Yearbook of Anesthesiology - 9 9389188903, 9789389188905

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Yearbook of

Anesthesiology-9

Editorial Board 1. VP Kumra MD DAc FICA

Emeritus Consultant and Advisor Department of Anesthesiology, Pain and Perioperative Medicine Sir Ganga Ram Hospital, New Delhi, India Past President and Advisor Indian College of Anaesthesiologists Former Vice President Indian Society of Anaesthesiologists (National) [email protected]

2. B Radhakrishnan MD MPhil FICA Senior Professor and Consultant Sree Gokulam Medical College and GG Hospital Trivandrum, Kerala, India President Indian College of Anaesthesiologists Former President Indian Society of Anaesthesiologists (National) [email protected]

3. Jayashree Sood MD FFARCS PGDHHM FICA Professor and Chairperson Department of Anesthesiology, Pain and Perioperative Medicine Honorary Joint Secretary, Board of Management Sir Ganga Ram Hospital, New Delhi, India CEO, Indian College of Anaesthesiologists [email protected]

4. Baljit Singh MD FICA Former Director Professor GB Pant Institute of Postgraduate Medical Education and Research New Delhi Professor Anesthesia Faculty of Medicine and Health Sciences SGT University, Gurugram, Haryana, India CEO, Indian College of Anaesthesiologists [email protected]

Yearbook of

Anesthesiology-9 Editors Raminder Sehgal  MD DA FICA

Former Director Professor Maulana Azad Medical College, New Delhi Former Senior Consultant Sir Ganga Ram Hospital, New Delhi, India [email protected]

Anjan Trikha  MD FICA

Professor All India Institute of Medical Sciences New Delhi, India [email protected]

Indian College of Anaesthesiologists

Foreword Baljit Singh

JAYPEE BROTHERS MEDICAL PUBLISHERS The Health Sciences Publisher New Delhi | London

Jaypee Brothers Medical Publishers (P) Ltd Headquarters Jaypee Brothers Medical Publishers (P) Ltd 4838/24, Ansari Road, Daryaganj New Delhi 110 002, India Phone: +91-11-43574357 Fax: +91-11-43574314 E-mail: [email protected] Overseas Office JP Medical Ltd 83 Victoria Street, London SW1H 0HW (UK) Phone: +44 20 3170 8910 Fax: +44 (0)20 3008 6180 E-mail: [email protected] Website: www.jaypeebrothers.com Website: www.jaypeedigital.com © 2020, Jaypee Brothers Medical Publishers The views and opinions expressed in this book are solely those of the original contributor(s)/ author(s) and do not necessarily represent those of editor(s) of the book. All rights reserved. No part of this publication may be reproduced, stored or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission in writing of the publishers. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. Medical knowledge and practice change constantly. This book is designed to provide accurate, authoritative information about the subject matter in question. However, readers are advised to check the most current information available on procedures included and check information from the manufacturer of each product to be administered, to verify the recommended dose, formula, method and duration of administration, adverse effects and contraindications. It is the responsibility of the practitioner to take all appropriate safety precautions. Neither the publisher nor the author(s)/ editor(s) assume any liability for any injury and/or damage to persons or property arising from or related to use of material in this book. This book is sold on the understanding that the publisher is not engaged in providing professional medical services. If such advice or services are required, the services of a competent medical professional should be sought. Every effort has been made where necessary to contact holders of copyright to obtain permission to reproduce copyright material. If any have been inadvertently overlooked, the publisher will be pleased to make the necessary arrangements at the first opportunity. The CD/DVD-ROM (if any) provided in the sealed envelope with this book is complimentary and free of cost. Not meant for sale. Inquiries for bulk sales may be solicited at: [email protected]

Yearbook of Anesthesiology-9 First Edition: 2020 ISBN: 978-93-89188-90-5

Contributors Anita Mathew MD Assistant Professor Department of Anesthesiology Believers Church Medical College Hospital Thiruvalla, Kerala, India [email protected] Anju Romina Bhalotra MD Director Professor Department of Anesthesiology Maulana Azad Medical College New Delhi, India [email protected] Anoop Raj Gogia MD Consultant and Professor Department of Anesthesia and Intensive Care Vardhman Mahavir Medical College and Safdarjang Hospital New Delhi, India [email protected] Arun Maheshwari MD Chairman (Cardiac Anesthesia) Dharma Vira Heart Centre Sir Ganga Ram Hospital New Delhi, India [email protected] Asha Tyagi  MD DNB MNAMS Director Professor Department of Anesthesiology and Critical Care University College of Medical Sciences and Guru Teg Bahadur Hospital New Delhi, India [email protected] Ashu Sara Mathai MD Vice Principal and Professor Department of Anesthesiology Believers Church Medical College Hospital Thiruvalla, Kerala, India [email protected]

Babita Ghai MD Professor Department of Anesthesiology and Intensive Care Postgraduate Institute of Medical Education and Research Chandigarh, India [email protected] Bhuwan Chand Panday MD Consultant Department of Anesthesiology, Pain and Perioperative Medicine Sir Ganga Ram Hospital New Delhi, India [email protected] Brig RM Sharma MD Consultant and Head Anesthesiology and Critical Care Army Hospital (R&R) New Delhi, India [email protected] CK Dua  DA MD FICA Former Director Professor and Head Anesthesiology Maulana Azad Medical College and Lok Nayak Jai Prakash Hospital, New Delhi Former Professor and Head (Anesthesiology) Santosh Medical College and Hospital Ghaziabad, Uttar Pradesh, India [email protected] Deep Arora MD Director (Orthopedic Anesthesia) Medanta—The Medicity Gurugram, Haryana, India [email protected] Deepak Pahwa MD Consultant (Orthopedic Anesthesia) Medanta—The Medicity Gurugram, Haryana, India [email protected]

vi  Yearbook of Anesthesiology-9 Devalina Goswami MD Associate Professor Department of Anesthesiology, Pain Medicine and Critical Care All India Institute of Medical Sciences (AIIMS) New Delhi, India [email protected] Elvin Daniel  MD FIACTA Associate Consultant (Cardiac Anesthesia) Dharma Vira Heart Centre Sir Ganga Ram Hospital New Delhi, India [email protected] Gita Nath  MD DA DNB FFARCS Consultant (Anesthesia and Intensive Care) Axon Anesthesia Associates Hyderabad, Telangana, India [email protected] Himanshu Suri DA Senior Consultant Department of Anesthesia Medanta Institute of Musculoskeletal Disorders and Orthopedics Medanta—The Medicity Gurugram, Haryana, India [email protected] JP Attri MD Professor Department of Anesthesia Government Medical College Amritsar, Punjab, India [email protected] Kapil Dev Soni MD Associate Professor Critical and Intensive Care Jai Prakash Narayan Apex Trauma Centre All India Institute of Medical Sciences New Delhi [email protected]

Kumar G Belani  MS FACA FAAP Professor Department of Anesthesiology University of Minnesota Minneapolis, Minnesota, USA [email protected] Lakesh Kumar Anand  MD FIMSA FCCP MAMS Professor of Anesthesia Department of Anesthesia and Intensive Care Government Medical College and Hospital Chandigarh, India [email protected] Lokesh Kashyap MD Professor Department of Anesthesiology, Pain Medicine and Critical Care All India Institute of Medical Sciences (AIIMS) New Delhi, India [email protected] M Subrahmanyam  MD DNB DA (UK) FRCA Consultant (Anesthesia and Intensive Care) Axon Anesthesia Associates Hyderabad, Telangana, India [email protected] Magesh Parthiban MD Senior Resident Department of Anesthesiology, Pain Medicine and Critical Care All India Institute of Medical Sciences (AIIMS) New Delhi, India [email protected] Maj Gen Rashmi Datta  VSM MD MG (Med) Senior Consultant Anesthesiology and Critical Care Base Hospital, Delhi Cantt and Army Hospital (R&R), New Delhi, India [email protected] Manpreet Singh  MD FCCP FIMSA FACEE FCCS

Kirti N Saxena MD Director Professor and Head Department of Anesthesiology and Intensive Care Maulana Azad Medical College New Delhi, India [email protected]

MAMS

Associate Professor Department of Anesthesia and Intensive Care Government Medical College and Hospital Chandigarh, India manpreetdawar@ hotmail.com, [email protected]

Contributors  vii Neetu Jain  MD DNB Senior Consultant Department of Anesthesiology, Pain and Perioperative Medicine Sir Ganga Ram Hospital New Delhi, India [email protected] Neha Agrawal  DA DNB MBA (HCA) Regional Quality Head (North)—Narayana Health Senior Consultant Anesthesiology Dharamshila Narayana Superspecialty Hospital New Delhi, India [email protected] Nitika Goel MD Assistant Professor Department of Anesthesiology and Intensive Care Postgraduate Institute of Medical Education and Research Chandigarh, India [email protected] Pallavi Ahluwalia  MD PDGHHM CCEPC FIMSA Professor of Anesthesiology Department of Anesthesia, Pain and Palliative Medicine Teerthanker Mahaveer Medical College and Research Center Moradabad, Uttar Pradesh, India [email protected] Payal Jain MD Assistant Professor Department of Anesthesia, Pain and Perioperative Medicine Teerthanker Mahaveer Medical College and Research Center Moradabad, Uttar Pradesh, India [email protected] Preet Mohinder Singh MD Assistant Professor of Anesthesiology Washington University School of Medicine Saint Louis, Missouri, USA [email protected]

Purnima Dhar MD Senior Consultant (Anesthesia and Critical Care) Indraprastha Apollo Hospital New Delhi, India [email protected] Rahil Singh  DA DNB Assistant Professor Department of Anesthesiology Maulana Azad Medical College New Delhi, India [email protected] Ranjana Khetarpal MD Professor Department of Anesthesia Government Medical College Amritsar, Punjab, India [email protected] Rashmi Salhotra MD Associate Professor Department of Anesthesiology and Critical Care University College of Medical Sciences and Guru Teg Bahadur Hospital New Delhi, India [email protected] Reeta Singh  MD DNBE MBA (HCS) Dip Interventional Pain

Consultant Anesthesiologist Awali Hospital Kingdom of Bahrain [email protected] Richa Aggarwal MD Associate Professor Critical and Intensive Care Jai Prakash Narayan Apex Trauma Centre All India Institute of Medical Sciences New Delhi, India [email protected] Roberto C Blanco MD Assistant Professor Department of Anesthesiology Regional Anesthesia Division Co-director Regional Anesthesia Fellowship University of Minnesota Minneapolis, Minnesota, USA [email protected]

viii  Yearbook of Anesthesiology-9 Sanjay Sharma  MD FANZCA GCCS MHSM Associate Professor and Deputy Director Department of Anesthesia Ballarat Health Services Ballarat, Victoria, Australia [email protected] Saurabh Kumar Das  MD PDCC IFCCM EDIC Senior Consultant (Critical Care) Artemis Hospital Gurugram, Haryana, India [email protected] Shreya Goswami MD Clinical Research Associate Department of Anesthesiology University of Washington St Louis, Missouri, USA [email protected] Sumit Ray  MD FICCM Chairperson of Critical Care Artemis Hospital Gurugram, Haryana, India [email protected] Surinder Mohan Sharma  MD DMICAc FICA Chairman Department of Anesthesia Medanta Institute of Musculoskeletal Disorders and Orthopedics Medanta—The Medicity Gurugram, Haryana, India [email protected]

Susheela Taxak  DA MD DNBE Senior Professor Department of Anesthesiology Pt Bhagwat Dayal Sharma Postgraduate Institute of Medical Sciences Rohtak, Haryana, India [email protected] Swarup Sri Varaday  MD FRCA FCARSI Associate Professor of Anesthesiology Washington University School of Medicine Saint Louis, Missouri, USA [email protected] Vinh Nguyen DO Assistant Professor Department of Anesthesiology University of Minnesota Minneapolis, Minnesota, USA [email protected], nguyenv@umn. edu

Foreword Anesthesiology is a rapidly growing specialty and anesthesiologists need to keep pace with the ever-increasing demands of patients with associated medical disorders presenting for surgery. From behind the curtain role to a commanding position in the management of patients, anesthesiologists play a significant role not only in the operating room but beyond also. Indian College of Anaesthesiologists has been playing an important role by bringing out the new developments in the field of anesthesiology through Yearbook of Anesthesiology every year for the last eight years. Yearbook of Anesthesiology-9, now ready for release has topics that have been very well chosen with regard to coverage in the previous editions and the impact of the latest research on the practice of anesthesiology. The editors, Drs Raminder Sehgal and Anjan Trikha have been doing a great job in selecting the contributors who have exceled in their chosen fields. The chapters have been written and edited to make the text easy-tounderstand and comprehend. Yearbook of Anesthesiology-9 promises to be an invaluable asset to learning process for the anesthesiologists of every stature, particularly the younger generation. The book is unique in the sense that it does not follow the conventional “system by system” chapters but brings out the newer insights into the science of patient care that would widen the knowledge base of all those reading it. I sincerely believe this book would go far and wide and adorn the tables of the scientifically oriented. Congratulations to the editors for a well-crafted work of science and my compliments to the contributing authors for the excellent write up. Baljit Singh  MD FICA Former Director Professor GB Pant Institute of Postgraduate Medical Education and Research New Delhi Professor Anesthesia Faculty of Medicine and Health Sciences SGT University, Gurugram, Haryana, India CEO, Indian College of Anaesthesiologists [email protected]

Preface The present Yearbook of Anesthesiology is the 9th edition in the series of yearly handbook published under the auspices of the Indian College of Anaesthesiologists. All the previous editions have been appreciated by all– practicing anesthesiologists, teaching faculty members in anesthesia and the postgraduate students. It is our endeavor to choose topics from all fields of anesthesiology; especially those that have importance in the present times of changing patient profile or anesthesia practice in our country. In this regard, the chapter on management of an obese parturient and pregnancy induced hypertension are very informative. Indian population is a mix of malnourished and overweight patient, and it is very relevant in todays practice to be aware of issues that need to be addressed in obese parturients. The use of smart phones has changed the way, medicine is practiced in today’s world especially as far as drug interactions, side effects and doses are concerned. The chapter of smart phones discusses its advantages and the nuisance values in anesthesia practice. A very informative detailed yet concise article is on sugammadex, the new reversal agent that has been introduced in our country. We are sure that both students and practicing personnel would find it very informative and useful. In the same context, the recently available high flow nasal cannula systems have been discussed in another chapter. Of special interest to all anesthesiologists practicing regional anesthesia would be the chapter on phrenic nerve sparing brachial plexus blocks. Other issues of importance include errors in medicine, health hazards in the anesthesiologists, infection prevention and intraoperative thermoregulation. Chapters on weaning from mechanical ventilation and nutrition should interest those managing critically ill patients. Anesthetic issues in the management of patients from extreme of age, whether geriatric or pediatric, have been dealt with in detail. The chapter on the present status of platelet rich plasma in chronic pain conditions and degenerative diseases is likely to be of immense benefit to all pain specialists. Such injections are being used very frequently in our country for a lot of conditions with varying results. Two chapters that are likely to be of extreme importance to postgraduates are those on double lumen endotracheal tubes and gas embolism. Both manuscripts have all possible information on the subjects in a very condensed form with details of standard references for future readings. Perioperative management of high altitude pulmonary edema, hyperglycemia, daycare arthroplasty and

xii  Yearbook of Anesthesiology-9

neurovascular procedures have been covered along with complications such as postoperative myocardial injury and postoperative delirium. Like in all previous editions, this yearbook also has a section on Journal Scan where landmark articles in the previous year are opined upon by leading experts in their fields. Both of us would take this opportunity to thank all the authors form India and abroad who were able to accept our invitations to write the manuscripts and submit them within the time frame required. A special word of appreciation is in order for the staff of M/s Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, India, for their support for patiently working with us in bringing out this edition of the Yearbook of Anesthesiology.

Raminder Sehgal Anjan Trikha

Contents 1. Errors in Medicine: A Perioperative Perspective....................1 Sanjay Sharma

• Incidence  2 • Classification of Errors Based on Causation— Active or Latent  2 • Is the Term “Error” the Most Appropriate and Suitable?  5 • Role of Human Factors in Genesis of Error  6 • “Highly Complex, Tightly Coupled”  6 • Changing Approach to Error  7 • Causation of Errors also Mired in Myths  8 • Medication Errors in the Hospital  9 • Classification of Medical Errors Based on Impact  10 • Medication Errors Specific to the Practice of Anesthesia  10 • Error Reduction and Prevention—Harm Minimization  14 • Management of Erroneous Administration of Medication  16

2. Perioperative Care of the Frail Elderly: Current Knowledge and Future Directions............................22 Asha Tyagi, Rashmi Salhotra

• • • • • • • • • •

Who is an Old Patient?  22 What is Frailty?  22 How to Recognize Frailty?  23 Pathophysiology of Frailty  25 Risk Factors for Frailty  25 Implications of Frailty  26 “Frail Body” or “Frail Organ System”  26 Should Preoperative Assessment Focus on Frailty Only?  28 Anesthesia in the Frail Elderly  28 Interventions to Improve or Modify Outcome in Frailty  30

3. Pregnancy-induced Hypertension: An Update .....................34 CK Dua

• • • •

Classification of Pregnancy-induced Hypertension  34 Definition of Pregnancy-induced Hypertension Disorders  35 Pathogenesis of Pre-eclampsia  37 Risk Prediction and Prophylaxis of Pre-eclampsia  38

xiv  Yearbook of Anesthesiology-9 • • • • •

Systemic Manifestations of Severe Pre-eclampsia  40 Obstetric Management  42 Anesthetic Management of Pre-eclampsia  46 Nonoperative Delivery: Labor Analgesia  46 Operative Delivery: Anesthetic Management  47

4. Sugammadex and Beyond......................................................55 Vinh Nguyen, Kumar Belani

• • • • •

Sugammadex versus Anticholinesterase Inhibitors  55 Special Considerations  57 Adverse Effects  59 Relative Contraindications and Cautions  60 Future Reversal Agents  61

5. Issues and Management of Obese Parturient.......................68 Swarup Sri Varaday, Preet Mohinder Singh

• • • • • • • •

Defining Obesity in Pregnancy—the Dilemma!  69 Epidemiology—the Change in Lifestyle  69 Pathophysiology of Obesity in Pregnancy  70 Obese Parturient and Anesthesiologist  70 Obstructive Sleep Apnea  71 Labor Analgesia  76 Anesthesia for Cesarean Section  77 Postoperative Management  79

6. Postoperative Delirium: A Bane of Daycare Surgery............85 Deep Arora, Deepak Pahwa

• • • • • • • • • • •

Importance of Postoperative Delirium  85 Definition and Incidence  86 Pathophysiology of Postoperative Delirium  86 Risk Factors for Development of Postoperative Delirium  87 Clinical Presentation and Diagnosis  88 Delirium Screening  89 Differential Diagnoses  91 Prediction of Postoperative Delirium  91 Biomarkers  93 Prevention and Treatment of Postoperative Delirium  93 Cognitive Outcome of Postoperative Delirium  95

7. Gas Embolism: An Update......................................................99 Anju Romina Bhalotra, Rahil Singh

• Epidemiology  99 • Etiology  100

Contents  xv • • • • • • •

Pathophysiology  101 Clinical Presentation  103 Detection  104 Differential Diagnosis  106 Prevention  106 Management  107 Special Situations  109

8. Nutrition in the Intensive Care Unit......................................115 Richa Aggarwal, Kapil Dev Soni

• • • • • • • • • • • •

Assessment of Nutritional Status  116 Patients at Risk of Malnutrition  116 Initiating Nutrition  116 Early Enteral Nutrition versus Delayed Enteral Nutrition versus Parenteral Nutrition  117 Energy and Protein Requirement of Critically Ill Patients  118 How to Provide Enteral Nutrition?  119 Parenteral Nutrition  121 Adjunctive Therapy  122 Nutrition in Various Disease Conditions  124 Monitoring Nutrition  125 Appendix 1: Nutric Score  127 Appendix 2: Comparison of Various Parenteral Formulations Available  128

9. Smartphones in Anesthesia: Game Changers or Mere Distractions? ................................................................133 Ranjana Khetarpal, JP Attri

• Mobile Information Technology Applications in Hospital Scenario  134 • Disease Prevention and Health Promotion  136 • Smartphone as a Cost-effective Ventilator  136 • Concerns Arising Out of Mobile Use in Hospitals  137 • Smartphones and the Medical Equipment  139 • Guidelines Regarding Safe Use of Smartphones  140 • Ethical and Legal Issues with Smartphone Use  140 • Summary and Conclusions  140

10. Health Hazards for an Anesthesiologist: A Myth or Reality?..................................................................145 Susheela Taxak, Reeta Singh

• Physical Hazards  147 • Mental Hazards  150 • Other Hazards  152

xvi  Yearbook of Anesthesiology-9

11. Effect of Anesthesia on the Developing Brain: A Review of Recent Evidence ..............................................157 M Subrahmanyam, Gita Nath

• • • •

Neurotransmitters in the Brain  157 Evidence from Animal Studies  159 Clinical Studies  161 Maternal Anesthesia and its Effects on the Fetus  165

12. Weaning from Mechanical Ventilation .................................173 Saurabh Kumar Das, Sumit Ray

• • • • • • • •

Stages of Mechanical Ventilation  174 Conventional Methods of Weaning  177 Comparison of Different Conventional Modes of Weaning  178 Ventilator Modes for Weaning  178 Weaning Protocol  180 Weaning Failure  180 Management of Prolonged Weaning Failure  183 Other Related Issues  184

13. Intraoperative Thermoregulation .........................................190 Ashu Sara Mathai, Anita Mathew

• • • • • • •

Mechanisms Underlying Thermoregulation  191 Monitoring of Body Temperature  192 Causes of Thermal Dysregulation in the Perioperative Period  192 Extent of the Problem  194 Consequences of Inadvertent Perioperative Hypothermia  194 Management of Intraoperative Hypothermia  196 Methods of Warming  198

14. Platelet-rich Plasma for Management of Chronic Pain and Degenerative Conditions: A Critical Review of Evidence ...............................................................203 Babita Ghai, Nitika Goel

• • • •

What is Platelet-rich Plasma?  203 Types of Platelet-rich Plasma  204 Proposed Mechanism of Platelet-rich Plasma?  204 Does Proposed Mechanism of Platelet-rich Plasma Work in vivo?  205 • Clinical Evidence of Platelet-rich Plasma in Osteoarthritis Knee  205 • Clinical Evidence of Platelet-rich Plasma in Chronic Low Back Pain  206

Contents  xvii • Current Use of Platelet-rich Plasma in Musculoskeletal Tissues  209 • Adverse Events with Platelet-rich Plasma  210

15. Postoperative Myocardial Injury: Causes and Management ..........................................................................215 Arun Maheshwari, Elvin Daniel

• Definition of Myocardial Infarction: Does Postoperative Myocardial Injury Fit In?  215 • Does Postoperative Myocardial Injury always mean Myocardial Infarction?  216 • Pathophysiology  216 • Diagnosis  217 • Risk Prediction  219 • Prevention and Management  220

16. Management of Hyperglycemia in the Perioperative Period .............................................................226 Pallavi Ahluwalia, Payal Jain

• • • • • • • • • • • • • •

Diagnostic Criteria for Diabetes Mellitus  226 Implications of Surgery on Blood Sugar Levels  227 Types of Anesthesia and its Effect on Blood Glucose  227 Anesthetic Drugs and their Effects on Blood Glucose  228 Assessment during Perioperative Period and Management Goals  229 Glycemic Goals in Perioperative Period  229 Nutrition and Nutritional Intake  230 Approaches to Improve Perioperative Glycemic Control  230 New and Improved Insulin Delivery Devices  234 Glycemic Management in Intraoperative Period  234 Hypoglycemia  236 Glycemic Management in Postoperative Period  236 Special Scenarios  238 Conflict of Interest  240

17. Challenges and Issues in Daycare Arthroplasty ................244 Surinder Mohan Sharma, Himanshu Suri

• Definition of Daycare or Outpatient Arthroplasty  244 • Why Daycare Total Joint Arthroplasty  245 • Components of an Outpatient Total Joint Arthroplasty Program  245 • Patient Selection  246

xviii  Yearbook of Anesthesiology-9 • • • • • • • •

Patient Education and Social Optimization  247 Intraoperative Considerations  248 Anesthesia  248 Surgical Technique  249 Analgesia  250 Deep Venous Thrombosis Prophylaxis  250 Postdischarge Care  250 The Indian Perspective  251

18. Anesthesia for Neurovascular Procedures ........................256 Neetu Jain, Bhuwan Chand Panday

• Intracranial Aneurysms  256 • Arteriovenous Malformation  268 • Endovascular Therapy for Other Procedures  273

19. High-flow Nasal Oxygenation: A Fad? ................................277 Manpreet Singh, Lakesh Kumar Anand

• • • • •

Equipment for High-flow Nasal Oxygenation  278 Physiological Basis for Use of High-flow Nasal Oxygen  278 Current Clinical Applications  279 Indications of High-flow Nasal Oxygen in Critical Care  281 Indications and Procedures in Anesthesia  284

20. Double-lumen Endotracheal Tubes: From History to Present and the Future .........................................................293 Lokesh Kashyap, Magesh Parthiban

• • • • • •

History of Double-lumen Tubes  295 Modern Double-lumen Tubes  297 Selection of Appropriate Size  300 Method of Insertion and Confirmation of Proper Placement  301 Confirmation of Proper Placement  301 Recent Advances in Double-lumen Tube  303

21. High-altitude Pulmonary Edema...........................................308 Rashmi Datta, RM Sharma

• • • • • • • • •

History  309 Physiology at High Altitude  312 Pathophysiology  314 Epidemiology and Risk Factors  315 Clinical Presentation  317 Investigations  318 Differential Diagnosis  319 Treatment  320 Prevention  323

Contents  xix

22. Infection Prevention in the Operating Room.......................328 Neha Agrawal

• • • • •

Infrastructure Measures  329 Behavioral Measures  333 Clinical Measures  341 Disinfection and Sterilization Measures  341 Surveillance Protocol  346

23. Regional Blocks for Shoulder Surgery: Sparing the Phrenic Nerve....................................................353 Roberto C Blanco, Kumar G Belani

• Anatomical Considerations  354 • Practical Implications  356 • Specific Blocks  358

24. Current Status of Methylene Blue in Anesthesia and Intensive Care.........................................................................363 Devalina Goswami

• • • • • • • • • • • • • • • • •

Historical Background  363 Physiochemical Properties  363 Mechanism of Action  364 Effect of Methylene Blue on Anesthetics  365 Treatment of Methemoglobinemia  365 Vasodilatory Shock  366 Cardiac Surgery and Vasoplegia  366 Sepsis  368 Anaphylactic Shock  368 Orthotopic Liver Transplantation  369 Cardiovascular Drug Poisoning  369 Ifosfamide Toxicity  369 Hydrogen Sulfite Toxicity  370 As An Indicator Dye  371 Adverse Effects  371 Serotonin Toxicity  372 Contraindications  372

25. Journal Scan ..........................................................................377 Kirti N Saxena, Shreya Goswami, Purnima Dhar, Anup Raj Gogia

• • • •

Journal Scan 1—Kirti N Saxena 377 Journal Scan 2—Shreya Goswami 380 Journal Scan 3—Purnima Dhar 384 Journal Scan 4—Anup Gogia 388

  Index...............................................................................................395

Errors in Medicine: A Perioperative Perspective  1

CHAPTER

1

Errors in Medicine: A Perioperative Perspective Sanjay Sharma

INTRODUCTION There is increasing emphasis on minimizing medical errors, which have been described as “an act of omission or commission in planning or execution that contributes or could contribute to an unintended result”.1 Realistically, this would include both the implementation of an inappropriate plan, or a good plan not executed as intended. These errors are usually unintentional and not malicious or deliberate. The errors of omission or commission, in both planning and execution of various processes, are included irrespective of whether the adverse outcome actually occurred or was likely. It thus provides a useful template for research into faulty processes that contribute to majority of errors that could fly under the radar, as they do not actually cause harm. Equally, it takes focus away from trivial “slip ups” that do not have the potential to actually result in an adverse outcome. The healthcare industry is inspired by, and follows the model of the airline industry by investigating every near miss and error. This initiative, to analyze each event irrespective of whether it actually eventuates in a bad outcome, would improve reliability and safety. The healthcare industry aspires to achieving this level of investigation in the absence of a culture of blame. As opposed to unplanned errors, the term violation applies to planned and deliberate deviation from accepted protocols and standard operating procedure.2 Violations may sometimes involve extenuating circumstances with pressures of time or staffing, and also include deliberate flouting of rules in some instances. Omission of an appropriate preoperative assessment, waiving the “time out” process, and omitting to check the anesthetic machine prior to commencement of procedure all constitute violations. Moyen et al.3 clearly defined these errors, but then also further defined medication errors, especially those that were preventable. Other definitions, with errors subdivided into slips and lapses have also been alluded to, and these will be discussed further in the chapter.

2  Yearbook of Anesthesiology-9

INCIDENCE There is increasing recognition and attention to medical errors irrespective of the actual severity of outcome. “The real problem is not how to stop bad doctors from harming, even killing, their patients. It is how to prevent good doctors from doing so”.4 The Institute of Medicine report,5 aptly titled “To Err is Human”, estimated that between 44,000 and 98,000 hospitalized patients die annually in the USA as a result of medical errors. Australian Healthcare Quality study,6 found that adverse events (unintended injury or complication caused by healthcare) occurred in 16.6% of hospital admissions, with 51% of these events judged to be “highly preventable”. UK report7 found that medical errors caused harm (death and injury) to in excess of 850,000 patients admitted to National Health Service Hospitals annually. Other reports, published worldwide, show widespread acceptance of the impact of medical errors on patients admitted to hospitals.8-11

CLASSIFICATION OF ERRORS BASED ON CAUSATION—ACTIVE OR LATENT Errors can broadly be classified into active errors as those occurring around an incident, and latent or systemic errors that may not be immediately evident or visible.12 Active errors are usually attributable to personnel directly caring for patients, such as nursing and medical staff. An example of an active error is inadvertent administration of a wrong medication, operation performed on wrong site, or even wrong patient. These errors may sometimes be oneoff, due to carelessness or negligence, but sometimes a reflection of latent errors—an accident waiting to happen. Latent errors are often systemic, resulting from poor planning or execution. In the scenario of a wrong medication being administered, the latent error potentially is that of two distinctly different medications packaged in similar looking ampoules, and placed close together on the trolley—an absolute recipe for disaster. This error would not be identifiable until an active error was made and attributed to this problem on one or more occasions.

Active Errors Active errors, directly attributable to personnel, have further been classified into simple omissions such as slips and lapses, and a third category of fixation errors.12,13 Slips and lapses are exactly occurring frequently when one is preoccupied or distracted and hence cannot focus appropriately on the job they are meant to do.12 Slips and lapses can involve errors attributable to subconscious and conscious cognition.13

Errors in Medicine: A Perioperative Perspective  3

Slips Explanation of the etymology of slip suggests an unintended action or word, such as slip of the tongue or slip up. Rotating the wrong knob on an anesthetic machine, thus delivering nitrous oxide instead of air, is a classic example of anesthetic slip. Though slips seem fairly innocuous, they can sometimes result in adverse outcomes. Clarity on slips in anesthesia was provided by Norman14 who categorized slips into sequence errors, description errors, and mode errors. • Sequence errors: Elements of a task are all performed, but in an incorrect order or sequence. A typical example would be injection of muscle relaxant before actually giving induction agent. • Description errors: Correct action performed, but on the wrong agent or object. This is exemplified by an appropriate action such as turning off the knob, but wrongly the knob of nitrous oxide rather than oxygen. • Mode errors: Performance of correct action but the setting of equipment is in the incorrect or wrong mode. Once the circuit switch is set to ventilator mode, attempts to squeeze a breathing bag to ventilate the patient highlights a mode error.

Lapse When an intended action is missed, often due to distraction or time pressure, it qualifies as a lapse. Leaving one’s car unlocked and rushing into a shopping center is a typical example of a lapse. In clinical work, a lapse occurs when a medication is not given though it was intended to.

Fixation Error This is a third variety of active error, seen more commonly in a crisis or stressful situation. Allnutt14 describes extreme concentration on one action at the cost of other more useful actions as “coning of attention”. He describes this tendency to focus on a particular task or source of information without “taking a step back” to review others options. Some emergency situations call for a change in plan or diagnosis but the persistent failure to recognize this and stick to the original unsuccessful action is a classic example of fixation error.15 An example would be the ongoing attempt to “fight” with a piece of jammed essential lifesaving equipment rather than picking an alternative which may be easily available. Few common types of fixation errors are: • “This and only this”: In this scenario, the caregiver is fixated on a diagnosis and will not consider alternative plans despite investigations suggesting otherwise.

4  Yearbook of Anesthesiology-9

• “Everything but this”: Another variety where the caregiver does not acknowledge a major problem and hence this is left unattended, while minor issues are attended to. • “Everything’s okay”: Similar to the above, where evidence is ignored to the detriment of the condition. A classic example of fixation error was evidenced in a 1972 plane crash, where the crew gave all their attention to a defective indicator light. So fixated were they on this light that they ignored a major looming disaster with autopilot disengaging until the plane actually crashed. Simulation exercises for anesthetic emergencies often display fixation errors, irrespective of the seniority and experience of the anesthesiologist.16,17 A positive approach to this error and reflection on methods to avoid this in real life serves a purpose of simulation exercise.

Latent Errors Why do errors occur repeatedly? Bogner’s theory of error scripts—“all the men and women are merely players”.18 He suggests that the script may incorporate faults, which induce or provoke errors, and this sets the stage for adverse outcomes. The individuals held responsible are actually merely “actors” and should not be the focus of punitive action, since they are mostly “following a script”. Anesthesia is unique in that one practitioner singlehandedly decides the medication to be administered, prepares, and administers it and then monitors the patient to ensure that no complication ensues. This is complex at the best of times, and provides a template for mishaps and errors especially in times of stress or crisis. Recently, there have been news items relating to adverse outcome when tranexamic acid was injected intrathecally as the ampoule was similar to bupivacaine, and easily mistaken. Both had orange-colored lettering, and were placed side-by-side on a trolley. Another such potential disaster related to similarity between ondansetron and vasopressin causing accidental injection of the wrong agent. Errors relating to accidental intrathecal injection of chemotherapeutic agents meant for intravenous administration have been reported on many occasions both in UK and Australia.19 Despite extensive publicity, litigation and large payouts, beside a manslaughter conviction, these errors have recurred. It emphasizes the lesson from Bogner’s theory that the script is error-prone. Two medications, one intended for intravenous administration and the other for intrathecal injection, are packaged similarly, in similar volumes, and presented to the doctor (“actor”) for administration. The error recurs despite changing doctors, because the script is unchanged. Whilst medical errors resulting in adverse outcomes are often the subject of scrutiny, root cause analysis, and litigation, it is moot to remember that

Errors in Medicine: A Perioperative Perspective  5

Fig. 1: James Reason’s “Swiss cheese” model of causation of errors.21 Typically, defense is formed by multiple layers, and when the holes align in the form of medical errors, a poor outcome ensues.

adverse outcomes actually follow only in a small proportion. The larger proportion of errors or “near misses” may not be associated with adverse outcomes either due to good fortune, or to being noted and dealt with in a timely manner.5,20 The Swiss cheese model of error causation proposed by James Reason has been extrapolated to healthcare.21 The principle of Swiss cheese theory suggests that several layers of defense are in place in most hospitals to protect against adverse outcomes relating to medical errors. These layers are represented by several slices of Swiss cheese, each with holes in them. These holes are representative of flaws in the system, predisposing to error. When a situation arises in which the holes in different layers align, or flaws “match up”, injury and adverse outcomes are likely as illustrated in Figure 1.21

IS THE TERM “ERROR” THE MOST APPROPRIATE AND SUITABLE? Near miss,1 incident, and accident23,24 are other terms that have been used in some safety critical industries. However, the term error carries a connotation of stigma, and is often associated with negative psychological impact on the clinician. An antagonistic term that strongly promotes the blame game, an error can also be used as the basis for a malpractice claim.25-27 This fear adds to feelings of anger, inadequacy, guilt, anxiety, and depression.5,20,28 A negative approach such as this carries the potential to decrease efficiency of the “accused” clinician, sometimes even resulting in them giving up an otherwise good career in medicine.20 It has been suggested that the term error be restricted to processes for redesigning of systems and improvement of patient safety. Identifying error and providing feedback and education have been acknowledged as good resources to improve patient safety.5,20,29,30

6  Yearbook of Anesthesiology-9

As per the Swiss cheese theory, multiple complex factors contribute to causation of errors.12,22 The human factor needs to be factored into the understanding of error occurrence, which is often lacking given intolerance by public and the law. Prevention of errors is more likely to be resolved by education, as well as addressing underlying systemic causes, and not by punitive action against clinicians. Ultimately errors can be reduced or mitigated once health systems are safer, not by apportioning blame and punishing individuals.5,20,22,31 Errors need to be recognized and acknowledged to then create educational opportunities and improvements in safety of healthcare.26

ROLE OF HUMAN FACTORS IN GENESIS OF ERROR Human factors involve the complex interaction between humans and environment or technology.22 In medical field, the subset most frequently studied was anesthesia and intensive care, which have similarities to previously studied fields such as engineering, design, management, and ergonomics.32 Not only is the field of anesthesia most studied for human factors in accident causation, but is also identified as significantly invested in strategies for patient safety.33,34 With inspiration from aviation industry especially in relation to checklists, drills and simulation, this specialty has made rapid advances in use of technology for patient monitoring and implementation of safety guidelines. Analysis of human factor in causation of errors suggests 64–83% of anesthetic accidents can be linked to human error.13 The causes of human error in aviation mishaps were identified but not limited to long working hours causing fatigue with flawed cognition and decision making processes. Team issues relating to teamwork, leadership, and interpersonal communication all potentially contribute to human error.35 Following this analysis, attempts were made to decrease errors through crew resource management (CRM), which has become increasingly sophisticated and had increasing uptake and approval.36 Initial resistance was overcome with improved training and evidence of human factors in causation of accidents. The specialty of anesthesia has followed the strategies implemented in the aviation industry toward safer practice. Besides technical skills and knowledge, anesthesiologists’ nontechnical skills (ANTS) including task management, teamwork, situation awareness, and decision-making are taught and assessed in the anesthesia training program.37

“HIGHLY COMPLEX, TIGHTLY COUPLED” Another similarity of anesthesia to aviation industry is that both are highly complex, dynamic, and tightly coupled. Not only are complex interactions

Errors in Medicine: A Perioperative Perspective  7

involved in ensuring a good outcome, but also the unpredictable characteristics and responses of the human undergoing anesthesia make this more difficult and need personalized planning.38,39 The term “tightly coupled” reflects the critical importance of time in the processes, which cannot wait or stand by.40 Induction of anesthesia is a tight time dependent process, where medication is administered followed by paralysis and intubation. These need to be performed in quick succession. The anesthesiologist cannot afford to be distracted, or undertake some other task leaving patient unattended, without dire consequences. These highly complex time coupled systems set the stage for increased likelihood of accidents.12 Perrow suggests that these accidents, very likely to occur in complex time coupled activities, should be viewed as inherent characteristics of such a system, so named “normal accidents”.40

CHANGING APPROACH TO ERROR The traditional approach to error has been to emphasize education and training, along with punitive measures and blame apportionment as a means of reducing errors and mitigating their effects.41 This was based on the premise that encouraging people to be more careful and motivated would improve safety by reducing errors. Whilst this seems obvious and straightforward, just focusing on individuals and pushing them to perform better has not really reduced accidents in industry analysis. The reason that person-focused approach has not worked is because accidents are often the result of interplay of systemic, organizational, and circumstantial factors rather than just one unsafe worker.32 Whilst encouraging and motivating people to do better, the culture of “naming, blaming, and shaming” the person deemed responsible deflects from the bigger picture to actually analyze the cause of error.42 The premise that blaming an individual for carelessness, negligence, and poor motivation will somehow eliminate errors, is flawed. One of the major “side effects” of this blame culture is inculcating fear, so errors are covered up rather than admitted to. Multiple factors contribute to this inability to acknowledge an error. The training of medical students and doctors has been to aim for zero errors, by being extra careful and trying hard. It follows that doctors then see themselves and their practice as infallible, which is really a setup for trouble. When an adverse event occurs, which is inevitable in some situations, doctors see this as a professional and personal failure, and fear the shame that will follow when colleagues see them as incompetent. The feelings of guilt, shame, and isolation are often major enough for the doctor to become the “second victim”.43 It has been said that, “..… medicine is often driven by the idea that perfection is possible and that mistakes are a personal and professional failure. This perfection mind-set … is laudable, admirable, and unworkable”.44

8  Yearbook of Anesthesiology-9

Recognition that errors are often based on complex interactions of human behavior with equipment and procedures forms the modern approach to understanding and addressing error. In contrast to the traditional approach, where human cognitive limitations have been targeted, the current approach is to accept these as the last link in events leading to adverse outcomes. It is accepted that fatigue and long hours of work, stress, preoccupation or distraction as well as forgetfulness can contribute to accidents, but this is certainly not the only major or leading cause of an adverse event.32 Acceptance of inevitability of errors in some situations and acceptance of human fallibility, besides designing and promoting safe systems is possibly the best way to improve safety.

CAUSATION OF ERRORS ALSO MIRED IN MYTHS Reason45 has listed some myths around error causation. These include: • Errors are made by bad people, casting a moral shadow of karma:42 Simply put, it suggests that people bring these bad events upon themselves, due to performing bad actions. This is clearly a myth, given that most errors occur to the best people performing the most difficult tasks or a good person having a bad day. • Errors are unpredictable and unpreventable: Another myth propagated around error causation relates to a perception of errors being random events, occurring without reason or warning. The reality is that errors do occur throughout a profession. • Highly trained individuals do not make errors: This is another myth, negated by the fact that errors are usual and common, though most are not associated with serious outcomes. Analysis from the aviation industry shows only about 100 major events a year on background of 100 million errors made by flight crew.46 • Highly trained individuals make huge errors: It is commonly believed that highly-trained professional makes huge errors invariably causing bad outcomes. However, similar to the previous myth, statistics show errors may be common, but serious adverse events are rare due good preventative systems in place (e.g. alarms on anesthetic machine). Also, individuals who are highly competent are also well trained to detect and recover from errors before they actually cause a bad outcome. Errors are not uniformly viewed, and like everything else, are subject to bias. They are largely classified into outcome bias and hindsight bias. • Outcome bias depends on adverse outcome. The worse the outcome, the more seriously an error is viewed.47 An interesting study where 112 anesthesiologists were asked their opinion about quality of care in 21 cases showed inverse relationship between worsening outcome and judgment of appropriate care.48 Put simply, the same set of circumstances

Errors in Medicine: A Perioperative Perspective  9

(in this case standard of care) was judged more critically (as being worse) when informed that it was associated with bad outcome. • The benefit of hindsight or retrospective analysis, once the outcome is known, definitely alters analysis of errors and adverse outcomes. Psychologists have studied and confirmed the phenomenon of this bias, when those reviewing a sequence of events after the outcome can clearly see disaster looming. On the other hand, an experienced person actually involved in real-time management of the events may not be able to see events unfolding in a linear fashion.12

MEDICATION ERRORS IN THE HOSPITAL Staggering statistics from the United States show that nearly 10% of hospital inpatient costs are attributable to potentially preventable complications, of which medication error is a substantial contributor. Figures from 2006 estimated national healthcare costs at $940 billion, and the 9.4% contribution from errors equates to $88 billion.49 One of the major errors encountered in health industry is that of drug administration errors. These are estimated to account for 7,000 deaths in the United States, and a much larger number of people suffering, along with increase health costs.50-52 Medication errors have been documented as the seventh most common cause of mortality in hospitalized patients, with worst culprits being antibiotics and anesthetic agents.53 Review and analysis of medication errors, and effective methods of prevention is one of the strategies pursued to reduce spiraling healthcare costs as well as adverse events. Other studies have also substantiated the above figures relating to costs and morbidity from medication errors. Bates et al. have analyzed figures from a medium sized 700-bed hospital, and calculated 1 in 50 in patients have a preventable adverse outcome related to medications. This translates into increased hospital costs of $4,700 per admission or $2.8 million annually, which is considered preventable.54 One of the top reasons of medication error during inpatient stay is linked to polypharmacy, given that a third of inpatients are on five or more different medications.55 Newer medications may carry specific risks include drug interactions, and certain groups may be more susceptible to the adverse effects. The elderly population, with some age-related physiological changes including reduced ability to metabolize drugs, combined with needing a large number of medications, are at high risk of drug-related adverse outcomes. Research has shown increased incidence of adverse events in those over 65, possibly influenced by age-related decrease in renal function and polypharmacy.56

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The other high-risk population is young children, as drug prescriptions need to be tightly linked to body weight. Patients with limited ability to understand and follow instructions would also be at risk of adverse events. A recent study showed that two-thirds of emergency hospital admission occurred due to unintentional overdosage of certain medications. Of these, only four groups, specifically warfarin, insulins, oral hypoglycemics, and antiplatelet agents, accounted for 7 out of 10 emergency hospital admissions.57 Medications taken in error, if not prescribed can also result in significant adverse events. Specific groups of medications that have this potential include opioids, sedatives, antibiotics, potassium chloride and hypoglycemic agents, among others. Adverse events could potentially occur due to allergic response, even when medications are correctly administered. This is considered to be more commonly preventable in older population (90%) than in younger population (24%).58

CLASSIFICATION OF MEDICAL ERRORS BASED ON IMPACT A medication error index adopted by the National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) in 1996 was later revised in 2001. This index classifies errors based on impact to the patient, ranging from whether it actually affected the patient to the degree of harm resulting in temporary or permanent morbidity/mortality as depicted in Figure 2.

MEDICATION ERRORS SPECIFIC TO THE PRACTICE OF ANESTHESIA Medication errors in anesthesia are a significant contributor to morbidity as well as mortality. Extrapolation from statistics suggests that most anes­ thesiologists would be involved in at least one major error over an average career, with about 7 errors per year.51,53 Medication errors, in association with infusion pump problems, are reported to be the leading cause of deaths related to anesthesia in Denmark.59 Studies from other regions and continents have shown similar results. A prospective study of 10,000 anesthesia episodes from New Zealand showed 1 error for every 130 anesthetics administered.60 This along with some other studies listed in Table 1 highlights incidence of drug errors. In a Canadian survey less than 70% anesthesiologists reported adhering to practice of labeling syringes and reading labels before administration on a regular basis.61 Anesthesiologists are uniquely placed as the only subset in medical practice to prescribe, draw up, dilute, and administer drugs and then monitor patients for any complications. Given the high usage of medications for induction and maintenance of anesthesia, the urgency and sometimes crisis

Errors in Medicine: A Perioperative Perspective  11

Fig. 2: National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP, 2001). Source: 2014 National Coordinating Council for Medication Error Reporting and Prevention.80

Table 1: Incidence of medication errors in key studies. Number of anesthetics delivered

Incidence of drug error

Percentage of drug error

Study

Study period

Webster et al.60

Feb 1998– Oct 1999

10,806

81

0.75%

Sakaguchi et al.65

1993–2007

64,285

50

0.078%

Llewellyn et al.

Jul 2005– Jan 2006

30,412

111

0.37%

Cooper et al.70

Aug 2007– Feb 2008

10,574

52

0.49%

Zhang et al.81

Mar 2011– Sep 2011

24,380

179

0.73%

66

12  Yearbook of Anesthesiology-9

like situations, it is anticipated this will set the scene for errors associated sometimes with severe adverse outcomes. An average anesthetic career would likely involve administration of 1 million anesthetics. A significant proportion of these would be elderly patients, presenting for high-risk surgery, sometimes in urgent and emergency situations. Drug interactions with medications the patients may currently be using, and failure to recognize or reconcile these can lead to disastrous situations. Emergency surgery and anesthesia can sometimes be dynamic and rapidly changing or deteriorating, which demands urgent medication possibly without rechecks. Other potential confounders are the factors that influence the patient’s ability to tolerate any errors, including reduced physiologic reserve due to emergency condition or trauma needing surgery, besides of course extremes of age, and other conditions such as pregnancy. The numbers for intensive care units appear to be a little higher with 133 medication errors reported per 1,000 patient days.62 It has been acknowledged that a widespread pattern of under-reporting in most healthcare systems means that the actual rate of medication errors would actually be much higher.63 Also, given that the actual outcome of an error is influenced by so many factors, studies need to focus and reflect on errors or near misses, irrespective of actual outcome of harm. As discussed, medication errors are often attributable to failure of pathways, processes, and systems, rather than individual negligence. Lack of protocols for administration of medications, and shortage of staff to assists with checks and other processes are typical systemic latent causes of medication errors. Staff shortage can also result in some practitioners needing to work beyond reasonable hours leading to fatigue or distractions/ interruptions from attempting to manage multiple cases. Australia and New Zealand College of Anaesthesia (ANZCA) has published statements on fatigue and distractions, and need for safe working hours. Active causes of failure or medication error include incorrect choice of medication or route of administration, and failure of memory or attention.64 Studies have identified the most common medications administered wrongly. They include vasopressors, opioids, and cardio-stimulants.65 A study by Llewellyn66 from South Africa reported the most frequent cause of error as being due to mislabeling of drugs. Sakaguchi also suggested that most errors were attributable to inexperience of the practitioner involved in drug administration.65 This issue was emphasized in many other studies, including one by Phillips, which correlated increased errors and the start of the new medical residents placement/rotation.67 The Journal of Patient Safety reported incorrect medication as causing nearly half of medication errors (48%), followed by incorrect or excess dosage (38%), and inappropriate route of administration (8%). Smaller

Errors in Medicine: A Perioperative Perspective  13

contributions of 4 and 2% respectively were attributable to administration of less dosage or missing out entirely.68 The analysis further involved breakdown of causes for administration of incorrect medication as syringe swap in 42%, drug ampoule swap in 33%, and wrong choice of medication in 17%. Incorrect and excess dosages were administered frequently due to misunderstanding of dosage, wrong usage of syringe pump (21%), and incorrect use of dilution (5%).53 Detailed breakdown of the actual process during which medication errors are most common revealed some interesting data.69 Administration of any medication in intensive care units involves well over a hundred little steps, right from prescription to administration and monitoring. Though administration is usually double-checked between two medical personnel, it was the most common step for error (53%), far more than prescription (17%), preparation (14%), or transcription (11%). The commonly involved medications include heparin, potassium chloride, inotropes, and antibiotics, which are possibly the most commonly used medications in intensive care unit. Analysis of medication errors in anesthetic practice70 reported events as occurring more frequently during the maintenance phase of anesthesia (42%) as opposed to induction (28%) or when surgery is commenced (17%). Errors in administration of anesthetic agents could involve route or order of administration or the actual dosage. The usual medications associated with these errors include induction agents, anticholinergics, opioids and neuromuscular blocking agents, among others. An impressive study by Phillips67 also suggested similar causative factors including incorrect dose (40.9%), incorrect medication (16%), and incorrect route (9.5%). Another analysis of over 2,000 medication errors in anesthesia from Australia also showed 61% events occurred during the administration of drugs. Most commonly, it was administration of wrong drug that was implicated, but in about 7% it was a correctly labeled syringe with wrong drug in it. Miscommunication during provider change was identified as the cause of error.71 An important and not uncommon cause of medication errors is medications that have similar packaging, appearance, or labeling, but very different pharmacological properties, as alluded to earlier. Examples abound of medications packaged similarly with potential for confusion and error, and anesthesia specific drugs are overrepresented in this section. The neuromuscular blocking agents, cisatracurium and rocuronium, have different properties including onset and duration but have similar labeling. While mortality occurs only in a small proportion of medication errors, the effects in many cases can be far reaching for both patients and healthcare professionals. Increased cost to the healthcare system from morbidity, readmission, prolonged hospital stays, lack of confidence, and

14  Yearbook of Anesthesiology-9 Table 2: Classification of drug errors.

Drawing up drugs and labeling phase

Drug administration phase

Documentation errors

Similar looking vials Unlabeled syringes: •• Not checking the label (including expiry date) prior to administration •• Different concentration in the syringe and incorrect label (incorrect dilutions esp. relevant in pediatric patients) Near misses: •• Incorrect dose (inadequate or in excess) esp. in pediatric patients Syringe swap: •• •• •• •• ••

Wrong route of administration Incorrect timing of administration Omission, repetition, or substitution of drug Adverse event not recognized or not documented Reluctance among doctors to admit the error

•• Failure to report an error during medication

litigation concerns in caregiver as well as damaged public perception are all consequences of these adverse events. Dhawan et al.72 simplified the classification (Table 2) of errors as applied particularly to anesthesia practice.

ERROR REDUCTION AND PREVENTION— HARM MINIMIZATION While much work remains to be done in prevention of medication errors, attitudes toward this are most important in determining the success of any strategy. To this end, Ashcroft et al. studied safety culture in community pharmacies across United Kingdom. Attitudes toward safety ranged from a total lack of understanding for the need of any risk management strategies to an integration of risk reduction steps in every process.73 They have classified attitudes toward medical errors as levels 1–5, from mast dangerous to most risk averse. Level 1 or “pathological” includes subjects who view risk management and safety issues as a waste of time. Level 2 is more “reactive” and responds to incidents appropriately, but actually waits for them to occur. Level 3 or the “calculative” group tries to plan in advance and anticipate possible scenarios. Level 4 is more “proactive” in that they are always on the alert, understanding the inevitability of errors, if the guard is dropped. Level 5 is “generative”, incorporating risk management strategies into every process, and constantly working toward risk minimization. Worldwide efforts are underway in an effort to reduce the burden of medication errors. Bar coding of medications, reconciliation of electronic

Errors in Medicine: A Perioperative Perspective  15

medical records, large labels highlighting high-risk drugs, and similar measures have been proposed and adopted in many institutions with an aim of reducing the burden of error. The reduction in errors was modest, and highlighted the need for finding alternative solutions to these complex problems. Some hospitals such as Virginia Mason have drawn on industry concepts such as Six Sigma to decrease variance and significantly improve safety in medication administration.74 Another example of extrapolating quality concepts from industry is demonstrable at Froedtert Hospital systems in Milwaukee.75 One main project relating to medication errors through the intravenous route elucidated lack of standardization as the most important cause. Six-Sigma approach was applied to identify systems errors and then implement methods to eliminate these errors. The causes highlighted as part of investigation included medication orders not received, defective faxes, lack of oversight, administration of medications on “standard” doses rather than adjusted for weight, and continuing these medications beyond necessary time frame. Confirmation that errors were more often system issues and not just individual or personal carelessness then produced system solutions. Intravenous pumps were redesigned with up-to-date information on preparing standard medications, based on industry approach using Six Sigma. This will be the way forward in identifying system failures and suggesting safety measures, though cost is usually a limiting factor. With strong emphasis worldwide on harm minimization and risk reduction, some strategies have been implemented. Some potential systems for safer drug administration include but are not limited to the following: • VEINROM: This is a novel design (still in development) for administration of medications intraoperatively, using a predisposition syringe with interlocking mechanism. The acronym stands for vasoconstrictors, emergency drugs, neuromuscular blockers, induction agents, reversal agents, opioids, and miscellaneous drugs. Ports and syringes are colorcoded. Bar code facilities allow the medication record to be updated simultaneously with administration.76 • ValiMed: This validation of medical systems device utilizes photoelectron spectroscopy to confirm the substance being administered when compared with control substance. This tabletop device uses ultraviolet (UV) light for ionization of electrons, and measures the energy of electrons to validate the drug being administered. During an extensive trial by Michigan health system, no drug error was reported during the duration of trial, and also reduced wastage of drugs. Constraints include cost and time required to run the test.77

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• Robot-assisted medication preparation: With accelerated progress of artificial intelligence and automation, robots are expected to undertake routine tasks of drug preparation and administration. A recent report from Italy (University of Ancona) showed no medication error after 19,000 (95%) chemotherapeutic drugs were prepared using robotic arm aid.78 • Purchase of prefilled syringes: Some medications are being made available in the form of prefilled syringes, and are anticipated to reduce medication errors significantly. The industry of prefilled syringes is projected to cross 5 billion used.79

MANAGEMENT OF ERRONEOUS ADMINISTRATION OF MEDICATION Medication errors in the anesthetic scenario can be associated with significant morbidity and mortality. Preparation of premed and anesthetic drugs with appropriate labeling prior to commencement of the case is the first step in anesthetic management. It follows that inaccurate labeling or identification of drugs, distraction and inexperience in a stressful operative environment can result in errors which can sometimes be fatal. Because some drug errors cannot be reversed, prevention is the best way to treat and minimize errors. Terminating services of an individual who commits an error has been commonly seen as effective prevention, though evidence really points to identification and management of system errors.12 Methods for prevention of errors include outsourcing of prefilled syringes, or the cheaper option of preprinted label stickers which can be peeled and stuck onto vials or syringes. Unlabeled vials and syringes should be compulsorily discarded. VEINROM, ValiMed, and robotic preparation/dispensation of medications may gain popularity once they become more affordable.

CONCLUSION While accepting that most errors are caused by unintentional mistakes, and are not always associated with bad outcomes, doctors need to be extremely vigilant to avoid these errors. With efforts at prevention, it is also important to report any near miss, so safety protocols can be further improved. This is important in the interest of patient safety as well as reduction in spiraling medicolegal costs. It follows that one of the principal stems in error prevention is education of anesthesiologists regarding the unique risks of their position. Being the only person responsible for prescribing, preparing, and administering drugs; the onus of checking and rechecking really falls on their shoulders. Beside this awareness and education, development of safer and error proof systems needs to be considered as a joint venture between

Errors in Medicine: A Perioperative Perspective  17

anesthesiologists and their institutions. It appears that there continues to be underreporting of medical errors, which then mask the extent and effects of the problem. Cultural differences may contribute to difficulty in acceptance of errors. Finally, these measures, both at individual and organizational level, need to be accepted and implemented.

KEY POINTS • Error is defined as an act of omission or commission in planning or execution that contributes or could contribute to an unintended result. • Medical errors can be classified into active errors occurring around an incident, or latent errors that may not be immediately evident or visible. • Multiple complex factors based on interactions of human behavior with equipment and procedures contribute to causation of errors. • The human factors such as fatigue, long hours of work, stress, preoccupation or distraction as well as forgetfulness can contribute to accidents. • Anesthesiology is the most studied field in medicine for human factors in accident causation. It is also identified as significantly invested in strategies for patient safety by using technology for patient monitoring and implementation of safety guidelines. • Errors are not uniformly viewed, and like everything else, are subject to outcome bias or hindsight bias. • Most errors are potentially preventable complications which can be avoided by education, as well as addressing underlying systemic causes. • Medication errors have been documented as the seventh most common cause of mortality in hospitalized patients, with worst culprits being antibiotics and anesthetic agents. • Errors can occur during drawing up drugs and labeling phase, drug administration phase, or documentation phase. • Bar coding of medications, reconciliation of electronic medical records, large labels highlighting high-risk drugs, and similar measures have been proposed and adopted in many institutions with an aim of reducing the burden of error.

REFERENCES 1. Grober ED, Bohnen JM. Defining medical error. Can J Surg. 2005;48(1):39-44. 2. Merry AF. How does the law recognize and deal with medical errors? JR Soc Med. 2009;102(7):265-71. 3. Moyen, E, Camiré E, Stelfox HT. Clinical review: medication errors in critical care. Crit care. 2008;12(2):208. 4. Gawande A. When doctors make mistakes. New Yorker. 1999;74:40-55. 5. Kohn LT, Corrigan JM, Donaldson MS (Eds). To Err is Human: Building a Safer Health System. Washington: Institute of Medicine, National Academy Press; 1999. 6. Wilson RML, Runciman WB, Gibberd RW, et al. The Quality in Australian Health-care Study. Med J Aust. 1995;163(9):458-71.

18  Yearbook of Anesthesiology-9 7. Department of Health. An organization with a memory: Report of an expert group on learning from adverse events in the National Health Service. Norwich: The Stationery Office; 2000. 8. Gaba DM, Fish KJ, Howard SK. Crisis Management in Anesthesiology. New York: Churchill Livingstone; 1994. 9. Thomas EJ, Studdert DM, Runciman WB, et al. A comparison of iatrogenic injury studies in Australia and the USA. I: Context, methods, casemix, population, patient and hospital characteristics. Int J Qual Health Care. 2000;12(5):371-8. 10. Brennan TA. The Institute of Medicine report on medical errors-could it do harm? N Eng J Med. 2000;342(15):1123-5. 11. Leape LL. Institute of medicine medical error figures are not exaggerated. JAMA. 2000;284:95-7. 12. van Beuzekom, Boer F, Akerboom, et al. Patient safety: latent risk factors. Br J Anaesth. 2010;105(1):52-9. 13. Helmreich RL, Foushee HC. Why crew resource management? Empirical and theoretical bases of human factors training in aviation. In: Weiner E, Kanki B, Helmreich R (Eds). Cockpit Resource Management. San Diego. Academic Press: 1993. pp. 3-45. 14. Allnutt MF. Human factors in accidents. Br J Anaesth. 1987;59:856-64. 15. Leape LL. Error in medicine. JAMA. 1994;272:851-7. 16. Gaba DM, De Anda A. The response of anesthesia trainees to simulated critical incidents. Anesth Analg. 1989;68:444-51. 17. De Anda A, Gaba DM. Unplanned incidents during comprehensive anesthesia simulation. Anesth Analg. 1990;71:77-82. 18. Bogner MS. All the men and women merely players. In: Bogner MS (Ed). Misadventures in Health Care: Inside stories. Mahwah: Lawrence Erlbaum; 2004. pp. 201-14. 19. Collier CB, Gatt SP. Hazard Warning: The risk of antiseptic contamination of neuraxial blocks. BJA. 2010:105(21). 20. Reason JT. Understanding adverse events: the human factor. In: Vincent C (ed). Clinical risk management: enhancing patient safety. London: BMJ Publishing Group; 2001. pp. 9-30. 21. Reason J. Managing the risks of organizational accidents. Aldershot: Ashgate; 1997. 22. Cook RI, Wood DD. Operating at the sharp end: the complexity of human error. Hillsdale (NJ): Erlbaum. 1994. 23. Federal Aviation Administration. Aviation glossary, Federal Aviation Regulations. In: Aviation safety data. Washington: FAA. Available: https://www. faa.gov/regulations_policies/handbooks_manuals/aviation/risk_management/ ss_handbook/media/app_a_1200.pdf. [Last accessed 2019 May 20]. 24. NUSAFE Nuclear Installation Safety Net. IAEA safety glossary. In: Regulatory control of nuclear power plants, 1st ed. 2002. Vienna (Austria): International Atomic Energy Agency; 2002. 25. Wears RL, Janiak B, Moorhead JC, et al. Human error in medicine: promise and pitfalls, part 2. Ann Emerg Med. 2000;36:142-4. 26. Fish JM. Human error in medicine: promise and pitfalls, part 2 [letter]. Ann Emerg Med. 2001;37(4):419-20. 27. Holloway RG, Panzer RJ. Lawyers, litigation, and liability: can they make patients safer? Neurology. 2001;56(8):991-3.

Errors in Medicine: A Perioperative Perspective  19 28. Hatch D. Incidence and acceptance of errors in medicine. Schweiz Arzte, Bull Med Swiss 2001;82:1339-43. 29. Weinger MB, Pantiskas C, Wiklund ME, et al. Incorporating human factors into the design of medical devices. JAMA. 1998;280(17):1484. 30. Andrews LB, Stocking C, Krizek T, et al. An alternative strategy for studying adverse events in medical care. Lancet. 1997;349(9048):309-13. 31. Deming WE. Elementary principles of the statistical control of quality: a series of lectures. Tokyo: Nippon Kagaku Gijutsu Remmei; 1952. 32. Vincent C, Reason J. Human factors approaches in medicine. In: Rosenthal MM, Mulcahy L, Lloyd-Bostock S (Eds). Medical Mishaps: Pieces of the puzzle. Buckingham: Open University Press; 1999. pp. 39-56. 33. Gaba DM. Anesthesiology as a model for patient safety in health care. BMJ. 2000;320:785-8. 34. Gaba D. No myth: anesthesia is a model for addressing patient safety. Anesthesiology. 2002;97:1335-7. 35. Helmreich RL, Merritt AC. Culture at work: national, organizational and professional influences. Aldershot UK: Ashgate; 1998. 36. Helmreich RL, Merritt AC, Wilhelm JA. The evolution of crew resource management training in commercial aviation. Int J Aviat Psychol. 1999;1:19-32. 37. Fletcher G, Flin R, McGeorge P, et al. Anaesthetists’ Non-Technical Skills (ANTS): evaluation of a behavioural marker system. Br J Anaesth. 2003;90(5):580-8. 38. Helmreich RL, Schaefer HG. Team performance in the operating room. In: Bogner MS (Ed). Human Error in Medicine. Hillside NJ: Lawrence Erlbaum; 1994. pp. 225-53. 39. Helmreich RL. On error management: lessons from aviation. Brit Med J. 2000;320:781-5. 40. Perrow C. Normal Accidents: Living with High Risk Technologies. USA: Basic Books; 1984. 41. Moray N. Error reduction as a systems problem. In: Bogner MS (Ed). Human Error in Medicine. Hillsdale NJ: Lawrence Erlbaum; 1994. pp. 67-91. 42. Reason J. Human error: models and management. Brit Med J. 2000;320:768-70. 43. Wu AW. Medical error: The second victim. Brit Med J. 2000;320:726-7. 44. Weick KE. The reduction of medical errors through mindful interdependence. In: Rosenthal MM, Sutcliffe KM (Eds). Medical Error: What do we know? What do we do? San Francisco: Jossey-Bass; 2002. pp. 177-99. 45. Reason J. Seven myths about human error and its management (Published in Italian as): Come limitare l’errore. KOS: Rivista di Medicina, Cultura e Scienze Umane. 2001;187:10-7. 46. Amalberti R, Woland L. Human error in aviation. In: Soekha H (Ed). Aviation Safety. Utrecht: VSP; 1997. pp. 91-108. 47. Merry A, McCall Smith A. Errors, medicine and the law. Cambridge: University Press; 2001. 48. Caplan RA, Posner KL, Cheney FW. Effect of outcome on physician judgments of appropriateness of care. JAMA. 1991;265:1957-60. 49. Fuller RL, McCullough EC, Bao MZ, et al. Estimating the costs of potentially preventable hospital acquired complications. Health Care Financ Rev. 2009;30(4):17-32. 50. Leape LL, Brennan TA, Laird N, et al. The nature of adverse events in hospitalized patients. Results of the Harvard Medical Practice Study II. N Engl J Med. 1991;324:377-84.

20  Yearbook of Anesthesiology-9 51. Glavin RJ. Drug errors: consequences, mechanisms, and avoidance. Br J Anaesth. 2010;105:76-82. 52. Phillips DP, Christenfeld N, Glynn LM. Increase in US medication error deaths between 1983 and 1993. Lancet. 1998;351:643-4. 53. Steflox HT, Palmisani S, Scurlock C, et al. The “To Err is Human” report and the patient safety literature. Qual Saf Health Care. 2006;15(3):174-8. 54. Bates DW, Spell N, Cullen DJ, et al. The costs of adverse drug events in hospitalized patients. Adverse Drug Events Prevention Study Group. JAMA. 1997;277(4):307-11. 55. Medication Errors. US Department of Health and Human Services: Patient Safety Primer. United States: Agency for Healthcare Research and Quality; 2015. 56. Nosek RA, McMeekin J, Rake GW. Standardizing medication error event reporting in the U.S. Department of Defense. In: Henriksen K, Battles JB, Marks ES, Lewin DI (Eds). Advances in Patient Safety: From Research to Implementation. United States: Agency for Healthcare Research and Quality (US). 2005. 57. Budnitz DS, Shehab N, Kegler SR, et al. Mediation use leading to emergency department visits for adverse drug events in older adults. Ann Intern Med. 2007;147(11):755-65. 58. Ruscin MJ, Linnebur SA. Drug-related problems in the elderly. USA: Merck Manuals; 2014. 59. Hove LD, Steinmetz J, Christoffersen JK, et al. Analysis of deaths related to anesthesia in the period 1996-2004 from closed claims registered by the Danish Patient Insurance Association. Anesthesiology. 2007;106:675-80. 60. Webster CS, Merry AF, Larsson L, et al. The frequency and nature of drug administration error during anaesthesia. Anaesth Intensive Care. 2001;29: 494-500. 61. Orser BA, Chen RJ, Yee Da. Medication errors in anesthetic practice: a survey of 687 practitioners. Can J Anaesth. 2001;48(2):139-46. 62. Rothschild JM, Landrigan CP, Cronin JW, et al. The critical care safety study: the incidence and nature of adverse events and serious medical errors in intensive care. Crit Care Med. 2005;33:1694-700. 63. Mahajan RP. Critical incident reporting and learning. Br J Anaesth. 2010;105: 69-75. 64. Australian and New Zealand College of Anaesthetists. Statement on fatigue and the anaesthetists (PS 43). [online] Available from: http://www.anzca. edu.au/documents/ps43-2007-statement-on-fatigue-and-the-anaesthetis [Last accessed July, 2019]. 65. Sakaguchi Y, Tokuda K, Yamaguchi K, et al. Incidence of anesthesia-related medication errors over a 15-year period in a university hospital. Fukuoka Igaku Zasshi. 2008;99:58-66. 66. Llewellyn RL, Gordon PC, Wheatcroft D, et al. Drug administration errors: a prospective survey from three South African teaching hospitals. Anaesth Intensive Care. 2009;37:93-8. 67. Phillips DP, Barker GE. A July spike in fatal medication errors: a possible effect of new medical residents. J Gen Intern Med. 2010;25(8):774-9. 68. James JT. A new, evidence-based estimate of patient harms associated with hospital care. J Patient Saf. 2013;9(3):122-8. 69. Krahenbuhl MA, Schlienger R, Lampert M, et al. Drug related problems in hospitals: a review of the recent literature. Drug Saf. 2007;30:379-407.

Errors in Medicine: A Perioperative Perspective  21 70. Cooper JB, Newbower RS, Long CD, et al. Preventable anaesthesia mishaps: a study of human factors. Anesthesiology. 1978;49:399-406. 71. Currie M, Webb RK, Williamson JA, et al. The Australian incident monitoring study. Clinical anaphylaxis: an analysis of 2000 incident reports. Anaesth Intensive Care. 1993;21(5):621-5. 72. Dhawan I, Tewari A, Sehgal S, et al. Medication errors in anesthesia: unacceptable or unavoidable?. Revista Brasileira de Anestesiologia. 2017;67(2):184-92. 73. Ashcroft DM, Morecroft C, Parker D, et al. Safety culture assessment in community pharmacy: development, face validity, and feasibility of the Manchester Patient Safety Assessment Framework. BMJ Quality and Safety. 2005;14(6):417-21. 74. Ching JM, Long C, Williams BL, et al. Using lean to improve medication administration safety: in search of the “perfect dose”. Jt Comm J Qual Patient Saf. 2013;39(5):195-204. 75. Buck C. Application of six sigma to reduce medical errors. Annual Quality Congress. 2001;55:739-42. 76. Tewari A, Palm B, Hines T, et al. VEINROM: A possible solution for erroneous intravenous drug administration. J Anaesthesiol Clin Pharmacol. 2014;30(2): 263-6. 77. Kaakeh Y, Phan H, DeSmet BD, et al. Enhanced photoemission spectroscopy for verification of high-risk IV medications. Am J Health Syst Pharm. 2008;65(1): 49-54. 78. Palma E, Bufarini C. Robot-assisted preparation of oncology drugs: the role of nurses. Int J Pharm. 2012;439(1-2):286-8. 79. Transparecy Market Research (2016). Prefilled Syringes Market (Material— Glass-based and Polymer-based; Distribution Channel—Hospitals, ASCs, and Mail Order Pharmacies. Application—Vaccines and Monoclonal Antibodies)— Global Industry Analysis, Size, Share, Growth, Trends, and Forecast 2016– 2024. [online] Available from https://www.transparencymarketresearch.com/ prefilled-syringes-market.html [Last accessed August, 2019]. 80. National Coordinating Council for Medication Error Reporting and Prevention (2001). NCC MERP Index for Categorizing Medication Errors. [online] Available from: https://www.nccmerp.org/types-medication-errors [Last accessed July, 2019]. 81. Zhang J, Patel VL, Johnson TR, et al. A cognitive taxonomy of medical errors. Journal of Biomedical Informatics. 2004;37(3):193-204.

22  Yearbook of Anesthesiology-9

CHAPTER

2

Perioperative Care of the Frail Elderly: Current Knowledge and Future Directions Asha Tyagi, Rashmi Salhotra

INTRODUCTION Aging is a universal, enigmatic, and complex phenomenon. A common hypothesis for aging relates it to irreversible changes at cellular level. Broadly, the mechanisms for aging could be divided into genomic instability and damage, senescence and stem cell exhaustion, along with altered intercellular communications.1

WHO IS AN OLD PATIENT? An adult more than 65 years of age is defined as an elderly;2 and more than 90 years as the oldest old.3 Average life expectancy in India is 67.4 years for males and 70.3 year for females as per the latest figures released by World Health Organization (WHO) in 2018.4 This positive change in life-expectancy has also manifested in an increasing number of elderly/older patients being encountered in operating room for various surgical interventions.5 In the USA, more than 40% of surgical patients are aged >65 years.6,7 The increased frequency of old/elderly in clinical practice has resulted in a change in perspective of healthcare personnel for these patients. It is long been accepted that age-related reduction in organ reserves and increase in comorbid conditions confers a challenge to the anesthesiologists during the perioperative period. Both these factors are well documented, and clinically accepted as special concerns in the elderly. However, of late much emphasis is laid on “frailty” amongst elderly surgical patients as a specific concern.

WHAT IS FRAILTY? A salient question in elderly patients is whether the surgical outcome will lead to residual disability hindering a return to preoperative functional capacity, or lead to a prolongation of end-of-life suffering in these patients.8 To enable a scientific answer to the above question, it is best to view the elderly as a heterogeneous population. The only unifying characteristic is

Perioperative Care of the Frail Elderly  23

perhaps their increased chronological age beyond 65 years. Elderlies could be represented by an active octogenarian who is free from any major disease, freely ambulant, and independently capable of tending to life on one hand; and a younger septuagenarian on the other who is frail and dependent on others for routine activities whether within home or in assisted living facility, despite even a lack of obvious comorbidities. This concept of “fit” versus “frail” elderly was promulgated as long back as 1988.9 “Frailty” also leads way to differentiation between chronological and biological age of an old patient in clinical practice. Frailty was thus a concept of “phenotype”2 defined essentially on the basis of functional and social factors. It is now known that frailty is contributed toward by psychological and physiological factors as well. Over time the concept of frailty has been dwelled upon in greater details. It has come to represent a decreased capacity to adapt to changes in external or internal environment; including to physiological stressors presented during perioperative period.2,9 Frailty is accompanied by cycles of self-perpetuating precipitating events also.10 These cycles prevent maintenance or regaining of homeostasis after a destabilizing event.11 The destabilizing events go much farther than the actual surgery to include even apparently innocuous ones such as fasting, opioids, pain, and postoperative immobility.12 It is important to dissociate frailty from age and medical illnesses. Not all frail patients are elderly or with medical illnesses. Similarly, not all elderly or those with medical illnesses are frail. However, mostly frailty is witnessed in elderly, with >20% incidence in those more than 80 years.2 The prevalence increases with age—approximately 26% population over 85 years,13 and 33% over 90 years fit into the frailty criteria.14 These age-related figures for incidence of frailty are mostly derived from community-based populations and not in surgical patients per se.

HOW TO RECOGNIZE FRAILTY? Frailty conceptualization has moved beyond the subjective impression of a “weak” patient. There are several scores promulgated to identify and quantify frailty, although more commonly in medical patients. More than 30 assessment tools have been identified.15 For surgical patients, the relevant and easily applicable ones have been reviewed.1 It is important to understand that the methods can be classified into either “clinical phenotype” or “deficit accumulation” type. The prototype of the “phenotype method” is index given by Fried et al.16 This classical phenotype method is based on the presence (or absence) of five criteria—(1) unintentional weight loss or shrinkage (>4.5 kg in the last year), (2) poor endurance or exhaustion, (3) slowness in walking, (4) low

24  Yearbook of Anesthesiology-9

activity (75 years also showed an increase in mortality with frailty (OR: 1.1–4.97).28 A significant decline in functional capacity, length of stay, and quality of life was also seen with frailty in surgical patients.28 In medical patients, frailty predicts different outcome measures such as increased incidence of falls, delirium, and general morbidity.14 Thus, frailty should be a factor for stratifying perioperative risk, and optimizing the outcome by specific interventions. Risk stratification may help in deciding whether surgery would be beneficial at all when keeping in mind a holistic picture. It can also help to counsel the patient for perioperative course. For optimization of outcome, there is a relative lack of preferred interventions in these patients that could decrease the risk.12

“FRAIL BODY” OR “FRAIL ORGAN SYSTEM” The concept of frailty evolved while considering the entire human body. In recent times, frailty of a specific organ system, most commonly the heart, has also been conceptualized. The physiological changes in various organ systems due to aging are often elaborated upon in several standard texts. However, there is scanty mention of their association with frailty. Below is a brief recapitulation of only the salient changes in certain organ systems where specific implication with frailty is also known.

Perioperative Care of the Frail Elderly  27

Cardiovascular System In elderlies, there is decreased contractility, increased myocardial stiffness translating to increased ventricular filling pressures and impaired diastolic filling. Diastolic dysfunction is thus a common finding on echocardiography. There may also be coexisting systolic dysfunction. In the aorta, there is a loss of elasticity and increased stiffness that gets manifested as an elevated mean arterial pressure and increased pulse pressure.29 Pulmonary arterial pressures may be raised as well. Additionally, there is a decreased response to β-receptor stimulation, making the elderly patients unable to increase the heart rate during stress. In frail elderlies, increased left atrial volume, decreased stroke volume index, and raised pulmonary artery systolic pressure were noted while no differences in ejection fraction or cardiac index were noted as compared to nonfrail group, after adjusting for age and comorbidities.30 An increased incidence of heart failure and decreased response of heart rate to postural change also occur in frail patients.31 In patients with heart failure, presence of frailty is associated with significantly worse outcomes.32 In addition, heart failure mimics the nonspecific symptoms such as fatigue and breathlessness seen with frailty that could confound the diagnosis.

Respiratory System Elderly patients have impaired ventilatory response to hypoxia and hypercapnia. There is a loss of elastic recoil of lung with early collapse of the small airways on exhalation. Increased closing capacity leads to increased ventilation perfusion mismatch and raised shunt fraction. There is increased anatomical dead space as well, and decreased diffusing capacity. What is worrisome in elderlies is the strong two-way association between respiratory impairment and frailty.33 Presence of either is associated with an increased occurrence of the other. The nature of respiratory impairment includes both airflow limitation as well as restrictive defect.

Nervous System Progressive loss of gray matter occurs as a result of neuronal shrinkage and to a lesser extent because of neuronal loss. Ventricular volume is increased. There is a reduction in the area of epidural space, number of myelinated fibers, inter-Schwann cell distance, and conduction velocity, making these patients highly sensitive to the neuraxial and peripheral nerve blocks.34 Memory loss, restriction in activities of daily living (ADL), is also frequently encountered. The elderly patients are more susceptible to sedatives and hypnotics. Pain threshold is elevated. Dementia and Alzheimer’s disease are dreadful problems that are commonly encountered in the patients coming

28  Yearbook of Anesthesiology-9

for surgery. Postoperative cognitive dysfunction (POCD) is a major concern in this subgroup of patients. Frailty is associated temporally with cognitive impairment and dementia in the long-term.35 In hospitalized elderlies also, there was an increased incidence of delirium (OR: 8.5; 95% CI: 4.8–14.8) as well as cognitive dysfunction (HR: 1.63; 95% CI: 1.27–2.08) with presence of frailty.36,37

Musculoskeletal System With increase in age, the muscle mass is replaced with fatty tissue and there is a decrease in total body water. The distinctive feature of frailty is sarcopenia (exaggerated loss of muscle mass). As a result, the consequences of muscle mass loss will be more extensive. Volume of distribution of hydrophilic drugs is reduced resulting in higher peak plasma concentrations. On the other hand, the reservoir of lipophilic drugs is increased. This translates into reduced clearance and prolonged duration of action for lipid soluble drugs such as benzodiazepines, narcotics, sedatives, and volatile anesthetics.

SHOULD PREOPERATIVE ASSESSMENT FOCUS ON FRAILTY ONLY? The association of frailty with poor surgical outcome cannot be negated. Its importance for preoperative assessment and optimization is reflected by inclusion in the guidelines for optimal preoperative assessment of geriatric surgical patients by the American National Surgical Quality Improvement Program (NSQIP).38 However, the search and focus on frailty cannot shift attention from the optimization of all aspects of the patient. A multidomain evaluation such as the Comprehensive Geriatric Assessment (CGA), along with inclusion of functional capacity, offers a more holistic approach to improve outcome. The CGA can be led by a geriatrician who then coordinates with the surgeon, e.g. in the proactive care of older people undergoing surgery (POPS) program.39 At the same time, there is no evidence to show that frailty can be attenuated or reversed. Assessment and intervention are based on the hope of improvement or optimization of coexisting or causative abnormalities.

ANESTHESIA IN THE FRAIL ELDERLY Preoperative Assessment and Optimization Specific to frailty, a concentrated preoperative exercise regimen aiming for resistive training can increase physical functions. However, its implementation as a focused, intensive “prehabilitation” program is associated with feasibility and cost issues; and remains debatable.1 Even so,

Perioperative Care of the Frail Elderly  29

prehabilitation defined as preoperative enhancement of patient condition with the aim to improve postoperative outcome is mentioned for frail elderlies. Dedicated preoperative programs such as POPS have shown to improve postoperative outcomes in high-risk elderlies, though not frail ones specifically.40 It involves identification of preoperative medical problems and geriatric syndromes, followed by postoperative education programs and multidisciplinary care led by POPS physician.

Anesthetic Technique No special techniques are advocated for the frail elderly. What is emphasized and logically required is a heightened perioperative care, after due consideration to the decreased physiological reserve and vulnerability to even trivial perioperative insults. The technique will depend on nature of surgery, comorbidities and should then be tailored individually. Emphasis during entire perioperative period should be on prevention of complications. One concern that could be extrapolated to frail elderlies relates to the depth of anesthesia. Presence of the “triple low state”, i.e. low mean arterial pressure, low minimum alveolar concentration of inhalational agent, and low bispectral index (BIS) is shown to increase postoperative mortality.41 Independently also, an intraoperatively low BIS of 1.1 mg/dL or ≥ twice the baseline value

Hepatic dysfunction

Epigastric pain and or right upper quadrant pain Liver enzymes are raised to twice the normal values

(CNS: central nervous system; DBP: diastolic blood pressure; SBP: systolic blood pressure)

Its definition was revised in 2014. Now proteinuria is not considered essential for the diagnosis of pre-eclampsia. Instead the presence of hypertension with new development of thrombocytopenia, renal dysfunction (raised serum creatinine levels), hepatic dysfunction (elevated serum transaminases), pulmonary edema, neurological and visual disturbances, and fetal growth restriction is diagnostic of pre-eclampsia even in the absence of proteinuria. Pre-eclampsia may be mild or severe in nature. Table 1 lists the diagnostic criteria for severe pre-eclampsia. Therefore, while defining pre-eclampsia it is important to remember that: • Edema as a criterion had been excluded earlier from the definition of pre-eclampsia since it lacked specificity. • The diagnosis of pre-eclampsia can now be made even in the absence of proteinuria.1,6 • Severe proteinuria > 5 g/24 hours and fetal growth restriction were earlier considered as features of severe pre-eclampsia. Now they have been excluded from the list of diagnostic markers of severe pre-eclampsia.1,6

Eclampsia It is characterized by the occurrence of new onset of generalized convulsions in patients fulfilling the criteria of pre-eclampsia during pregnancy, labor or within 48 hours in the postpartum period, in the absence of any other medical condition predisposing to convulsions. The incidence of eclampsia has decreased over time (5–8/10,000 cases).7

HELLP Syndrome It is a variant of pre-eclampsia with severe features of hemolysis, elevated liver enzymes, and low platelets (< 100,000/mm3).1 It can occur antepartum or postpartum. HELLP syndrome can lead to severe maternal complications such as hepatic hemorrhage or rupture, acute renal failure, disseminated

Pregnancy-induced Hypertension: An Update  37

intravascular coagulation (DIC), pericardial and pleural effusion, and placental abruption resulting in high maternal mortality.

Postpartum Hypertension It is characterized by the new onset of pre-eclampsia/eclampsia/HELLP syndrome that occurs in the postpartum period. Late postpartum hyper­ tension is defined as hypertension, usually mild, which develops in women with normotensive gestation, in the late postpartum period from 2 weeks to 6 months. It may be the predictor of future hypertension.1

PATHOGENESIS OF PRE-ECLAMPSIA The understanding of pathogenesis for the initiation and progression of pre-eclampsia has significantly advanced over the years. Global maternal endothelial cell dysfunction is the prime reason for the manifestations of pre-eclampsia. It is still not clear regarding the factors responsible for the same. A number of hypotheses have been proposed regarding the placental and maternal causes for the pathogenesis of severe pre-eclampsia.

Abnormal Placentation and Maternal Response2,6-9 Abnormal placentation and failure of trophoblastic invasion lead to incomplete spiral artery remodeling in the uterus. This results in placental underperfusion due to undilated myometrial segments. These changes occur early in pregnancy and there are no symptoms.2,8 Underperfused and ischemic placenta releases factors into the maternal circulation resulting in generalized inflammation and dysfunction of maternal endothelium. Due to maternal endothelial dysfunction, there is an increased production of the vasoconstrictor substances such as platelet-derived thromboxane A2 (TXA2), and the decreased production of endothelium-derived vasodilator such as prostacyclin (PGI2) and endo­ thelium derived relaxant factor (EDRF). There is also an imbalance between ET1, the most potent vasoconstrictor, and the vasodilator nitric oxide (NO). This imbalance between vasoconstrictors and vasodilators results in multisystem manifestations of maternal syndrome. This stage occurs late in pregnancy and is symptomatic.10

Genetic Factors Incidence of pre-eclampsia is higher amongst family members and in certain populations. It may be due to recessive genetic inheritance.2

Immunological Factors Abnormal maternal-fetal antigen-antibody reaction between maternal and fetoplacental tissues may be responsible for the pathogenesis of pre-eclampsia.2

38  Yearbook of Anesthesiology-9

Antiangiogenic Proteins Two antiangiogenic proteins of placental origin have now been identified. Soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) are increased in pre-eclampsia. Vascular endothelial growth factor (VEGF) and placental growth factor (PIGF) are antagonized by sFlt-1 resulting in dysfunction of maternal endothelial blood vessels.11 Cigarette smoking, which is considered to be a low risk factor, is associated with lower maternal sFlt-1 levels.12 sEng is elevated in cases of HELLP syndrome.13 Studies have reported that pre-eclamptic women with an increased ratio of sFlt-1-PIGF have adverse maternal and fetal outcome compared to the parturients with ratios of less than equal to 38.14,15 Based on pathogenesis, pre-eclampsia has been categorized into two broad categories: 1. Placental or early onset (34 weeks of gestation) is due to the interaction between normal placenta and a woman predisposed to the disease. Most of these patients have elements of both pathologies. Despite new advances, the pathogenesis of pre-eclampsia remains complex.8

RISK PREDICTION AND PROPHYLAXIS OF PRE-ECLAMPSIA Prophylactic aspirin therapy has been recommended in parturients with high and moderate risk factors for pre-eclampsia. The US Preventive Services Task Force16 and The National Institute for Health and Care Excellence (NICE)17 have identified certain maternal risk factors for pre-eclampsia which are listed in Table 2. • Vitamin D deficiency: It has been reported by some of the studies as a risk factor for development of pre-eclampsia.18 However, other studies did not report any difference with low vitamin D levels.19 • Calcium deficiency: Some of the studies observed that low serum calcium level due to low dietary intake is a risk factor for pre-eclampsia. They further observed that by supplementing high doses of calcium in pre-eclamptic women with calcium deficiency, the incidence of preeclampsia could be reduced.20 However, another study did not find any significant difference.21 • Glycosylated fibronectin (GlyFn) serum levels: It has been reported to be a risk predictor for the development of pre-eclampsia. Its levels

Pregnancy-induced Hypertension: An Update  39 Table 2: Risk factors for pre-eclampsia.2,16,17 High-risk factors

Moderate-risk factors

•• PIH in previous pregnancy, which was associated with maternal or fetal complications •• Chronic hypertension

•• History of pre-eclampsia in mother/sister •• History of low birth weight baby and/ or adverse outcome in the previous pregnancy

•• Multifetal gestation

•• Nulliparity •• > 10 years pregnancy interval

•• Chronic renal disease

•• Age 34 weeks of gestation) preeclampsia have better outcomes than early onset disease.

Cardiovascular Manifestations There is increased vascular tone, exaggerated response to circulating catecholamines, and vasoconstrictor influences. Systemic vascular resis­ tance (SVR), left ventricular work, and blood pressure are increased. Intravascular volume may be reduced to 40% in severe pre-eclampsia in spite of generalized vasoconstriction and retention of sodium and water. It leads to hemoconcentration and reduced hematocrit (HCT). Cardiac output may be normal or increased. Overall studies have found that 80% of patients have hyperdynamic circulation. Direct correlation between central venous pressure (CVP) and pulmonary capillary wedge pressure (PCWP) appears to be absent in severely pre-eclamptic patients. Volume expansion can lead to left ventricular overloading, left ventricular failure (LVF), and pulmonary edema. Left ventricular dysfunction and severe rise in SVR may result in cardiogenic edema.2,6

Respiratory Manifestations Increased vascular permeability, hypoproteinemia, decreased colloidal osmotic pressure, and loss of intravascular fluid and protein into the interstitium increase the risk of pulmonary edema in severely pre-eclamptic patients. It is one of the severe complications of pre-eclampsia and may occur even in the postpartum period.

Airway There is edema formation in the oral, pharyngeal, and laryngeal structures. This makes airway management difficult. Subglottic edema can cause airway obstruction.2,6

Pregnancy-induced Hypertension: An Update  41

Hematological Thrombocytopenia occurs in 15 to 30% of pre-eclamptic women. There may be significant effect on both the function and number of platelets. In severe pre-eclampsia, platelet counts may fall to less than 100,000/mm3. Platelet derived serotonin activates 5-HT2 receptors leading to platelet aggregation. There is increased tendency toward thromboembolism.2,6 • Coagulability: Women with mild pre-eclampsia are relatively hyper­ coagulable and those with severe pre-eclampsia are hypocoaguable.2,6 • Disseminated intravascular coagulation may occur in some patients with pre-eclampsia due to activation of coagulation system.2,6

Central Nervous System Manifestations Severe headache and hyperreflexia are warning signs of cerebral irritation. Visual disturbances and seizures may occur due to cerebral vasospasm and edema. Increased intracranial pressure may lead to cerebral hemorrhage and coma. In a review of stroke cases, it was reported that systolic blood pressure more than 160 mm Hg was a better predictor. Incidence of stroke was found to be higher in the postpartum period.27

Renal Manifestations Renal changes are characterized by proteinuria, reduced glomerular filtration rate, and oliguria. Serum creatinine is increased. Hyperuricemia was recognized as an early indicator of pre-eclampsia, however, a systematic review did not report it.28 Acute tubular necrosis and renal failure may occur following abruptio placentae, DIC, and hypovolemia.2,6

Hepatic Manifestations Hepatic changes range from mild hepatocellular dysfunction to severe changes in HELLP syndrome.2,6

Ophthalmic Manifestations Retinal arteriolar spasm may lead to retinal edema and detachment.2,6

Uteroplacental Blood Flow Reduced uteroplacental blood flow is responsible for increased fetal morbidity and mortality in parturients with severe pre-eclampsia. Placental hypoperfusion leads to intrauterine growth restriction (IUGR) and placental abruption. Incidence of premature labor, perinatal morbidity, and mortality is increased.2,6

42  Yearbook of Anesthesiology-9

Associated Complications of Severe Pre-eclampsia Severe pre-eclampsia may be associated with eclampsia, HELLP syndrome, and placental abruption.2,6

Long-term Implications of Pre-eclampsia There is an increased risk of cardiovascular and cerebrovascular disease, diabetes, renal disease, and thromboembolism later in life in both mother and the child.29,30 In recent guidelines, it has been suggested that the history of severe pre-eclampsia should be taken in women, to assess the risk of cardiovascular and cerebrovascular disease.31,32

OBSTETRIC MANAGEMENT Management of pre-eclampsia depends upon its severity of disease and gestational age. Its management requires team work between obstetricians, anesthesiologists, physicians, and intensivists.

Timing of Delivery The delivery of the fetus and placenta is the only definitive management of pre-eclampsia and should be considered for both maternal and fetal indications. In cases of preterm severe pre-eclampsia, obstetrician has to weigh the benefits and risks involved in relation to both mother and fetus for immediate versus expectant delivery. Preterm delivery is associated with prematurity and its sequele.1 ACOG1 and NICE17 have given guidelines regarding the timing of delivery (Box 1). Box 1: Timing of delivery. •• ≥37 weeks gestation: Delivery should be expedited irrespective of severity of disease. •• 100,000/mm3. In patients with platelet count 150/100 mm Hg for uncomplicated chronic hypertension, gestational hypertension, or pre-eclampsia with treatment goals of 80 mm Hg for chronic hypertension. Tight control of blood pressure (DBP 85 mm Hg) resulted in reduced rates of severe maternal hypertension as compared to less tight control (DBP 100 mm Hg) of blood pressure.33 However, a Cochrane analysis reported that progression to severe pre-eclampsia or eclampsia is not dependent on blood pressure levels.34 • Tight control of blood pressure may be preferred in patients with severe hypertension who are at a higher risk of developing complications.9

44  Yearbook of Anesthesiology-9

• Commonly used antihypertensive drugs to treat PIH include labetalol, hydralazine, and nifedipine. ▪▪ Labetalol is now preferred as the drug of choice for severe hypertension. It is a combined alpha and beta-adrenergic blocker and should be avoided in asthmatic and congestive heart failure (CHF) patients. It can be used orally as well intravenously. Initially, 20 mg of labetalol is given intravenously as a bolus. Additional doses are administered at intervals of 10–20 minutes as per requirement up to a total dose of 300 mg. It can also be administered by intravenous infusion titrated to effect.2,8 ▪▪ Hydralazine is also used for treatment of severe hypertension. It is a potent and direct vasodilator. It has the disadvantage of development of maternal tachycardia due to reflex sympathetic stimulation. It is administered intravenously with an initial dose of 5 mg. Dose can be repeated every 15–20 minutes to a maximum of 20 mg until target diastolic pressure is achieved. It can also be administered by intravenous infusion titrated to effect.2,8 ▪▪ Nifedipine predominantly affects the arterial and arteriolar smooth muscle. Although it is also short acting, intravenous labetalol and hydralazine have been the preferred agents. Success rates for treating severe hypertension with oral nifedipine were found to be similar to hydralazine or labetalol by a systematic review. It was suggested oral nifedipine is equally useful as an antihypertensive agent for acute management of hypertension in the peripartum period.35 Same findings have been reported by another meta-analysis.36 An initial dose of 10 mg is given orally and can be repeated after 30 minutes. Maintenance dose is 10–20 mg every 3–6 h. It is not clear whether nifedipine can potentiate the effects of magnesium sulfate.37 ACOG does not recommend the use of sublingual nifedipine. ▪▪ Sodium nitroprusside may be occasionally used in patients with severe hypertension, if they are unresponsive to conventionally preferred agents. An intravenous infusion of 0.3–0.5 µg/kg/min is given. It should be given for short duration. Infusion rates should not exceed 4-µg/kg/min for more than 4 h to avoid the risk of cyanide toxicity in the neonate.2,8 ▪▪ Nitroglycerine is again mostly used for short-term treatment of severe hypertension intraoperatively. Initially, it is administered at a rate of 5 µg/min by intravenous infusion. Infusion rate may be doubled every 5 minutes titrated to effect. Methemoglobinemia may result from high-dose 7 µg/kg/hour.37 ▪▪ Labetalol and nifedipine are better antihypertensive agents as com­ pared to Hydralazine.38

Pregnancy-induced Hypertension: An Update  45

Seizure Prophylaxis • Magnesium sulfate is now the preferred agent for seizure prophylaxis in severe pre-eclampsia as well as for control of convulsions in eclamptic patients without producing central nervous system depression in mother as well as neonate.39 There is no evidence of better maternal or neonatal outcome following its use in patients with pre-eclampsia.2,40 ACOG does not currently recommend its routine use in patients without severe features of pre-eclampsia.1 • Mechanism of action: Magnesium sulfate produces depression of central nervous system. It also potentiates the effects of nondepolarizing and depolarizing muscle relaxants due to its effect on the neuromuscular junction. It improves the uterine blood flow due to mild relaxant effect on uterine vasculature and smooth muscle. It is a mild vasodilator and has a mild antihypertensive effect. Magnesium sulfate easily crosses placenta and can cause neonatal depression. Since it is excreted by kidney, it should not be administered if urine output is inadequate, to safeguard against magnesium toxicity.2,6 • Administration: Initially an intravenous bolus of 4–6 g is given over 15–30 minutes. Subsequently intravenous infusion of 2 g/hour is given. Magnesium sulfate infusion is continued throughout the intrapartum period and for 24 hours in the postpartum period. Therapeutic levels of serum magnesium are 4–6 mEq/L.39,40 • Monitoring of magnesium therapy is essential to detect the early signs of its toxicity. It is done by monitoring the respiration, urine output, and patellar reflexes. In patients with significant impairment of renal function, serum concentrations of magnesium should also be monitored. Loss of deep tendon reflexes and ECG changes are seen at levels of 10 mEq/L, respiratory arrest occurs at 15 mEq/L and asystole appears at 20 mEq/L. Magnesium sulfate therapy should be immediately stopped on detecting the signs of toxicity. Calcium gluconate 1 g or calcium chloride 300 µgm is given to antagonize the effects of magnesium sulfate. Supportive therapy is given as per requirement.2,6

Fluid Therapy Severely pre-eclamptic patients are hypovolemic and need more fluids. At the same time, fluid overloading in a patient with leaky capillaries increases the risk of pulmonary edema. Fluid restriction is the usual practice in these patients to minimize the risk of pulmonary edema unless there is maternal hemorrhage. Fluid restriction should continue in the postoperative period till diuresis occurs. In the absence of fluid and blood losses, 60–125 mL/ hour of ringer lactate is administered.41 Others have advised isotonic crystalloid solutions at 100–125 mL/hour with additional requirements for

46  Yearbook of Anesthesiology-9

vasodilator therapy and regional anesthesia.37 Adjustments are made based on patient’s clinical condition, HCT, and urine output. In case central, invasive monitoring is being done, CVP measurement and PCWP can be the guide. Colloids solutions have a limited role.42 Data on ideal fluid therapy in severe pre-eclampsia is limited and further controlled studies are needed.42 Optimal fluid therapy in severe pre-eclampsia remains a controversial issue.

Coagulopathy and Disseminated Intravascular Coagulation Blood components are given as per requirements and WHO guidelines.

Treatment of Eclampsia If patient develops eclampsia, convulsions should be controlled immediately with benzodiazepines followed by magnesium sulfate. Airway, oxygenation, ventilation, and circulation are maintained and blood pressure is controlled. Guarded fluid therapy as per requirement is given. Delivery is expedited after maternal stabilization. After control of seizures, management is like that of severe pre-eclampsia.2,6

ANESTHETIC MANAGEMENT OF PRE-ECLAMPSIA Early involvement of anesthesiologist in the antenatal period allows timely preoperative assessment, decision making regarding choice of analgesic, anesthetic techniques, and monitoring. Mildly pre-eclamptic patients are managed like normal pregnant women but they should be monitored for the progression of the disease. Severely pre-eclamptic, eclamptic, and patients with HELLP syndrome should be adequately stabilized prior to operative and nonoperative delivery since they are critically ill.

Preanesthetic Evaluation A detailed preanesthetic evaluation should be done to find out the severity of pre-eclampsia, cardiovascular and pulmonary status, drug therapy, fluid status, renal function and urine output, coagulation status, monitoring requirements, and investigations. Aspiration prophylaxis is advised. A detailed airway assessment should be done and is repeated as the labor progresses. Difficult airway is anticipated in patients with severe pre-eclampsia.

NONOPERATIVE DELIVERY: LABOR ANALGESIA In the past, there were concerns regarding the use of regional analgesia and anesthesia in severely pre-eclamptic patients. These patients with

Pregnancy-induced Hypertension: An Update  47

volume contraction and reduced placental perfusion were thought to be at a higher risk of further deterioration due to the possibility of severe fall in blood pressure. Excessive fluid administration for hypotension increases the risk of developing pulmonary edema. There is also the risk of using vasopressors. Now with the use of lower concentrations of local anesthetic agents due to the adjuvants such as opioids, the safety of regional analgesia and anesthesia is now well established.40

Continuous Lumbar Epidural Continuous lumbar epidural is now the technique of choice in patients with severe pre-eclampsia for vaginal delivery, provided there are no contraindications to its use.43 Epidural analgesia should be administered early. It safeguards against pain-related maternal and fetal complications, and provides complete pain relief without the need for depressant drugs. Sympathetic blockade improves the uteroplacental blood flow.2 Epidural catheter can be easily and rapidly used for extending the block, if there is need for cesarean section. General anesthesia and its associated risk are avoided in the event of emergency cesarean section.40,44

Combined Spinal Epidural This technique can be safely used in severe pre-eclampsia. It provides the advantages of both the techniques. Spinal component provides the reliability and rapidity of the block and is technically easier to perform. Epidural catheter provides the flexibility to control the level of the block by administering graduated volumes of local anesthetics. However, there is a technical problem of testing the placement of epidural catheter due to the pre-existing spinal block.2

Intravenous Opioids Intravenous opioids may be used, if regional analgesia is contraindicated. Patient-controlled labor analgesia with remifentanil has been effectively used in pre-eclamptic patients.45

OPERATIVE DELIVERY: ANESTHETIC MANAGEMENT Regional versus General Anesthesia In severely pre-eclamptic patients, the preferred anesthetic technique is regional anesthesia for obvious advantages. General anesthesia carries the risk of morbidity and mortality associated with difficult intubation. Acute rise in blood pressure due to hypertensive responses to laryngoscopy

48  Yearbook of Anesthesiology-9

and intubation carries the risk of intracranial hemorrhage. According to Confidential Enquiry into Maternal and Child Health (CEMACH) report (2003–2005), the most common cause of maternal death was found to be intracranial hemorrhage.2 However, general anesthesia is the preferred technique, for emergent lower segment caesarean section (LSCS) in severe ongoing maternal hemorrhage, sustained fetal bradycardia with a reassuring airway, severe thrombocytopenia, HELLP syndrome, and coagulopathy.44

Epidural versus Spinal Anesthesia Epidural anesthesia is currently the safest technique of choice for operative delivery. Hemodynamic changes are minimized because anesthetic levels can be raised slowly by titrated doses. Epidural catheter can be inserted early during labor and the block can be rapidly extended in case the cesarean is required urgently. Spinal anesthesia is technically easier and has the advantage of rapid onset, reliability, and less risk of epidural venous trauma. Combined spinal epidural and single shot spinal anesthesia have been relatively contraindicated for operative delivery in women with severe preeclampsia. This was due to the acute fall in blood pressure following spinal in patients with pre-existing uteroplacental insufficiency. Increased fluid requirement following spinal as compared to epidural predisposes to fluid overloading and pulmonary edema. However, on the basis of more recent studies and clinical experience the use of spinal anesthesia for cesarean section is gaining popularity in severe pre-eclampsia. One of the studies reported that the incidence of spinalinduced hypotension was found to be significantly lower in severely preeclamptic parturients as compared to healthy parturients. Spinal-induced hypotension is short lived and can be easily treated.46 There is no clinically significant difference in maternal or neonatal outcome with spinal as compared to epidural anesthesia.47 Spinal anesthesia is a reasonably safe technique available in severely pre-eclamptic patients for emergent cesarean section, if there is no indwelling epidural catheter or contraindication to neuraxial anesthesia. It avoids the risk associated with emergency administration of general anesthesia.

Regional Anesthesia Considerations: Severe Pre-eclampsia Platelet Count and Regional It is safe to give regional anesthesia at a platelet count of more than 100,000/mm3. Neuraxial block is contraindicated at a platelet count less than 50,000/mm3. It was proposed that a platelet count threshold of 80,000/ mm3 is adequate for regional blocks in the absence of other risk factors.48

Pregnancy-induced Hypertension: An Update  49

At platelets count of 50,000–0.9 recovery in 2.1 min.9 Furthermore, sugammadex at 0.22 mg/kg dose effectively and comparably reverse a rocuronium-induced shallow residual neuromuscular block at a TOF ratio of 0.5 (Table 1).10 Currently, there is no dose recommendation for vecuronium-induced neuromuscular block. Sugammadex affinity for vecuronium-induced blockade is less compared to rocuronium. In fact, sugammadex had approximately 2.5 times the affinity for rocuronium.11 Vecuronium took twice as long as rocuronium (3.0 min vs 1.5 min) after sugammadex reversal.12 Similarly, Duvaldestin et al. showed a slow speed of recovery of 3.3 min with vecuronium when the PTC of 1–2.13 A dose-response

Table 1: Recommended sugammadex dose to reverse rocuronium blockade. Sugammadex dose

Depth of NMBA

Mean recovery time to TOF 0.9

Studies

16 mg/kg

After 1.2 mg/kg of rocuronium

1.5 minutes

De Boer et al.56

4 mg/kg–1

Deep block, PTC 1–2

3 minutes

Jones et al.7 Della Rocca et al.8

2 mg/kg–1

Moderate block, two twitches to TOF

2 minutes

Pland et al. Della Rocca et al.8

1 mg/kg–1

Four twitches to TOF

2 minutes

Pongracz et al.9

0.22 mg/kg–1

TOF 0.5

2 minutes

Schaller et al.10

–1

–1

(kg: kilogram; mg: milligram; NMBA: neuromuscular blocking agent; PTC: posttetanic count; TOF: train of four)

Sugammadex and Beyond  57

relationship between vecuronium and rocuronium at different dose of sugammadex was done and consistently showed a slower recovery from vecuronium.14

SPECIAL CONSIDERATIONS Morbid Obesity The use of NMBAs in morbidly obese patients can cause significant postoperative complications in the recovery phase, if reversal is inadequate. Critical respiratory events include airway obstruction, hypoventilation, hypoxia, hypercapnia, and aspiration, and these can lead to acute respiratory failure. Sugammadex had shown promising effect to rescue postoperative residual recurarization after neostigmine was ineffective in the recovery room for a morbidly obese patient.15 Patient receiving sugam­ madex compared to neostigmine recovered (TOFR 0.9) three time faster, 2.7 min versus 9.6 min, respectively.16 Furthermore, patients undergoing laparoscopic removal of adjustable gastric banding demonstrated faster postanesthesia care parameters; improved TOFR, ability to swallow, ability to get into bed independently, and discharge to surgical ward earlier.17 Thus, rapid recovery from sugammadex can be beneficial for morbidly obese patient to fast-track bariatric surgery and in ambulatory setting. Although the reversal of NMBAs with sugammadex was faster than neostigmine, postoperative respiratory complications had not been fully elucidated. Ezri et al. had found no difference in the incidence of respiratory complications but rather a higher SpO2 in the sugammadex group. Despite the statistical difference in SpO2, its clinical importance seemed to be minimal and no postoperative respiratory events were noted.18 There will need to be more large, prospective, randomized trials to evaluate the benefit of sugammadex to decrease postoperative respiratory complications in this population.

Pediatric Population Sugammadex has been widely studied in adults but has not received FDA approval in the pediatric population. The appropriate dose-response studies in the pediatric group have not been well defined. The pharmacokinetic (PK) and pharmacodynamic profile of rocuronium in infants and children differ from adult patients. In infants and children, the clinical duration was longer and the potency of rocuronium was greater compared to adults. The group from Europe employed a multicenter, randomized group study to explore the efficacy and safety in infants, children, adolescent, and adults. When the reappearance of T2 of the TOF was seen, either placebo or sugammadex was randomly assigned and the median recovery time to TOF 0.9 was measured. The placebo group recovery time was 21, 19, 23.4,

58  Yearbook of Anesthesiology-9

and 28.5 min in infants, children, adolescents, and adults, respectively. After 2.0 mg/kg sugammadex, the TOF 0.9 was 0.6, 1.2, 1.1, and 1.2 min, respectively. Therefore, this initial dose-response study explained the similarities in the recovery of neuromuscular blockade between the pediatric and adult group.19 Furthermore, a systematic review of nine studies comparing sugammadex to neostigmine indicated that sugammadex can reverse rocuronium-induced neuromuscular blockade more rapid with a lower incidence of bradycardia.20 One area that sugammadex may benefit pediatric patients was those with neuromyopathic conditions. In myotonic dystrophy patients, reversal with neostigmine can precipitate myotonia crisis therefore making sugammadex an attractive alternative. Sugammadex was successful in reversing myotonic dystrophy without perioperative complications or exacerbation.21,22 Certain other underlying conditions including Duchenne muscular dystrophy, myotonic dystrophy, and myasthenia gravis caused the neuromuscular junction to be highly sensitive to NMBAs and experience residual weakness.23-25 These case reports highlighted the importance of using sugammadex for a safe and rapid recovery from NMBAs. In another report, the role of sugammadex was essential for airway rescue and this needs to be entertained in the difficult airway algorithm. WoloszczukGebicka B et al. reported a case in a 9-month-old infant who fell into the “cannot intubate-cannot ventilate” scenario. Sugammadex (8 mg/kg–1) was administered and spontaneous ventilation was achieved within 25 sec.26

Elderly Population The increasing number of elderly patients with comorbidities has greatly impacted the clinical practice of anesthesia. The elderly patients are at high risk for postoperative residual neuromuscular blockade resulting in muscle weakness, airway obstruction, respiratory failure, hypoxemia, atelectasis, and pneumonia. Therefore, reversal drugs are an important part of the anesthetic practice. The use of neostigmine has reduced the risk of residual neuromuscular blockade but has not eliminated this complication in the recovery period. In the elderly group, the increase chronic disease and receptor sensitivity may alter the PKs of sugammadex. McDonagh et al. demonstrated a prolong recovery time to a TOFR 0.9 with old-elderly patients (>75 years) compared to adults (18–64 years) 3.6 min versus 2.3 min, respectively.27 In a recent prospective study by Yazar et al., TOF 0.9 recovery in older elderly (greater than 75 years) versus young elderly (65–74 years) was prolonged, 5.5 min versus 3.27 min, respectively.28 Muramatsu et al. suggested that elderly patients were at the greatest risk for recurarization and residual muscle paralysis when low dose sugammadex was administered. The slower spontaneous TOFR and impaired renal function were two major contributing factors that decreased TOFR change rate in response

Sugammadex and Beyond  59

to low-dose sugammadex.29 In a clinical series performed by Suzuki et al., a complete reversal of deep muscle paralysis using 4 mg/kg took longer in elderly patients.30 All these studies were consistent demonstrating a prolonged recovery in the older patient with either a moderate or deep block. On average, the rocuronium-induced NMBA reversal is prolonged by at least 1–2 minutes in the elderly than in young adults.

ADVERSE EFFECTS Hypersensitivity and Anaphylaxis The approval of sugammadex for USA was delayed until 2015 due to hypersensitivity concerns. In general, perioperative anaphylaxis is a lifethreatening condition most commonly reported occurring with NMBAs. Among the steroidal NMBAs, rocuronium has a higher rate of IgE-mediated anaphylaxis.31 With the availability and widespread use of sugammadex to encapsulate and reverse steroidal NMBA, there had been confirmed cases of allergic anaphylactic reactions with clinical doses triggering significant shock.32,33 However, the number of reported sugammadex-induced anaphylaxis was much less than those associated with NMBAs. Doserelated hypersensitivity reactions had been reported with its use. A joint study by de Kam et al. reported hypersensitivity or anaphylaxis reactions to sugammadex to be dose dependent. Hypersensitivity occurred in 0.7% and 4.7% after sugammadex 4 mg/kg–1 and 16 mg/kg–1, respectively.34 The incidence of hypersensitivity and anaphylaxis with sugammadex had a low overall score ( 35 kg/m2

A—Age

Over 50 years

N—Neck

Circumference over 40 cm

G—Gender

Male

High risk for OSA: ≥ 3 positive responses Low risk for OSA: ≤ 3 positive responses

mellitus, cardiomyopathy, and in-hospital mortality.4,21,22 STOPBANG questionnaire (Table 1) is the general screening tool for detecting OSA but is suboptimal in pregnancy. OSA in pregnancy is more a dynamic process and OSA predictors vary in each trimester and their value is improved with gestational age. Polysomnography still remains the gold standard test for OSA in pregnancy. A recent survey in the USA found that majority of the anesthesiologists were not aware of the risks of OSA and there was no antenatal screening for this condition. We recommend having a low threshold for evaluating possibility of OSA in pregnancy. If this is done in early pregnancy, corrective remedies not only are likely to improve maternal but also fetal outcomes as well. Pregnant females with OSA are likely to have lower oxygen saturations and thus fetal oxygen supply may not be ideal. Screening these patients early in pregnancy and eventual use of continuous positive airway pressure (CPAP) devices elevates the baseline oxygen saturation in these patients. It is not surprising to see higher incidence of intrauterine growth restriction (IUGR) in obese parturients, which may be directly linked to OSA.

Maternal and Fetal Considerations Obese parturients are at increased risk of developing complications such as gestational diabetes, pregnancy-induced hypertension, OSA, pre-eclampsia, fetal macrosomia, birth trauma, prolonged labor, shoulder dystocia, instrumental delivery, and increased incidence of emergent cesarean section (Flowchart 1). Chu et al. in their meta-analysis reported increased incidence of gestational diabetes in obese parturients when compared to nonobese parturients.23 O’Brien et al. in their systematic review of 13 cohort

Issues and Management of Obese Parturient  73 Flowchart 1:  Risks and complications associated with obesity in pregnancy.

studies demonstrated that increase in preconception BMI leads to increased risk of pre-eclampsia.24 Obesity is also associated with higher incidence of complications such as postpartum hemorrhage, thromboembolism, endometritis, and wound infection. Thromboembolism in pregnancy is a leading cause of maternal morbidity and mortality in the developed countries. Obesity in pregnancy further increases this risk. Obese parturient is at increased risk of deep vein thrombosis (DVT) because of chronic inflammation, hypercoagulable state in pregnancy, oxidative stress, and venous stasis.25 According to Center for Disease Control (CDC), birth by cesarean section is 31.9% of all births in America.26 In a large study Kominiark et al. reviewed 124,389 laboring patients, recorded their BMI and route of delivery, and assessed the impact of BMI on cesarean delivery in these patients. Their study showed that obese nulliparous women with BMI greater than 40 had higher cesarean section rate of nearly 42%.27 The success rate of trial of labor after cesarean delivery (TOLAC) is inversely related to obesity. Some studies suggest leptin, a hormone predominantly made by adipose cells has inhibitory effect on the uterine myometrial contraction. Obesity in pregnancy is known to increase the incidence of preterm delivery.28-30 Maternal obesity is associated with fetal anomalies such as macrosomia (fetal weight >4,000 g), congenital malformations and shoulder dystocia.31-34

Respiratory System In obese parturient, the respiratory system changes (Table 2) of pregnancy and obesity together have combined effect on the pulmonary mechanics.35 In pregnancy, functional residual capacity (FRC) is decreased due to cephalad displacement of the diaphragm by the gravid uterus. Obesity further impairs respiratory function by decreasing FRC, small airway collapse, basal

74  Yearbook of Anesthesiology-9 Table 2: Respiratory system changes in normal pregnancy, obesity, and in combination of both. Parameter

Pregnancy

Obesity

Combined

Progesterone level

↑

↔

↑

Sensitivity to CO2

↑

↓

↑

Tidal volume

↑

↓

↑

Respiratory rate

↑

↑↔

↑

Minute volume

↑

↓↔

↑

Inspiratory capacity

r

↓

↑

Inspiratory reserve volume

↑

↓

↑

Expiratory reserve volume

↓

↓↓

↓

Residual volume

↓

↓↔

↓

Functional residual capacity

↓↓

↓↓↓

↓↓

Vital capacity (VC)

↔

↓

↓

FEV1

↔

↓↔

↔

FEV1/VC

↔

↔

↔

Total lung capacity

↓

↓↓

↓

Compliance

↔

↓↓

↓

Work of breathing

↑

↑↑

↑

Resistance

↓

↑

↓

V/Q

↑

↑

↑↑

PaO2

↓

↓↓

↓

PaCO2

↓

↑

↓

↑ = Increase ↓ = Decrease ↔ = No change (FEV1: forced expiratory volume in 1 second; PaO2: partial pressure of oxygen; PaCO2: partial pressure of carbon dioxide; V/Q: ratio of ventilation/perfusion) Source: SAGE publications (with permission).

atelectasis, shunting in the dependent areas of the lungs, and increased ventilation-perfusion mismatch. At the same time, obesity increases resting metabolic rate, work of breathing, and increased oxygen demand. This combination results in rapid desaturation when lying in supine position or at the time of induction during cesarean delivery. Adequate preoxygenation with slightly head up position is vital at the time of induction of anesthesia. Obstructive sleep apnea is often associated with obesity in pregnancy. OSA worsens with gestation due increased upper airway congestion and

Issues and Management of Obese Parturient  75

hyperemia of normal pregnancy or pre-eclampsia. Thus, one should anticipate difficulty in mask ventilation in these patients. A previous history of easy airway does not rule out possibility of difficult airway or mask ventilation when it comes to pregnancy. This combination is deadly for an obese parturient in view of loss of reserves to compensate.

Cardiovascular System Cardiovascular changes normally seen in pregnancy are increase in blood volume by 50%, heart rate 20%, stroke volume by 30%, and cardiac output reaching 140% over the gestational period. Obese parturient may poorly tolerate these changes due to associated risk factors like systemic and pulmonary hypertension, ischemic heart disease, and congestive heart failure. Obese patients tend to have diastolic cardiac dysfunction. In a nonobese parturient, increase in blood volumes may be well tolerated. However, diastolic dysfunction in an obese parturient can tipple this fine balance to a clinically relevant heart failure. The lung changes discussed above can lead to lower PaO2 and thus chances of previous ischemic cardiac conditions becoming more detrimental in an obese parturient. An exacerbated supine hypotension response is observed in obese parturient due to aortocaval compression from gravid uterus and presence of excessive intra-abdominal fatty tissue.

Gastrointestinal System Obese pregnant mothers are more at risk for aspiration than nonobese parturients. In pregnancy progesterone relaxes smooth muscle, reduces lower esophageal sphincter tone, and increases gastric acidity by increasing the production of placental gastrin. Studies have shown that pregnancy as sole factor does not slow down gastric emptying36,37 but labor pain and opioids used for labor analgesia may delay gastric emptying. All women in labor are inevitably at risk of aspiration. Gastric emptying is further decreased in obese parturient with increased abdominal pressure due to large abdominal panniculus, presence of hiatal hernia, and diabetes mellitus. Fasting guidelines similar to nonobstetric patient for general anesthetic is applicable to all parturients whether obese or nonobese if proceeding with surgical intervention. Preoperative acid aspiration prophylaxis, rapid sequence induction and intubation with cricoid pressure are strictly indicated for all obese paturients undergoing general anesthesia for operative delivery.

76  Yearbook of Anesthesiology-9

LABOR ANALGESIA According to ACOG and American Society of Anesthesiologists (ASA), maternal request is sufficient indication for pain relief during labor, barring medical contraindications. Studies have shown that the duration of labor in obese women with high BMI is prolonged than in nonobese parturients.38 Melzack et al. reported labor contractions can be more painful in obese parturients due to fetal macrosomia, cephalopelvic disproportion, and labor induction showing a positive correlation between BMI and labor pain.39 However, these findings were questioned in a study by Ranta et al.40 Parenteral opioids such as meperidine (pethidine), fentanyl, and inhalational agents like Entonox (50% nitrous oxide in oxygen) are to be used with caution in the obese due to increased risk of sedation, respiratory depression, nausea, and vomiting. Neuraxial block remains the most preferred method of labor analgesia. This includes epidural, combined spinal epidural (CSE), dural puncture epidural (DPE), and continuous spinal analgesia. DPE is a modified version of CSE where the duramater is intentionally perforated by the spinal needle introduced through the epidural needle but no intrathecal medication is administered. This technique is known to have local anesthetic spread caudally and produce better block when compared to standard continuous epidural technique.41 Neuraxial analgesia provides excellent pain relief in labor. Maternal and fetal complications and risks associated neuraxial blocks are minimal, though the procedure is associated with technical challenges in obese parturient. Edward et al. in their study on lumbar punctures in neurology clinics noted that BMI as single factor has inverse correlation to success.42 Use of ultrasound imaging may overcome this problem. A good functional epidural not only helps in relieving pain during labor but also can be utilized in the event of emergent cesarean delivery in order to avoid the risks of general anesthesia.

Epidural for Labor Epidural placement can be challenging in the morbidly obese parturients due to obscured surface landmarks, requiring multiple attempts. Truncal obesity with thick subcutaneous fat causes misidentification of midline, increased depth of epidural space needing longer needles, misplacement of epidural catheter, and higher rate of accidental dural puncture. In obesity, the surface landmarks of the spine are better appreciated in sitting position than in lateral decubitus position. Excess subcutaneous fatty tissue can create false pockets and false loss of resistance during epidural placement. Preprocedural ultrasonography for epidural placement has become a popular bedside tool for identifying the midline, approximate depth of the epidural space, the point of insertion, and trajectory of the needle. Use of

Issues and Management of Obese Parturient  77

ultrasound has shown to reduce number of attempts in finding epidural space and lowered accidental dural puncture and epidural failure rates.43,44 However, in the presence of increased subcutaneous fatty tissue in the morbidly obese with depth of epidural space >10 cm makes ultrasound visualization more challenging and less predictable. In morbidly obese patient, the skin surface marking after identifying the epidural space for insertion of needle moves 1 or 2 more spaces when patient arches her back because of the loose skin sliding over the fatty subcutaneous adipose tissue. Increased movement of surface marking makes epidural placement very challenging even with use of ultrasound. Another important factor for failed epidural and inadequate analgesia in obese parturient is migration of epidural catheter due to excess movement of skin and subcutaneous tissue.45 Securing the epidural catheter firmly with adhesive tape at the point of insertion will reduce dislodgement.

ANESTHESIA FOR CESAREAN SECTION Neuraxial anesthesia still remains the preferred choice over general anesthesia for cesarean section unless there is a contraindication.

Equipment Many labor units are often caught unprepared when it comes to meeting the special needs of morbidly obese parturients. Sphygmomanometers with extra-large blood pressure cuffs are essential for measuring blood pressure in morbidly obese. If still not able to record blood pressure, invasive blood recording is advised for surgery by placing an arterial line. The weight and size of operating room tables must be sufficient to accommodate morbidly obese patients. The newer bariatric OR tables can accommodate weight capacities up to 1,000 pounds.

Spinal Anesthesia Single-shot spinal anesthesia with instillation of local anesthetic and opioid is a common technique for cesarean section. It provides a dense and reliable sensory motor block. Advantage of this block is quick onset, lower incidence of postdural puncture headache especially if smaller size pencil point needles (25 g, 27G Whitacre or Sprotte needles) are used. The biggest disadvantage of spinal anesthesia is that its duration of action is limited. Spinal block may not be ideal in a morbidly obese parturient because the total operative time for cesarean section can be more than 2 hours. The incidence of high spinal block rate is seen in morbidly obese parturient due increased intra-abdominal pressure from the panniculus and less cerebrospinal fluid (CSF) in the spinal space due to epidural fat.46,47 Use of

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spinal catheters may overcome these problems by providing slow titrating doses till desired sensory level is reached and maintained for the duration of surgery. Disadvantage with spinal catheters is postdural puncture headache, though less common in morbidly obese parturient.48

Epidural Anesthesia Epidural placement in morbidly obese can be technically more challenging. Usually encounter false loss of resistance due to thick subcutaneous adipose tissue is leading catheter misplacement and increased resistance is encountered in threading the catheter into the epidural space. Sacral sparing of sensory block is encountered with epidural blocks and may need some systemic analgesic supplementation. A good functioning epidural used for labor can be dosed with higher concentration local anesthetic for cesarean delivery. The advantage of epidural over spinal is that it can be used for the whole duration of surgery and for postoperative pain management if needed. High sensory motor block can occur with standard local anesthetic doses used due to decreased epidural space in morbidly parturient. It is prudent to use smaller volume of local anesthetic and administer intermittent doses to achieve desired level of anesthesia.

Combined Spinal Epidural Combined spinal epidural is a popular neuraxial technique for C-section in obese parturients. It has the advantage of providing quick and dense block from spinal component and has the benefit of epidural catheter in providing supplemental doses of local anesthetic, prolonging the anesthetic for the duration of cesarean section. Studies have shown CSE increases the success rate of epidural catheter placement in the correct anatomical space if CSF is visually confirmed in the spinal needle hub.49 To avoid causing high spinal block and profound hypotension in the morbidly obese, a low dose spinal with epidural (CSE) is recommended. In this technique, smaller dose of spinal and slow titrated doses of epidural local anesthetic are used to achieve adequate sensory level for operative delivery. Though CSE appears to take longer duration of time due to multiple steps involved, Ross et al. in their study demonstrated that there is no significant difference in the time taken for spinal block versus CSE.50

General Anesthesia The risk of aspiration is a big concern in every parturient for surgical intervention more so in obese parturient. Wong et al. in their recent study did not observe any difference in gastric emptying in obese versus

Issues and Management of Obese Parturient  79

nonobese nonlaboring parturients.36 Preoperative fasting guidelines for obese parturient are similar to general population scheduled for surgery. Point of care ultrasound for visualization of gastric contents is becoming more popular tool recently. Respiratory system changes in obese parturient have a great impact in pulmonary mechanics. Rapid oxygen desaturation in supine position occurs in obese due reduced chest compliance, cephalad displacement of diaphragm, reduced lung volume, and FRC with the combination of increased oxygen consumption resulting in rapid oxygen desaturation at the time of induction of anesthesia. Desaturation can be minimized by adequate preoxygenation with 100% oxygen for at least 3 minutes before induction or at minimum 3 large deep breaths (vital capacity) for emergent operative delivery. Ramped, head up position, or reversed Trendelenburg position is known to change respiratory mechanics and improve oxygenation in the obese parturient. Obesity is considered as an independent risk factor for difficult airway in pregnancy.51 Patients with large neck circumference, fat pad between the shoulders, and high Mallampati score are known to cause difficult laryngoscopy and intubation. The important component of laryngoscopy and intubation is proper positioning of the patient. Head up and ramped position with supporting blankets or commercially available foam ramp improves the intubating conditions by allowing alignment of oropharynx with larynx when compared to standard “sniff” position.52 The use of video laryngoscope in obese improves the laryngeal and Cormack and Lehane view of the glottis, reduces the number of failed attempts, incidence of desaturation (drop in SpO2), and airway trauma.53 If difficult airway is predicted in a morbidly obese parturient, fiberoptic bronchoscope should be readily available in the operating room for awake fiberoptic intubation. Distribution and dose response to anesthetics drugs are altered in obesity. Dosing of intravenous anesthetic agents and depolarizing muscle relaxants are calculated according to total body weight whereas nondepolarizing muscle relaxants dosage is based on ideal body weight.54 Prolonged sedation from anesthetics and opioid analgesics should be expected in obese patients. Desflurane is associated with faster recovery than sevoflurane in morbidly obese patients. It is recommended to insert orogastric tube and empty the stomach before emergence to avoid aspiration risk. Extubation is done in propped up position after confirming that the patient is adequately reversed, fully awake, and spontaneously breathing.

POSTOPERATIVE MANAGEMENT Obese parturients have higher incidence of complications such as airway obstruction, respiratory depression, CO2 retention, somnolence, atelectasis,

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and hypoxia in the immediate postoperative period. Respiratory support such high flow oxygen mask, nasopharyngeal airway (may cause bleeding), and non-invasive positive pressure ventilation [CPAP and biphasic positive airway pressure (BIPAP)] may be required in obese parturient with OSA. It is recommended to monitor these patients using telemetry in the labor ward or admission to high dependency observation unit depending on the severity of comorbidities. The medical and nursing staff in labor ward should be clear regarding instructions for monitoring and how anesthesiology providers can be contacted for advice. Multimodal analgesics with nonsteroidal antiinflammatory drugs and regional nerve blocks, e.g. transverse abdominis plane block, are preferred over opioids. Deep breathing exercises and incentive spirometry may prevent lung atelectasis and hypostatic pneumonia. Decreased mobility in obesity in combination with hypercoagulable state of pregnancy is associated with increased risk of developing DVT and pulmonary thromboembolism.55 It is strongly recommended to use pneumatic compression stockings and prophylactic anticoagulants (subcutaneous unfractionated or low molecular weight heparin) and early ambulation should be encouraged. The anticoagulant doses should be based on actual body weight to have optimal effect.

CONCLUSION Obesity has become more prevalent in pregnant population worldwide. Obesity in pregnancy is associated with increased morbidity and mortality and requires multidisciplinary management involving experienced anesthesiologists, obstetricians, neonatologists, and nursing staff. Early consultation with an obstetric anesthesiologist is recommended to evaluate for comorbidities and provide best peripartum care. It is encouraged to provide early epidural analgesia in labor and to periodically ensure that it is functional. Existing labor epidural can be utilized for neuraxial anesthesia if proceeding with cesarean delivery and may avoid the complications of general anesthesia. Providing adequate postoperative pain relief and thromboprophylaxis is very essential in this population. Careful postoperative monitoring with telemetry or high dependency unit admission is recommended.

KEY POINTS • Obesity in pregnancy is associated with several comorbidities and may lead to complications both in the mother and baby. • Experienced anesthesiologists as a part of multidisciplinary team should manage morbidly obese parturients. A comprehensive prenatal anesthesiology consultation is recommended.

Issues and Management of Obese Parturient  81 • Neuraxial anesthesia is recommended choice of labor analgesia and for cesarean section. Neuraxial procedures may be facilitated by ultrasound guidance. • A strategical plan for difficult airway management is essential and must be discussed in advance. A fully equipped difficult airway cart with fiberoptic bronchoscope must be readily available. • Additional specialized equipment may be necessary for logistics–operating tables that accommodate bariatric patients, large blood pressure cuffs, etc. • Head up ramp or sitting position may aid at the time of induction and endotracheal intubation for cesarean delivery. Video-assisted laryngoscopy is recommended. • Long acting opioids and sedatives used with caution to avoid respiratory depression. • Incidence of wound infection and venous thromboembolism (VTE) is high. Appropriate dosing of antibiotics and thromboprophylaxis recommended. (To follow institutional guidelines).

REFERENCES 1. Cedergren MI. Non-elective caesarean delivery due to ineffective uterine contractility or due to obstructed labour in relation to maternal body mass index. Eur J Obstet Gynecol Reprod Biol. 2009;145(2):163-6. 2. Practice Bulletin No 156: Obesity in Pregnancy. Obstet Gynecol. 2015; 126(6):e112-26. 3. Louis JM, Auckley D, Sokol RJ, et al. Maternal and neonatal morbidities associated with obstructive sleep apnea complicating pregnancy. Am J Obstet Gynecol. 2010;202(3):261.e1-5. 4. Lockhart EM, Ben Abdallah A, Tuuli MG, et al. Obstructive Sleep Apnea in Pregnancy: Assessment of Current Screening Tools. Obstet Gynecol. 2015;126(1):93-102. 5. Hameed AB, Lawton ES, McCain CL, et al. Pregnancy-related cardiovascular deaths in California: beyond peripartum cardiomyopathy. Am J Obstet Gynecol. 2015;213(3):379.e1-10. 6. Ng M, Fleming T, Robinson M, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet Lond Engl. 2014;384(9945):766-81. 7. Poston L, Caleyachetty R, Cnattingius S, et al. Preconceptional and maternal obesity: epidemiology and health consequences. Lancet Diabetes Endocrinol. 2016;4(12):1025-36. 8. Zeitlin J, Mohangoo AD, Delnord M, et al; EURO-PERISTAT Scientific Committee. The second European Perinatal Health Report: documenting changes over 6 years in the health of mothers and babies in Europe. J Epidemiol Community Health. 2013;67(12):983-5. 9. Kassebaum NJ, Barber RM, Bhutta ZA, et al. Global, regional, and national levels of maternal mortality, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1775-812. 10. MacDorman MF, Declercq E, Cabral H, et al. Recent Increases in the U.S. Maternal Mortality Rate: Disentangling Trends from Measurement Issues. Obstet Gynecol. 2016;128(3):447-55.

82  Yearbook of Anesthesiology-9 11. Wronska A, Kmiec Z. Structural and biochemical characteristics of various white adipose tissue depots. Acta Physiol Oxf Engl. 2012;205(2):194-208. 12. Cullen A, Ferguson A. Perioperative management of the severely obese patient: a selective pathophysiological review. Can J Anaesth J Can Anesth. 2012;59(10):974-96. 13. Royal College of Obstetricians & Gynaecologists. Care of Women with Obesity in Pregnancy (Green-top Guideline No. 72). [online] Available from: https://www.rcog.org.uk/en/guidelines-research-services/guidelines/gtg72/ [Last accessed August, 2019]. 14. American College of Obstetricians and Gynecologists. ACOG Committee opinion no. 549: obesity in pregnancy. Obstet Gynecol. 2013;121(1):213-7. 15. Samsoon GL, Young JR. Difficult tracheal intubation: a retrospective study. Anaesthesia. 1987;42(5):487-90. 16. Hood DD, Dewan DM. Anesthetic and obstetric outcome in morbidly obese parturients. Anesthesiology. 1993;79(6):1210-8. 17. Cooper GM, McClure JH. Anaesthesia chapter from Saving mothers’ lives; reviewing maternal deaths to make pregnancy safer. Br J Anaesth. 2008;100(1): 17-22. 18. Pien GW, Pack AI, Jackson N, et al. Risk factors for sleep-disordered breathing in pregnancy. Thorax. 2014;69(4):371-7. 19. Facco FL, Ouyang DW, Zee PC, et al. Sleep disordered breathing in a highrisk cohort prevalence and severity across pregnancy. Am J Perinatol. 2014;31(10):899-904. 20. Pamidi S, Pinto LM, Marc I, et al. Maternal sleep-disordered breathing and adverse pregnancy outcomes: a systematic review and metaanalysis. Am J Obstet Gynecol. 2014;210(1):52.e1-52.e14. 21. Louis JM, Mogos MF, Salemi JL, et al. Obstructive sleep apnea and severe maternal-infant morbidity/mortality in the United States, 1998-2009. Sleep. 2014;37(5):843-9. 22. Louis JM, Koch MA, Reddy UM, et al. Predictors of sleep-disordered breathing in pregnancy. Am J Obstet Gynecol. 2018;218(5):521.e1-521.e12. 23. Chu SY, Callaghan WM, Kim SY, et al. Maternal obesity and risk of gestational diabetes mellitus. Diabetes Care. 2007;30(8):2070-6. 24. O’Brien TE, Ray JG, Chan WS. Maternal body mass index and the risk of preeclampsia: a systematic overview. Epidemiol Camb Mass. 2003;14(3): 368-74. 25. Nightingale CE, Margarson MP, Shearer E, et al. Peri‐operative management of the obese surgical patient 2015. Anaesthesia. 2015;70(7):859-76. 26. Martin JA, Hamilton BE, Osterman MJK, et al. Births: Final Data for 2016. Natl Vital Stat Rep. 2018;67(1):1-55. 27. Kominiarek MA, Vanveldhuisen P, Hibbard J, et al. The maternal body mass index: a strong association with delivery route. Am J Obstet Gynecol. 2010;203(3):264.e1-7. 28. Cnattingius S, Villamor E, Johansson S, et al. Maternal obesity and risk of preterm delivery. JAMA. 2013;309(22):2362-70. 29. Baeten JM, Bukusi EA, Lambe M. Pregnancy complications and outcomes among overweight and obese nulliparous women. Am J Public Health. 2001;91(3):436-40. 30. Ruhstaller K. Induction of labor in the obese patient. Semin Perinatol. 2015;39(6):437-40.

Issues and Management of Obese Parturient  83 31. Cedergren MI. Maternal morbid obesity and the risk of adverse pregnancy outcome. Obstet Gynecol. 2004;103(2):219-24. 32. Andreasen KR, Andersen ML, Schantz AL. Obesity and pregnancy. Acta Obstet Gynecol Scand. 2004;83(11):1022-9. 33. Castro LC, Avina RL. Maternal obesity and pregnancy outcomes. Curr Opin Obstet Gynecol. 2002;14(6):601-6. 34. Stothard KJ, Tennant PWG, Bell R, et al. Maternal overweight and obesity and the risk of congenital anomalies: a systematic review and meta-analysis. JAMA. 2009;301(6):636-50. 35. Hegewald MJ, Crapo RO. Respiratory physiology in pregnancy. Clin Chest Med. 2011;32(1):1-13. 36. Wong CA, Loffredi M, Ganchiff JN, et al. Gastric emptying of water in term pregnancy. Anesthesiology. 2002;96(6):1395-400. 37. Wong CA, McCarthy RJ, Fitzgerald PC, et al. Gastric emptying of water in obese pregnant women at term. Anesth Analg. 2007;105(3):751-5. 38. Carlson NS, Hernandez TL, Hurt KJ. Parturition dysfunction in obesity: time to target the pathobiology. Reprod Biol Endocrinol. 2015;13(1):135. 39. Melzack R, Kinch R, Dobkin P, et al. Severity of labour pain: influence of physical as well as psychologic variables. Can Med Assoc J. 1984;130(5):579-84. 40. Ranta P, Jouppila P, Spalding M, et al. The effect of maternal obesity on labour and labour pain. Anaesthesia. 1995;50(4):322-6. 41. Chau A, Bibbo C, Huang CC, et al. Dural Puncture Epidural Technique Improves Labor Analgesia Quality With Fewer Side Effects Compared With Epidural and Combined Spinal Epidural Techniques: A Randomized Clinical Trial. Anesth Analg. 2017;124(2):560-9. 42. Edwards C, Leira EC, Gonzalez-Alegre P. Residency training: a failed lumbar puncture is more about obesity than lack of ability. Neurology. 2015;84(10): e69-72. 43. Grau T, Leipold RW, Conradi R, et al. Efficacy of ultrasound imaging in obstetric epidural anesthesia. J Clin Anesth. 2002;14(3):169-75. 44. Balki M, Lee Y, Halpern S, et al. Ultrasound imaging of the lumbar spine in the transverse plane: the correlation between estimated and actual depth to the epidural space in obese parturients. Anesth Analg. 2009;108(6):1876-81. 45. Soens MA, Birnbach DJ, Ranasinghe JS, et al. Obstetric anesthesia for the obese and morbidly obese patient: an ounce of prevention is worth more than a pound of treatment. Acta Anaesthesiol Scand. 2008;52(1):6-19. 46. Ngaka TC, Coetzee JF, Dyer RA. The Influence of Body Mass Index on Sensorimotor Block and Vasopressor Requirement During Spinal Anesthesia for Elective Cesarean Delivery. Anesth Analg. 2016;123(6):1527-34. 47. Lamon AM, Einhorn LM, Cooter M, et al. The impact of body mass index on the risk of high spinal block in parturients undergoing cesarean delivery: a retrospective cohort study. J Anesth. 2017;31(4):552-8. 48. Franz AM, Jia SY, Bahnson HT, et al. The effect of second-stage pushing and body mass index on postdural puncture headache. J Clin Anesth. 2017;37:77-81. 49. Booth JM, Pan JC, Ross VH, et al. Combined Spinal Epidural Technique for Labor Analgesia Does Not Delay Recognition of Epidural Catheter Failures: A Single-center Retrospective Cohort Survival Analysis. Anesthesiology. 2016;125(3):516-24. 50. Ross VH, Dean LS, Thomas JA, et al. A randomized controlled comparison between combined spinal-epidural and single-shot spinal techniques in

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51. 52.

53. 54. 55.



morbidly obese parturients undergoing cesarean delivery: time for initiation of anesthesia. Anesth Analg. 2014;118(1):168-72. Munnur U, de Boisblanc B, Suresh MS. Airway problems in pregnancy. Crit Care Med. 2005;33(10 Suppl):S259-68. Collins JS, Lemmens HJM, Brodsky JB, et al. Laryngoscopy and morbid obesity: a comparison of the “sniff” and “ramped” positions. Obes Surg. 2004;14(9): 1171-5. Aziz MF, Kim D, Mako J, et al. A retrospective study of the performance of video laryngoscopy in an obstetric unit. Anesth Analg. 2012;115(4):904-6. Ingrande J, Lemmens HJM. Dose adjustment of anaesthetics in the morbidly obese. Br J Anaesth. 2010;105(Suppl 1):i16-23. Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e691S-e736S.

Postoperative Delirium: A Bane of Daycare Surgery  85

CHAPTER

6

Postoperative Delirium: A Bane of Daycare Surgery Deep Arora, Deepak Pahwa

INTRODUCTION Last few decades have seen rapid advancements in the field of anesthesia as well as surgery. These advancements have helped in faster postoperative recovery of patients, leading to increasing popularity of daycare procedures. James Nicoll, first published his work on daycare surgery in British Medical Journal in 1909.1 A survey conducted in 2006 showed that almost 80% of surgeries performed in the United States and Canada are done as daycare surgeries.2 Bajwa et al. quoting unpublished sources estimating that daycare surgeries account for around 11–23% of total surgeries performed in hospital settings in India.3 As the daycare procedures are becoming popular, more and more patients at the extremes of age are presenting for surgeries. With the gradually increasing proportion of elderly in our population, daycare surgeries in this age group present their unique challenges for anesthesiologists. As per United Nations World Population Ageing report, the number of senior citizens is expected to grow to 2.1 billion by 2050.4

IMPORTANCE OF POSTOPERATIVE DELIRIUM Postoperative delirium (POD) in the context of daycare surgery is important because of its high incidence in postoperative elderly patients and its association with other complications. Postoperative delirium leads to increased duration of stay in the hospital, increased morbidity, mortality, increased cost of care and thus, can be the bane of daycare surgery. About one-third of POD may be preventable. Dr Julia R Berian and her colleagues have proposed that POD management should be seen as a target for surgical quality improvement and counted as a parameter of hospital performance.5 Weinrebe et al. through a retrospective study concluded that additional cost imposed on the hospital per hyperactive delirium patient was around 1200 euro.6

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DEFINITION AND INCIDENCE As per DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th edition) criteria, delirium is defined as disturbance of consciousness, with reduced ability to focus, sustain, or shift attention, change in cognition that is not better accounted for by a pre-existing, established, or evolving dementia, and that develops over a short period.7 Delirium that manifests after the patient has undergone a surgical procedure or anesthesia is called POD. There is wide variation in incidence of POD. It varies from 9–87% and depends on patient characteristics and the kind of surgery.8 Postoperative delirium usually manifests between 1 day and 3 days after surgery. It may be difficult to differentiate POD from emergence delirium and postanesthesia care unit (PACU) delirium. Emergence agitation is defined as agitation that starts once the inhaled anesthetics are discontinued. Emergence delirium is quite common, occurs in 8–20% of patients while awakening from general anesthesia and is more common in younger age group.9 Features of delirium that start at least 30 minutes after arrival in PACU are termed as PACU delirium. If signs of delirium are present on arrival in PACU, they should be labeled as emergence delirium.9 PACU delirium is significant as patients who develop PACU delirium are at a higher risk of developing POD.10

PATHOPHYSIOLOGY OF POSTOPERATIVE DELIRIUM Researchers have proposed a number of theories to explain delirium. The system integration failure hypothesis (SIFH) has been recently described to explain the clinical manifestations of delirium. Multiple theories that have been earlier proposed are brought together and taken into a paradigm in SIFH. It states that any insult in predisposed individuals results in altered levels of neurotransmitters and failure of complex brain interconnections, leading to abnormal and variable response by the brain which manifests as delirium. The changes in the levels of various neurotransmitters that are commonly seen in delirium include reduced availability of acetylcholine, increased levels of dopamine, norepinephrine, glutamine, and altered levels of gamma-aminobutyric acid (GABA), 5-hydroxytryptamine, and histamine. Such insults lead to aberrant activation of parasympathetic system and upregulation of pathological signaling of neurotransmitters. These signals activate both early as well as late triggers of apoptosis resulting in manifestations of acute as well as persistent delirium. The SIFH postulates that humans have various predisposing physiologically fragile characteristics. These fragile characteristics determine the susceptibility of individuals to various precipitating factors in an inverse relationship. Thus, more the fragile characteristics that an individual has, lesser the insult required to precipitate delirium.11

Postoperative Delirium: A Bane of Daycare Surgery  87

Helene et al.12 recently proposed the glymphatic theory of delirium. Glymphatic system is the perivascular transit passageway which helps in transporting metabolic waste from the brain. It is observed that glymphatic system transport is increased during sleep associated with slow delta waves on electroencephalogram (EEG). Any insult that leads to decrease in glymphatic system mediated transport of waste products from the brain leads to increased probability of delirium. They hypothesized that patients given drugs like dexmedetomidine have a lower incidence of delirium as these drugs improve the glymphatic system mediated drainage of waste metabolites from the brain.12

RISK FACTORS FOR DEVELOPMENT OF POSTOPERATIVE DELIRIUM Patients have various inherent risk factors in the preoperative period that predispose them for the development of delirium. Similarly, various precipitating events perioperatively trigger the onset of delirium. The chances of a patient developing delirium increase exponentially with the number of predisposing and precipitating factors that one has. These factors can be present preoperatively, intraoperatively or postoperatively (Table 1). Table 1: Risk factors for development of postoperative delirium. Preoperative

Intraoperative

Postoperative

•• •• •• •• •• •• •• •• •• •• •• ••

•• Duration of surgery •• Intraoperative blood loss •• Site of surgery (abdominal and thoracic) •• ?Depth of anesthesia monitoring •• Drugs: Opioids, benzodiazepines, antihistaminics, anticholinergics, and TCAs

•• Pain •• Complications •• Indwelling catheters

•• •• •• •• •• ••

Age History of stroke Cardiovascular disease Peripheral vascular disease Diabetes Anemia Parkinson’s disease Depression Chronic pain Anxiety disorders Higher ASA physical status Preoperative fasting and dehydration Sodium imbalance Drugs with anticholinergic effects Alcohol-related disorders Emergency surgery Hypothermia on admission Preoperative cognitive dysfunction

(ASA: American Society of Anesthesiologists; TCAs: tricyclic antidepressants)

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Anesthesia and delirium share a complex relationship which is not yet fully elucidated. A number of drugs have been found to be associated with delirium. Drugs like benzodiazepines, antihistaminics, anticholinergics, and tricyclic antidepressants should be avoided especially in vulnerable patients.13 Use of depth of anesthesia monitoring has been advised by European Society of Anesthesiology13 but not by the American Geriatric Society.14 A recent article published in Journal of American Medical Association (JAMA) also did not find reduced incidence of delirium by using depth of anesthesia monitoring.15 Hesse et al. found EEG burst suppression during maintenance of anesthesia and lack of dominance of spindles during emergence to be strongly linked with PACU delirium.16 There is no advantage of total intravenous anesthesia (TIVA) technique over inhalational technique for reducing the incidence of POD. A Cochrane review published in 2018 found no difference in the incidence of POD in elderly undergoing noncardiac surgery under inhalational anesthesia or TIVA. But the same review found low quality evidence that maintenance with propofol-based TIVA reduced the chances of cognitive dysfunction postoperatively in the elderly.17 Duan et al. in a meta-analysis found that dexmedetomidine use during or after surgery was associated with reduced incidence of POD. They suggested that dexmedetomidine should be used perioperatively to prevent POD. However, they concluded that further research is needed to determine the appropriate dose and timing of dexmedetomidine administration.18 Patients undergoing cardiac and vascular surgeries have higher chance of POD.13 Similarly, patients having any other complication in postoperative period have higher incidence of POD.13 Wang et al. used STOP-BANG questionnaire in patients undergoing thoracic surgery and found that patients with a score at least 3 had higher incidence of obstructive sleep apnea (OSA), longer duration of POD and coma. These subjects had 3.6 times more likelihood of developing POD and coma as compared to controls in this study.19

CLINICAL PRESENTATION AND DIAGNOSIS Any acute or subacute deterioration in behavior or cognition in predisposed individual should make a clinician to suspect delirium. Delirium can present as hypoactive form, hyperactive form or mixed form, the incidence of which is approximately 50%, 25%, and 25% respectively.20,21 Patients with hyperactive form of delirium usually present with agitation, restlessness, delusion, and hallucinations. On the other hand, patients with hypoactive delirium may present with reduced movements, decreased responsiveness and paucity of speech. Hypoactive delirium is usually misdiagnosed as depression. Farrell et al. concluded that up to 42% of patients referred to

Postoperative Delirium: A Bane of Daycare Surgery  89 Flowchart 1: Workup for postoperative delirium.

(CBC: complete blood count)

psychiatry consultation for evaluation and treatment of depression had delirium.22 Increased mortality rates have been observed in patients with undiagnosed hypoactive delirium.20 A thorough physical and neurological examination should be performed in all the patients. Patients presenting with features suggestive of delirium should be evaluated in detail. Electrolyte derangements, metabolic disturbances, sepsis or signs of organ dysfunction should be specifically looked for. Conditions like drug overdose, hepatic or uremic encephalopathy, substance abuse and withdrawal have targeted treatments and should not be overlooked while making the diagnosis (Flowchart 1).15 Neuroimaging can be helpful in presence of focal neurological deficits or deteriorating consciousness. It is advisable to perform lumbar puncture in patients with suspected meningitis or encephalitis. Early diagnosis of delirium improves the prognosis of the patient. Delayed diagnosis puts an additional burden on the finances of the healthcare system. Weinrebe et al. in a retrospective study found significantly shorter hospital stay (6.85 vs 13.61 days) in patients in whom delirium was detected early.6

DELIRIUM SCREENING Early diagnosis of delirium is important for faster and effective treatment. Patients should be shifted out of recovery room only after they are screened for delirium. For diagnosing delirium as per DSM-5 guidelines, patients with a severely reduced level of arousal, but above coma (of acute onset) should be considered as having delirium. (Since hypoactive delirium, the more common form of POD, is often missed). As patients are sedated in the recovery room, Richmond Agitation-Sedation Scale (RASS) along with another delirium screening tool should be used to recognize delirium in recovery area.13 RASS is a commonly used scale to assess the state of alertness in ICU patients where a score of +4 is given to a combative patient on one extreme while an unarousable patient scores –5. Getting a RASS score is the first step in screening for delirium in a postoperative patient (Fig. 1).

90  Yearbook of Anesthesiology-9

Fig. 1: Richmond Agitation-Sedation Scale (RASS).

Confusion Assessment Method (CAM) score is the most commonly used method for screening for delirium. CAM score incorporates four core features of delirium; acute onset, fluctuating course, inattention, and altered level of consciousness. It is especially useful in patients with pre-existing dementia with sensitivity of 94–100% and specificity of 90–95%.23 But, it requires specific training for its use in the recovery area. Nursing Delirium Screening Scale (NU-DESC) has the advantage that it can be easily used in the recovery area and does not require specific training. NU-DESC is based on 24 hour cycle of observation, so it cannot be used in daycare settings.24 4As test (4AT) can also be used for screening of delirium. It consists of two cognitive tests, assessment of level of consciousness, and an acute change in mental state.24 A two-item questionnaire with “months of years backward” and “what is the day of the week” can also be used to screen for delirium. It requires minimal time and training. Fick et al. in a study reported a sensitivity of 93% and specificity of 64% of two-item questionnaire for detecting delirium.25 Since detection of delirium requires an accurate history, which patients in delirium may not be able to give, the Family CAM (FAMCAM) questionnaire

Postoperative Delirium: A Bane of Daycare Surgery  91

has been developed. The source of history in FAMCAM is any informal caregiver who knows about the patient.26 This questionnaire is especially important since POD usually develops 1–3 days after surgery and thus can help in early detection of POD after discharge. Focused screening also helps in instituting preventive measures at the earliest thus reducing the complications and the cost of POD.27 American Geriatrics Society and the Association of Anaesthetists in Great Britain and Ireland recommend delirium risk assessment of elderly patients prior to administration of anesthesia.14 It is advisable that the whole team in a daycare center be involved to decide as to which screening tool is to be used. The team members should be trained regarding the basic features of delirium and the screening method that is going to be used.

DIFFERENTIAL DIAGNOSES Common conditions which need to be differentiated from delirium include dementia, depression and psychosis.28 Knowledge of patients’ baseline mental status is essential to make a diagnosis. One should look for acute variations in patient’s mental status: in delirium these changes occur over hours to days. A reliable informant is a must while obtaining history. Dementia often coexists with delirium and is a major predisposing factor for development of delirium. Acute alteration in patient’s cognition and consciousness goes more in favor of delirium. Inattention is more common in delirium while it occurs quite late in dementia.28 It is important to recognize the subset of patients who have delirium superimposed on preexisting dementia. This group of patients have earlier decline of cognition, frequent and prolonged hospitalizations, and increased mortality.15 Patients with hypoactive delirium can often present with features of depression. Patients with depression may have altered level of cognition but their level of consciousness is usually normal in contrast to patients with delirium.28 Patients with psychotic illnesses like schizophrenia also need to be differentiated from delirium. Patients with delirium often have acute or subacute presentation, they usually do not have any history of psychiatric illness, and they frequently have visual hallucinations, impaired memory and clouding of consciousness. These features are not present in schizophrenia.28

PREDICTION OF POSTOPERATIVE DELIRIUM Researchers have tried to formulate various nomograms to predict the chances of patients developing delirium. Delirium Elderly At-Risk (DEAR) instrument was proposed by Freter et al. in 2005.29 This instrument incorporates known risk factors for POD in routine preoperative nursing assessment. They found it to be useful in identifying elective arthroplasty

92  Yearbook of Anesthesiology-9 Table 2: Delirium Elderly At-Risk (DEAR) instrument. Domain

Yes

No

Elderly > 80 Hearing/visual aid Dependence in activities of daily living (bathing, dressing, grooming, toileting, feeding) Takes >3 times/week Alcohol Benzodiazepines Cognitive impairment

Fig. 2: Predictive nomogram for postoperative delirium devised by Zhang et al. (ASA: American Society of Anesthesiologists; ICU: intensive care unit; RBC: red blood cell)

patients at high-risk of developing POD. They used five domains to predict patients at enhanced risk of developing delirium. Affirmative answers to more than one domain placed patients into higher risk (for delirium) category. It is summarized below in the tabular form (Table 2). Zhang et al. did a retrospective study on 1,156 patients undergoing fracture neck of femur surgery at their institution. They developed a nomogram to predict the chances of POD in surgical patients as summarized in Figure 2.30 This predictive nomogram was constructed based on the multivariable model. To use the nomogram, a vertical line is drawn up to

Postoperative Delirium: A Bane of Daycare Surgery  93

the top point row to assign points for each variable. Then, the total number of points is calculated, and a vertical line is drawn downward from the total point row to obtain the probability of POD.

BIOMARKERS Various biomarkers have been proposed to be increased in delirium. These biomarkers can help in understanding the pathophysiology of POD, refining the treatment strategies, prognosticating the patients and identifying the high-risk patients. These include C-reactive protein (CRP), insulin-like growth factor 1, interleukin-6, apolipoprotein-E genotype, cholinesterases, GABA, and leptin. A recent review by Ayob et al. concluded that among all of the above markers, CRP was found to be linked with POD in 5 studies. They concluded that CRP as a biomarker showed the most potential to be used for POD but further research is still warranted before any biomarker gets incorporated in the guidelines for monitoring POD.31 Various studies set different cutoff values of CRP for identifying delirium but the authors in the above review concluded that a value of > 3 mg/L can be used reasonably for predicting POD.31

PREVENTION AND TREATMENT OF POSTOPERATIVE DELIRIUM There are many possible ways to prevent or reduce the incidence of POD. These may be nonpharmacological and pharmacological interventions. Nonpharmacological interventions should be started preoperatively (Table 3). They help in reducing the incidence of POD by half.8 Table 3: Nonpharmacological measures for preventing delirium. Preoperative

Intraoperative

Postoperative

•• Divide into low-risk and high-risk •• Decrease pain •• Avoid benzodiazepines •• Maintain circadian rhythm •• Use hearing and visual aids •• Fast-track surgery •• Minimize fasting time

•• Avoid fluctuations in BP •• Intraoperative depth of anesthesia monitoring •• Avoid benzodiazepines, antihistaminics, anticholinergics •• Minimize duration of surgery •• Minimize blood loss

•• Decrease pain •• Avoid benzodiazepines •• Maintain circadian rhythm •• Use hearing and visual aids •• Encourage communication •• Avoid indwelling catheters •• Avoid physical restraints •• Early mobilization and nutrition •• Minimize opioids

 BP: blood presssure

94  Yearbook of Anesthesiology-9 Box 1: HELP team interventions. •• •• •• •• •• •• ••

Geriatric nursing assessment and intervention: Screen all patients > 70 years Inclusion: Even if one risk factor Geriatrician consult Interdisciplinary meeting based on risk factors Individualized interventions Adherence: Compliance of all interventions Transitional care: Community linkage and telephone follow-up

(HELP: Hospital Elder Life Program)

The Hospital Elder Life Program (HELP) is a set of multicomponent interventions that are used to lessen the incidence of delirium in the elderly. It focuses on interventions aimed at six known risk factors for delirium: (1) impaired cognition, (2) volume depletion, (3) psychoactive medicines, (4) visual/hearing impairment, (5) immobilization, and (6) sleep deprivation.32 The members present in a typical HELP team include—Elder Life Specialist, Elder Life Nurse Specialist, and geriatrician along with trained volunteers.33 HELP team interventions are summarized in Box 1. A recent meta-analysis on effectiveness of HELP found that this program helped in significantly reducing the delirium incidence, rate of accidental falls as well as the duration of stay in the hospital.34 In the preoperative period, patients should be categorized into low-risk and high-risk categories based on the predisposing and precipitating risk factors present. Routine use of benzodiazepines as premedication should be avoided except in those patients who are highly anxious or alcohol dependent. Similarly, premedication with anticholinergic drugs should be avoided in all patients. Fasting time should be minimized and surgery fast tracked to reduce the incidence of delirium. Alpha 2 agonists can be used in high-risk patients either preoperatively or intraoperatively. Pain should be adequately assessed and treated perioperatively.13 Intraoperative depth of monitoring can be used, but whether it helps in reducing the incidence of delirium is still questionable. Nonpharmacological measures should be started at the earliest. They include maintaining orientation by keeping a clock near the patient, communicating frequently with the patient, encouraging the family members to interact with the patient, allowing the patient to use his/ her visual/hearing aids for the maximum time possible, reducing the unnecessary noise in the surroundings and facilitation of sleep by providing uninterrupted period for sleep during night, discouraging daytime napping, avoiding physical restraints, avoiding unnecessary indwelling catheters, mobilizing the patient as soon as possible postoperatively and by allowing early nutrition. Delirium should be diagnosed at the earliest and treatment

Postoperative Delirium: A Bane of Daycare Surgery  95

should be started immediately. One should aim to treat the underlying cause if found.13 Statins have been shown to produce mixed results in preventing delirium. Bouhout et al. found that “off-pump” coronary artery bypass patients receiving statins preoperatively had statistically significant reduction in the incidence of POD.35 Ketamine, in a small randomized controlled trial, in a dose of 0.5 mg/kg given intravenously only once, was found to decrease POD and CRP levels.36 Pharmacological treatment should be started as a last resort only if the patient tries to harm himself or others. For symptomatic treatment, if patient is admitted in a monitored environment like ICU, a loading dose of 2 mg haloperidol is administered intravenously. It can be repeated every 15–20 minutes if the agitation persists. If the agitation is severe, double the dose can be repeated after 15–20 minutes. If the patient is admitted in the ward, an initial dose of 1–2 mg haloperidol can be given orally, intramuscularly or intravenously followed by 0.25–0.5 mg every 4 hours.37 In both these settings haloperidol is tapered over several days.37 Other atypical neuroleptics like risperidone can be used, but are not found to be superior to haloperidol.38 While treating with neuroleptics one should watch for side effects like prolonged QT interval and extrapyramidal side effects.

COGNITIVE OUTCOME OF POSTOPERATIVE DELIRIUM Patients developing delirium have prolonged cognitive adverse effects. Those who do not develop delirium regain baseline cognitive function 1 month after surgery, while those who have delirium are not able to do so even 1 year postoperatively.39 Hudetz et al. found that cardiac surgery patients who develop POD have 14 times higher chances of postoperative cognitive dysfunction (POCD).40 There is also an increased incidence of dementia in those who had suffered from delirium. Witlox et al. in a meta-analysis found that patients with delirium were predisposed to develop dementia (62.5% vs 8.1%).41

CONCLUSION Due to advancements in technology, daycare surgeries are gaining popularity. Daycare surgeries help in improving patient satisfaction, early mobilization, faster recovery, and decrease health cost for both the patient and the healthcare system. These facilities help in fast tracking the surgeries, decreasing the fasting duration, personalized care, and recovery in a familiar environment, all these factors reduce the incidence of POD. Each and every patient should be screened for delirium before getting discharged. Daycare setup also requires facilities to take care of POD, if a patient develops it. Early

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recognition and initiation of treatment of POD by trained staff can help in reducing the incidence as well as severity of delirium. Nonpharmacological measures if initiated on time can manage most of the cases of POD.

KEY POINTS • Delirium that manifests after the patient has undergone a surgical procedure or anesthesia is called POD. • Postoperative delirium usually manifests between 1 day and 3 days after surgery. • The chances of a patient developing delirium increase exponentially with the number of predisposing and precipitating factors that one has. • Delirium risk assessment should be done in elderly patients prior to administering anesthesia. • Delirium can present as hypoactive form, hyperactive form or mixed form. • Delirium should be differentiated from dementia, depression, and psychosis. • Early diagnosis and treatment of POD helps in reducing the morbidity as well as mortality. • Nonpharmacological interventions form the mainstay of treatment of POD. • These interventions should be started in the preoperative period and should be continued till the patient recovers completely. • Pharmacological treatment should be reserved as a last resort only if the patient tries to harm himself or the others.

REFERENCES 1. Nicoll JM. The surgery of infancy. Br Med J. 1909;2:753-6. 2. Castoro C, Bertinato L, Baccaglini U, et al. (2007). Policy Brief—Day Surgery: making it happen. World Health Organization. [online] Available from http://www.euro.who.int/__data/assets/pdf_file/0011/108965/E90295.pdf [Last accessed August, 2019]. 3. Bajwa SJ, Sharma V, Sharma R, et al. Anesthesia for day-care surgeries: Current perspectives. Med J DY Patil Univ. 2017;10:327-33. 4. United Nations, Department of Economic and Social Affairs, Population Division (2017). World Population Ageing 2017- Highlights (ST/ESA/SER.A/397). 5. Brain JR, Zhou L, Russell MM, et al. Postoperative delirium as a Target for Surgical Quality Improvement. Ann Surg. 2018;268(1):93-9. 6. Weinrebe W, Johannsdottir E, Karaman M, et al. What does delirium cost? An economic evaluation of hyperactive delirium. Z Gerontol Geriat 2016;49:52-8. 7. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th edition. Washington, DC: American Psychiatric Association; 2013. 8. Whitlock EL, Vannucci A, Avidan MS. Postoperative delirium. Minerva Anestesiol. 2011;77:448-56. 9. Card E, Pandharipande P, Tomes C, et al. Emergence from general anaesthesia and evolution of delirium signs in the post-anaesthesia care unit. Br J Anaesth. 2015;115(3):411-7. 10. Hernandez BA, Lindroth H, Rowley P, et al. Post-anaesthesia care unit delirium: incidence, risk factors and associated adverse outcomes. Br J Anaesth. 2017;119:288-90.

Postoperative Delirium: A Bane of Daycare Surgery  97 11. Maldonado JR. Delirium pathophysiology: An updated hypothesis of the etiology of acute brain failure. Int J Geriatr Psychiatry. 2018;33:1428-57. 12. Benveniste H, Heerdt PM, Fontes M, et al. Glymphatic System Function in Relation to Anesthesia and Sleep States. Anesth Analg. 2019;128(4):747-8. 13. Aldecoa C, Bettelli G, Bilotta F, et al. European Society of Anaesthesiology evidence-based and consensus-based guideline on postoperative delirium. Eur J Anaesthesiol. 2017;34:192-214. 14. American Geriatrics Society Expert Panel on Postoperative Delirium in Older Adults. Postoperative delirium in older adults: best practice statement from the American Geriatrics Society. J Am Coll Surg. 2015;220:136-48.e1. 15. Oh ES, Fong TG, Hshieh TT, et al. Delirium in Older Persons: Advances in Diagnosis and Treatment. JAMA. 2017;318:1161-74. 16. Hesse S, Kreuzer M, Hight D, et al. Association of electroencephalogram trajectories during emergence from anaesthesia with delirium in the postanaesthesia care unit: an early sign of postoperative complications. Br J Anaesth. 2019;122:622-34. 17. Miller D, Lewis SR, Pritchard MW, et al. Intravenous versus inhalational maintenance of anaesthesia for postoperative cognitive outcomes in elderly people undergoing non‐cardiac surgery. Cochrane Database Syst Rev. 2018;8:CD012317. 18. Duan, X, Coburn M, Rossaint R, et al. Efficacy of perioperative dexmedetomidine on postoperative delirium: systematic review and meta-analysis with trial sequential analysis of randomised controlled trials. Br J Anaesth. 2018;121: 384-97. 19. Wang S, Sigua NL, Manchanda S, et al. Preoperative STOP-BANG Scores and Postoperative Delirium and Coma in Thoracic Surgery Patients. The Ann Thorac Surg. 2018;106:966-72. 20. Yang FM, Marcantonio ER, Inouye SK, et al. Phenomenological subtypes of delirium in older persons: patterns, prevalence, and prognosis. Psychosomatics. 2009;50:248-54. 21. Rudolph JL, Marcantonio ER. Delirium. In: Duthie EH, Katz PR, Malone M (Eds). Practice of Geriatrics. Philadelphia, PA: Saunders Elsevier; 2007. 22. Farrell KR, Ganzini L. Misdiagnosing delirium as depression in medically ill elderly patients. Arch Intern Med. 1995;155:2459-64. 23. Wei LA, Fearing MA, Sternberg EJ, et al. The Confusion Assessment Method: a systematic review of current usage. J Am Geriatr Soc. 2008;56(5):823-30. 24. De J, Wand AP. Delirium Screening: A Systematic Review of Delirium Screening Tools in Hospitalized Patients. Gerontologist. 2015;55:1079-99. 25. Fick DM, Inouye SK, Guess J, et al. Preliminary development of an ultrabrief two-item bedside test for delirium. J Hosp Med. 2015;10:645-50. 26. Steis MR, Evans L, Hirschman KB, et al. Screening for delirium using family caregivers: convergent validity of the Family Confusion Assessment Method and interviewer-rated Confusion Assessment Method. J Am Geriatr Soc. 2012;60(11):2121-6. 27. Markar SR, Smith IA, Karthikesalingam A, et al. The Clinical and Economic Costs of Delirium After Surgical Resection for Esophageal Malignancy. Ann Surg. 2013;258:77-81.

98  Yearbook of Anesthesiology-9 28. Hshieh TT, Inouye SK, Oh ES. Delirium in the Elderly. Psychiatr Clin North Am. 2018;41:1-17. 29. Feter SH, Dunbar MJ, MacLeod H, et al. Predicting post-operative delirium in elective orthopaedic patients: the Delirium Elderly At-Risk (DEAR) instrument. Age and Ageing. 2005;34(2):169-71. 30. Zhang X, Tong DK, Ji F, et al. Predictive nomogram for postoperative delirium in elderly patients with a hip fracture. Injury. 2019;50(2):392-7. 31. Ayob F, Lam E, Ho G, et al. Pre-operative biomarkers and imaging tests as predictors of post-operative delirium in non-cardiac surgical patients: a systematic review. BMC Anesthesiol. 2019;19:25. 32. Inouye SK, Baker DI, Fugal P, et al. Dissemination of the hospital elder life program: implementation, adaptation, and successes. J Am Geriatr Soc. 2006;54:1492-9. 33. Inouye SK, Bogardus ST, Baker DI, et al. The Hospital Elder Life Program: a model of care to prevent cognitive and functional decline in older hospitalized patients. J Am Geriatr Soc. 2000;48:1697-706. 34. Hshieh TT, Yang T, Gartaganis SL, et al. Hospital Elder Life Program: Systematic Review and Meta-analysis of Effectiveness. Am J Geriatr Psychiatry. 2018;26(10):1015-33. 35. Bouhout I, Ellouze M, Cartier R. Preoperative Statins Reduce Postoperative Delirium Following Off Pump Coronary Artery Bypass. Can J Cardiol. 2018;34:S8. 36. Hudetz JA, Patterson KM, Iqbal Z, et al. Ketamine attenuates delirium after cardiac surgery with cardiopulmonary bypass. J Cardiothorac Vasc Anesth. 2009;23:651-7. 37. Robinson TN, Eiseman B. Postoperative delirium in the elderly: diagnosis and management. Clin Interv Aging. 2008;3:351-5. 38. Han CS, Kim YK. A double-blind trial of risperidone and haloperidol for the treatment of delirium. Psychosomatics. 2004;45:297-301. 39. Saczynski JS, Marcantonio ER, Quach L, et al. Cognitive trajectories after postoperative delirium. NEJM. 2012;367:30-9. 40. Hudetz JA, Patterson KM, Byrne AJ, et al. Postoperative delirium is associated with postoperative cognitive dysfunction at one week after cardiac surgery with cardiopulmonary bypass. Psychol Rep. 2009;105:921-32. 41. Witlox J, Eurelings LS, de Jonghe JF, et al. Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, and dementia: a metaanalysis. JAMA. 2010;304(4):443-51.

Gas Embolism: An Update  99

CHAPTER

7

Gas Embolism: An Update

Anju Romina Bhalotra, Rahil Singh

INTRODUCTION Vascular air embolism (VAE) refers to the entry of gas into the vasculature, resulting in systemic manifestations.1 The term gas embolism indicates the presence of air, oxygen (O2), carbon dioxide (CO2), nitrogen (N2), etc. in the vasculature due to a pressure difference between the atmosphere and blood vessels which allows entry of the gas.2 Emboli can be venous, arterial, or paradoxical and can be distinguished by the likely etiology and the location of the embolus. The most common type of gas embolism seems to be air embolism, which is usually iatrogenic in nature. The solubility of the gas and the volume entrained determine the resulting physiologic effects. A wide spectrum of clinical presentations may be seen ranging from no/minor effects to even death.3 Improvements in monitoring indicate that occurrence of a VAE is relatively common during many surgical procedures1 and recent advances in surgical and interventional procedures have further increased the risk. Most episodes are preventable and meticulous precautions and early detection and proper management can reduce the associated morbidity and mortality. It is thus necessary for clinicians to know of the etiology and pathophysiology, predisposing factors, measures for prevention, and clinical presentation and recognition of VAE, to prompt timely management.

EPIDEMIOLOGY The true incidence and prevalence of VAE are impossible to ascertain because asymptomatic patients are often missed, signs and symptoms are nonspecific, and the diagnosis is difficult to establish. Also, much depends on the sensitivity of the methods used for detection. Procedures which carry a high risk (>25%) of VAE include neurosurgical procedures in sitting position and surgeries on the neck (10–100%),3-6 laparoscopic procedures (69% to 100%),7,8 orthopedic surgeries (57%),9 with 30%5 in total hip arthroplasty, obstetric-gynecological surgeries (11–97%),5,10,11 with 40% in cesarean delivery,5 and related to central venous access,12 and

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craniosynostosis repair.13 Procedures with a medium risk (5–25%) include prostatectomy, laminectomy (cervical spine), spinal fusion, gastrointestinal endoscopy, contrast radiography, blood transfusions, and cardiac surgery. There is a low risk of VAE ( 500 mL/6 hours Gut ischemia Bowel obstruction Abdominal compartment syndrome High output fistula without distal feeding access

Box 2: Benefits of enteral nutrition. •• •• •• •• ••

Maintains the tight junctions between the epithelial cells of gut mucosa Stimulates blood flow to the gut Induces the release of gastrin, cholecystokinin, and bile salts Supports IgA producing immunocytes (gut associated lymphoid tissue) Modulates the systemic immune response

diet. If patients are unable to take orally, then EN is the preferred route of nutrition. However, if there are immediate contraindications for EN (Box 1), then nutritional therapy depends on the previous health status of the patient. In nonmalnourished previously healthy patient, EN can be delayed, whereas in malnourished patients, early PN should be started.3 The benefits of EN are tabulated in Box 2.

EARLY ENTERAL NUTRITION VERSUS DELAYED ENTERAL NUTRITION VERSUS PARENTERAL NUTRITION Various studies have demonstrated significant reduction in infectious complications in early EN group as compared to delayed EN.3,12 Similarly, reduction in ICU infections, shorter ICU stay and shorter hospital length of stay, has been reported in EN group when compared with group receiving PN.13 However, there is no mortality benefit in EN versus PN group.14,15 Earlier, there were some reservations about starting early EN in patients with gastrointestinal surgery, aortic surgery, and pancreatitis but now guidelines recommend to start early EN in such cases.12 The EN should also be administered in patients receiving neuromuscular blockade, patients in prone position, and in patients on extracorporeal membrane oxygenation (ECMO).3,12 The important thing while initiating nutrition is that feeding in critically ill patients should be gradual. The estimated energy and protein goal should be achieved in incremental steps and not within first 48 hours.3 Full EN or PN should be prescribed over 3–7 days. The complications associated with EN are aspiration of intestinal contents, diarrhea, metabolic abnormalities, and mechanical complications.

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ENERGY AND PROTEIN REQUIREMENT OF CRITICALLY ILL PATIENTS The first step in initiating nutrition is to calculate the energy and protein requirements for the patient. These can be determined either by simple formulas, published predictive equations, or indirect calorimetry (IC).1 IC is the most accurate. There are around 200 predictive equations1 published; e.g. the Harris-Benedict, the Frankenfield, the Ireton–Jones, or the Fusco with the accuracy ranging from 40–75% when compared with IC.16,17 The resting energy expenditure (REE) of a critically ill patient is similar to that of a normal person. The best-recommended method to measure REE both by ASPEN1 and ESPEN3 is IC. However, it is not being used frequently due to nonavailability at all places and due to the cost involved. According to the recent ESPEN guidelines, if IC is not available, then calculation of REE should be done from the volume of carbon dioxide breathed out (VCO2) obtained from ventilators with the equation:3 REE = VCO2 × 8.19 If nothing is available, then simple weight-based equations can be used. REE = 25–30 Kcal/kg/d Weight of the patient for calculations of feeding requirement is calculated from ideal body weight and not actual body weight. The REE achieved may be multiplied by a factor of 1.2 in cases of mild stress, and by 1.9 in a severe hypercatabolic state. For the first few days of critical illness, feeding lower calories compared to full calories is beneficial.3 Hypocaloric feeding is associated with less gastrointestinal intolerance. Early full targeted feeding can cause overfeeding as there is endogenous energy production as well and it also augments the risk of refeeding syndrome in certain group of patients. Approximately 70% of the estimated energy requirements should be provided in the early phase and then, after 3 days, it can be increased to 80–100%. In a study comparing hypocaloric feeding with normocaloric feeding, the authors demonstrated decreased infection rate in hypocaloric group.18 However, similar results were not achieved in another important trial permissive underfeeding versus target enteral feeding in adult critically ill patients (PermiT Trial) which evaluated low calorie feeding (40–60% of calorie requirement) with standard feeding (70–100% of calorie requirement). There was no difference in mortality, infectious complications and length of hospital stay between the two groups.19 Later, Marik and Hooper in a metaanalysis20 reported lower hospital mortality in patients with low calorie feeding versus normocaloric feeding. The protein requirement needs to be determined separately from the energy requirements. It is variable during the critical illness depending on the phases of illness. Protein requirement may vary from 0.8–1.2 g/kg to

Nutrition in the Intensive Care Unit  119

1.5–2.0 g/kg body weight. The requirement of proteins increases with the severity of illness. High protein EN (1.2–2 g per kg of ideal body weight per day) is recommended by various guidelines.1,3 There is a huge evidence that adequate protein supplementation improves survival in critically ill patients.21-23 A large number of studies have been conducted with different combinations of protein and calorie intake in critically ill patients but the high protein diet is beneficial only if associated with adequate calories.3

HOW TO PROVIDE ENTERAL NUTRITION? Patients who are critically ill exhibit varying degrees of gastrointestinal dysfunction and its incidence ranges from 30% to 70%.1 Enough data exist that bowel sounds or features of bowel motility like passing of flatus or stool are not essential before starting of EN as was earlier advocated. The standard approach to start EN is through gastric access either with orogastric or nasogastric tube. The position of the tube should be checked and confirmed radiographically before it is used.24 However, in patients at high risk of aspiration or intolerance to EN, postpyloric feeding should be used.1 Davis et al. in a large multicentric trial compared gastric versus small bowel EN and found no difference in clinical outcomes between the two groups.25 Other alternative approaches available include percutaneous endoscopic gastrostomy (PEG) or surgical gastrostomy. In some group of patients, if there is intolerance to EN, trophic feeding can be started initially. Trophic feeds are small quantity of feeds given at the rate of 10–20 mL/hour or 10–20 kcal/hour and are sufficient to prevent mucosal atrophy and maintain gut integrity.1

Dosing of Enteral Nutrition Dosing of EN depends on three factors: 1. The nutritional status of the patient 2. Risk of malnutrition 3. Disease severity. Patients who have adequate baseline nutrition status, who are at low risk of malnutrition and whose disease severity is low, i.e. patients with NRS 2002 ≤3 OR NUTRIC score 60% of energy and protein requirements, then PN should be added to EN. ASPEN/SCCM recommends that PN should be added only after 7–10 days of EN.1 Absorption of fat is impaired in critical illness and has to be kept in account. Mixture of fatty acids should be administered including mediumchain triglycerides, monounsaturated fatty acids, and polyunsaturated fatty acids. The upper limit of glucose to be administered is 5 mg/kg body weight and for lipid is 1.5 g/kg/day. The only problem with EN is the risk of aspiration and development of ventilator-associated pneumonia (VAP). The two strategies to decrease this risk are elevation of the head end of the bed to 30–45° at the time of feeding31 and chlorhexidine mouthwash twice a day.32

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Diarrhea is also common in ICU with the incidence ranging from 2% to 95%. It may result in electrolyte imbalance, dehydration, and can lead to bedsores after perineal skin breakdown.33 EN should not be interrupted for diarrhea but in fact, it should be continued while evaluating its etiology (infectious diarrhea/osmotic diarrhea) and appropriate treatment should be started.

PARENTERAL NUTRITION Parenteral nutrition may be delivered either through a central line or peripheral line. There are two kinds of preparations available: 1. Preparations for central line which have high osmolality 2. Preparations for peripheral line with low osmolality. For short duration, the central line preparations can be administered through central catheters or peripherally inserted central catheters, but long-term PN requires tunneled central venous catheters.

Components of Parenteral Nutrition The components of total PN (TPN) solutions are dextrose solutions, amino acids, and lipids. • Dextrose is available in 40, 50, and 70% concentrations. The calories delivered by dextrose are 3.4 kcal/g. • Amino acids consist of essential and nonessential amino acids. The concentration of amino acids 5–15%. The calories delivered through amino acids are 4 kcal/g. • Lipids are in the form of emulsions. Either they have to be given separately or can be mixed to the amino acids and carbohydrate components at the time of delivery to the patient. Lipid emulsions are derived from soya bean oil, saffron oil, or refined olive oil. The calories delivered are 10–11 kcal/g. Lipid emulsions based only on soya bean oils (rich in omega 6 fatty acids) should be avoided. Lipid emulsions that are based on olive oil, fish oil, and coconut oil should be added and are advantageous.34 Different studies have demonstrated decrease in length of stay in ICU and decrease in infection rate with fish oil, and mixed chain triglycerides as compared to soya bean oil based preparations.35 Vitamins and trace elements must be provided along with PN to prevent deficiency. A daily-recommended dosage is required. Comparison of different PN solutions available is listed in Appendix 2. Strict monitoring is required during PN administration. This includes fluid intake/output, serum electrolytes, glucose, calcium, magnesium, and phosphorus daily. Liver enzymes and bilirubin also need to be monitored depending on the illness state. The complications associated with PN are tabulated in Box 3.

122  Yearbook of Anesthesiology-9 Box 3: Complications of parenteral nutrition. Bloodstream infection (bacterial and fungal) Metabolic complications: •• Hyperglycemia. •• Dyselectrolytemia Deficiency of micronutrients: •• Vitamins •• Minerals Refeeding syndrome Hepatic dysfunction

Box 4: Patients at risk of refeeding syndrome. Body mass index (BMI) 10 days •• Low potassium, phosphorus, and magnesium levels before refeeding •• Chronic alcoholics •• Severe chronic malnutrition •• Depleted patients with acute illness

The most important and feared complication of PN is bloodstream infection, both bacterial and fungal.36 To prevent this, there should be a single dedicated port for PN in double or triple lumen catheters.

Refeeding Syndrome Refeeding syndrome occurs when malnourished patients are restarted feeding. It is a serious condition that occurs due to rapid changes in fluids and electrolytes. Clinical symptoms include symptoms of fluid overload like peripheral edema, congestive heart failure, respiratory failure, encephalopathy, and multiorgan dysfunction. The main electrolyte imbalance includes hypophosphatemia, hypokalemia, hypomagnesemia, and hypocalcemia. The patients who are at risk of refeeding syndrome are mentioned in Box 4.

ADJUNCTIVE THERAPY Omega 3 Fatty Acids Various studies have reported conflicting results in relation to supple­ mentation of omega 3 fatty acids and antioxidants to standard EN. Earlier studies in patients with acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), and sepsis showed improvement in length of ICU stay, duration of ventilation and improvement in mortality in patients receiving these supplements,37-39 but later post hoc analysis of MetaPlus study40

Nutrition in the Intensive Care Unit  123

demonstrated potential harm of adding these and other meta-analysis reported no benefit.3 Therefore, these are not recommended presently on routine basis.

Glutamine Amino acid glutamine serves as a metabolic fuel for the rapidly proliferating cells. The plasma glutamine levels are usually low in critically ill patients and low levels are associated with poor outcomes.41-43 There have been conflicting results of various trials about the use of glutamine in the past. In the present day, enteral glutamine is recommended only in burn and trauma patients and not in other critically ill patients.3 Supplemental glutamine reduces infectious complications and mortality in burn patients.44 Glutamine has also been found to be beneficial in trauma patients in reducing infections. The recommended duration of glutamine supplementation is 5 days in uncomplicated trauma and for 10–15 days in burns and complicated wound healing.45 Parenteral glutamine is not recommended. The investigators of recently conducted large trial, REDOX (REducing Deaths Due to OXidative Stress) TRIAL46 reported higher mortality in severely ill patients with the administration of combined enteral and parenteral glutamine in doses higher than recommended.

Fiber/Immune Modulators/Micronutrients/Antioxidants Fiber can be added to EN in patients with diarrhea. Immune modulators have no proven efficacy so are not recommended. Micronutrients include trace elements and vitamins in the diet. They are required for the metabolism of carbohydrates, proteins, and lipids. These micronutrients should be provided daily with PN as parenteral solutions lack these. Antioxidant micronutrients include copper, zinc, selenium, vitamin E, and vitamin C. ASPEN 2016 guidelines recommend the addition of these antioxidants in safe dosages.1

Vitamin D Supplementation Vitamin D supplementation is required in the patients with measured low plasma levels of 25 hydroxy vitamin D levels (levels less than 12.5 ng/mL or 50 nmol/L. Various trials have shown poor outcome with higher incidence of sepsis and mortality in patients with deficiency of vitamin D.47,48 Single dose of vitamin D3 (500,000 IU) in the first week of ICU stay is sufficient and can be repeated if required.

Phosphate Supplements Hypophosphatemia is common in ICU patients. The incidence of moderate to severe hypophosphatemia is approximately 30% in ICU patients.49

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Improving phosphate levels improves the respiratory muscle effort and helps in weaning.50

NUTRITION IN VARIOUS DISEASE CONDITIONS Sepsis Patients in sepsis require special attention. There are increased metabolic needs in patients with sepsis and on the other hand, these patients may not be able to tolerate enteral feeds due to ileus and gastrointestinal intolerance. This may lead to malnutrition in septic patients and if not provided, adequate amount of nutrition can lead to reduced survival.51 Hypocaloric or trophic feeding can be started in such patients but if they are unable to tolerate even after 3 days, PN can be added in septic patients. However, in septic shock patients, EN is contraindicated. There is already decreased splanchnic perfusion in shock patients and there are chances of bowel ischemia or gut necrosis with EN. It should only be started after resuscitation is complete.

Trauma Trauma patients are usually optimally nourished on admission but may become malnourished during critical illness. Studies indicate that an early EN in this group of patients is associated with decreased mortality and hence should be encouraged.52 Moreover, these patients have huge protein losses and protein intake should be kept high around 1.5–2.0 g/kg/day.

Pulmonary Failure There are no special nutritional requirements for patients with respiratory failure. Earlier studies indicated some benefit with high fat and low carbohydrate EN in these patients. High fat and low carbohydrate were suggested in order to decrease the CO2 production and alter the respiratory quotient, but these findings were refuted in later larger studies and therefore should not be used.1 Overfeeding needs to be avoided in patients who are prone to high CO2 production. Rapid infusions of intravenous fat emulsions also should not be administered in these patients. Fluid-restricted concentrated EN should be used in patients with volume overload.1

Renal Failure In patients with acute kidney injury/renal failure, standard diet with proteins (1.2–2 g/kg/day actual body weight) and energy (25–30 kcal/kg/day) should be provided. The formulations may be altered if there are significant changes in electrolytes, e.g. diet low in potassium and phosphate can be prescribed, if hyperkalemia or hyperphosphatemia exists.53 However, in patients

Nutrition in the Intensive Care Unit  125

undergoing frequent hemodialysis or continuous renal replacement therapy (CRRT), high protein diet is recommended, as there are significant protein losses.54

Hepatic Failure Malnourishment is common in patients with chronic liver disease or cirrhosis. Earlier, protein restriction was advocated in such patients to reduce the risk of hepatic encephalopathy but studies have proven that low protein diet can further worsen the nutritional status in such patients.55 Standard formulations with standard protein contents should be provided. In patients with volume overload and ascites, dry body weight should be considered instead of actual body weight. PN should be avoided in such patients as it may worsen the liver functions.56 There is no role of branchedchain amino acids in patients with hepatic encephalopathy who are already on treatment.

Acute Pancreatitis Early EN is recommended in patients with acute pancreatitis. Initially EN is started as trophic feed and then increased to goal levels in 24–48 hours of admission. Early EN has proven benefit in terms of reduced infection, organ failure, ICU length of stay, and systemic inflammatory response syndrome (SIRS) than delayed EN in these patients.57 PN should be avoided. Large body of evidence indicates decreased length of stay, reduced infection, and improved mortality with EN as compared to PN.58 There is no difference in the outcome, if either gastric or jejunal route of feeding is used.

MONITORING NUTRITION Like any other monitoring in ICU, monitoring for nutrition therapy is also required. Inappropriate nutrition, which can be either underfeeding or overfeeding can have dire consequences. This becomes more important in chronically ill critical patients.59 Monitoring includes clinical monitoring and monitoring of laboratory values (Box 5).

Glucose and Electrolytes Monitoring Both hypoglycemia and hyperglycemia are associated with high mortality in critically ill patients.60 The blood glucose levels in the range of 110–150 mg/dL are associated with good outcomes.61,62 Insulin therapy should be started when blood glucose levels exceed 180 mg/dL. Electrolytes including potassium, magnesium, and phosphates should be measured daily in the first week of the nutrition.

126  Yearbook of Anesthesiology-9 Box 5: Monitoring the nutritional therapy. Clinical monitoring: •• Abdominal examination for distension, presence of stools, and nature of gastrointestinal (GI) contents •• Gastric residual volume •• Intra-abdominal pressure •• Detection of dysphagia postextubation •• Delivery of nutrients—in terms of volume, energy, and proteins Monitoring of laboratory values: •• Blood glucose and insulin requirements •• Concentration of electrolytes like sodium, potassium, magnesium, and chloride •• Phosphate levels •• Liver function tests •• Triglycerides •• Urea •• Albumin levels •• Micronutrients—vitamins, copper, selenium, and zinc levels

CONCLUSION Providing adequate nutrition to critically ill patients is challenging. Critical illness poses a major catabolic stress and timely, adequate nutrition therapy is required to limit this stress and affect the outcome. Various available guidelines help us to evaluate and prescribe nutritional components but nutritional therapy needs to be individualized depending on the phase of illness.

KEY POINTS • Nutritional therapy moderates and restores physiological immune response to critical illness. • The requirements of a critically ill patient differ according to the severity of illness and physiological stress. • Assessment of nutrition is difficult in ICU and general clinical assessment is recommended to assess malnutrition. • Any patient staying in ICU for more than 48 hours is considered to be at risk of malnutrition. • The most preferred way of nutrition is early (within 48 hours of ICU stay) enteral nutrition. • The best method to measure resting energy expenditure is indirect calorimetry. • Approximately 70% of the estimated energy requirements should be provided in the early phase. • Both underfeeding and overfeeding can have dire consequences in critically ill patients. • Like any other monitoring in ICU, monitoring for nutrition therapy is also required.

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APPENDIX 1: NUTRIC SCORE Variable

Range

Points

Age

36.0°C but below normal (37°C), active warming should be provided for at least 30 minutes prior to initiation of anesthesia (unless there is need for emergency surgery). • On transfer to the operating room, active warming is to be continued. Wherever possible, patients may be encouraged to walk into the theater complex.

Intraoperative Phase • Body temperature should be recorded before, during and at every half an hour intervals after the induction of anesthesia. • Ideally, anesthesia should be delayed if the patient’s temperature is below 36.0°C (unless the clinical condition of the patient warrants an urgent surgery). • The ambient temperature in the operating room should be at least 21°C while the patient is exposed. Once the patient has been adequately and actively warmed, the room temperature may be reduced to allow better working conditions for the surgeons. The NICE guidelines recommend that if the ambient temperature is too uncomfortable for the operating surgeons, cooling equipment may be additionally considered for them. • Wherever possible, the patient’s body should be well covered and the drapes uncovered only at the time of the surgical preparation. This ensures that heat is conserved and radiation and conductive heat losses are minimized. • All intravenous fluid bottles/blood products/other irrigating fluids should be warmed to 37°C before use. • In all surgeries where the duration of anesthesia is likely to be more than half an hour, active forced-air warmers should be used. In patients with high risk of IPH, warmers should be employed even when the surgical duration is less.

Postoperative Phase Postoperatively up to 24 hours after entering the recovery area, monitoring of all postoperative patients must include temperature monitoring commencing from the time the patient enters the recovery room followed by measurements at 15-minute intervals. Prompt corrective measures must be employed if the patient’s temperature falls below 36.0°C, including the use of blankets, forced air warmers, and warm IV fluids. Patients may be transferred to the ward only when body temperatures reach more than 36°C.

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METHODS OF WARMING Some of the methods currently being used in the management of hypo­ thermia include the following:

Active Warming Mechanisms • Forced-air blankets: These are one of the most effective and commonly used means of warming patients and work on the principles of convection and radiation. They are convenient to use and ideal in the preoperative and intraoperative periods to prevent IPH. The patient is attached to a portable heater which blows warm air through a flexible hose into a receptacle, usually a two-layer blanket, which is spread over the patient’s body. The forced air creates a warm air-filled layer over the body and heat transfer results from the movement of warm air across the surface of the patient’s skin. While the benefit of using forced air warmers for patients under GA has been well established,40 it has been shown that even patients undergoing surgery under neuraxial block benefit well from warming with forced air warmers. A recent systematic review of 1,587 case records included in randomized controlled trials studying the efficacy of warming devices (active vs passive) in patients undergoing surgery under neuraxial block indicated that the former is more efficient in preventing perioperative hypothermia.41 • Electric blanket • Water mattress • Radiant heating • Warmed blankets • Heating gel pad • Humidification and warming of inspired gases: Cold and dry anesthetic gases may potentially cause heat loss in patients receiving general anesthesia. However, as recent studies indicate, this may not be as significant as earlier believed. It is found that very less heat is actually lost via respiration and airway heating/humidification does not increase the core body temperature significantly.42 Hence, heated circuits are not used routinely in contemporary clinical practice. • Warm IV fluids: It has been well recognized that cold intravenous and irrigating fluids significantly reduce the core body temperature. Many fluid warming methods have been studied and employed for the same including, use of water baths, counter-current heat exchange, use of microwave radiations to heat fluids, and conductive warming of fluids. Warm fluids, especially when used in conjunction with forced-air warming devices, aid in the maintenance of normothermia. A large Cochrane database review of 24 studies (1,250 participants) comparing different methods of warming IV fluids reported that patients receiving warmed IV fluids (41°C) had a warmer core body temperature (at

Intraoperative Thermoregulation  199

least 0.5°C more) perioperatively than their counterparts who received IV fluids at room temperature (37°C). The former patients also had a reduced incidence of shivering postoperatively.43 • Unclear evidence: (a) Role of pharmacologic vasoconstriction with use of ketamine, atropine, phenylephrine, and (b) use of IV nutrients to counteract hypothermia. More research is needed in these areas.

Thermal Insulation Mechanisms • Reflective blanket • Reflective clothing. The use of warming devices is not without risk, however, especially when they are used without proper precautions. The closed claims project database of the ASA,44 found that burns and infections topped the list of reported complications, and this was particularly more in patients undergoing long surgeries. The combination of heat and pressure applied by the warming devices, especially over bony prominences resulted in the majority of these injuries. By 2004, the total claims in the same database had raised to 6,449 of which, 145 were burned injuries, with the majority of these caused by heated material followed by air warming devices.45 There have been some concerns that forced-air warmers could potentially increase the risk of infections by disrupting the laminar airflow in the operation theater, by harboring microorganisms on their surfaces, and in instances when warming blankets have been reused.46 However, most of these can be minimized by the correct and proper use of these devices.47 Despite all the evidence regarding the benefits of preventing intraoperative hypothermia, in the real world scenario, ideal temperature targets are hard to achieve and remains a challenge for most perioperative physicians. The results of a 6-month intervention among 3,228 patients to prevent perioperative hypothermia in clinical practice revealed it is difficult to abolish intraoperative hypothermia completely. Even with prewarming and continuous intraoperative warming, hypothermia occurred in close to 32% patients during the intraoperative period and close to 19% postoperatively. The patients who received prewarming prior to surgery, however, fared significantly better than patients who only received intraoperative warming, with the latter being at a 1.8 times greater risk for hypothermia than the former.48

CONCLUSION Despite clear and well-researched data regarding the consequences, both in terms of poor patient outcomes as well as increased costs associated with IPH, it continues to be an under-recognized and neglected problem in most operating rooms. It is to be understood that all forms of anesthesia, including, general, regional or field block can contribute to hypothermia.

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Unless well-planned, concrete and proactive measures are implemented, the risk of developing IPH and its attendant complications are high, especially in vulnerable patients at the extremes of age and patients with higher ASA risk classifications. All perioperative healthcare workers, especially anesthesiologists, surgeons, perioperative and postoperative nurses, and critical care nurses, need to have a thorough understanding of the need for monitoring for IPH, the risk factors contributing to increased patient vulnerability, management of some of the adverse outcomes following IPH and the ways to prevent and treat this all too common intraoperative complication. All personnel must work toward promoting normothermia, not only in the intraoperative period but more importantly as a continuous goal during the entire perioperative period. This is key to increasing patient safety, patient satisfaction, and improving overall patient outcomes.

KEY POINTS • Inadvertent perioperative hypothermia continues to remain an underrecognized complication in most operating rooms. • Both general and regional anesthesia may cause IPH. • Prevention is key to management and begins with warming in the preoperative phase itself. • Effective maintenance of normothermia in the perioperative period not only reduces the risk of major complications like increased bleeding, cardiac complications, and shivering but also significantly brings down the costs of hospitalization and improves patient satisfaction. • Data from India is lacking in this regard. Young researchers are encouraged to explore lacunae in this area, especially innovation of cost-effective warming devices in the operating room for use in developing countries.

REFERENCES 1. Bindu B, Bindra A, Rath G. Temperature management under general anesthesia: compulsion or option. J Anaesthesiol Clin Pharmacol. 2017;33:306-16. 2. İnal MA, Ural SG, Çakmak HŞ, et al. Approach to perioperative hypothermia by anaesthesiology and reanimation specialist in Turkey: a survey investigation. Turk J Anaesthesiol Reanim. 2017;45:139-45. 3. Torossian A, TEMMP (Thermoregulation in Europe Monitoring and Managing Patient Temperature) Study Group. Survey on intraoperative temperature management in Europe. Eur J Anesthesia. 2007;24:668-75. 4. Satinoff E. Neural organization and evolution of thermal regulation in mammals: several hierarchically arranged integrating systems may have evolved to achieve precise thermoregulation. Science. 1978;201:16-22. 5. Sessler DI. Temperature regulation and monitoring. In: Miller RD (Ed). Miller’s Anesthesia, 8th edition. San Diego: Churchill Livingstone; 2015. pp. 1623-46. 6. Horosz B, Malec-Milewska M. Inadvertent intraoperative hypothermia. Anaesthesiol Intensive Ther. 2013;45:38-43. 7. Lenhardt R. The effect of anesthesia on body temperature control. Front Biosci (Schol Ed). 2010;2:1145-54. 8. McSwain JR, Yared M, Doty JW, et al. Perioperative hypothermia: causes, consequences and treatment. World J Anesthesiol. 2015;4:58-65.

Intraoperative Thermoregulation  201 9. Sessler DI. Perioperative thermoregulation and heat balance. Lancet. 2016;387:2655-64. 10. Matsukawa T, Kurz A, Sessler DI, et al. Propofol linearly reduces the vaso­ constriction and shivering thresholds. Anaesthesiology. 1995;82:1169-80. 11. Kurz A, Go JC, Sessler DI, et al. Alfentanil slightly increases the sweating threshold and markedly reduces the vasoconstriction and shivering thresholds. Anaesthesiology. 1995;83:293-9. 12. Talke P, Tayefeh F, Sessler DI, et al. Dexmedetomidine does not alter the sweating threshold but comparably and linearly reduces the vasoconstriction and shivering thresholds. Anesthesiology. 1997;87:835-41. 13. Xiong J, Kurz A, Sessler DI, et al. Isoflurane produces marked and nonlinear decreases in the vasoconstriction and shivering thresholds. Anaesthesiology. 1996;85:240-5. 14. Annadata R, Sessler DI, Tayefeh F, et al. Desflurane slightly increases the sweating threshold, but produces marked, nonlinear decreases in the vasoconstriction and sweating thresholds. Anesthesiology. 1995;83:1205-11. 15. Plattner O, Semsroth M, Sessler DI, et al. Lack of nonshivering thermogenesis in infants anesthetized with fentanyl and propofol. Anesthesiology. 1997;86:772-7. 16. Bissonnette B, Sessler DI. The thermoregulatory threshold in infants and children anesthetized with isoflurane and caudal bupivacaine. Anesthesiology. 1990;73:1114-8. 17. Bissonnette B, Sessler DI. Thermoregulatory thresholds for vasoconstriction in pediatric patients anesthetized with halothane or halothane and caudal bupivacaine. Anesthesiology. 1992;76:387-92. 18. Sessler DI, McGuire J, Moayeri A, et al. Isoflurane-induced vasodilation minimally increases cutaneous heat loss. Anesthesiology. 1991;74:226-32. 19. Matsukawa T, Sessler DI, Sessler AM, et al. Heat flow and distribution during induction of general anesthesia. Anesthesiology. 1995;82:662-73. 20. Glosten B, Sessler DI, Faure EA, et al. Central temperature changes are poorly perceived during epidural anesthesia. Anesthesiology. 1992;80:268-77. 21. Leslie K, Sessler DI. Reduction in the shivering threshold is proportional to spinal block height. Anesthesiology. 1996;84:1327-31. 22. Burns SM, Piotrowski K, Caraffa G, et al. Incidence of postoperative hypothermia and the relationship to clinical variables. J Perianesth Nurs. 2010;25:286-9. 23. Belayneh T, Gebeyehu A, Abdissa Z. Post-operative hypothermia in surgical patients at University of Gondar Hospital, Ethiopia. J Anesth Clin Res. 2014;5:461-4. 24. Yi J, Lei Y, Xu S, et al. Intraoperative hypothermia and its clinical outcomes in patients undergoing general anesthesia: national study in China. PLoS One. 2017;12:e0177221. 25. Polderman KH. Hypothermia and coagulation. Crit Care. 2012;16:A20. 26. Michelson AD, MacGregor H, Barnard MR, et al. Reversible inhibition of human platelet activation by hypothermia in vivo and in vitro. Thromb Haemost. 1994;71:633‑40. 27. Rajagopalan S, Mascha E, Na J, et al. The effects of mild perioperative hypothermia on blood loss and transfusion requirement. Anesthesiology. 2008;108:71‑7. 28. van Oss CJ, Absolom DR, Moore LL, et al. Effect of temperature on the chemotaxis, phagocytic engulfment, digestion and O2 consumption of human polymorphonuclear leukocytes. J Reticuloendothel Soc. 1980;27:561‑5. 29. Geurts M, Macleod MR, Kollmar R, et al. Therapeutic hypothermia and the risk of infection: a systematic review and meta-analysis. Critical Care Med. 2014;42:231-42.

202  Yearbook of Anesthesiology-9 30. Frank SM, Higgins MS, Breslow MJ, et al. The catecholamine, cortisol, and hemodynamic responses to mild perioperative hypothermia. A randomized clinical trial. Anesthesiology. 1995;82:83-93. 31. Frank SM, Fleisher LA, Breslow MJ, et al. Perioperative maintenance of normothermia reduces the incidence of morbid cardiac events. A randomized clinical trial. JAMA. 1997;277:1127-34. 32. Gurajala I, Ramachandran G, Iyengar R, et al. The preoperative and intra­ operative risk factors for early postoperative mechanical ventilation after scoliosis surgery: a retrospective study. Indian J Anaesth. 2013;57:14-8. 33. Morozumi K, Mitsuzuka K, Takai Y, et al. Intraoperative hypothermia is a significant prognostic predictor of radical cystectomy especially for stage II muscle-invasive bladder cancer. Medicine (Baltimore). 2019;98:e13962. 34. American Society of PeriAnesthesia Nurses (ASPAN). Clinical guideline for the prevention of unplanned perioperative hypothermia. J Perianesth Nurs. 2001;16:305-14. 35. Mahoney CB, Odom J. Maintaining intraoperative normothermia: a metaanalysis of outcomes with costs. AANA J. 1999;67:155-63. 36. Bush HL Jr, Hydo LJ, Fischer E, et al. Hypothermia during elective abdominal aortic aneurysm repair: the high price of avoidable morbidity. J Vasc Surg. 1995;21:392-402. 37. Kurz A, Sessler DI, Lenhardt R. Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. New Engl J Med. 1996;334:1209-15. 38. Grote R, Wetz AJ, Bräuer A, et al. Prewarming according to the AWMF S3 guidelines on preventing inadvertent perioperative hypothermia 2014: retrospective analysis of 7786 patients. Anaesthesist. 2018;67:27-33. 39. National Institute for Health and Clinical Evidence. (2019). Clinical practice guideline: the management of inadvertent perioperative hypothermia in adults. [online] http://www.nice.org.uk/nicemedia/pdf/CG65Guidance.pdf [Last accessed August, 2019]. 40. Ouellette RG. Comparison of four intraoperative warming devices. AANA J. 1993;61:394-6. 41. Shaw CA, Steelman VM, DeBerg J, et al. Effectiveness of active and passive warming for the prevention of inadvertent hypothermia in patients receiving neuraxial anesthesia: a systematic review and meta-analysis of randomized controlled trials. J Clin Anesth. 2017;38:93-104. 42. Hynson JM, Sessler DI. Intraoperative warming therapies: a comparison of three devices. J Clin Anesth. 1992;4:194-9. 43. Campbell G, Alderson P, Smith AF, et al. Warming of intravenous and irrigation fluids for preventing inadvertent perioperative hypothermia. Cochrane Database Syst Rev. 2015;13:CD009891. 44. Cheney FW, Posner KL, Caplan RA, et al. Burns from warming devices in anesthesia: a closed claims analysis. Anesthesiology. 1994;80:810. 45. Kressin KA. Burn injury in the operating room: a closed claims analysis. ASA Newsl. 2004;68:9-11. 46. Sigg DC, Houlton AJ, Iaizzo PA. The potential for increased risk of infection due to the reuse of convective air-warming/cooling coverlets. Acta Anaesthesiol Scand. 1999;43:173-6. 47. John M, Ford J, Harper M. Perioperative warming devices: performance and clinical application. Anaesthesia. 2014;69:623-38. 48. Menzel M, Grote R, Leuchtmann D, et al. Implementation of a thermal management concept to prevent perioperative hypothermia: results of a 6 month period in clinical practice. Anaesthesist. 2016;65:423-9.

Platelet-rich Plasma for Management of Chronic Pain...  203

CHAPTER

14

Platelet-rich Plasma for Management of Chronic Pain and Degenerative Conditions: A Critical Review of Evidence Babita Ghai, Nitika Goel

INTRODUCTION The administration of platelet-rich plasma (PRP) is increasing in recent past in the field of chronic pain management, orthopedics, and sports medicine for its alleged regenerative ability.1,2 Several studies have found the beneficial effects in clinical outcome after injecting PRP, however, many others report little or no clinical benefits. PRP has been studied for various degenerative diseases such as osteoarthritis (OA) knee, intervertebral disk (IVD) degeneration and multitudes of ligamental injuries. In OA knee, a high number of studies demonstrate better outcomes with PRP injections while others report to the contrary. Its use to treat ligament, tendon, and skeletal muscle injuries have also shown conflicting results. Current evidence of PRP effectiveness in the management of skeletal tissue injury remains inconclusive. For chronic pain management, similar contrary results were reported ranging from no or little pain relief to reduction in pain.3 Numerous variables have been found which increase or decrease the analgesic efficacy of PRP. Therefore, in none of the conditions, strong evidence in improvement of symptoms has been found. This is most probably due to lack of standardization of PRP preparation, underpowered studies, dearth of high-quality randomized trials, inclusion of too many variables, and poor patient stratification.3

WHAT IS PLATELET-RICH PLASMA? Platelet-rich plasma is centrifuged autologous blood concentrate containing 3–6 times higher than normal concentration of platelets.4 To prepare PRP, the patient’s blood is drawn and then this autologous blood is centrifuged. Based on relative density, various components of blood separate allowing separation of platelet-poor plasma from other components.5 Further centrifugation leads to separation of buffy coat layer containing PRP and or leukocytes. There are abundant devices being used for the preparation

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of PRP and PRP composition differs largely depending on the device being used. Different devices yield platelet concentrates ranging from 1.99 to 9.3folds above baseline.3 There are various formulations of PRP available which differ in terms of platelet concentration, cell content, method of activation, and many other features. This heterogenicity in preparation is considered as one of the major limiting factors for its clinical use and may lead to its reduced applications.3 Also, the optimal platelet concentration inducing benefit is still unknown.

TYPES OF PLATELET-RICH PLASMA Various classifications of PRP are described in literature due to lack of standardization of PRP preparation. PRP can either be in activated form or nonactivated form and can be either leukocyte-poor or leukocyte-rich. Mishra et al. classified PRP into four types depending on leukocyte content and state of activation.6 For activation form, PRP is prepared with calcium chloride with or without thrombin.6-8 The activation results in the release of granules from platelets and hence are proposed to be in abundance upon injection.8 While nonactivated form is proposed to get activated with intrinsic collagen and thromboplastin within the connective tissue.8 Another type of PRP classification is as leukocyte-poor and leukocyterich. The role of leukocyte in PRP is not very clear. It is projected to play a role in inhibiting bacterial growth and promote wound healing. However, it is also proposed to exaggerate inflammatory response by stimulating inflammatory cytokines and may stimulate the release of reactive oxygen species.8 Platelet-rich plasma has also been classified extensively by various other authors.9,10

PROPOSED MECHANISM OF PLATELET-RICH PLASMA? Though the exact mechanism as of how PRP works is still unknown, there are various postulated mechanisms. It is hypothesized that platelet concentrate increases the secretion of growth factors, hence theoretically improving the healing process.4,5,11 Another proposed mechanism is that this platelet concentrate may promote mitogenesis of capable healing cells.7 Few of the growth factors proposed to be present in PRP are platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), epithelial growth factor (EGF), and transforming growth factor-beta (RGF-b). Additionally, it is postulated that PRP may promote bone formation containing adhesion molecules such as fibrin, fibronectin, and vitronectin.4

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DOES PROPOSED MECHANISM OF PLATELET-RICH PLASMA WORK IN VIVO? In vitro studies have reported an increased amount of growth factors in PRP.12 However, this finding has not been replicated in vivo studies in terms of better patient outcome and improvement in healing.13 In clinical practice, the role of PRP to enable the growth factors and proteins to promote healing and regeneration is still in a very preliminary state with a very low scientific level of evidence.14,15

CLINICAL EVIDENCE OF PLATELET-RICH PLASMA IN OSTEOARTHRITIS KNEE Osteoarthritis knee is reported with an incidence of 10–15% in patients aged 60 years and above and is considered among the most common degenerative disorders in elderly.16-18 There is a gradual progression of disease due to limited regeneration capability of articular cartilage.16 Treatment of OA knee includes nonsurgical and surgical modalities. Although the definitive treatment is surgical, nonsurgical treatment has gained popularity in the initial stages of the disease and includes administration of nonsteroidal antiinflammatory drugs (NSAIDs), intraarticular injection of steroids, genicular nerve blocks, and more recently, injection of PRP.18 Role of PRP is most extensively studied in OA knee. Extensive data is available for the use of PRP for OA knee, but the present literature discloses contradictory evidence. A recent systematic review has reported no longterm benefit in patient primary and secondary outcomes in patients with OA knee or after total knee replacement (TKR).19 Although PRP demonstrated effectiveness, it was for short- to medium-term pain control only. In another meta-analysis comparing intra-articular hyaluronic acid (IAHA) versus intraarticular PRP (IAPRP), the author concluded that IAPRP was no way superior to IAHA.20 In another systematic review and meta-analysis including five RCT and five nonrandomized trials, authors demonstrated that PRP reduced pain score with functional improvement at 6-month follow-up.21 Similar findings at 12 months were reported in comparison to HA alone, though significant effects were not found at 6 months.22 Shen et al., reported significant improvement in WOMAC scores at 3 and 6-month follow-up.18 However, it is pertinent to note that both these meta-analysis reported significant diversity in the outcome.18,22

Limitations for Platelet-rich Plasma Studies for Osteoarthritis Knee Many authors while examining the data in systematic reviews and metaanalysis have pointed out large heterogenicity in PRP preparation and in

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methodology. The major variable, which is accounted for this heterogeneity, is PRP composition due to variable PRP processing devices and technique. This heterogenicity in preparation is considered as one of the major limiting factors for its clinical use and may lead to its reduced applications.3 Also, the optimal platelet concentration inducing benefit is still unknown.23 Most studies reporting positive outcome usually report minimizing symptoms, that is, decline in pain without much benefit to disability and usually do not have long-term follow-up. Studies with follow-up to 12 months report decline in pain relief with passage of time. Other limitations are underpowered studies, the dearth of high-quality randomized trials, and the inclusion of too many variables and poor patient stratification.

Summary of Evidence about the Role of Platelet-rich Plasma in Osteoarthritis Knee There is a low level of evidence to support the application of PRP in OA knee for improvement in patient-reported outcome. Evidence reveals that PRP probably exhibits better outcome in younger patients with less severe grading of OA knee. More high-quality randomized controlled research needs to be done on the effectiveness of PRP with each KL grade of OA. With current evidence, it is obvious that PRP is not as efficacious for pain control and functional improvement in advance OA knee and cartilage degeneration.23 Hence, when looking at the evidence, current guidelines from National Institute for Health Care Excellence (NICE), UK and American Academy of Orthopaedic Surgeons (AAOS) suggest that the evidence is inconclusive for the use of PRP for OA knee.24

Recommendations for Further Research for the Role of Platelet-rich Plasma in Osteoarthritis Knee High-quality future studies in need to be conducted with adequate power including optimization and standardization of PRP preparation in each grade of OA knee with long-term follow-up. Studies delineating and proving in vivo mechanism of PRP are also needed. Moreover, optimization of dosage, volume, frequency, and timing need to be evaluated.25 Before widely implementing PRP for management of OA knee, all these concerns should be attended to.14,26,27 The economical aspect and cost-effectiveness also needs to be addressed.28

CLINICAL EVIDENCE OF PLATELET-RICH PLASMA IN CHRONIC LOW BACK PAIN Low back pain (LBP) is one of the most common health problems, affecting 80–85% of population over their entire lifetime. The point prevalence of

Platelet-rich Plasma for Management of Chronic Pain...  207

activity limiting LBP has been estimated to be around 12% while the 1-month prevalence is 23%.29 Intervertebral disk degeneration is the most common pathology in LBP. Disk degeneration involves circumferential tears in the annulus fibrosus that progresses to a radial tear leading to disk herniation, loss of disk height, and resorption.30 Because of decreased blood supply of the IVD, tissues have very little capacity for self-repair. The therapeutic effect of platelets is proposed to occur by approximating the torn edges of degenerated disk, leading to healing of cells.30 Many in vitro studies have shown PRP to have potential in stimulating cell proliferation and also increase the metabolic activity of IVD cells.31,32 Akeda et al. reported PRP having stronger effects in the annulus fibrosus region than in the nucleus pulposus in the alginate cultured porcine IVD cells.31 Few in vivo studies also report similar results as in vitro, showing the regenerative potential of PRP on IVD.32,33 However, owing to negligible standardization in preparation and activation of PRP, variation in results is expected. In their first preclinical experimental study, Nagae et al. reported the effectiveness of PRP-impregnated gelatin hydrogel microspheres (PRPGHMs) in minimizing the IVD degeneration. They demonstrated minimal efficacy of PRP injections without microspheres. They suggested PRP-GHMs that immobilized growth factors as a better therapeutic option compared to PRP alone.33

Clinical Studies of Platelet-rich Plasma for Low Back Pain Patients Intradiskal Injection Most of the evidence of PRP for intradiskal injection includes small observational studies and case series34-36 with only one high-quality randomized controlled trial.37 In their prospective observational study on 14 patients, Akeda et al. reported a decrease in mean pain scores in 70% patients over 1-month follow-up.34 In a case series of six patients, Navani et al. reported decreased pain scores and improvement in mental and physical health at 6 months with an intradiskal injection of PRP.35 In another observational trial of 22 patients, Levi et al. documented a decrease of 50% in visual analog scale (VAS) and at least 30% decrease in Oswestry Disability Index at 6-month follow-up.36 In the first randomized double-blind controlled trial of intradiskal PRP therapy for discogenic LBP, performed by Tuakli-Wosornu et al., 58 participants were grouped into treatment or control groups in 2:1 ratio.37 The study group received intradiskal PRP injection while the control group received a contrast injection after provocative discography. The study group reported statistically significant improvements in numerical rating scale (NRS) best pain, Functional Rating Index (FRI), and patient satisfaction

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[North American Spine Society (NASS) outcome questionnaire], compared to the control group at the 8-week follow-up. Moreover, the effect of PRP in the study group was sustained for 2 years. The main limitation of this study was the limited follow-up of the control group of just 8 weeks.37

Nonintradiskal Platelet-rich Plasma Injections Other than intradiskal injections, facet joint and sacroiliac joint (SIJ) PRP injections have also been used in LBP patients. Again, most of the literature is of small case series, retrospective data and underpowered studies with dearth of good quality randomized trial. In a case series reported by Aufiero et al.,38 improvement in symptoms was seen by more than 50% in five patients following PRP facet joint injection. In a retrospective observational study performed by Kirchner and Anitua et al.39,40 in 86 patients, intradiskal and intra-articular facet infiltrations of PRP were performed. VAS scores declined significantly in 90% patients. Wu et al. in an observational uncontrolled study performed a lumbar facet joint PRP injection in 19 patients only. On 3-month follow-up, VAS, Roland-Morris Disability Questionnaire (RDQ), and Oswestry Disability Index (ODI) scores significantly improved.41 PRP when compared to corticosteroid injection in 46 patients randomized to two groups, showed significant analgesic effects at all-time points during PRP injections, scores in corticosteroid group reversed and worsened at the 2-month time point after injection, whereas those of the PRP group steadily improved.42 Hence, from the above data, it is clear that the high-quality randomized trial of facet joint PRP injection is lacking. Hussein and Hussein43 studied the effect of intramuscular injection of PRP on 108 LBP patients presenting with atrophied lumbar multifidus muscle and monosegmental degenerated IVD. Patients were treated with weekly injections for 6 weeks and thereafter followed-up for 24 months. Significant improvement in NRS and ODI scores were reported by them at 12 months. Moreover, the improvement was sustained till the 24-month follow-up. Platelet-rich plasma was injected in a circumferential manner subfascially into the lateral masses, facet joints, and the other posterior spine areas. Significant improvement of VAS was noted by 77%.44 PRP suspended in stromal vascular fraction (SVF) has been injected intradiskally in 15 patients. All patients reported significant improvements in VAS, present pain intensity (PPI), and short-form McGill Pain Questionnaire (SF-MPQ), and short-form 12-physical component summary.45

Sacroiliac Joint Injection Injection of PRP into SIJ have been reported to decrease the intensity of LBP due to the pathology of these joints.46,47 Singla et al. compared steroid SIJ

Platelet-rich Plasma for Management of Chronic Pain...  209

injection and PRP SIJ injection for LBP and found decrease in pain intensity by 90% in PRP group as compared to steroid group (25%).47

Summary of Evidence of Platelet-rich Plasma for Chronic Low Back Pain Despite preclinical encouraging results and increasing clinical interest, most of the evidence for PRP for management of chronic LBP remain inconclusive due to small sample size, nonrandomized uncontrolled trials and heterogenicity of studies. Based on the available literature, the American Society of Interventional Pain Physicians (ASIPP) Guidelines synthesized evidence for various LBP pathologies. The level of evidence for lumbar disk injections and SIJ injections of PRP has been level III as compared to lumbar facet joint injections of PRP which is level IV.48 Currently, more high-quality randomized controlled trial is required with proper standardization of PRP preparation and activation techniques before embarking on PRP as definitive therapy for LBP.

CURRENT USE OF PLATELET-RICH PLASMA IN MUSCULOSKELETAL TISSUES Though in the United States of America, Food and Drug Administration (FDA) approved the use of PRP with ligament grafting and the approximation of bony matrices during reconstructive procedures, its use across many studies to treat ligament, tendon, and skeletal muscle has shown conflicting results. The current evidence for the effectiveness of PRP in treating sports injuries is inconclusive, uncertain, and inconsistent.49 Literature reports numerous studies documenting ineffectiveness of PRP in tendon injuries and muscle strain in terms of activity scores and pain levels. It is concluded across various studies that PRP is no more effective than a placebo injection or intensive rehabilitation.50-54 A very recent cohort study by Everhart et al. reported that PRP does not decrease the risk of meniscal repair failure in the setting of anterior cruciate ligament (ACL) that in the setting of concurrent ACL reconstruction.55 Another very recent randomized controlled trial (RCT) by Schwitzguébel et al. concluded that PRP as compared to saline injection did not improve clinical scores or tendon healing when injected within interstitial supraspinatus tear but was associated with more adverse events.56 However, in a systemic review and meta-analysis, PRP has been known to reduce pain in rotator cuff injuries and lateral epicondylitis.57 Between all these conflicting reports, no concrete evidence exists regarding the effectiveness of PRP in various sports injuries, again mainly due to indwelling heterogeneity among them.

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ADVERSE EVENTS WITH PLATELET-RICH PLASMA Many authors highlighted the safety of PRP due to its autogenic nature; it is not devoid of side effects/adverse event. Clear safety of PRP is difficult to report, as most of the studies are not adequately powered to detect the complication or adverse vent of PRP. A very recent case report of allergic reaction to PRP in a 14-year-old boy has been reported when the PRP was injected for treatment of bone cyst of distal tibia.58 An exuberant inflammatory reaction has also been reported after one injection of PRP used to treat jumpers knee in a 35-year-old male.59 Reports of dermatitis, infection in existing ulcer, thrombophlebitis has been reported60 besides increased thrombin time and activated thromboplastin time.61 These reports highlight that the safety of PRP is not clearly sure. The pure autologous tissue may be safe but its preparation can considerably reduce the safety.

CONCLUSION Platelet-rich plasma is now being used with growing interest in the treatment of almost all degenerative and tendinous injuries and for chronic pain management. Though few studies have proved the effectiveness of PRP in the treatment of LBP and OA knee, its superiority over other treatment modalities in various conditions, still needs to be established. Furthermore, defining details of pathologic condition, standardized PRP preparation, ideal PRP concentration, frequency, and timing of injection need to be investigated before its widespread use. The use of PRP based on current evidence across different skeletomuscular injuries has been critiqued for being inconsistent and uncertain.48 The studies showed marked variations in number of PRP injections (single, multiple), initial blood volume withdrawn for PRP isolation, volume of PRP injected (1–5 mL) and variable follow-up periods ranging from 8 weeks to 18 months, thus leading to a lot of heterogeneity in results. To conclude, there are many questions open with regard to the basic in vitro and in vivo biology of PRP, advantages and disadvantages and its most applicable indication especially with respect to other management approaches. Due to huge variability, the comparative analyses of current evidence does not provide sufficient conclusion for PRP as an analgesic. Hence, more high-quality trials are required to offer clear indications for the use of PRP.

KEY POINTS • Platelet-rich plasma use has greatly increased in recent past, for the management of chronic pain and degenerative musculoskeletal diseases.

Platelet-rich Plasma for Management of Chronic Pain...  211 • Despite encouraging basic, experimental and preclinical results, literature reports conflicting and variable results. • The heterogenicity in preparation of PRP is considered as one of the major limiting factors for its clinical use and may lead to its reduced applications. • Platelet-rich plasma is most widely studied for the management of osteoarthritis knee and current guidelines advocate inconclusive evidence of PRP for OA knee. • For chronic low back pain, level of evidence for lumbar disk injections and sacroiliac joint injections of PRP has been level III as compared to lumbar facet joint injections of PRP which is level IV. • For skeletomuscular injuries, current evidence across different studies is not proven. • Despite FDA approving its use with ligament grafting and the approximation of bony matrices during reconstructive procedures, the use of PRP for different injuries has been criticized for being uncertain and inconsistent. • The safety of PRP is not proven. The pure autologous tissue may be safe but its preparation can considerably reduce the safety. • Due to huge heterogenicity of studies, small sample size and nonrandomized uncontrolled trials, the current evidence does not provide sufficient conclusion for PRP as an analgesic. Hence, more high-quality trials are required to offer clear indications for the use of PRP.

REFERENCES 1. Alsousou J, Ali A, Willett K, et al. The role of platelet-rich plasma in tissue regeneration. Platelets. 2013;24:173-82. 2. Xie X, Zhang C, Tuan RS. Biology of platelet-rich plasma and its clinical application in cartilage repair. Arthritis Res Ther. 2014;16:204. 3. Kuffler DP. Variables affecting the potential efficacy of PRP in providing chronic pain relief. J Pain Res. 2018;12:109-16. 4. Dhillon MS, Behera P, Patel S, et al. Orthobiologics and platelet rich plasma. Indian J Orthop. 2014;48:1-9. 5. Marx RE. Platelet-rich plasma (PRP): what is PRP and what is not PRP? Implant Dent. 2001;10:225-8. 6. Mishra A, Harmon K, Woodall J, et al. Sports medicine applications of platelet rich plasma. Curr Pharm Biotechnol. 2012;13:1185-95. 7. Eppley BL, Pietrzak WS, Blanton M. Platelet-rich plasma: a review of biology and applications in plastic surgery. Plast Reconstr Surg. 2006;118:147e-59e. 8. Arnoczky SP, Sheibani-Rad S, Shebani-Rad S. The basic science of platelet-rich plasma (PRP): what clinicians need to know. Sports Med Arthrosc. 2013;21: 80-185. 9. Ehrenfest DM, Andia I, Zumstein MA, et al. Classification of platelet concentrates (platelet-rich plasma-PRP, platelet-rich fibrin-PRF) for topical and infiltrative use in orthopedic and sports medicine: current consensus, clinical implications and perspectives. Muscles Ligaments Tendons J. 2014;4:3-9. 10. Lana JF, Weglein A, Sampson SE, et al. Randomized controlled trial comparing hyaluronic acid, platelet-rich plasma and the combination of both in the treatment of mild and moderate osteoarthritis of the knee. J Stem Cells Regen Med. 2016;12:69-78.

212  Yearbook of Anesthesiology-9 11. Marx RE. Platelet-rich plasma: evidence to support its use. J Oral Maxillofac Surg. 2004;62:489-96. 12. Sundman EA, Cole BJ, Fortier LA. Growth factor and catabolic cytokine concentrations are influenced by the cellular composition of platelet-rich plasma. Am J Sports Med. 2011;39:2135-40. 13. Mazzocca AD, McCarthy MBR, Chowaniec DM, et al. The positive effects of different platelet-rich plasma methods on human muscle, bone, and tendon cells. Am J Sports Med. 2012;40:1742-9. 14. Marx RG, Stump TJ, Jones EC, et al. Development and evaluation of an activity rating scale for disorders of the knee. Am J Sports Med. 2001;29:213-8. 15. O’Connell B, Wragg NM, Wilson SL. The use of PRP injections in the management of knee osteoarthritis. Cell Tissue Res. 2019;376:143. 16. Zhu Y, Yuan M, Meng HY, et al. Basic science and clinical application of plateletrich plasma for cartilage defects and osteoarthritis: a review. Osteoarthritis Cartilage. 2013;21:1627-37. 17. Mlynarek RA, Kuhn AW, Bedi A. Platelet-rich plasma (PRP) in orthopedic sports medicine. Am J Orthop (Belle Mead NJ). 2016;45:290-326. 18. Shen L, Yuan T, Chen S, et al. The temporal effect of platelet-rich plasma on pain and physical function in the treatment of knee osteoarthritis: systematic review and meta-analysis of randomized controlled trials. J Orthop Surg Res. 2017;12:16. 19. Muchedzi TA, Roberts SB. A systematic review of the effects of platelet rich plasma on outcomes for patients with knee osteoarthritis and following total knee arthroplasty. Surgeon. 2018;16:250-8. 20. Zhang HF, Wang CG, Li H, et al. Intra-articular platelet-rich plasma versus hyaluronic acid in the treatment of knee osteoarthritis: a meta-analysis. Drug Des Devel Ther. 2018;12:445-53. 21. Laudy AB, Bakker EW, Rekers M, et al. Efficacy of platelet-rich plasma injections in osteoarthritis of the knee: a systematic review and meta-analysis. Br J Sports Med. 2015;49:657-72. 22. Dai WL, Zhou AG, Zhang H, et al. Efficacy of platelet-rich plasma in the treatment of knee osteoarthritis: a meta-analysis of randomized controlled trials. Arthroscopy. 2017;33:659-70. 23. Southworth TM, Naveen NB, Tauro TM, et al. The use of platelet-rich plasma in symptomatic knee osteoarthritis. J Knee Surg. 2019;32:37-45. 24. Hussain N, Johal H, Bhandari M. An evidence-based evaluation on the use of platelet rich plasma in orthopaedics: a review of the literature. SICOT J.2017;3:57. 25. Engebretsen L, Steffen K, Alsousou J, et al. IOC consensus paper on the use of platelet-rich plasma in sports medicine. Br J Sports Med. 2010;44:1072-81. 26. Rodriguez-Merchan EC. Intraarticular injections of platelet-rich plasma (PRP) in the management of knee osteoarthritis. Arch Bone Jt Surg. 2013;1:5-8. 27. Lai LP, Stitik TP, Foye PM, et al. Use of platelet-rich plasma in intra-articular knee injections for osteoarthritis: a systematic review. PMR. 2015;7:637-48. 28. Bennell KL, Hunter DJ, Paterson KL. Platelet-rich plasma for the management of hip and knee osteoarthritis. Curr Rheumatol Rep. 2017;19:24. 29. Hoy D, Bain C, Williams G, et al. A systematic review of the global prevalence of low back pain. Arthritis Rheum. 2012;64:2028-37. 30. Bodor M, Toy A, Aufiero D. Disc regeneration with platelets and growth factors. In: Duarte Lana JFS, Andrade Santana MH, Belangero WD, et al. (Eds). Plateletrich Plasma: Regenerative Medicine: Sports Medicine, Orthopaedic, and

Platelet-rich Plasma for Management of Chronic Pain...  213 Recovery of Musculoskeletal Injuries. Berlin, Heidelberg: Springer; 2014. pp. 265-79. 31. Akeda K, An HS, Okuma M, et al. Platelet-rich plasma stimulates porcine articular chondrocyte proliferation and matrix biosynthesis. Osteoarthritis Cartilage. 2006;14:1272-80. 32. Chen WH, Liu HY, Lo WC, et al. Intervertebral disc regeneration in an ex vivo culture system using mesenchymal stem cells and platelet-rich plasma. Biomaterials. 2009;30:5523-33. 33. Nagae M, Ikeda T, Mikami Y, et al. Intervertebral disc regeneration using platelet-rich plasma and biodegradable gelatin hydrogel microspheres. Tissue Eng. 2007;13:147-58. 34. Akeda K, Ohishi K, Masuda K, et al. Intradiscal injection of autologous plateletrich plasma releasate to treat discogenic low back pain: a preliminary clinical trial. Asian Spine J. 2017;11:380-9. 35. Navani A, Hames A. Platelet-rich plasma injections for lumbar discogenic pain: a preliminary assessment of structural and functional changes. Tech Reg Anesth Pain Manag. 2015;19:38-44. 36. Levi D, Horn S, Tyszko S, et al. Intradiscal platelet-rich plasma injection for chronic discogenic low back pain: preliminary results from a prospective trial. Pain Med. 2016;17:1010-22. 37. Tuakli-Wosornu YA, Terry A, Boachie-Adjei K, et al. Lumbar intradiskal platelet-rich plasma (PrP) injections: a prospective, double-blind, randomized controlled study. PMR. 2016;8:1-10. 38. Aufiero D, Vincent H, Sampson S, et al. Regenerative injection treatment in the spine: review and case series with platelet rich plasma. J Stem Cells Res Rev Rep. 2015;2:1019. 39. Kirchner F, Anitua E. Intradiscal and intra-articular facet infiltrations with plasma rich in growth factors reduce pain in patients with chronic low back pain. J Craniovertebr Junction Spine. 2016;7:250-6. 40. Kirchner F, Anitua E. Minimally invasive PRGF treatment for low back pain and degenerative disc disease. In: Anitua E, Cugat R, Sánchez M (Eds). Platelet Rich Plasma in Orthopaedics and Sports Medicine. Cham: Springer International Publishing; 2018. pp. 259-75. 41. Wu J, du Z, Lv Y, et al. A new technique for the treatment of lumbar facet joint syndrome using intra-articular injection with autologous platelet rich plasma. Pain Physician. 2016;19:617-25. 42. Wu J, Zhou J, Liu C, et al. A prospective study comparing platelet-rich plasma and local anesthetic (LA)/corticosteroid in intra-articular injection for the treatment of lumbar facet joint syndrome. Pain Pract. 2017;17:914-24. 43. Hussein M, Hussein T. Effect of autologous platelet leukocyte rich plasma injections on atrophied lumbar multifidus muscle in low back pain patients with monosegmental degenerative disc disease. Sicot J. 2016;2:12. 44. Cameron JA, Thielen KM. Autologous platelet rich plasma for neck and lower back pain secondary to spinal disc herniation: midterm results. Spine Res. 2017;03:10. 45. Comella K, Silbert R, Parlo M. Effects of the intradiscal implantation of stromal vascular fraction plus platelet rich plasma in patients with degenerative disc disease. J Transl Med. 2017;15:12. 46. Ko GD, Mindra S, Lawson GE, et al. Case series of ultrasound-guided plateletrich plasma injections for sacroiliac joint dysfunction. J Back Musculoskelet Rehabil. 2017;30:363-70.

214  Yearbook of Anesthesiology-9 47. Singla V, Batra YK, Bharti N, et al. Steroid vs. platelet-rich plasma in ultrasoundguided sacroiliac joint injection for chronic low back pain. Pain Pract. 2017;17:782-91. 48. Navani A, Manchikanti L, Albers SL, et al. Responsible, safe, and effective use of biologics in the management of low back pain: American Society of Interventional Pain Physicians (ASIPP) Guidelines. Pain Physician. 2019;22: S1-74. 49. McNamee MJ, Coveney CM, Faulkner A, et al. Ethics, evidence based sports medicine, and the use of platelet rich plasma in the English Premier League. Health Care Anal. 2018;26:344-61. 50. de Vos RJ, Weir A, van Schie HT, et al. Platelet-rich plasma injection for chronic Achilles tendinopathy: a randomized controlled trial. JAMA. 2010;303:144-9. 51. de Jonge S, de Vos RJ, Weir A, et al. One-year follow-up of platelet-rich plasma treatment in chronic Achilles tendinopathy: a double-blind randomized placebo-controlled trial. Am J Sports Med. 2011;39:1623-9. 52. Krogh TP, Fredberg U, Stengaard-Pedersen K, et al. Treatment of lateral epicondylitis with platelet-rich plasma, glucocorticoid, or saline: a randomized, double-blind, placebo-controlled trial. Am J Sports Med. 2013;41:625-35. 53. Liddle AD, Rodríguez-Merchán EC. Platelet-rich plasma in the treatment of patellar tendinopathy: a systematic review. Am J Sports Med. 2015;43:2583-90. 54. Hamid MS, Yusof A, Mohamed Ali MR. Platelet-rich plasma (PRP) for acute muscle injury: a systematic review. PLoS One. 2014;9:e90538. 55. Everhart JS, Cavendish PA, Eikenberry A, et al. Platelet-rich plasma reduces failure risk for isolated meniscal repairs but provides no benefit for meniscal repairs with anterior cruciate ligament reconstruction. Am J Sports Med. 2019;47:1789-96. 56. Schwitzguebel AJ, Kolo FC, Tirefort J, et al. Efficacy of platelet-rich plasma for the treatment of interstitial supraspinatus tears: a double-blinded, randomized controlled trial. Am J Sports Med. 2019;47:1885-92. 57. Chen X, Jones IA, Park C, et al. The efficacy of platelet-rich plasma on tendon and ligament healing: a systematic review and meta-analysis with bias assessment. Am J Sports Med. 2018;46:2020-32. 58. Latalski M, Walczyk A, Fatyga M, et al. Allergic reaction to platelet-rich plasma (PRP): case report. Medicine (Baltimore). 2019;98:e14702. 59. Kaux JF, Croisier JL, Léonard P, et al. Exuberant inflammatory reaction as a side effect of platelet-rich plasma injection in treating one case of tendinopathy. Clin J Sport Med. 2014;24:150-2. 60. Senet P, Bon FX, Benbunan M, et al. Randomized trial and local biological effect of autologous platelets used as adjuvant therapy for chronic venous leg ulcers. J Vasc Surg. 2003; 38:1342-8. 61. Driver VR, Hanft J, Fylling CP, et al. A prospective, randomized, controlled trial of autologous platelet rich plasma gel for the treatment of diabetic foot ulcers. Ostomy Wound Manage. 2006;52:68-87.

Postoperative Myocardial Injury: Causes and Management  215

CHAPTER

15

Postoperative Myocardial Injury: Causes and Management Arun Maheshwari, Elvin Daniel

INTRODUCTION Postoperative cardiac complications carry high mortality and morbidity. All over the world, major adverse postoperative cardiac event occurs in approximately 5–10 million patients,1-3 and about 1 million adults succumbed to death within 1 month of noncardiac surgery.2 Postoperative myocardial injury (PMI) is reported to occur in 1–17% in all varieties of surgery with in-hospital mortality of 15–25%,1-3 being particularly high in the first 30 days. Surgical stress can trigger cardiovascular events such as ventricular arrhythmia and myocardial infarction (MI) in individuals at high risk, leading to PMI which can be a contributor to mortality after noncardiac surgery.4-6 Because the vast majority of PMIs are asymptomatic, it is usually missed in the absence of systemic screening.

DEFINITION OF MYOCARDIAL INFARCTION: DOES POSTOPERATIVE MYOCARDIAL INJURY FIT IN? As per the third Global MI Task Force,7 MI constitutes myocardial ischemia, accompanied by raised cardiac biomarkers along with any of the following: • Ischemic angina pain or distress. • Electrocardiogram (ECG) changes. • New regional wall-motion abnormality. • Coronary angiography (CAG) showing thrombus. The third universal definition describes five types of MI,7 as follows: Type 1: Atherosclerotic plaque rupture and intraluminal thrombus causing spontaneous MI. Type 2: Imbalance between myocardial oxygen demand or supply leading to myocardial ischemia. Type 3: Sudden cardiac mortality with cardiac ischemic symptoms of MI and new ECG changes. Type 4a: MI associated with percutaneous coronary intervention (PCI) with ischemic symptoms and raised biomarkers.

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Type 4b: MI due to stent thrombosis. Type 5: MI associated with coronary artery bypass grafting surgery. Current diagnostic criteria for MI may be inadequate as found in evolving evidence. Latest advances in the biomarker assays have led to more accurate diagnosis of PMI, better prediction of risk, and their prognostic value can help to diagnose PMI more accurately.8-11 Recently introduced clinical concept of myocardial injury after noncardiac surgery (MINS), defined myocardial injury due to ischemia prognostically relevant occurring within 30 days after noncardiac surgery.8 The main focus of this definition of MINS is prognostic relevance of a peak in the high-sensitivity cTnT (hs-cTnT) assay. High-sensitivity cTnT assay allows the detection of very low levels of cTnT. Overall diagnostic accuracy of suspected PMI is improved with the help of this assay, and a negative result also carries a high negative predictive value. This assay is really helpful not only in diagnosing PMI but also predicting 30-day mortality.10,11

DOES POSTOPERATIVE MYOCARDIAL INJURY ALWAYS MEAN MYOCARDIAL INFARCTION? Indeed, a MI is observed in only 14–40% of the patients with PMI as per the definition. In almost 30% of patients with PMI, obstructive coronary artery disease (CAD) is absent.12-15 Hence, the potential relevance of noncardiac triggers of PMI cannot be underestimated. This emphasizes the knowledge of different causative factors of PMI in order to get a better outcome of such patients.

PATHOPHYSIOLOGY The pathophysiological mechanism of PMI is debated. The most sought explanation is supply-demand mismatch due to tachycardia, hypertension, hypotension, or coronary artery obstruction (Flowchart 1). However, the scientific literature supporting this explanation is not strong. Approximately half of the patients had plaque instability causing perioperative acute coronary syndrome (ACS) in one angiographic study.16 In another study where optical coherence tomography was used to identify coronary artery pathology. Thrombus was identified as the main lesion in 13% of the perioperative MI cases and 67% of the nonoperative cases.17 Apart from PMI, proponents of the term MINS describe nonischemic etiology such as pulmonary embolism, sepsis, or cardioversion.18 Postoperative myocardial injury is mainly because of type I or type II myocardial ischemia.4,6,16 Vulnerable plaque rupture with acute coronary thrombosis and influenced by hemodynamic fluctuations, inflammation, hypercoagulability can lead to type I ischemia.2,19 Type II myocardial ischemia

Postoperative Myocardial Injury: Causes and Management  217 Flowchart 1: Pathophysiology of perioperative myocardial injury.

(CAD: coronary artery disease; IL: interleukin: TNF: tumor necrosis factor).

is explained by oxygen supply-demand mismatch such as tachycardia, hyper or hypotension, and anemia.2,19 Hitherto, PMI was mainly believed to occur in patients with CAD. However, scientific studies have raised the question on this assumption. In a study of 955 noncardiac surgery patients, 28% of MI was observed in patients with absence of CAD.15 In another study of old patients, it was found that obstructive CAD on postoperative cardiac computed tomography angiography (CCTA) scan was seen in only 50% of the patients with PMI.20 However, microvascular damage cannot be assessed in CCTA. Microvascular injury can lead to PMI in patients with chronic hypertension. Plaque instability leading to PMI cannot be excluded by the absence of obstructive CAD. Even mild obstructive lesions can also lead to type I myocardial ischemia.21 The fact that the absence of obstructive CAD in 30–50% of patients with PMI suggests noncoronary causes like sepsis, pulmonary embolism, and cardiac arrhythmias which play a significant role in patients with PMI.14,22,23

DIAGNOSIS Patients with PMI may not have classical ischemic pain due to pain medications. Vascular Events in Noncardiac Surgery Patients Cohort Evaluation (VISION) study 2017 demonstrated that up to 90% patients with PMI experience no anginal symptoms,3,10 and half of such cases remain unidentified.24 We must depend on clinical signs and available technological advances, not symptoms, for timely detection of PMI. A study reported that only 14% of such patients experience chest pain.1 Most common initial signs in such

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scenario are the hypotension, diaphoresis, nausea, and low saturation, and ECG changes.25

Hypotension Prognostic clinical implications of intraoperative hypotension remain questionable. However, it was found every minute with systolic blood pressure below 80 mm Hg increases 1-year mortality by 3.6%.26 One study also demonstrated that intraoperative hypotension and anemia can greatly influence postoperative myocardial ischemic events.24,27

Electrocardiographic Changes As per American College of Cardiology,24 ECG changes such as new Q-wave changes, ST-segment elevation or depression in any two consecutive leads can be used in diagnosing PMI. VISION study found that postoperative ECG changes like ischemic ST-segment changes and left bundle branch block along with troponin elevation were found to be associated with 1-month mortality.9

Biomarkers A near-absolute myocardial tissue-specific biomarker is troponin. However, there are certain fallacies associated with its measurement. Major factor in the recognition of PMI is believed to be peak troponin concentrations. It has been found that noncardiac complications such as sepsis, respiratory insufficiency, and bleeding were associated with a postoperative troponin increase of over 100% compared to preoperative baseline measurements. Conventionally, it is presumed that ischemic cardiac damages can cause a major rise in postoperative troponin and noncardiac complications have only a mild effect on the troponin.28,29 However, it should be also kept in mind that noncardiac complication with cardiac implications such as pulmonary embolism can also cause a significant elevation in troponin. Pulmonary embolism is great stress on myocardium due to increased right ventricular pressures, hypoxia, and hypotension.30,31 Troponin monitoring can help us in recognizing not only MI but also other serious yet manageable postoperative complications. Troponin elevations, therefore, still robustly predict mortality.10,32,33 It is worthy to note that excessive importance on myocardial ischemia may lead to failure of recognition of noncoronary causes of PMI. Raised TnT levels should be measured at 3 and 6 hours. Hs-cTnT assay is more precise in detecting more subtle elevations indicative of cardiac injury.34 Canadian Cardiovascular Society guidelines strongly recommend every day TnT measurements for 2–3 days after surgery in high-risk patients.35

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Swan-Ganz Catheter and Arterial Waveformderived Cardiac Output Elevated pulmonary artery wedge pressure and left ventricular enddiastolic pressure can arise from decreased left ventricular compliance from ischemia. The presence of tall V waves in the PA waveform suggests mitral insufficiency. Systolic dysfunction can lead to low mixed venous oxygen saturation and low cardiac output calculated by Swan-Ganz catheter. Hypovolemia as a cause for hypotension can be easily ruled by measuring of stroke-volume variation (SVV). Thereby, it can give a clue toward myocardial dysfunction as a potential cause of decreased cardiac output.

Transesophageal Echocardiography Regional wall-motion abnormalities are highly sensitive and specific indicators of myocardial ischemia.36 Transesophageal echocardiography (TEE) is now an essential and vital part of monitoring in such patients.37

Angiography In patients with PMI as confirmed by biomarker assays or TEE, CAG ultimately defines the cause of ischemia. CAG can very well differentiate between type 1 ischemia (plaque instability) or type 2 ischemia (demandsupply mismatch). Type 1 ischemia can be effectively addressed by the PCI.

RISK PREDICTION Perioperative risk can be stratified with the help of the revised cardiac risk index (RCRI).38 Echocardiography gives us a lot of information in patients undergoing high-risk surgery. Any valvular abnormalities and myocardial dysfunction can independently predict adverse cardiac events after the noncardiac operation.38,39 ACC and the American Heart Association (AHA) 2014 guidelines have suggested the use of online National Surgical Quality Improvement Program (NSQIP) risk calculator.40,41 Preoperative cardiac biomarkers strongly predict PMI and mortality.42,43 Magnitude and time of elevation of troponin are related with the mortality risk found in a study.44 Additionally, natriuretic peptide such as N-terminal pro-BNP can also independently predict PMI.43,45 Raised BNP levels imply increased ventricular filling pressures which need to be optimized preoperatively. Troponin and/or NT-pro-BNP monitoring can potentially make us understand the pathophysiology of PMI. Even different causes of PMI can be distinguished using these biomarkers.

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Other interesting biomarkers such as proinflammatory lipoproteinassociated phospholipase A2 (Lp-PLA2) also been studied to predict the risk of any major cardiac event.46,47 Such novel biomarkers can be useful in such patients in the future.

PREVENTION AND MANAGEMENT Prevention of PMI is always the aim of the perioperative physician and anesthesiologist. Thorough history, previous health records, and a detailed and meticulous physical examination are very helpful to estimate the risk of CAD. Risk stratification of such population is essential so that aggressive preventive measures can be taken. Patients with limited functional capacity and having a risk of major adverse cardiac event (MACE) higher than 1% are recommended to undergo preoperative cardiac stress testing.48 Significant CAD can be managed by a cardiac specialist with proper management strategies of revascularization. Invasive cardiac investigation and interventions are not generally recommended for patients with stable disease, based on the result of landmark coronary artery revascularization prophylaxis (CARP) trial.49 These patients should be stabilized by optimizing their medical condition. Surgical stress response should be minimized.50 Appropriate drug therapy has been suggested to reduce ischemic complications. Reduced postoperative hemoglobin levels carry a high rate of complications.51-53 However, a blood transfusion may not offer advantages always to asymptomatic patients. It is suggested to follow a restricted transfusion strategy to symptomatic patients having hemoglobin levels less than 8 g/dL.45

Pharmacologic Treatment and Prophylaxis Aspirin has got a vital role in the acute management of spontaneous ACS and also in prophylaxis strategies. Aspirin reduces platelet aggregation and has antithrombotic effect.2 However, the Perioperative Ischemic Evaluation (POISE)-2 trial found that it elevated the probabilities of major bleeding.54 Patients already receiving a beta-blocker and statin, should continue these drugs during the perioperative period. It was found that aspirin and statin therapy can offer substantial cardiac protection.55 If angiotensinconverting enzyme (ACE) inhibitors are withheld considering the risk of aggravating the risk of intraoperative hypotension, they can be restarted postoperatively.56 In the perioperative period, beta-blockers can be commenced even if the patient is not on chronic beta-blocker use. However, to assess effectiveness, it is preferred to begin beta-blocker therapy at least 1 week before surgery.56 Alpha-2-adrenergic receptor agonists can attenuate the stress response by dilating poststenotic coronary vessels. However, these

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proposed benefits suggested in POISE-2 trial are not reflected in general rates of cerebrovascular event, myocardial ischemia or mortality. Perioperative clinician must be capable enough to manage unprecedented cardiac events acutely in all patients. Recognizing and managing myocardial injury is essential during crucial intraoperative and postoperative periods. Conditions increasing the stress on the heart (tachycardia, anemia, etc.) must be avoided. Monitoring as per American Society of Anesthesiologists (ASA) should be carried out along with more invasive monitoring for highrisk patients, e.g. central venous catheter placement with a pulmonary artery catheter, arterial line placement, cardiac output measurement instruments, and TEE.

CONCLUSION Conventionally, the focus of PMI is always on CAD, yet recent evidence suggests that noncoronary causes of PMI should not be ignored. It is imperative to be aware of underlying pathophysiological mechanisms of PMI so that both effective preventive measures and treatment strategies can be applied. Better identifying high-risk patients is the first step in preventive measures.

ACKNOWLEDGMENT Authors wish to acknowledge the contributions of Dr Monish S Raut, Senior Consultant, Artemis Hospital Gurgaon toward the preparation of this manuscript.

KEY POINTS • Revised cardiac risk index is useful in preoperative risk stratification. Recently, National Surgical Quality Improvement Program has also been added. • Addition of marker like troponin to the scoring risk index will better predict adverse cardiac events. • Appropriate invasive monitoring should be used in such susceptible patients. • Electrocardiography can be substantially used for early detection of myocardial injury in the postoperative period. • Mismatch between myocardial oxygen supply and demand should be minimized. • Perioperative stressful triggers such as hypoxia, electrolyte imbalance, etc. should be reduced. • Maintenance of coronary perfusion pressure is vital by appropriate use of vasopressors and optimizing intravascular fluid balance. • Myocardial oxygen delivery should be optimized by correcting anemia and induction of coronary vasodilation. • Judicious use of inotropic-vasopressor infusions to support hemodynamics along with due consideration for the possible need of extracorporeal membrane oxygenation (ECMO) and intra-aortic balloon pump.

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REFERENCES 1. Devereaux PJ, Goldman L, Cook DJ, et al. Perioperative cardiac events in patients undergoing noncardiac surgery: a review of the magnitude of the problem, the pathophysiology of the events and methods to estimate and communicate risk. CMAJ. 2005;173(6):627-34. 2. Devereaux PJ, Sessler DI. Cardiac complications in patients undergoing major noncardiac surgery. N Engl J Med. 2015;373(23):2258-69. 3. Devereaux PJ, Yang H, Yusuf S, et al. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet. 2008;371(9627):1839-47. 4. Devereaux PJ, Xavier D, Pogue J, et al. Characteristics and short-term prognosis of perioperative myocardial infarction in patients undergoing noncardiac surgery: a cohort study. Ann Intern Med. 2011;154:523-8. 5. Landesberg G, Beattie WS, Mosseri M, et al. Perioperative myocardial infarction. Circulation. 2009;119:2936-44. 6. Landesberg G, Shatz V, Akopnik I, et al. Association of cardiac troponin, CK-MB, and postoperative myocardial ischemia with long-term survival after major vascular surgery. J Am Coll Cardiol. 2003;42:1547-54. 7. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Circulation. 2012;126(16):2020-35. 8. Botto F, Alonso-Coello P, Chan MT, et al. Myocardial injury after noncardiac surgery: a large, international, prospective cohort study establishing diagnostic criteria, characteristics, predictors, and 30-day outcomes. Anesthesiology. 2014;120(3):564-78. 9. Devereaux PJ, Chan MT, Alonso-Coello P, et al. Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery. JAMA. 2012;307(21):2295-304. 10. Devereaux PJ, Biccard BM, Sigamani A, et al. Association of postoperative highsensitivity troponin levels with myocardial injury and 30-day mortality among patients undergoing noncardiac surgery. JAMA. 2017;317(16):1642-51. 11. Kopec M, Duma A, Helwani MA, et al. Improving prediction of postoperative myocardial infarction with high-sensitivity cardiac troponin T and NT-pro BNP. Anesth Analg. 2017;124(2):398-405. 12. Nathoe HM, van Klei WA, Beattie WS. Perioperative troponin elevation: always myocardial injury, but not always myocardial infarction. Anesth Analg. 2014;119:1014-6. 13. Horr S, Reed G, Menon V. Troponin elevation after noncardiac surgery: significance and management. Cleve Clin J Med. 2015;82:595-602. 14. van Waes JAR, Grobben RB, Nathoe HM, et al. One-year mortality, causes of death, and cardiac interventions in patients with postoperative myocardial injury. Anesth Analg. 2016;123:29-37. 15. Sheth T, Chan M, Butler C, et al. Prognostic capabilities of coronary computed tomographic angiography before non-cardiac surgery: prospective cohort study. BMJ. 2015;350:h1907. 16. Gualandro DM, Campos CA, Calderaro D, et al. Coronary plaque rupture in patients with myocardial infarction after noncardiac surgery: frequent and dangerous. Atherosclerosis. 2012;222:191. 17. Sheth T, Natarajan MK, Hsieh V, et al. Incidence of thrombosis in perioperative and non-operative myocardial infarction. Br J Anaesth. 2018;120:725.

Postoperative Myocardial Injury: Causes and Management  223 18. Landesberg G, Mosseri M, Shatz V, et al. Cardiac troponin after major vascular surgery: the role of perioperative ischemia, preoperative thallium scanning, and coronary revascularization. J Am Coll Cardiol. 2004;44:569. 19. Grobben RB, van Klei WA, Grobbee DE, et al. The aetiology of myocardial injury after non-cardiac surgery. Neth Heart J. 2013;21:380-8. 20. Grobben RB, van Waes JA, Leiner T, et al. Unexpected cardiac CT findings in patients with postoperative myocardial injury. Anesth Analg. 2018;126:1462-8. 21. Pizzi C, Xhyheri B, Costa GM, et al. Nonobstructive versus obstructive coronary artery disease in acute coronary syndrome: a meta-analysis. J Am Heart Assoc. 2016;5:1-15. 22. van Klei WA, Grobbee DE, Grobben RB, et al. Detection and management of asymptomatic myocardial injury after noncardiac surgery. Eur J Prev Cardiol. 2013;20:918-21. 23. Sellers D, Srinivas C, Djaiani G. Cardiovascular complications after non-cardiac surgery. Anaesthesia. 2018;73:34-42. 24. Devereaux PJ, Goldman L, Yusuf S, et al. Surveillance and prevention of major perioperative ischemic cardiac events in patients undergoing noncardiac surgery: a review. CMAJ. 2005;173(7):779-88. 25. Singh A, Antognini JF. Perioperative hypotension and myocardial ischemia: diagnostic and therapeutic approaches. Ann Card Anaesth. 2011;14(2):127-32. 26. Monk TG, Saini V, Weldon BC, et al. Anesthetic management and one-year mortality after noncardiac surgery. Anesth Analg. 2005;100(1):4-10. 27. Lienhart A, Auroy Y, Péquignot F, et al. Survey of anesthesia-related mortality in France. Anesthesiology. 2006;105(6):1087-97. 28. Landesberg G, Jaffe AS. “Paradox” of troponin elevations after non-cardiac surgery. Br J Anaesth. 2015;114:863-5. 29. Mauermann E, Puelacher C, Buse GL. Myocardial injury after noncardiac surgery: an underappreciated problem and current challenges. Curr Opin Anaesthesiol. 2016;29:403-12. 30. Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35:3033-80. 31. Matthews JC, McLaughlin V. Acute right ventricular failure in the setting of acute pulmonary embolism or chronic pulmonary hypertension: a detailed review of the pathophysiology, diagnosis, and management. Curr Cardiol Rev. 2008;4:49-59. 32. van Waes JAR, Nathoe HM, de Graaff JC, et al. Myocardial injury after noncardiac surgery and its association with short-term mortality. Circulation. 2013;127:2264-71. 33. Beattie WS, Karkouti K, Tait G, et al. Use of clinically based troponin underestimates the cardiac injury in non-cardiac surgery: a single-centre cohort study in 51,701 consecutive patients. Can J Anaesth. 2012;59:1013-22. 34. Xu RY, Zhu XF, Yang Y, et al. High-sensitive cardiac troponin T. J Geriatr Cardiol. 2013;10(1):102-9. 35. Rodseth RN, Biccard BM, Le Manach Y, et al. The prognostic value of preoperative and post-operative B-type natriuretic peptides in patients undergoing noncardiac surgery: B-type natriuretic peptide and N-terminal fragment of pro-B-type natriuretic peptide: a systematic review and individual patient data meta-analysis. J Am Coll Cardiol. 2014;63(2):170-80.

224  Yearbook of Anesthesiology-9 36. Smith JS, Cahalan MK, Benefiel DJ, et al. Intraoperative detection of myocardial ischemia in high-risk patients: electrocardiography versus two-dimensional transesophageal echocardiography. Circulation. 1985;72(5):1015-21. 37. Suriani RJ, Neustein S, Shore-Lesserson L, et al. Intraoperative transesophageal echocardiography during noncardiac surgery. J Cardiothorac Vasc Anesth. 1998;12(3):274-80. 38. Kristensen SD, Knuuti J, Saraste A, et al. 2014 ESC/ESA Guidelines on noncardiac surgery: cardiovascular assessment and management: the Joint Task Force on non-cardiac surgery: cardiovascular assessment and management of the European Society of Cardiology (ESC) and the European Society of Anaesthesiology. Eur Hear J. 2014;35:2383-431. 39. Rohde LE, Polanczyk CA, Goldman L, et al. Usefulness of transthoracic echocardiography as a tool for risk stratification of patients undergoing major noncardiac surgery. Am J Cardiol. 2001;87:505-9. 40. Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130(24):e278-333. 41. Devereaux PJ, Chan M, Eikelboom J. Major vascular complications in patients undergoing noncardiac surgery: the magnitude of the problem, risk prediction, surveillance, and prevention. In: Yusuf S, Cairns JA, Camm AJ, Fallen EL, Gersh BJ (Eds). Evidence-Based Cardiology, 3rd edition. London: BMJ; 2009. pp. 47-62. 42. Nagele P, Brown F, Gage BF, et al. High-sensitivity cardiac troponin T in prediction and diagnosis of myocardial infarction and long-term mortality after noncardiac surgery. Am Heart J. 2013;166:325-32. 43. Ryding A, Kumar S, Worthington AM, et al. Prognostic value of brain natriuretic peptide in noncardiac surgery: a meta-analysis. Anesthesiology. 2009;111:3119. 44. Maile MD, Jewell ES, Engoren MC. Timing of preoperative troponin elevations and postoperative mortality after noncardiac surgery. Anesth Analg. 2016;123:135-40. 45. Rodseth RN, Biccard BM, Le Manach Y, et al. The prognostic value of preoperative and post-operative B-type natriuretic peptides in patients undergoing noncardiac surgery. J Am Coll Cardiol. 2014;63:170-80. 46. Maiolino G, Bisogni V, Rossitto G, et al. Lipoprotein-associated phospholipase A2 prognostic role in atherosclerotic complications. World J Cardiol. 2015;7:60920. 47. Chung H, Kwon HM, Kim J, et al. Lipoprotein-associated phospholipase A2 is related to plaque stability and is a potential biomarker for acute coronary syndrome. Yonsei Med J. 2014;55:1507-15. 48. McFalls EO, Ward HB, Moritz TE, et al. Predictors and outcomes of a perioperative myocardial infarction following elective vascular surgery in patients with documented coronary artery disease: results of the CARP trial. Eur Heart J. 2008;29(3):394-401. 49. Gupta PK, Gupta H, Sundaram A, et al. Development and validation of a risk calculator for prediction of cardiac risk after surgery. Circulation. 2011;124(4):381-7. 50. Carson JL, Duff A, Poses RM, et al. Effect of anaemia and cardiovascular disease on surgical mortality and morbidity. Lancet. 1996;348:1055-60.

Postoperative Myocardial Injury: Causes and Management  225 51. Chatterjee S, Wetterslev J, Sharma A, et al. Association of blood transfusion with increased mortality in myocardial infarction: a meta-analysis and diversityadjusted study sequential analysis. JAMA Intern Med. 2013;173:132-9. 52. Valentijn TM, Hoeks SE, Martienus KA, et al. Impact of haemoglobin concentration on cardiovascular outcome after vascular surgery: a retrospective observational cohort study. Eur J Anaesthesiol. 2013;30:664-70. 53. Carson JL, Grossman BJ, Kleinman S, et al. Red blood cell transfusion: a clinical practice guideline from the AABB. Ann Intern Med. 2012;157:49-58. 54. Biccard BM. Detection and management of perioperative myocardial ischemia. Curr Opin Anaesthesiol. 2014;27(3):336-43. 55. Biccard BM, Sear JW, Foëx P. Statin therapy: a potentially useful perioperative intervention in patients with cardiovascular disease. Anaesthesia. 2005;60(11):1106-14. 56. Gombar S, Khanna AK, Gombar KK. Perioperative myocardial ischaemia and infarction. Indian J Anaesth. 2007;51:287.

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CHAPTER

16

Management of Hyperglycemia in the Perioperative Period Pallavi Ahluwalia, Payal Jain

INTRODUCTION Literature clearly shows the relation between perioperative blood glucose (BG) control and incidence of adverse clinical outcomes like cerebrovascular accidents, myocardial infarction, diabetic ketoacidosis (DKA), hypoglycemic episodes, postoperative wound infections, and length of stay.1-3 The prevalence of diabetes is increasing. In the South-East Asia region, about 71 million people were estimated to be living with diabetes in 2010 and an equal number had impaired glucose tolerance. If left uncontrolled, the burden will almost double by 2030 in this region. Perioperative hyperglycemia has been seen in almost 15–45% of patients undergoing general surgery. Diabetes accounts for up to 10% of healthcare expenditure in developed nations, and these huge costs are related in part to the excess number of hospital admissions.4 Hyperglycemia or dysglycemia is the most common issue encountered by anesthesiologist in perioperative settings. Anesthesiologists play a crucial role in the assessment, initiation of treatment, and management of these patients during the perioperative period. Due to varied spectrum of population, it is extremely difficult to follow one standard protocol for perioperative BG control, which is appropriate for all patients. Risks can be reduced by early identification and timely intervention. The overall goal of management is avoidance of hypoglycemia and providing adequate BG control, which lies midway between strict control (BG levels of 78–108 mg/dL) and overt hyperglycemia (BG levels of >200 mg/dL) and. The reports suggest evidence of perioperative hyperglycemia is between 20% and 40% following noncardiac general surgery2,5,6 and nearly 80% in patients following cardiac surgery.7,8

DIAGNOSTIC CRITERIA FOR DIABETES MELLITUS The American Diabetes Association (ADA) has set the following criteria for the diagnosis of diabetes mellitus: • A fasting plasma glucose level (defined as plasma sample taken after no calorie intake for 8 hours) greater than or equal to 126 mg/dL.

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• Following “oral glucose tolerance test”, a 2-hour plasma glucose level greater than or equal to 200 mg/dL. Test is done after a glucose load of 75 g (glucose in anhydrous state dissolved in water). • HbA1c ≥ 6.5%. This test is recommended in a standard laboratory utilizing a method that is the National Glycohemoglobin Standardization Program (NGSP) certified. Test is standardized by the Diabetes Control and Complications Trial (DCCT) assay.9 • Patients presenting with classic symptoms because of hyperglycemia or in hyperglycemic crisis, with a random plasma glucose level more than 200 mg/dL are considered diabetic.

IMPLICATIONS OF SURGERY ON BLOOD SUGAR LEVELS Majority of patients with hyperglycemia are usually diagnosed cases of diabetes but 12–25% of patients are without any prior history of diabetes before surgery,2 and are often in a state described as “stress hyperglycemia”.10 Perioperative problems in a diabetic patient can be categorized according to the site of surgery, magnitude of tissue damage, given, intraoperative fluid shifts, type of anesthesia, and preoperative control of blood sugar levels. Stress response to surgery leads to secretion of cortisol, catecholamine, and growth hormone which inhibit glucose homeostasis by stimulating gluconeogenesis and glycogenolysis leading to increase in sugar levels and ketosis. Secondly, damage of tissue due to surgical procedure starts a reaction in the body causing release of inflammatory cytokines such as tumor necrosis factor (TNF), interleukin 1, interleukin 6, which causes decrease insulin sensitivity leading to hyperglycemia. Additionally, an increase in stress hormones leads to an increase in free fatty acid concentrations which limits insulin-stimulated glucose uptake. All these reasons lead to altered body responses to glucose loading which can continue up to 3 weeks postoperatively.

TYPES OF ANESTHESIA AND ITS EFFECT ON BLOOD GLUCOSE General anesthesia leads to higher incidence of hyperglycemic episodes because of relatively more release of stress hormones like catecholamines, cortisol, and glucagon in comparison to local or epidural anesthesia.11 Combined spinal-epidural anesthesia is a preferred mode of anesthesia as it attenuates the neurohormonal stress response of body by decreasing catecholamine release and thereby preventing elevation in BG levels.12 Also, it blunts the stress response mediated by sympathetic efferent signal blockade, reducing enhanced fibrinolytic activity which is normally the root cause of hyperglycemia.13 However, one must be aware that the diabetic

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patients are quite prone to autonomic neuropathies. Injudicious use of local anesthetics can lead to life-threatening consequences such as hypotension due to blunted compensatory baroreceptor reflex mechanism. Regardless of technique used, it should lead to rapid recovery to avoid concealment of hyper as well as hypoglycemic episodes.11 Diabetes is a multisystem disease affecting the peripheral nerves as well, but studies have shown that plexus block like brachial plexus block has shown the same efficacy as in normal patients for shoulder surgeries but for distal surgeries like that of elbow, supplementation may be necessary.14

ANESTHETIC DRUGS AND THEIR EFFECTS ON BLOOD GLUCOSE • Benzodiazepines and opioids produce hormonal and metabolic stability by decreasing adrenocorticotropic hormone (ACTH) secretion and reducing the production of cortisol in high doses. They act by reducing the sympathetic stimulation thereby decrease the glycemic effect of surgery.15 When given in usual sedative doses, these effects are minimal. • Atropine can mask the symptoms of hypoglycemia due to its anticholinergic action. • Inhalational agents lead to increase in blood sugar levels. This effect is mediated in a dose-dependent manner by inhibiting the insulin response to glucose.16-18 • Etomidate decreases cortisol production by blocking adrenal steroidogenesis (11β-hydroxylase enzyme is blocked) thus decreases blood sugar levels.19,20 • Propofol has no effect on insulin secretion. However, due to lipid formulation, its metabolism and excretion are decreased in diabetic patients thus leading to delayed awakening. Moreover, it may lead to excessive hypotension especially in patients with autonomic neuropathies.18,21 • Ketamine stimulates sympathetic nervous system and thus leads to hyperglycemia.22 • Thiopentone causes either no change in the BG levels or slight hyperglycemia due to decrease glucose tolerance.23 • Muscle relaxants do not have direct effect on glucose metabolism, but in patients with neuropathies or neuromuscular junction abnormalities aberrant response may occur.24 • Reversal agent sugammadex is a cyclodextrin molecule that is consisted of bounded sugar. Thus, because of its chemical structure, it can lead to increase in blood sugar levels.25 • Opioid anesthetic techniques utilizing high doses of opioids produce hemodynamic, metabolic, and hormonal stability. However, midazolam

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and fentanyl may cause hyperglycemia by reducing glucose clearance.26 In vitro studies done on rats showed reduced clearance of glucose by fentanyl.27 • β-blockers use is associated with slower recovery from hypoglycemia. In insulin-dependent diabetics, beta-blockers can prolong, enhance, or alter the symptoms of hypoglycemia, while hyperglycemia appears to be the major risk in noninsulin-dependent diabetics. Beta-blockers can potentially increase BG concentrations and antagonize the action of oral hypoglycemic drugs.28

ASSESSMENT DURING PERIOPERATIVE PERIOD AND MANAGEMENT GOALS In a patient with diabetes, the perioperative period can be quite challenging for the anesthesiologists as it is important to manage uncontrolled hyperglycemia against avoiding hypoglycemia. The aim of the anesthesiologists will be to: • Decrease morbidity and mortality by avoiding DKA as well as hypo­ glycemia.11,29 • Assess airway of the patients as these patients are prone to diabetic cheiroarthropathy;30 a condition leading to limited joint mobility because of glycosylation of collagen present in joints especially axial and atlantooccipital joints, which could lead to difficulty in intubation because of restricted neck extension. It is checked with the help of palm print sign and prayer sign. • Assess for autonomic neuropathy as this affects the compensatory mechanism of the cardiovascular system (e.g. baroreceptor reflex) for any change in intravascular volume or patient position. Moreover, these patients are prone to silent myocardial ischemia. • Be cautious for gastroparesis which may precipitate regurgitation and aspiration. • Assess the respiratory system. Pulmonary microangiopathies and chronic systemic inflammation of diabetes lead to decrease in lung volumes, diffusing capacity, and hypoxia-induced ventilator drive. • Maintain intravascular volume and electrolyte check. • Look for diabetic nephropathy. • Regulate the hypoglycemic drug and insulin intake prior to surgery, and finally. • Establishment of certain glycemic target levels,11,29 3 mmol/L or ketonuria >2+ by dipstick method • Blood sugar >200 mg/dL • Venous pH 2,500 m, HAPE > 3,000 m, and HACE > 4,000–5,000 m, although susceptible individuals can be affected below these altitudes.

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• Pre-existing conditions or anatomic abnormalities that lead to increased pulmonary blood flow, pulmonary arterial hypertension, or increased pulmonary vascular reactivity may predispose to HAPE, even at altitudes below 2,500 m. Some of the conditions which may predispose to HAPE are: ▪▪ Primary pulmonary hypertension (PPHN). ▪▪ Congenital absence of one pulmonary artery. ▪▪ Left-to-right intracardiac shunts, such as atrial septal defects (ASDs) and ventricular septal defects (VSDs). ▪▪ Hyperresponsive pulmonary circulation to hypoxia or exercise at sea level. • Other factors associated with an increased incidence of HAPE include:27,28 ▪▪ Male gender. ▪▪ Cold ambient temperatures. ▪▪ Pre-existing respiratory infection. ▪▪ Vigorous exertion. • Genetics clearly plays an important role in the risk of HAPE, as seen by the marked variance in individual susceptibility and the higher rates of recurrence among some individuals. Individuals who are prone to develop HAPE may also develop flash pulmonary edema at sea level if exposed at any inciting event. However, HAPE genetic studies are conflicting and no clear conclusions can be derived. Healthy Tibetans are protected against AMS and maintain good adaptation to HA, even after a long period of stay at low altitudes. They have been found to have a significantly higher plasma concentration of NO by-products. Impaired NO synthesis occurring with NO-synthase polymorphisms has been postulated as a genetic cause of HAPE susceptibility.24,26,31 Genetic and epigenetic variation in the genes that code for hypoxiainducible factors, transcription factors, heat shock protein (HSP 70), may alter expression of these factors in response to low cellular oxygen concentrations. This may also be responsible for variation in individual susceptibility to HAPE. Genes for the pathways for renin-angiotensin-aldosterone and pulmonary surfactant proteins A1 and A2 have also been studied. Variation in alveolar fluid clearance related to sodium channel phenotype, aquaporin-5 may also be implicated.35 Patent foramen ovale (PFO), deserves a special mention. PFO was found in 25–30% of individuals in an autopsy study and in a communitybased transesophageal echocardiography (TEE) study  ranging from 34.3% during the  first  three  decades of  life  to 25.4% during the 4th through 8th  decades  and to 20.2% during the 9th and 10th  decades.36,37 A rising PVR during HPV may reverse the direction of blood flow, shunting blood from right to left and further exacerbating hypoxemia. PFO is four times

High-altitude Pulmonary Edema  317

more common among HAPE-susceptible individuals. Larger PFOs correlate directly with increased arterial hypoxemia, and a trend toward an increased risk of developing HAPE. Whether PFO contributes to HAPE or is merely a marker of increased vascular reactivity and susceptibility remains unknown. However, there is currently no indication for preventively closing PFO in HAPE-susceptible persons.2,12,13,38

CLINICAL PRESENTATION3-5,11,12,14 High-altitude pulmonary edema generally begins with a subtle, nonproductive cough, dyspnea on exertion, especially on walking uphill. Initial symptoms typically appear within 2–4 days after arrival at HA or a new altitude and are easily mistaken for a benign upper respiratory tract infection or attributed to normal breathlessness at altitude or exhaustion. Occasionally, HAPE develops precipitously. This occurs more often at night or after severe exertion. Patients of HAPE may have symptoms of AMS initially before becoming breathless. HAPE almost never develops after a week at the same altitude. As HAPE progresses, dyspnea becomes noticeable at rest and severe with any attempt at exertion. Even walking on a level surface becomes an effort. A cardinal clinical feature of HAPE is the rapid worsening of the presenting dyspnea on exertion to dyspnea at rest. As symptoms progress, the initial dry cough becomes productive and frothy with frank blood at times. Severe hypoxemia may cause drowsiness or concomitant HACE with ataxia and altered consciousness generally without neurological deficit. Persons with genetic or acquired (e.g. carotid endarterectomy, neck radiation) blunted carotid body function may present without respiratory symptoms and instead with drowsiness, confusion and other central nervous system (CNS) symptoms and findings. The examination usually reveals tachycardia, tachypnea, and low-grade fever (up to 38°C). Central cyanosis may be appreciated and inspiratory crackles are more prominent in the right middle lobe initially. Auscultation of the right middle lobe is best performed at the mid-lateral chest wall. As severity of HAPE increases, there is worsening of breathlessness and tachycardia and the inspiratory crackles become diffuse and bilateral with development of an accentuated pulmonary component of 2nd heart sound and features of right heart failure. The diagnosis is primarily clinical, requiring at least two symptoms and two clinical signs as given in Table 2. About 52% of patients with HAPE have concurrent AMS and 14% have concurrent HACE.2,23 Pulse oximetry is a useful tool to not only to document hypoxia and to monitor response to therapy but also to assess the degree of acclimatization. SpO2 is low, being lowest on the first day at HAA, being at least 10 points

318  Yearbook of Anesthesiology-9

lower than expected for the altitude, and absolute values may be as low as 40–50%. Values rise over 4 days to a near-maximum value, usually 3–5 points higher than day 1. In a study of HAPE patients at an altitude of 4,559 m, observed values for SaO2 was 48±8% and for PaO2 23±3 mm Hg as against healthy control values of 78±7% and 40±5 mm Hg, respectively.39 Both the clinical status and SpO2 rapidly correct (usually within 10–15 min) with supplemental oxygen and this in the setting of a severe infiltrative lung process seen on radiograph is virtually pathognomonic for HAPE, as this does not occur with other similar clinical pulmonary conditions [e.g. pneumonia, acute decompensated heart failure (ADHF)]. However, expected SpO2 values vary with a number of factors, including the altitude, degree, and rate of acclimatization, patient’s hypoxic ventilatory drive, and method of measurement (e.g. variation among pulse oximeters), and therefore should be interpreted carefully.40 A prospective cohort study of all troops reporting to a transit camp of the Indian Army for the first stage of acclimatization (see below, “Prevention”) located at a height of 3,142 m was conducted over a 3-month period. The participants were divided into two groups—those troops reporting to HAA for the first time (first entry; FE) and those reporting after absence of more than 10 days but less than 30 days from HAA (reentry; RE). A total of 278 transients were FE and 244 RE were included. Apart from routine epidemiological data recording, monitoring of pulse, blood pressure, and SpO2 were done on Day 1 and Day 6. Only 7 FE and 2 RE troops (4.70%) were found unfit to proceed to higher altitudes when subjected to a brisk walk of 1 km after the period of acclimatization. Tachycardia with a SpO2 below 90% by digital pulse oximetry were the parameters found to be statistically significant as an indicator to declare a person as not fully acclimatized or otherwise.41 A study on a group of climbers at 3,600 m during an expedition to the Bolivian Andes found that acclimatized subjects could maintain their SpO2 during prolonged exercise better than unacclimatized subjects. The authors concluded that two parameters were statistically significant as an indicator to declare a person as not fully acclimatized or otherwise—tachycardia and oxygen saturation below 90% by digital pulse oximetry. Although expected values can vary widely in normal individuals at any given altitude, comparing SpO2 measurements with others in the same group who arrived at altitude together can help to establish relative “normal” values.42

INVESTIGATIONS None of the investigations are specific for diagnosis, that being based on clinical suspicion, history, and physical examination.

High-altitude Pulmonary Edema  319

Laboratory tests: No laboratory test is specific to diagnose HAPE. Mild leukocytosis is present and brain natriuretic peptide (BNP) and related tests (e.g. pro-BNP) may be slightly elevated at HAs. Troponin may be elevated in the setting of HAPE associated with right heart strain. Electrocardiogram (ECG) is nonspecific with sinus tachycardia, right bundle branch block pattern, right axis deviation, or right heart strain. Chest radiography is useful and reveals characteristic patchy alveolar infiltrates, predominantly in the right central hemithorax, which become more confluent and bilateral as the illness progresses. However, in some cases, the infiltrates may start in the left lung. The picture is similar to that of noncardiogenic pulmonary edema. The only difference noted is the milder clinical profile and the steady, rapid improvement with oxygen therapy.38,43 Computerized tomography (CT) of the chest reveals a patchy lobular ground-glass appearance and consolidative opacities, reflecting heterogeneous alveolar filling. Echocardiography can demonstrate increased PA pressure and sometimes right heart dysfunction and paradoxical septal motion. Ultrasound of the chest is a highly-sensitive and semiquantitative means of detecting increased extravascular lung water (EVLW). If traditional chest radiography is unavailable (e.g. at a remote clinic or in the field), HAPE can be confirmed by the presence of ultrasound lung comets (ULCs). While the quantity of ULCs corresponds closely to clinical and oximetry findings, it is not known what number of ULCs is an appropriate diagnostic threshold for HAPE, as opposed to subclinical pulmonary edema. Nevertheless, the technique for identifying ULCs is easily performed and may be useful in the proper clinical setting, such as when the cause of dyspnea is unclear despite a careful history and physical examination. Limitations of ultrasound include:44 • Lack of specificity: Ultrasound cannot differentiate HAPE from cardiogenic pulmonary edema and other causes of increased EVLW. • Ultrasound findings may not be clinically relevant at altitude, as clinically insignificant ULCs are commonly seen in recreational climbers who are asymptomatic and do not develop HAPE, especially older persons.15,19 • Ultrasound findings may not add to what is already known from examination findings and oximetry.

DIFFERENTIAL DIAGNOSIS High-altitude pulmonary edema can be confused with pneumonia, pulmonary embolism, ADHF, acute coronary syndrome, reactive airway disease, and exercise-associated hyponatremia (EAH).26,30 Rapid response over hours to oxygen therapy strongly suggests the diagnosis of HAPE in

320  Yearbook of Anesthesiology-9

this setting. Rapid improvement with descent is another important clue to the diagnosis of HAPE.

TREATMENT General Management2,5,11,22,29,38,42,45-47 Aim of management is an urgent reduction of PA pressure. This can be achieved either by nonpharmacologic interventions or pharmacologic inter­ ventions.

Nonpharmacologic Interventions Nonpharmacologic interventions include the following: • Limiting physical exertion and cold exposure: Strenuous physical exertion and cold stress both elevate PA pressure and can exacerbate HAPE.3 A patient with HAPE should not carry a pack while descending. • Evacuation to a lower altitude: Immediate descent is not mandatory in all settings. Its usefulness varies depending upon a number of factors, including severity of illness, altitude, available treatments, setting, clinician experience, and patient factors. In remote high-altitude settings where supplemental oxygen is unavailable, descent should begin as soon as HAPE is suspected.2,5 HAPE can progress rapidly and the opportunity for evacuation may be lost if there is any delay. At higher elevations (>4,000 m), the descent is mandatory, in part because of the risk of developing HACE. Ideally, immediate evacuation is undertaken to a hospital below 3,000 m that is capable of providing high-flow oxygen. Nevertheless, in practice, scores of HAPE patients are treated successfully in remote clinics or base camps with modest descent and rest, sometimes in combination with hyperbaric therapy, low-flow supplemental oxygen, and medication. Many remote clinics are located only 500–1,000 m below the elevation of HAPE onset. When HAPE is diagnosed early and treated, many climbers go on to re-ascend slowly after 2–3 days of recovery. Recurrence of HAPE in such circumstances has not been reported. Severe cases require evacuation to a medical facility at lower elevation. • Simulating descent using hyperbaric therapy: In remote settings, light weight portable hyperbaric chambers (“HAPE Bags”) bags may be lifesaving, particularly when supplemental oxygen is unavailable or in short supply. These devices, although costly, are well-suited to mountaineering and trekking expeditions at HA, where compressed oxygen cylinders are too heavy and bulky to transport and are difficult to maintain.46 These hyperbaric chambers should not be used in cases of mild AMS for either prevention or treatment.  Pressurized bags are NOT designed to

High-altitude Pulmonary Edema  321

treat mild symptoms of AMS or to facilitate continued ascent just to proceed the next day without adequate acclimatization. In the case of mild symptoms, the advice is to slow the ascent rate and consider taking a rest day. Use that time to retreat from altitude. A HAPE bag is a cylindrical inflatable pressure bag large enough to accommodate a person. It is made up of medium-heavy impermeable coated fabric with an air-proof zipper. Various valves are integrated to facilitate the ease of operation and safety. The bag is sealed and inflated with either a foot pump or a power-operated compressor with rapid decrease in the “effective altitude” within minutes to 1,000–3,000 ms (3,281–9,743 ft). The pressure inside the HAPE bag ranges from 105 mm Hg to 220 mm Hg with an approximate volume of 600 L to accommodate an average person even with multiple layers of clothing. There is a preleak control valve which bleeds approximately 20 L/min in order to avoid build-up of carbon dioxide. Patients typically are treated in 1-hour increments and then are reevaluated. While on a HAPE bag, the patient should never retreat unaccompanied. • Oxygen: Supplemental oxygen is first-line management for HAPE. Relieving hypoxemia is the most effective method of reducing PA pressure, reversing capillary leak, and protecting the brain and other organs. Supplemental oxygen immediately increases PaO2 and reduces both the respiratory rate and pulse. While some studies have shown that oxygen combined with medication is more effective than oxygen alone in lowering PA pressure, clinical outcomes were not assessed.15,40,45 • A common regimen in North American hospitals near ski resorts (elevation approximately 2,500–3,000 m) is to treat with high flow supplemental oxygen by nasal cannula or face mask for several hours until the patient’s oxygen requirement is ≤3 L/min with the SpO2 maintained at 90% or higher. If the patient is clinically improved and appropriate for outpatient therapy, he or she may be sent home with an oxygen concentrator to be used continuously and strict instructions to rest. The patient’s condition and SpO2 are rechecked daily until an ambulatory SpO2, measured while the patient breathes room air, is ≥90%. At this point, supplemental oxygen is discontinued and the patient is advised to slowly return to activity over the following 1–3 days. Descent is not mandatory but is always an option in this setting.42 Positive airway pressure: The use of a breathing mask providing expiratory positive airway pressure (EPAP) has been shown to improve gas exchange in HAPE, and may be useful as a temporizing measure.35 A similar effect may be achievable by having the patient breathe through pursed lips. Continuous positive airway pressure (CPAP) is used in some ski resort clinics with anecdotal success. Nevertheless, no study has established that CPAP improves clinical outcome in patients with HAPE. A CPAP helmet has been used in the field.36

322  Yearbook of Anesthesiology-9

Pharmacologic Interventions17,44-49 Interpretation of studies conducted for the prevention and treatment of HAPE is problematic as selection bias for inclusion of subjects who are known to be highly susceptible to HAPE cannot be ruled out. Extrapolation of the results to a general population needs validation. Nifedipine: This is a nonspecific calcium channel blocker that acts by reducing PVR and PA pressure, as well as systemic vascular resistance and blood pressure. It also slightly improves PaO2. Recommended dosages vary, but a common regimen is to give 20 mg three times a day, preferably as slowrelease tablets. It is recommended as the first-line adjunct in Wilderness Medical Society guidelines,49  although a recent study in HAPE recovery reported no additional benefit if descent and oxygen supplementation is  adequate.47,49  Short-acting preparations of nifedipine should be avoided in view of the risk of cerebral hypoperfusion.17 Precautions: It is normally well tolerated and does not cause significant hypotension in previously healthy persons. Clinicians should give or be prepared to give isotonic intravenous fluid (e.g. normal saline) to any critically ill HAPE patient who may be intravascularly depleted and is receiving nifedipine. Phosphodiesterase-5 (PDE-5) inhibitors: Both tadalafil and sildenafil may be the effective adjunct treatment for established HAPE when neither oxygen nor descent is an available option. These augment the pulmonary vasodilatory effects of NO by blocking the degradation of cyclic guanosine monophosphate (cGMP), the intracellular mediator of NO. Nitric oxide is a potent pulmonary vasodilator and reduces HPV and pulmonary hypertension in HAPE.31 These drugs may have advantages over nifedipine because they lower PA pressure with less risk of lowering systemic blood pressure.18,47,50,51 Dose of tadalafil is 10 mg twice daily and that of sildenafil is 50 mg three times a day. Dexamethasone:  The mechanism of action of dexamethasone remains unclear. It may involve upregulation of both NO production and of alveolar epithelial membrane sodium channels and sodium-potassium ATPase.47,51 This is usually reserved for treatment of AMS or HACE, which may coexist with HAPE. Ineffective or contraindicated therapies:  Diuretic therapy, nitrates, betablockers, and morphine are not currently recommended because of limited trial data in the susceptible population.18,47 To summarize, the key principle in successful treatment of HAPE is a strong clinical suspicion. Descent (simulated or actual) and supplemental oxygen are often effective alone and appear to be superior to any pharmacologic therapy. In isolated mountain settings, oxygen may be

High-altitude Pulmonary Edema  323

limited, precluding its use as the sole treatment. Hyperbaric therapy is commonly combined with pharmacotherapy and supplemental oxygen, if available. In the hospital setting, the elevation is generally lower and high-flow oxygen is readily available. Hyperbaric therapy is not practical or necessary in such hospitals or clinics. No trials have been performed in patients with HAPE that directly compare treatment using oxygen and descent with pharmacologic therapy. Nevertheless, the clinical outcomes reported in studies in which nifedipine alone (see below) was used for treatment were poor compared with those involving oxygen and descent without medication.23 Pharmacotherapy (nifedipine) was of no added clinical benefit in patients who received oxygen and descent.29

PREVENTION Acclimatization: A three-stage acclimatization schedule is recommended by the Indian Army (see Table 3):52 • Stage I acclimatization lasts for 6 days for altitudes ranging from 2,700 m to 3,600 m. • Stage II and stage III require an additional 4 days each, for altitudes 3,600 m to 4,500 m and >4,500 m. • During reentry to HAA, after 10–30 days of absence from HAA, 4 days at each stage need to be spent. • After a break of more than 30 days, full acclimatization schedule as fresh inductees needs to be followed. Gradual ascent remains the primary method for preventing all forms of HA illness, including HAPE. Those susceptible to HAPE should not ascend greater than 300 m per day.

Pharmacological Prophylaxis18,47,49-51 • For patients with no history of medical problems at HA or of pulmonary hypertension, the risk of HAPE is low and routine prophylaxis is not warranted. • In individuals at high-risk, particularly those with a history of HAPE, pharmacologic prophylaxis may be prudent, especially when the time does not allow for adequate acclimatization. Nifedipine is the drug of choice for prophylaxis against HAPE and is recommended only in high-risk individuals and only when acclimatization is not possible. It has been reported to reduce the incidence of HAPE from 63% to 10% when ascending over 4,500 m. Ideally, treatment is started 24 hours prior to ascent and continued for 5 days at the destination altitude or until descent below 2,500 m is completed. In higher-risk scenarios, treatment may be continued for a longer period.

324  Yearbook of Anesthesiology-9

• Both tadalafil and sildenafil have been shown to be effective as prophylaxis for HAPE. Optimal doses have not been established. Tadalafil 10 mg twice daily has similar efficacy to nifedipine in HAPE prevention. However, a recent randomized controlled trial testing sildenafil for HAPE prophylaxis reported an increase in incidence and severity of AMS. Sildenafil has shorter dosing intervals because its half-life is 4–5 hours; tadalafil’s half-life is 17 hours.50 Dexamethasone: Glucocorticoids act through an improved alveolar fluid absorption and may have a role in prophylaxis, but to be effective must be taken prior to ascent. In one randomized trial of 29 individuals with a history of HAPE, none of the 10 participants given dexamethasone prophylaxis (8 mg every 12 hours) developed HAPE during a rapid ascent from 490 m to 4,559 m with an overnight stay. Prophylaxis with dexamethasone has the added advantage of preventing  AMS/HACE, whereas  nifedipine  and the PDE-5 inhibitors have no such effect.18 • Salmeterol should be considered only as an adjunct treatment to  nifedipine  in high-risk individuals with a clear history of recurrent HAPE. Salmeterol prevented HAPE in 50% of subjects in one small study and thus appears less effective than other agents.47,48 • Acetazolamide is a reasonable medication for HAPE prophylaxis, but formal studies are lacking.

CONCLUSION Exposure of human beings to altitude above 1,500 m puts them at risk of developing acute HA illnesses such as AMS, HAPE, and HACE. This happens primarily due to fall in barometric pressure resulting in low atmospheric oxygen pressure which affects physiological parameters. Hypoxia affects ventilation, systemic, pulmonary, and cerebral circulation. The maladaptive response to hypoxia causes alteration in ventilation and circulation causing high permeability HAPE. There are various modifiable and nonmodifiable risk factors for the development of HAPE. The diagnosis of HAPE is clinical. Pulse oximetry is a useful tool not only to document hypoxia and to monitor response to therapy but also to assess the degree of acclimatization. Treatment of HAPE is descent to lower altitude (actual or using hyperbaric chamber) and supplemental oxygen therapy. For prevention of HAPE, one should follow a three-stage acclimatization schedule recommended by the Indian Army and pharmacologic prophylaxis for high-risk individuals.

KEY POINTS • High altitude illnesses can result in sudden morbidity and at times mortality in apparently healthy individuals. • The common factor among HA illnesses is hypobaria resulting in hypoxia.

High-altitude Pulmonary Edema  325 The hypoxia leads to abnormal physiological responses in susceptible individuals. • Primarily, hypoxia causes pulmonary arterial hypertension which in turn causes high permeability pulmonary edema. • Rapid ascent to HA especially over 3,500 m in 1 day is the biggest risk factor for developing high-altitude pulmonary edema. • Pre-existing conditions like cold ambient temperatures, male gender, physical exertion, and genetics are associated with an increased incidence of HAPE. • High-altitude pulmonary edema generally begins as nonproductive cough, dyspnea on exertion, and difficulty walking uphill. Examination reveals tachycardia, tachypnea, and respiratory crackles. • Pulse oximetry is a useful tool to detect hypoxemia and to monitor response to oxygen therapy. • Treatment of HAPE includes limiting physical exertion and exposure to cold, evacuation to lower altitude, and oxygen administration. • Gradual ascent remains the primary method for preventing all forms of HA illnesses. A three-stage acclimatization schedule recommended by the Indian Army is most appropriate.

REFERENCES 1. Sutton J, Coates G, Houston C.  The Lake Louise consensus on the definition and quantification of altitude illness.  In: Hypoxia and Mountain Medicine. Burlington, Vermont: Queen City Printers; 1992. pp. 327-30. 2. Hackett PH, Roach RC. High altitude medicine and physiology. In: Auerbach PS (Ed). Wilderness Medicine, 6th edition. Philadelphia: Elsevier Mosby; 2012. pp. 19-25. 3. Paralikar SJ. High altitude pulmonary edema: clinical features, pathophysiology, prevention and treatment. Indian J Occup Environ Med. 2012;16(2):59-62. 4. Pennardt A. High-altitude  pulmonary edema: diagnosis, prevention and treatment. Curr Sports Med Rep. 2013;12(2):115-9. 5. Imray C, Wright A, Subudhi A, et al. Acute mountain sickness: pathophysiology, prevention, and treatment. Prog Cardiovasc Dis. 2010; 52(6):467-84. 6. Ebert-Santos C. High-altitude pulmonary edema in mountain community residents. High Alt Med Biol. 2017;18:278. 7. Gilbert DL. The first documented report of mountain sickness: the China or headache story. Respir Physiol 1983;52:315-26. 8. Haidar M. A history of the Moguls of Central Asia. In: Elias N (Translator). The Tarikh-IRashida, Mirza Haidar Dughlat as Depicted in Persian Sources; 1896. 9. Simons E,  Oelz O. The mysterious death of Dr. Jacottet on Mont Blanc. High Alt Med Biol.  2000;1(3):213-6. 10. Ravenhill TH. Some experiences of mountain sickness in the Andes. J Trop Med Hyg. 1913;1620:313-20. 11. Houston CS. Acute pulmonary edema of high altitude. N Engl J Med. 1960; 263(10):478-80. 12. Fred HL, Schmidt AM, Bates T, et al. Acute pulmonary edema at altitude. Clinical and psychological observations. Circulation. 1962;25:929-37. 13. Hultgren HN, Lopez CE, Lundberg E, et al. Physiologic studies of pulmonary edema at high altitude. Circulation. 1964;29:393-408.

326  Yearbook of Anesthesiology-9 14. Singh I, Kapila C, Khanna PK. High altitude pulmonary edema. Lancet. 1965;1:229-34. 15. Sitaram M. High altitude pulmonary oedema: a review of 85 cases. J Assoc Phys India.  1988;36:70. 16. Taneja VP. Pulmonary oedema of high altitude.  Med J Armed Forces India.  1980;36:231-6. 17. Deshwal R, Iqbal M, Basnet S.  Nifedipine for the treatment of high altitude pulmonary edema.  Wild Environ Med.  2012;23:7-10. 18. Bates MG, Thompson AA, Baillie JK. Phosphodiesterase type 5 inhibitors in the treatment and prevention of high altitude pulmonary edema. Curr Opin Investig Drugs. 2007;8:226. 19. Virmani SK. High altitude pulmonary oedema: an experience in Eastern Himalaya.  Med J Armed Forces India. 1997;53(3):163-8. 20. Menon ND. High altitude pulmonary edema. N. Engl J Med. 1965;273(2):66-73. 21. Bhalwar R, Singh R, Ahuja RC, et al. Nested case–control analysis of the risk factors for high altitude pulmonary oedema. Med J Armed Forces India. 1995;51:189-93. 22. Stream JO, Grissom CK. Update on high-altitude pulmonary edema: patho­ genesis, prevention, and treatment. Wilderness Environ Med. 2008;19:293. 23. Puthon L, Bouzat P, Rupp T, et al. Physiological characteristics of elite highaltitude climbers. Scand J Med Sci Sports. 2016;26(9):1052-9. 24. Dehnert C, Grunig E, Mereles D, et al. Identification of individuals susceptible to high-altitude pulmonary oedema at low altitude. Eur Respir J. 2005;25: 545-51. 25. Bartsch P, Mairbauri H, Maggiorini M, et al. Physiological aspects of highaltitude pulmonary edema. J Appl Physiol. 2005;98:1101-10. 26. Semenza GL. HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol. 2000;88:1474-80. 27. Bouzat P, Walther G, Rupp T, et al. Time course of asymptomatic interstitial pulmonary oedema at high altitude. Respir Physiol Neurobiol. 2013;186:16. 28. Bhaumik G, Dass D, Bhattacharyya D, et al. Heart rate variabilty changes during first week of acclimatization to 3500 m  altitude  in Indian military personnel. Indian J Physiol Pharmacol. 2013;57(1):16-22. 29. Scherrer U, Allemann Y, Rexhaj E, et al. Mechanisms and drug therapy of pulmonary hypertension at high altitude. High Alt Med Biol. 2013;14:126. 30. Groves BM, Reeves JT, Sutton JR,  et al. Operation Everest II: elevated highaltitude pulmonary resistance unresponsive to oxygen. J Appl Physiol. 1987;63:521-30. 31. Gonggalanzi, Labasangzhu, Bjertness E, et al. Acute mountain sickness, arterial oxygen saturation and heart rate among Tibetan students who reascend to Lhasa after 7 years at low altitude: a prospective cohort study. BMJ Open. 2017; 7(7): e016460. 32. Boos CJ, Woods DR, Varias A, et al. High altitude and acute mountain sickness and changes in circulating endothelin-1, interleukin-6, and interleukin-17a. High  Alt Med Biol. 2016;17(1):25-31. 33. Ebert-Santos C. High-altitude pulmonary edema in mountain community residents. High Alt Med Biol. 2017;18:278. 34. Bloch KE, Turk AJ, Maggiorini M, et al. Effect of ascent protocol on acute mountain sickness and success at Muztagh Ata, 7546 m. High Alt Med Biol. 2009;10:25-32.

High-altitude Pulmonary Edema  327 35. Sartori C, Duplain H, Lepori M, et al. High altitude impairs nasal transepithelial sodium transport in HAPE-prone subjects.  Eur Respir J.  2004;23:916-20. 36. Hagen PT, Scholz DG, Edwards WD. Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc. 1984;59(1):17-20. 37. Meissner I, Whisnant JP, Khandheria BK, et al. Prevalence of potential risk factors for stroke assessed by transesophageal echocardiography and carotid ultrasonography: the SPARC study. Stroke prevention: assessment of risk in a community. Mayo Clin Proc. 1999;74(9):862-9. 38. Maggiorini M, Melot C, Pierre S, et al. High altitude pulmonary edema is initially caused by an increase in capillary pressure. Circulation. 2001;103:2078-83. 39. Breuer H-WM, Groeben H, SchoÈndeling H, et al. Comparative analysis of arterial oxygen saturations during exercise by pulse oximetry, photometric measurements, and calculation procedures. Int J Sports Med. 1990;11:22-5. 40. Luks AM, McIntosh SE, Grissom CK, et al. Wilderness Medical Society consensus guidelines for the prevention and treatment of acute altitude illness. Wild Environ Med. 2010;21:146-55. 41. Syed VS, Sharma S, Singh RP. Determinants of acclimatisation in high altitude. Med J Armed Forces India. 2010;66(3):261-5. 42. Hultgren HN, Honigman B, Theis K, et al. High-altitude pulmonary edema at a ski resort. West J Med. 1996;164:222. 43. Vock P, Brutsche MH, Nanzer A, et al. Variable radiomorphologic data of high altitude pulmonary edema. Features from 60 patients. Chest. 1991;100:1306. 44. Wimalasena Y, Windsor J, Edsell M. Using ultrasound lung comets in the diagnosis of high altitude pulmonary edema: fact or fiction? Wilderness Environ Med. 2013;24:159. 45. Marticorena E, Hultgren HN. Evaluation of therapeutic methods in high altitude pulmonary edema. Am J Cardiol. 1979;43:307. 46. Freeman K, Shalit M, Stroh G. Use of the Gamow Bag by EMT-basic park rangers for treatment of high-altitude pulmonary edema and high-altitude cerebral edema. Wilderness Environ Med. 2004;15:198. 47. Bärtsch P, Swenson ER, Maggiorini M. Update: high altitude pulmonary edema. Adv Exp Med Biol. 2001;502:89. 48. Hackett PH, Roach RC, Hartig GS, et al. The effect of vasodilators on pulmonary hemodynamics in high altitude pulmonary edema: a comparison. Int J Sports Med. 1992;13(Suppl 1):S68. 49. Oelz O, Maggiorini M, Ritter M, et al. Prevention and treatment of high altitude pulmonary edema by a calcium channel blocker. Int J Sports Med. 1992;13(Suppl 1):S65. 50. Maggiorini M, Brunner-La Rocca HP, Peth S, et al. Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema: a randomized trial. Ann Intern Med. 2006;145:497. 51. Luks AM, McIntosh SE, Grissom CK, et al. Wilderness Medical Society consensus guidelines for the prevention and treatment of acute altitude illness.  Wild Environ Med. 2010;21:146-55. 52. Director General Armed Forces Medical Service. Medical memoranda in problems of high altitude 1997;140:31-2.

328  Yearbook of Anesthesiology-9

CHAPTER

22

Infection Prevention in the Operating Room Neha Agrawal

INTRODUCTION Operating room (OR) is one of the most critical areas of any healthcare organization in which infection prevention and controlled practices are challenging for administrators as well as clinicians. Various studies have shown the cross-contamination in the OR as a result of certain problematic practices by the anesthesia providers,1 breach in engineering controls or improper environment cleaning and disinfection. Although inoculation of the operative site by the endogenous patient flora intraoperatively is the major cause of surgical site infections (SSI), contaminated OR environment has been identified as an important source of SSI in some settings. Surgical site infection is a significant cause of morbidity and mortality and is responsible for 38% of hospital-acquired infections in surgical patients.2 Various endogenous (patient-related) and exogenous factors influence the risk of SSI. Malnutrition, old age, coexistent infection, and diabetes are patient-related factors whereas external risk factors are multifaceted. The quality of preoperative skin preparation, type, and duration of surgery, timing, adequacy, and appropriateness of antibiotic prophylaxis, surgeons’ skill, insertion of implants, anesthesia provider’s practices, inadequate sterilization of surgical instruments are the external risk factors.3 Besides this, OR quality has a significant association with surgical wound infection4 which is affected by OR design, layout, heating, ventilation, and air conditioning (HVAC), management, and behavior of healthcare workers. Hence, it is imperative that appropriate measures are taken to prevent infection in OR beginning from designing to routine intervention, the involvement of clinicians, staff and senior leaders for implementation of those infection prevention strategies.1,4-14

Infection Prevention in the Operating Room  329

INFRASTRUCTURE MEASURES Operating Room Complex Design Location Operating room complex should preferably be located where the patient movement is minimal and hence, the ground floor location should be avoided as there is maximum traffic of patients.

Zoning of Operating Room Complex As an infection control measure, OR complex layout has four zones: 1. Protective zone: Change rooms, staff rooms, preoperative area, recovery beds, stores, and records lie in the protective zone. 2. Clean zone (semisterile zone): After the protective zone and before sterile zone lies the clean zone. All personnel need to change in OR dress before entering the clean zone. The scrub station, sterile disposable storing areas lie in this zone. 3. Sterile zone: The main operating area (OR) lies in this zone. 4. Disposal zone: All unsterile items from the OR should come out through a separate exit (other than the entry of OR) directly into the disposal zone.

Heating Ventilation and Air Conditioning System Operating room air quality is maintained by an HVAC system which is an important determinant of surgical wound contamination intraoperatively. The HVAC system consists of the following components:5 • Air handling unit (AHU) • Inflow and outflow ducts • Air conditioning compressor • Air blower • Pre-high efficiency particulate air (HEPA) filters (3 and 5 µ filters) • Laminar airflow (LAF) plenum • Terminal 0.3 µ HEPA filter. The AHU should be operational round the clock to maintain the air quality. A variable flow device if installed reduces the electrical load consumption and regulates the air exchanges in the OR without the cooling effect. Cleaning of filters needs to be done on a regular basis. Prefilters can be reused. The terminal 0.3 µ HEPA filter needs to be changed when the particulate counts and air qualities are not up to the required standards.5 The maximum allowable particle concentration of ISO Class 4, 5 and 6 rooms as per ISO 14644-1:201515 cleanroom classification is given in Table 1.

330  Yearbook of Anesthesiology-9 Table 1: Maximum allowable particle concentration of ISO Class 4, 5, and 6 as per ISO 14644-1:2015.15 ISO Class number

Maximum allowable concentration (particles/m3) for particles equal to and bigger than below-mentioned sizes O.1 µm

0.2 µm

0.3 µm

0.5 µm

1 µm

5 µm

4

10,000

2,370

1,020

352

83

–

5

100,000

23,700

10,200

3,520

832

293

6

1,000,000

237,000

102,000

35,200

8,320

2,930

In 2008, the American National Standards Institute, the American Society of Heating Refrigerating and Air Conditioning Engineers and the American Society for Health Care Engineering of the American Hospital Association jointly developed the ventilation and air conditioning guidelines which was further revised in 2017.16 Some features of guidelines state the requirement of positive pressure within the OR as compared to adjacent areas, to have at least 20 air changes/h (4 or more should be fresh air). Average OR temperature range is from 20°C to 23°C, except for certain type of surgical procedure, e.g. cardiac (17°C) and pediatric surgeries (27°C).17 Centers for Medicare & Medicaid Services (CMS) recommend separate temperature controls for each OR.18 Recently, there has been a change in requirements of relative humidity levels in ORs. Instead of the requirement of maintenance of more than 35% relative humidity, it has now been recommended to have relative humidity between 20% and 60%.18 National Accreditation Board for Hospitals & Healthcare Providers (NABH) has also given air conditioning guidelines for OR. The latest NABH guidelines6 of air conditioning in OR are summarized in Table 2. In addition, NABH guidelines recommend dedicated AHU for each OR. In case there is one AHU for multiple ORs, there should be backup OR so that surgeries can be performed in these ORs in case of breach of sterility in ORs with single AHU. AHU should be located where there are no source of contamination, e.g. vehicle parking area, DG exhaust hoods, and lab exhaust vents. The window and split AC should not be used in any type of OR. Cleaning of preHEPA filters is recommended at the interval of 30 days. NABH recommends the validation of the system bi-annually and as per ISO 14644 standards.6 Table 3 mentions the checks during the validation process. Although above-stated guidelines have mentioned the use of LAF system to minimize the contamination of the surgical field with airborne microorganisms and its contribution in the reduction of SSI, few publications have questioned the use of LAF. Further to this, Jain and Reed reviewed contemporary laminar airflow handling systems and made recommendations for effective laminar airflow use.19 Table 4 lists these recommendations.

20

Type B (erstwhile general OR)

4

4

Fresh

FPM

Unidirectional 25–35 and downward on OR table

Unidirectional 25–35 and downward on OR table

Pattern

Air velocity (FPM)

2.5

2.5

Pascal

Positive pressure

90%

90%

10 µ

99.97%

99.97%

5µ

Pre-HEPA filter

(FPM: feet per minute; HEPA: high-efficiency particulate air; OR: operating room)

20

Total

Type A (erstwhile super-specialty OR), e.g. neurosciences OR, orthopedic (joint replacement), cardiothoracic and transplant surgery OR

Type of OR

Minimum air changes per hour Class 100/ ISO Class 5 (at rest condition)

Air quality at grill level

May be Class 1000/ provided ISO Class 6 (at rest condition)

99%

0.3 µ

HEPA filter

Air filtration

21°C ±3°C

21°C ± 3°C (joint replacement 18°C ±2°C)

Temperature

Table 2: National Accreditation Board for Hospitals  and  Healthcare Providers (NABH) guidelines for air conditioning in OR.

20–60% ideal 55%

20–60% ideal 55%

Relative humidity

Infection Prevention in the Operating Room  331

332  Yearbook of Anesthesiology-9 Table 3: Biannual OR checkpoints during validation as per the National Accreditation Board for Hospitals and Healthcare Providers (NABH) 2018 guidelines.6 Temperature Humidity Air change rate Air velocity at the outlet of terminal filters Pressure differential levels HEPA filters efficiency (HEPA: high-efficiency particulate air; OR: operating room)

Table 4: Recommendations for effective laminar airflow (LAF) use.19 Element

Action

Operating room (OR) door opening after Minimal the start of surgery Number of staff in OR

Restrict

OR light position

Should not be directly over the surgical site

Opening of instrument trays and implants

At the time of the beginning of surgery

Air warming appliance

Blanket or resistive heating mattress preferred

Duration of C-Arm use within the ultraclean enclosure

Should be limited

Physical actions near the surgical field and instrument trays

Minimal

Position of surgeon

Should not cut off vertical airflow stream

Changing of gloves

Not near surgical site or instrument trays

Periphery of the ultraclean enclosure

Keep clear

Water Distribution System Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Acinetobacter spp., etc. cause healthcare-associated infections through the water distribution system in hospitals. Taps are the common source of P. aeruginosa. Hence, water used in dental surgery and for surgical hand scrubs in OR needs strict quality control to prevent infection. Microperforation of gloves happens in around 18% cases at the end of surgery and in 35% of cases after 2 hours of surgery. Although with the double gloving technique, the risk of puncture is reduced to 4%, the

Infection Prevention in the Operating Room  333

surgical handwash is an important step before wearing sterile gloves, further emphasizing the strict quality control of water distribution system.4,20,21

Trained Personnel Infection control team persons must be trained in SSI surveillance methods, able to use knowledge of SSI and should be able to apply SSI definition in different settings. Besides this, they must have basic computer skills and be skilled and trained to provide feedback and education to healthcare personnel when required.

Education Measures and Methods Regular education should be provided to surgeons, anesthesiologists, and perioperative personnel for implementation of recommended process measures in order to minimize SSI.

Computer-aided Decision-making System and Electronic Reminders The application of this technology has been successful at several hospitals in improving the rate of the timely administration of prophylactic antibiotic in OR, although an increase of adverse drug reaction has been reported by one study.22

Application of Electronic Data Information technology infrastructure helps in appropriate compilation and analysis of data so that process and outcome measures can be tracked and required interventions can be implemented.

BEHAVIORAL MEASURES Anesthesia Providers Practices Various studies have reported contamination of anesthesia work area by anesthesia provider practices; for example, use of multiple-dose vials in more than one patient, airway management without the use of gloves, nonperformance of hand hygiene (HH) after removing gloves, use of anesthesia trolley drawers without performing HH. The Society for Healthcare Epidemiology of America (SHEA) has provided recommendations specific to the anesthesia work area to improve infection prevention through HH, environmental disinfection, and implementation of effective improvement efforts.1 Table 5 summarizes the SHEA guidance statement, recommendations, and rationale behind each recommendation.

Recommendation

At the minimum: •• Before aseptic tasks (e.g. inserting a central venous catheter, drawing medication, piercing I/V bags). •• After removing gloves. •• When hands are soiled or contaminated. •• Before touching the anesthesia cart. •• When entering and exiting OR (even after removing gloves). •• Increase access to ABHR near anesthesia cart.

Double gloves should be used during airway management and outer gloves are to be removed immediately after airway handling. Inner glove is to be removed as soon as possible and HH performed.

Locate ABHR dispensers at the entrances to ORs and near anesthesia providers inside OR.

HH should be performed after changing gloves. •• In case it is not feasible to perform HH then ABHR on gloves is better than no HH.

Guidance statement

1. When should anesthesia providers use hand hygiene (HH)?

2. Use of double gloves during airway management.

3. What should be the location of ABHR dispensers in the OR?

4. Can ABHR be applied on contaminated gloves and further work performed with the same gloves on?

Contd…

•• Application of ABHR on gloves may interfere with the integrity of gloves. •• In certain outbreaks of infection, CDC has recommended use of ABHR multiple times on gloves.39

•• Facilitates use of ABHR for hand hygiene at the time of entry and exit from OR. •• ABHR dispenser location on the anesthesia machine has shown increased compliance with HH.

•• Anesthesia providers hand may become contaminated with upper airway secretions. •• Contamination of anesthesia work environment decreased after removal of the outer layer but was not completely eliminated38 and hence HH to be performed after removal of the second layer.

•• If WHO 5 moments for HH is used as the standard, it can be as high as 54/h which is logistically unfeasible especially during induction. •• Hand hygiene by anesthesia staff is increased with increased access to ABHR.37

Rationale

Table 5: Summary of Society for Healthcare Epidemiology of America (SHEA) expert guidance for infection prevention in anesthesia work area.1

334  Yearbook of Anesthesiology-9

Recommendation

•• Reusable laryngoscope handles and blades should undergo high-level disinfection or sterilization. OR  Use single-use laryngoscopes. •• After cleaning blades and handles should be packaged until just prior to use. •• Do not use handles that cannot undergo high-level disinfection. •• Same principles to be applied to supraglottic airway masks.

Data inadequate to make any such recommendations.

Clean and disinfect high-touch surfaces on the anesthesia machine and anesthesia work environment between OR uses (e.g. anesthesia machine work surface, gas flow controls, vaporizer dials, adjustable pressure limiting (APL) valve, I/V stands, and fluid warmers). •• All equipments which are in physical contact with patients should be cleaned thoroughly, e.g. pulse oximeter, ECG leads and cable, reusable blood pressure cuffs.

Guidance statement

5. Should single-use laryngoscopes be used instead of reusable ones?

6. Can covering of anesthesia machines with disposable covers prevent crosscontamination?

7. How the cleaning and disinfection of the anesthesia machine and work environment be done between two cases?

Contd…

Contd…

Various studies have demonstrated the contamination of anesthesia machine and work area with potentially pathogenic microbes which can be further transmitted to patients through direct contact with contaminated equipments, hands of anesthesia providers or contaminated medications. 23-25

___

•• Low-level disinfection does not remove blood and bacteria from laryngoscope handles.40 •• Reports have shown that contaminated laryngoscopes have been responsible for the outbreak of infectious disease.41

Rationale

Infection Prevention in the Operating Room  335

Recommendation

Rationale

Necks of ampules, medication vials, and rubber stoppers should be wiped with 70% alcohol before use.

All central venous catheters (CVCs) and axillary and femoral arterial lines should be inserted with full sterile barrier precautions, i.e. mask, cap, sterile gown, sterile gloves, and large sterile drape. •• Place peripheral arterial lines (e.g. radial, brachial) with a minimum of a cap, mask, sterile gloves, and a small sterile perforated drape. •• These measures are recommended even when exchanging catheter over a guidewire.

9. How should vials of anesthesia drug be disinfected at the time of use?

10. What barrier precautions should be used at the time of insertion of intravenous catheters?

Contd…

Based on the compendium of strategies to prevent bloodstream infections in Acute Care Hospitals43 and 2011 Healthcare Infection Control Practices Advisory Committee (HICPAC) guidelines.44

Caps of anesthesia medications are not sterile.

8. How should anesthesia •• Anesthesia providers should only use disinfected ports •• Peripheral intravenous tubing stopcocks and injection providers use injection for intravenous access. ports used for medication administration frequently get ports in OR? •• Scrub the port with a sterile alcohol-based contaminated. disinfectant before each use immediately prior to each •• Reduction in central line-associated bloodstream use or cover the ports continuously with isopropyl infections (CLABSI) by disinfecting catheter hubs, alcohol-containing caps. needleless connectors, and injection ports43 have been •• For rapid successions of injections as during reported. induction of anesthesia, ports should be disinfected at the beginning. •• Compliance of disinfection of injection ports increases with the use of sterile alcohol-containing caps.42

Guidance statement

Contd…

336  Yearbook of Anesthesiology-9

•• Disinfect accessible outer surface of anesthesia supply trolley between cases. •• Always perform HH before opening anesthesia trolley drawers. •• As far as possible, anesthesia trolley’s top surface should be free of supplies.

Use provider prepared sterile injectable drugs as soon as practically possible but may be used until the end of the case in a setting of air less clean than ISO Class 5.46

Minimal time duration should be there after piercing I/V ____ bags and their use. No specific time limit is identified.

12. How should be cross-contamination of anesthesia trolley clean supplies be prevented?

13. How long the injectable drugs prepared by the anesthesia providers can be kept?

14. What is the time duration for which I/V bags can be pierced before starting the use?

Contd…

•• Austin et al.47 found that contamination of the drugs prepared in the clinical setting is more than prepared in a pharmaceutical setting. •• Studies have shown that propofol after preparation in syringes can expire within 6 hours.48

Various studies have shown contamination of anesthesia workspace,27,45 anesthesia provider hands, BP cuff, pulse oximeter probe, and have shown the cross-contamination association with surgical site infection.26

The risk of cross-contamination from the anesthesia provider’s hand and work environment will be reduced by capping of the syringe.

Cap the needleless syringes used to administer multiple doses of the drug in the same patient, after each use so that it covers the Luer connector on the syringe.

11. When should be recapping of medication syringe be done?

Rationale

Recommendation

Guidance statement

Contd…

Infection Prevention in the Operating Room  337

Cleaning and disinfection of monitor touch screen and other surfaces in anesthesia workspace be done after each case and when there are obvious soiling and contamination.

•• Guidelines as per hospital infection control policy should be followed for such patients in OR, e.g. performing hand hygiene and use of personal protective equipment (PPE). •• Do environmental disinfection in-between cases, irrespective of patient’s multidrug-resistant organism status.

16. When should the disinfection of touch screens of monitors in the anesthesia work environment be done?

17. What infection prevention measures should be taken for patients in contact isolation?

Contd…

•• Contaminated hands of anesthesia providers have been implicated in cross-contamination of anesthesia workspace, e.g. anesthesia machine, anesthesia trolley, I/V stopcocks etc.23,26,52,53 •• Routine cleaning does not decontaminate anesthesia workspace which is responsible for maximum crosscontamination between cases.26 •• Maximum risk of contamination of anesthesia workspace occurs during induction and emergence of anesthesia.26,52

Studies have shown contamination with bacteria such as coagulase-negative staphylococci, Bacillus spp., and MRSA.45

•• Use single-dose medication vials and flushes whenever Various guidelines for safe injection practices.49-51 possible. In case of mandatory use of multiple-dose medicine vials, its use should be restricted to a single patient only. New syringe and needle should be used for each access. •• Syringes and needles should not be used from one patient to another.

15. What is the protocol for the reuse of syringes and medication vials?

Rationale

Recommendation

Guidance statement

Contd…

338  Yearbook of Anesthesiology-9

•• Infection prevention practices should be regularly monitored and evaluated. •• Management and physician leaders should: –– Facilitate the use of process measures to improve performance. –– Share data which is real.

Feedback on hand hygiene performance by the anesthesia providers should be given to bring overall improvement.

•• Apply measures to assess the appropriateness and adequacy of environmental disinfection and track the measures. •• Share the results with stakeholders for optimization of adherence to recommended disinfection practices

18. What measures can bring improvement in infection prevention practices by anesthesia providers?

19. What is the effect of feedback about data on hand hygiene?

20. What is the effect of providing measurement and feedback data on environmental disinfection?

Various studies have shown the improvement in the thoroughness of cleaning with different measures and feedback. One study has shown improvement in anesthesia providers adherence following engagement by coaching.30

•• Institutions have used various types of monitoring and feedback to increase providers’ compliance to HH. •• Compliance with HH has improved with an intermittent electronic reminder.

•• Monitoring, evaluation, and feedback to providers are important. Audit and feedback programs based on theory and evidence are effective.54 •• Reminder cards and checklists have improved adherence to transmission-based precautions.55,56 •• Literature shows improvement with leadership involvement.

Rationale

Staphylococcus aureus; OR: operating room)

(ABHR: alcohol-based hand rub; CDC: centers for disease control and prevention; ECG: electrocardiogram; MRSA: Methicilin–Resistant

Recommendation

Guidance statement

Contd…

Infection Prevention in the Operating Room  339

340  Yearbook of Anesthesiology-9

An extensive literature review has revealed that anesthesia workspace can become contaminated with pathogens.23-26 The bacteria population includes coagulase-negative Staphylococcus, Bacillus spp., Streptococcus, S. aureus, Acinetobacter, and other gram-negative bacilli. The bacterial strains which contaminate the anesthesia machine’s adjustable pressure-limiting valve have been implicated more in cross-contamination of IV stopcock than the bacterial strains which are found colonizing the patient’s nasopharynx and axilla and on anesthesia providers’ hands.27 This contamination of I/V stopcock was attributed to low hand hygiene by the anesthesia provider. Cole et al.28 have demonstrated the bacterial growth in I/V stopcock where even preservative containing propofol has been used for the case. Loftus et al.29 in their study showed that after induction of anesthesia the bacterial contamination of closed stopcock with alcohol disinfection was 0%, whereas the same device with no disinfection before induction showed 4% bacterial growth. Various publications have emphasized the role of environmental cleaning in reducing the bioburden of the anesthesia workspace and resultant cross contamination.30-32 Gonzalez et al.33 in his study compared the commercial disinfectant wipes with bleach and water and sodium hypochlorite. They found that sodium hypochlorite was better than gauze and bleach and water. They emphasized that bacteria should be physically removed from anesthesia device surfaces when being used in different cases. Anesthesia provider’s practice of airway management has also resulted in bacterial contamination of laryngoscopes handles and blades and have further resulted in cross-contamination of anesthesia workspace.34,35-37 “Double gloving” during airway management and sheathing of the laryngoscope with the outer glove while it is being removed has resulted in further reduction of contamination.35,36 As a future course of action Munoz et al.1 have suggested a need for redesigning of anesthesia machine so that it can be effectively disinfected in-between cases. They have also quoted examples where anesthesia trolley is kept in the zone labeled as clean where only hands after hand hygiene are allowed although this practice has been found to be challenging.

Staff Behavior Airborne particles after coming in contact with walls, floor, skin or other surfaces act as a vector for bacterial transmission. Foot traffic and opening of doors generate air eddies which disperse these particles settled on an unsterile floor. The role of minimizing OR staff movement in and out of OR in decreasing surgical site infection rates in hospitals has been reported.57

Infection Prevention in the Operating Room  341

Restricting the number of personnel in the OR to 5 or 6 ensures the airborne bacterial count to up to 10 CFU/m3.58

Surgical Team Preparation Noguchi et al.59 demonstrated the dispersion of particles in OR at the time of unfolding of surgical drape by OR nurse at the time of preparing instrument trolley, at the time of wearing of the gown and at the time of wearing and removal of gloves. As mentioned above, airborne particles can act as a vector for transmission of bacteria after coming in contact with unsterile areas.11 They recommended that OR staff should avoid above mentioned actions near surgical site or sterile instruments. The timing of the preparation of instrument trolley should be coordinated with the draping of the patient as the rate of contamination increases with increase in the duration of opening of instrument tray (4% after 30 minutes, 15% after 1 hour, and 30% after 4 hours).11 The containers and instruments must remain covered until the time of starting of operation.

CLINICAL MEASURES The literature search revealed various publications which have mentioned clinical preventive measures for surgical site infection in the OR.7,8,11,13,14,60 WHO has provided evidence-based global recommendations for pre-, intra- and postoperative period interventions.61 The guidelines have been developed considering the source availability, values, and preferences. Table 6 summarizes the interventions to be carried out in OR for prevention of SSI as per WHO global guidelines along with the strength of recommendation and quality of evidence. Besides the above measures, redosing of prophylactic antibiotics have been recommended in case of long procedures and in the case with excessive blood loss during the surgical procedures.7,8,62 Redosing has to be done at an interval of 2 half-lives (measured from the time the preoperative dose was administered) and for every 1,500 mL estimated blood loss. Studies have shown a lower rate of surgical site infection and death with use of surgical safety checklist in OR.63-65

DISINFECTION AND STERILIZATION MEASURES Proper biomedical waste (BMW) handling, disinfection, and sterilization techniques of OR, surgical instruments, anesthesia equipments, and devices play a significant role in infection prevention and reduction in associated healthcare-acquired infections/SSI.

How safe and effective is the perioperative use of an increased fraction of inspired oxygen in reducing the risk of SSI?

Should systemic body warming versus no warming be used for the prevention of SSI in surgical patients?

3. Perioperative oxygenation

4. Maintaining normal body temperature (normothermia)

The panel suggests the use of warming devices in the operating room and during the surgical procedure for the patient body warming with the purpose of reducing SSI.

The panel suggests that adult patients undergoing general anesthesia with tracheal intubation for surgical procedures should receive an 80% fraction of inspired oxygen intraoperatively and, if feasible, in the immediate postoperative period for 2–6 hours to reduce the risk of SSI.

The panel recommends alcohol-based antiseptic solutions-based CHG for surgical site skin preparation in patients undergoing surgical procedures.

Should alcohol-based antiseptic solutions or aqueous solutions be used for skin preparation in surgical patients and, more specifically, should CHG or PVP-I solutions be used?

2. Surgical site preparation

Recommendations •• The panel recommends that SAP should be administered prior to the surgical incision when indicated (depending on the type of operation). •• The panel recommends the administration of SAP within 120 minutes before the incision while considering the half-life of the antibiotic.

Research questions

1. Optimal timing for How does the timing of SAP preoperative SAP administration impact on the risk of SSI and what is the precise optimal timing?

Topic

Conditional

Conditional

Contd…

Moderate

Moderate

Low to moderate

Moderate

Strong

Strong

Low

Quality of evidence

Strong

Strength

Table 6: Summary points for clinical intervention in the operating room (OR) to prevent SSI as per WHO Guidelines, 2018.61

342  Yearbook of Anesthesiology-9

Research questions

•• Do protocols aiming to maintain optimal perioperative blood glucose levels reduce the risk of SSI? •• What are the optimal perioperative glucose target levels in diabetic and nondiabetic patients?

Does the use of specific fluid management strategies during surgery affect the incidence of SSI?

Does the use of wound protector devices reduce the rate of SSI in open abdominal surgery?

Does intraoperative wound irrigation reduce the risk of SSI?

Topic

5. Use of protocols for intensive perioperative blood glucose control

6. Maintenance of adequate circulating volume control/ normovolemia

7. Wound protector devices

8. Incisional wound irrigation

Contd…

Conditional

Conditional

Conditional

Strength

The panel considered that there is insufficient evidence NA to recommend for or against saline irrigation of incisional wounds before closure for the purpose of preventing SSI.

The panel suggests considering the use of wound protector devices in clean-contaminated, contaminated and dirty abdominal surgical procedures for the purpose of reducing the rate of SSI.

The panel suggests the use of goal-directed fluid therapy intraoperatively to reduce the risk of SSI.

The panel suggests the use of protocols for intensive perioperative blood glucose control for both diabetic and nondiabetic adult patients undergoing surgical procedures to reduce the risk of SSI. The panel decided not to formulate a recommendation on this topic due to the lack of evidence to answer question 2.

Recommendations

NA

Contd…

Very low

Low

Low

Quality of Evidence

Infection Prevention in the Operating Room  343

Does prophylactic negative pressure wound therapy reduce the rate of SSI compared to the use of conventional dressings?

At the time of wound closure, is there a difference in SSI when instruments are changed for fascial, subcutaneous, and skin closure using a new set of sterile instruments?

Are antimicrobial-coated sutures effective to prevent SSI? If yes, when and how should they be used?

9. Prophylactic negative pressure wound therapy

10. Changing of surgical instruments

11. Antimicrobialcoated sutures

Conditional

The panel suggests that antibiotic incisional wound irrigation should not be used for the purpose of preventing SSI.

The panel suggests the use of triclosan-coated sutures for the purpose of reducing the risk of SSI, independent of the type of surgery.

The panel decided not to formulate a recommendation on this topic due to the lack of evidence.

Conditional

NA

Conditional

Conditional

The panel suggests considering the use of irrigation of the incisional wound with an aqueous PVP-I solution before closure for the purpose of preventing SSI, particularly in clean and clean-contaminated wounds.

The panel suggests the use of prophylactic negative pressure wound therapy in adult patients on primarily closed surgical incisions in high-risk wounds for the purpose of the prevention of SSI, while taking resources into account.

Strength

Recommendations

Under open licence: CC BY-NC-SA 3.0 IGO. (CHG: chlorhexidine gluconate; PVP-I: povidone-iodine; SAP: surgical antibiotic prophylaxis; SSI: surgical site infection)

Research questions

Topic

Contd…

Moderate

NA

Low

Low

Low

Quality of Evidence

344  Yearbook of Anesthesiology-9

Infection Prevention in the Operating Room  345

Operating Room Biomedical Waste Management Appropriate segregation, transportation, and treatment of BMW as per local and national guidelines are recommended.

Cleaning Routine cleaning of OR removes contaminants, dust, and organic matter. The floor is to be kept clean and dry which cause the natural death of bacteria except for spores. Detergent decrease bacterial flora by 80% and disinfection further reduces it to 95%. Wet mops instead of brooms are to be used. Walls should be washed weekly with water, soap, and disinfectants.

Disinfection Daily mopping of floors and walls with a disinfectant is to be done in the morning before starting the procedures and at the end of the daily scheduled cases. In between the operative procedures, the floor is to be mopped with disinfectant.

Surgical Instruments Associations of Perioperative Registered Nurses (AORN) have recommended practices for cleaning and sterilization of surgical instruments.66 Preliminary cleaning is done and all instruments are initially rinsed with water followed by ultrasonic cleaning with disinfectant. Mechanic scrubbing is done with soft bristle brush followed by air drying of instruments with high flow jet air gun. After drying, packing of instruments done which are finally sterilized as per protocol either by steam sterilization, ethylene oxide (ETO) sterilization or plasma sterilization.

Anesthesia Equipment and Devices Western world trend toward the use of disposable or single-use equipment poses a problem in countries with limited resources. In case of reuse of equipments or devices, decontamination is done before disinfection or sterilization which reduces the bioburden. Further, disinfection and sterilization are followed as per national/international guidelines set as a protocol in association with hospital infection control policy. Various methods are; chemical disinfection, autoclaving, ETO sterilization/ plasma sterilization which are used as per identification of type of items (critical, semicritical, or noncritical) and required level of disinfection (high, intermediate, or low-level disinfection) and sterilization.67 Necessary

346  Yearbook of Anesthesiology-9

personal protective equipment (PPE) should be used by personnel involved in cleaning equipment as a protective measure to prevent injuries and infection.68

SURVEILLANCE PROTOCOL Microbiological surveillance of OR is done as monitoring for infection prevention and is done based on the amount of surgical load, the occurrence of SSI, availability of resources, funds, access to microbiologist, and the maintenance of air quality in OR.5 Sampling involves: • Air sampling • Particulate counts • HEPA filter efficiency test • Swabs from anesthesia work area: ▪▪ Adjustable pressure limiting (APL) valve ▪▪ Vaporizer dials ▪▪ Gas flow controls. • Culture of in use disinfection solution, e.g. from the disinfectant solution used for endoscope cleaning and for disinfecting the reusable item. • OR staff: nasal swabs, hand culture.

CONCLUSION Infection prevention in the OR is a multidisciplinary approach. Flowchart 1 depicts the strategical measures to be taken to prevent infection at the level of the OR staff, anesthesiologist and surgeons with collaborative support from the infection control team and senior leaders of any healthcare organization. An efficient HVAC system, preventing contamination of anesthesia work area, appropriate and timely surgical antibiotic prophylaxis, disinfection and sterilization of OR, surgical instruments, anesthesia equipments and devices, microbiological surveillance protocol of OR play a significant role in reducing cross-contamination in the OR and a further reduction in health care-associated and surgical site infection.

KEY POINTS • Efficient HVAC system to control temperature, humidity, pressure gradient, microbial, and air particle contamination is to be installed at the time of designing of OR as an infection prevention measure. • Effective LAF use requires the restriction of personnel in OR, minimal door openings, no change of gloves over surgical site or instrument tray, avoidance of obstruction of vertical airflow by surgeon’s heads minimal physical actions near the surgical fields and instruments.

(AWA: anesthesia work area; BMW: biomedical waste; HH: hand hygiene; HEPA: high-efficiency particulate air; HVAC: heating, ventilation, and air conditioning; OR: operating room)

Flowchart 1: Strategical measures to prevent infection in the operating room.

Infection Prevention in the Operating Room  347

348  Yearbook of Anesthesiology-9 • Frequent HH is recommended to reduce cross-contamination from the anesthesia provider’s hands. • Disinfection of anesthesia work environment is mandatory in between two cases and at the end of all cases to reduce the intraoperative bacterial transmission and for further reduction in surgical site infection. • Safe injection practices are to be followed at all times by the anesthesia providers and other staff in OR as per WHO guidelines. • Taking precautions at the time of preparation of trolleys, draping of the patient, and while changing gloves helps to minimize dispersion of airborne particles. • Appropriate time, type and dose of prophylactic surgical antibiotic, surgical site preparation, use of increased concentration of perioperative oxygenation, maintenance of normothermia, normovolemia, blood sugar control, use of wound protection device, use of triclosan-coated sutures are the elements for infection prevention in the OR. • Cleaning and disinfection of OR floors and walls are equally important as the appropriate segregation, transportation, and treatment of BMW. • Surgical instruments, anesthesia equipment, and devices should be disinfected and sterilized with utmost care to prevent any breach in sterility. • Surveillance protocols in OR, monitoring, evaluation, feedback to stakeholders, teaching and training with the involvement of infection control team, OR staff, clinicians in OR and senior leaders impact infection prevention in the OR.

REFERENCES 1. Munoz-Price LS, Bowdle A, Johnston BL, et al. Infection prevention in the operating room anesthesia work area. Infect Control Hosp Epidemiol. 2019;40: 1-17. 2. Weigelt JA, Lipsky BA, Tabak YP, et  al. Surgical site infections: causative pathogens and associated outcomes. Am J Infect Control. 2010;38:112-20. 3. Dharan S, Pittet D. Environmental controls in operating theatres. J Hosp Infect. 2002;51(2):79-84. 4. Spagnolo AM, Ottria G, Amicizia D, et al. Operating theater quality and prevention of surgical site infections. J Prev Med Hyg. 2013;54:131-7. 5. Fredrick TN, Kumaram M. Operation theaters and sterilization requirements: design consideration and standards for infection control. TNOAJ Ophthalmic Sci Res. 2018;56:84-90. 6. NABH. (2018). Revised guidelines for air conditioning in operation theaters. [online] Available at https://www.nabh.co/Announcement/RevisedGuidelines_ AirConditioning.pdf [Accessed May 2019]. 7. Anderson DJ, Podgorny K, Berríos Torres SI, et al. Strategies to prevent surgical site infections in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol. 2014;35(6):605-27. 8. Ban KA, Minei JP, Laronga C, et al. American College of Surgeons and Surgical Infection Society: surgical site infection guidelines, 2016 Update. J Am Coll Surg. 2017;224:59-74. 9. Katz, JD. Control of the environment in the operating room. Anesth Analg. 2017;125(4):1214-8.

Infection Prevention in the Operating Room  349 10. Wahr JA, Hines R, Nussmeier NA. Operating room hazards and approaches to improve patient safety. [online] Available at https://www.uptodate.com/ contents/operating-room-hazards-and-approaches-to-improve-patient-safety/ print?search=undefined [Accessed April 2019]. 11. Chauveaux D. Preventing surgical-site infections: measures other than antibiotics. Orthop Traumatol Surg Res. 2015;101:S77-83. 12. Pellegrini JE, Toledo P, Soper DE, et al. Consensus bundle on prevention of surgical site infections after major gynecologic surgery. Anesth Analg. 2017;124(1):233-42. 13. Allegranzi B, Zayed B, Bischoff P, et al. New WHO recommendations on intraoperative and postoperative measures for surgical site infection prevention: an evidence-based global perspective. Lancet Infect Dis. 2016;16:e288-303. 14. Berríos-Torres SI, Umscheid CA, Bratzler DW, et al. Centers for Disease Control and Prevention guidelines for the prevention of surgical site infection, 2017. JAMA Surg. 2017;152(8):784-91. 15. ISO 14644-1:2015. (2015). [online] Available at http://drug.fda.moph.go.th/ drug/zone_gmp/files/GMP2549_2/Aug2106/7.ISO14644.pdf [Accessed April 2019]. 16. ANSI/ASHRAE/ASHE. (2017). Addendum d to ANSI/ASHRAE/ASHE Standard 170–2017: Ventilation of Health Care Facilities. [online] Available at https:// www.nafahq.org/wp-content/uploads/Moeller.pdf [Accessed May 2019]. 17. Balaras CA, Dascalaki E, Gaglia A. HVAC and indoor thermal conditions in hospital operating rooms. Energ Build. 2007;39:454-70. 18. Centers for Medicare and Medicaid Services. State Operations Manual. Appendix A—Survey Protocol, Regulations and Interpretive Guidelines for Hospitals. §482.41(c) (4). [online] Available at https://www.cms.gov/ Regulations-and-Guidance/Guidance/Manuals/downloads/som107ap_a_ hospitals.pdf [Accessed June 2019]. 19. Jain S, Reed M. Laminar air flow handling systems in the operating room. Surg Infect. 2019;20(2):151-8. 20. Gonçalves KJ, Graziano KU, Kawagoe JY. A systematic review of surgical hand antisepsis utilizing an alcohol preparation compared to traditional products. Rev Esc Enferm USP. 2012;46:1484-93. 21. World Health Organization (WHO). WHO Guidelines on Hand Hygiene in Health Care: A Summary. First Global Patient Safety Challenge. Clean Care is Safe Care. Geneva: World Health Organization; 2009. 22. Berger RG, Kichak JP. Computerized physician order entry: helpful or harmful? J Am Med Inform Assoc. 2004;11(2):100-3. 23. Loftus RW, Koff MD, Brown JR, et al. The epidemiology of Staphylococcus aureus transmission in the anesthesia work area. Anesth Analg. 2015;120:80718. 24. Loftus RW, Brown JR, Patel HM, et al. Transmission dynamics of gram-negative bacterial pathogens in the anesthesia work area. Anesth Analg. 2015;120:81926. 25. Loftus RW, Koff MD, Brown JR, et al. The dynamics of Enterococcus transmission from bacterial reservoirs commonly encountered by anesthesia providers. Anesth Analg. 2015;120:827-36. 26. Loftus RW, Koff MD, Birnbach DJ. The dynamics and implications of bacterial transmission events arising from the anesthesia work area. Anesth Analg. 2015;120:853-60.

350  Yearbook of Anesthesiology-9 27. Loftus RW, Brown JR, Koff MD, et al. Multiple reservoirs contribute to intraoperative bacterial transmission. Anesth Analg. 2012;114:1236-48. 28. Cole DC, Baslanti TO, Gravenstein NL, et al. Leaving more than your fingerprint on the intravenous line: a prospective study on propofol anesthesia and implications of stopcock contamination. Anesth Analg. 2015;120:861-7. 29. Loftus RW, Patel HM, Huysman BC, et al. Prevention of intravenous bacterial injection from health care provider hands: the importance of catheter design and handling. Anesth Analg. 2012;115:1109-19. 30. Martin LD, Rampersad SE, Geiduschek JM, et al. Modification of anesthesia practice reduces catheter-associated bloodstream infections: a quality improvement initiative. Paediatr Anesth. 2013;23:588-96. 31. Association of Peri-Operative Registered Nurses. Guideline for Environmental Cleaning. AORN Guidelines for Perioperative Practice. Denver: AORN; 2018. pp. 7-28. 32. Clark C, Taenzer A, Charette K, et al. Decreasing contamination of the anesthesia environment. Am J Infect Control. 2014;42:1223-5. 33. Gonzalez EA, Nandy P, Lucas AD, et al. Ability of cleaning-disinfecting wipes to remove bacteria from medical device surfaces. Am J Infect Control. 2015;43:1331-5. 34. Munoz-Price LS, Lubarsky DA, Arheart KL, et al. Interactions between anesthesiologists and the environment while providing anesthesia care in the operating room. Am J Infect Control. 2013;41:922-4. 35. Birnbach DJ, Rosen LF, Fitzpatrick M, et al. Double gloves: a randomized trial to evaluate a simple strategy to reduce contamination in the operating room. Anesth Analg. 2015;120:848-52. 36. Birnbach DJ, Rosen LF, Fitzpatrick M, et al. A new approach to pathogen containment in the operating room: sheathing the laryngoscope after intubation. Anesth Analg. 2015;121:1209-14. 37. Munoz-Price LS, Riley B, Banks S, et al. Frequency of interactions and hand disinfections among anesthesiologists while providing anesthesia care in the operating room: induction versus maintenance. Infect Control Hosp Epidemiol. 2014;35:1056-9. 38. Biddle C, Robinson K, Pike B, et al. Quantifying the rambunctious journey of the anesthesia provider’s hands during simulated, routine care. Am J Infect Control. 2016;44:873-8. 39. Centers for Disease Control and Prevention. (2015). Guidance on personal protective equipment (PPE) to be used by healthcare workers during management of patients with confirmed Ebola or persons under investigation (PUIs) for Ebola who are clinically unstable or have bleeding, vomiting, or diarrhea in US hospitals, including procedures for donning and doffing PPE 2015. [online] Centers for Disease Control and Prevention website. https:// www.cdc.gov/vhf/ebola/healthcare-us/ppe/guidance.html [Accessed May 2019]. 40. Lowman W, Venter L, Scribante J. Bacterial contamination of re-usable laryngoscope blades during the course of daily anesthetic practice. S Afr Med J. 2013;103:386-9. 41. Muscarella LF. Reassessment of the risk of healthcare-acquired infection during rigid laryngoscopy. J Hosp Infect. 2008;68:101-7. 42. Moureau NL, Flynn J. Disinfection of needleless connector hubs: clinical evidence systematic review. Nurs Res Pract. 2015:796762.

Infection Prevention in the Operating Room  351 43. Yokoe DS, Anderson DJ, Berenholtz SM, et al. A compendium of strategies to prevent healthcare-associated infections in acute care hospitals: 2014 updates. Infect Control Hosp Epidemiol. 2014;35:967-77. 44. O’Grady NP, Alexander M, Burns LA, et al. Summary of recommendations: guidelines for the prevention of intravascular catheter-related infections. Clin Infect Dis. 2011;52:1087-99. 45. Link T, Kleiner C, Mancuso MP, et al. Determining high touch areas in the operating room with levels of contamination. Am J Infect Control. 2016;44: 1350-5. 46. United States Pharmacopeia (USP). (2018) Proposed revision to general chapter 797: pharmaceutical compounding—Sterile preparations 2018. July 27 proposed revision for public comment. [online] USP website. http://www. usp. org/compounding/797-download. Updated July 27, 2018 [Accessed October 2018]. 47. Austin PD, Hand KS, Elia M. Systematic review and meta-analysis of the risk of microbial contamination of parenteral doses prepared under aseptic techniques in clinical and pharmaceutical environments: an update. J Hosp Infect. 2015;91:306-18. 48. Jelacic S, Bowdle A, Nair BG, et al. A system for anesthesia drug administration using barcode technology: the Codonics Safe Label System and Smart Anesthesia Manager. Anesth Analg. 2015;121:410-21. 49. Centers for Disease Control and Prevention. (2011). Safe injection practices to prevent transmission to patients. [online] Centers for Disease Control and Prevention website. www.cdc.gov/injectionsafety/ip07_standardprecaution. html [Accessed October 2018]. 50. Joint Commission. Preventing infection from the misuse of vials. Sentinel Event Alert. 2014;52:1-6. 51. American Association of Nurse Anesthetists. Safe injection guidelines for needle and syringe use. AANA. 2014. 52. Rowlands J, Yeager MP, Beach M, et al. Video observation to map hand contact and bacterial transmission in operating rooms. Am J Infect Control. 2014;42:698-701. 53. Birnbach DJ, Rosen LF, Fitzpatrick M, et al. The use of a novel technology to study dynamics of pathogen transmission in the operating room. Anesth Analg. 2015;120:844-7. 54. Hysong SJ, Kell HJ, Petersen LA, et al. Theory-based and evidence-based design of audit and feedback programmes: examples from two clinical intervention studies. BMJ Qual Saf. 2017;26:323-34. 55. Russell CD, Young I, Leung V, et al. Healthcare workers’ decision-making about transmission-based infection control precautions is improved by a guidance summary card. J Hosp Infect. 2015;90:235-9. 56. Denton A, Topping A, Humphreys P. Evolution of an audit and monitoring tool into an infection prevention and control process. J Hosp Infect. 2016;94:32-40. 57. Campbell DA Jr, Henderson WG, Englesbe MJ, et al. Surgical site infection prevention: the importance of operative duration and blood transfusion—results of the first American College of Surgeons–National surgical quality improvement program best practices initiative. J Am Coll Surg. 2008;207:810-20. 58. Sadrizadeh S, Tammelin A, Ekolind P, et al. Influence of staff number and internal constellation on surgical site infection in an operating room. Particuology. 2014;4(13):42-51.

352  Yearbook of Anesthesiology-9 59. Noguchi C, Koseki H, Horiuchi H, et al. Factors contributing to airborne particle dispersal in the operating room. BMC Surg. 2017;17:78. 60. Roy M-C, Stevens M (Eds). Guide to Infection Control in the Hospital. Boston, MA: International Society for Infectious Diseases, chapter 22; 2018. pp. 1-15. 61. World Health Organization (WHO). Global Guidelines for the Prevention of Surgical Site Infection, 2nd edition. Geneva: World Health Organization; 2018. Licence: CCBY-NC-SA 3.0 IGO. 62. Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70(3): 195-283. 63. Haynes AB, Weiser TG, Berry WR, et al. A surgical safety checklist to reduce morbidity and mortality in a global population. N Engl J Med. 2009;360(5): 491-9. 64. Weiser TG, Haynes AB, Dziekan G, et al. Effect of a 19-item surgical safety checklist during urgent operations in a global patient population. Ann Surg. 2010;251(5):976-80. 65. van Klei WA, Hoff RG, van Aarnhem EE, et al. Effects of the introduction of the WHO “Surgical Safety Checklist” on in-hospital mortality: a cohort study. Ann Surg. 2012;255(1):44-9. 66. Associations of Perioperative Registered Nurses. Recommended Practices for Sterilization in Perioperative Practise settings. AORN Standards, Recommended Practises and Guidelines. Denver: AORN; 2008. 67. Juwarkar CS. Cleaning and sterilisation of anesthetic equipment. Indian J Anesth. 2013;57(5):541-50. 68. Vaz K, McGrowder D, Alexander-Lindo R, et al. Knowledge, awareness and compliance with universal precautions among health care workers at the University Hospital of the West Indies, Jamaica. Int J Occup Environ Med. 2010;1:171-81.

Regional Blocks for Shoulder Surgery: Sparing the Phrenic Nerve  353

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23

Regional Blocks for Shoulder Surgery: Sparing the Phrenic Nerve Roberto C Blanco, Kumar G Belani

INTRODUCTION Current standard care for any surgery include strategies that provide an acceptable margin of safety, patient satisfaction, a reduction in time spent in the medical facility, minimal or absent unwanted effects with built-in economic efficiencies. For successful implementation of these strategies, pain control plays a pivotal role. Patients with appropriate pain control have fewer side effects, reduced length of stay and complications. Better pain control is one of the indices of patient satisfaction. During the last two decades, the practice of medicine has changed substantially. Access to the internet has allowed physicians around the globe to communicate efforts and share knowledge, translating to a faster pace and development of strategies for patient care. At the same time, the evolution of technology, particularly the application of ultrasound, has allowed for a radical change in the way we perform bedside procedures in our patients. In anesthesia, one of the specific applications of this technology has been in the field of regional anesthesia. More importantly, ultrasound has opened the door for clinicians seeking alternative therapies for patients, e.g. being able to do the traditional nerve blocks with reasonable success. The performance of traditional nerve blocks, like the interscalene block (ISB), has evolved from anatomical landmarks through nerve stimulation, to ultrasound-based techniques that have improved the quality, reliability, and standardization of this block, with a decreased rate of occurrence of local anesthetic toxicity.1 Interscalene block has become increasingly popular and its use has risen during the last decade. This regional technique permits patients going through moderate to severe shoulder painful procedures to recover faster and return home after surgery with a lower incidence of readmission and complications. Despite this, practitioners are challenged with its routine application in patients with reduced pulmonary reserve, as most of the time the ipsilateral phrenic nerve (PN) gets blocked during this procedure. Several strategies are available to avoid the paralysis of the PN during shoulder regional anesthesia. Decreasing the volume, slowing the speed of

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injection, and moving the insertion point distal in the plexus, have been attempted to reduce this risk. However, none of these strategies guarantee the PN is always going to be spared. A more definitive approach is possible and requires a review of anatomy, particularly innervation of the joints and structures that are part of the shoulder, and demonstrated during cadaveric studies and dissections looking specifically into those terminal branches covering selected areas of the shoulder joint area. This, along with the availability of ultrasound has let us develop blocks that mitigate the pain of shoulder surgery while avoiding PN paralysis.

ANATOMICAL CONSIDERATIONS The nerves innervating the shoulder most consistently are the suprascapular nerve (SSN), axillary nerve (AN), nerves to subscapularis (NS), with the occasional contribution of the lateral pectoral nerve (LPN) and brachial plexus posterior cord (PC) (Fig. 1). The two main joints around the shoulder are the glenohumeral joint (GHJ) and the acromioclavicular joint (ACJ). In a recent study, Tran et al.2 detailed the innervation of the GHJ and ACJs. To better understand the innervation of the GHJ, they divided this joint into four quadrants (Fig. 2). As indicated in the Figure 2, the GHJ is innervated mainly by the SSN, AN, and NS. There is an occasional contribution by the LPN and direct branches of the PC. In the case of the ACJ, the innervation comes from the SSN and LPN (Figs. 3A to C). The SSN branches off the upper trunk of the brachial plexus early, traveling laterally to the shoulder, giving off its acromial branch just before crossing the suprascapular notch (SN). This acromial branch provides innervation to the ACJ. After crossing the notch, the SSN divides into medial and lateral branches, with the medial branch providing coverage to the

Fig. 1: Branches of the brachial plexus branches involved in shoulder innervation.

Regional Blocks for Shoulder Surgery: Sparing the Phrenic Nerve  355

Fig. 2: Innervation of quadrants of the glenohumeral joint capsule. (AC: acromion process; AN: axillary nerve; CP: coracoid process; LPN: lateral pectoral nerve; NS: nerves to subscapularis; PC: posterior cord; SSN: suprascapular nerve) Source: With permission from BMJ Publishing Group Ltd.

supraspinatus muscle and the lateral branch innervates the posterosuperior GHJ and infraspinatus muscle. The AN leaves the PC of the brachial plexus behind the pectoralis minor muscle, from where it takes an inferolateral direction. The main trunk of AN provides 1–3 articular branches to the anteroinferior GHJ quadrant prior to its bifurcation into the anterior and posterior divisions. These branches travel with the anterior circumflex humeral artery and course laterally between the tendons of the subscapularis and latissimus dorsi. Coursing through the quadrilateral space the AN divides into an anterior and posterior divisions. The posterior division, after emerging from the quadrilateral space gives off 1–3 articular branches to the GHJ posteroinferior capsule, while the anterior division occasionally gives off 2–3 articular branches that terminate in the transverse humeral ligament. Besides the joint, the AN provides motor fibers to the infraspinatus and teres minor muscles as well as sensory fibers to the skin. The NS has two components, upper and lower, both branching from the PC. The upper component travels along the superior border of the subscapularis, providing 1–2 branches to the anterosuperior part of the GHJ. Occasionally, this innervation is derived directly from the PC of the brachial plexus.

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Figs. 3A to C: Frequency map of innervation of GHJ and ACJ. Numbered arrows in A to C indicate course of: (1) medial trunk of SSN; (2) motor branches of SSN supplying infraspinatus; (3) anterior and posterior divisions of AN. (AC: acromion process; ACJ: acromioclavicular joint; AN: axillary nerve; BG: bicipital groove; br: branch; CL: clavicle; PC: posterior cord; div: division; GHJ: glenohumeral joint; HH: humeral head; ISF: infraspinous fossa; LPN: lateral pectoral nerve; SBF: subscapular fossa; SGN: spinoglenoid notch; SN: suprascapular notch; SS: spine of scapula; SSF: supraspinous fossa; SSN: suprascapular nerve; *: coracoid process) Source: With permission from BMJ Publishing Group Ltd.

The LPN derived from the lateral cord of the brachial plexus runs in the deltopectoral triangle. After traveling within the neurovascular bundle with the acromial branch of the thoracoacromial artery, it usually provides 1–2 articular branches to innervate the ACJ, and occasionally sends a branch to the GHJ superoanterior or inferoanterior quadrants.

PRACTICAL IMPLICATIONS For a proper approach to the surgical care of the patient requiring shoulder surgery, we need to define the following: • Patient comorbidities and suitability for general anesthesia • Type of surgery • Analgesic versus anesthetic block.

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Even with pulmonary pathology precluding the use of the ISB, it is important to confirm if the patient otherwise can tolerate the physiological changes of general anesthesia. Many shoulder surgeries are done in the sitting position and maintaining a proper perfusion pressure to the brain is vital. With an asleep patient, we rely on electroencephalogram (EEG) or brain near-infrared spectroscopy as surrogates of perfusion. However, in some instances, mild sedation or a patient awake and responsive may be necessary to evaluate cerebral function closely. With the latter patient in mind, we need a block that provides comprehensive shoulder coverage. In the awake or lightly sedated patient that is scheduled for shoulder arthroplasty or extensive arthroscopic intervention [Superior labrum anterior and posterior (SLAP) or dislocation], one needs to block the SSN3 (this is done at the level of the SN). (The subomohyoid approach carries some risk as the local anesthetic may spread cephalad to the PN).4 One also needs to block the brachial plexus, distal to the clavicle (costoclavicular5,6 or infraclavicular approach7), and the supraclavicular nerves8 (at the emergence of the cervical superficial plexus) so as to provide comprehensive anesthetic coverage. During the superficial cervical block, the needle must remain superficial to avoid puncture of the prevertebral fascia, with the potential spreading of the local anesthetic to the PN. In the same awake patient with a less extensive surgery (arthroscopy for rotator cuff repair only for example), the SSN block, along with AN block (the anterior approach9 can have better coverage than the inferior axilla,10 and the quadrilateral space approaches11), and superficial cervical block conveys an anesthetic block that is adequate. With this block combination, direct branches of the posterior brachial plexus cord, SN, and LPN are not covered, increasing the chance for needing intravenous (IV) supplementation or sedation. When the patient is going to receive general anesthesia, minimizing the amount of general anesthesia can allow fast-tracking, improve patient satisfaction, and reduce side effects. For some patients, the ability to feel and move the distal part of the upper extremity may also be important in patient satisfaction. Because the patient is asleep, the amount of block options increases and depends upon the expected desired result. As with the awake patient, the combination LPN and brachial plexus block distal to the clavicle will provide excellent analgesic coverage after most shoulder procedures. In this case, coverage of the upper part of the shoulder skin with superficial cervical block might not be necessary. Aliste et al.12 demonstrated in their study that costoclavicular block (CCB) alone versus ISB was not inferior for postoperative analgesia after shoulder arthroscopic surgery. However, the authors did not quantify the amount of general anesthesia used, which may be important in patients with limited physiologic reserve.

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If the patient expresses a desire to maintain the motor and sensory function of the ipsilateral upper extremity, blocking the SSN and AN alone will provide adequate analgesia to most of the GHJ and ACJ areas while sparing the distal arm. With the option to add block adjuncts (dexamethasone, clonidine, etc.) or use liposomal bupivacaine (instead of or in addition to regular bupivacaine), the duration of these blocks can be extended. This prolongation may reduce the incidence of opioid-related adverse drug events, the likelihood of chronic pain after surgery, and hospital length of stay.

SPECIFIC BLOCKS The specific description of each block is beyond the scope of this review. However, the reference to each one is attached, as well as the reasons why the authors desire a preference for one approach over another.

Suprascapular Nerve Block Suprascapular Fossa The US approach was originally described by Harmon and Connor.3 Block at this level covers all the SSN innervation relevant to the shoulder with no chance of local anesthetic spreading to the PN. Podgórski et al.13 described a pseudo-SN that can make the identification of the true notch challenging, making the use of nerve stimulator necessary in some cases.

Subomohyoid In a cadaveric study, 10 SSN blocks were done in five fresh cadavers. Sehmbi et al.4 showed that despite the low volume used (5 mL), the PN was still stained in 20% of the injections, making this approach less desirable when sparing the PN is a priority.

Brachial Plexus Block Costoclavicular The costoclavicular space has been anatomically defined6 and the block technique described by Karmakar et al.5 Although more literature is still needed, the theoretical advantages of the CCB approach are the consistent location and closer proximity of the brachial plexus cords, as well as easier visualization in many patients. This makes the injection of the medication and the coverage of the three cords more reliable. Caution should be used with volume, speed, and pressure of injection as this location is almost posterior to the clavicle and can have some risk of cephalad spreading.

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Infraclavicular When compared with the CCB block, traditional lateral fossa infraclavicular block takes a little longer to set up.14,15 Either performed as a single or double injection its quality is similar.16 The main caveat may be needle visualization, especially in obese patients, due to the steep angle of approach. On the other hand, it is a technique that more people are familiar with.

Retroclavicular In the retroclavicular approach to the infraclavicular fossa, the needle is usually parallel to the ultrasound beam and therefore the visualization, especially of the needle tip, is typically better than with the infraclavicular approach. One of the dogmas of ultrasound-guided blocks is to keep the needle, and needle tip, under direct vision at all times, so the risk of trauma, especially to neural structures, is minimized. During this approach, the needle is advanced without a direct vision for the segment behind the clavicle. Sancheti et al.17 showed in a study performed in three cadavers that the SSN and vessels are not free of risk. Therefore, this block may not be the safest approach to the brachial plexus below the clavicle.

Axillary Nerve Anterior Approach The novel approach described by Gonzalez-Arnay et al.9 in a cadaveric study produces coverage of the subscapularis muscle fascial space in the anterolateral part of the muscle, where the AN runs after leaving the posterior trunk. As the nerve is reached, soon after leaving the plexus, this approach is going to cover all the AN branches. This approach may be difficult in a patient unable to extend and externally rotate the upper extremity.

Inferior Axilla In this technique, recently described by Chang et al.10 the AN is directly visualized in the long axis when it passes medial to the humeral head and before emerging through the quadrilateral space. This approach covers some branches missed during the quadrilateral approach. To be performed, the patient must be able to abduct the upper extremity.

Posterior Approach (Quadrilateral Space) Described by Rothe et al.11 this block is not difficult to perform. Unfortunately, it may miss branches coming off the AN before its crossing through the

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quadrilateral space. This may explain why the study by Dhir et al.14 showed differences in quality of SSN and AN block combination versus ISB.

Supraclavicular Nerves Described by Tran et al.16 the supraclavicular nerves can be blocked at their emergence from the superficial cervical plexus. Again, always consider staying superficial to avoid puncture of the prevertebral fascia with potential direct spreading to the PN. The goal of this block is to anesthetize the skin covering the supraclavicular area.

CONCLUSION With our current knowledge of shoulder innervation, as well as the availability of ultrasound, it is possible to provide complete shoulder analgesia and anesthesia for patients with limited pulmonary reserve. This is accomplished through careful and slow injection of limited volumes of local anesthetic performed at both the level of the SSN and brachial plexus below the clavicle. A more comprehensive block can be obtained if the supraclavicular nerves are also blocked, covering the skin around the supraclavicular area. The use of ultrasound, as well as nerve stimulator and injection pressure monitoring, are optional tools to complement safety when the anesthesiologist judges that they are necessary. An important factor when deciding what type of block or block combination is going to be used should weigh not only type of surgery, patient reserve, and type of anesthesia, but also practitioners experience and familiarity with the blocks being chosen. The most comprehensive SSN block coverage is obtained when the procedure is performed at the level of the SN. In the case of the AN block, the anterior approach seems to render the best coverage for this nerve. Finally, if the brachial plexus is going to be blocked, the decision between costoclavicular versus lateral infraclavicular approach can be made based on the quality of the US image obtained, favoring the one that provides a clearer picture of the brachial plexus cords. New information is becoming available constantly, and by the time this paper will reach you, chances are, new data might be favoring one approach over another, with even new options already available.

KEY POINTS • The use of the traditional ISB for shoulder surgery is almost always associated with blockade of the PN. Strategies of decreasing anesthetic volume and concentration, or moving the approaching point caudally above the clavicle, have proven to be not reliable in sparing the PN.

Regional Blocks for Shoulder Surgery: Sparing the Phrenic Nerve  361 • Two important sources of pain after shoulder arthroplasty are the GHJ and the ACJ. • Suprascapular nerve, AN, NS, with the occasional contribution of the LPN and brachial plexus PC encompass the innervation for the GHJ. • The ACJ is innervated by the SSN and the LPN. • Selective blocks of these contributing nerves make it possible to perform shoulder surgery while avoiding paralysis of the diaphragm. • The extent of block coverage by these nerves will be dictated by the type and extent of surgery. Patient comorbidities, additional anesthetics, and practitioner familiarity with the blocks described also play a role.

REFERENCES 1. Neal JM, Brull R, Horn J, et al. The Second American Society of Regional Anesthesia and Pain Medicine evidence-based medicine assessment of ultrasound-guided regional anesthesia: executive summary. Reg Anesth Pain Med. 2016;41:181-94. 2. Tran J, Peng PWH, Agur AMR. Anatomical study of the innervation of glenohumeral and acromioclavicular joint capsules: implications for imageguided intervention. Reg Anesth Pain Med. 2019;44:452-8. 3. Harmon D, Conor H. Ultrasound-guided suprascapular nerve block technique. Pain Physician. 2007;10(6):743-6. 4. Sehmbi H, Johnson M, Dhir S. Ultrasound-guided subomohyoid suprascapular nerve block and phrenic nerve involvement: a cadaveric dye study. Reg Anesth Pain Med. 2019;44:561-4. 5. Karmakar MK, Sala-Blanch X, Songthamwat B, et al. Benefits of the costoclavicular space for ultrasound-guided infraclavicular brachial plexus block: description of a costoclavicular approach. Reg Anesth Pain Med. 2015;40(3):287-8. 6. Sala-Blanch X, Reina MA, Pangthipampai P, et al. Anatomic Basis for Brachial Plexus Block at the Costoclavicular Space: A Cadaver Anatomic Study. Reg Anesth Pain Med. 2016;41(3):387-91. 7. Sandhu NS, Capan LM. Ultrasound-guided infraclavicular brachial plexus block. Br J Anaesth. 2002;89:254-9. 8. Tran DQ, Dugani S, Finlayson RJ. A randomized comparison between ultrasound-guided and landmark-based superficial cervical plexus block. Reg Anesth Pain Med. 2010;35:539-43. 9. González-Arnay E, Jiménez-Sánchez L, García-Simón D, et al. Ultrasonographyguided anterior approach for axillary nerve blockade: An anatomical study. Clin Anat. 2019:23394. 10. Chang KV, Lin CP, Lin CS, et al. A novel approach for ultrasound guided axillary nerve block: the inferior axilla technique. Med Ultrasonogr. 2017;19(4):457-61. 11. Rothe C, Asghar S, Andersen HL, et al. Ultrasound-guided block of the axillary nerve: a volunteer study of a new method. Acta Anaesthesiol Scand. 2011;55(5):565-70. 12. Aliste J, Bravo D, Layera S, et al. Randomized comparison between interscalene and costoclavicular blocks for arthroscopic shoulder surgery. Reg Anesth Pain Med. 2019;44:472-7. 13. Podgórski M, Rusinek M, Cichosz M, et al “Pseudo-suprascapular notch”: is it a sonographic trap in suprascapular nerve block? Reg Anesth Pain Med. 2019;44:77-80.

362  Yearbook of Anesthesiology-9 14. Dhir S, Sondekoppam RV, Sharma R, et al. A Comparison of Combined Suprascapular and Axillary Nerve Blocks to Interscalene Nerve Block for Analgesia in Arthroscopic Shoulder Surgery: An Equivalence Study. Reg Anesth Pain Med. 2016;41(5):564-71. 15. Songthamwat B, Karmakar MK, Li JW, et al. Ultrasound-guided infraclavicular brachial plexus block: prospective randomized comparison of the lateral sagittal and costoclavicular approach. Reg Anesth Pain Med. 2018;43:825-31. 16. Tran DQ, Bertini P, Zaouter C, et al. A prospective, randomized comparison between single- and double-injection ultrasound-guided infraclavicular brachial plexus block. Reg Anesth Pain Med. 2010;35(1):16-21. 17. Sancheti SF, Uppal V, Sandeski R, et al. A Cadaver Study Investigating Structures Encountered by the Needle During a Retroclavicular Approach to Infraclavicular Brachial Plexus Block. Reg Anesth Pain Med. 2018;43(7):752-5.

Current Status of Methylene Blue in Anesthesia and Intensive Care  363

CHAPTER

24

Current Status of Methylene Blue in Anesthesia and Intensive Care Devalina Goswami

INTRODUCTION Methylene blue (MB) has the credit of being the first totally synthetic compound used for medicinal purposes. The properties of MB have found extensive use in medicine for a variety of purposes. Initial medical literature mentions its use in the treatment of malaria.1 It’s color and staining properties have been utilized in diagnostic procedures of gynecology, urology, and in surgery of the parathyroid glands. In anesthesia and intensive care as well, it has proved valuable in several ways. It has been used extensively in the treatment of methemoglobinemia (MHgb) and as an indicator/staining dye. Current interest in MB among anesthesiologists and intensivists revolve mostly around its vasopressor (noncatecholamine) properties, its ability to counteract and reverse many of the effects of MHgb, ifosfamide toxicity, and hydrogen sulfite poisoning. It is also used as a dye in regional blocks to delineate tissue planes and anatomical structures.

HISTORICAL BACKGROUND Methylene blue is an aniline dye derivative, first synthesized by Heinrich Caro in 1876 for the textile industry. Robert Koch used it for staining tuberculosis bacilli. Later in 1891, Ehrlich and Guttman applied it in the treatment of malaria.2

PHYSIOCHEMICAL PROPERTIES Methylene blue is chemically known as methylthioninium chloride and is represented by the formula C16H18CIN3S. It is a heterocyclic aromatic molecule, available as an odorless dark green powder that yields a blue color on dissolving in water.3,4 Nicotinamide adenine dinucleotide phosphate (NADPH) metabolizes MB to leukomethylene blue (LMB), which is excreted primarily in the urine, giving it a bluish-green color. A small portion of the MB gets excreted unchanged in the urine. MB has a terminal half-life (t½) of 5.25 hours.5

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MECHANISM OF ACTION In Methemoglobinemia Red blood cells carry O2 in very high concentrations; as a result, they are exposed to O2 free radicals, which results in formation of methemoglobin. Methemoglobin is produced by the process of oxidation of iron from the ferrous (Fe2+) to the ferric (Fe3+) form in the normal hemoglobin molecule. The ensuing structural change of the hemoglobin molecule renders it incapable of binding and subsequently delivering oxygen to tissues resulting in hypoxemia. This change of hemoglobin structure causes the oxygen dissociation curve to be shifted to the left. Normal methemoglobin concentration in the blood is ≤1%.6 The levels of methemoglobin are maintained at a normal physiological level by several endogenous reduction systems. The predominant system responsible for 99% of methemoglo­ bin reduction is the cytochrome-b-5 reduction system. NADPH methemo­ globin reductase usually contributes negligible amount of methemoglobin reduction under normal circumstances. However, it has a special affinity for exogenous dyes like MB. MB is reduced by NADPH methemoglobin reductase in the body to LMB, which in turn reduces methemoglobin to hemoglobin.7,8 Nicotinamide adenine dinucleotide phosphate methemoglobin reductase pathway is deficient in patients with G6PD deficiency leading to high levels of MB, which could, in turn, lead to more oxidative stress and more oxidation of methemoglobin. Therefore, treatment of severe acute MHgb by MB is contraindicated in G6PD deficiency.7

As a Vasopressor In states of shock, MB serves its action as a vasopressor by increasing peripheral vascular resistance and reversing the myocardial depression. This action is mediated through inhibition of soluble guanylyl cyclase (sGC) and nitric oxide synthase (NOS) activity.9,10 NOS produce nitric oxide (NO) via two subsets of NOS. One is the constitutive NOS (cNOS) that remain constantly active and the second is the inducible NOS (iNOS), which gets activated in the presence of cytokines and endotoxins produced during inflammation or sepsis. iNOS is present in cardiac myocytes and vascular smooth muscle cells.2 NO activates sGC, which in turn produces cyclic guanosine monophosphate (cGMP). As the concentration of cGMP increases, relaxation of the vascular smooth muscle cells and the myocardium occurs. In addition, an elevated level of cGMP increases the vascular permeability.2 Methylene blue binds to the iron heme moiety of sGC, which prevents an increase in the levels of cGMP. MB also has direct inhibitory effect on the NOS. MB competitively blocks the target enzymes of NO production

Current Status of Methylene Blue in Anesthesia and Intensive Care  365

thereby reducing the responsiveness of vessels to cGMP thus restoring the vascular tone.3

EFFECT OF METHYLENE BLUE ON ANESTHETICS Literature describing the effect of MB on anesthetics in humans are few and with inconclusive evidence. A randomized controlled trial studied the effects of MB on the requirement of propofol during induction and maintenance of anesthesia of parathyroid surgery. It was observed that patients pretreated with MB had 50% reduced propofol requirements both during induction and maintenance of anesthesia along with delayed emergence.11 The potential target in the brain for the action of the anesthetic agents like propofol is considered to be the glutamate-NO-cGMP pathway. Evidence from animal studies shows MB causing interference with the effects of anesthetic agents within the brain by inhibiting both the NOS and guanylate cyclase (GC) activity.12 It has been speculated that MB-induced blockade of the NO-cGMP could result in a smaller volume of distribution and a lower elimination clearance owing to a reduced hepatic blood flow, eventually contributing to increased propofol plasma and effect-site concentrations.12 Experiments in animals where MB was administered in the ventricles have demonstrated a decrease in the minimum alveolar anesthetic concen­ tration (MAC) of volatile anesthetic agents.13 Pre-emptive MB infusion in a dose of 2 mg/kg over 20 minutes before induction of anesthesia in hemodynamically stable patients of perforation peritonitis have shown more stable postinduction hemodynamics as compared to patients who received normal saline.14 A case report has described prophylactic administration of preoperative MB in a patient with congenital methemoglobinemia. There was a significant decrease in the methemoglobin levels and increase in the fractional oxygen saturation from a preoperative value of 80.7–94.7% within 5 minutes of MB administration and 97.7% after 2 hours. This had improved the safety margin against perioperative hypoxemia.15 Transient interference of pulse oximetry readings is seen with MB. However, extreme vigilance is mandatory while interpreting the pulse oximetry readings, as MB is known to cause pulmonary edema.16 A case report has described dramatic reduction in the bispectral index while using MB infusion for the treatment of dapsone-induced MHgb.17 Whether MB has any significant effect on anesthetics or not will only be known from future research.

TREATMENT OF METHEMOGLOBINEMIA The only Food and Drug Administration (FDA) approved indication for the use of MB is in pediatric and adult acquired MHgb.

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The first step in the treatment of MHgb is aimed at removing the causative agent. If MHgb is symptomatic, which usually occurs with MHgb levels >15%, administration of MB as 1–2 mg/kg over 5 minutes should be attempted. If cyanosis persists, a second dose of MB may be given. Exchange transfusion or hyperbaric oxygen may be beneficial if treatment with MB fails to alleviate the symptoms.8 It is a paradox, however, that MB can cause MHgb as well. It has been suggested that MB can act as an oxidizing or reducing agent in different clinical situations. In contrast to the ability of MB to reduce methemoglobin to Hgb, through enzymatic reduction pathways, MB also has the capacity to oxidize Hgb to methemoglobin. In normal circumstances, MB favors the reduction of methemoglobin to Hgb unless large doses of MB are administered or if MB is administered too quickly. A local high concentration of the drug results in methemoglobin formation.8 Worsening of undiagnosed congenital MHgb was seen after treatment with MB.18

VASODILATORY SHOCK Fluid replacement and catecholamines remain the first line of treatment in vasodilatory shock. Catecholamines are often implicated in the causation of arrhythmias and increased myocardial oxygen demand. Prolonged treatment with high dose catecholamines leads to downregulation and desensitization of adrenergic receptors. The focus has now shifted to noncatecholamine vasopressor like vasopressin, terlipressin, and MB.19 Meta-analysis of MB in vasoplegic shock reveals it to be effective in increasing blood pressure and systemic vascular resistance (SVR) without having any detrimental effect on survival.20

CARDIAC SURGERY AND VASOPLEGIA Methylene blue has found itself a place as a noncatecholamine vasopressor in the treatment of vasoplegia unresponsive to fluid and catecholamine therapy. The term vasoplegia is used to describe a distributive shock-like status caused by excessive loss of vascular tone.21 Vasoplegic syndrome (VS) is a common complication following major cardiovascular surgery. It has been reported to occur in 5–25% of patients during or after cardiopulmonary bypass (CPB).3,22 The incidence of VS may be as high as 30–50% if there are associated predisposing factors.23 Gomes et al. were the first to describe VS in 1994. It is a clinical condition defined by the presence of all of the following criteria: • A mean arterial pressure (MAP) < 50 mm Hg • Cardiac index > 2.5/L/m2 • Right atrial pressure < 5 mm Hg

Current Status of Methylene Blue in Anesthesia and Intensive Care  367

• Left atrial pressure < 10 mm Hg, and • Low SVR (0.5 µg/kg/min).24 The mechanism leading to the development of VS is largely unknown. The etiology is postulated to be multifactorial. Hemodilution, baroreceptor reflexes, complement activation, and endogenous compounds like NO, carbon monoxide, and oxygen-free radicals have been implicated for causing vasodilation.23 Vasoplegic syndrome is associated with a systemic inflammatory response that results in endothelial cell dysfunction and formation of NO from L-arginine in response to the enzyme iNOS. The newly formed NO escalates the production of cGMP which is responsible for vasoplegia. Excessive formation of NO and cGMP is related to profound vasodilatation, myocardial depression, and decreased response to catecholamines.21 Methylene blue is often administered as a rescue agent for treating post-CPB vasoplegia. It directly competes with NO for activation of GC. Furthermore, MB inhibits iNOS, potentially reducing the escalation of NO concentration that occurs with CPB and other physiologic stress. MB thus prevents NO-mediated dephosphorylation of myosin and the ensuing vasodilation.21 Methylene blue has been reported to be successful in treating VS arising out of a variety of situations in cardiac surgery. Successful treatment of VS arising after tricuspid valve repair of a patient of carcinoid syndrome has been reported with the use of MB.25 MB has been used to reverse reactionary vasoplegia occurring after protamine sulfate administration in a patient undergoing coronary artery bypass grafting.26 Case report on the successful use of MB in pediatric patient who developed VS following cardiac transplant is described in the literature. MB was used in a dose of 1 mg/kg in the catecholamine unresponsive 5-year-old patient. Significant improvement was seen with an increase in the MAP and subsequent tapering off of the vasopressor support.27 The authors, however, suggest that MB should be considered as a rescue vasopressor for pediatric patients only when the conventional therapy fails. Furthermore, they have noted that dosing regimens and protocols for the use of MB in the treatment of catecholamine resistant VS are poorly defined in the pediatric patients. The most commonly used dosage in cardiac surgery is reported to be 2 mg/kg intravenous bolus, followed by a continuous infusion of 2 mg/kg/h.28 Early administration of MB after cardiac surgery was seen to be associated with reduced renal failure and perioperative mortality versus late administration.29 It has been postulated that MB works best in the first 8 hours of shock where there is upregulation of NOS and sGC activity. The

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next 8 hours see a downregulation of NOS and sGC followed by upregulation in the third 8 hours. But effectiveness of MB decreases in the third 8 hours, as there are metabolic acidosis and circulatory failure in states of prolonged shock.28

SEPSIS The mechanism of action in septic shock is also mediated via inhibition of NOS and sGC which are responsible for the increased intracellular cGMP concentration which eventually leads to relaxation of vascular smooth muscles and myocardium, and also increased vascular permeability. Methylene blue administration in patients of septic shock results in an increase in the MAP and decrease in the requirements of catecholamines. However, conclusive effects of MB on morbidity and mortality in patients of septic shock still remain unknown due to lack of well-designed prospective studies.10,19

ANAPHYLACTIC SHOCK Anaphylactic reactions occur due to antigen and antibody [Immunoglobulin E (IgE) produced from previous exposure] reaction leading to degranulation of mast cells along with release of chemical mediators like prostaglandins, leukotrienes, and histamine. Among these chemicals, histamine is implicated in causing the profound effects of anaphylaxis. Endothelial NOS activity is upregulated by histamine leading to NO production, which in turn activates GC with a consequent increase in cGMP. The role of MB in anaphylactic shock has been described in literature. The proposed mechanism of action of MB in anaphylactic shock is through blocking GC activity. Inhibition of GC interrupts excessive activation of NO-cGMP pathway resulting in reversal of the vasodilatation mediated via histamine.2 Severe anaphylaxis has been reported from exposure to latex in surgeon’s gloves, in a patient with history of previous three surgeries. IgE typically mediates a latex anaphylactic reaction. MB was used when conventional therapy with high doses of catecholamines was ineffective. Administration of MB was associated with concomitant improvement in hemodynamics and tissue perfusion. Based on several studies, the authors have mentioned the following dosing patterns in shock:10 • Vasodilatory shock: A therapeutic bolus of 1–2 mg/kg over 10–20 minutes. As the terminal half-life of IV administration of MB is 5–6 hours, a continuous infusion for 2–3 days may be beneficial. • Septic shock: IV bolus of 2 mg/kg followed by continuous infusion of 0.25 mg/kg/h for up to 6 hours.

Current Status of Methylene Blue in Anesthesia and Intensive Care  369

Bolus doses in the range of 1–3 mg/kg have shown favorable hemo­ dynamic profiles without deleterious effects on splanchnic perfusion, but higher doses (7 mg/kg) have shown to decrease splanchnic perfusion. Continuous infusion rates of 1 mg/kg/h have shown favorable hemo­ dynamic augmentation without compromising splanchnic perfusion. The most suitable time for administration of MB has been studied. It has been observed that MB is more effective when administered early at a time when MAP is still higher.30

ORTHOTOPIC LIVER TRANSPLANTATION The use of MB has been extended to the treatment of hypovolemic shock and ischemia-reperfusion injury following orthotopic liver transplantation (OLT). A randomized controlled trial to study the preventive effect of MB on hypotension upon vascular clamp release following OLT was studied on 36 patients. The group receiving MB as a bolus of 1.5 mg/kg just before graft reperfusion had significantly increased MAP, reduced epinephrine dosages, higher cardiac indices, and reduced serum lactate levels at 1 hour after administration, compared with the control group who received normal saline bolus.31 In contrast, in a retrospective study where MB was administered just prior to reperfusion at a dose of 1–1.5 mg/kg neither did prevent postreperfusion hypotension nor did decrease vasopressor requirements.32 However, recent case reports give a favorable picture of MB in OLT as it has shown to improve hemodynamics when used as a rescue drug in refractory hypotension after hepatic reperfusion during transplantation. A recent review article on the use of MB in intraoperative vasoplegia opines that routine use during liver transplantation cannot be supported at this time because of the paucity of data.10

CARDIOVASCULAR DRUG POISONING A case report describes the use of MB to treat refractory distributive shock caused by cardiovascular drug overdose with amlodipine. Dihydropyridine calcium channel blockers causes phosphorylation of endothelial NOS resulting in increased NO production. MB blocks the pathway resulting in the reversal of the symptoms.33

IFOSFAMIDE TOXICITY Ifosfamide-induced encephalopathy (IIE) occurs in about 10–40% of patients receiving high doses of the drug. The clinical spectrum ranges from mild somnolence, agitation, confusion, and hallucinations to deep coma.

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Its occurrence is reported to be more common with oral intake than IV administration.34 Ifosfamide is an alkylating agent and oxazaphosphorine antineoplastic agent (a nitrogen mustard derivative). It is a prodrug dependent on hepatic activation to its cytotoxic metabolite ifosfamide mustard. Cytochrome p450 metabolizes ifosfamide mustard to generate the active alkylating agents, 4-hydroxy-ifosfamide and isophosphoramide mustard. Both ifosfamide and its metabolites are capable of crossing the blood–brain barrier (BBB) to cause IIE.35,36 The metabolites can inhibit the electron-binding flavoproteins in the mitochondrial respiratory chain. The inhibition of the mitochondrial respiratory chain may also lead the accumulation of reduced form of nicotinamide adenine dinucleotide (NADH). This, in turn, prevents the dehydrogenation of aldehydes, such as the ifosfamide metabolite chloroacetaldehyde (CAA) a potential neurotoxic substance, which needs NAD for their oxidation.34,36 Methylene blue has been found to counteract some of these metabolic pathways by acting as an alternative electron acceptor, replacing the inhibited flavoproteins thereby restoring the mitochondrial respiratory chain function. It also has the capacity to oxidate NADH, allowing dehydrogenation of the aldehydes. A preventive action of MB in the causation of IIE is assumed to be due to inhibition of the plasma and extrahepatic monoamine oxidases.34 The recommended IV dose of MB for treatment of IIE is 50 mg every 4 hours and the dose for secondary prophylaxis of IIE is 50 mg every 6 hours, either intravenously or orally.35

HYDROGEN SULFITE TOXICITY Hydrogen sulfide (H2S) is a chemical product with significant hazards in the gas and farming industry. It is used for suicidal purposes as well as it is easily producible and causes rapid death when taken in high doses. Death due to H2S poisoning is secondary to a pulseless electrical activity (PEA). Long-term cognitive or motor deficits develop due to direct toxicity of H2S on neurons combined with the consequences of a prolonged apnea and circulatory failure. The toxicity of H2S is partly attributed to the inhibition of mitochondrial cytochrome c oxidase thus preventing adenosine triphosphate (ATP) formation and promoting the production of reactive oxygen species (ROS). H2S is also thought to affect cysteine residues of numerous proteins by direct sulfhydration or sulfuration of free cysteine residues (S-SH bonds).37,38 There is no FDA approved antidote for H2S. MB, with its potential rescuing effects on the mitochondrial activity, has been tried as an antidote against H2S intoxication.39 Methylene blue and its reduced metabolite LMB interact with the mitochondrial complexes and can antagonize the formation excess of

Current Status of Methylene Blue in Anesthesia and Intensive Care  371

ROS by H2S. MB promotes transfer of protons through the mitochondrial membrane, against a concentration gradient, thus helping in the production of ATP needed for mitochondrial respiration. MB has shown to counteract the H2S toxicity-induced cardiac depression by cardiac ion channel dysfunction and ATP reduction.40 Low dose MB (0.5 mg/kg) was reported to be beneficial for a 4-yearold child of shock following polytrauma that was refractory to volume replacement and maximal vasoactive support.41

AS AN INDICATOR DYE The anesthesiologists have utilized MB for a variety of procedures because of its distinct color, which can be easily appreciated against the normal tissue and for being nontoxic as an indicator dye. Interestingly, MB does not cause an increase in blood pressure when it is used as a dye in nonvasoplegic patients. It has been noted that MB exerts its vasoconstrictive effect only in the states of NO upregulation.3 A few examples of the studies that have used MB as an indicator dye in patients are: • To study bronchial mucus transport velocity42 (mucociliary function) during pharyngeal spread of topical local anesthetic administered orally during general anesthesia in children by mixing lignocaine with MB,43 to detect gastric aspiration while comparing different supraglottic devices,44 the spreading patterns from the paravertebral space using a solution of MB and local anesthetic.45 • It has been used in cadaveric studies to see the spread of drugs in different anatomical planes like the serratus anterior plane block,46 thoracic paravertebral space,47 etc.

ADVERSE EFFECTS Although rare, complications are described in literature following the use of MB, which can be potentially fatal. Rarely, MB may cause shortness of breath, tremors, vomiting, bluish discoloration of body fluids, and hemolytic anemia in very high doses. Serious complications noted with the use of MB include coronary vasoconstriction, increases in pulmonary vascular resistance, and decreases in splanchnic blood flow. These vasoconstrictive states in multiple organ systems are explained by the global antagonism of NO-mediated vasodilation.23 Mesenteric perfusion decreases with high dose (7 mg/kg) of MB. Slight increase in serum glutamic pyruvic transaminase has been observed for a transient phase. Increase in pulmonary vascular resistance and interference in gas exchange occur with the use of MB in large doses.21

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Methylene blue and LMB are excreted in the urine, giving it a green color and the sclera might also get bluish coloration. While MB is being used to treat vasoplegia and various shocks like states, it is important for the anesthetist to know that MB itself might cause anaphylactic shock.48

SEROTONIN TOXICITY Serotonin toxicity is caused by the excess of serotonergic drugs or interaction with inhibitors of serotonin metabolism like monoamine oxidase inhibitors (MAOI).4 The signs and symptoms of serotonin toxicity are caused due to stimulation of 5-hydroxytryptamine (5-HT) and can be broadly divided into three categories: 1. Altered mental status (agitation, excitement, confusion, and coma). 2. Altered neuromuscular excitability (tremor, clonus, hyperreflexia, myoclonus, and pyramidal rigidity). 3. Autonomic instability (tachypnea, tachycardia, hyperthermia, dia­ phoresis, and mydriasis). Life-threatening serotonin toxicity has been reported after administering MB to treat VS, in patients on chronic selective serotonin reuptake inhibitor (SSRI) therapy, and had undergone cardiac surgery.49 Methylene blue has an MAOI activity, with an important MAO-A inhibition, thus reducing synaptic clearance of serotonin. After being absorbed rapidly in the nervous system, it reaches high concentrations in the brain tissue after intravenous administration. The major metabolite of MB, azure-B, is a potent inhibitor of MAO-A and MAO-B, further enhancing the serotonergic activity of this drug. • US FDA Safety Communication Recommendations: ▪▪ In emergency situations: Alternative vasopressor to MB should be considered. If MB has to be used then stop serotonergic drugs immediately and monitor patients for emergent symptoms of central nervous system (CNS) toxicity for 2 weeks (5 weeks for fluoxetine) or until 24 hours of the last dose of MB, whichever comes first. ▪▪ In nonemergency situations: When MB is contemplated for use, serotonergic psychiatric medication should be stopped 2 weeks in advance (5 weeks for fluoxetine) of MB treatment. Serotonergic drugs can be resumed after 24 hours of the last dose of MB.24,50

CONTRAINDICATIONS Absolute contraindications for the use of MB are for severe hypersensitivity to MB and in patients with G6PD deficiency as it can precipitate hemolytic anemia.3,17

Current Status of Methylene Blue in Anesthesia and Intensive Care  373

Caution should be exercised while using MB in patients with compromised renal and hepatic function. The drug is excreted mostly by the kidneys and extensively metabolized by the liver, therefore if used; such patients should be monitored for a longer time.17 MB should preferably be avoided in the presence of pulmonary hypertension and acute lung injury.4

CONCLUSION Methylene blue is valuable in anesthesia and intensive care practice. It serves as an antidote for MHgb, it is effective as a noncatecholamine vasopressor in refractory shock, and it has also proved useful in the management of ifosfamide toxicity and hydrogen sulfite poisoning. Serious complications might occur if used injudiciously. Controversies and lack of definite guideline for its use in a variety of clinical scenarios will exist till further research clears the existing doubts.

KEY POINTS • Methylene blue has been an integral part of the treatment regime of acquired MHgb. • In MHgb, it acts as a reducing agent to convert methemoglobin to hemoglobin. • It is beneficial in the treatment of refractory vasoplegia arising after major cardiovascular surgery. • Methylene blue has served as a rescue therapy in varied types of distributive shock when conventional therapy with fluids and catecholamine vasopressors fail. • It acts by blocking the nitrous oxide-cyclic GMP pathway of vasodilatation. • Antineoplastic agent, ifosfamide toxicity is reversed to certain extent by MB. • Serotonin syndrome is a major complication of methylene blue treatment in patients taking serotonergic drugs.

REFERENCES 1. Giles GM. Recent German Researches on Malaria: Its Treatment by Methylene Blue. With Introductory Remarks. Ind Med Gaz. 1892;27(11):326-30. 2. Lo JC, Darracq MA, Clark RF. A review of methylene blue treatment for cardiovascular collapse. J Emerg Med. 2014;46(5):670-9. 3. Hosseinian L, Weiner M, Levin MA, et al. Methylene blue: magic bullet for vasoplegia? Anesth Analg. 2016;122(1):194-201. 4. Jang DH, Nelson LS, Hoffman RS. Methylene blue for distributive shock: a potential new use of an old antidote. J Med Toxicol. 2013;9(3):242-9. 5. McDonagh EM, Bautista JM, Youngster I, et al. PharmGKB summary: methylene blue pathway. Pharmacogenet Genomics. 2013;23:498-508. 6. Carrodeguas L, Szomstein S, Jacobs J, et al. Topical anesthesia-induced methemoglobinemia in bariatric surgery patients. Obes Surg. 2005;15(2):282-5.

374  Yearbook of Anesthesiology-9 7. Kuiper-Prins E, Kerkhof GF, Reijnen CG, et al. A 12-day-old boy with methemo­ globinemia after circumcision with local anesthesia (lidocaine/prilocaine). Drug Saf Case Rep. 2016;3(1):12. 8. McRobb CM, Holt DW. Methylene blue-induced methemoglobinemia during cardiopulmonary bypass? A case report and literature review. J Extra Corpor Technol. 2008;40(3):206-14. 9. Zeng LA, Hwang NC. Vasoplegia: more magic bullets? J Cardiothorac Vasc Anesth. 2019;33(5):1308-9. 10. McCartney SL, Duce L, Ghadimi K. Intraoperative vasoplegia: methylene blue to the rescue! Curr Opin Anaesthesiol. 2018;31(1):43-9. 11. Licker M, Diaper J, Robert J, et al. Effects of methylene blue on propofol requirement during anaesthesia induction and surgery. Anaesthesia. 2008;63(4):352-7. 12. Miyawaki I, Nakamura K, Yokubol B, et al. Suppression of cyclic guanosine monophosphate formation in rat cerebellar slices by propofol, ketamine and midazolam. Can J Anaesth. 1997;44:1301-7. 13. Masaki E, Kondo I. Methylene blue, a soluble guanylyl cyclase inhibitor, reduces the sevoflurane minimum alveolar anesthetic concentration and decreases the brain cyclic guanosine monophosphate content in rats. Anesth Analg. 1999;89:484-9. 14. Senthilnathan M, Cherian A, Balachander H, et al. Role of methylene blue in the maintenance of postinduction hemodynamic status in patients with perforation peritonitis: a pilot study. Anesth Essays Res. 2017;11(3):665-9. 15. Baraka AS, Ayoub CM, Yazbeck-Karam V, et al. Prophylactic methylene blue in a patient with congenital methemoglobinemia. Can J Anaesth. 2005;52(3): 258-61. 16. Hariharan U, Sood R, Choudhury A, et al. Oxygen desaturation following methylene blue injection: Not always spurious. Saudi J Anaesth. 2011;5(1): 113-4. 17. Matisoff J, Panni MK. Methylene blue treatment for methemoglobinemia and subsequent dramatic bispectral index reduction. Anesthesiology. 2006;105:228. 18. Yamaji F, Soeda A, Shibata H, et al. A new mutation of congenital methemo­ globinemia exacerbated after methylene blue treatment. Acute Med Surg. 2018;5(2):199-201. 19. Belletti A, Musu M, Silvetti S, et al. Non-adrenergic vasopressors in patients with or at risk for vasodilatory shock. A systematic review and meta-analysis of randomized trials. PLoS One. 2015;10(11):e0142605. 20. Pasin L, Umbrello M, Greco T, et al. Methylene blue as a vasopressor: a metaanalysis of randomised trials. Crit Care Resusc. 2013;15(1):42-8. 21. Habib AM, Elsherbeny AG, Almehizia RA. Methylene blue for vasoplegic Syndrome postcardiac surgery. Indian J Crit Care Med. 2018;22(3):168-73. 22. Fischer GW, Levin MA. Vasoplegia during cardiac surgery: current concepts and management. Semin Thorac Cardiovasc Surg. 2010;22:140-4. 23. Shaefi S, Mittel A, Klick J, et al. Vasoplegia After Cardiovascular ProceduresPathophysiology and Targeted Therapy. J Cardiothorac Vasc Anesth. 2018; 32(2):1013-22. 24. Ortoleva JP, Cobey FC. A systematic approach to the treatment of vasoplegia based on recent advances in pharmacotherapy. J Cardiothorac Vasc Anesth. 2019;33(5):1310-4.

Current Status of Methylene Blue in Anesthesia and Intensive Care  375 25. Raikhelkar JK, Weiss AJ, Maysick L, et al. Adjuvant therapy with methylene blue in the treatment of postoperative vasoplegic syndrome caused by carcinoid crisis after tricuspid valve replacement. J Cardiothorac Vasc Anesth. 2012;26(5):878-9. 26. Lutjen DL, Arndt KL. Methylene blue to treat vasoplegia due to a severe protamine reaction: a case report. AANA J. 2012;80(3):170-3. 27. Bhalla T, Sawardekar A, Russell H, et al. The role of methylene blue in the pediatric patient with vasoplegic syndrome. World J Pediatr Congenit Heart Surg. 2011;2(4):652-5. 28. Evora PR, Alves Junior L, Ferreira CA, et al. Twenty years of vasoplegic syndrome treatment in heart surgery. Methylene blue revised. Rev Bras Cir Cardiovasc. 2015;30(1):84-92. 29. Mehaffey JH, Johnston LE, Hawkins RB, et al. Methylene blue for vasoplegic syndrome after cardiac operation: early administration improves survival. Ann Thorac Surg. 2017;104:36-41. 30. Mazzeffi M, Hammer B, Chen E, et al. Methylene blue for postcardiopulmonary bypass vasoplegic syndrome: a cohort study. Ann Card Anaesth. 2017;20: 178-81. 31. Koelzow H, Gedney JA, Baumann J, et al. The effect of methylene blue on the hemodynamic changes during ischemia reperfusion injury in orthotopic liver transplantation. Anesth Analg. 2002;94(4):824-9. 32. Fukazawa K, Pretto EA. The effect of methylene blue during orthoptic liver transplantation on post reperfusion syndrome and postoperative graft function. J Hepatobiliary Pancreat Sci. 2011;18(3):406-13. 33. Jang DH, Nelson LS, Hoffman RS. Methylene blue in the treatment of refractory shock from an amlodipine overdose. Ann Emerg Med. 2011;58(6):565-7. 34. Pelgrims J, De Vos F, Van den Brande J, et al. Methylene blue in the treatment and prevention of ifosfamide-induced encephalopathy: report of 12 cases and a review of the literature. Br J Cancer. 2000;82(2):291-4. 35. Shin YJ, Kim JY, Moon JW, et al. Fatal ifosfamide-induced metabolic encephalopathy in patients with recurrent epithelial ovarian cancer: report of two cases. Cancer Res Treat. 2011;43(4):260-3. 36. Kataria PS, Kendre PP, Patel AA. Ifosfamide induced Encephalopathy Precipitated by Aprepitant: A Rarely Manifested Side Effect of Drug Interaction. J Pharmacol Pharmacother. 2017;8(1):38-40. 37. Haouzi P, Sonobe T, Judenherc-Haouzi A. Developing effective countermeasures against acute hydrogen sulfide intoxication: challenges and limitations. Ann N Y Acad Sci. 2016;1374(1):29-40. 38. Haouzi P, Sonobe T, Judenherc-Haouzi A. Hydrogen sulfide intoxication induced brain injury and methylene blue. Neurobiol Dis. 2019;104474. [Epub ahead of print]. 39. Ng PC, Hendry-Hofer TB, Witeof AE, et al. Hydrogen Sulfide Toxicity: Mechanism of Action, Clinical Presentation, and Countermeasure Development. J Med Toxicol. 2019. [Epub ahead of print]. 40. Cheung JY, Wang J, Zhang XQ, et al. Methylene Blue Counteracts H2S-Induced Cardiac Ion Channel Dysfunction and ATP Reduction. Cardiovasc Toxicol. 2018;18(5):407-19. 41. Volpon LC, Evora PRB, Teixeira GD, et al. Methylene blue for refractory shock in polytraumatized patient: a case report. J Emerg Med. 2018;55(4):553-8.

376  Yearbook of Anesthesiology-9 42. Seo H, Kim SH, Choi JH, et al. Effect of heated humidified ventilation on bronchial mucus transport velocity in general anaesthesia: a randomized trial. J Int Med Res. 2014;42(6):1222-31. 43. Beringer R, Skeahan N, Sheppard S, et al. Study to assess the laryngeal and pharyngeal spread of topical local anesthetic administered orally during general anesthesia in children. Paediatr Anaesth. 2010;20(8):757-62. 44. Polat R, Aydin GB, Ergil J, et al. [Comparison of the i-gel™ and the Laryngeal Mask Airway Classic™ in terms of clinical performance]. Rev Bras Anestesiol. 2015;65(5):343-8. 45. Agnoletti V, Piraccini E, Corso R, et al. Methylene blue diffusion after multilevel thoracic paravertebral blocks. J Cardiothorac Vasc Anesth. 2011;25(2):e5-6. 46. Biswas A, Castanov V, Li Z, et al. Serratus Plane Block: A Cadaveric Study to Evaluate Optimal Injectate Spread. Reg Anesth Pain Med. 2018;43(8):854-8. 47. Sabouri AS, Crawford L, Bick SK, et al. Is a Retrolaminar Approach to the Thoracic Paravertebral Space Possible?: A Human Cadaveric Study. Reg Anesth Pain Med. 2018;43(8):864-8. 48. Dewachter P, Mouton-Faivre C, Tréchot P, et al. Severe anaphylactic shock with methylene blue instillation. Anesth Analg. 2005;101(1):149-50. 49. Martino EA, Winterton D, Nardelli P, et al. The Blue Coma: The Role of Methylene Blue in Unexplained Coma After Cardiac Surgery. J Cardiothorac Vasc Anesth. 2016;30(2):423-7. 50. Grubb KJ, Kennedy JL, Bergin JD, et al. The role of methylene blue in serotonin syndrome following cardiac transplantation: a case report and review of the literature. J Thorac Cardiovasc Surg. 2012;144(5):e113-6.

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CHAPTER

25

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Kirti N Saxena, Shreya Goswami, Purnima Dhar, Anup Gogia

JOURNAL SCAN 1—Kirti N Saxena Preoperative Echocardiography for Patients with Hip Fractures Under­ going Surgery: A Retrospective Cohort Study Using a Nationwide Database. Yonekura H, Ide K, Onishi Y et al. Anesth Analg. 2019;128(2):213-20.

BACKGROUND Elderly patients have a high incidence of comorbidities with significant cardiopulmonary involvement. Transthoracic echocardiography (TTE) is an important tool for the assessment of cardiac function. However, it is not clear if its routine preanesthetic use can affect the clinical outcomes of patients. The authors hypothesized that preoperative TTE is associated with reduced postoperative morbidity and improved patient survival after surgical repair of hip fractures.

ABSTRACT In this retrospective study, records of 66,620 patients who underwent hip fracture surgery within 2 days of admission, over an 8-year period (2008–2016), were examined from a nationwide administrative database. The association of preoperative echocardiography with the incidence of in-hospital mortality was analyzed using propensity score matching. The incidence of postoperative complications, intensive care unit (ICU) admissions and length of hospital stay were also examined as secondary outcomes. Overall 52.1% patients underwent preoperative TEE screening. The propensity score matched to nonscreened patients did not show in-hospital mortality differences (P = 0.45). There was no reduction in postoperative complications and ICU admissions (P = 0.53). Findings were also consistent with other sensitivity analyses and subgroup analyses. The duration of hospital stay was more in those who underwent TTE compared to those who did not. The authors concluded that preoperative echocardiography was not associated with reduced in-hospital mortality or postoperative complications.

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COMMENTARY It is well known that elderly patients form a large percentage of those suffering from hip fractures. This population has a high incidence of comorbidities such as pulmonary and cardiac diseases. Due to the advanced age of these patients, they may not give function-related history after sustaining fractures. Perioperative concerns are more in these patients since geriatric patients have a number of comorbidities. Cardiac and lung diseases have major implications for the postoperative outcome. TTE is an important tool for the assessment of cardiac function. However, most guidelines such as those of the American heart association (AHA) recommend the use of TTE as a diagnostic tool for heart disease after clinical assessment suggests compromised cardiac function.1 Several multivariate risk scores such as American College of Surgeons National Surgical Quality Improvement Program (NSQIP) Surgical Risk Calculator and the Duke activity status index (DASI) have been suggested to assess the perioperative risk of a major adverse cardiac event (MACE) of death or myocardial infarction (MI). These indices take into account the age, functional status, comorbidities, type of surgery, whether emergent or elective and biochemical parameters. Recent literature suggests that assessment of geriatric patients should not be focused on single systems but must be comprehensive including comorbidities with their medical management, nutritional and mental health, functional capacity, social circumstances, and surgery-specific risk scores.2 Several reviews on the use of preoperative TTE have suggested definite indications for it, with reduced functional capacity before the surgical condition being a strong indicator for it. They failed to report any evidence that routine preoperative evaluation using TTE can result in improved outcomes in geriatric patients postoperatively.3 Contrary to this, Bøtker et al. in a prospective study found that preoperative focused cardiopulmonary ultrasound revealed unexpected pathologies and recommended it routinely for elderly patients.4 This argument was carried further by Heiberg et al. who conducted a meta-analysis of retrospective studies on this subject.5 They included studies on patients admitted in intensive care as well as those undergoing surgery. They found that focused cardiac ultrasonography had the potential to change the diagnosis as well as the interventions resulting from it. Since most of the studies were retrospective in nature, they concluded that well-designed prospective studies were required to conclusively decide whether TTE should be made part of the routine preoperative screening of surgical patients. Undiagnosed cardiopulmonary disease is likely to result in increased postoperative complications. Based on a previous study6 which showed a rise in Troponin T levels following surgery for fracture femur suggesting

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a perioperative cardiac event, Yonekura in their article opined that preoperative TTE would help in uncovering any undiagnosed heart disease that may not have manifested in this group of patients. However, there is a paucity of studies demonstrating a clear link between preoperative TTE and improved postoperative outcomes. This retrospective cohort study was conducted using multiple claims database of diagnosis, procedure, and combination data of patients above 60 years of age admitted between 2008 and 2016 in acute care hospitals in Japan. Hip fracture was clearly defined (fracture of the femoral neck or intertrochantric fracture), and only those patients undergoing surgery defined as the open reduction of fracture with internal fixation, hemiarthroplasty, or total hip arthroplasty were included in the analysis. Preoperative data included the type of fracture and operative procedure, the status of the patient on admission, and any medical intervention before surgery. The comorbidities were evaluated using the Charlson and Elixhauser comorbidity scores. Two groups were compared fulfilling these criteria: those who underwent TTE before surgery and those who did not. The primary outcome was defined as mortality and secondary outcome was cardiopulmonary complications, postoperative admission to intensive care unit (ICU) and length of hospital stay. The results of the study showed that there was no significant difference in the primary outcome, that is, in-hospital mortality in the two groups. There was no significant difference in the postoperative complications and admission to ICU between the groups. ICU admissions reflect serious postoperative morbidity with no difference between the groups. The only difference was that the length of hospital stay both before and after surgery was significantly higher in the group that underwent TTE preoperatively compared to the group that did not. They ascribed this to increased medical interventions in these patients and suggested prospective studies to find whether TTE should be done routinely in elderly patients undergoing surgery. The results need cautious analysis since TTE can alter the course of management of the surgical patients. However, this may lead to early medical intervention benefitting certain patients. This may have resulted in significantly increased length of stay of patients preoperatively due to medical interventions. This retrospective study may help in guiding future prospective studies. The shortcomings of the study as pointed out by the authors are that firstly, strict exclusion criteria were used so the results cannot be generalized. Secondly, this study was conducted in Japan where patients are admitted for longer periods in hospital compared to Western countries. Better access to healthcare and better socioeconomic status of Japanese patients result in lower mortality rates compared to those across the world. Thirdly, the database has a certain degree of anonymity and failed

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to identify any association between certain groups of surgeons being more likely to order a TTE before surgery. To conclude, preoperative TTE was found to have no association with in-hospital mortality in elderly patients undergoing surgery for hip fracture. Further prospective studies are needed.

REFERENCES 1. Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/ American Heart Association Task Force on practice guidelines. J Am Coll Cardiol. 2014;64(22):e77-137. 2. Chan SP, Ip KY, Irwin MG. Peri-operative optimisation of elderly and frail patients: a narrative review. Anaesthesia. 2019;74(Suppl 1):80-9. 3. Shim CY. Preoperative cardiac evaluation with transthoracic echocardiography before non-cardiac surgery. Korean J Anesthesiol. 2017;70(4):390-7. 4. Bøtker MT, Vang ML, Grøfte T, et al. Routine pre‐operative focused ultrasonography by anesthesiologists in patients undergoing urgent surgical procedures. Acta Anaesthesiol Scand. 2014;58(7):807-14. 5. Heiberg J, El-Ansary D, Canty DJ, et al. Focused echocardiography: a systematic review of diagnostic and clinical decision-making in anaesthesia and critical care. Anaesthesia. 2016;71(9):1091-100. 6. Dawson-Bowling S, Chettiar K, Cottam H, et al. Troponin T as a predictive marker of morbidity in patients with fractured neck of femur. Injury. 2008;39(7): 775-80.

JOURNAL SCAN 2—Shreya Goswami Post-anaesthesia pulmonary complications after use of muscle relaxants (POPULAR): a multicentre, prospective observational study. Kirmeier E, Eriksson LI, Lewald H, et al. POPULAR Contributors. Lancet Respir Med. 2019;7(2):129-40.

BACKGROUND Postoperative pulmonary complications (POPC) are one of the most common, serious adverse events affecting a significant number of patients undergoing surgery under general anesthesia. It was first suggested that inadequate antagonism of neuromuscular blockers (NMBs) may contribute to postoperative pulmonary adverse events.1 There is now evidence that almost 75% of the patients receiving NMB develop some form of alteration in the respiratory mechanics and it takes 6 weeks to return to the preoperative physiological state.2 Among the various risk factors of POPC, NMBs are considered to have a significant contribution. The present study was conducted to assess the role of NMBs in producing POPC and whether the use of reversal agents and intraoperative neuromuscular monitoring, can assist to alleviate POPC.

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ABSTRACT Postoperative pulmonary complications can be widely defined as conditions affecting the respiratory system contributing to the postoperative morbidity and mortality of patients after surgery. The incidence of POPC widely varies between 1% and 23% and the suggested incidence of POPC even surpasses the cardiac complications.2 This multicenter prospective observational cohort study looked at whether the patient receiving NMB are at increased risk of developing postoperative pulmonary complications and whether the use of antagonism of neuromuscular blockade or neuromuscular monitoring can prevent POPC. Data from 22,803 patients from 211 hospitals in 28 European countries were collected. Patients ≥ 18 years posted for noncardiac surgery under general anesthesia were included and patients’ demographics, perioperative details, and chart review at discharge were prospectively collected over 2 weeks. The primary outcome was the incidence of POPC up to 28 days after surgery. The study found 7.6% increased incidence of POPC in patients who received NMBs. About 2.3% patients with high risk (both surgical and respiratory) were not administered any NMBs. The investigators observed that the use of neuromuscular monitoring and extubation at a train of four (TOF) ratio of 0.9 or more, as well as the use of reversal, were not associated with a decrease in POPC. Interestingly the use of sugammadex instead of neostigmine did not prove to be beneficial in alleviating POPC. Hence, the overall potential benefits of neuromuscular blockade need to be balanced against the increased risk of POPC.

COMMENTARY Postoperative pulmonary complications is a broad term attributed to any complication involving the respiratory system after surgery increasing the morbidity and mortality of the patient. The authors of the current study used the predictive model formulated by Canet et al.3 to prognosticate POPC. The predictive index was based on any one of the following complications like respiratory failure, bronchospasm, atelectasis, pleural effusion, pneumothorax or aspiration pneumonitis. Their study demonstrated a 5% incidence of POPC with an increase in 30-day mortality in such patients. The index served as a risk assessment tool to assess POPC in patients scheduled for surgery.3,4 The authors in their study (POPULAR) observed that among the multiple modifiable and nonmodifiable factors, NMBs are considered to have a significant contribution to the development of POPC. This is the first retrospective study of such high magnitude to provide prospective data for the role of NMBs in developing POPC. The study is well designed and adequately powered. In order to obtain a standardized and uniform data collection, a

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constant collaboration between the national and local coordinators were ensured and any queries throughout the study were continuously addressed. The plan for statistical analysis was thorough. PERISCOPE study by Canet et al.3,4 was used as a reference for sample size calculation. The authors tried to negate the effects of multiple confounding factors like surgery per se as well as patient’s preoperative comorbid conditions that can independently contribute to the development of POPC. The researchers included the known causes of POPC as confounding variables in data analysis. Logistic regression was used and further sensitivity analysis was carried out to negate the effects of confounder variables which could modify the result of the study. Adjusted values of odds ratio (ORadj) and absolute risk reduction (ARRadj) were provided. However, in my view, cardiorespiratory reserves of the patients included in the study may not have been the same. Some of them may have been on regular physical exercise schedule as a part of their daily routine. There is evidence now to show that patients who are subjected to physical “conditioning” prior to operative stresses (prehabilitation) with exercise and incentive spirometry have enhanced functional capacity and lesser propensity to develop POPC.5 The incidence of POPC is less even when enhanced recovery after surgery (ERAS) protocol is used.6 There is no mention about the following situations in the present study which have the potential to modify the end result of the study. The authors of the POPULAR study defined the following seven key factors for the analysis of neuromuscular management: use of NMBs, expected duration of blockade, use of neuromuscular monitoring technique (quantitative vs qualitative), adherence to the recommended TOF 0.9 or more for extubation of trachea, use of reversal agents and type of reversal used (neostigmine vs sugammadex). The investigators constructed five subcohorts as all the seven key factors were not applicable to all the patients. The subcohorts are: patients receiving general anesthesia, the patient receiving NMBs, patients receiving neuromuscular monitoring (quantitative versus qualitative), and patients receiving a reversal agent. The POPULAR study demonstrated that the use of neuromuscular blockade was associated with an increased incidence of POPC and even a single dose of NMB contributed to the development of POPC. This finding correlates with the previous retrospective studies which have also found the association of POPC with the use of NMBs.7 However, the multivariate analysis could not confirm any association between duration of NMBs and the use of a high dose of NMBs with development of POPC. It is prudent to observe that preservation of the tone of diaphragm plays a significant role in the preservation of lung volume and reserve. Once the diaphragm is paralyzed (even if it is a single dose of NMB), basal atelectasis can be induced.8 Hence, maneuvers to retain lung volume have to be employed to ensure

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these atelectatic areas are expanded by repeated recruitment maneuvers in addition to continuous positive end-expiratory pressure (PEEP). These maneuvers ought to be undertaken during mechanical ventilation and before extubation to show an impact on the incidence of POPC.9 A still more useful and balanced approach can be to employ regional anesthesia techniques along with general anesthesia which is widely practiced in ERAS multispecialty protocols. The study demonstrated that the use of neuromuscular monitoring, both qualitative as well as quantitative (tracheal extubation on TOF ≥ 0.9) does not decrease the incidence of POPC. The use of reversal also has a similar finding. Both neostigmine and sugammadex failed to alleviate the risk of POPC in patients receiving neuromuscular blockade. This contradicts the finding of Brueckmann and colleagues, who looked at the reversal of rocuronium-induced neuromuscular blockade by sugammadex after abdominal surgery. The incidence of residual blockade (TOF < 0.9) and operating room discharge readiness were recorded. The study showed that sugammadex administration abolished residual neuromuscular blockade in the postanesthesia care unit and stepped up the discharge readiness of the study population.10 To conclude, the POPULAR study has consolidated on the evidence that NMBs are associated with an increased incidence of POPC. Hence, it is prudent to limit the usage of NMBs to provide surgical relaxation, avoid indiscriminate use in short surgeries and in patients with minor risk factors to decrease the risk of POPC in those patient population. If used, the author recommends the use of recruitment maneuvers and PEEP to restore the lung volume repeatedly during mechanical ventilation and just before extubation.

ACKNOWLEDGMENT The author would like to express her gratitude to Professor Pankaj Kundra for his valuable inputs and his contribution for this write-up.

REFERENCES 1. Berg H, Roed J, Viby-Mogensen J, et al. Residual neuromuscular block is a risk factor for postoperative pulmonary complications. A prospective, randomised, and blinded study of postoperative pulmonary complications after atracurium, vecuronium and pancuronium. Acta Anaesthesiol Scand. 1997;41(9):1095-103. 2. Miscovic A, Lumb AB. Postoperative pulmonary complications. Br J Anaesth. 2017;118(3):317-34. 3. Canet J, Gallart L, Gomar C, et al. Prediction of postoperative pulmonary complications in a population-based surgical cohort. Anesthesiology. 2010;113(6):1338-50.

384  Yearbook of Anesthesiology-9 4. Canet J, Sabaté S, Mazo V, et al. Development and validation of a score to predict postoperative respiratory failure in a multicentre European cohort: A prospective, observational study. Eur J Anaesthesiol. 2015;32(7):458-70. 5. Kundra P, Vitheeswaran M, Nagappa M, et al. Effect of preoperative and postoperative incentive spirometry on lung functions after laparoscopic cholecystectomy. Surg Laparosc Endosc Percutan Tech. 2010;20(3):170-2. 6. Gillis C, Li C, Lee L, et al. Prehabilitation versus rehabilitation: a randomized control trial in patients undergoing colorectal resection for cancer. Anesthesiology. 2014;121(5):937-47. 7. Bulka CM, Terekhov MA, Martin BJ, et al. Nondepolarizing Neuromuscular Blocking Agents, Reversal, and Risk of Postoperative Pneumonia. Anesthesiology. 2016;125(4):647-55. 8. Kundra P, Subramani Y, Ravishankar M, et al. Cardiorespiratory effects of balancing PEEP with intra-abdominal pressures during laparoscopic cholecystectomy. Surg Laparosc Endosc Percutan Tech. 2014;24(3):232-9. 9. Kundra P, Garg R, Patwa A, et al. All India Difficult Airway Association 2016 guidelines for the management of anticipated difficult extubation. Indian J Anaesth. 2016;60:915-21. 10. Brueckmann B, Sasaki N, Grobara P, et al. Effects of sugammadex on incidence of postoperative residual neuromuscular blockade: a randomized, controlled study. Br J Anaesth. 2015;115:743-51.

JOURNAL SCAN 3—Purnima Dhar Perioperative Quality Initiative consensus statement on intraoperative blood pressure, risk and outcomes for elective surgery. Sessler DI, Bloomston JA, Aronson S, et al. Perioperative Quality Initiative-3 workgroup. Br J Anaesth. 2019:122(5):563-74.

BACKGROUND Research in anesthesia is largely about reducing the morbidity and mortality after surgery. Over the years, there has been a drastic reduction in perioperative mortality and morbidity due to various improvements in preoperative assessment, intraoperative monitoring, and postoperative care. However, the medium- and long-term outcomes continue to be a source of concern. Severe hypotension/hypertension as a cause of adverse postoperative outcome is understandable, but the patients who survive the immediate postoperative period may die later of acute kidney injury, MI, stroke, or sepsis. There is mounting evidence that one of the factors which may cause any of these may be extended periods of less than severe hypotension intraoperatively. The effect of intraoperative hypotension on organ functions has been a subject of research ever since we started doing deliberate hypotension for ease of surgery. But there has been a lack of consensus on the definition of unacceptable intraoperative hypotension. A varying incidence of intraoperative hypotension, ranging from 5% to 99%

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was reported in a meta-analysis published in 2004.1 The lack of consensus on the definition of intraoperative hypotension may be responsible for the very wide range in the number of adverse outcomes that have been previously reported in the literature.2 However, despite the widely-presumed importance of blood pressure management during the perioperative period, doubts have also been raised.3 This consensus statement was hence needed to clarify and answer the usual questions one faces every day while conducting anesthesia and put at least some doubts to rest.

ABSTRACT There is evidence that long-term outcomes after surgery can be due to blood pressure fluctuations. To collect the evidence and formulate a consensus on the issue of intraoperative blood pressure a Perioperative Quality Initiative Consensus-Building Conference was held in London in July 2017. Eleven experts from the world over and the Perioperative Quality Initiative-3 workgroup were involved in the process. They used the modified Delphi method and came out with three consensus statements. The article has details of the consensus statements and also talks about the issues where consensus was not reached and therefore need further research.

COMMENTARY Effect of intraoperative blood pressure fluctuations, especially hypotension, on kidneys, heart, and brain (and other organs) has been addressed many times before by individual institutions. This time, it comes from Perioperative Quality Initiative (POQI), an international multidisciplinary nonprofit organization that organizes consensus conferences on topics of interest related to perioperative medicine. For this consensus, the modified Delphi method was used. In this method, all possible questions regarding a topic are raised over several rounds and sent to a panel of experts. The anonymous responses are shared with the group. An extensive review of literature is done and opinions shared. Finally, they seek to reach a correct response through a consensus at a conference. Four papers on different aspects of perioperative blood pressure have been published regarding physiology, preoperative control, intraoperative control, and postoperative management of blood pressure. This scan is about the consensus statement on intraoperative blood pressure management. The authors have come out with three consensus statements. The first consensus statement tries to define intraoperative hypotension. It states: Consensus statement 1: “Intraoperative mean arterial blood pressures below 60–70 mm Hg are associated with myocardial injury, acute kidney injury,

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and death. Systolic arterial pressures below 100 mm Hg are associated with myocardial injury and death. Injury is a function of hypotension severity and duration.” The statement has confined itself to absolute threshold values. The threshold relative to preoperative blood pressure values is not clearly defined. Several studies reviewed have taken a fall of ≥20% as a threshold while others have taken ≥30% and even 40% as a threshold. As the blood pressures are taken immediately preoperatively are often unreliable and real preoperative blood pressures often unavailable, the panel concurs with Salmasi et al. that the associations based on relative thresholds were no stronger than those based on absolute thresholds.4 They did not find clinically important interaction with preoperative pressure and have concluded that anesthetic management can be based on intraoperative pressure without regard to preoperative pressure.4 However, a large prospective multicenter trial used the baseline blood pressure as received from the medical records and found the best outcome results with tight control (±10% of baseline) in high-risk patients.5 A meta-analysis of studies in orthopedic patients finds support for the use of deliberate hypotension in reducing blood loss and transfusion requirements in orthopedic surgery,6 but these results are tempered by the small sample sizes and poor methodological quality of published studies.2 The panel is not very clear about the management strategy for tachycardia. A recent retrospective study found no relationship between heart rate and outcomes7 and the panel seems to endorse that. The study concluded that there was no apparent association between various measures of tachycardia and a composite of myocardial injury after noncardiac surgery (MINS) and death,7 a result that contradicts previously reported associations. So, the study showing that a tachycardia of more than 100 beats/min is an independent factor for adverse outcomes in long-duration surgeries,8 has not been given credence in the final statement which clubs tachycardia of more than 100 beats/min with hypotension to predict increased organspecific risks.2 The statement regarding inadvisability of treating tachycardia at the cost of causing hypotension is important and hence gives guidance.2 There is no clear guidance regarding the duration of hypotension in the consensus statement. One of the quoted studies on 1-year mortality in elderly patients confirms the clinical experience that besides the absolute or relative blood pressure thresholds, the duration of low blood pressure is equally important in the possible association of intraoperative hypotension with adverse outcome, i.e. lower blood pressures were tolerated for shorter durations.9 Consensus statement 2 deals with intraoperative hypertension in noncardiac surgery and states:

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Consensus statement 2: “For adults having noncardiac surgery, there is insufficient evidence to recommend a general upper limit of blood pressure at which therapy should be initiated.” The statement fails to give us a clear upper limit of systolic/mean blood pressure above which the outcome suffers. Going through the eight studies analyzed for intraoperative hypertension, a systolic blood pressure of more than 160 mm Hg seems to be the cut-off most authors have taken. Recent trials are equivocal about there being any adverse postoperative outcome with intraoperative hypertension. Data available from a secondary analysis of the vascular events in noncardiac surgery cohort evaluation (VISION) trial suggest that intraoperative systolic arterial pressures (SAP) >160 mm Hg are associated with myocardial injury and infarction.2 But a large retrospective analysis of >52,000 adults, noncardiac surgical patients reported that those with mean arterial pressure (MAP) >120 mm Hg did not exhibit complications within the perioperative period. Contrary to common belief, increased lability was associated with decreased 30-day mortality.10 The panel found paucity and heterogeneity of the published evidence and conclude that a general upper limit of blood pressure at which therapy should be initiated remains to be defined. “Overall, the available data suggest that elevated intraoperative blood pressures are not as strongly associated with postoperative morbidity as hypotension. That said, intraoperative arterial pressure management should be individualized in consideration of underlying organ function and the surgical procedure being performed.”2 The consensus statement 3 is about intraoperative hypertension in cardiac surgery. Consensus statement 3: “During cardiac surgery, intraoperative systolic blood pressure greater than 140 mm Hg is associated with increased 30-day mortality. Injury is a function of severity and duration.” The panel seems to have based their statement on two independent studies and there is a clear message. The importance of preoperative pulse pressure being a surrogate of vascular health is emphasized. The panel finds evidence that preoperative pulse pressure >70–80 mm Hg is a good predictor for stroke, cardiac complications, and death.2 Besides these consensus statements, the panel has listed unanswered questions and recommends research in these areas. Some of these questions include: What is the safe lower/upper limit of blood pressure? Which component of blood pressure is more important? How long can one give deliberate hypotension? Which drugs are safer for treating hypotension? Which patients/situations are more vulnerable? Overall, the article is important, as it emphasizes issues related to the importance of maintaining intraoperative blood pressure and defining thresholds for the same. In addition, the authors have also identified key areas for further research.

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REFERENCES 1. Howell SJ. Consensus statements and expert guidance: interpret with care. Br J Anaesth. 2019;122:719-22. 2. Sessler DI, Bloomstone JA, Aronson S, et al. Perioperative quality initiative consensus statement on intraoperative blood pressure, risk and outcomes for elective surgery. Br J Anaesth. 2019;122:563-74. 3. Li D, Bohringer C, Liu H. What is “normal” intraoperative blood pressure and do deviations from it really affect postoperative outcome? J Biomed Res. 2017;31(2):79-81. 4. Salmasi V, Maheshwari K, Yang D, et al. Relationship between Intraoperative Hypotension, Defined by Either Reduction from Baseline or Absolute Thresholds, and Acute Kidney and Myocardial Injury after Noncardiac Surgery: A Retrospective Cohort Analysis. Anesthesiology. 2017;126(1):47-65. 5. Futier E, Lefrant JY, Guinot PG, et al. Effect of Individualized vs Standard Blood Pressure Management Strategies on Postoperative Organ Dysfunction Among High-Risk Patients Undergoing Major Surgery: A Randomized Clinical Trial. JAMA. 2017;318(14):1346-57. 6. Paul JE, Ling E, Lalonde C, et al. Deliberate hypotension in orthopedic surgery reduces blood loss and transfusion requirements: a meta-analysis of randomized controlled trials. Can J Anesthes. 2007;54:799-810. 7. Ruetzier K, Yilmaz HO, Turan A, et al. Intra-operative tachycardia is not associated with a composite of myocardial injury and mortality after noncardiac surgery: A retrospective cohort analysis. Eur J Anaesthesiol. 2019;36(2):105-13. 8. Reich DL, Bennett-Guerrero E, Bodian CA, et al. Intraoperative tachycardia and hypertension are independently associated with adverse outcome in noncardiac surgery of long duration. Anesth Analg. 2002;95:273-7. 9. Bijker JB, van Klei WAV, Vergouwe Y, et al. Intraoperative hypotension and 1-year mortality after noncardiac surgery. Anesthesiology. 2009;111:1217-26. 10. Levin M, Fischer G, Lin HM, et al. Intraoperative arterial blood pressure lability is associated with improved 30 day survival. Br J Anaesth. 2015;115(5):716-26.

JOURNAL SCAN 4—Anup Gogia Effect on Morphine Requirement of Early Administration of Oral Acetamino­phen vs. Acetaminophen/Tramadol Combination in Acute Pain. Bouida W, Beltaief K, Msolli MA, et al. Pain Pract. 2019;19(3):275-82.

BACKGROUND Pain is considered as fifth vital sign and is often the presenting complaint in the emergency department. However, despite an armamentarium of available analgesics, pain remains inadequately managed leading to patient dissatisfaction. Opioids are mainstay of treating severe pain but are associated with serious side effects including hypoxia, hypotension, abuse potential, and even death. Use of multiple drugs with different mechanisms of action can be effective in reducing the opioid dose and related side effects. The authors studied the impact of starting acetaminophen or

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tramadol/acetaminophen combination on morphine requirement and patient satisfaction in emergency department.

ABSTRACT In this multicentric, randomized, single blind trial, patients over 18 years of age with pain [Visual analog scale (VAS) equal to or higher than 30/100] in triage area were included. Patients were randomly assigned to receive either placebo, acetaminophen (1000 mg) or tramadol/acetaminophen combination (75 mg/650 mg). Primary outcome measure was need for rescue morphine during emergency department (ED) stay. Secondary outcome included patient satisfaction regarding overall management quality in the ED, ED length of stay and percentage of patients discharged from the ED with VAS < 30. Visual analog scale pain score assessment was repeated 30 minutes after the medications were given and at ED discharge. Patients having VAS > 70 at 30 minutes post triage assessment were given intravenous (IV) morphine as rescue analgesia. Patients having a VAS score between 30 and 70 at 30 minutes triages were given first step analgesics at the discretion of the treating physician. A total of 1,485 patients completed the study (mean age 37.9 years). In 54.15% of participants pain was traumatic in origin. The mean VAS at triage was comparable in all three groups as well as between trauma and non-trauma pain patients (63 ± 14 vs 63 ± 15). The mean VAS decrease 30 minutes post triage was statistically significant between group tramadol/acetaminophen combination and group placebo but not significant between group acetaminophen and placebo (P < 0.001). The difference between group tramadol/acetaminophen combination and group acetaminophen was not significant (P = 0.59). The difference in the need for rescue morphine was significant only between tramadol/ acetaminophen combination and placebo group. Emergency department length of stay was significantly shorter in tramadol/acetaminophen group compared to other groups. Patient satisfaction was highest in tramadol/ acetaminophen group (77%), compared to acetaminophen group (69%) and placebo groups (68%). The difference in the percentage of patients discharged with VAS score