Pediatric critical care medicine [Volume 1. Care of the Critically Ill or Injured Child, 2 ed.] 9781447163619, 1447163613

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Derek S. Wheeler Hector R. Wong Thomas P. Shanley Editors

Pediatric Critical Care Medicine Volume 1: Care of the Critically Ill or Injured Child Second Edition

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Pediatric Critical Care Medicine

Derek S. Wheeler • Hector R. Wong Thomas P. Shanley Editors

Pediatric Critical Care Medicine Volume 1: Care of the Critically Ill or Injured Child Second Edition

Editors Derek S. Wheeler, MD, MMM Division of Critical Care Medicine Cincinnati Children’s Hospital Medical Center University of Cincinnati College of Medicine Cincinnati, OH USA

Thomas P. Shanley, MD Michigan Institute for Clinical and Health Research University of Michigan Medical School Ann Arbor, MI USA

Hector R. Wong, MD Division of Critical Care Medicine Cincinnati Children’s Hospital Medical Center University of Cincinnati College of Medicine Cincinnati, OH USA

ISBN 978-1-4471-6361-9 ISBN 978-1-4471-6362-6 DOI 10.1007/978-1-4471-6362-6 Springer London Heidelberg New York Dordrecht

(eBook)

Library of Congress Control Number: 2014937450 © Springer-Verlag London 2014 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher's location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

For Cathy, Ryan, Katie, Maggie, and Molly “You don’t choose your family. They are God’s gift to you…” Desmond Tutu

Foreword to the First Edition

The practitioner of Pediatric Critical Care Medicine should be facile with a broad scope of knowledge from human developmental biology, to pathophysiologic dysfunction of virtually every organ system, and to complex organizational management. The practitioner should select, synthesize and apply the information in a discriminative manner. And finally and most importantly, the practitioner should constantly “listen” to the patient and the responses to interventions in order to understand the basis for the disturbances that create life-threatening or severely debilitating conditions. Whether learning the specialty as a trainee or growing as a practitioner, the pediatric intensivist must adopt the mantle of a perpetual student. Every professional colleague, specialist and generalist alike, provides new knowledge or fresh insight on familiar subjects. Every patient presents a new combination of challenges and a new volley of important questions to the receptive and inquiring mind. A textbook of pediatric critical care fills special niches for the discipline and the student of the discipline. As an historical document, this compilation records the progress of the specialty. Future versions will undoubtedly show advances in the basic biology that are most important to bedside care. However, the prevalence and manifestation of disease invariably will shift, driven by epidemiologic forces, and genetic factors, improvements in care and, hopefully, by successful prevention of disease. Whether the specialty will remain as broadly comprehensive as is currently practiced is not clear, or whether sub-specialties such as cardiacand neurointensive care will warrant separate study and practice remains to be determined. As a repository of and reference for current knowledge, textbooks face increasing and imposing limitations compared with the dynamic and virtually limitless information gateway available through the internet. Nonetheless, a central standard serves as a defining anchor from which students and their teachers can begin with a common understanding and vocabulary and thereby support their mutual professional advancement. Moreover, it permits perspective, punctuation and guidance to be superimposed by a thoughtful expert who is familiar with the expanding mass of medical information. Pediatric intensivists owe Drs. Wheeler, Wong, and Shanley a great debt for their work in authoring and editing this volume. Their effort was enormously ambitious, but matched to the discipline itself in depth, breadth, and vigor. The scientific basis of critical care is integrally woven with the details of bedside management throughout the work, providing both a satisfying rationale for current practice, as well as a clearer picture of where we can improve. The coverage of specialized areas such as intensive care of trauma victims and patients following congenital heart surgery make this a uniquely comprehensive text. The editors have assembled an outstanding collection of expert authors for this work. The large number of international contributors is striking, but speaks to the rapid growth of this specialty throughout the world. We hope that this volume will achieve a wide readership, thereby enhancing the exchange of current scientific and managerial knowledge for the care of critically ill children, and stimulating the student to seek answers to fill our obvious gaps in understanding. Chicago, Illinois, USA New Haven, CT, USA

Thomas P. Green George Lister vii

Preface to the Second Edition

The specialty of pediatric critical care medicine continues to grow and evolve! The modern PICU of today is vastly different, even compared to as recently as 5 years ago. Technological innovations in monitoring, information management, and even medical documentation have seemed to change virtually overnight. We have witnessed the gradual disappearance of some time-honored, traditional devices such as the pulmonary artery catheter. At the same time, we have observed the rapid evolution and adoption of newer monitoring techniques such as continuous venous oximetry and near-infrared spectroscopy. Some PICUs are even now using telemedicine to remotely provide care for critically ill children. Many of us can recall a time when cellular phones were prohibited in the PICU – today, many of us can remotely monitor the status of our patients from these same cellular phones! Advances in molecular biology have led to the era of personalized medicine – we can now individualize our treatment approach to the unique and specific needs of a patient. We now routinely rely on a vast array of conditionspecific biomarkers to initiate and titrate therapy. Some of these advances in molecular biology have uncovered new diseases and conditions altogether! At the same time, pediatric critical care medicine has become more global. We are sharing our knowledge with the world community. Through our collective efforts, we are advancing the care of our patients. Pediatric critical care medicine will continue to grow and evolve – more technological advancements and scientific achievements will surely come in the future. We will become even more global in scope. However, the human element of what pediatric critical care providers do will never change. “For all of the science inherent in the specialty of pediatric critical care medicine, there is still art in providing comfort and solace to our patients and their families. No technology will ever replace the compassion in the touch of a hand or the soothing words of a calm and gentle voice” [1]. I remain humbled by the gifts that I have received in my life. And I still remember the promise I made to myself so many years ago – the promise that I would dedicate the rest of my professional career to advancing the field of pediatric critical care medicine as payment for these gifts. It is my sincere hope that the second edition of this textbook will educate a whole new generation of critical care professionals, and in so-doing help me continue my promise. Cincinnati, OH, USA

Derek S. Wheeler, MD, MMM

Reference 1. Wheeler DS. Care of the critically ill pediatric patient. Pediatr Clin North Am 2013;60:xv–xvi. Copied with permission by Elsevier, Inc.

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Preface to the First Edition

Promises to Keep The field of critical care medicine is growing at a tremendous pace, and tremendous advances in the understanding of critical illness have been realized in the last decade. My family has directly benefited from some of the technological and scientific advances made in the care of critically ill children. My son Ryan was born during my third year of medical school. By some peculiar happenstance, I was nearing completion of a 4-week rotation in the Newborn Intensive Care Unit. The head of the Pediatrics clerkship was kind enough to let me have a few days off around the time of the delivery – my wife Cathy was 2 weeks past her due date and had been scheduled for elective induction. Ryan was delivered through thick meconium-stained amniotic fluid and developed breathing difficulty shortly after delivery. His breathing worsened over the next few hours, so he was placed on the ventilator. I will never forget the feelings of utter helplessness my wife and I felt as the NICU Transport Team wheeled Ryan away in the transport isolette. The transport physician, one of my supervising third year pediatrics residents during my rotation the past month, told me that Ryan was more than likely going to require ECMO. I knew enough about ECMO at that time to know that I should be scared! The next 4 days were some of the most difficult moments I have ever experienced as a parent, watching the blood being pumped out of my tiny son’s body through the membrane oxygenator and roller pump, slowly back into his body (Figs. 1 and 2). I remember the fear of each day when we would be told of the results of his daily head ultrasound, looking for evidence of

Fig. 1 xi

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Preface to the First Edition

Fig. 2

intracranial hemorrhage, and then the relief when we were told that there was no bleeding. I remember the hope and excitement on the day Ryan came off ECMO, as well as the concern when he had to be sent home on supplemental oxygen. Today, Ryan is happy, healthy, and strong. We are thankful to all the doctors, nurses, respiratory therapists, and ECMO specialists who cared for Ryan and made him well. We still keep in touch with many of them. Without the technological advances and medical breakthroughs made in the fields of neonatal intensive care and pediatric critical care medicine, things very well could have been much different. I made a promise to myself long ago that I would dedicate the rest of my professional career to advancing the field of pediatric critical care medicine as payment for the gifts that we, my wife and I, have been truly blessed. It is my sincere hope that this textbook, which has truly been a labor of joy, will educate a whole new generation of critical care professionals, and in so-doing help make that first step towards keeping my promise. Cincinnati, OH, USA

Derek S. Wheeler, MD, MMM

Acknowledgements

With any such undertaking, there are people along the way who, save for their dedication, inspiration, and assistance, a project such as this would never be completed. I am personally indebted to Michael D. Sova, our Developmental Editor, who has been a true blessing. He has kept this project going the entire way and has been an incredible help to me personally throughout the completion of this textbook. There were days when I thought that we would never finish – and he was always there to lift my spirits and keep me focused on the task at hand. I will be forever grateful to him. I am also grateful for the continued assistance of Grant Weston at Springer. Grant has been with me since the very beginning of the first edition of this textbook. He has been a tremendous advocate for our specialty, as well as a great mentor and friend. I would be remiss if I did not thank Brenda Robb for her clerical and administrative assistance during the completion of this project. Juggling my schedule and keeping me on time during this whole process was not easy! I have been extremely fortunate throughout my career to have had incredible mentors, including Jim Lemons, Brad Poss, Hector Wong, and Tom Shanley. All four are gifted and dedicated clinicians and remain passionate advocates for critically ill children, the specialties of neonatology and pediatric critical care medicine, and me! I want to personally thank both Hector and Tom for serving again as Associate Editors for the second edition of this textbook. Their guidance and advice has been immeasurable. I have been truly fortunate to work with an outstanding group of contributors. All of them are my colleagues and many have been my friends for several years. It goes without saying that writing textbook chapters is a difficult and arduous task that often comes without a lot of benefits. Their expertise and dedication to our specialty and to the care of critically ill children have made this project possible. The textbook you now hold in your hands is truly their gift to the future of our specialty. I would also like to acknowledge the spouses and families of our contributors – participating in a project such as this takes a lot of time and energy (most of which occurs outside of the hospital!). Last, but certainly not least, I would like to especially thank my family – my wife Cathy, who has been my best friend and companion, number one advocate, and sounding board for the last 22 years, as well as my four children – Ryan, Katie, Maggie, and Molly, to whom I dedicate this textbook and all that I do.

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Contents

Part I

The Practice of Pediatric Critical Care Medicine Susan L. Bratton

1

Pediatric Critical Care: A Global View . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Andrew C. Argent and Niranjan Kissoon

3

2

Pediatric Critical Care and the Law: Medical Malpractice . . . . . . . . . . . . . . . Ramesh C. Sachdeva

11

3

Architectural Design of Critical Care Units: A Comparison of Best Practice Units and Design. . . . . . . . . . . . . . . . . . . . . . . . Charles D. Cadenhead

17

4

PICU Administration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cortney B. Foster and David C. Stockwell

33

5

Nursing Care in the Pediatric Intensive Care Unit. . . . . . . . . . . . . . . . . . . . . . . Franco A. Carnevale and Maryse Dagenais

41

6

Scoring Systems in Critical Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sandra D.W. Buttram, Paul R. Bakerman, and Murray M. Pollack

47

7

Pharmacology in the PICU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . James B. Besunder and John Pope

55

8

Telemedicine in the Pediatric Intensive Care Unit . . . . . . . . . . . . . . . . . . . . . . . James P. Marcin, Madan Dharmar, and Candace Sadorra

75

9

Quality Improvement Science in the PICU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Matthew F. Niedner

83

10

Patient Safety in the PICU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Matthew C. Scanlon

101

11

Outcomes Research in the PICU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Folafoluwa Olutobi Odetola

107

12

Resident and Nurse Education in Pediatric Intensive Care Unit . . . . . . . . . . . Girish G. Deshpande, Gwen J. Lombard, and Adalberto Torres Jr.

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13

Epidemiology of Critical Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . R. Scott Watson and Mary Elizabeth Hartman

125

14

Ethics in the Pediatric Intensive Care Unit: Controversies and Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rani Ganesan and K. Sarah Hoehn

133

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Contents

15

Palliative Care in the PICU. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kelly Nicole Michelson and Linda B. Siegel

141

16

Evidence-based Pediatric Critical Care Medicine . . . . . . . . . . . . . . . . . . . . . . . Donald L. Boyer and Adrienne G. Randolph

149

17

Simulation Training in Pediatric Critical Care Medicine . . . . . . . . . . . . . . . . . Catherine K. Allan, Ravi R. Thiagarajan, and Peter H. Weinstock

157

18

Career Development in Pediatric Critical Care Medicine . . . . . . . . . . . . . . . . . M. Michele Mariscalco

167

Part II

The Science of Pediatric Critical Care Medicine Michael W. Quasney

19

Genetic Polymorphisms in Critical Illness and Injury . . . . . . . . . . . . . . . . . . . . Mary K. Dahmer and Michael W. Quasney

177

20

Genomics in Critical Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hector R. Wong

203

21

Signal Transduction Pathways in Critical Illness and Injury . . . . . . . . . . . . . . Timothy T. Cornell, Waseem Ostwani, Lei Sun, Steven L. Kunkel, and Thomas P. Shanley

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22

Pro-inflammatory and Anti-inflammatory Mediators in Critical Illness and Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jennifer A. Muszynski, W. Joshua Frazier, and Mark W. Hall

231

23

Oxidative and Nitrosative Stress in Critical Illness and Injury. . . . . . . . . . . . . Katherine Mason

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24

Ischemia-Reperfusion Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Michael J. Hobson and Basilia Zingarelli

251

Part III

Resuscitation, Stabilization, and Transport of the Critically Ill or Injured Child Vinay Nadkarni

25

Post-resuscitation Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Monica E. Kleinman and Meredith G. van der Velden

271

26

Predicting Outcomes Following Resuscitation . . . . . . . . . . . . . . . . . . . . . . . . . . Akira Nishisaki

291

27

Basic Management of the Pediatric Airway . . . . . . . . . . . . . . . . . . . . . . . . . . . . Derek S. Wheeler

299

28

Pediatric Difficult Airway Management: Principles and Approach in the Critical Care Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Paul A. Stricker, John Fiadjoe, and Todd J. Kilbaugh

329

29

Central Venous Vascular Access. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jennifer Kaplan, Matthew F. Niedner, and Richard J. Brilli

345

30

Shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Derek S. Wheeler and Joseph A. Carcillo Jr.

371

31

Acute Respiratory Failure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kyle J. Rehder, Jennifer L. Turi, and Ira M. Cheifetz

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32

The Multiply Injured Child . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gad Bar-Joseph, Amir Hadash, Anat Ilivitzki, and Hany Bahouth

413

33

Coma and Altered Mental Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alexis Topjian and Nicholas S. Abend

433

34

Interfacility Transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cecilia D. Thompson, Michael T. Bigham, and John S. Giuliano Jr.

447

35

Multiple Organ Dysfunction Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . François Proulx, Stéphane Leteurtre, Jean Sébastien Joyal, and Philippe Jouvet

457

36

Withdrawal of Life Support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ajit A. Sarnaik and Kathleen L. Meert

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37

Brain Death. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sam D. Shemie and Sonny Dhanani

481

38

The Physiology of Brain Death and Organ Donor Management . . . . . . . . . . . Sam D. Shemie and Sonny Dhanani

497

Part IV

Monitoring the Critically Ill or Injured Child Shane M. Tibby

39

Respiratory Monitoring. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Derek S. Wheeler and Peter C. Rimensberger

521

40

Hemodynamic Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Shane M. Tibby

543

41

Neurological Monitoring of the Critically-Ill Child . . . . . . . . . . . . . . . . . . . . . . Elizabeth A. Newell, Bokhary Abdulmohsen, and Michael J. Bell

569

42

Nutrition Monitoring in the PICU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . George Briassoulis

579

43

Monitoring Kidney Function in the Pediatric Intensive Care Unit. . . . . . . . . . Catherine D. Krawczeski, Stuart L. Goldstein, Rajit K. Basu, Prasad Devarajan, and Derek S. Wheeler

603

Part V

Special Situations in Pediatric Critical Care Medicine W. Bradley Poss

44

Principles of Mass Casualty and Disaster Medicine. . . . . . . . . . . . . . . . . . . . . . David Markenson

621

45

Care in an Austere Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jennifer S. Storch and Philip C. Spinella

637

46

Agents of Biological and Chemical Terrorism. . . . . . . . . . . . . . . . . . . . . . . . . . . Michael T. Meyer, Philip C. Spinella, and Ted Cieslak

645

47

Pandemic Influenza . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jill S. Sweney, Eric J. Kasowski, and W. Bradley Poss

657

48

Pediatric Drowning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jason Coryell and Laura M. Ibsen

665

49

Heat Illness and Hypothermia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Luke A. Zabrocki, David K. Shellington, and Susan L. Bratton

677

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Contents

50

Toxic Ingestions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Janice E. Sullivan and Mark J. McDonald

695

51

Envenomations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . James Tibballs, Christopher P. Holstege, and Derek S. Wheeler

729

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

751

Contributors

Bokhary Abdulmohsen, MD Department of Pediatric Critical Care, Al Hada Armed Forces Hospital, Tai, Kingdom of Saudi Arabia Nicholas S. Abend, MD Department of Neurology and Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA Catherine K. Allan, MD Division of Cardiac Intensive Care, Department of Cardiology, Boston Children’s Hospital, Boston, MA, USA Andrew C. Argent, MB, BCh, MMed, FCPaeds, DCH School of Child and Adolescent Health, University of Cape Town, Cape Town, South Africa Paediatric Intensive Care Unit, Red Cross War Memorial Children’s Hospital, Cape Town, South Africa Hany Bahouth, MD Department of Trauma and Emergency Surgery, Rambam Medical Center, Haifa, Israel Paul R. Bakerman, MD Critical Care Medicine, Phoeniz Children’s Hospital, Phoenix, AZ, USA Gad Bar-Joseph, MD Department of Pediatric Intensive Care, Meyer Children’s Hospital, Rambam Medical Center, Haifa, Israel Rajit K. Basu, MD, FAAP Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Michael J. Bell, MD Department of Critical Care Medicine, Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA James B. Besunder, DO Department of Pediatrics, Akron Children’s Hospital, Akron, OH, USA Michael T. Bigham, MD Division of Critical Care Medicine, Department of Pediatrics, Akron Children’s Hospital, Akron, OH, USA Donald L. Boyer, MD Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA Susan L. Bratton, MD, MPH Department of Pediatrics, Primary Children’s Medical Center, Salt Lake City, UT, USA George Briassoulis, MD, PhD PICU, University Hospital, University of Crete, Heraklion, Crete, Greece Richard J. Brilli, MD Division of Critical Care Medicine, Department of Pediatrics, Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, OH, USA

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Sandra D.W. Buttram, MD Critical Care Medicine, Phoenix Children’s Hospital, Phoenix, AZ, USA Charles D. Cadenhead, FAIA, FACHA, FCCM WHR Architects, Houston, TX, USA Joseph A. Carcillo Jr., MD Pediatric Intensive Care Unit, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA Franco A. Carnevale, RN, PhD Pediatric Critical Care, Montreal Children’s Hospital, McGill University, Montreal, QC, Canada Ira M. Cheifetz, MD, FCCM, FAARC Division of Pediatric Critical Care Medicine, Department of Pediatrics, Duke Children’s Hospital, Durham, NC, USA Ted Cieslak, MD Clinical Services Division, US Army Medical Command, Army Surgeon General, Fort Sam Houston, TX, USA Timothy T. Cornell, MD Department of Pediatrics and Communicable Diseases, C.S. Mott Children’s Hospital University of Michigan, Ann Arbor, MI, USA Jason Coryell, MD Department of Pediatrics, Doernbecher Children’s Hospital, Oregon Health and Sciences University, Portland, OR, USA Maryse Dagenais, RN, MSc (A) Pediatric Intensive Care Unit, Montreal Children’s Hospital, Montreal, QC, Canada Mary K. Dahmer, PhD Department of Pediatrics, Critical Care Medicine, The University of Michigan, Ann Arbor, MI, USA Girish G. Deshpande, MD Department of Pediatrics, Children’s Hospital of Illinois, Peoria, IL, USA Prasad Devarajan, MD Division of Nephrology and Hypertension, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Sonny Dhanani, BSc (Pharm), MD, FRCPC Pediatric Intensive Care Unit, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada Madan Dharmar, MBBS, PhD Department of Pediatrics, UC Davis Children’s Hospital, Sacramento, CA, USA John Fiadjoe, MD Department of Anesthesiology and Critical Care Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA, USA Cortney B. Foster, DO Department of Pediatric Critical Care, University of Maryland School of Medicine, Baltimore, MD, USA W. Joshua Frazier, MD Division of Critical Care Medicine, Nationwide Children’s Hospital, Columbus, OH, USA Rani Ganesan, MD Department of Pediatrics, Rush University Medical Center, Chicago, IL, USA John S. Giuliano Jr., MD Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA Stuart L. Goldstein, MD Division of Nephrology and Hypertension, Center for Acute Care Nephrology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Amir Hadash, MD Department of Pediatric Intensive Care, Meyer Children’s Hospital, Rambam Medical Center, Haifa, Israel Mark W. Hall, MD Division of Critical Care Medicine, Nationwide Children’s Hospital, Columbus, OH, USA

Contributors

Contributors

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Mary Elizabeth Hartman, MD, MPH Department of Pediatric Critical Care Medicine, St. Louis Children’s Hospital, Washington University in St. Louis, St. Louis, MO, USA Michael J. Hobson, MD Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA K. Sarah Hoehn, MD, MBe University of Kansas Medical Center, Kansas City, KS, USA Christopher P. Holstege, MD Department of Emergency Medicine, University of Virginia Health System, Charlottesville, VA, USA Laura M. Ibsen, MD Department of Pediatrics, Doernbecher Children’s Hospital, Oregon Health and Sciences University, Portland, OR, USA Anat Ilivitzki, MD Department of Radiology, Rambam Medical Center, Haifa, Israel Philippe Jouvet, MD, PhD Department of Pediatrics, Sainte-Justine, Montreal, QC, Canada Jean Sébastien Joyal, MD, PhD Department of Pediatrics, Sainte-Justine, Montreal, QC, Canada Jennifer Kaplan, MD, MS Division of Critical Care Medicine, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA Eric J. Kasowski, DVM, MD, MPH US Centers for Disease Control and Prevention, Atlanta, GA, USA Todd J. Kilbaugh, MD Department of Anesthesiology and Critical Care Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA, USA Niranjan Kissoon, MD, FRCP(C), FAAP, FCCM, FACPE Department of Pediatrics and Emergency Medicine, The University of British Columbia, Vancouver, BC, Canada Department of Medical Affairs, BC Children’s Hospital and Sunny Hill Health Centre for Children, Vancouver, BC, Canada Monica E. Kleinman, MD Division of Critical Care Medicine, Department of Anesthesiology, Children’s Hospital Boston, Boston, MA, USA Catherine D. Krawczeski, MD Division of Pediatric Cardiology, Stanford University School of Medicine, Palo Alto, CA, USA Steven L. Kunkel, MS, PhD Department of Pathology, University of Michigan, Ann Arbor, MI, USA Stéphane Leteurtre, MD, PhD Department of Pediatrics, Jeanne de Flandre, Lille, France Gwen J. Lombard, PhD, RN Department of Neurosurgery, University of Florida, Gainesville, FL, USA James P. Marcin, MD, MPH Department of Pediatrics, UC Davis Children’s Hospital, Sacramento, CA, USA M. Michele Mariscalco, MD Department of Pediatrics, University of Illinois College of medicine at Urbana Champaign, Urbana, IL, USA David Markenson, MD Disaster Medicine and Regional Emergency Services, Maria Fareri Children’s Hospital and Westchester Medical Center, Valhalla, NY, USA Katherine Mason, MD Department of Pediatrics, Rainbow Babies Children’s Hospital, Cleveland, OH, USA

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Mark J. McDonald, MD Department of Pediatrics, University of Louisville, Louisville, KY, USA Kathleen L. Meert, MD Department of Pediatrics, Children’s Hospital of Michigan, Detroit, MI, USA Michael T. Meyer, MD Division of Pediatric Critical Care Medicine, Medical College of Wisconsin, Children’s Hospital of Wisconsin, Milwaukee, WI, USA Kelly Nicole Michelson, MD, PhD Division of Pediatric Critical Care Medicine, Department of Pediatrics, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA Jennifer A. Muszynski, MD Division of Critical Care Medicine, The Ohio State University College of Medicine, Nationwide Children’s Hospital, Columbus, OH, USA Elizabeth A. Newell, MD Department of Critical Care Medicine, Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA Matthew F. Niedner, MD Pediatric Intensive Care Unit, Division of Critical Care Medicine, Department of Pediatrics, University of Michigan Medical Center, Mott Children’s Hospital, Ann Arbor, MI, USA Akira Nishisaki, MD, MSCE Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA Folafoluwa Olutobi Odetola, MD, MPH Pediatrics and Communicable Diseases, University of Michigan Hospital and Health Systems, Ann Arbor, MI, USA Waseem Ostwani, MD Department of Pediatric Critical Care Medicine, C.S. Mott Children’s Hospital, Ann Arbor, MI, USA Murray M. Pollack, MD Department of Child Health, University of Arizona College of Medicine – Phoenix, Phoenix, AZ, USA John Pope, MD Department of Pediatrics, Akron Children’s Hospital, Akron, OH, USA W. Bradley Poss, MD Department of Pediatric Critical Care, University of Utah, Salt Lake, UT, USA François Proulx, MD Department of Pediatrics, Sainte-Justine, Montreal, QC, Canada Michael W. Quasney, MD, PhD Department of Pediatrics, Critical Care Medicine, The University of Michigan, Ann Arbor, MI, USA Adrienne G. Randolph, MD, MSc Division of Critical Care Medicine, Department of Anesthesia, Perioperative and Pain Medicine, Children’s Hospital Boston, Boston, MA, USA Kyle J. Rehder, MD Division of Pediatric Critical Care Medicine, Department of Pediatrics, Duke Children’s Hospital, Durham, NC, USA Peter C. Rimensberger, MD Department of Pediatrics, Service of Neonatology and Pediatric Intensive Care, University Hospital of Geneva, Geneva, Switzerland Ramesh C. Sachdeva, MD, PhD, JD, FAAP, FCCM Department of Pediatric Critical Care, Medical College of Wisconsin, Milwaukee, WI, USA Candace Sadorra, BS Department of Pediatrics, UC Davis Children’s Hospital, Sacramento, CA, USA Ajit A. Sarnaik, MD Department of Pediatrics, Children’s Hospital of Michigan, Detroit, MI, USA

Contributors

Contributors

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Matthew C. Scanlon, MD Department of Pediatric Critical Care, Medical College of Wisconsin, Children’s Hospital of Wisconsin, Milwaukee, WI, USA Thomas P. Shanley, MD Michigan Institute for Clinical and Health Research, University of Michigan Medical School, Ann Arbor, MI, USA David K. Shellington, MD Division of Pediatric Critical Care, University of California, San Diego, San Diego, CA, USA Sam D. Shemie, PhD Department of Critical Care, Montreal Children’s Hospital, Montreal, QC, Canada Linda B. Siegel, MD, FAAP Divisions of Pediatric Critical Care Medicine and Pediatric Palliative CareCohen, Children’s Medical Center, New Hyde Park, NY, USA Philip C. Spinella, MD, FCCM Division of Critical Care, Critical Care Translation Research Program, Washington University in St. Louis Medical School, St. Louis, MO, USA David C. Stockwell, MD, MBA Department of Critical Care Medicine, Children’s National, Washington, DC, USA Jennifer S. Storch, RN, CNRN, CCRN Regional Burn Center ICU, University of California San Diego Medical Center, San Diego, CA, USA Paul A. Stricker, MD Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA Janice E. Sullivan, MD Department of Pediatrics and Pharmacology & Toxicology, University of Louisville, Louisville, KY, USA Lei Sun, PhD Department of Pediatrics and Communicable Diseases, University of Michigan, C.S.Mott Children’s Hospital, Von Voigtlander Women’s hospital, Ann Arbor, MI, USA Jill S. Sweney, MD Department of Pediatric Critical Care, University of Utah, Salt Lake City, UT, USA Ravi R. Thiagarajan, MBBS, MPH Department of Cardiology, Boston Children’s Hospital, Boston, MA, USA Cecilia D. Thompson, MD Division of Critical Care Medicine, Mount Sinai Kravis Children’s Hospital, New York, NY, USA James Tibballs, MBBS, MEd, MBA, MD Pediatric Intensive Care Unit, Royal Children’s Hospital, Melbourne, Melbourne, VIC, Australia Shane M. Tibby, MBChB, MRCP, MSc (appl stat) PICU Department, Evelina London Children’s Hospital, London, UK Alexis Topjian, MD, MSCE Department of Anesthesia and Critical Care, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA Adalberto Torres Jr., MD, MS Department of Pediatrics, University of Illinois College of Medicine at Peoria, Peoria, IL, USA Jennifer L. Turi, MD Division of Pediatric Critical Care Medicine, Department of Pediatrics, Duke Children’s Hospital, Durham, NC, USA Meredith G. van der Velden, MD Department of Anesthesia, Children’s Hospital Boston, Boston, MA, USA

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R. Scott Watson, MD, MPH Department of Pediatric Critical Care Medicine, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA Peter H. Weinstock, MD, PhD Division of Critical Care, Department of Anesthesia, Perioperative and Pain Medicine, Boston Children’s Hospital, Boston, MA, USA Derek S. Wheeler, MD, MMM Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH, USA Hector R. Wong, MD Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA Luke A. Zabrocki, MD Division of Pediatric Critical Care, Naval Medical Center San Diego, San Diego, CA, USA Basilia Zingarelli, MD, PhD Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

Contributors

Part I The Practice of Pediatric Critical Care Medicine Susan L. Bratton

1

Pediatric Critical Care: A Global View Andrew C. Argent and Niranjan Kissoon

Abstract

Pediatric critical care aims on saving the lives of sick and injured children, however, most children die without access to pediatric critical care. With progress towards attainment of the Millennium Development Goals across the world, there has been a significant drop in child mortality in most countries. As issues such as nutrition, immunization, access to clean water and sanitation, and access to healthcare are addressed, pediatric critical care will become an increasingly important part of any strategy to reduce childhood deaths. Critical care can only be beneficial in an integrated health system, but the time –sensitive nature of the care required by sick children poses specific challenges. As processes to recognize and treat sick children improve, the role of and need for intensive care services will increase. It is important that these services should be efficient as possible and should not develop de novo but within an integrated network for the provision of care for critically ill children. Keywords

Critical care • Children • Developing world • Resource-limited settings • Mortality

Introduction The ultimate aim of critical care services is to save lives and limit morbidity in the critically ill. However, globally the majority of children live in poorer countries and most childhood deaths occur in a few poor countries. Most children,

A.C. Argent, MB, BCh, MMed, FCPaeds, DCH School of Child and Adolescent Health, University of Cape Town, Cape Town, South Africa Paediatric Intensive Care Unit, Red Cross War Memorial Children’s Hospital, Klipfontein Road, Rondebosch, Cape Town 7700, South Africa e-mail: [email protected] N. Kissoon, MD, FRCP(C), FAAP, FCCM, FACPE (*) Department of Pediatrics and Emergency Medicine, The University of British Columbia, Vancouver, BC Canada Acute and Critical Care – Global Child Health, BC Children’s Hospital and The University of British Columbia, 4480 Oak Street, Room B245, Vancouver, BC V6H3V4, Canada e-mail: [email protected] D.S. Wheeler et al. (eds.), Pediatric Critical Care Medicine, DOI 10.1007/978-1-4471-6362-6_1, © Springer-Verlag London 2014

who die, live in circumstances where they have extremely limited access to any medical services and no intensive care facilities. Indeed, there is a link between mortality among children C and G-572 > C) development and/or predictors of sepsis severity in children Polymorphisms for IL-6, IL-1, TNFα, IL-10, The IL-6(−174) G/G and the IL-10(−1082) A/A genotypes Balding et al. [15] and IL-1Ra were more frequent among nonsurvivors of meningococcal sepsis Multiple [17–19, 30] Deletion/insertion (4G/5G) polymorphism of the The 4G allele increases susceptibility to and severity of septic plasminogen-activator inhibitor type-1 (PAI-1) shock, and increased risk of mortality in children with promoter region. The 4G allele is associated with meningococcal sepsis higher PAI-1 plasma levels

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this challenge is the development of multi-institutional and multi-national research consortia specifically dedicated to gene association studies.

Genome-Wide Expression Profiling Genome-wide expression profiling (a.k.a. transcriptomics) refers to the simultaneous and efficient measurement of steady-state mRNA abundance of thousands of transcripts from a given tissue source. The general approach involves variations of microarray technology [31–33], and there is a new, potentially more powerful technique referred to as RNA Sequencing (RNA Seq) [34]. While gene expression profiling has important limitations, this discovery-oriented approach has nonetheless provided an unprecedented opportunity to gain a broader, genome-level “picture” of complex and heterogeneous clinical syndromes encountered in critical care medicine. In addition, this genome-level approach has the potential to reduce investigator bias, and thus increase discovery capability, in as much as all genes are potentially interrogated, rather than a specific set of genes chosen by the investigator based on a priori and potentially biased assumptions. Genome-wide expression profiling in sepsis will be discussed below as an example of how this approach can be applied to critically ill patients. All of the studies discussed below have used the blood compartment as the RNA source. Several fundamental physiologic and biologic principles of the sepsis paradigms are derived from experiments involving human volunteers subjected to intravenous endotoxin challenge [35–38]. More recently, the genome-level response during experimental human endotoxemia has been studied using microarray technology [39–41]. For example, Talwar et al. compared eight volunteers challenged with intravenous endotoxin to four controls challenged with saline [39]. Mononuclear cell-specific RNA was obtained at four different time points after endotoxin challenge and analyzed via microarray. As expected, a large number of transcripts related to inflammation and innate immunity were substantially up regulated in response to endotoxin challenge. Interestingly, the peak transcriptomic response to the single endotoxin challenge occurred within six hours and mRNA levels generally returned to control levels within 24 h. The investigators also reported endotoxin-mediated differential regulation of over 100 genes not typically associated with acute inflammation. Genome-wide expression has also been conducted in critically ill patients with sepsis and septic shock. These studies present considerable experimental challenges due to the inherent heterogeneity of clinical sepsis and septic shock. Nonetheless, several studies have provided novel insight into the overall genome-level response to sepsis [42–53]. A common theme across many of these studies is the massive up

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regulation of inflammation- and innate immunity-related genes in patients with sepsis and septic shock. These observations are not intrinsically novel, but they are consistent with the long-standing sepsis paradigms centered on a hyperactive inflammatory response, and thus provide a component of biological plausibility with regard to overall microarray data output in the context of clinical sepsis. Another common paradigm in the sepsis field involves a two-phase model consisting of an initial hyper-inflammatory phase, followed by a compensatory anti-inflammatory phase, but this has been recently challenged, in large part due to the multiple failures of interventional clinical trials founded on this paradigm [54–56]. Recently, Tang et al. conducted a formal systematic review of a carefully selected group of microarray-based human sepsis studies [33]. The major conclusion of this systematic review is that, in aggregate, the transcriptome-level data does not consistently separate sepsis into distinct pro- and anti-inflammatory phases. This conclusion has been questioned [57], but is supported by several recent cytokine- and inflammatory mediator-based studies in clinical and experimental sepsis [58–60]. Another prevailing paradigm in the sepsis field involves the concept of immune-paralysis, or immune-suppression, which frames sepsis as an adaptive immune problem and the inability to adequately clear infection [61, 62]. Recently, this paradigm was elegantly corroborated in mice subjected to sepsis and rescued by administration of interleukin-7, an anti-apoptotic cytokine essential for lymphocyte survival and expansion [63, 64]. In studies focused on mononuclear cell-specific expression profiles, Tang et al. have reported early repression of adaptive immunity genes in patients with sepsis [48, 50]. Finally, multiple studies in children with septic shock have reported, and validated, early and persistent repression of adaptive immunity-related gene programs: T cell activation, T cell receptor signaling, and antigen presentation [42, 47, 51–53, 65–67]. Thus, the concept of adaptive immune dysfunction as an early and prominent feature of clinical sepsis and septic shock seems to be well supported by the available genome-wide expression data. Developmental age is thought to be a major contributor to sepsis heterogeneity. Recently, a microarray-based study in children with septic shock corroborated this concept at the genomic level [68]. Four developmental age groups of children were compared based on whole-blood derived gene expression profiles. Children in the “neonate” group (5 days. Umbilical venous catheters should be removed as soon as possible when no longer needed, but can be used up to 14 days if managed aseptically

coagulopathy may be at greater risk from inadvertent arterial puncture, especially if the access site does not easily allow for direct pressure to the artery. This could make subclavian venipuncture higher risk compared to the femoral approach. For patients breathing spontaneously (less likely to hold still for the procedure) or those requiring high ventilator settings, the risk of an unplanned pneumothorax associated with the subclavian or internal jugular approach could make the femoral vein the preferred site. Subclavian and internal jugular sites may have lower catheter maintenance risks including lower infection rates compared to the femoral vein and thus may be preferred when central venous access is performed electively and the duration of cannulation is expected to be prolonged [2, 13]. Additionally, vein caliber can limit the size of catheter that can be inserted. This is of particular concern for infants and toddlers where lower extremity vessels are disproportionally smaller compared to above the diaphragm vessels. If a large-caliber vessel is required for flow-dependent extracorporeal therapies (e.g., CRRT, ECMO), then site selection may be determined by the necessary cannula size.

Femoral Venous Catheterization Demographic and Historical Data Studies from the 1950s reported high complication rates from femoral vein cannulation and as a result femoral venous access fell out of favor [14]. Today, femoral vein catheterization is frequently used in critically ill children because of its relatively low risk profile and high insertion success rate, in a variety of clinical settings.

Indications and Contraindications for Placement Femoral veins are excellent central venous access sites in critically ill children. The femoral veins are attractive because they are perceived as a simple site for percutaneous insertion, especially by inexperienced operators and the cannulation can often be performed with minimal supplemental sedation. This

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is particularly important in children who are not receiving mechanical ventilation at the time of catheter placement. In addition, risks of life-threatening complications at the time of insertion are reduced because of easy compressibility of local vessels (femoral artery) and the remote location from the lung. The femoral vessels are also preferred if there are relative or absolute contraindications to accessing the jugular or subclavian veins. For example, in patients at risk for intracranial hypertension, placement of central venous catheters in the jugular or subclavian veins may precipitate vascular thrombosis, which could create obstruction to cerebral venous drainage and potentially life threatening increases in intracranial hypertension. In this clinical setting, a femoral venous catheter may be preferred [8]. In addition, patients with severe respiratory failure who require high mechanical ventilatory pressures may be at increased risk should a pneumothorax develop during the placement of a cervicothoracic central venous catheter. In this setting the femoral site may be preferred as well. In patients with a recognized coagulopathy, the femoral site is preferable because direct compression of the femoral vessels can occur, especially in the event of inadvertent puncture of the femoral artery [8]. Multiple studies demonstrate that femoral vein catheterization is a rapid and safe route for obtaining intravenous access in patients requiring massive intravenous fluid infusions or following cardiac arrest [4, 15, 16]. Furthermore, the femoral artery provides an easily recognized landmark to facilitate straightforward catheter insertion. Some clinical situations warrant placement of central venous catheters at sites other than the femoral vein. Trauma to the lower extremity, pelvis, or inferior vena cava is a relative contraindication for femoral vein catheterization [8]. In addition, bulky abdominal tumors, inferior vena cava, common iliac, or femoral thrombosis, abdominal hematomas, venous anomalies and prior pelvic radiation are associated with increased risk of complications from femoral venous catheter placement [17]. In adult patients, practitioners have traditionally avoided femoral CVC placement because of concerns about the risk of deep venous thrombosis, excess infectious risks compared to other sites, and potentially inaccurate central venous pressure measurements derived from the femoral vessels [18–21]. While the jury may still be out in the adult critical care community regarding the use femoral catheters, evidence in children suggests a safer risk profile for femoral catheters than is observed in adults, especially when catheters are used for short periods of time [22, 23]. Perceived ease of insertion combined with a low insertion risk profile, often make the femoral vessels the preferred site in children [23, 24]. In adults and children, there is a wide range of reported rates for venous thrombosis associated with central venous catheters (1–60 %), however the thrombosis rates in children, are not significantly different between the femoral vessels and cervicothoracic vessels [25, 26]. Furthermore, in children, infectious complications associated with femoral venous catheters are similar and in one report less than that reported for cervicothoracic central venous catheters [27–29]. Finally, multiple studies have demonstrated that

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Anterior superior iliac spine

Femoral nerve

Inguinal ligament

Femoral artery Femoral vein Pubic tubercle

Fig. 29.1 Femoral Vein Anatomy (Source: PALS Provider Manual © 1997, American Heart Association, Inc)

in the absence of elevated intraabdominal pressures and even in the presence of high mechanical ventilatory support, central venous pressure measurements derived from femoroiliac veins are similar to measurements obtained from cervicothoracic veins and may accurately predict right atrial pressures [30–33].

Anatomy The femoral vein lies in the femoral sheath, medial to the femoral artery immediately below the inguinal ligament (Fig. 29.1). The femoral triangle is an anatomic region of the upper thigh with the boundaries including the inguinal ligament cephalad, sartorius muscle laterally, and adductor longus muscle medially. The contents of the femoral triangle from lateral to medial are the femoral nerve, femoral artery and femoral vein. The femoral sheath lies within the femoral triangle and includes the femoral artery, femoral vein and lymph nodes. The femoral vein runs superficially in the thigh approaching the inguinal ligament in the femoral triangle. The vein dives steeply in a posterior direction, superior to the inguinal ligament, as it becomes the iliac vein. The femoral vein lies medial to the femoral artery in the femoral sheath inferior to the inguinal ligament. In patients with a palpable pulse, the femoral vein can be located just medial to the femoral arterial pulse inferior to the inguinal ligament. In pulseless patients, the femoral artery can be assumed to be at a point half-way along a line drawn from the pubic tubercle to the anterior superior iliac spine, at a level 1–2 cm inferior to the inguinal ligament. The femoral vein is located 0.5– 1.5 cm medial to the center of the femoral artery, depending upon the size of the patient [34].

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b

c

d

Fig. 29.2 Seldinger Technique for central venous catheter insertion. (a) Insert needle into the target vessel and pass the flexible end of the guidewire into the vessel. (b) Remove the needle, leaving the guidewire in place. (c) Using a twisting motion, advance the catheter into the ves-

sel. (d) Remove the guidewire, and connect the catheter to an appropriate flow device or monitoring device (Source: PALS Provider Manual © 2002, American Heart Association, Inc)

Insertion Technique

placed in the vein by venipuncture with a small size needle (Fig. 29.2). The femoral site should be prepared and draped as for any surgical procedure and in non-emergent clinical situations, using full sterile barrier (Fig. 29.3) [36]. The optimal position of the leg can vary according to the preference of the operator – some prefer slight external rotation

Femoral vein insertion should be performed using the Seldinger technique [35]. The Seldinger technique was first described by Sven Seldinger in 1953 and enabled practitioners to insert a large size catheter over a guidewire that was

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at the hip and others prefer full “frog leg” external rotation. The location of the femoral vein is 0.5–2 cm inferior to the inguinal ligament, just medial to the femoral artery. Because the overlying skin in the inquinal region, especially in babies, is often slack and redundant, it can be important to develop a method to maintain traction on the skin while palpating for the arterial pulse and then maintaining this traction while inserting the needle (Fig. 29.4a, b). The syringe should be held at a 30–45° angle from the skin, aimed cephalad over the femoral vein site. Some operators approach the vessel from the side maintaining traction on the skin

Fig. 29.3 Full sterile barrier during elective insertion of central venous catheter

a

and palpating the pulse with the opposite hand (Fig. 29.5), while others approach the vessel directly (Fig. 29.4b). Most operators locate the vein and obtain venous blood flashback by advancing the needle/syringe at a 30° angle toward the ischial ramus while withdrawing the syringe plunger, creating negative pressure within the syringe (Fig. 29.5). If venous blood is not returned, the needle/syringe should be slowly withdrawn, pulling back constantly on the plunger. If the vein is not located, redirect the needle searching from medial to lateral until the vein is located. To avoid lacerating the vessels, the needle should be withdrawn to the skin surface prior to changing direction. Puncture of the vein is indicated by blood return (flashback in the syringe) while advancing or slowly withdrawing the needle. An alternative method to locate the vein is to advance the needle/syringe over the vein site toward the ischial ramus to a depth of 1–2 cm without negative pressure in the syringe and then withdraw the needle applying negative pressure to the syringe, thus obtaining venous blood flashback on the withdrawal of the needle. The advantage of this method is that it allows the operator to firmly rest the hand on the thigh during needle/syringe withdrawal, which allows the operator to freeze when venous blood flashback occurs. This is especially important in small infants where the cross-sectional area of the needle and that of the vein are similar in size and as a result it is easy for the needle to move outside the lumen of the vessel as the syringe is gently removed from the needle. By freezing the operator’s hand in position, this method allows for greater success with guidewire placement (Fig. 29.6). Kanter et al. demonstrated by use of ultrasound that the greatest probability of successful puncture of the

b

Fig. 29.4 (a) Palpation of femoral pulse with traction on redundant skin. (b) Skin traction is maintained as initial skin puncture occurs. The needle is advanced through the vessel and venous flashback occurs as the needle is withdrawn using negative pressure on the syringe

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45°

Fig. 29.5 One approach to the femoral vessel – needle and syringe advanced at 45° angle to the skin (Source: PALS Provider Manual © 1997, American Heart Association, Inc)

Fig. 29.6 Operator’s hand resting on infant’s thigh allowing the hand to freeze when venous flashback occurs

femoral vein was located 4–5 mm medial to the femoral artery pulse [37]. In addition, if it is assumed that entry into the central half of the vein will result in successful catheterization, successive attempts 5 mm and 6 mm medial to the pulse would result in cumulative successful insertion in 53 and 61 %, respectively, with no arterial punctures. A third attempt 4 mm medial to the pulse further increases cumulative success to 78 %, but the arterial puncture rate would increase to 3 %. Ultrasound guided central venous puncture is becoming common practice in adults and may increase insertion success rates and reduce insertion complication rates, especially for inexperienced operators or in difficult

access patients such as obese patients, patients with poor arterial pulses, or those with partial vessel thrombosis [38]. As described by Seldinger, after observing blood return, the syringe is disconnected from the needle hub and the guidewire is advanced through the needle and into the vein. It is important to leave part of the wire in view at all times. The advancement of the wire should be smooth without meeting any resistance. If resistance occurs during guidewire advancement, it is possible the wire is meeting a previously unrecognized thrombus, is advancing into the subcutaneous tissue, or most likely is advancing into the ascending lumbar veins which drain into the common iliac veins proximal to the femoral vein. Once the wire is in good position, remove the needle over the wire, holding the guidewire in place. Make a small ¼ to ½ cm skin incision at the site of entry of the guidewire into the skin. Be certain that the bevel of the scalpel blade is away from the guidewire. Hold the dilator near its tip and advance the dilator over the guidewire into the femoral vein. The dilator should be advanced using a gentle boring motion. Holding the guidewire in place, remove the dilator while applying light pressure to the femoral site, as bleeding is likely to occur when the dilator is removed. Place the catheter over the guidewire and insert into the femoral vessel. Once the catheter is inserted, remove the guidewire and aspirate blood through the catheter to ascertain placement and patency of the catheter. Secure the catheter in place and cover with a sterile dressing. Important warnings to consider during cannulation of the femoral vein include: (1) puncture of the femoral artery requires application of direct pressure for 5–10 min or until hemostasis is achieved; (2) never push the guidewire or catheter against resistance, properly placed guidewires float freely; (3) the guidewire can be sheared off if pulled out of the needle against resistance, if resistance is met on withdrawal of the guidewire, pull out the needle and the guidewire simultaneously; (4) the guidewire should remain in view at all times because guidewires have remained in vessels or have floated into the central circulation when not properly monitored (Fig. 29.7).

Confirmation of Placement Confirmation of proper CVC position is required after placement of all CVCs. A post-procedure x-ray is the initial and usually only confirmatory test needed after femoral vein catheter insertion [39]. Some have questioned the value of confirmatory x-rays for uncomplicated placement of femoral venous catheters, however unsuspected catheter tip placement in the ascending lumbar veins can occur with potentially serious consequences, especially if such placement is unrecognized [40]. Several clinical variables can alert the clinician to possible improper femoral catheter placement: (1) guidewire

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that meets resistance during advancement - suspect ascending lumbar placement or thrombosis; (2) bright red blood or arterial pulsation when vessel puncture takes place – suspect arterial placement; (3) catheter tip on x-ray that points too

cephalad – suspect ascending lumbar placement (Fig. 29.8); (4) catheter tip on x-ray that crosses the midline from the right groin position or tip that is too cephalad from the left – suspect arterial placement (Fig. 29.9). If the location of the catheter tip is in question a dye study should be performed to confirm proper placement in the vascular bed (Figs. 29.8b and 29.9b). Placing a transducer on the end of the catheter or sending blood from the catheter for blood gas determination may help distinguish arterial from venous placement.

Complications and Risks

Fig. 29.7 Guidewire left in right femoral vein hemodialysis catheter (arrow)

a

Femoral venous catheterization in children is generally regarded as safe, but as with all central venous catheters, complications do occur. In a prospective study evaluating femoral vascular catheterization in children, Venkataraman et al. reported that 74 of 89 (83 %) femoral venous catheterizations had no complications during catheter insertion and the other 15 (17 %) had either minor bleeding or hematomas at the insertion site [6]. During 13 of these femoral vein catheterizations, there was inadvertent puncture of the femoral artery. Overall catheterization success rate was 94.4 %. Less experienced operators required significantly more attempts (2.6 ± 1.5) to attain success than experienced operators (1.5 ± 0.5). Forty-five (51 %) patients were ≤1 year of age. The median duration of catheterization was 5 days

b

Fig. 29.8 (a) Left femoral venous catheter tip pointing cephalad. (b) Dye confirmation of ascending lumbar catheter placement

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b

Fig. 29.9 (a) Left femoral catheter considered venous in patient with low blood pressure and marginal oxygenation. (b) Dye study (aortagram) confirming unexpected arterial placement

with 21 % as ≤3 days duration, 43 % as 4–7 days, 26 % as 7–14 days, and 10 % as >14 days. Long-term complications were uncommon. Sixty-eight patients had no long-term complications, eight had leg swelling (all 100 cm in height. This author has had anecdotal success in predicting proper catheter tip placement by using a “paper tape measure” to determine the distance on the chest surface from the proposed insertion site to the sternal-manubrium junction, which approximates the superior vena cava – right atrial junction. After subclavian vein catheterization, confirmation of catheter tip placement is usually done by chest radiography however controversy exists regarding the necessity for post-procedural chest radiographs following cervicothoracic central venous catheter placement. McGee et al. described the results of a prospective, randomized, multicenter trial in adults and found that using conventional insertion techniques, the initial position of the catheter tip was in the heart in 47 % of 112 catheterizations [60]. Gladwin et al. demonstrated that the incidence of axillary vein or right atrial catheter malposition from internal jugular venous catheterization was 14 % [61]. The positive predictive value of a decision rule based on a questionnaire designed to detect potential mechanical complications and malpositioned catheters was 15 %. The sensitivity and specificity of the decision rule for detecting complications and malpositions was 44 and 55 %, respectively. This suggests that clinical factors alone do not reliably identify malpositioned catheters. Others report that chest radiography may not be necessary to confirm proper catheter placement if: (1) the procedure is performed by an experienced operator; (2) the procedure is “straightforward”; and (3) the operator requires 1 cm lateral to the carotid artery, in 2 % the IJV was

positioned medially over the carotid artery, and in 5 % the IJV was positioned outside the area which is predicted by surface landmarks [76]. Suk et al. reported that using a skin traction method using tape to stretch and secure the skin in the cephalad and caudal positions increased the ultrasoundmeasured cross-sectional area of the IJV by 40 % in infants and 34 % in children [77].

Insertion Technique Detailed step by step videos on the placement of central venous catheters and the use of ultrasound guidance have

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b

a

Nipple

ward

Aim to

Sternal head and clavicular head of sternocleidomastoid muscle

30˚

C M L

SCM Midpoint

30˚

Fig. 29.16 Internal jugular vein anatomy: (a) Medial approach (Source: PALS Provider Manual © 1997, American Heart Association, Inc). (b) Medial approach with triangle between bellies of SCM (Reprinted from Todres and Cote [122]. With permission from Elsevier)

been published [78, 79]. Here we detail the insertion technique using the surface landmark method. The patient is positioned in Trendelenburg position (unless contraindicated, such as with elevated intracranial pressure) with head down 15–30º. For the medial approach (Fig. 29.16) the two bellies of the SCM should be palpated by placing the index finger in the triangle created by the clavicle and the sternal and clavicular bellies of the SCM. Retract the skin cephalad to the insertion site prior to inserting the needle into the skin. This may increase the vessel lumen crosssectional area. During actual venipuncture, avoid trying to retract the carotid artery medially and away from the IJV as this is likely to decrease the IJV lumen diameter. For the medial approach, the approximate insertion site is one half the distance along a line from the sternal notch to the mastoid prominence. Insert the needle at an angle about 20–30º above the plane of the skin. Advance the needle while applying slight negative pressure on the syringe. Venous flashback indicating venipuncture may occur during needle advancement or withdrawal, therefore if unsuccessful during advancement then the needle should be withdrawn slowly. The needle should be completely removed from the skin prior to redirecting to avoid vessel laceration. This is particularly important in small infants. Before attempting to place the guidewire (Seldinger technique), it is important to demonstrate free flow of “blue” blood into the syringe. Do not try to place the wire if blood cannot be easily withdrawn, if the blood in the syringe is pulsating, or if the blood is obviously very oxygenated (bright red). Gently twist the syringe off the needle hub, maintain the needle in the same position and always occlude the needle hub with your finger

to prevent air aspiration. The guidewire should be advanced without meeting any resistance. Resistance to wire advancement usually means the lumen of the needle is now outside the vessel. In this case, the wire can be removed and needle position slightly adjusted. If in trying to remove the wire, resistance is encountered, this can mean the wire is bent near the needle bevel. In this case the wire and needle should be removed together. This reduces the risk of shearing off the end of the wire. Once the guidewire is successfully advanced, the needle can be removed while holding the guidewire in place. Be careful not to advance the guidewire to its full length as cardiac arrhythmias may occur. Make a small ¼–½ cm skin incision at the site of entry of the guidewire into the skin. Be certain that the bevel of the scalpel blade is away from the guidewire. Hold the dilator near its tip and advance the dilator over the guidewire into the IJV. The dilator should not be fully advanced as its purpose is to dilate the subcutaneous tissue and make a hole in the vessel. Holding the guidewire in place, remove the dilator while applying light pressure to site. Place the catheter over the guidewire and insert into the IJV. Once the catheter is inserted, remove the guidewire and aspirate blood through the catheter to ascertain placement and patency of the catheter. Secure the catheter in place. Posterior and anterior approaches to the IJV can also be used. These have similar success rates for cannulation and because the insertion sites are higher (more cephalad) in the neck, these approaches may carry lower risk of pneumothorax. Figures 29.16 and 29.17 depict all three approaches. Some have suggested that using a “finder needle” to locate the IJV both reduces the incidence of carotid artery puncture

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b

Internal jugular vein

Ai m

Suprasternal notch

towa

rd

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External jugular vein

Common carotid artery

30° Sternocleidomastoid muscle

Fig. 29.17 Alternative approaches to IJV catheterization: (a) Anterior. (b) Posterior (Source: PALS Provider Manual © 1997, American Heart Association, Inc)

and if advertent arterial puncture occurs, the smaller bore “finder needle” will cause less damage to the arterial wall and reduce the sequelae that might occur from carotid artery hematoma. Figure 29.13 demonstrates first finding the IJV with a small bore needle and then advancing the larger bore needle along the same trajectory as the “finder needle.” Alternatively, the finder needle can be removed and the large bore introducer needle advanced in the same plane as the initial finder needle. This technique may be most useful in obese patients with poor surface landmarks or in patients with coagulopathy wherein puncture of the artery may be more problematic than usual.

Confirmation of Placement Optimal location of a catheter in the internal jugular vein is in the superior vena cava near the junction with the right atrium, but not in it. Chest radiography is commonly used to confirm the position of the central venous catheter tip. Clinical controversy regarding the need for post procedure chest radiography is similar to that described for subclavian vein catheterization. As reported previously, Gladwin found that 14 % of IJV catheter tips were malpositioned in a series of 107 consecutive adult patients [61]. Given the risk of unrecognized catheter malposition, which because of small patient size, may be greater in children than adults, post procedure chest radiography is warranted even in patients who are clinically unchanged post procedure.

Complications Other than complications related to catheter maintenance (infections and thrombosis), complications related to catheter insertion are uncommon. Arterial puncture is the most common complication and is usually easily resolved with direct pressure to the punctured vessel. Nicolson reported an 8 % incidence of arterial puncture but minimal sequelae from the arterial puncture because she used the finder needle technique to avoid puncturing the artery with the large bore needle that is needed to pass the guidewire [80, 81]. Arterial puncture is significantly more common with IJV catheterization than with subclavian vein catheterization, with a reported incidence of 2–11 % in adults [52, 73, 82]. Pneumothorax or hemothorax are rare complications with an average incidence of 0–0.2 % [27, 76, 83, 84]. Catheter tip malposition is a frequent complication of all central venous catheters and IJV catheters are no exception. As previously described, dysrhythmias, pericardial tamponade, and mediastinal effusions have been reported when stiff plastic catheters erode through thin vessel walls [58, 85, 86]. Figure 29.18 depicts several IJV catheter malpositions in children. Figure 29.18b shows a short left IJV catheter with its tip at the IJV – innominate junction. Subsequent chest radiograph reveals a widened mediastinum filled with lipid as a result of vessel erosion by the catheter and extravasation of parenterally administered lipid into the mediastinum (Fig. 29.18c). Figures 29.19 and 29.15 depict both correctly positioned and malpositioned cervicothoracic catheters. Malpositioned catheters are at high risk for vessel erosion.

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a

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b

c

Fig. 29.18 (a) Left IJV catheter malposition in right subclavian vein – no recognized complications. (b) Left IJV malpositioned in innominate vein. (c) Catheter erodes through vessel wall – widened mediastinum with lipid extravasation

Axillary Vein Catheterization Demographic and Historical Data: Indications for Use The axillary vein is an alternative, and less commonly discussed, access site for central venous catheterization in children. A percutaneous approach to axillary vein catheterization was first described in 1981 and a modified technique further described in very low birth weight infants [87, 88]. These reports demonstrated a high success rate for cannulation with

minimal complication rates. Oriot’s report included axillary vein catheterization in 226 neonates with only nine failures [88]. In a few patients, non-persisting extrasystoles occurred during catheter insertion but disappeared with correct positioning of the catheter. No intrathoracic complications were noted. Metz reported on a cohort of 47 critically ill children (age 14 days to 9 years) who underwent 52 separate attempts at axillary vein catheterization. His reported success rate for cannulation was 79 % [89]. The most common reasons the axillary vein was used included: (1) poor alternative access sites; (2) need for hyperalimentation; (3) need for central

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Jugular Vs.

Thorocic duct Innominate Vs.

L. Subclavian V. R. Subclavian V. Superior vena cava

A R. Atrium V R. Ventricle

a

b

A V

c Fig. 29.19 Cervicothoracic catheter placement – proper catheter tip positions: (a) Normal vascular anatomy. (b) Right IJV. (c) Right subclavian vein (Reprinted from Todres and Cote [122]. With permission from Elsevier)

venous pressure monitoring; and (4) preservation of femoral vessels for cardiac catheterization. Martin has recently reported his experience with single lumen axillary catheters placed in 60 adults in a surgical intensive care unit [90]. Insertion complications were

infrequent and deep venous upper extremity thrombosis occurred in 11 % of the patients. He concluded that because the thrombosis rates were similar between axillary vein and cervicothoracic catheters, the axillary vein offered an attractive alternative when other sites were unavailable.

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Complications

Median N. Radial N. Ulnar N. Axillary A. Axillary V.

Fig. 29.20 Axillary vein anatomy (Reprinted from Metz et al. [89]. With permission from American Academy of Pediatrics)

Anatomy The axillary vein begins at the junction of the basilic and brachial veins running medial, anterior and caudal to the axillary artery. In the chest at the lateral border of the first rib it becomes the subclavian vein. The artery and vein lie within the axillary fascia and the brachial plexus runs between the artery and vein (Fig. 29.20).

Technique Catheter insertion is accomplished with the child placed in the Trendelenburg position, if not contraindicated, and the arm abducted between 100º and 130º. The position of the axillary artery is determined by palpation while retracting the redundant axillary skin with the opposite hand. The vein is punctured parallel and inferior to the artery as described by Gouin [91]. A 22-gauge short Teflon catheter can be used to cannulate the vein as if inserting a peripheral venous catheter. Alternatively, a thin-walled needle appropriate for the central venous catheter use can be used to obtain venous flashback. The needle/syringe should be inserted using negative pressure on the syringe hub. Once venous blood is obtained, the syringe is carefully disconnected from the needle and the guidewire inserted as per standard Seldinger technique. The axillary vein in children is very mobile in the axillary soft tissue and the greatest challenge to cannulation is fixing the vein in position so that the needle can enter the vessel. Firm traction of the redundant skin can help with this issue.

Complications associated with axillary vein insertion include failed cannulation, catheter malposition, arterial puncture, transient paresthesia, pneumothorax and axillary hematoma [92, 93]. The frequency of complications reported by Metz in a pediatric cohort is low – with complications of insertion occurring in 3.8 % – one pneumothorax and one hematoma [89]. Four additional complications occurred while the catheter was in place and these included venous stasis of the arm, venous thrombosis of the subclavian vein proximal to the catheter tip, parenteral nutrition infiltration secondary to catheter dislodgment, and one catheter-related infection. The axillary vein route has a lower rate of successful cannulation and results in higher incidence of catheter malposition and arterial puncture when compared with IJV catheterization, however the IJV route had a greater risk of pneumothorax [93]. Axillary vein catheter insertion success was 84 %, which is lower than IJV catheterization. Martin concluded that this rate of success was acceptable when other sites are less unavailable.

Ultrasound-Guided Central Vein Catheterization: The New Standard? Traditionally percutaneous insertions of CVCs have been performed by utilizing anatomic surface landmarks. Recently, bedside use of Doppler ultrasound has been used to facilitate vessel visualization. In some settings, the use of ultrasound increases catheter placement success rates, especially for novice operators, and reduces complications. Doppler ultrasound assist with catheter placement was first reported in 1984 [94]. Gualtieri et al. demonstrated in a prospective, randomized study that subclavian vein catheterization was successful in 23 of 25 (92 %) attempts using ultrasound guidance compared to 12 of 27 (44 %) using conventional landmark techniques [51]. In the hands of less experienced operators, ultrasound guidance improves subclavian vein cannulation success and in high-risk patients with obesity or coagulopathy, the use of ultrasound improved cannulation success with fewer significant complications [95]. In adults, multiple reports have shown that ultrasound guided central venous access is associated with decreased number of attempts, higher access success rates, and fewer catheter insertion related complications compared to surface landmark techniques [50, 96–98]. A randomized, controlled clinical trial in adults compared the overall success rate for IJV cannula placement by comparing dynamic (real-time) ultrasound, static ultrasound and surface anatomical landmarks. The odds for successful cannulation using dynamic ultrasound was 54 (95 % CI 6.6–44.0) times higher compared to landmark methodology [38]. Recently, Fragou et al.

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Fig. 29.21 Ultrasound image of internal jugular (IJ) vein and carotid artery (CA) with the ultrasound probe lightly touching the skin (a) and with gentle pressure compressing the IJ vein but maintaining the diameter of the CA (b)

compared ultrasound-guided infraclavicular subclavian vein cannulation to landmark methodology and found significantly shorter access time, fewer attempts, and complications in the ultrasound group compared to the landmark group. Catheter misplacement was not different between groups. They suggest that ultrasound-guided subclavian vein cannulation should be the method of choice [68]. Similar findings regarding the benefits of ultrasound guidance have been demonstrated in pediatric patients. The success rate for IJ catheter placement in infants prior to cardiac surgery was 100 % in the ultrasound group compared with a 77 % success rate in the group who underwent catheter placement by landmarks only [99]. In a separate study, Verghese also demonstrated that US-guidance for IJ catheter placement led to quicker cannulation times and fewer attempts [100]. In a recent meta-analysis, Sigaut et al. analyzed five clinical trials that compared ultrasound guidance to anatomical landmarks during IJV access in pediatric patients [101]. The authors found that ultrasound guidance had no effect on the rate of complications or IJV failure rate. However, in this study, four of the five studies were performed in cardiac surgery patients and therefore the results may not be generalizable to the heterogeneous pediatric intensive care unit population. Prospective clinical data on the use of ultrasound guidance in the general PICU population is limited. Froehlich et al. performed a prospective study in a quaternary

multidisciplinary pediatric intensive care unit [102]. The overall success rate and time to success of CVC placement was not significantly different between the landmark and ultrasound groups. However, 40 % (37/93) of the patients in the landmark group required four or more attempts compared with only 20 % (24/119) of the patients in the ultrasound group. The number of inadvertent arterial punctures was less in the ultrasound group compared with the landmark group, and all arterial punctures occurred at the femoral site. A national survey of the use of bedside ultrasound in pediatric critical care was recently conducted by Lambert et al. [103]. Seventy percent of responders stated they currently use bedside ultrasound. Pediatric ICUs with greater than 12 beds, greater than 1,000 yearly admissions, and universitybased institutions with either a pediatric critical care medicine fellowship or a cardiovascular thoracic surgery program were more likely to use bedside ultrasound for CVC placement. The preferred site for bedside ultrasound was “almost always” or “frequently” the IJV. Importantly, formal training on bedside ultrasound use occurred in 20 % of ultrasound using responders. Figure 29.21 depicts IJV and carotid artery images as observed using ultrasound guidance. The advantages associated with ultrasound guided central venous catheter placement include detection of anatomic variations and exact vessel location, avoidance of central veins with pre-existing thrombosis that may prevent

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successful central venous catheter placement, and guidance of both guidewire and catheter placement after initial needle insertion. The greatest benefit for use of ultrasound guidance may occur for the inexperienced operator and for all operators in high-risk clinical situations. The results from randomized controlled clinical trial in adults, comparing success rates for catheterization and complication rates were so compelling in favor of real-time ultrasound guided placement of percutaneous central venous catheters that some have called ultrasound guidance the “new standard of care” [36, 104]. In summary, the use of ultrasound guided CVC placement in pediatrics occurs commonly and should be in the arsenal available to all practitioners who place central catheters. These authors believe that the data in children pertaining to ultrasound use is sufficient to require that it be available for bedside use, but not sufficient to require its use in all circumstances. Clinicians should continue to use their judgment about when to apply this important adjunct for line placement. Furthermore inexperienced operators and physicians in training may benefit the most from the use of bedside ultrasound during CVC placement.

Complications Associated With Central Venous Catheter Placement Central venous catheters are associated with numerous complications, some minor and others life-threatening. These complications are primarily related to mechanical complications at the time of catheter insertion or complications that occur during maintenance of the catheter. Catheter associated blood stream infections and catheter related thrombosis are major complications that occur during catheter maintenance and have been the subject of excellent recent reviews and are topics of other chapters in this text [105, 106]. They will not be the subject of this review. Furthermore, mechanical complications associated with insertion have been previously discussed under the heading for each type of catheterization and the reader is referred to those sections. A brief summary will be included here. A retrospective review of over 1,400 central venous catheters placed in children demonstrated that age, sex, type of catheter, primary disease, indication for placement, level of physician training, and operator experience were not associated with increased complication risks [22]. Conversely, in a study by Sznajder et al. the complication rate for inexperienced physicians was double the rate of more experienced physicians when performing central venous catheter insertion [67].

Pneumothorax In children, pneumothorax is reported as a complication in 1–2 % of CVC insertions placed by surgical staff surgical and in 4 % of patients when performed by nonsurgical staff

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[10, 22, 107]. More recent data indicates that a pneumothorax occurred in only two out of 156 patients (1.2 %) who underwent central venous catheter placement by pediatricians skilled in emergency procedures [108].

Arterial Puncture Using classic Seldinger technique arterial puncture occurs during central venous catheter insertion in 1.5–15 % [8–10, 22, 94, 109]. Merrer et al. demonstrated that catheter insertion during the night was significantly associated with the occurrence of mechanical complications including arterial puncture [19].

Catheter Malposition: Femoral Catheters It is important to determine catheter placement because malposition of central venous catheters can result in both morbidity and mortality [40, 110]. Malposition of femoral catheters in the ascending lumbar vein is an infrequent complication but if left in place can result in tetraplegia. Zenker et al. reviewed contrast radiographs taken immediately after insertion of 44 transfemoral catheters in a neonatal intensive care unit [40]. Malposition of catheters in the left ascending lumbar vein was detected in two newborns. Paravertebral malposition has been previously reported in neonates [111– 113]. These reports demonstrate that catheter position was initially misinterpreted or assessed inadequately until the onset of complications. In newborns, the vertebrolumbar and azygous systems represent an extensive, highly variable, intercommunicating network in which alterations in pressure and flow direction may occur. The large capacity of the lumbar veins and the vertebral plexus can compensate for occlusion of the inferior vena cava. Use of catheters misplaced in this posterior system can give rise to retroperitoneal, peritoneal or spinal epidural fluid extravasation [98, 114, 115]. Ultrasonography, lateral radiography, or venogram is required in cases in which the location of the catheter tip is in question. Catheters in the ascending lumbar vein or vertebral plexus should be removed immediately. Warning signs that may indicate catheter malposition include: (1) loss of blood return on aspiration; (2) subtle lateral deviation, or “hump,” of the catheter at the level of L4 or L5 on frontal abdominal radiographs in catheters placed from the left side (Fig. 29.8); (3) a catheter path directly overlying the vertebral column rather than the expected path to the right of midline for a catheter in the inferior vena cava; (4) resistance to guidewire advancement during insertion [96]. A lateral abdominal radiograph may confirm the posterior position of the catheter, however this author has found that a venogram (injecting dye directly into the catheter – Fig. 29.8) is the best method to confirm proper placement of these catheters.

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Catheter Malposition and Post Procedure Chest Radiographs: Cervicothoracic Catheters As noted previously, Fig. 29.15 depicts cervicothoracic catheter malpositions that are potentially hazardous. Three recent reports describing experience in adult patients conclude that a postprocedure chest radiograph is unnecessary in the asymptomatic patient after IJV catheterization when using fluoroscopy or ultrasound during catheter placement [116–118]. Similar recommendations are made for subclavian vein approach. A study in adults focusing on the subclavian vein catheterization concluded that postprocedure chest radiograph has minimal benefit and is not necessary, unless the patient shows sign of clinical deterioration post procedure [119]. Others have advocated that a postprocedure chest x-ray may be omitted in cases after line placement when experienced clinicians use good technique and good clinical judgment [61, 120]. In pediatrics little data driven recommendations are available, however Janik reports that routine chest x-ray is not indicated after uneventful central venous catheter insertion when monitored with concurrent fluoroscopy [121]. These recommendations were based on a low rate of complications of 1.6 %. In addition, all children who had pulmonary complications displayed signs and symptoms suggestive of impaired respiratory function. This recommendation may not be relevant to the pediatric ICU setting where catheters are rarely placed with fluoroscopic guidance. In the ICU, these authors recommend chest radiography after all percutaneously placed central venous catheters, regardless of post procedure clinical status.

References 1. Food and Drug Administration: precautions with central venous catheters. FDA Taskforce. FDA Drug Bulletin. 1989. p. 15–6. 2. O’Grady NP, Alexander M, Dellinger EP, et al. Guidelines for the prevention of intravascular catheter-related infections. Pediatrics. 2002;110(5):e51. 3. Abraham E, Shapiro M, Podolsky S. Central venous catheterization in the emergency department. Crit Care Med. 1983;11:515–7. 4. Getzen LC, Pollak EW. Short-term femoral vein catheterization – a safe alternative venous access? Am J Surg. 1979;138:876–8. 5. Chiang VW, Baskin MN. Uses and complications of central venous catheters inserted in a pediatric emergency department. Pediatr Emerg Care. 2000;16(4):230–2. 6. Venkataraman ST, Thompson AE, Orr RA. Femoral vascular catheterization in critically ill infants and children. Clin Pediatr. 1997;36:311–9. 7. Vascular access. In: Zaritsky AL, Nadkarni V, Hickey R, et al., editors. PALS provider manual. Dallas: American Heart Association; 2002. p. 155–72. 8. Kanter RK, Zimmerman JJ, Strauss RH, Stoeckel KA. Central venous catheter insertion by femoral vein: safety and effectiveness for the pediatric patient. Pediatrics. 1986;77(6):842–7. 9. Durbec O, Viviand X, Potie F, et al. A prospective evaluation of the use of femoral venous catheters in critically ill adults. Crit Care Med. 1997;25:1986–9.

J. Kaplan et al. 10. Venkataraman ST, Orr RA, Thompson AE. Percutaneous infraclavicular subclavian vein catheterization in critically ill infants and children. J Pediatr. 1988;113(3):480–5. 11. Finck C, Smith S, Jackson R, et al. Percutaneous subclavian central venous catheterization in children younger than one year of age. Am Surg. 2002;68:401–6. 12. Centers for Disease Control and Prevention. Guidelines for the prevention of intravascular catheter-related infections. 2011. www.cdc. gov/hicpac/BSI/BSI-guidelines-2011.html. Accessed Oct 2011. 13. Niedner MF, Huskins WC, Colantuoni E, et al. Epidemiology of central line associated bloodstream infections in the pediatric intensive care unit. Infect Control Hosp Epidemiol. 2011;32:1200–8. 14. Moncrief JA. Femoral catheters. Ann Surg. 1958;147:166–72. 15. Swanson RS, Uhlig PN, Gross PL, McCabe CJ. Emergency intravenous access through the femoral vein. Ann Emerg Med. 1984; 13(4):244–7. 16. Goldstein AM, Weber JM, Sheridan RL. Femoral venous access is safe in burned children: an analysis of 224 catheters. J Pediatr. 1997;130(3):442–6. 17. Nidus B, Speyer J, Bottino J, et al. Repeated femoral vein cannulation for administration of chemotherapeutic agents. Ca Treat Rep. 1983;67:186. 18. Bansmer G, Keith D, Tesluk H. Complication following use of indwelling catheters of the inferior vena cava. JAMA. 1958;167: 1606–11. 19. Merrer J, De Jonghe B, Golliot F, Lefrant JY, Raffy B, Barre E, et al. Complications of femoral and subclavian venous catheterization in critically ill patients: a randomized controlled trial. JAMA. 2001;286(6):700–7. 20. Seneff MG, Rippe JM. Central venous catheters. In: Rippe JM, Irwin RS, Alpert JS, et al., editors. Intensive care medicine. Boston: Little Brown; 1985. p. 16–33. 21. McIntyre KM, Lewis AJ, editors. Textbook of advance cardiac life support. Dallas: American Heart Association; 1990. 22. Smyrnios NA, Irwin RS. The jury on femoral vein catheterization is still out. Crit Care Med. 1997;25:1943–6. 23. de Jonge RC, Polderman KH, Gemke RJ. Central venous catheter use in the pediatric patient: mechanical and infectious complications. Pediatr Crit Care Med. 2005;6:329–39. 24. Johnson EM, Saltzman DA, Suh G, Dahms RA, Leonard AS. Complications and risks of central venous catheter placement in children. Surgery. 1998;124:911–6. 25. Beck C, Dubois J, Grignon A, Lacroix J, David M. Incidence and risk factors of catheter-related deep vein thrombosis in a pediatric intensive care unit: a prospective study. J Pediatr. 1998;133(2): 237–41. 26. Jacobs B, Brilli R, Babcock D. High incidence of vascular thrombosis after placement of subclavian & internal jugular venous catheters in children. Crit Care Med. 1999;27:A29. 27. Casado-Flores J, Barja J, Martino R, et al. Complications of central venous catheterization in critically ill children. Pediatr Crit Care Med. 2001;2:57–62. 28. Richards M, Edwards J, Culver D, et al. Nosocomial infections in pediatric intensive care units in the United States. National Nosocomial Infections Surveillance System. Pediatrics. 1999;103: 103–9. 29. Stenzel JP, Green TP, Fuhrman BP, et al. Percutaneous femoral venous catheterizations: a prospective study of complications. J Pediatr. 1989;114:411–5. 30. Fernendez E, Green T, Sweeney M. Low inferior vena caval catheters for hemodynamic and pulmonary function monitoring in pediatric critical care patients. Ped Crit Care Med. 2004;5:14–8. 31. Lloyd R, Donnerstein R, Berg R. Accuracy of central venous pressure measurement from the abdominal inferior vena cava. Pediatrics. 1992;89:506–8.

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32. Ho K, Joynt G, Tan P. A comparison of central venous pressure and common iliac venous pressure in critically ill mechanically ventilated patients. Crit Care Med. 1998;26:461–4. 33. Dillon P, Columb M, Hume D. Comparison of superior vena caval and femoroiliac venous pressure measurements during normal and inverse ratio ventilation. Crit Care Med. 2001;29:37–9. 34. Tribett D, Brenner M. Peripheral and femoral vein cannulation. In: Venus B, Mallory D, editors. Problems in critical care – vascular access. Philadelphia: JB Lippincott; 1988. p. 266–85. 35. Seldinger SI. Catheter replacement of the needle in percutaneous arteriography; a new technique. Acta Radiol. 1953;39(5): 368–76. 36. Raad I, Hohn D, Gilbreath B, et al. Prevention of central venous catheter-related infection by using maximal sterile barrier precautions during insertion. Infect Control Hosp Epidemiol. 1994;15: 231–8. 37. Kanter R, Gorton J, Palmieri K, et al. Anatomy of femoral vessels in infants and guidelines for venous catheterization. Pediatrics. 1989;83:1020–2. 38. Milling T, Rose J, Briggs W, et al. Randomized, controlled clinical trial of point-of-care limited ultrasonography assistance of central venous cannulation: the Third Sonography Outcomes Assessment Program (SOAP-3) Trial. Crit Care Med. 2005;33:1764–9. 39. Otto C. Central venous pressure monitoring. In: Blitt C, Hines R, editors. Monitoring in anesthesia and critical care medicine. 3rd ed. New York: Churchill Livingston; 1995. p. 173–212. 40. Zenker M, Rupprecht T, Hofbeck M, et al. Paravertebral and intraspinal malposition of transfemoral central venous catheters in newborns. J Pediatr. 2000;136(6):837–40. 41. Aubaniac R. L’injection intraveineuse sous-claviculaire. Presse Med. 1952;60:1656–9. 42. Sterner S, Plummer D, Clinton I, et al. A comparison of the supraclavicular approach and the infraclavicular approach for subclavian vein catheterization. Ann Emerg Med. 1986;15:421–4. 43. Groff S, Ahmed N. Subclavian vein catheterization in the infant. J Ped Surg. 1974;9:171–4. 44. Casado-Flores J, Valdivielso-Serna A, Perez-Jurado L, et al. Subclavian vein catheterization in critically ill children: analysis of 322 cannulations. Intensive Care Med. 1991;17:350–4. 45. McGovern T, Brandt B. Percutaneous infraclavicular subclavian venous access in infants and children. Contemp Surg. 1994;45(6): 335–9. 46. Stovroff M, Teague W. Intravenous access in infants and children. Pediatr Clin N Am. 1998;45:1373–93. 47. Novak R, Venus B. Clavicular approaches for central vein cannulation. In: Venus B, Mallory D, editors. Problems in critical care – vascular access. Philadelphia: JB Lippincott; 1988. p. 242–65. 48. Kaye W, Dubin H. Vascular cannulation. In: Civetta J, Taylor W, Kirby R, editors. Critical care. 1st ed. Philadelphia: JB Lippincott; 1988. p. 211–25. 49. Mansfield PF, Hohn DC, Fornage BD, et al. Complications and failures of subclavian-vein catheterization. N Engl J Med. 1994;331: 1735–8. 50. Randolph AG, Cook DJ, Gonzales CA, et al. Ultrasound guidance for placement of central venous catheters: a meta-analysis of literature. Crit Care Med. 1996;24:2053–8. 51. Gualtieri E, Deppe S, Sipperly M, et al. Subclavian venous catheterization: greater success rate for less experienced operators using ultrasound guidance. Crit Care Med. 1995;23(4):692–7. 52. Ruesch S, Walder B, Tramer MR. Complications of central venous catheters: internal jugular versus subclavian access – a systematic review. Crit Care Med. 2002;30(2):454–60. 53. Jung C, Bahk J, Kim M, et al. Head position for facilitating the superior vena caval placement of catheters during right subclavian approach in children. Crit Care Med. 2002;30:297–9.

369 54. Land RE. Anatomic relationships of the right subclavian vein. A radiologic study pertinent to percutaneous subclavian venous catheterization. Arch Surg. 1971;102(3):178–80. 55. Tan BK, Hong SW, Huang MH, Lee ST. Anatomic basis of safe percutaneous subclavian venous catheterization. J Trauma. 2000; 48(1):82–6. 56. van Engelenburg K, Festen C. Cardiac tamponade: a rare but lifethreatening complication of central venous catheters in children. J Pediatr Surg. 1998;33(12):1822–4. 57. Beattie PG, Kuschel CA, Harding JE. Pericardial effusion complicating a percutaneous central venous line in a neonate. Acta Paediatr. 1993;82(1):105–7. 58. Nowlen TT, Rosenthal GL, Johnson GL, et al. Pericardial effusion and tamponade in infants with central catheters. Pediatrics. 2002;110:137–42. 59. Andropoulos D, Bent S, Skjonsby B, et al. The optimal length of insertion of central venous catheters for pediatric patients. Anesth Analg. 2001;93:883–6. 60. McGee W, Ackerman B, Rouben L, et al. Accurate placement of central venous catheters: a prospective, randomized, multicenter trial. Crit Care Med. 1993;21:1118–23. 61. Gladwin MT, Slonim A, Landucci DL, et al. Cannulation of the internal jugular vein: is postprocedural chest radiography always necessary? Crit Care Med. 1999;27(9):1819–23. 62. Bailey S, Shapiro S, Mone M, et al. Is immediate chest radiograph necessary after central venous catheter placement in a surgical intensive care unit? Am J Surg. 2000;180:517–22. 63. Puls L, Twedt C, Hunter J, et al. Confirmatory chest radiographs after central line placement: are they warranted? South Med J. 2003;96:1138–41. 64. Lessnau K. Is chest radiography necessary after uncomplicated insertion of a triple-lumen catheter in the right internal jugular vein, using the anterior approach? Chest. 2005;127:220–3. 65. Conces D, Holden R. Aberrant locations and complications in initial placement of subclavian vein catheters. Arch Surg. 1984;119:293–5. 66. Defalque R, Gletcher M. Neurological complications of central venous cannulation. J Parenter Enter Nutr. 1988;12:406–9. 67. Sznajder J, Zveibil F, Bitterman H, et al. Central vein catheterization: failure and complication rates by three percutaneous approaches. Arch Intern Med. 1986;146(2):259–61. 68. Fragou M, Gravvanis A, Dimitriou V, et al. Real-time ultrasoundguided subclavian vein cannulation versus the landmark method in critical care patients: a prospective randomized study. Crit Care Med. 2011;39:1607–12. 69. English I, Frew R, Pigott J, et al. Percutaneous catheterization of the internal jugular vein. Anaesthesia. 1969;24:521–31. 70. Prince S, Sullivan R, Hackel A. Percutaneous catheterization of the internal jugular vein in infants and children. Anesthesiology. 1976;44:170–4. 71. Hall D, Geefhuysen J. Percutaneous catheterization of the internal jugular vein in infants and children. J Ped Surg. 1977;12: 719–22. 72. Wyte S, Barker W. Central venous catheterization: internal jugular approach and alternatives. In: Roberts J, Hedges J, editors. Clinical procedures in emergency medicine. Philadelphia: WB Saunders; 1985. p. 321–32. 73. McGee W, Mallory D. Cannulation of the internal and external jugular veins. In: Venus B, Mallory D, editors. Problems in critical care – vascular access. Philadelphia: JB Lippincott; 1988. p. 217–41. 74. Roth B, Marciniak B, Engelhardt T, Bissonnette B. Anatomic relationship between the internal jugular vein and the carotid artery in preschool children – an ultrasonographic study. Pediatr Anesth. 2008;18:752–6.

370 75. Mallory D, Shawker T, Evans R, et al. Effects of clinical maneuvers on sonographically determined internal jugular vein size during venous cannulation. Crit Care Med. 1990;18:1269–73. 76. Denys B, Uretsky B. Anatomical variations of internal jugular vein location: impact on central venous access. Crit Care Med. 1991;19:1516–9. 77. Suk E, Kim D, Kil H, Kweon TD. Effects of skin traction on cross-sectional area of the internal jugular vein in infants and young children. Anesth Intensive Care. 2010;38:342–5. 78. Graham A, Ozment C, Tegtmeyer K, Lai S, Braner D. Videos in clinical medicine. Central venous catherization. N Engl J Med. 2007;356:e21. 79. Ortega R, Song M, Hansen CJ, Barash P. Videos in clinical medicine. Ultrasound-guided internal jugular vein cannulation. N Engl J Med. 2010;362:e57. 80. Nicolson S, Sweeney M, Moore R, et al. Comparison of internal and external jugular cannulation of the central circulation in the pediatric patient. Crit Care Med. 1985;13:747–9. 81. Jobes D, Schwartz A, Greenhow D, et al. Safer jugular vein cannulation: recognition of arterial puncture and preferential use of the external jugular route. Anesthesiology. 1983;59:353. 82. Vaughan RW, Weygandt GR. Reliable percutaneous central venous pressure measurement. Anesth Analg. 1973;52:709–16. 83. Johnson F. Internal jugular vein catheterization. N Y State J Med. 1978;78(14):2168–71. 84. Brinkman A, Costley D. Internal jugular venipuncture. JAMA. 1973;223:182–3. 85. Daniels S, Hannon D, Meyer R, et al. Paroxysmal supraventricular tachycardia: a complication of jugular central venous catheters in neonates. AJDC. 1984;138:474–5. 86. Smith-Wright D, Green T, Lock J, et al. Complications of vascular catheterization in critically ill children. Crit Care Med. 1984;12:1015–7. 87. Meignier M, Nicolas F. [Perfusion by axillary approach in the child (author’s transl)]. Ann Pediatr (Paris). 1981;28:291–2. 88. Oriot D, Defawe G. Percutaneous catheterization of the axillary vein in neonates. Crit Care Med. 1988;16:285–6. 89. Metz R, Lucking S, Chaten F, et al. Percutaneous catheterization of the axillary vein in infants and children. Pediatrics. 1990;85:531–3. 90. Martin C, Viviand X, Saux P, et al. Upper-extremity deep vein thrombosis after central venous catheterization via the axillary vein. Crit Care Med. 1999;27:2626–9. 91. Gouin F, Martin C, Saux P. Central and pulmonary artery catheterizations via the axillary vein. Acta Anaesth Scand. 1985;81:27–9. 92. Taylor B, Yellowlees I. Central venous cannulation using the infraclavicular axillary vein. Anesthesiology. 1990;72:55–8. 93. Martin C, Eon B, Auffray J, et al. Axillary or internal jugular central venous catheterization. Crit Care Med. 1990;18:400–2. 94. Legler D, Nugent M. Doppler localization of the internal jugular vein facilitates central venous cannulation. Anesthesiology. 1984; 60:481–2. 95. Gilbert T, Seneff M, Becker R. Facilitation of internal jugular venous cannulation using an audio-guided Doppler ultrasound vascular access device: results from a prospective, dual-center, randomized, crossover clinical study. Crit Care Med. 1995; 23:60–5. 96. Miller A, Roth B, Mills T, et al. Ultrasound guidance versus the landmark technique for the placement of central venous catheters in the emergency department. Acad Emerg Med. 2002;9:800–5. 97. Keenan S. Use of ultrasound to place central lines. J Crit Care. 2002;17:126–37. 98. Hind D, Calvert N, McWilliams R, et al. Ultrasonic locating devices for central venous cannulation: meta-analysis. BMJ. 2003;327:361. 99. Verghese S, Magill W, Patel R, et al. Ultrasound-guided internal jugular venous cannulation in infants: a prospective comparison with the traditional palpation method. Anesthesiology. 1999;91:71–7.

J. Kaplan et al. 100. Verghese S, Magill W, Patel R, et al. Comparison of three techinques for internal jugular vein cannulation in infants. Paediatr Anaesth. 2000;10:505–11. 101. Sigaut S, Skhiri A, Stany I, et al. Ultrasound guided internal jugular vein access in children and infant: a meta-analysis of published studies. Paediatr Anaesth. 2009;19:1199–206. 102. Froehlich C, Rigby M, Rosenberg E, et al. Ultrasound-guided central venous catheter placement decreases complications and decreases placement attempts compared with the landmark technique in patients in a pediatric intensive care unit. Crit Care Med. 2009;37:1090–6. 103. Lambert R, Boker J, Maffei F. National survey of bedside ultrasound use in pediatric critical care. Pediatr Crit Care Med. 2011;12:655–9. 104. Feller-Kopman D. Ultrasound guided central venous catheter placement: the new standard of care ? Crit Care Med. 2005; 33:1875–6. 105. Rowin M, Patel V, Christenson J. Pediatric intensive care unit nosocomial infections: epidemiology, sources and solutions. Crit Care Clin – Pediatric Crit Care. 2003;19(3):473–88. 106. Jacobs B. Central venous catheter occlusion and thrombosis. Crit Care Clin – Pediatric Crit Care. 2003;19:489–514. 107. Gauderer M, Stellato T. Subclavian broviac catheters in children – technical considerations in 146 consecutive placements. J Pediatr Surg. 1985;20:402–5. 108. Citak A, Karabocuoglu M, Ucsel R, et al. Central venous catheters in pediatric patients-subclavian venous approach as the first choice. Pediatr Int. 2002;44:83–6. 109. Conz P, Dissegna D, Rodighiero M, et al. Cannulation of the internal jugular vein: comparison of the classic Seldinger technique and an ultrasound guided method. J Nephrol. 1997;10:311–3. 110. Lavandosky G, Gomez R, Montes J. Potentially lethal misplacement of femoral central venous catheters. Crit Care Med. 1996;24:893–6. 111. Bass W, Lewis D. Neonatal segmental myoclonus associated with hyperglycorrhachia. Pediatr Neurol. 1995;13:77–9. 112. Lussky R, Trower N, Fisher D, et al. Unusual misplacement sites of percutaneous central venous lines in the very low birth weight neonate. Am J Perinatol. 1997;14:63–7. 113. Kelly M, Finer N, Dunbar L. Fatal neurologic complication of parenteral feeding through a central vein catheter. Am J Dis Child. 1984;138:352–3. 114. Odaibo F, Fajardo CA, Cronin C. Recovery of intralipid from lumbar puncture after migration of saphenous vein catheter. Arch Dis Child. 1992;67:1201–3. 115. Bonadio W, Losek J, Melzer-Lange M. An unusual complication from a femoral venous catheter. Pediatr Emerg Care. 1988;4:27–9. 116. Lucey B, Varghese JC, Haslam P, et al. Routine chest radiographs after central line insertion: mandatory postprocedural evaluation or unnecessary waste of resources? Cardiovasc Intervent Radiol. 1999;22:381–4. 117. Guth A. Routine chest X-rays after insertion of implantable longterm venous catheters: necessary or not? Am Surg. 2001;67:26–9. 118. Chang T, Funaki B, Szymski G. Are routine chest radiographs necessary after image-guided placement of internal jugular central venous access devices? Am J Roentgenol. 1998;170:335–7. 119. Burn P, Skewes D, King D. Role of chest radiography after the insertion of a subclavian vein catheter for ambulatory chemotherapy. Can Assoc Radiol J. 2001;52:392–4. 120. Molgaard O, Nielsen M, Handberg B, et al. Routine X-ray control of upper central venous lines: is it necessary? Acta Anaesthesiol Scand. 2004;48:685–9. 121. Janik J, Cothren C, Janik J, et al. Is a routine chest x-ray necessary for children after fluoroscopically assisted central venous access? J Pediatr Surg. 2003;38:1199–202. 122. Todres D, Cote C. Procedures. In: Cote C, Ryan J, Todres D, Goudsouzian N, editors. A practice of anesthesia for infants and children. 2nd ed. Philadelphia: WB Saunders; 1993. p. 508.

30

Shock Derek S. Wheeler and Joseph A. Carcillo Jr.

Abstract

Shock is one of the most frequently diagnosed, yet poorly understood disorders in the pediatric intensive care unit (PICU). Shock is defined by an imbalance between oxygen and substrate delivery versus metabolic demand (oxygen consumption is often used as a surrogate of metabolic demand). The epidemiology, pathophysiology, and management of critically ill children with shock are distinctly different from that in critically ill adults. Early recognition of the features of shock leads to early treatment and better outcomes. Keywords

Shock • Sepsis • Septic shock • Distributive shock • Obstructive shock • Hypovolemic shock • Cardiogenic shock • Neurogenic shock • Anaphylactic shock • Compensated shock • Uncompensated shock • Irreversible shock • Fluid resuscitation

Historical Perspective Shock is one of the most frequently diagnosed, yet poorly understood disorders in the pediatric intensive care unit (PICU). The very definition of what constellation of physical signs and symptoms comprise shock remains controversial, in part due to the vast array of disorders that cause shock in critically ill and injured children (Table 30.1). Webster’s Dictionary defines shock as any sudden disturbance or agitation of the mind or emotions [1]. Indeed, at one time in history, shock was thought to be due to a “nervous condition” and was treated with all manner of treatments, such as stimulants, depressants, and even electrical shock therapy [2]. A more appropriate and contemporary definition, however, D.S. Wheeler, MD, MMM (*) Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA e-mail: [email protected] J.A. Carcillo Jr., MD Pediatric Intensive Care Unit, Children’s Hospital of Pittsburgh of UPMC, 4401 Forbes Avenue, FP 2118, Pittsburgh, PA 15224, USA e-mail: [email protected] D.S. Wheeler et al. (eds.), Pediatric Critical Care Medicine, DOI 10.1007/978-1-4471-6362-6_30, © Springer-Verlag London 2014

would define shock as a sudden disturbance or agitation of the body’s normal homeostasis. Obtaining a more accurate, scientific definition of the clinical state known as shock has become increasingly difficult with the recognition of the complexity of the biochemical and molecular perturbations of the shock state. Although Hippocrates was perhaps the first to describe the constellation of signs and symptoms of shock, the French surgeon Henri Francois Le Dran is widely credited with the first use of the medical term shock (literally translated from the French verb choquer) in 1737 in his textbook, A Treatise of Reflections Drawn from Experience with Gunshot Wounds [3]. Le Dran had used the term to describe a sudden impact or jolt, and by happenstance, a mistranslation by the English physician Clare in 1743 introduced the term into the English language to describe the sudden deterioration of a patient’s condition following major trauma [4]. The term was further popularized by the English physician, Edwin A. Morris, who used the term in his article A practical treatise on shock after operations and injuries in 1867 [5]. Samuel Gross called shock the rude unhinging of the machinery of life in 1872 [6]. John Warren called shock a momentary pause in the act of death in 1895 [7]. Blalock defined shock as a peripheral circulatory failure, resulting from a discrepancy in the size of 371

372 Table 30.1  Common causes of shock in children Hypovolemic shock   Fluid and electrolye losses   Vomiting   Diarrhea   Nasogastric tube drainage renal losses (via excessive urinary output)    Diuretic administration    Diabetes mellitus    Diabetes insipidus    Adrenal insufficiency   Fever   Heat stroke   Excessive sweating   Water deprivation   Sepsis   Burns   Pancreatitis    Small bowel obstruction   Hemorrhage   Trauma    Fractures    Spleen laceration    Liver laceration    Major vessel injury     Intracranial bleeding (especially neonates)   Hastrointestinal bleeding   Surgery Cardiogenic shock  Myocarditis  Cardiomyopathy  Myocardial ischemia (e.g. kawasaki’s disease, anomalous origin of the left coronary artery, etc)   Ventricular outflow tract obstruction   Acute dysrhythmias   Post cardiopulmonary bypass Obstructive shock   Tension pneumothorax   Cardiac tamponade   Pulmonary embolism Distributive shock  Sepsis  Anaphylaxis   Neurogenic shock

the vascular bed and the volume of the intravascular fluid in 1940 [8]. Finally, the famed physiologist Carl Wiggers offered the following definition in 1942: Shock is a syndrome resulting from a depression of many functions but in which reduction of the effective circulating blood volume is of basic importance and in which impairment of the circulation steadily progresses until it eventuates into a state of irreversible circulatory failure [9]. While all of these descriptions are appropriate, shock is very simply placed in economic terms as supply not matching demand, in that there is an inadequate delivery

D.S. Wheeler and J.A. Carcillo Jr.

of oxygen and metabolic substrates to meet the metabolic demands of the cells and tissues of the body. We now recognize Gross’ machinery of life as the mechanisms that assure adequate oxygen delivery and utilization at the cellular level. Inadequate oxygen delivery results in cellular hypoxia, anaerobic metabolism and resultant lactic acidosis, activation of the host inflammatory response, and eventual vital organ dysfunction. Left untreated, shock leads to progressively worsening organ dysfunction and eventually organ failure and subsequent death. Shock is a clinical diagnosis and is characterized by hyoperfusion of several organ systems. The initial diagnosis is often based upon the clinical presence of tachycardia, decreased urine output, mottled skin, and altered levels of consciousness. Shock may occur with a decreased, normal, or even increased cardiac output as well as a decreased, normal, or increased blood pressure [10, 11]. Just as important, shock may occur in the scenario of globally decreased tissue perfusion, as in the case with profound hypotension, or decreased regional tissue perfusion. Hypovolemic shock, the most common cause of shock in children [10], has been described in the medical literature for over 150 years. For example, a pandemic of cholera claimed more than 23,000 lives in England during 1831 [12]. The accepted treatment at that time was blood-letting, which not surprisingly often failed. A 22 year-old medical graduate of Edinburgh University named William O’Shaughnessy was the first to note that the blood from patients suffering from cholera had lost a large portion of its water and later suggested a novel treatment by returning the blood to its natural specific gravity by replacing its deficient saline. O’Shaughnessy sent a letter to the Lancet [13] that included the following description of terminal cholera: On the floor, before the fireplace. . .lay a girl of slender make and juvenile height; with the face of a superannuated hag. She uttered no moan, gave expression of no pain, … The colour of her countenance was that of lead – a silver blue, ghastly tint; her eyes were sunk deep into the sockets, as though they had been driven in an inch behind their natural position; her mouth was squared; her features flattened; her eyelids black; her fingers shrunk, bent, and inky in their hue. All pulse was gone at the wrist, and a tenacious sweat moistened her bosom. In short, Sir, that face and form I never can forget, were I to live to beyond the period of man’s natural age. O’Shaughnessy offers a highly accurate and classic portrayal of the late stages of uncompensated and irreversible shock. However, it was Thomas Latta who followed O’Shaughnessy’s advice and first attempted intravenous fluid resuscitation in 1832. Ironically, William O’Shaughnessy received a knighthood for his work on the electric telegraph and not for his work on cholera, and Thomas Latta died a relative unknown less than 1 year after his classic observations [14]. The modern era of pediatric shock did not begin until much later, when intravenous therapy replaced s­ ubcutaneous

30 Shock

therapy as a means of fluid resuscitation during the 1960s and 1970s. Deaths associated with diarrheal disease in the U.S. decreased from 67 per 100,000 infants to 23 per 100,000 infants following the widespread use of metal intravenous catheters, with a further reduction from 23 to 2.6 per 100,000 infants noted by 1985 associated with the use of plastic intravenous catheters [15]. Thomas et al. [15] reviewed data from the Vital Statistics of the United States from 1960 to 1991 and noted an eightfold reduction in the mortality rate from hypovolemic shock from 1/1,000 infants in 1960 to 0.12/1,000 infants in 1991. Significantly, the steepest decrease in mortality occurred during the decade between 1975 and 1985 coinciding with implementation of IV fluid therapy using plastic catheters in children. While numerous factors are responsible for this decline, the development of pediatric critical care medicine as a subspecialty, along with the aggressive use of intravenous fluids has certainly contributed substantially to this profound reduction in mortality and undoubtedly represents one of modern pediatric medicine’s great accomplishments. Although significant progress has been made in elucidating the molecular and cellular basis of shock, morbidity and mortality from shock remain unacceptably high. For example, Watson and colleagues evaluated a U.S. population sample for all-cause mortality in children in 1995 and noted that the two leading causes of death were trauma and severe sepsis [16]. Orr and colleagues evaluated a 5,000 patient database of children referred from the community setting to five separate pediatric hospitals in 2000 [17]. Shock, defined in this report by the presence of either hypotension or a capillary refill >2 s was the leading cause of death in these children, regardless of trauma status. Although head trauma was more common among patients who died, shock at the outside community hospital was a major predictor of subsequent death. Of major concern, only 7 % of the 5,000 patients were referred for a diagnosis of shock, yet more than 40 % of these children did, in fact, meet prospectively defined criteria for the diagnosis of shock. Community physicians were more likely to refer these children for respiratory distress when shock was present, even though the presence of shock was a significant risk factor for subsequent mortality. Therefore, despite the dramatic advances in the care of children with shock over the last 50 years, shock remains both common and often underappreciated in children transported to tertiary care pediatric hospitals.

 Brief Overview of Cellular Respiration A and the Cellular Basis of Shock Adenosine triphosphate (ATP) is the energy currency of the cell – therefore, shock is a state of acute energy failure in which there is insufficient ATP production to support

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s­ystemic cellular function. During stress and periods of increased energy demand, glucose is produced from glycogenolysis and gluconeogenesis. Fat metabolism is the secondary source of energy in this scenario. Long chain fatty acids are oxidized and carnitine is utilized to shuttle acetyl coenzyme A (acetyl CoA) into mitochondria. Protein catabolism can also contribute acetyl CoA to the Krebs cycle for energy production. Aerobic metabolism provides 20 times more energy than anaerobic metabolism. Glucose is oxidized to pyruvate via glycolysis (also called the Embden-Meyerhof pathway), generating only two molecules of ATP in the process. When oxygen supply is adequate, pyruvate enters the mitochondria and is converted to acetyl CoA by the pyruvate dehydrogenase enzyme complex, after which it is completely oxidized to CO2 and H2O via the Kreb’s cycle (also known as the tricarboxylic acid or citric acid cycle) and oxidative phosphorylation, generating a net total of 36–38 mol of ATP for every mole of glucose. Conversely, when oxygen supply is inadequate, pyruvate is reduced by NADH and lactate dehydrogenase to lactate, a relatively inefficient process that generates considerably less ATP. Cells do not have the means to store oxygen and are therefore dependent upon a continuous supply that closely matches the changing metabolic needs that are necessary for normal metabolism and cellular function. If oxygen supply is not aligned with these metabolic requirements, hypoxia will ensue, eventually resulting in cellular injury and/or death. As defined above, shock is a state characterized by an inadequate delivery of oxygen and metabolic substrates to meet the metabolic demands of the cells and tissues of the body. Alterations in cellular function and structure result directly from the consequent derangements in cellular metabolism and energy production. Eventually, these derangements lead to cellular necrosis, with subsequent release of proteolytic enzymes and other toxic products which produce a systemic inflammatory response. In practical terms, using this operational definition, a state of shock may result from inadequate oxygen delivery, inadequate substrate delivery (glycopenia), or mitochondrial dysfunction (cellular dysoxia). Oxygen delivery to the cells and tissues is dependent primarily upon three factors: (i) hemoglobin concentration (Hb), (ii) cardiac output (CO), and (iii) the relative proportion of oxyhemoglobin, i.e. percent oxygen saturation (SaO2). Oxygen is transported in the blood combined with hemoglobin, though a relatively small amount is freely dissolved in the plasma fraction of the blood. When fully saturated, each gram of hemoglobin can carry approximately 1.34 mL of oxygen at normal body temperature, such that the oxygen content of arterial blood is determined by Eq. 30.1.



CaO 2 ( g O 2 / mL ) = ( Hb × 1.34 × SaO 2 ) + ( 0.003 × PaO 2 ) (30.1)

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Oxygen delivery (DO2) is therefore determined by Eq. 30.2.

“Supply-dependent’’

“Supply-independent’’

DO 2 = CO × CaO 2 (30.2)

It can easily be shown that one of the most important elements of CaO2 (and hence, tissue oxygen delivery) is the arterial hemoglobin concentration. While oxygen delivery from the left ventricle is linearly related to the hemoglobin concentration, capillary flow may be impaired at an extremely high hematocrit due to increased viscosity of the blood. The optimal hemoglobin concentration to maximize tissue oxygen delivery appears to be around 10 g/dL. Generally, more oxygen is delivered to the cells of the body than the cells actually require for normal metabolism. However, a low cardiac output (stagnant hypoxia), low hemoglobin concentration (anemic hypoxia), or low hemoglobin saturation (hypoxic hypoxia) will result in inadequate delivery of oxygen unless a compensatory change occurs in any of the other factors. Finally, even when oxygen delivery and glucose delivery is adequate, shock may occur as a result of mitochondrial dysfunction. For example, cyanide poisons the oxidative phosphorylation chain preventing production of ATP. Cellular dysoxia (also known as cytopathic hypoxia) may theoretically occur from one or a combination of several mechanisms, including diminished delivery of a key substrate (e.g., pyruvate) to the Kreb’s cycle, inhibition of a key enzyme involved in either the Kreb’s cycle or the electron transport chain, or uncoupling of oxidative phosphorylation. One additional mechanism is through activation of the mitochondrial DNA repair enzyme, poly (ADP-ribose) synthetase, or PARS, which is also commonly known as poly (ADP-ribose) polymerase, or PARP, in which more NAD+ is consumed than ATP is being produced [18–20]. As stated above, under resting conditions, given a normal distribution of cardiac output, global oxygen delivery (Eq.  30.2) is more than adequate to meet the total oxygen requirements of the tissues needed to maintain aerobic metabolism, referred to as oxygen consumption (VO2). This excess delivery or oxygen reserve serves as a buffer, such that a modest reduction in oxygen delivery is more than adequately compensated by increased extraction of the delivered oxygen, without any significant reduction in oxygen consumption. During stress or vigorous exercise, oxygen consumption markedly increases, as does oxygen delivery. Therefore, in the majority of circumstances, the metabolic demands of the cells and tissues of the body dictate the level of oxygen delivery. However, very little oxygen is stored in the cells and tissues of the body. Therefore, as oxygen delivery falls with critical illness, oxygen extraction must necessarily increase to meet metabolic demands, and oxygen consumption remains relatively constant (i.e., delivery-­ independent). However, there is a critical level of oxygen delivery (“critical DO2) at which the body’s compensatory

VO2

“Critical DO2’’ DO2

Fig. 30.1  The oxygen delivery – oxygen consumption relationship. See text for explanation

mechanisms are no longer able to keep up with metabolic needs (i.e. the point at which oxygen extraction is maximal). Once oxygen delivery falls below this level, oxygen consumption must also fall and is said to become supply-­ dependent (Fig. 30.1). This point also corresponds to the so-called anaerobic threshold, the point at which aerobic metabolism shifts to anaerobic metabolism and lactate production increases significantly. Theoretically, oxygen delivery can be augmented by increasing either the cardiac output or the arterial oxygen content.

DO 2 = CO × ( Hb × 1.34 × SaO 2 ) + ( 0.003 × PaO 2 )  (30.3)

However, in clinical practice, global oxygen delivery (as calculated mathematically by the equations above) is not necessarily a true reflection of what occurs at the local tissue capillary beds. Regional oxygen delivery may therefore significantly differ between different tissue capillary beds, such that increasing global oxygen delivery has relatively little effect on augmenting oxygen delivery to different tissue capillary beds (Table 30.2) [21]. This may be one reason (among many) that efforts to improve outcomes by increasing oxygen delivery to supranormal levels have almost universally failed [22–27]. In years past, a so-called pathologic supply-dependency was believed to exist in association with certain disease processes (e.g., sepsis, ARDS, etc.). Early experimental models of sepsis [28–30] and clinical data [31] reported that the critical oxygen extraction ratio was lower than normal during these critical illnesses; that is oxygen consumption became delivery-dependent at a higher critical DO2 in critically ill patients. This observation implied an intrinsic defect at the cellular level in oxygen extraction. However, most of the

30 Shock

375

Table 30.2 Differences in regional blood flow and oxygen ­consumption at rest Regional circulation Cerebral Coronary Renal GI tract and liver Skeletal muscle Skin Other

% Cardiac output 13 4 19 24 21 9 10

% VO2 20 11 7 25 30 2 5

subsequent clinical data on which this concept of a pathologic supply-dependency was based is suspect due to the fact that most of the studies determined oxygen consumption (VO2) using the Fick equation (Eq. 30.4). As can be readily observed, Eqs. 30.3 and 30.4 share several common variables.



 Hb × 1.34 × ( SaO 2 − SvO 2 )  VO 2 = CO ×   (30.4)  +0.003 × ( PaO 2 − PvO 2 ) 

The potential for computation error arises because the measurements of these variables in the calculation of DO2 and VO2 result in a mathematical coupling of measurement errors in the shared variables resulting in false correlation between oxygen delivery and consumption. In order to avoid potential mathematical coupling, oxygen consumption and delivery should be determined independent of each other. Studies in which VO2 was directly measured (rather than calculated using the Fick principle) largely have disproved this pathologic supply dependency hypothesis [32–36]. The true answer, given the stark differences in regional circulation (that are likely compounded during critical illness) probably lies somewhere in the middle. In other words, augmenting oxygen delivery is undoubtedly one of the first and foremost priorities in the management of critically ill children, though until better methods and techniques are available to monitor regional differences in oxygen delivery and consumption, focusing on supranormal levels of oxygen delivery or attempts at titrating therapy to the so-called critical DO2 (i.e. by titrating therapy until oxygen consumption no longer increases, such that the patient is on the supply-independent portion of the oxygen delivery/oxygen consumption curve) is unwarranted.

 ifferences Between Pediatric Shock D and Adult Shock Children are not small adults is an oft repeated axiom in the subspecialty of pediatric critical care medicine. The ­developmental differences between children and adults have very important implications on the pathophysiology and

management of shock and have been reviewed extensively [37–40]. Age-specific differences in hemoglobin concentration and composition, heart rate, stroke volume, blood pressure, pulmonary vascular resistance, systemic vascular resistance, metabolic rate, glycogen stores, and protein mass are the basis for many age-specific differences in the cardiovascular and metabolic responses to shock [15, 37, 41–43]. For example, newborns have a higher hemoglobin concentration (mostly fetal hemoglobin) but low total blood volumes. They also have the highest total body water composition (Fig. 30.2). Newborns have comparatively higher heart rates, lower stroke volumes, near systemic pulmonary artery blood pressures, and higher metabolic rates with high energy needs, but the lowest glycogen stores and protein mass for glucose production [15, 43]. At birth, the normal newborn transitions from fetal to neonatal circulation when inhalation of oxygen reduces pulmonary vascular resistance and allows blood to flow through the lungs, rather than bypass the lungs through the patent ductus arteriosus. When pulmonary circulation is firmly established, the ductus arteriosus closes and newborn circulation is assured. In the presence of shock, acidosis prevents the ductus arteriosus from closing and elevated pulmonary vascular resistance persists. If untreated, persistent pulmonary hypertension results in right ventricular failure with septal bowing and inadequate cardiac output from the left ventricle. Resuscitation of the newborn with shock therefore requires meticulous attention to maintaining (i) adequate heart rates with chronotropes (newborns predominantly have high parasympathetic tone and do not fully develop sympathetic vesicles until the age of 6 months), (ii) blood volume (the newborn only has approximately one cup (approximately 80 mL/kg) of blood [44], and (iii) newborn circulation (using pulmonary vasodilators such as inhaled nitric oxide, and reversing metabolic acidosis). In addition, glucose infusion rates of 8 mg/kg/min or higher are often necessary to prevent hypoglycemia in the presence of low glycogen and protein gluconeogenesis stores. Newborns with refractory shock respond well to extracardiac support life support (ECLS) because mortality is uniformly caused by low cardiac output with high pulmonary and/or systemic vascular resistance. Neonates, infants, and young children also have high systemic vascular resistance and vasoactive capacity, such that hypotension is a very late sign of shock (Fig. 30.3). This is a survival mechanism designed to counterbalance the limited cardiac reserve of the young. For example, neonates and infants, in particular, have relatively decreased left ventricular mass compared to adults [45, 46], as well as an increased ratio of type I collagen (decreased elasticity) to type III collagen (increased elasticity) [47]. In addition, the ­myocardium in neonates and infants functions at a relatively high contractile state, even at baseline [48, 49], such that neonates and infants have a relatively limited capacity to increase stroke

376

D.S. Wheeler and J.A. Carcillo Jr.

Percent of control

140

80 70 60 %Total body water (TBW)

Fig. 30.2  Total body water (TBW), which consists of the intracellular (ICF) and extracellular (ECF) fluid compartments, as a percentage of body weight decreases rapidly with age. The ECF compartment consists of the plasma volume (5 % TBW) and the interstitial volume (15 % TBW). The ECF volume decreases rapidly during the first year of life, while the ICF volume remains relatively constant. Fluid losses usually affect either the interstitial or intracellular compartments. Infants have a proportionately higher ratio of ECF to ICF, which predisposes them to rapid fluid losses. For example, 10 % dehydration in a 6 month-old child weighing 7-kg is equivalent to approximately 700 mL, which is roughly one-tenth the total volume loss required to produce the same degree of dehydration in a 70-kg adult (approximately 7,000 mL fluid loss) [15]

35

50

35

40

40

30 40

20

30 20

10

Newborn

1–12 months Extracellular fluid (ECF)

Vascular resistance

60 Cardiac output

25

25

0

100

20

30

Blood pressure

50 Percent of volume deficit

75

Fig. 30.3  As shown in the figure, children may lose up to approximately 25 % of the blood volume before they become hypotensive. As cardiac output falls, systemic vascular resistance increases, so that mean arterial blood pressure remains constant. Recall that by HagenPoiseuille’s law (analogous to Ohm’s law of electrical current flow), the fluid flow (Q) through a system is related to the pressure drop aross the system divided by the resistance of the system. In other words, Q (cardiac output) = MAP/SVR. Similarly, MAP = Q × SVR. If Q decreases and SVR increases, MAP remains constant

volume during stress [46, 49, 50]. Neonates and infants are therefore critically dependent upon an increase in heart rate to generate increased cardiac output during stress. However, coronary artery (and hence, myocardial) perfusion occurs to the greatest degree during diastole and is directly proportional to the difference between diastolic blood pressure and

1–12 years

Adult

Intracellular fluid (ICF)

left atrial pressure, and inversely proportional to the heart rate (as an indirect measure of diatolic filling time). Under conditions of hypovolemia, an adult can easily double the heart rate from 70 to 140 beats per minute (bpm) to maintain an adequate cardiac output (cardiac reserve); however, the newborn or infant cannot double heart rate from 140 to 280 bpm or 120 to 240 bpm respectively, because these heart rates will not allow adequate coronary artery perfusion. Indeed supraventricular tachycardia with heart rates of 240 bpm or higher frequently lead to inadequate cardiac filling and subsequent poor tissue perfusion. During states of shock, newborns, infants, and children compensate by peripheral vasoconstriction to maintain adequate perfusion to the heart, brain, and kidney, and hypotension is an extremely late and poor p­ rognostic sign. These differences between pediatric and adult shock are perhaps best illustrated by a now classic study by Ceneviva and colleagues [51]. These investigators categorized 50 children with (in this case) fluid-refractory septic shock according to hemodynamic state, based upon hemodynamic data obtained with the Pulmonary Artery (PA) catheter, into one of three possible cardiovascular derangements (i) a ­hyperdynamic state characterized by a high cardiac output (>5.5 L/min/m2 BSA) and low systemic vascular resistance (8 mmHg). In contrast to adults in which the early stages of septic shock is characterized by a high cardiac output and low SVR, most of these children were in a hypodynamic state characterized by low cardiac output and high systemic vascular resistance (cold shock) and required the addition of vasodilators to decrease SVR, increase CI, and improve peripheral perfusion [51]. Children with low cardiac output (as defined by a cardiac index less than 2.0 L/min/ m2 BSA) had the highest risk of mortality. These findings have been confirmed in multiple studies using a variety of methods to measure cardiac output and vascular resistance [52–58]. Collectively, these studies all point to the fact that hypotension in children is a very late sign that portends a poor prognosis. Moreover, children more commonly present with cold shock, as opposed to warm shock. Early recognition and appropriate treatment (guided to the relevant hemodynamic derangements) of children with shock is therefore crucial.

Pathophysiology of Shock Hemodynamic Relationships in Shock An understanding of the relationship between flow (i.e. cardiac output), perfusion pressure (i.e. mean arterial blood pressure [MAP] – central venous pressure [CVP]), and vascular resistance (systemic vascular resistance, or SVR) is vital to the understanding of the pathophysiology of shock. Hagen-Poiseuille’s Law (analogous to Ohm’s Law of electrical flow) states that flow (i.e. cardiac output) is directly proportional to the pressure difference (MAP-CVP), i.e. perfusion pressure (or driving pressure) divided by the resistance.

CO = ∆P / R = ( MAP − CVP ) / SVR

(30.5)

Under ideal laminar flow conditions, in which vascular resistance is independent of flow and pressure, the relationship between pressure, flow, and resistance is shown by Fig.  30.4. In other words, an increase in resistance will decrease blood flow at any given perfusion pressure (and vice versa). At any given blood flow, an increase in resistance will increase the perfusion pressure (and vice versa). This relationship does not hold under conditions of turbulent (or pulsatile) flow, as turbulence decreases the flow at any given pressure according to Hagen-Poiseulle’s Law. The perfusion pressure may be a more important determinant of flow than blood pressure alone. According to

Low resistance

Flow

High resistance

Perfusion Pressure (MAP - CVP)

Fig. 30.4  The relationship between pressure, flow, and resistance

Eq. 30.5, one can theoretically have a normal MAP but no forward flow (CO), e.g. if CVP is equal to MAP (which would of course be rare and catastrophic). Conceptually, however, when fluid resuscitation is used to improve blood pressure, the increase in MAP must be greater than the concomitant increase in CVP. If the increase in MAP is less than the increase in CVP then the perfusion pressure is actually reduced, and hence cardiac output is reduced. Inotropic agents, and not additional fluid resuscitation, are indicated to improve cardiac output in this scenario. Understanding this relationship helps guide the management of blood flow reflected as cardiac output. Cardiac output can be decreased when perfusion pressure (MAP-CVP) is decreased, but it can also be decreased when the perfusion pressure (MAP-CVP) is normal and vascular resistance is increased (by Eq. 30.5). Hence, children with normal blood pressure can have inadequate cardiac output because systemic vascular tone is too high. Cardiac output can be improved in this scenario with the use of inotropes, vasodilators, and volume loading. The cardiovascular pathophysiology of shock can therefore be attributed either to reduced cardiac output, reduced perfusion pressure (MAP-CVP or DBP-CVP), or both. Reduced cardiac output is caused either by reduced heart rate or reduced stroke volume caused by hypovolemia (inadequate preload), decreased contractility (insufficient inotropy), or excess vascular resistance (increased afterload). Reduced perfusion pressure can be caused by reduced MAP or increased CVP.

Compensatory Mechanisms in Shock Following the onset of hemodynamic dysfunction, several homeostatic compensatory mechanisms (summarized in Table 30.3) are initiated in an attempt to maintain end organ perfusion and function. Many of these compensatory mechanisms can be clinically recognized during the early stages

378 Table 30.3  Compensatory responses to the shock state 1. Mechanisms to maintain effective circulating blood volume  (a) Decreased venous capacitance (via venoconstriction)    Increased sympathetic tone    Release of epinephrine from the adrenal medulla    Increased angiotensin II (activation of the renin-angiotensinaldosterone axis)    Increased circulating vasopressin via release from the posterior pituitary gland  (b) Decreased renal fluid losses    Decreased Glomerular Filtration Rate (GFR)    Increased aldosterone release (activation of the renin-angiotensin-aldosterone axis)    Increased vasopressin release from the posterior pituitary gland  (c) Fluid redistribution to the vascular space    Starling effect (fluid redistribution from the interstitial space)    Osmotic effect (fluid redistribution from the intracellular space) 2. Mechanisms to maximize cardiac performance  (a) Increase heart rate    Increased sympathetic tone    Release of epinephrine from the adrenal medulla  (b) Increase contractility    Increased sympathetic tone    Release of epinephrine from the adrenal medulla   (c) Increased Frank-Starling mechanism (increased preload = increased cardiac output)    Decreased venous capacitance (see above)    Decreased renal losses of fluid (see above)    Fluid redistribution to the vascular space (see above) 3. Mechanisms to maintain preferential perfusion to the vital organs (dive reflex)   (a) Extrinsic regulation of systemic arterial tone   (b) Autoegulation of vital organs (brain, heart, kidneys) 4. Mechanisms to optimize conditions for oxygen unloading   (a) Increased concentration of red blood cell 2,3-DPG   (b) Tissue acidosis (Bohr Effect)   (c) Decreased Tissue PO2

of shock. The progression of shock is commonly divided into three phases: compensated, uncompensated, and irreversible shock [10, 11] (Table 30.4). During compensated shock, oxygen delivery to the brain, heart, and kidney is often maintained at the expense of less vital organs. Signs and symptoms of the shock state, though often subtle, may be apparent even at this early stage. Notably, hypotension is not a feature during this stage – rather, increased peripheral vascular tone and increased heart rate maintain a normal cardiac output and a normal blood pressure. As shock progresses to the uncompensated stage, the body’s compensatory mechanisms eventually contribute to the further progression of the shock state (e.g., blood is shunted away from the skin, muscles, and gastrointestinal tract in order to maintain perfusion of the brain, heart, and kidneys, leading to ischemia in these vascular beds with subsequent release

D.S. Wheeler and J.A. Carcillo Jr.

of toxic substances, further perpetuating the shock state). Cellular function deteriorates further, culminating in endorgan dysfunction. The terminal or irreversible stage of shock implies irreversible organ injury, especially of the vital organs (brain, heart, and kidneys). Intervention at this late stage is unsuccessful, and death occurs even if therapeutic intervention restores cardiovascular measurements such as heart rate, blood pressure, cardiac output, and oxygen saturation to normal.

Functional Classification of Shock Hinshaw and Cox [44] proposed a classification scheme for shock in 1972 that is still relevant today. The four major categories of shock include (i) hypovolemic shock (shock as a consequence of inadequate circulating volume), (ii) obstructive shock (shock caused by obstruction of blood flow to and from the heart), (iii) cardiogenic shock (shock caused by primary pump failure), and (iv) distributive shock (shock caused by maldistribution of the circulating volume) (Table 30.5). Notably, distributive shock encompasses septic shock, anaphylactic shock, and neurogenic shock (all subtypes of vasodilatory shock) [59]. This classification scheme is relatively arbitrary, especially when viewed in the context that different features of each category may be present at the same time (e.g. septic shock is often characterized by manifestations of hypovolemic shock, cardiogenic shock, and distributive shock). However, this kind of simplistic view of the different types of shock can provide valuable information about the pathophysiological alterations involved, and knowledge of these pathophysiological alterations can then be used to guide appropriate management.

Hypovolemic Shock Hypovolemic shock is the most common cause of shock in children and claims the lives of millions of children each year worldwide [10, 15, 60–63]. Diarrheal illnesses leading to dehydration and hypovolemic shock account for as many as 30 % of all deaths in infants and young children worldwide. Dengue shock syndrome (DSS) is another important cause of hypovolemic shock worldwide [64, 65]. Nearly 8,000 children less than 5 years of age die every day from dehydration and hypovolemic shock [60, 61, 66]. While diarrheal illnesses are an important cause of hypovolemic shock in children in developing nations, hypovolemic shock is an important problem that affects children in the U.S. and other developed nations as well [67]. For example, hypovolemic shock accounts for nearly 10 % of all hospital admissions and 300 annual deaths in children younger than 5 years of age in the U.S. alone [60, 68].

30 Shock

379

Table 30.4  Stages of shock Organ system Central nervous system

Heart

Lungs Kidneys

Gastrointestinal tract

Liver Hematologic

Metabolic

Immune system

Compensated shock Agitation Anxiety   ↓ Lethargy Somnolence Tachycardia

Tachypnea Increased WOB Oliguria ↑ urinary osmolality ↑ urinary sodium FENa 16 mEq/L can be used as a surrogate marker for ATP depletion and energy failure. When oxygen delivery is inadequate, anaerobic metabolism occurs through glycolysis with pyruvate being converted to lactate and lactic acid, which is largely responsible for the anion gap. Glycopenic shock can be diagnosed when an anion gap exists in the presence of hypoglycemia (inadequate substrate), hyperglycemia (insulin resistance), or euglycemia (inadequate substrate + insulin resistance). When glucose utilization is inadequate, the anion gap is caused by organic acid intermediates produced by catabolism of protein and or fat to fuel the Krebs cycle. It cannot be over-emphasized that early recognition of shock is critical as time-sensitive, early reversal of clinical signs of shock has been shown to influence outcomes in critically ill patients. In adults, Rivers and colleagues [102] demonstrated the importance of early goal-directed therapies, which maintain not only blood pressure but also oxygen delivery, in improving outcome [102–107]. In this study, adults presenting to the emergency department in severe sepsis or septic shock were randomized early on to receive either therapies directed at achieving normal blood pressure or therapies directed towards achieving not only normal blood pressure but also a superior vena cava (SVC) oxygen saturation ≥70 %. In this latter arm, investigators used packed red blood cell transfusion (for patients with a hemoglobin less than 10 g/dL to reverse anemic shock) and/ or fluids and inotropic support (to reverse ischemic shock) if the SVC saturation remained less than 70 %. The theory behind this approach is based on the concept of oxygen delivery reviewed above in which DO2 depends on oxygen carrying capacity (hemoglobin), oxygen content of arterial blood (percent oxyhemoglobin plus dissolved oxygen), and cardiac output. Thus, if the hemoglobin and arterial oxygen saturation are normal, then cardiac output predominantly determines oxygen delivery. As cardiac output decreases and metabolic demands remain the same, the mitochondria extract more oxygen to maintain a similar amount of energy production; therefore, the oxygen saturation of blood returning to the heart (normally ~75 %) decreases. Rivers et al. [102] observed that patients in the first arm attained a normal blood pressure but had an average SVC oxygen saturation of only 65 %. In contrast, those in the second treatment arm received more blood transfusions, fluid resuscitation, and inotrope use to both maintain normal blood pressure and achieve an SVC saturation >70 %. Of note, this early

30 Shock

(within 6 h), goal-­directed (SVC saturation >70 %) therapy resulted in a nearly 50 % reduction in mortality. In a second analysis of this study, the authors evaluated patients who had shock characterized by tachycardia and decreased SVC O2 saturation with normal or high blood pressure. Interestingly, these patients had higher mortality rates than those patients presenting with hypotension. When this group of patients with tachycardia, low SVC O2 saturation, and normotension were evaluated by treatment arms, those who received therapies directed towards a goal SVC O2 saturation >70 % had reduced multiple organ failure and mortality. The authors described this type of shock without hypotension as cryptic or ischemic shock. Ischemic shock without hypotension can be represented by the following equation: Decreased cardiac output = (normal or high mean arterial pressure – central venous pressure)/ increased systemic vascular resistance. Their data suggests that reversal of this normotensive ischemic shock can reduce organ failure and mortality. De Oliviera and colleagues also demonstrated similar findings in a randomized interventional trial in children with septic shock. In the control arm, therapies were directed to normalizing capillary refill time and blood pressure. In the intervntional arm, therapies were also directed to maintaining an SVC O2 sat >70 %. This intervention resulted in the use of more fluid resuscitation, blood tranfusions, and intrope and vasodilator infusions, as well as a reduction in mortality from 39 to 12 % [108]. Emergency departments place central lines for measurement of SVC oxygen saturations less frequently in children than in adults making a corresponding study in children unlikely, though the feasibility of this approach in adults has been confirmed by multiple studies [109–114]. However, in a similar manner, a recent landmark study showed that the predominant factor that reduces mortality and neurologic morbidity in children transported to tertiary care pediatric hospitals is the reversal of shock through early recognition and resuscitation in the referring emergency department [115]. In this study, Han and colleagues examined early goal directed therapy for neonatal and pediatric shock in community hospital emergency departments, using prolonged capillary refill >2 s as a practical though inferior surrogate marker of decreased SVC O2 saturation. In all patients with shock, both mortality and morbidity increased with the following progression of clinical signs: tachycardia alone → hypotension with normal capillary refill → prolonged capillary refill without hypotension → and finally, the combination of prolonged capillary refill with hypotension (which carried the highest mortality risk). Reversal of these clinical signs in the emergency department reduced mortality and morbidity by more than 50 % and each hour that passed without reversal of hypotension or reduction in capillary refill was associated with a twofold increased odds ratio of death. Thus, the ability to both

385

r­ecognize and reverse shock in children may be the most important lessons to be learned in the practice of pediatric critical care medicine.

 herapeutic Endpoints of Resuscitation T in Pediatrics Traditional Endpoints Resuscitation to clinical goals remains the first priority in the management of shock. Children should be resuscitated to normal mental status, normal pulse quality proximally and distally, equal central and peripheral temperatures, capillary refill 1 mL/kg/h. Many of these clinical features of shock lack interrater reliability and validity, especially when used as “stand alone” therapeutic endpoints [116–121]. However, serial examination of multiple clinical features by the same clinician can be used to effectively identify and monitor children with shock [122]. Because 20 % of blood flow goes to both the brain and the kidney, clinical assessment of the function of these two organs can be informative and a normal mental status and urine output generally suggest adequately compensated oxygen delivery. However, the clinician should not necessarily be reassured by a normal mental status, as altered mental status is a very late sign of shock. Distal pulse quality, temperature, and capillary refill reflect systemic vascular tone and cardiac output. Normal capillary refill and toe temperature assures a cardiac index greater than 2.0 L/min/m2 and superior vena cava oxygen saturation ≥70 % [123]. Fluid resuscitation should be monitored using a combination of physical exam findings (palpation of the liver edge, increasing tachypnea, onset of basilar rales on auscultation, etc.) in addition to monitoring tools (central venous or atrial pressures) as surrogate indicators of when fluid resuscitation has likely been adequate and it is necessary to initiate inotropic therapy. The predictive hemodynamic response to a fluid bolus can often be ascertained by applying gentle but constant pressure over the liver in the right upper quadrant to provide an auto transfusion while assessing the immediate hemodynamic response in terms of heart rate and blood pressure changes. The recent studies referenced above add support to the concept that titrating resuscitation to simple clinical parameters is likely to be as effective as utilizing advanced hemodynamic parameters such as SVC O2 saturation. Normal heart rate and perfusion pressure for age (MAP-­ CVP) should be the initial hemodynamic goals. Fluid resuscitation can be monitored by observing the effects on heart rate and MAP-CVP. The heart rate should decrease and MAP-CVP increase when fluid resuscitation is effective. In contrast, the heart rate may increase and MAP-CVP will narrow if too much fluid is given. The shock index (HR/SBP)

386 Fig. 30.5 (a) Max Harry Weil’s “5-2 Rule” for CVP-titrated Fluid Management. A volume of 50, 100, or 200 mL of fluid (depending upon the initial CVP) is administered through a peripheral intravenous catheter over 10 min. If at any time during the administration of this fluid the CVP rises by more than 5 cmH2O, the infusion should be stopped. Following the infusion, the “5-2” rule is applied. If the CVP has risen by more than 2 cm, but less than 5 cm, the patient should be monitored at 10 min intervals. If the CVP has risen by more than 2 cm and remains elevated, no additional fluid is administered. If the CVP has declined to within 2 cm of the initial value, another fluid challenge (again, the amount will depend upon the CVP) is administered. (b) Max Harry Weil’s “7-3” Rule for PAOP-titrated Fluid Management. A volume of 50, 100, or 200 mL of fluid (depending upon the initial PAOP) is administered through a peripheral intravenous catheter over 10 min. If at any time during the administration of this fluid the PAOP rises by more than 7 cmH2O, the infusion should be stopped. Following the infusion, the “7-3” rule is applied. If the PAOP has risen by more than 3 cm, but less than 7 cm, the patient should be monitored at 10 min intervals. If the PAOP has risen by more than 3 cm and remains elevated, no additional fluid is administered. If the PAOP has declined to within 3 cm of the initial value, another fluid challenge (again, the amount will depend upon the PAOP) is administered (Reprinted from Weil and Henning [130]. With permission from Wolters Kluwer Health)

D.S. Wheeler and J.A. Carcillo Jr.

a

Observe CVP for 10 min

CVP < 8 cmH2O

CVP < 14 cmH2O

200 mL × 10 min

CVP ≥ 14 cmH2O

100 mL × 10 min

↑ CVP > 5 cmH2O

During Infusion 0–9 min

STOP

Wait 10 min and repeat STOP Repeat infusion

CVP > 2 cm < 5 cm CVP > 2 cm persists CVP ≤ 2 cm

After Infusion 0–9 min

50 mL × 10 min

b

Observe PAOP for 10 min

CVP < 12 cmH2O

200 mL × 10 min

During Infusion 0–9 min

After Infusion 0–9 min

[107, 124–128] can also be used to assess the effectiveness of fluid and inotrope therapy. If the applied therapy (e.g. preload or inotropy) increases the stroke volume, then the heart rate will decrease and systolic blood pressure will increase resulting in a lower shock index value. However, if stroke volume does not improve with resuscitation then heart rate will not decrease, systolic blood pressure will not increase, and shock index will not improve.

Cardiac Filling Pressures Both the right-sided cardiac filling pressures (central venous pressure, CVP; right atrial pressure) and left-sided cardiac filling pressures (pulmonary artery occlusion pressure, PAOP, also known as the wedge pressure and/or

CVP < 16 cmH2O

100 mL × 10 min

CVP ≥ 16 cmH2O

50 mL × 10 min

↑ PAOP > 7 cmH2O STOP

PAOP > 3 cm < 7 cm PAOP > 3 cm persists PAOP ≤ 3 cm

Wait 10 min and repeat STOP Repeat infusion

p­ ulmonary capillary wedge pressure; left atrial pressure) have also been used as therapeutic endpoints of resuscitation [118, 129]. For example, Max Harry Weil developed a resuscitation protocol based upon CVP and PAOP in the early days of critical care medicine (Fig. 30.5) [130]. Importantly, the site in which CVP is measured (femoral vein, internal jugular vein, subclavian vein) does not matter, as the CVP measured in the femoral vein appears to adequately approximate right atrial pressure in children, particularly in the absence of intra-­abdominal pathology [131–135]. Unfortunately, the vast majority of clinical studies have shown that CVP does not reliably or accurately predict fluid responsiveness in critically ill patients [136, 137]. In addition, a meta-analysis of 13 randomized clinical trials showed that invasive hemodynamic monitoring with the pulmonary artery catheter (PAC) increased overall

30 Shock

­ ortality in critically ill patients [138]. Finally, a multim center, randomized clinical trial comparing PAC-guided therapy versus central venous catheter (CVC)-guided therapy in critically ill adults with acute lung injury showed that use of the PAC increased complications and hospital costs without improving outcome [139, 140]. However, it should be noted that CVP was used as a resuscitation endpoint in the Early Goal-Directed Therapy trial of severe sepsis/septic shock [102], as well as the Surviving Sepsis Campaign [113, 114]. Therefore, it would seem that cardiac filling pressures should not be used as the sole therapeutic endpoint of resuscitation, but as part of an entire set of resuscitation endpoints. Importantly, there are few (if any) randomized, controlled trials of CVP- or PAOP-titrated fluid management in critically ill children with shock, and any current recommendations are based upon anecdotal experience and translation from adult studies.

 enous Oximetry and Near-Infrared V Spectroscopy In the era of early goal-directed therapy, an increasing number of pediatric intensivists are placing superior vena cava (SVC) central venous catheters in order to monitor SVC oxygen saturation (SVC O2). Due to the increased relative size and weight of the head versus the body in infants and young children, blood flow through the SVC comprises a much larger percentage of total cardiac output compared to the inferior vena cava (IVC) [76], perhaps making SVC O2 an ideal therapeutic endpoint in children. The SVC O2 (directly measured via co-oximetry) has a reasonable correlation with the mixed venous oxygen saturation [141]. There is a commercially available central venous catheter (PediaSat Oximetry Catheter, Edwards Life Sciences, Irvine, CA) with a sensor on the tip that continuously measures SVC O2 [142– 145]. However, there remains some question as to the accuracy of these catheters, particularly at lower SVC O2 (70 % is an oft quoted goal. Similar to the approach in adults, the critically ill child in shock should be transfused if the hemoglobiin is sub-optimal and if normalized, then inotropes and vasodilators can be used to improve cardiac output until the SVC saturation is >70 %.

387

AVDO2 An additional target sometimes used by clinicians is to maintain a normal arterial to venous oxygen content difference, the so-called AVDO2. The AVDO2 can be calculated as follows: CaO 2 = (1.39 × Hgb ) × art.saturation + ( PaO 2 × 0.003) = ml O 2 /100 ml blood (30.6) CvO 2 = (1.39 × Hgb ) × ven.saturation + ( PvO 2 × 0.003) = ml O 2 /100 ml blood (30.7)

AVDO 2 ( ml O 2 /100 ml blood ) = CaO 2 − CvO 2 (30.8)

Typical normal values (Hgb  =  14, paO2 90 and SaO2 = 100  %, pvO2 40 and SvO2 = 75 %) would show an average difference of usually less than 5 ml O2/ 100 ml blood which corresponds to a saturation difference of 25 %. When the AVDO2 is greater than 5, suggesting increased oxygen extraction because of inadequate oxygen delivery (i.e. an oxygen deficit), then cardiac output should be increased with inotrope and vasodilator therapy until the AVDO2 returns to the normal range. The AVDO2 is most accurately determined when the venous saturation is measured in the pulmonary artery. In these circumstances, cardiac output can be measured using either the pulmonary artery catheter and thermodilution or PICCO as reviewed in the chapter on Hemodynamic Monitoring, later in this textbook. In this setting, a typical goal cardiac index is ≥2.5 L/min/m2 in cardiogenic shock and between 3.5 and 6.0 L/min/m2 in septic shock. Furthermore, with the aid of either a pulmonary artery catheter (to measure the capillary wedge pressure as an estimate of LVEDP) or a left atrial catheter (as commonly provided by the cardiac surgeon), these surrogates of LVEDP can be trended to that value at which the best cardiac output can be achieved. For example, higher filling pressures may be required to attain the required end diastolic volume to achieve optimal stroke volume in a non-compliant, post-­ operative myocardium that can be determined during the wean from cardiopulmonary bypass.

Lactate Many clinicians use lactate as a serum measure of anaerobic metabolism [152–155]; however, lactate can be elevated by a number of conditions in the absence of shock, including metabolic disorders, lymphoproliferative disorders, liver failure, and sepsis. Following lactate levels has been most useful in the setting of pre-operative and post-operative cardiogenic shock (although levels can be increased even in the absence

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of the low flow state). For these patients, mortality risk increases as serum lactate levels rise above 2.0 mmol/L. More helpful may be trending the change in lactate, as it has been shown that a change in lactate level of ≥0.75 mmol/L per hour was associated with worse outcomes and was superior to predicting a poor outcome (89 % sensitivity, 100 % specificity and a 100 % positive predictive value) as compared to single worse values [156]. When used as a hemodynamic goal, a diminishing value over time with an ultimate value 30 % [173]. The blood viscosity increased substantially and reduced blood flow through glass capillaries of fixed diameter as the hematocrit increased. Based on their results, these investigators calculated that the hematocrit for optimal oxygen delivery was around 30 %. Experimental evidence in animals has further suggested that viscosity begins to compromise blood flow at hematocrits approaching 40–45 % [172]. Again, it is interesting to note that one of the therapeutic endpoints in the EGDT trial was a hematocrit of 30 % [102].

Vasoactive Medications There are several different vasoactive medications (Table  30.9) that are commonly used in the PICU [174]. These are routinely placed into different categories based upon their principal hemodynamic effect. Inotropic agents (inotropes) are used to increase contractility and as a result, stroke volume and cardiac output. Most of the inotropic agents are adrenergic receptor agonists and include both endogenously produced catecholamines (e.g. dopamine,

Table 30.9  Vasoactive pharmacologic agents commonly used in the management of pediatric shock Agent Dopaminea, b, c

Dose range 3–5 μg/kg/min

5–10 μg/kg/min 10–20 μg/kg/min Dobutaminea, b

5–10 μg/kg/min

Epinephrinea, b

0.03–0.1 μg/kg/min

0.1–1 μg/kg/min Norepinephrinea, b

0.1–1 μg/kg/min

Phenylephrinea, b, d

0.1–0.5 μg/kg/min

Vasopressina, b, e

0.0003–0.002 units/kg/min (0.018–0.12 units/kg/h) 0.5–3 μg/kg/min

Nitroglycerina, d, f

Comments Renal-dose dopamine (primarily dopaminergic agonist activity); increases renal and mesenteric blood flow, increases natriuresis and urine output Inotropic (β1 agonist) effects predominate; increases cardiac contractility, heart rate, and blood pressure Vasopressor (α1 agonist) effects predominate; increases peripheral vascular resistance and blood pressure Inotropic effects (β1 agonist) predominate; increases contractility and reduces afterload Inotropic effects (β1 and β2 agonist) predominate, increases contractility and heart rate; may reduce afterload to a slight extent via β2 effects Vasopressor effects (α1 agonist) predominate; increases peripheral vascular resistance and blood pressure Potent vasopressor (α1 and β1 agonist); increases heart rate, contractility, and peripheral vascular resistance; absent β2 effect distinguishes it from epinephrine Potent vasopressor with primarily α1 agonist effects; indicated in tetralogy of Fallot hypercyanotic spells (tet spells) Vasopressor (via V1) without inotrope activity; may be indicated in refractory shock Dose dependent venodilator and vasodilator (cGMP mediated) (continued)

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D.S. Wheeler and J.A. Carcillo Jr.

Table 30.9 (continued) Agent Nitroprussidea, g Inamrinonea, h

Dose range 0.5–3 μg/kg/min 0.75 mg/kg I.V. bolus over 2–3 min followed by maintenance infusion 5–10 μg/kg/min Milrinonea, i 50 μg/kg administered over 15 min followed by a continuous infusion of 0.5–0.75 μg/kg/min Prostaglandin E1 (PGE1)j 0.3–0.1 μg/kg/min

Comments Systemic arterial vasodilator (c GMP mediated) Inodilator (Type III phosphodiesterase inhibitor); increases cardiac output via increased contractility and afterload reduction Inodilator (Type III phosphodiesterase inhibitor); increases cardiac output via increased contractility and afterload reduction Maintains patent ductus arteriosus (cAMP effect)

Correct volume depletion prior to starting infusion Extravasation may produce tissue necrosis (as a general recommendation, should be administered via central venous access). Treatment with subcutaneous administration of phentolamine as follows:  Neonates: infiltrate area with a small amount (e.g., 1 mL) of solution (made by diluting 2.5–5 mg in 10 mL of preservative free NS) within 12 h of extravasation; do not exceed 0.1 mg/kg or 2.5 mg total  Infants, children, and adults: infiltrate area with a small amount (eg, 1 mL) of solution (made by diluting 5–10 mg in 10 mL of NS) within 12 h of extravasation; do not exceed 0.1–0.2 mg/kg or 5 mg total c Dopamine has exhibited nonlinear kinetics in children (dose changes may not achieve steady-state for approximately 1 h, compared to 20 min in adults) d Exhibits rapid tachyphylaxis (dose may need to be increased with time to achieve same clinical effect) e Dose not well established in children or adults; abrupt discontinuation of infusion may result in hypotension (gradually taper dose to discontinue the infusion); May be associated with profound peripheral vasoconstriction (leading to tissue ischemia) f May cause profound hypotension in volume-depleted patients; nitroglycerin adsorbs to plastics; I.V. must be prepared in glass bottles and special administration sets intended for nitroglycerin (nonpolyvinyl chloride) must be used g Converted to cyanide by erythrocyte and tissue sulfhydryl group interactions; cyanide is converted in the liver by the enzyme rhodanase to thiocyanate (thiocyanate levels should be monitored) h Metabolized in the liver; causes thrombocytopenia (may be dose-related); milrinone is now preferred agent i Metabolized in the kidney; relatively long half-life (use with caution in children with hemodynamic instability) j Dose may be decreased once the ductus arteriosus has opened with very little change in therapeutic effects; may cause hypotension, apnea, cutaneous flushing a

b

e­ pinephrine, and norepinephrine) as well as synthetic analogs (e.g. dobutamine). The exceptions to this pharmacologic mechanism are agents that inhibit type III phosphodiesterase (e.g. inamrinone, milrinone, and enoximone), resulting in elevated cAMP, as well as those agents that increase sensitivity of the myofilament to calcium (e.g. levosimendan). Vasodilators are used to decrease systemic vascular resistance (recall again that CO = MAP/SVR, so that by reducing SVR, CO will increase). The most commonly used vasodilators are nitroprusside and nitroglycerin. Vasopressors are used to increase systemic vascular resistance, in order to increase perfusion pressure (discussed above). Most of the currently available vasopressors are adrenergic receptor agonists (e.g., dopamine, epinephrine, norepinephrine, phenylephrine).

Inotropes Most of the currently available inotropes act through either direct stimulation of the adrenergic receptors or through inhibition of phosphodiesterases to increase cAMP. Adrenergic receptors fall into three categories: α-adrenergic, β-adrenergic and dopaminergic (DA) receptors. The receptors responsible for inotropic stimulation are the β1-­ adrenoreceptors located on the myocardium, while the β2-receptors exist on the vascular and bronchial smooth muscle and mediate vaso- and broncho- dilation, respectively. α-adrenoreceptors include the α1 subtype located on peripheral vasculature and stimulation mediates smooth muscle

contraction and thus, vasopressor effects (discussed below). Following their initial descriptions α2-receptors were identified on the presynaptic terminals of sympathetic nerves and stimulation inhibited norepinephrine release. They have also been identified on postsynaptic smooth muscle where stimulation results in contraction, though the contribution of this mechanism to vasopressor effects of adrenergic agonists is not fully known [175]. From a pharmacokinetic standpoint, nearly all the inotropes used clinically are cleared by first-­ order kinetics, such that changes in infusion rates linearly correlate to plasma concentrations, making them practical to titrate to clinical effect. In addition, the adrenergic receptor agonists are rapidly metabolized by circulating catechol-O-­ methyltransferase (COMT) followed by deamination (via monoamine oxidase) or sulfoconjugation (by phenolsulfotransferase) such that effective half-life of these agents is on the order of minutes. Therefore, these agents are preferably administered via continuous infusion – most commonly via a central venous catheter. Of note, the phosphodiesterase inhibitors are cleared by the kidneys (requiring dosage adjustments in renal failure) and possess a half-life estimated to be 45–60 min.

Dopamine Historically, the mainstay of inotropic therapy in pediatrics has been dopamine which is the immediate precursor in the catecholamine biosynthetic pathway. Because of its unique properties of being able to stimulate dopaminergic (0–3 μg/

30 Shock

kg/min), β-adrenergic (3–10 μg/kg/min) and α-adrenergic receptors (>10 μg/kg/min) in a dose-dependent manner, some clinicians refer to this agent as an inovasopressor, as both inotropic and vasopressor activity can be observed with escalating dosage. The pharmacologic effect of dopamine is derived from two relatively equipotent properties – direct agonist stimulation of the receptors and indirect release of norepinephrine from the sympathetic vesicles. Because infants less than 6 months have been considered to not possess their full number of sympathetic vesicles (corroborated in studies of immature animals), it has been suggested that there is a relative age-specific insensitivity to the drug, such that increased infusion rates may be necessary [176]. However, this data remains controversial in that Seri et al. [177] have demonstrated clear physiologic responses to normal dopamine infusion rates (3–7 μg/kg/min) in premature infants. Relative dopamine insensitivity can also be observed in older children and adults who may have exhausted endogenous catecholamine reserves because of prolonged stress responses prior to reaching the clinical care setting. When infused at 3–10 μg/kg/min, dopamine increases cardiac contractility and cardiac output with only modest effects on heart rate and systemic vascular resistance. Because of its general effectiveness and the vast familiarity and experience with this agent, dopamine has remained the first line inotropic agent for fluid refractory shock. Infusion rates can be increased gradually in order to titrate its inotropic effect to the goals outlined above. Surveys of common practice suggest that while infusion rates as high as 40 μg/ kg/min have been reported, most clinicians stop escalating at 20 μg/kg/min and choose instead to add a second vasoactive agent. It should also be noted that dopamine administration through a peripheral intravenous catheter is not any safer compared to other vasoactive medications, as is commonly believed. Because of the imprecise ability to differentiate infusion rates mediating strictly inotropic effects from vasopressor effects during the transition from β to α-adrenergic receptor stimulation, some clinicians express concern for the use of dopamine alone in cardiogenic shock. Though relatively few studies have been performed, it has been suggested that because dopamine alone increases not only mean arterial blood pressure, but also pulmonary capillary wedge pressure and myocardial oxygen extraction, clinicians consider adding a vasodilator (e.g. dobutamine) as the combination may be more beneficial than dopamine alone in this setting [178]. Another major effect of dopamine is to selectively increase renal and splanchnic perfusion. However, the ascribed renal protective effect of renal-dose dopamine has not been substantiated in several large clinical trials designed to examine this possible benefit and more likely to be related to modest improvements in cardiac output associated with even low infusion rates [179].

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Dopamine, similar to most inotropic agents, will worsen ventilation/perfusion matching such that intrapulmonary shunt increases and as a result, PaO2 may decrease. In addition, dopamine also inhibits prolactin secretion [180], which may have adverse results on the host immune response [181]. Finally, dopamine has been shown to increase VO2 and oxygen extraction to a greater extent than the improvements observed in cardiac output and DO2 in critically ill children following the Norwood procedure [182]. As an interesting aside, a multicenter, cohort study in critically ill adults with sepsis noted that patients who were treated with dopamine had a higher mortality compared to those who were treated with other agents [183]. Moreover, a meta-analysis of studies comparing dopamine to norepinephrine in critically ill adults with severe sepsis/septic shock again showed that dopamine increases mortality [184]. However, while the evidence against dopamine is growing, dopamine remains the first-­ line vasoactive medication in many PICUs.

Dobutamine Dobutamine is an inotropic agent synthetically derived from the catecholamine parent structure that possesses mixed β-receptor agonist activities. Thus, dobutamine possesses both chronotropic and inotropic properties mediated through β1-adrenergic receptor stimulation as well as modest vasodilating effects related to its β2-adrenergic receptor agonist property. The limitation of vasodilating effects relate to its preparation as a racemic mixture where the (+) isomer has potent effects at the β-receptor and modest α-adrenergic antagonist effects, but conversely the (−) isomer is a selective α1-adrenergic receptor agonist mediating vasoconstrictor effects [185]. In addition, it has been observed that at infusion rates >10 μg/kg/min, dobutamine can lead to significant afterload reduction and at times hypotension. This is thought to occur because dobutamine at this infusion rate may possess α2 agonist effects which inhibit release of norepinephrine from the pre-synaptic terminals to further reduce vascular tone. Similar to dopamine, there may be an age-­specific insensitivity to dobutamine in children. Perkin and co-workers demonstrated that children under the age of 2 years have a reduced response to dobutamine [186]. Despite these complex properties, the primary hemodynamic effects are to increase contractility, most often with little change in the heart rate or mean arterial blood pressure despite substantial increases in cardiac output. Because of these properties, dobutamine is most commonly indicated in the clinical setting that necessitates increasing inotropy without augmenting systemic vascular resistance, as occurs most commonly with pure cardiogenic shock (e.g. myocarditis). In these cases, dobutamine will increase stroke volume while decreasing central venous pressure and often improves the ratio between myocardial oxygen supply and demand. However, a growing body of evidence suggests that inotropic

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agents, such as dobutamine and milrinone increase long-­term mortality in patients with heart failure, leading many experts to recommend against their use in this setting [187–190].

D.S. Wheeler and J.A. Carcillo Jr.

e­noximone, or pentoxyfilline) and/or cGMP (Type V PDE inhibitors, e.g. sildenafil, dipyrimadole, or pentoxyfilline). When type III PDE inhibitors are administered alone, the increase in cAMP improves contractility and also causes Epinephrine vasodilation of pulmonary and systemic arterial vasculature Epinephrine is the endogenous circulating neurohormone resulting in decreased ventricular afterload. Unique to this released from the adrenal medulla during stress which pos- class of agents, PDE inhibitors improve ventricular relaxsesses β1, β2, α1, and α2 adrenergic receptor agonist activity. ation (so called lusitropic property). This effect is mediated It is a commonly used adjuvant inotrope for patients who fail by decreased breakdown of cAMP resulting in activation of to respond adequately to dopamine therapy or are too hypo- protein kinase A which subsequently phosphorylates the sartensive to tolerate the vasodilating effects of inodilators such coplasmic reticulum protein, phospholamban. This phosphoras dobutamine or milrinone. Adults and children who are ylation modulates the activation of sarcoplasmic reticulum resistant to either dopamine or dobutamine therapy will fre- ATPase (SERCA) resulting in more rapid uptake of cytosolic quently respond to epinephrine. At the lower dosage or infu- calcium thus facilitating more rapid and improved myocyte sion rates (0.03 toward 0.1–0.3 μg/kg/min, so called low relaxation [192, 193]. As a result of these pharmacologic dose epinephrine) its β-adrenergic effects predominate such properties, the main hemodynamic effects of PDE inhibitors that it is principally an inotropic agent. Based on this princi- are to decrease both systemic and pulmonary vascular resispal, epinephrine has become an increasingly utilized second-­ tances, decrease filling pressures, and substantially augment line inotropic agent in the setting of low cardiac output states cardiac output, most often with very little change in heart rate. (e.g. post-cardiopulmonary bypass). The α-adrenergic effect Other effects noted with the use of PDE inhibitors include coron increasing systemic vascular resistance becomes more onary artery dilation, thus there is little change in myocardial prominent as the epinephrine infusion rate approaches and oxygen consumption, and putative anti-inflammatory effects exceeds 0.3 μg/kg/min, in which case it is sometimes which have made it an attractive option in fluid-resuscitated, described as an inovasopressor. Though epinephrine can low cardiac output shock as most commonly occurs in pedimediate splanchnic vasoconstriction and theoretically lead to atric septic shock [96]. Finally, it is notable that PDE inhibiintestinal ischemia, this adverse effect is thought to be less tors mediate their effects independent of β-adrenergic receptor significant in the critical care setting as it is countered by ligation. It has become increasingly appreciated that β-receptor significant augmentation of cardiac output [191]. Patients down-regulation (e.g. in congestive heart failure), signaling with heart failure and increased systemic vascular resistance disruption (e.g. in sepsis), and polymorphisms all may affect may be harmed by higher dosage epinephrine unless it is the manner by which this receptor-based pharmacologic concomitantly administered with a vasodilator or inodilator. mechanism can be utilized clinically, so that PDE inhibitors Non-cardiac related effects of epinephrine include increas- may provide superior clinical effects in these settings. ing plasma glucose levels, increasing fatty acid levels, and The interaction of PDE inhibitors with concomitant inoincreased renin activity with a concomitant decrease in tropes, vasodilators, and even vasopressors can be used to serum potassium and aldosterone levels. therapeutic advantages in patients with a variety of forms of shock. For example, epinephrine can remain a potent and relatively pure inotrope at higher dosages when combined Norepinephrine While norepinephrine is classically considered to be with a type III PDE inhibitor that will prevent breakdown of a vasopressor, it does have mixed α-adrenergic and cAMP produced by β1 and β2 adrenergic stimulation such that β-adrenergic effects. Again, these effects are dose-depen- increased cAMP inhibits the usual effects of epinephrine-­ dent. Norepinephrine is an endogenous neurotransmitter mediated α1 adrenergic stimulation. In a similar manner, in the sympathetic nervous system. At lower doses (typi- norepinephrine may be a more effective inotrope while maincally on the order of 0.01–0.05 μg/kg/min), norepinephrine taining vasopressor effectiveness, when administered with a can improve contractility and hence cardiac output via its Type III PDE inhibitor. The hydrolysis of norepinephrine-­ β1-­adrenergic effects. At higher doses, it is almost a pure mediated β1-receptor cAMP production is inhibited so that α-adrenergic agonist with primarily vasopressor effects. increased cAMP improves both contractility and relaxation. In addition, norepinephrine-mediated α1 and α2 adrener hosphodiesterase Inhibitors P gic effects remain unopposed because milrinone possesses The phosphodiesterase (PDE) inhibitors are a class of drugs no specific β1 receptor activity and therefore has minimal called bipyridines which mediate both inotropy and vaso- vasodilatory effect in the face of potent α-adrenergic vasodilation, and as a result are often referred to as inodilators. constriction. In a related manner, the type V PDE inhibitors These agents mediate their effects by preventing hydrolysis (e.g. sildenafil, dipyridamole) may potentiate the pulmonary of cAMP (Type III PDE inhibitorsI, e.g. milrinone, a­ mrinone, vasodilator effects of inhaled nitric oxide.

30 Shock

As alluded to above, one major challenge posed by the use of currently licensed PDE inhibitors is their relatively prolonged half-life as compared to catecholamines and nitrosovasodilators. Although the latter agents are eliminated within minutes, PDE inhibitors are not eliminated for hours. Milrinone is primarily bound to plasma proteins (~75 %) and predominantly eliminated by the kidney while inamrinone is predominantly eliminated by the liver, thus, this half-life elimination is even more important in the setting of organ failure. When untoward side effects are encountered (e.g. hypotension), these drugs should be discontinued immediately. Of note, norepinephrine has been reported as being an effective antidote for these toxicities. As mentioned above, norepinephrine, on the basis of its α1 and β1, but not β2 adrenergic activity will increase blood pressure via vasoconstriction (α1 effect) and cardiac output (β1 effect), but not exacerbate the vasodilatory effect of the phosphodiesterase inhibitor.

Other Agents Of historic note, isoproterenol was an important and commonly used inodilator that possesses both β1 and β2 adrenergic activity. It used to be considered an important drug in the treatment of heart block, refractory status asthmaticus, and pulmonary hypertensive crises with right ventricular failure although its unfavorable safety profile with regards to increasing myocardial oxygen demand resulting in ischemic injury has substantially tempered its use over the past decade. Levosimendan represents a relatively newer class of inodilators which sensitizes calcium binding in the actin-­tropomyosin complex to improve contractility, while simultaneously hyperpolarizing potassium channels to cause vasodilation [194]. There is a growing body of literature on levosimendan use in critically ill children [195–202]. However, at the time of this writing, levosimendan is not available in the United States. Calcium chloride infusions have also been used as inotropic agents, though there are limited studies in children and adults [203–205]. Some of the unique developmental differences in excitation-contraction coupling in the pediatric myocardium are importantly considered here. The relative immaturity of intracellular calcium regulation (T tubules, sarcoplasmic reticulum, L-type Ca2+ channels) causes alterations in the normal mechanisms leading to the Ca2+-induced Ca2+ release (CICR) that triggers excitation-contraction coupling, such that the neonatal myocardium is more dependent upon extracellular calcium versus intracellular calcium for contractility compared to the mature heart [206–210]. These developmental differences also explain the extreme sensitivity of neonates to calcium channel antagonists [207]. Tri-iodothyronine is also an effective inotropic agent which has long been used to preserve cardiac function in patients who are brain dead and have low T3 levels [211].

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A r­andomized controlled trial in neonates showed that use of tri-iodothyronine as a post cardiac surgery inotrope improved outcomes [212, 213].

Vasodilators Vasodilators (Table 30.9) are used to reduce either pulmonary or systemic vascular resistance and improve cardiac output. The nitrosovasodilators depend on release of nitrosothiols (nitric oxide donor) to activate soluble guanylate cyclase and release cGMP. Sodium nitroprusside is both a systemic and pulmonary vasodilator. In the setting of a failing myocardium, careful titration of nitroprusside to achieve lower afterload may improve cardiac output even though changes in blood pressure may not be observed. The usual starting infusion rate is on the order of 0.5–1 μg/kg/min. Nitroglycerin has a somewhat selective dose-dependent effect in that at 10 μg/kg/min) and epinephrine (>0.3 μg/kg/min) infusion rates increase SVR. Without the concomitant increase in inotropy provided by these agents, a simple escalation in afterload will increase blood pressure, but at the expense of less stroke volume and greater ventricular work. In a similar manner, norepinephrine, which possesses predominantly α-adrenergic stimulation, also possesses β-receptor activity so that it can be effective for dopamine-resistant shock on the basis of both inotropic and vasopressor activity. As a result, dopamine and norepinephrine may have their greatest role in the maintenance of adequate perfusion pressure in children with shock.

D.S. Wheeler and J.A. Carcillo Jr.

role of either low-dose, hormonal-level dosing or higher vasoconstrictive dosing of vasopressin in various forms of shock. In current clinical practice, it is most commonly instituted in catecholamine-resistant, refractory, vasodilatory shock, though earlier indications may be identified by ongoing studies.

Hydrocortisone

Clinical use of hydrocortisone in shock has also been re-­ examined in recent years. Centrally and peripherally-­ mediated adrenal insufficiency is increasingly common in the pediatric intensive care setting [223–225]. Many children are being treated for chronic illnesses with corticosteroids with subsequent pituitary-adrenal axis suppression. Many children have central nervous system anomalies and acquired Phenylephrine illnesses. Some children have purpura fulminans and Different from these mixed agonists, phenylephrine is a pure Waterhouse-Friedrichsen Syndrome [226]. Other investigaα-adenergic receptor agonist that can be effectively titrated tors have reported reduced cytochrome P450 activity and to augment systemic afterload. Because of this property, decreased endogenous production of cortisol and aldosteone of its principal roles in pediatrics historically has been rone in some children. Interestingly, adrenal insufficiency for reversal of tet spells (hypercyanotic spells) in children can present with low cardiac output and high systemic vascuwith tetralogy of Fallot. Infants and children with tetralogy lar resistance or with high cardiac output and low systemic of Fallot have a thickened infundibulum which spasms and vascular resistance. The diagnosis should be considered in causes right to left blood flow through the ventricular septal any child with catecholamine-resistant vasodilatory shock. defect, which substantially reduces pulmonary blood flow The dose recommended for stress dosing of methylprednisoand leads to life-threatening hypoxemia. Therapies used to lone is 2 mg/kg follow by the same dose over 24 h, but practreat this spell include oxygen and morphine to relax the tice varies greatly among intensivists [227]. Central or infundibulum, and knee-to-chest positioning to increase peripheral adrenal insufficiency may be diagnosed in adequately volume resuscitated infants or children who afterload and help generate left to right flow across the ­ ventricular septal defect. When these maneuvers fail, phen- require epinephrine or norepinephrine infusions for shock, ylephrine is implemented to increase systemic arterial vaso- and have a baseline cortisol level 18 >14

Leukocyte count, (109/L) >34 >19.5 or 17.5 or 15.5 or 13.5 or 11 or 300. Lungs were subsequently transplanted without differences in ICU length of stay or 30-day mortality compared to recipients of ideal donors [221]. Hemodynamic and reperfusion injury seem to play a significant role in donor lung injury [222]. The early use of norepinephrine or vasopressin may reduce lung injury [223]. Recent guidelines suggest that there should be no predefined lower limit for the P/F ratio that precludes consideration for transplantation. Timing of evaluation, temporal changes, response to alveolar recruitment and recipient status should be considered [69]. In cases of unilateral lung injury, pulmonary venous partial pressure of oxygen during intraoperative assessment is required to reliably evaluate contralateral lung function.

Bronchoscopy and Bronchopulmonary Infections The consensus of expert opinion supports the use of bronchoscopy for the purposes of examining the tracheobronchial tree for abnormalities and collecting microbiological specimens [68, 129, 211]. Pathological studies of lungs rejected for donation have indicated that bronchopneumonia, diffuse alveolar damage, and diffuse lung consolidation are the three most common reasons for being deemed unsuitable [214]. Between 76 % and 97 % of bronchoalveolar lavages (BAL) will grow at least one organism [224, 225]. The most commonly identified organisms included Staphylococcus aureus and Enterobacter, and in 43 % of transplants, similar organisms were isolated from recipient bronchoscopy. Pulmonary infection in the graft recipient results in significantly lower survival compared with recipients who do not develop early graft infection [226]. Recipients with donor BAL cultures positive for either gram positive or gram negative bacteria had longer mean mechanical ventilation times and inferior 6-month to 4-year survival than those with negative bacterial BAL cultures [227]. Trauma donors (versus intracerebral hemorrhage) may be at higher risk for aspiration and for intubation under less sterile field conditions and were generally ventilated longer [228]. The etiology of donor death is not associated with lung transplant mortality [204] but may influence the type of organisms found on BAL and subsequent graft infection risk. The high rates of positive bacterial and fungal BAL results suggest the need for more aggressive critical care management and antibiotic therapy [229].

Liver Liver transplantation from deceased donors has become accepted as standard of care for many children with liver failure. Advances in donor and recipient management has optimized graft survival with 80–90 % 5 year survival rates

38

The Physiology of Brain Death and Organ Donor Management

[230]. Whole liver transplants are still more successful with less morbidity and mortality than split liver grafts [231, 232]. Potential liver donors should be assessed by the following: aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin (direct and indirect where available), INR (or prothrombin time [PT]) (repeat q6h), serum electrolytes, creatinine, urea, Hepatitis B surface antigen (HBsAG), hepatitis B antibody (HBcAb), hepatitis C virus antibody positive (HCV Ab). There is no indication for routine liver imaging. The use of donor characteristics (donor risk index) and recipient matching using bicochemical models in end stage liver disease (MELD) are becoming more useful in predicting liver transplant outcomes [233–235]. There is variation in organ quality and recipient outcomes; larger volume centers tend to use higher risk organs but also have higher disease severity resulting in worse outcomes [236]. Predictors of early graft dysfunction or failure for whole or split liver transplantation include donor history of cardiac arrest, older donor age in adult transplantation (>40 years), [113, 237, 238], very young age in pediatric transplantation [113], reduced size livers, moderate to severe steatosis on liver biopsy, prolonged cold ischemia time (>6 h) [121, 239, 240] and donor hypernatremia (Na > 155 mmol/L). Donor hypernatremia is independently associated with death or retransplantation at 30 days [121] but this risk reverses with the correction of hypernatremia [124]. Although liver allograft dysfunction has been reported to be associated with prolonged ICU stay [113, 241], this was supported by univariate analysis but did not hold true by multivariate analysis [241]. In a cohort of 323 orthotopic liver transplants (OLT), longer donor hospitalization was not found to be associated with primary liver graft dysfunction [239]. Large platelet transfusion requirements during surgery are independently associated with more severe hepatic dysfunction after transplantation [115], although this may be indicative of a more technically complicated procedure, sicker recipient, or poor quality graft with subsequently greater sequestration of platelets within the donor liver [242]. As with other organs, the mechanisms of brain death itself impact the donor liver [243]. With the use of marginal livers for transplantation, studies are identifying more factors that may impact graft survival such as the liver’s gross appearance, the donor P/F ratio, and the donor hemoglobin [244]. The sinusoidal lining cells (SLC) of the liver are particularly vulnerable to the effects of preservation-reperfusion injury, the extent of which depends on the duration of cold ischemia rather than reperfusion. Cold preservation causes the SLC to become edematous and detach into the sinusoidal lumen [245]. While some authors recommend routine donor liver biopsies in all liver donors in an effort to decrease the rate of early graft dysfunction or failure [246, 247], the use of a biopsy in the decision making of liver suitability has generally been restricted to evaluating the amount of steatosis or in the presence of active hepatitis C in the appropriate risk groups.

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Kidney Donor age ≥ 40 or ≤10 years were thought to be independently associated with risk for graft failure [248, 249]. Now, recipients of kidneys from young donors < 5 years old have equivalent patient and graft survival [250]. En bloc kidneys from pediatric donors now show comparable outcomes with living kidney donation [251]. Older kidneys have a higher incidence of renovascular or parenchymal injury [249]. Adult donor characteristics that are independently associated with graft failure risk include creatinine > 133 μmol/L, history of hypertension independent of duration and cerebrovascular accident (CVA) as the cause of donor death [248]. During the past few years, there has been a renewed interest in the use of expanded criteria donors for kidney transplantation to increase number of donations with improving outcomes [252]. However, these kidneys have worse long-term survival and are only recommended for older recipients [253, 254]. A normal creatinine clearance (>80 ml/min/1.73 m2), as estimated by the Schwartz formula [255], defines the optimal function threshold for transplantation. However, an abnormal serum creatinine or calculated creatinine clearance in a donor does not necessarily preclude use of the kidneys [256]. Urinalysis is essential to rule out kidney abnormalities and serum creatinine and serum urea (blood urea nitrogen) measurements should be obtained q6h. Ultrasound with Doppler flow of renal vessels is often requested if creatinine levels are abnormal. If contrast angiography is performed (e.g. cerebral, coronary) N-acetylcysteine with hydration should be administered both before and after the angiographic procedure in order reduce the risk of contrast nephropathy [257] in potential donors, particularly in those with reduced renal function. Delayed graft function predicts the development of adverse events such as decreased graft survival, decreased recipient survival and increased allograft nephropathy [258]. Most studies do not link a specific cause of brain death as a predictor of graft function in children [259]. The brain death process itself can affect acute rejection in renal transplantation [260, 261]. Greater sympathetic activity during the process produces endothelial damage, complement activation, and a proinflammatory state increases organ immunogenicity, then promoting rejection after transplant [262, 263]. Targeting this inflammatory state may improve outcomes of recipients [264, 265]. Other donor risk factors predicting kidney allograft dysfunction include hemodynamics, age, last creatinine level prior to donation, and cold ischemic time [266]. Donor hemodynamic instability is correlated with post-transplant acute tubular necrosis in adults [77, 267, 268] and children [2]. Reduced graft survival or acute tubular necrosis may occur in organs retrieved from donors receiving high-dose dopamine (>10 μg/kg/min) but these effects may be limited to donors who are hypotensive at the time of organ retrieval

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[268]. Hemodynamic resuscitation may improve outcome as donor use of dopamine and/or noradrenaline is independently associated with a lower risk of acute rejection [269], lower rate of delayed graft function [84, 270], and reduces the need for recipient dialysis [271]. In adults, donor hypertension is also a risk factor for inferior outcomes [272]. It is suggested that the time taken to optimize donor cardiovascular status may reduce renal ischemic injury and optimize donor yield [273, 274]. In an analysis of the Collaborative Transplant Study database of kidney transplants, cold ischemic preservation time > 12 h resulted in progressively worsening recipient graft survival, particularly once the cold ischemia time (CIT) was ≥48 h [275]. Other analyses have suggested that CIT is predictive of poorer graft survival [248] or function [267] if it was >24 h. Preservation incorporating pulsatile perfusion, rather than cold storage, may reduce the incidence of delayed graft function [276, 277].

Intestine Small bowel transplantation has been become an increasingly feasible option for short bowel syndrome and liver failure [278]. Long term survival following intestinal transplant is above 60 %, but the incidence of morbidity and mortality is still significant [279, 280]. Because of this, many feel that intestinal transplantation as an option is still premature and remains unique to specialized centres only [281, 282]. For the brain dead donor, non-absorbable antibiotics for selective bowel decontamination are sometimes used for liver and intestine transplantation to prevent postoperative infections. Results are best if given >3 days prior to transplantation [283]. A meta-analysis showed an 84 % relative risk reduction in the incidence of gram negative infection following liver transplantation; however, the risk of antimicrobial resistance should be considered [284]. More recent studies have not duplicated these results. At this time, selective bowel decontamination is not routinely administered [285].

Logistics of Organ Donation Donor Management Protocols and Education One of the main reasons for insufficient organ procurement has been low organ yield due to poor multiorgan failure management in the potential donor [82]. Evidence has shown that multidisciplinary donor management protocols can improve donation outcomes [286, 287]. When these strategies are used, there are a significantly improved number of organs transplanted per donor [3, 4]. This is mostly

S.D. Shemie and S. Dhanani

attributed to the improvement in basic cardiovascular and respiratory monitoring and treatment [288–290]. Improved multimodal strategies aimed at preserving organ function specifically may increase numbers of potential donors, especially with the increasing use of “marginal” donors [81]. These protocols need to be supported with appropriate medical and nursing education [291–293] and influencing attitudinal changes for the role of donor [294]. Policies for organ donation and management should be developed with aim to change the culture at the bedside and with hospital administration [295, 296].

Optimal Time of Organ Procurement In general, after brain death has been declared and consent to organ donation has been granted, all efforts are made to complete logistics and initiate procurement as quickly as possible. Expediting the interval from brain death to surgical procurement may allow grieving families to leave the hospital sooner and reduce ICU length of stay. This approach may also have been influenced by the misperception that brain dead patients are irretrievably unstable [77]. As a concept fundamental to ICU multiorgan support, resuscitation of the cardiopulmonary system benefits all end organs. Neurogenic myocardial injury related to primary brain injury is largely reversible with time and treatment [30, 65, 184]. Australian investigators advocate a delay in organ procurement until marginal donor lungs have been optimized with aggressive bronchial toilet using bronchoscopy, physiotherapy, increasing tidal volume and increasing (PEEP) [152, 221]. In a large cohort study of 1,106 renal transplant recipients, longer duration of brain death (time from declaration of brain death to onset of cold ischemia) was associated with improved initial graft function and graft survival, suggesting that the time taken to optimize donor cardiovascular status may reduce ischemic injury [273]. Despite early reports to the contrary [113], liver allograft dysfunction is not associated with prolonged ICU stay by multivariate analysis [239, 241]. A period of time may be needed to determine the trend of elevated AST or ALT, as generally accepted upper limits may be exceeded if the levels are falling rapidly (e.g., following a hypotensive episode with resuscitation). Temporal changes in multi-organ function after brain death demand flexibility in identifying the optimal time of procurement. Recent consensus guidelines stress the importance of taking the necessary time in the ICU to optimize multi-organ function for the purposes of improving organ utilization and transplant outcomes [69]. Reversible organ dysfunction can be improved with resuscitation and re-evaluation and may include:

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• Myocardial/cardiovascular dysfunction • Oxygenation impairment related to potentially reversible lung injury • Invasive bacterial infections • Hypernatremia • The need to evaluate temporal trends in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) • The need to evaluate temporal trends in creatinine • Any other potentially treatable situation. This treatment period may be extended 24–48 or longer and should be accompanied by frequent re-evaluation to demonstrate improvement in organ function toward defined targets. Extending the interval of donor care in the ICU to optimize transplant outcomes should be factored into donation consent discussions and should be consistent with the wishes of the family or surrogate decision maker. Adequate PICU resource allocation should be anticipated.

Decisions Regarding Transplantability End-of-life care in the ICU includes all efforts to actualize the opportunity and expressed intent to donate organs. Given the management of brain death and the organ donor is the exclusive domain of ICU practice, it is incumbent on critical care practitioners to assume leadership in this regard, in collaboration with organ procurement agencies and transplant programs. Table 38.3 provides an example of standing orders for pediatric donors to help guide practice [69]. It is important for ICU staff to know that individual programs may have different function thresholds for accepting organs, dependent on program experience and urgency of recipient need. Although the non-utilization of organs is most commonly related to organ dysfunction, it is also related to donor characteristics and/or flaws in the processes of transplant evaluation and decision making. A four-center Canadian review of heart and lung utilization identified deficits in the consent to individual organs, the offering of organs, and the utilization of offered organs unrelated to organ dysfunction [297]. Consent should be requested for all organs regardless of baseline function and all organs should be offered. Ideally, final decisions about transplantability should rest with the individual transplant programs represented by the organ-specific transplant doctors. Management of marginal organs should include resuscitation and reevaluation to allow for potential organ rescue and utilization. Transplant programs should be accountable to the donor family and ICU donation efforts for the nonutilization of organs, to ensure that all useable organs are used. This evolving collaboration to establish best donor management practices in the ICU must be linked to ensuring optimal organ utilization, which in turn, must be linked to transplant graft and patient outcomes.

509 Table 38.3 Standing orders for organ donor management: pediatrics Standard monitoring 1. Urine catheter to straight drainage, strict intake and output 2. Nasogastric tube to straight drainage 3. Vital signs q1h 4. Pulse oximetry, 3-lead electrocardiogram (EKG) 5. Central venous pressure (CVP) monitoring 6. Arterial line pressure monitoring Laboratory investigations 1. Arterial blood gas (ABG), electrolytes, glucose q4h and PRN 2. CBC q8h 3. Blood urea nitrogen (BUN), creatinine q6h 4. Urine analysis 5. AST, ALT, bilirubin (total and direct), international normalized ratio (INR) (or prothrombin time [PT]), partial thromboplastin time (PTT) q6h Hemodynamic monitoring and therapy General targets: age-related norms for pulse and blood pressure (BP) 1. Fluid resuscitation to maintain normovolemia, CVP 6–10 mmHg 2. Age-related treatment thresholds for arterial hypertension: Newborns–3 months >90/60 >3 m–1 year >110/70 >1 year–12 year >130/80 >12 year–18 year >140/90 a. Wean inotropes and vasopressors, and, if necessary b. Start Nitroprusside 0.5–5.0 μg/kg/min, or Esmolol 100–500 μg/kg bolus followed by 100–300 μg/kg/min 3. Serum lactate q2–4h 4. Central venous oximetry q2–4h; titrate therapy to central SVO2 ≥ 60 % Agents for hemodynamic support 1. Dopamine 1–10 μg/kg/min 2. Vasopressin 0.0003–0.0007 U/kg/min (0.3–0.7 mU/kg/min) to a maximum dose of 2.4 U/h 3. Norepinephrine, epinephrine, phenylephrine (caution with doses > 0.2 μg/kg/min) Glycemia and nutrition 1. Routine intravenous (iv) dextrose infusions 2. Continue enteral feeding as tolerated 3. Continue parenteral nutrition if already initiated 4. Initiate and titrate insulin infusion to maintain serum glucose 6–10 mmol/L Fluid and electrolytes Targets: 1. Urine output 0.5–3 ml/kg/h 2. Serum sodium (Na) ≥ 130 ≤ 150 mM 3. Normal ranges for potassium, calcium, magnesium, phosphate Diabetes insipidus Defined as: 1. Urine output > 4 ml/kg/h, associated with: a. Rising serum Na ≥ 145 mmol/L and/or b. Rising serum osmolarity ≥ 300 mosM and/or c. Decreasing urine osmolarity ≤ 200 mosM (continued)

510 Table 38.3 (continued) Diabetes insipidus therapy 1. Titrate therapy to urine output ≤ 3 ml/kg/h a. iv vasopressin infusion 0.0003–0.0007 U/kg/min (0.3– 0.7 mU/kg/min) to a maximum dose of 2.4 U/h, and/or b. Intermittent 1-desamino-D-arginine vasopression (DDAVP) 0.25–10 μg iv q6h Combined hormonal therapy Defined as: 1. Tetra-iodothyronine (T4) 20 μg iv bolus followed by 10 μg/h iv infusion (or 50–100 μg iv bolus followed by 25–50 μg iv bolus q12h) 2. Vasopressin 0.0003–0.0007 U/kg/min (0.3–0.7 mU/kg/min) to a maximum dose of 2.4 U/h 3. Methylprednisolone 15 mg/kg (≤1 g) iv q24h Indications: 1. 2D echocardiographic ejection fraction ≤ 40 %, or 2. Hemodynamic instability (includes shock unresponsive to restoration of normovolemia and requiring vasoactive support [dopamine >10 μg/min or any other vasopressor agent]) 3. Consideration should be given to its use in all donors Hematology 1. Hemoglobin (Hgb) optimal ≥ 100 g/L for unstable donors, lowest acceptable ≥ 70 g/L 2. Platelets, INR, PTT no predefined targets, transfuse in cases of clinically relevant bleeding 3. No special transfusion requirements Microbiology (baseline, Q24h and PRN) 1. Daily blood cultures 2. Daily urine cultures 3. Daily endotracheal tube (ETT) cultures 4. Antibiotics for presumed or proven infection Heart Specific 1. 12-lead EKG 2. Troponin I or T, q12h 3. 2D echocardiography a. Should only be performed after fluid and hemodynamic resuscitation b. If 2D echo ejection fraction ≤ 40 % then repeat echocardiography at q6–12 h intervals Lung specific 1. Chest x-ray q24h and PRN 2. Bronchoscopy and bronchial wash gram stain and culture 3. Routine ETT suctioning, rotation to lateral position q2h 4. Mechanical ventilation targets: a. Tidal volume (Vt) 8–10 ml/kg, positive end expiratory pressure (PEEP) 5 cm H20, peak inspiratory pressure (PIP) ≤ 30 cm H2O b. pH 7.35–7.45, partial pressure of arterial carbon dioxide (PaCO2) 35–45 mmHg, partial pressure of arterial oxygen (PaO2) ≥ 80 mmHg, oxygen (O2) sat ≥ 95 % 5. Recruitment maneuvers for oxygenation impairment may include: a. Periodic increases in PEEP up to 15 cm H2O b. Sustained inflations (PIP @ 30 cm H2O × 30–60 s) c. Diuresis to normovolemia [Based on data from ref. 69]

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S.D. Shemie and S. Dhanani Hugo C, Pisarski P, Krämer BK, Lopau K, Rahmel A, Benck U, Birck R, Yard BA. Effects of donor pretreatment with dopamine on graft function after kidney transplantation: a randomized controlled trial. JAMA. 2009;302(10):1067–75. Singh RP, Farney AC, Rogers J, Gautreaux M, Reeves-Daniel A, Hartmann E, Doares W, Iskandar S, Adams P, Stratta RJ. Hypertension in standard criteria deceased donors is associated with inferior outcomes following kidney transplantation. Clin Transplant. 2011;25(4):E437–46. Kunzendorf U, Hohenstein B, Oberbarnscheid M, Muller E, Renders L, Schott GE, Offermann G. Duration of donor brain death and its influence on kidney graft function. Am J Transplant. 2002;2:282–94. Nijboer WN, Moers C, Leuvenink HG, Ploeg RJ. How important is the duration of the brain death period for the outcome in kidney transplantation? Transpl Int. 2011;24(1):14–20. Opelz G. Cadaver kidney graft outcome in relation to ischemia time and HLA match. Collaborative Transplant Study. Transplant Proc. 1998;30:4294–6. Wight JP, Chilcott JB, Holmes MW, Brewer N. Pulsatile machine perfusion vs. cold storage of kidneys for transplantation: a rapid and systemic review. Clin Transplant. 2003;17:293–307. Ojo AO, Hanson JA, Meier-Kriesche H, Okechukwu CN, Wolfe RA, Leichtman AB, Agodoa LY, Kaplan B, Port FK. Survival in recipients of marginal cadaveric donor kidneys compared with other recipients and wait-listed transplant candidates. J Am Soc Nephrol. 2001;12:589–97. Berg CL, Steffick DE, Edwards EB, Heimbach JK, Magee JC, Washburn WK, Mazariegos GV. Liver and intestine transplantation in the United States 1998-2007. Am J Transplant. 2009; 9(4 Pt 2):907–31. Kaufman SS, Atkinson JB, Bianchi A, Goulet OJ, Grant D, Langnas AN, McDiarmid SV, Mittal N, Reyes J, Tzakis AG, American Society of Transplantation. Indications for pediatric intestinal transplantation: a position paper of the American Society of Transplantation. Pediatr Transplant. 2001;5(2):80–7. Gupte GL, Beath SV, Protheroe S, Murphy MS, Davies P, Sharif K, McKiernan PJ, de Ville de Goyet J, Booth IW, Kelly DA. Improved outcome of referrals for intestinal transplantation in the UK. Arch Dis Child. 2007;92(2):147–52. Goulet O, Sauvat F. Short bowel syndrome and intestinal transplantation in children. Curr Opin Clin Nutr Metab Care. 2006;9(3):304–13. Sudan D. Long-term outcomes and quality of life after intestine transplantation. Curr Opin Organ Transplant. 2010;15(3):357–60. Arnow PM, Carandang GC, Zabner R, Irwin ME. Randomized controlled trial of selective bowel decontamination for prevention of infections following liver transplantation. Clin Infect Dis. 1996;22(6):997–1003. Safdar N, Said A, Lucey MR. The role of selective digestive decontamination for reducing infection in patients undergoing liver transplantation: a systematic review and meta-analysis. Liver Transpl. 2004;10(7):817–27.

285. Hellinger WC, Yao JD, Alvarez S, Blair JE, Cawley JJ, Paya CV, O’Brien PC, Spivey JR, Dickson RC, Harnois DM, Douglas DD, Hughes CB, Nguyen JH, Mulligan DC, Steers JL. A randomized, prospective, double-blinded evaluation of selective bowel decontamination in liver transplantation. Transplantation. 2002;73(12):1904–9. 286. Arbour R. Clinical management of the organ donor. AACN Clin Issues. 2005;16(4):551–80. 287. Kong AP, Barrios C, Salim A, Willis L, Cinat ME, Dolich MO, Lekawa ME, Malinoski DJ. A multidisciplinary organ donor council and performance improvement initiative can improve donation outcomes. Am Surg. 2010;76(10):1059–62. 288. Salim A, Martin M, Brown C, Rhee P, Demetriades D, Belzberg H. The effect of a protocol of aggressive donor management: implications for the national organ donor shortage. J Trauma. 2006;61(2):429–33. 289. DuBose J, Salim A. Aggressive organ donor management protocol. J Intensive Care Med. 2008;23(6):367–75. 290. Kirschbaum CE, Hudson S. Increasing organ yield through a lung management protocol. Prog Transplant. 2010;20(1):28–32. 291. Bardell T, Hunter DJ, Kent WD, Jain MK. Do medical students have the knowledge needed to maximize organ donation rates? Can J Surg. 2003;46(6):453–7. 292. Cohen J, Ami SB, Ashkenazi T, Singer P. Attitude of health care professionals to brain death: influence on the organ donation process. Clin Transplant. 2008;22(2):211–5. 293. Bener A, El-Shoubaki H, Al-Maslamani Y. Do we need to maximize the knowledge and attitude level of physicians and nurses toward organ donation and transplant? Exp Clin Transplant. 2008;6(4):249–53. 294. Hobeika MJ, Simon R, Malik R, Pachter HL, Frangos S, Bholat O, Teperman S, Teperman L. U.S. surgeon and medical student attitudes toward organ donation. J Trauma. 2009;67(2):372–5. 295. Griffiths J, Verble M, Falvey S, Bell S, Logan L, Morgan K, Wellington F. Culture change initiatives in the procurement of organs in the United Kingdom. Transplant Proc. 2009; 41(5):1459–62. 296. Committee on Hospital Care, Section on Surgery, and Section on Critical Care. Policy statement- -pediatric organ donation and transplantation. Pediatrics. 2010;125(4):822–8. 297. Hornby K, Ross H, Keshavjee S, Rao V, Shemie SD. Factors contributing to non-utilization of heart and lungs after consent for donation: a Canadian multicentre study. Can J Anaesth. in press, 2006. 298. Scheinkestel CD, Tuxen DV, Cooper DJ, Butt W. Medical management of the (potential) organ donor. Anaesth Intensive Care. 1995;23(1):51–9. 299. U.S. Department of Health & Human Services. Organ procurement and transplantation network. Donors : donation year (2009– 2010) by donor type, age type, organ. Based on OPTN data as of October 7, 2011. http://optn.transplant.hrsa.gov. Accessed 10 Aug 2012.

Part IV Monitoring the Critically Ill or Injured Child Shane M. Tibby

Respiratory Monitoring

39

Derek S. Wheeler and Peter C. Rimensberger

Abstract

Vital functions such as respiration have to be continuously monitored in a critically ill or injured child. The two main components of respiratory function that can be monitored at the bedside are gas exchange and mechanical behavior of the respiratory system. The goals of respiratory monitoring are twofold. First, respiratory monitoring should help the clinician to be able to recognize acute respiratory failure and to quantify its severity and progression. Second, respiratory monitoring should provide the necessary therapeutic endpoints for management of acute respiratory failure and lung disease in the pediatric intensive care unit (PICU). This chapter will review the various techniques available for respiratory monitoring and discuss how multimodal respiratory m ­ onitoring might help to improve ventilator settings during non-invasive or invasive mechanical ventilation. Keywords

Respiratory failure • Respiratory monitoring • Respiratory mechanics • End-tidal CO2 • Capnography • Respiratory graphics

Introduction The lungs are highly unique in that they are internal organs, yet at the same time they are constantly exposed to the external environment. For example, with each breath, the lungs are exposed to pollens, viruses, bacteria, smoke and other pollutants, and all of the other substances in the environment. At the same time, at any one point in time the lungs receive approximately half of the cardiac output and all of the p­ otential i­ nternal

D.S. Wheeler, MD, MMM (*) Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA e-mail: [email protected] P.C. Rimensberger, MD Department of Pediatrics, Service of Neonatology and Pediatric Intensive Care, University Hospital of Geneva, 6, Rue Willy-­Donzé, Geneva CH-1211, Switzerland e-mail: [email protected] D.S. Wheeler et al. (eds.), Pediatric Critical Care Medicine, DOI 10.1007/978-1-4471-6362-6_39, © Springer-Verlag London 2014

toxins (proinflammatory cytokines, drugs, etc). As such, there is a vast array of diseases that affect the human respiratory tract. Dr. George A. Gregory, one of the founding fathers of pediatric critical care medicine, once stated that acute respiratory failure accounts for approximately 50 % of all admissions to the pediatric intensive care unit (PICU) [1]. More recent studies continue to support Dr. Gregory’s claim – acute respiratory failure and the need for respiratory support remains one of the most common reasons children are admitted to the PICU [2–5]. In this context, monitoring the function of the respiratory system assumes critical importance. The two main components of respiratory function that can be monitored at the bedside are gas exchange and mechanical behavior of the respiratory system. The goals of respiratory monitoring are twofold. First, respiratory monitoring should help the clinician to be able to recognize acute respiratory failure and to quantify its severity and progression. Second, respiratory monitoring should provide the necessary therapeutic endpoints for management of acute respiratory failure and lung disease in the PICU. This chapter will review the various techniques available for respiratory monitoring and discuss how multimodal respiratory 521

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D.S. Wheeler and P.C. Rimensberger

Monitoring Gas Exchange Gas exchange consists of two mutually independent processes – oxygenation and ventilation (i.e. CO2 elimination). Hypoxemia is generally defined as a PaO2 ≤60 mmHg and most often occurs due to ventilation-perfusion mismatching, the presence of either fixed or physiologic shunts, global hypoventilation, impairment of diffusion, and low ambient oxygen (as would occur at altitude with a lower than normal PAO2 due to a low atmospheric pressure, or lowered FIO2, as in the setting of manipulating pulmonary vascular resistance and Qp/Qs ratio in critically ill infants with single ventricle physiology). Conversely, hypercarbia (an elevated PaCO2) is usually due to low alveolar minute ventilation (recall that PaCO2 is inversely proportional to minute ventilation).

Monitoring Oxygenation  rterial Blood Gas Monitoring A There are multiple methods for monitoring the systemic arterial oxygen saturation (SaO2). Invasive methods include arterial blood gas (ABG) monitoring, while the most common non-invasive method is pulse oximetry. The primary purpose of monitoring SaO2 is to assure adequate oxygen delivery. Importantly, oxygen delivery is dependent upon cardiac output (CO) (L/min) and arterial oxygen content (CaO2) (mL/dL). CaO2 in turn is dependent upon the hemoglobin concentration (Hb, mg/dL), SaO2, and PaO2 (mm Hg), which comprises a very small proportion of the total arterial oxygen content.



(1.34 × Hb × SaO 2 )  DO 2 = CO × CaO 2 = CO ×    + ( 0.003 × PaO 2 )  (39.1)

The Hb and PaO2 can be easily measured in the clinical laboratory or with a point-of-care (POC) test, while the ­oxygen saturation can be obtained via pulse oximetry (see below). The measurement of cardiac output is more difficult,

100 90 Oxyhemoglobin (% saturation)

monitoring might help to improve ventilator settings during non-­invasive or invasive mechanical ventilation. Importantly, in the interest of space limitations, we will not discuss physical examination of the respiratory system and imaging techniques (i.e. chest radiograph, ultrasound, CT, etc.). Even with all of the dramatic advances in technology pertaining to monitoring of the respiratory system, the physical examination continues to remain a vital aspect of the evaluation and management of the critically ill and/or injured child. The importance of the physical examination can’t be overemphasized. Indeed, tachypnea, nasal flaring, retractions, and accessory muscle use are the earliest and usually most sensitive signs of impending respiratory failure in the PICU.

↑ pH ↓ DPG ↓ Temp

80 70

↓ pH ↑ DPG ↑ Temp

60 50 40 30 20 10 0

10

20

30

40

50

60

70

80

90

100

PO2 (mmHg)

Fig. 39.1  Oxygen-hemoglobin dissociation curve

though there are now several non-invasive methods of monitoring cardiac output in critically ill children currently used in the PICU setting (please see Chap. 40). While the partial pressure of oxygen dissolved in plasma (PaO2) is only a small part of the total arterial oxygen content, the relationship between PaO2 and the amount of oxygen bound to hemoglobin (Hb) is described by the sigmoid shaped oxyhemoglobin dissociation curve. The most important factors that influence the shape and position of the dissociation curve are temperature, pH, 2,3 diphosphoglycerate (2,3-DPG) levels in the blood, and the type of hemoglobin (Fig. 39.1). There are a couple of rules of thumb – first, assuming normal physiologic conditions, the oxygen saturation at a PaO2 of 50 mmHg should be around 80 %, while the oxygen saturation at a PaO2 of 60 mmHg should be around 90 %. The P50 is defined as the PaO2 at which the hemoglobin is 50 % saturated (which is approximately 25 mmHg in most cases). A rightward shift of the oxyhemoglobin dissociation curve implies an increase in the P50 and is due to a lower affinity of hemoglobin for oxygen (oxygen is released to the tissues). Conversely, a leftward shift of the oxyhemoglobin dissociation curve implies a decrease in the P50 and is due to a higher affinity of hemoglobin for oxygen (oxygen is more tightly bound). The factors that affect the standard oxyhemoglobin dissociation curve are listed in Table 39.1 and shown in Fig. 39.1. Factors that shift the curve to the right are theoretically advantageous to the patient since this means that more oxygen can be released from hemoglobin to the tissues (i.e. reduced affinity of oxygen for hemoglobin). Inversely, factors that shift the curve to the left (e.g. in the case of anemia) will be less advantageous for oxygen delivery to the tissue.

39  Respiratory Monitoring

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Table 39.1  Factors that affect the standard oxyhemoglobin dissociation curve

Temperature 2, 3-DPG CO2 pH (Bohr effect) Type of Hb

Left shift (↓P50, high affinity for O2) Decrease Decrease Decrease Increase (alkalosis) Fetal hemoglobin

Right shift (↑P50, low affinity for O2) Increase Increase Increase Decrease (acidosis) Adult hemoglobin

Given that dissolved oxygen comprises such a small (and insignificant) portion of the total arterial oxygen content, one could certainly question the utility of measuring PaO2 in the clinical setting. The information provided by an isolated PaO2 measurement is not very helpful. Knowing where on the oxyhemoglobin dissociation curve an individual patient’s oxygenation status is at a particular moment in time could potentially be of use – for example, if the patient is on the steep portion of the oxyhemoglobin dissociation curve, small changes in PaO2 will be associated with large changes in oxygen saturation. For similar reasons, if avoiding toxic levels of oxygen is the concern, PaO2 is much better than the oxygen saturation. On the flat portion of the oxyhemoglobin dissociation curve, oxygen saturation remains at or near 100 % despite marked changes in PaO2. Regardless, a single measurement of PaO2 only provides information at a specific point in time – serial PaO2 measurements would be of significantly greater utility. There are several clinically relevant measures of oxygenation that require knowledge of the PaO2 (Table 39.2). The ‘gold standard’ for assessing oxygenation is the venous admixture, or shunt fraction (Qs/Qt), which quantifies the extent of venous blood that bypasses oxygenation in the pulmonary capillaries.

Qs / Qt = ( CcO 2 − CaO 2 ) / ( CcO 2 − CvO 2 ) (39.2)

where Qs/Qt is the intra-pulmonary shunt fraction, CcO2 is the capillary oxygen content, CaO2 is the arterial oxygen content, and CvO2 is the mixed venous oxygen content (Fig. 39.2). The derivation of the shunt fraction is an important concept that is provided in the Table 39.3.

CcO 2 = ( Hb × 1.34 × 1.0 ) + ( 0.003 × PaO 2 ) (39.3)



CvO 2 = ( Hb × 1.34 × SvO 2 ) + ( 0.003 × PvO 2 ) (39.4)

Under normal conditions, approximately 2–5 % of the cardiac output bypasses the pulmonary capillaries (includes venous blood from the bronchial veins, the thebesian veins, and the pleural veins – this is the normal anatomic shunt, often called the physiologic shunt). Note that calculation of the shunt fraction requires invasive hemodynamic monitoring, e.g. Swan-Ganz or

PAO2

CcO2

Qt × CvO2

Qs

Qt × CaO2

Fig. 39.2  Single compartment model of the lung and pulmonary circulation. PAO2 is the partial pressure of oxygen in the alveolus. Qt is the total cardiac output, while Qs is that portion of the cardiac output that passes through the pulmonary circulation without becoming oxygenated. CcO2, CvO2, and CaO2 refer to the oxygen content of the pulmonary capillaries (fully saturated blood with oxygen saturation of 100 %), mixed venous blood, and arterial blood. The model is useful for deriving the Qs/Qt shunt equation (venous admixture)

Pulmonary Artery (PA) catheter. The shunt fraction can be estimated using the ISO shunt diagram (Fig. 39.3), which assumes normal ranges of Hb, PaCO2, and cardiac output. However, the shunt fraction most accurately reflects intrapulmonary shunt when the patient is breathing 100 % oxygen. When the FIO2 is less than 1.0, the shunt fraction will include true shunt (venous blood completely bypasses the pulmonary capillaries, i.e. V/Q is zero), as well as areas of low V/Q and diffusion impairment [7]. In essence, this is the basis for the oxygen challenge test for neonates with suspected cyanotic congenital heart disease (increasing the FIO2 to 1.0 should increase PaO2 in patients with lung disease, but not anatomic shunts). Therefore, as shown in multiple studies and computer models, there is a lot of variation in the shunt fraction in critically ill patients with lung disease (especially when the FIO2 is 10 mOsm/L [6, 83]. Fomepizole is the drug of choice for methanol poisoning and should be given as soon as possible to stop formic acid production. Early administration of fomepizole to patients without metabolic acidosis may obviate the need for hemodialysis [92]. Folinic acid is a safe drug that enhances formic acid metabolism and may be considered in the methanol poisoned patient [6]. Hemodialysis still plays an important role in methanol poisoning because of the slow elimination of formic acid. Indications for hemodialysis include severe metabolic acidosis (base deficit > −15 mM), vision disturbance, renal failure, hemodynamic instability and a methanol level > 50 mg/dL [6, 92]. Lack of a methanol level should not delay treatment because the degree of acidosis correlates better with prognosis and permanent visual impairment [6]. During hemodialysis, it is important to continue fomepizole at a shortened dosing interval to maintain plasma levels to continue ADH inhibition. Hemodialysis is continued with a goal to resolve acidosis and achieve methanol levels < 25 mg/dL [6]. Following redistribution, methanol levels may rebound within 36 h and repeat hemodialysis may be needed. Therefore, pH, osmolal gap, electrolytes, and methanol levels should be monitored 36 h following cessation of hemodialysis [6].

Isopropyl Alcohol (Isopropanol) Isopropanol is a bitter alcohol used in automotive and cleaning products as well as being the solvent in rubbing alcohol. It is metabolized to acetone in the liver. Toxic effects are secondary to isopropanol, not acetone. The minimal lethal dose for children has not been described, but approximately 100 mL may be lethal in an adult [93]. Levels are not routinely available, but can be useful. Levels > 400 mg/dL indicate a need for hemodialysis [93, 94]. Hemodialysis should also be considered for isopropanol levels > 200 mg/dL, especially when hypotension and coma exist [95]. Isopropanol is absorbed rapidly and elimination half-life is 3–7 h [96]. Clinical signs of isopropanol may include a fruity order, altered mental status, coma, vomiting, abdominal pain, hematemesis, and hypotension. Isopropanol should be strongly suspected when laboratory studies show an elevated osmolal gap and a positive serum acetone test accompanied without a metabolic acidosis. Other clues to the diagnosis include the presence of urine ketones, renal failure and hypoglycemia [93]. Activated charcoal may be considered for toxic co-ingestions. Supportive treatment is usually sufficient if coma and hypotension are not present.

J.E. Sullivan and M.J. McDonald

Ethanol Ethanol exposures accounted for over 3,500 calls to American poison centers in 2009 [1]. Alcoholic beverages, mouthwashes containing ethanol, aftershaves, colognes, and perfumes allow children access to ethanol in the home [97]. Oxidation of ethanol in the liver by alcohol dehydrogenase produces acetaldehyde which leads to the production of ketone bodies [95]. Ethanol ingestion may produce intoxication, altered mental status, coma, vomiting and hypothermia. Metabolic acidosis, ketosis, hypoglycemia, hypokalemia, hypernatremia, hypochloremia, and osmolal gap may also occur [98]. Ethanol is rapidly absorbed and activated charcoal should be reserved for toxic co-ingestions. Ethanol levels are readily available and supportive care is the mainstay of treatment. Management should focus on maintenance of airway, breathing and circulation. Vomiting with aspiration pneumonitis may occur. Hypoglycemia and hypotension should be appropriately addressed. Treatment usually includes volume replacement and dextrose containing fluids until the patient returns to baseline. Currently, a threshold on when to perform hemodialysis does not exist for the severely intoxicated ethanol patient.

Psychoactive Drugs Antipsychotics Small amounts of antipsychotics can cause significant toxicity in children. The antipsychotics exert their effects over a large number of different receptors: serotonin, dopamine, histamine, α-adrenergic, and muscarinic. Classes of antipsychotics include the phenothiazines, butyrophenones, and the newer atypical antipsychotics. An aliphatic phenothiazine, chlorpromazine, produces CNS depression, profound sedation, and miosis in overdose. Extrapyramidal symptoms (EPS), neuroleptic malignant syndrome (NMS), dystonic reactions, and seizures may also occur. Thioridazine, a piperidine phenothiazine, is the most cardiotoxic antipsychotic in overdose in adults. Strong sedation effects, miosis and QT prolongation have been seen with pediatric ingestions. Trifluoperazine, perphenazine and fluphenazine are piperazine phenothiazines and cause dystonic reactions, EPS, and CNS depression following overdose. The most widely used butyrophenone antipsychotic is haloperidol. Drowsiness, tremor, dystonic reactions, and EPS are found most commonly with overdose. Olanzapine is an atypical antipsychotic classified as a thienobenzodiazepine. CNS depression, tachycardia and agitation are common, but EPS, miosis, hypersalivation and anticholinergic effects also occur. The atypical antipsychotic risperidone in overdose may cause altered mental status, EPS, tachycardia and hypotension [99]. Ziprasidone is another atypical antipsychotic that usually causes drowsiness, lethargy and tachycardia. Rarely,

50 Toxic Ingestions

QTc prolongation may be seen [100, 101]. Aripiprazole, an atypical antidepressant and antipsychotic, causes CNS depression, vomiting, tachycardia and hypotension in overdose. And finally pimozide, an antipsychotic drug with a special indication to treat tics and Tourette syndrome, may cause seizures, EPS, dystonic reactions, CNS depression and hypotension with overdoses. Symptomatic care is the mainstay of treatment for all antipsychotic overdoses. Severe CNS depression may necessitate the need for intubation. Hypotension usually resolves with fluid administration. Activated charcoal should be administered within 1 h to the non-sedated patient. Benzatropine or diphenhydramine should be administered to patients with dystonic reactions or EPS. Antipsychotic EPS may require days of treatment before resolving [99]. The combination of fever, tachycardia, muscle rigidity and altered mental status in patients exposed to atypical antipsychotics requires CPK evaluation and NMS consideration. Of note, children and adolescents with atypical antipsychotic NMS had a shorter duration of illness when treated with bromocriptine when compared to dantrolene [102].

Selective Serotonin Reuptake Inhibitors (SSRIs) Increased use of SSRIs in depression can be traced to less toxicity following overdoses and an improved adverse effect profile in comparison to TCAs [103]. Commonly used SSRIs include sertraline, paroxetine, fluvoxamine, fluoxetine, and citalopram. SSRIs take approximately 4 h to reach peak serum concentration after ingestion [104]. In general, SSRI ingestions are well tolerated in children [105]. There is potential for a clinical serotonin syndrome to occur consisting of tachycardia, hyperthermia, mydriasis, myoclonus, hyperreflexia, shivering, diaphoresis, diarrhea, muscle rigidity, delirium, and agitation [69]. Activated charcoal is indicated for the non-sedated patient following ingestion. Serotonin toxidromes are generally treated with supportive care. Do not confuse serotonin syndrome with NMS. NMS will lack mydriasis, will show lead pipe rigidity and have a history of exposure to neuroleptics. Nonspecific serotonin receptor antagonists (β-blockers, cyproheptadine, methysergide, and chlorpromazine) have been studied in animals, but routine use in humans cannot be recommended at this time [106]. However, a case using cyproheptadine in a 24 month old for a SSRI induced serotonin syndrome has been reported [107]. Tricyclic Antidepressants (TCAs) TCAs continue to be widely available because of continued clinical use treating a wide variety of disorders including depression, anxiety, chronic pain, headache, and attention deficit hyperactivity disorder. TCAs include amitriptyline, clomipramine, desipramine, dosulepin, doxepin, imipramine, lofepramine, nortriptyline, protriptyline and trimipramine. A dose of 5 mg/kg for all TCAs is a significant

707

ingestion warranting evaluation. Desipramine, nortriptyline, and trimipramine may cause toxicity with 2.5 mg/kg and a dose of 1 mg/kg of protriptyline warrants evaluation for toxicity [108]. TCAs exert their toxicity through anticholinergic effects, antagonism of peripheral α1 receptors, blockade of cardiac and CNS sodium channels, and by blocking CNS monoamine reuptake. Within 6 h of ingestion, the presence of hypotension, respiratory depression, altered mental status, seizures, cardiac dysrhythmias, or a QRS duration > 100 milliseconds (ms) puts the patient at high risk for complications [109]. Cardiac toxicity from TCA poisoning results from blockade of cardiac sodium channels. ECG changes include widened QRS interval, prolonged PR and QT intervals, right axis deviation, abnormal T waves and ST segments, and atrioventricular (AV) block. Sinus tachycardia is the most common rhythm observed, although supraventricular tachycardia, ventricular tachycardia, and bradydysrhythmias associated with AV block can also occur. Torsades de pointes is uncommon. A QRS duration > 100 ms and right axis deviation appear to be the strongest predictors of cardiac toxicity. A QRS > 160 ms should prompt immediate attention to prevent a ventricular dysrhythmia. ECG changes usually occur within the first 6 h and may last for days. Serious cardiac complications most commonly occur within 24 h of ingestion and rapid deterioration can be common [109]. Hypotension from TCA ingestion may occur because of cardiac toxicity as well as α1 adrenergic receptor blockade. Systemic anticholinergic effects are often present. Norepinephrine and serotonin reuptake blockade, sodium channel inhibition, anticholinergic effects, and hypotension may all have direct effects on the CNS. Agitation, altered mental status, seizures and coma can all result from TCA poisoning and are signs of a significant TCA ingestion. Glasgow Coma Scale (GCS) levels < 8 predict serious complications [110]. Initial treatment of the TCA poisoned patient should focus on airway, breathing, circulation and neurological status. Gastric decontamination should be performed with activated charcoal. Enterohepatic recirculation accounts for 15 % of TCA elimination [111]. Because activated charcoal is well tolerated, the authors recommend multiple dose activated charcoal for TCA poisonings. However, intubation with a cuffed endotracheal tube should be considered prior to the administration of activated charcoal if the patient has altered mental status and may not be able to protect their airway. Gastric lavage, hemodialysis and charcoal hemoperfusion are not indicated. Again, QRS duration of >100 ms, right axis deviation and abnormal heart rhythm on ECG indicate potential cardiac toxicity. TCA toxicity seems to be worsened by acidosis. Treatment centers on sodium loading and alkalinization by the administration of sodium bicarbonate with a goal blood pH of 7.5–7.55. Hyperventilation may be

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used to alkalinize the patient in the short term if bicarbonate alkalinization is delayed. Alkalinization increases the proportion of nonionized drug because TCAs are weak bases. This may decrease the cardiac toxic effects. Hypotension is treated with fluid resuscitation and the addition of α 1 adrenergic agonists (norepinephrine, phenylephrine) when necessary [112]. Anticholinergic effects are managed symptomatically. Benzodiazepines may be used to control agitation. Seizures may be treated with benzodiazepines or barbiturates. Sodium channel blockers should theoretically be avoided because of the potential to worsen cardiac and CNS toxicity, although both lidocaine and phenytoin have been used for TCA seizure treatment and have lower cardiac sodium channel blocking activity being class 1B antiarrhythmic agents.

Antihypertensives Calcium Channel Blockers (CCBs) CCBs are prescribed for multiple conditions including hypertension, migraine headaches and adult angina. Extended and immediate release preparations exist. The type of CCB ingested is important since CCBs are classified as dihydropyridines and nondihydropyridines. The dihydropyridines cause more vascular vasodilatation and less myocardial contractility effect and include amlodipine, isradipine, felodipine, nicardipine, and nifedipine [113]. The nondihydropyridines, including verapamil and diltiazem, decrease myocardial contractility to a greater degree, affect myocardial conduction, and are weak vasodilators [113]. Management of the CCB poisoned patient should initially focus on airway, breathing, and circulation. Activated charcoal is indicated and multiple doses may be considered if sustained release preparations have been ingested [114]. An ECG should be obtained in all ingestions. Significant ingestions may have hypotension and bradycardia; isotonic fluid resuscitation should be attempted but may not be effective. Atropine can be given for severe bradycardia but may also be ineffective [115]. Calcium gluconate or calcium chloride can be given IV as a bolus or drip to overload the calcium channel and increase contractility and blood pressure [116]. Serum ionized calcium levels should be monitored frequently when using a calcium drip. If ineffective, glucagon may be administered intravenously. Glucagon increases c-AMP in the myocardial cell which can increase contractility. The half-life of glucagon is extremely short so, if effective, a glucagon drip should also be administered. High dose insulin with dextrose can also be given as a bolus or a continuous drip. Insulin affects several intracellular mechanisms in the myocardial cell that contribute to inotropy [117]. If hypotension still exists, vasopressors should be initiated. Epinephrine and norepinephrine are good choices secondary

J.E. Sullivan and M.J. McDonald

to their vasoconstrictive and inotropic effects and should be titrated to effect. ILE infusions have shown benefit in animal and human case reports in CCB overdoses [17]. ILE therapy may be considered in life threatening situations. A phosphodiesterase inhibitor may increase contractility but may also cause unwanted vasodilatation. Levosimendan has been used in CCB overdose after conventional therapy failed with improvement of bradycardia but continued hypotension [118]. Temporary cardiac pacing has produced varying outcomes [114]. ECMO has been used with success in refractory cases [119].

Beta-blockers (β-blockers) β-blockers are available treatment options for a wide range of medical disorders. Their prevalence and toxic potential make β-blocker poisoning a significant cause of morbidity and mortality. In general, children less than 6 years of age, who usually do not ingest a large quantity of pills, do not develop toxicity from β-blocker ingestions [120]. Most patients will develop symptoms of β-blocker toxicity within 6 h of ingestion [121]. Potential toxicity from β-blockers include hypotension, bradycardia, bronchospasm and hypoglycemia [122]. Significant ingestions may cause cardiogenic shock, seizures, altered mental status, respiratory depression, ventricular arrhythmias and asystole [123, 124]. ECG changes include widening of the QRS interval and prolonged PR and QTc intervals [125]. Management of β-blocker toxicity begins with airway, breathing and circulation assessment. ECG and blood glucose are mandatory in any β-blocker ingestion. Activated charcoal, unless contraindicated, should be given to all β-blocker ingestions within 1–2 h of ingestion. Hypotension may be treated with fluids and atropine may treat symptomatic bradycardia. If an artificial airway is needed, atropine should be administered prior to intubation. Benzodiazepines should be used to treat seizures if present. If cardiovascular instability continues despite fluids and atropine, additional treatment includes glucagon, IV calcium, vasopressors, and high dose insulin and glucose. Other therapies supported by case reports and animal studies include a phosphodiesterase inhibitor infusion, sodium bicarbonate, levosimendan, ILE, temporary pacing, and ECMO. Glucagon increases c-AMP in the myocardial cell which can increase contractility. Glucagon therapy in β-blocker poisoning stems from multiple animal studies showing increased cardiac function and human case reports [126]. Again, the half-life of glucagon is extremely short. Therefore, if effective, a glucagon drip should be administered. Case reports have shown cardiovascular improvement with both calcium gluconate and calcium chloride infusions [127]. If a response is seen, a calcium drip can be continued. Serum ionized calcium levels should be monitored frequently when using a calcium drip. If cardiac function does not improve, vasopressor therapy should be

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started. An epinephrine infusion should be titrated to effect based on desired blood pressure. Insulin affects several intracellular mechanisms in the myocardial cell that contribute to inotropy [117]. High dose insulin with dextrose can also be given as a bolus or a continuous drip. A phosphodiesterase inhibitor can be considered and may increase contractility by also increasing c-AMP in the myocardial cell [128]. Sodium bicarbonate may restore cardiac output and narrow the QRS complex [129]. Levosimendan improved cardiac function and survival from propranolol intoxication in an animal model [130]. ILE has been beneficial in a case report and may be considered following routine therapy [124]. When all else fails, temporary pacing may be attempted and ECMO has previously been life-saving [131].

Clonidine Clonidine hydrochloride stimulates the imidazoline receptor and the presynaptic α-2 receptor in the brain leading to inhibition of norepinephrine release. This decrease in sympathetic outflow results in decreased peripheral resistance, renal vascular resistance, heart rate and blood pressure. Clonidine is approved for the management of hypertension, however off-label uses in children for opioid withdrawal, management of attention-deficit/hyperactivity disorder (ADHD) and Tourette syndrome has resulted in increased availability of this agent in homes with children. Although most children with clonidine exposure have minimal toxicity, a number of children have serious toxicity and very rarely death has occurred [132]. Toxicity can occur with ingestion of just 0.1 mg or one tablet [133]. Clonidine is available in pill or patch formulations. The patch is changed weekly, therefore significant exposure can occur if a child ingests a patch. Absorption of clonidine occurs rapidly and peak levels occur within 1–3 h and the majority of patients develop symptoms within 4–6 h of ingestion. Clonidine is renally excreted and has no active metabolites. Patients who have ingested clonidine are at risk for abrupt changes in mental status, therefore caution should be used in treating them with activated charcoal unless it is early after exposure. Whole bowel irrigation may be of benefit if a clonidine patch is ingested. Transient hypertension is seen due to stimulation of peripheral α-1 receptors. Subsequent altered mental status, hypotension, bradycardia, respiratory depression, hyporeflexia, and hypotonia occurs due to stimulation of central α-2 receptors resulting in decreased sympathetic outflow. Hypertension is usually not treated because it is transient and frequently is followed by prolonged hypotension. Hypotension should be treated with fluid followed by norepinephrine if needed. Bradycardia does not usually require treatment other than stimulation, but if it is significant and persistent, atropine may be indicated. Naloxone as a bolus dose or continuous infusion has been utilized with variable

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success for central nervous system depression and respiratory depression [133, 134]. If the patient does not respond to a bolus dose of naloxone, then no further doses should be given. Patients with significant CNS depression and respiratory depression require intubation. Supportive care is usually effective therapy.

Analgesics, Analgesics, Sedatives, and Antipyretics Opioids Opioids produce analgesia and anxiolysis as pain relievers and can also be found in cough suppressants and antidiarrheals. They are abused for their euphoric properties. Opioids react with μ (mu), κ (kappa), σ (sigma) and δ (delta)-receptors throughout the nervous system and gastrointestinal tract. Opioids commonly encountered include, but are not limited to, codeine, morphine, fentanyl, methadone, heroin, hydrocodone, oxycodone and meperidine. Opioids continue to be a major drug abuse problem and a cause of significant morbidity and mortality. Opioids may be used intravenously, subcutaneously, intramuscularly, transdermally, orally, nasally or inhaled. Transdermal administration of opioids in opioid naïve patients has resulted in significant morbidity and outof-hospital deaths. Length of clinical effects varies depending on the half-life of the opioid ingested with methadone lasting the longest and fentanyl the shortest. An opioid toxidrome is characterized by bradycardia, hypotension, miosis, respiratory depression, confusion, lethargy, ataxia, and coma (Table 50.3). Opioid induced respiratory depression occurs as a result of opioids decreasing central and peripheral chemoreceptor activity [135]. Noncardiogenic pulmonary edema can also occur with uncertain etiology, but may be related to inspiration against an obstructed airway and disruption of the endothelial-alveolar barrier [136]. The noncardiogenic pulmonary edema usually resolves rapidly over hours to 1–2 days with supportive care [137]. Respiratory depression from μ 2-receptor stimulation can eventually lead to apnea, respiratory arrest and death. Urine toxicology screening for opioids should be positive. Initial treatment is supportive focusing on airway, breathing and circulation. Respiratory compromise may be treated with naloxone or bag-mask ventilation and intubation. Naloxone is a short acting opioid antagonist with a long history of use in narcotic overdoses both for treatment and diagnostic purposes. If IV access is not available, naloxone should be administered intramuscularly. However, naloxone administration is not without risk. The half-life of naloxone is very short and if used as a reversal agent, opioid toxidrome symptoms may recur once naloxone disappears if the offending agent has a long half-life. An acute withdrawal syndrome can be induced with naloxone in the

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opioid-dependent patient. And lastly, naloxone may induce severe pain in patients receiving narcotics for acute pain [138]. In this situation, nalbuphrine, an opioid agonist-antagonist, would be a good drug choice to reverse the μ2 respiratory depression while preserving κ and σ narcotic receptor stimulation [139]. Nalmefene is a long-acting opioid antagonist with a half-life of 8–9 h that has been used in the pediatric population [140]. This could be of benefit in acute opioid ingestions when narcotic dependence and acute pain issues do not exist. Initial hypotension should be addressed with fluid boluses as needed. Activated charcoal should be given unless contraindicated. Activated charcoal is also very valuable in sustained-release, long-acting, and delayed absorption (dephenoxylate-atropine) opiates. Atypical opioids may also produce toxicity. Tramadol is a weak μ-receptor agonist while also causing inhibition of serotonin and norepinephrine in the CNS. Toxicity can result in CNS depression, respiratory depression, miosis, and even seizure activity [135, 141]. Benzodiazepines can be used to treat seizures, otherwise symptomatic care and activated charcoal administration is the mainstay of treatment. Buprenorphine is an opioid partial agonist, meaning that it still binds to opioid receptors. Clinically, in the correct dosing, it may produce decreased opioid effects. But in overdose, presentation and treatment should proceed as any other opioid ingestion. Buprenorphine/naloxone is a drug used to treat withdrawal symptoms but can still produce the typical CNS and respiratory opioid effects in overdose [142]. Again, treatment should be the same as any opioid ingestion.

Benzodiazepines The prevalence of benzodiazepines stems from their wide use in treatment for seizures, anxiety, hyperactivity, insomnia, and drug withdrawal. The benzodiazepines exert their effect in the CNS by binding to the GABAA chloride channel complex. This potentiates the action of GABA which causes the movement of chloride into the cell causing hyperpolarization [143]. Numerous benzodiazepines exist including diazepam, lorazepam, midazolam, flunitrazepam, alprazolam, chlordiazepoxide, and zolpidem. While some act faster than others, all tend to have peak effect within 2 h but differ in their duration of action. Clinical toxicity produces the sedativehypnotic toxidrome including bradycardia, hypotension, respiratory depression, hypothermia, confusion, stupor, and coma (Table 50.1). Sertraline and oxaprozin (nonsteroidal anti-inflammatory drug) may cause a false positive benzodiazepine urine drug screen [144]. Some evidence suggests that benzodiazepines with differing chemical structure, such as midazolam, chlordiazepoxide, and flunitrazepam, are not detected in many assays causing a false negative result on urine drug screening [144]. Initial treatment is supportive with attention to airway breathing and circulation. Intubation may be necessary

J.E. Sullivan and M.J. McDonald

depending on the degree of respiratory depression. Fluid boluses are indicated for hypotension. Flumazenil, a competitive antagonist at the GABAA receptor complex, can be used for diagnosis or treatment but its use remains controversial due to its association with a number of adverse events. Numerous studies report seizures and cardiac dysrhythmias following flumazenil use, especially when associated with TCAs and chloral hydrate [145–147]. Chronic benzodiazepine use prior to flumazenil exposure may precipitate seizure activity. It should be noted that flumazenil is short-acting, therefore, caution and close patient observation should be exercised if flumazenil is given for a long-acting benzodiazepine ingestion. Activated charcoal should be given unless contraindicated. It should be noted that propylene glycol is a diluent in diazepam and lorazepam and may cause adverse effects if taken in large quantities.

Acetaminophen Acetaminophen (N-acetyl-p-aminophenol; APAP; paracetamol) accounts for a significant proportion of accidental and intentional toxic exposures in pediatric patients which can lead to irreversible hepatotoxicity and death. The American Association of Poison Control Centers in 2009 received 170 reports of death associated with APAP alone and 240 deaths when APAP combination drugs were ingested [1]. More than 600 over-the-counter and prescription products contain APAP. Most patients present early in the course following APAP ingestion and do not require critical care unless they have signs of hepatoxicity, have co-ingested other potentially toxic agents, are symptomatic, or have other significant medical problems that place them at risk. Activated charcoal should be given within 1–2 h of ingestion as it does not interfere significantly with the oral antidote N-acetylcysteine [9]. Federal regulations in 2011 resulted in new recommended maximum therapeutic doses of acetaminophen for children and adults [148]. The infant formulation of 80 mg/mL is no longer available, therefore only the pediatric formulation of 160 mg/5 mL liquid exists and it must come with a measuring device. The therapeutic dose of APAP for children under 12 years of age is 10–15 mg/kg/dose every 4–6 h with a maximum recommended dose from the manufacturer of 75 mg/kg/day. For adults the maximal single dose was reduced to 650 mg with a maximum daily dose of 3,250 mg. These changes in formulations and dosing recommendations are aimed at decreasing unintentional and intentional overdose leading to liver injury from acetaminophen containing products [148]. In 2011 the AAP published a clinical report related to the use of antipyretics that discourages treating fever unless the child is uncomfortable or the child does not tolerate the increased metabolic demands caused by the fever due to an underlying disease process [149]. If healthcare providers and parents implement this practice, fewer children

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may be at risk for acetaminophen overdoses with subsequent hepatotoxicity. Normally, more than 90 % of APAP is conjugated with glucuronide or sulfate to form nontoxic renally excreted metabolites. Approximately 2 % is renally excreted and 5 % is metabolized by the hepatic cytochrome p450 mixedfunction oxidase enzyme (CYP2E1) to the toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI) which is then rapidly detoxified by conjugation to intracellular glutathione (GSH) forming a nontoxic conjugate (APAP-GSH). When the conjugation pathways in the liver are overwhelmed in APAP overdose, metabolism of APAP is shunted to the cytochrome p450 pathway which results in an increased production of the toxic metabolite NAPQI and depletion of glutathione [150, 151]. The exact mechanism of hepatocyte death is still not completely elucidated, however it does correlate with the activity of the catalyzing enzyme systems and GSH availability. When GSH stores are reduced by 70–80 %, the detoxification capacity of the liver is exceeded and NAPQI accumulates subsequently destroying hepatocytes and other cells. In the absence of GSH, covalent binding of NAPQI to the cysteine groups on hepatocyte macromolecules occurs forming NAPQI-protein adducts [152]. This process is the initial and irreversible step in development of cell injury. NAPQI binds to critical cellular targets such as mitochondrial proteins. The hepatocytic cellular necrosis occurs due to mitochondrial dysfunction with ATP depletion, DNA damage, alterations in calcium homeostasis and modifications of intracellular proteins. Newer data suggest that inflammatory mediators trigger the innate immune system with subsequent propagation of hepatocyte injury [151, 153]. Although not definitive, factors that may influence the risk for development of hepatotoxicity include age (younger being protective), chronic alcohol ingestion, poor nutritional status, tobacco use and concomitant use of drugs that induce the CYP2E1 system. Infants and children process APAP predominantly through sulfation at a younger age with glucuronidation increasing with age. Children less than 5 years of age appear less susceptible to APAP hepatoxicity which may be due to a lower production of NAPQI and conjugation as the predominant metabolic pathway [151, 153]. Acute ingestions of greater than 200 mg/kg in children and 8–10 g in an adult may result in hepatotoxicity. Initial signs (first 24 h) of acetaminophen are generally mild and the patient may have nonspecific gastrointestinal symptoms of nausea, vomiting, abdominal pain, anorexia, and malaise. Laboratory tests are usually normal at this time, however hypoglycemia may occur and reflects impaired hepatic gluconeogenesis, inability to mobilize hepatic glycogen stores and elevated levels of circulating insulin [153]. Over the next 24–72 h, the patient may have improvement of clinical symptoms but still have the onset of subclinical

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hepatotoxicity with rising aminotransferases, PT and total bilirubin. Metabolic acidosis occurs in approximately 50 % of patients and may reflect inhibition of uptake and metabolism of lactic acid by the liver and impaired hepatic clearance [153]. Patients may develop right upper quadrant pain during this time. Between 72 and 96 h the patient has signs of overt hepatocellular necrosis with marked elevations of aminotransferases, PT and total bilirubin. Signs and symptoms are variable depending on the extent of hepatic injury but many patients experience anorexia, nausea, vomiting, abdominal pain, malaise and may develop hepatic encephalopathy. Patients who develop acute liver failure may develop cerebral edema with increased intracranial pressure and fatal uncal herniation. Renal insufficiency may occur secondary to APAP-induced acute tubular necrosis and dehydration. The degree of hypophosphatemia reflects the severity of the overdose. A rising PT and bilirubin beyond 96 h is ominous. Approximately 70 % of patients survive acute liver failure and recover over 4 days to 2 weeks following ingestion. If there are significant signs of worsening of severe hepatotoxicity, early evaluation for liver transplant should be initiated [151, 153]. Mahadevan et al. identified the following poor prognostic indicators and the potential need for a liver transplant based on a retrospective review of APAP-induced hepatotoxicity in pediatric patients: (1) delayed presentation to the emergency department; (2) delay in treatment; (3) PT greater than 100 s; (4) serum creatinine greater than 2.3 mg/dL; (5) hypoglycemia; (6) metabolic acidosis; and (7) hepatic encephalopathy grade III or higher. According to this review, markedly elevated hepatic transaminase levels were not predictive of a poor outcome [154]. Initial therapy for APAP ingestions includes supportive care and obtaining serum APAP levels approximately 4 h post-acute ingestion. This result is plotted on the RumackMatthew nomogram (Fig. 50.1). If the APAP level falls above the “possible toxicity” line, therapy with oral, nasogastric or intravenous (IV) NAC should be initiated. Although the cost for the IV formulation is significantly higher than oral NAC, shorter hospitalization stays and less laboratory testing should ultimately reduce overall costs [2, 156]. The normal half-life of APAP is 2–4 h, but it may be prolonged in APAP overdose or co-ingestion with other substances, particularly those that delay gastric emptying. The nomogram cannot be used for prediction of risk for patients who have chronic ingestion of APAP or have taken extended-release products [157]. For these patients, NAC is usually administered if they have elevated liver enzymes or they are at risk for hepatotoxicity. A second APAP level may be obtained 4–6 h after the first level if the time of ingestion is unclear to determine if the level is rising or declining. N-acetylcysteine (NAC), the antidote for APAP toxicity, replenishes glutathione stores in the liver. It is very effective at preventing significant hepatic injury if it is initiated within

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J.E. Sullivan and M.J. McDonald Acetaminophen Toxicity Nomogram

pruritis, hypotension, tachycardia, bronchospasm and respiratory distress, which most commonly occur during the initial loading dose and may occur in up to 10 % of patients [2, 158]. Due to these adverse events, it has been recommended to use a maximum ceiling weight of 110 kg when calculating the dose [158]. The following laboratory tests should be collected at baseline and at 48–72 h if on oral NAC and at the end of the 21 h treatment regimen if on IV NAC: alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, creatinine, electrolytes, complete blood count, prothrombin (PT)/International Normalized Ratio (INR). If the liver or coagulation laboratory results are abnormal and the patient is on IV NAC, therapy should be continued at a rate of 6.3 mg/kg/h until these laboratory values improve.

500

Probable hepatic toxicity 200 150 Possible hepatic toxicity

Acetaminophen (µg/mL plasma)

100

50

10 Hepatic toxicity unlikely

25%

5

1 4

8

12 16 Hours after ingestion

20

24

Fig. 50.1 The Rumack-Matthew nomogram, relating expected severity or live toxicity to serum acetaminophen concentrations (Reprinted from Smilkstein et al. [155]. With permission from Elsevier.)

8–10 h of ingestion. However, many clinicians will institute NAC therapy if the patient presents within 16–24 h of ingestion and is at risk for severe hepatotoxicity. Historically, NAC was administered orally with a loading dose of 140 mg/ kg followed by 17 doses of 70 mg/kg every 4 h. However, intravenous NAC (Acetadote®) is now available. For adult IV dosing, the loading dose is 150 mg/kg in 200 mL of 5 % dextrose for 60 min, followed by 50 mg/kg in 500 mL of 5 % dextrose for 4 h, and 100 mg/kg in 1,000 mL of 5 % dextrose for 16 h. For children, standard IV dosing can cause hyponatremia and secondary seizures due to the free water load. Therefore, the resolution is to dilute 20 % NAC to a final concentration of 40 mg/mL (Table 50.6). The final mg/ kg dosing (loading dose, 150 mg/kg; 50 mg/kg for 4 h and 100 mg/kg for 16 h) is the same, but the free water is less than in the adult schedule. Adverse reactions to IV NAC include anaphylactoid reactions including rash, urticaria,

Salicylates The association of aspirin with the occurrence of Reye’s syndrome in the early 1980s resulted in a marked decrease in the use of salicylate products in children. However, although salicylates are not recommended for children, there continues to be a number of exposures and even deaths in pediatric patients. Salicylates are used for their analgesic, antipyretic, anti-inflammatory and antiplatelet effects. They are in many over-the-counter oral and topical formulations as a single agent or combination product. Products that may include salicylates include aspirin, antidiarrheal preparations (e.g. Pepto-Bismol®, Kaopectate®, etc.), analgesics (in combination with codeine, opiates or caffeine), antihistamines, cough/cold combination products with aspirin and acetaminophen, topical wart removers, and oil of wintergreen (methyl salicylate). Pure oil of wintergreen, used as a food flavoring agent, contains 7 g of salicylate in 1 teaspoon, which may be fatal. Many liniments and ointments contain methyl salicylate and are used as rubifacients. Dermal absorption of topical preparations can be significant, particularly after repeated applications. Sustained release and enteric coated products are also available. Salicylates are rapidly absorbed in the proximal GI tract, however in overdose the absorption may be delayed, bezoars may form and levels may continue to rise for hours, particularly with enteric coated products. Peak serum concentrations are achieved within 1 h of ingestion unless it is an extended release product, which extends the peak level to 4–14 h. The half-life at therapeutic dose is about 2–4 h but can be as long as 18–36 h in an overdose. Peak levels are achieved within 0.5–2 h with therapeutic doses. With therapeutic doses, 80–90 % of salicylate remains intravascular and protein bound which is evident by the small volume of distribution of 0.1–0.3 L/kg. However, the volume of distribution of salicylates increases with the dose, due to saturation of plasma protein binding [159, 160]. Salicylates undergo first order kinetics with serum concentrations proportional to dose concentrations. Hepatic metabolism is via glucuronidation, oxidation and glycine

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Table 50.6 N-acetylcysteine dosage guidelines N-acetylcysteine dosage guidelines: Acetadote® 20 % (200 mg/mL) Note: The 3 doses are administered sequentially for a continuous 21 h infusion Dosage calculator available at http://www.acetadote.net/dosecalc.php Weight Loading dose (over 60 min) Second dose (over 4 h) ® Acetadote® (mL) 5 % Dextrose Acetadote (mL) kg mg mL (mL) mg mL 5 750 3.75 15 250 1.25 10 1,500 7.5 30 500 2.5 15 2,250 11.25 45 750 3.75 20 3,000 15 60 1,000 5 25 3,750 18.75 100 1,250 6.25 30 4,500 22.5 100 1,500 7.5 35 5,250 26.25 100 1,750 8.75 40 6,000 30 200 2,000 10 50 7,500 37.5 200 2,500 12.5 60 9,000 45 200 3,000 15 70 10,500 52.5 200 3,500 17.5 75 11,250 56.25 200 3,750 18.75 80 12,000 60 200 4,000 20 85 12,750 63.75 200 4,250 21.25 90 13,500 67.5 200 4,500 22.50 95 14,250 71.25 200 4,750 23.75 ≥100 15,000 75 200 5,000 25

5 % Dextrose (mL) 35 70 105 140 250 250 250 500 500 500 500 500 500 500 500 500 500

Third dose (over 16 h) Acetadote® (mL) mg mL 500 2.5 1,000 5 1,500 7.5 2,000 10 2,500 12.5 3,000 15 3,500 17.5 4,000 20 5,000 25 6,000 30 7,000 35 7,500 37.5 8,000 40 8,500 42.5 9,000 45 9,500 47.5 10,000 50

5 % Dextrose (mL) 70 140 210 280 500 500 500 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000

Acetadote® is hyperosmolar (2,600 MOsm/L) and is compatible with 5 % dextrose, 0.5 normal saline (0.45 % sodium chloride injection), and water for injection (Adapted from Package insert, Acetadote®, Cumberland Pharmaceuticals.)

conjugation. However, in overdose, the enzyme systems become saturated at salicylate concentrations of 20–30 mg/dL and elimination changes from first-order to zero order (Michaelis-Menton) kinetics resulting in exponential increases in serum concentrations. Salicylate serum concentrations should be obtained at least 4 h following ingestion. Acute toxicity is defined as exposure of less than 8 h, whereas chronic toxicity is defined as exposure longer than this duration. For acute exposure, serum concentrations above 90 mg/dL are associated with severe toxicity and for chronic exposure, levels above 60 mg/dL are associated with significant toxicity. The Done nomogram is not useful for management of salicylate toxicity. Mild toxicity occurs with ingestions of 150–200 mg/kg. Severe toxicity following 300–500 mg/kg and more than 500 mg/kg may be fatal. Patients with more severe poisoning usually have a large anion gap metabolic acidosis and altered mental status. Clinical decisions should be based on overall clinical signs and symptoms of salicylism and not on the salicylate level alone as they do not reflect the severity of toxicity [159, 160]. Symptoms associated with salicylate poisoning are dose-related. Symptoms from mild toxicity include nausea, vomiting, tinnitus, tachypnea, and respiratory alkalosis. Symptoms from severe toxicity include nausea, vomiting, diarrhea, tinnitus, vertigo, metabolic acidosis, hyperpnea,

hyperventilation, diaphoresis, hyperthermia, altered mental status, seizures, coma, cerebral edema, hypotension, dysrhythmias, noncardiogenic pulmonary edema and death. Cerebral edema is a common autopsy finding. Pancreatitis is a rare complication. PT prolongation is fairly common. Chronic overdoses present more insidiously and cause more severe toxicity than acute ingestions. Symptoms with chronic exposure may consist primarily of neurologic manifestations such as confusion, delirium, and agitation. Onset of clinical toxicity and peak serum levels may be delayed in patients with ingestion of sustained release or enteric coated aspirin or if a bezoar develops. If the patient requires intubation, respiratory alkalosis from pre-intubation self-hyperventilation must be maintained by achieving pre-intubation minute ventilation through mechanical ventilation. If not, abrupt decompensation may occur due to worsening acidemia increasing the salicylate concentration in the brain [160, 161]. It is suggested that if the patient requires intubation, hemodialysis should start simultaneously [160]. Salicylates are metabolic poisons. In toxic concentrations, they stimulate the respiratory center in the brainstem (medulla), interfere with the Krebs cycle (limiting ATP production), uncouple oxidative phosphorylation (causing accumulation of pyruvic and lactic acid and heat production), and increase fatty acid metabolism (generating

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ketone bodies) [159, 160]. The net result is a mixed respiratory alkalosis and metabolic acidosis. Respiratory alkalosis develops early and may be the only acid base disturbance with mild salicylism. A primary respiratory alkalosis with compensatory metabolic acidosis develops in most adults with moderate intoxication. A primary metabolic acidosis and compensatory respiratory alkalosis develops in severe overdose and is associated with a higher rate of complications and death. Patients with marked metabolic acidosis are at risk for cerebral and pulmonary edema. Myocardial depression, hypotension, and central nervous system toxicity may precede cardiopulmonary arrest. Respiratory alkalosis may be brief or not occur at all in infants and young children who primarily develop a primary metabolic acidosis. Hypoglycemia may also develop and is more common in children [159–161]. Salicylate-induced pulmonary edema is a known complication associated with acute or chronic salicylate overdoses. Salicylate toxicity should be considered in patients presenting with non-cardiogenic pulmonary edema and neurological changes, anion-gap metabolic acidosis, or presumed sepsis. The biochemical cause of pulmonary edema may be related to an increase in permeability within the capillaries of the lung leading to “protein leakage” and transudation of fluid in pulmonary tissue [161]. Initial therapy includes monitoring a patient’s mental status, vital signs and administering intravenous fluids to correct hypovolemia. Serial salicylate levels should be obtained every 1–2 h until levels have peaked and are declining and the patient’s clinical symptoms have improved. Single determinations of salicylate levels are not sufficient because absorption may be delayed and erratic. Activated charcoal should be administered to patients with large ingestions even if after 2 h of ingestion because salicylate absorption can be delayed and erratic. A second dose of activated charcoal may be administered if salicylate levels continue to rise despite urine alkalinization. Whole bowel irrigation with polyethylene glycol should be considered in patients with large ingestions of enteric coated products if their airway is protected. Electrolytes should be monitored every 2 h and corrected as clinically indicated until the patient is clinically improved. Arterial or venous blood gases should be monitored for patients with moderate to severe toxicity and in all patients undergoing serum and urinary alkalinization. In patients with moderate to severe toxicity, a complete blood count, liver enzymes, electrolytes, blood urea nitrogen, creatinine, INR and partial thromboplastin time (PTT) should be obtained at baseline and periodically as indicated. A CT of the head may be indicated for patients with altered mental status as they may have cerebral edema and may require mannitol therapy [159, 160]. Administration of intravenous sodium bicarbonate and initial hyperventilation of intubated patients is used to

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maintain a goal target arterial pH for serum alkalinization of 7.50–7.55. Urine alkalinization to a urine pH greater than 7.5 facilitates urinary excretion of unbound salicylate. Urine alkalinization also promotes salicylate mobilization from the tissues to the plasma. If the initial serum salicylate concentration is greater than 30 mg/dL and rising, serum and urine alkalinization should be initiated by administering 1–2 mEq/ kg sodium bicarbonate by intravenous bolus followed by a continuous infusion of sodium bicarbonate containing intravenous fluids. Sodium bicarbonate (150 mEq or 3 ampules) in 1 l of 5 % dextrose with 20–40 mEq/L of potassium chloride will create an isotonic fluid and should be infused at 2–3 mL/kg/h. Alkalosis decreases the amount of non-ionized salicylate in the blood which should decrease penetration across the blood brain barrier and into other tissues [159– 161]. Urine output should be monitored hourly. Blood gases and urinary pH should be monitored every 2 h and used to titrate the sodium bicarbonate infusion rate. Alkalinization may cause hypokalemia, hypocalcemia, hypernatremia, and dysrhythmias. Hypokalemia should be corrected because it causes increased bicarbonate absorption in the renal tubules which decreases the effectiveness of urinary alkalinization. Patients who should be considered for hemodialysis include those with renal failure, refractory or severe acidosis, progressive clinical deterioration despite appropriate fluid therapy and urinary alkalinization, inability to maintain appropriate respiratory alkalosis, altered mental status, seizures, evidence of cerebral edema, or rising serum concentrations despite adequate therapy (above 90–100 mg/dL for acute exposure and 50–60 mg/dL for chronic exposure). A declining salicylate concentration in a patient who is not improving or is clinically deteriorating requires immediate interventions including dialysis to reverse the process. In addition, a patient who appears clinically stable but has increasing salicylate concentrations may have ongoing absorption and is at risk of decompensation. Hemodialysis may improve acid-base balance and help correct electrolyte abnormalities [159–161].

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) NSAIDs are used as analgesics, antiypyretics and antiinflammatory drugs. These drugs inhibit cyclooxygenase enzymes (COX-1 and COX-2) which results in decreased prostaglandin production and decreased pain and inflammation. Severe overdose, although very rare, may result in a significant metabolic acidosis that may be related to the formation of acidic metabolites, however death is almost non-existent [162, 163]. Other signs and symptoms of severe toxicity include seizures, delirium, coma, hypotension, tachycardia, renal failure, hepatic dysfunction, hypoprothrombinemia, gastrointestinal bleeding and hyperkalemia. Most symptoms are manifested within the first 4 h after ingestions. There have been several case reports of children who presented

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with severe toxicity [164–168]. Furthermore, there have been several reported cases of severe hypokalemia secondary to ibuprofen induced renal tubular acidosis which resolved with discontinuation of ibuprofen [169]. Serum electrolytes, blood urea nitrogen, creatinine and acid-base status should be determined in severe overdose. Intubation may be needed in patients with central nervous system depression or recurrent seizures. Hypotension responds well to intravenous fluids. Supportive care is generally effective and further interventions are usually not required. Anaphylactoid reactions have been reported with some NSAIDs [162].

Organophosphates and Carbamates Organophosphates and carbamates are insecticides that are usually used in rural areas. These products are readily absorbed through the skin, lungs, mucous membranes and gastrointestinal tract. Organophosphates induce a competitive and irreversible inhibition of pseudocholinesterase and acetylcholinesterase (AChE) whereas carbamates have competitive but reversible inhibition (transient) as they spontaneously hydrolyze within 48 h. Organophosphates phosphorylate the serine hydroxyl group of AChE preventing hydrolysis and inactivation of AChE. This leads to accumulation of AChE at the cholinergic synapses leading to dysfunction of the sympathetic, parasympathetic, peripheral and CNS [170, 171]. Clinical signs of cholinergic excess develop. Serious toxicity is rare in the United States now, but is more common in developing countries. The onset, duration and extent of effect depend on the agent, rate of absorption, amount of exposure, and rate of metabolic breakdown. The diagnosis is based on the clinical signs and symptoms although a history of known exposure is helpful. Most patients develop symptoms within 6 h of exposure although lipophilic organophosphates may have subtle early signs that progress to severe toxicity over many hours. Some organophosphates undergo “aging”, a process by which the bond of the organophosphate to AChE becomes stronger and cannot be reversed by oximes (pralidoxime in the USA; obidoxime in some other countries). For these agents, early administration of an oxime may prevent aging and shorten clinical manifestations of toxicity. There continues to be ongoing debate about the efficacy of oximes for organophosphate poisoning [172]. Muscarinic effects include bronchorrhea, bronchospasm, salivation, lacrimation, diaphoresis, vomiting, diarrhea, urination and miosis (Table 50.3). Nicotinic effects include tachycardia, hypertension, mydriasis, muscle fasiculations and cramps, weakness, and respiratory failure (Table 50.3). CNS effects include depression, agitation, confusion, delirium, coma and seizures. Children may have fewer muscarinic and nicotinic signs compared to adults [171, 173].

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Other clinical effects may include hypotension, ventricular dysrhythmias, heart block, metabolic acidosis, pancreatitis and hyperglycemia. Delayed effects include intermediate syndrome which is characterized by paralysis of respiratory, cranial motor, neck flexor and proximal limb muscles. This can occur 1–4 days after apparent recovery from cholinergic toxicity and prior to development of delayed peripheral neuropathy. Recovery usually requires months, however some deficits may only partially recover. Chemical pneumonitis may also occur due to exposure to the hydrocarbon component of the product. Initial therapy includes immediate decontamination of the skin, continuous monitoring of vital signs and cardiac rhythm, and monitoring neurological status. Healthcare workers must protect themselves to avoid contamination. Serial electrocardiograms should be performed to identify prolongation of the QTc and premature ventricular contractions. Red blood cell cholinesterase activity should be measured if available as it can help predict the degree of toxicity as it is a reflection of the activity in the brain and neuromuscular junction. Greater than 50 % reduction of RBC cholinesterase activity is associated with severe poisoning. Plasma cholinesterase levels are usually available and are a marker of exposure. However, they do not correlate with the degree of toxicity. Therefore many times these are not measured because the clinical symptoms are classic. Serum electrolytes and lipase should be obtained at baseline and monitored periodically. Negative inspiratory force (NIF) may be used to monitor for signs of impending respiratory failure and the need for intubation. Many children may require intubation and mechanical ventilation. Administration of the antidotes atropine and pralidoxime (an oxime) should be initiated immediately to reverse the muscarinic and nicotinic effects, respectively, because earlier intervention results in better efficacy [171–175]. Atropine dosing should be titrated to decrease bronchorrhea, however the patient should be monitored closely for cholinergic effects or atropine toxicity. Tachycardia is not a contraindication to atropine therapy. The initial intravenous atropine dose is 0.02 mg/kg (adult dose 1–3 mg). If the response is inadequate in 3–5 min the dose should be doubled. The intravenous dose can be increased and given every 3–5 min as needed to dry pulmonary secretions. Once secretions are dried, a maintenance infusion at 10–20 % of the loading dose may be given every hour. Pralidoxime is generally started on any patient who requires atropine therapy and is continued for at least 12 h. A loading dose of 25–50 mg/kg followed by a repetitive administration or a continuous infusion of 10–20 mg/kg per hour is administered until muscle weakness and fasiculations resolve. Pralidoxime does not cross the blood-brain barrier to reverse CNS effects. Inhaled ipratropium or glycopyrrolate may reduce bronchospasm. Fluid resuscitation and vasoactive agents may be needed if

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Table 50.7 Clinical stages of iron poisoning Clinical stages of iron poisoning Stage or phase Symptoms 1 Vomiting, diarrhea, gastrointestinal blood and fluid loss, abdominal pain, hematemesis, hematochezia, lethargy, shock, acidosis, coagulopathy 2 Transient resolution of gastrointestinal symptoms; subtle signs 3 Recurrence of gastrointestinal symptoms, severe metabolic acidosis, profound shock, acute respiratory syndrome, hypotension, CNS depression, hypovolemia 4 Hepatotoxicity to recovery; may develop acute lung injury 5 Vomiting, gastric outlet obstruction, strictures

Time from ingestiona 0–6 h 6–24 h 12–48 h 48–96 h 2–4 weeks

(Adapted from Madiwale and Liebelt [179]. With permission from Lippincott Williams & Wilkins) Note: There may be variability in duration of the stages and symptoms

a

the patient develops hypotension. Organophosphate-induced seizures should be treated with benzodiazepines. There has been a single study that showed that adding magnesium sulfate to conventional therapy reduced hospital length of stay and decreased mortality [176]. There is a single case report of improved cholinesterase levels following plasmaphoresis for sepsis in a patient who had organophosphate poisoning [177]. Patients should be monitored closely for 48 h after discontinuation of atropine and pralidoxime for signs of recurrent toxicity or development of intermediate syndrome.

Iron Iron exposure continues to be a significant problem in children, particularly younger children. In 2009 there were over 20,000 exposures in children reported to the American Association of Poison Control Centers but no reported deaths. The youngest reported patient with iron toxicity was a 7 week old ex-28 week infant who was given an accidental overdose which was recognized early and she survived without sequelae [178]. Because ion products are available in multiple formulations, it is important to obtain a good history of the product ingested as the elemental iron content varies by product, but it is the standard for determining risk of toxicity. Ingestion of 40–60 mg/kg of elemental iron in children places them at risk for significant toxicity. Under normal circumstances, damage from free radicals does not occur because of transport and storage proteins such as transferrin and ferritin [179]. In iron overdose, however, these protective mechanisms become overwhelmed and free radicals are produced which poison mitochondria, uncouple oxidative phosphorylation and inhibit the Kreb’s cycle [179]. Poisoning with iron salts produces five classic stages (Table 50.7) which may not occur in all cases but include: (1) gastrointestinal toxicity which occurs within a few hours after ingestion and is due to the corrosive effects of iron; it is characterized by vomiting and diarrhea which varies from mild to bloody and severe; gastrointestinal hemorrhagic necrosis may result in large fluid losses; anion gap metabolic acidosis and shock may occur in this stage; (2) apparent stability for up to 24 h, however this stage may

not be present in patients with severe toxicity; (3) shock and acidosis occurring 12–48 h after exposure caused by free iron depositing in tissues and disrupting cellular function; coma, seizures, respiratory distress and renal dysfunction may occur in severe poisoning; distributive shock as a result of hypovolemia and cardiogenic shock as a result of direct iron toxicity on the myocardium; (4) hepatotoxicity; and 5) gastrointestinal scarring and strictures which occurs 2–4 weeks after exposure. Most deaths are due to circulatory collapse. Postmortem examinations of fatal cases show corrosive injury to the gastrointestinal tract, hepatic necrosis, renal tubular necrosis, and deposition of iron in cardiac muscle and the brain [178–180]. Initial management includes treating hypovolemia, metabolic acidosis and shock. Some patients may require tracheal intubation. Useful laboratory tests include electrolytes, blood urea nitrogen, creatinine, liver function tests, coagulation tests (PT and PTT) and blood gas analysis. Significant elevations of aminotransferases, lactate dehydrogenase and bilirubin may occur 1–4 days post-ingestion in severe poisoning. Total iron binding capacity (TIBC) is unreliable in iron overdose. A serum iron concentration should be obtained between 2 and 6 h after ingestion if possible and interpreted based on the history and clinical signs and symptoms. Peak concentration usually occurs between 4 and 6 h post-ingestion. Patients with serum iron levels between 300 and 500 μg/dL are either asymptomatic or have mild symptoms. Moderate to severe toxicity occurs in patients with levels between 500 and 1,000 μg/dL. Patients that have levels greater than 1,000 μg/dL usually have serious toxicity and have the highest mortality risk. The serum iron level may be lower than expected if chelation therapy was initiated prior to the level. An elevated white blood cell count of 15 × 103/mm3 and a serum glucose level of 150 mg/dL have only a 50 % sensitivity to identify patients with serum iron levels greater than 300 μg/dL, therefore they are not a predictor of toxicity [179]. An abdominal radiograph is considered standard for pure iron ingestions, however the pills may not always be visualized radiographically due to differing concentrations or if absorption was complete prior to the radiograph. The number of pills seen on the radiograph may not correlate with toxicity.

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Iron absorption increases during an overdose because of disruption of GI mucosa as well as increased passive absorption across a larger concentration gradient. Gastric lavage, including the use of complexing and chelating agents in lavage fluid, is not indicated. Formation of an iron bezoar could cause a slower rate of absorption with delayed clinical effects. PEG-ES may be given orally or by nasogastric tube. The dose for children 6–12 years is 1,000 mL/h, children 9 months to 6 years is 500 mL/h and adolescents 1.5–2 L/h. This should be continued until rectal effluent is clear and there is no radiographic evidence of iron in the gastrointestinal tract. There is a case report of laparoscopic-assisted gastrotomy for the treatment of an iron bezoar in an adolescent who ingested a potentially lethal dose [181]. Chelation therapy with deferoxamine should be initiated if there is evidence of hypovolemia, shock, lethargy, persistent vomiting, diarrhea, positive anion gap metabolic acidosis, large number of pills on abdominal radiograph, or a serum iron level > 500 μg/dL. Deferoxamine works by binding the ferric form of iron (Fe3+) and forms the water-soluble complex ferrioxamine, which is then excreted in the urine and is responsible for the brick-orange ‘vin-rosé’ urine color. Vin-rosé colored urine occurs in about one-third of patients. Deferoxamine is most effective when given as a continuous intravenous infusion. The starting dose is 15 mg/kg per hour and is titrated up to a maximum of 35 mg/kg per hour based on the severity of clinical symptoms. The most frequent side effect is hypotension, therefore it is essential to adequately volume resuscitate the patient prior to starting deferoxamine. If hypotension develops, the rate of deferoxamine infusion may need to be decreased. Deferoxamine therapy is usually stopped when clinical signs and symptoms of systemic iron poisoning resolve, radio-opaque iron pills on abdominal radiographs are gone, and return of normal urine color if vin-rosé colored urine was present. Sometimes deferoxamine will be continued until the serum iron level is below 150–300 μg/dL. Following discontinuation, the patient should continue to be monitored closely and deferoxamine infusion may be resumed if clinical deterioration occurs. If deferoxamine infusion continues longer than 24–48 h, there may be a risk of developing acute respiratory distress syndrome. Other chelation therapies are being investigated but are not currently recommended [182, 183].

Hydrocarbons and Inhalation Abuse Hydrocarbons are a diverse group of organic compounds that include gasoline, kerosene, lamp oils, diesel fuels, mineral oils, naphtha, lighter fluids, carbon tetrachloride, mineral spirits, turpentine, lubricating oils and many other products commercially available. In 2009 there were over 43,000 single substance exposures to hydrocarbons reported to the American Association of Poison Control Centers with nearly half of those in infants, children and adolescents [1]. Usually,

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in young children, it is an accidental ingestion or aspiration, however in older children and adolescents, it may be due to inhalation abuse or intentional ingestion. Two key factors that increase the risks related to hydrocarbon exposures are their viscosity and surface tension properties. Low viscosity hydrocarbons that are absorbed systemically have the highest potential for toxicity [184]. Aspiration with subsequent pneumonitis, respiratory failure and acute respiratory distress syndrome are the most common adverse effects seen following hydrocarbon exposure. The aspiration risk is highest with those substances that have high volatility and low viscosity and surface tension. Surfactant is solubilized leading to atelectasis, interstitial inflammation and formation of hyaline membranes. Patients may have signs of a systemic inflammatory response. The chest radiograph may initially appear normal, but by 12–24 h post-aspiration significant changes are usually seen. Patients with significant aspiration will usually have a history of coughing, choking, respiratory distress and possibly vomiting. Clinical signs may include tachypnea, dyspnea, retractions, cyanosis and anxiety. Pulmonary auscultation may reveal rales, rhonchi or decreased breath sounds. Antibiotics and corticosteroids are not indicated. Oxygen and positive pressure ventilation may be indicated based on the clinical examination and blood gas results. Surfactant may be considered, however there is limited data on its benefits. Extracorporeal membrane oxygenation has been used successfully in patients who failed conventional ventilation therapy. Halogenated and aromatic hydrocarbons are readily absorbed through the skin, respiratory and gastrointestinal systems which can result in systemic toxicity including CNS depression, seizures and cardiac dysrhythmias (Table 50.8). These patients may also have nausea, vomiting and diarrhea. Rarely, renal dysfunction or failure will occur following an acute exposure to hydrocarbons. Gastric decontamination may be indicated, but only with very large ingestions or ingestion of certain halogenated, aromatic or substituted hydrocarbons (Table 50.8). Prior to emptying the stomach and gastric lavage, the airway must be protected with a cuffed endotracheal tube, sedation and possible paralysis should occur to minimize the risk of vomiting and aspiration. Inhalation abuse is the intentional inhalation of a volatile substance for the purpose of achieving a euphoric state or “high”. It is known as sniffing, huffing, snorting, solvent abuse, volatile substance abuse, bagging, and other names [185]. It is an under-recognized entity with more than 2.1 million children in the United States experimenting annually with approximately 20 % of middle and high schoolers having experimented. The peak age of abuse is 13–15 years and males experiment more than females. The substances abused are volatile, capable of producing a pleasurable sensory experience, readily available, legal, and may be region specific. Many of the products are hydrocarbons and contain

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Table 50.8 Hydrocarbons with potential adverse effects on CNS, cardiac, hepatic, renal and pulmonary systems Aromatic hydrocarbons Benzene Xylene Toluene

Halogenated (with chlorine, bromine or fluoride) Chloroform Carbon tetrachlorize Trichloroethylene Carbon tetrachloride Ethylene dichloride Tetrachloroethane Fluorocarbons Brominated hydrocarbons Vinyl trichloride (1,1,2-trichloroethane) Methylene chloride

Petroleum distillates and other substituted hydrocarbons Hydrocarbon with toxic additives Insecticides Nitrobenzene Aniline Heavy metals Kerosenea Gasolinea Furniture polisha Mineral spiritsa Lighter fluida

a

Primary risks are chemical pneumonitis and ARDS associated with aspiration

propellants and solvents. The vapors are readily absorbed from the lungs and reach high concentrations in the CNS due to their lipid solubility. Inhalants are depressants, however the user is initially stimulated, uninhibited, prone to impulsive behavior, and may appear “drunk.” The most common cause of death is “sudden sniffing death syndrome.” This is thought to be a result of hydrocarbon induced myocardial sensitivity to epinephrine, hypercarbia and hypoxia. Other adverse effects, depending on the product abused, include laryngospasm, respiratory distress, chemical pneumonitis, seizures, altered mental status and renal failure. Rarely methemoglobinemia may occur. Patients should have an initial electrocardiogram followed by continuous cardiopulmonary monitoring. Laboratory studies should include a complete blood count, comprehensive chemistry panel and blood gases if indicated. A chest radiograph may be indicated if respiratory symptoms are present. Supportive care and specific treatment for seizures and dysrhythmias are the primary interventions [186].

Caustic Agents Caustic agents are readily available and include products such as drain cleaners, household cleaners, hair relaxers and automatic dishwasher soaps. Alkaline agents are more common than acidic agents but both can cause significant mucosal injury and long-term sequelae. Exposures in young children are usually accidental and involve small volumes, however exposures in adolescents and adults may be intentional with larger volumes ingested and greater risk of significant injury. Alkaline corrosives cause liquefaction necrosis. They destroy the cell and allow deep penetration into mucosal tissue which may result in perforation. The initial inflammation is followed by tissue necrosis, granulation and eventually stricture formation. Acids cause coagulation necrosis with eschar formation which is usually limited in depth compared to alkaline necrosis. Inflammation follows necrosis with development

of vascular thrombosis, granulation tissue, fibrogenesis and strictures. The risk of perforation is increased during the time granulation tissue forms. Determinants of the extent of injury with both alkaline and acidic products include the concentration, pH, viscosity, the amount ingested and the duration of contact with the tissue [187]. Ingestions may result in burns to the lips, mouth, pharynx, esophagus, stomach and even airway. Esophageal burns result in the most serious complications. Patients with mild ingestions may only develop irritation, edema, erythema and are classified as Grade I burns. Patients with moderate toxicity may develop Grade II (a or b) burns (superficial blisters and ulcerations) and are at risk for subsequent stricture formation. Patients with severe exposure may develop deep circumferential burns, necrosis, and even perforation of the gastrointestinal mucosa [Grade III (a or b)]. Other complications include fistula formation (tracheoesophageal), gastrointestinal bleeding and later stricture formation. Hypotension, tachycardia, tachypnea and fever may develop but usually occur later due to severe gastrointestinal bleeding or necrosis. Young children are at risk for life threatening upper airway edema even with less severe ingestions. Fortunately, severe toxicity is generally limited to deliberate ingestions in adults because alkaline products available in the home are generally of low concentration. Spontaneous vomiting may occur and may worsen the exposure. The absence of visible oral burns does NOT exclude the presence of esophageal or gastric burns. More serious esophageal injury should be considered in patients with stridor, vomiting, drooling, and abdominal pain. Dysphagia is the most common symptom of significant esophageal injury. Patients with hypotension, a rigid abdomen or radiographic evidence of intraperitoneal or mediastinal air may require surgical intervention. Dermal exposure may result in skin irritation and partial thickness burns. Prolonged exposure or products with high concentrations can cause full thickness burns. Ocular exposure can produce severe conjunctival irritation, corneal injury, or permanent visual loss. An ophthalmologist should be consulted early in the course.

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Supportive therapy should be initiated and should include administration of anti-emetics if needed to decrease the risk of vomiting. Neutralizing agents results in heat production increasing tissue injury and should be avoided. Corticosteroids and antibiotics are generally not recommended. Endoscopy should be performed within 12–24 h of ingestion in patients with stridor, vomiting, drooling, significant oral burns, difficulty swallowing or abdominal pain. The earlier it is performed, the less risk there is of perforation with the examination. The grade of mucosal injury at the initial endoscopy is the best predictive factor for development of esophageal and gastrointestinal complications and mortality. A nasogastric tube should be placed under direct visualization if there are extensive burns and a gastrostomy tube may be indicated. If there are Grade II or III burns, then a barium swallow should be performed in several weeks and endoscopy repeated. Children with strictures are at risk for obstruction in the future. Esophageal dilation can be performed once the tissues have granulated. The length of the esophageal stricture may indicate those who can successfully be treated with dilation. However, if extensive strictures are present, a gastrostomy tube may be indicated. Stent placement or esophagectomy and colonic interposition grafts may be necessary [187–190].

Smoke Exposure, Cyanide (CN) and Carbon Monoxide (CO) Smoke exposure may result is a range of signs and symptoms based on the type and length of exposure. Important information includes if the exposure was in an open or enclosed space, length of exposure, type of burning material, presence of fire or explosion, loss of consciousness, status of other victims, and the amount, color, and odor of smoke. The preliminary evaluation should include arterial blood gases with co-oximetry to determine presence of carboxyhemoglobin (COHb), chest radiograph, cyanide level, electrocardiogram (ECG), comprehensive chemistry panel, and indirect laryngoscopy if the patient is not tracheally intubated. Symptoms are usually related to the effects of the irritants and asphyxiants in the smoke. Neurological symptoms may be related to chemical exposure or to hypoxemia. CN poisoning is initially manifested as transient hyperpnea and tachycardia accompanied by headache, dizziness, nausea and vomiting. Hypoxia leads to hypoventilation, hypotension, myocardial depression, cardiac dysrhythmias, stupor, coma, and seizures. Cardiorespiratory arrest and death may occur. The breath of some patients may have a bitter, almond-like odor, however this is not always present. The symptoms of carbon monoxide poisoning are similar to CN. The cherry-red discoloration of the skin and mucus membranes is not commonly found. Other clinical findings from smoke inhalation

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include a nonproductive cough, eye irritation, lacrimation, confusion, anxiety, vertigo, respiratory distress, and trauma. Acute pulmonary edema and lactic acidosis may be seen. Intubation and mechanical ventilation with higher PEEP may be required to maintain adequate oxygenation in patients with smoke inhalation. ARDS may occur and should be treated accordingly. Good pulmonary toilet should be maintained regularly. Fluid resuscitation will be required if burns of the skin are present. Bronchodilators such as albuterol and ipratropium may be used to treat bronchospasm.

Cyanide Combustion of many plastics and fabrics produces hydrocyanic acid (HCN) gas which is one of the leading causes of death in patients with smoke exposure and the most common cause of CN toxicity [191–193]. HCN may be inhaled or absorbed through the skin. It is a rapidly fatal asphyxiant that causes cellular hypoxia by formation of a stable complex with cytochrome oxidase leading to disruption of the mitochondrial electron transport chain. The cells switch from aerobic to anaerobic metabolism which results in decreased availability of adenosine triphosphate (ATP) and increased production of byproducts such as lactic acid [193–195]. The heart, brain and liver are primary targets because of their oxygen requirement [193–195]. CN toxicity is a medical emergency because from the time of onset of symptoms to death can be short depending on the exposure. Another potential exposure to cyanide is the highly toxic acetonitrile-containing cosmetics, particularly false-fingernail removers, which may be confused with the less-toxic acetone-containing fingernail-polish removers [193]. Two treatment options are approved in many countries and include the Cyanide Antidote Kit (amyl nitrite pearls, sodium nitrite and sodium thiosulfate) and the Cyanokit® (hydroxocobalamin). Both the nitrite/thiosulfate combination and hydroxocobalamin are effective antidotes, however hydroxocobalamin appears to offer an improved safety profile, especially for children, pregnant women and victims of smoke inhalation [195–197]. Therapy should be administered emergently to any patient with signs and symptoms of CN poisoning. This includes those patients who present with coma, severe metabolic acidosis, severe cardiac dysrhythmias, and COHb level greater than 15 %. Hydroxocobalamin combines with cyanide to form cyanocobalamin which is a nontoxic, water soluble metabolite that is eliminated in the urine. Sodium thiosulfate may also be administered with hydroxocobalamin in the critically ill patient, but it is not part of the kit [197]. The main adverse effects from hydroxocobalamin, which itself is red, is red discoloration of the mucous membranes, skin, urine, and serum, but this is thought to be benign [191, 198]. Allergic reactions and transient hypertension also have been rarely reported [195]. Hydroxocobalamin can also interfere with

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Carbon Monoxide Carbon monoxide exposure most commonly occurs due to faulty furnaces, automobile fumes, space heaters, portable generators, or from smoke exposure in a fire. CO rapidly crosses the pulmonary capillary membrane and combines with hemoglobin at 200–250 times the affinity of oxygen, binds at the same site and shifts the oxyhemoglobin curve to the left resulting in hypoxia (Fig. 50.2) [170, 202]. In addition

100

Leftward Shift (Increased affinity)

90 80 Hemoglobin (% saturation)

many colorimetric based tests and has also been shown to interfere with tests for carboxyhemoglobin, metHb, and oxyhemoglobin, all potentially pertinent tests for victims of smoke inhalation or cyanide poisoning [199]. The standard adult dose of hydroxocobalamin is 5 g intravenously over 15 min. A second 5 g dose can be given in patients with severe toxicity. For pediatric patients, 70 mg/kg (maximum of 5 g) has been administered, but there are only case reports but no prospective trials evaluating this therapy in children [195, 200, 201]. It can be followed by a repeat dose of 35 mg/kg if needed [195]. If hydroxocobalamin is not available, amyl nitrite is administered first to stabilize the patient and is inhaled or held close to the patient’s nose or mouth with 1.00 FiO2 for 30 s of each minute until intravenous access is established. It is followed by intravenous sodium nitrite (pediatrics: 10 mg/kg IV/adults 300 mg IV over 3–5 min) and finally sodium thiosulfate (pediatrics: 400 mg/kg IV; adults: 12.5 g IV). The goal of both amyl nitrite and sodium nitrite treatment is to produce methemoglobin by oxidizing iron in hemoglobin from the ferrous (Fe2+) to ferric form (Fe3+). The ferric form rapidly removes cyanide from cytochrome oxidase forming cyanomethemoglobin and subsequent restoration of cellular respiration. Cyanomethemoglobin then reacts with sodium thiosulfate to form thiocyante which is renally excreted leaving methemoglobin free to bind to more cyanide. Patients with renal failure may require hemodialysis to eliminate thiocyanate. Seizures that occur secondary to thiocyanate accumulation are effectively treated with a benzodiazepine. Blood methemoglobin levels should be monitored for 30–60 min following the infusion to prevent severe toxicity. If the methemoglobin concentration is greater than 30 %, methylene blue 1 % should be administered. The components of the cyanide antidote kit have potentially serious toxicity. Nitrites may cause significant vasodilation and hypotension which may require treatment with fluids or vasoactive agents. Nitrite-induced methemoglobinemia reduces the oxygen-carrying capacity of the blood which may already be compromised if the patient has carbon monoxide toxicity or shock. In children, if an immediate hemoglobin measurement is unavailable, nitrites should be avoided because hemoglobin kinetics vary with age. Therefore, methemoglobinemia associated with nitrite-based antidotes, may be excessive and result in death [4, 191, 193].

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70

pH paCO2 Temperature 2,3 DPG

Rightward shift (reduced affinity)

60

pH paCO2

50

Temperature 2,3 DPG

40 Normal

30 20 10 0 10

20

30

40

50

60

70

80

90

100

PaO2 (mm Hg)

Fig. 50.2 Oxyhemoglobin dissociation curve

to generating carboxyhemoglobin, other mechanisms of toxicity include direct disruption of cellular oxidative processes by binding to myoglobin and cytochromes. During recovery, there may be marked oxidative stress and inflammatory responses [202]. Patients with carboxyhemoglobin levels less than 10 % are usually asymptomatic, levels of 20 % or greater usually have a headache, dyspnea, and difficulty in concentrating, and those with levels of 30–40 % have irritability, nausea, confusion, tachypnea, chest pain, ST segment depression, AV conduction block and ventricular dysrhythmias. Patients with levels of 40–60 % may experience seizures, coma, and death [170]. Other complications that rarely occur (2–10 %) and may be delayed for days to several weeks after the initial hypoxic insult include diffuse cerebral demyelination resulting in gradual neurological deterioration with apathy, apraxia, gait disturbances, incontinence, movement disorders (parkinsonism, choreoathetosis), hallucinations, seizures, cortical blindness, dementia and coma [170, 202]. Unconscious patients should be intubated and ventilated with 100 % oxygen. The elimination half-life of carboxyhemoglobin decreases from 350 to 90 min when the patient breathes 100 % oxygen and increases when normocarbia is maintained [170]. Oxygen supplementation should continue until CO is 5 mg/L) most accurately reflect clinical effects, however they are not always available. Total phenytoin levels of >30 mg/L result in evidence of neurotoxicity. Death from overdose is a rare complication. Supportive care is the mainstay of treatment. AC is often recommended in the initial treatment and there is some evidence that multipledose AC reduces half-life and enhances elimination of phenytoin, but does not alter outcome. Whole-bowel irrigation with large doses of PEG-ES by nasogastric tube until a clear rectal effluent is obtained may be useful in the patient with an overdose of sustained-release phenytoin or in those patients whose serum phenytoin levels continue to rise after 24 h in the setting of a large overdose. The airway should be protected prior to administering activated charcoal or PEG-ES if the patient has an altered state of consciousness [213].

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Valproic Acid (VPA) VPA toxicity is usually mild, self-limiting and may require supportive care although CNS depression, serious toxicity, and even death may occur [214]. CNS depression, the most common sign of toxicity, ranges from mild drowsiness to profound coma and fatal cerebral edema [214]. An exact mechanism for the action of the drug has yet to be determined. The net result of the actions of the drug is thought to be an increase in brain concentrations of γ-aminobutyric acid (GABA). VPA is also thought to inhibit neuronal firing by prolonging recovery from inactivation of voltagesensitive sodium channels and to reduce the flow of calcium ions through T-type calcium channels, thus reducing neuronal pacemaker current [215]. Respiratory and multiorgan failure may occur in those patients with significant toxicity. Plasma valproic acid concentrations do not correlate with the severity of CNS toxicity [214]. Patients who ingest more than 200 mg/kg VPA or have plasma concentrations greater than 450 mg/L usually develop severe CNS depression. Other signs and symptoms include respiratory depression, nausea, vomiting, diarrhea, hypothermia or fever, hypotension, tachycardia, miosis, agitation, hallucinations, tremors, myoclonus, and seizures. Rarely, heart block, pancreatitis, acute renal failure or acute respiratory distress syndrome will develop. Hyperammonemia, anion gap metabolic acidosis, hyperosmolality, hypernatremia, and hypocalcaemia may also develop [214]. Administration of AC is recommended. Other interventions may involve blood pressure support with intravenous fluids and vasopressors, correction of electrolyte abnormalities such as hypernatremia or anion gap metabolic acidosis. Because valproic acid depletes carnitine stores, supplementation with L-carnitine may attenuate some of these adverse effects and reverse hyperammonemia. Severely toxic patients who have renal dysfunction, refractory hypotension, severe metabolic abnormalities, recurrent seizures, persistent coma or levels greater than 1,000 mg/L may benefit from hemodialysis although there are no controlled trials that demonstrate improved outcome [214, 216–218].

gas if indicated. Carbamazepine levels should be collected every 4 h until they have peaked and are declining. Levels of 20 μg/mL or greater may be associated with significant toxicity [222]. Diphenhydramine may be administered if the patient develops a dystonic reaction. Interventional treatment for seizures, respiratory depression and cardiac dysrhythmias may be necessary. The airway will need to be protected in those patients with severe toxicity prior to nasogastric tube placement for AC administration. There is no evidence that multiple doses of AC improves clinical outcome although it is frequently administered. Carbamazepine induced bowel hypomotility may increase the risks associated with multiple dose activated charcoal [219]. Whole bowel irrigation is effective for patients who have ingested a large amount of the sustained release product.

Carbamazepine

Methemoglobinemia is rare, but the intensivist must recognize and treat it promptly. Methemoglobinemia results from exposure to chemicals that oxidize the ferrous iron (Fe2+) in hemoglobin to the ferric state (Fe3+) and the rate of methemoglobin production exceeds the rate of reduction [226]. The oxygen-dissociation curve shifts to the left resulting in tissue hypoxia due to reduced-oxygen carrying capacity (Fig. 50.2). Causes of methemoglobinemia include but are not limited to local anesthetic agents, dapsone, nitrites, nitrates, sulfonamides, aniline dyes, contaminated wellwater, naphthalene and nitrous gases. Nonspecific findings that help clinicians differentiate methemoglobin from other life-threatening conditions include persistent cyanosis, tachypnea, low pulse oximetry

Toxicity related to carbamazepine is due to its anticholinergic activity, sodium channel blockade, and CNS and myocardial depression effects. Signs of severe toxicity include coma, seizures, respiratory depression, pulmonary edema, poor myocardial contractility, hypotension, tachycardia, and dysrhythmias with conduction delays that may include PR, QRS and QTc prolongation [219]. Mydriasis and nystagmus are common clinical signs, but may also be present in therapeutic doses [220]. Children may manifest signs of overdose at lower concentrations than adults. Neurologic symptoms and tachycardia are the most common presentation in children [220, 221]. Laboratory tests should include a comprehensive metabolic panel, complete blood count, and arterial blood

Oxcarbazepine Oxcarbazepine has a similar profile to carbamazepine but has lower toxicity and is better tolerated. Overdose data is limited. Hyponatremia has been reported which may lead to seizures and coma [223]. Other adverse effects include bradycardia, hypotension, tinnitus, vertigo and lethargy for which supportive care is usually sufficient. Administration of AC is recommended.

Levetiracetam This drug is newer to the market, therefore the toxicologic data is limited. Awaad reported an overdose of 4 and 10 times the recommended daily dosage in two children without significant adverse effects [224]. Vomiting, drowsiness, coma and respiratory depression have been reported [225]. Treatment for the patient with a toxic ingestion is supportive and directed at the presenting symptoms. Discretion should be used regarding administration of AC due to the potential for deterioration of the patient’s mental status.

Methemoglobinemia

50 Toxic Ingestions

and a lack of response despite therapy with 100 % oxygen therapy. Additional confirmation is provided by the results of the arterial blood gas accompanied by the classic chocolatebrown color appearance of the arterial blood sample. The diagnosis should be confirmed by at least one of the following: methemoglobin measurement, positive co-oximetry result, or confirmation of the oxygen saturation gap. Co-oximetry cannot be repeated after the administration of methylene blue because it will be read as methemoglobin. Methemoglobin levels of 10–25 % are associated with cyanosis. Headache, fatigue, dizziness, and dyspnea occur at levels of 35–40 % and levels of 60 % may cause arrhythmias, seizures, lethargy, and stupor. Levels greater than 70 % may result in vascular collapse and death [226, 227]. Administration of oxygen and removal of the offending agent should be done immediately. Therapy with methylene blue 1 % is directed at restoration of adequate oxygen-carrying capacity by the reduction of methemoglobin if the patient is symptomatic or has a level above 20 %. Methylene blue is the co-factor that acts as an electron acceptor for the hexose monophosphate shunt pathway (NADPH) within erythrocytes resulting in ferric to be reduced to ferrous. It is given intravenously at a dose of 1–2 mg/kg over 5 min. The dose may be repeated 30–60 min later if the patient remains cyanotic. At high doses, methylene blue can actually cause methemoglobinemia. Patients with G6PD deficiency should not be given methylene blue because they cannot generate sufficient NADPH, therefore it will cause a severe oxidant hemolysis [226]. Patients should be monitored for an additional 24 h following treatment due to the risk of rebound methemoglobinemia.

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J.E. Sullivan and M.J. McDonald 166. al-Harbi NN, Domrongkitchaiporn S, Lirenman DS. Hypocalcemia and hypomagnesemia after ibuprofen overdose. Ann Pharmacother. 1997;31(4):432–4. 167. Oker EE, et al. Serious toxicity in a young child due to ibuprofen. Acad Emerg Med. 2000;7(7):821–3. 168. Linden CH, Townsend PL. Metabolic acidosis after acute ibuprofen overdosage. J Pediatr. 1987;111(6 Pt 1):922–5. 169. Ng JL, et al. Life-threatening hypokalaemia associated with ibuprofen-induced renal tubular acidosis. Med J Aust. 2011; 194(6):313–6. 170. Worthley LI. Clinical toxicology: part II. Diagnosis and management of uncommon poisonings. Crit Care Resusc. 2002;4(3): 216–30. 171. van Heel W, Hachimi-Idrissi S. Accidental organophosphate insecticide intoxication in children: a reminder. Int J Emerg Med. 2011;4(1):32. 172. Buckley NA, et al. Oximes for acute organophosphate pesticide poisoning. Cochrane Database Syst Rev. 2011;2:CD005085. 173. El-Naggar Ael R, et al. Clinical findings and cholinesterase levels in children of organophosphates and carbamates poisoning. Eur J Pediatr. 2009;168(8):951–6. 174. Peter JV, Moran JL, Graham PL. Advances in the management of organophosphate poisoning. Expert Opin Pharmacother. 2007; 8(10):1451–64. 175. Farrar HC, Wells TG, Kearns GL. Use of continuous infusion of pralidoxime for treatment of organophosphate poisoning in children. J Pediatr. 1990;116(4):658–61. 176. Pajoumand A, et al. Benefits of magnesium sulfate in the management of acute human poisoning by organophosphorus insecticides. Hum Exp Toxicol. 2004;23(12):565–9. 177. Guven M, Sungur M, Eser B. The effect of plasmapheresis on plasma cholinesterase levels in a patient with organophosphate poisoning. Hum Exp Toxicol. 2004;23(7):365–8. 178. Valentine K, Mastropietro C, Sarnaik AP. Infantile iron poisoning: challenges in diagnosis and management. Pediatr Crit Care Med. 2009;10(3):e31–3. 179. Madiwale T, Liebelt E. Iron: not a benign therapeutic drug. Curr Opin Pediatr. 2006;18(2):174–9. 180. Manoguerra AS, et al. Iron ingestion: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila). 2005;43(6):553–70. 181. Haider F, et al. Emergency laparoscopic-assisted gastrotomy for the treatment of an iron bezoar. J Laparoendosc Adv Surg Tech A. 2009;19 Suppl 1:S141–3. 182. Porter JB, et al. Ethical issues and risk/benefit assessment of iron chelation therapy: advances with deferiprone/deferoxamine combinations and concerns about the safety, efficacy and costs of deferasirox [Kontoghiorghes GJ, Hemoglobin 2008; 32(1-2):115.]. Hemoglobin. 2008;32(6):601–7. 183. Kontoghiorghes GJ. Ethical issues and risk/benefit assessment of iron chelation therapy: advances with deferiprone/deferoxamine combinations and concerns about the safety, efficacy and costs of deferasirox. Hemoglobin. 2008;32(1–2):1–15. 184. Cobaugh DJ, Seger DL, Krenzelok EP. Hydrocarbon toxicity: an analysis of AAPCC TESS data. Przegl Lek. 2007;64(4–5):194–6. 185. McGarvey EL, et al. Adolescent inhalant abuse: environments of use. Am J Drug Alcohol Abuse. 1999;25(4):731–41. 186. Research report series: inhalant abuse. H.a.H. Services, editor. National Institute of Drug Abuse; 2010. 187. Abaskharoun RD, Depew WT, Hookey LC. Nonsurgical management of severe esophageal and gastric injury following alkali ingestion. Can J Gastroenterol. 2007;21(11):757–60. 188. Bicakci U, et al. Minimally invasive management of children with caustic ingestion: less pain for patients. Pediatr Surg Int. 2010;26(3):251–5. 189. Erdogan E, et al. Management of esophagogastric corrosive injuries in children. Eur J Pediatr Surg. 2003;13(5):289–93.

50 Toxic Ingestions 190. Thirlwall AS, et al. Caustic soda ingestion – a case presentation and review of the literature. Int J Pediatr Otorhinolaryngol. 2001;59(2):129–35. 191. Dart RC. Hydroxocobalamin for acute cyanide poisoning: new data from preclinical and clinical studies; new results from the prehospital emergency setting. Clin Toxicol (Phila). 2006;44 Suppl 1:1–3. 192. Eckstein M, Maniscalco PM. Focus on smoke inhalation–the most common cause of acute cyanide poisoning. Prehosp Disaster Med. 2006;21(2):s49–55. 193. Geller RJ, et al. Pediatric cyanide poisoning: causes, manifestations, management, and unmet needs. Pediatrics. 2006;118(5):2146–58. 194. Guidotti T. Acute cyanide poisoning in prehospital care: new challenges, new tools for intervention. Prehosp Disaster Med. 2006;21(2):s40–8. 195. Shepherd G, Velez LI. Role of hydroxocobalamin in acute cyanide poisoning. Ann Pharmacother. 2008;42(5):661–9. 196. Hall AH, Saiers J, Baud F. Which cyanide antidote? Crit Rev Toxicol. 2009;39(7):541–52. 197. Borron SW, et al. Hydroxocobalamin for severe acute cyanide poisoning by ingestion or inhalation. Am J Emerg Med. 2007;25(5):551–8. 198. Uhl W, et al. Safety of hydroxocobalamin in healthy volunteers in a randomized, placebo-controlled study. Clin Toxicol (Phila). 2006;44 Suppl 1:17–28. 199. Lee J, et al. Potential interference by hydroxocobalamin on cooximetry hemoglobin measurements during cyanide and smoke inhalation treatments. Ann Emerg Med. 2007;49(6):802–5. 200. Haouach H, Fortin JL, LaPostolle F. Prehospital use of hydroxocobalamin in children exposed to fire smoke. Ann Emerg Med. 2005;46:S30. 201. Espinoza OB, Perez M, Ramirez MS. Bitter cassava poisoning in eight children: a case report. Vet Hum Toxicol. 1992;34(1):65. 202. Weaver LK. Clinical practice. Carbon monoxide poisoning. N Engl J Med. 2009;360(12):1217–25. 203. Lo Vecchio F, Gerkin RD, Curry SC. CO poisoning and hyperbaric oxygen therapy: more studies need to be done. Am J Respir Crit Care Med. 2008;178(3):314. author reply 314-5. 204. Hampson NB, Hauff NM. Risk factors for short-term mortality from carbon monoxide poisoning treated with hyperbaric oxygen. Crit Care Med. 2008;36(9):2523–7. 205. Buckley NA, et al. Hyperbaric oxygen for carbon monoxide poisoning. Cochrane Database Syst Rev. 2011;4:CD002041. 206. Teksam O, et al. Acute cardiac effects of carbon monoxide poisoning in children. Eur J Emerg Med. 2010;17(4):192–6. 207. Scott J, et al. Prolonged anticholinergic delirium following antihistamine overdose. Australas Psychiatry. 2007;15(3):242–4. 208. Jang DH, et al. Status epilepticus and wide-complex tachycardia secondary to diphenhydramine overdose. Clin Toxicol (Phila). 2010;48(9):945–8.

727 209. Benson BE, et al. Diphenhydramine dose-response: a novel approach to determine triage thresholds. Clin Toxicol (Phila). 2010;48(8):820–31. 210. Scharman EJ, et al. Diphenhydramine and dimenhydrinate poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila). 2006;44(3):205–23. 211. Roberts DM, Buckley NA. Enhanced elimination in acute barbiturate poisoning – a systematic review. Clin Toxicol (Phila). 2011;49(1):2–12. 212. Index of suspicion. Pediatr Rev. 2002;23(7):249–53. 213. Craig S. Phenytoin poisoning. Neurocrit Care. 2005;3(2): 161–70. 214. Eyer F, et al. Acute valproate poisoning: pharmacokinetics, alteration in fatty acid metabolism, and changes during therapy. J Clin Psychopharmacol. 2005;25(4):376–80. 215. Manoguerra AS, et al. Valproic acid poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila). 2008;46(7):661–76. 216. Lheureux PE, Hantson P. Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol (Phila). 2009;47(2):101–11. 217. Hicks LK, McFarlane PA. Valproic acid overdose and haemodialysis. Nephrol Dial Transplant. 2001;16(7):1483–6. 218. Sztajnkrycer MD. Valproic acid toxicity: overview and management. J Toxicol Clin Toxicol. 2002;40(6):789–801. 219. Spiller HA. Management of carbamazepine overdose. Pediatr Emerg Care. 2001;17(6):452–6. 220. Lifshitz M, Gavrilov V, Sofer S. Signs and symptoms of carbamazepine overdose in young children. Pediatr Emerg Care. 2000; 16(1):26–7. 221. Perez A, Wiley JF. Pediatric carbamazepine suspension overdoseclinical manifestations and toxicokinetics. Pediatr Emerg Care. 2005;21(4):252–4. 222. Montgomery VL, et al. Severity and carbamazepine level at time of initial poison center contact correlate with outcome in carbamazepine poisoning. J Toxicol Clin Toxicol. 1995;33(4): 311–23. 223. Wade JF, et al. Emergent complications of the newer anticonvulsants. J Emerg Med. 2010;38(2):231–7. 224. Awaad Y. Accidental overdosage of levetiracetam in two children caused no side effects. Epilepsy Behav. 2007;11(2):247. 225. Barrueto Jr F, et al. A case of levetiracetam (Keppra) poisoning with clinical and toxicokinetic data. J Toxicol Clin Toxicol. 2002;40(7):881–4. 226. El-Husseini A, Azarov N. Is threshold for treatment of methemoglobinemia the same for all? A case report and literature review. Am J Emerg Med. 2010;28(6):748 e5–748 e10. 227. Alapat PM, Zimmerman JL. Toxicology in the critical care unit. Chest. 2008;133(4):1006–13.

51

Envenomations James Tibballs, Christopher P. Holstege, and Derek S. Wheeler

Abstract

This chapter discusses the type, incidence and management of envenomation caused by a wide variety of terrestrial and marine creatures in North America and Australia including snakes, spiders, scorpions, bees, wasps, ants, jellyfish, octopuses, stinging fish and cone shells. Death from snake bite and scorpion stings world-wide are respectively estimated at 20,000–94,000 and 3,000 per year. While few deaths from envenomation by snakes and other creatures occur in North America and other developed countries such as Australia, serious injury and hospitalizations are not infrequent. Principles of management of snake bite include first-aid, administration of antivenom (antivenin) and intensive supportive treatment. Spider bites are the most frequent type of envenomation, but deaths are rare with the availability of antivenoms. Important spider species in North America are widow spiders and the brown recluse spider, while in Australia important species are funnel-web spiders and the red-back spider. Mortality from anaphylactic reactions to bee, wasp and ant stings in developed countries equals or exceeds that from snake bite. Envenomation by jellyfish is frequent world-wide but mortality is very low except after envenomation by chirodropid species common in the Indo-Pacific region. Immunological responses to jellyfish stings are a relatively unrecognized phenomenon. Injury from species of stinging fish account for many hospitalizations while envenomations by specific octopuses and cone shells occur sporadically. Keywords

Envenomation • Snake • Spider • Scorpion • Bee • Wasp • Ant • Jellyfish • Stinging fish

J. Tibballs, MBBS, MEd, MBA, MD (*) Paediatric Intensive Care Unit, Royal Children’s Hospital, 50 Flemington Road, Parkville, Melbourne, Victoria, Australia e-mail: [email protected] C.P. Holstege, MD Department of Emergency Medicine, University of Virginia Health System, Room 4601, 4th Floor Poison Center Suite, Charlottesville, VA, USA e-mail: [email protected] D.S. Wheeler, MD, MMM Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA e-mail: [email protected] D.S. Wheeler et al. (eds.), Pediatric Critical Care Medicine, DOI 10.1007/978-1-4471-6362-6_51, © Springer-Verlag London 2014

Introduction The specialty of pediatric critical care medicine crosses both the boundaries separating several different medical disciplines as well as the geographical boundaries that separate different regions around the world. In the past, textbook chapters dealing with the recognition and management of bites and stings by venomous animals have dealt almost exclusively with those species found within the continental United States and Canada, often with only a passing reference to species found outside North America. As pediatric critical care medicine is a global specialty, this chapter will emphasize the recognition and management of bites and stings by venomous animals found within and outside North 729

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America, in the latter case using Australia as a reference, though the principles are applicable universally. This is particularly pertinent to all pediatric critical care clinicians as amateur collection of non-endemic, exotic species is a growing problem in the United States and other countries, and therefore envenomations by non-endemic species will be mentioned briefly as well. A large proportion of the injuries that result from such exotic bites and stings frequently involve the pediatric age group, many of which are often severe enough to necessitate admission to the pediatric intensive care unit (PICU). Advice on management of envenomation by Australian venomous creatures may be obtained from the Australian Venom Research Unit (AVRU) advisory service on their 24-h telephone number: 1300 760 451. Advice on management of envenomation in the United States may be obtained through the regional Poison Control Center (which may be accessed through the national hotline at 1 800 222 1222).

Venomous Snakes There are over 2,500-3,000 species of snakes worldwide, of which approximately 375 species are considered venomous, belonging to one of five families (i) the Viperidae family (Old World Vipers), including adders and asps; (ii) the Crotalidae family (pit vipers), including several species found in North America such as the copperhead, rattlesnake, and cottonmouth; (iii) the Elapidae family, including the coral snake (North America), cobra, krait, mamba, brown snake (Australia), and black snake (Australia); (iv) the family Colubridae, including the boomslang; and (v) the family Hydrophiidae (sea snakes). In Australia, of approximately 130 species of terrestrial and marine snakes (all of which are found in either the Elapidae or Hydrophiidae family), the majority are venomous and more than 20 species are dangerous to humans. The terrestrial species belong to genera Pseudonaja (brown snakes), Notechis (tiger snakes), Oxyuranus (taipans), Pseudechis (black snakes), and Acanthophis (death adders). All are elapids, including death adders. The last group, belonging to the Hydrophiidae family are the sea snakes. Nearly 2,000 people require hospitalization after a snake bite in Australia each year [1], and of these at least 300 require treatment with antivenom. The mean death rate from snake bite in Australia from 1981 to 1999 was 2.6 deaths per year (approximately 0.14 cases/one million population) [2]. Several venomous snake species are found in North America as well, and with the exception of the coral snake (Elapidae family), all are found exclusively in the Crotalidae (pit-viper) family [3]. The pit-vipers are so-named because of small,

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heat-sensitive pits between the eye and nostril that allow these snakes to sense their prey. These snakes can regulate the amount of venom they inject during a bite based upon their ability to sense the size of their prey with the aid of these specialized pits, though the amount of venom injected in a defensive bites are often less controlled. The pit vipers are further distinguished from other species by the presence of a triangular-shaped head with an elliptical pupil, a single row of subcaudal scales (as opposed to a double row in nonvenomous snakes), and a venom apparatus consisting of two glands situated in the maxilla, two ducts, and two hollow maxillary teeth or fangs. These fangs are long and retract posteriorly when the mouth is closed. Several pairs of replacement fangs (usually at least three pairs) in various stages of development lie posterior to these fangs and move forward to replace shed or broken fangs. At least one indigenous species of venomous snake has been identified in every state but Alaska, Maine, and Hawaii [4]. Coral snakes account for only 1-2 % of all venomous snakebites in the United States and belong to the genus’ Micruroides and Micrurus. They are not overly aggressive and rarely bite unless provoked – these snakes transfer their venom by chewing rather than injecting. Coral snakes are indigenous to the Southwestern and Southeastern United States. The pit vipers (family Crotalidae) include several species of rattlesnakes (genus Crotalus and Sistrurus) (Fig. 51.1), copperheads (genus Agkistrodon) (Fig. 51.2), and cottonmouths (genus Agkistrodon). Because of their widespread distribution, rattlesnakes are responsible for the majority of fatalities from snakebites in North America – the eastern diamondback and western diamondback varieties, in fact, account for almost 95 % of these deaths [3, 5, 6]. Copperheads are common to the eastern United States and require less utilization of antivenom therapy due to a modestly potent venom and neglible fatality rate. Cottonmouths, also known as water moccasins, are highly aggressive, semi-aquatic snakes found primarily in the southeastern United States. These snakes are so-named from the distinctive white color of their open mouths. The American Association of Poison Control Centers reports almost 6,000 snakebites in the United States each year, of which at least 2,000 involve venomous snakes [5]. The true incidence of snakebites is probably vastly underestimated, as reporting is not mandatory and most snakebites probably go unreported. Experts estimate that the number of venomous snakebites in the United States is probably closer to 7,000– 8,000 per year, resulting in 5–6 deaths per year [6]. For example, 57 deaths from snakebites were reported during the period between 1991 and 2001, yielding an annual rate of 0.019 cases/one million population [7]. Worldwide, it is estimated that as many as 5.5 million snake bites occur on an annual basis, with between 0.42 and 1.84 million envenomations and between 20,000 and 94,000 deaths every year, most of which

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Envenomations

Fig. 51.1 Western diamond-back rattlesnake (Used with permission of Christopher P. Holstege, MD, University of Virginia, Charlottesville, Virginia)

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Bite marks may resemble everyday minor limb trauma. Due to higher venom to body mass ratio, the onset of envenomation is more rapid and more severe than in adults. Equally, parents often bring their child to medical attention when they fear or suspect snake bite after seeing a snake in the child’s vicinity but saw no contact. The question then is whether the child has been bitten, and if so, has he or she been envenomated. Finally, herpetologists and amateur snake collectors are also prone to snake bite – it is merely a question of time until they sustain a bite. Herpetologists sustain on average 4–5 bites in their working life and a life-threatening bite every 10 years [11]. Persons who are repeatedly bitten have a risk of developing allergic reactions to venoms and to the antivenoms used in their treatment. Amateur snake collectors endanger themselves and others who share their environments and may not know the true identity of captive specimens.

Snake Venoms and Toxins

Fig. 51.2 Copperhead (Used with permission of Christopher P. Holstege, MD, University of Virginia, Charlottesville, Virginia)

occur in South Asia, Southeast asia and sub-Saharan Africa [8]. Snake envenomations are therefore a global problem that result in significant morbidity and mortality. The typical victims in most cases, at least in North America and Australia, are males between 17 and 27 years of age [3, 4, 8–10]. The vast majority of bites affect the hands or arms and result from deliberate attempts to handle or harm the snake. Not surprisingly, alcohol intoxication is a factor in a large percentage of these envenomations [3, 4, 8–10]. Children are also unwitting victims due to their natural inquisitiveness and adventurous spirits. In most cases involving young children, snake bites are accidental, as when a snake is trodden upon or suddenly disturbed. In such cases, the lower extremities are more commonly affected. The management of snake bite in young children poses additional problems. Diagnosis of envenomation is difficult when a bite has not been observed by an adult. The symptoms of early envenomation may pass unsuspected or misinterpreted and early neurological signs are difficult to elicit.

Death and critical illness after snake bite is usually due to (i) respiratory failure secondary to neuromuscular paralysis, (ii) hypotension secondary to hemorrhage, or (iii) renal failure occurring secondarily to rhabdomyolysis, disseminated intravascular coagulation (DIC), hypotension, hemolysis, or to their combinations. Rapid collapse, not accompanied by respiratory failure, within minutes after a snake bite may be due to anaphylaxis to venom or possibly due to the myocardial ischemia [12] secondary to effects of DIC. Snake venoms are complex mixtures of proteins ranging from 6 to 100 kDa, many of which have enzymatic properties, e.g. phospholipases (especially phospholipase A2), proteases, collagenases, hyaluronidases, acetylcholinesterase, metalloproteinases, lactate dehydrogenase, thrombin-like enzymes, etc. Inorganic substances, such as zinc and magnesium are variably present as well and may serve as cofactors for the aforementioned enzymes. Histamine-like factors are also present, which increase capillary permeability and lead to local tissue edema. Many of the toxins are specific to a given species, with the quantity, composition, and lethality varying with the species, geographic location, and the time of the year [10, 13]. It is probably inaccurate to classify any one particular venom as a neurotoxin, hemotoxin, myotoxin, cardiotoxin, etc., as venom exerts its effect on multiple organ systems [13, 14]. The main toxins in venoms of Australian snake genera cause paralysis, coagulopathy (disordered coagulation), rhabdomyolysis, and hemolysis (Table 51.1). Local tissue destruction is not usually a feature. There is variation of effects within a genus – for example, the venom of the Eastern brown snake (Pseudonaja textilis) causes paralysis

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Table 51.1 Main components of venoms and their effects in poisonous snakes found in North American and Australia Neurotoxins (brown snakesa, tiger snakes, taipans, death adders, black snakes, coral snakes, mojave rattlesnake) Presynaptic and postsynaptic neuromuscular blockers cause paralysis Postsynaptic blockers readily reversed by antivenom Presynaptic blockers are more difficult to reverse, particularly if treatment is delayed Some presynaptic blockers are also rhabdomyolysins Prothrombin activators (brown snakes, tiger snakes, taipans, crotalids) Cause disseminated intravascular coagulation with consumption of clotting factors including fibrinogen Intrinsic fibrin(ogen)lysis generates fibrin(ogen) degradation products Significant risk of haemorrhage Anticoagulants (black snakes, death adders, crotalids) Present in a relatively small number of dangerous species Prevent blood clotting without consumption of clotting factors Rhabdomyolysins (taipans, black snakes, sea snakes, crotalids) Some presynaptic neurotoxins also cause lysis of skeletal and cardiac muscle Myoglobinuria may cause renal failure Hemolysins Present in a few species Rarely a serious clinical effect a

Some species of brown snakes do not contain neurotoxins

whereas the Western brown snake (Pseudonaja nuchalis) does not, while the dugite (Pseudonaja affinis) has weak paralytic activity. Coagulopathy is often due to a procoagulation effect of prothrombin activators (Factor Xa-like enzymes). This process consumes clotting factors (consumption coagulopathy) forming fibrin which undergoes endogenous fibrinolysis to generate fibrin degradation products. Australian snake venoms, in contrast to some exotic venoms, do not cause primary fibrinolysis. The appearance of fibrin degradation products is therefore evidence that procoagulation has occurred. However, in a limited number of species coagulopathy is due to a direct anti-coagulant effect which does not generate fibrin degradation products. Pit viper venoms also affect almost every major organ system (Table 51.1). In contrast to the Australian snake genera, pit viper venoms contain toxins that cause local tissue damage, thereby allowing the venom to penetrate deeper into the tissues. Hemotoxins directly damage the vascular endothelium, resulting in third-spacing of fluids and extravasation of erythrocytes [15], clinically manifest as edema, ecchymosis, and bleb formation. Pit-viper venoms, in particular, contain several hemostatically active components, some of which have been used in preclinical trials as anticoagulants [16]. Venom metalloproteinases cleave pro-tumor necrosis factor (TNF)-α, and the subsequent release of activated TNF-α leads to further inflammation and tissue destruction

Fig. 51.3 Snake envenomation site – dry bite (Used with permission of Christopher P. Holstege, MD, University of Virginia, Charlottesville, Virginia)

[17, 18]. Myotoxin A is found in several species and produces direct necrosis of skeletal muscle tissue [19]. The venom of the Mojave rattlesnake (Crotalus scutulatus scutulatus) contains several neurotoxins as well as hemotoxins and toxins that cause tissue necrosis (myotoxins) [20–23]. Coral snake venom, also contains several neurotoxins, hemotoxins, and myotoxins [24–26].

Clinical Manifestations of Envenomation Bites are usually observed by the victim but are relatively painless and occasionally go unnoticed, especially in cases associated with alcohol intoxication. Paired fang marks surrounded by inflammation or bruising are usually evident but sometimes only scratches or single puncture wounds are found (Fig. 51.3). Infrequently, when the snake strikes a second time, there will be two sets of paired fang marks. The bite-site may continue to bleed slightly. In some venomous snake bites, there will also be a second row of smaller teeth marks (which can occasionally be mistaken for a nonvenomous snakebite). Australian snake venoms do not cause extensive damage to local tissues, though occasionally the viability of a digit may be threatened or a small skin graft required. This contrasts markedly with bites by the North American pit vipers, where massive local reaction, hemorrhage, and tissue necrosis are often major features of envenomation and frequently threaten the viability of the affected limb (Figs. 51.4 and 51.5). Envenomation does not always accompany a bite (a so-called dry bite) – in several studies the incidence of clinical envenomation after observed snake bite was approximately 25–50 % [2, 10, 13, 15, 26], presumably because no or very little venom was injected.

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Fig. 51.5 Chest wall ecchymosis and death following timber rattlesnake (Crotalus horridus horridus) envenomation with the bite site noted in the mid thorax (Used with permission of Christopher P. Holstege, MD, University of Virginia, Charlottesville, Virginia) Table 51.2 Onset of major systemic symptoms and signs of envenomation (Elapids)

Fig. 51.4 Marked arm ecchymosis following timber rattlesnake (Crotalus horridus horridus) envenomation (Used with permission of Alexander B. Baer, MD, University of Virginia, Charlottesville, Virginia)

The time course of symptoms and signs after effective envenomation is somewhat predictable (Tables 51.2 and 51.3), but sometimes one symptom or sign may predominate or may wax and wane. These phenomena may be explained by variations in venom toxins of the same species in different geographical areas, or by variable absorption rates of different toxins. The fear associated with the snakebite itself may lead to symptoms of nausea, vomiting, diarrhea, syncope, and tachycardia almost immediately. These signs and symptoms must be differentiated from systemic signs and symptoms of envenomation (see below), though this may at times be quite difficult. As stated above, local findings such as pain, edema, erythema, or ecchymosis commonly emerge at the site of the bite and surrounding areas within 30–60 min following pit-viper envenomation. Bullae (containing either serous fluid or hemorrhage), lymphangitis, and tender, swollen regional lymph nodes soon follow (Fig. 51.6). Regional lymphadenitis also occurs

3 h after bite Paresis/paralysis of truncal and limb muscles Paresis/paralysis of respiratory muscles (respiratory failure) Peripheral circulatory failure (shock), hypoxemia, cyanosis Rhabdomyolysis Dark urine (due to myoglobinuria or hemoglobin) Renal failure In massive envenomation or in a child, a critical illness may develop in minutes rather than hours

with bites by mildly venomous snakes in the absence of serious systemic illness. Localized pain is almost immediate and occurs in more than 90 % of cases associated with pit viper envenomation, though a bite by the Mojave rattlesnake may produce numbness without pain. Similarly, coral snake envenomation produces little pain, but occasionally may produce tremors, marked salivation, and altered mental status. Local tissue injury, especially when it affects an

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J. Tibballs et al.

Table 51.3 Onset of major systemic symptoms and signs of envenomation (crotalids) 3 h after bite Peripheral circulatory failure (shock), hypoxemia, cyanosis DIC Rhabdomyolysis Dark urine (due to myoglobinuria or hemoglobinuria) Acute renal failure In massive envenomation or in a child, a critical illness may develop in minutes rather than hours

extremity, may result in compartment syndrome, rarely necessitating fasciotomy. Australian species are less commonly associated with local tissue injury. Neurotoxic effects (i.e. coral snake, most of the Australian species, Mojave rattlesnake, and occasionally the eastern diamonback rattlesnake) include headache, nausea, vomiting, and cranial nerve palsies – these are manifest by ptosis, dysarthria, dysphagia, and dyspnea. Gross muscle weakness usually occurs over several hours, eventually culminating in neuromuscular respiratory failure. Coagulopathy, determined by laboratory tests (see below), is likely to be present within 15 min after envenomation by a coagulopathy-producing species. Venom-induced thrombocytopenia, fibrinolysis, and DIC have all been reported and may clinically manifest as epistaxis, hemoptysis, mucosal bleeding, bleeding from the wound itself, or petechiae (Fig. 51.7) [27]. Massive envenomation may cause rapid cardiovascular collapse, though this occurs in less than 7 % of pit viper envenomations [28] and contrary to popular belief, pit viper bites are usually not immediately fatal (unless the venom enters a blood vessel directly). The cause of transient hypotension not accompanied by respiratory failure or hemorrhage within 30 min after envenomation, is obscure but it may be related to intravascular coagulation since prothrombin activators gain access to the circulation within a number of minutes after subcutaneous

Fig. 51.6 Hemorrhagic bullae of the finger following copperhead (Agkistrodon contortrix) envenomation (Used with permission of Christopher P. Holstege, MD, University of Virginia, Charlottesville, Virginia)

injection and this effect is prevented experimentally by heparin [29–32]. Third space loss of fluids may also lead to hypotension and shock. Tachycardia and relatively minor electrocardiogram abnormalities are common. Direct myocardial toxicity may occur in species causing rhabdomyolysis, but this does not explain rapid cardiovascular collapse. Other sequelae are less common. Coagulopathy-induced intracranial hemorrhage may occur. General rhabdomyolysis is caused by some species but even so is not common unless massive envenomation has occurred or delayed, inadequate or incorrect antivenom (antivenin) has been given. Rhabdomyolysis involves all skeletal musculature and sometimes cardiac muscle. Myoglobinuria (secondary to cell lysis and extravasation of erythrocytes) may cause acute renal failure. The etiology of nephrotoxicity is mutifactorial. A high intake of alcohol by adults before snake-bite is common, and may complicate management such as delay in presentation and multiple bites. Pre-existing anticoagulant therapy or ulcerative gastro-intestinal tract disease may also complicate coagulopathy management.

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Fig. 51.7 Marked thrombocytopenia, left arm ecchymosis and edema following timber rattlesnake (Crotalus horridus horridus) envenomation of the left hand. Note the petechaie of the right upper arm following blood pressure cuff insufflation (Used with permission of Alexander B. Baer, MD, University of Virginia, Charlottesville, Virginia)

Identification of the Snake Identification of the snake stipulates the selection of antivenin, if needed, and forewarns the doctor of characteristic clinical problems. Although physical identification of the species is helpful, it is not usually mandatory for good management. Misidentification of the species may lead to administration of an antivenin which has little or no venom neutralizing capability and may, in fact, produce untoward and potentially dangerous adverse effects (see below). Finally, safety should always be the main priority, and no attempt should be made to capture or kill the snake. Even if the snake is dead, it should not be picked up with the hands as envenomation by reflex biting after death of the snake has been reported [33]. Physicians in North America are quite fortunate in that all of the pit viper envenomations are treated with the same antivenin. Coral snake envenomation requires a different antivenin, but the clinical features of this envenomation are usually easily distinguished from a pit viper envenomation. A venom detection kit (VDK; CSL [Commonwealth Serum Laboratories Ltd]) is available in Australia that is designed for bedside use – the kit indicates which genus of snake is involved and which antivenin is appropriate. It is an in vitro enzyme immunoassay test for detection and identification of snake venom swabbed from the bite site or in the urine, blood, or other tissue of the victim of snake bite in Australia and Papua New Guinea. The kit is widely available. It is a bank of test wells containing specific rabbit antibodies to the venoms of the main genera of snakes. By a series of reactions with chromogen and peroxide solutions a positive reaction with venom antigen and venom antibody is

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indicated within 25 min by a color change, thereby indicating the type of antivenin to be administered, if required. The kit detects venoms from tiger, brown, black, death adder, and taipan genera. It does not identify an individual species of snake and several genera may yield a positive result in a specified well. The sensitivity and specificity of the test is unknown, but are generally regarded as high. The test is able to detect venom in very low concentration ( 30 mmHg) should be managed with mannitol (1–2 g/kg IV), elevation of the affected extremity, and administration of four to six vials of CroFab over 1 h [10, 32]. Compartment syndrome arises in part from the extensive tissue necrosis produced by the crotalid venom, hence the justification for additional antivenin to neutralize the venom and hopefully reduce compartment pressures. Fasciotomy is required if these measures fail to relieve the compartment syndrome, or if there is neurologic or circulatory compromise.

J. Tibballs et al.

Fig. 51.10 Red-back spider (Latrodectus hasselti)

cases of bites from at least 29 different exotic, venomous species between 1977 and 1995 [58]. The most common species was the cobra, which was involved in 40 % of the cases [58]. Assistance with these exotic envenomations (cobra, mamba, etc.) is available either through the American Association of Poison Control Centers (800 222 1222), the American Zoo and Aquarium Association (301 562 0777), or the Australian Venom Research Unit (AVRU) (1300 760 451).

Spiders Sea-Snake Bite The venoms of some sea-snakes cause widespread rhabdomyolysis, neuromuscular paralysis, and direct renal damage. Many species of sea-snakes exist in northern Australian waters but are rare in southern waters. Many have not been researched. The principles of treatment are essentially the same as for envenomation by terrestrial snakes. The venoms of significant species are neutralized adequately with CSL Ltd beaked sea-snake (Enhydrina schistosa) antivenom. If that preparation is not available, tiger snake or polyvalent antivenin should be used. Sea-snake bites are rare in Australia waters but common among fishermen of nearby Asian countries.

Although several thousand species of spiders exist in Australia, only funnel-web spiders (genera Atrax and Hadronyche) and the red-back spider (Latrodectus hasselti) (Fig. 51.10) have caused death or significant illness. In North America, the arthropods of medical importance include the black widow spider (genus Lactrodectus) (Fig. 51.11), brown recluse spider (genus Loxosceles) (Fig. 51.12), and scorpions. All spiders have venom but although some are capable of causing local injury and necrosis [59], the necrotic effects of these spider bites have been over-rated [60]. In the interest of space, the present discussion will concentrate on the most common spider envenomations in Australia and North America and briefly consider scorpion envenomations. The interested reader is directed to other sources for additional information [2, 13, 15, 27, 61].

Uncommon and Exotic Snake Bites Zoo personnel, herpetologists, and amateur collectors who catch, maintain, and breed species of uncommon or exotic snakes or who import or breed exotic (overseas) snakes are at risk. Illegal importation sometimes endangers customs services personnel. Minton reported that he consulted on 54

Funnel-Web Spiders Numerous species of the genera Atrax and Hadronyche inhabit the Australian states of New South Wales and Queensland. Several species cause significant illness and are

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Fig. 51.11 Black widow spider (Latrodectus mactans) (Used with permission of Christopher P. Holstege, MD, University of Virginia, Charlottesville, Virginia)

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venom contains polypeptides which stimulate the release of acetylcholine at neuromuscular junctions and within the autonomic nervous system, and release catecholamines. The early features of the envenomation syndrome include nausea, vomiting, profuse sweating, salivation, and abdominal pain. Life threatening features of envenomation are usually preceded by the onset of muscle fasciculation at the bite site, which quickly involves distant muscle groups. Hypertension, tachyarrhythmias, vasoconstriction, hypersalivation and bronchorrhoea quickly follow. The victim may lapse into coma, develop central hypoventilation and have difficulty maintaining an airway free of secretions. Finally, respiratory failure, pulmonary oedema and severe hypotension culminate in death. The syndrome usually develops within several hours but it may be more rapid. Several children have died within 90 min of envenomation, and one died within 15 min. First aid treatment is application of a pressureimmobilization bandage which delays the onset of the envenomation syndrome and appears to enable some inactivation of venom at the bite site [2]. Definitive treatment is intravenous administration of antivenom and support of vital functions, which may include airway support and mechanical ventilation. No deaths or serious morbidity have been reported since the introduction of antivenom in 1981.

Red-Back Spider

Fig. 51.12 Brown recluse spider (Loxosceles reclusa) (Used with permission of Sue Kell, PhD, University of Virginia Health System, Charlottesville, Virginia)

potentially lethal. Atrax robustus (Sydney Funnel-web Spider) is a large aggressive spider inhabiting an area within an approximate 160 km radius of Sydney. It has caused more than a dozen deaths. The male spider is more dangerous than the female, in contrast to other species, and is inclined to roam after rainfall. In doing so, it may enter houses and seek shelter among clothes or bedding. Its bite is painful and it may be difficult to dislodge. Bites do not always result in envenomation, but envenomation may be rapidly fatal. The

This spider (Latrodectus hasselti) is distributed throughout Australia where it is found outdoors in household gardens in suburban and rural areas. Related species occur in many parts of the world (e.g., black widow spider in North America). All produce a similar syndrome of envenomation – Latrodectism. Red-back spider bite is the most common cause for antivenom administration in Australia at 300–400/annum and responsible for 2,300 of 11,600 (20 %) of annual hospital admissions for envenomation [1]. The adult female spider is identified easily – its body is about 1 cm in size and has a distinct red or orange dorsal stripe over its abdomen. The hallmark of envenomation is severe local and distal pain. The spider gives a pin prick-like bite. The site quickly becomes inflamed. During the following minutes to several hours, severe pain, exacerbated by movement, commences locally and may extend up the limb or radiate elsewhere. Pain may be accompanied by profuse sweating, headache, nausea, vomiting, abdominal pain, fever, hypertension, paraesthesias, and rashes. Historically, in a small percentage of cases progressive muscle paralysis occurred over many hours, requiring mechanical ventilation. If untreated or treated inadequately, muscle weakness, spasm and arthralgia may persist for months after the bite. In this circumstance, antivenom treatment is still beneficial. No fatalities have occurred since introduction of an antivenom in 1956. If the

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effects of a bite are minor and confined to the bite site, antivenom may be withheld but otherwise, antivenom should be given intramuscularly. Several doses or intravenous administration may be required. The rate of anaphylaxis to antivenom is low (