardial effusion, J Small Anim Pract 55:254-257, 2014. 39. Rancilio NJ, Higuchi T, Gagnon J, et al: Use of three-dimensional conformal radiation therapy for treatment of a heart base chemodectoma in a dog, J Am Vet Med Assoc 241:472-476, 2012. 40. Nolan MW, Arkans MM, LaVine D, et al: Pilot study to determine the feasibility of radiation therapy for dogs with right atrial masses and hemorrhagic pericardial effusion, J Vet Cardiol 19:132-143, 2017. 41. Burns CG, Bergh MS, McLoughlin MA: Surgical and nonsurgical treatment of peritoneopericardial diaphragmatic hernia in dogs and cats: 58 cases (1999-2008), J Am Vet Med Assoc 242:643-650, 2013.

48 Bradyarrhythmias and Conduction Disturbances Romain Pariaut, DVM, DACVIM (Cardiology), DECVIM-CA (Cardiology) KEY POINTS • Sinus bradycardia is usually secondary to a systemic disease causing high vagal tone. • Bradyarrhythmias are more common in dogs than cats. • Third-degree atrioventricular block and sick sinus syndrome account for the majority of bradyarrhythmias that require treatment.

DEFINITION Bradyarrhythmias are defined as slow rhythms (heart rate below 60 beats/min in dogs, 100 beats/min in cats) that cannot be linked to a normal physiologic response, for example, during sleep, and are usually associated with clinical signs such as lethargy, exercise intolerance, decreased appetite, right-sided congestive heart failure, and syncope. During the diagnostic workup of a bradycardic animal, it is important to determine whether the arrhythmia results from extrinsic factors and is therefore likely to resolve when the primary problem is corrected or if it is associated with a disease of the conduction system. Diseases of the conduction system are divided into abnormalities of electrical impulse formation and propagation. The normal cardiac impulse originates within the sinus node, which is referred to as the dominant pacemaker. A decrease in impulse discharge rate from nodal cells results in sinus bradycardia. Other abnormalities of impulse formation include sinus block and sinus arrest, which are characterized by long asystolic pauses. These pauses may extend beyond 6 to 8 seconds and lead to syncopal episodes if subsidiary pacemaker cells present in the atrioventricular node region and the ventricles fail to initiate an escape rhythm. Abnormalities of impulse propagation include bundle branch blocks and first-, second-, and third-degree atrioventricular (AV) blocks. Bundle branch blocks and first-degree AV blocks are conduction abnormalities that are not associated with bradycardia and clinical signs.

DIFFERENTIAL DIAGNOSIS Bradyarrhythmias can result from alterations in autonomic tone, drug exposure, electrolyte abnormalities, trauma, hypoxia, inflammation or infiltration of the myocardium, and more commonly a degenerative age-related process. Although an etiology cannot always be definitively identified, the clinician needs to decide (1) whether extracardiac factors are the cause for the arrhythmia, (2) if treatment is needed, and (3) how to choose between medical and pacemaker therapy. Determining the rhythm diagnosis from the electrocardiogram (ECG) is the essential first step (Fig. 48.1). The common types of bradyarrhythmias in small animal patients are outlined next.

• In the presence of suspected atrial standstill, rule out hyperkalemia. • The medical management of bradyarrhythmias is rarely successful.

Sinus Bradycardia Sinus bradycardia (or slow sinus arrhythmia) is rarely a primary disorder or a cause of clinical signs in the small animal patient. Rather, it is much more likely secondary to systemic disease causing increased vagal tone, particularly gastrointestinal, respiratory, neurologic, and ocular diseases. Respiratory diseases seem to have a profound effect on vagal tone. Examples include chronic upper airway obstruction in brachycephalic breeds, pulmonary hypertension secondary to pulmonary parenchymal diseases, or lung worms in cats. In these cases, resolution of the primary disease results in an increased heart rate with no need for medical or pacemaker therapy. On the surface ECG, P waves and QRS complexes are associated. The P waves are typically positive in leads I, II, III and aVF, which indicates an origin of the electrical impulse in the dorsal region of the right atrium where the sinus node is located. When vagal tone is the cause for the bradycardia, a wandering pacemaker, which corresponds to a variation in the amplitude of the P wave in relation to the respiratory cycle, is usually present. Specifically, the P wave displays a higher amplitude when the heart rate is faster during inspiration and a smaller amplitude when the heart rate decreases during expiration. The QRS complexes are usually narrow (60 msec in dogs; 40 msec in cats) unless a bundle branch block is present. Right bundle branch block may result from right-sided heart diseases or may occur in some animals without clinical evidence of structural and functional cardiac disease. Left bundle branch block results from extensive disruption of the left ventricular myocardium, commonly in association with a dilated cardiomyopathy phenotype and infiltrative diseases (myocarditis, neoplasia). The presence of persistent sinus bradycardia in an animal with impaired consciousness should raise the suspicion of increased intracranial pressure. Systemic hypertension and an abnormal breathing pattern complete the clinical picture of this physiologic response known as the Cushing reflex. Measures to lower intracranial pressure should be rapidly initiated. Anticholinergic agents or pacing therapy are warranted if bradycardia is severe (see Chapter 85, Intracranial Hypertension).1

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A

B

C Fig. 48.1  Electrocardiographic characteristics of bradyarrhythmias. A, Third-degree atrioventricular block. PP and RR intervals are regular, but the P waves bear no constant relation to the R waves. Ventricular escape rhythm at a rate of 37 beats/min (recording speed: 50  mm/sec; amplitude: 10  mm/mV). B, Sick sinus syndrome. Two sinus beats are followed by a period of sinus arrest (3.9 seconds), which is terminated by an escape beat originating from the atrioventricular junction or the ventricles. The last beat is originating in the atrium. Its negative P wave is consistent with a wandering pacemaker or an impulse initiated at the bottom of the atrium. C, Acquired atrial standstill secondary to hyperkalemia. Note the bradycardia (38 beats/min), the tall and peaked T waves, and the absence of P waves (recording speed: 50 mm/sec; amplitude: 10 mm/mV).

Transient and extreme bradycardia can occur in response to a sudden increase in vagal tone resulting in a syncopal event. This form of syncope is called vasovagal syncope. Other terms for this condition include neurocardiogenic, neurally-mediated and reflex syncope. It is commonly triggered by intense activity/excitement, cough, and vomiting. The underlying mechanism is typically attributed to the Bezold– Jarish reflex, which is characterized by bradycardia, vasodilation and hypotension secondary to the stimulation of intraventricular receptors (type C vagal fibers) during tachycardia and a hypercontractile ventricle.2 Whenever an ECG tracing is recorded around the time of a vasovagal syncope, it shows a brief period of sinus tachycardia before a sudden drop in heart rate and a long period with no or few beats before a progressive return to a normal heart rate. The bradycardic period is characterized by an absence of sinus node activity in some cases, and in other cases there are occasional P waves that do not conduct through the AV node, reflecting the extreme depression of the conduction system by a sudden increase in vagal tone (Fig. 48.2). On occasion, the rhythm after the pause returns in the form of paroxysmal atrial fibrillation, which spontaneously terminates after a few minutes.3 These forms of syncope are usually benign.

Sinus Node Dysfunction Sinus arrest and sinus block are identified as a sudden and prolonged pause with no atrial activation or P wave on the ECG. Sinus arrest corresponds to the failure of the nodal pacemaker cells to depolarize and generate an impulse. Sinus block is the failure of an electrical impulse to leave the sinus node and propagate to the atrial myocardium. Sinus block cannot be easily distinguished from sinus arrest on a surface ECG, and the two terms are frequently used interchangeably. The drop in cardiac output from a pause of 6 to 8 seconds results in syncope. Sick sinus syndrome is a disease of the conduction system characterized by periods of normal sinus rhythm or sinus bradycardia, interspersed with long sinus arrest/block that can last up to 10 or 12 seconds because junctional and ventricular pacemakers fail to initiate escape beats. The absence of an escape beat after a 3- to 4-second

pause suggests that the disease is not limited to the sinus node, but rather affects the entire conduction system. When the disease is not associated with clinical signs, typically in its early stages, the term sinus node dysfunction is preferred. Sick sinus syndrome is not associated with a high risk of sudden cardiac death.4 However, as the disease progresses the frequency of syncope increases, sometimes reaching 10 to 15 episodes per day. Moreover, the use of opioids as sedatives often results in a prolongation of the periods of asystole. It is therefore not uncommon that dogs that were not clinical while awake become hemodynamically unstable after sedation or under anesthesia and require temporary external or intravenous pacing. A variant of the disease, sometimes called bradycardia-tachycardia syndrome, is characterized by periods of paroxysmal atrial tachycardia followed by a temporary failure of the sinus rhythm to resume when the tachycardia abruptly terminates. It corresponds to an exaggeration of a normal physiologic response of the sinus node to the effect of a tachyarrhythmia, a mechanism known as overdrive suppression. Older Miniature Schnauzers and Terrier breeds are more commonly affected with sick sinus syndrome.

Atrioventricular Block With first-degree AV block, all the atrial impulses are conducted to the ventricles, but the PR interval is prolonged on the ECG (PR .130 msec in dogs, PR .90 msec in cats). It frequently results from AV node fibrosis, increased vagal tone, or drugs that delay AV node conduction, including digoxin, calcium channel blockers, and b-blockers. Second-degree AV block is diagnosed when some P waves are not followed by a QRS complex on the surface ECG. The hemodynamic consequences of this rhythm depend on the duration of the block. Second-degree AV block is said to be high grade when more atrial impulses fail to be conducted to the ventricles than are conducted. This can result in syncope or other signs of low cardiac output. Alternatively, a single P wave that does not get conducted can occur in normal dogs or those with increased vagal tone; it does not require treatment. Two types of second-degree AV blocks are recognized. Mobitz type I second-degree AV block is characterized by a progressive

CHAPTER 48  Bradyarrhythmias and Conduction Disturbances

Interval (ms)

Detected

281

Term

1500 1200 900 600

400

200

A

–480 –440

–400

–360

–320

–280 –240 –200 Time (sec)

–160

–120

–80

–40

0

Asystole detected

B

Fig. 48.2  Recording from an implantable event loop recorder (Reveal XR, Medtronic plc) during an episode in a dog with neurocardiogenic/vasovagal syncope. A, The y-axis represents the instantaneous heart rate (one dot corresponds to one R-R interval) in msec. The x-axis represents time before the end of the recording (Term.) in sec. Initially, the heart rate varies between 400 and 600 msec (100 to 150 bpm). At -120 sec, the heart rate increases rapidly and peaks at approximately 200 bpm (R-R interval of 300 msec), then suddenly drops dramatically (Detected) and remains low (R-R intervals of 1500 msec or longer) for approximately 20 sec before progressively returning to baseline values. B, Snapshot of the ECG at the onset of the bradycardiac event. Beats with R-R intervals of 231, 207, and 194 msec, likely corresponding to a rapid sinus tachycardia, precede a long asystolic pause with a single ventricular escape beat (VS) and no clear evidence of atrial and ventricular activity, although atrial activity (P waves) can be difficult to differentiate from baseline motion artifacts associated with the syncope.

increase in the PR interval duration ending by a blocked P wave. It is known as the Wenckebach phenomenon. It usually results from a combination of AV node fibrosis and a progressive increase in vagal tone. This form of AV block is usually benign and does not require specific treatment. Mobitz type II second-degree AV block is characterized by the unexpected occurrence of blocked P waves. PR intervals before and after the blocked P waves are identical. The QRS complexes of conducted beats are usually wide because the area of block is below the His bundle, causing bundle branch blocks and intraventricular conduction delays. This form of block is more likely to worsen and result in clinical signs. Administration of atropine (0.04 mg/kg IV) can help the clinician to differentiate between the two forms of block. Type I usually improves after atropine and type II is unchanged or worsens. Third-degree, or complete, AV block is characterized by the absence of conducted P waves to the ventricles. The ECG displays independent atrial and ventricular activities. Cardiac output is dramatically reduced. In response, the atrial rate, which is under the control of the adrenergic tone, is elevated. Electrical activation of the ventricles is dependent on an escape rhythm beyond the site of block. The QRS complexes are generally wide and bizarre at rates around 20 to 60 beats/min in dogs and 60 to 140 beats/min in cats. In addition, the ventricular rate is regular unless ventricular premature beats originating from an ischemic myocardium are present. Causes of AV block include myocardial fibrosis, inflammation or infiltration, and potentially drug toxicity (calcium channel blockers,

b-blockers, or digoxin). Age-related fibrodegenerative disease is the most common cause of AV block in dogs. An echocardiogram is indicated to identify concomitant structural cardiac disease. Although a mild elevation of plasma cardiac troponin I level is common in dogs with complete AV block, marked increase in concentration suggests myocarditis as the cause for the bradyarrhythmia.5,6 Third-degree AV block in cats is often associated with structural heart disease.7 Clinical signs depend on the rate of ventricular contraction. Cats, and occasionally dogs, may show no apparent signs, and bradycardia is detected on physical examination. The reason why cats may not be clinical with third-degree AV block is that their ventricular escape rhythm is usually between 100 to 140 bpm, which allows them to maintain an activity level that is not perceived as decreased by their owner. More commonly, animals present with signs of low cardiac output such as syncope, congestive heart failure, or weakness. Syncope is more common with paroxysmal second-degree AV block because it is the abrupt drop in heart rate that triggers the syncopal event. It is noteworthy that syncope in cats tends to mimic seizures and is often accompanied by loud vocalizations.

Atrial Standstill Atrial standstill is a rhythm defined by the absence of atrial electrical activity on the surface ECG. Atrial standstill is rare and usually associated with an atrial myopathy that seems more prevalent in English Springer Spaniels.8 It affects young dogs, and a genetic etiology or an

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inflammatory process is likely involved. Long-term prognosis is guarded, although two dogs have been reported to live approximately 7 years after pacemaker implantation.9 The ECG is characterized by the absence of P waves and a regular ventricular or AV nodal escape rhythm at rates of 20 to 60 beats/min in dogs. Hyperkalemia can affect the ECG in a way that resembles atrial standstill. As plasma potassium concentration increases above 5.5 to 6 mmol/L, the initial change on the surface ECG is a narrowing of the T wave and an increase in its amplitude. As potassium concentration continues to rise, it leads to a decrease in heart rate associated with reduced P wave amplitude and a widening of the QRS complexes. P waves then become invisible, suggesting a diagnosis of atrial standstill. However, this rhythm should be referred to as sino-ventricular. The main difference with atrial standstill is that the electrical impulse still originates in the sinus node and propagates to the AV node via preferential conduction pathways. Therefore, the AV node and the ventricles remain under the control of the sinus node, and as a result, the heart rate can still be modulated by variations of the autonomic tone on sinus node firing rate. The absence of P waves is explained by the failure of the sinus impulses to propagate to the rest of the atrial myocardium because of an alteration of the myocyte membrane potential by the elevated potassium concentration. Conversely, in the case of atrial standstill the absence of P waves results from the inability of the sinus impulse to leave the sinus node because of extensive replacement fibrosis and a lack of functioning myocytes to propagate the electrical impulse beyond the sinus node region.10

TREATMENT Medical Treatment Vagally induced bradyarrhythmias and sick sinus syndrome may respond to the administration of parasympatholytic medications. An increase in heart rate after intravenous administration of atropine (0.04  mg/kg) or glycopyrrolate (0.01  mg/kg) confirms the contribution of vagal tone to the bradyarrhythmia. Usually, an ECG is obtained after 15 minutes if the drugs are administered intravenously and 30 minutes if they are administered subcutaneously. An appropriate response to atropine implies a 50% to 100% increase in heart rate from baseline. Side effects resulting from repeated injections limit their chronic use. They include mydriasis, dry mouth, constipation, urinary retention, and on occasion, neurologic signs.4,10 Sympathomimetic inotropes increase heart rate by b-adrenergic stimulation. Agents with b2 effects cause systemic vasodilation, whereas drugs with associated a stimulation cause vasoconstriction. Dopamine (5 to 10 mcg/kg/min IV) and dobutamine (dog: 2 to 20 mcg/kg/min IV; cat: 1 to 5 mcg/kg/min IV) may contribute to an increase in heart rate and systolic function (see Chapter 147, Catecholamines). They are usually administered as a constant rate infusion and the dose is increased to effect. Isoproterenol, a pure b agonist, improves conduction in the AV node and the His–Purkinje system, which may result in the partial or complete resolution of AV block. It may also increase the rate of a ventricular escape rhythm in complete AV block, but usually with limited success. It is administered as a constant rate infusion and its dose adjusted to effect. However, it causes a significant decrease in diastolic blood pressure via ß2 stimulation. Finally, respiratory and metabolic acidosis decrease its effectiveness.11 Terbutaline (0.2 mg/kg orally q8-12h, 0.01 mg/kg IV) is a selective b2 agonist commonly used as a bronchodilator. Aminophylline (10 mg/ kg twice orally q12h, or 10 mg/kg IV) is a phosphodiesterase inhibitor

and bronchodilator with mild chronotropic effect. These drugs may temporarily increase heart rate in dogs with sick sinus syndrome.

Pacemaker Therapy Pacemaker therapy can be temporary or permanent. The emergency and critical care clinicians are more likely to encounter situations that require pacing for short periods of time. The most common indications for temporary pacing would be an acute onset of AV block causing frequent syncope or a severe bradyarrhythmia associated with hemodynamic instability during anesthesia. The most practical technique for animals that require temporary pacing is the transcutaneous approach. Transcutaneous pacing is a quick and effective means of increasing the heart rate in an emergency situation. A pacing mode is integrated in most external defibrillators that are already available in emergency rooms. The pacing electrodes are the same adhesive pads that are used for external defibrillation. Transcutaneous pacing is reported to be safe and effective.12,13 The major drawback of this method is that stimulation of the local skeletal muscles and associated discomfort. It usually requires deep sedation or general anesthesia. Temporary transvenous pacing is an alternative to the transcutaneous approach that requires jugular or femoral venous access. Pacemaker therapy is further detailed in Chapter 203, Temporary Cardiac Pacing.

REFERENCES 1. Agrawal A, Timothy J, Cincu R, et al: Bradycardia in neurosurgery, Clin Neurol Neurosurg 110:321, 2008. 2. Warltier DC, Campagna JA, Carter C: Clinical relevance of the BezoldJarisch reflex, Anesthesiology 98(5):1250-1260, 2003. 3. Porteiro Vázquez DM, Perego M, Santos L, Gerou-Ferriani M, Martin MW, Santilli RA: Paroxysmal atrial fibrillation in seven dogs with presumed neurally medicated syncope, J Vet Cardiol 18(1):1-9, 2016. 4. Ward JL, DeFrancesco TC, Tou SP, Atkins CE, Griffith EH, Keene BW: Outcome and survival in canine sick sinus syndrome and sinus node dysfunction: 93 cases (2002-2014), J Vet Cardiol 18(3):199-212, 2016. 5. Trafney DJ, Oyama MA, Wormser C, Reynolds CA, Singletary GE, Peddle GD: Cardiac troponin-I concentrations in dogs with bradyarrhythmias before and after artificial pacing, J Vet Cardiol 12(3):183-190, 2010. 6. Church WM, Sisson DD, Oyama MA, Zachary JF: Third degree atrioventricular block and sudden death secondary to acute myocarditis in a dog, J Vet Cardiol 9(1):53-57, 2007. 7. Kellum H, Stepien R: Third-degree atrioventricular block in 21 cats (1997-2004), J Vet Intern Med 20(1):97-103, 2006. 8. Fonfara S, Loureiro JF, Swift S, et al: English springer spaniels with significant bradyarrhythmias—presentation, troponin I and follow-up after pacemaker implantation, J Small Anim Pract 51(3):155-161, 2010. 9. Schmitt KE, Lefbom BK: Long-term management of atrial myopathy in two dogs with single chamber permanent transvenous pacemakers, J Vet Cardiol 18(2):187-193, 2016. 10. Santilli RA, Giacomazzi F, Porteiro Vázquez DM, Perego M: Indications for permanent pacing in dogs and cats, J Vet Cardiol 22:20-39, 2019. 11. Guzman SV, Deleon AC Jr, West JW, Bellet S: Cardiac effects of isoproterenol, norepinephrine and epinephrine in complete A-V heart block during experimental acidosis and hyperkalemia, Circ Res 7(4): 666-672, 1959. 12. DeFrancesco TC, Hansen BD, Atkins CE, Sidley JA, Keene BW: Noninvasive transthoracic temporary cardiac pacing in dogs, J Vet Intern Med 17(5):663-667, 2003. 13. Noomanová N, Perego M, Perini A, Santilli RA: Use of transcutaneous external pacing during transvenous pacemaker implantation in dogs, Vet Rec 167(7):241-244, 2010.

49 Supraventricular Tachyarrhythmias Teresa C. DeFrancesco, DVM, DACVIM (Cardiology), DACVECC

KEY POINTS • Supraventricular tachyarrhythmia (SVT) is a general term used to describe a tachycardia that requires either atrial or atrioventricular nodal tissue or both for its initiation and maintenance. • Atrial fibrillation is the most common SVT seen in emergent and critical care settings, often in large-breed dogs in congestive heart failure with underlying structural heart disease. • SVT generally refers to a rapid, narrow QRS tachycardia with regular RR intervals. SVT represents several underlying electrophysiologic mechanisms, such as atrial flutter, atrial tachycardia, junctional tachycardia, and atrioventricular reentrant tachycardia.

INTRODUCTION Supraventricular tachyarrhythmias (SVTs) are rapid cardiac rhythms that require atrial or atrioventricular (AV) nodal tissue or both for their initiation and maintenance.1 These arrhythmias are typically detected in the critically ill patient on cardiac auscultation or on electrocardiogram (ECG) monitoring as either sustained or paroxysmal bursts of tachycardia, generally at heart rates of 180–300 per minute. SVTs can occur with a wide range of diseases and vary greatly in their clinical signs from asymptomatic to collapse, depending on the rate, frequency of the arrhythmia, and the severity of any organic cardiac dysfunction or other noncardiac diseases. SVTs, especially atrial fibrillation, commonly occur in patients with advanced underlying structural heart disease often in the setting of congestive heart failure due to cardiomyopathies or end-stage degenerative mitral valve disease.2,3 Atrial fibrillation is uncommon in the cat.4 Other structural heart diseases such as end-stage congenital heart disease, cardiac neoplasia, myocarditis, or endocarditis can also be associated with SVTs.1,5 SVTs can also occur as in dogs with severe systemic illnesses such as sepsis, pancreatitis, splenic torsion, or gastricdilatation-volvulus.5-11 Less commonly, SVTs can be detected in minimally symptomatic or asymptomatic patients undergoing a routine exam or an exam for an unrelated issue.5,12-14 Lone atrial fibrillation can be seen in asymptomatic giant breed dogs such as Irish Wolfhounds or Great Danes in the absence of overt structural heart disease.15 The detection of paroxysms of SVT in a young or middle-aged dog that is not systemically ill is concerning for an atrioventricular accessory pathway.12-14 Accessory pathways consist of congenital muscular bundles that penetrate the normal fibrous skeleton between the atria and ventricles. Under normal conditions, this fibrous skeleton electrically insulates the atria from the ventricles. Accessory pathways allow an alternate route of conduction (aside from the atrioventricular node) between the atria and ventricles. In dogs, accessory pathways are most often concealed, meaning they only conduct in a retrograde

• SVTs can be associated with underlying structural heart diseases or noncardiac diseases such as sepsis, pancreatitis, splenic torsion, or gastric-dilatation-volvulus. • If a pathologic SVT is persistent and deemed hemodynamically significant, oral or IV diltiazem is commonly used for the acute and chronic management. • Chronic, sustained SVT may result in a tachycardia-induced cardiomyopathy and congestive heart failure, which is reversible if resolved.

direction (ventricle to atria), which makes them difficult to diagnose with a surface ECG as there is no evidence of preexcitation suggested by a short PR interval and early depolarization of the ventricles noted by a delta wave on the ECG. In humans, most patients with accessory pathway SVTs, such as Wolff-Parkinson-White syndrome, do not have structural heart disease as they are diagnosed as a result of mild symptoms such as palpitations and light-headedness. However, many dogs with an accessory pathway related SVT are diagnosed with evidence of pacing-induced or tachycardia-induced cardiomyopathy, likely because early symptoms are missed until myocardial dysfunction ensues causing congestive heart failure or collapse.16-18 The negative consequence of uncontrolled pathologic SV tachyarrhythmias are primarily related to diminished ventricular filling and subsequent low cardiac output associated with the rapid heart rates and myocardial dysfunction that can eventually lead to tachycardia-induced cardiomyopathy if SVT is frequent and sustained.19 Tachycardia-induced cardiomyopathy is reversible if the SVT is controlled, resulting in a better long-term prognosis.16-17 The myocardial dysfunction associated with uncontrolled SVT is the basis for the pacing-induced experimental model for congestive heart failure used in dogs and other large animals. There are several proposed mechanisms for the myocardial dysfunction associated with sustained tachycardias: myocardial energy depletion and impaired energy utilization, manifested as reduced myocardial energy stores; myocardial ischemia due to persistent supra-physiologic heart rates resulting in impaired coronary blood flow; and abnormal calcium handling at persistent high heart rates.19 Uncontrolled SVTs in the setting of myocardial failure can be the result of primary dilated cardiomyopathy or the cause of the myocardial failure due to tachycardia-induced cardiomyopathy. For patients with severe sepsis and septic shock, there is recent interest in the role of tachycardia and high-adrenergic stimulation in the development of sepsis-associated myocardial dysfunction. In addition to diminished ventricular filling, myocardial ischemia, and abnormal

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calcium handling effects of tachycardia, excessive sympathetic activation also leads to catecholamine-induced cardiomyocyte toxic effects characterized by inflammation, oxidative stress, apoptosis, and necrosis.6 The negative consequences of adrenergic stimulation have led to clinical trials in humans evaluating the role of lowering heart rates with esmolol or amiodarone.6-8 While still somewhat controversial, conservative lowering of heart rates appears to be associated with improvement in mortality and other secondary clinical outcomes without increased adverse events. The use of esmolol in managing tachycardia was recently reported in two dogs with severe sepsis who had favorable outcomes.9 With the development of intracardiac electrophysiologic studies, the classification of SVT has evolved. Various underlying mechanisms have been identified resulting in a classification scheme in which the rhythm is either an atrial tachyarrhythmia or an AV tachyarrhythmia based on their site of origin and dependence of the AV node1 (Box 49.1). Although several clues on the ECG may assist in defining the underlying mechanism of the SVT, an electrophysiologic mapping study is typically needed for a definitive diagnosis and ultimately definitive treatment, especially if an accessory pathway is suspected. However, at the bedside in a critical care setting, the more practical approach to a narrow QRS tachycardia is primarily dependent on the regularity of the RR interval as well as clinical integration of the ECG with the patient’s other findings and response to vagal maneuvers20,21 (Fig. 49.1 and Table 49.1). If the RR intervals are irregular, atrial fibrillation, atrial flutter with varying block, or multifocal atrial tachycardia are considered. All other mechanisms of SVT typically have regular RR intervals. Additionally, in an emergency and critical care setting, the diagnosis of the underlying mechanism of the SVT is usually not needed for acute management. The challenge is ensuring that narrow QRS tachycardia is accurately diagnosed as sinus tachycardia, atrial fibrillation, or other SVT and not erroneously diagnosed as ventricular tachycardia. Careful study of the ECG is necessary to further characterize the tachycardia as a sinus tachycardia, a supraventricular tachycardia, atrial fibrillation, or ventricular tachycardia. Comparing the QRS complexes during the tachycardia in question with those QRS complexes from either a previous ECG or to sinus complexes if the tachyarrhythmia is intermittent can be most helpful. SVTs typically have narrow-complex QRS while ventricular tachycardias have wide QRS complexes. Printing an ECG strip at a fast paper speed of 50 mm/s and performing a diagnostic multichannel ECG recording for the more challenging ECGs may be helpful.22

ELECTROCARDIOGRAPHIC DIAGNOSIS Narrow-complex tachycardias with QRS duration less than 70 ms in dogs and less than 40 ms in cats are usually of supraventricular origin, with the extremely rare exception of high septal or fascicular ventricular

BOX 49.1  Classification of Supraventricular Tachycardias Atrial tachyarrhythmias: Sinus tachycardia (appropriate or inappropriate) Sinus nodal reentrant tachycardia Atrial tachycardia Multifocal atrial tachycardia Atrial flutter Atrial fibrillation AV nodal tachyarrhythmias: AV nodal reentrant tachycardia AV reentrant tachycardia (accessory pathway) Junctional tachycardias

tachycardias.20 The QRS duration and polarity (mean electrical axis) are typically normal in SVTs because ventricular activation occurs via the normal intraventricular conduction system. The duration of the QRS complex is the most useful tool to differentiate supraventricular tachycardias from ventricular tachycardia (wide QRS tachycardia). However, SVTs can uncommonly conduct with either a right, or less commonly a left, bundle branch block resulting in a wide and altered QRS morphology, making the distinction between a supraventricular tachycardia and ventricular tachycardia more challenging.23 Atrial fibrillation is a common SVT in large-breed dogs with advanced structural heart disease. Although atrial fibrillation is a supraventricular tachyarrhythmia, it is usually not called an SVT, and it can easily be diagnosed on the surface ECG because of its irregular rhythm and lack of P waves (Figs. 49.2–49.5). Atrial fibrillation is usually associated with a rapid ventricular response; however, it can rarely manifest as a slow or normal ventricular response rate. The ECG reveals no organized atrial activity (no P waves); instead, there are slight fluctuations in the baseline representing atrial activity called fibrillation waves. The RR intervals will be irregular with QRS complexes that usually look normal and can vary slightly in height. As with other SVTs, atrial fibrillation can be conducted aberrantly in ventricles resulting in a wide and bizarre QRS complex.

Distinguishing Supraventricular Tachycardia from Ventricular Tachycardia As mentioned previously, the most important criteria to distinguish between a supraventricular and ventricular tachycardia is the QRS duration. The QRS duration in SVT is typically normal (,70 ms in dogs and ,40 ms in cats), whereas the QRS duration in ventricular tachycardia is prolonged. The QRS complex of a supraventricular beat will look similar to a beat initiated from the sinoatrial node. The challenge is the aberrantly conducted SVT. Other helpful tips include the following: 1. The presence of atrioventricular dissociation that is a fortuitously timed and clearly discernable normal P wave independent of a regular QRS rhythm is strongly suggestive of ventricular tachycardia. 2. P’ waves can sometimes be seen in the ST or TP segments of the ECG with some SVTs. P’ waves represent atrial depolarization initiated outside the sinoatrial node. P’ waves look different than the normal P waves and have a consistent relationship with the QRS complexes. 3. A fortuitously timed sinus beat fused with an undetermined QRS complex that creates a fusion beat is suggestive of ventricular tachycardia. 4. The mean QRS axis is usually normal in SVT and is usually abnormal in ventricular tachycardia (upside down QRS), except in Boxers with arrhythmogenic right ventricular cardiomyopathy (ARVC) in which the ventricular tachycardia has a normal QRS axis with a wide QRS duration. 5. The ventricular rate is typically faster in SVT than ventricular tachycardia, often exceeding .240/min. However, the ventricular tachycardia in Boxer ARVC can also be quite fast. 6. The T wave is typically in the opposite direction of QRS in ventricular tachycardia, whereas the T wave can be positive or negative in SVT with a more distinct J-point (junction between the QRS and ST segment). 7. Positive response to a vagal maneuver (abrupt termination) suggests a supraventricular tachycardia. 8. If the tachycardia is still undetermined, response to short-acting drugs such as IV diltiazem, esmolol, or lidocaine may help to break the rhythm and help in the diagnosis. Resolution of the tachycardia with lidocaine typically suggests a ventricular tachycardia; however, even an SVT rarely responds to lidocaine.24

CHAPTER 49  Supraventricular Tachyarrhythmias

Tachycardia Dogs >180/min, Cats >240/min

Ventricular tachycardia or rarely SVT with aberrant conduction

No

Atrial fibrillation, Atrial flutter-variable AV conduction, Multifocal atrial tachycardia

Narrow QRS?

Yes

Supraventricular tachyarrhythmia

No

Regular RR?

Yes Response to vagal maneuver? Gradual response

No Yes

Gradual slowing of HR suggestive of sinus tachycardia

Abrupt slowing of ventricular rate or termination of rhythm, even transiently, suggestive of SVT (atrial flutter, orthodromic AV reentry tachycardia, atrial or junctional tachycardia, or rarely AV nodal reentry)

Response to short acting IV drugs. Abrupt slowing of ventricular rate or termination of rhythm with IV diltiazem suggestive of SVT

Fig. 49.1  Flow chart for the diagnosis of tachycardia in a critical care setting.

TABLE 49.1  Common Supraventricular Rhythms, ECG Characteristics, Clinical Associations,

and Response to Vagal Maneuvers Rhythm

ECG Characteristics

Clinical Associations

Vagal Maneuver

Sinus tachycardia (ST)- appropriate

Normal P-QRS-T but at a fast rate (dog .150 bpm, cat .220 bpm) Sustained ST is usually #220 in dogs Mostly regular RR intervals with no abrupt starts or termination of rhythm ST with electrical alternans (amplitude of P-QRS-T wave alternates with every beat) is highly suggestive of pericardial effusion and cardiac tamponade

Accelerated sinus rate that is a physioMay see a gradual logic response to a stressor such as hyslowing of rate poxia, anemia, hypovolemia (real or effective), sepsis, anxiety, or pain ST can be associated with sympathomimetic toxicity (chocolate or bronchodilator toxicity) ST associated with pheochromocytoma and hyperthyroidism due to increase sympathetic stimulation

Atrial Fibrillation (Afib)

No P waves “f” or fibrillation waves Fast ventricular response rate (.160 in dog, .220 in cat) Irregularly irregular (chaotic) rhythm Normal QRS morphology with varying QRS height

Middle-aged large or giant breed dogs. Typically no response Afib is uncommon in cats Often presenting in heart failure, typically associated with advanced heart disease in the dog due to dilated cardiomyopathy or advanced valvular heart disease Lone Afib – no obvious structural heart disease in giant breed dog (uncommon)

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TABLE 49.1  Common Supraventricular Rhythms, ECG Characteristics, Clinical Associations,

and Response to Vagal Maneuvers—cont’d Rhythm Atrial Flutter

ECG Characteristics Clinical Associations Either structural cardiac disease leading No P waves to atrial enlargement or noncardiac “F” or flutter waves (saw-tooth atrial activity) when diseases rhythm is slowed Atrial flutter is an unstable rhythm and Fast ventricular response rate will typically degenerate into Afib RR can be regular or irregular contingent atrioventricular conduction from 1:1 to 6:1, often 2:1 Bix rule – positive deflection representing flutter wave seen midway between RR interval if 2:1 conduction

Vagal Maneuver May slow ventricular response rate transiently to visualize the F waves

Multifocal atrial tachycardia

Rapid irregular RR interval with isoelectric baseline Usually associated with pulmonary Usually intermittent disease P’ present with variable conformations due several atrial Cardiac diseases, digitalis toxicity, ectopic foci metabolic or electrolyte disorders Variable P’R intervals Often degenerates to Afib

May slow ventricular response rate transiently

Focal atrial tachycardia

Usually regular R-R intervals, isoelectric baseline Sustained or paroxysmal P” visible with the possibility of periods of irregularities (cycle length irregularity) P’ waves, if visible, are typically positive in lead 2 P’R interval shorter than RP’

Transient positive Cardiac and systemic diseases response with an Cardiac disease (acquired or congenital) abrupt cessation of often with atrial enlargement, myocarthe SVT ditis, cardiac tumors Digoxin toxicity, hyperthyroidism, electrolyte abnormalities (hypokalemia)

Atrioventricular reentry tachycardia mediated by accessory pathway

Regular RR interval Sustained or paroxysmal P’ present- usually with retrograde conduction (negative in lead 2) P’R interval greater than the RP’ Typically concealed conduction via an accessory pathway may result in orthodromic atrioventricular reentry tachycardia

Young adult dog presenting with heart failure or collapse Sustained SVT likely to cause tachycardia-induced cardiomyopathy and congestive heart failure Can be an incidental finding

Distinguishing Sinus Tachycardia from Supraventricular Tachycardia Sometimes the differentiation between sinus tachycardia and SVT can be challenging. Sinus tachycardia is usually an appropriate physiologic rhythm that originates in the sinus node and occurs in response to the increased need for cardiac output or increased sympathetic tone. Sinus tachycardia is often associated with the many conditions encountered in a critical care setting such as hypovolemia (real or effective), hypotension, sepsis, anemia, hypoxemia, congestive heart failure, pain, and fear. Extreme sinus tachycardias can be observed in sympathomimetic toxicity, such as in chocolate or albuterol toxicity or in a disease with accentuated sympathetic activity such as hyperthyroidism or pheochromocytoma. Clinical integration of the cardiac rhythm is of the utmost importance in achieving an accurate diagnosis. In addition to evaluating for underlying conditions that could lead to sinus tachycardia, the patient profile may be helpful. For example, a young adult Labrador Retriever in congestive heart failure with a narrow QRS tachycardia of 300 beats per minute is highly suggestive of an SVT via a concealed orthodromic atrioventricular reentry tachycardia due to an accessory pathway. Careful study of the ECG can be helpful in distinguishing sinus tachycardia from SVT. 1. Intermittent SVT is likely to abruptly start and stop versus sinus tachycardia, which is likely to gradually speed up or slow down. 2. If the tachycardia is intermittent, look at the PR interval carefully when not in tachycardia. If PR interval is short with a widening of the initial QRS upstroke, pre-excitation is likely, which supports SVT. 3. Examining the preceding T wave for atrial activity may provide some clues as the P or P’ wave can be hidden in the preceding

4.

5. 6.

7.

Transient positive response with an abrupt cessation of the SVT

T wave. The P wave morphology is normal with sinus tachycardia, whereas it is abnormal with SVT. Supraventricular tachycardia is generally faster than sinus tachycardia. The rates of some sustained SVTs can be as high as 300 beats per minute. Sustained heart rates of 300 beats per minute would be extremely rare with sinus tachycardia. Sustained sinus tachycardia is usually ,220 beats per minute in the dog. Response to a vagal maneuver may be helpful. Tachycardia that stops abruptly, even for one or two beats, is suggestive of SVT. If sinus tachycardia is prioritized and hypovolemia (real or effective) is suspected, an IV fluid bolus may be both diagnostic and therapeutic. If sustained SVT is suspected, evaluating the response to shortacting IV drugs such as diltiazem or esmolol can be of diagnostic and therapeutic value.

Vagal Maneuvers Vagal maneuvers are techniques often used in the initial management of a narrow-complex tachycardia. They can help to differentiate SVT from ventricular tachycardia and SVT from sinus tachycardia.25 Common vagal maneuvers include applying pressure to the carotid sinuses, ocular and periorbital regions, and the nasal planum in the cat. The increase in pressure in these regions triggers an increase in parasympathetic output to the heart via the vagus nerve resulting in slowing of AV nodal conduction. Slowing AV nodal conduction can either terminate the SVT or slow the ventricular response rate, which can be both diagnostic and therapeutic. The success rate for vagal maneuvers in humans for terminating SVT ranges from 19% to 54%.25,26 Accurate

CHAPTER 49  Supraventricular Tachyarrhythmias

Fig. 49.2  The top strip is a lead II electrocardiogram (paper speed 25 mm/sec) from a 4-year-old Labrador Retriever with sustained SVT at a rate of 300 beats per minute with suspected orthodromic atrioventricular tachycardia due to an accessory pathway. The rhythm abruptly terminates transiently with a vagal maneuver (arrow) and eventually is converted to sinus rhythm (lower strip) with diltiazem.

Fig. 49.3  Lead II electrocardiogram (paper speed 25 mm/sec) from a large-breed dog with rapid atrial fibrillation and congestive heart failure. Note the lack of P waves, the presence of fibrillation waves, the irregularly irregular rhythm, and normal QRS duration with slight variation in R wave height.

Fig. 49.4  Lead II electrocardiogram (ECG) (paper speed 25 mm/sec) from a large-breed dog immediately post gastric dilation-volvulus surgery. The ECG shows a rapid narrow-complex tachycardia that is most compatible with atrial flutter based on the saw-tooth based (arrows) noted with the tachycardia intermittently and abruptly slows. The dog’s SVT responded favorably to IV diltiazem.

Fig. 49.5  Lead II electrocardiogram (ECG) (paper speed 25 mm/sec) from a collapsed German Shepherd dog with cardiac tamponade and pericardial effusion. ECG shows an extreme sinus tachycardia at a rate of 250 beats per minute with electrical alternans.

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location, adequacy, and direction of the digital force applied are important factors in producing an effective result. The carotid sinus is located in the region of the neck just below the angle of the mandible and ventral to the wing of the atlas. Deep firm medially directed pressure is applied to one or both carotid sinuses for 10 seconds. The ocular vagal maneuver is more effective when both eyes are firmly massaged with the flats of the fingers with the pressure directed toward the mediodorsal portion of the orbit. One must be careful to not cause any pain or injury to the eye or retrobulbar region. In a study of healthy cats, both the ocular and nasal planum massage temporarily decreased the heart rates.27 The rhinarium, the non-haired surface of the nose, is firmly massaged (but not too firmly such that it is objectionable to the cat) in a rotating motion.

TREATMENT Acute management of SVT is somewhat contingent on the underlying disease as well as the nature, rate, and frequency of the arrhythmia. Short and infrequent runs of SVT that do not cause hemodynamic compromise may not require specific antiarrhythmic therapy; however, the patient should be continuously monitored while in the hospital and possibly via ambulatory ECG monitor (Holter monitor) after hospital discharge. In general, the approach to a supraventricular tachyarrhythmias should be comprehensive, including treatment of the underlying associated condition; general systemic support, such as hemodynamic, respiratory, metabolic and electrolyte support; medical management, typically with drugs that slow AV conduction such as calcium channel and b-adrenergic blockers; and electrical therapy for medically refractory tachyarrhythmias. Electrical cardioversion is used, albeit uncommonly, to convert a newly diagnosed atrial fibrillation or medically refractory SVT in a hemodynamically compromised patient. In a nonurgent setting, electrophysiological mapping and radiofrequency ablation may be an option for a dog suspected to have an accessory pathway-mediated SVT.

Supraventricular Tachycardia Urgent termination of a rapid sustained SVT causing hemodynamic compromise usually requires IV calcium channel blocker or b-blocker. Continuous ECG and blood pressure should be monitored during the management of hemodynamically compromising SVT. In the dog, IV diltiazem is usually more effective than IV esmolol in terminating SVT with less negative inotropic effect when compared with esmolol.28 IV diltiazem should be given slowly over 2–3 minutes, and its response may take up to 10 minutes to see an effect. The author typically starts with 0.05–0.1 mg/kg of IV diltiazem, which can be repeated as needed up to a total dose of 0.3 mg/kg. The response duration of the IV diltiazem can vary from a few minutes to a couple of hours. If a continuous rate infusion (CRI) of diltiazem is deemed necessary, the CRI rate should be reflective of the total dose needed to terminate the rhythm and the duration of effect of the initial bolus dosing. Avoid flushing of the catheter or IV lines containing the diltiazem as serious transient bradycardia may result. Oral diltiazem can also be used in urgent settings if IV diltiazem is not available or if the patient is stable. It should be emphasized that oral diltiazem is available in sustained and regularrelease formulations. Regular-release oral diltiazem would be preferred in the initial management of a hemodynamically significant SVT as the dose can be escalated more effectively due to its shorter duration of

action. Long-term management with sustained release diltiazem is indicated in the transition to long-term management or in nonurgent management of SVTs. If the SVT is refractory to adequate doses of diltiazem, a second antiarrhythmic drug such as an IV esmolol, procainamide, or lidocaine can be used cautiously for both diagnostic and therapeutic purposes. Careful monitoring of blood pressure and ECG is advised during these infusions as hypotension, bradycardia, or other arrhythmias may develop, especially in an animal with concurrent myocardial failure.29 Long-term management of SVTs is tailored to the underlying mechanism, the patient’s structural heart disease, and any possible comorbidities, specifically renal or hepatic dysfunction. As with urgent management of SVT, oral diltiazem is often used because of its action to slow AV nodal conduction. However, in some cases with inadequate control of the SVT with a single agent, sotalol or amiodarone can be added to the diltiazem therapy. These drugs are helpful because of their antiarrhythmic effects on the atrial myocardium, further slowing of the AV nodal conduction, and if present, the accessory pathway (Table 49.2).

Sinus Tachycardia Appropriate sinus tachycardias are managed primarily by addressing the underlying condition resulting in the fast rate. Treatment maneuvers include giving fluid boluses or a blood transfusion if significant hypovolemia or anemia is identified. Managing congestive heart failure to optimize cardiac output, relieving respiratory distress, or performing a pericardiocentesis should improve worrisome sinus tachycardia. In sympathomimetic toxicity, such as chocolate or albuterol toxicity, with extreme sinus tachycardia, b-blocker therapy with IV esmolol or propranolol may be helpful to slow the rate.10 Esmolol has a very short half-life (,5 minutes); therefore, CRI is often used to manage the tachycardia. In a recent case series, the median esmolol CRI dose and duration were 50 ug/kg/min for 480 minutes in dogs.

Atrial Fibrillation Treatment of rapid atrial fibrillation typically involves a rate control strategy together with the management of the underlying heart disease. The most commonly used medication to slow the ventricular response rate of atrial fibrillation in a critical care setting is diltiazem, either IV or oral contingent on the rate, severity of the clinical signs, and availability. If dilated cardiomyopathy and congestive heart failure are also diagnosed, then digoxin is often added to the diltiazem as the heart rate will be more effectively controlled with the combination of digoxin and diltiazem than with either medication alone.30 If severe concurrent ventricular arrhythmias need to be suppressed in addition to controlling the atrial fibrillation rate, then sotalol or amiodarone could be used alternatively. However, sotalol should be used with extreme caution in an animal with congestive heart failure as it may diminish myocardial function and worsen heart failure. A recent human trial evaluated the addition of IV magnesium sulfate in the early management of rapid atrial fibrillation.31 IV magnesium had a synergistic effect when combined with other drugs that block the AV node resulting in improved rate control. The target ventricular response rate for in-hospital management of atrial fibrillation in the dog is usually 160–180 beats per minute.32 Electrical cardioversion under general anesthesia is considered for lone atrial fibrillation or recent onset atrial fibrillation in a dog in the absence of severe underlying structural heart disease.

CHAPTER 49  Supraventricular Tachyarrhythmias

289

TABLE 49.2  Classification, Routes of Administration, and Dosages of Commonly Used

Medications in the Management of Supraventricular Tachyarrhythmias Beta Blockers Atenolol

Dog

PO

0.25–1.0 mg/kg q12h (start low, up titrate)

Cat

PO

6.25 mg q12h, up to 12.5 mg q12h

D/C

IV

0.1 mg/kg slow bolus; up to 0.5 mg/kg (max effect 2–4 min)

CRI

0.05–0.1 mg/kg/min

D/C

IV

0.02 mg/kg slow bolus over 5 min (can repeat 3–4 times as needed)

Dog

IV

2 mg/kg slow bolus up to 4 times; 30–50 mcg/kg/min CRI

Cat

IV

0.2–0.75 mg/kg slow bolus up to 3 times

Dog

IV

2–4 mg/kg slow bolus up to maximum 16 mg/kg; 25–40 mcg/kg/min CRI

Dog

PO

1.5–3 mg/kg q12h

Cat

PO

2 mg/kg q12h

Dog

IV aqueous

2–5 mg/kg bolus over 10 min, CRI 0.8 mg/kg/hr 3 6 hr, then 0.4 mg/kg/hr if needed

Dog

PO

10 mg/kg q12hr 3 7d, then 5–7 mg/kg q12h 3 7–14 d, then 5–7 mg/kg q24h

D/C

IV

0.1 mg/kg slow bolus up to 3 times (dilute in saline give over 5 min)

D/C

CRI

0.125–0.3 mg/kg/hr (start low, up titrate as needed)

Dog

PO

0.5–1.5 mg/kg q8h (start low, up titrate)

Cat

PO

7.5 mg q8h

Diltiazem XR (Dilacor) extendedrelease inner tablets inside capsule

Dog

PO

3–6 mg/kg q12h

Cat

PO

30 mg q12h

Cardizem CD (extended release)

Cat

PO

10 mg/kg q24h (fill small part of #4 capsule with granules)

Dog

IV

0.0025 mg/kg slow bolus q1h 3 4 doses (total 0.01mg/kg) loading

Dog

PO

0.003–0.005 mg/kg q12h; 6–8 hr post-pill levels 0.5–1.2 ng/m

Dog

IV

0.3 mEq/kg slow over 15 min

Esmolol Propranolol Sodium Channel Blockers Lidocaine Procainamide Potassium Channel Blockers Sotalol Amiodarone Calcium Channel Blockers Diltiazem (regular)

Other Drugs Digoxin Magnesium chloride

REFERENCES 1. Santilli R, Moise NS, Pariaut R, Perego M: Supraventricular tachycardias. In Electrocardiography of the dog and cat, diagnosis of arrhythmias, ed 2, Milano, 2018, Edra, pp 160-201. 2. Pedro B, Fontes-Sousa AP, Gelzer AR: Canine atrial fibrillation: pathophysiology, epidemiology and classification, Vet J 265:105548, 2020. doi:10.1016/j.tvjl.2020.105548. 3. Pariaut R: Atrial fibrillation: current therapies, Vet Clin North Am Small Anim Pract 47:977-988, 2017. 4. Côté E, Harpster NK, Laste NJ, et al: Atrial fibrillation in cats: 50 cases (1979-2002), J Am Vet Med Assoc 225:256-260, 2004. 5. Finster ST, DeFrancesco TC, Atkins CE, Hansen BD, Keene BW: Supraventricular tachycardia in dogs: patient characteristics, clinical findings and prognosis, J Vet Emerg Crit Care 18:503-510, 2008. 6. Morelli A, Ertmer C, Westphal M, et al: Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial, JAMA 310:1683-1691, 2013. 7. Brown SM, Beesley SJ, Lanspa MJ, et al: Esmolol infusion in patients with septic shock and tachycardia: a prospective, single-arm, feasibility study, Pilot Feasibility Stud 4:132, 2018. 8. Khataminia M, Najmeddin F, Najafi A, et al: Effect of heart rate control with amiodarone infusion on hemodynamic and clinical outcomes in septic shock patients with tachycardia: a prospective, single-arm clinical study, J Pharm Health Care Sci 7:37, 2021.

9. Beer KS, Balakrishnan A, Hart SK: Successful management of persistent tachycardia using esmolol in 2 dogs with septic shock, J Vet Emerg Crit Care 29(3):326-330, 2019. 10. Verschoor-Kirss M, Rozanski E, Rush JE: Use of esmolol for control of tachycardia in 28 dogs and cats (2003-2020), J Vet Emerg Crit Care 32:243-248, 2022. doi:10.1111/vec.13162. 11. Tyszko C, Bright JM, Swist SL: Recurrent supraventricular arrhythmias in a dog with atrial myocarditis and gastritis, J Small Anim Pract 48: 335-338, 2007. 12. Wright KN, Atkins CE, Kanter R: Supraventricular tachycardia in four young dogs, J Am Vet Med Assoc 208(1):75-80, 1996. 13. Wright KN, Connor CE, Irvin HM, Knilans TK, Webber D, Kass PH: Atrioventricular accessory pathways in 89 dogs: clinical features and outcome after radiofrequency catheter ablation, J Vet Intern Med 32:15171529, 2018. 14. Santilli RA, Mateos Pañero M, Porteiro Vázquez DM, Perini A, Perego M: Radiofrequency catheter ablation of accessory pathways in the dog: the Italian experience (2008-2016), J Vet Cardiol 20:384-397, 2018. 15. Vollmar C, Vollmar A, Keene B, Fox PR, Reese S, Kohn B: Irish wolfhounds with subclinical atrial fibrillation: progression of disease and causes of death, J Vet Cardiol 24:48-57, 2019. 16. Wright KN, Mehdirad AA, Giacobe P, Grubb T, Maxson T: Radiofrequency catheter ablation of atrioventricular accessory pathways in three dogs with subsequent resolution of tachycardia-induced cardiomyopathy, J Vet Intern Med 13:361-71, 1999.

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17. Foster SF, Hunt GB, Thomas SP, Ross DL, Pearson MRB, Malik R: Tachycardiainduced cardiomyopathy in a young Boxer dog with supraventricular tachycardia due to an accessory pathway, Aust Vet J 84:326-331, 2006. 18. Santilli RA, Spadacini G, Moretti P, et al: Radiofrequency catheter ablation of concealed accessory pathways in two dogs with symptomatic atrioventricular reciprocating tachycardia, J Vet Cardiol 8:157-165, 2006. 19. Umana E, Solares CA, Alpert MA: Tachycardia-induced cardiomyopathy, Am J Med 114:51-55, 2003. 20. Katritsis DG, Josephson ME: Differential diagnosis of regular, narrowQRS tachycardias, Heart Rhythm 12:1667-1676, 2015. 21. Kotadia ID, Williams SE, O’Neill M: Supraventricular tachycardia: an overview of diagnosis and management, Clin Med 20:43-47, 2020. 22. Santilli RA, Perego M, Crosara S, et al: Utility of 12-lead electrocardiogram for differentiating paroxysmal supraventricular tachycardias in dogs, J Vet Intern Med 22:915-923, 2008. 23. Santilli RA, Diana A, Baron Toaldo M: Orthodromic atrioventricular reciprocating tachycardia conducted with intraventricular conduction disturbance mimicking ventricular tachycardia in an English Bulldog, J Vet Cardiol 14(2):363-370, 2012. 24. Johnson MS, Martin M, Smith P: Cardioversion of supraventricular tachycardia using lidocaine in five dogs, J Vet Intern Med 20:272-276, 2006. 25. Smith GD, Fry MM, Taylor D, Morgans A, Cantwell K: Effectiveness of the Valsalva manoeuvre for reversion of supraventricular tachycardia, Cochrane Database Syst Rev 2015(2):CD009502, 2015.

26. Ceylan E, Ozpolat C, Onur O, Akoglu H, Denizbasi A: Initial and sustained response effects of 3 vagal maneuvers in supraventricular tachycardia: a randomized, clinical trial, J Emerg Med 57(3):299-305, 2019. 27. Smith DN, Schober KE: Effects of vagal maneuvers on heart rate and Doppler variables of left ventricular filling in health cats, J Vet Cardiol 15:33-40, 2013. 28. Wright KN, Schwartz DS, Hamlin R: Electrophysiologic and hemodynamic responses to adenosine, diltiazem and esmolol in dogs, J Vet Intern Med 12:201, 1998. 29. Seo J, Spalla I, Porteiro Vázquez DM, Luis Fuentes V, Tinson E, Connolly DJ: Rhythm disturbances associated with lidocaine administration in four dogs with supraventricular tachyarrhythmias, J Vet Emerg Crit Care 32:106-112, 2022. 30. Gelzer AR, Kraus MS, Rishniw M, et al: Combination therapy with digoxin and diltiazem controls ventricular rate in chronic atrial fibrillation in dogs better than digoxin or diltiazem monotherapy: a randomized crossover study in 18 dogs, J Vet Intern Med 23:499-508, 2009. 31. Bouida W, Beltaief K, Msolli MA, et al: Low-dose magnesium sulfate versus high dose in the early management of rapid atrial fibrillation: randomized controlled double-blind study (LOMAGHI Study), Acad Emerg Med 26(2):183-191, 2019. 32. Gelzer AR, Kraus MS, Rishniw M: Evaluation of in-hospital electrocardiography versus 24-hour Holter for rate control in dogs with atrial fibrillation, J Small Anim Pract 56:456-462, 2015.

50 Ventricular Tachyarrhythmias Romain Pariaut, DVM, DACVIM (Cardiology), DECVIM-CA (Cardiology)

KEY POINTS • Wide QRS complex tachycardia with atrioventricular dissociation, fusion beats, and capture beats are electrocardiographic features diagnostic of ventricular tachycardia (VT). • Clinical signs secondary to VT are determined by its rate and duration. • The most common noncardiac causes of VT are hypoxemia, electrolyte imbalances (hypokalemia), acid-base disorders, and drugs.

INTRODUCTION There are many challenges associated with the management of ventricular tachycardia (VT), the main one being the identification of animals that will benefit from treatment. We treat VT because of the presence of clinical signs or because we presume that the arrhythmia impacts cardiac function or indicates an imminent risk of sudden cardiac death. However, identifying the animals that will respond to and benefit from antiarrhythmic therapy remains very challenging in clinical practice.

DEFINITIONS Physiologically, specialized ventricular cells known as Purkinje fibers play the role of surrogate pacemakers when the sinus and atrioventricular nodes fail to function appropriately, resulting in a ventricular escape rhythm (also known as idioventricular rhythm) at a rate of approximately 30 to 40 beats/min in dogs and 60 to 130 beats/min in cats.1,2 Three arrhythmogenic mechanisms known as enhanced automaticity, triggered activity, and reentry (Box 50.1) may affect Purkinje cells or any excitable ventricular tissue and result in VT.3 Ventricular tachycardia is defined as three or more consecutive ventricular beats occurring at a rate faster than 160 to 180 beats/min. This lowest cutoff rate is chosen arbitrarily, and some clinicians may choose a minimum rate of 200 beats/min for VT. Clinically significant VTs typically have rates of 250 beats/min and above in dogs and cats.4 If a ventricular rhythm is faster than the physiologic idioventricular rhythm but slower than VT, it is called accelerated idioventricular rhythm (AIVR). The rate of AIVR is within 10% the rate of the underlying sinus rhythm. Therefore, both rhythms are seen competing on a surface electrocardiogram (ECG) because the faster rhythm inhibits the slower one, a property known as overdrive suppression.2 In addition to rate, an important feature of VT is duration because both determine the clinical consequences of the arrhythmia. VT is described as nonsustained if it lasts less than 30 sec and sustained if it is longer. Nonsustained VT is usually asymptomatic because of its short duration. The terms incessant VT and VT storm are used to describe recurrent episodes of

• The most common cardiac diseases associated with clinical VT are arrhythmogenic cardiomyopathy in Boxers and dilated cardiomyopathy in Doberman Pinschers. • Antiarrhythmic medications have not been shown to prevent sudden death. • Antiarrhythmic therapy is initiated if clinical signs associated with VT are present.

sustained VT during a 24-hour period. VT storm is a life-threatening emergency. Ventricular tachycardia can also be classified based on its morphology: monomorphic, pleomorphic, and polymorphic. Monomorphic ventricular tachycardia is characterized by a single QRS complex morphology. The electrophysiologic mechanism is typically reentry. This is the most common type of VT seen in clinical practice. Importantly, some variation in morphology during tachycardia does not rule out a reentrant mechanism. Whenever two or more morphologies occur during the same episode of tachycardia, it is called pleomorphic. Polymorphic ventricular tachycardia has a variable morphology on a beat-to-beat basis. It usually also displays a variation of the R-R intervals5 (Fig. 50.1A–B).

ELECTROCARDIOGRAPHIC DIAGNOSIS In the ICU, VT is first suspected on physical examination or detected on a continuous ECG monitor. Confirmation of VT relies on a goodquality six-lead surface ECG recording with the patient placed in right lateral recumbency. VT is identified as a broad QRS tachycardia with complexes wider than 0.07 sec in dogs and 0.04 sec in cats. Each QRS complex is followed by a large T wave, directed opposite to the QRS deflection. The challenge of ECG interpretation is to differentiate VT from supraventricular tachycardias (SVTs) with wide QRS complexes because of delayed conduction of the electrical impulse within the ventricles. Delayed ventricular conduction results from a structural bundle branch block, a functional or rate-related bundle branch block, or rarely an accessory atrioventricular pathway causing preexcitation.5 However, it is important to remember that VT is much more common than broad QRS complex SVT in dogs and cats. Moreover, the ECG should not be evaluated without prior knowledge of the animal’s medical history, clinical presentation, and cardiac function. A dog presenting for syncope and an arrhythmia is more likely to have ventricular tachycardia than supraventricular tachycardia; Boxers and Doberman Pinschers usually have VT. Syncope is very uncommon with SVT.

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BOX 50.1  Electrophysiologic Mechanisms of Ventricular Tachycardia Reentry: Requires an impulse to leave a point of departure and return to its starting point with a sufficient delay that the cardiac tissue has recovered its excitability. It usually circles around an area of nonconductive tissue (fibrosis, vessel). Shortening of the refractory period and slow conduction favor this self-perpetuating mechanism. Enhanced automaticity: Any myocardial cell can acquire the property of spontaneous depolarization when its environment is altered. Its membrane potential becomes less negative, which gives it the ability to generate an action potential similar to that of the sinus node. Triggered activity: Results from small membrane depolarizations that appear after and are dependent on the upstroke of the action potential. They trigger an action potential when they reach the threshold potential. When they occur during the process of repolarization, they are called early afterdepolarizations (EADs), and when they occur after full repolarization, they are called delayed afterdepolarizations (DADs). Hypokalemia and drug-induced prolongation of the QT segment increase the risk of EADs. DADs occur secondary to intracellular calcium overload associated with sustained tachycardia and digoxin toxicity.

The three most reliable diagnostic criteria of VT are atrioventricular dissociation, fusion beats, and capture beats (Fig. 50.2). Atrioventricular dissociation is demonstrated when P waves are occasionally seen on the ECG tracing but are not related to ventricular complexes. These P waves reflect atrial activity independently from the ventricle. On occasion, apparent atrioventricular association may be seen, or ventricular beats can conduct in a retrograde fashion to the atrium in a 1:1 ratio. Therefore, signs of atrioventricular association do not completely rule out VT. Although rarely effective, vagal maneuvers can be done to slow the atrioventricular conduction, revealing P waves associated to the QRS complexes in case of SVT. Fusion beats and capture beats are seen with paroxysmal VT and AIVR. Fusion beats result from the summation of a ventricular impulse and a simultaneous supraventricular impulse resulting in a QRS complex of intermediate morphology and preceded by a P wave (unless there is concurrent atrial fibrillation or the P wave is hidden within the previous T wave). A capture beat is a supraventricular impulse conducting through the normal conduction pathways to the ventricle during an episode of VT or AIVR. This complex occurs earlier than expected and is narrow if the conduction system is intact.4 In order to detect rare fusion and capture beats, it might be necessary to obtain long recordings (5-minute duration or longer). The regularity of the rhythm is a less accurate criterion because VT can be slightly irregular. However, a broad QRS tachycardia with R-R intervals that vary on a beat-to-beat basis, sometimes changing by 100 msec or more, is atrial fibrillation with aberrant ventricular conduction until proven otherwise (Fig. 50.1C). Although VT is frequently encountered in animals hospitalized in the ICU, atrial fibrillation remains the most common arrhythmia in dogs with underlying cardiac disease and should be considered in the presence of a tachyarrhythmia. Atrial fibrillation and left bundle branch block are common consequences of dilated cardiomyopathy, which combines enlargement of the left atrium and severe remodeling of the left ventricle.

CAUSES OF VENTRICULAR TACHYCARDIA Once VT is confirmed on a surface ECG, the possible causes for the initiation and maintenance of the arrhythmia must be identified. This knowledge will help to plan an effective treatment protocol and predict

A

B

C Fig. 50.1  Electrocardiographic recordings from three dogs with wide QRS complex tachycardia (paper speed 50 mm/sec; amplitude 5 mm/mV). A, Monomorphic VT at a rate of 300 bpm. There is only one QRS complex morphology during the tachycardia and the rhythm is regular. Note that the QRS complexes have a negative polarity in lead I and positive polarity in II, III, and aVF, which is not consistent with a left bundle branch block; therefore, the rhythm is more likely VT than a wide QRS complex SVT. B, Paroxysmal polymorphic VT during sinus rhythm in a young German Shepherd dog with inherited ventricular arrhythmia. The QRS morphology is variable during the episode of VT. C, Atrial fibrillation with a left bundle branch block in a dog with dilated cardiomyopathy. Although the QRS complexes are wide, the rhythm is irregular (RR intervals variable), which indicates atrial fibrillation. Note that the QRS complexes have a positive polarity in lead I, II, III and aVF, which is consistent with a left bundle branch block.

the short-term and long-term prognoses. It is useful to differentiate cardiac from noncardiac causes of VT.

Noncardiac Causes of Ventricular Tachycardia Ventricular cells are sensitive to hypoxemia, electrolyte and acid-base imbalances, sympathetic stimulation, and various drugs. These changes

CHAPTER 50  Ventricular Tachyarrhythmias

F

V

p

C

293

S

Fig. 50.2  Electrocardiographic recording from a dog; paper speed is 25 mm/sec. There is ventricular tachycardia (V) at a rate of 150 beats/min. P waves (P) not related to the wide QRS complexes (V) indicate atrioventricular (AV) dissociation. There are fusion beats (F) with an intermediate morphology and capture beats (C). Note that the PR interval of the capture beat is prolonged compared with a normal sinus beat (S). It results from retrograde depolarization of the AV node by the preceding ventricular impulse and secondary slowing of the propagation of the sinus impulse in a partially refractory node, a phenomenon known as concealed AV conduction.

typically affect the passive and energy-dependent ion exchanges across the cellular membrane of the myocyte during the initiation and propagation of the action potential. Hypokalemia is the most commonly reported electrolyte disturbance responsible for or contributing to VT. It increases phase 4 depolarization, increasing spontaneous automaticity, and prolongs the action potential duration, which promotes arrhythmias from triggered activity.6 Similar arrhythmias result from hypomagnesemia because magnesium is necessary for proper functioning of the sodium-potassium ATP pump, which maintains normal intracellular potassium concentration. Hypocalcemia and hypercalcemia are also responsible for ventricular arrhythmias. Increased adrenergic tone potentiates arrhythmias through various mechanisms. In the ICU, drugs with sympathetic or sympatholytic activity are commonly used and should be stopped when possible to assess their role in the perpetuation of VT. The mechanism of AIVR that develops after gastric dilatation torsion surgery, after a trauma, or in some animals with pancreatitis, large hepatic and liver masses is uncertain, but likely shares similarities with the reperfusion arrhythmia observed in human patients after an acute myocardial infarction. Key chemical mediators of reperfusion arrhythmias include circulating free oxygen radicals and cytokines, which are responsible for complex changes at the ion channel level.3,6 It is also important to evaluate the potential proarrhythmic effects of all the medications given to a patient with VT. Some drugs can induce a prolongation of the QT segment. Prolongation of the QT segment reflects delayed cardiac cell membrane repolarization and indicates a risk of ventricular arrhythmia from triggered activity. Antiarrhythmic drugs such as procainamide and sotalol, but also domperidone, cisapride, chlorpromazine, and erythromycin, are known to prolong the QT segment. Bradycardia and hypokalemia add to this effect on repolarization and increase the risk of VT.7 Oxygen therapy, identification and correction of all electrolyte disturbances, and discontinuation of proarrhythmic medications are the initial and necessary first steps in the treatment of all patients with VT.

Cardiac Causes of Ventricular Tachycardia In most patients with rapid VT an echocardiogram is indicated as soon as possible to identify an underlying cardiac disease as the cause for the arrhythmia. In humans the association of sustained VT and heart failure is an indicator of an increased risk for sudden death from arrhythmia, and this is probably true in our patients as well.8 Identification of cardiac disease may help to elaborate an effective treatment strategy, to know what to expect from the intervention, and to give the most accurate prognosis to the owner. Today there is valuable information on some breed-specific VTs. As most animals with AIVR typically do not have an underlying cardiac condition, an echocardiogram is only indicated if they become hemodynamically unstable. VT is on occasion observed in patients with cardiac tumors (with or without associated tamponade), myocarditis, endocarditis, and ischemia. VT is an important part of the clinical picture of dilated cardiomyopathy in some breeds. The prevalence of ventricular arrhythmias was 21% in a pool of breeds with dilated cardiomyopathy, 16% in Newfoundlands, and 92% in Doberman Pinschers. The natural history of the disease has been studied extensively in Doberman Pinschers. There is an occult stage of the disease with no clinical signs but with echocardiographic indicators of left ventricular dysfunction and a risk of sudden death of approximately 30%. It can last 2 to 4 years. In the overt stage of the disease, congestive heart failure is present, and the risk of sudden death is about 30% to 50%. In Doberman Pinschers, most ventricular ectopies have a right bundle branch block morphology in lead II of the surface ECG, indicating their origin in the left ventricle.9 Cardiomyopathy of Boxers is known as arrhythmogenic right ventricular cardiomyopathy (ARVC). It is an adult-onset disease with a concealed form characterized by occasional ventricular ectopies only, followed by an overt form with VT associated with exercise intolerance and collapse. On occasion myocardial failure is observed. In ARVC, ventricular ectopies typically have a left bundle branch block morphology, indicating their right-sided origin.10 Recently it was shown that the disease not only affects the right ventricle but also the left ventricle and the atria. It is therefore not unusual to observe VT originating

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from the left side and supraventricular arrhythmias in Boxers.11,12 A form of ARVC has been described in English Bulldogs. In this breed, the disease is centered in the region of the right ventricular outflow tract, which is the site of origin of the ventricular tachycardia. On echocardiogram, an aneurysmal dilation in the right ventricular outflow tract can be found in the right parasternal short axis view. In ARVC, the VT is monomorphic. It supports reentry as the arrhythmia mechanism. In addition, the QRS complexes have a left bundle branch block morphology, that is, they are wide and have a positive polarity in lead I, II, III, and aVF.13 An inherited ventricular arrhythmia has been identified in some German Shepherds. In the most severe form of the disease, these dogs have a propensity for sudden death until 18 months of age. The form of VT responsible for sudden death is polymorphic, rapid (.300 beats/min), unsustained, and usually during periods of slow heartrate or after a pause. It is caused by triggering of the arrhythmia mechanism by activity with early afterdepolarizations as the initiating factor. Some dogs are mildly affected and only have occasional single ventricular premature beats, but other dogs have runs of paroxysmal VT throughout the day. The risk for sudden arrythmias is estimated at 50% in young German Shepherds that have VT.14 Dogs with severe subaortic stenosis and pulmonic stenosis are prone to syncope and sudden death. VT progressing to ventricular fibrillation may contribute to some of these episodes. In cats, VT may be seen in association with idiopathic hypertrophic cardiomyopathy and with concentric hypertrophy secondary to hypertension, hyperthyroidism, and transient myocardial thickening (i.e., acute myocarditis).

PRACTICAL APPROACH TO VENTRICULAR TACHYCARDIA TREATMENT When to Treat? Once the ECG diagnosis of a sustained and rapid ventricular rhythm (.200–220 bpm) is made, decision to treat should be based on the hemodynamic status of the animal. The question to ask is: Is this patient stable or unstable? An animal that is hemodynamically unstable will usually be managed with intravenous antiarrhythmics, and occasionally electrical cardioversion (see Chapter 204, Cardioversion). Conversely, an animal that is presented with sustained VT but is hemodynamically stable, in other words, alert and responsive, does not necessarily require urgent termination of the tachycardia. For example, it is not uncommon for Boxers with ARVC to experience hour-long episodes of sustained VT at rates exceeding 250 bpm but to only display mild signs of discomfort. Dogs are more likely to be stable with tachycardia if their underlying cardiac function is normal and their vasomotor reflex (i.e., their ability to maintain blood pressure despite a reduced cardiac output) is intact. It is also important to differentiate true VT from AIVR. AIVR is a rhythm that does not require treatment as it is not fast and occurs in response to systemic diseases rather than primary cardiopathies. AIVR is common after motor vehicle-related trauma, gastric dilation-volvulus, or metabolic imbalances. It resolves spontaneously, with no antiarrhythmic medications, within 4 days.15 Another ECG finding that is commonly thought to indicate a high risk for sudden cardiac death and a need for treatment is the R-on-T phenomenon. R-on-T describes the superimposition of an ectopic beat on the T wave of the preceding beat, also known as the “vulnerable period.” Some observations suggest that it may represent an increased risk for VT and sudden death from ventricular fibrillation. In an experimental study in dogs, ventricular fibrillation could be reliably induced by delivering an electrical impulse on the peak of the T wave

seen from lead II on the surface ECG.16 However, ECG recordings collected from implantable cardiac defibrillators in human patients showed that ventricular tachycardia was as likely to be initiated by a late-occurring ventricular premature complex than from one originating on the T wave.17 In veterinary patients, strong evidence is lacking and the presence of R-on-T alone cannot justify treatment.

Which Antiarrhythmics for the Unstable Patient with Ventricular Tachycardia? Drugs typically accessible to veterinarians include lidocaine, procainamide, b-blockers, sotalol, and aqueous amiodarone (Table 50.1). There is very limited evidence-based data about acute VT treatment in veterinary medicine. Drug selection and the order in which they are administered when VT does not terminate after the first drug injection is mainly based on drug availability and clinicians’ personal experience and comfort level with specific antiarrhythmics. In theory, procainamide might be the best treatment option for monomorphic VT because it can not only stop VT but also slow its rate whenever it fails to terminate it. A reduction in VT rate might be enough to improve the hemodynamic status of the animal. In people lidocaine consistently demonstrates a lower efficacy than procainamide.18 Because of its binding kinetic to the sodium channel, lidocaine is not able to block a sufficient number of sodium channels unless the tachycardia is very fast or the cells are already partially depolarized during myocardial ischemia and hypoxia. However, there are some limitations in extrapolating results from human studies to veterinary patients. Dogs have a much faster heart rate during VT than people, and therefore lidocaine may be a better option for dogs. The author reviewed medical records of 20 dogs with monomorphic VT that received lidocaine; successful

TABLE 50.1  Drug Dosages Class 2 (b-blockers) • Atenolol Oral: 0.2 to 1 mg/kg q12-24 h (D,C) • Esmolol IV bolus: 0.2 to 0.5 mg/kg over 1 min (D,C) Class 1A (Na-blockers) • Procainamide IV bolus: 5 to 15 mg/kg over 1 min. CRI 20 to 50 mg/kg/min (D) IV bolus: 1 to 2 mg/kg (C) Class 1B (Na-blockers) • Lidocaine IV bolus: 2 mg/kg over 30 sec. Maximum 3 boluses. CRI 30 to 70 mg/ kg/min (D) IV bolus: 0.25-0.5 mg/kg (C) Class 2 and 3 (K-blockers) • Sotalol Oral: 1 to 3 mg/kg q12h (D,C) Class 3 and 1,2,4 • Amiodarone Oral: Loading dose of 10 to 30 mg/kg q24h for 2–14 days. Maintenance dose of 6 to 15 mg/kg q24h (D) IV (Aqueous formulation): 2 mg/kg bolus over 10 min, followed by 0.8 mg/kg/hr for 6 hours, then 0.4 mg/kg/hr for 18 hours (Sanders R, et al. 2016) (D) C, cat; D, dog.

CHAPTER 50  Ventricular Tachyarrhythmias cardioversion occurred in 17 of them. While many VT episodes will stop after lidocaine injection, a small number of dogs will not respond, and their clinical status may deteriorate if the vasodilatory effect of lidocaine combined to a low cardiac output from the tachycardia result in hypotension. Importantly lidocaine does not slow VT rate. Lidocaine is also indicated for the treatment of the less common episodes of polymorphic VT, especially the type seen in young German Shepherd dogs. Aqueous amiodarone, which has only recently become available, may at the current time be considered a third antiarrhythmic option after one or both of the more commonly used antiarrhythmics have failed to control VT.19 See Chapter 168, Antiarrhythmic Agents for more information. The variable response to antiarrhythmics highlights that not all animals and ventricular tachycardias are the same. An alternative to antiarrhythmics is electrical cardioversion, which is the recommended treatment in people with hemodynamically unstable monomorphic VT and of unstable polymorphic VT.

Which Antiarrhythmics for the Stable Patient with Ventricular Tachycardia? Whenever an animal is stable despite VT, it is not always necessary to use intravenous agents. The author commonly uses oral sotalol in Boxers presented with VT secondary to ARVC. Many dogs respond successfully within 2 to 3 hours after oral sotalol administration.

Ventricular Tachycardia in Cats Tachyarrhythmias that require treatment rarely occur in cats. If oral administration of a drug is possible, sotalol is a good option. Esmolol is a short-acting b-blocker that can help control sympathetically driven VTs such as those associated with thyrotoxic disease in cats, but its negative inotropic effects may be too pronounced in some patients and cause cardiovascular collapse. Lidocaine should be used with caution as cats are more likely to develop neurologic side effects from the drug.

Other Treatments Anesthesia Sedation and anesthesia may be used to decrease high sympathetic output contributing to VT maintenance. Sedation is recommended for the management of VT storm in human patients. Benzodiazepines and short-acting anesthetics such as propofol have been used.20

Electrical Therapies Rapid pacing is indicated to overdrive suppress some ventricular arrhythmias. In German Shepherds with inherited ventricular arrhythmias, bradycardia and pauses increase the risk of polymorphic VT. Therefore, atrial or ventricular pacing can be used to maintain a regular and faster heart rate, which prevents periods of slower rate and initiation of VT. Finally, when antiarrhythmics fail to control VT, the arrhythmia can be terminated via synchronized electrical cardioversion or defibrillation. See Chapter 204, Cardioversion and Chapter 205, Defibrillation for further discussion of electrical therapies for the management of ventricular tachyarrhythmias.

Postintervention Monitoring Because the response to antiarrhythmic agents cannot be predicted, continuous ECG monitoring is essential after the medication is started

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and for a minimum of 24 hours. It will give valuable information on the control of the arrhythmia and the possible proarrhythmic effects of the drugs. Twenty-four-hour Holter recording is more adapted to long-term management of the arrhythmia.

REFERENCES 1. Opie LH: Pacemakers, conduction system and electrocardiogram. In Opie LH, editor: The heart physiology, from cell to circulation, ed 3, Philadelphia, 1998, Lippincott-Raven. 2. Kittleson MD: Diagnosis and treatment of arrhythmias (dysrhythmias). In Kittleson MD, Kienle RD, editors: Small animal cardiovascular medicine, ed 1, St Louis, 1998, Mosby. 3. Marriott HJL, Boudreau Conover M: Arrhythmogenic mechanisms and their modulation. In Marriott HJL, Boudreau Conover M, editors: Advanced concepts in arrhythmias, ed 3, St Louis, 1998, Mosby. 4. Santilli RA, Moise NS, Pariaut R, Perego M: Ventricular arrhythmias. In Santilli RA, Moise NS, Pariaut R, Perego M, editors: Electrocardiography of the dog and cat. Diagnosis of arrhythmias, ed 2, Milano, 2018, Edra. 5. Brady WJ, Skiles J: Wide QRS complex tachycardia: ECG differential diagnosis, Am J Emerg Med 17(4):376-381, 1999. 6. Opie LH: Ventricular arrhythmias. In Opie LH, editor: The heart physiology, from cell to circulation, ed 3, Philadelphia, 1998, Lippincott-Raven. 7. Finley MR, Lillich JD, Gilmour RF Jr, Freeman LC: Structural and functional basis for the long QT syndrome: relevance to veterinary patients, J Vet Intern Med 17(4):473-488, 2003. 8. Huikuri HV, Castellanos A, Myerburg RJ: Sudden death due to cardiac arrhythmias, N Engl J Med 345(20):1473-1482, 2001. 9. O’Grady MR, O’Sullivan ML: Dilated cardiomyopathy: an update, Vet Clin North Am Small Anim Pract 34(5):1187-1207, 2004. 10. Meurs KM: Arrhythmogenic right ventricular cardiomyopathy in the Boxer dog: an update, Vet Clin North Am Small Anim Pract 47(5):1103-1111, 2017. 11. Oxford EM, Danko CG, Kornreich BG, et al: Ultrastructural changes in cardiac myocytes from Boxer dogs with arrhythmogenic right ventricular cardiomyopathy, J Vet Cardiol 13(2):101-113, 2011. 12. Vila J, Pariaut R, Moise NS, et al: Structural and molecular pathology of the atrium in boxer arrhythmogenic right ventricular cardiomyopathy, J Vet Cardiol 19(1):57-67, 2017. 13. Santilli RA, Bontempi LV, Perego M: Ventricular tachycardia in English bulldogs with localised right ventricular outflow tract enlargement, J Small Anim Pract 52(11):574-580, 2011. 14. Moïse NS, Gilmour RF Jr, Riccio ML, Flahive WF Jr: Diagnosis of inherited ventricular tachycardia in German shepherd dogs, J Am Vet Med Assoc 210(3):403-410, 1997. 15. Snyder PS, Cooke KL, Murphy ST, Shaw NG, Lewis DD, Lanz OI: Electrocardiographic findings in dogs with motor vehicle-related trauma, J Am Anim Hosp Assoc 37(1):55-63, 2001. 16. Pariaut R, Saelinger C, Vila J, et al: Evaluation of shock waveform configuration on the defibrillation capacity of implantable cardioverter defibrillators in dogs, J Vet Cardiol 14(3):389-398, 2012. 17. Fries R, Steuer M, Schäfers HJ, Böhm M: The R-on-T phenomenon in patients with implantable cardioverter-defibrillators, Am J Cardiol 91(6):752-755, 2003. 18. Horowitz LN, Josephson ME, Farshidi A, Spielman SR, Michelson EL, Greenspan AM: Recurrent sustained ventricular tachycardia 3. Role of the electrophysiologic study in selection of antiarrhythmic regimens, Circulation 58(6):986-997, 1978. 19. Levy NA, Koenigshof AM, Sanders RA: Retrospective evaluation of intravenous premixed amiodarone use and adverse effects in dogs (17 cases: 2011-2014), J Vet Cardiol 18(1):10-14, 2016. 20. Eifling M, Razavi M, Massumi A: The evaluation and management of electrical storm, Tex Heart Inst J 38(2):111-121, 2011.

51 Myocarditis Sara R. Brethel, DVM, Meg M. Sleeper, VMD, DACVIM (Cardiology)

KEY POINTS • Myocarditis is an inflammatory process involving the heart. Inflammation may include the myocytes, interstitium, or the vascular tree. • Myocarditis has been associated with a wide variety of diseases. Infectious agents (viral, bacterial, protozoal) may cause myocardial

damage by myocardial invasion, production of myocardial toxins, or activation of immune-mediated disease. • Myocarditis has also been associated with physical agents (doxorubicin), underlying metabolic disorders (uremia), toxins (heavy metals), or physical agents (heat stroke).

Myocarditis is a rare cause of heart failure in dogs and cats. Clinical features vary, including those of asymptomatic patients who may have electrocardiographic abnormalities and patients with or without heart enlargement, systolic dysfunction, or even full-blown congestive heart failure (CHF). The patient’s history (i.e., environment and exposure) is often critical in determining likely risk and suggesting appropriate diagnostic tests. Clinical reports of canine myocarditis are most common in immunocompromised or immunonaïve patients.

myocarditis, suggesting these pathogens are not commonly associated with DCM or active myocarditis in the dog.3 Distemper virus–associated cardiomyopathy with a mild inflammatory infiltrate has been produced by experimental infection of immunonaïve puppies.4 Natural infection with West Nile virus was associated with myocarditis in a wolf and a dog in 2002, the third season of the West Nile virus epidemic in the United States.5 Viral genomic DNA has also been identified in feline myocardial tissue from patients with hypertrophic cardiomyopathy, DCM, and restrictive cardiomyopathy, suggesting that viral myocarditis may be a factor in these feline-acquired diseases.1 Feline myocarditis has been diagnosed in cats infected with feline immunodeficiency virus (FIV) that were also affected by hypertrophic cardiomyopathy (HCM).6 While the specific causal relationship between the myocarditis, FIV, and HCM is unknown, it is an important consideration when managing patients.

INFECTIOUS MYOCARDITIS Viral Myocarditis Numerous viruses have been associated with myocarditis in humans. In dogs, viral myocarditis appears most commonly in immunonaïve patients, and the virus most commonly associated with the disease is parvovirus. However, at this time the entity appears to be very rare. In the late 1970s and early 1980s, when the parvovirus pandemic first was recognized, puppies did not receive maternal antibodies, and very young puppies developed a fulminant infection with acute death as a result of pulmonary edema when exposed to the virus. Older puppies (2 to 4 months) often died subacutely from CHF, but others developed a milder myocarditis and later developed dilated cardiomyopathy (DCM), usually as young adults. Basophilic intranuclear inclusion bodies are found in the myocardium of acutely affected younger puppies but may be absent in older puppies.1 Older dogs typically have gross myocardial scarring. Rare cases of parvovirus-induced myocarditis have been reported since the early to mid-1980s, and despite vaccinations it remains an important cause of myocardial damage in dogs.2 Rarely other viruses have been associated with myocarditis in dogs. In 2001 Maxson and others evaluated myocardial tissue from 18 dogs with an antemortem diagnosis of DCM and 9 dogs with a histopathologic diagnosis of myocarditis based on a polymerase chain reaction analysis to screen for canine parvovirus, adenovirus types 1 and 2, and herpesvirus. Canine adenovirus type 1 was identified in the myocardium of only one dog with DCM and none of the dogs with

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Protozoal Myocarditis Chagas Disease Chagas disease is caused by Trypanosoma cruzi, a protozoal parasite. Chagas disease is the leading cause of DCM in humans in Latin America, but it is rare in North America. In North American dogs, Chagas disease occurs most commonly in Texas and Louisiana. There have been no reported feline cases in North America. The organism is transmitted by an insect vector (Reduviidae), and reservoir hosts include rodents, raccoons, opossums, dogs, cats, and humans. The trypomastigote is the infective stage, but on entering host cells the organism enters the reproductive stage and becomes an amastigote. Amastigotes multiply until the host cell ruptures.1,7 Dogs with clinical Chagas disease have an acute or a chronic syndrome. In the acute stage, circulating trypomastigotes may be seen in a thick blood smear, and most dogs are presented for veterinary care because of the sudden development of signs of right-sided heart failure (ascites, tachycardia, lethargy). Dogs with chronic Chagas disease may enter a quiescent stage free of clinical signs for months or even years. Nervous system damage often causes ataxia and weakness in these patients.1,7

CHAPTER 51  Myocarditis

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Fig. 51.1  Electrocardiogram from a mixed breed dog with trichinosis involving the heart. The dog was brought in for collapse caused by complex arrhythmias. Note the ventricular escape beats. An underlying supraventricular tachycardia is likely as well.

Bacterial and Other Causes of Myocarditis Bacterial myocarditis is possible whenever bacteremia or sepsis is present, with the most common agents being staphylococcal and streptococcal species.1 Myocarditis associated with Citrobacter koseri, an opportunistic pathogen of immunosuppressed human patients, has been described in two 12-week-old sibling Boxer puppies.8 Tyzzer disease (infection with Bacillus piliformis) was associated with severe necrotizing myocarditis in a wolf-dog hybrid puppy.5 Two cases of feline Streptococcus canis myocarditis have been reported,9,10 along with one case of Salmonella typhimurium in an 8-month neutered male domestic shorthair.11 Myocarditis has also been recognized secondary to rickettsial organisms such as Rickettsia rickettsii, Ehrlichia canis, and various Bartonella species.1 Myocarditis has been noted in 2 of 12 dogs diagnosed with endocarditis, 11 of which were seroreactive to Bartonella vinsonii subspecies.12 Lymphoplasmacytic myocarditis was observed in 8 cats experimentally infected with Bartonella; however, clinical signs consistent with heart disease were not observed.13 Bartonellae have been implicated as an important cause of endocarditis in humans and dogs. Recently, the organism has also been linked to endocarditis in the cat, and a few case reports suggest cats may develop myocarditis associated with Bartonellae as well.14,15 Lyme disease (secondary to infection by the spirochete Borrelia burgdorferi) has been implicated as a cause of myocarditis in dogs, but documented cases are rare. There is a cases series describing 10 Boxer puppies that suffered from fatal pyogranulomatous myocarditis thought to be secondary to Borrelia burgdorferi.16 Clinical signs are often vague and nonspecific, and serologic testing is not a reliable method to determine active infection.1 In humans, Lyme myocarditis may be due to direct toxic effects or immune-mediated mechanisms, and the disease is usually selflimiting.17 Fungal infections of the myocardium are extremely rare but have occurred in immunocompromised patients.1 A group of cats was described with transient fever and depression that appeared to be infectious in nature. Postmortem examination revealed microscopic lesions consistent with myonecrosis and an inflammatory cell infiltrate. A viral etiology was suspected, but no organism was identified.9 In a retrospective study reviewing 1472 feline necropsies over a 7-year period, 37 cases were diagnosed with endomyocarditis. The cats with endomyocarditis had a mean age at death of 3.4 years, and 62% of them had a history of a stressful event 5 to 10 days before being brought for treatment. Interstitial pneumonia was present in 77% of the cats at postmortem examination. Special stains for bacteria and fungi were negative.18 Parasitic agents can also lead to myocarditis. Toxoplasma gondii bradyzoites can encyst in the canine myocardium, resulting in chronic infection. Eventually the cysts rupture, leading to myocardial necrosis and hypersensitivity reactions.1 Toxoplasmosis has also been reported to be a cause of myocarditis in cats.19 Neospora caninum can infect multiple tissues, including the heart, peripheral muscles, and central nervous system. Clinical signs associated with noncardiac tissues typically predominate; however, collapse and sudden death have been

reported in affected dogs.1 Infestation with Trichinella spiralis is a common cause of mild myocarditis in humans.17 The parasite has been associated with at least one case of canine myocarditis complicated by arrhythmias (Fig. 51.1).20

NONINFECTIOUS MYOCARDITIS Doxorubicin Toxicity Doxorubicin cardiotoxicity may be manifested as arrhythmias, myocardial failure, or both. Cardiotoxicity is dosage-dependent, irreversible, and more common at cumulative doses exceeding 250 mg/m2.21 However, in one study in which only two doses of 30 mg/m2 were administered, 3% of dogs developed cardiomyopathy.1,9 The time to onset of CHF in affected dogs is highly variable. Although pathologic changes have been seen in the feline myocardium after administration, no antemortem echocardiographic or electrocardiographic changes associated with doxorubicin toxicity have been reported in this species to date. Other causes of noninfectious myocarditis, although rarely recognized in veterinary medicine, include allergic reactions, systemic diseases such as vasculitis, and physical agents such as radiation or heat stroke.17 Numerous chemicals and drugs may lead to cardiac damage and dysfunction. A severe reversible DCM has been observed in humans with pheochromocytoma,17 and similar findings have been observed in experimental animals receiving prolonged infusions of norepinephrine.17 Myocardial coagulative necrosis was found in a dog that died suddenly after an episode of severe aggression, restraint, and sedation for grooming.22 Myocardial lesions were presumed to be caused by catecholamine toxicity. A canine case of immune-mediated polymyositis with cardiac involvement has also been reported.23

DIAGNOSIS Definitive diagnosis, unless the history clearly suggests myocarditis (e.g., doxorubicin toxicity), is elusive (Box 51.1). Supportive clinical laboratory tests include leukocytosis or eosinophilia, particularly in parasitic or allergic myocarditis. Elevated cardiac troponin I levels

BOX 51.1  Characteristics Suggestive of

Myocarditis

• History suggests it is possible (e.g., oncology patient receiving doxorubicin, dog lives in Texas) • Unusual signalment for heart disease (e.g., Irish Setter, German Shepherd) • Supportive electrocardiographic findings include conduction abnormalities or arrhythmias • Supportive echocardiographic findings include myocardial dysfunction (which may be regional) with or without heart enlargement • Supportive clinical laboratory findings include leukocytosis, eosinophilia, and elevated cardiac troponin I levels

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Fig. 51.2  Photograph showing a bioptome used for endomyocardial biopsies via intravascular access.

provide evidence of myocardial cell damage in patients suspected of having myocarditis. If a high suspicion for Chagas disease is present, serologic examination for T. cruzi is diagnostic. Demonstration of a rising titer is also helpful to establish the diagnosis of myocarditis associated with T. gondii or N. caninum. Viral and rickettsial testing should be performed if indicated. Blood cultures should be performed if a bacterial cause is suspected. Thoracic radiographs may show normal heart size or heart enlargement with or without evidence of CHF. The electrocardiographic findings may also be varied, and ventricular arrhythmias or conduction disturbances are common. Echocardiography most often demonstrates systolic dysfunction, either global or regional, and cardiac chambers may be normal or increased in size. Endomyocardial biopsy (the gold standard for diagnosis of myocarditis in humans)24 may allow definitive antemortem diagnosis (Fig. 51.2). However, a focal myocarditis can still be missed because the sample size is small. At postmortem examination, immunohistochemistry or electron microscopy can confirm the diagnosis of N. caninum infection.25 Gross pathology findings may be insignificant, or they may reveal cardiac dilation or ventricular hypertrophy, focal petechiae, and myocardial abscesses.1 Specific findings depend on the underlying etiology. Focal or diffuse myocarditis is definitively diagnosed by histopathology when myocyte necrosis, degeneration, or both are associated with an inflammatory infiltrate.1

TREATMENT Most recommendations for managing myocarditis in dogs and cats are extrapolated from human medicine or research with models of viral myocarditis. Supportive care is the first line of therapy for patients with myocarditis. In those patients with signs of CHF, typical therapy should include preload reduction with diuretics and afterload reduction with angiotensin-converting enzyme inhibitors (see Chapter 42, Ventricular Failure and Myocardial Infarction). Digoxin increased the expression of proinflammatory cytokines and increased mortality in experimental myocarditis, so it should be used with caution and at low dosages.24 Intravenous inotropic therapy in the form of dobutamine can be useful if significant systolic dysfunction is present. Alternatively, pimobendan may be beneficial to address systolic dysfunction and reduce afterload.26 Eliminating unnecessary medications may help reduce the possibility of allergic myocarditis. Results of recent studies suggest that immunosuppression is not routinely helpful in myocarditis patients,

but it may have an important role in patients with myocardial dysfunction caused by systemic autoimmune disease.24 Nonsteroidal antiinflammatory agents are contraindicated during the acute phase of myocarditis in humans (during the first 2 weeks) because they increase myocardial damage. However, they appear to be safe later in the course of disease.17 In a murine model of viral myocarditis, angiotensinconverting enzyme inhibition (with captopril) was beneficial. Similarly, interferon therapy is beneficial in the experimental model of myocarditis and may be useful clinically.17 When diagnosis of acute Chagas disease is possible, several agents appear to inhibit T. cruzi; however, by the time a diagnosis is made, it is often too late for this approach. Patients with chronic Chagas disease are treated symptomatically for CHF. Similarly, successful treatment has been reported using several agents in dogs affected with N. caninum myocarditis, but severely ill dogs often die.1 Clindamycin is the drug of choice for treating clinical toxoplasmosis in dogs and cats; however, significant damage to the heart is irreversible.25 In one report of a cat with presumed toxoplasmosis, signs of heart disease did resolve with clindamycin treatment.27 Dogs with evidence of bacteremia should be treated with antibiotics pending culture and susceptibility results. Empiric treatment should be effective against staphylococcal and streptococcal species (see Chapter 91, Bacterial Infections). Animals with suspected rickettsial disease should be treated with doxycycline (5 to 10 mg/kg PO or IV q12-24h) pending titer results.

REFERENCES 1. Fox PR, Sisson DK, Moise S: Textbook of canine and feline cardiology principles and clinical practice, ed 2, Philadelphia, 1999, W.B. Saunders. 2. Ford J, McEndaffer L, Renshaw R, Molesan A, Kelly K: Parvovirus infection is associated with myocarditis and myocardial fibrosis in young dogs, Vet Pathol 54(6):964-971, 2017. 3. Maxson TR, Meurs KM, Lehmkuhl LB, Magnon AL, Weisbrode SE, Atkins CE: Polymerase chain reaction analysis for viruses in paraffin-embedded myocardium from dogs with dilated cardiomyopathy or myocarditis, Am J Vet Res 62(1):130-135, 2001. 4. Higgins RJ, Krakowka S, Metzler AE, Koestner A: Canine distemper virusassociated cardiac necrosis in the dog, Vet Pathol 18(4):472-486, 1981. 5. Lichtensteiger CA, Heinz-Taheny K, Osborne TS, Novak RJ, Lewis BA, Firth ML: West Nile virus encephalitis and myocarditis in wolf and dog, Emerg Infect Dis 9(10):1303-1306, 2003. 6. Rolim VM, Casagrande RA, Wouters ATB, Driemeier D, Pavarini SP: Myocarditis caused by feline immunodeficiency virus in five cats with hypertrophic cardiomyopathy, J Comp Pathol 154:3-8, 2016. 7. Kittleson MD: Small animal cardiovascular medicine textbook, ed 2, St. Louis, 2005, Mosby. 8. Cassidy JP, Callanan JJ, McCarthy G, O’Mahony MC: Myocarditis in sibling boxer puppies associated with Citrobacter koseri infection, Vet Pathol 39(3):393-395. 2002. 9. Sura R, Hinckley LS, Risatti GR, Smyth JA: Fatal nectrotising fasciitis and myositis in a cat associated with Streptococcus canis, Vet Rec 162:450-453, 2008. 10. Matsuu A, Kanda T, Sugiyama A, Murase T, Hikasa Y: Mitral stenosis with bacterial myocarditis in a cat, J Vet Med Sci 69(11):1171-1174, 2007. 11. Vercelli A, Lo Cicero E, Pazzini L: Salmonella typhimurium endocarditis and myocarditis in a cat, Case Rep Vet Med. 2019:7390530, 2019. 12. Breitschwerdt EB, Atkins CE, Brown TT, Kordick DL, Snyder PS: Bartonella vinsonii subsp. berkhoffii and related members of the alpha subdivision of the Proteobacteria in dogs with cardiac arrhythmias, endocarditis, or myocarditis, J Clin Microbiol 37(11):3618-3626, 1999. 13. Kordick DL, Brown TT, Shin K, Breitschwerdt EB: Clinical and pathologic evaluation of chronic Bartonella henselae or Bartonella clarridgeiae infection in cats, J Clin Microbiol 37(5):1536-1547, 1999.

CHAPTER 51  Myocarditis 14. Nakamura RK, Zimmerman SA, Lesser MB: Suspected Bartonella-associated myocarditis and supraventricular tachycardia in a cat, J Vet Cardiol 13(4): 277-281, 2011. 15. Varanat M, Broadhurst J, Linder KE, Maggi RG, Breitschwerdt EB: Identification of Bartonella henselae in 2 cats with pyogranulomatous myocarditis and diaphragmatic myositis, Vet Pathol 49(4):608-611, 2012. 16. Detmer SE, Bouljihad M, Hayden DW, Schefers JM, Armien A, Wünschmann A: Fatal pyogranulomatous myocarditis in 10 Boxer puppies, J Vet Diagn Invest 28(2):144-149, 2016. 17. Liu, Peter Baughman KL: Myocarditis. In Braunwald E, Bonow RO, editors: Braunwald’s heart disease: a textbook of cardiovascular medicine, Vol 14, ed 9, Philadelphia, 2008, Elsevier, pp 1595-1610. 18. Stalis IH, Bossbaly MJ, Van Winkle TJ: Feline endomyocarditis and left ventricular endocardial fibrosis, Vet Pathol 32(2):122-126, 1995. 19. Dubey JP, Carpenter JL: Histologically confirmed clinical toxoplasmosis in cats: 100 cases (1952-1990), J Am Vet Med Assoc 203(11):1556-1566, 1993. 20. Sleeper MM, Bissett S, Craig L: Canine trichinosis presenting with syncope and AV conduction disturbance, J Veterinary Intern Med 20:1228-1231, 2006.

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21. Hallman BE, Hauck ML, Williams LE, Hess PR, Suter SE: Incidence and risk factors associated with development of clinical cardiotoxicity in dogs receiving doxorubicin, J Vet Intern Med 33:783-791, 2019. 22. Pinson DM: Myocardial necrosis and sudden death after an episode of aggressive behavior in a dog, J Am Vet Med Assoc 211(11):1371-1373, 1997. 23. Warman S, Pearson G, Barrett E, Shelton GD: Dilatation of the right atrium in a dog with polymyositis and myocarditis, J Small Anim Pract 49(6):302-305, 2008. 24. Feldman AM, McNamara D: Myocarditis, N Engl J Med 343:1388-1398, 2000. 25. Green CE: Infectious diseases of the dog and cat, ed 4, St. Louis, 2012, Saunders. 26. Boswood A, Häggström J, Gordon SG, et al: Effect of pimobendan in dogs with preclinical myxomatous mitral valve disease and cardiomegaly: the EPIC study—a randomized clinical trial, J Vet Intern Med 30(6): 1765-1779, 2012. 27. Simpson KE, Devine BC, Gunn-Moore D: Suspected toxoplasma–associated myocarditis in a cat, J Feline Med Surg 7(3):203-208, 2005.

52 Cardiac Biomarkers Mark A. Oyama, DVM, MSCE, DACVIM (Cardiology)

KEY POINTS • Biomarkers are biological substances that measure the presence or severity of a given disease state. • The most common cardiac biomarkers used in the critical care setting are N-terminal B-type natriuretic peptide (NT-proBNP), which is primarily used for the differentiation of cardiac versus noncardiac causes of respiratory distress, and cardiac troponin-I (cTnI), which is primarily used for the detection of myocardial injury.

• Biomarker testing is most valuable in patients wherein traditional diagnostics yield equivocal results or definitive diagnostic tests are not immediately available. • Cardiac biomarker testing comes with substantial limitations; careful patient selection and proper interpretation of results are important.

Biomarkers are biological substances found in body fluids or tissues that signify health or disease or the likelihood of the presence or absence of a particular condition or disease. The biomarker itself might not be directly related with clinical signs or state. Rather, many are markers of the underlying clinicopathological processes. Broadly, biomarkers provide diagnostic and prognostic information and represent a potential means to guide and modify treatment. In animals with acute or subacute critical illness, the diagnostic value of biomarkers is a subject of considerable interest, and in particular, the differentiation of cardiac versus noncardiac causes of respiratory distress. The utility of various cardiac biomarkers in this and other conditions that require intensive care is the focus of this chapter.

called N-terminal pro-BNP (NT-proBNP) that possesses a longer halflife than BNP. NT-proBNP is produced by the body in a 1:1 relationship with BNP but is less susceptible to degradation, which avoids the use of special collection, handling, and storage methods that accompany assays for BNP. Assays for ANP and its related forms are typically limited to research applications. The main use of NT-proBNP and BNP assay in emergency and critical care medicine relates to the differentiation of cardiac versus noncardiac causes of respiratory distress in both the dog3-5 and cat.6-9 Other uses, less applicable to the critically ill patient, include detection of asymptomatic (occult) underlying heart disease, prognostication, and as a potential guide to therapy.

BLOOD-BASED CARDIAC BIOMARKERS

Troponin refers to a group of three related molecules located on the actin filaments of myocytes that represent the site of calcium binding and subsequent initiation of actin-myosin cross-bridging and cardiac contraction. Two of these troponin molecules, cardiac troponin-I (cTnI) and cardiac troponin-T (cTnT), are specific to cardiac (as opposed to skeletal) muscle and have clinical utility.10 The third troponin molecule is not specific to cardiac muscle and therefore not used in clinical practice. Smooth muscle does not contain troponin; hence, both cTnI and cTnT are highly specific to cardiac muscle. In health, cardiac troponin is tightly bound to the actin backbone, and circulating concentrations of cTnI and cTnT are extremely low to undetectable. In cases of myocyte injury, ischemia, or necrosis, cTnI and cTnT are displaced from the actin filament and leak into the circulation where they can be detected by a variety of different assays. The circulating concentrations of cTnI and cTnT are proportional to the extent of myocardial injury. Most veterinary troponin studies focus on cTnI, which tends to be released in greater amounts following injury compared with cTnI. Many assays designed for the detection of human cTnI cross-react with cTnI from both dogs and cats,11-15 which facilitates clinical utility, and a variety of veterinary laboratories offer cTnI testing for veterinary species. In contrast, assay of cTnT is limited to a single manufacturer, and the amount of data pertaining to use in dogs and cats is minimal. For these reasons, the remainder of this chapter focuses on cTnI. In the emergency setting, cTnI assay is used to detect

The two most commonly measured blood-based cardiac biomarkers in critically ill patient include a form of B-type natriuretic peptide (BNP) and cardiac troponin. The biology of these two biomarkers is distinct and influences their clinical utility.

B-type Natriuretic Peptide The myocardium produces a variety of peptides that help regulate blood volume by stimulating natriuresis and diuresis. Stretch of the atrial and ventricular myocardium induces production and release of these natriuretic peptides into circulation where they eventually bind to natriuretic peptide receptors located in a wide variety of tissues, including the kidney. There are two main natriuretic peptides involved in cardiorenal function, including atrial natriuretic peptide (ANP), which is primarily produced in atrial myocardium, and BNP, which is produced in both the atrial and ventricular myocardium. BNP is sometimes referred to as brain natriuretic peptide as it was first isolated from porcine brain tissue. The diagnostic value of ANP and BNP and their associated forms lies in the fact that their circulating concentrations are correlated with the presence and severity of cardiac overload, and in particular, diastolic filling pressures.1,2 The half-lives of both ANP and BNP are short, which complicates clinical detection. The most extensively studied natriuretic peptide assay detects a related form of BNP

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Cardiac Troponin

CHAPTER 52  Cardiac Biomarkers and quantify myocardial injury, help diagnose underlying heart disease, and in particular, myocarditis, and to provide prognosis, typically through use of serial testing.

CLINICAL USE OF NT-PROBNP AND BNP TESTING IN THE EMERGENCY SETTING As previously stated, one of the primary uses of NT-proBNP and BNP testing in the critical care setting is the differentiation of cardiac versus noncardiac causes of respiratory distress in both the dog and cat. Respiratory distress due to cardiac disease typically involves congestive heart failure (CHF), primarily either pulmonary edema or pleural effusion, and less commonly, ascites (see Part II, Respiratory Disorders). A hallmark of CHF is volume overload of the heart and circulatory system, resulting in increased production and release of NT-proBNP and BNP. In contrast, most noncardiac causes of respiratory distress, such as airway or pulmonary parenchymal disease, are not associated with increased cardiac pressure or volume, and production of NTproBNP and BNP is not reliably increased. As such, increased or normal plasma NT-proBNP and BNP concentrations are associated with CHF and noncardiac causes of respiratory distress, respectively. Previous studies6,7 in cats with respiratory distress reported that NTproBNP concentrations .200–277 pmol/L were highly sensitive and specific for CHF. Current commercial assay guidelines suggest that NT-proBNP .270 pmol/L supports a diagnosis of CHF, whereas NTproBNP ,100 pmol/L does not support a diagnosis of CHF in cats with respiratory distress. Previous studies in dogs3,4,16 indicated that NT-proBNP .1,158–2,447 pmol/L demonstrated high sensitivity and specificity for CHF in dogs with respiratory signs. Current commercial assay guidelines suggest that plasma NT-proBNP .1,800 pmol/L supports a diagnosis of CHF, whereas NT-proBNP ,900 pmol/L does not support a diagnosis of CHF in dogs with respiratory distress. Assay of NT-proBNP in the dog and cat involves collection of 1 ml of EDTA plasma that is separated into a plain glass (red-top) or plastic tube. One major limitation of reference laboratory NT-proBNP assays is the need to send out samples to the reference laboratory, which prohibits immediate point-of-care decision making in the emergency room. There are fewer studies17,18 examining BNP than studies examining NT-proBNP. Currently, a dog-specific BNP assay is commercially available and involves special collection and handling methods to prevent degradation of the BNP. Assay guidelines suggest that BNP .6 pg/ml is highly suggestive of a diagnosis of CHF in dogs with respiratory signs; values ,3 pg/ml indicate that CHF is an unlikely etiology of respiratory distress in these patients. Also available to emergency clinics is a cat-specific lateral flow enzyme-linked immunosorbent assay (ELISA) device that permits point-of-care semiquantitative measurement of feline NT-proBNP.19,20 The device is similar in design to devices that detect heartworm antigen and antibodies to Borrelia (Lyme), Ehrlichia, and Anaplasma spp. in dogs. The device utilizes a colorimetric assay in which three drops of serum or EDTA plasma are mixed with assay conjugate and pipetted into the sample well of the device. The device is then activated by pushing down on the plastic activator. After 10 minutes, if the color intensity of the patient sample spot is equal or greater than the intensity of the reference spot, this indicates an abnormally increased NT-proBNP. It is critical to note that the development and design of this point-of-care assay were not specifically intended to help differentiate cardiac vs. noncardiac causes of respiratory distress in cats. Rather, the assay was designed to detect moderate to severe occult (preclinical) cardiomyopathy in ostensibly healthy cats. As such, the NT-proBNP con­ centration at which the patient spot indicates a positive test is .100 pmol/L, which is considerably less than the recommended cut-off

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BOX 52.1  Interpretation of NT-proBNP Assay Results in Dogs and Cats Presenting to Emergency Services with Respiratory Distress in Which the Etiology is Unknown After Conventional Diagnostics Dog: ,900 pmol/L Cat: ,270 pmol/L

Likelihood of CHF is low. Noncardiac causes should be considered

Dog: 900–1,800 pmol/L

Reliable differentiation of etiology is not possible in this range of results

Dog: .1,800 pmol/L Cat: 270 pmol/L

Likelihood of CHF is high

Point-of-care feline NT-proBNP assay Positive Negative

Likelihood of CHF is moderately increased Likelihood of CHF is low

value of .270 pmol/L associated with the reference laboratory test. Thus, the specificity of a positive point-of-care test for CHF in cats with respiratory distress is typically lower than the reference laboratory assay. Previous studies9,21,22 indicate that a positive point-of-care test has a sensitivity ranging from 93% to 100% and specificity of 72%–87% for diagnosis of CHF. In the author’s experience, the point-of-care NTproBNP test is a good test to rule out CHF in cats, meaning a negative test makes the likelihood of CHF very remote, whereas a positive test is of less clinical utility. Finally, point-of-care or reference assay of NT-proBNP concentration of pleural effusions from cats might be helpful in differentiating the cause of respiratory distress.21-23 This might be particularly useful when thoracocentesis is possible but venipuncture is difficult because of patient compliance, cardiopulmonary instability, or poor venous access. Studies indicate that a positive point-of-care NT-proBNP assay had sensitivity of 100% and specificity of 64% in cats. Due to the greater concentration of NT-proBNP in pleural effusion as compared to plasma, one study21 recommended that pleural effusion be diluted 1:1 with 0.9% saline prior to point-of-care testing, which resulted in sensitivity of 100% and specificity of 87%. When considering use of the point-of-care NT-proBNP test in cats with respiratory signs, regardless of whether using plasma, serum, or pleural effusion, the critical care provider is reminded that the test was not specifically intended for this use, and results should be interpreted in conjunction with the medical history, clinical findings, and other diagnostic results to avoid false-positive results. (Box 52.1).

CLINICAL USE OF CARDIAC TROPONIN IN THE EMERGENCY SETTING As previously stated, one of the primary uses of cTnI (and to a lesser extent, cTnT) assays in the critical care setting is to detect and quantify myocardial injury. Diseases or conditions associated with increased cTnI in dogs and cats are both numerous and wide-ranging. They involve primary cardiac and extracardiac causes, including cardiomyopathy, degenerative valve disease, myocarditis, infectious disease (i.e., Chagas, dirofilariasis, ehrlichiosis, leptospirosis), cardiac trauma, pancreatitis, heatstroke, hyperthyroidism, and neoplasia, among others.10 As a result, increased cTnI is sensitive to myocardial injury but nonspecific to the etiology. Cardiac troponin concentrations have prognostic value in cats with hypertrophic cardiomyopathy and dogs with degenerative valve

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PART IV  Cardiovascular Disorders

disease, dilated cardiomyopathy, and various other primary heart diseases.24-28 As such, patients with low cardiac troponin concentrations have better survival than those with increased values. In the author’s experience, the greatest value of cardiac troponin testing in the emergency or critical care setting is in dogs (and lesser so in cats) that present with clinically significant supraventricular or ventricular arrhythmias (including both tachyarrhythmias and bradyarrhythmias) of unknown etiology and are suspected of having myocarditis (see Chapter 51, Myocarditis). Myocarditis refers to the inflammation of the myocardium and can be caused by a wide range of infectious, toxic, metabolic, inflammatory and immune-mediated conditions. Definitive diagnosis of myocarditis requires endomyocardial biopsy, which is rarely performed. Increased cardiac troponin along with cardiac arrhythmias in the absence of a readily identifiable cause (i.e., degenerative valve disease, cardiomyopathy) is generally regarded as indicative of myocarditis, and should prompt a search for possible etiologies.29-31 In the author’s experience, dogs with suspected myocarditis possess cTnI concentrations that greatly exceed the upper reference value, by as much as 10 to 100 times, as opposed to more modest increases that commonly accompany CHF due to valvular disease or cardiomyopathy. The half-life of cTnI is relatively brief, approximately 2 hours. As such, serial measurements might offer information about the temporal nature of the cardiac injury.32,33 A rapidly decreasing cTnI concentration and resolution of clinical signs suggest a single episode of injury and hope for recovery in contrast to increasing or persistently elevated cTnI concentrations that suggest ongoing injury and a poorer prognosis. At the author’s institution, serial cTnI testing is often performed 5–14 days after the initial measurement. Over time, cTnI assays have improved their ability to detect very low serum or plasma concentrations of cTnI, and some of these assays have been labeled as “high sensitivity” assays.34 The exact definition of high sensitivity has not been established but is generally thought to include those assays that are capable of detecting cTnI down to 0.001 ng/ml or lower.34 The wide variety of assays require that different clinical laboratories establish their own reference values, which can complicate interpretation.35 In general, healthy dogs typically have cTnI ,0.1 ng/ml.

IMPORTANT LIMITATIONS AND CONSIDERATIONS INVOLVING CARDIAC BIOMARKER TESTING No diagnostic test, including cardiac biomarkers, is 100% accurate or free from inappropriate usage or interpretation. Important limitations of natriuretic peptide and cardiac troponin testing stem from the diverse nature of their production, release, and clearance; the presence of a substantial “grey zone” of assay results that add little diagnostic value; and overreliance on a diagnostic test result that is interpreted in isolation of other clinicopathological findings by clincians.36 The biology of BNP and cardiac troponin in the dog and cat has been previously reviewed.10,36,37 In virtually all emergent situations, the decision whether to test for cardiac biomarkers and the subsequent interpretation of results requires consideration of the complete clinical picture, including medical history, physical and diagnostic examination findings, and importantly, the likelihood that the patient being tested has the disease condition that motivated the biomarker test. Importantly, extracardiac disease can elicit biomarker detection in circulation. Renal disease, systemic hypertension, hyperthyroidism, and intravenous fluid administration, amongst other conditions, can increase BNP, NTproBNP, and cardiac troponin concentrations, resulting in false-positive diagnosis of CHF or primary heart disease. In general, NT-proBNP elevations due to extracardiac conditions are relatively modest and the greater the elevation, the more likely that there is underlying primary cardiac disease. As previously mentioned, increased cTnI is sensitive to

BOX 52.2  Clinical Scenarios in Which Cardiac Biomarker Testing Might be Most Useful • Definitive diagnostic testing is not immediately available or will not be safely tolerated. • Results of available testing are inconclusive. • Likelihood of condition under testing is approximately the same as the alternative condition. • Presence and severity of any comorbidities that can affect test results is known. • Test results are incorporated into the fuller clinical picture and do not form the sole basis for diagnosis.

myocyte injury but nonspecific as to the cause. Due to these considerations, assay guidelines include a grey zone of values in which the assay results are inconclusive as to the implication of primary cardiac disease as the cause of clinical signs. One often overlooked consideration involving cardiac biomarker testing is patient selection. In the author’s experience, this is the single greatest pitfall surrounding the appropriate use of cardiac biomarker testing. Natriuretic peptide and cardiac troponin assays are not definitive diagnostic assays in the sense of specifically identifying the presence or absence of a disease condition, as is the case for instance, of a heartworm antigen test. Rather, cardiac biomarker testing increases or decreases the likelihood of a particular condition relative to the clinician’s suspicion based on the totality of the clinical picture. As an example, diagnosis of CHF is best made by a conglomeration of many different findings, and the added value of biomarker testing should be considered prior to running the test. In an elderly small breed dog with a loud mitral murmur, substantial radiographic and echocardiographic left heart enlargement, increased respiratory rate and effort, and radiographs showing a perihilar alveolar pattern, the likelihood of CHF is extremely high, and NT-proBNP testing will add little. An increased concentration does little to further increase the confidence of diagnosis. In a coughing cat with mild chronic kidney disease, severe radiographic bronchial pulmonary pattern, and normal left atrial size on point-of-care fast thoracic ultrasound, the likelihood of CHF is low, and if NT-proBNP is tested, a mild elevation might cause the clinician to mistakenly pursue CHF. In both examples, the existing clinical picture is relatively clear and cardiac biomarker testing for purpose of diagnosis is unnecessary. Where cardiac biomarker testing is most valuable is when the pretest probabilities of the suspected and alternative conditions are both roughly 50% based on the existing information.36 This uncertainty might be due to the absence of certain diagnostic modalities, such as echocardiography, or equivocal results of existing diagnostics. In these instances, the results of cardiac biomarker testing can increase diagnostic accuracy (Box 52.2).

REFERENCES 1. Hori Y, Sano N, Kanai K, et al: Acute cardiac volume load-related changes in plasma atrial natriuretic peptide and N-terminal pro-B-type natriuretic peptide concentrations in healthy dogs, Vet J 185:317-321, 2010. 2. Asano K, Masuda K, Okumura M, et al: Plasma atrial and brain natriuretic peptide levels in dogs with congestive heart failure, J Vet Med Sci 61:523529, 1999. 3. Fox PR, Oyama MA, Hezzell MJ, et al: Relationship of plasma N-terminal pro-brain natriuretic peptide concentrations to heart failure classification

CHAPTER 52  Cardiac Biomarkers and cause of respiratory distress in dogs using a 2nd generation ELISA assay, J Vet Intern Med 29:171-179, 2015. 4. Fine DM, Declue AE, Reinero CR: Evaluation of circulating amino terminal-pro-B-type natriuretic peptide concentration in dogs with respiratory distress attributable to congestive heart failure or primary pulmonary disease, J Am Vet Med Assoc 232:1674-1679, 2008. 5. Oyama MA, Rush JE, Rozanski EA, et al: Assessment of serum N-terminal pro-B-type natriuretic peptide concentration for differentiation of congestive heart failure from primary respiratory tract disease as the cause of respiratory signs in dogs, J Am Vet Med Assoc 235:1319-1325, 2009. 6. Connolly DJ, Soares Magalhaes RJ, Fuentes VL, et al: Assessment of the diagnostic accuracy of circulating natriuretic peptide concentrations to distinguish between cats with cardiac and non-cardiac causes of respiratory distress, J Vet Cardiol 11(Suppl 1):S41-S50, 2009. 7. Fox PR, Oyama MA, Reynolds C, et al: Utility of plasma N-terminal probrain natriuretic peptide (NT-proBNP) to distinguish between congestive heart failure and non-cardiac causes of acute dyspnea in cats, J Vet Cardiol 11(Suppl 1):S51-S61, 2009. 8. Singletary GE, Rush JE, Fox PR, et al: Effect of NT-pro-BNP assay on accuracy and confidence of general practitioners in diagnosing heart failure or respiratory disease in cats with respiratory signs, J Vet Intern Med 26:542-546, 2012. 9. Ward JL, Lisciandro GR, Ware WA, et al: Evaluation of point-of-care thoracic ultrasound and NT-proBNP for the diagnosis of congestive heart failure in cats with respiratory distress, J Vet Intern Med 32:1530-1540, 2018. 10. Langhorn R, Willesen JL: Cardiac troponins in dogs and cats, J Vet Intern Med 30:36-50, 2016. 11. Langhorn R, Willesen JL, Tarnow I, et al: Evaluation of a high-sensitivity assay for measurement of canine and feline serum cardiac troponin I, Vet Clin Pathol 42:490-498, 2013. 12. Langhorn R, Yrfelt JD, Stjernegaard CS, et al: Analytical validation of a conventional cardiac troponin I assay for dogs and cats, Vet Clin Pathol 48:36-41, 2019. 13. Winter RL, Saunders AB, Gordon SG, et al: Analytical validation and clinical evaluation of a commercially available high-sensitivity immunoassay for the measurement of troponin I in humans for use in dogs, J Vet Cardiol 16:81-89, 2014. 14. Adin DB, Oyama MA, Sleeper MM, et al: Comparison of canine cardiac troponin I concentrations as determined by 3 analyzers, J Vet Intern Med 20:1136-1142, 2006. 15. Oyama MA, Solter PF: Validation of a commercially available human immunoassay (AccuTnI, Beckman Coulter, Inc.) for the measurement of canine cardiac troponin-I, J Vet Intern Med 17:437, 2003. 16. Oyama MA, Fox PR, Rush JE, et al: Clinical utility of serum N-terminal pro-B-type natriuretic peptide concentration for identifying cardiac disease in dogs and assessing disease severity, J Am Vet Med Assoc 232:14961503, 2008. 17. Schellenberg S, Grenacher B, Kaufmann K, et al: Analytical validation of various immunoassays for the quantification of cardiovascular peptides in dogs, Vet J 178:85-90, 2008. 18. DeFrancesco TC, Rush JE, Rozanski EA, et al: Prospective clinical evaluation of an ELISA B-type natriuretic peptide assay in the diagnosis of congestive heart failure in dogs presenting with cough or dyspnea, J Vet Intern Med 21:243-250, 2007. 19. Machen MC, Oyama MA, Gordon SG, et al: Multi-centered investigation of a point-of-care NT-proBNP ELISA assay to detect moderate to severe occult (pre-clinical) feline heart disease in cats referred for cardiac evaluation, J Vet Cardiol 16:245-255, 2014.

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20. Harris AN, Beatty SS, Estrada AH, et al: Investigation of an n-terminal prohormone of brain natriuretic peptide point-of-care ELISA in clinically normal cats and cats with cardiac disease, J Vet Intern Med 31:994-999, 2017. 21. Wurtinger G, Henrich E, Hildebrandt N, et al: Assessment of a bedside test for N-terminal pro B-type natriuretic peptide (NT-proBNP) to differentiate cardiac from non-cardiac causes of pleural effusion in cats, BMC Vet Res 13:394, 2017. 22. Hezzell MJ, Rush JE, Humm K, et al: Differentiation of cardiac from noncardiac pleural effusions in cats using second-generation quantitative and point-of-care NT-proBNP measurements, J Vet Intern Med 30:536-542, 2016. 23. Humm K, Hezzell M, Sargent J, et al: Differentiating between feline pleural effusions of cardiac and non-cardiac origin using pleural fluid NTproBNP concentrations, J Small Anim Pract 54:656-661, 2013. 24. Langhorn R, Tarnow I, Willesen JL, et al: Cardiac troponin I and T as prognostic markers in cats with hypertrophic cardiomyopathy, J Vet Intern Med 28:1485-1491, 2014. 25. Borgeat K, Sherwood K, Payne JR, et al: Plasma cardiac troponin I concentration and cardiac death in cats with hypertrophic cardiomyopathy, J Vet Intern Med 28:1731-1737, 2014. 26. Hezzell MJ, Boswood A, Chang YM, et al: The combined prognostic potential of serum high-sensitivity cardiac troponin I and N-terminal proB-type natriuretic peptide concentrations in dogs with degenerative mitral valve disease, J Vet Intern Med 26:302-311, 2012. 27. Noszczyk-Nowak A: NT-pro-BNP and troponin I as predictors of mortality in dogs with heart failure, Pol J Vet Sci 14:551-556, 2011. 28. Oyama MA, Sisson DD: Cardiac troponin-I concentration in dogs with cardiac disease, J Vet Intern Med 18:831-839, 2004. 29. Keeshen TP, Chalkley M, Stauthammer C: A case of an unexplained eosinophilic myocarditis in a dog, J Vet Cardiol 18:278-283, 2016. 30. Church WM, Sisson DD, Oyama MA, et al: Third degree atrioventricular block and sudden death secondary to acute myocarditis in a dog, J Vet Cardiol 9:53-57, 2007. 31. Wesselowski S, Cusack K, Gordon SG, et al: Artificial cardiac pacemaker placement in dogs with a cohort of myocarditis suspects and association of ultrasensitive cardiac troponin I with survival, J Vet Cardiol 22:84-95, 2019. 32. Aona BD, Rush JE, Rozanski EA, et al: Evaluation of echocardiography and cardiac biomarker concentrations in dogs with gastric dilatation volvulus, J Vet Emerg Crit Care 27:631-637, 2017. 33. Langhorn R, Oyama MA, King LG, et al: Prognostic importance of myocardial injury in critically ill dogs with systemic inflammation, J Vet Intern Med 27:895-903, 2013. 34. Apple FS, Collinson PO, IFCC Task Force on Clinical Applications of Cardiac Biomarkers: Analytical characteristics of high-sensitivity cardiac troponin assays, Clin Chem 58:54-61, 2012. 35. Irvine KL, McLeish SA, Sarvani E, et al: Analytical quality assessment and method comparison of two immunoassays for the measurement of serum cardiac Troponin I in dogs and cats, Vet Clin Pathol 48(Suppl 1):70-77, 2019. 36. Oyama MA, Boswood A, Connolly DJ, et al: Clinical usefulness of an assay for measurement of circulating N-terminal pro-B-type natriuretic peptide concentration in dogs and cats with heart disease, J Am Vet Med Assoc 243:71-82, 2013. 37. Smith KF, Quinn RL, Rahilly LJ: Biomarkers for the differentiation of causes of respiratory distress in the dogs and cats: part 1—cardiac diseases and pulmonary hypertension, J Vet Emerg Crit Care 25:311-329, 2015.

53 Systemic Hypertension Edward S. Cooper, VMD, MS, DACVECC

KEY POINTS • Systemic hypertension is associated with several disease processes including acute and chronic kidney disease, hyperadrenocorticism, and hyperthyroidism. • Hypertension can result in end-organ injury, particularly in the renal, ocular, cardiovascular, and central nervous systems. • Diagnosis is based on the elevation of blood pressure and determining the underlying cause if one is present.

• Treatment is geared to a controlled reduction of blood pressure with agents such as calcium channel blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers, as well as addressing any predisposing disease(s).

NORMAL DETERMINANTS OF BLOOD PRESSURE

demand, muscle activity, vascular injury, and/or to circumvent systemic vascular control. Examples include vasodilatory substances such as nitric oxide (NO), histamine, prostacyclin, and carbon dioxide, as well as vasoconstrictive agents such as endothelin, thromboxane, and thrombin.1 While their effects are to meant to alter local vascular tone, excessive/systemic release can result in significant changes to SVR and thereby overall blood pressure.

Systemic arterial blood pressure provides the hydraulic force that drives blood flow and thereby significantly impacts tissue perfusion. More specifically, it is the force exerted by blood against any unit area of the vessel wall.1 Arterial blood pressure will vary depending on the phase of the cardiac cycle (systolic vs. diastolic), but it is the mean arterial pressure (MAP) that plays the biggest role in tissue perfusion.2 Systolic blood pressure (SBP), on the other hand, will reflect the peak pressure to which tissues are exposed. Understanding the main cardiovascular elements that determine blood pressure are essential to understanding the development of systemic hypertension (SHT). These factors can be represented by the so-called tree of life (Fig. 53.1). True of any fluid that is pumped through a closed system, pressure is primarily determined by the product of flow (cardiac output [CO]) and resistance (systemic vascular resistance [SVR]). CO, in turn, is a function of the volume of blood ejected with each contraction of the heart (stroke volume [SV]) times the number of contractions per minute (heart rate [HR]). The determinants of SV are preload (stretching of the ventricle prior to contraction, largely a function of venous return), contractility (force of ventricular contraction), and afterload (the force needed to overcome aortic pressure and achieve left ventricular outflow). HR, the other major contributor to CO, is dictated by the relative balance between input from the sympathetic nervous system (SNS) and parasympathetic nervous system. Regulation of SVR is another major factor that serves to determine MAP. Vascular tone, and thereby SVR, is affected by both systemic and local mediators that cause either vasoconstriction or vasodilation. Catecholamines released by the SNS are primarily responsible for basal systemic vascular tone, as well as the minute-to-minute regulation of blood pressure.2 Angiotensin II and vasopressin also have vasoconstrictive effects and play more of a role in long-term regulation of vascular tone. In addition to these systemic mediators, local factors can also serve to affect blood flow in response to changes in metabolic

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PATHOGENESIS OF SYSTEMIC HYPERTENSION The development of SHT typically involves dysregulation of the mechanisms described above, particularly regarding increased SVR (with or without a concurrent increase in circulating volume). Given the role of catecholamines in vasomotor tone and the contribution to sodium and water retention, excessive upregulation of the SNS can be a major contributor to hypertension. As cortisol plays a supportive role to the SNS and serves to increase vascular reactivity to catecholamines, unregulated release of glucocorticoids can be associated with SHT.3 Similarly, activation of the renin-angiotensin-aldosterone system (RAAS) can also play a significant role. Angiotensin II (ATII) is a potent vasoconstrictive agent, and along with aldosterone will promote sodium and water retention. Systemic increases in the production of local vasoconstrictive substances such as endothelin 1 and thromboxane or decreased production of vasodilatory mediators such as NO or prostacyclin would also serve to increase SVR.4 As such, various pathological triggers such as the stress response, acute and chronic kidney disease, heart disease, and effective circulating volume depletion can all lead to dysregulation, excessive activation, and increased risk of SHT. With kidney disease in particular, development of SHT is multifactorial. Progressive nephron loss can trigger RAAS activation in effort to increase GFR; ATII preferentially causes efferent arteriolar vasoconstriction (and increased glomerular filtration pressure). Decreased renal blood flow also triggers activation of the SNS, and chronic endothelial dysfunction results in decreased production of

CHAPTER 53  Systemic Hypertension

MAP = CO X SVR

SV

Preload

X

HR

Afterload Contractility

Local CO2 PGs NO Histamine Systemic Vasopressin angiotensin II SNS SNS vs. PNS

Fig. 53.1  The tree of life, representing the key physiological factors that determine mean arterial pressure (MAP). CO, cardiac output; CO2, carbon dioxide; HR, heart rate; NO, nitric oxide; PGs, prostaglandins; PNS, parasympathetic nervous system; SNS, sympathetic nervous system; SV, stroke volume; SVR, systemic vascular resistance.

NO. While increased sodium intake and primary vascular disease (such as atherosclerosis) seem to play a major in human hypertension,3 these are not common causes of SHT in dogs and cats.5-6

DEFINITIONS AND CAUSES OF SYSTEMIC HYPERTENSION SHT is typically categorized into three different groups or types: situational, idiopathic, and secondary.5 Situational hypertension represents an artificial elevation in blood pressure created by the stress of being in the hospital setting, patient handling, and the very act of obtaining blood pressure. This can be difficult to distinguish from true SHT, particularly as some patients may demonstrate this to a much greater degree than others. This can lead to a false diagnosis of SHT, with the potential to start unnecessary antihypertensive medications. Repeated measurement of blood pressure, evidence of target organ injury, and diagnosis of a disease process that predisposes to SHT may be helpful in distinguishing situational from SHT (see section below on diagnosis).5,7 The presence high blood pressure in the context of a known predisposing disease process is classified as secondary hypertension (Table 53.1).5 Among these, kidney disease is considered the most common cause.5-6 While previously this was thought to be primarily with chronic kidney disease (CKD), recent studies have shown a high incidence of SHT with acute kidney injury in both dogs (75%)8 and cats (58.7%)9 either at the time of admission or during hospitalization. Hyperadrenocorticism (dogs) and hyperthyroidism (cats) are

the next most common causes, with variable incidence reported. While diabetes mellitus is a very common disease, the incidence associated of SHT appears to be moderate in dogs (24%–67%)10-11 and very low in cats (0%–15%).12-13 Patients with pheochromocytoma (dogs) and hyperaldosteronism (cats) are very likely to have SHT, but these diseases are seen very rarely.14-16 Hypertension may also occur secondary to exposure to certain medications and sympathetic stimulant intoxications (Table 53.1). Idiopathic hypertension (formerly primary or essential) indicates the presence of SHT without a discernable underlying cause. This would ideally entail an extensive diagnostic work-up to rule out the diseases previously mentioned before this classification could be assigned (see diagnosis section below). While there have been more limited reports in dogs,17-18 this may be more common than was previously thought in cats, with reported incidence of up to 24%.19-20 As it is possible for subclinical disease to be present (such as kidney disease), these numbers may be an over-representation.7

ADVERSE EFFECTS ASSOCIATED WITH SYSTEMIC HYPERTENSION Regardless of the underlying process, SHT can have significant adverse effects resulting in target organ damage (TOD). Normally, local autoregulatory mechanisms help to maintain consistent blood flow to tissues despite changes in systemic blood pressure, primarily by modulating precapillary sphincter tone (Fig. 53.2).21 However, if systemic blood pressure is high enough, these mechanisms are exceeded, with resulting transmission to the microcirculatory unit and potential tissue damage. Proposed mechanisms for this injury include increased vascular permeability and edema, vessel rupture and hemorrhage, or excessive vasoconstriction and ischemic injury.22 The main organ systems affected by TOD include ocular, renal, neurologic, and cardiovascular.

Ocular Injury Hypertensive retinopathy can result in a number of clinical signs and can be one of the more apparent manifestations of TOD, with frequent reporting in both dogs and cats.23-25 The most common changes include retinal detachment, tortuous vessels, edema, retinal hemorrhage, acute blindness, and mydriasis (Fig. 53.3).5 While hypertensive retinopathy has been reported at SBP less than 180 mm Hg, the risk is much greater when this pressure is acutely exceeded.17,26 With treatment of hypertension there may be retinal reattachment, but visual acuity might not be regained.

TABLE 53.1  Diseases and Medications/

Diseases

Medications/Toxins

Chronic kidney disease

Glucocorticoids

Acute kidney disease

Mineralocorticoids

Diabetes mellitus

Erythropoiesis-stimulating agents

Hyperadrenocorticism

Phenylpropanolamine

Hyperthyroidism

Phenylephrine

Pheochromocytoma

Ephedrine/pseudoephedrine

Hyperaldosteronism

Cocaine Methamphetamine/amphetamine

Vessel dilation Tissue blood flow

Toxins Associated with the Development of Systemic Hypertension in Dogs and Cats5

305

Autoregulatory range

Vessel constriction

0

60 160 Mean arterial pressure (mm Hg)

Fig. 53.2  Autoregulation of tissue blood flow over a range of mean arterial pressure and associated vasodilation or vasoconstriction.

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PART IV  Cardiovascular Disorders

A

B Fig. 53.3  Feline fundus demonstrating multifocal petechial retinal hemorrhages (arrows) and diffuse retinal edema with multifocal areas coalescing to bullae formation (stars) retinal detachment and tortuous retinal vessels (A), and multifocal petechiae and subretinal edema (B) representing ocular target organ damage. Images courtesy of Eric Miller, DVM, MS, DACVO

Renal Injury The relationship between the kidneys and hypertension could be considered a vicious cycle. Both acute and CKD can cause hypertension, and hypertension can add to the progression of the underlying disease. Increased glomerular filtration pressure can promote glomerular sclerosis and an increase in albumin loss into Bowman’s capsule, which has been shown to worsen the severity of renal disease and increase mortality.27 In addition, autoregulatory mechanisms and tubuloglomerular feedback can serve to promote afferent arteriolar vasoconstriction, thus decreasing renal blood flow. Finally, intrarenal hypertension can also promote ischemic injury and release of inflammatory mediators, which can result in tubulointerstitial fibrosis.28

Neurologic Injury Hypertensive encephalopathy is another potential sequela to severe hypertension, particularly with sudden increases in SBP over 180 mm Hg.29 Clinical signs can include mentation change, disorientation, seizures, and vestibular signs (head tilt, nystagmus, ataxia). Acute vascular events (ischemic or hemorrhagic) can also occur and manifest similar clinical signs. As a potential way to distinguish between the two potential etiologies, hypertensive encephalopathy tends to improve with reduction in SBP, while neurological deficits caused by vascular events do not resolve as quickly.30

Cardiovascular Sequelae There can be several potential cardiovascular manifestations of SHT, including systolic murmurs and/or gallop heart sounds secondary to changes in flow dynamics. As SHT is typically associated with a significant increase in SVR and afterload, it can also be associated with left ventricular hypertrophy. However, in cats this may be difficult to distinguish from hypertrophic cardiomyopathy.5 Hypertensive cats may also be at an increased risk for congestive heart failure with fluid administration, but this is unlikely to occur spontaneously.5

DIAGNOSIS OF SYSTEMIC HYPERTENSION Clinical concern for the presence of SHT should largely stem from either evidence of TOD or the identification of a predisposing disease process (Table 53.1). Because of the potential to have falsely elevated values (situational hypertension, technical challenges), routine blood pressure monitoring is not recommended for patients ,9 years of age.5 However, given the increased likelihood of underlying diseases in older dogs and cats, annual screening would be reasonable in patients that are 9 years old.5 Ultimately, diagnosis of SHT requires the accurate determination of blood pressure in a patient with a clinical picture that fits the concern. With evidence of TOD, a single elevated measurement may warrant treatment, though in most other circumstances the presence SHT should be confirmed with multiple measurements.5 Consensus criteria have been established to classify SHT based on the risk of TOD, with SBP 180 carrying the greatest concern (Table 53.2).5 One of the biggest challenges/limitations in the diagnosis of SHT is consistent and reliable methodology for blood pressure measurement. While direct arterial pressure monitoring would be considered the gold standard,

TABLE 53.2  Classification of Hypertension

Based on Systolic Blood Pressure and the Risk of Target Organ Damage in Dogs and Cats5 Classification

Associated SBP

Normotensive (minimal TOD risk)

,140 mm Hg

Prehypertensive (low TOD risk)

140–159 mm Hg

Hypertensive (moderate TOD risk)

160–179 mm Hg

Severely hypertensive (high TOD risk)

180 mm Hg

SBP, systolic blood pressure; TOD, target organ damage.

CHAPTER 53  Systemic Hypertension this is often impractical and unnecessary in most patients. Further information regarding indirect blood pressure monitoring can be found elsewhere in this text (Chapter 181, Hemodynamic Monitoring) and in other resources.6,7,32 If not already determined, the presence of SHT should warrant a complete diagnostic evaluation for any underlying disease processes that need to be addressed as well. This should include complete blood count, serum biochemistry, and urinalysis as the initial screening. Based on these results, urine culture with susceptibility testing, urine protein to creatinine ratio, serum symmetric dimethylarginine concentration, serum thyroxine hormone concentration (cat), adrenal axis testing (dog), thoracic radiographs, and/or abdominal ultrasound may be warranted.5 If the index of suspicion is sufficient, serum/urine aldosterone (cats) or catecholamine (dogs) concentrations may be warranted.5

TREATMENT OF SYSTEMIC HYPERTENSION The decision to treat SHT should be based on confirmation of SBP in the categories of hypertensive (160–179 mm Hg) or severely hypertensive (180mm Hg). As most patients have developed SHT over time, more gradual control is acceptable along with treatment geared toward any underlying disease(s).5 However, the presence of TOD typically represents a hypertensive crisis in which case emergency intervention is warranted. Below is a brief overview of recommended approaches for both circumstances. Specific information about the mechanisms of action for the various antihypertensive medications, as well as more specific protocols, is provided elsewhere in the text (Chapter 149, Antihypertensives).

Hypertensive Crisis A hypertensive crisis constitutes the presence of severe hypertension (SBP 180 mm Hg) in conjunction with overt evidence of TOD (particularly ocular or neurological).5 These circumstances warrant immediate reduction in blood pressure; however, this needs to be done in an incremental and controlled fashion. Patients with chronic hypertension will have an adjusted autoregulatory set point such that a rapid reduction to normal blood pressure may result in reduced tissue perfusion. As such, a reduction in SBP of 10% over the first hour, and then 15% over the next several hours is recommended.5,32 In order to allow this titration, intravenous administration is preferred over oral. Potential treatment options include medications such as fenoldopam, nitroglycerine, labetalol, or hydralazine with frequent monitoring of blood pressure.5 This would be most effectively accomplished with continuous monitoring of direct arterial blood pressure, though this may be impractical in many clinic settings. Instead, serial monitoring with indirect modalities (oscillometric or Doppler) can help to track the impact of these medications. Patients with a significant increase in blood pressure but without evidence of TOD constitute a hypertensive urgency. In these circumstances oral medications with a faster onset of action may be sufficient, with hydralazine or amlodipine as the most likely choices.5

Chronic Management Long-term management of SHT entails addressing any predisposing disease processes (when identified) in addition to blood pressure control. For most owners and patients once daily dosing with a single agent would be ideal, but some patients will require multiple medications to achieve adequate blood pressure control.5 Target blood pressure initially should be ,160 mm Hg, and ultimately ,140 mm Hg, with the goal of reducing the risk of TOD.5 As vasodilation and blood pressure reduction may stimulate the RAAS system in many of these patients, concurrent inhibition of this pathway with angiotensin

307

converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) may be needed. While dietary salt restriction plays a major in control of SHT in human patients, the association in veterinary patients is less clear. A diet high in sodium and chloride should be avoided, but a diet with significant reductions will not likely be of benefit.5 In dogs, the selection of antihypertensive medications should be geared toward the underlying disease process. For example, a- or bblockers might be best served for addressing hypertension associated with pheochromocytoma, whereas an aldosterone antagonist might be better suited to address hyperaldosteronism. For dogs with CKD, an ACEi can be used as a first-line therapy to help decrease blood pressure as well as potential associated proteinuria.5 However, if blood pressure is markedly elevated (.200 mm Hg), combination with a calcium channel blocker (CCB) is recommended.5 A CCB should not be used as sole therapy to avoid causing afferent arteriolar dilation, which may worsen intraglomerular pressure.5 Unlike dogs, management of SHT in cats involves using a CCB such as amlodipine as the first-line medication, whether treating for idiopathic or CKD-associated hypertension. Routine use of an ACEi is not recommended, particularly as a first-line agent.5 Use of an ARB such as telmisartan can also be considered and may be more effective compared with an ACEi such as benazepril, though either of these medications could be associated with a reduction in glomerular filtration rate and worsening of renal values in a dehydrated azotemic patient.5 Please see Chapter 149, Antihypertensives, for more information.

REFERENCES 1. Hall ME, Hall JE: Overview of the circulation: pressure, flow and resistance. In Hall JE, Hall ME Guyton and Hall textbook of medical physiology, ed 14, Philadelphia, 2020, Elsevier, pp 171-182. 2. Ganong W: Cardiovascular Regulatory Mechanisms. In Barrett KE, Barman SM, Brooks HL, Yuan J, editors: Review of medical physiology, ed 26, New York, 2019, Lange-McGraw-Hill, pp 575-588. 3. Foëx P, Sear JW: Hypertension: pathophysiology and treatment, Cont Ed Anaesth Crit Care and Pain 4(3):71-75, 2004. 4. Donahoe M: Very high systemic arterial blood pressure. In Vincent JL, Abraham E, Moore FA, et al, editors: Textbook of critical care, ed 6, Philadelphia, 2011, Elsevier, pp 17-23. 5. Acierno MJ, Brown S, Coleman AE, et al: ACVIM consensus statement: guidelines for the identification, evaluation, and management of systemic hypertension in dogs and cats, J Vet Intern Med 32(6):1803-1822, 2018. 6. Taylor SS, Sparkes AH, Briscoe K, et al: ISFM consensus guidelines on the diagnosis and management of hypertension in cats, J Feline Med Surg 19(3):288-303, 2017. 7. Geddes RF: Hypertension: why is it critical? Vet Clin North Am Small Anim Pract 50(5):1037-1052, 2020. 8. Cole LP, Jepson R, Dawson C, Humm K: Hypertension, retinopathy, and acute kidney injury in dogs: a prospective study, J Vet Intern Med 34:1940-1947, 2020. 9. Cole LP, Jepson R, Humm K: Systemic hypertension in cats with acute kidney injury, J Small Anim Pract 58:577-581, 2017. 10. Rapoport GS, Stepien RL: Direct arterial blood pressure measurement in 54 dogs presented for systemic hypertension screening 1998-2001. In Proc 11th European College of Veterinary Internal Medicine Annual Congress 2001, p 62. 11. Marynissen SJ, Smets PM, Ghys LF, et al: Long-term follow-up of renal function assessing serum cystatin C in dogs with diabetes mellitus or hyperadrenocorticism, Vet Clin Pathol 45:320-329, 2016. 12. Sennello KA, Schulman RL, Prosek R, Siegel AM: Systolic blood pressure in cats with diabetes mellitus, J Am Vet Med Assoc 223:198-201, 2003. 13. Al-Ghazlat SA, Langston CE, Greco DS, et al: The prevalence of microalbuminuria and proteinuria in cats with diabetes mellitus, Top Companion Anim Med 26:154-157, 2011.

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14. Gilson SD, Withrow SJ, Wheeler SL, Twedt DC: Pheochromocytoma in 50 dogs, J Vet Intern Med 8:228-232, 1994. 15. Herrera MA, Mehl ML, Kass PH, Pascoe PJ, Feldman EC, Nelson RW: Predictive factors and the effect of phenoxybenzamine on outcome in dogs undergoing adrenalectomy for pheochromocytoma, J Vet Intern Med 22:1333-1339, 2008. 16. Ash RA, Harvey AM, Tasker S: Primary hyperaldosteronism in the cat: a series of 13 cases, J Feline Med Surg 7:173-182, 2005. 17. Littman MP, Robertson JL, Bovee KC: Spontaneous systemic hypertension in dogs: five cases (1981-1983), J Am Vet Med Assoc 193:486-494, 1988. 18. Tippett FE, Padgett GA, Eyster G, Blanchard G, Bell T: Primary hypertension in a colony of dogs, Hypertension 9:49-58, 1987. 19. Jepson RE, Elliott J, Brodbelt D, et al: Effect of control of systolic blood pressure on survival in cats with systemic hypertension, J Vet Intern Med 21(3):402-409, 2007. 20. Maggio F, DeFrancesco TC, Atkins CE, et al: Ocular lesions associated with systemic hypertension in cats: 69 cases (1985-1998), J Am Vet Med Assoc 217(5):695-702, 2000. 21. Segal S: Regulation of blood flow in the microcirculation, Microcirculation 12:33-45, 2005. 22. Stepien RL: Systemic hypertension. In Bruyette DS, editor: Clinical small animal internal medicine, Hoboken, NJ, 2020, Wiley and Sons, pp 219-224. 23. Leblanc NL, Stepien RL, Bentley E: Ocular lesions associated with systemic hypertension in dogs: 65 cases (2005-2007), J Am Vet Med Assoc 238:915-921, 2011.

24. Maggio F, DeFrancesco TC, Atkins CE, et al: Ocular lesions associated with systemic hypertension in cats: 69 cases (1985-1998), J Am Vet Med Assoc 217:695-702, 2000. 25. Sansom J, Rogers K, Wood JL: Blood pressure assessment in healthy cats and cats with hypertensive retinopathy, Am J Vet Res 65:245-252, 2004. 26. Sansom J, Barnett K, Dunn K, et al: Ocular disease associated with hypertension in 16 cats, J Small Anim Pract 35:604-611, 1994. 27. Syme HM, Markwell PJ, Pfeiffer D, Elliott J: Survival of cats with naturally occurring chronic renal failure is related to severity of proteinuria, J Vet Intern Med 20:528-535, 2006. 28. Seccia TM, Caroccia B, Calo LA: Hypertensive nephropathy. Moving from classic to emerging pathogenetic mechanisms, J Hypertens 35(2): 205-212, 2017. 29. Mathur S, Syme H, Brown CA, et al: Effects of the calcium channel antagonist amlodipine in cats with surgically induced hypertensive renal insufficiency, Am J Vet Res 63:833-839, 2002. 30. Hopper K, Brown S: Hypertensive crisis. In Silverstein DC, Hopper K, editors: Small animal critical care medicine, ed 2, Philadelphia, 2015, Elsevier, pp 51-54. 31. Williamson JA, Leone S: Noninvasive arterial blood pressure monitoring. In Burkitt Creedon JM, Davis H, editors: Advanced monitoring and procedures for small animal emergency and critical care, Hoboken, NJ, 2012, Wiley and Sons, pp 134-144. 32. Elliott WJ: Management of hypertension emergencies, Curr Hypertens Rep 5:486-492, 2003.

54 Cardiopulmonary Bypass Thomas D. Greensmith, BVetMed, MVetMed, DACVECC, DECVECC, FHEA, MRCVS, Dominic Barfield, BSc, BVSc, MVetMed, DACVECC, DECVECC, FHEA, MRCVS

KEY POINTS • Cardiopulmonary bypass involves the mechanical support of blood flow coupled with extracorporeal gaseous exchange and can be used to divert blood flow away from the cardiac and pulmonary circulation. • Intracardiac surgery commonly requires inducing asystole using cardioplegia. Cardioplegia has varying compositions and can be administered via the coronary circulation using different strategies to induce reversible diastolic arrest. • Major indications for cardiopulmonary bypass utilizing cardioplegia include any open-heart surgery that requires a motionless, bloodless surgical field (e.g., valvular repair), and those in which opening cardiac chambers could lead to systemic air embolism

INTRODUCTION Cardiopulmonary bypass (CPB) technology has evolved rapidly since the first integrated pump and oxygenator machine was codeveloped by John Gibbon and IBM in 1953. There are a dizzying array of different circuit components, tubing systems and oxygenators available, with little evidence of superiority of one over another. CPB causes a range of pathophysiologic aberrations; exposure to the extracorporeal circuit and pump mechanism directly traumatizes red blood cells;1-3 activates the inflammatory, coagulation and fibrinolytic pathways;4 and predisposes patients to embolic disease (including air, tissue, and plastic particles5). The use of cardioplegia and therapeutic hypothermia to improve the safety of CPB have their own clinical and pathophysiologic implications (see Table 54.1). This chapter focuses on the most basic tenets of CPB in small animal patients. As patients are frequently admitted to the ICU following surgery, knowledge of CPB may improve the understanding of the deranged physiology, guide postoperative therapy and enhance the management of complications.

FUNDAMENTALS OF CARDIOPULMONARY BYPASS CPB technology involves drainage of the patient’s blood from the venous circulation into a reservoir. Blood is then pumped from this reservoir through a heat exchanger and gaseous exchange system (often integrated units) before returning to the patient under pressure into the arterial circulation. While commonly used in situations where asystole is required, CPB can also be used in patients without inducing

(e.g., left sided cardiac surgery or right sided cardiac surgery with intracardiac shunts). • Exposure of blood to the extracorporeal circuit causes a multitude of physiologic derangements, including activation of coagulation, fibrinolysis and inflammatory pathways, along with immune dysfunction. • The use of cardioplegia, therapeutic hypothermia, and systemic anticoagulation all lead to further physiologic aberrations that may have major implications in postoperative care. • Common postoperative complications include ongoing hemorrhage, hypotension, acute kidney injury, arrhythmias, and electrolyte derangements. Rare complications include thrombosis and endocarditis.

cardiac arrest, allowing augmentation of circulatory flow, temperature, and blood composition.

Indications In veterinary medicine, at the current time, appropriate indications for CPB in small animal patients include any cardiac procedure that requires a bloodless and motionless surgical field (and thus cessation of native cardiac function), such as mitral and tricuspid valve repair, closure of atrial or ventricular septal defects, and the repair of other congenital atrial or ventricular pathology (such as cor triatriatum dexter/sinister, common atria, or double-chambered ventricles). Surgery of the right side of the heart may be performed using CPB without the use of cardioplegia, permitting no intracardiac shunts are present (which may otherwise lead to systemic air embolism). Depending on the surgical team, beating heart surgery (for example, utilizing inflow occlusion) may be appropriate for correction of some right-sided defects (pulmonic stenosis and double-chambered right ventricle among others), as the pulmonary circulation affords some degree of safety in reducing air emboli from reaching the systemic circulation.

Cannulation Sites Cannulation is required for CPB and can be peripheral (femoral or carotid artery and femoral vein), central (vena cavae, right atrium and aorta), or a combination of the two. In small animals, the smaller size of the vasculature renders central cannulation more feasible. The exact site of central venous cannulation may vary according to the procedure being performed (such as bicaval cannulation for tricuspid surgery versus right atrial cannulation for mitral valve surgery), and given the

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TABLE 54.1  Pathophysiologic Implications of Some Modular Aspects of CPB Benefits

Complications

Therapeutic hypothermia

Reduced metabolic rate of tissues; reduced ischemic risk to organs; reduced CPB pump flow; attenuation of reperfusion-mediated injury; reduced free radical formation6 Increased oxygen solubility7 Reduced expression of cell surface adhesion molecules8

Acid-base alterations8,9 Cold induced diuresis Coagulopathy (thrombocytopathia, platelet sequestration, reduced serine protease function)6,8,10 Heterogenous organ blood flow; intracellular sodium accumulation; hormonal alterations; reduced red blood cell deformation8 Arrhythmias; myocardial ischemia; immunodysfunction6 Impaired oxygen unloading from hemoglobin11 Pharmacodynamic and pharmacokinetic alterations12

Cardioplegia

Motionless surgical field; reduced myocardial oxygen demand13

Myocardial edema (with high infusion pressures)11 Vasodilation (with hyperkalemic solutions) Impaired surgical visualization during delivery

Systemic anticoagulation

Prevents thrombosis

Hemorrhage

Protamine

Heparin antagonism

Protamine reactions10 Paradoxical anticoagulant activity (inhibition of FII activation)

Hemofiltration

Inflammatory cytokine removal; crystalloid removal14,15 Improved postoperative pulmonary function16

Increased priming volume

friable nature of the canine aorta, it is common at the authors’ institution to place the arterial cannula in the left carotid artery. Cannulation site is an important consideration as it may lead to postoperative problems (e.g., sinoatrial node dysfunction with bicaval cannulation).

Circuit Components Box 54.1 sets out several components of the circuit and their function during the provision of CPB. Fig. 54.1 describes the most common assembly used by the authors for mitral valve repair. The modular nature of the circuit allows it to be constructed in several ways. It is vital the perfusionist be familiar with the circuit (including any shunts and recirculation lines), as technical errors with the circuit and machine can rapidly prove fatal. All centers are advised to have institutional safety checklists and protocols for CPB to reduce the risk of avoidable mistakes.17

Priming Solutions The circuit priming volume varies with the number of circuit components, size of the tubing, reservoir, and oxygenator and can be over 500 ml. A degree of hemodilution is desirable during CPB due to improvements in tissue blood flow,18 tissue oxygen delivery19 and venous return,20 though not for weaning from CPB, nor postoperatively. Given the potential for severe hemodilution, it is reasonable to consider priming with a solution containing red blood cells; however, we have experienced marked hemolysis of the prime prior to initiating bypass in several cases. Priming solutions often have additives, many without evidence of a clinical benefit and often with large institutional variation in protocol. At the authors’ institution, the priming solution is routinely composed of fresh frozen plasma and compound sodium lactate, with sodium bicarbonate, mannitol, calcium gluconate, and unfractionated heparin. The fluid within the CPB machine is termed perfusate.

Anticoagulation Prior to cannula insertion the patient requires systemic anticoagulation. Firstly, a baseline activated clotting time (ACT) for the patient is obtained, then 300 IU/kg of unfractionated heparin is given intravenously. The safe minimum ACT for CPB is unknown; the authors

BOX 54.1  Circuit Components of CPB Component Venous line

Function

Drains blood from the venous circulation into the venous reservoir, either by gravity or vacuum assisted Venous reservoir Stores venous blood. De-airs and de-foams the blood Main pump boot Connects the venous reservoir to the heat exchanger/oxygenator unit Heat exchangers Allow precise temperature control. Main heat exchanger is placed before the oxygenator to reduce gas emboli formation that could otherwise occur Oxygenator The site of oxygen (and volatile inhalant) delivery and carbon dioxide removal Recirculation lines Designed to allow bypass of individual circuit components in case replacement or dysfunction occurs during CPB. Also needed for appropriate priming and de-airing of the circuit Pressure transducers Allow pressure measurement of some lines, commonly main arterial line pressure and cardioplegia delivery pressures Arterial line Connects the oxygenator to the arterial circulation Suction/vent lines Scavenge blood from the surgical field into the CPB machine. Can also be used to “vent” air from the heart before restoring spontaneous rhythm to reduce the risk of air embolism Hemofilter Allows the removal of water and solutes from the perfusate via convection. Can also be modified to perform diffusive clearance Cardioplegia circuit Variable composition depending on the nature of the cardioplegia. This circuit allows modification of the cardioplegia (for example, the ratio of crystalloid to blood used) and often has its own heat exchanger for regional myocardial temperature control

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Fig. 54.1  A simplified schematic of CPB in preparation for mitral valve repair. Recirc., recirculation lines.

maintain an ACT of over 400s while the CPB pump is in motion. Following surgical repair, protamine is administered to normalize ACT. Administration of protamine is not without risks (as several distinct reactions can occur), and the optimum dosing regime in veterinary patients is unknown; the authors institutional protocol is slow administration (over 15-60 minutes) of 3mg/kg protamine IV, slowing or stopping the infusion if complications occur. The most common reaction seen by the authors is a nonimmunologic histamine-mediated reaction during administration (manifest as vasodilation, hypotension, and reduced cardiac contractility), which can be ameliorated by slowing or stopping protamine infusion. Immunologic reactions also occur including those mediated by antiprotamine IgE antibodies, complement activation due to heparin-protamine complexes, and a spectrum of thromboxane A2-mediated reactions leading to pulmonary vasoconstriction with variable onset and severity, ranging from delayed noncardiogenic pulmonary edema to acute catastrophic pulmonary vasoconstriction.

Ultrafiltration The presence of a hemofilter within the CPB circuit allows the com­ position of the perfusate to be altered as needed. Usually used for

convective clearance (opposed to diffusive), benefits include resolving the degree of hemodilution caused by the priming solution and fluid removal from the patient which is associated with improved outcomes14 and a reduction in inflammatory cytokine concentration;15 removal of these inflammatory cytokines has been shown to improve postoperative pulmonary function in children.16

Therapeutic Hypothermia and Metabolic Management (Alpha Stat and pH Stat) Therapeutic hypothermia used during CPB reduces the metabolic rate of tissues; for example, cerebral metabolic rate decreases by 6%–7% for every 1°C reduction in brain temperature, thus reducing the risk of ischemia and allowing slower circulatory flow rates during CPB.6 The mechanisms by which therapeutic hypothermia are protective are more complex than this simplified approach, and work has documented the suppression of proapoptotic genes and the expression of “cold shock” proteins, both of which may aid in cell survival.6 The temperature used will vary depending on procedure and surgeon preference, and despite its many benefits, therapeutic hypothermia also carries many risks (see Table 54.1). As blood cools pH becomes more alkaline due to alterations in the dissociation of water molecules,9 and both CO2 and O2 become more

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soluble.7 This has led to the development of two metabolic strategies during CPB: pH stat and alpha stat. pH stat involves correcting results to the patient’s systemic temperature, and as this would yield alkalemia and a reduced PCO2, exogenous CO2 is added to the perfusate to normalize PCO2 and thus pH. This has the effect of causing cerebral vasodilation, therefore improving cerebral blood flow and cerebral cooling however the increased cerebral blood flow also increases the risk of cerebral embolism. Alpha stat management does not temperature correct the results, and PCO2 and pH are maintained at normal levels for 37°C. Alpha stat maintains a normal [OH-]:[H1] ratio and is believed to lead to preserved intracellular function.9 Although it may lead to reduced cerebral perfusion and cooling, it avoids the increased risk of cerebral embolic events seen with pH stat management. Running CPB at systemic temperatures over 28°C, there is little difference in outcome regardless of the strategy used.21 During deep hypothermic circulatory arrest (marked systemic cooling as low as 18°C followed by stopping the CPB pump to cease all circulatory movement), an improvement in outcome was seen in human neonatal and pediatric populations when adopting a pH stat approach during cooling and an alpha stat approach during rewarming.7

Cardioplegia Cardioplegia is the substance responsible for the cessation of cardiac function. It is delivered anterograde or retrograde, via the aortic root (and thus coronary ostia) or the coronary sinus respectively. Although there are many different compositions of cardioplegia, those clinically used in dogs22 induce diastolic arrest due to extracellular myocardial hyperkalemia, which prevents cardiomyocyte repolarization. This cardioplegia solution is either infused in crystalloid, or it can be mixed with the patient’s own blood prior to delivery. The temperature of the cardioplegia solution can be altered independently of the systemic temperature, allowing regional myocardial cooling or warming. The infusion pressure varies with the delivery method; however, it is important to monitor as excessive delivery pressure may lead to myocardial edema11 and worsen postoperative cardiac function, while insufficient pressure may lead to heterogenous delivery and inadequate myocardial protection. We deliver cold (4°C) cardioplegia, which, in combination with chemically induced diastolic arrest, has been documented to reduce myocardial oxygen requirements by approximately 97%,13 although it has been shown to worsen postoperative cardiac function.23 Our cold cardioplegia is also delivered in blood, as this has been shown to reduce the incidence of ventricular fibrillation after aortic cross-clamp removal in dogs.24

POSTOPERATIVE MANAGEMENT AND COMPLICATIONS The postoperative course of patients following open-heart surgery using CPB is different than for other critical postoperative patients. Deranged physiology and the behavior of a heart following cardioplegia may require a different approach compared with the normal methods of assessing fluid responsiveness and monitoring of vital parameters. After 24 hours following cardiopulmonary bypass, much of the abnormal physiologic aberrations have abated, and these patients can be often be managed as for any other critically ill patient from such time onwards. Following intracardiac surgery, patients often present back to the ICU with central venous access, invasive blood pressure monitoring, thoracic drain(s), and urinary catheters. Rare cases may also have postoperative epicardial temporary pacing wires in situ if there is a concern for dysfunction of the cardiac pacemaker sites or conducting system.

Postoperative Management Considerations Fluid Balance and Routine Transfusions Despite the ability to remove fluid (using the hemofilter) during CPB, patients may still receive a large crystalloid load due to priming fluid and crystalloid cardioplegia. Reducing the fluid load is associated with reduced mortality,14 and every attempt should be made to reduce unnecessary crystalloid administration. We commonly provide a fresh whole blood (FWB) transfusion to alleviate the primary hemostatic dysfunction that occurs with CPB,25 and this transfusion normally begins as protamine is started at the end of surgery. Although FWB may be considered ideal, we have successfully utilized packed red blood cell transfusions when FWB is unavailable without overt difference in the post-operative course. The transfusion rate is dictated by cardiovascular stability and the degree of thoracic drain outputs; urine output is not routinely taken into consideration as we wish the patient to return to either a normal or a negative fluid balance to limit the risk of pulmonary edema and excessive strain on the intracardiac surgical sites. While this may seem abnormal in the context of many ICU patients, an early net negative fluid balance has been shown to improve survival in people,26 and providing there is no cardiovascular instability, we transition toward a negative fluid balance within the first few hours after surgery. Urine output can often become high (occasionally 10–15 ml/kg/hr) for several hours postoperatively due to the multifactorial effects of cold induced diuresis, mannitol,27 altered cortisol, and catecholamine levels28 along with renal tubular dysfunction.29 After 4-5 hours the FWB transfusion is stopped, and as long as thoracic drain outputs have fallen appropriately, the patient is cardiovascularly stable, and their systemic PCV is acceptable, then balanced isotonic crystalloids are started (with supplemental potassium as needed) at a nominal rate of 1–2 ml/kg/hr for the first night after surgery. This plan is altered if ongoing thoracic bleeding occurs or if marked hypernatremia develops.

Electrolytes and Acid-Base Management Patients often develop numerous mild electrolyte and acid-base derangements perioperatively. The frequent use of diuretics often leads patients to have a whole-body potassium deficit that frequently becomes marked in the postoperative period where urine output is often elevated. Hyperchloremia of unknown etiology is often seen in our patients and is reportedly common in children following CPB,30 for which no specific therapy is provided. Supplementation of potassium is almost always required followed the completion of FWB transfusion, and occasionally severe hypokalemia (with its associated respiratory muscle and arrhythmogenic potential) may mandate bolus potassium therapy. As noted earlier, marked elevations in urine output often occur following CPB, and this, in concert with a desire to reduce fluid input and reduced oral water intake due to sedation, may lead to hypernatremia. The authors currently treat hypernatremia if it exceeds 165 mmol/L by altering the balanced isotonic electrolyte solution to a hypotonic solution (either 0.45% NaCl or D5W depending on severity; see Chapter 55, Sodium Disorders). It should be noted that perioperative hyperglycemia is known to reduce survival in people; thus, persistent hyperglycemia should be avoided by treatment with insulin if blood glucose is over 140–180 mg/dl (7.8–10mmol/L).31 However, in the authors’ experience, this is rarely necessary in small animal patients due to the transient nature of the hyperglycemia. Finally, given the frequent use of blood products, close monitoring of ionized calcium is important; hypercalcemia may theoretically worsen ischemia–reperfusion injury, while hypocalcemia may worsen ongoing bleeding and affect myocardial electrical activity. Similarly, ionized magnesium should also be monitored and supplemented as needed.

CHAPTER 54  Cardiopulmonary Bypass

Analgesia (see also Chapter 134, Analgesia and Constant Rate Infusions) Acute postoperative pain can have negative consequences for almost all organ systems, as well as the welfare of the patient. Acute postoperative pain in people may worsen myocardial ischemia, reduce urine output, and cause myriad pulmonary effects, including hypoventilation, reduced vital capacity, and increased risk of pulmonary infection,32 all of which can be deleterious in the postoperative cardiac patient. Analgesia should be individually tailored, but ideally consists of multimodal systemic analgesia alongside regional and local techniques. The authors commonly use a fentanyl CRI in combination with both intrapleural bupivacaine and thoracic paravertebral blockade. Due to alterations in the pharmacokinetics of drugs in postoperative cardiac patients,12 the plan should be continually reassessed as sudden sedation or breakthrough pain can develop.

Antibiotics, Antithrombotic Agents and Cardiac Medications As surgery invariably lasts longer than 90 minutes and involves the placement of intracardiac implants, perioperative use of antimicrobials effective against cutaneous microorganisms is recommended for 24 hours.33 Routine use of a more extended course of antimicrobials is not recommended, and these should be used only when concern for bacterial infection (such as endocarditis or a urinary tract infection) is present. Routine antiplatelet and anticoagulant therapies are recommended to reduce the risk of thrombotic complications; low-molecular-weight heparin is started within 12–24 hours of surgery (as long as there is no concern for ongoing intrathoracic bleeding) and continued for a minimum of 10 days at the author’s hospital. In people, aspirin and clopidogrel are recommended within 48 hours of the end of surgery as this has proven to reduce mortality.33 The authors routinely begin aspirin and clopidogrel the morning following surgery and continue for 90 days postoperatively. Preoperative cardiac medications often change following surgery in our cohort; the majority of patients no longer require diuretics or ACE inhibitors after surgery. The authors commonly administer pimobendan to patients who had this medication preoperatively and continue to do so until reverse cardiac remodeling has occurred.

Postoperative Complications The ICU team has little control over several postoperative complications; thankfully these are rare, but include thrombotic/embolic events, coronary dysfunction (such as ligation or vasospasm), and acute failure of the surgical repair. Thrombotic or embolic events may occur in any organ system but are often most readily recognized when the brain is affected. Supportive care of the affected organ is needed, and if thrombosis is the cause, earlier and/or more aggressive anticoagulant and antiplatelet therapy may be warranted. Acute severe postoperative coronary dysfunction is uncommon and may be caused by ligation, obstruction, or spasm of a main coronary artery; signs include regional myocardial dyskinesia, ST segment alterations, and the development of arrhythmias. With the exception of arrhythmias (see later) targeted therapy is not usually possible, and patients will either recover or their infarction will worsen and potentially prove fatal. Acute failure of the surgical repair will likely manifest as reversion to heart failure. Echocardiography may document movement of the intracardiac prostheses; revision surgery is the only mechanism by which this can be effectively treated.

Hypotension Hypotension must be assessed based on the location of the arterial measurement site. In people, peripheral arterial pressure has reduced correlation with central arterial pressure following cardiopulmonary bypass (with peripheral 14 6 9 mm Hg lower than central), and this may persist for up to 24 hours after surgery.34 If hypotension is deemed accurate, the clinician must decide if this is likely to be due to hypovolemia (either

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relative or absolute) or myocardial stunning. Hypovolemia should be suspected in patients with large volume thoracic fluid production or excessive urine output, as well as smaller patients that are aggressively rewarmed. A bolus of FWB or isotonic crystalloid (5–10 ml/kg over 5–15 minutes) is used and can be repeated based on serial reevaluation. Hypervolemia must be avoided as this may risk atrial dilation and subsequent stress on the annuloplasty. Anecdotally in some patients this has led to persistent pulmonary edema extending time in ICU by several days. Low systemic vascular resistance (SVR) has been documented in just over 20% of people after CPB, although the etiology is incompletely understood.35 The low SVR occurs despite the fact that the parasympathetic system is suppressed immediately postoperatively,36 and therefore some patients will require judicious use of vasoconstrictors. This reduction in SVR is usually short lived (hours); therefore, persistent vasodilation mandates the assessment of other contributing factors (i.e., infection).37 A vasoplegic syndrome is also well characterized in people following CPB and is associated with a poor prognosis; the syndrome is associated with patients who have more severe systolic preoperative dysfunction (ejection fraction ,35%), concurrent endocrinopathies (i.e., diabetes mellitus), and those on some long-term medications (such as ACE inhibitors and calcium channel antagonists).38 For those patients deemed to have adequate volume status and vascular tone, other causes for hypotension (such as electrolyte abnormalities, poor systolic function) must be identified and addressed. Systolic function severe enough to lead to hypotension may require inotropic support, although poor diastolic function may also result from a stunned myocardium. Therefore, in patients with marked tachycardia or those with abnormal atrial activity (such as atrial fibrillation), there may be insufficient atrial assisted filling of the ventricle and thus poor ejection; using the most appropriate method to reduce heart rate is optimal.

Bleeding Thrombocytopenia, thrombocytopathia, hypofibrinogenemia, hyperfibrinolysis, consumption of coagulation factors, endothelial dysfunction, and hemodilution are all well recognized sequelae to CPB that precipitate a bleeding tendency.39 If one then adds surgical incisions in the myocardium and great vessels, along with surgical trauma from the thoracotomy, it becomes clear why some degree of bleeding is considered normal followed CPB. Point-of-care testing and transfusion algorithms are well established in human cardiac centers and are proven to reduce bleeding tendencies and transfusion requirements.10 In addition to those factors listed above, bleeding may be exacerbated by inadequate protamine administration, suboptimal surgical hemostasis, and markedly elevated systolic blood pressure and CVP, leading to potential hemorrhage from the aortic and right atrial cannulation sites, respectively. In people there are protocolized guidelines for revision surgery if thoracic hemorrhage exceeds a certain volume within a given timeframe; unfortunately, such guidelines are not available in veterinary medicine. Perioperative antifibrinolytics are routinely recommended in people;40 however, severe thrombotic events have occurred even in the absence of such agents at the authors institution, and risk-to-benefit should be considered in each case. Given the differences in fibrinolytic activity in dogs and cats, it is currently unknown if routine use is beneficial for veterinary CPB. It is our experience that even patients with marked thoracic hemorrhage immediately postoperatively can often be managed with judicious use of blood products, antifibrinolytic agents, and supportive care. The authors have rarely performed revision surgery due to intractable thoracic hemorrhage; however, this should be considered if medical management fails.

Pulmonary and Renal Injury Following surgery, CPB patients experience a dramatic and multifactorial reduction in functional residual capacity (by up to 50%). Patients

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frequently have some degree of pleural space disease (pneumothorax and hemothorax) as well as thoracic wall pain, which may lead to pulmonary dysfunction, although altered pulmonary blood flow, interstitial edema, and cytokine mediated alterations also affect functional residual capacity and pulmonary function.41 Mechanical ventilation during CPB is not required (unless the heart is able to eject blood into the pulmonary circulation), and its absence may lead to marked atelectasis. Atelectasis after CPB is more marked than would occur with thoracic surgery or anesthesia alone42 so the authors’ institution utilizes a fraction of inspired oxygen (FiO2) of ,50% with either CPAP (5–7.5 cm H2O) or low frequency mechanical ventilation (four breaths per minute with PEEP of 5 cm H2O); a similar approach in people has proven to reduce atelectasis and improve postoperative pulmonary function.43 Neutrophil activation, pulmonary neutrophil trapping, and pulmonary endothelial dysfunction are all known to occur and can last for several days postoperatively.44 Although rare, complement mediated bronchospasm is reported in people and is another mechanism that may increase the work of breathing. Given the propensity for marked postoperative pulmonary dysfunction and pleural space disease, both oxygenation and adequacy of ventilation should be carefully monitored. Supplemental oxygen is routinely provided; though the most appropriate method for oxygen delivery is not known, those that can lead to self-trauma (such as nasal cannulas) should be avoided due to the risk for hemorrhage secondary to anticoagulant and antithrombotic medication. Other safer options might include nasal prongs, an oxygen cage, or high-flow nasal oxygen therapy. Although a high FiO2 is needed initially, supplemental oxygen can frequently be weaned within 12–24 hours of surgery. Careful monitoring and appropriate thoracic drainage, along with multimodal analgesia should help limit reductions in alveolar ventilation that could otherwise occur. Acute kidney injury is common in patients undergoing CPB, with 28.2% of dogs developing acute kidney injury (AKI) after CPB45 and over 50% of people following thoracic aortic surgery.46 The causes of AKI after CPB are multifactorial and include CPB-mediated systemic inflammatory response syndrome, emboli, altered renal blood flow, and changes in vasomotor tone.29,47 The use of therapeutic hypothermia also contributes to AKI. Although it lowers metabolic rate and therefore the risk of renal ischemia, it also leads to increased renal vascular resistance, a proportional reduction in renal blood flow, and tubular injury.8 Optimizing vascular volume and fluid balance, along with limiting any further renal insults (e.g., nephrotoxic drugs and hypotension) is often all that is required for most dogs with AKI following CPB, although close monitoring for progression is recommended. Hemodialysis may be indicated in selected cases.

Arrhythmias and Electrical System Dysfunction (see Chapters 48–50, Bradyarrhythmias and Conduction Disturbances, Supraventricular Tachyarrhythmias, and Ventricular Tachyarrhythmias, respectively) Arrhythmias are common following CPB, and these may include both ventricular and supraventricular ectopic beats. If these are mild and cause no hemodynamic compromise, no treatment is indicated; if arrhythmias lead to low cardiac output, they should be treated aggressively by eliminating or ameliorating extracardiac causes and administering pharmacologic therapy directed at the arrhythmia itself. Postoperative arrhythmias may occur due to many factors in people, including structural heart disease, surgical trauma, and myocardial ischemia (e.g., due to electrolyte abnormalities, hypoxemia, and elevated catecholamines), among others.48 Dogs at highest risk of arrhythmias include those with preoperative rhythm disturbances, animals requiring intracardiac suturing in close proximity to pacemaker

or conducting tissue, cases with known pre-/intra- or postoperative myocardial infarction and those with certain cannulation techniques. Pacemaker dysfunction and conduction disturbances may be transient, and appropriate time should be given to allow recovery before placing a permanent pacemaker. At the author’s hospital, a small number of cases have required temporary epicardial pacing wires (placed at the end of surgery, while weaning from CPB) to remain in place for several days until the nodal tissue recovered appropriate function.

Gastrointestinal Complications A range of gastrointestinal complications can occur in people, including pancreatitis, intestinal ischemia, cholecystitis, and gastrointestinal ulceration. Although these complications are very infrequent (depending on diagnostic criteria their incidence may range from 0.3%–5.5%), they are associated with increased in-hospital mortality.49 Their etiology is likely multifactorial and includes ischemia–reperfusion injury, emboli, hypoxemia, and inflammation-mediated alterations in microvascular blood flow. Aggressive supportive care is required, although surgery is indicated in rare cases.

Immunocompromise and Infection Risk Cardiopulmonary bypass induces immunodeficiency due to altered complement and immunoglobulin levels,50 as well as a decreased number and function of natural killer cells and T lymphocyte subsets.51 In addition, intracardiac surgery inevitably induces the risk of a direct bacterial load to the heart, and perioperative antimicrobials have altered pharmacokinetics due to the use of the CPB machine, its priming volume, and the inflammation it causes.12 These patients routinely have numerous invasive in-dwelling devices, all of which can serve as a site for infection; therefore, the strictest barrier nursing must be performed in all cases. For these reasons, patients are at high risk of infection following CPB and a high index of suspicion should exist for any patient who fails to follow the normal postoperative clinical and clinicopathologic course.

SUMMARY The use of cardiopulmonary bypass has allowed us to perform ever more complex surgical repairs of the heart but introduces a new and difficult patient population into veterinary ICUs. Due to the very technology employed to allow CPB to be conducted safely, numerous physiologic abnormalities occur, many of which are either seldom or never seen in other ICU patients. CPB for cardiac surgery can prove very rewarding for patients as their long-term outcome can be immeasurably improved with surgery in contrast to medical therapy. Other uses of CPB may also be on the horizon, such as the use of therapeutic hypothermia for neurosurgical and invasive vascular procedures, resuscitation from trauma, mechanical support of circulatory failure, and even extracorporeal membrane oxygenation for patients with severe pulmonary disease.

ACKNOWLEDGMENTS The authors wish to thank Mr. Nigel Cross CCCP for his expert guidance and training in clinical perfusion allowing translation of human clinical perfusion conduct to be translated to our veterinary population.

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CHAPTER 54  Cardiopulmonary Bypass 3. Svenmarker S, Jansson E, Stenlund H, et al: Red blood cell trauma during cardiopulmonary bypass: narrow pore filterability versus free haemoglobin, Perfusion 15:33-40, 2000. 4. Landis RC, Brown JR, Fitzgerald D, et al: Attenuating the systemic inflammatory response to adult cardiopulmonary bypass: a critical review of the evidence base, J Extra Corpor Technol 46:197-211, 2014. 5. Uretzky G, Landsburg G, Cohn D, et al: Analysis of microembolic particles originating in extracorporeal circuits, Perfusion 2:9-17, 1987. 6. Saad H, Aladawy M: Temperature management in cardiac surgery, Glob Cardiol Sci Pract 2013(1):44-62, 2013. 7. Conolly S, Arrowsmith JE, Klein AA: Deep hypothermic circulatory arrest, Contin Educ Anaesth Crit Care Pain 10(5):138-142, 2010. 8. Davies LK, Reed H: Temperature management in cardiac surgery. In Gravlee GP, Davis RF, Hammon JW, et al, editors: Cardiopulmonary bypass and mechanical support principles and practice, ed 4, Philadelphia, 2016, Wolters Kluwer. 9. Reeves RB: An imidazole alphastat hypothesis for vertebrate acid-base regulation: tissue carbon dioxide content and body temperature in bullfrogs, Respir Physiol 14(1):219-236, 1972. 10. Enriquez L, Shore-Lesserson L: Anticoagulation, coagulopathies, blood transfusion, and conservation in cardiac surgery. In Ghosh S, Falter F, Perrino AC, editors: Cardiopulmonary bypass, ed 2, Cambridge, 2015, Cambridge University Press. 11. Hogan M, Jenkins D: Myocardial protection and cardioplegia. In Ghosh S, Falter F, Perrino AC, editors: Cardiopulmonary bypass, ed 2, Cambridge, 2015, Cambridge University Press. 12. Pea F, Pavan F, Furlanut M: Clinical relevance of pharmacokinetics and pharmacodynamics in cardiac critical care patients, Clin Pharmacokinet 47(7):449-462, 2008. 13. Vinten-Johansen J, Dobson GP, Shi W, et al: Surgical myocardial protection. In Franco KL, Thourani VH, editors: Cardiothoracic surgery review, Philadelphia, 2012, Wolters Kluwer. 14. Grist G, Whittaker C, Merrigan K, et al: The correlation of fluid balance changes during cardiopulmonary bypass to mortality in pediatric and congenital heart surgery patients, J Extra Corpor Technol 43:215-226, 2011. 15. Bierer J, Stanzel R, Henderson M, et al: Ultrafiltration in pediatric cardiac surgery review, World J Pediatr Congenit Heart Surg 10(6):778-788, 2019. 16. Zhou G, Feng Z, Xiong H, et al: A combined ultrafiltration strategy during pediatric cardiac surgery: a prospective, randomized, controlled study with clinical outcomes, J Cardiothorac Vasc Anesth 27(5):897-902, 2013. 17. Kunst G, Milojevic M, Boer C, et al: 2019 EACTS/EACTA/EBCP guidelines on cardiopulmonary bypass in adult cardiac surgery, Br J Anaesth 123(6):713-757, 2019. 18. Lundar T, Lindegaard KF, Frøysaker T, et al: Cerebral perfusion during non-pulsatile cardiopulmonary bypass, Ann Thorac Surg 40:144-150, 1985. 19. Messmer K: Hemodilution, Surg Clin North Am 55:659-678, 1975. 20. Guyton AC, Richardson TQ: The effect of hematocrit on venous return, Circ Res 9:157-164, 1961. 21. Aziz KAA, Meduoye A: Is pH-stat or alpha-stat the best technique to follow in patients undergoing deep hypothermic circulatory arrest? Interact Cardiovasc Thorac Surg 10:271-282, 2010. 22. Uechi M, Mizukoshi T, Mizuno T, et al: Mitral valve repair under cardiopulmonary bypass in small-breed dogs: 48 cases (2006-2009), J Am Vet Med Assoc 240:1194-1201, 2012. 23. Fan Y, Zhang AM, Xiao YB, et al: Warm versus cold cardioplegia for heart surgery: a meta-analysis, Eur J Cardiothorac Surg 37(4):912-919, 2010. 24. Mamada K, Takamura K, Mori T, Uechi M: Risk factors for ventricular fibrillation following aortic cross-clamping release during mitral valve repair in dogs, Vet Surg 47(5):E53, 2018. 25. Lavee J, Martinowitz U, Mohr R, et al: The effect of transfusion of fresh whole blood versus platelet concentrates after cardiac operations. A scanning electron microscope study of platelet aggregation on extracellular matrix, J Thorac Cardiovasc Surg 97(2):204-212, 1989. 26. Li C, Wang H, Liu N, et al: Early negative fluid balance is associated with lower mortality after cardiovascular surgery, Perfusion 33(8):630-637, 2018. 27. Bragadottir G, Redfors B, Ricksten S: Mannitol increases renal blood flow and maintains filtration fraction in post-operative acute kidney injury: a prospective interventional study, Crit Care 16(4):R159, 2012.

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28. Naguib AN, Tobias JD, Hall MW, et al: The role of different anesthetic techniques in altering the stress response during cardiac surgery in children: a prospective, double-blinded, and randomized study, Pediatr Crit Care Med 14(5):481-490, 2013. 29. Kumar AB, Suneja M: Cardiopulmonary bypass-associated acute kidney injury, Anesthesiology 114(4):964-970, 2011. 30. Hatherhill M, Salie S, Waggie Z, et al: Hyperchloraemic metabolic acidosis following open cardiac surgery, Arch Dis Child 90:1288-1292, 2005. 31. Szekely A, Levin J, Miao Y, et al: Impact of hyperglycemia on perioperative mortality after coronary artery bypass graft surgery, J Thorac Cardiovasc Surg 142:430-437, 2011. 32. Gan TJ: Poorly controlled postoperative pain: prevalence, consequences, and prevention, J Pain Res 10:2287-2298, 2017. 33. Sousa-Uva M, Head SJ, Milojevic M, et al: 2017 EACTS guidelines on perioperative medication in adult cardiac surgery, Eur J Cardiothorac Surg 53:5-33, 2018. 34. Sun J, Ding Z, Qian Y, et al: Central-radial artery pressure gradient after cardiopulmonary bypass is associated with cardiac function and may affect therapeutic direction, PLoS One 8(7):e68890, 2013. 35. Carrel T, Englberger L, Mohacsi P, et al: Low systemic vascular resistance after cardiopulmonary bypass: incidence, etiology, and clinical importance, J Card Surg 15:347-353, 2000. 36. Bauernschmitt R, Malberg H, Wessel N, et al: Impairment of cardiovascular autonomic control in patients early after cardiac surgery, Eur J Cardiothorac Surg 25:320-326, 2004. 37. Shahul S, Talmor D, Lisbon A: Management of the postoperative cardiac surgical patient. In Vincent JL, Abraham E, Moore FA, et al, editors: Textbook of critical care, ed 6, Philadelphia, 2011, Elsevier Saunders. 38. Levin MA, Lin HM, Castillo JG, et al: Early on-cardiopulmonary bypass hypotension and other factors associated with vasoplegic syndrome, Circulation 120:1664-1671, 2009. 39. Despotis GJ, Hogue CW: Pathophysiology, prevention, and treatment of bleeding after cardiac surgery: a primer for cardiologists and an update for the cardiothoracic team, Am J Cardiol 83:15B-30B, 1999. 40. Pagano D, Milojevic M, Meesters MI, et al: 2017 EACTS/EACTA guidelines on patient blood management for adult cardiac surgery, Eur J Cardiothorac Surg 53:79-111, 2017. 41. von Ungern-Sternberg BS, Petak F, Saudan S, et al: Effect of cardiopulmonary bypass and aortic clamping on functional residual capacity and ventilation distribution in children, J Thorac Cardiovasc Surg 134(5):1193-1198, 2007. 42. Magnusson L, Zemgulis V, Wicky S, et al: Atelectasis is a major cause of hypoxemia and shunt after cardiopulmonary bypass: an experimental study, Anesthesiology 87(5):1153-1163, 1997. 43. Imura H, Caputo M, Lim K, et al: Pulmonary injury after cardiopulmonary bypass: beneficial effects of low-frequency mechanical ventilation, J Thorac Cardiovasc Surg 137:1530-1537, 2009. 44. Badenes R, Lozano A, Belda FJ: Postoperative pulmonary dysfunction and mechanical ventilation in cardiac surgery, Crit Care Res Prac 2015:420513, 2015. 45. Luby J, Starybrat D, Cortellini S, et al: Retrospective evaluation of the incidence of acute kidney injury in dogs undergoing surgery under cardiopulmonary bypass: sixty-four dogs (2005-2018) (abstract), J Vet Emer Crit Care 29(S1):S42, 2019. 46. Roh GU, Lee JW, Nam SB, et al: Incidence and risk factors of acute kidney injury after thoracic aortic surgery for acute dissection, Ann Thorac Surg 94:766-771, 2012. 47. Thiele RH, Isbell JM, Rosner MH: AKI associated with cardiac surgery, Clin J Am Soc Nephrol 10:500-514, 2015. 48. Peretto G, Durante A, Limite LR, et al: Postoperative arrhythmias after cardiac surgery: incidence, risk factors, and therapeutic management, Cardiol Res Pract 2014:615987, 2014. 49. Allen SJ: Gastrointestinal complications and cardiac surgery, J Extra Corpor Technol 46:142-149, 2014. 50. Bartels K, Zakkar M: Inflammatory responses to cardiopulmonary bypass. In Gravlee GP, Davis RF, Hammon JW, et al, editors: Cardiopulmonary bypass and mechanical support principles and practice, ed 4, Philadelphia, 2016, Wolters Kluwer. 51. Nguyen DM, Mulder D, Shennib H: Effect of cardiopulmonary bypass on circulating lymphocyte function, Ann Thorac Surg 53(4):611-616, 1992.

PART V   Electrolyte and Acid-Base Disturbances

55 Sodium Disorders Jamie M. Burkitt Creedon, DVM, DACVECC

KEY POINTS • Most disorders of plasma sodium concentration ([Na1]) result from changes in water balance. • Plasma sodium concentration is the major determinant of extracellular fluid (ECF) osmolality because Na1 is the most plentiful molecule dissolved in the ECF. • Differences between extracellular and intracellular osmolalities cause water to shift between the extracellular and intracellular compartments along an osmotic pressure gradient.

• Dysnatremia can cause central nervous system (CNS) disturbances resulting from changes in neuron cell volume and function. • Rapid changes in [Na1] can cause osmotic demyelination syndrome or fatal cerebral edema. • Patients with dysnatremia that require rapid intravascular volume expansion should be treated with intravenous fluids with a sodium concentration similar to patient [Na1].

Plasma sodium concentration ([Na1]) is important. Alterations in [Na1] are associated with poor outcome in critically ill people1,2 and small animals.3,4 Even [Na1] changes within the reference interval are associated with increased mortality risk.1,5 It is unclear whether small fluctuations in [Na1] are themselves detrimental or if they are associated with poorer prognosis because they indicate more severe disease.6 Blood sodium concentration is expressed as milliequivalents (mEq) or millimoles (mmol) of sodium per liter of serum or plasma. In most cases, disorders of [Na1] in dogs and cats result from changes in body water volume (the solvent in which sodium molecules are dissolved) rather than an increased or decreased number of sodium molecules. To understand what determines [Na1] and how changes in [Na1] affect cellular function, it helps to understand the distribution of water in the body and the concept and determinants of osmolality.

compartment, are freely permeable to water molecules. Thus, at equilibrium, when 1 L of water is added to the animal, approximately 667 ml will distribute to the intracellular space and 333 ml to the extracellular space. Of the 333 ml added to the extracellular space, approximately 250 ml (75% of 333 ml) will remain in the interstitial fluid space and 83 ml (25% of 333 ml) will be distributed to the intravascular compartment.

DISTRIBUTION OF BODY WATER The terms water, electrolyte-free water, and free water are used interchangeably to describe body water. Water makes up approximately 60% of an adult animal’s body weight; two-thirds of it is intracellular and one-thirds is extracellular. Extracellular water is distributed between the interstitial and intravascular compartments, which contain approximately 75% and 25% of the extracellular water, respectively (see Fig. 55.1). Both the endothelium, which separates the intravascular compartment from the interstitial space, and the cell membrane, which separates the interstitial from the intracellular

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OSMOLALITY AND OSMOTIC PRESSURE An osmole is 1 mole (6.02214076 3 1023 molecules) of any fully dissociated substance dissolved in solvent, and in biologic systems that solvent is water. Osmolality is the concentration of osmoles in a mass of solvent and in clinical medicine is expressed as mOsm/kg of water. Osmolarity is the concentration of osmoles in a volume of solvent and in biologic systems is expressed as mOsm/L of water. Because 1 liter of water weighs 1 kilogram, there is no clinically relevant difference between osmolality and osmolarity in medicine, and the term osmolality will be used for the rest of this chapter. Every individual molecule dissolved in the body water contributes equally to osmolality regardless of size, weight, charge, or composition.7 The most abundant osmoles in the extracellular fluid are sodium (and its accompanying anions chloride and bicarbonate), glucose, and urea. Because they are the most plentiful, these molecules are the main determinants of plasma osmolality in healthy dogs and cats. Plasma osmolality (mOsm/kg) in healthy animals can be estimated by the equation shown in Box 55.1.8,9 As this equation shows, [Na1] is the major determinant of plasma osmolality.

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Fig. 55.1  Total body water (TBW). Water makes up approximately 60% of an adult animal’s body weight. Two-thirds of body water is in the intracellular fluid space (ICF; pink) and one-third is in the extracellular fluid space (ECF, light blue and red combined). Interstitial fluid (light blue) makes up approximately 75% and intravascular fluid (red) makes up approximately 25% of the ECF, respectively. Red blood cells (RBC), white blood cells (WBC), and the majority of albumin molecules (alb) remain in the vascular space because the endothelium is functionally impermeable to these larger elements under standard conditions. The endothelial layer is freely permeable to water (H2O), sodium (Na1), potassium (K1), chloride, bicarbonate, urea, glucose, and other small molecules; thus, the concentration of these elements is identical throughout the ECF at equilibrium. The cell membrane is functionally impermeable to Na1, K1, and their accompanying anions because of the 3Na1–2K1-ATPase pump, which removes Na1 from the cell in exchange for K1. Na1 and K1 are effective osmoles because they do not freely cross the cell membrane and thus contribute to generation of osmotic pressure; urea (U ) is an ineffective osmole because it freely crosses the cell membrane and thus does not generate such an osmotic pressure gradient. Artwork by Chrisoula Toupadakis Skouritakis, PhD; University of California, Davis, Veterinary Surgical and Radiological Sciences MediaLab.

BOX 55.1  Calculation of Serum Osmolality Osmolality (mOsm/L)  2([Na ])  ([BUN, mg/dl]  2.8)  ([glucose, mg/dl]  18) Where [Na1] 5 plasma sodium concentration and blood urea nitrogen (BUN) is the concentration of BUN. The BUN and glucose concentrations are divided by 2.8 and 18, respectively, to convert them from mg/dl to mmol/L.

Osmoles that do not freely cross the cell membrane are considered effective osmoles, whereas those that cross freely are ineffective osmoles; this difference in “efficacy” refers to these molecules’ ability (effective) or inability (ineffective) to incite water movement across that cell membrane. Only molecules that cannot themselves freely cross that membrane are effective osmoles; their retention on one side of the membrane incites water to cross the membrane toward the side with a higher concentration of effective osmoles (Fig. 55.2). Sodium, potassium, and glucose are effective osmoles across the cell membrane while urea is an ineffective osmole; the first three are effective osmoles because they do not freely cross the cell membrane

while urea is an ineffective osmole because it does (Fig. 55.1). As explanation, the water-permeable cell membrane is functionally impermeable to sodium and potassium: the Na1-K1-ATPase pump returns any Na1 or K1 molecules that leak across the membrane back to their appropriate side. Because Na1 is maintained outside the cell by the Na1-K1-ATPase pump, during hypernatremia, [Na1] and thus osmolality become higher in the extracellular than in the intracellular compartment. Thus, osmotic pressure is created such that water moves along its osmotic gradient from the intracellular compartment, across the water-permeable cell membrane, and into the relatively hyperosmolar extracellular compartment. This water movement causes cell volume loss. The opposite occurs during hyponatremia, when osmotic pressure drives water into cells and they swell (Fig. 55.3).

REGULATION OF PLASMA OSMOLALITY Hypothalamic osmoreceptors sense changes in plasma osmolality, and changes of only 2–3 mOsm/L induce compensatory mechanisms to return the plasma osmolality to its hypothalamic setpoint.10 The two

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Fig. 55.2  Effective osmoles and the generation of an osmotic pressure gradient. Each pane is oriented such that the pane’s bottom is dependent (closer to the ground) and the pane’s top is non-dependent (closer to the sky). A.  A U-shaped test tube, open to the atmosphere at the top, has a semipermeable membrane at its base that is permeable only to water molecules. Only water is in the tube, and because the membrane is freely permeable to water, the water level on each side of the tube is the same. B.  Salt (NaCl) is added to the left side of the tube. Salt cannot cross the semipermeable membrane, and so is an “effective” osmole across this membrane because its retention on the left side causes water movement (osmosis) across the membrane. C.  Since NaCl is caught on only the left side of the semipermeable membrane, water molecules cross the membrane from the right side of the tube to the left side of the tube along the osmotic pressure gradient created by the salt. D.  The difference in water height between the left side of the tube and the right side of the tube is the osmotic pressure generated by this amount of salt in this given volume of water. Artwork by Chrisoula Toupadakis Skouritakis, PhD; University of California, Davis, Veterinary Surgical and Radiological Sciences MediaLab.

major physiologic mechanisms for controlling plasma osmolality are the antidiuretic hormone (ADH) system and thirst.

Antidiuretic Hormone ADH is a small peptide secreted by the posterior pituitary gland. There are two major stimuli for ADH release: elevated plasma osmolality and decreased effective circulating volume. Increased plasma osmolality (increased plasma solute concentration) causes shrinkage of a specialized group of cells in the hypothalamus called osmoreceptors. When their volume decreases, these hypothalamic osmoreceptor cells send impulses via neural afferents to the posterior pituitary,

which then releases ADH.11 When effective circulating volume is low, baroreceptor cells in the aortic arch and carotid bodies send neural impulses to the pituitary gland that stimulate ADH release. In the absence of ADH, renal tubular collecting cells are impermeable to water. When ADH activates the V2 receptor on the renal collecting tubular cell, aquaporin-2 molecules insert into the cell’s luminal membrane. Aquaporins are channels that allow water to move from the tubular lumen into the renal tubular cell. Water then crosses into the hyperosmolar renal medullary interstitium and into the vasa recta along its osmotic gradient; the water is thereby returned to the general circulation. If the kidney is unable to generate

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volume, thirst and ADH release increase irrespective of plasma osmolality. The resultant increased water intake (from drinking) and water retention (from ADH action at the level of the kidney) decrease plasma [Na1] and can lead to hyponatremia (and thus hypoosmolality) in patients with poor effective circulating volume. An example of the defense of effective circulating volume at the expense of normal plasma osmolality is seen in patients with chronic heart failure that present with hyponatremia.12

TOTAL BODY SODIUM CONTENT VERSUS PLASMA SODIUM CONCENTRATION Plasma sodium concentration is different than, and independent of, total body sodium content. Total body sodium content refers to the total number of sodium molecules in the body, regardless of the ratio of sodium molecules to water molecules. Sodium content determines the hydration status of the animal. As used clinically, “hydration” and “dehydration” are misnomers because findings such as skin tenting and moistness of the mucous membranes and conjunctival sac are determined primarily by body sodium content. Patients may be normally hydrated, dehydrated, or overhydrated (normal, decreased, or increased total body sodium content) and be normonatremic, hypernatremic, or hyponatremic.

Overhydration When patients have increased total body sodium, an increased quantity of fluid is maintained within the interstitial space and the animal appears overhydrated, regardless of the [Na1]. Overhydrated patients may manifest a gelatinous subcutis, peripheral or ventral pitting edema, chemosis, or excessive serous nasal discharge.

Dehydration Fig. 55.3  Effect of water movement into or out of cells due to changes in extracellular [Na1]. Hypernatremia causes water to move out of cells along its osmotic pressure gradient, which causes cell volume loss (shrinkage). Hyponatremia causes water to move into cells along its osmotic pressure gradient, which causes cell volume increase (swelling). Artwork by Chrisoula Toupadakis Skouritakis, PhD; University of California, Davis, Veterinary Surgical and Radiological Sciences MediaLab.

a hyperosmolar renal medulla because of disease or diuretic administration, water will not be reabsorbed effectively, even with high concentrations of ADH. Circulating ADH concentration and ADH’s effect on the normal kidney are the primary physiologic determinants of water retention and excretion.

Thirst Hyperosmolality and decreased effective circulating volume also stimulate thirst. The mechanisms by which hyperosmolality and hypovolemia stimulate thirst are similar to those that stimulate ADH release. Thirst and the resultant water drinking are the main physiologic determinants of water intake.

Prioritization of Osmolality and Effective Circulating Volume Under normal physiologic conditions, the renin-angiotensin-aldosterone system monitors and fine-tunes effective circulating volume, and the ADH system maintains normal plasma osmolality. However, maintenance of effective circulating volume is prioritized over maintenance of normal plasma osmolality, so in patients with poor effective circulating

When patients have decreased total body sodium content, a decreased quantity of fluid is maintained within the interstitial space and the animal appears dehydrated, regardless of the [Na1]. Once a patient has lost 5% of its body weight in isotonic fluid (i.e., appears 5% “dehydrated”), it may manifest decreased skin turgor, tacky or dry mucous membranes, decreased fluid in the conjunctival sac, and in extreme cases sunken eye position. Patients that are ,5% dehydrated appear clinically hydrated. Patients with dehydration can become hypovolemic because fluid moves from the intravascular space into the interstitial space as a result of decreased interstitial hydrostatic pressure, leaving a fluid deficit in the intravascular space. Hydration status and [Na1] are unrelated clinically because they are not regulated by identical body systems.

HYPERNATREMIA Hypernatremia is defined as plasma or serum sodium concentration above the reference interval.

Causes of Hypernatremia Most dogs and cats with hypernatremia have a deficit in total body water due to water loss or inadequate intake, rather than increased sodium intake or retention.3

Water Deficit – Excessive Water Loss Renal water loss is a common cause of hypernatremia. Osmotic diuresis due to glucosuria or mannitol causes an electrolyte-free water loss and thus can cause hypernatremia in animals that do not have access to water or are too ill to drink and hold it down. Diabetes insipidus (DI), a syndrome of inadequate release of or response to ADH, can also cause

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hypernatremia (see Chapter 76, Diabetes Insipidus). Animals with DI depend on oral water intake to maintain normal plasma [Na1] because they cannot adequately reabsorb free water in the renal collecting duct; thus, animals with DI become severely hypernatremic when they do not drink and hold down water. Acute or critical illness can unmask previously undiagnosed DI.13 Gastrointestinal (GI) losses may at times contain electrolyte-free water, and in such cases, excessive vomiting or diarrhea could lead to hypernatremia. One example of this is the hypernatremia that can occur after the administration of cathartic-containing activated charcoal suspension: in this case the cathartic draws electrolyte-free water out of the extracellular space into the GI tract.

Water Deficit – Inadequate Water Intake Animals with hypernatremia due to inadequate water intake are usually either those without access to water or those with illness that prevents them drinking. Normal animals can become hypernatremic if denied access to water for extended periods, whether in the community or while hospitalized on isotonic or hypertonic fluid therapy. A syndrome of hypodipsic hypernatremia has been reported in Miniature Schnauzers.14-16 This syndrome most likely is due to impaired osmoreceptor or thirst center function. In other dog breeds and cats, hypodipsic hypernatremia has been associated with diseases such as hypothalamic granulomatous meningoencephalitis, hydrocephalus, other CNS deformities, and CNS lymphoma.17-21

Increased Sodium Intake or Retention Severe hypernatremia can also occur with the introduction of large quantities of sodium such as from hypertonic fluid administration3 (hypertonic saline, sodium bicarbonate), sodium phosphate enemas,22 or ingestion of seawater, beef jerky, or salt-flour dough mixtures.23 Hyperaldosteronism can also cause hypernatremia due to excessive renal sodium retention.

Clinical Signs of Hypernatremia Hypernatremia causes no overt clinical signs in many cases; however, if it is severe (usually .170 mEq/L) or occurs rapidly, clinical signs may ensue. Neurons are particularly intolerant of the cell volume change that can occur when [Na1] changes rapidly. Thus, CNS signs such as obtundation, head pressing, seizures, coma, and death are the signs most commonly associated with clinical hypernatremia. Patients that develop hypernatremia slowly are often asymptomatic for reasons explained in the Physiologic Adaptation to Hypernatremia section.

Physiologic Adaptation to Hypernatremia All cells that have Na1/K1-ATPase pumps tend to lose volume (shrink) as a result of hypernatremia because water moves freely through the water-permeable cell membrane while these plentiful electrolytes do not. Hypernatremia causes free water to move out of the relatively hypoosmolar intracellular space into the hyperosmolar extracellular space, leading to decreased cell volume. The brain has multiple ways to protect against neuronal water loss during hypernatremia. In the early minutes to hours of a hyperosmolal state, as neuronal water is lost to the hypernatremic circulation, decreased interstitial hydrostatic pressure draws fluid from the cerebrospinal fluid (CSF) into the brain interstitium.24 As plasma osmolality rises, sodium and chloride molecules move rapidly from the CSF into cerebral tissue, which helps minimize brain volume loss by increasing neuronal osmolality and thus drawing water back into the cells.25 These early fluid and ionic shifts protect the brain from the magnitude of volume loss that would be expected for a given hyperosmolal state. Additionally, within 24 hours, neurons begin to accumulate organic solutes to increase intracellular osmolality and help shift lost water back into the cell.

Accumulated organic solutes are called idiogenic osmoles, or osmolytes, and include molecules such as inositol and glutamate.24,26 Generation and retention of these idiogenic osmoles begin within a few hours of neuron volume loss, though full compensation may take as long as 2–7 days.25 Restoration of neuronal cell volume is important for cellular function and is an important consideration during treatment of hypernatremia, as discussed later.

Treating the Normovolemic, Hypernatremic Patient Hypernatremia should be treated even if no clinical signs are apparent because even minor changes in [Na1] have been associated with poor outcome in people.5,27 Patients with hypernatremia have a water deficit, and thus water should be replaced using fluid with a lower effective osmolality than the patient’s. Water may be supplemented intravenously (as 5% dextrose in water) or orally on an hourly schedule in animals that are alert, willing to drink, and not vomiting. Regardless of the route of water administration or the chosen time course (see below), the free water deficit equation11 can be used to determine the volume of electrolyte-free water needed to reach a target plasma [Na1] (Box 55.2). The target [Na1] would ideally be the patient’s usual value, if known. However, in dogs and cats this value is often unknown and thus the goal [Na1] is usually arbitrary; the high end or the mid-value of the reference interval is a reasonable target. The calculated water volume is administered over the desired number of hours needed to reach the target plasma [Na1] at the desired time. Basic recommendations for the timing of sodium correction are described below.

When No Clinical Signs of Hypernatremia are Present Evidence-based recommendations to correct hypernatremia in adult people and animals are lacking.6,26,28 Recent, limited evidence in adults suggests that [Na1] can be decreased by 0.5–1 mEq/L/hr in most situations of chronic or subacute hypernatremia without complication.28 A relatively slow decrease in [Na1] has traditionally been recommended to prevent neuronal swelling secondary to water movement back into adapted, osmolyte-rich neurons during treatment, though risk of this putative complication has recently come into question.6,26,28 An example calculation to drop an animal’s plasma [Na1] by 1 mEq/L/ hr is shown in Box 55.3. This rate of water replacement may be inadequate in cases of ongoing electrolyte-free water loss, such as seen with DI or unregulated diabetes mellitus; in such cases, water administration may need to be more aggressive until the underlying cause of water loss is addressed. Frequent [Na1] measurement during treatment with plan adjustment is important.

When Clinical Signs of Hypernatremia are Present In animals with CNS signs attributable to hypernatremia (obtundation, head pressing, disorientation, seizures, coma), water replacement must be more rapid. A recent recommendation in people is to drop [Na1] in such cases by 2 mEq/L/hr until the [Na1] is high-normal.26 The free water deficit equation is used to determine the required water volume and that volume divided over time needed to reach the target [Na1] at a drop of 2 mEq/L/hr (see example in Box 55.4).

BOX 55.2  Calculation of Free Water Deficit Free water deficit (L)  ([current [Na ]  normal [Na ]]  1)  0.6  (body weight in kg) where current [Na1] is the patient’s current [Na1] and normal [Na1] is the patient’s normal [Na1].

CHAPTER 55  Sodium Disorders

BOX 55.3  Example Calculation to Decrease a 20-kg Patient’s [Na1] by 1 mEq/L/hr Patient [Na1] 5 180 mEq/L Mid-normal range [Na1] 5 150 mEq/L Free water deficit (L) 5 ([180 mEq/L 4 150 mEq/L] – 1) 3 (0.6 3 20 kg) Free water deficit (L) 5 (1.2 – 1) 3 (12 kg) 5 0.2 3 12 kg 5 2.4 L free water deficit To drop from [Na1] of 180 mEq/L to 150mEq/L: 180 mEq/L – 150 mEq/L 5 30 mEq/L total To drop by 1 mEq/L/hr will require 30 hours 2.4 L 5 2400 ml over 30 hours 5 80 ml/hr of free water (offered orally or IV as 5% dextrose in water) for 30 hours. The [Na1] should be monitored frequently, ideally no less often than every 4 hours, on a single machine so that appropriate adjustments can be made to the water rate to achieve adequate drop in [Na1].

BOX 55.4  Example Calculation to Decrease a 10-kg Patient’s [Na1] by 2 mEq/L/hr Patient [Na1] 5 175 mEq/L Mid-normal range [Na1] 5 150 mEq/L Free water deficit (L) 5 ([175 mEq/L 4 150 mEq/L] – 1) 3 (0.6 3 10 kg) Free water deficit (L) 5 (1.17 – 1) 3 (6 L) 5 0.17 3 6 L 5 1.02 L free water deficit To drop from [Na1] of 175 mEq/L to 150 mEq/L: 175 mEq/L – 150 mEq/L 5 25 mEq/L total To drop by 2 mEq/L/hr will require 12.5 hours 1.02 L 5 1020 ml over 12.5 hours 5 81.6 ml/hr of free water (offered orally or IV as 5% dextrose in water) for 12.5 hours. The [Na1] should be monitored frequently, in a clinical patient, ideally every 2 hours, on a single machine so that appropriate adjustments can be made to the water rate to achieve adequate drop in [Na1].

Treatment of Acute Sodium Intoxication There are recommendations in people for immediate correction of acute hypernatremia, such as due to massive salt ingestion or iatrogenic sodium bicarbonate overdose. In such cases, some authors recommend rapid infusion of 5% dextrose in water paired with hemodialysis to restore normal [Na1] as calculated using the water deficit equation.26 When hemodialysis is not possible, aggressive water replacement over #12 hours seems reasonable. Again, the free water deficit equation would be used to determine the required water volume and that volume divided over time needed to reach the target [Na1] within 12 hours.

Monitoring During Treatment Plasma sodium concentration should be monitored no less often than every 2–4 hours to assess the adequacy of treatment, and CNS status should be monitored continuously. The rate of free water supplementation should be adjusted as needed to ensure an appropriate drop in [Na1] with the target rate in mind because a too-slow correction in [Na1] is associated with poor outcome.29-31 Free water replacement alone will not correct clinical dehydration or hypovolemia because free water replacement does not provide the sodium required to correct those problems (see the Total Body Sodium Content Versus Plasma Sodium Concentration section). Free water replacement in the hypernatremic patient is relatively safe, even in animals with cardiac or kidney disease, because the two-thirds of the infused volume that enters the cells cannot cause “fluid overload” or edema.

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HYPONATREMIA Hyponatremia is defined as plasma or serum sodium concentration below the reference interval. Clinical signs secondary to hyponatremia are uncommon in critically ill dogs and cats because signs are not usually seen unless [Na1] is very low, usually ,120 mEq/L.

Causes of Hyponatremia Dogs and cats with hyponatremia almost always have free water retention in excess of sodium retention; they may or may not have sodium loss. Generation of hyponatremia usually requires water intake in addition to decreased renal water excretion.

Decreased Effective Circulating Volume A common cause of hyponatremia in dogs and cats is decreased effective circulating volume, which leads to ADH release and water intake in defense of intravascular volume; this in turn decreases [Na1]. Possible causes include congestive heart failure,4,32 excessive GI or urinary losses,4,33,34 body cavity effusions,4 and edematous states.4 In the cases of congestive heart failure and edematous states, the patient has increased total body sodium because of activation of the renin-angiotensin-aldosterone system, yet they may be hyponatremic because of increased water retention in excess of sodium retention. In the case of excessive salt and water losses from the GI or urinary tract, the patient is total body sodium depleted (“dehydrated”) and may be hyponatremic as a result of compensatory water drinking and retention to maintain effective circulating volume.

Hypoadrenocorticism Hypoadrenocorticism leads to hyponatremia through decreased sodium retention (caused by hypoaldosteronism) combined with increased water drinking and retention in defense of inadequate circulating volume. Also, low circulating cortisol concentration leads to increased ADH release and resultant water retention regardless of intravascular volume status.35 Thus, animals with atypical hypoadrenocorticism, whose aldosterone production and release are normal, may also develop hyponatremia.

Renal Tubular Dysfunction: Diuretics, Kidney Failure Loop or thiazide diuretic administration can lead to hyponatremia by induction of hypovolemia, hypokalemia that causes sodium ions to shift into cells in exchange for potassium ions, and the inability to create dilute urine.35 Kidney failure can cause hyponatremia by similar mechanisms.

Syndrome of Inappropriate Antidiuretic Hormone Secretion Syndrome of inappropriate ADH secretion causes hyponatremia through water retention in response to improperly high circulating concentrations of ADH. The syndrome has been reported in dogs4,36-39 and cats4,40 and has many known causes in people35 (see Chapter 77, Syndrome of Inappropriate Antidiuretic Hormone).

Other Causes of Hyponatremia Hyponatremia has been reported in animals with GI parasitism,33,41 infectious and inflammatory diseases,42-45 psychogenic polydipsia, and pregnancy.46 It has also been reported in a puppy fed a low-sodium, home-prepared diet.47 Newborn puppies normally have a lower [Na1] than older puppies and adult dogs.48 Hyponatremia has been found in dogs with parvoviral enteritis,49,50 though it is unclear how much this may be due to the dogs’ young ages or persistent compromise in effective circulating volume.

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CLINICAL SIGNS OF HYPONATREMIA All cells that have Na1/K1-ATPase pumps swell as a result of hyponatremia because water moves into the relatively hyperosmolar cell from the hypoosmolar extracellular space. Cells in the brain are clinically the least tolerant of this change in cell volume. Mild to moderate hyponatremia usually causes no specific clinical signs. However, if hyponatremia is severe (usually ,120 mEq/L) or if it occurs rapidly, it may be associated with CNS signs consistent with cerebral edema, such as obtundation, head pressing, seizures, coma, and ultimately death from brain herniation. Hyponatremia also decreases renal concentrating ability in dogs,51 so dogs with hyponatremia may have inappropriately low urine specific gravity even if renal tubular function is adequate.

Physiologic Adaptation to Hyponatremia Hyponatremia causes free water to move into the relatively hyperosmolar cell from the hypoosmolar extracellular space, leading to increased cell volume. Interstitial and intracellular CNS edema increases intracranial tissue hydrostatic pressure. This pressure enhances fluid movement out of neurons and into the CSF, which flows out of the cranium, through the subarachnoid space and central canal of the spinal cord, and back into venous circulation. Swollen neurons also expel solutes such as sodium, potassium, and organic osmolytes to decrease intracellular osmolality and encourage water loss to the ECF, returning cell volume toward normal. Ion expulsion occurs rapidly, but loss of organic osmolytes requires hours to days.25 Therefore clinical signs associated with hyponatremia, and potential complications of management, are associated with both the magnitude and rate of [Na1] change.

Treating the Normovolemic, Hyponatremic Patient Potential Complications of Therapy for Hyponatremia: Osmotic Demyelination Syndrome Treatment to correct chronic or subacute hyponatremia requires care and diligence because treatment complications can be permanently debilitating or fatal. The major complication of treatment for hyponatremia is osmotic demyelination syndrome (ODS), or myelinolysis. ODS is the result of neuronal shrinking away from the myelin sheath as water moves out of the neuron during correction of hyponatremia. Clinical signs of ODS usually manifest days after intervention, so the clinician cannot assume that a rapid change in plasma [Na1] has been well tolerated simply because no CNS signs are present during initial treatment. Overzealous correction of severe hyponatremia has led to paresis, ataxia, dysphagia, obtundation, and other neurologic signs in dogs.52-55 All of these dogs had initial [Na1] ,110 mEq/L, and all had [Na1] corrections that exceeded the recommended guidelines below. Myelinolysis lesions in dogs are commonly seen in the thalamus. Patients with ODS may recover with intensive supportive treatment, although some do not.

Treating Asymptomatic Hyponatremia Many hyponatremic animals have no outward clinical signs associated with hyponatremia. For instance, hyponatremia caused by decreased effective circulating volume usually evolves over time, is most often mild (usually [Na1] 130 mEq/L), and thus usually causes no overt clinical signs. Hyponatremia due to poor effective circulating volume usually self-corrects with improvement in perfusion, as ADH secretion drops and water is eliminated by the kidney. If fluid therapy is indicated for the underlying problem, fluids with a sodium concentration less than that of the patient should be avoided.

The patient’s [Na1] and CNS status should be monitored regularly, but complications of hyponatremia or its treatment are unlikely to occur in these situations. Patients with hyponatremia caused by congestive heart failure will likely remain hyponatremic as a result of diuretic administration, the resultant polydipsia, and ingestion of a low-sodium diet. Asymptomatic patients that are edematous may be treated with water restriction alone, and those that are asymptomatic and normally hydrated or dehydrated may be treated with administration of fluids with a sodium concentration that exceeds the patient’s [Na1].

Initial Treatment When Clinical Signs of Hyponatremia are Present Whether it is acute or chronic, symptomatic hyponatremia requires emergency treatment with hypertonic saline. Patients clinical for hyponatremia usually have [Na1] #120 mEq/L. The aim is to increase patient [Na1] enough to improve clinical signs without causing complications. Complications are unlikely if the hyponatremia is known to have occurred acutely (within the prior 48 hours),56 or when patient [Na1] exceeds 110 mEq/L. Specific recommendations for salt administration in the acute setting vary somewhat. One approach is to administer 2 ml/kg of 3% NaCl over 20 minutes, recheck patient [Na1], and repeat as needed to increase patient [Na1] by 5 mEq/L57 as soon as possible. An example case using 3% NaCl is presented in Box 55.5. A similar approach is to administer 1.5 ml/kg of 3% NaCl over 10 minutes, repeating up to two times as needed to achieve a measured increase in patient [Na1] by 4–6 mEq/L.56 This rapid, small increase in patient [Na1] can help prevent fatal brain herniation and is thus key to immediate treatment. Fluid losses should be replenished with standard replacement intravenous fluids unless the patient is overhydrated and fluid loss desired.

Continued Treatment for Acute, Clinical Hyponatremia If evolution of hyponatremia is known to have occurred within the prior 48 hours, after the above immediate ∼5 mEq/L increase in [Na1], 3% NaCl can be infused at a rate of 0.5–2 ml/kg/hr until patient [Na1] reaches the low end of the reference interval.56 In these acutely affected patients, some guidelines state that [Na1] need not be re-lowered if patient [Na1] increases more quickly than planned.6,56

BOX 55.5  Example Calculation for Immediate Treatment of a 20-kg Patient with Symptomatic Hyponatremia Patient [Na1] 5 108 mEq/L (20 kg) 3 (2 ml/kg 3% NaCl) 5 40 ml of 3% NaCl over 20 minutes To make 40 ml of 3% NaCl from 7.2% NaCl: Solution on hand: 7.2% NaCl (1232 mEq Na1/L) Target solution: 3% NaCl (513 mEq Na1/L) C1V1 5 C2V2 – This equation can be applied to any stock hypertonic saline solution (e.g., 7%, 7.2%, 7.5%, 23%) to yield the stock volume to add to sterile water in order to make 3% NaCl. (7.2% NaCl) 3 V1 5 (3% NaCl) 3 40 ml V1 5 [(3% NaCl) 3 40 ml] 4 (7.2% NaCl) V1 5 16.7 ml of 7.2% NaCl added to (40 ml total desired – 16.7 ml of 7.2% NaCl 5 23.3 ml sterile water for injection) Add 16.7 ml of 7.2% NaCl to 23.3 ml sterile water for injection to make 40 ml of 3% NaCl Administer 40 ml of 3% NaCl intravenously over 20 minutes; rate 5 120 ml/hr Written order: 40 ml 3% NaCl at 120 ml/hr IV

CHAPTER 55  Sodium Disorders

Continued Treatment for Chronic (Or Unknown Time Course) Clinical Hyponatremia If the hyponatremia is chronic or the evolutionary timeline is unknown, the goal is to raise patient [Na1] by no more than 10 mEq/L during the first 24 hours and by no more than 8 mEq/L during each following 24-hour period, not to exceed the low end of the reference interval;57 some authors recommend an increase of no more than 8 mEq/L over any 24-hour period, particularly if risk for ODS is high due to severity or chronicity of the hyponatremia.26 Another strategy is to target a new [Na1] of no more than 10%–15% higher than current [Na1] within 24 hours. The amount of sodium to administer when attempting a controlled [Na1] increase is determined by calculating the sodium deficit using the formula in Box 55.6; see an example in Box 55.7. The limit of ∼10 mEq/L increase in [Na1] during the first 24 hours of treatment is probably more important than the rate over a specific period within that 24 hours. Coadministration of loop diuretics can aid in the excretion of free water and may be necessary in patients with concentrated urine. In general, monitoring [Na1] no less often than every 4 hours on the same equipment is key. Special care should be taken when correcting hyponatremia in animals being treated for concurrent hypokalemia, in that potassium supplementation will speed the correction of hyponatremia.

Relowering Overcorrected Hyponatremia Immediate therapeutic relowering of [Na1] may help prevent ODS in cases of accidental overcorrection.26,56 Because the signs of ODS are delayed, it is uncommon for a patient to develop abnormal CNS signs during initial treatment of hyponatremia. However, if new neurologic signs develop during treatment and higher than intended [Na1] is documented, or if accidental overcorrection of [Na1] is noted on routine monitoring lab work, administration of any fluid that is hyperosmolar to the patient (mannitol, hypertonic or isotonic fluids) should be stopped. In these cases, relowering of patient [Na1] is appropriate.26,56 Treatment for new CNS signs or relowering of patient [Na1] requires administration of free water. Consistent guidelines for relowering [Na1] are not available but attempting to drop the [Na1] to achieve no more than 10 mEq/L total correction during the first 24 hours and no more than 8 mEq/L over each additional 24 hours is reasonable. This can be achieved by calculating the water volume to administer using the free water deficit

BOX 55.6  Calculation of Sodium Deficit Sodium Deficit  (target [Na ]  patient [Na ])  (0.6  body weight in kg) where target [Na1] is the desired plasma [Na1] and patient [Na1] is the patient’s current plasma [Na1].

BOX 55.7  Example Calculation to Increase a 10-kg Patient’s [Na1] by 8 mEq/L over 24 Hours. Patient’s current [Na1] 5 115 mEq/L Target [Na1] 5 123 mEq/L in 24 hours Sodium deficit 5 (123 mEq/L – 115 mEq/L) 3 0.6 3 10 kg Sodium deficit 5 (8 mEq/L) 3 0.6 3 10 kg Sodium deficit 5 48 mEq Na1 to be administered over 24 hours

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equation in Box 55.2, inserting the desired [Na1] in place of “normal [Na1].” Another strategy is to administer water enterally or as 5% dextrose in water intravenously at 3 ml/kg/hr until the target [Na1] is reached.56 Decreasing [Na1] in an already hyponatremic animal can be difficult unless the patient is treated with a loop diuretic such as furosemide to clamp urine osmolality, while water is replaced simultaneously. Concomitant administration of desmopressin (synthetic ADH) can also be helpful; further details about using desmopressin to relower [Na1] can be found elsewhere.58

A RAPID DROP IN PLASMA SODIUM CONCENTRATION AND CEREBRAL EDEMA Patients with severe, acute hyponatremia may develop cerebral edema because rapid water influx into neurons may exceed these cells’ ability to expel solute and water quickly enough. Additionally, authors have historically cautioned against aggressive treatment of hypernatremia due to the putative risk of iatrogenic cerebral edema from rapidly dropping plasma [Na1]. However, while cerebral edema has been reported as a consequence of overzealous hypernatremia correction in infants, evidence supporting this complication in adults (or dogs and cats) is lacking.6,26,28 Clinical signs of cerebral edema include obtundation, head pressing, coma, seizures, and other disorders of behavior or movement. If these signs occur in an animal with severe, acute hyponatremia (usually #120 mEq/L) or if they develop during the treatment of hypernatremia, discontinue administration of any fluid that has a lower [Na1] than the patient and disallow drinking. Cerebral edema is treated with 7.0%–7.5% sodium chloride (hypertonic saline) at 3 to 5 ml/kg over 20 minutes. It should be delivered via a central vein if possible. Hypertonic saline should not be administered as a rapid bolus because it can cause vasodilation. If hypertonic saline is not available, or if a single dose does not improve signs, consider a dose of mannitol at 0.5 to 1 g/kg IV over 20 to 30 minutes. Mannitol should be administered via a central vein if possible, but it may be diluted 1:1 in sterile water and given through a peripheral vein in an emergency situation.

Pseudohyponatremia Pseudohyponatremia is the term used to describe hyponatremia in a patient with normal or elevated plasma osmolality. The most common cause of pseudohyponatremia in dogs and cats is hyperglycemia. Glucose is an effective osmole, so when hyperglycemia is present, the excess glucose molecules cause an increase in ECF water, diluting sodium to a lower concentration. For each 100 mg/dl increase in blood glucose, [Na1] drops by approximately 1.6–2.4 mEq/L.35 This effect is nonlinear, however; mild hyperglycemia leads to smaller changes in plasma [Na1] than more severe hyperglycemia. Pseudohyponatremia does not require specific treatment, and the [Na1] increases as hyperglycemia resolves. The other common cause of pseudohyponatremia in dogs and cats is mannitol infusion with retention (rather than renal excretion) of mannitol molecules.

VOLUME EXPANSION IN THE HYPOVOLEMIC PATIENT THAT IS HYPONATREMIC OR HYPERNATREMIC Patients with moderate to severe abnormalities in [Na1] (such as [Na1]p ,130 or .170) that require intravascular volume expansion should be resuscitated with a fluid with a sodium concentration close to the patient’s (66mEq/L). Hyponatremic animals may be resuscitated with a

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balanced electrolyte solution containing 130 mEq/L Na1 if appropriate, or with a maintenance solution that has NaCl added to bring the solution’s sodium concentration up to that of the patient. Hypernatremic animals should be resuscitated with a balanced electrolyte solution with NaCl added in a quantity sufficient to bring the solution’s sodium concentration up to that of the animal. The simplest way to add sodium to a bag of commercially available fluid is to add 23.4% NaCl to the bag. This product contains 4 mEq NaCl/ml, so it adds a significant quantity of sodium in a small volume.

REFERENCES 1. Sakr Y, Rother S, Ferreira AM, et al: Fluctuations in serum sodium level are associated with an increased risk of death in surgical ICU patients, Crit Care Med 41:133-142, 2013. 2. Hoorn EJ, Betjes MG, Weigel J, et al: Hypernatraemia in critically ill patients: too little water and too much salt, Nephrol Dial Transplant 23:1562-1568, 2008. 3. Ueda Y, Hopper K, Epstein SE: Incidence, severity and prognosis associated with hypernatremia in dogs and cats, J Vet Intern Med 29:794-800, 2015. 4. Ueda Y, Hopper K, Epstein SE: Incidence, severity and prognosis associated with hyponatremia in dogs and cats, J Vet Intern Med 29:801-807, 2015. 5. Thongprayoon C, Cheungpasitporn W, Yap JQ, et al: Increased mortality risk associated with serum sodium variations and borderline hypoand hypernatremia in hospitalized adults, Nephrol Dial Transplant 35:1746-1752, 2020. 6. Seay NW, Lehrich RW, Greenberg A: Diagnosis and management of disorders of body tonicity-hyponatremia and hypernatremia: core curriculum 2020, Am J Kidney Dis 75:272-286, 2020. 7. Rose BD, Post TW: Introduction to renal function. In Rose BD, Post TW, editors: Clinical physiology of acid-base and electrolyte disorders, ed 5, New York, 2001, McGraw-Hill, pp 3-20. 8. Dugger DT, Mellema MS, Hopper K, et al: Comparative accuracy of several published formulae for the estimation of serum osmolality in cats, J Small Anim Pract 54:184-189, 2013. 9. Dugger DT, Epstein SE, Hopper K, et al: A comparison of the clinical utility of several published formulae for estimated osmolality of canine serum, J Vet Emerg Crit Care (San Antonio) 24:188-193, 2014. 10. Giebisch G, Windhager E: Integration of salt and water balance. In Boron WF, Boulpaep EL, editors: Medical physiology, Philadelphia, 2003, Saunders, pp 861-876. 11. Rose BD, Post TW: Effects of hormones on renal function. In Rose BD, Post TW, editors: Clinical physiology of acid-base and electrolyte disorders, ed 5, New York, 2001, McGraw-Hill, pp 163-238. 12. Brady CA, Hughes D, Drobatz KJ: Association of hyponatremia and hyperglycemia with outcome in dogs with congestive heart failure, J Vet Emerg Crit Care 14:177-182, 2004. 13. Edwards DF, Richardson DC, Russell RG: Hypernatremic, hypertonic dehydration in a dog with diabetes insipidus and gastric dilation-volvulus, J Am Vet Med Assoc 182:973-977, 1983. 14. Sullivan SA, Harmon BG, Purinton PT, et al: Lobar holoprosencephaly in a Miniature Schnauzer with hypodipsic hypernatremia, J Am Vet Med Assoc 223:1783-1787, 1778, 2003. 15. Van Heerden J, Geel J, Moore DJ: Hypodipsic hypernatraemia in a miniature schnauzer, J S Afr Vet Assoc 63:39-42, 1992. 16. Crawford MA, Kittleson MD, Fink GD: Hypernatremia and adipsia in a dog, J Am Vet Med Assoc 184:818-821, 1984. 17. DiBartola SP, Johnson SE, Johnson GC, et al: Hypodipsic hypernatremia in a dog with defective osmoregulation of antidiuretic hormone, J Am Vet Med Assoc 204:922-925, 1994. 18. Dow SW, Fettman MJ, LeCouteur RA, et al: Hypodipsic hypernatremia and associated myopathy in a hydrocephalic cat with transient hypopituitarism, J Am Vet Med Assoc 191:217-221, 1987.

19. Hanselman B, Kruth S, Poma R, et al: Hypernatremia and hyperlipidemia in a dog with central nervous system lymphosarcoma, J Vet Intern Med 20:1029-1032, 2006. 20. Mackay BM, Curtis N: Adipsia and hypernatraemia in a dog with focal hypothalamic granulomatous meningoencephalitis, Aust Vet J 77:14-17, 1999. 21. Morrison JA, Fales-Williams A: Hypernatremia associated with intracranial B-cell lymphoma in a cat, Vet Clin Pathol 35:362-365, 2006. 22. Atkins CE, Tyler R, Greenlee P: Clinical, biochemical, acid-base, and electrolyte abnormalities in cats after hypertonic sodium phosphate enema administration, Am J Vet Res 46:980-988, 1985. 23. Barr JM, Khan SA, McCullough SM, et al: Hypernatremia secondary to homemade play dough ingestion in dogs: a review of 14 cases from 1998 to 2001, J Vet Emerg Crit Care 14:196-202, 2004. 24. Rose BD, Post TW: Hyperosmolal states–hypernatremia. In Rose BD,Post TW, editors: Clinical physiology of acid-base and electrolyte disorders, New York, 2001, McGraw-Hill, pp 746-793. 25. Verbalis JG: Brain volume regulation in response to changes in osmolality, Neuroscience 168:862-870, 2010. 26. Sterns RH: Disorders of plasma sodium—causes, consequences, and correction, N Engl J Med 372:55-65, 2015. 27. Chewcharat A, Thongprayoon C, Cheungpasitporn W, et al: Trajectories of serum sodium on in-hospital and 1-year survival among hospitalized patients, Clin J Am Soc Nephrol 15:600-607, 2020. 28. Chauhan K, Pattharanitima P, Patel N, et al: Rate of correction of hypernatremia and health outcomes in critically Ill patients, Clin J Am Soc Nephrol 14:656-663, 2019. 29. Darmon M, Pichon M, Schwebel C, et al: Influence of early dysnatremia correction on survival of critically ill patients, Shock 41:394-399, 2014. 30. Bataille S, Baralla C, Torro D, et al: Undercorrection of hypernatremia is frequent and associated with mortality, BMC Nephrol 15:37, 2014. 31. Alshayeb HM, Showkat A, Babar F, et al: Severe hypernatremia correction rate and mortality in hospitalized patients, Am J Med Sci 341:356-360, 2011. 32. Brady CA, Hughes D, Drobatz KJ: Association of hyponatremia and hyperglycemia with outcome in dogs with congestive heart failure, J Vet Emerg Crit Care 14:177-182, 2004. 33. DiBartola SP, Johnson SE, Davenport DJ, et al: Clinicopathologic findings resembling hypoadrenocorticism in dogs with primary gastrointestinal disease, J Am Vet Med Assoc 187:60-63, 1985. 34. Boag AK, Coe RJ, Martinez TA, et al: Acid-base and electrolyte abnormalities in dogs with gastrointestinal foreign bodies, J Vet Intern Med 19: 816-821, 2005. 35. Rose BD, Post TW: Hypoosmolal states–hyponatremia. In Rose BD, Post TW, editors: Clinical physiology of acid-base and electrolyte disorders, ed 5, New York, 2001, McGraw-Hill, pp 1696-1745. 36. Shiel RE, Pinilla M, Mooney CT: Syndrome of inappropriate antidiuretic hormone secretion associated with congenital hydrocephalus in a dog, J Am Anim Hosp Assoc 45:249-252, 2009. 37. Rijnberk A, Biewenga WJ, Mol JA: Inappropriate vasopressin secretion in two dogs, Acta Endocrinol (Copenh) 117:59-64, 1988. 38. Kang MH, Park HM: Syndrome of inappropriate antidiuretic hormone secretion concurrent with liver disease in a dog, J Vet Med Sci 74:645-649, 2012. 39. Breitschwerdt EB, Root CR: Inappropriate secretion of antidiuretic hormone in a dog, J Am Vet Med Assoc 175:181-186, 1979. 40. Cameron K, Gallagher A: Syndrome of inappropriate antidiuretic hormone secretion in a cat, J Am Anim Hosp Assoc 46:425-432, 2010. 41. Pak SI: The clinical implication of sodium-potassium ratios in dogs, J Vet Sci 1:61-65, 2000. 42. Son TT, Thompson L, Serrano S, et al: Surgical intervention in the management of severe acute pancreatitis in cats: 8 cases (2003-2007), J Vet Emerg Crit Care (San Antonio) 20:426-435, 2010. 43. Lobetti RG, Jacobson LS: Renal involvement in dogs with babesiosis, J S Afr Vet Assoc 72:23-28, 2001. 44. Declue AE, Delgado C, Chang CH, et al: Clinical and immunologic assessment of sepsis and the systemic inflammatory response syndrome in cats, J Am Vet Med Assoc 238:890-897, 2011.

CHAPTER 55  Sodium Disorders 45. Adaszek L, Gorna M, Winiarczyk S: Electrolyte level and blood pH in dogs infected by various 18S RNA strains of Babaesia canis canis on the early stage of babesiosis, Berl Munch Tierarztl Wochenschr 125:45-51, 2012. 46. Schaer M, Halling KB, Collins KE, et al: Combined hyponatremia and hyperkalemia mimicking acute hypoadrenocorticism in three pregnant dogs, J Am Vet Med Assoc 218:897-899, 2001. 47. Hutchinson D, Freeman LM, McCarthy R, et al: Seizures and severe nutrient deficiencies in a puppy fed a homemade diet, J Am Vet Med Assoc 241:477-483, 2012. 48. Lucio CF, Garcia Silva LC, Vannucchi CI: Haematological and biochemical analysis of healthy neonatal puppies during the immediate foetal-toneonatal transition, Reprod Domest Anim 54:1419-1422, 2019. 49. Chalifoux NV, Burgess HJ, Cosford KL: The association between serial point-of-care test results and hospitalization time in canine parvovirus infection (2003-2015), Can Vet J 60:725-730, 2019. 50. Burchell RK, Gal A, Friedlein R, et al: Role of electrolyte abnormalities and unmeasured anions in the metabolic acid-base abnormalities in dogs with parvoviral enteritis, J Vet Intern Med 34:857-866, 2020.

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56 Potassium Disorders Samantha Wigglesworth, VMD, DACVECC, Michael Schaer, DVM, DACVIM, DACVECC

KEY POINTS • A normal serum potassium concentration is essential for proper neuromuscular function. • Common conditions that may cause hypokalemia include diabetes mellitus, chronic renal disease (especially in cats), prolonged anorexia, diarrhea, hyperaldosteronism, and metabolic alkalosis. • The main clinical manifestation in the dog and cat is hypokalemic myopathy. • Rate of potassium infusion rather than total amount infused is of major therapeutic importance. • Mild to moderate hypokalemia (serum potassium 2.5 to 3.5 mEq/L) can be corrected at a rate up to 0.5 mEq/kg/hr. • While 20 mEq/L is the usual potassium supplement concentration in maintenance fluid solutions, increased amounts ranging from 30 to 60 mEq/L are often necessary in animals that are hypokalemic with serum potassium concentrations ranging from 3.4 to ,2.0 mEq/L. • Decreased urinary excretion is the most common cause of hyperkalemia in small animal patients.

• In patients with severe hyperkalemia caused by urinary obstructions and uroabdomen, prompt treatment of hyperkalemia and resolution of the underlying cause are the optimal treatment objectives. • Renal failure, hypoadrenocorticism, and gastrointestinal disease are the most common causes of sodium/potassium ratios less than 27:1. • When serum potassium exceeds 7.5 mEq/L, immediate therapy directed toward reducing and antagonizing the effects of serum potassium is warranted (i.e., calcium, dextrose with or without insulin, b2 agonists). • The absence of electrocardiogram abnormalities in the hyperkalemic patient does not mitigate the hyperkalemia; treatment should still be initiated. • Hemodialysis and hemoperfusion can effectively and rapidly lower serum potassium levels and may be part of the necessary treatment plan for acute kidney injury patients with low glomerular filtration rate.

Few of the disturbances in fluid and electrolyte metabolism are as commonly encountered or as immediately life-threatening as disturbances in potassium balance. Many clinicians are already sensitized to the detrimental effects of potassium disorders, especially hyperkalemia, but sometimes the adverse effects of hypokalemia are nearly as harmful. This chapter discusses the clinical essentials of hypokalemia and hyperkalemia in the critically ill dog and cat and shows why both are important to successful patient care.

osmolality, and several hormones including insulin, catecholamines, and aldosterone. In patients with a metabolic alkalosis, the body maintains pH via a change in transcellular potassium distribution, causing potassium to move intracellularly in exchange for cellular H1 ions. Hyperosmolality causes the translocation of water from the cellular space, which drags cellular potassium into the extracellular fluid space (“solvent drag”). Insulin, catecholamines, and aldosterone transfer potassium from the extracellular space to the intracellular space.3 Any increase in extracellular fluid potassium concentration triggers aldosterone release, which acts at the distal renal tubules to increase Na-KATPase activity, which promotes the transluminal transfer of potassium ions through the collecting duct principal cells into the renal tubular lumen, thus allowing for potassium excretion and sodium reabsorption. There is another less frequent potassium control mechanism known as kaliuretic feedforward control that responds to signals in the external environment and involves sensors in the stomach and the hepatic portal regions.3 These sensors detect local changes in potassium concentrations resulting from potassium ingestion and signal the kidney to alter potassium excretion to restore potassium balance. This is done without the influence of aldosterone. The exact sensor in the stomach has not

NORMAL DISTRIBUTION OF POTASSIUM IN THE BODY AND ITS STEADY STATE REGULATION Potassium is the most abundant intracellular cation, with 98% to 99% located in the intracellular compartment. Most intracellular potassium lies in the skeletal muscle cells. The average potassium concentration in the intracellular space of dogs and cats is 140 mEq/L, and that in the plasma space averages 4 mEq/L.1,2 Serum potassium levels therefore do not reflect whole body content or tissue concentrations. The body’s potassium regulation involves feedback mechanisms based on the potassium concentration and include pH regulation, changes in

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CHAPTER 56  Potassium Disorders been identified, and it might even involve gastric mechanical receptors that stimulate kaliuresis.4 The hepatic portal sensors in the portal venous circulation also stimulate the renal kaliuretic mechanism. This feedforward regulation functions to protect the internal environment from too much potassium accumulation as a result of ingestion and its adverse effects on organ function. When excess potassium is accumulating in the bowel lumen, the gut sensors stimulate the kidneys to increase potassium excretion, thus preventing hyperkalemia.4,5 Hypokalemia is counteracted by the body’s transfer of potassium from the intracellular space into the extracellular space. This is illustrated in humans: a serum potassium decline to 3.0 mEq/L represents a deficit of 200 mEq of total body potassium, thus exemplifying the fact that 98% of the total body potassium is located in the intracellular department.5

HYPOKALEMIA: DEFINITION AND CAUSES Hypokalemia occurs when the serum potassium concentration is less than 3.5 mEq/L (normal range 3.5 to 5.5 mEq/L). The general causes of hypokalemia are (1) disorders of internal balance and (2) disorders of external balance. The clinical conditions most commonly

BOX 56.1  Causes of Hypokalemia3,8-14 Disorders of Internal Balance (Redistribution) Metabolic alkalosis Insulin administration Increased levels of catecholamines b-Adrenergic agonist therapy or intoxication Refeeding syndrome Disorders of External Balance (Depletion) Renal potassium wasting Prolonged inadequate intake Diuretic drugs Osmotic or postobstructive diuresis Chronic liver disease Inadequate parenteral fluid supplementation Aldosterone-secreting tumor or any cause of hyperaldosteronism Prolonged vomiting associated with pyloric outflow obstruction Diabetic ketoacidosis Renal tubular acidosis Severe diarrhea Ingestion of barium-containing party sparklers glucocorticoid drugs Glucocorticoid drug administration

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associated with each of these causes are provided in Box 56.1. Recently, there has been a heightened recognition of feline hyperaldosteronism as the cause of marked hypokalemia, usually secondary to either an aldosteronoma or adrenocortical hyperplasia. It has also been associated with an adrenocortical adenoma in ferrets.6 Consequences of hypokalemia are divided into four categories: metabolic, neuromuscular, renal, and cardiovascular. Glucose intolerance is the most notable adverse metabolic effect of hypokalemia. There is evidence to suggest that release of insulin from the pancreatic b-cells is impaired when total body potassium levels are decreased.7 Potassium is necessary for maintenance of normal resting membrane potential. Subsequently, the most significant neuromuscular abnormality induced by hypokalemia in dogs and cats is skeletal muscle weakness from hyperpolarized (less excitable) myocyte plasma membranes that may progress to hypopolarized membranes.15-17 Ventroflexion of the head and neck; a stiff, stilted gait; and a plantigrade stance may also be evident. In cats, hypokalemic myopathy typically is associated with chronic renal disease, hyperaldosteronism, and poorly regulated diabetes mellitus.8 It can also result from a potassium-deficient diet or prolonged anorexia.8,16 Cats with hyperaldosteronism may present with visual impairment due to retinal hemorrhage caused by hypertension, which results from aldosterone-induced total body sodium retention.18 In these same severely affected cats, frank paralysis and death can occur from diaphragmatic and respiratory muscle failure.19 Hypokalemia can also cause rhabdomyolysis, which may have a toxic effect on the renal tubules in some speciaes.8,16,17 Smooth muscle impairment can also occur, theoretically complicating other factors predisposing to paralytic ileus and gastric atony.20 These neuromuscular signs are seldom present until serum potassium levels fall below 2.5 mEq/L. Cats with chronic renal disease can become markedly potassium depleted, and the resulting hypokalemia may further impair renal tubular function.8,21 In the myocardial cell, a high intracellular/extracellular potassium concentration ratio induces a state of electrical hyperpolarization leading to prolongation of the action potential. This may predispose the patient to atrial and ventricular tachyarrhythmias, atrioventricular dissociation, and ventricular fibrillation. The predicted appearance of abnormal electrocardiogram (ECG) findings in animals with hypokalemia are less reliable than in those with hyperkalemia.22 Canine ECG abnormalities include depression of the ST segment and prolongation of the QT interval (Fig. 56.1).23 Increased P wave amplitude, prolongation of the PR interval, and widening of the QRS complex may also occur. In addition, hypokalemia predisposes to digitalis-induced cardiac arrhythmias and causes the myocardium to become refractory to the effects of class I antiarrhythmic agents (i.e., lidocaine, quinidine, and procainamide).

Fig. 56.1  Lead II electrocardiogram taken from a dog with a serum potassium measuring 2.1 mEq/L. Note the increased P wave amplitude, the depressed ST segment, and the depressed T waves.

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PART V  Electrolyte and Acid-Base Disturbances

MANAGEMENT OF HYPOKALEMIA The main management objectives include deterring continued potassium losses, replacing potassium deficits while considering the preparation type and the route of administration, and correcting the primary disease process. Treating hypokalemia associated with metabolic alkalosis entails normalizing the blood pH, replacing the potassium deficit, and correcting the cause of the alkalosis. Primary hyperaldosteronism requires removing the cause of the excess aldosterone and/or counteracting the hormone’s effect at the distal renal tubule by treating the patient with an aldosterone antagonist such as spironolactone. Other diseases such as chronic renal disease or diabetes mellitus must be treated appropriately in order to curtail or minimize continued potassium losses. Treatment of moderate (2.5 to 3.4 mEq/L) to severe (,2.5 mEq/L) hypokalemia in the anorectic or vomiting patient requires parenteral administration of potassium chloride solution (or potassium phosphate in hypophosphatemic patients; Table 56.1). The rate of potassium infusion should seldom exceed 0.5 mEq/kg/hr for treatment of patients with mild to moderate hypokalemia.24 In profoundly hypokalemic patients (serum potassium ,2.5 mEq/L) with normal or increased urine output, the rate can be increased cautiously to 1 to 1.5 mEq/kg/hr along with close ECG monitoring.24,25 Adding 20 mEq potassium chloride solution to one liter of isotonic lactated Ringer’s, 0.9% sodium chloride, and Plasma-Lyte A solutions will change the osmolality of those solutions to 312, 348, and 334 mEq/L, respectively, but this should be of no consequence to most patients.26 Conditions that may predispose an animal to adverse effects of a potassium infusion include oliguria and anuria, hypoaldosteronism (Addison’s disease), and coadministration of potassium-sparing drugs (spironolactone, triamterene). In patients with a primary metabolic acidosis, potassium chloride can be added to the buffer-containing intravenous fluids (lactated, acetated Ringer’s or Plasma-Lyte A solutions), whereas potassium chloride is added preferentially to normal saline solution for most patients with metabolic alkalosis. It is important to remember that these values are only ranges that must be adjusted to each patient’s pathophysiologic needs. This is exemplified by the severely oliguric or anuric animal requiring minimal maintenance amounts of parenteral potassium chloride, in contrast to the polyuric ketoacidotic or ketoalkalotic diabetic patient receiving regular crystalline insulin who will require much higher amounts. Animals with rapidly administered fluid-responsive shock states should be resuscitated with an isotonic crystalloid solution before adding potassium chloride to the crystalloid fluid infusion. In the severely hypokalemic patient (serum potassium ,2 mEq/L), it is prudent to begin potassium treatment during the rehydration period, either as a separate infusion or at a slower fluid rate in order to stay

within acceptable guidelines for safe potassium infusion rates (0.5 to 1.5 mEq/kg/hr).24-26 One notable exception to the recommended “safe” rate of administration is when marked hypokalemia causes apnea, under which circumstance an intravenous bolus of 0.01 ml/kg of a 2 mEq/ml solution of potassium chloride can be life-saving until the slower infusion takes effect (author’s experience—M.S.)25. These patients must have meticulous ECG monitoring. Administration of sodium bicarbonate or insulin to hypokalemic diabetic patients should be postponed for the first 4 to 8 hours, or until the serum potassium level is greater than 3.5 mEq/L. Failure to do so can lead to marked, life-threatening hypokalemia secondary to translocation of serum potassium into the intracellular space. Potassium gluconate powder (Tumil-K, Virbac, Ft. Worth, TX, USA) is a convenient form of dietary supplementation for stable dogs and cats with mild hypokalemia. It is given orally in food twice daily at a recommended dosage of ¼ teaspoonful (2 mEq) per 4.5 kg body weight. The maintenance dose should be titrated to effect. Its use is limited to animals that can be fed by mouth or by large bore feeding tubes.

ANTICIPATED COMPLICATIONS Hyperkalemia can occur from excessive potassium supplementation (see next section). It is important to use caution when drawing blood samples from indwelling catheters that are also used for administration of electrolyte supplementation. Hypokalemic neuromuscular dysfunction is worsened, and refractoriness to therapy may be evident when metabolic alkalosis, hypomagnesemia and hypocalcemia coexist.28 It is important to correct all acid-base disorders and serum electrolyte deficiencies to attain normal neuromuscular function.

HYPERKALEMIA: DEFINITION AND CAUSES Hyperkalemia occurs when the serum potassium concentration exceeds 5.5 mEq/L and is considered life-threatening at serum concentrations greater than 7.5 mEq/L.24,29 Hyperkalemia can result from four basic disturbances: increased intake or administration, translocation from the intracellular to the extracellular fluid space, decreased renal excretion, or an artifactual or pseudohyperkalemia (Box 56.2). The most common cause of moderate to severe hyperkalemia in dogs is urinary tract disease.30 Excessive potassium supplementation (potassium chloride or potassium phosphate) in the intravenous fluids or overly rapid rates of administration can lead to hyperkalemia. To avoid life-threatening neuromuscular side effects, the intravenous rate generally should not exceed 0.5 mEq/kg/hr.24 Hyperkalemia can also occur from the administration of packed red blood cells that are past the expiration date or

TABLE 56.1  Guidelines for Routine Intravenous Supplementation of Potassium in Dogs and Cats27 Serum Potassium Concentration (mEq/L) ,2.0 2.1 to 2.5 2.6 to 3.0 3.1 to 3.5 3.6 to 5.0

mEq KCl to Add to 250 ml Fluida 20 15 10  7  5

mEq KCl to Add to 1 L Fluid 80 60 40 28 20

Maximal Fluid Infusion Rateb (ml/kg/hr)  6  8 12 18 25

a It is essential to shut off the flow valve to the patient and that the fluid container contents are thoroughly mixed during and after adding potassium to the parenteral fluids. b So as not to exceed 0.5 mEq/kg/hr.

CHAPTER 56  Potassium Disorders

BOX 56.2  Causes of Hyperkalemia9-12,24,30-41 Increased Intake or Supplementation Intravenous potassium-containing fluids Expired RBC transfusion Drugs (potassium penicillin G, KCl, KPhos) Translocation from ICF to ECF Mineral acidosis (respiratory acidosis, NH4Cl, HCl, uremia) Insulin deficiency Acute tumor lysis syndrome Extremity reperfusion following therapy for thromboembolism Drugs (nonspecific b-blockers, cardiac glycosides)a Cardiopulmonary arrest Decreased Urinary Excretion Anuric or oliguric renal injury Urethral obstruction, bilateral ureteral obstruction Uroabdomen Hypoadrenocorticism Gastrointestinal disease (trichuriasis, salmonellosis, perforated duodenum) Chylothorax or pleural or peritoneal effusions Drugs (ACE inhibitors, angiotensin receptor blockers, heparin, cyclosporine and tacrolimus, non-steroidal anti- inflammatory drugs, trimethoprim)a Pseudohyperkalemia Thrombocytosis or leukocytosis (.1,000,000 platelets or .100,000 leukocytes) Akita dog and other dogs of Japanese origin Idiopathic General anesthesia in healthy dogs (most notably Greyhounds) ACE, angiotensin-converting enzyme; ECF, extracellular fluid; HCl, hydrogen chloride; ICF, intracellular fluid; NH4Cl, ammonium chloride; RBC, red blood cell. a Unlikely to cause hyperkalemia solely; may induce with other factors such as other drugs, acute kidney injury, or potassium supplements.

the combined use of potassium supplementation with certain medications such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, potassium-sparing diuretics (e.g., spironolactone), or nonselective b-blocking drugs (e.g., propranolol), heparin, cyclosporine, and tacrolimus.24 An increased movement of potassium out of cells can lead to hyperkalemia, as seen with a mineral acidosis (respiratory acidosis, uremia or pharmacologic induction by ammonium chloride, hydrogen chloride, or calcium chloride infusions) causing potassium to move out of the intracellular space in exchange for hydrogen ions. Organic acids such as lactate and ketoacids rarely cause this effect because of their ability to maintain electroneutrality across the cell membrane.24 The extracellular translocation of potassium can also occur with heat stroke, crushing injuries, or tumor lysis syndrome associated with chemotherapy, and after radiation therapy in dogs with lymphosarcoma.31,32 Hyperkalemia has also been reported in cats treated with thrombolytic agents for aortic thromboembolism as a result of reperfusion of the affected limbs.33 Hyperkalemia also occurs commonly during cardiopulmonary resuscitation and immediately following the

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return of spontaneous circulation due to ischemia induced cellular damage and release of large amounts of intracellular potassium.34 Diabetic patients, though typically thought to have a total body potassium depletion, are at risk for hyperkalemia due to a multitude of factors. Some of these factors include insulin deficiency that results in a decreased cellular uptake of potassium, hyperosmolality that potentiates potassium translocation with water due to “solute drag” effect, and decreased potassium excretion related to renal dysfunction (comorbidities, a prerenal component, or an acute kidney injury relative to hypovolemia/perfusion).24,42 Insulin therapy normalizes the serum potassium concentration by correcting the insulin deficiency and hyperosmolality, enabling relocation of the potassium to the intracellular space and decreasing the need for further protein catabolism while potassium replacement helps replace the total body deficit. Decreased urinary excretion secondary to prerenal, renal, or postrenal disease is the most common cause of hyperkalemia in small animal patients.30 Depending on the underlying etiology and rapidity of increase in potassium levels, stabilization of these patients varies. Commonly associated ECG changes may occur in patients with hyperkalemia (peaked, narrow T waves; prolonged QRS complex and interval; depressed ST segment; depressed P wave; atrial standstill, as seen in Fig. 56.2; ventricular flutter/fibrillation). However, some studies show no correlation between potassium levels and heart rate in dogs and cats.22,43 In one group of hyperkalemic cats, a significant correlation in heart rate and potassium levels occurred only at a serum potassium of .8.5 mEq/L.43 These hyperkalemic critical patients should be treated emergently and effectively for their hyperkalemia with or without ECG changes (see Treatment of Hyperkalemia section). These patients should be quickly evaluated for urinary obstruction and/or uroabdomen with concurrent treatment of hyperkalemia in order to provide prompt stabilization. Balanced electrolyte solutions containing potassium such as LRS or Normosol-R can be utilized to stabilize these patients. A study in hyperkalemic cats with urinary obstructions found no difference in rate to normalization of potassium between a balanced electrolyte IV fluid containing potassium and 0.9% NaCl, however, the balanced solutions led to a more rapid correction in acid-base status.27 Oliguria and anuria are most commonly associated with both acute and end-stage chronic renal tubular damage. In animals with chronic renal disease, adaptation in the kidneys promotes an increase in fractional potassium excretion as well as adaptations in the gastrointestinal system with increased fecal excretion.24 The distal tubule is dependent on both adequate glomerular filtration rate and urine flow to excrete potassium. The severe reduction in both of these determinants with acute kidney injury significantly impairs the ability of the distal tubule to excrete sufficient potassium. The complete loss of potassium excretion in oliguric or anuric states complicates management of these cases because of their susceptibility to intravenous fluid overload. Though several of the treatment modalities listed in the following section may help to stabilize the patient, they only function to shift potassium intracellularly and offset any myocardiotoxicity temporarily. Until effective urine output and improvement of GFR return, any reduction of potassium levels can only occur with therapies such as hemodialysis or peritoneal dialysis (see Chapter 178, Renal Replacement Therapies).

Fig. 56.2  Lead II electrocardiogram in a dog with hyperkalemia. Absent P waves are noted in this patient with atrial standstill. Bradycardia and tachyarrhythmias may occur secondary to hyperkalemia.

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Chronic kidney disease can also be associated with hyperkalemia in dogs. This may be due to dietary potassium intake exceeding renal excretion as well as angiotensin-converting enzyme (ACE) inhibitor therapy that may be used to treat hypertension and proteinuria in select patients. It has been demonstrated that feeding a potassiumreduced diet can resolve hyperkalemia in these animals.9 Other drug therapies such as nonspecific b-blockers, cardiac glycosides, ACE inhibitors, angiotensin receptor blockers, cyclosporin, tacrolimus heparin, and trimethoprim may also contribute to hyperkalemia in these patients with diminished renal function.24 Careful evaluation of medications in the hyperkalemic patient is advised and discontinuation or dose modifications may be required. Patients with classic, severe hypoadrenocorticism typically have hyperkalemia and hyponatremia and a sodium:potassium ratio less than 27:1 (note that other medical disorders can also cause ratios as low as 20:1 or less, as mentioned below). An adrenocorticotropic hormone (ACTH) stimulation test is essential to differentiate this disease from acute kidney injury because these patients might also be azotemic and have resting serum cortisol values ,1.0 µg/dl. In the absence of aldosterone, the resulting natriuresis causes a reduced effective circulating volume, which further impairs distal tubule potassium excretion. This volume depletion also leads to reduced renal perfusion, prerenal azotemia, and further potassium retention. Initial therapy should include restoration of the effective circulating volume (see Chapter 68, Shock Fluid Therapy). A case of hyporeninemic hypoaldosteronism has been reported in the dog. This condition results in low baseline and post-ACTH concentrations of aldosterone but normal baseline and post-ACTH concentrations of cortisol. Hyporeninemic hypoaldosteronism should be considered in patients with persistent hyperkalemia in which other more common causes have been ruled out.10 Gastrointestinal disease, especially that associated with trichuriasis, salmonellosis, or duodenal perforation, can lead to hyperkalemia and a reduced sodium/potassium ratio (,27:1).11,12 Chronic chylothorax managed by intermittent or continual drainage can also result in hyperkalemia and hyponatremia.35,36 In addition, these abnormalities were reported in a dog with a lung lobe torsion, another with a neoplastic pleural effusion, and three at-term pregnant Greyhounds.37,38,44 Several cases of acute hyperkalemia have been reported in in systemically healthy Greyhounds and a Rottweiler while under general anesthesia.39-41 Although the mechanism of hyperkalemia in such patients is unclear, a reduction in effective circulating volume and subsequent reduced distal renal tubular flow could lead to deficient urinary potassium excretion.

PSEUDOHYPERKALEMIA Potassium can be released from increased numbers of circulating blood cells, especially platelets and leukocytes, causing an artifactual increase in potassium (termed pseudohyperkalemia). This typically occurs with significantly elevated counts (.1,000,000 platelets and .100,000 leukocytes).24 Pseudohyperkalemia can also be seen in Akita dogs (or other dogs of Japanese origin) secondary to in-vitro hemolysis because their erythrocytes have high levels of sodium-potassium adenosine triphosphatase pumps and, as such, have high intracellular potassium concentrations.24 This potassium is released and causes an artifactual hyperkalemia if hemolysis occurs in the serum blood tube. Confirmation of pseudohyperkalemia can be made by determining the plasma potassium concentration (blood collected in a heparinized tube) because this should not be affected by changes in platelet or white blood cell numbers (unless the patient suffers from leukemia).

CONSEQUENCES Hyperkalemia results in changes in the cell membrane excitability, causing changes in cardiac myocyte excitation and conduction. Muscle weakness can occur when the serum potassium concentration exceeds 7.5 mEq/L. The ratio of intracellular to extracellular potassium is the main factor in determining the cardiac resting membrane potential.43 In hyperkalemic patients, the concentration gradient across the cardiac cell membranes is reduced, leading to a less negative resting membrane potential. A smaller difference between the threshold potential and resting membrane potential makes these cardiac cell membranes more excitable. Elevated potassium also inactivates some of the sodiumpotassium channels during the resting phase, making these cells slower to reach threshold potential. Additionally, an overall decrease in potassium permeability also means that efflux of potassium in repolarization is delayed, slowing the cell’s recovery.45 Other factors typically found in critically ill patients, such as metabolic acidosis and abnormal calcium levels, will also affect neuromuscular activity; hypocalcemia enhances the lowering of the threshold potential, enhancing the cardiotoxicity of hyperkalemia. Calcium is also vital to the plateau phase of the cardiac cell’s action potential and a low calcium will also prolong this phase.43 Acidemia results in extracellular shift in potassium as well as decreasing the b-adrenergic receptors in cardiac tissues.24 The described classical changes in ECG such as peaked T waves, wide QRS complexes, and absent P waves may occur in hyperkalemic patients. Atrial standstill, ventricular flutter, and asystole are all reported effects. Sinus tachycardia, third degree heart block, ventricular premature complexes, and atrioventricular dissociation have also been reported in animals with hyperkalemia.24

TREATMENT OF HYPERKALEMIA Identification of hyperkalemia in the critically ill patient mandates rapid, aggressive treatment and monitoring. Concurrent ECG and blood pressure monitoring are recommended. In all hyperkalemic patients, exogenous potassium administration should be discontinued. A physical examination to evaluate vital parameters, as well as help determine the presence of an overly distended bladder indicative of possible outflow obstruction, is also indicated. The use of imaging, including ultrasound and radiographs, may help identify urinary tract abnormalities (uroabdomen, ureteral obstructions, urinary stones). In cases of hyperkalemia associated with bladder outflow obstruction or uroabdomen, quick diagnosis and treatment are vital. In asymptomatic animals with normal urine output, serum potassium concentrations between 5.5 and 6.5 mEq/L rarely require immediate therapy; however, the cause of the hyperkalemia should be investigated. Replacement fluids such as lactated Ringer’s solution, Normosol-R, or Plasma-Lyte-148 can be utilized to help rehydrate the patient and correct for a prerenal azotemia as well as promote diuresis, and this alone may help to correct mild hyperkalemia (,6 mEq/L). Loop diuretics (furosemide 0.5–4 mg/kg IV) or thiazide diuretics (chlorothiazide 20–40 mg/kg IV) can increase urinary potassium excretion; however, their use must follow rehydration and may not benefit the oliguric patient. Drugs that promote hyperkalemia, such as ACE inhibitors, b-adrenergic antagonists, and potassium-sparing diuretics, should be discontinued. In patients with chronic renal failure, a potassium-reduced diet should also be considered.9,24 Treatment should be initiated emergently in hyperkalemic patients with potassium .7.5 mEq/L. Therapy is initiated by counteracting cardiotoxicity followed by promoting potassium excretion or shifting potassium intracellularly. Ten percent calcium gluconate or calcium chloride can be administered to antagonize the cardiotoxic effects of hyperkalemia, but this has

CHAPTER 56  Potassium Disorders

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TABLE 56.2  Treatment of Life-Threatening Hyperkalemia Drug

Dosage

Mechanism of Action

Onset of Action

10% Calcium gluconate

0.5 to 1.5 ml/kg IV slowly over 15 to 20 minutes with ECG monitoring 1 to 2 mEq/kg IV slowly

Increases threshold voltage but will not lower serum potassium Causes metabolic alkalosis allowing for potassium to move intracellularly, paradoxical CNS acidosis with rapid administration Allows for translocation of potassium into the intracellular space in the presence of endogenous insulin As above

3 to 5 minutes

Sodium bicarbonate

50% Dextrose

0.5 to 1 ml/kg diluted 1:1 IV over 3 to 5 minutes

50% Dextrose with insulin

Regular insulin at 0.25–0.5 U/kga IV with IV dextrose at 1 g/unit of insulin diluted 1:1 with continued 2.5%–5% dextrose in fluids for 4–6 h 0.01 mg/kg IM, SC, IV

Terbutaline

Stimulates Na1/K1-ATPase to cause translocation of potassium into the cell

15–300 min depending on severity of laboratory and clinical signs ,1 hour

15 to 30 minutes

20 to 40 minutes

With hypoadrenocorticism the insulin dosage should be reduced to 0.25 U/kg IV because of the patient’s predisposition to hypoglycemia. ECG, electrocardiogram; IV, intravenously; IM, intramuscular; Na1/K1- ATPase, sodium-potassium adenosine triphosphatase; SC, subcutaneous. a

no effect on serum potassium concentration. Calcium functions by increasing the threshold potential to maintain the gradient between that and the resting membrane potentials. This reduces membrane excitability in hyperkalemic patients. Intravenous calcium infusions should be given slowly (over 15–20 minutes) with continuous ECG monitoring as this drug can also result in arrhythmias, especially with rapid administration. b-Adrenergic agonists (terbutaline, albuterol, epinephrine), sodium bicarbonate, and dextrose with or without insulin can be administered to reduce serum potassium concentrations as described in Table 56.2. These drugs function to shift potassium intracellularly, thereby lowering the serum potassium. Caution must be exercised with sodium bicarbonate because of its need for slow administration and the potential to cause severe alkalosis and paradoxical cerebral acidosis and, as such, is rarely utilized (see Chapter 59, Traditional Acid Base Analysis). Typically, calcium gluconate, dextrose/insulin, and b-adrenergic agonists are first-line therapies for management of hyperkalemia treatment. Glucose as a single agent can be administered at a dose of 0.5 gm/kg IV in milder cases to stimulate endogenous insulin secretion. Moderate to severely affected animals benefit from regular insulin given intravenously, then followed by a dextrose bolus (1 g per 1 unit of insulin). Continued dextrose supplementation in the fluids (2.5%–5%) for 4–6 hours following the insulin is generally recommended to avoid hypoglycemia. Reducing the total body potassium in the oliguric or anuric patient relies on extracorporeal therapy. These modalities include peritoneal dialysis, hemodialysis, or continuous renal replacement therapy to effectively remove potassium in unresponsive hyperkalemia cases (see Chapter 178, Renal Replacement Therapies).

ACKNOWLEDGEMENTS Special acknowledgement to Dr. Laura Riordan, who authored the previous Hyperkalemia chapter.

REFERENCES 1. Faubel S, Topf J: The fluid, electrolyte and acid-base companion, San Diego, 1999, Alert and Oriented Publishers. 2. Wellman ML, DiBartola SP, Kohn: Applied physiology of body fluids in dogs and cats. In DiBartola SP, editor: Fluid therapy, electrolyte, and

acid-base disorders in small animal practice, ed 4, St Louis, 2012, Saunders Elsevier. 3. Greenlee M, Wingo CS, McDonough AA, et al: Narrative review: evolving concepts in potassium homeostasis and hypokalemia, Ann Intern Med 150:619-625, 2009. 4. Lee FN, Oh G, McDonough AA, et al: Evidence for gut factor in K1 homeostasis, Am J Physiol Renal Physiol 293:F541-F547, 2007. 5. Asmar A, Mohandas R, Wingo CS: A physiologic-based approach to the treatment of a patient with hypokalemia, Am J Kidney Dis 60(3):492-497, 2012. 6. Desmarchelier M, Lair S, Dunn M, et al: Primary hyperaldosteronism in a domestic ferret with an adrenocortical adenoma, J Am Vet Med Assoc 233:1297, 2008. 7. Rowe JW, Tobin JD, Rosa RM, et al: Effect of experimental potassium deficiency on glucose and insulin metabolism, Metabolism 29:498, 1980. 8. Dow SW, Fettman MJ, LeCouteur RA, et al: Potassium depletion in cats: renal and dietary influences, J Am Vet Med Assoc 191:1569, 1987. 9. Segev G, Fascetti AJ, Weeth LP, et al: Correction of hyperkalemia in dogs with chronic kidney disease consuming commercial renal therapeutic diets—a potassium reduced home-prepared diet, J Vet Intern Med 24: 546, 2010. 10. Kreissler JJ, Langston CE: A case of hyporeninemic hypoaldosteronism in the dog, J Vet Intern Med 25:944, 2011. 11. DiBartola SP, Johnson SE, Davenport DJ, et al: Clinicopathologic findings resembling hypoadrenocorticism in dogs with primary gastrointestinal disease, J Am Vet Med Assoc 187:60, 1985. 12. Malik R, Hunt GB, Hinchliffe JM, et al: Severe whipworm infection in the dog, J Small Anim Pract 31:185, 1990. 13. Stanley MK, Kelers K, Boller E: Acute barium poisoning in a dog after ingestion of handheld fireworks (party sparklers), J Vet Emerg Crit Care 29:201-207, 2019. 14. Baltar M, Costa A, Carreira LM, et al: A pilot study exploring the plasma potassium variation in dogs undergoing steroid therapy and its clinical importance, Top Companion Anim Med 31:73-77, 2016. 15. Gennari JF: Hypokalemia, N Engl J Med 339:451, 1998. 16. Dow SW, LeCouteur RA, Fettman MJ, et al: Potassium depletion in cats: hypokalemic polymyopathy, J Am Vet Med Assoc 191:1563, 1987. 17. Harrington ML, Bagley RS, Braund KG: Suspect hypokalemic myopathy in a dog, Prog Vet Neurol 7:130, 1996. 18. Shiel R, Mooney C: Diagnosis and management of primary hyperaldosteronism in cats, In Pract 29:194, 2007. 19. Hammond TN, Holm JL: Successful use of short-term mechanical ventilation to manage respiratory failure secondary to profound hypokalemia in a cat with hyperaldosteronism, J Vet Emerg Crit Care 18(5):1476, 2008.

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20. Brown RS: Potassium homeostasis and clinical implications, Am J Med 77:3, 1984. 21. Theisen SK, DiBartola SP, Radin MJ, et al: Muscle potassium content and potassium gluconate supplementation in normokalemic cats with naturally occurring chronic renal failure, J Vet Intern Med 11:212, 1997. 22. Janse MJ, Opthof T, Kleber AG: Animal models for cardiac arrhythmias, Cardiovasc Res 39:165-177, 1998. 23. Tilley LP: Essentials of canine and feline electrocardiography, ed 2, Philadelphia, 1985, Lea and Febiger. 24. DiBartola SP, DeMorais HA: Disorders of potassium: hypokalemia and hyperkalemia. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders in small animal practice, ed 4, St Louis, 2012, Saunders Elsevier. 25. Allen AE, Buckley GJ, Schaer M: Successful treatment of severe hypokalemia in a dog with acute kidney injury caused by leptospirosis, J Vet Emerg Crit Care 26(6):837-843, 2016. 26. Bond D: Fluids and electrolytes in children. In Vincent JL, Abraham E, Moore FA, Kochanek PM, Fink MP, editors: Textbook of critical care, ed 6, Philadelphia, 2011, Elsevier. 27. Drobatz KJ, Cole SG: The influence of crystalloid type on acid-base and electrolyte status of cats with urethral obstruction, J Vet Emerg Crit Care 18(4):355-361, 2008. 28. McNutt MA, Kozar RA: Disorders of calcium and magnesium metabolism. In Vincent JL, Abraham E, Moore FA, Kochanek PM, Fink MP, editors: Textbook of critical care, ed 6, Philadelphia, 2011, Elsevier. 29. Fox PR, Sisson D, Moise NS: Textbook of canine and feline cardiology, Philadelphia, 1999, WB Saunders. 30. Hoehne SN, Hopper K, Epstein SE: Retrospective evaluation of the severity and prognosis associated with potassium abnormalities in dogs and cats presenting to an emergency room (January 2014- August 2015): 2441 cases, J Vet Emerg Crit Care 29:653-661, 2019. 31. Laing EJ, Carter RF: Acute tumor lysis syndrome following therapy treatment of canine lymphoma, J Am Anim Hosp Assoc 24:691, 1988. 32. Laing EJ, Fitzpatrick PJ, Binnington AG, et al: Half-body radiotherapy in the treatment of canine lymphoma, J Vet Intern Med 3:102, 1989.

33. Rodriquez DB, Harpster N: Aortic thromboembolism associated with feline hypertrophic cardiomyopathy, Compend Contin Educ Pract Vet 24:478, 2002. 34. Hopper K, Brochers A, Epstein SE: Acid base, electrolyte, glucose, and lactate values during cardiopulmonary resuscitation in dogs and cats, J Vet Emerg Crit Care 24(2):208-214, 2014. 35. Willard MD, Fossum TW, Torrance A, et al: Hyponatremia and hyperkalemia associated with idiopathic or experimentally induced chylothorax in four dogs, J Am Vet Med Assoc 199:353, 1991. 36. Thompson MD, Carr AP: Hyponatremia and hyperkalemia associated with chylous pleural and peritoneal effusion in a cat, Can Vet J 43(8): 610-613, 2002. 37. Zenger E: Persistent hyperkalemia associated with nonchylous pleural effusion in a dog, J Am Anim Hosp Assoc 28:411, 1992. 38. Lamb WA, Muir P: Lymphangiosarcoma associated with hyponatremia and hyperkalemia in a dog, J Small Anim Pract 35:374, 1994. 39. McFadzean W, Macfarlane P, Khenissi L, et al: Repeated hyperkalemia during two separate episodes of general anesthesia in a nine-year-old, female neutered greyhound, Vet Rec Case Rep 6(3):e000658, 2018. 40. Jones S, Mama KR, Brock N, et al: Hyperkalemia during general anesthesia in two Greyhounds, J Am Vet Med Assoc 254(11): 1329-1334, 2019. 41. Boustead KJ, Zeiler G: Life-threatening hyperkalemia in a five-year old rottweiler undergoing bilateral elbow arthroscopy, Vet Rec Case Rep 7(3):e000893, 2019. 42. Liamis G, Liberopoulos E, Barkas F, Elisaf E: Diabetes mellitus and electrolyte disorders, World J Clin Cases 2(10):488-496, 2014. 43. Tag LT, Day TK: Electrocardiographic assessment of hyperkalemia in dogs and cats, J Vet Emerg Crit Care 18(1):61-67, 2008. 44. Schaer M, Halling KB, Collins KB, et al: Combined hyponatremia and hyperkalemia mimicking acute hypoadrenocorticism in three pregnant dogs, J Am Vet Med Assoc 218:897, 2001. 45. Surawicz B: Relationships between electrocardiogram and electrolytes, Am Heart J 73(6):814-831, 1967.

57 Calcium Disorders Joao Felipe de Brito Galvao, MV, MS, DACVIM (SAIM), Dennis J. Chew, DVM, Dipl ACVIM, Todd A. Green, DVM, MS, DACVIM

KEY POINTS • Severe hypercalcemia or hypocalcemia can be lethal in dogs and cats, especially if rapid changes in serum calcium concentration occur. • Toxicity from hypercalcemia is greatly magnified if the serum phosphorus concentration is also increased. • Hypercalcemic crisis is most likely to occur when there is toxicity from excess vitamin D metabolites circulating in the body.

CALCIUM HOMEOSTASIS Calcium is an important electrolyte that is crucial for numerous intracellular and extracellular functions as well as skeletal bone support. Calcium is necessary for muscle contraction and for neuromuscular function. In muscle contraction, ionized calcium mediates acetylcholine release during neuromuscular transmission. Calcium also stabilizes nerve cell membranes by decreasing membrane permeability to sodium. Because of the complexity of its functions, normal homeostatic control mechanisms attempt to keep serum calcium within a narrow range, but only the circulating ionized component of total calcium is regulated. When these homeostatic mechanisms are disrupted or overwhelmed, conditions of hypocalcemia or hypercalcemia can occur and may be life threatening. Three forms of circulating calcium exist in serum and plasma: ionized (free), protein bound, and complexed (calcium bound to phosphate, bicarbonate, lactate, citrate, oxalate).1 Total calcium routinely measured on serum automated biochemical analyzers measures all three of these components. The ionized form of calcium is the biologically active form in the body and is considered the most important indicator of functional calcium levels. Calcium regulation is a complex process involving primarily parathyroid hormone (PTH), vitamin D metabolites, and calcitonin. These calcium regulatory hormones exert most of their effects on the intestine, kidney, and bone. PTH is synthesized and secreted by the chief cells of the parathyroid gland in response to hypocalcemia, low calcitriol levels (also known as 1,25(OH)2D3, the principal active vitamin D metabolite), and low levels of 25(OH) vitamin D3 (calcidiol). PTH is synthesized and secreted constantly at sufficient rates to maintain serum ionized calcium levels within a narrow range in healthy animals. PTH secretion is normally inhibited by increased serum ionized calcium levels, as well as by increased concentrations of circulating calcitriol. The principal action of PTH is to increase blood calcium levels through increased tubular reabsorption of calcium, increased osteoclastic bone resorption, and increased production of calcitriol that then increases intestinal absorption of calcium.

• Acute treatment of moderate to severe ionized hypercalcemia involves intravenous saline, furosemide, calcitonin, and glucocorticoids. Severe cases may benefit from bisphosphonate treatment. • In many instances, treatment of severe and symptomatic hypocalcemia involves the administration of immediate intravenous boluses of calcium salts followed by a constant rate infusion to maintain normal serum ionized calcium levels.

Vitamin D and its metabolites also play a central role in calcium homeostasis. Dogs and cats, unlike humans, photosynthesize vitamin D inefficiently in their skin and therefore depend on vitamin D in their diet.2 After ingestion and uptake, vitamin D (cholecalciferol) is first hydroxylated in the liver to 25(OH)D3 (calcidiol), and then it is further hydroxylated to calcitriol by the proximal tubular cells of the kidney. This final hydroxylation by the 1a-hydroxylase enzyme system to form active calcitriol is under tight regulation and is influenced primarily by serum PTH, calcitriol, phosphorus, ionized calcium, and fibroblast growth factor 23 (FGF-23) concentrations. Decreased levels of phosphorus, calcitriol, and calcium promote calcitriol synthesis, and increased levels of these substances all cause a decrease in calcitriol synthesis. Increased PTH has a potent effect to enhance calcitriol synthesis, whereas FGF-23 inhibits the synthesis of calcitriol.3 With regard to calcium homeostasis, calcitriol primarily acts on the intestine, bone, kidney, and parathyroid gland. In the intestine, calcitriol enhances the absorption of calcium and phosphate at the level of the enterocyte. In the bone, calcitriol promotes bone formation and mineralization by regulation of proteins produced by osteoblasts. In addition, calcitriol is also necessary for normal bone resorption because of its effect on osteoclast differentiation. In the kidney, calcitriol acts to inhibit the 1a-hydroxylase enzyme system, as well as promote calcium and phosphorus reabsorption from the glomerular filtrate. In the parathyroid gland, calcitriol acts genomically to inhibit the synthesis of PTH. Although minor when compared with the effects of PTH and vitamin D metabolites, calcitonin also plays a role in calcium homeostasis. It is produced by the parafollicular C cells in the thyroid gland in response to an increased concentration of calcium after a calcium-rich meal and also during hypercalcemia. Calcitonin acts mostly on the bone to inhibit osteoclastic bone resorption activity but also decreases renal tubular reabsorption of calcium.

333

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CALCIUM MEASUREMENT

BOX 57.11  Differential Diagnoses for

Sample Handling Techniques

Hypercalcemia

When collecting blood samples from patients for calcium measurements, the patient should be fasted before collection, if possible, to minimize postprandial increases in calcium. Both serum and heparinized plasma samples can be used, however certain anticoagulants (i.e., oxalate, citrate, and ethylenediaminetetraacetic acid) should not be used because they bind calcium, which can dramatically lower measured calcium levels. When measuring ionized calcium using ion specific electrodes, serum is preferred over whole or heparinized blood because of less variation in results. Heparinized samples are satisfactory for use when a standardized protocol of heparin and fill volume to tubes is used (see Chapter 202, Blood Gas Sampling). In addition, anaerobic samples are preferred for ionized calcium measurement because pH can alter the concentration. In aerobic conditions, carbon dioxide can be lost, thus raising the pH in the sample. An alkalotic pH may increase the binding of calcium to protein, especially albumin, and therefore artificially decrease the amount of ionized calcium in the sample.4 Handheld pointof-care analyzers report ionized calcium values that are less than those from bench machines; this error increases with the magnitude of the calcium being measured.5 You can use whole blood without anticoagulant directly into the ionized calcium cartridge, but it must be promptly applied immediately after blood collection. This needs to be done quickly to avoid clotting of the lines in the cartridge.

Nonpathologic Postprandial Juvenile, growing animal Laboratory error Lipemia

Ionized Versus Total Calcium The calcium status of most animals is usually obtained first via measurement of total calcium (tCa). However, this parameter often does not reflect the ionized calcium concentration of the diseased patient,6,7 especially in critically ill animals. When attempts are made to predict ionized calcium concentrations in the cat based on total calcium measurements, hypercalcemia and normocalcemia are often underestimated, whereas hypocalcemia is often overestimated.7 In dogs, the opposite appears to be true; the frequency of hypercalcemia and normocalcemia is overestimated and hypocalcemia underestimated.6 In nonhyperphosphatemic dogs, an optimal tCa concentration threshold of 12.0 mg/dl resulted in a positive predictive value of 93% (95% CI, 84%298%) and sensitivity of 52% (95% CI, 43%261%) for ionized hypercalcemia.8 In dogs with chronic renal failure or hyperphosphatemia, the magnitude of error greatly increases, with hypercalcemia being over diagnosed (total calcium is high while ionized calcium is normal, likely due to increased binding to circulating complexes during chronic kidney disease [CKD]).7,8 A tCa .11.8 mg/dl and ionized hypercalcemia commonly occur in azotemic cats. However, there are many azotemic and nonazotemic cats with ionized hypercalcemia with a tCa ,11.8 mg/dl.9 Multivariate predictive models of ionized calcium concentration have been developed in both the dog and cat and are superior to the use of tCa or corrected total calcium alone to predict ionized calcium.10,11 However, use of these surrogates for ionized calcium measurement should only be considered when it is not possible to measure ionized calcium as there is a discordance of 5.1%.11 Therefore, for accurate assessment of patient calcium status, measurement of ionized calcium is recommended. The first developed correction formulas that were used to predict ionized calcium status from total serum calcium were quite inaccurate.6

HYPERCALCEMIA Hypercalcemia can be caused by numerous disease processes (Box 57.1) and may exert toxic systemic effects on multiple organs when ionized hypercalcemia is present.

Transient or Inconsequential Hemoconcentration Hyperproteinemia Hypoadrenocorticism Pathologic or Persistent/Consequential Parathyroid Dependent Primary hyperparathyroidism Adenoma Adenocarcinoma Hyperplasia Overdose of recombinant PTH Parathyroid Independent Malignancy Humoral hypercalcemia of malignancy Lymphosarcoma Anal sac apocrine gland adenocarcinoma Carcinoma (e.g., thyroid, prostate, mammary) Thymoma Hematologic malignancies (bone marrow osteolysis, local osteolytic disease) Lymphosarcoma Multiple myeloma Leukemia Myeloproliferative disorders Bone neoplasia (primary or metastatic) Idiopathic hypercalcemia (cats) Chronic renal failure Calcinosis cutis during recovery, especially after dimethyl sulfoxide (DMSO) Hypervitaminosis D Iatrogenic Plants (calcitriol glycosides) Rodenticide (cholecalciferol) Antipsoriasis creams (calcipotriene or calcipotriol) Granulomatous disease (calcitriol synthesis) Fungal infections Injection site reaction Sterile dermatitis Acute kidney injury Skeletal lesions Osteomyelitis Hypertrophic osteodystrophy Disuse osteoporosis Bone infarction Excessive oral or injectable calcium administration Calcium-containing intestinal phosphate binders Calcium supplementation (calcium carbonate, calcium gluconate, calcium chloride) Hypervitaminosis A Raisin/grape toxicity DMSO treatment of calcinosis cutis

CHAPTER 57  Calcium Disorders

Clinical Signs and Diagnosis Clinical signs associated with hypercalcemia loosely parallel the severity of the calcium elevation, though there are exceptions by individual animals. Common signs include polyuria and polydipsia (uncommon in cats), anorexia, constipation, lethargy, and weakness. Severely affected animals may display ataxia, obtundation, listlessness, muscle twitching, seizures, or coma. Bradycardia may be detected on physical examination, and electrocardiographic (ECG) monitoring may reveal a prolonged PR interval, widened QRS complex, shortened QT interval, shortened or absent ST segment, and a widened T wave. Bradyarrhythmia may progress to complete heart block, asystole, and cardiac arrest in severely affected animals. Other abnormalities may also be secondary to the underlying disease process causing the hypercalcemia. Usually, hypercalcemia is initially documented when total serum calcium is measured as part of the animal’s diagnostic workup for clinical signs. Normal calcium values for dogs and cats can have a wide range and differ from laboratory to laboratory, so reference values should be used from the laboratory to which the sample was submitted. In general, normal total calcium values are approximately 10 mg/ dl for dogs and 9 mg/dl for cats, although each machine should have its own reference ranges. These values are for mature animals because growing animals (dogs especially) can have higher total calcium values, likely secondary to normal bone growth. Once a diagnosis of hypercalcemia is suspected based on the total calcium value (.12 mg/dl in the dog and .11 mg/dl in the cat), an ionized calcium measurement should be performed to confirm the diagnosis. Measurement of ionized calcium can be valuable in animals with a total calcium within the reference range since ionized calcium is elevated before the total calcium increases with certain disease states. In patients with trending increases in total calcium, the ionized calcium may already be increased or predicted to continue to increase, as seen in CKD cats.12 A diagnosis of hypercalcemia is confirmed with an ionized calcium measurement generally greater than 6 mg/dl or 1.5 mmol/L in the dog or greater than 5.7 mg/dl or 1.4 mmol/L in the cat. The reference range of the analyzer employed should be used for this cutoff. Once the hypercalcemia is confirmed, a thorough physical examination should be repeated. The clinician should palpate the anal sacs (dogs) and peripheral lymph nodes for any enlargement, perform a fundic examination (e.g., systemic disease, mycoses, neoplasia), and do a thorough evaluation for any masses that may have been missed on initial examination (e.g., mammary tumors). Further diagnostic maneuvers should be tailored to the individual patient based on clinical signs, physical examination findings, initial laboratory testing, and suspected etiology but may include a complete blood cell count, chemistry panel, urinalysis, imaging (thoracic radiographs, abdominal radiographs, abdominal ultrasonography, parathyroid ultrasonography), fine-needle aspiration with cytologic evaluation of any masses found, PTH measurement, PTH-related protein measurement, calcidiol and calcitriol measurement, bone biopsy, and bone marrow aspiration. Thoracic radiographs are especially important in ill dogs with ionized hypercalcemia, and the absence of anal sac changes as T-cell lymphoma commonly affects the mediastinum. Thoracic radiographs are recommended in all cases in an attempt to rule out metastatic diseases and thymic masses.

Differential Diagnoses A list of differential diagnoses for hypercalcemia is presented in Box 57.1, with neoplasia-associated hypercalcemia (specifically lymphoma) being the most common cause in dogs, followed by renal failure, hyperparathyroidism, and hypoadrenocorticism.13 Rat bait containing cholecalciferol has the potential to again become an important cause of hypercalcemia in the United States due to recent regulatory changes limiting the use of more toxic products. In cats, neoplasia was

335

BOX 57.21  Clinical Signs Associated with

Hypocalcemia

Common None Muscle tremors or fasciculations Facial rubbing Muscle cramping Stiff gait Behavioral change Restlessness or excitation Aggression Hypersensitivity to stimuli Disorientation

Pyrexia Lethargy Anorexia Prolapse of third eyelid (cats) Posterior lenticular cataracts Tachycardia or ECG alterations (i.e., prolonged QT interval) Uncommon Polyuria or polydipsia Hypotension Respiratory arrest or death

Occasional Seizures Panting ECG, electrocardiography.

reported as the most common underlying diagnosis based on total calcium with renal failure as the second most common. In another more report based on the results of ionized calcium, idiopathic hypercalcemia was the most common diagnosis (48%), followed by CKD (35%), urolithiasis (14%), neoplasia (13%) and primary hyperparathyroidism (3%).14 Serum phosphorus levels tend to be normal or low in animals with primary hyperparathyroidism or malignancies with an elevated PTH or PTH-related protein. Dogs with neoplasia-associated ionized hypercalcemia (specifically lymphoma and anal sac adenocarcinoma) often have higher serum ionized calcium concentrations than those with renal failure, hypoadrenocorticism, and other types of neoplasia.13 However, the magnitude of ionized hypercalcemia alone does not predict specific disease states.13 A thorough discussion of the pathophysiology of hypercalcemia in various disease processes is beyond the scope of this chapter; however, a thorough understanding of these principles is important because they serve as a guide for diagnosis and treatment.1

Treatment of Hypercalcemia The consequences of hypercalcemia can be severe and affect multiple body systems including the central nervous system (CNS), gastrointestinal tract, heart, and kidneys. Therefore, a timely diagnosis and rapid intervention can be vital, especially in animals with acute development of severe hypercalcemia. However, there is no absolute calcium value that should serve as a guide for initiating aggressive treatment. Rather, intervention should be guided by multiple factors, including the magnitude of hypercalcemia, rate of development, stable or progressive disease, clinical signs associated with hypercalcemia, organ dysfunction (renal, cardiac, CNS), clinical condition of the patient, and suspected etiology of the hypercalcemia (Fig. 57.1). In addition, evaluation of phosphorus concentrations may help in guiding therapy because a calcium-phosphorus product greater than 60 represents an increased risk for soft tissue mineralization. Definitive treatment for hypercalcemia involves removing the underlying cause. However, in many cases the cause is not readily apparent, and sometimes palliative therapy must be instituted before treating the primary disease (Table 57.1). Acute therapy often involves the use of one or more of the following: intravenous fluids, diuretics (furosemide), glucocorticoids, and calcitonin (Fig. 57.2A). The therapeutic fluid of choice for animals with hypercalcemia is 0.9% sodium chloride because the additional

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PART V  Electrolyte and Acid-Base Disturbances

Cardiac arrhythmias Rapid ↓ renal function

Seizures

Hypercalcemic crisis Rapid ↑ encephalopathy

Muscle twitching High level hypercalcemia With or without clinical signs

7.0 mg/dl 1.75 mmol/L Ionized calcium (cats)

7.5 mg/dl 1.88 mmol/L Ionized calcium (dogs)

Fig. 57.1  Definition of hypercalcemic crisis.

sodium ions provide competition for renal tubular calcium reabsorption, resulting in enhanced calciuria. In addition, 0.9% sodium chloride is calcium-free, unlike other isotonic crystalloids (see Chapter 65, Crystalloid Solutions). Intravenous fluid therapy should be used to correct dehydration and then given at rates of at least 1.5 to 2 times maintenance, if possible (see Chapter 67, Daily Intravenous Fluid Therapy). Potassium supplementation is often needed with this fluid protocol (see Chapter 56, Potassium Disorders). Systemic blood pressure should be determined before and during IV fluid therapy since hypercalcemia can contribute to the development of hypertension secondary to vasoconstriction. Furosemide enhances urinary calcium loss but should not be used in volume-depleted animals. Suggested dosages of furosemide are 1 to 2 mg/kg IV, subcutaneously (SC), or PO q6-12h. A constant rate infusion (CRI) of 0.2 to 1 mg/kg/hr may be beneficial during a hypercalcemic crisis.15 Meticulous attention to fluid balance is essential when this method is used to avoid serious volume depletion. It is beneficial to place a urinary catheter to match the amount of fluid administered with urinary losses to ensure adequate volume replacement during aggressive diuresis. Glucocorticoids can cause a reduction in serum calcium concentration in many animals with hypercalcemia due to a combination of nonspecific mechanisms. Glucocorticoids lead to reduced bone resorption, decreased intestinal calcium absorption, and increased renal calcium excretion. The magnitude of decline with therapy depends on the cause of the hypercalcemia. Dexamethasone often is given at dosages of 0.1 to 0.22 mg/kg SC or IV q12-24h or prednisone at dosages of 1 to 2.2 mg/kg PO, SC, or IV q12h. However, in patients that have no definitive diagnosis for the hypercalcemia, calcitonin or bisphosphonate therapy should be considered instead of glucocorticoids to avoid interference with obtaining an accurate cytologic or histopathologic diagnosis as a result of steroid-induced cytolytic effects on lymphoid and plasma cells (e.g., lymphosarcoma, myeloma). Calcitonin acts to decrease serum calcium concentrations mostly by reducing the activity and formation of osteoclasts. Calcitoninsalmon can be used at a dosage of 4 to 6 IU/kg SC q8-12h. Vomiting may occur after several days of administration in dogs. The effectiveness of calcitonin to control hypercalcemia can diminish after several

days. Sodium bicarbonate can also be considered for crisis therapy because it decreases the ionized and total calcium; effects on the bound fractions of calcium have not been examined in this situation.16 Sodium bicarbonate is given at a dosage of 0.521 mEq/kg IV over 0.524 hours (up to 4 mEq/kg total dose if repeated) when patients are at risk for death (see Table 57.1). Acid-base status should be monitored closely to avoid inducing alkalemia or other complications of bicarbonate therapy (i.e., paradoxical cerebral acidosis, hypernatremia, hypokalemia). Peritoneal or hemodialysis using calcium-free dialysate can be considered in cases refractory to traditional therapy, but this is rarely performed in these instances. Fluid therapy should always be considered as the first treatment option and other modalities added based on response to therapy and the status of the patient. Subacute or long-term treatment to decrease calcium levels may be needed in some cases, rather than acute rescue therapy. Glucocorticoids and furosemide can be used for long-term therapy and are usually administered orally. In addition, subcutaneous fluids (0.9% sodium chloride) can be given at dosages of 75 to 100 ml/kg q24h as needed. Bisphosphonates are a class of drugs that have been used in human and veterinary medicine for management of hypercalcemia.17 These drugs decrease osteoclastic activity, thus decreasing bone resorption. Bisphosphonates can take 1 to 3 days to maximally inhibit bone resorption, so they are not considered drugs of choice for acute or crisis therapy.18 Pamidronate has been the most commonly used bisphosphonate in veterinary medicine for the management of hypercalcemia; zoledronate is more potent than pamidronate and can be considered for use in selected patients.19 Pamidronate can be given IV at dosages of 1.3 to 2 mg/kg in 150 ml 0.9% saline as a 2-hour to 4-hour infusion.17 This dose can be repeated in 1 week, if needed, but the salutary effect may last for 1 month in some instances. Zoledronate has become a popular alternative to pamidronate. Zoledronate has been previously shown to be superior to pamidronate in the treatment of hypercalcemia in human patients.20 Zoledronate caused a median total and ionized calcium concentration decrease of 26.5% and 19%, respectively, in four dogs.19 This median total calcium decrease was similar to reported pamidronate use of 28.5%.17 Zoledronate can be given IV at dosages of

CHAPTER 57  Calcium Disorders

337

↑ Renal calcium excretion

Dilute calcium in plasma

Mild volume expansion 2-3 times maintenance

Correct dehydration

Calcitoninsalmon 4-6 U/kg SQ TID to QID

Short-lived effect

0.9% NaCl  Add KCI

IV fluids

Furosemide Bolus IV 1 mg/kg

Quick onset of effect

CRI 0.2-1 mg/kg/hr

Monitor urine output

Vomiting and anorexia

Tachyphylaxis

A

Prednisolone 1-2.2 mg/kg BID PO, SQ, or IV Dexamethasone 0.1-0.22 mg/kg PO, SQ, IV

If hypercalcemia expected to be protracted

Sub-acute onset of effect

Match “ins and outs”

Avoid if definitive diagnosis unknown

If genesis of hypercalcemia  bone origin

IV Bisphosphonates

IV fluids before, during, after Pamidronate 1.3-2.0 mg/kg IV in 150 mL NaCl over 4 hours

B

Expect major ↓ ionized calcium within 72 hours

Repeat every 2-4 weeks as needed

Zolendronate 0.1-0.25 mg/kg in 45-100 ml NaCl over 30 min

Fig. 57.2  A, Acute and subacute treatment of critically ill patients with ionized hypercalcemia. CRI, constant rate infusion; SC, subcutaneous. B, Bisphosphonates for subacute and chronic treatment of clinically ill patients with ionized hypercalcemia.

0.1 to 0.25 mg/kg in 452100 ml 0.9% NaCl over 30 minute infusion (Fig. 57.2B). Crisis management for idiopathic hypercalcemia in cats is almost never needed because of the insidious development of hypercalcemia. Oral alendronate starting at 1 to 3 mg/kg/wk or 10240 mg/cat/wk has been used for the chronic treatment of idiopathic hypercalcemia in cats.21,22 This medication may provide more long-term control of idiopathic hypercalcemia in cats compared with other proposed treatments (author’s unpublished observations). However, it should be noted that oral alendronate is not as effective as intravenous bisphosphonate

therapy in the acute setting. Oral bisphosphonates can cause esophageal irritation and have been reported to cause abdominal discomfort, nausea, and vomiting in humans,23 so standard precautionary measures should be taken to decrease esophageal transit time in patients receiving these medications. This may include giving several milliliters of water orally24 after the administration of these pills and also “buttering”25 of the lips to encourage salivation and to decrease transit time of the pills into the stomach. Splitting of tablets is not recommended because of the potential for more severe corrosive effects. Bone toxicity from longterm treatment with bisphosphonates has been reported in the dog26

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PART V  Electrolyte and Acid-Base Disturbances

TABLE 57.1  Treatment of Hypercalcemia1 Treatment

Dosage

Indications

Comments

0.9% NaCl

426 ml/kg/hr IV CRI

Moderate to severe hypercalcemia

Contraindicated in congestive heart failure and hypertension

Furosemide

1 to 2 mg/kg IV, SC, PO q6-12h CRI 0.2 to 1 mg/kg/hr

Moderate to severe hypercalcemia

Ensure adequate volume status before administration Rapid onset

Dexamethasone

0.1 to 0.22 mg/kg SC, IV q12-24h

Moderate to severe hypercalcemia

Use before identification of etiology may make definitive diagnosis difficult or impossible

Prednisone

1 to 2.2 mg/kg PO, SC, IV q12h

Moderate to severe hypercalcemia

Use prior to identification of etiology may make definitive diagnosis difficult or impossible

Calcitonin-salmon

4 to 6 IU/kg SC q8-12h

Hypervitaminosis D

Response may be short lived Vomiting may occur after multiple doses Rapid onset

Sodium bicarbonate 1 mEq/kg IV over 0.524 h (may give up to 4 mEq/kg total dosage)

Severe, life-threatening hypercalcemia

Requires close monitoring of pH and electrolytes Rapid onset Contraindicated if hypoventilation present

Pamidronate (bisphosphonate)

1.3 to 2.0 mg/kg in 150 ml 0.9% NaCl IV over 2 to 4 hr

Moderate to severe hypercalcemia

Generic affordable Delayed onset 123 days

Zoledronate (bisphosphonate)

0.120.25 mg/kg in 45-100 ml 0.9% NaCl over 30 min

Moderate to severe hypercalcemia

More potent than pamidronate; generic affordable

Cinacalcet (calcimimetic)

anecdotally 0.5 mg/kg (starting dose)

Tertiary hyperparathyroidism Malignant primary hyperparathyroidism Nonsurgical patients with primary hyperparathyroidism

Calcimimetic drug May have future uses in veterinary medicine

CRI, constant rate infusion; NaCl, sodium chloride; SC, subcutaneous.

and cat27,28 with osteonecrosis of the jaw. Pathologic fractures of both patellae were reported in one cat on long-term oral alendronate; this cat also had increased cortical bone thickness to the tibia as a possible indicator of ongoing bone toxicity.29 Calcimimetics belong to a class of drugs that are rarely used in veterinary medicine to treat cases of hypercalcemia in which the underlying cause cannot be treated adequately by other means (tertiary hyperparathyroidism, primary hyperparathyroidism caused by carcinoma). These drugs activate the calcium-sensing receptor and thus decrease PTH secretion. Cinacalcet has been marketed for use in humans to treat renal secondary hyperparathyroidism and nonsurgical primary hyperparathyroidism but reports for the use of cinacalcet in animals are lacking. There are anecdotal reports on list serves describing this use for primary hyperparathyroidism in dogs.

HYPOCALCEMIA Decreased total serum calcium is a common electrolyte disturbance in critically ill dogs and cats. Decreased total serum calcium is particularly common in those with low circulating albumin status but it may not match up with the ionized calcium status. In two previous studies, the prevalence of ionized hypocalcemia was 31% in sick dogs and 27% in cats.6,7 It has been suggested that dogs with ionized hypocalcemia that are critically ill or that underwent trauma may have a worse prognosis than normocalcemic dogs. More commonly, these dogs required blood transfusions, colloid therapy, and vasopressors.30 Additionally, septic dogs with positive cultures were more likely to have ionized hypocalcemia and require longer hospitalization.31 Similar findings are noted in cats where 89% of them had ionized hypocalcemia at the time of septic peritonitis diagnosis.32 Failure to normalize ionized hypocalcemia during hospitalization was associated with decreased survival rate to discharge.32 It is not uncommon for cats with pancreatitis to have ionized hypocalcemia (58.3% in one study).33 In this cohort of

cats with pancreatitis and ionized hypocalcemia, ,1.0 mmol/L were considered to have a poor prognosis. Seventy-five percent of male cats with urethral obstruction had ionized calcium below the reference range in one study. Hypocalcemia was considered mild in 38%, moderate in 25%, and severe in 12.5%. It was suggested that low circulating ionized calcium can contribute to electrical and mechanical cardiac changes in very sick cats that are affected by urethral obstruction.34 Eclampsia in dogs is the diagnosis most likely to require emergency treatment of acute hypocalcemia in primary care practices.

Clinical Signs and Diagnosis A list of clinical signs that occur with hypocalcemia is presented in Box 57.2. Signs of hypocalcemia are often not seen until serum total calcium concentrations are less than 6.5 mg/dl (,4 mg/dl or ,1 mmol/L ionized calcium), and many animals show few signs even with lower calcium levels. Most animals with rapid development of hypocalcemia show clinical signs. Severely affected animals may have decreased inotropy and chronotropy (bradycardia), and ECG abnormalities may include a prolonged QT interval (because of prolonged ST segment); deep, wide T waves; or atrioventricular block. Hypocalcemia is often discovered fortuitously after routine measurement of serum total calcium concentration. Hypocalcemia is defined as a total calcium concentration less than 8 mg/dl in dogs and less than 7 mg/dl in cats. When hypocalcemia is diagnosed via total calcium concentrations, it should always be confirmed with an ionized calcium measurement. Using ionized calcium concentrations, hypocalcemia is generally defined as less than 5 mg/dl (1.25 mmol/L) in dogs and less than 4.5 mg/dl (1.1 mmol/L) in cats, but these cutoff points should be refined based on the reference range for the specific analyzer. After hypocalcemia is confirmed, other diagnostic strategies such as a complete blood cell count, chemistry panel, urinalysis, PTH measurement, and vitamin D metabolite measurements should be considered to establish a definitive diagnosis.

CHAPTER 57  Calcium Disorders

Differential Diagnoses A list of differential diagnoses for hypocalcemia is presented in Box 57.3. The most common cause of a total serum hypocalcemia is hypoalbuminemia. However, the hypocalcemia associated with this is usually mild and typically no clinical signs result. Correction formulas have been advocated in the past to correct calcium levels for a low albumin, but these formulas do not accurately predict ionized or total calcium concentrations and are therefore not recommended.6,7 Renal dysfunction appears to be the second most common cause of hypocalcemia in dogs. Primary hypoparathyroidism is the one condition that will require long-term calcium-specific treatment. If the serum phosphorus level is above the reference range at the same time that hypocalcemia is discovered, the most likely diagnoses to rule out include renal dysfunction, pancreatitis (with or without prerenal azotemia), excessive phosphorous intake, and primary hypoparathyroidism.

Treatment The consequences of untreated severe ionized hypocalcemia can be life threatening because of myocardial failure and respiratory arrest. This may be particularly important in dogs with sepsis because the presence of ionized hypocalcemia has been shown to be a negative prognostic

BOX 57.3  Differential Diagnoses for Hypocalcemia Hypoalbuminemia Chronic renal failure Eclampsia Acute kidney injury Pancreatitis Soft tissue trauma or rhabdomyolysis Hypoparathyroidism Primary hypoparathyroidism Idiopathic Iatrogenic (postoperative bilateral thyroidectomy) After sudden reversal of chronic hypercalcemia Secondary to magnesium depletion, retention Ethylene glycol Phosphate enema Bicarbonate administration Improper sample anticoagulant (EDTA) Infarction of parathyroid gland adenoma Rapid IV infusion of phosphates Acute calcium-free IV infusion Intestinal malabsorption, PLE, starvation Hypovitaminosis D Blood transfusion (with citrate-containing anticoagulant) Hypomagnesemia (PTH secretion and receptor effects) Nutritional secondary hyperparathyroidism Acute tumor lysis syndrome Chelating agents Calcium EDTA, dimercaprol (British anti-Lewisite), d-penicillamine, and meso-2,3-dimercaptosuccinic acid (succimer, IV radiocontrast) Excessive bisphosphonate treatment Hypocalcemia of critical illness EDTA, ethylenediaminetetraacetic acid; PLE, protein-losing enteropathy; PTH, parathyroid hormone. Modified from Schenck PA, Chew DJ, Nagode LA, Rosol TJ: Disorders of calcium: hypercalcemia and hypocalcemia. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders in small animal practice, ed 4, St Louis, 2012, Saunders Elsevier, pp 120-194.

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indicator.35 Septic cats also have a high prevalence of ionized hypocalcemia; failure to normalize during hospitalization is associated with a longer length of hospitalization and ICU stay.32 The decision to treat hypocalcemia should be based on multiple factors, including severity of clinical signs, rate of development of hypocalcemia, and etiology of the primary disease. Hypermagnesemia and hypomagnesemia can impair the secretion of PTH and PTH actions on its receptor, so measurement of serum magnesium (preferably ionized magnesium) is important, especially in animals with refractory hypocalcemia. Ionized hypocalcemia, low serum 25-hydroxyvitamin D (25[OH]D) concentrations, and elevated PTH serum concentrations have been reported in dogs with protein-losing enteropathies.36 Many of these animals often undergo anesthetic procedures for diagnostic purposes (e.g., intestinal biopsy); therefore it may be warranted to treat ionized hypocalcemia, if present, because tachycardia, ECG alterations (i.e., prolonged QT interval), refractory hypotension, and respiratory arrest are all possible complications of ionized hypocalcemia. Patients with decreased total calcium concentrations but normal ionized calcium concentrations require no treatment. If a decreased ionized calcium concentration is found, the clinician must decide if therapy is warranted. If the patient is stable, no clinical signs referable to hypocalcemia are documented, and the ionized calcium is not progressively decreasing, then it is reasonable to consider not treating these patients. Patients with a severe decrease in ionized calcium concentration warrant calcium-specific treatment regardless of clinical signs.34, 37 Therapy may also be initiated in an asymptomatic patient with moderate progressive ionized hypocalcemia to prevent the development of signs (as often happens after parathyroidectomy for parathyroid gland adenoma). Patients with clinical signs attributed to hypocalcemia clearly should receive calcium-specific rescue therapy. Treatment of hypocalcemia can be divided into acute and subacute to long term. As with all cases of hypocalcemia, attempts should always be made to treat the primary disease causing the disorder. Most cases of hypocalcemia do not require long-term therapy, with hypoparathyroidism being the exception. Many cases will require acute treatment, especially those with tetany, seizures, or muscle fasciculations. Therapy typically involves the administration of calcium salts, as well as vitamin D metabolites. For acute therapy, calcium should be administered intravenously to effect over a 10- to 20-minute period. Calcium gluconate and calcium chloride are both available for treatment, but calcium gluconate is preferred because it is not irritating if injected perivascularly (unlike calcium chloride). Calcium salts should NEVER be given subcutaneously because they can cause skin necrosis and abscess formation severe enough to warrant euthanasia, even when diluted calcium preparations are administered. Calcium gluconate (10% solution, calcium 9.3 mg/ml) can be given at dosages of 0.5 to 1.5 ml/kg IV slowly to effect. Heart rate and ECG should be monitored closely during administration to look for bradycardia; prolonged PR interval; widened QRS complex; shortened QT interval; elevated, shortened, or absent ST segment; and widened T wave, all of which may indicate cardiac toxicity. It is important to note that it may take up to 30 to 60 minutes for all clinical signs to resolve after correction of hypocalcemia, and some behavioral changes and panting may persist during this time. For subacute management, the initial bolus of calcium salts often needs to be followed with a CRI of calcium, especially if the hypocalcemia is expected to persist. A CRI of elemental calcium can be delivered at a rate of 1 to 3 mg/kg/hr IV based on the severity of hypocalcemia to maintain normal calcium levels until oral calcium administration and or vitamin D metabolites can be used to control serum calcium concentrations. Vitamin D metabolites should also be started early if the hypocalcemia is expected to persist because it may take several days for

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PART V  Electrolyte and Acid-Base Disturbances

TABLE 57.2  Treatment of Hypocalcemia40 Drug Parenteral Calcium

Calcium gluconate

Preparation

Calcium Comment

Dose

Content Not recommended to give calcium salts in SQ fluids (even when diluted) due to possible abscess formation, skin necrosis, and mineralization

a

10% solution

9.3 mg of Ca/ml

a. Slow IV to effect (0.5–1.5 ml/kg IV) acute crisis: 502150 mg/kg over 20230 min

Stop if bradycardia or shortened QT interval occurs

Infusion to maintain normal calcium b. 5–15 mg/kg/h IV 1000-1500 mg/kg/day or (42263 mg/kg/hr) Calcium chloride

10% solution

27.2 mg of Ca/ml 5–15 mg/kg/h IV

Only given IV as extremely caustic perivascularly

Calcium carbonate

Many sizes

40% tablet

25–50 mg/kg/day

Most common calcium supplement

Calcium lactate

325, 650 mg tablets 13% tablet

25–50 mg/kg/day

Calcium chloride

Powder

27.2%

25–50 mg/kg/day

Calcium gluconate

Many sizes

10%

25–50 mg/kg/day

Oral Calciumb

May cause gastric irritation

Vitamin D

Time for Maximal Effect to occur:

Time for Toxicity Effect to Resolve: 1218 weeks

Vitamin D2 (ergocalciferol)

Initial: 4000–6000 U/kg/day Maintenance:1000–2000 U/kg once daily to once weekly

5221 days

Vitamin D3 (cholecalciferol)

100 IU /kg/day

Typically given for 6 Over the counter weeks. Then, recheck 25(OH) vitamin D level and calcium level

Dihydrotachysterol

Initial: 20230 mcg/kg/day

1–7 days

123 weeks

1–4 days

2–14 days

prescription only

Maintenance: 10220 mcg/kg q24-48h 1,25-(OH)2 D3 (calcitriol)

Initial: 20230 ng/kg/day for 324 days Maintenance: 5215 ng/kg/day

Do not mix calcium solution with bicarbonate-containing fluids as precipitation may occur. Calculate dose on elemental calcium content. Modified from de Brito Galvao JF, Schenck PA, Chew DJ: A quick reference on hypocalcemia, Vet Clin North Am Small Anim Pract 47(2):249-256, 2017.

a

b

intestinal calcium transport to be maximized. Calcitriol is the preferred active vitamin D metabolite because it has a quick onset of action, short plasma half-life, and relatively short biologic effect half-life (important if overshoot hypercalcemia occurs). Calcitriol is dosed at 20 to 30 ng/kg (up to 60 ng/kg in some instances) PO divided twice a day for 3 to 4 days for induction, then 5 to 15 ng/kg q24h divided twice a day for maintenance therapy and titrated to the desired level of serum calcium concentration. For long-term therapy (e.g., primary hypoparathyroidism), oral calcium usually is needed to control serum calcium levels. It should be noted, however, that the goal of therapy with hypoparathyroidism is not to return calcium levels completely to normal because this can have deleterious effects (hypercalciuria despite normocalcemia in the absence of basal effects that PTH normally has on renal tubules). One should aim to control signs and correct calcium levels to just below normal. Many forms of oral calcium are available (calcium carbonate, calcium lactate, calcium chloride, calcium gluconate) and all are dosed at 25 to 50 mg/kg q24h (divided and given twice a day) (Table 57.2). Calcium carbonate is the most common form of calcium used and is generally well tolerated. Calcitriol can also be used at the previously mentioned dosages. Calcilytics are a relatively new class of drugs that antagonize the calcium-sensing receptor and thus stimulate PTH secretion. They

may have future use in veterinary medicine to treat some cases of hypocalcemia that are refractory to current therapies. Calcilytics are currently being investigated for their use in humans to treat osteoporosis and autosomal dominant hypocalcemia (familial hypercalciuric hypocalcemia).38,39

REFERENCES 1. Schenck PA, Chew DJ, Nagode LA: Disorders of calcium. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders in small animal practice, ed 4, St Louis, 2012, Saunders-Elsevier, pp 120-194. 2. How KL, Hazewinkel HA, Mol JA: Dietary vitamin D dependence of cat and dog due to inadequate cutaneous synthesis of vitamin D, Gen Comp Endocrinol 96(1):12-18, 1994. doi:10.1006/gcen.1994.1154. 3. de Brito Galvao JF, Nagode LA, Schenck PA, Chew DJ: Calcitriol, calcidiol, parathyroid hormone, and fibroblast growth factor-23 interactions in chronic kidney disease, J Vet Emerg Crit Care (San Antonio) 23(2):134-162, 2013. doi:10.1111/vec.12036. 4. Mazaki-Tovi M, Topol S, Aroch I: Effect of pH and storage conditions on measured ionised calcium concentration in dogs and cats, Vet Rec 187(9):e72, 2020. doi:10.1136/vr.105900. 5. Grosenbaugh DA, Gadawski JE, Muir WW: Evaluation of a portable clinical analyzer in a veterinary hospital setting, J Am Vet Med Assoc 213(5): 691-694, 1998.

CHAPTER 57  Calcium Disorders 6. Schenck PA, Chew DJ: Prediction of serum ionized calcium concentration by use of serum total calcium concentration in dogs, Am J Vet Res 66(8):1330-1336, 2005. doi:10.2460/ajvr.2005.66.1330. 7. Schenck PA, Chew DJ: Prediction of serum ionized calcium concentration by serum total calcium measurement in cats, Can J Vet Res 74(3):209-213, 2010. 8. Groth EM, Chew DJ, Lulich JP, et al: Determination of a serum total calcium concentration threshold for accurate prediction of ionized hypercalcemia in dogs with and without hyperphosphatemia, J Vet Intern Med 34(1):74-82, 2020. doi:10.1111/jvim.15654. 9. van den Broek DH, Chang YM, Elliott J, Jepson RE: Chronic kidney disease in cats and the risk of total hypercalcemia, J Vet Intern Med 31(2):465-475, 2017. doi:10.1111/jvim.14643. 10. Danner J, Ridgway MD, Rubin SI, Le Boedec K: Development of a multivariate predictive model to estimate ionized calcium concentration from serum biochemical profile results in dogs, J Vet Intern Med 31(5): 1392-1402, 2017. doi:10.1111/jvim.14800. 11. Robin E, Cuq B, Sharman MJ, Le Boedec K: The multivariate predictive model to estimate ionized calcium concentration from serum biochemical results in dogs: external validation, Vet Clin Pathol 49(1):48-58, 2020. doi:10.1111/vcp.12835. 12. Geddes RF, van den Broek DHN, Chang YM, Biourge V, Elliott J, Jepson RE: The effect of attenuating dietary phosphate restriction on blood ionized calcium concentrations in cats with chronic kidney disease and ionized hypercalcemia, J Vet Intern Med 35(2):997-1007, 2021. doi:10.1111/jvim.16050. 13. Messinger JS, Windham WR, Ward CR: Ionized hypercalcemia in dogs: a retrospective study of 109 cases (1998-2003), J Vet Intern Med 23(3): 514-519, 2009. doi:10.1111/j.1939-1676.2009.0288.x. 14. Sayyid M, Gilor C, Parker VJ, Rudinsky AJ, Chew DJ: Ionized hypercalcemia in cats: etiologies and associated clinical signs, J Vet Intern Med 30(4):1450, 2016. 15. Adin D, Atkins C, Papich MG: Pharmacodynamic assessment of diuretic efficacy and braking in a furosemide continuous infusion model, J Vet Cardiol 20(2):92-101, 2018. doi:10.1016/j.jvc.2018.01.003. 16. Chew DJ, Leonard M, Muir W III: Effect of sodium bicarbonate infusions on ionized calcium and total calcium concentrations in serum of clinically normal cats, Am J Vet Res 50(1):145-150, 1989. 17. Hostutler RA, Chew DJ, Jaeger JQ, Klein S, Henderson D, DiBartola SP: Uses and effectiveness of pamidronate disodium for treatment of dogs and cats with hypercalcemia, J Vet Intern Med 19(1):29-33, 2005. doi:10.1892/0891-6640(2005)19,29:uaeopd.2.0.co;2. 18. Guay DR: Ibandronate, an experimental intravenous bisphosphonate for osteoporosis, bone metastases, and hypercalcemia of malignancy, Pharmacotherapy 26(5):655-673, 2006. doi:10.1592/phco.26.5.655. 19. Schenk A, Lux C, Lane J, Martin O: Evaluation of zoledronate as treatment for hypercalcemia in four dogs, J Am Anim Hosp Assoc 54(6):e54604, 2018. doi:10.5326/JAAHA-MS-6681. 20. Major P, Lortholary A, Hon J, et al: Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials, J Clin Oncol 19(2): 558-567, 2001. doi:10.1200/JCO.2001.19.2.558. 21. Whitney JL, Barrs VR, Wilkinson MR, Briscoe KA, Beatty JA: Use of bisphosphonates to treat severe idiopathic hypercalcaemia in a young Ragdoll cat, J Feline Med Surg 13(2):129-134, 2011. doi:10.1016/j. jfms.2010.09.011. 22. Hardy BT, de Brito Galvao JF, Green TA, et al: Treatment of ionized hypercalcemia in 12 cats (2006-2008) using PO-administered alendronate, J Vet Intern Med 29(1):200-206, 2015. doi:10.1111/jvim.12507.

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23. Twiss IM, van den Berk AH, de Kam ML, et al: A comparison of the gastrointestinal effects of the nitrogen-containing bisphosphonates pamidronate, alendronate, and olpadronate in humans, J Clin Pharmacol 46(4):483-487, 2006. doi:10.1177/0091270006286781. 24. Westfall DS, Twedt DC, Steyn PF, Oberhauser EB, VanCleave JW: Evaluation of esophageal transit of tablets and capsules in 30 cats, J Vet Intern Med 15(5):467-470, 2001. doi:10.1892/0891-6640(2001)015,0467:eoetot .2.3.co;2. 25. Griffin B, Beard DM, Klopfenstein KA: Use of butter to facilitate the passage of tablets through the esophagus in cats, 445, 2003. 26. Lundberg AP, Roady PJ, Somrak AJ, Howes ME, Fan TM: Zoledronate- associated osteonecrosis of the jaw in a dog with appendicular osteosarcoma, J Vet Intern Med 30(4):1235-1240, 2016. doi:10.1111/jvim.13980. 27. Rogers-Smith E: Suspected bisphosphate-related osteonecrosis of the jaw in a cat being treated with alendronate for idiopathic hypercalcaemia, Vet Rec Case Reports 7(3):e000798, 2019. 28. Larson MJ, Oakes AB, Epperson E, Chew DJ: Medication-related osteonecrosis of the jaw after long-term bisphosphonate treatment in a cat, J Vet Intern Med 33(2):862-867, 2019. doi:10.1111/jvim.15409. 29. Council N, Dyce J, Drost WT, de Brito Galvao JF, Rosol TJ, Chew DJ: Bilateral patellar fractures and increased cortical bone thickness associated with long-term oral alendronate treatment in a cat, JFMS Open Rep 3(2):2055116917727137, 2017. doi:10.1177/2055116917727137. 30. Holowaychuk MK, Monteith G: Ionized hypocalcemia as a prognostic indicator in dogs following trauma, J Vet Emerg Crit Care (San Antonio) 21(5):521-530, 2011. doi:10.1111/j.1476-4431.2011.00675.x. 31. Holowaychuk MK, Hansen BD, DeFrancesco TC, Marks SL: Ionized hypocalcemia in critically ill dogs, J Vet Intern Med 23(3):509-513, 2009. doi:10.1111/j.1939-1676.2009.0280.x. 32. Kellett-Gregory LM, Mittleman Boller E, Brown DC, Silverstein DC: Ionized calcium concentrations in cats with septic peritonitis: 55 cases (19902008), J Vet Emerg Crit Care (San Antonio) 20(4):398-405, 2010. doi:10.1111/j.1476-4431.2010.00562.x. 33. Dias C, Carreira LM: Serum ionised calcium as a prognostic risk factor in the clinical course of pancreatitis in cats, J Feline Med Surg 17(12): 984-990, 2015. doi:10.1177/1098612X14564203. 34. Drobatz KJ, Hughes D: Concentration of ionized calcium in plasma from cats with urethral obstruction, J Am Vet Med Assoc 211(11):1392-1395, 1997. 35. Luschini MA, Fletcher DJ, Schoeffler GL: Incidence of ionized hypocalcemia in septic dogs and its association with morbidity and mortality: 58 cases (2006-2007), J Vet Emerg Crit Care (San Antonio) 20(4):406-412, 2010. doi:10.1111/j.1476-4431.2010.00553.x. 36. Mellanby RJ, Mellor PJ, Roulois A, et al: Hypocalcaemia associated with low serum vitamin D metabolite concentrations in two dogs with proteinlosing enteropathies, J Small Anim Pract 46(7):345-351, 2005. doi:10.111 1/j.1748-5827.2005.tb00331.x. 37. Drobatz KJ, Casey KK: Eclampsia in dogs: 31 cases (1995-1998), J Am Vet Med Assoc 217(2):216-219, 2000. doi:10.2460/javma.2000.217.216. 38. Widler L, Altmann E, Beerli R, et al: 1-Alkyl-4-phenyl-6-alkoxy-1H- quinazolin-2-ones: a novel series of potent calcium-sensing receptor antagonists, J Med Chem 53(5):2250-2263, 2010. doi:10.1021/jm901811v. 39. Park SY, Mun HC, Eom YS, et al: Identification and characterization of D410E, a novel mutation in the loop 3 domain of CASR, in autosomal dominant hypocalcemia and a therapeutic approach using a novel calcilytic, AXT914, Clin Endocrinol (Oxf) 78(5):687-693, 2013. doi:10.1111/cen.12056. 40. de Brito Galvao JF, Schenck PA, Chew DJ: A quick reference on hypocalcemia, Vet Clin North Am Small Anim Pract 47(2):249-256, 2017. doi:10.1016/j.cvsm.2016.10.017.

58 Magnesium and Phosphate Disorders Linda G. Martin, DVM, MS, DACVECC, Ashley E. Allen-Durrance, DVM, DACVECC KEY POINTS • Given that less than 1% of total body magnesium is in the serum, serum magnesium concentrations do not always reflect total body magnesium stores. Consequently, a normal serum magnesium concentration can occur when there is a total body magnesium deficiency. • Magnesium homeostasis is primarily a function of intestinal absorption and urinary excretion; therefore, hypomagnesemia is almost always caused by disturbances in one or both organ systems. Most cases of hypermagnesemia involve a component of renal insufficiency. • Severe hypomagnesemia and hypermagnesemia cause clinical signs associated with the cardiovascular and neuromuscular systems. • Phosphate is a key component of many physiologic processes, such as cellular energy regulation, synthesis of cell membranes

MAGNESIUM Magnesium disorders are common in both feline and canine critically ill patients. Increased morbidity, mortality, and prevalence of concurrent electrolyte disorders occur in critically ill animals with abnormal total serum magnesium concentrations when compared with normomagnesemic critically ill animals.1-3 Magnesium is the second most abundant intracellular cation, exceeded only by potassium. Most of the magnesium is found in bone and muscle. Sixty percent of total body magnesium content is present in bone. Twenty percent is in skeletal muscle, and the remainder is in other tissues, primarily the heart and liver. Less than 1% of total body magnesium is present in the serum.4,5 In the serum, magnesium exists in three distinct forms: ionized, anion-complexed, and protein-bound fractions. The ionized fraction is thought to be the physiologically active component and accounts for approximately 66% and 63% of the total serum magnesium concentration in cats and dogs, respectively. Approximately 4% and 6% are complexed to compounds such as phosphate, bicarbonate, sulfate, citrate, and lactate in cats and dogs, respectively. The remaining 30% and 31% of total serum magnesium are bound to protein (primarily albumin) in cats and dogs, respectively.6,7 Magnesium is required for many metabolic functions, most notably those involved in the production and use of ATP. Magnesium is a coenzyme for the membrane-bound sodium-potassium ATPase pump and functions to maintain the sodium-potassium gradient across all membranes. Calcium ATPase and proton pumps also require magnesium. Magnesium is essential for protein and nucleic acid synthesis, regulation of vascular smooth muscle tone, cellular second messenger systems, and signal transduction. In addition, magnesium also exerts an important influence on lymphocyte activation, cytokine production, and systemic inflammation.8,9

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and nucleic acids, bone mineralization, acid-base regulation, and cell signaling. • Hypophosphatemia is common in critically ill patients and is most often associated with transcellular shifts. Severe hypophosphatemia with depletion of total body stores can cause detrimental clinical consequences, including hemolytic anemia, impaired platelet function, immune suppression, myocardial dysfunction, and neurologic abnormalities. • Hyperphosphatemia is most often associated with acute or chronic kidney disease, and clinical signs are typically a consequence of hypocalcemia and metastatic soft tissue mineralization.

Magnesium homeostasis is achieved through intestinal absorption and renal excretion. Absorption occurs primarily in the small intestine (jejunum and ileum), with little or no absorption occurring in the large intestine. The loop of Henle and distal convoluted tubule are the main sites of magnesium reabsorption in the kidney. The kidney is the main regulator of serum magnesium concentration and total body magnesium content; regulation is achieved by both glomerular filtration and tubular reabsorption.5,8 Renal magnesium excretion will increase in proportion to the load presented to the kidney or in response to increased prostaglandin E2; conversely, the kidney conserves magnesium in response to a deficiency or in response to parathyroid hormone, calcitonin, arginine vasopressin, beta-adrenergic agonists, and epidermal growth factor.8,10 Lactation appears to play a role in gastrointestinal (GI) and renal handling of magnesium. Increased concentrations of parathyroid hormone, in addition to calcium concentration, most likely participate in magnesium conservation during lactation to supply the mammary glands with a sufficient amount.11 No primary regulatory hormone has been identified for magnesium homeostasis, although the parathyroid, thyroid, and adrenal glands are likely involved.12

Hypomagnesemia Most magnesium-related disorders are caused by conditions that lead to the depletion of total body stores. Hypomagnesemia is a common electrolyte abnormality in critically ill feline and canine patients.1-3 Ionized hypomagnesemia has been documented in perioperative feline renal transplant recipients, as well as cats with diabetes mellitus and diabetic ketoacidosis.13,14 Other evidence suggests that animals receiving peritoneal dialysis, dogs with congestive heart failure receiving furosemide therapy, dogs with protein-losing enteropathy, and lactating dogs are also at risk for hypomagnesemia.11,15-17

CHAPTER 58  Magnesium and Phosphate Disorders

Causes Causes of magnesium deficiency are both numerous and complex. Three general categories are involved: decreased intake (or absorption), increased losses, and alterations in distribution. Potential causes are listed in Box 58.1. Decreased dietary intake, if sustained for several weeks, can lead to significant magnesium depletion. In addition, catabolic illness and intravenous fluid therapy or parenteral nutrition with insufficient magnesium supplementation can contribute to depletion.4,8,15 Magnesium losses can occur through the GI tract, kidneys, or both. Because magnesium balance is primarily a function of intestinal absorption and urinary excretion, depletion is almost always caused by disturbances in one or both organ systems. Increased GI losses can result from inflammatory bowel disease, malabsorptive or short-bowel syndromes, or other diseases that cause prolonged diarrhea. Fluid from the intestinal tract contains a high concentration of magnesium. For this reason, patients with protracted episodes of large-volume diarrhea are prone to significant magnesium depletion.4,9 Hypomagnesemia has also been described with the chronic use (usually .1 year) of proton

BOX 58.1  Causes of Hypomagnesemia I. Decreased Intake A. Prolonged inadequate nutritional intake B. Magnesium-deficient intravenous fluid therapy or parenteral nutrition II. Increased Losses A. Gastrointestinal 1. Malabsorption syndromes 2. Extensive small bowel resection 3. Chronic diarrhea 4. Inflammatory bowel disease 5. Prolonged use of proton pump inhibitors B. Renal 1. Intrinsic tubular disorders a. Glomerulonephritis b. Acute tubular necrosis c. Postobstructive diuresis d. Drug-induced tubular injury (1) Aminoglycosides (2) Amphotericin B (3) Cisplatin (4) Cyclosporine 2. Extrarenal factors influencing renal magnesium handling a. Diuretic-induced states (1) Furosemide (2) Thiazides (3) Mannitol b. Diabetic ketoacidosis c. Hyperthyroidism d. Primary hyperparathyroidism C. Lactation III. Alterations in Distribution A. Extracellular to intracellular shifts 1. Glucose, insulin, or amino acid administration B. Chelation 1. Elevation in circulating catecholamines a. Sepsis b. Shock c. Trauma 2. Massive blood transfusion C. Sequestration 1. Pancreatitis

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pump inhibitors in people. The presumed mechanism is thought to be due to impaired absorption of magnesium by intestinal epithelial cells caused by proton pump inhibitor-induced inhibition of the transient receptor potential melastatin 6 and 7 ion channels.4 Because the kidney is the primary pathway of magnesium excretion, it often serves as a focal point for the development of hypomagnesemia secondary to urinary loss. Acute renal dysfunction as a consequence of glomerulonephritis or the nonoliguric phase of acute tubular necrosis is often associated with a rise in the fractional excretion of magnesium (see Chapter 121, Acute Kidney Injury). Several endocrinopathies are also associated with an increase in the fractional excretion of magnesium, including diabetic ketoacidosis and hyperthyroidism.9,14 Drugs that are commonly administered to critically ill patients can increase renal magnesium loss. Most of the commonly administered diuretic agents (furosemide, thiazides, mannitol) induce hypomagnesemia by increasing urinary excretion. Other drugs, such as aminoglycosides, amphotericin B, cisplatin, and cyclosporine, predispose to renal tubular injury and excessive magnesium loss.4,8 Disease states or therapeutic modalities can cause the redistribution of circulating magnesium by producing extracellular to intracellular shifts, chelation, or sequestration. Administration of glucose, insulin, bicarbonate, or amino acids causes magnesium to shift intracellularly. Also, catecholamine elevations in animals with sepsis, shock, or trauma may cause ionized hypomagnesemia. Beta-adrenergic stimulation of lipolysis generates free fatty acids that chelate magnesium, thereby producing insoluble salts. In addition, citrated blood products can actively chelate magnesium ions when administered in large quantities. In animals with acute pancreatitis, magnesium can form insoluble soaps, and magnesium sequestration may occur in areas of fat necrosis surrounding the pancreas.4,8

Clinical Signs Clinical signs of magnesium depletion are often related to its effects on the cell membrane that result in changes in resting membrane potential, signal transduction, and smooth muscle tone. The effects of magnesium on the myocardium are linked to its role as a regulator of other electrolytes, primarily calcium and potassium. For this reason, one of the most dramatic clinical signs associated with hypomagnesemia is cardiac arrhythmias, including atrial fibrillation, supraventricular tachycardia, ventricular tachycardia, and ventricular fibrillation. Before overt arrhythmia development, subtle electrocardiographic (ECG) changes may be seen. These include prolongation of the PR interval, widening of the QRS complex, depression of the ST segment, and peaking of the T wave. In addition to these changes, hypomagnesemia can cause hypertension, coronary artery vasospasm, and platelet aggregation.9,18 Hypomagnesemia can cause various nonspecific neuromuscular signs. Concurrent hypocalcemia and hypokalemia may also contribute. Magnesium deficiency increases acetylcholine release from nerve terminals and enhances the excitability of nerve and muscle membranes. It also increases the intracellular calcium content in skeletal muscle. Clinical manifestations of magnesium deficiency can include generalized muscle weakness, muscle fasciculations, ataxia, and seizures. Esophageal or respiratory muscle weakness can be manifested as dysphagia or dyspnea, respectively.4,9 Because magnesium is necessary for the movement of sodium, potassium, and calcium into and out of cells, other manifestations of hypomagnesemia include metabolic abnormalities such as concurrent hypokalemia, hyponatremia, and hypocalcemia. Concurrent hypokalemia that is refractory to aggressive potassium supplementation may be due to magnesium deficiency causing excessive potassium loss through the kidneys. When hypokalemia is refractory to potassium

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PART V  Electrolyte and Acid-Base Disturbances

supplementation, assessment of magnesium status and subsequent magnesium supplementation are recommended, if indicated. Hypocalcemia is another manifestation of magnesium deficiency. Because hypomagnesemia impairs parathyroid hormone release and enhances calcium movement from extracellular fluid to bone, total and ionized hypocalcemia often accompanies magnesium depletion. Therefore, clinical signs of hypocalcemia are often observed in patients with magnesium deficiency.4,9

Diagnosis Magnesium deficiency should be suspected in patients predisposed to its development (those patients with disease processes or therapeutic modalities that can lead to hypomagnesemia) and exhibiting clinical signs and laboratory features consistent with magnesium depletion. Determination of total serum magnesium concentration is usually the most readily available technique for estimation of magnesium status. However, the precise clinical diagnosis of hypomagnesemia can be difficult. Because more than 99% of total body magnesium is located in the intracellular compartment, total serum concentration does not always reflect total body stores. Therefore, a normal total serum magnesium concentration can occur in an animal with a total body magnesium deficiency.4,5 However, a low total serum concentration in a patient at risk for deficiency is usually significant. The reported reference range for total serum magnesium is 1.75 to 2.99 mg/dl in cats, and 1.89 to 2.51 mg/dl in dogs, although laboratory-specific reference ranges should be established.3,14 The ionized magnesium concentration is thought to provide a more accurate reflection of intracellular ionized magnesium status and represents the “active” component. Ionized magnesium appears to equilibrate rapidly across the cell membrane; thus, extracellular ionized magnesium values may be more reflective of intracellular stores.19 The feline reference range for ionized magnesium is 0.43 to 0.7 mmol/L, and the canine reference range is 0.43 to 0.6 mmol/L.7

Therapy The amount and route of magnesium replacement depend on both the degree of hypomagnesemia and the patient’s clinical condition. Mild hypomagnesemia may resolve with management of the underlying disorder and oral supplementation. Supplementation should be considered if total serum magnesium concentrations are lower than 1.5 mg/dl, ionized serum magnesium concentrations are less than the reference range, and at any concentration of total or ionized serum magnesium if clinical signs (cardiac arrhythmias, muscle tremors, refractory hypokalemia) are present. Renal function and cardiac conduction must be assessed before magnesium administration. Because magnesium is excreted primarily by the kidneys, the dosage should be reduced by 50% in azotemic patients and serum concentrations should be monitored frequently to prevent hypermagnesemia. Magnesium prolongs conduction through the atrioventricular node. Therefore, any patient with cardiac conduction disturbances should have judicious supplementation and continuous ECG monitoring. Both sulfate and chloride salts are available for parenteral supplementation. The intravenous route is preferred for rapid repletion of magnesium concentrations because the intramuscular route is generally painful. An initial dosage of 0.25 to 1 mEq/kg/24h can be administered by continuous rate infusion in 0.9% sodium chloride or 5% dextrose in water. A lower dosage of 0.25 to 0.5 mEq/kg/24h can be used for an additional 3 to 5 days. For management of life-threatening ventricular arrhythmias, a dose of 0.15 to 0.3 mEq/kg of magnesium diluted in normal saline or 5% dextrose in water can be administered slowly over 5 to 15 minutes.20 Parenteral administration of magnesium sulfate may result in hypocalcemia because of chelation of calcium

with sulfate. Therefore, magnesium chloride should be given if hypocalcemia is also present. Other side effects of magnesium therapy include hypotension, atrioventricular block, and bundle branch blocks. Adverse effects usually are associated with intravenous boluses rather than continuous rate infusions. Chloride, gluconate, oxide, and hydroxide magnesium salts are available for oral administration. The suggested dosage is 1 to 2 mEq/kg/24h. The main side effect of oral administration is diarrhea.20 It is important to recognize that many veterinary critical care diets contain low concentrations of magnesium (0.1 to 0.22 mg/kcal).21 Given that many critically ill patients are fed at or below their resting energy requirement, the actual intake of magnesium may be well below the concentration needed to replete a magnesium deficiency.21 Additionally, magnesium supplementation in standard total parenteral nutrition formulations (0.13 to 0.22 mEq/kg/day) is also below the concentration recommended to treat hypomagnesemia (0.3 to 1.0 mEq/kg/day).21 Based on the low concentrations of magnesium in critical care diets and total parenteral nutrition formulations, animals with moderate to severe hypomagnesemia will likely require additional intravenous or oral magnesium supplementation to normalize serum magnesium concentrations, especially if they have diseases resulting in continued loss of magnesium from the gastrointestinal tract or kidneys.

Hypermagnesemia Hypermagnesemia appears to be a less common and simpler clinical entity than hypomagnesemia. Because large quantities of magnesium can be eliminated easily by the kidneys, it is unusual to encounter hypermagnesemia in the absence of azotemia.

Causes Conditions in which hypermagnesemia has been noted include renal failure/kidney injury, endocrinopathies, and iatrogenic overdose, especially in patients with impaired renal function. It appears that absolute magnesium excretion decreases as the glomerular filtration rate decreases, so it is not surprising that most patients with hypermagnesemia have some degree of renal insufficiency. In general, the degree of hypermagnesemia parallels the degree of renal failure. Acute kidney injury (AKI) is more likely to be associated with clinically significant hypermagnesemia than chronic renal failure, but it may also occur in the latter.5 Several endocrinopathies may be associated with hypermagnesemia, although the mechanisms are not well understood. These diseases include hypoadrenocorticism, hyperparathyroidism, and hypothyroidism, although the degree of hypermagnesemia is often milder than in animals with renal failure. The prerenal azotemic state present in most patients with hypoadrenocorticism may contribute to hypermagnesemia.21 Improper dosing of magnesium replacement therapy or a lack of consideration of the underlying renal function generally plays a role in iatrogenic hypermagnesemia.21 Many cathartics, laxatives, and antacids contain magnesium, so care should be exercised, especially if multiple doses are given to a patient with underlying renal disease.5,18

Clinical Signs Nonspecific clinical signs of hypermagnesemia include lethargy, depression, and weakness. Other clinical signs reflect the electrolyte’s action on the nervous and cardiovascular systems. Hypermagnesemia usually results in varying degrees of neuromuscular blockade. One of the earliest clinical signs of magnesium toxicity is hyporeflexia. Profound elevations in serum magnesium concentration have been associated with respiratory depression secondary to respiratory muscle

CHAPTER 58  Magnesium and Phosphate Disorders paralysis. Severe respiratory depression can result in hypoventilation and subsequent hypoxemia. An absent menace and palpebral reflex have been reported in one cat and one dog that developed acute hypermagnesemia secondary to iatrogenic overdose.22 Hypermagnesemia can also lead to blockade of the autonomic nervous system and vascular collapse.18,21 Cardiac effects of hypermagnesemia result in ECG changes, including prolongation of the PR interval and widening of the QRS complex. This is due to delayed atrioventricular and interventricular conduction. Bradycardia is common in hypermagnesemic patients, and at severely high serum magnesium concentrations, complete heart block and asystole can occur. Ectopy does not appear to be enhanced by elevated serum magnesium concentrations. Hypermagnesemia has also been reported to produce hypotension secondary to relaxation of vascular resistance vessels. Additionally, hypermagnesemia may impair platelet function and coagulation.21

Diagnosis Unlike magnesium deficiency, normal serum concentrations cannot hide increased magnesium stores. Total serum magnesium concentrations greater than 2.99 mg/dl in cats and 2.51 mg/dl in dogs are considered indicative of hypermagnesemia.3,14 Ionized magnesium concentrations above 0.7 mmol/L in cats and 0.6 mmol/L in dogs are considered ionized hypermagnesemia.7

Therapy Therapy consists first and foremost of stopping all exogenous magnesium administration. Further treatment is based on the degree of hypermagnesemia, clinical signs, and renal function. A patient with mild clinical signs such as depression and hyporeflexia can be treated with supportive care and observation, provided that renal function is normal. Saline diuresis and furosemide can also be used to accelerate renal magnesium excretion. More severe cases involving unresponsiveness, respiratory depression, and any degree of hemodynamic instability should be treated with intravenous calcium. Calcium is a direct antagonist of magnesium at the neuromuscular junction and may be beneficial in reversing the cardiovascular effects of hypermagnesemia. Calcium gluconate (10%) can be given at 0.5 to 1.5 ml/kg as a slow intravenous bolus over 15 to 30 minutes. Hypermagnesemic patients with severely impaired renal function may require peritoneal dialysis or hemodialysis. In patients with severe clinical signs, anticholinesterase treatment may be administered to offset the neurotoxic effects of hypermagnesemia. Physostigmine can be given at 0.02 mg/kg IV q12h until clinical signs subside. In severe cases complicated by cardiopulmonary arrest, intubation and mechanical ventilation are recommended (see Chapter 4, Cardiopulmonary Resuscitation of the Hospitalized Patient). Hypermagnesemic shock may be refractory to epinephrine, norepinephrine, and other vasopressors, making resuscitation efforts extremely difficult.5,21

PHOSPHATE Phosphorous is essential in numerous biologic processes and forms the body’s major intracellular anion, phosphate. It is essential for the production of ATP, guanosine triphosphate, cyclic adenosine monophosphate, and phosphocreatine, all of which function to maintain cellular membrane integrity, energy stores, metabolic processes, and biochemical messenger systems.23,24 A major role of phosphate is maintenance of normal bone and teeth matrix in the form of hydroxyapatite. Other roles include regulation of tissue oxygenation by way of 2,3-di-phosphoglycerate (2,3-DPG), which decreases the affinity of

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oxygen to hemoglobin, support of cellular membrane structure and ionic charge via phospholipids, mitochondrial production of ATP through the electron transport system by phosphoproteins, and buffering acidotic conditions in the body.23,25 Technically, phosphorus is an element, and phosphate is a molecular anion (e.g., HPO422); however, the terms are often used interchangeably. For simplicity, phosphate is used in this chapter to refer to either phosphorus or phosphate.23 Distribution of whole-body phosphate is as follows: 80% to 85% in the bone and teeth as inorganic hydroxyapatite, 14% to 15% in soft tissues, and less than 1% in the extracellular space.23,24 Phosphorus is present in the body as organic and inorganic phosphates. Organic phosphate is mostly intracellular and inorganic phosphate is mostly extracellular.23,26 Organic phosphates are components of phospholipids, phosphoproteins, nucleic acids, enzymes, cofactors, and biochemical intermediates.26 Approximately two-thirds of organic phosphate is in the form of phospholipids. Inorganic phosphate is further divided into orthophosphates and pyrophosphates. The quantity of pyrophosphates is insignificant; therefore, most extracellular inorganic phosphate is in the form of orthophosphates. Approximately 85% of orthophosphates are free in circulation as monohydrogen phosphate (HPO422) or dihydrogen phosphate (H2PO42) with a ratio of 4:1 (HPO422:H2PO42) at a normal blood pH of 7.4. Alkalosis increases and acidosis decreases the ratio of divalent to monovalent phosphates.23 The remaining 15% is either protein-bound (10%) or complexed (5%) to magnesium, calcium, or sodium.23,24 Inorganic phosphate in the form of 2,3-DPG accounts for 70% to 80% of phosphate in red blood cells.27 Both organic and inorganic phosphates are present in plasma; organic phosphates include phosphate esters and phospholipids, and inorganic phosphates are composed primarily of the orthophosphates (free, protein-bound, and complexed). It is important to note that blood chemistry analyzers only measure the inorganic phosphates (units: mmol/L or mEq/L). Conversion of units results in a normal plasma phosphate concentration of 3.1 mg/dl 5 1 mmol/L phosphate 5 1.8 mEq/L phosphate.23 Serum or heparinized plasma, separated from cells within 1 hour, can be used to measure inorganic phosphate. Serum phosphate transiently peaks 6 to 8 hours after meals; therefore, blood samples ideally should be collected after a 12-hour fast.28 Spurious hyperphosphatemia can occur secondary to in vitro hemolysis or rupture of other blood cells, hypertriglyceridemia, and the presence of a monoclonal gammopathy.25,29 Phosphate balance is a complex interaction between phosphate intake and phosphate excretion. Intestinal absorption is linearly related to intake, and 60% to 70% of ingested phosphate is absorbed in the duodenum, jejunum, and ileum. In states of phosphate deficiency, calcitriol (1,25-dihydroxycholecalciferol) can increase the active transport of inorganic phosphate.23,24 Serum phosphate balance is dependent on glomerular filtration rate and tubular reabsorption, which occurs primarily in the proximal convoluted tubule.24 Normally, 60% to 90% of filtered phosphate is reabsorbed in the proximal convoluted tubule.23,25 The amount of phosphate reabsorbed is dependent on dietary intake, with maximal reabsorption occurring in animals consuming phosphate-deficient diets.24 Parathyroid hormone (PTH) is a phosphaturic hormone because it decreases the tubular transport maximum for phosphate reabsorption. Growth hormone, insulin, insulin-like growth factor 1, and thyroxine increase tubular phosphate reabsorption.23,24 Growth hormone partially accounts for the expected hyperphosphatemia in young, growing animals.30 Phosphatonins, calcitonin, atrial natriuretic peptide, supraphysiologic doses of vasopressin, high doses of dexamethasone, and adrenocorticotropic hormone increase urinary phosphate excretion.23,24 Phosphatonins are circulating substances that increase renal phosphate excretion. Fibroblast

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growth factor 23 is a phosphatonin that is heavily involved in the regulation of phosphate and vitamin D homeostasis.24,25 The skeleton is the body’s phosphate reservoir and provides a readily available source of phosphate during periods of hypophosphatemia under the regulation of PTH and calcitonin. PTH-mediated osteolysis is rapid and accounts for the acute changes (minutes to hours) in calcium and phosphate, whereas PTH-mediated activation of osteoclasts is a slower process (days to weeks). Hyperphosphatemia does not occur during this process because of the phosphaturic effects of PTH discussed earlier.23,24

Hypophosphatemia Serum concentrations of phosphate measured by blood chemistry analyzers do not necessarily reflect whole-body phosphate balance. Phosphate is the predominant intracellular anion; therefore, rapid shifts from the extracellular to intracellular space, or vice versa, can occur.23 Blood chemistry analyzers measure serum phosphate (normal range 2.9 to 5.3 mg/dl depending on the age of the patient and chemistry analyzer).25,30 Mild to moderate hypophosphatemia (1.0 to 2.5 mg/dl) may or may not be clinically significant and typically is not associated with phosphate depletion.25,26,31 Severe hypophosphatemia (,1 mg/dl) is generally clinically significant and associated with total body phosphate depletion. However, a patient can suffer from phosphorous depletion despite a normal serum phosphate.26 The decision to treat should be based on the clinical assessment of the individual patient and measured serum phosphate concentration.

Causes In general, hypophosphatemia can be caused by decreased intestinal absorption, transcellular shifts, or increased urinary excretion; the most common cause is transcellular shifts.24,26 In many clinical situations of hypophosphatemia, the etiology is often multifactorial. Potential causes of hypophosphatemia are listed in Box 58.2. Decreased intestinal absorption is associated with chronic malnourishment, malabsorptive conditions (severe infiltrative disease), steatorrhea, vitamin D (1,25-dihydroxychcolecalciferol) deficiency, and administration of phosphate-binding antacids.25,26 Steatorrhea (increased fat content in feces) and diseases causing chronic diarrhea result in decreased intestinal phosphate absorption and secondary hyperparathyroidism due to vitamin D deficiency. Both mechanisms contribute to hypophosphatemia in this subset of patients. Iatrogenic hypophosphatemia can occur as a result of increased fecal excretion associated with phosphate-binding drugs such as aluminum hydroxide or lanthanum carbonate.32 Transcellular shifting of phosphate is associated with alkalemia, hyperventilation, refeeding syndrome, parenteral nutrition, insulin administration, glucose administration, catecholamine administration or release, and salicylate toxicity.23,26 In critically ill patients, hypophosphatemia can occur as a result of hyperventilation caused by pain, anxiety, sepsis, heat stroke, and central nervous system disorders. Hyperventilation causes respiratory alkalosis, leading to rapid diffusion of carbon dioxide from the intracellular space to the extracellular space. The increase in intracellular pH activates phosphofructokinase and glycolysis, causing phosphate to rapidly shift into cells.33 Hypophosphatemia is the most common and critical electrolyte disturbance associated with refeeding syndrome. During chronic malnutrition, phosphate depletion can occur and may not be reflected by a decrease in serum phosphate concentration. Administration of enteral or parental nutrition to a patient with chronic malnutrition stimulates insulin release, which promotes intracellular uptake of phosphate and glucose for glycolysis; this transcellular shift may result in severe hypophosphatemia.34 Insulin and glucose administration can cause severe hypophosphatemia in a patient with total body phosphate depletion, such

BOX 58.2  Causes of Hypophosphatemia I. Decreased Gastrointestinal Absorption A. Chronic malnutrition B. Malabsorptive syndromes C. Steatorrhea D. Chronic vomiting and/or diarrhea E. Vitamin D deficiency F. Phosphate-binding antacids II. Transcellular Shifts A. Alkalosis (respiratory or metabolic) B. Intravenous dextrose administration C. Insulin therapy D. Refeeding syndrome E. Catecholamines (endogenous or exogenous) F. Salicylate poisoning G. Eclampsia H. Hypercalcemia of malignancy III. Increased Urinary Loss A. Diuresis 1. Osmotic a. Diabetes mellitus/diabetic ketoacidosis b. Hyperosmolar hyperglycemic nonketotic syndrome c. Recovery phase of third-degree burns 2. Drug induced a. Carbonic anhydrase inhibitors b. Mannitol 3. Postobstructive 4. Hypothermia induced 5. Parenteral fluid therapy B. Hyperparathyroidism 1. Primary 2. Nutritional secondary C. Hyperaldosteronism D. Glucocorticoid therapy with or without hyperadrenocorticism IV. Spurious or Laboratory Error A. Monoclonal gammopathy B. Hemolysis C. Hyperbilirubinemia D. Mannitol (blood levels .25 mmol/L)

as patients receiving treatment for diabetic ketoacidosis or hyperglycemic hyperosmolar nonketotic syndrome. Insulin and glucose stimulate glycolysis, promoting the synthesis of phosphorylated glucose compounds and intracellular shifts of phosphate.25,31 Catecholamines (endogenous or exogenous) such as epinephrine or norepinephrine and b-receptor agonists such as terbutaline may cause hypophosphatemia as a result of b-adrenergic receptor-mediated cellular uptake of phosphate.32 Salicylate toxicity causes uncoupling of oxidative phosphorylation and inhibition of the Krebs cycle. Initially it causes hyperphosphatemia, which is thought to be a result of transcellular shifts from the intracellular to the extracellular compartment; however, this is rapidly (30 to 60 minutes) followed by hypophosphatemia caused by excessive urinary excretion.35 Excessive loss of phosphate through the kidneys can cause hypophosphatemia and phosphate depletion. This is more severe in patients with multifactorial causes of hypophosphatemia. For example, patients with diabetes mellitus have a high risk for phosphate depletion because of osmotic diuresis promoting phosphate excretion, loss of muscle mass, and impaired tissue phosphate utilization as a result of

CHAPTER 58  Magnesium and Phosphate Disorders insulin deficiency. The severity of hypophosphatemia often worsens after treatment with insulin and intravenous fluid therapy because of transcellular shifts.36 PTH is a phosphaturic hormone; therefore, primary or nutritional secondary hyperparathyroidism may result in hypophosphatemia.24 Primary hyperaldosteronism causes renal loss of calcium, resulting in hypocalcemia, which stimulates secretion of PTH and may result in normal or low serum phosphate. Hyperadrenocorticism is a reported cause of hypophosphatemia in humans; however, controversy exists regarding its role in veterinary medicine. Initially it was thought that glucocorticoids decrease intestinal calcium absorption, leading to secondary hyperparathyroidism, and increase urinary excretion of phosphate, causing subsequent hypophosphatemia. However, in a prospective study, dogs with hyperadrenocorticism were found to have increased PTH concentrations and normal serum phosphate concentrations.37 In humans, induction of therapeutic hypothermia for treatment of head trauma has resulted in severe electrolyte abnormalities, including depletion of magnesium, phosphate, potassium, and calcium. Increased urinary loss of electrolytes associated with hypothermia-induced diuresis is one possible mechanism of electrolyte depletion.38 Hypophosphatemia occurs in patients with thirddegree burns and is more significant in patients with higher total body surface area burns. The mechanism for hypophosphatemia is thought to be multifactorial; increased loss through the skin and increased urinary excretion during the recovery phase are likely mechanisms.39 Mannitol administration may cause spurious hypophosphatemia depending on the method used to measure serum phosphate. Mannitol, in concentrations as low as 25 mmol/L, interferes with the DuPont automatic clinical analyzer (ACA) colorimetric test by interfering with the formation of phosphomolybdate. This compound absorbs light and is proportional to serum phosphate concentrations. This has not been reported in the veterinary literature; however, it is feasible if the DuPont ACA endpoint method is used to measure serum phosphate.32 Mannitol administration could theoretically also be associated with phosphate wasting because of its diuretic effects. Sepsis has been associated with hypophosphatemia in people and may be attributable to increased concentrations of inflammatory cytokines, especially interleukin-6 and tumor necrosis factor a.40 Currently the mechanism by which cytokines cause hypophosphatemia is unknown. Acute respiratory alkalosis stimulates phosphofructokinase and glycolysis, which may play a role in the transcellular shift of phosphate during sepsis. Septic humans with severe hypophosphatemia (serum phosphate concentration ,1 mg/dl) are reported to have an eightfold increase in mortality.38

Clinical Signs Mild to moderate hypophosphatemia is typically asymptomatic; however, severe hypophosphatemia and total body phosphate depletion can result in widespread cellular dysfunction.25,26 Depletion of ATP and 2,3-DPG is responsible for most of the severe clinical signs and can affect most cells in the body. Intracellular inorganic phosphate concentration is the critical determinant of cellular injury because it is necessary for the synthesis of ATP from adenosine diphosphate. Hemolysis can occur with severe hypophosphatemia because of decreased concentrations of red blood cell ATP and 2,3-DPG, spherocytosis, red cell membrane rigidity, and shorted red blood cell survival in some cats and dogs.27 Decreased intracellular 2,3-DPG impairs release of oxygen by hemoglobin to tissues, leading to tissue hypoxia.24 Severe hypophosphatemia causes impaired chemotaxis, phagocytosis, and bactericidal activity of leukocytes, which increases the risk of infection in critically ill animals.41 Additionally, platelets have a shortened survival time with impaired clot retraction, which increases the risk of hemorrhage. Reversible myocardial dysfunction occurs with phosphate

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depletion and is a proposed mechanism for cardiac dysrhythmias associated with induction of therapeutic hypothermia in humans.38 Clinical signs of severe hypophosphatemia-induced skeletal muscle changes include generalized weakness, tremors, and muscle pain (which can manifest as difficulty in weaning patients from mechanical ventilation). Rhabdomyolysis secondary to acute hypophosphatemia may occur during refeeding syndrome.33 Neurologic signs may include ataxia, seizures, and coma associated with metabolic encephalopathy. Gastrointestinal signs can include anorexia, nausea, functional ileus, vomiting, and diarrhea.26

Diagnosis Ideally the clinician should differentiate hypophosphatemia (decreased serum phosphate) from phosphate depletion (decreased total body phosphate). Unfortunately, differentiation may be difficult because phosphate is predominately intracellular, a fluid compartment that cannot easily be sampled for analysis. Hypophosphatemia refers to a decreased serum phosphate below the lower limit of the reference range and may occur with low, normal, or high total body phosphate. Mild to moderate hypophosphatemia correlates with a serum phosphate concentration of 1 to 2.5 mg/dl, and severe hypophosphatemia correlates with a serum phosphate of less than 1 mg/dl.24,25 Phosphate depletion is a reduction in total body phosphate, usually resulting from decreased intake/absorption or increased loss through the kidneys and can be compounded by transcellular shifts. Phosphate depletion can occur in the face of normal or high measured serum phosphate; therefore, phosphate depletion should be suspected in patients with predisposing causes and associated clinical signs.25,31

Therapy The decision to treat a patient with hypophosphatemia will depend on the severity of the phosphate deficit, whether total body phosphate depletion is suspected or impending, anticipated duration of illness, clinical signs of the patient, and the presence of concurrent illnesses associated with decreased intake or increased loss of phosphate. The focus should be on treating the primary disease. Many cases of mild to moderate hypophosphatemia will subsequently resolve in this manner. For example, hypophosphatemia associated with respiratory alkalosis typically resolves when the patient’s ventilatory and acid-base status normalizes.26 Phosphate replacement can be administered orally or intravenously. Oral replacement is indicated in asymptomatic patients with mild to moderate (1 to 2.5 mg/dl) hypophosphatemia, and the amount supplemented is often empirical. Bovine milk contains 0.032 mmol/ml of elemental phosphorous and can be used as an oral phosphate supplement.31 Parenteral replacement is indicated in patients with severe hypophosphatemia (,1 mg/dl) that are at high risk of deleterious sequelae due to phosphate depletion. Commercially available hypertonic sodium and potassium phosphate solutions are available for parenteral use; they require dilution, typically in 0.9% saline, before administration. Dilution of phosphate salts in lactated Ringer’s solution should be avoided because of the potential for precipitation with calcium.25 Sodium phosphate (Na2HPO4) contains 3 mmol/ml (93 mg/ml) phosphate and 4 mEq/L sodium. Potassium phosphate (KH2PO4) contains 3 mmol/ml (99.1 mg/ml) phosphate and 4.36 mEq/L potassium. When using potassium phosphate, it is important to account for the total amount of potassium supplementation in the patient’s fluid therapy plan to avoid iatrogenic hyperkalemia. Reported dose ranges for intravenous phosphate therapy are 0.01 to 0.12 mmol/kg/hr.25,26,36 Serum phosphate, ionized calcium, and serum potassium concentrations should initially be rechecked every 4 to 6 hours after starting parenteral phosphate replacement therapy. Potential adverse effects of overzealous supplementation include

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hyperphosphatemia, hypocalcemia with associated tetany, metastatic calcification, and renal failure. If potassium phosphate is oversupplemented, hyperkalemia may also occur.25,31

Hyperphosphatemia The definition of hyperphosphatemia should vary depending on the age of the patient. A baseline normal serum phosphate range is 2.9 to 5.3 mg/dl, although machine-specific reference ranges should be established for each machine; however, concentrations of 10 mg/dl have been reported in healthy puppies.30

Causes Hyperphosphatemia can be caused by decreased renal excretion, increased intake or iatrogenic administration, and transcellular shifts. The most common cause in veterinary medicine is decreased renal excretion associated with AKI or chronic kidney disease (CKD).25,41 Hyperphosphatemia inhibits 1a-hydroxylase activity and stimulates secretion of PTH. Conversion of vitamin D to its active metabolite, calcitriol, is catalyzed by 1a-hydroxylase. Decreased calcitriol reduces intestinal absorption of phosphate; however, increased PTH enhances intestinal absorption and urinary excretion of phosphate, resulting in a small net effect of increased phosphate excretion. Calcitriol concentrations are subsequently restored by increased PTH. Initially, this restores serum phosphate; however, when PTH decreases, serum phosphate increases because of a decreased glomerular filtration rate and the cycle continues to preserve phosphate balance. Eventually, as CKD progresses, maximal inhibition of phosphate tubular reabsorption is surpassed, causing persistent hyperphosphatemia. As the number of functional tubular cells decrease, renal calcitriol synthesis tapers, and the magnitude of hyperphosphatemia progresses in spite of increased PTH. Renal secondary hyperparathyroidism occurs in 47% to 100% of cats and dogs with CKD, with a higher incidence in patients with more severe CKD (IRIS stage 3 and 4).41 In the critical care setting, other common causes of hyperphosphatemia as a result of decreased excretion are AKI, acute-on-chronic kidney disease, urethral obstruction, and uroabdomen. Because of insufficient time for physiologic compensatory mechanisms to develop, AKI is often associated with significant hyperphosphatemia. The most notable causes of transcellular shifts of phosphate resulting in hyperphosphatemia occur with tumor lysis syndrome, rhabdomyolysis, and hemolysis. Tumor lysis syndrome is the clinical manifestation and laboratory sequelae of acute death of tumor cells that release potassium, phosphate, and nucleic acids into circulation and may cause AKI. Renal tubular mineralization is thought to play a role in the pathogenesis of AKI associated with tumor lysis syndrome. Patients with a high tumor cell burden that respond rapidly to chemotherapy or radiation, such as stage IV and V lymphoma, are thought to be at higher risk for tumor lysis syndrome because these cells contain up to four times as much phosphate as normal cells.24,25 Rhabdomyolysis is a syndrome of massive skeletal muscle tissue injury and can cause hyperphosphatemia directly from release of intracellular contents and indirectly by decreased renal excretion from resulting myoglobin-induced AKI (although is rare in cats or dogs). Release of intracellular phosphate is the mechanism by which hemolysis is thought to cause hyperphosphatemia.24,34 Iatrogenic overdose and toxicities are conditions related to increased intake of phosphate. As mentioned in the previous section, parenteral administration of phosphate is not without risk, and supplementation requires close monitoring to avoid iatrogenic overdose. Acute administration of large doses of parenteral phosphate can cause not only hyperphosphatemia but also hypomagnesemia, hypocalcemia, and hypotension.31 Phosphate-containing enemas (e.g., Fleet) can

cause severe hyperphosphatemia with the associated clinical consequences and can be fatal. Ingestion of cholecalciferol rodenticides and vitamin D3 skin creams (e.g., calcipotriene) can rapidly increase serum phosphate concentration by increased intestinal absorption and release from bones.24 Hypoparathyroidism is rare in veterinary medicine but should be suspected in a patient presenting on emergency with acute tetany, muscle fasciculations, seizures, hypocalcemia, and normal kidney function (normal kidney values with appropriate urine specific gravity). In this disease, hyperphosphatemia may or may not be present.25 Hyperthyroidism has also been associated with hyperphosphatemia because thyroxine increases renal tubular reabsorption of phosphate.24

Clinical Signs Clinical signs of hyperphosphatemia include anorexia, nausea, vomiting, weakness, tetany, seizures, and dysrhythmias. Hyperphosphatemia is often associated with hypocalcemia, hypomagnesemia, hypernatremia, and metabolic acidosis.24,31 Clinical manifestations of hyperphosphatemia predominantly are due to hypocalcemia and ectopic soft tissue calcification. Tetany and seizures can develop in patients with severe hypocalcemia. Soft tissue calcium phosphate deposition occurs when the calcium phosphate product is greater than 58 to 70 mg2/dl2 and represents one mechanism for hypocalcemia. Tissues primarily affected by ectopic calcification include cardiac, vasculature, renal tubules, pulmonary, articular, periarticular, conjunctival, skeletal muscle, and skin.24,25 Arrhythmias, such as polymorphic ventricular tachycardia or torsades de pointes caused by prolongation of the QT interval, are also associated with subsequent hypocalcemia and hypomagnesemia.24

Diagnosis Diagnosis of hyperphosphatemia is based on a serum phosphate greater than 5.3 to 6 mg/dl in an adult cat or dog. Age of the patient should be considered when interpreting serum phosphate concentrations. Puppies and kittens less than 8 weeks of age have the highest plasma phosphate concentrations; this value steadily decreases as the animal ages, with normal adult values expected by 1 year of age.24,25,30

Treatment A thorough investigation for the underlying cause should be sought to most effectively treat hyperphosphatemia. If rapid correction of hyperphosphatemia is needed, treatment includes crystalloid fluid therapy and dextrose administration with a goal of correcting azotemia (if present) and increasing intracellular uptake of phosphate. For patients with hyperphosphatemia caused by oliguric or anuric AKI, continuous renal replacement therapy or hemodialysis may be necessary.24 Feeding a low-phosphate diet and administering phosphate binders such as aluminum hydroxide, calcium carbonate/chitosan (Ipakitine), lanthanum carbonate, or sevelamer should be considered when treating animals with hyperphosphatemia caused by CKD.25

REFERENCES 1. Dhupa N: Serum magnesium abnormalities in a small animal intensive care population, J Vet Intern Med 8:156, 1994. 2. Toll J, Erb H, Birnbaum N, et al: Prevalence and incidence of serum magnesium abnormalities in hospitalized cats, J Vet Intern Med 16:217, 2002. 3. Martin LG, Matteson VL, Wingfield WE, et al: Abnormalities of serum magnesium in critically ill dogs: incidence and implications, J Vet Emerg Crit Care 4:15, 1994. 4. Ahmed F, Mohammed A: Magnesium: the forgotten electrolyte—a review on hypomagnesemia, Med Sci 7:56, 2019.

CHAPTER 58  Magnesium and Phosphate Disorders 5. Sachter JJ: Magnesium in the 1990s: implications for acute care, Top Emerg Med 14:23, 1992. 6. Schenck PA: Fractionation of canine serum magnesium, Vet Clin Pathol 34:137, 2005. 7. Schenck PA, Chew DJ: Understanding recent developments in hypocalcemia and hypomagnesemia, Proceedings of the 23rd American College of Veterinary Internal Medicine Forum, Baltimore, June 2005. 8. Friday BA, Reinhart RA: Magnesium metabolism: a case report and literature review, Crit Care Nurse 11:62, 1990. 9. Tong GM, Rude RK: Magnesium deficiency in critical illness, J Intensive Care Med 20:3, 2005. 10. Houillier P: Magnesium homeostasis. In Turner NN, Lameire N, Goldsmith DJ, editors: Oxford textbook of clinical nephrology, ed 4, Oxford, 2015, Oxford University Press. 11. Bateman S: Disorders of magnesium: magnesium deficit and excess. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders in small animal practice, ed 4, St Louis, 2012, Elsevier Saunders. 12. Dhupa N, Proulx J: Hypocalcemia and hypomagnesemia, Vet Clin North Am Small Anim Pract 28:587, 1998. 13. Wooldridge JD, Gregory CR: Ionized and total serum magnesium concentrations in feline renal transplant recipients, Vet Surg 28:31, 1999. 14. Norris CR, Nelson RW, Christopher MM: Serum total and ionized magnesium concentrations and urinary fractional excretion of magnesium in cats with diabetes mellitus and diabetic ketoacidosis, J Am Vet Med Assoc 215:1455, 1999. 15. Crisp MS, Chew DJ, DiBartola SP, et al: Peritoneal dialysis in dogs and cats: 27 cases (1976-1987), J Am Vet Med Assoc 195:1262, 1989. 16. Cobb M, Michell AR: Plasma electrolyte concentrations in dogs receiving diuretic therapy for cardiac failure, J Small Anim Pract 33:526, 1992. 17. Kimmel SE, Waddell LS, Michel KE: Hypomagnesemia and hypocalcemia associated with protein-losing enteropathy in Yorkshire Terriers: five cases (1992-1998), J Am Vet Med Assoc 217:703, 2000. 18. Arsenian M: Magnesium and cardiovascular disease, Prog Cardiovasc Dis 35:271, 1993. 19. Murray ME, Boiron L, Buriko Y, et al: Serum and ionized magnesium concentrations in healthy and sick dogs, J Vet Emerg Crit Care 30:S10, 2020. 20. Dhupa N: Magnesium therapy. In Bonagura JD, editor: Kirk’s current veterinary therapy XII, ed 12, Philadelphia, 1995, Saunders. 21. Fascetti AJ: Magnesium: pathophysiological, clinical, and therapeutic aspects, Proceedings of the 21st American College of Veterinary Internal Medicine Forum, Charlotte, NC, June 2003. 22. Jackson CB, Drobatz KJ: Iatrogenic magnesium overdose: 2 case reports, J Vet Emerg Crit Care 14:115, 2004. 23. Yanagawa N, Nakhoul F, Kurokawa K, et al: Physiology of phosphorus metabolism. In Narins RG, editor: Maxwell & Kleeman’s clinical disorders of fluid and electrolyte metabolism, ed 5, New York, 1994, McGraw-Hill.

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24. DiBartola SP, Willard MD: Disorders of phosphorus: hypophosphatemia and hyperphosphatemia. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders in small animal practice, ed 4, St Louis, 2012, Elsevier Saunders. 25. Schropp DM, Kovacic J: Phosphorous and phosphate metabolism in veterinary patients, J Vet Emerg Crit Care 17:127, 2007. 26. Forrester DS, Moreland KJ: Hypophosphatemia: causes and clinical consequences, J Vet Intern Med 3:149, 1989. 27. Yawata Y, Hebbel RP, Silvis S, et al: Blood cell abnormalities complicating the hypophosphatemia of hyperalimentation: erythrocyte and platelet ATP deficiency associated with hemolytic anemia and bleeding in hyperalimented dogs, J Lab Clin Med 84:643, 1974. 28. Lopez E, Aguilera-Tejero E, Estepa JC, et al: Diurnal variations in the plasma concentration of parathyroid hormone in dogs, Vet Rec 157:344, 2005. 29. Kristensen AT, Klausner JS, Weiss DJ, et al: Spurious hyperphosphatemia in a dog with chronic lymphocytic leukemia and an IgM monoclonal gammopathy, Vet Clin Pathol 20:45, 1991. 30. Harper EJ, Hackett RM, Wilkinson J: Age-related variations in hematologic and plasma biochemical test results in Beagles and Labrador Retrievers, J Am Vet Med Assoc 223:1436, 2003. 31. Geerse DA, Bindels AJ, Kuiper MA, et al: Treatment of hypophosphatemia in the intensive care unit: a review, Crit Care 14:R147, 2010. 32. Knochel JP, Barcenas C, Cotton JR, et al: Hypophosphatemia and rhabdomyolysis, J Clin Invest 62:1240, 1978. 33. Justin RB, Hohenhaus AE: Hypophosphatemia associated with enteral alimentation in cats, J Vet Intern Med 9:228, 1995. 34. Quintanilla A, Kessler RH: Direct effects of salicylate on renal function in the dog, J Clin Invest 52:3143, 1973. 35. Adams LG, Hardy RM, Weiss DJ, et al: Hypophosphatemia and hemolytic anemia associated with diabetes mellitus and hepatic lipidosis in cats, J Vet Intern Med 7:266, 1993. 36. Ramsey IK, Tebb A, Harris, et al: Hyperparathyroidism in dogs with hyperadrenocorticism, J Small Anim Pract 46:531, 2005. 37. Polderman KH, Peerdeman SM, Girbes ARJ: Hypophosphatemia and hypomagnesemia induced by cooling in patients with severe head injury, J Neurosurg 94:697, 2001. 38. Loghmani S, Maracy MR, Kheirmand R: Serum phosphate level in burn patients, Burns 36:1112, 2010. 39. Barak V, Schwartz A, Kalickman I, et al: Prevalence of hypophosphatemia in sepsis and infection: the role of cytokines, Am J Med 104:40, 1998. 40. Shor R, Halabe A, Rishver S, et al: Severe hypophosphatemia in sepsis as a mortality predictor, Ann Clin Lab Sci 36:67, 2006. 41. Cortadellas O, Fernandez del Palacio MJ, Talavera J, et al: Calcium and phosphorus homeostasis in dogs with spontaneous chronic kidney disease at different stages of severity, J Vet Intern Med 24:73, 2010.

59 Traditional Acid-Base Analysis Kate Hopper, BVSc, PhD, DACVECC

KEY POINTS • Traditional acid-base analysis uses the Henderson-Hasselbalch equation to evaluate the blood pH as a direct consequence of partial pressure of carbon dioxide (PCO2) and bicarbonate. • Blood pH is a measure of hydrogen ion concentration and is dependent on the ratio of bicarbonate to PCO2. • PCO2 behaves as an acid in the body and represents the respiratory contribution to acid-base balance.

INTRODUCTION The evaluation of acid-base balance is an integral aspect of managing critically ill patients. Acid-base balance has been a focus of research and discussion in the medical literature since the beginning of the 20th century.1-5 There are two fundamentally different approaches to acidbase evaluation: the Henderson-Hasselbalch based approach, which is referred to as the traditional approach in this chapter, and the physicochemical, or nontraditional approach (see Chapter 60). The traditional approach offers the advantage of rapid analysis based on readily available parameters in the clinical setting. The normal concentration of hydrogen ions is very small (40 nmol/L) compared with other ions in the body, such as sodium (145 million nmol/L in the dog).6 By convention, the concentration of hydrogen ions is described as pH, a dimensionless measure that is calculated as the negative logarithm of the hydrogen ion activity and allows the representation of a wide range of hydrogen ion concentrations in a simplified manner. The pH scale ranges from 0 (for a 1 M solution of hydrogen ion) to 14 (for a 10-14 M solution).4 The hydrogen ion concentration considered compatible with life for a mammalian system ranges from 10 to 160 nmol/L, which correlates with a pH from 8 to 6.8, respectively.7 Regulation of hydrogen ion concentration is essential for homeostasis, and recognition of acid-base disorders can have diagnostic and prognostic significance, in addition to helping guide therapy.

SAMPLE COLLECTION AND HANDLING It is important to appreciate the potential for preanalytical error in acidbase evaluation if inappropriate sample collection and/or handling occurs. The site of sample collection will impact acid-base variables. In healthy research dogs there was a statistically significant difference between arterial and venous values for pH, partial pressure of carbon dioxide (PCO2), partial pressure of oxygen (PO2) and bicarbonate concentration. pH and PCO2 were also different between jugular and cephalic venous samples (Appendix X).8 These differences are relatively small, and for the purpose of acid-base analysis, venous samples are an acceptable replacement for arterial values in critically ill human

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• Bicarbonate, base excess, and TCO2 are all representations of the metabolic contribution to acid-base balance. • The anion gap is a diagnostic tool that may help identify the cause of a metabolic acidosis. • The treatment of most acid-base disorders is focused on resolution of the underlying disease.

patients.9,10 In states of poor peripheral perfusion, peripheral venous samples can have elevations in PCO2 and lactate concentration, which will contribute to lower pH values that are not representative of central venous or arterial values.10 Other sources of preanalytical error for acid-base analysis include time delays between sample collection and sample analysis, sample exposure to air, and inappropriate sample anticoagulation (see Chapter 202, Blood Gas Sampling).

TRADITIONAL APPROACH The traditional approach is based on the Henderson-Hasselbalch equation (Box 59.1) for carbonic acid (H2CO3) and uses pH, PCO2 and bicarbonate concentration. From this equation, it is clear that pH has a direct relationship with bicarbonate concentration and an inverse relationship with PCO2. Modern blood gas machines measure the hydrogen ion activity (pH) and PCO2 of a blood or plasma sample and use the Henderson-Hasselbalch equation to derive the concentration of bicarbonate. The base excess (BE) and anion gap (AG) parameters have been added to the traditional approach to improve its diagnostic utility. The body relies on three major processes to maintain acid-base balance: regulation of PCO2 by alveolar ventilation, buffering of acids by bicarbonate and nonbicarbonate buffer systems, and changes in renal excretion of acid or base. PCO2 represents the respiratory component, controlled by the lungs, and the bicarbonate concentration represents the metabolic component, influenced by both buffering systems and renal handling of acid. As described by the Henderson-Hasselbalch equation, pH is not dependent on having a specific PCO2 and bicarbonate concentration. Rather, pH is the consequence of the ratio of bicarbonate to PCO2. For example, a patient can have a high bicarbonate concentration, but as long as the PCO2 has increased by a similar magnitude, the HCO3/PCO2 ratio will remain normal and hence pH will remain in the normal range. As maintenance of an acceptable pH is optimal to maintain physiological processes, it is no surprise that when an abnormality in one system (respiratory or metabolic) occurs, changes are made in the opposing system in an attempt to return the

CHAPTER 59  Traditional Acid-Base Analysis

BOX 59.1  Henderson-Hasselbalch Equation pH  6.1  log ([HCO3 ] [0.03  PCO2 ]) where 6.1 is the pKa in body fluids; HCO3 is the concentration of HCO3 measured in mmol/L; 0.03 is the solubility coefficient for carbon dioxide in plasma; and PCO2 is the partial pressure of carbon dioxide in mm Hg

ratio of bicarbonate to PCO2 towards normal; hence pH is driven back towards a more normal value. This process is known as compensation and tends to drive pH towards normal, but as a general rule, compensation will not return pH to the normal range and will never overcompensate. See below for further discussion of compensation.

pH pH is measured directly by blood gas machines and is inversely proportional to the hydrogen ion concentration. A blood pH below the normal range for the species is termed acidemia, indicating an increased hydrogen ion concentration, and an elevated blood pH is termed alkalemia.

PCO2 Carbon dioxide acts as an acid in the body because of its ability to react with water to produce carbonic acid. With increases in PCO2, the ratio of bicarbonate to PCO2 is decreased; hence pH falls. Another way to consider this process is that with an increase in PCO2, the carbonic acid equation (below) will be driven to the right, increasing the hydrogen ion concentration. CO 2  H 2O ←→ H 2CO3 ←→ H  HCO 

 3

The concentration of PCO2 in the blood is controlled by pulmonary ventilation, and as a consequence, the lung plays an important role in controlling acid-base status. Changes in alveolar ventilation occur rapidly and can alter blood pH within minutes. An increased PCO2 has an acidotic influence (a respiratory acidosis), and a decreased PCO2 represents a respiratory alkalosis.

Bicarbonate The value of bicarbonate is most commonly calculated by blood gas machines, although some clinical laboratories do measure it directly. Elevations in bicarbonate concentration will drive the pH higher and represent a metabolic alkalosis while decreases in bicarbonate concentration represent a metabolic acidosis. One of the major criticisms of using bicarbonate as the measure of the metabolic component is that it is not independent of changes in PCO2.11-13 As the carbonic acid equilibration equation demonstrates, elevations in PCO2 will lead to elevations in bicarbonate while decreases in PCO2 will lead to a decrease in bicarbonate. It is therefore important that changes in bicarbonate concentration are always evaluated in light of the pH and PCO2.

Base Excess The BE parameter is a calculated value developed as a measure of the metabolic acid-base system that is independent of changes in PCO2. BE is the titratable acidity (or base) of the blood sample. It is defined as the amount of strong acid or strong base (in mmol/L) that must be added to 1 liter of fully oxygenated whole blood to restore the pH to 7.4 at 37°C and with a PCO2 of 40 mm Hg.14 Under normal conditions, an individual with a pH of 7.4 and PCO2 of 40 mm Hg has a BE of zero by definition. Purists would reserve the term BE for situations where this value is increased and use base deficit for when the value is more

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negative than normal. These terms have become interchangeable and for the purpose of this discussion, BE will be used exclusively. An increased BE (more positive value) is consistent with a metabolic alkalosis (either gain of bicarbonate or loss of acid). A decreased BE (more negative value) represents a metabolic acidosis. The original algorithm for BE, known as actual BE, was developed from experiments on whole blood in vitro and is believed to overestimate the buffering capacity of the in vivo system. Blood acid-base balance is in equilibrium with the entire extracellular fluid space, the majority of which has minimal buffering capacity due to the low hemoglobin and protein content of interstitial fluid. A modification of the algorithm to account for this discrepancy provides the value known as standard BE (SBE) or the extracellular fluid BE.15 In clinical medicine, SBE is generally considered the most appropriate value to assess. Commercial blood gas machines use a human algorithm for BE where the normal value is ,0 mmol/L. Unfortunately, veterinary species do not have the same acid-base balance as humans. Herbivores have a more positive normal BE than people while carnivores tend to have a more negative normal BE than people. See Appendix X for a reported normal range of acid-base values for dogs and cats. The major advantage of using BE over bicarbonate concentration is that it is independent of changes in the respiratory system. When there are minimal changes in PCO2 present, the BE and bicarbonate should correlate well. The BE can be estimated by the measured bicarbonate concentration minus the normal bicarbonate concentration. In the face of substantial abnormalities in PCO2, the BE is a more reliable measure of the metabolic component.11,12,16

Total Carbon Dioxide Many blood gas machines and most diagnostic laboratories will provide a parameter called total carbon dioxide (TCO2). This is a misleading name as this represents the metabolic acid-base component, not the respiratory system component. The TCO2 is a measure of all the CO2 in a blood sample, and the majority of CO2 is carried as bicarbonate in the blood. In general, TCO2 will be 1 to 2 mmol/L higher than the true bicarbonate concentration.6

Anion Gap AG was developed in order to help identify the cause of a metabolic acidosis. Electroneutrality requires there to be an equal number of anions and cations in a physiologic system. In reality there is no actual AG; the apparent AG exists because more cations in the system are readily measured than anions. The AG is a reflection of unmeasured ions. The AG is calculated according to the equation in Box 59.2. The AG of a normal individual is primarily composed of negatively charged plasma proteins, mostly albumin.17 Metabolic acidosis can develop through one of two main mechanisms. Bicarbonate concentration can fall in conjunction with a rise in chloride concentration, hyperchloremic metabolic acidosis. This can be due to disease processes causing bicarbonate loss in the gastrointestinal tract, or kidneys or can be iatrogenic, secondary to administration of sodium chloride (Box 59.3). Alternatively, metabolic acidosis can occur from the gain of acid. When there is excess acid in the system, hydrogen ions will titrate (combine) with bicarbonate, leading

BOX 59.2  Anion Gap Equation Anion gap*  ([Na ]  [K ])  ([HCO3 ]  [C l ]) *Physiologically, there is no actual anion gap; rather, this is a measure of unmeasured anions and cations in the system. An increase in the anion gap usually reflects an increase in unmeasured anions.

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PART V  Electrolyte and Acid-Base Disturbances

BOX 59.3  Possible Causes of Metabolic

Acidosis

Increased Anion Gap Metabolic Acidosis DUEL • Diabetic ketoacidosis • Uremia • Ethylene glycol intoxication • L-Lactic acidosis Other Less Common Causes • D-Lactic acidosis • Salicylate ingestion • Methanol intoxication

Hyperchloremic Metabolic Acidosis • Renal bicarbonate loss • Gastrointestinal bicarbonate loss • Sodium chloride administration • Hypoadrenocorticism

to a fall in bicarbonate concentration. The anion that accompanied the hydrogen ion (the conjugate base) will accumulate, maintaining electroneutrality and increasing the AG. Common acids associated with an increased AG include lactic acid, ketone bodies, uremic acids such as sulfate and phosphate, and toxins such as ethylene glycol.18 A useful mnemonic for common causes of increased AG metabolic acidosis in small animals is DUEL, standing for Diabetic ketoacidosis, Uremic acids, Ethylene glycol, and Lactic acidosis (Box 59.3). It is important to note that hypoalbuminemia can mask the presence of unmeasured anions. Albumin and phosphorus are the major unmeasured anions in the normal animal. In states of hypoalbuminemia, abnormal unmeasured anions (e.g., lactate or ketones) may be present, but the calculated AG may remain within the reported normal range. As a result, the AG is not reliable in hypoalbuminemic patients.19,20 Conversely, hyperalbuminemia will increase AG, and it is ideal to interpret AG in light of the albumin concentration, if available.

to the calculated, expected response, it is consistent with compensation and the assessment is a simple acid-base disorder. In other words, the change in the secondary system is completely attributed to compensation and no other acid-base abnormality is suspected. A mixed acid-base disorder is diagnosed when the changes in the secondary system are less than or greater than the expected compensation for the primary disorder. The assumption is that there is some disturbance of the secondary system preventing appropriate compensation from occurring or causing the appearance of overcompensation (which does not occur). Some caution is necessary when interpreting the appropriateness of metabolic compensation to a primary respiratory disorder, as it will depend on the chronicity of the respiratory abnormality, which may or may not be accurately determined. There are no published guidelines for the compensatory responses of cats. Cats may demonstrate similar metabolic compensation for respiratory disorders as dogs, although two of the three studies on this topic were performed in anesthetized cats.24-26 There is a single study in the literature reporting that cats do not develop respiratory compensation in response to a metabolic acidosis, and there are no studies evaluating the respiratory response of adult cats to a metabolic alkalosis.27 Extrapolation of the canine calculations of expected respiratory compensation to metabolic disorders cannot be recommended in cats.

ACID-BASE ANALYSIS

Traditional acid-base analysis can identify primary (or simple) acidbase disorders in which there is an abnormality of one system (respiratory or metabolic), and any changes evident in the opposing system are considered consistent with normal compensation (Table 59.1). For example, a primary metabolic acidosis should have respiratory compensation. The respiratory response to a primary metabolic abnormality is rapid in onset and complete within hours (assuming a stable level of the metabolic abnormality).21,22 In comparison, the metabolic compensatory response to a primary respiratory disorder takes hours to begin and 2 to 5 days to complete.22,23 The degree of expected compensation in dogs is commonly estimated from guidelines derived from healthy experimental animals (Appendix Y).22 If the change observed in the secondary system is similar in magnitude

Traditional acid-base analysis can identify four simple disorders, defined as a single acid-base abnormality and any changes in the opposing system are attributed solely to compensation (Box 59.5). In addition, mixed disorders can be diagnosed; these are situations in which there is an abnormality in both the metabolic and respiratory components. Mixed disorders are evident when both the respiratory and metabolic components have the same influence on acid-base balance (i.e., metabolic acidosis and respiratory acidosis or metabolic alkalosis and respiratory alkalosis). A mixed disorder is also present when there are abnormalities evident in both the metabolic and respiratory components, but the pH is in the normal range. In this situation, it is important to recall the rule that compensation never returns pH to normal. Lastly, a mixed disorder maybe identified when the change in the opposing system is not consistent with expected compensation. There are numerous possible approaches to diagnosing an acidbase disturbance using the traditional approach. The author has provided one such approach in Box 59.4. In this method the pH is assessed as representing acidemia or alkalemia for that species. Then the respiratory component and the metabolic component are both assessed for their influence on the acid-base balance as either acidosis, alkalosis, or normal. The process that is influencing acid-base balance in the same direction as the pH abnormality is the primary disorder. For example:

TABLE 59.1  Simple Acid-Base Disturbances

Parameter Patient Value Reference Range Assessment

Compensation

Identified with the Traditional Acid-Base Approach Acid-Base Disturbance Respiratory acidosis Respiratory alkalosis Metabolic acidosis Metabolic alkalosis

pH Decreased Increased Decreased Increased

Primary Disorder Increased PCO2 Decreased PCO2 Decreased HCO3 Increased HCO3

Compensation Increased HCO3 Decreased HCO3 Decreased PCO2 Increased PCO2

HCO3, bicarbonate concentration; PCO2, partial pressure of carbon dioxide.

pH

    7.18

(7.35 to 7.42)

Acidemia

PvCO2

33

(38 to 42 mm Hg)

Respiratory alkalosis

HCO3

12

(18 to 22 mmol/L)

Metabolic acidosis

The only process that can be considered responsible for the change in pH (acidemia) in this example is the metabolic system; the primary disturbance is therefore a metabolic acidosis. The next step is to determine if the opposing system (in this example the respiratory system) is

CHAPTER 59  Traditional Acid-Base Analysis

BOX 59.4  Approach to Acid-Base Analysis . Was the sample collection and handling appropriate? 1 2. Evaluate the pH (select one) In the normal range Acidemia Alkalemia 3. Evaluate the respiratory component – PCO2 (select one) In the normal range Acidotic process (increased CO2) Alkalotic process (decreased CO2) 4. Evaluate the metabolic component – HCO3 or SBE (select one) In the normal range Acidotic process (decreased HCO3, negative SBE) Alkalotic process (increased HCO3, positive SBE) 5. Define the primary process – respiratory or metabolic i.e., Which process is causing a change in the same direction as the pH change? 6. Compensation as expected? 7. What is your overall acid-base analysis? 8. Metabolic acidosis? Yes – calculate the anion gap

consistent with expected compensation. First, the direction of the change in the opposing system is evaluated to see if it is appropriate for compensation (Table 59.1), keeping in mind the time required for metabolic compensation to occur. In many cases the presence of a change in the opposing system in the direction expected for compensation is sufficient to diagnose a simple disorder. In dogs, the expected compensatory change can be calculated (see Appendix Y) and, if the change in the opposing system is similar to that calculated, a simple disorder is then diagnosed. If the change in the opposing system is not similar to that expected (calculated), a mixed disorder is diagnosed. In this example the predicted respiratory compensation for a bicarbonate concentration of 12 mmol/L would be a PvCO2 in the range of 3463 mm Hg. The patient has a PvCO2 of 33 mm Hg, consistent with compensation and a simple metabolic acidosis is the diagnosis. Lastly, if a metabolic acidosis has been identified, the AG can be calculated in an effort to help determine the underlying cause of the abnormality, assuming the patient is not hypoalbuminemic. The advantage of the traditional approach to acid-base analysis is its relative simplicity and adherence to sound chemical principles. It has been tried and tested for the best part of a century in both the experimental and clinical setting and has been proven reliable and accurate. The major criticism of the traditional approach to metabolic acid-base disorders is its failure to identify individual disease processes that are contributing to the acid-base abnormality. Although the AG may help to determine cause(s) of a metabolic acidosis, it is prone to error and only narrows the possible diagnoses but does not provide a definitive diagnosis.

CAUSES OF ACID-BASE ABNORMALITIES Respiratory Acidosis Elevations in PCO2 can represent a primary respiratory acidosis or can occur as compensation for a primary metabolic alkalosis. Respiratory acidosis results from an imbalance in CO2 production via metabolism and CO2 excretion via alveolar minute ventilation of the lung. It is best described by the equation: PaCO2 ∼

 VCO 2 VA

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 • Where VCO 2 is the production of CO2 by the tissues and VA is alveolar minute ventilation.28 Respiratory acidosis is the consequence of increased CO2 production or decreased VA. Clinically the most common causes of changes in PaCO2 are a result of changes in VA. When primary metabolic acidbase abnormalities alter pH, it is sensed by both central and peripheral chemoreceptors, and there is a resultant alteration in VA to change PaCO2 in a manner to reduce the magnitude of pH change (respiratory compensation). In cardiovascularly stable patients, PvCO2 accurately reflects PaCO2, and venous blood gases can be used to identify changes in alveolar ventilation. In patients with hemodynamic instability, the relationship of PvCO2 with PaCO2 is lost and elevations in PvCO2 may not reflect alveolar hypoventilation. As minute ventilation is the product of respiratory rate and tidal volume, common causes of a respiratory acidosis are diseases that reduce respiratory rate, tidal volume, or both. Airway obstruction can impair tidal volume. Depression of the respiratory center of the brainstem as a consequence of drugs (e.g., many anesthetics and sedatives), brain injury, mass lesions, etc. can lead to lack of stimulus for VA. Diseases that prevent the transmission of impulses from the respiratory center to the respiratory muscles, such as cervical spinal cord disease, peripheral neuropathies and diseases of the neuromuscular junction, can all cause respiratory paralysis and respiratory acidosis. Myopathies or muscular fatigue can also occur, impairing respiratory muscle function. Increases in CO2 production can occur in patients with hyperthermia, seizures, fever and malignant hyperthermia. However, the awake, neurologically intact animal should  increase VA to compensate for an increase in VCO 2, so generally these abnormalities cause respiratory acidosis in the compromised or anesthetized animal. See Chapter 17, Hypoventilation for further discussion of this topic. The ideal treatment for respiratory acidosis is the resolution of the underlying disease, when possible. In severe cases of hypoventilation that persists despite therapy, mechanical ventilation is indicated (see Chapter 32, Basic Mechanical Ventilation). Elevated levels of PaCO2 can cause hypoxemia in patients breathing room air, and all animals with significant hypercapnia (.60 mm Hg) should receive oxygen therapy. Elevated PvCO2 in the cardiovascularly unstable patient can be a consequence of poor perfusion where blood spends more time in the tissues, collecting a larger quantity of CO2 before returning to the lungs. As such, changes in PvCO2 in the shock patient cannot be used to comment on VA. It is important to note that bicarbonate therapy is contraindicated in patients with a respiratory acidosis.

Respiratory Alkalosis From the discussion above, it is evident that a decreased PCO2 is the result of an increase in VA (decreased CO2 production is not a clinically relevant issue). A low PCO2 may also occur as an appropriate compensatory response to a metabolic acidosis. Primary disease processes that may stimulate an increased respiratory rate and/or tidal volume include significant hypoxemia, pulmonary parenchymal disease (causing stimulation of stretch receptors or nociceptors), and airway inflammation.29 In addition, central stimulation of respiratory rate and effort by the respiratory center can occur. This can be a pathologic process resulting from brain injury, or it could be behavioral as a result of pain or anxiety. An animal’s respiratory rate cannot be used to determine if it has hyper- or hypoventilation. An increase in dead space ventilation, as occurs with panting, can allow a very rapid respiratory rate without a change to PCO2, while slow respiratory rates can be associated with hyperventilation if larger tidal volumes are generated. Ventilatory status is most accurately determined

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PART V  Electrolyte and Acid-Base Disturbances

by measurement of PaCO2. As mentioned previously, PvCO2 can be used to evaluate ventilation if the animal is cardiovascularly stable. Treatment of respiratory alkalosis is focused on treatment of the underlying disease; specific therapy for the respiratory alkalosis itself is rarely necessary.

Metabolic Acidosis Metabolic acidosis occurs relatively frequently in small animal patients, identified in 43% of dogs and cats that had blood gas analysis at a University Teaching Hospital.30 As described previously, calculation of the AG may aid in determining the cause of metabolic acidosis. Hyperchloremic metabolic acidosis in association with small bowel diarrhea has been well reported in human patients and large animal species but is an infrequent occurrence in dogs and cats. Renal loss of bicarbonate can be an appropriate response to a persistent respiratory alkalosis (metabolic compensation). When this occurs as a primary disease process, it is known as renal tubular acidosis (RTA). It can be broadly categorized as proximal or distal tubular dysfunction. In animals with proximal RTA, there is inadequate reabsorption of bicarbonate in the proximal nephron. Reported causes in dogs and cats include congenital abnormalities (e.g., Fanconi syndrome), as well as acquired abnormalities secondary to toxins, drugs, and various diseases (e.g., hypoparathyroidism and multiple myeloma). Distal RTA is a disorder involving inadequate hydrogen ion secretion in the distal tubule that prevents maximal acidification of the urine; it is frequently accompanied by hypokalemia and is more rarely reported in the veterinary literature than proximal RTA. Potential causes include pyelonephritis and immune-mediated hemolytic anemia. The interested reader is directed to reference 31 for further reading on RTA. Hypoadrenocorticism not only leads to hypovolemia and a lactic acidosis, but also impairs urine acidification, leading to metabolic acidosis.31 The focus of treatment of metabolic acidosis secondary to bicarbonate loss is resolution of any underlying diseases. In addition, intravenous fluid therapy may speed up the resolution of the acid-base abnormality. Fluids containing a buffer such as lactated Ringer’s solution will aid in the metabolism of hydrogen ions. When treating patients with a hyperchloremic metabolic acidosis, use of lower chloride containing fluids (i.e., avoiding 0.9% NaCl) will also be of benefit. When the acidosis is severe or the compensatory respiratory alkalosis is considered detrimental to the patient, bicarbonate administration is indicated (see bicarbonate therapy below). Metabolic acidosis due to a gain in acid is typified by normochloremia and an elevated AG. The common causes in dogs and cats were mentioned previously: diabetic ketoacidosis (DKA), uremia, lactic acidosis, and ethylene glycol intoxication. Less common causes include D-lactic acidosis and various additional intoxications, including salicylates and methanol.18,31 Treatment of metabolic acidosis due to an acid gain is primarily focused on the resolution of the underlying cause and appropriate selection of IV fluid therapy, as described above. Bicarbonate administration may be beneficial in some uremic patients but is not typically indicated for treatment of other causes of high AG metabolic acidosis. It is interesting to note that in a retrospective study of metabolic acidosis in dogs and cats, 25% of dogs and 34% of cats had neither an elevated AG nor hyperchloremia, suggesting there are limitations to this categorization of metabolic acidosis.30

Metabolic Alkalosis Metabolic alkalosis appears to be less common in small animal patients, evident in 15% of a population of dogs and cats compared with the occurrence of metabolic acidosis in 43% of these animals.32 Metabolic alkalosis can broadly be considered to occur due to either acid

loss or bicarbonate gain. Causes of acid loss include selective gastric acid loss such as can occur with gastrointestinal obstructive processes (leading to sequestration or vomiting) and nasogastric tube suctioning. Renal acid loss can occur due to loop diuretic administration, mineralocorticoid excess, and the presence of nonresorbable anions such as carbenicillins.33,34 Acid loss invariably occurs along with chloride in the gastrointestinal tract and renal system, and as a result, many animals with metabolic alkalosis will also be hypochloremic. Increases in bicarbonate concentration can occur as appropriate renal compensation to respiratory acidosis. Pathologic increases in bicarbonate concentration can also occur with contraction alkaloses, iatrogenic administration of an alkalinizing therapy (e.g., sodium bicarbonate), or metabolism of organic anions such as lactate, ketones, acetate, and citrate. Hypokalemia can play a significant role in the generation and maintenance of metabolic alkalosis. Intracellular shifts of hydrogen ions in exchange for potassium ions leaving the cells will increase the pH of the extracellular fluid. Further, hypokalemia promotes renal acid loss.33,34 The kidney has the ability to excrete large quantities of bicarbonate, such that metabolic alkalosis should be rectified rapidly. When metabolic alkalosis is persistent, there must be factors limiting renal bicarbonate excretion. Decreased effective circulating volume and hypochloremia can both limit renal bicarbonate excretion. Hypokalemia and aldosterone excess further impair renal bicarbonate excretion. There are three important aspects to treatment of metabolic alkalosis: ensure there is adequate effective circulating volume, normalize electrolytes, and when possible, correct the primary disease.34

BICARBONATE THERAPY There are many potential adverse effects of metabolic acidosis, including decreased myocardial contractility, arterial vasodilation, impaired coagulation, increased work of breathing secondary to carbon dioxide production, decreased renal and hepatic blood flow, insulin resistance, and altered central nervous function.35-37 It is no surprise that clinicians are eager to resolve metabolic acidosis by treatment of the primary disease, IV fluid administration, and in some instances, alkalinizing therapy. Sodium bicarbonate is the most common alkali therapy used in veterinary medicine. Alternative alkalinizing therapies include trishydroxymethyl aminomethane (aka tromethamine; THAM) and Carbicarb, an equimolar mixture of sodium bicarbonate and sodium carbonate. These alternative buffer therapies may have the advantage of having no (THAM) or less (Carbicarb) associated CO2 production than sodium bicarbonate. The interested reader is directed to reference 36 for further reading on this topic. The indications for sodium bicarbonate administration have been somewhat controversial over the years given the potential adverse effects associated with bicarbonate therapy (see Box 59.5). The first is that its use is based on the premise that acidemia has substantial negative consequences to the patient. Numerous human studies have demonstrated that a low pH is well tolerated; this includes patients subjected to permissive hypercapnia and patients with DKA.38,39 One of the most commonly cited adverse effects of acidemia is decreased myocardial contractility and vascular tone. Investigations have not been able to consistently demonstrate these negative hemodynamic effects in clinical patients; in addition, studies have failed to demonstrate that bicarbonate administration will improve hemodynamic performance in the face of acidemia (in some studies hemodynamic performance actually deteriorates following bicarbonate administration).40-42 Another concern is that sodium bicarbonate therapy does not reliably increase pH.

CHAPTER 59  Traditional Acid-Base Analysis

BOX 59.5  Potential Adverse Effects

Associated with Sodium Bicarbonate Administration44 • Increased hemoglobin affinity for oxygen • Increased blood lactate concentration • Paradoxical intracellular acidosis • Hypercapnia • Hypervolemia • Hyperosmolality • Hypernatremia • Hypocalcemia (ionized) • Hypomagnesemia (ionized) • Hypokalemia • Phlebitis

Following administration, the bicarbonate binds hydrogen ions (hence the alkalinizing effect) to form carbonic acid; this rapidly dissociates to CO2 and water. If ventilation does not increase appropriately, an elevated PCO2 will cause a decrease in pH. For this reason, sodium bicarbonate therapy is strictly contraindicated in patients with evidence of hypoventilation. Of greater concern is the paradoxical intracellular acidosis that has been shown to occur following sodium bicarbonate administration. Bicarbonate cannot freely cross cell membranes, but the CO2 produced as bicarbonate is metabolized can freely enter cells. Once intracellular, the CO2 combines with water leading to hydrogen ion release, causing intracellular acidosis. Many animal studies have demonstrated decreases in cellular and cerebrospinal fluid pH following bicarbonate therapy.43,45-47 Bicarbonate therapy has also been associated with increases in blood lactate concentration in studies of lactic acidosis, hemorrhagic shock, and DKA.38,41,45,46 The exact mechanism for this response is not known, but left shifting of the oxygen-hemoglobin dissociation curve due to increases in blood pH may play a role. Sodium bicarbonate therapy can be associated with other adverse effects including hypervolemia, hyperosmolality, hypernatremia, hypocalcemia (ionized), hypomagnesemia (ionized), hypokalemia, and decreases in PaO2 (Box 59.5).44 The many potential negative consequences of sodium bicarbonate therapy must be weighed against the potential benefits when considering its use in the clinical setting. If a specific therapy exists for the underlying cause of a metabolic acidosis, this should be the focus of treatment in combination with appropriate IV fluid therapy. Bicarbonate therapy is not indicated in these patients, particularly when animals suffer from lactic acidosis and/or DKA, diseases in which bicarbonate therapy has been associated with no improvement in outcome or clinical deterioration despite severe acidemia.42,49 It is likely that bicarbonate therapy will be beneficial in the treatment of diseases causing bicarbonate loss, such as chronic kidney disease and some forms of diarrhea (an uncommon cause of metabolic acidosis in small animal patients).50,51 The role of bicarbonate therapy in the management of patients with acute kidney injury (AKI) is less well defined, although there is evidence that bicarbonate therapy can improve the outcome of human patients with AKI in the intensive care setting.52

Dose and Administration There is no exact method by which to determine a sodium bicarbonate dose. An approximate dose can be calculated from the following formula, and further treatment should be given to effect. sodium bicarbonate dose (mmol)  0.3  BW (kg)  base excess

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• Where 0.3 is an approximate value for the distribution of bicarbonate, BW (kg) is the patient body weight in kilograms, and base excess (mmol/L) is a calculated value provided by the blood gas machine (or can be approximated by patients measured bicarbonate concentration minus the normal bicarbonate concentration). This dose would theoretically return the blood bicarbonate concentration back to normal. It is common practice to only give a portion of this calculated dose (50% to 80%) in order to avoid causing iatrogenic metabolic alkalosis. This is of particular concern when other simultaneous therapies may contribute to resolution of the metabolic acidosis. Hypertonic sodium bicarbonate should never be administered rapidly (other than in the cardiopulmonary resuscitation setting) as it can cause vasodilation and increases in intracranial pressure, which can be fatal.53 The clinician has the choice of giving the dose slowly (over 30 minutes or longer) or diluting it with sterile water to make it a less hypertonic solution. Dilution usually results in a significant volume for administration; the rate of infusion should then be governed by the perceived fluid tolerance of the patient. If the hypertonic sodium bicarbonate solution is not diluted to an osmolality of less than 600 mOsm/L, it should be given via a central catheter to avoid phlebitis.54 The commercially available 8.4% sodium bicarbonate has an osmolality of 2000 mOsm/L, so a dilution of one part sodium bicarbonate to three parts diluent (e.g., sterile water for injection) or greater is appropriate for peripheral venous administration. Before giving sodium bicarbonate, the clinician should consider the level of concern for the increase in intravascular volume and the potential for hypernatremia, hyperosmolality, hypercapnia, hypokalemia, hypocalcemia (ionized), and hypomagnesemia (ionized) in the patient. These concerns may necessitate initiating other therapy prior to bicarbonate administration, a very slow administration rate, or even withholding the therapy if the level of concern outweighs the proposed benefit of the drug.

REFERENCES 1. Arrhenius SA: On the dissociation of substances dissociated in water, Z Phys Chem 1:631, 1887. 2. Brønsted JN: Some remarks on the concept of acids and bases, Recueil des Travaux Chimiques des Pays-Bas 42:718-728, 1923. 3. Henderson JL: Das Gleichgewicht zwischen Basen Und Sauren im Tierischen Organismus, Ergebn Physiol 8:254, 1909. 4. Sørenson SPL: Uber die Messung und Beeutung der Wasserstoffionenkonzentration bei biologischen Prozessen, Ergebn Physiol 12:393-532, 1912. 5. Van Slyke DD: Studies of acidosis, J Biol Chem 495-498, 1922. 6. DiBartola SP: Introduction to acid-base disorders. In DiBartola SP, editor: Fluid, electrolyte and acid-base disorders, ed 4, St Louis, 2012, Elsevier Saunders, pp 231-252. 7. Masoro EJ, Siegel PD: Acid-base regulation: its physiology, pathophysiology and the interpretation of blood-gas analysis, ed 2, WB Saunders Co, 1977, Philadelphia, pp 1-25. 8. Ilkiw JE, Rose RJ, Martin ICA: A comparison of simultaneously collected arterial, mixed venous, jugular venous and cephalic venous blood samples and the assessment of blood-gas and acid-base status in the dog, J Vet Intern Med 5:294-298, 1991. 9. Yildizdas D, Yapicioglu H, Yilmaz HL, Sertdemir Y: Correlation of simultaneously obtained capillary, venous, and arterial blood gases of patients in a paediatric intensive care unit, Arch Dis Child 89:176-180, 2004. 10. Treger R, Pirouz S, Kamangar N, Corry D: Agreement between central venous and arterial blood gas measurements in the intensive care unit, 5:390-394, 2010. 11. Corey HE: Stewart and beyond: new models of acid-base balance, Kid Int 64:777-787, 2003.

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12. Kellum JA: Determinants of plasma acid-base balance, Crit Care Clin 21:329-346, 2005. 13. Stewart PA: Modern quantitative acid base chemistry, Can J Physiol Pharmacol 61:1444-1461, 1983. 14. Siggaard Andersen O: The acid-base status of the blood, Scand J Clin Lab Invest 15:1-134, 1963. 15. Siggaard-Andersen O: The van Slyke equation, Scand J Clin Lab Invest Suppl 146:15-20, 1977. 16. Constable PD: Clinical assessment of acid-base status: comparison of the Henderson-Hasselbalch and strong ion approaches, Vet Clin Pathol 29:115-128, 2000. 17. Figge J, Rossing TH, Fencl V: The role of serum proteins in acid-base equilibria, J Lab Clin Med 117:453-467, 1991. 18. Oh MS, Carroll HJ: The anion gap, N Engl J Med 297(15):814-817, 1977. 19. Feldman M, Soni N, Dickson B: Influence of hypoalbuminemia or hyperalbuminemia on the serum anion gap, J Lab Clin Med 146:317-320, 2005. 20. Corey HE: The anion gap (AG): studies in the nephrotic syndrome and diabetic ketoacidosis (DKA), J Lab Clin Med 147:121-125, 2006. 21. Pierce NF, Fedson DS, Brigham KL, et al: The ventilatory response to acute base deficit in humans. The time course during development and correction of metabolic acidosis, Ann Intern Med 72:633-640, 1970. 22. de Morais HSA, DiBartola SP: Ventilatory and metabolic compensation in dogs with acid-base disturbances, J Vet Emerg Crit Care 1:39-42, 1991. 23. Polak A, Haynie GD, Hays RM, Schwartz WB: Effects of chronic hypercapnia on electrolyte and acid base equilibrium. I. Adaptation, J Clin Invest 40:1223-1237, 1961. 24. Szlyk PC, Jennings DB: Effects of hypercapnia on variability of normal respiratory behavior in awake cats, Am J Physiol 21:R538-R547, 1987. 25. Lemieux G, Lemieux C, Duplessis S, Berkofsky J: Metabolic characteristics of cat kidney: failure to adapt to metabolic acidosis, Am J Physiol 28:R277-R281, 1990. 26. Hampson NB, Jobsis-VanderVliet FF, Piantadosi CA: Skeletal muscle oxygen availability during respiratory acid-base disturbances in cats, Respir Physiol 70:143-158, 1987. 27. Ching SV, Fettman MJ, Hamar DW, et al: The effect of chronic dietary acidification using ammonium chloride on acid-base and mineral metabolism in the adult cat, J Nutr 119:902-915, 1989. 28. Lumb AB: Carbon dioxide. In Nunn’s applied respiratory physiology, ed 7, Philadelphia, 2010, Churchill Livingstone, pp 159-177. 29. Lumb AB: Control of breathing. In Nunn’s applied respiratory physiology, ed 7, Philadelphia, 2010, Churchill Livingstone, pp 61-82. 30. Hopper K, Epstein SE: Incidence, nature and etiology of metabolic acidosis in dogs and cats, J Vet Intern Med 26:1107-1114, 2012. 31. DiBartola SP: Metabolic acid-base disorders. In DiBartola SP, editor: Fluid, electrolyte and acid-base disorders, St Louis, 2012, Elsevier Saunders, pp 253-286. 32. Hu S, Hopper K, Epstein SE: Incidence, nature and etiology of metabolic alkalosis in dogs and cats, J Vet Intern Med 27:847-853, 2013. 33. Galla JH: Metabolic alkalosis, J Am Soc Nephrol 11:369-375, 2000. 34. Rose BD, Post TW: Metabolic alkalosis. In Clinical physiology of acid-base and electrolyte disorders, ed 5, New York, 2001, McGraw-Hill, pp 551-577. 35. Gauthier PM, Szerlip HM: Metabolic acidosis in the intensive care unit, Crit Care Clin 18:289-308, 2002.

36. Gehlbach BK, Schmidt GA: Bench-to-bedside review: treating acid-base abnormalities in the intensive care unit – the role of buffers, Crit Care 8:259-265, 2004. 37. Thorsen K, Ringdal KG, Strand K, et al: Clinical and cellular effects of hypothermia, acidosis and coagulopathy in major injury, Br J Surg 98: 894-907, 2011. 38. Thorens JB, Jolliet P, Ritz M, Chevrolet JC: Effects of rapid permissive hypercapnia on hemodynamics, gas exchange, and oxygen transport and consumption during mechanical ventilation for the acute respiratory distress syndrome, Intensive Care Med 22(3):182-191, 1996. 39. Viallon A, Zeni F, Lafond P, et al: Does bicarbonate therapy improve the management of severe diabetic ketoacidosis? Crit Care Med 27:2690-2693, 1999. 40. Graf H, Leach W, Arieff AI: Evidence for a detrimental effect of bicarbonate therapy in hypoxic lactic acidosis, Science 227(4688):754-756, 1985. 41. Rhee KH, Toro LO, McDonald GG, Nunnally RL, Levin DL: Carbicarb, sodium bicarbonate, and sodium chloride in hypoxic lactic acidosis. Effect on arterial blood gases, lactate concentrations, hemodynamic variables, and myocardial intracellular pH, Chest 104(3):913-918, 1993. 42. Cooper DJ, Walley KR, Wiggs BR, Russell JA: Bicarbonate does not improve hemodynamics in critically ill patients who have lactic acidosis. A prospective, controlled clinical study, Ann Intern Med 112:492-498, 1990. 43. Bureau MA, Bégin R, Berthiaume Y, et al: Cerebral hypoxia from bicarbonate infusion in diabetic acidosis, J Pediatr 96:968-973, 1980. 44. Glatstein M, Mimouni FB, Dollberg S, Mandel D: Effect of bicarbonate on neonatal serum ionized magnesium in vivo, Am J Ther 18(6):463-465, 2011. 45. Arieff AI, Leach W, Park R, Lazarowitz VC: Systemic effects of NaHCO3 in experimental lactic acidosis in dogs, Am J Physiol 242:F586-F591, 1982. 46. Kucera RR, Shapiro JI, Whalen MA, et al: Brain pH effects of NaHCO3 and Carbicarb in lactic acidosis, Crit Care Med 17(12):1320-1323, 1989. 47. Chua HR, Schneider A, Bellomo R: Bicarbonate in diabetic ketoacidosis – a systematic review, Ann Intensive Care 1:23-35, 2011. 48. Graf H, Leach W, Arieff AI: Metabolic effects of sodium bicarbonate in hypoxic lactic acidosis in dogs, Am J Physiol 249(5 Pt 2):F630-F635, 1985. 49. Beech JS, Williams SC, Iles RA, et al: Haemodynamic and metabolic effects in diabetic ketoacidosis in rats of treatment with sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, Diabetologia 38(8):889-898, 1995. 50. Trefz FM, Lorch A, Feist M, et al: Construction and validation of a decision tree for treating metabolic acidosis in calves with neonatal diarrhea, BMC Vet Res 8:238, 2012. 51. Kraut JA, Madias NE: Consequences and therapy of the metabolic acidosis of chronic kidney disease, Pediatr Nephrol 26(1):19-28, 2011. 52. Jaber S, Paugam C, Futier E, et al: Sodium bicarbonate therapy for patents with severe metabolic acidemia in the intensive care unit (BICAR-ICU): a multicenter, open-label, randomised controlled, phase 3 trial, Lancet 392(10141):31-40, 2018. 53. Huseby JS, Gumprecht DG: Hemodynamic effects of rapid bolus hypertonic sodium bicarbonate, Chest 79(5):552-554, 1981. 54. Kuwahara T, Asanami S, Kubo S: Experimental infusion phlebitis: tolerance osmolality of peripheral venous endothelial cell, Nutrition 14:496-501, 1988.

60 Nontraditional Acid-Base Analysis Kate Hopper, BVSc, PhD, DACVECC

KEY POINTS • The nontraditional approaches to acid-base analysis may provide greater insight into the underlying mechanisms of metabolic acid-base abnormalities. • The Strong Ion Difference approach identifies three independent determinants of acid-base balance: partial pressure of carbon dioxide, strong ion difference, and total weak acids. • Strong ion gap is the Stewart measure of unmeasured anions or cations and is not affected by changes in albumin concentration.

• The semiquantitative approach to acid-base analysis calculates the effects of five parameters on base excess: free water (marked by sodium concentration), changes in chloride concentration, albumin, phosphorus, and lactate. • The parameter XA is the semiquantitative evaluation of unmeasured anions or cations.

Acid-base analysis involves evaluation of both the respiratory and metabolic contributions to blood pH. Evaluation of respiratory acidbase balance is similar across all diagnostic approaches (see Chapter 59, Traditional Acid-Base Analyses). The nontraditional or quantitative approaches to acid-base analysis provide alternative methods to evaluate the metabolic contribution. The major criticism of the traditional approach to metabolic acid-base disorders is its failure to identify individual disease processes that contribute to a metabolic acid-base abnormality. The nontraditional approaches may provide greater insight into underlying causes of metabolic acid-base abnormalities.

is important to note that changes in SID will reflect changes in bicarbonate concentration if ATOT remains constant (Fig. 60.1). Decreased SID metabolic acidosis can be due to hyponatremia, hyperchloremia, or a combination of the two. Conversely, increased SID metabolic alkalosis may be due to hypernatremia, hypochloremia, or both. Treatment of abnormalities in SID generally focuses on fluid therapy to restore SID to normal. The SID of intravenous fluids can be determined as it is for plasma. This value can help guide fluid selection for patients with SID abnormalities. For example, a patient with an increased SID alkalosis may benefit from a fluid with a low SID such as 0.9% saline (SID 5 0). In contrast, a patient with a decreased SID acidosis may be best treated with an IV fluid with a higher SID, such as lactated Ringer’s with an effective SID of approximately 28 mmol/L (after the lactate is metabolized).4 Sodium bicarbonate is a fluid with a very high SID because bicarbonate is not considered a strong ion. As a result, sodium bicarbonate 8.4% with a sodium concentration of 1000 mmol/L has a SID of 1000 mmol/L and is therefore considered an effective treatment of patients with a low SID metabolic acidosis.

THE STRONG ION DIFFERENCE APPROACH The strong ion difference (SID), also known as the Stewart approach, considers only three independent determinants of acid-base balance: partial pressure of carbon dioxide (PCO2); the difference between strong cations and strong anions, known as the SID; and total nonvolatile weak acids (ATOT).1 The quantity of hydrogen (or bicarbonate) ions added to, or removed from, the system is not considered relevant to the final pH because hydrogen ion concentration is not an “independent” variable. SID and ATOT are proposed to affect hydrogen ion concentration directly by altering the dissociation of water via electrochemical forces. Ultimately, the SID approach is able to identify five metabolic acid-base abnormalities (Box 60.1).2

Strong Ion Difference Strong ions are ions that are fully dissociated at physiologic pH. The major strong ions include sodium, potassium, calcium, magnesium, and chloride. Some authors include other anions as strong ions, such as lactate and ketoacids. The formula used to calculate SID is based on the total quantity of strong cations minus the quantity of strong anions. The exact formula used varies depending on the ions included in the calculation.2,3 Quantitatively, sodium and chloride are the most important strong ions in the body and SID is commonly simplified as the difference between serum sodium and chloride concentrations. It

Total Weak Acids (ATOT) Weak acids are only partially dissociated at physiologic pH. The major contributors to ATOT are albumin and phosphorus. Because the dissociation of these substances varies with pH, there are complex formulas to calculate ATOT.2,3,5 Constable and colleagues have also developed simplified equations to estimate the plasma protein contribution to ATOT using a species-specific dissociation constant (Ka), for dogs and cats. For dogs the net protein charge is 0.25 mEq/g for total protein or 0.42 mEq/g for albumin. The net protein charge for cats is 0.19 mEq/g of total protein or 0.41 mEq/g of albumin.6,7 Because ATOT represents a value for weak acids, increases in ATOT indicate a metabolic acidosis and decreases in ATOT (primarily from decreased albumin) indicate a metabolic alkalosis. Treatment of abnormalities of ATOT aims to normalize the levels of albumin and phosphorus when possible.

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PART V  Electrolyte and Acid-Base Disturbances

BOX 60.1  Metabolic Acid-Base

TABLE 60.1  Formulas for Calculation of

• Increased SID metabolic alkalosis • Decreased SID metabolic acidosis • Increased A TOT metabolic acidosis • Decreased A TOT metabolic alkalosis • Increased SIG metabolic acidosis

Parameter

Strong Ion Difference and Semiquantitative Acid-Base Parameters

Abnormalities Identified by the Strong Ion Difference Approach

ATOT, total weak acids; SID, strong ion difference; SIG, strong ion gap. 150 Ion concentration (mmol/L)

HCO3 Na 100

K

SID Alb/Phos

ATOT SIG

Cl 50

Anions Cations Fig. 60.1  Gamblegram of normal plasma ion concentration. Alb/Phos, albumin and phosphorus concentration; ATOT, total weak acid concentration; Cl 2, chloride concentration; HCO32, bicarbonate concentration; K1, potassium concentration; Na1, sodium concentration; SID, strong ion difference; SIG, strong ion gap.

Strong Ion Gap The strong ion gap (SIG) is the evaluation of unmeasured anions in the SID approach and is similar to the use of anion gap (AG) in traditional acid-base analysis. Readers are directed to Chapter 59 for an explanation of AG. The SIG can be calculated from the SID (also known as SID apparent) minus the contribution of bicarbonate and ATOT (also known as SID effective). As the Gamblegram in Fig. 60.1 demonstrates, if there are no unmeasured anions (SIG 5 0) in the system, the SID should equal the sum of the contributions of bicarbonate and ATOT. The presence of unmeasured anions will cause a more positive value for SIG. A simplified formula for the calculation of SIG has been developed by Constable for dogs and cats (Table 60.1).6,7 The reference interval for the simplified SIG formula in dogs was reported to be -8.6 to 3.7 mmol/L,8 and the presence of increased unmeasured anions will be evident by a more negative value. This simplified approach does not account for changes in phosphorus concentration; in the presence of hyperphosphatemia the SIGsimplified is determined by first modifying the AG equation with the formula listed in Table 60.1.6,7,9 Increases in SIG, like increases in AG, reflect the presence of unmeasured anions (e.g., lactate, sulfates, ethylene glycol, and ketones), which are assumed to have an acidifying influence on the system. There are many different formulas for the determination of SID in the literature, some of which include additional anions, such as lactate, and therefore affect interpretation of the SIG. A major advantage of SIG over AG is that it is independent of changes in albumin concentration. As a result, SIG is more sensitive to the presence of unmeasured anions in hypoalbuminemic patients.

Formula

Strong Ion Difference Approach Strong ion difference (SID) (sodium 1 potassium) 2 (chloride) Albumin effect (measured albumin 3 10 3 [(0.123 3 pH) 2 0.631]) Phosphorus effect (measured phosphorus 3 0.323 3 [0.309 3 pH 2 0.469]) A TOT albumin effect 1 phosphorus effect Strong ion gap (SIG) [SID 2 (bicarbonate 1 ATOT)] Simplified SIG6,7 SIGsimplified 5 [albumin] 3 4.9 – AG Dogs SIGsimplified 5 [albumin] 3 7.4 2 AG Cats AGphosphorus-adjusted AG 1 (2.52 – 5.58 3 measured phosphorus) Semiquantitative Approach Free water effect Dogs 0.25([Na1] 2 mid-normal [Na1]) Cats 0.22([Na1] 2 mid-normal [Na1]) Corrected chloride measured [Cl2] 3 (mid-normal [Na1]/ measured [Na1]) Chloride effect mid-normal [Cl2] 2 corrected [Cl2] Phosphorus effect 0.58 3 (mid-normal [phosphorus] 2 measured [phosphorus]) Albumin effect 3.7 3 (mid-normal [albumin] 2 measured [albumin]) Lactate effect 21 3 [lactate] Sum of effects free water effect 1 chloride effect 1 phosphorus effect 1 albumin effect 1 lactate effect Unmeasured ion effect (XA2) base excess 2 sum of effects AG, anion gap; [albumin], albumin concentration in g/dl; base excess in mmol/L; ATOT, total weak acid concentration; [Cl 2], chloride concentration in mmol/L; [K1], potassium concentration in mmol/L; [lactate], lactate concentration in mmol/L; [Na1], sodium concentration in mmol/L; [phosphorus], phosphorus concentration in mg/dl.

A full explanation of the SID approach is beyond the scope of this chapter, and the interested reader is directed to references 2 and 3 for further discussion of the topic.

SEMIQUANTITATIVE APPROACH Several researchers have developed a clinical approach to acid-base analysis that is a combination of the traditional and SID methods.10-13 This approach has been variably called the Stewart–Fencl approach, the Stewart–Figge approach, semiquantitative analysis, and base excess partitioning. In this chapter the term semiquantitative metabolic acidbase analysis is used. This approach uses equations to estimate the magnitude of effect of individual acid-base processes on base excess (BE); each acid-base process is represented by one of five parameters. These parameters are as follows: (1) a free water effect (marked by sodium concentration), (2) an effect represented by changes in chloride concentration, (3) an albumin effect, (4) a phosphorus effect, and (5) a lactate effect. Differences between the sum total of all these known, calculated effects, and the BE are attributed to the presence of unmeasured (unknown) acids or bases. The formulas used to determine these effects are provided in

CHAPTER 60  Nontraditional Acid-Base Analysis

TABLE 60.2  Suggested Shorthand

Formulas for Estimation of Semiquantitative Acid-Base Effects Effect Free water effect Corrected chloride Chloride effect Albumin effect Phosphorus effect Lactate effect Sum Unmeasured ion effect (XA2)

Shorthand Formula (measured sodium 2 mid-normal sodium) / 4 measured chloride 3 (mid-normal sodium / measured sodium) mid-normal chloride 2 corrected chloride (mid-normal albumin 2 measured albumin) 3 4 (mid-normal phosphorus 2 measured phosphorus) / 2 measured lactate 3 21 free water effect 1 chloride effect 1 albumin effect 1 phosphorus effect 1 lactate effect base excess 2 sum

Table 60.1.13,14 A simplified or shorthand version of these formulas is provided in Table 60.2. These can be used to make a rough estimate of these parameters and allow the clinical application of this approach without use of a computer spreadsheet. Semiquantitative metabolic acid-base analysis as presented here requires determination of BE, and measurement of as many of the following parameters as possible: sodium, chloride, albumin, lactate, and phosphorus. From these measured parameters, 10 metabolic acid-base influences can be identified and the magnitude of their contribution to the overall BE estimated. Negative contributions indicate an acidotic influence on BE, whereas a positive calculated effect indicates an alkalinizing influence. For full acid-base evaluation, this information would need to be integrated with evaluation of the pH and PCO2 of the patient. This approach has been applied to several veterinary populations, including emergency room patients, those with typical hypoadrenocorticism, and parvoviral enteritis.15-18

Free Water Effect The free water effect on BE is due to changes in the water balance. Clinically, the free water concentration is reflected by sodium concentration; a deficit of free water causing hypernatremia and an excess of free water causing hyponatremia. An excess of free water (hyponatremia) will be evident by a negative free water effect indicating an acidotic effect—a dilutional acidosis. A deficit of free water (hypernatremia) will be evident by a positive free water effect indicating an alkalinizing effect—a contraction alkalosis.19

Chloride Effect In many processes within the body, chloride and bicarbonate are reciprocally linked (i.e., when a chloride ion is excreted, a bicarbonate ion is retained and vice versa). Such processes include gastric acid secretion, intestinal bicarbonate secretion, renal acid-base handling, and transcellular ion exchange. Evaluation of the change in chloride concentration can therefore be used to estimate the contribution to BE made by these processes. Changes in free water will also alter chloride concentration, and this impact needs to be accounted for before calculation of the chloride effect. The formula for determining the corrected chloride value removes the effect of free water changes and is provided in Table 60.2. The difference between this corrected chloride concentration and the patient’s normal chloride concentration (the midnormal value for chloride for that species is usually used) estimates the

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contribution to BE by processes associated with the change in chloride concentration (see Table 60.1). An increased (positive) chloride effect (reflecting hypochloremia) is associated with a process that increases bicarbonate concentration and is indicative of an alkalinizing process; a decreased chloride effect (negative) marks an acidotic process (see Table 60.2). An alternative method for assessing chloride abnormalities is the Cl:Na ratio. One study in dogs and cats found that a normal Cl:Na ratio ruled out acid-base abnormalities associated with changes in chloride. An increased Cl:Na ratio identified a corrected hyperchloremia and a decreased Cl:Na ratio identified a corrected hypochloremia in almost all cases of dogs and cats.20 The normal Cl:Na ratio should be determined from a species-specific laboratory reference range.

Albumin Effect Albumin acts as a weak acid. It has many H1 binding sites associated with the imidazole group of the amino acid histidine. Hypoalbuminemia is equivalent to the removal of a weak acid from the system; it will be evident as a positive effect, indicating an alkalinizing effect. Conversely, hyperalbuminemia will be evident as a negative effect, indicating an acidotic influence.6,12

Phosphorus Effect Phosphoric and sulfuric acids are products of protein metabolism and are normally excreted by the kidneys. Patients with acute kidney injury or failure retain these acids, resulting in a metabolic acidosis. The phosphoric acid contribution toward BE, from a given inorganic phosphorus concentration, is determined by use of the equation in Table 60.1. Elevated phosphorus will cause a negative effect and indicates an acidotic influence on BE. Because serum phosphorus concentration is normally low, hypophosphatemia does not cause a clinically significant alkalosis. Sulfate is not usually measured and is therefore one of the unmeasured anions.

Lactate Effect Lactate is produced from the conversion of pyruvate by lactate dehydrogenase, a reaction that consumes hydrogen ions. Lactic acidosis occurs when there is a concurrent accumulation of hydrogen ions from the hydrolysis of ATP. In health these hydrogen ions (along with pyruvate) enter the mitochondria for ongoing metabolism. In diseases where mitochondrial function is impaired, such as cellular hypoxia, there is accumulation of both lactate and hydrogen ions leading to lactic acidosis (see Chapter 61, Hyperlactatemia).21 In acute clinical scenarios of lactic acidosis caused by anaerobic metabolism, lactate has an equimolar effect on BE (see Table 60.1). Elevations in lactate concentration during these states results in a negative calculated effect—an acidotic influence on BE. As not all causes of hyperlactatemia are associated with acidosis, clinical judgment should be used to determine if lactate should be included in the calculation of semiquantitative effects on BE.22 In addition, blood samples contaminated with sodium lactate (e.g., from lactated Ringer’s solution) will also show an increase in lactate with no acidosis.23 As a result, some clinical judgment is required when including the lactate value in the calculations.

Unmeasured Ions (XA2) The quantitative approach identifies many of the relevant contributors to the metabolic acid-base component. The difference between the sum of these identified effects and the patient’s BE represents unidentified acids or bases contributing to the acid-base equilibrium (see Table 60.1). Unmeasured acids include ketoacids, sulfuric acid, ethylene glycol, salicylic acid, propylene glycol, and metaldehyde. As with

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PART V  Electrolyte and Acid-Base Disturbances

the SIG value, the parameter XA- is not affected by changes in albumin concentration, making it a more sensitive measure of unmeasured anions in hypoalbuminemic patients.

CONCLUSION The major advantage of the SID and semiquantitative approaches is the ability to recognize underlying mechanisms of acid-base disorders, in particular the effect of changes in albumin concentration. A limitation of the nontraditional approaches is that they do not recognize compensatory changes to primary respiratory acid-base disorders; therefore, all changes in the metabolic system will be identified as pathologic. The SID approach is far more confusing and intimidating than the traditional approach for clinicians to use; it requires measurement of albumin (and ideally phosphorus) concentration and really is best used with a computer spreadsheet. It is unknown if the increase in cost and complexity of this approach has sufficient clinical benefit to warrant its routine use. The semiquantitative approach is also more complex than the traditional approach, although use of the simplified formulas may allow it to be more readily applied in the clinical setting. Another limitation of the SID approach is that SID and ATOT are aggregate indices, much like the AG. They will reflect general acid-base abnormalities, but unfortunately, they are not specific. The semiquantitative approach may provide a more useful clinical approach to acidbase analysis because it attempts to recognize the individual role of specific disease mechanisms. The semiquantitative approach calculates

small acid-base effects for each parameter. It is important to recognize that the inherent degree of error for each laboratory value could contribute to variability in these results. The semiquantitative approach has not been validated in dogs and cats.

CLINICAL EXAMPLES Case 1 A 13-year-old female spayed Terrier cross dog is presented with a history of vomiting and collapse. The bloodwork provided in Table 60.3 was obtained at presentation. The traditional acid-base diagnosis of this case is a mixed disorder with a concurrent respiratory alkalosis and a metabolic acidosis resulting in a normal pH. The AG is slightly lower than the reference range. The SID approach reveals little more than the traditional approach in this case with essentially normal values for SID, ATOT, and SIG. It is interesting to note that the alkalinizing influence of the hypoalbuminemia is counteracted by the acidotic influence of the hyperphosphatemia, resulting in an almost normal value for ATOT. In comparison, the semiquantitative approach reveals a mild alkalinizing effect attributable to a small free water deficit, an acidosis associated with bicarbonate-chloride exchange, and an acidosis caused by hyperphosphatemia. The hypoalbuminemia is exerting a strong alkalinizing influence, which is reducing the severity of the metabolic acidosis. The sum of effects accounts for the majority of the BE with a small quantity of unmeasured anions identified. These are likely to be

TABLE 60.3  Clinical Examples of Acid-Base Abnormalities Using Equations from Table 60.1 Parameter

Case 1: Dog Patient Value (Reference Range) [mid-normal value]

Case 2: Cat Patient Value (Reference Range) [mid-normal value]

Sodium mmol/L Potassium mmol/L Chloride mmol/L Albumin g/dl Phosphorus mg/dl pH PvCO2 mm Hg Bicarbonate mmol/L BE mmol/L Lactate mmol/L

152 (144–152) [148] 3 (3.6–4.7) [4.1] 125 (111–121) [116] 1.1 (3.4–4.3) [3.9] 12.1 (2.6–5.2) [3.9] 7.383 (7.32–7.43) 28 (37–45) 16 (18–26) 27.8 (24 to 21) 1.1 (,2)

128 (148–156) [152] 2.2 (3.4–4.6) [3.0] 82 (115–125) [120] 3.7 (2.2–4.6) [3.4] 2.2 (3.2–6.4) [4.8] 7.395 (7.34–7.43) 44.5 (34–39) 26.7 (20–23) 2.2 (25 to 0) 2 (,2)

Calculated Acid-Base Values (mmol/L) Anion gap 14 (8–16)

21.5 (16–20)

Strong Ion Difference Analysis SID A TOT SIG

30 (32–45) 9.8 (10–11) 4.2 (0–8)

48.2 (40–44) 11.6 (8–17) 9.9 (6–9)

Semiquantitative Analysis Corrected chloride Free water effect Chloride effect Lactate effect Albumin effect Phosphorus effect Sum XA

122 11.0 26 21.1 110.4 24.8 20.6 27.2

97 25.3 123 22 21.2 11.5 116.2 214

A TOT , quantity of weak acids; SID, strong ion difference; SIG, strong ion gap; XA, unmeasured ion effect. Calculation of acid-base parameters were based on formulas shown in Table 60.1.

CHAPTER 60  Nontraditional Acid-Base Analysis other uremic acids such as sulfates that are not measured routinely. In this example, the semiquantitative approach identified several coexisting metabolic alkalotic and acidotic acid-base abnormalities, whereas the traditional approach diagnosed only a metabolic acidosis and the SID approach suggested an essentially normal metabolic acid-base balance. This dog was ultimately diagnosed with pancreatitis and pyelonephritis.

Case 2 A 10-year-old male castrated cat with a 3-month history of diabetes mellitus presented for inappetence and constipation. The initial bloodwork is provided in Table 60.3. The traditional approach reveals a mixed disorder of a mild respiratory acidosis and a coexisting mild metabolic alkalosis with a small increase in AG. The SID approach shows a slightly elevated SID indicating a mildly increased SID metabolic alkalosis and a minimal increase in SIG. The semiquantitative approach indicates a substantial alkalinizing effect on BE associated with chloride-bicarbonate exchange, an acidotic effect associated with free water gain, and a significant acidotic contribution from unmeasured anions. This cat was found to have a large fluid-filled stomach, and selective gastric acid loss was suspected to be the cause of the large alkalinizing chloride effect. This case is a good example of the value of correcting the chloride concentration for changes in free water balance. Although this patient does have true hypochloremia, the measured value would overestimate this effect given the concurrent increase in free water. The SID underestimates the severity of the metabolic alkalosis due to the coexisting hyponatremia. Both the AG and the SIG fail to identify the magnitude of the unmeasured anion contribution to this acid-base balance. The AG is reduced by the hypophosphatemia and the SIG is influenced by the concurrent changes in SID, phosphorus, and bicarbonate levels. This cat was found to have a large quantity of ketones in the plasma and urine. The semiquantitative approach was able to demonstrate a metabolic alkalosis that was largely counteracted by the acidotic influence of free water gain and the accumulation of ketoacids. In addition to treatment of the diabetic ketoacidosis, this cat will benefit from resolution of the disease process leading to gastric acid loss as well as fluid therapy to support normalization of serum chloride concentration.

REFERENCES 1. Stewart PA: Modern quantitative acid-base chemistry, Can J Physiol Pharmacol 61:1444, 1983. 2. Kellum JA: Determinants of plasma acid-base balance, Crit Care Clin 21: 329, 2005. 3. Constable PD: Clinical assessment of acid-base status: comparison of the Henderson-Hasselbalch and strong ion approaches, Vet Clin Pathol 29:115, 2000.

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4. Morgan TJ, Balasubramanian V, Hall J: Crystalloid strong ion difference determines metabolic acid-base change during in vitro hemodilution, Crit Care Med 30:157, 2002. 5. Figge J, Mydosh T, Fencl V: Serum proteins and acid-base equilibria: a follow-up, J Lab Clin Med 120:713, 1992. 6. Constable PD, Stampfli HR: Experimental determination of net protein charge and Atot and Ka of nonvolatile buffers in canine plasma, J Vet Intern Med 19:507, 2005. 7. McCullough SM, Constable PD: Calculation of the total plasma concentration of nonvolatile weak acids and the effective dissociation constant of nonvolatile buffers in plasma for use in the strong ion approach to acid-base balance in cats, Am J Vet Res 64:1047, 2003. 8. Vanova-Uhrikova I, Rauserova-Lexmaulova L, Rehakova K, Scheer P, Doubek J: Determination of reference intervals of acid-base parameters in clinically healthy dogs, J Vet Emerg Crit Care 27(3):325-332, 2017. 9. Kaae J, de Morais HA: Anion gap and strong ion gap: a quick reference, Vet Clin Small Anim 38:443, 2008. 10. Fencl V, Rossing TH: Acid-base disorders in critical care medicine, Annu Rev Med 40:17, 1989. 11. Fencl V, Jabor A, Kazda A, et al: Diagnosis of metabolic acid-base disturbances in critically ill patients, Am J Respir Crit Care Med 162:2246, 2000. 12. Figge J, Rossing TH, Fencl V: The role of serum proteins in acid-base equilibria, J Lab Clin Med 117:453, 1991. 13. Leith DE: The new acid-base; power and simplicity, Proceedings of the 9th ACVIM Forum, New Orleans, 1991, pp 611-617. 14. de Morais HAS: A nontraditional approach to acid-base disorders. In DiBartola SP, editor: Fluid therapy in small animal practice, ed 1, Philadelphia, 1992, WB Saunders, pp 297-320. 15. Burchell RK, Gal A, Friedlein R, Leisewitz AL: Role of electrolyte abnormalities and unmeasured anions in the metabolic acid-base abnormalities in dogs with parvoviral enteritis, J Vet Intern Med 34(2):857-866, 2020. 16. Osborne LG, Burkitt-Creedon JM, Epstein SE, Hopper K: Semiquantitative acid-base analysis in dogs with typical hypoadrenocorticism, J Vet Emerg Crit Care 31(1):99-105, 2021. doi:10.1111/vec.13016. 17. Hopper K, Epstein SE, Kass PH, Mellema MS: Evaluation of acid-base disorders in dogs and cats presenting to an emergency room. Part 1: comparison of three methods of acid-base analysis, J Vet Emerg Crit Care 24(5):493-501, 2014. 18. Hopper K, Epstein SE, Kass PH, Mellema MS: Evaluation of acid-base disorders in dogs and cats presenting to an emergency room. Part 2: comparison of anion gap, strong ion gap, and semiquantitative analysis, J Vet Emerg Crit Care 24(5):502-508, 2014. 19. Haskins SC, Hopper K, Rezende ML: The acid-base impact of free water removal from, and addition to, plasma, J Lab Clin Med 147:114, 2006. 20. Goggs R, Myers M, De Rosa S, Zager E, Fletcher DJ: Chloride:sodium ratio may accurately predict corrected chloride disorders and the presence of unmeasured anions in dogs and cats, Front Vet Sci 4:122, 2017. 21. Suetrong B, Walley KR: Lactic acidosis in sepsis: it’s not all anaerobic: indications for diagnosis and management, Chest 149(1):252-261, 2016. 22. Mizock BA: Controversies in lactic acidosis: implications in critically ill patients, J Am Med Assoc 258:497-501, 1987. 23. Jackson EV, Wiese J, Sigal B, et al: Effects of crystalloid solutions on circulating lactate concentrations. Part 1: implications for the proper handling of blood specimens obtained from critically ill patients, Crit Care Med 25:1840-1846, 1997.

61 Hyperlactatemia Patricia G. Rosenstein, DVM, DACVECC, Dez Hughes, BVSc (Hons), DACVECC

KEY POINTS • Plasma lactate is a late but quantitative indicator of tissue hypoperfusion and can be used as a prognostic indicator and a guide to treatment and diagnostics. • Lactate is an intermediary metabolite of glucose oxidation that serves as a carbohydrate energy substrate reservoir. • Lactate production is an adaptive and protective response to cellular energy deficiency that allows rapid or continued energy

production when cellular energy requirements exceed the capacity of cellular aerobic respiration. • In critical illness, particularly sepsis, lactate is produced by aerobic and anaerobic mechanisms and is a surrogate of the adrenergic stress response in addition to tissue hypoperfusion.

The main use of plasma lactate concentration in clinical practice is as an adjunct to a shrewd physical examination to detect and monitor hypoperfusion. The clinical utility of lactate was first recognized after the first World War and reported definitively in 1964.1 Its use became widespread in human and veterinary medicine in the 1990s with the advent of cheaper and simpler assays. Once considered a dead end waste product of anaerobiosis, lactate is now recognized as an integral part of the cellular energy shuttle and as a metabolic regulator.

allow glycolysis to continue, NAD1 is replenished and pyruvate and H1 ions are removed by conversion of pyruvate to lactate. Although glycolysis produces only 2 moles of ATP per glucose molecule, it is very fast and so can temporarily satisfy energy demands. Contrary to popular belief, the metabolic acidosis associated with lactate production is due to ATP use, not lactate production per se.2 Glycolysis produces the lactate ion rather than lactic acid.3 When the ATP made by glycolysis is utilized, H1 is released into the cytosol. This proton would usually enter the mitochondrion and be used to maintain the proton gradient required for the electron transport chain and oxidative phosphorylation. When oxygen supplies are insufficient, this cannot happen and H1 ions accumulate and are then transported out of the cell. Hence, the acidosis from increased lactate production is mostly due to reduced H1 consumption, not increased lactate production per se. Importantly, lactate is conserved across species from bacteria and reptiles through to higher mammals and presumably must convey a selective evolutionary advantage. Using the Stewart approach to acid-base balance, lactate is a strong anion and, similar to chloride, will have an acidifying effect if not accompanied by an increase in sodium. The semiquantitative approach to acid-base balance suggests each 1 mmol/L increase in lactate is associated with a concomitant reduction of the standardized base excess of 1 mmol/L. The precise relationship between lactate and acidosis is, however, complex and controversial.4,5 As changes in lactate concentration do not always reflect a change in hydrogen ion concentration, clinical judgment should be used in application of the semiquantitative approach. See Chapter 60, Non-Traditional Acid-Base Analysis for further discussion of these concepts.

BIOCHEMISTRY Lactate and lactic acid are not synonymous. Lactic acid (CH3CH(OH) COOH) is a strong acid that, at physiologic pH, is almost completely dissociated to the lactate anion (CH3CH(OH)COO2) and H1. Increased plasma lactate concentration is termed hyperlactatemia, which may or may not be associated with a net acidemia depending on the cause of the increased lactate, concurrent acid/base disturbances, and buffer reserves. Glycolysis is the cytosolic process (which occurs in the presence or absence of oxygen) by which 1 mole of glucose is oxidized to 2 moles of pyruvate, ATP, and reduced nicotinamide adenine dinucleotide (NADH). Pyruvate enters the mitochondria and is converted into acetyl CoA, which then, in the presence of sufficient oxygen, proceeds through the tricarboxylic acid (TCA) cycle, the electron transport chain, and oxidative phosphorylation to produce 36 moles of ATP (Fig. 61.1). Under normal aerobic conditions, only a small quantity of pyruvate is converted into lactate, catalyzed by lactate dehydrogenase (LDH) (see Fig. 61.1). Lactate may then be either transported out of the cell or used within the same cell. Ultimately lactate is either converted back into pyruvate in local or distant tissues and oxidized to produce energy or converted back into glucose by gluconeogenesis. Glycolysis consumes NAD1 and produces NADH and pyruvate. If there is a relative or absolute cellular oxygen deficiency, the TCA cycle and oxidative phosphorylation are slowed so NAD1 levels fall and pyruvate and NADH buildup, thereby slowing ongoing glycolysis. To

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PHYSIOLOGY Lactate Pharmacokinetics in Health Lactate is produced in the cytosol and then either converted back to pyruvate to proceed through local aerobic cellular metabolism or exported out of the cell and transported to distant tissues in the bloodstream. Although all tissues are capable of producing lactate, in resting

CHAPTER 61  Hyperlactatemia

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Glucose ATP ADP Fructose-6-phosphate Phosphofructokinase

ATP ADP

Fructose-1,6-bisphosphate NAD NADH

Cytosol

Electron transport chain and oxidative phosphorylation

ATP

2 x per molecule of glucose

2 x ADP 2 x ATP NAD NADH Lactate

LDH

H  Pyruvate

Pyruvate dehydrogenase Acetyl CoA

Tricarboxylic acid cycle

FADH2 NADH  H Electrons

ATPase ATP  H2O ADP  Pi  H Mitochondrial matrix

CO2

Fig. 61.1  The biochemical pathways of cellular energy production: glycolysis, lactate production, the tricarboxylic acid cycle, oxidative phosphorylation, and the electron transport chain.

conditions the majority of lactate production occurs in skeletal muscle, brain, and adipose tissue by virtue of their inherent production capacities and mass relative to body weight.6 Under conditions of health and aerobiosis, the liver and renal cortex are the predominant lactateconsuming organs. Hepatic metabolism accounts for 30% to 60% of lactate consumption, and the liver is capable of metabolizing markedly increased lactate loads.7-9 The renal cortex metabolizes 20% to 30% of circulating lactate.4,10,11 In keeping with its role as a carbohydrate energy substrate (essentially half a glucose molecule), lactate is not excreted in the urine until its plasma concentration is high. It is reabsorbed by the proximal convoluted tubule, and the renal threshold is 6 to 10 mmol/L.12-14

Lactate Pharmacokinetics in Disease Tissue lactate production, distribution, metabolism, consumption, and excretion can all differ in disease states compared with normal homeostasis in healthy animals. During global hypoperfusion, lactate production in tissue beds depends on whether the blood flow is reduced or selectively preserved. Local disease can also affect tissue lactate production; for example, in acute lung injury the lungs increase lactate production.15,16 During hyperlactatemia, some tissues, such as skeletal muscle, cardiac muscle, and brain tissue, increase their lactate uptake, sometimes even preferentially to glucose.6,12,13,17-19 The liver continues to extract lactate until hepatic blood flow is less than 30% of normal,20 but it can actually become a net lactate producer with poor perfusion, severe hypoxia, or hepatic failure.20-22 Lactate produced by tissues is exported by the cell into the interstitium, then passes into plasma. Once in plasma it then equilibrates with the intracellular space of erythrocytes. Whole blood lactate refers to the mean of intraerythrocytic and plasma lactate. Almost all analyzers measure lactate from plasma even though whole blood is aspirated by most machines.

ETIOLOGY OF HYPERLACTATEMIA Hyperlactatemia is one of the most common conditions associated with metabolic acidosis in the dog and cat and occurs when lactate production exceeds consumption. Lactic acidosis has been defined as hyperlactatemia with a concurrent metabolic acidosis. Hyperlactatemia is divided into two categories: type A and type B. Type A (the most common) occurs with clinical evidence of a relative or absolute tissue oxygen deficiency. Type B occurs in the absence of clinical evidence of decreased oxygen delivery (Table 61.1).23 Type A and B may exist concurrently. Clinical experience suggests that type B usually results in a mild to moderate increase in lactate (3 to 6 mmol/L). Conversely, severe hyperlactatemia (6-.20 mmol/L) is usually primarily due to global hypoperfusion.

Type A Hyperlactatemia Increased Oxygen Demand Common causes of increased oxygen demand relate to muscle activity such as exercise, struggling, shivering, trembling, tremors, and seizures. Maximal exercise-related hyperlactatemia ranges from 6.31 mmol/L in Labrador Retrievers during field training24 to more than 30 mmol/L in racing Greyhounds.25,26 Physiologic hyperlactatemia should resolve uneventfully once muscle activity ceases, with an elimination half-life of 20 to 60 minutes.25,27 If resolution does not occur in a clinical patient within this time frame, a concurrent disease process is likely.

Decreased Oxygen Delivery Hyperlactatemia is most commonly associated with decreased oxygen delivery secondary to systemic hypoperfusion (i.e., hypovolemic, maldistributive, cardiogenic, or obstructive shock). In dogs, progressively worsening hypoperfusion shows a fairly linear relationship with plasma lactate concentration. Mild hypoperfusion is associated with

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TABLE 61.1  Causes of Hyperlactatemia TYPE A HYPERLACTATEMIA Increased Oxygen Demand

Decreased Oxygen Delivery

Exercise Trembling/shivering Muscle tremors Seizure activity Struggling

Systemic hypoperfusion Local hypoperfusion Severe anemia Severe hypoxemia Carbon monoxide poisoning

TYPE B HYPERLACTATEMIA B1: Associated with Underlying Disease Sepsis Neoplasia Diabetes mellitus Liver disease Thiamine deficiency Pheochromocytoma Hyperthyroidism Alkalosis

B2: Associated with Drugs or Toxins Acetaminophen Activated charcoal b2 agonists Bicarbonate Corticosteroids Cyanide Epinephrine Ethanol Ethylene gylcol Glucose Insulin

Lactulose Methanol Methylxanthines Nitroprusside Propofol Propylene glycol Salicylates Strychnine Sorbitol TPN Xylitol

B3: Inborn Errors in Metabolism Mitochondrial myopathies Enzymatic deficiencies MELAS

MISCELLANEOUS d-Lactic acidosis TPN, total parenteral nutrition; LRS, lactated Ringer’s solution, MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

lactate concentrations of 3 to 4 mmol/L, moderate with 4 to 6 mmol/L, and severe with concentrations greater than 6 mmol/L. In the authors’ clinical experience, it seems that cats demonstrate an exponential increase with a lesser increase in mild and moderate hypoperfusion, then a rapid rise when it is severe. Just as we recognize that falling blood pressure is a late indicator of hypovolemia, so is hyperlactatemia: a corollary being that subclinical hypoperfusion may exist with a normal blood lactate concentration. Hyperlactatemia caused by decreased oxygen content and oxygen delivery due to anemia or hypoxemia is rare without coexisting hypovolemia and/or hypotension. Anemia-related hyperlactatemia is highly dependent on intravascular volume status and chronicity. In experimental, acute, severe, euvolemic anemia, hyperlactatemia does not develop until the packed cell volume (PCV) drops below 15%.28 Dogs and cats with chronic, euvolemic anemia may remain eulactatemic with a PCV of 10% or even less. Dogs with anemia from hemolysis caused by immune-mediated hemolytic anemia (IMHA) have been reported to have hyperlactatemia, although this could also have been secondary to concurrent hypoperfusion.29 Similarly, hypoxemia must also be very severe (partial pressure of oxygen [PaO2] 25 to 40 mm Hg) before pure hypoxemia-related hyperlactatemia develops.23,28 Hence, anemia or hypoxemia should only rarely be considered as a sole diagnosis for increased lactate. Local hypoperfusion, such as occurs with aortic thromboembolism or organ volvulus, causes local increases in lactate concentration in the veins draining that tissue. However, the effect on systemic plasma lactate concentration varies according to the remaining blood flow through the ischemic tissue and therefore how much lactate is washed into circulation. If there is little washout, then systemic lactate may not increase appreciably. Clinical experience suggests that organ torsion such as lung lobes, liver lobes, or spleens do not release much lactate

and the systemic lactate concentration actually reflects the global perfusion status.

Type B Hyperlactatemia Type B hyperlactatemia has conventionally been divided into three subcategories (see Table 61.1). Type B1 is associated with underlying disease, B2 with drugs or toxins, and B3 with congenital or hereditary metabolic defects.

Type B1 – Underlying Disease Hyperlactatemia occurs commonly in sepsis and septic shock and may persist despite aggressive correction of hypoperfusion, anemia, and hypoxemia.30 The pathophysiology of sepsis-associated hyperlactatemia is complex and multifactorial. Suggested mechanisms include stimulation of skeletal muscle Na1/K1-ATPase by catecholamines31; mitochondrial dysfunction, including direct cytochrome inhibition32; increased hepatic lactate production; reduced hepatic lactate extraction33; impaired tissue oxygen extraction34; and capillary shunting.34 Enhanced nitric oxide production, altered neurohormonal control of endothelial smooth muscle, reduced erythrocyte flexibility, increased leukocyte activation, and pyruvate dehydrogenase inhibition35,36 have also been implicated. There is compelling evidence that increased aerobic glycolysis secondary to adrenergic stimulation significantly contributes to sepsis-associated hyperlactatemia.37 Hyperlactatemia associated with neoplasia may be due to hypoperfusion in some cases, but malignant cells are known to exhibit atypical carbohydrate metabolism by preferentially utilizing glycolytic pathways for energy production despite sufficient oxygen availability (Warburg effect).38,39 Rare cases of lymphoma and hemangiosarcoma may exhibit hyperlactatemia despite apparently normal perfusion. Some dogs with diabetes mellitus have increased lactate concentrations,

CHAPTER 61  Hyperlactatemia but this could also be due to concurrent type A causes.40,41 Hepatic disease resulting in hyperlactatemia likely only occurs with severe hepatic dysfunction or failure or concurrent hypoperfusion.42

Type B2 – Drugs and Toxins Many drugs and toxins can cause hyperlactatemia, and these are being increasingly reported (see Table 61.1). Both antiinflammatory and immunosuppressive doses of prednisone cause mild to moderate increases in lactate (mean 6 SD up to 3.4 6 0.9 and 4.3 6 0.7 mmol/L, respectively) in clinically normal dogs.43 Metabolism of ethylene glycol (EG) and ethanol increase the NADH/NAD1 ratio, which drives the LDH reaction toward lactate production.44 But the severe metabolic acidosis and anion gap associated with EG toxicity is predominantly from acidic EG metabolites.44,45 Propylene glycol, found in food items, chemical agents, and drugs, is metabolized to l-lactate, d-lactate, and pyruvate and can result in hyperlactatemia when ingested or administered in excess.46 Some formulations of activated charcoal contain propylene glycol as well as the lactate precursor, glycerol, and can cause increased lactate concentrations.47,48 Epinephrine increases Na+/K+-ATPase activity and glycogenolysis resulting in hyperlactatemia.49 Not surprisingly, conditions resulting in excess endogenous catecholamine release, such as pheochromocytoma, have also been associated with hyperlactatemia.50 Rapid infusion of lactated Ringer’s solution can impact plasma lactate concentrations, particularly when there is altered lactate handling (such as with liver failure or neoplasia51) or if the nonracemic levorotatory solution (containing 28 mmol/L L-lactate) is used.52

Type B3 – Hereditary Metabolic Defects Congenital errors in metabolism that cause hyperlactatemia in people include glucose-6-phosphatase deficiency, pyruvate dehydrogenase deficiency and mitochondrial encephalopathy, lactic acidosis, and stroke-like syndrome (MELAS). Mitochondrial myopathies have been reported in the Jack Russell Terrier, German Shepherd, and Old English Sheepdog.53-55 Pyruvate dehydrogenase deficiency has been recognized in the Clumber Spaniel and Sussex Spaniel.56

Cryptic Shock The term cryptic shock has been used to describe ill or injured patients with high lactate concentrations without hypotension. It is unclear whether this increase in lactate is a consequence of decreased oxygen delivery on a macrocirculatory level, microcirculatory impairment, cellular dysfunction, or simply a reflection of intense sympathetic drive. Regardless, it is noteworthy in that it may reflect a serious underlying cause that warrants investigation. Septic, normotensive people in the emergency department or ICU with increased lactate concentrations demonstrate comparable or worse survival than those experiencing hypotension without hyperlactatemia.57-60 Furthermore, an increased lactate has been shown to predict the need for massive transfusion in hemodynamically normal human trauma patients.61 Evidence evaluating cryptic shock in dogs and cats is limited. In one study wherein dogs presenting in hypovolemic or septic shock were resuscitated to satisfy traditional hemodynamic targets, 20% had persistently increased lactate and 37% had persistently low central venous oxygen, suggesting ongoing tissue hypoperfusion despite normotension.62 d-LACTATE Lactate exists in levorotatory and dextrorotatory stereoisomeric forms: l-lactate and d-lactate. l-Lactate is the predominant form produced by mammalian cells. It is also the only stereoisomer measured by

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common clinical technology. d-Lactate is not detected by routine lactate analyzers and can only be measured by specialist laboratories. In health, d-lactate is present at ,1% of the concentration of l-lactate.63 Both d- and l-lactate are produced by some bacteria under anaerobic conditions.64 In people, d-hyperlactatemia associated with short bowel syndrome and exocrine pancreatic disease is thought to contribute to encephalopathy.65-67 dHyperlactatemia has been reported in cats with diabetic ketoacidosis,68 propylene glycol intoxication,69 and exocrine pancreatic insufficiency with bacterial dysbioisis.70 Cats with gastrointestinal disease also have significantly higher d-lactate concentrations than cats without gastrointestinal disease.71 In ruminants, hyperlactatemia caused by d-lactate is well documented with conditions such as grain overload.72 d-Hyperlactatemia should be considered as a rare but possible cause of a high anion gap metabolic acidosis in dogs and cats.

CLINICAL USE Because increased muscle activity causes hyperlactatemia, venipuncture should be performed with minimal struggling or trembling. If there is muscle activity, then this should be considered when interpreting results. Mild to moderate struggling seems to have minor effects on plasma lactate concentration,73 but higher levels of muscle activity can significantly increase lactate (e.g., lots of struggling, trembling, tremors, marked exercise, and seizures). Lactate measured in pulmonary arterial or peripheral arterial blood essentially reflects the mixture of all venous effluents in the body. In contrast, a venous sample reflects the net balance of the lactate entering that specific tissue in arterial blood and what happens in that tissue bed. If blood flow is normal and the animal is clinically healthy, cephalic vein lactate is slightly higher than arterial, but the difference is very small and clinically irrelevant.74 If tissue blood flow is low and the tissue is producing lactate (e.g., a limb in an animal with global hypoperfusion), then venous lactate exceeds arterial by a larger amount. Hence, repeat lactate measurements should be taken from the same site. There is usually no clinical reason to use arterial blood samples for lactate measurement. There are now a variety of handheld and benchtop lactate analyzers. Accuracy, precision, bias, and linearity differ among machines, and benchtop analyzers are superior to handhelds. Importantly, handheld analyzers may be inaccurate and imprecise at lactate concentrations within and just above the reference range. This means that a lactate concentration of approximately 3 mmol/L measured using a handheld may be artifactually high or a true high value. The reference interval for plasma lactate concentration for dogs between 6 months and 12 years of age is 0.3 to 2.5 mmol/L.74 Puppies may have higher blood lactate levels than adults during the first 2 to 3 months of life.75 Reference intervals in cats from two small studies were 0.3 to 1.776 and 0.37 to 2.81 mmol/L.73 A larger study (47 cats) reported a wider reference interval of 0.67 to 5.44 mmol/L.77 As noted by the authors, caution must be exercised in using this unexpected higher upper limit until additional research is performed. Lactate is an insensitive indicator of tissue hypoperfusion. Even a small rise is therefore very significant once other causes of hyperlactatemia have been ruled out.

PROGNOSTIC USE Lactate is a useful prognostic indicator provided it is interpreted cautiously and appropriately. Low values make survival more likely and very high values make it less likely. Importantly, this depends on the underlying condition. If the process causing hyperlactatemia has a high mortality, then lactate is more likely to be prognostically useful (e.g., sepsis), but it is less helpful if the cause is easily correctable (e.g.,

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simple hemorrhage that can be easily stopped). With hypoperfusion, a high initial lactate reflects the degree of hypoperfusion but not necessarily the reversibility. A decrease in lactate concentration with treatment is a more reliable prognostic indicator than initial lactate. In general, with severe disease processes, if plasma lactate concentration does not fall back to normal within 24 to 48 hours, survival is less likely. In people, lactate has shown prognostic value in trauma, sepsis, septic shock, cardiac arrest, carbon monoxide toxicity, head trauma, malaria, and liver failure.78-80 Importantly, increased lactate is associated with worse prognoses regardless of macrohemodynamic status.57-61 Some degree of prognostic utility has been reported for ill and injured dogs81-83; systemically ill dogs84; and dogs with systemic inflammatory response syndrome,85 IMHA,29 head trauma,86 gastric dilationvolvulus,87 severe soft tissue infections,88 heartworm-associated caval syndrome,89 babesiosis,90 trauma91 and septic peritonitis.92 Lactate has also been demonstrated to have some prognostic value in hypotensive cats,93 cats admitted to intensive care requiring intravenous fluid therapy,94 cats presenting to an emergency service,82 and cats with septic peritonitis.95 Others, however, have failed to find an association between lactate and mortality in cats.96-100 Overall, it appears that the prognostic value of lactate may be less consistent in cats than dogs.101 The acute patient physiologic and laboratory evaluation (APPLE) for dogs and cats found lactate to be one of the most significant variables associated with mortality and included lactate in both the full and fast scoring systems for both species.102,103

DIAGNOSTIC USE Lactate can be used as an adjunctive diagnostic tool for septic peritonitis. It can be measured on abdominal fluid and used in conjunction with glucose, pH, partial pressure of oxygen (PO2), and partial pressure of carbon dioxide (PCO2). Septic abdominal fluid may have low glucose (,50 mg/dl; 2.8 mmol/L), PO2, and pH (,7.0) and high PCO2 and lactate. Intraabdominal values for glucose, PO2, and pH will also often be lower than peripheral venous blood and PCO2 and lactate will be higher.104,105 Many noninfectious causes of abdominal effusion may not show these changes. Increased peritoneal lactate concentration or peritoneal fluid-to-blood gradients also occur with aseptic abdominal crises such as small bowel strangulation106 and mesenteric vascular thrombosis.107 The cause of high peritoneal fluid lactate concentrations with septic peritonitis has not been definitively confirmed. It is likely due to a combination of production by leukocytes, red blood cells (RBCs), bacteria, neoplastic cells, and tissue anaerobiosis. Abdominal fluid lactate may not, therefore, be able to differentiate abdominal sepsis from highly inflammatory conditions such as severe pancreatitis or abdominal neoplasia.108 The only studies of septic peritonitis published to date in dogs had such low numbers of patients that these diagnostic guidelines should not be used as a sole method for diagnosis of septic peritonitis. In addition, the presence of abdominal drains has been shown to influence abdominal fluid lactate concentrations.109,110

LACTATE AS A THERAPEUTIC ENDPOINT The most common clinical cause of hyperlactatemia in veterinary practice is thought to be hypovolemia.83 Lactate can be used to guide resuscitative efforts in hypovolemia, particularly in the early phase of resuscitation.111 The underlying cause of hypoperfusion must be identified and treated, and therapy should be tailored to each patient. In certain cases, interventions may be indicated to increase oxygen

content (RBC transfusions and oxygen supplementation) and oxygen delivery (fluid therapy, vasopressors and inotropes). If hyperlactatemia is the result of hypoperfusion secondary to cardiac dysfunction, specific cardiovascular therapeutics may be needed to restore perfusion and volume resuscitation may be contraindicated. Persistent hyperlactatemia in the subacute phase is more likely to be multifactorial in origin. As such, interventions must be carefully considered to avoid iatrogenic harm, particularly from overzealous fluid therapy in a patient that is no longer fluid responsive.111 This is particularly true in septic patients.112 Hyperlactatemia from hypovolemia should rapidly improve with volume resuscitation in the absence of severe ongoing losses. As an approximate guideline, plasma lactate concentration should decrease by half every 1 to 2 hours. If this does not occur, it should raise suspicion for another source of lactate such as ongoing hypovolemia, maldistributive shock, obstructive shock, an internal focus of ischemia, or cause of type B hyperlactatemia. The use of sodium bicarbonate or other buffers is not usually recommended. Because thiamine pyrophosphate is a coenzyme associated with pyruvate dehydrogenase, thiamine supplementation may have theoretical benefits and can be considered as an adjunctive treatment.113 Physiologic hyperlactatemia, such as after exercise or an uncomplicated seizure, does not require treatment and should resolve rapidly without intervention.

REFERENCES 1. Broder G, Weil MH: Excess lactate: an index of reversibility of shock in human patients, Science 143:1457, 1964. 2. Robergs RA: Exercise-induced metabolic acidosis: where do the protons come from, Sportscience 5 (2), 2001. 3. Robergs RA, Ghiasvand F, Parker D: Biochemistry of exercise-induced metabolic acidosis, Am J Physiol Regul Integr Comp Physiol 287:R502, 2004. 4. Robergs RA: Invited review: quantifying proton exchange from chemical reactions – implications for the biochemistry of metabolic acidosis, Comp Biochem Physiol 235:29, 2019. 5. Ferguson BS, Rogatzki MJ, Goodwin ML, et al: Lactate metabolism: historical context, prior misinterpretations, and current understanding, Eur J Appl Physiol 118:691, 2018. 6. van Hall G: Lactate kinetics in human tissues at rest and during exercise, Acta Physiol 199:499, 2010. 7. Kamel KS, Oh MS, Halperin ML: L-lactic acidosis: pathophysiology, classification, and causes; emphasis on biochemical and metabolic basis, Kidney Int 97(1):75-88, 2020. 8. Kreisberg RA: Lactate homeostasis and lactic acidosis, Ann Int Med 92: 227, 1980. 9. Madias NE: Lactic acidosis, Kidney Int 29:752, 1986. 10. Bellomo R: Bench-to-bedside review: lactate and the kidney, Crit Care 6:322, 2002. 11. Yudkin J, Cohen RD: The contribution of the kidney to the removal of a lactic acid load under normal and acidotic conditions in the conscious rat, Clin Sci Mol Med 48:121, 1975. 12. Miller AT, Miller JO: Renal excretion of lactic acid in exercise, J Appl Physiol 1:614, 1949. 13. Craig FN: Renal tubular reabsorption, metabolic utilization and isomeric fractionation of lactic acid in the dog, Am J Physiol 146:146, 1946. 14. Seheult J, Fitzpatrick G, Boran G: Lactic acidosis: an update, Clin Chem Lab Med 55:322, 2017. 15. Kellum JA, Kramer DJ, Lee K, et al: Release of lactate by the lung in acute lung injury, Chest 111:1301, 1997. 16. De Backer D, Creteur J, Zhang H, et al: Lactate production by the lungs in acute lung injury, Am J Respir Crit Care Med 156:1099, 1997.

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45. Verelst S, Vermeersch P, Desmet K: Ethylene glycol poisoning presenting with a falsely elevated lactate level, Clin Toxicol 47:236, 2009. 46. Claus MA, Jandrey KE, Poppenga RH: Propylene glycol intoxication in a dog, J Vet Emerg Crit Care (San Antonio) 21:679-683, 2011. 47. Burkitt JM, Haskins SC, Aldrich J, et al: Effects of oral administration of a commercial activated charcoal suspension on serum osmolality and lactate concentration in the dog, J Vet Intern Med 19:683, 2005. 48. Mix KA, Stafford J, Hofmeister E: Effect of single dose administration activated charcoal containing sorbitol on serum sodium concentration and hydration status in dogs, J Vet Emerg Crit Care 29:616, 2019. 49. Levy B, Mansart A, Bollaert PE, et al: Effects of epinephrine and norepinephrine on hemodynamics, oxidative metabolism, and organ energetics in endotoxemic rats, Intensive Care Med 29:292, 2003. 50. Radhi S, Nugent K, Alalawi R: Pheochromocytoma presenting as systemic inflammatory response syndrome and lactic acidosis, ICU Dir 1:257, 2010. 51. Vail DM, Ogilvie GK, Fettman MJ, et al: Exacerbation of hyperlactatemia by infusion of lactated Ringer’s solution in dogs with lymphoma, J Vet Intern Med 4:228, 1990. 52. Boysen SR, Dorval P: Effects of rapid intravenous 100% L-isomer lactated Ringer’s administration on plasma lactate concentrations in healthy dogs, J Vet Emerg Crit Care 24:571, 2014. 53. Breitschwerdt EB, Kornegay JN, Wheeler SJ, et al: Episodic weakness associated with exertional lactic acidosis and myopathy in Old English sheepdog littermates, J Am Vet Med Assoc 201:731, 1992. 54. Vijayasarathy C, Giger U, Prociuk U, et al: Canine mitochondrial myopathy associated with reduced mitochondrial mRNA and altered cytochrome c oxidase activities in fibroblasts and skeletal muscle, Comp Biochem Physiol 109:887, 1994. 55. Olby NJ, Chan KK, Targett MP, et al: Suspected mitochondrial myopathy in a Jack Russell terrier, J Small Anim Pract 38:213, 1997. 56. Cameron JM, Maj MC, Levandovskiy V, et al: Identification of a canine model of pyruvate dehydrogenase phosphatase 1 deficiency, Mol Genet Metab 90:15, 2007. 57. Puskarich MA, Trzeciak S, Shapiro NI, et al: Outcomes of patients undergoing early sepsis resuscitation for cryptic shock compared with overt shock, Resuscitation 82:1289-1293, 2011. 58. Thomas-Rueddel DO, Poidinger B, Weiss M, et al: Hyperlactatemia is an independent predictor of mortality and denotes distinct subtypes of severe sepsis and septic shock, J Crit Care 30;439.e1-e6, 2015. 59. Yang WS, Kang HD, Jung SK, et al: A mortality analysis of septic shock, vasoplegic shock and cryptic shock classified by the third international consensus definitions (Sepsis-3), Clin Respir J 14:857-863, 2020. 60. April MD, Donaldson C, Tannenbaum LI, et al: Emergency department septic shock patient mortality with refractory hypotension vs hyperlactatemia: a retrospective cohort study, Am J Emerg Med 35:1474-1479, 2017. 61. Brooke M, Yeung L, Miraflor E, et al: Lactate predicts massive transfusion in hemodynamically normal patients, J Surg Res 204:139-144, 2016. 62. Young BC, Prittie JE, Fox P, et al: Decreased central venous oxygen saturation despite normalization of heart rate and blood pressure post shock resuscitation in sick dogs, J Vet Emerg Crit Care 24:154-161, 2014. 63. McLellan AC, Phillips SA, Thornalley PJ: Fluorimetric assay of D-lactate, Anal Biochem 206;12, 1992. 64. Nielsen C, Mortensen FV, Erlandsen EJ, et al: l- and d-lactate as biomarkers of arterial-induced intestinal ischemia: an experimental study in pigs, Int J Surg 10:296, 2012. 65. Uribarri J, Oh MS, Carroll HJ: D-lactic acidosis. A review of clinical presentation, biochemical features, and pathophysiologic mechanisms, Medicine 77:73, 1998. 66. Zhang DL: D-lactic acidosis secondary to short bowel syndrome, Postgrad Med J 79:110, 2003. 67. Hove H, Mortensen PB: Colonic lactate metabolism and D-lactic acidosis, Dig Dis Sci 40:320, 1995. 68. Christopher MM, Broussard JD, Fallin CW, et al: Increased serum D-lactate associated with diabetic ketoacidosis, Metabolism 44:287, 1995. 69. Christopher MM, Eckfeldt JH, Eaton JW: Propylene glycol ingestion causes D-lactic acidosis, Lab Invest 62:114, 1990. 70. Packer RA, Cohn LA, Wohlstadter DR, et al: D-lactic acidosis secondary to exocrine pancreatic insufficiency in a cat, J Vet Intern Med 19:106, 2005.

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71. Packer RA, Moore GE, Chang CY, et al: Serum D-lactate concentrations in cats with gastrointestinal disease, J Vet Intern Med 26:905, 2012. 72. Gentile A, Sconza S, Lorenz I, et al: D-Lactic acidosis in calves as a consequence of experimentally induced ruminal acidosis, J Vet Med A Physiol Pathol Clin Med 51:64, 2004. 73. Redavid LA, Sharp CR, Mitchell MA, et al: Plasma lactate measurements in healthy cats, J Vet Emerg Crit Care (San Antonio) 22:580, 2012. 74. Hughes D, Rozanski ER, Shofer FS, et al: Effect of sampling site, repeated sampling, pH, and PCO2 on plasma lactate concentration in healthy dogs, Am J Vet Res 60:521, 1999. 75. McMichael MA, Lees GE, Hennessey J, et al: Serial plasma lactate concentrations in 68 puppies aged 4 to 80 days, J Vet Emerg Crit Care (San Antonio) 15:17, 2005. 76. Rand JS, Kinnaird E, Baglioni A, et al: Acute stress hyperglycemia in cats is associated with struggling and increased concentrations of lactate and norepinephrine, J Vet Intern Med 16:123, 2002. 77. Tynan B, Kerl ME, Jackson ML, et al: Plasma lactate concentrations and comparison of two point-of-care lactate analyzers to a laboratory analyzer in a population of healthy cats, J Vet Emerg Crit Care 25:521, 2015. 78. Moon JM, Shin MH, Chun BJ: The value of initial lactate in patients with carbon monoxide intoxication: in the emergency department, Hum Exp Toxicol 30:836, 2011. 79. Okorie ON, Dellinger P: Lactate: biomarker and potential therapeutic target, Crit Care Clin 27:299, 2011. 80. Levy MM, Evans LE, Rhodes A: The surviving sepsis campaign bundle: 2018 update, Int Care Med 44:925, 2018. 81. Lagutchik MS, Ogilvie GK, Hackett TB, et al: Increased lactate concentrations in III and injured dogs, J Vet Emerg Crit Care (San Antonio) 8:117, 1998. 82. Kohen CJ, Hopper K, Kass PH, et al: Retrospective evaluation of the prognostic utility of plasma lactate concentration, base deficit, pH, and anion gap in canine and feline emergency patients, J Vet Emerg Crit Care 28:54, 2018. 83. Saint-Pierre LM, Hopper K, Esptein SE: Retrospective evaluation of the prognostic utility of plasma lactate concentration and serial lactate measurements in dogs and cats presented to the emergency room (January 2012 – December 2016): 4863 cases, J Vet Emerg Crit Care 32:42, 2022. 84. Stevenson CK, Kidney BA, Duke T, et al: Serial blood lactate concentrations in systemically ill dogs, Vet Clin Pathol 36:234-239, 2007. 85. Butler AL, Campbell VL, Wagner AE, et al: Lithium dilution cardiac output and oxygen delivery in conscious dogs with systemic inflammatory response syndrome, J Vet Emerg Crit Care 18:246, 2008. 86. Sharma D, Holowaychuk MK: Retrospective evaluation of prognostic indicators in dogs with head trauma: 72 cases (January-March 2011), J Vet Emerg Crit Care 25:631, 2015. 87. Beer KAS, Syring RS, Drobatz KJ: Evaluation of plasma lactate concentration and base excess at the time of hospital admission as predictors of gastric necrosis and outcome and correlation between those variables in dogs with gastric dilatation-volvulus: 78 cases (2004-2009), J Am Vet Med Assoc 242:54, 2013. 88. Buriko Y, Van Winkle TJ, Drobatz KJ, et al: Severe soft tissue infections in dogs: 47 cases (1996-2006), J Vet Emerg Crit Care (San Antonio) 18:608, 2008. 89. Kitagawa H, Yasuda K, Kitoh K, et al: Blood gas analysis in dogs with heartworm caval syndrome, J Vet Med Sci 56:861, 1994. 90. Nel M, Lobetti RG, Keller N, et al: Prognostic value of blood lactate, blood glucose, and hematocrit in canine babesiosis, J Vet Intern Med 18:471, 2004. 91. Hall KE, Holowaychuk MK, Sharp CR, et al: Multicenter prospective evaluation of dogs with trauma, J Am Vet Med Assoc 244:300, 2014. 92. Cortellini S, Seth M, Kellett Gregory LM: Plasma lactate concentrations in septic peritonitis: a retrospective study of 83 dogs (2007-2012), J Vet Emerg Crit Care 25:388, 2014.

93. Shea EK, Dombrowski SC, Silverstein DC: Survival analysis of hypotensive cats admitted to an intensive care unit with or without hyperlactatemia: 39 cases (2005–2011), J Am Vet Med Assoc 250:887, 2017. 94. Trigg NL, McAlees TJ: Blood lactate concentration as a prognostic indicator in cats admitted to intensive care, Aust Vet Pract 45:17, 2015. 95. Parsons KJ, Owen LJ, Lee K, et al: A retrospective study of surgically treated cases of septic peritonitis in the cat (2000-2007), J Small Anim Prac 50:518, 2009. 96. Reineke EL, Rees C, Drobatz KJ: Association of blood lactate concentration with physical perfusion variables, blood pressure, and outcome for cats treated at an emergency service, J Am Vet Med Assoc 247:79, 2015. 97. Redavid LA, Sharp CR, Mitchell MA, et al: Hyperlactatemia and serial lactate measurements in sick cats, J Vet Emerg Crit Care 26:495, 2016. 98. Costello MF, Drobatz KJ, Aronson LR, et al: Underlying cause, pathophysiologic abnormalities, and response to treatment in cats with septic peritonitis: 51 cases (1990–2001), J Am Vet Med Assoc 225:897, 2004. 99. Lyons BM, Ateca LB, Otto CM: Clinicopathologic abnormalities associated with increased animal triage trauma score in cats with bite wound injuries: 43 cases (1998–2009), J Vet Emerg Crit Care 29:296, 2019. 100. Scotti KM, Koenigshof A, Sri-Jayantha LSH, et al: Prognostic indicators in cats with septic peritonitis (2002-2015): 83 cases, J Vet Emer Crit Care 29:647, 2019. 101. Rosenstein PG, Tennent Brown BS, Hughes D: Clinical use of plasma lactate concentration. Part 2: prognostic and diagnostic utility and the clinical management of hyperlactatemia, J Vet Emerg Crit Care 28:106, 2018. 102. Hayes G, Mathews K, Doig G, et al: The acute patient physiologic and laboratory evaluation (APPLE) score: a severity of illness stratification system for hospitalized dogs, J Vet Intern Med 24:1034, 2010. 103. Hayes G, Mathews K, Doig G, et al: The Feline Acute Patient Physiologic and Laboratory Evaluation (Feline APPLE) Score: a severity of illness stratification system for hospitalized cats, J Vet Intern Med 25:26, 2011. 104. Levin GM, Bonczynski JJ, Ludwig LL, et al: Lactate as a diagnostic test for septic peritoneal effusions in dogs and cats, J Am Anim Hosp Assoc 40:364, 2004. 105. Swann HM, Hughes D, Drobatz KJ: Use of abdominal fluid pH, pO2, pCO2, [glucose], and [lactate] to differentiate bacterial peritonitis from non-bacterial causes of abdominal effusion in dogs and cats, J Vet Emerg Crit Care 6:114, 1996. 106. DeLaurier GA, Cannon RM, Johnson RH Jr, et al: Increased peritoneal fluid lactic acid values and progressive bowel strangulation in dogs, Am J Surg 158:32, 1989. 107. Currao RL, Buote NJ, Flory AB, et al: Mesenteric vascular thrombosis associated with disseminated abdominal visceral hemangiosarcoma in a cat, J Am Anim Hosp Assoc 47:e168, 2011. 108. Nestor DD, McCullough SM, Schaeffer DJ: Biochemical analysis of neoplastic versus nonneoplastic abdominal effusions in dogs, J Am Anim Hosp Assoc 40:372, 2004. 109. Szabo SD, Jermyn K, Neel J, et al: Evaluation of postceliotomy peritoneal drain fluid volume, cytology, and blood-to-peritoneal fluid lactate and glucose differences in normal dogs, Vet Surg 40:444-449, 2011. 110. Mouat EE, Davis GJ, Drobatz KJ, Wallace KA: Evaluation of data from 35 dogs pertaining to dehiscence following intestinal resection and anastomosis, J Am Anim Hosp Assoc 50:254-263, 2014. 111. Kiyatkin ME, Bakker J: Lactate and microcirculation as suitable targets for hemodynamic optimization in resuscitation of circulatory shock, Curr Opin Crit Care 23(4):348-354, 2019. 112. Hernandez G, Ospina-Tascon GA, Damiani LP, et al: Effect of a resuscitation strategy targeting peripheral perfusion status vs serum lactate levels on 28-day mortality among patients with septic shock. The ANDROMEDA-SHOCK randomized clinical trial, J Am Vet Assoc 321(7):654-664, 2019. 113. Chadda K, Raynard B, Antoun S, et al: Acute lactic acidosis with Wernicke’s encephalopathy due to acute thiamine deficiency, Intensive Care Med 28: 1499, 2002.

62 Urine Osmolality and Electrolytes Justin Duval, BSc, DVM, DACVECC, Kate Hopper, BVSc, PhD, DACVECC KEY POINTS • Accurate interpretation of urine osmolality and electrolytes relies on the consideration of the expected renal response for the patient’s individual clinical scenario. • Urine electrolytes can be used to calculate urinary free water clearance, which can be of particular relevance to determining the differential diagnosis of dysnatremia.

INTRODUCTION The kidney is responsible for the continuous maintenance of an adequate circulating volume, appropriate water balance, and electrolyte and acidbase homeostasis. As such, it is able to respond rapidly to alterations in extracellular body fluid volume and content. Measurement of urine osmolality and electrolyte concentration can provide valuable insight regarding water balance, effective circulating volume (ECV), and electrolyte and acid-base disorders. As there are no normal values for urine electrolyte and water content, interpretation of these results relies on consideration of the measured values in comparison to the expected renal response. While constructing differential diagnoses, urine osmolality, electrolyte concentrations, and free water clearance are most relevant when interpreted in conjunction with a complete assessment of patient clinical status.

URINE OSMOLALITY Osmolality is a measure of total solute concentration in a solution. It is expressed as the number of osmoles (osmotically active particles) per kilogram mass of solvent (mOsm/kg). In biological systems the terms osmolality (mOsm/kg) and osmolarity (mOsm/L) may be used interchangeably as the solution of interest is water and 1 L of water is equal to 1 kg of solvent (see Chapter 185, Colloid Osmotic Pressure and Osmolality). Measurement of urine osmolality yields a quantified value for the concentration of solute in the urine and is considered the most accurate measure of urine concentrating ability. Previously reported ranges of urine osmolality in healthy dogs are between 161 and 2830 mOsm/kg with high variability both within and between individual dogs throughout a single day.1,2 Retrospective data have been used to suggest reference intervals of 369–2416 mOsm/kg in young, adult dogs, and 366–2178 mOsm/kg in senior animals.2 Urine osmolality has been used to document decreasing urine concentrating ability with age. It has also been shown to be lower in intact versus spayed females.2 Urine osmolality may provide insight into renal handling of water and electrolytes for patients with disturbances in extracellular fluid volume or content. As the most precise measurement of urine concentrating ability,

• In patients with normal renal function, a urine sodium concentration of ,30 mmol/L is suggestive of low effective circulating blood volume and stimulation of the renin-angiotensin-aldosterone system. • The transtubular potassium gradient is an index that may be used to distinguish between renal and nonrenal causes of dyskalemia based on the patient’s expected response.

urine osmolality can provide an approximation of renal water conservation or elimination (see Free Water Clearance section below). Diagnostically, urine osmolality may be helpful in determining the nature of a patient’s polyuria and evaluating specific serum electrolyte abnormalities. Polyuria is generally the result of solute or water diuresis. The presence of osmotically active agents such as glucose or mannitol is expected to increase urine osmolality to .300 mOsm/kg. Conversely, free water diuresis secondary to polydipsia, excess water administration, and diabetes insipidus are expected to produce a urine osmolality of ,200 mOsm.3 Evaluation of urine osmolality can be important when determining the cause of hyponatremia (see Chapter 55, Sodium Disorders, for more details). Formulas that employ measurement of urine osmolality do so in an attempt to account for states of variable water excretion when interpreting the amount of solute in the urine. For example, the transtubular potassium gradient requires measurement of urine osmolality when determining the cause of dyskalemia (see Urinary Potassium section below). A common substitute for the evaluation of urine concentrating ability is the measurement of urine specific gravity by light refractometry. A handheld light refractometer is more readily available in the clinical setting and has been shown to correlate with urine osmolality in healthy dogs as well as dogs with various medical conditions.2,4,5 However, the index of light refraction technique employed by common refractometer devices can be affected by physical properties of the solute (molecular weight) and temperature of solution, such that it no longer correlates with urine osmolality in certain clinical scenarios. For example, exogenous substances administered to veterinary patients while in hospital such as synthetic colloids (hydroxyethyl starches) and radiocontrast agents will increase urine specific gravity, making it an inaccurate measure of renal concentrating ability while these substances are present (see Table 62.1).

URINARY SODIUM Urine sodium concentration has many applications and may be considered for the evaluation of free water clearance and the assessment of ECV

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TABLE 62.1  Interpretation of Urine Osmolality and Electrolytes (see Box 62.1 for Relevant

Formulas) Analyte

Use

Value

Results are Consistent with:

Urine [Na] mmol/L

Assessment of ECV

,20

Decreased ECV (Na avid) Aldosterone presence

.40

Adequate effective circulating volume

20–40

Equivocal result

,1%

Suggestive of volume responsive renal injury

.1%

Suggestive of intrinsic renal injury

,25

Decreased ECV

,15–25

Chloride responsive metabolic alkalosis

.15–25

Chloride unresponsive metabolic alkalosis

,15–20

Nonrenal K loss

FeNa Urine [Cl] mmol/L

Urine [K] mmol/L

Transtubular potassium gradient

Free water clearance

Assessment of AKI Assessment of ECV Assessment of metabolic alkalosis Assessment of hypokalemia

.40

Renal K wasting

Assessment of hyperkalemia

.40

Nonrenal cause (e.g., hypoadrenocorticism)

Hyperkalemia

.6 ,6

Nonrenal cause Renal cause (aldosterone deficiency)

Hypokalemia

.3 ,7

Renal cause Nonrenal cause

Assessment of solute free water excretion

Positive Negative

Free water excretion (absence of ADH secretion and/or response) Free water retention (ADH secretion and response)

ADH, antidiuretic hormone; AKI, acute kidney injury; ECV, Effective circulating volume; FeNa, fractional excretion of sodium; [K], potassium concentration; [Na], sodium concentration.

status (Box 62.1). Urine sodium concentration can only be used as a diagnostic tool if there is no evidence of selective renal hypoperfusion and renal function is intact. The final concentration of urine sodium is influenced by both renal sodium excretion and renal water handling. The majority (.90%) of filtered sodium is reabsorbed by the proximal tubule and loop of Henle, while the regulation of net sodium excretion or absorption is determined by the presence of aldosterone in the distal tubule. The most important stimulus for aldosterone release is activation of the renin-angiotensin-aldosterone system in response to decreased ECV.6 Patients with adequate ECV are expected to excrete all of the dietary sodium that is in excess of their extra-renal losses (sweat, feces) in order to maintain their steady state. There is no normal value for urine sodium concentration in health since it depends on dietary intake and renal water handling. Decreased ECV will lead to activation of the renin- angiotensin-aldosterone system. This results in aldosterone-mediated maximal sodium reabsorption in the distal nephron; subsequently, a urine sodium concentration of less than 20 mmol/L (and as low as 1 mmol/L) will ensue.7 A urine sodium concentration of .40 mmol/L suggests the absence of aldosterone activity and urine sodium concentrations between 20 and 40 mmol/L are equivocal and should be interpreted in light of other clinical findings. Urine sodium concentration may not reflect ECV in the presence of metabolic alkalosis. Renal excretion of bicarbonate requires concomitant excretion of sodium and as such urine sodium will be elevated regardless of ECV. Evaluation of urine chloride concentration may be of benefit in this situation. In order to remove the confounding effect of concurrent water transport, urine sodium concentration in the form of fractional excretion (FeNa) has previously been suggested as an aid for distinguishing between volume responsive and intrinsic kidney injury (Formula 1, Box 62.1). The fractional excretion of sodium represents the proportion of filtered sodium that is excreted and allows for the examination of renal sodium handling without the effect of the rate of water reabsorption. The ability of FeNa to identify intrinsic kidney injury and predict survival has been evaluated in dogs with naturally occurring kidney

BOX 62.1  Formulas Utilizing Urine Osmolality and/or Electrolytes 1. Fractional excretion of sodium (FeNa) (%) Urine [Na ]  Plasma [Creatinine ]  100     Plasma [Na ]  Urine [Creatinine ]  2. Transtubular potassium gradient (Urine [K ]  Plasma [osmolality ])  (Urine [osmolality ]  Plasma [K ]) 3. Urinary free water clearance 5 urine volume  Urine [Na ]  Urine [K ]    1   Serum [Na ]    • [Na] 5 concentration of sodium in mmol/L (or mEq/L); [Cr] 5 concentration of creatinine in mg/dl; [K] 5 concentration of potassium in mmol/L (or mEq/L)

injury;8-10 however, its use in critically ill patients has been criticized given concerns regarding its accuracy in a number of clinical scenarios. The interpretation of FeNa is further compromised by the administration of diuretics, intravenous fluids, and vasoactive drugs.11 Lastly, the FeNa requires measurement of urine and serum sodium and creatinine concentrations, making it less readily available at the bedside. Ultimately, the role of FeNa in the evaluation of renal injury is controversial in people and remains undefined in the veterinary population. For further detail on this topic, the reader is referred to additional resources.3,11 Renal water handling is similar to sodium in that the majority of filtered water is reabsorbed in the proximal tubule and loop of Henle. The regulation of water balance is dependent on the action of antidiuretic hormone (ADH) in the distal nephron.6 The urine sodium concentration will vary with urine water content. As a result, it can be used to help determine the quantity of water excretion as part of the calculation for free water clearance, discussed later in this chapter.

CHAPTER 62  Urine Osmolality and Electrolytes

URINE POTASSIUM Urine potassium concentration can be useful for the evaluation of potassium disorders and the calculation of free water clearance (Box 62.1). The regulation of renal potassium excretion depends on both neurohormonal control mechanisms and the tubular flow rate in the distal nephron. In the distal convoluted tubule, secretion of urinary potassium is dependent on the concentration of circulating aldosterone, plasma potassium concentration, and anions present in the urinary tubule. Excretion of urinary potassium in the cortical collecting duct is largely determined by the rate of delivery of sodium and other osmoles as well as the presence of ADH. There is no normal value for urine potassium concentration as it will depend on potassium intake and water excretion by the kidney. Urine potassium concentration can, however, aid in determining whether hypo- or hyperkalemia is due to renal or extrarenal causes. In a patient with hypokalemia, a spot urine potassium of ,15–20 mmol/L suggests an extrarenal cause, while higher values are consistent with renal wasting of potassium. In patients with hyperkalemia, a spot urine potassium of .40 mmol/L is considered an appropriate renal response, indicating a nonrenal cause for the abnormality.12,13 A more accurate evaluation of the origin of hypo- or hyperkalemia can be determined using the transtubular potassium gradient (TTKG) (Formula 2, Box 62.1). This is an index that estimates the concentration of urinary potassium compared with plasma potassium and is used to determine the role of the distal nephron in the pathogenesis of potassium disorders. The formula contains a plasma to urine osmolality ratio to account for the impact of water reabsorption in the distal nephron on urine potassium concentration. The TTKG should not be used if urine sodium concentration is ,25 mmol/L or if urine osmolality is less than serum osmolality.14 It should be noted that the cutoff values cited here for the TTKG are taken from studies in adult human patients and have not been validated in dogs or cats. The TTKG reflects aldosterone activity, and its main diagnostic role is to identify inadequate or excess mineralocorticoid activity. In the hyperkalemic patient, a TTKG .6 suggests impaired renal potassium excretion while a TTKG ,6 in the hyperkalemic patient is consistent with the absence or resistance of mineralocorticoids. In states of hypokalemia, the distal nephron should minimize potassium excretion and a TTKG ,3 is appropriate and indicates a nonrenal cause for hypokalemia. A TTKG .7 in the hypokalemic patient suggests a renal potassium wasting.14,15 In order to use the TTKG, certain assumptions must be met. Urine osmolality must be isoosmolar to plasma or higher, indicating the patient has adequate ADH concentrations and response. Second, a urine sodium concentration of greater than 20 mmol/L confirms that there is adequate solute delivery to the distal nephron for potassium secretion. Lastly, very high flow rates to the distal nephron may be too great to allow adequate time for equilibration across the tubule membrane, resulting in low potassium excretion and underestimation of potassium secretory capacity in the hyperkalemic patient.15 Therefore, the TTGK may be less reliable in situations of polyuria or dilute urine.

URINE CHLORIDE Urinary chloride may be obtained for the assessment of ECV and the evaluation of acid-base disorders. Similar to urine sodium concentration, urinary chloride varies in response to dietary load. It may serve as an indirect indicator of volume status as it is also reabsorbed with sodium in response to decreased ECV and renin-angiotensin-aldosterone

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system activation. Low urine chloride concentration (,25 mmol/L) is consistent with low ECV.16,17 There are circumstances in which urine chloride concentration is low but urine sodium concentration is not. The most common explanation for this is the presence of an acid-base disorder in conjunction with low ECV. As previously mentioned, urine sodium may remain .40 mmol/L in the face of decreased ECV when there is a concurrent metabolic alkalosis, as sodium excretion will accompany bicarbonate excretion.16,17 The presence of a nonresorbable anion such as piperacillin or ticarcillin can also increase urine sodium excretion.17 For these reasons, when using urine electrolytes to aid in evaluation of ECV, assessment of both urine sodium and chloride concentration is recommended. Urine chloride concentration can also be used to determine whether metabolic alkalosis is chloride responsive. Chloride responsive metabolic alkalosis is typified by low urine chloride (,15–25 mmol/L) and may be caused by diuretic administration, vomiting, or nasogastric suction. Chloride- or saline-resistant metabolic alkalosis is associated with a high urine chloride (.15–25 mmol/L), and etiologies include congenital tubular (transporter) deficits, hyperaldosteronism, and iatrogenic bicarbonate administration.16,17 Urine chloride concentration is required for calculation of the urine anion gap, which can be helpful in determining the etiology of hyperchloremic metabolic acidosis.

FREE WATER CLEARANCE Urine electrolyte concentrations are required for the calculation of urinary free water clearance (Formula 3, Box 62.1), which is the volume of urine excreted that is free of solute. Most commonly, free water clearance is used to evaluate the nature of dysnatremias, which often represent a gain or loss of free water. This calculation requires measurement of serum sodium concentration, urine sodium concentration, and urine potassium concentration. The result is a percentage of the urine volume, so free water clearance should always be interpreted in the context of urine output. In health, the amount of water excreted in the urine (urinary free water clearance) is primarily determined by the amount of water ingested and is regulated by ADH.16 Extracellular fluid hyperosmolality and inadequate ECV are major stimuli for increased ADH release, which results in renal water reabsorption. ADH release leads to free water retention; therefore, free water clearance should be negative. Conversely, a positive free water clearance is expected in the absence of ADH release, such as in states of hypoosmolality. Urinary free water clearance is useful in the investigation of dysnatremias. In the hypernatremic patient, a negative free water clearance would indicate an appropriate renal response secondary to ADH stimulating renal water reabsorption. In contrast, a positive free water clearance suggests that renal free water loss is the cause of hypernatremia. In hyponatremic patients, a positive free water clearance suggests an appropriate renal response while a negative free water clearance would be inappropriate and suggests a renal cause for the hyponatremia (see Chapter 55, Sodium Disorders). Additional urine analytes and electrolytes have been clinically studied in human medicine. Largely, the utility of urine anions such as chloride and bicarbonate concentration have been investigated for the assessment of various acid-base derangements, as well as the calculation of a urine anion gap, urine osmolal gap, and the assessment of urinary ammonia. For further discussion of this topic, the reader is referred to the following references.16-18

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REFERENCES 1. Van Vonderen IK, Kooistra HS, Rijnberk A: Intra- and interindividual variation in urine osmolality and urine specific gravity in healthy pet dogs of various ages, J Vet Inter Med 1(11):30-35, 1997. 2. Guerrero S, Pastor J, Tvarijonaviciute A, et al: Analytical validation and reference intervals for freezing point depression osmometer measurements of urine osmolality in dogs, J Vet Intern Med 29(6):791-796, 2017. 3. Rowan S, Anderson RJ: Assessment of fluid and electrolyte problems: urine biochemistry. In Ronco C, Bellemo R, Kellum JA, editors: Critical care nephrology, ed 2, Philadelphia, 2009, Saunders Elsevier, pp 495-499. 4. Dossin O, Germain C, Braun JP: Comparison of the techniques of evaluation of urine dilution/concentration in the dog, J Vet Med A Physiol Pathol Clin Med 50(6):322-325, 2003. 5. Ayoub JA, Beaufrere H, Acierno MJ: Association between urine osmolality and specific gravity in dogs and the effect of commonly measured urine solutes on that association, Am J Vet Res 74(12):1542-1545, 2013. 6. Feraille E: The physiology of the collecting duct. In Ronco C, Bellemo R, Kellum JA, editors: Critical care nephrology, ed 2, Philadelphia, 2009, Saunders Elsevier, pp 150-155. 7. Rose DB, Post TW: Regulation of the effective circulating volume. In Rose DB, Post TW, editors: Clinical physiology of acid-base and electrolyte disorders, ed 5, New York, 2001, McGraw-Hill Med Pub, pp 258-271. 8. Segev G, Daminet S, Meyer E, et al: Characterization of kidney damage using several renal biomarkers in dogs with naturally occurring heatstroke, Vet J 206(2):231-235, 2015. 9. Brown N, Segev G, Francy T, et al: Glomerular filtration rate, urine production, and fractional clearance of electrolytes in acute kidney injury in dogs and their association with survival, J Vet Intern Med 29(1):28-34, 2015.

10. Troia R, Gruarin M, Grisett C, et al: Fractional excretion of electrolytes in volume responsive and intrinsic acute kidney injury in dogs: diagnostic and prognostic implications, J Vet Intern Med 32(4):1372-1382, 2018. 11. Prowle J, Bagshaw SM, Bellomo R: Renal blood flow, fractional excretion of sodium and acute kidney injury: time for a new paradigm? Curr Opin Crit Care 18(6):585-592, 2012. 12. Rose DB, Post TW: Hypokalemia. In Rose DB, Post TW, editors: Clinical physiology of acid-base and electrolyte disorders, ed 5, New York, 2001, McGraw-Hill Med Pub, pp 836-887. 13. Lin S, Lin Y, Chen D, et al: Laboratory tests to determine the cause of hypokalemia and paralysis, Arch Intern Med 164(16):1561-1566, 2004. 14. Choi MJ, Ziyadeh FN: The utility of transtubular potassium gradient in the evaluation of hyperkalemia, J Am Soc Nephrol 19(3):424-426, 2008. 15. Rose DB, Post TW: Hyperkalemia. In Rose DB, Post TW, editors: Clinical physiology of acid-base and electrolyte disorders, ed 5, New York, 2001, McGraw-Hill Med Pub, pp 888-930. 16. Villeneuve PM, Bagshaw SM: Assessment of urine biochemistry. In Ronco C, Bellomo R, Kellum JA, Ricci Z, editors: Critical care nephrology, ed 3, Philadelphia, 2019, Elsevier, pp 323-328. 17. Palmer BF, Clegg DJ: The use of selected urine chemistries in the diagnosis of kidney disorders, Clin J Am Soc Nephrol 14:306-316, 2019. 18. Reddi AS: Fluid, electrolyte, and acid-base disorders clinical evaluation and management, New York, 2014, Springer. 19. Kamel S, Kamel JH, Richardson RMA, et al: Urine electrolytes and osmolality: when and how to use them, Am J Nephrol 10(2):89-102, 1990. 20. Batlle D, Chin-Theodorou J, Tucker BM: Metabolic acidosis or respiratory alkalosis? Evaluation of a low plasma bicarbonate using the urine anion gap, Am J Kidney Dis 70(3):440-444, 2017.

PART VI  Fluid Therapy

63 Assessment of Hydration Elke Rudloff, DVM, DACVECC, cVMA

KEY POINTS • Water is an essential component of organ homeostasis, and alterations in body water composition can affect patient outcome. • Clinical factors such as physical examination parameters, plasma osmolality, urine osmolality, urine specific gravity, packed cell volume, total protein, and serum sodium concentration are used in the overall assessment of hydration status. • There is no single index that accurately and easily measures hydration and individual fluid compartment water in the critical patient.

• A change in body weight may be the most practical method for estimating changes in total body water over a short period. • Physical examination can only detect changes in extracellular fluid volume. • The minimal degree of dehydration detectable on physical examination is 5% of body weight (kg).

Water is the single most important medium for sustaining life. It is the medium that provides form to every organ and cell in the body, transports oxygen-carrying red blood cells, electrolytes, and nutrients in plasma, carries substrates across membranes, evaporates to cool the body, is a solvent for organic and inorganic molecules, and is essential for most metabolic functions. Water imbalances can contribute to morbidity and mortality and need to be rapidly identified and corrected in the critically ill. Water deficits affect body temperature regulation and neurologic function; severe deficits can result in electrolyte imbalances and hypovolemia resulting in reduced oxygen delivery, acute kidney injury, and death.1,2 Excess water can result in altered ventilation and lung function, gastrointestinal dysfunction, and electrolyte imbalances.3

DISTRIBUTION AND CONTROL OF TOTAL BODY WATER

VARIABILITY IN ASSESSING HYDRATION The total body water (TBW) is continuously in flux because it is being lost through evaporation, elimination, and metabolic processes and gained from food and water intake. An individual’s overall body condition and illness will also affect water retention and losses, globally and in local fluid compartments. There is no single index that accurately and easily measures hydration and individual fluid compartment water in the critical patient. Although extracellular volume can be determined through a number of tests, the continuum of fluid movement from one moment to the next makes it impossible for a static moment in time to be reflected in any single measurement taken to assess TBW.4 The veterinarian has to be familiar with the distribution and control of body water in order to understand how examination skills and point-of-care laboratory indices can be used to make an estimation of a patient’s TBW and individual compartment hydration status and fluid needs.

The TBW that occupies the intra- and extracellular compartments is approximately 0.6 L/kg or 60% of body mass.5 The proportion of TBW increases in the very young and decreases in overweight subjects. The intracellular fluid (ICF) compartment contains approximately 0.4 L/kg or 66% of TBW, and the extracellular fluid (ECF) compartment approximately 0.2 L/kg or approximately 33% of TBW (Fig. 63.1). The ECF is further compartmentalized into the intravascular portion, which is approximately 25% of ECF volume (8% of TBW), and the remaining 75% of ECF volume (25% TBW) is interstitial fluid. Pregnancy, increased salt intake, exercise, and malnutrition as well as acute and chronic conditions will affect TBW and the division of water between the compartments.6 Body water is distributed across two compartmentalizing membranes: the endothelial cell lining of capillaries separating the intravascular from the interstitial space, and the cell membranes separating the ICF from the ECF. The forces that dictate water movement across these two barriers differ. Water moves without restriction across all cell membranes under the influence of osmosis. The osmotic gradient across the cell membrane dividing the ICF from ECF is dictated by the concentration of osmotically active particles on either side of the membrane and in the normal state is primarily the product of the relative sodium and potassium concentrations, which is controlled by the Na1/K1-ATPase pump on the cell membrane. In contrast, water movement across the capillary wall is dictated by the modified Starling’s forces (see Chapter 11, Interstitial Edema).7 It is important to note that osmolality does not affect distribution between the interstitial and intravascular space because the capillary wall is freely permeable to small solutes such as sodium and glucose.

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Intracellular fluid (~66% of TBW)

Extracellular fluid (~33% of TBW)

Interstitial fluid (~75% of the extracellular fluid)

Intravascular fluid (~25% of the extracellular fluid) Fig. 63.1  Graphical representation of the division of total body water (TBW) in the body, also known as the Yannet–Darrow diagram. The intracellular and extracellular fluid compartments are separated by the cell membrane, and water movement across this barrier is dictated by osmotic gradients. The intravascular and interstitial compartments are separated by the capillary wall; water movement across this barrier is dictated by (modified) Starling’s forces.

The volume and distribution of TBW are under the control of hormonal mechanisms that maintain water and sodium balance by regulating renal water and salt excretion and reabsorption, whereas thirst mechanisms influence water intake.8-11 Loss of fluid with little or no solute (i.e., hypotonic fluid loss) will increase plasma solutes per kilogram water (osmolality). An increase in the plasma osmolality is detected by the supraoptic and paraventricular nuclei in the hypothalamus and causes the release of antidiuretic hormone (ADH; arginine vasopressin), an increase in water reabsorption by the renal collecting ducts, and produces a more concentrated urine.12-13 An increase in plasma osmolality and a reduction in baroreceptor stretch will stimulate the thirst center, located near the supraoptic and preoptic nuclei in the anteroventral region of the third ventricle in the brain, and produce the sensation of thirst resulting in water intake.14 Hypovolemia stimulates baroreceptors that cause the hypothalamic-pituitary-adrenal axis to produce and release ADH, aldosterone, renin, and cortisol, which act in concert to cause renal conservation of water and sodium.12 An overexpansion of the cardiovascular system causes stretch of the atria and release of atrial natriuretic peptide, which increases renal water and sodium excretion.15,16

MEASURING TOTAL BODY WATER Most experiments investigating changes in TBW and hydration status are performed on athletes and normal subjects. The most accurate method of determining TBW is under controlled experimental conditions, when body water compartment volumes have equilibrated and are stable. Some consider that the gold standard for assessing hydration is determining TBW using isotope dilution and neutron activation analysis techniques.4 These techniques have not been investigated in the critically ill patient. Bioelectrical impedance analysis measures the bioelectrical properties of tissue and dispersement of an electrical current to determine body water content. Multifrequency bioelectrical impedance analysis (MF-BIA) is a method that has been used to identify acute fluid shifts in critically ill people17-19 and racing horses.20 Controversies exist on its reliability, and specific studies in veterinary emergency and critical care medicine have not yet been performed using MF-BIA.21 Until such time that sophisticated measurement techniques make their way to the ICU cage, the veterinarian must rely on using a combination of physical examination findings and point-of-care laboratory indices to make an estimation of a patient’s hydration status.

Ninety percent of acute changes in body mass can be attributed to a change in TBW. This makes body weight measurements the most clinically practical way to monitor acute changes in TBW and estimating volumes gained or lost, where 1 kg change in TBW may be equivalent to 1 L change in TBW.22-26 However, changes in body weight may not reliably correspond to clinical parameters of hydration in the small animal ICU population.27 For example, the critical patient with abdominal effusion and peritonitis associated with acute pancreatitis may have a simultaneous collection of fluid in third space fluid compartments and reduction in interstitial and intravascular water. Although the body weight may not have changed, individual fluid compartment water volume has. Therefore, because they may not correlate with physical examination findings of hydration, body weight changes should not be used alone in determining a patient’s level of hydration.

CLINICAL ASSESSMENT OF HYDRATION STATUS Distinguishing between intravascular, interstitial, and intracellular water deficits is necessary for determining the fluid type to use for replenishment (see Chapter 65, Crystalloid Solutions).

Interstitial Volume Changes The interstitial fluid compartment is clinically evaluated by examining mucous membrane moisture, skin tent response, eye position, and corneal moisture as well as other parameters (Table 63.1).28-33 Loss of interstitial volume causes mucous membranes to become “sticky” when touched (tacky); decreased subcutaneous fluidity, identified by decreased skin turgor (decreased skin elasticity evidenced by increased skin tent); and, when severe, results in dry corneas and retraction of the eye within the orbit. The clinician must estimate the degree of dehydration as a percentage of body weight in kilograms based on these parameters. As a general guideline the minimum degree of interstitial dehydration that can be detected in the average patient is approximately 5% of body weight.33 Interstitial dehydration greater than 12% is likely to be fatal, so the clinician estimates dehydration in the range of 5% to 12% of body weight (see Table 63.1). It is important to note that there is substantial clinical variation in the correlation between clinical signs and degree of dehydration, so this is an estimate only. Testing skin turgor over the top of the sagittal crest may be a standardized area that is less influenced by subcutaneous fat and body position and can be repeatedly evaluated.34

CHAPTER 63  Assessment of Hydration

TABLE 63.1  Physical Examination Findings

Used to Estimate Percent Interstitial Dehydration33 Estimated % Dehydration ,5% 5%–6% 6%–8% 8%–10% 10%–12%

.12%

Physical Examination Findings Not detectable Tacky mucous membranes 6 some change in skin turgor Mild decreased skin turgor Dry mucous membranes Obvious decreased skin turgor Retracted globes within orbits Persistent skin tent due to complete loss of skin elasticity Dull corneas Evidence of hypovolemia Hypovolemic shock Death

Note: There is substantial clinical variation in the correlation between clinical signs and degree of dehydration, so this is an estimate only.

As changes to the fluid volume of the interstitial space equilibrate with the intravascular space, all patients with evidence of interstitial dehydration will also have a degree of hypovolemia, although interstitial dehydration must be severe (.10% to 12%) before clinically detectable changes in perfusion are likely to occur.35 Interstitial overhydration causes increased turgor of the skin and subcutaneous tissue, giving it a gelatinous character; peripheral or ventral pitting edema can also occur. Chemosis and clear nasal discharge may also be evident. As fluid volumes are equilibrated between the interstitial space and the intravascular space, interstitial overhydration is associated with hypervolemia and dilution of the packed cell volume (PCV) and total protein (TP); in severe cases, pulmonary and other organ edema may occur. Factors unrelated to hydration status that can alter parameters used to assess interstitial hydration include atropine administration (which reduces mucous membrane [MM] moisture), hypersalivation from nausea or pain, advanced age (which reduces skin elasticity), and changes in body fat content. It may be more challenging to appreciate dehydration in obese animals, whereas emaciated animals may appear to have decreased skin turgor even when euhydrated. Young puppies and kittens can also be difficult to assess because they have very elastic skin, so changes in skin turgor may be harder to detect. Frequent reassessment and reevaluation are required to monitor response to treatment and adjust therapy accordingly.

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(primarily changes in sodium concentration) to mark changes in cell volume. With decreases in ECF effective osmolality, there will be an associated movement of water into the ICF compartment and a subsequent increase in intracellular volume. With increases in ECF effective osmolality there will be decreases in intracellular volume. Readers are directed to Chapter 55, Sodium Disorders for further discussion of this topic.

HYPOTONIC FLUID LOSS If TBW loss is due to loss of a fluid with little or no salt content (i.e., hypotonic fluid loss), the clinical consequences are different than the loss of isotonic fluid from the body (the more common clinical scenario). Hypotonic fluid losses will result in increases in ECF osmolality, reflected by increases in serum sodium concentration. As a consequence, water will move from the ICF compartment to the ECF compartment until osmolality is equalized. The loss of ICF volume has the greatest impact on the central nervous system, and if the degree of solute-free water loss is severe and acute it can result in neurologic abnormalities and possibly death as a result of neuronal cell shrinkage. In cases of substantial hypotonic fluid losses, as might happen with uncontrolled diabetes insipidus, the neurologic consequences will be fatal before there is clinically detectable dehydration (i.e., less than approximately 5%).

ISOTONIC FLUID LOSS The net loss or gain of fluid with a salt concentration similar to that of the ECF will cause changes in the ECF volume with little change in ECF osmolality, and hence there will be no change in the ICF volume. Isotonic fluid loss will lead to interstitial dehydration, causing the clinical signs listed in Table 63.2; isotonic fluid gain would cause interstitial overhydration. There will be minimal change in serum sodium concentration with isotonic fluid gain or loss. Isotonic fluid losses are a common cause of fluid imbalance in critically ill animals and are associated with gastrointestinal fluid loss, renal fluid loss, and translocation of interstitial fluid into a third space fluid compartment. Changes in the ECF volume affect both the interstitial and intravascular volumes and manifest in changes in PCV and TP measurements. Measurements of PCV and TP may not reflect the ECF hydration status if the patient is anemic, polycythemic, or hyper/hypo-proteinemic unless a baseline sample can be used for comparison. If the decrease in ECF volume is significant, it can be associated with elevations in kidney enzymes (prerenal azotemia). Urine osmolality and urine specific gravity (USG) may also provide valuable information regarding ECF hydration status.36,37 Urine

Intravascular Volume Changes Clinically, intravascular volume is assessed through the examination of perfusion parameters (MM color, capillary refill time, heart rate, and pulse quality) and determination of jugular venous distensibility (see Chapter 64, Assessment of Intravascular Volume). Although intravascular and interstitial water content equilibrates easily, rapid intravascular losses such as hemorrhage can cause hypovolemia without causing clinically detectable changes in the interstitial fluid compartment. Excessive intravascular volume will manifest in increased jugular venous distention, in addition to increased central venous pressure. The most obvious and concerning clinical consequence of hypervolemia is pulmonary edema (see Chapter 23, Pulmonary Edema).

Intracellular Volume Changes Intracellular volume changes cannot be identified on physical examination. The clinician must rely on changes in the effective osmolality of ECF

TABLE 63.2  Laboratory and Clinical

Parameters Used During the Assessment of a Patient’s Extracellular Hydration Status and Expected Changes from Baseline with Hypohydration and Overhydration Parameter Skin turgor Mucous membrane moisture Packed cell volume Total protein Blood urea nitrogen Urine osmolality Urine specific gravity

Hypohydration ↓ ↓ ↑ ↑ ↑ ↑ ↑

Overhydration ↑ ↑ ↓ ↓ ↓ ↓ ↓

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osmolality reflects the total number of solutes per kilogram of urine,38 whereas USG is a measurement of the density (mass) of urine compared with water (which has a specific gravity of 1.000).39 Urine osmolality and USG measured by refractometer show linear changes when urine water content changes (see Chapter 62, Urine Osmolality and Electrolytes).30,38-40 Urine osmolality and USG will increase as water is reabsorbed from the urine filtrate in states of ECF dehydration and decrease as water is excreted from the urine in states of ECF over hydration. Evaluation of urine concentration will be limited if the patient has received IV fluid therapy or diuretic administration before urinalysis. Urine output can also reflect fluctuations in ECF volume, although it is a late marker for changes in the body fluid compartment,40 particularly in situations of rapid volume turnover. In the critically ill patient, comparing the volume of fluids taken in (e.g., IV fluid therapy, enteral support, voluntary ingestion) with the volume of all fluid losses (e.g., urine, vomitus, gastric suction, stool, and surgical drains) can identify potential fluid excess or deficits. Should the volume of fluid lost greatly exceed the volume taken in, the patient is assessed for signs of hypohydration. Should the volume of fluid taken in greatly exceed the volume of fluid lost, the patient is assessed for signs of overhydration, third space fluid compartment sequestration, or oliguric renal failure.

SPECIAL CHALLENGES Although the intravascular and interstitial compartments interact in a dynamic and continuous manner, alterations in any component of the modified Starling’s forces can result in an imbalance, making interpretation of physical examination findings challenging. For example, a patient with severe systemic inflammation, burns, and/or trauma may have increased capillary permeability leading to hypovolemia in conjunction with interstitial overhydration. A congestive heart failure patient can have local increases in pulmonary vascular volume leading to local interstitial overhydration (pulmonary edema) yet have reduced total circulating volume and global interstitial hypohydration because of chronic treatment with diuretics and afterload reducers. Osmotic diuretic therapy (mannitol, hypertonic saline) and uncontrolled hyperglycemia can increase intravascular volume at the expense of interstitial and intracellular water loss. These scenarios pose a challenge in both assessment of hydration as well as therapeutic management to target euhydration and optimal fluid balance.

CONCLUSION Assessment of hydration is primarily dependent on the evaluation of physical and laboratory parameters that represent the water content of a dynamic medium involving interconnected fluid compartments. No single parameter should be used to estimate the hydration status of a patient. Changes in the clinical parameters of hydration (skin turgor, MM moistness, and eye position) all reflect changes in interstitial volume and can only occur with a combination of both salt and water losses. Changes in ICF volume cannot be detected on physical examination.

REFERENCES 1. Armstrong LE, Maresh CM, Gabaree CV, et al: Thermal and circulatory responses during exercise: effects of hypohydration, dehydration, and water intake, J Appl Physiol 82:2028, 1997. 2. Leaf A: Regulation of intracellular fluid volume and disease, Am J Med 49:291, 1970. 3. Lee JY, Rozanski E, Anastasio M, et al: Iatrogenic water intoxication in two cats, J Vet Emerg Crit Care 23:53, 2013. 4. Armstrong LE: Assessing hydration status: the elusive gold standard, J Am Coll Nutr 26:575S, 2007. 5. Wamburg S, Sandgaard NCF, Bie P: Simultaneous determination of total body water and plasma volume in conscious dogs by the indicator dilution principle, J Nutr 132:1711S, 2002. 6. Armstrong LE, Kenefick RW, Castellani JW, et al: Bioimpedance spectroscopy technique: intra-, extracellular, and total body water, Med Sci Sports Exerc 29:1657, 1997. 7. Woodcock TE, Woodcock TM: Revised Starling equation and the glycocalyx model of transvascular fluid exchange: an improved paradigm for prescribing intravenous fluid therapy, Br J Anaesth 108:384, 2012. 8. Schrier RW, Berl T, Anderson RJ: Osmotic and non osmotic control of vasopressin release, Am J Physiol 236:F321, 1979. 9. Stachenfeld NS, Gleim GW, Zabetakis PM, et al: Fluid balance and renal response following dehydrating exercise in well-trained men and women, Eur J Appl Physiol Occup Physiol 72:468, 1996. 10. Robertson GL, Athar S: The interaction of blood osmolality and blood volume in regulating plasma vasopressin in man, J Clin Endocrinol Metab 42:613, 1976. 11. Robertson GL, Shelton RL, Athar S: The osmoregulation of vasopressin, Kidney Int 10:25, 1976. 12. Zucker A, Gleason SD, Schneider EG: Renal and endocrine response to water deprivation in dog, Am J Physiol 242:R296, 1982. 13. Metzler GH, Thrasher TN, Keil LC, et al: Endocrine mechanisms regulating sodium excretion during water deprivation in dogs, Am J Physiol 251:R560, 1986. 14. Fitzsimons JT: The physiological basis of thirst, Kidney Int 10:3, 1976. 15. Ackermann U, Irizawa TG, Milojevic S, et al: Cardiovascular effects of atrial extracts in anesthetized rats, Can J Physiol Pharmacol 62:819, 1984. 16. Genest J, Cantin M: Atrial natriuretic factor, Circulation 75:118, 1987. 17. Baldwin CE, Paratz JD, Bersten AD: Body composition analysis in critically ill survivors: a comparison of bioelectrical impedance spectroscopy devices, J Parenter Enteral Nutr 36:306, 2012. 18. Savalle M, Gillaizeau F, Maruani G, et al: Assessment of body cell mass at bedside in critically ill patients, Am J Physiol Endocrinol Metab 333:E389, 2012. 19. Baldwin CE, Paratz JD, Bersten AD: Body composition analysis in critically ill survivors: a comparison of bioelectrical impedance spectroscopy devices, J Parenter Enteral Nutr 36:306, 2012. 20. Waller A, Lindinger MI: Hydration of exercised Standardbred racehorses assessed noninvasively using multi-frequency bioelectrical impedance analysis, Equine Vet J 36:285, 2006. 21. Bordelon DJ, Wingfield W: Monitoring acute fluid shifts with bioelectrical impedance analysis: a review, J Vet Emerg Crit Care 12:153, 2002. 22. Cheuvront SN, Ely BR, Kenefick RW, Sawka MN: Biological variation and diagnostic accuracy of dehydration assessment markers, Am J Clin Nutr 92:565, 2010. 23. Shirreffs SM: Markers of hydration status, Eur J Clin Nutr 57:S6, 2003. 24. Kavouras S: Assessing hydration status, Curr Opin Clin Nutr Metab Care 5:519, 2002. 25. Opplinger RA, Bartok C: Hydration testing of athletes, Sports Med 32:959, 2002. 26. Armstrong LE: Hydration assessment techniques, Nutr Rev 63:S40, 2005. 27. Hansen B, DeFrancesco T: Relationship between hydration estimate and body weight change after fluid therapy in critically ill dogs and cats, J Vet Emerg Crit Care 12:235, 2002. 28. Armstrong LE, Soto JA, Hacker FT Jr, et al: Urinary indices during dehydration, exercise, and rehydration, Int J Sport Nutr 8:345, 1998.

CHAPTER 63  Assessment of Hydration 29. Hardy RM, Osborne CA: Water deprivation test in the dog: maximum normal values, J Am Vet Med Assoc 174:479, 1979. 30. Finco DR: Fluid therapy—detecting deviations from normal, J Am Anim Hosp Assoc 8:155, 1972. 31. Harrison JB, Sussman HH, Peckering DE: Fluid and electrolyte therapy in small animals, J Am Vet Med Assoc 137:637, 1960. 32. Cornelius LM: Fluid therapy in small animal practice, J Am Vet Med Assoc 176:110, 1980. 33. Langston C: Managing fluid and electrolyte disorders in renal failure. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders in small animal practice, ed 4, St Louis, 2012, Saunders Elsevier, pp 545-556. 34. Goucher TK, Hrtzell AM, Seales TS, et al: Evaluation of skin turgor and capillary refill time as predictors of dehydration in exercising dogs, Am J Vet Res 80:123, 2019.

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35. Francesconi RP, Hubbard RW, Szlyk PC, et al: Urinary and hematological indexes of hydration, J Appl Physiol 62:1271, 1987. 36. Popowski LA, Oppliger RA, Lambert GP, et al: Blood and urinary measures of hydration status during progressive acute dehydration, Med Sci Sports Exerc 33:747, 2001. 37. Shirreffs SM, Maughan RJ: Urine osmolality and conductivity as indices of hydration status in athletes in the heat, Med Sci Sport Exerc 30:1598, 1998. 38. Bovee KC: Urine osmolarity as a definitive indicator of renal concentrating ability, J Am Vet Med Assoc 155:30, 1969. 39. George JW: The usefulness and limitations of hand-held refractometers in veterinary laboratory medicine: an historical and technical review, Vet Clin Pathol 30:201, 2001. 40. Dossin O, Germain C, Braun JP: Comparison of the techniques of evaluation of urine dilution/concentration in the dog, J Vet Med A Physiol Pathol Clin Med 50:322, 2003.

64 Assessment of Intravascular Volume Søren R. Boysen, DVM, DACVECC, Kris Gommeren, DMV, MSc, PhD, DECVIM-CA (Internal Medicine), DECVECC

KEY POINTS • Intravascular volume assessment is important in all critically ill patients, as both hypo-and hypervolemia are associated with significant morbidity and mortality. • Assessment of intravascular volume status with static markers is difficult, as no gold standard exists. • Clinical findings can indicate volume status derangements but are not sensitive or specific at predicting intravascular volume status or fluid responsiveness. • A universal definition for “fluid bolus” is lacking, making clinical recommendations and comparison between studies challenging. • Passive leg raising combined with mini-fluid boluses may decrease the risk of hypervolemia during intravascular volume loading in humans.

INTRODUCTION The benefits of intravenous fluid administration have been clearly demonstrated.1 However, the detrimental effect of overzealous fluid administration has also been proven.2 This has shifted the focus from volume loading to establishing normovolemia and an optimal fluid balance, particularly in patients with systemic inflammation or sepsis. The ROSE principle (Fig. 64.1) describes four phases of fluid administration in critically ill human patients and nicely illustrates newer fluid therapy objectives: resuscitation, optimization, stabilization, and evacuation.3 Although the ROSE principles apply to human critical care patients with prolonged illness, they can be applied to all ICU patients. During fluid resuscitation two key clinical questions must be considered: (1) what is the patient’s intravascular volume status, and (2) what is the patient’s physiologic response to a fluid bolus? In general, fluid therapy tends to focus on volume status (achieving normovolemia) through assessment of static markers or fluid responsiveness (benefit to risk ratio of additional fluid boluses) via assessment of dynamic markers. Static markers assess volume and/or pressure indices to estimate the amount of fluid in the entire cardiovascular system of a patient. Static markers are influenced by many factors in the clinical setting, making them imprecise. As such they are often used when values fall well outside normovolemic ranges (e.g., they serve as alarm markers) and fail to perform well at tailoring optimal intravascular volume levels in individual patients. In contrast, dynamic markers are based on the principle of invoking short-term changes in cardiac preload using heart–lung interactions, the passive leg raise, or the infusion of small volumes of fluid while monitoring the subsequent change in stroke volume or its derivatives (i.e., pulse pressure). They are indicated to

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• Fluid responsiveness, which is based on the Frank–Starling curve and assessed via dynamic markers, is recommended to guide fluid bolus therapy. • Point-of-care ultrasound shows promise in estimating volume status and fluid responsiveness in spontaneously breathing and positive pressure ventilated human patients; further research is needed to determine its value in veterinary medicine. • In specific controlled situations (e.g., patients receiving positive pressure ventilation without arrythmias), pulse pressure variation, systolic pressure variation, and stroke volume variation are reliable dynamic markers of fluid responsiveness.

assess fluid responsiveness and decrease the complications associated with fluid overload. Some methodologies, such as point-of-care ultrasound (POCUS), assess both static and dynamic parameters. For example, the caudal vena cava (CVC) diameter and left atrial to aortic root ratio (LA:Ao) are static markers, while the CVC collapsibility index is a dynamic marker (see below). Furthermore, certain techniques are noninvasive and are rapidly and easily applicable in a less controlled environment. Others require invasive lines, expensive equipment, and patient cooperation, and thus a more controlled environment. An overview of the different techniques is presented in the Eisenhower matrix in Fig. 64.2. Different techniques will be more time efficient but less precise, and the clinician must decide which technique best fits a specific patient’s clinical scenario.

DEFINING A FLUID BOLUS The treatment of shock has evolved significantly over the years (Fig. 64.3). Early guidelines for hypovolemic shock recommended the administration of 80–90 ml/kg/h (dog) or 50–60 ml/kg/h (cat) based on the patient’s circulatory volume and the goal of replacing intravascular fluid deficits within an hour. The availability of hypertonic and hyperoncotic fluids, and the understanding of their speed and volume of distribution have resulted in different guidelines for different fluid types (see Chapter 68, Shock Fluid Therapy).4 With a greater understanding of the detrimental effects of hypervolemia, recognition of greater pathophysiologic variation between forms of shock, including changes in vascular permeability and tone, and considerations of myocardial dysfunction, general guidelines for closer patient monitoring, and reassessment of response to fluid therapy have been recommended.

CHAPTER 64  Assessment of Intravascular Volume

Cumulative fluid balance ( ml)

R

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3

379

E

4

1 minutes

hours

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Fig. 64.1  ROSE principle: Cumulative fluid volume status over time during the distinct phases of resuscitation: resuscitation (1), optimization (2), stabilization (3), and evacuation (4), followed by a possible risk of hypoperfusion (5) in case of too aggressive deresuscitation. More Controlled Environment

CVC collapsibility

PPV SPV SVV

Clinical exam Blood pressure/lactate POCUS Focal echocardiography CVC diameter

Central venous pressure

Urgent

Not Urgent

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Volume Status First impression

Timing Fig. 64.2  Eisenhower matrix of volume assessment showing the application of different methodologies used to assess volume status and fluid responsiveness, how they interrelate with each other as well as the relative degree of environmental control, degree of precision, and timing for each. CVC, caudal vena cava; POCUS, point-of-care ultrasound; PPV, pulse pressure variation; SPV, systolic pressure variation; SVV, stroke volume variation.

Although closer patient monitoring and assessment of fluid responsiveness is simple in theory, it is difficult to apply in practice, leaving many questions unanswered: What volume defines a fluid bolus? At what rate should a fluid bolus be delivered? How often should the clinician reassess the efficacy of fluid bolus therapy? These questions generally remain unanswered in both veterinary and human medicine.5-8 In companion animals, a fluid bolus is often defined as a 10–20 ml/kg volume of isotonic crystalloid fluid administered over 10 to 15 minutes.9 In reality, these numbers are not strictly adhered to in the clinical setting, making it difficult to compare results of different studies. Every critical care patient has a unique combination of disease, comorbidities, and an individual genetic response to insults, suggesting individual patient management is beneficial. Although studies have demonstrated protocolized care, particularly sepsis bundles, may improve patient outcome, the benefit is limited, and personalized care

remains important.10,11 Starling’s forces and the Frank–Starling curves of individual patients illustrate how the various forms of shock mandate different therapeutic and fluid management strategies. Therefore, a general fluid bolus strategy for all patients is unrealistic and likely detrimental for many patients. More frequent assessment allows for more precise titration but is less time efficient and more labor intensive. This tradeoff should be frequently evaluated for each patient, as different scenarios require different approaches, and a patient’s ICU status is dynamic and constantly changing. A patient presenting in hypovolemic shock secondary to acute hypovolemia from gastrointestinal losses in the absence of a systemic inflammatory response and with a systolic pressure of 40 mm Hg is unlikely to have determinantal effects from starting 80 ml/kg/h of isotonic fluid during the primary assessment. Delaying fluid administration to assess the effect of a first bolus would reduce time efficiency. Inversely, a ventilated intensive care patient in septic

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EVLW SV Large increase in EVLW

Sepsis b a

Small increase in CO Large increase in CO Small increase in EVLW

Preload Fig. 64.3  Superimposition of the Frank–Starling and Marik–Phillips curves demonstrating the effects of increasing preload on stroke volume (SV) and lung water in a patient who is preload responsive (a) and nonresponsive (b). With sepsis, the extravascular lung water (EVLW) curve is shifted to the left. CO; cardiac output, CVP; central venous pressure. Reproduced with permission from Marik and Lemson.

shock, stabilized and receiving a vasopressor, is arguably at higher risk for fluid overload and more likely to benefit from small fluid challenges and frequent reassessment to evaluate the impact of each fluid bolus. These examples illustrate different phases of the ROSE principle; the first patient being in the resuscitation phase and patient 2 in the optimization and stabilization phases. Different fluid strategies are applied during different phases of ROSE, although considerable overlap exists between the phases, and not all patients will progress through all phases.

MINI-BOLUS AND PASSIVE LEG RAISING The administration of mini-boluses of isotonic crystalloids as low as 3–5 ml/kg, administered within 5 minutes (referred to as a fluid challenge) have been described in dogs (see Chapter 68, Shock Fluid Therapy).12 In human medicine, the administration of a virtual fluid bolus has also been described, applying passive leg raising (PLR).13 PLR shifts the volume from the venous system of the legs to the central circulation, mimicking the effect of a fluid bolus. The advantage of a PLR maneuver is the fact that fluids have not really been administered; if the patient fails to respond appropriately or shows signs of volume overload, the virtual bolus can be removed by simply lowering the legs. Additionally, unlike some techniques that assess fluid responsiveness (see below), the PLR maneuver can be performed in spontaneously breathing patients, patients with cardiac arrhythmias, and those receiving low tidal volume ventilation. However, as PLR maneuvers require changes in patient positioning, they may elicit an adrenergic/ sympathetic or white coat response in awake companion animals, which will affect hemodynamic parameters and confound changes induced by a virtual fluid bolus. The clinical practicality of PLR maneuvers limits their application to anaesthetized veterinary patients. This fact, coupled with the difficulty of being able to precisely and rapidly assess a response to mini-fluid or PLR challenges, limits the clinical applications of both.

Volume Assessment The physiology describing mean systemic filling pressure (MSFP) is complex and well described elsewhere,14 but a brief overview is provided, as it allows a clearer understanding of CVC changes in relation

to blood volume. The venous system contains the majority of blood volume in highly distensible capacitance veins that do not contribute to transmural pressure. Blood volume that does not contribute to transmural pressure is referred to as unstressed volume. In contrast, the blood volume that creates transmural pressure above zero is referred to as the stressed volume, which is the main contributor to MSFP. MSFP, right atrial pressure (RAP), and the resistance to venous flow (Rv) are the main driving forces of venous return and can be expressed through the following formula: venous return 5 (MSFP – RAP/Rv).14 In other words, venous return can be increased by one of three mechanisms: (1) lowering RAP, (2) decreasing Rv, and (3) increasing MSFP. Methods to decrease RAP are limited, and venous collapse at the thoracic inlet may occur if RAP falls too low, resulting in an increase in Rv and decrease in venous return. Rv may be decreased through venodilation and an increase in venous compliance.14 However, increased venous compliance will also decrease MSFP through an increase of unstressed volume at the expense of stressed volume. Therefore, depending on the relative changes of Rv and MSFP, the net effect on venous return is uncertain. MSFP can be increased through venoconstriction or fluid loading. Vasoconstriction, because it will increase Rv, may result in a limited increase in venous return. Fluid loading is therefore often used to try and increase venous return; however, for fluid loading to be effective it must increase the stressed volume to a greater degree than it increases RAP.14 Ultrasound assessment of the major veins has been used to track the relative ratios of stressed versus unstressed blood volume: as the major veins have a thin and elastic wall, they decrease in size during hypovolemia as the relative proportion of unstressed to stressed vascular volume increases and become distended in states of hypervolemia as the stressed vascular volume increases (See Chapter 189, POCUS in the ICU).

Gold Standard Techniques such as thermodilution, lithium dilution CO, pulse contour analysis, and transthoracic impedance are considered the gold standard to assess volume status (see Chapter 182, Cardiac Output Monitoring). However, most techniques are invasive, require special equipment or training, and are rarely available in a clinical setting; they are therefore largely confined to the research setting.

Physical Examination Findings Historically, the clinical findings of dry mucous membranes, prolonged skin tent, paleness, slow capillary refill time, cool extremities, hypothermia, weak or nonpalpable pulses, tachycardia, tachypnea, venous collapse, high urine specific gravity, and decreased urine output have been used as markers of hypovolemia. Inversely, a serous nasal discharge, moist gums, a gelatinous skinfold, peripheral edema, bounding pulses, distended jugular veins, elevated jugular pulses, low urine specific gravity, and an increased urine output have been used as markers of hypervolemia. These parameters remain integral to the assessment of emergency and critical care (ECC) patients, but their poor sensitivity and specificity to accurately assess volume status are well established.15,16 In humans the sensitivity of physical examination parameters (auscultation, jugular vein assessment, peripheral edema and/or ascites) to detect hypervolemia is only 8%, with a specificity of 74%.17 Subsequently detecting signs of hypo- or hypervolemia on clinical assessment suggests significant volume changes and should prompt the clinician to more thoroughly assess other parameters of volume status.

Radiographic Assessment of Volume Status Severe fluid balance derangements can be detected by radiography. The accuracy of chest radiographs to detect signs of hypo- or hypervolemia

CHAPTER 64  Assessment of Intravascular Volume through changes in cardiac size, CVC, and pulmonary vessel diameter has been reported at 44% in humans.17 In veterinary medicine, the sensitivity of chest radiographs to detect hypovolemia in traumatized cats was 19% in one study.18

Perfusion Parameters Circulatory performance and volume status are often assessed indirectly through upstream and downstream measures of perfusion (e.g., arterial blood pressure and lactate, respectively). Both upstream and downstream markers of perfusion are influenced by factors other than blood volume (see Chapters 61 and 181, Hyperlactatemia and Hemodynamic Monitoring, respectively). Additionally, values at which indirect markers become reflective of volume status tend to occur with more advanced states of hyper- and hypovolemia (i.e., they miss subtle states of hyper and hypovolemia). Therefore, these perfusion parameters similarly are good alarm signals, indicating a degree of urgency, but may fail when it comes to precision fluid therapy for the individual patient. Pleura and lung ultrasound (PLUS). In human medicine, fluid administration limited by lung sonography (FALLS) protocols have been used to guide initial fluid administration in patients presenting in shock.19 The FALLS protocol is based on the principle that patients with uncomplicated hypovolemic shock that have not yet received fluid boluses will have dry lungs. Appropriate fluid therapy in these patients should correct hypovolemia without leading to the development of wet lungs (see Chapter 189, POCUS in the ICU). Wet lungs are characterized by the appearance of an increased number (.3) of B-lines in a single lung ultrasound window. Patients that present with cardiogenic shock and left-sided congestive heart failure will likely have wet lungs on initial lung ultrasound evaluation. Finally, a patient in distributive shock is more likely to develop wet lungs during fluid loading, despite remaining clinically unstable. In any situation, if a patient progresses from dry to wet lungs, further patient evaluation and reassessment of the fluid therapy plan is indicated. As there are numerous pathologies that may result in wet lungs (e.g., any cause of alveolar interstitial alveolar syndrome; see Chapter 189, POCUS in the ICU) it is important to identify the underlying cause to direct appropriate diagnostics and therapy. Gall bladder wall edema. Although the development of gallbladder wall edema (halo sign) is nonspecific and commonly associated with anaphylaxis, the appearance of a halo sign during fluid loading can be suggestive of hypervolemia20 (see Chapter 189, POCUS in the ICU). If the halo sign occurs secondary to hypervolemia with increased RAP, it is often associated with other sonographic findings suggestive of volume overload, such as an enlarged CVC (see below) and the appearance of free abdominal fluid.20

Static Markers Static Pressure Measurements: Central Venous Pressure and Pulmonary Arterial Occlusion Pressure Central venous pressure (CVP) and pulmonary arterial occlusion pressure (PAOP) have commonly been used to assess volume status in well-controlled human and veterinary critical care hospitals. Recent studies question the value of both CVP and PAOP, with evidence suggesting neither can predict intravascular volume.21 CVP is a poor surrogate for RAP, cardiac filling pressure, or preload changes since the ventricular pressure–volume curve is not linear and the CVP is affected by alterations in cardiac, lung and intrathoracic pressures. Both CVP and PAOP are invasive, relatively expensive, technically demanding to place, and have been associated with complications; however, if a central line is placed for other reasons, extreme CVP values or reliable trends over time may still help identify severe hypo- and hypervolemic states.

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Static POCUS measurements: caudal vena cava diameter and cardiac POCUS. Human studies have demonstrated that a decreased, or small/flat, inferior vena cava diameter (IVCd) correlates with hypovolemia and is associated with a poor prognosis in human trauma and acute surgical cases.22 Similarly, poor IVC dilation following fluid resuscitation in human trauma patients suggests inadequate intravascular volume, independent of arterial blood pressure. The IVCd has been shown to be a better predictor of shock recurrence than either blood pressure or heart rate,23,24 and assessment of IVCd has become well established in human ECC.25 The caudal vena cava diameter (CVCd) has been shown to correlate with volume status and CVP in dogs.19 Blood donation in dogs resulting in mild (roughly 8%), clinically undetectable hypovolemia has demonstrated mixed results ranging from no significant change to a mild decrease in the CVCd.26-28 Inversely, in dogs with chronic degenerative mitral valve disease (DMVD), increasing American College of Veterinary Internal Medicine (ACVIM) stage is associated with higher CVCd secondary to fluid retention and hypervolemia.29 In companion animals, CVC assessment has been described at the suprailiac (kidney), the right intercostal (transhepatic), and the subxiphoid (diaphragmatic) levels (see Chapter 189, POCUS in the ICU).30 Research suggests all three sites can easily be assessed in dogs, although inter-rater variability at the subxiphoid view is lower than the suprailiac or right intercostal approaches.30 In contrast to human medicine where the IVC is commonly used in the ECC setting,31 recent surveys demonstrate many veterinarians lack confidence and require further training to feel comfortable evaluating the CVC.32,33 Assessing the CVC may also be challenging in patients with abdominal discomfort. Cardiac POCUS. Abbreviated echocardiography, referred to as cardiac POCUS, has become standard of care in training human intensivists in several countries, predominantly due to the role it plays in the assessment of volume status.34 Studies demonstrate improved medical decision making and changes to therapeutic plans when cardiac POCUS is applied to human patients with an indeterminate volume status.31 Abbreviated cardiac POCUS techniques subjectively score contractility, ventricular lumen size, ventricular wall thickness, and atrial lumen size, and require minimal training to learn.31 The ventricular lumen, and more importantly the atria, will demonstrate a change in lumen size in cases of both hypo- and hypervolemia. Similar to humans, dogs with clinical signs of hypovolemia have smaller left ventricular and left atrial lumen sizes, and thicker left ventricular walls.35 These changes are proportional to the severity of hypovolemia. Patients with normal clinical parameters may display smaller left ventricular cavity size, indicating a suboptimal volume status.35,36 The higher sensitivity of cardiac POCUS to detect changes in volume status when compared with clinical parameters has been demonstrated in dogs.35 Similarly, increased ventricular wall size, and decreased ventricular and atrial lumen size has been observed in cats following volume depletion (7%–10% body weight), while volume administration results in increasing left atrial and ventricular lumen size.36 Left atrial size is probably the most sensitive cardiac POCUS parameter to detect volume changes in dogs and cats (see Chapter 189, POCUS in the ICU). Although a decrease in atrial lumen size is strongly suggestive of a hypovolemic state, obstructive disease cannot be ruled out; inversely, an increased size may occur secondary to hypervolemia, severe arrhythmias, congestive heart disease, or dilated cardiomyopathy. The interpretation of left atrial size provides a noninvasive, inexpensive, repeatable, rapid, and available tool in an emergency setting, requiring minimal training37 (Chapter 189, POCUS in the ICU). However, a recent veterinary survey found that only half of

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emergency clinicians are comfortable assessing the left atrium with ultrasound.32 This shows a remarkable parallel with data in human medicine, where only half of pediatric intensive care doctors apply POCUS to guide fluid bolus therapy in children.8

Dynamic Markers Knowing the intravascular volume status of the patient does not predict if the patient will be fluid responsive or if vasopressors and/or positive inotropes should be initiated. Fluid responsiveness refers to the capacity to improve perfusion following a fluid challenge. Human studies demonstrate roughly 50% of hemodynamically unstable ICU children and adults, will not respond to a fluid challenge. In contrast to human ICU patients, preliminary evidence in dogs suggests 60%– 65% of dogs that present to the ECC service with hypotension (Doppler blood pressure ,90 mm Hg) will respond to fluid bolus therapy, defined as normalization of blood pressure.38 Although response did not vary with the underlying cause, the sample size was small and the sensitivity of using normalization of blood pressure (a static marker of fluid responsiveness) may have failed to detect some fluid responsive dogs, depending on how fluid response is defined: larger canine and feline studies are required to further explore these findings. Dynamic markers evaluate the change in volume/pressure induced by a known volume or factor, and thus assess whether the patient benefits from an additional fluid challenges (fluid responders) or not (fluid nonresponders). Given that fluid responsiveness aims to precisely titrate fluids, it is more commonly utilized in the optimization and stabilization phases of fluid therapy, and less so in the resuscitation phases. It is also frequently applied in more controlled clinical settings, such as during anesthetic procedures or during positive pressure ventilation (Fig. 64.2). However, the authors commonly assess parameters such as the CVC collapsibility index (CVCCI) and LA:Ao ratio in the resuscitation phase of fluid therapy to obtain subjective baseline values, as these parameters can be obtained quickly and are easy to subjectively assess.

Frank–Starling and Marik–Philips Curve Septic shock patients may be more susceptible to hypervolemia compared with hypovolemic shock patients. This is illustrated by the Frank–Starling and Marik–Philips curve (Fig. 64.3). A fluid responsive patient (A) will increase preload following a fluid bolus, without a significant increase in extravascular lung water (EVLW). As preload increases, stroke volume (SV) will also increase until the optimal preload is achieved. A fluid nonresponsive patient (B) will have a marginal to no increase in preload, and thus no improvement in SV, but a significant increase in EVLW.

HIGH EFFICIENCY

Each individual patient has a unique curve. However, septic patients have a higher tendency to accumulate EVLW, and thus fluid administration should be titrated more carefully in such patients.39 Patients on the flat portion of the Frank–Starling curve are unresponsive to fluid challenges and are more likely to benefit from vasopressors and positive inotropes. Additional fluid boluses will not increase SV and will likely be harmful; this is because of the curvilinear shape of the left ventricular pressure–volume curve, the result of altered diastolic compliance at higher filling pressures. As atrial pressures increase, increasing venous and pulmonary hydrostatic pressures and the increased release of natriuretic peptides will cause fluids to shift to the interstitial space, increasing pulmonary and tissue edema (see Chapter 11, Interstitial Edema). This tissue edema impairs oxygen and metabolite diffusion, distorts tissue architecture, impedes capillary blood flow and lymphatic drainage, and disturbs cell–cell interactions. When the clinician’s concern shifts from volume status to fluid responsiveness, smaller fluid boluses, a virtual bolus applying PLR, and/ or the Valsalva principle of lung–heart interactions becomes more important in assessing fluid responsiveness and avoiding complications associated with fluid overload (Fig. 64.4).40

Pulse Pressure, Systolic Pressure, and Stroke Volume Variation These dynamic measures of fluid responsiveness are reserved for the more controlled setting, such as monitoring of patients receiving positive pressure ventilation or general anesthesia. In these patients, respiratory pressure changes, via the previously described lung–heart interactions, induce stroke volume variations (SVVs), pulse pressure variations (PPVs), and systolic pressure variations (SPVs) (Fig. 64.5). A lower position on the Frank–Starling curve will induce larger variations during the respiratory cycle; positive fluid responders will demonstrate higher variations then nonresponders.41-44 Several parameters affect these measurements, including several that can be tightly controlled, such as tidal volume, positive inspiratory pressure, and positive end expiratory pressure, and some that are more difficult to control, such as spontaneous respiratory effort, altered chest wall compliance, cardiac disorders (e.g., arrhythmias), right heart failure, and altered intraabdominal pressures. Changes to these variables result in slight variations in the dynamic measures obtained, making direct comparison between studies challenging. However, fluid responsiveness is typically defined as a variation of greater than 10% to 15% in the dynamic parameter measured. Moreover, the greater the variation, provided other variables remain constant, the more likely the patient will benefit from additional fluid boluses (see the gray zone approach further on).

Guidelines for the administration of isotonic crystalloids Shock rate 90–80 ml/kg/h Dog – 60–50 ml/kg/h Cat Shock bolus 10–20 ml/kg over 5–10 minutes Mini bolus 5 ml/kg over 1–3 minutes

LOW PRECISION

Passive leg raising

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Valsalva effects ...

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Fig. 64.4  Fluid administration recommendations and the relative efficiency and precision of each.

CHAPTER 64  Assessment of Intravascular Volume Inspiration

Expiration

Inspiration

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Expiration

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Fig. 64.5  Mechanical ventilation induced variations in the arterial pressure curve showing stroke volume (SV) maximum (max) and minimum (min), pulse pressure (PP) maximum and minimum, and systolic pressure variation (SPV).

Plethysmographic Variability Index Plethysmographic variability index (PVI) has recently been assessed in human and veterinary medicine.9,43,45 PVI relies on similar principles to PPV, SSV, and SPV and may prove to be a less invasive means of dynamically assessing fluid responsiveness. PVI does require calculation of the area under the curve of the plethysmograph signal and built-in calculation software, which is currently only calibrated for humans. Moreover, it requires a reliably detectable plethysmographic signal, and therefore depends on variables such as skin pigmentation, vascular tone, and peripheral perfusion. Although it does not require an invasive line, it remains to be determined whether PVI is applicable in unstable patients due to interference from the parameters listed before.

Dynamic CVC Index and Advanced Cardiac POCUS In addition to the correlation of the caval diameter with blood volume, the thin elastic nature of the CVC also makes it a responsive and dynamic vessel. The size and geometry fluctuate in response to relative and absolute intravascular volume changes depending on the cardiac and respiratory cycle. Breathing causes changes in intrapleural pressures, generating heart–lung interactions according to the Valsalva principle, thereby influencing the intravascular volume within the thorax and abdomen. This size change between inspiration and expiration is referred to as CVC collapsibility and is calculated as the CVCCI. The CVCCI expresses the change (%) in the diameter of the CVC during the respiratory cycle: CVCCI 5 CVCd

max

– CVCd

min

/ CVCd

max

The IVC collapsibility index (IVCCI) has shown promise in human medicine to predict fluid responsiveness.46 A fat IVC, subjectively defined as wide IVC with an IVCCI ,50%, is associated with a high CVP secondary to hypervolemia, congestive heart disease, or cardiac tamponade. Inversely, a flat IVC, defined as a narrow IVC with an IVCCI .50%, is correlated with a low CVP and is indicative of hypovolemia. Mean IVCCI values reported in healthy adult humans are 47.3% 6 8.9%.47 Although, IVCCI assessment was first performed in human patients undergoing positive pressure ventilation, recent studies demonstrated it can also be performed in critically ill spontaneously breathing patients.48,49 Although the threshold to distinguish fluid responders from nonresponders in spontaneously breathing patients varies between studies (see gray zone approach below), an IVCCI $ 48% predicts fluid responsiveness with a sensitivity of 84% and a specificity of 90%.48 Despite these promising findings, IVC assessment is influenced by factors such as cardiac function, respiratory effort, intraabdominal pressure, and pressure artifact.50 There are limited veterinary studies examining the use of CVCCI in dogs or cats to assess fluid responsiveness. Blood donation in dogs

appears to be associated with an increased CVCCI.27 Similarly more advanced ACVIM stage of DMVD in dogs also is associated with a decreased CVCCI.28 A canine study indicated CVCCI can predict fluid responsiveness under controlled circumstances in anesthetized and mechanically ventilated dogs. Although these findings suggest the CVCCI is a promising marker of fluid responsiveness in companion animals, further research is required before guidelines on its application can be recommended. At a more advanced level of echocardiography, cardiac output can be directly calculated based on the surface of the descending aorta and the volume time integral in the left ventricular outflow tract (VTIAO). The product of these factors is equal to the column of blood that is ejected from the heart during each contraction. As with the previous parameters, Valsalva principles induce a change in VTIAO. Alternatively, a mini-fluid bolus can be administered to assess if significant changes in VTIAO occur following the bolus. A recent study demonstrated the accurate assessment of fluid responsiveness in conscious dogs using the VTIAO.51 A higher skill level is required to measure VTIAO with ultrasound. A small error in the calculation of the aortic surface, as well as a slightly altered angle when assessing the VTIAO by Doppler ultrasound, can induce changes in measurements that are greater than the expected change induced by a mini-bolus or the Valsalva principle (Fig. 64.6).

Gray Zone Approach Recently the importance of a gray zone approach to the interpretation of dynamic markers has started to receive attention. The basic

Fig. 64.6  Subcostal standard echocardiographic view optimized to visualize the left ventricular outflow tract.

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PART VI  Fluid Therapy

idea behind assessing fluid responsiveness is to help the clinician decide in real time if additional fluid boluses will be beneficial (improve cardiac output) or detrimental (cause volume overload). Answering this question with a simple “yes” or “no” is an oversimplification. In severely hypovolemic patients, additional fluid challenges have a high benefit to risk ratio (as stated above, volume status is the focus over fluid responsiveness in the resuscitation phase of fluid therapy). Inversely, additional fluid boluses will be detrimental in markedly hypervolemic patients. Between these two extremes there is considerable overlap. The gray zone approach suggests a three-level decision tree: Yes – Maybe – No. The gray zone is defined as the interval of values between a sensitivity or specificity lower than 90% to classify patients as fluid responders or nonresponders (Fig. 64.7). In Fig. 64.7,51 a VTIAO under 10.45 cm identifies a fluid nonresponder with .90% confidence. Inversely, a VTIAO above 11.86 cm identifies a fluid responder with .90% confidence. Values in the gray zone do not allow the patient’s response to a fluid challenge to be determined with any degree of confidence. Fluid strategies should be based on other available clinical parameters and at the clinician’s discretion, ideally performed serially to track changes over time. In summary, based on the gray zone approach, the further from the gray zone the measurement lies, the greater the confidence of accurately classifying the patient.

CONCLUSIONS The ROSE principle has caused a renewed interest in fluid therapy by ECC clinicians. Volume assessment should be defined as either the

100 90 Sensitivity(%) Specificity(%)

80 70

Percentage

60 50 40 30 20 10 0 0

5

10 15 20 VTIAo (cm) Fig. 64.7  Plot of sensitivity (blue line) and specificity (green line) of volume time integral aortic outflow at various cutoffs for discriminating between responder and nonresponder status. The interval of values between a sensitivity or specificity ,90% is defined by the gray zone (shaded gray region). VTlAO, volume time integral in the left ventricular outflow tract.

assessment of volume status or the assessment of fluid responsiveness. For both questions, different techniques exist that are applied depending on how well the patient’s environment can be controlled. The clinician should incorporate techniques considering the clinical scenario. As more precise titration of fluids becomes paramount, small bolus administration, PLR or Valsalva effects should be considered to avoid fluid overload. POCUS provides readily available information that can guide volume status and fluid responsiveness assessment regardless of the setting. The clinician should avoid binary or black and white thinking when it comes to volume status and fluid responsiveness. Approaching fluid therapy with a gray zone approach should minimize clinically relevant hypo- or hypervolemia and ensure optimal fluid status in critical care patients.

REFERENCES 1. Latta T: No. 3. Letter from DR. LATTA, of Leith, detailing Three Cases, of which one was successful, Lancet 18(460):370-373, 1832. 2. Maitland K, Kiguli S, Opoka RO, et al: Mortality after fluid bolus in African children with severe infection, N Engl J Med 364(26):2483-2495, 2011. 3. Malbrain ML, Marik PE, Witters I, et al: Fluid overload, de-resuscitation, and outcomes in critically ill or injured patients: a systematic review with suggestions for clinical practice, Anaesthesiol Intensive Ther 46(5): 361-380, 2014. 4. Silverstein DC, Aldrich J, Haskins SC, et al: Assessment of changes in blood volume in response to resuscitative fluid administration in dogs, J Vet Emerg Crit Care 15(3):185-192, 2005. 5. Hopper K, Garcia Rojas A, Barter L: An online survey of small animal veterinarians regarding current fluid therapy practices in dogs and cats, J Am Vet Med Assoc 252(5):553-559, 2018. 6. Yozova ID, Howard J, Sigrist NE, Adamik KN: Current trends in volume replacement therapy and the use of synthetic colloids in small animals-an internet-based survey (2016), Front Vet Sci 4:140, 2017. 7. Glassford NJ, Ma˚ rtensson J, Eastwood GM, et al: Defining the characteristics and expectations of fluid bolus therapy: a worldwide perspective, J Crit Care 35:126-132, 2016. 8. Gelbart B, Schlapbach L, Ganeshalingham A, et al: Fluid bolus therapy in critically ill children: a survey of practice among paediatric intensive care doctors in Australia and New Zealand, Crit Care Resusc 20(2):131-138, 2018. 9. Celeita-Rodríguez N, Teixeira-Neto FJ, Garofalo NA, et al: Comparison of the diagnostic accuracy of dynamic and static preload indexes to predict fluid responsiveness in mechanically ventilated, isoflurane anesthetized dogs, Vet Anaesth Analg 46(3):276-288, 2019. 10. Lilly CM: The ProCESS trial—a new era of sepsis management, N Engl J Med 370(18):1750-1751, 2014. 11. Cameron PA, Cooper DJ, Higgins AM, et al: Goal-directed resuscitation for patients with early septic shock, N Engl J Med 371(16):1496-1506, 2014. 12. Rabozzi R, Oricco S, Meneghiniet C, et al: Evaluation of the caudal vena cava diameter to abdominal aortic diameter ratio and the caudal vena cava respiratory collapsibility for predicting fluid responsiveness in a heterogeneous population of hospitalized conscious dogs, J Vet Med Sci 82(3):337-344, 2020. 13. Pickett JD, Bridges E, Kritek PA, Whitney JD: Passive leg-raising and prediction of fluid responsiveness: systematic review, Crit Care Nurse 37(2):32-47, 2017. 14. Cherpanath TG, Geerts BF, Lagrand WK, Schultz MJ, Groeneveld AB: Basic concepts of fluid responsiveness, Neth Heart J 21(12):530-536, 2013. 15. McGee S, Abernethy WB III, Simel DL: The rational clinical examination. Is this patient hypovolemic? JAMA 281(11):1022-1029, 1999. 16. Boscan P, Pypendop BH, Siao KT, et al: Fluid balance, glomerular filtration rate, and urine output in dogs anesthetized for an orthopedic surgical procedure, Am J Vet Res 71(5):501-507, 2010.

CHAPTER 64  Assessment of Intravascular Volume 17. Saugel B, Ringmaier S, Holzapfel K, et al: Physical examination, central venous pressure, and chest radiography for the prediction of transpulmonary thermodilution-derived hemodynamic parameters in critically ill patients: a prospective trial, J Crit Care 26(4):402-410, 2011. 18. Zulauf D, Kaser-Hotz B, Hässig M, et al: Radiographic examination and outcome in consecutive feline trauma patients, Vet Comp Orthop Traumatol 21(1):36-40, 2008. 19. Lichtenstein D: Fluid administration limited by lung sonography: the place of lung ultrasound in assessment of acute circulatory failure (the FALLS-protocol), Expert Rev Respir Med 6(2):155-162, 2012. 20. Nelson NC, Drost WT, Lerche P, et al: Noninvasive estimation of central venous pressure in anesthetized dogs by measurement of hepatic venous blood flow velocity and abdominal venous diameter, Vet Radiol Ultrasound 51(3):313-323, 2010. 21 . Marik PE, Baram M, Vahid B: Does central venous pressure predict fluid responsiveness? A systematic review of the literature and the tale of seven mares, Chest 134(1):172-178, 2008. 22. Ferrada P, Vanguri P, Anand RJ, et al: Flat inferior vena cava: indicator of poor prognosis in trauma and acute care surgery patients, Am Surg 78(12):1396-1398, 2012. 23. Yanagawa Y, Nishi K, Sakamoto T, Okada Y: Early diagnosis of hypovolemic shock by sonographic measurement of inferior vena cava in trauma patients, J Trauma 58(4):825-829, 2005. 24. Yanagawa Y, Sakamoto T, Okada Y: Hypovolemic shock evaluated by sonographic measurement of the inferior vena cava during resuscitation in trauma patients, J Trauma 63(6):1245-1248, 2007. 25. Dipti A, Soucy Z, Surana A, Chandra S: Role of inferior vena cava diameter in assessment of volume status: a meta-analysis, Am J Emerg Med 30(8):1414-1419, 2012. 26. Cambournac M, Goy-Thollot I, Violé A, et al: Sonographic assessment of volaemia: development and validation of a new method in dogs, J Small Anim Pract 59(3):174-182, 2018. 27. Marshall KA, Thomovsky EJ, Brooks AC: Ultrasound measurements of the caudal vena cava before and after blood donation in 9 greyhound dogs, Can Vet J 59(9):973-980, 2018. 28. Herreria-Bustillo VJ, Fitzgerald E, Humm KR: Caval-aortic ratio and caudal vena cava diameter in dogs before and after blood donation, J Vet Emerg Crit Care 29(6):643-646, 2019. 29. Giraud L, Gommeren K, Merveille AC: Point of care ultrasound of the caudal vena cava in canine DMVD. Abstract, J Vet Intern Med 34(1):349, 2020. 30. Darnis E, Boysen S, Merveille AC, et al: Establishment of reference values of the caudal vena cava by fast-ultrasonography through different views in healthy dogs, J Vet Intern Med 32(4):1308-1318, 2018. 31. Spencer KT: Heart. In Soni NJ, Arntfield A, Kory P, editors: Point-of-care ultrasound, Philadelphia, 2015, Elsevier Saunders, pp 85-88. 32. Aitken JB, Freeman LA, Leicester D, et al: Questionnaire on cardiovascular point-of-care ultrasound application in first opinion emergency settings in the United Kingdom, J Vet Emerg Crit Care 29(S1):S2, 2019. 33. Pelchat J, Chalhoub S, Boysen S: The use of veterinary point of care ultrasound by veterinarians: a nationwide Canadian survey, Can Vet J 61(12):1278-1282, 2020. 34. Poelaert J: Assessment of loading conditions with cardiac ultrasound. In Malbrain ML, editor: CACU: a comprehensive book on critical and acute care ultrasound, Antwerp, Belgium, 2017, iMERiT. 35. Durkan SD, Rush J, Rozanski E, et al: Echocardiographic findings in dogs with hypovolemia, J Vet Emerg Crit Care 15(s1):S1-S13, 2005.

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36. Campbell FE, Kittleson MD: The effect of hydration status on the echocardiographic measurements of normal cats, J Vet Intern Med 21(5):1008-1015, 2007. 37. Darnis E, Merveille AC, Desquilbet L, et al: Interobserver agreement between non-cardiologist veterinarians and a cardiologist after a 6-hour training course for echographic evaluation of basic echocardiographic parameters and caudal vena cava diameter in 15 healthy Beagles, J Vet Emerg Crit Care 29(5):495-504, 2019. 38. Silverstein DC, Kleiner J, Drobatz KJ: The effectiveness of intravenous fluid resuscitation for the treatment of emergency room hypotension in dogs, J Vet Emerg Crit Care 22:666-673, 2012. 39. Marik P, Bellomo R: A rational approach to fluid therapy in sepsis, Br J Anaesth 116(3):339-349, 2016. 40. Magder S: Heart-Lung interaction in spontaneous breathing subjects: the basics, Ann Transl Med 6(18):348, 2018. 41. Endo Y, Tamura J, Ishizuka T, et al: Stroke volume variation (SVV) and pulse pressure variation (PPV) as indicators of fluid responsiveness in sevoflurane anesthetized mechanically ventilated euvolemic dogs, J Vet Med Sci 79(8):1437-1445, 2017. 42. Sano H, Seo J, Wightman P, et al: Evaluation of pulse pressure variation and pleth variability index to predict fluid responsiveness in mechanically ventilated isoflurane-anesthetized dogs, J Vet Emerg Crit Care 28(4): 301-309, 2018. 43. Endo Y, Kawase K, Miyasho T, et al: Plethysmography variability index for prediction of fluid responsiveness during graded haemorrhage and transfusion in sevoflurane-anaesthetized mechanically ventilated dogs, Vet Anaesth Analg 44(6):1303-1312, 2017. 44. Drozdzynska MJ, Chang YM, Stanzani G, Pelligand L: Evaluation of the dynamic predictors of fluid responsiveness in dogs receiving goal-directed fluid therapy, Vet Anaesth Analg 45(1):22-30, 2018. 45. Klein AV, Teixeira-Neto FJ, Garofaloet NA, et al: Changes in pulse pressure variation and plethysmographic variability index caused by hypotensioninducing hemorrhage followed by volume replacement in isofluraneanesthetized dogs, Am J Vet Res 77(3):280-287, 2016. 46. Pereira RM, Campelo da Silva AJL, Faller J, et al: Comparative analysis of the collapsibility index and distensibility index of the inferior vena cava through echocardiography with pulse pressure variation that predicts fluid responsiveness in surgical patients: an observational controlled trial, J Cardiothorac Vasc Anesth 34(8):2162-2168, 2020. doi:10.1053/j. jvca.2020.02.007. 47. Gui J, Guo J, Nong F, et al: Impact of individual characteristics on sonographic IVC diameter and the IVC diameter/aorta diameter index, Am J Emerg Med 33:1602-1605, 2015. 48. Preau S, Bortolotti P, Colling D, et al: Diagnostic accuracy of the inferior vena cava collapsibility to predict fluid responsiveness in spontaneously breathing patients with sepsis and acute circulatory failure, Crit Care Med 45(3):e290-e297, 2017. 49. Corl KA, George NR, Romanoff J, et al: Inferior vena cava collapsibility detects fluid responsiveness among spontaneously breathing critically-ill patients, J Crit Care 41:130-137, 2017. 50. Huang SJ, McLean AS: Appreciating the strengths and weaknesses of transthoracic echocardiography in hemodynamic assessments, Cardiol Res Pract 2012:894308, 2012. https://doi. org/10.1155/2012/894308. 51. Oricco S, Rabozzi R, Meneghini C, Franci P: Usefulness of focused cardiac ultrasonography for predicting fluid responsiveness in conscious, spontaneously breathing dogs, Am J Vet Res 80(4):369-377, 2019.

65 Crystalloids and Hemoglobin-Based Oxygen-Carrying Solutions Ta-Ying Debra Liu, DVM, DACVECC, Deborah C. Silverstein, DVM, DACVECC

KEY POINTS • Crystalloid fluid therapy is invaluable in treating hemodynamic, electrolyte, and acid-base derangements. • The tonicity of a fluid is determined by the concentration of effective osmoles. • The volume distribution of a crystalloid solution in the body depends on its tonicity relative to the extracellular fluid. The lower the tonicity of a crystalloid solution, the higher proportion of the fluid volume administered will move into the intracellular space as a result of osmotic pressure differences. • Potential serious complications of fluid therapy include organ edema, cavitary effusion, electrolyte disturbances and osmotic

demyelination syndrome, which may be life-threatening. Individualized treatment and close monitoring for potential side effects are the essence of safe fluid therapy. • Hemoglobin-based oxygen-carrying solutions (HBOCs) are colloidal solutions with oxygen-carrying capacity. Although the oxygen content of the blood is improved, tissue oxygenation and the hemodynamic effects of HBOCs may be unpredictable because of their strong vasopressor effect.

Since the advent of intravenous fluid therapy in the early 1900s, many humans and animals have benefited from this life-saving treatment. Understanding the physiologic implications of different fluid losses from the body is equally important as having familiarity with the various solutions available commercially. In addition to individual patient factors, fluid composition, osmolarity, tonicity, oncotic pressure, and acid-base effects of a given fluid must be considered before administration. Different volumes of distribution, rheologic properties (viscosity), oxygen-carrying abilities, and metabolism of the respective fluids also influence the hemodynamics in concert. Readers are directed to Chapters 67 and 68, Daily Intravenous Fluid Therapy and Shock Fluid Therapy, respectively, for further details regarding dosages and administration options. Further information regarding colloids can be found in Chapter 66, Colloid Solutions. Fundamentally, the osmolar gradient between the intravascular, interstitial, and intracellular fluid compartments dictates fluid shifts. During periods of homeostasis, the osmolarity and tonicity of the intracellular compartment are equal to that of the extracellular (both intravascular and interstitial) compartment. Osmolarity includes all osmoles in solution, whereas tonicity refers solely to effective osmoles, which do not freely permeate most cell membranes. It is changes in tonicity that will drive fluid movement in or out of cells. Sodium and its associated anions are the predominant extracellular effective osmoles, whereas potassium and its associated anions are the predominant intracellular effective osmoles. The Na1/K1-ATPase pumps on the cell membrane are the primary regulators of cell volume by maintaining an appropriate distribution of intracellular potassium and extracellular sodium. Most sodium ions of the body stay extracellular because of these Na1/K1-ATPase pumps.1 Modified Starling’s forces (i.e., hydrostatic and colloid osmotic pressure [COP] in the intraluminal and extraluminal spaces), as well

as vascular endothelial permeability, govern the magnitude of fluid filtration from the capillary into the interstitial compartment. Normally, plasma albumin accounts for 80% of plasma COP, which is essential for minimizing fluid loss from the intravascular compartment into the interstitial space.2 Readers are directed to Chapter 67, Daily Intravenous Fluid Therapy, for further discussion about fluid distribution in the body. Fluid may be administered orally or via a feeding tube to be absorbed by the gastrointestinal tract, subcutaneously to be resorbed by the lymphatic system, or intravenously into the cardiovascular system. Potential adverse effects of fluid therapy include volume overload (e.g., pulmonary, peripheral tissue and other organ edema), inappropriate fluid shifts (e.g., cerebral edema as an example of intracellular overhydration), and electrolyte and acid-base derangements. Large volumes of fluid therapy may lead to a coagulopathy secondary to hemodilution and functional disturbances of primary hemostasis (e.g., synthetic colloidal fluids).3 Aggressive volume resuscitation may exacerbate hemorrhage in bleeding patients. The clinical impacts of various fluids on the immune system and the causal relationship of synthetic starch colloids to kidney injury remain obscure and unproven in veterinary medicine.4,5 Therefore a judicious approach to fluid therapy is necessary to minimize occurrences of these side effects.

386

CRYSTALLOIDS Crystalloids are fluids containing small solutes with molecular weights less than 500 g/mole (1 g/mole 5 1 dalton [Da]). Most solutes are electrolytes (,50 g/mole), which readily cross the capillary endothelium and equilibrate throughout the extracellular fluid compartment. There is a lag time of 20 to 30 minutes for electrolytes to distribute evenly in the extracellular fluid compartments (i.e., intravascular and

CHAPTER 65  Crystalloids and Hemoglobin-Based Oxygen-Carrying Solutions interstitial fluid compartments). The net result of fluid shifts (i.e., osmosis) is dictated by the relative tonicity between different fluid compartments. Sodium and its respective anions (i.e., chloride mostly) are the most abundant effective osmoles in most crystalloids. Other small solutes such as glucose and lactate are readily metabolized; hence 5% dextrose in water is considered free water because after dextrose metabolism it does not contain an effective osmole. The lack of large molecules precludes crystalloids from exerting a colloidal effect. Less than one-third of the volume of crystalloids administered remains in the intravascular space 30 minutes after administration.6 The lower the fluid tonicity, the greater the dilutional effect on extracellular fluid tonicity, resulting in an osmotic gradient favoring free water movement into the intracellular space and leaving less of the administered fluid volume in the extracellular space. Crystalloids are the most widely used fluids for treating clinical patients suffering from dehydration, cardiovascular shock, free water deficits, and electrolyte and acid-base imbalances. Crystalloids are often classified according to their tonicity. Features of isotonic, hypotonic, and hypertonic solutions are discussed below.

Isotonic Fluids The osmolarity and sodium concentration of isotonic fluids are similar to that of plasma and extracellular fluid. Normal plasma osmolarity is 290 to 310 mOsm/L for dogs and 311 to 322 mOsm/L for cats, and isotonic fluids generally have an osmolality in the range of 270 to 310 mOsm/L (see Table 65.1).7,8 These fluids are therefore useful for the treatment of hypovolemic shock when rapid intravascular volume expansion is desired. Strictly speaking, isotonic fluid does not cause significant fluid shifts between intracellular and extracellular fluid compartments in normal animals (tonicities of the intracellular and extracellular fluids are unchanged; therefore, there is no net osmotic shift). Isotonic fluids are also commonly used for treating interstitial dehydration. Normal or abnormal body fluid losses are generally hypotonic or isotonic in nature. Although isotonic crystalloids are best suited for the treatment of dehydration secondary to isotonic fluid loss, they are commonly used to replace hypotonic loss as well. Although excess electrolytes are typically excreted by the kidneys, patients with compromised renal function should have their electrolytes closely monitored. Examples of balanced isotonic fluids include Plasma-Lyte 148, PlasmaLyte A, Normosol-R, and lactated Ringer’s solution (LRS). Isotonic (0.9%) saline, an unbalanced isotonic crystalloid, contains a much higher chloride concentration (154 mmol/L) than canine or feline plasma (see Table 65.1). It is useful for treating animals with a hypochloremic metabolic alkalosis (e.g., pyloric obstruction). Conversely, patients with a normal chloride concentration may develop a

387

hyperchloremic metabolic acidosis when 0.9% saline is administered in large volumes.

HYPOTONIC FLUIDS In comparison to extracellular fluid and plasma, the osmolarity and sodium concentration of hypotonic fluids are much lower (e.g., 0.45% saline has an osmolarity of 154 mOsm/L with a sodium [and chloride] concentration of 77 mEq/L each; see Table 65.2). Five percent dextrose in free water is a unique isoosmotic solution (252 mOsm/L) with hypotonic effects since dextrose is rapidly metabolized and free water remains (osmolarity of 0 mOsm/L). Sterile water with an osmolarity of 0 mOsm/L should never be administered directly intravenously because of the risk of intravascular hemolysis and endothelial damage. Hypotonic fluids replenish free water deficits and are useful for treating animals with hypernatremia secondary to hypotonic fluid loss. Hypotonic fluids distribute throughout both intracellular and extracellular fluid compartments, with less remaining extracellularly in comparison to isotonic fluids. The large volume of distribution and free water content make hypotonic fluid a safer choice for slowly treating animals that have a decreased ability to excrete excess sodium or tolerate an increase in intravascular volume (e.g., kidney and heart diseases, respectively). Additionally, the low chloride content minimizes bromide loss in animals receiving potassium bromide therapy for seizure control.9,10 Hypotonic fluids should never be used as bolus therapy for intravascular volume resuscitation. Not only are these fluids inefficient at expanding the intravascular volume, they may also lead to lifethreatening cerebral edema. A rapid intravenous administration of hypotonic fluids drops plasma and extracellular fluid osmolarity (mainly determined by sodium level) quickly; consequently, water shifts from the extracellular fluid space to the intracellular space. Frequent sodium level monitoring during hypotonic fluids administration is recommended.

HYPERTONIC FLUIDS In contrast to hypotonic solutions, the high osmolarity and sodium concentration of hypertonic solutions, such as 7.5% saline, causes a free water shift (i.e., osmosis) from the intracellular space to the extracellular space, expanding the extracellular fluid volume by 3 to 5 times the volume administered (see Table 65.1). Osmotic fluid shifts from the interstitial space into the intravascular space start immediately after intravenous administration of hypertonic solution, even sooner than the uniform distribution of the electrolytes throughout the extracellular space. Free water from the intracellular fluid compartment

TABLE 65.1  Isotonic and Hypertonic Crystalloid Fluid Compositions Fluid Type 0.9% NaCl Lactated Ringer’s Solution Plasma-Lyte 148 Normosol-R Plasma-Lyte A 3% NaCl 7.5% NaCl 23.4% NaCl NaCl, sodium chloride.

Osmolality (mOsm/L) 308 273 294 294 294 1026 2566 8000

[Na1] (mEq/L) 154 130 140 140 140 513 1283 4000

[K1] (mEq/L) – 4 5 5 5 – – –

[Cl2] (mEq/L) 154 109 98 98 98 513 1283 4000

[Mg21] (mEq/L) – – 1.5–3 1.5–3 3 – – –

[Ca21] (mEq/L) – 1.5–3 – – – – – –

Lactate (mEq/L) – 28 – – – – – –

Acetate (mEq/L) – – 27 27 27 – – –

Gluconate (mEq/L) – – 23 23 23 – – –

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PART VI  Fluid Therapy

TABLE 65.2  Maintenance and Free Water Solution Compositions Fluid Type 0.45% NaCl 0.45% NaCl with 2.5% Dextrose Plasma-lyte 56 Normosol-M with 5% dextrose 1/2 Lactated Ringer’s Solution with 2.5% Dextrose 5% Dextrose in Water (D5W)

Osmolality (mOsm/L) 154 280 110 363 263

[Na1] (mEq/L) 77 77 40 40 65.5

[K1] (mEq/L) 0 – 13 13 2

[Cl2] (mEq/L) 77 77 40 40 55

[Mg21] (mEq/L) – – 3 3 –

[Ca21] (mEq/L) – – – – 1.5

Lactate (mEq/L) – – – – 14

Acetate (mEq/L) – – 16 16 –

Dextrose – 2.5% – 5% 2.5%

252

–

–

–

–

–

–

–

5%

then moves into the extracellular fluid compartment as the interstitial fluid osmolarity rises. Hypertonic saline ranging from 3% to 7.5% is used for the treatment of hypovolemic shock, intracranial hypertension, and severe hyponatremia (see Chapter 55, Sodium Disorders). Similar to isotonic and hypotonic crystalloids, the intravascular volume expansion effect of hypertonic saline is transient (,30 minutes) because of the redistribution of electrolytes (i.e., sodium and its associated anions) throughout the extravascular space and osmotic diuresis.6 To prolong the intravascular volume-expanding effect of hypertonic saline, it is often combined with a colloidal solution. A common preparation is made by mixing a stock solution of 23.4% hypertonic saline with 6% hetastarch or other starch solution in a 1:2 ratio and dosed at 3 to 5 ml/kg slowly intravenously for the treatment of hypovolemia. Hypertonic saline has several beneficial effects on the cardiovascular system beyond increasing vascular volume. It transiently improves cardiac output and tissue perfusion via arteriolar vasodilation (decreased afterload), volume loading (increased preload), and reduced endothelial swelling, and has a weak positive inotropic effect.11-13 It is important that administration rates do not exceed 1 ml/kg/min because hypotension may result from central vasomotor center inhibition or peripheral vasomotor effects mediated by the acute hyperosmolarity (bradycardia and vasodilation).11 Hypertonic saline also has immune-modulatory effects including suppression of neutrophil respiratory burst activity and cytotoxic effects. The antiinflammatory effects of hypertonic saline may be especially advantageous in trauma patients.13,14 Additionally, hypertonic saline improves cerebral perfusion pressure in head trauma patients by augmenting mean arterial blood pressure and decreasing intracranial pressure. At equal osmolar dosages, similar osmotic effects are achieved with either hypertonic saline or mannitol to reduce cerebral edema.13,15 Hypernatremia and hyperchloremia are potential side effects that prevent the safe use of repeated doses of hypertonic saline. A dose of 4 ml/kg of 7.5% saline will transiently expand intravascular volume by 12 to 16 ml/kg (a fraction of total shock dose). Therefore, additional volumes of isotonic crystalloids, colloids, or blood products are required to stabilize a patient suffering from hypovolemic or distributive shock (see Chapter 68, Shock Fluid Therapy). Repeated administration of hyperosmotic solutions may lead to hemolysis and phlebitis if given into small peripheral veins.16

ACID-BASE EFFECTS OF CRYSTALLOIDS The pH of intravenous fluids is usually acidic; this is largely due to dissolved carbon dioxide, polyvinyl chloride packaging,17 and the acidic nature of dextrose solutions. This low pH does not influence the acid-base balance of patients because of the lack of titratable acidity. Essentially the total quantity of free hydrogen ions in an intravenous

fluid is small and easily buffered in the body and should not be considered as relevant to the acid-base effects of fluid therapy. The acid-base effects of crystalloid administration depend largely on the buffer content of the fluid. Further discussion of the effects of various fluids on the pH of the blood is beyond the scope of this chapter but can be found in Chapters 59 and 60, Traditional Acid-Base Analysis and Non-Traditional Acid-Base Analysis, respectively. Acetate and lactate are weak buffers included in some crystalloids such as Normosol-R, LRS, and Plasma-Lyte 148. Metabolism of these buffers consumes hydrogen ions, resulting in an alkalinizing effect.18 As such they are considered beneficial when treating patients with a metabolic acidosis. These fluids may not be as ideal for animals with a hypochloremic metabolic alkalosis, for which 0.9% saline is considered the fluid of choice. In patients suffering from hypovolemic shock, lactic acidosis is common. Although treatment with a buffered fluid may allow resolution of this metabolic acidosis slightly faster than treatment with an unbuffered fluid such as 0.9% saline, the greatest benefit to the patient is restoring adequate perfusion and the type of isotonic crystalloid utilized to achieve this is of less importance.19-21 The metabolism of lactate occurs mainly in the liver; therefore, its use in animals with significant liver dysfunction is not recommended. LRS may be the ideal fluid for neonates because lactate is the preferred metabolic fuel in early life. The lactate anion found in crystalloids such as LRS does not contribute to metabolic acidosis; it can, however, increase the measured lactate concentration in the blood if it is not yet metabolized. This can confuse the clinical picture if lactate is being used to help assess the hemodynamic status of the patient. If blood samples are contaminated with lactate containing fluids (e.g., inadequate scavenging from an IV catheter through which LRS is being administered), it can lead to spuriously high measured lactate levels. Acetate is metabolized primarily in the skeletal muscle although most cells in body can metabolize it. Hypotension due to vasodilation is associated with rapid infusion of acetate and has been reported in humans and experimental dogs.22-25 This has led to concerns of use of acetate containing crystalloids for shock resuscitation. Anecdotally, these fluids are used commonly for resuscitation, but further investigations of the hemodynamic effects of rapid administration of acetate containing fluids to hypovolemic animals are needed. Normal saline is the most commonly used crystalloid in human medicine for fluid resuscitation. The supraphysiologic content of chloride in 0.9% saline has recently been studied for its side effect in resuscitating critically ill human patients and animal models. Increased mortality and frequency of acute kidney injury have been observed although not consistently seen across all studies.26-34 Liberal chloride use in fluid prescription contributes to hyperchloremia, metabolic acidosis, altered immune response, and impaired microcirculation.35-38

CHAPTER 65  Crystalloids and Hemoglobin-Based Oxygen-Carrying Solutions Further studies are underway to investigate clinical effects of 0.9% saline in comparison to balanced crystalloids.

HEMOGLOBIN-BASED OXYGEN-CARRYING SOLUTIONS Oxyglobin is the only veterinary FDA-approved hemoglobin-based oxygen-carrying solution for the treatment of canine anemia, although it is no longer made in the United States. It contains 13 g/dl of polymerized bovine hemoglobin that is ultrapurified and free of antigenic red blood cell stroma and is suspended in a modified LRS. Bovine hemoglobin depends on chloride instead of 2,3-diphosphoglycerate in the red blood cells to regulate its oxygen affinity; readily available chloride in the extracellular fluid aids in the excellent oxygen transport ability of bovine hemoglobin.39 Bovine hemoglobin has a P50 of 34 mm Hg, similar to that of canine and feline hemoglobin (P50 of canine and feline hemoglobin in red blood cells are 31.5 and 35.6 mm Hg, respectively).40,41 Polymerization of bovine hemoglobin tetramers creates a more stable, larger molecule, which prolongs its half-life and eliminates the renal toxicity associated with hemoglobin dimers (derived from rapid breakdown of individual hemoglobin tetramers).39 Oxyglobin is a polydiverse colloidal solution with an average weight molecular weight of 200 kDa (molecular weight range of 64 to 500 kDa). It is isoosmotic (300 mOsm/kg) and hyperoncotic (COP of 43 mm Hg). Free of cells, the viscosity of Oxyglobin is low (,2 cP). Increased preload, stroke volume, and cardiac output are observed after Oxyglobin administration. However, the hemodynamic effect of Oxyglobin is complicated by its nitric oxide scavenging effect. Normally, nitric oxide has a vasodilatory effect. Peripheral vasoconstriction subsequent to the decrease in nitric oxide with Oxyglobin therapy may ironically compromise tissue perfusion and oxygen delivery. In addition, the local regulatory response to improved tissue oxygenation may also lead to peripheral vasoconstriction after Oxyglobin administration.42-44 It is plausible that low doses of this fluid could circumvent the adverse effects while increasing oxygen delivery to the tissues. Blood typing and cross-matching are not necessary before Oxyglobin administration. Improvements in clinical signs of anemia mirror the increase of hemoglobin level. Hematocrit is no longer a useful measure of blood carrying capacity and may decrease after Oxyglobin administration because of its dilutional effect. The most concerning side effect of Oxyglobin is volume overload. Judicious dosing and close monitoring are imperative. The half-life of Oxyglobin is dose-dependent and ranges from 18 to 43 hours after infusion of 10 to 30 ml/kg. It has a labeled shelf life of 36 months at room temperature. Transient yellow-orange discoloration of the skin, mucous membranes, and sclera and orange- to brown-colored urine are increasingly obvious with higher dosages of Oxyglobin. Some serum chemistry and urine dipstick parameters will be invalidated because of serum discoloration.

CONCLUSION Fluid therapy is versatile and plays a major role in the supportive care of hospitalized veterinary patients. To maximize the benefits and minimize side effects, treatment goals should be clearly delineated while formulating a fluid prescription. Familiarity with different fluid products, rational fluid prescription, and close patient monitoring (via physical examination and bloodwork) are the three major elements of proper fluid therapy.

ACKNOWLEDGEMENT Special thanks to Dr. Natalie Kovak for her assistance with the tables in this chapter.

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REFERENCES 1. DiBartola SP, de Morais HA: Disorders of potassium: hypokalemia and hyperkalemia. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders in small animal practice, ed 3, St Louis, 2006, Elsevier. 2. Mazzaferro EM, Rudloff E, Kirby R: The role of albumin replacement in the critically ill veterinary patient, J Vet Emerg Crit Care 12(2):113, 2002. 3. Kozek-Langenecker SA: Influence of fluid therapy on the haemostatic system of intensive care patients, Best Pract Res Clin Anaesthesiol 23:225, 2009. 4. Alam HB, Stanton K, Koustova E, et al: Effect of different resuscitation strategies on neutrophil activation in a swine model of hemorrhagic shock, Resuscitation 60:91, 2004. 5. Perner A, Haase N, Guttormsen AB, et al: Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis, N Engl J Med 367:124, 2012. 6. Silverstein DC, Aldrich J, Haskins SC, et al: Assessment of changes in blood volume in response to resuscitative fluid administration in dogs, J Vet Emerg Crit Care 15(3):185, 2005. 7. DiBartola SP: Disorders of sodium and water: hypernatremia and hyponatremia. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders in small animal practice, ed 3, St Louis, 2006, Elsevier. 8. Dugger DT, Mellema MS, Hopper K, et al: Comparative accuracy of several published formulae for the estimation of serum osmolality in cats, J Small Anim Pract 54:184, 2013. 9. Shaw N, Trepanier LA, Center SA, et al: High dietary chloride content associated with loss of therapeutic serum bromide concentrations in an epileptic dog, J Am Vet Med Assoc 208:234, 1996. 10. Nichols ES, Trepanier LA, Linn K: Bromide toxicosis secondary to renal insufficiency in an epileptic dog, J Am Vet Med Assoc 208:231, 1996. 11. Kien ND, Kramer GC, White DA: Acute hypotension caused by rapid hypertonic saline infusion in anesthetized dogs, Anesth Analg 73:597, 1991. 12. Kien ND, Reitan JA, White DA, et al: Cardiac contractility and blood flow distribution following resuscitation with 7.5% hypertonic saline in anesthetized dogs, Circ Shock 35:109, 1991. 13. Bulger EM, Hoyt DB: Hypertonic resuscitation after severe injury: is it of benefit? Adv Surg 46:73, 2012. 14. Rizoli SB, Rhind SG, Shek PN, et al: The immunomodulatory effects of hypertonic saline resuscitation in patients sustaining traumatic hemorrhagic shock: a randomized, controlled, double-blinded trial, Ann Surg 243:47, 2006. 15. Cottenceau V, Masson F, Mahamid E, et al: Comparison of effects of equiosmolar doses of mannitol and hypertonic saline on cerebral blood flow and metabolism in traumatic brain injury, J Neurotrauma 28:2003, 2011. 16. Rocha e Silva M, Velasco IT, Porfirio MF: Hypertonic saline resuscitation: saturated salt-dextran solutions are equally effective, but induce hemolysis in dogs, Crit Care Med 18:203, 1990. 17. Story DA, Thistlethwaite P, Bellomo: The effect of PVC packaging on the acidity of 0.9% saline, Anaesth Intensive Care 28:287, 2000. 18. DiBartola SP, Bateman S: Introduction to fluid therapy. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders in small animal practice, ed 3, St Louis, 2006, Elsevier. 19. Silverstein DC, Kleiner J, Drobatz KJ: Effectiveness of intravenous fluid resuscitation in the emergency room for treatment of hypotension in dogs: 35 cases (2000-2010), J Vet Emerg Crit Care (San Antonio) 22:666, 2012. 20. Driessen B, Brainard B: Fluid therapy for the traumatized patient, J Vet Emerg Crit Care 16:276, 2006. 21. Drobatz KJ, Cole SG: The influence of crystalloid type on acid-base and electrolyte status of cats with urethral obstruction, J Vet Emerg Crit Care 18:355, 2008. 22. Daugirdas JT, Nawab ZM, Ing TS: Acute hypotension during acetate-buffered dialysis in chemically sympathectomized dogs, Trans Am Soc Artif Intern Organs 31:517, 1985. 23. Noris M, Todeschini M, Casiraghi F, et al: Effect of acetate, bicarbonate dialysis, and acetate-free biofiltration on nitric oxide synthesis: implications for dialysis hypotension, Am J Kidney Dis 32:115, 1998. 24. Saragoça MA, Bessa AM, Mulinari RA, et al: Sodium acetate, an arterial vasodilator: haemodynamic characterisation in normal dogs, Proc Eur Dial Transplant Assoc Eur Ren Assoc 21:221-224, 1985.

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25. Saragoça MA, Mulinari RA, Bessa AM, et al: Comparison of the hemodynamic effects of sodium acetate in euvolemic dogs and in dogs submitted to hemorrhagic shock, Braz J Med Biol Res 19:455-458, 1986. 26. Hammond DA, Lam SW, Rech MA, et al: Balanced crystalloids versus saline in critically Ill adults: a systematic review and meta-analysis, Ann Pharmacother 54(1):5, 2020. 27. Liu C, Lu G, Wang D, et al: Balanced crystalloids versus normal saline for fluid resuscitation in critically ill patients: a systematic review and metaanalysis with trial sequential analysis, Am J Emerg Med 37(11):2072, 2019. 28. Zhou F, Peng ZY, Bishop JV, et al: Effects of fluid resuscitation with 0.9% saline versus a balanced electrolyte solution on acute kidney injury in a rat model of sepsis, Crit Care Med 42(4):e270, 2014. 29. Yunos NM, Bellomo R, Hegarty C, et al: Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults, JAMA 308:1566, 2012. 30. Shaw AD, Bagshaw SM, Goldstein SL, et al: Major complications, mortality, and resource utilization after open abdominal surgery: 0.9% saline compared to Plasma-Lyte, Ann Surg 255(5):821, 2012. 31. Raghunathan K, Shaw A, Nathanson B, et al: Association between the choice of IV crystalloid and in-hospital mortality among critically ill adults with sepsis, Crit Care Med 42(7):1585, 2014. 32. Brown RM, Wang L, Coston TD, et al: Balanced crystalloids versus saline in sepsis. A secondary analysis of the SMART clinical trial, Am J Respir Crit Care Med 200(12):1487, 2019. 33. Semler MW, Wanderer JP, Ehrenfeld JM, et al: Balanced crystalloids versus saline in the intensive care unit. The SALT randomized trial, Am J Respir Crit Care Med 195(10):1362, 2017.

34. Weiss SL, Keele L, Balamuth F, et al: Crystalloid fluid choice and clinical outcomes in pediatric sepsis: a matched retrospective cohort study, J Pediatr 182:304, 2017. 35. Kellum JA, Song M, Almasri E: Hyperchloremic acidosis increases circulating inflammatory molecules in experimental sepsis, Chest 130:962, 2006. 36. Kellum JA, Song M, Venkataraman R: Effects of hyperchloremic acidosis on arterial pressure and circulating inflammatory molecules in experimental sepsis, Chest 125:243, 2004. 37. Orbegozo D, Su F, Santacruz C, et al: Effects of different crystalloid solutions on hemodynamics, peripheral perfusion, and the microcirculation in experimental abdominal sepsis, Anesthesiology 125:744, 2016. 38. Volta CA, Trentini A, Farabegoli L, et al: Effects of two different strategies of fluid administration on inflammatory mediators, plasma electrolytes and acid/base disorders in patients undergoing major abdominal surgery: a randomized double blind study, J Inflamm 10:29, 2013. 39. Eike JH, Palmer AF: Effect of Cl2 and H1 on the oxygen binding properties of glutaraldehyde-polymerized bovine hemoglobin-based blood substitutes, Biotechnol Prog 20:1543, 2004. 40. Rossing R, Cain S: A nomogram relating pO2, pH, temperature, and hemoglobin saturation in the dog, J Appl Physiol 21(1):195, 1966. 41. Herrmann K, Haskins S: Determination of P50 for feline hemoglobin, J Vet Emerg Crit Care 15:26, 2005. 42. Malhotra AK, Schweitzer JB, Fox JL, et al: Cerebral perfusion pressure elevation with oxygen-carrying pressor after traumatic brain injury and hypotension in swine, J Trauma 56:1049, 2004. 43. Knudson MM, Lee S, Erickson V, et al: Tissue oxygen monitoring during hemorrhagic shock and resuscitation: a comparison of lactated Ringer’s solution, hypertonic saline Dextran, and HBOC-201, J Trauma 54:242, 2003. 44. Elmer J, Alam HB, Wilcox SR: Hemoglobin-based oxygen carriers for hemorrhagic shock, Resuscitation 83:285, 2012.

66 Colloid Solutions Steven J. Centola, BVMS, MRCVS, DACVECC, Deborah C. Silverstein, DVM, DACVECC

KEY POINTS • Colloid solutions contain large hydrophilic molecules (.10,000 Da) that do not readily cross the vascular endothelium and remain within the intravascular space in patients with an uncompromised, intact vascular barrier. • Hydroxyethyl starch (HES) solutions are synthetic branched polymers of glucose that are the most frequently used plasma expanding colloids in human and veterinary medicine in the United States. • HES solutions are characterized by the concentration of colloidal particles in solution, weight-average molecular weight in kilodaltons,

number average molecular weight, molar substitutions, and ratio of hydroxyethyl substitutions at the C2 versus C6 position. • The coagulation impairment associated with HES administration has several potential mechanisms, including decreased platelet function, decreased concentrations of von Willebrand factor, factor VIII coagulant activity (FVIII:C), factor VIII-related antigen, factor VIII ristocetin cofactor, as well as impaired fibrinogen polymerization, and a dilutional coagulopathy. • Albumin makes up 70%–80% of colloid osmotic pressure within the body in health.

Achieving an adequate intravascular volume status can prove difficult in critically ill patients, but it is important for maintaining adequate cardiac output, tissue perfusion, and subsequent oxygen delivery to the peripheral tissues. Starling’s (revised) principle governs the balance between the intravascular, subglycocalyx, and interstitial hydrostatic and colloid osmotic pressures. The traditional Starling’s principle describes how an increased intravascular to interstitial hydrostatic pressure gradient leads to transvascular fluid flux into the interstitial space at the arteriolar end of the capillary; fluid is subsequently reabsorbed into the intravascular space at venous end of the capillary due to an increased intravascular colloid osmotic pressure (COP).1 The revised Starling’s equation introduces the paradigm of the endothelial glycocalyx layer, the endothelial basement membrane, and the extracellular matrix. The subglycocalyx COP replaces the interstitial fluid COP as a determinant of transendothelial flow. It has now been recognized that fluid reabsorption at the venular end of the capillary does not occur as previously thought, and plasma COP opposes, but does not reverse fluid filtration into the interstitial space.1 Impairment of the endothelial glycocalyx has been observed in disease states such as systemic inflammatory response syndrome, hypervolemia, diabetes, surgery, trauma, and sepsis.1-3 A compromised endothelial glycocalyx has been shown to increase capillary permeability and lead to the formation of tissue edema (see Chapters 9 and 11, Endothelial Glycocalyx and Interstitial Edema, respectively).4 Colloid solutions contain large hydrophilic molecules (.10,000 Da) that do not readily cross the vascular endothelium and remain within the intravascular space in patients with an uncompromised, intact vascular barrier. This property makes colloid solutions an appealing fluid selection for hypoalbuminemic patients and possibly those with disease states causing increased vascular permeability; a volume-sparing effect may be beneficial to decrease the risk of an iatrogenic positive fluid balance.5 When the intravascular plasma COP is greater than the

subendothelial glycocalyx COP, the oncotic forces favor fluid reabsorption into the capillary lumen. Normal COP is 15.3 to 26.3 mm Hg in dogs and 17.6 to 33.1 mm Hg in cats (whole blood).6 Normal human COP is 25 to 27 mm Hg.8 Endogenous colloid particles within the circulation include albumin, globulins, and fibrinogen. Colloid solutions available for use are categorized into synthetic starch colloids, allogenic blood products, and human albumin (see Table 66.1). Synthetic gelatin and dextran colloids are rarely used due to their adverse effects and are not discussed.

SYNTHETIC STARCH COLLOIDS Hydroxyethyl starch (HES) solutions are synthetic branched polymers of glucose that are the most frequently used plasma expanding colloids in human and veterinary medicine in the United States.9 The major use of HES solutions is to rapidly expand the intravascular volume with small volume resuscitation by increasing the COP. HES is synthesized from amylopectin, which is a naturally occurring starch, derived from either potatoes or corn, and is hydroxylated to prevent rapid degradation by a-amylase. HES solutions are commercially available as hetastarch, hexastarch, pentastarch, or tetrastarch formulations.10 HES solutions are characterized by the concentration of colloidal particles in solution, weight-average molecular weight in kilodaltons (WAMW), number average molecular weight (NAMW), molar substitutions (MS), and ratio of hydroxyethyl substitutions at the C2 versus C6 position (Table 66.2).11 HES solutions are available in 3%, 6%, and 10% concentrations. The HES concentration influences the plasma expanding volume effect. The WAMW is the arithmetic mean of the molecular weights of all particles in the solution; the NAMW is equal to the median value of the molecular weights of the particles and although considered more accurate, is rarely reported. The WAMW:NAMW ratio is the polydispersity index.10 HES molecules with a molecular weight (MW) below the renal threshold

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TABLE 66.1  Commonly Used Synthetic Colloids, Pertinent Characteristics, and Suggested

Maximum Daily Doses Synthetic Colloid

Solution Strength

Source

COP (mm Hg)

WAMW (kDa)

Degree of Substitution

C2:C6

Maximum Dose per 24 h

Hespan

6% HES

Amylopectin

32

450

0.7

4.5:1

20 ml/kg

Hextend

6% HES

Amylopectin

31

670

0.75

4.6:1

20 ml/kg

Pentaspan

10% HES

Amylopectin

36

260

0.45

5:1

40 ml/kg

Vetstarch, Voluven or Hydravol

6% HES

Amylopectin

37

130

0.4

9.1

50 ml/kg

Fresh frozen plasma

12.73

Cryopoor plasma

14.5

5% Albumin

20

COP, colloid osmotic pressure; WAMW, weight-average molecular weight.

TABLE 66.2  Synthetic Colloid Pharmacological Characteristics Abbreviation WAMW NAMW MS C2:C6

Pharmacological Properties Weight-average molecular weight Number average molecular weight Molar substitutions Ratio of hydroxyethyl substitutions at the C2 versus C6 position

(45–60 kDa) are rapidly excreted via the urine, thus reducing their intravascular oncotic effect. HES molecules with a MW above the renal threshold are hydrolyzed into smaller particles within the circulation via a-amylase and are eventually excreted via the urine. The MS describes the average number of HE residues per glucose subunit on the HES molecule. The number of substitution sites will determine the size and shape of the HES molecule and where a-amylase will attach for hydrolysis. Larger MW, higher degree of substitutions, and a higher C2:C6 ratio are associated with a longer half-life of the HES solution.12 The MS number of the HES solution indicates the degree of substitution and how long the solution will last in circulation before hydrolysis to smaller particles that are renally excreted. As an example, tetrastarch 0.4 (4 substitutions), pentastarch 0.5 (5 substitutions), hexastarch 0.6 (6 substitutions), and hetastarch 0.7 (7 substitutions) are all available, with hetastarch having the longest half-life of the various colloid solutions. Hydroxyethyl groups are substituted on the C2, C3, and C6 carbons on the glucose subunits. The pattern of the C2:C6 ratio describes the locations of the HE residues on the glucose subunits and the overall a-amylase affinity and degradation capability. HE residues substituted on the C2 position inhibit a-amylase activity and therefore prolong the half-life of the solution in circulation.5 The MS and pattern of substitutions are the most important properties contributing to the pharmacokinetics of the HES solutions. The half-life of hetastarch (6% HES 450/0.75) in healthy dogs is 7.45 days compared with 12.8 days in humans and has been accredited to dogs having higher serum a-amylase activity than humans.13 The primary route of elimination of HES solutions is via renal excretion (70%). A secondary route of elimination occurs via the reticuloendothelial cells of the liver, spleen, and lymph nodes when leakage of the HES into the tissues occurs. A third route of elimination occurs via biliary excretion. Most studies examining the use of HES solutions differ in the dose, type, concentration, and specific population investigated. Additionally, there may be speciesspecific differences in small animals when compared with the data extrapolated from human medicine.10,14 The adverse effects associated with HES solution administration occur as the result of cumulative

Definition Mean of the molecular weights of all particles in the solution Median value of the molecular weights of the particles Average number of HE residues per glucose subunit on the HES molecule Determines the size and shape of the HES molecule and where a-amylase will attach for hydrolysis

dose rather than the daily infusion dose; these side effects include acute kidney injury (AKI), coagulopathy, proinflammatory effects, anaphylaxis, and volume overload.15-17 Foamy macrophage syndrome and delayed onset pruritus have been reported in humans after administration of HES solutions; however, these effects have not been reported in the veterinary literature.15-17

Acute Kidney Injury The pathophysiology of HES-associated AKI is not completely understood; however, several mechanisms have been postulated as the cause of tubular renal. One mechanism suggests HES molecules are reabsorbed into the proximal renal tubular cells, causing an osmotic nephrosis and subsequent vacuolization and swelling of these cells.18,19 Similar histopathologic findings have also been reported after administration of sucrose, dextrans, mannitol, lactated Ringer’s solution, and contrast media. However, the significance of these histopathologic changes with respect to renal function is unknown since these lesions have also been observed in patients without AKI.20,21 HES uptake occurs in proximal tubular luminal epithelial cells via pinocytosis; intracellular lysosomal storage can lead to accumulation of intracellular water causing cytoplasmic swelling, altered cellular integrity and function, and tubular injury.18,19 Another proposed theory for HES-associated AKI is a hyperoncotic-induced renal dysfunction. Intravenous administration of HES solutions leads to increased circulation of colloid particles and an increase in the COP. This, coupled with low renal perfusion pressure in the glomerular arterioles, is believed to cause alterations of the intraglomerular colloid osmotic forces, leading to a decrease in glomerular filtration.22-24 There have been several veterinary studies evaluating the adverse effects of colloid solutions. Hayes et al. found that HES administration showed an independent association with increased risk of in-hospital adverse effects in dogs, including AKI and death. Additionally, they identified a dose-dependent relationship between higher daily doses and an increased risk of adverse effects.25 Sigrist et al. retrospectively investigated the effects of 6% HES 130/0.4 in nonazotemic cats and did not identify an increase in serum creatinine concentrations both within 10 days (short-term) and within

CHAPTER 66  Colloid Solutions 90 days (long-term) when compared to untreated cats.26 Boyd et al. compared the effects of 6% HES 130/0.4 and 4% succinylated gelatin to fresh whole blood and balanced isotonic crystalloid solution on urine biomarkers of AKI and renal histology in canine experimental models of atraumatic experimental shock. They discovered that dogs treated with succinylated gelatin had a greater increase in biomarker levels of renal tubular injury following hemorrhagic shock and reperfusion compared with other fluid types evaluated. Additionally, the succinylated gelatin treated group showed marked microvesiculation of renal tubular epithelial cells. Interestingly, these renal biomarkers are predictive of AKI and the need for renal replacement therapy in human ICU patients.27 Zersen et al. retrospectively evaluated changes in serum creatinine and chloride concentrations in anesthetized dogs that received 6% HES 670/0.7 to treat either hypotension, low COP, or patients with concern for fluid overload. In this study, postanesthetic creatinine concentrations were lower and chloride concentrations were higher when compared with preanesthetic values.28 Diniz et al. observed that 6% tetrastarch caused less extravascular lung water accumulation measured by transpulmonary thermodilution cardiac output methods when compared to lactated Ringer’s solution after volume replacement in experimental dogs; however, neither fluid led to production of pulmonary edema or oxygenation impairment as assessed by PaO2/FiO2 ratio. Additionally, neither fluid led to AKI when evaluated by creatinine and neutrophil gelatinase associated lipocalin plasma and urine concentrations in this population of dogs when used for volume replacement.29 Yozova et al. evaluated the effects of administering 6% HES 130/0.4 solution compared with isotonic crystalloid solution on plasma creatinine in a population of canine ICU patients with various diseases and found no significant difference between study groups.30 Sigrist et al. investigated whether the administration of 6% HES 130/0.4 is associated with an increase in serum creatinine concentration and AKI grade defined by International Renal Interest Society guidelines. They did not find a significant difference in the incidence of AKI in HES-treated vs. HES-untreated dogs; however, the number of HES days was significantly associated with an increase AKI grade within 10 days post-HES administration.31 It is unclear whether the sicker dogs with a higher risk of AKI were the patients that required long-term colloidal support. Further studies are necessary to discern whether there is a definitive link between synthetic colloids and AKI in small animals.

Coagulation Effects The coagulation impairment associated with HES administration has several potential mechanisms, including decreased platelet function, decreased concentrations of von Willebrand factor (vWF), factor VIII coagulant activity, factor VIII-related antigen, factor VIII ristocetin cofactor, as well as impaired fibrinogen polymerization, and a dilutional coagulopathy.25,32,33 Additionally, accelerated excretion of factor VIII/vWF complexes and reduced vWF-mediated rolling and adhesion of platelets to subendothelial collagen may also contribute.32 Reduced platelet counts secondary to dilutional effects, colloid osmotic shrinkage of platelets, and increased platelet degradation have been observed following HES administration.34,35 HES-coated platelets have dysfunctional platelet adhesion and aggregation secondary to decreased expression and activation of the surface receptor GPIIb/IIIa, which binds vWF and fibrinogen. Reduced GPIIb/IIIa impairs adhesion to surfacebound fibrinogen, and soluble fibrinogen ligand binding between adjacent platelets is necessary for platelet aggregation.36-39 HES solutions also exert a profibrinolytic effect when integrated into a formed blood clot, thus leading to accelerated conversion of fibrinogen to fibrin, causing reduced clot strength and decreased interactions between FXIII and fibrin.40-44

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NATURAL COLLOIDS Several allogenic blood products provide albumin and oncotic support following intravenous administration. Fresh whole blood contains all the components of blood, including packed red blood cells, platelets, and coagulation factors. It is typically used when animals suffer from large volume blood loss (.50% blood volume), require platelet therapy, or would benefit from all components of blood. However, following storage of fresh whole blood in the refrigerator, platelet function decreases due to clustering of the vWF receptors in response to reduced temperature, leading to increase clearance by hepatic macrophages.45 Plasma contains albumin, globulins, anticoagulants, and clotting factors and can be further stored and separated into several products (see Chapter 69, Transfusion Medicine). Available plasma products include fresh frozen plasma (FFP), frozen plasma, cryopoor plasma (CPP), cryoprecipitate (CRYO), human serum albumin (HSA), canine albumin, and intravenous immunoglobulin. FFP is plasma that has been separated from red blood cells and frozen within 8 hours of collection. FFP contains all of the coagulation factors, anticoagulants, alpha macroglobulins, albumin, fibrinogen, and fibronectin. If frozen for less than 1 year at less than or equal to 220˚C, it is considered FFP. If fresh plasma is frozen for more than a year (frozen plasma) or kept at room temperature for more than 8 hours, it loses its labile clotting factors (factors V and VIII). Frozen plasma contains clotting factors II, VII, IX, X and plasma proteins. Plasma is not an efficient colloid to increase COP, especially in large, hypoalbuminemic dogs; 22.5 ml/kg of plasma is necessary to increase the serum albumin by 0.5g/dl. In these situations, human or canine albumin may be a more logical, affordable, and effective choice (see section below). CRYO is created by slowly thawing and centrifuging FFP. The centrifuged supernatant is discarded, and the remaining solution (CRYO) contains vWF, factor VIII, fibrinogen, and fibronectin. The major indications for the use of CRYO is for the treatment of active hemorrhage secondary to von Willebrand disease or hemophilia A or prophylactically in affected patients prior to a surgical procedure. CPP is the supernatant removed after FFP has been centrifuged. CPP contains albumin, globulin, antithrombin, protein C, protein S, and factors II, VII, IX, and X. Culler et al. found that the mean albumin concentration and COP were highest in CPP compared with CRYO or FFP, with 3.17 g/dl albumin in CPP compared with 2.89 g/dl in FFP, 2.31 g/dl in CRYO, and 14.5 mm Hg in CPP compared with 12.73 mm Hg in FFP and 9.8 mm Hg in CRYO, respectively. This information suggests that CPP is a reasonable alternative to FFP for albumin replacement and oncotic support.46,47

Albumin Albumin makes up 70%–80% of COP within the body. Administration of HSA or canine serum albumin (CSA) has been used in the treatment of hypoalbuminemic veterinary patients that are susceptible to the development of interstitial edema. Disease states associated with hypoalbuminemia such as protein-losing nephropathy, protein-losing enteropathy, end-stage liver failure, malnutrition, and systemic inflammatory states are commonly encountered in veterinary medicine; however, the use of albumin therapy is generally limited to dogs or cats with acute, severe, and progressive hypoalbuminemia (,1.5 g/dl) due to a potentially treatable illness such as trauma, sepsis, or extensive surgical intervention. Hypoalbuminemia has been associated with increased morbidity and mortality in dogs and people hospitalized for treatment of critical illness as well as septic peritonitis.48 Albumin also plays an important role in wound healing; as an antioxidant, free-radical scavenger, and transport agent; and in preserving normal platelet function. Craft et al. investigated the use of CSA in dogs with septic peritonitis and observed an increased albumin concentration, COP, and Doppler blood pressure 2 hours after administration; albumin levels remained elevated

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24 hours post-albumin administration compared to nonalbumin treated dogs.49 The administration of intravenous albumin as a resuscitative fluid in critical veterinary patients is not well studied and remains controversial in human medicine. The SAFE study compared the administration intravenous 4% HSA versus 0.9% saline to human patients admitted to the ICU but did not find a decrease in 28-day mortality.50 Albumin dosage is calculated by determining the patient’s albumin deficit and delivering this volume over 6–12 hours: [albumin deficit (g) 5 10 3 0.3 3 BW (kg) 3 (desired albumin – patient albumin]. Alternatively, 2 ml/kg 25% HSA is administered IV over 2 hours followed by 0.1 to 0.2 ml/kg/hr for 10 hours, for a total dose of up to 2 g/kg.51 Alternatively, HSA has been evaluated in dogs and cats using a protocol that delivers a 5% albumin solution (via dilution with the preferred crystalloid) at 2 ml/kg/hour for a total dose of 10-20 ml/kg/day.52 Type I and type III hypersensitivity reactions have been observed in dogs after treatment with HSA. This is likely because HSA acts as foreign antigen and binds with circulating antibodies to form immune complexes in the blood; deposition of these complexes can then occur in arteries, glomeruli, and synovia. The classic histologic lesions associated with immune complex deposition is a leukocytoclastic vasculitis. Powel et al. described a type III hypersensitivity reaction with immune complex deposition in two critically ill dogs 8–16 days after administration of HSA.53 Repeat administration of HSA is not recommended due to the rapid development of anti-HSA antibodies. Mathews et al. reported that two animals received repeat 25% HSA transfusions several months apart but did not experience type I hypersensitivity reactions. It was not possible to observe the development of delayed reactions in these dogs as both animals were euthanized 2 days later for progressive illness.54 CSA is generally considered safer for use in dogs than HSA because it is less immunogenic, but further prospective studies are necessary.

CONCLUSION Critically ill animals require a specific fluid therapy strategy tailored to the individual’s fluid requirements based on the clinician’s assessment of the patient’s intravascular volume status, hydration parameters, ongoing losses, underlying disease processes, comorbidities, COP, and anticipated complications. HES is the most frequently utilized synthetic colloid administered in the veterinary profession. HES may be beneficial in animals with low COP, hypotension, and increased vascular permeability leading to interstitial edema and third spacing, although recent advances in our understanding of the endothelial glycocalyx and subglycocalyx space may change future colloid use. Synthetic colloids have been associated with coagulopathy and AKI in humans, and studies examining its potentially deleterious effects in companion animals are ongoing. Currently, there is no definitive evidence to suggest the type of HES or specified dose that may lead to coagulopathy or AKI in dogs and cats. This could be due to the vast differences across study populations, standardized treatment protocols, fluid type and dose administered, timing of fluid administration, and individual comorbidities. Synthetic colloids likely have speciesspecific variability in their effectiveness and adverse effects. Future large scale, prospective, controlled studies with standardized treatment protocols are recommended before a collective agreement can be reached regarding indications, optimal drug choice, and use of synthetic colloids.

REFERENCES 1. Woodcock TE, Woodcock TM: Revised Starling equation and the glycocalyx model of transvascular fluid exchange: an improved paradigm for prescribing intravenous fluid therapy, Br J Anaesth 108(3):384-394, 2012. 2. Chappell D, Jacob M: Role of the glycocalyx in fluid management: small things matter, Best Pract Res Clin Anaesthesiol 28(3):227-234, 2014.

3. Wong C, Koenig A: The colloid controversy: are colloids bad and what are the options? Vet Clin Small Anim 47(2):411-421, 2017. 4. Curry FR, Adamson RH: Vascular permeability modulation at the cell, microvessel, or whole organ level: towards closing gaps in our knowledge, Cardiovasc Res 87:218-229, 2010. 5. Cazzolli D, Prittie J: The crystalloid-colloid debate: consequences of resuscitation fluid selection in veterinary critical care, J Vet Emerg Crit Care 25(1):6-19, 2015. 6. Mathews K: Monitoring fluid therapy and complications of fluid therapy. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders in small animal practice, ed 3, St Louis, 2006, Elsevier. 7. Bumpus SE, Haskins SC, Kass PH: Effect of synthetic colloids on refractometric readings of total solids, J Vet Emerg Crit Care 8(1):21, 1998. 8. Griffel M, Kaufman BS: Pharmacology of crystalloid and colloids, Crit Care Clin 8(2):235-253, 1992. 9. Westphal M, James MF, Kozek-Langenecker S, et al: Hydroxyethyl starches: different products, different effects, Anesthesiology 111(1):187-202, 2009. 10. Glover PA, Rudloff E, Kirby R: Hydroxyethyl starch: a review of pharmacokinetics, pharmacodynamics, current products, and potential clinical risks, benefits, and use, J Vet Emerg Crit Care 24(6):642-661, 2014. 11. Liu DT, Silverstein DC: Crystalloids, colloids, and hemoglobin-based oxygen carrying solutions. In Silverstein DC, Hopper K, editors: Small animal critical care medicine, ed 2, Saunders Elsevier, 2014, pp 311-316. 12. Mizzi A, Tran T, Karlnoski R, et al: Voluven, a new colloid solution, Anesthesiol Clin 29:547, 2011. 13. Yacobi A, Gibson TP, McEntegart CM, et al: Pharmacokinetics of high molecular weight hydroxyethyl starch in dogs, Res Commun Chem Pathol Pharmacol 36:199-204, 1982. 14. Rioux JP, Lessard M, De Bortoli B, et al: Pentastarch 10% (250kDa/0.45) is an independent risk factor of acute kidney in- jury following cardiac surgery, Crit Care Med 37:1293-1298, 2009. 15. Richter AW, de Belder AN: Antibodies against hydroxyethyl- starch produced in rabbits by immunization with a protein- hydroxyetylstarch conjugate, Int Arch Allergy Appl Immunol 52(1-4):307–314, 1976. 16. Ring J, Messmer K: Incidence and severity of anaphylactoid reactions to colloid volume substitutes, Lancet 1:466-468, 1977. 17. Ring J: Anaphylactoid reactions to plasma substitutes, Int Anesthesiol Clin 23:67-95, 1985. 18. Huter L, Simon TP, Weinmann L, et al: Hydroxyethylstarch impairs renal function and induces interstitial proliferation, macrophage infiltration and tubular damage in an isolated renal perfusion model, Crit Care 13(1):R23, 2009. 19. Dickenmann M, Oettl T, Mihatsch MJ: Osmotic nephrosis: acute kidney injury with accumulation of proximal tubular lysosomes due administration of exogenous solutes, Am J Kidney Dis 51(3):491-503, 2008. 20. Baron JF: Adverse effects of colloids on renal function. In Vincent JL, editor: Yearbook of intensive care and emergency medicine, Berlin, 2000, Springer, pp 486-493. 21. Baron JF: Crystalloids versus colloids in the treatment of hypo-volemic shock. In Vincent JL, editor: Yearbook of intensive care and emergency medicine, Berlin, 2000, Springer, pp 443-466. 22. Schortgen F, Girou E, Deye N, et al: The risk associated with hyperoncotic colloids in patients with shock, Intensive Care Med 34:2157-2168, 2008. 23. Moran M, Kapsner C: Acute renal failure associated with elevated plasma oncotic pressure, N Engl J Med 317:150-153, 1987. 24. Gore DC, Dalton JM, Gehr TW: Colloid infusions reduce glomerular filtration in resuscitated burn victims, J Trauma 40:356-360, 1996. 25. Hayes G, Benedicenti L, Mathews C: Retrospective cohort study on the incidence of acute kidney injury and death following hydroxyethyl starch (HES 10% 250/0.5/5:1) administration in dogs (2007–2010), J Vet Emerg Crit Care 26:35-40, 2016. 26. Sigrist NE, Kalin N, Dreyfus A: Effects of hydroxyethyl starch 130/0.4 on serum creatinine concentration and development of acute kidney injury in nonazotemic cats, J Vet Intern Med 31:1749-1756, 2017. 27. Boyd CJ, Claus MA, Raisis AL, et al: Evaluation of biomarkers of kidney injury following 4% succinylated gelatin and 6% hydroxyethyl starch 130/0.4 administration in a canine hemorrhagic shock model, J Vet Emerg Crit Care 29:132-142, 2019.

CHAPTER 66  Colloid Solutions 28. Zersen KM, Mama K, Mathis JC: Retrospective evaluation of paired plasma creatinine and chloride concentrations following hetastarch administration in anesthetized dogs (2002–2015): 244 cases, J Vet Emerg Crit Care 29:309-313, 2019. 29. Diniz MS, Teixeira FJ, Celeita-Rodríguez N, et al: Effects of 6% tetrastarch and lactated Ringer’s solution on extravascular lung water and markers of acute renal injury in hemorrhaged, isoflurane-anesthetized healthy dogs, J Vet Intern Med 32:712-721, 2018. 30. Yozova ID, Howard J, Adamik KN: Retrospective evaluation of the effects of administration of tetrastarch (hydroxyethyl starch 130/0.4) on plasma creatinine concentration in dogs (2010-2013): 201 dogs, J Vet Emerg Crit Care 26(4):568-577, 2016. 31. Sigrist NE, Kalin N, Dreyfus A: Changes in serum creatinine concentration and Acute Kidney Injury (AKI) grade in dogs treated with hydroxyethyl starch 130/0.4 from 2013 to 2015, J Vet Intern Med 31:434-441, 2017. 32. Kozek-Langenecker SA: Effects of hydroxyethyl starch solutions on hemostasis, Anesthesiology 103:654-660, 2005. 33. Treib J, Haass A, Pindur G, et al: HES 200/0.5 is not HES 200/0.5. Influence of the C2/C6 hydroxyethylation ratio of hydroxyethyl starch (HES) on hemorheology, coagulation and elimination kinetics, Thromb Haemost 74:1452-1456, 1995. 34. Fenger-Eriksen C, Tønnesen E, Ingerslev J, et al: Mechanisms of hydroxyethyl starch-induced dilutional coagulopathy, J Thromb Haemost 7(7):1099-1105, 2009. 35. Stump DC, Strauss RG, Henriksen RA, et al: Effects of hydroxyethyl starch on blood coagulation, particularly factor VIII, Transfusion 25:349-354, 1985. 36. Treib J, Haass A, Pindur G, et al: Influence of low and medium molecular weight hydroxyethyl starch on platelets during a long- term hemodilution in patients with cerebrovascular diseases, Arzneimittelforschung 46:10641066, 1996. 37. Franz A, Braunlich P, Gamsjager T, et al: The effects of hydroxyethyl starches of varying molecular weights on platelet function, Anesth Analg 92:1402-1407, 2001. 38. Deusch E, Gamsjager T, Kress HG, et al: Binding of hydroxyethyl starch molecules to the platelet surface, Anesth Analg 97:680-683, 2003. 39. Jin SL, Yu BW: Effects of artificial colloids on haemostasis, Br J Hosp Med 70:101-103, 2009. 40. Omar MN, Shouk TA, Khaleq MA: Activity of blood coagulation and fibrinolysis during and after hydroxyethyl starch (HES) colloidal volume replacement, Clin Biochem 32:269-274, 1999.

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41. Strauss RG, Pennell BJ, Stump DC: A randomized, blinded trial comparing the hemostatic effects of pentastarch versus hetastarch, Transfusion 42:27-36, 2002. 42. Nielsen VG: Colloids decrease clot propagation and strength: role of factor XIII-fibrin polymer and thrombin-fibrinogen interactions, Acta Anaesthesiol Scand 49:1163-1171, 2005. 43. Nielsen VG: Hemodilution modulates the time of onset and rate of fibrinolysis in human and rabbit plasma, J Heart Lung Transplant 25:13441352, 2006. 44. Nielsen VG: Effects of Hextend hemodilution on plasma coagulation kinetics in the rabbit: role of factor XIII-mediated fibrin polymer crosslinking, J Surg Res 132:17-22, 2006. 45. Davidow B: Transfusion medicine in small animal, Vet Clin North Am Small Anim Pract 43:735-756, 2013. 46. Culler CA, Iazbik C, Guillaumin J: Comparison of albumin, colloid osmotic pressure, von Willebrand factor, and coagulation factors in canine cryopoor plasma, cryoprecipitate, and fresh frozen plasma, J Vet Emerg Crit Care 27(6):638-644, 2017. 47. Culler CA, Balakrishnan A, Yaxley P, Guillaumin J: Clinical use of cryopoor plasma continuous rate infusion in critically ill, hypoalbuminemic dogs, J Vet Emerg Crit Care 29:314-320, 2019. 48. Bentley AM, Otto CM, Shofer FS: Comparison of dogs with septic peritonitis: 1988–1993 versus 1999–2003, J Vet Emerg Crit Care 17(4):391-398, 2007. 49. Craft EM, Powell LL: The use of canine specific albumin in dogs with septic peritonitis, J Vet Emerg Crit Care 22(6):631-639, 2012. 50. The SAFE Study Investigators: A comparison of albumin and saline for fluid resuscitation in the intensive care unit, N Engl J Med 350:2247, 2004. 51. Balakrishnan A, Silverstein DC: Shock fluids and fluid challenge. In Silverstein DC, Hopper K, editors: Small animal critical care medicine, ed 2, Saunders Elsevier, 2014, 382-400. 52. Viganó F, Perissinotto L, Bosco VRF: Administration of 5% human serum albumin in critically ill small animal patients with hypoalbuminemia: 418 dogs and 170 cats (1994-2008). J Vet Emerg Crit Care 20(2):237–243, 2010. 53. Powell C, Thompson L, Murtaugh RJ: Type III hypersensitivity reaction with immune complex deposition in 2 critically ill dogs administered human serum albumin, J Vet Emerg Crit Care 23(6):598-604, 2013. 54. Mathews KA, Barry M: The use of 25% human serum albumin: outcome and efficacy in raising serum albumin and systemic blood pressure in critically ill dogs and cats, J Vet Emerg Crit Care 15(2):110-118, 2005.

67 Daily Intravenous Fluid Therapy Natalie Kovak, DVM, DACVECC, Deborah C. Silverstein, DVM, DACVECC

KEY POINTS • Daily intravenous fluids are used to provide replacement of fluid deficits, maintenance fluid, and electrolytes, as well as replace ongoing losses. • The hydrostatic and oncotic pressures within the intracellular and extracellular compartments, as well as the vascular endothelial permeability and plasma osmolality, determine the movement of fluid in the body. • The most common fluid types for daily intravenous fluid administration include isotonic crystalloids, hypotonic crystalloids, synthetic colloids, and free water solutions.

• A tailored daily fluid therapy plan should be developed for individual patients, with frequent reevaluation and modification based on patient response, physical exam, and clinical laboratory changes. • Possible complications associated with fluid therapy include interstitial edema, including pulmonary edema, and electrolyte imbalances.

Intravenous fluid therapy is vital in critically ill small animal patients for the management of daily maintenance fluid requirements and the treatment of several disorders including cardiovascular shock and interstitial dehydration (see Part VI, Fluid Therapy). This chapter focuses on the distribution of total body water, patient assessment of fluid therapy needs, and the delivery of synthetic intravenous fluids in order to maintain normal water, electrolytes, and acid-base status in hemodynamically stable critically ill dogs and cats. Patients in the ICU often have variable fluid intake, ongoing fluid losses, and electrolyte and acid-base derangements; thus, therapy is dependent on early recognition and appropriate treatment of these abnormalities in addition to the diagnosis and treatment of the underlying disease processes.

all cell membranes is the Na1/K1-ATPase pump, which is responsible for maintaining the normal electrochemical gradient across cell membranes. The pump extrudes three sodium ions from the cell in exchange for two potassium ions pumped into the cell. This creates a high intracellular concentration of potassium, high extracellular concentration of sodium, and a negative resting membrane potential. Thus, the major cation of the ICF is potassium with smaller contributions made by magnesium and sodium. The major anions of the ICF are phosphates and the polyanionic charges of intracellular proteins.1,2 The ECF is located outside of the cells and contributes to one-third (33%) of total body water and one-fifth (20%) of body weight. It is further subdivided into the interstitial (75% of ECF) and intravascular (25% of ECF) fluid compartments. The interstitial fluid bathes all cells and allows for the movement of ions, proteins, and nutrients across cell membranes. The intravascular fluid compartment allows for the movement of blood cells, proteins, ions, and other nutrients to tissues throughout the body. The major cation of the ECF is sodium, and the major anions include chloride and bicarbonate.1,2 See Chapter 63, Assessment of Hydration for further discussion of this topic.

TOTAL BODY WATER All living organisms are mostly composed of water. Total body water content comprises 60% of the total body weight in a nonobese adult dog or cat. Neonatal dogs and cats (,12 weeks of age) have higher extracellular fluid on a volume per kilogram basis and thus higher total water content (approximately 80%) compared with adult animals. Total body water is distributed between two main compartments: intracellular fluid (ICF) and extracellular fluid (ECF) (Fig. 67.1). Each compartment is composed of solutes, mainly electrolytes, dissolved in water. The quantity of solutes within each compartment is the major determinant of the size of the body fluid compartments.1-3 The ICF compartment comprises approximately two-thirds (66%) of the total body water and two-fifths (40%) of the body weight. This compartment is separated from the ECF by a semipermeable cell membrane that is very permeable to water but impermeable to most solutes. The most important active solute pump located on

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MOVEMENT OF FLUIDS WITHIN THE BODY The movement of fluids between compartments is important for the exchange of nutrients and removal of cellular waste products. Water moves freely between the intracellular and extracellular compartments primarily according to the differences in osmotic pressure. Electrolytes and other small molecules can move freely between the intravascular and interstitial compartments, but they require a special transport system (i.e., a protein channel) in order to enter or leave the intracellular compartment. Changes in osmolality between the extracellular and

CHAPTER 67  Daily Intravenous Fluid Therapy

ECF (33% TBW) P L A S M A

Interstitial fluid

ICF (66% TBW) Intracellular fluid

Fig. 67.1  The distribution of total body water (TBW ). ECF, extracellular fluid; ICF, intracellular fluid.

intracellular compartments will cause free water movement across the cellular membrane. Larger molecules (.10–20,000 Daltons) do not readily cross the vascular endothelium and are responsible for generating a colloid osmotic pressure (COP) on either side of the vascular wall. The three main natural colloid agents include: albumin, globulins, and fibrinogen. An increase in the pressure of a fluid within the intravascular or interstitial fluid compartment is known as the hydrostatic pressure. Classically, fluid distribution within the ECF compartment has been described using the traditional Starling model, which describes the balance between interstitial and intravascular hydrostatic and oncotic pressures in conjunction with the reflection coefficient of the vascular barrier. More recent research describing the role of the glycocalyx layer located on the luminal surface of the endothelium has resulted in the development of a newer revised Starling model (see Chapters 11 and 185, Interstitial Edema and Colloid Osmotic Pressure and Osmolality, respectively). The revised model takes into account the influence of the endothelial glycocalyx layer and its role in transvascular fluid flux and pressure gradients. This model subsequently suggests that the effects of interstitial oncotic pressure on fluid balance are negligible; rather the oncotic pressure gradient between the intravascular lumen and subglycocalyx layer determines the balance of COP forces between the intravascular and extravascular compartment. In many disease states, patients are at risk for dehydration with both increased fluid losses or reduced fluid intake. The subsequent changes in osmolality are determined by the nature of the fluid loss (hypotonic, isotonic, or hypertonic). Additionally, the endothelial glycocalyx may be damaged secondary to diseases such as systemic inflammation, sepsis, ischemic reperfusion injury, and volume overload, thus contributing to an abnormal fluid balance. See Chapter 63, Assessment for Hydration for further discussion on this topic.

Hypotonic Fluid Loss Hypotonic fluid loss is defined as a loss of fluid with a lower osmolality than that of the ECF, resulting in a hypertonic dehydration and hypernatremia. This leads to fluid shifting from the ICF space to the ECF space, and consequently, the fluid depletion is shared by both compartments. Examples of possible etiologies include diabetes insipidus, hypotonic third spacing of fluids, and excessive panting. Treatment of dehydration with isotonic crystalloid fluid therapy may be sufficient; however, animals with significant hypotonic losses may require hypotonic or free water administration. Careful attention must be made to avoid rapid reductions in serum sodium concentrations to avoid the development of cerebral edema (see Chapter 55, Sodium Disorders).

Isotonic Fluid Loss Isotonic fluid loss is defined as a loss of fluid with an equal osmolality to that of the ECF, resulting in an isotonic dehydration. Causes of isotonic fluid loss include hemorrhage, polyuric renal failure, vomiting, isotonic third space losses, or diarrhea. Because the ECF osmolality remains the same, there is no stimulus for fluid to shift from the ICF space to the ECF

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space, thus the ICF volume remains the same. If severe ECF losses are not replaced, clinically apparent hypovolemia and hypoperfusion will develop. Replacement of isotonic fluid losses are best accomplished with administration of isotonic crystalloids (see Chapter 65 and 68, Crystalloid Solutions and Shock Fluid Therapy, respectively).

Hypertonic Fluid Loss Hypertonic fluid loss is defined as a loss of fluid resulting in hypotonic depletion. Rather than direct loss of hypertonic fluid, clinically this is more likely to occur with the combination of isotonic or hypotonic fluid loss and concomitant free water ingestion and retention that occurs in response to hypovolemia. Hypertonic fluid loss occurs infrequently in small animals; however, it may be observed in conditions such as hypoadrenocorticism, diuretic administration, and some causes of third space losses (pleural effusion and peritoneal effusion). A hypertonic fluid loss results in decreased ECF osmolality, which provides a gradient for water to move into the ICF space and ultimately causes cellular swelling. In cases of significant hyponatremia or hypoosmolality, careful attention to fluid administration should be performed to avoid rapid changes in serum sodium concentration and subsequent osmotic demyelination syndrome (see Chapter 55, Sodium Disorders).

Increased Vascular Permeability Leakage of high-protein fluid from the intravascular space into the interstitial compartment may occur secondary to increased vascular permeability. This fluid loss will not alter the osmolality of the ECF; thus, it has minimal to no effect on ICF volume. A thorough patient history, physical examination, and evaluation of laboratory data will provide important information regarding the route and type of fluid loss, timeline of losses, and severity of the patient’s clinical condition. This will guide formulation of an individualized and appropriate fluid therapy plan.

FLUID THERAPY PLAN Developing a tailored daily fluid therapy plan is essential for all critically ill patient with dehydration, inadequate fluid intake, or evidence of ongoing fluid losses, in addition to providing maintenance fluid needs. The appropriate fluid type, volume, and rate of administration are determined by physical examination findings and laboratory data. Patients with signs of chronic dehydration that are otherwise hemodynamically stable should have fluid deficits replaced over 4 to 24 hours depending on the severity of dehydration and the patient’s risk for hypervolemia or other complications. Isotonic crystalloids should be administered for replacement of fluid deficits based on the estimated level of dehydration, as well as maintenance requirements and anticipated or measured ongoing losses. The most common reasons for calculation errors when developing a fluid therapy plan are inappropriate estimation of a patient’s level of dehydration, larger losses than anticipated, and increased insensible losses (panting, fever, polyuria). To determine the volume of fluids needed for a hemodynamically stable patient with evidence of dehydration, the following formula should be used: [body weight (kg)  1000]  [percentage dehydration/100]  deficit (ml)  estimated ongoing losses (ml)  volume to be administered over the next 4 to 24 hours in addition to hourly maintenance rate (ml)

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Fluid Deficit A perfect method for measuring a patient’s level of dehydration or volume deficit does not exist; thus, multiple tools (clinical signs, physical examination, laboratory data) must be utilized to closely determine a patient’s replacement needs (see Chapter 63, Assessment of Hydration). Fluid deficits will result in different clinical signs depending on the fluid compartment affected. ICF deficits may result in signs of cerebral obtundation, hypernatremia and hyperosmolality, and clinical examination findings of dehydration will be evident if significant ECF losses also occur. Interstitial volume deficits typically result in clinical evidence of dehydration such as decreased skin turgor and dry mucous membranes. Note that skin turgor can be an inaccurate estimate of patient hydration status depending on body condition and age. Serial body weights can be used as a more objective measurement of dehydration in hospitalized patients. Intravascular volume deficits will cause clinical signs of hypovolemia and hypoperfusion, the severity of which depends on the duration and severity of intravascular volume loss. Signs often include decreased mentation, compensatory tachycardia (or bradycardia in cats), vasoconstriction, pale mucous membranes, poor pulse quality, prolonged capillary refill time, and cool extremities. These signs are suggestive of poor tissue perfusion and more rapid resuscitation is required. Further discussion on fluid resuscitation can be found in Chapter 69, Shock Fluid Therapy.

Maintenance Fluid Therapy The goal of maintenance fluid therapy in critically ill patients is to provide water and major electrolytes to replace the physiologic losses that occur through urine, feces, and evaporation. Maintenance fluids are commonly administered in conjunction with replacement fluids or following replacement of fluid deficits. Water and electrolyte maintenance requirements vary greatly depending on age, species, body condition, sex, activity, season, gestation, lactation, and other factors. Additionally, a patient’s disease process and the dynamic nature of critical illness can alter the maintenance fluid requirements substantially. Research in dogs and cats has demonstrated that daily maintenance fluid requirements are likely proportional to resting energy requirements at a rate of 1 kcal of energy 5 1 ml of water.4,5 The resting energy requirement (RER) is the amount of energy (or water) needed to maintain normal homeostatic functions while a patient is at rest, expelling no additional energy, in a fed state and thermoneutral environment. The recommended formula to calculate the RER and hence daily fluid requirement is as follows: 70*(BWkg )0.75/24 h = ml of maintenance fluids per hour Multiple alternative formulas are available; however, the author suggests this formula as the most accurate to account for alterations in body surface area and lean body mass as seen in very small animals (,2 kg) and large animals (.40 kg). Although 2–4 ml/kg/hr is commonly used, this may overestimate the fluid requirements, especially in obese or large/giant breed dogs. Frequent physical examinations and reassessments are imperative to maintain appropriate daily fluid administration in critically ill patients, especially when clinical status is regularly changing in a hospital environment. For example, previously anorexic patients that begin eating and drinking will require adjustments in their fluid therapy plan. Although maintenance fluid requirements are typically hypotonic, both isotonic and hypotonic crystalloid fluids may be appropriate choices for maintenance fluid therapy. More recent evidence in human medicine may suggest an association between iatrogenic hyponatremia and the use of hypotonic fluid administration, especially in hospitalized

pediatric patients; thus, more balanced replacement fluids may be desirable for maintenance of hydration.6 Ultimately, the appropriate crystalloid type should be chosen based on the patient’s volume/hydration status, changes in serum electrolytes concentrations, and anticipated ongoing losses.

Ongoing Losses Ongoing losses, such as through vomiting, diarrhea or hemorrhage, should be considered a part of the fluid therapy prescription for any critically ill patient. These losses are estimated based on knowledge of the underlying disease process and historical data. A predicted volume and frequency of losses is generated and incorporated into an initial fluid therapy plan; however, close monitoring and reevaluation of the patient is important. Significant changes from the estimated ongoing losses should be noted and adjustments made to the fluid therapy plan accordingly.

Route of Administration Common routes of fluid administration include intravenous, subcutaneous, and intraosseous (see Chapters 193, 194, and 195, Peripheral Venous Catheterization, Intraosseous Catheterization, and Central Venous Catheterization, respectively). Subcutaneous fluid therapy may be appropriate in certain cases to replace mild fluid deficits; however, this route of administration is not adequate for most ICU patients. Hospitalized critically ill patients should receive fluids via an intravenous or intraosseous catheter. Intraosseous catheters are most commonly utilized in patients with poor or difficult venous access, as seen in severely vasoconstricted patients or very small patients such as neonates. In general, fluids with an osmolality of less than 500–600 mOsm/L can be administered safely through a peripheral venous catheter, but those greater than 700 mOsm/L or drugs with a pH ,5 or .9 should be administered through a central venous catheter due to the increased risk for phlebitis and thrombosis. Peripheral catheter insertion sites should be monitored at least every 24 hours for evidence of phlebitis or inadvertent subcutaneous administration.

FLUID TYPE The type of fluid administered for daily fluid therapy is dependent on multiple patient factors. The general fluid choice options for ICU patients include isotonic replacement fluids, hypotonic maintenance fluids, free water solutions, and synthetic colloids.

Replacement Fluids (see also Chapter 65, Crystalloid Solutions) Replacement fluids, otherwise known as isotonic crystalloids, are electrolyte-containing solutions with an osmolality similar to that of normal plasma (290–310 mOsm/L).9,10 Balanced isotonic crystalloids have a similar electrolyte composition to that of the normal ECF compartment, while unbalanced isotonic crystalloids (e.g., 0.9% sodium chloride) contain only certain electrolytes such as sodium and chloride. Since sodium has the largest effect on the osmolality of the extracellular fluid, the patient’s serum sodium concentration should be taken into account when choosing a replacement fluid. Balanced crystalloids contain buffers that aid in the resolution of metabolic acidosis while isotonic saline is considered an acidifying fluid, indicated for the treatment of metabolic alkalosis. Both replacement fluids and maintenance fluids can be supplemented with additional electrolytes, such as potassium, if needed. Isotonic crystalloids are commonly used to expand the intravascular space and interstitial space as well as to maintain hydration. Approximately one-third of administered isotonic crystalloids will remain in

CHAPTER 67  Daily Intravenous Fluid Therapy the intravascular space and two-thirds will disperse into the interstitial space 30 minutes after administration. Although these solutions are considered replacement fluids, they are commonly used in hospital settings for maintenance fluid therapy because many critically ill patients have ongoing losses and poor enteral intake; excess electrolytes are typically excreted. The previously outlined formula should be referenced for calculating the rate of administration of isotonic crystalloids. The different constituents of the commonly used isotonic crystalloids can be found in Table 65.1. Isotonic saline (0.9% NaCl) contains a higher concentration of sodium and chloride than the normal dog or cat blood (154 mEq/L of each), and administration may cause a proportional increase in these electrolytes. Thus, large volumes of 0.9% NaCl may result in a mild increase in serum sodium, marked increase in serum chloride, and moderate decreases in serum potassium and bicarbonate. Rapid infusions of 0.9% NaCl may cause a hyperchloremic metabolic acidosis. Normal functioning kidneys should be able to compensate by excreting excess electrolytes and conserving potassium. The other commonly used isotonic crystalloids (lactated Ringer’s solution [LRS], Plasma-Lyte 148, Normosol-R) contain potassium concentrations similar to that of normal plasma. Certain clinical situations may benefit from the use of one type of isotonic crystalloid over another. For example, patients with excessive vomiting often have metabolic derangements resulting in a hypochloremic metabolic alkalosis and may benefit from 0.9% NaCl administration because it contains the highest chloride concentration. Additionally, animals with diabetic ketoacidosis or severe liver dysfunction or failure should preferentially not be administered LRS because of their decreased ability to metabolize the additional lactate into bicarbonate in the liver. However, LRS may be the fluid of choice for neonates because lactate is the preferred metabolic fuel in hypoglycemic young animals. Isotonic saline should be considered in patients with head trauma or increased intracranial pressure because its higher osmolality may reduce the risk of a decrease in plasma osmolality and subsequent water shift into the brain. As with any fluid therapy, inappropriately high volumes and/or rates or inadequate monitoring of fluid therapy can prove harmful. Hypervolemia, as well as hemodilution of blood constituents, may occur with large-volume administration. Volume overload is common in critically ill animals secondary to excessive fluid administration combined with the physiologic impairment of sodium and water excretion. The stress response of critical illness commonly results in increased sympathetic nervous system outflow and activation of the renin-angiotensin-aldosterone system, leading to vasoconstriction and sodium and water retention. Additionally, disease processes such as acute kidney injury or cardiac disease will affect normal fluid homeostasis or tolerance, respectively, and contribute to the risk of volume overload. Other factors that predispose patients to complications of edema include decreased mobility, which impairs lymphatic drainage and increased capillary permeability as a consequence of systemic inflammation. Interstitial edema causes increased morbidity and complications, including impaired pulmonary gas exchange, decreased renal function, decreased intestinal motility, reduced tissue oxygenation, and increased surgical infection rates.6 The importance of monitoring patients closely for early signs of fluid overload and adjusting fluids accordingly is of utmost importance for these reasons.

Maintenance Fluids (see also Chapter 65, Crystalloid Solutions) Maintenance fluids more closely represent the volume of water and electrolytes necessary to maintain normal fluid and electrolyte homeostasis. Conventional maintenance fluids, otherwise known as hypotonic

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crystalloids, are solutions lower in sodium, chloride, and osmolality but higher in potassium concentration compared with the normal ECF compartment (Table 65.2). These solutions are formulated to replace the normal physiologic losses of sodium and are appropriate for long-term fluid administration. As stated earlier, isotonic crystalloids are often used for maintenance in addition to replacement fluid therapy for simplicity rather than preparing two different fluid bags for each patient. The rate and choice of maintenance fluids should be continuously evaluated and adjusted based on frequent patient assessments and changes in fluid losses or electrolyte status. In patients with impaired renal function, the risk of volume overload and associated complications must be considered when developing a maintenance fluid plan. The clinician should also note that drug infusions and enteral or parenteral nutrition will provide additional volume that should be taken into account when calculating the fluid plan. Maintenance fluids should never be administered as rapid bolus infusions due to the risk of acute life-threatening decreases in the serum osmolality.

Free Water Administration (see also Chapter 56, Sodium Disorders) Patients with a free water deficit (i.e., hypernatremia) or ongoing losses of free water (i.e., diabetes insipidus) require replacement of this deficit with free water administration (fluids containing no electrolytes or buffers). However, because free water by itself is dangerously hypotonic (0 mOsm/kg) and administration will cause hemolysis, sterile water is combined with dextrose to make a 5% concentration (D5W) with an osmolality of approximately 252 mOsm/kg (safe for intravenous administration). The dextrose in this solution is rapidly metabolized to carbon dioxide and water. The following formula is used to calculate a patient’s free water deficit: Free water deficit (L)  ([patient [Na] ÷ normal [Na]] – 1)  (0.6  body weightkg ) This formula gives the total volume of free water that should be administered to return the sodium concentration to normal. Replacement of the free water deficit should be performed at a rate to safely lower the sodium concentration and frequent monitoring of electrolytes is important (see Chapter 55, Sodium Disorders). Free water administration alone will not correct clinical dehydration or provide adequate maintenance requirements, thus D5W or other sources of free water should be administered along with a crystalloid solution. Additionally, D5W should never be administered as a rapid bolus infusion because acute decreases in serum osmolality can cause potentially fatal cerebral edema.

Synthetic Colloids (see also Chapter 66, Colloid Solutions) Colloid solutions are large hydrophilic molecules (.10,000 Daltons) that do not readily cross the vascular endothelium and result in a volume-sparing effect by increasing intravascular COP. Because these solutions are polydisperse (contain molecules with a variety of molecular weights suspended in an isotonic crystalloid) and hyperoncotic compared with normal plasma, they cause movement of fluid from the extraluminal to the intraluminal vascular space (likely from the subglycocalyx compartment to the vascular lumen based on the modified Starling’s formula). Colloids result in an increased blood volume greater than the infused volume in the presence of an intact vascular barrier and increase the duration of retention of fluids in the vascular space compared to crystalloids. The most common synthetic colloid solutions are made from hydroxyethyl starch (HES), with hetastarch and tetrastarch being the most widely used in veterinary medicine. For

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specific details regarding the composition, use, and effects of these synthetic colloids please refer to Chapter 66, Colloid Solutions. Research in human medicine has shown that HES causes platelet dysfunction, enhanced fibrinolysis, factor VIII dysfunction, and decreased concentration of von Willebrand factor. Several multicenter randomized controlled studies on the use of synthetic colloids in critically ill humans have identified an increased risk of acute kidney injury (AKI), need for renal replacement therapy, and mortality. Although there is criticism surrounding the data derived from these studies, the nature of the findings has led to implementation of a “black box” warning in 2013 by the US Food and Drug Administration for the use of synthetic colloids in people with renal insufficiency, sepsis, or coagulopathy. Whether HES causes an increased risk for AKI in veterinary species remains unclear at this time; however, as similar pathophysiology can occur, it is prudent to consider the possibility of HES causing renal damage in animals, especially in patients with impaired renal function or those already at higher risk for AKI.10,11 Studies in veterinary medicine of HES administration in dogs have revealed dose-dependent impairment of coagulation times, platelet function, and thromboelastographic parameters. However, further studies to evaluate the clinical significance of these findings are needed. Synthetic colloids are typically used in combination with isotonic crystalloids to maintain adequate vascular volume expansion and COP with lower interstitial fluid volume expansion. Constant rate infusions are commonly used at 0.5–2 ml/kg/hr in patients with acute decreases in COP or total protein levels.14,15 Research suggests that HES is most effective when utilized in hypovolemic patients with intact vascular barriers and administered as bolus therapy in combination with crystalloids for intravascular volume support. Standard bolus infusions are in 2–5 ml/kg increments and titrated to effect (see Chapter 66, Colloid Solutions).

several factors affect this measurement that are unrelated to intravascular volume (see Chapter 181, Hemodynamic Monitoring). Additional tools that may be helpful in monitoring patients receiving intravenous fluid therapy include invasive or noninvasive arterial blood pressure, electrocardiogram, and serial measurements of electrolytes, blood glucose, and acid-base status.

DISCONTINUATION OF FLUID THERAPY There is a dearth of evidence to guide discontinuation of fluid therapy, but general guidelines have suggested that the clinician use clinical judgement based on the status and oral intake of the patient. There is some published and clinical evidence to support weaning from high rates of fluid therapy in people and animals with postobstructive diuresis; a more abrupt discontinuation of fluids is not deleterious in most patients, and slower weaning practices may prolong hospitalization.17,18,19 In conclusion, fluid therapy is an essential component of the complete treatment plan for most critically ill patients. An understanding of the body’s fluid compartments and the distribution of various fluid types is essential. Intravenous fluid therapy should be used to provide replacement of fluid deficits and maintenance of normal water, electrolyte, and acid-base status. The fluid therapy plan must be tailored to the individual’s hydration status, maintenance needs, anticipated ongoing losses, underlying disease processes, and laboratory abnormalities. Judicious monitoring of patients is vital to ensure adequate fluid therapy plan as well as avoid complications associated with fluid overload. Finally, weaning from fluid therapy may benefit select patients, but is not well studied.

ACKNOWLEDGEMENTS A special acknowledgement from the authors is made to Kari SantoroBeer, DVM, DACVECC, for her previous contributions to this chapter.

MONITORING All animals receiving intravenous fluid therapy require close monitoring. Critically ill patients should have a thorough physical examination performed at least twice daily to evaluate mentation, mucous membrane color and hydration, capillary refill time, skin turgor, heart rate, pulse quality, respiratory rate and effort, and body temperature (including extremities). Serial auscultation of the thorax to evaluate for increased breath sounds, crackles, wheezes, or abnormal heart sounds such arrhythmias or a new heart murmur should be performed. Additionally, body weight should be checked at least once daily or more, if indicated. Clinical signs of fluid overload may include serous nasal discharge, chemosis, jugular venous distention, and interstitial pitting edema. Signs of pulmonary edema will typically start with increased respiratory rate and/or effort, followed by crackles and later dyspnea. See Chapters 63 and 64, Assessment of Hydration and Assessment of Intravascular Volume, respectively, for further information. Other more objective measurements can be utilized to ensure appropriate fluid therapy is being provided. Urine output (UOP) should be compared with administered fluid volumes to evaluate a patient’s fluid needs. This is most accurately assessed in patients with indwelling urinary catheters, although weighing soiled diaper pads is a practical option. Normal UOP is 1–2 ml/kg/hr. Monitoring of serum blood urea nitrogen and creatinine, serial measurement of packed cell volume and total protein, and blood lactate levels may help guide fluid therapy. Patients receiving synthetic colloids will have altered total protein and urine specific gravity readings when using a refractometer. Central venous pressure, monitored in patients with a central venous catheter, measures right atrial pressure, and changes may correlate with effective circulating blood volume and preload, although

REFERENCES 1. Greco DS: The distribution of body water and general approach to the patient, Vet Clin North Am Small Anim Pract 28:473, 1998. 2. Guyton AC, Hall JE: Functional organization of the human body and control of the “internal environment.” In Guyton AC, Hall JE, editors: Textbook of medical physiology, ed 11, Philadelphia, 2005, Saunders. 3. Lee JA, Cohn LA: Fluid therapy for pediatric patients, Vet Clin Small Anim 47:375, 2016. 4. Holliday MA, Segar WE: The maintenance need for water in parenteral fluid therapy, Pediatrics 19:823-832, 1957. Pediatrics. 1998 Jul;102(1 Pt 2): 229-30. 5. National Research Council (NRC): Nutrient requirements of dogs and cats, Washington, DC, 2006, National Academies Press. 6. Byers C: Fluid therapy: options and rational selection, Vet Clin Small Anim 47:359-371, 2017. 7. Hansen B, Vigani A: Maintenance fluid therapy, isotonic versus hypotonic solutions, Vet Clin Small Anim 47:383-395, 2017. 8. Abrams JT: The nutrition of the dog. In Rechcigl M, editor: CRC handbook series in nutrition and food. Section G: diets, culture media and food supplements, Boca Raton, FL, 1977, CRC Press, p 1. 9. Haskins SC: A simple fluid therapy planning guide, Semin Vet Med Surg (Small Anim) 3:227, 1988. 10. DiBartola SP: Fluid, electrolyte and acid-base disorders in small animal practice, ed 4, St Louis, 2012, WB Saunders. 11. Hayes G, Benedicenti L, Mathews K: Retrospective cohort study on the incidence of acute kidney injury and death following hydroxyethyl starch (HES 10% 250/0.5/5:1) administration in dogs (2007-2010), J Vet Emerg Crit Care 26(1):35, 2016. 12. Brooks A, Thomovsky E, Johnson P: Natural and synthetic colloids in veterinary medicine, Top Companion Anim Med 31:54-60, 2016.

CHAPTER 67  Daily Intravenous Fluid Therapy 13. Mathews KA: The various types of parenteral fluids and their indications, Vet Clin North Am Small Anim Pract 28:483, 1998. 14. Griffel MI, Kaufman BS: Pharmacology of colloids and crystalloids, Crit Care Clin 8:235, 1992. 15. Rudloff E, Kirby R: Fluid therapy. Crystalloids and colloids, Vet Clin North Am Small Anim Pract 28:297, 1998. 16. Kirby R, Rudloff E: The critical need for colloids: maintaining fluid balance, Comp Cont Educ Pract Vet 19:705, 1997. 17. Frohlich L, Hartmann K, Sautter-Louis C, Dorsch R: Postobstructive diuresis in cats with naturally occurring lower urinary tract obstruction:

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incidence, severity and association with laboratory parameters on admission, J Feline Med Surg 18(10):809-817, 2016. 18. Roth JD, Lesier JD, Casey JT, et al: Incidence of pathologic postobstructive diuresis after resolution of ureteropelvic junction obstruction with a normal contralateral kidney, J Pediat Urol 14(6):557.e1-557.e6, 2018. 19. Otto AM: IV fluid weaning unnecessary after gastroenteritis rehydration, HM20 Virtual Conference in Review, Aug. 6, 2019.

68 Shock Fluids and Fluid Challenge Anusha Balakrishnan, BVSc, DACVECC, Deborah C. Silverstein, DVM, DACVECC

KEY POINTS • Several treatment options are available for the rapid reversal of hypovolemic shock, including crystalloids, synthetic colloids, albumin, hypertonic saline, and blood products. • Shock fluids are best administered by intravenous or intraosseous routes. • Isotonic crystalloids are typically the first choice for shock resuscitation but can cause interstitial and pulmonary edema. • Synthetic colloids may be beneficial in hypooncotic states but can cause coagulopathies and potentially acute kidney injury in higher doses.

Fluid therapy is one of the mainstays of treatment in emergency and critical care medicine. Shock is a condition commonly seen in patients presenting to the emergency room as well in a large proportion of dynamic critically ill patients. Shock is defined as an inadequate production of energy at the cellular level (see Chapter 6, Pathophysiology and Mechanisms of Shock). This usually occurs secondary to decreased delivery of oxygen and nutrients to tissues. Shock can occur secondary to an absolute decrease in the intravascular circulating volume (hypovolemic shock), a marked decrease in oxygen content in the blood (e.g., severe anemia or hypoxemia), maldistribution of the intravascular circulating volume secondary to widespread vasoconstriction or vasodilation (causing a relative hypovolemia, e.g., anaphylaxis or systemic inflammatory response syndrome), or because of cardiac pump failure (cardiogenic shock). A variety of metabolic causes for shock have also been identified, including hypoglycemia, various toxin exposures, and cytopathic hypoxia. The treatment of shock aims to improve tissue perfusion and restore optimal oxygen and nutrient delivery to tissues. In animals with shock secondary to an absolute or relative decrease in the effective circulating intravascular volume, such as in hypovolemic or distributive shock, IV fluid therapy is the cornerstone of management. Various factors should be taken into consideration while administering IV fluid therapy for the treatment of shock, including timing; volume and rate of fluid administration; and safety, efficacy, and cost-effectiveness of the fluids. In recent years there has been an ongoing debate in the medical field regarding the optimal type of fluid for shock therapy, with a growing body of evidence suggesting that certain types of fluids may influence outcome in specific conditions such as trauma, sepsis, or septic shock. Regardless, it has been shown that rapid normalization of blood pressure in hypotensive, emergent dogs is associated with a greater survival-to-discharge rate.1

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• Albumin and blood products (packed red blood cells, fresh frozen plasma, and fresh whole blood) are other options available for shock resuscitation in certain conditions. • Performing a fluid challenge is a useful tool to help guide therapeutic decisions during resuscitation in hemodynamically unstable patients.

ADMINISTRATION OF SHOCK FLUIDS Shock fluids are best administered intravenously, when possible. This is easily accomplished in patients that are already hospitalized and have adequate vascular access. However, patients that present to the emergency room in a state of shock typically lack vascular access. Under these circumstances, establishing venous access can be extremely challenging. When possible, cephalic or saphenous venous access is quickly obtained by placement of the largest gauge, shortest length IV catheter that is appropriate for that particular patient (see Chapter 193, Peripheral Venous Catheterization). If rapid, large-volume shock fluid administration is necessary (e.g., large breed dogs with severe hypovolemic shock secondary to acute gastric dilation-volvulus), multiple large-bore peripheral IV catheters may be beneficial.2 When peripheral venous access is difficult to achieve because of severe intravascular volume depletion, jugular venous access can be attempted with a short, large-bore, over-the-needle catheter. These are typically secured by suturing in place. Longer catheters can later be placed through the short catheter if long-term jugular venous access is desired after initial resuscitation. Occasionally, extremely unstable patients may be presented where vascular access is only possible via a cutdown procedure. In these cases, placement of an intraosseous catheter can be placed for shock fluid administration. This can be achieved with a regular hypodermic needle in pediatric or neonatal animals. In older animals a commercially available intraosseous access device or bone marrow aspiration device is usually necessary (see Chapter 194, Intraosseous Catheterization). Other fluid administration routes such as subcutaneous or intraperitoneal are generally not recommended for shock fluid administration because of longer absorption times.

RESUSCITATION ENDPOINTS AND MONITORING Fluid therapy for the treatment of shock is performed under extremely close monitoring and should continue until various resuscitation

CHAPTER 68  Shock Fluids and Fluid Challenge endpoints have been reached (see Chapters 64 and 181, Assessment of Intravascular Volume and Hemodynamic Monitoring, respectively). In general, these endpoints include physical examination parameters such as improvement in heart rate, pulse quality, capillary refill time, temperature of extremities, and mentation. Normalization of arterial blood pressure is another clinical parameter that is often used to guide shock fluid therapy.1 Bloodwork parameters such as lactate concentration and central venous oxygen saturation, when available, can be serially monitored to ensure improvement with fluid therapy. Recent advances in the use and understanding of point-of-care ultrasound as a means of dynamically assessing intravascular volume has made this modality a useful adjunct in evaluation of unstable patients before, during, and after resuscitation (see Chapter 189, Point-of-Care Ultrasound in the ICU).3,4 More recently, evaluation of the microcirculation has been studied as an endpoint for resuscitation in humans, particularly in septic patients. This is because of growing evidence to suggest that normalization of conventional macrohemodynamic parameters does not necessarily reflect improved oxygen delivery and perfusion at the tissue level.5,6 The concept of early goal-directed therapy for treatment of septic shock, first proposed in 20017 and widely accepted in the following decade, has now been questioned in more recent studies, including several large trials such as the ARISE, ProCESS and ProMISE trials.8-11 While the Surviving Sepsis guidelines mandated the use of early goal directed therapy (targeted therapies that are to be instituted within the first 3 to 6 hours of presentation), the most recent set of guidelines published in 2016 differ significantly.12 Previous guidelines recommended the following targets during the first 6 hours of resuscitation: central venous pressure of 8–12 mm Hg, mean arterial pressure (MAP) .65 mm Hg, urine output .0.5 ml/kg/hr, and central or mixed venous oxygen saturation of 70% or 65%, respectively. The most recent Surviving Sepsis guidelines recommend administering at least 30 ml/kg of crystalloids within the first 3 hours of presentation to treat sepsis-induced hypotension. However, the guidelines stop short of outlining specific physiologic targets other than an initial MAP target of 65 mm Hg, and instead recommend additional fluid therapy based on frequent reassessment of hemodynamic status (heart rate, blood pressure, arterial oxygen saturation, respiratory rate, temperature, urine output as well as other invasive monitoring). These guidelines also recommend the use of dynamic variables to predict fluid responsiveness (such as passive leg raise or pulse pressure variation) over static variables, when available. The concept of goal-directed therapy for managing critically ill dogs and cats has not been evaluated thoroughly in recent years. One veterinary study evaluating canine patients with septic shock emphasized the importance of goal-directed hemodynamic optimization in improving outcomes.13 However, further studies in this regard are lacking in small animals. Regardless, both human and veterinary medicine prioritize the use of fluid therapy for the rapid treatment of shock. While lactate-targeted fluid resuscitation is the gold-standard under current human guidelines, one of the main pitfalls with this strategy is the potential for nonperfusion-related hyperlactatemia confounding assessment in various patient disease states. To evaluate this further, a recent trial evaluated the use of peripheral perfusion parameters such as normalization of capillary refill time compared with normalization of lactate levels.14 This trial found that while peripheral perfusion-targeted resuscitation was associated with less organ dysfunction at 72 hours, there was no significant difference in mortality.

SHOCK FLUIDS The various types of fluids available for shock resuscitation include isotonic and hypertonic crystalloids, synthetic colloids, hemoglobin-based

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oxygen carrying solutions, albumin, and other blood products (fresh whole blood, fresh frozen plasma, and packed red blood cells).

Isotonic Crystalloids Isotonic crystalloids are fluids that have a composition similar to that of the extracellular fluid (see Chapter 65, Crystalloid Solutions). The principal component of crystalloid fluids is the inorganic salt sodium chloride (NaCl), with 0.9% NaCl being the prototype isotonic crystalloid. Sodium is the most abundant solute in the extracellular fluid, and it is distributed uniformly throughout the extracellular space. Because 75% of the extracellular fluids is located in the extravascular (interstitial) space, a similar proportion of the total body sodium is in the interstitial fluids. Exogenously administered sodium follows the same distribution, so 75% of the volume of sodium based IV fluids is rapidly redistributed into the interstitium. Theoretically, this means that to increase plasma volume by a given amount, four times the desired volume must be administered to account for the interstitial redistribution. However, when administered rapidly as a bolus, isotonic crystalloids can effectively expand plasma volume. A 2005 study showed that a rapid infusion of 80 ml/kg of 0.9% saline to four healthy dogs caused a 76.4% increase in intravascular volume. While rapid redistribution did occur, leaving a net intravascular volume increase of only 35% at 30 minutes and 18% at 4 hours postinfusion,15 it is possible that a similar volume of infusion to hypovolemic animals may have resulted in a greater, more prolonged expansion of the vascular volume. Isotonic crystalloids are inexpensive and readily available and as such are typically the first choice for shock resuscitation in most cases.16 When used for shock resuscitation, the classic shock dose is approximately 60 to 90 ml/kg in dogs and approximately 45 to 60 ml/kg in cats, which reflects the approximate blood volumes in each species (Table 68.1). However, it is now recognized that shock doses are rarely necessary, and excessive volume administration is associated with increased organ dysfunction and mortality (see below). The actual dose needed to treat patients with evidence of shock varies widely and is influenced by the species, individual patient, severity of shock, chronicity of disease, and any other comorbidities (e.g., cardiac disease). A common recommendation in small animals is to begin shock treatment using a bolus of 10 to 20 ml/kg administered over 15 to 30 minutes. The patient should be closely monitored during delivery of the bolus, and it should be slowed or discontinued if any adverse effects are seen or if perfusion parameters improve before the end of the predetermined amount.

Adverse Effects Aggressive crystalloid-based resuscitation strategies can lead to several adverse effects, especially in patients predisposed to volume overload (e.g., patients with severe hypoproteinemia or kidney or cardiac disease). Because crystalloids redistribute into the interstitium, organ edema can occur and may be life threatening (see Chapter 11, Interstitial Edema). Pulmonary edema and acute lung injury are among the most commonly seen adverse effects of shock resuscitation, particularly in patients with increased vascular permeability secondary to systemic inflammation or sepsis.17 Other consequences of aggressive and overzealous crystalloid administration include changes to the gastrointestinal (GI) tract resulting in decreased motility, increased intestinal permeability predisposing the patient to bacterial translocation, and increased risk for abdominal compartment syndrome. Cardiac effects of crystalloid therapy have also been documented and include an increased risk of ventricular arrhythmias, disruption of cardiac contractility, and decreased cardiac output. This can be demonstrated by Starling’s myocardial performance curve; when beyond a designated point on the curve, further increases in enddiastolic volume cause a decrease in cardiac output. Coagulation disturbances can also occur as a result of dilution of coagulation factors and

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TABLE 68.1  Suggested Doses for Shock Fluid Resuscitation Shock Fluid Isotonic crystalloids

Dose Typical bolus dose: 10–20 ml/kg IV over 15–30 minutes Total shock dose: 60–90 ml/kg in dogs, 45–60 ml/kg in cats

Comments Rapid redistribution with short-lived intravascular volume expansion effect. Caution with use in patients with decreased colloid osmotic pressure or increased vascular permeability due to increased risk of pulmonary and interstitial edema.

Examples of Products 0.9% NaCl, lactated Ringer’s solution, Normosol-R, PlasmaLyte 148, Hartmann’s solution

Synthetic colloids

Typical bolus dose: 2–5 ml/kg IV over 10–30 minutes Total shock dose: 10–20 ml/kg in dogs, 5–10 ml/kg in cats

Sustained intravascular volume expansion. Increased risk of coagulation disturbances with use of large doses. May cause or exacerbate preexisting acute kidney injury.

Hespan (6% hetastarch in 0.9% NaCl) Hextend (6% hetastarch in lactated electrolyte solution) Pentaspan (10% pentastarch in 0.9% NaCl) Vetstarch, Voluven, HydraVol (6% tetrastarch in 0.9% NaCl)

Hypertonic solutions

Typical dose: 3–5 ml/kg of 7%–7.5% NaCl solution over 10–20 minutes Can be combined in a 1:2 ratio of 23.4% NaCl to a synthetic colloid for sustained intravascular volume expansion

Monitor electrolytes, particularly sodium. Use with caution in chronic hyponatremia. Can exacerbate interstitial volume depletion in dehydrated patients. Good for small-volume resuscitation, particularly in septic shock, hemorrhagic shock, and traumatic brain injury.

Commercially available in concentrations ranging from 3% to 23.4% NaCl

Blood products

Typical dose: pRBCs and fresh frozen plasma: 10–20 ml/kg given IV over 2–4 hours (can be given faster in rapidly decompensating patients up to a rate of 1.5 ml/kg/min over 15–20 minutes) Fresh whole blood: 20–30 ml/kg over 2–4 hours

Check blood type before administration and crossmatch if indicated and time allows. Monitor for transfusion reactions throughout duration of administration. Ideal for patients presenting in acute hemorrhagic shock.

Canine and feline pRBCs Canine and feline FFP Canine and feline fresh whole blood (where donors available)

FFP, fresh frozen plasma; pRBCs, packed red blood cells.

decreased blood viscosity; however, these effects are significantly less than changes caused by synthetic colloids.17,18 Isotonic crystalloids, particularly lactated Ringer’s solution, have been associated with alterations of the inflammatory cascade. Many formulations of this crystalloid contain racemic mixtures of both the l- and d-lactate stereoisomers. The d-lactate has been associated with an increase in neutrophil stimulation, whereas the l-lactate is rapidly metabolized by the liver.19,20 Administration of lactated Ringer’s solution that contains only the l-isomer may even decrease inflammation in humans with pancreatitis.21 However, even mild decreases in osmolality can lead to cellular swelling and subsequent activation of phospholipase A2, resulting in an increased production of prostaglandins, lipoxygenases, leukotrienes, and epoxyeicosatrienoic acids. Acute increases in cellular volume also stimulate production and release of tumor necrosis factor =a from macrophages. Increased levels of proinflammatory cytokines (e.g., interleukins such as IL-6, IL-8, and IL-10) may also occur; this can have deleterious effects on an already compromised microcirculation and further increase the risk of edema and fluid overload.17,18,22,23 Aggressive crystalloid resuscitation has been associated with a negative outcome in various human patient populations including pediatric patients, burn patients, and septic and blunt trauma patients.24-27 “Overzealous resuscitation with crystalloids has also been shown to negatively impact the health of the endothelial glycocalyx. Recent studies have demonstrated that the volume of crystalloids administered in patients with septic shock is independently associated with the degree of glycocalyx degradation.28 The reader is directed to Chapter 9 (Endothelial Surface Layer) for a more detailed review of the endothelial glycocalyx and the impact of fluid therapy on its health.”

Synthetic Colloids Colloids are large molecules (.10,000 Daltons) of varying sizes that do not readily cross diffusion barriers across normal blood vessels as crystalloids do. Colloids that are infused into the vascular space therefore tend to remain in the vascular space rather than redistribute to the interstitial space. This leads to a more sustained intravascular expansion effect. These fluids increase the colloid osmotic pressure of serum, creating a force that opposes the hydrostatic pressure in the vasculature and helps retain fluid in the vascular space (see Chapter 66, Colloid Solutions). Commercially available synthetic colloids typically contain large colloid molecules suspended in an isotonic crystalloid solution. Some of the more commonly available synthetic colloids are derivatives of hydroxyethyl starches (HESs) including hetastarch (available as a 6% solution suspended in an isotonic crystalloid solution such as 0.9% saline [Hespana] or a lactated electrolyte solution [Hextendb]), pentastarch (Pentaspanc) and tetrastarch (Vetstarchd, Hydravole). The clearance of starch molecules from the intravascular space depends on the rate of their absorption by tissues (liver, spleen, kidney, and heart), uptake by the reticuloendothelial system, clearance through urine and bile, and enzymatic degradation to small particles by serum amylase. Alpha-amylase-mediated hydrolysis can reduce the molecular weight

a

Hespan®, B.Braun Medical Inc, Irvine CA Hextend®, Hospira Inc, Lake Forest IL c Pentaspan®, Bristol-Myers Squibb, Montreal, QU, Canada d Vetstarch®, Zoetis Inc, Kalamazoo, MI e Hydravol, Vedco, St Joseph, MO b

CHAPTER 68  Shock Fluids and Fluid Challenge of these particles to less than 72 kDa. The degree of hydroxyl substitution in these starches is the primary determinant of how long they survive in the blood (see Chapter 66, Colloid Solutions). The recommended rates and volumes of administration of these fluids are typically much lower than that of crystalloids. When synthetic colloids are used for the treatment of shock, the typical dose is 5 to 20 ml/kg in the dog and 2.5 to 10 ml/kg in the cat (see Table 68.1). This is commonly administered to effect in incremental boluses over 10 to 20 minutes.

Adverse Effects Much emphasis has been placed in recent years on the various potential adverse effects of synthetic colloids, especially in human medicine. There has been recent evidence in several human trials and metaanalyses that high molecular-weight starches (MW 200) may cause acute kidney injury (AKI) in patients with severe sepsis, although a HES 130/0.4 is considered to be less harmful.16,29-36 However, a recently published study did not support this hypothesis and showed that even 6% HES 130/0.4 can cause more impairment of renal function than resuscitation with crystalloids alone in patients with severe sepsis.34 This particular adverse effect of starches has been the subject of a great deal of interest in veterinary medicine. Recent studies have shown mixed results, with some studies finding an increased risk of development of AKI,37,38 or an increase in grade of AKI proportional to the duration of starch therapy39 and death in dogs,37 while several other studies have shown no differences in creatinine concentrations in anesthetized dogs,40 or dogs hospitalized in the ICU.41 One study evaluating biomarkers for AKI found marginally increased levels of markers of both tubular injury and renal inflammation in dogs receiving starches compared with those receiving crystalloids.42 There are currently two studies evaluating the use of starches in critically ill cats, neither of which found an increased risk of AKI or mortality with the use of these products.43,44 It is important to note that no randomized controlled trials of HES have been performed in veterinary patients so the risk of AKI remains to be determined. Another concern with the use of synthetic colloids is their effect on coagulation. All colloidal plasma substitutes are known to interfere with the physiologic mechanisms of hemostasis either through a nonspecific effect correlated to the degree of hemodilution or through specific actions of these macromolecules on platelet function, coagulation proteins, and the fibrinolytic system. High molecular-weight starches can cause decreases in the activity of von Willebrand’s factor and its associated factor VIII and ristocetin cofactor activities, as well as some degree of platelet dysfunction.45-51 Several veterinary studies have investigated the effect of starches on canine hemostasis, but very little data exist describing effects on feline hemostasis. A single in vitro study evaluated the effects of tetrastarch on feline whole blood coagulation and found clinically insignificant effects on duration of clot formation measured via thromboelastometry.52 Studies have shown that the administration of more than 20 ml/kg/ day of hetastarch in animals can cause coagulation derangements. This maximal limit is often exceeded in practice, but the potential for coagulopathic sequelae should be recognized. Because tetrastarch may have fewer adverse effects on coagulation, higher doses may potentially be administered (up to 40 ml/kg/day).53,54 Ultimately, the safety of these starches in critically ill small animals is still unclear, and additional prospective studies in various patient populations would be highly beneficial. The authors recommend exercising caution, however, when using these solutions in at-risk patients (e.g., sepsis) or with preexisting renal injury to avoid causing exacerbation.

Hypertonic Solutions A hypertonic crystalloid solution is any saline solution that has an effective osmolarity exceeding that of normal plasma (see Chapter 65,

405

Crystalloid Solutions). Hypertonic saline solutions are available commercially in variable concentrations of 3% to 23.4%. Hypertonic saline has several beneficial properties that make it an excellent choice for rapid, small-volume resuscitation in shock patients. A 2005 study evaluating the changes in blood volume after a bolus of 4 ml/kg of 7.5% sodium chloride showed that the postinfusion plasma volume change was only about 17% despite a brief increase in blood volume about three times the volume of fluid administered.15 Its ability to cause intravascular volume expansion in excess of the volume infused is due to the osmotic gradient generated by the sudden, dramatic increase in plasma osmolarity after administration, thus making it a good option for small-volume resuscitation. In addition to its volume expansion ability, hypertonic saline has numerous other properties that make it an attractive choice for shock resuscitation, particularly in animals with septic shock, hemorrhagic shock, and traumatic brain injury. These properties include immunomodulatory effects, such as decreased neutrophil activation and adherence, stimulation of lymphocyte proliferation, and inhibition of proinflammatory cytokine production by macrophages. It also improves the rheologic properties of circulating blood, reduces endothelial cell swelling, and helps reduce intracranial pressure in patients with traumatic brain injury.55-58 There is evidence to suggest that hypertonic saline administration improves myocardial function and causes coronary vasodilation, thereby improving overall cardiac function.55,59 However, the clinical effect on cardiac contractility in dogs and cats requires further evaluation. Hypertonic saline is most commonly used as either a 3% or 7.0% to 7.5% solution. Typically, a 3 to 5 ml/kg dose of 7% to 7.5% solution given over 10–20 minutes is used for small-volume resuscitation (see Table 68.1). Because hypertonic saline rapidly redistributes into the interstitium within 30 minutes after administration and may cause a mild increase in urine output, its volume expansion effect is short lived. For this reason, it is often combined with a synthetic colloid.60 This combined solution, sometimes referred to as turbostarch, is administered at a dose of 3 to 5 ml/kg and is prepared by mixing a stock solution of 23.4% hypertonic saline with 6% hydroxyethyl starch in a 1:2 ratio to arrive at a total volume of 3 to 5 ml/kg. For example, a 5 ml/kg dose for a 12-kg dog would be 60 ml. Therefore 1 part 23.4% hypertonic saline (20 ml) with 2 parts (40 ml) 6% hydroxyethyl starch would create an approximately 7.5% hypertonic saline solution.

Adverse Effects The primary adverse effects of hypertonic saline are hypernatremia and hyperchloremia. These are seen immediately after administration but are usually transient. There is a risk for hypernatremia-induced osmotic demyelination syndrome when administered to patients with preexisting chronic hyponatremia; however, this has rarely been reported. Most critical patients have frequent monitoring of electrolytes, and the risk of transient hypernatremia does not outweigh the potential benefits of hypertonic saline therapy. Hypertonic saline should be used cautiously in patients with preexisting cardiac or pulmonary abnormalities because the increase in intravascular volume and hydrostatic pressure may lead to volume overload or pulmonary edema. It can also cause significant interstitial (and intravascular) volume depletion, particularly in patients that are already dehydrated. Therefore, hypertonic fluid administration should be followed by additional fluid therapy as indicated.

Albumin Albumin is one of the most important plasma proteins because of its many physiologic effects in the body, including maintenance of colloid osmotic pressure and endothelial integrity, wound healing, metabolic and acid-base functions, coagulation, and free radical scavenging.

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Albumin levels are often low in critically ill patients because of loss, vascular leak, third-spacing, and decreased production as a result of shifting of hepatic production toward acute-phase proteins. Hypoalbuminemic patients that require fluid resuscitation may be at increased risk for interstitial edema after large-volume crystalloid administration, although the modified Starling equation has questioned this theory. Natural or synthetic colloid therapy may be considered in these patients. Albumin, a natural colloid, confers various additional advantages as outlined earlier that are not provided by synthetic colloids, particularly in patients with systemic inflammatory syndromes and vascular leak disorders. The use of albumin in dogs is typically reserved for dogs with clinically severe hypoalbuminemia (usually ,1 g/dl) secondary to severe sepsis, septic shock, or trauma or those with prolonged critical illness and continued decreases in albumin, especially after major surgery. Further details on its use can be found in Chapter 66, Colloid Solutions. Historically, 25% human serum albumin has been most commonly used albumin solution. However, lyophilized canine albumin products have become more consistently available in recent years. Given that human serum albumin can be associated with significant adverse effects (see Chapter 66, Colloid Solutions), bolus dosing of these solutions in shock states is not recommended. Canine albumin solutions are dosed by calculating the patient’s albumin deficit and can be administered as 5%, 10%, or 16% solutions (with the latter being reserved for hemodynamically unstable patients as a means of shock resuscitation). There is a single veterinary study evaluating the use of canine albumin in critically ill dogs that did not report any significant acute or delayed hypersensitivity reactions.59

also known as hypotensive resuscitation (see Chapter 71, Hemorrhagic Shock).63-66 Restoration of a lower-than-normal systolic blood pressure (approximately 80 to 90 mm Hg) helps facilitate control of hemorrhage and reduces the risk of rebleeding but at the same time ensures preserved blood flow to vital organs such as the kidney and GI tract. It is important to emphasize, however, that hypotensive resuscitation is a temporary solution and is only meant to bridge the gap between presentation and definitive hemostatic control (usually via surgical intervention). Hypotensive resuscitation should not be used as a long-term or permanent treatment approach because this puts the patient at risk for complications resulting from impairment of tissue perfusion.

FLUID CHALLENGE

The use of blood products (whole blood, fresh frozen plasma [FFP], or packed red blood cells [pRBCs]) is of significant value in shock resuscitation, particularly in animals that present with signs of hemorrhagic shock secondary to trauma, nontraumatic hemoabdomen, gastrointestinal bleeding, rodenticide intoxication, or other primary or secondary coagulopathies (see Chapters 69 and 71, Blood Transfusions and Hemorrhagic Shock, respectively). Fresh whole blood transfusions carry the benefit of increased levels of clotting factors, fibrinogen, and platelets compared with component therapy. Current recommendations in trauma resuscitation advocate minimizing or altogether avoiding crystalloid use in these patients. Aggressive use of FFP is recommended in situations where whole blood is not easily available, with FFP/pRBCs given in the ratio of 1:1.60,61 Typical management of the patient presenting in acute hemorrhagic shock includes pRBCs and FFP at a dose of 10 to 20 ml/kg (see Chapters 69 and 71, Blood Transfusions and Hemorrhagic Shock, respectively). Although transfusions are usually administered over a period of 2 to 4 hours, rapidly decompensating patients may require faster infusion rates (i.e., 1.5 ml/kg/min over 15 to 20 minutes) (see Table 68.1). The term massive transfusion has come into widespread use, defined as the replacement of a volume of whole blood or blood components that is greater than the patient’s estimated blood volume. Massive transfusions carry a much higher risk of adverse transfusion related effects (e.g., electrolyte imbalances, acute lung injury, and immunologic reactions); they can be extremely cost prohibitive but lifesaving in certain patients.62

A fluid challenge is defined as the administration of fluids to patients that are hemodynamically unstable in order to assess their response to fluid therapy and guide further treatment decisions. This is usually reserved for critically ill patients and allows for subjective and objective assessment of the cardiovascular response during fluid infusion and rapid expansion of intravascular volume. It also helps guide therapy, particularly when hypovolemia may be subtle, while minimizing the risk of volume overload that can occur as a result of overzealous or unnecessary fluid therapy. Performing a fluid challenge with specific targets helps provide a more objective method of guiding fluid therapy decisions.67 While performing a fluid challenge, the following factors should be considered: • Type of fluid: Crystalloids or synthetic colloids are typically used to perform a fluid challenge. Because colloids are retained in the intravascular space longer than crystalloids, smaller volumes are required to complete a fluid challenge (e.g., a typical crystalloid volume for fluid challenge in a dog might be 10 to 20 ml/kg, whereas a synthetic colloid dose would be 3 to 5 ml/kg). • Rate of fluid administration: Fluid challenges are typically performed over a period of 10 to 30 minutes. • End points: Identify the parameters that are abnormal and indicative of hemodynamic instability and aim to assess changes in these parameters after a fluid challenge. For example, dull mentation, hypotension, weak pulse quality, prolonged capillary refill time, tachycardia, or oliguria might be identified. Assess for reversal or improvement in these abnormalities after completion of a fluid challenge with specific endpoints. A decrease in vasopressor requirements may also be considered a marker of a successful fluid challenge. Lactate and central venous oxygen saturation (ScVO2) monitoring, if available, can also be serially evaluated. (See Chapters 181 and 184, Hemodynamic Monitoring and Oximetry Monitoring, respectively.) More recently, the role of static markers of preload such as central venous pressure or pulmonary artery occlusion pressure has been questioned, and dynamic indices of preload are now recommended, such as arterial waveform derived variables (stroke volume variation, pulse pressure variation) and passive leg raises in humans.66 • Safety of the fluid challenge: Patients must be watched closely for signs of volume overload, particularly pulmonary edema, during any fluid challenge. Respiratory rate and effort, pulse oximetry, and arterial blood gases should be frequently monitored.

HYPOTENSIVE RESUSCITATION

REFERENCES

Traditional fluid resuscitation for patients with hemorrhagic shock involves resuscitation until a normal systolic blood pressure is achieved. However, in recent years literature has pointed toward an improved survival (particularly in trauma patients) when a more conservative resuscitation strategy is employed in the acute setting during active hemorrhage,

1. Silverstein DC, Kleiner J, Drobatz KJ: Effectiveness of intravenous fluid resuscitation in the emergency room for treatment of hypotension in dogs, J Vet Emerg Crit Care 22:666, 2012. 2. Reddick AD, Ronald J, Morrison WG: Intravenous fluid resuscitation: was Poiseuille right? Emerg Med J 28:201-202, 2011.

Blood Products

CHAPTER 68  Shock Fluids and Fluid Challenge 3. McMurray J, Boysen S, Chalhoub S, et al: Focused assessment with sonography in nontraumatized dogs and cats in the emergency and critical care setting, J Vet Emerg Crit Care 26(1):64-73, 2016. 4. Lisciandro GR: Cageside ultrasonography in the emergency room, Vet Clin North Am Small Anim Pract 50(6):P1445-P1467, 2020. 5. Trzeciak S, McCoy JV, Dellinger RP, et al: Early increases in microcirculatory perfusion during protocol-directed resuscitation are associated with reduced multi-organ failure at 24h in patients with sepsis, Int Care Med 34:2210, 2008. 6. Vincent J, De Backer D: Microvascular dysfunction as a cause of organ dysfunction in severe sepsis, Crit Care 9(4):S9, 2005. 7. Rivers E, Nguyen B, Havstad S, et al: Early goal directed therapy in the treatment of severe sepsis and septic shock, N Engl J Med 345(19):1368, 2001. 6. Process Investigators, Yealy DM, Kellum JA, et al: A randomized trial of protocol-based care for early septic shock, N Engl J Med 370(18):16831693, 2014. 7. ARISE Investigators, ANZICS Clinical Trials Group, Peake SL, et al: Goaldirected resuscitation for patients with early septic shock, N Engl J Med 371(16):1496-1506, 2014. 8. Mouncey PR, Osborn TM, Power GS, et al: Trial of early, goal-directed resuscitation for septic shock, N Engl J Med 372(14):1301-1311, 2015. 9. The PRISM Investigators: Early, goal-directed therapy for septic shock- a patient-level meta-analysis, N Engl J Med 376:2223-2234, 2017. 10. Conti-Patara A, de Araújo Caldeira J, de Mattos-Junior E, et al: Changes in tissue perfusion parameters in dogs with severe sepsis/septic shock in response to goal-directed hemodynamic optimization at admission to ICU and the relation to outcome, J Vet Emerg Crit Care 22:409, 2012. 11. Hernández G, Ospina-Tascón GA, Damiani LP, et al: Effect of a resuscitation strategy targeting peripheral perfusion status vs serum lactate levels on 28-day mortality among patients with septic shock: the ANDROMEDA-SHOCK randomized clinical trial, J Am Med Assoc 321(7):654-664, 2019. 12. Singer M, Deutschman CS, Seymour CW, et al: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3), JAMA 315(8):801-810, 2016. doi:10.1001/jama.2016.0287. 13. Silverstein DC, Aldrich J, Haskins SC, et al: Assessment of changes in blood volume in response to resuscitative fluid administration in dogs, J Vet Emerg Crit Care 15(3):185, 2005. 14. Perel P, Roberts I: Colloids versus crystalloids for fluid resuscitation in critically ill patients, Cochrane Database Syst Rev 6:CD000567, 2012. 15. Cotton BA, Guy JS, Morris JA, et al: The cellular, metabolic and systemic consequences of aggressive fluid resuscitation strategies, Shock 26(2):115, 2006. 16. Shoemaker WC, Hauser CJ: Critique of crystalloid versus colloid therapy in shock and shock lung, Crit Care Med 7:117, 1979. 17. Rhee P, Burris D, Kaufmann C, et al: Lactated Ringer’s solution causes neutrophil activation after hemorrhagic shock, J Trauma 44(2):313, 1998. 18. Alam HB, Stanton K, Koustova E, et al: Effect of different resuscitation strategies on neutrophil activation in a swine model of hemorrhagic shock, Resuscitation 60:91, 2004. 19. Wu BU, Hwang JQ, Gardner TH, et al: Lactated Ringer’s solution reduces systemic inflammation compared with saline in patients with acute pancreatitis, Clin Gastroenterol Hepatol 9(8):710, 2011. 20. Ng KF, Lam CK, Chan LC: In vivo effect of hemodilution with saline on coagulation: a randomized controlled trial, Br J Anaesth 88:475, 2002. 21. Lang F, Busch GL, Ritter M, et al: Functional significance of cell volume regulatory mechanisms, Physiol Rev 78:248, 1998. 22. Maitland K, Kiguli S, Opoka RO, et al: Mortality after fluid bolus in African children with severe infection, N Engl J Med 364(26):2483-2495, 2011. 23. Klein MB, Hayden D, Elson C, et al: The association between fluid administration and outcome following major burn: a multicenter study, Ann Surg 245(4):622-628, 2007. 24. Bouchard J, Mehta RL: Fluid balance issues in the critically ill patient, Contrib Nephrol 164:69-78, 2010. 25. Kasotakis G, Sideris A, Yang Y, et al: Aggressive early crystalloid resuscitation adversely affects outcomes in adult blunt trauma patients: an analysis of the Glue Grant database, J Trauma Acute Care Surg 74(5):1215-1222, 2013.

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26. Baron JF: A new hydroxyethyl starch: HES 130/0.4 Voluven®, Transfusion Altern Transfusion Med 2(2):13, 2000. 27. Langeron O, Doelberg M, Ang ET, et al: Voluven®, a lower substituted novel hydroxyethyl starch (HES 130/0.4), causes fewer effects on coagulation in major orthopedic surgery than HES 200/0.5, Anesth Analg 92(4):855, 2001. 28. Hippensteel JA, Uchimido R, Tyler PD, et al: Intravenous fluid resuscitation is associated with septic endothelial glycocalyx degradation Crit Care 23:259, 2019. https://doi.org/10.1186/s13054-019-2534-2. 29. Strauss RG, Pennell BJ, Stump DC: A randomized, blinded trial comparing the hemostatic effects of pentastarch versus hetastarch, Transfusion 42(1):27, 2002. 30. Bunn F, Trivedi D, Ashraf S: Colloid solutions for fluid resuscitation, Cochrane Database Syst Rev (3):CD001319, 2011. 31. Roberts I, Alderson P, Bunn F, et al: Colloids versus crystalloids for fluid resuscitation in critically ill patients, Cochrane Database Syst Rev (4):CD000567, 2004. 32. Perner A, Haase N, Wetterslev J, et al: Comparing the effect of hydroxyethyl starch 130/0.4 with balanced crystalloid solution on mortality and kidney failure in patients with severe sepsis (6S-Scandinavian Starch for Severe Sepsis/Septic Shock trial): study protocol, design and rationale for a double-blinded, randomized clinical trial, Trials 12(1):24, 2011. 33. Schortgen F, Girou E, Deye N, et al: The risk associated with hyperoncotic colloids in patients with shock, Intensive Care Med 34(12):2157, 2008. 34. Bayer O, Reinhart K, Sakr Y, et al: Renal effects of synthetic colloids and crystalloids in patients with severe sepsis: a prospective sequential comparison, Crit Care Med 39(6):1335, 2012. 35. Hayes G, Benedicenti L, Mathews K: Retrospective cohort study on the incidence of acute kidney injury and death following hydroxyethyl starch (HES 10% 250/0.5/5:1) administration in dogs (2007-2010), J Vet Emerg Crit Care 26(1):35-40, 2016. 36. Bae J, Soliman M, Kim H, et al: Rapid exacerbation of renal function after administration of hydroxyethyl starch in a dog, J Vet Med Sci 79(9): 1591-1595, 2017. 37. Sigrist NE, Kalin N, Dreyfus A: Changes in serum creatinine concentration and acute kidney injury (AKI) grade in dogs treated with hydroxyethyl starch 130/0.4 from 2013 to 2015, J Vet Intern Med 31:434-441, 2017. 38. Zersen KM, Mama K, Mathis JC: Retrospective evaluation of paired plasma creatinine and chloride concentrations following hetastarch administration in anesthetized dogs (2002-2015): 244 cases, J Vet Emerg Crit Care 29(3):309-313, 2019. 39. Yozov ID, Howard J, Adamik K: Retrospective evaluation of the effects of administration of tetrastarch (hydroxyethyl starch 130/0.4) on plasma creatinine concentrations in dogs (2010-2013): 201 dogs, J Vet Emerg Crit Care 26(4):568-577, 2016. 40. Boyd CJ, Claus MA, Raisis AL, et al: Evaluation of biomarkers of kidney injury following 4% succinylated gelatin and 6% hydroxyethyl starch 130/0.4 administration in a canine hemorrhagic shock model, J Vet Emerg Crit Care 29(2):132-142, 2019. 41. Sigrist NE, Kalin N, Dreyfus A: Effects of hydroxyethyl starch 130/0.4 on serum creatinine concentration and development of acute kidney injury in non-azotemic cats, J Vet Intern Med 31:1749-1756, 2017. 42. Yozova ID, Howard J, Adamik K: Effect of tetrastarch (hydroxyethyl starch 130/0.4) on plasma creatinine concentration in cats: a retrospective analysis (2010-2015), J Feline Med Surg 19(10):1073-1079, 2017. 43. Ekseth K, Abildgaard L, Vegfors M, et al: The in vitro effects of crystalloids and colloids on coagulation, Anaesthesia 57(11):1102, 2002. 44. Mortier E, Ongenae M, De Baerdemaeker L, et al: In vitro evaluation of the effect of profound hemodilution with hydroxyethyl starch 6%, modified fluid gelatin 4% and dextran 40 10% on coagulation profile measured by thromboelastography, Anaesthesia 52(11):1061, 2005. 45. Falco S, Bruno B, Maurella C, et al: In vitro evaluation of canine hemostasis following dilution with hydroxyethyl starch (130/0.4) via thromboelastometry, J Vet Intern Med 22(6):640-645, 2012. 46. Fenger-Eriksen C, Tonnesen E, Ingerslev J, et al: Mechanisms of hydroxyethyl starch induced dilutional coagulopathy, J Thromb Haemost 7(7):1099-1105, 2009.

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47. Classen J, Adamik KN, Weber K, et al: In vitro effect of hydroxyethyl starch 130/0.4 on canine platelet function, Am J Vet Res 73(12):19081912, 2012. 48. Gauthier V, Holowaychuk MK, Kerr CL, et al: Effect of synthetic colloid administration on coagulation in healthy dogs and dogs with systemic inflammation, J Vet Intern Med 29:276-285, 2015. 49. Smart L, Jandrey KE, Kass PH, et al: The effect of Hetastarch (670/0.5) in vivo on platelet closure time in the dog, J Vet Emerg Crit Care 19(5):444449, 2009. 50. Albrecht NA, Howard J, Kovacevic A, et al: In vitro effects of 6% hydroxyethyl starch 130/0.42 solution on feline whole blood coagulation measured by rotational thromboelastometry, BMC Vet Res 12(1):155, 2016. 51. Entholzner EK, Mielke LL, Calatzis AN, et al: Coagulation effects of a recently developed hydroxyethyl starch (130/0.4) compared to hydroxyethyl starches of higher molecular weight, Acta Anaesthesiol Scand 44(9): 1116-1121, 2000. 52. Botto A, Bruno B, Maurella C, et al: Thromboelastometric assessment of hemostasis following hydroxyethyl starch (130/0.4) administration as a constant rate infusion in hypoalbuminemic dogs, BMC Vet Res 14(1):33, 2018. 53. Rizoli SB, Rhind SG, Shek PN, et al: The immunomodulatory effects of hypertonic saline resuscitation in patients sustaining traumatic hemorrhagic shock, Ann Surg 243(1):47, 2006. 54. Bulger EM, Jurkovich GJ, Nathens AB, et al: Hypertonic resuscitation of hypovolemic shock after blunt trauma: a randomized controlled trial, Arch Surg 143(2):139, 2008. 55. Mortazavi MM, Romeo AK, Deep A, et al: Hypertonic saline for treating raised intracranial pressure: literature review with meta-analyses, J Neurosurg 116:210, 2012.

56. Balbino M, Neto AC, Prist R, et al: Fluid resuscitation with isotonic or hypertonic saline solution avoids intraneural calcium influx after traumatic brain injury associated with hemorrhagic shock, J Trauma 68:859, 2010. 57. Mouren S, Delayance S, Mion G, et al: Mechanisms of increased myocardial contractility with hypertonic saline solutions in isolated blood perfused rabbit hearts, Anesth Analg 81:777, 1995. 58. Bentsen G, Breivik H, Lundar T, et al: Predictable reduction of intracranial hypertension with hypertonic saline hydroxyethyl starch: a prospective clinical trial in critically ill patients with subarachnoid hemorrhage, Acta Anaesthesiol Scand 48(9):1089-1095, 2004. 59. Craft EM, Powell LL: The use of canine-specific albumin in dogs with septic peritonitis, J Vet Emerg Crit Care 22(6):631-639, 2012. 60. Como JJ, Dutton RP, Scalea TM, Edelman BB, Hess JR: Blood transfusion rates in the care of acute trauma, Transfusion 44:809, 2004. 61. Repine TB, Perkins JG, Kauvar DS, et al: The use of fresh whole blood in massive transfusion, J Trauma 60(Suppl 6):S59, 2006. 62. Jutkowitz AL, Rozanski EA, Moreau JA, et al: Massive transfusion in dogs: 15 cases (1997-2001), J Am Vet Med Assoc 220:1664, 2002. 63. Holcomb JB, Jenkins D, Rhee P, et al: Damage control resuscitation: directly addressing the coagulopathy of trauma, J Trauma 62:307, 2007. 64. Duchesne JC, McSwain NE, Cotton BA, et al: Damage control resuscitation: the new face of damage control, J Trauma 69:976, 2010. 65. Morrison AC, Carrick MM, Normal MA, et al: Hypotensive resuscitation strategy reduces transfusion requirements and severe postoperative coagulopathy in trauma patients with hemorrhagic shock: preliminary results of a randomized controlled trial, J Trauma 70:652, 2011. 66. Vincent JL, Weil MH: Fluid challenge revisited, Crit Care Med 34:1333, 2006. 67. Cecconi M, Hofer C, Teboul J, et al: Fluid challenges in intensive care: the FENICE study, Intensive Care Med 41:1529-1537, 2015.

69 Transfusion Medicine Sarah E. Musulin, DVM, DACVECC

KEY POINTS • Donated blood can be transfused or stored as whole blood or further processed into components, such as packed red blood cells, plasma products and platelet products to address specific deficiencies. • Physiologic and circumstantial transfusion triggers should guide transfusion therapy decisions.

• Blood donor programs should follow best practices to ensure donor health, safety and comfort while producing safe and efficacious transfusion products. • Optimal storage, practical inventory strategies, and judicious allocation of transfusion products are necessary in the management of a limited resource.

INTRODUCTION

fibrinogen) are lost; thus logic follows that these patients should receive all of the components in a balanced ratio or WB. Massive transfusion is most commonly defined in small animals as the transfusion of a volume of WB or blood components that is greater than or equal to the recipient’s estimated blood volume in a 24-hour period or the transfusion of half of the recipient’s estimated blood volume within 3 hours. Massive transfusion protocols that incorporate separate component units of stored pRBCs, plasma, and PLTs in a 1:1:1 ratio contain a larger amount of anticoagulant and additives compared with WB. The use of WB in massive hemorrhage has reemerged in human trauma medicine.

The transfusion of blood and its components can be a lifesaving therapeutic when treating critically ill small animals. How we manage patients with blood loss and/or blood component deficiencies has evolved over the years in both human and veterinary medicine. The administration of large volumes of crystalloids in the hemorrhaging trauma patient has been linked to complications such as dilutional coagulopathy and fluid overload conditions. The use of synthetic colloids in human resuscitation is no longer advocated due to the lack of superiority over crystalloids and proven associations with renal injury and hemostatic dysfunction. The potential negative renal impact of synthetic colloids in veterinary patients is less clear and undergoing investigation. The negative impact of synthetic colloids on both primary and secondary hemostasis has been demonstrated in humans, dogs, and cats. In light of these complications associated with highvolume crystalloids and synthetic colloids, transfusion products have reemerged as the optimal fluid for volume and hemostatic resuscitation in the hemorrhaging patient. Advances in small animal veterinary medicine continue to create a demand for readily available high-quality blood transfusion products. Table 69.1 summarizes the available veterinary transfusion products, storage conditions, indications for use and dosing recommendations. The careful consideration of patient transfusion triggers should be balanced with possible complications and use of a limited resource. Processing whole blood (WB) into components, such as packed red blood cells (pRBCs) and plasma products, allows for maximization of donors and product. Storage times and conditions can also be optimized with component processing. The practice of transfusion medicine has evolved around improved understanding of how to tailor your transfusion decisions to your patient. Precision transfusion therapy dictates that only the deficient components are provided: anemic patients receive pRBCs, coagulopathic patients receive plasma, thrombocytopenic patients receive platelets (PLTs), and hypoalbuminemic patients receive albumin. Potential adverse effects may be avoided by minimizing the transfusion of unnecessary components and volume. In patients with significant hemorrhage, all blood components (RBCs, coagulation factors, PLTs, albumin,

ANEMIA AND RBC TRANSFUSIONS The decision to transfuse an anemic patient is primarily focused on the patient’s physiologic response to their anemia and associated oxygen debt. As with any therapeutic, the risk versus benefit of transfusing must be carefully evaluated. Patients that are chronically anemic are more tolerant of their anemia due to adaptive responses, such as increased cardiac output and off-loading of oxygen to the tissues via increases in 2,3-diphosphoglycerate, whereas patients that become acutely anemic are often more hemodynamically unstable with even mild drops in their PCV. With peracute blood loss, splenic contraction may mask a notable decrement in PCV until fluid shifts from the interstitial compartment occur and neurohormonal mechanisms (renin-angiotensin-aldosterone system, antidiuretic hormone) are induced or intravascular fluids are administered. A patient is considered clinically compromised by their anemia when they are weak, easily fatigued, mentally dull, collapsing, tachycardic, tachypneic, and/ or hyperlactatemic. Anemic patients with respiratory or cardiac disease or higher oxygen demand, such as with sepsis, may benefit from a more liberal transfusion trigger as a means of increasing oxygen delivery. Similarly, patients undergoing anesthetic or surgical procedures may warrant transfusion at higher PCVs. Conservative (hemoglobin [Hb] maintained between 7 and 9 g/dl) versus liberal (Hb maintained between 10 and 12 g/dl) transfusion strategies have been evaluated in various human patient populations. A 2015 metaanalysis concluded that liberal transfusion strategies do not convey a

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benefit to patients and that restrictive strategies were associated with a reduction in number of RBC units transfused and number of patients transfused without altering mortality or morbidity.1 Transfusion products available that provide RBCs include fresh whole blood (FWB), stored whole blood (SWB) and pRBCs. WB collected in a fixed ratio with an anticoagulant and transfused immediately is referred to as FWB. FWB may be held at room temperature (20°C222°C) for up to 24 hours with no deleterious effects on RBC or PLT recovery and survival and plasma functionality.2 FWB may be indicated in patients with severe hemorrhage that would benefit from the balanced replacement of all blood components, including RBCs, plasma, and fresh PLTs. FWB may also be selected for thrombocytopenic or coagulopathic patients that are anemic. FWB may be a more available product in settings where blood is not stored and blood donors are available as needed for emergency donations. SWB is WB collected into an anticoagulant-preservative solution at a fixed ratio and refrigerated at 2°C26°C for up to 35 days.3,4,5 A concentrated source of RBCs can be fractionated by processing FWB into pRBC and plasma components via centrifugation and separation. Packed RBCs are refrigerator stored (2°C26°C) with preservative additive solutions for 35242 days. The benefit of pRBCs is that a specific deficiency (RBC oxygen carrying capacity) can be addressed without the risk of adverse effects from the unnecessary components and volume.

PLATELET TRANSFUSIONS The transfusion triggers for thrombocytopenic patients are highly variable and clinician dependent. When severely thrombocytopenic (,50,000/ml) or thrombocytopathic patients have significant blood loss or bleed into vital organs or spaces (e.g., central nervous system, lungs, myocardium, pleural cavity), intervention is warranted. However, it is difficult to predict if patients with severe thrombocytopenia with or without superficial evidence of bleeding (e.g., petechia, mucosal bleeding) will progress to severe or life-threatening hemorrhage. There is yet to be a consensus in medicine that prophylactic PLT transfusions prevent more bleeding than a therapeutic-only PLT transfusion policy. Although it is generally accepted that PLT therapy prior to an invasive or surgical procedure would benefit hemostasis in thrombocytopenic/pathic patients, it is less clear at what PLT count or what comorbidities mandate this. PLT transfusions are an important element of hemostatic control in damage control resuscitation of the massively hemorrhaging patient. PLT transfusion products include fresh products such as FWB, platelet-rich plasma (PRP) and platelet concentrate (PC) and stored products such as SWB, cryopreserved PC, and lyophilized platelets. FWB has utility in thrombocytopenic/pathic patients that are also anemic. Although the PLTs in FWB are not concentrated, they have been minimally manipulated thus optimizing functionality and number. The dose of 10 ml/kg of FWB is expected to raise the PLT count by 10 3 109/L (10,000/ml).6 SWB is widely referenced as a source of RBCs and coagulation factors that is devoid of viable or functional PLTs due to refrigerated storage (2°C26°C). More recent investigations in human medicine reveal that cold-stored PLTs aggregate better and produce stronger clots than those stored between 20°C and 24°C.7 The hemostatic capacity of canine SWB refrigerated at 4°C (also known as cold or chilled whole blood) has been evaluated; these findings were presented in abstract form at the 2019 International Veterinary Emergency and Critical Care Symposium by Edwards et al. Edwards et al concluded that canine WB refrigerated at 4°C retains its ability to achieve maximum clot strength assessed via thromboelastography through 21 days of storage.8 The utility of an easily stored refrigerated PLT product that retains hemostatic capacity for weeks is profound.

Further published veterinary studies investigating the cold storage and handling (e.g., agitation) of PLTs for viability and optimal function are warranted to determine best practices. Concentrated PLT products may be acquired from WB donation and centrifugation or from apheresis. PRP and PC are fresh PLT components made from FWB. Human blood banking research determined that PLT products produced after an ambient hold (20°C224°C) for up to 24 hours may be of higher quality than those produced within 8 hours of donation.9 PRP and PC have utility in thrombocytopenic patients that are not anemic. PRP and fresh PC may be stored at room temperature for up to 5 days with gentle agitation. Cryopreservation technology of PC with dimethyl sulfoxide (DMSO) has allowed for longer storage time (280°C for 1 year) compared with fresh PLT products, although in vitro data of DMSO cryopreserved canine frozen PC suggest a decrease in quantity and function as well as an increase in activation during the freeze-thaw process.10,11 The in vivo hemostatic function and clinical efficacy of cryopreserved PC in bleeding patients warrant prospective investigation.12 Recent technology has led to the development of lyophilized PLTs (“freeze-dried”) PLTs. Although clinical research is currently underway, it is likely that lyophilized PLTs have a role in the treatment of active hemorrhage in thrombocytopenic/pathic patients. Significant advantages of lyophilized PLTs are the long-term storage (up to 24 months) at room temperature, ease of use (i.e., no thaw time), and sterility. Disadvantages include cost and short PLT lifespan. A final consideration in thrombocytopenic patients is that RBCs aid in hemostasis via multiple mechanisms including improvement of blood rheology (pushing the PLTs to the periphery to allow for endothelial contact), release of PLT-activating substances such as ADP and thromboxane A2, and the scavenging of nitric oxide by Hb allowing for PLT aggregation.

PLASMA TRANSFUSIONS Plasma constituents include water, inorganic salts, organic compounds and numerous proteins including albumin (ALB), immunoglobulins, hemostatic proteins, anticoagulants, fibrinolytic pathway proteins and protease inhibitors. The trend in reported reasons for the administration of plasma products has evolved over the years. The provision of deficient hemostatic proteins, such procoagulant clotting factors and fibrinogen, is the mainstay of plasma transfusions. Plasma can be used to replace multiple coagulation factors for acquired conditions such as hepatic failure or anticoagulant rodenticide toxicity or single factor deficiencies such as von Willebrand disease (vWD) or hemophilia A. Fresh frozen plasma (FFP) is produced by separating and freezing the plasma component of WB within 8 hours of collection. Although there is variability in donor hemostatic profiles,13,14 FFP is considered a source of all coagulation proteins when stored up to a year at ,230°C.15 Plasma prepared from WB held at ambient or refrigerator temperature for up to 24 hours is known as FP24. Canine FP24 has been evaluated, and the median coagulation factor activities for all units were above 50% and well above the minimum values set in human transfusion medicine for hemostasis.13 Liquid plasma (LP) is stored at refrigerator temperature for up to 2 weeks resulting in only minor loss of coagulation factor activity in canine plasma.16 Although the shelf-life of LP is significantly shorter than FFP, eliminating the need to thaw a plasma product in the acute management of critically ill patients may be lifesaving. After a year of frozen storage, FFP is relabeled as frozen plasma (FP) with some loss of clotting FVIII and FX activity over time.17 FP can be stored at 230°C for up to 5 years while maintaining hemostatic activity.17 FFP can be further processed into cryoprecipitate (CRYO) and cryopoor plasma (CPP). CRYO contains higher activities of vWF and factor VIII, and thus may be used as a

CHAPTER 69  Transfusion Medicine concentrated source of these factors in vWD or hemophilia A. The general indication for using a plasma product for coagulation factor replenishment is in patients that are not only significantly deficient in these hemostatic proteins but also bleeding, requiring massive transfusion, or undergoing an invasive procedure. The utility of plasma to replace ALB, anti-proteases and immunoglobulins in noncoagulopathic patients is debated. FFP, FP, FP24, and LP all contain ALB in low concentration to volume ratios. Calculations suggest that 45 ml/kg of plasma would need to be transfused to increase ALB serum concentration by 1 g/dl. In a study comparing canine CPP, CRYO, and FFP, the mean ALB concentration and colloid oncotic pressure (COP) were highest in CPP.18 The use of plasma as a source of anti-proteases for patients with pancreatitis is not recommended in human or veterinary medicine. A single retrospective veterinary study showed no benefit for administration in dogs with pancreatitis.19 The use of canine parvovirus-immune plasma was prospectively investigated in 14 dogs with naturally occurring canine parvoviral enteritis but was found ineffective in ameliorating clinical signs, reducing viremia, or hastening hematological recovery.20

ALBUMIN TRANSFUSIONS ALB-containing transfusion products have utility in hypoalbuminemic or inflammatory patients with increased vascular permeability requiring oncotic and volume support. ALB is the primary oncotic protein in plasma and serves to maintain vascular endothelial integrity, bind and carry serum exogenous drugs and endogenous hormones, and act as an antioxidant, antiinflammatory, and anticoagulant. Plasma transfusion products contain ALB in low concentration to volume ratios. Human and canine-specific ALB are concentrated sources of ALB. Prior to the availability of canine-specific albumin (CSA), human serum albumin (HSA) was clinically used and evaluated in canine patients despite incomplete homology between human and canine ALB. Initial studies examining the use of HSA in critically ill dogs demonstrated improvements in serum ALB concentration with few adverse effects.21,22 Further studies in healthy and sick dogs raised significant concerns regarding the use of HSA in dogs after severe, even fatal, type III hypersensitivity reactions were reported.23,24,25,26,27 Lyophilized CSA is a species-specific product. There are two commercially available products with extended shelf lives up to 24 months. The repeated infusion of 1 g/kg of a lyophilized CSA product (HemoSolutions) was found to be safe and effective in increasing serum ALB and COP in healthy Beagle dogs.28 No adverse events or evidence of type III hypersensitivities were noted after repeated infusions.28 The use of another lyophilized CSA product (Animal Blood Resources International) was evaluated in dogs with septic peritonitis with minimal adverse events attributed to the transfusion product.29 Dogs enrolled in the CSA group received of 800 mg/kg of CSA within 24 hours following surgical intervention and demonstrated an increase in serum ALB, COP, and Doppler blood pressure (BP) 2 hours after administration.29

BLOOD SOURCES AND DONOR MANAGEMENT Blood products can be purchased from commercial veterinary blood banks, or donor programs can be managed by individual hospitals. The organization of blood donor programs and veterinary blood banks requires the responsible balance of ensuring donor health and comfort while producing safe and efficacious transfusion products. A blood donor pool may consist of volunteer community-owned dogs and cats or animals that are kept as part of an in-house colony. Donors should be selected for their calm demeanor and be at ease with

411

transportation and the donation environment and process. Educating community donor owners on the importance of avoiding exposure of their pets to infectious diseases and complying with ectoparasite prevention is important. Predonation questionnaires can aid in the identification of potential exposures or risk behaviors. For in-house donor colonies, the housing environment must be clean and comfortable following standards such as those developed by Institutional Animal Use and Care Committees. In-house donors should be provided ample enrichment, socialization, and exercise opportunities. Donors should be observed for stress behaviors such as trembling, hiding, hypersalivation, and inappropriate voiding, and should be adopted out of the program if concerns arise. Donors should be young adults with no history of prior transfusion, infectious disease, or chronic/active health conditions. The screening process should begin with temperament testing in animals that have historically demonstrated comfort in unfamiliar environments and minimal stress with handling. Temperament testing may include mock donations that evaluate ease with restraint, shaving and venipuncture. Initial and regular health screening may include physical examination and blood work. The goal of donor health screening is to minimize the risk that the donor’s health is compromised by regular blood donation. Standard laboratory screening may include complete blood count, chemistry panel, urinalysis and fecal. More extensive donor screening for WB or plasma donations may include clotting times and/or coagulation factor quantification for product quality assurance. Some donor programs may rely solely on history (i.e., lack of bleeding events, uneventful surgical procedures) to assume adequate coagulation status in donors. Blood type must be determined in all donors and may be complemented with plasma antibody screening for anti-DEA antibodies in canine donors. Infectious disease testing should be guided by knowledge of blood-borne pathogens endemic to the donor’s geographical area. The American College of Veterinary Internal Medicine published updated consensus guidelines in 2016 for infectious disease testing for canine and feline blood donors in North America.30 Health screening and infectious disease testing should be completed annually or more frequently in donors that become ill, have high vector exposure, and/or live in blood-borne pathogen endemic areas. Screening for blood-borne pathogens prior to each donation is limited in veterinary medicine due to turnaround time and costs of testing. Blood bank surveillance programs may include saving an aliquot from each donation for random or circumstantial testing for blood-borne pathogens or contaminants. Optimal preventative healthcare should be ensured in all donors including vaccinations, deworming, flea, tick, and heartworm prevention. In general, administration of vaccines and other medications are discouraged in the peri-donation period.

BLOOD DONATION Canine Donors Mild sedation and anxiolysis may be utilized for the comfort of canine donors during collection. No sedation may be considered in donors selected for their calm demeanors. Positive reinforcement methods are recommended for donors, such as clicker training, affection, and/ or treats. Human closed blood collection multi-bag systems containing anticoagulant (e.g., citrate-phosphate-dextrose [CPD] or citratephosphate-dextrose-adenine-1 [CPDA-1]) and a RBC preservative (e.g., AS-1 Adsol or AS-5 Optisol) work well for canine WB donations for component processing. Standard sets containing 63270 ml of anticoagulant are intended for a 450–500 6 45 ml WB donation, necessitating that healthy canine donors weigh at least 50 pounds to

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safely donate.31 There is no consensus on donation volume and frequency in canine donors. The collection of 450 ml of blood in Greyhounds (,17%222% of total blood volume, TBV, in an average sized Greyhound) was found to be safe but resulted in a statistically significant but transient decrease in systolic BP post-donation.31 Another study suggested blood donation up to 15% (,13.5 ml/kg) is safe in nonsedated dogs, but the hemodynamic variations observed in sedated (ketamine/diazepam) dogs donating 15% TBV compromise the harmlessness of the procedure.32 Early investigation of donation frequency based on the RBC regenerative capacity of dogs suggest that dogs may donate blood (,20% TBV, ,18 ml/kg) up to every 4 weeks for 1 year without developing anemia.33 Iron parameters may be more appropriate when determining ideal donation frequency. Regular blood donation (6 times annually) can lead to decreases in iron stores that may not be evidenced as anemia.32,34,35 Considerations for donor programs may include selecting for larger donors, increasing donation interval, providing iron supplementation, and monitoring donors for iron deficiency.

Feline Donors Feline donors are expected to require sedation for donation. Various methods of chemical restraint have been investigated including injectable sedatives and inhalant anesthetics. Considerations for chemical restraint in cats include depth of sedation or anesthesia, ease of administration, capacity for reversal, adverse side effects, and recovery. Injectable sedatives should be given through the cephalic or medial saphenous vein to avoid the jugular veins used for donation. Unexpected events occurring during collection of blood donations performed with and without sedation in cats has been retrospectively evaluated.36 Although movement during donation and signs of donor anxiety were significantly more frequent in unsedated cats, the authors concluded that these issues were minor and unsedated donations in cats is an acceptable alternative.36 Veterinary blood collection sets are available for small volume donations. Animal Blood Resources International manufactures a variety of small animal blood collection systems, including a 100 ml double bag set for component processing that incorporates a 60-ml syringe for suction. These collection sets are “semi-closed” because they require the addition of an anticoagulant-preservative solution in order to prolong the storage of blood components. Individual doses of the anticoagulant-preservative solution, such as CPDA-1, can be aseptically aliquoted in a hood and stored according to manufacturer’s recommendations and then aseptically added to the collection set just prior to donation. Feline donors should weigh at least 5 kg based on lean body mass to safely donate a unit (,50 ml) of blood. This donation volume has been shown to lead to a decrease in arterial BP, PCV, and heart rate in cats anesthetized with sevoflurane for donation, although these changes were not considered clinically relevant.37 Parenteral fluids can be administered after each donation. There is no consensus on

recommended donation frequency or iron supplementation in feline donors.

Blood Collection Prior to each donation, an updated health and medication history should be completed as well as a physical examination and PCV or Hb level assessment. Predonation PCV should be 40% in dogs and 35% in cats. All necessary equipment and supplies should be arranged in a comfortable and familiar room prior to each donation. Skilled personnel (2–3) are necessary to perform the phlebotomy, comfort the donor with petting and minimal restraint, and monitor the procedure. The donation can be performed on a raised table with clean and adequate cushioning. The donor is placed in lateral recumbency for shaving a generous area around the identified jugular vein. The skin is aseptically prepared and locally blocked with lidocaine at the site of venipuncture. Strict aseptic technique including donning gloves and sterile equipment is mandated to prevent contamination of the product. The donor’s tolerance to the procedure should be monitored throughout, including movement, mucous membrane color, pulse rate and quality, and respiratory rate and effort. The procedure should be aborted if any concerns are noted. The collection of WB can be performed via gravity or suction. With the gravity method, the collection bag is positioned below the patient onto an electric mixer with an integrated scale placed on the floor. For collection by suction, a vacuum-assisted blood collection chamber is positioned on a scale and connected to wall suction.

BLOOD BANKING Having an available inventory of transfusion products for the management of emergent and critically ill patients requires specialized storage equipment. Refrigerated RBC products should be stored in a dedicated refrigerator with continuous temperature monitoring that alarms to alert personnel to temperatures outside of 2°C–6°C. Each blood unit should be partitioned in an upright position and rotated daily to allow for admixture of preservative solution and RBCs. Plasma freezers should be laboratory grade quality to allow for low temperatures and temperature stability. Household refrigerators and freezers undergo cooling and freeze-thaw cycles that may damage blood constituents. Inadequate storage conditions can result in ineffective and even harmful product.38 Veterinary transfusion products are a valuable resource warranting practical and shrewd inventory management. Inventory should be sufficient to supply patient demand, but with minimal to no waste due to product expiration. This delicate balance is compounded by concern over the biomechanical, biochemical, and immunomodulating changes that occur during the storage of blood constituents, called storage lesion. Computer-based blood donor and inventory management systems can be created to meet individual blood bank and/or hospital needs.

CHAPTER 69  Transfusion Medicine

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TABLE 69.1  Veterinary Transfusion Products Transfusion Product FRESH WHOLE BLOOD (FWB) WB collected with anticoagulant (1/2 RBC preservatives)

STORED WHOLE BLOOD (SWB) COLD WHOLE BLOOD (CWB) WB collected with anticoagulant and RBC preservatives

Storage Conditions

Components

Indications

Immediately transfused OR Stored up to 24 h with continuous gentle agitation at room tempb when mixed with preservatives

All blood components - RBCs, WBCs, PLTs, coagulation factors, albumin, globulins

Massive hemorrhage Thrombocytopenic/pathic anemic patients Coagulopathic anemic patients

2°C–6°C for 28–35 da

RBCs Coagulation factors - Gradual loss of labile coagulation FVIII, FV

Blood loss anemia Coagulopathic anemic patients

2°C–6°C for 21 da

RBCs Coagulation factors - Gradual loss of labile coagulation FVIII, FV PLTs

Massive hemorrhage Coagulopathic anemic patients Thrombocytopenic/pathic anemic patients

RBCs

Anemia

PACKED RED BLOOD CELLS (pRBCs) 2°C–6°C for 35–42 da Produced from hard spin centrifugation of WB, removal of plasma supernatant and addition of preservative solution to remaining pRBCs

Dosing Recommendations

VT (ml) of WB 5 2 3 PCV rise desired (%) 3 BW (kg) OR 2 ml of WB/kg raises the PCV by ,1 % OR ,20 ml/kg

VT of pRBC (ml) 5 PCV rise desired (%) 3 1.5 3 BW (kg) OR VT of pRBC (ml)  desired PCV  patient PCV

 donor unit PCV blood volume (ml/kg)  BW (kg)

Dog blood volume 5 90 ml/kg Cat blood volume 5 60 ml/kg FRESH FROZEN PLASMA (FFP) Produced from hard spin centrifugation of WB and removal of plasma supernatant. Process to FFP and freeze within 24 h of WB collection.39

#-30°C for 1 yr15

Coagulation factors Albumin, other proteins

Coagulopathy Hypoalbuminemia

FROZEN PLASMA (FP) FFP .1 yr storage

#-30°C for 5 yr17

Coagulation factors - Gradual loss of FVIII and FX17 Albumin, other proteins

Coagulopathy Hypoalbuminemia

LIQUID PLASMA (LP) REFRIGERATED PLASMA (RP) Produced from hard spin centrifugation of WB within 8 hours of collection and removal of plasma supernatant

2°C–6°C for 14 d

Coagulation factors - Fibrinogen - 20% decrease over 14 days, although remain within reference range - FVIII, FX decline over 14 days with maintenance of coagulation activity

Coagulopathy

CRYOPRECIPITATE (CRYO) #-30°C for 12 mos (from Concentrated source of Produced from FFP FFP collection) coagulation FVIII, FXIII, - Slow (,8–10 h) refrigerator (,4°C) von Willebrand factor (vWf), fibrinogen, and thawing of FFP unit(s) until the fibronectin in plasma plasma reaches a slushy consistency, hard spin centrifuged for 7 min at 4°C and expressing off the supernatant (cryo-poor plasma) for remaining CRYO

,10–20 ml/kg Notes: - Reassess patient parameters as needed for redosing (e.g., clotting times, bleeding) - 1/3 of canine plasma volume is 15–20 ml/kg

Coagulopathy - Hemophilia A, 1 unit of CRYO (obtained from a 250 vWf deficiency, hypofibrinoml bag of FFP) per 10–12 kg BW genemia Note: - Reassess patient parameters as needed for redosing (e.g., clotting times, bleeding)

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TABLE 69.1  Veterinary Transfusion Products—Cont’d Transfusion Product CRYO-POOR PLASMA (CRYO-PP, CPP) CRYO-SUPERNATANT Resulting supernatant produced during cryoprecipitate preparation

Storage Conditions #-30°C for 12 months (from FFP collection)

Components Coagulation factors - FII, FVII, FX18 Albumin18

Indications Coagulopathy - Anticoagulant rodenticide coagulopathy Hypoalbuminemia

Dosing Recommendations ,6–20 ml/kg Note: - Reassess patient parameters as needed for redosing (e.g., clotting times, bleeding, albumin)

PLATELET-RICH PLASMA (PRP) Soft spin centrifugation of FWB at 22°C followed by PRP extraction from RBC product into satellite bag

PRP may be immediately Platelets transfused or stored Clotting factors at room tempb with Mean platelet yield from continuous gentle WB to PRP is ,78% agitation up to 5 d

Thrombocytopenia/pathia

1 unit of WB-derived PRP (,8 3 1010 platelets) per 10 kg BW

PLATELET CONCENTRATE (PC) Hard spin (,2000 g for 10 min) of PRP at 22°C Buffy coat-derived PC method Plateletpheresis

Fresh PC may be imme- Platelets (Mean platelet yield from diately transfused or FWB to PC is ,74%40) stored at room tempb with continuous gentle agitation up to 5 d Cryopreservation (DMSO 1/2 thrombosol) allows for freezer storage (-80°C for 1 yr, -20°C for 6 mos)

Thrombocytopenia/pathia

WB-derived fresh PC (,8 3 1010 platelets) - 1 unit per 10 kg BW Cryopreserved PC (,0.5 3 1011 platelets) - 1 unit per 10 kg BW

LYOPHILIZED PLATELETS Room temperature A trehalose-loaded freeze-dried (18°C–30°C) for platelet concentrate is produced 12 mos from platelets collected via apheresis or whole blood donation

Platelets in circulation 4–8 h

Hemostatic control in the StablePlate RX Suggested Dosing: presence of thrombocytope- - Severe hemorrhage - 1.6 ml/kg nia/pathia - Moderate hemorrhage - 0.8 ml/kg - Preventative prior to invasive procedure - 0.8 ml/kg

ALBUMIN - CANINE Room temperature Obtained from separation of canine (18°C–24°C) for FP by a modified heat shock method 24 mos (heated to 60°C and concentrated Store at 2°C–6°C after by precipitation and ultrafiltration) rehydration up to 24 h

Albumin

Hypoalbuminemia

Dose albumin (g) 5 10 3 (2.0 g/dl patient albumin g/dl) 3 BW (kg)  0.3 ,450 mg/kg canine albumin will increase the serum albumin by 0.5 g/dl

Storage times depend on the anticoagulant-preservative solution used. Room temperature 5 20°C–22°C BW, body weight; d, days; h, hours; min, minutes; mos, months; PLT, platelet(s); RBC, red blood cell; temp, temperature; VT, volume transfused; WB, whole blood; yr, year..

a

b

REFERENCES 1. Holst LB, Petersen MW, Haase N, Perner A, Wetterslev J: Restrictive versus liberal transfusion strategy for red blood cell transfusion: a systematic review of randomized trials with meta-analysis and trial sequential analysis, BMJ 350:h1354, 2015. 2. Van der Meer PF, de Korte D: The effect of holding times of whole blood and its components during processing on in vitro and in vivo quality, Transfus Med Rev 29(1):24-34, 2014. 3. Marion RS, Smith JE: Posttransfusion viability of feline erythrocytes stored in acid-citrate-dextrose solution, J Am Vet Med Assoc 183(12):1459-1460, 1983. 4. Bucheler J, Cotter SM: Storage of feline and canine whole blood in CPDA-1 and determination of post-transfusion viability, J Vet Intern Med 8:172, 1994. 5. Crestani C, Stefani A, Carminato A, et al: In vitro assessment of quality of citrate-phosphate-dextrose-adenine-1 preserved feline blood collected by a commercial closed system, J Vet Intern Med 32:1051-1059, 2018. 6. Hux BD, Martin LG: Platelet transfusions: treatment options for hemorrhage secondary to thrombocytopenia, J Vet Emerg Crit Care 22(1):73-80, 2012. 7. Spinella PC, Pidcoke HF, Strandenes G, et al: Whole blood for hemostatic resuscitation of major bleeding, Transfusion 56:S190-S202, 2016.

8. Edwards TH, Darlington DN, Pusateri AE, et al: Hemostatic capacity of canine chilled whole blood, J Vet Emerg Crit Care 29(S1):S5, 2019. 9. Thomas S: Ambient overnight hold of whole blood prior to the manufacture of blood components, Trans Med 20:361-368, 2010. 10. Guillaumin J, Jandrey KE, Norris JW, Tablin F: Assessment of a dimethyl sulfoxide-stabilized frozen canine platelet concentrate, Am J Vet Res 69:1580-1586, 2008. 11. Guillaumin J, Jandrey KE, Norris JW, Tablin F: Analysis of a commercial dimethyl-sulfoxide-stabilized frozen canine platelet concentrate by turbidometric aggregometry, J Vet Emerg Crit Care 20(6):571-577, 2010. 12. Ng ZY, Stokes JE, Alvarez L, Bartges JW: Cryopreserved platelet concentrate transfusions in 434 dogs: a retrospective study (2007-2013), J Vet Emerg Crit Care 26(5):720-728, 2016. 13. Walton JE, Hale AS, Brooks MB, et al: Coagulation factor and hemostatic protein content of canine plasma after storage of whole blood at ambient temperature, J Vet Intern Med 28:571-575, 2014. 14. Drinkhouse M, Brooks MB, Stefanovski D, et al: Influence of canine donor plasma hemostatic protein concentration on quality of cryoprecipitate, J Vet Intern Med 33:124-131, 2019. 15. Wardrop KJ, Brooks MB: Stability of hemostatic proteins in canine fresh frozen plasma units, Vet Clin Path 30:91-95, 2001.

CHAPTER 69  Transfusion Medicine 16. Grochowsky AR, Rozanski EA, de Laforcade AM, et al: An ex vivo evaluation of efficacy of refrigerated canine plasma, J Vet Emerg Crit Care 24(4):388-397, 2014. 17. Urban R, Couto CG, Iazbik MC: Evaluation of hemostatic activity of canine frozen plasma for transfusion by thromboelastography, J Vet Intern Med 27:964-969, 2013. 18. Culler CA, Iazbik C, Guillaumin J: Comparison of albumin, colloid osmotic pressure, von Willebrand factor, and coagulation factors present in canine cryopoor plasma, cryoprecipitate, and fresh frozen plasma, J Vet Emerg Crit Care 27(6):638-644, 2017. 19. Weatherton LK, Streeter EM: Evaluation of fresh frozen plasma administration in dogs with pancreatitis: 77 cases (1995-2005), J Vet Emerg Crit Care 19(6):617-622, 2009. 20. Bragg RF, Duffy AL, DeCecco FA, et al: Clinical evaluation of a single dose of immune plasma or treatment of canine parvovirus infection, J Am Vet Med Assoc 240:700-704, 2012. 21. Chan DL, Rozanski EA, Freeman LM, et al: Retrospective evaluation of human serum albumin use in critically ill dogs, J Vet Emerg Crit Care 14(Suppl 1):S8, 2004. 22. Mathews KA, Barry M: The use of 25% human serum albumin: outcome and efficacy in raising serum albumin and systemic blood pressure in critically ill dogs and cats, J Vet Emerg Crit Care 15(2):110-118, 2005. 23. Cohn LA, Kerl ME, Lenox CE, et al: Response of healthy dogs to infusions of human serum albumin, Am J Vet Res 68:657-663, 2007. 24. Francis AH, Martin LG, Haldorson GJ, et al: Adverse reactions suggestive of type III hypersensitivity in six healthy dogs given human albumin, J Am Vet Med Assoc 230:873-879, 2007. 25. Powell C, Thompson L, Murtaugh RJ: Type III hypersensitivity reaction with immune complex deposition in 2 critically ill dogs administered human serum albumin, J Vet Emerg Crit Care 23(6):598-604, 2013. 26. Loyd KA, Cocayne CG, Cridland JM, Hause WR: Retrospective evaluation of the administration of 25% human albumin to dogs with protein-losing enteropathy: 21 cases (2003-2013), J Vet Emerg Crit Care 26(4):587-592, 2016. 27. Mazzaferro EM, Balakrishnan A, Hackner SG, et al: Delayed type III hypersensitivity reaction with acute kidney injury in two dogs following administration of concentrated human albumin during treatment for hypoalbuminemia secondary to septic peritonitis, J Vet Emerg Crit Care 30(5):574-580, 2020. doi.10.1111/vec.12976.

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28. Enders BD, Musulin SE, Holowaychuk, MK, et al: Repeated infusion of lyophilized canine albumin safely and effectively increases serum albumin and colloid oncotic pressure in healthy dogs, J Vet Emerg Crit Care 28(Suppl 1):S5, 2018. 29. Craft EM, Powell LL: The use of canine-specific albumin in dogs with septic peritonitis, J Vet Emerg Crit Care 22(6):631-639, 2012. 30. Wardrop KJ, Birkenheuer A, Blais MC, et al: Update on canine and feline blood donor screening for blood-borne pathogens, J Vet Intern Med 30:15-35, 2016. 31. Couto CG, Iazbik MC: Effect of blood donation on arterial blood pressure in retired racing greyhounds, J Vet Intern Med 19:845-848, 2005. 32. Ferreira RRF, Gopegue RR, Araujo MMRC, Matos AJF: Effects of repeated blood donations on iron status and hematologic variables of canine blood donors, J Am Vet Med Assoc 244:1298-1303, 2014. 33. Potkay S, Zinn RD: Effects of collection interval, body weight, and season on the hemograms of canine blood donors, Lab Anim Care 19:192-197, 1969. 34. Zaldivar-Lopez S, Iazbik MC, Marin LM, Couto CG: Iron status in blood donor dogs, J Vet Intern Med 28:211-214, 2014. 35. Foy DS, Friedrichs KR, Bach JF: Evaluation of iron deficiency using reticulocyte indices in dogs enrolled in a blood donor program, J Vet Intern Med 29:1376-1380, 2015. 36. Doolin KS, Chan DL, Adamantos S, Humm K: Retrospective evaluation of unexpected events during collection of blood donations performed with and without sedation in cats (2010-2013), J Vet Emerg Crit Care 27(5):555-560, 2017. 37. Iazbik MC, Gomez OP, Westendorf N, et al: Effects of blood collection for transfusion on arterial blood pressure, heart rate and PCV in cats, J Vet Intern Med 21(6):1181-1184, 2007. 38. Patterson J, Rousseau A, Kessler RJ, Giger U: In vitro lysis and acute transfusion reactions with hemolysis by inappropriate storage of canine red blood cell products, J Vet Intern Med 25:927-933, 2011. 39. Cardigan R, Van der Meer PF, Cookson P, et al: Coagulation factor content of plasma produced from whole blood stored for 24 hours at ambient temperature: results from an international multicenter BEST collaborative study, Transfusion 51(Suppl 1):50S-57S, 2011. 40. Abrams-Ogg AC, Kruth SA, Carter RF, et al: Preparation and transfusion of canine platelet concentrates, Am J Vet Res 54(4):635-642, 1993.

70 Blood Types, Pretransfusion Compatibility, and Transfusion Reactions Sarah E. Musulin, DVM, DACVECC

KEY POINTS • Canine and feline blood types are based on the characterization of species-specific red blood cell antigens. An understanding of canine and feline blood types is necessary when navigating transfusion decisions. • The transfusion of blood is a lifesaving therapeutic that carries the risk of adverse reactions and transfusion-associated complications. • Pretransfusion compatibility tests include blood typing, crossmatching, and antibody screening.

BLOOD TYPES Canine Traditional canine blood group classification is based on the dog erythrocyte antigen (DEA) system followed by a number denoting the blood type. Newly identified canine red blood cell (RBC) antigens, such as Dal and Kai 1 and 2, do not follow the DEA system. For most blood groups, individual dogs exhibit one phenotype for each system; for example, a dog may be DEA 4, 7, and Dal-positive and 3, 5, and Kai 1- and 2-negative. One exception to this is the DEA 1 blood group system. Historically, the DEA 1 system as assessed by polyclonal alloantibodies was considered a three factor, four phenotype system: DEA 1.1, 1.2, 1.3, and null. In 2014, Acierno et al. determined that the variation in DEA 1 involves the same DEA 1 epitope with different surface expression.1 Aligning with this understanding, a dog can be DEA 1 (2) or weakly to strongly DEA 1 (1). The distribution of DEA 1 in the canine population is nearly equal but varies geographically and among breeds. DEA 1 is considered the most immunogenic RBC antigen and thus is the most clinically significant blood group in dogs. Naturally occurring anti-DEA 1 antibodies have not been documented in dogs, although sensitization does occur. Sensitization of a DEA 1 (2) dog with DEA 1 (1) blood will lead to the formation of hemolyzing and strongly agglutinating antibodies against DEA 1 (1) RBCs and reexposure can lead to an acute hemolytic transfusion reaction (AHTR). Further investigation is needed to determine the differences in the immune responses to weakly to strongly DEA 1 (1) dogs. In a preliminary study by Canard et al., they utilized mean fluorescence intensity in flow cytometry to show that transfusion between dogs expressing different levels of DEA 1 antigen does not induce the formation of alloantibodies.2 This study included two weakly DEA 1 (1) dogs and one moderately DEA 1 (1) dog that received strongly DEA 1 (1) RBCs, none of which developed anti-DEA 1 (1) alloantibodies 2 months after transfusion.2

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• Pretransfusion compatibility tests can circumvent some immunological transfusion reactions such as acute hemolytic transfusion reactions; they do not guarantee transfusion efficacy or posttransfusion red blood cell viability or eliminate the risk of other transfusion reactions. • Optimization of pretransfusion compatibility, storage conditions, administration techniques, and monitoring are instrumental in stewarding safe and effective transfusion.

The DEA 3, 4, 5, and 7 blood groups adhere to the single factor, two phenotype system with DEA 3, 4, 5, and 7 (1) being the dominant phenotypes. Approximately 6%–7% of the general canine population in the United States is DEA 3 (1) with a higher prevalence in Greyhounds. Naturally occurring anti-DEA 3 alloantibodies have been identified in up to 20% of DEA 3 (2) dogs. The majority (.99%) of dogs are DEA 4 (1); therefore sensitization is rare. Naturally occurring anti-DEA 4 alloantibodies have not been identified. There is a case report of a sensitized DEA 4 (2) dog that exhibited a severe AHTR when transfused with DEA 4 (1) blood.3 The prevalence of DEA 5 is approximately 11% in the general canine population with a higher percentage identified in Greyhounds. Naturally occurring anti-DEA 5 alloantibody has been reported in ,10% of dogs. The administration of DEA 3, 5, or 7 (1) RBCs to a sensitized DEA 3, 5, or 7 (2) recipient, respectively, is reported to result in delayed clearance of transfused cells within 3 to 5 days.4 Typing sera are no longer available for DEA 6 and 8. The DEA 7 antigen is expressed in 9.8%–55% of dogs.5-8 There are conflicting reports in the literature regarding the presence of anti-DEA 7 alloantibodies in DEA 7 (2) dogs, ranging from 0% to 38%.7-10 The clinical significance of naturally occurring anti-DEA 7 antibodies in DEA 7 (2) dogs transfused with DEA 7 (1) cells is debated. Spada et al. further classified the activity, specificity, and titer of naturally occurring anti-DEA 7 antibodies as low-titered (73% having ,1:2 titer), warm, weakly agglutinating, mostly naturally occurring IgM (69%) anti-DEA 7 antibodies.7 The anti-DEA 7 antibodies that were evaluated in vitro showed no hemolytic activity, although titers were low and samples were collected in EDTA, which can inhibit complement-based lytic activity.7 In vivo evaluation of the transfusion of DEA 7 (1) RBCs to the patients with naturally occurring anti-DEA 7 antibodies was not performed.7 In 2007, a new canine RBC antigen was identified when a sensitized Dalmatian developed alloantibodies not related to known DEA types. The index Dalmatian dog in this study developed anti-Dal alloantibodies (IgG class) after transfusion.11 Further investigation revealed

CHAPTER 70  Blood Types, Pretransfusion Compatibility, and Transfusion Reactions that the prevalence of this RBC antigen, coined Dal, appears to be quite high (,93%) in most dog breeds, but low in some breeds. Dal (-) dogs have been identified in Dalmatians, Doberman Pinschers, Shih Tzus, Lhasa Apsos, Beagles, Bichon Frises, and mixed-breed dogs.12 Naturally occurring anti-Dal alloantibodies have not been identified in Dal (2) dogs. The Kai blood group was originally identified in South Korea in 2016. The prevalence of these two new Kai antigens, Kai 1 and Kai 2, has been surveyed in North America by Euler et al. in 2016.13 The majority of dogs evaluated (94%) were Kai 1 (1) and Kai 2 (2) to include all of the Greyhounds tested (n 5 70).13 No detectable naturally occurring alloantibodies against Kai 1 or Kai 2 were identified.13 The clinical relevance of the Kai 1 and Kai 2 antigens remains to be determined.

Feline Feline blood groups are classified using an AB nomenclature with three alleles: type A, type B, and type AB in decreasing order of frequency. Breed and geography influence blood type frequency and prevalence studies. The majority (.95%) of domestic short- and longhair cats in the United States are type A followed by type B and then extremely rare type AB. Approximately 50% of Turkish Van, Devon Rex, and British Shorthair cats are type B. Clinically significant naturally occurring alloantibodies do exist in type A and type B cats, but not in type AB cats. Type A cats may have no or relatively weak anti-B alloantibody titers (generally # 1:32 and often # 1:8) of both the IgG and IgM classes that can cause agglutination and hemolysis.14 Type B cats have strong, predominately IgM, high-titered (1:64–1024) anti-A alloantibodies that can result in severe agglutination, AHTR, and neonatal isoerythrolysis.14 A new feline RBC antigen, coined Mik, was identified in 2007 after a hemolytic transfusion reaction (HTR) was identified in a cat transfused with AB-compatible blood.15

PRECOMPATIBILITY TESTING In addition to donor screening and prudent transfusion product handling, pretransfusion compatibility testing is recommended to minimize transfusion reactions related to immunologic incompatibility. Precompatibility testing may include blood group typing, antibody screening and identification, and crossmatching. Blood typing methods detect hemagglutination of patient RBCs with known RBC antibody to determine blood type. Point-of-care blood typing kits are available to determine DEA 1, 4, 5, and Dal status in dogs and AB status in cats. More extensive blood typing is available in specialized laboratories. Blood types should be determined for both blood donors and recipients. Type-compatible transfusions are recommended to ensure the likelihood of RBC survival posttransfusion and to avoid sensitization. In dogs, the DEA 1 blood group is the most immunogenic and clinically significant blood type for compatibility. Cats do possess naturally occurring RBC alloantibodies, thus necessitating type-compatible transfusions for both RBC and plasma products. The major crossmatch is designed to test the compatibility between donor RBCs and recipient plasma. The minor crossmatch is designed to test compatibility between donor plasma with recipient RBCs. A positive test reveals visible hemolysis and/or hemagglutination consistent with incompatibility. A negative test is void of hemagglutination (macroagglutination 1/2 microagglutination depending on crossmatch methodology) or hemolysis and implies compatibility. Blood typing, antibody screening, and crossmatching are performed to prevent immune-mediated HTRs and alloimmunization. Because AHTRs have not been described in dogs receiving first-time transfusions, the utility of crossmatching dogs prior to their first transfusion is debated. In 2017 Odunayo et al. retrospectively determined the incidence of incompatible crossmatch in a group transfusion naïve

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dogs to be 17%, where 25 of 149 dogs evaluated were incompatible (any agglutination at room temperature or at 37°C) with one or two of the three potential donors.16 This percentage of incompatible crossmatches on transfusion naïve patients may have been accentuated by incomplete owner knowledge of dogs’ previous transfusion history. Odunayo et al. further evaluated the mean change in posttransfusion hematocrit (Hct) in a group (n 5 57) of crossmatch-compatible dogs and 20 other dogs that underwent transfusion without prior crossmatching. The mean change in Hct 1/2 SD (not indexed to ml/ kg transfused) was significantly higher (P 5 0.026) in dogs that had crossmatching performed (12.5 1/2 8.6%) than in dogs that did not undergo crossmatching (9.0 1/2 4.3%).16 The packed cell volumes (PCVs) of the donor units transfused were not evaluated in this study. The consequences of an incompatible crossmatch were not evaluated. The discovery of clinically significant naturally occurring antiMik alloantibodies in domestic shorthair cats suggests the utility of performing a crossmatch in AB-compatible transfusions in transfusion naïve cats, although studies have had conflicting results (see Table 70.1). Crossmatching is necessary in dogs and cats that have been previously transfused with an appropriate time lapse for alloantibody formation. In dogs that have previously been transfused 4 days prior, it is necessary to determine crossmatch compatibility prior to transfusion. In 2017 Goulet and Blais characterized anti-Dal alloantibodies following sensitization via transfusion of Dal (1) pRBCs in two Dal (2) dogs.17 Anti-Dal IgG alloantibodies were detectable as soon as 4 days posttransfusion and remained detectable for as long as 2 years.17 Pregnancy does not induce alloantibody formation in dogs; therefore, no additional pretransfusion compatibility testing is required.18 A 2017 prospective study by Hourani et al. evaluated the occurrence of alloimmunization in transfused feline patients by performing serial crossmatching in a population of hospitalized cats.19 The majority of cats (15/21, 71.4%) had negative major crossmatches 1 and 12 days (median 5 days) after initial transfusion.19 Five of 20 (25%) transfusion naïve cats had a positive major crossmatch after initial transfusion.19 The earliest occurrence of alloimmunization was 2 days (range 2–10 days, median 5 days) after the first AB-compatible transfusion.19 Further investigations are warranted to examine if crossmatching is advisable as early as 2 days posttransfusion in cats.

TRANSFUSION REACTIONS The incidence of transfusion reactions in large retrospective veterinary studies has ranged from to 3.3% to 28% in dogs and cats.20-26 Transfusion reactions can occur acutely during or shortly after a transfusion or can be delayed days to weeks. Acute transfusion reactions are defined as within 24 hours of transfusion completion. Delayed transfusion reactions are defined as greater than 24 hours after transfusion completion. Transfusion reactions can be secondary to the recipient’s immune system response to a foreign antigen or nonimmunologic, such as transmission of a blood-borne pathogen, circulatory overload, or citrate toxicity. Because the clinical signs associated with transfusion reactions and complications can be nonspecific or indistinguishable from the patient’s disease process(es), the true incidence of transfusion reactions is unclear. Additionally, there is variability in how transfusion reactions are defined in the literature. A working group of the Association of Veterinary Hematology and Transfusion Medicine has created the Transfusion Reaction Small Animal Consensus Statement (TRACS) guidelines for defining, preventing, and treating veterinary transfusion reactions.27-29 The definitions provided in this chapter reflect these working guidelines.27

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TABLE 70.1  Summary of Veterinary Literature Evaluating the Utility of Red Blood Cell

Crossmatching in Cats

Transfusion Naïve Crossmatch Incompatibilities

Mean Δ in PCV XM1 crossmatched XM2 not crossmatched

Transfusion Reactions

0/112 (0%)

N/A

N/A

N/A

XM1 1.02 1/2 0.51%PCV /ml/kg XM2 0.74 1/2 0.65%PCV /ml/kg

N/A

Sylvane JVIM 201848 Prospective

10/52 (19%)

No significant difference at 1-, 12-, and 24-hours No significant difference in AHTR posttransfusion 1 cat in crossmatch group had (%  in PCV/ml/kg) AHTR

McClosky JVIM 201849 Retrospective

23/154 (14.9%)

XM1 0.76 %/ml/kg XM2 0.97 %/ml/kg

FNHTRs more common in noncrossmatched cats

Goy-Thollot JVIM 201914

14/636 (2.2%)

N/A

N/A

Humm JSAP 2020 Prospective

27% and 10% major and minor incompatibility - The administration of crossmatchlaboratory slide agglutination method compatible blood did not lead to a greater 4% - Commercial crossmatching test increase in PCV at 12 hours (Poor kappa agreement between crossmatching methods)

The commercial crossmatching test appeared to be most specific for predicting hemolytic transfusion reactions

Martinez-Sogues JSAP 202051 Retrospective

N/A

No significant difference at 1- and 5-hours posttransfusion DPCV 24 hours after transfusion: XM1 7.2% XM2 4.0% (The number of cats with crossmatches performed was low, limiting capacity to compare transfusion efficacy between the two groups; P,0.53.)

The administration of XMcompatible transfusions was not associated with a decreased rate of transfusionassociated complications

Binvel JVIM 2021 Prospective

18/258 (7%)

N/A

N/A

Study Tasker JSAP 201446 Weltman JVECC 2014 Retrospective

50

47

AHTR, acute hemolytic transfusion reaction; FNHTR, febrile nonhemolytic transfusion reaction; PCV, packed cell volume; XM, crossmatch.

Hemolytic Transfusion Reactions Hemolytic transfusion reactions may be immunologic or nonimmunologic in nature. Immunologic transfusion reactions involve antigen– antibody reactions. The quantity and ability of an RBC antigen to provoke an immune response and the anti-RBC alloantibody response determine the consequences of potential RBC incompatibilities. Antibody factors, such as titer, immunoglobulin class (IgG, IgM), and ability to bind complement, thermal range, specificity, and mode of reactivity can all influence the pathological effects of an antibody. Nonimmunologic HTRs occur due to thermal, osmotic, mechanical, or chemical factors that damage transfused RBCs, causing acute or delayed hemolysis. Ex vivo cellular damage may occur prior to transfusion with improper or prolonged storage or bacterial contamination. RBC damage can occur secondary to improper administration techniques, such as coadministration with medications or hypotonic fluids or trauma from administration pumps and extracorporeal devices. An AHTR is defined as a noninfectious, immunologic, or nonimmunologic reaction that occurs secondary to accelerated destruction of transfused or recipient RBCs during or within 24 hours of blood product administration. Immunologic AHTRs are type II hypersensitivity reactions that occur due to major or minor RBC incompatibility. AHTRs are classically associated with IgM immunoglobulin and complement activation leading to intravascular hemolysis, hemoglobinemia, and hemoglobinuria. Additional clinical signs may include fever, tachycardia, tachypnea, restlessness, vomiting, and defecation. More severe reactions may include hypotension and hemodynamic compromise, disseminated intravascular coagulation, kidney injury,

and death. The crossmatch test is designed to determine compatibility by detecting acute hemolysis and agglutination and prevent AHTRs. A delayed hemolytic transfusion reaction (DHTR) is a noninfectious, immunologic, or nonimmunologic reaction that occurs secondary to lysis or accelerated clearance of transfused RBCs greater than 24 hours to 28 days after blood product administration. Immunologic DHTRs are classically caused by a secondary immune response involving IgG antibodies leading to extravascular hemolysis. Clinical signs may be nonapparent or vague signs of anemia, such as lethargy, weakness, and/or inappetence. In more severe DHTRs, patients may exhibit fever, nausea or vomiting, tachycardia, hypotension, tachypnea, and pain. Clinicopathological findings are associated with extravascular hemolysis including anemia, hyperbilirubinemia, bilirubinuria, and icterus.

Allergic Reactions An allergic reaction is an acute type 1 hypersensitivity response to an antigen within a transfusion product. Allergic reactions range in severity from mild to life-threatening anaphylactic reactions. Allergic reactions typically occur within 1 hour of initiating a transfusion but may occur up to 4 hours after cessation. Allergic reactions may be localized to cutaneous manifestations such as angioedema, erythema, urticaria, and pruritus. Gastrointestinal signs such as vomiting and diarrhea may be also seen with generalized or systemic allergic reactions. Mild allergic reactions in cats typically manifest in lethargy, vomiting, anorexia, facial edema, and/or generalized pruritus. Respiratory signs may manifest in cats experiencing more severe allergic reactions. Anaphylactic reactions in dogs are characterized by hemodynamic

CHAPTER 70  Blood Types, Pretransfusion Compatibility, and Transfusion Reactions instability (tachycardia, hypotension, collapse), gastrointestinal signs (vomiting, diarrhea), coagulopathy, and hemoabdomen. More recently recognized signs of canine anaphylaxis include elevated alanine transaminase and increased gallbladder wall thickness.30 Mild to moderate allergic reactions respond rapidly with completion of the transfusion and supportive care, which may include diphenhydramine and anti-emetics. Anaphylactic transfusion reactions require emergency treatment with epinephrine, intravenous fluids, oxygen therapy, and hemodynamic monitoring and support as indicated.

Febrile Nonhemolytic Transfusion Reactions A febrile nonhemolytic transfusion reaction (FNHTR) is characterized by a temperature over 39°C (102.5°F) with an increase in temperature .1°C (1.8°F) from the pretransfusion temperature that occurs during or within 4 hours of the completion of a transfusion. To be defined as a FNHTR, other etiologies of hyperthermia must be ruled out such as external warming, underlying patient condition or infection, or other transfusion reactions such as an AHTR, transfusion-related lung injury, and transfusion-related infection. The pathogenesis of FHNTRs likely involves recipient reactions to white blood cells, or platelet antigens or other biological response modifiers present in blood products, such as pyrogenic cytokines, complement components, or lipids. Prestorage leukoreduction has been shown to reduce the incidence of FNHTRs in humans and attenuate cytokine production in stored canine pRBC.36 FHTRs are the most common transfusion reaction in veterinary medicine. They are classically mild and self-limiting. When hyperthermia is noted during a transfusion, the transfusion may be paused while potential etiologies, including more severe transfusion reactions such as AHTR or TRALI, are investigated. Essential transfusions may be restarted, given slowly and monitored closely in patients experiencing FHTRs. The administration of antipyretics during FHTR is rarely indicated.

Transfusion-related Acute Lung Injury Transfusion-related acute lung injury (TRALI) is defined as an acute clinical syndrome of respiratory distress with hypoxemia and noncardiogenic pulmonary edema during or within 6 hours of a transfusion. Hypoxemia is further defined as a partial pressure of oxygen (PaO2)/ fraction of inspired oxygen (FiO2) ratio #300 mm Hg or oxygen saturation ,90% or room air. Radiographs demonstrate bilateral pulmonary edema with no evidence of circulatory overload, such as left atrial enlargement or pulmonary venous distension. Type 1 TRALI includes patients who have no concomitant risk factors for acute respiratory distress syndrome, whereas type II TRALI is reserved for those with acute respiratory distress syndrome (ARDS) risk factors or those that have existing mild ARDS and their respiratory status deteriorates in association with transfusion. TRALI is most commonly associated with high-plasma-volume transfusion products, although all transfusion products carry a risk. Two mechanisms have been proposed in the pathogenesis of TRALI, both of which culminate in pulmonary microvascular endothelial damage and leakage associated with high-protein non-cardiogenic edema formation. The transfusion of biologically active mediators, such as antibodies (i.e., antibodies to human leukocyte antigen class I and II), various neutrophil antigens, lipids, and soluble CD40 ligand, have all been associated with the development of TRALI. The “two-hit” mechanism for TRALI is described in patients that already have primed neutrophils and endothelium from their underlying condition (“first hit”), and the transfusion becomes the “second hit” activating those neutrophils. The severity of clinical signs, such as fever, hypotension and respiratory distress, dictate therapy from oxygen supplementation to hemodynamic support and mechanical ventilation.

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Transfusion-associated Circulatory Overload Transfusion-associated circulatory overload (TACO) is defined by acute respiratory distress secondary to increased circulatory volume from transfusion product administration and consequent hydrostatic pulmonary edema. Demonstration of volume overload during or within 6 hours of transfusion can be assessed via clinical, radiographic, and echocardiographic findings. Clinical signs and physical examination findings may include jugular vein distension, tachypnea, dyspnea, orthopnea, cough, or pulmonary crackles. Radiographs demonstrate bilateral pulmonary edema, pleural effusion, pulmonary venous distention, and/or cardiomegaly. Left atrial and ventricular enlargement and a reduced ejection fraction may be seen on echocardiography. Preexisting patient factors that may predispose a patient to TACO include cardiac dysfunction, renal failure, pulmonary disease, or chronic anemia. TACO is also associated with large volume or rapid administration transfusions. Treatment of TACO may include oxygen supplementation, slowing or cessation of transfusion, and diuretic therapy as needed.

STORAGE LESION The storage of transfusion products allows for immediate access to lifesaving products. During the storage of RBCs, biomechanical, biochemical, and immunologic changes occur that may adversely affect the RBCs and the recipient. These changes may affect the viability, deformability, and oxygen carrying capacity of transfused RBCs as well as the microcirculatory flow and immune response in the recipient. The human experimental and clinical research on the significance of storage lesion is vast, with evidence both supporting and negating these potential adverse consequences. A 2018 Cochrane analysis that includes the most recent randomized controlled trials concluded that the transfusion of fresher RBCs does not reduce mortality when compared with older RBCs.31 These findings fall in line with the American Association of Blood Banks’ revised 2016 RBC transfusion guidelines that state that patients “should receive red blood cell units selected at any point within their licensed dating period (standard issue) rather than limiting patients to transfusion of only fresher units.”32 In veterinary medicine, there is evidence of increased in vivo hemolysis with transfusion of stored versus fresher RBCs in multiple canine studies.26,33-35 In a 2013 experimental study using a canine model of pneumonia-associated sepsis, the authors concluded that the demonstration of increased in vivo hemolysis with end-date (42 days versus 7 days) pRBC transfusion contributed to pulmonary hypertension, pulmonary vascular damage at the sites of injury, and gas exchange abnormalties.33 Inflammatory markers such as increased cytokine concentrations have been shown to be progressive with storage of canine RBCs.36 The duration of RBC storage has not been shown to be a major contributing factor on outcome (discharge, death, euthanasia or 30-day survival) in the general canine clinical population.26,37 The transfusion of fresher RBC transfusion products may be considered in patients with protracted, severe anemia, or septic shock. Transfusion product inventory should be managed with the goals to reduce storage time, meet hospital needs, and reduce waste.

LEUKOREDUCTION Leukoreduction is the use of an inline filter to remove white blood cells (WBCs) 6 platelets depending on the filter. Prestorage leukoreduction removes WBCs and platelets before they undergo apoptosis or necrosis and release potentially undesirable cytokines or breakdown products during storage. The reported benefits include decreased FNTRs, decreased inflammatory mediators36,38 and response in recipients,39 decreased alloimmunization against leukocyte and platelet antigens,

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decreased microaggregation, prevention of transfusion-related immunomodulation, decreased postoperative infections, reduced procoagulant properties (decreased microparticle formation)40,41, decreased transmission of infectious diseases or contaminating bacteria, and improved RBC function and survival.42 Universal leukoreduction is performed in many countries with the notable exception of the United States. Leukoreduction is an uncommon practice in veterinary medicine.42 The major disadvantages of leukoreduction are costs and logistics. Not all studies support a substantive or clinical benefit of leukoreduction.39,44

TRANSFUSION ADMINISTRATION AND MONITORING The safe and effective administration of transfusion products requires attention to detail and thorough record keeping. Once a transfusion has been requested, the product should be examined for label accuracy (species, blood type, donor match, expiration date, etc.) and quality (color, intact bag, hemolysis, clots). Stored RBC products do not require warming prior to administration, except in hypothermic, massive transfusion or small patients. Frozen transfusion products, such as plasma, can be thawed in a temperaturecontrolled water bath or commercial thawing device. Sterility must be maintained when preparing blood products. Medications should not be added to the blood product. Blood products are typically administered intravenously but may be given via the intraosseous route. An aggregate filter is required for administration of all blood products (including plasma). Transfusion administration infusion sets are available with in line filters (170–260 µm) for larger volume transfusions. Gravity-flow administration is preferred, although volumetric peristaltic pumps are available that are manufacturer approved for safe transfusion. Smaller 18-µm microaggregate filters (Hemo-Nate) are available for small volume (#50 ml whole blood, #20 ml pRBCs) transfusions administered via the syringe pump method. Coadministration of transfusion products and hypotonic or hypertonic fluids within the same line is contraindicated. Coadministration of blood products with calcium containing fluids should be avoided due to clotting, although lactated Ringer’s solution has been shown to be safe with rapid infusion (#60 minutes).45 The volume and rate of transfusion are patient-dependent. Ideally the initial rate of infusion should be slow regardless of precompatibility testing and monitored closely before increasing the rate. Once a transfusion product is connected to a patient, the transfusion time for that bag should not exceed 4 hours. In critically ill patients that require expedited delivery, transfusion products may be administered more quickly or even bolused. Transfusion recipients should be monitored closely with baseline evaluation of temperature, pulse rate, and respiratory rate (TPR) and PCV, total protein, and serum color. Monitoring during the transfusion should include TPR, mucous membrane color, capillary refill time, mentation, blood pressure, and any signs of a transfusion reaction to include angioedema, erythema, pruritus, vomiting, or diarrhea. It is advised that serum color is rechecked ,15 minutes into the transfusion to evaluate for evidence of hemolysis and an AHTR, which would mandate discontinuation of the transfusion. The technician and veterinarian should be aware of clinical signs associated with transfusion reactions. Hospital transfusion administration monitoring forms should be completed for each transfusion as part of the medical record. A sample transfusion monitoring sheet is provided in the AVHTM TRACS guidelines.28 A hospital log of transfusion reactions may allow for quality surveillance of transfusion products, storage, and administration techniques.

REFERENCES 1. Acierno MM, Raj K, Giger U: DEA 1 expression on dog erythrocytes analyzed by immunochromatographic and flow cytometric techniques, J Vet Intern Med 28:592-598, 2014. 2. Canard B, Barthelemy A, Felix N, et al: Stability of DEA 1 1 antigen expression and production of alloantibodies after transfusion in dogs. A preliminary study, J Vet Emerg Crit Care 23:S12, 2013. 3. Melzer KJ, Wardrop KJ, Hale AS, Wong VM: A hemolytic transfusion reaction due to DEA 4 alloantibodies in a dog, J Vet Intern Med 17: 931-933, 2003. 4. Swisher SN, Young LE, Trabold N: In vitro and in vivo studies of the behavior of canine erythrocyte-isoantibody systems, Ann N Y Acad Sci 97:15-25, 1962. 5. Hale AS, Werfelmann J: Incidence of canine serum antibody to known dog erythrocyte antigens in potential donor population, J Vet Intern Med 20(3):768-769, 2006. 6. Iazbik MC, O’Donnell M, Marin L, et al: Prevalence of dog erythrocyte antigens in retired racing Greyhounds, Vet Clin Path 39:433-435, 2010. 7. Spada E, Proverbio D, Baggiani L, et al: Activity, specificity, and titer of naturally occurring canine anti-DEA 7 antibodies, J Vet Diagn Invest 28:705-708, 2016. 8. Spada E, Proverbio D, Priolo V, et al: Dog erythrocyte antigens (DEA) 1, 4, 7, and suspected naturally occurring anti-DEA 7 antibodies in Italian Corso dogs, Vet J 222:17-21, 2017. 9. Spada E, Proverbio D, Vinals Florez LM, et al: Prevalence of naturally occurring antibodies against dog erythrocyte antigen 7 in a population of dog erythrocyte antigen 7-negative dogs from Spain and Italy, Am J Vet Res 77:877-881, 2016. 10. Goy-Thollot I, Giger U, Boisvineau C, et al: Pre- and post-transfusion alloimmunization in dogs characterized by 2 antiglobulin-enhanced crossmatch test, J Vet Intern Med 31:1420-1429, 2017. 11. Blais M, Berman L, Oakley DA, Giger U: Canine Dal blood type: a red cell antigen lacking in some Dalmatians, J Vet Intern Med 21:281-286, 2007. 12. Goulet S, Giger U, Arsenault J, et al: Prevalence and mode of inheritance of the Dal blood group in dogs in North America, J Vet Intern Med 31:751-758, 2017. 13. Euler CC, Lee JH, Kim HY, et al: Survey of two new (Kai 1 and Kai 2) and other blood groups in dogs of north America, J Vet Intern Med 30: 1642-1647, 2016. 14. Goy-Thollot I, Nectoux A, Guidetti M, et al: Detection of naturally occurring alloantibody by an in-clinic antiglobulin-enhanced and standard crossmatch gel column test in non-transfused domestic shorthair cats, J Vet Intern Med 33:588-595, 2019. 15. Weinstein NM, Blais MC, Harris K, et al: A newly recognized blood group in domestic shorthair cats: the Mik red cell antigen, J Vet Intern Med 21:287-292, 2007. 16. Odunayo A, Garraway K, Rohrbach BW, et al: Incidence of incompatible crossmatch results in dogs admitted to a veterinary teaching hospital with no history of prior red blood cell transfusion, J Am Vet Med Assoc 250:303-308, 2017. 17. Goulet S, Blais MC: Characterization of anti-Dal alloantibodies following sensitization of two Dal-negative dogs, Vet Pathol 55(1):108-115, 2018. 18. Blais MC, Rozanski EA, Hale AS, et al: Lack of evidence of pregnancy- induced alloantibodies in dogs, J Vet Intern Med 23:462-465, 2009. 19. Hourani L, Weingart C, Kohn B: Alloimmunisation in transfused patients: serial cross-matching in a population of hospitalized cats, J Feline Med Surg 19(12):1231-1237, 2017. 20. Kerl ME, Hohenhaus AE: Packed red blood cell transfusions in dogs: 131 cases (1989), J Am Vet Med Assoc 202(9):1495-1499, 1993. 21. Callan MB, Oakley DA, Shofer FS, Giger U: Canine red blood cell transfusion practice, J Am Anim Hosp Assoc 32(4):303-311, 1996. 22. Castellanos I, Couto CG, Gray TL: Clinical use of blood products in cats: a retrospective study (1997-2000), J Vet Intern Med 18(4):529-532, 2004. 23. Klaser DA, Reine NJ, Hohenhaus AE: Red blood cell transfusions in cats: 126 cases (1999), J Am Vet Med Assoc 226(6):920-923, 2005. 24. Holowaychuk MK, Leader JL, Monteith G: Risk factors for transfusion- associated complications and nonsurvival in dogs receiving packed red

CHAPTER 70  Blood Types, Pretransfusion Compatibility, and Transfusion Reactions blood cell transfusions: 211 cases (2008-2011), J Am Vet Med Assoc 244(4):431-437, 2014. 25. Bruce JA, Kriese-Anderson L, Bruce AM, Pittman JR: Effect of premedication and other factors on the occurrence of acute transfusion reactions in dogs, J Vet Emerg Crit Care 25(5):620-630, 2015. 26. Maglaras CH, Koenig A, Bedard DL, Brainard BM: Retrospective evaluation of the effect of red blood cell product age on occurrence of acute transfusion-related complications in dogs: 210 cases (2010-2012), J Vet Emerg Crit Care 27(1):108-120, 2017. 27. Davidow EB, Blois SL, Goy-Thollot I, et al: Association of Veterinary Hematology and Transfusion Medicine (AVHTM) Transfusion Reaction Small Animal Consensus Statement (TRACs) part 1: definitions and clinical signs, J Vet Emerg Crit Care 31:141-166, 2021. 28. Davidow EB, Blois SL, Goy-Thollot I, et al: Association of Veterinary Hematology and Transfusion Medicine (AVHTM) Transfusion Reaction Small Animal Consensus Statement (TRACs) part 2: prevention and monitoring, J Vet Emerg Crit Care 31:167-188, 2021. 29. Odunayo A, Nash KJ, Davidow EB, et al: Association of Veterinary Hematology and Transfusion Medicine (AVHTM) Transfusion Reaction Small Animal Consensus Statement (TRACs) part 3: diagnosis and treatment, J Vet Emerg Crit Care 31:189-203, 2021. 30. Quantz JE, Miles MS, Reed AL, White GA: Elevation of alanine transaminase and gallbladder wall abnormalities as biomarkers of anaphylaxis in canine hypersensitivity patients, J Vet Emerg Crit Care 19(6):536-544, 2009. 31. Shah A, Brunskill SJ, Desborough MJR, et al: Transfusion of red blood cells stored for shorter versus longer duration for all conditions, Cochrane Database Syst Rev 12(12):CD010801, 2018. 32. Carson JL, Guyatt G, Heddle NM, et al: Clinical practice guidelines from the AABB red blood cell transfusion thresholds and storage, J Am Med Assoc 316(19):2025-2035, 2016. 33. Solomon SB, Wang D, Sun J, et al: Mortality increases after massive exchange transfusion with older stored blood in canines with experimental pneumonia, Blood 121:1663-1672, 2013. 34. Solomon SB, Cortes-Puch I, Sun J, et al: Transfused older stored red blood cells improve the clinical course and outcome in a canine lethal hemorrhage/reperfusion model, Transfusion 55(11):2552-2563, 2015. 35. Wurlod VA, Smith SA, McMichael MA, et al: Iron metabolism following intravenous transfusion with stored versus fresh autologous erythrocyte concentrate in healthy dogs, Am J Vet Res 76(11):996-1004, 2015. 36. Corsi R, McMichael MA, Smith SA, et al: Cytokine concentration in stored canine erythrocyte concentrates, J Vet Emerg Crit Care 24(3): 259-263, 2014. 37. Hann L, Brown DC, King LG, Callan MB: Effect of duration of packed red blood cell storage on morbidity and mortality in dogs after transfusion: 3,095 cases (2001-2010), J Vet Intern Med 28:1830-1837, 2014.

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38. Purcell SL, Claus M, Hosgood G, Smart L: Effect of leukoreduction on concentrations of interleukin-8, interleukin-1B, and tumor necrosis factor-alpha in canine packed red blood cells during storage, Am J Vet Res 76:969-974, 2015. 39. Callan MB, Patel RT, Rux AH, et al: Transfusion of 28-day-old leucoreduced or non-leucoreduced stored red blood cells induces an inflammatory response in healthy dogs, Vox Sang 105:319-327, 2013. 40. Herring JM, Smith SA, McMichael MA, et al: Microparticles in stored canine RBC concentrates, Vet Clin Path 42(2):163-169, 2013. 41. Smith SA, Ngwenyama TR, O’Brien M, et al: Procoagulant phospholipid concentration in canine erythrocyte concentrates stored with or without prestorage leukoreduction, Am J Vet Res 76:35-41, 2015. 42. Ergul Ekiz E, Arslan M, Akyazi I, et al: The effects of prestorage leukoreduction and storage duration on the in vitro quality of canine packed red blood cells, Turk J Vet Anim Sci 36(6):711-717, 2012. 43. Jagodich TA, Holowaychuk MK: Transfusion practice in dogs and cats: an Internet-based survey, J Vet Emerg Crit Care 26(3):360-372, 2016. 44. Muro SM, Lee JH, Stokes MK, et al: Effects of leukoreduction and storage on erythrocyte phosphatidylserine expression and eicosanoid concentrations in units of canine packed red blood cells, J Vet Intern Med 31:410-418, 2017. 45. Levac B, Parlow JL, van Vlymen J, et al: Ringer’s acetate is compatible with saline-adenine-glucose-mannitol preserved packed red blood cells for rapid transfusion, Can J Anaesth 57:1071-1077, 2010. 46. Tasker S, Barker EN, Day MJ, Helps CR: Feline blood genotyping versus phenotyping, and detection of non-AB blood type incompatibilities in UK cats, J Small Anim Pract 55:185-189, 2014. 47. Weltman JG, Fletcher DJ, Rogers C: Influence of cross-match on posttransfusion packed cell volume in feline packed red blood cell transfusions, J Vet Emerg Crit Care 24(4):429-436, 2014. 48. Sylvane B, Prittie J, Hohenhaus AE, Tozier E: Effect of cross-match on packed cell volume after transfusion of packed red blood cells in transfusion-naïve anemic cats, J Vet Intern Med 32(3):1077-1083, 2018. 49. McClosky ME, Cimino Brown D, Weinstein NM, et al: Prevalence of naturally occurring non-AB blood type incompatibilities in cats and influence of crossmatch on transfusion outcomes, J Vet Intern Med 32(6):1934-1942, 2018. 50. Humm KR, Chan DL: Prospective evaluation of the utility of crossmatching prior to first transfusion in cats: 101 cases, J Small Anim Pract 61:285-291, 2020. 51. Martinez-Sogues L, Blois SL, Manzanilla EG, et al: Exploration of risk factors for non-survival and for transfusion-associated complications in cats receiving red cell transfusions: 450 cases (2009-2017), J Small Anim Pract 61:177-184, 2020. 52. Binvel M, Arsenault J, Depre B, Blais M: Identification of 5 novel feline erythrocyte antigens based on the presence of naturally occurring alloantibodies, J Vet Intern Med 35:234-244, 2021.

71 Hemorrhagic Shock Corrin Boyd, BSc, BVMS (Hons), GradDipEd, MVetClinStud, MANZCVS, DACVECC, Lisa Smart, BVSc, DACVECC, PhD

KEY POINTS • Intensive care patients at risk of hemorrhage, such as those with trauma, coagulopathy, or recent surgery require close monitoring for hemorrhagic shock. • Initial assessment of the hemorrhagic shock patient focuses on determining the source of hemorrhage, classifying it as controlled or uncontrolled, assessing the severity of perfusion impairment, and identifying concurrent physiologic perturbations. • Management of controlled hemorrhage involves volume replacement with synthetic crystalloid or colloid fluids, followed by blood transfusion, if necessary.

Hemorrhagic shock refers to the impairment of oxygen delivery (DO2) as a result of whole blood loss. Reduced preload and a subsequent reduction in cardiac output activate compensatory responses that include activation of the sympathetic nervous system (causing tachycardia and vasoconstriction) and the renin-angiotensin-aldosterone system (leading to sodium reabsorption). As hemorrhagic shock progresses, decreased hemoglobin concentration can contribute to impaired DO2. This is further exacerbated by intravenous administration of crystalloid fluid. For further discussion of the pathophysiology of shock, see Chapter 6, Pathophysiology and Mechanisms of Shock. Hemorrhagic shock is a life-threatening condition that requires prompt recognition, assessment, and goal-directed management. For the purposes of this chapter, focus is placed on recognizing and treating hemorrhagic shock in the ICU setting, which can have a slightly different approach than treating hemorrhagic shock on initial presentation in the emergency room.

ASSESSMENT OF THE HEMORRHAGIC SHOCK PATIENT Patients at risk of hemorrhage, such as those with trauma, coagulopathy, or recent surgery (Box 71.1), should have close monitoring in order to detect ongoing or new hemorrhage (Box 71.2). Hemorrhagic shock is typically first identified in the ICU patient by recognition of alterations in perfusion parameters that indicate vasoconstrictive shock. Alternatively, identification of internal or external hemorrhage may prompt closer evaluation of perfusion and recognition of hemorrhagic shock. Rapid management of hemorrhagic shock includes controlling hemorrhage, restoring adequate DO2, and managing the secondary consequences of hemorrhagic shock. This requires a focused assessment to determine the source of hemorrhage, if it is controlled or uncontrolled, and the severity of perfusion impairment. It is also important to identify concurrent physiologic perturbations that can perpetuate shock and increase morbidity and mortality.

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• Management of severe uncontrolled hemorrhage involves massive transfusion, achieving rapid definitive hemostasis when possible, and utilization of appropriate adjunct therapies. • Additional therapeutic considerations apply to intensive care patients with spontaneous hemorrhage, severe thrombocytopenia, coagulopathy, and postoperative hemorrhage.

Source of Hemorrhage Location is an important factor for determining whether hemorrhage is controlled or uncontrolled and whether any procedures are indicated to achieve control of hemorrhage. Controlled hemorrhage includes spontaneous resolution of hemorrhage due to effective coagulation or cessation of hemorrhage via a procedure such as bandage placement. When the site of hemorrhage is not visible, such as in a body cavity, cardiovascular stability and maintenance of hemoglobin concentration indicate controlled hemorrhage. Uncontrolled hemorrhage occurs when ongoing hemorrhage cannot be immediately stopped. Again, if the source of hemorrhage cannot be visualized then the lack of cardiovascular stability despite blood volume expansion and a falling hemoglobin concentration indicate uncontrolled hemorrhage. This determination should be made early in the assessment, as the treatment approach can differ considerably. External hemorrhage from skin wounds or severe epistaxis is usually obvious on physical examination, although it is possible that hemorrhage into a thick bandage could cause hemorrhagic shock prior to the recognition of strikethrough. Internal hemorrhage of sufficient severity to cause hemorrhagic shock usually occurs into the thoracic or abdominal cavities, the gastrointestinal tract, or a fracture site. Severe urinary tract, mediastinal, or retroperitoneal hemorrhage can also cause hemorrhagic shock. Point-of-care ultrasound using the abdominal focused assessment with sonography for trauma (AFAST) and thoracic focused assessment with sonography for trauma (TFAST) protocols (see Chapter 189, Point-of-Care Ultrasound in the ICU) and paracentesis are invaluable in identifying cavitary hemorrhage. Severe gastrointestinal hemorrhage may manifest as hematemesis, melena, or large-volume hematochezia. Suctioning of gastric fluid and digital rectal examination can aid diagnosis. Hemorrhage into a fracture site, such as the humerus, femur, or pelvis, should be considered in cases of trauma when the severity of shock is not explained by the degree of external or cavitary hemorrhage. Increasing limb swelling and bruising are sometimes, but not always, identified. Severe urinary tract hemorrhage causes frank hematuria, and

CHAPTER 71  Hemorrhagic Shock

BOX 71.1  Patients at Risk of Developing

Hemorrhagic Shock in the ICU Setting

Trauma Spontaneous hemoabdomen (presurgical) Splenic, hepatic, or adrenal mass Severe hematemesis or melena Severe thrombocytopenia or thrombocytopathia Immune-mediated thrombocytopenia von Willebrand disease Coagulopathy Acute coagulopathy of trauma shock Anticoagulant rodenticide toxicosis Acute liver failure Disseminated intravascular coagulation with consumptive coagulopathy Hemophilia A Venom-induced consumptive coagulopathy Antithrombotic therapy Postoperative patients Liver lobectomy Cardiovascular surgery Adrenalectomy Gastric dilation and volvulus Nasal turbinectomy or biopsy with epistaxis

intraluminal echogenic material consistent with blood clots may be identified in the urinary bladder during AFAST examination. Definitive diagnosis of internal hemorrhage may require advanced imaging, endoscopy, or exploratory surgery. The timing of these is dependent on whether hemorrhage is controlled or uncontrolled (see below). While knowledge of the site of hemorrhage can assist in determining if it is controlled or uncontrolled, this determination is not always straightforward. Sometimes uncontrolled hemorrhage must be assumed from the severity and fluid-refractory nature of shock.

Assessment of Perfusion Assessment of the severity of perfusion impairment should include six physical examination perfusion parameters: heart rate, pulse quality, mucous membrane color, capillary refill time, peripheral temperature, and mentation (see Chapter 1, Evaluation and Triage of the Critically Ill Patient).1 These parameters, which reflect both direct effects of the decreased perfusion and the sympathetic compensatory response, change predictably with acute hemorrhage of increasing severity. Serial monitoring is necessary throughout resuscitation, and lack of improvement

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or worsening may indicate ongoing uncontrolled hemorrhage. Hemoglobin concentration or packed cell volume is often initially normal; however, a baseline value is helpful for serial monitoring. There are several confounding factors that can decrease the reliability of the perfusion parameters to accurately reflect the severity of hemorrhagic shock in critically ill patients, including pain, hypo- or hyperthermia, sedation, underlying cardiac disease, effects of drugs on heart rate and vascular tone, and vasodilation from systemic inflammation. Thus, rapid bedside diagnostic tests can be a useful aid in the assessment of perfusion in the hemorrhagic shock patient. Arterial blood pressure (see Chapter 181, Hemodynamic Monitoring) is often maintained in patients with mild to moderate hemorrhagic shock with an intact compensatory response. Progressive hypotension develops in severe shock or when there is a reduced capacity for compensatory vasoconstriction. Direct measurement via an arterial catheter is more accurate than noninvasive methods,2 and it is prudent to preemptively instrument patients at high risk of bleeding. Patients with an arterial catheter (especially those receiving positive pressure ventilation) with a pulse pressure variation greater than 10%–15%, will likely benefit from an increase in preload to improve stroke volume.3-8 Blood lactate concentration (see Chapter 61, Hyperlactatemia) increases in animals with moderate to severe hemorrhagic shock and promptly decreases following adequate resuscitation.9,10 However, this is a nonspecific finding, and critically ill patients may have concurrent conditions that either increase lactate or delay its metabolism.10 Regardless, persistent or worsening hyperlactatemia should prompt careful evaluation for inadequate resuscitation or uncontrolled hemorrhage. Point-of-care ultrasound (see Chapters 64 and 189, Assessment of Intravascular Volume and Point-of-Care Ultrasound in the ICU, respectively) of the heart and caudal vena cava provides further information about intravascular volume status.8,11-14 A trend in decreasing central or mixed venous oxygen saturation also indicates inadequacy of tissue oxygenation.15,16 Tissue oximetry using near infrared spectroscopy is under investigation as a noninvasive surrogate.17-19 Box 71.2 summarizes the monitoring tools that are useful for the assessment of patients with hemorrhagic shock, with a suggested frequency as to how often these monitoring tools should be used in the ICU.

Assessment of Concurrent Physiologic Perturbations Hemorrhagic shock can rapidly result in a combination of coagulopathy, acidosis, and hypothermia. This is frequently termed the lethal triad due to the association of these conditions with greater morbidity and mortality in human medicine.20 These factors lead to a vicious cycle, as hypothermia and acidosis can worsen coagulopathy, which in turn can perpetuate hemorrhage and shock, which can further worsen

BOX 71.2  Suggested Monitoring and Triggers for Intervention for Patients at Risk of Ongoing Hemorrhage in the ICU Essential Monitoring Vital signs or basic perfusion parameters (every 2–4 hours) Heart rate .120 (dogs) or 180 (cats) Pale mucus membranes with capillary refill time .2 seconds Reduced pulse quality Cool extremities Arterial blood pressure (every 4–8 hours) Mean blood pressure ,80 mm Hg or decrease of 20 mm Hg from baseline Systolic blood pressure ,100 mm Hg or decrease of 40 mm Hg from baseline Hemoglobin concentration or packed cell volume (PCV) (every 8–12 hours) PCV below reference interval or acute decrease in 5 percentage points from baseline

Adjunctive Monitoring (Performed as Needed According to Abnormal Perfusion Parameters) Focused sonography (as indicated by abnormal perfusion) Decrease in ratio of caudal vena cava and aortic diameters Collapsibility of caudal vena cava .50% Noticeable increase in any hemorrhagic effusion Lactate (above reference interval) Base excess (lower than reference interval) Central venous oxygen saturation (,65%) Pulse pressure variation during mechanical ventilation (.15%) Tissue oxygen saturation (,75%)

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PART VI  Fluid Therapy

hypothermia and acidosis. Thus, the assessment of coagulation (see Chapters 186 and 187, Coagulation and Platelet Monitoring and Viscoelastic Testing, respectively), acid-base status (see Chapters 59 and 60, Traditional and Non-Traditional Acid-Base Balance, respectively), and body temperature is important for the hemorrhagic shock patient. Viscoelastic coagulation assessment with thromboelastography (TEG) or rotational thromboelastometry (ROTEM) provides point-of-care information on ex vivo clot formation and lysis. If viscoelastic monitoring is not available, coagulation can be assessed with platelet count, coagulation times, and fibrinogen concentration. Coagulation status will require serial reassessment during fluid resuscitation; however, it is important to avoid blood sampling during administration of rapid fluid infusions. Coagulopathy may be more pronounced in patients with major trauma due to direct anticoagulant and profibrinolytic and consumptive processes and requires aggressive treatment.21 This phenomenon is known as the acute coagulopathy of trauma shock and is distinct from dilutional coagulopathy. Anaerobic metabolism not only produces lactate but is a major contributor to acidosis in hemorrhagic shock. Hyperchloremic metabolic acidosis, especially with saline resuscitation, and respiratory acidosis may further contribute to acidemia. Thus, serial reassessment of a complete blood gas panel is preferable to measurement of lactate concentration alone. Body temperature should be frequently monitored, ideally constantly in the shock patient by placement of a rectal or esophageal temperature probe.

Hemorrhagic shock, especially if severe or prolonged, can cause subsequent organ dysfunction due to direct hypoxic injury, followed by reperfusion injury and systemic inflammation (see Chapter 8, Oxygen Toxicity).22 Organs commonly affected include the kidneys, liver, gastrointestinal tract, and lungs. Thus, close monitoring of vital signs, gastrointestinal function, electrolyte concentrations, and blood gases is warranted. Further diagnostics following resolution of hemorrhagic shock may include serial serum biochemistry and urinalysis, as well as thoracic radiographs. Hemorrhagic shock can cause shedding of the endothelial glycocalyx, which is compounded by dilution of plasma components and atrial natriuretic peptide release secondary to rapid crystalloid administration.23 This may increase susceptibility to tissue edema formation, and judicious assessment of ongoing fluid therapy requirement is necessary.24

MANAGEMENT OF CONTROLLED HEMORRHAGE The management of patients with controlled hemorrhage typically includes restoration of preload with bolus administration of synthetic clear fluids (see Chapter 68, Shock Fluid Therapy), followed by supplementation of hemoglobin and clotting factors/platelets by blood transfusion, if necessary (Fig. 71.1). Isotonic crystalloids form the mainstay of fluid resuscitation for controlled hemorrhagic shock. Balanced crystalloids such as lactated

Severity of hemorrhagic shock

Severe uncontrolled hemorrhage

Controlled or slow hemorrhage

PCV > 30%

PCV < 30%

Bolus 10–40 ml/kg balanced isotonic crystalloid

Bolus 10–20 ml/kg balanced isotonic crystalloid

Yes

Still in shock?

Recheck PCV and transfuse PRBC urgently (5–15 ml/kg/hr) Administer 10–20 ml/kg plasma if >10 ml/kg of PRBC administered

Achieve definitive hemostasis if possible Commence massive transfusion protocol • Administer PRBC as a bolus • Administer plasma ± platelets based on a fixed ratio or coagulation tests • Monitor and treat hypothermia, acidosis, and hypocalcemia Consider adjunctive therapies

No

Recheck PCV and transfuse PRBC according to severity of anemia (3–5 ml/kg/hr) Administer 10–20 ml/kg plasma if coagulopathy evident

After resolution of shock and anemia • Continue to monitor (see Box 71.2) • Address underlying cause Fig. 71.1  Flow chart for management of ICU patients with hemorrhagic shock. This is a general guide, and special considerations apply to some patients. Fluid volumes and packed cell volume (PCV) values are intended as a guide only and will vary based on individual case details. PRBC, packed red blood cells.

CHAPTER 71  Hemorrhagic Shock Ringer’s solution are recommended, as 0.9% NaCl can cause a hyperchloremic metabolic acidosis and may contribute to acute kidney injury.20,25-28 Some clinicians recommend avoiding acetate-containing crystalloids as they may cause vasodilation,29 although data from the authors’ canine hemorrhagic shock model do not provide any evidence for this phenomenon after 80 ml/kg Plasmalyte-148.23 Initial isotonic crystalloid boluses of 10 to 20 ml/kg are given and can be repeated based on serial reassessment of perfusion parameters and adjunct tests. The requirement for more than 40 ml/kg of isotonic crystalloid should prompt careful reassessment for uncontrolled hemorrhage. While rapid fluid administration is typically recommended for hypovolemia, fast administration may disturb fragile blood clots and restart hemorrhage. The ideal rate for any given patient is unknown, but choosing a conservative infusion rate (i.e., over 20 minutes rather than 10 minutes) should be considered when treating a patient with a mild spectrum of shock abnormalities (see more on hypotensive resuscitation in the Alternative Resuscitation Strategies section below). Hypertonic crystalloids such as 3% to 7.5% NaCl increase blood volume to a small degree30 and can be especially useful in very large patients or those with head trauma. Synthetic colloid fluids such as hydroxyethyl starch solutions may allow for stabilization of shock with a smaller volume of fluid,23,30 although whether this provides a survival benefit is controversial.20,31-34 Theoretically, these fluids may help to mitigate interstitial overhydration secondary to crystalloid administration. While administration of any clear fluids can cause dilutional coagulopathy, synthetic colloid fluids directly cause platelet dysfunction, hypocoagulability, and enhanced fibrinolysis (see Chapter 66, Colloid Solutions).35 Additionally, use of synthetic colloid fluids in human critical care has substantially decreased over concern of acute kidney injury.20,33,34 Current research has not demonstrated an increased risk of renal injury in dogs when hydroxyethyl starch is administered in hemorrhagic shock;36,37 however, research in this area is ongoing.38 Circulating hemoglobin concentration is usually within normal limits in the initial stages of acute hemorrhagic shock. Subsequently, transvascular fluid shifts and clear fluid resuscitation lead to progressive anemia. Hemoglobin concentration and/or packed cell volume should be compared with baseline values following fluid resuscitation. If isotonic crystalloid boluses were used, it is prudent to wait 30–60 minutes after the completion of the last fluid bolus to allow redistribution.30 If anemia is moderate to severe and associated with signs of an ongoing DO2 deficit, blood transfusion (see Chapter 69, Transfusion Medicine) should proceed according to standard protocols (Fig. 71.1). Typical signs of an ongoing DO2 deficit include persistent tachycardia and hyperlactatemia despite resolution of other abnormal perfusion parameters. Rapid bolus blood administration is rarely necessary for patients with controlled hemorrhage, but fast administration may be necessary in patients with hemorrhagic shock combined with severe anemia.

MANAGEMENT OF UNCONTROLLED HEMORRHAGE Patients with severe uncontrolled hemorrhage are at high risk of death and must be managed aggressively. While a short initial period of clear fluid resuscitation is typically employed, rapid recognition of uncontrolled hemorrhage and severe hemodynamic instability should prompt a change in the resuscitation strategy to massive transfusion, achieving rapid definitive hemostasis where possible, and utilization of appropriate adjunct therapies (Fig. 71.1).

Massive Transfusion Massive transfusion has been defined as the transfusion of blood products totaling an estimated entire blood volume in 24 hours, 50% of

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blood volume in 3–4 hours, or administration at 1.5 ml/kg/min for 20 minutes.39 Regardless of the specific definition, this conceptually refers to the situation where blood products are administered as a bolus to treat hypovolemia, rather than traditional slower administration. Traditional blood transfusion triggers, or the point at which transfusion commences, usually consider both evidence of impaired DO2 and the circulating hemoglobin concentration. However, the latter will often be within normal limits in acute hemorrhagic shock. Thus, massive transfusion is often triggered by the recognition that the patient has uncontrolled hemorrhage coupled with severe shock. Due to the major logistical requirements, this decision usually triggers a defined protocol in human hospitals.20,40 Modifications of such protocols may also be useful for veterinary hospitals. Placement of at least two large bore, short intravenous catheters is recommended to achieve the required flow rates for multiple blood products and medications. Blood typing is recommended for dogs and essential for cats using a rapid point-of-care assay. There is typically insufficient time to perform crossmatching. Blood bank managers should be immediately notified, as massive transfusion will place stress on blood bank resources. Due to this stress, massive transfusion typically should not be offered for a patient deemed to have a nonsurvivable illness or injury, although this determination can be difficult in the acute setting. The ideal product for massive transfusion is fresh whole blood, but this is rarely available fast enough and in sufficient volume for massive transfusion. Most veterinary blood banks store primarily packed red blood cells (PRBC). Administration of PRBC alone will lead to dilutional coagulopathy, hypofibrinogenemia, and thrombocytopenia, contributing to the lethal triad. Thus, human massive transfusion protocols recommend concurrent administration of plasma and platelet products. One unit each of plasma and platelets are typically recommended for every one to two units of PRBC.40 An alternate approach is serial monitoring of viscoelastic coagulation tests to guide blood product administration.20 In veterinary medicine, blood banks that store PRBC usually have fresh frozen plasma available, although thawing times may delay its use. Refrigerated plasma retains sufficient coagulation factor activity for at least 14 days;41 therefore, it is prudent for hospitals that have adequate plasma turnover to make refrigerated plasma available for massive transfusion. Refrigerated whole blood may also retain some coagulation factor and platelet activity, and continued research is investigating the stability of individual blood components over time.42-44 Patients undergoing massive transfusion are often already hypothermic secondary to shock, which can be perpetuated by administration of refrigerated blood products. Rapid flow fluid warmers such as the Level 1 (Smiths Medical) are rarely available in veterinary medicine. However, attempts can be made to at least warm blood products to room temperature if there is time, as well as providing active warming to the patient. Massive transfusion can cause ionized hypocalcemia and hypomagnesemia due to chelation by citrate anticoagulant.20,39 Dogs with experimental hemorrhagic shock administered a rapid 20 ml/kg bolus of autologous blood developed a moderate ionized hypocalcemia.23 Traditionally, treatment of hypocalcemia is only recommended if clinical signs are present (see Chapter 57, Calcium Disorders). However, hypocalcemia can impair coagulation and contribute to a decrease in myocardial contractility and vascular tone.20,45,46 For this reason, the authors recommend close monitoring for hypocalcemia during massive transfusion. The presence of ionized hypocalcemia in a hemodynamically unstable patient warrants therapy to normalize the ionized calcium concentration (see Chapter 57, Calcium Disorders).20 It is recommended to administer calcium solutions through a separate intravenous catheter to blood products, as the calcium may initiate

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coagulation ex vivo. Although serum ionized magnesium concentration can also be reduced by anticoagulant chelation, magnesium supplementation is rarely administered in the clinical setting. This is likely due to lack of rapid point-of-care measurement and unclear clinical benefit. One of the most challenging aspects of massive transfusion is recognition of appropriate resuscitation endpoints. If definitive hemorrhage control via surgery or interventional methods (see below) is necessary, resuscitation should continue until hemostasis is achieved and normal perfusion is restored. If relying on endogenous hemostasis, resolution of shock prompts a cautious pause in blood product administration with close monitoring of perfusion. A subsequent deterioration of perfusion parameters means that massive transfusion should continue, and the possibility of definitive hemorrhage control reassessed. Massive transfusion can rapidly deplete available allogenic blood products. In cases with uncontaminated cavitary hemorrhage, autotransfusion can provide a source of autologous red blood cells, although platelets and coagulation factors deplete.47-49 Confirming the lack of contamination in abdominal trauma is not likely to be achieved in the emergent setting and is often presumed unless there is overt evidence of gastrointestinal perforation. Risk of contamination needs to be weighed against benefit of transfusing autologous blood in the face of no alternative.

Alternate Resuscitation Strategies While massive transfusion can be effective in preventing life-threatening tissue hypoxia, rapid fluid (including blood product) administration can disturb fragile blood clots and perpetuate hemorrhage. Thus, in select cases where definitive hemorrhage control can be achieved rapidly, an alternate approach to resuscitation may be feasible. Hypotensive resuscitation refers to fluid resuscitation to a blood pressure target that is subnormal but sufficient to support major organ function, such as a systolic arterial pressure of 90 mm Hg or a mean arterial pressure of 60 mm Hg. Delayed resuscitation refers to the withholding of all fluid resuscitation until definitive control of hemorrhage has been achieved. These approaches are temporary solutions that require the ability to achieve definitive control of hemorrhage within minutes (for delayed resuscitation) to hours (for hypotensive resuscitation). There is controversy regarding the use of small volume resuscitation with other fluid types in order to avoid spikes in hydrostatic pressure that may be associated with crystalloid infusion.30 This includes use of synthetic colloids and hypertonic saline, or a combination of both.50,51 These fluid types have less interstitial redistribution; therefore, less volume is required for blood volume expansion compared with crystalloid fluid. However, these fluids can adversely affect coagulation20,35,52 and therefore may not be appropriate for the bleeding patient. Despite the theoretical benefit, no studies have shown the superiority of these fluids for the treatment of hemorrhagic shock in the clinical setting over crystalloid fluid.

Definitive Control of Hemorrhage Definitive control of hemorrhage is usually necessary, if possible, in uncontrolled hemorrhage requiring massive transfusion. Often this requires surgery, although it depends on the underlying cause of hemorrhage (see also Special Considerations, below). While general anesthesia is associated with a higher risk of complications in these patients, a careful multimodal approach that minimizes cardiovascular depressant drugs (see Chapter 133, Anesthesia of the Critical Patient) while continuing resuscitation can be successful. Physical examination and point-of-care diagnostic tests will sometimes provide sufficient information to plan definitive hemorrhage control. When more

information is required, whole-body computed tomography with intravenous contrast generally provides the most information in the least time. Surgical procedures required to control hemorrhage will depend on the source. In some cases, such as a bleeding splenic mass, definitive control can be rapidly achieved in a single surgical procedure. In other cases, especially traumatic hemorrhage, performing complete repair can be a lengthy and complicated surgery. In these cases, there is growing evidence in human trauma medicine to support the use of damage control surgery, where an initial brief procedure is performed to achieve hemostasis and limit contamination, followed by resuscitation in the ICU. Subsequent definitive surgery is planned when the patient is stable.20,53 The importance of damage control surgery and its impact on survival in veterinary medicine remains unclear. Some cases of uncontrolled hemorrhage may be amenable to minimally invasive means of achieving hemostasis. Upper gastrointestinal endoscopy can identify severe gastric hemorrhage and may allow for treatment via sclerotherapy, thermal ablation, clip application, or topical hemostatic agent application.54 Interventional radiology is emerging in veterinary medicine as a minimally invasive means of achieving hemostasis by embolization of hemorrhaging vessels in a range of organs.55 When determining the best technique(s) to pursue, it is important to consider experience of the operator and if an open technique would be safer, as the noninvasive procedure needs to be completed quickly and accurately.

Adjunct Therapies Some adjunct therapies can assist in achieving hemostasis in uncontrolled hemorrhage. Antifibrinolytic medications (see Chapter 167, Hemostatic Drugs) such as tranexamic acid or aminocaproic acid can assist in stabilizing clots and are associated with improved survival in human trauma.56 Desmopressin may be used to assist in the formation of a platelet plug when there is suspicion of a congenital or acquired thrombocytopathia. Noncompressible external hemorrhage, primarily severe epistaxis, may benefit from topical application of vasoconstrictive agents (e.g., epinephrine, phenylephrine), antifibrinolytics, and cold packs. Areas that can be compressed may also benefit from the application of cold packs. Surgically accessible hemorrhage that is not amenable to ligation may be treated with topical hemostatic agents such as Gelfoam (Pfizer) (see Chapter 167, Hemostatic Drugs).

SPECIAL CONSIDERATIONS The Spontaneous Hemorrhage Patient Spontaneous hemorrhage causing shock most commonly occurs due to thrombocytopenia, coagulopathy, rupture of neoplasia, or gastric ulceration. Thrombocytopenia and coagulopathy are discussed separately below. In cases of ruptured neoplasia or gastric ulceration, surgery is usually necessary. The key decision is whether to attempt initial resuscitation and proceed to imaging and surgery once the patient is stable, or whether immediate surgery is necessary. This decision is primarily based on the severity of shock and whether there is a positive response to initial therapy. Shock that does not rapidly improve or recrudesces following resuscitation requires immediate surgical management. In these situations, preoperative planning may be limited, and the surgeon should be prepared for several possibilities. For example, a patient may be suspected to have a bleeding splenic mass from point-of-care diagnostic tests but actually have a bleeding hepatic or adrenal mass, necessitating more complex surgical management.

CHAPTER 71  Hemorrhagic Shock

The Thrombocytopenic Patient Severe thrombocytopenia (,20 3 109/ml) can result in spontaneous hemorrhage of sufficient severity to cause shock (see Chapter 103, Platelet Disorders). Speed of onset is usually insidious; therefore, patients with evidence of some bleeding should have frequent monitoring of vital signs. Point-of-care assessment of platelet count and secondary coagulation can aid in the diagnosis of the underlying etiology. Platelet transfusion (fresh, lyophilized, or cryopreserved) can be considered, although it is unclear to what degree they aid in achieving hemostasis.57-59 Fresh whole blood is an alternate source of functional platelets, along with red blood cells and coagulation factors. Refrigerated stored whole blood may retain some platelet activity, contrary to traditional beliefs.42-44 Severe thrombocytopenia without coagulopathy is often due to immune-mediated thrombocytopenia; in these cases, the development of hemorrhagic shock should prompt reassessment of immunosuppressive therapy (see Chapter 103, Platelet Disorders).

The Coagulopathic Patient Shock can result from spontaneous hemorrhage in severe coagulopathies such as anticoagulant rodenticide toxicosis, liver failure, disseminated intravascular coagulation or hemophilia A (see Chapter 104, Coagulopathy in the ICU). Diagnosis is based on history and point-of-care coagulation assessment (traditional or viscoelastic). Aside from bleeding secondary to minor trauma, such as venipuncture, the location of bleeding is most commonly into body cavities. Prompt administration of plasma products is required to correct coagulopathy. Concurrent administration of synthetic clear fluids or PRBC may be needed for resolution of hypovolemia or anemia, respectively.

The Postsurgical Hemorrhage Patient The key decision in postsurgical hemorrhage is to determine whether return to surgery is necessary for hemostasis. Postsurgical hemorrhage can be due to a single bleeding vessel that was not obviously bleeding during surgery due to hypotension, vasoconstrictive drugs, or hypothermia. Patients at particular risk of postoperative bleeding include those undergoing hepatic, cardiovascular, or adrenal surgery (see Box 71.1). Patients with gastric dilation and volvulus may hemorrhage from ruptured short gastric vessels. Once perfusion is restored, bleeding may become apparent, often within 1–3 hours of recovery from general anesthesia. One of the major challenges in the early stages is separating pain from hypovolemia as the cause of postoperative tachycardia. Repeat physical examinations, close monitoring of blood pressure, response to analgesia and small crystalloid fluid boluses, and frequent point-of-care ultrasound may assist with distinguishing between the two. These patients need to be carefully monitored until tachycardia is resolved. If hemorrhagic shock becomes apparent in the postoperative period, the cause may also be generalized oozing from small vessels, usually due to impaired coagulation. Initial management includes a careful assessment of coagulation, as discussed above, and consultation with the surgeon to discuss if they have a suspicion of the source. Any coagulopathy should be aggressively corrected, as reoperation of a coagulopathic animal can worsen hemorrhage. If hemorrhage persists despite normalization of coagulation tests or there is rapid blood loss requiring transfusion of PRBC, an exploratory surgery to identify the source of the bleeding is indicated.

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REFERENCES 1. Boyd C, Smart L: Hypovolemic shock. In Drobatz K, Hopper K, Rozanski E, Silverstein D, editors: Textbook of small animal emergency medicine, Hoboken, NJ, USA, 2018, John Wiley and Sons, Inc., pp 986-992. 2. Shih A, Robertson S, Vigani A, Da Cunha A, Pablo L, Bandt C: Evaluation of an indirect oscillometric blood pressure monitor in normotensive and hypotensive anesthetized dogs, J Vet Emerg Crit Care 20(3):313-318, 2010. 3. Fantoni DT, Ida KK, Gimenes AM, et al: Pulse pressure variation as a guide for volume expansion in dogs undergoing orthopedic surgery, Vet Anaesth Analg 44(4):710-718, 2017. 4. Sano H, Seo J, Wightman P, et al: Evaluation of pulse pressure variation and pleth variability index to predict fluid responsiveness in mechanically ventilated isoflurane-anesthetized dogs, J Vet Emerg Crit Care 28(4): 301-309, 2018. 5. Michard F: Changes in arterial pressure during mechanical ventilation, Anesthesiology 103(2):419-428, 2005. 6. Berkenstadt H, Friedman Z, Preisman S, Keidan I, Livingstone D, Perel A: Pulse pressure and stroke volume variations during severe haemorrhage in ventilated dogs, Br J Anaesth 94(6):721-726, 2005. 7. Klein AV, Teixeira-Neto FJ, Garofalo NA, Lagos-Carvajal AP, Diniz MS, Becerra-Velásquez DR: Changes in pulse pressure variation and plethysmographic variability index caused by hypotension-inducing hemorrhage followed by volume replacement in isoflurane-anesthetized dogs, Am J Vet Res 77(3):280-287, 2016. 8. Jalil BA, Cavallazzi R: Predicting fluid responsiveness: a review of literature and a guide for the clinician, Am J Emerg Med 36(11):2093-2102, 2018. 9. Rosenstein PG, Tennent-Brown BS, Hughes D: Clinical use of plasma lactate concentration. Part 2: prognostic and diagnostic utility and the clinical management of hyperlactatemia, J Vet Emerg Crit Care 28(2): 106-121, 2018. 10. Rosenstein PG, Tennent-Brown BS, Hughes D: Clinical use of plasma lactate concentration. Part 1: physiology, pathophysiology, and measurement, J Vet Emerg Crit Care 28(2):85-105, 2018. 11. Rabozzi R, Oricco S, Meneghini C, Bucci M, Franci P: Evaluation of the caudal vena cava diameter to abdominal aortic diameter ratio and the caudal vena cava respiratory collapsibility for predicting fluid responsiveness in a heterogeneous population of hospitalized conscious dogs, J Vet Med Sci 82(3):337-344, 2020. 12. Meneghini C, Rabozzi R, Franci P: Correlation of the ratio of caudal vena cava diameter and aorta diameter with systolic pressure variation in anesthetized dogs, Am J Vet Res 77(2):137-143, 2016. 13. Oricco S, Rabozzi R, Meneghini C, Franci P: Usefulness of focused cardiac ultrasonography for predicting fluid responsiveness in conscious, spontaneously breathing dogs, Am J Vet Res 80(4):369-377, 2019. 14. Bucci M, Rabozzi R, Guglielmini C, Franci P: Respiratory variation in aortic blood peak velocity and caudal vena cava diameter can predict fluid responsiveness in anaesthetised and mechanically ventilated dogs, Vet J 227:30-35, 2017. 15. Walton RA, Hansen BD: Venous oxygen saturation in critical illness, J Vet Emerg Crit Care 28(5):387-397, 2018. 16. Walley KR: Use of central venous oxygen saturation to guide therapy, Am J Respir Crit Care Med 184(5):514-520, 2011. 17. Salcedo MC, Tart K, Hall K: A systematic review of human and veterinary applications of noninvasive tissue oxygen monitoring, J Vet Emerg Crit Care 26(3):323-332, 2016. 18. Gray SL, Hall KE, Powell LL, Schildt J, Brearley AM, Beilman GJ: Tissue oxygen saturation in dogs with acute hemorrhage, J Vet Emerg Crit Care 28(5):408-414, 2018. 19. Pavlisko ND, Henao-Guerrero N, Killos MB, et al: Evaluation of tissue oxygen saturation with near-infrared spectroscopy during experimental acute hemorrhagic shock and resuscitation in dogs, Am J Vet Res 75(1):48-53, 2014.

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20. Spahn DR, Bouillon B, Cerny V, et al: The European guideline on management of major bleeding and coagulopathy following trauma, Crit Care 23(1):98, 2019. 21. Palmer L, Martin L: Traumatic coagulopathy-Part 1: pathophysiology and diagnosis, J Vet Emerg Crit Care 24(1):63-74, 2014. 22. McMichael M, Moore RM: Ischemia–reperfusion injury pathophysiology, part I, J Vet Emerg Crit Care 14(4):231-241, 2004. 23. Smart L, Boyd CJ, Claus MA, Bosio E, Hosgood G, Raisis A: Large-volume crystalloid fluid is associated with increased hyaluronan shedding and inflammation in a canine hemorrhagic shock model, Inflammation 41(4):1515-1523, 2018. 24. Hoste EA, Maitland K, Brudney CS, et al: Four phases of intravenous fluid therapy: a conceptual model, Br J Anaesth 113(5):740-747, 2014. 25. Rein JL, Coca SG: “I don’t get no respect”: the role of chloride in acute kidney injury, Am J Physiol Renal Physiol 316(3):F587-F605, 2019. 26. Self WH, Semler MW, Wanderer JP, et al: Balanced crystalloids versus saline in noncritically ill adults, N Engl J Med 378(9):819-828, 2018. 27. Semler MW, Self WH, Wanderer JP, et al: Balanced crystalloids versus saline in critically ill adults, N Engl J Med 378(9):829-839, 2018. 28. Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M: Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults, JAMA 308(15):1566-1572, 2012. 29. Daugirdas JT, Nawab ZM, Klok M: Acetate relaxation of isolated vascular smooth muscle, Kidney Int 32(1):39-46, 1987. 30. Silverstein DC, Aldrich J, Haskins SC, Drobatz KJ, Cowgill LD: Assessment of changes in blood volume in response to resuscitative fluid administration in dogs, J Vet Emerg Crit Care 15(3):185-192, 2005. 31. Annane D, Siami S, Jaber S, et al: Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial, JAMA 310(17):1809-1817, 2013. 32. James M, Michell W, Joubert I, Nicol A, Navsaria P, Gillespie R: Resuscitation with hydroxyethyl starch improves renal function and lactate clearance in penetrating trauma in a randomized controlled study: the FIRST trial (Fluids in Resuscitation of Severe Trauma), Br J Anaesth 107(5):693-702, 2011. 33. Myburgh JA, Finfer S, Bellomo R, et al: Hydroxyethyl starch or saline for fluid resuscitation in intensive care, N Engl J Med 367(20):1901-1911, 2012. 34. Perner A, Haase N, Guttormsen AB, et al: Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis, N Engl J Med 367(2):124-134, 2012. 35. Boyd C, Claus M, Raisis A, Hosgood G, Sharp C, Smart L: Hypocoagulability and platelet dysfunction are exacerbated by synthetic colloids in a canine hemorrhagic shock model, Front Vet Sci 5:279, 2018. 36. Boyd CJ, Claus MA, Raisis AL, et al: Evaluation of biomarkers of kidney injury following 4% succinylated gelatin and 6% hydroxyethyl starch 130/0.4 administration in a canine hemorrhagic shock model, J Vet Emerg Crit Care 29(2):132-142, 2019. 37. Diniz M, Teixeira-Neto F, Celeita-Rodríguez N, et al: Effects of 6% tetrastarch and lactated Ringer’s solution on extravascular lung water and markers of acute renal injury in hemorrhaged, isoflurane-anesthetized healthy dogs, J Vet Intern Med 32(2):712-721, 2018. 38. Boyd CJ, Claus MA, Sharp CR, Raisis AL, Hosgood G, Smart L: Biomarkers of acute kidney injury in dogs after 6% hydroxyethyl starch 130/0.4 or Hartmann’s solution: a randomized blinded clinical trial [abstract], J Vet Emerg Crit Care 29(S1):S3, 2019. 39. Jutkowitz LA, Rozanski EA, Moreau JA, Rush JE: Massive transfusion in dogs: 15 cases (1997–2001), J Am Vet Med Assoc 220(11):1664-1669, 2002.

40. Holcomb JB, Tilley BC, Baraniuk S, et al: Transfusion of plasma, platelets, and red blood cells in a 1: 1: 1 vs a 1: 1: 2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial, JAMA 313(5):471-482, 2015. 41. Grochowsky AR, Rozanski EA, de Laforcade AM, et al: An ex vivo evaluation of efficacy of refrigerated canine plasma, J Vet Emerg Crit Care 24(4):388-397, 2014. 42. Edwards T, Darlington D, Pusateri A, et al: Hemostatic capacity of canine chilled whole blood, J Vet Emerg Crit Care 29(S1):S5-S6, 2019. 43. Pidcoke HF, McFaul SJ, Ramasubramanian AK, et al: Primary hemostatic capacity of whole blood: a comprehensive analysis of pathogen reduction and refrigeration effects over time, Transfusion 53:137S-149S, 2013. 44. Strandenes G, Austlid I, Apelseth TO, et al: Coagulation function of stored whole blood is preserved for 14 days in austere conditions: a ROTEM feasibility study during a Norwegian antipiracy mission and comparison to equal ratio reconstituted blood, J Trauma Acute Care Surg 78(6):S31-S38, 2015. 45. Erdmann E, Reuschel-Janetschek E: Calcium for resuscitation? Br J Anaesth 67(2):178-184, 1991. 46. Kelly A, Levine MA: Hypocalcemia in the critically ill patient, J Intensive Care Med 28(3):166-177, 2013. 47. Cole LP, Humm K: Twelve autologous blood transfusions in eight cats with haemoperitoneum, J Feline Med Surg 21(6):481-487, 2019. 48. Robinson DA, Kiefer K, Bassett R, Quandt J: Autotransfusion in dogs using a 2-syringe technique, J Vet Emerg Crit Care 26(6):766-774, 2016. 49. Higgs VA, Rudloff E, Kirby R, Linklater AK: Autologous blood transfusion in dogs with thoracic or abdominal hemorrhage: 25 cases (2007–2012), J Vet Emerg Crit Care 25(6):731-738, 2015. 50. Hammond TN, Holm JL: Limited fluid volume resuscitation, Compendium 31(7):309-320, 2009. 51. Hammond TN, Holm JL, Sharp CR: A pilot comparison of limited versus large fluid volume resuscitation in canine spontaneous hemoperitoneum, J Am Anim Hosp Assoc 50(3):159-166, 2014. 52. Wurlod VA, Howard J, Francey T, Schweighauser A, Adamik KN: Comparison of the in vitro effects of saline, hypertonic hydroxyethyl starch, hypertonic saline, and two forms of hydroxyethyl starch on whole blood coagulation and platelet function in dogs, J Vet Emerg Crit Care 25(4):474-487, 2015. 53. Palmer L, Martin L: Traumatic coagulopathy-Part 2: resuscitative strategies, J Vet Emerg Crit Care 24(1):75-92, 2014. 54. Parsi MA, Schulman AR, Aslanian HR, et al: Devices for endoscopic hemostasis of nonvariceal GI bleeding (with videos), VideoGIE 4(7):285-299, 2019. 55. Weisse CW, Berent AC, Todd KL, Solomon JA: Potential applications of interventional radiology in veterinary medicine, J Am Vet Med Assoc 233(10):1564-1574, 2008. 56. Shakur H, Roberts I, Bautista R, et al: Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial, Lancet 376(9734):23-32, 2010. 57. Hux BD, Martin LG: Platelet transfusions: treatment options for hemorrhage secondary to thrombocytopenia, J Vet Emerg Crit Care 22(1):73-80, 2012. 58. Ng ZY, Stokes JE, Alvarez L, Bartges JW: Cryopreserved platelet concentrate transfusions in 43 dogs: a retrospective study (2007–2013), J Vet Emerg Crit Care 26(5):720-728, 2016. 59. Davidow EB, Brainard B, Martin LG, et al: Use of fresh platelet concentrate or lyophilized platelets in thrombocytopenic dogs with clinical signs of hemorrhage: a preliminary trial in 37 dogs, J Vet Emerg Crit Care 22(1):116-125, 2012.

PART VII  Endocrine Disorders

72 The Diabetic Patient in the ICU Elizabeth Rozanski, DVM, DACVIM (SA-IM), DACVECC, Orla Mahoney-Wages, MVB, DACVIM (SA-IM), DECVIM

KEY POINTS • Management of critically ill small animals with concurrent diabetes requires special attention to glucose, electrolytes, acidbase balance, and volume status. • Insulin is essential for inhibiting ketogenesis (metabolizing ketones) and reversing acidosis. • Fluid requirements in diabetic ketoacidosis may be very high (.180 ml/kg/day).

• Many animals have an underlying comorbidity that causes insulin resistance and may result in ketoacidosis. • Insulin requirements may be higher in the face of exogenous glucocorticoid administration.

Diabetes mellitus is one of the most common endocrine diseases in dogs and cats and perhaps the most frequent endocrinopathy to result in presentation to an intensive care service. A strong working knowledge of diabetes and enthusiasm by the clinician are necessary for frequent reevaluation of the affected pet, as diabetic pets often need reassessment of treatment orders. Animals that have diabetes in association with another disease process may also be admitted to the ICU, and while their primary disease should be aggressively managed, it is wise to actively control hyperglycemia, monitor electrolytes and acid-bases status, and assess volume status frequently. Occasionally, animals that are periarrest or otherwise critically ill are inadvertently thought to have diabetes due to profound hyperglycemia (.500 mg/dl; 27.7 mmol/L). Additionally, animals may be presented following inadvertent insulin overdosage or underdosage. Diabetic remission is important to rule out for cats that present following a hypoglycemic event. Diabetic dogs have an absolute deficiency of insulin, with autoimmune destruction of beta cells, pancreatitis, and genetic factors all thought to play a role. Diabetes mellitus is thought to develop in dogs due to immune-mediated destruction of the islet cells; there may be a genetic tendency, as certain breeds are clearly overrepresented.1,2 Without insulin, glucose is unable to enter the cells, resulting in osmotic diuresis and compensatory polydipsia with the potential for severe dehydration if the patient is unable to keep up with the water requirements or if vomiting develops. Diabetes in dogs is considered more similar to type 1 diabetes in people, while cats have insulin resistance and a relative deficiency of insulin comparable to people with type 2 diabetes. Secondary causes of diabetes include hypersomatotropism, hyperadrenocorticism, exogenous glucocorticoids, diestrus, and pregnancy

in dogs. Glucotoxicity refers to beta cell damage caused by persistent hyperglycemia and is reversible if caught early, especially in cats, and is an argument for prompt insulin therapy. Untreated diabetes may progress to diabetic ketoacidosis (DKA); this is magnified and may develop more rapidly if there is a stressor (infection, pancreatitis, hyperadrenocorticism, exogenous glucocorticoids). Some cats and less commonly dogs have no apparently detectable signs prior to the onset of the DKA or a hyperosmolar nonketotic (HONK) crisis. For animals presenting with a DKA crises, 40%–50% of have been previously receiving insulin, and it may not be clear why DKA or HONK developed.3-7 From the critical care perspective, a variety of questions are important to consider when admitting a critically ill pet with DKA to an ICU. The key discussion points revolve around the when and what kind of insulin to start, how to transition to long-acting insulin, vascular access, fluid rates, continuous glucose measuring devices, additional treatments, and other diagnostic testing to be considered (see Chapter 73, Diabetic Ketoacidosis). While diabetic animals are often divided into those with nonketotic diabetes versus animals with diabetic ketoacidosis, it is perhaps better to consider differentiating animals with diabetes into “sick diabetics” and “not sick diabetics”, with sick being defined as weakness, vomiting, icterus, moderate to severe dehydration, and/ or marked acid-base disturbances, and not sick diabetic animals being those patients that are bright and alert, with a good appetite and no vomiting despite having very high blood glucoses and even ketones. Sick diabetic animals should be hospitalized if at all possible, while not sick diabetic animals may often be successfully treated as an outpatient if additional comorbidities are not severe or lifethreatening.

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INSULIN Immediate control of glucose is not required, but it is important to start insulin promptly. There is significant debate in the veterinary community as to how quickly can you start insulin, with some individuals advocating prompt (,6 hours) initiation, while others advocate for 12–24 hours of fluid resuscitation prior to starting insulin. There are no prospective studies. The argument for starting insulin quickly is that in order to reverse ketosis and resolve acidosis, insulin is required. The argument against starting quickly is the concern for cerebral edema brought about by too rapid of a drop of glucose or the presence of hypokalemia that should be corrected before starting insulin. A survey of criticalists (October 2020) described near universal support for starting insulin within 6 hours of admission. DiFazio and Fletcher found that early insulin administration was associated with more rapid resolution of diabetic ketosis (DK)/DKA without an associated increase in complication rates when evaluated retrospectively.8 DK/DKA took longer to resolve in animals with more severe ketonuria.8 Prospective studies are warranted to identify specific time targets for insulin administration in DK/DKA patients. Urgent insulin therapy can be provided with either rapidly acting (Lispro or Aspart) or shortacting insulin (regular), given either IM or as a continuous rate infusion (CRI).3-6 (see Table 73.1 in Chapter 73). A CRI requires more intensive management and may require a higher level of nursing care. The advantage of a CRI is the ability to change the rate frequently and predictable delivery in a dehydrated patient. Intermittent intramuscular administration of regular insulin is easily undertaken in patients with limited vascular access. It is important to give hourly initially until the glucose is less than 250 mg/dl (13.9 mmol/L). It is also acceptable to start with longer acting insulin (e.g., NPH or glargine) for the treatment of DKA and add additional short/rapid acting insulin. Glargine acts rapidly if given IM, and it may be a useful option if repeated every 2 to 4 hours IM or every 12 hours SQ.9,10 The clinician’s goal should be to keep glucose levels between 150 and 250 mg/dl (8.3–13.9 mmol/L); ideally, insulin should be continuously given, so if the glucose level is low, supplementation with dextrose and continuation of the insulin infusion are recommended.

How Much Fluid Does a Diabetic Pet Need? Fluid therapy for diabetic animals, particularly DKA and HONK patients, is essential for resolution. The clinician should recall that in the presence of hyperglycemia, the fluid needs of an individual patient can be very high, with rates commonly in excess of 180 ml/kg/day. In animals that are not drinking well or nonambulatory or appear excessively polyuric, an aseptically placed urinary catheter may be useful for quantification of urinary losses. If a urinary catheter is not placed, careful attention to body weight, urine production (e.g., weighing urine pads), skin turgor, and mucous membrane moistness is recommended. Diabetic animals have an obligate diuresis associated with the hyperglycemia, and even if profoundly dehydrated, these animals will continue to produce urine. Medullary washout associated with preexisting polyuria/polydipsia may also contribute. Urine output and body weight should be monitored, although in smaller patients clinically relevant water loss may occur without clear weight differences. Sodium concentration is useful for the detection of free water deficits, although pseudohyponatremia should be considered when interpreting the sodium value. For example, in a 15 kg dog, if the sodium level goes from 145 to 160 mEq/L, then the free water deficit of this dog would be 15 3 (160/145 -1) 3 0.6 5 930 ml of free water (see Chapter 55, Sodium Disorders). The use of sodium concentration in diabetics as a monitoring tool requires the correction of sodium for hyperglycemia

using formula Corrected sodium 5 Measured sodium 1 0.016 3 (Serum glucose 2 100). The fluid type used is rarely of specific concern, but in general a balanced electrolyte replacement solution (Plasma-Lyte/lactated Ringer’s solution) is most popular. Some clinicians prefer 0.9% saline, but this is an acidifying fluid with a high chloride concentration that may have deleterious renal effects. The key feature for fluid therapy for DKA patients is to give enough fluids to maintain total body hydration (see Chapters 63 and 64, Assessment of Hydration and Assessment of Intravascular Volume, respectively).

Vascular Access and Continuous Glucose Monitors A catheter that permits sampling, such as a double lumen catheter, is helpful for frequent blood draws to measure glucose and electrolytes. Care should be taken to ensure the pet is adequately hydrated and has visible vessels before attempting to place a lumen catheter unless extenuating circumstances exist. Continuous glucose monitors (e.g., the FreeStyle Libre-Abbott Laboratories, Chicago, IL) represent a novel method to monitor interstitial glucose in dogs and cats. Minimally invasive, they lie under the skin, and allow for painless, real-time monitoring of interstitial glucose within as little as 1 hour of placement. A recent study of the Libre flash glucose monitoring system in dogs with DKA showed acceptable accuracy. Blood glucose measurement is recommended to periodically double check interstitial glucose readings and whenever there are unexpected readings or the glucose is either above 500 mg/dl (27.7 mmol/L) or below 60 mg/dl (3.33 mmol/L). Continuous glucose monitors are rapidly emerging as a useful tool, even in newly diagnosed diabetic patients with ketones.11 Many internists support placing them early in the course of hospitalization after rehydration, and as the ketosis resolves, they permit simpler and painless evaluation of glucose levels. The patient can continue to wear the sensor upon discharge from the hospital, permitting at-home adjustment of insulin as appetite improves and the adverse effects of DKA resolve. From an emergency standpoint, it is likely that early placement will permit more frequent monitoring of the glucose, which may lead to more rapid resolution of ketosis and for smaller patients, minimize iatrogenic anemia secondary to frequent phlebotomy.

Electrolytes Hypokalemia is very common in sick diabetic animals and results from a combination of lack of dietary intake, vomiting, and massive renal losses from polyuria. The severity of the hypokalemia may be initially masked by acidosis combined with lack of insulin, resulting in more extracellular potassium (see Chapter 56, Potassium Disorders). Potassium should be aggressively supplemented and frequently monitored. If the starting serum potassium is unavailable, it is wise to start with at least 40 mEq/L, although the fluid rate should be considered. Recall that the maximum rate of potassium infusion (Kmax) is 0.5 mEq/kg/hr, so a safe starting point is 0.1–0.25 mEq/kg/hr until the potassium level can be determined. Tables designed to help determine potassium supplementation (i.e., Sliding Scale of Scott) use maintenance type fluid rates, so care should be taken to avoid overzealous supplementation if higher fluid rates are chosen. It is often preferable to calculate out the Kmax rate (0.5 mEq/kg/hr) and then place into a dedicated fluid bag, separate syringe pump, or the regular infusion bag, with clear labelling to prevent inadvertent overdosage. If hypokalemia does not correct promptly, supplemental magnesium may be considered, ideally after measurement, at a rate of 1 mEq/kg/day (0.04 mEq/kg/hr). See Chapter 58, Magnesium and Phosphate Disorders for further information. Hypophosphatemia may develop within 24 hours of therapy; this occurs secondary to osmotic diuresis, metabolic acidosis, insulin therapy,

CHAPTER 72  The Diabetic Patient in the ICU and fluid therapy. Severe hypophosphatemia may result in hemolytic anemia and muscle weakness, so supplementation may be considered if the starting value is at the low end of the reference range or falls after treatment if started. Animals that are azotemic rarely if ever have low phosphorus due to lower renal clearance. Cats are more commonly affected than dogs. Anemia can be dramatic and develop quickly. Supplementation is typically provided using potassium phosphate, either as a CRI at 0.06–0.12 mmol/kg/hr or by splitting the overall potassium rate 1:1 with potassium chloride:potassium phosphate (4.4 mmol of Phos and 3 mEq of K in 1 ml of KPhos). See Chapter 58, Magnesium and Phosphate Disorders for further information. Other recommended monitoring including checking electrolytes every 4–8 hours initially, phosphorus q12-24h, and hydration (weight, attitude, and mucous membranes) as well as glucose q1-2h. It is important to keep increasing the insulin dose if the pH remains low or the ketones are not resolving, even if the glucose levels are acceptable. Some of these patients are remarkably insulin resistant and require supplemental dextrose as well as higher doses of insulin. These high doses of insulin may be reduced over time as ketosis resolves. An abdominal ultrasound might be helpful to rule out comorbidities such as pancreatitis and other causes of insulin resistance. A urine culture is also warranted to exclude infection, even without evidence of infection on urinalysis. Transitioning to long-term insulin may be done immediately (rare) or when ketones have cleared or when appetite returns. There is no evidence that one method of timing is better than another, but it is crucial to continue to carefully monitor the pet after the transition. The best long-term insulin is debatable and may reflect clinician preference and cost to the owners. Most insulin formulations work well in all pets, although in some cases there is apparent improvement when a different type is used. In recent years, in the USA, the cost of some insulin products may be prohibitive. Two veterinary specific insulin products (Vetsulin or Caninsulin, Merck [Merck Animal Health, Kenilworth, NJ]) and PZI (B-I) are available, and both are good/reasonable choices. Other commonly used insulin types include NPH and insulin glargine (Lantus [Sanofi US, Bridgewater, NJ]). Different brands of insulin vary significantly in price, and it is prudent to understand this variability and inform owners of the cost.

NUTRITIONAL SUPPORT Nutritional support is essential for the resolution of severe diabetes. A typical diabetic patient has a ravenous appetite, but due to combinations of acid-base disturbance, azotemia, pancreatitis, and hepatic lipidosis, DKA and HONK, patients are commonly anorexic. Supplemental feeding via a nasogastric tube or E-tube may be considered in patients that remain persistently anorexic. Nasogastric tubes may be placed with less or no sedation, but they are less useful for long-term support due to limitations in the diet that may be delivered due to the size of the tube (see Chapter 126, Enteral Nutrition). The ICU team should also remember that “offering a smorgasbord” to a sick patient may perpetuate food aversion; a normal diabetic patient should be hungry, and it is possible to magnify food aversion by offering foods if nausea is present. Small amounts of food should be offered and

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then removed if not consumed. Food may be warmed, and different types (dry versus canned) should be offered. Capromorelin (Entyce) may be administered; this new medication is a ghrelin agonist and may improve appetite but may increase insulin resistance by raising IGF1 levels. The benefits of increased appetite, even with the potential for raised glucose, can be addressed with additional insulin. In cats, low carbohydrate, high protein foods (e.g., Purina DM) may be useful in helping get a cat into remission. Remission is exceedingly rare in dogs. Parenteral nutrition is an option, but as total or partial parenteral nutrition has a high concentration of dextrose, it will escalate insulin requirements. Parenteral nutrition has also been falling from favor in the ICU due to the potential immunosuppressive risk (see Chapter 127, Parenteral Nutrition). If a blood transfusion is required, the blood is anticoagulated in citrate phosphate dextrose adenine. Subsequently, additional insulin may be required during and immediately following the transfusion.

REFERENCES 1. Hess R, Henthorn P, Devoto M, Wang F, Feng R: An exploratory association analysis of the insulin gene region with diabetes mellitus in two dog breeds, J Hered 110(7):793-800, 2019. 2. Cai SV, Famula TR, Oberbauer AM, Hess RS: Heritability and complex segregation analysis of diabetes mellitus in American Eskimo Dogs, J Vet Intern Med 33(5):1926-1934, 2019. 3. Malerba E, Mazzarino M, Del Baldo F, et al: Use of lispro insulin for treatment of diabetic ketoacidosis in cats, J Feline Med Surg 21(2):115123, 2019. 4. Anderson JD, Rondeau DA, Hess RS: Lispro insulin and electrolyte supplementation for treatment of diabetic ketoacidosis in cats, J Vet Intern Med 33(4):1593-1601, 2019. 5. Walsh ES, Drobatz KJ, Hess RS: Use of intravenous insulin aspart for treatment of naturally occurring diabetic ketoacidosis in dogs, J Vet Emerg Crit Care 26(1):101-107, 2016. 6. Sears KW, Drobatz KJ, Hess RS: Use of lispro insulin for treatment of diabetic ketoacidosis in dogs, J Vet Emerg Crit Care 22(2):211-218, 2012. 7. Hume DZ, Drobatz KJ, Hess RS: Outcome of dogs with diabetic ketoacidosis: 127 dogs (1993-2003), J Vet Intern Med 20(3):547-555, 2006. 8. DiFazio J, Fletcher DJ: Retrospective comparison of early- versus lateinsulin therapy regarding effect on time to resolution of diabetic ketosis and ketoacidosis in dogs and cats: 60 cases (2003-2013), J Vet Emerg Crit Care 26(1):108-115, 2016. 9. Marshall RD, Rand JS, Gunew MN, Menrath VH: Intramuscular glargine with or without concurrent subcutaneous administration for treatment of feline diabetic ketoacidosis, J Vet Emerg Crit Care 23(3):286-290, 2013. 10. Gallagher BR, Mahony OM, Rozanski EA, Buob S, Freeman LM: A pilot study comparing a protocol using intermittent administration of glargine and regular insulin to a continuous rate infusion of regular insulin in cats with naturally occurring diabetic ketoacidosis, J Vet Emerg Crit Care 25(2):234-239, 2015. 11. Malerba E, Cattani C, Del Baldo F, et al: Accuracy of a flash glucose monitoring system in dogs with diabetic ketoacidosis, J Vet Intern Med 34(1):83-91, 2020.

73 Diabetic Ketoacidosis Sabrina N. Hoehne, Dr med vet, DACVECC, DECVECC

KEY POINTS • Diabetic ketoacidosis (DKA) is a potentially life-threatening complication of diabetes mellitus that requires emergent medical attention. • DKA is characterized by hyperglycemia/glucosuria, ketonemia/ ketonuria, and high anion gap metabolic acidosis. • Concurrent diseases contribute to the pathogenesis of DKA, and they must be identified and treated for successful DKA resolution and diabetic control.

• Hypokalemia, hypophosphatemia, and hypomagnesemia commonly develop during DKA therapy, and electrolyte concentrations must be closely monitored. • Restoring intravascular and interstitial fluid deficits, correcting electrolyte and acid-base abnormalities, and administering exogenous insulin are the cornerstones of DKA therapy. • Up to 81% of dogs and 100% of cats can be discharged from the hospital after a DKA episode, depending on the severity of concurrent diseases.

Diabetic ketoacidosis (DKA) is a severe and potentially life-threatening complication of diabetes mellitus (DM) that requires emergent medical care. Characterized by hyperglycemia, glucosuria, ketonemia or ketonuria, and metabolic acidosis, this condition occurs in up to 15% of canine patients suffering from DM presenting to a tertiary veterinary facility.1 The pathogenesis of DKA involves a combination of factors, including contributing concurrent diseases, hormonal alterations, and the resulting synthesis of ketone bodies from free fatty acids when intracellular glucose concentration is inadequate to meet metabolic needs.

energy deficient in the face of rising serum glucose concentrations. The extracellular hyperglycemia leads to glucosuria, osmotic diuresis, and dehydration. As dehydration progresses, renal perfusion and renal glucose excretion decrease, further exacerbating hyperglycemia. Once cellular metabolic needs cannot be met through glucose uptake, counterregulatory hormones increase to mobilize alternative energy sources but contribute to worsening hyperglycemia through hepatic glycogenolysis and gluconeogenesis.2 While it was previously believed that DKA developed due to an absolute lack of insulin, recent studies have shown that cytokine dysregulation may contribute to ketogenesis, along with increases in glucagon despite detectable to even normal insulin levels.8–10 The combination of insufficient insulin action and increased concentrations of counterregulatory hormones and cytokines contributes to increased lipolysis and decreased fatty acid storage, resulting in increased circulating concentrations of free fatty acids.2 Free fatty acids undergo mitochondrial beta oxidation to form acetyl-coenzyme A (acetyl-CoA), which then enters the citric acid cycle to contribute to ATP production. In diabetic patients, the number of acetyl-CoA carriers in the citric acid cycle is reduced, leading to the oxidation of excess acetyl-CoA into ketone bodies: acetoacetate, which can then be metabolized to b-hydroxybutyrate (the predominant ketone body in dogs and cats suffering from DKA), and acetone. Acetoacetate and b-hydroxybutyrate are anions of moderately strong acids that dissociate to a significant degree at physiologic pH, resulting in a metabolic acidosis. The accumulation of the associated ketone anions leads to an increase in anion gap. Acetone does not dissociate and contribute to the high anion gap metabolic acidosis, but it does contribute to the occasionally described characteristic odor of DKA patients.2,11

PATHOPHYSIOLOGY Concurrent diseases are very common in DKA patients and have been documented in up to 74% of dogs and 93% of cats.2–4 These disease processes initiate hormonal changes and alterations to the intermediary metabolism that culminate in ketone body formation and the development of DKA. The most common diseases thought to predispose previously stable diabetic dogs to the development of DKA include pancreatitis, bacterial urinary tract infections, neoplasia, and hyperadrenocorticism.1,3,5,6 Common concurrent diseases identified in cats with DKA are hepatic lipidosis, cholangiohepatitis, pancreatitis, bacterial and viral infections, and neoplasia.4,7 Any of the aforementioned disease processes have the potential to trigger the secretion of insulin counterregulatory hormones such as glucagon, catecholamines, cortisol, and growth hormone. Along with an absolute or relative lack of insulin in diabetic patients, an increase in counterregulatory hormones will lead to the exacerbation of hyperglycemia, increased fat and protein catabolism, and ketogenesis.2 Apart from in the brain, insulin facilitates cellular glucose uptake and utilization through glycolysis or by promoting storage in the form of glycogen. Furthermore, as an anabolic hormone, insulin enhances storage of amino acids as proteins, storage of fatty acids as triglycerides, and inhibits lipolysis and the release of free fatty acids. If insulin is lacking, tissue glucose uptake is severely reduced, and cells become

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SIGNALMENT Dogs and cats with DKA are most commonly middle-aged (median age of 8 to 9 years in dogs and mean age of 9 years in cats) at the time

CHAPTER 73  Diabetic Ketoacidosis of diagnosis.4–6 No clear breed or sex predisposition for DKA has been identified, although one retrospective study reported an overrepresentation of intact female dogs comprising 43% of its DKA patient population.4–6

HISTORY AND CLINICAL MANIFESTATION Most dogs and cats are newly diagnosed diabetics at the time of DKA detection, and it remains possible that exogenous insulin therapy reduces the risk of DKA development.4–6 Presenting complaints and physical examination findings in DKA patients can therefore vary considerably and represent clinical signs of the acute decompensation to DKA, undiagnosed or poorly regulated DM, or those of concurrent diseases. The most commonly noted clinical signs in dogs and cats with DKA include lethargy, anorexia, polyuria and polydipsia, and weight loss. Dog owners also may report vomiting, diarrhea, and pollakiuria in affected animals.4,6 On physical examination, signs of circulatory shock or interstitial dehydration are commonly seen (see Chapters 63 and 64, Assessment of Hydration and Assessment of Intravascular Volume, respectively).4–6 Dogs can present in variable body condition, while cats are more frequently underweight at the time of diagnosis.4–6 Peripheral neuropathies are described in both dogs and cats with DKA, but the classical plantigrade stance is more common in cats.5,6 Additional findings are dependent on concurrent disease processes and can include abdominal pain, cranial abdominal organomegaly, icterus, cardiac murmur, dyspnea, coughing, abnormal breath sounds, dermatologic, and ophthalmologic abnormalities.4,5

DIAGNOSIS The diagnostic criteria for DKA in veterinary medicine include a diagnosis of DM based on compatible clinical signs and the presence of persistent hyperglycemia and glucosuria, the documentation of ketonemia or ketonuria, and the presence of metabolic acidosis based on reduced serum bicarbonate concentrations.2 Serum hyperglycemia and glucosuria are present in 98% to 100% of dogs at the time of DKA diagnosis and can be readily detected using chemical laboratory analyzers or portable blood glucose meters and enzymatic urine dipsticks, respectively.5,6,11 Ketonuria is present in 94% to 100% of dogs at the time of DKA diagnosis but might not be reliably detected using urine dipsticks.5,6 The commonly used nitroprusside reagent strips react with acetoacetate and to a lesser extent acetone, but not the predominant ketone body b-hydroxybutyrate.11 The addition of 3% hydrogen peroxide to patient samples to promote b-hydroxybutyrate conversion to acetoacetate and increase the diagnostic yield of nitroprusside reagent strips does not improve urinary ketone detection.11 Furthermore, it is possible that ketonuria is not yet present in early disease. If DKA is highly suspected despite the absence of ketonuria, plasma or serum from a microhematocrit tube can be used on urine reagent strips to test for acetoacetate and acetone with better sensitivity and specificity than urine.11 If ketonemia cannot be confirmed with urine reagent strips, blood should be tested specifically for the presence of b-hydroxybutyrate using more sensitive quantitative enzymatic assays or a portable ketone analyzer.11 Concentrations of .3.5 mmol/L in dogs and .2.4 mmol/L in cats are associated with DKA.11 Venous pH in dogs with DKA is typically below reference range, and the acidemia is characterized by a metabolic acidosis with decreased bicarbonate concentrations in 93% of dogs and an increased anion gap in 77%.5

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ADDITIONAL DIAGNOSTIC EVALUATION To identify concurrent disease processes in DKA patients, a thorough workup including a complete blood count, serum biochemical analysis, thoracic and abdominal imaging studies, urinalysis and bacterial culture and susceptibility testing of urine or other sites of suspected infection is indicated. Abnormalities reflecting concurrent diseases are commonly seen on abdominal ultrasound; abdominal radiographs are less sensitive.5,6 Depending on the history, physical examination findings, and suspected concurrent diseases, additional diagnostic modalities could include echocardiography, endocrine testing (adrenal or thyroid axis, pancreatic lipase immunoreactivity), infectious disease testing, and cytological evaluation of fine-needle aspirates. Approximately half of the dogs with DKA show normochromicnormocytic anemia, leukocytosis characterized by neutrophilia with a left shift, and thrombocytosis.5,6 Anemia and neutrophilia with a left shift are also commonly reported in feline DKA.4 Serum biochemical analysis of dogs with DKA reveals increased alkaline phosphatase activity in up to 97% of cases and increases in alanine aminotransferase, aspartate aminotransferase, gamma glutamyl-transferase, cholesterol, lipase, and amylase in approximately half of the affected dogs.5,6 Hypercholesterolemia and increases in alanine aminotransferase are also common features of feline DKA.4 While azotemia can be observed in both species, it appears to be less common in dogs with DKA compared with cats.4–6 Electrolyte abnormalities are common in DKA patients and should be taken into account and monitored closely when formulating treatment plans for both dogs and cats. Hyperglycemia and hyperosmolality lead to shifting of water, potassium, phosphorus, and magnesium ions from the intracellular to the extracellular space.2 Glucosuria-induced osmotic diuresis subsequently causes significant urinary water and electrolyte losses leading to dehydration, hypovolemia, and total body potassium, phosphorus, and magnesium depletion.2 As volume depletion and acidosis progress, decreased renal perfusion, renal excretion, and hypoinsulinemia may make extracellular potassium, phosphorus, and magnesium concentrations appear normal in untreated DKA.2 Acidosis can further contribute to normal extracellular potassium concentration due to shifting of potassium ions to the extracellular space in exchange for hydrogen ions. Once intravenous fluid therapy restores renal perfusion and insulin therapy is initiated, rapid declines in both potassium and phosphorus concentrations can be observed in 84% and 48% of dogs, respectively.5,6 Similarly, a decrease in total magnesium can be observed in dogs and cats after initiation of DKA therapy.5,12 The most life-threatening consequences of severe hypokalemia and hypophosphatemia include muscle weakness, respiratory paralysis, cardiac conduction abnormalities, and hemolysis.2 Hyponatremia, hypochloremia, and ionized hypocalcemia is reported in more than 50% of dogs with DKA.5,6 Free water retention as a result of hypovolemia-induced antidiuretic hormone release and urinary sodium losses likely contribute to the development of hyponatremia but the degree of hyperglycemia has to be taken into account when assessing its severity. An increase in extracellular osmolality results in fluid shifts that cause a dilutional reduction in extracellular sodium concentration by 1.6 mEq/L for every 100 mg/dl of plasma glucose above the reference range.2 On urinalysis, glucosuria, ketonuria, proteinuria, elevated urine protein to creatinine ratio, hemoglobinuria, and hypersthenuria (due to pronounced glucosuria) are present in a large proportion of dogs.2,5,6 Pyuria is rarely reported, and urine cultures are negative in up to 87% of dogs.5,6 In animals with a positive urine culture, the most commonly reported bacterial isolate is Escherichia coli.5,6

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THERAPY Treatment of DKA includes restoring intravascular and interstitial fluid deficits, managing electrolyte imbalances, correcting acidbase status by clearing the body of detectable ketones, decreasing blood glucose concentration, and managing underlying concurrent diseases (see Box 73.1).

Intravenous Fluid Administration Adequate IV fluid therapy is one of the most important aspects of DKA treatment as fluid therapy alone can significantly increase renal perfusion and excretion of blood glucose and decrease production of counterregulatory hormones.2,13 Patients with DKA have often suffered significant intravascular and interstitial fluid losses and continue to have increased urinary losses due to osmotic diuresis while severely hyperglycemic. The fluid therapy plan should therefore include intravascular volume replacement, rehydration, replacement of ongoing losses, and the provision of maintenance needs (see Chapters 67 and 68, Daily Intravenous Fluid Therapy and Shock Fluid Therapy, respectively). Any commercially available isotonic replacement type crystalloid solution (e.g., 0.9% sodium chloride (NaCl), lactated Ringer’s solution, Plasma-Lyte 148, or Normosol®-R) may be used in the treatment of DKA. Historically, 0.9% NaCl has been advocated as the fluid of choice due to its high sodium concentration and ability to rapidly replace whole body sodium deficits. More recently, benefits of buffered isotonic crystalloids in DKA patients have been investigated. IV fluids containing bicarbonate precursors (such as lactate, acetate, or gluconate; see Chapter 65, Crystalloid Solutions) appear to aid in faster resolution of metabolic acidosis and decrease the incidence of hyperchloremia, which has been associated with negative effects such as increased time to DKA resolution, risk of acute kidney injury, and increased hospital length of stay.14–16 The small amount of potassium in buffered isotonic crystalloids may further blunt the sudden decline in potassium concentration after initiation of DKA therapy. Hyponatremia is expected to improve as hyperglycemia and hyperosmolarity decrease, but if hyponatremia and/or hypochloremia persist, administration of a crystalloid with a higher sodium and chloride content than that of the patient can be considered (see Chapter 55, Sodium Disorders).

Electrolytes Frequent monitoring of electrolyte concentrations and adjustments to the fluid therapy plan are the second most important component of DKA therapy as hypokalemia, hypophosphatemia, and hypomagnesemia are frequently observed in DKA patients. Hypokalemia should be addressed by administering a continuous rate infusion (CRI) of potassium chloride according to a previously published sliding scale (see Chapter 56, Potassium Disorders). Care must be taken to not exceed a potassium administration rate of 0.5 mEq/kg/hr without close clinical and electrocardiographic monitoring. Hypophosphatemia is corrected with a CRI of potassium phosphate at a rate of 0.03 to 0.12 mmol/kg/hr IV. If potassium phosphate is administered concurrently with potassium chloride for potassium supplementation, the potassium amount administered in the form of potassium phosphate should be subtracted from the total amount of potassium to be administered as a potassium chloride solution (see Chapter 58, Magnesium and Phosphate Disorders). In patients with documented hypomagnesemia, a magnesium sulfate CRI of 0.25 to 1 mEq/kg/day is administered (see Chapter 58, Magnesium and Phosphate Disorders).

Insulin The administration of exogenous insulin is a vital part of DKA treatment that is ultimately always required to halt ketogenesis and correct hyperglycemia.17,18 The optimal timing to start insulin therapy is unknown in veterinary medicine, but it is most commonly recommended to wait until hypovolemia, dehydration, and electrolyte derangements have been fully corrected. Early insulin therapy may not be required as IV fluid therapy may significantly improve hyperglycemia and electrolyte disturbances could be exacerbated by premature insulin administration.12,13,17–22 Furthermore, too rapid of a reduction in serum osmolarity was previously thought to be associated with the development of cerebral edema.21 Conversely, it has been shown that inadequate normalization of serum sodium concentration with resolution of hyperglycemia is more important for the development of neurologic complications, which might make the concern over rapid correction of hyperglycemia unwarranted.23–26 A study in dogs and cats comparing the timing of short-acting insulin administration after a median of 4 hours to a median of 8.25 hours after admission found that early insulin administration leads to a more rapid resolution of DKA without a difference in complication rate.27 While further prospective studies are warranted, it appears that insulin therapy may not need to be delayed and is not associated with as many complications as previously believed. Regular crystalline insulin is most commonly used for the treatment of DKA and can be administered as an IV CRI (see Table 73.1) or as intermittent IM dosing; subcutaneous (SQ) insulin administration is not recommended due to unreliable absorption in dehydrated animals.21,28,29 The goal with both protocols is to decrease blood glucose concentration to ,250 mg/dl by no more than 50 to 75 mg/dl/hr.2,30 If the blood glucose concentration is dropping too rapidly or too slowly, the insulin dosage should be adjusted. When regular insulin is administered as an IV CRI, 2.2 U/kg of regular insulin is added to a 250 ml bag of 0.9% NaCl solution, blood glucose is monitored every 2 hours, and insulin delivery rate is adjusted accordingly.21,29 A lower dosage of 1.1 U/kg for cats is occasionally recommended because of a suspected higher risk for neurologic adverse effects from rapid correction of hyperglycemia in this species.29 However, a recent study treating cats with the canine insulin dosage of 2.2 U/kg/day did not show an increased frequency of adverse neurological or biochemical events when using a sliding scale to limit the amount of insulin the cats received.20 With intermittent IM dosing of regular insulin, the initial dose is 0.2 U/kg IM followed by hourly injections at lower dosages dependent on hourly preinjection blood glucose measurements.28 If the blood glucose concentration drops by .75 mg/dl, 50 to 75 mg/dl, or by ,50 mg/dl, regular insulin is administered IM at 0.05 U/kg, 0.1 U/kg, or 0.2 U/kg, respectively.28 In recent years, genetically engineered rapid-acting and ultrashortacting human insulin analogues have been investigated as alternatives to regular insulin for the treatment of DKA. Preliminary studies in dogs and cats randomized to receive either an IV CRI low-dose regular or lispro insulin showed that lispro insulin is a safe and equally effective alternative to regular insulin.7,13,31 In a small cohort of six dogs, IV CRI of insulin aspart showed a similarly shortened time to biochemical resolution of DKA with no adverse effects.22 While it appears that insulin lispro and aspart could be used as safe alternatives to regular insulin, larger prospective studies are needed before recommending them as standard of care. In children, the addition of SQ insulin glargine to low-dose IV CRI regular insulin has been shown to lead to faster biochemical resolution of DKA.32 No studies have evaluated this protocol in dogs or cats with DKA, but two studies in cats evaluated the safety and efficacy of other

CHAPTER 73  Diabetic Ketoacidosis

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TABLE 73.1  Insulin and Dextrose Administration Rates Using the Continuous Low-Dose IV

Insulin CRI Protocol in Dogs and Cats with Diabetic Ketoacidosis19,21,29 Blood Glucose Concentration (mg/dl) .250

Intravenous Fluid Composition 0.9% NaCl

Administration Rate of Insulin Solution (ml/hr)* 10

200 to 250

0.9% NaCl 1 2.5% Dextrose

7

150 to 199

0.9% NaCl 1 2.5% Dextrose

5

100 to 149

0.9% NaCl 1 5% Dextrose

5

,100

0.9% NaCl 1 5% Dextrose

Stop insulin administration

CRI, constant rate infusion; IV, intravenous; 0.9% NaCl, 0.9% sodium chloride solution. *2.2 U/kg of regular crystalline insulin is added to a 250 ml bag of 0.9% NaCl solution. The administration set is then primed, and because insulin binds to the plastic IV tubing, 50 ml of the solution should be allowed to flow through the administration set and be discarded prior to administration to the patient.29

intermittent insulin glargine protocols.33,34 One study that randomized 16 cats to either receive an IV CRI regular insulin or SQ glargine twice daily plus IM regular insulin up to every 6 hours showed significantly shorter time to biochemical resolution of DKA and hospital discharge in the combined SQ/IM insulin group.34 Another study treating 15 cats with a combination of SQ and IM insulin glargine showed the protocol to be effective in resolving DKA; however, two cats required a blood transfusion due to hypophosphatemia-induced hemolysis.33 While novel insulin protocols show some promise for the treatment of dogs and cats suffering from DKA, larger prospective trials are necessary before their routine use can be recommended as an alternative to a low-dose regular insulin CRI.

Bicarbonate Therapy The metabolic acidosis of DKA typically resolves with IV fluid and insulin therapy; therefore, bicarbonate administration is not needed in most cases.13,20,22 Replacement of bicarbonate may not be appropriate, as the metabolic acidosis in DKA is associated with an accumulation of organic anions rather than a loss of bicarbonate.35 Bicarbonate administration in human DKA is controversial due to concerns of worsening of hypokalemia, decreased tissue oxygen delivery, and paradoxical intracellular acidosis.17,35 Due to the concern for metabolic acidosis-induced insulin resistance, the American Diabetes Association recommends IV bicarbonate therapy in patients with an arterial pH of ,7.0 after 1 hour of intravenous fluid therapy.30 If bicarbonate therapy is considered in veterinary patients with severe metabolic acidosis, it should be administered at one-third to onehalf of the calculated sodium bicarbonate dose (see Chapter 59, Traditional Acid-Base Analysis).

Monitoring Close clinical and biochemical monitoring of DKA patients is important to ensure a successful outcome and minimize treatment complications. Assessment of volume and hydration status should occur at least every 2 to 6 hours during the initial stages of therapy (see Chapters 63 and 64, Assessment of Hydration and Assessment of Intravascular Volume, respectively). Serum electrolytes, acid-base status, and ketone concentration should initially be monitored every 4 to 6 hours and then every 8 to 24 hours as patients become more metabolically stable. Phosphorus and magnesium concentrations should initially be measured one to two times daily. During sodium bicarbonate therapy, pH should be checked every 1 to 4 hours.17 Continuous electrocardiogram monitoring is recommended in patients with severe dyskalemia. Complete blood count and serum biochemistry panels should be performed daily. Placement of a sampling line or multi-lumen central venous catheter should be considered

to facilitate noninvasive serial blood sampling and medication administration. Blood glucose concentrations should be checked prior to initiating insulin therapy and rechecked every 1 to 2 hours, depending on the insulin administration protocol. Continuous glucose monitoring systems that measure interstitial glucose concentration and display an average extrapolated blood glucose value every 5 minutes have been shown to be an accurate alternative to repeat capillary or venous blood glucose measurements, not only in stable diabetics but also in DKA patients.11,36 Sensors are most commonly placed on the lateral thorax, but it appears that the dorsal cervical region might be a superior placement site in cats.11 Depending on the device used, continuous glucose monitoring systems can have several limitations, including the continued need for blood sampling for device calibration, time delays to display rapid changes in blood glucose concentration, and decreased accuracy in the hypoglycemic range and in dehydrated patients.11 Anytime the clinical picture does not fit with the interstitial sensor glucose measurement, a blood glucose measurement should be obtained.

Concurrent Diseases Concurrent diseases play an important role in hormonal dysregulation that favors the development of DKA in diabetic animals. Their identification and tailored treatment are therefore of utmost importance for the resolution of DKA and long-term diabetic control.

Long-Term Therapy IV fluid therapy and administration of short-acting insulins should be continued until patients are reliably eating and drinking and are no longer ketotic. During the diabetic crisis, it is more important that patients eat something versus eating a specific diet for long-term diabetic control. Diabetic maintenance therapy can then be initiated once the animal is feeling better, including twice daily SQ administration of an intermediate to long-acting insulin, transitioning to a high-fiber diet for dogs and high-protein, carbohydrate restricted diet for cats, and the generation of a regular monitoring schedule.37 Adequate DM therapy is especially important in cats, as DM remission remains possible in cats developing DKA.38

OUTCOME The majority of dogs and cats treated for DKA survive to hospital discharge. Survival rates in dogs range from 52% to 81% and in cats from 61% to 100% but remain influenced by underlying disease processes and euthanasia rates.3–6,20,21,33,39,40 Median hospitalization time for dogs is approximately 6 days and can range from 3 to 7 days for cats.3–5,20,33,39,40 Dogs with concurrent hyperadrenocorticism, lower

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BOX 73.1  Recommended Treatment and Monitoring Schedule for Dogs and Cats with Diabetic Ketoacidosis Intravenous Fluid Therapy • Assess intravascular volume status every 2–6 hours • If in shock, administer replacement isotonic crystalloid solutions rapidly in 10–30 ml/kg increments up to 90 ml/kg IV for dogs and up to 60 ml/kg IV for cats (see Chapter 68) • Assess interstitial hydration every 2–6 hours • If dehydrated, calculate fluid amount to be replaced using the following formula: (body weight [kg] 3 1000) 3 (% dehydration/100) 5 deficit (ml) • Rehydrate over 4–24 hours using replacement type isotonic crystalloids • Continue maintenance rate fluid therapy at 2–4 ml/kg/hr (see Chapter 67) and replace ongoing losses • Weigh every 4–8 hours • Check PCV/TP every 12 hours Electrolyte Imbalances and Acid-Base Status • Measure serum electrolytes every 4–6 hours • Measure phosphorus and magnesium concentrations every 12–24 hours

calcium concentration, anemia, and more severe acidosis were less likely to survive to hospital discharge in one study.5 Cats were less likely to survive to hospital discharge in the presence of more severe azotemia, metabolic acidosis, and hyperosmolarity.4 Up to 17% of dogs and 42% of cats experience recurrent DKA episodes after hospital discharge, and owners of pets with DKA should be prepared for the likely lifelong need for insulin therapy and the potential for repeated hospitalizations for treatment of recurrent diabetic complications.4–6

REFERENCES 1. Hess RS, Saunders HM, Winkle TJV, Ward CR: Concurrent disorders in dogs with diabetes mellitus: 221 cases (1993–1998), J Am Vet Med Assoc 217(8):1166-1173, 2000. doi:10.2460/javma.2000.217.1166. 2. Nelson RW: Diabetic ketoacidosis. In Feldman E, Nelson R, Reusch C, Scott-Moncrieff CJ, editors: Canine and Feline Endocrinology, 2015, W.B. Saunders, pp 315-347. doi:10.1016/B978-1-4557-4456-5.00008-0. 3. Kasabalis D (Κασαμπαλής Δ), Chouzouris TP (Χουζούρης ΤΠ), Timiou DT (Τιμίου ΔΤ) et al: Canine diabetic ketosis-ketoacidosis: a retrospective study of 23 cases (1997-2013), J Hellenic Vet Med Soc 66(2): 80-92, 2015. doi:10.12681/jhvms.15613. 4. Bruskiewicz KA, Nelson RW, Feldman EC, Griffey SM: Diabetic ketosis and ketoacidosis in cats: 42 cases (1980-1995), J Am Vet Med Assoc 211(2): 188-192, 1997. 5. Hume DZ, Drobatz KJ, Hess RS: Outcome of dogs with diabetic ketoacidosis: 127 dogs (1993–2003), J Vet Intern Med 20(3):547-555, 2006. doi:10 .1111/j.1939-1676.2006.tb02895.x. 6. Causmaecker V de, Daminet S, Paepe D: Diabetes ketoacidosis and diabetes ketosis in 54 dogs: a retrospective study, Vlaams Diergeneeskundig Tijdschrift 78(5):327-337, 2009. 7. Anderson JD, Rondeau DA, Hess RS: Lispro insulin and electrolyte supplementation for treatment of diabetic ketoacidosis in cats, J Vet Intern Med 33(4):1593-1601, 2019. doi:10.1111/jvim.15518. 8. Parsons SE, Drobatz KJ, Lamb SV, Ward CR, Hess RS: Endogenous serum insulin concentration in dogs with diabetic ketoacidosis, J Vet Emerg Crit Care 12(3):147-152, 2002. doi:10.1046/j.1435-6935.2002.00036.x. 9. Durocher LL, Hinchcliff KW, DiBartola SP, Johnson SE: Acid-base and hormonal abnormalities in dogs with naturally occurring diabetes mellitus, J Am Vet Med Assoc 232(9):1310-1320, 2008. doi:10.2460/javma. 232.9.1310.

• In case of hypokalemia, administer CRI of potassium chloride according to previously published sliding scale (see Chapter 56) • In case of hypophosphatemia, administer CRI of potassium phosphate at 0.03 to 0.12 mmol/kg/hr IV (see Chapter 58) • In case of hypomagnesemia, administer CRI of magnesium sulfate at 0.25 to 1 mEq/kg/day IV (see Chapter 58) • If pH ,7.0 consider sodium bicarbonate therapy • Replace one-third to one-half of the bicarbonate dose calculated using the following formula (see Chapter 59): Sodium bicarbonate dose (mmol) 5 0.3 3 body weight (kg) 3 base deficit • Measure pH every 1–4 hours during sodium bicarbonate therapy Insulin Therapy • Initiate IM or IV CRI insulin administration after 6–8 hours of rehydration (see Table 73.1) • Measure blood glucose concentration or record interstitial glucose concentration every 1–4 hours depending on protocol

10. O’Neill S, Drobatz K, Satyaraj E, Hess R: Evaluation of cytokines and hormones in dogs before and after treatment of diabetic ketoacidosis and in uncomplicated diabetes mellitus, Vet Immunol Immunopathol 148(3):276-283, 2012. doi:10.1016/j.vetimm.2012.06.027. 11. Chong SK, Reineke EL: Point-of-care glucose and ketone monitoring, Top Companion Anim Med 31(1):18-26, 2016. doi:10.1053/j.tcam. 2016.05.005. 12. Norris CR, Nelson RW, Christopher MM: Serum total and ionized magnesium concentrations and urinary fractional excretion of magnesium in cats with diabetes mellitus and diabetic ketoacidosis, J Am Vet Med Assoc 215(10):1455-1459, 1999. 13. Sears KW, Drobatz KJ, Hess RS: Use of lispro insulin for treatment of diabetic ketoacidosis in dogs, J Vet Emerg Crit Care 22(2):211-218, 2012. doi:10.1111/j.1476-4431.2012.00719.x. 14. Chua HR, Venkatesh B, Stachowski E, et al: Plasma-Lyte 148 vs 0.9% saline for fluid resuscitation in diabetic ketoacidosis, J Crit Care 27(2): 138-145, 2012. doi:10.1016/j.jcrc.2012.01.007. 15. Oliver WD, Willis GC, Hines MC, Hayes BD: Comparison of Plasma-Lyte A and sodium chloride 0.9% for fluid resuscitation of patients with diabetic ketoacidosis, Hosp Pharm 53(5):326-330, 2018. doi:10.1177/ 0018578718757517. 16. Goad NT, Bakhru RN, Pirkle JL, Kenes MT: Association of hyperchloremia with unfavorable clinical outcomes in adults with diabetic ketoacidosis, J Intensive Care Med 35(11):1307-1313, 2020. doi:10.1177/0885066619865469. 17. Chiasson JL, Aris-Jilwan N, Bélanger R, et al: Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state, CMAJ 168(7):859-866, 2003. 18. Kitabchi AE, Umpierrez GE, Murphy MB, et al: Management of hyperglycemic crises in patients with diabetes, Diabetes Care 24(1):131-153, 2001. doi:10.2337/diacare.24.1.131. 19. Boysen SR: Fluid and electrolyte therapy in endocrine disorders: diabetes mellitus and hypoadrenocorticism, Vet Clin North Am Small Anim Pract 38(3):699-717, 2008. doi:10.1016/j.cvsm.2008.01.001. 20. Claus MA, Silverstein DC, Shofer FS, Mellema MS: Comparison of regular insulin infusion doses in critically ill diabetic cats: 29 cases (1999–2007), J Vet Emerg Crit Care 20(5):509-517, 2010. doi:10.1111/j.1476-4431. 2010.00567.x. 21. Macintire DK: Treatment of diabetic ketoacidosis in dogs by continuous low-dose intravenous infusion of insulin, J Am Vet Med Assoc 202(8): 1266-1272, 1993. 22. Walsh ES, Drobatz KJ, Hess RS: Use of intravenous insulin aspart for treatment of naturally occurring diabetic ketoacidosis in dogs, J Vet Emerg Crit Care 26(1):101-107, 2016. doi:10.1111/vec.12375.

CHAPTER 73  Diabetic Ketoacidosis 23. Durward A, Ferguson LP, Taylor D, Murdoch IA, Tibby SM: The temporal relationship between glucose-corrected serum sodium and neurological status in severe diabetic ketoacidosis, Arch Dis Child 96(1):50-57, 2011. doi:10.1136/adc.2009.170530. 24. Hoorn EJ, Carlotti APCP, Costa LAA, et al: Preventing a drop in effective plasma osmolality to minimize the likelihood of cerebral edema during treatment of children with diabetic ketoacidosis, J Pediatr 150(5):467-473, 2007. doi:10.1016/j.jpeds.2006.11.062. 25. Schermerhorn T, Barr SC: Relationships between glucose, sodium and effective osmolality in diabetic dogs and cats, J Vet Emerg Crit Care 16(1):19-24, 2006. doi:10.1111/j.1476-4431.2005.00161.x. 26. Kotas S, Gerber L, Moore LE, Schermerhorn T: Changes in serum glucose, sodium, and tonicity in cats treated for diabetic ketosis, J Vet Emerg Crit Care 18(5):488-495, 2008. doi:10.1111/j.1476-4431.2008.00342.x. 27. DiFazio J, Fletcher DJ: Retrospective comparison of early- versus lateinsulin therapy regarding effect on time to resolution of diabetic ketosis and ketoacidosis in dogs and cats: 60 cases (2003–2013), J Vet Emerg Crit Care 26(1):108-115, 2016. doi:10.1111/vec.12415. 28. Chastain CB, Nichols CE: Low-dose intramuscular insulin therapy for diabetic ketoacidosis in dogs, J Am Vet Med Assoc 178(6):561-564, 1981. 29. Macintire DK: Emergency therapy of diabetic crises: insulin overdose, diabetic ketoacidosis, and hyperosmolar coma, Vet Clin North Am Small Anim Pract 25(3):639-650, 1995. doi:10.1016/S0195-5616(95)50059-2. 30. American Diabetes Association Position Statement: Hyperglycemic crises in diabetes, Diabetes Care 27(Suppl 1):s94-s102, 2004. doi:10.2337/ diacare.27.2007.S94. 31. Malerba E, Mazzarino M, Del Baldo F, et al: Use of lispro insulin for treatment of diabetic ketoacidosis in cats, J Feline Med Surg 21(2):115-123, 2019. doi:10.1177/1098612X18761696. 32. Shankar V, Haque A, Churchwell KB, Russell W: Insulin glargine supplementation during early management phase of diabetic ketoacidosis in

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children, Intensive Care Med 33(7):1173-1178, 2007. doi:10.1007/s00134007-0674-3. 33. Marshall RD, Rand JS, Gunew MN, Menrath VH: Intramuscular glargine with or without concurrent subcutaneous administration for treatment of feline diabetic ketoacidosis, J Vet Emerg Crit Care 23(3):286-290, 2013. doi:10.1111/vec.12038. 34. Gallagher BR, Mahony OM, Rozanski EA, Buob S, Freeman LM: A pilot study comparing a protocol using intermittent administration of glargine and regular insulin to a continuous rate infusion of regular insulin in cats with naturally occurring diabetic ketoacidosis, J Vet Emerg Crit Care 25(2):234-239, 2015. doi:10.1111/vec.12269. 35. Aschner JL, Poland RL: Sodium bicarbonate: basically useless therapy, Pediatrics 122(4):831-835, 2008. doi:10.1542/peds.2007-2400. 36. Malerba E, Cattani C, Baldo FD, et al: Accuracy of a flash glucose monitoring system in dogs with diabetic ketoacidosis, J Vet Intern Med 34(1):83-91, 2020. doi:10.1111/jvim.15657. 37. Behrend E, Holford A, Lathan P, Rucinsky R, Schulman R: 2018 AAHA diabetes management guidelines for dogs and cats, J Am Anim Hosp Assoc 54(1):1-21, 2018. doi:10.5326/JAAHA-MS-6822. 38. Sieber-Ruckstuhl NS, Kley S, Tschuor F, et al: Remission of diabetes mellitus in cats with diabetic ketoacidosis, J Vet Intern Med 22(6):1326-1332, 2008. doi:10.1111/j.1939-1676.2008.0201.x. 39. Cooper RL, Drobatz KJ, Lennon EM, Hess RS: Retrospective evaluation of risk factors and outcome predictors in cats with diabetic ketoacidosis (1997–2007): 93 cases, J Vet Emerg Crit Care 25(2):263-272, 2015. doi:10.1111/vec.12298. 40. Fertig AJ, Rudloff E, Kirby R, Thamm DH: Presentation laboratory values, administration of sodium bicarbonate and outcome of cats treated for diabetic ketoacidosis, J Vet Emerg Crit Care 14(S1):S1-S17, 2004. doi:10.1111/j.1476-4431.2004.t01-26-04035.x.

74 Hyperglycemic Hyperosmolar Syndrome Amie Koenig, DVM, DACVIM (SAIM), DACVECC KEY POINTS • Hyperglycemic hyperosmolar syndrome (HHS) is a form of diabetic crisis marked by severe hyperglycemia (.600 mg/dl) and hyperosmolality with no or minimal ketones. • Absence or resistance to insulin and increases in diabetogenic hormone levels stimulate glycogenolysis, and gluconeogenesis, hyperglycemia, osmotic diuresis, and dehydration result. • Reduction of glomerular filtration rate (GFR) is essential to attain the severe, progressive hyperglycemia associated with HHS. • Renal failure and congestive heart failure are common concurrent diseases that likely contribute to HHS via reduction of GFR.

• The most important goals of therapy are to replace fluid deficits and then slowly decrease the glucose concentration, thereby avoiding rapid shifts in vascular volume and osmolality and preventing cerebral edema. Fluid therapy will start to reduce blood glucose levels via dilution and by increasing GFR and subsequent urinary glucose excretion. • Prognosis for feline HHS patients is reportedly poor (12% longterm survival), primarily as a result of concurrent disease. Dogs have a better prognosis (62% discharged from hospital).

Hyperglycemic hyperosmolar syndrome (HHS) is an uncommon form of diabetic crisis marked by severe hyperglycemia (.600 mg/dl), minimal or absent urine ketones, and serum osmolality more than 350 mOsm/kg.1-3 Other names for this syndrome include hyperosmolar hyperglycemic nonketotic state, and hyperosmolar nonketotic coma. These terms have been replaced by hyperglycemic hyperosmolar syndrome to better reflect the variable degrees of ketosis and inconsistent incidence of coma that occur with this syndrome.4,5 Coma appears to be an uncommon form of this syndrome in animals. HHS is an infrequent, albeit well-documented, complication of diabetes mellitus.2,3,6-8 The incidence in humans with diabetes has been estimated to represent less than 1% of all adult human diabetic hospital admissions,5,9,10 and is more common in elderly humans with type 2 diabetes.11 Incidence has been on the rise among children with diabetes over the last decade,12,13 and it has also been documented as a consequence of methadone toxicity in toddlers.14 In comparison, HHS accounted for 6.4% of total emergency room visits by diabetic cats,2 and HHS, with or without ketosis, was identified in 5% of dogs with diabetes mellitus.3 This chapter reviews the pathogenesis, clinical findings, diagnostic evaluation, and treatment of HHS.

and glucagon inhibit insulin-mediated glucose uptake in muscle and stimulate hepatic glycogenolysis and gluconeogenesis, increasing circulating glucose concentration. Cortisol and growth hormone inhibit insulin activity and potentiate the effects of glucagon and epinephrine on hepatic glycogenolysis and gluconeogenesis. In conjunction with insulin deficiency, increases in the diabetogenic hormones increase protein catabolism, which in turn impairs insulin activity in muscle and provides amino acids for hepatic gluconeogenesis.14 Pathogenesis of HHS is very similar to that of diabetic ketoacidosis except that, in HHS, the hyperosmolar state; hepatic glucagon resistance; and small amounts of circulating insulin, which inhibits lipolysis at a fraction of the dose needed for glucose uptake,5,11 all inhibit lipolysis and ketosis5,16,17 and instead promote HHS. Lower levels of growth hormone have also been documented in patients with HHS.17,18 Hyperglycemia is the primary result of these hormonal alterations. It promotes osmotic diuresis, and osmotic diuresis increases the magnitude of the hyperglycemia, thus leading to a vicious circle of progressive diuresis, dehydration, and hyperosmolality. Neurologic signs are thought to develop secondary to cerebral dehydration induced by the severe hyperosmolality;5,19,20 and in people, cerebral edema is rare.20 In humans, elevated blood urea nitrogen (BUN) levels, acidemia, elevated sodium concentration, and osmolality, but not glucose concentration, are correlated with the severity of neurologic signs.21 Diabetic crises are also associated with a rise in proinflammatory cytokines, such as TNF-a, interleukins, and C-reactive protein, and increases in reactive oxygen species and plasminogen activator inhibitor-1.22

PATHOGENESIS The pathogenesis of HHS involves hormonal alterations, reduction of glomerular filtration rate (GFR), and contributions from concurrent disease.

Hormonal Alterations HHS begins with a relative or absolute lack of insulin coupled with increases in circulating levels of counterregulatory hormones including glucagon, epinephrine, cortisol, and growth hormone. These counterregulatory hormones are elevated in response to an additional stressor, such as infection or other concurrent disease. Epinephrine

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Reduction of Glomerular Filtration Rate Osmotic diuresis, additional losses such as via vomiting, and decreased water intake all contribute to progressive dehydration, hypovolemia, and ultimately a reduction in the GFR as the syndrome progresses. Severe hyperglycemia can occur only in the presence of reduced GFR because there is no maximum rate of glucose loss via the kidney.23,24 That is, all glucose that enters the kidney in excess of the renal threshold will

CHAPTER 74  Hyperglycemic Hyperosmolar Syndrome be excreted in the urine. An inverse correlation exists between GFR and serum glucose in diabetic humans.23 Reductions in GFR increase the magnitude of hyperglycemia, which exacerbates glucosuria and osmotic diuresis. Human HHS survivors have also shown a reduced thirst response to rising vasopressin levels, which may also contribute to dehydration25 and decreased GFR.

Influence of Concurrent Disease Concurrent disease is important for initiating the hormonal changes associated with HHS and can also be important for exacerbating hyperglycemia. Diseases that are thought to predispose previously stable diabetics to a diabetic crisis include renal failure, congestive heart failure (CHF), infection, neoplasia, and other endocrinopathies,1,26 although any disease can occur. Pancreatitis and hepatic disease appear to be uncommon concurrent diseases in cats with HHS,2 while pancreatitis was more common in dogs, and has been identified in approximately one-third of all canine HHS patients.3 Renal failure and CHF also exacerbate the hyperglycemia associated with HHS because of their effects on GFR. Decreased GFR is inherent to renal failure. Inability to concentrate urine provides another source for obligatory diuresis. Myocardial failure, diuretic use, and third spacing of fluids associated with CHF may decrease GFR. Cardiac medications such as b-blockers and diuretics are also known to alter carbohydrate metabolism, thus predisposing to diabetic crisis.5

HISTORY AND CLINICAL SIGNS Animals diagnosed with HHS may be previously diagnosed diabetics receiving insulin or may be newly diagnosed at the time HHS is recognized. The most common client complaints are fairly nonspecific and include decreased appetite, lethargy, vomiting, behavior changes, and weakness. Owners may report polyuria, polydipsia, and polyphagia consistent with diabetes, although these clinical signs may have gone unrecognized. History may also reveal recent onset of neurologic signs including circling, pacing, mentation changes, or seizure. Weight loss is an inconsistent finding. Recent steroid administration was seen in approximately 18% of dogs with HHS.3

PHYSICAL EXAMINATION Vital parameters (temperature, pulse, and respiration) and body weight vary considerably with severity of the syndrome and the presence and chronicity of comorbid diseases. Hypothermia is not uncommon as the syndrome progresses. Dehydration, marked by decreased skin turgor, dry or tacky mucous membranes, sunken eyes, and possibly prolonged capillary refill time, are common findings on physical examination in both dogs and cats. Mentation changes are also common. Most animals are reported as being depressed, but severely affected patients may be obtunded, stuporous, or comatose. Additional neurologic abnormalities including weakness or ataxia, abnormal pupillary light reflexes or other cranial nerve abnormalities, twitching, or seizure activity may be noted. Plantigrade stance, especially in cats, may be present subsequent to unregulated diabetes mellitus. Other findings in patients with HHS are dependent on coexisting diseases. Animals should be examined closely for signs of heart disease, which may include any of the following: heart murmur, gallop, bradycardia, tachycardia or other arrhythmias, dull lung sounds, crackles, increased respiratory rate and effort, pallor, prolonged capillary refill time, and decreased blood pressure. Increased respiratory rate and effort may suggest cardiac failure but could also be secondary to infection, hyperosmolality, acidosis, asthma, or neoplasia. Animals with renal failure may have kidneys of abnormal size, oral ulceration, and

439

pallor from anemia and may smell of uremia. Dogs with pancreatitis may have abdominal pain and vomiting.

DIAGNOSTIC CRITERIA The criteria for diagnosis of HHS in veterinary medicine are a serum glucose concentration greater than 600 mg/dl, absence of urine ketones, and serum osmolality greater than 325 mOsm/kg in dogs and greater than 350 mOsm/kg in cats.1-3 Human patients with HHS may have small quantities of urine and serum ketones, measured by the nitroprusside method,4,5 and a mixed state of HHS and diabetic ketoacidosis (DKA) has been described.27 Dogs with HHS have also been classified as being ketotic or nonketotic at the time of the hyperosmolar event.3 Glucose concentrations can reach 1600 mg/dl in severely affected animals.1 Blood glucose concentration may exceed the readable range on patient-side analyzers. Clinical suspicion for HHS should remain high in this situation, and additional diagnostic methods should be instituted to better define the severity of hyperglycemia, state of diabetes, and presence of coexisting diseases. Measuring glucose is also vital to rule out hypoglycemia as a cause of neurologic signs. Osmolality measured by freezing point depression is not a commonly available patient-side test. Estimated serum osmolality can be calculated for dogs and cats using the following formula provided in Box 74.1.28,29 Because BUN equilibrates readily across cell membranes, calculating effective osmolality (Box 74.1) for the diagnosis of HHS is recommended.24 The median value of serum osmolality in normal dogs was found to be 302 mOsm/kg and in normal cats 318 mOsm/kg.28,29 Neurologic signs have been documented in animals when osmolality exceeds 340 mOsm/kg (Box 74.1).30 As previously stated, high effective osmolality is required for the diagnosis of HHS in contrast to DKA where effective osmolality is expected to be less than or equal to normal, despite the hyperglycemia; which is the result of the dilutional hyponatremia that occurs due to free water movement into the extracellular fluid compartment. Ketones can be assessed quickly using a blood ketone meter or urine dipsticks, or by placing a few drops of serum on urine dipsticks.31-33

Additional Diagnostic Evaluation Additional diagnostic parameters, including serum chemistry analysis (with precise glucose measurement), complete blood cell count, urinalysis, urine culture, and (venous) blood gas, should be pursued in patients with confirmed or suspected HHS. Blood cell count abnormalities are varied and nonspecific. The packed cell volume and total protein level may be high secondary to dehydration. Chemistry abnormalities are dependent on the degree of dehydration and presence of

BOX 74.1  Important Calculations Dehydration deficit: Fluid deficit (ml) 5 body wt (kg) 3 % dehydration (as decimal) 3 1000 (ml/L) Osmolality: Serum osm(calc) 5 2[Na1] 1 [BUN (mg/dl) 4 2.8] 1 [glucose (mg/dl) 4 18] Effective osmolality: Effective osm 5 2[Na1] 1 [glucose (mg/dl) 4 18] Corrected sodium: Na1(corr) 5 Na1(meas) 1 1.6 ([measured glucose – 100] 4 100) BUN, blood urea nitrogen; K1, potassium; Na1, sodium; Na1(meas), measured sodium concentration; osm, osmolality. Note: BUN and glucose measured in mg/dl, electrolytes in mEq/L.

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PART VII  Endocrine Disorders

underlying disease. The most common biochemical abnormalities in cats with HHS include azotemia, hyperphosphatemia, elevated aspartate transaminase, acidosis, elevated lactate concentration, and hypochloremia.2 Azotemia may be prerenal or renal in origin. Dogs with HHS and ketosis are less likely to be azotemic than their nonketotic counterparts.3 Venous blood gas analysis should be used to assess the degree of acidemia. It is not possible to differentiate HHS from DKA in cats based on the degree of metabolic acidosis.2 In dogs, low pH has been associated with poorer outcome.3 In HHS, metabolic acidosis is caused by accumulation of uremic acids and lactic acid, rather than large quantities of ketones. Lactic acidosis is an indicator of poor tissue perfusion secondary to dehydration and hypovolemia. Serum electrolytes should be monitored to help in choosing fluid therapy and to calculate the osmolality. Hyperglycemia will cause free water movement into the extracellular fluid compartment via osmosis.34 This will “dilute” the serum sodium concentration proportionally and can mask an underlying hypernatremia. The HHS patient suffers significant free water loss secondary to osmotic diuresis, but the resulting hypernatremia may be difficult to appreciate due to the dilutional effect of the concurrent hyperglycemia. Calculation of the corrected value for sodium concentration will aid in determining the free water deficit present (see below). See Chapter 55, Sodium Disorders, for further discussion of assessment and treatment of dysnatremia. Sodium concentration is the prime determinate of serum osmolality. Serum sodium is decreased due to hyperglycemia-induced osmotic pull of water into the vasculature34 and increased by free water diuresis. Diabetes mellitus itself mellitus itself, independent of hyperglycemia, can contribute to hyponatremia via altered vasopressin metabolism, insulin-potentiation of vasopressin induced aquaporin expression, and slower gastric emptying.35,36

Corrected Sodium Concentration Measured serum sodium levels are expected to rise as glucose levels return to normal. Calculating the corrected serum sodium value, that is, the serum sodium concentration anticipated after resolution of the hyperglycemia, can give a better indication of severity of free water loss. A multitude of correction coefficients, ranging from 1.3 to 2.8 mEq/dl decrease in sodium per 100 mg/dl increase in blood glucose concentration, have been used to estimate the corrected sodium concentration. It is important to recognize that the formulas are less accurate when patients have severe loss (or gain) of extracellular fluid volume, as might occur in HHS. Additionally, the formulas represent one point in time, and the corrected sodium calculation may change as the vascular volume and GFR improve and lead to excretion of glucose and concurrent large osmotic free water loss.37 Although there is still no official consensus in human medicine, recent models in both open (with changes in water balance via intake and diuresis) and closed (no change in external body water or monovalent cations) clinical and theoretical systems suggest that the Al-Kudsi formula,38 based on the original by Katz,34 for corrected sodium is reasonably accurate in people (see Box 74.1).37,39 This holds true even in instances of extreme hyperglycemia and osmotic diuresis, though recalculating corrected sodium frequently during treatment to account for ongoing fluid losses is recommended.37,39 The formula states that for every 100 mg/dl increase in glucose above normal (100 mg/dl), the measured serum sodium decreases by 1.6 mEq/dl.34,38 A corrected serum sodium level can be calculated as show in Box 74.1. Sodium is measured in mEq/L and glucose is measured in mg/ dl. This effect is nonlinear, however. Mild hyperglycemia leads to

smaller changes in plasma sodium concentration than more severe hyperglycemia. Animals in diabetic crisis are classically expected to have low total body potassium concentrations,1 although cats with HHS tend to have a normal serum potassium concentration.2 Dogs with nonketotic HHS had average potassium concentrations that were higher than dogs with HHS and ketosis.3 Potassium losses are expected via diuresis, vomiting, and decreased intake; increases in potassium may occur secondary to acidosis, severe hyperosmolality,27,40 insulin deficiency, and poor renal perfusion. Potassium levels are expected to decrease as acidosis improves and with insulin-induced movement of potassium into cells.27 A thorough search for underlying disease should be undertaken in all patients with HHS. Additional diagnostic techniques, including thoracic and abdominal radiographs, abdominal ultrasonography, echocardiogram, retroviral testing (cats), and endocrine testing (thyroid hormone in cats and adrenal axis testing for dogs), may be indicated based on historical or physical findings or results of preliminary diagnostic results.

TREATMENT Goals of therapy for patients with HHS include replacing the fluid deficit, slowly reducing serum glucose levels, addressing electrolyte abnormalities, and treating concurrent disease.4,19,27

Fluids The fluid therapy plan should include resuscitation, dehydration deficit, ongoing losses, and maintenance fluid needs (see Box 74.1). To prevent cardiovascular collapse and exacerbation of neurologic signs, it is important not to lower the serum glucose or osmolality too rapidly. In humans, fluid losses in HHS are estimated to be double that of a DKA patient. As intravascular glucose and osmolality decline, vascular volume is anticipated to decrease as water moves to the interstitium and intracellular space. As such, administration of insulin prior to adequate fluid resuscitation can contribute to cardiovascular collapse and death.5,27,42-46 The first goal of therapy is to replace vascular volume. An initial 15 ml/kg (cat) to 30 ml/kg (dog) bolus of an isotonic replacement crystalloid is recommended, after which the patient is reevaluated and the need for more boluses assessed. Isotonic saline (0.9% saline) has been recommended as the initial fluid of choice in people11,19,27 because it both addresses the fluid deficits and minimizes decreases in serum osmolality. Recent human studies showed balanced isotonic replacement crystalloids were not inferior and may be superior to normal saline for severe DKA patients.47-51 However, a paucity of data exists regarding the optimal fluid type for HHS, although a systematic review may be forthcoming.52 In lieu of 0.9% NaCl, for most HHS patients, the author initially utilizes one of the higher sodium-containing balanced crystalloids, such as Normosol R or Plasma-Lyte 148, or similar. On its own, fluid therapy will start to reduce blood glucose levels via dilution and by increasing GFR and subsequent urinary glucose excretion.53 After vascular volume has been restored, dehydration deficits should be replaced more slowly using crystalloid solutions of varying sodium concentrations as needed to achieve or maintain eunatremia. The improved GFR will promote osmotic diuresis and associated free water loss, which can contribute to a rise in sodium concentration.37,39 Therefore, as osmotic diuresis ensues, repeated calculations of the corrected sodium and measurement of urine output will be needed to prevent inadvertent rise in sodium.37,39 Ultimately, animals with a corrected sodium in the hypernatremic range will require addition of more free water in their fluid regimen, such as by combination of the

CHAPTER 74  Hyperglycemic Hyperosmolar Syndrome balanced replacement crystalloid with enteral water or intravenous hypotonic fluid such as 0.45% saline. Administration of 5% dextrose in water is also a source of free water, but it is used cautiously until serum glucose is closer to the reference range. Hypernatremia should be corrected slowly with a decrease of no more than 0.5–1 mEq/L/hr.27,37,54 While lower sodium-containing fluids may be needed to reduce the serum sodium, it may also become necessary to switch back to higher sodium replacement fluids if the sodium is dropping to quickly or if there are problems maintaining vascular volume as the hyperglycemia is corrected and water moves out of the vascular space.55 Chapter 55 provides further discussion of the treatment of hypernatremia. In humans with HHS, the fluid deficit is assumed to be 12% to 15% of body weight,5,43-45 and this substantial dehydration deficit is often best replaced over 24 to 48 hours. Because of the massive osmotic diuresis in people, different than therapy for DKA, it is recommended to include urine losses as part of the replacement volumes in an HHS fluid plan.27 In veterinary patients, customizing fluid therapy using the estimated dehydration deficit for the individual animal with frequent patient reassessment and modification of the plan is recommended (see Chapter 67, Daily Intravenous Fluid Therapy). Treating a patient with HHS and concurrent CHF presents a dilemma. Even maintenance amounts of parenteral fluids could be detrimental, so rehydration must be done more slowly and with care. Forced enteral fluid supplementation, as via a nasoesophageal tube, may be a viable option to aid in the rehydration of some patients with CHF that are not vomiting. Furthermore, CHF is classically associated with hypervolemia, and the true vascular volume status of these animals has not been elucidated.

TABLE 74.1  Insulin Protocols for Use in

Insulin

.300

10

No dextrose

Unlike in DKA, where insulin therapy is vital because of its role in reducing ketogenesis, insulin therapy is not as critical for reversal of HHS because much of the syndrome can be improved just by correcting fluid deficit and GFR. In the nonketotic HHS patient, insulin should not be given until the hypovolemia has resolved, the dehydration has improved, and the glucose concentrations are no longer adequately declining (,50 mg/dl/hr) with appropriate fluid therapy alone.27,55 In the ketotic, HHS patient, low-dose insulin may be needed somewhat sooner to reverse ketogenesis. Regardless, insulin therapy should be instituted only after vascular volume is restored, usually after a bolus and several hours of fluid therapy, and only if any potassium, magnesium, and phosphorus deficiencies have been corrected. Mechanics of insulin therapy for HHS are similar to those used in DKA, with protocol modifications designed to lower the glucose levels more slowly. The ideal insulin protocol for treating HHS in cats and dogs is unknown. Using intramuscular or intravenous protocols of regular insulin at lower dosages than those used for DKA should reduce the risk of a too rapid decline of serum glucose.1 Insulin boluses are not recommended.27 An intravenous protocol using lispro insulin has been reported for treating veterinary DKA patients but has yet to be reported for treating HHS patients.56 See Tables 74.1 and 74.2 for insulin protocols. With both protocols, the goal is to decrease the glucose levels by no more than 50 to 75 mg/dl/hr.2,27,55,57 If the blood glucose concentration is dropping too rapidly, the insulin dosage should be decreased by 25% to 50% or dextrose should be added to the fluids, especially if blood glucose is dropping too fast on fluids alone after the first few hours as GFR is restored.

250–300

7

2.5% dextrose

200–250

5

2.5% dextrose

100–200

5

5% dextrose

,100

0

5% dextrose

441

Treating HHS Insulin Protocol Intermittent intramuscular (IM)

Starting Dose Administer 0.1 U/kg of regular insulin, then 0.05 U/kg q2-4h.

Intravenous constant rate infusion (IV CRI)

Dilute 1–2 U/kg of regular insulin in 250 ml 0.9% NaCl. Start this solution at 10 ml/hr.

Subsequent Management Check blood glucose q2-4h. Goal is to reduce blood glucose by 50–75 mg/dl/ hr. Subsequent insulin doses are increased or decreased by ,25% to meet this goal. Add dextrose to fluids when glucose 50%?

No Stop corticosteroids

Yes Continue hydrocortisone for 5 days, then taper over 2–3 days or Continue hydrocortisone for 7 days at full dose then stop

Fig. 81.1  Decision tree for the practical use of corticosteroids in dogs and cats with septic shock.

REFERENCES 1. Marik PE, Pastores SM, Annane D, et al: Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine, Crit Care Med 36: 1937-1949, 2008. 2. Annane D, Sebille V, Charpentier C, et al: Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock, JAMA 288:862-871, 2002. 3. Sprung CL, Annane D, Keh D, et al: Hydrocortisone therapy for patients with septic shock, N Engl J Med 358:111-124, 2008. 4. Annane D, Renault A, Brun-Buisson C, et al: Hydrocortisone plus fludrocortisone for adults with septic shock, N Engl J Med 378:809-818, 2018. 5. Venkatesh B, Finfer S, Cohen J, et al: Adjunctive glucocorticoid therapy in patients with septic shock, N Engl J Med 378:797-808, 2018. 6. Bone RC, Balk RA, Cerra FB, et al: American College of Chest Physicians/ Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis, Crit Care Med 20:864-874, 1992. 7. Yang Y, Liu L, Jiang D, et al: Critical illness-related corticosteroid insufficiency after multiple traumas: a multicenter, prospective cohort study, J Trauma Acute Care Surg 76:1390-1396, 2014. 8. Sun WP, Yuan GX, Hu YJ, et al: Effect of low-dose glucocorticoid on corticosteroid insufficient patients with acute exacerbation of chronic obstructive pulmonary disease, World J Emerg Med 6:34-39, 2015. 9. Ducrocq N, Biferi P, Girerd N, et al: Critical illness-related corticosteroid insufficiency in cardiogenic shock patients: prevalence and prognostic role, Shock 50:408-413, 2018. 10. Piano S, Favaretto E, Tonon M, et al: Including relative adrenal insufficiency in definition and classification of acute-on-chronic liver failure, Clin Gastroenterol Hepatol 2020 May;18(5):1188-1196.

11. Chen X, Chai Y, Wang SB, et al: Risk factors for corticosteroid insufficiency during the sub-acute phase of acute traumatic brain injury, Neural Regen Res 15:1259-1265, 2020. 12. Song JH, Kim JH, Lee SM, et al: Prognostic implication of adrenocortical response during the course of critical illness, Acute Crit Care 34: 38-45, 2019. 13. Annane D, Pastores SM, Arlt W, et al: Critical illness-related corticosteroid insufficiency (CIRCI): a narrative review from a multispecialty task force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM), Crit Care Med 45: 2089-2098, 2017. 14. Teblick A, Peeters B, Langouche L, et al: Adrenal function and dysfunction in critically ill patients, Nat Rev Endocrinol 15:417-427, 2019. 15. Rhodes A, Evans LE, Alhazzani W, et al: Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016, Crit Care Med 45:486-552, 2017. 16. Annane D, Pastores SM, Rochwerg B, et al: Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017, Crit Care Med 45:2078-2088, 2017. 17. Pastores SM, Annane D, Rochwerg B, et al: Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part II): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017, Crit Care Med 46:146-148, 2018. 18. Moreno R, Sprung CL, Annane D, et al: Time course of organ failure in patients with septic shock treated with hydrocortisone: results of the Corticus study, Intensive Care Med 37:1765-1772, 2011. 19. Lamontagne F, Meade MO: Low-dose hydrocortisone did not improve survival in patients with septic shock but reversed shock earlier, ACP J Club 148:6, 2008.

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20. Chaudhury P, Marshall JC, Solomkin JS: CAGS and ACS evidence based reviews in surgery. 35: efficacy and safety of low-dose hydrocortisone therapy in the treatment of septic shock, Can J Surg 53:415-417, 2010. 21. Marik PE: Glucocorticoids in sepsis: dissecting facts from fiction, Crit Care 15:158, 2011. 22. Lu NZ, Cidlowski JA: Glucocorticoid receptor isoforms generate transcription specificity, Trends Cell Biol 16:301-307, 2006. 23. Peeters B, Guiza F, Boonen E, et al: Drug-induced HPA axis alterations during acute critical illness: a multivariable association study, Clin Endocrinol (Oxf) 86:26-36, 2017. 24. Boonen E, Vervenne H, Meersseman P, et al: Reduced cortisol metabolism during critical illness, N Engl J Med 368:1477-1488, 2013. 25. Boonen E, Meersseman P, Vervenne H, et al: Reduced nocturnal ACTHdriven cortisol secretion during critical illness, Am J Physiol Endocrinol Metab 306:E883-892, 2014. 26. Peeters B, Meersseman P, Vander Perre S, et al: Adrenocortical function during prolonged critical illness and beyond: a prospective observational study, Intensive Care Med 44:1720-1729, 2018. 27. Vermes I, Beishuizen A, Hampsink RM, et al: Dissociation of plasma adrenocorticotropin and cortisol levels in critically ill patients: possible role of endothelin and atrial natriuretic hormone, J Clin Endocrinol Metab 80:1238-1242, 1995. 28. Bornstein SR, Ziegler CG, Krug AW, et al: The role of toll-like receptors in the immune-adrenal crosstalk, Ann N Y Acad Sci 1088:307-318, 2006. 29. Nenke MA, Rankin W, Chapman MJ, et al: Depletion of high-affinity corticosteroid-binding globulin corresponds to illness severity in sepsis and septic shock; clinical implications, Clin Endocrinol (Oxf) 82: 801-807, 2015. 30. Pemberton PA, Stein PE, Pepys MB, et al: Hormone binding globulins undergo serpin conformational change in inflammation, Nature 336:257-258, 1988. 31. Henley D, Lightman S, Carrell R: Cortisol and CBG - getting cortisol to the right place at the right time, Pharmacol Ther 166:128-135, 2016. 32. McNeilly AD, Macfarlane DP, O’Flaherty E, et al: Bile acids modulate glucocorticoid metabolism and the hypothalamic-pituitary-adrenal axis in obstructive jaundice, J Hepatol 52:705-711, 2010. 33. van den Akker EL, Koper JW, Joosten K, et al: Glucocorticoid receptor mRNA levels are selectively decreased in neutrophils of children with sepsis, Intensive Care Med 35:1247-1254, 2009.

34. Guerrero J, Gatica HA, Rodriguez M, et al: Septic serum induces glucocorticoid resistance and modifies the expression of glucocorticoid isoforms receptors: a prospective cohort study and in vitro experimental assay, Crit Care 17:R107, 2013. 35. Burkitt JM, Haskins SC, Nelson RW, et al: Relative adrenal insufficiency in dogs with sepsis, J Vet Intern Med 21:226-231, 2007. 36. Martin LG, Groman RP, Fletcher DJ, et al: Pituitary-adrenal function in dogs with acute critical illness, J Am Vet Med Assoc 233:87-95, 2008. 37. Durkan S, de Laforcade A, Rozanski E, et al: Suspected relative adrenal insufficiency in a critically ill cat, J Vet Emerg Crit Care 17:197-201, 2007. 38. Pisano SRR, Howard J, Posthaus H, et al: Hydrocortisone therapy in a cat with vasopressor-refractory septic shock and suspected critical illnessrelated corticosteroid insufficiency, Clin Case Rep 5:1123-1129, 2017. 39. Peyton JL, Burkitt JM: Critical illness-related corticosteroid insufficiency in a dog with septic shock, J Vet Emerg Crit Care 19:262-268, 2009. 40. Annane D, Sebille V, Troche G, et al: A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin, Jama 283:1038-1045, 2000. 41. Prittie JE, Barton LJ, Peterson ME, et al: Hypothalamo-pituitary-adrenal (HPA) axis function in critically ill cats, J Vet Emerg Crit Care 13:165, 2003. 42. Costello MF, Fletcher DJ, Silverstein DC, et al: Adrenal insufficiency in feline sepsis. In: Proceedings of the ACVECC postgraduate course 2006: sepsis in veterinary medicine, 2006, p 41. 43. COIITSS Study Investigators: Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial, JAMA 303:341-348, 2010. 44. Gunst J, Van den Berghe G: Glucocorticoids with or without fludrocortisone in septic shock, N Engl J Med 379:894, 2018. 45. Burkitt Creedon JM, Hopper K: Low-dose hydrocortisone in dogs with septic shock. In 17th International Veterinary Emergency and Critical Care Symposium 2011, p 736. 46. Summers AM, Culler CA, Yaxley P, Guillaumin J: Retrospective evaluation of the use of hydrocortisone for treatment of suspected critical illness related corticosteroid insufficiency (CIRCI) in dogs with septic shock, J Vet Emerg Crit Care 31(3):371-379, 2021. 47. Briegel J, Schelling G, Haller M, et al: A comparison of the adrenocortical response during septic shock and after complete recovery, Intensive Care Med 22:894-899, 1996.

82 Hypoadrenocorticism Jamie M. Burkitt Creedon, DVM, DACVECC

KEY POINTS • Primary hypoadrenocorticism (Addison’s disease) is due to failure of the adrenal glands, whereas secondary hypoadrenocorticism is due to pituitary or hypothalamic dysfunction. • Young to middle-aged female dogs are predisposed; the disease is rare in cats. Some dog breeds are overrepresented, though many dogs with hypoadrenocorticism are mixed breed dogs. • Definitive diagnosis is by adrenocorticotropic hormone (ACTH) stimulation test, ideally coupled with an endogenous ACTH concentration.

• Treatment of the animal in crisis consists of aggressive, appropriate fluid resuscitation followed by hormone replacement. • Hyperkalemia leading to electrocardiographic changes can be life threatening and should be treated promptly. • Long-term prognosis is very good with lifelong hormone supplementation.

The adrenal cortex secretes many important hormones, including cortisol and aldosterone. Cortisol is a glucocorticoid released in small amounts in a circadian rhythm and in larger amounts during times of physiologic stress. It has many important homeostatic functions, including regulation of carbohydrate, lipid, and protein metabolism; modulation of immune system function; and ensuring proper production of catecholamines and function of adrenergic receptors. Serum cortisol concentration is determined by the hormonal cascade and negative feedback mechanisms of the hypothalamic-pituitary-adrenal axis. The hypothalamus produces corticotropin-releasing hormone (CRH), which stimulates adrenocorticotropic hormone (ACTH) release from the anterior pituitary. ACTH stimulates the zona fasciculata and zona reticularis of the adrenal cortex to produce and release cortisol. Cortisol exerts negative feedback on both the hypothalamic release of CRH and the pituitary release of ACTH. Thus, when serum cortisol concentration is low, serum CRH and ACTH concentrations increase, stimulating the adrenals to produce more cortisol. Increased serum cortisol concentration then inhibits further CRH and ACTH release. Aldosterone is a mineralocorticoid released from the zona glomerulosa of the adrenal cortex under the influence of a complex hormonal cascade that starts in the kidney. Aldosterone’s main purposes are to maintain normovolemia and to enhance renal potassium excretion. When effective circulating volume is poor, glomerular filtration decreases. The macula densa, a group of specialized cells in the distal portion of the thick ascending loop of Henle, senses decreased filtrate (specifically chloride) delivery. The macula densa then induces renin release from the nearby juxtaglomerular cells of the afferent arteriole serving that nephron. Renin cleaves the circulating protein angiotensinogen into angiotensin I. Angiotensin I is then converted to angiotensin II by endothelial angiotensin-converting enzyme, which is concentrated in the lung. Angiotensin II stimulates the zona glomerulosa to release aldosterone, which stimulates cells of the renal collecting duct to reabsorb sodium and excrete potassium. Sodium reabsorption leads to water retention and thus augmentation of effective circulating volume. The adrenal cortex also releases aldosterone in direct response to hyperkalemia and a minimal amount in response to ACTH.

Hypoadrenocorticism is uncommon in dogs and is rare in cats, and its clinical presentation mimics that of other more common diseases. Primary hypoadrenocorticism, also called Addison’s disease, is caused by adrenal gland dysfunction, whereas secondary hypoadrenocorticism occurs when hypothalamic or pituitary dysfunction prevents the release of CRH or ACTH, respectively. In most cases, patients with primary hypoadrenocorticism have both glucocorticoid and mineralocorticoid insufficiency. However, there are many reports of dogs with atypical primary hypoadrenocorticism that have only glucocorticoid insufficiency.1-4 Dogs with atypical primary hypoadrenocorticism may go on to develop mineralocorticoid deficiency.1,2,4,5 Rarely, mineralocorticoid deficiency may occur before glucocorticoid deficiency.6 Because aldosterone release is mediated primarily by the reninangiotensin cascade and serum potassium concentration, patients with secondary hypoadrenocorticism do not typically have the classic electrolyte abnormalities seen in patients with typical primary hypoadrenocorticism (see Clinicopathologic Findings).

WHO IS AFFECTED? Hypoadrenocorticism usually occurs in young to middle-aged dogs. Females are more commonly affected than males,7-11 though the disease has no gender predisposition in some breeds.11 Spayed and neutered dogs have a higher risk for developing hypoadrenocorticism than their sexually intact counterparts.12 Although the average age of onset is approximately 4 years,3,7-10 naturally occurring hypoadrenocorticism has been documented in dogs as young as 2 months,10 as well as in geriatric dogs. Dogs with only glucocorticoid deficiency may be older at time of onset than those with classic hypoadrenocorticism.3 The most commonly affected pure breeds vary by report and include the Portuguese Water Dog; Standard Poodle; Great Dane; Bearded Collie; West Highland White, Wheaton, and Cairn Terriers; Cocker Spaniel; and Rottweiler.8,11 Primary hypoadrenocorticism is rare in cats.5 There is no sex predisposition in cats, and nearly all are mixed breed cats.5,13 Most cats are young to middle aged at diagnosis, with ages ranging from 1 to 14 years.13 There is a single report of glucocorticoid-only hypoadrenocorticism in a cat.14

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ETIOLOGY The cause of naturally occurring primary hypoadrenocorticism in dogs and cats is unknown, but it is thought to be immune-mediated in most cases. Naturally occurring primary hypoadrenocorticism in people is caused by immune-mediated destruction of the adrenal cortices, and autoantibodies against steroid synthesis enzymes have been found in some dogs with the disease.15 Histopathology of adrenal glands of affected animals show atrophy, infiltration with leukocytes, and fibrosis, consistent with prior immune-mediated destruction.13,16 Other reported causes of primary hypoadrenocorticism in dogs and cats include surgical adrenalectomy; infiltration of adrenal glands with neoplasia or infectious organisms; trauma, hemorrhage, or hypoperfusion; and iatrogenic caused by treatment with mitotane, trilostane,17 or ketoconazole. Secondary hypoadrenocorticism is due to hypothalamic or pituitary dysfunction; decreased CRH or ACTH secretion leads to decreased adrenal cortisol production. Secondary hypoadrenocorticism is commonly iatrogenic, due to steroid withdrawal after long-term glucocorticoid therapy.5 Long-term steroid administration causes negative feedback on the hypothalamus and pituitary, which decreases ACTH production and thus leads to adrenal cortical atrophy. Other documented causes of secondary hypoadrenocorticism in dogs and cats include hypothalamic or pituitary neoplasia, immune-mediated hypophysitis, trauma, and hypophysectomy.

CLINICAL PRESENTATION The clinical picture of hypoadrenocorticism is often vague and mimics other more common problems such as kidney and gastrointestinal diseases. The classic signs and initial diagnostic test results for hypoadrenocorticism are generally nonspecific, and many Addisonian patients do not have all the classic signs.

History The history is often nonspecific and usually includes days to weeks of decreased appetite, lethargy, gastrointestinal (GI) disturbance, and weight loss. GI bleeding manifested as hematemesis, hematochezia, or melena may be present.1,9,18,19 Other historical findings may include polyuria, polydipsia, weakness, shaking, pain, muscle cramps, and other nonspecific problems.1,4,7,8,20 Because clinical signs are vague, patients may be presented in acute crisis without specific prior clinical signs.

Physical Examination Physical examination findings vary depending on whether the hypoadrenocorticism involves hypoaldosteronism and on the severity and duration of illness. The most common physical examination findings include lethargy, weakness, poor body and coat condition, and dehydration. Collapse, hypovolemic shock, GI bleeding, abdominal pain, bradycardia (relative or absolute), and hypothermia are common during a classic Addisonian crisis due to both glucocorticoid and mineralocorticoid deficiency.1,7-9,13,19 Patients with secondary hypoadrenocorticism or atypical primary hypoadrenocorticism are less likely to experience crisis because they have adequate aldosterone to maintain intravascular volume and normal electrolyte concentrations.1,3

Clinicopathologic Findings The most common clinicopathologic findings are a decrease in the sodium/potassium ratio, azotemia with an inappropriately low urine specific gravity, anemia, and a leukogram with higher lymphocyte and lower neutrophil counts than would be expected for the patient’s degree of illness. The normal sodium/potassium ratio is 27:1 to 40:1. Patients with typical primary hypoadrenocorticism (i.e., with

aldosterone insufficiency) usually have a pretreatment sodium/potassium ratio (Na:K) ,28:1.10,19 Hyperkalemia is nearly ubiquitous, whereas hyponatremia is seen in approximately 80% of Addisonian dogs.8 Patients with only glucocorticoid insufficiency are unlikely to have these electrolyte changes.1-3 Though hypoadrenocorticism appears to be the disease most commonly associated with low Na:K,21 low Na:K can also be seen with other conditions such as kidney failure or postrenal obstruction,21-23 severe GI disease,21,23,24 parasitic infestation,22,24,25 pregnancy,26 body cavity effusions,23 and others.5,23 Most Addisonian patients are azotemic and hyperphosphatemic at presentation.7-9,13 These changes are generally attributed to hypovolemia. Most dogs and cats with hypoadrenocorticism have inappropriately low urine specific gravity (i.e., ,1.030). The inability to appropriately concentrate urine has been attributed to lack of sodium retention and resultant renal medullary washout.5,27 Renal concentrating ability returns with mineralocorticoid supplementation. The complete blood count (CBC) usually reveals a mild to moderate anemia that is usually nonregenerative due to lack of cortisol’s tropism on the bone marrow. Patients with significant concomitant GI bleeding can have severe anemia that may be nonregenerative.18 The degree of anemia may be masked initially by dehydration and resultant hemoconcentration. The CBC may reveal a “reverse stress leukogram,” with relative or absolute neutropenia, lymphocytosis, and eosinophilia, though the CBC can show neutrophilia and lymphopenia commonly seen with severe illness. A normal leukogram or the “reverse stress leukogram” in a sick animal raises suspicion for hypoadrenocorticism. Other blood work may reveal hypoglycemia, hypercalcemia, metabolic acidosis, hypoalbuminemia, and hypocholesterolemia. Hypoglycemia may be severe; interestingly, however, hyperglycemia has also been reported in dogs with hypoadrenocorticism;7-9 thus, its presence does not exclude the diagnosis. Both total and ionized hypercalcemia have been reported in dogs and cats with hypoadrenocorticism;1,8,13,28-30 the mechanism is unclear. Metabolic acidosis is seen commonly in dogs with hypoadrenocorticism and is primarily attributed to decreased renal tubular hydrogen ion excretion,31 which is enhanced by aldosterone. Hypoalbuminemia and hypocholesterolemia have both been reported in association with hypoadrenocorticism.4,32,33

Electrocardiographic Findings An electrocardiogram (ECG) should be performed in patients with clinical signs of hypovolemia or established hyperkalemia. Hypoadrenal patients may have bradycardia whether or not they have hyperkalemia.1,9 Those with hyperkalemia may have bradycardia, diminished or absent P waves, “tented” T waves, wide or bizarre QRS complexes, ventricular fibrillation, or asystole. Other cardiac arrhythmias have also been reported in association with hypoadrenocorticism.

Diagnostic Imaging Radiographic findings in patients with hypoadrenocorticism may include microcardia, decreased pulmonary vessel size, small caudal vena cava, and microhepatica.8,9,13,34 One study found that approximately 80% of dogs in Addisonian crisis had at least one of these radiographic abnormalities.34 Abdominal ultrasound may reveal adrenal glands of decreased thickness compared to normal.35

DIAGNOSIS Definitive Diagnosis A definitive diagnosis of hypoadrenocorticism is generally made using the ACTH stimulation test. A standard ACTH stimulation test can be performed using 250 mcg cosyntropin per dog or 125 mcg cosyntropin

CHAPTER 82  Hypoadrenocorticism per cat; the drug can be given IM or IV in dogs and is recommended IM in cats. Blood is collected for serum cortisol measurement before and 60 minutes after ACTH administration in dogs, and both 30 and 60 minutes after ACTH administration in cats.5 Low-dose ACTH stimulation tests using 1 mcg/kg36 or 5 mcg/kg37 of cosyntropin IV appear to be as effective as the standard ACTH stimulation test to diagnose hypoadrenocorticism in dogs. If cosyntropin is not available, ACTH gel can be used. The protocol is 2.2 IU/kg ACTH gel IM in dogs and cats. Cortisol measurements are made before and 2 hours after ACTH gel administration in dogs and before and 1 and 2 hours after administration in cats.5 Endogenous ACTH concentration is useful to differentiate primary from secondary hypoadrenocorticism. The distinction is particularly important in hypoadrenal patients with normal electrolyte values: if they have low endogenous ACTH concentration, they have secondary hypoadrenocorticism (hypothalamic or pituitary dysfunction) and are unlikely to develop mineralocorticoid deficiency. However, the hypoadrenal patient with normal electrolyte values and an increased endogenous ACTH concentration (atypical primary hypoadrenocorticism) may develop mineralocorticoid deficiency and therefore requires close electrolyte monitoring. The blood sample for endogenous ACTH concentration should be drawn along with the sample for baseline cortisol, before exogenous ACTH administration. Most exogenously administered glucocorticoids interfere with adrenal function testing by affecting baseline cortisol, stimulated cortisol, and endogenous ACTH concentrations. Therefore, if the patient has a history of recent steroid administration, these tests should be delayed while glucocorticoids are withheld and the patient is treated symptomatically. The patient in crisis requires fluid resuscitation first and foremost; it is appropriate to collect an endogenous ACTH sample and complete the ACTH stimulation test before steroid administration.

Screening Synthetic ACTH for stimulation tests can be expensive. Hence, groups have evaluated other tests to screen dogs for hypoadrenocorticism when deciding whether to perform a confirmatory ACTH stimulation test. Basal (also called resting, baseline, endogenous) cortisol measurement is the most common screening test at this time. Dogs with a single basal plasma or serum cortisol concentration .2 mcg/dl are unlikely to have hypoadrenocorticism, as long as they are not receiving medications that may alter the hypothalamic-pituitary-adrenal axis.38 More recent studies have confirmed that dogs with a basal cortisol concentration .2 mcg/dl are unlikely to have hypoadrenocorticism.39,40 Many normal dogs have a basal cortisol concentration ,2 mcg/dl. Therefore, one group evaluated the impact of continuous or bursts of unpleasant noise (a wet-dry vacuum) on basal cortisol concentration in normal dogs and unfortunately found no difference in the number of normal dogs with basal cortisol ,2 mcg/dl whether they were exposed to no, continuous, or bursts of unpleasant noise prior to blood sampling.41 One study showed that lower Na:K ratio in combination with relatively higher lymphocyte count was more accurate than Na:K ratio alone at predicting hypoadrenocorticism in dogs.19 A more recent study described the use of a computer model that incorporated routine CBC, serum biochemical, and baseline cortisol results to predict hypoadrenocorticism in dogs more accurately than the combination of Na:K ratio and lymphocyte count.33 A pilot study of hyponatremic dogs found that dogs with hypoadrenocorticism were unlikely to have a urine sodium concentration of ,30 mmol/L, which distinguished them from hyponatremic dogs with nonadrenal illness.42 A dog’s cortisol:ACTH ratio, calculated from baseline cortisol and endogenous ACTH, can be used to screen for primary hypoadrenocorticism,43-45 though false positives can occur particularly in dogs with

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nonadrenal illness mimicking Addison’s disease.45 A dog’s ratio of plasma aldosterone concentration/plasma renin activity may be used to distinguish between typical and atypical primary hypoadrenocorticism.43

TREATMENT Patients presenting to the emergency or intensive care setting for Addison’s disease are likely to be in crisis. The most important treatment for patients with acute hypoadrenocorticism is adequate and appropriate IV fluid therapy. Patients should be treated for shock as indicated by their physical examination and intensive monitoring results (see Chapter 6, Classification and Initial Management of Shock States, and Chapter 68, Shock Fluid Therapy).

Fluid Therapy Traditionally, 0.9% NaCl has been recommended for initial fluid treatment of Addisonian patients because it has fluid and sodium to replace fluid and electrolyte deficits and no potassium to exacerbate hyperkalemia. However, hyponatremic patients can suffer severe neurologic consequences if their serum sodium concentration is raised too rapidly; such complications have been reported in dogs treated for hypoadrenocorticism (see Chapter 55, Sodium Disorders).46-48 Because of the risks of rapidly raising the serum sodium concentration, balanced electrolyte solution with a lower sodium concentration (130 to 140 mEq/L) is probably more appropriate treatment. In addition to reducing the risk of changing sodium concentration too rapidly, lower sodium solutions have been found to decrease serum potassium concentration faster than 0.9% NaCl despite containing 4 or 5 mEq potassium per liter.49,50 Restoration of effective circulating volume and subsequent improvement in glomerular filtration will be of benefit by helping the kidneys eliminate potassium. Frequent serum electrolyte measurements and neurologic examinations will help guide therapy.

Treatment for Hyperkalemia Hyperkalemia can create life-threatening cardiac arrhythmias, and hyperkalemia in animals with ECG changes should be treated promptly. Ventricular fibrillation and asystole are noncirculatory rhythms and require immediate cardiopulmonary resuscitation (see Chapter 4, Cardiopulmonary Resuscitation of the Hospitalized Patient). Since many animals with hypoadrenocorticism are hypoglycemic, insulin treatment for hyperkalemia should be used judiciously with adequate concomitant dextrose supplementation. One recent study reported management of hyperkalemia in 16 Addisonian dogs with fluid therapy and hydrocortisone alone.48 Specific treatment strategies for hyperkalemia are discussed elsewhere (see Chapter 56, Potassium Disorders).

Initial Hormonal Replacement After endogenous ACTH measurement and ACTH stimulation testing, mineralocorticoid treatment should begin if there is a strong suspicion for acute adrenal crisis. Mineralocorticoid supplementation should be provided for patients with confirmed aldosterone deficiency or those with low Na:K in the form of desoxycorticosterone pivalate at a dosage of 2.2 mg/kg IM or SC once.5 Hydrocortisone is equipotent in mineralocorticoid and glucocorticoid activity and provides a potentially more rapid onset of mineralocorticoid activity in the emergency patient. A case series using 0.5 to 0.625 mg/kg/hour of hydrocortisone in 30 dogs with hypoadrenocorticism described rapid resolution of hyperkalemia in 12 to 24 hours.48 Fludrocortisone can also be used at 0.02 mg/kg PO q24h, but it is only available in oral form, which can be challenging to provide if the animal is vomiting. Unfortunately, fludrocortisone often creates iatrogenic hyperadrenocorticism at doses still too low to control hyperkalemia.5

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Glucocorticoid supplementation during the adrenal crisis is appropriate and is usually also required long term. Hydrocortisone, prednisolone, and dexamethasone are all available in injectable form; hydrocortisone is closest to endogenous cortisol, but any of these choices work. Hydrocortisone is recommended at an initial dosage of 1.25 mg/ kg IV once, followed by 0.5 to 1 mg/kg IV q6h on a tapering schedule. Prednisolone can be given at an initial dosage of 1 to 2 mg/kg IV followed by 0.5 to 1 mg/kg IV q8h on a tapering schedule. A reasonable initial dosage of dexamethasone is 0.1 mg/kg IV, with subsequent doses of 0.05 mg/kg q12-24h on a tapering schedule.

Supportive Therapies Other therapy includes supportive care measures. Hypoglycemia should be corrected as required. Patients with GI disturbance may be treated with gastric protectants and antiemetics. Patients with abdominal or muscular pain may require analgesia. Opioid medications are suitable for this purpose. Nonsteroidal antiinflammatory drugs should be avoided in patients with GI disturbance or azotemia and as such are generally not used in the hypoadrenal crisis. Concurrent disease such as aspiration pneumonia or sepsis should be treated appropriately.

Timeline for Clinical Improvement Cats respond to therapy more slowly than dogs. Although a clinical response can be seen within hours in dogs, it may take 3 to 5 days for cats to show significant clinical improvement.13

ASSOCIATED DISORDERS There are reports of Addisonian dogs concurrently diagnosed with other immune-mediated diseases including immune-mediated cytopenias, hypothyroidism,1,8,51 myasthenia gravis,1 keratoconjunctivitis sicca, and vitiligo. These findings support an immune-mediated etiology for primary hypoadrenocorticism in dogs. Megaesophagus is seen commonly in dogs with uncontrolled hypoadrenocorticism. The connection between the two problems is unclear. It has been reported in dogs with typical hypoadrenocorticism as well as those deficient only in glucocorticoid. Megaesophagus generally resolves with treatment of the hypoadrenocorticism.

PROGNOSIS If animals survive the initial crisis, prognosis for both dogs and cats with naturally occurring primary hypoadrenocorticism is very good with appropriate, lifelong mineralocorticoid and glucocorticoid supplementation. Many patients with atypical primary hypoadrenocorticism (adrenal failure with normal electrolytes and normal pituitary function) become aldosterone deficient. Thus, patients with atypical primary hypoadrenocorticism require frequent reexamination, electrolyte evaluation, and monitoring by the owner to avoid a life-threatening crisis. Those with secondary hypoadrenocorticism are well controlled on lifelong glucocorticoid therapy.

REFERENCES 1. Lifton SJ, King LG, Zerbe CA: Glucocorticoid deficient hypoadrenocorticism in dogs: 18 cases (1986-1995), J Am Vet Med Assoc 209:2076-2081, 1996. 2. Sadek D, Schaer M: Atypical Addison’s disease in the dog: a retrospective survey of 14 cases, J Am Anim Hosp Assoc 32:159-163, 1996. 3. Thompson AL, Scott-Moncrieff JC, Anderson JD: Comparison of classic hypoadrenocorticism with glucocorticoid-deficient hypoadrenocorticism in dogs: 46 cases (1985-2005), J Am Vet Med Assoc 230:1190-1194, 2007.

4. Wakayama JA, Furrow E, Merkel LK, et al: A retrospective study of dogs with atypical hypoadrenocorticism: a diagnostic cut-off or continuum? J Small Anim Pract 58:365-371, 2017. 5. Scott-Moncrieff JC: Hypoadrenocorticism. In Feldman EC, Nelson RW, Reusch CE, et al., editors: Canine and feline endocrinology, ed 4, St Louis, 2015, Elsevier Saunders, pp 485-520. 6. McGonigle KM, Randolph JF, Center SA, et al: Mineralocorticoid before glucocorticoid deficiency in a dog with primary hypoadrenocorticism and hypothyroidism, J Am Anim Hosp Assoc 49:54-57, 2013. 7. Willard MD, Schall WD, McCaw DE, et al: Canine hypoadrenocorticism: report of 37 cases and review of 39 previously reported cases, J Am Vet Med Assoc 180:59-62, 1982. 8. Peterson ME, Kintzer PP, Kass PH: Pretreatment clinical and laboratory findings in dogs with hypoadrenocorticism: 225 cases (1979-1993), J Am Vet Med Assoc 208:85-91, 1996. 9. Melian C, Peterson ME: Diagnosis and treatment of naturally occurring hypoadrenocorticism in 42 dogs, J Small Anim Pract 37:268-275, 1996. 10. Adler JA, Drobatz KJ, Hess RS: Abnormalities of serum electrolyte concentrations in dogs with hypoadrenocorticism, J Vet Intern Med 21:11681173, 2007. 11. Hanson JM, Tengvall K, Bonnett BN, et al: Naturally occurring adrenocortical insufficiency—an epidemiological study based on a Swedishinsured dog population of 525,028 dogs, J Vet Intern Med 30:76-84, 2016. 12. Sundburg CR, Belanger JM, Bannasch DL, et al: Gonadectomy effects on the risk of immune disorders in the dog: a retrospective study, BMC Vet Res 12:278, 2016. 13. Peterson ME, Greco DS, Orth DN: Primary hypoadrenocorticism in ten cats, J Vet Intern Med 3:55-58, 1989. 14. Hock CE: Atypical hypoadrenocorticism in a Birman cat, Can Vet J 52:893-896, 2011. 15. Boag AM, Christie MR, McLaughlin KA, et al: Autoantibodies against cytochrome P450 side-chain cleavage enzyme in dogs (canis lupus familiaris) affected with hypoadrenocorticism (Addison’s disease), PLoS One 10:e0143458, 2015. 16. Frank CB, Valentin SY, Scott-Moncrieff JC, et al: Correlation of inflammation with adrenocortical atrophy in canine adrenalitis, J Comp Pathol 149:268-279, 2013. 17. King JB, Morton JM: Incidence and risk factors for hypoadrenocorticism in dogs treated with trilostane, Vet J 230:24-29, 2017. 18. Medinger TL, Williams DA, Bruyette DS: Severe gastrointestinal tract hemorrhage in three dogs with hypoadrenocorticism, J Am Vet Med Assoc 202:1869-1872, 1993. 19. Seth M, Drobatz KJ, Church DB, et al: White blood cell count and the sodium to potassium ratio to screen for hypoadrenocorticism in dogs, J Vet Intern Med 25:1351-1356, 2011. 20. Saito M, Olby NJ, Obledo L, et al: Muscle cramps in two standard poodles with hypoadrenocorticism, J Am Anim Hosp Assoc 38:437-443, 2002. 21. Nielsen L, Bell R, Zoia A, et al: Low ratios of sodium to potassium in the serum of 238 dogs, Vet Rec 162:431-435, 2008. 22. Pak SI: The clinical implication of sodium-potassium ratios in dogs, J Vet Sci 1:61-65, 2000. 23. Bell R, Mellor DJ, Ramsey I, et al: Decreased sodium:potassium ratios in cats: 49 cases, Vet Clin Pathol 34:110-114, 2005. 24. DiBartola SP, Johnson SE, Davenport DJ, et al: Clinicopathologic findings resembling hypoadrenocorticism in dogs with primary gastrointestinal disease, J Am Vet Med Assoc 187:60-63, 1985. 25. Graves TK, Schall WD, Refsal K, et al: Basal and ACTH-stimulated plasma aldosterone concentrations are normal or increased in dogs with trichuriasis-associated pseudohypoadrenocorticism, J Vet Intern Med 8:287-289, 1994. 26. Schaer M, Halling KB, Collins KE, et al: Combined hyponatremia and hyperkalemia mimicking acute hypoadrenocorticism in three pregnant dogs, J Am Vet Med Assoc 218:897-899, 2001. 27. Tyler RD, Qualls CW Jr, Heald RD, et al: Renal concentrating ability in dehydrated hyponatremic dogs, J Am Vet Med Assoc 191:1095-1100, 1987. 28. Adamantos S, Boag A: Total and ionised calcium concentrations in dogs with hypoadrenocorticism, Vet Rec 163:25-26, 2008.

CHAPTER 82  Hypoadrenocorticism 29. Messinger JS, Windham WR, Ward CR: Ionized hypercalcemia in dogs: a retrospective study of 109 cases (1998-2003), J Vet Intern Med 23:514-519, 2009. 30. Coady M, Fletcher DJ, Goggs R: Severity of ionized hypercalcemia and hypocalcemia is associated with etiology in dogs and cats, Front Vet Sci 6:276, 2019. 31. Osborne LG, Burkitt JM, Epstein SE, Hopper K: Semi-quantitative acidbase analysis in dogs with typical hypoadrenocorticism, J Vet Emerg Crit Care 31:99-105, 2021. 32. Langlais-Burgess L, Lumsden JH, Mackin A: Concurrent hypoadrenocorticism and hypoalbuminemia in dogs: a retrospective study, J Am Anim Hosp Assoc 31:307-311, 1995. 33. Reagan KL, Reagan BA, Gilor C: Machine learning algorithm as a diagnostic tool for hypoadrenocorticism in dogs, Domest Anim Endocrinol 72:106396, 2019. 34. Melian C, Stefanacci J, Peterson ME, et al: Radiographic findings in dogs with naturally-occurring primary hypoadrenocorticism, J Am Anim Hosp Assoc 35:208-212, 1999. 35. Wenger M, Mueller C, Kook PH, et al: Ultrasonographic evaluation of adrenal glands in dogs with primary hypoadrenocorticism or mimicking diseases, Vet Rec 167:207-210, 2010. 36. Botsford A, Behrend EN, Kemppainen RJ, et al: Low-dose ACTH stimulation testing in dogs suspected of hypoadrenocorticism, J Vet Intern Med 32:1886-1890, 2018. 37. Lathan P, Moore GE, Zambon S, et al: Use of a low-dose ACTH stimulation test for diagnosis of hypoadrenocorticism in dogs, J Vet Intern Med 22:1070-1073, 2008. 38. Lennon EM, Boyle TE, Hutchins RG, et al: Use of basal serum or plasma cortisol concentrations to rule out a diagnosis of hypoadrenocorticism in dogs: 123 cases (2000-2005), J Am Vet Med Assoc 231:413-416, 2007. 39. Bovens C, Tennant K, Reeve J, et al: Basal serum cortisol concentration as a screening test for hypoadrenocorticism in dogs, J Vet Intern Med 28:1541-1545, 2014. 40. Gold AJ, Langlois DK, Refsal KR: Evaluation of basal serum or plasma cortisol concentrations for the diagnosis of hypoadrenocorticism in dogs, J Vet Intern Med 30:1798-1805, 2016.

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41. Gin TE, Puchot ML, Cook AK: Impact of an auditory stimulus on baseline cortisol concentrations in clinically normal dogs, Domest Anim Endocrinol 64:66-69, 2018. 42. Lennon EM, Hummel JB, Vaden SL: Urine sodium concentrations are predictive of hypoadrenocorticism in hyponatraemic dogs: a retrospective pilot study, J Small Anim Pract 59:228-231, 2018. 43. Javadi S, Galac S, Boer P, et al: Aldosterone-to-renin and cortisol-toadrenocorticotropic hormone ratios in healthy dogs and dogs with primary hypoadrenocorticism, J Vet Intern Med 20:556-561, 2006. 44. Lathan P, Scott-Moncrieff JC, Wills RW: Use of the cortisol-to-ACTH ratio for diagnosis of primary hypoadrenocorticism in dogs, J Vet Intern Med 28:1546-1550, 2014. 45. Boretti FS, Meyer F, Burkhardt WA, et al: Evaluation of the cortisol-toACTH ratio in dogs with hypoadrenocorticism, dogs with diseases mimicking hypoadrenocorticism and in healthy dogs, J Vet Intern Med 29:1335-1341, 2015. 46. Brady CA, Vite CH, Drobatz KJ: Severe neurologic sequelae in a dog after treatment of hypoadrenal crisis, J Am Vet Med Assoc 215:222-225, 210, 1999. 47. MacMillan KL: Neurologic complications following treatment of canine hypoadrenocorticism, Can Vet J 44:490-492, 2003. 48. Gunn E, Shiel RE, Mooney CT: Hydrocortisone in the management of acute hypoadrenocorticism in dogs: a retrospective series of 30 cases, J Small Anim Pract 57:227-233, 2016. 49. Weinberg L, Harris L, Bellomo R, et al: Effects of intraoperative and early postoperative normal saline or Plasma-Lyte 148 on hyperkalaemia in deceased donor renal transplantation: a double-blind randomized trial, Br J Anaesthesia 119(4):606-615, 2017. 50. Adwaney A, Randall DW, Blunden MJ, et al: Perioperative Plasma-Lyte use reduces incidence of renal replacement therapy and hyperkalemia following renal transplantation when compared with 0.9% saline: a retrospective cohort study, Clin Kidney J 10(6):838-844, 2017. 51. Blois SL, Dickie E, Kruth SA, et al: Multiple endocrine diseases in dogs: 35 cases (1996-2009), J Am Vet Med Assoc 238:1616-1621, 2011.

PART VIII  Neurologic Disorders

83 Neurological Evaluation of the ICU Patient Marguerite F. Knipe, BA, DVM, DACVIM (Neurology)

KEY POINTS • Determining whether neurological abnormalities in the ICU patient are primary or secondary to underlying systemic disease is a frequent clinical dilemma. • Many critical illnesses have sequelae that can result in structural neurological lesions. • Prognosis for neurological recovery is based on the neurological examination, making comfort and confidence in interpretation of a neurological examination paramount for the ICU clinician.

• Focal or asymmetrical neurological deficits are more consistent with a structural lesion than diffuse or symmetrical signs. • Since many advanced neurodiagnostics require general anesthesia, judicious assessment of potential diagnostic gain vs. risks of anesthesia in the critical patient is essential.

Assessment of the critical patient’s neurological status and function is often very challenging. Sometimes determining whether the patient is truly neurologically normal or abnormal is close to impossible because the neurological examination is frequently altered by medication, trauma, or the polypathology of the critically ill animal. The mission of the critical care specialist or neurologist is to interpret despite many of these confounding factors and determine the presence and significance of neurological dysfunction in their patients. This chapter briefly describes the mechanics of the neurological examination, since complete descriptions are best delineated in other texts,1-3 and focuses primarily on challenges and how to troubleshoot interpretation and localization in the ICU patient. The complete neurological examination comprises the following sections: • Mentation/general observations • Gait/posture • Cranial nerves • Segmental reflexes • Proprioceptive placing • Palpation • 6 Pain sensation/nociception Ideally, all aspects are evaluated in every patient; however, clinical judgement may necessitate a limited examination based on the patient’s clinical status and concerns. Fortunately, for the observant and experienced clinician, much of the neurological examination can be done with minimal manipulation of the patient.

• Obtunded (mild/moderate/severe): decreased responsiveness to normal environmental stimuli • Stuporous or semicomatose: responds only to vigorous or noxious stimuli • Comatose: not responsive to any stimulus, including noxious stimuli

MENTATION Mentation is categorized as one of the following: • Normal

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Localization Normal mentation requires a normal cerebrum (conscious reactions/ interpretation of environment, personality) and a normal brainstem (contains the reticular activating system, which projects to activate cerebrum) (Fig. 83.1). Thus, abnormal mentation implies either cerebrum or brainstem dysfunction; if there is brainstem involvement, then often cranial nerve deficits are present as well (see Cranial Nerve section). If there are no evident cranial nerve deficits, then the abnormal mentation is more likely the result of a lesion in the cerebrum or thalamus (rostral to the brainstem cranial nerve nuclei). Level of mentation/consciousness is one of the primary assessments in the modified Glasgow Coma Scale (MGCS),4 which is an objective score (3–18) shown to correlate with survival in veterinary patients with head trauma (Box 83.1).5,6

Troubleshooting Mentation Abnormalities Abnormal mentation is probably the most frequent clinical complaint in ICU patients. Level of arousal and the ability to interact appropriately with surroundings are almost always altered in patients experiencing pain, receiving medications for pain management, or in patients with severe metabolic derangements. Any medication can affect individual patients adversely, although there are some more likely than others (for example, anticonvulsants, opioids, benzodiazepines). Mentation is one of the easiest aspects for clinicians to appreciate improvement or decline; however, determining whether abnormalities result from primary brain

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Fig. 83.1  Sagittal diagram of the brain illustrating the diffuse brainstem reticular activating system (RAS) that projects to the cerebrum to maintain mentation, as well as the main brainstem divisions and corresponding cranial nerves. See also Video 83.2. (Courtesy Chrisoula Toupadakis Skouritakis, PhD.)

BOX 83.1  Modified Glasgow Coma Scale4 Score Motor activity 6 Normal gait, normal spinal reflexes 5 Hemiparesis, tetraparesis 4 Recumbent, intermittent extensor rigidity 3 Recumbent, constant extensor rigidity 2 Recumbent, constant extensor rigidity with opisthotonus 1 Recumbent, hypotonia of muscles, depressed or absent spinal reflexes Brainstem reflexes 6 Normal pupillary light reflexes and oculocephalic reflexes 5 Slow pupillary light reflexes and normal to reduced oculocephalic reflexes 4 Bilateral unresponsive miosis with normal to reduced oculocephalic reflexes 3 Pinpoint pupils with reduced to absent oculocephalic reflexes 2 Unilateral, unresponsive mydriasis with reduced to absent oculocephalic reflexes 1 Bilateral, unresponsive mydriasis with reduced to absent oculocephalic reflexes Level of consciousness 6 Occasional periods of alertness and responsive to environment 5 Depression or delirium, capable of responding but response may be inappropriate 4 Semicomatose, responsive to visual stimuli 3 Semicomatose, responsive to auditory stimuli 2 Semicomatose, responsive only to repeated noxious stimuli 1 Comatose, unresponsive to repeated noxious stimuli

disease or secondary to metabolic derangements or pharmacological intervention is very challenging. A common dilemma is determining whether a patient is sick enough to have the observed degree of altered mentation or if primary brain disease is a likely component. The MGCS can be used as a monitoring tool; however, the correlation with survival has only been shown in patients with traumatic injury (see also Chapter 128).5,6 The principles of neurological improvement or decline in the MGCS are similar for any patient with brain disease, but caution should be used if trying to directly correlate outcome in patients

with nontraumatic brain disease. Management and evaluation of the ICU patient with abnormal mentation should include: • Maximize metabolic state, especially hypoglycemia • Work to manage apparent pain • Evaluate patient prior to pain medication dosing; withdraw or decrease dosage, or even partially reverse, if needed • Assess for other signs of structural brain disease (asymmetry, cranial nerve deficits, etc.)

GAIT AND POSTURE Evaluation of gait and posture should include the following: • Ambulatory or nonambulatory: Must be able to take at least a few unassisted steps with all limbs to be considered ambulatory • If nonambulatory, is voluntary movement present or absent (plegia)? • Limbs: Which limbs are affected? All four limbs? Just pelvic limbs? Limbs on one side (hemiparesis/plegia) • Circling (direction): Even if nonambulatory, some patients may turn their head and body as if they would circle (Fig. 83.2B). • Posture (position of the head and body): head tilt (Fig. 83.2A), head turn (Fig. 83.2B), torticollis, and opisthotonus (Fig. 83.3)

Localization • Head tilt: vestibular disease (see Box 83.2 and Fig. 83.2A) • Head turn: most consistent with cerebral/thalamic or forebrain lesion, ipsilateral (Fig. 83.2B) • Circling: seen with cerebral disease (towards the side of the lesion; see Box 83.3) or vestibular disease (either towards or away from the lesion; see Box 83.2) • Decerebrate posture (Fig. 83.3 and Video 83.1): severe midbrain lesion, poor to grave prognosis • Decerebellate posture (Fig. 83.3 and Video 83.1): cerebellar lesion • Shiff–Sherrington posture (Video 83.1): T3–L7 lesion

Troubleshooting Gait Determining whether or not the thoracic limbs or just the pelvic limbs are affected creates a delineation in localization:

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Top view

A

B

Fig. 83.2  A, Head tilt consistent with vestibular disease. See also Box 83.2. B, Head turn consistent with cerebral/thalamic (forebrain) disease. See also Box 83.3. (Courtesy Chrisoula Toupadakis Skouritakis, PhD.)

BOX 83.2  Vestibular Disease General vestibular dysfunction rules: • Head tilt, rolling, circling, leaning, falling: toward the lesion (Fig. 83.2A) • Nystagmus: spontaneous, unchanging (nonpositional), horizontal/rotary, fast phase away from the lesion • Strabismus: positional, ventrolateral, ipsilateral to the lesion • Generalized ataxia • CN VII facial nerve: possible Peripheral vs. Central Peripheral vestibular disease obeys all the rules, while central vestibular disease may obey the rules but also can break them (e.g., head tilt away from the lesion) Central vestibular disease: localize lesion based on nonvestibular deficits • Mentation changes (involvement of brainstem reticular activating system [Fig. 83.1]) • Cranial nerves other than CN VII affected (ipsilateral to lesion) • Cerebellar signs (ipsilateral to lesion) • Proprioceptive placing deficits/paresis (ipsilateral to lesion) Differential Diagnoses Peripheral: involving CN VIII/semicircular canals • Idiopathic (geriatric vestibular disease)

• Infectious (otitis media/interna [OMI]) • Neoplasia (bone tumors or aural structure tumors) • Trauma (injury to petrous temporal bone at skull base) • Toxic (topical otic medications, aminoglycosides) Central: involving vestibular nuclei in brainstem, flocculonocular lobe of cerebellum, or caudal cerebellar peduncle (connection between vestibular nuclei and cerebellum) • Neoplasia (primary, metastatic) • Infectious (OMI with extension, infectious encephalitis) • Inflammatory/immune-mediated: granulomatous meningoencephalomyelitis, necrotizing meningoencephalitis, meningoencephalitis of unknown origin • Trauma • Toxic: metronidazole toxicity • Vascular: hemorrhage, infarct; vascular event may be secondary to underlying metabolic disease

BOX 83.3  Brain Localization Signs of cerebral/thalamic (forebrain) disease • Mentation/behavior changes • Circling, compulsive movement (towards side of lesion, or both sides if diffuse disease) • Seizures • Central (cortical) blindness (contralateral to lesion or bilateral if diffuse disease) • Head-pressing • Placing deficits (contralateral to lesion, or all limbs if diffuse disease), with minimal gait abnormalities or paresis Signs of brainstem (midbrain-medulla) disease • Cranial nerve deficits III–XII (ipsilateral to lesion) • Mentation changes (RAS) • Placing deficits, paresis (UMN signs ipsilateral to lesion), paresis usually moderate/severe • Respiratory abnormalities • Decerebrate posture: severe midbrain lesion, comatose (Fig. 83.3 and Video 83.1) RAS, reticular activating system; UMN, upper motor neuron.

Signs of cerebellar disease • Generalized ataxia • Dysmetria, hypermetria (ipsilateral to lesion) • Intention tremors • Truncal sway/ataxia • True vestibular signs (head tilt, nystagmus, etc.). See also Box 83.2 • Normal mentation if no other structures involved • Decerebellate posture (Fig. 83.3 and Video 83.1) Management concerns for the patient with brain disease • Seizures (see Chapter 84) • Nonconvulsive status epilepticus • Intracranial pressure (see Chapter 85 and Chapter 191) • Aspiration pneumonia • Determining brain death (see text in this chapter)

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Fig. 83.3  Decerebellate and decerebrate postures. Both postures exhibit opisthotonus. Decerebellate posture is secondary to an acute cerebellar lesion. Many times, pelvic limbs are flexed, but could be extended, depending on the somatotopic localization of the lesion. Decerebrate posture is secondary to a severe midbrain lesion, with extensor rigidity of all four limbs and a patient that is comatose. See also Video 83.1 for more on these postures, as well as the Shiff–Sherrington posture. (Courtesy Chrisoula Toupadakis Skouritakis, PhD.)

• If thoracic and pelvic limbs affected, lesion can involve the brain, C1–5 or C6–T2 spinal cord (Fig. 83.4), or generalized neuromuscular disease • If just pelvic limbs are affected, lesion is caudal to T2 (T3–S2 spinal cord) (Fig. 83.4)

Paresis vs. Weakness Weakness, or loss of strength, implies pathology involving the motor unit in the lower motor neuron (LMN) cell body in the spinal cord, peripheral nerve axon and/or myelin, neuromuscular junction, or muscle, while paresis describes decreased voluntary movement, from either the upper motor neuron (UMN) or LMN lesion. Depending on the disease process, or if a traumatic injury is likely, it may not be practical or safe for the clinician to attempt extensive gait analysis.

Can’t Walk vs. Won’t Walk Determining a patient’s ability to ambulate, or certainly the presence or absence of voluntary movement, is one of the more telling findings of a neurological exam. Many factors may make patients unwilling to walk or move: pain, fear/behavior, or severe illness/malaise. Several tricks can be used to evaluate for voluntary movement or ambulation, but most importantly, assume that your patient can and will run away from you and ensure there is some form of restraint (leash) or other means of controlling egress (enclosed room). • Supported walking: Lift and support patient by hand or with a sling device and encourage walking. This works well for most animals; however, in nervous, fearful, or compliant animals, the proximity and handling by a human may cause them to freeze and not move, and escape motivation or abandonment motivation (below) might be more effective. Supported walking to assess movement is very effective in patients with weakness and neuromuscular disease when voluntary movement is often very good, but their strength to support their full body weight is limited. • Owner motivation: Have the owner distant from the animal and call to them. May help to support the patient, if appropriate. • Escape motivation: Provide an escape route (open room door, open cage to return to) to motivate ambulation trying to get away from the examiner.

• Abandonment motivation: Walk away from the patient or exit the room to motivate the animal to follow.

CRANIAL NERVES See Box 83.4 and Video 83.2. Menace response: response because it involves recognition and processing in the cerebral cortex vs. reflexes that do not. Afferent: ipsilateral CN II, contralateral thalamus and occipital cortex Efferent: contralateral motor cortex, ipsilateral cerebellum, ipsilateral CN VII Pupillary light reflexes (PLRs): midbrain Afferent: CN II Efferent: CN III parasympathetic Trigeminofacial reflexes: (palpebral, vibrissae, lip pinch): pons Afferent: CN V Efferent: CN VII Corneal reflex: pons Afferent: CN V ophthalmic branch Efferent: CN VI (globe retraction), CN VII (blink) Physiologic nystagmus: pons, midbrain Afferent: CN VIII Efferent: CN III, IV, VI Gag reflex: medulla Afferent: CN IX, X Efferent: CN IX, X, XII

Localization Cranial nerve deficits usually support an ipsilateral lesion in the brainstem or the peripheral cranial nerve. The menace response is frequently affected by lesions elsewhere in the brain (cerebral dysfunction, see Box 83.3) and requires evaluation of other cranial nerve tests to determine whether the afferent or efferent nerve are involved.

Troubleshooting Cranial Nerves Other than the menace response and reaction to nasal stimulation, most of the tests of cranial nerves are reflexes and require no cerebral

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Fig. 83.4  Delineation of the major spinal cord segments of the small animal patient. See also Box 83.6. (Courtesy Chrisoula Toupadakis Skouritakis, PhD.)

BOX 83.4  Cranial Nerves I – Olfactory (not usually evaluated) II – Optic nerve III – Oculomotor nerve IV – Trochlear nerve V – Trigeminal nerve VI – Abducens nerve VII – Facial nerve VIII – Vestibulocochlear nerve IX – Glossopharyngeal nerve X – Vagus nerve XI – (Spinal) Accessory nerve XII – Hypoglossal nerve

or conscious execution, so the loss of a reflex is abnormal and usually indicative of a lesion, particularly if asymmetrical (Fig. 83.1). • Animals with heavy sedation or recovering from anesthesia may not have CN reflexes. As a result, similar to the rest of the neuro examination, cranial nerve function is most reliably assessed in patients when they are the least affected by medications. • Animals without an eye or with ocular trauma are challenging because many CN reflexes involve the eyes (PLRs, physiologic nystagmus, among others), so look for other reflexes to assess brainstem function. • Systemic anticholinergic medications such as atropine or glycopyrrolate can alter resting pupil size (mydriatic) and amount of constriction when assessing PLRs. Similarly, other drugs often result in miotic pupils (benzodiazepines). See Chapter 85 for more on pupillary assessment in the patient with increased intracranial pressure.

PROPRIOCEPTIVE POSITIONING Assessment of proprioceptive placing can include the following: • Paw knuckling, hopping, extensor postural thrust, visual and tactile placing, etc. Recognition that the limb is improperly placed for

weightbearing, and conscious movement of the limb to an appropriate position.

Localization Normal placing reactions require intact peripheral nerves and the spinal cord, brainstem, and cerebrum, so they are probably the least specific tests for neurological disease since they are frequently abnormal in patients with any kind of neurological dysfunction. Clinicians must use the rest of the neurological examination to help localize a lesion. • Cerebral disease: deficits contralateral to lesion or symmetrical if diffusely affected • Brainstem, spinal cord, peripheral nerve: deficits ipsilateral to lesion

Troubleshooting Proprioceptive Placing Because these evaluations involve more manipulation of the patient, they are often not assessed in patients with concerns for spinal trauma. Placing reactions are often more interesting if the placing is normal in the patient being evaluated. Because the pathways involve so many aspects of both the peripheral and central nervous system, if placing reactions are normal, the clinician should seriously consider a nonneurologic cause for the patient’s problem. False normals: struggling patients, feeling off-balance and constantly shifting weight and moving.

Potential False Absents • Sedation/anticonvulsants/pain medications/severe metabolic derangement. These are conscious, voluntary reactions, so any pharmacological or physiological impairment of mentation or awareness may result in abnormal or absent reactions, usually symmetrical. • Limb trauma/fracture/luxation: Again, these are voluntary placing reactions, so if a limb is severely injured and painful, the animal may not want to move it to an appropriate position. *This is very challenging, since neurological function of a limb in a trauma patient plays an important role in prognosis and decisions for any possible surgical intervention. A limb with both a humeral fracture and a brachial plexus avulsion has a poor prognosis for return to

CHAPTER 83  Neurological Evaluation of the ICU Patient function and is not a good candidate for fracture repair. In these cases, careful evaluation of limb reflexes and sensation/nociception is essential.

SEGMENTAL REFLEXES Thoracic limb reflexes • Biceps: musculocutaneous nerve • Triceps: radial nerve (main weightbearing) • Flexion/withdrawal: mostly musculocutaneous nerve Pelvic limb reflexes • Patellar: femoral nerve (L4–L6 spinal cord segments) (main weightbearing) • Gastrocnemius: sciatic nerve (L6–S1) • Perineal: pudendal nerve (S1–S3) • Flexion/withdrawal: mostly sciatic with some femoral for hip flexion Cutaneous trunci muscle reflex • Afferent: T3–L3 spinal nerves/cord • Efferent: C8–T1 spinal nerves forming lateral thoracic nerve

Localization Evaluation of segmental reflexes is essential to localizing spinal cord lesions (Fig. 83.4) and determining whether the UMN system is affected (UMN signs) or the LMNs are affected (LMN signs) (Box 83.5). The UMN system originates in the cerebrum and brainstem and synapses on the LMNs in the brainstem (cranial nerves) and spinal cord to effect voluntary movement (Box 83.6). UMNs and LMNs are required for normal voluntary movement, so a lesion in either system can affect the ability to move the limb resulting in paresis or paralysis and/or ability to replace the limb.

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Troubleshooting Segmental Reflexes Trauma If the humerus or femur is fractured, then the lever arm for the reflex mechanism is lost, so even if all neural structures are intact, the reflex may not be present. Similarly, the voluntary movement of a limb may also be affected, certainly the ability to bear weight with a proximal limb fracture. This is particularly challenging to evaluate in the polytrauma patient, where whether a limb has neurological function often determines whether to repair a fracture. Utilize cutaneous testing and sensation to determine the presence and extent of any possible neurological lesion.

Spinal Shock Spinal shock is the transient loss of muscle tone and segmental reflexes caudal to an acute spinal cord injury. This is appreciated on clinical examination by noting LMN signs (decreased/absent reflexes) in a patient with an otherwise UMN spinal cord localization.7,8 Spinal shock results from physiologic dysfunction of the LMN versus a true structural injury to the LMNs. Various theories for transient disruption of spinal cord synaptic and interneuronal conduction are proposed, but excessive inhibitory neurotransmitters secondary to the injury have a prominent role in the pathophysiology.8,9 Awareness of spinal shock phenomenon is essential for accurate neuroanatomical localization and understanding that the loss of reflexes may not reflect a multifocal disease process. • Clinically, loss of the flexion/withdrawal reflex seems most common,7,8 but loss of tendon reflexes is also possible. • Rate of recovery of reflexes is variable, ranging from hours to weeks,7,8,10 but improvement is noted in most patients. • Recheck reflexes over time, especially if localization seems multifocal; if spinal shock, reflexes will improve with time.

Spinal Shock vs. Myelomalacia BOX 83.5  Clinical Signs of Upper Motor

Neuron (UMN) and Lower Motor Neuron (LMN) Lesions UMN Signs

LMN Signs

• Normal to increased reflexes • Normal to increased tone • Disuse atrophy (weeks/months) • Paresis/paralysis • Proprioceptive placing deficits

• Decreased to absent reflexes • Decreased to absent tone • Denervation atrophy (days/weeks) • Paresis/paralysis • Proprioceptive placing deficits

BOX 83.6  Spinal Cord Localization (see

Fig. 83.4)

C1–C5 myelopathy: ipsilateral UMN signs to thoracic and pelvic limbs C6–T2 myelopathy: ipsilateral LMN signs to thoracic limbs, UMN signs to pelvic limbs T3–L3 myelopathy: normal thoracic limbs, ipsilateral UMN signs to pelvic limbs L4-caudal myelopathy: normal thoracic limbs, ipsilateral LMN signs to pelvic limbs Management concerns for the myelopathy patient • Recumbent care • Bladder management • Muscle atrophy, range of motion • Aspiration pneumonia LMN, lower motor neuron; UMN, upper motor neuron.

In thoracolumbar spinal cord injury, LMN signs to the pelvic limbs are highly concerning for descending myelomalacia, with a grave to poor prognosis for any return to function.11 • Spinal shock reflex deficits are often partial (i.e., absent flexion/ withdrawal but present tendon reflexes) and may be asymmetric, while loss of reflexes with myelomalacia tends to be complete in both limbs. • Patients with myelomalacia will not have deep pain perception (see below). This reflects the severe and irreversible pathology of myelomalacia. • Patients with spinal shock may also not have deep pain perception, depending on the severity of the lesion, but will have improvement of reflexes and tone to be more consistent with an UMN lesion, even if the spinal cord is functionally transected.10

SENSATION/NOCICEPTION • Superficial pain perception (nociception): noxious stimulus to interdigital skin; look for evidence of conscious reaction (whining/ crying, attempting to bite or escape, looking at stimulus, may be as subtle as pupillary dilation or pausing in panting). • Deep pain perception (nociception): noxious stimulus applied over the digit; goal to stimulate the periosteum; look for conscious reaction.

Localization Important for assessment of spinal cord injury, peripheral nerve injury, and brain disease (i.e., coma). Loss of pain perception, particularly deep pain, is strongly associated with a poor prognosis for recovery of

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function.12 Confidence in distinguishing the flexion/withdrawal reflex from a conscious reaction to a noxious stimulus is essential for accurate assessment of patient prognosis.

Troubleshooting Nociceptive Assessment Potential False Negatives (Seems Like Pain Sensation is Absent) • Behavior: stoic or frozen-fearful animal • Because we are evaluating a conscious reaction, patients with stoic temperaments or are frozen with fear may not react as we might expect. • If there is no reaction in the limb(s) you are evaluating, try pinching a normal limb to gauge the animal’s level of reactivity. If there is minimal reaction in an apparently normal limb, then interpretation of pain perception may not be reliable. • Opioids and other pain or sedation medications • By definition, may decrease reactivity to stimuli. Reverse or partially reverse or wait until they wear off to reevaluate sensation. • Try pinching a normal limb to gauge level of reactivity, similar to Behavior above. • Animal does not flex the limb • Look for the conscious reaction to the stimulus, not the flexion of the limb. The action of flexing or moving the limb can be just a reflex (see Reflexes previously) and does not equate to conscious sensation. There are many reasons the animal may not move the limb, fracture and pain or mechanical inability to flex the limb, LMN disease (e.g., polyradiculoneuritis, botulism) where the motor capabilities are affected, but the sensory pathways are intact.

Potential False Positives (Seems Like Pain Sensation is Present When it May Not Be) • Exaggerated flexion of the limb, where the animal may react to the general movement of the body, not the noxious stimulus • UMN reflexes can be extremely exaggerated, with the brisk flexion movement causing the body to move. The animal may react to the movement, and that could be interpreted as a reaction to the noxious stimulus applied to the digit. • Eliminate the vigorous flexion movement from the equation by holding the limb in flexion before pinching. • Behavior: very reactive or anxious patient • Animals that are anxious or constantly vocalizing may seem to be reacting to a stimulus, but it may just be coincident with ongoing episodes of vocalizing. • Repeat assessment at a different time to see if the reaction is consistent and repeatable.

BOX 83.7  Neuromuscular Localization Primary neuromuscular disease patients in ICU: polyradiculoneuritis, botulism, myasthenia gravis Numerous metabolic diseases will have secondary neuromuscular effects (See Box 83.8) Signs of neuromuscular disease for ICU patient • Decreased/absent segmental reflexes • Generalized weakness • Megaesophagus, regurgitation • Hypoventilation Management concerns for the neuromuscular patient • Hypoventilation • Aspiration pneumonia • Muscle atrophy, range of motion

with this clinical challenge. In human adults, the American Academy of Neurology lists three mandatory clinical findings necessary to indicate irreversible cessation of brain function: coma, absence of brainstem reflexes, and apnea.13 These are straightforward clinical evaluations in the veterinary ICU patient, and in the absence of anesthetic drugs and an appropriate withdrawal time from these medications indicate a poor prognosis. Additional functional assessment of the cerebrum (electroencephalogram [EEG]) and brainstem (brainstem auditory evoked response [BAER]) may assist in the clinical decision for euthanasia. These are functional modalities utilized at our institution to confirm severe cerebrocortical and brainstem dysfunction, in addition to the clinical status of comatose, absent brainstem reflexes, and apneic.

BAER More than just a hearing test, the BAER evaluates brainstem function and may provide additional diagnostic support for severe brainstem injury. • Use caution in the interpretation of no waveforms/flatline BAER. These may be secondary to deafness, middle or external ear disease, or even technical problems. • It is most helpful clinically if early waveforms, but not later, waveforms are noted. This indicates that peripheral portions of the auditory pathway are intact, but not the central (brainstem) portions.

Electroencephalogram

If abnormal, localize first to the following: • Brain • Spinal cord • Neuromuscular Then localize better within the division (see Box 83.2, Box 83.3, Box 83.5, Box 83.6, Box 83.7), and finally lateralization, if present.

For humans, the American Clinical Neurophysiology Society states 11 guidelines for EEG recording in suspected cerebral death,14 many of which would be possible to meet in veterinary facilities with EEG capabilities, but other guidelines are specific to the larger size of the human skull (e.g., 8–20 electrodes 10 cm apart). Even in veterinary patients, documenting electrocerebral inactivity or burst-suppression patterns in the prolonged absence of anesthetic drugs supports the clinical diagnosis of brain death. • EEG in an ICU setting is notoriously fraught with artifacts from electrical or mechanical interference (ventilator, ECG, movement, etc.) but is absolutely possible with patience and persistence.

CLINICAL CHALLENGES IN THE CRITICAL PATIENT WITH NEUROLOGICAL DISEASE

Distinguishing if Neurological Deficits are Primary or Secondary to Systemic Disease

NEUROLOGICALLY ABNORMAL

Determining Brain Death There are currently no standards to determine brain death in veterinary medicine, although the critical care clinician will likely be faced

Even if the deficits are primary, are they sequelae of a systemic disease (e.g., embolism or hemorrhage secondary to hypercoagulability; seizures secondary to hypoglycemia) or a new separate problem (see also Box 83.8)?

CHAPTER 83  Neurological Evaluation of the ICU Patient

BOX 83.8  Diseases With Frequent

Secondary Neurological Dysfunction Generalized cerebral dysfunction or generalized neuromuscular disease are most common secondary to underlying processes Systemic diseases most often presenting with secondary diffuse neurological signs • Hepatic encephalopathy • Uremic encephalopathy • Heat stroke • Hypoxia/hypoxemia • Hypertension • Electrolyte disorders • Hypoglycemia • SIRS/MODS, sepsis • Endocrine dysfunction (e.g., hypoadrenocorticism, pheochromocytoma, diabetes mellitus [especially hyperosmolar]) Patient’s neurological deficits are more likely to be structural if: • They are asymmetrical • Cranial nerve deficits III–XII (see Fig. 83.1 and Video 83.2) Disease processes that may likely cause secondary structural neurological lesion • Hyper/hypocoagulability: IMHA, ITP, SIRS, hypothyroidism, nephrotic syndrome, toxicities • Hypoglycemic seizures/status epilepticus: seizure activity can result in cortical necrosis and secondary permanent seizure focus IMHA, immune-mediated hemolytic anemia; ITP, immune-mediated thrombocytopenia; MODS, multiple organ dysfunction syndrome; SIRS, systemic inflammatory response syndrome.

If magnetic resonance imaging (MRI) was a simple and inexpensive diagnostic test, it would be easy to screen the central nervous system (CNS) in our patients; however, in the critically ill animal, general anesthesia can put the patient at risk for more problems and may not be necessary for adequate management of the case.

Is Imaging Indicated? It would be easy, of course, if advanced imaging did not require anesthesia.

What About Sedated Computed Tomography? • It is fast and can be done without general anesthesia. • Unless you are screening for skull or vertebral column fractures or are trying to rule out a large extraparenchymal compressive lesion or mass, computed tomography (CT) will not provide the amount of detail for parenchymal disease that MRI does, and in the critically ill patient, parenchymal inflammatory or vascular lesions are very high on the list of most likely causes, and would not likely be visible on CT.

Doesn’t Imaging Help Determine Prognosis? • No. Prognosis should always be based on the neurological examination, regardless of findings on radiographs, CT, or MRI. Imaging can only evaluate the location and extent of the lesion and contributes more information about the most likely cause. A patient can have a T3–L3 myelopathy with absent deep pain perception and a normal appearance of the spinal cord on MRI. The prognosis is still poor.

Will Imaging Findings Change the Treatment Plan? It is important to weigh the personal curiosity desire to know against the clinical need-to-know for best patient management.

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Situations where considering imaging may be worth the risk/expense include the following: • Patient’s systemic problems are improved, but the neurological deficits are not • This is a common dilemma. How long is “long enough” to wait for neurological improvement? Depending on the underlying etiology (infarct, hemorrhage, necrosis), a neurological deficit resulting from sequelae of a primary systemic disease could be permanent, even if the underlying disease improves. A patient’s hypercoagulable state may resolve, but if the patient is paraplegic secondary to thromboembolism, the myelopathy may take weeks to months to improve, if at all. • Keep in mind that your neurological examination is the basis for prognosis (see above). Imaging can only localize and further characterize any lesions. • Neurological deficits progress despite apparent adequate management of the systemic disease • Deterioration of neurological status warrants strong consideration to discover if there are other specific interventions possible for the patient. • Again, prognosis is still based on neurological examination, so a patient that has progressed from obtunded to stupor to coma has a poor prognosis, regardless of etiology. • Deficits are unlikely to be secondary to the primary systemic disease process • For example: A patient with hypoglycemia may be expected to have seizures secondary to that metabolic dysfunction; however, if that patient develops new central vestibular signs, that is a lesion unlikely to be a direct consequence of the hypoglycemia. It may still be a CNS lesion secondary to another systemic problem (perhaps the patient is hypercoagulable and prone to thromboembolic events) but unlikely to be a sequela to the original problem of hypoglycemia, so it is worth considering imaging. • Owners are unlikely to proceed with continued care if a second problem is found. Findings will change case management.

NEXT STEPS Fluctuations in patients’ well-being in the ICU are closely monitored, and this includes the neurological examination. The ICU clinician’s vigilance of the patient’s neurological status and valuation of advanced neurodiagnostics guides best recommendations to both clients and other primary clinicians with critically ill patients.

Keep in Mind: • Prognosis is based on the neurological examination • Appreciate that the nervous system is often secondarily affected in the ICU patient and may not need specific diagnostics/treatment, but neurological lesions will change the management of the patient (bladder management, recumbent care, ventilatory support, etc.) • Recognize what deficits fall into the realm of likely secondary to underlying disease and what deficits are likely separate • Asymmetrical signs should increase the suspicion of a structural lesion

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REFERENCES 1. Dewey CW, da Costa RC: Practical guide to canine and feline neurology, ed 3, Ames, IA, 2016, Wiley. 2. Platt S, Olby NJ: BSAVA manual of canine and feline neurology, ed 4, Gloucester, 2013, BSAVA. 3. Lorenz MD, Coates JR, Kent M: Handbook of veterinary neurology, ed 5, St Louis, 2011, Elsevier Saunders. 4. Shores A: Craniocerebral trauma. In Kirk RW, editor: Current veterinary therapy X, Philadelphia, 1983, WB Saunders, pp 847-885. 5. Platt SR, Radaelli ST, McDonnell JJ: The prognostic value of the modified Glasgow Coma Scale in head trauma in dogs, J Vet Intern Med 15(6): 581-584, 2001. 6. Sharma D, Holowaychuk MD: Retrospective evaluation of prognostic indicators in dogs with head trauma: 72 cases (January-March 2011), J Vet Emerg Crit Care 25(5):631-639, 2015. 7. Full AM, Heller HL, Mercier M: Prevalence, clinical presentation, prognosis, and outcome of 17 dogs with spinal shock and acute thoracolumbar spinal cord disease, J Vet Emerg Crit Care 26(3):412-418, 2016. 8. Smith PM, Jeffery ND: Spinal shock – comparative aspects and clinical relevance, J Vet Intern Med 19:788-793, 2005.

9. Ko HY: Revisit spinal shock: pattern of reflex evolution during spinal shock, Korean J Neurotrauma 14(2):47-54, 2018. 10. Handa Y, Naito A, Watanabe S, et al: Functional recovery of locomotive behavior in the adult spinal dog, Tohoku J Exp Med 148:373-384, 1986. 11. Castel A, Olby NJ, Ru H, et al: Risk factors associated with progressive myelomalacia in dogs with complete sensorimotor loss following intervertebral disc extrusion: a retrospective case-control study, BMC Vet Res 15:433, 2019. 12. Langerhuus L, Miles J: Proportion recovery and times to ambulation for non-ambulatory dogs with thoracolumbar disc extrusion treated with hemilaminectomy or conservative treatment: a systematic review and meta-analysis of case-series studies, Vet J 220:7-16, 2017. 13. Wijdicks EFM, Varelas PN, Gronseth GS, et al: Evidence-based guideline update: determining brain death in adults - report of the Quality Standards Subcommittee of the American Academy of Neurology, Neurology 74:1911-1918, 2010. 14. Stecker MM, Sabau D, Sullivan LR, et al: American Clinical Neurophysiology Society Guideline 6: minimum technical standards for EEG recording in suspected cerebral death, Neurodiagn J 56(4):276-284, 2016. https:// doi.org/10.1080/21646821.2016.1245575.

e1 Video 83.1  This video illustrates and explains differences between some acute postures seen in patients with neurological injury.

Video 83.2  This video demonstrates the cranial nerve exam and illustrates related anatomy for interpretation.

84 Seizures and Status Epilepticus Chai-Fei Li, DVM, DACVIM (Neurology), Karen M. Vernau, DVM, MAS, DACVIM (Neurology)

KEY POINTS • Epilepsy refers to recurrent seizures of any type resulting from an intracranial cause and may be further classified by etiology into idiopathic epilepsy and structural epilepsy. • Seizures may also be classified by type of seizure: focal or generalized. Generalized seizures are the most common. • Status epilepticus is a life-threatening neurologic emergency and a common presenting complaint at the emergency hospital. • Status epilepticus may cause serious systemic problems such as tissue hypoxia, hyperthermia, systemic lactic acidosis, shock, and acute kidney injury. • A complete history, physical examination, neurologic examination, and minimum diagnostic database are recommended for all animals with a seizure disorder.

• Further investigation of intracranial diseases using electroencephalography, magnetic resonance imaging or computed tomography imaging, cerebrospinal fluid analysis, serology, and biopsy may be indicated. • Seizure management is based on control of seizures by selection and appropriate administration of an anticonvulsant drug. When an underlying disease is present, it should be treated concurrently. Seizures associated with status epilepticus should be stopped as quickly as possible. an underlying disease is present, it should be treated concurrently. Seizures associated with status epilepticus should be stopped as quickly as possible.

The epidemiology of seizures in cats and dogs is unknown, despite reports of the rate, prevalence, and incidence.1-4 Population-based animal studies are difficult to execute; thus, most studies are based on data from groups of veterinary hospitals or referral-based veterinary teaching hospitals.5 The epidemiology of seizures in selected groups of purebred dogs or colonies of research dogs with epilepsy has been reported.4,6 Although these studies are interesting, the information cannot be extrapolated beyond the research colony, hospital, or specific purebred dog breed population. Despite the lack of prevalence or incidence data, it is accepted that seizure disorders are common in dogs and cats and that seizures occur more frequently in dogs than in cats. Estimates of lifetime seizure frequencies are 0.5% to 5.7% in dogs and 0.5% to 1.0% in cats.5 Status epilepticus (SE) is a life-threatening neurologic emergency and a common presenting complaint at an emergency hospital. Although the population prevalence of SE is not known, in one report the prevalence of SE and cluster seizures in dogs was 0.44% of all hospital admissions.7 Although different types of seizures occur in dogs and cats, like people, terminology and a classification system universally accepted by veterinary neurologists had not been established historically.8,9 However, in 2015, a group of veterinary neurologists and non-specialists formed the International Veterinary Epilepsy Task Force (IVETF) in order to establish terminology, definitions, classifications, and guidelines for seizures in companion animals.10 In order to diagnose and treat dogs and cats with seizure disorders, including SE, it is important to understand the terminology, pathophysiology, and causes of seizures.

electrical neuronal discharge, originating from the cerebral cortex.7 The updated definition of seizure is any sudden, short-lasting and transient event that is not necessary epileptic in nature.10 Reactive seizure: The normal brain’s natural response to a transient disturbance in function, usually metabolic or toxic in nature. This is usually reversible when the inciting cause is removed or corrected (e.g., hypoglycemia).10 Epileptic seizure: A manifestation of excessive synchronous epileptic activity of neurons in the brain.10 Epilepsy is recurrent seizures of at least two unprovoked epileptic seizures (of any type) in a 24-hour period, resulting from a disease in the brain causing a predisposition to generate epileptic seizures.10 Cluster seizures are two or more seizures within a 24-hour period.7 Status epilepticus is a neurologic emergency requiring immediate therapy. A universally accepted definition for SE in humans or animals does not exist,7,11 but it is now generally accepted that SE is “continuous seizures, or two or more discrete seizures between which there is incomplete recovery of consciousness, lasting at least 5 minutes.”12

DEFINITIONS Previously, a seizure was defined as the clinical manifestation of a paroxysmal cerebral disorder, caused by a synchronous and excessive

CLASSIFICATION Epilepsy may be classified based on cause, or seizure type.

Classification Based on Cause 1. Idiopathic epilepsy: Epilepsy in which no underlying cause can be found, with no evidence of a physical cause (structural epilepsy). The underlying cause of the epilepsy may be genetically determined, or the cause may be suspected to be genetic based on high breed prevalence. 2. Structural epilepsy: Epilepsy caused by underlying physical intracranial disorder.

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Classification Based on Seizure Type Epileptic seizures in dogs and cats may also be classified by seizure type, which may be focal or generalized seizures. This classification of seizure type is based on clinical observations rather than electroencephalography (EEG) characteristics. Focal seizures originate from a focus in one cerebral hemisphere and usually manifest localized or regional clinical signs, which may include involuntary or compulsive actions such as chewing, licking, and defensive or aggressive behavior. Previously, focal seizures were termed partial seizures and were further classified as simple partial seizures or complex partial seizures based on whether the patient had an alteration in consciousness during the seizure. However, since the assessment of the patient’s consciousness is subjective, classifying patients with focal epileptic seizures further based on loss/no loss of consciousness is not considered meaningful and is no longer recommended. Generalized seizures are the most recognized seizures in dogs and cats; the most common type is the tonic-clonic seizure. Other types of generalized seizures such as tonic, clonic, or myoclonic seizures are also recognized. In tonic-clonic seizures, animals lose consciousness. In the tonic phase, increased muscle tone results in limb and head extension, causing the animal to fall to the side. In the clonic phase, alternating extension and flexion of the limbs, and exaggerated chewing movements may occur. The animal usually urinates, defecates, and salivates.13

PATHOPHYSIOLOGY An epileptic seizure arises from hypersynchronous neuronal electrical activity in the cerebral cortex. The normal brain is capable of seizures in response to a variety of intracranial and extracranial stimuli. When the brain’s homeostasis is overcome, cerebrocortical excitability is altered and the seizure threshold is decreased. Normal animals with a low seizure threshold may be induced to have a seizure by many factors, including fatigue, fever, estrus, and photic stimulation. Experimentally, repeated stimulation of the rat cerebral cortex by a subconvulsive electrical stimulus caused generalized seizures over time. This phenomenon is referred to as kindling. Following establishment of a focal seizure focus, abnormal electrical activity may be recorded over the contralateral cerebral cortex. This secondary seizure focus is termed a mirror focus.14 Either the primary or secondary focus, or both, may cause seizures. The mirror focus may cause seizures even if the primary seizure focus is removed.15 Although kindling and mirror foci are observed as experimental phenomena, they may be relevant clinically in the therapy of animals with seizure disorders. Most epileptic seizures are brief and self-limited. In SE, there is failure of the normal brain homeostasis mechanisms that terminate an epileptic seizure. Much of the pathophysiology is poorly understood. The proposed mechanisms for the development of SE include excessive, sustained neuronal excitation, inadequate neuronal inhibition, or both.16 These changes contribute the self-perpetuating nature of SE. Extra-synaptic factors may be important in spreading and maintaining the seizure. An excess of excitatory neurotransmitters such as glutamate, aspartate, or acetylcholine, or antagonists of gaminobutyric acid (GABA) (an inhibitory neurotransmitter) may contribute to SE. SE lasting 30 to 45 minutes results in brain injury in experimental animals.17 However, brain injury likely occurs in clinical patients after a much shorter time period. SE may cause neuronal necrosis, particularly in brain regions with high metabolic rates. In early SE, an increase in cerebral blood flow may be protective for the brain. In late SE, cerebral blood flow decreases simultaneously as blood pressure decreases and cerebral metabolic rate (e.g., glucose and

oxygen use) increases. This leads to ATP depletion and lactate accumulation, which contribute to neuronal necrosis. SE may be associated with systemic problems, including hypoxemia, hyperthermia, aspiration pneumonia, systemic lactic acidosis, hyperkalemia, hypoglycemia, shock, cardiac arrhythmias, neurogenic pulmonary edema, and acute kidney injury.

ETIOLOGY Disorders that induce seizures and SE arise either outside the nervous system (reactive seizures) or within the nervous system (intracranial, idiopathic, or structural epilepsy). Causes of reactive seizures may be divided into those that originate outside the body (e.g., toxins) and those that originate within the body but outside the nervous system (e.g., liver disease). Intracranial causes of seizures are divided into progressive and nonprogressive diseases.13 Causes of reactive seizures may result in generalized seizures because they affect the brain globally. Causes of progressive intracranial disease include inflammation (e.g., granulomatous meningoencephalitis), neoplasia, nutritional alterations (e.g., thiamine deficiency), infection, anomalous entities (e.g., hydrocephalus), and trauma. Most animals with progressive intracranial disease are clinically abnormal between seizures and usually have progression of clinical signs. However, seizures may be the only clinical sign for a prolonged time before others become apparent. Examples of nonprogressive causes of seizures include idiopathic epilepsy, which may be further classified (genetic epilepsy, suspected genetic epilepsy, epilepsy of unknown cause), and previously active cerebral diseases such as infections and traumatic lesions that are no longer active. Dogs with idiopathic epilepsy usually are 6 months to 5 years of age. Many dog breeds are known or suspected to have inherited epilepsy. In animals with idiopathic epilepsy, the seizures are caused by a functional problem with the brain and are therefore are generalized and symmetric. While the underlying cause of the epilepsy may not be progressive, the epilepsy may worsen (frequency, duration, severity) over time.6 Few veterinary studies have evaluated the clinical features of SE; therefore, it is not possible to make generalizations concerning underlying causes or concerning short-term and long-term outcomes. One study18 evaluated a cohort of 50 dogs with SE. Of those, 28% had idiopathic epilepsy, 32% had structural epilepsy, and 12% had seizures secondary to a systemic insult or to physiologic stress; 44% had not had SE previously. Many dogs were euthanized, and thus a mortality rate was not reported. In another study19 of SE in dogs with idiopathic epilepsy, 59% of the dogs had one or more episodes of SE. Survival time was shorter in dogs with both idiopathic epilepsy and SE than in those with idiopathic epilepsy alone. In another study of SE or cluster seizures in dogs, a poor outcome was reported in dogs with granulomatous meningoencephalitis, poor seizure control after 6 hours of hospitalization, or SE manifest by partial seizures. Of the dogs in this study, 59% died or were euthanized.7 It is essential to distinguish between reactive seizures and intracranial (progressive and nonprogressive) diseases that cause epileptic seizures. Therapy for reactive seizures and progressive intracranial diseases requires not only control of seizures but also therapy for the underlying disease.

DIAGNOSTIC PLAN A seizure disorder is essentially a manifestation of an underlying disease; therapy is most effective when the underlying disease is diagnosed and treated. Therefore, an accurate diagnosis should be

CHAPTER 84  Seizures and Status Epilepticus established in a timely manner. In some animals, an underlying cause may not be identified, as with idiopathic epilepsy. A complete history and physical and neurologic examination are necessary for all animals with a seizure disorder.

History A complete general history should be obtained from the owner, as well as a specific seizure history: age at onset, frequency, and description of seizures, behavior between seizures, and temporal associations (e.g., associated with eating or not eating). A video of a seizure may be useful, as an adjunct to the owner’s description of the event.

Age and Breed The age at onset is necessary to determine the most likely cause of a seizure disorder. Dogs 5 years and older usually have an acquired seizure disorder, such as a primary brain tumor. The breed is important because inherited epilepsy is reported in certain breeds such as Beagles, German Shepherds, Poodles, and others. Some breeds may have a higher prevalence of intracranial tumors (Boxers) or inflammatory disease (Maltese dogs).

Physical Examination A complete physical examination is important in all animals with seizures to recognize systemic problems or local problems (e.g., skull mass) that may affect the brain.

Neurologic Examination A complete neurologic examination should be done in all animals with seizures. In animals with idiopathic epilepsy, neurologic examination findings between seizures most often are normal. Dogs and cats with reactive seizures or progressive intracranial disease and structural epilepsy may have neurologic abnormalities between seizures. Animals may be abnormal neurologically for days after a seizure. Therefore multiple serial neurologic examinations may be necessary before neurologic deficits can be attributed to a progressive intracranial disorder.

Minimum Database A minimum database (complete blood count, serum chemistry panel, 24-hour fasting blood glucose, urinalysis) is recommended on admission for all animals with seizures. In some animals, serum triglycerides and preprandial and postprandial bile acid levels should be obtained to evaluate the possibility of an underlying metabolic problem (e.g., portosystemic shunt or hypertriglyceridemia). If systemic disease or intracranial disease is suspected, thoracic radiography and abdominal ultrasonography should be performed to screen further for secondary neoplastic and systemic infectious disease.

Diagnostic Tests for Intracranial Disease Further investigation of intracranial diseases, including EEG, magnetic resonance imaging (MRI) (or computed tomography [CT] if MRI is not available), cerebrospinal fluid (CSF) analysis, biopsy (for cytology, histopathology, or both), and serology, may be indicated after a minimum database is completed. EEG is useful in some animals. When a seizure disorder is a possible cause for a paroxysmal event, abnormal findings on EEG may help to distinguish the presence of seizures from other paroxysmal non-seizure events. In dogs and cats, EEG is done under sedation, with a recording duration of approximately 30 minutes. Recently, due to advances in EEG devices, long-term ambulatory EEG recordings are currently provided in a few veterinary institutions. EEG findings may help the clinician to evaluate the anticonvulsant therapy, particularly in a patient undergoing treatment for SE, because

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the external manifestations of seizures may be abolished by drugs.20 In the future, EEG may be useful in further classification of canine and feline seizure disorders and in assessing anticonvulsant efficiency. If continuous intracranial EEG monitoring technology is to become more widely adopted in clinical patients, this technology may change the way that veterinarians and owners monitor and treat dogs with seizure disorders.21 MRI is preferred over CT imaging, unless acute head trauma or an acute intracranial hemorrhage is suspected. MRI and CT imaging are noninvasive and yield the most diagnostic information with respect to location, extent, and type of disease in animals with progressive intracranial problems. The results of advanced imaging may help to define the underlying cause of the seizure disorder. Ideally, CSF is collected after MRI or CT imaging. Usually, CSF is collected from the cisterna magna. Because there is risk to the patient undergoing CSF puncture, CSF is not collected in all animals with intracranial disease (see Chapter 206, Cerebrospinal Fluid Sampling). In most patients, CSF analysis results are supportive of a diagnosis, rather than providing a definitive diagnosis. However, CSF occasionally provides diagnostic information with some infections (e.g., Cryptococcus neoformans) and with some neoplasms (e.g., lymphoma) and is therefore an essential part of an intracranial workup in most animals.

TREATMENT PLAN Regardless of the underlying cause, seizure control is based on selection and administration of an appropriate anticonvulsant drug or drugs. Underlying disease, if present, should be treated concurrently. Adverse effects may limit the usefulness of a particular anticonvulsant drug; therefore, knowledge of the mechanisms of action and drug interactions is essential. Selection of an anticonvulsant drug should be based on results of pharmacokinetic studies in the species in which the drug is to be used. The goal of anticonvulsant therapy is to eradicate all seizure activity; however, this goal is rarely achieved. A more realistic goal is to reduce the severity, frequency, and duration of seizures to a level that is acceptable to the owner, without intolerable or unacceptable adverse effects on the animal. The 2015 consensus statement written by the IVETF suggested initiating maintenance anticonvulsant treatment when there is a seizure frequency of greater than two seizures every 6 months.10 The authors feel that a more realistic guideline is to consider anticonvulsant drug therapy when the seizure frequency is greater than once every 6 weeks. Immediate, short-term (acute) anticonvulsant therapy is required to manage SE, cluster seizures, and seizures resulting from some toxicities. Chronic (or maintenance) anticonvulsant therapy is used to manage epilepsy. Seizure control with anticonvulsant drugs is most effective when started early on in a patient with a seizure disorder because each seizure may increase the probability of additional seizures secondary to effects such as kindling and mirror foci development.

Status Epilepticus The goal of therapy for patients with SE is to stop the seizure as soon as possible. In veterinary medicine, telemetric EEG monitoring is not routinely done in the intensive care unit, so effectiveness of SE therapy is evaluated by the cessation of the outward physical manifestations. Therefore, in some animals, although no clinical signs of SE are obvious, the brain still may have ongoing seizure activity that may affect outcome negatively. As with many disorders in veterinary medicine, there are no controlled, double-blinded, placebo-controlled clinical trials for patients with SE that may be used to guide therapy. Therefore, recommended treatments are guidelines only (Table 84.1).

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TABLE 84.1  Anticonvulsant Drugs for Status Epilepticus in Dogs and Cats Drug Diazepam (first-line)

Dose

Comments

IV bolus: 0.5–1.0 mg/kg; repeat 2–3 times as necessary CRI: 0.5–1 mg/kg/hr

IV injections and infusions should be administered into a central vein

CRI duration: 12 hours. If seizures recur, CRI duration 24 hours

Owners can be trained to administer PR at home

Per rectum: 0.5–1 mg/kg (2 mg/kg if receiving concurrent phenobarbital) Intranasal: 1 mg/kg (used with an atomizer). PR is recommended over the IN route Midazolam (first-line)

IV bolus: 0.2 mg/kg; may be repeated 2–3 times. CRI: 0.2– 0.4 mg/kg/hr

Per rectum route not recommended

CRI duration: 12 hours. If seizures recur, CRI duration 24 hours IN: 0.2 mg/kg (used with an atomizer) Phenobarbital (use concurrently with diazepam or midazolam)

Levetiracetam (use concurrently with diazepam or midazolam)

2–4 mg/kg IV every 20–30 minutes to a total loading of 18–20 mg/kg

Administer concurrently with diazepam or midazolam to prevent recurrence of seizures once benzodiazepine brain levels are reduced

Once seizures are controlled, a maintenance dose of phenobarbital is used (3–5 mg/kg IV/IM/PO q12h for 24–48 hr)

Oral anticonvulsant therapy should be resumed or initiated every 12 hours as soon as they can safely tolerate oral medication

30–60 mg/kg IV 40 mg/kg PR Then 30 mg/kg q8h PO or IV

Administer concurrently with diazepam or midazolam to prevent recurrence of seizures once benzodiazepine brain levels are reduced Administer once status epilepticus is treated to prevent cluster seizures or additional episodes of status epilepticus

Pentobarbital (fourth option)

6–15 mg/kg IV slow bolus, followed by a CRI of 0.5–2 mg/kg/hr Strict monitoring of physiologic parameters is required

Propofol (third-line)

2–8 mg/kg slow IV bolus, given as 25% of the total dose every 30 seconds until desired effect achieved

Strict monitoring of physiologic parameters is required. Mechanical ventilation may be required

CRI should be considered (0.1–0.4 mg/kg/min) CRI duration: 12 hours. If seizures recur, CRI duration 24 hours CRI, constant rate infusion; IM, intramuscular; IN, intranasal; IV, intravenous; PR, per rectum.

Treatment should be divided into the immediate emergency evaluation and treatment (such as airway, breathing, cardiovascular function, body temperature, glucose concentration, and blood pressure) and pharmacologic treatment (see Table 84.1). Animals that are admitted in SE or with cluster seizures may have cerebral edema, and mannitol administration should be considered (see Chapter 85, Intracranial Hypertension).

Pharmacologic Therapy for Status Epilepticus Benzodiazepines. Diazepam and midazolam are the first-line drugs for treatment of SE in dogs and cats. Diazepam is lipid soluble and enters the brain rapidly when given intravenously, intranasally (IN), or per rectum (PR). Midazolam is water soluble. Benzodiazepines bind to the GABA receptors and enhance neuronal hyperpolarization, reducing neuronal firing. The duration of action is short, so a maintenance anticonvulsant (such as phenobarbital or levetiracetam) should be administered concurrently to avoid recurrence of seizures or SE when diazepam or midazolam levels in the brain decrease. For animals not currently receiving phenobarbital or levetiracetam, a loading dose is administered followed by a maintenance dose. Owners may be trained to administer PR diazepam to their pets at home. Midazolam is a water-soluble benzodiazepine and may be used to manage SE. Although the IV route is preferred, midazolam may be given IN (using an atomizer) and IM if IV access cannot be obtained. A study comparing PR diazepam with IN midazolam in terminating SE showed that IN midazolam may be superior.22 Because of variable and erratic

plasma concentrations with PR administration of midazolam, the PR route of administration is not recommended for the treatment of SE.23 If SE continues or further seizures occur, additional boluses of diazepam or midazolam may be given, or a constant rate infusion (CRI) may be used. Generally, a CRI for 12 hours is recommended, followed by 24 hours if the SE or cluster seizures are not well controlled. Barbiturates. Barbiturates potentiate the action of GABA by interfering with sodium and potassium transmission in the neuronal membrane. Because the half-life of most drugs used to manage SE is short, a maintenance anticonvulsant must be part of the treatment regimen. Phenobarbital and levetiracetam are administered most commonly because both drugs can be given intravenously. Pentobarbital may be used as a second-line drug if benzodiazepines fail to treat SE, but the drug has a limited anticonvulsant effect. Pentobarbital is administered as a bolus, followed by a CRI. Pentobarbital may cause sedation, respiratory depression, hypotension, and death. Animals that are heavily sedated or anesthetized should be intubated so that an open airway is maintained. Other physiologic parameters (e.g., heart rate, blood pressure, oxygenation) should be monitored regularly or continuously. Therefore, the dosage should be titrated carefully to stop or reduce the motor activity from the seizure but to avoid anesthesia if possible. During recovery, it may be difficult to determine if the animal is recovering from the pentobarbital or still is having seizures. Levetiracetam (Keppra). Levetiracetam has been used in people for oral treatment of seizures since 1998, and the parenteral formulation

CHAPTER 84  Seizures and Status Epilepticus has been approved since early 2000s. Its anticonvulsant activity is likely due to the binding of the synaptic vesicular protein (SV2A), which inhibits neurotransmitter release. Levetiracetam also has other mechanisms of action that may include inhibition of voltage gated calcium channels. In a study in dogs with SE or acute repetitive seizures, levetiracetam administration (30 mg/kg or 60 mg/kg IV) after receiving IV diazepam resulted in a 56% response rate over a 10% response rate in the placebo group.24 Although not statistically significant in that study, IV levetiracetam is considered safe and potentially effective for the treatment of SE in dogs. In another study, rectal levetiracetam at a dosage of 40 mg/kg was used in dogs with SE after treatment with IV or PR diazepam and IV phenobarbital in an open label study. Dogs given rectal levetiracetam in addition to the standard of care (diazepam and phenobarbital) had better seizure control than those dogs who did not receive levetiracetam.25 Propofol. Propofol is a rapid-acting, lipid-soluble general anesthetic agent. It is a third-line drug for the management of SE in dogs and cats. The anticonvulsant effect of propofol is likely because of its GABA agonist activity.26 There are case series describing its use in animals and humans with SE.26,27 However, propofol use is controversial because seizures are associated with its use in humans28 and in a dog.29 In one study, humans with SE who were treated with propofol had a higher mortality rate than those treated with midazolam.27 Chronic Seizure Disorders. Successful anticonvulsant therapy depends on the maintenance of plasma concentrations of appropriate anticonvulsant drugs within a therapeutic range defined for the species in which the drug is to be administered. Therefore, anticonvulsant drugs that are eliminated slowly should be employed. The elimination half-life of anticonvulsant drugs varies considerably between species. Few anticonvulsant drugs used in humans are suitable for use in dogs and cats, largely because of species differences in pharmacokinetics. Pharmacokinetic data and clinical experience with many anticonvulsant drugs are lacking in cats. Selection should be based on the known pharmacokinetic properties of a drug in the species in which it is to be administered. (See Chapter 163 for further discussion of anticonvulsant drugs.)

REFERENCES 1. Bunch SE: Anticonvulsant therapy in companion animals. In Kirk RW, editor: Current veterinary therapy IX, St. Louis, 1986, Saunders, pp 836-844. 2. Kearsley-Fleet L, O’Neill DG, Volk HA, Church DB, Brodbelt DC: Prevalence and risk factors for canine epilepsy of unknown origin in the UK, Vet Rec 172(13):338, 2013. 3. Heske L, Nodtvedt A, Jaderlund KH, Berendt M, Egenvall A: A cohort study of epilepsy among 665,000 insured dogs: incidence, mortality and survival after diagnosis, Vet J 202(3):471-476, 2014. 4. Bielfelt SW, Redman HC, McClellan RO: Sire- and sex-related differences in rates of epileptiform seizures in a purebred beagle dog colony, Am J Vet Res 32(12):2039-2048, 1971. 5. Schwartz-Porsche D: Epidemiological, clinical, and pharmacological studies in spontaneously epileptic dogs and cats. Paper presented at: 4th Forum of the American College of Veterinary Internal Medicine; May 22-24, 1986, 1986; Washington, DC. 6. Hulsmeyer VI, Fischer A, Mandigers PJ, et al: International Veterinary Epilepsy Task Force’s current understanding of idiopathic epilepsy of genetic or suspected genetic origin in purebred dogs, BMC Vet Res 11:175, 2015.

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7. Bateman SW, Parent JM: Clinical findings, treatment, and outcome of dogs with status epilepticus or cluster seizures: 156 cases (1990-1995), J Am Vet Med Assoc 215(10):1463-1468, 1999. 8. Podell M: Epilepsy and seizure classification: a lesson from Leonardo, J Vet Intern Med 13(1):3-4, 1999. 9. Berendt M, Gram L: Epilepsy and seizure classification in 63 dogs: a reappraisal of veterinary epilepsy terminology, J Vet Intern Med 13(1):14-20, 1999. 10. Berendt M, Farquhar RG, Mandigers PJ, et al: International Veterinary Epilepsy Task Force consensus report on epilepsy definition, classification and terminology in companion animals, BMC Vet Res 11:182, 2015. 11. Schwartz M, Munana KR, Nettifee-Osborne J: Assessment of the prevalence and clinical features of cryptogenic epilepsy in dogs: 45 cases (2003-2011), J Am Vet Med Assoc 242(5):651-657, 2013. 12. Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy, Epilepsia 30(4):389-399, 1989. 13. LeCouteur RA, Child G: Clinical management of epilepsy of dogs and cats, Probl Vet Med 1(4):578-595, 1989. 14. Lowenstein DH, Bleck T, Macdonald RL: It’s time to revise the definition of status epilepticus, Epilepsia 40(1):120-122, 1999. 15. Goddard GV, McIntyre DC, Leech CK: A permanent change in brain function resulting from daily electrical stimulation, Exp Neurol 25(3): 295-330, 1969. 16. Betjemann JP, Lowenstein DH: Status epilepticus in adults, Lancet Neurol 14(6):615-624, 2015. 17. Morrell F: Secondary epileptogenic lesions, Epilepsia 1:538-560, 1960. 18. Platt SR, Haag M: Canine status epilepticus: a retrospective study of 50 cases, J Small Anim Pract 43(4):151-153, 2002. 19. Saito M, Munana KR, Sharp NJ, Olby NJ: Risk factors for development of status epilepticus in dogs with idiopathic epilepsy and effects of status epilepticus on outcome and survival time: 32 cases (1990-1996), J Am Vet Med Assoc 219(5):618-623, 2001. 20. Markand ON: Pearls, perils, and pitfalls in the use of the electroencephalogram, Semin Neurol 23(1):7-46, 2003. 21. Davis KA, Sturges BK, Vite CH, et al: A novel implanted device to wirelessly record and analyze continuous intracranial canine EEG, Epilepsy Res 96(1-2):116-122, 2011. 22. Charalambous M, Bhatti SFM, Van Ham L, et al: Intranasal midazolam versus rectal diazepam for the management of canine status epilepticus: a multicenter randomized parallel-group clinical trial, J Vet Intern Med 31(4):1149-1158, 2017. 23. Schwartz M, Munana KR, Nettifee-Osborne JA, Messenger KM, Papich MG: The pharmacokinetics of midazolam after intravenous, intramuscular, and rectal administration in healthy dogs, J Vet Pharmacol Ther 36(5):471-477, 2013. 24. Hardy BT, Patterson EE, Cloyd JM, Hardy RM, Leppik IE: Doublemasked, placebo-controlled study of intravenous levetiracetam for the treatment of status epilepticus and acute repetitive seizures in dogs, J Vet Intern Med 26(2):334-340, 2012. 25. Cagnotti G, Odore R, Bertone I, et al: Open-label clinical trial of rectally administered levetiracetam as supplemental treatment in dogs with cluster seizures, J Vet Intern Med 33(4):1714-1718, 2019. 26. Steffen F, Grasmueck S: Propofol for treatment of refractory seizures in dogs and a cat with intracranial disorders, J Small Anim Pract 41(11): 496-499, 2000. 27. Prasad A, Worrall BB, Bertram EH, Bleck TP: Propofol and midazolam in the treatment of refractory status epilepticus, Epilepsia 42(3):380-386, 2001. 28. Makela JP, Iivanainen M, Pieninkeroinen IP, Waltimo O, Lahdensuu M: Seizures associated with propofol anesthesia, Epilepsia 34(5):832-835, 1993. 29. Smedile LE, Duke T, Taylor SM: Excitatory movements in a dog following propofol anesthesia, J Am Anim Hosp Assoc 32(4):365-368, 1996.

85 Intracranial Hypertension Chai-Fei Li, DVM, DACVIM (Neurology), Beverly K. Sturges, DVM, MS, MaS, DACVIM (Neurology)

KEY POINTS • Intracranial hypertension (ICH) is the persistent elevation of intracranial pressure above the normal range of 5–12 mm Hg. • ICH develops when the volume of the intracranial contents rises beyond the ability of compensatory mechanisms to accommodate added volume commonly caused by edema, inflammation, hemorrhage, masses, and cerebrospinal outflow obstruction. • Cushing’s triad of bradycardia, hypertension, and irregular breathing, in the face of marked mentation change, represents severe, late-stage ICH.

• ICH damages the brain through its deleterious effects on cerebral blood flow and oxygen delivery, causing ischemia, neuronal injury, brain herniation, and death. • Hyperosmolar agents and other treatments aimed at controlling intracranial volume remain the cornerstone of effective treatment.

Normal pressure exerted between the brain and the skull in dogs and cats is generally low. Various underlying pathologies (Box 85.1) may lead to a rise in intracranial pressure (ICP). Appropriate and timely management of this is important for favorable patient outcome. Most of the evidence for managing ICH in domestic animals is extrapolated from human studies and experiences. While there are some clear recommendations and guidelines, ongoing controversies in some areas remain. In this chapter, we describe a stepwise, systematic approach to the assessment and management of ICH in small animal veterinary patients.

to increase CBF and thereby CBV and may lead to increased ICP; conversely, cerebral vasoconstriction decreases CBF and CBV and therefore reduces ICP but may result in hypoxia and neuronal ischemia.1,3,4

NORMAL PHYSIOLOGY OF THE BRAIN

Since the content of the intracranial vault is housed within the rigid confines of the skull, distensibility is limited. Since an increase in the volume of one component must accompany a compensatory decrease in one or both of the others if ICP is to remain unchanged, volume changes, or buffering, occurs to maintain a relatively constant ICP. This occurs initially through displacement of CSF extracranially. As ICP increases and CSF displacement is exhausted, blood volume (flow) becomes compromised. As ICP continues to increase, lack of blood to the brain will result in ischemia and neuronal damage, thus promoting further increase in volume and ICP. This process is depicted by the pressure-volume curve, which relates the temporal change in ICP to expanding intracranial volume (see Fig. 85.1).

The brain resides within the bony confinement of the rigid skull. Three components occupy the cranial vault: brain parenchyma, cerebrospinal fluid (CSF), and blood. The Monro-Kellie doctrine states that with an intact skull, the volume of these contents is constant. An increase in one component must accompany a decrease in one or both of the other components in order to maintain a stable and constant pressure (Fig. 85.1). ICP is the pressure inside the cranial vault exerted by the tissues and fluids against the rigid, encasing bone. Normal ICP in the dog ranges from 5 to 12 mm Hg, above which therapies aiming to reduce ICP should be considered. The high metabolic demands and small storage capacity of the brain require cerebral blood flow (CBF) to be maintained in the normal range at all times. To a large degree, CBF is dependent on cerebral perfusion pressure (CPP), which is calculated as mean arterial pressure (MAP) minus ICP: CPP 5 MAP – ICP.1-3 The volume of blood in the brain (cerebral blood volume [CBV]) is affected by factors that typically alter CBF, such as changes in vascular tone or those that impair venous outflow such as jugular vein compression, low head posture and increased intrathoracic pressure.1,3,4 Cerebrovascular vasodilation serves

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Homeostatic Responses of the Brain In a normal brain, homeostatic mechanisms maintain pressure within a range where the brain is optimally functional. These mechanisms include volume buffering, autoregulation, and Cushing’s response.1-4

Volume Buffering

Autoregulatory Mechanisms Pressure autoregulation: Cerebral perfusion is largely maintained via arteriolar (myogenic) reflexes that alter vascular resistance in response to changes in transmural pressure. This mechanism normally functions at perfusion pressures between 50 and 150 mm Hg, preventing hypo- and hyper- perfusion of the brain. Outside this range, blood flow in the brain becomes linear with MAP predisposing to conditions of under- and overperfusion.1,3,4 (Fig. 85.2).

CHAPTER 85  Intracranial Hypertension

BOX 85.1  Common Causes of Intracranial

Hypertension

Traumatic brain injury Intracranial mass Inflammatory encephalopathy Infectious, non-infectious Status epilepticus Obstructive hydrocephalus

Intracranial pressure

ICH, intracranial hypertension.

3

2 1 Intracranial volume Skull Subarachnoid space Brain Ventricle Normal

Vasculature

Fig. 85.1  Pressure-volume curve. An idealized elastance curve that illustrates changes in ICP accompanying the progressive addition of intracranial volume. First segment: Compliance is high and compensatory mechanisms are functioning well, primarily due to expansion of the dura mater in the cranial and cervical spinal space, allowing for added volume with no or little increase in ICP. Second segment: As volume is added to the system, displacement of CSF and blood allow for further volume additions with progressive changes in ICP. Third segment: The vertical portion of the elastance curve shows the high pressure, low compliance situation that occurs when the volume buffering capacity is exhausted. Further displacement of intracranial fluids is not possible, and the addition of more volume causes an exponential rise in ICP. Decompensation is occurring and any volume buffering at this point is due to distention, compression, and eventual herniation of neural tissues.

Chemical autoregulation: Chemical constituents of the brain’s environment function to control blood flow in the brain by altering cerebral vascular resistance, and by effect, ICP. PaCO2: In the brain, vascular resistance or diameter is directly responsive to changes in global and local PaCO2 concentrations. As CO2 in water forms H2CO3 and subsequently dissociates to H1 and HCO3-, an increase in [H1] stimulates cerebral vasodilation, whereas a decrease in [H1] will lead to cerebral vascular constriction. In the normally functioning brain, hyperventilation (decreased PaCO2) will lower ICP by causing vasoconstriction and a reduction in CBV.

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Elevated PaCO2, through effects of vasodilation and increased blood volume, will lead to increases in ICP; conversely, low CO2 levels in the brain and cerebral vasoconstriction can lead to tissue hypoxia. PaO2: PaO2 also affects cerebral vascular resistance, although this effect is not thought to be as potent as that of global measures of PaCO2. Decreases in PaO2 lead to vasodilation, increased CBF, increased CBV, and elevated ICP. Cerebral metabolic rate of oxygen of oxygen utilization: The cerebral metabolic rate of oxygen of oxygen utilization (CMRO2) is thought to be a direct index of energy homeostasis and brain health. Since CBF is coupled to local cerebral metabolism, pH alterations in perivascular environment, in regions of high cerebral metabolic activity, will have a direct influence on cerebral vascular tone. Increased H1 concentration, as seen with lactic acidosis or other acids formed in the course of cerebral metabolism, will cause an increase in CBF. In situations of decreased CMRO2, low levels of H1 concentration will result in decreased CBF locally due to arteriolar constriction. Autoregulation is often impaired in intracranial disease with pressure autoregulation generally affected first, in the more acute phase of injury, whereas chemically mediated regulation is significantly compromised as ICP elevation becomes marked and brain injury progresses. Cushing response: Under acute elevations of ICP causing global ischemia, a physiological nervous system response, the Cushing response results in a triad of clinical signs: systemic hypertension, bradycardia, and irregular respirations. Since CPP is a function of MAP and ICP, MAP must overcome the pressure (ICP) present in the brain to maintain adequate tissue perfusion. The exact physiological mechanisms of what stimulates the Cushing reflex remain to be determined but ultimately systemic hypertension results from sympathetic activation, and this can lead to bradycardia subsequent to a baroreceptor response. Irregular respiratory patterns observed in the Cushing triad are believed to be the result of brainstem compression secondary to an increased in ICP (see section below). The Cushing triad represents a late stage of ICH and, in conjunction with a markedly reduced mental state, signifies impending brain herniation and death. This must be differentiated from a commonly observed occurrence of mild to moderate hypertension and bradycardia in a patient under general anesthesia, which is often misinterpreted as a Cushing triad but does not fulfill the requirements. More likely this is caused by the use of a-2 agonists, which cause hypertension from vasoconstriction and bradycardia from a baroreflex as well as from its sympatholytic and sinoatrial node effects.

CLINICAL ASSESSMENT OF INTRACRANIAL HYPERTENSION Detailed clinical evaluation is the mainstay in assessing the patient with suspected ICH. Following history and physical examination, careful neurologic examination is needed to arrive at a clinical diagnosis of ICH and determine a baseline to which results of future neurological examinations can be compared. Aspects of the neurological examination that are of particular importance when assessing ICH include level of consciousness, brainstem reflexes, motor responses, postures, and breathing patterns. Papilledema identified on fundic examination, although very uncommon, is a reliable sign of ICH. A clinical diagnosis of ICH is usually based on the neurological examination unless ICP monitoring is in place. The modified Glasgow Coma Score (MGCS) (see Box 83.1) provides a useful guideline of focused neurological assessments for emergency clinicians and technicians. In basic terms, the clinical presentation of ICH is the result of two major derangements: the significant decrease in CPP resulting in regional or global tissue ischemia and shifts in parenchyma that may

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Fig. 85.2  Classic cerebral pressure autoregulation curve. Cerebral autoregulation maintains a relatively constant rate of cerebral blood flow across a wide of range of cerebral perfusion pressures as shown (50– 150 mm Hg). With intact autoregulation, cerebrovascular tone appears to respond to transmural pressure, which is approximately the same as CPP. Note the marked rise and fall in cerebral blood flow as CPP changes above and below the normal limits of autoregulation, respectively. With impairment of autoregulation in the injured brain, cerebral blood flow will passively follow systemic arterial blood pressure.

lead to forcible movement of brain tissue, or herniation. The clinical syndrome of brain herniation is considered to be the final and irreversible stage of ICH (see Fig. 85.1 - third segment) in the animal with acute-onset ICH. However, the clinical syndromes of brain herniation and image-diagnosed herniation are often confused. In more chronic conditions, where brain atrophy may occur, clinical signs of ICH may lag behind structural changes seen on imaging. The intracranial content has had adequate time to compensate for the intracranial hypertension (see Fig. 85.1 – second segment). For example, a slow-growing brain mass may cause significant cerebellar protrusion into the foramen magnum on magnetic resonance imaging in a patient with only mild or moderate clinical signs of brain herniation (Fig. 85.3). Therefore, care must be taken that patient prognosis is based fully on the clinical assessment of ICH and suspected herniation. In veterinary patients, brain death usually is indicated clinically by deep coma, absence of spontaneous respiration, and loss of brainstem reflexes (i.e., fixed, dilated pupils). In human medicine, the guidelines for brain death are very similar.6 In patients where the neurological examination findings are equivocal, ancillary tests are recommended to confirm the diagnosis of brain death. These include findings of an isoelectric electroencephalogram (EEG), absence of CBF on arteriographic evaluation,4 and others.7 In veterinary patients, no consensus for brain death has been reached. Electroencephalogram and the brainstem auditory evoke response test have been reported to be helpful in assessing cerebral activities and brainstem function in these patients.8 See Chapter 83 (Neurological Evaluation of the ICU Patient) for further discussion on brain death.

Systemic Assessment Initial assessments should include breathing, airway, and circulation, and resuscitation should be initiated if needed. Assessment for shock, packed cell volume, blood pressure, blood glucose, and acid-base disturbance can often aid in identifying patients that suffer from nonneurological diseases primarily. Moreover, systemic abnormalities often exacerbate injuries to the central nervous system (CNS). Electrolyte abnormalities are also important in patients with ICH. In human patients with moderate to severe traumatic brain injury

resulting in ICH, electrolyte imbalances are commonly found. The most commonly reported electrolyte abnormalities following traumatic brain injury (TBI) include hypo- or hypernatremia and hypokalemia. This is thought to be the result of a combination of intravenous fluid therapy, administration of hyperosmotic agent or diuretics, blood loss, and intracranial pathology. There have been reports of inappropriate antidiuretic hormone (SIADH) and transient hypothalamic pituitary adrenal dysfunction resulting in secondary adrenal insufficiency in humans with TBI. These early (,24 hours after TBI) electrolyte abnormalities have been found to be associated with a higher risk of postsurgical death in people. While no large-scale clinical studies have been done in veterinary patients, a previous study found hypernatremia to occur in a significant portion of dogs who suffer from TBI.9 Electrolyte (sodium, potassium) imbalances, including SIADH, are also anecdotally reported frequently following brain injury and treatment. It is likely that early identification and treatment of electrolyte imbalances may lead to improved outcome in the patients with brain injury.

Neurological Assessment Once a patient is hemodynamically stable, detailed assessment of the entire patient should be performed. The initial neurological assessment is best done prior to the administration of analgesic or sedative drugs, which may alter the level of consciousness. Serial/repeat neurological examinations are the most important aspect of clinical monitoring, and progression with special focus is given to the interpretation of mental state, brainstem function and voluntary motor ability. For emergency clinicians and technicians, the MGCS provides an excellent guideline for neurological examinations and provide an easy-to-follow scoring system for continual tracking of the clinical progress.

Modified Glasgow Coma Scale The MGCS had been widely used in dogs and is effective as a prognostic indicator, especially in the assessment of patients with TBI.10 However, any given patient presenting with a specific MGCS score may ultimately have a wide range of outcomes, depending on the

CHAPTER 85  Intracranial Hypertension

Fig. 85.3  MRI of a patient with imaging evidence of foramen magnum herniation without clinical evidence of ICH. This MRI is taken from a cat who had suffered from a large extra-axial intracranial mass in the left parietal lobe, causing a slow, chronic increase of intracranial pressure. As seen in this T2-weighted image (sagittal), the cerebellum appears to be herniated from the foramen magnum. Clinically, this patient is ambulatory in all four limbs. Aside from mild obtundation and cranial nerve abnormalities consistent with a left forebrain lesion, no additional neurological abnormalities were noted. His MGCS was 17/18 at the time of imaging, which demonstrates that the imaging diagnosis of cerebellum protrusion into the foramen magnum does not always correlate with the clinical picture.

type of structural injury, the relative degree of secondary injury burden, the development of neurologic or systemic complications, and a host of known and unknown genetic and epigenetic factors. Therefore, recognizing progression or change in a patient’s neurological function remains the most useful prognostic indicator of all. The MGCS is essentially an ongoing neurological examination with a quantitative scoring system. It divides the assessment into three major areas (level of consciousness, brainstem reflexes and motor activity), all of which are essential in assessing patients with suspected ICH. The relationship of many neurological examination findings with major MGCS assessment criteria that may indicate ICH are shown in Box 83.1. The following three areas of the MGCS (i.e., the neurological examination) along with assessment of respiratory character and/or patterns are essential when determining if patients are likely to have ICH.

Assessing the Level of Consciousness Four levels of consciousness are recognized: • Alert and responsive: normal responses to environmental and applied sensory stimuli, i.e., expected behavior for that individual patient • MGCS 6 points. Animals with this level of consciousness and responsiveness are unlikely to be suffering from ICH. The patient is likely on the initial segment of the P-V curve (see Fig. 85.1). • Obtunded (depressed): slow or inappropriate response to sensory stimuli • This level of consciousness has the widest variation of severity, and as such, the MGCS divides it into three different scoring categories (5, 4, 3 points), with decreasing scores indicating increasing severity (see Box 83.1). Mild to moderate ICH my be present and should be suspected. The patient is likely on the middle segment 2 of the P-V curve, and with progressive

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intracranial disease, may continue to show clinical deterioration (see Fig. 85.1). Recognition of a patient at this stage of ICH is crucial for effecting the best outcome with treatment. • Stuporous: generally unresponsive except to noxious stimuli • This scores 2 points in the MGCS. Marked ICH should be suspected in patients with this level of consciousness. This patient is likely heading into the final segment of the P-V curve (see Fig. 85.1). • Comatose: unresponsive to noxious stimulation • MGCS 1 point. For patients with this level of consciousness, ICH with herniation should be strongly suspected. This patient is likely on the far right of the P-V curve (see Fig. 85.1). The mechanisms responsible for consciousness are located in the rostral brainstem, the ascending reticular activation system, and diffusely throughout the cerebrum. While significant decline of consciousness can be easy to recognize, mild changes in consciousness (mild obtundation) can be challenging to recognize. An animal progressing from a higher to a lower level of consciousness is a general indicator for an increase in ICP. Although focal loss of autoregulation is not recognized clinically, unconscious animals are likely to have global loss of autoregulatory responses.1,4

Assessing Brainstem Reflexes Ocular assessments and cranial nerve reflexes assessments are a portion of the neurological examination that may provide the most information about brainstem function. The MGCS assesses brainstem reflexes using pupillary light reflexes (PLR), oculocephalic reflexes, and pupil size to allow for easy, subjective scoring. Patents with normal PLR and pupil size have the greatest score (6 points), while bilateral, unresponsive mydriasis with reduced to absent oculocephalic reflexes (1 point) are concerning for brainstem dysfunction, which is commonly seen with ICH. Below, the significance of these dysfunction noted with PLR and pupil size is described. 1. Size and reactivity of pupils The midbrain and efferent parasympathetic fibers of the third cranial nerve are responsible for pupillary constriction. In the absence of ophthalmic injury, abnormalities in pupil size or reactivity indicate brainstem dysfunction and/or oculomotor nerve injury. Several patterns of pupillary abnormality are commonly recognized in patients with ICH: a. Mydriasis usually denotes a lesion (ipsilateral or bilateral) of the midbrain or the third cranial nerve. b. Miosis may occur ipsilateral to severe brainstem injury or as part of Horner syndrome (ptosis, enophthalmus, third eyelid protrusion) indicating a lesion along the sympathetic pathway. c. Severe bilateral miosis is a sign of acute, extensive brain disturbance and probably occurs due to functional disturbance of higher centers, with release of oculomotor efferent from their inhibition. d. Severe unresponsive bilateral mydriasis generally indicates a grave prognosis and often accompanies brain herniation. The return of pupils to normal size and response to light is a favorable prognostic sign. 2. Resting eye position, eye movements, and oculocephalic reflexes a. Resting eye position and the presence of spontaneous nystagmus should be noted. Eye abduction is caused by paresis of the medial rectus muscle due to cranial nerve III damage. Adduction of the globe is caused by lateral rectus muscle paresis due to injury of CN VI or damage to the rostral medulla oblongata or pons. Spontaneous positional nystagmus most often signifies dysfunction of the vestibular system, a common finding in patients with increasing ICP.

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b. Oculocephalic reflexes are elicited by moving the head from side to side or vertically. Conjugate oculocephalic movements require integrity of the brainstem pathways from the cranial cervical spinal cord and medulla oblongata rostrally to the third, fourth, and sixth cranial nerve nuclei via the medial longitudinal fasciculus. Thus, the oculocephalic maneuver is a convenient method for the examination of the functional integrity of a large segment of brainstem segmental pathways and the cranial nerves involved in eye movements. 3. Corneal reflexes Corneal reflexes are rarely a useful reflex alone; hence, it is not part of the evaluation based on MGCS. However, their findings may corroborate eye movement abnormalities. Touching the cornea with a cotton tip should cause globe retraction and bilateral eyelid closure. The corneal reflex may be absent when the afferent fifth cranial nerve, the efferent sixth and/or seventh cranial nerve, or their reflex connections within the pons and medulla oblongata are damaged.

such as hypotension or hypoxia, that may lead to decreased MAP and subsequent CPP or delivery of cellular nutrients will worsen injury to the CNS. Circulatory shock is most often due to tissue damage and blood loss from other organs; intracranial disease alone, including head trauma, rarely results in vascular collapse. In most cases of TBI, as the patient is systemically stabilized, the CNS benefits accordingly and the neurological exam may appear improved. 1. Avoid hypoxia The animal should be placed in an oxygen-rich environment with its head elevated and a clear airway. Oxygen supplementation will not prevent hypercapnia in a hypoventilating animal. Tracheal intubation and mechanical ventilation are indicated in apneic or hypoventilating patients.11,12 2. Treat hypovolemia and avoid hypotension Prevention and treatment of hypotension is central to the treatment of ICH; hence, intensive monitoring of arterial blood pressure is essential.4,6,12

Assessing motor activity

After general supportive measures have been completed, medical treatment is instituted to reduce brain edema, decrease ICP, and maintain cerebrovascular perfusion and tissue oxygenation. The patient should be assessed (at least) every 30 minutes until stabilized. A response should be seen within 2 to 4 hours; if this does not occur, medical therapy should be reassessed and additional diagnostic tests and surgical therapy considered.

Assessment of motor activity (and posture) is the final assessment group in MGCS. If an animal is ambulatory, ataxia and paresis are determined by observation of gait and response to testing of postural reactions. If an animal is recumbent, voluntary movement in the limbs can be determined based on response to (painful) stimuli.

Posture

Guidelines for Specific Therapy of ICH

The MGCS provides a scoring system for the assessment of posture under the category of assessment for motor activity. Recognizing abnormal postures aids in localization of the neuroanatomical dysfunction and formulation of differential list and may impart an indication of overall prognosis. Decerebrate rigidity occurs with midbrain lesions and is characterized by unconsciousness, recumbency, opisthotonos, and rigid extension of all limbs. It signifies a grave prognosis. This posture must be distinguished from decerebellate posture and the Schiff-Sherrington posture, in which extensor rigidity is present in the thoracic limbs but the animal is conscious. Prognosis varies from good to poor with these postures.

1. Maintain Adequate CPP

Assessing Respiratory Function

Head elevation promotes drainage of venous blood to reduce ICP. Neck wraps, improper positioning of the head and neck, or positive end-expiratory pressure may impair venous drainage, causing an increase in brain volume.

Although not part of the assessment in MGCS, breathing pattern is important the systemic assessment of a patient with suspected ICH. Breathing control is principally regulated by respiratory centers in the caudal brainstem between the mid-pons and cervicomedullary junction. Respiratory patterns may be useful, albeit inconsistent, in localizing brain injury, although this has not been well documented in veterinary medicine. In general, if a patient is deemed to have ICH and has accompanying unusual breathing patterns that are not explained by alterations in pulmonary function, they are likely due to brainstem dysfunction.

Maintaining adequate CPP is currently the theoretical basis of managing ICH.1,13,14 For CPP to remain constant, the MAP must increase when ICP increases. If the ICP cannot be controlled after adequate fluid resuscitation, vasopressors may be used to increase MAP.14 However, in the absence of cerebral ischemia, aggressive attempts to maintain CPP at .70 mm Hg with pressors should be avoided.13,14 CPP in dogs and cats is ideally maintained at 50–90 mm Hg. When it is not possible to monitor ICP, mean arterial blood pressure should be maintained at or above 80 mm Hg.

2. Decrease Cerebral (Venous) Blood Volume

3. Control PaCO2

Appropriate treatment of ICH is often more important to the shortterm survival of the patient than primary treatment of the underlying brain disease. Treatment goals include reduction of intracranial volume and prevention of secondary brain injury by restoration and maintenance of circulating blood volume, blood pressure, oxygenation, and ventilation.4,6,11

The most important factor controlling cerebral volume and flow is PaCO2.5 Controlled ventilation, used judiciously, can lower ICH by vasoconstriction and reduced CBF. Although prophylactic hyperventilation was recommended historically as a temporary measure for the reduction of ICP in humans, a significant benefit was not demonstrated. Thus, prolonged prophylactic hyperventilation (PaCO2 ,25 mm Hg) is not currently recommended by the Brain Trauma Foundation.15 Normal ventilation, with a target range of PaCO2 of 35–45 mm Hg, in mild to moderate TBI is recommended. However, in severe cases of head injury, hyperventilation with a target PaCO2 of 30–35 mm Hg is still recommended as a temporary measure despite a lack of evidence basis. Lower values may lead to neuronal ischemia and exacerbation of ICH.5,13,15

General Supportive Care

4. Control PaO2 and O2 Content

The initial step is to recognize and correct life-threatening, non-neural injuries, especially in the case of brain trauma.11,12 Any systemic abnormalities,

CBF begins to increase when PaO2 falls below 60 mm Hg. However, the brain is even more sensitive to arterial O2 content. For example

TREATMENT OF ICH

CHAPTER 85  Intracranial Hypertension halving the hematocrit will double the CBF even if PaO2 is greater than 60 mm Hg.5

5. Reduce Cerebral Edema Hyperosmolar fluid therapy. Reduction of brain water content has long been theorized to be an effective means of controlling acute ICH. As such, hyperosmolar therapy is the mainstay of all current treatment protocols for acute brain injury.11,13,14 Hyperosmotic agents create an osmotic gradient that moves water out of the interstitium and into the circulating blood volume, resulting in overall reduction of ICP and promoting CBF.16 Mannitol and hypertonic saline are routinely used for this purpose. There are ongoing studies and debate in determining which of these two agents are superior for use in brain injury. Although the Brain Trauma Foundation historically recommended mannitol as the first-choice hyperosmolar agent, recent updates, based on mounting evidence in people, report insufficient evidence to determine which agent is superior in lowering ICP.17 In general, similar efficacy has been shown between the two agents and a few human studies suggesting that hypertonic saline may be more effective at lowering ICP.18-20 With the lack of studies specific to veterinary medicine, it is reasonable to follow Brain Trauma Foundation guidelines when treating brain-injured animals. With interest and debate surrounding this topic in humans and in animals, ongoing and additional studies are likely to define the best use for both of these agents in the near future. Regardless of the hyperosmotic agent of choice, the patient’s fluid and electrolyte balance should be evaluated prior to starting hyperosmolar therapy as both of these agents can have undesirable or detrimental effects on patient with abnormal fluid and electrolyte balance. Due to the lack of definitive evidence of mannitol versus hypertonic saline as hyperosmotic agent to reduce intracranial hypertension, their different effects on hydration and electrolytes, and the changes in efficacy with repeat dosages, the authors often will use mannitol and hypertonic saline in an alternating manner for patients that require repeat treatment. a. Mannitol. The short-term beneficial effects of mannitol on ICH, CPP, and CBF are widely accepted.11,13,14,21 There is controversy about its mechanism, but it likely has the following effects: • An immediate (within minutes) plasma expanding effect, which reduces blood viscosity, thus increasing CBF and the delivery of oxygen and blood constituents to the brain. • A delayed osmotic effect occurs 15–30 minutes after administration when gradients are established between plasma and cells causing a reduction in brain water content. An osmotic increase of at least 10 mOsm is thought to be required for this effect to be seen. This delayed effect persists for 1 to 3 hours. It is generally considered best not to exceed a plasma osmolality of 320 mOsm/kg. However, the authors have routinely used hyperosmolar therapy in animals with blood osmolalities higher than this, without adverse effects, in situations of severe, unresponsive ICH. Strict maintenance of fluid and electrolyte balance is essential. • Mannitol has been shown to have some free-scavenging properties that can be beneficial in injured neural tissues. • Recommended dose: Mannitol 20% solution: 0.5–1.0 g/kg IV over 20 minutes. Mannitol should be administered as boluses, not as a continuous infusion. While it will continue to have some efficacy with repeated administration, due to delayed osmotic effects, efficacy in lowering ICP may be dampened. Given its negative effect on electrolytes and hydration with repeat dosing, mannitol is not recommended for prophylactic use in patients with TBI. Mannitol should only be administered in patients that are euvolemic and appropriate fluid therapy following mannitol is recommended to avoid hypovolemia caused by its diuretic effects (Box 85.2).

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b. Hypertonic saline. Increasing evidence has surfaced in hypertonic saline’s effect in treatment of intracranial hypertension.11,14,22,23 Animal models and human studies have shown hypertonic saline to be similarly effective as mannitol in reducing cerebral water content.22 Hypertonic saline had also been shown to have an effect in reducing blood viscosity, similar to mannitol, leading to improved cerebral perfusion. In addition, it may also have beneficial effects on excitatory neurotransmitters as well as on the immune system.24-29 Recommended dose: NaCl, 7.5% solution 4 ml/kg IV over 5– 10 minutes; NaCl, 3% solution, 5.4 ml/kg over 5–10 minutes. Corticosteroids. Historically, corticosteroids were reported to be beneficial in the management of brain edema since the early 1960s. Based on this, corticosteroids were used in patients with TBI as a matter of course. However, a beneficial role for glucocorticoids in the management of head trauma remains unproven.13 The Corticosteroid Randomization After Significant Head Injury Trial was designed to evaluate the effect of methylprednisolone on human patients with traumatic injury.30,31 The study failed to show a benefit of using corticosteroid in treatment of ICH caused by trauma. Several additional studies in people also failed to demonstrate a benefit to using corticosteroid in brain-injured patients.32-34 Until such time as appropriate studies show support of using corticosteroids to treat ICH caused by TBI, their use is not routinely recommended.13 However, in veterinary medicine, vasogenic edema associated with primary inflammatory diseases, tumor-associated edema and acute ischemia are valid indications for considering the use of corticosteroids to treat ICH.35 Recommended dose: Dexamethasone sodium phosphate (0.1– 0.25 mg/kg IV) 6. Controlling Brain Oxygen Demand Cerebral metabolic rate and CBF are coupled so that an increase in one is accompanied by a rise in the other. Reducing the oxygen requirement of the brain may reduce ICP by reducing intracranial blood volume. Pain, hyperthermia/fever, seizures, and some drugs (e.g., ketamine) increase the oxygen requirement of the brain. Measures to reduce cerebral metabolism include pain control, sedation, anticonvulsants, and active cooling. Interested readers are directed to references 10 and 11 for further discussion of this topic.

7. Surgical Therapy Indications for surgery include debulking of mass lesions, drainage of intracranial abscesses, and treatment of open skull fractures, depressed skull fractures, or fractures involving a venous sinus or middle

BOX 85.2  Precautions for the Use of

Mannitol

1. Maintain euvolemia. Correct hypovolemia prior to use, but do not overhydrate. A urinary catheter to monitor urine output facilitates this aspect of management. 2. Use a fluid line filter when administering mannitol or dissolve visible crystals in solution prior to use. 3. Administer as a slow bolus over 20 minutes. 4. If possible, monitor and maintain serum osmolality at or below 320 mOsm/L, particularly when there is concern for renal failure. 5. Avoid prophylactic administration and multiple repeat dosage (typically ,3 doses/d). 6. Monitor serum electrolytes and maintain in normal range. 7. Monitor urine output. If urine production is not evident within 15 minutes of mannitol administration, give furosemide to induce diuresis. 8. Do not use when ongoing intracranial hemorrhage is suspected.

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meningeal artery.1,21 Intraventricular catheterization may be useful in some forms of CSF outflow obstruction when the underlying disease may eventually be treated but immediate relief of ICP is needed emergently. Wide decompressive craniectomy may be considered in animals with ICH refractory to medical decompression in which an underlying, treatable condition is diagnosed but time is needed to respond to definitive treatment.

8. Cerebrospinal Fluid Drainage In human medicine, aspiration of CSF via intraventricular catheterization, except for treatment of severe ICH, has become a controversial topic.14,17 Current guidelines from the Brain Trauma Foundation recommend CSF drainage be considered in patients with an initial Glasgow Coma Scale (GCS) ,6 during the first 12 hours after injury. Although it may be possible to aspirate CSF from animals with ventriculomegaly or via ultrasound-guidance in animals with fontanelles, it is not routinely performed in most animals with ICH.

9. Other Considerations Intensive supportive care as discussed in various sections of this text is essential. Factors such as frequent turning, prevention of pressure sores, and attention to bladder and bowel function are of paramount importance in preventing complications associated with recumbency. Most animals with ICH have depressed swallowing and gag reflexes, so oral feeding should be avoided, as aspiration pneumonia may result. Alternative methods of nutritional support, such as a feeding tube or total parenteral nutrition, should be considered early in the course of management until more normal brainstem function occurs.

PROGNOSIS In general, animals with brainstem lesions, especially persistent coma, abnormal respiration, or progressive loss of reflex function have a poorer prognosis than those with cerebrocortical involvement. This correlates with a generally poor prognosis in patients with a lower MGCS. Clinicians should remember that the prognosis is multifactorial and, as such, the progression of the patient’s neurological function remains the most useful tool for prognostication. Compensatory mechanisms of the CNS often require many months for maximum development. Patience and persistence are essential in the recovery from severe ICH, allowing time for resolution of edema, necrosis, hemorrhage and cellular damage. Even animals with the most severe injuries and residual deficits may prove to be functional pets.

REFERENCES 1. Lee KR, Hoff JT: Intracranial pressure. In Youmans JR, editor: Neurological surgery, ed 4, vol 1, Philadelphia, 1996, Saunders, pp 491-514. 2. Marmarou AM, Beaumont A: Physiology of the cerebrospinal fluid and intracranial pressure. In Winn HR, editor: Youmans neurological surgery, ed 5, vol 1, Oxford, 2004, Saunders, pp 175-194. 3. Vandevelde M, Zurbriggen A, Bailey CS, et al: Veterinary pathophysiology. In Dunlop RH, Malbert CH, editors: Veterinary pathophysiology, vol 1, Oxford, 2004, Blackwell Publishing, pp 277-335. 4. Bagley RS: Pathophysiology of nervous system disease. In Bagley RS, editor: Fundamentals of veterinary clinical neurology, ed 1, vol 1, Oxford, 2005, Blackwell Publishing, 2005, pp 41-56. 5. Khurana VG, Benarroch EE, Katusic ZS, et al: Cerebral blood flow and metabolism. In Winn HR, editor: Youmans neurological surgery, ed 4, vol 1, Oxford, 2004, Saunders, pp 524-567. 6. Proulx J, Dhupa N: Severe brain injury. Part I. Pathophysiology, Comp Cont Educ Pract Vet 20:897-905, 1998.

7. Fishman RA: Brain edema and disorders of intracranial pressure. In Rowland LP, editor: Merritt’s neurology, ed 11, Philadelphia, 2005, Lippincott Williams & Wilkins, pp 357-365. 8. Aleman M, Williams DC, Guedes A, et al: Cerebral and brainstem electrophysiologic activity during euthanasia with pentobarbital sodium in horses, J Vet Intern Med 29:663-672, 2015. 9. Riese F, Rohn K, Hoppe S, et al: Hypernatremia and coagulopathy may or may not be useful clinical biomarkers in dogs with head trauma: a retrospective study, J Neurotrauma 35:2820-2826, 2018. 10. Platt SR, Radaelli ST, McDonnell JJ: The prognostic value of the modified Glasgow Coma Scale in head trauma in dogs, J Vet Intern Med 15: 581-584, 2001. 11. Proulx J, Dhupa N: Severe brain injury. Part II. Therapy, Comp Cont Educ Pract Vet 20:993-1006, 1998. 12. Sinson G, Reilly PM, Grady MS: Moderate and severe traumatic brain injury. Initial resuscitation and patient evaluation. In Winn HR, editor: Youmans neurological surgery, vol 4, Philadelphia, 2004, Saunders, pp 5083-5101. 13. Bullock RM, Chestnut RM, Clifton GL, et al: Guidelines for the management of severe traumatic brain injury, Brain Trauma Foundation, J Neuro-Trauma 17:449-554, 2000. 14. Vincent JL, Berre J: Primer on medical management of severe brain injury, Crit Care Med 33:1392-1399, 2005. 15. Stocchetti N, Maas AI, Chieregato A, et al: Hyperventilation in head injury: a review, Chest 127:1812-1827, 2005. 16. Blissitt PA: Controversies in the management of adults with severe traumatic brain injury, AACN Adv Crit Care 23:188-203, 2012. 17. Carney N, Totten AM, O’Reilly C, et al: Guidelines for the management of severe traumatic brain injury, fourth edition, Neurosurgery 80:6-15, 2017. 18. Anstey JR, Taccone FS, Udy AA, et al: Early osmotherapy in severe traumatic brain injury: an international multicenter study, J Neurotrauma 37:178-184, 2020. 19. Gu J, Huang H, Huang Y, et al: Hypertonic saline or mannitol for treating elevated intracranial pressure in traumatic brain injury: a meta-analysis of randomized controlled trials, Neurosurg Rev 42:499-509, 2019. 20. Mangat HS, Wu X, Gerber LM, et al: Hypertonic saline is superior to mannitol for the combined effect on intracranial pressure and cerebral perfusion pressure burdens in patients with severe traumatic brain injury, Neurosurgery 86:221-230, 2020. 21. Bagley RS: Treatment of important and common diseases involving the intracranial nervous system of dogs and cats. In Bagley RS, editor: Fundamentals of veterinary clinical neurology, ed 1, Oxford, 2005, Blackwell, pp 303-322. 22. Ogden AT: Hyperosmolar agents in neurosurgical practice: the evolving role of hypertonic saline, Neurosurgery 58:E1003, 2006. 23. Ogden AT, Mayer SA, Connolly ES Jr: Hyperosmolar agents in neurosurgical practice: the evolving role of hypertonic saline, Neurosurgery 57:207-215; discussion 207-215, 2005. 24. Coleman JR, Moore EE, Silliman CC, et al: Examining the effect of hypertonic saline administered for reduction of intracranial hypertension on coagulation, J Am Coll Surg 230:322-330.e2, 2020. 25. Chen H, Song Z, Dennis JA: Hypertonic saline versus other intracranial pressure-lowering agents for people with acute traumatic brain injury, Cochrane Database Syst Rev 1(1):CD010904, 2020. 26. Stopa BM, Dolmans RGF, Broekman MLD, et al: Hyperosmolar therapy in pediatric severe traumatic brain injury-a systematic review, Crit Care Med 47:e1022-e1031, 2019. 27. Patil H, Gupta R: A comparative study of bolus dose of hypertonic saline, mannitol, and mannitol plus glycerol combination in patients with severe traumatic brain injury, World Neurosurg 125:e221-e228, 2019. 28. DeNett T, Feltner C: Hypertonic saline versus mannitol for the treatment of increased intracranial pressure in traumatic brain injury, J Am Assoc Nurse Pract 33:283-293, 2019. 29. Rossi S, Picetti E, Zoerle T, et al: Fluid management in acute brain injury, Curr Neurol Neurosci Rep 18:74, 2018. 30. Edwards P, Arango M, Balica L, et al: Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months, Lancet 365:1957-1959, 2005.

CHAPTER 85  Intracranial Hypertension 31. Roberts I, Yates D, Sandercock P, et al: Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial, Lancet 364:1321-1328, 2004. 32. Watson NF, Barber JK, Doherty MJ, et al: Does glucocorticoid administration prevent late seizures after head injury? Epilepsia 45:690-694, 2004.

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33. Marshall LF, Maas AI, Marshall SB, et al: A multicenter trial on the efficacy of using tirilazad mesylate in cases of head injury, J Neurosurg 89:519-525, 1998. 34. Saul TG, Ducker TB, Salcman M, et al: Steroids in severe head injury: a prospective randomized clinical trial, J Neurosurg 54:596-600, 1981. 35. Sarin R, Murthy V: Medical decompressive therapy for primary and metastatic intracranial tumours, Lancet Neurol 2:357-365, 2003.

86 Tetanus Simon Platt, BVM&S, FRCVS, Dipl ACVIM (Neurology), Dipl ECVN KEY POINTS • Tetanus is the result of a bacterial infection by Clostridium tetani. • The clinical signs are due to the effects of an exotoxin produced by the bacillus that prevents neurotransmitter release. • Common signs include spasms of the masticatory, pharyngeal, and facial muscles, but the whole body can be involved. • Tetanus antitoxin can prevent further patient deterioration from unbound toxin at the time of administration, but improvement relies on regrowth of axons and nerve terminals.

• Broad-spectrum anaerobic antimicrobial therapy, wound cleansing, muscle relaxants, and sedatives are the important constituents of medical management. • A quiet environment and intensive nursing care are essential for success of treatment.

ETIOLOGY

glycine and -aminobutyric acid (GABA).1,3,4 Interneurons inhibiting a-motor neurons are first affected, and the motor neurons lose inhibitory control. Disinhibited autonomic discharge leads to disturbances in autonomic control, with sympathetic overactivity and excessive plasma catecholamine levels. Neuronal binding of the toxin is thought to be irreversible. Recovery requires the growth of new nerve terminals, which explains the long duration of tetanus.1,4

Tetanus is caused by the neurotoxins released by Clostridium tetani, an environmental motile, Gram-positive, nonencapsulated, anaerobic, spore-forming bacterium. The toxin is produced during vegetative growth of the organism in a suitable environment.1 The organism’s resistant spores are ubiquitous, with a natural habitat in moist, fertile soil; however, they can survive indefinitely in dusty indoor environments. The spores are resistant to boiling water and an autoclave temperature of 120°C for up to 20 minutes.1 Cats and dogs are considered to be relatively resistant to infection by the bacterium, especially compared with horses and humans. Cats are approximately 10 times more resistant to infection than dogs; dogs are 600 times more resistant to tetanus than horses. The resistance in these species is due in part to the inability of the toxin to penetrate and bind to nervous tissue.1

PATHOGENESIS Most cases develop after contamination of skin wounds with the spores, but infection can follow teething, parturition, or ovariohysterectomy.2 Under anaerobic conditions found in necrotic or infected tissue, the tetanus bacillus secretes two exotoxins: tetanospasmin and tetanolysin. Tetanolysin is capable of locally damaging otherwise viable tissue surrounding the infected area and optimizing the conditions for bacterial multiplication.1 Tetanospasmin leads to the clinical syndrome of tetanus after binding to the membranes of the local motor nerve terminals. The toxin is internalized and transported intraaxonally and in a retrograde fashion, first in motor and later in sensory and autonomic nerves, potentially spreading to the brainstem in a bilateral fashion up the spinal cord. Neurotransmitter release is prevented by cleaving and inactivating synaptobrevin, a membrane or “docking” protein necessary for the export of intracellular vesicles containing the neurotransmitter.1,3,4 The toxin predominantly affects inhibitory interneurons, inhibiting release of

502

CLINICAL PRESENTATION Tetanus most commonly affects young, large breed dogs and is rare in cats.5-9 Clinical signs can take up to 4 weeks from the onset of infection to be apparent, although most cases exhibit symptoms within 5 to 12 days.2,5-9 The clinical signs initially can be localized or generalized. Only a few cats with tetanus have been documented in the literature; most had predominantly localized clinical signs.7,8 A study of 38 dogs with tetanus revealed that ocular and facial changes were the most common initial signs.2 Involvement of the head can lead to spasms of the masticatory and pharyngeal muscles, causing trismus (lockjaw) and dysphagia. This can be exacerbated functionally by increased salivation, increased bronchial secretions, and increased respiratory rate resulting from involvement of the parasympathetic and somatic cranial nerve nuclei. Excessive contraction of the facial muscles causes erect ears and a wrinkled forehead (Fig. 86.1) and gives the animal a characteristic sneering of the lips known as risus sardonicus, or the sardonic grin (Fig. 86.2).1,9 In addition, the patient can exhibit protrusion of the third eyelid and enophthalmos resulting from retraction of the globe because of hypertonus of the extraocular muscles.1,9 Reflex muscle spasms can occur in animals with generalized tetanus or intracranial involvement; these may be painful and resemble seizure activity, affecting agonist and antagonist muscle groups together.1 Stimulation can exacerbate clinical signs, occasionally causing a mild form of the disease to progress to a crisis situation. Generalized signs include a stiff gait affecting all limbs, increased muscle tone, dyspnea, an elevated tail and a “sawhorse stance.” At least 50% of dogs progress within

CHAPTER 86  Tetanus

Fig. 86.1  A 2-year-old female Rhodesian Ridgeback with tetanus demonstrates classic spasms of facial musculature.

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If general anesthesia is used for diagnostic tests such as cerebrospinal fluid acquisition, the muscle spasms can be reduced but are rarely abolished. Intubation may be difficult in patients with trismus, and a styletassisted intubation should be anticipated in severely affected animals. A complete blood count may suggest an infectious process from a wound, whereas serum biochemistry (with the exception of muscle enzymes) and cerebrospinal fluid analysis findings are normal.1 Muscle enzymes may be elevated in patients with tetanus because of the persistent muscle spasticity; high activities of creatine kinase (1599– 18405 U/L [reference range 61 to 394 U/L]) have been documented in more than 50% of dogs.6 Radiographs may be helpful to identify involvement of the esophagus, diaphragm, and secondary changes in the lungs resulting from aspiration pneumonia. Electrodiagnostic abnormalities in patients with tetanus are nonspecific and consist of prolonged electrical discharges after needle insertion on electromyography. There is a subsequent persistence of motor unit discharges occurring as “doublets,” which are double discharges of the same motor unit at short intervals and often simultaneous activity of agonist and antagonist muscles. Nerve conduction velocities are normal.11 Attempts to isolate C. tetani from wounds have been successful in up to 33% of cases.9 Serum detection of the toxin is rarely reported.1 A Gram stain of a smear from an open wound may identify Grampositive rods and dark-staining spherical endospores, but the morphology of the bacterium is nonspecific and similar to that of many other bacteria.1 Antibodies against the toxin are usually not detected in animals because the low concentration of toxin does not usually induce an immune response.1

TREATMENT

Fig. 86.2  A 6-year-old female spayed Labrador Retriever with tetanus exhibiting marked accumulation of saliva and a facial grimace often seen with this disease.

Treatment strategies involve three principles: toxins present in the body outside of the central nervous system (CNS) should be neutralized, organisms present in the body should be destroyed to prevent further toxin release, and the effects of the toxin already in the CNS should be minimized.

Neutralization of Unbound Toxin a median of 4 days (range 0 to 14 days) to recumbency with severe muscle spasms.2,5,6 Severe progression of signs can cause opisthotonus, seizure-like activity, respiratory paralysis, and central respiratory arrest, potentially causing death if not rapidly recognized and managed.1,9 Mortality ranges between 18% and 50% of dogs, with a mean survival time of 6.9 days (2–11 days);9 many that die demonstrate concurrent autonomic signs, which include episodes of bradycardia and tachycardia, hypertension, marked vasoconstriction, and pyrexia.1,5-7,9 Approximately half of surviving dogs develop sleepassociated disorders including rapid eye movement and repeated episodes of vocalization; antiepileptic medications are ineffective but spontaneous resolution can be seen in at least 40% of cases within 6 months.9

DIAGNOSIS The patient’s history and clinical signs are usually sufficient to make a presumptive diagnosis of tetanus. Differential diagnoses considered in patients with tetanus could include immune-mediated polymyositis, strychnine toxicity, spinal trauma, hypocalcemia, or meningoencephalitis. The differential diagnoses for “lockjaw” should include temporomandibular joint (TMJ) ankylosis, which can be secondary to fracture, masticatory muscle myositis, neoplasia, TMJ luxation and dysplasia, osteoarthritis, retrobulbar abscess, and severe ear disease.10

Antitoxin neutralizes any toxin that is unbound to the CNS or has yet to be formed. Therefore, the timing of administration in relation to the onset of the disease is essential to its effectiveness. The antitoxin used can be either antitetanus equine serum or human tetanus immune globulin. The latter may be more likely to produce reactions if given intravenously. A study of 20 dogs with tetanus reported that equine antitoxin was used in 16 (80%), with no statistically significant differences in survival, severity of clinical signs, or duration of clinical signs between dogs treated with antitoxin and those that did not receive antitoxin.5 Another retrospective study of 38 dogs documented antitoxin use in 29 cases; there was no association between earlier administration of antitoxin and progression of clinical signs (i.e., worsening tetanus severity classification) or 28-day mortality rate.2 The recommended dosage of equine tetanus antitoxin for dogs and cats is 100 to 1000 U/kg (maximum 20,000 U/kg) IV, SC, or IM. Intravenous administration is preferred to intramuscular or subcutaneous administration. Although intravenous use of antitoxin is associated with a higher incidence of anaphylaxis, the reported rate of hypersensitivity reactions in dogs is relatively low. Epinephrine (0.01 mg/kg IM of a 1mg// ml solution (1:1000) with a maximum dose of 0.3 mg.), glucocorticoids, and an antihistamine (e.g., diphenhydramine) should be readily available in case of an adverse reaction. Repeated doses of antitoxin are more likely to cause adverse reactions and are not recommended or necessary because therapeutic levels persist for approximately 14 days.

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Removal of Source of Infection Any obvious wounds should be radically debrided after the administration of antitoxin. Flushing the wound with hydrogen peroxide increases oxygen tension, which inhibits anaerobic organisms, although wound healing also may be impaired (see Chapter 129, Wound Management). Antimicrobials are essential to kill vegetative C. tetani organisms and thereby reduce the amount of circulating toxin. Metronidazole (7 to 10  mg/kg PO or IV q8-12h for 10 days) has been shown superior to penicillin G in clinical tetanus because it achieves bactericidal therapeutic concentrations in anaerobic tissues.12 Other options include clindamycin (10 mg/kg PO, IV, or IM q8-12h) and tetracycline (22 mg/kg PO or IV q8h) or doxycycline (5 to 10 mg/kg PO or IV q12h).

Control of Rigidity and Spasms Prevention of unnecessary stimulation is mandatory, but the mainstay of treatment is sedation with a benzodiazepine. Benzodiazepines augment GABA agonism at the GABAA receptor. Diazepam (0.5 to 1 mg/ kg PO q8h in dogs [maximum 10  mg], 0.25 to 0.5  mg/kg in cats [maximum 5 mg, caution with oral diazepam in cats because of hepatotoxicity], or a continuous intravenous infusion of 0.1 to 1 mg/kg/hr in dogs and cats) or clorazepate (0.5 to 1 mg/kg PO q8h in dogs; 0.2 to 0.5  mg/kg PO q12-24h in cats) can be used in this regard, although both may cause oversedation in some patients. As an alternative, midazolam can be used as a continuous intravenous infusion (0.2 to 0.5 mg/kg/hr). Additional sedation can be provided with anticonvulsant therapy, particularly phenobarbital (1 to 4  mg/kg PO or IM/IV q 4-6h as needed, while monitoring for excessive sedation), which further enhances GABAergic activity. Phenothiazines may be highly effective in controlling the hyperexcitable state; chlorpromazine (0.05 to 0.5  mg/kg IM, IV, or PO q6-12h) is the drug of choice, although acetylpromazine (0.005 to 0.05  mg/kg IV q2h as needed [maximum 3 mg in any dog]) is a useful substitute. With severe signs such as generalized tonic-clonic seizure activity, generalized body stiffness, and opisthotonus, a propofol (or pentobarbital, if available) infusion may be necessary, but cardiovascular parameters should be monitored closely, and careful consideration should be given to whether the patient should be intubated and placed on positive-pressure ventilation. Recently, the use of magnesium sulfate infusions has been documented as a potential adjunct therapy in the management of spastic paralysis in humans and dogs with tetanus.13-15 A dose of 18.75-70 mg/kg (0.15-0.57 mEq/kg) over 30 minutes followed by a constant rate infusion of 0.8 mEq/ kg/day has been recommended for dogs. (Note that 1 mg/kg of magnesium sulfate contains 0.0081 mEq of magnesium). The goal of this treatment is to increase total serum magnesium to 2 to 4 mmol/L (4.86 to 9.73 mg/dl) based on a target therapeutic range derived from the human literature.13 Caution should be exercised in animals with renal insufficiency. The use of botulinum toxin for tetanus-induced rigidity in humans has been suggested.16 Botulinum toxins enter nerve terminals of lower motor neurons. The toxins are zinc metalloproteinases that attack synaptic vesicle proteins, but they do so differentially: botulinum toxin A cleaves synaptosomal-associated protein (SNAP-25); botulinum toxins B, D, F, and G cleave synaptobrevin (which also is attacked by tetanus toxin); botulinum toxin C cleaves SNAP-25 and syntaxin.16 The effects of botulinum toxins remain fairly confined to the nerve terminals of lower motor neurons, inhibiting the release of acetylcholine and activation of voluntary muscles. For this reason, they may have a role in reducing the muscular hyperactivity in tetanus patients, but further research is necessary.

Supportive Intensive Care Intensive nursing care is essential for successful treatment of patients with tetanus. The dog or cat should be isolated in a dark and quiet

Fig. 86.3  A dog with tetanus that has a nasoesophageal feeding tube for enteral nutritional support and tracheostomy for airway protection and ventilator support, if needed. Note the cotton in the external ear canals to help prevent noise-induced tetanic spasms.

environment, with cotton wool balls placed in the external ear canals (Fig. 86.3). Minimal handling is optimal, and all treatments therefore should be coordinated to occur together at set times through the day. Weight loss and dehydration are common in patients with tetanus resulting from poor prehending, mastication, and swallowing capabilities, reduced gastrointestinal function in the presence of autonomic dysfunction, increased metabolic rate, and hyperthermia from the muscular activity and prolonged critical illness. Nutrition and fluid therapy therefore should be established as early as possible. Enteral nutrition may be associated with a lower incidence of complications and is less expensive than parenteral nutrition, but the latter may be necessary in select cases. If airway obstruction develops because of laryngeal spasm or a buildup of saliva or tracheal secretions, intubation and mechanical ventilation may be necessary. A tracheostomy often is performed in these patients to decrease the need for continuous anesthesia. Urinary and fecal retention occur in some patients with hypertonic anal and urinary sphincters. An indwelling urinary catheter may be beneficial in these patients, although the urine should be analyzed regularly for evidence of nosocomial infection. Pressure sores or decubital ulcers should be prevented with appropriate soft or padded bedding and frequent turning and physiotherapy. However, the balance between frequent physiotherapy and isolated rest is difficult to achieve, and pharmacologic sedation may be necessary before physical manipulation.

PROGNOSIS Recovery depends on successful support of the animal while new axonal terminals form. Most dogs that recover (58% to 77%) show some improvement within 5 to 12 days, although the presence of autonomic abnormalities is a poor prognostic indicator.2,5 A tetanus severity classification system has been proposed in dogs:2 class I dogs have only facial signs of tetanus; class II dogs have generalized rigidity or dysphagia, with or without class I signs; class III dogs have class I or II signs and are recumbent or have seizures; and class IV dogs have class I, II, or III signs as well as abnormal heart rate, respiratory rate, or blood pressure.2 One study found that all dogs with class I or II clinical signs survived and only 58% of class III or IV signs survived.2 A full recovery may not be possible in at least 15% of dogs that survive, but continued improvement may be seen for 3 to 5 months (see Video 86.1).2,5,6,9 Natural infection does not provide effective, long-lasting immunity. Cats are reported to recover well from localized tetanus with some residual deficits remaining several months later;7,8 there are no large studies assessing the prognosis in cats with generalized tetanus.

CHAPTER 86  Tetanus

REFERENCES 1. Popoff MR: Tetanus in animals, J Vet Diagn Invest 32(2):184-191, 2020. doi:10.1177/1040638720906814. 2. Burkitt JM, Sturges BK, Jandrey KE, Kass PH: Risk factors associated with outcome in dogs with tetanus: 38 cases (1987-2005), J Am Vet Med Assoc 230:76, 2007. 3. Connan C, Popoff MR: Uptake of clostridial neurotoxins into cells and dissemination, Curr Top Microbiol Immunol 406:39, 2017. 4. Rossetto O, Pirazzini M, Bolognese P, Rigoni M, Montecucco C: An update on the mechanism of action of tetanus and botulinum neurotoxins, Acta Chim Slov 58:702, 2011. 5. Bandt C, Rozanski EA, Steinberg T, Shaw SP: Retrospective study of tetanus in 20 dogs: 1988-2004, J Am Anim Hosp Assoc 43:143, 2007. 6. Adamantos S, Boag A: Thirteen cases of tetanus in dogs, Vet Rec 161:298, 2007. 7. Langner KF, Schenk HC, Leithaeuser C, et al: Localised tetanus in a cat, Vet Rec 169:126, 2011. 8. Polizopoulou ZS, Kazakos G, Georgiadis G, et al: Presumed localized tetanus in two cats, J Feline Med Surg 4:209, 2002.

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9. Shea A, Hatch A, De Risio L, Beltran E: Association between clinically probable REM sleep behavior disorder and tetanus in dogs, J Vet Intern Med 32:2029, 2018. 10. Gatineau M, El-Warrak AO, Marretta SM, et al: Locked jaw syndrome in dogs and cats: 37 cases (1998-2005), J Vet Dent 25:16, 2008. 11. De Risio L, Zavattiero S, Venzi C, et al: Focal canine tetanus: diagnostic value of electromyography, J Small Anim Pract 47:278, 2006. 12. Greene CE: Tetanus. In Greene CE, editor: Infectious diseases of the dog and cat, ed 4, St Louis, 2011, Saunders. 13. Simmonds EE, Alwood AJ, Costello MF: Magnesium sulfate as an adjunct therapy in the management of severe generalized tetanus in a dog, J Vet Emerg Crit Care 21:542, 2011. 14. Rodrigo C, Samarakoon L, Fernando SD, Rajapakse S: A meta-analysis of magnesium for tetanus, Anaesthesia 67:1370, 2012. 15. Shanbag P, Mauskar A, Masavkar S: Intravenous magnesium sulphate infusion as first-line therapy in the control of spasms and muscular rigidity in childhood tetanus, Paediatr Int Child Health 39:201, 2019. 16. Hassel B: Tetanus: pathophysiology, treatment, and the possibility of using botulinum toxin against tetanus-induced rigidity and spasms, Toxins 5:73, 2013.

1 e1 Video 86.1  A 7-year-old male neutered mix breed dog presented with exercise intolerance causing tetraparesis with limited activity; marked involvement of the left thoracic limb after a few steps can be seen. After a short rest period, the improvement in the dog can be observed. The dog was treated with antibiotics and symptomatic support; the improvement experienced by the dog after 8 weeks can be seen at the end of the video, courtesy of the owner.

87 Hepatic Encephalopathy Alex Lynch, BVSc (Hons), DACVECC, MRCVS

KEY POINTS • The symptoms of hepatic encephalopathy (HE) in animals can be subtle and episodic in nature. Portosystemic shunting is the most common cause of HE in dogs and cats. • A confident clinical diagnosis of HE requires documentation of hyperammonemia and liver dysfunction in the face of compatible neurological signs. Several nonammonia substances also contribute to the pathogenesis of HE but are harder to assess in individual patients.

• Most treatments for HE are aimed at attenuating the effects of hyperammonemia (e.g., lactulose, antibiotics, protein restricted diet, intravenous fluids). • Confounding factors, including hypoglycemia, electrolyte derangements, and acid-base disturbances, should be investigated in animals with HE and addressed when appropriate.

Hepatic encephalopathy (HE) represents cerebral dysfunction secondary to intrinsic liver disease or abnormal hepatic perfusion. The pathophysiology of HE is complex.1-3 While the role of ammonia in HE is well characterized, several other substances have also been implicated in its development. These substances include, but are not limited to, glutamate, gamma-aminobutyric acid (GABA), endogenous benzodiazepines and opioids, aromatic amino acids, mercaptans, manganese, and alterations in the tryptophan–serotonin system.1-3

DIAGNOSING HEPATIC ENCEPHALOPATHY

CAUSES OF HEPATIC ENCEPHALOPATHY Causes of HE are categorized as type A (acute), B (bypass) or C (chronic/cirrhosis).2,3 Type A causes represent acute fulminant liver dysfunction that may develop secondary to exposure to hepatotoxicants (e.g., xylitol, amanita mushrooms, sago palm). Type B refers to abnormal liver perfusion secondary to congenital portosystemic shunting (PSS) and is the most common type seen in dogs.1 Type C develops during the terminal stages of chronic hepatopathies associated with portal hypertension and acquired shunting. Disease chronicity impacts the pathological lesions identified in patients with HE. The most prominent feature of acute HE is cytotoxic brain edema. Cytotoxic brain edema is characterized by abnormal intracellular fluid shifts leading to cellular swelling.4 An alternative form of brain edema, termed vasogenic or peritumoral edema, is noted in other disease states (e.g., brain tumors).4 Inflammation is a key feature of vasogenic edema that leads to protein-rich fluid accumulation in brain tissues associated with increased vascular permeability. Corticosteroids are only appropriate for the management of vasogenic edema and may cause worsening of intracellular fluid accumulation in patients with cytotoxic edema. Hyperosmotic therapies (e.g., mannitol, hypertonic saline) are usually appropriate for both types of brain edema, however. In contrast, more chronic cases of HE develop characteristic histological changes (e.g., Alzheimer type II astrocytosis) but with a lower likelihood of cerebral edema.5

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A diagnosis of HE ideally requires recognition of three concurrent clinical features: (1) signs compatible with cerebral dysfunction, (2) hyperammonemia, and (3) documented abnormal liver function.

Compatible Clinical Signs The clinical signs associated with HE in individual animals can vary in severity. Symptoms may also be episodic in nature and triggered by an inciting event (e.g., ingestion of a protein meal). Common symptoms include altered mentation, lethargy, head pressing, inappropriate vocalizing, and seizures. Ptyalism is an important symptom of HE specific to cats. Certain clinical presentations (e.g., young, small breed dogs with waxing and waning neurological symptoms) increase the index of suspicion for HE.

Hyperammonemia If HE is suspected, it is helpful to measure ammonia early in the diagnostic workup. Despite its infamous association with HE, ammonia concentration is imperfectly associated with the severity of HE. Measurement of ammonia in individual patients is problematic given its labile nature, although point-of-care analyzers are increasingly available.6 Ammonia is usually measured using EDTA or heparinized plasma samples that are stored on ice and run within 30–60 minutes of collection. Nonhepatic differential diagnoses for hyperammonemia may be encountered from time to time. In dogs, hypocobalaminemia secondary to intestinal malabsorption has been described.7 In cats, arginine deficiency may develop in patients with hepatic lipidosis following a period of anorexia, even in the face of normal hepatic perfusion and function. Arginine is an essential amino acid in cats and an important intermediary in the urea cycle.8,9 Most ammonia comes from the breakdown of dietary proteins by urease-producing bacteria in the gastrointestinal (GI) tract. The unionized form of ammonia (NH3) can cross plasma membranes and hence leave the GI tract transported via the portal circulation to the liver, while ammonium ions (NH41) remain trapped within the

CHAPTER 87  Hepatic Encephalopathy intestinal lumen. Ammonia metabolism occurs in one of two ways. The first, occurring in the periportal hepatocytes, involves the conversion of ammonia to urea [(NH2)2CO)] via the urea or ornithine cycle. The second method, termed transamination, occurs within the perivenous hepatocytes, brain, and skeletal muscle. Transamination involves the addition of ammonia to glutamate (i.e., amination) producing the relatively inert glutamine. The process of amination is catalyzed by glutamine synthase. Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) but can be taken up by astrocytes, thereby limiting central excitatory stimulation. Within astrocytes, glutamate undergoes amination to produce glutamine, which eventually enables regeneration of glutamate. Ammonia detoxification via the urea cycle or transamination may not occur in patients with severe liver dysfunction or PSS. Ammonia readily crosses the blood–brain barrier in hyperammonemic states, interfering with the normal glutamine–glutamate recycling system. Specifically, ammonia inhibits glutamine release from astrocytes. Glutamine is osmotically active, and excessive intracellular accumulation promotes cellular swelling (i.e., cytotoxic edema). This process is facilitated by the insertion of specific aquaporin-4 channels into astrocyte cell membranes.10 The accumulated intracellular glutamine moves into the mitochondria, where deamination occurs producing glutamate and ammonia. This process leads to the deleterious production of reactive oxygen and nitrogen species secondary to ammonia liberation.1-3 To this extent, movement of the relatively innocuous glutamine into mitochondria results in reactive oxygen and nitrogen species production. This has been described as the “Trojan horse” hypothesis.

Liver Dysfunction The considerable reserve capacity of a healthy liver means severe intrinsic pathology or abnormal perfusion must be present in order for hyperammonemia to develop. A clinical diagnosis of HE should therefore also involve evidence of liver dysfunction. Biochemical alterations suggestive of synthetic liver dysfunction may be present (e.g., hypoglycemia, hypocholesterolemia, low blood urea nitrogen, hypoalbuminemia). Normal pre- and postprandial bile acids with normal ammonia concentration in symptomatic dogs effectively rule out HE.11 Alternative indicators of liver function could also be considered instead of bile acids.12 The anticoagulant protein C is synthesized by the liver and can be used as a biomarker of hepatic function and perfusion. Serial protein C assessment has also been used to gauge the success of PSS attenuation in dogs.12 Hyperbilirubinemia is not a feature of congenital PSS but may be seen in dogs with HE associated with intrinsic liver disease or hepatotoxin-induced necrosis.13

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Nonammonia Contributors to HE The nonammonia contributors to HE are harder to assess in individual patients since laboratory assays for these substances are rarely available. From a mechanistic perspective, it is helpful to consider the cumulative effects of the nonammonia factors as tipping the balance between CNS excitation and inhibition. Glutamate reuptake, for instance, is inhibited in hyperammonemic states and promotes an excitatory environment that could lower the seizure threshold. Overall, an inhibitory tendency predominates in animals with HE. The major inhibitory neurotransmitter in the CNS is GABA. Most GABA is of intestinal origin, and excessive blood concentrations of GABA may occur if there is acute intrinsic liver failure. Excessive agonism of GABA receptors consequently produces an inhibitory effect. In addition, endogenous benzodiazepines may be produced in animals with HE, which would further stimulate central GABA receptors.14,15 Another contribution to HE in some patients involves the abnormal production of catecholamine neurotransmitters from aromatic amino acids (e.g., phenylalanine, tyrosine, tryptophan). In patients with liver dysfunction or PSS, the ability to convert aromatic amino acids to the typical neurotransmitters may be overwhelmed. In this situation, false neurotransmitters (e.g., octopamine, phenylethanolamine) may be synthesized that also exert an inhibitory effect. Branched chain amino acid concentrations (e.g., leucine, valine) may also be decreased in these patients. Manganese elimination is impaired in dogs with chronic hepatopathies, and elevated manganese concentrations have also been noted in dogs with congenital PSS.16 Dogs with type B HE have been shown to have increased concentrations of glutamine, as well as tryptophan and its metabolites. Glutamine, from the amination of glutamate, is exchanged across the blood–brain barrier for tryptophan.17 Tryptophan is a precursor to serotonin, as well as quinolinic acid that acts upon NMDA receptors. Disruption of the tryptophan–serotonin system, therefore, may be an important contributor to HE in dogs with PSS.17

MANAGING HEPATIC ENCEPHALOPATHY Most treatments for HE are aimed at attenuating the effects of hyperammonemia (Table 87.1). Lactulose is a nonabsorbable disaccharide broken down in the gut to acidic byproducts. These products convert unionized NH3 to NH41, effectively trapping ammonia within the gut and preventing absorption. Lactulose can either be given orally or as a retention enema in more severely compromised animals. Lactulose is also an osmotic cathartic, decreasing GI transit time, which may have additional benefits in the HE patient. Due consideration for

TABLE 87.1  Therapeutic Strategies for Hepatic Encephalopathy Intervention Antiepileptic drugs

Dosing Scheme Levetiracetam: 50–60 mg/kg IV loading dose, then 20 mg/kg IV q8h Midazolam: 0.25–0.5 mg/kg IV (*controversial since endogenous benzodiazepines may contribute to hepatic encephalopathy) Propofol CRI: 0.5–2 mg/kg IV loading dose, then 0.05–1 mg/kg/minute CRI Antimicrobials Ampicillin: 22 mg/kg IV q8h Metronidazole: 7.5 mg/kg IV or PO q24h Neomycin: 22 mg/kg PO q12h Cathartics Lactulose (retention enema): 1–3 ml/10 kg bodyweight (diluted 1:1 to 1:3) q6-8h Warm water enema: 10 ml/kg q4-6h Hyperosmotic therapies Hypertonic saline: 3 ml/kg IV Mannitol: 0.5–1 g/kg IV CRI, constant rate infusion; GI, gastrointestinal.

Rationale Acute management of seizure activity

Alter GI microflora, reducing urease-producing bacterial burden Ammonium ion trapping in GI tract, hasten GI elimination Management of acute cytotoxic cerebral edema

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PART VIII  Neurologic Disorders

patient fluid balance is needed after lactulose administration in case of excessive fluid losses via the GI tract. Several antibiotics have been used in the management of patient with HE; ampicillin, metronidazole, and neomycin are commonly chosen in small animals. The rationale behind antibiotic prescription is to reduce the number of ureases producing bacteria in the gut. More data are needed to establish if there may be a role for probiotics in the alteration of GI flora in small animals. Nutritional optimization is also an important consideration for animals with HE. Recommendations include the administration of highly digestible protein rather than protein restriction, arginine supplementation for cats, restricted zinc, and a higher ratio of branched:aromatic amino acids.2,3 As mentioned earlier, osmotic therapies (e.g., hypertonic saline, mannitol) can also be considered in patients with an acute onset of HE. Levetiracetam is the most commonly used antiepileptic drug in animals that have seizures associated with HE. Initial data reported a potential protective effect against seizures when levetiracetam was administered preoperatively to dogs with PSS, but this was not replicated in a more recent study.19,20 In the event of an acute seizure, the use of benzodiazepines is somewhat controversial due to the potential for endogenous benzodiazepine synthesis in HE. In fact, there is a low level of evidence that flumazenil may exert a beneficial effect in a subset of people with HE,21 although its benefit in small animals has not been established. Alternative antiseizure strategies may be necessary in the event of intractable seizure activity (e.g., propofol constant rate infusion, potassium bromide or phenobarbital loading). Whenever a patient with suspected or confirmed HE is encountered, it is important to consider the potential impact of any cofounding factors that may be present in that individual patient. Hypoglycemia should be ruled out and treated promptly if detected. Other putative factors that could worsen the severity of HE symptoms (Table 87.2) include hypokalemia, hyponatremia, metabolic alkalosis, GI bleeding, protein ingestion, dehydration, constipation, renal insufficiency, and diuretic administration.22 Hypokalemia promotes metabolic alkalosis, which increases the ratio of NH3:NH41 form. Hypokalemia also significantly increases renal ammonia production.23 Administration of intravenous replacement fluids can attenuate hyperammonemia in animals with hypovolemia and/or dehydration. Alternatively, plasma products may be considered as alternative replacement fluids for HE patients with significant, acute hypoproteinemia. When considering maintenance fluid therapy, a lower sodium containing maintenance fluid (e.g., 0.45% NaCl) is preferable over isotonic replacement fluids (e.g., 0.9% NaCl, lactated Ringer’s solution) in the long term. Interestingly, a recent study in dogs did not find that any of the aforementioned metabolic derangements were more likely to be present in dogs with HE at admission to a teaching hospital.22 However, attention to the presence of

TABLE 87.2  Confounding Factors

Implicated in Worsening the Signs of Hepatic Encephalopathy Hypoglycemia Hypokalemia Hyponatremia Metabolic alkalosis Gastrointestinal bleeding Protein ingestion Dehydration Constipation Renal insufficiency Diuretic administration

metabolic derangements is important since therapeutic measures to correct them have been associated with successful amelioration of HE symptoms.22 This is especially relevant for animals presented with overt signs of HE around the time of diagnosis, as well as animals recovering from definitive treatment of PSS. Systemic inflammation has also been associated with increased severity of HE symptoms.24,25 Clinical indicators of inflammation (e.g., systemic inflammatory response syndrome criteria, C reactive protein) have been associated with more severe HE symptoms in dogs.22,23,26 Occult sources of infection, including blood stream infections, aspiration pneumonia, and urinary tract infections should be considered in patients with HE. Urinary tract infections may be particularly relevant in dogs with PSS, since urate uroliths could act as a nidus for infection. The cross talk between inflammation and coagulation should also be considered in patients with HE, since a prothrombotic tendency has been associated with worsening inflammatory states (see Chapter 101, Hypercoagulable States). One study in dogs with PSS identified that a hypercoagulable tendency, based on evaluation of thromboelastography, was more common in dogs with HE compared to nonencephalopathic dogs.27 Both congenital and acquired PSS, in addition to other liver diseases, have been associated with portal vein thrombosis in dogs.28 If GI hemorrhage is confirmed or suspected, gastroprotectant medications should be administered for the treatment or prevention of ongoing hemorrhage, respectively.

REFERENCES 1. Salgado M, Cortes Y: Hepatic encephalopathy: etiology, pathogenesis, and clinical signs, Compend Contin Educ Vet 35(6):E1-E8; quiz E9, 2013. 2. Gow AG: Hepatic encephalopathy, Vet Clin North Am Small Anim Pract 47(3):585-599, 2017. doi:S0195-5616(16)30154-1. 3. Lidbury JA, Cook AK, Steiner JM: Hepatic encephalopathy in dogs and cats, J Vet Emerg Crit Care (San Antonio) 26(4):471-487, 2016. doi:10.1111/vec.12473. 4. Stokum JA, Gerzanich V, Simard JM: Molecular pathophysiology of cerebral edema, J Cereb Blood Flow Metab 36(3):513-538, 2016. doi:10.1177/0271678X15617172. 5. Norenberg MD, Jayakumar AR, Rama Rao KV, Panickar KS: New concepts in the mechanism of ammonia-induced astrocyte swelling, Metab Brain Dis 22(3-4):219-234, 2007. doi:10.1007/s11011-007-9062-5. 6. Goggs R, Serrano S, Szladovits B, Keir I, Ong R, Hughes D: Clinical investigation of a point-of-care blood ammonia analyzer, Vet Clin Pathol 37(2):198-206, 2008. doi:10.1111/j.1939-165X.2008.00024.x. 7. Battersby IA, Giger U, Hall EJ: Hyperammonaemic encephalopathy secondary to selective cobalamin deficiency in a juvenile border collie, J Small Anim Pract 46(7):339-344, 2005. doi:10.1111/j.1748-5827.2005. tb00330.x. 8. Stewart PM, Batshaw M, Valle D, Walser M: Effects of arginine-free meals on ureagenesis in cats, Am J Physiol 241(4):310, 1981. doi:10.1152/ ajpendo.1981.241.4.E310. 9. Morris JG, Rogers QR: Ammonia intoxication in the near-adult cat as a result of a dietary deficiency of arginine, Science 199(4327):431-432, 1978. doi:10.1126/science.619464. 10. Rama Rao KV, Norenberg MD: Aquaporin-4 in hepatic encephalopathy, Metab Brain Dis 22(3-4):265-275, 2007. doi:10.1007/s11011-007-9063-4. 11. van Straten G, Spee B, Rothuizen J, van Straten M, Favier RP: Diagnostic value of the rectal ammonia tolerance test, fasting plasma ammonia and fasting plasma bile acids for canine portosystemic shunting, Vet J 204(3):282-286, 2015. doi:10.1016/j.tvjl.2015.04.020. 12. Toulza O, Center SA, Brooks MB, Erb HN, Warner KL, Deal W: Evaluation of plasma protein C activity for detection of hepatobiliary disease and portosystemic shunting in dogs, J Am Vet Med Assoc 229(11):17611771, 2006. doi:10.2460/javma.229.11.1761. 13. Adam FH, German AJ, McConnell JF, et al: Clinical and clinicopathologic abnormalities in young dogs with acquired and congenital portosystemic

CHAPTER 87  Hepatic Encephalopathy shunts: 93 cases (2003-2008), J Am Vet Med Assoc 241(6):760-765, 2012. doi:10.2460/javma.241.6.760. 14. Norenberg MD, Huo Z, Neary JT, Roig-Cantesano A: The glial glutamate transporter in hyperammonemia and hepatic encephalopathy: relation to energy metabolism and glutamatergic neurotransmission, Glia 21(1): 124-133, 1997. 15. Zeneroli ML, Venturini I, Corsi L, et al: Benzodiazepine-like compounds in the plasma of patients with fulminant hepatic failure, Scand J Gastroenterol 33(3):310-313, 1998. doi:10.1080/00365529850170919. 16. Kilpatrick S, Jacinto A, Foale RD, et al: Whole blood manganese concentrations in dogs with primary hepatitis, J Small Anim Pract 55(5):241-246, 2014. doi:10.1111/jsap.12196. 17. Holt DE, Washabau RJ, Djali S, et al: Cerebrospinal fluid glutamine, tryptophan, and tryptophan metabolite concentrations in dogs with portosystemic shunts, Am J Vet Res 63(8):1167-1171, 2002. 18. Holecek M: Ammonia and amino acid profiles in liver cirrhosis: effects of variables leading to hepatic encephalopathy, Nutrition 31(1):14-20, 2015. doi:10.1016/j.nut.2014.03.016. 19. Mullins RA, Sanchez Villamil C, de Rooster H, et al: Effect of prophylactic treatment with levetiracetam on the incidence of postattenuation seizures in dogs undergoing surgical management of single congenital extrahepatic portosystemic shunts, Vet Surg 48(2):164-172, 2019. doi:10.1111/vsu. 13141. 20. Fryer KJ, Levine JM, Peycke LE, Thompson JA, Cohen ND: Incidence of postoperative seizures with and without levetiracetam pretreatment in dogs undergoing portosystemic shunt attenuation, J Vet Intern Med 25(6):1379-1384, 2011. doi:10.1111/j.1939-1676.2011.00819.x.

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21. Goh ET, Andersen ML, Morgan MY, Gluud LL: Flumazenil versus placebo or no intervention for people with cirrhosis and hepatic encephalopathy, Cochrane Database Syst Rev 8:CD002798, 2017. doi:10.1002/14651858. CD002798.pub4. 22. Kilpatrick S, Gow AG, Foale RD, et al: Plasma cytokine concentrations in dogs with a congenital portosystemic shunt, Vet J 200(1):197-199, 2014. doi:10.1016/j.tvjl.2014.01.007. 23. Tivers MS, Handel I, Gow AG, Lipscomb VJ, Jalan R, Mellanby RJ: Hyperammonemia and systemic inflammatory response syndrome predicts presence of hepatic encephalopathy in dogs with congenital portosystemic shunts, PLoS One 9(1):e82303, 2014. doi:10.1371/journal.pone.0082303. 24. Shawcross D, Jalan R: The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation, Cell Mol Life Sci 62(1920):2295-2304, 2005. doi:10.1007/s00018-005-5089-0. 25. Coltart I, Tranah TH, Shawcross DL: Inflammation and hepatic encephalopathy, Arch Biochem Biophys 536(2):189-196, 2013. doi:10.1016/j. abb.2013.03.016. 26. Gow AG, Marques AI, Yool DA, et al: Dogs with congenital porto-systemic shunting (cPSS) and hepatic encephalopathy have higher serum concentrations of C-reactive protein than asymptomatic dogs with cPSS, Metab Brain Dis 27(2):227-229, 2012. doi:10.1007/s11011-012-9278-x. 27. Kelley D, Lester C, DeLaforcade A, Webster CR: Thromboelastographic evaluation of dogs with congenital portosystemic shunts, J Vet Intern Med 27(5):1262-1267, 2013. doi:10.1111/jvim.12130. 28. Respess M, O’Toole TE, Taeymans O, Rogers CL, Johnston A, Webster CR: Portal vein thrombosis in 33 dogs: 1998-2011, J Vet Intern Med 26(2): 230-237, 2012. doi:10.1111/j.1939-1676.2012.00893.x.

PART IX  Infectious Disorders

88 Hospital-Associated Infections and Zoonoses Shelley C. Rankin, BSc (Hons), PhD KEY POINTS • Hospital-associated (nosocomial) infection (HAI) is defined as an infectious event that is diagnosed .48 hours after hospital admission, or more specifically, on or after the third hospital day without proven prior incubation. • Risk factors for HAI in ICU patients include severity of underlying illness, prolonged length of stay, mechanical ventilation, indwelling devices, and antimicrobial use. • The reservoirs of pathogens include people, animals, fomites, air currents, water, food sources, insects, and rodents. The spread of pathogens in hospitals occurs primarily via the hands of personnel.

• Establishment of biosecurity and infection prevention programs must become a priority in veterinary hospitals. • The simplest definition of a zoonosis is any disease or infection that is naturally transmissible from vertebrate animals to humans. • Multiple drug-resistant bacteria are common causes of HAI. • Carbapenem-resistant Enterobacteriaceae are emerging HAI pathogens and must be regarded as a very serious threat to hospitalized animals in the ICU.

Any hospital-acquired sickness is referred to as nosocomial. In recent years, there have been new definitions proposed to better classify nosocomial infections as community or hospital acquired.1 Healthcareassociated infections (HCAIs) are those infections that patients acquire while receiving health care, and that term was proposed by both Siegman-Igra et al. and Friedman et al. in 2002.2,3 The definition of HCAI proposed by Siegman-Igra et al. and Friedman differ from each other, and the definition from Frieddman and colleagues has been more frequently used. Nosocomial infection is now generally referred to as hospital-associated infection (HAI) and is still defined using the widely accepted US Centers for Disease Control and Prevention (CDC) guidelines, as an infectious event that is diagnosed .48 hours after hospital admission, or more specifically, on or after the third hospital day without proven prior incubation.4 These definitions are now widely accepted in human health care, and HAI will be used throughout this chapter. There is recent work suggesting that not all multiple drug-resistant (MDR) organisms detected more than 48 hours after admission are health care acquired.5 It is also possible that future studies will show that the definitions may require modification in veterinary medicine. Hospitalization of sick animals can lead to an increased risk of HAI,6 and various policies have been proposed to reduce the risk of HAIs in veterinary medicine.7-10 Syndromic surveillance data collected from four veterinary critical care units suggested that nosocomial events are common in dogs (16.3% of the dog studies) and cats (12%).11 The study documented nosocomial syndromes without presuming whether or not an event had an infectious etiology. This approach may overestimate or underestimate the true rate of HAI because infection was not lab confirmed.

HAI IN DOGS AND CATS

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One of the first published reports of HAI in a veterinary hospital described Klebsiella infection in dogs and one cat in the ICU at the New York State College of Veterinary Medicine in 1978.10 Since that time there have been few well-characterized studies, and many have centered on large animal facilities with various Salmonella enterica serovars as the causative organisms.12-15 Organisms such as Serratia marcescens, Salmonella spp., Clostridium perfringens, Acinetobacter baumannii, Escherichia coli, and Clostridioides difficile have been implicated as causes of HAI in dogs and cats.12,16-20 However, there are very few new studies that document HAIs specifically in the veterinary ICU. The bacteria responsible for HAIs in the ICU are thought to originate either from the patient’s own endogenous flora or from exogenous sources. HAIs derived from endogenous flora may occur in patients receiving chemotherapy, glucocorticoid therapy, or antimicrobial therapy. In contrast to endogenous infections, exogenous infections are prevented more easily by standard or specific precautions devised to reduce the overall rate of transmission.21 Recent reports from human medicine suggest that the CDC definition of HAI might actually overestimate the proportion of infections that are acquired in the health care institution.5 There are many reasons proposed for this, such as delayed sampling, lack of admission screening, and variable incubation times of some infections. Some community-acquired infections may not necessarily be identified within 48 hours of admission. Therefore, it is important to emphasize the difference between infections acquired in the hospital, which are potentially preventable, and infections detected in the hospital.5 Including endogenous infections in the total number

CHAPTER 88  Hospital-Associated Infections and Zoonoses of HAIs will also overestimate the true proportion of infections that are acquired in the ICU. Review of HAI data in veterinary medicine provides information on the pathogenesis, diagnosis, treatment, and strategies for the prevention of urinary tract infections, surgical site infections, bloodstream infections, pneumonia, and diarrhea.6,22,23 In 1989 Murtaugh and Mason proposed the establishment of nosocomial infection control committees in veterinary hospitals, especially the larger teaching and referral centers.24 Some veterinary institutions were receptive to this proposal, but there are still no national or international standards for veterinary hospital infection control. In 2015, the journal Veterinary Clinics of North America: Small Animal Practice published a special edition on infection control that reviewed many of the key areas and provides some practical guidance to minimize HAI in small animal practice.25

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Bacterial resistance to b-lactam antibiotics and b-lactamase inhibitors is becoming increasingly common and threatens to reduce the clinical spectrum of these drugs. In particular, organisms that produce extended-spectrum b-lactamases (ESBLs) and plasmidmediated AmpC enzymes are posing unique challenges in clinical situations.30-32 Organisms that produce ESBLs are found commonly in those areas of the hospital environment where antimicrobial use is frequent and the patient’s condition is critical, and these resistant organisms cause increased morbidity and mortality.33 Risk factors for dogs becoming carriers of MDR E. coli during hospitalization include hospitalization for more than 6 days, treatment with cephalosporins before admission, treatment with cephalosporins for less than 1 day, and treatment with metronidazole while hospitalized.34 Extended hospital stays (.3 days) have also been associated with the acquisition of MDR E. coli and methicillin-resistant Staphylococcus aureus (MRSA).35

RISK FACTORS Although ill-defined in veterinary medicine, independent risk factors for HAI acquisition in the critically ill patient can be extrapolated from human studies. Prolonged length of hospital stay, mechanical ventilation, and indwelling devices (i.e., intravascular or urinary catheters and nasogastric or endotracheal tubes) are wellrecognized risk factors.11,26 Many intrinsic, patient-related factors also have been identified and include patient demographics (e.g., age, sex, sex status), comorbidities, and severity of underlying illness, which is the most widely reported risk factor in humans. Patient-specific risk factors are related to general health and immune status, respiratory status, neurologic status, and fluid status. The most significant risk factors in the ICU are trauma, especially when associated with open fractures and antimicrobial use.26 Ruple-Czerniak and colleagues showed that intravenous catheterization, surgical procedures, antimicrobial drugs given other than perioperatively, anti-ulcer medication and duration of hospitalization were all factors associated with the development of a HAI.11 Suthar and colleagues developed an individual-based model of transmission of bacteria in a veterinary hospital and the model suggested that transmission resulting from contact with health care workers was common.27 They showed that specific transmission points in the hospital such as the ICU, the housing wards, and the recovery room have more influence on transmission of colonization than other locations in the hospital.

ANTIMICROBIAL-RESISTANT NOSOCOMIAL PATHOGENS It is often speculated that organisms isolated from HAIs in animals have an increasingly broad spectrum of antimicrobial resistance, but there are no active HAI surveillance systems in veterinary medicine that collect such data. The impact of MDR bacteria with regard to HAI is an area of current investigation; the data that have been published agree that antibiotic-resistant bacteria can reduce the effectiveness of management.28 There is a paucity of data on trends in resistance patterns among HAI pathogens from veterinary medical facilities. Surveillance data from human health care systems, such as data reported to the CDC’s National Healthcare Safety Network, can however, be used as a predictor of what to expect from HAI pathogens in veterinary patients.29 Local surveillance of antibiotic resistance in animal isolates is preferred, but in the absence of such data, extrapolation from human surveillance data is encouraged.

ZOONOSES, ANTHROPOZOONOSES AND HAI’S IN THE ICU In addition to patient care concerns, many nosocomial pathogens are well recognized as zoonotic agents. Therefore, infection control policies should address the issue of animal to human and human to animal transmission.7. The list of potential zoonotic agents found in veterinary hospitals is long, but the enteric pathogens, such as Campylobacter, Salmonella, and Clostridioides difficile, are commonly isolated from animals in the ICU. All of these organisms have been responsible for nosocomial outbreaks in that setting.13,14,20 In addition, pathogenic Leptospira species have the potential to infect humans and also cause HAI in animals housed with infected or shedding animals in the ICU. E. coli is the most common cause of urinary tract infections in dogs and cats in the ICU, and many strains are now resistant to a wide spectrum of antimicrobial agents.28,30,31 C. difficile and Enterococcus species are now considered emerging zoonotic agents, and this is also true of some veterinary staphylococci, particularly methicillin-resistant S. pseudintermedius (MRSP) and methicillin-resistant S. schleiferi (MRSS).36-38 Vancomycin-resistant Enterococcus faecium (VRE) has not been implicated in HAIs in dogs and cats. However, VRE has been identified in a canine urinary tract infection, and monitoring at veterinary teaching hospitals in the United States and Europe has revealed VRE carriage in healthy dogs.38,39 Dogs treated with antimicrobials for 2 to 9 days in a veterinary ICU were shown to carry a large drug-resistant population of enterococci.39 The emergence of carbapenem-resistant Enterobacteriaceae (CRE) in companion animal veterinary medicine was inevitable, and CRE must now be regarded as a very serious threat to critically ill animals.40 The CDC have designated these organisms as an urgent public health threat because they are not only carbapenem-resistant, but are typically resistant to most, or all, other antimicrobial classes. Overall, there has been an increase in the number of reports of infection or colonization in animals with pathogens that were traditionally thought to have a reservoir only in humans. This trend of “sharing” organisms, particularly in health care settings, can be considered a significant public health concern. It is reasonable to assume that if humans can be infected with MDR pathogenic organisms in health care settings, the same can apply in veterinary health care. It is also plausible that humans caring for animals in the veterinary hospital can also be a reservoir and share their MDR and pathogenic infectious agents with dogs and cats.

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CONCLUSIONS In conclusion, the importance of hospital transmission of infectious organisms, particularly in the ICU, cannot be overemphasized. Although the intrinsic risk factors of individual animal patients for the development of HAI in veterinary medicine are difficult to assess, the risk of transmission of pathogenic and MDR organisms can, and should, be reduced to a minimum whenever possible.

REFERENCES 1. Cardoso T, Almeida M, Friedman ND, et al: Classification of healthcareassociated infection: a systematic review 10 years after the first proposal, BMC Medicine 12:40-52, 2014. 2. Siegman-Igra Y, Fourer B, Orni-Wasserlauf R, et al: Reappraisal of community-acquired bacteremia: a proposal of a new classification for the spectrum of acquisition of bacteremia, Clin Infect Dis 34:1431-1439, 2002. 3. Friedman ND, Kaye KS, Stout JE, et al: Health care-associated bloodstream infections in adults: a reason to change the accepted definition of community-acquired infections, Ann Intern Med 137:791-797, 2002. 4. Identifying Healthcare-Associated Infections (HAI) for NHSN Surveillance. Centers for Disease Control and Prevention website. https://www. cdc.gov/nhsn/PDFs/pscManual/2PSC_IdentifyingHAIs_NHSNcurrent. pdf. Published January 2016. Accessed February 2, 2020. 5. Erb S, Frei R, Dangel M, Widmer AF: Multidrug-resistant organisms detected more than 48 hours after hospital admission are not necessarily hospital-acquired, Infect Control Hosp Epidemiol 38(1):18-23, 2017. 6. Stull JW, Weese JS: Hospital associated infections in small animal practice, Vet Clin North Am Small Anim Pract 45(2):217-233, 2015. 7. Morley PS: Biosecurity of veterinary practices, Vet Clin North Am Food Anim Pract 18(1):133-155, 2002. 8. Weese JS: Barrier precautions, isolation protocols, and personal hygiene in veterinary hospitals, Vet Clin North Am Equine Pract 20(3):543-549, 2004. 9. Portner JA, Johnson JA: Guidelines for reducing pathogens in veterinary hospitals: disinfectant selection, cleaning protocols and hand hygiene, Compend Contin Educ Vet 32(5):E1-E11, 2010. 10. Glickman LT: Veterinary nosocomial (hospital acquired) Klebsiella infections, J Am Vet Med Assoc 179(12):1389-1392, 1989. 11. Ruple-Czerniak A, Aceto HW, Bender JB, et al: Using syndromic surveillance to estimate baseline rates for healthcare-associated infections in critical care units of small animal referral hospitals, J Vet Intern Med 27(6):1392-1399, 2013. 12. Sanchez S, McCrackin Stevenson MA, Hudson CR, et al: Characterization of multidrug-resistant Escherichia coli isolates associated with nosocomial infections in dogs, J Clin Microbiol 40(10):3586-3595, 2002. 13. Cherry B, Burns A, Johnson GS, et al: Salmonella typhimurium outbreak associated with a veterinary clinic, Emerg Infect Dis 10(12):2249-2251, 2004. 14. Wright JG, Tengelsen LA, Smith KE, et al: Multidrug-resistant Salmonella typhimurium in four animal facilities, Emerg Infect Dis 11(8):1235-1241, 2005. 15. Dallap Schaer BL, Aceto H, Rankin SC: Outbreak of salmonellosis caused by Salmonella enterica serovar Newport MDR-AmpC in a large animal veterinary teaching hospital, J Vet Intern Med 24:1138-1146, 2010. 16. Fox JG, Beaucage CM, Folta CA, et al: Nosocomial transmission of Serratia marcescens in a veterinary hospital due to contamination by benzalkonium chloride, J Clin Microbiol 14(2):157-160, 1981. 17. Uhaa IJ, Hird DW, Hirsch DC, et al: Case-control study of risk factors associated with nosocomial Salmonella krefeld infection in dogs, Am J Vet Res 49:1501-1505, 1988. 18. Kruth SA, Prescott JF, Welch MK, et al: Nosocomial diarrhea associated with enterotoxigenic Clostridium perfringens infection in dogs, J Am Vet Med Assoc 195(3):331-334, 1989.

19. Francey T, Gaschen F, Nicolet J, et al: The role of Acinetobacter baumannii as a nosocomial pathogen for dogs and cats in an intensive care unit, J Vet Intern Med 14:177-183, 2000. 20. Weese JS, Armstrong J: Outbreak of Clostridium difficile-associated disease in a small animal veterinary teaching hospital, J Vet Intern Med 17:813816, 2003. 21. Grundmann H, Barwolf S, Tami A, et al: How many infections are caused by patient to patient transmission in intensive care units? Crit Care Med 23(5):946-951, 2005. 22. Johnson JA: Nosocomial infections, Vet Clin North Am Small Anim Pract 32(5):1101-1126, 2002. 23. Nakamura RK, Tompkins E: Nosocomial infections, Compend Contin Educ Vet 34(4): E1-E10, 2012. 24. Murtaugh RJ, Mason GD: Antibiotic pressure and nosocomial disease, Vet Clin North Am Small Anim Pract 19(6):1259-1274, 1989. 25. Stull JW, Weese JS: Infection control, Vet Clin North Am Small Anim Pract 45(2):217-436, 2015. 26. Eggimann P, Pittet D: Infection control in the ICU, Chest 120(6):20592093, 2001. 27. Suthar N, Roy S, Call DR, et al: An individual-based model of transmission of resistant bacteria in a veterinary teaching hospital, PLoS ONE 9(6):e98589, 2014. 28. Ogeer-Gyles JS, Matthews KA, Boerlin P: Nosocomial infections and antimicrobial resistance in critical care medicine, J Vet Emerg Crit Care 16:118, 2006. 29. Weiner LM, Webb AK, Limbago B, et al: Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2011–2014, Infect Control Hosp Epidemiol 37(11):1288-1301, 2016. 30. O’Keefe A, Hutton TA, Schifferli DM, et al: First detection of CTX-M and SHV extended-spectrum beta-lactamases in Escherichia coli urinary tract isolates from dogs and cats in the United States, Antimicrob Agents Chemother 54:3489-3492, 2010. 31. Wieler LH, Ewers C, Guenther S, et al: Methicillin-resistant staphylococci (MRS) and extended-spectrum beta-lactamases (ESBL)-producing Enterobacteriaceae in companion animals: nosocomial infections as one reason for the rising prevalence of these potential zoonotic pathogens in clinical samples, Int J Med Microbiol 301:635-641, 2011. 32. Belas A, Salazar AS, da Gama LT, et al: Risk factors for faecal colonisation with Escherichia coli producing extended-spectrum and plasmid mediated AmpC b -lactamases in dogs, Vet Rec 175(8):202, 2014. 33. Shah AA, Hasan F, Ahmed S, et al: Characteristics, epidemiology and clinical importance of emerging strains of Gram-negative bacilli producing extended-spectrum beta-lactamases, Res Microbiol 155:409-421, 2004. 34. Gibson JS, Morton JM, Cobbold RN, et al: Risk factors for dogs becoming rectal carriers of multidrug-resistant Escherichia coli during hospitalization, Epidemiol Infect 139:1511-1521, 2011. 35. Hamilton E, Kruger JM, Schall W, et al: Acquisition and persistence of antimicrobial-resistant bacteria isolated from dogs and cats admitted to a veterinary teaching hospital, J Am Vet Med Assoc 243:990-1000, 2013. 36. Morris DO, Boston RC, O’Shea K, et al: The prevalence of carriage of methicillin-resistant staphylococci by veterinary dermatology practice staff and their respective pets, Vet Dermatol 21:400-407, 2010. 37. Simjee S, White DG, McDermott PF, et al: Characterization of Tn1546 in vancomycin-resistant Enterococcus faecium isolated from canine urinary tract infections: evidence of gene exchange between human and animal enterococci, J Clin Microbiol 40(12):4659-4665, 2002. 38. Damborg P, Top J, Hendrickx APA, et al: Dogs are a reservoir of ampicillin resistant Enterococcus faecium lineages associated with human infections, Appl Environ Microbiol 75:2360-2365, 2009. 39. Ghosh A, Dowd SE, Zurek L: Dogs leaving the ICU carry a very large multi-drug resistant enterococcal population with capacity for biofilm formation and horizontal gene transfer, PLoS ONE 6(7):e22451, 2011. 40. Tyson GH, Li C, Ceric O, et al: Complete genome sequence of a carbapenem-resistant Escherichia coli isolate with blaNDM-5 from a dog in the United States, Microbiol Resour Announc 8:e00872-19, 2019.

89 Febrile Neutropenia Melissa A. Claus, DVM, DACVECC

KEY POINTS • Neutropenia is defined broadly as less than 2.9 3 109/L neutrophils in dogs and less than 2.0 3 109/L in cats. • Three primary mechanisms by which febrile neutropenia can develop include increased tissue use of neutrophils, decreased egress of neutrophils from the bone marrow, and immunemediated destruction of neutrophils. • Animals with febrile neutropenia should receive broad-spectrum antibiotics using an antipseudomonal b-lactam. Neutropenic patients in septic shock should receive an antipseudomonal b-lactam coupled with an aminoglycoside. These regimens should be deescalated with receipt of the susceptibility profiles of cultured organisms.

• Recombinant human and canine granulocyte colony-stimulating factors (rhG-CSF and rcG-CSF) should not be used in parvovirus infection-induced neutropenia because of poor efficacy (rh-GCSF) and lack of safety data (rcG-CSF). • Recombinant canine G-CSF has demonstrated efficacy in generating myelopoiesis in dogs with chemotherapy-induced neutropenia and cyclic hematopoiesis. • Prevention of nosocomial infections is paramount, with key strategies including meticulous hand washing, application of alcohol-based hand sanitizer, and utilization of clean exam gloves before and after handling neutropenic patients and their indwelling devices.

Febrile neutropenia in dogs and cats has multiple etiologies. Regardless of the underlying cause, insufficient numbers of circulating neutrophils can impact patient morbidity and mortality. Without these vital cells of the innate immune system, patients with febrile neutropenia have little protection against invading pathogens and are even at risk of developing life-threatening infections from their own commensal microflora. This chapter discusses the normal processes and production of neutrophils, the etiologies of febrile neutropenia, and diagnostic tests and recommended treatments for patients with this condition.

neutrophil outer membrane that enable migration, phagocytosis, and preparation for the deadly oxidative burst.1,2 Neutrophils have three main ways of killing pathogens. First, they degranulate to release destructive peptides and proteases into the extracellular matrix or into an intracytoplasmic phagosome containing ingested pathogens. Second, they assemble a reactive oxygen species generator (NADPH oxidase complex) on the membrane of a phagosome or on the outer cell membrane, which produces an oxidative burst when activated by microorganisms. Third, they form neutrophil extracellular traps (NETs). During this process, deoxyribonucleic acid, histones, and other nuclear material combine with destructive peptides and proteases from intracytoplasmic granules and are expelled from the cell into the extracellular space. This web of cytotoxic material ensnares and kills pathogens while also containing the destructive molecules to prevent damage to regional tissues. Formation of NETs is called NETosis. When it was first described, NETosis was thought to be a form of programmed cell death. However, a recently developed specialized microscopic technique has enabled real-time visualization of NETosis, and has shown that following NETosis, anuclear neutrophils continue to live and retain their normal behavior, moving through tissues and phagocytizing microbes.2-4

NEUTROPHIL PHYSIOLOGY Neutrophil Function Neutrophils are the most abundant leukocyte in dogs and cats. They are a crucial part of the innate immune system because they are often the first phagocytes to recognize and destroy invading pathogens, including bacteria and fungi. They move from circulation into the tissues by attaching first loosely and then tightly to receptors on activated endothelial cells. Once adhered, they move between or through endothelial cells and pericytes into the interstitial space. There, they become activated when their cellular transmembrane proteins called pattern recognition receptors (PRRs) bind to pathogen-associated molecular patterns (PAMPs) on the cell walls of pathogens. Neutrophils also become activated when PRRs bind damage-associated molecular patterns (DAMPs) found on a variety of molecules released from stressed, injured, or dying cells. Via this mechanism, the neutrophilic response that occurs with sterile inflammation can mimic that occurring with infection. Once activated, neutrophils begin the process of degranulation, whereby intracytoplasmic granules fuse to the outer plasma membrane. This serves two purposes: first, it releases substances into the interstitial space that improve migration through the extracellular matrix, and second, it allows specific receptors to be expressed on the

Neutrophil Production The driving factors behind myelopoiesis and neutrophil homeostasis are not completely understood. The production of neutrophils depends in part on the presence of the cytokine granulocyte colonystimulating factor (G-CSF). G-CSF is produced primarily by bone marrow stromal cells but also is secreted from a variety of other cells, including macrophages, monocytes, endothelial cells, and fibroblasts. It is the most important cytokine responsible for maintaining neutrophil homeostasis. It promotes progenitor differentiation into committed production of neutrophils, increases cell division, decreases the

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time to maturation, and increases release of neutrophils from the bone marrow.5 A distinction is sometimes made between steady-state myelopoiesis and the uptick of neutrophil production that occurs in the presence of inflammation, known as emergency myelopoiesis. Emergency myelopoiesis is described to be driven by cytokine stimulation and the binding of PAMPs/DAMPs to PRRs on hematopoietic stem cells, which promotes proliferation of progenitor cells and directed differentiation into the granulocyte cell line. Recent research, however, suggests that myelopoiesis more likely exists along a continuum, rather than in a switched on (emergency) or switched off (steady-state) form, thought to be due to the constant presence of PRR signaling in hematopoietic stem cells and progenitors stimulated by commensal microflora. This idea was exemplified in a study of germ-free mice living in a pathogenfree environment. These mice were healthy with no clinical evidence of neutropenia, but all had markedly attenuated neutrophil steady states with circulating neutrophil counts at just 10% of normal. Additionally, they had low serum G-CSF concentrations, demonstrating no stimulation to increase myelopoiesis.6 Neutrophils are present in several different locations in the body, including bone marrow, blood vessels, marginated in the microcirculation, and within the extracellular matrix. Neutrophils are produced by progenitor cells in the bone marrow. There, they mature into segmented neutrophils. In dogs and cats, the bone marrow houses a fairly large reserve pool of mature neutrophils. Under the stimulation of growth factors and cytokines including G-CSF, granulocyte- macrophage (GM)-CSF, TNF-a, TNF-b, and complement 5a, neutrophils are released from the bone marrow.7 Once they enter the bloodstream, they are found in one of two pools: the circulating pool or the marginated pool. The circulating pool neutrophils travel rapidly through the center of larger vessels along with red blood cells. These neutrophils are the ones that are sampled and counted in a complete blood count. The marginated pool neutrophils roll slowly along the endothelium of smaller vessels and capillaries and tend to stagnate in postcapillary venules. In dogs, about half of the neutrophils in the bloodstream are in the circulating pool and half are in the marginated pool. In cats, only about a quarter of neutrophils are in the circulating pool, whereas three-quarters are in the marginated pool. This distinction affects the definition of neutropenia in dogs versus cats. Neutropenia is defined broadly as less than 2.9 3 109/L.7 However, it may be more appropriate to consider a different definition in cats, whereby the majority of neutrophils in the bloodstream are marginated and not within the blood collected when assessing a complete blood count. For this reason, neutropenia in cats may be better defined as less than 2.0 3 109/L.8

PATHOPHYSIOLOGY OF NEUTROPENIA Neutropenia compromises innate immunity and increases a patient’s risk for developing overwhelming infections. Invading opportunistic pathogens unchecked by the incapacitated innate immune system stimulate the onset of fever. Febrile neutropenia can occur with a multitude of disease processes. Animals may become neutropenic during hospitalization, or severe febrile neutropenia may be the reason they are admitted to the ICU. Febrile neutropenia develops by three main mechanisms, including increased use of neutrophils, decreased egress from bone marrow, and immune-mediated destruction.

Increased Utilization As discussed above, an inflammatory cascade is sparked with innate immune cell activation after exposure to PAMPs from invading pathogens, or DAMPs from tissue injury. Cytokines and chemokines are generated by tissue macrophages and neutrophils. These molecules

promote the margination and extravasation of circulating neutrophils into the tissues, where they depopulate invading pathogens or necrotic tissue via the mechanisms described above, phagocytosis with degranulation, oxidative burst, or NETosis. The larger the population of pathogens or the more extensive the tissue injury, the stronger the inflammatory response and the higher the concentration of secreted cytokines. Acutely, tissue recruitment of neutrophils depletes the neutrophils in circulation. Inflammation leads to a change in the balance between bone marrow homing chemokines/receptors and circulation recruitment chemokines/receptors, which overall promotes neutrophil mobilization. This allows the stored mature neutrophils to egress into circulation.6,9 Ultimately, this can deplete the reserve pool of mature neutrophils in the bone marrow. If inflammation is overwhelming and persistent, it can exceed the ability of the bone marrow to generate new neutrophils, thus leading to neutropenia. The severity of neutropenia may not be due entirely to increased extravasation, but also to decreased bone marrow production. An experimental murine study found that sepsis compromised the ability of the bone marrow to replete the population of circulating neutrophils by preventing differentiation of the hematopoietic stem and progenitor cells into committed myeloid progenitor cells.10 Decreasing the differentiating capacity of the bone marrow maximally affects the neutrophil concentration because this cell line has the shortest half-life of the blood cells, especially during periods of increased extravasation.

Decreased Egress from the Bone Marrow Depletion of granulocyte progenitor cells and ineffective granulopoiesis are two bone marrow-centric causes of circulating neutropenia. Generalized bone marrow hypoplasia reduces quantities of granulocyte progenitor cells along with the other hematopoietic cell lines. Bone marrow hypoplasia can result from a variety of processes, including infectious diseases, exposure to some drugs and toxicants, radiation, myelophthisis, and cyclic hematopoiesis (gray Collie syndrome). Ineffective granulopoiesis is the term used to describe the presence of adequate granulocyte precursors in the bone marrow coupled with peripheral neutropenia. This can be due to maturational arrest of the neutrophil cell line or retention and/or destruction of mature neutrophils in the bone marrow. Ineffective granulopoiesis can occur with infectious diseases (feline leukemia virus, feline immunodeficiency virus), myelodysplasia, lithium administration in cats, acute myeloid leukemia, and trapped neutrophil syndrome of Border Collies.

Depletion of Granulocyte Progenitor Cells Infectious diseases. Parvovirus in dogs and cats infects rapidly dividing cell populations, including hematopoietic precursor cells. This leads to apoptosis of the cells, depopulation of the bone marrow, and severe leukopenia results.11 Neutrophils are affected early and severely because of the short half-life of this cell population. This is especially significant in the presence of increased extravasation and activation of neutrophils in the gut, where parvovirus causes severe compromise to the gut mucosal barrier, allowing translocation of gut flora. Although not consistently present, neutropenia may be seen with different rickettsial infections. It is reported more consistently with Ehrlichia canis, a monocyte-infecting bacterium, than with Anaplasma phagocytophilum and Ehrlichia ewingii, granulocytic ehrlichioses. The mechanism by which neutropenia is induced in acute infections is unknown, although severe generalized bone marrow hypoplasia with secondary pancytopenia is described to occur with chronic infections.12 Cats infected with one of the retroviruses, feline leukemia virus or feline immunodeficiency virus, have an increased risk of developing neutropenia, although neither disease routinely leads to neutropenia.13

CHAPTER 89  Febrile Neutropenia Underlying causes for the development of neutropenia are varied and depend on the virus involved. Cats with feline leukemia virus tend to develop myelophthisis and myelodysplastic disorders secondary to round cell neoplasms infiltrating the bone marrow.13 One mechanism for the development of neutropenia in cats with feline immunodeficiency virus is that infected bone marrow stromal cells secrete myelosuppression factors that depress granulopoiesis.14 Neutropenia also may develop in feline immunodeficiency virus-infected cats as a result of myelodysplasia occurring with infection of bone marrow and stromal cells.15 Medications, toxicants, and radiation. Several drugs, including antiinfective agents, antiepileptics, colchicine, captopril, methimazole, and phenylbutazone, have been reported to induce neutropenia idiosyncratically.7 The mechanisms causing neutropenia vary between different drugs and often are unknown. Potential causes may include bone marrow necrosis or fibrosis, suppression of granulopoiesis, immune-mediated destruction of granulocytic precursors or mature granulocytes, or a combination of these effects.16-18 Chemotherapeutic drugs are the most common medications associated with the development of severe neutropenia. In one retrospective observational assessment of the causes of neutropenia in dogs and cats, two-thirds of the dogs and the only cat with suspected drug-induced neutropenia were due to antineoplastic agents.8 These drugs are effective in the treatment of neoplasia because they primarily decimate colonies of rapidly dividing cells. Thus, myelotoxicity is a common side effect of administration of these agents. Likewise, radiation as a treatment for cancer can induce mitotic failure and apoptosis of hematopoietic progenitor cells, leading to bone marrow failure and severe neutropenia.19 Estrogens have been demonstrated to be myelotoxic in dogs.20,21 Dogs are exposed to this steroid hormone by ingestion of an estrogen analog or from estrogen-secreting tumors (Sertoli cell tumors). Doses at which granulopoiesis is depressed are variable in dogs, but significant neutropenia should not occur unless the dose ingested exceeds the recommended therapeutic dose. Studies in dogs and mice demonstrate no direct effect of estrogen on the hematopoietic progenitor cells. Instead, some evidence suggests that a myelopoiesis inhibitory factor is produced by thymic stromal cells exposed to estrogen.21 Myelophthisis. Myelophthisis is the failure of bone marrow to continue normal hematopoiesis because of its decimation by infiltrating abnormal tissue, typically neoplastic cells or collagen (myelofibrosis), and rarely osteoid (osteosclerosis) or diffuse intramedullary inflammation (e.g., fungal osteomyelitis).22 Neoplasms associated with myelophthisis are usually round cell neoplasms, including leukemias, lymphomas, multiple myeloma, and histiocytic sarcoma. Myelofibrosis has been found in dogs with a variety of diseases, including immunemediated hemolytic anemia, medullary lymphoma, and extramedullary neoplasia. It has also been documented in dogs receiving chronic treatment with different medications. Of 19 dogs reported to have myelofibrosis in one retrospective study, only two were reported to be neutropenic, despite all dogs displaying a poorly regenerative anemia.16 The main mechanism by which neutropenia develops with myelophthisis is due to a loss of granulocytic progenitor cells coupled with a loss of the nurturing marrow microenvironment following destruction of bone marrow stromal cells.23,24 Cyclic hematopoiesis. Canine cyclic hematopoiesis is an autosomal recessive genetic disorder also known as gray Collie syndrome because it is found in Collies with a diluted (gray) coat color. The disease is characterized by severe neutropenia developing every 10 to 14 days. Assessment of the bone marrow before a neutropenic episode shows a drastic decline in the myeloid lines, whereas myeloid hyperplasia prefaces the recovery of circulating neutrophil numbers.25 The disease in

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gray Collies is associated with a mutation in the ELANE gene, which encodes neutrophil elastase. One proposed mechanism by which this mutation leads to neutropenia is that the newly formed mutant neutrophil elastase becomes mislocalized within the myeloid precursor cells. Accumulation of this protease within the cytoplasm and endoplasmic reticulum rather than inside cytoplasmic granules induces the unfolded protein response, which leads to endoplasmic reticulum stress, failure of cell line differentiation, and cell death via apoptosis.26

Ineffective Granulopoiesis Despite Normal to Excessive Quantities of Progenitor Cells Dysgranulopoiesis describes the presence of dysplastic granulocyte progenitor cells that lead to a peripheral circulating neutropenia. This neutropenia occurs in the presence of normal to excessive quantities of progenitor cells in the bone marrow. Dysmyelopoiesis is a more general term used to describe the presence of dysplastic hematopoietic cells, not just granulocyte precursors. Three major classifications of dysmyelopoiesis include myelodysplastic syndrome (MDS), secondary dysmyelopoiesis, and congenital dysmyelopoiesis (which is rare and will not be discussed further).27 MDS occurs as a result of clonal expansion of a mutated hematopoietic progenitor cell. The cells arising from the mutant cell do not follow the normal maturation pathway and undergo apoptosis before they are released from the marrow. Thus, the bone marrow appears hyperplastic and contains an abnormally high number of blasts, but there are insufficient cells in circulation.27 MDS can be one cause of neutropenia in cats with feline leukemia virus.28 Secondary dysmyelopoiesis is similar to MDS with the exception that the number of blasts present in the marrow is not increased from normal. Secondary dysmyelopoiesis can occur with different diseases, including immune-mediated hemolytic anemia, immune-mediated thrombocytopenia, and lymphoma. Secondary dysmyelopoiesis also can be seen with the administration of some drugs, including antineoplastic drugs, estrogen, phenobarbital, cephalosporins, chloramphenicol, and colchicine, as well as lithium in cats.27,28 Many of these drugs also lead to hypoplastic bone marrow, as described above. Separate to dysmyelopoiesis, a heritable disease has been described in Border Collies, in which the bone marrow displays hyperplastic granulopoiesis and no evidence of maturation arrest or dysplasia but a severe circulating neutropenia.29 This disease is known as trapped neutrophil syndrome (TNS). Although the gene mutation that causes TNS has been identified, the underlying mechanism by which this mutation leads to decreased release of segmented neutrophils into circulation remains unknown.30

Immune-Mediated Destruction Two main types of immune-mediated destruction of neutrophils are applicable to small animal veterinary patients: (1) primary or idiopathic immune-mediated neutropenia and (2) secondary immunemediated neutropenia that results from an underlying trigger such as infection, drugs, or neoplasia. Idiopathic immune-mediated neutropenia occurs when antibodies are produced against neutrophil surface proteins. These antibodies bind to the surface proteins and either activate complement-mediated death of the neutrophil or opsonize the cell for phagocytosis by macrophages.31 The gold standard for definitive diagnosis of immune-mediated neutropenia is to demonstrate the presence of anti-neutrophil antibodies in the serum of the patient. Although successful detection of antineutrophil antibodies has been reported in dogs with immune-mediated neutropenia using flow cytometry, this test has a low sensitivity and is not widely available.32,33 Thus, the veterinary literature includes few reports of patients with confirmed immune-mediated neutropenia. Instead, diagnosis is based

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on the exclusion of other causes of neutropenia discussed above, in conjunction with improvement in neutrophil counts when treated with immunosuppressing agents.

CLINICAL PRESENTATION AND DIAGNOSTIC TESTS The clinical signs exhibited by patients with febrile neutropenia can vary depending on the underlying cause for neutropenia. Animals with increased tissue demand and extravasation of neutrophils often demonstrate signs of sepsis or septic shock, typically with a marked suppurative exudate at the focus of infection or inflammation. In addition, these patients often display a marked degenerative left shift on a complete blood count. If neutropenia precedes infection, as occurs with decreased egress from bone marrow or immune-mediated destruction, patients may develop opportunistic skin, lung, or urinary tract infections, but show minimal pathologic changes on visual inspection, thoracic imaging, or urinalysis because of marked suppression of the normal inflammatory response.34 Some animals, despite being profoundly neutropenic, may not have a fever on presentation. For example, many septic cats and decompensated septic dogs are hypothermic on presentation to the emergency clinic. In addition, neutropenic patients that have received glucocorticoids or nonsteroidal antiinflammatory drugs may have suppression of their fever from inhibition of prostaglandin formation. Determining the underlying cause of neutropenia helps to develop an appropriate treatment plan. In many cases, the underlying cause for neutropenia may be clear: an obvious septic focus or a recent history of chemotherapy administration. In other cases, exhaustive diagnostics may be necessary to determine the underlying cause. Diagnostic tests to consider in a patient with neutropenia include obtaining cultures of blood, urine, and infected tissues; diagnostic imaging of the thorax and abdomen; and a bone marrow evaluation. Obtaining cultures is essential in the management of patients with febrile neutropenia, especially those showing signs of sepsis. Blood cultures should be performed as early as possible and ideally before administering antimicrobials. The 2016 Surviving Sepsis Guidelines recommend taking at least two blood samples from different blood vessels or indwelling catheters before starting antimicrobial therapy, provided blood collection does not delay the administration of antimicrobial therapy by more than 45 minutes.35 Blood cultures allow for conclusive diagnosis of sepsis, and the susceptibility profile allows for appropriate deescalation of antimicrobial therapy.35 Urine culture should be performed even in the absence of an active sediment on urinalysis, as severe neutropenia may preclude the patient’s ability to mount an inflammatory response. Finally, culturing of any overtly infected site prior to antimicrobial therapy should be considered, provided culture collection does not delay the administration of antimicrobial therapy by more than 45 minutes. This usually precludes the ability to collect preantimicrobial cultures from any region that would require a general anesthetic to collect. In these cases, obtaining postantimicrobial cultures is still recommended. Imaging of the thorax and abdomen using radiographs, ultrasound, and computed tomography can help determine if there is a septic focus that has led to neutropenia. It also can help assess for other causes of neutropenia or for the presence of multiple organ dysfunction as a result of neutropenia (e.g., acute respiratory distress syndrome). Echocardiography to image the cardiac valves for evidence of vegetative endocarditis may be indicated in a neutropenic patient with a new murmur. In the absence of overt causes for neutropenia, bone marrow aspiration and/or core biopsy can be used to differentiate between the other causes of neutropenia, including infiltrative neoplasia,

myelofibrosis, osteosclerosis, and dysmyelopoiesis. Evidence of maturation arrest in a bone marrow aspirate also may help support a presumptive diagnosis of immune-mediated neutropenia.7 Repeat bone marrow aspiration may help determine if a patient is responding to therapy and may help assess the likelihood of recovery from neutropenia.

TREATMENT AND SUPPORTIVE CARE Much of the literature evaluating appropriate treatment in febrile neutropenic patients consists of studies of oncology patients with febrile neutropenia arising from chemotherapy or radiation. It is important to consider that this subset of patients is unique and not representative of all patients with febrile neutropenia, and therefore not all recommendations will apply to all neutropenic patients. While there is reasonable evidence that asymptomatic afebrile neutropenic oncology patients do not require prophylactic antimicrobial therapy above a neutrophil count of 0.75 3 109/L, broad-spectrum antimicrobial therapy should be initiated in all neutropenic patients with fever.36 Decisions as to which antimicrobial therapy to choose should be based on the individual patient’s characteristics, including previous antimicrobial exposure, previous culture results, suspected pathogen based on clinical signs, and regional microbe infection patterns, and hospital antibiograms. In people, monotherapy using an antipseudomonal blactam (e.g., piperacillin-tazobactam, ticarcillin-clavulanate, meropenem, ceftazidime) has been shown to be effective in stable febrile neutropenic patients. In neutropenic people exhibiting signs of septic shock, the recommendation is to combine a b-lactam with an aminoglycoside (e.g., amikacin).37 If infection with a fungal organism is suspected, antifungals also are recommended.35 Once the susceptibility results of blood culture and urine culture are available, the antimicrobial therapy is changed to target specifically the pathogen(s) cultured. This can decrease the risk for the development of secondary infections with microorganisms that are multidrug resistant.35 It also can help decrease the risk of organ damage that can develop with the use of some antimicrobials. Length of treatment with antimicrobial therapy is dependent on many factors including resolution of neutropenia. With a few exceptions, most infections will not need to be treated with antimicrobials beyond 5–7 days, providing the neutropenia has resolved.35 Any patient that is neutropenic and has clinical signs of sepsis or septic shock should be resuscitated using intravenous crystalloids and vasopressors as needed, and broad-spectrum antimicrobial therapy should be initiated as soon as possible.35 If present and identified, source control of the septic focus should occur as soon as possible. Intensive monitoring for the development of multiple organ dysfunction syndrome and meticulous supportive care has to be provided to these patients. Another medication that can be considered for the treatment of febrile neutropenia is recombinant G-CSF. G-CSF increases the differentiation of progenitor cells into neutrophils, increases release of neutrophils into circulation, and acts on mature neutrophils to increase chemotaxis, enhance the respiratory burst, and improve IgAmediated phagocytosis.38 In specific situations, recombinant human G-CSF (rhG-CSF) is recommended as a prophylactic treatment in people receiving chemotherapy because it has been shown to decrease the incidence of febrile neutropenia and secondary infection in this population.39 rhG-CSF has reported efficacy in stimulating granulopoiesis in dogs and cats.40,41 However, it was demonstrated to be ineffective in treating dogs with neutropenia secondary to parvovirus.42,43 In addition, administration of this human protein to dogs may lead to the development of antibodies against rhG-CSF. These antibodies cross-react with and neutralize canine G-CSF, which causes a chronic neutropenia.44

CHAPTER 89  Febrile Neutropenia Recombinant canine G-CSF (rcG-CSF) has been developed but is not widely available for clinical use. Limited evidence has shown it can increase granulopoiesis in both dogs and cats,45,46 with accelerated recovery from neutropenia associated with parvovirus, chemotherapeutics, and cyclic hematopoiesis in dogs.38,47,48 Some questions remain regarding its safety and efficacy, however. In one clinical trial in parvovirus-infected dogs, the group treated with rcG-CSF had increased neutrophils, but also increased mortality compared with the control group.38 Another study found fewer deaths in dogs with parvovirus treated with rcG-CSF; however, they also found no difference in neutrophil count over time between treated and untreated dogs.49 In addition, no studies have been performed in cats to determine if long-term or repeat rcG-CSF use may induce antibody formation and lead to chronic neutropenia as seen with rhG-CSF use in dogs and rcG-CSF use in rabbits.50 Use of this medication to treat dogs with neutropenia should be at the discretion of the clinician. Given lack of safety data and some evidence there may be harm, it is not recommended to use rcG-CSF in dogs with parvovirus infections or in noncanine species. Frequently recommended nursing practices include isolating severely neutropenic patients from other hospitalized animals and practicing barrier nursing, in which carers wear gowns, gloves, and masks before handling neutropenic patients. No literature reviews the efficacy of these practices in veterinary medicine, and the studies available in people tend to be small and uncontrolled with multiple interventions occurring simultaneously, making their results difficult to interpret.51 Arguments against going to these lengths include the cost associated with maintaining a clean isolation ward and providing disposable barrier clothing. Additionally, there is a risk for provision of a decreased level of nursing care as a result of the increased preparation required to care for these patients.52 The current recommendation is to focus on meticulous hand hygiene, ensuring thorough washing of the hands before and after handling a neutropenic patient, in addition to using alcohol-based hand sanitizer and donning gloves before handling any indwelling devices including intravenous catheters, urinary catheters, feeding tubes, or tracheostomy tubes. Because these patients are at risk of developing infections secondary to their own commensal flora, keeping these patients clean and dry and preventing fecal and urine contamination of skin and indwelling devices are imperative.

REFERENCES 1. Thomas CJ, Schroder K: Pattern recognition receptor function in neutrophils, Trends Immunol 34(7):317-328, 2013. 2. Nauseef WM, Borregaard N: Neutrophils at work, Nat Immunol 15(7):602-611, 2014. 3. Hostetter SJ: Neutrophil function in small animals, Vet Clin North Am Small Anim Pract 42(1):157-171, 2012. 4. Yipp BG, Petri B, Salina D, et al: Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo, Nat Med 18(9): 1386-1393, 2012. 5. Bugl S, Wirths S, Muller MR, Radsak MP, Kopp HG: Current insights into neutrophil homeostasis, Ann N Y Acad Sci 1266:171-178, 2012. 6. Bugl S, Wirths S, Radsak MP, et al: Steady-state neutrophil homeostasis is dependent on TLR4/TRIF signaling, Blood 121(5):723-733, 2013. 7. Schnelle AN, Barger AM: Neutropenia in dogs and cats: causes and consequences, Vet Clin North Am Small Anim Pract 42(1):111-122, 2012. 8. Brown MR, Rogers KS: Neutropenia in dogs and cats: a retrospective study of 261 cases, J Am Anim Hosp Assoc 37(2):131-139, 2001. 9. Strydom N, Rankin SM: Regulation of circulating neutrophil numbers under homeostasis and in disease, J Innate Immun 5(4):304-314, 2013. 10. Rodriguez S, Chora A, Goumnerov B, et al: Dysfunctional expansion of hematopoietic stem cells and block of myeloid differentiation in lethal sepsis, Blood 114(19):4064-4076, 2009.

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11. Breuer W, Stahr K, Majzoub M, Hermanns W: Bone-marrow changes in infectious diseases and lymphohaemopoietic neoplasias in dogs and cats—a retrospective study, J Comp Pathol 119(1):57-66, 1998. 12. Little SE: Ehrlichiosis and anaplasmosis in dogs and cats, Vet Clin North Am Small Anim Pract 40(6):1121-1140, 2010. 13. Gleich S, Hartmann K: Hematology and serum biochemistry of feline immunodeficiency virus-infected and feline leukemia virus-infected cats, J Vet Intern Med 23(3):552-558, 2009. 14. Tanabe T, Yamamoto JK: Phenotypic and functional characteristics of FIV infection in the bone marrow stroma, Virology 282(1):113-122, 2001. 15. Fujino Y, Horiuchi H, Mizukoshi F, et al: Prevalence of hematological abnormalities and detection of infected bone marrow cells in asymptomatic cats with feline immunodeficiency virus infection, Vet Microbiol 136(34):217-225, 2009. 16. Weiss DJ, Smith SA: A retrospective study of 19 cases of canine myelofibrosis, J Vet Intern Med 16(2):174-178, 2002. 17. Weiss DJ: Bone marrow necrosis in dogs: 34 cases (1996-2004), J Am Vet Med Assoc 227(2):263-267, 2005. 18. Garbe E: Non-chemotherapy drug-induced agranulocytosis, Expert Opin Drug Saf 6(3):323-335, 2007. 19. Kulkarni S, Ghosh SP, Hauer-Jensen M, Kumar KS: Hematological targets of radiation damage, Curr Drug Targets 11(11):1375-1385, 2010. 20. Hart JE: Endocrine pathology of estrogens: species differences, Pharmacol Ther 47(2):203-218, 1990. 21. Sontas HB, Dokuzeylu B, Turna O, Ekici H: Estrogen-induced myelotoxicity in dogs: a review, Can Vet J 50(10):1054-1058, 2009. 22. Topper MJ: Hemostasis. In Latimer KS, Mahaffey EA, Prasse KW, editors: Duncan & Prasse’s veterinary laboratory medicine clinical pathology, ed 4, Ames, IA, 2003, Blackwell Publishing Company, pp 99-135. 23. Makoni SN, Laber DA: Clinical spectrum of myelophthisis in cancer patients, Am J Hematol 76(1):92-93, 2004. 24. Harvey JW, editor: Evaluation of leukocytic disorders. In Veterinary Hematology: A Diagnostic Guide and Color Atlas. St Louis, MO, 2012, Elsevier Saunders, pp 122-176. 25. Dale DC, Ward SB, Kimball HR, Wolff SM: Studies of neutrophil production and turnover in grey collie dogs with cyclic neutropenia, J Clin Invest 51(8):2190-2196, 1972. 26. Nayak RC, Trump LR, Aronow BJ, et al: Pathogenesis of ELANE-mutant severe neutropenia revealed by induced pluripotent stem cells, J Clin Invest 125(8):3103-3116, 2015. 27. Weiss DJ: Recognition and classification of dysmyelopoiesis in the dog: a review, J Vet Intern Med 19(2):147-154, 2005. 28. Weiss DJ: Evaluation of dysmyelopoiesis in cats: 34 cases (1996-2005), J Am Vet Med Assoc 228(6):893-897, 2006. 29. Allan FJ, Thompson KG, Jones BR, Burbidge HM, McKinley RL: Neutropenia with a probable hereditary basis in Border Collies, N Z Vet J 44(2):67-72, 1996. 30. Shearman JR, Wilton AN: A canine model of Cohen syndrome: trapped neutrophil syndrome, BMC Genomics 12:258, 2011. 31. Chickering WR, Prasse KW: Immune mediated neutropenia in man and animals: a review, Vet Clin Pathol 10(1):6-16, 1981. 32. Weiss DJ: Evaluation of antineutrophil IgG antibodies in persistently neutropenic dogs, J Vet Intern Med 21(3):440-444, 2007. 33. Brunson B: Immune-mediated neutropenia in a miniature poodle, J Am Anim Hosp Assoc 55(1):e551-e553, 2019. 34. Bodey GP: Unusual presentations of infection in neutropenic patients, Int J Antimicrob Agents 16(2):93-95, 2000. 35. Rhodes A, Evans LE, Alhazzani W, et al: Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016, Intensive Care Med 43(3):304-377, 2017. 36. Bisson JL, Fournier Q, Johnston E, Handel I, Bavcar S: Evaluation of a 0.75 X 109/L absolute neutrophil count cut-off for antimicrobial prophylaxis in canine cancer chemotherapy patients, Vet Comp Oncol 18(3):258-268, 2020. https://doi.org/10.1111/vco.12544. 37. Tam CS, O’Reilly M, Andresen D, et al: Use of empiric antimicrobial therapy in neutropenic fever. Australian Consensus Guidelines 2011 Steering Committee, Intern Med J 41(1b):90-101, 2011. 38. Duffy A, Dow S, Ogilvie G, Rao S, Hackett T: Hematologic improvement in dogs with parvovirus infection treated with recombinant canine

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granulocyte-colony stimulating factor, J Vet Pharmacol Ther 33(4): 352-356, 2010. 39. Aapro MS, Bohlius J, Cameron DA, et al: 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours, Eur J Cancer 47(1):8-32, 2011. 40. Fulton R, Gasper PW, Ogilvie GK, Boone TC, Dornsife RE: Effect of recombinant human granulocyte colony-stimulating factor on hematopoiesis in normal cats, Exp Hematol 19(8):759-767, 1991. 41. Lothrop CD Jr, Warren DJ, Souza LM, Jones JB, Moore MA: Correction of canine cyclic hematopoiesis with recombinant human granulocyte colony-stimulating factor, Blood 72(4):1324-1328, 1988. 42. Rewerts JM, McCaw DL, Cohn LA, Wagner-Mann C, Harrington D: Recombinant human granulocyte colony-stimulating factor for treatment of puppies with neutropenia secondary to canine parvovirus infection, J Am Vet Med Assoc 213(7):991-992, 1998. 43. Mischke R, Barth T, Wohlsein P, Rohn K, Nolte I: Effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on leukocyte count and survival rate of dogs with parvoviral enteritis, Res Vet Sci 70(3):221-225, 2001. 44. Hammond WP, Csiba E, Canin A, et al: Chronic neutropenia. A new canine model induced by human granulocyte colony-stimulating factor, J Clin Invest 87(2):704-710, 1991. 45. Obradovich JE, Ogilvie GK, Powers BE, Boone T: Evaluation of recombinant canine granulocyte colony-stimulating factor as an inducer of granulopoiesis. A pilot study, J Vet Intern Med 5(2):75-79, 1991.

46. Obradovich JE, Ogilvie GK, Stadler-Morris S, Schmidt BR, Cooper MF, Boone TC: Effect of recombinant canine granulocyte colony-stimulating factor on peripheral blood neutrophil counts in normal cats, J Vet Intern Med 7(2):65-67, 1993. 47. Yamamoto A, Fujino M, Tsuchiya T, Iwata A: Recombinant canine granulocyte colony-stimulating factor accelerates recovery from cyclophosphamide-induced neutropenia in dogs, Vet Immunol Immunopathol 142(34):271-275, 2011. 48. Mishu L, Callahan G, Allebban Z, et al: Effects of recombinant canine granulocyte colony-stimulating factor on white blood cell production in clinically normal and neutropenic dogs, J Am Vet Med Assoc 200(12):1957-1964, 1992. 49. Armenise A, Trerotoli P, Cirone F, et al: Use of recombinant canine granulocyte-colony stimulating factor to increase leukocyte count in dogs naturally infected by canine parvovirus, Vet Microbiol 231:177-182, 2019. 50. Reagan WJ, Murphy D, Battaglino M, Bonney P, Boone TC: Antibodies to canine granulocyte colony-stimulating factor induce persistent neutropenia, Vet Pathol 32(4):374-378, 1995. 51. Larson E, Nirenberg A: Evidence-based nursing practice to prevent infection in hospitalized neutropenic patients with cancer, Oncol Nurs Forum 31(4):717-725, 2004. 52. Mank A, van der Lelie H: Is there still an indication for nursing patients with prolonged neutropenia in protective isolation? An evidence-based nursing and medical study of 4 years experience for nursing patients with neutropenia without isolation, Eur J Oncol Nurs 7(1):17-23, 2003.

90 Sepsis and Septic Shock Elise Mittleman Boller, DVM, DACVECC, Deborah C. Silverstein, DVM, DACVECC KEY POINTS • Sepsis is a life-threatening organ dysfunction cause by a dysregulated host response to infection;1 septic shock is defined as a subset of sepsis in which underlying circulatory and cellular metabolism abnormalities are profound enough to substantially increase mortality. • Current understanding of the pathobiology of sepsis involves a model of deranged homeostatic mechanisms responsible for regulating the immune and neurohumoral response and along with loss of barrier functions. • Sepsis is the most common cause of death associated with infection; untreated sepsis can be characterized by organ dysfunction,

hypotension, vascular leak, and microvascular dysfunction. This macrocirculatory and microcirculatory impairment leads to tissue and global oxygen debt, organ failure, and possibly death. • The morbidity and mortality associated with sepsis are a result of both pathogen and host factors. • Management of sepsis and septic shock should begin immediately at presentation; treatment should be directed at rapid and targeted resuscitation, early administration of antimicrobials, and controlling the source of infection.

INTRODUCTION

are an insensitive tool for the identification of septic veterinary patients. Further, SIRS criteria do not necessarily portend a life-threatening, host-dysregulated response, given that many nonseptic patients display these criteria and many septic patients do not (see Chapter 7, SIRS, MODS, and Sepsis). Though the use of clinical systemic inflammatory parameters will continue to be useful in identifying patients that may have an infection, it should be noted that mounting an inflammatory response to infection is a normal, adaptive response; the definitions of sepsis and septic shock were created to call attention to the dysregulated host response and to organ dysfunction and risk of mortality, thereby crafting a conceptual model that is more than just “infection plus systemic inflammation.” There were also historical problems with reporting variability using illness severity scoring systems, as well as inconsistent use of the term septic shock. The definitions and the clinical use of these terms are aimed at highlighting the fact that sepsis is the primary cause of death associated with infection and that quick action due to the substantial potential lethality associated with sepsis is essential. As such, in the Sepsis-3 consensus definitions, sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection.10 Septic shock is defined as a subset of sepsis in which underlying circulatory and cellular metabolism abnormalities are profound enough to substantially increase mortality.10 The task force emphasis on organ dysfunction is reflective of cellular and metabolic defects within organ systems; with these definitions and conceptual models, the term severe sepsis becomes redundant and was abandoned in Sepsis-3 (Box 90.1).

Sepsis and septic shock are common causes of morbidity and mortality in both people and animals. In one systematic review aimed at summarizing the epidemiological information about sepsis in people, investigators estimated 31.5 million cases of sepsis worldwide, with potentially 5.3 million deaths annually, with data severely lacking in low- and middle-income countries.2 The incidence of sepsis in veterinary medicine is unknown, but the mortality rates appear to be high, ranging from 20% to 70% or more.3-8 The incidence of sepsis is increasing in human health care, likely because of advanced and invasive treatments, widespread use of antimicrobials, increased incidence of resistant infections, the recent COVID-19 pandemic, and increased numbers of elderly, debilitated, and immunocompromised patients.9 Early recognition, aggressive intervention, and intensive supportive care are key to the treatment of sepsis and septic shock.

CURRENT SEPSIS DEFINITIONS In 2016, through a process of evidence review and evaluation, the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) were published for use in people10 in an effort to improve the understanding of the differentiation between infection and sepsis and to incorporate new understanding of the pathobiology of sepsis. Though a similar process and consensus have not been achieved for sepsis in veterinary medicine, several of the “drivers” behind updating the definitions are of interest and importance to the veterinary community. For instance, the task force unanimously agreed that the previous use of systemic inflammatory response syndrome (SIRS) criteria was unhelpful in defining sepsis in people. As in human medicine, animals may manifest changes in SIRS criteria,5 e.g., white blood cell count, heart rate, temperature, in response to infection or other insults; similarly, an array of comorbidities, medications, and differences in immune response may not lead to such response(s). As such, SIRS criteria

PATHOBIOLOGY OF SEPSIS In the past, the clinical syndrome of sepsis was seen on a continuum that paralleled the host inflammatory response of both human and veterinary patients; thus SIRS criteria were at the heart of sepsis identification and definitions. An evolving understanding of the pathobiology of sepsis now conceptualizes the syndrome in terms of changes

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BOX 90.1  Definitions of Sepsis and Septic

Shock

1

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Septic shock is defined as a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality. Patients with septic shock can be identified with a clinical construct of sepsis with persisting hypotension requiring vasopressors to maintain a mean arterial pressure 65 mm Hg and having a serum lactate level .2 mmol/L (18 mg/dl) despite adequate volume resuscitation.

that may be present with regards to organ function, biochemistry and cell biology, immunology, and neurologic, circulatory and microcirculatory function. There is also increasing emphasis on the biological and clinical heterogeneity, or the sepsis phenotype of affected individuals. Thus, clinical manifestations, course and severity of disease, and prognosis in patients with sepsis ultimately depend on a wide variety of host and pathogen factors, as well as epigenetic mechanisms, and can therefore be complicated.11 Current understanding of pathobiology of sepsis based on clinical and experimental studies in people and in animals involve a model of deranged homeostatic mechanisms responsible for regulating the immune and neurohumoral response and along with loss of barrier functions.12,13 A recent area of investigation has examined the role of the gastrointestinal tract in the development, maintenance, and outcome of sepsis.14 Research in this area is likely to shed much light on the pathogenesis and treatment of sepsis in the future.

Loss of Immunoregulatory Homeostatic Mechanisms in Sepsis The innate immune system perceives invading pathogens by recognizing pathogen-associated molecular patterns (PAMPs), which are pathogenassociated molecular ligands that can bind host through a variety of pattern recognition receptors (PRRs). The pathogen load, virulence, and PAMPs are among pathogen factors that affect the extent and direction of the inflammatory response. On the host side, genetic characteristics, age, coexisting illnesses, and medications contribute. The innate immune response usually clears the pathogen; however, when it does not, the host response itself can be sustained and harmful. There is variability in the type and extent of response; for example, lipopolysaccharide (LPS) from Gram-negative bacteria is recognized as a very potent stimulus of the host immune response (see Chapter 91, Bacterial Infections). Tissue injury from infectious (and noninfectious) insults result in the release of damage-associated molecular patterns (DAMPs, also known as alarmins), which in turn are recognized by and further activate PRRs, thereby giving rise to a cycle of sustained immune activation and tissue damage.12 Alarmins are also in play in sterile inflammation and tissue trauma, suggesting that infectious and noninfectious organ damage may be, in some ways, quite similar. Translocation of nuclear factor-kB (NFkB) into the nucleus of the cell and subsequent activation of genetic transcription of a variety of pro- and antiinflammatory cytokines is critical to the host immune response. In the broadest sense, the proinflammatory response leads to activation of leukocytes, complement, and coagulation systems, and the antiinflammatory response leads to inhibition of proinflammatory cytokines, impairment of immune cell function, and inhibition of proinflammatory gene transcription.15 Of note, the role of the neuroendocrine system is more well understood and appreciated in the context of the pathobiology of sepsis. As with other neural pathways, the neuroendocrine homeostatic mechanisms

involved in the inflammatory response include an afferent (sensor) and efferent (effector) reflex that modulates the extent and direction of the immune response, or the inflammatory reflex13 or the neuroinflammatory reflex.12 Pathways along the afferent arm of the system include afferent neuronal pathways, cytokine transit across the blood–brain barrier to influence the pituitary gland output, and cytokine production by cells of the central nervous system themselves.13 The efferent arm effects immune modulation via the splenic nerve via the vagus nerve and coeliac plexus, resulting in norepinephrine and dopamine release that may enhance or suppress the cytokine release depending on the receptors that are activated. A host of factors and hormones can be involved in this reflex, including thyroid-stimulating hormone, adrenocorticotropic hormone, and glucocorticoids among many others.13

Dysregulation of Inflammation and Coagulation Sepsis is associated with disrupted homeostasis of the coagulation system, resulting in a net procoagulant state, at least early on. This is a result of several broad mechanisms, including increased tissue factor-mediated thrombin production, impaired fibrinolysis, and dysfunctional endogenous anticoagulant mechanisms. Bacterial infection and host inflammatory cytokines upregulate tissue factor (TF) levels; TF then combines with factor VIIa to initiate the coagulation cascade.12,16 The TF-fVIIa complex and its downstream products (i.e., thrombin) can also trigger the elaboration of inflammatory cytokines and platelet activation.12,16 Normally, initiation of the coagulant pathway causes a counterregulatory activation of fibrinolytic and anticoagulant pathways to maintain hemostasis without excessive thrombosis. In septic patients, however, natural anticoagulant and fibrinolytic processes (as well as other complex processes) are inhibited via downregulation of antithrombin, tissue factor pathway inhibitor (TFPI), and tissue plasminogen activator (tPA) and increased plasminogen activator inhibitor (PAI-1).12,16 Normally, the anticoagulant properties of antithrombin and TFPI are augmented by the presence and function of the endothelial glycocalyx; disruption of this endothelial layer in septic patients is present and contributes to the procoagulant state.12 The protein C/S pathway is also inhibited, leading to a reduction of the normal activated protein C anticoagulant and antiinflammatory effects. Platelets also play a major role in this procoagulant state. Platelets exacerbate expression of procoagulant products such as TF, factor Va, and VIIIa; express the fibrinogen receptor; recruit additional platelets; and serve as part of the support structure of clots.17 The hemostatic balance in septic patients, therefore, favors the procoagulant and antifibrinolytic state initially. Progression over time to a hypocoagulable state depends on host protein synthesis, effectiveness of natural coagulation inhibitors, virulence of the invading organism, and resolution of the inflammatory source (see Chapters 101 and 104, Hypercoagulable States and Coagulopathy in the ICU, respectively). Hemostatic dysfunction has been reported in septic dogs and cats.17-19 One study showed that septic dogs had significantly lower protein C levels and antithrombin (AT) activities and higher prothrombin time, partial thromboplastin time, d-dimer, and fibrin(ogen) degradation products than did controls.20 In a prospective study of dogs with naturally occurring septic peritonitis, lower AT activity, lower protein C, and less hypercoagulable thromboelastograms were associated with decreased survival.19 Dogs with naturally occurring parvoviral enteritis had decreased AT activity and increased maximum amplitude on the thromboelastogram, consistent with hypercoagulability.21 Clinicopathologic testing may identify these and other hematologic and hemostatic changes.5,17,19,20,22,23 Septic cats were found to have higher activated partial thromboplastin times and ddimer concentrations, as well as lower total protein C and antithrombin activities, than healthy cats.24 There was no relationship between these

CHAPTER 90  Sepsis and Septic Shock values and risk of death, and disseminated intravascular coagulation (DIC) was uncommon in septic cats (4/22 cats).24

Loss of Barrier Function: Endothelial, Microcirculatory, and Mitochondrial Dysfunction A hallmark of sepsis and septic shock is the development of a positive fluid balance; this is a known negative prognostic indicator and is thought to be due to loss of barrier function between the intravascular and interstitial compartments; however, this is not the only barrier that is compromised in sepsis. The current conceptual models include loss of barrier function more generally, including endothelial and epithelial cells throughout the body, in addition to the mitochondrial membranes. This barrier incompetency is implicated in organ dysfunction. Alterations in the endothelial surface layer, increased vascular permeability, and microcirculatory derangements can be caused by many different and complicated mechanisms, including endothelial dysfunction,25,26 alterations and damage to the endothelial glycocalyx layer,27 rheologic changes to red blood cells,28 leukocyte activation, microthrombosis, and loss of vascular smooth muscle autoregulation.29,30 The overall regulation of vascular permeability is complicated (see Chapter 11, Interstitial Edema). The decreased functional capillary density, increased diffusional distance for oxygen, and heterogenous microvascular blood flow all lead to alterations in tissue oxygen extraction and tissue hypoxia.31 Importantly, serious microcirculatory disturbances can occur prior to changes in macrohemodynamic variables (e.g., blood pressure); this disconnect between systemic hemodynamics and microcirculatory perfusion, also known as cryptic shock, is characteristic of septic patients.32 Microcirculatory improvement over the course of hospitalization has also been correlated with decreased mortality rates.33-36 The revised Starling equation that followed the discovery of the endothelial glycocalyx explains how the vascular endothelial lining plays a vital role in maintaining the vascular to interstitial barrier; the colloid osmotic pressure difference between the capillary blood and interstitium is of less importance than the gradient between the capillary blood and subglycocalyx space.37,38 The delicate vascular endothelial lining that is now known as the endothelial glycocalyx comprises proteoglycans and glycosaminoglycans and plays many roles in the processes of inflammation, permeability, and mechanotransduction (see Chapter 9, Endothelial Surface Layer).39 Endothelial dysfunction and glycocalyx shedding often occur early in septic patients, thus leading to further activation of coagulation, capillary leakage, and upregulation of adhesion molecules and neutrophil adherence.25,26 One can think of the microvasculature itself as an organ, subject to injury and dysfunction and failure in sepsis, just as the heart, kidneys, and brain (and others) can become dysfunctional. There are likely regional and temporal differences in microcirculatory function and dysfunction. Areas that are very dysfunctional contribute to arteriovenous shunting due to functional and mechanical obstruction; the associated tissue suffers from a hypoxic insult. The dysfunctional endothelium has been proposed as the “motor” of multiple organ dysfunction syndrome. Both in vivo video microscopy and sidestream dark-field microscopy have been used to directly or indirectly visualize the microcirculation and endothelial glycocalyx.40,41 A strong association between the sublingual microcirculation and endothelial glycocalyx properties was found in a population-based prospective cohort study in people.42 Numerous methods for measurement of glycocalyx damage have been studied in experimental models, including measurement43 of transmembrane proteins (e.g., thrombomodulin and adhesion molecules), extracellular vesicles, circulating endothelial progenitor cells, and circulating glycocalyx components (e.g., syndecan-1, endocan, and heparan sulfate).

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Even if the microcirculation is functional, mitochondrial changes and metabolic down regulation may still occur secondary to sepsis.44,45 Mitochondria themselves can become dysfunctional in septic patients (termed cytopathic hypoxia), which contributes further to heterogenous hypoxic tissue beds.44,46 In addition to their critical role in oxidative phosphorylation, mitochondria are also involved in apoptotic pathways and cell death.

Loss of Vasomotor Tone In patients with sepsis and septic shock, loss of the normal homeostatic balance between endogenous vasoconstrictors and vasodilators occurs results in dysregulation of vasomotor tone. Overproduction of nitric oxide (NO) during sepsis is a major contributing factor.47 NO is a powerful vascular smooth muscle relaxant that contributes to the vasodilatory state of patients with septic shock, leading to clinical signs such as hyperemic mucous membranes, short capillary refill time, and tachycardia in dogs and in people.5,22,47-49 Cats do not typically display the hyperemic, hyperdynamic state; rather they experience bradycardia, hypotension and hypothermia.23,50,51 In response to stimulation with endotoxin, TNF-a, IL-1, or platelet-activating factor, inducible nitric oxide synthase accumulates and generates high levels of NO, thereby contributing to signs of vasodilatory shock.47,52 In one prospective observational study in dogs, the NO breakdown products nitrate/nitrite in plasma were significantly greater in septic dogs or in dogs with SIRS than in healthy controls.53

DIAGNOSIS Sepsis is, at present, a syndrome without a validated standard diagnostic test. Studies in both human and veterinary medicine are seeking to identify reliable and specific biomarkers of infection and inflammation that can be used to identify infection and sepsis, to assess the host inflammatory response to infection, to identify organ dysfunction, and to prognosticate. Given that clinical criteria of systemic inflammation such as temperature, heart rate, respiratory rate, and white blood cell count lack specificity (many nonseptic patients can fit the criteria and many septic patients do not), use of these criteria alone rarely dictate interventions but can help increase the index of suspicion for sepsis. One should also bear in mind that patients with diseases or treatments that cause immune suppression may not only be more at risk for sepsis but may also not show typical clinical signs, thus the index of suspicion should be adjusted accordingly. It should be noted that though bacteria are the most commonly recognized type of pathogen associated with sepsis, viral, fungal and even protozoal sepsis also occurs. The most common hematologic abnormalities noted with sepsis in small animals include leukocytosis, leukopenia, increased percentages of bands, toxic neutrophils, thrombocytopenia, and coagulation abnormalities. Cats are frequently anemic, and may even have metarubricytes, whereas dogs will often have an elevated hematocrit reflecting hemoconcentration secondary to volume depletion, splenic contraction, or a combination of both.24 Changes in the serum biochemistry panel are typically reflective of the underlying disease process. With progression of disease, the biochemical profile may reveal evidence of organ dysfunction. Variable abnormalities in blood glucose are common in dogs and cats with sepsis. Decreased serum albumin occurs frequently in septic animals, likely due to loss of albumin (either lost from the body or into interstitial spaces resulting from vascular permeability), hepatic dysfunction, or preferential synthesis of acute phase proteins by the liver. Mild to moderate hyperbilirubinemia may be present and is thought to occur secondary to cholestasis in dogs and possibly hemolysis in cats.54 Ionized hypocalcemia is not uncommon in dogs and cats with sepsis and has been associated with mortality risk in dogs.55-56 Coagulation testing may reveal abnormalities associated with DIC such as prolonged

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prothrombin time and partial thromboplastin time, decreased antithrombin and protein C, and elevated D-dimers and fibrinogen/fibrin degradation products. Many patients will have a metabolic acidosis reflecting poor tissue perfusion secondary to hypovolemia and increases in lactate. Hypoperfusion may also lead to a pre-renal azotemia, elevated alanine aminotransferase, and decreased urine output. Sepsis biomarkers have not been shown to be consistently dependable as a diagnostic or prognostic aid in septic dogs and cats. Felines with sepsis have been found to have elevations of TNF, IL-6, IL-8, serum amyloid A,57 keratinocyte chemoattractant-like (KC-like), and regulated upon activation, normal T-cell expressed and secreted (RANTES), although none are consistently predictive of mortality.58 Studies examining dogs with sepsis have similarly found a decrease in IL-1059 and adinopectin60 and increases in concentrations of IL-6,61,62 procalcitonin,63 TNF, NT-pro C-type natriuretic peptide,64 cell-free DNA, C-X-C motif chemokine, KC-like, C-C motif chemokine ligand, nitrate/nitrite,65,66 and high mobility group box-1,67 although their ability to differentiate between septic from nonseptic dogs is not well determined.59 Variable results regarding the use of these markers for survival prediction have also been found, although procalcitonin clearance and IL-6 levels may prove useful as a prognostic indicator.68 Effusion biomarkers may also hold promise for differentiating septic from nonseptic peritonitis.69 In the current Surviving Sepsis Campaign Guidelines, organ dysfunction is defined as an acute change in total sequential organ failure assessment (SOFA) score of 2 points consequent to infection; however, given the complexity and variability of illness severity scoring systems, the task force also recommended a simple way of identifying patients who were at risk of a prolonged ICU stay or death in hospital, the qSOFA score, which includes altered mental status, systolic blood pressure of # 100 mm Hg, or respiratory rate of  22 breaths per minute. Human patients with septic shock can be identified as those displaying signs of sepsis, but with persisting hypotension requiring vasopressors to maintain a mean arterial blood pressure (MAP) 65 mm Hg and a serum lactate level of .2.0 mmol/L, despite adequate volume resuscitation. Note that the mortality rate of people reaching these criteria is greater than 40%.10 Studies in veterinary patients report similar mortality rates with a range in cats and dogs of 20%–71%.5,20,70-73

RESUSCITATION AND TREATMENT OF SEPSIS AND SEPTIC SHOCK Introduction to the Bundle Concept Major improvements in outcome in septic human patients have been accomplished through use of sepsis treatment bundles. A bundle of care refers to a group of therapies that, when instituted together, result in better outcomes than if each individual component were to be implemented alone.74 Evidence-based guidelines for sepsis management are published in the Surviving Sepsis Campaign Guidelines and have gone through several updates, most recently the 2018 Surviving Sepsis Guidelines in which the previous (2016) 3- and 6-hour bundles were combined into a single “hour-1 bundle” with the aim of beginning resuscitation immediately.75 This update shifted the focus to a more realistic clinical experience of management beginning immediately rather than extending resuscitation measures over longer periods. Although there is still controversy regarding the best individual bundle components, evidence and expert consensus suggests that implementation of a sepsis bundle reduces mortality76 and that the important components include fluid resuscitation, administration of antimicrobials, collection of samples for culture and lactate measurement, and possibly initiation of vasopressor therapy. Enthusiasm remains for the bundle approach (even in veterinary medicine), and it stands to reason

BOX 90.2  Key Strategies for Treatment of the Septic Patient • Judicious fluid resuscitation • Source control and acquisition of samples for culture and susceptibility testing • Early empiric antimicrobial therapy • Vasopressor and/or inotropic therapy, as indicated • Physiologic corticosteroid supplementation, as indicated • Diligent monitoring of vital parameters, physical examination and body weight changes, point-of-care ultrasound, organ function, and laboratory indices

that the same approach may improve outcomes in veterinary patients, although data are lacking.77-79 Box 90.2 lists general treatment strategies for treatment of the septic dog or cat.

Bundle Element: Lactate Lactate production is a result of anaerobic metabolism, most commonly as a result of hypoperfusion, increased circulating catecholamines and sometimes by the underlying process itself. Some studies show that high initial lactate levels are associated with poorer outcomes, particularly if the hyperlactatemia persists and/or is accompanied by hypotension.80-86 However, lactate clearance as it relates to traditional (e.g., blood pressure) and more recent (e.g., ScvO2) parameters remain unclear. The 2018 hour-1 update of the Surviving Sepsis Campaign Guidelines recommends measuring lactate within the first hour of admission and, if the initial lactate is elevated (. 2.0 mmol/L), then it should be remeasured within 2–4 hours and resuscitation continued until normalized. The available veterinary literature, though minimal, along with widespread clinical experience and expertise, supports this recommendation (see Chapter 61, Hyperlactatemia).77,80,81

Bundle Element: Samples for Culture (Blood, Tissue, or Fluid Cultures) In human health care, obtaining blood cultures in patients with sepsis or suspected sepsis is the standard of care, and blood cultures are positive in 30% to 50% of patients with severe sepsis or septic shock.87 In veterinary medicine, blood cultures seem to be less routinely performed. In one study, however, 49% of critically ill dogs and cats had positive blood cultures.88 Another study reported that 43% of dogs with gastric dilation and volvulus developed positive blood cultures.89 The importance of obtaining samples for culture to aid in selection (and refinement) of antimicrobial therapy cannot be overemphasized; however, obtaining the samples should not cause a delay in initiating resuscitation nor put the patient at risk. There are clearly cases where obtaining cultures would be dangerous or impractical within the first hour of management. It is unclear as to how quickly samples will become sterile after a single dose of antibiotics; in people samples for blood culture have been shown to become sterile quickly (i.e., minutes),90 but the relevance of this finding in the veterinary context is unclear. Regardless, it is crucial not to delay initiation of appropriate antimicrobial therapy to collect samples (see Chapter 172, Antimicrobial Use in the Critical Care Patient).

Bundle Element: Early Antibiotic Administration and Source Control Of paramount importance in treating the septic patient is early administration of parenteral antimicrobials to cover any possible organism, and the identification and removal of the septic focus (source control). In human patients with septic shock, elapsed time from shock recognition and qualification for early goal-directed therapy to appropriate

CHAPTER 90  Sepsis and Septic Shock antimicrobial therapy has been shown to be a primary determinant of mortality.91-93 Thus, for many years now, early, parenteral and broadspectrum antimicrobial therapy is now conceptually bundled with more traditional aspects of resuscitation such as hemodynamic stabilization in patients with sepsis and septic shock. Studies in veterinary patients have also shown the feasibility of achieving timely administration of antibiotics;94 animals that receive appropriate empirical antimicrobial therapy may be more likely to survive,51,70 although some studies did not show a difference in survival related to appropriateness of antibiotic therapy. 94,95 It is important to bear in mind that other factors may affect response, i.e., the importance of effective source control and lavage in surgical sepsis, or the in vitro vs in vivo effects of the selected antibiotic(s) and patient variation and comorbidities, in addition to epidemiologic factors. Epidemiologic information regarding sepsis is available and describes common sources and pathogens in dogs and cats (see Chapter 91, Bacterial Infections). Common causes of sepsis in both species include septic peritonitis, urosepsis, pleural space disease, and pneumonia. The most common sources of septic peritonitis in dogs are the gastrointestinal tract and hepatobiliary systems.51,95,96 Gastrointestinal leakage is also common in cats; however, primary septic peritonitis, in which an infectious focus is not identified at exploratory laparotomy, is not uncommon.6,23,51 Leakage of contents from the gastrointestinal tract most commonly occurs secondary to ingestion of foreign bodies (and subsequent perforation), gastrointestinal neoplasia, dehiscence of biopsy sites, enterotomies or resected intestine, and nonsteroidal antiinflammatory drug (NSAID)–associated perforation. Other causes of septic peritonitis include contamination from the hepatobiliary system, urinary bladder, gallbladder, or uterus, foreign body (e.g., grass awn) migration, abscess formation (e.g., hepatic, renal, lymph node, splenic), and penetrating wounds. Aside from septic peritonitis, other common causes of sepsis include bite wounds, pneumonia, pyothorax, and pyelonephritis. Less common causes include septic arthritis, deep pyoderma, bacterial endocarditis, tick-borne diseases, septic meningitis, osteomyelitis, severe dental disease, and bacterial prostatitis. Gram-negative enteric bacteria are commonly identified organisms in sepsis in dogs and cats; however, mixed infections and Gram- positive infections are also common; Enterococcus, Clostridium, and Streptococcus spp. are commonly identified.23,51,95,97,98 In cats with either primary or secondary septic peritonitis, Gram-negative organisms were identified in approximately 55% of cases and Gram-positive organisms in about 40% of cases.51 Septic patients require an empiric broad-spectrum combination antimicrobial regimen directed at the most likely bacterial pathogens that is administered via the intravenous route (see Part XIX, Antimicrobial Therapy, Chapters 172–177). The terminology and definitions used by the Surviving Sepsis Campaign are valuable when selecting antibiotic(s) since determination of appropriate antimicrobials for a given patient is often challenging and should consider the location of the infection (and the ability of the antibiotic to penetrate the site) and the suspected bacterial pathogen(s).76 Drug selection should also take into account the possibility of multidrug-resistant pathogens, such as community source versus a nosocomial infection, duration of hospitalization, and previous exposure to antimicrobials (see Chapter 172, Antimicrobial Use in the Critical Care Patient). The chances of acquiring a nosocomial infection (potentially with multidrug- resistant bacteria) increase in patients that are hospitalized, so careful consideration of hospital antibiograms should be employed when choosing empiric antimicrobial therapy.99 Combination therapy, which involves the use of multiple bactericidal antibiotics,76 usually with different mechanistic actions aimed at rapid clearance of a known or suspected pathogen(s), should be considered for patients with high mortality risk.

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Early de-escalation, in particular when using combination therapy, should be considered after patient stabilization and possibly before susceptibility results are available.76,100 Overall, the Surviving Sepsis Campaign Guidelines state that most infections, even severe ones, can be treated in 7–10 days. This is particularly true when source control has been achieved and is likely relevant to septic veterinary patients.

Bundle Element: Assessment of Volume Status, Fluid Choices, and Vasopressor Therapy Because septic shock patients are, by definition, in circulatory collapse despite volume resuscitation, cardiovascular support is of key importance. Fluid therapy is essential to maintain adequate tissue oxygen delivery and prevent the development of multiple organ dysfunction syndrome (MODS) and death (see Chapter 68, Shock Fluid Therapy). The assessment of volume status and the potential for volume responsiveness is often challenging. Traditionally, static measures to indirectly measure preload, such as pulmonary artery occlusion pressure (PAOP) and central venous pressure (CVP), have been used. However, they can be cumbersome (PAOP) and not predictive of volume responsiveness (CVP).101 Dynamic measures of fluid responsiveness may include point-of-care ultrasound evaluation of the heart and vena cava diameter as well as pulse pressure variation, systolic pressure variation, and stroke volume variation in ventilated patients (see Chapter 64, Assessment of Intravascular Volume).102,103 Frequent monitoring of body weight is useful in the assessment of volume status. The first line of resuscitation in septic patients is fluid therapy. Isotonic crystalloids, hypertonic crystalloid solutions, synthetic colloids, and blood component therapy may be used for fluid therapy in the septic patient. The choice of fluids depends on the overall clinical and clinicopathologic picture as well as owner resources (see Chapter 68, Shock Fluid Therapy). The need for, and efficacy of, colloid therapy in patients with hypoproteinemia is controversial given recent insights into the endothelial glycocalyx and revised Starling equation (see Chapters 9 and 11, Endothelial Surface Layer and Interstitial Edema, respectively). The cost and potential side effects associated with human or canine albumin administration have made the use of synthetic colloids more popular in veterinary medicine than in human medicine, although their safety in septic veterinary patients remains an area of potential concern and further research is necessary (see Chapter 66, Colloid Solutions, for further details). The use of blood products for severely anemic or coagulopathic patients should be considered, when indicated (see Chapters 69, 104, 106, Transfusion Medicine, Coagulopathy in the ICU, and Anemia in the ICU, respectively). Hypotension that persists after restoration of intravascular volume (septic shock) is an indication for vasopressors or inotropic agents to support flow to tissues (see Chapters 147 and 148, Catecholamines and Vasopressin, respectively). A target MAP of 65 mm Hg has been recommended during or after the initial resuscitation of patients with septic shock based on the 2016 Surviving Sepsis Guidelines (strong recommendation, moderate quality of evidence), although patients with chronic systemic hypertension may require higher MAP targets.104 Earlier research did not find a mortality benefit when using a target MAP of 80–85 mm Hg,105 although a more recent retrospective analysis found a progressively increased risk for mortality, acute kidney injury, and myocardial injury in septic patients with MAP thresholds lower than 85 mm Hg.106 The decision to use a vasopressor or cardiotonic drug depends on the clinical presentation and objective information obtained from the septic patient (e.g., assessment of cardiac contractility). Vasopressors such as norepinephrine, vasopressin, dopamine, and epinephrine are most commonly used in patients with peripheral vasodilation (Table 90.1).107,108 Norepinephrine is preferred to dopamine in septic human patients, and vasopressin is also considered a reasonable first-line vasopressor.104

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TABLE 90.1  Commonly Used Constant

Rate Infusion Vasopressor Therapy

a

Vasopressor

Dose Rate

Norepinephrine

0.1–1 mcg/kg/min IV

Epinephrine

0.05–1 mcg/kg/min IV

Vasopressin

0.5–5 mU/kg/min IV

Dopamine

5–15 mcg/kg/min IV

See Chapters 147 and 148, Catecholamines and Vasopressin, respectively, for further details.

a

Studies in septic veterinary patients are ongoing; one study in experimental dogs with sepsis found both norepinephrine and vasopressin to have better risk: benefit profiles than epinephrine.109 Although vasopressors may improve arterial blood pressure, they can also result in excessive vasoconstriction, particularly to the splanchnic and renal circulation, thereby causing gastrointestinal and renal ischemia. Positive inotropic agents such as dobutamine are generally used in patients with evidence of impaired myocardial contractility (decreased fractional shortening on M-mode echocardiography, decreased cardiac output per invasive, or noninvasive measurements). They might also be combined with more selective vasoconstrictors such as vasopressin or phenylephrine.

PROGNOSIS The prognosis for septic humans and veterinary patients depends on several factors, including the overall health of the patient, genetic predispositions, early diagnosis, disease severity, presence of multiorgan involvement, and treatment options.4,7,8,62,110 The presence of cardiovascular instability upon presentation may increase the odds ratio for mortality in felines with sepsis,111 and failure to normalize blood pressure with fluid resuscitation in the emergency room is a poor prognostic indicator in dogs.112 The presence of MODS is a poor prognostic indicator in both dogs and cats.3,111 Although mortality rates in small animals vary considerably in the literature (20%–70%), many studies do not differentiate between natural death versus euthanasia. As mentioned above, the use of sepsis biomarkers as indicators of sepsis, prognostic aids, and markers of treatment success may improve the veterinarian’s ability to diagnose, prognosticate, and appropriately treat patients in the future.

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CHAPTER 90  Sepsis and Septic Shock 34. Edul VS, Enrico C, Laviolle B, et al: Quantitative assessment of the microcirculation in healthy volunteers and in patients with septic shock, Crit Care Med 40:1443-1448, 2012. 35. Trzeciak S, Dellinger RP, Parrillo JE, et al: Early microcirculatory perfusion derangements in patients with severe sepsis and septic shock: relationship to hemodynamics, oxygen transport, and survival, Ann Emerg Med 49: 88-98.e2, 2007. 36. Hernandez G, Boerma EC, Dubin A, et al: Severe abnormalities in microvascular perfused vessel density are associated to organ dysfunctions and mortality and can be predicted by hyperlactatemia and norepinephrine requirements in septic shock patients, J Crit Care 28:538.e9-e14, 2013. 37. Woodcock TE, Woodcock TM: Revised Starling equation and the glycocalyx model of transvascular fluid exchange: an improved paradigm for prescribing intravenous fluid therapy, Br J Anaesth 108:384-394, 2012. 38. Levick JR, Michel CC: Microvascular fluid exchange and the revised Starling principle, Cardiovasc Res 87:198-210, 2010. 39. Henrich M, Gruss M, Weigand MA: Sepsis-induced degradation of endothelial glycocalix, ScientificWorldJournal 10:917-923, 2010. 40. Goedhart PT, Khalilzada M, Bezemer R, et al: Sidestream Dark Field (SDF) imaging: a novel stroboscopic LED ring-based imaging modality for clinical assessment of the microcirculation, Opt Express 15: 15101-15114, 2007. 41. Donati A, Damiani E, Domizi R, et al: Alteration of the sublingual microvascular glycocalyx in critically ill patients, Microvasc Res 90:86-89, 2013. 42. Lee DH, Dane MJ, van den Berg BM, et al: Deeper penetration of erythrocytes into the endothelial glycocalyx is associated with impaired microvascular perfusion, PLoS One 9:e96477, 2014. 43. Graham JK, Stacy K: Mitochondrial dysregulation in sepsis: a literature review, Clin Nurse Spec 34:170-177, 2020. 44. Levy RJ: Mitochondrial dysfunction, bioenergetic impairment, and metabolic down-regulation in sepsis, Shock 28:24-28, 2007. 45. Ince C, Mik EG: Microcirculatory and mitochondrial hypoxia in sepsis, shock, and resuscitation, J Appl Physiol (1985) 120:226-235, 2016. 46. Fink MP: Cytopathic hypoxia. Mitochondrial dysfunction as mechanism contributing to organ dysfunction in sepsis, Crit Care Clin 17:219-237, 2001. 47. Fernandes D, Assreuy J: Nitric oxide and vascular reactivity in sepsis, Shock 30(Suppl 1):10-13, 2008. 48. Aird WC: Endothelium in health and disease, Pharmacol Rep 60:139-143, 2008. 49. Brady CA, Otto CM: Systemic inflammatory response syndrome, sepsis, and multiple organ dysfunction, Vet Clin North Am Small Anim Pract 31:1147-1162, v-vi, 2001. 50. Brady CA, Otto CM, Van Winkle TJ, et al: Severe sepsis in cats: 29 cases (1986-1998), J Am Vet Med Assoc 217:531-535, 2000. 51. Scotti KM, Koenigshof A, Sri-Jayantha LSH, et al: Prognostic indicators in cats with septic peritonitis (2002–2015): 83 cases, J Vet Emerg Crit Care 29:647-652, 2019. 52. De Kock I, Van Daele C, Poelaert J: Sepsis and septic shock: pathophysiological and cardiovascular background as basis for therapy, Acta Clin Belg 65:323-329, 2010. 53. Osterbur K, Whitehead Z, Sharp CR, et al: Plasma nitrate/nitrite concentrations in dogs with naturally developing sepsis and non-infectious forms of the systemic inflammatory response syndrome, Vet Rec 169:554, 2011. 54. Troìa R, Gruarin M, Foglia A, et al: Serum amyloid A in the diagnosis of feline sepsis, J Vet Diagn Invest 29:856-859, 2017. 55. Luschini MA, Fletcher DJ, Schoeffler GL: Incidence of ionized hypocalcemia in septic dogs and its association with morbidity and mortality: 58 cases (2006-2007), J Vet Emerg Crit Care 20(4):406-412, 2010. doi:10.1111/j.1476-4431.2010.00553.x. 56. Kellett-Gregory LM, Mittleman Boller E, Brown DC, Silverstein DC: Ionized calcium concentrations in cats with septic peritonitis: 55 cases (1990-2008), J Vet Emerg Crit Care 20(4):398-405, 2010. doi:10.1111/j. 1476-4431.2010.00562.x. 57. Troia R, Mascalzoni G, Agnoli C, et al: Cytokine and chemokine profiling in cats with sepsis and septic shock, Front Vet Sci 7:305, 2020. 58. Declue AE, Delgado C, Chang CH, et al: Clinical and immunologic assessment of sepsis and the systemic inflammatory response syndrome in cats, J Am Vet Med Assoc 238:890-897, 2011.

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59. DeClue AE, Sharp CR, Harmon M: Plasma inflammatory mediator concentrations at ICU admission in dogs with naturally developing sepsis, J Vet Intern Med 26:624-630, 2012. 60. Torrente C, Manzanilla EG, Bosch L, et al: Adiponectin as a sepsis biomarker in dogs: diagnostic and prognostic value, Vet Clin Pathol 49: 333-344, 2020. 61. Goggs R, Letendre JA: Evaluation of the host cytokine response in dogs with sepsis and noninfectious systemic inflammatory response syndrome, J Vet Emerg Crit Care (San Antonio) 29:593-603, 2019. 62. Rau S, Kohn B, Richter C, et al: Plasma interleukin-6 response is predictive for severity and mortality in canine systemic inflammatory response syndrome and sepsis, Vet Clin Pathol 36:253-260, 2007. 63. Goggs R, Milloway M, Troia R, et al: Plasma procalcitonin concentrations are increased in dogs with sepsis, Vet Rec Open 5:e000255, 2018. 64. DeClue AE, Osterbur K, Bigio A, et al: Evaluation of serum NT-pCNP as a diagnostic and prognostic biomarker for sepsis in dogs, J Vet Intern Med 25:453-459, 2011. 65. Osterbur K, Whitehead Z, Sharp CR, et al: Plasma nitrate/nitrite concentrations in dogs with naturally developing sepsis and non-infectious forms of the systemic inflammatory response syndrome, Vet Rec 169:554, 2011. 66. Torrente C, Manzanilla EG, Bosch L, et al: Adiponectin as a sepsis biomarker in dogs: diagnostic and prognostic value, Vet Clin Pathol 49:333-344, 2020. 67. Yu DH, Nho DH, Song RH, et al: High-mobility group box 1 as a surrogate prognostic marker in dogs with systemic inflammatory response syndrome, J Vet Emerg Crit Care (San Antonio) 20:298-302, 2010. 68. Troia R, Giunti M, Goggs R: Plasma procalcitonin concentrations predict organ dysfunction and outcome in dogs with sepsis, BMC Vet Res 14:111, 2018. 69. Martiny P, Goggs R: Biomarker guided diagnosis of septic peritonitis in dogs, Front Vet Sci 6:208, 2019. 70. King LG: Postoperative complications and prognostic indicators in dogs and cats with septic peritonitis: 23 cases (1989-1992), J Am Vet Med Assoc 204:407-414, 1994. 71. Babyak JM, Sharp CR: Epidemiology of systemic inflammatory response syndrome and sepsis in cats hospitalized in a veterinary teaching hospital, J Am Vet Med Assoc 249:65-71, 2016. 72. Goggs R, Letendre JA: Evaluation of the host cytokine response in dogs with sepsis and noninfectious systemic inflammatory response syndrome, J Vet Emerg Crit Care 29:593-603, 2019. 73. Johnson V, Burgess B, Morley P, et al: Comparison of cytokine responses between dogs with sepsis and dogs with immune-mediated hemolytic anemia, Vet Immunol Immunopathol 180:15-20, 2016. 74. Cinel I, Dellinger RP: Guidelines for severe infections: are they useful? Curr Opin Crit Care 12:483-488, 2006. 75. Levy MM, Evans LE, Rhodes A: The surviving sepsis campaign bundle: 2018 update, Intensive Care Med 44:925-928, 2018. 76. Rhodes A, Evans LE, Alhazzani W, et al: Surviving sepsis campaign: International Guidelines for management of sepsis and septic shock: 2016, Intensive Care Med 43:304-377, 2016. 77. Silverstein D: Tornadoes, sepsis, and goal-directed therapy in dogs, J Vet Emerg Crit Care (San Antonio) 22:395-397, 2012. 78. Butler AL: Goal-directed therapy in small animal critical illness, Vet Clin North Am Small Anim Pract 41:817-838, vii, 2011. 79. Conti-Patara A, de Araujo Caldeira J, de Mattos-Junior E, et al: Changes in tissue perfusion parameters in dogs with severe sepsis/septic shock in response to goal-directed hemodynamic optimization at admission to ICU and the relation to outcome, J Vet Emerg Crit Care (San Antonio) 22:409-418, 2012. 80. Stevenson CK, Kidney BA, Duke T, et al: Serial blood lactate concentrations in systemically ill dogs, Vet Clin Pathol 36:234-239, 2007. 81. Conti-Patara A, de Araújo Caldeira J, de Mattos-Junior E, et al: Changes in tissue perfusion parameters in dogs with severe sepsis/septic shock in response to goal-directed hemodynamic optimization at admission to ICU and the relation to outcome, J Vet Emerg Crit Care 22:409-418, 2012. 82. Puskarich MA, Trzeciak S, Shapiro NI, et al: Prognostic value and agreement of achieving lactate clearance or central venous oxygen saturation goals during early sepsis resuscitation, Acad Emerg Med 19:252-258, 2012.

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83. Napoli AM, Seigel TA: The role of lactate clearance in the resuscitation bundle, Crit Care 15:199, 2011. 84. Nguyen HB, Rivers EP, Knoblich BP, et al: Early lactate clearance is associated with improved outcome in severe sepsis and septic shock, Crit Care Med 32:1637-1642, 2004. 85. Cortellini S, Seth M, Kellett-Gregory LM: Plasma lactate concentrations in septic peritonitis: a retrospective study of 83 dogs (2007-2012), J Vet Emerg Crit Care 25:388-395, 2015. 86. Jansen TC, Van Bommel J, Schoonderbeek FJ, et al: Early lactate-guided therapy in intensive care unit patients: a multicenter, open- label, randomized controlled trial, Am J Respir Crit Care Med 182: 752-761, 2010. 87. Angus DC, Linde-Zwirble WT, Lidicker J, et al: Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care, Crit Care Med 29:1303-1310, 2001. 88. Dow SW, Curtis CR, Jones RL, et al: Bacterial culture of blood from critically ill dogs and cats: 100 cases (1985-1987), J Am Vet Med Assoc 195:113-117, 1989. 89. Winkler KP, Greenfield CL, Schaeffer DJ: Bacteremia and bacterial translocation in the naturally occurring canine gastric dilatation- volvulus patient, J Am Anim Hosp Assoc 39:361-368, 2003. 90. Zadroga R, Williams DN, Gottschall R, et al: Comparison of 2 blood culture media shows significant differences in bacterial recovery for patients on antimicrobial therapy, Clin Infect Dis 56:790-797, 2013. 91. Nguyen HB, Corbett SW, Steele R, et al: Implementation of a bundle of quality indicators for the early management of severe sepsis and septic shock is associated with decreased mortality, Crit Care Med 35:1105-1112, 2007. 92. Levy MM, Dellinger RP, Townsend SR, et al: The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis, Intensive Care Med 36:222-231, 2010. 93. Kumar A, Roberts D, Wood KE, et al: Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock, Crit Care Med 34:1589-1596, 2006. 94. Abelson AL, Buckley GJ, Rozanski EA: Positive impact of an emergency department protocol on time to antimicrobial administration in dogs with septic peritonitis, J Vet Emerg Crit Care 23:551-556, 2013. 95. Dickinson AE, Summers JF, Wignal J, et al: Impact of appropriate empirical antimicrobial therapy on outcome of dogs with septic peritonitis, J Vet Emerg Crit Care 25:152-159, 2015. 96. Barfield DM, Tivers MS, Holahan M, et al: Retrospective evaluation of recurrent secondary septic peritonitis in dogs (2000-2011): 41 cases, J Vet Emerg Crit Care 26:281-287, 2016.

97. Marshall H, Sinnott-Stutzman V, Ewing P, et al: Effect of peritoneal lavage on bacterial isolates in 40 dogs with confirmed septic peritonitis, J Vet Emerg Crit Care 29:635-642, 2019. 98. Radhakrishnan A, Drobatz KJ, Culp WT, et al: Community-acquired infectious pneumonia in puppies: 65 cases (1993-2002), J Am Vet Med Assoc 230:1493-1497, 2007. 99. Black DM, Rankin SC, King LG: Antimicrobial therapy and aerobic bacteriologic culture patterns in canine intensive care unit patients: 74 dogs (January-June 2006), J Vet Emerg Crit Care (San Antonio) 19:489-495, 2009. 100. Lakbar I, De Waele JJ, Tabah A, et al: Antimicrobial de-escalation in the ICU: from recommendations to level of evidence, Adv Ther 37:3083-3096, 2020. 101. Marik PE, Baram M, Vahid B: Does central venous pressure predict fluid responsiveness? A systematic review of the literature and the tale of seven mares, Chest 134:172-178, 2008. 102. Drozdzynska MJ, Chang YM, Stanzani G, et al: Evaluation of the dynamic predictors of fluid responsiveness in dogs receiving goal-directed fluid therapy, Vet Anaesth Analg 45:22-30, 2018. 103. Cambournac M, Goy-Thollot I, Violé A, et al: Sonographic assessment of volaemia: development and validation of a new method in dogs, J Small Anim Pract 59:174-182, 2018. 104. Rhodes A, Evans LE, Alhazzani W, et al: Surviving sepsis campaign: International Guidelines for management of sepsis and septic shock: 2016, Intensive Care Med 43:304-377, 2017. 105. Asfar P, Meziani F, Hamel JF, et al: High versus low blood-pressure target in patients with septic shock, N Engl J Med 370:1583-1593, 2014. 106. Maheshwari K, Nathanson BH, Munson SH, et al: The relationship between ICU hypotension and in-hospital mortality and morbidity in septic patients, Intensive Care Med 44:857-867, 2018. 107. Russell JA: Vasopressor therapy in critically ill patients with shock, Intensive Care Med 45:1503-1517, 2019. 108. Scheeren TWL, Bakker J, De Backer D, et al: Current use of vasopressors in septic shock, Ann Intensive Care 9:20, 2019. 109. Minneci PC, Deans KJ, Banks SM, et al: Differing effects of epinephrine, norepinephrine, and vasopressin on survival in a canine model of septic shock, Am J Physiol Heart Circ Physiol 287:H2545-H2554, 2004. 110. Hinton LE, McLoughlin MA, Johnson SE, et al: Spontaneous gastroduodenal perforation in 16 dogs and seven cats (1982-1999), J Am Anim Hosp Assoc 38:176-187, 2002. 111. Troia R, Mascalzoni G, Calipa S, et al: Multiorgan dysfunction syndrome in feline sepsis: prevalence and prognostic implication, J Feline Med Surg 21:559-565, 2019. 112. Silverstein DC, Kleiner J, Drobatz KJ: Effectiveness of intravenous fluid resuscitation in the emergency room for treatment of hypotension in dogs: 35 cases (2000-2010), J Vet Emerg Crit Care (San Antonio) 22: 666-673, 2012.

91 Bacterial Infections Stephen Cole, VMD, MS, DACVM (Bacteriology/Mycology, Immunology, Virology) KEY POINTS • Bacterial infections in small animals are commonly caused by normal flora introduced into a sterile site. They can present with a wide spectrum of clinical manifestations ranging from mild to severe. • Bacterial culture with paired antimicrobial susceptibility testing remains the gold standard to diagnose infections. Some fastidious

bacteria (i.e., Borrelia, Rickettsia, Leptospira) require alternative methods (PCR, immunoassay) to diagnose infection. • Potential for contamination should be considered when interpreting culture results. • Intensive infection prevention and appropriate use of antimicrobials are critical to the safe operation of an effective intensive care unit.

INTRODUCTION

GRAM-POSITIVE BACTERIA OF CLINICAL IMPORTANCE

Bacterial infections are common in small animals and may be the primary reason for hospitalization (e.g., leptospirosis) or a secondary complication of treatment for a noninfectious problem (e.g., catheter site infections). Bacterial infections can be monomicrobial (caused by a single organism) or polymicrobial (caused by multiple organisms). Understanding the common pathogens in the small animal ICU is important for all criticalists.

BACTERIAL STRUCTURE AND TAXONOMY Bacteria are single-celled organisms with no nucleus. They are divided into two groups based on cell wall structure. Gram-positive bacteria (purple on Gram stain) have a thick outer cell wall made of peptidoglycan and a single inner phospholipid membrane. Gram-negative bacteria (pink) have outer and inner phospholipid membranes that surround a thin layer of peptidoglycan in the periplasmic space. The outer membrane of Gram-negative bacteria is covered with lipopolysaccharide, which is a potent stimulator of the inflammatory response via Toll-like receptor 4. Another way to classify bacteria is as either aerobic or anaerobic.1-3 Table 91.1 characterizes common organisms isolated from small animals by these divisions. Bacteria are taxonomically divided by phylum, class, order, family, genus, and species. Some bacterial species are also divided into serovars/serotypes based on their antigenic properties.1-2

DIAGNOSIS OF BACTERIAL INFECTIONS Bacterial infections are diagnosed by immunoassay (e.g., enzyme-linked immunosorbent assay [ELISA], immunofluorescence assay), by molecular assay (e.g., PCR, RT-PCR), and by traditional culture. Culture remains the mainstay of bacterial diagnostics because it can often be paired with antimicrobial susceptibility testing. Contamination of cultures occurs frequently, and it is important to not overinterpret the clinical relevance of suspected contaminants. Consultation with a clinical microbiologist is recommended when atypical organisms are isolated.4

Staphylococcus spp. Bacteria of the genus Staphylococcus are normal flora of the skin and mucous membranes of animals.1-2,5 Microscopically, they often appear perfectly round and clustered. The most common species isolated from dogs include Staphylococcus pseudintermedius and S. schleiferi.5,6 In cats, S. pseudintermedius is most common. S. aureus is not a common organism isolated from companion animals but is more commonly isolated from cats than dogs.7 Isolation of S. aureus from companion animals may represent transfer from people to animals.8 Infections caused by this species of staphylococci can be mild (e.g., superficial bacterial folliculitis, otitis externa) to severe (e.g., sepsis, endocarditis, osteomyelitis).2,4,5-6 They are the most common agent of postsurgical infections, which makes them particularly important in the management of the postsurgical patient.9 S. pseudintermedius produces a urease enzyme that is involved in the pathogenesis of struvite urolithiasis.10 Treatment of infections caused by S. pseudintermedius and S. schleiferi has become particularly challenging because of the spread of methicillin-resistant strains, which are resistant to all veterinary b-lactam antimicrobials (e.g., cephalosporins, carbapenems) and are often cross resistant to other classes of antimicrobials.5,6

Streptococcus spp. Streptococcus is a genus of bacteria that contains both pathogens and normal flora of animals. They appear in chains microscopically. In the diagnostic lab, they are characterized as either beta (complete), alpha (partial), or gamma (non) hemolytic.1-3 As a rule of thumb, the beta hemolytic streptococci are most virulent. The most common species of Streptococcus isolated from dogs and cats is S. canis (group G Streptococcus) which is beta hemolytic. S. canis is normal flora of the dog. S. canis is reported to cause pneumonia, urinary tract infections, and wound infections in dogs and cats.2-4 S. canis has also been associated with toxic shock syndrome and necrotizing fasciitis in dogs.11,12 The use of fluoroquinolones is discouraged because of clinical inefficacy and potential for bacteriophage activation.13 An important emerging

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TABLE 91.1  Common Organisms Isolated from Small Animals Aerobic/Facultative Anaerobes

Strict Anaerobes

Gram Positive

Gram Negative

Staphylococcus spp. Streptococcus spp. Enterococcus spp. Nocardia spp. Mycobacterium spp. Clostridium spp. Actinomyces spp. Peptostreptococcus spp.

Enterobacteriaceae (E. coli, Klebsiella, Enterobacter, Salmonella, Yersinia, Proteus) Pasteurella multocida (canis) Bordetella bronchiseptica Campylobacter spp. Fusobacterium spp. Bacteroides spp. Prevotella spp. Capnocytophaga canimorsus

pathogen in dogs is Streptococcus equi subsp. zooepidemicus, which has been associated with outbreaks of hemorrhagic pneumonia in shelter settings and often results in rapid death.14

Enterococcus spp. Group D streptococci, which includes bacteria from the genus Enterococcus, are normal inhabitants of the gastrointestinal tract. The most common isolates from dogs and cats are E. faecalis and E. faecium. Members of this genus are inherently resistant to cephalosporins, macrolides, sulfonamides, fluoroquinolones and low concentrations of aminoglycosides.4 Most isolates of E. faecalis are susceptible to penicillin (the drug of choice), but most isolates of E. faecium are resistant.15 An easy way to remember this is: “E. faecalis is easy to treat but for E. faecium then um... what do you treat with?” Infections caused by Enterococcus include urinary tract infections, cholangiohepatitis, and wound infections. It is important to remember that Enterococcus isolation may represent fecal contamination, and the need to treat should be interpreted with skepticism.

Actinomycetales The order Actinomycetales contains mainly saprophytic bacteria but also includes several important small animal pathogens. Important members include the genera Actinomyces, Nocardia, and Mycobacterium. Table 91.2 highlights cytologic differences and testing. Actinomyces spp. are normal flora of the oral cavity and can cause severe deep bite wound infections.1-3 Recommended treatment of Actinomyces is high-dose penicillin (or aminopenicillin) with high frequency (three times daily) for extended duration.4 Nocardia and Mycobacterium are found in the environment and can cause opportunistic soft tissue infections. The drug of choice for treatment of Nocardia spp. is trimethoprim-sulfamethoxazole, but species identification and susceptibility testing at reference labs may be useful.4 Identification to the species level and susceptibility testing are often required for the treatment of Mycobacterium infections, but empiric therapy may include a macrolide (i.e., clarithromycin) with or without rifampin, clofazimine, or pradofloxacin.16 Actinomyces and Nocardia are common bacteria isolated alone or in conjunction with other bacteria from animals with

septic pyothorax.17 Rare cases of the reportable organisms M. tuberculosis and M. bovis have been described in cats and dogs.18,19

Clostridium spp. and Clostridioides difficile Members of the genus Clostridium are spore-forming, obligate anaerobes that inhabit the gastrointestinal tract. Clostridia, when inoculated by a penetrating wound, can cause severe, often fatal, necrotizing soft tissue infections or gas gangrene. The significance of C. perfringens as an agent of the diarrhea is unclear. Clostridium is considered normal flora in the majority of dogs and many cats. Some strains produce an enterotoxin, and detection of this toxin has been associated diarrhea in dogs; however, it can also be detected in nondiarrheic dogs. The clinical data are also complex for determining the role of Clostridioides (formerly Clostridium) difficile in dogs and cats. C. difficile infections in dogs is thought to be related to previous antimicrobial exposure. Diagnosis of both C. perfringens and C. difficile infections is made by a combination of PCR toxin gene detection and toxin detection by ELISA.20

GRAM-NEGATIVE BACTERIA OF CLINICAL IMPORTANCE Enterobacterales Enterobacterales is an order of bacteria that mainly consists of bacteria that inhabit the gastrointestinal tract. Within the order there are several important families of bacteria including Enterobacteriaceae, Morganellaceae and Yersiniaceae. Escherichia coli is the most studied and clinically important member of the Enterobacteriaceae. It is important to understand that there are many “types” of E. coli and that the presentation for E. coli infection can vary greatly dependent of the site of infection and the strain’s virulence factors.1-4 E. coli can cause many opportunistic infections in small animals including urinary tract infection, aspiration pneumonia, and cholangiohepatitis. E. coli is also the most common cause of pyometra. The role of diarrheagenic pathotypes such as enteropathogenic E. coli and enterohemorrhagic E. coli is poorly defined in dogs and cats.20 A well-characterized granulomatous colitis syndrome caused by strains of adherent-invasive E. coli exists in dogs (Boxers, French Bulldogs

TABLE 91.2  Cytologic Differences and Testing Among Nocardia spp., Actinomyces spp.,

and Mycobacterium spp. Recommended culture method Cytologic appearance Acid fast results

Nocardia spp.

Actinomyces spp.

Mycobacterium spp.

Aerobic Filamentous, branching rods Partial positive (beaded in appearance)

Anaerobic Filamentous, branching rods Negative

Aerobic on specialized medium Negatively staining nonbranching short-to-long rods Positive

CHAPTER 91  Bacterial Infections and Border Collies are overrepresented).21 The current recommendation for therapy is enrofloxacin at 10–20 mg/kg every 24 hours for 8 weeks.22 Salmonella enterica is a pathogenic and diarrheagenic member of Enterobacteriaceae. Clinical signs of salmonellosis can range from subclinical colonization with shedding to severe systemic manifestations including fever, neutropenia, and profuse diarrhea. Across several studies the most common risk factor for salmonellosis is consumption of a raw meat. Salmonella is zoonotic, and appropriate precautions should be taken when caring for diarrheic patients on a raw diet.20,23 Klebsiella spp. and Enterobacter spp. are other members of Enterobacteriaceae that are relatively common agents of opportunistic infections (i.e., urinary tract infections, wound infections) in dogs and cats.1-3 Proteus mirabilis, a member of the Morganellaceae, causes opportunistic infections in dogs and cats and is associated with urease-mediated struvite urolithiasis.10 Yersinia pestis is the reportable agent of “plague.” Animals, particularly cats, can develop the bubonic form characterized by fever and mandibular lymphadenopathy. Cases of pneumonic plague have been reported in both dogs and cats. Geographically, Y. pestis is limited to the western United States; hunting of prairie dogs and other rural rodents is likely a major risk factor.24

Pseudomonas aeruginosa and other Nonfermenters Pseudomonas aeruginosa is a common pathogen that causes opportunistic infections such as pneumonia and surgical implant infections.25 Postgrooming furunculosis is a deep infection of the skin often caused by P. aeruginosa that has been linked to bathing with contaminated shampoos.26 Animals present with fever, lethargy, and severe dorsal pain secondary to skin lesions. P. aeruginosa is inherently resistant to many antimicrobials including aminopenicillins (including amoxicillin-clavulanate), most cephalosporins, trimethoprim-sulfonamide, chloramphenicol, and tetracyclines. Acquired resistance to aminoglycosides and fluoroquinolones is common.27 Use of anti-pseudomonal b-lactams (ceftazidime, piperacillin) is off label and should be reserved for life-threatening systemic infections and is best administered in hospital to ensure proper use. Several other nonfermenters (named such because of their limited carbohydrate fermentation) such as Stenotrophomonas maltophilia, Burkholderia cepacia complex, and Acinetobacter spp. can cause a variety of infections in small animals. These organisms are found in the environment and are inherently resistant to multiple or all relevant classes of antimicrobials.4

Pasteurella spp. Pasteurella multocida and Pasteurella canis are normal flora of the oral cavity and upper respiratory tract of companion animals. They are commonly isolated from bite wound infections and lower respiratory (pneumonia) samples. These organisms are susceptible to many classes of antimicrobials, but penicillins or aminopenicillins remain the drug of choice.1-3,28

Bordetella bronchiseptica Bordetella bronchiseptica is the most important bacterial pathogen in the canine infectious respiratory disease complex. Disease ranges from very mild tracheitis to life-threatening pneumonia. B. bronchiseptica is highly transmissible, and patients should be isolated and personal protective equipment used to prevent fomite spread. Culture is the gold standard diagnostic test, but PCR can be helpful.29 There are no Clinical Laboratory Standards Institute guidelines for antimicrobial susceptibility testing of B. bronchiseptica from dogs.27 Recommended pneumonia therapy is oral doxycycline or parenteral enrofloxacin.29

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Campylobacter spp. Campylobacter are spirochete-like bacteria that may be normal flora of the gastrointestinal tract of dogs and cats. Similar carriage rates in diarrheic and nondiarrheic dogs and cats can be found. C. jejuni has been associated with diarrhea and may cause severe disease in young animals. C. jejuni is zoonotic, and the infectious dose is very low (,500 cells).20 Macrolides (erythromycin and tylosin) remain the mainstay of therapy. The use of fluoroquinolones is discouraged because of the rising rates of resistance and the need as an effective therapeutic in people.20

Leptospira spp. Leptospirosis is a major cause of acute kidney injury in under-vaccinated dogs (see also Chapter 121, Acute Kidney Injury). It is caused by several serovars (e.g., Pomona, Canicola, Icterohaemorrhagiae) of the spirochete bacterium Leptospira interrogans (or L. kirschneri serovar Grippotyphosa). Other common clinical pathologic findings include evidence of liver injury and thrombocytopenia. Potential for zoonotic transmission should be considered. PCR of the urine or blood is now considered the gold standard for diagnosis. Serologic testing results are still useful (including new point-of-care options such as Witness Lepto [Zoetis] and SNAP Lepto Test [Idexx]), but they must be interpreted with an accurate vaccination history. A two-week course of doxycycline is recommended to eliminate urine shedding, but during acute hospitalization intravenous ampicillin is recommended. Leptospiral pulmonary hemorrhagic syndrome is a severe manifestation that may be reported with more frequency. Reports of leptospirosis in cats are very rare.30

Borrelia burgdorferi Borrelia burgdorferi, the agent of human Lyme disease, has been the subject of many debates in small animal medicine. It is transmitted by the Ixodes tick and can lead to a self-limiting polyarthritis. In the ICU setting, kidney injury associated with Lyme nephritis secondary to immune complex deposition is most important. The use of antimicrobials is common but not well-studied. Doxycycline is considered the drug of choice for therapy.31

MYCOPLASMA AND INTRACELLULAR BACTERIA OF CLINICAL IMPORTANCE Mycoplasma spp. Mycoplasma is a genus of bacteria that lack a cell wall (“mollicutes”), which makes them inherently resistant to the action of b-lactam antimicrobials. Mycoplasma haemofelis can lead to severe immune-mediated hemolytic anemia in cats. Several other species have been identified in dogs and cats, but clinical relevance is unknown.32 Diagnosis can be made by review of blood smears by a clinical pathologist or PCR. The role of Mycoplasma in respiratory infection is unclear. The only species in dogs consistently associated with disease is Mycoplasma cynos; however, identification is common in healthy dogs. Diagnosis by PCR and/ or culture is recommended. Therapy with doxycycline is most common, but fluoroquinolones have also been recommended.29,33,34

Rickettsiaceae Rickettsiaceae is a family of obligate intracellular, vector-borne bacteria. The most common organisms identified in dogs are Anaplasma phagocytophilum, Anaplasma platys, Ehrlichia ewingii, and Ehrlichia canis. Clinical signs include lethargy, lameness, and fever of unknown origin. The most common hematologic abnormality is thrombocytopenia. A less common but very life-threatening infection is called Rocky Mountain spotted fever, which is caused by Rickettsia rickettsii.35 This organism infects endothelial cells and can lead to widespread

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petechial hemorrhage and edema, which can lead to shock and death. In the Pacific Northwest of the United States, Neorickettsia helminthoeca should be considered in dogs who have eaten raw salmon (containing the fluke Nanophyetus salmonicola) and present with vomiting, fever, diarrhea, and lymphadenopathy.4 Definitive diagnosis of rickettsial infection requires identification of bacteria on blood smear or cytology with or without PCR confirmation. Positive in-house serologic tests should be interpreted as exposure to a pathogen and contextualized with a patient’s clinical signs. Doxycycline is the drug of choice for treatment of all rickettsial diseases.35

Bartonella spp. Bartonella spp. are facultative intracellular, Gram-negative bacteria that have been linked to a spectrum of disease. Severe manifestations include encephalitis and endocarditis. B. henselae (the agent of cat scratch disease or fever), B. koehlerae, and B. vinsonii are among the most commonly identified in dogs and cats. Culture is still considered the gold standard, but the methodology is complex and not widely available. Molecular identification by PCR is a useful clinical tool, and PCR following enrichment culture is the most sensitive method. Combination antimicrobial therapy is thought to be most effective (e.g., doxycycline and a fluoroquinolone).36

Brucella spp. Brucella canis is an obligate intracellular pathogen that causes abortion in pregnant bitches. Infertility and orchitis are the most common presentations in male dogs. Puppies born with B. canis infection often fail to thrive. B. canis should also be considered in patients with discospondylitis. Transmission is venereal, and infections are most common in intact animals.37 Transmission from transfused blood is possible, and donor testing is therefore recommended. B. suis is an emerging pathogen in dogs, especially in regions where feral swine are abundant. Clinical signs are similar, but it is important to note that cross-reaction does not occur with B. canis serology, and separate testing should be requested.38 Canine brucellosis is reportable in many jurisdictions. Prolonged courses of combination or monotherapy with tetracycline, aminoglycoside, and/ or fluoroquinolone antimicrobials have been attempted; however, antimicrobial therapy is not thought to aid in elimination of B. canis from persistently infected animals.38

TREATMENT AND PREVENTION OF BACTERIAL INFECTIONS Part XIX discusses the use of antimicrobials that are critical for the treatment of infections. With the rapid rise of antimicrobial resistance, culture and susceptibility testing should be performed when possible in order to guide therapy for organisms with variable resistance patterns. Other principles of antimicrobial stewardship (i.e., IV to PO conversion, deescalation) should also be practiced routinely.39 Infection control in the ICU is critical to prevent the spread of bacteria. Box 91.1 lists important parts of an ICU infection control program.40 See Chapter 172, Antimicrobial Use in the Critical Care Patient for further details.

CONCLUSION Bacterial infections are common among patients in the small animal ICU. They can affect all organ systems and can range from mild to severe. Use of accurate diagnostic tests, targeted therapeutic regimens and thorough preventative measures can have a significant and positive impact on the outcomes of your patients.

BOX 91.1  Important Components of an ICU Infection Control Program Infection control programs of the ICU should include: • Support from administration • Designated personnel who are “champions” • Training and recertification processes • Methods for rapid identification of high-risk patients • Strict hand hygiene and glove protocols • Transmission-based personal protective equipment policies • Environmental cleaning policies that adhere to product manufacturer’s instructions for use

REFERENCES 1. Hirsch DC, MacLachlan NJ: Veterinary microbiology, Ames, IA, 2004, Blackwell. 2. Quinn PJ, Markey BK, Leonard FC, et al: Veterinary microbiology and microbial disease, Chiches-ter, West Sussex, UK, 2011, Wiley-Blackwell. 3. Greene CE, Prescott JF, editors: Mycoplasmal and Bacterial Diseases: In Infectious diseases of the dog and cat, St Louis, 2012, Elsevier. 4. Sykes J: Canine and feline infectious diseases, St. Louis, 2014, Elsevier. 5. Bannoehr J, Guardabassi L: Staphylococcus pseudintermedius in the dog: taxonomy, diagnostics, ecology, epidemiology and pathogenicity, Vet Dermatol 23:253-66, e51-2, 2012. 6. Cain CL, Morris DO, Rankin SC: Clinical characterization of Staphylococcus schleiferi infections and identification of risk factors for acquisition of oxacillin-resistant strains in dogs: 225 cases (2003–2009), J Am Vet Med Assoc 239(12):1566-1573, 2011. 7. Unpublished laboratory data. S. Cole 2019. 8. Bierowiec K, Płoneczka-Janeczko K, Rypuła K: Is the colonisation of Staphylococcus aureus in pets associated with their close contact with owners? PloS One 11(5):e0156052, 2016. doi:10.1371/journal. pone.0156052. 9. Windahl U, Bengtsson B, Nyman AK, Holst BS: The distribution of pathogens and their antimicrobial susceptibility patterns among canine surgical wound infections in Sweden in relation to different risk factors, Acta Vet Scand 57:11, 2015. doi:10.1186/s13028-015-0102-6. 10. Lulich JP, Berent AC, Adams LG, et al: ACVIM small animal consensus recommendations on the treatment and prevention of uroliths in dogs and cats, J Vet Intern Med 30(5):1564-1574, 2016. doi:10.1111/jvim.14559. 11. Prescott JF, Miller CW, Mathews KA, et al: Update on canine streptococcal toxic shock syndrome and necrotizing fasciitis, Can Vet J 38:241-242, 1997. 12. Naidoo SL, Campbell DL, Miller LM, et al: Necrotizing fasciitis: a review, J Am Anim Hosp Assoc 41(2):104-109 2005. 13. Ingrey KT, Ren J, Prescott JF: A fluoroquinolone induces a novel mitogenencoding bacteriophage in Streptococcus canis, Infect Immun 71:30283033, 2003. 14. Kim MK, Jee H, Shin SW, et al: Outbreak and control of haemorrhagic pneumonia due to Streptococcus equi subspecies zooepidemicus in dogs, Vet Rec 161(15):528-530, 2007. 15. Iseppi R, Messi P, Anacarso I, et al: Antimicrobial resistance and virulence traits in Enterococcus strains isolated from dogs and cats, New Microbiol 38(3):369-378, 2015. 16. Malik R, Smits B, Reppas G, Laprie C, O’Brien C, Fyfe J: Ulcerated and nonulcerated nontuberculous cutaneous mycobacterial granulomas in cats and dogs, Vet Dermatol 24(1):146-153.e32-3, 2013. 17. Epstein SE, Balsa IM: Canine and feline exudative pleural diseases, Vet Clin North Am Small Anim Pract 50(2):467-487, 2020. 18. Ribeiro MG, Lima MCF, Franco MMJ, et al: Pre-multidrug-resistant mycobacterium tuberculosis infection causing fatal enteric disease in a dog

CHAPTER 91  Bacterial Infections from a family with history of human tuberculosis, Transbound Emerg Dis 64(5):e4-e7, 2017. doi:10.1111/tbed.12513. 19. Elkins P: Hunting hounds and bovine TB, Vet Rec 183(13):419-420, 2018. doi:10.1136/vr.k4144. 20. Marks SL, Rankin SC, Byrne BA, Weese JS: Enteropathogenic bacteria in dogs and cats: diagnosis, epidemiology, treatment, and control, J Vet Intern Med 25(6):1195-1208, 2011. doi:10.1111/j.1939-1676.2011.00821.x. 21. Craven M, Mansfield CS, Simpson KW: Granulomatous colitis of boxer dogs, Vet Clin North Am Small Anim Pract 41(2):433-445, 2011. doi:10.1016/j.cvsm.2011.01.003. 22. Manchester AC, Hill S, Sabatino B, et al: Association between granulomatous colitis in French Bulldogs and invasive Escherichia coli and response to fluoroquinolone antimicrobials, J Vet Intern Med 27(1):56-61, 2013. doi:10.1111/jvim.12020. 23. Reimschuessel R, Grabenstein M, Guag J, et al: Multilaboratory survey to evaluate salmonella prevalence in diarrheic and nondiarrheic dogs and cats in the United States between 2012 and 2014, J Clin Microbiol 55(5):1350-1368, 2017. doi:10.1128/JCM.02137-16. 24. Oyston PC, Williamson D: Plague: infections of companion animals and opportunities for intervention, Animals (Basel) 1(2):242-255, 2011. doi:10.3390/ani1020242. 25. Šeol B, Naglic´ T, Madic´ J, Bedekovic´ M: In vitro antimicrobial susceptibility of 183 Pseudomonas aeruginosa strains isolated from dogs to selected antipseudomonal agents, J Vet Med B 49:188-192, 2002. 26. Cain CL, Mauldin EA: Clinical and histopathologic features of dorsally located furunculosis in dogs following water immersion or exposure to grooming products: 22 cases (2005-2013), J Am Vet Med Assoc 246(5):522-529, 2015. doi:10.2460/javma.246.5.522. 27. CLSI: Performance standards for antimicrobial disk and dilution susceptibility tests for bacteria isolated from animals. 4th Edition CLSI Standard Vet 08, Wayne, PA, 2018, Clinical Laboratories and Standards Institute. 28. Meyers B, Schoeman JP, Goddard A, Picard J: The bacteriology and antimicrobial susceptibility of infected and non-infected dog bite wounds: fifty cases, Vet Microbiol 127:360-368, 2008. 29. Lappin MR, Blondeau J, Boothe D, et al: Antimicrobial use guidelines for treatment of respiratory tract disease in dogs and cats: Antimicrobial

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Guidelines Working Group of the International Society for Companion Animal Infectious Diseases, J Vet Intern Med 31(2):279-294, 2017. doi:10.1111/jvim.14627. 30. Sykes JE, Hartmann K, Lunn KF, Moore GE, Stoddard RA, Goldstein RE: 2010 ACVIM small animal consensus statement on leptospirosis: diagnosis, epidemiology, treatment, and prevention, J Vet Intern Med 25(1):1-13, 2011. doi:10.1111/j.1939-1676.2010.0654.x. 31. Littman MP, Gerber B, Goldstein RE, Labato MA, Lappin MR, Moore GE: ACVIM consensus update on Lyme borreliosis in dogs and cats, J Vet Intern Med 32(3):887-903, 2018. doi:10.1111/jvim.15085. 32. Garden OA, Kidd L, Mexas AM, et al: ACVIM consensus statement on the diagnosis of immune-mediated hemolytic anemia in dogs and cats, J Vet Intern Med 33(2):313-334, 2019. doi:10.1111/jvim.1544. 33. Spindel ME, Veir JK, Radecki SV, Lappin MR: Evaluation of pradofloxacin for the treatment of feline rhinitis, J Feline Med Surg 10(5):472-479, 2008. doi:10.1016/j.jfms.2008.04.003. 34. Dowers KL, Tasker S, Radecki SV, Lappin MR: Use of pradofloxacin to treat experimentally induced Mycoplasma hemofelis infection in cats, Am J Vet Res 70(1):105-111, 2009. doi:10.2460/ajvr.70.1.105. 35. Little SE: Ehrlichiosis and anaplasmosis in dogs and cats, Vet Clin North Am Small Anim Pract 40(6):1121-1140, 2010. doi:10.1016/j. cvsm.2010.07.004. 36. Ålvarez-Fernández A, Breitschwerdt EB, Solano-Gallego L: Bartonella infections in cats and dogs including zoonotic aspects, Parasit Vectors 11(1):624, 2018. doi:10.1186/s13071-018-3152-6. 37. Cosford KL: Brucella canis: an update on research and clinical management, Can Vet J 59(1):74-81, 2018. 38. Ramamoorthy S, Woldemeskel M, Ligett A, et al: Brucella suis infection in dogs, Georgia, USA, Emerg Infect Dis 17(12):2386-2387, 2011. doi:10.3201/eid1712.111127. 39. Guardabassi L, Prescott JF: Antimicrobial stewardship in small animal veterinary practice: from theory to practice, Vet Clin North Am Small Anim Pract 45(2):361-376, 2015. 40. Stull JW, Bjorvik E, Bub J, Dvorak G, Petersen C, Troyer HL: 2018 AAHA infection control, prevention, and biosecurity guidelines, J Am Anim Hosp Assoc 54(6):297-326, 2018.

92 Fungal Infections Elizabeth J. Thomovsky, DVM, MS, DACVECC

KEY POINTS • The gold standard for diagnosis of any fungal disease is visualization of the fungus either via cytology, histopathology, or culture. • In addition to antifungal therapy, treatment is tailored to the clinical signs present in that patient.

• • • •

Most fungal diseases are contracted by dogs and cats from the environment. In contrast, Candida species are part of the normal flora and act as opportunistic pathogens, primarily in the immunocompromised. This chapter presents a broad overview of the most common fungal organisms found in small animal practice.

FUNGAL ORGANISMS

reproducing itself and takes up a dark blue color with Romanowski stains leading to the cytologic description “big, blue, budding” yeast. The most common sites for disease in dogs are the lungs, bones, skin, eyes, and central nervous system. Similarly, the most common sites in cats are the lungs, skin, eyes, and central nervous system. Blastomyces can disseminate to nearly any other location in the body in either species.

Blastomycosis

Clinical Signs

Blastomyces dermatitidis is found in the soil in the Ohio and Mississippi River valleys, mid-Atlantic states, and parts of upstate New York. It primarily affects dogs but has been reported in both outdoor and indoor cats.1 Mycelial spores are inhaled into the lungs; body temperatures stimulate conversion of the fungus into a yeast that replicates and is transmitted through the bloodstream and lymphatics. The yeast form is typically found at the site of disease and is 5–20 mm in size and surrounded by a thick cell wall (Fig. 92.1). The yeast is often seen

Clinical signs of blastomycosis are variable and often nonspecific (lethargy, anorexia, weight loss or fever). More specific clinical signs like hyphema, coughing, respiratory distress, lameness, or dermal lesions can occur depending on the site of disease.

A

Cryptococcus gattii is an emerging zoonotic pathogen. The most common fungal disease in cats is cryptococcosis. Candidiasis typically indicates host immunocompromise. Aspergillus is the most prevalent fungal pathogen in the world.

Cryptococcosis Cryptococcus neoformans and C. gattii are the primary organisms causing disease in dogs and cats. Their source is desiccated pigeon (and

B Fig. 92.1  A, Blastomyces dermatitidis in cerebrospinal fluid from a dog with central nervous system signs. Note the dark blue staining and the size of the organisms relative to the surrounding neutrophils. (Courtesy Natalia Strandberg, Purdue University.) B, Blastomyces dermatitidis from an aspirate of a bony lesion in the tibia of a dog with rear limb lameness. Note that the yeast pictured is budding. (Courtesy Natalia Strandberg, Purdue University).

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Fig. 92.2  Cryptococcus neoformans in an aspirate from a nasal mass in a cat. Note the distinctive large clear staining capsule surrounding the organisms. (Courtesy Natalia Strandberg, Purdue University.)

Fig. 92.3  Coccidioides immitis in an aspirate from a dog. Note the size of the spherule relative to the surrounding neutrophils and the endospores visible within the largest spherules.  (Courtesy Christina Jeffries, Colorado State University.)

other bird) guano and decaying wood bark, respectively. Cryptococcus neoformans is divided into multiple genetic varieties which, taken together, have a wide distribution across the world.2,3 Typically C. neoformans causes disease in immunocompromised hosts. Cryptococcus gattii is considered an emerging source of disease and affects immunocompetent humans and animals. It was initially found largely in tropical and subtropical regions of Australia, South America, Southeast Asia, and Africa. More recently C. gattii is emerging as a reportable disease in the Pacific Northwest of the United States and British Columbia in Canada due to its risk to humans.2,3 Typically, the Cryptococcus organism is inhaled as a spore or yeast cell that converts to a yeast form that spreads hematogenously through the body. The Cryptococcus yeast form is an encapsulated organism 10–60 mm in diameter (Fig. 92.2). The distinctive capsule is believed to help the organism avoid detection and clearance by the immune system.3 Cryptococcus is the principle fungal pathogen in cats. Disease is primarily in the nasal cavity but also commonly affects the skin and central nervous system.4 In dogs, Cryptococcus causes central nervous system disease but is often found in more than one organ system; other involved systems include the eyes, nasal cavity, and urinary system.3,4

spherule formation; spherules are large (20–100 mm), double walled, and often filled with visible endospores (3–5 mm diameter) (Fig. 92.3). Spherules eventually release endospores that disseminate and proliferate into new spherules to continue infection. The most common sites of infection in dogs are the lung or bone, but disease can disseminate to the central nervous system, heart, skin, and other locations. Coccidioidomycosis is rare in cats, but affected cats can show skin, respiratory, musculoskeletal, neurologic, or ocular signs.

Clinical Signs Animals with cryptococcosis can display lethargy, decreased appetite, and weight loss. Other signs are related to the location of the Cryptococcus organism. Cats often display upper respiratory signs including sneezing, stertor, visible nasal planum deformity, or nasal discharge. Dogs frequently exhibit neurologic signs, but ocular changes, cutaneous lesions, or respiratory distress also occur.

Coccidioidomycosis Coccidioides immitis and C. posadasii are the causative organisms of coccidioidomycosis in dogs and cats. This fungus is found in the semiarid desert regions of southern and central California, Arizona, New Mexico, Nevada, Utah, western Texas and parts of Central and South America. The fungal mycelium proliferates with rainfall and releases arthrospores into the environment in subsequent dry periods. These arthrospores are usually inhaled but can also be inoculated into dermal wounds. Carbon dioxide and phagocytic cells in the lungs stimulate

Clinical Signs Dogs with primary respiratory coccidioidomycosis exhibit cough, fever, lethargy, weight loss, and anorexia.5,6 Disseminated disease in dogs presents as fever, lethargy, and anorexia coupled with more specific signs associated with location of infection (e.g., lameness from osteomyelitis or cutaneous lesions).5,6 Central nervous system signs can be multifocal in cases of meningoencephalitis or consistent with localized disease from a solitary fungal granuloma.5,6 In cats, dermal lesions (nodular or nonhealing lesions) are the most common followed by respiratory signs.7,8 Less than half of cats have nonspecific signs like decreased appetite or fever but will display specific signs related to organ system involvement such as lameness from osteomyelitis or paresis/paralysis with central nervous system disease.7,8

Histoplasmosis Histoplasma capsulatum is the causative agent of histoplasmosis. It is found in the midwestern and southern United States as well as parts of Central and South America. Microconidia are found in soil, especially warm, moist, and humid areas, and grow best in bat or bird excrement. Microconidia are inhaled, convert to the yeast form at body temperatures, and disseminate by traveling within macrophages via the bloodstream and lymphatics. The yeast are commonly found within the cytoplasm of macrophages or neutrophils, are 2–4 mm in size, and have a basophilic (blue) staining center surrounded by a lighter halo caused by cell shrinkage during staining (Fig. 92.4).9 Common sites for Histoplasma infection in dogs include the gastrointestinal tract, eye, lymph nodes, liver, and spleen; in one study, most dogs had disseminated disease (57%) with primary gastrointestinal (34%) and primary pulmonary disease (9%) occurring less commonly.10 Cats typically have disseminated, pulmonary, and gastrointestinal signs;

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Fig. 92.4  Histoplasma capsulatum in a peripheral blood smear from a dog presenting with dyspnea and peripheral lymphadenomegaly. Histoplasma organisms are most frequently found within macrophages and neutrophils and have a thin colorless halo. (Courtesy Natalia Strandberg, Purdue University.)

in one study, disseminated disease was most common (68%) followed by primary pulmonary (18%) and primary gastrointestinal disease (14%).11

Clinical Signs Clinical signs of histoplasmosis in dogs include lethargy, decreased appetite, weight loss, and diarrhea; other signs more specific to the involved organ systems also occur.10 Cats usually present with weakness, weight loss, and anorexia, although half of cats show signs attributed to the pulmonary system including increased respiratory rate or effort and coughing.11 Interestingly, lymphadenopathy is three times more common in cats than dogs.10,11

Aspergillosis Aspergillosis can be caused by a wide array of Aspergillus organisms; Aspergillus is one of the most prevalent types of molds in the world. It is found in soil and decaying vegetation, recycling carbon and nitrogen. Conidia (2–3 mm in size) are inhaled into the nasal passages from the air or almost any object and, if not cleared by local innate immune mechanisms, are taken up by macrophages and dendritic cells and transported hematogenously throughout the body (Fig. 92.5). Clinical aspergillosis is divided into three main types: sinonasal aspergillosis (SNA), sino-orbital aspergillosis (SOA), and invasive aspergillosis (IA), which is typically disseminated. Dogs rarely suffer from SOA, while it is relatively common in cats. Common causes of SNA and SOA are A. fumigatus and A. niger. Immunocompromised dogs (especially German shepherds) have IA caused by A. terreus or A. fumigatus. Cats rarely contract IA and causative organisms are relatively uncharacterized.12

Fig. 92.5  Aspergillus sp. from a frontal sinus impression smear in a dog with nasal discharge and intermittent epistaxis. Note the visible hyphae are septate and branching and may have a deeply basophilic internal structure or may be completely clear/pale blue when stained. Fungal culture is required for definitive diagnosis as Aspergillus sp. closely resembles Penicillium sp. in cytologic samples. (Courtesy Natalia Strandberg, Purdue University.)

Candidiasis Candida species are commensal organisms and part of the normal mucosal surface flora in animals. Disease occurs when there are local disruptions to the mucosa and/or systemic immunocompromise in the host. Candida is usually found as a small 3–6 mm round yeast or pseudohyphae (Fig. 92.6). The most common species causing disease in dogs and cats is C. albicans. Generally, predisposing factors in animals for Candida colonization include chronic antibiotic use, endocrinopathies believed to affect immune function (e.g., diabetes mellitus, hyperadrenocorticism, hypothyroidism), chemotherapy, urinary catheterization in cats, and possibly concurrent feline retroviral disease (although this is not clearly established).14,15 Candidiasis in dogs receiving multiple serial abdominal exploratory surgeries for a variety of

Clinical Signs Clinical signs are dependent upon the form of aspergillosis. Sneezing, nasal discharge, epistaxis and other signs of rhinosinusitis are consistent with SNA while facial malformation, exophthalmos, and pain upon opening the mouth 1/2 nasal signs occur in cases of SOA. In contrast, IA in dogs is a chronic nonspecific disease causing anorexia, weight loss, pyrexia, and lethargy. Many dogs are diagnosed at the end stage of IA with signs of paraparesis or paraplegia secondary to osteomyelitis and/or central nervous system spread.13

Fig. 92.6  Candida organism in urine from a dog with a urethral stricture and persistent lower urinary signs. Note both the yeast form as well as the pseudohyphae, which do not have parallel cell walls and instead resemble yeast joined end to end in chains to form a hyphal-like structure. (Courtesy Natalia Strandberg, Purdue University.)

CHAPTER 92  Fungal Infections causes has also been reported.16 However, Candida sp. are also reported as a cause of disseminated disease in a young dog17 and were found in a focal gastrointestinal granuloma in a healthy young cat.18

DIAGNOSIS In many cases, clinical diagnosis of fungal disease stems from the appearance of lesions on thoracic and extremity radiographs or computed tomography (CT) and magnetic resonance imaging scans coupled with the clinical presentation of the animal. However, the gold standard for diagnosis of fungal disease is visualization of the fungus via cytology, histopathology, or culture. When it is difficult to obtain a diagnostic sample for cytology or histopathology, when waiting for culture or histopathology results presents too much of a delay, or when trying to rule out fungal disease in an animal with otherwise vague clinical signs, antibody and antigen testing should be performed.

Antibody testing Blastomycosis Antibody testing for blastomycosis in dogs is fraught with complications, including the inherent time delay for the patient to develop enough serum antibodies for detection. Regardless of modality (agar gel immunodiffusion [AGID] or enzyme immunoassay), antibody testing for detection of Blastomyces in dogs has low sensitivity (Se) and is considered unreliable and not recommended.19,20 There is no published information about antibody testing in cats.

Coccidioidomycosis AGID testing for IgG and IgM antibodies exists for canine coccidioidomycosis. It is specific but time consuming and not sensitive, leading to many false negatives.6 More recently, an enzyme immunoassay (EIA) to detect IgG antibodies against canine coccidioidomycosis has been shown to be more sensitive (86%) than AGID (73%) in detecting IgG and has a high specificity (Sp; 97.2%).21 It also has a low level of cross-reactivity with H. capsulatum IgG (7.7%) and B. dermatitidis IgG (6.4%).21 A lateral flow antigen test for rapid in-clinic detection of Coccidioides exists, which is a reasonable rapid screening test in dogs where there is a clinical suspicion of Coccidioides, but it still showed discordant results in 7/56 cases requiring further confirmatory testing.22 Feline coccidiomycosis can be detected with AGID with a reasonable Se (83%).8 However, false-negative results occur for the first 2 months of infection, necessitating the use of cytology, histopathology, and AGID in combination to detect Coccidioides.

Histoplasmosis No reliable antibody testing is available for dogs and cats.9

Aspergillosis Because Aspergillus is ubiquitous in the environment and all animals are exposed to it, antibody production was historically deemed unreliable. However, an AGID and IgG enzyme linked immunosorbent assay (ELISA) for anti-Aspergillus antibodies were recently found to have reasonable Se (76.5% and 88.2%, respectively) and excellent specificities (100% and 96.8%, respectively) to detect SNA in dogs.23 No similar testing has been published in cats but preliminary information suggests that feline antiAspergillus antibodies would react as favorably as those in dogs.12

Candida No antibody testing has been developed for the diagnosis of Candida organisms in dogs and cats.

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Antigen Testing Blastomycosis Antigen testing for blastomycosis is extremely useful in dogs. The recognized antigen is a fungal cell wall galactomannan present in both B. dermatitidis and H. capsulatum, causing cross reaction. Therefore, a positive test result is consistent with the presence of either fungal organism. Clinically, this is relatively unimportant since both fungi are treated and managed the same way. Both canine urine and serum can be tested for the antigen via EIA and have Se of 93.5% in urine and 87% in serum for blastomycosis.20 A study in dogs reported that serial urine and serum testing showed statistically significant decreases in the quantity of urine blastomycosis antigen at clinical remission (P ,0.001) and that antigen levels have high Sp for determining clinical relapse (100%).24 There is no information published related to antigen detection of Blastomyces in cats.

Cryptococcus Latex antigen agglutination serology is performed on serum or other body fluids in dogs and cats and can detect the capsular antigen found in all known Cryptococcus organisms with high Se and Sp. Decreasing antigen titers typically indicate resolution of disease, but there may be delays in detection of the antigen early in disease. Also, titers may initially increase when treatment is initiated and capsular antigen is released in large quantities from dead Cryptococcus organisms.2,3 Newer point-of-care immunochromatographic lateral flow antigen assay tests to more quickly diagnose Cryptococcus have high Se and Sp in both dogs and cats.25,26

Coccidioidomycosis An antigen test developed for Coccidioides cell wall galactomannan has an extremely low Se and Sp and should not be used as a single test for coccidioidomycosis.27 However, when used in combination with EIA and AGID for detection of Coccidioides antibodies, the Se for detection of the organism was 100%.21 No antigen testing exists for cats.

Histoplasmosis An EIA test to detect the Histoplasma fungal cell wall galactomannan in canine urine is available (the same test used to detect B. dermatitidis). It had an overall Se of 89.5% and Sp of 100% for H. capsulatum when compared to cytology and histopathology in a population of animals with histoplasmosis, but testing in a population of animals with fungal diseases other than histoplasmosis would likely reduce the Sp significantly.28

Aspergillosis Antigen testing for canine and feline SNA and SOA galactomannan has low Se and Sp, largely attributed to the fact that galactomannan and other Aspergillus antigens are not consistently elevated in disease.29 In disseminated canine IA, one study showed good Se and Sp with an Aspergillus galactomannan ELISA test for urine or serum (Se 5 89% or 93%, respectively; Sp 5 93% both urine and serum).30 No similar testing procedure has been determined for feline IA.

Candida A PCR test for rapid diagnosis of Candida organisms exists for animals, but its availability may be limited.

TREATMENT AND OUTCOME In general, treatment for fungal diseases involves the long-term (.6–12 month) administration of antifungal agents (Chapter 176, Antifungal Therapy). Supportive care is targeted toward the specific clinical signs the animal is demonstrating. Common supportive care measures

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for fungal diseases include oxygen therapy for dyspneic patients (Chapter 15, Oxygen Therapy), topical ophthalmic treatments for associated uveitis or glaucomatous changes in the eyes (and even enucleation in some cases; Chapter 144, Ocular Disease in the Intensive Care Unit), pain medications for animals with lameness from osteomyelitis (Chapter 134, Analgesia and Constant Rate Infusions), anticonvulsant therapies for seizures associated with central nervous system disease (Chapter 84, Seizures and Status Epilepticus), etc.

Blastomycosis Some sources recommend routine treatment with antiinflammatories in cases of pulmonary blastomycosis to reduce inflammation both associated with the disease and occurring subsequent to death of fungal organisms from antifungal therapies. The only study to evaluate the efficacy of antiinflammatories in blastomycosis did not find any improvement in survival when dogs received nonsteroidal antiinflammatories, steroids, both, or neither.31 A future avenue for treatment of blastomycosis may involve supplementation with vitamin D during treatment. Vitamin D is known to play a role in immunomodulation and mucosal immunity. In one recent study, dogs with blastomycosis were found to have significantly lower concentrations of vitamin D and parathyroid hormone levels than control animals (P ,0.001).32 Outcomes for blastomycosis are variable depending on the severity of disease. In general, dogs with localized nonpulmonary disease tend to have good outcomes. Pulmonary blastomycosis carries a more guarded prognosis with one study reporting death or euthanasia in 37% of cases33 and another study reporting that dogs requiring oxygen therapy had a significantly lower 30-day survival than those not requiring oxygen.31

Cryptococcosis Treatments for Cryptococcus vary depending on the organ system involved. If there are mass lesions such as commonly found in the nasal passages, surgical debulking can greatly improve response to treatment. Greater dissemination and/or involvement of the central nervous system are both negative prognostic indicators; cats tend to have more localized disease and are considered to have better overall outcomes than dogs. In general, if animals survive the first few days to week of treatment, they have a reasonable prognosis.2,3

Coccidioidomycosis As with blastomycosis, some sources suggest the use of antiinflammatories in addition to antifungal medications in cases of pulmonary coccidioidomycosis but no studies document the efficacy of this treatment. Outcomes with coccidioidomycosis vary depending on the location and extent of disease. Disseminated disease has the worst outcomes, especially when there is concurrent bony involvement.6 Recurrence is common in both dogs and cats with at least 25% of cats in one study having repeat bouts of coccidiomycosis.7 Limiting access to the outdoors, especially immediately post rainfall and preventing digging in soil may reduce reinfection or recurrence.6

Histoplasmosis In dogs, outcomes from histoplasmosis are generally positive, with 95% of dogs surviving to hospital discharge and at least two-thirds of dogs surviving at 6 months of treatment.10 Outcomes in cats are more guarded, with only 55% of cats in one study surviving to discharge and many cats being euthanized within 6 months of treatment.11

Aspergillosis Canine SNA is typically treated by debulking the fungal lesions via surgery or rhinoscopy in addition to local topical administration of

antifungal agents such as clotrimazole or enilconazole in a variety of preparations. Topical treatments have the advantage of reducing systemic side effects of antifungal medications and are administered via a variety of techniques including surgically implanted sinus tubes, topical infusion under anesthesia, and sinus trephination. Historically, the use of topical treatment was limited to cases where the cribriform plate was intact on CT scanning, but newer publications indicate that there are no side effects noted with topical administration in these cases.34,35 Feline SNA is treated by debulking in combination with either topical therapy, systemic antifungal therapy, or both systemic and topical antifungal treatments.12 Debulking large lesions in feline SOA has not been shown to be advantageous over systemic therapy alone.12 Most dogs with SNA are cured after one or two topical treatments regardless of whether there was damage to the cribriform plate.34,35 Similarly, outcomes in cats with SNA are good while outcomes with SOA are more variable and generally considered more guarded than SNA, requiring long-term treatment with antifungal drugs. Invasive disseminated aspergillosis in cats and dogs is treated with systemic antifungal medications. Cure of canine disseminated IA is difficult to achieve, especially with the classic azole drugs (Chapter 176, Antifungal Therapy). Aspergillus organisms are intrinsically resistant to fluconazole and other azole drugs secondary to a relative lack of ergosterol in their cell walls. In a recent study of canine IA using the newer drug posaconazole, 4/10 dogs achieved cure with long-term drug therapy, although 50% of those dogs relapsed once treatment was discontinued.36 In the same study, 6/10 dogs saw clinical improvement with three of those dogs relapsing once treatment was discontinued and three dogs relapsing during treatment.36 Average survival for disseminated IA was less than 1 year in most studies, but some dogs were alive years later, sometimes still on indefinite duration antifungal treatment.37 Little information exists about outcome and treatment in cats with IA.

Candida The cases of candidiasis in the veterinary literature are variable in their outcomes. In general since Candida organisms are opportunistic and cause disease in concert with another underlying condition, often with concurrent immune dysfunction, outcomes are guarded. Disseminated candidiasis always indicates an incompetent immune system, which suggests a poor outcome. However, appropriate control of the primary disease process and concurrent systemic antifungal therapy can lead to survival.15,16,18

REFERENCES 1. Blondin N, Baumgardner DJ, Moore GE, Glickman LT: Blastomycosis in indoor cats: suburban Chicago, Illinois, USA, Mycopathologia 163:59-66, 2007. 2. Vorathavorn VI, Sykes JE, Feldman DG: Cryptococcus as an emerging systemic mycosis in dogs, J Vet Emerg Crit Care 23(5):489-497, 2013. 3. Lester SJ, Malik R, Bartlett KH, Duncan CG: Cryptococcus: update and emergence of Cryptococcus gattii, Vet Clin Path 40:4-17, 2011. 4. Trivedi SR, Sykes, JE, Cannon MS, et al: Clinical features and epidemiology of cryptococcosis in cats and dogs in California: 93 cases (1988-2010), J Am Vet Med Assoc 239:357-369, 2011. 5. Davidson AP, Shubitz LF, Alcott CJ, Sykes JE: Selected clinical features of coccidioidomycosis in dogs, Med Mycol 57:S67-S75, 2019. 6. Graupmann-Kuzma A, Valentine BA, Shubitz LF, Dial SM, Watrous B, Tornquist SJ: Coccidioidomycosis in dogs and cats: a review, J Am Anim Hosp Assoc 44:226-235, 2008. 7. Arbona N, Butkiewicz CD, Keyes M, Shubitz LF: Clinical features of cats diagnosed with coccidioidomycosis in Arizona, 2004-2018, J Fel Med Surg 22:129-137, 2020.

CHAPTER 92  Fungal Infections 8. Greene RT, Troy GC: Coccidioidomycosis in 48 cats: a retrospective study (1984-1993), J Vet Int Med 9(2):86-91, 1995. 9. Bromel C, Greene CE: Histoplasmosis. In Greene CE, editor: Infectious diseases of the dog and cat, ed 4, St. Louis, 2012, Elsevier Saunders, pp 614-621. 10. Wilson AG, KuKanich KS, Hanzlicek AS, Payton ME: Clinical signs, treatment, and prognostic factors for dogs with histoplasmosis, J Am Vet Med Assoc 252:201-209, 2018. 11. Aulakh HK, Aulakh KS, Troy GC: Feline histoplasmosis: a retrospective study of 22 cases (1986-2009), J Am Anim Hosp Assoc 48:182-187, 2012. 12. Barrs VR, Talbot JJ: Feline aspergillosis, Vet Clin Small Anim 44:51-73, 2014. 13. Day MJ: Canine disseminated aspergillosis. In Greene CE, editor: Infectious diseases of the dog and cat, ed 4, St. Louis. 2012, Elsevier Saunders, pp 663-666. 14. Bieganska M, Dardzinska W, Dworecka-Kaszak B: Fungal colonization- an additional risk factor for diseased dogs and cats? Ann parasitol 60:139-146, 2014. 15. Reagan KL, Dear JD, Kass PH, Sykes JE: Risk factors for Candida urinary tract infections in dogs and cats, J Vet Int Med 33:648-653, 2019. 16. Bradford K, Meinkoth J, McKeirnen K, Love B: Candida peritonitis in dogs: report of 5 cases, Vet Clin Pathol 42:227-233, 2013. 17. Willems N, Houwers DJ, Schlotter YM, Theelen B, Boekhout T: Disseminated candidiasis in a young, previous healthy dog and review of literature, Mycopathologia 182:591-596, 2017. 18. Duchaussoy A, Rose A, Talbot JJ, Barrs VR: Gastrointestinal granuloma due to Candida albicans in an immunocompetent cat, Med Mycol Case Rep 10:14-17, 2015. 19. Legendre AM, Becker PU: Evaluation of the agar-gel diffusion test in the diagnosis of canine blastomycosis, Am J Vet Res 41:2109-2111, 1980. 20. Spector D, Legendre AM, Wheat J, et al: Antigen and antibody testing for the diagnosis of blastomycosis in dogs, J Vet Int Med 22:839-843, 2008. 21. Holbrook ED, Greene RT, Rubin SI, et al: Novel canine anti-Coccidioides immunoglobulin G enzyme immunoassay aids in diagnosis of coccidioidomycosis in dogs, Med Mycol 57:800-806, 2019. 22. Schlacks S, Vishkautsan P, Butkiewicz C, Shubitz L: Evaluation of a commercially available, point-of-care Coccidioides antibody lateral flow assay to aid in rapid diagnosis of coccidioidomycosis in dogs, Med Mycol 58:328-332, 2019. 23. Billen F, Peeters D, Peters IR, et al: Comparison of the value of measurement of serum galactomannan and Aspergillus-specific antibodies in the

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diagnosis of canine sino-nasal aspergillosis, Vet Microbiol 133:358-365, 2009. 24. Foy DS, Trepanier LA, Kirsch EJ, Wheat LJ: Serum and urine blastomycosis antigen concentrations as markers of clinical remission in dogs treated for systemic blastomycosis, J Vet Int Med 28:305-310, 2014. 25. Krockenberger MB, Marschner C, Martin P, et al: Comparing immunochromatography with latex antigen agglutination testing for the diagnosis of cryptococosis in cats, dogs, and koalas, Med Mycol 58:39-46, 2020. 26. Reagan Kl, McHardy I, Thompson GR III, Sykes JE: Evaluation of the clinical performance of two point-of-care cryptococcal antigen tests in dogs and cats, J Vet Intern Med 33:2082-2089, 2019. 27. Kirsch EJ, Greene RT, Prahl A, et al: Evaluation of Coccidioides antigen detection in dogs with coccidioidomycosis, Clin Vaccine Immunol 19: 343-345, 2012. 28. Cunningham L, Cook A, Hanzlicek A, et al: Sensitivity and specificity of Histoplasma antigen detected by enzyme immunoassay, J Am Anim Assoc 51:306-310, 2015. 29. Sharman MJ, Mansfield CS: Sinonasal aspergillosis in dogs: a review, J Sm Anim Pract 53:434-444, 2012. 30. Garcia RS, Wheat LJ, Cook AK, Kirsch EJ, Sykes JE: Sensitivity and specificity of a blood and urine galactomannan antigen assay for diagnosis of systemic aspergillosis in dogs, J Vet Int Med 26:911-919, 2012. 31. Walton RA, Wey A, Hall KE: A retrospective study of anti-inflammatory use in dogs with pulmonary blastomycosis: 139 cases (2002-2012), J Vet Emerg Crit Care 27:439-443, 2017. 32. O’Brien MA, McMichael MA, Le Boedec K: 25-hydroxyvitamin D concentrations in dogs with naturally acquired blastomycosis, J Vet Int Med 32:1684-1691, 2018. 33. Crews LJ, Feeney DA, Jessen CR, Newman AB, Sharkey LC: Utility of diagnostic tests for and medical treatment of pulmonary blastomycosis in dogs: 125 cases (1989-2006), J Am Vet Med Assoc 232:222-227, 2008. 34. Balber C, Hill TL, Bommer NX: Minimally invasive treatment of sino-nasal aspergillosis in dogs, J Vet Int Med 32:2069-2073, 2018. 35. Belda B, Petrovitch N, Mathews KG: Sinonasal aspergillosis: outcome after topical treatment in dogs with cribriform plate lysis, J Vet Int Med 32;1353-1358, 2018. 36. Corrigan VK, Legendre AM, Wheat LJ, et al: Treatment of disseminated aspergillosis with posaconazole in 10 dogs, J Vet Int Med 30:167-173, 2016. 37. Elad D: Disseminated canine mold infections, Vet J 243:82-90, 2019.

93 Viral Infections Jane E. Sykes, BVSc (Hons), PhD, MBA, DACVIM

KEY POINTS • A number of viral infections may be associated with acute and severe illness, leading to presentation of affected dogs and cats to emergency and critical care veterinarians. • Treatment of viral infections is generally supportive and includes intravenous fluid therapy, early nutrition, antiemetic therapy, supplemental oxygen therapy, and antimicrobials for secondary bacterial infections. Hospitalization in isolation may be required.

• The feline leukemia virus and feline immunodeficiency virus status of all cats should be known. • The use of antiviral medications is limited, and few controlled studies evaluate their effectiveness in dogs and cats. Famciclovir can be effective for treatment of severe infections by feline herpesvirus 1, and new drugs have shown success for treatment of feline infectious peritonitis.

A large number of viruses can cause acute and severe illness in dogs and cats (Table 93.1). The most common or important viral infections that may come to the attention of emergency and critical care veterinarians are infections caused by canine parvovirus (CPV), canine distemper virus (CDV), canine influenza viruses (CIVs), feline panleukopenia virus, feline herpesvirus 1 (FHV-1), feline calicivirus (FCV), feline infectious peritonitis virus (FIPV), feline immunodeficiency virus (FIV), feline leukemia virus (FeLV), and rabies virus infection. The possibility of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a consideration in cats with acute cardiorespiratory illness. The FIV and FeLV status of all cats should be determined on arrival by questioning the owner or testing using in-house enzyme-linked immunosorbent assays (ELISAs) for FeLV antigen and FIV antibody. Because cats may be infected subclinically by these viruses and because some cats subsequently undergo regressive FeLV infections, positive test results alone are not reason for euthanasia. CPV infection is covered in the following chapter. Other viral diseases that emergency and critical care veterinarians may be faced with include enteric viral infections such as rotavirus and coronavirus infections, feline paramyxovirus infection, pseudorabies virus infection, vector-borne viral infections such as West Nile virus infection, infectious canine viral hepatitis, and canine herpesvirus infection. An extensive discussion of the etiology, clinical signs, diagnosis, treatment, and prevention of every one of these infections is beyond the scope of this chapter. Instead, the purpose of this chapter is to provide the reader with an update on selected common and important viral infections in dogs and cats that may be evaluated by emergency and critical care veterinarians. Treatment of viral infections is largely supportive and usually includes intravenous fluid therapy, early enteral or parenteral nutrition, antiemetics, analgesia, and oxygen therapy when pulmonary disease is present. Blood products may be needed for cats with retroviral infections. Antibiotics may be needed for secondary bacterial infections. Attempts to culture secondary bacterial invaders and determine susceptibility to antimicrobial agents should be considered before commencing antimicrobial therapy. Use of antiviral medications is still limited in dogs and cats, but famciclovir can be

effective for treatment of severe infections with FHV-1, and novel compounds recently have been identified for treatment of FIP in cats.

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CANINE DISTEMPER VIRUS INFECTION CDV infection is a contagious disease of dogs that may involve the gastrointestinal (GI), respiratory, or neurologic systems. Distemper still occurs sporadically, even in vaccinated dog populations. Disease most commonly occurs in dogs 3 to 6 months of age, when maternal antibody level is declining, but can occur in older dogs that have been vaccinated infrequently or improperly, especially after stress, immunosuppression, or contact with other affected dogs.1 CDV is an enveloped RNA virus that belongs to the family Paramyxoviridae. The virus survives for about 3 hours at room temperature and is highly susceptible to routine hospital disinfectants such as quaternary ammonium compounds. Several geographic lineages of CDV exist that contain strains that vary in pathogenicity. Some, such as the Snyder Hill strain, are more likely to produce neurologic disease than others. Although concern has been raised that vaccine strains may not provide adequate protection against strains circulating in North America, cross-neutralization studies suggest that differences are not sufficient to warrant changes in the current vaccines. The development of distemper in vaccinated dogs instead usually reflects failure of immunization as a result of the improper administration of vaccines, improperly timed vaccination, or the use of vaccines that have been stored and handled inappropriately. CDV is shed in respiratory secretions for up to 90 days after infection. Initial replication of CDV is in lymphoid tissue, and viral destruction of lymphocytes results in lymphopenia and pyrexia. Approximately 1 week after infection the virus spreads to epithelial tissues (lungs, GI tract, kidney, bladder) and the central nervous system (CNS), and virus shedding begins. Poor cell-mediated immunity (CMI) is associated with spread of the virus to a variety of tissues, severe respiratory and GI signs with or without CNS involvement, and death. Dogs with an intermediate or delayed CMI response may develop persistent infection of the uvea, CNS, and footpad and nasal

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TABLE 93.1  Viral Infections That Should Be Included on the List of Differential Diagnosis in

Dogs and Cats with Respiratory, Gastrointestinal, or Neurologic Signs AFFECTED BODY SYSTEM Species Dog

Respiratory Canine distemper

Gastrointestinal Canine distemper

Neurologic Canine distemper

Influenza viruses

Canine parvovirus

Rabies

Canine parainfluenza

Canine enteric coronavirus

Canine adenovirus

Rotaviruses, astroviruses, adenoviruses, caliciviruses, and several other novel viruses such as norovirus

Arthropod-borne infections (togaviruses, bunyaviruses, and flaviviruses)a

Canine herpesvirus Canine respiratory coronavirus Possibly other viruses such as canine pneumovirus Cat

Feline calicivirus

Feline panleukopenia

Feline panleukopenia

Feline herpesvirus

Feline coronavirus

Feline infectious peritonitis

Feline infectious peritonitis

Rotavirus

Rabies

Influenza viruses

Retrovirusesb

FIV

SARS-CoV-2

Retrovirusesb

Retrovirusesb

Paramyxoviruses

FIV, feline immunodeficiency virus; SARS-CoV-2, severe acute respiratory syndrome coronavirus. a These also have the potential to cause disease in cats, but disease has been reported more often in dogs. Most animals are infected subclinically. b Feline retrovirus infections also may be associated with these signs through induction of neoplastic disease or secondary infections resulting from immunosuppression.

epithelium, leading to neurologic, cutaneous (hard pad), and ocular signs such as chorioretinitis. Infection with CDV is highly immunosuppressive, and secondary infections with opportunistic pathogens such as Nocardia and Salmonella spp. may occur. Distemper should be high on the list of differential diagnoses for any dog with respiratory and/or CNS signs. Mild signs are common and resemble those of kennel cough. Severe, generalized distemper may begin with a serous to mucopurulent conjunctivitis and rhinitis and progress to include signs of lower respiratory disease, lethargy, anorexia, vomiting and diarrhea, severe dehydration, and death. Neurologic signs then occur in some dogs, either with systemic illness or after a several-week delay. Neurologic signs are frequently progressive despite treatment and are a poor prognostic sign. Myoclonus, an involuntary twitching of various muscle groups, can be most pronounced when affected dogs are at rest and is virtually pathognomonic for CDV infection. Ocular signs may consist of sudden blindness resulting from optic neuritis, chorioretinitis, or retinal detachment. Footpad and nasal hyperkeratosis often are accompanied by neurologic complications, whereas the presence of vesicular and pustular dermatitis implies a good CMI response and rarely is associated with neurologic complications. Physical examination of dogs suspected to have distemper should include a fundic examination, careful inspection of the skin, including the nose and footpads, and careful thoracic auscultation. Any dog suspected to have distemper should be placed in isolation if possible. This may be complicated by a requirement for oxygen therapy. Acutely, cytologic examination of conjunctival scrapings may show cytoplasmic inclusions in epithelial cells when stained with Wright or Diff-Quik stain (Fig. 93.1). The sensitivity of cytology is increased after application of immunofluorescent antibody to smears by regional diagnostic laboratories, but specificity may suffer when nonspecific fluorescence is interpreted erroneously as a positive result.

Fig. 93.1  Distemper virus inclusion within the cytoplasm of a conjunctival epithelial cell. Diff-Quik stain.

Intracytoplasmic inclusions also may be seen in erythrocytes, lymphocytes, other white blood cells, and cells within the cerebrospinal fluid (CSF). Thoracic radiography may reveal an interstitial pattern or an alveolar pattern with secondary bacterial bronchopneumonia. Analysis of CSF may show increased protein and cell count. The use of real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assays now has largely replaced the use of immunocytochemistry and immunohistochemistry for diagnosis of distemper. Specimens suitable for RT-PCR testing include conjunctival swabs, buffy coat cells, whole blood, serum, CSF, and urine. The author recommends use of whole blood for RT-PCR diagnosis of distemper. Quantitative assays may be useful for differentiation of natural infection from vaccination.2 Immunohistochemistry for CDV antigen can also be performed on biopsies of nasal mucosa and footpad epithelium.

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Administration of attenuated live vaccines can prevent canine distemper and should provide at least partial protection even in the face of variant strains. The interested reader is referred to a comprehensive review of vaccination for CDV for further information on the topic.1

INFLUENZA VIRUS INFECTIONS Canine influenza H3N8 first appeared in racing Greyhounds in Florida between 1999 and 2003.3 Subsequently, evidence of CIV H3N8 infection was detected in dogs in animal shelters, adoption groups, pet stores, boarding kennels, and veterinary clinics across the USA. The most significant outbreaks of disease resulting from CIV occurred in Florida, New England, Colorado, Wyoming, and Texas. All the genes from canine isolates were of equine influenza virus origin, providing evidence that the virus crossed the species barrier. The prevalence of infection among dogs with this virus in the USA has been decreasing, and the virus may be extinct in the USA at the time of writing.4 An H3N2 virus strain was introduced into the Chicago area in an imported dog from Korea in February–March of 2015, after which it spread to several other states within the United States, especially North Carolina and Georgia. Additional importation events have contributed to outbreaks of infections elsewhere in the USA, including an outbreak in southern California at the time of writing. Spillover infections have also been described in domestic cats, although these have been confined to the shelter populations where they emerged, and the viruses do not appear to undergo prolonged transmission in household cats. In 2016, an outbreak of avian influenza H7N2 occurred in cats in a New York shelter, with evidence of limited transmission to shelter workers.6 More detail on these and other influenza virus strains identified in dogs and cats can be found elsewhere in the literature.4 As enveloped viruses, influenza viruses are susceptible to routine hospital disinfection practices. Clinical signs occur 2 to 5 days after exposure. As with distemper, canine influenza virus causes a syndrome that may mimic kennel cough, although fever may be more likely to occur with influenza virus infections than with infections with other common respiratory pathogens. Signs consist of a cough that persists for 2 to 3 weeks despite therapy, serous to mucopurulent nasal discharge, and a low-grade fever. Some dogs develop more severe pneumonia with a high fever (104°F to 106°F), tachypnea, and respiratory distress. Shedding of virus occurs for 7 to 10 days after the onset of clinical signs, although dogs infected with H3N2 influenza virus have occasionally been noted to shed for 20 days.5 Dogs with these signs should be placed in isolation. Findings on thoracic radiography are the same as those described above for distemper. Nucleic acid testing using RT-PCR can be performed on pharyngeal swab specimens. Detection of virus appears to be difficult beyond 3 to 4 days after the onset of clinical signs; the same is true for virus isolation.4 Virus isolation and RT-PCR also can be successful when performed on lung tissue from dogs that have died within 2 to 3 days of the onset of clinical signs. Swabs for virus isolation must be placed in virus transport medium. Treatment of serious influenza virus infection in human patients has involved the use of the neuraminidase inhibitor oseltamivir phosphate, which inhibits spread of the virus from cell to cell. Anecdotal reports exist regarding treatment of dogs with this drug, but no published studies are available, and nothing is known regarding the optimal dosage in dogs to inhibit viral replication. Until the results of such studies become available, use of this drug to treat dogs that have been diagnosed definitively with influenza virus infections is not recommended.

OTHER EMERGING RESPIRATORY VIRAL INFECTIONS OF DOGS Other emerging respiratory viral pathogens of dogs include canine respiratory coronavirus (CRCoV) and canine pneumovirus. CRCoV was reported first in 2003 in a group of dogs with respiratory disease in a rehoming facility in England that had been vaccinated against canine adenovirus-2, CDV, and canine parainfluenza virus.6 It is distinct from canine enteric coronavirus. Alone, CRCoV causes subclinical infections or mild respiratory disease, but like human respiratory coronaviruses, it may cause reversible damage to, or loss of, the respiratory epithelial cell cilia. As a result, infected dogs become predisposed to secondary infections. Canine pneumovirus is a parainfluenza virus that belongs to the genus Pneumovirus. It was isolated first from dogs with acute respiratory disease in shelters in the United States in 2010.7 There is mounting evidence that this virus is associated with respiratory disease in dogs worldwide.8,9

FELINE PANLEUKOPENIA Feline panleukopenia is caused by a small, single-stranded DNA virus closely related to CPV. Cats with feline panleukopenia also may be infected with CPV strains 2a, 2b, and 2c.10 Although most cats shed virus for just a few days after infection, it may be shed for as long as 6 weeks, and viral persistence in the environment plays an important role in disease transmission. The virus can survive for a year at room temperature on fomites and survives disinfection with routine hospital disinfectants; inactivation generally requires a 1:30 dilution of household bleach, potassium peroxymonosulfate, or concentrated accelerated hydrogen peroxide solutions. Feline panleukopenia should be suspected in poorly vaccinated kittens with acute illness including fever, lethargy, anorexia, vomiting and, less commonly, diarrhea. Oral ulceration and icterus may be noted in complicated infections. Death may result from severe dehydration, secondary bacterial infections, and disseminated intravascular coagulation. Cats between 3 and 5 months of age may be most susceptible to severe disease, which is exacerbated by concurrent gastrointestinal infections. Cats suspected to have feline panleukopenia should be placed in isolation. Supportive treatment is similar to that recommended for CPV. Diagnosis is based on clinical signs along with the finding of leukopenia on a complete blood count. Leukopenia is not always present and may occur with other diseases such as salmonellosis. In-house fecal ELISAs for CPV are suitable for diagnosis of feline panleukopenia, although false-negative results may occur, so a negative test result does not rule out feline panleukopenia. Sensitivity in one study ranged from 50% to 80% depending on the kit used, and specificity ranged from 94% to 100%. False-positive fecal antigen assay results after vaccination with attenuated live viral vaccines appear to be uncommon but vary with the test used.11 PCR assays are also available for detection of viral DNA in fecal and tissue specimens from affected cats. Cats with panleukopenia that survive the first 5 days of treatment usually recover, although recovery is often more prolonged than it is for dogs with parvoviral enteritis. In 244 cats with feline panleukopenia from Europe, the survival rate was 51%.12 Nonsurvivors had lower leukocyte and platelet counts than survivors, and cats with white cell counts below 1000/µl were almost twice as likely to die than those with white cell counts above 2500/µl. Only total leukopenia, and not lymphopenia, was correlated with mortality. Hypoalbuminemia and hypokalemia also were associated with an increased risk of mortality.

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FELINE RESPIRATORY VIRAL DISEASE The most common causes of feline respiratory viral disease are FHV-1 and FCV. FHV-1 is an enveloped DNA virus. It survives a maximum of 1 day at room temperature and is susceptible to destruction by common disinfectants. FCV is a nonenveloped RNA virus, which can survive weeks at room temperature. Inactivation requires hypochlorite solutions, concentrated accelerated hydrogen peroxide solutions, or potassium peroxymonosulfate; quaternary ammonium compounds are not effective.13 FHV-1 and FCV infections may be acquired by contact with acutely infected cats, contact with organisms in the environment, or by contact with carrier cats. Both viruses replicate mainly in the tonsils and respiratory tissues. In addition to the nasal, conjunctival, and oral shedding common to both viruses, FCV also is shed in the feces and occasionally in the urine. Almost all cats infected with FHV-1 develop lifelong latent infections of the trigeminal ganglia. Reactivation of virus shedding occurs in roughly 50% of infected cats, with or without concurrent clinical signs. This may occur spontaneously or after stressful events. Shedding occurs 4 to 11 days after the stress and lasts 1 to 2 weeks. In contrast, shedding of FCV by persistently infected cats is continuous and not affected by stress. In some cats, shedding is lifelong; in others, it ceases after several weeks. Acute disease caused by FCV and FHV-1 occurs after an incubation period of 2 to 10 days. The most severe signs tend to occur in very young and elderly debilitated cats. Concurrent immunosuppressive illness or infection with other respiratory pathogens and opportunistic bacteria can influence dramatically the severity of disease. Clinical signs common to both infections include conjunctivitis, serous or mucopurulent nasal discharge and sneezing and, less commonly, cough and dyspnea. Lethargy, anorexia, hypersalivation, and pyrexia also may be present in acute infections. FHV-1, but not FCV, may be associated with corneal ulceration and keratitis. Ulcerative glossitis is more common and severe with FCV infection but may be associated with FHV-1 infection. A small proportion of FCV carriers develop chronic lymphoplasmacytic or chronic ulceroproliferative gingivostomatitis, which is often refractory to therapy. Transient lameness and pyrexia have been reported in association with acute FCV infection and after FCV vaccination. Highly virulent strains of FCV have been isolated from outbreaks of severe systemic febrile illness.14 This condition is characterized by a high mortality, fever, anorexia, ulcerative facial dermatitis, and diffuse cutaneous edema (Fig. 93.2). Coagulopathies can also develop, along with hypoproteinemia and mild hyperbilirubinemia. Suspected or confirmed outbreaks of infection report shared several significant features: (1) in every outbreak in which a suspected index case was identified, a hospitalized shelter cat appeared to be the source of infection; (2) otherwise healthy, adult, vaccinated cats have been affected prominently, whereas kittens tended to show less severe signs; (3) spread occurred very readily, including via fomites to cats belonging to hospital employees and clients; (4) spread of disease was limited to the affected clinic(s) or shelter, with no spread within the community reported; and (5) the outbreak resolved within approximately 2 months. Attempts to make a diagnosis in cases of feline respiratory viral illness are encouraged especially in catteries because knowledge of the causative organism can assist with treatment strategies. Because of the communicability and high mortality associated with virulent FCV infection, testing is essential for cats suspected to have the systemic febrile syndrome, and suspect cats should immediately be handled as if they were infected with the organism. Infection with FCV and FHV-1 can be diagnosed using virus isolation or PCR assays from nasal, conjunctival,

Fig. 93.2  A kitten suffering from virulent systemic calicivirus disease (FCV-Kaos strain) showing characteristic signs of facial edema and crusting and alopecia of the face and pinnae.(From August J: Consultations in feline internal medicine, vol 5, St. Louis, 2006, Elsevier.)

or oropharyngeal swabs, although oropharyngeal swabs are most likely to yield a diagnosis. However, because apparently healthy cats commonly have positive results using PCR assays for FHV-1, it may not be possible to prove an association with a particular disease.15 Results should be interpreted carefully in light of the clinical signs present. Cats with severe upper respiratory tract signs and suspected or confirmed FHV-1 infection may benefit from treatment with systemic or topical antiherpes viral drugs. The most effective and safe systemic antiherpes viral drug is famciclovir. Famciclovir is a prodrug that is converted to penciclovir. The latter is a guanosine analog that inhibits the viral DNA polymerase. Famciclovir has been used safely in kittens as young as 12 days of age. The dosage of famciclovir is 40 to 90 mg/kg PO q8h.16 Cats with herpetic keratitis can be treated with topical ophthalmic antivirals such as trifluridine, idoxuridine, vidarabine, or a 0.5% solution of cidofovir. Although more expensive, cidofovir has the advantage of requiring only twice daily administration, whereas idoxuridine, trifluridine, and vidarabine must be administered 5 to 6 times a day. The outbreaks of systemic febrile caliciviral disease have demonstrated the importance of control measures to limit the spread of feline respiratory viruses because of the high mortality, poor efficacy of vaccines, and lack of specific treatments. Quick recognition and implementation of effective control measures, including disinfection, quarantine, and testing procedures, are critical to reduce the impact of this disease. An adjuvanted, inactivated vaccine that contained a hypervirulent strain was introduced in the United States in 2007. However, the degree to which this vaccine cross-protected against other hypervirulent strains was unknown, and in every outbreak, the strain differed, and the outbreak ceased when infection control measures were implemented. Subsequently, a bivalent inactivated FCV vaccine was marketed for protection against FCV infections that contains a hypervirulent and non-hypervirulent FCV strain together with attenuated live FHV-1 and FPV viruses (Ultra Hybrid FCRCP, Elanco, USA); the advantage of this vaccine is the broader cross-protection it may offer against all strains of FCV.

FELINE INFECTIOUS PERITONITIS FIPV infection is caused by feline coronavirus, an enveloped RNA virus. It is hypothesized that a relatively nonpathogenic feline coronavirus that replicates within the gastrointestinal tract (FCoV) mutates

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within the host to form virulent FIPV (internal mutation theory). Mutation occurs soon after infection with FCoV, or years later. Spread of FIP from cat to cat does not occur, so affected cats do not have to be isolated. Up to 1 in 4 cats in single-cat households have antibodies to FCoV, whereas in some multi-cat households, all cats may have positive titers. In contrast, 1 in 5000 cats in single-cat households develop FIP compared with 5% of cats in catteries. The incidence of FIP is related to levels of virus in the environment, immunosuppression resulting from overcrowding and other stressors, and genetic factors. Purebred cats are more susceptible, and affected cats are usually 3 months to 3 years of age. However, older cats can also be affected, perhaps because of waning immune function. Feline coronavirus is highly infectious and is spread via the fecal– oral route. FCoV replicates in enterocytes and destroys the villus tips, sometimes resulting in mild gastrointestinal signs. Virulent FIPV strains possess the ability to replicate within macrophages and possibly lose the ability to replicate in enterocytes. Cats with a poor CMI response develop pyogranulomatous vasculitis because of deposition of antigen-antibody complexes within the venular epithelium. Pleural and peritoneal effusions develop (effusive FIP). Cats with a partial CMI response are able to slow replication of the virus, with subsequent granuloma formation in a variety of tissues (non-effusive FIP). This may deteriorate to effusive FIP if the CMI response wanes. Cats with FIP often are evaluated for fever, weight loss, anorexia, and lethargy. Other signs and physical examination abnormalities may include respiratory distress resulting from pleural effusion or pneumonia, abdominal distention because of ascites, abdominal masses, icterus, splenomegaly, irregular renomegaly, anterior uveitis, retinal detachments, multifocal neurologic signs, and GI signs relating to organ failure or obstructive intestinal masses. FIP remains an antemortem diagnostic challenge. The presence of hyperglobulinemia on the complete blood count may increase suspicion for FIP, but it is not present in all cats and may occur with other diseases. The presence of high-protein (5 to 12 g/dl), low-cellularity (predominantly neutrophils) effusion fluid is also supportive of the diagnosis. However, tests such as the serum or effusion albumin-toglobulin ratio, effusion g-globulin concentration, and the Rivalta test can be associated with false-positive and false-negative results, especially in populations in which the prevalence of FIP is low. Serologic tests that detect anti-FCoV antibody are not FIP tests. Positive test results mean only exposure to a coronavirus, and many healthy cats have positive titers but never develop FIP. In one study, titers of 1:1600 or greater in cats that were suspected to have FIP had a 94% chance of truly having FIP, but cats that had any coronavirus antibody titer had a 44% chance of truly having FIP.17 However, considerable interlaboratory variation in assay results occurs, so this may not be true for serology performed at all laboratories. Although it lacked sensitivity, positive immunocytochemistry for feline coronavirus on macrophages in effusion fluid was believed to be specific. Subsequent research showed that false positives can occur, possibly due to nonspecific staining or FCoV viremia.18 Mutations that occur when FCoV becomes a virulent FIPV strain are not predictable, and there is no way to consistently distinguish the viruses based on nucleotide sequence. IDEXX’s FIP Virus Real PCR test detects mutations in locations associated with systemic spread of the virus, but positive results can still occur in cats that do not have FIP. Because FCoV may be found within tissues and body fluids, positive results when testing tissues or fluids using RT-PCR do not indicate FIP, although high viral loads are more likely to be associated with FIP. Identification of high viral mRNA loads is the basis for one veterinary diagnostic RT-PCR assay.19 The standard for diagnosis of FIP is detection of

pyogranulomatous vasculitis on histopathologic examination of biopsy specimens, with intralesional virus antigen as detected using immunostaining techniques. Treatment of FIP remains a challenge, but recent discovery of antiviral compounds active against coronaviruses has resulted in new hope for cure of this disease. Before this, the only medication that appears to slow the progression of the disease in cats was prednisolone. With prednisolone alone, most cats typically live only a few months after diagnosis, although occasionally survival times of up to 2 years have been documented when the disease has been detected early. The most promising antiviral agent that has been identified for treatment has been the adenosine nucleotide analog GS-441524, a metabolite of the antiviral drug remdesivir, which was developed for treatment of COVID-19. Use of this drug at 4 mg/kg q24h SC for 12 weeks was associated with recovery over a 2-week period in 84% of 31 treated cats.20 Some cats relapsed, and some of those cats were successfully treated with another course of treatment. At the time of publication, GS-441524 is not FDA approved and cannot be purchased legally from a regulated source. In the future, remdesivir may represent an alternative and more available treatment for FIP.

SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS-2 SARS-CoV-2 first appeared in late 2019 as a cause of human respiratory illness in Wuhan, China, and spread to cause a global pandemic of human illness in 2020, with the emergence of several variants of concern, including the highly transmissible Delta variant that continued to create major public health challenges despite efforts to vaccinate the majority of the human population. The virus infects cells using the angiotensin converting enzyme 2 (ACE2) receptor, and similarities between this receptor in humans and a variety of animal species may in part explain broad susceptibility of multiple host species to infection. Over the 18 months that followed the appearance of SARS-CoV-2, infections were reported in dogs and cats that were in contact with infected humans worldwide, with most infections being subclinical. In a study from Texas that was conducted in late 2020, 3/17 cats and 1/59 dogs in contact with humans with COVID-19 tested positive for SARS-CoV-2.21 Although some naturally infected dogs showed clinical signs of illness, the signs were thought to be due to comorbidities, with SARS-CoV-2 infection an incidental finding. In contrast, cats appear to be more susceptible to natural infection, and although most infections also appear to be subclinical, mild to severe respiratory disease has been described in some cats, with shedding of virus for over a week. Intralesional virus antigen was detected in the lungs of one cat that died of pneumonia in the United Kingdom.22 In another cat from Virginia, SARS-CoV-2 infection was also considered to be the primary cause of death, and hypertrophic cardiomyopathy was thought to have predisposed to severe disease.23 Infection with the B.1.1.7 variant in the United Kingdom was also associated with an increased incidence of myocarditis in dogs and cats seen at a specialty hospital, and it has been suggested that the virus may infect cardiomyocytes in cats, although further studies are required.24 Susceptibility to infection and disease may also relate to the density and distribution of ACE2 receptors in the respiratory tract and other tissues.25 Dogs and cats are not thought to represent a significant source of infection for humans, although it remains possible that cats could transmit infection based on the quantity of virus shed in some studies; experimentally infected cats can transmit infection to incontact cats.26 Emergency and critical care veterinarians should consider SARS-CoV-2 as a potential cause of illness in cats presenting with acute respiratory or cardiorespiratory disease, especially if there

CHAPTER 93  Viral Infections is a history of human infection in the household. Readers are referred to CDC guidance for prevention and control of infection in veterinary clinics treating companion animals.27

REFERENCES 1. Sykes JE, Vandevelde M: Canine distemper virus infection. In Sykes JE, editor: Greene’s infectious diseases of the dog and cat, ed 6, Philadelphia, 2021, Saunders Elsevier. In press. 2. IDEXX Laboratories. 2017. Available at: https://www.idexx.com/files/ idexx-introduces-cdv-quant-realpcr.pdf. Last accessed August 15, 2021. 3. Crawford PC, Dubovi EJ, Castleman WL, et al: Transmission of equine influenza virus to dogs, Science 310:482, 2005. 4. Parrish CR, Voorhees IEH: H3N8 and H3N2 canine influenza viruses: understanding these new viruses in dogs, Vet Clin North Am Small Anim Pract 49:643-649, 2019. 5. Newbury S, Godhardt-Cooper J, Poulsen KP, et al: Prolonged intermittent virus shedding during an outbreak of canine influenza A H3N2 virus infection in dogs in three Chicago area shelters: 16 cases (March to May 2015), J Am Vet Med Assoc 248:1022–1026, 2016. 6. Erles K, Toomey C, Brooks HW, et al: Detection of a group 2 coronavirus in dogs with canine infectious respiratory disease, Virology 310:216-223, 2003. 7. Renshaw RW, Zylich NC, Laverack MA, et al: Pneumovirus in dogs with acute respiratory disease, Emerg Infect Dis 16:993-995, 2010. 8. More GD, Cave NJ, Biggs PJ, et al: A molecular survey of canine respiratory viruses in New Zealand, N Z Vet J 69:224-233, 2021. 9. Day MJ, Carey S, Clercx C, et al: Aetiology of canine respiratory disease complex and prevalence of its pathogens in Europe, J Comp Pathol 176:86-108, 2020. 10. Ikeda Y, Nakamura K, Miyazawa T, et al: Feline host range of canine parvovirus: recent emergence of new antigenic types in cats, Emerg Infect Dis 8:341, 2002. 11. Patterson EV, Reese MJ, Tucker SJ, et al: Effect of vaccination on parvovirus antigen testing in kittens, J Am Vet Med Assoc 230:359-363, 2007. 12. Kruse BD, Unterer S, Horlacher K, et al: Prognostic factors in cats with feline panleukopenia, J Vet Intern Med 24:1271-1276, 2010. 13. Doultree JC, Druce JD, Birch CJ, et al: Inactivation of feline calicivirus, a Norwalk virus surrogate, J Hosp Infect 41:51, 1999.

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14. Hurley KF, Pesavento PA, Pedersen NC, et al: An outbreak of virulent systemic feline calicivirus disease, J Am Vet Med Assoc 224:241, 2004. 15. Lappin MR, Blondeau J, Boothe D, et al: Antimicrobial use guidelines for treatment of respiratory disease in dogs and cats: antimicrobial guidelines working group of the International Society for Companion Animal Infectious Diseases, J Vet Intern Med 31:279-294, 2017. 16. Thomasy SM, Shull O, Outerbridge CA, et al: Oral administration of famciclovir for treatment of spontaneous ocular, respiratory, or dermatologic disease attributed to feline herpesvirus type 1: 59 cases (2006-2013), 249:526-538, 2016. 17. Hartmann K, Binder C, Hirschberger J, et al: Comparison of different tests to diagnose feline infectious peritonitis, J Vet Intern Med 17:781, 2003. 18. Felten S, Matiasek K, Gruendl S, et al. Investigation into the utility of an immunocytochemical assay in body cavity effusions for diagnosis of feline infectious peritonitis, J Feline Med Surg 19(4):410-418, 2017. 19. https://www.vetmed.auburn.edu/wp-content/uploads/2015/03/FIP-virus.pdf. 20. Pedersen NC, Perron M, Bannasch M, et al: Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis, J Feline Med Surg 21:271-281, 2019. 21. Hamer SA, Pauvolid-Correa A, Zecca IB, et al: SARS-CoV-2 infections, and viral isolations among serially tested cats and dogs in households with infected owners in Texas, USA, Viruses 13:938, 2021. 22. Hosie MJ, Epifano I, Herder V, et al: Detection of SARS-CoV-2 in respiratory samples from cats in the UK associated with human-to-cat transmission. Vet Rec 188:e247, 2021. 23. Carvallo FR, Martins M, Joshi LR, et al: Severe SARS-CoV-2 infection in a cat with hypertrophic cardiomyopathy. Viruses. 13:1510, 2021. 24. Ferasin L, Fritz M, Ferasin H, et al: Infection with SARS-CoV-2 variant B.1.1.7 detected in a group of dogs and cats with suspected myocarditis. Vet Rec 189:e944,2021. 25. Lean FZX, Nunez A, Spiro S, et al: Differential susceptibility of SARSCoV-2 in animals: evidence of ACE2 host receptor distribution in companion animals, livestock and wildlife by immunohistochemical characterisation, Transbound Emerg Dis 2021. [ePub ahead of print]. 26. Bosco-Lauth AM, Hartwig AE, Porter SM, et al: Pathogenesis, transmission, and response to re-exposure in cats, Proc Natl Acad Sci 117:42, 2020. 27. Centers for Disease Control and Prevention: Information about COVID-19, pets, and other animals. Available at: https://www.cdc.gov/ healthypets/covid-19/veterinarians.html. Last accessed August 15, 2021.

94 Canine Parvovirus Infection Rachael Birkbeck, DVM, PGCert, MVetMed, DACVECC, MRCVS, Karen Humm, MA, VetMB, MSc, CertVA, DACVECC, DipECVECC, FHEA, MRCVS KEY POINTS • Canine parvovirus (CPV) is a common pathogen in young dogs, generally causing disease between the ages of 6 and 20 weeks. • Canine parvovirus is a highly pathogenic virus that can cause severe vomiting and diarrhea and may be fatal. • Vaccination against CPV is practiced widely, but maternal antibodies can prevent a normal response to vaccination. • A fecal enzyme-linked immunosorbent assay allows for a rapid inhouse diagnosis, but a negative result does not rule out infection. • Treatment is mainly supportive with fluid therapy, nutritional support, antiemetics, and, in neutropenic dogs, antibiotics.

• Reported survival rates for dogs treated for CPV infection vary widely (4% to 96%), but prompt and aggressive treatment maximizes the chances of success; the first few days are crucial. • Parvoviridae are very stable, surviving a pH range of 3 to 9 and temperatures of 60°C for 60 minutes. The virus can also survive for up to 1 year in the environment. Therefore, isolation of affected patients and thorough environmental decontamination is vital to decrease the risk of transmission.

PARVOVIRIDAE

antibodies, unsanitary or overcrowded environments, and endo-parasitism.4 Pedigree dog breeds are reported to be at increased risk of CPV-2 infection; it is not clear if this finding is related to genetics, husbandry, and/or environmental factors.2 Prior to 6 months of age sex predilection is equal; however, in dogs older than 6 months, sexually intact males were twice as likely as sexually intact females to develop CPV-2 enteritis in one study.2 Seasonality is reported, with an increased incidence of clinical disease between July and September in the Northern Hemisphere.2

Canine parvovirus is a small, nonenveloped, single-stranded DNA virus that replicates in the nucleus of dividing cells. This leads to the preferential infection of rapidly dividing cells, such as lymphoid tissue, intestinal epithelium, and bone marrow. Canine parvovirus (CPV-1) was discovered in 1967 and was found to cause mild diarrhea. In 1978 a completely new species of the genus Parvoviridae named CPV-2 was recognized. CPV-2 infection caused severe clinical disease resembling panleukopenia in cats.

EPIDEMIOLOGY Historically, infection was characterized by clinical signs occurring simultaneously in immunologically naïve young and mature dogs, resulting in high morbidity and mortality. Today most adult dogs are immune to CPV-2 due to vaccination protocols or prior infection. Subclinical disease, resulting in seroconversion without clinical signs, is reported to occur in unvaccinated adult dogs.1 As such, clinical disease is most frequently reported in dogs less than 6 months of age, generally between the ages of 6 and 20 weeks.2 Immunity to CPV-2 in puppies is dependent on the transfer of maternal anti-CPV-2 antibodies produced in response to vaccination or prior natural infection. Neonates typically achieve an antibody titer equivalent to 50%–60% of the maternal titer and the ingested maternal anti-CPV-2 antibodies have a half-life of approximately 10 days.3 Puppies become vulnerable to infection as maternal antibody levels decline. There is a window of increased susceptibility to infection, which occurs when maternal antibody interferes with the immune response to CPV-2 vaccine but cannot protect against CPV-2 infection.3

RISK FACTORS FOR INFECTION Predisposing factors for the development of parvoviral enteritis in puppies include lack of, or inadequate, transfer of maternal anti-CPV-2

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TRANSMISSION AND PATHOGENESIS CPV-2 infection occurs due to fecal–oral transmission, and clinical signs occur within 4 to 10 days postinfection. The virus replicates initially in oropharyngeal lymphoid tissue and then enters the circulation, resulting in systemic viremia. Infection of the intestinal crypt epithelium occurs due to systemic viremia with fecal viral shedding detected from day 4 postinfection.5 Myocarditis may develop in neonates infected within the first 2 weeks postpartum, as myocardial cell proliferation is incomplete and rapid myocyte division is still occurring. Myocarditis is an extremely rare occurrence today due to widespread maternal immunity and transfer of anti-CPV-2 antibodies.

CLINICAL SIGNS The clinical signs of CPV-2 are primarily related to the effects of the virus on the immune system and gastrointestinal tract. Infrequently, cardiogenic shock, arrhythmias, and pulmonary edema occur in neonates with CPV-2 induced myocarditis. In severely affected animals, clinical findings consistent with sepsis, systemic inflammatory response syndrome, coagulopathy, and multiple organ dysfunction are also observed.

CHAPTER 94  Canine Parvovirus Infection CPV-2 infection is commonly associated with acute-onset lethargy, anorexia, vomiting, abdominal pain, and pyrexia, followed 12 to 48 hours later by small intestinal diarrhea. There may be evidence of gastrointestinal hemorrhage in the vomitus or diarrhea secondary to viral destruction of the intestinal crypts. The vomiting and diarrhea associated with CPV-2 infection are typically severe, resulting in dehydration and hypovolemic shock. Impaired tissue perfusion and oxygenation manifest clinically as obtundation, pale mucous membranes, increased capillary refill time, tachycardia, poor pulse quality, cool extremities, and hypothermia. Abdominal pain may occur secondary to gastroenteritis, pancreatitis, or intestinal intussusception. In dogs with sepsis or systemic inflammatory response syndrome, the mucous membranes may appear injected with a brisk capillary refill time.

CLINICAL PATHOLOGY Leukopenia is frequently observed in dogs with CPV-2 infection; however, white blood cell count may also be normal or increased. Lymphopenia occurs initially as a result of direct lymphocytolysis. The lymphopenia is typically followed by neutropenia because of peripheral consumption and destruction of white blood cell precursors in the bone marrow. Anemia, which may be poorly regenerative, can develop due to repeated blood sampling, gastrointestinal hemorrhage, and an inflammation-related reduction in red blood cell lifespan and suppression of erythropoiesis.6 One study reported that a lymphocyte count over 1.0 3 103/ml in CPV-2 infected dogs on admission and at 24 and 48 hours postadmission had a positive predictive value of 100% for survival.7 Nonsurvivors in the same study failed to develop a degenerative left shift and continued to have significant leukopenia, lymphopenia, eosinopenia, and monocytopenia at 24 and 48 hours after admission. Interestingly, severe neutropenia was not a useful prognostic indictor.7 Biochemical changes in affected dogs may include hypoproteinemia, hyperbilirubinemia, elevated alkaline phosphatase and alanine aminotransferase, hyponatremia, hypochloremia, hypokalemia, hypoglycemia, and a prerenal azotemia. One study reported that dogs with CPV-2 had evidence of acute kidney injury, which was revealed by assessing urine protein:creatinine and novel urinary biomarkers, but was not evident when assessing serum creatinine, urea, or urine specific gravity.8

SEPSIS, SYSTEMIC INFLAMMATORY RESPONSE SYNDROME, AND COAGULATION Parvoviral-induced compromise of intestinal integrity, in combination with neutropenia, is thought to increase the risk of sepsis due to bacterial translocation from the gastrointestinal tract. This appears to occur frequently, with Escherichia coli being cultured from postmortem lung and liver samples in 90% of dogs with parvoviral enteritis, consistent with bacterial translocation from the gastrointestinal tract.9 Significant physiological derangements can occur even in the absence of sepsis due to bacterial endotoxin. Both endotoxin and tumor necrosis factor alpha have been detected in puppies with CPV-2, the latter of which was associated with increased mortality.10 Bacterial endotoxin stimulates a cascade of inflammatory cytokines resulting in vasodilation, increased vascular permeability, decreased cardiac output, acute respiratory distress syndrome, and activation of coagulation (see Chapter 7, SIRS, MODS and Sepsis). Evidence of hypercoagulability without disseminated intravascular coagulation has been documented in dogs with CPV-2 enteritis.11 Proposed mechanisms of hypercoagulability in dogs with CPV-2 include hyperfibrinogenemia, the procoagulant effect of endotoxin and cytokines on the vascular endothelium, antithrombin loss from the

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gastrointestinal tract, and increased antithrombin consumption and dilution.11 The risk of jugular thrombosis should be considered prior to central venous catheter placement.

DIAGNOSTIC INVESTIGATIONS PCR testing is the gold standard for diagnosing CPV-2, and both conventional and real-time laboratory techniques are available. Within a clinical setting, point-of-care enzyme-linked immunosorbent assay (ELISA) tests utilizing immunochromatography to detect CPV-2 fecal antigen are simple to use, rapid, and inexpensive. Depending on the method of validation, fecal antigen ELISA testing has a sensitivity between 18% and 82% and a specificity of up to 100%.12-15 False-negative ELISA fecal antigen results occur due to test failure to detect low levels of fecal antigen early in the course of disease, insufficient sample size, antibody binding of CPV-2 antigen within the gastrointestinal tract, and/or the dilutional effect of diarrhea.15 Further diagnostic testing should be pursued in dogs with a negative in-house fecal CPV-2 antigen ELISA test result if a high clinical index of suspicion for parvoviral enteritis is present. Ideally samples should be submitted for RT-PCR and the fecal ELISA antigen repeated within 36-48 hours while the results are pending. Vaccination with modified live CPV virus can result in low levels of fecal antigen shedding as the virus replicates in the mucosal epithelium.16 However, available evidence suggests that vaccination with modified live CPV-2 does not result in detectable levels of CPV-2 fecal antigen as assessed by SNAP ELISA antigen testing post vaccination.34 Given the high specificity of ELISA fecal antigen testing and the improbability of a false-positive result secondary to vaccination, a positive result likely indicates true infection.

DIAGNOSTIC IMAGING Abdominal radiography may initially be unremarkable in dogs with CPV-2; however, as the disease progresses, diffusely dilated small intestinal loops are frequently observed.18 The administration of radiographic contrast material may be considered to differentiate functional versus mechanical obstruction. However, contrast studies may be abnormal in dogs with parvoviral enteritis and show delayed transit time due to profound ileus, and there is also the risk of contrast material aspiration.18 Abdominal ultrasound may also be used to rule out surgical causes of vomiting, such as gastrointestinal foreign bodies, and also to diagnose intussusception, which may occur in dogs with CPV-2 infection. Abdominal ultrasonographic findings that are consistent with CPV-2 may include ileus, thinning of the duodenal and jejunal mucosa with altered wall layering, hyperechoic mucosal speckling, and undulation of the luminal-mucosal interface.19 These findings are not pathognomonic for CPV-2 enteritis.19 Clinicians should be cognizant that intestinal intussusception is a reported sequela to CPV-2 enteritis and may develop at any time point during the disease course. Abdominal diagnostic imaging should be repeated if sudden changes in clinical signs, physical examination, and/ or pain score occur. Dogs with vomiting and regurgitation are at increased risk of developing aspiration pneumonia. Thoracic imaging should be considered in all dogs with CPV-2 infection that develop dyspnea, coughing, or a new pyrexia. Lung ultrasound is useful for surveillance in dogs with CPV-2 who are at risk of aspiration pneumonia, and thoracic ultrasound can also be used to aid in the assessment of volume status and cardiac contractility (see Chapter 189, Point of Care Ultrasound in the ICU).20-22 In addition, Point-of-Care abdominal ultrasonography can be used to monitor ileus and assess gastric dilation.

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TREATMENT Fluid Therapy Correction of hypovolemia with an isotonic, balanced crystalloid solution should be performed rapidly with the aim to achieve cardiovascular resuscitation (see Chapter 65, Crystalloid Solutions & Chapter 68, Shock Fluid Therapy). The use of vasopressors in critically ill dogs with CPV-2 enteritis can be considered when hypovolemia has been corrected and hypotension is refractory (see Chapter 6, Classification and Initial Management of Shock States). The use of synthetic colloids as a resuscitation fluid is controversial as they are associated with acute kidney injury, coagulopathy, and pathological tissue uptake (see Chapter 66, Colloid Solutions). Plasma can be considered as a resuscitation fluid in dogs that have received significant volumes of crystalloids or are coagulopathic. Correction of dehydration should occur following cardiovascular resuscitation. Dogs with CPV-2 enteritis can have dramatic ongoing fluid losses into the gastrointestinal tract that may not be externally obvious. Reassessment of volume and hydration status may need to be performed as regularly as every 2–4 hours.

Antibiosis Antimicrobials should be reserved for dogs with evidence of bacterial infection, or those with a predisposition for bacterial translocation or increased risk of sepsis. Antibiotic therapy is required in the treatment of CPV-2 in dogs with evidence of bacterial infection and prophylactic therapy is considered appropriate in the management of severely neutropenic dogs with disruption of the intestinal epithelium. Bacterial infection may occur in dogs with CPV-2 due to catheterassociated infections, aspiration pneumonia, and bacterial translocation from the gastrointestinal tract. Whenever possible, antibiotic therapy should be guided by culture and sensitivity results. Parenteral administration of antibiotics to dogs with CPV-2 is preferred as vomiting and gastroparesis may result in reduced absorption of oral preparations. Intravenous administration is ideal because dehydration and hypovolemia may result in decreased absorption of subcutaneous drugs. Neutropenic dogs should be treated with a broad-spectrum antibiotic until the neutropenia has resolved, which can occur as rapidly as within 24 hours. In people with sepsis, the prescription of short courses of antibiotics is not associated with increased mortality and may reduce the risk of bacterial resistance developing.27 If evidence of sepsis is present, antibiotics with activities against Gram-positive, Gram-negative, and anaerobic organisms are recommended (see Chapter 172, Antimicrobial Use in the Critical Care Patient).

Antiemetic/Nausea and Gastroprotectants Maropitant, metoclopramide, and ondansetron or dolasetron can all be utilized in the management of nausea and vomiting (see Chapter 154, Antiemetic and Prokinetic Drugs). Manufacturer toxicity studies have documented a dose-dependent bone marrow hypoplasia in puppies up to 10 weeks of age treated with maropitant. However, many of these dogs were prematurely weaned and also had concurrent infection with Coccidia and parvovirus, so interpretation of these studies is difficult. There is a lack of compelling evidence to support the efficacy of gastroprotectants such as antacids, histamine-2 receptor antagonists, and proton pump inhibitors in dogs with esophageal and gastrointestinal disease.

NUTRITION It is not necessary to withhold nutrition until vomiting and regurgitation resolve as enteral nutrition is generally well tolerated.28 Early enteral nutrition (EEN) is associated with faster clinical improvement and weight gain.28 In addition, evidence suggests that EEN may improve

intestinal barrier function and therefore potentially limit bacterial or endotoxin translocation.28 Ideally dogs with CPV-2 should be fed small, frequent meals consisting of a low-fat, highly digestible diet. The calculated resting energy requirement should be increased by 25%–50% if there is a decline in body weight or condition. If enteral nutrition is not tolerated then parenteral nutrition should be considered (see Chapter 127, Parenteral Nutrition).

ANTIVIRAL DRUGS Type I interferons enhance the ability of the immune system to recognize microbes and establish a connection between the innate and acquired immune system. Furthermore, type I interferons have antiviral properties and are capable of blocking viral replication and inducing apoptosis of infected cells. Administration of recombinant feline interferon omega is associated with significantly decreased mortality rates in dogs with CPV-2 enteritis.29,30 Neuraminidase inhibitors are used for treating human influenza because the neuraminidase enzyme is required for viral penetration of respiratory mucin barriers. It has been suggested that oseltamivir administration to dogs with CPV-2 enteritis could reduce bacterial translocation by preventing viral degradation of the intestinal mucin barrier. Thus far, a clear outcome benefit associated with oseltamivir treatment in dogs with CPV-2 has not been demonstrated, although treatment has been associated with decreased weight loss during hospitalization and higher mean white blood cell count.31

OUTPATIENT PROTOCOL Hospitalization can be cost-prohibitive for the owners of dogs with CPV-2, particularly as clusters of disease outbreaks are reported more frequently in disadvantaged socioeconomic areas.32 Outpatient management of cardiovascularly stable dogs with CPV-2 can be considered prior to euthanasia if cost constraints prohibit hospitalization. One study comparing inpatient and outpatient protocols did not demonstrate a statistically significant difference in survival.33 The outpatient protocol was performed by veterinary professionals within a hospital setting and reported an 80% survival rate. Rescue medications such as opioid analgesia and additional antiemetic drugs were infrequently required.33 In another study, survival at 3 days post diagnosis was reported to be 75% when clients administered a nonstandardized outpatient treatment protocol to their dogs at home.34 Appropriate outpatient management of dogs with CPV-2 requires a significant time commitment from veterinary staff. To protect patient welfare, it is important to obtain daily progress reports and consider regular clinical reassessment of the patient (which can be performed in a safe location outside the clinic for infection control purposes). Hospitalization should be reconsidered in dogs who fail to improve or deteriorate while being managed as outpatients.

CONTROVERSIAL THERAPIES Equine hyperimmune serum antiendotoxin has been utilized in the treatment of CPV-2. Conflicting results have been published; two studies reported significantly decreased mortality rates in dogs treated with antiendotoxin alongside conventional therapy.35,36 Another study reported increased mortality associated with antiendotoxin administration in puppies ages 16 weeks or younger.37 Canine granulocyte colony-stimulating factor has been shown to increase mean white blood cell count and decrease hospitalization times in dogs with CPV-2.38 However, the same study also reported significantly decreased 7-day survival in the treated group compared with the untreated group, raising safety concerns.38

CHAPTER 94  Canine Parvovirus Infection Passive immunotherapy using CPV-2-immune plasma has been reported. One clinical trial did not document any significant difference in leukocyte count, duration of hospitalization, treatment cost, and magnitude of viremia between the treatment and placebo groups.39 The lack of treatment efficacy may have been influenced by the frequency and timing of administration in addition to the fact that the same dose was administered regardless of body weight. Improvement in markers of shock within the first 24 hours of hospitalization is reported in dogs with naturally occurring CPV-2 infection treated with canine hyperimmune CPV-2 plasma when compared with a placebo group. There was no significance difference in the duration of hospitalization or mortality between the treatment and placebo groups; however, the study was underpowered to detect this effect.40 The efficacy of feline antiparvovirus antibodies in the treatment of CPV was also evaluated, and excellent in vitro viral neutralisation was reported. Unfortunately, this failed to translate into a clinical benefit in vivo.41 Fecal microbiota transplantation has been assessed in puppies with CPV-2 and was associated with significantly faster resolution of diarrhea and shorter duration of hospitalization.42

PREVENTION OF TRANSMISSION Dogs who have recovered from CPV have been shown to shed the virus for up to 54 days postinfection.5 Parvovirus shed into the environment is ubiquitous and hardy, surviving up to 1 year. Thorough cleaning of the environment to remove organic material should be performed prior to disinfection. If the efficacy of disinfection of the home environment is uncertain, then discontinuation of breeding is advised, and only vaccinated dogs with proven CPV-2 titers should be permitted on the property for a period of 1 year following infection outbreak. Suitable cleaning products for disinfection of CPV-2 include sodium hypochlorite (household bleach), potassium peroxymonosulfate (e.g., Trifectant or Virkon) and accelerated hydrogen peroxide (e.g., Accel/Rescue). Bleach cleaning products are ineffective at killing CPV-2 in the presence of organic material, have limited penetration on porous surfaces, and require prolonged contact times.43 Both potassium peroxymonosulfate and accelerated hydrogen peroxide are effective in the presence of organic material.44 Despite label claims of efficacy, independent studies have failed to demonstrate that quaternary ammonium compounds (e.g., Triple Two, Rocal) have consistent viricidal activity against parvovirus.44

PROGNOSIS Mortality rates for CPV-2 enteritis are reported to be as low as 4% for aggressively treated hospitalized dogs and as high as 91% for untreated patients.37,45 Dogs who survive a clinical manifestation of CPV-2 infection are reported to have a higher risk of developing chronic gastrointestinal signs.46 However, this study identified a number of factors, including the comparison with a significantly older control group, which could have confounded results.

REFERENCES 1. Mason MJ, Gillet NA, Muggenburh BA: Clinical, pathological, and epidemiological aspects of canine parvovirus in an unvaccinated beagle colony: 1978–1985, Amer Anim Hosp Assoc 23:183-192, 1987. 2. Houston DM, Ribble CS, Head LL: Risk factors associated with parvovirus enteritis in dogs: 283 cases (1982-1991), J Am Vet Med Assoc 208(4): 542-546, 1996.

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3. Pollock RV, Carmichael LE: Maternally derived immunity to canine parvovirus infection: transfer, decline, and interference with vaccination, J Am Vet Med Assoc 180(1):37-42, 1982. 4. Prittie J: Canine parvoviral enteritis: a review of diagnosis, management, and prevention, J Vet Emerg Crit Care 14:167-176, 2004. 5. Decaro N, Desario C, Campolo M, et al: Clinical and virological findings in pups naturally infected by canine parvovirus type 2 Glu-426 mutant, J Vet Diagn Invest 17(2):133-138, 2005. 6. Lynch AM, Respess M, Boll AE, et al: Hospital-acquired anemia in critically ill dogs and cats: a multi-institutional study, J Vet Intern Med 30(1):141-146, 2016. 7. Goddard A, Leisewitz AL, Christopher MM, Duncan NM, Becker PJ: Prognostic usefulness of blood leukocyte changes in canine parvoviral enteritis, J Vet Intern Med 22(2):309-316, 2008. 8. van den Berg MF, Schoeman JP, Defauw P, et al: Assessment of acute kidney injury in canine parvovirus infection: comparison of kidney injury biomarkers with routine renal functional parameters, 242:8-14, 2018. 9. Turk J, Miller M, Brown T, et al: Coliform septicemia and pulmonary disease associated with canine parvoviral enteritis: 88 cases (1987-1988), J Am Vet Med Assoc 196(5):771-773, 1990. 10. Otto CM, Drobatz KJ, Soter C: Endotoxemia and tumor necrosis factor activity in dogs with naturally occurring parvoviral enteritis, J Vet Intern Med 11(2):65-70, 2019. 11. Otto CM, Rieser TM, Brooks MB, Russell MW: Evidence of hypercoagulability in dogs with parvoviral enteritis, J Am Vet Med Assoc 217(10): 1500-1504, 2000. 12. Decaro N, Desario C, Billi M, et al: Evaluation of an in-clinic assay for the diagnosis of canine parvovirus, Vet J 198(2):504-507, 2013. 13. Desario C, Decaro N, Campolo M, et al: Canine parvovirus infection: which diagnostic test for virus? J Virol Methods 126(1-2):179-185, 2005. 14. Schmitz S, Coenen C, Matthias K, et al: Comparison of three rapid commercial canine parvovirus antigen detection tests with electron microscopy and polymerase chain reaction, J Vet Diagn Invest 21(3):344-345, 2009. 15. Proksch AL, Unterer S, Speck S, et al: Influence of clinical and laboratory variables on faecal antigen ELISA results in dogs with canine parvovirus infection, Vet J 204(3):304-308, 2015. 16. Decaro N, Crescenzo G, Desario C, et al: Long-term viremia and fecal shedding in pups after modified-live canine parvovirus vaccination, Vaccine 32(30):3850-3853, 2014. 17. Schultz R, Larson L, Lorentzen L: Effects of modified live canine parvovirus vaccine on the SNAP ELISA antigen assay, Abstract Int Vet Emerg Crit Care Symp 18(4):415, 2008. 18. Farrow CS: Radiographic appearance of canine parvovirus enteritis, J Am Vet Med Assoc 180(1):43-47, 1982. 19. Stander N, Wagner WM, Goddard A, Kirberger RM: Ultrasonographic appearance of canine parvoviral enteritis in puppies, Vet Radiol Ultrasound 51(1):69-74, 2010. 20. Lichtenstein D: Fluid administration limited by lung sonography: the place of lung ultrasound in assessment of acute circulatory failure (the FALLS-protocol), Expert Rev Respir Med 6:155-162, 2012. 21. Lichtenstein D, Karakitsos D: Integrating lung ultrasound in the hemodynamic evaluation of acute circulatory failure (the fluid administration limited by lung sonography protocol), J Crit Care 27:533, 2012. 22. Chavez MA, Shams N, Ellington LE, et al: Lung ultrasound for the diagnosis of pneumonia in adults: a systematic review and meta-analysis, Respir Res 15(1):50, 2014. 23. Kozek-Langenecker SA: Effects of hydroxyethyl starch solutions on hemostasis, Anesthesiology 103:654-660, 2005. 24. Wierenga JR, Jandrey KE, Haskins SC, Tablin F: In vitro comparison of the effects of two forms of hydroxyethyl starch solutions on platelet function in dogs, Am J Vet Res 68(6):605-609, 2007. 25. Wiedermann CJ, Dunzendorfer S, Gaioni LU, et al: Hyperoncotic colloids and acute kidney injury: a meta-analysis of randomized trials, Crit Care 14(5):R191, 2010. 26. Wiedermann CJ, Joannidis M: Accumulation of hydroxyethyl starch in human and animal tissues: a systematic review, Intensive Care Med 40:160-170, 2014.

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27. Sawyer RG, Claridge JA, Nathens AB, et al: Trial of short-course antimicrobial therapy for intraabdominal infection, N Engl J Med Massachusetts Medical Society, 372(21):1996-2005, 2015. 28. Mohr AJ, Leisewitz AL, Jacobson LS, et al: Effect of early enteral nutrition on intestinal permeability, intestinal protein loss, and outcome in dogs with severe parvoviral enteritis, J Vet Intern Med 17(6):791-798, 2003. 29. De Mari K, Maynard L, Eun HM, Lebreux B: Treatment of canine parvoviral enteritis with interferon-omega in a placebo-controlled field trial, Vet Rec 152(4):105-108, 2003. 30. Uchino T, Matsumoto H, Sakamoto T, Sakurai T: Treatment of canine parovirus infection with recombinant feline interferon-v JVCS 1(4): 130-137, 2008. 31. Savigny MR, Macintire DK: Use of oseltamivir in the treatment of canine parvoviral enteritis, J Vet Emerg Crit Care (San Antonio) 20(1):132-142, 2010. 32. Brady S, Norris JM, Kelman M, Ward MP: Canine parvovirus in Australia: the role of socio-economic factors in disease clusters, Vet J 193(2):522528, 2012. 33. Venn EC, Preisner K, Boscan PL, Twedt DC, Sullivan LA: Evaluation of an outpatient protocol in the treatment of canine parvoviral enteritis, J Vet Emerg Crit Care (San Antonio) 27(1):52-65, 2017. 34. Sarpong KJ, Lukowski JM, Knapp CG: Evaluation of mortality rate and predictors of outcome in dogs receiving outpatient treatment for parvoviral enteritis, J Am Vet Med Assoc 251(9):1035-1041, 2017. 35. Wessels BC, Gaffin SL: Anti-endotoxin immunotherapy for canine parvovirus endotoxaemia, J Small Anim Pract 27(10):609-615, 1986. 36. Dimmitt R: Clinical experience with cross-protective antiendotoxin antiserum in dogs with parvoviral enteritis, Canine Pract 16(3):23-26, 1991.

37. Mann FA, Boon GD, Wagner-Mann CC, et al: Ionized and total magnesium concentrations in blood from dogs with naturally acquired parvoviral enteritis, J Am Vet Med Assoc 212(9):1398-1401, 1998. 38. Duffy A, Dow S, Ogilvie G, et al: Hematologic improvement in dogs with parvovirus infection treated with recombinant canine granulocyte-colony stimulating factor, J Vet Pharmacol Ther 33(4):352-356, 2010. 39. Bragg RF, Duffy AL, DeCecco FA, et al: Clinical evaluation of a single dose of immune plasma for treatment of canine parvovirus infection, J Am Vet Med Assoc 240(6):700-704, 2012. 40. Acciacca RA, Sullivan LA, Webb TL, et al: Clinical evaluation of hyperimmune plasma for the treatment of dogs with naturally occurring parvoviral enteritis, J Vet Emerg Crit Care 30:525-533, 2020. 41. Gerlach M, Proksch AL, Unterer S, et al: Efficacy of feline anti-parvovirus antibodies in the treatment of canine parvovirus infection, J Small Anim Pract 58(7):408-415, 2017. 42. Pereira GQ, Gomes LA, Santos IS, et al: Fecal microbiota transplantation in puppies with canine parvovirus infection, J Vet Intern Med 32(2):707-711, 2018. 43. Cavalli A, Marinaro M, Desario C, et al: In vitro virucidal activity of sodium hypochlorite against canine parvovirus type 2, Epidemiol Infect 146(15):2010-2013, 2018. 44. Eleraky NZ, Potgieter LND, Kennedy MA: Virucidal efficacy of four new disinfectants, J Am Anim Hosp Assoc 38(3):231-234, 2002. 45. Kariuki NM, Nyaga PN, Buoro IBJ, et al: Effectiveness of fluids and antibiotics as supportive therapy of canine parvovirus-2 enteritis in puppies, Bull Anim Heal Prod Afr 38:379-389, 1990. 46. Kilian E, Suchodolski JS, Hartmann K, Mueller RS, Wess G, Unterer S: Long-term effects of canine parvovirus infection in dogs, PLoS One 13(3):e0192198, 2018.

95 Infective Endocarditis Kristin A. MacDonald, DVM, PhD, DACVIM (Cardiology), Steven E. Epstein, DVM DACVECC

KEY POINTS • Infective endocarditis is an uncommon clinical disease associated with high mortality. • Diagnosis is challenging because the signs are nonspecific and a variety of organ systems can be affected. • Using criteria extrapolated from human medicine may improve diagnostic capabilities. • The vegetative lesions associated with infective endocarditis make eradication of the infectious organism difficult.

• Antimicrobial therapy should consist of long-term bactericidal administration. • The prognosis for patients with infective endocarditis is poor. • Antimicrobial prophylaxis should be considered in high-risk patients (i.e., patients with subaortic stenosis) that are undergoing surgical or dental procedures.

Infective endocarditis (IE) is an uncommon, often fatal disease in dogs that typically involves the mitral and/or the aortic valves. Medium to large breed male dogs are affected most commonly. Cats with IE have been reported to represent ,0.01% of a university teaching hospital caseload.1 Severe pathophysiologic sequelae to IE may include congestive heart failure; immune-mediated diseases, including polyarthritis or glomerulonephritis; thromboembolism (sterile or septic); or severe cardiac arrhythmias. Echocardiographic evidence of a vegetative valvular lesion and valvular insufficiency is the mainstay in diagnosis of IE, and additional criteria help support a clinical diagnosis. Although blood cultures are important to submit to identify a bacterial cause and assess microbial susceptibility, unfortunately they are often negative because of concurrent antimicrobial use or infection with a fastidious organism. Treatment includes long-term broad-spectrum antimicrobials for 6 to 8 weeks; the first week of therapy ideally is given intravenously.

of the expression of special receptors called microbial surface components recognizing adhesive matrix molecules; these include Staphylococcus and Streptococcus spp.2 These bacteria can trigger tissue factor production and induce platelet aggregation. Platelets release bactericidal proteins, but many of the bacteria that cause IE are resistant to these proteins. Bacteria such as S. aureus and Bartonella spp. may become internalized within the endothelial cells and escape detection by the immune system. Bacteria also can excrete enzymes that lead to destruction of valve tissue and proliferation of the vegetative lesion. A therapeutic sanctuary of bacteria clustered within the fibrinous vegetative lesion with little access to phagocytes limits host-mediated defenses and provides a formidable obstacle for antimicrobial penetration.

PATHOPHYSIOLOGY Microbial Adherence and Endothelial Invasion The inciting event in formation of IE is bacterial adherence to the disrupted endothelial surface of a cardiac valve (Fig. 95.1). Mechanical lesions (i.e., subaortic stenosis, cardiac catheterization procedure) or inflammatory disease can promote bacterial seeding within the endothelium. Extracellular matrix proteins, thromboplastin, and tissue factor are exposed by the damaged endothelium, which trigger coagulation. A coagulum containing fibrinogen, fibrin, and platelet proteins forms and avidly binds bacteria. Fibrinogen binding mediates the primary attachment of bacteria to the disrupted endothelium, and subsequent fibronectin binding triggers endothelial cell internalization and local proinflammatory and procoagulant responses. Inflammation induces endothelial cell expression of integrins that bind bacteria and fibronectin to the extracellular matrix. Some bacteria (i.e., Staphylococcus aureus) carry fibronectin-binding proteins and also can trigger active internalization by host cells. Organisms that commonly cause IE are those that have the greatest ability to adhere to damaged valves because

Congestive Heart Failure Congestive heart failure (CHF) is the most common sequela of IE in both dogs and cats and is the most common cause of death. Acute heart failure is a common feature of this rapidly progressive, virulent disease. Damage to either the mitral or aortic valve leads to valvular insufficiency, which is typically severe, and causes volume overload to the left heart and increases left ventricular end diastolic volume and pressure.3 As most cases of IE result in acute and severe valvular insufficiency and a rapid increase in left ventricular filling pressure, it causes fulminant pulmonary edema with alveolar flooding, often before the development of left atrial dilation. Typically, pulmonary veins are distended despite the lack of marked radiographic cardiomegaly. Measurement of pulmonary capillary wedge pressure may be useful to document left heart failure in these acute cases.

Immune-Mediated Disease Patients with IE tend to develop high antibody titers against causative microorganisms, and there is continuous formation of circulating immune complexes consisting of IgM, IgG, and C3 (complement).4 Factors such as rheumatoid factor may impair the ability of complement to solubilize immune complexes and may lead to the formation of large immune complexes. Extracardiac disease manifestations are caused by immune complex deposition and further complement

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PART IX  Infectious Disorders Anterior mitral leaflet

Posterior mitral leaflet

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Anterior papillary muscle (sectioned) Mitral valve

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Bacterial adhesion to platelet fibronectin and fibrin matrix

Adhesion and incorporation of microbials into vegetation

Vegetative lesion Ruptured chordae tendinae Fig. 95.1  Pathophysiologic mechanisms of infective endocarditis. A normal mitral valve (including leaflets and chordae tendineae) is represented (top) and a magnified view shows intact normal endothelium (bottom). The initiating step in the development of infective endocarditis is an injury to the endothelium, which exposes extracellular matrix proteins. A coagulum of platelets (yellow), fibrinogen, fibronectin, and fibrin (orange) develops. The fibronectin receptor on platelets and extracellular matrix proteins avidly bind bacteria that contain microbial surface components recognizing adhesive matrix molecules (MSCRAMMs). The microorganism becomes embedded and incorporated into a vegetative lesion and multiplies. The vegetative lesion may extend to the chordae tendineae, opposing leaflet, or atrial endothelium and may cause rupture of chordae tendineae. The result is severe mitral regurgitation and congestive heart failure. (From MacDonald K: Infective endocarditis in dogs: diagnosis and therapy, Vet Clin North Am Small Anim Pract 40(4):665-684, 2010.)

CHAPTER 95  Infective Endocarditis activation and tissue destruction in the glomerular basement membrane, joint capsule, or dermis. Shortly after antimicrobial therapy, circulating immune complexes are reduced greatly in people with IE. Immune-mediated disease, including polyarthritis and glomerulonephritis, is seen commonly in dogs with IE (75% and 36%, respectively).5 Joint fluid analysis and culture should be performed in any dog with lameness to evaluate for immune-mediated polyarthritis or septic arthritis. A urine protein:creatinine ratio should be evaluated in any dog with proteinuria to support the diagnosis of glomerulonephritis.

Thromboembolism Thromboembolism (septic and aseptic) is a common sequela to IE in dogs, was documented on pathology in 70% to 80% of dogs, and was suspected clinically antemortem in 44% of dogs with IE.5,6 Like people, dogs are more likely to suffer from thromboembolic disease with mitral valve IE.6 The highest risk factors for thromboembolic disease in people with IE include mitral valve involvement, large mobile vegetative lesions more than 1 to 1.5  cm, or increasing lesion size during antimicrobial therapy.7,8 Infarction of the kidneys and spleen are most common in dogs, followed by myocardium, brain, and limbs. Vascular encephalopathy occurs in approximately one-third of people with IE and is uncommon in dogs. Central nervous system thromboembolism most commonly occurs in the middle cerebral artery in people and dogs and results in brain ischemia and possibly ischemic necrosis if persistent.

INCIDENCE, SIGNALMENT, AND PRESENTING COMPLAINT IE is an uncommon disease in dogs, with an estimated incidence of 0.05% to 6.6% in dogs referred to a veterinary teaching hospital, and is rarely is seen in cats.5,6,9 Most dogs are medium to large breed dogs weighing more than 15 kg and are typically middle-aged to old (more than 5 years in more than 75% of cases in one study), with a male sex predisposition.6 Overrepresented breeds include Labrador Retriever, German Shepherd, Boxer, and Golden Retriever. The most common presenting complaint is lameness, followed by nonspecific signs, including lethargy, anorexia, respiratory abnormalities, weakness, and collapse. Neurologic abnormalities (i.e., seizures, ataxia, deficits of conscious proprioception, obtundation, cranial nerve deficits, and vestibular signs), vomiting, and epistaxis are less common presenting complaints.

PREDISPOSING FACTORS Presence of bacteremia and endothelial disruption are necessary for the development of IE. Subaortic stenosis is the only structural heart disease that significantly predisposes dogs to development of IE, and no other cardiac disease has been identified statistically as a predisposing cause.10,11 Myxomatous valve degeneration is the most common heart disease in dogs, but it occurs most frequently in small breed, aged dogs that rarely develop IE, making it unlikely to be a predisposing factor for IE. Common sources of bacteremia in dogs include diskospondylitis, prostatitis, pneumonia, urinary tract infection, pyoderma, periodontal disease, and long-term indwelling central venous catheters. The role of immunosuppression as a predisposing factor for IE is controversial: in one study, only 1 of 18 dogs (5%) recently had been administered immunosuppressive therapy, yet another earlier study reported 17 of 45 dogs (38%) had received corticosteroids at some time during the course of disease.5,9 Dental prophylaxis has long been suspected anecdotally as a predisposing factor, which has been rejected by a study showing no association of IE and dental procedures, oral surgical procedures, or

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oral infection in the preceding 3 months.11 However, a more recent investigation identified seven identical Enterococcus spp. from the mouth and IE lesions in 32 dogs.12 Prophylactic antimicrobials are recommended for dogs with subaortic or valvular aortic stenosis, and may be considered in other congenital heart diseases undergoing a dental procedure or surgery. Broad-spectrum antimicrobials such as firstgeneration cephalosporins or ticarcillin can be administered 1 hour prior to the procedure and during the procedure.

ETIOLOGIC AGENTS In order of frequency, the most common causes of IE in dogs include Staphylococcus spp. (S. aureus and S. pseudintermedius, and coagulase negative Staphylococcus), Streptococcus spp. (S. canis and S. bovis), and Escherichia coli (Box 95.1). Less common bacterial isolates include Enterococcus spp., Pseudomonas spp., Erysipelothrix rhusiopathiae, Enterobacter spp., Pasteurella spp., Corynebacterium spp., and Proteus spp. Rare causes of IE include Bordetella avium-like organism, Erysipelothrix tonsillarum, Actinomyces turicensis, Blastomyces dermatitidis, and Mycobacterium spp.5,13,14

BOX 95.1  Suggested Criteria for Diagnosis of Infective Endocarditis in Dogs Major Criteria 1. Positive echocardiogram Vegetative, oscillating lesion Erosive lesion Abscess 2. New valvular insufficiency 3. More than mild AI in absence of subaortic stenosis 4. Positive blood culture 2 positive blood cultures $3 with common skin contaminant Minor Criteria 1. Fever 2. Medium to large dog (.15 kg) 3. Subaortic stenosis 4. Thromboembolic disease 5. Immune-mediated disease Polyarthritis Glomerulonephritis 6. Positive blood culture not meeting major criteria 7. Bartonella serology $1:1024 Diagnosis Definite Pathology of the valve Two major criteria One major and two minor criteria Possible One major and one minor criterion Three minor criteria Unlikely Other diagnosis made Resolved in ,4 days of treatment No evidence at necropsy AI, aortic insufficiency.

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Bartonella spp. have emerged as an important cause of culturenegative IE in people and in dogs and was the cause of IE in 28% of dogs living in Northern California, including 45% of dogs with negative blood cultures.5,15 This may be an unusually high prevalence of IE caused by Bartonella spp. compared with other parts of the country but highlights the importance of testing for bartonellosis in dogs with IE. Bartonella vinsonii spp. berkhoffii is the most important species of Bartonella causing IE in dogs.5,16 Other, less common Bartonella species that cause IE in dogs include B. clarridgeiae, B. washoensis, B. quintana, B. rochalimae, B. clarridgeiae-like, and B. koehlerae.17,18 In dogs, Bartonella spp. primarily affect the aortic valve and less commonly affect the mitral valve. The clinical characteristics of dogs with IE resulting from Bartonella spp. are not different than dogs with IE resulting from traditional bacteria. In the author’s experience, dogs with IE resulting from traditional bacteria do not have coinfections with Bartonella spp.5,19 Several epidemiologic studies have suggested that ticks and fleas may be vectors for Bartonella spp. Concurrent seroreactivity to Anaplasma phagocytophilum, Ehrlichia canis, or Rickettsia rickettsii is common in dogs with IE resulting from Bartonella spp., and titers should be submitted for tick-borne diseases in any dog that is seroreactive to Bartonella spp. antigens.5,15

CLINICAL ABNORMALITIES A murmur is ausculted in a majority of dogs with IE (89% to 96%).5,10 The presence of a new or changing (i.e., increased intensity) murmur is the prototypical auscultation abnormality, but in one study only 41% of dogs with IE had a new murmur.9 Clinical findings of a diastolic murmur and bounding femoral pulses should trigger a high level of suspicion of aortic valve IE, although diastolic murmurs can be challenging to identify because they are typically of low intensity. Fever is often, but not always, present (50% to 74%) but may be masked by concurrent antimicrobial therapy as was reported in 80% of dogs in one study.5 Dogs infected with Bartonella spp. are less likely to have a fever compared with other causative agents.13 Arrhythmias are common (40% 70%) with dogs with IE and include, in order of frequency, ventricular arrhythmias, supraventricular tachycardia, third-degree atrioventricular block (because of periannular abscess from aortic IE), and atrial fibrillation. Dogs with IE of the aortic valve appear to be prone particularly to develop arrhythmias, including 62% of dogs having ventricular arrhythmias reported in one study.10 CHF is present in almost half of patients and is diagnosed by identification of perihilar to caudodorsal pulmonary infiltrates, often in the absence of left atrial dilation in 75% of cases in one study because of the acute nature of the disease.5 The occurrence of CHF does not differ between IE of the mitral or aortic valves.5

CLINICOPATHOLOGIC ABNORMALITIES The most common clinicopathologic abnormality is leukocytosis, which occurred in 89% of dogs in a case series.6 Typically there is a mature neutrophilia and monocytosis. Mild to severe thrombocytopenia and/or anemia (typically mild and nonregenerative) are seen commonly in half of dogs.6 There is often evidence of a procoagulable state in dogs with IE, including an elevated D-dimer or fibrin degradation products in 87% of dogs, in which they were measured, as well as hyperfibrinogenemia in 83% of dogs, in which it was measured in one study.6 Serum chemistry often shows hypoalbuminemia (95% of dogs), elevated hepatic enzyme activity, and acidosis. Renal complications are seen in at least half of dogs with IE and include prerenal or renal azotemia, glomerulonephritis, pyelonephritis, and renal thrombosis. Moderate to severe renal failure was present in approximately

one-third of dogs in a case series.5 The most common abnormalities on urinalysis include cystitis (60% of dogs), proteinuria (50% to 60% of dogs), and hematuria (18% to 62%). The urine protein:creatinine (UPC) ratio is a necessary test in dogs with proteinuria to establish if there is excess protein loss from the kidneys, which may lead to a hypercoagulable state by loss of antithrombin III. Anticoagulant or antiplatelet therapy may be indicated in patients with evidence of a hypercoagulable state. An increased UPC ratio was present in 77% of dogs, in which it was measured and was moderate or severely elevated in 58% of these dogs.6

DIAGNOSIS Echocardiography The cornerstone of diagnosing IE in dogs is identification of a vegetative valvular lesion on echocardiography (ECHO) or at necropsy. The pathognomonic echocardiographic lesion is a hyperechoic, oscillating, irregular-shaped (i.e., shaggy) mass adherent to, yet distinct from, the endothelial cardiac surface (Fig. 95.2). The term oscillating means that the lesion is mobile with high-frequency movement independent from the underlying valve structure; this finding highly supports the echocardiographic diagnosis of a vegetative lesion. The mitral and aortic valves are almost exclusively affected in small animals. Erosive and minimally proliferative lesions are less common and may be challenging to visualize on ECHO. Valvular insufficiency of the affected valve (i.e., mitral insufficiency and/or aortic insufficiency) is always present and is identified using color flow Doppler (Fig. 95.2F). In a recent report in cats, the aortic valve was affected 62% of the time, and the mitral valve in 38% of cases.1 The presence of moderate or severe aortic insufficiency on color flow Doppler should raise the suspicion of aortic IE, and careful interrogation of the aortic cusps is necessary. The severity of aortic insufficiency may be estimated by the length of the insufficiency jet on color flow Doppler and the slope of the aortic insufficiency on continuous wave Doppler of the left apical five-chamber view (i.e., steep slope, severe aortic insufficiency), and in chronic cases the severity of the left ventricular eccentric hypertrophy (Fig. 95.2D). Left atrial enlargement or eccentric hypertrophy of the left ventricle may not be present if the IE is acute. Myocardial failure often occurs secondary to chronic severe aortic insufficiency in dogs with aortic IE, if they survive long enough (Fig. 95.2C). A myocardial abscess may appear as a heterogenous, thickened, hyperechoic region or mass in the myocardium or annulus. A fistula or septal defect may be seen between two chambers if the abscess has ruptured (see video 95.1 and 95.2).

Blood Culture Blood and urine cultures are important to obtain but are frequently negative (60% to 70%) because of concurrent antimicrobial use in a majority (80%) of dogs.5 Three or four blood samples (5 to 10  ml each) should be collected aseptically from different venous sites at least 30 minutes to 1 hour apart and submitted for aerobic culture. If antimicrobials have been given, the blood collection should be done at the estimated trough of the drug level. It is important to collect adequate volumes of blood (if clinically appropriate based on patient size) because the concentration of bacteria in blood is very low (less than 5 to 10 bacteria/ml).20 The combination of blood culture and PCR of 16S rDNA identified bacteria in 61% of dogs with suspected IE compared with either test alone (33% and 39%, respectively), making this combination an attractive option to increase diagnostic yield in suspected IE cases.21 Bartonella spp. are fastidious organisms that rarely grow on culture medium, so routine culture is not recommended. Culture on Bartonella alpha proteobacteria growth medium (BAPGM) for at least a

CHAPTER 95  Infective Endocarditis

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Fig. 95.2  Echocardiogram of a dog with infective endocarditis of the aortic valve. There is a large vegetative lesion on the aortic valve seen in multiple views including the right parasternal left ventricular outflow tract view (A), the short axis view of the aortic valve at the heart base (C), and the left apical fivechamber view (E). The aortic valve is severely thickened with a hyperechoic, shaggy, oscillating mass lesion (arrow) that extends backwards into the left ventricular outflow tract. Color flow Doppler interrogation of the aortic valve from the right parasternal long axis left ventricular outflow tract view (B) and the left apical five-chamber view (F) shows severe aortic insufficiency (AI, green), which is turbulent blood flow leaking back from the aorta into the left ventricle during diastole. Severe AI causes a severe volume overload and eccentric hypertrophy of the left ventricle (increased end diastolic diameter) and secondary myocardial failure (increased end systolic diameter) on M-mode echocardiography (D). The left atrial to aortic dimension is only mildly increased despite the presence of severe AI and left heart failure due to the acute nature of the IE (C). Continuous wave Doppler measurement of the aortic blood flow velocity identifies the AI as a high velocity turbulent flow backwards into the left ventricle during diastole (above the line), and normal systolic aortic blood flow velocity (below the line) (G). The severe AI causes a rapid increase in the left ventricular diastolic pressure and a rapid decrease in the aortic to left ventricular pressure difference, creating a steep slope of the AI jet on CW Doppler. AI, aortic insufficiency; Ao, aorta; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

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week, followed by plating on agar for up to 5 weeks may be needed. The combination of preenrichment blood culture on BAPGM for 7 days followed by highly sensitive PCR targeting of the 16S-23S ITS region has allowed quantification of Bartonella infection in different body fluids.

Modified Duke Criteria for Diagnosis of Infective Endocarditis The modified Duke criteria have been developed to identify humans at high risk for IE and have been modified further for use in dogs evaluated for possible IE (see Box 95.1). Cases of possible IE with high clinical suspicion should undergo transesophageal ECHO if available to better evaluate the valve morphology, or transthoracic ECHO should be repeated in a few days. Based on the veterinary literature, high seroreactivity to Bartonella spp. (greater than 1:1024) may be an additional minor criterion for diagnosis of IE caused by Bartonella spp. in dogs. Because Bartonella spp. commonly live within endothelial cells or erythrocytes, PCR on serum may have limited yield and frequent false negatives. For example, direct PCR on serum was positive in only 8 of 61 dogs (13%) with bartonellosis, but when performed after prolonged incubation (for up to 1 month) in special enrichment media, 40 of 61 dogs were PCR positive.22

Table 95.1  Common Etiologic Agents and Treatment Recommendations for Dogs with Infective Endocarditis Etiological Agent Methicillin susceptible Staphylococcus spp.

Recommended Antimicrobial Acute: ampicillin or ampicillin/sulbactam IV Chronic: amoxicillin with clavulanic acid PO

Methicillin resistant Staphylococcus spp.

Acute: amikacin IV or vancomycin IV Chronic: doxycycline or chloramphenicol PO if susceptible May need to consider linezolid PO if no other oral options

Streptococcus spp.

Acute: ampicillin or ampicillin/sulbactam IV Chronic: amoxicillin with or without clavulanic acid PO

Enteric species

Acute: amikacin and/or ampicillin/sulbactam IV Chronic: based on susceptibility, may need subcutaneous injections

Pseudomonas spp.

Acute: amikacin or piperacillin/tazobactam IV Chronic: based on susceptibility, may need subcutaneous injections

Bartonella spp.

Acute: amikacin 20 mg/kg IV 3 1–2 weeks Chronic: doxycycline AND enrofloxacin .6–8 weeks; may add azithromycin 5 mg/kg PO q24h 3 7 days then EOD if lack of response

Culture negative

Acute: amikacin and piperacillin/tazobactam IV Chronic: amoxicillin with clavulanic acid and enrofloxacin PO

TREATMENT Antimicrobial Therapy The mainstay of treatment of IE is early antimicrobial drug treatment. The initial choice of antimicrobial drugs should be based on knowledge of the prevalent bacterial species and their antimicrobial drug susceptibilities for each hospital and/or geographic region, as well as the likely source of infection (which can provide information about the likely bacterial species involved). Along with aggressive (broadspectrum, bacteriocidal) intravenous antimicrobials, in human medicine up to half of patients require surgery for valve replacement.2 Valve replacement is performed rarely in dogs with IE, which limits treatment to chronic antimicrobials and likely contributes to the high mortality rate seen in dogs with IE.23 Long-term bactericidal antimicrobials are the mainstay therapy of IE. Patients are often continued on antimicrobials for over a year, given the lack of vascularity within the vegetative lesion and the impaired host defense against bacteria tightly encased in a fibrin meshwork, free from phagocytes. Empiric broadspectrum antimicrobial therapy is started while blood and urine cultures are pending and may be continued in cases with no identifiable pathogen. Based on local data from UC Davis, a combination of ampicillin/sulbactam and amikacin are recommended to achieve this in patients without renal disease. For patients with renal disease or with risk factors for multidrug resistance, substitution of amikacin with enrofloxacin or a third-generation cephalosporin (ceftazidime or cefotaxime) should be considered (see Chapter 99). Furosemide may potentiate renal toxicity of amikacin, which must be considered in patients with acute heart failure requiring aggressive loop diuretics. High serum concentration of antimicrobials with good tissue and intracellular penetrating properties is needed to penetrate within the vegetative lesion to kill the bacteria. Antimicrobial doses used are on the high end of the range to achieve high blood levels. The optimal antimicrobial treatment depends on culture of the microorganism and minimum inhibitory concentration (MIC) of the antimicrobials, which is often impossible because of culture-negative cases from previous antimicrobial use. Common etiologic agents, their typical susceptibility profile, and therapeutic regimens are included in Table 95.1. Typically, 1 to 2 weeks of intravenous antimicrobial therapy is necessary for acute aggressive treatment of IE. This may be challenging

Note: Specific drug doses should be based on the high end of the recommended range with consideration of patient factors such as renal disease. Acute treatment guidelines usually provided for 7–14 days, then switch to chronic. EOD, every other day.

to owners because it involves chronic hospitalization and expensive treatment and monitoring for this period of time. Placement of an indwelling vascular access port is an option in these patients that ideally should be treated with intravenous antimicrobials for several weeks. After the first 1 to 2 weeks of intravenous antimicrobials, chronic long-term oral antimicrobials are needed for at least 6 to 8 weeks or longer. Subcutaneous administration of antimicrobials on an outpatient basis rather than oral antimicrobials has been suggested by some clinicians, but this has no clear advantage over chronic oral treatment using antimicrobials with high bioavailability and blood levels. One exception is in the chronic treatment of resistant infections using a carbapenem such as imipenem administered subcutaneously after an initial 1- to 2-week course administered intravenously, although subcutaneous administration may cause discomfort with this drug.24 Often it is challenging to decide when chronic antimicrobial therapy may be discontinued because the affected valve often has residual thickening even with a sterile lesion. Serial monitoring of echocardiograms, as well as other parameters such as complete blood count, recheck of urine or blood cultures (if previously positive), and body temperature are needed to follow the response to antimicrobials. Lack of improvement in an oscillating vegetative lesion after the first week of antimicrobial therapy in an animal without a previous bacterial isolate and MIC may indicate a more aggressive, resistant bacterium that may require switching antimicrobials or starting additional antimicrobials. During chronic therapy, the presence of an oscillating mass, recurrent fever, leukocytosis, or positive follow-up urine or

CHAPTER 95  Infective Endocarditis blood cultures necessitates continued chronic therapy, possibly with a different antimicrobial combination. The superior antimicrobial for treatment of Bartonella spp. infections in dogs has not been defined, but multiple antimicrobials have been used, including doxycycline, azithromycin, fluoroquinolones, amoxicillin/clavulanate, and aminoglycosides.25 Treatment with at least 2 weeks of aminoglycosides has been shown to improve survival in people with Bartonella IE.26 In dogs with severe life-threatening IE resulting from Bartonella spp., aggressive treatment with aminoglycosides may be necessary, with careful monitoring of renal values and cautiously administered intravenous fluids. Azithromycin appears to have the least minimum bactericidal activity compared with the other medications listed above and is susceptible to rapid development of resistance and should not be a first-line sole antimicrobial treatment for bartonellosis.27

Anticoagulant Therapy Anticoagulant therapy currently is not recommended because there has been a trend of increased bleeding episodes and no benefit in vegetation resolution or reduced embolic events in humans with IE treated with aspirin.4 Although the use of antithrombotic therapy in IE in humans is somewhat controversial, a recent summary of European guidelines for IE in people stated, “There is no indication for the initiation of antithrombotic drugs (thrombolytic drugs, anticoagulant, or antiplatelet therapy) during the active phase of IE” because of increased risk of intracranial hemorrhage.28 An early diagnosis, prompt antimicrobial treatment, and a careful selection of patients who benefit from early surgical intervention remain essential in the prevention of embolic complications in people with IE.29 Surgery is often the therapy of choice in human patients at high risk for thromboembolism, including patients with vegetative lesions larger than 10 mm or patients with recurrent thromboembolism despite antimicrobial therapy. Because there is no data regarding effects of anticoagulants on thromboembolic complications of IE in dogs, the author tends to extrapolate human results and does not recommend anticoagulants in dogs with IE, much like anticoagulants are not recommended for dogs with heartworm disease to lessen thromboembolic complications.

Treatment of Heart Failure Standard heart failure therapy including furosemide, an ACE inhibitor, and pimobendan is appropriate in dogs with IE of the mitral or aortic valves (see Chapter 41). Parenteral vasodilatory agents may be necessary in patients with acute fulminant heart failure resulting from severe mitral or aortic IE (see Chapter 41).

PROGNOSIS Dogs with aortic IE have a grave prognosis, and median survival in one study was only 3 days compared with a median survival of 476 days for dogs with mitral valve IE.6 Likewise, dogs with Bartonella IE have short survival times because the aortic valve is affected almost exclusively. Another case series of dogs with aortic IE reported similar outcomes, including 33% mortality in the first week and 92% mortality within 5 months of diagnosis.10 Other risk factors for early cardiovascular death include glucocorticoid administration before treatment, presence of thrombocytopenia, high serum creatinine concentration, renal complications, and thromboembolic disease.6,9 Death occurring soon after diagnosis most often is due to CHF or sudden cardiac death from a lethal arrhythmia. Other causes of death within the first week of treatment in dogs with IE include renal failure, pulmonary hemorrhage, and severe neurologic disease.

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REFERENCES 1. Palerme JS, Jones AE, Ward JL, et al: Infective endocarditis in 13 cats, J Vet Cardiol 18:213-225, 2016. 2. Que YA, Moreillon P: Infective endocarditis, Nat Rev Cardiol 8:322-336, 2011. 3. Guyton AC, Lindsay AW: Effect of elevated left atrial pressure and decreased plasma protein concentration on the development of pulmonary edema, Circ Res 7:649-657, 1959. 4. Baddour LM, Wilson WR, Bayer AS, et al: Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America, Circulation 111:e394-e434, 2005. 5. MacDonald KA, Chomel BB, Kittleson M, et al: A prospective study of canine infective endocarditis in northern California (1999-2001): emergence of Bartonella as a prevalent etiologic agent, J Vet Intern Med 18:56-64, 2004. 6. Sykes JE, Kittleson MD, Chomel BB, et al: Clinicopathologic findings and outcome in dogs with infective endocarditis: 71 cases (1992-2005), J Am Vet Med Assoc 228:1735-1747, 2006. 7. Mugge A, Daniel WG, Frank G, Lichtlen PR: Echocardiography in infective endocarditis: reassessment of prognostic implications of vegetation size determined by the transthoracic and the transesophageal approach, J Am Coll Cardiol 14:631-638, 1989. 8. Macarie C, Iliuta L, Savulescu C, et al: Echocardiographic predictors of embolic events in infective endocarditis, Kardiol Pol 60:535-540, 2004. 9. Calvert CA: Valvular bacterial endocarditis in the dog, J Am Vet Med Assoc 180:1080-1084, 1982. 10. Sisson D, Thomas WP: Endocarditis of the aortic valve in the dog, J Am Vet Med Assoc 184:570-577, 1984. 11. Peddle GD, Drobatz KJ, Harvey CE, et al: Association of periodontal disease, oral procedures, and other clinical findings with bacterial endocarditis in dogs, J Am Vet Med Assoc 234:100-107, 2009. 12. Semedo Lemsaddek T, Tavares M, Sao Braz B, Tavares L, Oliveira M: Enterococcal infective endocarditis following periodontal disease in dogs, Plos One 11(1):e0146860, 2016. doi:10.1371/journal.pone.0146860. 13. Sykes JE, Kittleson MD, Pesavento PA, et al: Evaluation of the relationship between causative organisms and clinical characteristics of infective endocarditis in dogs: 71 cases (1992-2005), J Am Vet Med Assoc 228:1723-1734, 2006. 14. Schmiedt C, Kellum H, Legendre AM, et al: Cardiovascular involvement in 8 dogs with blastomyces dermatitidis infection, J Vet Intern Med 20:1351-1354, 2006. 15. Breitschwerdt EB, Hegarty BC, Hancock SI: Sequential evaluation of dogs naturally infected with Ehrlichia canis, Ehrlichia chaffeensis, Ehrlichia equi, Ehrlichia ewingii, or Bartonella vinsonii, J Clin Microbiol 36:2645-2651, 1998. 16. Breitschwerdt EB, Atkins CE, Brown TT, et al: Bartonella vinsonii subsp. berkhoffii and related members of the alpha subdivision of the Proteobacteria in dogs with cardiac arrhythmias, endocarditis, or myocarditis, J Clin Microbiol 37:3618-3626, 1999. 17. Chomel BB, Kasten RW, Williams C, et al: Bartonella endocarditis: a pathology shared by animal reservoirs and patients, Ann N Y Acad Sci 1166:120-126, 2009. 18. Ohad DG, Morick D, Avidor B, et al: Molecular detection of Bartonella henselae and Bartonella koehlerae from aortic valves of Boxer dogs with infective endocarditis, Vet Microbiol 141:182-185, 2010. 19. Pesavento PA, Chomel BB, Kasten RW, et al: Pathology of bartonella endocarditis in six dogs, Vet Pathol 42:370-373, 2005. 20. Peddle G, Sleeper MM: Canine bacterial endocarditis: a review, J Am Anim Hosp Assoc 43:258-263, 2007. 21. Meurs KM, Heaney AM, Atkins CE, et al: Comparison of polymerase chain reaction with bacterial 16s primers to blood culture to identify bacteremia in dogs with suspected bacterial endocarditis, J Vet Intern Med 25:959-962, 2011. 22. Perez C, Maggi RG, Diniz PP, et al: Molecular and serological diagnosis of Bartonella infection in 61 dogs from the United States, J Vet Intern Med 25:805-810, 2011.

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23. Arai S, Wright BD, Miyake Y, et al: Heterotopic implantation of a porcine bioprosthetic heart valve in a dog with aortic valve endocarditis, J Am Vet Med Assoc 231:727-730, 2007. 24. Barker CW, Zhang W, Sanchez S, et al: Pharmacokinetics of imipenem in dogs, Am J Vet Res 64:694-699, 2003. 25. Breitschwerdt EB, Blann KR, Stebbins ME, et al: Clinicopathological abnormalities and treatment response in 24 dogs seroreactive to Bartonella vinsonii (berkhoffii) antigens, J Am Anim Hosp Assoc 40:92-101, 2004. 26. Raoult D, Fournier PE, Vandenesch F, et al: Outcome and treatment of Bartonella endocarditis, Arch Intern Med 163:226-230, 2003.

27. Biswas S, Maggi RG, Papich MG, et al: Molecular mechanisms of Bartonella henselae resistance to azithromycin, pradofloxacin and enrofloxacin, J Antimicrob Chemother 65:581-582, 2010. 28. Tornos P, Gonzalez-Alujas T, Thuny F, et al: Infective endocarditis: the European viewpoint, Curr Probl Cardiol 36:175-222, 2011. 29. Vanassche T, Peetermans WE, Herregods MC, et al: Anti-thrombotic therapy in infective endocarditis, Expert Rev Cardiovasc Ther 9:1203-1219, 2011.

96 Urosepsis Lillian Ruth Aronson, VMD, DACVS

KEY POINTS • Urosepsis is an uncommonly diagnosed condition in the small animal patient. • Escherichia coli is the most frequently diagnosed uropathogen in patients with urosepsis. • In most animals with urosepsis, bacteria from the rectum, genital, and perineal areas serve as the principal source of infection. • Patients with a urinary tract infection and risk factors including the presence of an anatomic abnormality, a urinary tract obstruction, nephrolithiasis, prior urinary tract disease, renal failure, neurological disease, diabetes mellitus, hyperadrenocorticism,

and immunosuppression are more prone to the development of urosepsis. • Causes of urosepsis that have been identified in the veterinary patient include pyelonephritis, bladder rupture, prostatic infection, testicular and vaginal abscessation, pyometra and catheter-associated urinary tract infections. • Treatment should be instituted as soon as possible and often includes a combination of intravenous fluid and broad-spectrum antimicrobial therapy, correction of the underlying condition, and attempting to correct any predisposing or complicating factors.

INTRODUCTION

principal source of infection.9 These bacteria can then migrate from the genital tract to the lower and then upper urinary tract.9 The development of a UTI and subsequent urosepsis in both human and veterinary patients often represents a balance between the quantity and pathogenicity of the infectious agents and host defenses. The following local host defense mechanisms typically prevent ascending UTIs: normal micturition, extensive renal blood supply, normal urinary tract anatomy (i.e., urethral length and high pressure zones within the urethra), urethral and ureteral peristalsis, mucosal defense barriers, antimicrobial properties of the urine, and systemic immunocompetence.9-11 Systemic defenses are most important for the prevention of hematogenous spread from the urinary tract.9 Patients with a UTI and risk factors including the presence of an anatomic abnormality, a urinary tract obstruction, nephrolithiasis, prior urinary tract disease, renal failure, indwelling urethral catheters, nephrostomy tubes, and ureteral stents and SUBs, neurological disease, diabetes mellitus, neoplasia, hyperadrenocorticism, feline leukemia or immunodeficiency virus, and/or immunosuppression should be considered to have a complicated UTI and are more prone to the development of urosepsis.9,12-15 Additionally, a UTI in pregnant or intact dogs and cats is considered complicated. Similar to human patients, E. coli is the most common uropathogen affecting dogs and cats and accounts for up to 50% of urine isolates.9-11,16-19 Gram-positive cocci, including Staphylococci, Streptococci, and Enterococci account for up to one-third of bacteria isolated and, although less commonly diagnosed, Proteus, Enterobacter, Pseudomonas, Klebsiella, Pasteurella, Corynebacterium, and Mycoplasma account for the remaining isolates.11,20-22 In humans, Gram-negative sepsis is frequently caused by infections originating from the urinary tract.6,16 Since E. coli is the most common pathogen affecting the urinary tract of both human and veterinary patients, and consequently the most commonly isolated pathogen in patients with urosepsis, its virulence has been extensively investigated. Most E. coli UTIs are caused by

Urosepsis, an uncommonly reported condition in veterinary medicine, refers to sepsis associated with a complicated urinary tract infection (UTI). In humans, the source of the infection can be the kidney, bladder, prostate, or genital tract.1 More specifically, urosepsis in humans has been associated with acute bacterial pyelonephritis, emphysematous pyelonephritis, pyonephrosis, renal abscessation, fungal infections, bladder perforation, urinary tract obstruction and, prostatic and testicular infections.2-5 Additionally, in human patients, urinary catheter-associated infections have also resulted in sepsis.6,7 Although many of these conditions are often diagnosed in the veterinary patient, little information currently exists in the veterinary literature regarding the incidence of urosepsis as a complication of these conditions. In one retrospective study that analyzed sepsis in small animal surgical patients, the urogenital tract was identified as the source of infection in approximately 50% of the cases.8 Of 61 dogs included in the study, sources of urosepsis included a pyometra (14), prostatic abscessation or suppuration (12), testicular abscessation (3), renal abscessation (3; see Fig. 96.1A–B), and vaginal abscessation (1). Of four cats included in the study, one cat had a pyometra and a second cat had a ruptured uterus. This chapter discusses the pathogenesis, as well as a review of the current veterinary literature to determine what conditions in veterinary medicine have been associated with urosepsis. Accurate recognition of these complicated UTIs and appropriate treatment is necessary to prevent associated morbidity and mortality.

PATHOGENESIS Urosepsis is a clinical condition that occurs secondary to a systemic bacterial infection originating from the urogenital tract and the associated systemic inflammatory response. In most cases of urosepsis, bacteria isolated from the rectum, genital, and perineal areas serve as the

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A

B Fig. 96.1  A, Renal and ureteral abscessation in a dog that presented with urosepsis. The kidney was not salvageable, and a nephrectomy was performed (B).

pathogenic E. coli from the phylogenetic group B2 and to a lesser extent, group D.23 Additionally, the E.coli phylogenetic group B2 has zoonotic potential that can result in UTIs in humans.24 Although several hundred serotypes of E. coli are known, fewer than 20 account for most bacterial UTIs.25 In dogs and humans, the majority of strains associated with urovirulence belong to a small number of serogroups (O, K, and H; see Chapter 91, Bacterial Infections).16 Certain properties that may enhance the bacterial virulence include the presence of a particular pilus that mediates attachment to uroepithelium, hemolysin, aerobactin, resistance to the bactericidal action of serum, biofilm formation and the rapid replication time in urine.9-11,16,26 In mouse models of human disease, uropathogenic E. coli have been shown to possess multiple adaptations allowing them to survive and persist in the urinary tract.27-31 Recently, a novel method of serum resistance by uropathogenic E. coli has been identified in which the expression of inhibitory antibodies is hypothesized to prevent normal serum-mediated killing by coating the bacterial surface and preventing bacterial lysis.32 Bacterial virulence is also demonstrated by Proteus, a Gramnegative bacteria that produces urease, an enzyme that diminishes the

antimicrobial properties of urine. In patients with structural or functional abnormalities of the urinary tract or altered defenses, infections can be caused by Gram-negative aerobic bacilli other than E.coli, Gram-positive cocci including Staphylococci and Enterococcus, and bacterial strains that normally lack uropathogenic properties.5,17 In patients that have septic peritonitis associated with a urinary tract disorder, the visceral and parietal peritoneum provide a large surface area for absorption of bacteria and endotoxins, resulting in septic shock (see Chapters 90 and 120, Sepsis and Septic Shock and Peritonitis, respectively).33 Clinical and laboratory findings in patients with urosepsis are often similar to patients whose sepsis originated from another source; these may include lethargy, fever or hypothermia, hyperemic mucous membranes, tachycardia, tachypnea, bounding pulses, a leukogram that reveals a leukocytosis or leukopenia with or without a left shift, and a positive blood culture (see Chapters 7 and 90, SIRS, MODS and Sepsis and Sepsis and Septic Shock, respectively).34 However, patients with urosepsis may display early laboratory changes that identify abnormalities specifically related to the urinary tract, including azotemia, an active urine sediment and a positive urine bacterial culture. A positive urine culture is extremely important in these patients to confirm the results of the blood culture by isolation of the same organism(s) with identical antimicrobial profiles.6 In cases of severe sepsis, multiple organ dysfunction and vasoconstrictive shock may develop and carry a more guarded prognosis. Additionally, in cats, diffuse abdominal pain, bradycardia, anemia, and icterus may be identified.34 Aggressive treatment is necessary and typically includes a combination of intravenous fluids and broad-spectrum antimicrobial therapy. However, specific treatment protocols vary depending on the source of the infection and the complications resulting from sepsis. Current recommendations in human medicine recommend administering antimicrobial therapy within 1 hour of identification of urosepsis.35 Antimicrobial choice in cases of urosepsis should be based on concentrations achieved in urine rather than the serum. Antimicrobial choice is critical and when possible, samples should be obtained prior to administering antimicrobial therapy. Once the culture and susceptibility testing results are available, antimicrobial coverage should be modified to treat the isolated organisms (see Chapter 91, Bacterial Infections). There are continued concerns regarding the increasing resistance of canine urinary tract isolates to common antimicrobials including fluoroquinolones, clavulanic acid-potentiated beta-lactams, and thirdgeneration cephalosporins.36-39 In a recent report evaluating antimicrobial susceptibility patterns in canine UTIs, multidrug resistance of E. coli and Staphylococcus spp. were more common in dogs diagnosed with complicated UTI compared to uncomplicated UTI.19 Interestingly, similar to humans, canine E.coli isolates resistant to fluoroquinolones have a lower prevalence for many of the virulence genes and are more likely to be from phylogenetic groups A and B1 and less likely from phylogenetic group B2.40 Prudent use of antimicrobials is critical to reduce the incidence of antimicrobial resistance. Additionally, the clinician should address the underlying condition and attempt to correct any complicating factors.17 Although there is some overlap in the clinical picture for different causes of urosepsis in the veterinary patient, some clinical findings, laboratory results, and treatments are unique to each condition. The rest of this chapter will discuss the different causes of urosepsis that have been identified in small animals.

CAUSES OF UROSEPSIS Pyelonephritis The kidneys and ureters are most commonly affected by ascending bacteria rather than via hematogenous infections. Renal trauma or the

CHAPTER 96  Urosepsis presence of a urinary tract obstruction may increase the incidence of hematogenous spread of infection to the urinary tract because of interference with the renal microcirculation.41,42 In human patients, hematogenous pyelonephritis occurs most commonly in patients that are debilitated from either chronic illness or those receiving immunosuppressive therapy.16 Urosepsis resulting from pyelonephritis has been uncommonly reported in the veterinary literature. In a retrospective study evaluating 61 dogs with severe sepsis, a renal abscess in conjunction with pyelonephritis was the source of the infection in only 3 dogs.8 In a second retrospective study of 47 dogs with a histopathological diagnosis of pyelonephritis, 7 of the 47 dogs were diagnosed with sepsis and in 5 of those 7 dogs, pyelonephritis was suspected to be the source of sepsis.43 In a retrospective study evaluating 29 cats with sepsis, pyelonephritis was the cause in only 2 cats.34 The author has identified 7 cats with obstructive calcium oxalate urolithiasis that were also diagnosed with a pyelonephritis based upon a positive bacteriologic culture result from urine collected by pyelocentesis. Human patients with infected stones or renal pelvic urine were found to be at a greater risk for the development of urosepsis than those with a lower UTI.44 Independent risk factors for ureteral stone-associated urosepsis included female sex, having a solitary kidney, higher computed tomography attenuation values of hydronephrosis suggesting more viscous fluid within the renal pelvis, urine nitrite, and urine white blood cell count.45 The use of endoscopic procedures including ureteroscopic lithotripsy and percutaneous nephrolithotomy to treat stones in the face of infection can also result in urosepsis. Additionally, because of the increasing complexity of endoscopic equipment, decontamination can be challenging and there is an increasing incidence of endoscopic equipment-associated infections.46 As minimally invasive endourologic procedures gain more popularity in veterinary medicine, clinicians should be aware that urosepsis is not only a potential complication of endoscopic procedures to treat urolithiasis, but it has also been associated with the equipment itself. In acute cases of pyelonephritis, one or both kidneys may be enlarged and painful, and the animal may have signs of polyuria, polydipsia, and vomiting. Azotemia may be present and blood work often reveals a neutrophilic leukocytosis with a left shift and a metabolic acidosis. In both acute and chronic cases, imaging may reveal mild to moderate pelvic dilation and ureteral dilation. The renal cortex as well as the surrounding retroperitoneal space may appear hyperechoic. In chronic cases, poor corticomedullary definition, distortion of the renal collecting system, irregular renal shape, and reduced kidney size may be seen. The urinalysis may reveal impaired urine concentrating ability, bacteriuria, pyuria, proteinuria, hematuria, and/or granular casts.10,47 Treatment includes the removal of predisposing factors, intravenous fluid therapy and broad-spectrum antimicrobial administration. Efficacy against Enterobacteriaceae include a fluoroquinolone or third-generation cephalosporin as reasonable first choices until urine or blood culture results become available. Antimicrobial therapy targeted against the isolated organism should continue for 4–6 weeks although a shorter course may be adequate. In humans, a course of 2–3 weeks is standard therapy. A urinalysis and bacterial culture should be performed after 1 week of treatment and prior to discontinuation of antimicrobial therapy. Additionally, a urine culture should be performed 2–4 weeks after cessation of therapy to confirm that the infection has cleared. In cases of unilateral advanced pyelonephritis, pyonephrosis or the presence of a renal abscess, placement of a ureteral stent, surgical drainage, or partial or total nephrectomy in addition to antimicrobial therapy may be recommended.48,49

Bladder Rupture Although rare, urosepsis may result from a bladder and/or a proximal urethral rupture in a patient with a lower UTI.50 Rupture of the urinary

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Fig. 96.2  An adult beagle of unknown history presented after being hit by a car. A uroperitoneum and uroretroperitoneum were diagnosed on presentation. Abdominal exploratory revealed necrosis of two-thirds of the bladder and avulsion of the bladder from the prostatic urethra.

tract in dogs and cats most commonly occurs following blunt trauma secondary to being hit by a car (Fig. 96.2). Other causes include penetrating injuries, neoplasia, aggressive catheterization, cystocentesis, rupture secondary to prolonged urethral obstruction, injury to the urinary tract during abdominal surgery, or excessive force during bladder expression. Physical examination may reveal dehydration, lack of a bladder on palpation, abdominal pain, fluid accumulation within the peritoneal cavity, and ventral abdominal bruising. Clinical signs are often vague initially but can worsen as the uremia and inflammation/sepsis progress. Abdominocentesis and abdominal fluid to peripheral blood creatinine and/or potassium ratios are often diagnostic of uroperitoneum,51,52 and the presence of bacteria on cytology confirms a septic peritonitis (see Chapter 120, Peritonitis). Urosepsis following bladder rupture has been reported in patients with a concomitant infection or those receiving peritoneal dialysis. In a retrospective study evaluating 23 dogs and cats with septic peritonitis, only one cat had septic peritonitis associated with intestinal herniation and bladder rupture.53 In a second study evaluating 26 cases of uroperitoneum in cats, five patients had aerobic bacterial cultures performed from the peritoneum or bladder, and of those, three were positive. Organisms isolated included Enterococcus, Staphylococcus, and alpha-Streptococcus.51 In a study evaluating peritoneal dialysis in cats with acute kidney injury, 1 of 22 cats developed urosepsis caused by Klebsiella pneumonia. Of the 22 patients in the study, this cat had spent the longest time on dialysis (10 days).54 If septic peritonitis is confirmed from bladder or urethral injury, early repair and/or urinary diversion using a closed indwelling urethral catheter and/or cystostomy tube is recommended to halt continued accumulation of septic urine in the abdominal cavity.

Prostatic Infection In addition to normal host defense mechanisms previously mentioned, prostatic fluid contains a zinc-associated antibacterial factor that is important in serving as a natural defense mechanism. Despite these defense mechanisms, bacterial colonization of the prostate can occur through both ascension of urethral flora, reflux of urine into prostatic ducts, inoculation of bacteria through biopsy needles, or by the hematogenous route.55,56 Suppurative prostatitis and prostatic abscessation are some of the most common causes of urosepsis in canine surgical patients, with 12/61 cases diagnosed in one study.8 Dogs with suppurative prostatitis

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usually have a history of an acute onset of illness. In addition to signs previously noted, pain upon rectal examination, caudal abdominal discomfort, and/or pain in the pelvic and lumbar region, a stiff or stilted gait, and an unwillingness to breed may be identified.57,58 Additionally, hematuria, pyuria, stranguria, hemorrhagic preputial discharge, urinary incontinence, or the inability to urinate may also be present. Left untreated, microabscesses can form and eventually coalesce into a large abscess. Septicemia and endotoxemia quickly develop, particularly if the abscess has ruptured.59 Following rupture, the peritoneal surface provides a large surface area for absorption of bacteria and bacterial byproducts, thus leading to the development of septic shock. Hindlimb edema has also been identified and can result from both altered vascular permeability as well as the presence of an abscess interfering with normal lymphatic and venous drainage from the regional lymph nodes. A definitive diagnosis can be confirmed following identification of a septic exudate from an ejaculated sample (third fraction), prostatic wash, traumatic catheterization, urethral discharge, or fine-needle aspirate. Inflammatory changes identified in prostatic fluid are associated with histologic inflammation in greater than 80% of the cases.60 Because of the potential of inducing septicemia during prostatic palpation or rupturing an abscess with fine-needle aspiration, it can be difficult and even clinically dangerous to collect prostatic fluid using some of the abovementioned should be hyphenated techniques from dogs with acute prostatitis. In dogs, similar to humans with acute bacterial prostatitis, bacteremia may result from manipulation of the inflamed gland.13 Since the infectious agent can often be identified on a Gram stain of the urine and bacterial culture collected via cystocentesis, vigorous prostatic palpation is generally avoided.13 It is important to note that discrepancies between prostatic and urine culture results occasionally occur.61 Abdominal radiographs often reveal prostatomegaly; the area near the bladder neck may have poor detail due to localized peritonitis. Abdominal ultrasound may reveal varying echogenicity with symmetrical or asymmetrical enlargement of the gland. Cyst-like structures as well as hypoechoic areas may also be present and could represent abscess formation. Rectal examination may reveal fluctuant areas when the abscess is near the dorsal periphery of the gland. It is important to note that dogs with prostatitis may have a normal ultrasound examination, especially if the prostate is not visible within the abdomen, underscoring the need to make a definitive diagnosis using the previously mentioned techniques. Suppurative prostatitis and prostatic abscessation are serious lifethreatening disorders. If the urine culture is negative, but the suspicion for prostatitis is high, collection of prostatic fluid should be performed. The blood prostate barrier may limit penetration of many antimicrobials; therefore, empiric treatment with drugs known to reach therapeutic concentrations within prostatic tissue (e.g., enrofloxacin and trimethoprim-sulfonamide) should be used pending culture and susceptibility results. Antimicrobials should be administered for a minimum of 4–6 weeks, then the urine or prostatic fluid should be cultured following discontinuation of antimicrobial therapy and again in 2–4 weeks to determine if the infection is completely eliminated.55,57,58 If the infection is not eliminated, resistant bacterial infections of both the prostate and urinary tract may have developed. Castration is also recommended once the infection is controlled and appears to be beneficial in the resolution of experimentally induced chronic bacterial prostatitis.60,62 In addition to the abovementioned should be hyphenated treatments, surgical drainage or excision is often the treatment of choice in a patient with a prostatic abscess. Antimicrobial therapy in conjunction with castration alone has been ineffective at resolving large abscesses.58 Prior to surgery, ultrasonography is used to determine the location(s) of the abscess(es). Surgical techniques that have been described to treat

prostatic abscessation include prostatic omentalization, placement of Penrose drains, marsupialization of the abscess, ultrasound-guided percutaneous drainage, and subtotal or excisional prostatectomy50,63,64 In one study, of the three dogs that presented with prostatic abscessation, two already had signs of sepsis.63 In a second study, 15/92 dogs died in the postoperative period because of sepsis; E. coli was the most common bacteria isolated.59 Sepsis and shock were common postoperative complications in 33% of the dogs surviving surgery. Approximately half of the dogs that died had rupture of the abscess and secondary septic peritonitis and shock prior to performing surgery.

Pyometra Pyometra is a serious condition affecting older, intact dogs in the luteal stage of the estrus cycle. It has been associated with neutrophilia and impaired immune function, including a decrease in lymphocyte activity.65 Urosepsis can occur in both dogs and cats diagnosed with pyometra with or without uterine rupture. In the largest retrospective study to date evaluating sepsis in the small animal surgical patient, pyometra was the most common source of urosepsis, with 14/61 dogs reported. Of four cats included in the study, urosepsis occurred secondary to a pyometra in one cat and a ruptured uterus in a second cat.8 In a review of 80 cases of pyometra, 3/73 dogs developed complications from generalized septicemia and thromboembolic disease in the immediate postoperative period and one dog died from endotoxic shock due to a ruptured uterus.66 In a second canine study of 356 dogs diagnosed with pyometra, peritonitis was diagnosed in 40 dogs (11.2%), and leukopenia and fever/hypothermia were associated with an 18-fold and 3-fold increased risk for peritonitis, respectively.67 In a retrospective study evaluating 183 cats diagnosed with pyometra, uterine rupture was present in seven cats. Postoperatively, four of seven cats died of septic peritonitis following uterine rupture.68 Although many aerobic and some anaerobic bacteria have been identified in both dogs and cats with pyometra, including Staphylococcus, Streptococcus, Pasteurella, Klebsiella, Proteus, Pseudomonas, Aerobacter, Haemophilus, Enterococcus, Moraxella spp., and Serratia marcescens, E. coli is the most common bacteria isolated. Strains of E. coli in cases of canine pyometra display a strong similarity to isolates obtained from UTIs, likely because of the similar pathogenesis (i.e., ascending from the host’s intestinal or vaginal flora).69 UTIs are common complications of pyometra. Although culture results are rarely negative in the dog, aerobic culture results are negative in 15%–31% of affected cats.68 In addition to clinical signs previously mentioned, dogs diagnosed with pyometra often present with vaginal discharge if the cervix is patent. When abdominal pain is present, septic peritonitis is likely.68 E. coli pyometra has been commonly associated with renal dysfunction in dogs, albeit typically transient.70-73 A recent study evaluating urinary biomarkers in these patients has identified the glomerulus and proximal tubules of the nephron as the main sites of injury.73 Some pathogenic strains of E. coli produce the bacterial endotoxin lipopolysaccharide, which can cause insensitivity to antidiuretic hormone in these regions of the kidney.74 Body temperature may be normal, elevated, or subnormal. Clinical signs in cats are similar, but often more subtle. Clinicopathological abnormalities in both species can occur to varying degrees and may include anemia, leukocytosis or leukopenia with a left shift, azotemia, hypoalbuminemia, hypo- or hyperglycemia, hyperglobulinemia, increased alkaline phosphatase, and metabolic acidosis.68,72,75 Prior to surgery, medical therapy should be instituted to correct deficits and concurrent metabolic derangements (see Chapters 68 and 90, Shock Fluid Therapy and Sepsis and Septic Shock, respectively). Surgery is not postponed in the very sick animals for more than a few hours because of the worsening septicemia that

CHAPTER 96  Urosepsis

Fig. 96.3  Ovariohysterectomy performed in a cat with pyometra.

occurs. Treatment for pyometra is ovariohysterectomy (Fig. 96.3). If the uterus ruptures at surgery, the abdomen is lavaged and the patient treated for septic peritonitis (see Chapter 120, Peritonitis).

Catheter-associated Urinary Tract Infection (see also Chapter 207, Urinary Catheterization) In human patients, bacteriuria occurs in up to 20% of hospitalized patients with indwelling urinary catheters and of these patients, 1%–2% will develop Gram-negative bacteremia.16 The catheterized urinary tract has repeatedly been demonstrated to be the most common source of Gram-negative sepsis in human patients16 and, although rare, the mortality rate of these bacteremias in these patients can reach 30%.16 In human patients, bacteremia can occur immediately as a result of mucosal trauma associated with catheter placement and removal or secondary to mucosal ulceration.16 Many infecting bacterial strains, including E. coli, Proteus, Pseudomonas, Klebsiella, and Serratia, show marked antimicrobial resistance compared with organisms identified in uncomplicated UTIs. Although nosocomial UTIs following the use of an indwelling urinary catheter in both dogs and cats is reported to be a common complication by some authors, the subsequent development of urosepsis is uncommon. Bacterial UTIs developed in 20% of healthy adult female dogs after intermittent catheterization, in 33% of male dogs during repeated catheterization, and in 65% of healthy male cats within 3–5 days of open indwelling catheterization.9,76 A few studies in the veterinary literature have looked at the incidence of UTIs or bacteriuria in dogs and cats when a closed catheter system was used. In one study, 11/21 animals (52%), and in a second study, 9/28 animals (32%) developed catheter-associated infections.77,78 Both of these studies suggested that the risk of infection increased with the duration of catheterization and that antimicrobial therapy was associated with increasingly resistant Gram-negative organisms. Although the incidence of catheter-associated infections was high in both studies, urosepsis was not identified. In a study looking at the incidence of catheter-associated UTIs in 39 dogs in a small animal intensive care unit, only 4/39 dogs (10.3%) developed a UTI.76 The lower incidence reported in this study was attributed to a shorter duration of catheterization, stricter definition of infection, different indications for catheterization, urine sample collection technique, and the protocol for catheter placement and maintenance. Urosepsis was not a reported complication.

561

Two recent studies have investigated the incidence of bacteriuria following catheterization and the use of a closed urine collection system for obstructive lower urinary tract disease in cats. For both studies, initial cultures on presentation for all cats yielded no growth. In the first study, 4/31 cats (13%) had positive bacterial cultures 24 hours following catheterization. Bacteria identified included Streptococcus (3) and Pasteurella (1). Based on the negative cultures at presentation, the authors did not recommend empirical antibiotic therapy.79 In the second study, 6/18 cats (33.3%) had positive bacterial cultures, the prevalence doubling between 24 and 48 hours of catheterization with three cats having a positive culture at 24 hours and an additional three cats by 48 hours following catheterization. In that study, 10 catheter tips were culture positive and included the six cats with positive urine cultures. Bacteria identified included E. coli, Staphylococcus spp., and Streptococcus bovis, and one of the six cats developed urosepsis.80 Bacteria cultured from catheter tips are likely associated with the development of a biofilm leading to the overdiagnosis of infection. Similar to the first report, the authors of this study do not recommend routine use of antimicrobial prophylaxis in catheterized cats that develop significant bacteriuria. Many veterinary hospitals utilize used intravenous fluid bags as part of their urine collection system resulting in an open system. In a study investigating the use of fluid bags for this purpose, 95 properly stored (,7 days) used intravenous bags were cultured to see if they were a potential source of contamination for the patient. No aerobic bacterial contamination or growth was identified in the system.81 In a second report, the use of an open versus closed collection system for a short duration of catheterization (,7 days) was evaluated with regards to the development of nosocomial bacteriuria. The study included 51 dogs and found an overall incidence of bacteriuria of 9.8%; the type of collection system (open vs. closed) was not associated with the development of bacteriuria. The authors concluded that the low incidence of bacteriuria was likely associated with a strict standard protocol of catheter placement and maintenance as well as the short duration of indwelling catheterization.82 Regardless, to avoid intraluminal migration of bacteria, open collections should be avoided if possible.83 In both veterinary and in human hospitals, pathogens can be introduced from the hands of hospital staff, via instrumentation or contaminated disinfectants. The most common location for bacteria to enter the system can occur at the catheter-collecting tube junction or at the drainage bag portal. Intestinal flora can also migrate along the catheter into the bladder from the perineal area of the patient.16 Intraluminal migration of bacteria can also occur secondary to poor catheter management. In a study evaluating multidrug-resistant (MDR) E. coli isolates from urine collected from dogs with an indwelling urinary catheter, the electrophoresis pattern of the MDR isolate from one dog was similar to the rectal isolate from the same dog.84 In order to prevent or minimize the incidence of catheter-associated infections, clinicians should avoid indiscriminate use of catheters, and urinary catheters should be inspected carefully to look for breaks in the catheter as well as any gross contamination. Catheter replacement or removal is not required in cases of subclinical bacteriuria since exchange might increase the risk of infection from mucosal trauma or contamination.85 In one study, the risk of infection increased by 27% for each day increase in catheterization. For this reason, the shortest duration of catheterization necessary is recommended. Since one cannot predict the duration of catheterization and longer duration of catheterization has been associated with antimicrobial resistant bacteria, prophylactic use of antimicrobials is not recommended.86 Diagnostic and therapeutic procedures that may result in the introduction of bacteria into the urinary system should also be minimized.9,16 Finally, catheters should be used cautiously in patients

562

PART IX  Infectious Disorders

with preexisting urinary tract disease, cats or female dogs with voluminous diarrhea or those whose immune system is compromised. If indicated, appropriate antimicrobial therapy should be rapidly instituted should an infection occur.

CONCLUSION Urosepsis is an uncommonly diagnosed, but serious, problem that can affect both dogs and cats. Conditions in veterinary medicine that have been associated with urosepsis include bacterial pyelonephritis and renal abscessation, bladder rupture in patients with a UTI, prostatic suppuration and abscessation, testicular and vaginal abscessation, pyometra, and catheter-associated UTIs. Risk factors that may cause patients to be more prone to the development of urosepsis or complicate treatment include the presence of an anatomic abnormality, a urinary tract obstruction, nephrolithiasis, prior urinary tract disease, acute kidney injury, neurological disease, diabetes, Cushing’s, and immunosuppression. Accurate recognition and aggressive therapy addressing the underlying condition, complicating risk factors, and the associated inflammatory response are necessary to prevent significant morbidity and mortality.

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CHAPTER 96  Urosepsis 43. Bouillon J, Snead E, Caswell C, et al: Pyelonephritis in dogs: retrospective study of 47 histologically diagnose cases (2005-2015), J Vet Intern Med 32:249-259, 2018. 44. Mariappan P, Smith G, Bariol SV, et al: Stone and pelvic urine culture and sensitivity are better than bladder urine as predictors of urosepsis following percutaneous nephrolithotomy: a prospective clinical study, J Urol 173:1610-1614, 2005. 45. Hu M, Zhong X, Cui X, et al: Development and validation of a risk-prediction nomogram for patients with ureteral calculi associated with urospesis: a retrospective analysis, PLOS ONE 13:1-14, 2018. 46. Kumarage J, Khonyongwa K, Khan A, et al: Transmission of multi-drug resistant Pseudomonas aeruginosa between two flexible ureteroscopes and an outbreak of urinary tract infection: the fragility of endoscope decontamination, J Hosp Infect 102:89-94, 2019. 47. Dibartola SP, Rutgers HC: Diseases of the kidney. In Sherding RG, editor: The cat: diseases and clinical management, St Louis, 1994, Saunders, pp 1353-1395. 48. Rawlings CA, Bjorling DE, Christie BA: Kidneys. In Slatter D, editor: Textbook of small animal surgery, ed 3, Philadelphia, 2003, Saunders, pp 1606-1619. 49. Kuntz JA, Berent AC, Weisse CW, et al: Double pigtail ureteral stenting and renal pelvic lavage for renal-sparing treatment of obstructive pyonephrosis in dogs: 13 cases (2008–2012), J Am Vet Med Assoc 246:216-225, 2015. 50. McGrotty Y, Doust R: Management of peritonitis in dogs and cats, Compan Anim Pract Jul/Aug:360-367, 2004. 51. Aumann M, Worth LT, Drobatz KJ: Uroperitoneum in cats: 26 cases (1986-1995), J Am Anim Hosp Assoc 34:315-324, 1998. 52. Schmiedt C, Tobias KM, Otto CM: Evaluation of abdominal fluid: peripheral blood creatinine and potassium ratios for diagnosis of uroperitoneum in dogs, J Vet Emerg Crit Care 11:275-280, 2001. 53. King LG: Postoperative complications and prognostic indicators in dogs and cats with septic peritonitis: 23 cases (1989-1992), J Am Vet Med Assoc 204:407-413, 1994. 54. Cooper RL, Labato MA: Peritoneal dialysis in cats with acute kidney injury:22 cases (2001-2006), J Vet Intern Med 25:14-19, 2011. 55. Johnson C: Reproductive system disorders. In Nelson RW, Couto CG, editors: Small animal internal medicine, St Louis, 2003, Mosby, pp 930-932. 56. Magri V, Boltri M, Cai T, et al: Multidisciplinary approach to prostatitis, Archivio Italiano di Urologia e Andrologia 90:227-248, 2018. 57. Basinger RR, Robinette CL, Spaulding KA: Prostate. In Slatter D, editor: Textbook of small animal surgery, ed 3, Philadelphia, 2003, Saunders, pp 1542-1557. 58. Kutzler MA, Yeager A: Prostatic diseases. In Ettinger SG and Feldman EC, editors: Textbook of veterinary internal medicine, ed 7, St Louis, 2010, Elsevier, pp 1809-1819. 59. Mullen HS, Matthiesen DT, Scavelli TD: Results of surgery and postoperative complications in 92 dogs treated for prostatic abscessation by a multiple Penrose drain technique, J Am Anim Hosp Assoc 26:370-379, 1990. 60. Barsanti JA, Finco DR: Canine prostatic disease, Vet Clin North Am 16:587-599, 1986. 61. Black GM, Ling GV, Nyland TG, et al: Prevalence of prostatic cysts in adult, large breed dogs, J Am Anim Hosp Assoc 34:177-180, 1998. 62. Cowan LA, Barsanti JA, Crowell W, et al: Effects of castration on chronic bacterial prostatitis in dogs, J Am Vet Med Assoc 199:346-350, 1991. 63. Apparicio M, Vicenti WRR, Pires EA, et al: Omentalisation as a treatment for prostatic cysts and abscesses, Aust Vet Pract 34:157-159, 2004. 64. Boland LE, Hardie RJ, Gregory SP, et al: Ultrasound-guided percutaneous drainage as the primary treatment for prostatic abscesses and cysts in dogs, J Am Anim Hosp Assoc 39:151-159, 2003. 65. Faldyna M, Laznicka A, Toman M: Immunosuppression in bitches with pyometra, J Small Anim Pract 42:5-10, 2001.

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66. Wheaton LG, Johnson AL, Parker AJ, et al: Results and complications of surgical treatment of pyometra: a review of 80 cases, J Am Anim Hosp Assoc 25:563-568, 1989. 67. Jitpean S, Ström-Holst B, Hoglund OV, et al: Outcome of pyometra in female dogs and predictors of peritonitis and prolonged postoperative hospitalization in surgically treated cases, BMC Vet Res 10:1-12, 2014. 68. Kenney KJ, Matthiessen DT, Brown NO, et al: Pyometra in cats: 183 cases (1979-1984), J Am Vet Med Assoc 191:1130-1131, 1987. 69. Hagman R, Kühn I: Escherichia coli strains isolated from the uterus and urinary bladder of bitches suffering from pyometra: comparison by restriction enzyme digestion and pulsed-field gel electrophoresis, Vet Microbiol 84:143-153, 2002. 70. Asheim A: Pathogenesis of renal damage and polydipsia in dogs with pyometra, J Am Vet Med Assoc 147:736-745, 1965. 71. Heiene R, Kristiansen V, Teige J, et al: Renal histomorphology in dogs with pyometra and control dogs, and long term clinical outcome with respect to signs of kidney disease, Acta Vet Scand 49:13-22, 2007. 72. Stone EA, Littman MP, Robertson JL, et al: Renal dysfunction in dogs with pyometra, J Am Vet Med Assoc 193:457-464, 1988. 73. Maddens B, Daminet S, Smets P, et al: Escherichia coli Pyometra induces transient glomerular and tubular dysfunction in dogs, J Vet Intern Med 24:1263-1270, 2010. 74. Wallace GB, Casal ML: A review of pyometra in small animal medicine: incidence, pathophysiology, clinical diagnosis, and medical management, Clin Ther 10:435-452, 2018. 75. Marretta SM, Matthiessen DT, Nichols R: Pyometra and its complications, Probl Vet Med 1:50-61, 1989. 76. Smarick SD, Haskins SC, Aldrich J, et al: Incidence of catheter-associated urinary tract infection among dogs in a small animal intensive care unit, J Am Vet Med Assoc 224:1936-1940, 2004. 77. Lippert AC, Fulton RB, Parr AM: Nosocomial infection surveillance in a small animal intensive care unit, J Am Anim Hosp Assoc 24:627-636, 1988. 78. Barsanti JA, Blue J, Edmunds J: Urinary tract infection due to indwelling bladder catheters in dogs and cats, J Am Vet Med Assoc 187:384-387, 1985. 79. Cooper ES, Lasley E, Daniels JB, et al: Incidence of bacteriuria at presentation and resulting from urinary catheterization in feline urethral obstruction, J Vet Emerg Crit Care 29:472-477, 2019. 80. Hugonnard M, Chalvet-Monfray K, Dernis J, et al: Occurrence of bacteriuria in 18 catheterised cats with obstructive lower urinary tract disease: a pilot study, J Feline Med Surg 15:843-848, 2013. 81. Barrett M, Campbell VL: Aerobic bacterial culture of used intravenous fluid bags intended for use as urine collection reservoirs, J Am Anim Hosp Assoc 44:1-6, 2008. 82. Sullivan LA, Campbell VL, Onuma SC: Evaluation of open versus closed urine collection systems and development of nosocomial bacteriuria in dogs, J Am Vet Med Assoc 237:187-190, 2010. 83. Hooton TM, Bradley SF, Cardenas DD, et al: Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: International Clinical Practice Guidelines from the Infectious Disease Society of America, Clin Infect Dis 50:625-663, 2010. 84. Ogeer-Gyles J, Mathews K, Weeses S, et al: Evaluation of catheter-associated urinary tract infections and multi-drug resistant Escherichia coli isolates from the urine of dogs with indwelling urinary catheters, J Am Vet Med Assoc 229:1584-1590, 2006. 85. Weese JS, Blondeau J, Boothe D, et al: International Society for Companion Animal Infectious Diseases guidelines for the diagnosis and management of bacterial urinary tract infections in dogs and cats, Vet J 247:8-25, 2019. 86. Bubenik LJ, Hosgood GL, Waldron DR, et al: Frequency of urinary tract infection in catheterized dogs and comparison of bacterial culture and susceptibility testing results for catheterized and non-catheterized dogs with urinary tract infections, J Am Vet Med Assoc 231:893-899, 2007.

97 Necrotizing Soft Tissue Infections Elke Rudloff, DVM, DACVECC, cVMA Kevin Winkler, DVM, DACVS

KEY POINTS • Necrotizing soft tissue infections (NSTIs) and toxic shock syndrome can be rapidly fatal if not identified and treated aggressively. • Signs of circulatory shock must be treated rapidly using fluid resuscitation and analgesia. • Because of the lack of obvious skin changes in many cases of necrotizing soft tissue infections, a high index of suspicion is necessary for diagnosis.

• Broad-spectrum intravenous antimicrobial therapy should be instituted early. • Surgery is the cornerstone of treatment in NSTI, and radical debridement including amputation may be necessary to eliminate the infection. • Antibiotic therapy should be broad spectrum until directed by culture and susceptibility results.

Necrotizing soft tissue infection (NSTI) is the term used to describe a subset of soft tissue infections involving skin, subcutaneous tissue, muscle, and fascia that cause vascular occlusion, ischemia, and necrosis. NSTIs are associated with virulent bacterial and fungal organisms and encompass syndromes including Fournier gangrene, Ludwig angina, flesh-eating disease, hemolytic streptococcal gangrene, necrotizing fasciitis (NF), and myonecrosis.1,2 In contrast to uncomplicated soft tissue infections, NSTIs are progressive and rapidly spread along tissue planes. Uncontrolled NSTIs are lethal. The term severe soft tissue infection (SSTI) also has been used to describe lesions with or without necrosis.3 Toxic shock syndrome (TSS) is an acute, severe, systemic inflammatory response initiated by a microbial infection at a normally sterile site, usually exotoxin-releasing Staphylococcus or Streptococcus spp. Unlike other invasive infections, TSS manifests as an acute, early occurrence of circulatory shock and multiorgan dysfunction that can include renal and/or hepatic dysfunction, coagulopathy, acute respiratory distress syndrome, and/or an erythematous rash.4 In people, TSS commonly is associated with NF and pleuropulmonary infection.5 NSTI and SSTI have been described in dogs and cats and are associated with virulent Streptococcus spp. and other bacterial organisms.3,6-18 Human mortality rates for NSTI are reported to be between 6% and greater than 70%.19-21 Increased awareness and knowledge of the importance of early debridement have resulted in a trend toward an improved outcome. A report of 47 dogs with NSTI found a 53% mortality rate, but the majority of deaths were due to euthanasia, so this outcome is difficult to interpret.3 Risk factors identified in human medicine include age more than 50 years, atherosclerosis or peripheral vascular disease, obesity, trauma, hypoalbuminemia, diabetes mellitus, and glucocorticoid usage.1,22,23 NSTI can be stratified into four categories based on type of infection (Box 97.1). Type I NSTI is polymicrobial, type II NSTI is monomicrobial, type III NSTI is associated with Gram-negative, often marine-related organisms, and type IV NSTI is associated with fungal infection.23-25 The majority of the human cases are categorized as type I.26 Most of the veterinary cases reported could be categorized as type II NSTI3 associated with a history of minor trauma and inoculation

with virulent bacteria. Infection can spread rapidly, and seemingly limited infections can cause limb-threatening and life-threatening systemic sequelae. Fibrous attachments between the subcutaneous and fascial tissue can form a boundary to limit spread of organisms; however, such boundaries do not exist in the extremities or truncal regions, making these areas more susceptible to widespread infection and NF.27,28 Despite their severity and rapid progression, relatively little is known about the pathophysiology of TSS and NSTI. Enhanced toxicity of virulent streptococci through the release of exotoxin superantigens, cell envelope proteinases, hyaluronidase, complement inhibitor, M-protein, protein F, and streptolysins amplifies cytokine release and induction of a systemic inflammatory response and septic shock. Clostridial toxins can cause hemolysis, platelet aggregation, leukocyte destruction, and histamine release, in addition to damage to the vascular endothelium, collagen, and hyaluronic acid. Microbial invasion associated with localized thrombosis leading to liquefactive necrosis of the superficial fascia and soft tissue is a key pathologic process of NSTI. Occlusion of nutrient vessels can lead to extensive undermining of apparently normal-appearing skin, followed by gangrene of the subcutaneous fat, dermis, and epidermis, evolving into ischemic necrosis.1 Preliminary diagnosis is initially based on clinical suspicion because definitive diagnosis requires tissue sampling and time for test results to return.

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DIAGNOSIS Clinical Signs The clinical signs of NSTI and TSS can be nonspecific. Skin changes, fever, respiratory signs, increased urination frequency, or signs of malaise may be described by the pet owner. Surgery or a recent traumatic event may be included in the history, although there may be no history or evidence of trauma. NSTI is typified by an area of soft tissue with pain and swelling, and once shaved, a defined area of erythema maybe appreciated. Fever and general malaise are commonly evident. The affected area of the tissue can show signs of bruising, edema, cellulitis, or crepitus from subcutaneous emphysema (Figs. 97.1 and 97.2). Cutaneous bullae are

CHAPTER 97  Necrotizing Soft Tissue Infections

BOX 97.1  Categories of Necrotizing Soft

Tissue Infections24,25

Type I Infections: Polymicrobial • Mixed anaerobes and aerobes • Usually isolate four or more organisms Type II Infections: Monomicrobial • Commonly b-hemolytic Streptococcus Type III Infections: Gram-Negative Monomicrobials • Clostridia infections • Includes marine organisms Type IV Infections: Fungal • Such as Candida infections

Fig. 97.1  Necrotizing soft tissue infection of the medial aspect of the elbow of a dog.

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progression of the discoloration can be followed. Rapid progression (extension within a few hours) and disproportionate localized pain are hallmark signs of NSTI; however, NSTI associated with postoperative, gut flora-associated infection may progress more slowly (hours to days).24 Protective gloves should be worn during examination of the lesions and patient handling to prevent inadvertent contamination of a cut on the examiner’s hand or another patient with potentially virulent pathogens. TSS occurs in a subset of type II NSTIs and is associated with severe systemic disease including septic shock and multiorgan dysfunction.

Laboratory Findings Fine-needle aspirate from an affected tissue site can help confirm an infectious origin and differentiate between type I and type II NSTI. Cytology as well as Gram stain, culture, and susceptibility testing are recommended. Blood work findings cannot be used to diagnose NSTI or TSS, but they may reflect changes associated with infection and a systemic inflammatory response syndrome. They may include hemoconcentration, anemia, hypoalbuminemia, neutrophilia or neutropenia, left shift (often severe), hyperlactatemia, coagulation alterations consistent with disseminated intravascular coagulation, hypoglycemia, elevated creatinine phosphokinase levels, elevated C-reactive protein, and organ dysfunction (elevated serum alanine transaminase, alkaline phosphatase, bilirubin, creatinine levels). Hypocalcemia can occur when extensive fat necrosis has developed with NF.22 A diagnostic scoring system called the laboratory risk indicator for necrotizing fasciitis (LRINEC) score is based on the measurement of Creactive protein, white blood cell count, hemoglobin, sodium, creatinine, and glucose and has been used in human patients to predict NF, although it has failed to detect some cases, and its role is under debate.29,30 An unvalidated NSTI assessment score incorporates mean arterial pressure into the LRINEC score, which may increase the diagnostic accuracy for identifying NF in people.31

Imaging

Fig. 97.2  Necrotizing soft tissue infection of the right tibiotarsus of a dog with toxic shock syndrome. The skin is erythematous and the tissues edematous. The serosanguinous discharge is from the fine-needle aspirate puncture. Cytology of the aspirate showed numerous chains of intra- and extracellular cocci that were identified as beta-hemolytic Streptococcus with culture.

considered an important indicator of impending dermal necrosis in humans; however, this has not been a frequent finding in veterinary patients.8 Although a skin wound or discoloration is common, the epidermis can appear unscathed with deep tissue necrosis. When skin lesions are seen, they should be outlined with a marker so that

A variety of imaging findings are associated with NSTI. Subcutaneous air seen on plain film radiographs is rare but characteristic of necrotizing lesions with gas-producing organisms (Fig. 97.3). Ultrasound evidence of fluid accumulation along the deep fascia and fluid accumulation at a depth of .2 mm support the diagnosis of NSTI in people with clinical signs of NF (Fig. 97.4).32 Computed tomography features suggestive of NSTI include asymmetric fascial thickening, hypodermal fat inflammation, and gas in the soft tissue planes.33,34 Magnetic resonance imaging (MRI) may prove helpful in determining the extent of deep tissue infections not readily identified from the skin surface because of its soft tissue and multiplanar imaging capabilities. Thickened fascia with high signal intensity in T2 images is commonly seen on MRI.34 Absence of deep fascial involvement can exclude NF. However, MRI cannot differentiate NSTI from nonnecrotizing problems, and the time involved in obtaining MRI results may delay surgery.35 Advanced diagnostic imaging should never delay time to surgical intervention.

Definitive Diagnosis Definitive diagnosis of TSS requires positive streptococcal or staphylococcal culture findings and evidence of septic shock. Definitive diagnosis of NSTI is based on the histopathologic findings, including fascial necrosis and myonecrosis. Pathologic descriptions also include deep angiothrombotic microbial invasion and liquefactive necrosis.36,37 Frozen section biopsy can provide a rapid diagnosis at the time of surgical exposure.38 Because of the rapid progression of disease and the time in obtaining results, rapid treatment and immediate surgical evaluation are necessary when there is a clinical suspicion of a NSTI.

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PART IX  Infectious Disorders unresponsive to fluid infusion may require vasopressor therapy (see Chapter 6, Pathophysiology and Mechanisms of Shock). Heart rate may not return to normal until analgesics are administered. Because there may be a high degree of pain associated with NSTI, strong analgesic intervention is necessary (see Chapter 134, Analgesia and Constant Rate Infusions). Injectable opioid agonists (e.g., hydromorphone, fentanyl) and ketamine in combination with regional or local anesthesia can be effective approaches. Nonsteroidal antiinflammatory analgesic medications are not recommended given the potential for septic shock and organ dysfunction. General supportive care of the septic patient is an important part of management as described in other chapters in this book.

Antimicrobial Therapy

Fig. 97.3  Radiographs of necrotizing fasciitis may demonstrate soft tissue swelling and occasionally subcutaneous emphysema. The extent of the necrosis may not be reflected by the size of the skin lesion.

Fascial plane

Subfascia fluid accumulation

Muscle

Rapid administration of appropriate antimicrobial therapy is an essential part of treatment. Samples for cytology, Gram stain, and aerobic, anaerobic, and fungal culture and susceptibility testing of the affected area are collected, ideally before injectable broad-spectrum antimicrobial coverage is instituted. Antimicrobial therapy should not be delayed beyond the first hour following recognition of a NSTI or TSS. A second set of culture and susceptibility samples should always be acquired during the debridement procedure. Penicillin G, aminopenicillins (ampicillin, amoxicillin), and cephalosporins target Grampositive and many Gram-negative organisms and should be part of the initial antimicrobial therapy plan. However, high tissue concentrations of Group A streptococcal organisms can put them in a stationary phase, causing penicillins to become ineffective.39 Clindamycin remains effective during the stationary phase and turns off exotoxin synthesis, inhibits streptococcal M-protein synthesis (which facilitates mononuclear phagocytosis), and suppresses lipopolysaccharide-induced monocyte synthesis of tumor necrosis factor.40 It also provides coverage for anaerobic organisms. Aminoglycosides and third-generation cephalosporins may increase Gram-negative organism coverage. Gentamicin has a synergistic effect with penicillin against streptococci. For broad-spectrum coverage in the compromised patient, the authors would recommend clindamycin in combination with an aminoglycoside or third-generation cephalosporin. Fluoroquinolone administration, specifically enrofloxacin, is not recommended, because it may have limited activity against streptococcal infection and may cause bacteriophage-induced lysis of S. canis, enhancing its pathogenicity.40 In the severely immunocompromised patient, antifungal therapy also may be considered pending fungal culture results.

Surgical Debridement

Fig. 97.4  Ultrasound image of a dog (see Fig. 97.2) with necrotizing fasciitis demonstrating edema under the fascial plane of a pelvic limb.

TREATMENT Successful management of TSS and NSTI requires treatment of the entire patient, not just the infected site, although cardiovascular stabilization of patients in septic shock may be difficult without surgical intervention. Patients in circulatory shock are resuscitated rapidly with fluid therapy titrated to perfusion end points, namely, normal heart rate, arterial blood pressure, mucous membrane color, and capillary refill time (see Chapter 68, Shock Fluid Therapy). Circulatory shock

Necrosis and underlying loss of blood supply limit tissue penetration of systemic antibiotics. Necrotic tissue serves as a culture medium, creating an anaerobic environment that impairs polymorphonuclear cell activity. Therefore, the most important part of treatment of NSTI is surgical debridement. Inadequate debridement promotes continuing spread of infection and may result in an inoperable condition or death. Surgical intervention should occur within 4 to 6 hours of presentation, once the cardiovascular system is stabilized as best as possible. Higher amputation and mortality rates have been documented in humans when surgery was delayed more than 12 hours.41,42 Surgical preparation should include a generous area surrounding the affected tissue because significant undermining of the tissue planes may not be evident until surgical exposure. Because of the lack of purulent discharge, typical drainage techniques are ineffective. With no large pockets of purulent material for drainage, appropriate debridement often requires removal of large amounts of tissue, including skin and open wound management. Adequate initial debridement is essential, and a delay in debridement may result in increased mortality

CHAPTER 97  Necrotizing Soft Tissue Infections rates.23 Successful debridement frequently requires multiple procedures, not just a single surgery. The use of negative pressure wound therapy may reduce the need for additional surgical procedures and may be limb-sparing.43,44 Removal of nonviable tissue may involve resection of muscle and tendons. Muscle viability can be tested by its response to stimulation from an electrocautery device. When contraction is absent, the muscle may not be viable and should be debrided. If the wound is on the limb, debridement can result in loss of limb function. Therefore, amputation may be the best option for limiting morbidity and mortality in addition to minimizing postoperative cost of treatment. This is a difficult emotional decision for the owner. Often the pet has deteriorated in such a rapid fashion that the owner may not understand the necessity for an amputation. Because a delay in surgery can result in loss of life, appropriate client communication to emphasize the severity and rapid progression of an NSTI is essential.

Postoperative Care Postoperative monitoring should follow Kirby’s Rule of 20.45 Crystalloid and colloid fluids are continued as appropriate to maintain intravascular volume and replace ongoing fluid losses. The cardiovascular system is monitored closely for decompensation, and frequent evaluation of glucose, albumin, and electrolyte levels should uncover any abnormalities that require intervention. Bandage removal for evaluation of the wound edges is done frequently (initially every 30 to 60 minutes) to determine if necrosis is continuing to spread despite surgery, indicating the need for repeat debridement. After the initial infection is controlled, vacuum closure devices may be employed. Antimicrobial therapy is adjusted once culture and susceptibility results are available. Nutritional support is an important consideration because of increased protein loss in the exudates and demands of healing. There also may be a decrease in voluntary food intake associated with pain or fever. Partial parenteral nutrition and/or enteral feeding via nasogastric or esophagostomy tube facilitates protein metabolism and limits protein catabolism during recovery. Caloric requirements should be calculated, and nutritional supplementation started immediately postoperatively, with full caloric supplementation reached within 48 hours. See Chapter 126, Enteral Nutrition and Chapter 127, Parenteral Nutrition. High-dose intravenous immunoglobulin G (IVIg) therapy has shown some benefit in cases with streptococcal TSS. Its efficacy in NSTI has not been recognized and may depend on the IVIg preparation (IgM-enriched or IgM-deficient), therapeutic timing, dose, and individual patient profile. Its use in veterinary medicine for TSS or NSTI has not been established.

Hyperbaric Oxygen Hyperbaric oxygen therapy is the delivery of oxygen at higher than atmospheric pressure to compromised tissue. Hyperbaric oxygen therapy may enhance host antimicrobial activity and the action of various antibiotic agents by facilitating their transport across the bacterial cell wall.46 Unfortunately, most reports are either anecdotal or have yielded conflicting results.8,46-48 There are no prospective, controlled veterinary studies demonstrating efficacy of hyperbaric oxygen in NSTI, but it has been described in two canine cases with limb NF and gas gangrene.8,49

EXTRACORPOREAL PLASMA TREATMENT Hemofiltration, plasmapheresis, and plasma exchange have been used in people to remove circulating inflammatory mediators and toxins. Clinical trials are inconsistent in demonstrating that relevant concentrations of these substances are in circulation at the time of the procedure, that

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they are consistently removed during filtration, and that the process attenuates severe sepsis. Adjunctive interventions should never preclude the administration of antimicrobials or surgical debridement of devitalized tissue.

CONCLUSION NSTI and TSS can be treated successfully if medical and surgical therapy is provided rapidly. A delay in therapy worsens the prognosis. Circulatory shock and laboratory abnormalities must be corrected immediately, and aggressive analgesia provided. Broad-spectrum intravenous antimicrobial therapy should be administered as soon as possible, and prompt surgery with radical debridement and appropriate antimicrobial therapy is required for successful treatment of NSTI. The extent of the lesion may not be appreciated fully until surgery is performed, and amputation or multiple surgical procedures may be necessary to remove diseased tissue. Major reconstructive procedures may be required once diseased tissue has been removed successfully.

REFERENCES 1. Wong CH, Chang HC, Pasupathy S, et al: Necrotizing fasciitis: clinical presentation, microbiology, and determinants of mortality, J Bone Joint Surg Am 85:1454, 2003. 2. Phan HH, Cocanour CS: Necrotizing soft tissue infections in the intensive care unit, Crit Care Med 38:S460, 2010. 3. Buriko Y, Van Winkle TJ, Drobatz KJ, et al: Severe soft tissue infections in dogs: 47 cases (1996-2006), J Vet Emerg Crit Care 18:608, 2008. 4. Defining the group A streptococcal toxic shock syndrome. Rationale and consensus definition. The Working Group on Severe Streptococcal Infections, J Am Med Assoc 269:390, 1993. 5. Plainvert C, Doloy A, Loubinoux J, et al: CNR-Strep network. Invasive group A streptococcal infections in adults, France (2006-2010), Clin Microbiol Infect 18:702, 2012. 6. Prescott JF, Miller CW, Mathews KA, et al: Update on canine streptococcal toxic shock syndrome and necrotizing fasciitis, Can Vet J 38:241, 1997. 7. Miller CW, Prescott, JF, Mathews KA, et al: Streptococcal toxic shock syndrome in dogs, J Am Vet Med Assoc 209:1421, 1996. 8. Jenkins CM, Winkler K, Rudloff E, et al: Necrotizing fasciitis in a dog, J Vet Emerg Crit Care 11:299, 2001. 9. DeWinter LM, Low DE, Prescott JF: Virulence of Streptococcus canis from canine streptococcal toxic shock syndrome and necrotizing fasciitis, Vet Microbiol 70:95, 1999. 10. Declercq J: Suspected toxic shock-like syndrome in a dog with closedcervix pyometra, Vet Dermatol 18:41, 2007. 11. Sura R, Hinckley LS, Risatti GR, et al: Fatal necrotising fasciitis and myositis in a cat associated with Streptococcus canis, Vet Record 162:450, 2008. 12. Crosse PA, Soares K, Wheeler JI, et al: Chromobacterium violaceum infection in two dogs, J Am Anim Hosp Assoc 42:154, 2006. 13. Slovak J, Parker VJ, Deitz KL: Toxic shock syndrome in two dogs, J Am Anim Hosp Assoc 48:434-438, 2012. 14. Taillefer M, Dunn M: Group G streptococcal toxic shock-like syndrome in three cats, J Am Anim Hosp Assoc 40:418, 2004. 15. Worth AJ, Marshall N, Thompson KG: Necrotising fasciitis associated with Escherichia coli in a dog, N Z Vet J 53:257, 2005. 16. Kulendra E, Corr S: Necrotising fasciitis with sub-periosteal Streptococcus canis infection in two puppies, Vet Comp Orthop Traumatol 21:474, 2008. 17. Weese JS, Poma Rr, James F, et al: Staphylococcus pseudointermedius necrotizing fasciitis in a dog, Can Vet J 50:655, 2009. 18. Csiszer AB, Towle HA, Daly CM: Successful treatment of necrotizing fasciitis in the hind limb of a Great Dane, J Am Anim Hosp Assoc 46:433, 2012. 19. Mills MK, Faraklas I, Davis C, et al: Outcomes from treatment of necrotizing soft tissue infections: results from the National Surgical Quality Improvement Program database, Am J Surg 200:790, 2010.

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20. George SMC, Harrison DA, Welch CA, et al: Dermatological conditions in intensive care: a secondary analysis of the Intensive Care National Audit & Research Centre (ICNArc) Case Mix Programme Database, Crit Care 12:S1, 2008. 21. May AK, Stafford RE, Bulger EM, et al: Treatment of complicated skin and soft tissue infections, Surg Infect 10:467, 2019. 22. McHenry CR, Piotrowski JJ, Petrinic D, et al: Determinants of mortality for necrotizing soft tissue infections, Ann Surg 221:558, 1995. 23. Sarani B, Strong M, Pascual J, et al: Necrotizing fasciitis: current concepts and review of the literature, J Am Coll Surg 208:279, 2009. 24. Morgan MS: Diagnosis and management of necrotising fasciitis: a multiparametric approach, J Hosp Infect 5:249, 2010. 25. Ustin JS, Sevransky JE: Necrotizing soft tissue infection, Crit Care Med 39:2156, 2011. 26. Park SY, Yu SN, Lee EJ, et al: Monomicrobial gram-negative necrotizing fasciitis: an uncommon but fatal syndrome, Diagn Microbiol Infect Dis 94:183, 2019. 27. Hill MK, Sanders CV: Necrotizing and gangrenous soft tissue infections. In Nesbitt LT Jr, Saunders CV, editors: The skin and infection: a color atlas and text, Baltimore, 1995, Williams & Wilkins. 28. Bosshardt TL, Henderson VJ, Organ CH Jr: Necrotizing soft tissue infections, Arch Surg 131:846, 1996. 29. Wall DB, Klein SR, Black S, et al: A simple model to help distinguish necrotizing fasciitis from nonnecrotizing soft tissue infection, J Am Coll Surg 191:227, 2000. 30. Wilson MP, Schneir AB: A case of necrotizing fasciitis with a LRINEC score of zero: clinical suspicion should trump scoring systems, J Emerg Med 44(5):928, 2013. 31. Harasawa T, Kawai-Kowase K, Tamura J, Nakamura M: Accurate and quick predictor of necrotizing soft tissue infection: usefulness of the LRINEC score and NSTI assessment score, J Infect Chemother 26(4):331, 2020. 32. Lin H, Hsiao C, Chang C, et al: The relationship between fluid accumulation in ultrasonography and the diagnosis and prognosis in patients with necrotizing fasciitis, Ultrasound Med Biol 45:1545, 2019. 33. Wysoki MG, Santora TA, Shah RM, et al: Necrotizing fasciitis: CT characteristics, Radiology 203:859, 1997. 34. Malghem J, Lecouvet FE, Omoumi P, et al: Necrotizing fasciitis: contribution and limitations of diagnostic imaging, Joint Bone Spine 80(2):146, 2013.

35. Loh NN, Ch’en IY, Cheung LP, et al: Deep fascial hyperintensity in softtissue abnormalities as revealed by T2-weighted MR imaging, Am J Roentgenol 168:1301, 1997. 36. Wong CH, Wang YS: The diagnosis of necrotizing fasciitis, Curr Opin Infect Dis 18:101, 2005. 37. Umbert IJ, Winkelmann RK, Oliver GF, et al: Necrotizing fasciitis: a clinical, microbiological, and histopathological study of 14 patients, J Am Acad Dermatol 20:774, 1989. 38. Stamenkovic I, Lew PD: Early recognition of potentially fatal necrotizing fasciitis. The use of frozen-section biopsy, N Engl J Med 310:1689, 1984. 39. Theis JC, Rietweld J, Danesh-Clough T: Severe necrotising soft tissue infections in orthopaedics surgery, J Orthop Surg 10:108, 2012. 40. Ingrey KT, Ren J, Prescott JF: A fluoroquinolone induces a novel mitogenencoding bacteriophage in Streptococcus canis, Infect Immun 71:3028, 2003. 41. Sudarsky LA, Laschinger JC, Coppa GF, Spencer FC: Improved results from standardized approach in treating patients with necrotizing fasciitis, Ann Surg 206:661, 1987. 42. Kaiser RE, Cerra FB: Progressive necrotizing surgical infections: a unified approach, J Trauma 21:349, 1981. 43. Téot L, Boissiere F, Fluieraru S: Novel foam dressing using negative pressure wound therapy with instillation to remove thick exudate, Int Wound J 14:842, 2017. 44. Maquire P, Azagrar JM, Carb A, Lesser A: The successful use of negative pressure wound therapy in two cases of canine necrotizing fasciitis, J Am Anim Hosp Assoc 51:43-48, 2015. 45. Kirby R, Linklater A, editor: Monitoring and intervention for the critically ill small animal: the rule of 20, Ames, IA, 2017, John Wiley and Sons. 46. Hosgood G, Kerwin SC, Lewis DD, et al: Clinical review of the mechanism and applications of hyperbaric oxygen therapy in small animal surgery, Vet Comp Orthop Traumatol 5:31, 1992. 47. Kerwin SC, Hosgood G, Strain GM, et al: The effect of hyperbaric oxygen treatment on a compromised axial pattern flap in the cat, Vet Surg 22:31, 1993. 48. Cooper NA, Unsworth IP, Turner DM, et al: Hyperbaric oxygen used in the treatment of gas gangrene in a dog, J Small Anim Pract 17:759, 1976. 49. George ME, Rueth NM, Skarda DE, et al: Hyperbaric oxygen does not improve outcome in patients with necrotizing soft tissue infection, Surg Infect (Larchmt) 10:21, 2009.

98 Catheter-Related Bloodstream Infections Christin L. Reminga, DVM, DACVECC

KEY POINTS • Intravenous catheters may become contaminated and can lead to local and distal infectious complications. Bacteremia caused by a colonized catheter is referred to as a catheter-related bloodstream infection (CRBSI). • CRBSIs most commonly occur secondary to skin flora migration; however, Gram-negative bacilli, enteric organisms, and fungi are also associated with CRBSIs in critically ill patients. • Clear definitions of catheter-related infections are paramount not only for treatment of CRBSIs but also to provide proper surveillance and preventative practices.

• The diagnosis of a CRBSI includes culturing the catheter and blood, but any fever of unknown origin, bacteremia, or infection at the insertion site should prompt the clinician to consider this type of complication. • Treatment of a known CRBSI includes removing the affected catheter and administering systemic antimicrobials. • The frequency of CRBSIs may be reduced by aseptically placing and maintaining catheters, as well as educating caretakers involved in these practices.

Catheters are commonly placed and maintained in critically ill patients to deliver life-saving medications, obtain blood for analysis, and provide intravascular monitoring, all while enhancing patient comfort. Catheters bypass the body’s innate immune system by breaking the integrity of the skin or traveling through a natural orifice. This can result in inoculation of caustic material, moisture, and surface organisms from the catheter insertion site into the surrounding tissue and bloodstream. The catheter’s inert surface can provide a suitable environment for bacterial colonization and biofilm formation. In addition, patients in the ICU are more susceptible to microbial catheter colonization, and therefore, hospital-acquired (nosocomial) infections.1 The incidence of nosocomial infections is increased in critically ill patients due to impaired defense mechanisms, direct transfer of organisms to catheters by medical personnel, prolonged hospitalization, and the mere presence of an indwelling device.2 Peripheral and central intravenous catheters are the focus of this chapter; however, any indwelling catheter can be a source of a catheter-related bloodstream infection (CRBSI).

Staphylococcus aureus, but Enterococci species are also common.3 Some bacteria (especially Staphylococcus aureus and coagulasenegative Staphylococci) and fungi produce a biofilm containing glycocalyces along with host salts and proteins that enhance adherence to foreign material. Some strains will also produce a mucoid exopolymeric biofilm (slime) that protects itself from host defenses by way of antibiotic ineffectiveness and interfering with neutrophil function. Skin flora is the most frequently cultured organism in veterinary species, primarily Staphylococcus pseudointermedius, Streptococcus species, and Acinetobacter species.1,4,5 When looking at critically ill patients in the ICU, both human and veterinary studies have identified a shift in the etiology of CRBSIs from skin flora to Gram-negative bacilli and enteric organisms, including Enterobacter species, Escherichia coli, Proteus mirabilis, Pseudomonas species, and Serratia species. There are many theories for this difference, including aseptic preparation of the skin prior to culturing, the presence of more invasive monitoring systems, complicated remote infections, hub and infusate contamination, and nosocomial spread from human hands and their associated fomites.1,3,5 It is also possible to have catheter-related anaerobic and fungal infections, but these are likely underrepresented due to inadequate diagnostic testing.3,5,6 Lastly, multiple studies have revealed an endemic source of infections, which emphasizes the need for environmental testing, contaminated material identification, and time lag required to eradicate certain persistent organisms from the hospital.4,5,7

PATHOPHYSIOLOGY The combination of bacterial adherence to intravenous catheters and impaired host defense mechanisms results in an increased risk of catheter infections via four possible pathways. The most common source of infection is skin flora that is either directly introduced during catheter placement or migrates by capillary action through the transcutaneous portion of the catheter’s dermal tunnel and along the external surface of the catheter. In addition, contamination of the catheter hub or infusate may lead to colonization of the internal surface. Less commonly, hematogenous organisms can seed the catheter from a distant septic focus.3 The most frequently isolated organisms in human patients with CRBSIs are coagulase-negative Staphylococcus epidermidis and

DEFINITIONS A major source of confusion for veterinary CRBSIs is inconsistent terminology and definitions related to catheter infections. These have been well established in human medicine and has improved accurate surveillance and preventative efforts.3,5,7,8 There are seven distinct terms that describe infectious catheter complications (Table 98.1). A

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TABLE 98.1  Definitions of Catheter Complications Type

Definition

Notes

Catheter site irritation

Localized catheter entrance site reaction with visible signs of bruising or erythema only

Culture negative

Catheter site inflammation/phlebitis

Localized catheter entrance site reaction with visible signs of erythema and at least one other physical abnormality (swelling, induration, discomfort, warmth, purulence)

. Sterile inflammation: culture negative 1 2. Catheter site contamination: culture positive or cytology positive for organisms

Catheter colonization

Significant growth of microorganisms in a quantitative or semiquantitative culture of the catheter tip, subcutaneous catheter segment, or catheter hub

Includes false-positive cultures (skin contaminant during catheter removal secondary to inadequate sterile skin preparation)

Catheter site infection

Visualized catheter site inflammation and confirmed organism identification

1. Microbiological: exudate at catheter site yields an organism with or without concomitant bloodstream infection 2. Clinical: phlebitis noted within 2 cm of catheter entrance site. May be associated with fever or mucopurulent exudate emerging from site, with or without concomitant bloodstream infection

Catheter-related bloodstream infection (CRBSI)

Catheter site infection or unexplained fever in a patient with identical organisms found on both catheter and blood culture

Patient exhibiting clinical symptoms of bloodstream infection without any other apparent source of infection

Catheter-related sepsis

Patient exhibiting signs of systemic inflammatory response syndrome and confirmed CRBSI

Catheter-associated bloodstream infection

An identified bloodstream infection, patient exhibiting signs of systemic inflammatory response syndrome or unexplained fever, in light of having an intravenous catheter in place with no confirmed or suspected organisms identified from the catheter tip

Fig. 98.1  A feline patient hospitalized for treatment of pancreatitis developed physical signs of peripheral catheter entrance site phlebitis including erythema, swelling, bruising, and mucopurulent discharge, warranting prompt removal.

catheter entrance site can show physical signs of irritation (bruising or erythema only) or inflammatory phlebitis (see Figs. 98.1 and 98.2). Only when there is a positive culture from the catheter entrance site can it be defined as catheter colonization. Since false-positive cultures are possible, the combination of phlebitis and a positive culture is defined as a catheter site infection. When catheter infection or colonization has a matching peripheral vein blood culture and no other source of infection, it is then characterized as a CRBSI. If a CRBSI has been confirmed and the patient is exhibiting signs of systemic inflammatory response syndrome (SIRS), the patient has catheter-related sepsis. Since paired cultures are not always possible or diagnostic, when a patient has an intravenous catheter and either a suspicion for a CRBSI,

• Unable to remove the catheter • Undiagnostic cultures • Unable to rule out another cause being the source of the bloodstream infection

Fig. 98.2  A feline hospitalized post renal transplantation developed an acute onset of a fever along with signs of phlebitis at the central venous jugular catheter (CVJC) entrance site including erythema, swelling, and bruising. The CVJC was removed and a paired catheter tip and blood culture were performed. Both cultures were negative, confirming a catheter site sterile inflammatory complication.

exhibiting signs of SIRS, or has an unexplained fever, this patient is said to be suffering from a catheter-associated bloodstream infection.

RISK FACTORS There are established patient predispositions and risk factors related to catheter infections. Catheters made of polyvinyl chloride or polyethylene appear to be less resistant to bacterial adherence than catheters made of silicon, Teflon, or polyurethane.6,9 Polyurethane and Teflon

CHAPTER 98  Catheter-Related Bloodstream Infections catheters have been shown to decrease the adherence of certain species including coagulase-negative Staphylococci, Acinetobacter species, and Pseudomonas aeruginosa,6,9,10 and are also less thrombogenic.6,10,11 Thrombosis has been associated with increased incidence of CRBSIs,6,12-14 most likely secondary to the clinically silent (prior to vascular occlusion) fibrin sheath that forms within 24 hours of catheter insertion. This sheath is very similar to a biofilm matrix, increasing bacterial and fungal adherence and promoting coagulase enzymes to escalate thrombogenesis, further enlarging the thrombus. The sheath or developing thrombus promotes repeat circulating organismal inoculation and the potential for a complicated persistent bacteremia and disseminated bloodstream infection.15 Conditions that promote thrombosis include multiple catheterization attempts, catheter site irritation or phlebitis, hypovolemia, hypotension, immobilization of the patient, a hypercoagulable state, and endothelial injury.6,12,13,16 Ultrasoundguided central venous catheter placements in human medicine have been well studied and consistently shown a significant decrease in the number of catheter placement attempts and hematoma formations, both known risk factors for increasing thrombophlebitis complications.17-19 However, this has not been explored in veterinary patients. Both human and veterinary studies have found that indwelling catheter duration is significantly associated with catheter infections.1,3,5 Other predisposing factors found in human patients include the use of the catheter for blood sampling, inexperienced operators, infusate type (dextrose additives, blood products, parenteral nutrition, and fluids for oncotic support), excessive manipulation of the catheter, and antibiotic and/or corticosteroid administration.5,20 Veterinary studies have attempted to examine these factors and found conflicting results.5,7,21 Further veterinary research is required to establish risk factors with larger sample sizes and accurate catheter infection definitions.

INCIDENCE Human studies have consistently shown increased morbidity and mortality, along with increased healthcare costs related to CRBSIs.5-7,20,22 CRBSIs have been reported in dogs and cats, but recent studies were unable to find an association with patient outcome.4,5,7,21-25 This may be because veterinary studies have smaller sample sizes, a narrower focus, different outcome parameters, inaccuracies in catheter-related infection surveillance, and a higher incidence of undiagnosed infections. In veterinary medicine, the incidence of catheter site infections versus colonization is not clearly divided. The peripheral catheter contamination rate is 10.4% to 24%1,4,5,7,23,26 and 0% to 26% for jugular catheters,5,7,21,27 where only four veterinary studies have identified central and peripheral CRBSI incidence rates, ranging from 0% to 26%.5,7,21,27 This is consistent with human reports.1,3,5,7,21,28 One veterinary study was able to confirm catheter-related sepsis in patients receiving total parenteral nutrition; the incidence rate was 5.9%.5 CRBSI is well studied in humans with a reported incidence of 0%–15%.29-32 Human studies have demonstrated a high association between catheter tip and hub colonization as a principal source of bloodstream infections; they account for a significant number of etiologies of sepsis and the majority of nosocomial infections in the ICU.1,3,22,30 This highlights the importance of catheter-related infection surveillance in critically ill veterinary patients. It is likely that the connection between CRBSI and morbidity and mortality is grossly underrecognized.

DIAGNOSIS The diagnosis of CRBSIs is difficult since it requires some level of clinical suspicion, and local signs may be completely absent. In addition, local catheter site inflammation may be sterile, such as thrombophlebitis, and

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this makes clinical criteria for CRBSIs neither sensitive nor specific.5,34 Therefore, CRBSIs should be considered in any febrile patient that has an intravascular catheter in place when no other source of infection is apparent. Phlebitis and especially purulent discharge at the catheter site may indicate that catheter colonization has resulted in a localized infection that could lead to a CRBSI. However, the lack of localized reaction does not rule out a CRBSI; close to 50% of humans show no local signs. Because clinical signs are not reliable, cultures are required for a definitive diagnosis of CRBSI.5,35,36 In patients with CRBSI, the catheter is the primary source of the bloodstream infection as determined by identical cultures from the catheter and blood. The diagnostic workup for a patient with suspicion of a catheter-related infection is provided in Fig. 98.3. Considering the relatively low incidence of CRBSI, routine screening of qualitative (i.e., positive versus negative) catheter tip or segment cultures is not recommended due to the high number of false-positive results.6,36,37 Numerous culturing methods of diagnosing a CRBSI have been reported, and the source (intraluminal versus extraluminal) of the infection, number of lumens of the catheter, availability of culturing methods, ability to aspirate the catheter, and need to keep the present catheter in place may dictate which method is to be used in individual patients. Culturing the skin insertion site may identify a dermal, subdermal, or local catheter-associated colonization, but is not adequate to identify a CRBSI and should not prompt catheter removal. It is ideal to obtain a distal tip culture due to its higher specificity for catheter-related infections, where the proximal intradermal portion can result in simple colonization identification.38 Multilumen catheters pose a challenge in that one or multiple lumens may be colonized, leading to false-negative results if blood from only one lumen is cultured. In humans, sampling only one lumen of a triple-lumen catheter missed more than two-thirds of CRBSIs.38,39 Ideally, quantitative cultures of blood obtained both percutaneously and through the catheter are performed. This technique has the highest sensitivity for detecting CRBSIs, but some are difficult to perform in routine practice. Because infections identified soon after catheter placement tend to originate on the external surface and infections of longterm catheters tend to originate on the internal lumen, culturing blood from the lumen of a short-term catheter may be a source of falsenegative cultures.36 Catheters do not necessarily have to be removed to diagnose a CRBSI. Considering the low number of true CRBSIs in febrile patients, catheters in such patients may remain unless they are no longer needed, have purulent discharge, or the patient is decompensating and there is a high index of suspicion for a CRBSI.35,36 Cathetersparing diagnostic methods include differential quantitative blood cultures and time to positivity testing, which have both shown reliable results.30 Using the differential quantitative culture approach, a positive result is one in which the bacterial concentration from the catheterobtained culture(s) is three to five times greater than the culture obtained percutaneously. If a quantitative culture cannot be obtained nor the catheter removed, using the time to positivity testing is another option for diagnosis. This technique confirms a CRBSI if a positive culture from the catheter precedes growth from the percutaneous culture by more than 2 hours. If neither method is available or if the catheter is removed, a semiquantitative culture obtained by rolling a 5-cm section of the catheter four times over a blood agar plate and finding .15 colony forming units (CFU) also has good sensitivity and specificity in human medicine.3 Growth of ,15 CFU/plate from both the insertion site and catheter hub cultures strongly suggests that the catheter is not the source of a bloodstream infection.37 Qualitative or quantitative (more than 100 CFU/ml) blood cultures drawn from the catheter and quantitative cultures (more than 1000 CFU/ml) of broth that was flushed through or sonicated with the catheter have also been described for diagnosing

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PART IX  Infectious Disorders

Febrile patient with IVC

Examine exit site and culture/cytology exudate

Local signs

Look for other infection sources

Obtain 2 blood samples: peripheral vein and through IVC

No local signs

Initiate appropriate therapy

(+) IVC blood culture; (–) peripheral vein

DTP  2 hr or quantitative culture 5:1

DTP < 2 hr or quantitative culture 13 years) have the highest prevalence (31%).13,14 Several reports exist of breed or familial associations with specific structural and functional lesions. A summary of these associations is presented in Box 122.1.8 Mild clinical signs (especially polyuria, polydipsia, and weight loss) may be present but unrecognized for months to years before

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TABLE 122.1  International Renal Interest

Society Staging Scheme for Chronic Kidney Disease1 Dogs

Cats

Plasma Creatinine (mg/dl) Stage I ,1.4 Stage II 1.4–2.8 Stage III 2.9–5.0 Stage IV .5.0

,1.6 1.6–2.8 2.9–5.0 .5.0

Substage Based on Urine Protein-to-Creatinine Ratio Nonproteinuric (NP) ,0.2 ,0.2 Borderline proteinuric (BP) 0.2–0.5 0.2–0.4 Proteinuric (P) .0.5 .0.4 Substage Based on Arterial Blood Pressure (same parameters for cats and dogs)

Normotensive Prehypertensive Hypertensive Severely hypertensive

Systolic Blood Pressure (mm Hg) ,140 140–159 160–179 $180

Risk of Future Target Organ Damage Minimal Low Moderate High

BOX 122.1  Congenital/Familial Nephropathies in Cats and Dogs8 Dogs Renal Dysplasia Lhasa Apso Shih Tzu Standard Poodle Soft-Coated Wheaten Terrier Chow Chow Alaskan Malamute Miniature Schnauzer Dutch Kooiker (Dutch Decoy) Dog

Amyloidosis Shar Pei English Foxhound Beagle

Primary Glomerulopathies Samoyed kindred Navasota kindred English Cocker Spaniel English Springer Spaniel Bull Terrier Dalmatian Doberman Pinscher Bullmastiff Newfoundland Rottweiler Pembroke Welsh Corgi Beagle Soft-Coated Wheaten Terrier

Miscellaneous Boxer—reflux nephropathy with segmental hypoplasia Basenji—Fanconi syndrome German Shepherd—multifocal cystadenocarcinoma Pembroke Welsh Corgi— telangiectasia

Polycystic Kidney Disease Bull Terrier Cairn Terrier West Highland White Terrier

Immune-Mediated Glomerulonephritis Bernese Mountain Dog (autosomal recessive, suspected) Brittany Spaniel (autosomal recessive)

Cats Polycystic Kidney Disease Persian Amyloidosis Abyssinian Siamese and Oriental

decompensation or the development of end-stage CKD. When patients finally present with decompensated or end-stage CKD, the clinical signs are frequently severe. Commonly reported clinical signs (in addition to those described above) include anorexia, vomiting, lethargy or somnolence, halitosis, dysphagia or oral discomfort, and weakness. Common physical examination findings include muscle atrophy and depleted fat stores, dehydration, small and irregular kidney shape, heart murmur, oral ulceration, halitosis, hypothermia, and pale mucous membranes. Severely affected animals may suffer from altered consciousness, seizures, or bleeding problems, and they may be presented moribund or comatose. Because many patients with CKD are geriatric, concurrent disease processes (e.g., chronic enteropathies, hyperthyroidism) with overlapping clinical signs may be also be present.

DIAGNOSIS The combination of historical and physical examination findings frequently leads to a clinical suspicion of decompensated or end-stage CKD. Clinicopathologic and imaging testing can confirm the diagnosis, occasionally indicate the underlying cause, and detect comorbidities and potentially treatable complications of uremia.

Laboratory Tests Common laboratory abnormalities include azotemia, hyperphosphatemia, hypokalemia, metabolic acidosis, hypercalcemia (total calcium), and an increased creatinine kinase concentration. Less commonly, hyperkalemia and clinically significant ionized hypocalcemia are noted. Serum or plasma concentrations of total calcium should not be used to predict the concentration of the biologically active fraction, ionized calcium, because the results of these two tests are frequently discordant.15 Venous blood gas analyses may aid in determining the requirement for alkali therapy. The combination of decreased red blood cell life span and inadequate production of erythropoietin, a hematopoietic hormone, leads to nonregenerative anemia. Chronic inflammation, altered iron metabolism, or iron deficiency from chronic gastrointestinal blood loss also may contribute to anemia.16,17 Some severely affected animals may become acutely anemic secondary to acute blood loss from gastrointestinal mucosal injury, as the degree of gastrointestinal hemorrhage may correlate with stage of CKD.18 The platelet count is usually normal, although platelet function may be impaired in the uremic state. A buccal mucosal bleeding time may be prolonged, but coagulation panel (prothrombin time and partial thromboplastin time) results are expected to be normal. Historically, poorly concentrated urine (urine specific gravity less than 1.035 in cats, less than 1.030 in dogs) with concurrent azotemia has been the hallmark of CKD. However, a subset of cats and, less frequently, dogs may be presented with azotemia and concentrated urine (urine specific gravity of at least 1.030). This phenomenon has been referred to as “glomerulotubular imbalance,” although the pathophysiologic process leading to this phenomenon has not been determined. Speculation exists that this imbalance is due to the presence of lipid in the urine, which increases the specific gravity, leading to the inaccurate inference of urine osmolality. Active urine sediment (white blood cells, red blood cells, bacteria) may indicate urinary tract infection as a cause or, more commonly, a consequence of CKD. However, subclinical bacteriuria (absence of clinical signs with or without the presence of an active sediment) is a common finding and, in many cases, likely clinically insignificant.19-21 Routine urinalysis and bacterial urine culture are recommended nonetheless because for many patients with

CHAPTER 122  Chronic Kidney Disease end-stage CKD manifesting severe, fulminant clinical signs it may be difficult to differentiate subclinical bacteriuria from pyelonephritis. The urine protein-to-creatinine (UPC) ratio should be evaluated in all cats and dogs with CKD because it has shown prognostic utility22-25 and may help the clinician to determine the microanatomic, morphologic lesion (glomerular versus exclusively tubulointerstitial). Typically, dogs with a UPC ratio of at least 2 are likely to have glomerular disease.26 No data implicate a UPC ratio threshold to indicate glomerular disease in cats, but it is accepted that values higher than 1 are likely to be associated with glomerular disease. In general, the severity increase in UPC ratio is proportionate to the likelihood of primary glomerular disease. In the acutely ill patient, UPC ratios must be measured on multiple occasions to confirm the presence of persistent, pathologic proteinuria because a single measurement may be affected by factors that may resolve as the acute illness is stabilized. Microalbuminuria is defined as a quantity of albuminuria that is abnormal but below the detection limit of standard urine dipstick assays. The role of microalbuminuria in the treatment, monitoring, or prognostication of CKD has not been determined because identification of this degree of proteinuria has not been shown to be prognostically superior to UPC ratios.

Imaging Abdominal radiographs may show abnormal kidney size or shape. Nephroliths or ureteroliths may be visualized (if large enough to be detected by radiography), although the presence of uroliths in the upper urinary tract is not always associated with azotemia.27 Abdominal ultrasonography frequently reveals diminished renal architecture resulting from progressive fibrosis. In cats with CKD, kidneys were subjectively assessed as being small in 42% and large in 34%, but objective measurement found 16% to be small and 6% to be large.28 Other changes that may be readily identified include renal pelvic mineralization, nephroliths or ureteroliths, polycystic kidney disease, and perinephric pseudocysts. Taking into consideration the variable of operator error, obstructive ureteroliths and other obstructive lesions may be better detected by ultrasonography versus radiography. However, in some cases, neither modality is sufficient to identify the cause of a ureteral obstruction. In these cases, a diagnosis of obstructive kidney disease is supported ultrasonographically by the presence of hydronephrosis29 or a progressive dilation in the width of the renal pelvis (even if a cause for the aforementioned abnormalities is not detected). In animals with normal renal function, median transverse renal pelvic width is usually less than 2 mm.29 This value may be modestly higher (median 2.5 mm) with diuresis. Historically, pyelonephritis has been associated with renal pelvic dilation of varying severity, although there are difficulties in differentiating the impact of pyelonephritis from partial obstruction. Obstructive disease is associated with larger pelvic measurements (median 15 mm in dogs, 6.8 mm in cats), although pelvic dilation may be minimal or absent in some cases.29 As a general guideline, a transverse renal pelvic width of 4 mm or higher in a cat prompts consideration of partial obstruction that may benefit from intervention, especially if there is progressive dilation or failure to respond to medical management.

Other Diagnostic Modalities Hypertension occurs in approximately 20% to 40% of cats30,31 and 31% of dogs32 with CKD, although many patients with decompensated or end-stage CKD are hypotensive because of dehydration and hypovolemia. Measurement of blood pressure by all commercially available devices is highly prone to misinterpretation, as validation of these devices has proven problematic, requiring highly trained personal and ample time dedicated to accurate measurement.33 It is the authors’ experience that in many instances in which hypertension is

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documented, the probable etiology is anxiety or excitement-induced situational hypertension. Microscopic assessment of renal tissue (either aspirates and cytology or needle/wedge biopsy and histopathology) is indicated when renomegaly is present to rule out lymphoma or feline infectious peritonitis. In addition, renal biopsy can be useful for the differentiation of acute and CKDs, when historical and clinical data do not allow for the determination of chronicity. The diagnostic yield of these procedures must be weighed against the potential risks because uremic inhibition of platelet function increases the risk of hemorrhage secondary to renal tissue sampling. Measurement of glomerular filtration rate rarely is used when azotemia is present because it can be assumed that this test shows severely diminished excretory function. Parathyroid hormone concentration may be elevated if renal secondary hyperparathyroidism is present.

TREATMENT The goal of therapy for decompensated or end-stage CKD is to specifically address the insult that resulted in deterioration of the patient’s status (if it can be identified) and/or remedy the accumulated sequelae of the deterioration in renal function. The clinician should strive to improve the patient’s quality of life, while minimizing hospitalization time.

Fluid Therapy A markedly dehydrated patient with decompensated or end-stage CKD likely needs hospitalization for intensive intravenous fluid therapy. Cats with CKD of any stage are frequently polyuric, whereas the volume of urine (relative to body mass) produced by dogs is more variable. Consequently, cats with decompensated or end-stage CKD common present with severe dehydration and hypovolemia. The large volume of fluid administration required by cats in a uremic crisis mandates the intravenous route. A balanced polyionic fluid is generally appropriate, provided that serum or plasma electrolyte concentrations are within or close to the normal range. The fluid deficit is calculated (% dehydration 3 body weight [kg] 5 volume of deficit in liters) and usually replaced over 6 to 24 hours, although some situations may necessitate more rapid replacement (e.g., hemodynamic instability or collapse, uncertain urine production capability) or slower replacement (e.g., severe cardiac disease). In addition to replacing the fluid deficit, ongoing losses (e.g., vomiting, diarrhea) should be replaced, and a maintenance rate of fluid administration should be added to the total fluid rate (see Chapter 67, Daily Intravenous Fluid Therapy). Frequently, cats hospitalized for decompensated or end-stage CKD require intravenous fluids at administration rates far exceeding fluid requirements of an anorectic cat with extrarenal disease. The purpose of continued, large-volume fluid administration for cats with decompensated CKD is not to induce a diuresis because these patients are experiencing diuresis independent of fluid administration as a consequence of impaired renal concentrating ability. Rather, these patients are commonly enduring massive urinary fluid losses and, more variably, solute losses for which they are unable to compensate with enteral intake. For this reason, fluid therapy should be directed towards normalization of hydration status and improvement in acid-base and electrolyte abnormalities, rather than towards inducing diuresis for the purpose of improving azotemia. Achievement of the former goal almost always results in achievement of the latter. However, if intravenous fluid is administered at volumes in excess of what is required to maintain normal fluid status, the patient will be at greatest risk for volume overload (most frequently manifested as congestive heart failure). Once the patient’s hydration status is normalized, the plasma or serum creatinine concentration decreases at variable rates which are

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PART XII  Urogenital Disorders

difficult to predict. When the creatinine concentration reaches a baseline value (i.e., it is no longer decreasing despite normal hydration status), intravenous fluid rates should be tapered over the course of 2 to 3 days in preparation for patient discharge. Slowly decreasing the intravenous fluid rate allows the clinician to assess the patient’s ability to maintain normal hydration with enteral intake of water and food and aids in the determination of whether the patient requires administration of subcutaneous fluid therapy to maintain hydration.

Acid-Base and Electrolyte Balance Because hypokalemia is a common manifestation of CKD, most cats (more so than dogs) benefit from potassium supplementation in the intravenous fluids. The amount of potassium supplemented can be based on calculations of potassium deficit determined from serum potassium levels or, more simply, standard concentrations can be added to intravenous fluids based on serum potassium concentration. Guidelines for potassium supplementation of intravenous fluids can be found in Chapter 56, Potassium Disorders. Frequently, the original amount of potassium supplemented to intravenous fluid formulations must be altered as dictated by regular monitoring of plasma or serum potassium concentrations and assessment of trends towards hypokalemia or hyperkalemia. If hypokalemia is refractory to aggressive supplementation, additional electrolyte abnormalities (e.g., hypomagnesemia, hypocalcemia) and/or endocrinopathies (e.g., hyperaldosteronemia) should be investigated. Hyperaldosteronism is a common finding in cats with azotemia and hypertension and, given its hypokalemic and hypomagnesemic effects, consideration should be given to measurement of blood aldosterone concentrations in cats with refractory hypokalemia and treatment with aldosterone antagonists (e.g., spironolactone) if aldosterone levels are increased in a hypokalemic cat.34,35 Frequently, patients that initially present with severe and/or refractory hypokalemia require enteral potassium supplementation (e.g., potassium gluconate or potassium citrate) after hospital discharge. Patients with decompensated or end-stage CKD are frequently acidemic at the time of initial presentation. Although the degree of acidemia frequently improves after correction of volume deficits and perfusion abnormalities, it rarely normalizes in cases of end-stage CKD. If the blood pH remains below 7.2 after restoration of normal hydration status, intravenous sodium bicarbonate supplementation should be considered (see Chapter 59, Traditional Acid-Base Analysis). For patients requiring intravenous sodium bicarbonate therapy, enteral alkali therapy (e.g., sodium bicarbonate or potassium citrate) should be considered for long-term management. In human medicine, chronic alkali therapy is emerging as a candidate therapy for slowing progression of kidney disease and is considered generally safe and inexpensive.36,37 Alkali supplementation is recommended by both the Kidney Disease Improving Global Outcomes (KDIGO) CKD Work Group and the National Kidney Foundation Disease Outcome Quality Initiative.38,39 However, the benefits in terms of slowing the progression of kidney disease in cats and dogs has yet to be investigated to the authors’ knowledge.

Management of Gastrointestinal Signs Acute management of the gastrointestinal manifestations of decompensated or end-stage CKD does not differ from that of acute kidney injury (see Chapter 121, Acute Kidney Injury). Although antacid therapy is commonly prescribed to dogs and cats with CKD, evidence does not support hypergastrinemia, gastric hyperacidity, or a high incidence of gastric ulceration.40 The authors are unaware of any evidence in the veterinary literature that shows a clinical benefit for the use of antisecretory drugs (e.g., histamine-2 receptor antagonists,

proton pump inhibitors) in the chronic management of these patients. In the author’s experience, the administration of these medications provides no benefit over the use of antiemetic drugs alone for the chronic management of end-stage CKD but does add to the daily pill burden, which may negatively affect the animal-human bond. Furthermore, evidence is emerging in human medicine that supports an association between the use of antisecretory drugs (proton pump inhibitors in particular) and kidney injury.41 The authors recommend the use of maropitant citrate or ondansetron citrate (both commercially available in parenteral and oral formulations) to combat nausea, vomiting, and hyporexia associated with uremia.42 It is unknown whether combining these medications is more effective than the sole use of either.

Nutritional Support Appetite stimulating drugs are frequently prescribed for CKD. Mirtazapine is the most commonly used appetite stimulant and appears most effective for use in cats. CKD prolongs the half-life of mirtazapine in cats, however, warranting a dose reduction. A safe and effective dose and dosing interval for mirtazapine in cats with CKD is 1.88 mg/ cat PO q48h.43 Transdermal mirtazapine has recently been approved by the Food and Drug Administration for use in cats and has been found to be effective at a dose of 2 mg/cat q24h.44 Capromorelin, a ghrelin receptor agonist, has recently been approved by the Food and Drug Administration for use in dogs to stimulate appetite (3 mg/kg PO q24h). While its effect in stimulating the appetite and increasing caloric intake of dogs and cats with CKD has not been determined and its pharmacokinetic profile in dogs with chronic kidney disease has not been specifically evaluated, long-term administration of higher than recommended doses to dogs did not result in adverse effects.45 Despite modest effectiveness in improving voluntary caloric intake, the appetite stimulating effects of both mirtazapine and capromorelin are often inadequate to result in a sustained increase in nutritional intake that would preclude the requirement of assisted feeding through a feeding tube. In cases of decompensated or end-stage CKD, assisted feeding is frequently indicated. During stabilization of a uremic crisis, a previously anorectic patient may begin to show an interest in food, but consumption frequently falls short of nutritional requirements. Placement of a feeding tube can ensure that nutritional requirements are met and can facilitate administration of fluids and medications by the owner. Nasogastric or nasoesophageal tubes can be placed easily without the need for general anesthesia or sedation and can provide appropriate short-term support (1 to 2 weeks). Esophagostomy tubes and percutaneous endoscopic gastrostomy (PEG) tubes are also relatively easy to place and have several advantages over nasal feeding tubes (see Chapter 126, Enteral Nutrition). Use of these types of feeding tubes in cats has been met with owner satisfaction.46 However, complications of both the placement procedure and the use of these devices should be discussed with the owner, as a high-rate complications have been documented to occur in patients in which esophagostomy tubes (43.1% of dogs and 45.5% of cats)47 and PEG tubes (43.3% of dogs and 41.8% of cats)48 are placed. Placement of esophagostomy and PEG tubes requires general anesthesia, so prior restoration of hydration, acid-base, and electrolyte abnormalities is recommended. The optimal composition of the diet fed to cats and dogs with decompensated or end-stage CKD is not known. Diets with restricted quantities of protein and phosphorus content have been shown to both prolong survival and decrease signs of uremia in patients with stable CKD.49,50 However, the patient may develop a food aversion to this type of diet if it is fed before stabilization, making long-term voluntary intake less likely. Initially, provision of the most calorically

CHAPTER 122  Chronic Kidney Disease

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dense diets or the most readily accepted diets available may offer the highest probability of weight gain and improvement of muscle mass. Emerging evidence in human medicine shows that protein energywasting is associated with hospitalization and mortality in hemodialysis patients. Thus, an ongoing catabolic state should be avoided. The dietary composition should be optimized to achieve both optimal caloric and limited protein/phosphorus intake. This balance is most readily obtained with the use of a feeding tube. Historically, the use of feeding tubes has been somewhat limited by the consistency of commercial diets, with most commercial diets requiring dilution and blending with large amounts of water to facilitate passage through feeding tubes with smaller luminal diameter. This requirement results in reduction of caloric density and an increase in the total volume of food necessary to meet caloric requirements. Many patients cannot tolerate the total volume of blended food necessary to achieve a neutral or positive energy balance and therefore catabolism continues despite nutritional support. Another consequence of diluting commercial diets with water is that the low sodium content of renal diets can predispose patients to severe hyponatremia and neurologic sequelae if large volumes of water are administered after being blended with the diet or separately for maintenance of hydration. Careful attention must be given to plasma or serum electrolyte concentrations, especially in small patients, or in those patients for which parenteral fluid therapy (a source of large amounts of sodium) is being tapered or discontinued. Provision of supplemental sodium may be necessary in these cases. Recently, commercial critical care, recovery, and renal diets have become available in both liquid and powder formulations (the latter of which is reconstituted with water). These formulations are specifically designed for use through feeding tubes and are therefore more calorically dense and have more appropriate electrolyte balance, which reduces the likelihood of the complications described above.

concluded that a starting dose of 1 mcg/kg SC once weekly resulted in an erythropoietic response in 13 of 14 patients.52 The authors currently use the following dosing schedules: 1 mcg/kg up to 25 mcg per dog SC or IV once weekly until the hematocrit is more than 35%, then the same dose administered every 2 to 3 weeks as determined by serial hematocrit measurements; either 1 mcg/kg or 6.25 mcg/cat SC or IV once weekly until the hematocrit is greater than 25%, then the same dose administered every 2 to 3 weeks as determined by serial hematocrit measurements. The hematocrit should initially be measured before each injection until the interval between administrations has stabilized between 2 and 3 weeks. Hypertension is a frequently recognized complication of epoetin a and darbepoetin a, so blood pressure should be measured each time a hematocrit is measured. Adequate iron stores are necessary for an optimal response, and iron administration usually is required during the initial treatment period. Iron sources include iron dextran (50 mg/cat; 10 to 20 mg/kg in dogs, deep IM injection monthly) or ferrous sulfate (50 to 100 mg/ cat, 100 to 300 mg/dog PO q24h). Cats and dogs with CKD that are administered ESAs generally show a response (increased hematocrit, reticulocytosis) after 2 weeks of treatment (median time to response was 29 days in the aforementioned study of dogs, and 21 days in the aforementioned study of cats),51,52 unless extraneous factors causing resistance are present (e.g., gastrointestinal hemorrhage, infection, or chronic inflammation).

Management of Anemia

Fluid Therapy

If clinical signs associated with anemia (weakness, tachycardia, tachypnea) are present, transfusion (whole blood, packed red blood cells, or hemoglobin based oxygen carrier) may be necessary for immediate stabilization. Given the high probability that the patient’s ability to synthesize and secrete endogenous erythropoietin is impaired, consideration should be given to administration of an erythropoiesis stimulating agent (ESA) early in the course of hospitalization. Epoetin  (Epogen or Procrit) traditionally has been used in veterinary medicine for this problem and is effective in stimulating erythropoiesis in cats and dogs. However, its use has been associated with the formation of antibodies directed against the exogenous ESA and endogenous erythropoietin, resulting in anemia. Once antibodies develop, the patient is typically transfusion-dependent and can require blood transfusions as frequently as once weekly for prolonged periods (several months). Currently, darbepoetin  (Aranesp) is considered the preferred treatment for dogs and cats with anemia of renal disease. Darbepoetin a is hyperglycosylated, which prolongs the circulating half-life of the molecule and may reduce immunogenicity. Anecdotal reports suggest a lower rate of anti-erythropoietin antibody development in cats and dogs compared with recombinant human erythropoietin. Because of the perceived safety of darbepoetin  compared with erythropoietin, early initiation of this treatment should be considered even if the patient does not require a blood transfusion. The optimal starting dose of darbepoetin  has not been determined. However, a retrospective case series describing the use of darbepoetin  in dogs suggested a dose-dependent response. Variable dosing regimens were used in this study, but 27% of dogs required a dose increase over the course of treatment.51 A retrospective study in cats with CKD

Pets with chronic dehydration may benefit from SC fluid therapy. Owners can be taught to administer fluids at home. Dosage is empiric, based on subjective assessment of the patient’s well-being and hydration status. Lactated Ringer’s solution and 0.9% saline are used most frequently. A typical starting dosage for a cat is 100 to 125 ml q24-72h. Animals with compensated disease that do not require ongoing SC fluid therapy may benefit from intermittent treatment during times of stress (exacerbation of uremia, other illness, boarding, traveling).

LONG-TERM MANAGEMENT Once the patient has been stabilized and can be managed on an outpatient basis, long-term care is generally undertaken by the primary veterinarian or a veterinary internist. A detailed discussion of longterm management of CKD is beyond the scope of this chapter. However, the following considerations should be made.

Additional Considerations If a diet restricted in phosphorus content is not sufficient to control hyperphosphatemia, a phosphate binding drug should be administered with food. As discussed above, the human or veterinary literature contains no evidence that long-term administration of antisecretory drugs (e.g., histamine-2 receptor antagonists and proton pump inhibitors) has any clinical benefit. However, chronic, intermittent administration of an antiemetic drug is recommended empirically and can be used at the discretion of the owner for symptomatic control of the gastrointestinal manifestations of uremia. Hypertension can be managed with amlodipine in cats and dogs. This medication can be used with or without an angiotensin converting enzyme (ACE) inhibitor (e.g., enalapril, benazepril) or angiotensin receptor blocker (e.g., telmisartan). An ACE inhibitor or telmisartan is recommended if proteinuria is present. See Chapter 149 for further discussion of antihypertensive therapy. The use of calcitriol may decrease mortality in dogs with CKD, possibly by normalizing parathyroid hormone concentrations.53 A similar benefit has yet to be demonstrated in cats but is likely to exist.

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Administration of calcitriol to a patient with hyperphosphatemia or ionized hypercalcemia is contraindicated because of the risk of soft tissue mineralization. Plasma or serum phosphorus and ionized calcium concentrations should be monitored closely if this drug is used.

ADVANCED THERAPEUTIC MODALITIES Renal transplantation may be appropriate for some cats, depending on availability. The best candidates for renal transplantation are those cats with stage II to III CKD, without concurrent illness or infection. Renal transplantation should be considered before end-stage CKD, rather than as an emergency or salvage procedure. However, decompensated or end-stage CKD is not an absolute contraindication for transplantation. The availability and success of canine renal transplantations are limited, and as a result, it is not commonly recommended in dogs unless a compatible relative of the recipient is available. Chronic hemodialysis is available in an increasing number of veterinary hospitals. Because of the need for frequent treatments (minimum of two to three times a week for the remainder of the patient’s life) and cost associated with these treatments, chronic hemodialysis is not commonly used for dogs or cats with CKD, but excellent results may be obtained in select cases. Complications associated with peritoneal dialysis (especially catheter occlusion and peritonitis) have limited its use to acute settings.

PROGNOSIS CKD is a progressive disease, but the rate of progression is highly variable. Multiple studies have been conducted to determine predictors of decompensation or mortality for cats with CKD. These studies have demonstrated that the following variables are associated with these endpoints: plasma creatinine concentration, UPC ratio, urine albumin-to-creatinine ratio, leukocytosis, hyperphosphatemia, and weight loss.23,24,54,55 A Kaplan–Meier survival curve for cats with CKD, stratified by IRIS stage, is displayed in Fig. 122.1. In the canine studies that investigated predictors of decompensation or mortality, degree of hypercreatininemia and hyperphosphatemia, the UPC concentration, hypoalbuminemia, and hypertension were readily available parameters that were positively associated with the decompensation or mortality, whereas body condition score and muscle condition were associated negatively with mortality.22,25,32,56 Kaplan–Meier survival curves for dogs with CKD stratified by IRIS stage and body condition score are displayed in Fig. 122.2. Most animals eventually die of CKD or related complications, although some maintain stable renal function and die of unrelated causes (such as neoplasia). In general, creatinine is the primary means of determining the severity and prognosis of canine and feline CKD in clinical practice.

100 90 80 Percent Survival

70 60 50 IRIS 1,2

40

IRIS 3,4

30 20 10 0 0

10

20

30

40

50

60

Survival time (months post-CKD diagnosis) Fig. 122.1  Kaplan–Meier survival curve of cats with chronic kidney disease (CKD) stratified by International Renal Interest Society (IRIS) stage.24

CHAPTER 122  Chronic Kidney Disease

Percent survival

100

IRIS Stage 2 IRIS Stage 3 IRIS Stage 4

50

0 0

10

20

30

40

Survival time (months post-CKD diagnosis) Fig. 122.2  Kaplan–Meier survival curve of dogs with chronic kidney disease (CKD) stratified by International Renal Interest Society (IRIS) stage.25

REFERENCES 1. Elliott J, Watson ADJ: Chronic kidney disease: staging and management. In Bonagura JD, Twedt DC, editors: Kirk’s current veterinary therapy, St Louis, 2009, Saunders Elsevier, pp 883-892. 2. Macdougall DF, Cook T, Steward AP, Cattell V: Canine chronic renal disease: prevalence and types of glomerulonephritis in the dog, Kidney Int 29(6):1144-1151, 1986. 3. Minkus G, Reusch C, Horauf A, et al: Evaluation of renal biopsies in cats and dogs - histopathology in comparison with clinical data, J Small Anim Prac 35(9):465-472, 1994. 4. Chakrabarti S, Syme HM, Brown CA, Elliott J: Histomorphometry of feline chronic kidney disease and correlation with markers of renal dysfunction, Vet Pathol 50(1):147-155, 2013. 5. McLeland SM, Cianciolo RE, Duncan CG, Quimby JM: A comparison of biochemical and histopathologic staging in cats with chronic kidney disease, Vet Pathol 52(3):524-534, 2015. 6. Martino-Costa AL, Malhao F, Lopes C, Dias-Pereira P: Renal interstitial lipid accumulation in cats with chronic kidney disease, J Comp Pathol 157(2-3):75-79, 2017. 7. Bouillon J, Snead E, Caswell J, Feng C, Helie P, Lemetayer J: Pyelonephritis in dogs: retrospective study of 47 histologically diagnosed cases (20052015), J Vet Intern Med 32(1):249-259, 2018. 8. Lees GE: Congenital kidney diseases. In Bartges J, Polzin D, editors: Nephrology and urology of small animals, vol 1, West Sussex, 2011, WileyBlackwell. 9. O’Neill DG, Elliott J, Church DB, McGreevy PD, Thomson PC, Brodbelt DC: Chronic kidney disease in dogs in UK veterinary practices: prevalence, risk factors, and survival, J Vet Intern Med 27(4):814-821, 2013. 10. Greene JP, Lefebvre SL, Wang M, Yang M, Lund EM, Polzin DJ: Risk factors associated with the development of chronic kidney disease in cats evaluated at primary care veterinary hospitals, J Am Vet Med Assoc 244(3):320-327, 2014. 11. Freeman LM, Abood SK, Fascetti AJ, et al: Disease prevalence among dogs and cats in the United States and Australia and proportions of dogs and cats that receive therapeutic diets or dietary supplements, J Am Vet Med Assoc 229(4):531-534, 2006. 12. Lund EM, Armstrong PJ, Kirk CA, Kolar LM, Klausner JS: Health status and population characteristics of dogs and cats examined at private veterinary practices in the United States, J Am Vet Med Assoc 214(9):13361341, 1999. 13. Conroy M, Brodbelt DC, O’Neill D, Chang YM, Elliott J: Chronic kidney disease in cats attending primary care practice in the UK: a VetCompass(TM) study, Vet Rec 184(17):526, 2019.

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14. Jepson RE, Brodbelt D, Vallance C, Syme HM, Elliott J: Evaluation of predictors of the development of azotemia in cats, J Vet Intern Med 23(4):806-813, 2009. 15. Schenck PA, Chew DJ: Prediction of serum ionized calcium concentration by serum total calcium measurement in cats, Can J Vet Res 74(3):209-213, 2010. 16. Javard R, Grimes C, Bau-Gaudreault L, Dunn M: Acute-phase proteins and iron status in cats with chronic kidney disease, J Vet Intern Med 31(2):457-464, 2017. 17. Gest J, Langston C, Eatroff A: Iron status of cats with chronic kidney disease, J Vet Intern Med 29(6):1488-1493, 2015. 18. Crivellenti LZ, Borin-Crivellenti S, Fertal KL, Contin CM, Miranda CM, Santana AE: Occult gastrointestinal bleeding is a common finding in dogs with chronic kidney disease, Vet Clin Pathol 46(1):132-137, 2017. 19. Lamoureux A, Da Riz F, Cappelle J, et al: Frequency of bacteriuria in dogs with chronic kidney disease: a retrospective study of 201 cases, J Vet Intern Med 33(2):640-647, 2019. 20. White JD, Stevenson M, Malik R, Snow D, Norris JM: Urinary tract infections in cats with chronic kidney disease, J Feline Med Surg 15(6):459-465, 2013. 21. Mayer-Roenne B, Goldstein RE, Erb HN: Urinary tract infections in cats with hyperthyroidism, diabetes mellitus and chronic kidney disease, J Feline Med Surg 9(2):124-132, 2007. 22. Jacob F, Polzin DJ, Osborne CA, et al: Evaluation of the association between initial proteinuria and morbidity rate or death in dogs with naturally occurring chronic renal failure, J Am Vet Med Assoc 226(3):393-400, 2005. 23. Syme HM, Markwell PJ, Pfeiffer D, Elliott J: Survival of cats with naturally occurring chronic renal failure is related to severity of proteinuria, J Vet Intern Med 20(3):528-535, 2006. 24. King JN, Tasker S, Gunn-Moore DA, Strehlau G: Prognostic factors in cats with chronic kidney disease, J Vet Intern Med 21(5):906-916, 2007. 25. Rudinsky AJ, Harjes LM, Byron J, et al: Factors associated with survival in dogs with chronic kidney disease, J Vet Intern Med 32(6):1977-1982, 2018. 26. Center SA, Wilkinson E, Smith CA, Erb H, Lewis RM: 24-Hour urine protein/creatinine ratio in dogs with protein-losing nephropathies, J Am Vet Med Assoc 187(8):820-824, 1985. 27. Kyles AE, Hardie EM, Wooden BG, et al: Clinical, clinicopathologic, radiographic, and ultrasonographic abnormalities in cats with ureteral calculi: 163 cases (1984-2002), J Am Vet Med Assoc 226(6):932-936, 2005. 28. Lamb CR, Dirrig H, Cortellini S: Comparison of ultrasonographic findings in cats with and without azotaemia, J Feline Med Surg 1098612X17736657, 2017. 29. D’Anjou MA, Bedard A, Dunn ME: Clinical significance of renal pelvic dilatation on ultrasound in dogs and cats, Vet Radiol Ultrasound 52(1):88-94, 2011. 30. Syme HM, Barber PJ, Markwell PJ, Elliott J: Prevalence of systolic hypertension in cats with chronic renal failure at initial evaluation, J Am Vet Med Assoc 220(12):1799-1804, 2002. 31. Bijsmans ES, Jepson RE, Chang YM, Syme HM, Elliott J: Changes in systolic blood pressure over time in healthy cats and cats with chronic kidney disease, J Vet Intern Med 29(3):855-861, 2015. 32. Jacob F, Polzin DJ, Osborne CA, et al: Association between initial systolic blood pressure and risk of developing a uremic crisis or of dying in dogs with chronic renal failure, J Am Vet Med Assoc 222(3):322-329, 2003. 33. Acierno MJ, Brown S, Coleman AE, et al: ACVIM consensus statement: guidelines for the identification, evaluation, and management of systemic hypertension in dogs and cats, J Vet Intern Med 32(6):1803-1822, 2018. 34. Jepson RE, Syme HM, Elliott J: Plasma renin activity and aldosterone concentrations in hypertensive cats with and without azotemia and in response to treatment with amlodipine besylate, J Vet Intern Med 28(1):144-153, 2014. 35. Jensen J, Henik RA, Brownfield M, Armstrong J: Plasma renin activity and angiotensin I and aldosterone concentrations in cats with hypertension associated with chronic renal disease, Am J Vet Res 58(5):535-540, 1997. 36. de Brito-Ashurst I, Varagunam M, Raftery MJ, Yaqoob MM: Bicarbonate supplementation slows progression of CKD and improves nutritional status, J Am Soc Nephrol 20(9):2075-2084, 2009. 37. Phisitkul S, Khanna A, Simoni J, et al: Amelioration of metabolic acidosis in patients with low GFR reduced kidney endothelin production and kidney injury, and better preserved GFR, Kidney Int 77(7):617-623, 2010.

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38. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease, Am J Kidney Dis 42(4 Suppl 3):S1-S201, 2003. 39. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group: KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD), Kidney Int Suppl (113):S1-S130, 2009. 40. Tolbert MK, Olin S, MacLane S, et al: Evaluation of gastric pH and serum gastrin concentrations in cats with chronic kidney disease, J Vet Intern Med 31(5):1414-1419, 2017. 41. Lazarus B, Chen Y, Wilson FP, et al: Proton pump inhibitor use and the risk of chronic kidney disease, JAMA Intern Med 176(2):238-246, 2016. 42. Quimby JM, Brock WT, Moses K, Bolotin D, Patricelli K: Chronic use of maropitant for the management of vomiting and inappetence in cats with chronic kidney disease: a blinded, placebo-controlled clinical trial, J Feline Med Surg 17(8):692-697, 2015. 43. Quimby JM, Gustafson DL, Lunn KF: The pharmacokinetics of mirtazapine in cats with chronic kidney disease and in age-matched control cats, J Vet Intern Med 25(5):985-989, 2011. 44. Poole M, Quimby JM, Hu T, Labelle D, Buhles W: A double-blind, placebo-controlled, randomized study to evaluate the weight gain drug, mirtazapine transdermal ointment, in cats with unintended weight loss, J Vet Pharmacol Ther 42(2):179-188, 2019. 45. Zollers B, Huebner M, Armintrout G, Rausch-Derra LC, Rhodes L: Evaluation of the safety in dogs of long-term, daily oral administration of capromorelin, a novel drug for stimulation of appetite, J Vet Pharmacol Ther 40(3):248-255, 2017. 46. Ireland LM, Hohenhaus AE, Broussard JD, Weissman BL: A comparison of owner management and complications in 67 cats with esophagostomy and percutaneous endoscopic gastrostomy feeding tubes, J Am Anim Hosp Assoc 39(3):241-246, 2003.

47. Nathanson O, McGonigle K, Michel K, Stefanovski D, Clarke D: Esophagostomy tube complications in dogs and cats: retrospective review of 225 cases, J Vet Intern Med 33(5):2014-2019, 2019. 48. Salinardi BJ, Harkin KR, Bulmer BJ, Roush JK: Comparison of complications of percutaneous endoscopic versus surgically placed gastrostomy tubes in 42 dogs and 52 cats, J Am Anim Hosp Assoc 42(1):51-56, 2006. 49. Jacob F, Polzin DJ, Osborne CA, et al: Clinical evaluation of dietary modification for treatment of spontaneous chronic renal failure in dogs, J Am Vet Med Assoc 220(8):1163-1170, 2002. 50. Ross SJ, Osborne CA, Kirk CA, Lowry SR, Koehler LA, Polzin DJ: Clinical evaluation of dietary modification for treatment of spontaneous chronic kidney disease in cats, J Am Vet Med Assoc 229(6):949-957, 2006. 51. Fiocchi EH, Cowgill LD, Brown DC, et al: The use of darbepoetin to stimulate erythropoiesis in the treatment of anemia of chronic kidney disease in dogs, J Vet Intern Med 31(2):476-485, 2017. 52. Chalhoub S, Langston CE, Farrelly J: The use of darbepoetin to stimulate erythropoiesis in anemia of chronic kidney disease in cats: 25 cases, J Vet Intern Med 26(2):363-369, 2012. 53. Polzin DJ, Ross S, Osborne CA, Lulich JP, Swanson LL: Clinical benefit of calcitriol in canine chronic kidney disease (abstr), J Vet Intern Med 19(3):433, 2005. 54. Boyd LM, Langston C, Thompson K, Zivin K, Imanishi M: Survival in cats with naturally occurring chronic kidney disease (2000-2002), J Vet Intern Med 22(5):1111-1117, 2008. 55. Freeman LM, Lachaud MP, Matthews S, Rhodes L, Zollers B: Evaluation of weight loss over time in cats with chronic kidney disease, J Vet Intern Med 30(5):1661-1666, 2016. 56. Parker VJ, Freeman LM: Association between body condition and survival in dogs with acquired chronic kidney disease, J Vet Intern Med 25(6):1306-1311, 2011.

123 Kidney Transplantation Lillian Ruth Aronson, VMD, DACVS

KEY POINTS • Kidney transplantation is a viable option for cats suffering from acute kidney injury or chronic renal failure. • Stringent case selection of a potential recipient is a critical part of patient evaluation to prevent both short- and long-term complications. • Fractious cats or those with a history of recurrent urinary tract infections are not good candidates for the procedure. • Lifelong immunosuppression is necessary and consists of a combination of cyclosporine and prednisolone.

• Risk factors associated with survival after discharge include increasing age, intraoperative hypotension, and length of anesthesia. • Successful treatment of complications secondary to chronic immunosuppressive therapy (i.e., infectious complications, diabetes mellitus, and neoplasia) still remains a significant challenge for the clinician.

Kidney transplantation, which was first introduced to the veterinary community in 1987 by Drs. Clare Gregory and Ira Gorley from the University of California at Davis School of Veterinary Medicine, continues to remain an accepted treatment option for cats with acute kidney injury or chronic renal failure. Since its introduction, it is estimated that between 600 and 700 cases of feline renal transplantation have been performed at various centers around the United States. Although there is some question as to whether there is justification for the technique as a treatment for cats suffering from kidney failure, successful transplantation can result in the disappearance of clinical signs previously associated with kidney disease, weight gain, an overall improvement in the quality of life, and prolonged survival time compared with medical management of the disease.1 Despite stringent case selection, improved surgical experience, and lessons learned over the years with regards to short- and long-term management of these cases, renal transplantation still remains a challenge for the veterinary clinician. This chapter discusses the most upto-date information with regard to appropriate case selection, pre- and postoperative care, anesthetic and surgical management, and treatment of the most common long-term complications. The procedure has been performed predominantly in felines and thus is the focus of this chapter. However, canine kidney transplantation is performed at selected facilities around the United States; further information is presented at the end of this chapter.

pyelonephritis or amyloidosis are appropriate candidates for the procedure because of the potential long-term effect on the allograft. Patients with acute kidney injury secondary to a ureteral obstruction or toxicosis often require hemodialysis for stabilization. Additionally, hemodialysis may be necessary for the removal of ethylene glycol and its toxic metabolites before transplantation (see Chapter 180, Extracorporeal Therapies for Blood Purification). In many cases of ureteral obstruction, relief of the obstruction prevents the need for immediate transplantation.

INDICATIONS The most common histopathologic diagnosis identified from native kidney biopsy samples of cats necessitating a renal transplant is chronic interstitial nephritis. Other underlying conditions for which transplantation has been performed include oxalate nephrosis, polycystic kidney disease, renal fibrosis, pyelonephritis, membranous glomerulonephropathy, amyloidosis, renal dysplasia, and toxic insults (e.g., ethylene glycol and lily toxicity). It is unclear if patients with

CASE SELECTION Thorough screening of a potential feline renal transplant recipient is critical to decrease the morbidity and mortality that can occur after the procedure. Although the best time to intervene with surgery is still subjective, clinicians with experience managing these patients suggest that surgical intervention should be performed in cats with early decompensated chronic kidney disease or irreversible acute kidney injury.2,3 Clinical signs that indicate decompensation include worsening of the azotemia and anemia as well as continued weight loss in the face of medical therapy. In a review of 168 cases performed at the authors’ facility from 1998 to 2018, 18% of the cats were in International Renal Interest Society (IRIS) stage 3 and 82% were in IRIS stage 4 at presentation. It is important to be aware that some candidates that are clinically stable can rapidly deteriorate and die without prior evidence of decompensation. At one center, indications for transplantation additionally include a serum creatinine (Cr) more than 4 mg/dl or significant aberrations in calcium and phosphorus levels.4 Some clinicians have been successful in preventing the physical deterioration of individual patients for up to 2 years by the placement of either a percutaneous endoscopic gastrostomy or esophagostomy feeding tube.3 Both physical and biochemical parameters need to be evaluated carefully to determine a cat’s candidacy. Feline candidates should be free of other disease conditions including advanced primary cardiomyopathy,

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feline leukemia virus/feline immunodeficiency virus (FeLV/FIV), recurrent urinary tract infections, uncontrolled hyperthyroidism, and underlying neoplasia. Cats with a fractious temperament that cannot be handled may also be declined as candidates. Renal transplantation is considered a treatment option for cats whose underlying cause of renal failure was associated with calcium oxalate urolithiasis.5 Additionally, cats with a history of inflammatory bowel disease, upper respiratory tract infections, and those with certain echocardiographic abnormalities have also been transplanted successfully. There are insufficient data to determine if cats with diabetes should be declined as potential candidates, but the immunosuppressive drugs will exacerbate the disease, especially if not well controlled prior to surgery. Additional risk factors have been associated with morbidity and mortality in this patient population. In one study, the degree of azotemia before transplantation was found to be a risk factor. Cats with a Cr greater than 10 and an increased blood urea nitrogen (BUN) were more likely to suffer mortality before discharge (BUN [mean 6 SE] of survivors 80.91 6 5.54 and nonsurvivors 110.73 6 80.91).1 In a second study, the level of azotemia was not related to long-term survival but did significantly increase the risk of neurologic complications in the perioperative period.6 It is possible that the use of preoperative hemodialysis in these patients may be beneficial to decrease complications postoperatively. Additionally, in two separate studies, recipient age was identified as a factor associated with survival after discharge. In the first study, cats older than 10 years had a higher mortality in the first 6 months after transplantation, and in the second study median survival times decreased with increasing age, with median survival times of 1423, 613, and 150 days for cats younger than 5 years, between 5 and 10 years, and older than 10 years, respectively.1,6 To date, the oldest cat that has been transplanted at our facility was 18 years of age. Finally, both preoperative hypertension (BP) and increased body weight have also been shown to influence overall survival.1 Preoperative examination involves various laboratory tests including a complete blood cell count, biochemical evaluation, blood type and thyroid evaluation, evaluation of the urinary tract (urinalysis, urine culture and susceptibility testing, urine protein/creatinine ratio, abdominal radiographs, abdominal ultrasound), evaluation for cardiovascular disease (thoracic radiography, electrocardiography, echocardiography, blood pressure), and screening for infectious disease (FeLV/FIV, Toxoplasma IgG, and IgM titers)4,7 (Box 123.1). There is currently no age restriction for a potential transplant recipient. The feline recipient must also have compatible blood (via crossmatch) to a prospective kidney donor and to two or three blood donor cats.

BOX 123.1  Preoperative Screening for a Potential Feline Renal Transplant Recipient Complete blood cell count Serum chemistry profile Blood type and major and minor crossmatch to donor Thyroid hormone level (T4) Urinalysis, urine culture, urine protein/creatinine ratio Abdominal radiography Abdominal ultrasonography Thoracic radiography Electrocardiography, echocardiography, arterial blood pressure Feline leukemia virus and feline immunodeficiency virus testing Toxoplasmosis titer (IgG and IgM)

Evaluation of the Urinary Tract Evaluation of the urinary tract is essential, particularly to rule out any underlying infection or neoplastic disease. If ultrasound findings are suggestive of feline infectious peritonitis or neoplasia, a fine-needle aspirate or biopsy with cytologic analysis or histopathology, respectively, is recommended. If a patient has recently been treated for a urinary tract infection or if a patient has had recurrent urinary tract infections but at the time of presentation has a negative urine culture, then a cyclosporine (CsA; Neoral, Novartis, East Hanover, NJ) challenge is recommended before transplantation to determine if the cat will “break” with an infection after immunosuppression. To perform this challenge, CsA is administered for approximately a 2-week period at the recommended dose for transplantation immunosuppression. The urine is evaluated for the presence of an infection after therapeutic CsA blood levels have been obtained and at the end of the 2-week period. It is important to note that a negative urine culture result after a challenge will not guarantee that a patient will remain infection-free after surgery and chronic immunosuppressive therapy. Another option is to place all potential candidates on CsA for 2 weeks before surgery to attempt to identify an occult infection.3 Finally, if unilateral or bilateral hydronephrosis is identified in any patient during the screening process, a pyelocentesis and culture/susceptibility testing are recommended before transplantation. Immunosuppression in a patient harboring an infection can not only potentiate the rejection process but also lead to increased morbidity and mortality secondary to urosepsis.

Cardiovascular Disease Limited information currently exists regarding the effect of pre- and postoperative hypertension on outcomes. In one feline study, preoperative blood pressure did influence overall survival.1 In a second report, preoperative hypertension did not predict postoperative episodes of hypertension, and the administration of antihypertensive medication preoperatively did not significantly decrease the postoperative incidence of hypertension.6 At the time of presentation for transplantation, a systolic murmur is commonly auscultated on physical examination. These murmurs may be a physiologic murmur associated with anemia of chronic renal failure and not represent significant heart disease.2 However, in a study from the University of California at Davis evaluating cardiac abnormalities in 84 potential transplant recipients, 78% of patients had abnormalities including both papillary muscle and septal muscle hypertrophy. The authors suggested that these changes may be related to chronic hypertension, chronic uremia, age, or early hypertrophic cardiomyopathy.8 An analysis of preoperative echocardiographic changes in that study found no significant predictors of 1-month survival. Another study found that duration of intraoperative hypotension and increased left ventricular wall thickness were risk factors for perioperative mortality.1 In a study evaluating 168 feline renal transplant recipients, preoperative hypertension as well as preoperative echocardiographic changes including the presence of an arrhythmia, radiographic evidence of heart failure at presentation, systolic anterior motion of the mitral valve, mitral and tricuspid regurgitation, septal muscle and left ventricular free wall hypertrophy, and increased LA:Ao ratio were not associated with survival to discharge or long-term survival.9 Cats with diffuse hypertrophic cardiomyopathy are declined as candidates for renal transplantation at our facility. A decision is made on a case-to-case basis in those cats with less severe cardiac disease.

Infectious Disease If a cat is FeLV-positive or has an active FIV infection, they are declined as candidates for transplantation. Additionally, all potential donor and recipients currently undergo serologic testing (IgG and IgM) for

CHAPTER 123  Kidney Transplantation toxoplasmosis. Toxoplasma gondii can cause significant morbidity and mortality in immunocompromised human and veterinary patients. As a matter of policy at the author’s facility, recipients that are IgGpositive are placed on lifelong prophylactic clindamycin (25 mg PO q12h), which is started when immunosuppression is initiated. Trimethoprim sulfamethoxazole (15 mg/kg PO q12h) has also been used in cats that do not tolerate clindamycin. If recipients are IgM-positive, they are treated for an active infection for 14–21 days (50 mg PO q12) prior to the initiation of immunosuppressive therapy and then continued on lifelong prophylactic clindamycin. Although seropositive donors are no longer used for seronegative recipients, at the author’s facility, successful transplantation has been performed between a seropositive donor and a seropositive recipient.

DONOR SELECTION Kidney donors are typically between 1 and 3 years of age and in excellent health. Standard evaluation includes a complete blood cell count and blood type, serum chemistry profile, urinalysis and culture, FeLV and FIV testing, and a toxoplasmosis titer (IgG and IgM). The feline kidney donor must also have a compatible blood crossmatch to the recipient and be of a similar size. Although a method for a lymphocytotoxic crossmatch test for feline renal transplantation has been described to investigate antilymphocyte antibodies in cats, it has not been used clinically.10 Rarely, incompatible crossmatch tests between AB compatible donor and recipient pairs have been identified. The absence of a novel red cell antigen identified as Mik has resulted in naturally occurring anti-Mik alloantibodies after an AB-matched blood transfusion (see Chapter 69, Transfusion Medicine).11 Additionally, computed tomography angiography is performed at the author’s institution on all of the donors to evaluate the renal vasculature as well as the renal parenchyma for any abnormalities that may preclude successful transplantation.12 The donor cat is adopted by the owner of the recipient and a suitable home is found for any donor that fails the screening process. There are three published studies evaluating the long-term effects of performing a unilateral nephrectomy in feline kidney donors. In a study published in 1995, 16 donors were followed between 24 and 67 months postoperatively.13 Fifteen of the 16 cats were clinically normal, and serum Cr concentrations for these cats remained within the reference range. One cat was diagnosed with chronic renal insufficiency 52 months after donation. Two recent studies have evaluated donor outcome following unilateral nephrectomy. In the first study, of 72 cats that had unilateral nephrectomy, complete medical record information was available for 28 cats. Five of 28 cats were considered to have developed kidney failure, at a mean of 4.5 years following nephrectomy, based on an elevation in BUN and creatinine and a urine specific gravity ,1.035.14 In a second study evaluating perioperative morbidity and long-term outcome following unilateral nephrectomy in 141 kidney donors, the study identified an acceptably low perioperative morbidity and the median time from surgery to hospital discharge was 3.6 days. Long-term follow-up was available for 99 donors. The median age of these cats at the time of follow-up was 12.2 years. Three cats had developed stable chronic kidney disease a median of 6.2 years postoperatively, and two cats were treated successfully for acute kidney injury, 4 and 6 years following nephrectomy. Two cats died of chronic renal failure 12 and 13 years following surgery, and four cats developed a ureteral obstruction from calcium oxalate urolithiasis a median of 7 years following surgery. Because of this potential complication, routine abdominal radiographs are recommended during yearly wellness visits to identify any stone formation so it can be addressed accordingly before resulting in morbidity or mortality.15

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PREOPERATIVE MANAGEMENT Upon admission to the transplant facility, the recipient is placed on intravenous fluid therapy of a balanced or maintenance electrolyte solution at 1.5 to 2 times the daily maintenance requirements. This rate may vary in cases of severe dehydration or in cats with underlying cardiac disease. In one study, cats that died before discharge were more likely to have received Hetastarch as part of their therapeutic protocol.1 At some centers, hemodialysis is performed before transplantation for cats that are anuric or those with severe azotemia (BUN .100 mg/dl, Cr .8 mg/dl).7 Additionally, if the cat is hypertensive, the calcium channel blocker amlodipine (Norvasc, 0.625 mg/cat PO q24h) may be indicated before surgery. Anemia is typically corrected at the time of surgery with crossmatch-compatible whole blood or packed red cell transfusions. If possible, the first unit that is administered is one that has been previously collected from the kidney donor. If the patient has evidence of decreased oxygen delivery from the anemia, blood products can be given at the time of admission to the transplant facility. If the patient will be traveling a long distance to the transplant clinic, it is worthwhile to have a blood sample sent before arrival to identify a compatible kidney donor as well as potential blood donors. If a delay in the transplant procedure is expected, darbepoetin (6.25 mcg/kg for 2 to 4 weeks until packed cell volume is approximately 25%, then every other week) can be administered and may greatly reduce the need for blood products at the time of surgery. Phosphate binders and gastrointestinal protectants are given if deemed necessary. If the patient is anorectic, a nasogastric tube is placed to administer nutritional support and prevent hepatic lipidosis. Because of complications encountered with esophagostomy tubes in some recipients on chronic immunosuppressive therapy, these tubes are no longer recommended by the author in this population of patients unless absolutely necessary.

Immunosuppression for the Feline Renal Transplant Recipient The immunosuppressive protocol currently used at the author’s facility consists of a combination of the calcineurin inhibitor CsA and the glucocorticoid prednisolone. Cyclosporine prevents the activation of a number of transcription factors that regulate cytokine genes with a role in allograft rejection, including interleukin 2 (IL-2), IL-4, interferon g (IFN-g), tumor necrosis factor-a (TNF-a), and granulocytemacrophage colony-stimulating factor (GM-CSF).16-18 Corticosteroids also inhibit these cytokines, but the exact mechanism of action is not fully understood. The effects of current therapy on feline cytokine production in vitro have recently been evaluated. In the first report, using real-time PCR (RT-PCR), CsA inhibited the expression of mRNA for IL-2, IL-4, IFN- g, and TNF-a in a dose-dependent manner.19 In the second report, CsA resulted in a significant decrease in the production of IFN-g, IL-2, and GM-CSF.20 Dexamethasone alone only suppressed the production of GM-CSF; however, when dexamethasone was combined with CsA, a significant decrease in the production of IFN-g, IL-2, and GM-CSF occurred.20 Because of the small dose of CsA that cats often require for immunosuppression, the liquid microemulsified formulation, Neoral (100 mg/ml), is recommended so the dose can be titrated for each individual cat. Neoral can be diluted in water or other oral solutions but must be administered immediately after dilution.2 Cyclosporine administration is started 72 to 96 hours before transplantation at a dose of 1 to 5 mg/kg PO q12h (depending on the cat’s appetite). In the author’s experience, cats that are anorexic or are eating a minimal amount have a much lower drug requirement to obtain appropriate drug levels before surgery. Additional drugs that inhibit P-450 hepatic enzymes may alter drug concentrations and should be used with

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caution in these patients. A 12-hour whole-blood trough concentration is obtained the day before surgery so that the dose can be adjusted before surgery if necessary. The drug level is measured using the technique of high-pressure liquid chromatography. The goal is to obtain a trough concentration of 300 to 500 ng/ml before surgery.7 This level is maintained for approximately 1 to 3 months after surgery and is then tapered to approximately 250 ng/ml for maintenance therapy. Prednisolone is administered beginning the morning of surgery. Prednisolone is preferred over prednisone for immunosuppression. In an abstract evaluating the bioavailability and activity of these two drugs in cats, serum prednisolone levels were significantly greater following oral prednisolone compared with oral prednisone.21 At the author’s facility, prednisolone is started at a dose range of 0.5 to 1 mg/kg q12h orally for the first 3–6 months and then tapered to q24h. It is important to note that protocols for both CsA and prednisolone vary between transplantation facilities. A second protocol used by some clinicians for feline immunosuppression combines the antifungal medication ketoconazole (10 mg/kg PO q24h) with the CsA and prednisolone.22,23 Ketoconazole can affect CsA metabolism by inhibiting both hepatic and intestinal cytochrome P450 oxidase activity, resulting in increased blood CsA concentrations.23 Once ketoconazole is added to the immunosuppressive protocol, CsA and prednisolone are administered once a day and CsA doses are adjusted into the therapeutic range by measuring q24h wholeblood trough levels. This protocol may reduce the cost of CsA and be more appealing for owners whose work schedule does not permit twice-a-day dosing of medication. If signs of hepatotoxicity are identified, ketoconazole administration should be discontinued. In two separate studies, the effect of multiple oral dosing of itraconazole and single oral dosing of clarithromycin on the pharmacokinetics of cyclosporine were evaluated in normal cats. Itraconazole, an antifungal with less toxicity than ketoconazole, and the macrolide antibiotic clarithromycin were each found to decrease the required cyclosporine dosage for renal transplantation.24,25 Clarithromycin, known to have immunosuppressive properties, has been used successfully in conjunction with cyclosporine and prednisolone for one feline renal transplant recipient.25

ANESTHETIC MANAGEMENT At the time of anesthetic induction, both the donor cat and the recipient are given cephalexin (22 mg/kg IV q2h). Additionally, an epidural is given to both cats (bupivacaine [0.1 mg/kg] and morphine [0.15 mg/ kg]) for analgesia. In addition to a peripheral catheter, a double (or triple) lumen indwelling jugular catheter is placed in the recipient. Using this catheter, blood products can be given as needed; blood is sampled regularly for evaluation of blood gases, electrolytes, glucose, acid-base status, packed cell volume and total protein, and central venous pressure monitored, if needed. Because the recipient procedure can last up to 6 hours, hypothermia is of serious concern. A Bair Hugger system and heating pads are used throughout the procedure and esophageal temperatures are monitored continuously. Systemic arterial blood pressure is monitored regularly throughout the procedure in both cats using a Doppler technique. Intraoperative hypertension is treated with the subcutaneous (SC) administration of hydralazine (2.5 mg SC for a 4-kg cat) and intraoperative hypotension corrected by decreasing the concentration of inhalant anesthetic or by the administration of fluid boluses, blood products, or vasopressor therapy. In a recent report evaluating the influence of anesthetic variables on long-term survival of 94 cats undergoing renal transplantation, intraoperative hypotension and the duration of anesthesia for the recipient negatively affected long-term survival.26

SURGERY Currently at the author’s facility each transplant procedure involves a team of three surgeons. The donor cat is brought into the surgical suite approximately 45–60 minutes before the recipient and the donor kidney prepared for nephrectomy. At the time of the abdominal incision, the donor is given a dose of mannitol (0.25 g/kg IV over 15 minutes) to help prevent renal arterial spasms, improve renal blood flow, scavenge free radicals, and protect against injury that can occur during the warm ischemia period. Some surgeons also recommend the administration of the a-adrenergic agonist acepromazine (0.01 mg/kg IV).22 The nephrectomy will be performed when the recipient is prepared to receive the kidney. For kidneys with a single renal artery, the artery is transected at the point where it joins the aorta. If multiple renal arteries are present, a Carrel patch technique can be performed.27 Fifteen minutes before nephrectomy, an additional dose of mannitol (1 g/kg IV) is given to the donor cat. The majority of the recipient surgery is performed using an operating microscope. The renal artery is anastomosed end-to-side to the abdominal aorta (proximal to the caudal mesenteric artery), and the renal vein is anastomosed end-toside to the caudal vena cava as previously described.7 An alternative technique is the use of hypothermic storage to preserve the donor kidney until the recipient surgery is performed. After donor kidney preparation and nephrectomy, the graft is flushed with a phosphate-buffered sucrose organ preservation solution and then placed in a stainless-steel bowl containing the same solution.22 The bowl is floated in an ice slush, the kidney agitated until cold to the touch, and then the bowl covered with a sterile drape until the recipient surgery is performed.22,28 This technique reduces personnel and resources needed for the transplantation procedure. Additionally, the cold preservation has been found to minimize ischemic injury that can occur to the kidney.29,30 Once the vascular anastomosis is complete, a ureteroneocystotomy is performed using either an intravesicular or extravesicular mucosal apposition technique.2,31-33 Before closure, the allograft is pexied to the abdominal wall using six interrupted sutures of 4-0 polypropylene. The recipient’s native kidneys are usually left in place to act as a reserve in case graft function is delayed (Fig. 123.1). Patients with polycystic kidney disease are an

Fig. 123.1  Image showing the venous anastomosis between the allograft renal vein and the recipient’s vena cava. Both the allograft and native kidney are shown. A biopsy of the native kidney was taken at the time of transplantation. The recipient’s native kidneys are usually left in place to act as a reserve in case graft function is delayed.

CHAPTER 123  Kidney Transplantation exception because at least one of the native kidneys often needs to be removed at the time of the transplantation procedure in order to create space in the abdomen for the allograft.

POSTOPERATIVE MANAGEMENT AND PERIOPERATIVE COMPLICATIONS After surgery the recipient is maintained on intravenous fluid therapy, which should be adjusted as needed based on the cat’s renal function, urine output, hydration status, oral intake of water, and coexisting cardiac disease. Blood transfusions are given only if necessary. Minimal stress and handling and prevention of hypothermia are critical during the early postoperative period. While a catheter is in place, the cat is maintained on intravenous antibiotic therapy (cefazolin 22 mg/kg IV q8h). Once all catheters are removed, the cat is then maintained on oral antibiotic therapy (amoxicillin plus clavulanic acid 62.5 mg PO q12h) for another 2 to 4 weeks until CsA levels regulated. If the cat is Toxoplasma-positive, clindamycin (25 mg PO/IV q12h) is administered in conjunction with the immunosuppression and continued for the lifetime of the cat. Postoperative pain has been controlled successfully at the author’s facility using buprenorphine (0.005 to 0.02 mg/kg IV q4-8h), hydromorphone (0.05 to 0.2 mg/kg IV, IM, or SC q4-6h), methadone (0.15 to 0.3 mg/kg IV q4-6h), or a constant rate infusion (CRI) of butorphanol (0.1 to 0.5 mg/kg/hr; see Chapter 134, Analgesia and Constant Rate Infusions). Initially, blood work is performed twice daily to evaluate acid-base status, packed cell volume, total protein, electrolytes, and blood glucose; these are tapered gradually depending on the stability of the cat. A renal panel is checked every 24 to 48 hours and a blood CsA level is checked every 3 to 4 days and the dose adjusted accordingly. Voided urine is weighed and recorded when possible (urinary catheters should be avoided to prevent ascending infection and damage to the ureteroneocystotomy site). Abdominal palpation is not performed during the postoperative period, although gentle point-of-care abdominal ultrasound is permissible, if indicated. With improvement in the azotemia and appropriate pain control, most cats will start eating within 24 to 48 hours after the surgical procedure. If continued anorexia is thought to be associated with altered gastric motility after surgery, metoclopramide administration (0.2 mg/kg SC q6-8h or 1 to 2 mg/kg/24 hours as a CRI) has been successful in improving appetite. If the cat remains anorexic, a feeding tube may be necessary if not already in place. Because of the association identified between postoperative hypertension and postoperative central nervous system (CNS) disorders (i.e., seizure activity), indirect blood pressure is measured every 1 to 2 hours during the first 24 to 48 hours after surgery to monitor for the development of hypertension and then tapered accordingly.34 If the systolic blood pressure is equal to or greater than 180 mm Hg and the animal appears comfortable, hydralazine (2.5 mg SC for a 4-kg cat) is administered. The hydralazine dose can be repeated if the systolic pressure has not decreased within 15 to 30 minutes. If the cat is refractory to hydralazine, acepromazine (0.005 to 0.01 mg/kg IV) has also been effective. It is important to note that the incidence of hypertension and CNS disorders is not seen with equal frequency between transplant centers and is rarely identified at the author’s facility; thus, the cause of CNS disorders in cats after renal transplantation still remains incompletely understood.22 In one recent study, an increase of 1 mg/dl in serum Cr or 10 mg/dl in BUN increased the likelihood of postoperative CNS disease by 1.6- and 1.8-fold, respectively.6 In addition to monitoring patients for postoperative hypertension, complications can also arise if postoperative hypotension occurs. Systolic blood pressure is commonly maintained at 100 mm Hg or greater. Sustained hypotension can lead to poor graft perfusion and must be

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treated aggressively to prevent acute tubular necrosis and delayed graft function. If surgery is technically successful, azotemia typically resolves within the first 24 to 72 hours after surgery. If improvement does not occur during this time or if improvement in renal function is initially identified but then worsens, an ultrasonographic examination of the allograft is recommended. The allograft should be evaluated for adequate blood flow as well as any signs of a ureteral obstruction, including hydronephrosis or hydroureter. Recently, contrast-enhanced ultrasonography has been evaluated to provide qualitative and quantitative information regarding allograft perfusion.35 If repeat ultrasonographic evaluations reveal worsening of the hydronephrosis, a ureteral obstruction should be suspected. Another laparotomy is performed so that the allograft can be evaluated. In some cases, the ureter may need to be reimplanted into the urinary bladder. If graft perfusion is adequate and no signs of obstruction are present, then delayed graft function should be considered. Cats are discharged from the hospital when graft function appears adequate and the cat is clinically stable. Cats with delayed graft function can also be discharged if the patient is otherwise clinically stable. In these cases, improvement in function often occurs within the first few weeks after surgery. Medical management of the renal failure can be continued in this subset of patients until graft function returns to normal. If the transplanted kidney fails to function, the kidney should be biopsied before retransplantation.

LONG-TERM MANAGEMENT AND COMPLICATIONS Patients should be evaluated by their veterinarian once a week for the first 6 to 8 weeks, then monthly rechecks depending on the cat’s condition. During each examination, the cat should be weighed and blood work performed, including a renal panel (e.g., BUN, creatinine, phosphorous total carbon dioxide, and magnesium), packed cell volume, total protein, cyclosporine level, and a urinalysis (only if a free-catch urine sample is available). Because of intra- and interpatient variability in the absorption of oral cyclosporine and its metabolism, it is essential that blood levels are checked regularly to maintain therapeutic concentrations and minimize toxic side effects. It is recommended that a complete blood cell count and serum chemistry panel are run at least every 3 to 4 months, and if the cat had been diagnosed with underlying cardiac disease, an echocardiogram should be performed every 6 to 12 months. If there are any concerns about allograft function, an abdominal ultrasound should be performed as an initial investigative step to identify any evidence of a urinary obstruction or vascular thrombosis. If a feeding tube was necessary, it is unclear how long it should be left in place once oral intake of food and water is deemed appropriate since these patients are receiving chronic immunosuppressive therapy. Renal complications after transplantation that have been reported include allograft rejection, calcium oxalate (CaOx) nephrosis, ureteral complications, hemolytic uremic syndrome, allograft rupture, retroperitoneal fibrosis, delayed graft function, and vascular pedicle complications. Acute rejection can occur at any time but is most common within the first few months after surgery.1,36 Cats that are experiencing a rejection episode may or may not have overt clinical signs including polyuria/ polydipsia, lethargy, depression, and anorexia. For this reason, weekly blood sampling is essential during the early postoperative period. Histopathologic as well as sonographic and scintigraphic examination of allograft rejection in cats has recently been described.37,38 Sonographic examination often reveals a significant increase in cross-sectional area to the allograft of at least 10% (mean 34%), a subjective increase in echogenicity, and a decrease in corticomedullary demarcation.38

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Although normal allograft enlargement is expected during the first week postoperatively, a gradual decline should then occur. In a study evaluating renal autografts in normal cats, cross-sectional area of the grafts increased by 63% at 1 week and remained at 60% above baseline by day 13.39 In a second study, an increase in cross-sectional area occurred between 1 and 3 days postoperatively, then declined over the next 3 weeks but did not return to baseline.40 Neither the resistive index (RI) nor glomerular filtration rate were sensitive indicators in normal grafts or those undergoing allograft rejection.38-41 In an ultrasonographic study of 69 clinical renal allografts, graft volume was a better indicator than RI of graft disease, including ureteral obstruction and those experiencing rejection episodes.42 If possible, before starting the rejection protocol, a urine sediment should be evaluated to rule out an underlying infection. Suspected acute rejection episodes are treated with intravenous administration of CsA (6.6 mg/kg q24h given over 4–6 hr) and prednisolone sodium succinate (Solu Delta Cortef, 10 mg/kg IV q12h). Each milliliter of the intravenous cyclosporine is diluted with 20 to 100 ml of either 0.9% NaCl or 5% dextrose.43 The infusion of CsA can be repeated. However, another potential cause for the azotemia should be considered if the creatinine concentration does not improve within 24 to 48 hours. Chronic rejection is characterized by gradual loss of organ function over months to years, often without evidence of a rejection episode. Histopathology of these grafts reveals severe narrowing of numerous arteries and thickening of the glomerular capillary basement membrane. The cause of chronic rejection is unknown at this time. Hemolytic uremic syndrome is a rare but fatal side effect of CsA therapy. Patients develop hemolytic anemia and thrombocytopenia with rapid deterioration of renal function secondary to glomerular and renal arteriolar platelet and fibrin thrombi.44 In the author’s experience, the mortality rate has been 100%. Renal transplantation is a treatment option for cats whose underlying cause of renal failure is associated with calcium oxalate urolithiasis. In a study evaluating these patients, no difference in longterm outcome was found between a group of cats with stones and a control group of cats whose underlying cause of renal failure was not related to urolithiasis.5 Additionally, in specifically evaluating 19 stone formers, 5 cats formed calculi within the allograft between 4 and 22 months postoperatively. Although formation of calculi in the allograft of five cats did not significantly reduce survival, the power of the study was low and there was a trend toward worse survival in cats that formed calculi in the allograft. Four of the five cats had calculi attached to the 8-0 nylon suture used to perform the ureteroneocystostomy, and two cats that formed calculi were diagnosed with a urinary tract infection. Based on these findings, absorbable suture material is now used to perform the ureteroneocystostomy in cats known to form stones. Additionally, thorough screening for infection is recommended. Another potential cause of recurrence of azotemia within the first few months after surgery is the development of retroperitoneal fibrosis.45,46 In a study of 138 feline recipients, 29/138 (21%) developed retroperitoneal fibrosis a median of 62 days (4 to 730 days) following renal transplantation.46 In human patients, the disease has been identified secondary to an inflammatory response to atherosclerotic disease within the abdominal aorta as well as patients diagnosed with a systemic autoimmune disease, suggesting that retroperitoneal fibrosis may be a manifestation of a systemic process. Abdominal ultrasound in these patients reveals hydronephrosis (often without the presence of hydroureter because of the compression of the ureter from scar tissue). Occasionally, a capsule can be identified surrounding the allograft, resulting in a partial or complete ureteral obstruction. Surgery has been successful in relieving the obstruction and restoring normal renal

A

B Fig. 123.2  A, Retroperitoneal fibrosis. Note the white scar tissue surrounding the renal allograft and bladder and the shortened length of the ureter because it is encased in fibrotic tissue. B, Surgical resection of the fibrotic tissue (ureterolysis) surrounding the allograft ureter allows the ureter to become unobstructed.

function; however, reformation of scar tissue resulting in a second obstruction has been identified in some patients (Fig. 123.2). The exact cause in our feline patients is unclear at this time. Finally, complications can occur secondary to chronic immunosuppressive therapy. These have included the development of infections including opportunistic infections, diabetes mellitus (DM), and neoplasia. In a large retrospective study evaluating the prevalence of infection in 169 cats that had undergone transplantation, 47 infections developed in 43 of 169 cats. The most common infections encountered were bacterial (25/47), followed by viral (13/47), fungal (6/47), and protozoal (3/47) infections.47 Infections not only cause direct morbidity and mortality because of the infection itself but may also activate the rejection process. Half of the infectious complications occurred within the first 2.5 months after surgery, when immunosuppression was kept at its highest level. The development of DM in this patient population significantly increased the risk of developing an infection.47 In these patients, a reduction in CsA dosage as well as a tapering of the steroid dose should be performed while carefully monitoring renal function. The prevalence of malignant neoplasia in cats after renal transplantation has been reported. In one study, the prevalence in cats was 9.5% with a median survival time of 14 months.48 This compares to a median survival time of 22 months for a group of 66 feline renal transplant recipients from the same facility that did not develop neoplasia. In a second report, malignant neoplasia after transplantation occurred

CHAPTER 123  Kidney Transplantation in 24% of the cases (median survival time was 1020 days [34 months] compared with 1146 days [38 months] for the control population).49 In this study, the development of neoplasia did not significantly affect overall survival. Additionally, CsA-based therapy in conjunction with transplantation was significantly associated with the development of neoplasia, and these cats were 6.1 times more likely to develop a malignancy compared with a control group.49 Similar to this report, recent work from our facility found a 22.5% incidence of malignant neoplasia in a group of 111 cats.50 In all three studies, lymphoma was the predominant type of neoplasia identified. Additionally, histopathologic review of either necropsy (five cats) or biopsy (two cats) samples from seven cats with lymphoma revealed that all samples were classified as mid- to high-grade, diffuse large B-cell lymphoma, similar to what is identified in human renal transplant recipients.51 In a multicenter study investigating the incidence and risk factors for the development of DM in a group of 187 feline renal transplant recipients, 13.9% of cats developed DM after transplantation; these patients were 5.45 times as likely to develop DM compared with cats with chronic renal failure.52 Glycemic control in these cats has been done successfully with dietary management, tapering immunosuppressive therapy, glipizide or insulin treatment, and in some cases, a combination of techniques. The mortality rate in this group of cats was 2.38 times the mortality rate of feline renal transplant recipients that did not develop DM.

CANINE TRANSPLANTATION Canine renal transplantation is an uncommonly performed procedure. At our facility, canine transplantation has been performed successfully between mixed lymphocyte response (MLR) matched donor and recipient pairs to treat animals with membranous glomerulonephropathy and renal dysplasia. Because the donor dog is a relative, the donor typically already has a home. Similar physical and biochemical parameters need to be evaluated carefully in order to determine if a dog is a suitable candidate for transplantation. The ideal immunosuppressive regimen for canine transplant recipients still remains a challenge, particularly in unrelated donor and recipient pairs. A number of immunosuppressive protocols have been used in both unrelated and related donor and recipient pairs with varying results.53,54 Currently at our facility, a combination of cyclosporine and prednisolone is being used. The recommended dosage of cyclosporine is 2.5 to 5 mg/kg PO q12h to attain a 12-hour whole-blood trough concentration of 300 to 500 ng/ml. This level is maintained for approximately 1 to 3 months after surgery and is then tapered to approximately 250 ng/ml for maintenance therapy. The cyclosporine is given in combination with prednisolone at a dose of 0.5 to 1 mg/ kg q12h orally for the first 3–6 months and then tapered to q24h. Similar to cats, ketoconazole can be added to the cyclosporine protocol to decrease the cost of therapy, particularly in medium- and large-breed dogs. Potential adverse effects in dogs include hepatotoxicity and cataract formation. The canine anesthetic protocol is similar to the feline protocol with a few exceptions. Because of the high incidence of intussusceptions after renal transplantation in the dog, morphine is used as a premedication, during the procedure (0.5 mg/kg IV as a bolus when the abdomen is entered), and for pain management postoperatively. Additionally, because of complications associated with thromboembolic disease, enoxaparin (0.5 to 1 mg/kg subcutaneously q24h) is started the day before surgery and continued for 7 days after surgery. The surgical techniques described for renal transplantation in the dog are similar to those described previously for the cat with a few minor differences. In addition to anastomosing the renal vasculature to the caudal

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aorta and vena cava, the iliac vessels of the recipient can also be used for the anastomosis.55 Because of the high incidence of intussusceptions after the procedure, enteroplication is performed before closure. Limited information currently exists regarding complications in clinical canine patients. Infection (bacterial, fungal, protozoal) involving the urinary tract, nasal cavity, CNS, and skin, allograft rejection, and thromboembolic disease have been reported.56-58 The majority of canine transplantation studies involve experimental animals and evaluate different immunosuppressive protocols. Complications reported in healthy animals are similar to those reported in clinical patients. Additionally, intussusception, hepatotoxicity, ocular toxicity, cardiac failure, neurotoxicity, and gingival hyperplasia have been reported.59-63

CONCLUSION Renal transplantation offers a unique method of treatment for cats (and dogs) in the advanced stages of renal failure. Compared with medical management, transplantation does appear to prolong the life expectancy in cats with end-stage renal disease. Based on both published and unpublished information, 70% to 91% of cats have been discharged from the hospital after transplantation and median survival times have ranged from 360 to 697 days. Continued clinical experience with short- and long-term management, as well as the ability to identify specific risk factors both pre- and postoperatively, will hopefully continue to improve long-term outcome in these patients. Clients need to understand the risks involved with the procedure and that it is a commitment for the life of the animal. Although renal transplantation is the treatment of choice for cats suffering from renal failure, the lack of an effective immunosuppressive protocol in unrelated dogs has limited its application in clinical practice.

REFERENCES 1. Schmiedt CW, Holzman G, Schwarz T, et al: Survival, complications and analysis of risk factors after renal transplantation in cats, Vet Surg 37:683, 2008. 2. Gregory CR, Bernsteen L: Organ transplantation in clinical veterinary practice. In Slatter DH, editor: Textbook of small animal surgery, Philadelphia, 2000, WB Saunders, pp 122-136. 3. Mathews KG: Renal transplantation in the management of chronic renal failure. In August JR, editor: Consultations in feline internal medicine, ed 4, Philadelphia, 2001, WB Saunders, pp 319-327. 4. Katayama M, McAnulty: Renal transplantation in cats: patient selection and preoperative management, Compend Contin Educ Pract Vet 24:868, 2002. 5. Aronson LR, Kyles AE, Preston A, et al: Renal transplantation in cats diagnosed with calcium oxalate urolithiasis: 19 cases (1997-2004), J Am Vet Med Assoc 228:743, 2006. 6. Adin CA, Gregory CR, Kyles AE, et al: Diagnostic predictors and survival after renal transplantation in cats, Vet Surg 30:515, 2001. 7. Bernsteen L, Gregory CR, Kyles AE, et al: Renal transplantation in cats, Clin Tech Small Anim Pract 15:40, 2000. 8. Adin DB, Thomas WP, Adin CA, et al: Echocardiographic evaluation of cats with chronic renal failure (abstract), ACVIM Proc, May 25, 2000, p 714. 9. Aronson LR, Phillips H, Oyama M: Characterization of preoperative cardiovascular status and association with outcome following feline renal allograft transplantation: 166 cases. JAVMA, pending publication. 10. Kuwahara Y, Kobayashi R, Iwata J, et al: Method of lymphocytotoxic crossmatch test for feline renal transplantation, J Vet Med Sci 61:481, 1999. 11. Weinstein NM, Blais MC, Harris K, et al: A newly recognized blood group in domestic shorthair cats: the Mik red cell antigen, J Vet Intern Med 21:287, 2007. 12. Bouma JL, Aronson LR, Keith DM, et al: Use of computed tomography renal angiography for screening feline renal transplant donors, Vet Radiol Ultrasound 44:636, 2003.

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13. Lirtzman RA, Gregory CR: Long-term renal and hematological effects of uninephrectomy in healthy feline kidney donors, J Am Vet Med Assoc 207:1044, 1995. 14. Danielson KC, Hardie RJ, McAnulty JF: Outcome of donor cats after unilateral nephrectomy as part of a clinical kidney transplant program, Vet Surg 44:914, 2015. 15. Wormser C, Aronson LR: Perioperative morbidity and long-term outcome of unilateral nephrectomy in feline kidney donors: 141 cases (1998-2013), J Am Vet Med Assoc 248:275, 2016. 16. Halloran PF, Leung Lui S: Approved immunosuppressants. In Primer on transplantation, Thorofare, NJ, 1998, American Society of Transplant Physicians, pp 93-102. 17. Kahan BD, Yoshimura N, Pellis, NR, et al: Pharmacodynamics of cyclosporine, Transplantation Proc 18:238, 1986. 18. Kim W, Cho ML, Kim SI, et al: Divergent effects of cyclosporine on Th1/ Th2 type cytokines in patients with severe, refractory rheumatoid arthritis, J Rheumatol 27:324-331, 2000. 19. Kuga K, Nishifuji K, Iwasaki T: Cyclosporine A inhibits transcription of cytokine genes and decreases the frequencies of IL-2 producing cells in feline mononuclear cells, J Vet Med Sci 70:1011, 2008. 20. Aronson LR, Stumhofer J, Drobatz KJ, et al: affect of cyclosporine, dexamethasone and CTLA4-Ig on production of cytokines in normal cats and those undergoing renal transplantation, Am J Vet Res 72:541, 2011. 21. Graham-Mize CA, Rosser EJ: Bioavailability and activity of prednisone and prednisolone in the feline patient, Dermatol Abstracts 15:9, 2004. 22. Katayama M, McAnulty JF: Renal transplantation in cats: techniques, complications, and immunosuppression, Compend Contin Educ Pract 24:874, 2002. 23. McAnulty JF, Lensmeyer GL: The effects of ketoconazole on the pharmacokinetics of cyclosporine A in cats, Vet Surg 28:448, 1999. 24. Katayama M, Katayama R, Kamishina H: Effects of multiple oral dosing of itraconazole on the pharmacokinetics of cyclosporine in cats, J Fel Med Surg 12:512, 2010. 25. Katayama M, Nishijima N, Okamura Y, et al: Interaction of clarithromycin with cyclosporine in cats: pharmacokinetic study and case report, J Fel Med Surg 14:257, 2012. 26. Snell W, Aronson LR, Phillips H, et al: Influence of anesthetic variables on short-term and overall survival in 94 cats undergoing renal transplantation surgery, J Am Vet Med Assoc 247:267, 2015. 27. Budgeon C, Hardie RJ, McAnulty JF: A carrel patch technique for renal transplantation in cats, Vet Surg 46:1139, 2017. 28. McAnulty JF: Hypothermic storage of feline kidneys for transplantation: successful ex vivo storage up to 7 hours, Vet Surg 27:312, 1998. 29. Katayama M, Okamura M, Shimamura S, et al: Influence of phosphatebuffered sucrose solution on early graft function in feline renal autotransplantation, Res Vet Sci 97:410, 2014. 30. Csomos RA, Hardie JH, Schmiedt CW, et al: Effect of cold storage on immediate graft function in an experimental model of renal transplantation in cats, Am J Vet Res 78:330, 2017. 31. Mehl ML, Kyles AE, Pollard R, et al: Comparison of 3 techniques for ureteroneocystostomy in cats, Vet Surg 34:114, 2005. 32. Hardie RJ, Schmiedt C, Phillips L, et al: Ureteral papilla implantation as a technique for neoureterocystotomy in cats, Vet Surg 34:393, 2005. 33. Sutherland BJ, McAnulty JF, Hardie RJ: Ureteral papilla implantation as a technique for neoureterocystostomy in cats undergoing renal transplantation: 30 cases, Vet Surg 45:443, 2016. 34. Kyles AE, Gregory CR, Wooldridge JD, et al: Management of hypertension controls postoperative neurological disorders after renal transplantation in cats, Vet Surg 28:436, 1999. 35. Greenberg EH, Jimenez DA, Nell LA, et al: Pilot study: use of contrastenhanced ultrasonography in feline renal transplant recipients, J Fel Med Surg 20:393, 2018. 36. Mathews KG, Gregory CR: Renal transplants in cats: 66 cases (1987-1996), J Am Vet Med Assoc 211:1432, 1997. 37. Kyles AE, Gregory CR, Griffey SM, et al: Evaluation of the clinical and histological features of renal allograft rejection in cats, Vet Surg 31:49, 2002. 38. Halling KB, Graham JP, Newell SP, et al: Sonographic and scintigraphic evaluation of acute renal allograft rejection in cats, Vet Radiol Ultrasound 44:707, 2003. 39. Pollard R, Nyland TG, Bernsteen L, et al: Ultrasonagraphic evaluation of renal autografts in normal cats, Vet Radiol Ultrasound 40:380, 1999.

40. Halling KB, Graham JP, Newell SP, et al: Sonographic and scintigraphic evaluation of acute renal allograft rejection in cats, Vet Radiol Ultrasound 44:707, 2003. 41. Newell SM, Ellison GW, Graham JP, et al: Scintigraphic, sonographic, and histologic evaluation of renal autotransplantation in cats, Am J Vet Res 60:775, 1999. 42. Schmiedt CW, Delaney FA, McAnulty JF: Ultrasonographic determination of resistive index and graft size for evaluating clinical feline renal allografts, Vet Rad Ultrasound 49:73, 2008. 43. Gregory CR. Renal transplantation. In Bojrab MJ, editor: Current techniques in small animal surgery, ed 5, Baltimore, 2014, Williams and Wilkins, pp 465-477. 44. Aronson LR, Gregory CR: Possible hemolytic uremic syndrome in three cats after renal transplantation and cyclosporine therapy, Vet Surg 28:135, 1999. 45. Aronson LR: Retroperitoneal fibrosis in four cats following renal transplantation, J Am Vet Med Assoc 221:984, 2002. 46. Wormser C, Phillips H, Aronson LR: Retroperitoneal fibrosis in the feline renal transplant recipient (29 cases), J Am Vet Med Assoc 243:1580, 2013. 47. Kadar E, Sykes JE, Kass PH, et al: Evaluation of the prevalence of infections in cats after renal transplantation: 169 cases (1987-2003), J Am Vet Med Assoc 227:948, 2005. 48. Wooldridge J, Gregory CR, Mathews KG, et al: The prevalence of malignant neoplasia in feline renal transplant recipients, Vet Surg 31:94, 2002. 49. Schmiedt CW, Grimes JA, Holzman G: Incidence and risk factors for development of malignant neoplasia after feline renal transplantation and cyclosporine-based immunosuppression, Vet Compar Oncol 7:45, 2009. 50. Wormser C, Mariano AD, Holmes ES, et al: Post-transplant malignant neoplasia associated with cyclosporine-based immunotherapy: prevalence, risk factors and survival in feline renal transplant recipients, Vet Comp Oncol 14:e126-e134, 2014. 51. Durham A, Mariano AD, Holmes E, et al: Characterization of post transplantation lymphoma in feline renal transplant recipients, J Comp Pathol 150:162, 2014. 52. Case JB, Kyles AE, Nelson RW, et al: Incidence of and risk factors for diabetes mellitus in cats that have undergone renal transplantation: 187 cases (1986-2005), J Am Vet Med Assoc 230:880, 2007. 53. Gregory CR, Kyles AE, Bernsteen L, et al: Results of clinical renal transplantation in 15 dogs using triple drug immunosuppressive therapy, Vet Surg 35:105, 2006. 54. Lirtzman RA, Gregory CR, Levitski RE, et al: Combined immunosuppression with Leflunomide and Cyclosporine prevents MLR-mismatched renal allograft rejection in a mongrel canine model, Transplantation Proc 28:945, 1996. 55. Phillips H, Aronson LR: Novel vascular technique for renal transplantation in dogs, J Am Vet Med Assoc 240:298, 2012. 56. Gregory CR, Gourley IM, Taylor NJ, et al: Preliminary results of clinical renal allograft transplantation in the dog and cat, J Vet Intern Med 1:53, 1987. 57. Mathews KA, Holmberg DL, Miller CW: Kidney transplantation in dogs with naturally occurring end stage renal disease, J Am Anim Hosp Assoc 36:294, 2000. 58. Bernsteen L, Gregory CR, Kyles AE, et al: Microemulsified cyclosporinebased immunosuppression for the prevention of acute renal allograft rejection in unrelated dogs: preliminary experimental study, Vet Surg 32:219, 2003. 59. Broaddus KD, Tillson DM, Lenz SD, et al: Renal allograft histopathology in dog leukocyte antigen mismatched dogs after renal transplantation, Vet Surg 35:125, 2006. 60. Kyles AE, Gregory CR, Griffey SM, et al: An evaluation of combined immunosuppression with MNA 715 and microemulsified cyclosporine on renal allograft rejection in mismatched mongrel dogs, Vet Surg 31:358, 2002. 61. Kyles AE, Gregory CR, Griffey SM, et al: Modified noble placation for the prevention of intestinal intussusception after renal transplantation in dogs, J Invest Surg 16:161, 2003. 62. Milovancev M, Schmiedt CW, Bentley E, et al: Use of capecitabine to prevent acute renal allograft rejection in dog erythrocyte antigen-mismatched mongrel dogs, Vet Surg 36:10, 2007. 63. Schmiedt C, Penzo C, Schwab M, et al: Use of Capecitabine after renal allograft transplantation in dog erythrocyte antigen matched dogs, Vet Surg 35:113, 2006.

PART XIII   Nutrition

124 Nutritional Assessment Cecilia Villaverde, BVSc, PhD, DACVN (Nutrition), DECVCN, Jennifer A. Larsen, DVM, MS, PhD, DACVN

KEY POINTS • Nutritional assessment is an important aspect of the management of hospitalized veterinary patients because malnutrition is a common yet often overlooked feature. • The use of nutritional assessment tools can help standardize protocols in the clinic.

• Nutritional support may reduce complications and improve outcomes, and proactive implementation is the goal. • In critical care settings, patients often have new or ongoing disease processes and altered physiology that complicate recovery and limit nutritional support options.

Hospitalized veterinary patients are often malnourished or are consuming inadequate diets, and preventing or reversing this problem should be a goal of all clinicians. One recent study reported that the provision of energy requirements was only achieved in 6.8% of a large population of hospitalized dogs, with 52.6% of the 500 dogs consuming less than 25% of their estimated needs.1 Malnutrition in people is associated with increased complication rates, increased mortality, and longer hospital stays,2,3 and there are standardized protocols for assessment and interventions.4,5 Similarly, poor outcomes in veterinary patients receiving inadequate nutritional support can be expected. To appropriately address this problem and minimize the adverse effects of malnutrition in hospitalized dogs and cats, clinicians and staff should proactively ensure adequate documentation and monitoring so that adequate interventions are pursued as needed.

individual patients is necessary to more accurately identify those with the most immediate needs as well as those at risk for greater complications.

IMPACTS OF NUTRITIONAL SUPPORT DURING CRITICAL ILLNESS Although still lacking in comparison to that in human medicine, there is a growing body of data describing the impact of nutritional support on hospitalized veterinary patients. One study showed that hospitalized dogs and cats that received less than one-third of their target energy requirements were more likely to have a poor outcome.6 Another study demonstrated that the provision of adequate amounts of energy was associated with a lower risk of death in hospitalized dogs.1 The mechanisms of how illness and other physiologic stressors lead to a hypermetabolic state are characterized by increases in circulating cytokines, catecholamines, and other stress mediators.7 These ultimately result in an inflammatory response with undesirable effects including increased protein catabolism and impaired healing ability.8,9 This preferential catabolism of lean body mass over glycogen and fat stores in animals that are critically ill has a profoundly negative effect on healing, immune function, and recovery from disease and trauma. As such, intervention and provision of appropriate and adequate nutritional support are necessary to promote positive outcomes in veterinary patients. Proactive assessment of

SCREENING SYSTEMS USED FOR NUTRITIONAL ASSESSMENTS Assessing the nutritional status of human patients is now routinely done in hospital settings4 and is important to identify patients suffering from or at risk of malnutrition. It is well accepted that early nutritional intervention is necessary to achieve positive outcomes in people, and efforts should be made to identify these patients before malnutrition is overt. Early risk assessments and proactive interventions are also important goals in veterinary medicine, even though data remain limited. In one small prospective study,10 early enteral feeding (within 12 hours of admission via a nasogastric feeding tube) in growing dogs with acute parvoviral gastroenteritis resulted in earlier resolution of clinical signs, better growth, and improvements in indirect measures of gut barrier function compared with late enteral feeding (on average 50 hours after admission). One retrospective study of dogs and cats6 reported a higher rate of hospital discharge in the patients eating voluntarily from day 1 compared with patients that were anorexic during hospitalization, with those receiving assisted feeding falling in the middle. Another retrospective study11 of dogs with septic peritonitis demonstrated that early nutritional support (either enteral or parenteral and defined as consistent caloric provision initiated within 24 hours postsurgery) was associated with a shorter hospitalization length compared with feeding more than 24 hours after surgery. Nutritional assessment in veterinary patients historically has not been standard practice, despite an understanding of its value in the promotion of more positive outcomes in critical illness.12 More recently, published information and formalized guidelines are available13,14 that aim to identify the nutritional status of the patient using data from the signalment, medical history, diet history, physical examination, and laboratory data. These guidelines were first published

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by the American Animal Hospital Association (AAHA)13 and subsequently adopted by the World Small Animal Veterinary Association (WSAVA).14 The guidelines propose that the nutritional assessment should be the fifth vital sign of the examination of small animals (after temperature, pulse, respiration, and pain assessment). The goal is to recognize patients at risk of nutritional problems; these patients are then identified as candidates for an extended nutritional evaluation. The evaluation focuses on three aspects: • Animal factors • Diet factors • Environmental factors (including feeding method) For critically ill patients, the most important information to be collected comes from the physical examination (including body weight and body composition) and the medical history (in particular the diet history). In all cases, patients with higher nutrient needs or lower body reserves (such as growing, reproducing, or geriatric animals) are more at risk than adult patients at maintenance.

Fig. 124.1  Overweight cat with a body condition score of 8 out of 9.

Body Weight Body weight is unquestionably valuable when evaluating the nutritional status of a patient, including serial assessments and historical measurements. During hospitalization, serial daily body weight measurements help determine if the energy intake is adequate or not. The goal for hospitalized patients is always to maintain body weight, regardless of whether the patient is an ideal body weight or overweight. If the patient is underweight, adjustments to achieve slow and steady gain are indicated. Similarly, a historical record of body weights for a particular patient will be very helpful to determine if the current body weight is typical or not. Patients that have lost more than 10% of their previous body weight involuntarily should be considered malnourished because of negative energy balance. However, body weight alone, despite being very useful, will not provide information about the patient’s body composition and can be affected by hydration status, fluid accumulation, organomegaly, or mass growth, so it is important to also assess and consider body composition.

Body Composition Dual-energy x-ray absorptiometry (DEXA) or deuterium oxide (D2O) dilution are accurate and objective tools for patient assessment.15-17 However, tools that measure body composition directly are typically only available at some academic and research institutions and are unlikely to be used at most primary and secondary referral clinics. Therefore, objectively assessing the proportions of adipose and lean body mass is not possible in most cases, and subjective assessments are commonly employed.

Adipose Tissue Although an increasing proportion of veterinary patients suffer from obesity, this condition is not necessarily correlated with adequate food intake during hospitalization. In fact, obese dogs and cats may be more likely to suffer malnutrition from a deficiency of intake of energy and other nutrients because of both clinician perception and the challenge of accurately assessing body weight and muscle mass changes. For example, clinical staff may not perceive any urgency in nutritional assessment and intervention for overweight or obese patients, with the assumption that such animals have a “reserve” of energy or even a need for acute weight loss. Further, because of the abundant subcutaneous adipose accumulation in many of these cases, assessment of lean body mass is very difficult. Of course, obesity does not preclude the risk of inadequate calorie and nutrient intake and is not an indication for withholding of nutritional support. Body condition score systems. Body condition score (BCS) systems in small animal medicine are used primarily to assess body fat in dogs and cats.18 The most commonly used systems are the 5-point scale and the 9-point scale. The 9-point BCS system was validated with

Fig. 124.2  Malnourished dog with a body condition score of 1 out of 9.

BOX 124.1  Resting Energy Requirement Formula for calculation of resting energy requirement: 70 3 body weight (kg)0.75

a more objective measure of body composition (DEXA) and showed very good correlation with body fat mass in both cats19 and dogs.20 There are 9-point BCS charts for both dogs and cats in the Nutrition Toolkit produced by the WSAVA.21 The BCS systems use visual and tactile data from the patient’s physical assessment to evaluate the fat depots and assign a corresponding numerical score. Important places to examine visually and palpate include over the ribs, above the spine, at the waistline, and at the abdominal tuck. On the 9-point scale, a score of 4 or 5 for dogs and 5 for cats is considered ideal, equivalent to 3 on a 5-point scale. Scores below ideal are underweight to emaciated and scores above ideal are overweight to obese (Fig. 124.1). For the 9-point scale, each point above 5 represents a 10% to 15% excess of body weight. Patients with lower BCS are at more immediate risk in the ICU setting than those with higher scores (Fig. 124.2), partly because of the likely chronic nature of the malnutrition; however, both are abnormal and require more detailed nutritional assessment and intervention.

Lean Body Mass The loss of lean body mass associated with various disease processes (cachexia) and with aging (sarcopenia) has been linked to increased morbidity and mortality in people, and these syndromes are an area of interest and active research in both humans and animals.22,23 Although negative nitrogen balance is likely common in hospitalized veterinary patients, more data are needed to identify causative or contributory

CHAPTER 124  Nutritional Assessment

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factors and to establish relationships with specific outcomes for dogs and cats. In addition, enabling clinicians to predict risk for individual patients or populations as well as guide specific interventions would have significant value. Besides measuring lean body mass with DEXA and D2O methodology, the protein balance of a patient can be estimated by measuring urea nitrogen loss in the urine because urea is the major protein breakdown product;24 increased losses indicate a negative nitrogen balance. However, this method may not be practical in the ICU setting. Although negative nitrogen balance can be assumed if negative energy balance is evident, the need for lean body mass assessment in the clinical setting is apparent. Muscle condition scoring. Of primary importance is the need to assess muscle mass of clinical patients. Muscle condition score (MCS) systems are developed for cats; however, this remains to be validated for dogs.25-27 There is some published work exploring the feasibility of imaging modalities such as computed tomography and ultrasound in assessments of muscle mass in dogs,28-30 which may be incorporated into future iterations of MCS systems. The AAHA and WSAVA guidelines propose a 4-point MCS system for both species, from normal muscle mass to mild, moderate, and severe atrophy, which is determined subjectively by the visual and tactile examination of muscles over the skull, scapulae, spine, and pelvis (Figs. 124.3 and 124.4). It is important to include these data in the assessment of each critical care patient because moderate and severe muscle atrophy are clear indications for nutritional intervention.

In many human nutritional assessment systems, historical food intake is a very important piece of information because of its high predictive value for poor food intake during hospitalization. One study in hospitalized dogs found that anorexia at admission was associated with poor outcomes, independently of other markers of disease severity.1 The exact duration of anorexia or hyporexia prior to and during hospitalization should be noted. In cases where the appetite is selective or overall reduced but not absent it is important to quantify intake. This may be challenging in cases of patients fed ad libitum or when the diet is highly variable on a regular basis, which often occurs in order to address inappetence. Often the fact that the patient is eating “something” delays nutritional intervention in patients that require it; therefore, a more targeted and quantitative guideline is indicated. A patient eating less than 75% of its RER should be considered hyporexic. In general, the recommendation is to institute nutritional support in patients that are anorexic for more than 3 to 5 days and hyporexic for more than 1 week.

Diet History

Laboratory Data

Current Intake It is important to account for all components of the daily diet, including the exact brand and formula of food given as meals as well as any snacks, treats, or supplements. Specifically inquiring about how medications are administered often reveals additional food items that owners do not always consider part of the pet’s diet, some of which contribute significant proportions of the daily energy intake. Quantifying the energy intake of the hospitalized patient should be done daily, and thus should have a dedicated space in the daily hospitalization chart in order to actively monitor and intervene if necessary. Attention should be paid to the amount consumed, not just the amount offered. The goal is for patients to eat enough calories to at least maintain body weight during hospitalization, independent of the BCS. Weight gain is desired in patients with low BCS and muscle atrophy, but it might not be possible in the critical care setting while underlying diseases remain uncontrolled. There is a lack of knowledge on the effect that disease has on energy requirements.31 One study32 looked at maintenance energy requirements (indirectly estimated by food intake) in chronically ill dogs and reported that some conditions (such orthopedic diseases) were associated with lower energy requirements compared with average needs, while other conditions (such as gastrointestinal and neoplastic diseases) were associated with higher needs. However, these patients were all ambulatory and these results are likely not applicable to the critical care setting. One study found that dogs that consumed close to their resting energy requirement (RER) during their hospitalization were able to better maintain a stable BCS, and the importance of an adequate energy intake in the nutritional status of the dogs was more marked in hospitalization periods longer than 3 days.1 At this time the consensus is that ICU patients should eat at least their RER determined in kcal per day (Box 124.1). The RER is lower than maintenance energy requirements primarily because of less physical activity during hospitalization, and no benefit to feeding above RER in this setting has been demonstrated. Adjustments should

be made as needed; however, starting at RER can help assess tolerance of the diet and the feeding method as well as avoid problems related with overfeeding (including gastrointestinal distress, hyperglycemia, and hyperlipidemia). Tools to assist in the nutritional management of hospitalized veterinary patients, such as a feeding guide, feeding instructions, and a monitoring chart, are available in the WSAVA Nutrition Toolkit.21

Historical Intake

Few data from the clinicopathologic database can support generalized or specific causes of malnutrition; however, hypoalbuminemia together with inadequate lean body mass can indicate poor long-term protein status.12 Certain types of anemia may support suspicions of poor B vitamins or trace minerals status. Differentiating abnormalities caused by poor intake (e.g., hypokalemia in cats with chronic kidney disease and poor appetite) from those resulting from malabsorption (e.g., hypocobalaminemia with inflammatory enteropathy) or abnormal losses (e.g., hypoalbuminemia with lymphangiectasia) can be challenging in some cases. However, these abnormalities are common with a variety of other disease processes. More commonly these data are used to guide nutritional interventions or to assess individual patient tolerance of specific nutrients. For example, hyperglycemia is commonly noted in critically ill cats33 and may preclude the use of dextrose-containing parenteral nutrition solutions or necessitate administration of insulin. Likewise, hyperkalemia sometimes develops in dogs with kidney disease and will significantly influence dietary options,34 as will fasting hyperlipidemia in both dogs and cats. Correlating concurrent dietary intake with clinicopathologic data is necessary for developing a customized and rational nutritional management plan for individual patients.

CONCLUSION Nutritional evaluation is very important in critically ill patients, which are at high risk of malnutrition secondary to their inappetence and their hypermetabolic state, which may result in a worse outcome. Standardized assessments help the clinician determine if careful monitoring or nutritional intervention is needed. As a general rule, patients that have been anorectic for more than 3 days or hyporectic for more than a week, have lost 10% of their body weight involuntarily, have a low BCS, or have moderate to severe muscle atrophy are candidates for nutritional intervention. Readers are directed to Chapters 126 and 127 for further discussion of the nutritional support of critically ill patients.

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Muscle Condition Score Muscle condition score is assessed by visualization and palpation of the spine, scapulae, skull, and wings of scles on each side of the spine; muscle loss at other sites can be more variable. Muscle condition score is graded as normal, mild loss, moderate loss, or severe loss. animals can have a low body condition score (< 4) but have minimal muscle loss. Therefore, assessing both body condition score and muscle condition score on every animal at every visit is important. Palpation is especially important when muscle loss is mild and in animals that are overweight. An example of each score is shown below.

Normal muscle mass

Mild muscle loss

Moderate muscle loss

Severe muscle loss

© Copyright Tufts University, 2013. Used with permission

wsava.org

Fig. 124.3  Muscle condition score chart in dogs. Provided courtesy of the World Small Animal Veterinary Association (WSAVA). Available at the WSAVA Global Nutrition Committee Nutritional Toolkit website: https://wsava. org/global-guidelines/global-nutrition-guidelines/. Accessed February 27, 2020. Copyright Tufts University, 2014.

CHAPTER 124  Nutritional Assessment

Fig. 124.4  Muscle condition score chart in cats.Provided courtesy of the World Small Animal Veterinary Association (WSAVA). Available at the WSAVA Global Nutrition Committee Nutritional Toolkit website: https://wsava. org/global-guidelines/global-nutrition-guidelines/. Accessed February 27, 2020. Copyright Tufts University, 2014.

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REFERENCES 1. Molina J, Hervera M, Manzanilla EG, et al: Evaluation of the prevalence and risk factors for undernutrition in hospitalized dogs, Front Vet Sci 5:205, 2018. 2. Stratton RJ, Elia M: Deprivation linked to malnutrition risk and mortality in hospital, Br J Nutr 96:870, 2006. 3. Koretz RL, Avenell A, Lipman TO, et al: Does enteral nutrition affect clinical outcome? A systematic review of the randomized trials, Am J Gastroenterol 102:412, 2007. 4. Taylor BE, McClave SA, Martindale RG, et al: Guidelines for the provision and assessment of nutrition support therapy in the adult critically Ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.), Crit Care Med 44:390, 2016. 5. Rasmussen HH, Holst M, Kondrup J: Measuring nutritional risk in hospitals, Clin Epidemiol 2:209, 2010. 6. Brunetto MA, Gomes MOS, Andre MR, et al: Effects of nutritional support on hospital outcome in dogs and cats, J Vet Emer Crit Care 20:224, 2010. 7. Coss-Bu JA, Klish WJ, Walding D, et al: Energy metabolism, nitrogen balance, and substrate utilization in critically ill children, Am J Clin Nutr 74:664, 2001. 8. Michel KE, King LG, Ostro E: Measurement of urinary urea nitrogen content as an estimate of the amount of total urinary nitrogen loss in dogs in intensive care units, J Am Vet Med Assoc 210:356, 1997. 9. Hasselgren PO, Fischer JE: Muscle cachexia: current concepts of intracellular mechanisms and molecular regulation, Ann Surg 233:9, 2001. 10. Mohr AJ, Leisewitz AL, Jacobson LS, et al: Effect of early enteral nutrition on intestinal permeability, intestinal protein loss, and outcome in dogs with severe parvoviral enteritis, J Vet Intern Med 17:791, 2003. 11. Liu DT, Brown DC, Silverstein DC: Early nutritional support is associated with decreased length of hospitalization in dogs with septic peritonitis: a retrospective study of 45 cases (2000-2009), J Vet Emerg Crit Care 22:453, 2012. 12. Michel KE: Prognostic value of clinical nutritional assessment in canine patients, J Vet Emerg Crit Care 3:96, 1993. 13. Baldwin K, Bartges J, Buffington T, et al: AAHA nutritional assessment guidelines for dogs and cats, J Am Anim Hosp Assoc 46:285, 2010. 14. Freeman L, Becvarova I, Cave N, et al: WSAVA nutritional assessment guidelines, J Small Anim Pract 52:385, 2011. 15. Santarossa A, Parr JM, Verbrugghe A: The importance of assessing body composition of dogs and cats and methods available for use in clinical practice, J Am Vet Med Assoc 251:521, 2017. 16. Zanghi BM, Cupp CJ, Pan Y, et al: Noninvasive measurements of body composition and body water via quantitative magnetic resonance, deuterium water, and dual-energy x-ray absorptiometry in cats, Am J Vet Res 74:721, 2013. 17. Zanghi BM, Cupp CJ, Pan Y, et al: Noninvasive measurements of body composition and body water via quantitative magnetic resonance, deute-

rium water, and dual-energy x-ray absorptiometry in awake and sedated dogs, Am J Vet Res 74:733, 2013. 18. Burkholder WJ: Use of body condition scores in clinical assessment of the provision of optimal nutrition, J Am Vet Med Assoc 217:650, 2000. 19. Laflamme D: Development and validation of a body condition score system for cats: a clinical tool, Feline Pract 25:13, 1997. 20. Laflamme D: Development and validation of a body condition score system for dogs, Canine Pract 22:10, 1997. 21. World Small Animal Veterinary Association Global Nutrition Committee: Nutrition toolkit. https://wsava.org/global-guidelines/global-nutritionguidelines/. Accessed February 27, 2020. 22. Miller J, Wells L, Nwulu U, et al: Validated screening tools for the assessment of cachexia, sarcopenia, and malnutrition: a systematic review, Am J Clin Nutr 108:1196, 2018. 23. Freeman LM: Cachexia and sarcopenia: emerging syndromes of importance in dogs and cats, J Vet Intern Med 26:3, 2012. 24. Michel KE, King LG, Ostro E: Measurement of urinary urea nitrogen content as an estimate of the amount of total urinary nitrogen loss in dogs in intensive care units, J Am Vet Med Assoc 210:356, 1997. 25. Michel KE, Anderson W, Cupp C, et al: Validation of a subjective muscle mass scoring system for cats, J Anim Physiol Anim Nutr 93:806, 2009. 26. Michel KE, Anderson W, Cupp C, et al: Correlation of a feline muscle mass score with body composition determined by dual-energy X-ray absorptiometry, Br J Nutr 106:S57, 2011. 27. Freeman LM, Michel KE, Zanghi BM, et al: Usefulness of muscle condition score and ultrasonographic measurements for assessment of muscle mass in cats with cachexia and sarcopenia, Am J Vet Res 81(3):254-259, 2020. 28. Hutchinson D, Sutherland-Smith J, Watson AL, et al: Assessment of methods of evaluating sarcopenia in old dogs, Am J Vet Res 73:1794, 2012. 29. Sutherland-Smith J, Hutchinson D, Freeman LM: Comparison of computed tomographic attenuation values for epaxial muscles in old and young dogs, Am J Vet Res 80:174, 2019. 30. Freeman LM, Michel KE, Zanghi BM, et al: Evaluation of the use of muscle condition score and ultrasonographic measurements for assessment of muscle mass in dogs, Am J Vet Res 80:595, 2019. 31. Burkholder WJ: Metabolic rates and nutrient requirements of sick dogs and cats, J Am Vet Med Assoc 206:614, 1995. 32. Pedrinelli V, Porsani MYH, Lima DM, et al: Predictive equations of maintenance energy requirement for healthy and chronically ill adult dogs, J Anim Physiol Anim Nutr 105(Suppl 2):63-69, 2021. 33. Chan DL, Freeman LM, Rozanski EA, et al: Alternations in carbohydrate metabolism in critically ill cats, J Vet Emerg Crit Care 16:s7, 2006. 34. Segev G, Fascetti AJ, Weeth LP, et al: Correction of hyperkalemia in dogs with chronic kidney disease consuming commercial renal therapeutic diets by a potassium-reduced home-prepared diet, J Vet Intern Med 24:546, 2010.

125 Nutritional Modulation of Critical Illness Daniel L. Chan, DVM, DACVECC, DECVECC, DACVIM(Nutrition), FHEA, MRCVS

KEY POINTS • Nutrients such as certain vitamins, amino acids, and polyunsaturated fatty acids have been shown to modulate inflammation and the immune response. • Nutritional modulation of diseases, dubbed therapeutic nutrition, may be a useful strategy for companion animals; however, until trials can elucidate which specific nutrients and what dosages confer beneficial effects to particular patient populations, a certain degree of caution is advised, particularly as the evidence in people is becoming less convincing.

• There may be significant species differences in the efficacy of therapeutic nutrition that may reduce the usefulness of some of these approaches in veterinary patients. • Therefore further research in veterinary patients is warranted to evaluate possible novel strategies for modulating various diseases in critically ill small animals.

In critically ill animals, the role of nutritional support in the overall management of patients is well established. However, nutrition is most often simply regarded as a supportive measure. Recently, further understanding of the underlying mechanisms of various disease processes and the recognition that certain nutrients possess pharmacologic properties have led to investigations into how nutritional therapies themselves could modify the behavior of various conditions and improve patient outcomes; this has been dubbed therapeutic nutrition.1 Nutrients such as certain vitamins, amino acids, and polyunsaturated fatty acids and even dextrose content can modulate inflammation and the immune response.2,3 A focus of research in the care of critically ill human patients involves the development of strategies that target key metabolic pathways, inflammation, and the immune system.3 Substrates were evaluated for their ability to improve three key targets: mucosal barrier function in the gastrointestinal tract, cellular defense function, and local and systemic inflammation.4 Exploiting pharmacologic effects of these nutrients and their impact on patient outcomes with acute diseases has been the subject of various clinical trials in people; however, a similar focus on clinical veterinary patients has of yet not taken place. The use of nutritional strategies in ameliorating animal diseases has been shown to be beneficial in the areas of chronic kidney disease5,6 (e.g., protein and phosphorous restriction) and cardiac disease7,8 (e.g., taurine, omega-3 fatty acids). In people there is conflicting evidence that certain nutrients such as glutamine, omega-3 fatty acids, and antioxidants can positively affect both morbidity and mortality in critically ill populations.4 Nevertheless, it is hoped that a greater understanding of how these nutrients can impart such beneficial effects may lead to the developments of novel strategies for modulating various diseases in small animals. To this end, a review of how nutritional strategies could be used to modulate disease, especially in critically ill animals, is the focus of this chapter and is discussed in greater detail.

therapy. Inflammation yields several lipid mediators that are involved in a complex regulatory array of the inflammatory process. Lipid mediators are synthesized by three main pathways, the cyclooxygenase, 5-lipoxygenase, and cytochrome P450 pathways, and they each use polyunsaturated fatty acids (PUFA) such as arachidonic acid (AA), eicosapentaenoic acid (EPA) and g-linolenic acid as substrates.9 Potent proinflammatory eicosanoids, leukotrienes, and thromboxanes of the 2 and 4 series are produced from AA metabolism. Classically, modulation of inflammation was thought to result from greater substitution of omega-6 fatty acids (i.e., AA) with the omega-3 fatty acids (i.e., EPA and docosahexaenoic acid [DHA]) in cell membranes, such that when these PUFAs were cleaved by phospholipases and oxidized by several enzymes it led to less inflammatory eicosanoids of the 3 and 5 series.9 However, it is now clear that the biologic antiinflammatory activities of omega-3 fatty acids are far beyond the simple regulation of eicosanoid production. Namely, these PUFAs can affect immune cell responses through the regulation of gene expression, subsequent downstream events by acting as ligands for nuclear receptors, and the control of some key transcription factors.10 EPA can also inhibit the activity of the proinflammatory transcription nuclear factor kappa B (NF-kB) at several levels, which regulates the expression of many proinflammatory mediators (e.g., cytokines, chemokines) and other effectors of the innate immune response system.10 In addition, recent research has revealed that free EPA and DHA also inhibit the activation of Toll-like receptor 4 by endotoxin and thereby further inhibit the inflammatory response.11 Finally, recent discoveries have identified that EPA and DHA are also substrates of two novel classes of mediators called resolvins and protectins, which are involved in the inhibition and resolution of the inflammatory process, which now appears to be a well-orchestrated, complex, active process involving these mediators.10,12 Therefore, in the context of disease modulation, omega-3 fatty acids help reduce the production of inflammatory mediators and are incorporated in the synthesis of antiinflammatory and “pro-resolution” factors, which serve to attenuate the inflammatory response and the innate immune response.

OMEGA-3 FATTY ACIDS Because inflammation plays a crucial role in many diseases, modulation of the inflammatory response has become an important target of

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In regard to the clinical use of omega-3 fatty acids in critically ill populations, the evidence is exclusively from human medicine. Enteral supplementation of EPA/DHA with concurrent antioxidants was once considered beneficial in ventilated patients with acute lung injury,13 and more recently it had been shown to improve outcome in patients with early sepsis.14 However, the data are not entirely conclusive, especially when omega-3 fatty acids are administered intravenously via parenteral nutrition. In a recent meta-analysis of studies evaluating supplemental omega-3 fatty acids in parenteral nutrition, no statistically significant benefits were identified in regard to mortality, infection, or ICU stay and only weak evidence that such supplementation shortens overall hospitalization.15,16 Despite apparent earlier successes associated with supplemental omega-3 fatty acids and antioxidants in this population, there is a great deal of uncertainty whether such therapy should be recommended in people with acute respiratory disease syndrome.16 Similarly, earlier successes associated with omega-3 fatty acid supplementation in septic patients are becoming less clear, as highlighted in a meta-analysis of randomized controlled trials, which found no significant effect on overall mortality or infectious complications.17 Interestingly, this analysis did find a marked reduction in the duration of mechanical ventilation in septic patients.17 Currently, no data are available on the use of omega-3 fatty acids in critically ill veterinary populations.

ANTIOXIDANTS Similar to inflammation, oxidative stress is also recognized as a prominent and common feature of many disease processes, including neoplasia, cardiac disease, trauma, burns, severe pancreatitis, sepsis, and critical illness. During various pathophysiologic states, particularly those typified by an inflammatory response, cells of the immune system such as neutrophils, macrophages, and eosinophils substantially contribute to the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). With the depletion of normal antioxidant defenses, the host is more vulnerable to free radical species and prone to cellular and subcellular damage (e.g., DNA, mitochondrial damage).18 The degree of antioxidant depletion appears to reflect the severity of illness in human patient populations.19 Oxidative stress is believed to be not only a promoter of inflammation but also a key factor leading to multiple organ failure.18 Replenishment of antioxidant defenses attempts to lessen the intensity of the injury caused by ROS and RNS. Antioxidants can be classified in three different systems: (1) antioxidant proteins such as albumin, haptoglobin, and ceruloplasmin; (2) enzymatic antioxidants such as superoxide dismutase, glutathione peroxidase, and catalase; and (3) nonenzymatic or small molecule antioxidants such as ascorbate (vitamin C), alpha-tocopherol (vitamin E), glutathione, selenium, lycopene, and beta-carotene. N-acetylcysteine is a powerful progenitor of glutathione and has been associated with some positive results in several patient populations. Treatment with N-acetylcysteine not only scavenges ROS but also enables continual production of glutathione and even blocks transcription of inflammatory cytokines.18 In regard to clinical evidence in critically ill people, again there have been mixed results, with a number of meta-analyses indicating that the administration of antioxidant micronutrients (both as in monotherapy or combination therapy or antioxidant cocktails) could be associated with a mortality risk reduction and reduced mechanical ventilator dependence,18,20,21 with others showing no significant treatment effect and no impact on ICU or hospital length of stay, kidney function, or ventilator dependence.22 It is interesting to note that the effect on mortality reduction was most apparent in populations with expected highest mortality rates, but a difference could not be detected when the

mortality rate between the critically ill population and control population was less than 10%.18 However, not all of the data regarding the use of antioxidants in the critically ill are positive. In a recent Cochrane review23 of the use of N-acetylcysteine for sepsis and systemic inflammatory response syndrome (SIRS) in adult human patients, the authors concluded that their analysis casts “doubt on the safety and utility of intravenous N-acetylcysteine as an adjuvant therapy in SIRS and sepsis. At best, N-acetylcysteine is ineffective in reducing mortality and complications in this patient population.”23 The analysis also highlighted concern that the administration of N-acetylcysteine after 24 hours of onset of symptoms could lead to cardiovascular depression.23 Typically, Cochrane reviews are very conservative in their analytical methods and seldom support novel interventions in critically ill populations. It is clear that further research is required to identify the most appropriate approach in modulating oxidative stress in the critically ill patients. Despite the clear importance of oxidative stress in various diseases in veterinary species, investigations evaluating the effect of antioxidants on disease processes are limited. Positive results have been demonstrated in experimental models of oxidative stress including in conditions such as congestive heart failure,24 acute pancreatitis,25 gastric dilatation volvulus,26 renal transplantation,27 gentamicin-induced nephrotoxicity,28 and acetaminophen toxicity.29,30 Supplementation of vitamin E alone did not prevent oxidative injury (i.e., development of Heinz body anemia) in cats fed onion powder or propylene glycol, but the same group of investigators later showed that supplementation of vitamin E with cysteine in cats decreased the production of methemoglobinemia after acetaminophen challenge.30 In naturally occurring disease such as chronic valvular disease8 and renal insufficiency,31 there have also been some positive results that support the need for further evaluation. Unfortunately, the use of antioxidants in the setting of critically ill veterinary patients has not been published.

IMMUNE-MODULATING NUTRIENTS Amino acids fulfill a vast array of functions in the body. They primarily serve as building blocks for protein synthesis and participate in various chemical reactions. Certain amino acids have immune-modulating properties, and they help maintain the functional integrity of immune cells and aid in wound healing and tissue repair. They may also serve as an energy source for certain cells, perhaps the most pertinent example being glutamine, which is the preferred fuel source for enterocytes (thereby supporting mucosal barrier function) and cells of the immune system. During disease states, the body undergoes marked alterations in substrate metabolism that could lead to a deficiency in these amino acids. In response to stress there may be a dramatic increase in demand by the host of particular amino acids such as arginine and glutamine. In health these amino acids are adequately synthesized by the host. However, during periods after severe trauma, infection, or inflammation, the demand for these amino acids cannot be met by the host and they become “conditionally essential” and must be obtained from the diet. Given the importance of these amino acids, the sudden depletion in these important substrates led to the hypothesis that dietary supplementation of these amino acids during disease would improve outcome. In addition, in times of injury and tissue repair and rapid cellular proliferation, nucleotide availability may become depleted and rate limiting for the synthesis of nucleotide-derived compounds.3

Arginine Arginine is a conditionally essential amino acid that is required for polyamine synthesis (for cell growth and proliferation) and proline

CHAPTER 125  Nutritional Modulation of Critical Illness synthesis (for wound healing) and is a precursor for nitric oxide (signaling molecule for immune cells). After extensive injury or surgery, immature cells of myeloid origin produce arginase-1, an enzyme that breaks down arginine. The ensuing arginine deficiency is associated with suppression of T-lymphocyte function.32 When steps are taken to replenish arginine along with omega-3 fatty acids, T cell number and function improve. There are also data that demonstrate a significant treatment benefit following supplementation after major surgery. Clinical benefits included fewer infectious complication rates and decreased overall length of stay when compared with standard nutritional support.3 The one population in whom arginine therapy is likely to be contraindicated is patients with severe sepsis.3 Causes of this detrimental effect likely relate to the promotion of excessive nitric oxide synthesis, worsening of cardiovascular tone, and decreasing organ perfusion.3

Glutamine Glutamine, another conditionally essential amino acid, is the most abundant free amino acid in circulation; however, stores are rapidly depleted during critical illness in people. A deficiency in glutamine has been documented to impair several important defense mechanisms of the host and impart worse outcome.33 Supplementation of glutamine during critical illness is believed to confer beneficial effects on patient outcomes. The evidence had been fairly strong that nutritional guidelines for critically ill people have included recommendations for supplemental glutamine to any patient receiving parenteral nutrition.34-36 The proposed mechanisms by which glutamine improves outcomes involve the following:1 1. Tissue protection (e.g., heat shock protein expression, maintenance of gut barrier integrity and function, and decreased apoptosis) 2. Antiinflammatory and immune modulation (e.g., decreased cytokine production, inhibition of NF-kB) 3. Preservation of metabolic function (e.g., improved insulin sensitivity, ATP synthesis) 4. Antioxidant effects (i.e., enhance glutathione generation) 5. Attenuation of inducible nitric oxide synthase activity The evidence supporting the use of glutamine in critically ill human patients had been positive until the publication of the largest randomized, placebo-controlled, double-blinded clinical trial evaluating high-dose glutamine and antioxidants in severely ill patients.37 In this seminal study, more than 1200 critically ill patients with at least two failing organ systems and requiring mechanical ventilation were randomly allocated to glutamine versus placebo treatment and antioxidants versus placebo treatment. Unexpectedly, the result was a trend for increased mortality associated with glutamine use.37 There was no effect of glutamine on rates of organ failure or infectious complications, and antioxidants had no discernible effects.37 The exact reasons for the observed trend in increased mortality were not identified, but it is worth noting that the dose of glutamine used in this study was much higher than any previous study to date and also that this study population included patients in shock being treated with nutritional support before achieving hemodynamic stability. Most recommendations for nutrition support (both enteral and parenteral) in the critically ill patient stipulate that cardiovascular stability must be achieved before commencing nutritional support.35 These confounding factors may explain the differences in outcome observed compared with previous studies. Despite evidence guiding treatment recommendations in people, there are no equivalent recommendations in the veterinary literature pertaining to glutamine use. This likely is due to the lack of supporting data and limited availability of parenteral glutamine for veterinary use. To date, only a few published veterinary trials have evaluated the use of

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glutamine (enteral or parenteral) in dogs and cats. In a trial of cats treated with methotrexate, enteral glutamine offered no intestinal protection in terms of reducing intestinal permeability or improving the severity of clinical signs.38 Another trial evaluating the effects of enteral glutamine on plasma glutamine concentrations and prostaglandin E2 concentrations in radiation-induced mucositis showed no measurable benefit.39 Possible reasons for the apparent failures in both these trials could be attributed to inadequate doses used or because of the form used, enteral, was not effective in these conditions. In contrast, a recent experimental canine model of postoperative ileus by Ohno et al.40 evaluated the effects of glutamine on the restoration of interdigestive migrating contraction in the intestines, and they were able to demonstrate a statistically significant reduction in the time to restore contractions in the glutamine-treated group. The authors hypothesized that the benefit was derived from the ability of glutamine to maintain glutathione concentration and thereby counteract the deleterious effects from surgical injury, inflammation, and oxidative stress. The authors concluded that the administration of glutamine after gastrectomy could shorten the duration of ileus (a major postoperative problem in critically ill people) and may protect against surgical stress in general.40 Given these positive results, further studies should evaluate the possible beneficial effects of glutamine supplementation in treating ileus and other gastrointestinal motility disorders in dogs with naturally occurring disease. Most recently Kang et al.41 demonstrated that the immune suppression induced by high-dose methylprednisolone sodium succinate therapy can be ameliorated by parenteral administration of L-alanylL-glutamine.41 The study was designed to address a common concern associated with high-dose glucocorticoid therapy, namely, immune suppression. The model employed demonstrated that such high doses of glucocorticoid can suppress oxidative burst activity and phagocytic capacity of neutrophils. Although the study used an experimental model, it does suggest that parenteral glutamine does have immunomodulatory effects in dogs and that more clinically applicable uses should be explored in the future. Unfortunately, parenteral glutamine is not routinely available in North America, and the majority of studies evaluating parenteral glutamine are performed in Europe and Asia.

NUCLEOTIDES Nucleotides, low-molecular-weight intracellular compounds (i.e., pyrimidine and purine), are the basic building blocks for the synthesis of DNA, RNA, ATP, and key coenzymes involved in essential metabolic reactions. Similar to amino acids, nucleotides can be synthesized de novo or can be salvaged and recycled from other molecules. The reason nucleotides are included in this discussion of therapeutic nutrition is that during disease states and injury, the rapid cell proliferation required for tissue healing leads to nucleotide depletion.3 Dietary supplementation can compensate for such depletions and support cell proliferation and differentiation. Because the cell types most affected by shortfalls in nucleotides are cells of the immune system and of the gastrointestinal tract, nucleotide supplementation is often included in “immune-enhancing diets.” The evidence for the beneficial effects of dietary nucleotides are mostly from preclinical trials and rodent models; therefore further research is still warranted.42 From the pathophysiologic point of view, supplementation of dietary nucleotides may be particularly important in animals with prolonged anorexia because supplementation in rodent models enhances intestinal repair, restores brush-border enzyme activity, and improves gut barrier function.42 Additional benefits of dietary nucleotides include positive effects on gut flora, gastrointestinal microcirculation, immune function, and inflammation.42 Given the plethora of potential beneficial effects

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without clear detrimental effects, it is not surprising that nucleotides have been included in some immune-enhancing diet cocktails despite the lack of definitive results. Although results of trials using these immune-enhancing cocktails are encouraging and mostly positive, it is unknown if these effects are synergistic or whether they result from the summation of the individual components. To date, no veterinary studies have evaluated the potential utility of supplementing nucleotides to critically ill patients.

containing three different Lactobacillus spp. strains in addition to novel protein diet was able to demonstrate a dramatic improvement in clinical signs after dietary change but no additional benefit attributed to the addition of a probiotic.48 Other studies have documented some positive effects such as improvements in immunologic markers or desirable changes in microbiota; however, these trials have mostly been performed on healthy dogs. It is uncertain whether these benefits would improve clinical signs in dogs with critical illness.

PROBIOTICS

CONCLUSION

Probiotics are live microorganisms that, when ingested in sufficient amounts, have a positive effect on the health of the host. Some of the benefits purportedly related to probiotics include reduced production of toxic bacterial metabolites, increased production of certain vitamins, enhanced resistance to bacterial colonization, and reinforced host natural defenses. Probiotics are also believed to shorten the duration of infections or decrease host susceptibility to pathogens.43 The proposed mechanisms underlying the positive effects include restoration of gastrointestinal barrier function; modification of the gut flora by inducing host cell antimicrobial peptides (i.e., defensins, cathelicidins), releasing probiotic antimicrobial factors (e.g., bacteriocins, microsins) competing for epithelial adherence; and immunomodulation.43 Probiotics are therefore believed to have a role in balancing gut microflora and increasing host resistance to pathogenic bacteria. It is worth bearing in mind that the effects of probiotics are not only dose-dependent but also both strain- and speciesspecific.44 In people, probiotics used include various species of Lactobacillus, Bifidobacterium, and Streptococcus.43 Microorganisms approved for use in animal feeds include strains belonging to the Bacillus, Enterococcus, and Lactobacillus bacterial groups. The mechanism by which probiotics enhance gut barrier function may involve how certain bacteria (e.g., Lactobacillus) stimulate mucin production and thereby inhibit pathogenic bacteria from invading and attaching to the gut epithelium.43 Concerns about the use of probiotics include the risk that certain microorganisms, such as enterococci, may harbor transmissible antimicrobial resistance determinants (i.e., plasmids), thus contributing to the problem of antimicrobial resistance. The use of probiotics in the critically ill is controversial, and guidelines recommend additional safety trials before further use in critically ill patients.44 In human critical care, probiotics have been used to combat antimicrobial-associated diarrhea, Clostridium difficile infections, and ventilator-associated pneumonia.43 The probiotic yeast Saccharomyces boulardii apparently produces a protease that degrades C. difficile toxins and may also stimulate immunoglobulin A (IgA) secretions against C. difficile toxins.44 The only meta-analysis evaluating probiotics to prevent ventilator-associated pneumonia demonstrated a significant reduction in the incidence of ventilator-associated pneumonia and length of ICU stay.45 Thus far, trials evaluating probiotics in critically ill patients have only demonstrated reduction in infectious complications, including ventilator-associated pneumonia but no benefit in reducing overall mortality.46 Probiotics have the theoretical risk of transferring antibiotic resistance genes, translocating from the intestine to other areas or developing adverse reactions via interactions with host’s microflora. Although bacteremia has not been documented with probiotic use in critically ill people, there are single case reports detailing infections with probiotic strains in immune-suppressed patients.47 In veterinary medicine there are no trials evaluating the use of probiotics in a critically ill patient population. However, there have been trials in dogs with gastrointestinal signs. A prospective placebocontrolled probiotic trial using a canine-specific probiotic cocktail

Despite the many pitfalls discussed, nutritional modulation of diseases remains a potentially useful strategy for companion animals. However, until trials can elucidate which specific nutrients and what dosages confer beneficial effects to particular patient populations, a certain degree of caution is advised. Of particular concern is the distinct possibility that significant species differences may reduce the usefulness of some of these approaches in veterinary patients. Before general recommendations for the use of immunomodulating nutrients in veterinary patients can be made, many questions must be answered. Central issues of safety, purity, and efficacy must be addressed. However, as our understanding of the interactions between nutrients and disease processes grows, we may yet identify specific nutrients that could modulate serious diseases. Based on the progress being made in the area of clinical nutrition, it is quite evident that there should be a greater appreciation for the role nutrients play in ameliorating diseases and how treatment strategies for certain conditions in companion animals may one day heavily depend on nutritional therapies.

REFERENCES 1. Wischmeyer PE, Heyland DK: The future of critical care nutrition therapy, Crit Care Clin 26:433, 2010. 2. Cahill NE, Dhaliwal R, Day AG, et al: Nutrition therapy in the critical care setting: what is “best achievable” practice? An international multicenter observational study, Crit Care Med 38:395, 2010. 3. Hegazi RA, Wischmeyer PE: Clinical review: optimizing enteral nutrition for critically ill patients—a simple data-driven formula, Crit Care 15:234, 2011. 4. McCarthy MS, Martindale RG: Immunonutrition in critical illness: what is the role? Nutr Clin Pract 33:348,2018. 5. Bauer JE, Markwell PJ, Rauly JM, et al: Effects of dietary fat and polyunsaturated fatty acids in dogs with naturally developing chronic renal failure, J Am Vet Med Assoc 215:1588, 1999. 6. Brown SA, Brown CA, Crowel WA, et al: Beneficial effects of chronic administration of dietary omega-3 polyunsaturated fatty acids in dogs with renal insufficiency, J Lab Clin Med 131:447, 1998. 7. Freeman LM, Rush JE, Khayias JJ, et al: Nutritional alterations and effect of fish oil supplementation in dogs with heart failure, J Vet Intern Med 12:440, 1998. 8. Smith CE, Freeman LM, Rush JE, et al: Omega-3 fatty acids in Boxer dogs with arrhythmogenic right ventricular cardiomyopathy, J Vet Intern Med 21:265, 2007. 9. Mayer K, Schaefer MB, Seeger W: Fish oil in the critically ill: from experimental to clinical data, Curr Opin Clin Nutr Metab Care 9:140, 2006. 10. Singer P, Shapiro H, Theilla M, et al: Anti-inflammatory properties of omega-3 fatty acids in critical illness: novel mechanisms and an integrative perspective, Intensive Care Med 34:1580, 2008. 11. Lee JY, Hwang DH: The modulation of inflammatory gene expression by lipids: mediation through Toll-like receptors, Mol Cell 21:176, 2006. 12. Willoughby DA, Moore AR, Colville-Nash PR, et al: Resolution of inflammation, Int J Immunopharmacol 22:1131, 2000. 13. Pontes-Arruda A, Demichele S, Seth A, et al: The use of an inflammationmodulating diet in patients with acute lung injury or acute respiratory

CHAPTER 125  Nutritional Modulation of Critical Illness distress syndrome: a meta-analysis of outcome data, JPEN J Parenter Enteral Nutr 32:596, 2008. 14. Pontes-Arruda A, Martins LF, de Lima SM, et al: Enteral nutrition with eicosapentaenoic acid, gamma-linolenic acid and antioxidants in the early treatment of sepsis: results from a multicenter, prospective, randomized, double-blinded, controlled study: the INTERSEPT Study, Crit Care 15: R144, 2011. 15. Palmer AJ, Ho CKM, Ajinola O, et al: The role of omega-3 fatty acid supplemented parenteral nutrition in critical illness in adults: a systemic review and meta-analysis, Crit Care Med 41:307, 2013. 16. Dushianthan A, Cusak R, Burgess VA, et al: Immunonutrition for adults with ARDS: results from a Cochrane systematic review and meta-analysis, Respir Care 65:99, 2020. 17. Tao W, Li PS, Shen Z, et al: Effect of omega-3 fatty acid nutrition on mortality in septic patients: a meta-analysis of randomized controlled trials, BMC Anesthesiol 16:39, 2016. 18. Manzanares W, Dhaliwal R, Jiang X, et al: Antioxidant micronutrients in the critically ill: a systemic review and meta-analysis, Crit Care 16:R66, 2012. 19. Alonso de Vega JM, Serrano E, Carbonell LF: Oxidative stress in critically ill patients with systemic inflammatory response syndrome, Crit Care Med 30:1782, 2002. 20. Heyland DK, Dhaliwal R, Suchner U, et al: Antioxidant nutrients: a systematic review of trace elements and vitamins in the critically ill patient, Intensive Care Med 31:327, 2005. 21. Visse J, Labadarios D, Blaauw R: Micronutrient supplementation for critically ill adults: a systemic review and meta-analysis, Nutrition 27:745, 2011. 22. Manzanares W, Lemieux M, Elke G, et al: High dose intravenous selenium does not improve clinical outcomes in the critically ill: a systematic review and meta-analysis, Crit Care 20:356, 2016. 23. Szakmany T, Hauser B, Radermacher P: N-acetylcysteine for sepsis and systemic inflammatory response in adults, Cochrane Database Syst Rev 9:CD006616, 2012. 24. Amado LC, Saliaris AP, Raju SV, et al: Xanthine oxidase inhibition ameliorates cardiovascular dysfunction in dogs with pacing induced heart failure, J Mol Cell Cardiol 39:531, 2005. 25. Marks JM, Dunkin BJ, Shillingstad BL, et al: Pretreatment with allopurinol diminishes pancreatography-induced pancreatitis in a canine model, Gastrointest Endosc 48:180, 1998. 26. Badylak SF, Lanz GC, Jeffries M: Prevention of reperfusion injury in surgical induced gastric dilatation volvulus in dogs, Am J Vet Res 51:294, 1990. 27. Lee JI, Son HY, Kim MC: Attenuation of ischemia-reperfusion injury by ascorbic acid in the canine renal transplantation, J Vet Sci 7:375, 2006. 28. Varzi HN, Esmailzadeh S, Morovvati H, et al: Effect of silymarin and vitamin E on gentamycin-induced nephrotoxicity in dogs, J Vet Pharmacol Ther 30:477, 2007. 29. Webb CB, Twedt DC, Fettman MJ, et al: S-adenosylmethionine (SAMe) in a feline acetaminophen model of oxidative injury, J Feline Med Surg 5:69, 2003. 30. Hill AS, Rogers QR, O’Neill SL, et al: Effects of dietary antioxidant supplementation before and after oral acetaminophen challenge in cats, Am J Vet Res 66:196, 2005.

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31. Plevraki K, Koutinas AF, Kaldrymidou H, et al: Effects of allopurinol treatment on the progression of chronic nephritis in Canine leishmaniosis (Leishmania infantum), J Vet Intern Med 20:228,2006. 32. Popovic PJ, Zeh HJ, Ochoa JB: Arginine and immunity, J Nutr 136:1681S, 2007. 33. Blaauw R, Nel DG, Schleicher GK: Plasma glutamine levels in relation to intensive care unit patient outcome, Nutrients 12:402, 2020. 34. Wernerman J: Glutamine supplementation, Ann Intensive Care 1:25, 2011. 35. McClave SA, Martindale RG, Vanek VW, et al: Guidelines for the provision and assessment of nutritional support therapy in adult critically ill patient: Society of Critical Care Medicine (SCCM) and the American Society for Parenteral and Enteral Nutrition (ASPEN), J Parenter Enteral Nutr 33:277, 2009. 36. Kreymann KG, Berger MM, Deutz NE, et al: ESPEN guidelines on enteral nutrition: intensive care, Clin Nutr 25:210, 2006. 37. Heyland D, Muscedere J, Wischmeyer PE, et al: A randomized trial of glutamine and antioxidants in critically ill patients, N Engl J Med 368:1489, 2013. 38. Marks SL, Cook AK, Reader R, et al: Effects of glutamine supplementation of an amino acid-based purified diet on intestinal mucosal integrity in cats with methotrexate-induced enteritis, Am J Vet Res 60:755, 1999. 39. Lana SE, Hansen RA, Kloer L, et al: The effects of oral glutamine supplementation on plasma glutamine concentrations and PGE2 concentrations in dogs experiencing radiation-induced mucositis, J Appl Res Vet Med 1:259, 2003. 40. Ohno T, Mochiki E, Ando H, et al: Glutamine decreases the duration of postoperative ileus after abdominal surgery: an experimental study of conscious dogs, Dig Dis Sci 54:1208, 2009. 41. Kang JH, Kim SS, Yang MP: Effect of parenteral L-alanyl-L-glutamine administration on phagocytic responses of polymorphonuclear neutrophilic leukocytes in dogs undergoing high-dose methylprednisolone sodium succinate treatment, Am J Vet Res 73:1410, 2011. 42. Hess JR, Greenberg NA: The role of nucleotides in the immune and gastrointestinal systems: potential clinical applications, Nutr Clin Pract 27:281, 2012. 43. Morrow LE, Gogineni V, Malesker MA: Probiotics in the intensive care unit, Nutr Clin Pract 27:235, 2012. 44. Petrof EO, Dhaliwal R, Manazanares W, et al: Probiotics in the critically ill: a systematic review of the randomized trial evidence, Crit Care Med 40:3290, 2012. 45. Siempos I, Ntaidou TK, Falagas ME: Impact of the administration of probiotics on the incidence of ventilator-associated pneumonia: a metaanalysis of randomized, controlled trials, Crit Care Med 38:954, 2010. 46. Manzanares W, Lemieux M, Langlois PL: Probiotic and symbiotic therapy in critical illness: a systematic review and meta-analysis, Crit Care 20:262, 2020. 47. Boyle RJ, Robbins-Browne RM, Tang MLK: Probiotic use in clinical practice: what are the risks? Am J Clin Nutr 83:1256, 2006. 48. Sauter SN, Benyacoub J, Allenspach K, et al: Effects of probiotic bacteria in dogs with food responsive diarrhoea treated with an elimination diet, J Anim Physiol Anim Nutr 90:269, 2006.

126 Enteral Nutrition Daniel L. Chan, DVM, DACVECC, DECVECC, DACVIM(Nutrition), FHEA, MRCVS

KEY POINTS • Every critically ill patient should have a nutritional assessment performed to determine the most appropriate nutritional plan. • Determining the route of nutritional support is an important step in the assessment and management of critical care patients. • Unless contraindicated, early enteral nutritional support should be integrated with the treatment plan of critically ill small animal patients to prevent the adverse consequences of malnutrition.

• Enteral nutritional intervention routes include the use of nasoesophageal, esophagostomy, gastrostomy, and jejunostomy feeding tubes. • Setting appropriate caloric targets that avoid under- and overfeeding (e.g., targeting the resting energy requirements) may be vitally important in reducing patient morbidity related to nutritional interventions and ultimately influence patient outcomes.

INTRODUCTION

of proper nutrition cannot be underestimated. There is growing evidence that with early nutritional support, animals can have improved outcomes.8-12 Therefore, it is vital that clinicians managing critically ill patients explore ways of initiating early nutritional support whenever possible.

Nutritional support is now considered an essential part of managing critically ill patients, especially if they are malnourished. Critically ill animals undergo several metabolic alterations that increase their risk for malnutrition.1-5 The risk of malnutrition in this patient population primarily relates to inadequate food intake and the catabolic effects of the primary disease. Because malnutrition can occur quickly in these animals, it is vital that clinicians identify animals at risk for malnutrition by carrying out a nutritional assessment and initiating early nutritional support.6 The goals of nutritional support are to treat malnutrition when present and, just as important, to prevent malnutrition from developing in at-risk patients. Whenever possible, the enteral route should be used because it is the safest, most convenient, and most physiologic method of providing nutritional support. Ensuring the successful nutritional management of critically ill patients involves identifying those most likely to benefit from nutritional support, making an appropriate nutritional assessment, and implementing a feasible and effective nutritional plan. This chapter aims to clarify the consequence of inadequate nutritional intake and provide guidance for initiating effective enteral nutritional supportive measures.

IMPORTANCE OF NUTRITIONAL SUPPORT Many of the challenges encountered when managing critically ill patients relate to the presence of organ dysfunction (e.g., ileus, diarrhea, azotemia), clinical signs suggestive of gastrointestinal intolerance (e.g., nausea, regurgitation, vomiting), metabolic complications (e.g., acidosis, hyperglycemia, hypokalemia, accelerated lean muscle loss) and the presence of comorbidities (e.g., anemia, chronic kidney disease, aspiration pneumonia), all of which can be barriers for effective feeding. Moreover, the lack of proper nutrition will only worsen the nutritional and metabolic state, making it more difficult for these patients to recover.1 Lack of enteral nutrition will contribute to abnormal gastrointestinal function such as dysmotility and loss of mucosal barrier function.7,8 Lack of proper nutrition also compromises the body’s ability to synthesize important substances such as albumin. For these reasons, the importance

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PATHOPHYSIOLOGY OF MALNUTRITION One of the major metabolic alterations associated with critical illness involves the catabolism of body protein, in which protein turnover rates may become markedly increased.1,13 Whereas healthy animals primarily lose fat when temporarily deprived of sufficient calories (i.e., simple starvation) as may be encountered by fasting animals before surgery, sick or traumatized patients catabolize lean body mass when they are not provided with sufficient calories (i.e., stressed starvation). During the initial stages of fasting in the healthy state, glycogen stores are used as the primary source of energy. Following depletion of glycogen stores, a metabolic shift occurs towards the preferential use of fat depots, sparing catabolic effects on lean muscle tissue. However, during diseased or stressed states, the inflammatory response triggers alterations in metabolism towards a catabolic state. Glycogen stores are quickly depleted, especially in strict carnivores such as the cat, and this leads to an early mobilization of amino acids from muscle stores. With continued lack of food intake, the predominant energy source is derived from accelerated proteolysis (muscle breakdown). Muscle catabolism that occurs during stress provides the liver with gluconeogenic precursors and other amino acids for glucose and acute-phase protein production. The resultant negative nitrogen balance or net protein loss has been documented in critically ill dogs and cats.2,14 One study estimated that 73% of hospitalized dogs (including postoperative patients) evaluated in four different veterinary referral centers were in a negative energy balance.15 Taken together, these studies highlight the need to ensure critically ill patients receive nutritional support during hospitalization. The consequences of continued lean body mass losses include negative effects on wound healing, immune function, skeletal and respiratory muscle strength, and ultimately on overall prognosis. In the context of

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CHAPTER 126  Enteral Nutrition postoperative patients, this could lead to greater risk of surgical wound dehiscence and postoperative infections. Due to the metabolic alterations associated with critical illness, and in part due to an inability or reluctance of many critically ill and postoperative dogs and cats to voluntarily eat sufficient calories, this patient population is at increased risk for developing complications related to their malnourished state. In dogs, a period as short as 3 days of anorexia has been documented to produce metabolic changes consistent with those seen associated with starvation in people.16 However, such dogs would not necessarily exhibit any easily detectable abnormalities on clinical assessment suggestive of being malnourished. Dogs with overt signs suggestive of malnutrition (e.g., severe muscle wasting, poor coat quality) usually have a more protracted history (usually weeks to months) of disease progression. In healthy cats, detectable impairment of immune function can be demonstrated during acute starvation by day 4, and so recommendations to institute some form of nutritional support in any ill cat with inadequate food intake for more than 3 days have been made.4 Based on growing evidence, it is logical to conclude that there is a need to implement a nutritional intervention (e.g., place feeding tube) when a dog or cat has not eaten for more than 5 days.

NUTRITIONAL ASSESSMENT The successful management of critically ill patients may involve the selection of patients most likely to benefit from nutritional support and the selection of the most appropriate route for providing nutrition. The technique for performing nutritional assessment (see Chapter 124) was designed to utilize readily available historical and physical examination parameters to identify malnourished patients who are at increased risk for complications and who will presumably benefit from nutritional intervention.6 The assessment involves determining whether nutrient assimilation has been restricted because of decreased food intake and/or maldigestion or malabsorption, whether any effects of malnutrition on organ function and body composition are evident, and whether the patient’s disease process influences its nutrient requirements. The findings of the historical and physical assessment are used to categorize the patient as well nourished, moderately malnourished, or at risk of becoming malnourished or severely malnourished.6 Checklists have been proposed to allow the assessment of a patient’s need for instituting nutritional support based on certain risk factors. A modified checklist for critically ill patients is found in Table 126.1. A patient with two or more high-risk factors should receive nutritional support as soon as they are stable. Patients with fewer than two highrisk factors should be closely monitored and reassessed every few days. The patient history should be assessed for indications of malnutrition including evidence of weight loss and the time frame in which it has occurred; there should be a determination of the adequacy of dietary intake, including the nutritional adequacy of the diet, the presence of persistent gastrointestinal signs, the patient’s functional capacity (e.g., evidence of weakness, exercise intolerance), and the metabolic demands of the patient’s underlying disease state. The physical examination should focus on changes in body composition, the presence of edema or ascites, and the appearance of the patient’s hair coat. With regard to assessing changes in body composition, it is important to recognize that while metabolically stressed patients experience catabolism of lean tissue, these changes may not be noted using standard body condition scoring systems if the patient has normal or excessive body fat. Since catabolism of lean tissue can have deleterious consequences for outcome, it is important that along with evaluation of body fat, patients undergo evaluation of muscle mass to assess lean tissue status. A muscle mass scoring system that has been used in dogs and cats is outlined in Table 126.2.17

TABLE 126.1  Assessment of Need For

Nutritional Support

A patient with two or more high-risk factors present should receive nutritional support as soon as they are stabilized. Patients with fewer than two high-risk factors should be closely monitored and reassessed every few days. Parameter Food intake ,80% RER for ,3 days

Low Risk 

Food intake ,80% RER for 3–5 days

Moderate Risk

High Risk



Food intake ,80% RER for .3 days



Presence of weight loss



Severe vomiting/diarrhea



Body condition score ,4/9



Muscle mass score ,2



Hypoalbuminemia



Expected course of illness ,3 days



Expected course of illness 2–3 days



Expected course of illness .3 days



RER, resting energy requirements.

TABLE 126.2  Description of a Muscle Mass

Scoring System for Dogs and Cats17 Score 0 (Severe) 1 (Moderate) 2 (Mild) 3 (Normal)

Muscle Mass On palpation over the spine, muscle mass is severely wasted On palpation over the spine, mass is moderately wasted On palpation over the spine, muscle mass is mildly wasted On palpation over the spine, muscle mass is normal

The next step in nutritional assessment is to determine whether or not the patient’s voluntary food intake is sufficient. To do this one must have a caloric goal in mind, select an appropriate food, and formulate a feeding plan for the patient. This will permit an accurate accounting of how much food is offered to the patient and will allow evaluation of the patient’s intake based on how much of the food is consumed. Providing nutrition via a functional digestive system is the preferred route of feeding; therefore care should be taken to evaluate whether the patient can tolerate enteral feedings. Even if the patient can tolerate only small amounts of enteral nutrition, this route of feeding should be pursued as there are benefits even when only a portion of energy needs are met.18 Supplementation with parenteral nutrition should only be considered when the use of enteral nutrition cannot meet at least 50% of the patient’s nutritional needs (i.e., 50% of the patient’s resting energy requirement; see Chapter 127, Parenteral Nutrition).19 On the basis of the nutritional assessment, the anticipated duration of nutritional support, and the appropriate route of delivery (i.e., enteral or parenteral), a nutritional plan is formulated to meet the patient’s nutritional needs. It is worth noting that before instituting the nutritional plan, patients should have their hydration status and electrolyte and acid-base disturbances addressed and should be hemodynamic stable. Commencing

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PART XIII  Nutrition

nutritional support before these abnormalities are addressed can increase the risk of complications and, in some cases, can further compromise the patient.20 It should be emphasized that this is not counter to the concept of early nutritional support, which has been documented to result in positive effects in several animal and human studies.8-11 Early nutritional support advocates feeding as soon as possible after hemodynamic stability is achieved, rather than delaying nutritional intervention by several days.21,22

ASSESSING NUTRITIONAL NEEDS There is much that remains unclear regarding the nutritional requirements of critically ill animals in general. In certain circumstances assumptions are made where nutritional requirements in animals are similar to that of people afflicted with similar diseases. However, it is important to recognize that there may be significant species and disease differences that make such direct comparisons or extrapolations less applicable. Experimental data suggest that there are dramatic changes in energy requirements in animals with thermal burns;23 however, this does not appear to apply to critically ill clinical patients. In the absence of definitive data to suggest otherwise, current recommendations are to start nutritional support as soon as it is deemed safe and initially target the resting energy requirements (RER). However it is important to reassess the patient continually as energy requirements may exceed 2 3 RER in some cases. These recommendations align with current guidelines for pediatric critically ill patients.21,22 The goal of nutritional support is to optimize protein synthesis and preserve lean body mass. With this in mind, the current enteral nutrition recommendation is to feed 5–6 g protein per 100 kcal (25%–35% of total energy) in dogs and 6–8 g protein per 100 kcal (30%–40% of total energy) in cats.5 Patients with protein intolerance, (e.g., hepatic encephalopathy, severe azotemia) should receive reduced amounts of protein (e.g., 3–4 g protein per 100 kcal). Similarly, patients with hyperglycemia or hyperlipidemia may also require decreased amounts of simple carbohydrates and fat, respectively. Other nutritional requirements will depend upon the patient’s underlying disease, clinical signs, and laboratory parameters.

WHEN TO INITIATE FEEDING As alluded to earlier, for many years conventional therapy actually ignored the nutritional needs of critically ill patients. As more and more

evidence illustrates the consequences of malnutrition, there has been a gradual change to ensure that all patients received adequate nutrition. Typical delays in starting nutrition decreased from weeks to 10 days,24 and now the debate has shifted to how many hours from admission should nutrition be delayed. In veterinary medicine, a similar transition also occurred, from the ineffective strategies such as force- or syringe-feeding, warming foods, and adding flavor enhancers, to more recent recommendations for early tube feeding in most if not all critically ill patients. Studies in canine patients with parvoviral enteritis, peritonitis, and acute pancreatitis support the premise that early nutritional intervention is well tolerated and produces little complications.8-12 The lack of any serious consequence to initiating feeding early in these patient populations dispels the myth that feeding early is fraught with complications. The overall effect of early nutrition on survival is beyond the limitations of these small trials, unfortunately. Commencing feeding after tube placement should be held at least until at least the animal has recovered from anesthesia. Recumbent animals receiving feedings are at risk of aspiration. Patients with compromised gastrointestinal motility or a decreased gag reflex (e.g., anesthetised patients, patients on opioids analgesics, patients with ileus) are also at risk for complications and should be monitored closely.

CHOOSING THE MOST APPROPRIATE FEEDING TUBE Determination of the route of nutritional support is an important step in the nutritional management of critical care patients. Nutritional support is broadly categorized into enteral and parenteral routes. Enteral routes include nasoesophageal, nasogastric esophageal, gastric, and jejunal feeding tubes, while parenteral routes include peripheral and central venous catheters. In most veterinary practices, nasoesophageal/nasogastric and esophagostomy feeding tubes are the most commonly considered feeding routes. The route selected for each patient will be ultimately be influenced by the patient’s medical and nutritional status, the anticipated length of time required for nutritional support, and consideration of the advantages and disadvantages presented by each route. Table 126.3 summarizes the major advantages and disadvantages associated with each feeding tube. Nasoesophageal and nasogastric feeding tubes are relatively easy and convenient methods of nutritional delivery for patients who will require short-term nutritional support for fewer than five days, or for

TABLE 126.3  Types of Feeding Tubes Used to Provide Nutritional Support in Critically Ill Patients Feeding Tube Nasoesophageal

Typical Duration of Use Short term (less than 5 days)

Esophagostomy

Extended (weeks to months)

Gastrostomy

Extended (weeks to months)

Jejunostomy

Long term (weeks)

Advantages • Inexpensive • Easy to place • No anesthesia required • Inexpensive • Simple to place • Can accommodate high calorie semi-liquid diets • Can accommodate high calorie semi-liquid diets

• Can bypass upper gastrointestinal tract

Disadvantages • Must use complete liquid diet • Prone to being dislodged or obstructed • Requires brief anesthesia • Prone to becoming obstructed • Incision can become inflamed or infected • Requires general anesthesia for placement • Endoscopic placement requires special equipment • Tube displacement may result in peritonitis • Requires general anesthesia • Requires laparotomy and special expertise for placement • Requires complete liquid diet • Tube displacement may result in peritonitis

CHAPTER 126  Enteral Nutrition patients who are not candidates for general anesthesia. The distinction between these techniques is whether the tip of the feeding tube remains within the esophagus or whether it is placed into the stomach. Concerns regarding possible interference of feeding tubes of the lower esophageal sphincter led to recommendations that the feeding tube should terminate into the distal esophagus. However, a recent study found no difference in complication rates between nasoesophageal and nasogastric tube; the importance of where these tubes terminate is unclear.25 The one advantage afforded by nasogastric tubes is that these provide access for aspirating to measure gastric residual volumes. In general, nasoesophageal and nasogastric feeding tubes have the advantages of being relatively easy to place and inexpensive. However, because of the risk of aspiration, nasoesophageal/nasogastric feeding should not be implemented in patients with protracted vomiting or those without a gag reflex. The major disadvantage of nasoesophageal and nasogastric feeding tubes is their smaller diameter (typically 3.5–5 French in cats and 6–8 French in dogs), which limits diet selection to liquid enteral formulas. Liquid formulations may be delivered via continuous or intermittent bolus feedings. Although continuous feeding can be helpful in pets in which high feeding volumes may not be tolerated, a recent study demonstrated that gastric residual volumes and clinical outcome did not differ between the two feeding methods.26 Placement of an esophagostomy feeding tube requires general anesthesia for placement but is still a relatively quick and simple procedure (see reference for placement details).27 Compared to nasoesophageal/nasogastric feeding tubes, esophagostomy tubes can be used for an extended period of time with some reporting over a year of use. Other advantages include increased comfort for the animal, and an increased tube diameter (12–14 French), allowing for a wider selection of diets including blenderized prescription formulated for specific medical conditions (e.g., novel protein diets, fat-restricted diets).

NUTRITIONAL PLAN Choosing the Most Appropriate Diet The guiding principle regarding the diet used for nutritional support will depend on the individual needs of each patient. The composition of the diet needs to reflect the patient’s dietary needs (e.g., higher protein requirements in catabolic patients, fat restriction in hyperlipidemic patients). Generally speaking, critically ill patients should be fed a calorically dense diet of high protein and fat. However, patients that have specific contraindications to high protein (e.g., chronic kidney failure, hepatic encephalopathy) should be fed a moderately restricted protein diet. In animals with gastrointestinal diseases, there may be a need to restrict the fat content of the diet. The chosen diet must also be compatible with the feeding tube of the patient. Liquid diets have the advantage that they can be delivered virtually via any feeding tube. However, it is important to consider the caloric density of these liquid diets. Diets that require a large amount of water to be blenderized in order to get through feeding tubes drop the caloric density of the diet and result in large volumes of the diet per feeding.

Calculation of Energy Requirements The patient’s RER is the number of calories required for maintaining homeostasis while the animal rests quietly. The RER is calculated using the following formula: RER  70  (body weight in kg)0.75 For animals weighing between 2 and 20 kg, the following formula gives a good approximation of energy needs: RER  (30  body weight in kg)  70

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For neonates and growing animals, the estimated energy expenditure can be up to 3 3 RER. Traditionally, the RER was then multiplied by an illness factor between 1.0 and 1.5 to account for increases in metabolism associated with different conditions and injuries. Recently, there has been less emphasis on these subjective illness factors, and current recommendations are to use more conservative energy estimates to avoid overfeeding. Therefore illness factors are usually not applied when formulating feeding plans of critically ill patients.28 Overfeeding can result in metabolic and gastrointestinal complications and hepatic dysfunction, increase carbon dioxide production, and weaken respiratory muscles. Of the metabolic complications, the development of hyperglycemia is most common.19 Currently, the RER is used as an initial estimate of a critically ill patient’s energy requirements. It should be emphasized that these general guidelines should be used as starting points, and animals receiving nutritional support should be closely monitored for tolerance of nutritional interventions. Continual decline in body weight or body condition should prompt the clinician to reassess and perhaps modify the nutritional plan (e.g., increasing the number of calories provided by 25%).

IMPLEMENTING NUTRITIONAL PLAN To implement enteral nutritional support, a feeding tube is typically required. Placement of a feeding tube is recommended whenever voluntary eating by the patient is lacking in sufficient amounts to meet at least 80% RER. Once a feeding tube is in place, a diet preparation that is suitable to meet the nutritional needs of the patient and appropriate for the tube is chosen. Small-bore tubes such as those typically used for nasoesophageal placement, or jejunostomy tubes, require complete liquid diets. Gruel-type diets require larger-bore tubes such as esophagostomy and gastrostomy tubes, and the preparation of these diets may require the use of a kitchen blender. Alternatively, there are veterinary diets that have been especially formulated for use via feeding tubes. Other considerations for choosing a diet include fat and protein contents and caloric density. The next consideration involves the manner in which food is delivered; animals with nasoesophageal, esophagostomy, and gastrostomy tubes tolerate bolus feedings in which the prescribed amount of food is administered over 15 to 20 minutes and fed every 4 to 6 hours. The volumes of food that can be fed per feeding should typically be less than 10 ml/kg; however, some patients will not tolerate being fed more than 2 ml/kg while some animals can tolerate 30–40 ml/kg per feed. Regardless of the severity of malnutrition, one must remember that the immediate goals of therapy in any critically ill patient should focus on proper cardiovascular resuscitation, stabilization of vital signs, and identification of primary disease process. As steps are taken to address the primary disease, formulation of a nutritional plan should aim to mitigate overt nutritional deficiencies and imbalances. By providing adequate energy substrates, protein, essential fatty acids, and micronutrients, the body can support wound healing, immune function, and tissue repair. A major goal of nutritional support is to minimize metabolic derangements and the catabolism of lean body tissue. During hospitalization, recovery of normal body weight is not the top priority as this should occur once the animal is discharged from the hospital and completed their recovery from critical illness at home.

MONITORING AND REASSESSMENT Body weight should be monitored daily in all patients receiving nutritional support, and the clinician should take into account fluid shifts when evaluating changes in body weight. For this reason, body condition score assessment is also important. The use of the RER as the

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PART XIII  Nutrition

patient’s caloric requirement is merely a starting point. The number of calories provided may need to be increased to keep up with the patient’s changing needs, typically by 25% if well tolerated. In patients unable to tolerate the prescribed amounts, the clinician should consider reducing the amounts of enteral feedings and supplementing the nutritional plan with some form of parenteral nutrition (see Chapter 127, Parenteral Nutrition). With continual reassessment, the clinician can determine when to transition the patient from assisted feeding to voluntary consumption of food. The discontinuation of nutritional support should only begin when the patient can consume approximately 75% of its RER without much coaxing.

securely sutured and wraps should be comfortable. An Elizabethan collar may be needed in some cases. Kinking can occur during tube placement or after vomiting and can be detected radiographically. Completely flushing the tube with water after every use decreases the risk of tube obstruction. The diet used should have the proper consistency to pass easily through the feeding tube. In addition, the administration of medications through the tube should be avoided or performed with caution as it could lead to clogging of the tube. Tube obstructions may dislodge with warm water by applying pressure and suction. Other methods include infusing a carbonated beverage or a solution of pancreatic enzyme (1/4 tsp) and sodium bicarbonate (325 mg) with 5 ml of water.35

COMPLICATIONS

CONCLUSIONS

Possible complications of enteral nutrition include mechanical complications such as clogging of the tube or early tube removal.29 Metabolic complications include electrolyte disturbances, hyperglycemia, volume overload, and gastrointestinal signs (e.g., vomiting, diarrhea, cramping, bloating).30-32 In critically ill patients receiving enteral nutritional support, the clinician must also be vigilant for the development of aspiration pneumonia. Monitoring parameters for patients receiving enteral nutrition include body weight, serum electrolytes, tube patency, appearance of tube exit site, gastrointestinal signs (e.g., vomiting, regurgitation, diarrhea), and signs of volume overload or pulmonary aspiration.29 The complications associated with nasoesophageal feeding tubes are relatively minor and are unlikely to result in significant morbidity. In one study, the most common complications seen with the use of nasogastric feeding tubes were vomiting, diarrhea and inadvertent tube removal, which occurred in 37% of patients.33 Other minor complications (e.g., irritation of nasal passages, sneezing) can occur during the placement of the tube or as a consequence of the indwelling tube. A recent study comparing complications associated with nasoesophageal versus nasogastric feeding tubes found no difference in complication rates.25 To prevent inadvertent use of the nasoesophageal tube for anything other feeding, the feeding tube should be clearly labelled. Complications associated with esophagostomy feeding tubes are relatively uncommon and typically are minor to moderate. In one retrospective study comparing esophagostomy tubes with percutaneous endoscopic gastrostomy tubes, there was no difference in complication rate or severity.34 Serious complications such as inadvertent placement in the airway or mediastinum or damage to the major vessels and nerves can be avoided by proper placement technique and verifying position of the tube radiographically. Midcervical placement minimizes the risk of gagging and partial airway obstruction. Proper tube size and material decrease the risk of esophageal irritation. A thorough patient evaluation to ensure the pet can protect its airway in the event of vomiting is critical to lessen the risk of pulmonary aspiration. If the patient vomits, tube placement should be verified to ensure it has not been displaced prior to use. Complications related to the stoma site or mechanical issues with the tube are possible.27,34 Peristomal cellulitis, infection, or abscess may occur. Peristomal inflammation is a more common complication. It can be managed in mild cases with thorough cleaning and topical antibiotics, while more severe cellulitis or abscessation may require systemic antimicrobials, tube removal, and surgical debridement and/or drain placement. These risks can be minimized by ensuring the tube is secured properly and the stoma site is kept clean and protected. Mechanical issues with the tube include premature removal, kinking, or clogging. Risk of premature removal can be minimized by using an appropriately sized tube size for patient comfort. The tube should be

While critically ill patients are often not regarded as in urgent need of nutritional support given their more pressing problems, the severity of their injuries, altered metabolic condition, and necessity of frequent fasting, they are at high risk of becoming malnourished during hospitalization. Proper identification of these patients and careful planning and execution of a nutrition plan can be key factors in their successful recovery. As our understanding of various disease processes and the interactions with metabolic pathways improves, along with the refinement of nutritional support techniques we can provide, there is indeed great optimism that nutrition can have a significant positive impact on the recovery of critically ill patients.

REFERENCES 1. Gagne JW, Wakshlag JJ: Pathophysiology and clinical approach to malnutrition in dogs and cats. In Chan DL, editor: Nutritional management of hospitalized small animals, Chichester, West Sussex, 2015, John Wiley & Sons, pp 117-127. 2. Michel KE: Nitrogen metabolism in critical care patients, Vet Clin Nutr (Suppl):20,1998. 3. Sakurai Y, Zhang X, Wolfe RR: Short-term effects of tumor necrosis factor on energy and substrate metabolism in dogs, J Clin Invest 91:2437, 1993. 4. Freitag KA, Saker KE, Thomas E, et al: Acute starvation and subsequent refeeding affect lymphocyte subsets and proliferation in cats, J Nutr 130: 2444, 2000. 5. Chan DL: Nutritional requirements of the critically ill patient, Clin Tech Small Anim Pract 19:1, 2004. 6. Michel KE: Nutritional assessment in small animals. In Chan DL, editor: Nutritional management of hospitalized small animals, Chichester, West Sussex, 2015, John Wiley & Sons, pp 1-6. 7. Whitehead K, Cortes Yonaira, Eirmann L: Gastrointestinal dysmotility disorders in critically ill dogs and cats, J Vet Emerg Crit Care 26:234, 2016. 8. Mohr AJ, Leisewitz AL, Jacobson LS, et al: Effect of early enteral nutrition on intestinal permeability, intestinal protein loss, and outcome in dogs with severe parvoviral enteritis, J Vet Intern Med 17:791, 2003. 9. Mansfield CS, James FE, Steiner JM, et al: A pilot study to assess tolerability of early enteral nutrition via esophagostomy tube feeding in dogs with severe acute pancreatitis, J Vet Intern Med 25:419-425, 2011. 10. Hoffberg JE, Koenigshof A: Evaluation of the safety of early compared to late enteral nutrition in canine septic peritonitis, J Am Anim Hosp Assoc 53:90, 2017. 11. Harris JP, Parnell NK, Griffith EH, et al: Retrospective evaluation of the impact of early enteral nutrition on clinical outcomes in dogs with pancreatitis: 34 cases (2010-13), J Vet Emerg Crit Care 27(4):425, 2017. 12. Liu DT, Brown DC, Silverstein DC: Early nutritional support is associated with decreased length of hospitalization in dogs with septic peritonitis: a retrospective study of 45 cases (2000-2009), J Vet Emerg Crit Care 22:453, 2012. 13. Biolo G, Toigo G, Ciocchi B, et al: Metabolic response to injury and sepsis: changes in protein metabolism, Nutrition 13:52S, 1997.

CHAPTER 126  Enteral Nutrition 14. Michel KE, King LG, Ostro E: Measurement of urinary urea nitrogen content as an estimate of the amount of total urinary nitrogen loss in dogs in intensive care units, J Am Vet Med Assoc 210:356, 1997. 15. Remillard RI, Darden DE, Michel KE, et al: An investigation of the relationship between caloric intake and outcome in hospitalized dogs, Vet Ther 2:301, 2001. 16. Owen OE, Reichard GA, Patel MS, et al: Energy metabolism in feasting and fasting, Adv Exp Med Biol 111:169, 1979. 17. Freeman LM, Michel KE, Zanghi BM, et al: Evaluation of the use of muscle condition score and ultrasonographic measurements for assessment of muscle mass in dogs, Am J Vet Res 80:595, 2019. 18. Brunetto MA, Gomes MOS, Andre MR, et al: Effects of nutritional support on hospitalized outcomes in dogs and cats, J Vet Emerg Crit Care 20:224, 2010. 19. Chan DL, Freeman LM: Parenteral nutrition in small animals. In Chan DL, editor: Nutritional management of hospitalized small animals, Chichester, West Sussex, 2015, John Wiley & Sons, pp 100-116. 20. Preiser JC, van Zanten AR, Berger MM, et al: Metabolic and nutritional support of critically ill patients: consensus and controversies, Crit Care 19:35, 2015. 21. Mehta NM, Skillman HE, Irving SY, et al: Guidelines for the provision and assessment of nutritional support therapy in the pediatric critically ill patient: Society of Critical Care Medicine and American Society for Parenteral and Enteral Nutrition, JPEN J Parenter Enteral Nutr 41:706, 2017. 22. Tume LN, Valla FV, Joosten K, et al: Nutritional support for children during critical illness; European Society of Pediatric and Neonatal Intensive Care (ESPNIC) metabolism, endocrine and nutrition section position statement and clinical recommendations, Intensive Care Med 46:411, 2020. 23. Tredget EE, Yu YM: The metabolic effects of thermal injury, World J Surg 16:68, 1992. 24. Wischmer PE: The evolution of nutrition in critical care: how much, how soon? Crit Care 17:S7, 2013.

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25. Yu MK, Freeman LM, Heinse CR, et al: Comparison of complication rates in dogs with nasoesophageal versus nasogastric feeding tubes, J Vet Emerg Crit Care 23:300, 2013. 26. Holahan M, Abood S, Hauptman J, et al: Intermittent and continuous enteral nutrition in critically ill dogs. A prospective randomized trial, J Vet Intern Med 24:520,2010. 27. Eirmann L: Esophagostomy feeding tubes in dogs and cats. In Chan DL, editor: Nutritional management of hospitalized small animals, Chichester, West Sussex, 2015, John Wiley & Sons, pp 29-40. 28. Chan DL: Estimating energy requirements of small animal patients. In Chan DL, editor: Nutritional management of hospitalized small animals, Chichester, West Sussex, 2015, John Wiley & Sons, pp 7-13. 29. Chan DL: Feeding tube complications. In Drobatz KJ, Hopper K, Rozanski EA, Silverstein DC, editors: Textbook of small animal emergency medicine, Hoboken, NJ, 2019, Wiley Blackwell, pp 578-581. 30. Justin RB, Hoenhaus AE: Hypophosphatemia associated with enteral alimentation in cats, J Vet Intern Med 9:228, 1995. 31. Pyle SC, Marks SL, Kass PH: Evaluation of complications and prognostic factors associated with administration of total parenteral nutrition in cats: 75 cases (1994-2001), J Am Vet Med Assoc 225:242, 2004. 32. Queau Y, Larsen JA, Kass PH, et al: Factors associated with adverse outcomes during parenteral nutrition administration in dogs and cats, J Vet Intern Med 25:446, 2011. 33. Abood SK, Buffington CA: Enteral feeding of dogs and cats: 51 cases (1989-91), J Am Vet Med Assoc 201:619, 1992. 34. Ireland LM, Hoenhaus AE, Broussard JD, et al: A comparison of owner management and complications in 67 cats with esophagostomy and percutaneous endoscopically guided feeding tubes, J Am Anim Hosp Assoc 39:241, 2003. 35. Parker VJ, Freeman LM: Comparison of various solutions to dissolve critical care diet clots, J Vet Emerg Crit Care 23:344, 2013.

127 Parenteral Nutrition Daniel L. Chan, DVM, DACVECC, DECVECC, DACVIM(Nutrition), FHEA, MRCVS

KEY POINTS • Parenteral nutrition (PN) is an important mode of nutritional support for hospitalized patients intolerant of enteral nutrition. • Before initiation of PN support, nutritional assessment should be carried out to assess the need for PN, identify complicating factors, and devise a plan for commencing PN. • Formulation of PN requires the calculation of energy and protein needs and facilities for safe compounding.

• The safe provision of PN requires special attention in the placement and maintenance of intravenous catheters, aseptic technique in compounding and handling of PN, and vigilant patient monitoring. • With appropriate protocols and safeguards in place, the use of PN can be successfully incorporated in the care of critically ill patients in many practice settings. • Transitioning to enteral nutrition should occur as soon as it is feasible.

INTRODUCTION

and therefore careful patient selection is particularly important when considering implementing PN.6 A large prospective controlled study found that early PN in critically ill patients with relative contraindications to early EN was not associated with any negative impact on survival and in fact identified decreased dependence on mechanical ventilation and better preservation of lean muscle mass.7 In light of these findings, the first step in considering patients for nutritional support is to perform a nutritional assessment. Following the nutritional assessment of the patient, the most appropriate route of nutritional support should be selected. The indications for PN support include situations in which malnourished animals cannot voluntarily or safely consume food (i.e., animals unable to protect their airways) or those that cannot tolerate EN despite attempts to improve tolerance to EN. Persistent hyporexia or anorexia is not sufficient justification for PN and should be considered an inappropriate use of PN. In patients that require nutritional support but have contraindications for placement of feeding tubes (e.g., coagulopathic, presence of cardiovascular or cardiopulmonary instability), short-term (e.g., ,3 days) administration of PN may be considered.

The provision of nutrition to animals via the parenteral route is an important therapeutic modality for hospitalized animals that cannot tolerate enteral nutrition (EN). Although parenteral nutrition (PN) can be an effective means of providing animals with calories, proteins, and other nutrients, there are a number of possible complications associated with its use that require careful patient selection, appropriate formulation, safe and effective administration practices, and close patient monitoring. In most cases, hospitalized patients that do not consume adequate quantities of food voluntarily should be supported with EN as it is the safest, most convenient, most physiologically sound, and least expensive method of nutritional support (see Chapter 126). While EN support is the preferred method of nutritional support in hospitalized patients, PN is the established method of providing nutritional support to patients whose gastrointestinal tracts cannot tolerate enteral feedings.1,2 While the use of PN support has certainly increased in recent years, there is a perception that this technique is technically difficult, associated with many complications, and limited to major referral centers. In reality, PN support can be adopted in many practices, and complications can be significantly reduced with proper and meticulous care. The goals of this chapter are to outline the proper identification of patients most likely to benefit from PN; to review the process of formulating, implementing, and monitoring parenteral nutritional support; and to discuss how PN can be incorporated into many practices.

INDICATIONS FOR PN SUPPORT Studies in people have shown that the use of PN in some patient populations could increase the risk of complications and worsens outcome.1,3,4 Moreover, some recent studies have demonstrated worse morbidity (e.g., increased risk of infectious complications, greater dependence on mechanical ventilation) in ICU patients when PN was initiated within the first 48 hours of ICU admission compared with delayed initiation until day 8 following ICU admission.5 The increase in complications may be related to premature initiation of PN in well-nourished ICU patients,

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PARENTERAL NUTRITION The terminology used to describe the use of PN in veterinary patients has evolved. Thus, it is worth reviewing the current terminology. Total parenteral nutrition was previously defined as the provision of all of the patient’s protein, calorie, and micronutrient requirements intravenously, whereas partial parenteral nutrition (PPN) was defined as the provision of only a part of this requirement (typically 40%–70% of the energy requirement).8 More recently, there has been a shift away from describing PN in terms of “meeting energy and nutrient requirements” as they remain largely unknown in animals, and as a result, recent recommendations emphasize categorizing PN by the mode of delivery such that PN delivered into a central vein is described as central PN, or CPN, and PN delivered into a peripheral vein is described as peripheral PN.9,10 For the purposes of this chapter, PPN will refer to peripheral PN. To enable the safe administration of PN solutions using peripheral veins, the osmolality of the solutions is decreased because osmolality is believed to be one of the main contributing factors for the development

CHAPTER 127  Parenteral Nutrition of thrombophlebitis. In order to achieve lower osmolarities (e.g., ,850 mOsm/L), the concentrations of amino acids and dextrose are decreased, and this also decreases the caloric density of these solutions. As such, because PPN only provides a portion of the patient’s resting energy requirements (RER), it should be used for short-term nutritional support in nondebilitated patients with average nutritional requirements. The administration of PN always requires a dedicated catheter that is newly placed using aseptic technique. Once placed, this catheter should not be used for anything other than PN administration. The use of long catheters composed of silicone or polyurethane is recommended for use with PN to reduce the risk of thrombophlebitis. Multilumen catheters are often recommended for PN because they can remain in place for longer periods of time (as compared with normal jugular catheters) and provide other ports for blood sampling and administration of additional fluids and IV medications.

COMPONENTS OF PARENTERAL NUTRITION Amino Acids Most PN solutions are composed of amino acids, a carbohydrate source (dextrose or glycerol), and lipids. Amino acid solutions vary from 3% to 10% concentrations. The most commonly cited concentration of amino acids used in veterinary patients is 8.5%, with an energy density of 0.34 kcal/ml and osmolarity of approximately 880 mOsm/L. Amino acid solutions are typically available with and without added electrolytes. The amino acid profile of these solutions is intended to meet the essential amino acid requirements in people. Currently, there are no amino acid solutions made specifically for dogs or cats, and therefore these solutions do not meet all amino acid requirements in these species. However, when used for short-term nutritional support, the use of these solutions is unlikely to result in clinically relevant deficiencies. The minimal protein requirement of healthy dogs supported via PN has been estimated to be 3 g/100 kcal.11 While the protein requirement of ill veterinary patients has not been extensively investigated, in order to support hospitalized animals with PN, the standard recommendations for protein provision is 4–6 g/100 kcal (15%–25% of total energy requirements) for dogs and 6–8 g/100 kcal (25%–35%) for cats.8 The presumed increase in protein requirements in ill animals relate to inadequate food intake that accompanies many diseases, increased protein losses, and altered metabolic and inflammatory pathways.12 Given the risk of protein malnutrition in hospitalized animals, the goal of PN support should be to provide sufficient amino acids to minimize muscle protein breakdown and maintain lean body mass. Whereas healthy animals that are deprived of food can adapt to conserve muscle mass and use stored fat for energy (simple starvation), critically ill animals that are malnourished may have accelerated muscle catabolism (stressed starvation) for generation of amino acids used for gluconeogenesis and synthesis of acute phase proteins.13 However, not all animals require increased protein during nutritional support; animals with protein intolerance (e.g., patients with hepatic encephalopathy, severe kidney failure) should be supported with reduced levels of protein (e.g., 3 g protein/100 kcal).

Carbohydrates For provision of carbohydrate calories, dextrose solutions ranging from 5% to 50% are typically used for PN solutions. In CPN, 50% dextrose is the most commonly used concentration of dextrose, with an osmolarity of 2523 mOsm/L and providing 1.7 kcal/ml. For PPN the typical dextrose solution used is 5% dextrose, which corresponds to 0.17 kcal/ ml and an osmolarity of 252 mOsm/L. The proportion of calories provided with carbohydrates depends on the patient’s individual

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circumstances (e.g., protein, carbohydrate, lipid intolerance) but is typically half of the nonprotein calories. The ratio of calories provided by carbohydrate and lipid can be adjusted as dictated by the patient’s needs. As dextrose infusion rates exceeding 4 mg/kg/min have been associated with the development of hyperglycemia in nondiabetic human patients, the author recommends limiting the amount of dextrose provided in PN to this amount.14 When formulating PN for diabetic patients, a greater proportion of calories should be provided from amino acids and lipids. In some patients, insulin therapy may be necessary to control hyperglycemia.

Lipids Lipid emulsions are used in PN to provide energy and essential fatty acids. The most commonly used lipid emulsion is a 20% solution, providing 2 kcal/ml with an osmolarity of 260 mOsm/L. The most common lipid emulsions used in PN are usually derived from soybean or safflower oil. As the principal type of lipid used in PN is composed primarily of omega-6 fatty acids, there are concerns regarding its effects on the inflammatory response. In vivo studies in people have shown an exaggerated inflammatory response to endotoxin following a long-chain triglyceride infusion.15 There have also been concerns with regard to the possible effects of omega-6 fatty acids on immune function, oxidative stress, and negative hemodynamic effects, as well as an increased risk for hyperlipidemia, lipid embolization, and microbial contamination.16-20 In order to reduce these effects, different lipid emulsions containing omega-3 fatty acids, omega-9 fatty acids, and medium-chain triglycerides have been developed.21,22 Until these different types of lipids are evaluated in dogs and cats and demonstrated to have clinical benefits, the authors recommend limiting the use of typical omega-6-based lipid emulsion dosage in dogs and cats to 2 g/kg/day (30%–40% of total calories provided) to decrease the risk of lipemia and possible immunosuppression. Animals with preexisting lipemia may also require lower doses of lipid or PN formulations without lipids.

Electrolytes and Trace Minerals PN can be formulated with or without electrolytes depending on patient needs. The most commonly adjusted electrolyte in PN solution is potassium and most formulations contain 20 to 30 mmol/L (20 to 30 mEq/L) potassium. Potassium chloride and potassium phosphate can be used to adjust potassium content. In patients requiring additional phosphorus supplementation (e.g., patient with hypophosphatemia), it is recommended that this is supplemented as a separate infusion as requirements may change frequently and there may be an increased risk of mineral precipitation with the addition of minerals to PN solutions. Adjusting electrolytes separately allows greater flexibility. Trace minerals are sometimes added to PN solutions, but the majority of veterinary patients receive PN without the addition of trace minerals. In patients that require prolonged PN support (e.g., .10 days) or are severely malnourished, the addition of zinc, copper, manganese, and chromium may be considered.

Vitamins As many hospitalized animals requiring PN may already have a degree of malnutrition, supplementation of PN with B vitamins may be of benefit. Because some B vitamins are light sensitive (e.g., riboflavin), it may be best to add B vitamins immediately before administration and dose it so that the dose is administered within the first 6 hours of infusion. Commercial vitamin B formulations (B vitamin complex, Veterinary Laboratories, Lenexa, KS) containing thiamine, niacin, pyridoxine, pantothenic acid, riboflavin, and cyanocobalamin are sufficient in most cases. The dosages that have been recommended for these B vitamins in

748

PART XIII  Nutrition

PN formulation (per 1000 kcal of PN solution) include: 0.29 mg thiamine, 0.63 mg riboflavin, 3.3 mg niacin, 2.9 mg pantothenic acid, 0.29 mg pyridoxine, and 6 µg cyanocobalamin.10

FORMULATION OF PARENTERAL NUTRITION SOLUTIONS Using parenteral nutrient admixtures that include amino acids, dextrose, and lipids in a single bag is preferred over single nutrient solutions. The author uses the calculations in Box 127.1 to formulate PN. The first step is to determine the animal’s calorie requirements. A sensible starting point in estimating energy requirements of most hospitalized animals is to calculate the RER. The author does not apply illness energy factors in determining the target calories to be administered due to concerns over overfeeding and its associated complications. It is worth noting that the method of calculating the distribution of energy from carbohydrate, amino acids, and lipids used in this chapter includes the contribution of energy provided by the amino acid solution. Some authors meet the

BOX 127.1  Worksheet for Calculating Parenteral Nutrition Using Commonly Available Components 1. Resting energy requirement (RER) 70 3 (current body weight in kilograms)0.75 5 kcal/day RER 5 _____kcal/day. This caloric target can be adjusted down (e.g., 70% RER) if necessary. 2. Protein requirements Canine Feline *Standard 4–5 g/100 kcal 6 g/100 kcal *Decreased requirements 2–3 g/100 kcal 4-5 g/100 kcal (hepatic/renal failure) *Increased requirements 5–6 g/100 kcal 6-8 g/100 kcal (protein-losing conditions) (RER  100) 3 _____g/100 kcal 5 _____g protein required/day (protein required) 3. Volumes of nutrient solutions required each day a. 8.5% amino acid solution 5 0.085 g protein/ml (Note: multiple concentrations of amino acids are available.) _____g protein required/day  0.085 g/ml 5 _____ml of amino acids/day b. Nonprotein calories: The calories supplied by protein (4 kcal/g) are subtracted from the RER to get total nonprotein calories needed: _____g protein required/day 3 4 kcal/g 5 _____kcal provided by protein RER 2 kcal provided by protein 5 _____nonprotein kcal needed/day c. Nonprotein calories are usually provided as a 50:50 mixture of lipid and dextrose. However, if the patient has a preexisting condition (e.g., diabetes, hypertriglyceridemia), this ratio may need to be adjusted: *20% lipid solution 5 2 kcal/ml To supply 50% of nonprotein kcal: _____lipid kcal required  2 kcal/ml 5 _____ml of lipid *50% dextrose solution 5 1.7 kcal/ml To supply 50% of nonprotein kcal: _____dextrose kcal required  1.7 kcal/ml 5 _____ml dextrose 4. Total daily requirements _____ml 8.5% amino acid solution _____ml 20% lipid solution _____ml 50% dextrose solution _____ml total volume of PN solution

target energy requirement with only the carbohydrate and lipid component, arguing that this results in a “protein sparring effect,” whereby the amino acids are solely used for protein synthesis when all the energy needs are met by the other components. However, this strategy risks overfeeding, so the calculations outlined in this chapter account for the calories provided by the amino acids (i.e., protein calories).

Compounding To compound the PN admixtures, aseptic conditions are required. Ideally, only individuals with the expertise and facilities who can ensure accurate and sterile preparation should compound PN solutions. This usually entails the use of automated compounders within sterile environments. However, these compounders are not widely available, expensive, and usually not cost-effective unless PN is used frequently. For this reason, it may be preferable for veterinary practices that infrequently use PN to obtain solutions from human hospitals or home-care companies that can compound PN to the required specifications for the patient. Recently, there is a shift away from individualized formulations to commercially available all-in-one solutions.2 These products have multi-chambered sealed bags that keep the components (e.g., amino acids, dextrose, lipids) separate until the seals are broken by squeezing the bag and mixing the contents. The advantages of these commercial combination products are their availability and the fact that they require no special compounding and have been associated with fewer infectious complications.2 There are two retrospective studies reporting the use of these all-in-one products, and the findings are not dissimilar to studies reporting the use of individualized preparations of PN.23,24 The major disadvantage of these products is that they do not allow the proportions of different components to be adjusted to suit the needs of the patient.

ADMINISTERING PARENTERAL NUTRITION Current recommendations are that bags of PN admixtures should not be at room temperature for more than 24 hours once breached for administration. During infusion the lines should not be disconnected from the patient (i.e., it should remain a closed system). Ideally, at the end of each 24-hour period, the infusion should be complete, and the empty bag, along with the lines, can be changed using aseptic technique and a new bag and lines substituted. All PN should be administered through a 1.2-µm in-line filter. The filter can help to prevent lipid globules or precipitates (particularly calcium phosphate) from being introduced to the patient. PN should be instituted gradually over 48 to 72 hours. Most animals tolerate receiving 50% of total requirements on the first day and 100% on the second day. Animals that have been without food for long periods may require slower introduction (i.e., 33% on the first day, 66% on the second day, and 100% on the third day). As PN solutions are crystalloid solutions, it is important to adjust the animal’s other intravenous fluids when initiating PN support to avoid fluid volume overload.

MONITORING The other critical aspect in reducing the risk of complications is vigilant monitoring. Checking the catheter site daily can identify malpositioning of the catheter and phlebitis or cellulitis early, before serious problems develop. Use of the RER as the patient’s caloric requirement is merely a starting point. The number of calories provided may need to be increased to prevent weight loss or to keep up with the patient’s changing needs. To avoid complications with PN, the patient should be monitored carefully and frequently. General attitude, body weight, temperature, blood glucose concentration, total plasma protein (also

CHAPTER 127  Parenteral Nutrition checking the serum for presence of gross lipemia or hemolysis), and serum electrolyte concentrations should be assessed daily or more frequently if indicated. Metabolic complications can occur frequently in animals receiving PN, and monitoring is crucial to detect and address them early, if necessary. The clinical situation should dictate the frequency and spectrum of monitoring required because some patients will need more intensive monitoring. The development of metabolic abnormalities usually does not require discontinuation of PN but may require reformulation (e.g., a reduction in the lipid content for animals that develop hypertriglyceridemia). Finally, the overall nutritional plan should be reassessed on a regular basis so that it can be adjusted to meet the animal’s changing needs.

COMPLICATIONS Metabolic Complications A number of possible complications can be associated with PN, and these generally are grouped into one of three categories. Metabolic complications are the most common, with hyperglycemia typically seen most frequently.9,25-29 Despite being the most commonly encountered complication, hyperglycemia was only associated with a poorer survival in one study in cats.28 In that study, cats that developed hyperglycemia after the first 24 hours of PN had a fivefold increase in mortality risk.28 It is worth noting that many of the cats in that study were fed in excess of RER. Although the development of hyperglycemia following PN administration may not necessarily worsen outcome, it may still be prudent to avoid this complication. Using conservative energy targets (i.e., initial target of RER), slowly increasing PN infusion rates during the first day, and close monitoring of patients receiving PN are recommended for minimizing the risk of developing hyperglycemia. Hyperlipidemia is also a commonly reported metabolic complication in dogs and cats receiving PN,25,27,29 although in two studies some animals experienced a resolution of hyperlipidemia following initiation of PN.26,28 The rates of hyperlipidemia appear to be decreasing from almost 70% in the Lippert study reported in 199325 to ,20% in more recent studies.26-29 A decrease in overall energy targets and a decrease in proportion of energy provided via lipids in more recent studies are likely reasons for improvement for this complication. Electrolyte disturbances can develop either after instituting nutritional support or may worsen in animals with preexisting abnormalities. Hyponatremia, hypokalemia, hypocalcemia, hypophosphatemia, and hypochloremia have been reported in various studies, although these complications were not associated with nonsurvival.9,25-29 In contrast, one report23 found that hyperkalemia occurred in approximately 24% of dogs receiving a commercially available amino acid and dextrose solution and that this complication was associated with a decrease in survival.

Mechanical Complications The most commonly reported mechanical complications reported in association with PN include catheter dislodgement, catheter disconnection, catheter occlusion, chewed lines, occluded lines, and thrombophlebitis. Mechanical complications appear to be more common in dogs compared with cats, with chewed lines and catheter disconnection occurring most frequently.25-27 In the study by Gajanayake et al,23 there was a particularly high rate of catheter dislodgement (40%), and this was mostly encountered in peripherally inserted catheters. As most other studies of PN in animals had predominantly used central catheters, it is difficult to draw conclusions whether the high rate of complication was related to PN administration, the formulation of PN (dextrose/amino acid combination), or no different if compared with peripheral catheters where PN was not used.

749

Septic Complications Although potentially the most devastating, septic complications appear to be uncommon in animals receiving PN. In all studies to date, septic complications have been described in ,7% of animals receiving PN (See Chapter 98, Catheter-related Bloodstream Infections).9,23,25-29 Catheter-related infections are the main concern in this patient population, and many patients respond with removal of the intravenous catheter. Although contamination of the PN admixture is said to pose a particular risk, especially if the admixture contains lipids, there are no reports of a positive bacterial culture of a PN admixture in any of the animal studies to date. The low rates of septic complications may be due to insistence on strict aseptic techniques during catheter placement, PN compounding, and handling of PN bags and infusing sets.

SUMMARY The provision of nutritional support in patients intolerant of EN can be challenging due to technical, logistical, and management issues. As many hospitalized animals may already have a degree of malnutrition present or are at high risk for becoming malnourished, the ability to implement PN support is an important technique in such cases. The proper identification of patients that will benefit from PN and being able to formulate and compound PN safely are critical for the successful management of these cases. As the patient population that requires PN support is usually afflicted with serious conditions, avoiding and minimizing complications are also important. Despite some of the technical challenges associated with the compounding and administration of PN in animals, this form of nutritional support can be successfully adopted in many practice settings and play an important role in the recovery of critically ill animals.

REFERENCES 1. Braunschweig CL, Lecy P, Sheean PM, et al: Enteral compared with parenteral nutrition: a meta-analysis, Am J Clin Nutr 74:534, 2001. 2. Itzhaki MH, Singer P: Advancements in medical nutrition therapy: parenteral nutrition, Nutrients 12:717, 2020. 3. Gramlich L, Kichian K, Pinilla J, el al: Does enteral nutrition compared to parental nutrition result in better outcomes in critically ill adult patients? A systematic review of the literature, Nutrition 20:843, 2004. 4. Simpson F, Doig GS: Parenteral vs. enteral nutrition in the critically ill patient. A meta-analysis of trials using the intention to treat principle, Intensive Care Med 31:12, 2005. 5. Casaer MP, Mesotten D, Hermans G, et al: Early versus late parenteral nutrition in critically ill adults, N Engl J Med 365:506-517, 2011. 6. Lee H, Chung KS, Parl MS, et al: Relationship of delayed parenteral nutrition protocol with the clinical outcomes in a medical intensive care unit, Clin Nutr Res 3:33, 2014. 7. Doig GS, Simpson F, Sweetman EA, et al: Early parenteral nutrition in critically ill patients with short-term relative contraindications to early enteral nutrition in a randomized controlled trial, J Am Med Assoc 309:2130, 2013. 8. Chan DL, Freeman LM: Parenteral nutrition. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders in small animal practice, ed 4, St Louis, 2012, Saunders Elsevier, pp 605-622. 9. Queau Y, Larsen JA, Kass PH, et al: Factors associated with adverse outcomes during parenteral nutrition administration in dogs and cats, J Vet Intern Med 25:446, 2013. 10. Perea SC: Parenteral nutrition. In Fascetti AJ, Delaney SJ, editors: Applied veterinary clinical nutrition, St Louis, 2012, Saunders Elsevier, pp 353-373. 11. Mauldin GE, Reynolds AJ, Mauldin N, et al: Nitrogen balance in clinically normal dogs receiving parenteral nutrition solutions, Am J Vet Res 62:912, 2001. 12. Michel KE, King LG, Ostro E: Measurement of urinary urea nitrogen content as an estimate of the amount of total urinary nitrogen loss in dogs in intensive care units, J Am Vet Med Assoc 210:356, 1997.

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13. Biolo G, Toigo G, Ciocchi B, et al: Metabolic response to injury and sepsis: changes in protein metabolism, Nutrition 13:52S, 1997. 14. Rosmarin DK, Wardlaw GM, Mirtallo J: Hyperglycemia associated with high, continuous infusion rates of total parenteral nutrition dextrose, Nutr Clin Pract 11:151, 1996. 15. Krogh-Madsen R, Plomgaard P, Akerstrom T, et al: Effect of short-term intralipid infusion on the immune response during low-dose endotoxemia in humans, Am J Physiol Endocrinol Metab 94:E37, 2008. 16. Wiernik A, Jarstrand C, Julander I: The effect of Intralipid on mononuclear and polymorphonuclear phagocytes, Am J Clin Nutr 37:256, 1983. 17. Mirtallo J, Canada T, Johnson D, et al: Task Force for the Revision of Safe Practices for Parenteral Nutrition. Safe practices for parenteral nutrition, J Parenter Enteral Nutr 28:S39, 2004. 18. Kang JH, Yang MP: Effect of a short-term infusion with soybean oil-based lipid emulsion on phagocytic responses of canine peripheral blood polymorphonuclear neutrophilic leukocytes, J Vet Intern Med 22:1166, 2008. 19. Calder PC, Jensen GL, Koletzko BV, et al: Lipid emulsions in parenteral nutrition of intensive care patients: current thinking and future directions, Intensive Care Med 36:735, 2010. 20. Kuwahara T, Kaneda S, Shimono K, et al: Growth of microorganisms in total parenteral nutrition solutions without lipid, Int J Med Sci 7:43, 2010.

21. Wanten GJA, Calder PC: Immune modulation by parenteral lipid emulsion, Am J Clin Nutr 85:1171, 2007. 22. Sala-Vila A, Barbosa VM, Calder PC: Olive oil in parenteral nutrition, Curr Opin Clin Nutr Metab Care 10:165, 2007. 23. Gajanayake I, Wylie CE, Chan DL: Clinical experience using a lipid-free, ready-made parenteral nutrition solution in dogs: 70 cases (2006-2012), J Vet Emerg Crit Care 23:305, 2013. 24. Olan NV, Prittie J: Retrospective evaluation of ProcalAmine administration in a population of hospitalized ICU dogs: 36 cases (2010-2013), J Vet Emerg Crit Care 25:405, 2014. 25. Lippert AC, Fulton RB, Parr AM: A retrospective study of the use of total parenteral nutrition in dogs and cats, J Vet Intern Med 7:52, 1993. 26. Reuter JD, Marks SL, Rogers QR, et al: Use of total parenteral nutrition in dogs: 209 cases (1988-1995), J Vet Emerg Crit Care 8:201-213, 1998. 27. Chan DL, Freeman LM, Labato MA, et al: Retrospective evaluation of partial parenteral nutrition in dogs and cats, J Vet Intern Med 16:440, 2002. 28. Pyle SC, Marks SL, Kass PH, et al: Evaluation of complication and prognostic factors associated with administration of parenteral nutrition in cats: 75 cases (1994-2001), J Am Vet Med Assoc 225:242, 2004. 29. Crabb SE, Chan DL, Freeman LM, et al: Retrospective evaluation of total parenteral nutrition in cats: 40 cases (1991-2003), J Vet Emerg Crit Care 16:S21, 2006.

PART XIV  Trauma

128 Traumatic Brain Injury Rebecca S. Syring, DVM, DACVECC, Daniel J. Fletcher, PhD, DVM, DACVECC

KEY POINTS • Identification and management of extracranial disorders, such as systemic hypotension, hypoxemia, and hypoventilation, should be the first priority when treating patients with acute traumatic brain injury (TBI). • Mannitol is effective in treating intracranial hypertension, but it can compromise cerebral perfusion if its osmotic diuretic effects are not ameliorated rapidly with intravascular volume replacement.

• Hypertonic saline (7% to 8%) is effective in treating intracranial hypertension and is less likely to lead to hypovolemia and decreased cerebral perfusion. • Corticosteroids are not recommended for the treatment of TBI. • Prognosis varies, but even patients with severe neurologic deficits can recover with aggressive supportive care.

INCIDENCE AND PREVALENCE OF HEAD INJURY

PATHOPHYSIOLOGY

Traumatic brain injury (TBI) is common in dogs and cats, with motor vehicle accidents, animal interactions, and unknown etiologies being the most common causes seen in a multicenter study of 1099 dogs and 191 cats.1 In that study, 26% of dogs and 42% of cats had evidence of head injury on physical examination. Other common causes of head injury in dogs and cats include falls from heights, blunt trauma, gunshot wounds, and other malicious human activity.2 The overall prevalence and incidence of head injury in veterinary medicine have not been well studied, but a retrospective study from a large, urban veterinary hospital reported an average of 145 cases of confirmed TBI per year from 1997 to 1999.3

The underlying injuries that result from head trauma can be separated into two categories: primary injury and secondary injury. Primary injury occurs as an immediate result of the traumatic event. Secondary injury occurs during the hours to days after trauma and is caused by a complex series of biochemical events, including release of inflammatory mediators and excitatory neurotransmitters, and changes in cellular membrane permeability.

GENERAL APPROACH TO THE PATIENT WITH A HEAD INJURY When treating a patient with an acute head injury, both extracranial and intracranial priorities must be considered. Identification of lifethreatening extracranial injuries such as hemorrhage, penetrating thoracic or abdominal wounds, airway obstruction, and compromised oxygenation, ventilation, or volume status is of paramount importance. Once life-threatening extracranial factors have been addressed, intracranial priorities should include maintenance of adequate cerebral perfusion pressure (CPP), ensuring adequate oxygen delivery to the brain, and treatment of acute intracranial hypertension (see Chapter 85, Intracranial Hypertension), as well as continued monitoring of neurologic status (see Chapter 83, Neurologic Evaluation of the ICU Patient).

Primary Injury The least severe primary brain injury is concussion, characterized by a brief loss of consciousness. Concussion is not associated with an underlying histopathologic lesion.4 Brain contusion consists of parenchymal hemorrhage and edema and clinical signs can range from mild to severe. Contusions can occur in the brain directly under the site of impact (“coup” lesions), in the opposite hemisphere (“contrecoup” lesions), or both, as a result of displacement of the brain within the skull. Although mild contusions can be difficult to differentiate from a concussion, unconsciousness for more than several minutes is most consistent with contusion.2 Laceration is the most severe type of primary brain injury and is characterized by physical disruption of the brain parenchyma. Axial hematomas within the brain parenchyma and extraaxial hematomas in the subarachnoid, subdural, and epidural spaces can occur, causing compression of the brain and leading to severe localizing signs or diffuse neurologic dysfunction.5 The older literature suggests that extraaxial hemorrhage is rare in dogs and cats after head injury; however, there is mounting evidence that this type of hemorrhage occurs in up

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PART XIV  Trauma

BOX 128.1  Most Common Factors Leading

to Secondary Brain Injury

• Excitotoxicity • Ischemia • Inflammation • ATP depletion • Production of reactive oxygen species • Accumulation of intracellular sodium and calcium • Nitric oxide accumulation • Cerebral lactic acidosis

to 10% of animals with mild head injury and more than 80% of dogs and cats with severe head injury.5,6

Secondary Injury TBI triggers a series of biochemical events that ultimately result in neuronal cell death. Box 128.1 provides a list of the most common types of secondary injury. These secondary injuries are caused by a combination of intracranial and systemic insults that occur in both independent and dependent ways. Systemic insults that contribute to secondary brain injury include hypotension, hypoxemia, systemic inflammation, hyperglycemia, hypoglycemia, hypercapnia, hypocapnia, hyperthermia, electrolyte imbalances, and acid-base disturbances. Intracranial insults include increased intracranial pressure (ICP), compromise of the blood–brain barrier, mass lesions, cerebral edema, infection, vasospasm, and seizures. All these factors ultimately lead to neuronal cell death.7 Immediately after brain injury there is massive release of excitatory neurotransmitters that causes influx of sodium and calcium into neurons, resulting in depolarization and further release of excitatory neurotransmitters. Increased influx of calcium overwhelms mechanisms for removal, causing severe intracellular damage and ultimately neuronal cell death.8 Excessive metabolic activity also results in depletion of ATP stores in the brain. Several factors favor the production of reactive oxygen species after TBI, including hypoperfusion and local tissue acidosis. Hemorrhage provides a source of iron, which favors the production of hydroxyl radicals. Catecholamines may also contribute to the production of free radicals by direct and indirect mechanisms. These reactive oxygen species then oxidize lipids, proteins, and DNA, resulting in further destruction of neurons. Because the brain provides a lipid-rich environment, it is particularly susceptible to oxidative injury. Nitric oxide has been associated with perpetuation of secondary brain injury after trauma, most likely because of its vasodilatory effects and its participation in free radical reactions, but the exact mechanism is not well understood.8 TBI is associated with the production of inflammatory mediators.9 These mediators perpetuate secondary brain injury via a number of mechanisms, including inducing nitric oxide production, triggering influx of inflammatory cells, activating the arachidonic acid and coagulation cascades, and disrupting the blood–brain barrier. Because studies have shown both neuroprotective and neurotoxic effects of inflammation, research is focusing on the development of targeted antiinflammatory agents that preferentially affect the more acute, destructive inflammatory processes.9 Primary and secondary intracranial injuries, in combination with systemic effects of the trauma, ultimately result in worsening of cerebral injury as a result of a compromised CPP, the force driving blood into the calvarium and providing the brain with essential oxygen and nutrients. CPP is defined as the difference between mean arterial blood pressure (MAP) and ICP.

Blood flow to the brain per unit time, or cerebral blood flow (CBF), is a function of CPP and cerebrovascular resistance. The normal brain is capable of maintaining a constant CBF over a wide range of MAP (50 to 150 mm Hg) via autoregulatory mechanisms. However, the traumatized brain often loses much of this autoregulatory capacity, making it susceptible to ischemic injury with even small decreases in MAP. The following equation summarizes the Monro-Kellie doctrine, developed in the early 19th century to describe intracranial dynamics: Vint racranial  Vbrain  VCSF  Vblood  Vmasslesion where V 5 volume. Sudden increases in any of these volumes as a result of primary and secondary brain injuries can lead to dramatic increases in ICP. Initially, increases in ICP will trigger Cushing’s reflex, or central nervous system (CNS) ischemic response, a characteristic rise in MAP, and reflex decrease in heart rate (see Chapter 85, Intracranial Hypertension). The CNS ischemic response in a patient with head trauma is a sign of a potentially life-threatening increase in ICP and should be treated promptly.

NEUROLOGIC ASSESSMENT Initial neurologic examination should focus on the level of consciousness, posture, and pupil size and response to light (Table 128.1). A more detailed neurologic examination can be performed once stabilizing therapy has been instituted (Chapter 83). Based on findings from this examination, a numeric score can be assigned to grade the severity of injury using the modified Glasgow Coma Scale, a system developed for animals with head injuries10. The initial neurologic examination should be interpreted in light of the cardiovascular and respiratory system because shock can have a significant effect on neurologic status, reducing the patient’s level of consciousness and pupillary responses.

DIAGNOSTIC TESTS AND MONITORING Because of the likelihood of multisystemic injury associated with head trauma, initial diagnostic tests and patient monitoring should focus upon a global assessment of patient stability. Emergency blood screening should consist of packed cell volume and total solids determination to assess for hemorrhage, blood glucose to assess the severity of injury,3 and a blood gas (venous or arterial) to assess ventilation, perfusion, and acid-base status. When available, electrolyte, lactate,

TABLE 128.1  Interpretation of Pupil Size

and Pupillary Light Response in Head Trauma Pupil Size

Response to Light

Level of Lesion

Prognosis

Midposition

Normal

—

Good

Bilateral miosis

Poor to none

Cannot localize

Variable

Unilateral mydriasis

Poor to none

Cranial nerve III

Guarded to poor

Unilateral mydriasis and ventrolateral strabismus

Poor to none

Midbrain

Guarded to poor

Midposition

None

Pons, medulla

Poor to grave

Bilateral mydriasis

Poor to none

—

Poor to grave

CHAPTER 128  Traumatic Brain Injury renal values, and markers of hepatic damage should also be evaluated at the onset of treatment. Serial monitoring of these values is essential because dramatic changes can occur with therapy. Jugular venipuncture should be avoided because occlusion of the jugular vein can result in marked increases in ICP as a result of decreased venous outflow from the brain. Diligent monitoring of the cardiovascular and respiratory systems is imperative to minimize the risk of secondary brain injury. With each episode of hypoxemia or hypotension, the prognosis for neurologic recovery dramatically decreases in human patients with TBI.11 Basic monitoring of the cardiovascular system focuses on maintenance of adequate tissue perfusion (pink mucous membranes, capillary refill time of 1 to 2 seconds, good peripheral pulse quality, and a normal heart rate). In addition, systemic blood pressure should be monitored routinely. MAP should be maintained at or above 80 mm Hg in order to maintain CPP. Blood pressure as measured with the Doppler technique should be maintained above 100 mm Hg. Heart rate should be assessed when hypertension (MAP .120 mm Hg or systolic .140 mm Hg) is present. If evidence of the CNS ischemic response is present, therapy directed toward lowering ICP should be instituted. Alternatively, hypertension associated with tachycardia suggests pain or anxiety, which should be treated as indicated. Monitoring of the respiratory system focuses on maintenance of oxygenation and ventilation. Oxygenation can be assessed via pulse oximetry, with a goal of maintaining saturation above 94%. When arterial sampling is possible, oxygen tension should be maintained above 80 mm Hg. If oxygenation cannot be monitored, oxygen supplementation should be provided. Failure to maintain oxygenation above these levels may warrant intubation and positive pressure ventilation (see Chapters 32–33 on Mechanical Ventilation). Ventilation can be assessed by blood gas analysis or end-tidal capnometry (see Chapter 190, Capnography). Although arterial blood gas sampling is the gold standard for assessing carbon dioxide tension, a venous blood gas can be substituted if tissue perfusion is normal. Venous carbon dioxide concentrations will exceed arterial by 2 to 5 mm Hg; however, this difference is exacerbated with poor tissue perfusion. End-tidal capnometry tends to underestimate arterial carbon dioxide tension by 5 mm Hg, and changes in cardiac output can significantly alter the value obtained. Radiographs of the skull in patients that have sustained head trauma are an insensitive diagnostic tool and rarely provide valuable information. Computed tomography (CT) is the preferred imaging method. CT scans are superior to magnetic resonance imaging (MRI) for assessing bone and areas of acute hemorrhage or edema. As the time from injury increases, or when subtle neurologic deficits are present, MRI becomes a more useful tool.12 Advanced imaging provides information about mass lesions (epidural, subdural, or intraparenchymal hemorrhage) or depressed skull fractures that may require surgical intervention. Such studies should be considered in patients with moderate to severe neurologic abnormalities on presentation, lateralizing signs, failure to improve significantly within the first few days, or those with an acute deterioration in neurologic status.

TREATMENT When formulating a treatment plan for a patient with TBI, both intracranial and extracranial concerns must be addressed. Extracranial priorities include ventilation, oxygenation, and maintenance of normal blood pressure, and intracranial priorities include treatment of intracranial hypertension and control of cerebral metabolic rate.

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Extracranial Therapy The first priority in treating a patient with head trauma is extracranial stabilization. As with any severely injured patient, the basics of airway, breathing, and circulation should be evaluated and addressed if necessary. Patency of the airway should be assessed as soon as possible and treated with endotracheal intubation or emergency tracheostomy, if indicated. The pharynx and larynx should be inspected visually and suctioned as needed to maintain airway patency. Hypoxia is also common, and supplemental oxygen is indicated in the initial treatment of all patients with significant head injury. Increases in the blood CO2 concentration can lead to cerebral vasodilation and increased intracranial blood volume, worsening ICP (see Secondary Injury section). Conversely, hypocapnia caused by hyperventilation can lead to cerebral vasoconstriction, decreasing CBF and leading to cerebral ischemia. Therefore, CO2 should be maintained at the low end of the normal range in patients with head trauma (e.g., venous CO2 40 to 45 mm Hg, arterial CO2 35 to 40 mm Hg).13 In some patients this will require mechanical ventilation (see Chapters 32–33, Mechanical Ventilation-Core Concepts and Mechanical Ventilation- Advanced Concepts, respectively). Patients with head trauma commonly present in hypovolemic shock, and volume resuscitation goals should be aggressive (MAP of 80 to 100 mm Hg; see Chapter 68, Shock Fluid Therapy). For patients without electrolyte disturbances, normal saline (0.9%) is the best initial choice for fluid resuscitation because it contains the smallest amount of free water (sodium concentration 154 mEq/L) of the isotonic fluids and is therefore least likely to contribute to cerebral edema. Synthetic colloid resuscitation is controversial but could be of benefit (see Chapter 66, Colloid Solutions). For hydrated patients with evidence of hypovolemia and increased ICP, a hyperosmotic (hypertonic saline) solution 6 a colloid may be beneficial (see Intracranial Therapy later in this chapter and Table 128.2). Patients that do not respond to volume resuscitation require vasopressor support (see Chapters 147 and 148, Catecholamines and Vasopressin, respectively).

Intracranial Therapy Hyperosmotic Agents Mannitol has been shown to decrease ICP, increase CPP and CBF, and have a beneficial effect on neurologic outcome in patients with head injury.14 Mannitol may also possess free radical scavenging properties. Its positive effects can be seen clinically within minutes of administration, most likely a result of its rheologic its effects (decreased blood viscosity) causing an increase in CBF and cerebral oxygen delivery. Within 15 to 30 minutes, its osmotic effects predominate, drawing water out of the brain parenchyma (primarily normal tissue) and into the intravascular space. These effects can last from 1.5 to 6 hours. In humans, mannitol may induce acute renal failure if serum osmolarity exceeds 320 mOsm/L, suggesting that serial measurement of serum osmolality may be useful in patients receiving repeated doses.15 Mannitol may cause increased permeability of the blood–brain barrier, allowing it to leak into the brain parenchyma where it can exacerbate edema. Because this effect is most pronounced when mannitol remains in the circulation for long periods, the drug should be administered as repeated boluses rather than as a constant rate infusion.14 Mannitol boluses of 0.5 to 1.5 g/kg have been recommended for the treatment of increased ICP in dogs and cats.16 Treatment must be followed with isotonic crystalloid solutions, to maintain intravascular volume. Hypertonic saline is an alternative hyperosmotic solution that may have advantages over mannitol in some patients with head injury. Because sodium does not freely cross the blood–brain barrier, hypertonic saline has similar rheologic and osmotic effects to mannitol. In addition, it improves hemodynamic status and has beneficial vasoregulatory

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PART XIV  Trauma

TABLE 128.2  Drugs, Fluids, and Dosages for the Treatment of Patients with Head Trauma Indication

Drug or Fluid

Dosage

Notes

Any patient with evidence of head trauma and hypotension

Isotonic crystalloid solution (0.9% saline preferred)

Administer boluses of one-fourth to one-third of the shock dose (shock dose 90 ml/kg for dogs, 50 ml/kg for cats)

May repeat as needed Consider colloid boluses if no response after 2 to 3 crystalloid boluses

Increased ICP in normotensive or hypertensive patients

Mannitol 25%

0.5 to 1.0 g/kg IV over 15 minutes May repeat

Use filter during administration; can lead to severe dehydration; follow with isotonic crystalloids or synthetic colloids to prevent dehydration and hypovolemia Closely monitor intake and output

Increased ICP in hypovolemic or hypotensive patients

HTS (7%)a plus hydroxyethyl starch

3 to 5 ml/kg IV over 15 minutes May repeat

Do not use in hyponatremic patients Monitor serum sodium levels

Increased ICP in normotensive, hypertensive, or hypotensive patients

HTS (7% to 7.8%)b

3 to 5 ml/kg IV over 15 minutes May repeat

Do not use in hyponatremic patients Monitor serum sodium levels

Seizures

Diazepam

0.5 mg/kg IV May repeat Consider CRI 0.2–1.0 mg/kg/hr if refractory

Monitor ventilation, may lead to profound sedation and hypoventilation Protect from light

Levetiracetam

20 mg/kg IV

May repeat as needed; very low toxicity potential Minimal sedation or ventilatory side effects

CRI, constant rate infusion; HTS, hypertonic saline; ICP, intracranial pressure. a If using 23.4% HTS, dilute 1 part HTS with 2 parts sterile water. b If using 23.4% HTS, dilute 1 part HTS with 2 parts hydroxyethyl starch. If using 7% to 7.5% HTS, administer separate doses of HTS and colloid (3 to 5 ml/kg HTS, 2 to 3 ml/kg artificial colloid).

and immunomodulatory effects.17 Because sodium is redistributed within the body and reabsorbed in the kidneys, hypotension is a less likely sequela than with mannitol, making it a better choice for patients with increased ICP and systemic hypotension. Hypertonic saline can be administered with a colloid in such cases to allow for a more prolonged volume expansion effect (see Table 128.2 and Chapter 68, Shock Fluid Therapy).

Decreasing Cerebral Blood Volume

Corticosteroids are potent antiinflammatory agents and have historically been used extensively in human and veterinary medicine to treat patients that have sustained head trauma. A clinical trial evaluating more than 10,000 human adults with head injury showed that corticosteroid treatment was associated with worse outcomes at 2 weeks and 6 months after injury.18,19 The Brain Trauma Foundation recommends against corticosteroid administration in patients with TBI.13

Techniques to decrease cerebral blood volume (CBV) have been proposed as methods for lowering increased ICP. Elevation of the head by 15 to 30 degrees reduces CBV by increasing venous drainage, decreasing ICP, and increasing CPP without deleterious changes in cerebral oxygenation.21 A slant board should be used instead of pillows or towels to prevent occlusion of the jugular veins by bending of the neck. Higher elevations of the head may cause a detrimental decrease in CPP. Prevention of hypoventilation, as described earlier, can reduce cerebral vasodilation and decrease CBV; the goal should be normocapnia (arterial carbon dioxide of 35 to 40 mm Hg). In animals with acute intracranial hypertension, short-term hyperventilation to an arterial carbon dioxide of 25 to 35 mm Hg may be used to reduce CBV and ICP, but long-term hyperventilation is not recommended based on evidence that the decrease in CBF leads to cerebral ischemia and worsens outcome.14

Furosemide

Seizure Treatment/Prophylaxis

Furosemide has been used in patients with head trauma either as a sole agent to reduce cerebral edema or in combination with mannitol to decrease the initial increase in intravascular volume and hydrostatic pressure associated with the drug. However, the use of this drug as a sole agent in patients with head trauma has been called into question because of the potential for intravascular volume depletion and systemic hypotension, leading to decreased CPP.20 The Brain Trauma Foundation guidelines do not recommend the administration of furosemide in combination with mannitol.14 Therefore it should be reserved for those patients in whom it is indicated for reasons other than cerebral edema, such as those with pulmonary edema or oligoanuric renal failure.

Post-TBI seizures are common in people, occurring within 3 years in 4.4% of patients with mild TBI, 7.6% of patients with moderate TBI, and 13.6% of patients with severe TBI as shown in one recent study.22 Recent veterinary studies have documented a similar phenomenon, with seizure rates of 6.8% in dogs and 0% in cats (although the 95% confidence interval was 0% to 5.6%).23,24 Unfortunately, prophylactic anticonvulsant therapy has not been shown to reduce development of delayed seizures after TBI in people.25 However, aggressive treatment of seizures while animals are hospitalized is recommended. Suggested anticonvulsant drugs and doses are listed in Table 128.2 (further details can be found in Chapter 163, Anticonvulsants).

Corticosteroids

CHAPTER 128  Traumatic Brain Injury

Decreasing Cerebral Metabolic Rate Increased cerebral metabolic rate because of excitotoxicity and inflammation after head injury can lead to cerebral ischemia and cellular swelling, thus increasing ICP. Interventions that decrease cerebral metabolic rate may lessen secondary brain injury. Although rarely used in veterinary medicine, induction of a barbiturate coma and therapeutic hypothermia have been used in experimental studies and clinical trials in humans and can be effective in decreasing ICP and improving outcome in patients with refractory intracranial hypertension.26 There is a single case report in the veterinary literature of successful use of therapeutic hypothermia to treat refractory seizures in a dog after TBI.27 The Brain Trauma Foundation states that there is insufficient evidence to publish treatment standards on the use of barbiturates, but this therapy may be considered in patients with elevated ICP that is refractory to medical and surgical therapy.14 A recent systematic review concluded that mild to moderate therapeutic hypothermia for 48 hours after injury is beneficial in human patients with severe TBI;28 further study evaluating the efficacy and practicality of these measures in veterinary medicine is needed.

PROGNOSIS The prognosis is difficult to predict after TBI. Although the initial neurologic status may be helpful in predicting outcome, reassessment after stabilizing therapy is recommended because the level of consciousness may improve once tissue perfusion has been corrected. Pupillary dilation, loss of pupillary light responses, and deterioration in the level of consciousness during therapy are poor prognostic indicators (see Table 128.1). It is likely that younger animals, particularly kittens, can make remarkable recoveries despite severe dysfunction immediately after trauma, although definitive research is lacking. Owners should be aware that animals that survive severe TBI may have persistent neurologic deficits for an indefinite period. These animals can also develop delayed seizure disorders. The Small Animal Coma Scale was developed to quantitatively assess the functional impact of brain injury. This scale assesses three major categories: motor activity, level of consciousness, and brainstem reflexes. Although this scale has not been validated prospectively in animals, it has been shown retrospectively to correlate with 48-hour outcome in dogs with head trauma.6 This may be most useful when evaluated serially in patients to determine if there has been improvement or deterioration after treatment. In human medicine, hyperglycemia at admission and persistence of hyperglycemia have been associated with worsened mortality and outcome.29 In a meta-analysis of the utility of admission laboratory parameters as prognostic indicators for people with TBI, increasing glucose concentrations and decreasing hemoglobin concentrations were the strongest with poor neurologic outcome.30 Hyperglycemia has been associated with more severe injury in head-injured veterinary patients3 but has not been validated as an independent predictor of outcome.

REFERENCES 1. Kolata RJ: Trauma in dogs and cats: an overview, Vet Clin North Am Small Anim Pract 10(3):515, 1980. 2. Shores A: Craniocerebral trauma. In Kirk RW, editor: Current veterinary therapy X, Philadelphia, 1989, WB Saunders, pp 847-854. 3. Syring RS, Otto CM, Drobatz KJ: Hyperglycemia in dogs and cats with head trauma: 122 cases (1997-1999), J Am Vet Med Assoc 218(7):1124, 2001.

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4. Dewey C, Budsberg S, Oliver J: Principles of head trauma management in dogs and cats. Part II, Compend Contin Educ Pract Vet 15(2):177, 1993. 5. Dewey C, Downs M, Aron D, et al: Acute traumatic intracranial haemorrhage in dogs and cats, Vet Comp Ortho Trauma 6:153, 1993. 6. Platt SR, Radaelli ST, McDonnell JJ: Computed tomography after mild head trauma in dogs, Vet Rec 151(8):243, 2002. 7. Chesnut RM: The management of severe traumatic brain injury, Emerg Med Clin North Am 15(3):581, 1997. 8. Zink BJ: Traumatic brain injury, Emerg Med Clin North Am 14(1):115, 1996. 9. Dietrich WD, Chatzipanteli K, Vitarbo E, et al: The role of inflammatory processes in the pathophysiology and treatment of brain and spinal cord trauma, Acta Neurochir Suppl 89:69, 2004. 10. Platt SR, Radaelli ST, McDonnell JJ: The prognostic value of the modified Glasgow Coma Scale in head trauma in dogs, J Vet Intern Med 15:581, 2001 11. Chesnut RM, Marshall LF, Klauber MR, et al: The role of secondary brain injury in determining outcome from severe head injury, J Trauma 34(2):216, 1993. 12. Lee B, Newberg A: Neuroimaging in traumatic brain imaging, NeuroRx 2(2):372, 2005. 13. Winter CD, Adamides AA, Lewis PM, et al: A review of the current management of severe traumatic brain injury, Surgeon 3(5):329, 2005. 14. Brain Trauma Foundation: Management and prognosis of severe traumatic brain injury, New York, 2000, Brain Trauma Foundation. 15. Dorman HR, Sondheimer JH, Cadnapaphornchai P: Mannitol-induced acute renal failure, Medicine (Baltimore) 69(3):153, 1990. 16. Plumb D: Plumb’s veterinary drug handbook, ed 7, Oxford, UK, 2011, Wiley-Blackwell. 17. Ware ML, Nemani VM, Meeker M, et al: Effects of 23.4% sodium chloride solution in reducing intracranial pressure in patients with traumatic brain injury: a preliminary study, Neurosurgery 57(4):727; discussion 727-736, 2005. 18. Edwards P, Arango M, Balica L, et al: Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months, Lancet 365(9475):1957, 2005. 19. Roberts I, Yates D, Sandercock P, et al: Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial, Lancet 364(9442):1321, 2005. 20. Chesnut RM, Gautille T, Blunt BA, et al: Neurogenic hypotension in patients with severe head injuries, J Trauma 44(6):958; discussion 963-964, 1998. 21. Ng I, Lim J, Wong HB: Effects of head posture on cerebral hemodynamics: its influences on intracranial pressure, cerebral perfusion pressure, and cerebral oxygenation, Neurosurgery 54(3):593; discussion 598, 2004. 22. Ferguson PL, Smith GM, Wannamaker BB, et al: A population-based study of risk of epilepsy after hospitalization for traumatic brain injury, Epilepsia 51(5):891, 2010. 23. Friedenberg SG, Butler AL, Wei L, et al: Seizures following head trauma in dogs: 259 cases (1999-2009), J Am Vet Med Assoc 241(11):1479, 2012. 24. Grohmann KS, Schmidt MJ, Moritz A, et al: Prevalence of seizures in cats after head trauma, J Am Vet Med Assoc 241(11):1467, 2012. 25. Temkin NR: Preventing and treating posttraumatic seizures: the human experience, Epilepsia 50(Suppl 2):10, 2009. 26. Vincent JL, Berré J: Primer on medical management of severe brain injury, Crit Care Med 33(6):1392, 2005. 27. Hayes GM: Severe seizures associated with traumatic brain injury managed by controlled hypothermia, pharmacologic coma, and mechanical ventilation in a dog, J Vet Emerg Crit Care (San Antonio) 19(6):629, 2009. 28. Fox JL, Vu EN, Doyle-Waters M, et al: Prophylactic hypothermia for traumatic brain injury: a quantitative systematic review, CJEM 12(4):355, 2010. 29. Lam AM, Winn HR, Cullen BF, et al: Hyperglycemia and neurological outcome in patients with head injury, J Neurosurg 75(4):545, 1991. 30. Van Beek JGM, Mushkudiani NA, Steyerberg EW, et al: Prognostic value of admission laboratory parameters in traumatic brain injury: results from the IMPACT study, J Neurotrauma 24(2):315, 2007.

129 Wound Management Caroline K. Garzotto, VMD, DACVS, CCRT

KEY POINTS • Proper wound management is especially important in critically ill patients. • Dogs or cats with severe wounds should always be stabilized and assessed for internal trauma before treating external wounds. • In the first aid care of wounds, it is important to keep the wound moist, clean, and covered until definitive treatment can be performed. • Open wounds containing penetrating foreign bodies or projecting bone should not be manipulated until the patient has been stabilized. • Once the patient is stable, all wounds should be cleaned and debrided, even if the animal will eventually be transferred to a

surgical specialist. Surgical exploration is indicated for all penetrating wounds. • Most wounds can be managed successfully with appropriate technique, close follow-up, cooperative owners, and minimal materials. • Moist wound management techniques and nonadherent dressings are standard of care and wet-to-dry bandaging has minimal current application. • The diagnosis and prognosis for full return to function should be discussed with the owner as soon as possible. In addition, the patient’s predicted treatment regimen (e.g., daily bandage changes) and total cost estimate should also be discussed.

Most traumatic wounds seen in the small animal veterinary patient include bite wounds, abrasions or shearing injuries resulting from motor vehicle trauma, degloving, lacerations, and punctures. Wounds can also result from decubitus ulcers in the recumbent animal secondary to poor nursing care, or wounds can appear in postoperative surgical incisions that dehisce or become infected.

• Grade II: Soft tissue trauma (.1 cm) contiguous with the fracture, often caused by external trauma (e.g., bite wound, low-velocity gunshot injuries) • Grade III: Extensive soft tissue injury, commonly in addition to a high degree of comminution of the bone (e.g., distal extremity shearing wounds, high-velocity gunshot injuries) Although definitive repair of an open fracture should be done as soon as possible for patient comfort, initial care of the soft tissues should not be delayed if a surgeon is not immediately available or if the patient is not stable enough to undergo general anesthesia for several hours. Any exposed bone should be covered with sterile lubricating jelly and a sterile bandage but should not be pushed back below the skin surface because this can cause deeper contamination of the wound or further injury to the tissues. Similar guidelines exist for wounds with penetrating foreign bodies such as arrows, large wooden splinters, or knives. The foreign body may tamponade a large vessel, and removal could lead to severe hemorrhage. These objects should be removed only under controlled surgical conditions. Other wound classifications describe the length of time that the wound has been open because this relates to how quickly bacteria can multiply in a wound. Although this is important to know, it is not as vital as assessing the current status of the patient and wound directly so that appropriate treatment can be initiated.

WOUND HEALING PRINCIPLES Wound Classification Wounds are classified based on degree of contamination as follows:1 • Clean: Atraumatic, surgically created under aseptic conditions (e.g., incisions) • Clean contaminated: Minor break in aseptic surgical technique (e.g., controlled entry into the gastrointestinal [GI], urogenital, or respiratory tracts) in which the contamination is minimal and easily removed • Contaminated: Recent wound related to trauma with bacterial contamination from street, soil, or oral cavity (e.g., shearing or bite wound); can also be a surgical wound with major breaks in asepsis (e.g., spillage from the GI or urogenital tracts) • Dirty or infected: Older wound with exudate or obvious infection (e.g., abscess in a bite wound, puncture wound, or traumatic wound with retained devitalized tissue); contains more than 105 organisms per gram of tissue If a wound is associated with a broken bone, this is called an open fracture, and these can be classified as follows:2 • Grade I: Small break in the skin (,1 cm) caused by the bone penetrating through (inside to out); surrounding soft tissues mild to moderately contused

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Phases of Healing A basic understanding of the phases of wound healing gives the clinician an idea of how long it will take for a wound to improve in appearance and for making wound management decisions. Wound healing can be described in three phases: (1) inflammation and debridement, (2) proliferation, and (3) maturation.3-6 The phases overlap, and the transitions are not visible to the naked eye.

CHAPTER 129  Wound Management The inflammatory phase occurs during the first 5 days after injury. Immediately after trauma there is hemorrhage caused by disruption of blood vessels, and then vasoconstriction and platelet aggregation limit the bleeding. Activated platelets release numerous growth factors that attract other cells required for wound healing, such as neutrophils and monocytes, to the wound initiating the debridement phase. The presence of leukotrienes, prostaglandins, histamine, and kinins causes subsequent vasodilation and increased blood flow and allows for leukocyte migration into the wound bed. Neutrophils are the first to appear in the wound approximately 6 hours after injury. They remove extracellular debris via enzyme release and phagocytosis. Monocytes appear approximately 12 hours after trauma, and they become macrophages within 24 to 48 hours. The monocytes stimulate fibroblastic activity, collagen synthesis, and angiogenesis. Macrophages remove necrotic tissue, bacteria, and foreign material. The proliferative phase begins about 4 days after injury and lasts about 2 to 3 weeks.5 This is the most dramatic healing phase and is characterized by angiogenesis, granulation tissue formation, and epithelialization. Fibroblasts proliferate and start synthesizing collagen, and then capillary beds grow in to form granulation tissue. Granulation tissue provides a surface for epithelialization and is a source of myofibroblasts that play a role in wound contraction. New epithelium is visible 4 to 5 days after injury and occurs faster in a moist environment. Wound contraction is first noticeable by 5 to 9 days after injury and continues into the maturation phase.6 Finally, the maturation phase occurs once adequate collagen deposition is present and is marked by wound contraction and remodeling of the collagen fiber bundles. It starts at about 17 to 20 days after injury and may continue for several years. Healed wounds are never as strong as the normal tissue; a scar is only about 80% as strong as the original tissue.6

INITIAL PATIENT ASSESSMENT Most ICU patients with severe wounds will have been stabilized, had baseline laboratory and imaging testing performed, and may suffer from multiple comorbidities; some of these may require surgical intervention for life-threatening injuries or hemorrhage. Any patient in the ICU should be handled with examination gloves, especially when wounds are present, to protect the clinician and the animal. Repeated evaluation and treatment of these patients should address the cardiac and respiratory system to ensure adequate oxygen delivery to the tissues (see Chapter 1, Evaluation and Triage of the Critically Ill Patient). Wounds that are managed in the critical patient may bleed excessively; direct pressure should always be applied initially. If bleeding cannot be controlled by direct pressure, emergent surgical intervention is often required. Bleeding from appendages can be controlled with tourniquets by using a pneumatic blood pressure cuff inflated to 200 mm Hg for up to 1 hour.7 It is important to remember that bite wounds commonly result from the penetration of both the upper and lower teeth. If bite marks are seen only on one side of the limb or trunk, then the other side should be shaved to search for the corresponding wounds. Wounds should always be kept clean and moist and protected from the hospital environment. A sterile, water-soluble lubricant and saline-soaked sponges can be applied to the wounds initially and then covered with a sterile towel and soft padded bandage if the patient must be moved. It is important that the damaged tissue remain moist because desiccation impairs wound healing.

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create a healthy wound bed with a good blood supply that is free of necrotic tissue and infection in order to promote healing.5 Many wounds require daily debridement and bandage changes, and the clinician should not be discouraged if the wound cannot be closed initially. The following summarizes the steps for daily wound treatment: 1. Assess the wound for infection. 2. Remove necrotic tissue. 3. Determine if the wound can be closed. 4. Protect the wound with a bandage, Elizabethan collar, or both. Initial debridement will require general anesthesia, local anesthesia, or neuroleptanalgesia. For future wound evaluations, the patient may require only sedation or analgesia and restraint (ideally fear free) if surgical debridement is minimal (see PART XV: Anesthesia and Pain Management). Local anesthetics are ideal in unstable patients that cannot tolerate general anesthesia but have significant injuries to the limbs. In these cases, wounds of the pelvic limbs can be debrided using epidural analgesia and thoracic limb wounds can be debrided using a brachial plexus block.8 Sterile lubricating jelly should be applied to the exposed wound to protect it from further contamination and a wide area of fur clipped from the skin around the wound. Gross dirt from the skin around the wound should be cleaned by applying surgical scrub solution (chlorhexidine or povidone-iodine) to unbroken skin, but not to the surface of the wound because these solutions are damaging to exposed tissues. Debridement should be done using aseptic technique: sterile gloves, sterile gown, and cap and mask, and the wound should be draped with sterile towels or water-impermeable drapes. At the time of initial assessment and subsequent bandage changes, necrotic tissue should be excised. All bite wounds should be explored, even if they look minor, because teeth exert a macerating or crushing force that can damage tissues deep below the skin surface (Fig. 129.1). The hole around the bite wound should be enlarged and then tented up to evaluate the subcutaneous tissues. A probe, such as a mosquito or Kelly forceps, can be used to assess for dead space or pockets under the skin that could form hematomas, seromas, and abscesses. Opening the skin between adjacent bite wounds will often reveal hair that has entered the wound and dead tissue from disrupted blood supply that should be removed. Obviously necrotic tissue (black, green, or gray) is removed first. In areas that have ample skin for closure, initial trimming of skin can

DEBRIDEMENT AND LAVAGE Once sedation or anesthesia can be administered safely to patients with severe wounds, assessment and debridement of the wound should be performed. The primary goal in the management of all wounds is to

Fig. 129.1  This 12-year-old Sheltie was bitten on the right hind limb by a Pit Bull and suffered extensive destruction of the skin and muscle on the lateral surface of the limb. (Courtesy O. Morgan.)

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PART XIV  Trauma

BOX 129.1  Materials for Dressing Changes • Clippers, surgical scrub, 18-gauge needles, 35- to 60-ml syringe, sterile lubricating jelly, sterile gauze or lap pads, umbilical tape, sterile impermeable drape material, cast padding, conforming rolled gauze, Vetrap, and/or Elastikon • Manuka honey or silver sulfadiazine; absorbent nonadherent sterile dressing • Isotonic crystalloids such as lactated Ringer’s solution or 0.9% saline • 4-0 to 0 monofilament, absorbable and nonabsorbable suture material • A variety of splints for forelimb and hind limb stabilization

Fig. 129.2  The wound from Fig. 129.1 after initial surgical debridement. Only the necrotic tissues were removed initially. Note the loops of sutures surrounding the wound used for a tie-over dressing.

be done more aggressively. In areas such as the distal limbs, trimming of skin should be done conservatively and questionable tissues given time to “declare” themselves (Fig. 129.2). Bone, tendons, nerves, and vessels are preserved as much as possible unless segments of these vital structures are completely separated from the tissue and obviously nonviable. The wound can be lavaged with a variety of solutions depending on the degree of contamination, but isotonic solutions are the best choice for all. Lactated Ringer’s solution or 0.9% saline are the most commonly used lavage solutions. An in vitro study demonstrated that normal saline and tap water cause mild and severe cytotoxic effects on fibroblasts, respectively, whereas lactated Ringer’s solution did not cause significant fibroblast injury.9 Lavage is performed by flushing with a bulb syringe or a 60-ml syringe with an 18-gauge needle. In order to facilitate refilling, the syringe and needle setup can be connected to a three-way stopcock and an intravenous fluid bag. After debridement and lavage of the wound, if the wound cannot be closed primarily, a moisture retentive dressing (MRD) and absorptive bandage is applied to protect the wound and promote healing by providing a more optimal environment for cells and proteases to function.10 Premature closure of traumatic wounds, such as bite wounds, before the tissues have declared themselves can result in frustration to both an owner and the veterinarian managing these cases due to unreasonable expectations and repeat surgeries.

DRESSING AND BANDAGING Good bandaging practice is essential to maintaining and protecting the wound. Ideally a bandage should cover all open wounds. A bandage consists of three layers: (1) primary, (2) secondary, and (3) tertiary. The necessary supplies are listed in Box 129.1. The primary layer is the dressing applied directly to the wound. This layer determines the purpose of the bandage by whether it is an adherent or nonadherent dressing. This layer may also contain a topical antimicrobial agent. The secondary layer is composed of padded material that aids in absorption of exudates. The tertiary layer is the outermost protective layer that holds the others in place. An adherent dressing is used when the wound is in the debridement phase, providing mechanical debridement. The most common of these

is the wet-to-dry dressing, in which sterile gauze sponges soaked with sterile lactated Ringer’s solution or 0.9% saline are wrung out and applied directly to the surface of the wound, then covered with dry, sterile gauze sponges. The dry sponges soak up moisture from the wet ones, and this wicking action causes necrotic tissue and debris to adhere to the sponges when they are removed. It is often necessary to wet the dressing slightly with sterile lactated Ringer’s solution or 0.9% saline to allow easier removal and to make it less uncomfortable for the patient. During the debridement phase, it is necessary to change the wet-todry dressing and bandage at least once daily. Sometimes it will be necessary to change it up to three times a day initially, depending on how dirty the wound is or if moisture quickly “strikes through” to the outer layer of the bandage. Although adherent dressings are still in common use in veterinary medicine during the debridement phase, they have received criticism because they nonselectively remove both necrotic and healthy tissue alike. Moist wound management principles are now standard of care in veterinary medicine because of improved wound understanding and technologic advances in wound products.10 The idea of moist wound healing was first promoted during the early 1960s after research conducted by Winter first demonstrated the benefit of a moist environment in optimizing wound healing by increasing epithelialization compared with leaving wounds open to air.11 By providing a moist wound environment, the process of autolytic debridement can be more effective, which means that the body’s own phagocytic processes will take care of wound debridement.4,12 Alginates, foams, hydrogels, hydrocolloids, and transparent films are examples of types of nonadherent dressings that can be selected based on their specific benefits to promote moist wound management through all phases of wound healing (Table 129.1). These products are more expensive than traditional gauze, but an overall cost savings can be realized because frequency of bandage changes decreases from several times a day to once every 1 to 3 days and improved wound healing leads to faster healing times.12 The more commonly used nonadherent dressings such as Telfa pads (Kendall, Mansfield, MA) and Adaptic (Johnson & Johnson, New Brunswick, NJ) are most appropriately used once a healthy, pink granulation bed has covered the surface of the wound and it is no longer infected. Once the primary layer is applied, the next layer can be either a soft padded bandage or a tie-over bandage. Soft padded bandages are used to protect soft tissue wounds on the limbs, and a splint can be incorporated between the second and third layers to stabilize distal fractures or ligamentous injuries. The secondary layer is most commonly rolled cotton that is held in place with rolled gauze. A splint if needed is placed over the cotton and under the gauze. The tertiary layer is often Vetrap (3M, St. Paul, MN) or Elastikon (Johnson & Johnson, New Brunswick, NJ) and is placed over the secondary layer but without compression of the bandage or wound.

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TABLE 129.1  Dressings4,12 Type Gauze

Uses Inexpensive, readily available Wet-to-dry nonselective debridement

Contraindications Not appropriate when healthy granulation tissue is present or when trying to get wound to epithelialize

Examples Surgical sponges

Impregnated gauze

Added zinc, iodine, or petrolatum nonadherent and helps prevent desiccation Absorbs bacteria and exudate

Although it increases wound contraction, it can delay epithelialization

Adaptic (J&J)

Polyester film with cotton

Used primarily during epithelialization phase on surgical wounds, wounds with good granulation tissue and with minimal exudate

May promote excessive granulation tissue

Telfa pads (Kendall)

Calcium alginates

Absorbs heavy exudate Pad, ribbon, or fiber forms gel when absorbing exudate Hemostatic, favors epithelialization and granulation

Do not use over exposed tendon, bone, or necrotic tissue

Curasorb (Kendall)

Hydrogels

Absorbs minimal exudate Autolytic debridement Rehydrates to soften dry wounds

Discontinue after healthy granulation tissue is present because it can promote exuberant granulation

Curafil (Kendall) BioDres (DVM Pharmaceuticals) Carravet (Carrington Labs)

Hydrocolloids

Autolytic debridement Increases epithelialization and comfort Promotes granulation

Not for use in exudative or infected wounds Can promote exuberant granulation

DuoDERM (Convatec)

Foams

Absorbent and comfortable Used in deep wounds with minimal exudate Promotes epithelialization and contraction

Reduces granulation May cause maceration if overlapped on skin

Hydrasorb (Kendall) Copa Plus (Kendall) Xtrasorb Foam (Derma Sciences)

Polyurethane films

Occlusive but permeable to air and water vapor, but impermeable to fluid and microorganisms Autolytic debridement Covering for sutured wounds

Because of occlusive, adherent property, may cause bacterial proliferation and tissue maceration. Should be changed every 1-3 days

Tegaderm (3M)

The tie-over bandage is used for wounds on areas of the body that are not amenable to soft padded bandages, such as the flank, perineum, or hip areas.5 Materials include 2-0 to 0 nylon, umbilical tape, gauze, and water-impermeable drape material. Loose suture loops are applied circumferentially around the wound (see Fig. 129.2). The secondary layer consists of several layers of dry gauze squares or laparotomy sponges that are applied for padding and moisture absorption. The tertiary layer is a water-impermeable drape cut to fit the wound, and then all three layers are held in place by the umbilical tape that is looped through the sutures in a shoelace fashion. The bandage should be protected from the patient by judicious use of an Elizabethan collar. If the bandage is on a limb, the foot should be covered with a strong plastic bag taped to the bandage when the patient is taken outside to keep it from getting wet or dirty. The bandage should be changed immediately when it gets wet, dirty, or slips, or when there is strikethrough from the wound.

Exposed Bone Exposed bone is prone to slow healing and must be covered with a granulation bed before skin graft or flap application. Injuries with exposed bone are seen most often with carpal or tarsal shearing injuries caused by motor vehicle trauma. In most cases exposed bone is eventually covered by advancing granulation tissue from surrounding healthy soft tissues when proper moist wound management techniques are applied. Bone perforation can enhance wound healing by encouraging growth of granulation tissue over the exposed bone.5,13 Once the wound has entered the repair phase, a Jacob’s chuck and 0.045- to 0.062-inch

K-wires may be used to perforate the surface of exposed bone through to the medullary cavity. Blood should not be wiped away. A nonadherent dressing with antibiotic ointment should be applied as the primary layer of the bandage. Bandage changes are done at 3- to 5-day intervals. Once a complete layer of granulation tissue is present (approximately 7 to 10 days), a free skin graft is applied, or ongoing wound management is continued until second-intention healing is complete. Negative pressure wound therapy has also been shown to improve coverage of exposed bone in the case of distal extremity shearing wounds in dogs.14

WOUND CLOSURE The decision as to when and how to close a wound depends on the cleanliness and extent of the wound. Clean fresh wounds, small contaminated wounds, or even infected wounds that can be excised completely should be closed primarily. Monofilament absorbable suture should be used in subcutaneous tissue and muscle, and nonabsorbable suture should be used on the skin. Tight sutures and tension on the suture line should be avoided. Closure should be delayed for contaminated wounds or large wounds with questionable viability. Closure can be performed when a healthy granulation bed is present, which occurs during the repair phase of healing. Healthy granulation tissue should be pink, smooth, or slightly bumpy, should cover the entire wound, and should bleed on the cut surface or when an adhered dressing is removed. If in doubt, the wound should be treated as an open infected wound until the granulation bed is more definitively healthy.

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Fig. 129.3  The wound from Fig. 129.2 2 weeks after a caudal superficial epigastric flap was performed. Note the healthy granulation bed in the distal half of the wound. Skin stretchers were applied to allow harvest of the opposite caudal superficial epigastric flap to cover the distal half of the wound. However, by the time the flap surgery was scheduled, the remainder of the wound contracted enough to allow primary closure by trimming the epithelialized skin edges and undermining the skin circumferentially.

Delayed primary closure of a wound is performed 2 to 5 days after the injury. Secondary closure of a wound is defined as closure of a wound 5 or more days after the inciting injury and is usually selected for wounds that were initially classified as dirty (Fig. 129.3).5 Granulation tissue and epithelialized skin edges may need to be excised to allow closure. If the wound is too large to be closed, the clinician should consider a skin graft or flap, or closure by second-intention healing. Second-intention healing occurs over a healthy granulation bed by the processes of wound contraction and epithelialization, which continue until the two epithelialized edges of the wound meet. Second-intention healing, even of very large wounds, can often be successful and does not require anything more than diligent bandaging and wound care.

Drains Drain placement is indicated during wound closure in areas with excessive dead space, areas with potential for fluid accumulation, or infected or contaminated areas (e.g., abscess, bite wound). The drain should exit from the dependent portion of the wound via a separate stab incision, not through the suture line. Ideally the drain should be covered with a bandage to prevent removal by the patient, to further compress dead space, and to keep the area clean. Drains are removed when drainage is clear or minimal (2 to 7 days). There are two types of drains, passive and active. A Penrose drain is the best means of passive gravitational drainage. This type of drain can be secured at the proximal extent of the wound pocket with a simple interrupted suture through the skin that catches the flimsy rubber tubing while it is held in position with a hemostat. A separate opening to secure a Penrose drain proximally should never be made because this allows bacteria to migrate into the wound. The Penrose drain should exit the wound pocket at its most dependent location and be secured with a simple interrupted or cruciate suture to the skin edge of the opening where it exits the wound pocket (Fig. 129.4). There are many types of active or closed-suction drains, which consist of a vacuum-generating reservoir connected to fenestrated tubing. These can be used only in areas that can be closed completely because a vacuum must be created within the wound. There are numerous commercially available closed-suction drains such as the J-VAC (Johnson & Johnson, Arlington, TX) and the Sil-Med vacuum drain

Fig. 129.4  This dog had a skin laceration over its right scapula after a run through the woods. This fresh wound was cleaned and closed primarily. A Penrose drain is seen exiting a wound pocket distal and caudal to the incision. It is secured in place with a tacking suture to the skin edge where it exits distally. Proximally the Penrose is secured also with a tacking suture; however, the drain does not exit the skin.

(Sil-Med Corp., Taunton, MA), which has a grenade-type reservoir. There are also several ways to make closed-suction devices.15 A butterfly catheter and red-top blood collection tube can be used for small spaces. For larger areas of dead space, a drain can be made of intravenous tubing with additional fenestrations cut out of the segment to be placed in the wound using a number 15 scalpel blade. The tubing is then connected to a 60-ml syringe, and the plunger is held open with a needle or pin.

Negative Pressure Wound Therapy Negative pressure wound therapy (NPWT) is the generic term used to describe the application of a vacuum to an open wound to promote and hasten healing by second intention and to prepare wounds for closure with skin flaps or grafts. NPWT is especially useful for wounds that are very large or located in hard to immobilize areas. Vacuumassisted closure (VAC) refers to a commercially available device (V.A.C., Kinect Concepts Inc., San Antonio, TX) that was used in some of the earliest published studies16,17 and is also used in the majority of published controlled clinical trials.18 Commercial units as well as homemade versions of these devices are used in veterinary medicine. The basic materials needed include open-pore polyurethane foam or open-weave gauze sponges for the contact layer, suction tubing, adhesive occlusive film, and a suction device with a canister to hold the evacuated fluid. The contact layer is fitted to the contours of the wound and then sealed with the adhesive occlusive film that overlaps the wound edges by at least 5 cm17 and that must form a leakproof seal to maintain the vacuum. A drainage tube is connected to the foam dressing through an opening in the adhesive film. The drainage tube is then connected to a vacuum source most commonly set at 2125 mm Hg19 (Fig. 129.5). Evidence-based reviews of the human literature looking at mechanisms of action of NPWT agree on the following mechanisms of

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bandaging of skin grafts,25,26 in cases of surgical dehiscence/infection over orthopedic implants, in degloving wounds, in chronic nonhealing wounds, and for postoperative edema and seroma prevention.26 Other uses include in cases of peritonitis, for open management of bite wounds over the thorax, and in compartment syndrome.26 Although there are many applications of NPWT for wounds, it is not proven to be a more effective treatment option in all cases.

ADDITIONAL WOUND MANAGEMENT MODALITIES

Fig. 129.5  This 7-year-old female spayed Boxer developed a large abscess over her right and left dorsal pelvic regions while on chemotherapy (prednisone and vinblastine) 1 month after complete excision of a high-grade mast cell tumor from this area. The wounds were opened, cultured, lavaged, and debrided, and a VAC (as seen in photo) was applied to decrease dead space, improve removal of exudate, and attain healthy granulation tissue. Interestingly, 24 hours after VAC application, swelling and hematoma formation were noted around the dressing. Tests for possible coagulopathy were negative, and biopsies showed no evidence of remaining mast cell disease. Although the VAC did help initially to clean up the wound, it is important to monitor for such complications. (Courtesy T. Hamilton.)

action:18,20 increased vascularization, improved granulation tissue formation, and a reduction in the wound volume/size. Clinical advantages of NPWT include more optimal fixation of skin grafts, better management of highly exudative wounds, and decreased costs because of the need for less frequent bandage changes.18,20,21 Many studies have attempted to prove that NPWT can decrease bacteria and edema in wounds; however, these studies are contradictory.18 A prospective, controlled veterinary study22 found that NPWT in dogs promoted earlier and less exuberant granulation tissue; however, prolonged use led to decreased wound contraction (at .7 days), higher bacterial load (at day 7), and decreased percent epithelialization (at .11 days) compared with a standard absorbent foam wound dressing (Copa Foam Dressing, Kendall Tyco Healthcare, Mansfield, MA). Contraindications for NPWT as reported by the FDA include the following:23 • Necrotic tissue with eschar present • Untreated osteomyelitis • Nonenteric and unexplored fistulas • Malignancy in the wound • Exposed vasculature • Exposed nerves • Exposed anastomotic site • Exposed organs Patients with active bleeding, bleeding disorders, or those that are receiving anticoagulant therapy should not be treated with NPWT. Deaths have been reported with the use of NPWT as a result of bleeding and worsening of wound infections.23 NPWT should only be applied after appropriate debridement to minimize the potential for fatal infections.24 Reports in the veterinary wound literature have described VAC use in distal limb injuries14 to decrease the size of large wounds and bolster

There are many additional strategies to advance wound healing, particularly for the management of difficult, chronic nonhealing wounds. Examples of treatments evaluated and used in veterinary medicine include hyperbaric oxygen therapy and low-level laser-light therapy (LLLT). Hyperbaric oxygen therapy involves placing patients in a chamber that replaces room air with 100% oxygen under pressure. Hyperbaric oxygen therapy has not been well studied in dogs and cats but may promote angiogenesis (which is fostered by the increased oxygen gradient), increase proliferation of fibroblasts, and increase leukocyte oxidative killing of bacteria.12,27 Currently there is limited access to hyperbaric oxygen chambers for dogs and cats, but they may become more commonplace in the future.27 Animals that are most likely to benefit include those with crush injuries, compromised skin grafts, severe burns, and infections with anaerobic organisms. LLLT, or cold laser therapy, is better described by the name photobiomodulation. This technology uses low levels of red and near- infrared light to penetrate tissue and increase ATP production in the mitochondria of chromophores, as well as promote healing via the activation of fibroblasts.28 Initial rodent studies in the 1960s showed that laser light stimulated hair growth and wound healing. LLLT is used routinely in human medicine,28 and more recently in veterinary medicine,29 to reduce inflammation and promote healing of chronic wounds and deeper tissues. Although there appears to be clinical evidence supporting the use of LLLT, good randomized controlled trials are lacking and results are often not repeatable because of differences in laser technology (e.g., LED vs. class 3B vs. class IV lasers) and the need to specify variable parameters, including wavelength, power density, pulse structure, and timing of the applied light. Dosing guidelines for treatments are currently set by the World Association of Laser (Photobiomodulation) Therapy (www.waltza.co.za), which is considered the authoritative body overseeing laser research. Before using one of these devices, the veterinarian must undergo specialized training in order to understand proper use of the equipment, indications, contraindications, and safety concerns. Although there is ongoing research and limited use of these technologies in private and specialty veterinary hospitals, fortunately a majority of wounds will heal uneventfully by following basic wound care principles and techniques.

ANTIMICROBIAL THERAPY The most common bacterial wound pathogens include Gram-positive Staphylococcus spp. and Streptococcus spp. and Gram-negative organisms such as Escherichia coli, Enterococcus, Proteus spp., and Pseudomonas spp.1,4,30,31 When humans (or animals) are bitten by dogs and cats, Pasteurella multocida is a common oral pathogen.30 The most common anaerobic isolates in bite wounds include Bacillus spp., Clostridium spp., and Corynebacterium spp.31 Often Pseudomonas will be an acquired infection on the surface of the granulation bed, noticeable by the wound’s slimy feel and obvious pungent odor. Rarely does this organism cause systemic infection, and thus it does not necessitate systemic antimicrobial therapy.

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TABLE 129.2  Antimicrobial Use

Recommendations in Wound Management Antimicrobial Use Indicated

1,32

Situation Obvious local or systemic signs of infection Wounds older than 6 hours Deep tissue injury involving muscle, fascia, bone, tendon Wounds likely to become infected such as bite wounds, penetrating wounds, and wounds involving body orifices Wounds requiring staged debridement Prophylactic use to prevent contamination of surrounding normal tissues To keep bacterial numbers low when planning a flap or graft Chronic nonhealing wounds with infection verified by culture Immunocompromised patient or one that has other condition that might jeopardize healing (e.g., diabetes)

May not be indicated

Clean wounds Superficial wounds less than 6 hours old A contaminated wound that can be converted easily to a clean wound with primary closure Wounds with a mature, healthy granulation bed

Antimicrobial drug therapy is not an excuse for inappropriate wound care. Long-term antimicrobial treatment without evidence on culture that the antibiotic is effective can result in multidrug-resistant bacteria. Debridement, lavage, and bandaging are the most important parts of wound management, as they promote healing of the tissues and create an environment that negatively affects the ability of bacteria to proliferate. Systemic antimicrobials are indicated for contaminated and infected wounds to help eliminate bacteria and promote healing.32 Some clean, recent wounds, such as sharp lacerations, do not require microbial evaluation,1 and superficial wounds that are easily debrided and closed may require only perioperative antimicrobial use (Table 129.2). If a wound appears infected on presentation, a Gram stain can be performed to determine the predominant bacterial population and guide the initial antimicrobial selection. Culture and susceptibility testing of the wound should be done after initial debridement and lavage. Superficial wounds in systemically stable animals are best treated with a bactericidal antimicrobial that is effective against Gram-positive bacteria, such as cefazolin or cephalexin, pending culture and susceptibility results (see PART XIX: Antimicrobial Therapy). Infected, deeper wounds may require a broader-spectrum antimicrobial such as amoxicillin with a b-lactamase inhibitor such as clavulanic acid. In one study the most commonly cultured bacteria from bite wounds (Staphylococcus, E. coli, Enterococcus spp.) were 100% sensitive to amoxicillin and clavulanic acid.31 Published recommendations for treatment of dog-bite wounds31 suggests that initial antimicrobial coverage for severe bite wounds include intravenous ampicillin and either a fluoroquinolone or aminoglycoside. If the wound becomes infected, re-culturing the wound is recommended because cultures taken during the first surgical debridement are of little value in predicting the organism

involved. These antimicrobial recommendations can also apply to most other types of severe wounds or trauma, resulting in extensive deep tissue disruption, including necrotizing soft tissue infections.33 Initially, empiric treatment is used by choosing antibiotics based on the suspected organism and only changing if necessary based on culture and susceptibility results.1 Wounds can be sampled for repeat culture after 3 to 4 days to determine the effectiveness of antimicrobial therapy. If wound healing is not progressing after the first 2 to 3 days or the animal’s condition is worsening, a change in antimicrobial therapy may be indicated. Once mature granulation tissue has become established, antimicrobial usage is usually unnecessary because this tissue is resistant to infection.5 Topical antimicrobial drugs are often used to decrease bacterial populations on the wound, but they should always be used in conjunction with debridement and lavage. The following medications are best used by spreading a thin layer onto a sterile nonadherent pad that serves as the primary layer of the bandage. Triple antibiotic ointment is more effective for preventing infection than treating it, and it has poor activity against Pseudomonas. Silver sulfadiazine cream has a favorable broad-spectrum bactericidal coverage and is the agent of choice for burn wounds. Silver impregnated dressings (e.g., Acticoat, Smith & Nephew, Andover, MA; Algicell, Derma Sciences, Plainsboro, NJ) have been developed to achieve sustained release of silver into the wound to decrease frequency of dressing changes from daily to every 3 days.12 Honey, in the form of Manuka honey or medicinal honey (Medihoney, Derma Sciences, Princeton, NJ), has antibacterial properties because of its high osmolarity, acidity, and hydrogen peroxide content. The hydrogen peroxide is present in levels that are harmless to healthy tissue. Honey can be used during the earliest phases of healing and also over infected granulation tissue.34 It has been shown to be more effective in some cases than more expensive commercial products, including silver sulfadiazine and conventional dressings (i.e., impregnated gauze, polyurethane films).35,36 Healing properties of honey are varied; honey decreases edema, accelerates sloughing of necrotic tissue, and provides a rich cellular energy source, promoting a healthy granulation bed. Honey is applied to the wound after debridement of necrotic tissue and lavage. Gauze sponges soaked in honey are placed directly on the wound as the primary layer, and then covered with an absorbent second layer to prevent it from leaking through the bandage. Dressings may need to be changed daily depending on strike through and the absorbency of the bandage placed.

PATIENT CARE Patients with extensive trauma and wounds that require daily debridement and bandage care often require intensive care initially. Triple lumen intravenous catheters, continuous electrocardiogram monitoring, urinary catheters, and oxygen therapy may all be important for monitoring and managing these often-critical patients depending on the severity of comorbidities. These patients are at particular risk for weight loss due to decreased appetite or need for fasting prior to sedated procedures. Hypoproteinemia due to poor nutrition and loss through open wounds can occur; proactive supplementation of caloric support is important (see Chapters 126 and 127, Enteral and Parenteral Nutrition, respectively). Pain, stress, and decreased appetite require close monitoring of the gastrointestinal systems. Gastrointestinal protectants, motility agents, and nasogastric tubes allow for management of reflux and aid in feeding these patients and are extremely important to help with patient comfort and healing (see Chapters 153 and 154, Gastrointestinal Protectants and Antiemetics and Prokinetics, respectively). These patients require pain management, and those that

CHAPTER 129  Wound Management are critically ill or severely painful often benefit from multimodal analgesia infusions (see Chapter 134, Analgesia and Constant Rate Infusions). Nonsteroidal antiinflammatory drugs are appropriate for more stable patients once the potential GI and renal side effects are of less concern (see Chapter 158, Nonsteroidal Antiinflammatory Drugs). Reversible and short acting anesthetics such as dexmedetomidine and propofol are useful for sedation during bandage changes. Diligent nursing care involving massage and range of motion of distal limbs, turning patients, and sling walking to improve circulation are helpful to decrease edema development in these often sedentary patients.

COMPLICATIONS The major concern for the clinician managing a patient with severe wounds is poor wound healing. Anemia, severe trauma, or hypovolemia can delay wound healing because of poor oxygen delivery to the wound. Poor perfusion and nutritional status can also have detrimental effects on healing. Serum total protein levels less than 2 g/dl impede wound repair by decreasing fibrous tissue deposition.6 Infection and foreign bodies cause intense inflammatory reactions that interfere with healing. Patients with cancer that are receiving chemotherapy or those who have had radiation therapy to the area of the wound will also be prone to delayed wound healing. Patients with diabetes, uremia, liver disease, or on steroids are susceptible to infection or delayed healing as well. Chronic nonhealing wounds should be biopsied, which could reveal recurrence of neoplasia in wounds from tumor removals or special stains could reveal fungal or mycobacterium that may not be easily cultured. Most wounded patients are dogs; however, cats often present the more challenging cases. Axillary wounds in cats can be particularly difficult to manage. An experimental study found that cats have significant differences in wound healing compared with dogs.37 Sutured wounds in cats are only half as strong as those in dogs by day 7, and cats demonstrate significantly less granulation tissue production than dogs in wounds that were evaluated for secondintention healing. Lack of bleeding or negative sensation in a limb indicates a poor prognosis and may necessitate amputation. These changes may not be predictable at the time of initial evaluation. As with any surgery other complications can include infection, dehiscence, and scarring. Contracture of limb wounds that are allowed to close by second intention can result in decreased mobility and may require referral to a specialized surgeon for skin reconstruction.

PROGNOSIS Owners should be advised as early as possible of the prognosis, extent of care involved, and cost. Prognosis depends on the extent of injury and the location. Some wounds may be irreparable, leading to the loss of a limb. Cost depends on the extent of the injury and increases with multiple injuries and if fracture repair or abdominal or thoracic exploration is required. Length of hospitalization depends on the extent of debilitation, whether intravenous fluids or a feeding tube is required, and whether daily bandage changes and wound debridement are needed. Costs of $5000 or more are common if injuries require daily bandage changes and wound debridement, and expenses can reach $15,000 or more if fracture repair or additional surgery is required. In some cases, patients can be treated on an outpatient basis with bandage changes every 2 to 7 days if using an appropriate MRD and bandage. Complicated wound healing can take several months and require multiple surgical procedures.

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REFERENCES 1. Brown DC: Wound infections and antimicrobial use. In Tobias KM, Johnston SA, editors: Veterinary surgery: small animal, St. Louis, 2012, Saunders, pp 135–139. 2. Millard RP, Towle HA: Open fractures. In Tobias KM, Johnston SA, editors: Veterinary surgery: small animal, St. Louis, 2012, Saunders, pp 572-575. 3. Cornell K: Wound healing. In Tobias KM, Johnston SA, editors: Veterinary surgery: small animal, St. Louis, 2012, Saunders, pp 125–134. 4. Fossum TW, Hedlund CS, Hulse DA, et al: Surgery of the integumentary system. In Fossum TW, editor: Small animal surgery, ed 3, St. Louis, 2007, Mosby, pp 251-253. 5. Pavletic MM: Basic principles of wound healing. In Atlas of small animal wound management and reconstructive surgery, ed 3, Ames, IA, 2010, Wiley-Blackwell, pp 33-52. 6. Hosgood G: Wound repair and specific tissue response to injury. In Slatter DH, editor: Textbook of small animal surgery, ed 3, St. Louis, 2003, Saunders, pp 66-86. 7. Crowe DT: Emergency care of wounds, DVM Best Practices Feb:11, 2002. 8. Muir WM, Hubbell JAE, Skarda RT, et al: Handbook of veterinary anesthesia, ed 3, St. Louis, 2000, Mosby. 9. Buffa EA, Lubbe AM, Verstraete FJM et al: The effects of wound lavage solutions on canine fibroblasts: an in vitro study, Vet Surg 26:460, 1997. 10. Campbell BG: The new standard of care: moist wound healing, Today’s Veterinary Practice, July/August 2015, pp 32-40. 11. Winter GD: Formation of the scab and the rate of epithelisation of superficial wounds in the skin of the young domestic pig, 1962, Nature 4:366, 1995. 12. Murphy PS, Evans GRD: Advances in wound healing: a review of current wound healing products, Plast Surg Int 2012:190436, 2012. 13. Clark GN: Bone perforation to enhance wound healing over exposed bone in dogs with shearing injuries, J Am Anim Hosp Assoc 37:215, 2001. 14. Ben-Amotz R, Lanz OI, Miller JM, et al: The use of vacuum-assisted closure therapy for the treatment of distal extremity wounds in 15 dogs, Vet Surg 36:684, 2007. 15. Davidson DB: Managing bite wounds in dogs and cats. Part II, Compend Contin Educ Pract Vet 20:974, 1998. 16. Morykwas MJ, Argenta LC, Shelton-Brown EI, et al: Vacuum-assisted closure: a new method for wound control and treatment: animal studies and basic foundation, Ann Plast Surg 38:553, 1997. 17. Argenta LC, Morykwas MJ: Vacuum-assisted closure: a new method for wound control and treatment: clinical experience, Ann Plast Surg 38:563, 1997. 18. Mouës CM, Heule F, Hovius SER: A review of topical negative pressure therapy in wound healing: sufficient evidence? Am J Surg 201:544, 2011. 19. Morykwas MJ, Faler BJ, Pearce DJ, et al: Effects of varying levels of subatmospheric pressure on the rate of granulation tissue formation in experimental wounds in swine, Ann Plast Surg 47:547, 2001. 20. Hunter JE, Teot L, Horch R, et al: Evidence-based medicine: vacuum-assisted closure in wound care management, Int Wound J 4:256, 2007. 21. Schneider AM, Morykwas MH, Argenta LC: A new and reliable method of securing skin graft to the difficult recipient bed, Plast Reconstr Surg 102:1195, 1998. 22. Demaria M, Stanley BJ, Hauptman JG, et al: Effects of negative pressure wound therapy on healing of open wounds in dogs, Vet Surg 40:658, 2011. 23. Division of Small Manufacturers, International and Consumer Assistance (DSMICA), U.S. Food and Drug Administration: Update on serious complications associated with negative pressure wound therapy systems, Silver Spring, MD, February 24, 2011, U.S. Dept. of Health and Human Services. Available at: http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ ucm244211.htm. 24. Orgill DP, Bayer LR: Update on negative-pressure wound therapy, Plast Reconstr Surg 127 (Suppl 1):105S, 2011. 25. Guille AE, Tseng LW, Orsher RJ: Use of vacuum-assisted closure for the management of a large skin wound in a cat, J Am Vet Med Assoc 230:1669, 2007. 26. Kirby K, Wheeler JL, Farese JP, et al: Vacuum-assisted wound closure: clinical applications, Compend Contin Educ Vet 32:E1, 2010.

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27. Braswell C, Crowe DT: Hyperbaric oxygen therapy, Compend Contin Educ Vet, 34:E1, 2012. 28. Chung H, Dai T, Sharma SK, et al: The nuts and bolts of low-level laser (light) therapy, Ann Biomed Eng 40:516, 2012. doi:10.1007/s10439-0110454-7. 29. Lucroy MD, Edwards BJ, Madewell BR: Low-intensity laser light-induced closure of a chronic wound in a dog, Vet Surg 28:292, 1999. 30. Davidson DB: Managing bite wounds in dogs and cats. Part I, Compend Contin Educ Pract Vet 20:811, 1998. 31. Griffin GM, Holt DE: Dog-bite wounds: bacteriology and treatment outcome in 37 cases, J Am Anim Hosp Assoc 37:453, 2001. 32. Walshaw R: Current concepts in antimicrobial therapy in the wounded patient, Proceedings of the ACVS Veterinary Symposium, San Diego, 2005.

33. Buriko Y, Van Winkle TJ, et al: Severe soft tissue infections in dogs: 47 cases (1996-2006), J Vet Emerg Crit Care 18(6):608, 2008. 34. Mathews KA, Binnington AG: Wound management using honey, Compend Contin Educ Pract Vet 24:53, 2002. 35. Subrahmanyam M: A prospective randomised clinical and histological study of superficial burn wound healing with honey and silver sulfadiazine, Burns 24:157, 1998. 36. Jull AB, Rodgers A, Walker N: Honey as a topical treatment for wounds, Cochrane Database Syst Rev (4), 2008 Oct 8. 37. Bohling MW, Henderson RA, Swaim SF, et al: Cutaneous wound healing in the cat: a macroscopic description and comparison with cutaneous wound healing in the dog, Vet Surg 33:579, 2004.

130 Thermal Burn Injury Caroline K. Garzotto, VMD, DACVS, CCRT

KEY POINTS • Electric heating pads, motor vehicles with hot mufflers, and fire exposures are the most common sources of burn injuries seen in the small animal veterinary patient. • If the injury is from a fire exposure, the patient should be assessed for evidence of pulmonary dysfunction caused by smoke inhalation. • If more than 20% of the total body surface area is involved, cardiovascular shock, major metabolic derangements, and sepsis may occur. These patients will need intensive medical and surgical treatment.

• Burn wounds may take several days to “declare” themselves because heat dissipates slowly from burned skin. • The eschar should be removed early to help establish a healthy granulation bed and prevent infection. • Silver sulfadiazine and medicinal honey have beneficial antibacterial and healing properties as topical treatments for most burn wounds. The cost of treatment and prognosis, especially in animals with severe metabolic derangements that necessitate intensive care, should be thoroughly discussed with owners.

Thermal burn wounds are relatively uncommon in veterinary medicine. The most common sources of burns in small animals include electric heating pads, fire exposure, scalding water, stovetops, radiators, heat lamps, automobile mufflers, improperly grounded electrocautery units, and radiation therapy.1 Most burn wounds can be managed the same as traumatic wounds (see Chapter 129, Wound Management). Like traumatic wounds, burn wounds can be labor intensive and expensive for the owner. In addition, numerous metabolic derangements can adversely affect the patient, prolong hospitalization, and complicate recovery.

superficial part of the dermis is affected, there will be thrombosis of blood vessels and leakage of plasma. The hair follicles are spared. In deeper partial-thickness burns, hair follicles are usually destroyed, the skin appears yellow-white or brown, and there is decreased sensation except to deep pressure.1 Third-degree burn wounds are full-thickness injuries that have destroyed the epidermis and entire dermis. The skin is leathery and charred and lacks sensation. Fourth-degree burn wounds have the same characteristics as third-degree burn wounds but also affect deeper tissues such as muscle, tendon, and bone.1-3 When burned, skin retains heat, so an accurate assessment of the degree of the wound may not be apparent initially.1 It can take up to 3 days or more for the burn to “declare” itself, and during that time thermal injury and circulatory compromise from thrombosed vessels can continue. Patients with burns involving more than 20% of their total body surface area (TBSA) can have serious cardiovascular, pulmonary, and metabolic derangements. Patients with more than 50% of their TBSA involved have a poor prognosis, and euthanasia should be discussed with the owners as a humane alternative. TBSA can be estimated in animals using percentages allotted to body area using the rule of nines as described in Table 130.2.1,4,5 When skin is severely burned, it forms an eschar within 7 to 10 days. Eschar is a deep cutaneous slough of tissue composed of fullthickness degenerated skin.6 It appears as a black, firm, thick movable crust that separates from the surrounding skin. Purulent exudates often lie beneath the eschar, particularly if it covers deep or extensive injuries, and sepsis can result if it is not treated promptly (Fig. 130.1).

DEFINITIONS Burn wounds are assessed using two major parameters: the depth of the injury and the percentage of body surface area involved. A review of skin anatomy is helpful in describing depth of burn injury.1 The most superficial layer of skin is the epidermis and the deeper layer of skin is the dermis. The dermis is composed of a superficial plexus and a middle plexus, where hair and glandular structures arise. Below the dermis lies the hypodermis, also known as the subcutaneous layer, which contains the deep or subdermal plexus and the panniculus muscle. The subdermal plexus brings the blood supply to overlying skin through the superficial and middle plexus. Capillary loops in the superficial plexus supply the epidermis; however, they are poorly developed in the dog and cat compared with humans, thus leading to less severe erythema and blisters in our small animal patients than in human burn victims.1,2 Although these are now considered older terms, many physicians still like to refer to burn wounds as first-degree, second-degree, thirddegree, and fourth-degree injuries (Table 130.1).1-3 First-degree burn wounds are superficial and are confined to the epidermis. The skin will be reddened, dry, and painful to touch. Second-degree burn wounds are partial-thickness injuries that involve the epidermis and a variable amount of the dermis. If only the

PATIENT ASSESSMENT AND MEDICAL MANAGEMENT The patient should be assessed immediately for airway, breathing, and circulatory compromise, as with all trauma patients (see Chapter 1,

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TABLE 130.1  Burn Wound Assessment and Healing Degree First

Depth Superficial (epidermis only)

Appearance Erythematous Painful to touch

Healing Healing is rapid; reepithelializes in 1 week with topical wound management No systemic effects

Second

Epidermis and superficial part of dermis

Epidermis will be charred and sloughs; plasma leakage occurs Hair follicles spared Painful to touch

Healing by epithelialization from the wound margin with minimal scar in 10 to 21 days May have systemic effects

Second

Epidermis and deeper part of dermis

Skin appears black or yellow-white Hair follicles destroyed Decreased pain sensation

Healing by contraction and epithelialization but scarring is significant without surgical intervention Significant systemic effects expected

Third

Full thickness (entire epidermis and dermis)

Skin is black, leathery; eschar insensitive to touch

Healing often requires extensive surgical intervention, possible skin grafts and flaps May have life-threatening systemic effects

Fourth

Full thickness (with extension to muscle, tendon, and bone)

Same as above

Skin grafts and flaps usually required to prevent scarring that could restrict joint movements

TABLE 130.2  Estimating Total Body

of packed cell volume, total solids, electrolyte values, lactate, and blood gas parameters, at the very minimum.

Area Head and neck

Percentage (%) 9

Total % 9

Metabolic Derangements

Each forelimb

9

18

Each rear limb

18

36

Dorsal trunk

18

18

Ventral trunk

18

18

Surface Area Burned

TOTAL

99

Fig. 130.1  This dog was burned by a hot paint can that exploded in a fire. Note the large eschar on the dorsum of the patient. This large area of full-thickness necrotic skin impedes granulation tissue formation and allows purulent exudates to accumulate beneath it. The dog was anesthetized to remove the eschar. (Courtesy M. Nicholson.)

Evaluation and Triage of the Critically Ill Patient). After a full physical examination, including inspection of the patient from head and mouth to foot pads, an assessment of the degree and TBSA of the burn wounds should be performed to help determine prognosis and the extent of treatment necessary. Blood should be collected for evaluation

If more than 20% of a patient’s TBSA is burned or if the wounds are classified as second or third-degree, hypovolemic shock often occurs. As a result of capillary thrombosis and plasma leakage, massive amounts of fluid are retained in the wound, often leading to burn wound edema.5 This results in the loss of fluid and electrolytes, with the most dramatic losses occurring within the first 12 hours. Systemic abnormalities should be anticipated, including anemia, hypoproteinemia, hypernatremia or hyponatremia, hyperkalemia or hypokalemia, acidosis (metabolic and respiratory), coagulopathy, oliguria, and prerenal azotemia. The course of the systemic abnormalities changes with time.4 Hemoconcentration will be noted initially because of the dramatic loss of plasma; however, red blood cell hemolysis also occurs from both direct damage and destruction through the damaged microcirculation. The patient should be monitored for disseminated intravascular coagulation (DIC), upper airway edema, oliguria, and multiple organ dysfunction syndrome (see Chapter 7, SIRS, MODS and Sepsis). Between days 2 and 6, the patient should be assessed for anemia, DIC, immune dysfunction, systemic inflammatory response syndrome, and early burn wound infection. From day 7 and thereafter, the clinician should watch for hyperthermia or fever, hypoxemia, pneumonia, sepsis, and wound demarcation. Fluid losses can result in hypovolemic shock (see Chapter 69, Shock Fluid Therapy). After initial shock resuscitation with isotonic crystalloids and synthetic colloids or blood products, if needed, total fluid delivery rate during the first 24 hours should be 1 to 4 ml/kg body weight 3 % TBSA burned.4 After 12 to 24 hours, when vascular permeability is stabilized, a constant rate infusion (CRI) of cryopoor plasma, frozen plasma, or synthetic colloids (e.g., hydroxyethyl starch) may be beneficial (see Chapters 67 and 70, Synthetic Colloid Solutions and Transfusion Medicine, respectively). Fresh frozen plasma is given at 0.5 ml/kg body weight 3 % TBSA burned in humans, although this has not been investigated in dogs and cats. By 48 hours after injury, plasma volume is mostly restored, and thus patients are at high risk for generalized edema and fluid overload from

CHAPTER 130  Thermal Burn Injury the high initial demands for fluid replacement.5 Ideally, fluid therapy should be tailored to the individual patient based on hemodynamic and perfusion indices.

Nutrition Because of their fragile metabolic state, the importance of adequate nutrition cannot be overemphasized in patients with healing burn wounds. Nutritional requirements should be based on the patient’s needs; an initial estimate is made by calculating the resting energy requirement. The diet should have high caloric density and high protein levels. It is best if the patient can eat voluntarily, but if the animal is not consuming adequate nutrition, a feeding tube should be placed or total parenteral nutrition commenced (see Section XIII, Nutrition). Gastrointestinal (GI) protectants and antiemetics are recommended to manage GI ulceration secondary to GI hypoperfusion and secondary nausea, as needed (see Chapters 154 and 155, Gastrointestinal Protectants and Antiemetics and Prokinetics, respectively).

Patient Comfort Although severely damaged skin is often numb, deeper viable tissues and surrounding areas are often hypersensitive and thermal damage may be ongoing; thus one should assume that burn patients experience extreme pain (see Part XV, Anesthesia and Pain Management). Good systemic analgesics include methadone (0.1 to 0.2 mg/kg IV q2-6h), hydromorphone (0.05 to 0.1 mg/kg IV q4-6h) or fentanyl as a CRI (2 to 5 mcg/kg/hr IV 1 2 mcg/kg bolus). A fentanyl patch is not appropriate in animals with more than 20% TBSA burned or who are still being treated for hypovolemic shock because of altered absorption. Good nursing care is important, and animals should be turned every 4 hours if recumbent to prevent decubitus ulcers. Passive range-ofmotion limb exercises can help prevent edema and maintain mobility.4

Antimicrobial Therapy Sepsis is one of the greatest threats to burn patients with extensive TBSA involvement because bacteria can colonize and proliferate in wounds that have lost the protective skin barrier (see Part XIX, Antimicrobial Therapy). The best way to prevent local and systemic infection is to protect the wound from contamination in the hospital environment and to remove all necrotic tissue and purulent exudates from the wound surface as aggressively as possible through serial debridement. Systemic antimicrobials are not indicated unless the patient is immunocompromised, has pneumonia or pulmonary injury, or sepsis is suspected (see Chapter 173, Antimicrobial Use in the Critical Patient). Topical antibiotics are the antimicrobial treatment of choice (see the following section). Because most invasive burn wound infections are caused by Pseudomonas or other Gram-negative organisms, antimicrobials against these bacteria are administered empirically until culture and susceptibility testing results are available.5

BURN WOUND MANAGEMENT Although early wound closure is the primary goal to decrease further electrolyte, protein, and fluid losses, this is not usually performed for at least 3 to 7 days while the wound is “declaring” itself. Daily wound care, however, is critical. Once systemically stable, the patient is sedated with neuroleptanalgesia or placed under general anesthesia and the fur is liberally clipped to assess the damage. If fur pulls easily out of the skin, the wound is likely a deep partial-thickness or full-thickness burn1 (see Table 130.1). If the patient presents within 2 hours of the burn injury (which is usually not the case), cold water lavage for 30 minutes will often help

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to release heat from the skin and limit the depth of injury.1 The temperature of the water should not be below 3°C, and if large body surface areas require treatment, it is important to prevent iatrogenic hypothermia. The affected area can be submerged in a cold water bath if it is on a limb, and cool towels or cool water from a spray nozzle can be applied to other areas. Treatment of the wound then depends on its depth. In patients with superficial burns or superficial partial-thickness burns, it may be appropriate to use daily lavage and topical agents alone until the extent and depth of the wound is determined.1 Deep partial-thickness and full-thickness burns require debridement, which can be done conservatively or surgically.1 Conservative debridement is often used for the first 3 to 7 days as the wound declares itself and the patient stabilizes; then more aggressive surgical debridement can be performed. In human burn patients, prompt removal of burn eschar is positively correlated with improved survival and reduced morbidity because of control of sepsis and reduced scarring.7,8 Daily treatment of burn wounds with conservative debridement involves hydrotherapy, removal of necrotic tissue, topical therapy, and bandaging. This may need to be done more than once a day initially for wounds that are necrotic or exudative. Hydrotherapy consists of gentle lavage of the wound with room temperature sterile saline or lactated Ringer’s solution. This helps to loosen and separate any nonviable or necrotic tissue from the surface of the burn. The lavage solutions should be delivered using a 35-ml syringe and a 19-gauge needle to create a pressure of 8 psi. Higher pressures may induce tissue trauma and cause deeper seeding of bacteria into the burn. A wet-to-wet dressing under a bandage can also be placed on burns for several hours at a time to slowly loosen the necrotic tissue and facilitate debridement.1,6 Conservative debridement is characterized by the daily serial piecemeal removal of necrotic tissue (black and hard, burned skin) using aseptic technique, with either sterile gauze or sterile scissors and thumb forceps. Because necrotic tissue is without sensation, this may not require daily general anesthesia; however, manipulation of deeper viable tissues and surrounding hyperemic areas likely will be painful during lavage. This form of debridement is acceptable initially, when there is no clear definition of nonviable tissue, or when it is prudent to be conservative in areas overlying tendons, ligaments, and bone.1 Aggressive surgical excision of an entire burn wound requires general anesthesia and is indicated in deep partial-thickness and fullthickness burn wounds that may otherwise take days or weeks with conservative debridement. This is done most easily on large areas of the trunk or small areas of the limbs, which can then be closed primarily (Figs. 130.2 and 130.3). If the area cannot be closed primarily, it will take about 1 to 2 weeks for a healthy granulation bed to form, at which time flap or skin graft surgery can be performed.1

Topical Agents After hydrotherapy and debridement, topical agents, dressings, and bandages are applied. Aloe vera and silver sulfadiazine are the most commonly used and readily available topical compounds for burn wounds. Aloe vera cream has antithromboxane effects that prevent vasoconstriction and thromboembolic seeding of the dermal vasculature.2,6 Ideally, using it within the first 24 hours can help prevent progression of superficial partial-thickness burns. Aloe vera is applied liberally to the surface of the wound with a sterile gloved finger while the patient is sedated because these wounds are painful when touched. The wound should then be covered with a nonadherent hydrophilic dressing and bandage.

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After the first 24 hours, silver sulfadiazine should be applied.2 It has a wide spectrum of bactericidal activity against Gram-positive and Gram-negative bacteria and Candida. The cream is placed directly on the wound under the contact layer of a bandage using sterile gloves. For very large areas that are not amenable to bandaging, silver sulfadiazine should be slathered over the wound and the patient confined within a low-fomite environment (empty clean cage with no blankets or stuffed toys).1,6 If needed, the cream can be rinsed off gently before reapplication, up to two to three times a day. Silver sulfadiazine can be used during both the early debridement stage under wet-to-wet dressings and through the repair stages of healing using nonadherent bandages. Alternatively, nanocrystalline silver dressings that allow for slow sustained release of silver are a slightly more expensive option that can be left on the wound for up to 3 to 7 days.2,9 Medicinal honey can also be used in the treatment of burn wounds; honey is beneficial during debridement and helps to control secondary infections. The benefits of honey for burn wounds include antibacterial,

antiinflammatory, antiedematous, and antioxidant effects.10 When topical honey is paired with nonadherent, absorptive dressings, these bandages can also be left on the wound for up to 3 to 7 days (see Figs. 130.4–130.6). Silver sulfadiazine and medicinal honey provide a moist wound environment to promote wound healing. Bandages should always be changed promptly when there is strike through of exudate, odor, or patient discomfort.

Closure Options and Healing Superficial and partial-thickness burn wounds have a favorable outcome with no surgical intervention. These wounds reepithelialize quickly and can heal within 1 to 3 weeks with open wound management. If only the superficial layer of the dermis is involved in partialthickness burns, healing is often rapid. The overlying burned epidermis will slough, and healthy epithelium will be apparent below. Deeper burns involving the hair follicles, especially if they are large, will heal more slowly (3 weeks or longer). Deep dermal partial-thickness and full-thickness burns heal by contraction and epithelialization once a healthy granulation bed has been created by diligent debridement. Eventually, these wounds can be closed primarily. Full-thickness burns covering large areas of the body, or those on the limbs, may require skin grafts or skin flaps for complete closure.

Complications Scarring and wound contracture are the biggest complications in patients with burn wounds left to heal by second intention.13 This is particularly a concern for patients with burn wounds in the axillary or inguinal areas, or around joints, which can lead to decreased mobility and range of motion of the limbs. Wounds in these areas should be managed by someone experienced in reconstructive surgery because they will likely require skin grafts or flaps.

Fig. 130.2  This is the dog from Fig. 130.1 4 weeks after escharectomy. Note the healthy granulation tissue and how the wound has become smaller via contraction and epithelialization. (Courtesy M. Nicholson.)

Fig. 130.3  Postoperative view of the burn wound of the dog from Figs. 130.1 and 130.2; it was closed primarily by elevating the skin edges and taking advantage of the loose, elastic skin over the body of the dog. (Courtesy M. Nicholson.)

Fig. 130.4  This dog was burned by a microwaved rice bag that was placed directly on his skin during recovery from a neuter to provide heat support. The wound became noticeable 7 days postoperative and was initially managed with just topical silver sulfadiazine. Given the appearance of the eschar, prompt removal of the eschar would have been more appropriate. At 2 weeks post-neuter this is the appearance of the burn eschar. Note: Due to the focal small area of this wound, this patient suffered no systemic illness from this burn.

CHAPTER 130  Thermal Burn Injury

A

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B

C Fig. 130.5  A, The wound was debrided of dead tissue only under heavy sedation (dexmedetomidine and methadone), revealing what was a deep second-degree burn wound with healthy underlying granulation tissue. B, A medicinal honey topical ointment and nonadherent absorptive bandage were used on this wound and secured with a tie-over dressing (C).

Fig. 130.6  Appearance of the wound 2.5 weeks after presentation in Fig. 130.4. This case was managed conservatively due to the owner’s cost constraints, but the patient did well with second intention healing because the wound was not close to a joint surface where contracture during healing could have affected mobility.

REFERENCES 1. Pavletic MM: Management of specific wounds: burns. In Atlas of small animal wound management and reconstructive surgery, ed 3, Ames, IA, 2010, Wiley-Blackwell, pp 170-180. 2. Fossum TW, Hedlund CS, Hulse DA, et al: Burns and other thermal injuries. In Fossum TW, editor: Small animal surgery, ed 3, St Louis, 2007, Mosby, pp 228-232.

3. Bohling MW: Burns. In Tobias KM, Johnston SA, editors: Veterinary surgery small animal, St Louis, 2012, Elsevier Saunders, pp 1291-1302. 4. Dhupa N, Pavletic MM: Burns. In Morgan R, Pavletic MM, editor: Handbook of small animal practice, ed 4, Philadelphia, PA, 2003, Saunders, pp 1789-1790. 5. Pope ER: Burns: thermal, electrical, and chemical burns and cold injuries. In Slatter DH, editor: Textbook of small animal surgery, ed 3, St Louis, 2003, Saunders, pp 356-372. 6. Swaim SF, Henderson RA: Small animal wound management, ed 2, Baltimore, 1997, Williams & Wilkins. 7. Scaffle JR: Critical care management of the severely burned patient. In Parrillo JE, Dellinger RP, editors: Critical care medicine—principles of diagnosis and management in the adult, ed 3, Philadelphia, 2008, Mosby Elsevier, pp 1423-1452. 8. Gallagher JJ: Burn wound management. In Cameron JL, Cameron AM, editors: Current surgical therapy, ed 10, Philadelphia, 2011, Elsevier Saunders; pp 1032-1036. 9. Murphy PS, Evans GRD: Advances in wound healing: a review of current wound healing products, Plastic Surg Int 2012;190436, 2012. 10. Zbuchea A: Up-to-date use of honey for burns treatment, Ann Burns Fire Disasters 27(1):22-30, 2014. 11. Wolsein P, Peters M, Schulze C, Baumgartner W: Thermal injuries in veterinary forensic pathology, Vet Pathol 53:1001, 2016. Provides more in-depth review of burn wound pathology. 12. Vaughn L, Beckel N: Severe burn injury, burn shock, and smoke inhalation injury in small animals. Part 1: burn classification and pathophysiology, J Vet Emerg Crit Care 22:179, 2012. 13. Vaughn L, Beckel N, Walters P: Severe burn injury, burn shock, and smoke inhalation injury in small animals. Part 2: diagnosis, therapy, complications and prognosis, J Vet Emerg Crit Care 22:187, 2012.

PART XV   Anesthesia and Pain Management

131 Pain Assessment Alessia Cenani, DVM, MS, DACVAA, Linda S. Barter, BVSc, PhD, DACVAA

KEY POINTS • The assessment and management of pain in critically ill small animals are moral imperatives and the inherent responsibility of all veterinary medical professionals. • Pain is unique to each individual. • The ability to properly recognize and quantify individual pain is crucial to its treatment. • No perfect pain assessment tool is available and using more than one assessment tool is recommended.

• Observation of the patient should be performed at first from a distance, then while interacting with the observer, and then palpation of the affected area can be performed. • Inadequate pain control may lead to animal suffering, increased morbidity, and adverse outcomes.

Pain is defined by the International Association for the Study of Pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage.” Effective pain management is a moral imperative, professional responsibility, and the duty of veterinary medical professionals. Pain differs in nature and origin, and its perception is unique to each individual and will depend on the extent of tissue damage, previous pain experiences, social position, and sex of the animal.1-4 Acute pain at the site of an injury has an initial protective function to minimize further injury and promote recovery. If not quickly controlled, sustained hyperactivation of the hypothalamic–pituitary–adrenal axis leads to increased blood pressure and heart rate, peripheral vasoconstriction, increased metabolic rate and oxygen consumption, decreased immune function, immobility, decreased pulmonary function and atelectasis, increased incidence of pneumonia, inappetence, restlessness, and insomnia. These consequences of unmanaged pain negatively affect quality of life, delay recovery, increase the risk of postsurgical complications, and can lead to persistent postsurgical pain.5 The goal of treating pain is to relieve patient suffering, promote healing, decrease length of hospitalization, and minimize long-term changes to the animal.

Acute pain indicators evaluated in the literature include physiologic and endocrine markers, changes in behavior, and changes in facial expression. Inclusion of multiple indicators of pain likely gives a better overall pain assessment. This forms the basis of many acute pain scoring systems. Patients should first be observed from a distance with no interaction, since both handling and distraction may alter pain perception.3,6 Stress, anxiety, delirium, nausea, need to urinate and/or defecate are all important confounding factors when evaluating pain. It is therefore crucial that both proper nursing care and a calm and quiet environment be provided for the animal. Side effects related to interventions and/or concurrent medications, especially sedatives, are additional confounding factors that should be considered when assessing pain. Following distance observation, the animal should be observed interacting with a caregiver, and then the animal’s response to manipulation of the suspected painful area as well as other nonpainful areas of the body should be assessed. There is no clear evidence on the optimal timing or frequency of pain assessment in people7 or animals. The type of injury and comorbidities, adequacy of pain relief, presence of treatment side effects, and changes in patient’s clinical status will all dictate frequency of reassessment. There is no evidence that routine reassessment of pain during a caregiver’s shift improves clinical outcomes, and it is recommended that patients who are resting should not be awoken solely for the purposes of pain assessment.7

PAIN ASSESSMENT GUIDELINES AND TOOLS Effective pain management requires the ability to recognize and quantify signs of pain. To enable this, a valid, reliable, easy to use, and sensitive tool is required. Unfortunately, there is no single objective test or pathognomonic behavior or marker to assess pain. To complicate this further, pain behavior can vary with the type of pain, species, breed, and temperament of the animal.

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Physiological Parameters and Endocrine Markers Physiologic parameters such as heart rate, respiratory rate, blood pressure, and pupil dilation are quantifiable and altered by pain. Unfortunately, they are also nonspecific indicators of pain and can also be altered

CHAPTER 131  Pain Assessment by a range of conditions including fear, stress, anxiety, and metabolic disturbances.8-10 Heart rate variability (HRV) describes the variation in R-R interval obtained from an electrocardiogram. There are various ways to analyze this data, but methods commonly employed define bands of frequency (i.e., high and low) and describe the number of R-R intervals that fit into each frequency band. Changes in parasympathetic and sympathetic nervous system (SNS) tone have bigger impacts on high and low frequency components, respectively. Low HRV suggests dominance of one branch of the autonomic nervous system, typically the SNS if the evaluation is being made during a time where SNS activity would be increased (noxious stimulation, stress, exercise). Reduced HRV has been correlated to chronic pain,11 but not consistently to acute pain.12,13 More studies are required before HRV can be used as a biomarker and diagnostic tool for pain assessment.11 In horses, HRV has been shown to be influenced by training and fitness levels, stress, and temperament, making it challenging to demonstrate correlations to pain.14 The analgesia nociception index (ANI) was developed for the assessment of nociceptive/antinociceptive balance in people undergoing anesthesia and surgery. It is based on both qualitative and quantitative analysis of HRV.15 The parasympathetic tone activity (PTA) monitor is a device developed for use in animals based on similar principles to the ANI, with algorithms for dog, cat, and horse. Such devices may be useful additions to pain assessment where behavioral responses to noxious stimulation are suppressed by drugs or disease. Limited evaluation of the PTA has not shown it to be any more sensitive than blood pressure or heart rate changes in response to noxious stimulation at this time. However, additional evaluation of its dynamic variation and refinement of its application and interpretation are needed.16,17 Blood concentrations of epinephrine, norepinephrine, and cortisol are often increased during pain states. Unfortunately, factors such as stress, fear, drugs, underlying diseases, and surgical trauma can also elevate these markers, making them very nonspecific indicators of pain.8,13,18-20

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Altered Behavior A change in behavior can be one of the first signs that an animal is unwell or in pain. Behavioral change is considered one of the better indicators of pain and is commonly used in its assessment. There is no pathognomonic behavior associated with pain. Additionally, the absence of a behavior often seen in painful animals does not necessarily mean the absence of pain. Behavioral change in a painful animal can be the display of a new abnormal behavior or the disappearance of a behavior normal for that animal (e.g., lack of tail wagging, changes in the animal’s social interaction and overall attitude). As an example, dogs receiving adequate opioid analgesia after ovariohysterectomy had a more rapid return to normal greeting behaviors than dogs receiving placebo.21 The context in which the behavior is displayed is also important. A normal behavior displayed in an abnormal place or at an abnormal time can also be a sign of pain (e.g., inappropriate urination and defecation). It should be kept in mind that behavior can be modified by the environment, presence of observers, presence of other animals, activity level, disease state, previous pain experiences, and stressors.2,3,4,8 Familiarity with typical behavior, not only for the species of animal being evaluated but for the individual being assessed, is important. This is evidenced by owner assessment of pet pain relief with medication correlating well with objective measurement of activity in dogs and cats with osteoarthritis.22,23 Some pain scales quantify the time spent by an animal displaying various behavior; however, it remains unclear if this is more sensitive than simply identifying the presence or absence of a behavior.24 Occasionally, behaviors mentioned in some pain scales are intangible and poorly defined (e.g., does the animal look depressed, anxious, or irritable?). Assessment of such behaviors is highly subjective, resulting in large inter- and intraobserver variability. Examples of behaviors commonly used for pain assessment in dogs and cats are listed in Table 131.1.

TABLE 131.1  Behaviors Often Observed in Dogs and Cats Experiencing Pain Category

Behavior

Comments

Posture

Abnormal posture displayed at rest or after manipulation20,21

Hunched back, base-wide stance position, prayer position (neck and head extended forward with front of body lowered to the ground), head and/or tail tucked under the body, tension and rigidity of the painful area, frequent position changes, reluctance to assume normal body positions (e.g., will not lie down, sit or stand when they normally would)

Gait

Gait abnormalities common20,22

Stiff gait, lameness, reluctance to move, and nonweight bearing

Abnormal movements

Shaking, trembling, continuous activity

May also occur secondary to conditions other than pain, such as anxiety and fear

Interaction

Social interaction usually reduced

Reduced willingness to interact with people, other animals, and surroundings (e.g., facing the back of the cage rather than looking out, not exploring surroundings)

Demeanor

Deviations from normal

Some animals become aggressive, while others show a submissive behavior20,21

Attention to painful area Usually increased

20,21

This ranges from increased time spent looking and staring at the area, to guarding, licking, chewing and biting it, to the extreme of self-mutilation

Palpation of the painful area

Applying pressure to the painful area usually triggers a response

This ranges from a turn or flinch, purposeful withdrawal, or escaping effort to biting and aggression. Some animals may vocalize (see below)

Vocalization

Deviation from normal vocalization patterns can indicate pain, particularly vocalizations evoked by palpation or movement of painful area21,22

Normally talkative animals may become quiet when in pain. Vocalizations elicited by palpation of painful area are suggestive of pain; however, lack of vocalization should not be mistaken as a sign of comfort. Other factors can influence propensity of an animal to vocalize such as anxiety, fear, disorientation, or postanesthetic delirium

Appetite

Hyporexia or anorexia is common in animals experiencing acute or chronic pain21

Nonspecific sign of pain with a myriad of other potential causes that should be investigated if these signs persist despite adequate pain management

Grooming

Excessive grooming or chewing of an area may indicate pain, as may lack of grooming

Appropriate grooming in cats tends to be decreased when in pain

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PART XV  Anesthesia and Pain Management

Pain Scales

Multidimensional Scoring Systems

Pain scales can be broadly classified as unidimensional or multidimensional scoring systems. They all rely on the recognition and/or interpretation of some behavior and may also consider changes in physiologic parameters. These pain assessment scales usually generate a pain score that can be used to trigger intervention and to compare changes in pain over time or between individuals. The ideal pain scale would be reliable, sensitive, specific, free of bias, valid, practical to use, and versatile for assessing different type of pain. Currently, there is no gold standard pain scale for acute pain assessment.

Multidimensional scoring systems were developed to create more comprehensive and less subjective pain evaluations and to gather more information about the pain than just the intensity. These composite pain scales usually incorporate a variety of behavioral categories (e.g., animal appearance, posture, response to palpation, interaction) with a list of descriptors and scores according to their associated pain severity. Some scales also include additional indicator(s), such as blood pressure. Evaluation of the animal usually consists of both an observational and a hands-on evaluation period. Individual scores in each category are added together to calculate a final overall pain score. These scales are commonly species-specific and usually designed and validated to assess one type of pain. Because they are used outside of the conditions in which they were created and validated, many of these multidimensional pain assessment scales do not perform as well. Some examples of multidimensional pain scales available for acute pain assessment in dogs and cats, and the conditions for which they are validated, are listed in Table 131.2. Multidimensional pain scales can be vulnerable to observer error and bias. The pain evaluation can still be quite subjective, particularly if variability in interpretation of listed behaviors is not minimized. Each scale has important strengths and weakness, and no one scale is recommended for use in all situations with all patient groups. Although not perfect, multidimensional pain scoring systems are easily accessible, practical to use, and most importantly bring attention to, and document, many different parameters and changes in behaviors that may be associated with pain. This raises awareness of the animal’s need for analgesia.

Unidimensional Scoring Systems Unidimensional scoring systems rate only one dimension of pain: intensity. They are not useful for detecting subtle changes in pain. Examples of these scoring systems include the simple descriptive scale (SDS), numeric rating scale, and visual analog scale (VAS) (Fig. 131.1). These systems are simple and can be used across multiple species and for different types of pain. Because the scales are highly subjective, there is poor interobserver agreement and sensitivity, which creates difficulties when multiple personnel care for a patient.10,25 These scores are also not linear; i.e., a score of 60 mm on a VAS does not necessarily represent twice as much pain as a score of 30 mm. Although these scales may seem like a less restrictive approach to pain evaluation, they require the observers to be familiar with the process of pain evaluation and behaviors suggestive of pain. Training is required to properly uses these scales, and they perform less well in the hands of inexperienced observers.26 The dynamic interactive visual analog scale (DIVAS) is an expansion of the VAS. Although still a VAS, the DIVAS is based on both observation of the animal and interaction with the animal and movement and palpation of the suspected painful area.

Simple descriptive scale

A

No pain

Mild pain

B

Moderate pain

Severe pain

Worst imaginable pain

Very severe pain

Numeric rating scale

1 C

No pain

2

3

4

5

6

7

8

9

10

Visual analog scale

Worst imaginable pain Fig. 131.1  A, Simple descriptive scale: Descriptors of the intensity of the pain are included to guide the observer in the pain evaluation. These descriptors can be assigned numbers used for data collection. B, Numeric rating scale: Numbers (e.g., 0 to 4; 0 to 10) are used instead of descriptors to indicate severity of pain from “no pain” to “worst imaginable pain”. The observer chooses a number that correlates with the assessment of the pain. C, Visual analog scale (VAS): A scale consisting of a 100-mm line (0 5 no pain and 100 5 worst imaginable pain for that specific condition). The verbal descriptors “no pain” and “worst imaginable pain” can be included at each end of the scale. The observer marks a point on the line that correlates with their assessment of pain.

Facial Expression of Pain Action units (AUs) are unique changes in facial expression produced by facial muscle activity. Pain AUs are involuntary in nature and cannot be properly suppressed, amplified, or simulated. In people, they are more sensitive to pain intensity than verbal self-report and are consistent across a range of cognitive capacities. These findings appear to be conserved across species. Pain AUs described in cats using morphometric methods include the bases of the pinna moving away from each other; dorsal movement of the nose, mouth and cheek areas; and eyes narrowing. The presence of the facial expressions in acute pain was significantly correlated with increasing pain scores obtained using the UNESP-Botucatu Multidimensional Composite Pain Scale.27,28 Facial pain AUs have yet to be described in the dog. In rats, pain AUs are consistently displayed during different types of pain, although the predominant AU depended on the pain model.29 Additional studies are required in dogs and cats to evaluate whether acute pain AUs are consistent across different types of pain, if their intensity correlates with the degree of pain, and how they are modified by stress, anxiety, and/or sedation. There is good to excellent interobserver agreement in identification of AUs, but the process is time consuming, and there is still some subjectivity. Automated computer analysis has helped overcome these issues in human medicine, and systems are in development for veterinary species.27,28

PAIN ASSESSMENT IN CRITICALLY ILL PATIENTS Pain is commonly reported in critically ill human patients during ICU hospitalization,30 and more than 50% of them experience some degree of pain during common care procedures, such as turning, endotracheal tube suctioning, tube or drain removal, wound care, and arterial line insertion.31-33

CHAPTER 131  Pain Assessment

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TABLE 131.2  Multidimensional Scoring Systems for Pain Assessment in Dogs and Cats Validated Yes/No (Type of Pain Investigated)

Presence of Suggested Cut-off Level for Analgesic Intervention

Multidimensional Scoring System

Species

4AVet scale

Dogs

Yes (acute orthopedic pain)

Yes

• Pain assessment severely biased 30 by the sedative side-effect of some analgesics • Numeric scoring system for comparison over time included

Glasgow Composite Measure Pain Score (CMPS-C)

Dogs

Yes (acute pain)

No

• Lacks a numeric scoring system for comparison over time • Lengthy

Glasgow Composite Measure Pain Score Short Form (CMPSSF-C)

Dogs

Yes (acute postoperative pain)

Yes

• More practical and simpler than www.newmetrica.com/ acute-painthe original scale; better suited measurement/ to routine clinical use • Numeric scoring system for comparison over time included

University of Melbourne Pain Scale

Dogs

Limited validation (acute pain)

No

32 • Easy to use • Includes physiologic data and behavioral responses • Numeric scoring system for comparison over time included • The types of patients and procedures for which this scale would be expected to be accurate have not been elucidated

Colorado State University Dogs and Cats No (acute pain) Acute Pain Scale

No

• Single-page, user-friendly design http://csu-cvmbs.colo• Numeric scoring system for com- state.edu/documents/ anesthesia-painparison over time included management-painscore-canine.pdf http://csu-cvmbs.colostate.edu/Documents/ anesthesia-painmanagement-painscore-feline.pdf

UNESP-Botucatu Multi­ Cats dimensional Composite Pain Scale for cats

Yes (acute postoperative pain following ovariohysterectomy)

Yes

• Videos for online training available at http://animalpain.com.br/en-us/ escala-multidimensional.php • Numeric scoring system for comparison over time included • Comprehensive validations for post-ovariohysterectomy • Includes blood pressure measurement as an optional variable

Glasgow Composite Measure Pain Score Feline (CMPS-F)

Yes (acute postoperative pain)

Yes

http://www.aprvt.com/ • Simpler and easier to use than uploads/5/3/0/5/ the UNESP-Botucatu scale • Numeric scoring system for com- 5305564/cmp_ feline_eng.pdf parison over time included • Revised version also includes facial expressions

Cats

The Society of Critical Care Medicine recommends routine pain monitoring in all human ICU patients,34 but underassessment of pain remains a major barrier to the adequate pain treatment in critically ill humans.35 In a recent study, pain assessment was performed in only 42% of human ICU patients, even though 90% were treated with opioids because they were believed to be in pain.36 Only 22% of dogs

Comments

Reference/Source

31

hospitalized in a teaching hospital ICU were considered painful based on results of three pain scales (Glasgow, VAS and SDS); however, this population consisted largely of postoperative patients that had already received pre- and postoperative analgesic therapy and would have been recovering from the effects of anesthesia.37 Pain assessment in critically ill patients is challenged by the presence of sedation/anesthesia,

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PART XV  Anesthesia and Pain Management

cognitive impairment, delirium, mechanical ventilation, and paralysis. These factors may explain why pain assessment in the human ICU setting remains low.36 Of 351 dogs and cats hospitalized in the ICU, 39% were prescribed analgesics, and in 36% of those cases, drug administration deviated from prescribed orders (62% decreased dose and 38% increased dose).38 The reasons for the dosing discrepancies were noted in roughly half the cases. Reasons for decreased dosing included concerns regarding sedation, hypothermia, hypotension, perceived absence of pain, and lack of access to controlled drugs. Reasons for increased dosing included perceived pain, vocalizing, and anxiety.38 Formal pain assessment was not performed on those patients; doing so may have helped better guide appropriate analgesic drug administration. Many critically ill humans receive less analgesic than prescribed yet remain painful. Implementation of systematic approaches to pain assessment in the human ICU setting correlates with more frequent documented reports of pain and its prompt identification and early and efficient management.39 Unrelieved pain in the ICU has been clearly linked to prolonged mechanical ventilation, hemodynamic instability, delirium, depressed immunity, and infections.40,41 While strong evidence is lacking, systematic pain assessment could be helpful in reducing ICU length of stay, mortality, and duration of mechanical ventilation.39

REFERENCES 1. Sternberg WF, Ritchie J, Mogil JS: Qualitative sex differences in k-opioid analgesia in mice are dependent on age, Neurosci Lett 363(2):178-181, 2004. doi:10.1016/j.neulet.2004.04.004. 2. Schmelzle-Lubiecki BM, Campbell KAA, Howard RH, Franck L, Fitzgerald M: Long-term consequences of early infant injury and trauma upon somatosensory processing, Eur J Pain 11(7):799-809, 2007. doi:10.1016/j. ejpain.2006.12.009. 3. Fleming GJ, Robertson SA: Assessments of thermal antinociceptive effects of butorphanol and human observer effect on quantitative evaluation of analgesia in green iguanas (Iguana iguana), Am J Vet Res 73(10):15071511, 2012. doi:10.2460/ajvr.73.10.1507. 4. Kohn DF, Martin TE, Foley PL, et al: Guidelines for the assessment and management of pain in rodents and rabbits, J Am Assoc Lab Anim Sci 46(2):97-108, 2007. 5. Gan TJ: Poorly controlled postoperative pain: prevalence, consequences, and prevention, J Pain Res 10:2287-2298, 2017. doi:10.2147/JPR.S144066. 6. di Giminiani P, Brierley VLMH, Scollo A, et al: The assessment of facial expressions in piglets undergoing tail docking and castration: toward the development of the Piglet Grimace Scale, Front Vet Sci 3:100, 2016. doi:10.3389/fvets.2016.00100. 7. Chou R, Gordon DB, De Leon-Casasola OA, et al: Management of postoperative pain: a clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists’ Committee on Regional Anesthesia, Executive Committee, and Administrative Council, J Pain 17(2):131-157, 2016. doi:10.1016/j.jpain.2015.12.008. 8. Cambridge AJ, Tobias KM, Newberry RC, Sarkar DK: Subjective and objective measurements of postoperative pain in cats, J Am Vet Med Assoc 217(5):685-690, 2000. doi:10.2460/javma.2000.217.685. 9. Watanabe R, Monteiro BP, Evangelista MC, Castonguay A, Edge D, Steagall PV: The analgesic effects of buprenorphine (Vetergesic or Simbadol) in combination with carprofen in dogs undergoing ovariohysterectomy: a randomized, blinded, clinical trial, BMC Vet Res 14(1):304, 2018. doi:10.1186/s12917-018-1628-4. 10. Holton LL, Scott EM, Nolan AM, Reid J, Welsh E: Relationship between physiological factors and clinical pain in dogs scored using a numerical rating scale, J Small Anim Pract 39(10):469-474, 1998. doi:10.1111/j.1748-5827.1998.tb03681.x. 11. Tracy LM, Ioannou L, Baker KS, Gibson SJ, Georgiou-Karistianis N, Giummarra MJ: Meta-analytic evidence for decreased heart rate variability

in chronic pain implicating parasympathetic nervous system dysregulation, Pain 157(1):7-29, 2016. doi:10.1097/j.pain.0000000000000360. 12. Koenig J, Jarczok MN, Ellis RJ, Hillecke TK, Thayer JF: Heart rate variability and experimentally induced pain in healthy adults: a systematic review, Eur J Pain 18(3):301-314, 2014. 13. Ledowski T, Reimer M, Chavez V, Kapoor V, Wenk M: Effects of acute postoperative pain on catecholamine plasma levels, hemodynamic parameters, and cardiac autonomic control, Pain 153(4):759-764, 2012. doi:10.1016/j.pain.2011.11.002. 14. Stucke D, Große Ruse M, Lebelt D: Measuring heart rate variability in horses to investigate the autonomic nervous system activity - pros and cons of different methods, Appl Anim Behav Sci 166:1-10, 2015. doi:10.1016/j.applanim.2015.02.007. 15. Jeanne M, Logier R, De Jonckheere J, Tavernier B: Validation of a graphic measurement of heart rate variability to assess analgesia/nociception balance during general anesthesia. In: Proceedings of the 31st Annual International Conference of the IEEE Engineering in Medicine and Biology Society: Engineering the Future of Biomedicine, EMBC 2009:1840–1843; 2009. doi:10.1109/IEMBS.2009.5332598. 16. Aguado D, Bustamante R, García-Sanz V, González-Blanco P, Gómez de Segura IA: Efficacy of the Parasympathetic Tone Activity monitor to assess nociception in healthy dogs anaesthetized with propofol and sevoflurane, Vet Anaesth Analg 47(1):103-110, 2020. doi:10.1016/j.vaa.2019.05.014. 17. Mansour C, Merlin T, Bonnet-Garin JM, et al: Evaluation of the Parasympathetic Tone Activity (PTA) index to assess the analgesia/nociception balance in anaesthetised dogs, Res Vet Sci 115:271-277, 2017. doi:10.1016/j. rvsc.2017.05.009. 18. Romano M, Portela DA, Breghi G, Otero PE: Stress-related biomarkers in dogs administered regional anaesthesia or fentanyl for analgesia during stifle surgery, Vet Anaesth Analg 43(1):44-54, 2016. doi:10.1111/vaa.12275. 19. Ambrisko TD, Hikasa Y, Sato K: Influence of medetomidine on stress-related neurohormonal and metabolic effects caused by butorphanol, fentanyl, and ketamine administration in dogs, Am J Vet Res 66(3):406-412, 2005. doi:10.2460/ajvr.2005.66.406. 20. Srithunyarat T, Hagman R, Höglund OV, et al: Catestatin, vasostatin, cortisol, and pain assessments in dogs suffering from traumatic bone fractures, BMC Res Notes 10(1):129, 2017. 21. Hardie EM, Hansen BD, Carroll GS: Behavior after ovariohysterectomy in the dog: what’s normal? Appl Anim Behav Sci 51(1-2):111-128, 1997. doi:10.1016/S0168-1591(96)01078-7. 22. Lascelles BDX, Hansen BD, Roe S, et al: Evaluation of client-specific outcome measures and activity monitoring to measure pain relief in cats with osteoarthritis, J Vet Intern Med 21(3):410-416, 2007. doi:10.1111/j.1939-1676.2007.tb02983.x. 23. Muller C, Gines JA, Conzemius M, Meyers R, Lascelles BDX: Evaluation of the effect of signalment and owner-reported impairment level on accelerometer-measured changes in activity in osteoarthritic dogs receiving a non-steroidal anti-inflammatory, Vet J 242:48-52, 2018. doi:10.1016/j. tvjl.2018.10.005. 24. Price J, Clarke N, Welsh EM, Waran N: Preliminary evaluation of subjective scoring systems for assessment of postoperative pain in horses, Vet Anaesth Analg 30(2):97, 2003. doi:10.1046/j.1467-2995.2003.00132_15.x. 25. Hudson JT, Slater MR, Taylor L, Scott HM, Kerwin SC: Assessing repeatability and validity of a visual analogue scale questionnaire for use in assessing pain and lameness in dogs, Am J Vet Res 65(12):1634-1643, 2004. doi:10.2460/ajvr.2004.65.1634. 26. Barletta M, Young CN, Quandt JE, Hofmeister EH: Agreement between veterinary students and anesthesiologists regarding postoperative pain assessment in dogs, Vet Anaesth Analg 43(1):91-98, 2016. doi:10.1111/ vaa.12269. 27. Holden E, Calvo G, Collins M, et al: Evaluation of facial expression in acute pain in cats, J Small Anim Pract 55(12):615-621, 2014. doi:10.1111/jsap.12283. 28. Finka LR, Luna SP, Brondani JT, et al: Geometric morphometrics for the study of facial expressions in non-human animals, using the domestic cat as an exemplar, Sci Rep 9(1):9883, 2019. doi:10.1038/s41598-019-46330-5. 29. Sotocinal SG, Sorge RE, Zaloum A, et al: The rat grimace scale: a partially automated method for quantifying pain in the laboratory rat via facial expressions, Mol Pain 7:55, 2011. doi:10.1186/1744-8069-7-55.

CHAPTER 131  Pain Assessment 30. Chanques G, Sebbane M, Barbotte E, Viel E, Eledjam JJ, Jaber S: A prospective study of pain at rest: incidence and characteristics of an unrecognized symptom in surgical and trauma versus medical intensive care unit patients, Anesthesiology 107(5):858-860, 2007. doi:10.1097/01. anes.0000287211.98642.51. 31. Gélinas C: Management of pain in cardiac surgery ICU patients: have we improved over time? Intensive Crit Care Nurs 23(5):298-303, 2007. doi:10.1016/j.iccn.2007.03.002. 32. Puntillo KA, White C, Morris AB, et al: Patients’ perceptions and responses to procedural pain: results from Thunder Project II, Am J Crit Care 10(4):238-251, 2001. doi:10.4037/ajcc2001.10.4.238. 33. Puntillo KA, Max A, Timsit JF, et al: Determinants of procedural pain intensity in the intensive care unit: the Europain® study, Am J Respir Crit Care Med 189(1):39-47, 2014. doi:10.1164/rccm.201306-1174OC. 34. Barr J, Fraser GL, Puntillo K, et al: Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit, Crit Care Med 41(1):263-306, 2013. doi:10.1097/ CCM.0b013e3182783b72. 35. Pasero C, Puntillo K, Li D, et al: Structured approaches to pain management in the ICU, Chest 135(6):1665-1672, 2009. doi:10.1378/ chest.08-2333.

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36. Payen JF, Chanques G, Mantz J, et al: Current practices in sedation and analgesia for mechanically ventilated critically ill patients: a prospective multicenter patient-based study, Anesthesiology 106(4):687-695, 2007. doi:10.1097/01.anes.0000264747.09017.da. 37. Moran CE, Hofmeister EH: Prevalence of pain in a university veterinary intensive care unit, J Vet Emerg Crit Care 23(1):29-36, 2013. doi:10.1111/ vec.12010. 38. Armitage EA, Wetmore LA, Chan DL, Lindsey JC: Evaluation of compliance among nursing staff in administration of prescribed analgesic drugs to critically ill dogs and cats, J Am Vet Med Assoc 227(3):425-429, 2005. doi:10.2460/javma.2005.227.425. 39. Georgiou E, Hadjibalassi M, Lambrinou E, Andreou P, Papathanassoglou EDE: The impact of pain assessment on critically ill patients’ outcomes: a systematic review, Biomed Res Int 2015:503830, 2015. doi:10.1155/ 2015/503830. 40. Puntillo K, Pasero C, Li D, et al: Evaluation of pain in ICU patients, Chest 135(4):1069-1074, 2009. doi:10.1378/chest.08-2369. 41. Skrobik Y, Ahern S, Leblanc M, Marquis F, Awissi DK, Kavanagh BP: Protocolized intensive care unit management of analgesia, sedation, and delirium improves analgesia and subsyndromal delirium rates, Anesth Analg 111(2):451-463, 2010. doi:10.1213/ANE.0b013e3181d7e1b8.

132 Sedation of the Critically Ill Patient Giacomo Gianotti, DVM, DVSc, DACVAA KEY POINTS • Sedation of the critically ill patient is commonly required in the ICU. • Critically ill sedated patients have the potential to develop severe cardiovascular, respiratory, and neurologic complications. • Stabilization of these patients is of key importance whenever possible prior to sedation in order to prevent anesthetic complications.

• Knowledge of sedative drug mechanisms of action, potential interactions, and their side effects is important to minimize morbidity associated with sedation of critically ill patients. • Appropriate monitoring and continued support of the sedated patient are vital. Reversal agents should be used when indicated.

INTRODUCTION

allows for adequate oxygen administration and ventilation. Also, a patient under general anesthesia is easier to instrument with a multiparameter anesthesia monitor, which allows for a more accurate assessment of vital physiologic parameters. This will allow for a faster response in case of undesired side effects or cardiac arrest. For this reason, it is of pivotal importance to always have IV access while sedating these patients. IV access with an indwelling catheter allows for more precise titration of drugs and immediate administration of reversals and emergency drugs if necessary. Monitoring vital parameters can be more challenging in sedated patients than in those under general anesthesia. This is because the lack of endotracheal intubation makes it challenging to adequately monitor ventilation (end-tidal carbon dioxide [CO2]), and the potential movement of the patient may alter blood pressure measurements and pulse oximeter readings. Commercially available nasal prongs can be used to monitor end-tidal CO2 without the invasiveness of an endotracheal tube. Also, new devices with modern microprocessors and algorithms make pulse oximetry and oscillometric arterial blood pressure monitors more accurate, even in the presence of movement. There should always be at least one experienced person exclusively dedicated to monitoring these patients during and immediately following the sedation event.

Critically ill patients admitted to an ICU frequently need some form of sedation or anxiolysis during hospitalization. This may be necessary for a variety of reasons, including obtaining vascular access, providing patient comfort, executing imaging procedures, reducing dysphoric effects of opioids in the postoperative period, or simply for mitigating the stress of being hospitalized in an unfamiliar environment. Furthermore, minor surgical procedures can be performed under sedation with the aid of loco-regional anesthesia.1 Sedating critically ill patients has the potential for the development of severe cardiovascular, respiratory, and neurologic side effects. This becomes even more clinically relevant in patients that may have reduced reserves due to severe underlying diseases. For this reason, it is of pivotal importance to perform an accurate patient assessment in order to tailor and titrate the sedative drugs to minimize and/or counteract any potential undesired effect. A complete physical examination and thorough history should be performed prior to any sedation. Patients with urgent requirements for sedation can be challenging since full assessment and stabilization may not be possible. The operator should prioritize supporting the cardiovascular, respiratory, and nervous system. This includes but is not limited to providing oxygen via facemask and addressing hypovolemia, hypotension, hypothermia, arrhythmias, severe electrolyte imbalances, and pain. Some patients require special attention during sedation (i.e., animals with brachycephalic syndrome, laryngeal paralysis, or space-occupying lesions around the airway). These patients may show mild signs of upper airway obstruction prior to giving any medications, but once sedated they may deteriorate quickly. It is vital to be prepared to perform orotracheal intubation or emergency tracheostomy in order to establish a patent airway. First and foremost, it is important to emphasize the characteristics that define a sedated patient. These include conservation of laryngeal function, gag reflex, and righting reflex. If the patient loses these physiologic mechanisms, it is no longer sedated, but rather under the influence of general anesthesia. It is a common misconception that sedation is safer than general anesthesia. It is always a better option for the critically ill patient to consider general anesthesia when a deep sedation is required, especially if the patient needs to remain perfectly still during manipulation (see Chapter 133, Anesthesia of the Critical Patient). General anesthesia with orotracheal intubation offers the ability to securely control the patient’s airway to prevent aspiration of ingesta during regurgitation, resolves upper airway obstruction, and

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SPECIFIC DRUG TECHNIQUES FOR SEDATION The most commonly used drug combinations for sedation in critically ill patients are opioids and benzodiazepines (see Chapters 155 and 156, Narcotic Agonists and Naloxone and Benzodiazepines). Opioids generally provide effective analgesia and sedation but have minimal cardiovascular side effects and maintain myocardial function, vascular tone, and increased parasympathetic tone.2 The latter can be counteracted easily with the administration of an anticholinergic agent such as atropine or glycopyrrolate. However, anticholinergic drugs should not be administered routinely, but used only when bradycardia is present in the absence of severe peripheral vasoconstriction. When using opioids for sedation, special attention is needed in patients with atrial-ventricular block, especially third-degree block, because the use of anticholinergics may not effectively treat the profound bradycardia, and opioids may further decrease the underlying escape rhythm. Opioids may also cause hypoventilation that may lead to hypoxemia and hypercarbia, especially when given in combination with other anesthetic drugs. Therefore, attention to ventilation, monitoring of oxygenation with pulse oximetry, and oxygen

CHAPTER 132  Sedation of the Critically Ill Patient supplementation is always warranted when sedating a critically ill patient with opioids. Animals with space-occupying lesions in the cranial vault or traumatic brain injury may experience high intracranial pressure; the hypoventilation and subsequent hypercarbia induced by opioids in these patients may precipitate worsening of their neurologic status (see Chapter 85, Intracranial Hypertension). The use of potent synthetic opioids for sedation in a critical care setting is a double-edged sword. On one side, it can be helpful to provide effective analgesia and narcosis with minimal cardiovascular effects, but often opioids at clinical doses can cause dysphoria, especially in cats. It is often difficult to distinguish dysphoria from discomfort, especially when a multimodal drug technique is used. If dysphoria from potent pure mu agonist opioids is suspected a small dose of butorphanol (0.01–0.05 mg/kg) can be slowly titrated by the intravenous route. This may successfully treat the dysphoria without completely removing the desired analgesic effects. However, if this technique is used, close monitoring of pain status should be prioritized because additional analgesia may be required. Care must be taken when using hydromorphone in cats because it may cause significant hyperthermia. It is advisable to use either methadone or fentanyl in this patient population whenever possible.3 Benzodiazepines like midazolam and diazepam are often used to sedate critically ill patients due to their wide therapeutic index. This is especially true for their minimal impact on the cardiovascular and respiratory systems and the fact that benzodiazepines can be antagonized with flumazenil.2 Care must be taken when using flumazenil in patients with a history of seizures because its administration may trigger episodes in these animals.4 Midazolam has the pharmacokinetic profile that allows for good bioavailability when administered by the intramuscular route. This can be advantageous when sedating a patient in order to obtain venous access. When benzodiazepines are used in conjunction with an opioid in anxious dogs and cats for sedation, they have a higher chance of causing paradoxical excitement. Care must be taken when using these drugs in animals with reduced liver function and are contraindicated in patients with portosystemic shunts (see Chapter 115, Portosystemic Shunt Management). Alpha-2 adrenoceptor agonists such as dexmedetomidine cause profound cardiovascular effects through vasoconstriction and reflex bradycardia. These drugs find limited application in the sedation of the critically ill patient, especially if cardiovascular instability is present.5 In the author’s opinion, however, these drugs are excellent sedatives and produce effective analgesia.6 Furthermore, they are widely used in the critical care setting at very low doses in constant rate infusion to achieve sedation and analgesia in anxious patients that require hospitalization in the intensive care unit (see Chapter 157, Alpha-2-Agonists and Antagonists). Most of the severe cardiovascular effects are seen with fast increments in plasma levels due to intravenous boluses; therefore, caution should be exercised with bolus therapy. Rather, a constant rate infusion of 2 micrograms/kg/hour for 15 minutes could be administered, and then the infusion can be decreased to 0.5–0.25 micrograms/kg /hour. This technique allows for effective sedation and analgesia without profound vasoconstriction and reflex bradycardia. Dexmedetomidine can be fully reversed with the alpha-2 adrenoceptor antagonist atipamezole. When reversing dexmedetomidine with atipamezole, both the sedative and analgesic actions of this drug will be antagonized. The phenothiazine acepromazine has been historically widely used in veterinary medicine for its dopaminergic mediated sedative and anxiolytic effects. However, it also has prominent non-dopaminergic effects. Specifically, it causes alpha adrenoceptor antagonism that may lead to clinically relevant hypotension.7,8 These effects are not dose-dependent and can be seen even after administration of low doses (0.005–0.02 mg/kg). For this reason, acepromazine should be used with caution in critical patients, particularly when cardiovascular function is compromised. Acepromazine has a relatively long duration of action (4–6 hours) without the benefit of

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reversibility. These significant characteristics limit the use of acepromazine in the critically ill patient. In recent years, the anxiolytic and mild sedative trazodone has been used to treat anxiety in critically ill patients where acepromazine is either contraindicated or ineffective (see Chapter 161, Trazodone).9 In the critical patient, it may be used in combination with opioids, benzodiazepines, and most commonly with gabapentin without adverse effects.10 When using the trazodone-gabapentin combination orally, it is necessary to allow 2 hours for the peak effect to be evident. Since trazodone interferes with central serotonin receptors, there may be the potential for serotonin syndrome in patients that are receiving other serotonergic agents, even if no reports exist in the literature for dogs or cats. Currently it is only available in the oral formulation, which can be an issue for patients where this route is not an option (e.g., head trauma with facial fractures, severe vomiting). Doses of 2–5 mg/kg every 8–24 hours have been reported.10 Anecdotally, trazodone has been combined with gabapentin at 10–15 mg/kg for sedation in cats and dogs. Gabapentin is a calcium channel antagonist that has been widely used in the treatment of seizures and as an adjuvant in the treatment of hyperalgesia and allodynia. Since two of its more common side effects are sedation and lethargy it is widely used as a sedative administered orally in combination with other sedative drugs and is a safer alternative to more traditional tranquilizers such as acepromazine and dexmedetomidine. Gabapentin has a long onset time and may take several hours to have a clinical effect (see Chapter 159, Gabapentin). An important part of sedating critically ill patients is the recovery phase. Continuing to closely monitor vital parameters and provide oxygen when necessary will decrease the risk of potential complications during this critical time. Even after sedative drugs have been fully reversed or their duration of action is considered terminated, there may still be residual effects, or the reversal drugs may wear off. This is especially relevant in sick patients with decreased organ function and inappropriate blood flow to the liver and kidneys.

REFERENCES 1. Barr C, Gianotti G: Alternatives to opioid analgesia in small animal anesthesia, Vet Clin Small Anim Pract 981-1156, 2019. 2. Machado CG, Dyson DH, Mathews KA: Evaluation of induction by use of a combination of oxymorphone and diazepam or hydromorphone and diazepam and maintenance of anesthesia by use of isoflurane in dogs with experimentally induced hypovolemia, Am J Vet Res 566:1227-1237, 2005. 3. Posener LP, Gleed R, Erb HN et al: Post-anesthetic hyperthermia in cats, Vet Anesth Analg 34:40-47, 2007. 4. Spivey WH: Flumazenil and seizures: analysis of 43 cases, Clin Ther 14: 292-305, 1992. 5. Sinclair MD: A review of the physiological effects of alpha2-agonists related to the clinical use of medetomidine in small animal practice, Can Vet J 44:885-897, 2003. 6. Devabhakthuni S, Pajoumand M, Williams C, et al: Evaluation of dexmedetomidine: safety and clinical outcomes in critically ill trauma patients, J Trauma 71:1164-1171, 2011. 7. Sinclair MD, Dyson DH: The impact of acepromazine on the efficacy of crystalloid, dextran or ephedrine treatment in hypotensive dogs under isoflurane anesthesia, Vet Anaesth Analg 39:563-573, 2012. 8. Martin-Flores M, Mostowy MM, Pittman E, et al: Investigation of associations between preoperative acepromazine or dexmedetomidine administration and development of arterial hypotension or bradycardia in dogs undergoing ovariohysterectomy, J Am Vet Med Assoc 255:193-199, 2019. 9. Gruen ME, Sherman BL: Use of trazodone as an adjunctive agent in the treatment of canine anxiety disorders: 56 cases (1995-2007), J Am Vet Med Assoc 233:1902-1907, 2008. 10. Gilbert-Gregory SE, Stull JW, Rice MR, et al: Effects of trazodone on behavioral signs of stress in hospitalized dogs, J Am Vet Med Assoc 249: 1281-1291, 2016.

133 Anesthesia in the Critically Ill Patient Jane Quandt, BS, DVM, MS, DACVAA, DACVECC

KEY POINTS • Appropriately stabilizing the condition of the critically ill animal before anesthesia is imperative to minimize anesthesia-related complications. • Problems should be anticipated and an appropriate and efficient treatment and therapeutic plan developed before induction of anesthesia.

• In the compromised, critically ill patient, the anesthetic drug doses often can be reduced to half of those for a normal, healthy patient. • The use of a balanced anesthesia technique should be considered to minimize potential deleterious effects of single-drug therapy. • Intensive monitoring of the anesthetized critically ill animal is essential.

In the critically ill patient, a thorough preoperative assessment is necessary to define what type of trauma or compromise the patient is undergoing. The critically ill patient has altered physiology and decreased reserves, which will affect the pharmacokinetic and pharmacodynamic behavior of anesthetic drugs. These patients benefit from the minimization of stress and optimization of oxygen delivery. Stabilizing the condition of the critically ill patient before anesthetic drug exposure is essential because induction of anesthesia in a patient in unstable condition increases the risk of anesthesia-related complications.

before anesthetic induction in patients in unstable condition. Blood products should be administered via a dedicated catheter, and no other fluids or drugs should be administered in the same line during the transfusion due to concerns of possible contamination and potential for bacterial growth. This is also true for those patients that are receiving PN. The catheter for PN should be a dedicated line (see Chapter 127, Parenteral Nutrition). It is also important to provide warm intravenous fluids before and during anesthesia to help maintain organ perfusion and body temperature. If fluids need to be given at a rapid, shock bolus rate, use of the shortest, largest-bore catheter (e.g., peripheral cephalic catheter) will allow for the most rapid fluid administration. Placement of an arterial catheter once the animal is under general anesthesia is recommended. An arterial catheter allows for direct arterial blood pressure measurement and can be used to collect samples for arterial blood gas analysis. A packed cell volume (PCV) greater than 25% is necessary for adequate oxygen-carrying capacity and oxygen delivery. During anesthesia the PCV can decrease by 3% to 5%; therefore even a small volume of blood loss may be significant in the anesthetized animal and may warrant a blood transfusion.1 Similarly, patients with hypoproteinemia (total protein #3.5 g/dl and/or albumin level #2 g/dl) may benefit from the use of colloids to help maintain normal colloid osmotic pressure (COP; normal 5 18 to 24 mm Hg) and to prevent edema formation or vascular leak.2,3 Measurement of COP before anesthesia maybe helpful in determining the need for colloid support and deciding when to terminate colloid therapy. If patients are hypoproteinemic, colloid options include Hetastarch, VetStarch, 5 g of lyophilized canine albumin, or species-specific plasma.4 High-molecular-weight hydroxyethyl starch synthetic colloids such as Hetastarch impair coagulation in a dose-dependent manner, and this may limit their use in hypocoagulable, hypoproteinemic surgical patients. VetStarch is a low-molecularweight tetrastarch that has far fewer coagulation effects than the Hetastarches. As a result it may have a role in the support of COP in the surgical patient, although it would seem prudent to minimize its use in high-risk patients with hypocoagulability (see Chapter 66, Colloid Solutions). Hydroxyethyl starch solutions have been associated with kidney injury in human patients, and although the risk in small animal patients has yet to be fully determined, it is recommended to avoid

STABILIZATION A thorough diagnostic assessment, including serial physical examinations, diagnostic imaging, blood chemistry testing, complete blood count, determination of coagulation profile, and measurement of acidbase status, blood glucose level, and lactate level should be performed as indicated before anesthesia. A dehydrated or hypovolemic state along with fluid, acid-base, and electrolyte deficits ideally should be corrected before anesthetic induction. Maintaining venous access is imperative in managing and anesthetizing the critical care patient because it is not uncommon for the critically ill animal to experience hypotension during the anesthesia period. Intravenous administration of drugs is usually preferred because drugs administered by the intramuscular or subcutaneous routes may have delayed absorption, particularly when the patient is dehydrated, hypovolemic, poorly perfused, or hypothermic. Critically ill patients often benefit from placement of more than one intravenous catheter; either multiple peripheral catheters or central line can be used. The patient that postoperatively is expected to require serial blood samples taken or even the necessity of parenteral nutrition (PN) would benefit from the placement of a central line prior to recovery. The intravenous catheter provides a port not only for drug administration but also for antibiotic delivery, vasopressor and inotropic support, blood products, and fluid therapy. Because of different fluid rate requirements and possible incompatibility of various agents such as vasopressors, sodium bicarbonate, and blood transfusion products, a minimum of two intravenous catheters should be placed

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CHAPTER 133  Anesthesia in the Critically Ill Patient hydroxyethyl starch solutions in animal with kidney disease or considered high risk. In small, hypocoagulable, or hypoalbuminemic patients, the use of fresh-frozen plasma (FFP) at 6 to 20 ml/kg is warranted. Unfortunately, size, dosing, and cost become a limiting factor in the use of FFP to treat hypoalbuminemia in larger patients because it takes a dose on the order of 45 ml/kg of FFP to increase the albumin level by 1 g/dl.5 Lyophilized canine albumin is a commercially available product that comes as 5 grams and can be reconstituted using 0.9% saline.4 Finally, patients should be carefully evaluated for underlying metabolic disease before anesthesia because this may affect the anesthetic protocol. In patients with renal insufficiency, a higher fluid rate may be required to maintain renal perfusion, and urine output should be monitored carefully during anesthesia.6 In addition, drugs excreted by the kidney (e.g., ketamine in cats) may have delayed excretion and should be used cautiously. In patients with liver disease, anesthetic protocols and monitoring may be affected due to decreased glucose and albumin production, altered drug metabolism via cytochrome P-450 enzymes, and decreased production of coagulation factors.6 The presence of a heart murmur may indicate the presence of valvular heart disease. Such patients may have a decreased ability to compensate under anesthesia, and fluid overload should be avoided. Blood pressure should also be carefully monitored if heart disease is suspected because anesthesia-induced hypotension may result in decompensation. Finally, one should always determine whether the patient is currently receiving any drug therapy, such as nonsteroidal antiinflammatory drugs, diuretics, anticonvulsants, or cardiac medications.

PREMEDICATION Premedication may not be necessary unless the animal is in severe pain or is extremely fractious. If it is decided that the critically ill patient would benefit from premedication, µ-agonist opioids such as hydromorphone, morphine or methadone, which also is a noncompetitive inhibitor of N-methyl-D-aspartate (NMDA), in combination with a tranquilizer such as midazolam or low-dose acepromazine (0.005 to 0.01 mg/kg), can be given intramuscularly to provide analgesia and sedation. If given to the critically ill, acepromazine should be used at lower doses than in a normal animal due to the profound hypotension that can result. A µ-agonist is preferred because the k-agonist butorphanol and the partial µ-agonist buprenorphine may not be sufficient for severe pain. In the fractious but fragile feline patient, alfaxalone combined with an opioid and benzodiazepine will provide analgesia, restraint, and muscle relaxation with fewer cardiovascular effects than can be seen with a2-agonists or dissociative agents. This combination is also useful in small breed dogs. The volume of alfaxalone needed makes this combination less appealing in the large breed dog when given IM. Although a µ-agonist narcotic can be combined with an a2-agonist and/or a dissociative drug and administered intramuscularly in an animal that is in severe pain or is extremely fractious, this is rarely indicated in a critically ill patient, which is usually obtunded and easily handled. Anticholinergics are not routinely used unless there is a need to treat bradycardia. Protocols should be implemented to minimize the amount of time the animal is under anesthesia; therefore, steps such as clipping the surgical site before induction should be performed if possible. Preoxygenation of the animal for several minutes prior to induction will allow for additional time that may be needed to intubate the animal; this is especially helpful for animals that are in respiratory distress or have a difficult airway. Finally, electrocardiographic and blood pressure monitoring should be in place before induction to detect evidence of arrhythmias, hypotension, or cardiovascular collapse that may occur during induction in the critically ill animal. In the severely compromised animal, cardiac arrest treatment drugs such as atropine

779

and epinephrine should be close at hand during the induction and anesthetic period.

INDUCTION In the compromised, critically ill patient, the anesthetic drug doses often can be reduced to half of those for a normal, healthy patient (Table 133.1). Induction drugs should be slowly titrated IV to effect, and the minimal amount of drug necessary to intubate the patient should be used. In addition, use of a balanced anesthetic technique helps to minimize the adverse effects from any single agent. One can consider the use of local anesthetic blocks and epidural anesthetics if appropriate to decrease the amount of general anesthetic that is required. Intubation should always be performed to provide the ability to ventilate the patient and to protect the airway from aspiration. The emergent patient should be considered to have a full stomach and therefore to be at risk of aspiration. A preinduction dose of maropitant, a neurokinin receptor antagonist anti-emetic, at 1 mg/kg IV can be given to dogs and cats to help prevent vomiting.7 A laryngoscope, endotracheal tubes in a variety of sizes, and a breathing circuit that matches the patient’s size should all be readily available. All supplies and machinery should be checked thoroughly before induction and intubation. One should be ready to implement positive pressure ventilation if the patient hypoventilates, becomes apneic, or is to undergo a thoracic procedure. Ideally there should be a slow transition to general anesthesia that would allow time for the cardiovascular and nervous systems to respond and accommodate appropriately.8 However, the critically ill patient may not be able to respond appropriately, and therapeutic intervention must be available to prevent the demise of the patient. For example, a patient in respiratory distress will require a rapid-sequence intubation to gain control of the airway and provide ventilation with 100% oxygen.

INDUCTION AGENTS Thiopental and Propofol A rapid-sequence induction can be accomplished with agents that have a short onset time, such as thiopental or propofol. These agents have an onset time of approximately 30 seconds and need to be given IV. Their duration of action is also short, with thiopental lasting 10 to 15 minutes and propofol lasting 5 to 10 minutes; propofol may be the preferred agent due to its shorter duration of action. Both of these drugs can be used in combination with diazepam or midazolam to improve relaxation and to decrease the overall dose needed. Both agents are capable of creating cardiac arrhythmias, hypotension, and apnea; hence, intermittent positive pressure ventilation may be necessary.9 Neither agent provides analgesia, so additional analgesics must be given before the surgical procedure. Thiopental and propofol do decrease intracranial and intraocular pressure and would be indicated for induction in a patient with head trauma.10 The new formulation of propofol, PropoFlo 28, is not labeled for use in cats. The new formulation contains the preservative benzyl alcohol, which can be toxic to cats when given in large doses. Cats have a low capacity for glucuronic acid conjugation and therefore have limited ability to metabolize benzoic acid. However, PropoFlo 28 has been used safely in healthy cats, with no indications of toxicity and with normal recoveries.11 Propofol as an agent is less well tolerated in cats than in dogs, with slower metabolism and excretion, and repeated doses or infusions are associated with prolonged recoveries. It has also been shown that propofol can increase the presence of Heinz bodies.11 It may be prudent to avoid the use of PropoFlo 28 in cats that are debilitated or have liver impairment.

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TABLE 133.1  Anesthetic Agents and Their Dosages Drugs

Dose

Comments

Anticholinergic agents

Atropine 0.04 mg/kg IM, 0.02 mg/kg IV Glycopyrrolate 0.01 mg/kg IM, IV

May make secretions more viscous Increase anatomic dead space Increase heart rate Can increase myocardial work and oxygen consumption Glycopyrrolate does not cross blood–brain barrier or the placenta

Morphine 0.2–2 mg/kg IM, SC; CRI: 0.1 to 0.3 loading dose, then 0.1 mg/kg/hr

Complete reversal with naloxone Analgesic Cause respiratory depression Cause bradycardia Minimal effect on CV performance Give anticholinergic drug before starting CRI Monitor for hyperthermia in cats

Opioids µ-Agonists

Oxymorphone 0.05–0.2 mg/kg IM, IV, SC Meperidine 2–5 mg/kg IM, SC Hydromorphone 0.05–0.2 mg/kg IV, IM, SC; CRI: 0.025– 0.05 mg/kg IV loading dose, then 0.01–0.04 mg/kg/hr Fentanyl 0.005–0.05 mg/kg IM, IV, SC; CRI for dogs: loading dose 5–10 mcg/kg, then 2 to 10 mcg/kg/hr; CRI for cats: loading dose 5 mcg/kg, then 2 to 10 mcg/kg/hr Remifentanil 3 mcg/kg IV; CRI: 0.1–0.3 mcg/kg/min Mu-agonist NMDA-antagonist

Methadone 0.2–1 mg/kg IV, IM

Can cause bradycardia Good for chronic and neuropathic pain

Partial µ-agonist

Buprenorphine 0.005–0.02 mg/kg IM, IV

Slow onset, effects difficult to reverse Good for moderate pain

k-agonist/µ-antagonist

Butorphanol 0.1–0.8 mg/kg IM, IV, SC; CRI: 0.1–0.2 mg/kg IV loading dose, then 0.1–0.2 mg/kg/hr

Partial reversal of µ-agonist drugs Minimal CV effects Not good for severe pain

Opioid antagonist

Naloxone 0.002–0.02 mg/kg IM, IV

Complete reversal of µ-agonist effects

Dissociative agents

Ketamine 4–11 mg/kg IV, IM; CRI: 0.5 mg/kg IV loading dose, then 0.1 to 1 mg/kg/hr Tiletamine and zolazepam (Telazol) 2–4 mg/kg IM, IV

Cause salivation Increase heart rate Increase ICP and intraocular pressure Analgesic Renal elimination in cat

Ketofol

Ketamine/propofol 1:1 200 mg of ketamine in 200 mg of propofol: 0.5 mg/kg IV or Ketamine 2 mg/kg followed by propofol 2 mg/kg IV

Good intubation and induction qualities Better pulse rate and MAP

Benzodiazepines

Diazepam 0.2–0.5 mg/kg IM, IV; CRI: 0.1–0.5 mg/kg/hr

Can decrease required dose of other drugs Mild sedative and muscle relaxant Anticonvulsant Not analgesic Diazepam formulation contains propylene glycol

Midazolam 0.07–0.4 mg/kg IM, IV; CRI: 0.1–0.5 mg/kg/hr

Phenothiazine

Acepromazine 0.01–0.1 mg/kg IM, IV; no more than 3 mg total dose

Vasodilatory Long duration of action Not analgesic

Barbiturates

Thiopental 4–20 mg/kg IV

Cause cardiovascular depression Cause respiratory depression Provide rapid induction Decrease ICP and intraocular pressure Effects may be potentiated by concurrent acidosis or hypoproteinemia

Methohexital 4–10 mg/kg IV

Propofol

2–8 mg/kg IV; CRI: 0.05–0.4 mg/kg/min

Rapidly acting with short duration of action Causes respiratory depression Causes peripheral vasodilation Myocardial depressant Not analgesic Use with caution in patients with volume depletion or cardiovascular compromise; can cause significant depression Can cause Heinz body anemia in cats

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TABLE 133.1  Anesthetic Agents and Their Dosages—cont’d Drugs Etomidate

Dose 0.5–4 mg/kg IV

Comments Maintains cardiovascular stability Not used alone Suppresses adrenocortical function for 2–6 hr following single bolus dose Contains propylene glycol

a2-Agonist

Dexmedetomidine 3–40 mcg/kg IM, IV; CRI: 1 mcg/kg IV loading dose, then 0.5–2 mcg/kg/hr

Causes cardiovascular depression Can cause vomiting Provides good sedation and analgesia Can be combined with butorphanol or ketamine

a2-Antagonist

Atipamezole 0.04–0.5 mg/kg IM, IV

Neuroleptanalgesic

Combination of opioid and tranquilizer

Analgesic Causes noise sensitivity Maintains cardiovascular stability

Alfaxalone

2–5 mg/kg IV 0.1 to 0.2 mg/kg/min CRI

Sedation may be needed to improve recovery

Lidocaine

CRI: 1–2 mg/kg IV loading dose, then 1–3 mg/kg/hr

Not recommended in cats

Inhalants

Isoflurane

Produces dose-dependent cardiovascular depression and peripheral vasodilation Anesthesia depth can be adjusted rapidly Potential for hypoxemia Isoflurane and sevoflurane show rapid uptake and recovery Nitrous oxide should be used with caution with closed gas spaces

Nitrous oxide Sevoflurane

Neuromuscular blocking agents

Atracurium 0.1 mg/kg IV; or CRI: 3–8 mcg/kg/min IV

Aminosteroidal neuromuscular blocking agents

Cisatracurium 0.1 mg/kg IV; incremental doses of 0.02–0.04 mg/kg IV Rocuronium 0.6 mg/kg IV Vecuronium 0.1 mg/kg IV

NMB reversal agents

Neostigmine 0.04–0.06 mg/kg IV

Atropine 0.02 mg/kg IV should be given with neostigmine to prevent bradycardia

Reversal agent for aminosteroidal NMB

Sugammadex 8 mg/kg IV

Can reverse profound block No cardiovascular side effects

CRI, constant rate infusion; CV, cardiovascular; ICP, intracranial pressure; IM, intramuscularly; NMB, neuromuscular blocking agents; SC, subcutaneously.

Alfaxalone

Etomidate

A new induction agent, alfaxalone, may be useful for anesthesia induction in the critically ill animal. Alfaxalone is a synthetic neuroactive steroid. It is rapidly metabolized and eliminated from the body. Alfaxalone, like thiopental and propofol, is associated with dose-dependent changes such as hypoventilation and apnea but has a wide margin of safety. It can also be used as a constant rate infusion (CRI) and provides good muscle relaxation and rapid recovery. There may be some excitement on recovery, with paddling and muscle twitching or even violent movements; sedation improves recovery. Alfaxalone has a short duration of action, 14 to 50 minutes.12 In dogs that were considered a poor anesthetic risk, alfaxalone administered at 1 to 2 mg/kg IV over 60 seconds was shown to be an acceptable induction agent with smooth recovery.13 Alfaxalone can be safely combined with a fentanyl CRI. Use of alfaxalone in cats results in a smooth induction, but there may be paddling and trembling in recovery, and the quality of recovery worsens as the dose of alfaxalone increases. Cats recovering from alfaxalone induction may be more disoriented and nervous than those recovering from propofol induction.14

The use of etomidate for anesthesia induction in critically ill patients is appealing due to its minimal cardiovascular effects, which would be helpful in the patient with cardiovascular instability. Etomidate should not be used as the sole induction agent because it may lead to retching and myoclonus. These adverse effects are minimized by giving a benzodiazepine or opioid IV before etomidate is administered. Repeated use of etomidate in cats may lead to hemolysis due to the propylene glycol vehicle.15 The use of etomidate in critically ill human patients is controversial due to its ability to cause adrenal dysfunction, which may lead to an increase in morbidity and mortality. The duration of the adrenal dysfunction can range from 24 to 48 hours in the critically ill patient.16 The use of hydrocortisone to treat the etomidate-induced adrenal insufficiency had no effect on outcome.17 The recommendation in human medicine is to use etomidate cautiously in patients with septic shock.

Ketamine Ketamine may be used IV as part of an induction protocol; it is commonly administered with a benzodiazepine. Ketamine has the potential

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to induce seizures when given as a sole agent.10 Ketamine increases heart rate, blood pressure, and cardiac output via a centrally mediated sympathetic response and endogenous catecholamine release. Because of the potential for increased cardiac contractility, it should be used cautiously in animals with hypertrophic cardiomyopathy. Ketamine can have direct myocardial depressant effects, and in debilitated patients with a decreased endogenous catecholamine response there may be hypotension and cardiovascular instability. As an NMDA receptor agonist, ketamine provides analgesia peripherally and somatically.18

Ketamine/Propofol (Ketofol) Coinduction is the use of a combination of two or more drugs to achieve induction and aims to decrease the doses and adverse effects of the drugs used. Propofol is a commonly used agent but has a rapid onset with a short duration and no analgesia. In addition, it can cause apnea and muscle twitching. The addition of ketamine will provide analgesia and a longer duration of action. The combination can be done in two ways: 200 mg of ketamine (100 mg/ml) can be added to 200 mg of propofol (10 mg/ml) and given at 0.5 ml/kg IV, with the mixture kept for a maximum of 12 hours. The second technique is to give ketamine at 2 mg/kg IV followed by a separate syringe of propofol at 2 mg/kg IV. The use of ketofol was associated with a higher pulse rate and mean arterial blood pressure with a superior quality of intubation and induction.19

Opioids In critically ill patients in stable condition, a more gradual induction technique can be implemented. This may be accomplished with the use of neuroleptanalgesics such as hydromorphone, methadone or fentanyl in combination with diazepam or midazolam with the addition of either propofol, alfaxalone or ketamine to facilitate induction. In dogs and cats with severe liver compromise, remifentanil may be considered for analgesia during general anesthesia. Remifentanil is a synthetic opioid that has a direct action on the µ receptors and an ultrashort duration of action. The elimination of remifentanil is independent of hepatic or renal function, which makes it an attractive agent for use in animals with hepatic or renal compromise. It is metabolized by nonspecific esterases in blood and tissues. Recovery from remifentanil effects is very rapid even following long-term intravenous infusions.20 It has been used in dogs at an initial dose of 3 mcg/kg IV and then a CRI of 0.1 to 0.3 mcg/kg/min, with the drug diluted in normal saline.20.21 Due to the drug’s short duration of action an additional analgesic must be administered upon termination of the remifentanil effects if the painful condition persists. The clinical effects of remifentanil are rapidly dissipated upon discontinuation of the infusion, with dogs recovering in 5 to 20 minutes regardless of the duration of the infusion. Remifentanil administered by CRI, like other opioid CRIs, is a potent respiratory depressant, and therefore mechanical ventilation may be required; however, this respiratory depression does not persist following recovery. Remifentanil has been used in cats. A dose higher than 1 mcg/kg/min was associated with dysphoric behavior and frenetic locomotor activity.22 Methadone is a µ-agonist and also a noncompetitive inhibitor of NMDA receptors. Methadone can reduce the reuptake of norepinephrine and serotonin, which may contribute to its analgesic effects. Methadone can cause bradycardia. Serotonin levels may be enhanced when methadone is given concurrently with serotonin modulators. The potential increase in serotonin may lead to serotonin syndrome and requires careful monitoring.23

Multimodal Anesthesia The use of multiple agents (e.g., hydromorphone, midazolam, ketamine, and lidocaine) is an example of balanced anesthesia. This

protocol produces a slower onset but provides analgesia and is more sparing of the cardiovascular system.24 Ketamine may be used to enhance analgesia and increases heart rate and blood pressure.25 When these drugs are used for induction, the dose also serves as the loading dose before their administration as a CRI. Morphine (3.3 mcg/kg/ min), lidocaine (50 mcg/kg/min), and ketamine (10 mcg/kg/min) can be administered as a CRI analgesic combination in dogs.24 In addition, lidocaine may retard the effects of compromised viscera, reperfusion injury, or ventricular arrhythmias due its free radical scavenging abilities, analgesic effects, and antiarrhythmic properties.26 Use of a lidocaine CRI is not recommended in cats due to its depressive effects on the cardiovascular system.27 Propofol is not recommended for use as a single agent for major surgical procedures because it does not prevent hemodynamic responses to noxious stimulation. It can be used in combination with other agents such as lidocaine and ketamine in dogs for total intravenous anesthesia. Propofol has negative chronotropic and inotropic effects and also causes venodilation, which can lead to a decrease in blood pressure.28 In animals with splenic disease such as a tumor or splenic fracture, the use of an appropriate induction agent is indicated because some agents are known to increase splenic size, which could lead to tumor rupture or increased hemorrhage. The administration of acepromazine, thiopental, and propofol can result in splenomegaly. It may be best to avoid these agents in animals with splenic disease or if laparoscopy is planned. Hydromorphone and dexmedetomidine were found not to result in increased splenic size. There was also a reduction in hematocrit in those dogs receiving acepromazine, thiopental, and propofol, which may be of concern in the anemic patient.29

MAINTENANCE ANESTHESIA Inhalants Once the animal is intubated, anesthesia can be maintained via an inhalant agent such as isoflurane or sevoflurane. These two agents are the most commonly used, but both agents cause cardiovascular and respiratory depression. Both agents have a rapid onset and recovery time and allow for rapid changes in anesthetic concentration.30

Constant Rate Infusion Maintenance anesthesia can also be achieved with a CRI if an animal cannot tolerate the hypotensive effects of inhalant anesthesia. Ketamine-propofol and ketamine-propofol-dexmedetomidine infusions have been used in cats during ovariectomy. Cats were given one of the two combinations IV for induction and then maintained on a ketamine-propofol infusion for the surgery. No adverse effects were seen with either group, but sedation was more profound in the group receiving dexmedetomidine.31 As stated previously, morphine, lidocaine, and ketamine can be used as a CRI to provide analgesia and to decrease the amount of inhalant required in dogs. Additional µ-agonists that can be used as a CRI include fentanyl, oxymorphone, and hydromorphone.10 An a2-agonist can also be used as a CRI to enhance analgesia and minimize the amount of inhalant needed.32 Such CRIs that have been used during surgery can be carried over into recovery to provide titratable analgesia, and the dose can usually be lower once surgical stimulation is over.

Neuromuscular Blocking Agents Neuromuscular blocking agents (NMBs) can be used to facilitate positive pressure ventilation as part of a balanced anesthetic technique or as part of an anesthetic technique for animals undergoing intensive care unit mechanical ventilation. Neuromuscular blockade helps to

CHAPTER 133  Anesthesia in the Critically Ill Patient prevent patient-ventilator dyssynchrony, stop spontaneous respiratory efforts and muscle movement, improve gas exchange, and facilitate inverse-ratio ventilation. NMBs may also be useful in managing increased intracranial pressure and the muscle spasms of tetanus, drug overdose, or seizures.33 Their use in surgery is to enhance skeletal muscle relaxation, to facilitate control of respiratory efforts during intrathoracic surgery, to immobilize the eye for ocular surgery, and to facilitate intubation of a difficult airway.34 These agents do not have anesthetic or analgesic properties, and therefore it is imperative that they be given only when the animal is adequately insensible to pain and awareness.35 Positive pressure ventilation is mandatory with their use. The duration of action of NMBs can be altered by hypothermia, acid-base abnormalities, and electrolyte disturbances, conditions commonly seen in critically ill patients. NMBs can be given by intermittent intravenous bolus or CRI. Intermittent bolus administration may offer some advantages, including control of tachyphylaxis, monitoring for accumulation, provision of analgesia and amnesia, and limiting of complications related to prolonged or excessive blockade.33 There must be constant supervision when an animal is receiving an NMB because the patient would be incapable of spontaneous respiration should a malfunction of the mechanical breathing circuit occur, and this would lead to death of the animal. The preferred relaxing agent is a nondepolarizing NMB. There are two types of nondepolarizing NMB: aminosteroidal and benzylisoquinolinium compounds. There are several different NMB drugs in each of these classes. The details of each class are beyond the scope of this chapter. For a full review of NMB drugs, the interested reader is directed to Hall et al.,34 Lukasik,35 and Keegan.36

Benzylisoquinolinium Agents The benzylisoquinolinium compounds are more commonly used and include atracurium, cisatracurium, doxacurium, and mivacurium. Atracurium is intermediate acting and has minimal cardiovascular effects.33 Atracurium is unusual in that its degradation process is independent of enzymatic function; it is inactivated in the plasma by ester hydrolysis and Hofmann elimination, with spontaneous degradation occurring at body temperature and pH.33,35,37 Atracurium is indicated for use in neonates and patients with significant hepatic or renal impairment.35 Atracurium blockade occurs within 3 to 5 minutes of administration and has a duration of 20 to 30 minutes.35 Atracurium can be redosed at 0.1 mg/kg IV or given as a CRI of 3 to 8.0 mcg/kg/min IV.10 Recovery of normal neuromuscular activity usually occurs within 1 to 2 hours after discontinuance of a CRI and is independent of organ function. Long-term CRIs have been associated with the development of tolerance, requiring dose increases or switching to another NMB.33 Atracurium can be used as part of an anesthetic induction protocol. It may be considered when it is desirable to avoid increases in intraocular, intracranial, or intraabdominal pressure caused by patient coughing or a Valsalva maneuver. It may also be used to provide faster control of ventilation in an animal in unstable condition.35 There are two induction techniques. In one method atracurium is given in divided doses of one-tenth to one-sixth of the calculated dose initially, and then 3 to 6 minutes later the rest of the calculated dose is given along with the induction agent. This method accelerates relaxation after induction. The second technique is to give a single bolus of atracurium and 3 minutes later, at the onset of muscle weakness, to give the induction agent.35 Potential adverse effects that may occur with the use of atracurium include laudanosine formation and histamine release. Laudanosine is a breakdown product of Hofmann elimination that has been associated

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with central nervous system excitement. This may be a concern in patients that have received extremely high doses of atracurium or that have hepatic failure because laudanosine undergoes liver metabolism.33 At clinically useful doses, 0.1 to 0.30 mg/kg IV, the potential for histamine release does not appear to be a problem.36 Long-term use of atracurium and other NMBs has been associated with persistent neuromuscular weakness.33 A study in dogs in which neuromuscular blockade was produced by atracurium and either sevoflurane or propofol CRI was used for anesthesia demonstrated that the duration of neuromuscular blockade was approximately 15 minutes longer when sevoflurane was used than when propofol was used.40 Cisatracurium is an isomer of atracurium. It is similar in duration of action, elimination profile, and production of laudanosine.33 It produces few if any cardiovascular effects and has a lesser tendency to produce histamine release and is more potent than atracurium.33,37 As with atracurium, prolonged weakness may occur following long-term use of cisatracurium.33 The dose is 0.1 mg/kg IV, with incremental doses of 0.02 to 0.04 mg/kg IV in the dog to maintain the blockade. The initial dose has a duration of effect of 27.2 6 9.3 minutes, the incremental doses appear to be noncumulative, and no adverse effects have been noted. The kidney and liver excrete the metabolites of laudanosine, but the hepatic excretion is less important in the dog. Laudanosine can cause hypotension and seizures, but this may be more likely in dogs with kidney or liver disease.37

Aminosteroidal Agents The two commonly used agents in this group are vecuronium and rocuronium. Vecuronium has onset time of 5 minutes with a duration of 30 minutes. It comes as a lyophilized powder that is reconstituted prior to use. It undergoes hepatic metabolism and renal elimination. Rocuronium has a more rapid onset with a similar duration of action. The primary route of elimination is hepatic metabolism. Both agents have minimal cardiovascular effects and do not cause histamine release.36 Doses that have been used for rocuronium are 0.6 mg/kg IV and for vecuronium 0.1 mg/kg IV.38

Monitoring of Neuromuscular Blocking Agents Monitoring of NMB effects using a peripheral nerve stimulator is recommended. Monitoring the depth of the blockade allows the lowest dose of NMB to be used and therefore minimizes adverse effects. It will also help to confirm that adequate neuromuscular function has returned before discontinuation of ventilator support and anesthesia. Monitoring is done by observing skeletal muscle movement and respiratory efforts and measuring the twitch response to transcutaneous delivery of electric current to induce peripheral nerve stimulation.33 The peripheral nerves most commonly used include the facial, ulnar, tibial, and superficial peroneal nerves.34 When NMB effects begin to diminish the animal may show decreased chest wall compliance and increased resistance to ventilation and greater peak inspiratory pressure will be generated at the same tidal volume.35 Nystagmus, papillary dilation, and palpebral reflex may be noted. To evaluate the recovery from NMB, one can assess the tidal volume using a Wright respirometer as well as the character of ventilation, the ability to swallow, the adequacy of pulse oximetry readings, and end-tidal carbon dioxide. If there is residual weakness, this can be serious and potentially life-threatening. If doubt exists about the strength of recovery, a reversal agent can be given. Acceleromyography (AMG) is a quantitative method to monitor neuromuscular blockade by the extent of maximal block and onset time. It is also used to indicate recovery of the neuromuscular transmission. The train-of-four stimulating needles are placed over the nerves, and the acceleration sensitive transducer crystal is placed on

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the paw. When the train-of-four stimulus occurs, the evoked twitch is quantified via the acceleromyograph. This measures the mechanical activity objectively.38,39

Reversal Agents for Neuromuscular Blocking Agents Reversal of the effects of nondepolarizing neuromuscular blocking agents is possible, although not always necessary. Reversal may be considered in the critically ill patient to improve respiratory muscle function. An anticholinesterase inhibitor, neostigmine, is used for reversal. Reversal should not be attempted when no twitches are seen with the train-of-four monitor. Twitch height must be a minimum of 10% of the baseline height for reversal to be successful.35 The accumulation of acetylcholine also produces muscarinic effects such as bradycardia, salivation, increased bronchial secretion, smooth muscle contraction, defecation, urination, and hypotension.34,35 These adverse effects can be minimized by concurrent administration of an anticholinergic agent such as atropine or glycopyrrolate. Neostigmine has peak effects at 7 to 10 minutes after administration and a duration of action of 60 to 70 minutes and is dosed at 0.04 to 0.06 mg/kg IV combined with glycopyrrolate 0.01 mg/kg IV to combat bradycardia.10,35 For further information on reversal of NMB agents, the interested reader is directed to Hall et al.,34 Lukasik,35 and Keegan.36 The aminosteroidal agents, vecuronium and rocuronium, can be reversed with sugammadex, 8 mg/kg IV. Sugammadex is a gammacyclodextrin used to reverse aminosteroidal NMB. It binds the drug by encapsulation in the blood and can be used to reverse profound neuromuscular block in less than 2 minutes. The interaction is tight and long-lasting, and the complex is biologically inert with excretion from the plasma by the kidneys. Sugammadex does not have the limitations seen with the other NMB reversal agent, acetylcholinesterase inhibitor, which is of limited effectiveness when trying to reverse a deep neuromuscular block or the cardiovascular side effects. A concern may be the encapsulation of other steroidal drugs or endogenous steroids.38

ANESTHESIA MONITORING Maintenance anesthesia requires careful and constant monitoring to avoid excessive depth of anesthesia and to preserve cardiovascular function. The electrocardiogram should be monitored closely for changes in heart rate and rhythm, and for the presence of malignant arrhythmias, which may be more prevalent in patients with trauma, splenic disease, septic peritonitis, hypoxia, or gastric dilatation-volvulus. Additional monitoring during the maintenance phase of anesthesia includes maintaining the mean arterial blood pressure above 60 mm Hg to maintain renal perfusion. Physical examination parameters indicative of perfusion, such as capillary refill time, mucous membrane color, and pulse quality, should also be monitored continuously. Depth of anesthesia should be frequently assessed by monitoring eye position, pupil size, jaw tone, response to stimulus, heart rate, blood pressure, and respiratory rate throughout the duration of anesthesia. Other monitoring techniques should be implemented, both during and after anesthesia, to enhance the quality of care and increase survival. The use of pulse oximetry adds information to hemoglobin saturation and oxygenation.41 It is important to remember that patients maintained on supplemental oxygen may have a normal pulse oximetry reading despite having abnormal oxygenating ability. The pulse oximeter (assuming it is accurate) will read less than 100% only when the arterial partial pressure of oxygen falls below approximately 140 mm Hg. As a result, patients breathing 100% oxygen can have significant decreases in oxygenating ability that the pulse oximeter cannot recognize. Because of this, arterial blood gas monitoring may be necessary as the gold standard in critically ill patients under anesthesia (see Chapter 16, Hypoxemia). Arterial

blood gas values will provide information on oxygenation, ventilation, hemoglobin saturation, acid-base balance, and electrolyte levels. Capnography allows monitoring of the adequacy of ventilatory function and provides an indication of adequate cardiac output. Capnography is also used to monitor for the occurrence of esophageal intubation, breathing circuit disconnection, and cardiac arrest, circumstances where it will not register any carbon dioxide.41 (For further information see Chapter 190, Capnography.) Urine output should be monitored carefully, and goals to achieve normal urine output of 1 to 2 ml/kg/hr should be achieved.6 The use of an indwelling urinary catheter can be considered to measure urinary output adequately in patients with renal impairment or inadequate blood volume (in which one would clinically see decreased urine output). Fluid balance can be assessed by comparing the volume of fluid administered during anesthesia with the measured losses during the same time period. Preexisting fluid deficits must be considered when making this evaluation. The measurement of central venous pressure may help in the evaluation of fluid therapy but has some limitations.6 Chapter 181 discusses hemodynamic monitoring in more detail. PCV, total protein, and COP should be monitored frequently because rapid changes can occur in the surgical patient. In the absence of colloid osmometry, the total protein measurements can be evaluated, although these do not reflect the presence of synthetic colloids accurately. Blood glucose levels should be closely monitored in pediatric animals and those with sepsis, diabetes, or severe liver disease. Finally, body temperature should be continuously monitored because anesthetic drugs disrupt normal thermoregulatory mechanisms and hypothermia leads to prolongation of recovery.42

Intraoperative Hypotension Because critically ill patients are often hypotensive during anesthesia, a mean arterial blood pressure of less than 60 mm Hg or a systolic pressure of less than 90 mm Hg requires prompt treatment to maintain appropriate organ perfusion.43 The initial step should be to decrease the administration of inhalant anesthetic agents due to their depressant and vasodilatory properties. Next, administration of a fluid bolus should be initiated. Either a crystalloid (without potassium supplementation) delivered at a rate of 10 to 20 ml/kg IV over 15 to 20 minutes or a colloid bolus of 5 to 10 ml/kg IV administered over 10 to 20 minutes should be given. If no effect is observed, administration of multiple small boluses can be attempted, with consideration of the total volume of fluids that have been given. If the hypotension persists despite fluid therapy, there may be a need for inotropic and/or vasopressor support in the form of dobutamine or dopamine. Because of their short half-life these agents are given as a CRI at 2 to 10 mcg/kg/min IV.43 Dobutamine and dopamine can be used concurrently. Patients receiving inotropes and vasopressors should be monitored carefully for tachycardia, which may necessitate a decrease in the rate of the infusion or the addition of another agent. Other vasopressors that may be used are ephedrine (0.05 to 0.5 mg/kg IV as a single bolus), norepinephrine (0.1 to 1 mcg/kg/min IV as a CRI), and vasopressin (1 to 5 mU/kg/min IV as a CRI).43,44 If the initial vasopressor or inotrope is not successful in correcting the hypotension, a second agent is added while continuing administration of the first agent. For example, norepinephrine is most often used in combination with dopamine or dobutamine, and vasopressin can be used in combination with these agents as well (see Chapters 147 and 148, Catecholamines and Vasopressin). If the animal continues to remain hypotensive even after appropriate fluid therapy and inotropic and vasopressor support, it may be necessary to consider discontinuing the inhalant anesthetic agent to eliminate the hypotensive effects of the inhalant and continuing the anesthesia maintenance using an injectable drug. This may involve

CHAPTER 133  Anesthesia in the Critically Ill Patient administration of a CRI of a µ-agonist such as fentanyl or morphine in combination with ketamine and lidocaine. Some patients may need only fentanyl as an intermittent intravenous bolus or as a CRI. Recent research suggests that a lidocaine CRI should not be used in the anesthetized cat due to its depressant effects on the cardiovascular system.27

RECOVERY In critically ill patients, continuous cardiovascular support, monitoring, supportive care, and analgesia are imperative during the recovery period. The recovering patient may still require inotropic and/or vasopressor support, which should be continued in the intensive care unit upon recovery. The patient should be kept dry and warm, and should recover in a quiet, stress-free place where the patient can be continuously and carefully monitored. A shivering animal has greatly increased demands for glucose and oxygen, and oxygen supplementation and heat support should be given until the animal is no longer shivering.9 Acid-base, electrolyte, PCV, total protein, and blood glucose levels should also be monitored in the recovering and shivering animal. The use of forced warm air heating blankets can help in the treatment of hypothermia. Finally, the use of analgesics is imperative in these critically ill patients in pain. Although these patients may not exhibit classic pain response symptoms due to their debilitated state, they should be carefully but appropriately treated with analgesics. Pain can lead to catabolism and complications such as delayed wound healing, sepsis, and nosocomial disease.45 (See Chapter 134, Analgesia and Constant Rate Infusions.)

SUMMARY The condition of critically ill patients should be stabilized aggressively before anesthesia. Appropriate monitoring should be performed at all times to ensure that these delicate patients survive their emergent surgery. Postoperative care includes continued vasopressor and inotropic support, appropriate fluid therapy, analgesic support, oxygen therapy, blood pressure monitoring, and nursing care to improve survival in this critically ill patient population.

REFERENCES 1. Trim CM: Anesthetic considerations and complications. In Paddleford RR, editor: Manual of small animal anesthesia, ed 1, New York, 1999, Churchill Livingstone. 2. Chan DL, Rozanski EA, Freeman LM, et al: Colloid osmotic pressure in health and disease, Compend Contin Educ Pract Vet 23:896, 2001. 3. Mathews KA, Barry M: The use of 25% human serum albumin: outcome and efficacy in raising serum albumin and systemic blood pressure in critically ill dogs and cats, J Vet Emerg Crit Care (San Antonio) 15:110-118, 2005. 4. Plumb DC: Canine albumin. In Plumb DC, editor: Plumb’s veterinary drug handbook, ed 9, 2018, Wiley-Blackwell, Ames, Iowa, pp 22-25. 5. Mazzaferro EM, Rudloff E, Kirby R: The role of albumin replacement in the critically ill veterinary patient, J Vet Emerg Crit Care (San Antonio) 12:113-124, 2002. 6. Raffe MR: Pre-operative and post-operative management of the emergency surgical patient. In Murtaugh RJ, Kaplan PM, editors: Veterinary emergency and critical care medicine, St. Louis, 1992, Mosby–Year Book. 7. Barletta M: Maropitant. In Plumb DC, editor: Plumb’s veterinary drug handbook, ed 9, 2018, Wiley-Blackwell, Ames, Iowa, pp 764-767. 8. Jacobson JD: Sedating and anesthetizing patients that have organ system dysfunction, Vet Med 518-524, 2005. 9. Hall LW, Clarke KW, Trim CM: General pharmacology of the injectable agents used in anaesthesia. In Hall LW, Clarke KW, Trim CM, editors: Veterinary anaesthesia, ed 10, London, 2001, Saunders.

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10. Macintire DK, Drobatz KJ, Haskins SC, et al: Anesthetic protocols for short procedures. In Macintire DK, Drobatz KJ, Haskins SC, et al, editors: Manual of small animal emergency and critical care, Philadelphia, 2005, Lippincott Williams & Wilkins, pp 38-54. 11. Taylor PM, Chengelis CP, Miller WR, et al: Evaluation of propofol containing 2% benzyl alcohol preservative in cats, J Feline Med Surg 14(8):516-526, 2012. 12. Jimenez CP, Mathis A, Mora SS, et al: Evaluation of the quality of the recovery after administration of propofol or alfaxalone for induction of anaesthesia in dogs anaesthetized for magnetic resonance imaging, Vet Anaesth Analg 39:151-159, 2012. 13. Psastha E, Alibhai HIK, Jimenez-Lozano A, et al: Clinical efficacy and cardiorespiratory effects of alfaxalone, or diazepam/fentanyl for induction of anaesthesia in dogs that are a poor anaesthetic risk, Vet Anaesth Analg 38:24-36, 2011. 14. Mathis A, Pinelas R, Brodbelt DC, et al: Comparison of quality of recovery from anaesthesia in cats induced with propofol or alfaxalone, Vet Anaesth Analg 39:282-290, 2012. 15. Carroll G, Martin DD: Trauma and critical patients. In Tranquilli WJ, Thurmon JC, Grimm KA, editors: Lumb and Jones’ veterinary anesthesia and analgesia, ed 4, Ames, IA, 2007, Blackwell, pp 969-984. 16. de la Granville B, Arroyo D, Walder B: Etomidate in critically ill patients. Con: do you really want to weaken the frail? Eur J Anaesthesiol 29:511-514, 2012. 17. Cuthbertson BH, Sprung CL, Annane D, et al: The effects of etomidate on adrenal responsiveness and mortality in patients with septic shock, Intensive Care Med 35:1868-1876, 2009. 18. Perkowski S: Sedation of the critically ill patient. In Silverstein DC, Hopper K, editors: Small animal critical care medicine, ed 1, St. Louis, 2009, Saunders, pp 700-704. 19. Martinez-Taboada F, Leece EA: Comparison of propofol with ketofol, a propofol-ketamine admixture, for induction of anaesthesia in healthy dogs, Vet Anaesth Analg 41:575-582, 2014. 20. Anagnostou TL, Kazakos GM, Savvas I, et al: Remifentanil/isoflurane anesthesia in five dogs with liver disease undergoing liver biopsy, J Am Anim Hosp Assoc 47:e103-e109, 2011. 21. Allweiler S, Brodbelt DC, Borer K, et al: The isoflurane-sparing and clinical effects of a constant rate infusion of remifentanil in dogs, Vet Anaesth Analg 34:388-393, 2007. 22. Brosnan RJ, Pypendop BH, Siao KT, et al: Effects of remifentanil on measures of anesthetic immobility and analgesia in cats, Am J Vet Res 70:1065-1071, 2009. 23. Barletta M: Methadone. In Plumb DC, editor: Plumb’s veterinary drug handbook, ed 9, 2018, Wiley-Blackwell, Ames, Iowa, pp 725-727. 24. Muir WW, Wiese AJ, March PA: Effects of morphine, lidocaine, ketamine, and morphine-lidocaine-ketamine drug combination on minimum alveolar concentration in dogs anesthetized with isoflurane, Am J Vet Res 64(9):1155-1160, 2003. 25. Wagnor AE, Walton JA, Hellyer PW, et al: Use of low doses of ketamine administered by constant rate infusion as an adjunct for postoperative analgesia in dogs, J Am Vet Med Assoc 221(1):72-75, 2002. 26. Cassutto BH, Gfeller RW: Use of intravenous lidocaine to prevent reperfusion injury and subsequent multiple organ dysfunction syndrome, J Vet Emerg Crit Care (San Antonio) 13:137-148, 2003. 27. Pypendop BH, Ilkiw JE: Assessment of the hemodynamic effects of lidocaine administered IV in isoflurane anesthetized cats, Am J Vet Res 66:661-668, 2005. 28. Mannarino R, Luna SPL, Monteiro ER, et al: Minimum infusion rate and hemodynamic effects of propofol, propofol-lidocaine and propofollidocaine-ketamine in dogs, Vet Anaesth Analg 39:160-173, 2012. 29. Baldo CF, Garcia-Pereira FL, Nelson NC, et al: Effects of anesthetic drugs on canine splenic volume determined via computed tomography, Am J Vet Res 73:1715-1719, 2012. 30. Hall LW, Clarke KW, Trim CM: General pharmacology of the inhalation anesthetics. In Hall LW, Clarke KW, Trim CM, editors: Veterinary anaesthesia, ed 10, London, 2001, Saunders, pp 133-178. 31. Ravasio G, Gallo M, Beccaglia M, et al: Evaluation of a ketamine-propofol drug combination with or without dexmedetomidine for intravenous anesthesia in cats undergoing ovariectomy, J Am Vet Med Assoc 241:1307-1313, 2012.

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32. Quandt JE, Lee JA: Analgesia and constant rate infusions. In Silverstein DC, Hopper K, editors: Small animal critical care medicine, ed 1, St. Louis, 2009, Saunders, pp 710-716. 33. Murray MJ, Cowen J, DeBlock H, et al: Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient, Crit Care Med 30:142-156, 2002. 34. Hall LW, Clarke KW, Trim CM: Relaxation of the skeletal muscle. In Hall LW, Clarke KW, Trim CM, editors: Veterinary anaesthesia, ed 10, London, 2001, Saunders, pp 149-178. 35. Lukasik VM: Neuromuscular blocking drugs and the critical care patient, J Vet Emerg Crit Care 5:99-113, 1995. 36. Keegan RD: Muscle relaxants and neuromuscular blockade. In Grimm KA, Lamont LA, Tranquilli WJ, Greene SA, Robertson SA, editors: Lumb and Jones’ veterinary anesthesia and analgesia, ed 5, Ames, IA, 2015, Wiley Blackwell, pp 260-276. 37. Adams WA, Robinson KJ, Senior JM, et al: The use of the nondepolarizing neuromuscular blocking drug cis-atracurium in dogs, Vet Anaesth Analg 28:156-160, 2001. 38. Mosing M, Auer U, West W, et al: Reversal of profound rocuronium or vecuronium-induced neuromuscular block with sugammadex in isofluraneanaesthetized dogs, Vet J 192:467-471, 2012.

39. Sakai DM, Martin-Flores M, Tomak EA, et al: Differences between acceleromyography and electromyography during neuromuscular function monitoring in anesthetized Beagle dogs, Vet Anaesth Analg 42:233-241, 2015. 40. Kastrup MR, Marsico FF, Ascoli FO, et al: Neuromuscular blocking properties of atracurium during sevoflurane or propofol anaesthesia in dogs, Vet Anaesth Analg 32:222-227, 2005. 41. Wright B, Hellyer PW: Respiratory monitoring during anesthesia: pulse oximetry and capnography, Compend Contin Educ Pract Vet 18:1083-1097, 1996. 42. Hall LW, Clarke KW, Trim CM: Patient monitoring and clinical measurement. In Hall LW, Clarke KW, Trim CM, editors: Veterinary anaesthesia, ed 10, London, 2001, Saunders, pp 29-60. 43. Hall LW, Clarke KW, Trim CM: Anaesthesia of the dog. In Hall LW, Clarke KW, Trim CM, editors: Veterinary anaesthesia, ed 10, London, 2001, Saunders, pp 385-439. 44. Pablo LS: The use of vasopressin in critical care patients. In: Proceedings North American Veterinary Conference, Gainesville FL, 2006, pp 280-282. 45. Muir WW: Physiology and pathophysiology of pain. In Gaynor JS, Muir WW, editors: Handbook of veterinary pain management, ed 1, St. Louis, 2002, Mosby.

134 Analgesia and Constant Rate Infusions Jane Quandt, BS, DVM, MS, DACVAA, DACVECC KEY POINTS • There are several general drug classes, administration routes, and techniques by which analgesia can be achieved. • The clinician should be able to develop an appropriate analgesic therapeutic plan that addresses the type and severity of pain.

• Patients should be frequently evaluated for response to treatment and treated appropriately with additional analgesics if necessary. • Multimodal or combination analgesic drug therapy may be beneficial in the critically ill patient.

ANALGESIA

Regardless of what type of analgesic or combination of analgesics is used, patients should be reassessed frequently to ensure that the analgesic regimen is adequate and appropriate. Finally, administration of analgesics may be diagnostic when pain behavior is difficult to recognize in stoic patients.4

The critically ill patient benefits from analgesia because it promotes an animal’s overall well-being and has a positive effect on the speed and quality of recovery.1 The goal of pain control is to achieve a state in which the pain is bearable but some of the protective aspects of pain, such as inhibiting use of a fractured leg, still remain.1 There are several general drug classes, administration routes, and techniques by which analgesia can be achieved. General drug classes that are commonly used include the following: opioids, nonsteroidal antiinflammatory drugs (NSAIDs), a2-adrenergic agonists (see Chapter 157 for more information on a2-agonists and antagonists), local anesthetics, N-methyl-d-aspartate (NMDA) antagonists, benzodiazepines, and phenothiazines. Analgesics can be administered by various methods including the intravenous, subcutaneous, intramuscular, epidural, transmucosal, transdermal, oral, intraarticular, intrapleural, and intraperitoneal routes as well as by local infiltration. The type of treatment depends on the severity of pain and the nature of the animal. Specific dosages of analgesic drugs are provided in Table 134.1. In ICU patients, analgesics should be administered as soon as possible after patient assessment and appropriate patient resuscitation to provide a significant benefit (see Chapter 131, Pain and Sedation Assessment).2 It is vital, however, that the underlying disease process be addressed while pain relief is provided because analgesic therapy may mask the underlying disorders or the hemodynamic status of a patient. Ideally analgesics should be administered before pain develops (e.g., preemptive analgesia) because less drug therapy may be necessary to control pain. This is especially important before surgery or other invasive procedures; however, this is not always feasible in trauma or emergent cases.2,3 Pain development and sensation may involve a multiplicity of pathways; therefore, it is important to develop an analgesic therapeutic plan that assesses the type and severity of the pain and the response to treatment. Because pain pathways are complex, it is often unlikely that one agent alone will completely alleviate pain, regardless of how high the dose is.4 The use of more than one class of drug can improve analgesia because the drugs affect multiple receptor types, and such combination therapy may also overcome the problem of varying onset times and durations of action of different drug classes. Examples of effective combinations of analgesic therapy are the administration of opioids with NSAIDs, local anesthetics (e.g., lidocaine patches) with opioids, and an epidural analgesic with systemic opioid therapy.

OPIOIDS Opioids act centrally to limit the input of nociceptive information to the central nervous system (CNS), which reduces central hypersensitivity.5 Receptors in the brain and dorsal horn of the spinal cord receive impulses from peripheral nerves, which are modulated before being transmitted to higher centers.6 Opioids are commonly used in critically ill patients because they have a rapid onset of action and are safe, reversible, and potent analgesics. As with all analgesic therapy in critically ill patients, opioids should be slowly titrated IV to effect due to altered drug pharmacokinetics.7 Opioid analgesics vary in effectiveness, depending on which receptor is stimulated and which class of opioid is being administered. The four classes of opioids are pure agonists, partial agonists, agonists-antagonists, and antagonists. Pure receptor agonist stimulation results in a pronounced analgesic effect, whereas partial agonists bind at the same receptor but produce a less pronounced effect.6 Agonists-antagonists have mixed effects, with an agonist effect on one type of receptor and an antagonist effect on a different type of receptor. This results in an analgesic effect on one receptor and no effect (or a less pronounced effect) on the other receptor. Opioid antagonists (e.g., naloxone) bind to the same receptor as agonists but cause no effect and can competitively displace the agonist from the receptor and therefore reverse the agonist effect.6 The partial agonist buprenorphine and mixed agonist-antagonist butorphanol reach maximal effect at the upper end of the dose range. If the pain is severe or the analgesia is inadequate, additional doses of partial or mixed agonists-antagonists are unlikely to be effective. Using a pure µ-agonist (e.g., morphine, hydromorphone, fentanyl, and remifentanil) would be more effective because there is no upper limit to the analgesia provided by a pure µ-agonist.5 Potent adverse effects such as respiratory depression and bradycardia may be seen at the higher end of the dose range with a pure µ-agonist; therefore the higher doses should be used cautiously in critically ill patients.5,6 Additional adverse effects of some µ-agonists (e.g., morphine and meperidine) include histamine release, which is of particular concern when these agents are given rapidly IV because this

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TABLE 134.1  Commonly Used Analgesic Agents Generic Name

Dosage

Acetylpromazine, acepromazine

0.01–0.05 mg/kg IM, IV q3-6h; do not exceed a total of 3 mg in large dogs

Atipamezole (reverses a2-adrenergic agonist drugs)

0.05–0.2 mg/kg IM, IV, SC

Bupivacaine

Nerve block: 1–2 mg/kg SC q6h

Nocita

5.3 mg/kg SC wound infiltration

Buprenorphine Simbadol long-acting buprenorphine

0.005–0.02 mg/kg IM, IV q6-8h Cats: 0.01–0.02 mg/kg q6-8h PO 0.12–0.24 mg/kg SC once every 24 hours for 3 days in the cat

Butorphanol

0.1–0.4 mg/kg IM, IV q1-4h Partial reversal of µ-opioid agonist: 0.05–0.1 mg/kg IV Loading dose for CRI: 0.1 mg/kg IV Maintenance for CRI: 0.03–0.4 mg/kg/hr IV

Carprofen

2–4 mg/kg SC (single dose)

Cyproheptadine

Dogs: 0.3–2 mg/kg PO q12h Cats: 2 mg/cat PO q12h

Deracoxib

Dogs: 1–2 mg/kg PO q24h Postoperative pain: 3–4 mg/kg PO q24h; do not give for .7 days

Dexmedetomidine

1–5 mcg/kg IV q4h Loading dose: 1 mcg/kg IV Maintenance: 0.5–3 mcg/kg/hr IV CRI

Etodolac

Dogs: 5–15 mg/kg PO q24h

Fentanyl

Dogs: Loading dose: 2 mcg/kg IV Maintenance: 2–5 mcg/kg/hr CRI Cats: Loading dose: 1 mcg/kg IV Maintenance: 1–4 mcg/kg/hr CRI

Fentanyl patch

Cats, dogs ,5 kg: 25-mcg patch Dogs 5–10 kg: 25-mcg patch Dogs 10–20 kg: 50-mcg patch Dogs 20–30 kg: 75-mcg patch Dogs .30 kg: 100-mcg patch

Gabapentin

1.25–4 mg/kg PO q24h

Hydromorphone HCl

Dogs: 0.05–0.2 mg/kg IM or SC; 0.05–0.1 mg/kg IV q2-4h Cats: 0.05–0.1 mg/kg IM or SC q3-4h; 0.03–0.05 mg/kg IV q3-4h

Indomethacin

No safe dose established

Ketamine

Analgesia without sedation: 0.1–1 mg/kg IV Loading dose: 0.5 mg/kg IV Maintenance during surgery: 10 mcg/kg/min IV CRI Maintenance after surgery: 2 mcg/kg/min CRI for 24 hr

Lidocaine

Nerve block: 1–2 mg/kg SC Loading dose: 1–2 mg/kg IV Maintenance: 2–3 mg/kg/hr IV CRI

2% Lidocaine

Nerve block: 1–2 mg/kg SC

Lidocaine patch

No animal dose established, but patch contains 700 mg of lidocaine. Significant systemic absorption has not been found to occur. Patch should be cut to fit size of area

Meloxicam

0.1–0.2 mg/kg IV or SC (single dose)

Methadone

0.2–1.0 mg/kg IV or IM

Morphine

Dogs: 0.25–1 mg/kg IM q4-6h

Morphine sulfate

Dogs: 0.5–2 mg/kg IM, SC q4h Cats: 0.05–0.4 mg/kg IM, SC q3-6h Loading dose: 0.15–0.5 mg/kg IV administered slowly to avoid histamine release Maintenance: 0.1–1 mg/kg/hr CRI

CHAPTER 134  Analgesia and Constant Rate Infusions

789

TABLE 134.1  Commonly Used Analgesic Agents—cont’d Generic Name Naloxone (opioid reversal)

Dosage 0.002–0.1 mg/kg IM, IV, or SC

Oxymorphone

Dogs: 0.03–0.1 mg/kg IM or IV q2-4h Cats: 0.01–0.05 mg/kg IM or IV q2-4h

Remifentanil

3 mcg/kg IV, then CRI of 0.1–0.3 mcg/kg/min

Tepoxalin

Dogs: 10 mg/kg PO q24h

Morphine-lidocaine-ketamine infusion

Morphine: 3.3 mcg/kg/min Lidocaine: 50 mcg/kg/min Ketamine: 10 mcg/kg/min Preparation: Mix 10 mg of morphine sulfate, 150 mg of 2% lidocaine, and 30 mg of ketamine into a 500-ml bag of lactated Ringer’s solution Administration rate: 10 ml/kg/hr

CRI, constant rate infusion; IM, intramuscularly; SC, subcutaneously.

can lead to severe hypotension due to vasodilation.6 Opioids can lead to gastroparesis and ileus, which may result in vomiting, regurgitation, and aspiration of gastrointestinal (GI) contents, particularly in depressed, sedated, weak, or critically ill patients. Gastric distention caused by opioids may also be a concern in patients with abdominal disease (e.g., pancreatitis) because stimulation of pancreatic secretions may occur. Patients at risk of pancreatitis or gastroparesis may require intermittent or constant gastric decompression (via nasogastric, esophagostomy, or gastrostomy tube) if they are treated with opioids for longer than 12 to 24 hours or may require motility drug therapy (e.g., metoclopramide) for treatment of ileus.8 Opioids can be safely administered to cats to provide analgesia.5 Morphine and hydromorphone can be administered for analgesia; however, adverse effects such as hyperexcitability or agitation may occur. It has been shown that the onset of mydriasis following administration of opioids correlates with adequate analgesia in cats; continual dosing after mydriasis is achieved may result in adverse effects such as dysphoria and agitation.8 Another option for cats is the mixed partial µ-agonist buprenorphine, which has been shown to be an effective analgesic.6 The newest µ-agonist, remifentanil, may offer some advantages over the more commonly used µ opioids. In dogs and cats with severe liver compromise, remifentanil may be considered for analgesia during general anesthesia and as a constant rate infusion (CRI) to provide analgesia in the ICU. Remifentanil is a synthetic opioid with direct action on the µ receptors. It has an ultrashort duration of action, which allows a rapid recovery even after long-term IV infusion. The elimination of remifentanil is independent of hepatic or renal function because the drug is metabolized by nonspecific esterases in blood and tissues, which makes it an attractive agent for use in patients with hepatic or renal compromise.9 Remifentanil has been used in dogs at an initial dose of 3 mcg/kg IV followed by a CRI of 0.1 to 0.3 mcg/kg/min. The clinical effects of remifentanil are rapidly dissipated upon discontinuation of the CRI, with dogs recovering within 5 to 20 minutes regardless of the duration of the infusion.9,10 Due to the drug’s short duration of action, additional analgesic therapy is necessary upon termination of the CRI if clinical signs of pain persist. Like other opioids, remifentanil is a potent respiratory depressant when used as a CRI, and the patient should be monitored for hypoventilation. If depression is severe, the use of naloxone or mechanical ventilation may be required. The respiratory depression associated with remifentanil typically does not persist following recovery.10 In cats, the use of remifentanil at dosages higher than 1 mcg/kg/min has been associated with dysphoric behavior and frenetic locomotor activity.11 Fentanyl, another pure µ-agonist, is commonly used in veterinary medicine. It has a short duration of action of 30 minutes when given

IV and up to 2 hours when given IM or SC. It is commonly given as a CRI and can be titrated depending on the level of analgesia required.12 It is also formulated as a transdermal analgesic patch (Duragesic). Methadone is an opioid that also has antagonist effects at the NMDA receptor. It is a full µ-agonist at the l-isomer and the d-isomer acts as an antagonist to the NMDA receptor. This antagonism of the NMDA receptor may provide prevention of central sensitization and secondary hyperalgesia. The µ-agonist effects are effective for moderate to severe pain. It can be dosed to effect.13 It can be used in dogs and cats at a dose range of 0.2 to 1.0 mg/kg IV or IM. A new formulation of buprenorphine (Simdadol) at 1.8 mg/ml is now available, and it is FDA approved for use in cats. It is indicated for the control of postoperative pain and is administered by subcutaneous injection at 0.24 mg/kg every 24 hours for up to 3 days.14 This agent has also been safely administered to cats by the oral transmucosal route. A lower dose, 0.12 mg/kg, can be used, which can result in a shorter duration of action.15 The lower dose may be used for smaller or more debilitated cats. Adverse effects such as hyperthermia, hypotension, bradycardia or tachycardia may occur, but buprenorphine can be difficult to reverse. One advantage of opioid administration in critically ill patients is that their effects can be reversed if necessary with a pure antagonist such as naloxone. Naloxone can reverse the CNS depression, respiratory depression, and bradycardia associated with the opioid; however, reversal of the sedative effect and analgesia effect can cause acute pain, excitement, emergence delirium, aggression, and hyperalgesia.16 Lowdose naloxone (0.004 mg/kg titrated slowly IV) has been recommended to reverse CNS depression without affecting analgesia.8 The duration of effect for naloxone is relatively short (20 to 30 minutes) because of its rapid metabolism in dogs and cats, which may predispose patients to renarcotization when the drug is used to reverse longacting opioids.16,17 Agonists-antagonists such as butorphanol (0.05 to 0.1 mg/kg IV) may also be used to reverse sedation and respiratory depression from µ-agonists.8,16 The benefit of using butorphanol as a reversal agent is that complete reversal of analgesia does not occur due to the k-agonist effects of butorphanol. Butorphanol administered as a reversal agent may produce additive analgesia with the µ-agonist.16 In contrast, buprenorphine is not as easily reversed as butorphanol because it is difficult to displace from the receptor.6 See Chapter 155, Narcotic Agonists and Naloxone, for more information.

NONSTEROIDAL ANTIINFLAMMATORY DRUGS Inflammation plays a significant role in the pain process, and therefore the use of NSAIDs to reduce or eliminate peripheral inflammation may be helpful. NSAIDs decrease the pain input to the CNS, which

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PART XV  Anesthesia and Pain Management

may aggravate central hypersensitivity.2 There are several commercially available veterinary NSAIDs, including carprofen (Rimadyl), deracoxib (Deramaxx), meloxicam (Metacam), etodolac (Etogesic), tepoxalin (Zubrin), and robenacoxib (Onsior). The analgesic and antiinflammatory effects associated with NSAIDs are related to inhibition of cyclooxygenase (COX) enzyme isoforms. COX-1 is primarily responsible for basal prostaglandin production for normal homeostatic processes within the body, including gastric mucus production, platelet function, and, indirectly, hemostasis, whereas COX-2 is found at sites of inflammation (although COX-2 is responsible for some basal production of constitutive prostaglandins as well). Ideally, selective inhibition of prostaglandins produced primarily by COX-2 would provide analgesic and antiinflammatory effects without the unwanted adverse effects of COX-1 inhibition.18 At present, there is no pure COX-2 inhibitor; rather, certain NSAIDs have varying degrees of COX-1 inhibition. For this reason, NSAIDs should be used cautiously in patients with hypotension, hypovolemia, preexisting renal disease (due to the increased potential for renal vascular vasoconstriction, which would lead to worsening of renal insufficiency), and GI disease or gastric ulceration.5,7,19 Ideally, enteral NSAIDs should be given with food when possible to decrease the incidence of gastric ulceration. In addition, NSAIDs should be used cautiously in the perioperative period because decreased platelet function may increase the incidence of operative hemorrhage. Injectable NSAIDs (e.g., carprofen, meloxicam) have an advantage over oral NSAIDs because injectable drug therapy can be administered to patients that cannot tolerate oral administration due to preoperative fasting for anesthesia, nausea, vomiting, or decreased mentation.5 Finally, although NSAIDs have a slow onset of action (requiring up to 45 to 60 minutes to take effect), they provide analgesia for an extended period of time.20 Carprofen has a 12-hour dosing frequency, whereas other NSAIDs (e.g., deracoxib, meloxicam, etodolac) are labeled for once-daily dosing.18 The new feline-specific NSAID Onsior contains robenacoxib and is a COX-2 inhibitor with a high safety index in cats.21 It has analgesic, antiinflammatory, and antipyretic effects in cats and selectively distributes to inflamed tissues, while sparing COX-1 at the clinically recommended dose.22 It can be given subcutaneously (SC) between the shoulder blades (2 mg/kg) or orally (PO) (6 mg per cat q24h for cats weighing 2.5 to 6 kg and 12 mg per cat q24h for cats weighing 6.1 to 12 kg for 3 days).22,23 Robenacoxib has a terminal half-life of 1.9 hours in cats, with efficacy persisting for 22 hours.22 As mentioned previously, NSAIDs can be used in combination with opioids for a combined therapeutic effect. However, the concurrent use of NSAIDs and corticosteroids is not recommended due to the potentiated adverse GI effects of COX-1 inhibition.5 See Chapter 158, Nonsteroidal Antiinflammatory Drugs, for more information.

2-ADRENERGIC AGONISTS The a2-adrenergic agonists bind to receptors in the CNS, which leads to sedation, peripheral vasoconstriction, bradycardia, respiratory depression, diuresis, muscle relaxation, and analgesia.8,24 Dexmedetomidine is the most common a2-adrenergic agonist administered to small animals. Dexmedetomidine is the dextrorotatory enantiomer of medetomidine, which is the active form. The clinical effects of both drugs are similar, and any comments made about medetomidine in the remainder of this discussion can be applied equally to dexmedetomidine (although the recommended doses differ). It is approved for use in dogs and cats,24 and both dexmedetomidine and medetomidine can be given IM or IV. These drugs are biotransformed by the liver, with inactive metabolites excreted in the urine. Both of these a2-adrenergic

agonists have a rapid onset of action.25 The sedative effects of medetomidine have a longer duration of action than do the analgesic effects, which last approximately 30 to 90 minutes.26 Low-dose medetomidine (1 to 10 mcg/kg IV) can be safely used in patients in stable condition or administered in conjunction with opioids to produce analgesic synergism and increase the duration of analgesia up to 4 hours.8,26 At higher doses, medetomidine can be used for sedation of distressed animals and for minor procedures (e.g., restraint and analgesia for radiographic positioning).8 In patients in stable cardiovascular condition, medetomidine can be used as a CRI for analgesia (initial loading dose of 1 mcg/kg IV then a CRI of 1 to 3 mcg/kg/hr).27 One should note that the dose range for dexmedetomidine is half that for medetomidine; see Table 134.1. As with opioids, the effects of a2-adrenergic agonists can be reversed. Atipamezole is a specific a2-adrenergic antagonist that reverses analgesia, sedation, and respiratory depression. Intramuscular or subcutaneous administration is preferred for reversal because intravenous administration can lead to abrupt hypotension and/or aggression.16 The cardiovascular effects of a2-adrenergic agonists consist of activation of peripheral a2-adrenorecptors in the vascular smooth muscle. This leads to vasoconstriction and increases the systemic vascular resistance, which in turn leads to arterial hypertension and reflex bradycardia.28 The use of anticholinergics can further increase the hypertension. These cardiovascular effects may not be tolerated by the critical patient. A novel drug, MK-467 (Vatinoxan), is being developed to minimize the cardiovascular effects. Vatinoxan is a peripherally acting a2-adrenergic antagonist that does not cross the blood–brain barrier, thereby preventing the peripherally cardiovascular effects induced by a2-adrenergic agonists, but maintaining the sedation and analgesia.28 Vatinoxan comes as a powder that is dissolved in normal saline to a concentration of 2 mg/ml. It can be mixed in the same syringe as the a2-adrenergic agonist and coadministered.28 It can be given IM or IV. A dose of 150 µg/kg of Vatinoxan improved cardiovascular stability in dogs given medetomidine.28 See Chapter 157 for more information on a2-agonists and antagonists.

TRANSDERMAL ANALGESICS Administration of topical analgesics in conjunction with other analgesic therapy is well tolerated by patients and has minimal systemic effects.29 Fentanyl patches can be used to provide long-term analgesia but may vary in time to onset of effects and steady-state concentrations.7,20,30 Because of this variability, systemic analgesia must be provided until the patch becomes effective (typically up to 24 hours in dogs).8 Fentanyl uptake is affected by dermal blood flow, hair, and obesity and may be greatly altered in hypovolemic or hypothermic patients. In cats the drug may reach therapeutic levels in 6 to 12 hours, and steady states can be maintained for approximately 5 days.20,30 It should be noted that therapeutic levels may not be reached with the patch in all animals. If the patient still appears to be in pain 12 to 24 hours after patch application, additional analgesic treatment may be necessary.8 Fentanyl patches are currently available in 25-, 75-, and 100-mcg formulations. Fentanyl patches should not be cut or otherwise altered because this may affect the amount of absorption or drug loss. The pet owner should be specifically instructed regarding the proper disposal of used fentanyl patches because there is potential for human abuse. Lidoderm, a 5% lidocaine patch, was recently introduced to the human and veterinary markets. Lidoderm was approved in 1999 by the US Food and Drug Administration for treatment of postherpetic neuralgia in humans.29 Lidoderm is a nonwoven, polyester, felt-backed patch covered with a polyethylene terephthalate film release liner that should

CHAPTER 134  Analgesia and Constant Rate Infusions be removed before the patch is applied to the skin. Each 10 3 14-cm adhesive patch contains 700 mg of lidocaine (50 mg per gram of adhesive) in an aqueous base. Lidocaine penetration into intact skin is sufficient to produce an analgesic effect but does not result in complete sensory block. The Lidoderm patch can be safely worn for as long as 24 hours and provides analgesia without numbness or loss of sensitivity to touch or temperature. Therapeutic levels are achieved via absorption within 30 minutes. Unlike the fentanyl patch, the lidocaine patch can be cut to fit patient size without affecting drug delivery. Lidocaine patches can be used back-to-back for continuous analgesia because toxic blood levels do not develop; however, the skin needs to be monitored for development of localized dermatitis because the most common adverse effects in humans are transient dermal reactions such as localized rash and pruritus.31 For application of analgesic patches in veterinary patients, the hair must be clipped and cleaned. The lidocaine patch can be stapled in place with surgical staples to ensure appropriate contact with skin.32 The use of staples to aid in adherence of fentanyl patches has not been evaluated. Anecdotally, the Lidoderm patch has been used in dogs and cats to provide analgesia for severe skin abrasions, bruising, and surgical incisions; no apparent toxic effects have been noted thus far. In addition, multimodal analgesia can be initiated with both the lidocaine patch and fentanyl patch applied simultaneously. The lidocaine patch will provide local analgesia, whereas the fentanyl patch will provide systemic analgesia.

N-METHYL-D-ASPARTATE RECEPTOR ANTAGONISTS NMDA receptor antagonists work by blocking multiple binding sites at this receptor, which results in analgesic, amnestic, and psychomimetic effects as well as neuroprotection.33 Ketamine, a noncompetitive NMDA receptor antagonist, can reverse central hypersensitivity by preventing the exaggerated response, wind-up activity, and central sensitization of wide-dynamic-range neurons in the dorsal horn of the spinal cord.5 Ketamine can be administered PO, SC, IM, or IV. Ketamine prevents the response to nociceptive stimuli carried by afferent pain neurons (e.g., C fibers).34,35 Ketamine causes minimal cardiovascular depression, does not depress laryngeal protective reflexes, and produces less ventilatory depression than opioids; however, adverse effects include tremors and sedation along with increased cardiac output due to increased sympathetic tone.35 Subanesthetic or low doses in dogs and cats (0.1 to 1 mg/kg IV, followed by a CRI of 2 mcg/kg/min) may produce analgesic effects without causing anesthesia or profound sedation.5,35 Oral ketamine can also be used (8 to 12 mg/kg PO q6h in dogs) to provide pain relief following burn injuries.7

ACEPROMAZINE The phenothiazine acepromazine (0.01 to 0.05 mg/kg IV, not to exceed a total dose of 3 mg) does not provide analgesia alone and should not be administered as a single agent if analgesia is desired. Rather, it should be used in combination with opioids as an anxiolytic and sedative. However, in the critically ill patient it should be used with caution due to the potential for vasodilation and resultant profound hypotension and hypothermia. Even with IV administration, up to 15 minutes may be required before the sedative effect of acepromazine is clinically observed; therefore, repeated doses should be avoided until the full effect is evident.8 Acepromazine can be safely administered to ICU patients if given at low doses (0.005 to 0.01 mg/ kg) in patients in hemodynamically stable condition with adequate respiratory function.36

791

INFILTRATIVE AND LOCAL ANESTHETICS Local anesthetics (e.g., lidocaine, bupivacaine) provide analgesia by blocking both specific nerve pathways and action potential transmission in nerve fibers (including nociceptive fibers).5 Local anesthetics can be used for local injection (e.g., small bite wounds), intercostal nerve blocks, and intrathoracic or intraperitoneal administration. In addition, 0.5% bupivacaine (2 mg/kg q6h) can be administered to provide analgesia for painful diseases and conditions (e.g., fractures, pancreatitis) or for procedures (e.g., thoracotomy, placement of a thoracostomy tube).5,20 Intercostal nerve blockade can be used to provide analgesia for rib fractures. Bupivacaine (1 to 1.5 mg/kg q6h, not to exceed 4 mg/kg on day 1) can be injected into the area of the intervertebral foramen on the caudal border of the rib to block the intercostal nerves.5 Bupivacaine can also be administered into the pleural space via a thoracostomy tube to provide analgesia following thoracic surgery or tube placement because the presence of the tube itself may be painful. In cases of pancreatitis or abdominal pain, bupivacaine (2 mg/ kg diluted in saline q6h intraperitoneally) can be administered via an aseptically placed, temporary butterfly catheter to provide analgesia. However, it may be ineffective when ascites is present due to dilution of the topical analgesic. When local anesthetics are used, use of an aseptic technique is imperative. The patient should be appropriately positioned so that the medication disperses over the desired site to enhance analgesia.5 In addition, sodium bicarbonate (1 mEq/ml) may be added to lidocaine (at a ratio of 1 to 2 parts bicarbonate to 8 to 9 parts lidocaine) to decrease the burning sensation caused by the administration of lidocaine alone, which is due to the acidity of the local anesthetic.8 When bupivacaine is used, a 1:30 ratio of sodium bicarbonate to bupivacaine is sufficient. Potential adverse effects of bupivacaine include arrhythmias and reduced cardiac output; therefore, the drug should not be administered to animals with preexisting life-threatening arrhythmias. Also, because bupivacaine is selectively cardiotoxic, only half the canine dose should be administered to cats.8 Certain contraindications to bupivacaine administration exist and warrant the use of alternative analgesics. In patients undergoing pericardectomy, intrapleural bupivacaine should be used judiciously due to the potential risk of cardiotoxicity.5 Although intrapleural bupivacaine has been used safely in healthy dogs with and without an open pericardium, its use in patients with underlying cardiovascular instability or other disease has not been assessed.37 Intrapleural bupivacaine may also interfere with ventilation by inducing diaphragmatic paralysis. Animals with good respiratory reserve capacity rarely develop clinically significant compromise, but administration of intrapleural anesthetics should be avoided in animals with marginal respiratory function.8 Finally, toxicity may occur with higher doses of lidocaine (.10 to 20 mg/kg) and bupivacaine (.4 mg/kg). Clinical signs of toxicosis may include seizures, cardiac arrhythmias, tachycardia, and cardiovascular collapse. The maximum safe dose for most species is 4 mg/kg of lidocaine and 1 to 2 mg/kg of bupivacaine.5 Administration of epinephrine, which normally enhances the duration of effect of local anesthetics, should be avoided in critically ill patients because it may lead to cardiac stimulation or ischemia from vasoconstriction.5 A prolonged-release bupivacaine liposome injectable suspension for use as a single-dose infiltration into the surgical site for postoperative analgesia is now available for use in the dog. This product can also be used for a peripheral nerve block in cats undergoing onychectomy. This product, Nocita, consists of multi-vesicular liposomes encapsulating bupivacaine. The bupivacaine is gradually released over several hours as the lipid bilayers break down.38 A moving needle technique is

792

PART XV  Anesthesia and Pain Management

used to inject the solution into all the tissue layers within the surgical field.38 A moving needle technique is where the needle is inserted to near the hub and the material is injected as the needle is pulled out. The needle is inserted at varying angles depending in order to deposit the bupivacaine within the tissues. The injections are repeated to create an area of infiltrated tissue around the whole wound and at all levels of the wound. A dose of 5.3 mg/kg has been shown to provide analgesia of up to 72 hours in dogs.38 Nocita can be diluted 1:1 with normal saline to increase the area of coverage.38

EPIDURAL ANALGESICS Epidural analgesia is an alternative way of delivering analgesia to the caudal half of the body. Depending on the dose or volume of drug used, analgesia of the forelimbs can also be achieved: an injected volume of 1 ml/5 kg blocks to the first lumbar vertebra and use of a larger volume results in a cranial spread of the analgesia. Lower concentrations of local anesthetics can provide analgesia without secondary motor deficits. Complete anesthesia can be achieved with higher doses of local anesthetics, which result in motor paralysis of the rear limbs. Epidural opioids can provide analgesia without affecting motor function; nociceptive input is reduced but not completely abolished. Higher doses of local anesthetics may also lead to vasodilation and subsequent hypotension.5 In critically ill patients, lower doses of local anesthetics should be used epidurally to avoid inducing hypotension. In general, critically ill patients often benefit from epidural analgesia because it decreases anesthetic requirements and provides analgesia without cardiorespiratory effects or excessive sedation. The technique for epidural analgesia has been described elsewhere,5 and readers are referred to those sources for further information on technique. Contraindications for the use of epidural analgesia or epidural catheter placement include trauma over the pelvic region (with loss of appropriate landmarks), sepsis, coagulopathy, CNS disease, skin infection over the site of injection, hypovolemic shock, and severe obesity.5,20,39,40 Epidural catheters can also be used to help maintain long-term analgesia, although stringent aseptic protocol must be followed; in addition, these catheters may be technically difficult to place. An epidural catheter can be placed using the same landmarks as those for administration of a single injection. The advantage of epidural catheterization is the ability to provide continuous analgesia without the need for repeated epidural needle punctures. In addition, the catheter can be advanced cranially to improve analgesia to the front limbs or thoracic structures. Catheters must be placed aseptically under anesthesia or heavy sedation and maintained with sterility and care. Proper location of the epidural catheter can be confirmed via lateral radiography or fluoroscopy after catheter placement. If the epidural catheter is not radiopaque, a low dose of myographic contrast agent can be injected into the catheter to allow evaluation and ensure appropriate placement. Catheters have been safely left in place from 1 to 332 hours.40 With epidural catheters, the total volume injected should be limited to 6 ml in a large dog.40 See Table 134.2 for epidural dosing. Adverse effects of epidural anesthesia include vomiting, urinary retention, pruritus, and delayed hair growth at the clipped epidural site.39 Additional complications associated with epidural catheters include catheter dislodgement, discharge from the site, fecal contamination, line or filter breakage, and localized dermatitis.41 When complications occur, removal of the epidural catheter is recommended. Adverse effects of epidural anesthesia should be treated symptomatically. Urinary retention can be treated or prevented by manually expressing the bladder or placing an indwelling urinary catheter. Another complication is inadvertent injection of drug into the subarachnoid space. In dogs, the dural sac ends before the lumbosacral

space, so inadvertent injection into the subarachnoid space is less likely. In cats, however, the dural sac ends past the lumbosacral space; therefore, care must be taken to avoid subarachnoid injection when administering epidural drugs. If the subarachnoid space is penetrated, the nonpreservative formulation of the drug may still be given; however, a significantly reduced dose (50% to 75% of the original dose) should be administered.40 The lower dose is sufficient for an analgesic response because the roots of the spinal cord are more accessible within the subarachnoid space, where they are not protected by the dura.42 The coccygeal epidural can be used to provide analgesia and relaxation to the urethra and penis of the cat with urethral obstruction. The coccygeal epidural block done with a local anesthetic will produce anesthesia of the perineum, penis, urethra, colon and anus.43 This will block the pudendal, pelvic, and caudal nerves but maintains motor function to the rear legs. Lidocaine, 2% without epinephrine, is most commonly used, with an onset time of 5 minutes and a duration of 60 minutes. Possible complications of this block would include infection of the injection site, failure of the block, and systemic absorption of the lidocaine, although the low doses used make this unlikely to have serious consequences.43 Relative contraindications would be coagulation disorders, septicemia, pyoderma at the injection site, severe hypotension or hypovolemia, and anatomical abnormalities.43 This technique is described elsewhere and the reader is referred to this information.43 The dose of 2% lidocaine is 0.1 to 0.2 ml/kg. There should be minimal resistance to injection, and care should take taken so that air is not injected as the bubbles may result in an incomplete block.43 Relaxation should be seen within 5 minutes; if the effect is not seen, a second dose can be given. No more than two doses should be given to avoid cranial spread of the lidocaine and weakness or paralysis of the rear legs. The coccygeal epidural can also be used for analgesia for vaginal delivery during a dystocia, tail amputations, or degloving injuries and perineal procedures.43

CONSTANT RATE INFUSIONS The administration of analgesics as a CRI has the advantage of maintaining effective plasma concentrations for continued pain relief. Anesthesia can also be maintained with a CRI if the animal cannot tolerate the hypotensive effects of inhalant anesthesia. The CRIs that have been administered during surgery can be carried over into recovery to provide titratable analgesia; the dose can usually be lower once surgical stimulation is over. All CRIs should be delivered by syringe pump for accurate dosing.35 To avoid histamine release, which may occur with rapid IV morphine administration, a morphine CRI (0.1 to 1 mg/kg/ hr) should be started after administration of an initial loading dose (0.15 to 0.5 mg/kg IV, diluted and delivered slowly over 5 to 10 minutes).7,44 A CRI of morphine (0.12 mg/kg/hr) reportedly induces effects similar to those of intramuscular morphine (1 mg/kg q4h) in dogs undergoing laparotomy.45 Regardless of how morphine is administered, its use may result in bradycardia, hypothermia, and panting. Other opioids (e.g., fentanyl, oxymorphone, hydromorphone) can also be administered as a CRI if undesirable adverse effects of morphine occur.3 In critically ill animals that are poor anesthetic candidates, fentanyl, in conjunction with propofol, can provide adequate, safe, cardiovascular system–sparing anesthesia and therefore reduce or minimize the amount of inhalant anesthesia necessary. Adverse effects such as bradycardia may require treatment with an anticholinergic.46 Butorphanol has been administered at a loading dose of 0.1 mg/ kg followed by 0.03 to 0.4 mg/kg/hr IV CRI.7 Lidocaine can also be administered for pain control at an initial loading dose of 1 to 2 mg/ kg followed by 0.025 mg/kg/min IV CRI.44 Lidocaine doses as high as 2 to 3 mg/kg/hr IV have been reported.19 The a2-agonists can also be

CHAPTER 134  Analgesia and Constant Rate Infusions

793

TABLE 134.2  Epidural Dosing36 Dog Dose and Duration of Action

Cat Dose and Duration of Action

Morphine (preservative free for epidural use)

0.1–0.4 mg/kg, with maximum volume of 6 ml36 Onset of action: 20–60 min Duration of action: 6–24 hr5,40

0.16 mg/kg

Buprenorphine

0.003–0.006 mg/kg

0.003–0.006 mg/kg

Bupivacaine

0.5–2 mg/kg; higher end of dose range may result in transient paralysis36 Onset of action and duration similar to those of morphine

0.5–1 mg/kg

Epidural Drug

Epidural catheter dosing

Duration of action: 20 hr36

Duration of action: 20 hr

36

Benefits

Cautions

Lipid soluble Long acting Longer duration of action than systemic dosing5 Can reverse with naloxone

Use preservative-free formulation when administering

Preservative free Not a schedule II drug High lipid solubility

Difficult to reverse

Less likely to result in urinary retention than morphine5,7,39,40

When an epidural catheter is used the following drugs and doses are recommended: Morphine 0.1 mg/kg Bupivacaine 0.05–0.12 mg/kg Buprenorphine 0.003–0.006 mg/kg39 When the agent is injected through the epidural catheter, the injection should be given slowly because rapid injection may precipitate vomiting. A CRI of morphine (0.3 mg/kg q24h) or bupivacaine (0.2–0.3 mg/kg q24h) can be given slowly into the epidural space using a syringe pump. Bupivacaine may be administered via CRI through an epidural catheter, but this may result in muscle weakness. If the weakness is excessive, the infusion should be promptly discontinued and the dose of bupivacaine reduced39

administered as a CRI to enhance analgesia and minimize the level of inhalant needed.47 The reader is directed to Table 134.1 for more information on drug dosing. Low doses of ketamine can be used perioperatively to prevent windup, do not have undesirable side effects such as dysphoria or hallucination, and can be used for intraoperative and postoperative analgesia in dogs. A loading dose of ketamine (0.5 mg/kg IV) should be immediately followed by a CRI of 10 mcg/kg/min. This should then be reduced to 2 mcg/kg/min during the recovery phase and postoperative phase.35 Combinations of multiple types of analgesics can also be used as a CRI to provide analgesia and to decrease the amount of inhalant required in dogs. Some examples include morphine-lidocaine-ketamine and fentanyl-lidocaine-ketamine, which are described further in the following sections.

MORPHINE-LIDOCAINE-KETAMINE Morphine (3.3 mcg/kg/min), lidocaine (50 mcg/kg/min), and ketamine (10 mcg/kg/min) can be administered as a CRI analgesic combination in dogs.34 These agents can be given separately or mixed together in a single bag. Use of a combination of agents may result in enhanced analgesia through synergism and multiple receptor activation. Ketamine has been found to attenuate and reverse morphine tolerance in rodents and humans, thereby yielding an opioid-sparing effect and providing superior analgesia compared with either drug alone.34 Recent work in the cat has shown that CRIs of lidocaine should be used cautiously (if at all) in this species due to cardiopulmonary depression; this would be an especially important consideration in the critically ill animal.48 Lidocaine has been used as a CRI along with fentanyl to provide analgesia in dogs undergoing ovariectomy. The intravenous dose of lidocaine was 2 mg/kg over 5 minutes followed by a CRI of 50 mcg/kg/ min, with fentanyl dosed at 4 mcg/kg over 5 minutes followed by a CRI of 8 mcg/kg/hour. The lidocaine did not enhance the analgesia but did not adversely affect recovery.49 Lidocaine may be more useful in those

dogs that are suspected to have ischemia-reperfusion injury. Lidocaine may help diminish the level of reperfusion injury by inhibiting Na1/ Ca21 exchange and Ca21 accumulation during ischemia, scavenging hydroxyl radicals, decreasing the release of superoxide from granulocytes, and decreasing polymorphonuclear leukocyte activation, migration into ischemic tissues, and subsequent endothelial dysfunction.50

CONCLUSION Administering analgesics in critically ill animals should be considered as an integral part of a treatment regimen. Critically ill patients may present a challenge when clinicians assess the presence of pain and evaluate the response to analgesic therapy. Because of the potential physiologic effects of some analgesics, the class of analgesic and route of administration should be chosen carefully for ICU patients. Using multimodal therapy that emphasizes lower doses of different classes of drugs may be a safer and more effective way of achieving analgesia in critically ill patients.

REFERENCES 1. Hellebrekers LJ: Pathophysiology of pain in animals and its consequences for analgesic therapy. In Hellebrekers LJ, editor: Animal pain: a practiceoriented approach to an effective pain control in animals, Utrecht, The Netherlands, 2000, Van Der Wees, pp 71-83. 2. Muir WW: Choosing and administering the right analgesic therapy. In Gaynor JS, Muir WW, editors: Handbook of veterinary pain management, St. Louis, 2002, Mosby, pp 329-345. 3. Muir WW, Birchard SJ: Questions and answers on analgesia, anesthesia, and sedation. In Proceedings of the North American Veterinary Conference, Orlando, FL, 1997, pp 1-24. 4. Lamont LA, Tranquilli WJ, Grimm KA: Physiology of pain, Vet Clin North Am Small Anim Pract 30(4):703-728, 2000. 5. Dobromylskyj P, Flecknell PA, Lascelles BD, et al: Management of postoperative and other acute pain. In Flecknell P, Waterman-Pearson A, editors: Pain management in animals, Philadelphia, 2000, Saunders, pp 81-145.

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6. Wagnor A: Opioids. In Gaynor JS, Muir WW, editors: Handbook of veterinary pain management, St. Louis, 2002, Mosby, pp 164-183. 7. Pascoe PJ: Problems of pain management. In Flecknell P, Waterman- Pearson A, editors: Pain management in animals, Philadelphia, 2000, Saunders, pp 161-177. 8. Hansen B: Acute pain management, Vet Clin North Am Small Anim Pract 30(4):899-916, 2000. 9. Anagnostou TL, Kazakos GM, Savvas I, et al: Remifentanil/isoflurane anesthesia in five dogs with liver disease undergoing liver biopsy, J Am Anim Hosp Assoc 47:e103-e109, 2011. 10. Allweiler S, Brodbelt DC, Borer K, et al: The isoflurane-sparing and clinical effects of a constant rate infusion of remifentanil in dogs, Vet Anaesth Analg 34:388-393, 2007. 11. Brosnan RJ, Pypendop BH, Siao KT, et al: Effects of remifentanil on measures of anesthetic immobility and analgesia in cats, Am J Vet Res 70:1065-1071, 2009. 12. Kukanich B, Wiese AJ: Opioids. In Grimm KA, Lamont LA, Tranquilli WJ, Greene SA, Robertson SA, editors: Lumb and Jones’ veterinary anesthesia and analgesia, ed 5, Ames, IA, 2015, Wiley Blackwell, pp 207-226. 13. Shah MD, Yates D, Hunt J, Murrell JC: A comparison between methadone and buprenorphine for perioperative analgesia in dogs undergoing ovariohysterectomy, J Small Anim Pract 59:539-546, 2018. 14. Doodnaught GM, Monteiro BP, Benito J, et al: Pharmacokinetic and pharmacodynamics modelling after subcutaneous, intravenous and buccal administration of a high-concentration formulation of buprenorphine in conscious cats, PLOS One 12(4):1-16, 2017. 15. Doodnaught GM, Monteiro B, Edge D, et al: Thermal antinociception after buccal administration of a high-concentration formulation of buprenorphine (Simbadol) at 0.24 mg/kg in conscious cats, Vet Anaesth Analg 45(5):714-716, 2018. 16. Muir WW: Drug antagonism and antagonists. In Gaynor JS, Muir WW, editors: Handbook of veterinary pain management, St. Louis, 2009, Mosby, pp 391-401. 17. Plumb DC: Naloxone. In Plumb DC, editor: Veterinary drug handbook, ed 4, Ames, IA, 2002, Iowa State University Press, pp 575-576. 18. Budsberg S: Nonsteroidal anti-inflammatory drugs. In Gaynor JS, Muir WW, editors: Handbook of veterinary pain management, St. Louis, 2009, Mosby, pp 183-209. 19. Hellebrekers LJ: Practical analgesic treatment in canine patients. In Hellebrekers LJ, editor: Animal pain: a practice-oriented approach to an effective pain control in animals, Utrecht, The Netherlands, 2000, Van Der Wees, pp 117-129. 20. Mathews KA: Management of pain in cats. In Hellebrekers LJ, editor: Animal pain: a practice-oriented approach to an effective pain control in animals, Utrecht, The Netherlands, 2000, Van Der Wees, pp 131-144. 21. Sano T, King JN, Seewald W, et al: Comparison of oral robenacoxib and ketoprofen for the treatment of acute pain and inflammation associated with musculoskeletal disorders in cats: a randomized clinical trial, Vet J 193(2):397-403, 2012. 22. Kamata M, King JN, Seewald W, et al: Comparison of injectable robenacoxib versus meloxicam for peri-operative use in cats: results of a randomized clinical trial, Vet J 193(1):114-118, 2012. 23. Onsior (robenacoxib) (package insert). Basel, Switzerland, 2012, Novartis Animal Health. 24. Plumb DC: Dexmedetomidine HCL. In Plumb DC, editor: Veterinary drug handbook, ed 7, Ames, IA, 2011, Iowa State University Press, pp 298-300. 25. Muir WW, McDonell WN, Kerr CL, et al: Anesthetic physiology and pharmacology. In Grimm KA, Tranquilli WJ, Lamont LA, editors: Essentials of small animal anesthesia and analgesia, ed 2, Ames, IA, 2011, WileyBlackwell, pp 15-81. 26. Lamont L: a2 Agonists. In Gaynor JS, Muir WW, editors: Handbook of veterinary pain management, St. Louis, 2009, Mosby, pp 210-230. 27. Campbell VL: Injectable anesthetic techniques. In Proceedings of the 11th International Veterinary Emergency and Critical Care Symposium, 2005, pp 21-24. 28. Siao KT, Pypendop BH, Honkavaara J, et al: Hemodynamic effects of dexmedetomidine, with and without MK-467, following intramuscular administration in cats anesthetized with isoflurane, Vet Anaesth Analg 44:1101-1115, 2017.

29. Gammaitoni AR, Alvarez NA, Galer BS: Safety and tolerability of the lidocaine patch 5%, a targeted peripheral analgesic: a review of the literature, J Clin Pharmacol 43:111-117, 2003. 30. Lee DD, Papich MG, Hardie EM: Comparison of pharmacokinetics of fentanyl after intravenous and transdermal administration in cats, Am J Vet Res 61(6):672-677, 2000. 31. Pasero C: Lidocaine patch 5%: how to use a topical method of controlling localized pain, Am J Nurs 103(9):75-78, 2003. 32. Bidwell LA, Wilson DV, Caron JP: Systemic lidocaine absorption after placement of Lidoderm patches on horses: preliminary findings. In Proceedings of the Veterinary Midwest Anesthesia and Analgesia Conference, 2004, p 15. 33. Lamont LA, Tranquilli WJ, Mathews KA: Adjunctive analgesic therapy, Vet Clin North Am Small Anim Pract 30(4):805-813, 2000. 34. Muir WW, Wiese AJ, March PA: Effects of morphine, lidocaine, ketamine, and morphine-lidocaine-ketamine drug combination on minimum alveolar concentration in dogs anesthetized with isoflurane, Am J Vet Res 64(9):1155-1160, 2003. 35. Wagnor AE, Walton JA, Hellyer PW, et al: Use of low doses of ketamine administered by constant rate infusion as an adjunct for postoperative analgesia in dogs, J Am Vet Med Assoc 221(1):72-75, 2002. 36. Flecknell P, Waterman-Pearson A, editors: Pain management in animals, Philadelphia, 2000, Saunders. 37. Bernard F, Kudnbig ST, Monnet E: Hemodynamic effects of interpleural lidocaine and bupivacaine combination in anesthetized dogs with and without an open pericardium, Vet Surg 35:252-258, 2006. 38. Lascelles BDX, Rausch-Derra LC, Wofford JA, et al: Pilot, randomized, placebo-controlled clinical field study to evaluate the effectiveness of bupivacaine liposome injectable suspension for the provision of post-surgical analgesia in dogs undergoing stifle surgery, BMC Vet Res 12:3-10, 2016. 39. Troncy E, Junot S, Keroack S, et al: Results of preemptive epidural administration of morphine with or without bupivacaine in dogs and cats undergoing surgery: 265 cases (1997-1999), J Am Vet Med Assoc 221(5): 666-672, 2002. 40. Hansen BD: Epidural catheter analgesia in dogs and cats: technique and review of 182 cases (1991-1999), J Vet Emerg Crit Care (San Antonio) 11(2):95-103, 2001. 41. Swalander DB, Crowe DT, Hittenmiller DH, et al: Complications associated with the use of indwelling epidural catheters in dogs: 81 cases (19961999), J Am Vet Med Assoc 216(3):368-370, 2000. 42. Muir WW, Skarda RT: Pain management in the horse. In Gaynor JS, Muir WW, editors: Handbook of veterinary pain management, St. Louis, 2002, Mosby, pp 420-444. 43. O’Hearn AK, Wright BD: Coccygeal epidural with local anesthetic for catheterization and pain management in the treatment of feline urethral obstruction, J Vet Emerg Crit Care 21(1):50-52, 2011. 44. Smith LJ, Bentley E, Shih A, et al: Systemic lidocaine infusion as an analgesic for intraocular surgery in dogs: a pilot study, Vet Anaesth Analg 31(1):53-63, 2004. 45. Lucas AN, Firth AM, Anderson GA, et al: Comparison of the effects of morphine administered by constant-rate intravenous infusion or intermittent intramuscular injection in dogs, J Am Vet Med Assoc 218(6):884-891, 2001. 46. Mendes GM, Selmi AL: Use of a combination of propofol and fentanyl, alfentanil, or sufentanil for total intravenous anesthesia in cats, J Am Vet Med Assoc 223(11):1608-1613, 2003. 47. Quandt JE, Lee JA: Analgesia and constant rate infusions. In Silverstein DC, Hopper K, editors: Small animal critical care medicine, ed 1, St. Louis, 2009, Saunders, pp 710-716. 48. Pypendop BH, Ilkiw JE: Assessment of the hemodynamic effects of lidocaine administered IV in isoflurane anesthetized cats, Am J Vet Res 66:661-668, 2005. 49. Columbano N, Secci F, Careddu GM, et al: Effects of lidocaine constant rate infusion on sevoflurane requirement, autonomic responses, and postoperative analgesia in dogs undergoing ovariectomy under opioid-based balanced anesthesia, Vet J 193:448-455, 2012. 50. Cassutto BH, Gfeller RW: Use of intravenous lidocaine to prevent reperfusion injury and subsequent multiple organ dysfunction syndrome, J Vet Emerg Crit Care (San Antonio) 13:137-148, 2003.

135 Physical Rehabilitation for the Critical Care Patient Molly J. Flaherty, DVM, CCRP, CVA, CVPP

KEY POINTS • Intensive care unit-acquired weakness is well recognized in both humans and animals. The severity of this weakness can be mitigated by starting rehabilitation therapy as soon as the patient is stable. • Passive and active therapies can be tailored to the patient’s abilities and specific needs.

• Rehabilitation modalities can provide safe adjunctive treatments for pain management during hospitalization. • Pulmonary therapy techniques can help improve lung ventilation and supplement mucociliary clearance. • Collaboration with the patient’s veterinary care team is essential to ensure safety and maximal benefits.

INTRODUCTION

including patients suffering from unstable spinal injury, liver or spleen lacerations, respiratory distress, and cardiovascular crisis. Basic rehabilitation therapies provided by veterinary clinicians and nursing staff can make a significant difference. Having a rehabilitation certified practitioner for training on application and modalities requiring more expertise is valuable in the critical care setting. It is important to collaborate with the primary clinician overseeing the patient’s hospital care and review their medical record before initiating therapy. Rehabilitation examination findings and treatment should be documented in medical records. Periodic reassessments of patients should be performed as status can change quickly.

Veterinary physical rehabilitation has developed considerably over the past decade. Rehabilitation specific to veterinary critical care patients is an area that remains open to further advancement. In human medicine, physical therapy for intensive care patients is established and routinely integrated into hospital care. Intensive care unit acquired weakness (ICUAW) is a known and much researched complication of human critical care patients. ICUAW is associated with generalized muscle weakness and reduced functional ability. The underlying mechanisms are complex, involving alterations in both muscles and nerves.1 As much as 25%–50% of human patients will experience ICUAW and is associated with long-lasting impairments.2 Decrease in functional ability following intensive care stay has been shown to persist up to 6 months in humans after hospitalization.3 Similar changes likely occur in animal patients as well. Muscle mass and strength loss occurs early in hospitalization. As much as 50% of muscle strength can be lost within 1 week of immobility.4 Early mobilization during hospitalization, after stabilization of physiologic disorders, is essential in prevention and improving functional outcome. As advanced medicine becomes more available to our veterinary patients, it is logical that supplemental care such as rehabilitation is involved to maximize outcome. A rehabilitation program in the critical care setting can reduce pain and complications associated with prolonged immobility and cage rest such as weakness, muscle mass loss, joint changes, decreased perfusion and ventilation, decubital ulcers, injury, prolonged recovery, and hospital stay time (Box 135.1). This can be achieved through use of modalities including laser, electrical stimulation, pulsed electromagnetic therapy, cryo- and thermotherapy, passive and active movement, and pulmonary therapy. The goals of this chapter are to review these modalities and potential benefits for critical care patients. Providing rehabilitation therapy to critical veterinary patients presents unique challenges; patients are often treated for multiple conditions and injuries simultaneously. Care should be taken with monitoring lines, supportive devices, and tubing attached to the patient. Necessary medical treatments should be given priority and avoid disruption. Certain medical conditions may necessitate delayed rehabilitation therapy,

PAIN MANAGEMENT Pain control in critical patients is of considerable importance for comfort and minimizing stress-related effects. Rehabilitation offers many adjunctive treatments to complement pain management. Rehabilitation can contribute to earlier return to mobility and reduce the need for pain medications that could have adverse side effects. Laser therapy, transcutaneous electrical nerve stimulation (TENS), pulsed electromagnetic therapy (PEMF), cryotherapy, and thermotherapy can be used in combination and customized for each patient.

Laser Laser therapy, also known as photobiomodulation, involves the direct application of light energy (photons) to induce cellular responses in tissues. Particular wavelengths of light are used because of their ability to penetrate tissues and produce biological reactions. The theory of photobiomodulation is that photons are absorbed by the cytochrome c complex in the mitochondria of target cells, which results in a biological cascade of events, including accelerated production of ATP, nitric oxide, and reactive oxygen species. These have combined benefits, including reduction of pain and inflammation, vasodilation, and acceleration of healing. Laser treatment is easily applied to critical patients since it requires minimal patient manipulation and is generally very well tolerated. Critically ill patients may have injuries that could benefit from laser treatment while in the hospital, particularly those that have suffered

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BOX 135.1  Benefits of Rehabilitation

Therapy in Critically Ill Patients • Decrease loss of muscle mass and strength • Maintain functional ability • Decrease pain and inflammation • Improve healing time • Reduce edema • Improve ventilation and circulation • Positive psychological benefits • Prevent injury • Decrease hospitalization time • Guide posthospitalization home care

trauma and those with healing wounds, pressure sores, or incisions. Laser treatment applied to wounds or incisions can improve healing time and scar appearance in animals.5,6 Treatments can also improve muscle repair after injury and counteract progressive muscle atrophy after peripheral nerve injury.7 Laser research has been shown to enhance recovery from central nervous system injury, which is associated with increased neuronal cell metabolism. Improved recovery time following intervertebral disc rupture has been found in canine patients with direct laser treatment postoperatively.8 Laser therapy should be prescribed by a clinician involved in the patient’s care. Those applying the treatments should be well trained in the use of laser therapy and the particular unit they are using. Protective eyewear use is recommended during application to avoid retinal damage. Contraindicated areas of treatment to be aware of include neoplastic lesions, near a pregnant uterus, gonads, or cornea, near the presence of active bleeding, the endocrine glands, and active epiphyses.

Transcutaneous Electrical Nerve Stimulation TENS is the application of high-frequency electrical current through electrodes placed on the skin. TENS activates large cutaneous Ab fibers, which is believed to stimulate inhibitory neurons in the spinal cord dorsal horn, interfering with transmission of C nerve fiber pain impulses to the brain (also known as the gate theory). The stimulation input with TENS is sensory and not intended to create a muscular contraction as with neuromuscular electrical stimulation (NMES). Settings used for conventional TENS for pain relief are high frequency, generally 80–130 Hz, to stimulate Ab fibers. Application involves the placement of electrodes with transducer gel parallel to an incision, surrounding an area of pain, or on two sides of a joint over clipped and cleaned skin. Segmental placement may also be done by placing the electrodes over the nerve root of the spinal segment corresponding with the regional area of pain. TENS can be used as an immediate pain-reducing modality for patients experiencing pain following surgical procedures such as fracture repairs and spinal surgery. Treatments are 15–20 minutes and can be used one to two times per day or as needed for pain relief. In humans, studies have shown that TENS treatment are beneficial in reducing pain and opioid medication needs postoperatively9-11 and reducing pain during ambulation in recovery following hip surgery.12 This can be applicable to animal patients following similar painful conditions.

Pulsed Electromagnetic Field Therapy PEMF treatment involves a device that transmits a nonthermal electromagnetic field when applied over an area of tissue to reduce pain and inflammation. Targeted PEMF (tPEMF) devices for pain relief are configured to increase intracellular Ca21, which leads to increased

calcium binding to calmodulin. It is believed that this reaction leads to a variety of downstream pathways, including the production of nitric oxide. Nitric oxide is associated with the reduction of inflammation and enhanced circulation secondary to vasodilation.13 In canine patients, there was a reduced need for pain medications and improved wound healing with PEMF use posthemilaminectomy.14 PEMF is a safe, noninvasive, and effective modality for postoperative pain control, inflammation reduction, and tissue healing.14-16 Treatment with PEMF is painless, athermal and does not produce sensation; therefore it is very well tolerated by animal patients. PEMF is a suitable option for critical patients that may be sensitive to sensory input. It can be used over areas of tissue trauma, bone fractures, healing wounds, and surgical incisions. Devices commonly used in veterinary medicine are small portable loops that emit the PEMF in an elliptical range around the loop. For treatment the loop is placed over or around the area of pain or trauma. Treatments are generally 15 minutes, starting three to four times per day and tapering. PEMF is a means to augment pain control during hospitalization and continue pain management after discharge. No adverse effects have been reported, although it is not advisable to apply PEMF over tumor sites of hemangiosarcoma due to a potential increase in blood flow. Similarly, it should not be used with animals that have a pacemaker because of potential electrical interference.

Cryotherapy Cryotherapy, the application of cold to tissues, results in vasoconstriction, which decreases local blood flow, inflammatory response, and edema, thereby reducing pain. Pain relieving effects are achieved by slowing of nerve conduction velocity, increasing pain threshold and pain tolerance.17 Cold therapy has been widely used for both acute and chronic musculoskeletal pain. Cryotherapy can be applied three to six times per day for 15–20 minutes, for 3 to 5 days to areas of pain and swelling following acute trauma or at the site of recent surgery. A towel or cloth should be placed between the patient and ice pack to prevent skin damage.

Thermotherapy Thermotherapy, the application of superficial heat to tissues, results in vasodilation, promotion of circulation of blood and lymphatics, edema reduction, release of muscular tension and spasm, pain reduction, and improved tissue elasticity. Critical care patients that may benefit from thermotherapy include those with muscular tension from reduced motion or from compensating for other injured areas of the body. When used prior to massage, heat can be beneficial in reducing edema, and when used prior to passive and active therapy, it can improve tissue flexibility and range of motion. Application is typically 10–20 minutes. A towel should be placed between the patient and the heat pack, and patients should be closely monitored for signs of overheating. Caution should be exercised when considering thermotherapy over areas of active bleeding, burns or skin lesions, neoplasia, acute inflammation, or in the presence of fever.

PASSIVE THERAPY Passive Range of Motion Passive range of motion (PROM) is a basic technique that is important to perform in recumbent patients or those with restricted motion during hospitalization. PROM allows for diffusion of nutrients from synovial fluid to cartilage, improves circulation and flexibility, and reduces the tension of periarticular muscles. In patients with femoral fractures, PROM is required to prevent quadriceps muscle contracture. The technique involves moving all limb joints through their normal and

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comfortable range of motion in extension and flexion. It is recommended to work with each joint individually from distal to proximal (Videos 135.1 and 135.2). Patients should be lying in lateral recumbency and calm. A joint that is painful or compromised or has limited range of motion will require slow, careful motion to apply PROM safely and without discomfort. Treatments should comprise 10–15 repetitions every 6–8 hours.

Massage Massage aids in myofascial release, enhances circulation, reduces edema, minimizes muscle contraction and scarring, and reduces painful muscle spasms. Techniques commonly used for animal patients are stroking, effleurage, and pétrissage. Stroking, slow gliding movement over the body using the palm of the hand in the direction of fur growth, cranial to caudal and proximal to distal. This helps in relaxation and increase blood flow to the areas applied. Effleurage helps with fluid mobilization and lymphatic drainage; the palms of the whole hand are used for long strokes with light to moderate pressure distal to proximal and along the direction of muscle fibers towards the flow of lymphatic and drainage back to the heart. Pétrissage uses kneading, compression, tissue squeezing, and skin rolling with moderate pressure. This technique helps restore tissue mobility and assist with lymphatic return. It is important to ensure that this technique is not uncomfortable to the patient and not used over areas of tissue trauma. Treatments can be done in the clinic and taught to owners for home care. Massage therapy should not be performed over areas of active infection or acute inflammation, near a tumor, over open wounds, in cases of deep vein thrombosis or coagulopathies, in patients with unstable fractures, over painful areas, in patients in shock, and animals adversely reactive to touch. Hands-on therapy can also help calm patients, provide positive stimulation, prevent depression, and improve sleep quality.

Fig. 135.1  Assisted sitting using a towel roll under the pelvis to aid in upright posture.

Neuromuscular Electrical Stimulation NMES should be applied by a trained veterinary rehabilitation therapist. This modality uses low frequency, high pulse duration electrical stimulation to the muscles percutaneously through electrodes placed on the skin. The current acts on motor nerves to achieve muscle contraction. This is useful for patients that have reduced voluntary motor function in one or more areas or those who are recumbent. Benefits include increased joint range of motion and maintaining muscle strength, tone, and function. Studies demonstrate that electrical muscle stimulation prevents muscle weakness in human critical care patients.18 If patients are physically able to produce active muscle contractions by active therapy, that should be started in lieu of NMES as soon as the patient is stable. Treatment duration is generally 15–20 minutes daily. It is contraindicated in animals with pacemakers or seizure disorders. Application is not recommended over areas of neoplasia, infection, impaired sensation or skin damage, thrombosis or thrombophlebitis, directly over the heart, carotid sinus, or trunk during pregnancy.

ACTIVE THERAPY Active movement allows for natural joint motion and muscle contractions to maintain muscle strength and joint health. Benefits also include augmenting perfusion and ventilation. Through stimulation of proprioception and balance, risks of injury are reduced. Assisted active therapy in critical patients is provided initially by supporting the patient with the necessary level to follow through with the task. This may begin with supported therapy in the sitting, standing, or walking position depending on the patient’s functional capacity at the time of treatment.

Fig. 135.2  Assisted standing using a physio roll and a body harness for support.

Supported sitting can be done with a bolster under the pelvis to support the low back if the animal is not able to sit to the ground with appropriate posture (Fig. 135.1). Supported standing is performed by standing over a physio roll that supports the animal’s torso while allowing their limbs to place on the ground in a standing position (Fig. 135.2) or using a sling or body harness for support. Using a physio roll is optimal for the weaker patients or those with difficulty with balance and coordination. Weight shifting can be performed while the animal is supported in a standing position; by providing gentle motion side to side and front to back, mild weight bearing occurs. This aids in proprioceptive input and mild muscular contractions. Supported walking should be done with a sling or full body harness support to prevent slipping or injury. If the floor surface does not allow good traction, booties can be used to prevent paws from slipping. Mobility carts can be used for patients that have significant weakness or neurologic deficiencies to allow more supported mobility. The treatment length will vary considerably. Some patients can only complete a couple minutes of active work initially. A

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rehabilitation therapist can be valuable for tailoring targeted therapy exercises according to physical requirements and goals for the individual patient.

propped in the semisternal position with bolsters, pillows, blankets, or V-shaped positioners.

PULMONARY THERAPY

Thoracic postural drainage can supplement mucociliary clearance of pulmonary airway secretions and increase the residual capacity of the lungs. Disease processes altering secretion production may include lung lobe abscess, pneumonia, bronchiectasis, atelectasis, or contusion. The process involves placing the body in a position that allows gravity to assist in mobilization of mucous from the affected lung to segmental bronchi and to the upper airway. These areas should first be identified and localized by appropriate diagnostic imaging. There are seven postural drainage positions in the canine illustrated in Fig. 135.3.19 The intention of the various positions is to place

Positioning For patients that are unable to change body position independently, altering recumbency is recommended every 4 hours. Positions should alternate from right, sternal, and left. This aids the pulmonary system by preventing atelectasis and accumulation of secretions in the down side. Positional rotation improves patient comfort and reduces risk of decubital ulcers, muscle pain, joint stiffness, and dependent limb edema. Patients that are unable to maintain sternal position can be

Postural Drainage

A

B

C

D

E

F

G Fig. 135.3  Positions for draining various portions of the lungs. A, Lateral segment of the left caudal lung lobe: The patient is in left lateral recumbency with the hind end elevated 40 degrees. B, Left and right caudal dorsal lung fields: the patient is in sternal recumbency with hind end elevated 40 degrees. C, Left and right caudal ventral lung fields: The patient is a dorsal recumbency with the hind end elevated 40 degrees. D, Left and right cranial ventral lung fields: the patient is in dorsal recumbency with the front end elevated 40 degrees. E, Left and right cranial dorsal lung fields: The patient is in sternal recumbency with the front end elevated 40 degrees. F, Right middle lung lobe: The patient is in dorsal recumbency. A pillow has been placed under the left side of the thorax so that the right side is higher than the left side. The hind end is elevated 40 degrees, and the front end is rotated one-quarter turn to the right. G, Lateral segment of the right caudal lung lobe: The patient is in left lateral recumbency with the hind end elevated 40 degrees. (From Manning AM, Vrbanac Z: Physical rehabilitation for the critically injured veterinary patient. In Millis DL, Levine D: Canine rehabilitation and physical therapy, ed 2, St Louis, 2014, Elsevier, p 655.)

CHAPTER 135  Physical Rehabilitation for the Critical Care Patient the segmental bronchi vertical to the affected lung segment. Treatment is 5–10 minutes for each lung section, two to four times per day.20 Care should be taken to monitor for respiratory distress and oxygen should be nearby in case of need. Postural drainage is most effective when followed by a method such as percussion and cough to propel secretions from the larger airway. Saline or water nebulization may be administered prior to percussion to enhance hydration and mobilization of secretions from the lower airways.

Percussion Thoracic percussion may be used after postural drainage in attempt to loosen mucous from bronchial walls. Percussion is the technique of rapidly tapping the thorax with cupped hands directly over the lung segment to be drained. Following this, cough can be elicited by gentle pressure over the larynx or proximal trachea. Active motion is superior to airway clearance techniques; therefore, patients that are mobile should be encouraged to stand and walk 5–10 minutes four to six times per day.19

Contraindications for Pulmonary Therapy Cautions for pulmonary therapy can include hypoxemia, increased intracranial pressure, rib fracture, spine instability, chest wounds, pneumothorax, congestive heart failure, arrhythmias, coagulopathy, shock, thoracic neoplasia, and regurgitation. Collaboration between the therapist and critical care clinician is essential before beginning treatment.

SUMMARY Rehabilitation for critical care patients should begin as soon as they are stable. Therapeutic strategies for the care of each patient should be individualized and collaborated with ICU clinicians. The longer a patient spends immobilized, the more difficult it is to regain muscle strength. Incorporating rehabilitation therapy can help prevent complications, reduce hospitalization time, and improve independent function. Even basic rehabilitation therapies can provide significant benefits to patient recovery. Clients are often overwhelmed with their pet’s illness and have concerns about managing their care at home. Pet owners may appreciate working with a rehabilitation therapist to gain better knowledge of recommended home therapy. A hands-on review of appropriate therapy can be very helpful to ensure they are not doing too much or too little in the animal’s home recovery. Telemedicine and premade video sources are also useful means to provide guidance for home therapy to clients.

REFERENCES 1. Hermans G, Van den Berghe G: Clinical review: intensive care unit acquired weakness, Crit Care 19:274, 2015. 2. Denehy L, Lanphere J, Needham DM: Ten reasons why ICU patients should be mobilized early, Intensive Care Med 43(1):86-90, 2017.

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3. Sidiras G, Patsaki I, Karatzanos E, et al: Long term follow-up of quality of life and functional ability in patients with ICU acquired weakness- a post hoc analysis, J Crit Care 53:223-230, 2019. 4. Huntingford JL, Fossum TW: Fundamentals for physical rehabilitation in small animal surgery. In Fossum TW, Cho J, Dewey CW, editors: Small animal surgery, ed 5, St Louis, 2019, Elsevier, pp 105-124. 5. Lima MMCT, da Silva Sergio LP, da Silva Neto Trajano LA, et al: Photobiomodulation by dual-wavelength low-power laser effects on infected pressure ulcers. Lasers Med Sci 35(3):651-660, 2020. doi:10.1007/s10103-01902901-6. 6. Wardlaw JL, Gazzola KM, Wagoner A, et al: Laser therapy for incision healing in 9 dogs, Front Vet Sci 5:349, 2019. 7. Mandelbaum-Livnat MM, Almog M, Nissan M, et al: Photobiomodulation triple treatment in peripheral nerve injury: nerve and muscle response, Photomed Laser Surg 34(12):638-645, 2016. 8. Draper WE, Schubert TA, Clemmons RM, Miles SA: Low-level laser therapy reduces time to ambulation in dogs after hemilaminectomy: a preliminary study, J Small Anim Pract 53(8):465-469, 2012. 9. Li J, Song Y: Transcutaneous electrical nerve stimulation for postoperative pain control after total knee arthroplasty: a meta-analysis of randomized controlled trials, Medicine 96(37):1-12, 2017. doi:10.1097/MD.0000000000008036. 10. Mahure SA, Rokito AS, Kwon YW: Transcutaneous electrical nerve stimulation for postoperative pain relief after arthroscopic rotator cuff repair: a prospective double-blinded randomized trial, J Shoulder Elbow Surg 26(9):1508-1513, 2017. 11. Platon B, Mannheimer C, Andréll P: Effects of high-frequency, high-intensity transcutaneous electrical nerve stimulation versus intravenous opioids for pain relief after gynecologic laparoscopic surgery: a randomized controlled study, Korean J Anesthesiol 71(2):149-156, 2018. 12. Elboim-Gabyzon M, Andrawus Najjar S, Shtarker H: Effects of transcutaneous electrical nerve stimulation (TENS) on acute postoperative pain intensity and mobility after hip fracture; a double-blinded, randomized trial, Clin Interv Aging 14:1841-1850, 2019. 13. Gaynor JS, Hagberg S, Gurfein BT: Veterinary applications of pulsed electromagnetic field therapy, Res Vet Sci 119:1-8, 2018. 14. Alvarez LX, McCue J, Lam NK, Askin G, Fox PR: Effect of targeted PEMF therapy on canine post-operative hemilaminectomy: a double-blind, randomized, placebo-controlled clinical trial, J Am Anim Hosp Assoc 55(2):83-91, 2019. 15. Rohde CH, Taylor EM, Alonso A, Ascherman JA, Hardy KL, Pilla AA: Pulsed electromagnetic fields reduce postoperative interleukin-1b, pain, and inflammation: a double blind, placebo-controlled study in TRAM flap breast reconstruction patients, Plast Reconstr Surg 135(5):808-817, 2015. 16. Zidan N, Fenn J, Griffith E, et al: The effect of electromagnetic fields on post-operative pain and locomotor recovery in dogs with acute, severe thoracolumbar intervertebral disc extrusion: a randomized placebo-controlled, prospective clinical trial, J Neurotrauma 35(15)1726-1736, 2018. 17. Algafly A, George K: The effect of cryotherapy on nerve conduction velocity, pain threshold and pain tolerance, Br J Sports Med 41(6):365-369, 2007. 18. Maffiuletti NA, Roig M, Karatzanos E, Nanas S: Neuromuscular electrical stimulation for preventing skeletal-muscle weakness and wasting in critically ill patients: a systematic review, BMC Med 11:137, 2013. 19. Manning AM, Vrbanac Z: Physical rehabilitation for the critically injured veterinary patient. In Millis DL, Levine D, editors: Canine rehabilitation and physical therapy, ed 2, St Louis, 2014, Elsevier, pp 652-658. 20. Dunning D, Halling KB, Ehrhart N: Rehabilitation of medical and acute care patients, Vet Clin Small Anim 35(6):1411-1426, 2005.

e1 Video 135.1  Passive range of motion (PROM) forelimb Video 135.2  Passive range of motion (PROM) hindlimb

136 Integrative Veterinary Medicine for the Intensive Care Unit Patient Narda G. Robinson, DO, DVM, MS, FAAMA

KEY POINTS • Several integrative medical approaches such as acupuncture, massage, laser therapy, and music therapy provide clinically meaningful benefits for hospitalized patients; for this reason, physical modalities such as these warrant consideration for early inclusion into treatment plans for veterinary intensive care unit patients. • Herbal remedies, on the other hand, can help or harm. Unlike approved medications, their pharmacologic and safety profiles

The ICU can be frightening, lonely, and stressful. In addition to the severity of their affliction, ICU inhabitants endure multiple stressors such as pain, tension, lack of sleep, loneliness, anxiety, and the inability to communicate their needs adequately.1 According to one of the leading researchers in the ethics of human critical care, “Alleviating the stresses and symptoms of critically ill patients will enhance the quality of their ICU stay, which itself achieves an important beneficial and ethical outcome, an outcome that should be a priority of every intensivist.”2 Sleep deprivation and immobilization impair recovery. They sensitize the central nervous system, causing “wind-up,” which amplifies pain and stress. As a result, cardiac demand, vasoconstriction, blood viscosity, platelet aggregation, and cellular catabolism increase. In fact, “in many patients with severe posttraumatic or postsurgical pain, the ensuing neuroendocrine responses are sufficient to initiate or maintain a state of shock.”3 Pharmaceutical analgesics and sedatives can worsen a patient’s status by slowing intestinal motility and inducing disorientation. Currently, many medications such as opioids have become more difficult to obtain and prescribe. As such, a compelling need exists to identify nondrug methods of addressing pain and other problematic morbidities in the critical care setting.4 Veterinary critical care personnel often welcome integrative medical interventions that support the animals’ quality of life and potentially improve survival. Nevertheless, as shown in the human hospital setting, acceptance and implementation of nonpharmacologic, integrative medical methodologies are highest when these therapies demonstrate a scientific basis for use and evidential support.5 A systematic review of randomized controlled trials in human patients found statistically significant improvements in pain, anxiety, agitation, sleep, level of arousal, and duration of mechanical ventilation with integrative medicine approaches such as music, nature-based sounds, aromatherapy, and massage.6 The sections that follow present several commonly employed integrative medicine measures for human and veterinary critical care patients. Approaches such as acupuncture, photomedicine, massage, and pulsed electromagnetic field (PEMF) therapy induce normalizing and restorative physiologic changes unparalleled by medications and

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are typically unavailable for veterinary patients. In addition, inadequate regulatory enforcement allows product sales without the demonstration of product purity and full disclosure of the types and quantities of contents. These factors present hurdles when prescribing plant-based drugs in veterinary medicine.

surgery. They open avenues for recovery with less risk of injury and death. They also lessen fear, anxiety, and stress. Moreover, the multiplicity of comorbidities encumbering critical care patients calls for therapeutic interventions with wide-ranging supportive influences at the beginning of care, not near the end, after invasive procedures and polypharmacy have failed. In human health care, the cost savings afforded by adding integrative medicine early and throughout a patient’s stay will be evident due to decreases in medication costs and length of patient stay.7

ACUPUNCTURE Acupuncture is one of the most well-researched integrative medicine measures for patients receiving critical care. It activates nerve endings and engages with connective tissues (e.g., muscle and fascia) by means of thin, solid, atraumatic acupuncture needles. Other forms of activation involve pressure, light, or electrical stimulation. This somatic afferent stimulation results in an outcome termed “neuromodulation” (i.e., a balancing of function in the central, peripheral, and autonomic nervous systems). It also normalizes muscle tone and releases fascial restriction. Acupuncture facilitates healing in a number of ways. First, reducing central and peripheral nervous system sensitization is analgesic and anxiolytic. Second, neuromodulating the autonomic nervous system brings it back toward balance. This impels digestive function, immunologic activity, and circulation in the direction of health. Specifically, it improves gastrointestinal motility, glandular function, immune surveillance, and tissue oxygenation. Relaxing myofascia improves comfort and mobility, making a patient better equipped to overcome a critical illness or injury.8 Box 136.1 lists the types of conditions that may respond to acupuncture therapy in human ICU patients.9 In addition, the antiinflammatory and renal-protective effects of electroacupuncture have demonstrated potential value in the treatment of sepsis.10 Relative contraindications to acupuncture include severe immune compromise or coagulopathy and widespread skin infections.

CHAPTER 136  Integrative Veterinary Medicine for the Intensive Care Unit Patient

BOX 136.1  Conditions for Which

Acupuncture May Be Beneficial in Intensive Care Unit Patients Cardiac Conditions • Adjunct to cardiopulmonary resuscitation measures • Arrhythmias • Peripheral edema • Acupuncture-assisted anesthesia for high-risk patients Respiratory Conditions • Nasal blockage • Sinusitis • Bronchospasm • Hiccoughs • Chest wall pain inhibiting diaphragmatic excursion Acute and Chronic Pain • Neuropathic pain (central or peripheral) • Arthritis pain • Back pain • Postsurgical pain • Phantom limb pain • Abdominal pain • Pain associated with cancer and its treatment • Ocular discomfort • Facial and dental pain Orthopedic Problems • Muscle tension and restriction • Contractures • Tendonitis, bursitis • Posttraumatic discomfort • Ligamentous injury • Sprain • Fracture • Contusions Neurologic Issues • Anxiety • Peripheral or cranial neuropathy, neuritis, or nerve trauma • Cerebrovascular accident • Seizures • Cognitive disorder • Spinal cord injury • Disk disease • Autonomic dysregulation Gastrointestinal Disorders • Nausea • Vomiting • Inappetence • Esophageal spasm • Ileus (posttraumatic and postsurgical) • Gastric hyperacidity • Intestinal motility disorders, including diarrhea, constipation, obstipation, megacolon Urinary Dysfunction • Renal impairment • Urinary retention or incontinence

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MASSAGE THERAPY In humans, massage, or gentle, rhythmic stroking, can reduce stress, alleviate pain, and help normalize physiologic function.11,12 Even a relatively brief back massage can promote sleep, a vital restorative process.13 Children with respiratory disease that receive massage therapy show improvements in spirometric parameters, immunologic function, and anxiety control.14 Adults receiving intermittent enteral nutrition delivered by nasogastric tube demonstrated less gastric residual volume, abdominal distention, and vomiting after receiving abdominal massage.15 Women treated with a technique called manual lymphatic drainage exhibit improved circulation in their thoracic limbs.16 Critically ill humans, following massage, show improvement in their vital signs as well as reduced pain and anxiety.17 End-of-life patients, given massage on a regular basis, appear more peaceful and comfortable.18 How does massage work? In general, the mechanisms of massage overlap strongly with those of acupuncture, although the method of nerve activation and connective tissue engagement differ. That is, mechanoreceptor stimulation by means of the stretch, compression, and pulsatile actions of massage engender endogenous analgesia through neuromodulatory trajectories that engage spinal cord and brain reflexes.19 Massage provides antiinflammatory effects and immunologic support as well through its balancing influences on the autonomic nervous system; these typically include dampening of sympathetic overactivation and encouragement of parasympathetic function. Because the physiologic changes from both acupuncture and massage resonate strongly with each other, the conditions listed in Box 136.1 would be similar indications for massage, too, though with less evidence-based medicine compared with acupuncture. Contraindications to massage depend on the patient’s medical status and receptivity to touch. Massage should be avoided near sites of fractures, contusions, thrombi, inflammation, pain, and/or infection.

PHOTOMEDICINE (LASER THERAPY AND LIGHT-EMITTING DIODE) The ability of laser therapy and light-emitting diodes (LEDs) to reduce pain, swelling, tissue necrosis, and inflammation has made photomedicine a notable approach for the management of critically ill human and veterinary patients suffering from conditions such as snake envenomation, postsurgical inflammation, and neurotrauma (spinal cord injury, traumatic brain disorders), and peripheral nerve damage.20-22 Photomedicine supports soft tissue and muscle healing after acute injury (e.g., trauma, surgery) through its effects on circulation, inflammation, growth factors, and cytokines.23-25 The process by which photomedicine works is called photobiomodulation (PBM). That is, photons (“photo”) influence living tissue (“bio”) to induce “modulation,” or normalization of function through a combination of stimulatory and inhibitory responses. PBM occurs when photons interact with the molecules, cells, and organelles in any type of tissue in the body. At the mitochondrial level, PBM increases ATP production, modulates the generation of reactive oxygen species, and promotes the release of transcription factors. These transcription factors cause downstream effects, including protein synthesis that stimulates cell proliferation and migration, normalizes production of cytokines, growth factors, and inflammatory mediators, and improves tissue oxygenation.26

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PART XV  Anesthesia and Pain Management

Because laser therapy speeds up cell division, promotes new vessel formation, and limits apoptosis, the safety of laser therapy in patients with cancer remains unknown.27 However, moderate to strong evidence has been gathered in favor of its use for the prevention and treatment of radiation therapy- and chemotherapy-induced mucositis in humans.28,29

PULSED ELECTROMAGNETIC FIELD THERAPY PEMF therapy has gained widespread acceptance in recent years as a nonthermal, noninvasive treatment for pain, inflammation, and tissue repair, most notably bone growth.30 Research indicates that PEMF exposure raises the release of intracellular Ca21. Ca21 then binds to calmodulin, a messenger protein, which leads to the production of nitric oxide by activating the enzyme constitutive nitric oxide synthase. Nitric oxide may then stimulate the formation of cyclic guanosine monophosphate by binding to soluble guanylyl cyclase. These molecular changes shift physiologic states toward recovery and repair by limiting proinflammatory processes and augmenting the release of growth factors that foster neovascularization, cellular division, and tissue remodeling, similar to what happens with PBM. PEMF applications for human and veterinary postoperative patients have demonstrated analgesic, antiinflammatory, and improved wound healing results.30 However, as with other physical medicine research, results vary according to treatment parameters, device capabilities, patient comorbidities, and several other factors. Thus, compared with pharmaceutical dosing, physical medicine techniques are far more flexible and therefore can be tailored to the individual needs of patients. Despite these advantages, some clinicians become reluctant to institute approaches without a clearly defined “dose”, having grown reliant on the manufacturer to state specifically what, where, when, and how to administer treatment.

MUSIC THERAPY Therapeutic music has been applied in the human medical setting since the 1800s after the invention of the phonograph, and sound was used to encourage sleep and stimulate endogenous analgesia. Over the past two decades, music therapy has undergone a resurgence, now entering the realm of veterinary medicine.31 How does music therapy work? Music causes widespread alterations in brain activity as well as neurohumoral, cardiovascular, and immune responses.32 While each individual, and even each species, may have acoustic preferences at different times, the nervous system responds fairly predictably to sound and rhythm based on hardwired brain and spinal cord circuitry. For critically ill patients, music therapy fills a significant niche as a supportive, nonpharmacologic intervention. In humans, the physiologic benefits of appropriately selected sound exposure include reduced respiratory rate, heart rate, pain, and anxiety.33 It improves the quality of sleep and lessens the need for sedatives. Music can also shorten recovery time in critically ill humans, putatively by reducing fear and anxiety.34,35

BOTANICAL MEDICATIONS AND CHALLENGES FOR THE CRITICALLY ILL PATIENT In veterinary medicine, the complexity of treating critically ill patients increases when patients have been receiving botanical remedies. From hemp extracts to Chinese herbs, herbal medicines can contribute to disease and dysfunction in a number of ways. For example, the plant ingredients themselves may have toxic effects36 (e.g., neurotoxic strychnine and cardiotoxic aconite in Chinese herbs) or be present in toxic amounts (e.g.,

undisclosed THC in hemp extracts). Alternatively, certain extraction techniques may leave behind toxic residues or heavy metals. In addition, plants, such as any xenobiotic, may interact with prescribed pharmaceuticals, changing circulating drug levels in unpredictable ways. All of these factors, in conjunction with minimal evidence of safety or effectiveness in target species, pose steep challenges for veterinary ICU clinicians.37 It is therefore crucial to obtain as detailed of a history as possible from clients regarding their use of botanicals and supplements. Unanticipated bleeding may result after surgery or trauma if patients have been taking platelet-inhibiting plant compounds, including ginkgo, ginseng, garlic, and ginger (collectively called “the four G’s”). Furthermore, various Western and Asian plant products affect blood glucose levels; these include Gymnema, psyllium, fenugreek, bilberry, garlic, ginseng, dandelion, burdock, prickly pear cactus, and bitter melon.38 Untoward reactions to phytomedicinals commonly involve the liver.39 As such, any animal presenting with hepatic injury and a history of herb or supplement use should raise the index of suspicion about one or more products causing or contributing to liver disease.

CONCLUSION The introduction of pharmacologically active, inadequately regulated, and largely untested botanical remedies into intensive care protocols raises the risk of adverse effects such as herb–drug interactions, altered hemostatic parameters, intrinsic toxicity, and patient intolerance. On the other hand, safe and scientifically justified medicine approaches including acupuncture, massage, photomedicine, music therapy, and PEMF therapy deserve consideration for most ICU patients, barring specific contraindications. Their ability to induce healing, relaxation, and pain relief helps patients recover more quickly and with fewer drugs than many conventional treatment approaches. Therefore, clinicians should consider incorporating scientifically verified integrative approaches upon admission into the ICU. Doing so often optimizes patient outcomes and client satisfaction.

REFERENCES 1. Rotondi AJ, Chelluri L, Sirio C, et al: Patients’ recollections of stressful experiences while receiving prolonged mechanical ventilation in an intensive care unit, Crit Care Med 30:746, 2002. 2. Silverman HJ: Symptom management in the intensive care unit: toward a more holistic approach, Crit Care Med 30:936, 2002. 3. Lamont LA, Tranquilli WJ, Grimm KA: Physiology of pain, Vet Clin North Am Small Anim Pract 30:703, 2003. 4. Sandvik RK: Pain relief from nonpharmacological interventions in the intensive care unit: a scoping review, J Clin Nurs 29(9-10):1488-1498, 2020. doi:10.1111/jocn.15194. 5. Roth I, Highfield L, Cuccaro P, et al: Employing evidence in evaluating complementary therapies: findings from an ethnography of integrative pain management at a large urban pediatric hospital, J Altern Complement Med 25(S1):S95-S105, 2019. 6. Thrane SE, Hsieh K, Donahue P, et al: Could complementary health approaches improve the symptom experience and outcomes of critically ill adults? A systematic review of randomized controlled trials, Complement Ther Med 47:102166, 2019. 7. Kligler B, Homel P, Hamson LB, et al: Cost savings in inpatient oncology through an integrative medicine approach, Am J Manag Care 17(12):779-784, 2011. 8. Cheng KJ: Neurobiological mechanisms of acupuncture for some common illnesses: a clinician’s perspective, J Acupunct Meridian Stud 7(3):105-114, 2014. 9. American Academy of Medical Acupuncture: Conditions for which medical acupuncture may be indicated in a hospital setting. Available at https:// medicalacupuncture.org/conditions-for-which-medical-acupuncture-maybe-indicated-in-a-hospital-setting/. Accessed March 2, 2021.

CHAPTER 136  Integrative Veterinary Medicine for the Intensive Care Unit Patient 10. Harpin D, Simadibrata CL, Mihardja H, et al: Effect of electroacupuncture on urea and creatinine levels in the Wistar sepsis model, Med Acupunct 32(1):29-37, 2020. 11. Boitor M, Martorella G, Maheu C, et al: Effects of massage in reducing the pain and anxiety of the cardiac surgery critically ill – a randomized controlled trial, Pain Med 19(12):2556-2569, 2018. 12. Boitor M, Gelinas C, Richard-Lalonde M, et al: The effect of massage on acute postoperative pain in critically and acutely ill adults post-thoracic surgery: systematic review and meta-analysis of randomized controlled trials, Heart Lung 46(5):339-346, 2017. 13. Hsu WC, Guo SE, Chang CH: Back massage intervention for improving health and sleep quality among intensive care unit patients, Nurs Crit Care 24(5):313-319, 2019. 14. Pepino VC, Ribeiro JD, Ribeiro MA, et al: Manual therapy for childhood respiratory disease: a systematic review, J Manipulative Physiol Ther 36(1):57-65, 2013. 15. Uysal N, Eser I, Akpinar H: The effect of abdominal massage on gastric residual volume: a randomized controlled trial, Gastroenterol Nurs 35(2):117-123, 2012. 16. Guerero RM, das Neves LMS, Guirro RRJ, et al: Manual lymphatic drainage in blood circulation of upper limb with lymphedema after breast cancer surgery, J Manipulative Physiol Ther 40(4):246-249, 2017. 17. Jagan S, Park T, Papathanassoglou E: Effects of massage on outcomes of adult intensive care unit patients: a systematic review, Nurs Crit Care 24(6):414-429, 2019. 18. Egeli D, Bainbridge L, Miller T, et al: Interdisciplinary perspectives on the value of massage therapy in a pediatric hospice, J Hosp Palliat Nurs 21(4):319-325, 2019. 19. Field T: Massage therapy research review, Complement Ther Clin Pract 120(4):224-229, 2014. 20. Silva LMG, Zamuner LF, David AC, et al: Photobiomodulation therapy on bothrops snake venom-induced local pathological effects: a systematic review, Toxicon 152:23-29, 2018. 21. Hashmi JT, Huang YY, Osmani BZ, et al: Role of low-level laser therapy in neurorehabilitation, PM R 2(12 Suppl 2):S292-S305, 2010. 22. Hentschke VS, Jaenisch RB, Schmeing LA, et al: Low-level laser therapy improves the inflammatory profile of rats with heart failure, Lasers Med Sci 28(3):1007-1016, 2013. 23. Yang Z, Wu Y, Zhang H, et al: Low-level laser irradiation alters cardiac cytokine expression following acute myocardial infarction: a potential mechanism for laser therapy, Photomed Laser Surg 29(6):391-398, 2011.

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24. Hamblin MR: Mechanisms and application of the anti-inflammatory effects of photobiomodulation, AIMS Biophys 4(3):337-361, 2017. 25. Heiskanen V, Hamblin MR: Photobiomodulation: lasers vs light emitting diodes? Photochem Photobiol Sci 17(8):1003-1017, 2018. 26. Chung H, Dai T, Sharma SK, et al: The nuts and bolts of low-level laser (light) therapy, Ann Biomed Eng 40(2):516-533, 2012. 27. Hamblin MR, Nelson ST, Strahan JR: Photobiomodulation and cancer: what is the truth? Photomed Laser Surg 36(5):241-245, 2018. 28. Zadik Y, Arany PR, Fregnani ER, et al: Systematic review of photobiomodulation for the management of oral mucositis in cancer patients and clinical practice guidelines, Support Care Cancer 27(10):3969-3983, 2019. 29. De Pauli Paglioni M, Araujo ALD, Arboleda LPA, et al: Tumor safety and side effects of photobiomodulation therapy used for prevention and management of cancer treatment toxicities. A systematic review, Oral Oncol 93:21-28, 2019. 30. Gaynor JS, Hagberg S, Gurfein BT: Veterinary applications of pulsed electromagnetic field therapy, Res Vet Sci 119:1-8, 2018. 31. Kogan LR, Schoenfeld-Tacher R, Simon AA: Behavioral effects of auditory stimulation on kenneled dogs, J Vet Behav 7:268-275, 2012. 32. Pauwels EK, Voleterrani D, Mariani G, et al: Mozart, music and medicine, Med Princ Pract 23(5):403-412, 2014. 33. Golino AJ, Leone R, Gollenberg A, et al: Impact of an active music therapy intervention on intensive care patients, Am J Crit Care 28(1):48-55, 2019. 34. Mofred A, Alaya S, Tassaioust K, et al: Music therapy, a review of the potential therapeutic benefits for the critically ill, J Crit Care 35:195-199, 2016. 35. Umbrello M, Sorrenti T, Mistraletti G, et al: Music therapy reduces stress and anxiety in critically ill patients: a systematic review of randomized clinical trials, Minerva Anestesiol 85(8):886-898, 2019. 36. Robinson NG: The hazards of Chinese herbs, Vet Pract News, January 2017. Available at https://www.veterinarypracticenews.com/the-hazardsof-chinese-herbs/. Accessed March 15, 2020. 37. Shmalberg J, Hill RC, Scott KC: Nutrient and metal analyses of Chinese herbal products marketed for veterinary use, J Anim Physiol Anim Nutr (Berl) 97:305-314, 2013. 38. Cicero AFG, Derosa G, Gaddi A: What do herbalists suggest to diabetic patients in order to improve glycemic control? Evaluation of scientific evidence and potential risks, Acta Diabetol 41:91, 2004. 39. Kaplowitz N: Herb-induced liver injury: a global concern, Chin J Integr Med 24(9):643-644, 2018.

PART XVI   Environmental Emergencies

137 Smoke Inhalation Tommaso Rosati, DVM, DACVECC, Kate Hopper, BVSc, PhD, DACVECC

KEY POINTS • Neurological signs following smoke inhalation are not exclusively a consequence of tissue hypoxia and can occur acutely or be delayed by hours to days. Carbon monoxide exposure is considered the major risk factor for neurological signs. • Immediate oxygen therapy is considered a priority in order to minimize carbon monoxide toxicity, even when hypoxemia is not suspected.

• Respiratory signs can occur acutely, particularly if upper airway injury has occurred. • Delayed respiratory signs are reported and can be consequence of chemical compound inhalation or secondary bacterial infection. • Despite significant neurological and respiratory signs, successful outcomes have been reported in veterinary patients receiving adequate medical therapy.

INTRODUCTION AND EPIDEMIOLOGY

largely oxygenated environments. Due to insufficient oxygen, household fires are characterized by incomplete combustion of organic and inorganic substrates resulting in the formation of multiple toxic chemicals.13 The smoke produced by fire combustion is composed of a mixture of airborne solids, superheated particulates, and fire gases. The composition of the smoke is unique for each fire and largely depends on the material combusted and availability of oxygen.14 A major contributor to the pathophysiology of smoke inhalation is the inspiration of superheated particulate matter (soot). These carbonaceous particles cause direct damage via their high temperature. Additionally particles can be impregnated with a large variety of toxins, and soot can facilitate the transport of toxins to the alveoli through the inhaled air.14 The severity of damage following smoke inhalation depends on numerous factors, including the material combusted, temperature reached by the environment, the length of exposure, and the concentration and solubility of toxic chemicals generated.12

Animals and humans that are trapped in a small confined space in the presence of fire and smoke are at risk of developing smoke inhalation injury. Smoke inhalation has been classically described as a constellation of clinical signs secondary to thermal injury, particulate matter inhalation, and toxicant inhalation. According to the US Fire Administration, approximately 3,000 people die in fires and 15,000 suffer fire-related injury annually in the United States.1 It has been reported that approximately 73% of humans with smoke inhalation injury experience respiratory failure, and 20% of these will progress to ARDS.2 In human fire victims the presence of inhalation injury increases the mortality from 7.2% to 41.5%.3 Due to the high incidence of prehospital mortality and the absence of a unified database, the incidence of smoke inhalation injury in small animal patients is unknown. A few isolated case reports and series are present in the veterinary literature.4-11 Smoke inhalation injuries have a multifactorial pathogenesis. The primary components of inhalation injury are upper airway injury, lower airway injury, pulmonary parenchymal injury, systemic injury, and systemic toxicity.12 Each of the different components of smoke inhalation injury has a different cause, pathophysiology, treatment, and prognosis. In small animal patients, the frequently encountered neurological signs are a consequence of impaired oxygen delivery, mitochondrial dysfunction, and direct neurological damage from systemic toxicity.

PATHOPHYSIOLOGY Burning results in the production of fire gases, heat, visible smoke, and toxicants. Complete combustion only occurs in controlled and

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Upper Airway Injury During household fires the environmental temperature approaches ~300°F (150°C). The inspired gas temperature induces direct thermal damage to the oral cavity, nasopharynx, nasal cavity, larynx, trachea and eventually the lower airways. The result is edema and inflammation of these tissues. The clinical consequence of soft tissue edema in the upper airway apparatus is the risk for airway obstruction. The degree of airway edema is variable in severity but usually peaks 24 hours postexposure.15 In a case report of a Beagle dog suffering smoke inhalation, laryngeal edema was noted approximately 24 hours after presentation and required management with a temporary tracheostomy tube that was removed 6 days later.6

CHAPTER 137  Smoke Inhalation

Lower Airway Injury Due to heat dissipation within the upper portion of the airway apparatus, direct thermal injury of the lower airway is unusual. The majority of injury to the lower airways is secondary to chemical inhalation. The bronchial system is innervated with a large number of vasomotor and sensory nerve endings. The inhalation of smoke containing chemical irritants incites the production of neuropeptides that leads to a severe inflammatory response by activating vagal nerve sensory fibers containing proinflammatory peptides, neurokinins, and calcitonin gene-related peptide.16 The major consequences of these responses are bronchoconstriction, pulmonary vasoconstriction, and airway fluid accumulation. Within a few hours following the initial insult, the accumulation of exudative fluid, mucus, and degenerated epithelial cells leads to the formation of occluding material in the airways, also known as airway casts.17 Occlusion of the bronchial tree prevents adequate airflow to the lower airways. Increased expression of nitric oxide synthase occurs following burn and smoke inhalation injury.18 The resulting elevated levels of nitric oxide impair pulmonary hypoxic vasoconstriction, further exacerbating ventilation–perfusion mismatch and dead space ventilation.12 The initial hyperreactive phase of smoke inhalation is followed by a prolonged recovery phase during which the disruption of the bronchial epithelium impairs the innate defense system, predisposing to development of bronchopneumonia. In human burn patients, bronchopneumonia is considered the leading complication, and the incidence is two to fourfold in patients with smoke inhalation injury.19,20 There is up to a 60% mortality rate in this subpopulation of patients.21

Pulmonary Parenchymal Injury The lung parenchymal injury secondary to smoke inhalation is classically delayed. Increased transvascular fluid efflux, lack of surfactant, and loss of hypoxic pulmonary vasoconstriction result in impaired oxygenation. Atelectasis develops and fibrin deposition in airways is promoted by the procoagulant status and concurrent reduced antifibrinolytic activity. Fibrin deposition leads to further surfactant inhibition and neutrophil chemotaxis. As demonstrated in multiple sheep models, activated neutrophils play a central role in the pathogenesis of smoke inhalation injury and perpetuate the inflammatory injury to the pulmonary parenchyma.12 In human patients it is estimated that approximately 20% of people that develop respiratory failure secondary to smoke inhalation injury will also develop ARDS.2

Systemic Injury The pulmonary damage secondary to smoke inhalation injury has several systemic consequences, including hypoxemia, hypercapnia, and systemic inflammation.16 The volatile compounds present in smoke can cause disruption of the corneal tear film and consequently ocular irritation and direct corneal damage and ulceration. Additionally, corneal damage can be promoted by direct thermal injury. Left ventricular dysfunction could be secondary to direct myocardial damage or a left-sided shift of the interventricular septum secondary to right ventricular hypertension.22 Sympathetic compensation is activated and leads to tachycardia and increased systemic vascular resistance, resulting in increased myocardial oxygen demand. In smoke inhalation victims without burn injury, the presence of carbon monoxide (CO) further compromises oxygen carrying capacity and oxygen delivery and predisposes to development of arrhythmias, congestive heart failure, and systemic hypotension.23 Inhalation of CO is considered a risk factor for the development of hypercoagulability in human patients. However, the evidence is still contradictory, and a precise correlation between smoke inhalation and

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hypercoagulability is not certain. Hypercoagulability might be more prevalent in burn victims with large body surface areas affected. Secondary bacterial infections are another systemic injury frequently observed in human patients. Severe smoke inhalation patients will require mechanical ventilation, which further increases the risk for developing ventilator-associated pneumonia (see Chapter 40, Ventilator Associated Pneumonia).

Systemic Toxicity One of the major systemic effects of smoke inhalation is due to exposure to toxic gases. The most toxic compounds present in the smoke are CO and hydrogen cyanide (HC). A complete list of toxic gases and material of origin is reported in Table 137.1.24

Carbon Monoxide CO is the most frequent cause of immediate death following smoke inhalation in humans. CO is produced by incomplete combustion of a large variety of cellulolytic fuels including wood, paper, and cotton. Because it is colorless and odorless, CO is undetectable in the environment without specialized equipment. The most significant toxic property of CO is due to its high affinity for hemoglobin (Hb) to form carboxyhemoglobin (COHb). CO has an affinity for Hb approximately 200 to 250 times higher than oxygen. Inhalation of a 0.1% CO mixture can lead to the formation of up to 50% COHb of the total Hb. The net effect is reduced oxygen delivery to tissues leading to cellular hypoxia. Compared with other organs, the brain and heart have a significantly higher oxygen extraction, and consequently are majorly affected during COHb circulation. Tissue oxygenation is further impacted by the presence of CO as it also causes a left shift of the oxy-hemoglobin dissociation curve (see Chapter 184, Oximetry Monitoring).25

TABLE 137.1  Selected Toxic Compounds

in Fire Smoke Material

Toxic Compound

Clinical Consequences

Acrylics Cellulose Polyamine resins

Aldehydes

Corrosive, protein denaturation Formaldehyde: RNA denaturation

Polyamide Polyamine resins Polyurethane Silk, wool

Ammonia

Airway irritation, cough, increased airway secretions and bronchoconstriction Ammonium hydroxide: tissue necrosis

All materials

Carbon monoxide

Tissue hypoxia, neurotoxicity, arrhythmias, organ failure, death

Polyester Polyvinyl chloride

Hydrogen chloride

Mucosal necrosis and acute bronchitis

Fire retardants Polyacrylonitrile Polyamide Polyamine resins Polyurethane Silk, wool

Hydrogen cyanide

Tissue hypoxia, tachypnea, neurotoxicity, arrhythmias, death

Rubber Silk, wool

Hydrogen sulfide

Airway irritation, corrosive

Rubber

Sulfur dioxide

Marked eye and airway irritation, lower airway injury, and pulmonary edema

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In addition to its effects on hemoglobin, other mechanisms of intracellular toxicity have been identified in CO poisoning. The cytochrome oxidase enzyme systems are inhibited by CO, resulting in intracellular inability to utilize oxygen.25 Additionally, inhibition of cytochrome-c oxidase results in electron chain dysfunction, electron leakage, superoxide production, and mitochondrial oxidative stress. The production of reactive oxygen species leads to neuronal necrosis and apoptosis.26 Multiple inflammatory pathways independent from the effects of hypoxia are activated by CO, resulting in neurological and cardiac injury. CO also increases platelet adherence leading to increased risk of thromboembolic events.25 It has been suggested that most cases of COinduced fatalities are primarily a result of cardiac dysfunction.27

Hydrogen Cyanide HC is a colorless gas. It is the gaseous form of cyanide and is generated by the combustion of substances such as wool, silk, cotton, and paper as well as plastic and other polymers. HC odor has been compared to bitter almonds, although its presence might be difficult to detect at the fire site. Cyanide is a normal metabolite in the body, and it is physiologically converted into thiocyanate, primarily in the liver. During intoxication, the liver may not be capable of metabolizing the cyanide, particularly when large concentrations are present. The primary toxic effect of HC is at the level of the mitochondria, where it inhibits the electron transport chain, impairing cellular ATP production.12,28 Depending on the dose, additional effects of HC toxicity include neurotoxicity, tachypnea through direct stimulation of chemoreceptors (aortic arch and carotid bodies), arrhythmias, and death.28

PHYSICAL EXAMINATION During the initial assessment phase, the clinician should focus on evaluation of the cardiovascular, respiratory, and neurological systems (see Chapter 1, Evaluation and Triage of the Critically Ill Patient). The level of mentation can be markedly abnormal in smoke injury victims due to circulatory compromise, hypoxemia, and/or CO toxicity. Other perfusion parameters, such as mucous membrane color and extremity temperature, can be significantly affected by the degree of burn injury. Cherry red mucous membrane coloration can be observed in patients with high circulating levels of COHb. However, in humans, it has been reported that this phenomenon is appreciable only when a lethal concentration of COHb is present, and clinicians are advised not to rely on this sign to identify CO intoxication.29 Circulatory shock, decreased oxygen delivery, and pain can lead to significant tachycardia. The respiratory pattern and/or noises should be carefully monitored for evidence of inspiratory effort or sounds consistent with upper airway obstruction. The oral cavity should be inspected for evidence of direct mucosal injury and the oropharynx inspected for the presence of soot. A thorough thoracic auscultation is important. The presence of stridor should prompt evaluation of the upper airway apparatus. Pulmonary crackles can be present on initial presentation due to direct thermal injury, and pulmonary wheezes can be present due to bronchoconstriction. As previously discussed, the onset of pulmonary parenchymal disease is often delayed; therefore repeated physical examinations should be performed during the initial 24–48 hours. Serial neurological examinations should also be performed in order to evaluate the progression of clinical signs. Delayed neurological signs may occur from 10 hours to 6 days after initial presentation.6 Altered mentation (stupor or coma), ataxia, seizures, aggressive behavior, blindness, and deafness have been previously reported in the veterinary literature in dogs with confirmed CO toxicity.4-6,8-11

The smoke injury victim’s coat tends to be covered with ashes and particulate matter, and a malodorous smell is commonly present. Conjunctival hyperemia is a common finding in patients that have been exposed to smoke for a prolonged period of time. If loss of consciousness has occurred during smoke inhalation, the inability to blink and the elevated environmental temperature may contribute to corneal damage. A full examination of the body surface for evidence of burn injuries is an important part of the evaluation of smoke inhalation patients.

DIAGNOSIS AND INITIAL ASSESSMENT Diagnosis of smoke inhalation injury is largely based on the history of smoke exposure and consistent physical examination findings. It is important to recognize that pulmonary dysfunction and neurological signs could have a delayed onset and might not be present on initial evaluation. The key historical factors to obtain are the mechanism (flame and smoke or steam), duration of exposure, and the environment.30 Information regarding materials present in the burning environment could raise suspicion for specific toxin exposure. Blood gas analysis is recommended in the initial assessment of patients following smoke exposure. If an upper airway obstruction is present, hypoventilation (hypercapnia) may occur. Hyperlactatemia in a patient with otherwise adequate perfusion raises the suspicion for CO intoxication. In the absence of substantial venous admixture, arterial partial pressure of oxygen may remain normal, despite the presence of COHb. In addition, conventional pulse oximetry does not reflect oxygenation accurately in the presence of COHb as it is unable to differentiate between COHb and oxyhemoglobin. The diagnosis of CO toxicity can be confirmed by measuring blood carboxyhemoglobin levels via cooximetry (see Chapter 184, Oximetry Monitoring). A rapid diagnostic test to detect plasma cyanide levels is not currently available. As such, clinicians must base their concern for HC toxicity on knowledge of the materials present at the fire. Serial thoracic studies are often required to evaluate for evolving pulmonary disease. The pattern of distribution of pulmonary infiltrates may be helpful to distinguish a primary smoke inhalation injury from a secondary bacterial infection or aspiration pneumonia. See Fig. 137.1

Fig. 137.1  Right lateral radiograph of a dog 5 days following smoke inhalation (household fire). Findings include severe tracheal narrowing secondary to tracheal necrosis, marked ventrally dependent interstitial to alveolar pulmonary pattern secondary to chemical pneumonitis and diffuse bronchitis secondary to bronchial necrosis. Note: This dog had no significant findings reported on thoracic radiographs on the day of presentation.

CHAPTER 137  Smoke Inhalation

Fig. 137.2  Necropsy image of the dog illustrated in Figure 137.1. Black arrows indicate severe diffuse tracheal mucosal necrosis and associated intraluminal tracheal obstruction. Diffuse pulmonary parenchymal edema and diffuse deposition of particulate material in the airways was described. (Photo Courtesy Dr. Katherine D. Watson, University of California, Davis.)

for an example of radiographic findings in a dog with smoke inhalation. Fig. 137.2 is a necropsy image of the respiratory tract of this same dog for comparison purposes. The large airways should be closely inspected for the presence of mechanical obstruction as could occur with bronchial casts. Thoracic computed tomography may provide additional information, including bronchial wall thickness, which can help determine the severity of injury.31 Fiberoptic bronchoscopy is primarily indicated in humans to identify who will benefit from endotracheal intubation versus those who will not.32 The use of bronchoscopy in small animal patients is more limited given the requirement for general anesthesia and endotracheal intubation. However, direct visualization of the trachea should be considered in animals where airway obstruction is highly suspected. If myocardial dysfunction is suspected, electrocardiogram analysis, echocardiography, and cardiac troponin levels should be considered. In patients that are hypercoagulable, spontaneous echo-contrast might be detected during echocardiographic evaluation (see Chapter 101, Hypercoagulable States). A full understanding of coagulation changes associated with smoke inhalation remains to be determined.

TREATMENT Initial treatment with humidified supplemental oxygen therapy is recommended in every patient with suspected smoke inhalation injury. Oxygen therapy improves oxygen delivery and effectively decreases the half-life of CO. CO has a half-life of 320 minutes in patients breathing room air; half-life is reduced to approximately 70 minutes when the patient is provided 100% oxygen at atmospheric pressure.25 Air humidification helps airway clearance by preventing conglomeration

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of secretions. Multiple studies have compared the efficacy of hyperbaric oxygen (HBO) therapy to treat CO toxicity in human patients.29 Despite clinical trials showing a more rapid reduction of COHb and an increase in the partial pressure of oxygen in patients treated with HBO, there is no evidence that HBO therapy significantly improves outcome compared with conventional oxygen supplementation.27 A major limitation of HBO treatment is that the patient is isolated in the chamber for a substantial period of time, which impairs the level of patient monitoring and care that can be provided. The exact role and optimal dose of HBO therapy in CO toxicity remains to be determined at this time. As a high FiO2 is desired during the initial stabilization period if CO toxicity is suspected, oxygen supplementation methods that can maximize FiO2 are recommended (see Chapter 15, Oxygen Therapy). The use of a nasal cannula or nasal prongs might be impeded by the presence of exudate in the nasal cavities or by the presence of fire induced excoriation. High-flow nasal oxygen therapy could be considered if it is not contraindicated by disease of the nasal cavity. Endotracheal intubation and temporary tracheostomy may be necessary in patients with upper airway obstruction. Mechanical ventilation is indicated to support oxygenation if pulmonary parenchymal disease is severe and also to maintain adequate ventilation if severe obtundation with hypercapnia is present (see Chapter 32, Mechanical VentilationCore Concepts). Clearing airways of secretions and casts is a major focus for the management of the inhalation injury patient in human medicine and is considered of similar importance in animals. Early ambulation, chest physical therapy, and airway suctioning are all emphasized.31 Bronchoscopic pulmonary toilet, which describes the physical removal of airway debris via bronchoscopy, is recommended in patients with respiratory failure. The role of glucocorticoids in the treatment of acute inhalation injury in human patients is controversial. The potential benefit of the antiinflammatory effects of steroids needs to be weighed against the potential increased risk of infection in these patients. Inhaled glucocorticoids are often used in an effort to reduce systemic side effects. The limited human studies on this subject have not demonstrated any clear benefit.33,34 Steroid therapy is not routinely recommended in the management of human patients with inhalation injury at this time.31,35 Intravenous fluid therapy should be titrated based on the assessment of perfusion and hydration parameters. In the presence of COHb, hyperlactatemia might be secondary to tissue hypoxia. For this reason, in smoke inhalation patients the use of lactate as a solo marker of perfusion is discouraged. Numerous studies have reported a significant increase in fluid requirements for resuscitation in patients with cutaneous burns and smoke inhalation injury.36 In a cutaneous burn and smoke inhalation sheep model, fluid restriction was associated with increased formation of pulmonary edema and pulmonary lymph formation.37 Although fluid overload should be avoided, adequate volume resuscitation in the smoke inhalation patient is an important part of the treatment plan, especially in patients with concurrent burn injuries (see Chapter 130, Thermal Burn Injury). The prophylactic use of antimicrobial therapy is not indicated in smoke inhalation patients. The use of antibiotics should be reserved for cases when there is clinical suspicion of a bacterial infection and is ideally confirmed by culture and susceptibility testing. Multiple aerosolized therapies have been described in the human literature. There is promising evidence for the role of inhaled b2-agonists in smoke inhalation where they may provide bronchodilation and antiinflammatory effects and promote alveolar fluid clearance.38 Although these benefits are yet to be established in prospective trials, inhaled albuterol is commonly recommended in human patients.

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Aerosolized epinephrine can be used to provide bronchodilation and vasoconstriction and aid in the breakup of airway secretions. Inhaled epinephrine has been shown to be safe in pediatric patients, and there is evidence of benefit in experimental animals with smoke inhalation.39–40 N-acetylcysteine (NAC) is a potent mucolytic agent, although the aerosolized use of this drug is associated with bronchoconstriction. Patients should be closely monitored during inhaled NAC treatment for evidence of increased airway resistance or systemic reaction.41 Limited information is available to determine the efficacy of intravenous NAC as a mucolytic agent. The use of intravenous and aerosolized heparin in smoke inhalation victims can reduce airway fibrin cast formation and the incidence of pulmonary edema.14 The combined use of aerosolized heparin and NAC in a pediatric study was associated with reduced risk of reintubation and reduced mortality.42 A recent meta-analysis of human patients with inhalation injury concluded that nebulized heparin improved lung function, shortened the period of mechanical ventilation, and reduced mortality.43 When cyanide toxicity is suspected, the use of specific antidotes might be considered. Amyl nitrate and sodium thiosulfate convert hemoglobin to methemoglobin and favor reduction of cyanide levels as it preferentially binds to methemoglobin. The use of these drugs leads to reduced oxygen carrying capacity as a consequence of methemoglobin formation and should be reserved for only those patients highly suspected of cyanide toxicity. Hydroxocobalamin (vitamin B12a) actively binds cyanide to form cyanocobalamin, which is directly excreted via the kidney. Hydroxocobalamin does not promote methemoglobin formation, and its use is thought to be safer than other antidote options.14 Treatment of concurrent ocular injuries or cutaneous burns should be performed as appropriate (see Chapters 144 and 130, Ocular Disease in the Intensive Care Unit and Thermal Burn Injury, respectively).

PROGNOSIS In a recent review article, the reported in-hospital mortality after smoke inhalation injury alone in human patients was 26% and in patients with associated severe burns it was 50%.44 A limited number of case reports and series are present in the veterinary literature and the reported mortality rate is variable. Of 27 dogs with smoke inhalation from residential fires, 19 dogs survived while a similar study of 22 cats with smoke inhalation reported 20 survived.4,5 In a more recent report of smoke inhalation in 9 dogs and 13 cats from Europe, one cat died and the remaining animals were discharged from the hospital.45 Due to prehospital mortality and frequently encountered financial limitations, an accurate understanding of the mortality rate of smoke inhalation is difficult to estimate in the small animal population. Delayed respiratory and neurological signs have been reported in several veterinary case series. In human CO toxicity victims, up to 10% of survivors are reported to have permanent neurological dysfunction. Owners of animals with smoke inhalation should be informed about risk of delayed and potentially permanent clinical signs. In small animal patients that received appropriate medical therapy, successful outcome has been reported despite significant neurological complications.6,10

REFERENCES 1. Fire in the United States 2008-2017, ed 20, 2019, U.S. Fire Administration. https://www.usfa.fema.gov. 2. Hollingsed TC, Saffle JR, Barton RG, Craft WB, Morris SE: Etiology and consequences of respiratory failure in thermally injured patients, Am J Surg 166:592-596, 1993.

3. El-Helbawy RH, Ghareeb FM: Inhalation injury as a prognostic factor for mortality in burn patients, Ann Burns Fire Disasters 24(2):82-88, 2011. 4. Drobatz KJ, Walker LM, Hendricks JC: Smoke exposure in dogs: 27 cases (1988-1997), J Am Vet Med Assoc 215(9):1306-1311, 1999. 5. Drobatz KJ, Walker LM, Hendricks JC: Smoke exposure in cats: 22 cases (1986-1997), J Am Vet Med Assoc 215(9):1312-1316, 1999. 6. Guillaumin J, Hopper K: Successful outcome in a dog with neurological and respiratory signs following smoke inhalation, J Vet Emerg Crit Care (San Antonio) 23(3):328-334, 2013. 7. Stern AW, Lewis RJ, Thompson KS: Toxic smoke inhalation in fire victim dogs, Vet Pathol 51(6):1165-1167, 2014. 8. Ashbaugh EA, Mazzaferro EM, McKiernan BC, Drobatz KJ: The association of physical examination abnormalities and carboxyhemoglobin concentrations in 21 dogs trapped in a kennel fire, J Vet Emerg Crit Care (San Antonio) 22(3):361-367, 2012. 9. Kent M, Creevy KE, Delahunta A: Clinical and neuropathological findings of acute carbon monoxide toxicity in chihuahuas following smoke inhalation, J Am Anim Hosp Assoc 46(4):259-264, 2010. 10. Mariani CL: Full recovery following delayed neurologic signs after smoke inhalation in a dog, J Vet Emerg Crit Care 13:235-239, 2003. 11. Weiss AT, Graf C, Gruber AD, Kohn B: Leukoencephalomalacia and laminar neuronal necrosis following smoke inhalation in a dog, Vet Pathol 48(5):1016-1019, 2011. 12. Enkhbaatar P, Sousse L, Cox RA, Herndon DN: The pathophysiology of inhalation injury. In Herndon DN editor: Total burn care, ed 5, Edinburgh, 2017, Elsevier Inc, pp 174-183. 13. Stefanidou M, Athanaselis S, Spiliopoulou C: Health impacts of fire smoke inhalation, Inhal Toxicol 20(8):761-766, 2008. 14. Toon MH, Maybauer MO, Greenwood JE, Maybauer DM, Fraser JF: Management of acute smoke inhalation injury, Crit Care Resusc 12(1):53-61, 2010. 15. Palmieri TL, Gamelli RL: Diagnosis and management of inhalation injury. In Jeschke MG, Kamolz LP, Sjöberg F, Wolf SE, editors: Handbook of burns, Vienna, 2012, Springer, pp 163-172. 16. Foncerrada G, Culnan DM, Capek KD, et al: Inhalation injury in the burned patient, Ann Plast Surg 80(3 Suppl 2):S98-S105, 2018. 17. Herndon DN, Traber LD, Linares H, et al: Etiology of the pulmonary pathophysiology associated with inhalation injury, Resuscitation 14(1-2):43-59, 1986. 18. Cox RA, Jacob S, Oliveras G, et al: Pulmonary expression of nitric oxide synthase isoforms in sheep with smoke inhalation and burn injury, Exp Lung Res 35(2):104-118, 2009. 19. Shirani KZ, Pruitt BA Jr, Mason AD Jr: The influence of inhalation injury and pneumonia on burn mortality, Ann Surg 205(1):82-87, 1987. 20. de La Cal MA, Cerdá E, García-Hierro P, et al: Pneumonia in patients with severe burns: a classification according to the concept of the carrier state, Chest 119(4):1160-1165, 2001. doi:10.1378/chest.119.4.1160. 21. Saffle JR, Davis B, Williams P: Recent outcomes in the treatment of burn injury in the United States: a report from the American Burn Association Patient Registry, J Burn Care Rehabil 16(3 Pt 1):219-289, 1995. 22. Schultz AM, Werba A, Wolrab C: Early cardiorespiratory patterns in severely burned patients with concomitant inhalation injury, Burns 23(5):421-425, 1997. 23. Stearns W, Drinker C, Shaughnessy T: The electrocardiographic changes found in 20 cases of carbon monoxide poisoning, Am Heart J 14:434-446, 1938. 24. Rehberg S, Maybauer MO, Enkhbaatar P, Maybauer DM, Yamamoto Y, Traber DL: Pathophysiology, management and treatment of smoke inhalation injury, Expert Rev Respir Med 3(3):283-297, 2009. 25. Rose JJ, Wang L, Xu Q, et al: Carbon monoxide poisoning: pathogenesis, management, and future directions of therapy [published correction appears in Am J Respir Crit Care Med. 2017 Aug 1;196 (3):398-399], Am J Respir Crit Care Med 195(5):596-606, 2017. 26. Weaver LK: Clinical practice. Carbon monoxide poisoning, N Engl J Med 360(12):1217-1225, 2009. 27. Roderique JD, Josef CS, Feldman MJ, Spiess BD: A modern literature review of carbon monoxide poisoning theories, therapies, and potential targets for therapy advancement, Toxicology 334:45-58, 2015. 28. Lawson-Smith P, Jansen EC, Hyldegaard O: Cyanide intoxication as part of smoke inhalation-a review on diagnosis and treatment from the emergency perspective, Scand J Trauma Resusc Emerg Med 19:14, 2011.

CHAPTER 137  Smoke Inhalation 29. Hampson NB, Piantadosi CA, Thom SR, Weaver LK: Practice recommendations in the diagnosis, management, and prevention of carbon monoxide poisoning, Am J Respir Crit Care Med 186(11):1095-1101, 2012. 30. Jones SW, Williams FN, Cairns BA, Cartotto R: Inhalation injury: pathophysiology, diagnosis, and treatment, Clin Plast Surg 44(3):505-511, 2017. 31. Walker PF, Buehner MF, Wood LA, et al: Diagnosis and management of inhalation injury: an updated review, Criti Care 19:351-363, 2015. 32. Cancio LC: Airway management and smoke inhalation injury in the burn patient, Clin Plast Surg 36(4):555-567, 2009. 33. Greenhalgh DG: Steroids in the treatment of smoke inhalation injury, J Burn Care Res 30(1):165-169, 2009. 34. Cha SI, Kim CH, Lee JH, et al: Isolated smoke inhalation injuries: acute respiratory dysfunction, clinical outcomes, and short-term evolution of pulmonary functions with the effects of steroids, J Burns 33(2):200-208, 2007. 35. Gill P, Martin RV: Smoke inhalation injury, BJA Education 15(3):143-148, 2015. 36. Navar PD, Saffle JR, Warden GD: Effect of inhalation injury on fluid resuscitation requirements after thermal injury, Am J Surg 150(6):716-720, 1985. 37. Herndon DN, Traber DL, Traber LD: The effect of resuscitation on inhalation injury, Surgery 100(2):248-251, 1986.

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38. Palmieri TL: Use of b-agonists in inhalation injury, J Burn Care Res 30:156-171, 2009. 39. Fukuda S, Lopez E, Ihara K, et al: Superior effects of nebulized epinephrine to nebulized albuterol and phenylephrine in burn and smoke inhalation-induced acute lung injury, Shock 54(6):774-782, 2020. 40. Foncerrada B, Lima F, Clayton RP, et al: Safety of nebulized epinephrine in smoke inhalation injury, J Burn Care Res 38(6):396-402, 2017. 41. Mlcak RP, Suman OE, Herndon DN: Respiratory management of inhalation injury, Burns 33(1):2-13, 2007. 42. Desai MH, Mlcak R, Richardson J, Nichols R, Herndon DN: Reduction in mortality in pediatric patients with inhalation injury with aerosolized heparin/N-acetylcystine [correction of acetylcystine] therapy [published correction appears in J Burn Care Rehabil 1999 Jan-Feb;20(1 Pt 1):49], J Burn Care Rehabil 19(3):210-212, 1998. 43. Lan X, Huang Z, Tan Z, et al: Nebulized heparin for inhalation injury in burn patients: a systematic review, Burns Trauma 8:tkaa015, 2020. 44. Kadri SS, Miller AC, Hohmann S, et al: Risk factors for in-hospital mortality in smoke inhalation-associated acute lung injury: data from 68 United States Hospitals, Chest 150(6):1260-1268, 2016. 45. Dorfelt R, Turkovic V, Teichmann S: Smoke inhalation in dogs and cats – a retrospective study over 5.5 years, Tierarztl Prax Ausg K Kleintiere Heimtiere 42(5):303-309, 2014.

138 Hypothermia Jeffrey Michael Todd, DVM, DACVECC

KEY POINTS • Hypothermia is common in small animal patients associated with critical or chronic illness, acute injury, medications, or anesthesia. • There can be significant deleterious effects to all major body systems regardless of the etiology of the unintentional hypothermia.

• Treatment of hypothermia is typically aimed at rewarming the core, before the periphery, with safe external methods. • Understanding the physiologic effects associated with hypothermia will assist the clinician in the management and/or prevention of the clinical consequences from unintentional or anticipated hypothermia.

Hypothermia is the end result of an animal’s inability to maintain thermoregulatory homeostasis. It occurs when the individual or combined effects of excessive heat loss, decreased heat production, or a disruption of the normal thermoregulatory functions permit the core (vital organ) body temperature (CBT) to drop below species-specific physiologic parameters. The sequelae of hypothermia can disrupt the normal physiologic processes of all organ systems. Hypothermia is a relatively common complication in both acutely ill or injured patients and chronically ill critical care patients. Deleterious effects may be observed on the cardiovascular, respiratory, and nervous systems as well as on acid-base balance, coagulation, and electrolyte levels. Although the normal behavioral thermoregulatory defense mechanisms, such as huddling or heat seeking, may be enough in healthy patients, critically ill patients must depend on their autonomic defenses and caretakers.1 The goal of therapy is to provide early and aggressive treatment to prevent further decreases in core temperature, stabilize the vital cardiopulmonary functions, and provide a means of achieving normothermia at a safe rewarming rate.

medicine, such as the Swiss System, are primarily utilized to assist first responders in rescue assessment when CBT measurements are not possible in the field.3 Briefly, in mild hypothermia the thermoregulatory mechanisms, such as shivering and heat-seeking behavior, are still intact, but ataxia may be observed. Moderate hypothermia brings about the progressive loss of the thermoregulatory system, with decreasing levels of consciousness and initial cardiovascular instability. Further progression into severe hypothermia is marked by complete loss of the thermoregulatory system, an inability to shiver, comatose states, and susceptibility to ventricular fibrillation.3,4

CLASSIFICATION Hypothermia is defined as either a primary or secondary condition in which the CBT is less than 37°C (see conversion table in the inside cover for conversion of Celsius values to Fahrenheit). Primary hypothermia is a subnormal temperature caused by excessive exposure to low environmental temperatures. Secondary hypothermia is a result of disease, trauma, surgery, or drug-induced alteration in heat production and thermoregulation.2 Although the underlying causes may differ, the clinical consequences associated with hypothermia are similar. Hypothermia traditionally has been classified as mild, moderate, or severe based purely on the CBT (Table 138.1). Although this classification is simple, it does not capture the functional changes that characterize the differing levels of symptoms not directly related to a specific CBT. Therefore, some have proposed classifying the severity of hypothermia based on the clinical consequences at each stage, not strictly on the CBT (see Table 138.1).2 Other staging systems used in human

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REVIEW OF THERMOREGULATION A normal CBT is maintained by an intricate balance of metabolic heat production and heat loss. The hypothalamus is the primary thermostat of the body, receiving thermal input and coordinating the appropriate physiologic response to maintain the hypothalamic set point temperature. The preoptic region of the anterior hypothalamus contains the primary temperature-sensing neurons that allow for immediate systemic responses to be directed toward returning the body towards homeostasis. The posterior hypothalamus combines this input, with additional core and peripheral temperature-sensing receptor input, to provide an integrated response to the thermal change. These secondary CBT sensors are located within the spinal cord and abdominal viscera and surround the great veins in the abdomen and thorax. Peripherally, the skin contains large numbers of temperature-sensing receptors that allow for rapid response to environmental factors.5 The core is defined by well-perfused tissues in which the temperature remains relatively uniform, such as within the abdominal and thoracic cavities, or the cerebrum. The peripheral temperatures can vary significantly based on activity, distance from areas of thermal production, environmental temperature, and vascular responses. This can lead to dramatic core/peripheral temperature gradients, which makes accurate CBT measurements important.6 As hypothermia develops, the normal thermoregulatory response is to produce and retain heat, and thereby maintain the CBT. This is

CHAPTER 138  Hypothermia

TABLE 138.1  Classification of Hypothermia Core Temperature

Severity of Hypothermia

Common Clinical Signs9,17

32°–37°C

Mild

Shivering, ataxia, vasoconstriction

28°–32°C

Moderate

Decreased level of consciousness, atrial dysrhythmias, hypotension, 6 shivering

20°–28°C

Severe

Loss of shivering, ventricular dysrhythmias, profound central nervous system deficits

,20°C

Profound/Critical

Apparent death, death

Normal Temperatures Canine 37.5°C–39.2°C (99.5°–102.5°F) Feline

37.8°C–39.5°C (100°–103°F)

accomplished by both behavioral responses such as huddling and curling, and reflex physiologic changes such as piloerection, peripheral vasoconstriction, and shivering.7 The initial autonomic response causes specialized anastomoses, linking arterioles with veins, to open as the CBT nears 37°C, which prevents heat loss to the distal extremities. This is followed by shivering, which is typically noted at a degree lower than the vasoconstrictive response. This is important because it can be metabolically inefficient and much of the heat can be lost to the environment.8 Shivering is characterized by involuntary oscillatory skeletal muscular activity and can increase the metabolic rate by a factor of 4 to 10.1,5 The energy substrate for shivering is usually carbohydrate oxidation, but in glycogen-depleted patients, lipid and protein reserves need to be used.9 Therefore this method of heat production may be diminished in the cachectic, the very old, and the very young.

Heat Loss Heat loss is typically required to maintain normothermia but when in excess it leads to hypothermia. There are four primary mechanisms of heat loss in the veterinary patient: • Convection is the transfer of heat from the body surfaces to air surrounding the body. This heat transfer is maximized when the air is circulated, as evidenced by the wind chill factor (perceived decrease in temperature with wind exposure). • Conduction is the transfer of heat from body surfaces to objects that come into contact with the body, such as the ground, examination tables, and kennels. Immersion hypothermia can cause a profound heat loss via this mechanism. • Radiation heat transfer is the loss of heat to surrounding structures that do not come into direct contact with the body, such as walls. Electromagnetic waves (photons) are emitted from any object that has a temperature above absolute zero, and this energy transfers heat.8 This heat transfer occurs regardless of the temperature of the intermediary substance, such as air. • Evaporative heat transfer is the loss of heat from moisture on the body surfaces or through the respiratory tract to the environment. Although dogs and cats have minimal perspiration, this loss can be significant if the patient is wet, either incidentally or in preparation for surgery.2,10 The distribution of heat loss under normal circumstances in dogs is similar to humans, with 70% lost via radiation and convection.5,11 Many factors contribute to the degree of heat loss and require special consideration. For example, neonates have a large surface area, which

811

allows for accelerated heat loss. Cachectic patients have decreased fat and muscle stores, which permits faster heat transfer and loss. Finally, severely debilitated patients may be less able to respond to hypothermia due to the inability either to seek and retain heat or to mount an appropriate physiologic response.

PHYSIOLOGIC EFFECTS OF HYPOTHERMIA Cardiovascular and Hemodynamic Effects The primary detrimental cardiovascular changes found in hypothermia include bradycardia, hypotension, cardiac dysrhythmias, decreased cardiac output, and ultimately asystole. The initial response to hypothermia includes a mild sinus tachycardia and an increase in arterial blood pressure secondary to catecholamine release via the autonomic nervous system.12,13 The vasoconstriction of the peripheral arteries leads to an increase in the central venous pressure.14 This, in addition to a left shift in the oxygen-hemoglobin dissociation curve, may lead to peripheral tissue hypoxia or dysoxia, causing an increase in systemic vascular resistance.12 As the hypothermia progresses, vascular responsiveness to norepinephrine at the a1-receptor begins to decrease, which leads to a loss of vasoconstriction and subsequent arterial vasodilation contributing to hypotension.2 Sinus bradycardia follows the initial tachycardia secondary to a decrease in the rate of diastolic repolarization in the cells of the sinus node.14 This makes the bradycardia nonresponsive to atropine administration. Although the bradycardia causes a decrease in cardiac output, the accompanying hypothermic decrease in metabolic rate may allow the balance between oxygen delivery and oxygen consumption to be maintained.15 Other electrocardiographic changes include prolongation of the action potential duration and a decrease in the rate of myocardial conduction. This leads to prolongation of the PR interval, widening of the QRS complex, and, in humans, associated Osborn waves. These waves, sometimes called J waves, are an acute ST-segment elevation at temperatures of 32°C to 33°C and have rarely been documented in small animals.9 As severe hypothermia develops, there is an increased risk of dysrhythmias. The initial is atrial fibrillation, which can progress to ventricular tachycardia and fibrillation.16 As CBT approaches 23.5°C, 50% of dogs demonstrate ventricular fibrillation.9

Respiratory Effects The respiratory effects of hypothermia include decreases in respiratory rate and depth (with CBT ,28°C), pulmonary tissue injury, and oxygen dissociation disturbances.2 Initial mild hypothermia results in tachypnea followed by a reduction in minute ventilation, bronchospasm, and bronchorrhea.4 As the hypothermia progresses, decreased cellular metabolism and lowered carbon dioxide production reduce the stimulus for respiration, which leads to lower tidal volumes and respiratory rates.4,12 Loss of airway protective reflexes and a reduction in ciliary clearance may predispose the patient to aspiration pneumonia. A degree of ventilation–perfusion mismatch may also occur as physiologic and anatomic dead space is increased secondary to bronchodilation. Finally, as the hypothermia becomes severe, apnea or, in rare cases, noncardiogenic pulmonary edema may develop.17

Neuromuscular Effects Human patients display progressive central neurologic effects with hypothermia, such as confusion, apathy, impaired judgment, and depression of consciousness culminating in coma at temperatures below 30°C. These signs are secondary to a progressive decrease in cerebral blood flow of 6% to 10% for each 1°C decrease in CBT.17 Although the early signs are difficult to assess in the veterinary patient, ataxia,

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hyporeflexia, and decreased level of consciousness may be observed in latter stages. Mild hypothermia activates shivering, and ataxia may be noted.18 As the CBT continues to decline into moderate hypothermia, there may be a loss of shivering, which in humans can occur at a wide range of temperatures (24°C to 35°C). Synovial fluid becomes more viscous and stiffness in muscles and joints appear, as well as hyporeflexia and pupillary sluggishness. Severe hypothermia brings about muscle rigidity, pupillary dilation, and areflexia at temperatures below 28°C. Below 25°C, there is loss of cerebrovascular autoregulation with a marked reduction in metabolic rate. This reduction in metabolic demand allows a degree of tolerance to cerebral ischemia, and an electroencephalogram will be flat at 20°C.19

Acid-Base Effects The primary effect on acid-base status is an acidemia, frequently a mixed respiratory and metabolic acidosis. A respiratory alkalosis may initially be present secondary to tachypnea, but as the hypothermia progresses, the respiratory drive decreases and a respiratory acidosis occurs. The solubility of carbon dioxide is increased in cooled blood, which leads to a lower PCO2 for a given blood carbon dioxide content. Although this change promotes a respiratory alkalosis, this effect tends to be outweighed by hypoventilation and metabolic acidosis. The metabolic acidosis that occurs is secondary to a decrease in hepatic metabolism, a decrease in acid excretion from the kidneys, an increase in lactate generation secondary to shivering and decreased tissue perfusion, and a decreased buffering capacity of cold blood.17

Coagulation Effects Hypothermia has dramatic effects on normal coagulation mechanisms. The changes are associated with an apparent thrombocytopenia, platelet and coagulation factor activity dysfunction, and disruption of fibrinolytic equilibrium. Primary hemostasis abnormalities include sequestration of platelets by the liver and spleen, which accounts for the quantitative platelet decrease. This is accompanied by decreased platelet aggregation secondary to decreased production of thromboxane B2, decreased platelet granule secretion, attenuation of P selectin expression, and diminished expression of the von Willebrand factor receptor as demonstrated by prolonged closure times on platelet function assays.20,21 Secondary hemostasis abnormalities develop due to the depressed enzymatic activity of the activated clotting factors in hypothermia. This may include prolongation of prothrombin time and activated partial thromboplastin time. Of significance is the disparity between the clinically observed coagulopathy and the “normal” result obtained on a coagulation assay. This is due to the fact that kinetic coagulation tests are performed on warmed blood. Therefore the standard clotting tests performed in the laboratory at 37°C will not reflect the effects of hypothermia on the patient’s clotting cascade.22 Thromboelastography studies have found prolonged clot formation time even in mild hypothermia, as evidenced by increased K time and decreased a angle in humans and dogs with no significant change to ultimate clots strength.22,23 Alternatively, the coagulation abnormality may include a physiologic hypercoagulability and disseminated intravascular coagulation. This may be caused by circulatory collapse, thromboplastin release from cold tissues, or release of catecholamines and steroids. An increase in blood viscosity due to hemoconcentration and red blood cell stiffening and decreased deformability may also play a part because hematocrit increases by about 2% for every 1°C decline in temperature.17,19

Renal and Metabolic Effects Renal, hepatic, and immunologic complications may be encountered in the hypothermic patient.

The initial renal effect observed in mild to moderate hypothermia is diuresis, regardless of hydration status. This is often referred to as cold diuresis and can cause significant hypovolemia and subsequent hypotension. The diuresis occurs as a result of an initially sensed increase in blood volume caused by peripheral vasoconstriction and begins before a drop in CBT.12,17,18 As the CBT drops, there is a decreased response to vasopressin (antidiuretic hormone) at the level of the distal tubule. This causes an inability to resorb water and a loss of electrolytes. In moderate hypothermia, the glomerular filtration rate decreases secondary to decreases in cardiac output and renal blood flow. This reduction in tubular function causes a reduction in renal clearance of glucose as well as the capacity for H1 ion secretion, which contributes to hyperglycemia and acidosis.4 Hyperglycemia may be identified in hypothermia due to renal changes, catecholamine-induced glycogenolysis, and a combination of decreased insulin sensitivity and reduced insulin secretion from the pancreatic islet cells. This may be important because the dosage of insulin required to correct a profound hyperglycemia will be increased.3,4 Electrolyte levels are frequently decreased due to the renal tubular dysfunction, which permits excess electrolyte loss, as well as a hypothermia-induced intracellular shift. Hypophosphatemia, hypomagnesemia, and hypokalemia may have negative consequences on the cardiac, nervous, and respiratory systems.14,15 Severe hypothermia may induce significant hyperkalemia due to acidosis and cell death.3 The hepatic consequence of hypothermia is related to the decreased hepatic enzyme activity and reduced perfusion of the liver.2,14,19 This leads to decreased metabolism of substances and prolonged drug clearances. Common medications that have been shown to have either increased potency or decreased clearance in hypothermia are fentanyl, pentobarbital, morphine, midazolam, phenobarbital, propofol, and volatile anesthetics.14,24 In a prospective human study, postanesthetic recovery time was lengthened by 40 minutes for each 2°C decrease in CBT.25 Hypothermia also causes direct impairment of primary immune functions, including impairment of chemotaxis and phagocytosis of granulocytes, leukocyte depletion, decreased mobility of macrophages, and impaired oxidative killing by neutrophils.19,26 This could predispose the patient to infection, although in a retrospective study in veterinary patients a correlation was not found between mild hypothermia and wound infection, at least for clean surgical wounds.27

CORE BODY TEMPERATURE MEASUREMENT An accurate CBT measurement is needed to determine the overall status of the thermoregulatory system as well as to monitor therapy. The pulmonary artery and thoracic esophageal temperatures are excellent references for CBT, but these measurements are technically difficult or impractical to obtain unless the patient is unconscious or anesthetized. Rectal temperatures are useful in steady-state conditions but are slow to change and can read slightly high (by 0.4°C).8 A comparison of auricular, rectal, and pulmonary artery thermometry in dogs found a strong correlation among the temperatures obtained by three methods, but measurements were evaluated only in mild hypothermia (36.6°C).28 Therefore the rectal temperature can be used as a guide but with the knowledge that it may not be the true CBT.

REWARMING The technique used for rewarming depends on the degree of hypothermia and the stability of the patient’s condition (Table 138.2). A thorough understanding of the basis of the available techniques allows the

CHAPTER 138  Hypothermia

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TABLE 138.2  Rewarming Techniques Passive External

Active External

Active Core

Active Core

Recommended for

Mild hypothermia

Mild/Moderate/Severe hypothermia

Moderate/Severe

Arrest or imminent arrest

Basis

Augmentation of patient’s own intrinsic heat production mechanisms

Application of exogenous heat to the skin

Application of exogenous heat directly to the core organs

Applications

Insulated blankets

Warm air convection Warm water blanket Radiant heat Warm water bottles

Heated infusions

Relative hypovolemia due to vasodilation Afterdrop Rewarming acidosis

Potentially invasive Hemorrhage

Reflective blankets Complications

Slow rewarming

clinician to choose applications that are most appropriate for the individual patient, not simply the CBT. Lack of evidence-based treatment guidelines requires therapy to be instituted based on the patient’s pathophysiology as well as the resources available.17 Passive external rewarming is simply augmentation of the patient’s own heat generation by minimizing loss of the generated heat to the environment. This is accomplished through insulation with cloth or reflective blankets to minimize the heat lost through conduction, convection, radiation, and evaporation. This technique works well for mildly hypothermic patients, particularly those that are shivering, because the patients will be generating additional heat and can slowly rewarm themselves. If patients are moderately or severely hypothermic, their bodies will be unable to shiver or produce significant endogenous heat, and this technique is applied only to assist in diminishing further CBT drops. Active rewarming, either through application of exogenous heat directly to the skin (active external warming) or to the vital organs (active core rewarming [ACR]), is typically required in moderate or severe hypothermia. In these hypothermic stages, the body is no longer able to generate enough heat to rewarm effectively. This may be due to the lack of a shivering response or to the underlying environment and pathologic condition that was the cause of the hypothermia.17 Active external rewarming (AER) is the application of exogenous heat to the skin through a variety of methods. Although AER can help rewarm a moderately hypothermic patient, there are a number of complications that must be considered. Surface rewarming causes peripheral vasodilation, and this can lead to a relative hypovolemia and hypotension termed rewarming shock. Along with this is the potential for core temperature afterdrop, in which the colder peripheral blood is returned back to vital organs and thereby decreases the CBT further.17 Finally, the returning colder blood and associated lactic acid are carried back to the core causing a rewarming acidosis. These complications are most likely to occur when the extremities are warmed before the core; therefore, application of external heat should be focused on the truncal regions of the body, not the extremities. Another consideration in the use of AER is that heat applied to the skin diminishes shivering, an effective source of heat generation. However, a benefit of AER over vigorous shivering is decreased metabolic stress and less afterdrop.29 Therefore clinical judgment is required to determine whether application of AER will provide more heat than the heat generation lost through cessation of shivering. Forced-air surface rewarming (e.g., 3M Bair Hugger) provides forced heated air, circulated through a blanket with apertures, to

Warmed humidified air

Peritoneal lavage with heated fluid Thoracic lavage with heated fluid

permit convective transfer of heat to the patient. This system minimizes the risk of thermal injury to hypothermic skin, which may be vasoconstricted and unable to conduct heat away, and may decrease the afterdrop effect.9,29 Resistive heating (e.g., Hot Dog warming blanket) transfers heat to the patient through low-voltage electricity embedded in a fabric. It has been shown to increase CBT in mildly to moderately hypothermic trauma victims.30 Blankets that circulate warm water can also be used with little risk of thermal injury to the patient. Radiant heat, hot water bottles, and electric heating pads are other techniques for providing AER, but the risk of thermal injury is higher than with the other techniques listed and therefore not recommended. ACR is the application of exogenous heat to core vital organs. In veterinary medicine, this may be accomplished effectively through warmed humidified air, heated infusions, and heated peritoneal or thoracic lavage. In human medicine, extracorporeal life support has become the gold standard for ACR for patients with imminent or current hypothermic cardiac arrest.3 The rates of rewarming achieved using several techniques are shown in Table 138.3.31 Previously described techniques for gastric, urinary bladder, and colonic lavage for rewarming are relatively ineffective due to the limited surface area involved. ACR is best suited for unstable patients with moderate to severe hypothermia, particularly those patients in cardiovascular arrest.17 Intravenous infusions of heated crystalloids (warmed to 40°C to 42°C) can provide exogenous heat to patients when large volumes of fluids are required. Clinically, it is challenging to provide warmed intravenous fluids to the veterinary patient because flow rates are relatively low and the warmed fluids will cool to ambient temperature before reaching the patient.32,33 At higher rates of fluid administration and in severely hypothermic patients, however, the results may improve. Airway rewarming can be accomplished through delivery of warmed (40°C to 45°C) humidified air via a facemask or endotracheal tube. The effectiveness depends on the humidification level, the delivery method, and the temperature of the inhaled air. The benefits of airway rewarming are that it is noninvasive, allows alveolar warming of the blood returning to the heart and conduction to contiguous structures in the mediastinum, prevents further respiratory heat loss, helps ensures adequate oxygenation, and reduces the amount and viscosity of secretions in cold-induced bronchorrhea.17 Although the amount of heat supplied is low (rewarming rate of 1°C to 2°C/hr), it is typically applied with other AER or ACR techniques to maximum effect. Most in-hospital humidifiers do not exceed 41°C and would require modification to reach the known maximum safe inhalation temperature of

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TABLE 138.3  Rewarming Rates (Degrees Celsius per Hour)31,3 Passive External Rewarming

Active External Rewarming

Inhalation of Warm Air

Peritoneal/Thoracic Lavage ECLS

Per Hour

0.5–5°C

0.5°–4°C

1.0–2.5°C

1.5–2.5°C

4–10°C

Notes

Dependent on patient’s ability to produce heat, particularly shivering

Dependent on dwell time

Preferred method in human hypothermic arrest

ECLS, extracorporeal life support.

45°C. High-flow nasal cannula has recently been investigated as an adjunctive method to provide heat support in humans with mild hypothermia, finding a 1.5°C/hour increase in body temperature without treatment side effects.34 Peritoneal lavage can be performed with heated (40°C to 45°C) isotonic dialysate (normal saline, lactated Ringer’s solution, or 1.5% dextrose dialysate solute) infused via a peritoneal catheter at 10 to 20 ml/kg. A dwell time of 20 to 30 minutes is allowed, and then the fluid is aspirated and the procedure repeated. This method allows transfer of heat to a large surface area, including great vessels and abdominal viscera. An additional benefit is direct hepatic rewarming, which reactivates detoxification and conversion enzymes.17 In a hypothermia model of dogs with cardiac arrest, the investigators found that peritoneal dialysis, with appropriate cardiopulmonary resuscitation (CPR), was as effective as partial cardiac bypass.35 The main disadvantages of peritoneal dialysis are that it is invasive, can complicate ongoing coagulopathies, and can cause electrolyte shifts requiring careful monitoring. Thoracic lavage is described in the human literature as an effective method of core rewarming in cardiac arrest, although no longer recommended if Extracorporeal Life Support is available.3,36 Heated (40°C to 41°C) normal saline is infused through large-bore thoracostomy tubes into the hemithorax and then extracted after a 2-minute dwell time. This allows for closed-chest CPR and defibrillation as indicated. Extracorporeal blood rewarming can be achieved through cardiopulmonary bypass, continuous arteriovenous warming, venovenous warming, and hemodialysis.17 Venoarterial extracorporeal membrane oxygenation or cardiopulmonary bypass are the recommended methods in human primary hypothermic cardiac arrest.4 To date, the author knows of no application of these techniques in veterinary medicine for rewarming in accidental hypothermia.

THERAPY The aggressiveness of therapy for hypothermia depends on the patient’s current clinical consequences. An initial approach is aimed at stabilizing the patient’s condition and starting a slow rewarming process as dictated by the severity of signs. Recommended monitoring parameters are listed in Table 138.4. Prevention of further decreases in CBT is indicated in all cases of hypothermia. This is best accomplished through passive rewarming techniques. Ideally, if the patient is wet, the patient should be dried, contact with cold surfaces should be prevented, and administration of large volumes of ambient-temperature intravenous fluids should be avoided. The rewarming rate is dictated by the severity of the hypothermia, although the optimal rewarming rate is unknown. Ventricular dysrhythmia cannot be defibrillated until the CBT is above 28°C, in which case rapid rewarming would be required,4 followed by active rewarming until the CBT has reached 37°C. Stability of the cardiopulmonary system should be achieved and maintained through appropriate fluid therapy. Most fluid shifts will be reversed by rewarming, and therefore in mild hypothermia only modest rates of fluid administration will be required. As the severity of hypothermia progresses, the complications of volume shifts and increased blood viscosity, increased vascular permeability, and lowflow states will dictate aggressive fluid resuscitation. It is important to note that, in severe hypothermia, it may be impossible to achieve complete stability without significant rewarming. Therefore, the aggressiveness of rewarming will need to be altered appropriately. Appropriate physiologic support should be provided as dictated by clinicopathologic findings. Glucose may need to be administered in mild to moderate hypothermia because there can be increased

TABLE 138.4  Monitoring Recommendations and Potential Errors Diagnostic Test

Common Result

Comment

Blood pressure

Hypotension

Peripheral vasoconstriction may make result unreliable; consider direct arterial or Doppler monitoring17

Electrocardiogram

Bradycardia, atrial/ventricular dysrhythmias

Glucose level

Hyperglycemia, hypoglycemia

Insulin administration may be ineffective until CBT is higher than 30°–32°C17

Electrolyte levels

Hypokalemia Hyperkalemia (in severe)

Vigilant monitoring needed for resultant hyperkalemia during rewarming due to extracellular shifts

Complete blood count

Hemoconcentration

Hematocrit increases by 2% for every 1°C drop in CBT19

Blood gas analysis

Mixed acidosis

Coagulation panel

Normal or hypocoagulable

Chemistry panel

Elevated levels of liver enzymes and lactate

Oxygen saturation (by pulse oximetry)

Hypoxemia

CBT, core body temperature.

Laboratory error is possible due to warming of blood Vasoconstriction limits usefulness

CHAPTER 138  Hypothermia catecholamine and cortisol production.2 In moderate to severe hypothermia, on the other hand, a profound hyperglycemia may develop secondary to decreased insulin sensitivity and secretion, and insulin therapy may be required. Electrolyte alterations may require supplementation, particularly of potassium. Acid-base alterations typically correct with rewarming, but cardiopulmonary support may require attention in patients with severe acidosis.13,14 Anticipation and prevention of known hypothermic complications should be part of the therapeutic plan. Coagulopathies require minimizing the use of invasive procedures. The patient should be monitored carefully for hypovolemia secondary to cold diuresis and natriuresis. The increased incidence of infection may require empirical antibiotic therapy and dysrhythmias associated with rewarming or overly aggressive handling may require antiarrhythmics.

CARDIOPULMONARY RESUSCITATION There are some unique challenges in hypothermic cardiopulmonary arrest that require consideration. Importantly, in severe hypothermia, the patient may appear pulseless, have a nonauscultable heartbeat, and even have an apparent asystolic rhythm on electrocardiogram. These changes are due to severe bradycardia, peripheral vasoconstriction, and hypotension, which can lead to the erroneous assessment of cardiopulmonary arrest.9,17 Lack of organized cardiac function can be confirmed with assessment of cardiac wall motion by echocardiogram if possible. Because return of spontaneous circulation may not occur until severe hypothermia has been addressed, the duration of CPR may depend on the length of time it takes to warm the patient. An extreme example is a human patient experiencing accidental hypothermia who was successfully resuscitated after 6.5 hours of closed chest compressions.37

REFERENCES 1. Sessler DI: Thermoregulatory defense mechanisms, Crit Care Med 37(Suppl 7):S203-S210, 2009. doi:10.1097/CCM.0b013e3181aa5568. 2. Oncken AK, Kirby R, Rudloff E: Hypothermia in critically ill dogs and cats, Compend Contin Educ Small Anim Pract 23(6):506-520, 2001. 3. Paal P, Gordon L, Strapazzon G, et al: Accidental hypothermia-an update, Scand J Trauma Resusc Emerg Med 24(1), 2016. doi:10.1186/s13049-0160303-7. 4. Paal P, Brugger H, Strapazzon G: Accidental hypothermia, Handb Clin Neurol 157:547-563, 2018. doi:10.1016/B978-0-444-64074-1.00033-1. 5. Hall JE, Hall ME: Body temperature regulation and fever. In Guyton AC, Hall JE, editors: Textbook of medical physiology, ed 14, Philadelphia, 2021, Elsevier, pp 901-912. 6. Clark-Price S: Inadvertent perianesthetic hypothermia in small animal patients, Vet Clin North Am Small Anim Pract 45(5):983-994, 2015. doi:10.1016/j.cvsm.2015.04.005. 7. Wingfield WE: Accidental hypothermia. In Wingfield WE, Raffe MR, editors: Veterinary ICU book, 2002, Teton New Media, pp 1116-1129. 8. Crawshaw LI, Nagashima K, Yoda T, et al: Thermoregulation. In Auerbach PS, editor: Wilderness medicine, ed 6, Philadelphia, 2012, Elsevier, pp 104-116. 9. Haman F, Peronnet F, Kenny GP, et al: Effects of carbohydrate availability on sustained shivering I. Oxidation of plasma glucose, muscle glycogen, and proteins, J Appl Physiol 96(1):32-40, 2004. doi:10.1152/japplphysiol.00427.2003. 10. Sessler DI: Perioperative heat balance, Anesthesiology (Philadelphia) 92(2):578-590, 2000. doi:10.1097/00000542-200002000-00042. 11. Bruchim Y, Horowitz M, Aroch I: Pathophysiology of heatstroke in dogs revisited, Temperature (Austin) 4(4):356-370, 2017. doi:10.1080/23328940. 2017.1367457. 12. Armstrong SR, Roberts BK, Aronsohn M: Perioperative hypothermia, J Vet Emerg Crit Care 15(1):32-37, 2005.

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13. Polderman KH: Application of therapeutic hypothermia in the intensive care unit, Intensive Care Med 30(5):757-769, 2004. doi:10.1007/s00134003-2151-y. 14. Polderman KH, Herold I: Therapeutic hypothermia and controlled normothermia in the intensive care unit: Practical considerations, side effects, and cooling methods, Crit Care Med 37(3):1101-1120, 2009. doi:10.1097/ CCM.0b013e3181962ad5. 15. Polderman KH: Mechanisms of action, physiological effects, and complications of hypothermia, Crit Care Med 37(Suppl 7):S186-S202, 2009. doi:10.1097/CCM.0b013e3181aa5241. 16. Campbell SA, Day TK: Spontaneous resolution of hypothermia-induced atrial fibrillation in a dog, J Vet Emerg Crit Care (San Antonio, Tex: 2000), 14(4):293-298, 2004. doi:10.1111/j.1476-4431.2004.04023.x. 17. Danzl DF, Huecker MR: Accidental hypothermia. In Auerbach PS, editor: Wilderness medicine, ed 7, Philadelphia, 2017, Elsevier, pp 135-162. 18. Giesbrecht GG: Emergency treatment of hypothermia, Emerg Med (Fremantle, WA). 13(1):9-16, 2001. doi:10.1046/j.1442-2026.2001.00172.x. 19. Mallet ML: Pathophysiology of accidental hypothermia, QJM: 95(12): 775-785, 2002. doi:10.1093/qjmed/95.12.775. 20. Lynn M, Jeroukhimov I, Klein Y, Martinowitz U: Updates in the management of severe coagulopathy in trauma patients, Intensive Care Med 28(S2):S241-S247, 2002. doi:10.1007/s00134-002-1471-7. 21. Ying CL., Tsang SF, Ng KF: The potential use of desmopressin to correct hypothermia-induced impairment of primary haemostasis—an in vitro study using PFA-100, Resuscitation 76(1):129-133, 2007. doi:10.1016/j. resuscitation.2007.07.009. 22. Wallner B, Schenk B, Hermann M, et al: Hypothermia-associated coagulopathy: a comparison of viscoelastic monitoring, platelet function, and real time live confocal microscopy at low blood temperatures, an in vitro Experimental Study, Front Physiol 11:843, 2020. doi:10.3389/fphys.2020. 00843. 23. Nitschke T, Groene P, Acevedo AC, Kammerer T, Schäfer S: Coagulation under mild hypothermia assessed by thromboelastometry, Transfus Med Hemother 48(4):203-209, 2021. doi:10.1159/000513922. 24. Tortorici MA, Kochanek PM, Poloyac SM: Effects of hypothermia on drug disposition, metabolism, and response: a focus of hypothermia-mediated alterations on the cytochrome P450 enzyme system, Crit Care Med 35(9):2196-2204, 2007. doi:10.1097/01.CCM.0000281517.97507.6E. 25. Lenhardt R, Marker E, Goll V, et al: Mild intraoperative hypothermia prolongs postanesthetic recovery, Anesthesiology (Philadelphia) 87(6):1318-1323, 1997. doi:10.1097/00000542-199712000-00009. 26. Kurz A, Sessler DI, Lenhardt R: Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization, N Engl J Med 334(19):1209-1216, 1996. doi:10.1056/NEJM199605093341901. 27. Beal MW, Brown DC, Shofer FS: The effects of perioperative hypothermia and the duration of anesthesia on postoperative wound infection rate in clean wounds: a retrospective study, Vet Surg 29(2):123-127, 2000. doi:10.1111/j.1532-950X.2000.00123.x. 28. Southward ES, Mann FA, Dodam J, Wagner-Mann CC: A comparison of auricular, rectal and pulmonary artery thermometry in dogs with anesthesia-induced hypothermia, J Vet Emerg Crit Care (San Antonio, Tex: 2000), 16(3):172-175, 2006. doi:10.1111/j.1476-4431.2005.00158.x. 29. Giesbrecht GG, Shroeder M, Bristow GK: Treatment of mild immersion hypothermia by forced-air warming, Aviat Space Environ Med 65:803, 1994. 30. Kober A, Scheck T, Fulesdi B, et al: Effectiveness of resistive heating compared with passive warming in treating hypothermia associated with minor trauma: a randomized trial, Mayo Clin Proc 76(4):369-375, 2001. doi:10.1016/S0025-6196(11)62384-7. 31. Danzl DF, Pozos RS, Auerbach PS, et al: Multicenter hypothermia survey, Ann Emerg Med 16(9):1042-1055, 1987. doi:10.1016/S0196-0644(87) 80757-6. 32. Chiang V, Hopper K, Mellema MS: In vitro evaluation of the efficacy of a veterinary dry heat fluid warmer, J Vet Emerg Crit Care (San Antonio, Tex: 2000) 21(6):639-647, 2011. doi:10.1111/j.1476-4431.2011.00684.x. 33. Soto N, Towle Millard HA, Lee RA, Weng HY: In vitro comparison of output fluid temperatures for room temperature and prewarmed fluids, J Small Anim Pract 55(8):415-419, 2014. doi:10.1111/jsap.12236.

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34. Gilardi E, Petrucci M, Sabia L, Wolde Sellasie K, Grieco DL, Pennisi MA: High-flow nasal cannula for body rewarming in hypothermia, Crit Care (London, England) 24(1):122-122, 2020. doi:10.1186/s13054-020-2839-1. 35. Moss JF, Haklin M, Southwick HW, Roseman DL: A model for the treatment of accidental severe hypothermia, J Trauma 26(1):68-74, 1986. doi:10.1097/00005373-198601000-00013.

36. Kjærgaard B, Bach P: Warming of patients with accidental hypothermia using warm water pleural lavage, Resuscitation 68(2):203-207, 2006. doi:10.1016/j.resuscitation.2005.06.019. 37. Lexow K: Severe accidental hypothermia: survival after 6 h 30 min of cardiopulmonary resuscitation, Arctic Med Res 50(6):112-114, 1991.

139 Heat Stroke Kenneth J. Drobatz, DVM, MSCE, DACVIM, DACVECC

KEY POINTS • Heat stroke is the most serious of the heat-associated illnesses. • Heat stroke can be classified as exertional (overheating while exercising) or nonexertional (classic heat stroke). • Heat stroke is generally associated with multiorgan derangements, but central nervous system dysfunction (ranging from mild to moderate altered mentation to seizures or coma) is the hallmark of the condition. • Every body system can be involved, but the major ones affected are the cardiovascular, central nervous, gastrointestinal, renal, and coagulation systems. • Treatment involves cooling the patient and providing aggressive supportive care.

• In human medicine and experimental dog models, no one cooling method has proved superior to others. • A worse prognosis in dogs has been associated with hypoglycemia, decreased cholesterol level, increased bilirubin concentration, decreased albumin level, ventricular arrhythmias, increased creatinine values, longer delay from incident to treatment, obesity, seizures, prolonged prothrombin time and activated partial thromboplastin time, disseminated intravascular coagulation, and increased number of nucleated red blood cells.

INTRODUCTION

and exercise) and heat-dissipating mechanisms controlled by temperature-sensitive centers in the hypothalamus. Body temperature increases when heat load exceeds heat dissipation. Heat dissipation may occur via four mechanisms: convection, conduction, radiation, and evaporation. As the body temperature increases, 70% of heat loss in dogs and cats occurs by radiation and convection through the skin. Heat loss is facilitated by increased cutaneous circulation as a result of increased cardiac output and sympathetically mediated peripheral vasodilation.2 Shunting of blood to the periphery involves a trade-off with blood supply to the viscera (intestines and kidneys). Significant heat loss also occurs as a result of evaporation from the respiratory tract through panting, and this becomes the predominant mechanism of heat loss when ambient temperature is equal to or greater than body temperature. A warm, humid environment and exercise are the two most common heat loads experienced by dogs that may cause extreme hyperthermia, even in animals with functional heat-dissipating mechanisms. Respiratory evaporative heat loss may be diminished by humid climatic conditions, confinement in a closed space with poor ventilation, and obstructive upper respiratory tract abnormalities (e.g., brachycephalic conformation, laryngeal paralysis, airway masses, or collapsing trachea). Additionally, the work of breathing in these latter conditions can contribute substantially to the heat load in these animals. Diminished radiational and convective heat loss from the skin may occur as a result of hypovolemia from any cause, poor cardiac output, obesity, extremely thick hair coat, or lack of acclimatization to heat. Situations that combine high heat load and diminished heat dissipation may result in a rapid and extreme body temperature increase. Most dogs with heat-induced illness are brought to the veterinarian when the warm, humid weather begins, so the seasonal pattern differs depending on climatic conditions and year-to-year variations

Three syndromes of heat-associated illness that represent a continuum from the least to the most severe are described in humans. Heat cramp is characterized by muscle spasms resulting from sodium and chloride depletion. When signs such as fatigue, weakness, muscle tremors, vomiting, and diarrhea occur, heat prostration or heat exhaustion is the most likely diagnosis. The hallmark of heat stroke is severe central nervous system (CNS) disturbance, and it is often associated with multiple organ dysfunction. A more recent definition of heat stroke describes it as a form of “hyperthermia associated with a systemic inflammatory response leading to a syndrome of multiorgan dysfunction in which encephalopathy predominates.”1 This latter definition is more physiologically based and gives a more informative description of what is seen clinically in dogs with heat stroke. Generally, clients seek veterinary attention when their pets are demonstrating signs consistent with heat prostration, heat exhaustion, or heat stroke. This chapter focuses primarily on dogs with heat-associated illness because cats rarely experience heat stroke.

PHYSIOLOGY, PATHOGENESIS, AND PATHOPHYSIOLOGY A hot environment or exercise in a hot environment does not equate to overheating and heat-associated illness. It is the increase in core body temperature that results in heat-associated illness (see Chapter 10, Hyperthermia and Fever). Therefore, the body has developed a relatively effective thermoregulation system to protect itself from overheating. Thermal homeostasis is maintained by a balance between heat load (environmental heat and heat generated through metabolism

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in temperature and humidity. In some instances, despite progressively warmer days later in the summer, heat-associated illness becomes less frequent.3 This may be related to the time available for acclimatization to the change in environmental temperature. In humans, acclimatization to heat can take 2 weeks or longer and is associated with enhanced cardiac performance, salt conservation by the kidney and sweat glands through activation of the renin-angiotensin-aldosterone axis, an increased capacity to sweat, plasma volume expansion, increased glomerular filtration rate, and increased ability to resist exertional rhabdomyolysis.4 Increased body heat induces three protective mechanisms: thermoregulation (mentioned previously), an acute-phase response, and increased expression of intracellular heat shock proteins.1 The acute-phase response involves a variety of proinflammatory and antiinflammatory cytokines. Proinflammatory mediators induce leukocytosis, promote synthesis of acute-phase proteins, stimulate the hypothalamic-pituitaryadrenal axis, and activate endothelial cells and white blood cells. These mediators are protective for the body when balance is maintained between the proinflammatory and antiinflammatory response systems (see Chapter 7, SIRS, MODS and Sepsis). The heat shock proteins protect the cell and the body against further heat insults and prevent denaturation of intracellular proteins. They also help to regulate the baroreceptor response during heat stress, thus preventing hypotension and conferring cardiovascular protection.5 Heat stroke results from a failure of thermoregulation followed by an exaggerated acute-phase response and alteration of heat shock proteins.1 Additionally, absorption of endotoxin from the gastrointestinal (GI) tract may fuel the inflammatory response because intestinal mucosal permeability is increased during heat stress.6 It has been noted that many of the mediators involved in heat stroke are the same mediators associated with sepsis and the systemic inflammatory response syndrome (see Chapters 7 and 90, SIRS, MODS and Sepsis and Sepsis and Septic Shock, respectively).1 The suggested pathophysiologic sequence in heat stroke involves initial production and release of interleukin-1 and interleukin-6 from the muscles into the circulation and increased systemic levels of endotoxin from the GI tract.1 These substances mediate excessive activation of leukocytes and endothelial cells, which results in the release of numerous proinflammatory and antiinflammatory cytokines as well as activation of coagulation and inhibition of fibrinolysis. Direct endothelial cell injury due to the heat, combined with an initial hypercoagulable state, results in microthrombosis and progressive tissue injury. These proinflammatory and procoagulation processes, in addition to direct heat injury, can lead to multiple organ dysfunction syndrome. Because of the multisystemic problems in patients with heat stroke, these animals should be assessed and monitored for multiple organ failure, with particular attention to the respiratory, cardiovascular, renal, GI, and central nervous systems, as well as the coagulation system.

PHYSICAL EXAMINATION The physical examination findings of dogs suffering from heatassociated illness vary with the intensity and duration of the increased body temperature and the individual pathophysiologic responses that are initiated.

Temperature, Pulse, and Respiratory Rate The rectal temperature may be decreased, normal, or increased depending on tissue perfusion and whether cooling measures have already been implemented. The pulse rate is usually increased as a result of a compensatory sinus tachycardia. The respiratory rate is very rapid,

usually in an attempt to improve heat dissipation rather than as a result of primary respiratory disease.

Cardiovascular System Most dogs arrive for treatment in a hyperdynamic state. The mucous membranes are usually hyperemic and the capillary refill time is very short. The pulses are often weak because of hypovolemia secondary to evaporative fluid loss, vomiting, diarrhea, and vasodilation (causing a relative hypovolemia). Sinus tachycardia is common. Rarely, a dog will have intermittent ventricular arrhythmias, which have been associated with a worse outcome in clinical cases of heat-associated illness.3 Electrocardiographic evaluation and monitoring should be performed for all patients with severe heat-associated illness.

Respiratory System Careful evaluation of the respiratory system is warranted because evaporation through the respiratory tract is a major mechanism for heat dissipation. Loud or noisy breathing that is heard without the stethoscope suggests an upper airway abnormality such as laryngeal paralysis, upper airway edema, obstruction (e.g., brachycephalic syndrome), or collapse. Careful auscultation for loud airway or adventitious lung sounds (e.g., pulmonary crackles) should be performed. Many dogs with heatassociated illness have been vomiting; therefore, aspiration pneumonia must be considered. Dogs suffering from disseminated intravascular coagulation (DIC; see Chapters 101 and 104, Hypercoagulable States and Coagulopathy in the ICU, respectively) may have pulmonary parenchymal hemorrhage resulting in crackles or loud airway sounds. However, in a retrospective study of clinical heat stroke cases, respiratory abnormalities were not common.3 More recently, a necropsy-based study of dogs that died due to heat stroke revealed that the majority had hyperemia, edema, and hemorrhage in the lungs.7

Central Nervous System Mentation may range from alert to comatose, with depression being the most common abnormality. The severely affected dog is comatose or stuporous at presentation. Pupil size may range from dilated to pinpoint, but pupils are usually responsive to light. Some dogs may be cortically blind when they are brought in, but this may resolve after several hours. Similarly, head bobbing or tremors occur transiently and resolve over hours. Ambulatory dogs may be ataxic. The causes of these neurologic abnormalities may include poor cerebral perfusion, direct thermal damage, cerebral edema, CNS hemorrhage, or metabolic abnormalities such as hypoglycemia or hepatoencephalopathy, although the latter has not been documented in clinical cases of dogs with heat stroke.

Renal System Physical evaluation of the renal system is very limited. Palpation of bladder size and the change in size as fluid therapy ensues may be helpful in assessing urine production. Acute kidney injury is a potential complication of heat stroke, and evaluation of the urine for casts, monitoring urine production and monitoring for gross abnormalities (e.g., pigmenturia) are valuable tools (see Chapter 121, Acute Kidney Injury).

Gastrointestinal System Many of the severely affected dogs have protracted vomiting and diarrhea. The diarrhea may range from watery to hemorrhagic with mucosal sloughing. This may occur secondary to DIC or poor visceral perfusion and reperfusion as volume resuscitation is provided. Gastric ulceration may occur as well, resulting in vomiting with or without blood and melena.

CHAPTER 139  Heat Stroke

Coagulation System DIC is a relatively common finding in dogs with heat-associated illness. The presence of petechiae and ecchymoses or blood in the urine, vomit, or stool suggests that DIC may be present (see Chapters 101 and 104, Hypercoagulable States and Coagulopathy in the ICU, respectively).

LABORATORY EVALUATION An initial data set including a blood smear, packed cell volume, total solids, dipstick blood urea nitrogen (BUN) level, whole blood glucose concentration, and blood sodium and potassium levels should be obtained, if possible. The packed cell volume and total solids are often elevated because of hemoconcentration. The dipstick BUN value may be increased, likely because of poor renal perfusion, although GI hemorrhage or acute kidney injury must also be considered. The blood glucose concentration may be very low in severely affected patients secondary to increased utilization from hyperthermia and/or early sepsis. Sodium and potassium concentrations are generally normal in these patients on arrival but warrant evaluation, especially if vomiting and diarrhea have occurred or an acidosis or kidney injury is suspected. In addition, excessive panting may quickly lead to hypernatremia due to a loss of free water. An increased number of nucleated red blood cells (NRBCs) may be noted on a blood smear and is associated with a worse outcome.8 Urinalysis should be performed, preferably before fluid therapy is initiated, to assess renal function or damage; however, collection by cystocentesis should be avoided because of potential coagulation abnormalities. Urine specific gravity should be interpreted in light of the patient’s hydration and perfusion status. Urine assessment by dipstick often yields positive results for protein and hemoglobin. Glucosuria may be detected despite normal or even low blood glucose levels, which may suggest proximal tubular damage or recent hyperglycemia with glucosuria. Urine sediment examination may reveal red blood cells, which indicates renal damage or coagulation abnormalities. The presence of casts in the urine indicates renal damage and warrants close monitoring of urine output and renal function. More recently, in a prospective canine heat stroke study, renal urine biomarkers were found to be much more sensitive in detecting acute kidney injury than traditional renal function parameters such as BUN and creatinine.9 Further laboratory evaluation should include a complete blood count, serum chemistry screen, measurement of serum creatinine kinase activity, and coagulation evaluation. The most common complete blood count abnormality reported is an increased number of NRBCs;3 as noted earlier, this is associated with a worse prognosis. In one canine heat stroke study, a value of 18 or more NRBCs per 100 leukocytes at presentation had a sensitivity and specificity of 91% and 88%, respectively, for predicting death.8 The NRBC level typically decreases rapidly over the first 24 hours. Serum alanine aminotransferase and creatinine kinase levels are often elevated and usually peak within 24 to 48 hours. Serum bilirubin level may be increased and serum cholesterol level decreased in more severely affected dogs. Serum creatinine and BUN concentrations may be increased as well. These increases may be a result of dehydration and poor renal perfusion but warrant serial evaluations because renal damage may be present; serial increases in renal clinicopathologic parameters are associated with a worse prognosis.3 Activation of the coagulation cascade is initiated by direct thermal injury to the tissues and endothelium and may result in consumption of platelets and coagulation factors. If prothrombin time, partial thromboplastin time, and platelet count measurements cannot be performed, then activated clotting time should be determined, and a blood

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smear may reveal red blood cell fragments (schistocytes) and allow for platelet count to be estimated. In general, there should be at least 8 to 15 platelets per 1003 oil immersion field on a well-executed blood smear (see Chapter 196, Blood Film Evaluation). In patients with DIC, the platelet count is often decreased secondary to increased consumption and/or loss. The finding of DIC was not found to be associated with mortality in one study. In this same comprehensive coagulation study in dogs with heat stroke, the number of abnormal coagulation parameters in the first 24 hours was associated with mortality.10

TREATMENT AND MONITORING Cooling Procedures Cooling measures involve taking advantage of the physics of heatdissipating mechanisms: evaporation, conduction, convection, and radiation. Evaporative methods include wetting the dog’s whole body with tepid water and blowing fans over the body. In humans, ice water is used in this method, but recommendations are to massage the muscles to maintain circulation because extreme cooling of the periphery may result in vasoconstriction and paradoxical inhibition of body cooling. Whole body alcohol bathing should be avoided because not only is this noxious to the animal, but it may present a significant fire hazard should defibrillation be required in dogs that experience cardiac arrest. Intuitively, wetting the footpads with alcohol seems like an ineffective cooling measure given the small surface area involved, although this technique has not been rigorously evaluated for efficacy. External conduction cooling techniques include application of ice packs over major vessels (e.g., jugular veins), tap water immersion, ice water immersion, and use of cooling blankets. Water immersion methods can be cumbersome, and ice water baths may be uncomfortable and produce peripheral vasoconstriction and thus diminish heat dissipation overall. Internal conduction techniques include iced gastric lavage, iced peritoneal lavage, and cold water enemas, although the latter may interfere with rectal temperature monitoring. These techniques are invasive and can result in serious complications (aspiration pneumonia, septic peritonitis). Pharmacologic techniques such as administration of dantrolene sodium have been evaluated experimentally and have not been effective.11 Cooling measures are the only therapies for heat stroke that have been thoroughly evaluated. Many of the techniques already mentioned have been evaluated rigorously, both clinically in humans and experimentally in dogs. No single technique has been proven superior to any other, and in experimental canine studies, rates of temperature decline ranged from 0.15°C to 0.23°C (0.27°F to 0.41°F) per minute.12,13 Not surprisingly, many owners recognize that their dogs are overheated and hose them down with water. This is very effective and often results in a normal body temperature (or even hypothermia) by the time of presentation to the veterinarian.3 Whole body wetting with water combined with muscle massage and blowing fans is commonly performed. Additionally, administration of room temperature intravenous fluids may be helpful. Rarely, whole body shaving is needed to facilitate cooling in dogs with very thick hair coats. Cooling measures should be discontinued when the rectal temperature reaches 39.4°C (103°F) to prevent rebound hypothermia. Despite this, it is not unusual for dogs to develop body temperatures between 35°C and 37.8°C (95°F and 100°F) within the first few hours of hospitalization.3 If hypothermia occurs, warm water bottles or blankets may be necessary to maintain normothermia.

Cardiovascular System Severely affected dogs often are in hypovolemic shock at presentation. If cardiovascular disease is unlikely, balanced electrolyte fluids of up to

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90 ml/kg should be administered intravenously to dogs (up to 50 ml/ kg in cats); perfusion status should be assessed continuously and the rate and volume of fluids titrated to effect (see Chapter 68, Shock Fluid Therapy). Excessive volume administration should be avoided. If large doses of intravenous fluids do not improve tissue perfusion and blood pressure, administration of synthetic colloids should be considered, with or without positive inotropic or vasopressor agents (see Part VI, Fluid Therapy and Chapter 147, Catecholamines). Dogs that cannot maintain an adequate blood pressure without pressure support (for prolonged periods) have a poor prognosis. Blood pressure and physical parameters of tissue perfusion should be monitored continuously in severely affected dogs (see Chapter 181, Hemodynamic Monitoring).

Respiratory System Oxygen should be administered at presentation and should be continued until it has been determined that the dog can maintain adequate arterial oxygenation (see Chapters 16, 15 and 184, Hypoxemia, Oxygen Therapy, and Oximetry Monitoring, respectively). Serial physical assessments of the respiratory system including thoracic auscultation, observation of respiratory rate and effort, and evaluation of mucous membrane color is warranted in dogs with heat illness. More objective assessments such as arterial blood gas analysis and pulse oximetry may be required, especially in dogs with physical evidence of respiratory compromise.

Central Nervous System At presentation, a full neurologic examination, including assessment of mentation level and cranial nerve function, should be performed to establish baseline parameters. More severely affected dogs may be stuporous or comatose at presentation. Serum electrolyte levels, packed cell volume, total solids, and blood glucose measurements should be performed and abnormalities corrected as warranted. Hypoglycemia is not unusual in the severely compromised dog with heat illness. An intravenous bolus of 0.25 to 0.5 g/kg of body weight of a diluted dextrose solution should be administered if hypoglycemia is documented, and dextrose should be added to the intravenous fluids to make a 2.5% to 5% concentration if hypoglycemia is persistent (see Chapter 75, Hypoglycemia). Poor tissue perfusion should be corrected and mentation reevaluated after perfusion is improved. If mentation continues to be abnormal after these abnormalities are corrected, then cerebral edema may be present (see Chapter 85, Intracranial Hypertension). Administration of mannitol (0.5 to 1 g/kg of body weight intravenously over 20 to 30 minutes) should be considered. The head should be elevated 15 to 30 degrees above the horizontal plane of the body while avoiding compression of the jugular veins. Progression of neurologic abnormalities despite therapy carries a poor prognosis.

Renal System A urinary catheter should be inserted at presentation for monitoring urine output in more severely affected dogs. Complete urinalysis should be performed initially and serially as treatment progresses to detect early signs of renal damage such as the presence of urinary casts. Urine output should be maintained at 2 ml/kg of body weight per hour or more, depending on the amount of fluid being administered. Mean arterial pressure ideally should be at least 80 mm Hg. If urine output remains insufficient despite adequate fluid replacement and blood pressure, then measures to manage oliguria or anuria should be instituted (see Chapter 121, Acute Kidney Injury). If urine output remains inadequate and renal parameters increase, hemodialysis may be necessary (see Chapter 178, Renal Replacement Therapies). Serum sodium and potassium concentrations, total solids, BUN, acid-base status, and creatinine should be monitored every 4 to 24 hours as indicated.

Coagulation System Evaluation of the coagulation system, including measurement of prothrombin time, partial thromboplastin time, platelet count, and levels of D-dimers and fibrin split products, should be performed at presentation and as indicated during therapy. Prolonged coagulation times, decreased platelet count, and increased levels of fibrin split products or D-dimers suggest DIC (see Chapter 104, Coagulopathy in the ICU). Thromboelastography may also prove useful, if available (see Chapter 187, Viscoelastic Monitoring).

Gastrointestinal System Direct thermal damage and poor visceral perfusion and/or reperfusion may result in GI mucosal sloughing and ulceration. This leads to vomiting and diarrhea that may or may not be bloody. Sucralfate (if vomiting is not present) and histamine-2 blockers can help manage gastric ulceration (see Chapters 153 and 154, Gastrointestinal Protectants and Anti-emetics and Prokinetics, respectively). Breakdown of the mucosal barrier may result in bacteremia or endotoxemia. Broad-spectrum antimicrobial therapy should be considered in severely affected animals with bloody diarrhea. There are anecdotal reports of the development of small intestinal intussusceptions in some dogs with heat stroke.

PROGNOSIS The degree of compromise depends on the prior physical health of the dog and the degree and duration of the heat insult. An increasing number of NRBCs is associated with more severe injury and worse outcome, and a severity of disease scoring system has been developed for dogs but it requires further testing and refinement before it can be applied for research purposes and practical clinical use. Dogs with multiple organ dysfunction or severe CNS disturbances have a more guarded prognosis.3 However, many dogs with severe CNS disturbances, DIC, and other organ dysfunction live without any residual problems. Severe heat-associated illness is challenging to treat, but with aggressive medical therapy dogs may recover and do well. Because cats rarely develop heat stroke, there is little information regarding the prognosis and outcome in this species.

REFERENCES 1 . Bouchama A, Knochel JP: Heat stroke, N Engl J Med 346:1978, 2002. 2. Flourroy WS, Wohl JS, Macintire DK: Heatstroke in dogs: pathophysiology and predisposing factors, Comp Contin Educ Pract Vet 25:410, 2003. 3. Drobatz KJ, Macintire DK: Heat-induced illness in dogs: 42 cases (19761993), J Am Vet Med Assoc 209:1894, 1996. 4. Knochel JP: Catastrophic medical events with exhaustive exercise: “white collar rhabdomyolysis,” Kidney Int 38:709, 1990. 5. Moseley PL: Heat shock proteins in heat adaptation of the whole organism, J Appl Physiol 83:1413, 1997. 6. Shapiro Y, Alkan M, Epstein Y, et al: Increase in rat intestinal permeability to endotoxin during hyperthermia, Eur J Appl Physiol Occup Physiol 55:410, 1986. 7. Bruchim Y, Loeb E, Saragusty J, et al: Pathological findings in dogs with fatal heatstroke, J Comp Pathol 140(2/3):97-104, 2009. 8. Aroch I, Segev G, Loeb E, et al: Peripheral nucleated red blood cells as a prognostic indicator in heatstroke in dogs, J Vet Intern Med 23(3):544-551, 2009. 9. Segev G, Daminet S, Meyer E, et al: Characterization of kidney damage using several renal biomarkers in dogs with naturally occurring heatstroke, Vet J 206(2):213-215, 2015.

CHAPTER 139  Heat Stroke 10. Bruchim Y, Kelmer E, Cohen A, Codner C, Segev G, Aroch I: Hemostatic abnormalities in dogs with naturally occurring heatstroke, J Vet Emerg Crit Care 27(3):315-324, 2017. 11. Amsterdam JT, Syverud SA, Barker WJ, et al: Dantrolene sodium for the treatment of heatstroke victims: lack of efficacy in a canine model, Am J Med 4:399, 1986.

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12. White JD, Kamath R, Nucci R, et al: Evaporative versus iced peritoneal lavage treatment of heatstroke: comparative efficacy in a canine model, Am J Emerg Med 11:1, 1993. 13. Hadad E, Rav-Acha M, Heled Y, et al: Heat stroke: a review of cooling methods, Sports Med 34:501, 2004.

140 Drowning and Submersion Injury Lisa Leigh Powell, DVM, DACVECC

KEY POINTS • The term near drowning is no longer used; instead, drowning is used to describe any event resulting in primary respiratory impairment from submersion or immersion in a liquid medium, whether it is fatal or not. • Drowning is a leading cause of morbidity and mortality in humans. • Reports of drowning in veterinary patients are sparse.

DEFINITIONS Drowning accounts for an estimated 320,000 human deaths annually worldwide. The number is thought to be grossly underestimated, primarily due to underreporting in less developed countries. Catastrophic natural disasters such as tsunamis, hurricanes, and floods add to the number of injuries and deaths attributable to drowning events. In the United States, drowning accounted for an average of 3500–4000 deaths per year, and is the leading cause of death in children aged 1 to 4 years.1 Because of the high incidence of drowning and nonfatal drowning injury, a consensus conference was held to establish guidelines for uniform reporting of data from drowning incidents and to stratify definitions for drowning and its associated pathologic complications.2 In addition, a systematic review of 43 articles addressing the definition of drowning found 33 different definitions describing drowning incidents: 20 for drowning and 13 for near drowning.3 The Consensus Conference on Drowning published its recommended guidelines for uniform reporting of data from drowning in 2003.2 The following definitions were presented by the consensus conference for use in research and data reporting associated with drowning and nonfatal drowning: • Drowning is a process resulting in primary respiratory impairment from submersion or immersion in a liquid medium. Liquid is present at the victim’s airway, preventing respiration of air. The victim may survive or die, but regardless of outcome, the victim has been involved in a drowning incident. This is in contrast to the definition proposed by the American Heart Association in 2000, in which the term drowning was reserved for cases in which the victim died from water submersion within 24 hours of the event.4 • Dry drowning describes cases in which liquid is not aspirated into the lungs, whereas wet drowning refers to aspiration of liquid. Victims of dry drowning often experience morbidity from laryngospasm, which results in the same hypoxemic and hypercarbic state seen in those who have aspirated liquid. • It was concluded in the consensus statement that near drowning be abandoned as a term used to describe victims of submersion injury who ultimately survive because the term drowning is inclusive of

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• The primary pathophysiologic abnormality seen in drowning victims is hypoxic tissue damage due to the inability to maintain adequate pulmonary gas exchange. • Treatment is aimed at providing neuroprotective therapy, cardiovascular support, and an oxygen-rich environment. • Prognosis in humans depends on submersion time, cardiopulmonary resuscitation time, and severity of acidemia.

both survivors and nonsurvivors. The term submersion victim was proposed as an alternative to near drowning victim by the American Heart Association and still is in use.

INCIDENCE AND EPIDEMIOLOGY Humans The incidence of drowning and submersion injury remains high in humans. Drowning is the third most common cause of accidental death in humans younger than 44 years of age, with 40% of all drowning deaths reported in children younger than 5 years of age.5 Another 15% to 20% of drowning victims are between the ages of 5 and 20 years, and male victims dominate in all age groups.5 Most drownings occur in fresh water, with children younger than 1 year of age most often drowning in bathtubs, buckets, or toilets.6 Drowning occurs most often in residential swimming pools in children aged 1 to 4 years.7,8 In contrast, adolescents most often drown in rivers, lakes, and canals, and drug or alcohol use is a contributing factor in about 50% of these cases.9,10 Male individuals are thought to have a higher incidence of drowning, especially during adolescence, because of the tendency toward risky activities and overestimation of their swimming abilities.11 Factors associated with a higher risk of drowning in humans include the use of alcohol or recreational drugs, lack of supervision in children, and medical conditions such as epilepsy and long QT syndrome.12,13

Veterinary Patients There are three published reports of veterinary patients describing submersion injury. The first is a case report of a gelding that recovered from a drowning incident in which he became entangled in a safety line attached to his harness while swimming in a chlorinated swimming pool. The reported adverse effects of the incident included metabolic acidosis, hypoxemia, and pulmonary infiltrates in the dorsocaudal lung fields. Successful therapy included antibiotic administration and bronchoalveolar lavage with surfactant.14 The second publication referring to drowning in veterinary patients describes animal abuse cases in a population of dogs and cats in

CHAPTER 140  Drowning and Submersion Injury the United Kingdom. In this sample of 243 dogs and 182 cats, drowning accounted for three of the feline abuse cases.15 The third veterinary publication is a retrospective study describing freshwater submersion injury in 25 dogs and 3 cats. In this case series, ten patients died, including all three cats, and the total mortality rate was 36%. Respiratory failure was the most common cause of death.16 The pathophysiology and clinical course in veterinary patients involved in drowning incidents correlates with the human progression of injury and directs diagnostics, therapy, and outcome in canine and feline drowning victims.

PATHOPHYSIOLOGY OF INJURY Pulmonary System Drowning occurs without aspiration of water in about 10% of victims, whereas 90% aspirate fluid into the lungs.17 All submersion victims experience hypoxemia, either from laryngospasm in which no aspiration occurs or from aspiration of fluid resulting in loss of surfactant that causes atelectasis and intrapulmonary shunt. Most submersion victims (about 85%) that survive are thought to have aspirated less than 22 ml/kg of water.17 Hypoxemia in submersion victims results from intrapulmonary shunting of blood. Bronchospasm, atelectasis due to surfactant washout, aspirated water or matter in the alveolar space, infectious or chemical pneumonitis, and acute respiratory distress syndrome (ARDS) all contribute to pulmonary oxygen shunting in submersion victims.18 Submersion victims may experience both ventilation-perfusion mismatch and intrapulmonary shunt from alveolar collapse. In submersion victims that aspirate water into the alveolar space, surfactant washout causes atelectasis. Ventilation-perfusion inequality may be present in submersion victims that aspirate water or particulate matter. Readers are directed to Chapter 16, Hypoxemia, for further description of the mechanisms of lung disease.

Fluids and Electrolytes In previous years, medical researchers tried to ascertain the differences in pathologic features when drowning victims aspirated fresh water versus saltwater. It was thought that the hypertonicity of aspirated saltwater would result in an osmotic gradient into the lungs, drawing plasma water into the pulmonary interstitium and alveolar spaces. This shift of plasma water would then result in hypernatremia and a decreased circulating blood volume. In contrast, aspiration of fresh water was hypothesized to shift fluid out of the lung and into circulation, which would result in hypervolemia, hyponatremia, and dilution of other electrolytes. Studies did not support these hypotheses. One experimental study showed that the amount of aspirated water needed to cause these fluid shifts was far greater than the amount normally aspirated by drowning victims.19 In another study involving a series of 91 submersion victims, no serious fluid or electrolyte abnormalities were noted.20 The most prominent pathologic feature in victims of both fresh water and saltwater submersion injury is the washout of surfactant from the alveoli, causing atelectasis, intrapulmonary shunt, and global hypoxia, which may then result in tissue injury, neurologic damage, cardiovascular collapse, and death.

Neurologic and Cardiovascular Systems In humans, about 10% of drowning victims experience severe neurologic effects.21 Neurologic abnormalities result from hypoxia-induced brain injury, and the severity of injury is primarily dependent on the duration of hypoxia.

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Cardiac arrhythmias and dysfunction may occur in submersion victims as a result of myocardial hypoxia and ischemia, acidemia, electrolyte abnormalities, and hypothermia. Blood pressure is affected by a variety of factors, including catecholamine release, hypercarbia, and hypovolemia from traumatic blood loss during the submersion event. Hypothermia may contribute to hypovolemia caused by inhibition of antidiuretic hormone and induction of diuresis; this results from shunting of blood to core organs, which gives a perception of hypervolemia via arterial stretch receptors.18

Effect of Water Temperature Water temperature has an important effect on the survival of submersion victims. Submersion in ice-cold water (,5°C [41°F]) increases the chances of survival, in part because of the diving reflex that is present in most mammals. Within seconds after a victim’s face contacts cold water and before unconsciousness ensues, a reflex mediated by the trigeminal nerve sends impulses to the central nervous system that cause bradycardia, hypertension, and preferential shunting of blood to the cerebral and coronary circulations.5,22 This reflex acts to protect the brain and heart from hypoxia-induced injury. Hypothermia also causes a decrease in metabolic need, which protects the brain from injury. The effects of this response are evidenced by good neurologic recovery in victims submerged in icy water, despite the initial presence of coma or other negative neurologic prognostic indicators. Hypothermia in patients injured by submersion in warm water, however, is a negative prognostic sign indicating poor peripheral perfusion and longer submersion times.5

DIAGNOSTIC TESTS AND MONITORING On presentation at a hospital, airway, breathing, and circulation should be assessed immediately in the submersion victim. Body temperature should be evaluated and appropriate treatment initiated. In patients with significant neurologic impairment, therapeutic hypothermia may be beneficial in protecting the brain from further injury.23 A minimum data set, including results of a complete blood count and chemistry panel, should be collected. Arterial blood gas analysis should be performed because many submersion victims experience hypoxemia, respiratory acidosis from hypoventilation, and metabolic acidosis from hypoperfusion and tissue hypoxia. Monitoring of the drowning victim includes continuous electrocardiography; determination of respiratory rate and effort; lung auscultation; and assessment of body temperature, mentation and pupil responsiveness, Modified Glasgow Coma Score (MGCS), arterial blood pressure, serum electrolyte levels, and arterial blood gas concentrations. Continuous pulse oximetry can be used to monitor hemoglobin saturation. Thoracic radiography should be performed when the patient is able to tolerate the procedure.

TREATMENT Most human submersion victims are pulled from the water and cardiopulmonary resuscitation is attempted at the scene. Cardiopulmonary resuscitation in canine or feline patients at the scene of the accident is much more difficult to perform without proper training. The owner should wrap the pet in a blanket, perform mouth-to-nose breathing if no respirations are noted, and bring the animal to an emergency veterinary clinic as quickly as possible. Therapy for the drowning victim is aimed at improving tissue oxygenation, resolving abnormal acid-base status, maintaining tissue perfusion, and stabilizing the cardiovascular and neurologic systems. Hypoxemia and respiratory and metabolic acidosis should be treated

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as early and aggressively as possible to prevent further organ damage. Oxygen should be administered and, if indicated, the patient should be intubated and mechanically ventilated.24 Guideline criteria used in human medicine to indicate the need for intubation and mechanical ventilation include an arterial partial pressure of oxygen (PaO2) of less than 60 mm Hg or an oxygen saturation of less than 90% despite oxygen therapy, worsening hypercapnia, and severe respiratory distress suggestive of impending respiratory failure.5 See Chapter 32, Mechanical Ventilation – Core Concepts for further information. Although the initial pulmonary injury of a drowning victim can resemble ARDS, it tends to resolve far more quickly than ARDS, and later pulmonary complications are uncommon in human patients.25 High-flow oxygen therapy is a method of oxygen delivery that has been reported in the veterinary literature recently and allows for increased inspirated oxygen concentrations through higher flow rates, with the use of nasal cannulas. Because intubation is not necessary, highflow oxygen therapy has less morbidity and cost. In addition, high-flow oxygen units are easy to access, set up, and use in an ICU setting. Many patients that require increased inspired oxygen concentrations due to unresponsive hypoxemia may respond to high-flow oxygen therapy, avoiding sedation, intubation, and mechanical ventilatory therapy.26,27 Artificial surfactant has been used with some success, and experimental therapies with liquid ventilation, inhaled nitric oxide, and intratracheal ventilation may be employed.28,29 Finally, submersion victims are prone to develop pneumonia, especially if the submersion medium was grossly contaminated or aspiration of dirt or sand occurred. Antibiotic therapy ideally should be instituted following the culture of bronchoalveolar fluid obtained via bronchoscopy or endotracheal wash. However, in patients in unstable condition, prophylactic use of a broad-spectrum antibiotic should be considered. Fluid therapy is necessary in drowning victims to restore circulating volume, correct acid-base abnormalities, and improve tissue perfusion. However, excessive crystalloid administration may worsen noncardiogenic pulmonary edema and cerebral edema. Fluid therapy should be monitored with serial measurements of body weight, central venous pressure, urine output, and arterial blood pressure. Neurologic resuscitation is aimed at preventing or decreasing cerebral edema and maintaining normal intracranial pressures. Elevations in arterial partial pressure of carbon dioxide cause cerebral vasodilation, which contributes to an increase in intracranial pressure and creates the potential for cerebral edema. It is recommended that normocapnia be maintained because hyperventilation to create hypocapnia may result in cerebral vasoconstriction and impair cerebral perfusion. Hypertonic therapy such as mannitol or hypertonic saline may be used in fluid-resuscitated patients if cerebral edema is suspected and neurologic status is deteriorating. Glucocorticoid therapy is not recommended because it has not been shown to improve neurologic outcome, and the possible resultant hyperglycemia may worsen cerebral cell damage through secondary neuronal injury.30 Significant quantities of liquid can be swallowed during a drowning event, and gastric distension should be evaluated in all drowning victims. Passage of an orogastric or nasogastric tube to empty the stomach may be indicated. In the retrospective study of 25 dogs and 3 cats with submersion injury, treatment included supplemental oxygen, antimicrobials, furosemide, glucocorticoids, aminophylline, and, when indicated, assisted ventilation.16

OUTCOME In one study, three factors were associated with 100% mortality in human submersion victims younger than 20 years of age: (1) submersion

duration longer than 25 minutes; (2) resuscitation duration longer than 25 minutes; and (3) pulseless cardiac arrest on presentation at the emergency department.31 Additional factors associated with a poor prognosis included ventricular tachycardia or ventricular fibrillation (93% mortality), fixed pupils (89% mortality), severe acidosis (89% mortality), and respiratory arrest in the emergency department (89% mortality).31 Patients experiencing acute pulmonary edema had mortality rates ranging from 5% to 19%. Level of consciousness and responsiveness also correlated with survival. Deaths occurred only among victims who remained comatose after presentation to the emergency department. No deaths occurred in patients who arrived alert or depressed but responsive.32 As mentioned earlier, mortality was reported as 36% in the study of 25 dogs and 3 cats with submersion injury, with all 3 cats included in the nonsurvivor group.16 Correlation with prognosis in human submersion victims may be made, although in many instances submersion duration may not be known and prehospital therapy, including cardiopulmonary resuscitation, is usually not performed. Drowning victims with minimal neurologic, respiratory, and cardiovascular abnormalities should have better outcomes; however, intensive treatment of more seriously affected submersion victims can result in a full recovery. The ability to supply adequate inspired oxygen levels, to provide high-flow oxygen therapy or mechanical ventilation if needed, to perform serial evaluations of arterial blood gas concentrations, and to house the patient in a 24-hour intensive care setting may improve the prognosis in severely affected patients.

REFERENCES 1. Centers for Disease Control and Prevention, National Center for Injury Prevention and Control: Web-based Injury Statistics Query and Reporting System (WISQARS). Available at: https://www.cdc.gov/injury/wisqars/ index.html. Accessed 16 April, 2021. 2. Idris AH, Berg RA, Bierens J, et al: Recommended guidelines for uniform reporting of data from drowning. The “Utstein Style,” Circulation 108:2565, 2003. 3. Papa L, Hoelle R, Idris A: Systematic review of definitions for drowning incidents, Resuscitation 65:255, 2005. 4. Part 8: Advanced challenges in resuscitation. Section 3: Special challenges in ECC. 3B: Submersion or near-drowning. European Resuscitation Council, Resuscitation 46:273, 2000. 5. DeNicola LK, Falk JL, Swanson ME, et al: Submersion injuries in children and adults, Crit Care Clin 13:477, 1997. 6. Brenner RA, Trumble AC, Smith GS, et al: Where children drown, United States 1995, Pediatrics 108:85, 2001. 7. Present P: Child drowning study. A report on the epidemiology of drowning in residential pools to children under age five, Washington, DC, 1987, Consumer Product Safety Commission. 8. Wintemute GJ, Kraus JF, Teret SP, et al: Drowning in childhood and adolescence: a population-based study, Am J Public Health 77:830, 1987. 9. Orlowski JP: Drowning, near-drowning, and ice-water submersions, Pediatr Clin North Am 34:75, 1987. 10. Howland J, Hingson R: Alcohol as a risk factor for drownings: a review of the literature (1950-1985), Accid Anal Prev 20:19, 1988. 11. Howland J, Hingson R, Mangione TW, et al: Why are most drowning victims men? Sex differences in aquatic skills and behaviors, Am J Public Health 86:93, 1996. 12. Besag FMC: Tonic seizures are a particular risk factor for drowning in people with epilepsy, BMJ 322:975, 2001. 13. Yoshinaga M, Kamimura J, Fukushige T, et al: Face immersion in cold water induces prolongation of the QT interval and T wave changes in children with nonfamilial long QT syndrome, Am J Cardiol 83:1494, 1999. 14. Humber KA: Near drowning of a gelding, J Am Vet Med Assoc 192:377, 1988.

CHAPTER 140  Drowning and Submersion Injury 15. Munro HMC, Thrusfield MV: “Battered pets”: nonaccidental physical injuries found in dogs and cats, J Small Anim Pract 42:279, 2001. 16. Heffner GG, Rozanski EA, Beal MW, et al: Evaluation of freshwater submersion in small animals: 28 cases (1996-2006), J Am Vet Med Assoc 232:244-248, 2008. 17. Modell JH: Drowning, N Engl J Med 328:253, 1993. 18. Burford AE, Ryan LM, Stone BJ, et al: Drowning and near-drowning in children and adolescents. A succinct review for emergency physicians and nurses, Pediatr Emerg Care 21:610, 2005. 19. Modell JH: Serum electrolyte changes in near-drowning victims, JAMA 253:557, 1995. 20. Modell JH, Graves SA, Ketover A: Clinical course of 91 consecutive neardrowning victims, Chest 70:231, 1976. 21. Quan L: Near-drowning, Pediatr Rev 20:255, 1999. 22. Levin DL, Morris FC, Toro LO, et al: Drowning and near-drowning, Pediatr Clin North Am 40:321, 1993. 23. Williamson JP, Illing R, Gertler P, et al: Near-drowning treated with therapeutic hypothermia, Med J Aust 181:500, 2004. 24. Szpilman D, Bierens JJ, Handley AL, et al: Drowning, N Engl J Med 366:2102, 2012. 25. Gregorakos L, Markou N, Psalida V, et al: Near-drowning: clinical course of lung injury in adults, Lung 187:93, 2009.

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26. Keir I, Daly J, Haggerty J, Guenther C: Retrospective evaluation of the effect of high flow oxygen therapy delivered by nasal cannula on PaO2 in dogs with moderate-to-severe hypoxemia, J Vet Emerg Crit Care 26(4):598-602, 2016. 27. Jagodich TA, Bersenas AME, Bateman SW, Kerr CL. Comparison of high flow nasal cannula oxygen administration to the traditional nasal cannula oxygen therapy in healthy dogs, J Vet Emerg Crit Care 29(3):246-255, 2019. 28. Norberg WJ, Agnew RF, Brunsvold R, et al: Successful resuscitation of a cold water submersion victim with the use of cardiopulmonary bypass, Crit Care Med 20:1355, 1992. 29. Möller JC, Schaible TF, Reiss I, et al: Treatment of severe nonneonatal ARDS in children with surfactant and nitric oxide in a “pre-ECMO” situation, Int J Artif Organs 18:598, 1995. 30. Arensman RM, Satter MB, Bastawrous AL, et al: Modern treatment modalities for neonatal and pediatric respiratory failure, Am J Surg 172:41, 1996. 31. Burkhead SR, Lally KP, Bristow F, et al: Intratracheal pulmonary ventilation provides effective ventilation in a near-drowning model, J Pediatr Surg 31:337, 1996. 32. Gabrielli A, Layon AJ: Drowning and near-drowning, J Fla Med Assoc 84:452, 1997.

PART XVII  Miscellaneous Disorders

141 Anaphylaxis Medora Pashmakova, DVM, DACVECC

KEY POINTS • Anaphylaxis is a severe, systemic, potentially fatal type I hypersensitivity reaction that may occur secondary to a variety of antigens, including insect stings, foods, vaccines, drugs, and venoms. • In dogs, signs of gastrointestinal compromise, hepatic congestion, and portal hypertension predominate. In cats, acute respiratory distress, airway edema, and bronchial secretions may be more prominent.

• Because the history and inciting event are often nonspecific, the emergency clinician should develop pattern recognition for anaphylactic syndrome. • Emergent treatment of life threatening cases can include epinephrine, antihistamines, fluid therapy and vasoactive drugs.

There is no consensus regarding the definition of anaphylaxis. A common description is a severe and potentially fatal systemic manifestation of acute hypersensitivity.1 Another definition in human medicine describes it as an acute onset of illness with involvement of skin, mucosal tissue, or both, with either respiratory compromise, reduced blood pressure, or symptoms of end organ damage.2 Anaphylaxis remains widely underrecognized and underreported in human medicine due to the lack of specific diagnostic criteria. Its recognition is equally challenging in veterinary medicine, where the concentration of mast cells and clinical signs of histamine release differ between species. Because a specific diagnostic test for anaphylaxis is not readily available and delay in treatment can be fatal, the clinician must use a combination of clinical suspicion and supportive diagnostic tools to reach a presumptive diagnosis and institute emergency treatment.

high-affinity Fc-epsilon-R1 receptors located on tissue mast cells and circulating basophils. Upon reexposure, the same antigen binds and cross-links two cell-bound IgE antibodies, resulting in a conformation change, calcium influx, second messenger system activation, and release of preformed as well as newly formed mediators. The genetic predisposition to produce IgE following exposure to antigens is known as atopy, and these individuals are at risk for hypersensitivity responses.1 Non-IgE immune-mediated mechanisms of anaphylaxis are not as well understood, and several mechanisms of mast cell activation have been proposed, including complement anaphylatoxin activation, immune complex generation, IgG-mediated mechanisms, neutrophilrelated events, and T-cell activation.10,11 Many of these mechanisms will require initial sensitization, and anaphylaxis occurs on repeat exposure to the antigen. There is little research in this area that is specific to dogs and cats. Nonimmune-mediated anaphylaxis can occur from direct stimulation of mast cell degranulation by physical factors such as heat and cold or exposure to some pharmaceutical agents. These mechanisms do not require sensitization and can occur on the first exposure to the insult.1 All mechanisms of anaphylaxis result in immune cell activation, in particular mast cells, basophils, and neutrophils. Mast cell degranulation releases numerous mediators including histamine, tryptase, heparin, and cytokines. Histamine is the best-known mediator of anaphylaxis, but it is important to recognize that a number of other inflammatory and vasoactive substances also play a role. Prostaglandins result in added constriction of coronary and bronchial smooth muscle, whereas leukotrienes and slow-reacting substances of anaphylaxis have a longer time to onset and longer duration of action, modulating the delayed phase. The coagulation system is involved in multiple ways, both due to the heightened inflammatory state of the system,

MECHANISMS OF ANAPHYLAXIS Anaphylaxis in dogs and cats has been reported secondary to vaccines, foods, bee venom, parasite death, snake venom, blood products, drugs, and environmental factors such as exercise and hypothermia.3-8 The former nomenclature of anaphylactic (immunoglobulin E [IgE]-mediated) and anaphylactoid (non-IgE-mediated) reactions has fallen out of favor due to the clinically identical presentation. Currently, anaphylactic reactions are classified as immune-mediated (insect and reptile bites/stings, food, transfusion reactions) and nonimmune-mediated (physical factors such as exercise and extreme temperatures).9 Medications have the potential to trigger anaphylaxis through both immune- and nonimmune-mediated mechanisms.1 The classic immune-mediated mechanism for anaphylaxis is an IgE-mediated event that requires an initial, clinically silent sensitization to an antigen. The subsequent IgE antibodies produced bind to

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CHAPTER 141  Anaphylaxis

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as well as directly with the release of platelet activating factor, which has many effects such as bronchoconstriction, increased vascular permeability, vasodilation, and platelet aggregation.11 Combined with the presence of tryptase, a powerful molecule that activates complement, the patient with severe anaphylaxis is primed for multiorgan dysregulation and disseminated intravascular coagulation. Interestingly, heparin is also contained in mast cells, which can result in a hypocoagulable state in some patients with anaphylaxis.

Histamine has other broad-reaching activities, such as mediating pruritus and stimulating gastric acid secretion. Because of the considerable mast cell distribution in the gastrointestinal mucosa, anaphylaxis can also be triggered by ingested food items, as is known to occur in people and has recently been documented in dogs.13,14

HISTAMINE

The mediators of anaphylaxis lead to smooth muscle contraction, increased vascular permeability, and vasodilation and impact the cutaneous, gastrointestinal, respiratory, and cardiovascular systems primarily. The clinical presentation of anaphylaxis will reflect abnormalities in one or more of these organ systems. Anaphylaxis occurs rapidly, with clinical signs within 30 minutes of antigen exposure and progression over the next minutes to hours. Due to differences in density and distribution of inflammatory cells and smooth muscle cells, the clinical response can differ by species. In the dog, the gastrointestinal tract and portal circulation are the primary organs affected, whereas in cats both respiratory and gastrointestinal signs are commonly reported. Severe anaphylaxis in either species can result in circulatory shock. Cutaneous manifestations of anaphylaxis can include urticaria, pruritus, and angioedema (Fig. 141.1A–B). Cutaneous signs are not always present with anaphylaxis, but evidence of cutaneous signs with systemic abnormalities should prompt clinicians to consider anaphylaxis as a possible cause. Gastrointestinal signs include abdominal pain, vomiting, and diarrhea. In dogs, histamine alters circulatory flow to and from the liver, resulting in arterial vasodilation and simultaneous venous congestion. This leads to significant portal hypertension, transudation of fluid, and decreased return of volume to the heart. Laboratory abnormalities may show an increase in alanine transaminase (ALT) in circulation,15 while brief ultrasound evaluation of the abdomen may show hepatic venous congestion, free fluid (which may be transudate or hemorrhage), and commonly the appearance of gallbladder wall thickening or halo sign (see Fig. 141.2).15 It is important to recognize that because of the broad systemic response to histamine, anaphylactic shock in

Histamine remains the primary mediator of anaphylaxis. It is important to note that mast cells distributed along mucosal surfaces mediate the histamine response from multiple routes of exposure, most commonly the dermal, enteral, or inhalational routes, though parenteral drug administration may also result in rapid histamine release. The diverse biological effects of histamine are mediated by G-protein coupled receptors H1–H4, whose potency and distribution vary between organ systems and between species.12 The H1 receptor activates smooth muscle contraction and endothelial changes resulting in vasodilation and increased vascular permeability. The H2 receptor is best known for modulating gastric acid secretion and regulation of cardiac myocytes. The less well-known H3 and H4 receptors are involved in peripheral and central neurotransmitter release, respectively, as well as mediating the immune response.12 The systemic release of histamine can, therefore, involve extreme responses from multiple organ systems. Cardiovascular collapse during anaphylaxis is characterized by the predominance of vasodilatory shock; however, due to the integral role of histamine in cardiac function, cardiogenic shock, dysrhythmias, and evidence of cardiac ischemia may also be present. Both peripheral and central release of vasoactive substances such as dopamine and norepinephrine is compromised during anaphylaxis, further perpetuating signs of shock. Respiratory signs can be particularly prominent in species (such as cats) in which the airways are equipped with a high density of mast cells. Similar to the cardiovascular system, histamine release causes smooth muscle contraction, bronchospasm, and mucus secretion and edema formation.

A

CLINICAL MANIFESTATIONS

B

Fig. 141.1  Images of cutaneous manifestations of anaphylaxis. A, Dog with angioedema of the face. B, Urticaria of the ventral abdomen.

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Acute onset of cutaneous signs AND • Respiratory compromise OR • Hypotension/collapse OR Exposure to likely allergen and two or more of the following: 1. Cutaneous signs 2. Respiratory compromise 3. Hypotension/collapse 4. Gastrointestinal signs

OR

Hypotension after exposure to known allergen

Fig. 141.2  Ultrasonographic appearance of gallbladder wall edema that can be evident in patients with anaphylaxis.

dogs may be a combination of vasodilatory, hypovolemic, and cardiogenic in nature. Respiratory signs of anaphylaxis are attributed to bronchoconstriction, increased airway secretions, and possibly laryngeal edema (see Chapters 18 and 20). Radiographic signs of noncardiogenic pulmonary edema may accompany anaphylaxis if respiratory signs are present.16 As previously mentioned, cardiovascular collapse can occur (anaphylactic shock) and is due to a combination of vasodilation, hypovolemia subsequent to increased vascular permeability, and possibly myocardial dysfunction. In rare cases, a patient may exhibit an initial improvement and then relapse, or “biphasic” anaphylaxis.9 Biphasic reactions have been reported to occur in 1% to 20% of human anaphylaxis patients, but the prevalence in veterinary patients is unknown. Biphasic reactions have not been associated with mortality in human patients and most commonly manifest as cutaneous and/or respiratory signs in hours to days after an initial acute anaphylactic event.17,18 Based on the author’s clinical experience, several other differentials should exist in the clinician’s mind when triaging a patient with suspected anaphylaxis: heat stroke, disseminated mast cell disease, pericardial effusion with tamponade, acute hemoabdomen, and sago palm toxicity may have overlapping signs (and should be gleaned more or less likely from the history and triage examination). A thorough search for a septic focus is also recommended based on similarities in clinical signs and laboratory values in some patients and the subsequent marked differences in treatment.19

DIAGNOSIS Diagnosis of anaphylaxis largely depends on pattern recognition. Information regarding recent or previous exposures to foods or medications, change in surroundings, or possibility of insect stings should be noted. The sudden onset of characteristic signs and organ systems involved for that species should raise the level of suspicion. Anaphylaxis is much less commonly reported in cats, and the veterinary literature has only scant information on signs and causes in this species. Anaphylaxis should be suspected in cats where acute respiratory and/or gastrointestinal signs, especially after recent exposure to a vaccine, medication, or food has taken place. An attempt at standardized criteria exists

Fig. 141.3  Diagnostic criteria for anaphylaxis in dogs and cats.

in human medicine, which may be applicable to veterinary species.20 See Fig. 141.3 for proposed criteria for the diagnosis of anaphylaxis in dogs and cats. Easily obtained biomarkers for anaphylaxis in veterinary species include serum chemistry values to evaluate liver enzyme activity and function as well as brief triage ultrasound examination of the chest and abdomen to exclude pericardial effusion and discern presence of gallbladder wall changes. A recent study documented 85% and 98% sensitivity and specificity for increased ALT and 93% and 98% sensitivity and specificity for gallbladder wall abnormalities in dogs suspected of having anaphylaxis.15 The author also obtains bedside clotting times (prothrombin time and activated partial thromboplastin time) in patients with severe liver enzyme increases, liver dysfunction, or evidence of bleeding/hemoabdomen. Bee sting envenomation should be suspected in patients with laboratory changes and clinical signs suggestive of acute hypocoagulability and liver dysfunction.

TREATMENT Emergency treatment should be instituted in all patients who meet clinical suspicion for anaphylaxis due to the potential for rapid deterioration. Epinephrine is considered an essential drug for the treatment of anaphylaxis by the World Allergy Oganization.1 Specifically, its a1-receptor activity results in vasoconstriction, ameliorating the vasodilatory shock state and improving blood pressure and coronary flow. Epinephrine induced vasoconstriction also stabilizes and relieves upper airway obstruction and mucosal edema. Its b1-receptor-mediated activity results in positive inotropy, chronotropy, and improvement in cardiac output, while its b2-receptor activity results in bronchodilation and stabilization of mast cells, preventing further degranulation and release of mediators of anaphylaxis. Based on these specific pharmacologic mechanisms of epinephrine as they pertain to the pathophysiology of anaphylaxis, it remains the central drug for its management. Initial intramuscular (IM) administration of epinephrine at a dose of 0.01 mg/kg may be used, followed by a continuous rate IV infusion of 0.05 µg/kg/min (titrated to the effective dose), which has been

CHAPTER 141  Anaphylaxis

TABLE 141.1  Suggested Treatment for

Anaphylaxis in Dogs and Cats Treatment Oxygen

Details Flow by for all patients until stabilized. Ongoing oxygen therapy for patients with respiratory compromise

IV catheter

All patients

IV fluid administration (isotonic crystalloids)

As indicated for treatment of hypovolemia. Initial dose: Dogs: 30 ml/kg dogs Cats: 10 ml/kg

Epinephrine

0.01 mg/kg IM or IV 0.05 mg/kg/min CRI

Diphenhydramine

Dogs: 1–4 mg/kg IM Cats: 0.5–2 mg/kg IM

Dexamethasone

0.1 mg/kg IV Note: dexamethasone is not indicated for the primary treatment of acute anaphylaxis

Bronchodilation (as needed with respiratory compromise/bronchoconstriction)

Albuterol two puffs via AeroKat inhaler Terbutaline 0.01 mg/kg IM or IV

CRI, constant rate infusion; IM, intramuscular.

shown to be superior in the treatment of anaphylaxis in dogs (Table 141.1).21 In animals with severe hypotension, initial IV epinephrine bolus maybe indicated. Due to the short half-life of parenteral vasopressors, epinephrine infusions must not be discontinued at any time (during nursing care, owner visits, etc.). Antihistamines may be used in conjunction with, but not in place of, epinephrine. There is a lack of data to support that antihistamines alone can control or prevent anaphylaxis. Antihistamines may, however, be used to relieve pruritus, lacrimation, and erythema, and there is no evidence that their use worsens outcomes.22 Diphenhydramine, an H1-receptor blocker, can be given in the acute stabilization period of anaphylaxis (Table 141.1). Some controversy exists around the use of glucocorticoids in anaphylaxis, though overall, they continue to be used frequently in the treatment of both nonanaphylactic and anaphylactic allergic reactions. Because glucocorticoids’ onset of action is hours after administration, they should not be considered a first-line drug for the management of anaphylaxis; rather, they downregulate the late-phase eosinophilic response and block the arachidonic acid cascade, tempering delayed inflammatory cascades.9 A 2012 Cochrane review could not find evidence to support the use of glucocorticoids in anaphylaxis, and they are not recommended as empiric therapy in the current human guidelines for treating the symptoms of severe anaphylaxis.23,24 If glucocorticoids are administered, antiinflammatory (not immunosuppressive) doses are recommended, such as 0.1 mg/kg intravenous dose of dexamethasone, which may be followed by a short tapering course of oral prednisone if needed (Table 141.1). Because of the absence of evidence that antihistamines prevent biphasic response and the limited evidence for the prolonged use of glucocorticoids beyond the immediate period, recommendations are difficult to make. Anecdotally, the author will use a 3-day course of antihistamines and/or tapering oral glucocorticoids in select patients (those with previous history of allergies, severe manifestations of histaminergic signs, respiratory signs, brachycephalic conformation, as examples).

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Treatment of circulatory shock by optimizing oxygen delivery with intravascular volume replacement and supplemental oxygen, especially in patients with respiratory signs, should take place concurrently to pharmacologic treatment. Balanced crystalloid solutions at 30 ml/kg partial shock dose boluses should be rapidly administered to dogs (~10 ml/kg in cats). Ongoing gastrointestinal losses may be significant, and vigilant fluid rate reassessment is recommended to keep up, especially in the first 12–24 hours. The use of synthetic colloids or blood products is largely unnecessary, except in patients with clinical signs of bleeding and documented hypocoagulability. Continual evaluation of blood pressure is essential and vasopressor support should be provided as necessary (see Chapter 6, Classification and Initial Management of Shock States). If respiratory distress does not respond to oxygen therapy and epinephrine administration, intubation and mechanical ventilation are indicated. Emergency intubation is indicated if severe upper airway obstruction is evident. In select patients, readiness for the provision of temporary tracheotomy and bypassing the upper airways may be needed. Additional measures to support gastrointestinal mucosal health with parenteral proton pump inhibitors (such as pantoprazole 1 mg/ kg IV q12-24h) is reasonable in patients with anaphylaxis, gastrointestinal compromise, and vasopressor support and may decrease gastrointestinal blood flow. Supportive care of any organ dysfunction that develops is essential, as with all critically ill patients.

Short-Term Considerations Patients with anaphylaxis should be hospitalized for a minimum of 24–48 hours for stabilization, ongoing supportive therapies aimed at volume status, cardiovascular stability, and gastrointestinal and respiratory support. The weaning of epinephrine constant rate infusions may be planned over 6–12 hours as patient stability dictates: faster if signs of tachyarrhythmias or systemic hypertension manifest and slower if vasodilation and hypotension recur. Daily monitoring of laboratory parameters and serial brief ultrasound scans should be performed to assess progress or resolution of hepatic/gallbladder changes and/or abdominal effusion. In some cases, ALT values dramatically increase at 24 hours, requiring sample dilution for accurate measurement. In dogs with documented hypocoagulability and clinical signs of bleeding or onset of liver dysfunction, transfusion with fresh frozen plasma may be necessary. A recent case report of spontaneous hemoabdomen following bee sting envenomation supports the need for serial monitoring of hemorrhage secondary to both venom and anaphylaxis mediators.23 In this report, initial prothrombin time/ activated partial thromboplastin time values were normal, and the patient recovered without the need for blood product administration.

Long-Term Considerations Multiple organ systems may be affected by anaphylaxis in the short and long term. It is advisable to confirm that laboratory values return to baseline within 1–2 weeks of the acute event, specifically in regards to liver enzyme activity and liver and kidney function. Persistent increases in ALT, even if mild, should raise suspicion for ongoing inflammation or damage. A recent case report documented acute kidney injury in a dog with mild chronic kidney disease (CKD) who was envenomated by 10 bees. Though this patient survived, the CKD progressed in International Renal Interest Society stage within a few months after hospitalization.26 Autoimmune disease may also be a sequela of a dysregulated allergic response, and a connection should be suspected in patients who develop hematologic autoimmune disease such as immune-mediated hemolytic anemia or immune-mediated thrombocytopenia following anaphylaxis.27

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Owners should be advised that recurrence of anaphylaxis is possible, since the inciting allergen is not always identified. In cases where patients that suffered an episode of severe anaphylaxis live far from emergency veterinary care or the owners have a medical background, the author has either prescribed commercial epinephrine autoinjectors (adult 0.3 mg autoinjectors for dogs ~30 kg or heavier, pediatric 0.15 mg autoinjectors for small to medium dogs), or specifically made a dose-specific (0.01 mg/kg) epinephrine injection in a light-protected syringe for home use, being mindful that the shelf-life of this is considered only 2–3 months compared with the more expensive but longer lasting commercial autoinjectors. Owners may be instructed how to administer this IM in the pelvic limb, similarly to how autoinjectors are used in people, in the event of suspected anaphylaxis at home or while en route to a veterinary facility. Because of the potential for an owner to be bitten during injection attempts, clinicians should consider the risk–benefit ratio of this option given the severity of anaphylaxis, distance from an emergency veterinary facility, and the comfort level/medical aptitude of the owner.

REFERENCES 1. Simons FE, Ardusso LR, Bilo MB, et al: World Allergy Organization anaphylaxis guidelines: summary, J Allergy Clin Immunol 1277(3):587-593, 2011. 2. Sampson HA, Muñoz-Furlong A, Campbell RL, et al: Second symposium on the definition and management of anaphylaxis: summary report–second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium, Ann Emerg Med 47(4):373-380, 2006. 3. Cohn LA, Kerl ME, Lenox CE, et al: Response of healthy dogs to infusions of human serum albumin, Am J Vet Res 68:657-663, 2007. 4. Hume-Smith KM, Groth AD, Rishniw M, et al: Anaphylactic events observed within 4 h of ocular application of an antibiotic-containing ophthalmic preparation: 61 cats (1993-2010), J Feline Med Surg 13:744-751, 2011. 5. Thomas E, Mandell DC, Waddell LS: Survival after anaphylaxis induced by a bumblebee sting in a dog, J Am Anim Hosp Assoc 49:210-215, 2013. 6. Carter JE, Chanoit G, Kata C: Anaphylactoid reaction in a heartworm-infected dog undergoing lung lobectomy, J Am Vet Med Assoc 238:13011304, 2011. 7. Biddick AA, Bacek LM, Taylor AR: A serious adverse event secondary to rapid intravenous levetiracetam injection in a dog, J Vet Emerg Crit Care 28(2):157-162, 2018. 8. Gershwin LJ: Adverse reactions to vaccination: from anaphylaxis to autoimmunity, Vet Clin North Am Small Anim Pract 48:279-290, 2018. 9. Reber LL, Hernandez JD, Galli SJ: The pathophysiology of sepsis, J Allergy Clin Immunol 140(2):335-348, 2017.

10. Peavy RD, Metcalf DD: Understanding the mechanisms of anaphylaxis, Curr Opin Allergy Clin Immunol 8(4):310-315, 2008. 11. Shmuel DL, Cortes Y: Anaphylaxis in dogs and cats, J Vet Emerg Crit Care 23(4):377-394, 2013. 12. Peters LJ, Kovacic JP: Histamine: metabolism, physiology, and pathophysiology with applications in veterinary medicine, J Vet Emerg Crit Care 19(4):311-328, 2009. 13. Rostaher A, Fischer NM, Kummerle-Fraune C, et al: Probably walnut-induced anaphylactic reaction in a dog, Vet Dermatol 28:251-e66, 2017. 14. Rostager A, Hofer-Inteeworn N, Kummerle-Fraune C, et al: Triggers, risk factors and clinico-pathological features of urticarial in dogs – a prospective observational study of 24 cases, Vet Dermatol 28:38-e9, 2017. 15. Quantz JE, Miles MS, Reed AL, et al: Elevation of alanine transaminase and gallbladder wall abnormalities as biomarkers of anaphylaxis in canine hypersensitivity patients, J Vet Emerg Crit Care 19(6):536-544, 2009. 16. Bouyssou S, Specchi S, Desquilbet L, et al: Radiographic appearance of presumed noncardiogenic pulmonary edema and correlation with the underlying cause in dogs and cats, Vet Radiol Ultrasound 58(3):259-265, 2017. 17. Rohacek M, Edenhofer H, Bircher A, Bingisser R: Biphasic anaphylactic reactions: occurrence and mortality, Allergy 69(6):791-797, 2014. 18. Pourmand A, Robinson C, Syed W, Mazer-Amirshahi M: Biphasic anaphylaxis: a review of the literature and implications for emergency management, Am J Emerg Med 36:1480-1485, 2018. 19. Walters AM, O’Brien MA, Selmic LA, et al: Comparison of clinical findings between dogs with suspected anaphylaxis and dogs with confirmed sepsis, J Am Vet Med Assoc 251:681-688, 2017. 20. Lieberman P, Nicklas MD, Oppenheimer J: The diagnosis and management of anaphylaxis practice parameter: 2010 update, J Allergy Clin Immunol 126(3):477-480, 2010. 21. Mink SN, Simons FE, Simons KJ, et al: Constant infusion of epinephrine, but not bolus treatment, improves hemodynamic recovery in anaphylactic shock in dogs, Clin Exp Allergy 34(11):1776-1783, 2004. 22. Sheikh A, Ten Broek V, Brown SG, et al: H1-antihistamines for the treatment of anaphylaxis: Cochrane systematic review, Allergy 62(8):830-837, 2007. 23. Choo KJL, Simons FER, Sheikh A: Glucocorticoids for the treatment of anaphylaxis, Cochrane Database Syst Rev 4:CD007596, 2012. 24. Shaker MS, Wallace DV, Golden DBK, et al: Anaphylaxis – a 2020 practice parameter update, systematic review, and grading of recommendations, assessment, development and evaluation (GRADE) analysis, J Allergy Clin Immunol 145(4):1082-1123, 2020. 25. Caldwell DJ, Petras KE, Mattison BL, et al: Spontaneous hemoperitoneum and anaphylactic shock associated with Hymenoptera envenomation in a dog, J Vet Emerg Crit Care 28(5):476-482, 2018. 26. Buckley GJ, Corrie C, Bandt C, et al: Kidney injury in a dog following bee sting-associated anaphylaxis, Can Vet J 58:265-269, 2017. 27. Nakamura RK, Fenty RK, Bianco D: Presumptive immune-mediated thrombocytopenia secondary to massive Africanized bee envenomation in a dog, J Vet Emerg Crit Care 23(6):652-656, 2013.

142 Gas Embolism Bonnie Wright, DVM, DACVAA

KEY POINTS • Air embolism occurs when a pocket of gas enters or is formed within the vascular compartment and subsequently causes an obstruction to blood flow. • Intravenous catheter placement and use, pressurized fluid pumps, laparoscopy, some surgeries, biopsies, and hyperbaric therapies can all be associated with this complication.

• Transesophageal echocardiography is the most sensitive tool for detection of air embolism, but capnography, blood gas analysis, and evaluation for newly arising heart murmurs may also be useful. • Oxygen administration is recommended after air embolism. Manual reduction involves aspirating the air from the embolus or reducing the size of the air bubble to restore limited perfusion around the bubble.

Because most veterinary patients do not scuba dive, air embolism is almost entirely an iatrogenic phenomenon in veterinary medicine. Simple procedures such as intravenous injection have the potential to cause this calamity, as do more complicated techniques gaining popularity in veterinary medicine such as laparoscopy, bronchoscopy and hyperbaric therapies. The size of bubble, rate of intravenous gas entry, and physiologic status of the patient combine to determine the severity of the pathophysiology. As small amounts of air enter into the venous circulation, the air will lodge either in the right atrium or pulmonary artery in a gravitydependent location (air weighs less than blood so it “floats” in a direction opposite to gravity). Smaller air emboli wedge into pulmonary vessels, creating ventilation–perfusion mismatching and pulmonary hypertension. Paradoxically, even in the absence of a visible anatomic shunt from the right to left side of the heart (such as in a patent foramen ovale or septal defect), air emboli may gain entry to the systemic circulation, where they wreak havoc by blocking blood flow and creating hypoxia in critical organs. The cerebral vasculature and coronary artery are vulnerable locations, and emboli in these locations have the most severe consequences. With a continuous influx of air, small emboli coalesce into larger air pockets leading to massive air embolism. Massive air embolism in the heart creates an absolute obstruction to blood flow. The compressible envelope of air contracts and expands with the working of the heart, and no blood gains entry into the airfilled right ventricle, which leads to cardiac failure and arrest. Because the heart is full of air, resuscitation using standard cardiopulmonary resuscitation techniques is not usually successful. When an embolus is discrete enough to allow circulation to persist, gas is absorbed into the tissues, which eventually reduces the volume of the embolus until it is completely dissolved or small enough to move to a more distal tissue bed. For this reason, the type of gas present in the bubble can have a tremendous impact on the amount of ischemia, as does the tissue bed in which the bubble becomes lodged. Administration of extremely insoluble gases (such as nitrous oxide) exacerbates gas emboli because the insoluble gas escapes from the blood supply and diffuses into the air pockets, causing expansion.1 Therefore, if an air embolus is suspected in any patient undergoing anesthesia or sedation with the use of nitrous oxide, it should be immediately discontinued.

Nitrous oxide should be avoided altogether in procedures that are more commonly associated with air embolism, such as laparoscopy and cardiopulmonary bypass. Redundant blood flow salvages the lungs from significant damage from many smaller air emboli, and the lungs serve as the primary sponge for venous air emboli. A constant influx of air can overload this “filter” for emboli, however, allowing bubbles to emerge into the arterial system. In dogs, this occurs in 50% of animals when 0.35 ml/kg/min of air (consisting of primarily nitrogen, an insoluble gas) is infused.2 Furthermore, lodging of air emboli in the lungs is not necessarily benign and may cause focal injury, edema, and the subsequent release of vasoactive mediators. Eventually this can culminate in alveolar collapse, atelectasis, and impaired gas exchange.3 The vascular changes are prevalent with nitrogen emboli and can include platelet activation, complement response, leukocyte adhesion, and endothelial cell damage, which appear to be mediated by mitochondrial dysfunction.4

GAS EMBOLIZATION ASSOCIATED WITH INTRAVENOUS ACCESS Anytime a vein is breached, there is the opportunity to introduce air into the venous system. In most circumstances, the amount of air available to be introduced is limited by normal medical practice. Exceptions may occur with use of pressurized fluid systems (especially when pressurized bags are used rather than pumps) or continuous air leaks. In ordinary-sized patients, small bubbles inadvertently injected are unlikely to achieve a large enough volume to create a clinically apparent embolism. For example, pigs have tolerated 2 ml/kg of air without irreversible hemodynamic collapse.1 Furthermore, pigs have a reduced ability to remove air during infusions compared with dogs, so dogs may be even more tolerant of small amounts of air introduced through IV catheters. An air delivery rate of only 0.1 ml/kg/min was associated with bubbles breaking through to the arterial system in pigs, whereas dogs tolerated up to three times higher rates of air delivery.5 Extrapolating from the pig single-dose data, a 1-kg dog could probably tolerate more than 2 ml of air as a single dose before cardiovascular collapse occurred, and a 20 kg dog would require more than 40 ml of air.

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Factors that increase the risk of air embolism include use of a venous access site at a level that is gravitationally higher than the heart. This can occur in standing dogs and cats during jugular catheterization or puncture, or when ear catheters are used. This has also been reported in lateral recumbency, although the rate of air entry is reduced due to reduced vertical distance above the heart. Nonetheless, great care should be taken when placing jugular catheters in very small patients, as unnoticed entrainment of air could accumulate and rapidly prove fatal. In larger dogs and cats, embolization generally occurs when elevated catheters are left open to room air or become disconnected from a sealed system. Air moves into the relatively negative intravascular space, causing air entrainment with subsequent coalescence into a complete venous or cardiac obstruction. Because this usually occurs in patients in room air, the bulk of the embolus is composed of nitrogen gas. Nitrogen is more dangerous than several of the other gases (such as oxygen or carbon dioxide) as it is relatively poorly soluble in tissues, so it takes several minutes for a nitrogen embolus to dissipate.6 This is one of the many reasons to always have catheterized patients under surveillance at all times. Small air bubbles are often administered during intravenous injections and fluid therapy, but these are well tolerated in normal individuals. However, larger volumes of air may be mistakenly administered via intravenous tubing or extension sets that were not appropriately primed before use. Standard intravenous tubing holds more than 10 ml, and a standard extension set holds 4 ml, which is enough air as a bolus to cause arrest in a 5-kg or 2-kg animal, respectively. Air emboli have also been known to occur when intravenous fluid bags are placed under pressure using a compression sleeve or fluid pump.7 Collapsible intravenous fluid bags may contain a variable amount of air, which can be delivered when the entire contents of the bag are pressurized for rapid administration to a patient.8 However, they are safer than rigid bottles for fluid administration, which have unlimited access to room air (in order to prevent vacuum formation as fluids are given) and can thus result in a continuous leak.9 When collapsible bags are pressurized with a fluid pump, there is added safety. Most modern fluid pump systems that infuse fluids under pressure have air detection or elimination capacity that is fairly effective.10 Although typical patients can tolerate a fairly large amount of air, increased caution is warranted in individuals with a right-to-left cardiac shunt. In these individuals the air may not circulate to the lungs, so they cannot filter out air bubbles. Rather these small bubbles will immediately enter the arterial system, where they are far more damaging. Consequently, these individuals may experience focal cerebral or coronary infarcts when even the smallest air bubbles are administered or allowed to form.

GAS EMBOLIZATION DURING SCOPING PROCEDURES Laparoscopy has gained enormous popularity as a less invasive method to diagnose or manage many conditions. However, visualization of organs requires the introduction of a sizeable volume of gas into the body cavity of interest. When this gas exists at a pressure midway between venous collapse and the intravenous pressure, it is then free to move into the vascular bed servicing the inflated region. To minimize the impact of gas bubble formation during laparoscopy, carbon dioxide is generally chosen as the inflation gas. Carbon dioxide is highly soluble in tissues, and so air bubbles of carbon dioxide rapidly resolve. For comparison with the reported volumes of nitrogen required to cause fatalities in dogs, when carbon dioxide is used as the carrier gas,

a dose of 300 ml was the mean dose to cause death for a 35-kg dog.11 Carbon dioxide can still form emboli, but because it is absorbed rapidly into tissues, it seldom causes clinical problems (0.001% to 0.59% incidence in humans).12 Carbon dioxide has an additional advantage over nitrogen: it does not produce bronchoconstriction or changes in pulmonary compliance to the same degree as nitrogen. With the advent of transesophageal echocardiography for diagnosis of air emboli, it has become evident that a far greater number of patients experience nonlethal emboli than had been realized. In one study, 100% of patients undergoing laparoscopic hysterectomy had emboli form in the right atrium, right ventricle, and right ventricular outflow tract, and 37% of these were grade III (occupying one half of these structures).13 This frequency of emboli is seldom clinical as the carbon dioxide is rapidly resorbed, but when it does become large enough, the results can be fatal.14 Insufflated gas can gain entry into the vascular system by mistaken placement of the needle into an artery, vein, or solid organ. It can also happen simply because of the positive intraabdominal pressure. In theory, for an embolus to enter the venous system during laparoscopy, there would have to be a defect in a vein or other vascular bed. If the intraabdominal inflation pressure matched the intravenous pressure, air could gain access to the circulation. If the inflation pressure were high enough to collapse the vein, air entrainment would cease, and if the inflation pressure were lower than venous pressure there would be hemorrhage from the vein without air entrainment. In general, inflation pressures higher than 15 mm Hg are not recommended during laparoscopy.12 Under normal conditions, veins collapse at 20 to 30 mm Hg; this is significantly higher than the recommended intracompartmental pressure. Therefore, when recommended inflation pressures are used, transected vessels should hemorrhage rather than entrain gas. Another factor that allows the early detection of air embolism (and reduced incidence of massive embolism leading to arrest) is slowing the rate of abdominal insufflation to less than 1 L/min.15 Although this slower speed of insufflation allows more time for pulmonary clearance of air bubbles, it is still very close to the insufflation rate capable of causing arrest in 60% of dogs studied (1.2 ml/kg/min).16 Even when these precautions are followed, embolization during laparoscopy occasionally occurs. Massive embolism is fatal in 28% of human patients, and the rate is likely much higher in veterinary patients. Although the use of carbon dioxide limits some of the negative effects of embolism compared with room air, there remains a risk that enough carbon dioxide will accumulate to cause an airlock and death. Rapid and complete ligation or cauterization of any injured vein will also limit the access points for gas emboli. Emboli are certainly a risk of laparoscopy, and monitoring for them is important during all laparoscopic procedures, as well as other forms of scoping. Endoscopy also uses air for distention of bowel and can occasionally create air embolism in humans, especially if mucosa or vasculature is breached during the procedure.17 Bronchoscopy has also been associated with infrequent air emboli. This is more likely to occur when laser surgeries are being performed via bronchoscopy, but cases have also been reported during routine diagnostic bronchoscopy.18

GAS EMBOLIZATION DURING SURGERY As during catheterization, gas embolization during surgery is most likely when the surgical site is higher, gravitationally speaking, than the heart. This situation can occur with most forms of neurosurgery (craniotomy and spinal surgeries) and many orthopedic surgeries (fracture repairs). Air entry is permitted via open veins or sometimes through bony routes (sinuses and long bones). Nitrogen is the predominant gas in room air, so slow absorption of entrained air can be anticipated. Nitrogen is far

CHAPTER 142  Gas Embolism more dangerous than carbon dioxide, and much smaller volumes can cause greater damage and are much slower for the body to clear. Prevention begins with surgical positioning, with excessive elevation of the surgical site avoided when possible. When this is not possible, keeping the surgical site filled with isotonic fluids will prevent gas from entering the bloodstream. In human neurosurgery, patients are often placed in a sitting position. Elevation of central venous pressures using positive end-expiratory pressure and volume loading reduce the incidence of air embolism in human and animal models.8,19 Craniotomy positioning in dogs and cats likewise results in surgical site elevation over the level of the heart.

GAS EMBOLIZATION DURING CARDIAC PROCEDURES Cardiopulmonary bypass is notorious for the introduction of air into the circulation. This air entry is extremely difficult to reduce because it arises from both the equipment functioning as the circulatory circuit and the surgery itself.20 In people, many postbypass complications are attributed, in part, to emboli or microemboli. Although unreported, the incidence may be even higher in veterinary patients because their smaller size magnifies the effect of the smallest air bubbles. Furthermore, many of these emboli are arterial, for which heightened consequences include cerebral and coronary artery obstruction. In veterinary medicine the field of cardiac catheterization is rapidly growing, and is significantly more common than cardiac bypass. Air can easily be introduced during different types of cardiac catheterization as well as angiography.21 Symptoms of intraoperative air embolism may be difficult to spot, as they fall into the hemodynamic or neurological category, and these systems are dramatically altered by anesthesia as well as the cardiac procedure being performed.

GAS EMBOLIZATION FROM LUNG BIOPSY A rarely reported consequence of lung biopsy in humans is air embolism.22 It is thought to occur due to the entry of the biopsy needle into a vascular bed, with entrainment of extrathoracic air or the creation of bronchovenous fistulas. Although not yet reported in veterinary species, it remains an important consideration for biopsy patients because it could easily be missed in the case of a slow leak with delayed onset cardiac arrest.

GAS EMBOLIZATION DURING HYPERBARIC THERAPY As mentioned before, pet dogs and cats seldom scuba dive or are subjected to dramatic increases in barometric pressure. One exception may be during intentional hyperbaric treatment for conditions such as anaerobic infections and inflammatory disorders. In a hyperbaric setting, gases dissolve more readily into tissues. When the pressure returns to normal these gases rapidly leave the tissues and form bubbles. When hyperbaric therapy is used, careful attention to recommended protocols is key. Even when protocols are followed, some individuals may experience embolism from gases emerging from a dissolved state into the bloodstream or organs. Appropriate evaluation, detection, and decompression therapy by qualified individuals is important to reduce the impact of this sequela. Unfortunately, there is an unpredictable individual variation as to when this occurs. Conversely, hyperbaric oxygen therapy is sometimes considered a treatment when air embolism has occurred. It both decreases the size of the emboli by facilitating gas reabsorption and improves tissue oxygenation and reduce reperfusion injury.23

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DETECTION OF AIR EMBOLI Air emboli should be considered in any situation in which air can be introduced by equipment or error, or when a surgical procedure produces an incised vascular bed with a hydrostatic pressure gradient favoring venous entry. During high-risk procedures, and when transesophageal echocardiography (TEE) is available, constant monitoring is ideal. Other signs of air embolism include neurologic deficits, changes in end-tidal carbon dioxide readings, the development of a distinct murmur, hypotension, and the development of increasing dead space ventilation as indicated by serial blood gas measurements. Neurologic signs of air embolism are difficult to detect in animals with the exception of seizures, unconsciousness, or poor, prolonged recovery. An astute observer might detect restlessness, agitation, or change in demeanor in a conscious patient. Advanced imaging can show pockets of air in the cerebral vasculature if it is performed before the air pockets have dissolved. Neurologic sequelae will outlast the presence of air due to hypoxic damage to brain tissue. Distinctive Doppler sounds over the heart or large vessels occur after 0.5 to 2 ml/kg air has entered the venous system, and the sound is described as a mill-wheel murmur. Mill-wheel murmurs are described as harsh, churning, splashing, and metallic. They have been reported near the time of cardiac arrest but are inconsistent.13 Tachypnea results from air embolism due to vagally and nonvagally mediated mechanisms, and an anesthetized patient that is not paralyzed may become tachypneic or begin to breathe over the ventilator even before the onset of hypoxemia.6 Unfortunately, air embolism in animals is often detected by the subsequent cardiovascular collapse. Clearly this is a late sign. Gas embolism in the lungs will cause an acute increase in dead space and a decrease in pulmonary compliance.24,25 Computed tomography and magnetic resonance imaging may be helpful in detecting emboli but are neither guaranteed nor time efficient in a crisis.26 Therefore clinical assessment is generally preferred. TEE is an extremely helpful tool for diagnosing intracardiac air embolism before cardiac arrest. Very small amounts of air can be detected by TEE, which has revealed far greater entrainment of air during laparoscopy than previously recognized.13 Once the amount of air or carbon dioxide becomes concerning (at grade III, when half of the right ventricle, right atrium, and right ventricular outflow tract are filled with air), definitive action to prevent further entrainment commences. TEE, however, is time consuming, requires constant vigilance by the operator, and is not commonly available in practice. Use of very specific views of the heart improves detection of air emboli, and this requires significant training and practice to master. This is a skill that should be mastered by anesthetists that are involved with procedures that are prone to air embolism.27

MANAGEMENT OF AIR EMBOLISM Immediate attention toward interrupting further air entrainment is the most important goal of management. This can be a combination of removing insufflated gas from the abdomen, addressing any nonligated vasculature, and increasing central venous pressure (to facilitate bleeding rather than entrainment of air). Once further intravascular gas flow is prevented, a venous air embolism may resolve, and the pulmonary filter may be sufficient to prevent further arterial spillover of air. Administration of 100% oxygen is recommended, and if nitrous oxide is being used it should be discontinued immediately.1 Positioning the patient so that the heart apex is elevated (head down, dorsal recumbency for most dogs and cats) may allow the remaining blood flow to bypass the air bubble and exit through the outflow tract, maintaining some perfusion

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if the air block is not complete. However, the use of body position as a treatment for air embolism is controversial. When manual reduction of an air embolism is possible, it can rapidly restore circulation. The goal is to place a catheter in the embolus and aspirate air or foam, a process that is conveniently diagnostic as well as therapeutic. Oxygen administration can manage hypoxemia and also provide a diffusion gradient if the embolized gas is anything other than oxygen.1,23,26 Work in pigs does not support the use of hyperventilation, but ventilatory support is still recommended because of the increased work of breathing associated with pulmonary air embolism.3 Immediately after embolization, blood pressure may become transiently high, which may facilitate movement of air bubbles into venous locations. Progressive hypotension is lethal, causing increased bubble entrapment and reductions in coronary and cerebral blood flow and thus compromising the organs most susceptible to anoxia.26 The goal is to establish and maintain normotension. Some controversy exists as to the utility of hyperbaric oxygen therapy (HBOT) for reversing gas emboli. Animal studies have given mixed results.3 HBOT can compress the bubble size (more relevant with air than with carbon dioxide due to solubility). Reduction in bubble size may restore circulation, and in the case of nitrogen, limits some of the blood–gas interface inflammatory effects. A reduction in intracranial pressure and increased dissolved oxygen in the plasma are additional positive effects of HBOT. Overall, if HBOT is available, early intervention is necessary for a beneficial effect, but where it is rapidly available it can be used to very good effect.23 The use of drugs in gas embolism is controversial. Hemodilution with colloid fluids improves neurologic recovery, with a target packed cell volume of 30%.28 Crystalloid fluids in excess of one quarter shock dose are not recommended because of their propensity to exacerbate cerebral edema. If seizures occur, barbiturates are recommended in lieu of benzodiazepines because of better inhibition of catecholamines and reduction in oxygen consumption and intracranial pressure.3 Glucocorticoids are not recommended because they appear to increase vessel occlusion and infarct size. Intravenous lidocaine has been shown to improve cerebral function and decrease infarct size in several studies.3 Essentially, preventing gas emboli is key. Failing this, early diagnosis using paired end-tidal carbon dioxide and partial pressure of carbon dioxide measurements or TEE improves survival. Management targets reduction of bubble size by a variety of mechanisms followed by brainprotective maneuvers. If hyperbaric oxygen is available, it may be life saving if it can be instituted rapidly enough, but it complicates access to the patient at a critical time.

REFERENCES 1. Kytta J, Tanskanen P, Randell T: Comparison of the effects of controlled ventilation with 100% oxygen, 50% oxygen in nitrogen, and 50% oxygen in nitrous oxide on responses to venous air embolism in pigs, Br J Anaesth 77:658-661, 1996. 2. Butler B, Robinson R, Sutton K, et al: Cardiovascular pressures with venous gas embolism and decompression, Aviat Space Environ Med 66:408-414, 1995. 3. Val Hulst R, Klein J, Lachmann B: Gas embolism: pathophysiology and treatment, Clin Physiol Funct Imaging 23(5):237-246, 2003. 4. Sobolewski P, Kandel J, Eckmann DM: Air bubble contact with endothelial cells causes a calcium-independent loss in mitochondrial membrane potential, PLoS One 7(10):e47254, 2012.

5. Vik A, Brubakk A, Hennessy T, et al: Venous air embolism in swine: transport of gas bubbles through the pulmonary circulation, J Appl Physiol 69:237-244, 1990. 6. Chen J, Kou Y: Vagal and mediator mechanisms underlying the tachypnea caused by pulmonary air embolism in dogs, J Appl Physiol 88:1247-1253, 2000. 7. Fibel KH, Barnes RP, Kinderknecht JJ: Pressurized intravenous fluid administration in the professional football player: a unique setting for venous air embolism, Clin J Sport Med 25(4):e67-e69, 2015. 8. Pant D, Narani K, Sood J: Significant air embolism: A possibility even with collapsible intravenous fluid containers when used with rapid infuser system, Indian J Anaesth 54(1):49-51, 2010. 9. Bakan M, Topuz U, Esen A, Basaranoglu G, Ozturk E: Inadvertent venous air embolism during cesarean section: collapsible intravenous fluid bags without self-sealing outlet have risks. Case report, Braz J Anesthesiol 63(4):362-365, 2013. 10. Zoremba N, Gruenewald C, Zoremba M, Rossaint R, Schaelte G: Air elimination capability in rapid infusion systems, Anaesthesia 66(11): 1031-1034, 2011. 11. Dion YM, Lévesque C, Doillon CJ: Experimental carbon dioxide pulmonary embolization after vena cava laceration under pneumoperitoneum, Surg Endosc 9:1065-1069, 1995. 12. Bazin J, Gillart T, Rasson P, et al: Haemodynamic conditions enhancing gas embolism after venous injury during laparoscopy in pigs, Br J Anaesth 78:570-575, 1997. 13. Park EY, Kwon JY, Kim KJ: Carbon dioxide embolism during laparoscopic surgery, Yonsei Med J 53(3):459-466, 2012. 14. Donepudi S: Air embolism complicating gastrointestinal endoscopy: a systematic review, World J Gastrointest Endosc 5(8):359, 2013. 15. Joris J: Anesthesia for laparoscopic surgery. In Miller R, editor: Anesthesia, ed 5, Philadelphia, 2000, Churchill Livingstone. 16. Mayer KL, Ho HS, Mathiesen KA, et al: Cardiopulmonary responses to experimental venous carbon dioxide embolism, Surg Endosc 12: 1025-1030, 1998. 17. Olaiya B, Adler DG: Air embolism secondary to endoscopy in hospitalized patients: results from the National Inpatient Sample (1998-2013), Ann Gastroenterol 32(5):476-481, 2019. 18. Tsuji T, Sonobe S, Koba T, Maekura T, Takeuchi N, Tachibana K: Systemic air embolism following diagnostic bronchoscopy, Intern Med 56(7): 819-821, 2017. 19. Pfitzner J, McLean A: Venous air embolism and active lung inflation at high and low CVP: a study in “upright” anesthetized sheep, Anesth Analg 66:1127-1134, 1987. 20. Branger A, Eckmann D: Theoretical and experimental intravascular gas embolism and absorption dynamics, J Appl Physiol 87(4):1287-1295, 1999. 21. Huang YY, Chen MR: Coronary air embolism during transcatheter closure of atrial septal defects, J Pediatr 164(3):669, 2014. 22. Wu YF, Huang TW, Kao CC, et al: Air embolism complicating computed tomography-guided core needle biopsy of the lung, Interact Cardiovasc Thorac Surg 14:771-772, 2012. 23. Malik N, Claus PL, Illman JE, et al: Air embolism: diagnosis and management, Future Cardiol 13(4):365-378, 2017. 24. Kytta J, Randell T, Tanskanene P, et al: Monitoring lung compliance and end-tidal oxygen content for the detection of venous air embolism, Br J Anaesth 75:447-451, 1995. 25. Annane D, Troche G, Delisle F, et al: Kinetics of elimination and acute consequences of cerebral air embolism, J Neuroimaging 5:183-189, 1995. 26. Muth C, Shank E: Gas embolism, N Engl J Med 342:476-482, 2000. 27. Adler AC: Images in anesthesiology: air embolism during cardiac catheterization and the role for anesthesia use of bedside ultrasound, Anesthesiology 127(5):890, 2017. 28. Reasoner D, Fyu K, Hindman B, et al: Marked hemodilution increases neurologic injury after focal cerebral ischemia in cats, Anesth Analg 81: 61-67, 1996.

143 Subcutaneous Emphysema Carissa W. Tong, BVM&S, DACVECC, Anusha Balakrishnan, BVSc, DACVECC KEY POINTS • Subcutaneous emphysema itself may not be life-threatening; however, it can be a symptom of a potentially serious underlying condition. • Subcutaneous emphysema is most often the result of traumatic injuries in veterinary patients. • Radiography is a simple, convenient, and easily accessible imaging modality commonly used to determine the location and extent of emphysema.

• Mild subcutaneous emphysema requires no treatment as it typically self-limiting. However, timely identification and treatment of the underlying cause are typically warranted to prevent recurrence and progression of emphysema.

INTRODUCTION

been performed, causing increased intrathoracic pressure, such as vomiting and coughing.8 There is a single case report in veterinary medicine describing a juvenile dog with a postmortem diagnosis of congenital emphysematous right middle lung lobe that presented for coughing and had subcutaneous emphysema.9 Coughing may have acted as a Valsalva maneuver in that dog, leading to alveolar rupture and subsequent pneumomediastinum and subcutaneous emphysema. Facial trauma,10 axillary wounds,11 esophageal rupture,12 and rib fractures13 are all reported causes of subcutaneous emphysema in people but have not been reported in small animals.

Subcutaneous emphysema occurs when air is present under the skin and in the soft tissue. Subcutaneous means “beneath the skin,” and emphysema means “trapped air.” It occurs secondary to an underlying defect that allows air to dissect through soft tissue, most commonly in the chest wall or neck, but can occur in other parts of the body. Subcutaneous emphysema itself may not be life-threatening; however, it is a symptom of a serious underlying pathology. Subcutaneous emphysema is most often seen as a result of traumatic injuries in veterinary patients, either through a bite wound or pneumothorax in the emergency setting. In hospitalized critically ill humans, it is commonly iatrogenic in origin, occurring after an invasive procedure (e.g., laparoscopic or maxillofacial surgery) or endotracheal intubation.1-3

CAUSES Subcutaneous emphysema can result from traumatic, iatrogenic, infectious, or rarely spontaneous causes.

Traumatic The most common cause of subcutaneous emphysema in both human and veterinary patients is trauma. Any bite wound that causes a fullthickness puncture has the ability to introduce free air into the subcutaneous space. There are various case reports in the veterinary literature documenting that a single cutaneous puncture wound can lead to generalized emphysema and pneumomediastinum.4,5 Bite wounds can also cause esophageal or airway trauma (e.g., tracheal tear). In a case series, 80% of dogs presenting with trauma-induced upper airway rupture had evidence of subcutaneous emphysema (Fig. 143.1).6 Subcutaneous emphysema associated with trauma often presents with underlying causes such as pneumothorax, pneumomediastinum, or pneumoperitoneum. A recent study showed that 66% of cats with pneumomediastinum had evidence of subcutaneous emphysema.7 In people, pneumomediastinum can develop if a Valsalva maneuver has

Iatrogenic Iatrogenic subcutaneous emphysema is another common cause of subcutaneous emphysema seen in veterinary patients. In cats, it is well recognized that overinflation of an endotracheal tube (ETT) cuff predisposes them to developing tracheal tears. In a retrospective study that evaluated tracheal rupture following intubation in cats, 100% of cats that suffered from iatrogenic tracheal tears developed subcutaneous emphysema.3 Overinflation of the ETT cuff often occurs during dental procedures in an attempt to prevent aspiration of fluid, blood, or calculi/oral contents. There is increased manipulation and repositioning of the head during these procedures, which may also predispose to tracheal injury. It is also thought that the high-pressure instillation of air by the pneumatic drill used in these procedures can disrupt the oral mucosa, allowing air to dissect through fascial sheaths to the subcutaneous tissue.2 However, this has not been proven in veterinary patients. Air leak from the peritoneum during laparoscopic procedures is a well-recognized complication. Subcutaneous emphysema occurs in 0.3–3% of all laparoscopic surgeries in people and 0.2% of canine laparoscopic ovariohysterectomies.14,15 In the abdomen, gas can pass through disruptions of the peritoneal cavity into the subcutaneous tissues or the retroperitoneal space; however, it can also extend into the mediastinum and pleura. Specific risk factors for subcutaneous emphysema have been identified in people, such as the use of an insufflator, intraabdominal pressure .15 mm Hg, repeated attempts

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Fig. 143.1  A dog with cervical trauma causing tracheal tear and subcutaneous emphysema.​

at abdominal entry, prolonged procedure times (.3.5 hours), and end-tidal carbon dioxide .50 mm Hg.15 Similar to laparoscopic surgery, placement of a percutaneous endoscopic gastrotomy tube in a feline patient was documented to cause subcutaneous emphysema, pneumoperitoneum, and pneumoretroperitoneum.16 It was thought that the air used for gastric insufflation may have entered damaged areas of the gastric mucosa and travelled via the perivascular and perineural tissues to reach the peritoneum, retroperitoneum, and local subcutaneous tissue.16 Other rare causes of iatrogenic causes of subcutaneous emphysema include positive pressure ventilation (specifically jet ventilation),17 colonic perforation,18 and aggressive hydrogen peroxide wound lavage.19

Infectious Subcutaneous emphysema can develop if gas-producing bacteria, such as Clostridium sp. and Bacteroides sp., produce gas that accumulates under the skin; concurrent cellulitis and fasciitis may be present in these animals. There is a report of feline herpesvirus-1 necrotizing bronchopneumonia in a kitten that developed generalized subcutaneous emphysema and pneumomediastinum.20 In people, emphysematous pyelonephritis has been reported to cause pneumomediastinum and subsequent subcutaneous emphysema.21 However, infectious and emphysematous bacterial infections are rare causes of subcutaneous emphysema in both veterinary and human patients.

Spontaneous Spontaneous emphysema is extremely rare in people and has not been reported in the veterinary literature. Spontaneous subcutaneous emphysema is thought to occur as a result of a break in the alveolar lining due to chronic pulmonary pathology (e.g., chronic obstructive pulmonary disease in people) or a spontaneous rupture of the chest wall, which allows air to escape into the subcutaneous space.22

PATHOPHYSIOLOGY Subcutaneous emphysema most commonly presents as a symptom of an underlying condition that allows air to freely dissect through fascial planes. Once air is under the tissue, dissection can occur along the connective tissue layers of adjoining adjacent muscle planes. Communication of fascial spaces allows air to move from one area to another. Subcutaneous emphysema can therefore arise from free air escaping from the trachea, mediastinum, pleural, peritoneal, or retroperitoneal spaces.

The mediastinum in most dogs and cats is fenestrated, which allows free communication between the mediastinum and the pleural space. The mediastinum is divided into the cranial portion (which communicates with fascial planes of the neck via the thoracic inlet), the middle portion (containing the heart), and the caudal portion (which communicates with the retroperitoneal space through the aortic hiatus).23 The presence of a pneumomediastinum allows air to move into the pleural cavity (pneumothorax), the retroperitoneal space (pneumoretroperitoneum), and under the skin (subcutaneous emphysema). Subcutaneous emphysema can also occur when there is a rupture in any portion of the tracheobronchial tree. When an alveolus ruptures, the air dissects through the peribronchovascular sheaths and the loose connective tissue surrounding the pulmonary vasculature and into the pulmonary interstitium. The air can track along the perivascular space into the pulmonary hila and into the mediastinum, and subsequently enter the pleural space; it is also known as the Macklin effect.24 The air can subsequently dissect into the subcutaneous tissues. Air that travels beneath the skin can be present in the cervical, thoracic, or abdominal regions. With massive accumulation of air, subcutaneous emphysema can act as a space occupying lesion. Rarely, this can progress to compartment syndrome.25,26 Compartment syndrome develops when there is increased pressure within a fixed space leading to decreased perfusion and ischemia, with subsequent organ or tissue dysfunction. Massive subcutaneous emphysema can be life-threatening. Upper airway obstruction can result from large amounts of emphysema in the cervical region; secondary perfusion deficits can also occur due to decreased venous return from compression of large vessels in the head and cervical regions.27 Concurrent pneumomediastinum and pneumothorax can decrease functional residual capacity, which can lead to various changes such as decreased lung compliance, increased airway resistance, and decreased tidal volume, all of which contribute to hypoventilation. Decreased cardiac venous return can also occur due to vena cava and azygous vein compression. Large amounts of subcutaneous emphysema over the chest wall can reduce chest wall compliance and restrict thoracic cage expansion. Tracheal tears, one of the reported causes of subcutaneous emphysema in veterinary patients, may lead to life-threatening tension pneumothorax if the tracheal defect acts as a one-way valve.3 However, this is rare. Other rarely reported sequelae of subcutaneous emphysema in a veterinary case report of a French Bulldog as well as human case reports include development of air emboli.17,27 In the veterinary case report, the air emboli developed in the middle cerebral and coronary arteries, which resulted in cardiopulmonary arrest.17 In both case reports, patients received positive pressure ventilation, which may enable pressurized air to enter the pulmonary interstitium and create subcutaneous emphysema via peribronchovascular sheath dissection. During that process, air can enter the venous circulation and result in air embolization.27

CLINICAL PRESENTATION Clinical History If presenting through the emergency department, patients with subcutaneous emphysema may have a history of recent trauma (e.g., bite wounds, vehicular trauma, fall from a height) or recent anesthetic event. They may present in respiratory distress if they are experiencing massive emphysema or have concurrent pneumomediastinum or pneumothorax. If a hospitalized patent develops subcutaneous emphysema, precipitating causes may include mechanical ventilation, general anesthesia for invasive procedures such as laparoscopic or endoscopic procedures, or maxillofacial/dental procedures.

CHAPTER 143  Subcutaneous Emphysema

Physical Examination There are no age, sex, or species predilections documented in veterinary medicine for subcutaneous emphysema. Patients with subcutaneous emphysema most commonly present due to owners observing a swelling under the skin that “crackles” (Fig. 143.2). Signs can occur immediately or be delayed for hours to weeks. Upon palpation of the swelling, nonpainful crepitus is appreciated. Swelling with crepitus is pathognomonic for subcutaneous emphysema. Crepitus essentially rules out other differentials for subcutaneous swelling such as angioedema or urticaria secondary to an allergic or anaphylactic reaction.

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patients presenting for subcutaneous emphysema that may have respiratory distress caused by concurrent conditions such as pneumothorax. Ideally, stabilization of these patients should be performed first, prior to performing imaging studies (see Chapter 198, Thoracocentesis). Advanced imaging modalities such as computed tomography (CT) are superior in sensitivity and specificity compared with conventional radiography. On CT, air pockets will appear as dark, hypoattenuating areas in the subcutaneous space. Bedside lung ultrasound has been gaining popularity in the past few years. It is an easily accessible imaging modality that requires

DIAGNOSTICS Obtaining radiographs of the affected areas is the first diagnostic step. Radiography is a simple, convenient, and easily accessible imaging modality. It can be used to identify the location and delineate the extent of emphysema (Figs. 143.3, 143.4, and 143.5). Subcutaneous emphysema appears as radiolucent areas in the soft tissue space. Sometimes, these areas can appear striated as the air outlines muscle fibers. Concurrent pneumomediastinum and pneumothorax are commonly seen. Radiography is limited by its relatively low sensitivity and the inability to identify underlying disease that caused subcutaneous emphysema. Care must be taken while performing radiographs of

Fig. 143.4  ​Lateral thoracic radiograph of a cat with endotracheal intubation-induced tracheal tear resulting in extensive subcutaneous emphysema, pneumomediastinum, and pneumothorax.

Fig. 143.2  ​Necropsy of dog with traumatic tracheal laceration.

Fig. 143.3  ​Lateral thoracic radiograph of a dog with pneumomediastinum and subcutanoeus emphysema secondary to bite wounds.

Fig. 143.5  ​VD thoracic radiograph of the cat in Fig. 143.4 with endotracheal intubation-induced tracheal tear resulting in extensive subcutaneous emphysema, pneumomediastinum, and pneumothorax.

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minimal patient restraint (see Chapter 189, Point-of-Care Ultrasound in the Intensive Care Unit). Air under the skin obscures normal structures and has been reported to cause artifactual B-lines. In people, emphysema lines, or E-lines, appear as well-defined vertical lines that arise from the subcutaneous tissue and are asynchronous with respiratory movement.28

TREATMENT Mild subcutaneous emphysema requires no treatment as this it typically self-limiting. However, timely identification and treatment of the underlying cause are warranted to prevent recurrence and progression of emphysema. In patients with subcutaneous emphysema and mild pneumomediastinum, provision of supplemental oxygen can hasten the resolution by reducing the partial pressure of nitrogen in the distended tissue and mediastinum.29 When a patient with air leaking into the pleural space is breathing 100% oxygen, the pleural gas will be composed mostly of oxygen without nitrogen. The pressure gradient between the pneumothorax and venous blood becomes larger because 100% oxygen washes out nitrogen from the alveoli. It is important to note that oxygen should not be provided using high-flow oxygen therapy as it may worsen preexisting pulmonary injury. Positive pressure ventilation should also be avoided, if possible, until subcutaneous emphysema has resolved. If occurring after a dental procedure and no obvious tracheal trauma is seen, another consideration is occurrence secondary to air dissecting through disrupted oral mucosa. It should be presumed that oral bacterial flora can follow the same route, which increases the risk of cellulitis and abscess formation. Conservative treatment with prophylactic antibiotics is recommended until emphysema resolves.29 In severe, massive emphysema with compartment syndrome, decompression via subcutaneous needle centesis, incision, or drain placement may be necessary. Infraclavicular small skin incisions (~2 cm) are frequently described in people to serve as a temporary “blowhole” for repeated manual decompressive massage of subcutaneous air.30 These tracts work for a short time, but factors such as tissue recoil and plasma clots can cause them to collapse and close the tract.31 A vacuum-assisted closure machine can also be attached to continuous suction at 100–150 mm Hg to aid with decompression.32 However, this is cost-prohibitive in veterinary medicine and cumbersome and may not be well tolerated by patients. Various other techniques have been described, but the use of a fenestrated catheter is most commonly reported in people.31 Depending on the size of the patient, a 16- to 20-gauge catheter can be used and fenestrations created by using a scalpel blade to cut the catheter over the steel stylet. The catheter should be inserted at a 45-degree angle until approximately a third of the catheter is deep into the skin expanded by the emphysema. Then, the angle should be flattened, and the catheter inserted until deep into the subcutaneous space.31 These catheters can be intermittently aspirated, or in cases of ongoing emphysema, they can be connected to continuous low-pressure suction at 5 cm H2O.33 Other techniques such as use of premade thoracostomy tubes or Jackson–Pratt drains have been described in people and could be considered, depending on patient size, in veterinary medicine. In animals with severe emphysema and progressive signs of upper airway obstruction, emergency intubation and/or tracheostomy tube placement may be necessary to provide relief until the inciting cause, such as a tracheal tear or esophageal tear, is definitively repaired. For the same reason, if patients are in distress due to pneumothorax, therapeutic thoracocentesis and/or placement of a thoracostomy tube

may be necessary. Once the patient is stabilized, surgical intervention should be considered to repair any injuries to the tracheobronchial tree.

OUTCOME In the majority of patients with mild subcutaneous emphysema, conservative medical management with serial monitoring is sufficient as the emphysema typically spontaneously resolves.3,4,9 It is uncommon for subcutaneous emphysema alone to cause significant mortality; however, it can contribute to the patient’s overall morbidity along with any underlying disease. As such, the outcome is ultimately dependent on the inciting cause of subcutaneous emphysema and whether that disease process is associated with a positive outcome.

REFERENCES 1. Ott DE: Subcutaneous emphysema—beyond the pneumoperitoneum, JSLS 18(1):1-7, 2016. 2. McKenzie WS, Rosenberg M: Iatrogenic subcutaneous emphysema of dental and surgical origin: a literature review, J Oral Maxillofac Surg 67(6):1265-1268, 2009. 3. Mitchell SL, McCarthy R, Rudloff E, et al: Tracheal rupture associated with intubation in cats: 20 cases (1996-1998), J Am Vet Med Assoc 216(10):1592-1595, 2000. 4. Bauer MS, Currie J: Generalized subcutaneous emphysema in a dog, Can Vet J 29(10):836-837, 1988. 5. Rajan SK: Subcutaneous emphysema and pneumomediastinum in kitten—a rare case report, Int J Agric Sci Vet Med 2(3):135-138, 2014. 6. Basdani E, Papazoglou LG, Patsikas MN, et al: Upper airway injury in dogs secondary to trauma: 10 dogs (2000-2011), J Am Anim Hosp Assoc 52(5):291-296, 2016. 7. Thomas EK, Syring RS: Pneumomediastinum in cats: 45 cases (20002010), J Vet Emerg Crit Care (San Antonio) 23(4):429-435, 2013. 8. Caceres M, Ali SZ, Braud R, et al: Spontaneous pneumomediastinum: a comparative study and review of the literature, Ann Thorac Surg 86(3):962-966, 2008. 9. Stephens JA, Parnell NK, Clarke K, et al: Subcutaneous emphysema, pneumomediastinum, and pulmonary emphysema in a young schipperke, J Am Anim Hosp Assoc 38(2):121-124, 2002. 10. Hong B, Hunt P: Pneumomediastinum secondary to facial trauma, Am J Emerg Med 35(1):192.e3-192.e5, 2017. 11. Hance SR, Robertson JT: Subcutaneous emphysema from an axillary wound that resulted in pneumomediastinum and bilateral pneumothorax in a horse, J Am Vet Med Assoc 200(8):1107-1110, 1992. 12. Korczynski P, Krenke R, Fangrat A, et al: Acute respiratory failure in a patient with spontaneous esophageal rupture (Boerhaave syndrome), Respir Care 56(3):347-350, 2011. 13. Porhomayon J, Doerr R: Pneumothorax and subcutaneous emphysema secondary to blunt chest injury, Int J Emerg Med 4:10, 2011. 14. Pope JF, Knowles TG: Retrospective analysis of the learning curve associated with laparoscopic ovariectomy in dogs and associated perioperative complication rates, Vet Surg 43(6):668-677, 2014. 15. Gutt CN, Oniu T, Mehrabi A, et al: Circulatory and respiratory complications of carbon dioxide insufflation, Dig Surg 21(2):95-105, 2004. 16. Mason NJ, Michel KE: Subcutaneous emphysema, pneumoperitoneum, and pneumoretroperitoneum after gastrostomy tube placement in a cat, J Am Vet Med Assoc 216(7):1096-1075, 2000. 17. Yaegashi M, Yamaya Y, Sano T, et al: Cardiac arrest and arterial air emboli associated with subcutaneous emphysema and pneumothorax in a French bulldog, Vet Anaesth Analg 40(6):651-653, 2013. 18. Muronoi T, Kidani A, Hira E, et al: Mediastinal, retroperitoneal, and subcutaneous emphysema due to sigmoid colon penetration: a case report and literature review, Int J Surg Case Rep 55:213-217, 2019.

CHAPTER 143  Subcutaneous Emphysema 19. Chung J, Jeong M: Oxygen embolism caused by accidental subcutaneous injection of hydrogen peroxide during orthopedic surgery: a case report, Medicine (Baltimore) 96(43):e8342, 2017. 20. Maes S, Van Goethem B, Saunders J, et al: Pneumomediastinum and subcutaneous emphysema in a cat associated with necrotizing bronchopneumonia caused by feline herpesvirus-1, Can Vet J 52(10):1119-1122, 2011. 21. Wang YC, Wang JM, Chow YC, et al: Pneumomediastinum and subcutaneous emphysema as the manifestation of emphysematous pyelonephritis, Int J Urol 11(10):909-911, 2004. 22. Muthu V, Dhooria S, Agarwal R, et al: Rare cause of spontaneous subcutaneous emphysema, Lung India 33(6):688-689, 2016. 23. Evans HE, de Lahunta A: The neck, thorax, and thoracic limb. In Evans HE, de Lahunta A, editors: Guide to the dissection of the dog, ed 7, St. Louis, MO, 2010, Elsevier, p 102. 24. Murayama S, Gibo S: Spontaneous pneumomediastinum and Macklin effect: overview and appearance on computed tomography, World J Radiol 6(11):850-854, 2014. 25. Reed R, D’Alessio F, Yarmus L, et al: Abdominal compartment syndrome due to subcutaneous emphysema, BMJ Case Rep 2012:bcr1120115089, 2012.

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26. Bagcioglu M, Karadag MA, Kocaaslan R, et al: It suddenly occurred: extensive subcutaneous emphysema after bipolar transurethral resection of prostate, Case Rep Urol 2015:134651, 2015. 27. Verelst W, Verbrugghe W, Lammens M, et al: Ventilation-induced massive lethal air embolism and subcutaneous emphysema in a patient with a lung cavern, Respir Care 60(1):e6-e10, 2015. 28. Francisco MJ Neto, Rahal A Junior, Vieira FA, et al: Advances in lung ultrasound, Einstein (Sao Paulo) 14(3):443-448, 2016. 29. Jeong CH, Yoon S, Chung SW, et al: Subcutaneous emphysema related to dental procedures, J Korean Assoc Oral Maxillofac Surg 44(5):212-219, 2018. 30. Cerfolio RJ, Bryant AS, Maniscalco LM: Management of subcutaneous emphysema after pulmonary resection, Ann Thorac Surg 85(5):1759-1765, 2008. 31. Beck PL, Heitman SJ, Mody CH: Simple construction of a subcutaneous catheter for treatment of severe subcutaneous emphysema, Chest 121(2):647-649, 2002. 32. Byun CS, Choi JH, Hwang JJ, et al: Vacuum-assisted closure therapy as an alternative treatment of subcutaneous emphysema, Korean J Thorac Cardiovasc Surg 46(5):383-387, 2013. 33. O’Reilly P, Chen HK, Wiseman R: Management of extensive subcutaneous emphysema with a subcutaneous drain, Respirol Case Rep 1(2):28-30, 2013.

144 Ocular Disease in the Intensive Care Unit Kathryn Good, DVM, DACVO KEY POINTS • Ocular disease is commonly seen in critically ill patients in the ICU. • A thorough ophthalmic examination of the entire eye (including Schirmer tear test, tonometry, and fluorescein stain) should be a part of the evaluation process in all ICU patients and repeated as needed if ophthalmic clinical signs develop (Box 144.1).

• Preventative measures to help preclude the development of ophthalmic complications should be instituted at the onset of hospitalization in the ICU (Box 144.2).

Eye care is an essential aspect of managing the critically ill patient as many of the mechanisms typically involved in protecting the eye from injury, inflammation, and infection are compromised when an individual is critically sick. This chapter focuses primarily on the ocular diseases most likely to develop in patients in the ICU, how to monitor for the development of those diseases, therapeutic options when the eye becomes diseased, and preventative measures to help preclude ocular disease from developing altogether.

outer barriers is altered, edema ensues, transparency is lost, and the cornea takes on a blue discoloration. Corneal ulceration leads to focal edema confined to the area of ulceration. Endothelial causes of edema that may develop acutely in the ICU patient include anterior uveitis and glaucoma, both of which lead to diffuse corneal edema. Pupil abnormalities: There are three pupillary abnormalities that can develop acutely in the ICU patient: miosis, mydriasis, and anisocoria. Change in pupil size may indicate development of primary ocular disease or a neurological disorder. In addition to ophthalmic drugs that can cause pupillary constriction (e.g., latanoprost, pilocarpine), miosis is most commonly seen in eyes with anterior uveitis or Horner syndrome. In patients with uveitis, episcleral hyperemia, low intraocular pressure (IOP), and/or aqueous flare are present. Patients with Horner syndrome often have concurrent signs including enophthalmos, ptosis, and/or third eyelid protrusion but no clinical signs indicative of uveitis. Pharmacologic mydriasis can be produced by topical or parenteral atropine and topical tropicamide. Mydriasis is also seen in aged patients due to iris atrophy. However, if mydriasis occurs acutely in an ICU patient, glaucoma, optic neuritis, chorioretinal inflammation, and retinal detachment should be ruled out. If a thorough evaluation for ocular disease is conducted and deemed normal (see Box 144.1), a full neurological examination is warranted.

WARNING SIGNS OF DEVELOPING OCULAR DISEASE Blepharospasm: Blepharospasm refers to squinting that occurs secondary to ocular irritation. Concurrent clinical signs that may be present include enophthalmos and third eyelid protrusion. Ocular surface redness: When the eye appears red, it usually means the patient either has episcleral hyperemia, conjunctival hyperemia, or both. Differentiating episcleral and conjunctival hyperemia is critical for distinguishing vision-threatening intraocular disease such as anterior uveitis and glaucoma (episcleral hyperemia) from less urgent conditions such as conjunctivitis (conjunctival hyperemia). Subconjunctival hemorrhage (petechial or diffuse) is often a sequela of direct ocular trauma. However, if first noticed in the ICU, coagulation disorders, septicemia, vasculitis, and/or systemic hypertension should be considered.1 Chemosis: Chemosis refers to conjunctival edema that results in notable conjunctival swelling (Fig. 144.1). It is commonly a sequela to diseases that result in acute inflammation, most notably exposure to allergens, topical toxicity (medications, caustic agents), and direct ocular trauma. Chemosis has also been reported as a late sign of fluid overload.2 Ocular discharge: Ocular discharge is a nonspecific sign of ocular irritation and can be serous, mucoid, mucopurulent, or hemorrhagic. Development of ocular discharge while in the ICU warrants vigilant evaluation of the affected eye(s) in order to determine the source of irritation. Corneal cloudiness/edema: The cornea is reliant on its epithelium and endothelium to keep fluid out of the stroma. If either of these

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OCULAR DISEASES MOST LIKELY TO DEVELOP IN THE ICU PATIENT Exposure Keratopathy and Corneal Ulceration Exposure keratopathy refers to dryness of the cornea due to incomplete eyelid closure. This lack of complete eyelid closure, termed lagophthalmos, leads to excessive tear evaporation and failure of the tears to be spread adequately across the surface of the eye. The overall health of the cornea is very dependent on a normal tear film (both quantity and quality), the ability of the patient to blink fully, and the ability of the patient to close its eyes fully when sleeping. All of these measures can be impaired in critically ill patients, either from their decreased state of consciousness and diminished reflexes, a reduced blink rate and impaired (or fully eliminated) blink reflex with the use of

CHAPTER 144  Ocular Disease in the Intensive Care Unit

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BOX 144.1  Ophthalmic Examination in the ICU Patient • Assess for discomfort (blepharospasm, rubbing eyes) • Assess vision (tracking of thrown cotton balls, maze testing if ambulatory) • Note presence/absence of ocular discharge (serous, mucoid, mucopurulent, or hemorrhagic) • Evaluate neuro-ophthalmic status (pupil size and symmetry, pupillary light reflexes [both direct and consensual], menace response, dazzle reflex, palpebral reflex) • Assess ability to fully close the eyelids (palpebral reflex and observation of unassisted blinking) • Evaluate conjunctiva for hyperemia, chemosis, petechia, icterus, hemorrhage • Evaluate sclera for prominent episcleral vessels (suggestive of intraocular disease), icterus • Assess cornea including topography (smooth, convex with no obvious depressions) and clarity (presence/absence of edema, vascularization, fibrosis, melanosis, cellular infiltrate) • Assess for aqueous flare (pathognomonic sign of breakdown of the blood– ocular barrier and leakage of plasma proteins, which is indicative of anterior uveitis) • Assess lens position and clarity • Perform a fundus examination: assess for retinal hemorrhage, retinal detachment, evidence of chorioretinitis, retinal degeneration, and/or optic neuritis • Perform an ocular minimum data base: STT, IOP, and Fluorescein stain • STT (normal $15 mm/min in dogs, $9 mm/min in cats) • IOP (normal 10–20 mm Hg in eyes without anterior uveitis, ,10 mm Hg in eyes with anterior uveitis or significantly lower than a contralateral eye without uveitis) • Fluorescein stain IOP, intraocular pressure; STT, Schirmer tear test.

sedation, or complete loss of the blink reflex due to general anesthesia. The loss of ocular surface protection by the tear film and blink reflex will subsequently lead to a breakdown in the corneal epithelium and ultimately the development of corneal ulceration. There is a strong correlation between lagophthalmos and the development of corneal ulceration which, if left untreated, can result in sight-threatening

Fig. 144.1  ​Marked chemosis (conjunctival edema) in the right eye of a dog. Photo courtesy of the UC Davis Veterinary Ophthalmology Service Collection.

consequences such as corneal rupture, particularly if the ulcer becomes infected.3,4

Corneal Ulcer Treatment Simple, epithelial-only ulcers: If a corneal ulcer is determined to be epithelial-only (no stromal loss detected) and free from infection, it is termed a simple or uncomplicated ulcer (Fig. 144.2). In that situation, a broadspectrum, prophylactic antibiotic (e.g., bacitracin-neomycin-polymyxin ophthalmic ointment) TID-QID is started. Given the likelihood of decreased blink rate and lagophthalmos in a critically ill patient, application of an artificial tears preparation (preferably one that contains hyaluronan or a petrolatum ophthalmic ointment if lagophthalmos is severe) at times other than when the antibiotic is being applied is recommended to maximize lubrication. Due to the iridociliary spasm and subsequent discomfort induced by corneal ulcers, topical atropine 1% can be applied once daily for iridocycloplegia. However, note that topical atropine has the potential to lower tear production in all patients;5 as such, a pretreatment Schirmer tear test (STT) should be performed and atropine only used if tear production is normal ($15 mm/min in dogs). Ulcers with stromal loss: Ulcers with stromal loss should be considered infected until proven otherwise. Infected corneal ulcers should be

BOX 144.2  Preventative Measures to Ensure Optimal Ocular Surface Health in the ICU • Assess eyelid closure at the start of patient management planning and then routinely throughout hospitalization in the ICU. • Apply artificial tear lubricants frequently in all ICU patients. If eyelid closure is impaired, frequency of lubrication should be much greater (at least every 2-4 hours depending on severity of impairment). Ointments are preferable to solutions due to their greater ocular surface contact time. Hyaluronancontaining gels are also beneficial if lagophthalmos is not too severe. • Assess eye(s) for redness, discharge, corneal cloudiness, corneal dullness and corneal opacification prior to each application of lubrication. If any abnormalities are seen, a full ophthalmic examination should be performed (see Box 144.1). • In ventilator patients, avoid positioning fans directly towards the face and keep warming devices on the lower half of the body. Both measures will help prevent ocular desiccation and subsequent corneal ulceration. In some instances, a temporary tarsorrhaphy may help provide more consistent corneal coverage and protection.

Fig. 144.2  ​Left eye of a dog with a large superficial ulcer occupying the majority of the corneal surface. Fluorescein stain has been applied. Note how the edges of the ulceration appear flush with the nonulcerated regions of the cornea, which is indicative of it only involving the epithelial layer. The lower lid has been pulled down to show moderate conjunctival hyperemia. There are strands of mucus overlying the cornea that also retain the fluorescein stain. Photo courtesy of the UC Davis Veterinary Ophthalmology Service Collection.

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Fig. 144.3.  ​Infected corneal ulcer in a dog with secondary (reflex) anterior uveitis. Note the sloping walls of the defect indicating stromal loss, soft-appearing edges of the stromal defect suggestive of mild keratomalacia, mild haziness of the entire cornea indicative of diffuse corneal edema, and 360-degree corneal vascularization extending axially for about 1 mm. This patient also has a substantial zone of white blood cells (hypopyon) in the ventral aspect of the anterior chamber indicative of anterior uveitis secondary to the presence of the ulceration. Corneal cytology and culture of the ulcer revealed infection with Staphylococcus pseudointermedius. Photo courtesy of the UC Davis Veterinary Ophthalmology Service Collection.

treated as an emergency due to the speed with which the ulcer can deteriorate, deepen, and subsequently place the eye at risk of rupture. Clinical signs of infection include any degree of stromal loss, stromal infiltrate, and/or corneal malacia (Fig. 144.3). In dogs and cats the most common organisms causing infection are bacteria. Depending on geographic location, fungal keratitis can also be prevalent.6 If infection is suspected, cytology and culture with sensitivity should be performed to guide therapy. Antimicrobials should be applied topically every 15 minutes for the first hour to increase corneal concentrations, then every 2 hours until signs of healing are seen at which point frequency can be gradually reduced. A topical fluoroquinolone (e.g., ofloxacin 0.3%, ciprofloxacin 0.3%) is the first drug of choice for infected ulcers. For added Gram-positive coverage, a compounded cefazolin preparation (33–50 mg/ml) or neomycin-polymyxin-gramicidin solution can be utilized. If a fungal infection is suspected, voriconazole 1% is the antifungal of choice given its superior corneal penetration.6 If stromal loss is present and particularly if keratomalacia is seen, the addition of an antiprotease such as topical serum (keep serum refrigerated and discard/replace after 7 days) is recommended. Topical oxytetracycline and oral doxycycline (10 mg/kg q24h) also have antiprotease activity and can be added if keratomalacia is not improving at the expected rate.8-10 In general, topical protease inhibitors should be instilled every 2 hours until keratomalacia has stopped and then decreased to four to six times a day. Evaluation for the presence of anterior uveitis in eyes with infected corneal ulcers is imperative given the subsequent risk for developing sight-threatening sequela such as posterior synechia, glaucoma, or

phthisis bulbi. If aqueous flare, hypopyon, and/or low IOP are noted on examination, anterior uveitis is present (Fig. 144.3). Therapy should include a systemic antiinflammatory if tolerated. Topical nonsteroidal antiinflammatory drugs (NSAIDs) should be avoided if possible as they have variable effects on ocular infection, may slow healing, and have been reported to potentiate corneal malacia.11-13 Topical steroids should never be used on corneal ulcers. Topical atropine should be considered to prevent anterior synechia, stabilize the blood–ocular barrier, and to control the iridociliary spasm that contributes to ocular discomfort. If possible, IOP should be obtained before starting atropine as its use can increase IOP in eyes predisposed to the development of glaucoma,14 as in eyes with uveitis.15 Ocular discomfort should be controlled with systemic analgesia if tolerated. In ulcers that have 50%–75% stromal loss, surgical stabilization may be required once the patient’s systemic status stabilizes. In the feline ICU patient, it is also important to consider the role that feline herpesvirus (FHV-1) may play in the presence of ocular surface disease. Clinical signs and historical information that may suggest the presence of FHV-1 involvement include dendritic corneal ulceration, symblepharon (indicative of chronic herpetic disease) and a history of recurrent ocular and/or upper respiratory disease. If FHV-1 recrudescence is suspected, therapy can involve topical cidofovir 0.5% q12h or idoxuridine q4-6h. Oral famciclovir at 90 mg/kg q12h is believed to be a superior treatment to topical antivirals given the high concentrations that can be obtained at all vascular sites affected by FHV-1, but caution should be utilized in critically ill cats with kidney disease given the renal clearance of this drug.16,17

Keratoconjunctivitis Sicca As stated above, a normal tear film plays a critical role in keeping the ocular surface healthy. In a relatively recent study, canine patients in the ICU with varying systemic diseases were shown to have decreased tear production compared with a healthy control population of dogs.18 Normal STT in dogs is $15 mm/min. In the aforementioned study, average STT in the control population was 24.5 mm/min versus 13.2 mm/min in the canine ICU population.18 Systemic sulfa derivatives, including trimethoprim-sulfamethoxazole, sulfadiazine, and sulfasalazine, have the potential to induce keratoconjunctivitis sicca (KCS) in dogs and therefore could further exacerbate ocular surface drying in the ICU patient. Up to 50% of affected dogs develop KCS within 30 days of treatment, and in some dogs the dry eye remains permanent after discontinuation of the medication.19-22 It is recommended to perform a STT every 2–3 days in ICU dogs receiving sulfa derivatives to catch a drop in tear production as early as possible. If KCS is diagnosed, discontinue the medication, start topical ophthalmic cyclosporine 0.2% ointment q12h, and increase the frequency of artificial tear lubrication until tear production recovers back to pretreatment values. In ICU patients that require general anesthesia, notably ventilator patients, tear production should be monitored closely as general anesthesia dramatically decreases (to nearly entirely suppresses) tear production and the reduction can persist for 24 hours after anesthetic recovery.23,24

Anterior Uveitis Intraocular inflammation can arise from a primary ocular disorder (e.g., cataracts, intraocular tumor, corneal ulceration). However, if anterior uveitis develops acutely in the ICU patient that is free from the abovementioned ocular diseases, uveitis secondary to the patient’s systemic disorder should be suspected. Anterior uveitis poses a significant risk for vision loss. The pathognomonic clinical sign of anterior uveitis is aqueous flare. Other clinical signs supportive of active uveitis include diffuse corneal edema, low IOP, intraocular fibrin, hypopyon,

CHAPTER 144  Ocular Disease in the Intensive Care Unit

Fig. 144.4  ​Photo of the face of a cat with anterior uveitis of the left eye (OS). Note the cloudy appearance of OS in comparison to the right eye (OD). Also note the anisocoria with OS mydriatic compared with OD, which was due to elevated intraocular pressure and the development of secondary glaucoma OS. Photo courtesy of the UC Davis Veterinary Ophthalmology Service Collection.

and/or hyphema (Fig. 144.4). Hyphema in particular should encourage systemic investigation for coagulation disorders, systemic hypertension, and neoplasia.25,26 The primary treatment for uveitis is topical corticosteroids (e.g., prednisolone acetate 1%, dexamethasone 0.1%). Note that hydrocortisone does not penetrate through the cornea and therefore is ineffective in the treatment of uveitis. Frequency of application depends on the severity of the uveitis, with a typical range of q4-12h. Topical NSAIDs (diclofenac 0.1%, ketorolac 0.5%) are usually not as potent as steroids but a good alternative if necessary. Topical atropine 1% can be used (q12-24h) for its iridocycloplegic effects and to help stabilize the blood aqueous barrier, but as stated earlier, precautions should be taken regarding IOP. If the uveitis is severe, an oral antiinflammatory agent (NSAID or steroid) should be included if it can be systemically tolerated. If uveitis is not treated early and aggressively, secondary glaucoma can be the blinding sequela. For that reason, IOPs should be evaluated in any red eye, and especially in eyes that have developed uveitis. Clinical signs of acute glaucoma include episcleral congestion, corneal edema, mydriasis, vision loss, 1/2 blepharospasm. Normal IOP in dogs and cats is approximately 10–20 mm Hg. In eyes with uveitis, IOP should be lower than normal. Therefore, if the IOP is high normal or elevated in the face of uveitis, the presence of or impending fate for glaucoma should be suspected and therapy instituted.27 Topical atropine should not be used in this situation. The ideal drug of choice in uveitis-induced glaucoma is a topical carbonic anhydrase inhibitor such as dorzolamide 2% or brinzolamide 1% q8h. Emergency osmotic therapy with IV mannitol to treat patients with acute glaucoma secondary to uveitis may be less effective, and potentially counterproductive, at lowering IOP than when given to patients with glaucoma secondary to other causes.28

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some affected cats, central neurological deficits are also seen. In cats, the maxillary artery, which is situated around the caudal aspect of the mandible, provides the main supply of blood to the brain and retina. Using dynamic computed tomography examination, nonselective digital subtraction angiography, electroretinography, brainstem auditory evoked response, and magnetic resonance angiography, studies have confirmed the reduction in maxillary arterial blood flow to the brain and retina when the mouth is opened maximally, thus resulting in cerebral and retinal ischemia.32-34 The use of smaller mouth gags and therefore submaximal mouth opening is associated with fewer alterations in maxillary artery blood flow.34 Recovery of useful vision has been reported in 70% of cats within 1 day to 6 weeks (mean 4.5 days), with 59% of cats having full recovery of their neurological abnormalities.31 These findings provide evidence to support that postanesthetic blindness can be related to maximal opening of the mouth and is not exclusively associated with decreased oxygen supply to the brain that can occur secondary to anesthesia-associated cardiovascular depression, hypotension, or hypoxemia. Systemic hypertension can also lead to acute vision loss in the critically ill patient.35 Common ocular sequela to systemic hypertension include preretinal, intraretinal, and subretinal hemorrhages; retinal and papillary edema; and choroidal effusion.36 With advancing subretinal fluid accumulation, the retina can detach, either focally, multifocally, or diffusely, leading to varying degrees of vision impairment, including complete vision loss (Fig. 144.5). Hyphema is seen in a subset of patients with systemic hypertension.25 Therefore, a systemic blood pressure measurement should be taken in patients with intraocular bleeding and, if elevated, antihypertensive therapy instituted. Enrofloxacin administration in cats may lead to acute vision loss. Although once believed to be an idiosyncratic reaction, retinal degeneration seen secondary to enrofloxacin usage is now widely thought to be both dose- and concentration-dependent.37,38 In addition, the reaction is no

Acute Blindness in the ICU Patient As mentioned above, anterior uveitis with or without secondary glaucoma should be considered when acute blindness is discovered in the ICU. In human ICU patients, blindness can be seen secondary to ischemic optic neuropathy.29 The underlying etiology remains poorly defined. Ischemic optic neuropathy in small animals is infrequently reported.30 However, another vascular occurrence leading to blindness in cats has been identified. Both temporary and permanent blindness has been seen in cats postanesthesia and attributed to the use of spring-loaded mouth gags.31 In

Fig. 144.5  ​Retinal detachment in the eye of a cat with systemic hypertension. Note the lack of clarity of the fundus image, particularly from the 2 to 11 o’clock position, which is characteristic of the appearance of a detached retina. There is a serous subretinal fluid accumulation, which leads to the hyporeflective nature of the tapetal region. Photo courtesy of the UC Davis Veterinary Ophthalmology Service Collection.

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longer believed to be unique to enrofloxacin as it may be seen with other fluoroquinolones as well.38 Affected cats become acutely blind after treatment, typically within a few days, with widely dilated, nonresponsive pupils. Bilateral diffuse retinal degeneration, characterized by increased tapetal reflectivity and retinal vascular attenuation, is indicative of the photoreceptor damage that occurs. Advanced age (.12 years old) and renal or hepatic impairment may predispose a patient to an adverse reaction.37,38 There is no specific treatment, and unfortunately the retinal degeneration is irreversible in most affected cats. However, there may be a degree of vision recovery if the association is recognized early and the drug stopped immediately. If a fluoroquinolone antibiotic is required for treatment in a feline patient, it is strongly recommended that the dose and frequency of administration should not exceed the manufacturer’s current dosing recommendations (e.g., enrofloxacin: 5 mg/kg q24h) and critical monitoring for mydriasis and/or visual impairment performed.

REFERENCES 1. Saastamoinen J, Rutter CR, Jeffery U: Subconjunctival haemorrhage in 147 dogs, J Small Anim Pract 60:755, 2019. 2. Hughston L: Go with the flow: the basics of fluid therapy for small animal veterinary technicians, Today’s Veterinary Nurse July/Aug, 2016. 3. Kim JY, Won H, Jeong S: A retrospective study of ulcerative keratitis in 32 dogs, Intern J Appl Res Vet Med 7:27, 2009. 4. Park YW, Son WG, Jeong MB, et al: Evaluation of risk factors for development of corneal ulcer after nonocular surgery in dogs: 14 cases (20092011), J Am Vet Med Assoc 242:1544, 2013. 5. Hollingsworth SR, Canton DD, Buyukmihci NC, et al: Effect of topically administered atropine on tear production in dogs, J Am Vet Med Assoc 200:1481, 1992. 6. Marlar A, Miller P, Canton D, et al: Canine keratomycosis: a report of 8 cases and literature review, J Am Anim Hosp Assoc 30:331, 1994. 7. Zhao X, Tong Y, Wang X, et al: Comparison of the ocular penetration and pharmacokinetics between natamycin and voriconazole after topical instillation in rabbits, J Ocul Pharmacol Ther 34:460, 2018. 8. Kimmitt BA, Moore GE, Stiles J: Comparison of the efficacy of various concentrations and combinations of serum, ethylenediaminetetraacetic acid, tetracycline, doxycycline, minocycline, and N-acetylcysteine for inhibition of collagenase activity in an in vitro corneal degradation model, Am J Vet Res 79:555, 2018. 9. Ollivier FJ, Brooks DE, Kallberg ME, et al: Evaluation of various compounds to inhibit activity of matrix metalloproteinases in the tear film of horses with ulcerative keratitis, Am J Vet Res 64:1081, 2003. 10. Collins SP, Labelle AL, Dirikolu L, et al: Tear film concentrations of doxycycline following oral administration in ophthalmoscopically normal dogs, J Am Vet Med Assoc 249:508, 2016. 11. Lin JC, Rapuano CJ, Laibson PR, et al: Corneal melting associated with use of topical nonsteroidal anti-inflammatory drugs after ocular surgery, Arch Ophthalmol 118:1129, 2000. 12. Flach AJ: Corneal melts associated with topically applied nonsteroidal anti-inflammatory drugs, Trans Am Ophthalmol Soc 99:205, 2001. 13. Guidera AC, Luchs JI, Udell IJ: Keratitis, ulceration, and perforation associated with topical nonsteroidal anti-inflammatory drugs, Ophthalmology 108:936, 2001. 14. Herring IP: Clinical pharmacology and therapeutics- part 4: Mydriatics/ Cycloplegics, anesthetics, and tear substitutes and stimulators. In Gelatt KN, editor: Veterinary ophthalmology, ed 5, Hoboken, 2013, Wiley-Blackwell, pp 423-434. 15. Johnsen DA, Maggs DJ, Kass PH: Evaluation of risk factors for development of secondary glaucoma in dogs: 156 cases (1999-2004), J Am Vet Med Assoc 229:1270, 2006.

16. Thomasy SM, Shull O, Outerbridge CA, et al: Oral administration of famciclovir for treatment of spontaneous ocular, respiratory, or dermatologic disease attributed to feline herpesvirus type 1: 59 cases (2006-2013), J Am Vet Med Assoc 249:526, 2016. 17. Sebbag L, Thomasy SM, Woodward AP, et al: Pharmacokinetic modeling of penciclovir and BRL42359 in the plasma and tears of healthy cats to optimize dosage recommendations for oral administration of famciclovir, Am J Vet Res 77:833, 2016. 18. Chandler JA, van der Woerdt A, Prittie JE, et al: Preliminary evaluation of tear production in dogs hospitalized in an intensive care unit, J Vet Emerg Crit Care 23:274, 2013. 19. Trepanier LA: Idiosyncratic toxicity associated with potentiated sulfonamides in the dog, J Vet Pharmacol Ther 27:129, 2004. 20. Diehl KJ, Roberts SM: Keratoconjunctivitis sicca in dogs associated with sulfonamide therapy: 16 cases (1980-1990), Prog Vet Comp Ophthalmol 1:276, 1991. 21. Collins BK, Moore CP, Hagee JH: Sulfonamide-associated keratoconjunctivitis sicca and corneal ulceration in a dysuric dog, J Am Vet Med Assoc 189:924, 1986. 22. Morgan RV, Bachrach A: Keratoconjunctivitis sicca associated with sulfonamide therapy in dogs, J Am Vet Med Assoc 180:432, 1982. 23. Shepard MK, Accola PJ, Lopez LA, et al: Effect of duration and type of anesthetic on tear production in dogs, Am J Vet Res 72:608, 2011. 24. Herring IP, Pickett JP, Champagne ES, et al: Evaluation of aqueous tear production in dogs following general anesthesia, J Am Anim Hosp Assoc 36:427, 2000. 25. Telle MR, Betbeze C: Hyphema: considerations in the small animal patient, Top Companion Anim Med 30:97, 2015. 26. Lakooraj HM, Ahmadi-hamedani M, Dezfoulian O, et al: Multicentric lymphoma in a Rottweiler dog with bilateral ocular involvement: a case report, Vet Res Forum 9:285, 2018. 27. Hendrix DVH: Diseases and surgery of the canine anterior uvea. In Gelatt KN, editor: Veterinary ophthalmology, ed 5, Hoboken, 2013, Wiley-Blackwell, pp 1146-1198. 28. Miller PE: The glaucomas. In Maggs DJ, Miller PE, Ofri R, editors: Slatter’s fundamentals of veterinary ophthalmology, ed 5, St. Louis, 2013, Elsevier, pp 247-271. 29. Lee LA, Nathens AB, Sires BS, et al: Blindness in the intensive care unit: possible role for vasopressors? Anesth Analg 100:192, 2005. 30. Mari L, Stavinohova R, Dominguez E, et al: Ischemic optic neuropathy in a dog with acute bilateral blindness and primary systemic hypertension, J Vet Intern Med 32:423, 2018. 31. Stiles J, Weil AB, Packer RA, et al: Post-anesthetic cortical blindness in cats: twenty cases, Vet J 193:367, 2012. 32. Barton-Lamb AL, Martin-Flores M, Scrivani PV, et al: Evaluation of maxillary arterial blood flow in anesthetized cats with the mouth closed and open, Vet J 196:325, 2013. 33. Scrivani PV, Martin-Flores M, van Hatten R, et al: Structural and functional changes relevant to maxillary arterial flow observed during computed tomography and nonselective digital subtraction angiography in cats with the mouth closed and opened, Vet Radiol Ultrasound 55:263, 2014. 34. Martin-Flores M, Scrivani PV, Loew E, et al: Maximal and submaximal mouth opening with mouth gags in cats: implications for maxillary artery blood flow, Vet J 200:60, 2014. 35. Young WM, Zheng C, Davidson MG, et al: Visual outcome in cats with hypertensive chorioretinopathy, Vet Ophthalmol 22:161, 2019. 36. Aroch I, Ofri R, Sutton GA: Ocular manifestations of systemic diseases. In Maggs DJ, Miller PE, Ofri R, editors: Slatter’s fundamentals of veterinary ophthalmology, ed 5, St. Louis, 2013, Elsevier, pp 394-436. 37. Gelatt KN, van der Woerdt A, Ketring KL, et al: Enrofloxacin-associated retinal degeneration in cats, Vet Ophthalmol 4:99, 2001. 38. Wiebe V, Hamilton P: Fluoroquinolone-induced retinal degeneration in cats, J Am Vet Med Assoc 221:1568, 2002.

145 Critically Ill Neonatal and Pediatric Patients Maureen A. McMichael, DVM, M.Ed., DACVECC, Katherine K. Gerken, DVM, MS, DACVECC

KEY POINTS • There are significant differences in the biochemical, hematologic, radiographic, pharmacologic, and monitoring parameters in neonatal and pediatric animals compared with adult animals. • Dramatic elevations in alkaline phosphatase and g-glutamyltransferase levels and very low values for serum levels of blood urea

nitrogen, albumin, and cholesterol occur in the neonate and can mimic hepatic failure. • The most common causes of dehydration in the neonate and pediatric patient are gastrointestinal losses and insufficient intake.

There are several crucial differences in the diagnosis, monitoring, and treatment of critically ill neonates and pediatric patients compared with critically ill adult patients, and it is essential for veterinarians with a neonatal and pediatric patient base to become familiar with normal biochemical, hematologic, radiographic, and physical examination values for this age group. In veterinary medicine, the term neonate encompasses animals from birth to 2 weeks of age, and the term pediatric refers to animals between 2 weeks and 6 months of age. This chapter reviews the hematologic, biochemical, nutritional, imaging, fluid treatment, monitoring, and pharmacologic aspects of the normal and critically ill neonate and pediatric cat and dog. Also included is a brief review of sepsis in the neonate.

to increase again. At 4 to 6 weeks of age, kittens reach a Hct nadir of 27%.3 Knowledge of this normal decrease in Hct is essential for assessment of any neonate, and during this period a rise in the Hct is usually indicative of dehydration. Conversely, the white blood cell count increases after birth, appearing as a mild to moderate leukocytosis in puppies and kittens 1–2 months of age. This is thought to be the result of initial antigen exposure and potential parasite load causing an increase in lymphocytes and eosinophils, respectively.2-3 Slight changes are seen in the biochemical profile of newborn puppies and kittens. In dogs there is a mild increase in bilirubin (0.5 mg/ dl; normal adult range, 0 to 0.4 mg/dl) and dramatic increases in serum levels of alkaline phosphatase (3845 IU/L; normal adult range, 4 to 107 IU/L) and g-glutamyltransferase (1111 IU/L; normal adult range, 0 to 7 IU/L).4 In kittens, the alkaline phosphatase level is threefold higher than that seen in adults (123 IU/L; normal adult range, 9 to 42 IU/L). Lower values of blood urea nitrogen (BUN), creatinine, albumin, cholesterol, and total protein are seen in neonates compared with adults (although the BUN concentration may be slightly elevated during the first week of life). Calcium and phosphorus levels are higher in neonates and young animals; this is the result of bone development, growth hormone, and renal tubular resorption.5 Urine is isosthenuric because the capacity to concentrate or dilute urine is limited in this age group. This is especially important when prescribing fluid therapy because overhydration is just as much of a concern as is underhydration.

PHYSICAL EXAMINATION FINDINGS Healthy neonates are lively and plump (Box 145.1). Illness is often recognized by incessant crying, lethargy, and flaccidity. Mucous membranes are often hyperemic during the first 4 to 7 days of life and may be pale, cyanotic, or gray in sick neonatal animals. The rectal temperature at birth is normally 35.2°C to 37°C (95.4°F to 98.6°F) and gradually increases to adult levels over the first 4 weeks of life. Using a pediatric stethoscope (ideally), many puppies and kittens will have an innocent murmur until 12 weeks of age, with some continuing beyond 6 months.1 However, other causes of murmur include a congenital cardiac defect, stress, fever, sepsis, anemia, and hypoproteinemia. The heart rate in the normal neonatal puppy and kitten is 200 and 250 beats/min, respectively. The heart rate decreases as the animal develops increased parasympathetic tone at 4 weeks of age. The respiratory rate following birth is normally 15 breaths/min but increases to 30 breaths/min within 1 to 3 hours. Because of the small tidal volume and increased interstitial fluid in the normal neonate, assessment of lung sounds is difficult. An increase or decrease in heart rate or respiratory rate should be assessed and rates should be monitored closely during treatment.

LABORATORY VALUES The hematocrit (Hct) decreases from 47.5% at birth to 29.9% by day 28 in puppies (Box 145.2).2 By the end of the first month, the Hct starts

IMAGING: RADIOGRAPHS Normal anatomic differences in the young may be significant. The thymus is located in the cranial thorax on the left side and can mimic a mediastinal mass or lung consolidation on thoracic radiographs. The heart takes up more space in the thorax than it does in adults and may appear enlarged. The lung parenchyma has increased water content and is more radiographically opaque in neonates.6 There is an absence of costochondral mineralization so that the liver appears to protrude further caudal from under the rib cage than expected, which is easily misdiagnosed as hepatomegaly. There is loss of abdominal detail due to minimal fat and a small amount of abdominal effusion.6 Radiographic

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BOX 145.1  Clinical Values for Normal

Puppies and Kittens (birth to 12 weeks)

• Heart rate: 200 beats/min (puppy) and 250 beats/min (kitten) • Respiratory rate: 15 breaths/min (birth) and 30 breaths/min (by 1 to 3 hours after birth) • Temperature: 35.2°C to 37°C (95.4°F to 98.6°F) at birth, normalizing to adult values at 4 weeks • Mean arterial pressure: 49 mm Hg at 1 month of age, 94 mm Hg at 9 months (puppies) • Central venous pressure: 8 cm H2O at 1 month of age, 2 cm H2O at 9 months (puppies)

BOX 145.2  Normal Laboratory Values for Puppies and Kittens Complete Blood Count—Pediatric Canine Hematocrit: 47% at birth, 29% at 28 days Leukocyte count: 12.0 3 103/mm3, day 7 Band count: 0.5 3 103/mm3, day 7 Lymphocyte count: 5 3 103/mm3, day 7 Eosinophil count: 0.8 3 103/mm3, day 7 Complete Blood Count—Pediatric Feline Hematocrit: 35% at birth, 27% at 28 days Leukocyte count: 9.6 3 103/mm3 at birth, 23.68 3 103/mm3 at 8 weeks Lymphocyte count: 10.17 3 103/mm3 at 8 weeks, 8.7 3 103/mm3 at 16 weeks Eosinophil count: 2.28 3 103/mm3 at 8 weeks, 1 3 103/mm3 at 16 weeks Biochemistry Profile—Pediatric Caninea Bilirubin: 0.5 mg/dl (range, 0.2 to 1; normal adult range, 0 to 0.4) Alkaline phosphatase: 3845 IU/L (range, 618 to 8760 IU/L; normal adult range, 4 to 107 IU/L) g-Glutamyltransferase: 1111 IU/L (range, 163 to 3558 IU/L; normal adult range, 0 to 7 IU/L) Total protein: 4.1 g/dl (range, 3.4 to 5.2 g/dl; normal adult range, 5.4 to 7.4 g/dl) Albumin: 1.8 g/dl at 2 to 4 weeks (range, 1.7 to 2 g/dl; normal adult range, 2.1 to 2.3 g/dl) Glucose: 88 mg/dl (range, 52 to 127 g/dl; normal adult range, 65 to 100 g/dl) Biochemistry Profile—Pediatric Felinea Bilirubin: 0.3 mg/dl (range, 0.1 to 1 mg/dl; normal adult range, 0 to 0.2 mg/dl) Alkaline phosphatase: 123 IU/L (range, 68 to 269 IU/L; normal adult range, 9 to 42 IU/L) g-Glutamyltransferase: 1 IU/L (range, 0 to 3 IU/L; normal adult range, 0 to 4 IU/L) Total protein: 4.4 g/dl (range, 4 to 5.2 g/dl; normal adult range, 5.8 to 8 g/dl) Albumin: 2.1 g/dl (range, 2 to 2.4 g/dl; normal adult range, 2.3 to 3 g/dl) Glucose: 117 mg/dl (range, 76 to 129 mg/dl; normal adult range, 63 to 144 mg/dl) At birth except where specified.

a

resolution may be improved by reducing the kilovoltage peak value to half of the adult setting and using detailed film or screens.

INTRAVENOUS AND INTRAOSSEOUS CATHETERIZATION When venous access is required, use of the intravenous route is preferred and should be attempted first. Neonates often require very smallgauge catheters (e.g., 24 or 27 gauge), which can develop burrs easily when advanced through the skin. To avoid this, a small skin puncture can be made with a 20-gauge needle (while the skin is elevated), and

then the catheter can be fed through the skin hole. In human neonates, ~90% of thromboembolic events are catheter related, and a catheter care plan is therefore essential.7 If attempts at intravenous catheter placement fail, an intraosseous catheter should be placed (see Chapter 194, Intraosseous Catheterization). An intraosseous catheter can be inserted in the proximal femur or humerus using an 18- to 22-gauge spinal needle or an 18- to 25-gauge hypodermic needle. An intraosseous catheter can be used for fluid and blood administration.8 The area must be prepared in a sterile manner and the needle inserted into the bone parallel to the long axis. Gentle aspiration will ensure patency, and the needle is secured with a sterile bandage. Intravenous access must be established as soon as possible, ideally within 2 hours, and the intraosseous catheter should be removed to minimize the risk of osteomyelitis or other complications. The incidence of intraosseous catheter complications correlates with duration of use.9

FLUID REQUIREMENTS Neonates have higher fluid requirements than adults because they have a higher percentage of total body water, a higher ratio of surface area to body weight, a higher metabolic rate, more permeable skin, a decreased renal concentrating ability, and less body fat. Both dehydration and overhydration are concerns because neonatal kidneys cannot concentrate or dilute urine as well as adult kidneys.5 A warm isotonic crystalloid bolus (30 to 40 ml/kg in puppies and 20 to 30 ml/kg in kittens) should be administered to moderately dehydrated neonates, followed by a constant rate infusion (CRI) of BW(kg)0.75 3 70/day plus ongoing losses or deficits. A liter of fluid warmed to 104°F will cool down to room temperature (70°F) within approximately 10 minutes; this can be prevented by placing an in-line fluid warmer. Lactated Ringer’s solution may be the ideal fluid because lactate is the preferred metabolic fuel in the neonate with hypoglycemia.10,11 Hypoglycemia in neonates commonly occurs as a result of inefficient hepatic gluconeogenesis, inadequate hepatic glycogen stores, and glucosuria. Urinary glucose reabsorption does not normalize until approximately 3 weeks of age in puppies.12,13 In addition, neonates have greater glucose requirements than do adults. The neonatal brain requires glucose for energy, and brain damage can occur with prolonged hypoglycemia.13 Fetal and neonatal myocardia use carbohydrates (glucose) for energy rather than the long-chain fatty acids used by the adult myocardium.14 In summary, neonates have an increased demand for, an increased loss of, and a decreased ability to synthesize glucose compared with adults. In adults, the counterregulatory hormones (i.e., cortisol, growth hormone, glucagon, and epinephrine) are released in response to low blood glucose levels and facilitate euglycemia by increasing gluconeogenesis and antagonizing insulin. Clinical signs of hypoglycemia can be challenging to recognize in neonates because of inefficient counterregulatory hormone release during hypoglycemia.13 Vomiting, diarrhea, infection, and decreased oral intake all result in hypoglycemia in neonates. A bolus of 1 to 3 ml/kg of 12.5% dextrose (i.e., 50% dextrose diluted 1:3 with sterile water) followed by a CRI of isotonic fluids supplemented with 2.5% to 10% dextrose is required to treat hypoglycemia. Any continuous supplementation higher than 5% dextrose must be given through a central line. To prevent rebound hypoglycemia, any bolus should be followed by a dextrose CRI. In addition, some neonates may have refractory hypoglycemia and respond only to hourly boluses of dextrose in addition to a CRI of crystalloids with supplemental dextrose. Carnitine supplementation may allow maximal utilization of glucose. The recommended dosage is 200 to 300 mg/kg orally q24h for both puppies and kittens.

CHAPTER 145  Critically Ill Neonatal and Pediatric Patients The most common causes of hypovolemia in neonates are gastrointestinal (GI) disturbances (e.g., vomiting, anorexia, diarrhea) and inadequate oral intake. The most common cause of diarrhea in neonatal puppies and kittens is iatrogenic (owner) overfeeding with formula. In adults with hypovolemia, compensation occurs through an increase in heart rate, concentration of the urine, and a decrease in urine output. In neonates, compensatory mechanisms may not be adequate. Contractile elements make up a smaller portion of the fetal myocardium (30%) than the adult myocardium (60%), which makes it difficult for the fetus to increase cardiac contractility in response to hypovolemia. Neonates also have immature sympathetic nerve fibers in the myocardium and cannot maximally increase heart rate in response to hypovolemia. Complete maturation of the autonomic nervous system does not occur until after 8 weeks in puppies.15,16 Because neonates have higher fluid requirements and increased losses (less renal concentrating ability, higher respiratory rate, higher metabolic rate), dehydration may progress rapidly to hypovolemia and shock if not treated promptly. The difficulties associated with assessing hypovolemia in neonates require constant vigilance and continuous monitoring. One must assume that all neonates with severe diarrhea, inadequate intake, or severe vomiting are dehydrated and potentially hypovolemic, and treatment should be initiated immediately. Fluid therapy, monitoring of electrolyte and glucose status, and nutritional support are the mainstays of treatment. The patient should be weighed every 6 to 12 hours. Dehydration is likely in pups greater than 4 weeks old when the urine specific gravity reaches 1.020, and this parameter should be monitored as an indicator of adequacy of rehydration.17 In severely dehydrated or hypovolemic animals, a bolus of 40 to 45 ml/kg (puppies) or 25 to 30 ml/kg (kittens) of warm isotonic fluids is given initially, followed by a CRI of maintenance fluids (80 to 100 ml/kg/day) and replacement of losses. Losses can be estimated (e.g., 2 tablespoons of diarrhea is equal to 30 ml of fluid). If the neonate is hypoglycemic or not able to eat, dextrose is added to the intravenous fluids at the lowest concentration that will maintain normoglycemia (treatment should start with 1.25% dextrose).

TEMPERATURE CONTROL Neonates are poikilothermic for the first 2 weeks of life and are prone to hypothermia when the ambient temperature is cool or when deprived of maternal and sibling body heat. Susceptibility to hypothermia is due to a higher ratio of surface area to volume, immature metabolism, and immature shivering reflex (develops at 6 days) and vasoconstrictive ability. Hypothermic patients should be rewarmed slowly. Animals that are separated from the mother should be placed in a neonatal incubator at a temperature of 85°F to 90°F and humidity of 55% to 65%. Heat lamps or heating pads and hot water bottles may also be used, but the neonate should be able to crawl away from the heat source. Heating pads should be covered with a towel to prevent burns.

NUTRITION Nutrition is crucial to neonatal health, and inadequate caloric intake must be addressed promptly to prevent malnutrition. A surrogate dam is ideal if the biologic dam is unavailable, but this is often difficult to arrange. Weighing the neonate on a pediatric gram scale before and after each feeding can help the clinician monitor intake. Bottle and tube feeding are other therapeutic options. Animals that are separated from the mother should be stabilized and rewarmed slowly before feeding because hypothermia prevents digestion and induces ileus. A human infant bottle is preferred for puppies because

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they often cannot latch onto the smaller kitten-size nipple supplied with most replacement formulas. Orogastric tube feeding is done using a 5-Fr red rubber catheter for neonates under 300 g and an 8- to 10-Fr catheter for larger neonates and should be performed only by experienced personnel.18 It is easy to improperly place the feeding tube in the trachea in neonates because the gag reflex does not develop until 10 days of age. Up to 10% of body weight may be lost within the first 24 hours following birth; additional weight loss or failure to gain weight is a poor prognostic indicator. Puppies should double their weight within 10 days of birth and gain 5% to 10% of their body weight per day for 8–12 weeks. Nursing kittens should also double their weight within the first 10 days of life, and normal kittens gain 10 to 15 g per day for 8–12 weeks. Formula-fed neonates grow at significantly slower rates, even with identical caloric intake. Although critically ill neonates and pediatric patients may not gain weight normally, weight loss should be prevented. Recently, the human microbiome project has begun to elucidate the critical nature of our symbiotic relationship with microflora.19 Intestinal commensal bacteria directly influence the development of immune functions and differentiation of the epithelium of the GI tract.20 Microflora produce enzymes that aid in mucus secretion, synthesis of certain vitamins, and absorption of calcium, magnesium, and iron. Protection against invading pathogens occurs via several mechanisms, including release of antibacterials (bacteriocins, lactic acid), competition for adhesion sites and nutrients, and the physical barrier itself.20 Critical illness combined with long-term medical therapy can disrupt the GI microbiome because of decreased GI perfusion, antimicrobial drug administration, use of histamine-2 antagonists and proton pump inhibitors, administration of drugs that cause GI stasis, and lack of enteral nutrition. Supplementation with prebiotics (foods that sustain the growth of intestinal microorganisms) and probiotics (microorganism strains that may help recolonize the GI tract) has been shown to be safe and cost effective, in addition to having few known adverse effects. Recent studies document significant shifts in the neonatal canine microbiome within the first 3–8 weeks of life.21 There is additional data from a feline pediatric microbiome study that followed the effects of diet and age over time. Researchers followed a cohort of related kittens from 8 weeks to 5 years of age and reported that over half of the observed taxa became altered over time with age. Bifidobacterium and Lactobacillus went down with age in all groups.22

MONITORING Monitoring disease progression and effectiveness of treatment can be challenging in neonates because the values of many parameters are significantly different from those in adults. Mean arterial pressure is lower (49 mm Hg at 1 month of age in puppies) and does not normalize (94 mm Hg) until 9 months of age.23 Central venous pressure is higher (8 cm H2O) at 1 month of age in puppies but decreases to 2 cm H2O by 9 months of age23 (see Box 145.1). Neonatal kidneys cannot autoregulate perfusion pressure with variations in systemic arterial pressure as adults do, resulting in a glomerular filtration rate that decreases as the systemic blood pressure decreases.23 This makes restoration of intravenous fluid volume critical in neonates. Appropriate renal concentration and dilution of urine does not occur until approximately 10 weeks of age.24,25 Simultaneously, BUN and creatinine concentrations are lower in neonates than in adults, which makes monitoring for azotemia difficult. The best way to monitor for dehydration or overhydration is to have an accurate pediatric gram scale and weigh the patient three or

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four times per day. Baseline thoracic radiographs are also helpful to establish a baseline since neonate lungs have more interstitial fluid than adult lungs. Other ways to monitor fluid therapy include checking Hct and total solids. As stated above, the Hct decreases progressively in normal neonates from day 1 to day 28, and total solids are lower than in adults (see the Laboratory Values section). Neonatal skin has a lower fat and higher water content than does that of adults, and therefore skin turgor cannot be used to assess dehydration. Mucous membranes remain moist in severely dehydrated neonates and are not useful for assessment of dehydration. Blood lactate levels, thought to be a good indicator of perfusion, are higher in normal puppies than in adult dogs (1.07 to 6.59 mmol/L at 4 days of age and 0.80 to 4.60 mmol/L from 10 to 28 days of age), likely secondary to underdeveloped hepatic clearance mechanisms.26 Hypothermia (rectal temperature of 25.6°C to 34.4°C [78°F to 94°F]) is common in neonates and is associated with a depressed respiratory rate, bradycardia, GI paralysis, and coma. Rectal temperature should be monitored using a normal digital thermometer. Temperatures above the normothermic range indicate fever or excessive external warming. Pulse oximetry-based determination of hemoglobin (Hb) level allows measurement of Hb noninvasively.27 The oximeter uses light absorption to determine levels of total Hb, oxyhemoglobin, and in some cases carboxyhemoglobin and methemoglobin as well. There are still significant issues with the currently approved devices, and no published studies in human pediatrics or neonatology used the technology.27 The current studies reveal problems with accuracy and precision, particularly in patients that are hypotensive or hypoperfused. The benefits of noninvasive Hb measurement are substantial, particularly in the smallest patients.

PHARMACOLOGY Drug metabolism in neonates differs significantly from that in adults because of differences in levels of body fat, total protein, and albumin (a protein to which many drugs bind). Renal clearance of drugs is decreased in neonates, and renal excretion of many drugs (e.g., diazepam, digoxin) is diminished, which increases the half-life of the drug in circulation.4 Hepatic clearance is more complicated. Drugs requiring activation via hepatic metabolism will have lower plasma concentrations, and drugs requiring metabolism for excretion will have higher plasma concentrations.28,29 The oral route of fluid and drug administration should be avoided during the first 72 hours of life because absorption is significantly higher due to increased GI permeability. Intestinal flora is very sensitive to disruption by oral antimicrobial agents. Administration via the intravenous (or intraosseous) route may be the most predictable and is preferred over intramuscular or subcutaneous administration in this age group.5 One of the safest classes of antimicrobials in neonates is the blactam group (i.e., penicillins and cephalosporins), but the dosing interval should be increased to every 12 hours rather than every 6–8 hours.5 Metronidazole is the preferred drug for treatment of giardiasis and anaerobic infections. The dose and/or frequency should be decreased in neonates. Antimicrobials to avoid or use cautiously include chloramphenicol (circulatory collapse), gentamicin/aminoglycosides (pathologic damage to renal cortex), tetracycline (skeletal muscle damage and enamel hypoplasia), and quinolones (destructive lesions of the cartilage). Dosages of cardiovascular drugs (e.g., epinephrine, dopamine, dobutamine) can be difficult to determine in neonates due to individual variations in the maturity of the autonomic nervous system. Vasopressin

may be a superior alternative as it does not depend on immature adrenergic receptors and has been shown to be associated with fewer side effects and equal vasoconstricting effects as dopamine in human neonates.30 Assessment of response to treatment and continuous monitoring of hemodynamic variables are essential when these drugs are used. Elevations in heart rate after administration of dopamine, dobutamine, or isoproterenol cannot be predicted until 9 to 10 weeks of age, and the response to atropine and lidocaine is decreased in the neonate.31-33 The blood–brain barrier is more permeable in neonates, allowing drugs to enter that do not normally cross over to the central nervous system.26 The normal neonatal respiratory rate is about two to three times higher than the normal adult rate as a result of higher airway resistance and higher oxygen demands. Drugs that depress respiration should be avoided in neonates. Neonates are very dependent on a high heart rate to increase cardiac output, so drugs that depress heart rate should be avoided. Opioids are a good choice for analgesia because of the reversibility of their effects, but the animal must be monitored closely because of the propensity of these drugs to depress heart and respiratory rate. Caution is advised when using heparinized saline flushes at the same volume (2–3 ml) used in adults. It is easy to over-heparinize young animals; therefore, a smaller volume of heparinized saline or plain isotonic saline should be used. Although recommendations vary, the maximum amount of blood withdrawn should not exceed 1% of the animal’s body weight (kg). For example, no more than 50 ml should be removed from a 5-kg cat, and this should not occur more frequently than once every 14 days.

SEPSIS In humans, sepsis is the third most frequent cause of neonatal mortality, and sepsis likely contributes to canine and feline neonatal mortality as well.34 Wounds, such as those from tail docking or umbilical cord ligation, as well as respiratory, urinary, and GI tract infections are most commonly implicated in neonatal sepsis. Common bacterial isolates include Staphylococcus, Streptococcus, Escherichia coli, Klebsiella, Enterobacter, Clostridium, and Salmonella. Additional possible causes of sepsis include brucellosis, viral infections (distemper, panleukopenia, herpesvirus infection, feline infectious peritonitis, and feline leukemia virus infection), and toxoplasmosis. Clinical signs, as with hypovolemia, are often subtle or absent, which makes the diagnosis difficult in this age group. Some clinical signs that may be associated with sepsis are crying and reluctance to nurse, decreased urine output, and cold extremities. Studies of sepsis in children and several animal models have documented improved survival with rapid, aggressive fluid resuscitation.35 Large volumes of fluid may be necessary in septic patients, but caution should be exercised to avoid volume overload, especially in patients with vascular leak syndromes or vasodilation.35,36 Although endothelial glycocalyx damage can occur with crystalloid and colloid administration, the detrimental effects are not yet well studied in neonatal and pediatric patients. Vasopressors may be helpful with vasodilatory states depending on the maturation of the neonate. Resuscitation should be started immediately with a bolus of 30 to 45 ml/kg (puppies) or 25 to 30 ml/kg (kittens) of warm isotonic fluids, followed by a reassessment of the parameters of perfusion (see later in this section). If perfusion normalizes, an appropriate fluid CRI at a maintenance fluid rate plus compensation for estimated dehydration and ongoing losses should be administered. If perfusion has not normalized, repeated boluses and/or vasopressors may be required. Monitoring includes serial checks of perfusion indicators including mucous membrane color, pulse quality, extremity temperature, lactate levels, and mentation. Failure of passive transfer may lead to immune compromise in neonates. Frozen canine colostrum from a healthy, vaccinated dam is the

CHAPTER 145  Critically Ill Neonatal and Pediatric Patients best substitute. When colostrum is unavailable, administration of a CRI of fresh or fresh frozen plasma or subcutaneous administration of serum from a well-vaccinated adult may help to augment immunity.37 There is evidence in kittens that both intraperitoneal and subcutaneous administration of adult cat serum in three 5-ml increments (at birth and at 12 and 24 hours) resulted in immunoglobulin G (IgG) concentrations equivalent to those seen in kittens that suckled normally.38 In puppies, subcutaneous administration of serum at 2 ml or 4 ml per 100 g body weight increased IgG to 2.6 or 4.5 g/L, respectively.39 Frequent checks of electrolyte levels, blood glucose concentration, body temperature, and nutritional status are done as indicated earlier. Septic neonates that have undergone adequate fluid resuscitation but remain in a hypoperfused state (e.g., cold extremities, high lactate levels, low urine output, low blood pressure) may benefit from vasopressor or inotropic support, or both (e.g., dopamine, dobutamine, phenylephrine, norepinephrine, vasopressin). Because of variations in the maturity of the autonomic nervous system, all pressor and inotropic drug therapy should be tailored to the individual animal. Acceptable endpoints of therapy to normalize perfusion include increases in extremity temperature, decreases in lactate levels, increased urine production, and improvement in attitude. Ideally, a sample from the area of possible or suspected infection is submitted for culture and susceptibility testing before antibiotic treatment is begun. Broad-spectrum antibiotics may be required if the source of infection cannot be identified. Penicillins or first-generation cephalosporins are good choices in the neonate. If oxygen therapy is needed, the inspired oxygen fraction should be kept at or below 0.4 to avoid oxygen toxicity, which can cause retrolental fibroplasia and lead to permanent blindness.40 Sepsis can be very difficult to detect in neonates. A high index of suspicion should be maintained for all neonates with risk factors, and treatment should be instituted rapidly and aggressively. The incidence of pediatric sepsis in humans is highest in premature newborns. Respiratory infections (37%) and primary bacteremia (25%) are the most common infections.41

CONCLUSION The unique anatomic and physiologic characteristics of critically ill neonatal and pediatric patients make diagnosis, monitoring, and treatment of these patients challenging. Parameters used in adults cannot be relied on in very young patients, and an awareness of the unique characteristics of very young patients is essential. In addition, many laboratory and pharmacologic data differ dramatically in neonates compared with adults of the same species. Familiarity with these variations is essential in the monitoring and treatment of neonatal or pediatric patients that may be experiencing hypovolemia, shock, or sepsis.

REFERENCES 1. van Stavern MDB, Szatmari V: Age when presumptive innocent cardiac murmurs spontaneously disappear in clinically healthy Cairn terrier puppies, Vet J 248:25-27, 2019. 2. Earl FL, Melveger BE, Wilson RL: The hemogram and bone marrow profile of normal neonatal and weanling Beagle dogs, Lab Anim Sci 23:690, 1973. 3. Meyers-Wallen V: Hematologic values in healthy neonatal, weanling and juvenile kittens, Am J Vet Res 45:1322, 1984. 4. Center S, Hornbuckle W, Hoskins JD: The liver and pancreas. In Hoskins JD, editor: Veterinary pediatrics: dogs and cats from birth to six months, ed 3, Philadelphia, 2001, Saunders, pp 200-224. 5. Boothe DM, Tannert K: Special considerations for drug and fluid therapy in the pediatric patient, Compend Contin Educ Pract Vet 14:313, 1992.

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6. Hoskins JD, Partington BP: The physical examination and diagnostic imaging techniques. In Hoskins JD, editor: Veterinary pediatrics: dogs and cats from birth to six months, ed 3, Philadelphia, 2001, Saunders, pp 1-21. 7. Bacciedoni V, Attie M, Donato H: Thrombosis in newborn infants, Arch Argent Pediatr 114(2):159-166, 2016. 8. Otto C, Kaufman G, Crowe D: Intraosseous infusion of fluids and therapeutics, Compend Contin Educ Vet Pract 11:421, 1989. 9. Fiser DH: Intraosseous infusion, N Engl J Med 322:1579, 1990. 10. Levitsky LL, Fisher DE, Paton JB, et al: Fasting plasma levels of glucose, acetoacetate, D-beta-hydroxybutyrate, glycerol, and lactate in the baboon infant: correlation with cerebral uptake of substrates and oxygen, Pediatr Res 11:298, 1977. 11. Hellmann J, Vannucci RC, Nardis EE: Blood-brain barrier permeability to lactic acid in the newborn dog: lactate as a cerebral metabolic fuel, Pediatr Res 16:40, 1982. 12. Bovie KC: Genetic and metabolic diseases of the kidney. In Bovie KC, editor: Canine nephrology, Philadelphia, 1984, Harel, pp 339-354. 13. Atkins C: Disorders of glucose homeostasis in neonatal and juvenile dogs: hypoglycemia: Part 1, Compend Contin Educ Vet Pract 6:197, 1984. 14. Textile D, Hoffman JIE: Coronary circulation and myocardial oxygen consumption. In Glickman PD, Heyman MA, editors: Pediatrics and perinatology: the scientific basis, London, 1996, Arnold, pp 731-736. 15. Textile D, Hoffman JIE: Ventricular function. In Glickman PD, Heyman MA, editors: Pediatrics and perinatology: the scientific basis, London, 1996, Arnold, pp 737-748. 16. Mace SE, Levy MN: Neural control of heart rate: a comparison between puppies and adult animals, Pediatr Res 17:491, 1983. 17. McIntire D: Pediatric intensive care, Vet Clin North Am Small Anim Pract 29:837, 1999. 18. Hoskins JD: Pediatric health care and management, Vet Clin North Am Small Anim Pract 29:837, 1999. 19. NIH Human Microbiome Project. Available at http://Hmpdacc.org. Accessed August 2013. 20. Papoff P, Ceccarelli G, d’Ettorre G, et al: Gut microbial translocation in critically ill children and effects of supplementation with pre- and probiotics, Int J Microbiol 2012:151393, 2012. 21. Guard BC, Mila H, Steiner JM, et al: Characterization of the fecal microbiome during neonatal and early pediatric development in puppies, PLOS One 12:e0175718, 2017. 22. Bermingham EN, Young W, Butowski CF, et al: The fecal microbiota in the domestic cat (Felis catus) is influenced by interactions between age and diet; a five year longitudinal study, Front Microbiol 9:1231, 2018. 23. Magrini F: Haemodynamic determinants of the arterial blood pressure rise during growth in conscious puppies, Cardiovasc Res 12:422, 1978. 24. Holster M, Keeler BJ: Intracortical distribution of number and volume of glomeruli during postnatal maturation in the dog, J Clin Invest 50:796, 1971. 25. Fetuin M, Allen T: Development aspects of fluid and electrolyte metabolism and renal function in neonates, Compend Contin Educ Vet Pract 13:392, 1991. 26. McMichael MA, Lees GE, Hennessey J, et al: Serial plasma lactate concentrations in 68 puppies aged 4 to 80 days, J Vet Emerg Crit Care (San Antonio) 15:17, 2005. 27. Holtby H, Skowno JJ, Kor DJ, et al: New technologies in pediatric anesthesia, Paediatr Anaesth 22:952-961, 2012. 28. Short CR: Drug disposition in neonatal animals, J Am Vet Med Assoc 184:1161, 1984. 29. Peters E, Farber T, Heider A: The development of drug metabolizing enzymes in the young dog, Fed Proc Am Soc Biol 30:560, 1971. 30. Rios DR, Kaiser JR: Vasopressin versus dopamine for treatment of hypotension in extremely low birth weight infants: a randomized, blinded pilot study, J Pediatr 166(4):850-855, 2015. 31. Driscoll DJ, Gillette PC, Lewis RM, et al: Comparative hemodynamic effects of isoproterenol, dopamine, and dobutamine in the newborn dog, Pediatr Res 13:1006, 1979. 32. Mary-Rabine L, Rosen MR: Lidocaine effects on action potentials of Purkinje fibers from neonatal and adult dogs, J Pharmacol Exp Ther 205: 204, 1978.

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33. Woods WT, Urthaler F, James TN: Progressive postnatal changes in sinus node response to atropine and propranolol, Am J Physiol 234:H412, 1978. 34. Wattal C, Kler N, Oberoi JK, et al: Neonatal sepsis: mortality and morbidity in neonatal sepsis due to multidrug resistant organisms: part 1, Indian J Pediatr 87(2):117-121, 2020. doi.org/10.1007/s12098-019-03106-z. 35. Thomas NJ, Carcillo JA: Hypovolemic shock in pediatric patients, New Horiz 6:120, 1998. 36. Davis A, Carcillo J, Aneja R, et al: American College of Critical Care Medicine Clinical Practice Parameters for hemodynamic support of pediatric and neonatal septic shock, Crit Care Med 45(6):1061-1093, 2017.

37. Poffenbarger EM, Olson PN, Chandler ML, et al: Use of adult dog serum as a substitute for colostrum in the neonatal dog, Am J Vet Res 52:1221, 1991. 38. Levy JK, Crawford PC, Collante WR, et al: Use of adult cat serum to correct failure of passive transfer in kittens, J Am Vet Med Assoc 219:1401, 2001. 39. Bouchard G, Plata-Madrid H, Youngquist RS, et al: Absorption of an alternate source of immunoglobulin in pups, Am J Vet Res 53:230-233, 1992. 40. Jenkinson S: Oxygen toxicity, Crit Care Med 3:137, 1988. 41. Watson RS, Carcillo JA, Linde-Zwirble WT, et al: The epidemiology of severe sepsis in children in the United States, Am J Respir Crit Care Med 167:695, 2003.

146 Critically Ill Geriatric Patients Maureen A. McMichael, DVM, M.Ed., DACVECC, Katherine K. Gerken, DVM, MS, DACVECC

KEY POINTS • The definition of geriatric in veterinary medicine is complex due to breed and species differences but is generally defined as a pet that has entered the last 25% of its expected lifespan. • The number of geriatric pet cats and dogs is growing rapidly in many parts of the world, especially the United States and Europe. • Maintenance energy requirements decrease in older dogs but appear to increase in older cats (.12 years), which affects nutritional requirements in this age group.

• Comorbid conditions are common, and clinicians should maintain an index of suspicion for those encountered most frequently. This is particularly important for comorbid conditions that mimic others (hearing impairment and cognitive dysfunction syndrome, diminished olfactory capacity and decreased appetite, etc.). • Older animals do not appear to possess sufficient physiologic reserves, and acute illness can significantly tax their organ systems.

The prevalence of small animal geriatric patients continues to climb as client education and veterinary medicine advance with time and pet owners seek ways to enhance and extend the longevity of companion animals.1,2 In human medicine, gerontology is a distinct specialty, and geriatric competencies have been introduced into emergency and critical care residency programs.3,4 Older patients tend to have complex clinical presentations that are frequently influenced by comorbid conditions. The goal of the geriatric competencies is to make clinicians more comfortable with the challenges of treating patients in this age group. Several studies have shown that older age alone does not predict mortality in elderly people despite the fact that aging affects the physiology of every organ system. The main determinants of mortality are prior health status and severity of the current disease process(es).5-7 Although similar studies have not been done in veterinary medicine, it seems prudent to offer aggressive treatment to the older dog and cat once comorbid diseases, quality of life of the pet, and the owner’s desires are taken into consideration. The term geriatric is difficult to define in veterinary medicine because it differs between dogs and cats and among breeds (e.g., a Great Dane has a much shorter life span than a Chihuahua). American Animal Hospital Association guidelines suggest that a pet is geriatric when it has entered the last 25% of its expected life span. In the majority of studies small animals older than 7 years are considered geriatric (Table 146.1). A recent prospective screening of 45 geriatric dogs (median age, 11.5 years) elucidated many of the comorbid conditions affecting this age group.8 Forty-nine percent of owners reported vision and/or hearing loss and 42% reported lameness/stiffness and/or slowing down in their pets.8 On physical examination, 24% of the dogs had decreased range of motion in their joints, 18% had suspected neoplastic masses, and only 34% had a normal urine dipstick. Overall, abnormalities unrecognized by owners were identified in 80% of the dogs in this study, with a mean of 7.8 abnormalities identified per dog. These comorbid conditions may require additional diagnostics, changes in fluid and drug administration, nutritional intervention, and analgesia.

This chapter reviews the physiologic changes that occur as a result of aging as they relate to critical care medicine.

LABORATORY VALUES In people at rest, the laboratory values for red blood cells, white blood cells, platelets, and hemoglobin do not change with age. However, there is a decrease in the ability of the bone marrow to increase neutrophil production in response to infection and red blood cell production in response to anemia in geriatric humans.9 Neutrophil function has also been shown to decrease with age in humans.9 There are no established reference ranges for geriatric small animal patients, perhaps because the term geriatric is difficult to define, and therefore the laboratory values are hard to quantify. Harper and others looked at age-related variations in laboratory values in Beagles and Labrador Retrievers. The dogs were grouped into categories, and the geriatric category included all animals older than 10 years of age. There were no differences between the laboratory values for dogs older than 10 years of age and the rest of the adult dogs.10 Strasser and colleagues11 investigated age-dependent changes in laboratory values before and after exercise in Beagles. There were no significant differences in the laboratory values for 5-year-old and 10-year-old Beagles at rest. After exercise, however, significant differences were seen in many of the parameters. The older dogs had lower hematocrits, red blood cell counts, and hemoglobin concentrations. They also had a significantly lower venous oxygen saturation and lower plasma glucose levels.11 In addition, older dogs have a slower hematopoietic response to acute anemia (phlebotomy) than younger dogs.9 It is therefore plausible that any disease process may place a large burden on the tenuous reserves of geriatric animals. Differentiating normal “healthy” aging in dogs and cats from disease is essential to provide the appropriate care and prognostication for these patients. Studies in veterinary medicine have offered a standardized approach to geriatric physical examination and health assessment to better characterize the pathophysiology of normal age-related changes.12,13 Similar findings have been previously reported in older

851

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TABLE 146.1  Senior and Geriatric Age

Chart for Cats and Dogs

BODY WEIGHT Age 4 5 6 7 8 9 10 11 12

0–9.0

Senior Senior Senior Geriatric

9.1–23

Senior Senior Senior Geriatric Geriatric Geriatric

23.1–55

.55

Senior Senior Geriatric Geriatric Geriatric Geriatric Geriatric

Senior Senior Geriatric Geriatric Geriatric Geriatric Geriatric Geriatric Geriatric

cats to include increased blood pressure, heart rate, platelet count, presence of cardiac murmur, increased serum urea and bilirubin, lower body condition scores, hematocrit, albumin, and total calcium.14 The coagulation system appears to shift toward hypercoagulability as humans age, and the incidence of pulmonary thromboembolism is increased fivefold in humans older than 85 years.9 Although changes in the coagulation system with age have not been investigated in small animal patients, diagnostic testing and consideration of prophylactic treatment for suspected hypercoagulability may be warranted in this age group, especially in animals with predisposing disease processes. The human thoracic cage becomes more rigid and the lungs lose elasticity with age. Respiratory muscle strength is decreased by 25%, and the alveolar–arterial gradient increases significantly.15 Loss of diaphragmatic and intercostal muscle mass are thought to be responsible for the decline in respiratory muscle strength. These aging-related changes may result in a decreased arterial partial pressure of oxygen in older veterinary patients during illness or exertion. One study found no changes in arterial blood gas values in healthy older dogs, but it is not known whether changes occur during illness.16 Diseases such as pneumonia, pulmonary thromboembolism, and pulmonary edema place great pressure on the limited pulmonary reserves in older patients and therefore may be more difficult to treat. Renal blood flow, glomerular filtration rate, urine concentrating and diluting ability, and creatinine clearance have been shown to decrease with age in people.15 Inability to conserve sodium or concentrate urine and decreased renal blood flow have been reported in geriatric small animals.17 This combination leads to the inability of the aged to respond appropriately to hypovolemia or hypervolemia and may restrict their ability to tolerate excessive or insufficient fluid and electrolyte therapy. Ongoing studies at the University of California–Davis have demonstrated a difference in some aspects of canine endothelial function with age.18 Older dogs (8 years of age) had a greater release of nitric oxide (NO) in response to anesthesia induction with propofol than did younger dogs, even at doses that do not result in clinically apparent hypotension. This was not accounted for by a change in propofol elimination because plasma propofol levels (determined by highperformance liquid chromatography) did not differ between the two age groups. A significant increase in levels of the NO metabolite (i.e., nitrite) was observed in the older age group, which suggests a functional change in endothelial response with age. A similar observation has been made in aged rats.19 Clinicians should be aware that the reported hypotension with propofol use in older dogs may result, in part, from increased NO release and not just reduced NO clearance.

IMAGING Thoracic radiographs of geriatric dogs and cats can show increased lung opacity due to calcification of the bronchial circulation and pulmonary interstitial changes. Mineralized costochondral junctions as well as degenerative changes in the sternebral junctions can also be observed. Heterotopic bone can be seen in the lungs in some older dogs, particularly Collie breeds. Collectively, these changes may be mistaken for pulmonary disease. The heart may appear to lie on the sternum in old cats because it takes on a more horizontal orientation. This can easily be mistaken for cardiomegaly because of increased sternal contact. The aorta may seem more prominent and undulating in older cats due to a “kink” in its appearance (Fig. 146.1). The liver may extend beyond the costal arch and appear enlarged in older animals because of stretching of the ligaments that attach it to the diaphragm. Spondylosis of the vertebrae is common in older dogs, and degenerative joint disease changes may be seen in both dogs and cats as they age.

FLUID THERAPY Significant changes in multiple organ systems in geriatric animals should be taken into account when the type, dosage, and administration rate of fluids are selected. Additionally, changes in muscle mass and fat stores should be noted since marked changes can affect total body water and therefore daily maintenance fluid requirements. Geriatric animals have increasing amounts of myocardial fibrosis, valvular dysfunction, and myocardial fiber atrophy.17 The decrease in ventricular compliance limits the intravascular volume they can tolerate while paradoxically increasing their dependence on this volume. Geriatric animals are highly dependent on end-diastolic volume to increase cardiac output and therefore do not tolerate volume depletion during times of stress (e.g., illness, anesthesia). Balanced isotonic crystalloids (e.g., lactated Ringer’s solution, 0.9% sodium chloride) are ideal for the dehydrated geriatric patient. Both natural colloids (fresh frozen plasma) and artificial colloids (hydroxyethyl starches) are additional options for the treatment of hypovolemia but should be administered at a slower rate in geriatric animals because of their propensity for volume overload. Supplements such as potassium chloride, vitamin B complex, and dextrose may prove beneficial in deficient animals. A thorough search for underlying or chronic disease processes (chronic valvular disease, renal failure) is essential when planning fluid therapy. It is imperative that fluid therapy be monitored both diligently

Fig. 146.1  Thoracic radiograph of a healthy geriatric cat. Note the horizontal heart and prominent aorta. (Courtesy of Dr. Robert O’Brien, DVM, DACVR)

CHAPTER 146  Critically Ill Geriatric Patients and frequently. Monitoring for optimal perfusion includes frequent checks of pulse quality, extremity temperature, venous lactate levels, central venous oxygen saturation, urine output, body weight, and mentation (see Chapter 181, Hemodynamic Monitoring). Monitoring for fluid overload includes frequent checks of respiratory rate, body weight, urine output, central venous pressure, and arterial blood gas concentrations or pulse oximetry readings, frequent thoracic auscultation, and thoracic radiography.

NUTRITION Maintenance energy requirements decrease with age in dogs but appear to increase after the age of 12 years in cats.20-22 In addition, there may be a decrease in the ability to digest fat and protein as cats age.23 These changes can lead to either weight gain (e.g., if an older dog is fed food with the same caloric content as it ages) or weight loss (e.g., if an older cat is fed food with the same caloric content as it ages). The reduced ability to digest fats can lead to deficiencies in fat-soluble vitamins (e.g., vitamin E) and the inability to concentrate urine can lead to reduced ability to retain water-soluble vitamins (e.g., B vitamins) and electrolytes.23 There is a high prevalence of malnutrition in elderly humans, and several supplements have been shown to slow cognitive decline, including cobalamin, blueberries, sage, and curcumin.24 In older dogs with a limited ability to digest fats due to a diminished ability to secrete pancreatic lipase or bile acids, medium-chain triglycerides may be beneficial as a concentrated and highly absorbable energy source. Gastric emptying takes two times longer in geriatric humans, putting them at a higher risk for aspiration pneumonia at anesthetic induction.25 This is likely similar in geriatric pets and should be taken into consideration when anesthesia is needed. Adequate protein intake is essential for optimal immune function and is critical in geriatric animals. Protein requirements actually increase in older dogs, and the old dogma recommending protein restriction for kidney protection has been discounted.26-29 Antioxidants are essential to combat oxidative stress, which has been shown to increase with age in many species.30 The free radical/ oxidative stress theory of aging suggests that levels of reactive oxygen species increase with age, and amelioration of this increase can retard the aging process.30 Oxidative stress represents an imbalance between oxidative damage (i.e., free radical damage) and endogenous antioxidant protection. Antioxidants can be administered exogenously and are thought to contribute to decreased levels of oxidative stress and perhaps increased quality of aging. Some supplements that can be added easily to the treatment regimen include vitamin B complex administered in the intravenous fluids (2–4 ml/L when given at a maintenance rate), S-adenosyl-L-methionine (20 mg/kg PO q24h), and Nacetylcysteine (50 to 70 mg/kg diluted 1:4 with 0.9% sodium chloride and filtered, administered IV over 1 hour q6-8h or 50 mg/kg PO q812h). Oral N-acetylcysteine can be found in health food stores in the amino acid section. If the animal develops inappetence or soft stool, the dosage should be decreased or the drug discontinued. A relatively new area of study is the effect of gastrointestinal microflora on cognitive decline in the elderly.31 Probiotics as well as prebiotics and synbiotics appear to be safe, are easily administered, may function as an appetite stimulant, and are potentially helpful, especially in animals receiving antimicrobial therapy. Quality control is an issue for some products, so clinicians should recommend reputable brands. Anorexia is common in the older critically ill patient and should be treated aggressively after a thorough search for underlying causes. Cat food should be delivered in wide, shallow food bowls to prevent the whiskers from touching the sides. Also, smell is an important appetite

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stimulant in both dogs and cats, and clogged nasal passages (e.g., from bilateral nasal catheters for the delivery of oxygen) may cause decreased appetite. Warming the food and placing a small amount on the tongue may help stimulate the animal to eat. There are a variety of appetite stimulants for both dogs and cats; see Chapter 152, Appetite Stimulants, for further details.32,33 Sarcopenia is common in geriatric animals and may be associated with frailty. In humans, frailty is defined as meeting three of the five criteria: low energy, slowed walking speed, low physical activity, unintentional weight loss, and low grip strength.34 The presence of frailty increases the odds of mortality by 2.9 in humans.34 Although frailty is likely present and may contribute to morbidity in pets, no definition or evidence exists yet in veterinary medicine.

PHARMACOLOGY The mantra used most often in geriatric pharmacology is “start low, go slow.” Unfortunately, this conflicts with the nature of emergent treatment in the ICU, and it is imperative that clinicians take into account the effect of age when choosing drug dosages. Aging imposes several changes in the absorption, distribution, metabolism, and elimination of many drugs. A good review of general guidelines for dosage adjustments in geriatric small animals can be found in the article by Dowling.35 Oral absorption may be decreased because gastrointestinal function slows as the animal ages. The loss of lean body mass can also alter intramuscular drug absorption. Distribution of drugs may be altered for several reasons. If fluid retention is present (such as with congestive heart failure, cirrhosis, or renal failure), drugs that are distributed to the extracellular space (e.g., penicillins, nonsteroidal antiinflammatory drugs, aminoglycosides) may have changes in their distribution. Albumin concentration decreases with age and therefore affects the levels of protein-bound drugs.35 With less albumin in circulation, more free drug is available, which could lead to an inadvertent increase in active drug. In addition, drug metabolism may change as the geriatric patient experiences a decline in hepatic mass and function. This may result in an increased plasma half-life of drugs that require hepatic excretion, metabolism, or conjugation.17 Decreased function of phase I metabolic reactions in the liver may also occur with age and cause a decrease in oxidation, reduction, dealkylation, and hydroxylation reactions. Phase II reactions do not appear to be altered.36 Drug elimination may be affected by a progressive decline in renal function with age. In geriatric humans there is a steady decline in renal function, with approximately 40% of the nephrons becoming sclerotic and renal blood flow and glomerular filtration rate decreasing by almost 50% by the age of 85.9 Because of the loss of lean body mass, creatinine levels may remain normal (decreased production and decreased clearance). Approximately 15% to 20% of dogs and cats are thought to suffer from some degree of renal insufficiency as they enter the geriatric years.36 There is a progressive decline in ventricular compliance and the number of cardiac myocytes in geriatric humans. Autonomic tissue is replaced by fat and connective tissue and shows decreased responsiveness to autonomic drugs.9 It is likely that some decline in cardiac function occurs with age in animals, and careful monitoring for specific endpoints is essential when cardiac drugs are prescribed. Appropriate drug dosing in geriatric animals may be optimized by including measurement of renal function, therapeutic drug monitoring with frequent dosage adjustments, and dose or interval reduction based on creatinine concentrations. Examples of drugs that are renally cleared are amoxicillin, allopurinol, and many antifungals. Clinicians should always check renal clearance of specific

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drugs before dosing. The most practical and cost efficient of the aforementioned options is dose or interval reduction.

NEUROLOGICAL FUNCTION Cognitive dysfunction syndrome is common in senior and geriatric pets and can significantly diminish quality of life. Recently the glymphatic (glial 1 lymphatic) pathway has been shown to clear soluble proteins and metabolites from the brain during sleep; accumulation of these solutes is associated with neurodegenerative diseases.38 In addition to elimination of waste, the glymphatic system also plays roles in the distribution of glucose, lipids, amino acids, and neurotransmitters in the brain, and this system is essentially turned off during wakefulness. Norepinephrine seems to play a role in the suppression of the glymphatic system during nonsleep hours. Sleep disturbances are common in older humans and animals and are thought to contribute to accumulation of solutes and dementia. Sleep disturbances also occur frequently in ICU patients due to the loss of circadian rhythm, constant noise, and continuous stress. Melatonin decreases with age, and supplementation may help prevent Cognitive Dysfunction Syndrome by allowing clearance of solutes from the brain during sleep and can be considered in hospitalized geriatric pets.39

CONCLUSION Geriatric animals experience a decline in physiologic reserves that may not be apparent at rest. During times of ill health, however, geriatric animals often cannot mobilize reserves to meet the demands of the disease process, which results in multiple organ dysfunction and possible failure. Because of changes in cardiovascular, renal, hepatic, nutritional, and immune function, the older animal will respond differently to both the stress of illness and its treatment compared with the young adult. It is essential that the critical care team be familiar with these changes in the older animal and be prepared for vigilant monitoring during diagnostic testing and treatment of the illness. The severity of illness has the biggest influence on outcome in critically ill geriatric people, and this is likely to be similar in animals. Aggressive and appropriate treatment, careful monitoring, and, of course, tender loving care are essential to a successful outcome in the critically ill geriatric patient.

REFERENCES 1. Stratton-Phelps M: AAFP and AFM panel report of feline senior health care, Comp Cont Educ Pract Vet 21:531, 1999. 2. Kraft W: Geriatrics in canine and feline internal medicine, Eur J Med Res 3:31, 1998. 3. Biese KJ, Roberts E, LaMantia M, et al: Effect of geriatric curriculum on emergency medicine resident attitudes, knowledge, and decision-making, Acad Emerg Med 18:S92-S96, 2011. 4. Hogan TM, Losman ED, Carpenter CR, et al: Development of geriatric competencies for emergency medicine residents using an expert consensus process, Acad Emerg Med 17(3):316-324, 2010. 5. Campion EW, Mulley AG, Goldstein RL, et al: Medical intensive care for the elderly. A study of current use, costs, and outcomes, JAMA 246:2052, 1981. 6. Fedullo AJ, Swinburne AJ: Relationship of patient age to cost and survival in a medical ICU, Crit Care Med 11:155, 1983. 7. Goldstein RL, Campion EW, Thibault GE, et al: Functional outcomes following medical intensive care, Crit Care Med 14:783, 1986. 8. Davies M: Geriatric screening in first opinion practice—results from 45 dogs, J Small Anim Pract 53:507-513, 2012. 9. Rosenthal RA, Kavic SM: Assessment and management of the geriatric patient, Crit Care Med 32:S92, 2004.

10. Harper EJ, Hackett RM, Wilkinson J, et al: Age-related variations in hematologic and plasma biochemical test results in Beagles and Labrador Retrievers, J Am Vet Med Assoc 223:1436, 2003. 11. Strasser A, Simunek M, Seiser M, et al: Age-dependent changes in cardiovascular and metabolic responses to exercise in Beagle dogs, Zentralbl Veterinarmed A 44:449, 1997. 12. Bellows J, Colitz CMH, Darstotle L, et al: Defining healthy aging in older dogs and differentiating healthy aging from disease. J Am Vet Med Assoc 246(1):77-89, 2015. 13. Willems A, Paepe D, Marynissen S, et al: Results of screening of apparently healthy senior and geriatric dogs, J Vet Intern Med 31:81, 2017. 14. Paepa D, Verjans G, Duchateau L, et al: Routine health screening: findings in apparently healthy middle-aged and old cats, J Feline Med Surg 15:8, 2013. 15. Nagappan R, Parkin G: Geriatric critical care, Crit Care Clin 19:253, 2003. 16. King LG, Anderson JG, Rhodes WH, et al: Arterial blood gas tensions in healthy aged dogs, Am J Vet Res 53(10):1744-1748, 1992. 17. Carpenter RE, Pettifer GR, Tranquilli WJ: Anesthesia for geriatric patients, Vet Clin North Am Small Anim Pract 35:571, 2005. 18. Mellema M, 2013, unpublished data. 19. Gragasin FS, Davidge ST: The effects of propofol on vascular function in mesenteric arteries of the aging rat, Am J Physiol Heart Circ Physiol 297(1):H466-H474, 2009. 20. Harper EJ: Changing perspectives on aging and energy requirements: aging and energy intakes in humans, dogs and cats, J Nutr 128:2623S, 1998. 21. Kienzle E, Rainbird A: Maintenance energy requirement of dogs: what is the correct value for the calculation of metabolic body weight in dogs? J Nutr 121:S39, 1991. 22. Laflamme DP, Ballam JM: Effect of age on maintenance energy requirements of adult cats, Compend Contin Educ Vet Pract 24:82, 2002. 23. Laflamme DP: Nutrition for aging cats and dogs and the importance of body condition, Vet Clin North Am Small Anim Pract 35:713, 2005. 24. Vauzour D: Dietary polyphenols as modulators of brain functions; biological actions and molecular mechanisms underpinning their beneficial effects, Oxid Med Cell Longev 2012:914273, 2012. 25. Alvis BD, Hughes CG: Physiology considerations in geriatric patients, Anesthesiolo Clin 33:447-456, 2015. 26. Finco DR, Brown SA, Crowell WA, et al: Effects of aging and dietary protein intake on uninephrectomized geriatric dogs, Am J Vet Res 55: 1282, 1994. 27. Wannemacher RW Jr, McCoy JR: Determination of optimal dietary protein requirements of young and old dogs, J Nutr 88:66, 1966. 28. Finco DR, Brown SA, Crowell WA: Effects of dietary protein intake on renal functions, Vet Forum 16:34, 1999. 29. Bovee KC: Mythology of protein restriction for dogs with reduced renal function, Compend Contin Educ Vet Pract 21:15, 1999. 30. Bokov A, Chaudhuri A, Richardson A: The role of oxidative damage and stress in aging, Mech Ageing Dev 125:811, 2004. 31. Ticines A, Nouvenne A, Cerundolo N, et. Al. Gut microbiota in aging: a focus on physical frailty, sarcopenia, muscle mass and function, Nutrients 11(7):E1633, 2019. doi:10.3390/nu11071633. 32. Rangel-Captillo A, Avendano-Carillo H, Reyes-Delgado F: Immediate appetite stimulation of anorexic cats with midazolam, Compend Contin Educ Vet Pract 26:61, 2004. 33. Avendano-Carillo H, Rangel-Captillo A, Reyes-Delgado F: Immediate appetite stimulation of anorexic dogs with propofol, Compend Contin Educ Vet Pract 26:64, 2004. 34. Pham KD, Fidelindo AL: The impact of geriatric specific triage tools among older adults in the emergency department. Crit Care Nurs Q 43(1):39-57, 2020. 35. Dowling PM: Geriatric pharmacology, Vet Clin North Am Small Anim Pract 35:557, 2005. 36. Ambrose PJ: Altered drug action with aging, Health Notes 1:12, 2003. 37. Burkholder WJ: Dietary considerations for dogs and cats with renal disease, J Am Vet Med Assoc 216:1730, 2000. 38. Rasmussen MK, Mestre H, Medergaard M: The glymphatic pathway in neurological disorders, Lancet Neurol 17(11):1016-1024, 2018. 39. Cardinali DP: Melatonin: clinical perspectives in neurodegeneration, Front Endocrinol 10:480, 2019. doi:10.3389/fendo.2019.00480.

PART XVIII  Pharmacology

147 Catecholamines Samantha Hart, BVMS (Hons), MS, DACVS, DACVECC, Deborah C. Silverstein, DVM, DACVECC

KEY POINTS • Catecholamines can be used in critically ill or anesthetized patients to support arterial blood pressure, cardiac output, and tissue perfusion. • Norepinephrine, epinephrine, dopamine, and dobutamine are the most commonly used catecholamines for general cardiovascular support in human and veterinary medicine. • Norepinephrine is recommended as the first-choice vasopressor in human medicine, with the addition of epinephrine or vasopressin

if required for blood pressure support. Dobutamine should be considered in cases of cardiogenic-induced hypotension. • The use of dopamine is currently only recommended as an alternative to norepinephrine in humans with a low risk of tachyarrhythmias or relative bradycardia.

Catecholamines are used in critically ill patients to augment arterial blood pressure, myocardial contractility, and cardiac output in a variety of clinical illnesses. The mainstay of cardiovascular dysfunction is effective treatment of the underlying disease process. But when the underlying problem cannot be identified or treated rapidly and the patient has an adequate intravascular blood volume, symptomatic catecholamine therapy may be necessary (see Chapter 64, Assessment of Intravascular Volume).

hypotension is often unclear in diseases such as sepsis, systemic inflammatory response syndrome or during general anesthesia, a thorough evaluation of the patient’s volume status, vascular tone, and cardiac contractility should be performed to determine the most appropriate treatment plan (see Chapters 64 and 68, Assessment of Intravascular Volume and Shock Fluid Therapy, respectively, for further details regarding vascular volume assessment and treatment). Patients with disease processes such as sepsis may benefit from earlier use of vasopressor therapy to avoid the deleterious effects of excessive volume administration.3

HYPOTENSION Hypotension is a reduction in systemic arterial blood pressure, which is determined by cardiac output and systemic vascular resistance. Mean arterial pressure (MAP) is the driving pressure for tissue perfusion, and as such, MAP is preferred for the overall assessment of blood pressure. However, normal diastolic pressure is also important to ensure adequate coronary perfusion. Hypotension is defined as a MAP of less than 80 mm Hg. Because MAP is not always measured in veterinary patients, a Doppler blood pressure less than 90 to 100 mm Hg is also used to define hypotension. Surviving Sepsis Campaign human guidelines recommend targeting a MAP $65 mm Hg during initial resuscitation.1 However, the optimal MAP for a patient should be individualized and may be higher in selected patients such as those with previously documented hypertension.2 In younger, otherwise healthy patients, a lower target may be acceptable if other markers of tissue perfusion (e.g., physical examination, lactate, etc.) are acceptable. When a patient is diagnosed with hypotension, the measurement should be used in conjunction with other variables to determine the best course of treatment. Since the underlying physiologic cause of the

DECREASED MYOCARDIAL CONTRACTILITY Decreased myocardial contractility may be suspected when preload parameters (history of recent fluid loading, caudal vena cava diameter, end-diastolic ventricular volume) suggest normal or high preload, and forward flow parameters (blood pressure, pulse quality, capillary refill time) and indicators of tissue perfusion (appendage temperature, metabolic acidosis, lactate, central venous oxygen pressure) suggest poor cardiac output in an animal without organic heart disease. In this situation, dobutamine (5–20 mcg/kg/min) is the first-choice inotrope for patients with suspected low cardiac output in the presence of adequate fluid resuscitation.4

Vasomotor Tone Of the two determinants of arterial blood pressure—cardiac output and vascular resistance—the latter is the much more powerful contributor. The effect of a drug or disease on blood pressure usually parallels its effect on vasomotor tone. Arteriolar vasomotor tone is also

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a primary determinant of visceral perfusion. In veterinary medicine, it is common to measure blood pressure and to initiate therapy when it is low. Parameters of tissue perfusion are less precise but no less important than blood pressure and receive less attention during therapy. Focusing therapy on arterial blood pressure, without reference to the adequacy of tissue perfusion, can be detrimental. Vasoconstriction is beneficial to the extent that it supports arterial blood pressure but is potentially dangerous if it impairs tissue perfusion. Vasodilatation, if accomplished without hypotension, would be an ideal cardiovascular goal to maintain microcirculatory flow. Dobutamine is beneficial in this regard, as it usually causes modest, but not excessive, vasodilatation coupled with augmentation of contractility; forward flow is increased, whereas blood pressure is minimally changed. Although blood pressure is important and continued vigilance of it is imperative, a focused consideration of flow parameters such as cardiac output, pulse quality, and indicators of tissue perfusion is also necessary when choosing and evaluating a cardiotonic/vasoactive therapy plan. Because vasoconstriction tends to decrease tissue perfusion, vasoconstrictors may be considered harmful and impair tissue perfusion. Such an all-or-nothing concept is incorrect. Vasoconstrictors can be very effective in the management of patients with unstable cardiovascular function (by increasing cardiac output, blood pressure, and visceral tissue perfusion). Norepinephrine is commonly used in critically ill human patients to improve blood pressure and can be administered without adversely affecting visceral tissue perfusion.5-8 While epinephrine has been shown to adversely affect splanchnic blood flow and increase lactate levels, especially at high doses, its use has not been shown to be associated with worse outcomes in critically ill patients.9 In addition, low-dose epinephrine stimulates b-receptors more than a-receptors and could help with perfusion with less vasoconstriction. Epinephrine is currently recommended as the first alternative to norepinephrine in septic human patients.1 Venular vasomotor tone is an important determinant of venous return. Venous return is also an important determinant of cardiac output. Veins have two important functions: to store blood volume and to serve as conduits for venous return. Venoconstrictor drugs have two significant effects: they decrease venous capacitance (which increases venous return and cardiac output), and they increase resistance to venous blood flow (which decreases venous return and cardiac output). Venodilators have the opposite effects. The net effect on venous return and cardiac output depends on the relative strengths of these two opposing influences.8 Potent vasoconstrictors such as norepinephrine and phenylephrine have been variously reported to increase or decrease cardiac

output, and the reason for this disparity is the relative effect on these two opposing processes. The net effect of vasoconstrictors is determined largely by the pretreatment status of the cardiovascular system, intravascular volume, and drug dosages. In patients with baseline venodilation or increased intravascular volume, one might expect an increase in venous return, whereas in patients with venoconstriction or a decrease in intravascular volume, one might expect a decrease in venous return. Venodilation is commonly present in diseases such as anaphylaxis and sepsis and during general anesthesia. Although administration of intravenous fluids may act to “refill” the expanded blood volume capacity and restore venous return in these patients, this therapy also carries the risk of fluid overload and associated adverse effects.10 For this reason, when infusion of a small dose of fluids to first restore cardiovascular homeostasis has failed, vasoconstrictor therapy should be considered. While vasopressors are commonly utilized later in the management of critically ill veterinary patients, early use may ultimately help to improve outcome in these patients.3,11,12 Venoconstriction might be expected as the normal response to hypovolemia (in which case fluids should be administered) and also the excessive administration of a vasoconstrictor (in which case the vasoconstrictor therapy should be reduced). Although vasoconstrictor treatment might improve arterial blood pressure in hypovolemic patients as a lifesaving maneuver in the short term, it will most likely diminish venous return, cardiac output, and tissue perfusion. This is of particular importance in patients with acute hemorrhagic shock and trauma, where vasopressor use is independently associated with increased mortality.13,14

CATECHOLAMINE DRUGS Table 147.1 lists the approximate receptor distributions, important cardiovascular effects, and dosages of the available catecholamines (vasopressin is not a catecholamine but is included here because its indications overlap with those of the catecholamines; structurally, ephedrine is not a catecholamine either). b1-Receptor agonists primarily augment heart rate, contractility, and ectopic pacemaker activity. b2-Receptor agonist activity primarily causes vasodilatation and bronchodilation. Postsynaptic a1-receptor and presynaptic a2-receptor agonists cause primarily vasoconstriction and may also lead to ectopic pacemaker activity. Arteriolar vasoconstriction increases blood pressure, but if excessive, can increase afterload and ultimately impede tissue perfusion. Venoconstriction increases venous return by decreasing venous capacitance, but if excessive, can decrease venous return by increasing resistance to venous return. When a drug exhibits both

TABLE 147.1  Receptor Activity, Cardiopressor Effects, and Dosages of Commonly

Administered Catecholamines

RECEPTOR ACTIVITY

EFFECT ONa Heart Rate

Cardiac Output

Vasomotor Tone

Blood Pressure

Dosage

hhh hh

hhh

hhh

ggg

ggg

0.02–0.5 mcg/kg/min

h

hh

g

5–20 mcg/kg/min

11

hh

hh

hh

1

1

h

h

Variable h

Variable hh

0.25–1 mg/kg

111

hhh

hhh

hh

Variable hhh

h

111

hhh

0.05–1 mcg/kg/min

1

0

111

h

Variable

hhh

hhh

0.05–1 mcg/kg/min

0

0

111

0

g

Variable g

hhh

hhh

0.5–5 mcg/kg/min

 

�1

�2

a1 & a2

Contractility

Isoproterenol

111

111

0

Dobutamine

11

1

1

Dopamine

11

1

Ephedrine

1

Epinephrine

111

Norepinephrine Phenylephrine

Effects are estimated for the higher dose ranges. Activity ranges from no activity (0) to maximal activity (111). Possible cardiopressor effects include a decrease (g), mild increase (h), moderate increase (hh), or marked increase (hhh). a

5–20 mcg/kg/min

CHAPTER 147  Catecholamines b2-receptor vasodilatation properties and a1-receptor vasoconstriction activity (dobutamine, epinephrine, dopamine), the net effect on vasomotor tone and blood pressure will be proportional to the relative power of each effect (see Table 147.1). The next section of the chapter summarizes the most commonly used vasopressors. It is important to recognize that a one-size-fits-all approach does not work in critically ill patients. Shock management should take into consideration the underlying disease process(es), comorbidities, and body’s own physiologic approach to blood pressure management (sympathetic nervous system, vasopressin pathway, and renin-angiotensin-aldosterone system [RAAS]), where multiple vasopressors may be combined to target a patient’s specific physiologic aberrations.4 Recent meta-analyses suggest that the use of vasopressor combination therapy may result in significantly decreased mortality compared to single vasopressor regimens.4,5

NOREPINEPHRINE Norepinephrine is primarily an a-receptor agonist and causes both arteriolar and venous constriction. It also exhibits minimal b1-receptor agonist activity. Therefore, in contrast to phenylephrine and vasopressin, norepinephrine may increase heart rate and myocardial contractility. Norepinephrine generally causes vasoconstriction and increases blood pressure, with variable effects on heart rate at doses of 0.05–1 mcg/kg/min. Norepinephrine is typically used at dosages ranging from 0.1 to 2 mcg/kg/min, starting at the low end of the dose range and titrating up as needed to achieve hemodynamic stability. Cardiac output may increase,5,15,16 decrease,16 or remain unchanged.17 These different effects on cardiac output are attributed to differences in baseline effective circulating volume and myocardial contractility, and the relative effect of venoconstriction on venous capacitance (decreased capacitance tends to increase venous return and stressed volume) and venous resistance to blood flow (increased resistance to flow tends to decrease venous return). Animals with an effective circulating volume but concurrent vasodilatation are expected to have an increase in cardiac output following norepinephrine administration due to venoconstriction of capacitance vessels. Hypovolemic animals typically have an endogenous catecholamine-mediated vasoconstriction; therefore, further venoconstriction of resistance vessels associated with the administration of a vasoconstrictor would lead to a further decrease in venous return and cardiac output. As mentioned above, norepinephrine has mild b1-receptor agonist activity, which may further increase contractility and cardiac output, particularly in patients with poor baseline myocardial contractility. According to the most recent human Surviving Sepsis Campaign 2016-2018 Guidelines,1,18 norepinephrine is recommended as the firstchoice vasopressor in the management of persistent hypotension associated with septic or hypovolemic shock (strong recommendation, moderate quality of evidence). This recommendation is based on recent studies and meta-analyses showing that the use of norepinephrine is overall associated with decreased mortality and lower risk of major adverse events compared with dopamine in human patients.3,6,19,20 Relatively early use of norepinephrine in the resuscitation and management of patients with hypotension and shock may benefit critically ill patients by increasing cardiac output, improving microcirculatory flow, and limit the potential for development of fluid overload.12,21 In addition, recent data suggest that early norepinephrine use may improve patient outcome.12,21,22

Epinephrine Epinephrine is a potent b1-, b2-, a1-, and a2-receptor agonist. It is a potent inotrope and chronotrope, arteriolar and venular vasoconstrictor,

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and bronchodilator. It potently increases arterial blood pressure and can cause ventricular ectopic pacemaker activity. Epinephrine administration increases heart rate, systemic vascular resistance, cardiac output, and arterial blood pressure in anesthetized cats,23 dogs with acute anaphylaxis,24 and humans with sepsis25 or heart failure.7 Epinephrine is used primarily in supraphysiologic doses (5–20 mcg/ kg/min) in emergency situations such as anaphylaxis and cardiac arrest, when sum of its effects is highly important. The most recent human Surviving Sepsis Campaign 2016-2018 Guidelines1,18 suggest using epinephrine or vasopressin in addition to norepinephrine to raise MAP. Therefore, epinephrine is considered a second-line vasopressor choice in human patients that are failing to respond to norepinephrine alone. Human and animal studies suggest that infusion of epinephrine at higher doses may have deleterious effects on the splanchnic circulation and produce hyperlactatemia;26-28 however, clinical trials do not demonstrate worsening of clinical outcomes when compared with norepinephrine administration alone or in combination with dobutamine.1,26,27 Lowest possible dosages should be used to achieve MAP goals.

Dopamine Dopamine is the endogenous precursor to norepinephrine and is an important neurotransmitter in the central nervous system. It has direct b- and a-agonist activity and also releases norepinephrine from the sympathetic nerve endings. It is also a dopamine receptor agonist and induces arterial vasodilatation in many vascular beds. Several different dopamine receptors have been identified: D1 postsynaptic receptors are responsible for the vasodilation, whereas D2 presynaptic receptors inhibit norepinephrine release from sympathetic nerve endings (which promotes less vasoconstriction). The effects of dopamine may be dose related, with dopaminergic vasodilatory effects predominating at low dosages (1–4 mcg/kg/min), b effects predominating at medium dosages (5–10 mcg/kg/min), and a effects predominating at high dosages (.10 mcg/kg/min). However, this scaling of effects is difficult to demonstrate clinically. Dopamine has been reported to increase renal blood flow at dosages of less than 5 mcg/kg/min (and to decrease it to baseline at 10 mcg/kg/min) and may increase urine output.29,30 However, low-dose dopamine therapy does not appear to provide any renal-protective efficacy in people.31 When administered to critically ill people,32 septic dogs,33 anesthetized dogs,34,35 and anesthetized cats,23 dopamine generally causes a modest vasoconstriction and increase in blood pressure, with little change or modest increases in cardiac output. According to the most recent human Surviving Sepsis Campaign 2016-2018 Guidelines,1,18 norepinephrine is a more potent vasopressor than dopamine and may be more effective at reversing hypotension in patients with septic shock. Additionally, the use of dopamine in the management of critically ill human patients has been associated with significantly poorer outcome and a higher incidence of arrhythmic events.6,19,20 Dopamine is currently recommended as an alternative vasopressor to norepinephrine only in highly selected patients (for example, patients with low risk of tachyarrhythmias and absolute or relative bradycardia).1 Research examining dopamine administration in critically ill canine or feline patients is lacking.

Dobutamine Dobutamine is a synthetic analog of dopamine with strong b1-agonist activity as well as milder effects on b2- and a1-receptors, but without dopaminergic effects. When dobutamine is given to critically ill humans,32 septic dogs,33 anesthetized dogs,34,35 and anesthetized cats,23 it generally causes modest vasodilatation and a marked increase in cardiac output with little change in blood pressure. Dobutamine is primarily used in critically ill patients to increase forward flow in patients

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with measured or suspected low cardiac output in the presence of adequate left ventricular filling pressures (or clinical assessment of adequate fluid resuscitation).1 Recommended dosing ranges from 5 to 20 mcg/kg/min in dogs, starting at the low end of the dose range and titrating upwards as needed. In cats, doses greater than 5 to 10 mcg/kg/ min may cause central nervous system effects such as tremors or seizures. The authors recommend the use of low doses only in cats, if indicated.

Phenylephrine Phenylephrine is an a-receptor agonist without b-agonist activity. Its administration causes vasoconstriction, an increase in arterial blood pressure, and a decrease in heart rate. Cardiac output may decrease36,37 or increase.23,38 Phenylephrine is most frequently used to raise blood pressure in patients with vasodilation after other vasopressors such as norepinephrine and/or dopamine have proven ineffective. Phenylephrine infusion has been shown to be comparable to norepinephrine in reversing hemodynamic and metabolic abnormalities of septic patients, with an additional benefit of a decrease in heart rate and improvement in stroke volume index.39 Recommended dosing ranges from 0.5 to 5 mcg/kg/min. Additionally, there has been recent interest in the use of push-dose phenylephrine during stabilization of critically ill, hypotensive patients.40-42 Intermittent administration of small doses of phenylephrine addresses hypotension and maintains adequate perfusion until definitive care can be initiated (i.e., fluid boluses or initiation of a vasopressor infusion).40-42

Ephedrine Ephedrine is a sympathomimetic amine (but not strictly speaking a catecholamine) that primarily acts by increasing the release of norepinephrine from sympathetic nerve endings. It may also have some direct b-agonist effects. Ephedrine is a general cardiovascular stimulant and bronchodilator. Ephedrine can be used as an alternative to norepinephrine and/or dopamine for cardiovascular support but may not be as effective or reliable given its mode of action. The administration of ephedrine to anesthetized dogs causes a modest decrease in heart rate and an increase in cardiac output, vascular resistance, and arterial blood pressure.43 The effects of a single dose of 0.25 to 1 mcg/kg may last 5–15 minutes; it may also be administered as a constant rate infusion (0.02–0.2 mg/kg/min). Prolonged use can deplete norepinephrine stores, which results in tachyphylaxis. Ephedrine crosses the blood– brain barrier and has a mild analeptic effect.

Isoproterenol Isoproterenol is a potent b-receptor agonist with no a-receptor activity. As such, it is a potent positive inotrope, chronotrope, vasodilator, and hypotensive agent. In anesthetized dogs, isoproterenol increases heart rate and cardiac output and decreases blood pressure.44 If isoproterenol is administered very carefully while blood pressure is monitored and maintained, it can provide potent augmentation of forward blood flow and tissue perfusion in patients with cardiogenic shock. Isoproterenol is typically given at a dose of 0.02 to 0.5 mcg/kg/min.

CHOOSING THE RIGHT CATECHOLAMINE There is much heterogeneity in patient response to an individual catecholamine drug. Since catecholamines have specific receptor activities and different vasculature beds have varying distributions of receptors, various dosages are expected to have different effects (e.g., low, physiologic, doses of epinephrine cause systemic vasodilatation, whereas high, pharmacologic, doses cause systemic vasoconstriction). In addition to individual and species variations, the underlying disease (or

experimental model) and the pretreatment baseline values have much to do with both the direction and the magnitude of the response to therapy. The coadministration of other drugs can also impact responses. For general cardiovascular support in critically ill human patients, the first-choice drug is norepinephrine. The vasopressor response to norepinephrine is stronger and more consistent than the response to dopamine, with more reliable improvement in hemodynamic parameters (in particular MAP).9 When augmentation of forward flow is the goal, dobutamine is the drug of choice to augment forward flow. Generally, and insofar as is possible, the specific problem or problems should be addressed in the therapy plan (bradycardia, poor contractility, low cardiac output, hypotension, weak pulse quality, poor tissue perfusion) and then treatment with either norepinephrine or dobutamine (or both) commenced in increasing dosages until the problem is resolved (or until it is decided that the chosen drug will not solve the problem). When, for instance, higher dosages of norepinephrine fail to increase blood pressure to acceptable levels, additional vasopressors such as epinephrine, vasopressin, phenylephrine, and/or dopamine can be added. Isoproterenol may lead to excessive vasodilation and is therefore not used routinely in critically ill patients with precariously balanced blood pressure. If it is used for forward flow augmentation, continuous accurate direct blood pressure monitoring is recommended.

COMBINATION THERAPIES Combinations of two or more of the vasopressors previously described can be used at the clinician’s discretion, and lower dosages may decrease the potential adverse effects of each. Norepinephrine is the current first-choice vasopressor for achieving hemodynamic stabilization in critically ill patients.1 When the administration of norepinephrine alone is not able to improve the hemodynamic status of a patient, other vasoactive medications should be added. The addition of either dobutamine, epinephrine, or vasopressin to norepinephrine has been shown to significantly decrease mortality in critically ill patients.4,5 It is important to identify patients that may benefit from dobutamine administration, as use in patients with normal cardiac function may increase the risk of cardiac arrhythmias.5 Sympathomimetic drugs can be administered in any combination. The clinician must be clear about what the treatment is intended to improve (inotropy, cardiac output, blood pressure, tissue perfusion) and select drugs and dosages that seem most likely to achieve these goals. Animals with catecholamine-refractory hypotension may benefit from physiologic corticosteroid supplementation (see Chapter 81, Critical Illness-Related Corticosteroid Insufficiency).

PUSH-DOSE VASOPRESSORS Traditionally, vasopressors are administered as a continuous rate infusion. Intermittent administration of small doses of vasopressors such as epinephrine, phenylephrine, and ephedrine to treat hypotension and maintain adequate tissue perfusion has been a long-standing evidence-based practice in anesthesiologists.40 The use of bolus-dose or push-dose vasopressors, particularly epinephrine and phenylephrine, can be used to temporarily manage hemodynamically unstable patients. Push-dose vasopressors can be used in patients who have transient hypotension, for example, immediately after a procedural sedation, or to increase MAP until a continuous rate infusion can be established.41,42 The onset of action of epinephrine and phenylephrine occurs within 1 minute of IV administration. The duration of action of phenylephrine is approximately 10–20 minutes in comparison to

CHAPTER 147  Catecholamines that of epinephrine, which lasts approximately 5–10 minutes.41,42 Recommended dosing in people is 5–20 mcg for epinephrine and 40–200 mcg for phenylephrine, typically diluted to deliver a dose in a volume of 0.5–2 ml.41,42 The preparation of push-dose vasopressors is associated with a high risk for medication errors. As such, it is extremely important to ensure proper dosing prior to administration. Additionally, the use of push-dose vasopressors should not be used in lieu of appropriate fluid resuscitation or otherwise addressing the underlying cause of a patient’s hypotension.

OTHER EFFECTS OF CATECHOLAMINES Catecholamine therapy has many other effects, of which users should be aware. For instance, blood glucose and lactate levels may increase, particularly with epinephrine infusion.9,28 The a-agonism tends to increase blood glucose levels by decreasing insulin secretion and stimulating glycogenolysis. The b-agonism contributes to the rise in blood glucose level by increasing glucagon and adrenocorticotropic hormone secretion (cortisol decreases tissue uptake of glucose), as well as stimulating lipolysis. The b2 agonism from catecholamine administration increases cellular potassium uptake, which reduces plasma potassium concentration.45 This may be important in animals that have severe total-body potassium depletion at presentation. Catecholamines are limited in their effectiveness for treating hyperkalemia due to their cardiovascular effects. Catecholamines increase metabolic oxygen consumption, primarily in cardiac muscle.46 The increase in oxygen delivery is usually greater than the increase in oxygen consumption, and so it is of limited clinical importance unless therapy fails to increase cardiac output and oxygen delivery. Exogenous catecholamine therapy may increase shear-induced platelet reactivity.47,48 This may be important in animals with underlying hypercoagulabilities. There is evidence that this effect may be caused by a-receptor agonism and the opening of a sodium-chloride cotransporter in the platelet membrane. Studies suggest that this effect could be diminished by blocking chloride transport with loop48 or thiazide diuretics.49 Additional nonhemodynamic effects of catecholamines include mitochondrial dysfunction and immunomodulation. In the mitochondria, catecholamines may promote mitochondrial uncoupling and aggravate oxidative stress, thereby contributing to the progression of mitochondrial dysfunction. Immunological side effects have also gained specific attention. Although both pro- and antiinflammatory effects have been described, current evidence strongly indicates an immunosuppressive effect, thereby making patients potentially vulnerable to secondary infections.50

ACKNOWLEDGEMENTS With special acknowledgement to Dr. Steve Haskins, our beloved colleague who was taken from us too soon.

REFERENCES 1. Rhodes A, Evans LE, Alhazzani W, et al: Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016, Intensive Care Med 43:304-377, 2017. 2. Levine AR, Chow JH, McCurdy MT: Argument for personalized vasopressors in septic shock, Crit Care Med 48:e439, 2020.

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3. Permpikul C, Tongyoo S, Viarasilpa T, et al: Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER): a randomized trial, Am J Respir Crit Care Med 199:1097-1105, 2019. 4. Cheng L, Yan J, Han S, et al: Comparative efficacy of vasoactive medications in patients with septic shock: a network meta-analysis of randomized controlled trials, Critical Care 23:168-181, 2019. 5. Chen C, Pang L, Wang Y, et al: Combination era, using combined vasopressors showed benefits in treating septic shock patients: a network meta-analysis of randomized controlled trials, Ann Transl Med 7:535-547, 2019. 6. De Backer D, Aldecoa C, Njimi H, Vincent JL: Dopamine versus norepinephrine in the treatment of septic shock: a meta-analysis, Crit Care Med 40:725-730, 2012. 7. Levy B, Perez P, Perny J, et al: Comparison of norepinephrine-dobutamine to epinephrine for hemodynamics, lactate metabolism, and organ function variables in cardiogenic shock. A prospective, randomized pilot study, Crit Care Med 39:450-455, 2011. 8. Persichini R, Silva S, Teboul JL, et al: Effects of norepinephrine on mean systemic pressure and venous return in human septic shock, Crit Care Med 40:3146-3153, 2012. 9. Pollard S, Edwin SB, Alaniz C: Vasopressor and inotropic management of patients with septic shock, P T 40:438-450, 2015. 10. Cavanagh AA, Sullivan LA, Hansen BD: Retrospective evaluation of fluid overload and relationship to outcome in critically ill dogs, J Vet Emerg Crit Care 26:578-586, 2016. 11. Nagendran M, Maruthappu M, Gordon AC, Gurusamy KS: Comparative safety and efficacy of vasopressors for mortality in septic shock: a network meta-analysis, J Intensive Care Soc 17:136-145, 2016. 12. Bai X, Yu W, Lin Z, et al: Early versus delayed administration of norepinephrine in patients with septic shock, Crit Care 18:532, 2014. 13. Plurad DS, Talving P, Lam L, et al: Early vasopressor use in critical injury is associated with mortality independent from volume status, J Trauma 71:565-572, 2011. 14. Sperry JL, Minei JP, Frankel HL, et al: Early use of vasopressors after injury: caution before constriction, J Trauma 64:9-14, 2008. 15. Nouira S, Elatrous S, Dimassi S, et al: Effects of norepinephrine on static and dynamic preload indicators in experimental hemorrhagic shock, Crit Care Med 33:2339-2343, 2005. 16. Maas JJ, Pinsky MR, de Wilde RB, et al: Cardiac output responses to norepinephrine in postoperative cardiac surgery patients: interpretation with venous return and cardiac function curves, Crit Care Med 41: 143-150, 2013. 17. Schreuder WO, Schneider AJ, Groeneveld ABJ, et al: Effect of dopamine vs norepinephrine on hemodynamics in septic shock, Chest 95:1282-1288, 1989. 18. Lesur O, Delile E, Asfar P, Radermacher P: Hemodynamic support in the early phase of septic shock: a review of challenges and unanswered questions, Ann Intensive Care 8:102, 2018. 19. De Backer D, Biston P, Devriendt J, et al: Comparison of dopamine and norepinephrine in the treatment of shock, N Engl J Med 36:779-789, 2010. 20. Vasu TS, Cavallazzi R, Hirani A, et al: Norepinephrine or dopamine for septic shock: systematic review of randomized clinical trials, J Intensive Care Med 27:172-178, 2012. 21. Hamzaoui O, Shi R: Early norepinephrine use in septic shock, J Thorac Dis 12:S72-S77, 2020. 22. Hamzaoui O, Georger JF, Monnet X, et al: Early administration of norepinephrine increases cardiac preload and cardiac output in septic patients with life-threatening hypotension, Crit Care 14:R142, 2010. 23. Pascoe PJ, Ilkiw JE, Pypendop BH: Effects of increasing infusion rates of dopamine, dobutamine, epinephrine, and phenylephrine in healthy anesthetized cats, Am J Vet Res 67:1491-1499, 2006. 24. Mink SN, Simons FER, Simons KJ, et al: Constant infusion of epinephrine, but not bolus treatment, improves haemodynamic recovery in anaphylactic shock in dogs, Clin Exp Allergy 34:1776-1783, 2004. 25. Day NPJ, Phu NH, Mai NTH, et al: Effects of dopamine and epinephrine infusions on renal hemodynamics in severe malaria and severe sepsis, Crit Care Med 28:1353-1362, 2000.

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26. Myburgh JA, Higgins A, Jovanovska A, et al: A comparison of epinephrine and norepinephrine in critically ill patients, Intensive Care Med 34:2226-2234, 2008. 27. Levy B, Bollaert PE, Charpentier C, et al: Comparison of norepinephrine and dobutamine to epinephrine for hemodynamics, lactate metabolism, and gastric tonometric variables in septic shock: a prospective, randomized study, Intensive Care Med 23:282-287, 1997. 28. Prengel AW, Lindner KH, Wenzel V, et al: Splanchnic and renal blood flow after cardiopulmonary resuscitation with epinephrine and vasopressin in pigs, Resuscitation 38:19-24, 1998. 29. Ichai C, Soubielle J, Carles M, et al: Comparison of the renal effects of low to high doses of dopamine and dobutamine in critically ill patients: a single-blind randomized study, Crit Care Med 28:921-928, 2000. 30. Ichai C, Passeron C, Caries M, et al: Prolonged low-dose dopamine infusion induces a transient improvement in renal function in hemodynamically stable, critically ill patients: a single-blind, prospective, controlled study, Crit Care Med 28:1329-1335, 2000. 31. Kellum JA, Decker JM: Use of dopamine in acute renal failure: a metaanalysis, Crit Care Med 29:1526-1531. 32. Shoemaker WC, Appel RI, Kram HB, et al: Comparison of hemodynamic and oxygen transport effects of dopamine and dobutamine in critically ill surgical patients, Chest 96:120-126, 1989. 33. Vincent JL, Van der Linden P, Domb M, et al: Dopamine compared with dobutamine in experimental septic shock: relevance to fluid administration, Anesth Analg 66:565-571, 1987. 34. Abdul-Rasool IH, Chamberlain JH, Swan PC, et al: Cardiorespiratory and metabolic effects of dopamine and dobutamine infusions in dogs, Crit Care Med 15:1044-1050, 1987. 35. Rosati M, Dyson DH, Sinclair MD, et al: Response of hypotensive dogs to dopamine hydrochloride and dobutamine hydrochloride during deep isoflurane anesthesia, Am J Vet Res 68:483-494, 2007. 36. Crystal GJ, Kim SJ, Salem R, et al: Myocardial oxygen supply/demand relations during phenylephrine infusions in dogs, Anesth Analg 73:283-288, 1991. 37. Nygren A, Thoren A, Ricksten SE: Vasopressors and intestinal mucosal perfusion after cardiac surgery: norepinephrine vs phenylephrine, Crit Care Med 34:722-729, 2006.

38. Wiese AJ, Barter LS, Ilkiw JE, et al: Cardiovascular and respiratory effects of incremental doses of dopamine and phenylephrine in the management of isoflurane-induced hypotension in cats with hypertrophic cardiomyopathy, Am J Vet Res 73:906-916, 2012. 39. Jain G, Singh DK: Comparison of phenylephrine and norepinephrine in the management of dopamine-resistant septic shock, Indian J Crit Care Med 14:29-34, 2010. 40. Swenson K, Rankin S, Daconti L, et al: Safety of bolus-dose phenylephrine for hypotensive emergency department patients, Am J Emerg Med 36: 1802-1806, 2018. 41. Holden D, Ramich J, Timm E, et al: Safety considerations and guidelinebased safe use recommendations for “bolus-dose” vasopressors in the emergency department, Ann Emerg Med 71:83-92, 2017. 42. Tilton LJ, Eginger KH: Utility of push-dose vasopressors for temporary treatment of hypotension in the emergency department, J Emerg Nurs 42:279-281, 2016. 43. Wagner AE, Dunlop CI, Chapman PL: Effects of ephedrine on cardiovascular function and oxygen delivery in isoflurane-anesthetized dogs, Am J Vet Res 54:1917-1922, 1993. 44. Driscoll DJ, Gillette PC, Fukushige J, et al: Comparison of the cardiovascular action of isoproterenol, dopamine, and dobutamine in the neonatal and mature dog, Pediatr Cardiol 1:307-314, 1980. 45. Follett DV, Loeb RG, Haskins SC, et al: Effects of epinephrine and ritodrine in dogs with acute hyperkalemia, Anesth Analg 40:400-406, 1990. 46. Scheeren TWL, Arndt JO: Different response of oxygen consumption and cardiac output to various endogenous and synthetic catecholamines in awake dogs, Crit Care Med 28:3861-3868, 2000. 47. Ikarugi H, Taka T, Nakajima S, et al: Norepinephrine, but not epinephrine, enhances platelet reactivity and coagulation after exercise in humans, J Appl Physiol 86:133-138, 1999. 48. Spalding A, Vaitkevicius H, Dill S, et al: Mechanism of epinephrineinduced platelet aggregation, Hypertension 31:603-607, 1998. 49. Vaitkevicius H, Turner I, Spalding A, et al: Chloride increases adrenergic receptor-mediated platelet and vascular responses, Am J Hypertens 15:492-498, 2002. 50. Hartmann C, Radermacher P, Wepler M, et al: Non-hemodynamic effects of catecholamines, Shock 48:390-400, 2017.

148 Vasopressin Deborah C. Silverstein, DVM, DACVECC, Samantha Hart, BVMS (Hons), MS, DACVS, DACVECC

KEY POINTS • Vasopressin, also known as antidiuretic hormone, is a peptide hormone synthesized in the hypothalamus and stored or released from the posterior pituitary gland. • There are four vasopressin receptors in the body: V1R, V2R, V3R, and the oxytocin receptor. • In health, vasopressin aids in the regulation of free water balance (via V2R) in the renal medullary and cortical collecting ducts.

• During states of circulatory shock, vasopressin levels are markedly increased, and vasopressin functions as a potent nonadrenergic vasoconstrictor (via V1R). Vasopressin also stimulates the release of adrenocorticotropic hormone (via V3R). • Vasopressin is used therapeutically for the management of pituitarydependent diabetes insipidus, von Willebrand disease, vasodilatory hypotension, hemorrhagic shock, and cardiopulmonary resuscitation.

PHYSIOLOGY OF VASOPRESSIN

tonically inhibit AVP secretion. Atrial stretch receptors respond to increases in blood volume, and the receptors in the aortic arch and carotid sinuses respond to increases in arterial blood pressure. A decrease in arterial baroreceptor activity causes “disinhibition” of AVP release during hypotensive states and results in increased AVP secretion.

Arginine vasopressin (AVP, also known as antidiuretic hormone, 8-argininevasopressin, and b-hypophamine) is a natural, nine-amino-acid glycopeptide with a disulfide bond that is synthesized in the magnocellular neurons in the hypothalamus before transport down the pituitary stalk for storage in the pars nervosa of the posterior pituitary gland.1 The entire process of AVP synthesis, transport, and storage in the pituitary takes 1 to 2 hours. AVP is metabolized rapidly by hepatic and renal vasopressinases, and the half-life of AVP is 10 to 35 minutes. Vasopressin has shown teleologic persistence and is found in more than 120 species spanning four invertebrate phyla and the seven major vertebrate families.2 In most mammals (dogs, cats, humans), the natural hormone is arginine vasopressin, but the porcine species has a lysine in place of arginine, which renders the compound less potent than AVP. The most potent stimuli for AVP release are increased plasma osmolality, decreased blood pressure, and a decrease in circulating blood volume.3-5 Additional abnormalities that cause AVP release include pain, nausea, hypoxia, hypercarbia, pharyngeal stimuli, glycopenia, drugs or chemicals (e.g., acetylcholine, high-dose opioids, dopamine, angiotensin II, prostaglandins, glutamine, histamine), certain malignant tumors, and mechanical ventilation.6-8 Release of AVP is inhibited by drugs such as glucocorticoids, lowdose opioids, atrial natriuretic factor, and g-aminobutyric acid. Hyperosmolality is sensed by both peripheral and central osmoreceptors. Central osmoreceptors are located in the third ventricle and detect changes in systemic osmolality. Peripheral osmoreceptors in the mesenteric and portal veins enable early detection of the osmolality of ingested food and liquids. Afferent impulses ascend via the vagus nerve to the paraventricular and supraoptic nuclei in the brain to stimulate AVP release. In addition, plasma hypertonicity depolarizes the magnocellular neurons of the hypothalamus to cause more AVP release. Decreases in blood volume or pressure also stimulate exponential increases in AVP. Hypovolemia and hypotension shift the osmolality– vasopressin response curve so that higher AVP levels are required to maintain a normal osmolality in hypotensive states.9 Afferent impulses from the left atrium, aortic arch, and carotid sinus stretch receptors

Vasopressin Receptors Vasopressin receptors are G protein-coupled receptors. The cellular effects of vasopressin are mediated by interactions of the hormone with several types of receptors (Table 148.1).10 V1 receptors (V1Rs), previously known as V1a receptors, are found primarily on vascular smooth muscle cells and cause vasoconstriction in most vascular beds that is mediated by Gq protein-coupled activation of the phospholipase C and phosphoinositide pathways. Increased levels of inositol phosphate and diacylglycerol activate voltage-gated calcium channels. This results in increased intracellular calcium levels and subsequent vasoconstriction. Vasopressin also causes inactivation of the potassium–ATP channels in vascular smooth muscle cells. Opening of these channels (as occurs with acidosis or hypoxia) allows an efflux of potassium from the endothelial cells, subsequent hyperpolarization, and prevention of calcium entry into the cells. (An increase in cytosolic calcium is essential for vasoconstriction.) In contrast, inactivation of the potassium– ATP channel by AVP leads to depolarization, opening of the voltagegated calcium channels, and an increase in cytosolic calcium with subsequent vasoconstriction. Interestingly, vasodilation may occur in some vascular beds, most likely mediated by nitric oxide. V1Rs are found in the vascular endothelium of the kidney, skin, skeletal muscle, pancreas, thyroid gland, myometrium, bladder, hepatocytes, adipocytes, and spleen. Platelets also express the V1R, which facilitates thrombosis due to an increase in intracellular calcium upon stimulation. V1Rs in the kidneys lead to reduced blood flow to the inner medulla, limit the antidiuretic effects of AVP, and selectively cause contraction of the efferent arterioles to increase glomerular filtration rate. There is considerable variation among species with respect to the location and function of the V1R. Vasopressin-2 receptors (V2Rs) are found primarily on the basolateral membrane of the distal tubule and in the principal cells of the

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TABLE 148.1  Vasopressin Receptors,

Tissues Affected, and Principal Effects Receptor

Tissues

Principal Effects

V1 (V1a)

Vascular smooth muscle

Vasoconstriction at high dosages Vasodilation in cerebral, renal, pulmonary, and mesenteric vessels at low dosages

V2

Renal collecting duct Endothelial cells

Increased water permeability Increased von Willebrand factor release Stimulation of aggregation Vasodilation

Platelets Vascular endothelium V3 (V1b)

Pituitary

Adrenocorticotropic hormone release

Oxytocin

Uterus, mammary gland, Gastrointestinal tract Endothelium

Contraction Vasodilation

cortical and medullary renal collecting duct. Coupling of the V2R with the Gs signaling pathway increases intracellular cyclic adenosine monophosphate (cAMP). The increased cAMP triggers fusion of the aquaporin-2-bearing vesicles with the apical plasma membrane of the collecting duct principal cells to increase free water absorption. AVP regulates water homeostasis in two ways: by regulating the fast shuttling of aquaporin-2 to the cell surface and by stimulating the synthesis of messenger ribonucleic acid-encoding aquaporin-2. Most animals with hereditary nephrogenic diabetes insipidus have V2R gene mutations. V2R activation also stimulates the release of platelets from the bone marrow and enhances the release of von Willebrand factor and factor VIII from endothelial cells. It causes a mild increase in the activity of factor VIII-related antigen and ristocetin cofactor. There are also V2Rs in the vascular endothelium; the potent V2R agonist 1-deamino-8-d-arginine vasopressin (DDAVP) therefore causes vasodilation in addition to the release of von Willebrand factor and factor VIII. The V3 pituitary receptors (V3Rs, previously known as V1bRs) are located in the anterior pituitary gland and activate Gq protein to release intracellular calcium after activation of phospholipase C and the phosphoinositol cascade. V3R activation stimulates the release of adrenocorticotropic hormone.11 These receptors are also responsible for the actions of AVP on the central nervous system, where they act as a neurotransmitter or a modulator of memory, blood pressure, body temperature, sleep cycles, and release of pituitary hormones. The oxytocin receptor is a nonselective vasopressin receptor with equal affinity for both AVP and oxytocin. Activation of the oxytocin receptor leads to smooth muscle contraction, primarily in the myometrium and mammary myoepithelial cells. AVP also acts on oxytocin receptors in the umbilical vein, aorta, and pulmonary artery, where it causes a nitric oxide-mediated vasodilation. Stimulation of cardiac oxytocin receptors leads to the release of atrial natriuretic peptide. Vasopressin also stimulates the P2 class of purinoreceptors (ATP receptors), which leads to vasodilation mediated by nitric oxide and prostacyclin. P2 receptors are also positive inotropic agents without direct effects on heart rate.

PHYSIOLOGIC EFFECTS OF VASOPRESSIN Vasopressin causes direct systemic vasoconstriction via the V1Rs. In vitro, AVP is a more potent vasoconstrictor than angiotensin II, norepinephrine,

or phenylephrine on a molar basis. It is vital for osmoregulation and maintenance of normovolemia, mediated by the V2Rs. In addition, AVP maintains hemostasis and assists with temperature modulation, memory, sleep, and secretion of adrenocorticotropic hormone. During normal physiologic states, the primary role of AVP is the regulation of free water balance. Vasopressin levels in fasting humans are less than 4 pg/ml. Small increases in plasma osmolality lead to an increase in AVP to 10 pg/ml. A maximum increase in urine osmolality is seen with AVP levels greater than 20 pg/ml. Vasopressin does not control vascular smooth muscle constriction in normal animals, but it is vital in states of hypotension.11-13 Plasma AVP levels of 50 pg/ml must be attained before a significant increase in arterial pressure is achieved in humans. The pressor (vasoconstrictive) effects of AVP are nonadrenergic and are thought to be mediated by its direct and indirect effects on arterial smooth muscle. Stimulation of the V1R leads to vasoconstriction of the skin, skeletal muscles, fat, bladder, myometrium, liver, spleen, pancreas, and thyroid gland. Low levels of AVP lead to vasodilation in the cerebral, pulmonary, mesenteric, and renal vessels. Even with potent stimuli for release, only 10% to 20% of the AVP stored in the pituitary can be readily released, and further release occurs at a much slower rate that results in a biphasic response to vasodilatory shock.11

PHARMACOLOGY Exogenous AVP (8-arginine vasopressin) is available as a sterile aqueous solution of synthetic AVP for intravenous, intramuscular, or subcutaneous administration. It is destroyed within the gastrointestinal tract and is therefore administered parenterally. It is not protein bound and has a volume of distribution of 140 ml/kg and a half-life of approximately 24 minutes. The drug is cleared by renal excretion (65%) and metabolism by tissue peptidases (35%). Terlipressin (triglycyllysine vasopressin) is a synthetic prodrug that is converted to lysine vasopressin in the circulation and has a greater V1R selectivity and prolonged duration of action, with an effective half-life of approximately 6 hours (versus 16-24 minutes for vasopressin). This form of vasopressin has been used in the management of hemorrhagic gastroenteritis in dogs with no improvement in outcomes.14 While terlipressin has been shown to be effective as monotherapy and in combination with other vasopressors (e.g., norepinephrine) to increase MAP, terlipressin may be associated with a significantly increased risk of adverse effects, in particular peripheral cyanosis/ischemia.15,16 As such, terlipressin should be used with caution until its ischemic risk and benefits are better understood.17-20 Selepressin, a novel selective V1R agonist, has been studied in humans with septic shock and experimental sheep with sepsis, as well as in healthy research dogs.21-23 Healthy experimental dogs given selepressin were found to have a reduced risk of coronary ischemia compared with those administered AVP.23 Selepressin causes significantly less adverse effects on mesenteric blood flow and gastric mucosal perfusion compared with AVP; however, norepinephrine was also shown to improve these parameters.24 Selepressin was shown to be an effective vasopressor substitute for norepinephrine by maintaining of MAP, reducing vascular leak and edema formation, and shortening the duration of shock.25-27 However, administration of selepressin was recently compared with placebo in human patients receiving norepinephrine and did not result in improved outcomes.28 Desmopressin acetate is a synthetic vasopressin analog that is available in both an intranasal and an injectable form. (An oral tablet form is also manufactured, but the bioavailability following oral ingestion is very low.) It binds primarily to V2Rs and therefore has more potent antidiuretic and procoagulant activity and less vasopressor action than AVP on a perweight basis. Both formulations of the drug should be stored in the refrigerator (although the nasal formulation is stable at room temperature for

CHAPTER 148  Vasopressin 3 weeks). Desmopressin acetate causes a dose-dependent increase in plasma levels of factor VIII and plasminogen factor. It also causes smaller increases in factor VIII-related antigen and ristocetin cofactor activities, but the effect is sustained for only 3 to 4 hours. The onset of antidiuretic action in dogs usually occurs within 2 hours of administration, peaks in 2 to 8 hours, and may persist for up to 24 hours. The metabolism of desmopressin is not well understood. The terminal half-life in humans after intravenous administration ranges from 0.4 to 4 hours.

CLINICAL USES Indications and dosages for the use of vasopressin or DDAVP are summarized in Table 148.2.

Cardiopulmonary Resuscitation The use of AVP to manage cardiac arrest has been studied extensively in laboratory animals and people. While earlier studies suggested that vasopressin was at least equivalent to epinephrine in its ability to aid in the return of spontaneous circulation (ROSC) or survival in humans,29 more recent studies suggest that there is no benefit of vasopressin with or without epinephrine when compared to epinephrine use alone.30,31 A randomized, prospective clinical study in 60 dogs did not reveal an advantage in survival or 6-minute ROSC when AVP (0.5 to 1 U/kg) was compared with low-dose epinephrine (0.01 to 0.02 mg/kg). Further studies would be helpful, especially since the dose of AVP used in most dogs was often below the recommended dose of 0.8 U/kg and the underlying disease states were extremely variable.32 Another observational study in canines reported a possible association between the use of AVP therapy and successful resuscitation.33 Additionally, experimental cardiopulmonary resuscitation (CPR) studies in pigs showed that AVP improved cerebral oxygen delivery, resuscitation success, neurologic outcome, and blood flow to major organs, compared with epinephrine. Vasopressin has been listed in the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care for the treatment of unstable ventricular tachycardia and ventricular fibrillation since 2000. However, the most recent update to these guidelines in 2019 reported that vasopressin may be considered in a cardiac arrest but offers no advantage as a substitute for epinephrine in cardiac arrest, and that

TABLE 148.2  Indications for and Dosages

of Vasopressin or DDAVP Therapy Indication

Dosage

Cardiopulmonary resuscitation

0.4–0.8 U/kg IV 6 1–4 mU/kg/min AVP IV CRI (dogs)a

Vasodilatory shock

0.5–5 mU/kg/min AVP IV CRI (dogs)a

Central diabetes insipidus

0.1 mg/ml intranasal solution DDAVP: 1–4 drops into conjunctival sac q12-24h or 0.01–0.05 ml SC q12-24h Alternatively, aqueous AVP may be used at 3–5 IU/dog or 0.5 IU/kg (cats) SC q4h or as needed; oral DDAVP tablets 0.1-0.2mg per dogb PO q8-12h; 25-50mcg PO q8-12h (cats)

von Willebrand disease

1–4 mcg/kg DDAVP SC q3-4h (dogs)

Gastrointestinal disease, hemorrhagic shock

Unknown

AVP, arginine vasopressin; CRI, constant rate infusion; DDAVP, 1-deamino8-d-arginine vasopressin; IV, intravenously; SC, subcutaneously. PO, per os a Extrapolated from human dosage; dosage in cats is unknown. b Bioavailability may limit effectiveness in dogs.

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vasopressin in combination with epinephrine may be considered during cardiac arrest but offers no advantage compared to epinephrine alone.34 The RECOVER veterinary guidelines also list AVP therapy (0.8 U/kg) as an acceptable alternative to epinephrine therapy during cardiopulmonary resuscitation in both dogs and cats.35 The increased cost of vasopressin in recent years has resulted in less common use, especially in veterinary medicine. Vasopressin levels are elevated following cardiopulmonary arrest, and levels are significantly higher in humans who are resuscitated than in patients who do not survive.36 Vasopressin has a shorter duration of effect and produces a greater vasoconstrictive effect during hypoxic and acidemic states of cardiopulmonary arrest than does epinephrine, although its efficacy in acidemic states has recently been challenged. Its use in newborn piglets with experimentally induced hypoxia37 and cardiac arrest38 has shown promising results; improved survival and less hemodynamic compromise were seen when compared with epinephrine.38 In normal experimental animals, the half-life of AVP is 10 to 20 minutes.39 Extrapolated doses in dogs are 0.4 to 0.8 U/kg given intravenously, with a constant rate infusion of 1 to 4 mU/kg/min, if needed. Endotracheal and endobronchial administration of vasopressin compared with epinephrine has previously been studied experimentally in dogs. Vasopressin administration resulted in a significantly higher diastolic blood pressure compared with epinephrine administration via both routes.40 Furthermore, endobronchial administration of vasopressin in a porcine model of CPR resulted in increased coronary perfusion pressure and increased chance of successful resuscitation compared to placebo.41 Endobronchial vasopressin may be considered as an alternative for vasopressor administration when intravenous access is delayed or not possible.40,41 Recently, intraosseous administration of vasopressin has been shown to be as effective as intravenous administration during experimental models of cardiopulmonary resuscitation in pigs.42,43

Vasodilatory Shock Vasopressin deficiency can play an important role in animals with vasoplegia secondary to sepsis, prolonged hemorrhagic shock, or cardiac arrest. Experimentally, exogenous AVP infusions that yield plasma AVP concentrations of 20 to 30 pg/ml can restore blood pressure with minimal adverse effects on organ perfusion. Previous studies in dogs have found concentrations of AVP in the range of 300 to 1000 pg/ml during the early phase of hemorrhagic shock, and 500 to 1200 pg/ml following experimentally induced endotoxemia (see below for further details). During the later phase of shock, however, the AVP levels are decreased, presumably as a result of degradation of released AVP and depletion of neurohypophyseal stores, which take time to replenish through resynthesis. The AVP concentration in the experimental dogs decreased to 29 pg/ml during the late phase of hemorrhagic shock. Humans with advanced vasodilatory shock have both a deficiency in AVP secretion and an enhanced sensitivity to AVP-induced blood pressure changes. Additionally, AVP levels are markedly increased in animal models of acute sepsis, but this increase is followed by a rapid decline over the ensuing few hours. Alternative hypotheses to explain the low levels of AVP include a decrease in baroreceptor stimulation of AVP release in hypotensive patients secondary to impaired autonomic reflexes, as seen in sepsis, or tonic inhibition by atrial stretch receptors secondary to volume loading or mechanical ventilation. Lastly, AVP release may be inhibited by nitric oxide or high circulating levels of norepinephrine. Several human studies and reports have demonstrated promising results in the treatment of refractory hypotension using an AVP intravenous infusion. Many human patients were subsequently weaned off

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catecholamine support by the addition of AVP therapy. Furthermore, there is an increase in urine output, presumably secondary to an increase in renal perfusion pressure due to renal efferent arteriolar constriction, as well as nitric oxide-induced vasodilation; oxytocin receptor stimulation, which increases natriuresis; and an increase in atrial natriuretic peptide. AVP therapy may reduce the rate of progression of acute kidney injury to renal failure and decrease the requirements for renal replacement therapy in critically ill patients.44-47 However, recent meta-analyses have shown that the use of vasopressin does not result in significantly improved mortality rates compared with the use of norepinephrine.45-47 The use of vasopressin in patients with septic shock may reduce catecholamine requirements and facilitate weaning of catecholamines.48 Additionally, the combination of vasopressin and norepinephrine may result in the resolution of hypotension faster compared with norepinephrine monotherapy.49,50 Interestingly, in one study, patients who received both physiologic levels of corticosteroids and AVP therapy had decreased mortality compared with those who were treated with norepinephrine and corticosteroids or with either drug without corticosteroid therapy.51 However, high-dose therapy is associated with excessive coronary and splanchnic vasoconstriction, as well as a hypercoagulable state. The excessive vasoconstriction can lead to a reduction in cardiac output or even fatal cardiac events, especially in patients with decreased myocardial function. Guzman et al.52 compared the effects of intravenous norepinephrine with those of intravenous AVP on systemic splanchnic and renal circulation in anesthetized dogs with experimentally induced endotoxic shock. Except for a more pronounced bradycardia in the AVP group, the systemic and splanchnic blood flow changes were comparable. However, the AVP infusion restored renal blood flow and oxygen delivery, but norepinephrine therapy did not. These types of studies are not representative of patients that have catecholamineresistant hypotension, but the end-organ results are expected to be similar. Another canine study by Morales et al.53 examined the effect of AVP administration in dogs with experimental hemorrhagic shock and subsequent requirement for a norepinephrine infusion (3 mcg/kg/ min) to maintain a MAP of 40 mm Hg. An AVP infusion resulted in increased in mean arterial pressures from 39 6 6 mm Hg to 128 6 9 mm Hg. The serum AVP levels were markedly elevated during the acute hemorrhage but decreased from 319 6 66 to 29 6 9 pg/ml before administration of AVP. Clinically, AVP has been used in dogs with refractory vasodilatory shock.54 A dosage of 0.5 mU/kg/min was administered intravenously and titrated up to 4 mU/kg/min to achieve a MAP above 70 mm Hg and a heart rate below 140 beats/min. There was a significant increase in MAP with minimal apparent adverse effects. The mean dosage used was 2.1 mU/kg/min. There is no information regarding survival because all of the dogs in this clinical study were euthanized or died.

Hemorrhagic Shock There have been several experimental animal studies and preliminary human clinical studies evaluating the use of AVP therapy for the treatment of hemorrhagic shock. Its ability to sustain arterial blood pressure and decrease blood loss during hemorrhage deserves further study. Because AVP redirects blood from the skin, skeletal muscle, gastrointestinal tract, mesentery, and periphery, it minimizes hemorrhage from these areas. AVP has been shown to previously decrease fluid requirements and mortality in one human trauma study.55 The use of AVP has recently been shown to significantly reduce blood transfusion requirements and the risk of deep vein thrombosis formation in human patients with acute trauma.56 In this study, a large proportion of patients had penetrating trauma. Further

research is therefore necessary to investigate whether low-dose vasopressin is effective in patients with more severe blunt trauma. A recent metaanalysis of experimental animal studies revealed that vasopressin appeared to be more effective than all other treatments in the management of hemorrhagic shock, including other vasopressor drugs. However, these results need to be confirmed in human (and animal) clinical studies.57

Central Diabetes Insipidus Animals with central diabetes insipidus caused by a deficiency in endogenous AVP may benefit from treatment with either aqueous vasopressin or DDAVP. Caution should be exercised to prevent water intoxication; serial electrolyte levels should be analyzed during treatment. DDAVP is often the preferred drug because it has more antidiuretic activity and less potential vasopressor properties than AVP. One to four drops of the 0.1 mg/ml intranasal solution is typically given into the conjunctival sac q6-24h. Alternatively, subcutaneous doses of 0.01 to 0.05 ml DDAVP have also been used in dogs q6-24h. Aqueous vasopressin has been administered subcutaneously at doses of 3 to 5 U per dog and 0.5 U/kg in cats q4h, or as needed (see Chapter 76, Diabetes Insipidus). The use of oral DDAVP tablets dosed at 25-50 mcg PO q8-12h in cats with central diabetes insipidus proved safe and variably effective in a small cohort study.58

von Willebrand Disease DDAVP therapy may be beneficial in patients with von Willebrand disease, except those animals with type IIB or platelet-type (pseudo) forms because platelet aggregation and thrombocytopenia may occur. In addition, treatment with DDAVP is often confounded by its short duration of activity (2 to 4 hours), expense, and development of resistance (tachyphylaxis), which makes repeated doses ineffective. It is not effective for dogs with severe type II and III von Willebrand disease. The dosage is 1 to 4 mcg/kg of DDAVP subcutaneously q3-4h. Onset of activity is typically within 30 minutes, and the effects last approximately 2 hours. DDAVP can improve platelet function in a range of other disease states (e.g., uremia) (see Chapter 103, Platelet Disorders).

Gastrointestinal and Pulmonary Disease AVP has several indications for use in humans that have not yet been studied in dogs. These include the acute treatment of esophageal varices and gastrointestinal hemorrhage,59 stimulation of peristalsis in patients with postoperative ileus, and dispelling of intestinal gas before abdominal imaging. AVP has also been shown to improve cardiopulmonary function in ovine acute lung injury secondary to burns and smoke inhalation.60 This looks like a promising area for further research.

ADVERSE EFFECTS AVP can cause contraction of the bladder and gallbladder smooth muscle and can increase peristalsis (especially of the colon). The drug may decrease gastric secretions and increase gastrointestinal sphincter pressure. Potential adverse effects of AVP administration include local irritation at the injection site, skin necrosis if extravasated, and skin reactions. Humans treated with AVP for vasodilatory shock have developed an increase in liver enzyme and bilirubin levels, decrease in platelet count, hyponatremia, anaphylaxis, bronchospasm, abdominal pain, hematuria, and urticaria, although the incidence of adverse effects appears to be quite low. Theoretically, because AVP causes a release of von Willebrand factor, it enhances platelet aggregation and may increase the risk of thrombosis. Water intoxication has been reported with high-dose therapy for the treatment of diabetes insipidus. Vasopressin or DDAVP may cause irritation when administered in the conjunctival sac.

CHAPTER 148  Vasopressin

VASOPRESSIN ANTAGONISTS Investigation into vasopressin antagonist therapy is currently underway for a variety of diseases. V1R antagonists may prove useful for the management of subarachnoid hemorrhage, whereas V2R antagonists may be preferable to the use of loop diuretics in people and dogs with congestive heart failure.61-63 A full review of these emerging treatments is beyond the scope of this chapter, but vasopressin antagonists hold great promise for the treatment of a variety of disease states in which elevated endogenous AVP levels are detrimental to the patient.

REFERENCES 1. Robinson A, Verbalis J: Posterior pituitary gland. In Larsen P, Kronenberg H, Melmed S, et al, editors: Williams textbook of endocrinology, Philadelphia, 2002, Saunders. 2. Hoyle CH: Neuropeptide families and their receptors: evolutionary perspectives, Brain Res 848:1, 1999. 3. Bourque CW, Oliet SH: Osmoreceptors in the central nervous system, Annu Rev Physiol 59:601, 1997. 4. Quail AW, Woods RL, Korner PI: Cardiac and arterial baroreceptor influences in release of vasopressin and renin during hemorrhage, Am J Physiol 252:H1120, 1987. 5. Norsk P, Ellegaard P, Videbaek R, et al: Arterial pulse pressure and vasopressin release in humans during lower body negative pressure, Am J Physiol 264:R1024, 1993. 6. Holmes CL, Landry DW, Granton JT: Science review: vasopressin and the cardiovascular system. Part 2: clinical physiology, Crit Care 8:15, 2004. 7. Leng G, Dyball RE, Luckman SM: Mechanisms of vasopressin secretion, Horm Res 37:33, 1992. 8. Day TA, Sibbald JR: Noxious somatic stimuli excite neurosecretory vasopressin cells via A1 cell group, Am J Physiol 258:R1516, 1990. 9. Kam PC, Williams S, Yoong FF: Vasopressin and terlipressin: pharmacology and its clinical relevance, Anaesthesia 59:993, 2004. 10. Holmes CL, Landry DW, Granton JT: Science review: vasopressin and the cardiovascular system. Part 1: receptor physiology, Crit Care 7:427, 2003. 11. Holmes CL, Patel BM, Russell JA, et al: Physiology of vasopressin relevant to management of septic shock, Chest 120:989, 2001. 12. Graybiel A, Glendy R: Circulatory effects following the intravenous administration of pitressin in normal persons and in patients with hypertension and angina pectoris, Am Heart J 21:481, 1941. 13. Schwartz J, Keil LC, Maselli J, et al: Role of vasopressin in blood pressure regulation during adrenal insufficiency, Endocrinology 112:234, 1983. 14. El-Mashad NE: Monitoring the efficacy of Terlipressin acetate in dogs suffering from hemorrhagic gastroenteritis (HGE), J Appl Vet Sci 1:48-55, 2016. 15. Rodriguez R, Cucci M, Kane S, et al: Novel vasopressors in the treatment of vasodilatory shock: a systematic review of angiotensin II, selepressin, and terlipressin, J Intensive Care Med 35:327-337, 2020. 16. Liu ZM, Chen J, Kou Q, et al: Terlipressin versus norepinephrine as infusion in patients with septic shock: a multicenter, randomized, double-blinded trial, Intensive Care Med 44:1816-1825, 2018. 17. Singer M: Arginine vasopressin vs. terlipressin in the treatment of shock states, Best Pract Res Clin Anaesthesiol 22(2):359-368, 2008. 18. Lange M, Ertmer C, Westphal M: Vasopressin vs. terlipressin in the treatment of cardiovascular failure in sepsis, Intensive Care Med 34(5): 821-832, 2008. 19. Rodriguez-Nunez A, Lopez-Herce J, Gil-Anton J, et al: Rescue treatment with terlipressin in children with refractory septic shock: a clinical study, Crit Care 10(1):R20, 2006. 20. Ishikawa K, Wan L, Calzavacca P, et al: The effects of terlipressin on regional hemodynamics and kidney function in experimental hyperdynamic sepsis, PLoS One 7(2):e29693, 2012. 21. Russell J, Vincent JL, Kjølbye AL, et al: Selepressin, a novel selective vasopressin V1a agonist, reduces norepinephrine requirements and shortens

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duration of organ dysfunction in septic shock patients, Crit Care Med 40(12):62, 2012. 22. Rehberg S, Ertmer C, Vincent JL, et al: Role of selective V1a receptor agonism in ovine septic shock, Crit Care Med 39(1):119-125, 2011. 23. Boucheix OB, Milano SP, Henriksson M, et al: Selepressin, a new V1A receptor agonist: hemodynamic comparison to vasopressin in dogs, Shock 39(6):533-538, 2013. 24. Milano SP, Boucheix OB, Reinheimer TM: Selepressin, a novel selective V1A receptor agonist: effect on mesenteric flow and gastric mucosa perfusion in the endotoxemic rabbit, Peptides 129:170318, 2020. 25. Russell JA, Vincent JL, Kjoblye AL, et al: Selepressin, a novel selective vasopressin V1A agonist, is an effective substitute for norepinephrine in a phase IIa randomized, placebo-controlled trial in septic shock patients, Crit Care 21:213, 2017. 26. He X, Su F, Taccone FS, et al: A selective V1A receptor agonist, selepressin, is superior to arginine vasopressin and norepinephrine in ovine septic shock, Crit Care Med 44:23-31, 2016. 27. Maybauer MO, Maybauer DM, Enkhbaatar P, et al: The selective V1a receptor agonist selepressin (FE202158) blocks vascular leak in ovine severe sepsis, Crit Care Med 42:e525-e533, 2014. 28. Laterre PF, Berry SM, Blemings A, et al: Effect of selepressin vs placebo on ventilator- and vasopressor-free days in patients with septic shock: the SEPSIS-ACT randomized clinical trial, JAMA 322: 1476-1485, 2019. 29. Aung K, Htay T: Vasopressin for cardiac arrest: a systematic review and meta-analysis, Arch Intern Med 165:17, 2005. 30. Finn J, Jacobs I, Williams TA, et al: Adrenaline and vasopressin for cardiac arrest, Cochrane Database Syst Rev 1:CD003179, 2019. doi:10.1002/ 14651858.CD003179.pub2. 31. Holmberg MJ, Issa MS, Moskowitz A, et al: Vasopressors during adult cardiac arrest: a systematic review and meta-analysis, Resuscitation 139: 106-121, 2019. 32. Buckley GJ, Rozanski EA, Rush JE: Randomized, blinded comparison of epinephrine and vasopressin for treatment of naturally occurring cardiopulmonary arrest in dogs, J Vet Intern Med 25:1334-1340, 2011. 33. Scroggin RD Jr, Quandt J: The use of vasopressin for treating vasodilatory shock and cardiopulmonary arrest, J Vet Emerg Crit Care (San Antonio) 19:145-157, 2009. 34. Panchal AR, Berg KM, Hirsch KG, et al: 2019 American Heart Association focused update on advanced cardiovascular life support: use of advanced airways, vasopressors, and extracorporeal cardiopulmonary resuscitation during cardiac arrest: an update to the American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care, Circulation 140:e881-e894, 2019. 35. Rozanski EA, Rush JE, Buckley GJ, et al: RECOVER evidence and knowledge gap analysis on veterinary CPR. Part 4: advanced life support, J Vet Emerg Crit Care (San Antonio) 22(Suppl 1):S44-S64, 2012. 36. Lindner KH, Strohmenger HU, Ensinger H, et al: Stress hormone response during and after cardiopulmonary resuscitation, Anesthesiology 77:662, 1992. 37. Cheung DC, Gill RS, Liu JQ, et al: Vasopressin improves systemic hemodynamics without compromising mesenteric perfusion in the resuscitation of asphyxiated newborn piglets: a dose-response study, Intensive Care Med 38(3):491-498, 2012. 38. McNamara PJ, Engelberts D, Finelli M, et al: Vasopressin improves survival compared with epinephrine in a neonatal piglet model of asphyxia cardiac arrest, Pediatr Res 75:738-748, 2014. 39. Errington ML, Rocha e Silva M Jr: The secretion and clearance of vasopressin during the development of irreversible haemorrhagic shock, J Physiol 217:43P, 1971. 40. Efrati O, Barak A, Ben-Abraham R, et al: Should vasopressin replace adrenaline for endotracheal drug administration? Crit Care Med 31: 572-576, 2003. 41. Wenzel V, Lindner KH, Prengel AW, et al: Endobronchial vasopressin improves survival during cardiopulmonary resuscitation in pigs, Anesthesiology 86:1375-1381, 1997. 42. Adams TS, Blouin D, Johnson D: Effects of tibial and humerus intraosseous and intravenous vasopressin in porcine cardiac arrest model, Am J Disaster Med 11:211-218, 2016.

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43. Wimmer MH, Heffner K, Smithers M, et al: The comparison of humeral intraosseous and intravenous administration of vasopressin on return of spontaneous circulation and pharmacokinetics in a hypovolemic cardiac arrest swine model, Am J Disaster Med 11:237-242, 2016. 44. Gordon AC, Russell JA, Walley KR, et al: The effects of vasopressin on acute kidney injury in septic shock, Intensive Care Med 36(1):83-91, 2010. 45. Gordon AC, Mason AJ, Thirunavukkarasu N: Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock: the VANISH randomized clinical trial, JAMA 316:509-518, 2016. 46. Nedel WL, Rech TH, Ribeiro RA, et al: Renal outcomes of vasopressin and its analogs in distributive shock: a systematic review and meta-analysis of randomized trials, Crit Care Med 47:e44-e51, 2019. 47. Nagendran M, Russell JA, Walley KR, et al: Vasopressin septic shock: an individual patient data meta-analysis of randomized controlled trials, Intensive Care Med 45:844-855, 2019. 48. Serpa NA, Nassar AJ, Cardoso SO, et al: Vasopressin and terlipressin in adult vasodilatory shock: a systematic review and meta-analysis of nine randomized controlled trials, Crit Care 16(4):R154, 2012. 49. Hammond DA, Cullen J, Painter JT, et al: Efficacy and safety of the early addition of vasopressin to norepinephrine in septic shock, J Intensive Care Med 34:910-916, 2019. 50. Hammond DA, Ficek OA, Painter JT, et al: Prospective open-label trial of early concomitant vasopressin and norepinephrine therapy versus initial norepinephrine monotherapy in septic shock, Pharmacotherapy 38: 531-538, 2018. 51. Russell JA, Walley KR, Gordon AC, et al: Interaction of vasopressin infusion, corticosteroid treatment, and mortality of septic shock, Crit Care Med 37(3):811-818, 2009. 52. Guzman JA, Rosado AE, Kruse JA: Vasopressin vs. norepinephrine in endotoxic shock: systemic, renal, and splanchnic hemodynamic and oxygen transport effects, J Appl Physiol 95:803, 2003. 53. Morales D, Madigan J, Cullinane S, et al: Reversal by vasopressin of intractable hypotension in the late phase of hemorrhagic shock, Circulation 100:226, 1999.

54. Silverstein DC, Waddell LS, Drobatz KJ, et al: Vasopressin therapy in dogs with dopamine-resistant hypotension and vasodilatory shock, J Vet Emerg Crit Care 17(4):399-408, 2007. 55. Cohn SM, McCarthy J, Stewart RM, et al: Impact of low-dose vasopressin on trauma outcome: prospective randomized study, World J Surg 35(2):430-439, 2011. 56. Sims CA, Holena D, Kim P, et al: Effect of low-dose supplementation of arginine vasopressin on need for blood product transfusions in patients with trauma and hemorrhagic shock: a randomized clinical trial, JAMA Surg 154:994-1003, 2019. 57. Sims CA, Holena D, Kim P, et al: Effect of low-dose supplementation of arginine vasopressin on need for blood product transfusions in patients with trauma and hemorrhagic shock: a randomized clinical trial, JAMA Surg 154:994-1003, 2019. 58. Aroch I, Mazaki-Toci M, Shemesh O, et al: Central diabetes insipidus in five cats: clinical presentation, diagnosis and oral desmopressin therapy, J Feline Med Surg 7:333e339, 2005. doi:10.1016/j.jfms.2005.03.008. 59. Ioannou GN, Doust J, Rockey DC: Systematic review: terlipressin in acute oesophageal variceal hemorrhage, Aliment Pharmacol Ther 17:53-64, 2003. 60. Westphal M, Rehberg S, Maybauer MO, et al: Cardiopulmonary effects of low-dose arginine vasopressin in ovine acute lung injury, Crit Care Med 39(2):357-363, 2011. 61. Laszlo FA, Laszlo F Jr, De Wied D: Pharmacology and clinical perspectives of vasopressin antagonists, Pharmacol Rev 43:73, 1991. 62. Onogawa T, Sakamoto Y, Nakamura S, et al: Effects of tolvaptan on systemic and renal hemodynamic function in dogs with congestive heart failure, Cardiovasc Drugs Ther 25(Suppl 1):S67-S76, 2011. 63. Gheorghiade M, Gattis WA, O’Connor CM, et al: Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial, JAMA 291(16):1963-1971, 2004.

149 Antihypertensives Edward S. Cooper, VMD, MS, DACVECC

KEY POINTS • Systemic hypertension is a common finding in dogs and cats. Immediate intervention may be warranted in animals with severe hypertension (systolic blood pressure .180 mm Hg) and/or evidence of target organ damage. • For patients with secondary systemic hypertension, identifying and treating the underlying cause is just as important as treating the hypertension itself. • There are a variety of antihypertensive medications that work by different mechanisms, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, adrenergic antagonists, and arteriolar vasodilators.

• Selection is based on several factors, including species, severity of hypertension, and acute versus chronic management. • Acute management in a hypertensive emergency can be achieved with injectable medications such as fenoldopam, nitroprusside, hydralazine, or labetalol, whereas more chronic management is achieved by medications such as amlodipine, enalapril/benazepril, and telmisartan. • Reduction of blood pressure must be done in a controlled fashion to prevent acutely normalizing chronic hypertension, which could result in tissue hypoperfusion.

Elevations in systolic blood pressure (SBP) can be a common finding for dogs and cats in both the emergency and ICU settings. The biggest challenge can be determining whether elevations in blood pressure are situational (secondary to stress of in-hospital measurement) or represent the true presence of systemic hypertension (SHT). See Chapter 53, Systemic Hypertension, for more information on definitions and diagnosis of this process, as well as general treatment considerations. Briefly, treatment of SHT is warranted with repeated (.2) measurements of elevated SBP (.140 mm Hg), or a single severely elevated SBP (.180 mm Hg) and the presence of target organ damage (TOD).1 What follows is an overview of the available medications that may be used in the treatment of SHT, with consideration of their mechanism of action, specific indications, and potential adverse effects. Specific dosing and treatment guidelines based on consensus criteria are also provided (see Table 149.1 and Figure 149.1).

protein loss through preferential efferent arteriole constriction. As a result, ACEi can serve to decrease proteinuria, as well as promote vasodilation, venodilation, and a reduction in plasma volume, with resultant reduction in SBP. In addition, ACEi also cause decreased metabolism of the vasodilatory agent bradykinin and further reduction in vascular tone. Use of ACEi is best applied to circumstances whereby SHT is caused by known or suspected increase in RAAS, and most commonly in circumstances related to chronic kidney disease and/or glomerular disease. For this reason, ACEi are often considered the first line for treating SHT in dogs.1 The most commonly used ACEi are enalapril and benazepril, though use of ramipril and lisinopril has also been reported.3 However, if an ACEi alone does not sufficiently reduce SBP, additional agents might be needed (see below). For cats, ACEi are not recommended as a first-line agent.1,4 These medications do not seem to sufficiently or consistently lower blood pressure in cats,5 but benazepril may be beneficial in conjunction with a calcium channel blocker.6 ACEi are generally well tolerated with few reported adverse effects. The biggest concern lies in the potential to worsen glomerular filtration rate and renal function through preferential dilation of the efferent arteriole (and thereby reduce glomerular filtration pressure). The overall risk of clinically relevant increases in creatinine is relatively low unless there is concurrent dehydration and/or use of diuretic therapy and/or the presence of severe azotemia.1,2,7 One study did demonstrate .30% increase in creatinine in 24% of cats with chronic kidney disease (CKD) after 30 days of treatment with benazepril; however, this did not appear to have an impact on long-term survival.8 Through inhibition of aldosterone, hyperkalemia is another potential adverse effect ACEi, though it is unlikely to be clinically relevant even when given in conjunction with an aldosterone antagonist such as spironolactone.9-10

ANTIHYPERTENSIVE DRUGS Angiotensin-converting Enzyme Inhibitors Angiotensin-converting enzyme inhibitors (ACEi) are a family of drugs designed to disrupt the renin-angiotensin-aldosterone system (RAAS). These medications function by inhibiting the conversion of angiotensin I to angiotensin II (ATII). ATII is a potent vasoconstrictor and promotes sodium and water retention both directly and by stimulating the release of aldosterone. Normally these functions are an important component of cardiovascular homeostasis in response to sympathetic stimulation, hypotension, hypovolemia, decreased glomerular filtration, and electrolyte changes.2 However, excess RAAS activation can have numerous deleterious effects, including the development of SHT.2 In addition, ATII can promote increased glomerular

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Fig. 149.1  Algorithm representing a general approach to initiating antihypertensive therapy (adapted from Acierno et al.1). ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; TOD, target organ damage.

TABLE 149.1  Oral Antihypertensive Medications Organized Based on Mechanism of Action

With Suggested Doses1,3,7 Mechanism Angiotensin-converting enzyme inhibitor

Medication Enalapril

Canine Dosage 0.25–0.5 mg/kg q12h-24h

Feline Dosage 0.25–0.5 mg/kg q12h-24h

Benazepril

0.25–0.5 mg/kg q12h-24h

0.25–0.5 mg/kg q12h

Angiotensin receptor blocker

Telmisartan

1–3 mg/kg q24h

1 mg/kg q24h

Aldosterone antagonist

Spironolactone

1–2 mg/kg q12h

1–2 mg/kg q12h

Calcium channel blocker

Amlodipine

0.1–0.4 mg/kg q12h-24h

0.625–1.25 mg/cat q24h

a1-Antagonist

Prazosin

0.5–2 mg/kg q8h-12h

0.25–0.5 mg/cat q12h-24h

Phenoxybenzamine

0.25 mg/kg q12h

2.5 mg/cat q8h-12h

0.5 mg/kg q24h

0.5 mg/kg q12h-24h

b-Antagonist Arteriolar vasodilator

Acepromazine

0.5–2 mg/kg q8h

0.5–2 mg/kg q8h

Atenolol

0.25–1.0 mg/kg q12h-24h

6.25–12.5 mg/cat q12h-24h

Propranolol

0.2–1.0 mg/kg q8h

2.5–5.0 mg/cat q8h

Hydralazine

0.5–2.0 mg/kg q12h

2.5 mg/cat q12h-24h

CHAPTER 149  Antihypertensives

Angiotensin Receptor Blockers Angiotensin receptor blockers (ARBs) are another class of drugs that can impact the RAAS system. Rather than preventing its production, ARBs block the ability of ATII to activate its receptor. The main difference with ARBs is that they will block ATII regardless of how it is formed (i.e., through mechanisms independent of ACE), and they do not affect the metabolism of bradykinin.2 Otherwise the pharmacological effects are similar to ACEi. Use of ARBs has been in explored both in dogs and cats as a potential alternative or adjunct to ACEi in patients with hypertension. In a retrospective study exploring use of ARBs in dogs with protein-losing nephropathy, telmisartan (dose ranging 0.5–2.0 mg/kg) combined with enalapril or benazepril was associated with a more significant reduction in blood pressure and proteinuria compared with either medication alone.11 There was also not significant difference in patients that received only the ARB or an ACEi. Another study evaluated the impact of telmisartan (dosed at 1 mg/kg q24h) in canine patients with proteinuric CKD. Telmisartan was associated with a decrease in SBP to ,160 mm Hg in 60% of dogs that were hypertensive at baseline.12 A randomized, prospective, blinded controlled trial assessed the use of telmisartan in hypertensive cats.13 This study found that 1.5–2.0 mg/kg telmisartan was effective at significantly reducing SBP (median 24 mm Hg) compared with placebo at 14 and 28 days. No significant adverse effects were reported. Another study demonstrated that telmisartan reduced blood pressure in healthy cats, but losartan did not.14 Based on these findings, it has been suggested that telmisartan could be considered in as monotherapy in cats with significant proteinuria.15 Based on their mechanism of action and disruption of ATII, ARBs would be expected to carry a similar side effect profile as ACEi. Specifically, they should be avoided or used cautiously in patients that are severely dehydrated and/or azotemic.1,2,15 Overall, there are very few side effects reported.

Aldosterone Antagonists Spironolactone is a selective antagonist of aldosterone by blocking its effects in the distal convoluted tubule and collecting duct. Aldosterone promotes sodium and water retention, as well as potassium and acid secretion. With chronic exposure, aldosterone can be proinflammatory and have adverse effects including promoting fibrosis and vascular remodeling (particularly in the glomerulus).2 These vascular changes, in addition to sodium and water retention, can contribute to SHT in the face of excessive RAAS activation or aldosterone secretion. Hyperaldosteronism would be the primary indication for the use of spironolactone as an antihypertensive. While this disease is seen uncommonly in cats, and very rarely in dogs,1 suspicion is reasonable in hypertensive feline patients with concurrent hypernatremia and severe hypokalemia.16 The main potential adverse effect of spironolactone is development of hyperkalemia, though this is unlikely unless used with ACEi, ARBs, or b-blockers.3

Calcium Channel Blockers Calcium channel blockers (CCBs) function by decreasing calcium influx into cardiac tissues and vascular smooth muscle cells. The family of dihydropyridines (like amlodipine and nicardipine) have relative selectivity for the latter and thereby promote vasorelaxation and reduce systemic vascular resistance. Overall, they have minimal effects on cardiac conduction, though the associated decrease in in blood pressure may trigger a reflex tachycardia. Amlodipine besylate is the first-line antihypertensive of choice for managing SHT in cats,1,3,4,15,17 particularly whether idiopathic or secondary to renal disease.1,3 Amlodipine has been shown to be more

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effective than ACEi, with reported decrease in SBP ranges from 28 to 55 mm Hg across numerous studies.18-20 Recommended starting doses for cats range from 0.625 mg to 1.25 mg (total dose) once daily, with the latter dose for more severe hypertension (.200 mm Hg).1,4,21 Patients refractory to amlodipine alone may need the addition of a second agent such as an ARB or an ACEi. As previously mentioned, an ACEi is more typically the first line for dogs, though some may require the addition of a CCB as adjunct therapy for more significant reduction of SBP.1,7 As previously mentioned, CCBs may cause reflex bradycardia, and other side effects could include weakness, lethargy, and decreased appetite. Another potential concern is the effect on intrarenal hemodynamics. Within the glomerulus, CCBs promote preferential afferent arteriolar dilation over the efferent arteriole. This would serve to increase intraglomerular pressure, which could be damaging to the glomerulus and worsen proteinuria.1 It is for this reason that use of amlodipine alone is not recommended for treatment of SHT in dogs, as concurrent administration of ACEi serves to offset this effect.1

Adrenergic Antagonists The sympathetic nervous system plays a major role in cardiovascular homeostasis, including modulation of vascular tone (predominantly through a1 receptors), as well as heart rate and contractility (predominantly through b1 receptors). Sympathetic activation can also promote sodium and water retention, and thereby circulating volume. It therefore stands to reason that adrenergic antagonists could play a role in the management of SHT, especially if the underlying mechanism is sympathetically driven. Prazosin and phenoxybenzamine are selective a1 receptor antagonists that promote vascular smooth muscle relaxation. While they may have an adjunctive role in the general management of SHT in dogs, their primary application is in the management of patients with pheochromocytoma.1,22 As an injectable option, acepromazine could also be considered. These medications are not typically used in management of SHT in cats. Potential adverse effects include excessive hypotension and gastrointestinal upset. Atenolol is a selective b1 and propranolol is a nonselective b receptor antagonist. Both serve to decrease heart rate and contractility, as well as decrease renin release and peripheral vascular resistance. Of these, atenolol is more often used in cats as an adjunct in the management of SHT associated with hyperthyroidism.1,17 In dogs, either can be used as an adjunct for refractory SHT, particularly if the patient is experiencing reflex tachycardia or tachycardia secondary to pheochromocytoma. Potential adverse effects could include excessive bradycardia and hyperkalemia. Labetalol is an injectable mixed - and -antagonist that has been explored as a potential intervention for the management of acute severe hypertension. Its combined effects promote vasodilation and prevent associated reflex tachycardia. Use of this medication has been explored in the intra- and postoperative management of canine patients undergoing craniotomy or adrenalectomy (both populations are at risk for acute SHT).23 In this study, a median dose of 1.1 mg/kg/hr (range 0.2–3.4) was used and resulted in significant reduction in blood pressure without an associated change in heart rate.

Arteriolar Vasodilators Hydralazine promotes vasodilation by altering smooth muscle intracellular calcium metabolism. Though the mechanism is not entirely understood, the end result is smooth muscle relaxation and a decrease in peripheral vascular resistance. Hydralazine is not used as a first-line agent for management of SHT in dogs or cats and is uncommonly

870

PART XVIII  Pharmacology

used as an adjunct in chronic management. Given its potent vasodilatory effects, rapid onset of action, and injectable formulation, hydralazine is most often used in the context of urgent or emergent hypertension (see below).1,7,17 Potential adverse effects include excessive and irreversible hypotension, reflex tachycardia, sodium/water retention, and gastrointestinal upset. Sodium nitroprusside (SNP) promotes potent vasodilation through the release of nitric oxide (NO). NO rapidly diffuses to vascular smooth muscle and decreases intracellular influx of calcium, activation of actin/ myosin chains, and overall contractile force. This results in smooth muscle relaxation and a significant decrease in vascular tone and peripheral vascular resistance. Given its injectable formulation and short half-life, SNP can be closely titrated to lower SBP. This makes it ideally suited to use in a hypertensive crisis. However, SNP is associated with several potential adverse effects, most notably the generation of cyanide and thiocyanate associated with high doses administered for prolonged periods of time. Owing to decreased metabolism and clearance, the risk of cyanide toxicity is increased in patients with significant liver or kidney disease. Patients must be monitored closely for dramatic changes in blood pressure, as well as signs of toxicosis (metabolic acidosis, depression, stupor, seizures).3 Concern for toxicity, decreased availability, and significant cost have more recently limited its use in veterinary medicine. For this reason, use of intravenous nitroglycerine may also be considered. The mechanism of action and potential for adverse effects are similar, though nitroglycerine does not carry the concern for cyanide or thiocyanate production. Experimental models in dogs have shown reduced systemic vascular resistance, mean arterial pressure, and aortic pressures with use of intravenous nitroglycerin.24-25 Published clinical experience is limited, with one case series describing use in three dogs with congestive heart failure at a dose range of 1–6 mcg/kg/min.26 No adverse effects were reported.

Fenoldopam Fenoldopam is selective agonist of the dopamine-1 receptor. Activation of dopamine receptors promotes peripheral and renal vasodilation, as well as natriuresis and increased glomerular filtration rate. Fenoldopam is injectable and has a short half-life, which makes it potentially applicable for use in an acute hypertensive crisis. For these reasons it is one of the emergency medications used in human medicine, particularly for patients with concurrent renal disease.27-28 While it has not been investigated for use specifically in this context, fenoldopam has been investigated in both healthy dogs and cats, as well as those with acute kidney injury.29 Further investigation is needed to determine a role for fenoldopam in veterinary SHT management.

GOALS OF TREATMENT As most SHT is secondary to systemic disease (see Chapter 53, Systemic Hypertension), identification and treatment of the underlying cause are first and foremost in the management of SHT. Further, the precipitating disease/mechanism and the patient’s species may impact antihypertensive selection. Another major factor impacting medication choice and goals of therapy is whether the elevation in SBP is associated with emergent (crisis), urgent, or nonurgent hypertension. A hypertensive crisis constitutes the presence of severe hypertension (SBP 180 mm Hg) in conjunction with overt evidence of TOD (particularly ocular or neurological).1 In order to prevent further organ damage from occurring, rapid control of SBP with close monitoring is essential. This will most effectively be achieved with injectable medications that can be titrated to achieve the target blood pressure. These may include use of fenoldopam, hydralazine, nitroprusside, nitroglycerin, or labetalol (see Table 149.2). While injectable CCBs like nicardipine and clevidipine are used in humans with hypertensive emergency,30 there is little clinical data for use in dogs or cats. Regardless of which medication is used, careful titration and monitoring are needed so that blood pressure is not decreased too rapidly or dramatically. If the development of SHT has resulted in a shift in the autoregulatory set point, a normal blood pressure could result in decreased tissue perfusion. As such, a reduction in SBP of 10% over the first hour, and then 15% over the next several hours is recommended.1,31 Ideally this will result in an SBP ,180 mm Hg to reduce the risk of further TOD. If injectable medications are not available, then oral hydralazine and/or amlodipine may be acceptable alternatives as they have rapid onset of action (see Table 149.2).7,17 As their effects will be more difficult to titrate, close blood pressure monitoring will be needed to achieve similar targets for SBP reduction. Once the hypertensive crisis has been resolved, the patient must be transitioned to a long-term management plan. Hypertensive urgency involves detection of a persistent increase in SBP that constitutes high risk (SBP .180 mm Hg), but no evidence that TOD has occurred. In these patients, blood pressure control can be more gradual than a hypertensive emergency (days/week compared to hours). Oral medications are typically sufficient, with amlodipine or hydralazine (1/- ACEi or ARB) being the main initial choices. To avoid overly rapid decreases in blood pressure, the patient should be maintained at the initial dose for at least 1–2 weeks to achieve steady state and determine effectiveness.1,32 Nonurgent hypertension involves a persistent SHT with a low to medium risk of TOD (SBP .140 mm Hg and ,180 mm Hg). For

TABLE 149.2  Medications Used in Patients With Hypertensive Emergency1,7 Mechanism

Medication

Canine Dosage

Feline Dosage

Calcium channel blocker

Amlodipine

0.2–0.6 mg/kg PO q24h

0.625–1.25 mg/cat q24h

a1-Antagonist

Acepromazine

0.05–0.1 mg/kg IV/SC

0.05–0.1 mg/kg IV/SC

a- and b-antagonist

Labetalol

0.25 mg/kg IV loading

Unknown

25 mcg/kg/min CRI Arteriolar vasodilator

Hydralazine

0.1 mg/kg IV loading

1–2.5 mg/cat SC

1.5–5.0 mcg/kg/min IV CRI

0.2 mg/kg IV or IM

0.5–2.0 mg/kg PO q12h

Dopamine agonist

Nitroprusside

1–3 mcg/kg/min IV CRI

1–2 mcg/kg/min IV CRI

Nitroglycerin

1–5 mcg/kg/min

1–6 mcg/kg/min IV CRI

Fenoldopam

0.1 mcg/kg/min titrated by 0.1 every 10 min to max of 1.6 mcg/kg/min

0.1 mcg/kg/min titrated by 0.1 every 10 min to max of 1.6 mcg/kg/min

CRI, constant rate infusion; IM, intramuscular; SC, subcutaneous.

CHAPTER 149  Antihypertensives these patients, monotherapy with a first-line agent (e.g., amlodipine for cats and enalapril for dogs) is reasonable, with a plan to recheck in 7–10 days.1 If target pressure is achieved (,160 mm Hg minimum goal, ,140 mm Hg optimal goal), then starting regiment is maintained and rechecked in 4–6 months.1 If SBP is still .160 mm Hg, then an increase in dosage or addition of another medication is indicated. For patients that have an SBP ,120 mm Hg and/or have signs consistent with hypotension, there should be a reduction in dose or frequency of medication(s). With either hypotension or hypertension, blood pressure should be rechecked 7–10 days after an adjustment is made until the target SBP is achieved.1

REFERENCES 1. Acierno MJ, Brown S, Coleman AE, et al: ACVIM consensus statement: guidelines for the identification, evaluation, and management of systemic hypertension in dogs and cats, J Vet Intern Med 32(6):1803-1822, 2018. 2. Ames MK, Atkins CE, Pitt B: The renin-angiotensin-aldosterone system and its suppression, J Vet Intern Med 33:363-382, 2019. 3. Labato MA: Antihypertensives. In Silverstein DC, Hopper K, editors: Small animal critical care medicine, ed 2, Philadelphia, 2015, Elsevier, pp 840-846. 4. Taylor SS, Sparkes AH, Briscoe K, et al: ISFM consensus guidelines on the diagnosis and management of hypertension in cats, J Feline Med Surg 19(3):288-303, 2017. 5. Brown SA, Brown CA, Jacobs G, Stiles J, Hendi RS, Wilson S: Effects of the angiotensin converting enzyme inhibitor benazepril in cats with induced renal insufficiency, Am J Vet Res 62:375-383, 2001. 6. Elliott J, Fletcher M, Souttar K, et al: Effect of concomitant amlodipine and benazepril therapy in the management of feline hypertension, J Vet Intern Med 18:788, 2004. 7. Ohad DG: Treatment of systemic hypertension, In Ettinger SJ, Feldman EC, Cote E, editors: Textbook of veterinary internal medicine, ed 8, Philadelphia, 2017, Elsevier, pp 666-671. 8. Lavallee JO, Norsworthy GD, Huston CL, Chew DJ: Safety of benazepril in 400 azotemic and 110 non-azotemic client-owned cats (2001-2012), J Am Anim Hosp Assoc 53:119-127, 2017. 9. Thomason JD, Rapoport G, Fallaw T, Calvert CA: The influence of enalapril and spironolactone on electrolyte concentrations in Doberman pinschers with dilated cardiomyopathy, Vet J 202(3):1-5, 2014. 10. Thomason JD, Rockwell JE, Fallaw TK, Calvert CA: Influence of combined angiotensin-converting enzyme inhibitors and spironolactone on serum K1, Mg21, and Na1 concentrations in small dogs with degenerative mitral valve disease, J Vet Cardiol 9(2):103-108, 2007. 11. Fowler BL, Stefanovski D, Hess RS, McGonigle K: Effect of telmisartan, angiotensin-converting enzyme inhibition, or both, on proteinuria and blood pressure in dogs, J Vet Intern Med 35:1231-1237, 2021. 12. Miyagawa Y, Akabane R, Sakatani A, et al: Effects of telmisartan on proteinuria and systolic blood pressure in dogs with chronic kidney disease, Res Vet Sci 133:150-156, 2020. 13. Coleman AE, Brown SA, Traas AM, et al: Safety and efficacy of orally administered telmisartan for treatment of systemic hypertension in cats:

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Results of a double-blind, placebo-controlled, randomized clinical trial, J Vet Intern Med 33:478-488, 2019. 14. Jenkins TL, Coleman AE, Schmiedt CW, Brown SA: Attenuation of the pressor response to exogenous angiotensin by angiotensin receptor blockers and benazepril hydrochloride in clinically normal cats, Am J Vet Res 76:807-813, 2015. 15. Lawson JS, Jepson RE, Feline comorbidities: the intermingled relationship between chronic kidney disease and hypertension, J Feline Med Surg 23:812-822, 2021. 16. Ash RA, Harvey AM, Tasker S: Primary hyperaldosteronism in the cat: a series of 13 cases, J Feline Med Surg 7:173-182, 2005. 17. Stepien RL: Systemic hypertension. In Bonagura JD, Twedt DC, editors: Kirk’s current veterinary therapy XV, Philadelphia, 2014, Elsevier, pp 726-730. 18. Huhtinen M, Derré G, Renoldi HJ, et al: Randomized placebo-controlled clinical trial of a chewable formulation of amlodipine for the treatment of hypertension in client-owned cats, J Vet Intern Med 29:786-793, 2015. 19. Henik RA, Snyder PS, Volk LM: Treatment of systemic hypertension in cats with amlodipine besylate, J Am Anim Hosp Assoc 33:226-234, 1997. 20. Elliott J, Barber PJ, Syme HM, Rawlings JM, Markwell PJ: Feline hypertension: clinical findings and response to antihypertensive treatment in 30 cases, J Small Anim Pract 42:122-129, 2001. 21. Bijsmans ES, Doig M, Jepson RE, et al: Factors influencing the relationship between the dose of amlodipine required for blood pressure control and change in blood pressure in hypertensive cats, J Vet Intern Med 30(5):1630-1636, 2016. 22. Herrera MA, Mehl ML, Kass PH, Pascoe PJ, Feldman EC, Nelson RW: Predictive factors and the effect of phenoxybenzamine on outcome in dogs undergoing adrenalectomy for pheochromocytoma, J Vet Intern Med 22:1333-1339, 2008. 23. Zublena F, Gennero CD, Corletto F: Retrospective evaluation of labetalol as antihypertensive agent in dogs, BMC Vet Res 16:256-264, 2020. 24. Noguchi K, Matsuzaki T, Ojiri Y, et al: Beneficial hemodynamic effects of nicorandil in a canine model of acute congestive heart failure: comparison with nitroglycerin and cromokalin, Fundam Clin Pharmacol 12: 270-280, 1998. 25. Kamijo T, Tomaru T, Miwa A, et al: The effects of dobutamine, propranolol and nitroglycerin on an experimental canine model of congestive heart failure, Jpn J Pharmacol 65:223-231, 1994. 26. Achiel E, Carver A, Sanders RA: Treatment of congestive heart failure with intravenous nitroglycerin in three dogs with degenerative valvular disease, J Am Anim Hosp Assoc 56(1):37-41, 2020. 27. Alshami A, Romero C, Avila A, Varon J: Management of hypertensive crises in the elderly, J Geriatr Cardiol 15(7):504-512, 2018. 28. Rodriguez MA, Kumar SK, De Caro M: Hypertensive crisis, Cardiol Rev 18:102-107, 2010. 29. Nielsen LK, Bracker K, Price LL: Administration of fenoldopam in critically ill small animal patients with acute kidney injury: 28 dogs and 34 cats (2008-2012), J Vet Emerg Crit Care 25:396-404, 2015. 30. Miller J, McNaughton C, Joyce K, et al: Hypertension management in emergency departments, Am J Hypertens 33(10):927-934, 2020. 31. Elliott WJ: Management of hypertension emergencies, Curr Hypertens Rep 5:486-492, 2003. 32. Acierno MJ, Labato MA: Hypertension in dogs and cats, Compend Contin Educ Pract Vet 26(5):336, 2004.

150 Pimobendan Joshua A. Stern, DVM, PhD, DACVIM (Cardiology), Ashley L. Walker, DVM

KEY POINTS • Pimobendan is an inodilator drug with both positive inotropic and arteriovenous dilatory effects. • Positive inotropy is achieved mainly via sensitization of the calcium binding affinity to cardiac troponin C and to a lesser extent via inhibition of phosphodiesterase (PDE) III, leading to increased intracellular calcium concentration. Venodilation occurs via PDE III inhibition, resulting in reduced calcium availability at the level of the vascular smooth muscle. • Pimobendan is rapidly absorbed and highly bioavailable in dogs. The oral formulation is Food and Drug Administration-approved for the treatment of congestive heart failure (CHF) secondary to canine myxomatous mitral valve degeneration (MMVD) and canine dilated cardiomyopathy (DCM).

• The use of pimobendan is considered standard of care for preclinical, advanced MMVD (Stage B2) in addition to MMVD and CHF. It is also standard of care in cases of preclinical DCM and DCM with CHF. The recommended starting dose is 0.25–0.3 mg/ kg PO q12h with dose escalation being commonly described in the literature for advanced disease. • The use of pimobendan in the treatment of feline cardiomyopathies is controversial; however, there is evidence that it confers a survival benefit to cats with hypertrophic cardiomyopathy and secondary CHF and in cats with systolic dysfunction and CHF. • Adverse effects of pimobendan are rare, with the most common including gastrointestinal upset and lethargy.

MECHANISMS OF ACTION

found in vascular smooth muscle, and their inhibition increases intracellular cAMP and cyclic guanosine 3’,5’-cyclic monophosphate (cGMP) levels. cAMP and cGMP facilitate calcium uptake through intracellular storage sites, and thus increasing levels of cAMP and cGMP result in a reduction in available calcium for contraction, leading to greater vascular smooth muscle relaxation. While some studies have shown a more pronounced effect on venous dilation, pimobendan is traditionally considered a balanced vasodilator, having equivalent arterial and venous dilatory effects.1,5 The PDE III inhibitory activity of pimobendan has also been shown to suppress the production of nitric oxide (NO), which could further increase cardiac contractility. This may also confer antiinflammatory properties to the drug, as proinflammatory cytokines induce NO synthesis, as shown in a murine model of viral myocarditis.7 Pimobendan has also been shown to have positive lusitropic effects, accelerating left ventricular isovolumetric relaxation and improving myocardial distensibility in dogs with tachycardia-induced heart failure.8 This effect may explain its perceived benefit when used in diseases of diastolic dysfunction such as feline hypertrophic cardiomyopathy, discussed later in this chapter. Pimobendan has been postulated to have antithrombotic activity via its PDE III inhibitory mechanism of action.1 cAMP plays a large role in the regulation of platelet aggregation and therefore increases in cAM