Yearbook of Anesthesiology‒8 [1 ed.] 9789354650116, 9789352706037

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Yearbook of Anesthesiology-8

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EDITORIAL BOARD

1. VP Kumra MD DAc FICA Past President and Advisor Indian College of Anaesthesiologists Ex-Vice President Indian Society of Anaesthesiologists (National) Emeritus Consultant and Advisor Department of Anaesthesiology Pain and Perioperative Medicine Sir Ganga Ram Hospital, New Delhi, India [email protected]

2. B Radhakrishnan MD MPhil FICA President Indian College of Anaesthesiologists Ex-President Indian Society of Anaesthesiologists (National) Principal Academy of Medical Sciences Kannur, Kerala, India [email protected]

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

4. Baljit Singh MD CEO, Indian College of Anaesthesiologist Director Professor GB Pant Institute of Postgraduate Medical Education and Research New Delhi, India [email protected]

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Yearbook of Anesthesiology-8 Editors Raminder Sehgal MD DA FICA Ex-Director Professor Maulana Azad Medical College, New Delhi, India Ex-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 Whole Constituent of

Indian Society of Anaesthesiologists (Member of the World Federation of Societies of Anaesthesiologists)

Foreword Jayashree Sood

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

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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 Email: [email protected]

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Jaypee-Highlights Medical Publishers Inc City of Knowledge, Bld. 235, 2nd Floor Clayton, Panama City, Panama Phone: +1 507-301-0496 Fax: +1 507-301-0499 Email: [email protected]

Jaypee Brothers Medical Publishers (P) Ltd Bhotahity, Kathmandu, Nepal Phone: +977-9741283608 Email: [email protected] Website: www.jaypeebrothers.com Website: www.jaypeedigital.com © 2019, 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-8 First Edition: 2019 ISBN 978-93-5270-603-7

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Contributors

Munisha Agarwal MD Director Professor Department of Anaesthesiology and Intensive Care Maulana Azad Medical College and Lok Nayak Hospital New Delhi, India E-mail: [email protected] Richa Aggarwal  Associate Professor Department of Critical and Intensive Care Jai Prakash Narayan Apex Trauma Center All India Institute of Medical Sciences New Delhi, India E-mail: [email protected] Deep Arora MD Director Orthopedic Anaesthesia Medanta—The Medicity Gurugram, Haryana, India E-mail: [email protected] Sukhminder Jit Singh Bajwa  MD MBA FACEE Ex-Professor and Director Anaesthesiology and Critical Care Gian Sagar Medical College and Hospital Patiala, Punjab, India Editor-in-chief-NJISA Associate Editor IJA/JOACP E-mail: [email protected] Pradeep Bhatia  MD FICCM FICA Professor and Head Department of Anaesthesiology and Critical Care All India Institute of Medical Sciences Jodhpur, Rajasthan, India Editor, “The Indian Anesthetists’ Forum” E-mail: [email protected]

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Chandrshish Chakravarty  MD EDIC Consultant Department of Critical Care Medicine Apollo Gleneagles Hospitals Kolkata, West Bengal, India E-mail: [email protected] Swati Chhabra  MD DNB MNAMS Assistant Professor Department of Anaesthesiology and Critical Care All India Institute of Medical Sciences Jodhpur, Rajasthan, India E-mail: [email protected] Gautam Girotra  MD PGDHM Senior Consultant Department of Anaesthesiology Max Superspecialty Hospital Saket, New Delhi, India E-mail: [email protected] Ramachandran Gopinath  MD DA (UK) FFARCSI

Senior Professor and Head Department of Anaesthesiology and Critical Care Nizam’s Institute of Medical Sciences Hyderabad, Telangana, India E-mail: [email protected] Sunanda Gupta  MD PhD FAMS Professor Department of Anaesthesia Geetanjali Medical College Founder President Association of Obstetric Anaesthesiologists Udaipur, Rajasthan, India E-mail: [email protected]

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Shiv Kumar Iyer MD Professor Critical Care Medicine Department of Medicine Bharatiya Vidyapeeth Medical College Pune, Maharashtra, India E-mail: [email protected] Ashok Jadon  MD DNB MNAMS FIPP FAMS Chief Consultant and Head Anaesthesia and Pain Relief Service Tata Motors Hospital Jamshedpur, Jharkhand, India E-mail: [email protected] Colonel Nikahat Jahan  MD DNB FNB Associate Professor Department of Anaesthesia and Critical Care Armed Forces Medical College Pune, Maharashtra, India E-mail: [email protected] Kajal Jain MD Professor Postgraduate Institute of Medical Education and Research Chandigarh, India E-mail: [email protected] Kiran Jangra  MD DM (Neuroanesthesia) Assistant Professor Postgraduate Institute of Medical Education and Research Chandigarh, India E-mail: [email protected] Muralidhar Kanchi  MD FIACTA FICA MBA FASE Director (Academic) Senior Consultant and Professor Anesthesia and Intensive Care Professor of International Health, University of Minnesota, USA Narayana Hrudayalaya Hospitals Bengaluru, Karnataka, India E-mail: muralidhar.kanchi.dr@ narayanahealth.org [email protected]

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Mukul Chandra Kapoor  MD DNB MNAMS FIACTA

Director Department of Anaesthesia Max Smart Super Specialty Hospital Saket, New Delhi, India E-mail: [email protected] [email protected] Pramod Kohli MD Director-Professor Department of Anaesthesiology Lady Hardinge Medical College New Delhi, India E-mail: [email protected] Archna Koul  MBBS MD Senior Consultant Department of Anaesthesia Pain and Perioperative Medicine Sir Ganga Ram Hospital New Delhi, India E-mail: [email protected] Krishna HM  MD DNB Professor Department of Anaesthesiology Kasturba Medical College Manipal, Karnataka, India E-mail: [email protected] Mritunjay Kumar  MD DNB DHM Associate Professor Department of Anaesthesiology and Critical Care All India Institute of Medical Sciences Jodhpur, Rajasthan, India E-mail: [email protected] Naveen Malhotra  MD DNB FIPM FICA Professor Anaesthesiology In Charge Pain Management Center Postgraduate Institute of Medical Sciences Rohtak, Haryana, India E-mail: [email protected]

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Contributors

Raj Kumar Mani  MD FRCP (London) FCCP FICCM Group CEO (Medical Services) and Chairman Critical Care, Pulmonology and Sleep Medicine Nayati Healthcare and Research Pvt Ltd Gurugram, Haryana, India E-mail: [email protected] Ian McConachie  MB ChB FRCA FRCPC Associate Professor Department of Anaesthesia and Perioperative Medicine Western University London, Ontario, Canada E-mail: [email protected] Deepak Pahwa MD Consultant Orthopedic Anaesthesia Medanta—The Medicity Gurugram, Haryana, India E-mail: [email protected] Deepanjali Pant  MBBS MD Senior Consultant Department of Anaesthesia Pain and Perioperative Medicine Sir Ganga Ram Hospital New Delhi, India E-mail: [email protected] Subrahmanyan Radhakrishna  MBBS DA FFARCS FRCA

Consultant Anaesthetist University Hospitals of Coventry and Warwickshire Coventry, UK E-mail: [email protected] Ekta Rai  MRCA MD Professor Department of Anaesthesia Christian Medical College Vellore, Tamil Nadu, India E-mail: [email protected]

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Rajendra Sahoo  MBBS MD CIPS FRACP ASRA Certified Ultrasound Pain and MSK Interventionist (USA) Senior Consultant Anaesthesiology and Pain Management Health World Hospitals Durgapur, West Bengal, India E-mail: [email protected] Ramesh Vedagiri Sai  MBBS DA MD FCARCSI Assistant Professor Department of Anaesthesia and Perioperative Medicine Western University London, Ontario, Canada E-mail: [email protected] Priyam Saikia MD Assistant Professor Department of Anaesthesiology and Critical Care Gauhati Medical College and Hospital Guwahati, Assam, India E-mail: [email protected] Anita Saran  DA DNB Assistant Professor Department of Anaesthesiology GS Medical College and KEM Hospital Mumbai, Maharashtra, India E-mail: [email protected] Rashi Sarna MD Assistant Professor Department of Anaesthesiology and Intensive Care Adesh Medical College and Hospital Shahbad, Haryana, India E-mail: [email protected] Saikat Sengupta  MD DNB MNAMS PGDMLS FICA Senior Consultant and Academic Coordinator Department of Anaesthesiology Perioperative Medicine and Pain Apollo Gleneagles Hospitals Professor Apollo Hospitals Education Research Foundation Kolkata, West Bengal, India E-mail: [email protected]

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Brigadier Rangraj Setlur  MD DNB MRCPI Consultant and Head Department of Anaesthesia and Critical Care Command Hospital (Eastern Command) Kolkata, West Bengal, India E-mail: [email protected] Prerana Nirav Shah  MD FICA Additional Professor Department of Anaesthesiology GS Medical College and KEM Hospital Mumbai, Maharashtra, India E-mail: [email protected] Ankur Sharma  MD DNB MNAMS   PDCC (Liver Transplant Anesthesia)

Assistant Professor Department of Anaesthesiology and Critical Care All India Institute of Medical Sciences Jodhpur, Rajasthan, India E-mail: [email protected] Ratender K Singh  MD (Medicine) PDCC (Critical Care) FICCM MNAMS

Professor and Head Department of Emergency Medicine Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS) Lucknow, Uttar Pradesh, India E-mail: [email protected]; [email protected] Aparna Sinha MD Director Anaesthesia and Perioperative Care Division Max Institute of Minimal Access Metabolic and Bariatric Surgery Max Superspecialty Hospital Saket, New Delhi, India E-mail: [email protected]

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Kapil Dev Soni  Associate Professor Department of Critical and Intensive Care Jai Prakash Narayan Apex Trauma Center All India Institute of Medical Sciences New Delhi, India E-mail: [email protected] Faiza Ahmed Talukdar MD Professor and Head Department of Anaesthesiology and Critical Care Gauhati Medical College and Hospital Guwahati, Assam, India E-mail: [email protected] Susheela Taxak  Senior Professor Department of Anaesthesiology Postgraduate Institute of Medical Sciences Rohtak, Haryana, India E-mail: [email protected] Raj Tobin  MD EDRA FICA PGDHHM Director and Head Department of Anaesthesiology Max Superspecialty Hospital Saket, New Delhi, India E-mail: [email protected] Monu Yadav MD Associate Professor Department of Anaesthesiology and Critical Care Nizam’s Institute of Medical Sciences Hyderabad, Telangana, India E-mail: [email protected] Narayana Yaddanapudi MD Professor Department of Anaesthesia and Intensive Care Postgraduate Institute of Medical Education and Research Chandigarh, India E-mail: [email protected]

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Foreword

The Indian College of Anaesthesiologists has regularly published the Yearbook of Anesthesiology since 2012. Now the Yearbook of Anesthesiology-8 is ready for its readers. The Yearbook is intended for use by the students and consultants. The topics have been well thought of and chosen by our very able editors, Dr Raminder Sehgal and Dr Anjan Trikha. All 25 chapters have been contributed by eminent anesthesiologists, both national and international, who have expertise in their fields of specialty. Each year the variety of topics and standard of editing are reaching new heights. The chapters included in this Yearbook have covered a wide range; from patient assessment, stress response to anesthesia and surgery, neuroprotection under anesthesia, making patients comfortable in end of life scenarios, and the latest topics like apneic ventilation and others. Congratulations to the editorial team and the contributors for the laudable team effort to disseminate knowledge pertaining to the basics and the latest in anesthesia practice. I am sure you will enjoy reading the book as much as I did.

Jayashree Sood Professor CEO, Indian College of Anaesthesiologists Honorary Joint Secretary, Board of Management Chairperson Department of Anesthesiology Pain and Perioperative Medicine Sir Ganga Ram Hospital New Delhi, India

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Preface

All earlier editions of the Yearbook of Anesthesiology have achieved unprecedented success in terms of the numbers printed and sold, not only in India but other countries also. For us, it is very gratifying to get queries regarding the date of publication of the next edition by both practicing anesthesiologists and postgraduate’ students. The present volume is the 8th in the series being printed under the auspices of the Indian College of Anaesthesiologists which is the academic wing of Indian Society of Anaesthesiologists. As always, the topics in this edition have been chosen from the subspecialties of general and regional anesthesia, intensive care, acute and chronic pain, authored by distinguished anesthesiologists from various parts of India. From overseas, we have two interesting chapters on the latest development in obstetric anesthesia and analgesia and implications of clinical practice guidelines. Chapters on basic sciences include topics like stress response to surgery and anesthesia, cerebral oxygenation, residual neuromuscular block, positioning hazards and postoperative pulmonary complications. In addition, there is a very interesting chapter on how to critically read a research article which would be very informative to a lot of postgraduates and young researchers. Another chapter in this edition, authored by distinguished anesthesiologists from the Indian Armed Forces on military trauma care is likely to be an eye opener for the anesthesiologists working in low resource areas. Related is a chapter, which not only carries all the information regarding transfusing massive quantities of blood, but will also be useful for setting up institutional protocols for the same. Specialty related chapters on cardiac risk assessment, neuroprotection, pulmonary hypertension, chronic kidney disease, noninvasive hemodynamic monitoring and apneic oxygenation will be of interest to students and practicing anesthesiologists alike. There are two very interesting and informative chapters on fluid management and use of extraglottic airway devices in children and neonates. Use of truncal blocks is in vogue these days and therefore has been included in this volume. The vexing problem of failed epidural has been nicely covered and is likely to be of immense help to all the postgraduates. In the field of intensive care, readers would find the chapter on renal replacement therapy and management of organophosphorus poisoning very beneficial. India needs a pragmatic medicolegal framework to improve end of life care. This has been covered by experts in the field. As in earlier three volumes the section on journal scan carries experts’ opinions on landmark articles published during the last year. The editorial team would like to express our gratitude to all the authors of various chapters for to this edition of the Yearbook of Anesthesiology without any kind of remuneration.

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We specially thank the staff of Jaypee Brothers Medical Publishers, New Delhi, India, for their support. Lastly, we have been able to incorporate all the suggestions that were received during the last year and would welcome opinions, suggestions and criticisms for our future editions.

Raminder Sehgal Anjan Trikha

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Contents

1. How to (Critically) Read A Research Article

1

Narayana Yaddanapudi Why we read?  1 Screening 1 Mechanics 3 Mental attitude  3 General tips  3 Organization of a research article  4

2. Residual Neuromuscular Block

8

Prerana Nirav Shah, Anita Saran Incidence 9 Consequences of residual block  9 Preventive strategies  9 Assessment of residual neuromuscular block  10 Differential sensitivity of different muscle groups  10 Reversal drugs  11 Treatment of residual neuromuscular blockade  12

3. Positioning Hazards: Role and Responsibilities of an Anesthesiologist

15

Sukhminder Jit Singh Bajwa, Rashi Sarna Anesthesia and positioning strategies  15 Significance of patient positioning  16 Prerequisites and precautions during positioning  16 Supine position  17 Lawn chair position  18 Frog-leg position  19 The Trendelenburg position  19 Reverse Trendelenburg position (head-up tilt)  20 Lithotomy position  20 Beach chair and sitting position  21 Prone position  23 Lateral decubitus position  25 Robotic surgery positioning  26 Anesthesia and critical care procedures  27

4. The Stress Response to Surgery and the Effect of Anesthesia

33

Munisha Agarwal The endocrine response to surgery  33 Metabolic effects of the endocrine response  35 Hematological and immunological effects of the stress response  36 Stimuli for the stress response  37

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Effect of anesthesia on the stress response to surgery  38 Evaluation of the stress response  40 Modulators of the surgical stress response  40

5. Cardiac Risk Assessment

46

Ramachandran Gopinath, Monu Yadav Approach to perioperative cardiac assessment for coronary artery disease patient  46 Assessment of the risk of perioperative MACE 47 Assessment of exercise and functional capacity  52 Ancillary preoperative cardiac testing  54

6. Anesthetic Implications of Pulmonary Hypertension

58

Mukul Chandra Kapoor Classification 58 Pathophysiology 60 Clinical features  61 Diagnostic evaluation  61 Medical therapy  63 Anesthetic implications  64

7. Cerebral Oxygenation

70

Kiran Jangra, Kajal Jain Applied physics  70 Monitoring of cerebral oxygenation  71

8. Neuroprotection under Anesthesia

79

Krishna HM Surgeries where neuroprotection is relevant  79 Physiologically-based neuroprotection  80 Pharmacologically-based neuroprotection  81 Surgical strategies for neuroprotection  83 Neuroprotection in select procedures  83

9. End of Life Care in India: Problems and Solutions

86

Raj Kumar Mani, Shiv Kumar Iyer Evolution of biomedical ethics  87 Need to bring ethical principles to the bedside  89 Shared decision-making model  89 Need to separate foregoing of life support from euthanasia  90 Contemporary practices across the world  91 Improving the legal framework for end of life care  91 Rationalizing the clinical decision-making and implementation  92 How to identify contexts for end of life care  92 Foregoing of life support pathway  93 End of life care improvement initiatives in India  94

10. Organophosphorus Poisoning

98

Saikat Sengupta, Chandrshish Chakravarty Chemical description  99 Pathophysiology 99

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Organophosphorus poisoning  99 Confirmation of diagnosis  101 Management of organophosphorus poisoning  102 Intermediate syndrome  105 Organophosphorus-induced delayed peripheral neuropathy  105 Factors affecting outcome in organophosphorus poisoning  106

11. Apneic Oxygenation

110

Pradeep Bhatia, Swati Chhabra Physiology of apneic oxygenation  110 Preoxygenation and apneic oxygenation  111 Techniques for apneic oxygenation  112 Clinical applications of apneic oxygenation  116 Limitations of apneic oxygenation  118 Step-by-step approach to apneic oxygenation  119

12. Noninvasive Hemodynamic Monitoring

123

Muralidhar Kanchi Types of hemodynamic monitors  124 Noninvasive measurement of arterial blood pressure  124 Determination of filling pressures  126 Determination of cardiac output  127

13. Role of Extraglottic Devices in Children

140

Deepanjali Pant, Archna Koul Indications 140 Types of extraglottic devices  141 Significance of anatomical differences from adults  141 Factors affecting correct placement  158 Selection of correct size or device  162 Removal of supraglottic airway devices  162 Extraglottic devices in pediatric trauma  163 Extraglottic devices and difficult airway  163 Neonates and extraglottic devices  165 Extraglottic devices in oral surgery  166 Nasopharyngeal airway versus laryngeal mask airway® for bronchoscopy  166 Advantages and disadvantages of extraglottic devices over endotracheal tube  167 Current overall status of extraglottic devices  167

14. Intraoperative Fluid Management for Neonates

172

Ekta Rai Historical facts  172 Neonatal physiology  172 Fluid loss  174 Coagulation system  174 Dextrose: To give or not to give  175 Surgical loss (isotonic fluid)  176 Role of colloids  176

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Assessment of the hemodynamic status intraoperatively   177 Blood transfusion  177 Hyponatremia 178

15. Role of Stem Cell Therapy for Pain

182

Naveen Malhotra Stem cells  182 Low back pain  183 Osteoarthritis 184 Musculoskeletal diseases  186 Neuropathic pain  188 Risks and potential adverse effects of stem cell therapy  189

16. Postoperative Pulmonary Complications Following Noncardiac Surgery 192 Faiza Ahmed Talukdar, Priyam Saikia Incidence 192 Impact of postoperative pulmonary complications  193 Pathophysiology 193 Risk factors for postoperative pulmonary complications  195 Predictive models for postoperative pulmonary complications  196 Preventive and management strategies  196 Anesthesia technique  198

17. Anesthetic Considerations in Patients with Chronic Kidney Disease

205

Raj Tobin, Gautam Girotra Classification and etiology  205 Preoperative evaluation and risk stratification  207 Cardiovascular concerns  209 Pulmonary concerns  210 Gastrointestinal concerns  210 Anemia and coagulation disorders  210 Immune status concerns (surgical site infections and sepsis)  211 Glycemic control  211 Management of concurrent drugs  212 General perioperative considerations  212 Intraoperative considerations  213 Postoperative concerns  217

18. Massive Blood Transfusion

221

Mritunjay Kumar, Ankur Sharma Definitions 221 Pathophysiology of massive blood loss  221 Massive blood transfusion guidelines  222 Massive transfusion protocols  222 Blood component ratios  224 Considerations during massive blood transfusion  224 Damage control resuscitation  226 Special population  226 When to terminate massive transfusion protocol  227 Limitations of massive transfusion protocols  227

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Recent developments  227 Hemostatic agents  229 Blood salvage techniques  231 Artificial oxygen carriers  231 Complications of massive transfusion  233 Appendix 1: Sample massive transfusion protocol for trauma  240

19. Clinical Practice Guidelines: Medical Tool or a Legal Noose?

242

Subrahmanyan Radhakrishna Do we need guidelines?  243 What makes a good guideline?  243 Designing patient care in a hospital and using guidelines  244 Human error and the law: Can guidelines help minimize human error?  246 Bolan principle and the Bolitho test and their impact on clinical guidelines  247 Building a legal defense as a department  247 Safe working in an anesthetic department  248 Using the wisdom of the wise  249

20. Role of Continuous Renal Replacement Therapy in the Management of Acute Kidney Injury

252

Kapil Dev Soni, Richa Aggarwal Acute kidney injury and renal replacement therapy  254 Modalities for renal replacement therapy  254 Timing of renal replacement therapy  255 Vascular access  256 Intermittent hemodialysis  256 Continuous renal replacement therapy  257

21. Truncal Blocks for Chronic Pain Management

267

Ashok Jadon, Rajendra Sahoo Classification of truncal blocks  267 Thoracic truncal blocks  267 Abdominal truncal blocks  273 Pathophysiology of chronic pain and mechanism of action of truncal block  275 Complications of truncal blocks  276

22. Military Trauma Care: A Review of Current Concepts

281

Brigadier Rangraj Setlur, Colonel Nikahat Jahan Assessment of blood loss  282 Quantum of fluid resuscitation  282 Choice of fluid  283 Stabilizing the clot  283 Other changes  285

23. What’s New in Obstetric Anesthesia and Analgesia

288

Ian McConachie, Ramesh Vedagiri Sai Labor analgesia  288 Ultrasound for obstetric anesthesia  289 Spinal anesthesia induced hypotension  290

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General anesthesia  293 Oxytocin 296 Maternal hemorrhage  297

24. Failed Epidural Block

303

Deep Arora, Deepak Pahwa Definition 303 Incidence 304 Epidural anesthesia technique and relevant anatomy  304 Factors contributing to failure of epidural  306 Prediction of epidural failure  311 Prevention of epidural failure  311 Management of a failed epidural block  314

25. Journal Scan

321

Sunanda Gupta, Aparna Sinha, Ratender K Singh, Susheela Taxak, Pramod Kohli Journal Scan 1—Sunanda Gupta  321 Journal Scan 2—Aparna Sinha  324 Journal Scan 3—Ratender K Singh  328 Journal Scan 4—Susheela Taxak  330 Journal Scan 5—Pramod Kohli  334

Index 337

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CHAPTER

1

How to (Critically) Read A Research Article Narayana Yaddanapudi

INTRODUCTION As long ago as 1981, Sackett pointed out that with the accelerating rate of publication of medical literature, we need to be efficient in selecting what we read to avoid being “smothered”.1 The intervening 37 years have not, to put it mildly, improved the situation. The ability to differentiate efficiently a valuable research article from one which would not contribute to one’s knowledge is an essential skill, not just for academics or researchers, but for all medical practitioners. This article attempts to suggest a strategy in that direction. The series of 11 articles published by Greenhalgh2 in the BMJ in 1997 are an excellent beginning, despite their age.

WHY WE READ? Because we are told to. Because it describes current research. Because it allows us to plan new research. Because it provides us with useful data. Because it gives us pre-digested ideas. Because it may help us to decide whether to publish our own work. Because it helps us to learn how to write. Because we have the bad luck or commitment to our discipline (take your pick) to be a peer reviewer or editor.

SCREENING I strongly advise you to screen what you read. Not every paper is worth reading. This cannot be emphasized enough. Not every published paper is worth your time and effort to read critically. Here I concentrate on randomized controlled trials (RCTs) and suggest a way of finding out whether an article is worth the effort of reading it actively. Believe me, active reading is energy-intensive and exhausting, but rewarding in the end.

Does the Study Ask a Clearly-focused Question? In case of an RCT, this should ideally be in a PICOT format (P: Patients, population, I: Intervention, C: Comparison group, O: Outcome, T: Time). These should be

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defined precisely. Studying the hypertensive response to intubation in ASA I patients with a view to generalizing it to at-risk patients is a futile exercise. Similarly, a wrong intervention with no biological basis does not make a good study, even if the rituals of randomization, blinding, concealment of allocation, intention to treat analysis, etc. are carried out meticulously. Surrogate outcomes instead of hard real outcomes do not lead to applicable conclusions.

Was this a Randomized Controlled Trial and was it Appropriate so? Why has this study been designed as an RCT? Is this the right approach? When a study compares femoral vein cannulation in infants undergoing cardiac surgery using ultrasound-guided or landmark technique performed by untrained residents, you can clearly decide that it is an inappropriate study using an inappropriate design. At this point, you will be able to discard the vast majority of articles. Let us go on.

Were Participants Appropriately Allocated to Intervention and Control Groups? Is the method of allocation truly random? Have the authors described how the randomization was done? Was any method used to balance the groups? Are there any differences between the groups that could have affected the outcome?

Were Participants, Staff and Study Personnel “Blind” to the Participants’ Study Group? It should be realized that blinding of all of the above is not always possible. However, it should be noted whether all efforts were made to blind as many categories of people as possible. Does blinding matter in this study? That is, is there a chance of observer bias?

Were all of the Participants who Entered the Trial Accounted for at its Conclusion? Did any intervention group participants received the control group option or vice versa? Did the authors do an “Intention To Treat” analysis? This would obviate the possibility of selective “drop-out” of patients.

Were Patients in all Groups Followed up and Data Collected the Same Way? Were all participants followed up equally? Were they reviewed at the same time intervals? Did they receive the same amount of attention from the researchers and care givers? By this point another large proportion of articles would have been discarded. Proceed further.

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3

How to (Critically) Read A Research Article

Did the Study have Enough Participants to Minimize the Play of Chance? Is there a power calculation or did the authors just write that they took the same number of patients as a previous study? Did they give enough data for you to reproduce the sample size calculation?

How are the Results Presented? What is the Main Result? How large is the size of this result? Does it make a clinical or practical difference in the management?

How Precise are the Results? Are they precise enough to make a decision? Did the authors report any confidence intervals around the effect they detected? Did they discuss the effect size?

Were all Important Outcomes Considered so the Results can be Applied? Are the people different? Are your local settings different? Can you provide the same treatment in your setting? The outcomes need to be considered not only from the point of view of the participant or the researcher, but also of the administrator, the policy-maker, the family of the participant, and the wider community. Do the benefits reported outweigh the harms and costs? If the article has passed through the above gauntlet, it qualifies for an active reading.

MECHANICS First, let us set the scene. Reading a scientific article is not an easy task, to be done on the mobile phone while walking back from the coffee shop. It is important to ensure that you allocate some time to do it with no distractions. I strongly encourage you to jot down notes while reading an article. I prefer a pen and paper. Please write down the article’s Vancouver style reference at the top. Save the paper.

MENTAL ATTITUDE Do not try to read the article from the beginning to the end. Feel free to jump around. Be an active reader, rather than one who treats articles as sedatives. When reading an article, you should be skeptical and question everything the authors have done. Find faults with the research question, the methods used, the outcomes selected, the analysis and the conclusions.

GENERAL TIPS Most research articles are not intended to be read straight through. It is important to understand the overall idea before you get into the details of the study.

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This is gained by reading the title, abstract and headings and by skimming the introduction and the conclusion. Look for definitions of terms and acronyms used in the article. Do not pass over concepts you do not understand. Review the tables and figures. These should reflect the data presented in the text. The legends of both tables and figures should be self-contained. By reading the legend you should be able to understand the data presented in its context. The overview you obtain from this exercise will stand you in good stead when you read the sections on methods, results and discussion. When reading the methods and results, ask yourself some of the following questions. How were the outcomes and their predictors measured? Do these actually measure what they are supposed to measure? What are the actual numbers? Look at both discussion and results to see the actual numbers of the findings emphasized in the discussion. Did the authors omit discussing any findings that do not fit their primary hypothesis? Reading a scientific article is difficult. Do not expect to read through an article. Most times you need to read it more than twice to understand it. This does not necessarily reflect on your capabilities, though it may point to some deficiencies. Take this opportunity to familiarize yourself with the relevant literature regarding the topic, the methods and the statistical techniques.

ORGANIZATION OF A RESEARCH ARTICLE Most research articles are organized similarly, starting with the Title and Author list, followed by the Abstract, Introduction and sections on the Materials and Methods, Results and Discussion/Conclusion. Many articles also contain a section on open problems at the end of the study. Firstly, note where the paper was published. If the work is similar to what you do, it should give you ideas about which journals you should target with your own work. Journal quality and the quality of papers in those journals are interdependent and over time you will be able judge one from the other. The “Title” of the article should tell you what it is about. Good titles are not vague (“Cerebral autoregulation in subjects adapted and not adapted to high altitude”) or framed as questions without giving answers (“Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment”). They might even give you a summary of the findings, if you’re lucky (“Echocardiographic and invasive measurements of pulmonary artery pressure correlate closely at high altitude”), so that you can concentrate on the methodology. In general, you should be able to figure out the major ideas and the participants in the study from the title itself. These days many journals require the study design to be explicitly mentioned in the title. The “Author List” tells you who did the work and where they are from. Author list conventions include listing all authors in alphabetical order, especially in articles written by huge groups of authors, in ascending or descending ranked order, or a modified rank order with the first name being the person who did the most work and the last being the senior most author. Spotting these patterns tells you how each research group is organized.

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The “Abstract” is a brief outline of the paper. A good abstract should give you the problem tackled, the theoretical background, an outline of the methods, the major results and a conclusion. There may also be a brief discussion. Many journals now ask for a structured abstract which explicitly identifies each section of the abstract. Can you understand what the paper is about? Do the conclusions make sense? Can you come up with a solution to the problem addressed by the paper? How comfortable will you be reading this paper? Do not stop with just reading the abstract. Though it is a great help in understanding the whole article, in many cases it is misleading and error-prone. Take particular note of the variables observed and the findings. Does the study purport to show a cause-and-effect relationship, or does it just show that a relationship exists? The “Introduction” of the article tells you the rationale of the paper: the problem(s) addressed, the state of the literature and the gaps in it. It should define the research question explicitly. It should define the primary and secondary outcomes studied separately. This is important because the sample size of an RCT is calculated based on the primary outcome variable. Definite conclusions regarding secondary outcomes are not usually possible because the study is usually underpowered with regard to them. After reading the Introduction, stop and ask yourself some of these questions: Can you think of a solution (or conclusion)? Is enough/any prior art listed? If not, why? Can you see why this paper is an advance over what was done in the past? Why was this article published? Introduction will also give you pointers to other papers you might want to read. “Material and Methods” is the “meat” of the paper. It tells you how the work was performed. You should spend a lot of time in this section. Is the study measuring what it purports to measure? If you are looking for signs of sepsis, using only temperature as an indicator is probably not going to be helpful. Similarly, if the outcome of interest is mortality in patients with septic shock, measuring the time the patients required inotropic support is misleading to say the least. These questions form part of the internal validity of the study. If the study is looking to minimize postoperative nausea and vomiting, doing the study in young active adults coming to the orthopedic trauma theater will not tell you anything about the results in a susceptible gynecological population. This point towards the study’s external validity. While reading this section you should test yourself: think of how you would solve each of the problems stated. What research techniques are used by the authors? Is the method employed a valid test of the predictions or hypotheses? Why has the researcher chosen this particular research design/set of patients/ procedures, etc.? Do you understand the paper on the basis of the information provided? In some cases, the actual methodology may have been published as another paper or an online annexure. You should make an effort to read these too. Look for any possible factor the authors may have overlooked which affects their conclusions. What techniques have other researchers used to investigate similar problems? How do those methods compare to the current ones?

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“Results” give you the verbose conclusions of the paper. What conclusions can you draw from the data presented? Try to answer this yourself before you read what the authors tell you what they think. Are the conclusions consistent with the data presented? Is there any alternative interpretation? If you were to perform this trial, how would you set it up? What changes will you make to the methodology? How do the results relate to the problem statement and the proposed hypothesis? Are the results reported and analyzed in an unbiased manner? The manner in which data are analyzed and reported could dramatically affect interpretation. Inappropriate statistical methods can lead to meaningless “significant” findings. Different types or formats of graphs can emphasize or de-emphasize the sizes of effects. Consider the initial problem statement in the Introduction as a promissory note. The Methods section should explicitly mention how each of the promises made in the Introduction are carried out, and the Results section should list the actual findings of each of those promises. The “Discussion” should summarize the main findings. What is the authors’ interpretation of the results? What do they think the findings say about their research question? Any discussion that concentrates solely on whether a particular finding has attained statistical significance or not, without talking about the effect size and the factors that have possibly affected it, is grossly unscientific in my opinion. Ideally, the authors should include a subsection on the limitations they perceive in their study. This would show insight and would also serve as a test for the active reader. At the end of the study do we know something new? Are there any new questions? Do the authors discuss real world implications of their findings? You should ask yourself whether there are any alternative explanations for the findings. Have the authors interpreted their results correctly? Is there any suspicion of bias in the authors’ analysis and presentation? Can these findings be generalizable? Most papers you read are analyzed using a frequentist framework. Based on this was the hypothesis rejected or not? What do the authors suggest for future research into this topic? The “Conclusions” are the authors’ summary of the contributions provided by the paper and hence is usually the repository of their grandiloquence. It is important that you are grounded when reading this section and are not carried away by the authors’ enthusiasm. Sometimes there is also philosophical discussion of the problem or field of research. You should ask yourself whether you agree with the authors’ conclusions. Formulate your own conclusions separately from the authors’. Do the authors’ conclusions derive logically from the material presented in the paper? “Wrong” conclusions are not uncommon. Some common ones are confusing superiority, equivalence and non-inferiority, assuming that the “Absence of a proof of a difference” is the same as the “Proof of an absence of a difference” and overbroad generalization. Also terming the study “Negative” when there is no p-value below 0.05 is very common. This pejorative term has distorted medical research immeasurably.

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Some papers end in an “Open Problems” section, questions the authors have asked themselves but cannot easily answer. This section is very important as it provides you with problems you might want to work on. It also tests your understanding of the paper, many open problems are questions you should have asked yourself while reading the paper.

CONCLUSION This article is but an introduction to the art of critical reading. It is also limited by the fact that it dealt mostly with RCTs. However, the principles listed here are widely applicable to other types of articles. Select the articles to read carefully by asking a few screening questions. Skim the selected articles. Read and re-read actively, constantly questioning what the authors said. A skeptical attitude, a curious mind familiar with the background literature, and an active imagination are essential for a critical reading of a research article.

KEY POINTS • • • • •

• • •

The number of publications in each specialty is overwhelming. Reading a research article critically is time- and energy-intensive. Not every published article deserves a critical reading. Screening questions are suggested which will help in identifying articles worth critical reading. Research articles have a structure that is usually followed. Understanding this structure and learning what to expect in each section helps in critical appraisal. Articles should not be read from beginning to end, but should be sampled, read and re-read. Active reading with a sceptical and questioning attitude is necessary. Specific questions are suggested.

REFERENCES 1. Sackett DL. How to read clinical journals: I. Why to read them and how to start reading them critically. Can Med Assoc J. 1981;124(5):555-8. 2. Greenhalgh T. How to read a paper: The Medline Database. BMJ. 1997;315:180-3.

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Residual Neuromuscular Block Prerana Nirav Shah, Anita Saran

INTRODUCTION Neuromuscular blocking agents (NMBAs) are in use during general anesthesia for last seventy-five years and consequently, have become essential elements of a balanced anesthetic technique.1 They may result in life-threatening complications if not dosed and monitored appropriately.2 At the conclusion of surgery, reversal agents are used to reverse the neuromuscular blockade. Despite the reversal, postoperative residual neuromuscular blockade (PRNB) may occur. It is often seen that substantial muscle paralysis is present in the immediate postoperative period even with use of intermediate acting muscle relaxants, routine monitoring and their reversal. Recent data suggests that the residual muscle weakness may result in impaired protective airway reflexes, airway obstruction, hypoxemia, delayed recovery in postoperative period and discomfort due to muscle weakness.3 Residual neuromuscular blockade, also called as residual paralysis or residual curarization is incomplete recovery of neuromuscular blockade with train of four ratio less than 0.9 as measured by quantitative neuromuscular monitoring.4 Earlier the “acceptable recovery” level was taken as TOF ratio of 0.7. This threshold TOF ratio was based on its correlation with various clinical parameters and qualitative neuromuscular monitoring (patient able to open eyes widely, coughing, tongue protrusion, vital capacity breathing of 15–20 mL/kg and absence of fade on tetanic stimulation).4 Over the period, based on further studies and advent of quantitative neuromuscular monitoring, TOF ratio of 0.9 is the new “acceptable recovery” parameter. Reversal of neuromuscular blocking agents is essential as the hazards of postoperative residual neuromuscular block are known. However, due to patient variability, many of them show residual muscle weakness even at acceptable recovery TOF ratio, while others recover completely despite inadequate TOF ratio. Clinically, adequate neuromuscular recovery is considered when baseline muscular function returns with patient breathing normally, maintaining airway patency and protecting airway by reflexes.

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INCIDENCE Undetected postoperative residual neuromuscular block is not rare postoperatively. The incidence of postoperative pulmonary complications using “Liverpool Anesthetic Technique” was 12.5%, and two anesthetic deaths were reported due to myocardial ischemia and hypoxia as found in postmortem.5 In a retrospective study by Beecher and Todd,6 higher incidence of postoperative mortality was noted when muscle relaxant was used. Payne et al.,7 reported it to be caused by excessive doses of neostigmine leading to usage of neostigmine 2.5 mg as the standard dose in adults. Fortier and colleagues found 56% residual block by using qualitative monitoring in a multicenter study.8 Reversal with neostigmine was associated with decreased postoperative pulmonary complications and a slight increase in 30-day mortality in patients who did not receive neostigmine.5 As compared to neostigmine, reversal with sugammadex resulted in much lesser incidence of postoperative residual neuromuscular blockade. In any anesthetic technique, there will not be any residual block if tracheal extubation is done at the TOF ratio of 1.0. In 1979, Jorgen Viby-Mogensen and colleagues reported 42% incidence rate of residual neuromuscular blockade in postoperative patients.9 Residual muscle paralysis is more common after abdominal surgery and older patients.10

CONSEQUENCES OF RESIDUAL BLOCK Residual block results in impaired pharyngeal, laryngeal and esophageal muscle tone leading to upper airway obstruction, reduction of upper airway volumes, reduced inspiratory air flow, impaired phonation and coughing, increased risk of aspiration. Respiratory muscle weakness results in impaired ventilation and oxygenation. Residual muscle weakness leads to visual disturbances, difficulty in swallowing and speaking, and generalized weakness and patient discomfort. Delayed complications of postoperative residual neuromuscular weakness are prolonged ventilator support, difficult weaning and postoperative pulmonary complications like atelectasis and pneumonia.11 Hypoxic ventilatory drive is abolished by neuromuscular blocking agents (NMBAs) by blocking the nicotinic Acetylcholine receptors in the carotid body. Residual muscle paralysis, TOF 0.7, results in 30% decrease in hypoxic ventilatory drive.12

PREVENTIVE STRATEGIES In order to prevent postoperative residual block, muscle relaxants should only be administered when clinically imperative. Whenever they are required intraoperatively, intermediate and short-acting ones should be preferred in lowest dose needed for optimal surgical relaxation. Likewise, minimum dose should be considered during the last hour of the surgery. The depth of the neuromuscular blockade should be quantitatively monitored during the surgery to prevent overdosing of muscle relaxants and just before the extubation to detect residual block. At the end of the surgery when TOF ratio is greater than or equal to 0.9, an

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appropriate dose of an anticholinesterase agent (neostigmine) or sugammadex should be administered to reverse the neuromuscular block. Ideally, neostigmine should not be administered until the TOF count of four appears. Titration of reversal agents with effect to eradicate postoperative residual block must be done by guidelines devised by all involved in perioperative medicine.13

ASSESSMENT OF RESIDUAL NEUROMUSCULAR BLOCK Neuromuscular monitoring is essential throughout anesthesia when a muscle relaxant is used. There are different modes of monitoring of residual muscle paralysis; clinical, qualitative and quantitative. Clinical criteria used to assess the sign of muscle weakness are categorized as unreliable and reliable. Few clinical criteria are unreliable to assess residual neuromuscular block such as sustained eye opening, tongue protrusion, lifting arms to the opposite shoulder, normal tidal volume and vital capacity, maximum inspiratory pressure less than 40–50 cm H2O. Some clinical criteria are more reliable such as sustained head lift, leg lift and hand grip for 5 sec; sustained tongue depressor test and maximum inspiratory pressure more than 40–50 cm H2O. Nonetheless, sustained head lift for 5 sec is observed at a TOF count of 0.5 or less, hence even reliable clinical criteria cannot rule out residual muscle paralysis definitively.14 Qualitative monitoring includes nerve stimulation by TOF, tetanic and double burst stimulation. They are useful in intraoperative period to detect recovery from neuromuscular blockade but cannot detect residual muscle paralysis postoperatively. Earlier, neuromuscular monitoring did not provide TOF ratio, clinicians used to count the twitches by visual or palpable methods and referred this as TOF count. This qualitative neuromuscular monitoring by peripheral nerve stimulator cannot reliably exclude the residual muscle paralysis as it is difficult to appreciate fade at TOF ratio of 0.4–0.9.9 Quantitative monitoring is the most reliable measure of degree of neuromuscular blockade by using TOF stimulus and single twitch stimulus. Different methods of quantitative monitoring are by mechanomyography, electromyography, acceleromyography, piezoelectric nerve stimulation and phonomyography. Acceleromyography is the most-accurate amongst them. With quantitative neuromuscular monitoring, it is possible to accurately measure and display numerically when TOF ratio is more than 0.4.15 Train-of-four ratio (TOFR) of 0.9 must be confirmed before reversal and extubation. In 2010, practice of neuromuscular monitoring was compared between Europe and America by Naguib and colleagues.16 They found that American anesthetists were not frequently provided with quantitative neuromuscular monitoring as compared to that in Europe. Kopman and Eikermann proposed an algorithm for reversal dose and timing of neostigmine administration, on the basis of available neuromuscular monitoring and response to TOF stimulation.17

DIFFERENTIAL SENSITIVITY OF DIFFERENT MUSCLE GROUPS There is difference in response to NMBAs among different muscle groups. The exact cause of this discrepancy is unknown. Certain probable explanations

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may be due to differences in acetylcholine (Ach) receptor density, release of acetylcholine, activity of acetylcholine esterases and composition of muscle fiber, number of neuromuscular junctions, blood supply and temperature of muscle. Abdominal muscles, orbicularis oculi, peripheral muscles of limb, geniohyoid, masseter, upper airway muscles have high sensitivity to NMBAs.18 Laryngeal adductors are next in line to be paralyzed in correspondence with corrugator supercilii muscle.19 Diaphragm is the most resistant muscle to the effect of NMBAs and requires 1.4–2 times the amount of muscle relaxant required to paralyze adductor pollicis, although the onset time is shorter for diaphragm.20 Similarly, recovery for diaphragm is faster than peripheral muscles. For clinical purposes, diaphragmatic paralysis is assessed by adductor pollicis muscle response to ulnar nerve stimulation, while laryngeal adductor and abdominal muscle paralysis is best assessed by corrugator supercilii response to facial nerve stimulation.19,20

REVERSAL DRUGS Commonly, reversal agents are to be given whenever muscle relaxant has been given to the patient for accelerating recovery from neuromuscular blockade. Neostigmine: An acetylcholinesterase inhibitor, was the only United States Food and Drug Administration (US FDA) approved reversal drug till 2015.5,21 However, it is not effective in reversing intense blockade and when given in large doses may even result in muscle weakness. Recently Murphy compared neostigmine 40 mcg/ kg to placebo in 120 patients after spontaneous recovery from rocuronium and stated that neostigmine does not induce weakness, strength test are unreliable, fade assessment is not great and monitoring is needed.22 However, the time to achieve acceptable neuromuscular recovery may be as much as 15 min, even after a large dose of neostigmine (0.06–0.07 mg/kg). At the end of surgery, neostigmine must be administered only if TOF ratio of 0.9 is obtained at adductor pollicis muscle. Sugammadex: It is an anionic derivative of γ-cyclodextrin and acts as a reversal agent which binds and inactivates steroidal NMBAs. It antagonizes block induced by amino steroidal muscle relaxants. It encapsulates steroidal muscle relaxants (vecuronium and rocuronium) into its hydrophobic cavity and reverses the blockade. In a dose of 2 mg/kg, it can quickly reverse the moderate neuromuscular block of rocuronium within 2 min.5 Profound neuromuscular block can be reversed with a dose of 4–8 mg/kg. To reverse the blockade immediately after rocuronium is given a dose up to 16 mg/kg can be used. It is useful in cannot intubate, cannot ventilate situation. However, it can cause hypersensitivity and dose dependent anti-coagulation (raised activated partial thromboplastin time and prothrombin time). It is not effective when benzylisoquinolines (atracurium, cisatracurium) are administered, as it doesn’t bind with them. Rocuronium and vecuronium can be readministered after 24-hour of reversal with administration of sugammadex.5 Calabadion: It belongs to a new class of drug that is an acyclic derivative of cucurbituril compounds and it forms a complex by binding with the steroidal relaxants like rocuronium, vecuronium and cisatracurium.21,23 In vitro studies

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show that as compared to sugammadex, calabadion binds less effectively with rocuronium. It can reverse deep blockade by cisatracurium by binding and encapsulation. Its later modification calabadion-2 is selective and binds muscle relaxants. As compared to acetylcholine, calabadion-2 is 18,900 times more selective for rocuronium whereas calabadion-1 is only 350 times more selective for rocuronium. Early studies in rats suggest that they can be used to reverse the blockade by both rocuronium and cisatracurium. It can rapidly reverse profound block from rocuronium, vecuronium and cisatracurium in a dose-dependent manner. It binds with 1:1 ratio and shows a higher affinity in vitro and higher potency to reverse block in vivo. Studies in rats show calabadion-2 is eliminated by kidney. Calabadion-2 is required in significantly low doses for reversing cisatracurium as compared to calabadion-1, due to its higher binding affinity for cisatracurium. CW002 and cysteine: CW002 is a fumarate derivative of tetrahydroisoquinolinium compounds.4,23 It is degraded by endogenous L-cysteine in the plasma. When used in humans in 1.8 times ED95 dose, its onset of action is in 200 sec and duration of action is 34 min. It produces profound block, which can be reversed by exogenously administered cysteine which is widely used in parenteral nutrition. Its use in healthy volunteers suggests that there is no histamine release after its administration, and when given in normal dose range, few autonomic changes are seen. It is in experimental stage and is not yet available for clinical practice.24

TREATMENT OF RESIDUAL NEUROMUSCULAR BLOCKADE • • •

•

•

Initial resuscitation, if required, should be immediately started to maintain airway patency, breathing and circulation. Quantitative monitoring should be done to confirm residual neuromuscular paralysis. Any potential cause of residual paralysis should be searched. If patient has not been reversed after neuromuscular blockade, reversal in appropriate dose should be administered and one should wait for its onset of action if permissible. If patient has already been administered reversal agent, then additional dose of reversal may not be helpful always. Diagnosis and treatment of precipitating factors like hypothermia, hypercarbia, hypoxia, acidosis and residual effects of opioids and inhalational agents should be done. Sugammadex can be considered for reversal of rocuronium and vecuronium.

CONCLUSION Postoperative residual neuromuscular blockade is a well-known entity which usually goes unnoticed but sometimes may prove to be disastrous. During perioperative patient care muscle relaxants should be meticulously used and timely reversed. Quantitative neuromuscular monitoring should be standard of care whenever muscle relaxants are used. Whenever encountered, perioperative physicians must be acquainted to diagnose and treat the residual neuromuscular blockade.

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KEY POINTS • •

•

• •

• • •

•

Postoperative residual paralysis is not an unknown entity and accounts for TOF ratio less than 0.9 in 30–50% patients in postoperative period. Nondepolarizing neuromuscular agents used in intraoperative period should always be pharmacologically reversed to prevent the adverse effects of residual paralysis. Residual neuromuscular blockade results in airway obstruction, increased risk of aspiration, hypoxia, muscle weakness, postoperative pulmonary complications and prolonged recovery. It may occur despite using reversal agents hence their dose and timing should be considered while reversing. Quantitative neuromuscular monitoring is recommended to assess the recovery of neuromuscular blockade. TOF ratio of ≥ 0.9 is considered as adequate recovery from neuromuscular blockade. Reversal agents include neostigmine, sugammadex and a newer agent calabadion which is in experimental phase. Neostigmine is an acetylcholine esterase inhibitor, which antagonizes moderate level of neuromuscular blockade when given in 30–70 µg/kg dose. Sugammadex is a γ-cyclodextrin derivative having higher affinity for steroidal neuromuscular blocking drugs (NMBDs) vecuronium and rocuronium. It can rapidly reverse intense neuromuscular blockade. Calabadion an acyclic derivative of cucurbituril compounds, binds and encapsulates vecuronium, rocuronium and cisatracurium to reverse the profound neuromuscular blockade.

REFERENCES 1. Griffith HR, Johnson GE. The use of curare in general anesthesia. Anesthesiology. 1942;3:418-20. 2. Bulka CM, Terekhov MA, Martin BJ, et al. Nondepolarizing neuromuscular blocking agents, reversal, and risk of postoperative pneumonia. Anesthesiology. 2016;125(4): 647-55. 3. Bevan DR. Recovery from neuromuscular block and its assessment. Anesth Analg. 2000;90:S7-13. 4. Murphy GS, Brull SJ. Residual neuromuscular block: Lessons Unlearned. Part I: Definitions, incidence, and adverse physiologic effects of residual neuromuscular block. Anesth Analg. 2010;111(1):120-8. 5. Hunter JM. Reversal of residual neuromuscular block: Complications associated with perioperative management of muscle relaxation. Br J Anesth. 2017;119 (Suppl1):i53-62. 6. Beecher HK, Todd DP. A study of the deaths associated with anesthesia and surgery. Ann Surg. 1954;140(1):2-34. 7. Payne JP, Hughes R, Al Azawi S. Neuromuscular blockade by neostigmine in anesthetized man. Br J Anesth. 1980;52(1):69-76. 8. Fortier L-P, McKeen D, Turner K, et al. A Canadian prospective, multicenter study of the incidence and severity of residual neuromuscular blockade. Anesth Analg. 2015;121(2):366-72. 9. Viby-Mogensen J, Jensen NH, Engbaek J, et al. Tactile and visual evaluation of the response to train-of-four nerve stimulation. Anesthesiology. 1985;63(4):440-3.

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10. Murphy GS, Szokol JW, Avram MJ, et al. Residual neuromuscular block in the elderly: Incidence and clinical implications. Anesthesiology. 2015;123(6):1322-36. 11. Murphy GS. Residual neuromuscular blockade: incidence, assessment, and relevance in the postoperative period. Minerva Anesthesiol. 2006;72(3):97-109. 12. Eriksson LI, Sato M, Severinghaus JW. Effect of a vecuronium-induced partial neuromuscular block on hypoxic ventilatory response. Anesthesiology 1993;78(4): 693-9. 13. Eikermann M. Hidden universality of residual neuromuscular block. Br J Anesth. 2016;116(3):435-6. 14. Eikermann M, Groeben H, Husing J, et al. Accelerometry of adductor pollicis muscle predicts recovery of respiratory function from neuromuscular blockade. Anesthesiology. 2003;98(6):1333-7. 15. Mortensen CR, Berg H, Mahdy A, et al. Perioperative monitoring of neuromuscular transmission using acceleromyography prevents residual neuromuscular block following pancuronium. Acta Anesthesiol Scand. 1995; 39(6):797-801. 16. Naguib M, Kopman AF, Lien CA, et al. A survey of current management of neuromuscular block in the United States and Europe. Anesth Analg. 2010;111(1):110-9. 17. Kopman AF, Eikermann M. Antagonism of non-depolarizing neuromuscular block: current practice. Anesthesia. 2009;64:S22-30. 18. Pavlin EG, Holle RH, Schoene RB. Recovery of airway protection compared with ventilation in humans after paralysis with curare. Anesthesiology. 1989;70(3):381-5. 19. Plaud B, Debaene B, Donati F. The corrugators’ supercilii, not the orbicularis oculi, reflects rocuronium neuromuscular blockade at the laryngeal adductor muscles. Anesthesiology. 2001;95(1):96-101. 20. Pansard JL, Chauvin M, Lebrault C, et al. effect of an intubating dose of succinylchoilne and atracurium on the diaphragm and the adductor pollicis muscle in humans. Anesthesiology. 1987;67(3):326-30. 21. Haerter F, Simons JC, Foerster U, et al. Comparative effectiveness of calabadion and sugammadex to reverse non-depolarizing neuromuscular blocking agents. Anesthesiology. 2015;123(6):1337-49. 22. Murphy GS, Szokol JW, Avram MJ, et al. Neostigmine administration after spontaneous recovery to a Train-of-Four ratio of 0.9 to 1.0: A randomized controlled trial of the effect on neuromuscular and clinical recovery. Anesthesiology. 2018;128(1):27-37. 23. Hoffmann U, Grosse-Sundrup M, Eikermann-Haerter K, et al. Calabadion: A new agent to reverse the effects of benzylisoquinoline and steroidal neuromuscular-blocking agents. Anesthesiology. 2013;119(2):317-25. 24. Heerdt PM, Sunaga H, Owen JS, et al. Dose-response and cardiopulmonary side effects of the novel neuromuscular blocking drug CW002 in man. Anesthesiology. 2016;125(6):1136-43.

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Positioning Hazards: Role and Responsibilities of an Anesthesiologist

Sukhminder Jit Singh Bajwa, Rashi Sarna

INTRODUCTION The surgical unit personnel, particularly anesthesiologist, plays a very crucial role while doing patient positioning for various surgical procedures. Apart from administering anesthesia the anesthesiologist has to take a lead role in making every staff member aware about the potential hazards associated with particular posture and has to complete the process of positioning directly under his or her supervision. With advancements in surgical techniques, perfect patient positioning has become an inseparable part of achieving precise surgical results. Any ill position during surgery not only increases procedural difficulties but can also result in unwarranted injuries pertaining to such poor positioning. Moreover, anesthetized patients especially those being administered general anesthesia (GA) cannot convey the harmful effects of compromised positioning. The increasing awareness among general public as a result of rampant social media as well as the prevalent medicolegal scenario in our nation has raised the surgical outcome bar to a different level with expectations of a near perfect result for every surgery irrespective of the patient’s American Society of Anesthesiologists (ASA) status. All the postgraduate students of anesthesiology and critical care are religiously taught and apprised so many times during their tenure about such potential complications related to ill positioning. However, sometimes such errors still occur during their clinical practice either due to lack of awareness of such hazards or due to casual approach during surgical procedure. The purpose of this chapter is to highlight such challenges and complications associated with various postures during surgical procedures and also to stress upon precautions with an emphasis on various physiological fluctuations and alterations occurring during surgery.

ANESTHESIA AND POSITIONING STRATEGIES The types of anesthesia also dictate the adoption of different strategies. For instance, if the patient is under GA, the entire process has to be done gradually

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and meticulously considering the zero percent input or cooperation from the patient. During regional and neuraxial anesthesia, patients can be counseled thoroughly preoperatively as well as intraoperatively so as to obtain their maximum cooperation while maneuvering the final position in which surgical procedure has to be carried out. Type of anesthesia; however has no impact on the difference of incidence of nerve injuries as has been shown by few prospective reviews. It is extremely difficult to ascertain the exact cause of injury but most commonly stretching, compression, ischemia or metabolic derangement are prime factors which can cause positioning injuries during surgery.

SIGNIFICANCE OF PATIENT POSITIONING Patient position during any surgical procedure is extremely important in achieving effective anesthetic targets and facilitating the surgical procedure without undue hemodynamic changes and risk of injury to the subject. Clear understanding of the anatomic and physiologic effects of each patient position is of paramount importance. Also, understanding the impact of anesthetic and surgical procedures on these aspects is also vital in preventing injury due to undue pressure on any part of the body, vascular obstruction or undue stretching. The principles of ideal patient positioning should always be considered during planning stage of anesthesia and few important aspects of positioning can be summarized as: • The position should not interfere with respiration • Should not interfere with circulation • Should not exert undue pressure on peripheral nerves • Should cause minimal pressure on skin • Provide good surgical site accessibility • Facilitate administration of anesthesia • Should not cause musculoskeletal discomfort • Should maintain the physiological requirements of the individual. The position of the patient during shifting to the operating room is also important. Hence, systematic consultation process and meticulous planning between all the involved healthcare personnel is crucial in this regard.

PREREQUISITES AND PRECAUTIONS DURING POSITIONING All relevant comorbidities need to be carefully reviewed and considered while deciding the patient position during transfer to the operating room and during the operation. The manpower required, the equipment needed and the monitoring during the transportation should be carefully planned considering the weight of the patient, comorbidities, intubation status, and likely hemodynamic changes during the patient movement in the operating room. Proper management of devices connected to the patient, including monitors, IV lines, and airways is extremely important. Protection of eyes by taping is also of paramount importance to prevent injuries to the cornea.

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SUPINE POSITION Also called as dorsal decubitus position is undoubtedly the most common position used during the patient transport and during the surgery. In this position, the head is usually rested on a foam pillow, to achieve neutral position of the neck. Positioning of arms is usually done by using padded arm boards to keep the arms in less than 90° abducted position or by tucking them at patient’s side secured by a bed sheet, which is usually placed under the body, brought above and around the arm, and then finally again tucked under the person’s body (Fig. 1). This will help in preventing injury to brachial plexus.1 Positioning of the hand and forearm is usually done either by keeping them in supine or neutral position (Fig. 1). This minimizes the undue pressure on spiral groove of the humerus and the ulnar nerve.2,3 The legs are usually placed with knees in slight flexion and rested on pillows to minimize strain on lumbar spine. Following are few of the common procedures performed in supine position: • Intracranial procedures • Otorhinolaryngology procedures • Ophthalmological procedures • Anterior cervical spine surgery • Cardiac surgery • Abdominal surgery • Gynecologic and obstetric procedures • Procedures on the lower extremity including hip, knee, ankle, and foot.

Physiologic Changes during Supine Position Alterations in Respiratory Dynamics

When the patient is placed from the upright to the supine position, cephalad shift of intra-abdominal contents and diaphragm will occur and adjacent lung tissue is compressed. This leads to a decrease in functional residual capacity (FRC). In an awake state, FRC decreases by 24% while during GA it decreases by 44%. This decrease in FRC could place normal tidal breathing at or below closing capacity, allowing airway collapse with normal ventilation leading to atelectasis and intrapulmonary shunt.4,5

Fig. 1: Patient placed in supine position.

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Cardiovascular and Hemodynamic Variations Placing a patient supine from an erect position increases venous return and leads to increase in cardiac output via preload augmentation. Heart rate, stroke volume, and contractility are reflexively decreased through baroreceptors from the aorta via the vagus nerve and from the carotid sinus via the glossopharyngeal nerve to maintain a constant blood pressure.6 During anesthesia, systemic vascular resistance (SVR) and venous return to the heart decrease. With derailed mechanisms to compensate for changes in position, the systemic blood pressure under anesthesia is more labile.

Complications Related to Supine Position The potential complications of supine position encountered during surgical procedure include: • Peripheral nerve injury: Although the mechanism of nerve injury is not always clear, internal and external compression, stretch, ischemia, metabolic derangement, direct trauma, and direct nerve laceration can all lead to postoperative nerve injury. Ulnar nerve is the most common nerve injured, followed by the brachial plexus and lumbosacral roots.7 • Pressure alopecia: It is due to pressure on the back of the head during prolonged procedures. Further areas of pressure-related injury and necrosis include the heel, sacrum, and other bony prominences. • Postoperative backache: It occurs due to loss of the natural lordotic curvature of supine and has been reported, especially in patients with preexisting back pain or kyphoscoliosis.8 The strategies to help minimize these complications include proper positioning, padding, and constant surveillance of the patient. Also, extreme rotation of the head should be avoided.9

LAWN CHAIR POSITION It is a variant of supine position. In this position, the hips and knees are kept in slightly flexed position (Fig. 2). This helps in reducing the stress on the back, hips, and knees. Patients who are awake or undergoing monitored anesthesia care

Fig. 2: The Lawn-chair position.

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may tolerate this position better. There will be better venous drainage from the legs, as the legs are slightly above the heart. Due to reduction in the xiphoid to pubic distance, tension on the ventral abdominal musculature is minimized and closure of laparotomy incisions will be easier. In this position, usually the back of the bed is elevated; the legs below knee are lowered to an equivalent angle, and if needed slight Trendelenburg tilt are applied to level the hips and shoulders. This may help in reducing the venous pooling in lower limbs and permit parallel positioning of the arm board or table with the floor if needed for surgeries on upper limb. The complications and hazards are almost similar to whatever is encountered during typical supine position.

FROG-LEG POSITION In this position, the hips and knees are kept in slight flexion, with hips in external rotation, with soles facing each other (Fig. 3). This position results in better access to the perineum, medial thighs, genitalia, and rectum. Undue strain on hips may lead to postoperative pain, hence to be avoided. Also, proper supporting of the knees is vital in preventing hip dislocation. Rest of the precautions and complications are almost same as that for supine position.

THE TRENDELENBURG POSITION In this position, the person is usually placed in the supine position and the bed is modified with a head‐down tilt of 35–45° (Fig. 4). This brings the head to lower position than pelvis. This aids in increasing the venous return following spinal anesthesia, enhances central venous volume, and creates better conditions for central venous cannulation. This position is also extremely helpful in preventing aspiration in patients who are at risk of regurgitation. But there are considerable changes in the cardiovascular and respiratory dynamics in this position. Central venous, intracranial, and intraocular pressures are raised due to downward tilt of the head. Head-down position for long period may also result in swelling of the face, conjunctiva, larynx, and tongue. This may increase the risk of upper airway obstruction in the postoperative period. The cephalic movement of abdominal viscera against the diaphragm results in lowering of FRC and lung compliance. Breathing effort will become more strenuous in spontaneously ventilated patients due to all these changes. Higher airway pressures may be needed for sufficient ventilation in mechanically ventilated patients, with corresponding raise in risk

Fig. 3: Frog-leg position—a variant of supine position.

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of postoperative airway related complications. The probability of regurgitation is higher due to higher position of the stomach than the glottis; hence for proper protection of the airways, endotracheal intubation is often preferred. Considering high risk of tracheal edema and airway mucosa, it may be prudent to verify an air leak around the endotracheal tube or visualize the larynx before extubation in patients kept on prolonged Trendelenburg position.

REVERSE TRENDELENBURG POSITION (HEAD-UP TILT) This position is often used to create better operating conditions for upper abdominal surgery (Fig. 4). This usually happens due to caudad shift of the abdominal contents. Care must be taken to prevent slipping of the person on the table. Also more frequent monitoring of arterial blood pressure is needed as there is possibility of hypotension resulting from diminished venous return. Positioning of the head above the heart and resulting reduction in cerebral perfusion pressure must be considered while determining optimal blood pressure. Every 2.5 cm change in vertical height above or below the reference point at heart level, usually results in 2 mm Hg change in MAP in the opposite direction. Apart from these concerns, rest of the complications and preventive strategies are almost similar to typical supine position.

LITHOTOMY POSITION This is another modification of the supine position. In this position the hips are flexed, the legs abducted, and knees flexed (Fig. 5). The legs are secured in leg supports such as the candy cane, knee crutch, or boot support. The arms can be positioned either by tucking them on the patient’s side or by resting them on padded arms in less than 90° abduction and supination. Surgical access to perineum can be achieved by lowering the foot section of operating room table. Common surgical procedures performed in lithotomy position include gynecologic, urologic, and colorectal procedures.

Fig. 4: The graphical depiction of both Trendelenburg and reverse Trendelenburg position.

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Fig. 5: The patient lying in lithotomy position.

In addition to physiological changes occurring in supine position, bilateral elevation of the legs, results in more decrease in FRC and pulmonary compliance. Cardiovascular effects of lithotomy positioning are also similar to those in the supine position. However, with leg elevation, there may brief increase in cardiac output due increased venous return. This position can also throw various challenges if the ideal position is not achieved prior to surgical procedure: • One of the complications reported following lithotomy position is peripheral nerve injury, most commonly involving common peroneal nerve. Other nerves which are injured include lateral femoral cutaneous nerve, femoral nerve, and sciatic nerve.10,11 • Preexisting back pain is reported to be aggravated due to loss of normal lordotic curvature of the lumbar spine.12 • Compartment syndrome: Of all standard surgical positions, lithotomy, followed by the lateral decubitus position, puts the patient at the greatest risk for compartment syndrome. Length of time spent in the lithotomy position is the only established evidence-based risk factor and 2 hours appears to be the point at which this risk substantially increases.13

BEACH CHAIR AND SITTING POSITION This is a modified recumbent position in which the legs are kept as high as possible to promote venous return (Fig. 6). This position may need specially manufactured operating tables. During neurosurgery in the sitting position “the head is held in a Mayfield headrest and pins and the patient’s hips and knees are flexed to avoid any stretch on the sciatic nerve”.14 The lower limbs are usually kept as high as possible to enhance venous return. This position provides an excellent surgical exposure, minimizes the blood loss, and provides better access to airway and better ventilation particularly in obese patients.15 Neurosurgical and shoulder arthroscopic procedures are few of the surgical interventions done in this position. Physiologic changes of this position in an

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Fig. 6: The beach chair lying position.

awake patient include an increase in SVR and blood pressure, which results in lowering of the cardiac output. But in patients undergoing surgery, there will be alteration of normal hemodynamic responses. Hence normal increase in SVR may be limited. This may decrease the mean arterial pressure and further decline in cardiac output. The resultant risk of hypotension can be mitigated by incremental positioning, appropriate use of IV fluids, vasopressors, and adjustments of depth of anesthesia. Maintenance of venous return can also be achieved by elastic stockings or active leg compression devices. The common complications associated with this positioning may manifest as: • Hypotension • Venous air embolism (VAE) and paradoxical embolism. Some degree of venous air has been demonstrated in majority of the patients undergoing neurosurgery in this position by transesophageal echocardiography (TEE)16,17 • Undue flexion of head may lead to arterial and venous obstruction and may result in upper airway edema, spinal cord injury, endotracheal tube obstruction, macroglossia, and postextubation airway obstruction • Rarely neurovascular injuries are also reported. Risk minimizing strategies for this position include: • Careful monitoring of blood pressure by noninvasive or invasive methods. Hypotension must be managed aggressively. Noninvasive blood pressure cuff should be tied to the arm rather than the leg. Zeroing the transducer at the level of the tragus or circle of Willis is ideal in case invasive blood pressure monitoring • Considering the risk of paradoxical embolus, patients may be screened with contrast echocardiography for patency of the interatrial septum. The occurrence in severity of venous air embolism can be minimized by proper hydration and early detection of entrained air with the use of TEE.17

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•

Securing the head in neutral position to prevent undue flexion or extension is of vital importance. Usually the sternum and mandible are separated by two fingerbreadth difference.18

PRONE POSITION The evolution of the prone position has provided improvements to allow for excellent surgical exposure and mitigate risk to the patient. Typically, anesthesia is induced on a stretcher next to the operating room table within reach of all anesthesia equipment. After the trachea is intubated and any invasive monitors are placed, the patient is placed in the prone position. This is safely performed as a coordinated effort of the anesthesia, surgical, and nursing personnel in the operating room. Once in the prone position, all monitors must be reestablished and continued adequate ventilation be confirmed. The head is usually placed on a foam pillow with cutouts to cover eyes, nose, and mouth, or held using the Mayfield headrest and pinning the head (Fig. 7). Mirror systems are available to facilitate intermittent visual confirmation. Arms are usually rested and secured at the patient’s side. Arms can also be placed in “prone superman” position, where arms are abducted less than 90° at the shoulder and flexed at the elbow and placed on resting pads and breasts are usually placed medial to the thoracic bolsters.19 Before surgical draping proper inspection has to be conducted. Proper positioning of the head and neck must be frequently checked while in the operating room, with careful attention to the eyes. At the conclusion of the operation, the patient must be safely returned to a stretcher in the supine position prior to extubation. Ideally neuromuscular blockade should be reversed after turning to supine position so that airway can be managed comfortably. The list of surgical procedures is unending which are performed in this position. However, the following procedures are commonly performed in prone position: • Posterior cranial fossa surgery • Posterior spine surgeries

Fig. 7: Prone position on operation table.

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• • •

Buttock and perirectal procedures Operations on the posterior components of the lower extremity Endoscopic retrograde cholangiopancreatography (ERCP) procedures.

Physiological Changes Cardiovascular Physiology

When positioning a patient prone, there is a predictable decrease in cardiac index of up to 20%. This decrease is caused by a reduction in stroke volume secondary to decreased venous return. Heart rate is minimally changed. However, mean arterial pressure usually remains unchanged secondary to an increase in SVR. Respiratory Physiology

Functional residual capacity decreases as compared to the erect position. However, compared to the supine patient, FRC increases in the prone position. Blood flow is distributed more uniformly throughout the lung in the prone position compared to the supine position. As with pulmonary perfusion, lung ventilation is probably less dependent on gravitational forces than was once thought. Recent work emphasizes that the architecture of the airway has a greater impact than gravity on the distribution of ventilation. Overall, this leads to improved matching of ventilation and perfusion, allowing for better oxygenation when properly placed in the prone position.20,21 If not positioned correctly, excess abdominal compression can cause cephalad movement of the diaphragm and encroach upon the lungs. This could lead to a reduction in FRC and lung compliance leading to ventilation and perfusion (V/Q) mismatch.

Complications Perioperative Visual Loss

Perioperative visual loss (POVL) is a devastating, but extremely rare event occurring in 0.0008% for all anesthetics.22 Spine and cardiac surgery has the highest reported frequency of POVL. Two main patterns of injury are seen in the prone position: ischemic optic neuropathy (ION) and central retinal artery occlusion (CRAO). Central retinal artery occlusion occurs due to improper positioning and direct external pressure on the eye, increasing intraocular pressure and leading to retinal ischemia.23 More often than not, CRAO is a preventable injury that takes diligence and frequent eye checks throughout the procedure. Following CRAO, overall prognosis is poor with limited treatment options available. For this reason, prevention must be the focus of the anesthesiologist with frequent eye checks and careful positioning of the head. Ischemic optic neuropathy has occurred following instrumented spine surgery in the prone position. The specific etiology and risk factors of ION remains unclear. Certain factors occur more frequently, including long surgical times, extensive blood loss, large crystalloid resuscitation, and hypotension.24,25

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Strategies to minimize the risk of injury include proper positioning of head while avoiding excessive flexion, extension, or rotation of the neck. Careful and repeated eye checks should be done and the head down position should be avoided. In this position, venous drainage from the head may be compromised. A neutral or slightly head up position will allow for better venous drainage of the head.26,27

LATERAL DECUBITUS POSITION Common procedures performed in this position include procedures on the lung, aorta, kidney, and hip. Patient is usually rested on the nonoperative side and is usually balanced with anterior and posterior support, with the use of bedding rolls or a deflatable beanbag. A pillow is usually placed between the legs to protect the bony prominences of the knees. Dependent leg is usually kept in flexion (Fig. 8). A modification of this position is achieved by raising the central bridge of the table for performing renal surgeries (Fig. 9). Care must be taken to position the arms properly. The lower arm is either placed on an arm board or rested on the procedure table. The nondependent arm is usually supported with the use of pillows or special holders. The head and neck are usually maintained in neutral position. Careful attention must be paid to the dependent eye and ear to avoid external pressure. In order to avoid compression on the axillary vessels or the brachial plexus, an axillary roll must be placed between the chest wall and operating room table caudal to the axillae.

Physiological Changes Lateral decubitus position may alter the normal physiology. Most importantly, the respiratory system undergoes alterations in ventilation and pulmonary perfusion, resulting in V/Q mismatch.

Fig. 8: Lateral decubitus position.

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Fig. 9: Kidney position.

Ventilation

In the awake, spontaneously breathing patient, the dependent portion of each lung is preferentially ventilated in the erect, supine, and lateral position. However, with the induction and maintenance of anesthesia in this position, ventilation of the nondependent lung is favored. In fact, it is reported that 55% of each tidal volume is delivered preferentially to the nondependent lung. Ventilation to the dependent lung may be further compromised by during opening of the chest, by allowing the mediastinum to shift and further compression. Pulmonary Perfusion

Pulmonary blood flow is the combination of both gravitational and nongravitational factors as well as the effects of HPV. In the lateral decubitus position, the dependent lung would receive greater blood flow compared to the nondependent lung. During positive pressure ventilation of both lungs, pulmonary blood flow is greater to the dependent lung, whereas the nondependent lung receives preferential ventilation. This leads to a predictable V/Q mismatch.28,29 Specific complications pertaining to lateral decubitus position include: • Brachial plexus injuries • Perioperative visual loss.

ROBOTIC SURGERY POSITIONING Robotic surgery is gaining progressive popularity nowadays. Shorter hospital stay, minimal invasive technique, reduced postoperative morbidity, quicker recovery are few of the many benefits which are making it highly popular across the globe. It is also increasingly being practiced in bigger institutes of India across many surgical disciples. Apart from benefits, it does have few drawbacks also. Positioning of patient during surgery is one of the difficult tasks as it is associated with

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Fig. 10: Robotic surgery position.

disturbances of various cardiorespiratory parameters, especially in the geriatric age group. The patient is put in a lithotomy position for a prolonged period with steep Trendelenburg angle of 30–45º (Fig. 10). For example, during the most commonly performed surgical procedure (prostatectomy), the physiological disturbances occur due to steep Trendelenburg position along with pneumoperitoneum which can have exaggerated effects in patients with cardiorespiratory, neurological, and endocrine comorbidities. Further such positioning is also detrimental in patients prone to raised intraocular pressure as well as patients poorly tolerating increased cerebral blood volume situations.30 The role and responsibilities of attending anesthesiologist during such prolonged surgeries include but are not limited to: • Preventing pressure on bony prominences and other vulnerable areas31 • Repeated checking of airway and ensuring stable position of endotracheal tube32 • Covering of patients face especially eyes to prevent any injury from reflux of gastric juice33 • Maintaining body temperature as prolonged pneumoperitoneum with cold and dry gasses can cause hypothermia30 • Extubation should be carefully planned as airway edema due to prolong positioning can cause potential obstruction31 • Meticulous training of every doctor and staff member in resuscitating the patient in such surgical suites as removing robot and reposition can consume vital time before effective cardiopulmonary resuscitation can begin.

ANESTHESIA AND CRITICAL CARE PROCEDURES Not just during surgical procedures, the task gets difficult for anesthesiologist sometimes even during anesthesia and critical care procedures also. Though recommendations are there for every procedure the problems can arise sometimes

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either due to casual approach and lack of awareness of anesthesiologist or due to anatomical variations in individual patients. The exact positioning during these procedures is of paramount importance as it may lead to many complications or sometimes failure of the procedure itself. Few such complications are highlighted in the ensuing section.

Eye Injuries during Mask Ventilation Corneal abrasion is one of the most frequent ocular complications of GA.34 The ocular surface can be directly injured by face‐masks, the anesthetist’s hands, their name tag, bell of the stethoscope, laryngoscope, and even with surgical drapes and instruments.35 This occurs due to anesthesia-induced increase in frequency of lagophthalmos, decrease in tear production and inhibition of protective Bell’s phenomenon.36 Protective measures should be taken in order to decrease the incidence of eye injury during perioperative period. The easiest way to avoid ocular damage is by taping the patient’s eyelids using adhesive tapes as soon as there is loss of eyelash reflex after induction.37

Facial Nerve Injury during Straps of Face Mask in Intensive Care Unit Patients in intensive care units (ICUs) are frequently given noninvasive ventilation using face masks. Face straps on the mask are tightly fitted across the patients face to avoid any air leak which is a potential source of facial nerve injury. There is also a risk of ischemic damage to the skin as a result of prolonged pressure. Adequate padding at various pressure points can prevent the above risks.

Central Venous Line Insertion The Trendelenburg position is the most preferred position for internal jugular and subclavian cannulation as it facilitates gravity-induced central venous filling thus creating a greater target for venipuncture.38 However for femoral vein cannulation, the reverse Trendelenburg position does not prove to be beneficial as it does not have much effect on the caliber of the vein. Studies show that during IJV cannulation contralateral rotation of head more than 40° can increase the possibility of arterial puncture as extreme rotation causes an overlap of the vein and the artery.39 Also extreme rotation of the head increases the failure rate as the sternocleidomastoid muscle comes anterior to the vein.40 So, one should rotate the patients head so as to provide access to the patient’s neck. The placement of a rolled towel between the shoulders may impede a successful cannulation of subclavian vein by its compression due to passive retraction of the shoulder blades.41

Caudal Block after General Anesthesia in Pediatric Patients Caudal block is frequently given in pediatric patients for pain relief. After induction, it is usually given in prone or lateral decubitus position. The positioning after induction of anesthesia has to be made very carefully and meticulously. Though it seems routine and easy, the correct positioning is of utmost importance as

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it may have a bearing on block failure and complications like dural puncture, dislodgment of LMA or endotracheal tube can occur.

Endotracheal Intubation Improper patient positioning is one of the main cause of failed intubation. Sniffing position in which “there is flexion of the neck on the body and extension of the head on the neck” is recognized as the optimal position for direct laryngoscopy. However in patients with suspected or documented cervical spine injury movement of the neck is contraindicated as it can worsen the injury thus causing permanent neurological deficit. The neck should be completely immobilized using collars or manual in line stabilization.

Ryle’s Tube Insertion Nasogastric tube insertion is a relatively simple and uncomplicated procedure performed by an anesthetist. The nasogastric tube is inserted through the nostril with concave side along the nasal floor, which is then rotated 180° upon reaching the oropharynx allowing the tip to be seated against posterior pharyngeal wall. This facilitates its passage into the esophagus. The simple maneuver of lifting the chin ensures an easy and smooth passage of nasogastric tube and has proved to be invaluable both in the ICU and in the operating theater. In an unconscious patient the procedure may be difficult and traumatic at times as the patient is unable to cooperate. Repeated attempts may lead to unwanted complications of mucosal bleeding, gag reflex, and may even lead to pneumothorax and pneumonia. A recent study concluded that changing the position to lateral decubitus facilitates the insertion of NG tube in unconscious patients. This prevents the decrease in space between tongue and posterior pharyngeal wall by moving the tongue forward and laterally thus preventing glossoptosis.42

Position during Extubation and Post-extubation Extubation has been of special concern as respiratory complications are three times more as compared to that during intubation. The conventional training of extubating the patients in left lateral, head down position was thought to be protective for the airway keeping it patent and safe from aspiration. The supine and sitting up extubation may be better than conventional extubation in select patients who are obese and have COPD and with anticipated difficult airway.43 The supine semi-upright position is also recommended in patient with obstructive sleep apnea and those who had undergone recent airway surgery as it aids in spontaneous breathing, increases FRC and reduces airway edema by encouraging lymphatic drainage.

CONCLUSION Awareness about potential complications related to positioning as well as a vigilant monitoring can help in reducing the incidence of complications to a larger extent. To prevent common injuries such as that of brachial plexus, proper positioning of

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the arms and monitoring of the patient’s pulse in the dependent arm may aid in early identification of any compression of axillary neurovascular structures. Lower saturation pulse oximetry may indicate compromised circulation and should be addressed immediately. A generalized protocol or a checklist can be formulated which can be distributed to all the staff members educating and making them aware about various positioning skills and hazards and how to proceed in precise and safe manner. At regular periods small drills can be exercised in operation theaters which should aim to revise all the safety precautions while positioning. These steps may include but are not limited to taking care of eye padding, care of IV lines, care of endotracheal tube and preventing accidental extubation, preventing fall of limbs or any part of body from the boundaries of the table, gradual rotation of body for lateral, prone or any other positioning, care of urinary catheters and drains, care of monitoring gadgets as well possible injuries from these gadgets, preventing any part of the body coming into direct contact with metallic part of table when moving the patient gradually to a final position and so on. In spite of all these precautions, complications can still occur but their incidence will be diminished significantly instilling a generalized feeling of satisfaction and betterment among clinicians and patients.

KEY POINTS • • •

•

• •

Anesthesiologist plays an important and vital role in carrying out final positioning after anesthesia is administered. Any ill position during surgery not only increase procedural difficulties but can also result in unwarranted injuries pertaining to such poor positioning. It is extremely difficult to ascertain the exact cause of injury but most commonly stretching, compression, ischemia or metabolic derangement are prime factors which can cause positioning injuries during surgery. Clear understanding of the anatomic and physiologic effects of each patient position is of paramount importance. Also, the understanding regarding the expected impact of the anesthetic and surgical procedures on these aspects is also vital in preventing injury due to undue pressure on any part of the body, obstruction of the blood vessels or undue stretching. Ulnar nerve is the most common nerve injured, followed by the brachial plexus and lumbosacral roots. Postoperative vision loss (POVL) is a devastating, but extremely rare event associated with occurring in prone position.

REFRENCES 1. Britt BA, Gordon RA. Peripheral nerve injuries associated with anesthesia. Can Anaesth Soc J. 1964;11:514-36. 2. Prielipp RC, Morell RC, Walker FO, et al. Ulnar nerve pressure: Influence of arm position and relationship to somatosensory evoked potentials. Anesthesiology. 1999;91:345-54. 3. Stewart JD, Shantz SH. Perioperative ulnar neuropathies: A medicolegal review. Can J Neurol Sci. 2003;30:15-9. 4. Hakim TS, Lisbona R, Dean GW. Gravity-independent inequality in pulmonary blood flow in humans. J Appl Physiol. 1987;63:1114-21.

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5. Galvin I, Drummond GB, Nirmalan M. Distribution of blood flow and ventilation in the lung: Gravity is not the only factor. Br J Anaesth. 2007;98:420-8. 6. O’Brien TJ, Ebert TJ. Physiologic changes associated with the supine position. In: Martin JT, Warner MA (Eds). Positioning in Anesthesia and Surgery, 3rd edition. Philadelphia: WB Saunders; 1997. 7. American Society of Anesthesiologists: Practice Advisory for the Prevention of Perioperative Peripheral Neuropathies: A report by the American Society of Anesthesiologists Task Force on Prevention of Perioperative Peripheral Neuropathies. Anesthesiology. 2000;92:1168-82. 8. Warner MA. Supine positions. In: Martin JT, Warner MA (Eds). Positioning in Anesthesia and Surgery, 3rd edition. Philadelphia: WB Saunders; 1997. 9. Coppieters MW, Van De Velde M, Stappaerts KH. Positioning in anesthesiology: Toward a better understanding of stretch-induced perioperative neuropathies. Anesthesiology. 2002;97:75-81. 10. Warner MA, Martin JT, Schroeder DR, et al. Lower-extremity motor neuropathy associated with surgery performed on patients in a lithotomy position. Anesthesiology. 1994;81:6-12. 11. Warner MA, Warner DO, Harper CM, et al. Lower extremity neuropathies associated with lithotomy positions. Anesthesiology. 2000;93:938-42. 12. Martin JT. Lithotomy. In: Martin JT, Warner MA (Eds). Positioning in Anesthesia and Surgery, 3rd edition. Philadelphia: WB Saunders; 1997. 13. Warner ME, LaMaster LM, Thoeming AK, et al. Compartment syndrome in surgical patients. Anesthesiology. 2001;94:705-8. 14. Newberg Milde L. The head-elevated positions. In: Martin JT, Warner MA, (Eds). Positioning in Anesthesia and Surgery, 3rd edition. Philadelphia: WB Saunders; 1997. 15. Black S, Ockert DB, Oliver Jr WC, et al. Outcome following posterior fossa craniectomy in patients in the sitting or horizontal positions. Anesthesiology. 1988;69:49-56. 16. Mammoto T, Hayashi Y, Ohnishi Y, et al. Incidence of venous and paradoxical air embolism in neurosurgical patients in the sitting position: Detection by transesophageal echocardiography. Acta Anaesthesiol Scand. 1998;42:643-7. 17. Papadopoulos G, Kuhly P, Brock M, et al. Venous and paradoxical air embolism in the sitting position: A prospective study with transoesophageal echocardiography. Acta Neurochir. 1994;126:140-3. 18. Warner MA. Positioning of the head and neck. In: Martin JT, Warner MA, (Eds). Positioning in Anesthesia and Surgery, 3rd edition. Philadelphia: WB Saunders; 1997. 19. Martin JT. The ventral decubitus (prone) positions. In: Martin JT, Warner MA, (Eds). Positioning in Anesthesia and Surgery, 3rd edition. Philadelphia: WB Saunders; 1997. 20. Douglas WW, Rehder K, Beynen FM, et al. Improved oxygenation in patients with acute respiratory failure: The prone position. Am Rev Respir Dis. 1977;115:559-66. 21. Lumb AB, Nunn JF. Respiratory function and ribcage contribution to ventilation in body positions commonly used during anesthesia. Anesth Analg. 1991;73:422-26. 22. Roth S, Thisted RA, Erickson JP, et al. Eye injuries after nonocular surgery: A study of 60,965 anesthetics from 1988 to 1992. Anesthesiology. 1996;85:1020-7. 23. Jampol LM, Goldbaum M, Rosenberg M, et al. Ischemia of ciliary arterial circulation from ocular compression. Arch Ophthalmol. 1975;93:1311-7. 24. Hunt K, Bajekal R, Calder I, et al. Changes in intraocular pressure in anesthetized prone patients. J Neurosurg Anesthesiol. 2004;16:287-90. 25. Cheng MA, Todorov A, Tempelhoff R, et al. The effect of prone positioning on intraocular pressure in anesthetized patients. Anesthesiology. 2001;95:1351-5. 26. Lee LA, Roth S, Posner L, et al. The American Society of Anesthesiologists Postoperative Visual Loss Registry. Analysis of 93 spine cases with postoperative visual loss. Anesthesiology. 2006;105:652-9. 27. Practice advisory for perioperative visual loss associated with spine surgery: A report by the American Society of Anesthesiologists Task Force on Perioperative Blindness. Anesthesiology. 2006;104:1319-28.

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28. Dunn PF. Physiology of the lateral decubitus position and one-lung ventilation. Int Anesthesiol Clin. 2000;38:25-53. 29. Choi YS, Bang SO, Shim JK, et al. Effects of head-down tilt on intrapulmonary shunt fraction and oxygenation during one-lung ventilation in the lateral decubitus position. J Thorac Cardiovasc Surg. 2007;134:613-8. 30. Irvine M, Patil V. Anesthesia for robot-assisted laparoscopic surgery. CEACCP. 2009;9:125-9. 31. Phong SV, Koh LK. Anesthesia for robotic-assisted radical prostatectomy: considerations for laparoscopy in the Trendelenburg position. Anaesth Intensive Care. 2007;35:281-5. 32. Pathan H, Gulati S. A case of airway occlusion in robotic surgery. J Robotic Surg. 2007;1:169-70. 33. Conacher ID, Soomro NA, Rix D. Anesthesia for laparoscopic urological surgery. Br J Anaesth. 2004;93:89-64. 34. Terry TH, Kearns TP, Grafton‐Loue J, et al. Untoward ophthalmic and neurological events of anesthesia. Surg Clin North Am. 1965;45:927-9. 35. Batra YK, Bali IM. Corneal abrasions during general anesthesia. Anesth Analg. 1977;56:363-5. 36. Gild WM, Posner KL, Caplan RA, et al. Eye injuries associated with anesthesia. Anesthesiology. 1992;72:204-8. 37. White E, Crosse M. The aetiology and prevention of perioperative corneal abrasions. Anaesthesia. 1998;53:157-61. 38. Marcus HE, Bonkat E, Dagtekin O, et al. The impact of Trendelenburg position and positive end-expiratory pressure on the internal jugular cross-sectional area. Anesth Analg. 2010;111:432-6. 39. Sulek CA, Gravenstein N, Blackshear RH, et al. Head rotation during internal jugular vein cannulation and the risk of carotid artery puncture. Anesth Analg. 1996;82:125-8. 40. Suarez T, Baerwald JP, Kraus C. Central venous access: The effects of approach, position, and head rotation on internal jugular vein cross-sectional area. Anesth Analg. 2002;95:1519-24. 41. Unal AE, Bayar S, Arat M, et al. Malpositioning of Hickman catheters, left versus right sided attempts. Transfus Apher Sci. 2003;28:9-12 42. Zhao W, Ge C, Zhang W, et al. The important role of positioning in nasogastric tube insertion in unconscious patients: A prospective, randomised, double-blind study. J Clin Nurs. 2018;27:162-8. 43. Vaughan RS. Extubation—yesterday and today. Anaesthesia. 2003;58:945-50.

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4

The Stress Response to Surgery and the Effect of Anesthesia

Munisha Agarwal

INTRODUCTION Stress response to surgery is the body’s response to surgical trauma characterized by the activation of sympathoadrenal system and increased secretions of pituitary hormones as well as immunological and hematological changes. Following surgical trauma, the stress response is activated via the afferent impulses from the injured site to the hypothalamus which in turn stimulates the pituitary to secrete hormones such as adrenocorticotropic hormone (ACTH), growth hormone (GH), thyroid-stimulating hormone (TSH), etc. These hormones then act on respective target organs to release various hormones and mediators like cortisol, glucagon, catecholamines, and inflammatory cytokines. The overall effect of these hormones is increased catabolism, which mobilizes substrate to provide energy sources and retention of water and salt to maintain fluid volume and cardiovascular homeostasis. Different surgical techniques as well as different anesthetic techniques for the same surgical procedure can trigger variable stress response. Surgery, which is more extensive and has a longer duration elicits a more extensive stress response.1 In 1932, Cuthbertson studied the metabolic responses of four patients who sustained lower limb fractures.2 The term “ebb” and “flow” was coined to describe an initial decrease followed later by an increase in metabolic activity. Presumably the stress response developed to allow a wounded animal to survive by catabolizing their own stored energy reserves. However, the stress response to surgery seems unnecessary and rather detrimental to the surgical outcome and has prompted wide range of research for methods to obtund or abolish the stress response.

THE ENDOCRINE RESPONSE TO SURGERY Sympathoadrenal Response Surgical trauma activates the sympathetic autonomic nervous system which stimulates the hypothalamus leading to rise in levels of both catecholamines secreted from the adrenal medulla and norepinephrine from presynaptic nerve terminals. These transmitters then lead to increased sympathetic activity

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expressed as tachycardia, hypertension, raised cardiac output, increased myocardial contractility. There is peripheral and splanchnic vasoconstriction, coronary and cerebral vasodilation. Also stimulation of efferent sympathetic fibers and/or circulating catecholamines modifies function of organs like liver, pancreas, and kidney.

Hypothalamic-Pituitary-Adrenal Axis Cortisol

Corticotropin-releasing hormone (CRH) secreted from the hypothalamus stimulates anterior pituitary to release ACTH into the circulation. ACTH stimulates the adrenal glands to produce the stress hormone, i.e. cortisol. Surgical trauma is one of the most-potent stimulus for ACTH and cortisol secretion. ACTH stimulates the adrenal glands to secrete cortisol as soon as the surgery begins and levels of cortisol rise rapidly thereafter. Cortisol concentration may increase to as high as greater than 1,500 nmol/L from baseline levels of about 400 nmol/L in about 4–6 hours from start of surgery, depending on the magnitude of surgical trauma. Raised concentration of cortisol inhibits further release of ACTH through a negative feedback mechanism. However, this mechanism becomes ineffective after surgery leading to high concentration of both ACTH as well as cortisol.1 Cortisol is a glucocorticoid hormone, mainly catabolic in nature and it mobilizes energy stores to prepare the body for an appropriate response to various stressors. It facilitates breakdown of proteins and gluconeogenesis in liver. Utilization of glucose by the cells is also inhibited which leads to increased blood glucose levels. Lipolysis promoted by cortisol increases production of precursors of gluconeogenesis from the breakdown of triglycerides into glycerol and fatty acids. Cortisol also has other important anti-inflammatory glucocorticoid actions due to which accumulation of macrophages and neutrophils into the inflammatory areas is inhibited and synthesis of various inflammatory mediators like prostaglandins is also hampered.1 Other Pituitary Hormones

Surgical trauma also stimulates the anterior pituitary to secrete GH and prolactin in increased amount. GH besides regulating growth, stimulates protein synthesis and inhibits protein breakdown, promotes lipolysis and has anti-insulin effect. The uptake and utilization of glucose by cells is inhibited by GH, which spares glucose to be used by the neurons whenever any scarcity occurs. Glycogenolysis is also stimulated by GH in the liver. Therefore, increased levels of GH in response to surgical stimulus leads to raised blood glucose levels.1 There is no significant change in the levels of other pituitary hormones like follicle stimulating-hormone (FSH), TSH, luteinizing hormone (LH) during surgery. Beta-endorphins secretion though increases following surgery, but has negligible metabolic effect. Arginine vasopressin is produced by the posterior pituitary and it has significant antidiuretic action. It also stimulates secretion of proopiomelanocortin from the anterior pituitary along with CRH.

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Insulin and Glucagon

Insulin is synthesized and secreted by β-cells of the pancreas and has dominant anabolic action. It facilitates uptake of glucose into the adipose tissue and the muscles and conversion of glucose into triglycerides and glycogen. It promotes glycogenesis in the liver. Insulin also inhibits breakdown of proteins and lipolysis. Thus, insulin plays a key role in controlling the glycemic levels in the blood. Following induction of anesthesia, insulin levels may decrease and they are unable to match the hyperglycemic response consequent to release of catabolic hormones. This may be caused due to alpha-adrenergic inhibition of β-cell secretion. Also insulin resistance, i.e. failure of the usual cellular response to insulin occurs during the perioperative period.1 Glucagon, which is produced by the α-cells of pancreas, stimulates glycogenolysis in the liver. It also promotes production of glucose from amino acids in the liver and has lipolytic action. There is slight increase in plasma glucagon levels after major surgery but this does not significantly contribute to the hyperglycemic response.1 Thyroid Hormones

Concentration of TSH decreases during first-two hours of surgery and return to baseline thereafter. Total and free T3 levels decrease after surgery and normalize after several days. These changes in thyroid hormone levels may be because of the close relationship between thyroid hormones, cortisol and catecholamines.1 Exogenous steroids suppress T3 and therefore hypercortisolemia following surgery may also decrease T3 concentration.3

METABOLIC EFFECTS OF THE ENDOCRINE RESPONSE The cumulative effect of the stress response to surgery is an excessive secretion of catabolic hormones. The classical “stress response” is characterized by increased levels of catecholamines, cortisol and glucose. These hormones in turn promote breakdown of carbohydrates, proteins and fat to provide food substrates. This kind of stress response perhaps evolved as a protective and a healing process following an injury. However, in modern day anesthetic and surgical practice, it is debatable whether such endocrinal stress response to surgery is useful for the patient or needs to be modulated or abolished by various interventions.

Carbohydrate Metabolism Concentration of blood glucose rises after surgery begins. Cortisol and catecholamines facilitate production of glucose because of increase in gluconeogenesis and glycogenolysis in the liver. Also utilization of glucose in peripheral tissues is impaired in the perioperative period. Relative lack of insulin along with peripheral insulin resistance also contributes to raised blood glucose levels. Levels of circulating cortisol hormone are very significant predictor of increase in degree of insulin resistance consequent to postsurgical stress response. Blood glucose levels are related to the magnitude of the surgical insult and the surge in catecholamines.4 During cardiac surgery, blood glucose concentration

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can rise as high as 10–12 mmol/L and remain elevated for more than 24 hours postoperatively. These changes are less significant after minor surgery.1 Healing of the surgical wounds is significantly affected by hyperglycemia, which in turn leads to increased morbidity and mortality in surgical patients. In patients undergoing cardiac surgery, a higher incidence of wound infection and mediastinitis was found in diabetics and nondiabetic patients in which blood glucose levels were greater than 200 mg/dL.5

Protein Metabolism Breakdown of proteins is stimulated by increased cortisol concentration as seen during surgery. Skeletal muscle and visceral muscle protein is catabolized to amino acids which may be broken down as substrates in the liver to provide energy or used to produce new acute phase proteins in the liver. Amino acids are also converted to glucose, fatty acids and ketones in liver. Protein catabolism results in increased muscle wasting weight loss in patients after major surgery and traumatic injury, which can lead to prolonged recovery time and hospital stay.1

Fat Metabolism Increased levels of cortisol, catecholamines and GH following surgery stimulate conversion of triglycerides to glycerol and fatty acids. Fatty acids can get converted into ketone bodies or may get re-esterified while glycerol acts as a substrate for gluconeogenesis in liver.

Water and Electrolyte Metabolism Endocrine response to surgery leads to secretion of various hormones leading to salt and water retention in an effort to maintain adequate body fluid volume. Arginine vasopressin facilitates water retention and stimulates the kidneys to produce concentrated urine. Concentration of vasopressin can remain high for 3–5 days postoperatively, depending on the magnitude of surgical trauma. Renin secretion due to increased sympathetic stimulation leads to increased production of angiotensin-II which in turn stimulates release of aldosterone from adrenal cortex leading to sodium and water reabsorption from the distal tubules of kidney.3

Temperature Alterations Preoptic area of hippocampus senses the change in temperature of the body, which stimulates the release of stress hormones. The stress hormones cause an increase in heat production, but clinical conditions like starvation, induced hypothermia, cardiopulmonary bypass (CPB), neurosurgery, sepsis are known to influence neuroendocrine responses.6,7

HEMATOLOGICAL AND IMMUNOLOGICAL EFFECTS OF THE STRESS RESPONSE Hypercoagulability and Fibrinolysis Due to the effects of cytokines and acute phase proteins (discussed later) on the coagulation pathway, there is hypercoagulation and fibrinolysis.

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The surgical stress response also leads to relative leukocytosis and lymphocytosis. Immunosuppression occurs because of the direct effects of increased cortisol secretion.8

Cytokines Discovery of cytokines led to the concept that besides endocrinal response to surgical stress, certain local substances are also released at the site of injury, which significantly contributes to surgical stress response. Cytokines are heterogeneous group of low molecular weight proteins like interleukins, lymphokines and interferons. They are produced from activated leukocytes, especially monocytes, and from endothelial cells and fibroblasts in the initial stage of tissue injury and play a significant role in the inflammatory response to surgery and trauma. The main cytokines released after major surgery are interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-α), and IL-6.9 Activated macrophages and monocytes secrete IL-6 and TNF-α in the initial phase of tissue injury. This stimulates further release of cytokines in particular IL-6, which is the most significant cytokine responsible for producing the systemic changes, i.e. acute phase response.9 Interleukin-6

Normal concentration of cytokines in the blood is usually very low or undetectable. IL-6 concentration increases within 30–60 minutes of start of surgery and maximum changes in its levels are seen after 2–4 hours. The production of cytokine is proportional to the extent of surgical trauma. Therefore, release of cytokine is lowest following minimally-invasive surgery and highest after major surgical procedures like joint replacement, colorectal surgery, etc. Cytokine concentration reaches peak at about 24 hours after a major surgery and elevated levels are found even at 48–72 hours after surgery.1

Acute Phase Response This phase is initiated by cytokines especially IL-6 following surgical trauma and mainly involves production of acute phase proteins by liver, i.e. C-reactive protein (CRP), fibrinogen, α-2 macroglobulin and antiproteinases. These act as inflammatory mediators, antiproteinases and scavengers in tissue repair. Following surgery, cytokines can increase the secretion of ACTH from pituitary, which then causes an increase in release of cortisol from adrenal glands. Glucocorticoids inhibit cytokine production through a negative feedback system. The cortisol response to surgery also decreases IL-6 concentration.4,10

STIMULI FOR THE STRESS RESPONSE The stress response to surgery can be triggered by a variety of stimuli ranging from changes in metabolic and volume status of the body to the chemical mediators released in response to surgical trauma. They are as follows: • Decrease in the effective circulating volume in the body due to any cause such as trauma, hemorrhage,11 sepsis, cardiac failure, act via baroreceptors to stimulate release of ACTH, AVP, GH and β-endorphins which lead to increase

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•

•

•

• •

in heart rate, blood pressure, stroke volume, sodium and water retention, hyperglycemia.12,13 Hypoxia, hypercarbia, hypo or hyperthermia, changes in H+ concentration in the blood activate peripheral chemoreceptors and cause hormonal reflex response.12 Pain, anxiety and distress via the limbic system and cerebral cortex stimulate sympathetic nervous system. Light plane of anesthesia and intraoperative periods of intense stimulation (skin incision, tissue handling, peritoneal stretching) show exaggerated stress response. Surgical tissue trauma—activates the endocrinal stress response. Minimallyinvasive surgery cause less tissue trauma and hence there is lesser rise of inflammatory mediators like IL-6, CRP, acute phase proteins. Stimuli from the surgical site, which elicit stress response and travel along peritoneal and visceral afferent nerve fibers along with those from the abdominal wall. Therefore, measures which decrease surgical trauma do not significantly reduce the classical stress response (raised levels of cortisol, glucose, catecholamines) to abdominal surgery like cholecystectomy.1 Acute phase proteins—produced by the liver on stimulation by cytokines mainly IL-6. Interaction between the neuroendocrine and the immune system—cytokines augment ACTH secretion from pituitary after surgery and hence increase release of cortisol. Glucocorticoids via negative feedback mechanism inhibit cytokine production. Anesthesia cannot influence tissue trauma and therefore it cannot affect the cytokine response to surgery.1 Regional anesthesia has no significant effect on cytokine production though it can reduce surgical stress response. Surgically induced stress response is less severe in magnitude as compared to that consequent to extensive trauma, burns, and sepsis.

EFFECT OF ANESTHESIA ON THE STRESS RESPONSE TO SURGERY The most important factors determining the level of surgical stress response have been found to be the patient and the type of anesthesia and surgery. In addition, anesthesia may also modify the stress response via afferent blockage (local anesthesia), central modulation (general anesthesia) and peripheral interaction with the endocrine system (e.g. etomidate).14

General Anesthesia General anesthesia (GA) can decrease the perception of sensations from the site of surgical trauma but cannot completely abolish the response because even in deeper planes of anesthesia, hypothalamus reacts to the noxious stimuli. Also, GA cannot influence the degree of surgical trauma and hence cannot significantly affect response of cytokines to surgery.1 Intravenous (IV) or volatile anesthetic agents have only minor influence on endocrine metabolic response to surgery in usual clinical dosages. In patients undergoing cardiac surgery, large doses of opioids like morphine (4 mg/kg) inhibit cortisol and GH secretion until the

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cardiopulmonary bypass (CPB) is started. Short-acting opioids like fentanyl (50–100 μg/kg), sufentanil (20 μg/kg) and alfentanil (1.4 mg/kg) suppress pituitary hormone secretion until CPB. After the initiation of CPB, opioids were unable to abolish the stress response even at very high dosages.15 For certain surgical procedures complete inhibition of stress response may be possible but at very high dosages of opioids at the cost of postoperative respiratory depression requiring ventilatory support. In patients undergoing pelvic surgery, fentanyl suppressed ACTH and cortisol secretion when administered before surgical incision but not when given after the start of surgery.16 Aldosterone and cortisol production is suppressed for 6–12 hours after the administration of a single induction dose of etomidate while cortisol synthesis is further inhibited for up to 24 hours following etomidate infusion for 1–2 hours.17 A single induction dose of propofol is known to influence sympathoadrenal axis and can suppress cortisol but does not block cortisol and aldosterone secretion in response to surgical stress.18,19 However, propofol infusion at deep anesthetic dosage, abolished cortisol secretion during surgery.18 Sevoflurane in laparoscopic surgery decreased plasma concentration of ACTH, GH and cortisol when compared to isoflurane.20 Perioperative use of dexmedetomidine reduces serum cortisol levels.21 Benzodiazepines may also inhibit steroid production but significance is not known. Midazolam obtunds the release of cortisol as a part of endocrinal stress response to both upper abdominal and peripheral surgery.22,23 Hypothalamicpituitary axis is not the site of action of benzodiazepines. However, they might exhibit a direct inhibitory action on steroid production. Clonidine, a centrally acting antihypertensive agent, reduces the sympathoadrenal and cardiovascular responses caused by noxious surgical stimuli by acting on α-2 adrenergic receptors.1 Nonsteroidal anti-inflammatory drugs (NSAIDs) have no direct role in classical stress response, but metabolites of arachidonic acid cascade are involved in various steps of preventing stress response. The normal communication between the hippocampus and the neocortex can get disturbed by increased levels of cortisol, seen as a part of stress response to surgery which in turn can disrupt the process of memory consolidation.24,25 Prolactin, another stress hormone is also involved in modulating memory function.26,27 The neuroendocrine stress response to surgery causes incomplete abolition of learning and memory during general anesthesia which can lead to awareness and subsequently posttraumatic stress disorder (PTSD). 25,28 Neuroinflammation due to metabolic stress response to major surgery was also found to be correlated with postoperative cognitive dysfunction (POCD).29 Both PTSD and POCD can perhaps be prevented by neuromonitoring during various surgical procedures. However, the stress response to surgery must be abolished to inhibit the process of neuroinflammation and memory consolidation.29,30,31

Regional Anesthesia Epidural block with local anesthetic agents involving majority of relevant dermatomes prevents a major part of metabolic endocrine response to surgery,

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more consistently during lower abdominal and lower extremity surgeries. In patients undergoing hysterectomy, epidural block from T4 to S5 dermatomal level administered before the start of surgery prevented increase in glucose as well cortisol levels.32 Afferent impulses from the site of surgery travel to the hypothalamic-pituitary axis and the efferent autonomic fibers to the liver and adrenal medulla get blocked. Therefore, the increase in glucose and cortisol levels is abolished. Neural blockade confined to fewer dermatomes does not completely obtund the metabolic and hormonal changes. However, in thoracic or upper abdominal surgery even an extensive epidural blockade cannot prevent the pituitary hormone responses completely though glycemic changes are inhibited.1 Till date, no anesthetic technique has been found to obtund completely the stress response to thoracic and upper abdominal surgery. GA combined with thoracic epidural analgesia has been shown to inhibit changes in catecholamine secretion during CPB for up to 24 hours after the beginning of the cardiac surgery. It may also attenuate the cortisol response to CPB.33 Myocardial sympathetic response was attenuated by combined thoracic epidural block and GA and was associated with decreased myocardial damage as evident by decreased release of Troponin T.34 The blockade of cardiac sympathetic fibers, both efferent and afferent can help in improving the balance between myocardial oxygen demand and supply.35

EVALUATION OF THE STRESS RESPONSE Evaluation of the stress response to surgery under anesthesia remains difficult as no method can directly measure or quantify it. Clinical parameters like heart rate and blood pressure, which are signs of autonomic reactions, have been used for assessing the stress response, though with less specificity. Entropy and bispectral index used for monitoring depth of anesthesia are again indirect measures to evaluate this response. Blood levels of various stress hormones like ACTH, cortisol, prolactin and chemical mediators like epinephrine, norepinephrine have also been used for evaluating stress or nociception level in surgery.1,36 Surgical stress index (SSI) is a recently developed tool to quantify intraoperative stress level during anesthesia and is derived from photoplethysmograph waveform amplitude (PPGA) and the heart beat to beat interval (HBI). SSI reflects nociceptionantinociception balance and ranges from 0 to 100. A high value is indicative of high level of stress.37

MODULATORS OF THE SURGICAL STRESS RESPONSE The continuous hypermetabolic state consequent to the stress response, may result in complete depletion of essential components of the body, e.g. glucose, proteins, fats, minerals which may lead to fatigue, weight loss, decrease in body resistance, delayed ambulation and increased morbidity and mortality. This knowledge about the detrimental effects of neuroendocrine stress response to surgery has led to increased interest in interventions, which can modulate the stress response to have a better surgical outcome.

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Regional Anesthesia Regional anesthetic techniques involving neuraxial blockade with local anesthetic agents maximally inhibits the stress response to surgery and it improves the functioning of specific organ systems. In patients undergoing pelvic and lower limb surgery, analgesia with regional neuraxial blocks lowers the incidence of thromboembolic complications.38 Continuous epidural infusions of local anesthetic agents decrease the incidence of pulmonary complications much more than that by epidural or systemic opioids. Continuous thoracic epidural analgesia decreases paralytic ileus following abdominal surgery.39 Early enteral nutrition can thus be resumed which significantly reduces the risk of infectious complications.40

Oral Glucose Preoperative administration of oral glucose has been found to reduce the rise in blood cortisol and glucose levels postoperatively compared with patients who were made to fast preoperatively.41 Oral glucose loading done twice (evening and morning) before surgery was found to be more effective in reducing the rise of cortisol level but not significant in reducing the rise in blood glucose level compared with patients who were administered oral glucose solution only once (morning) before surgery. Preoperative glucose loading obtunds postoperative insulin resistance, reduces protein and nitrogen losses, preserves skeletal muscle mass and decreases preoperative hunger, thirst and anxiety. In also promotes rapid recovery through early return of bowel function and shorter hospital stay, finally leading to an improved perioperative well-being.41,42

Insulin and Glycemic Control The degree of insulin suppression and resistance is proportional to the extent of surgical trauma. Intensive insulin therapy reduced insulin resistance along with reduction in the incidence of infections and sepsis significantly leading to improvement in organ function and also reversed the posttraumatic catabolic state. Maintenance of blood glucose levels within a reasonable range reduced morbidity and wound healing time in the postoperative patient.42

Enhanced Recovery after Surgery Despite several significant advances in surgical and anesthetic techniques aiming towards better patient care, major surgeries like radical cystectomy, colorectal surgery are still associated with morbidity and prolonged recovery periods. Enhanced recovery after surgery (ERAS) or fast-track programs are multimodal perioperative care pathways designed to achieve early recovery after surgical procedures by maintaining preoperative organ function and reducing the profound stress response following surgery. These programs have been shown to improve the cardiopulmonary functions and lead to earlier return of bowel function, reduction in complications and hospital stay along with early resumption of normal activities.43

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Preoperative planning in ERAS protocol includes preoperative optimization of nutrition and other medical ailments, avoiding prolonged fasting hours, carbohydrate loading up to 2 hours preoperatively, avoiding sedatives, and avoiding mechanical bowel preparation.44 Intraoperatively, it is advocated to use laparoscopic and laparoscopic-assisted surgical techniques which are associated with reduced effects of tissue injury, reduced length of hospital stay, early return of bowel function and minimized wound complications. Wound drains and nasogastric tubes should be avoided. Detrimental effects of over hydration, i.e. delay in return of bowel function, impaired wound healing and increased length of hospital stay, mandates use of goal directed fluid therapy. Use of thoracic epidural analgesic technique for major abdominal surgeries should be preferred. This provides good intra and postoperative analgesia, which reduces ileus in postoperative period by blocking sympathetic nervous system. Hypotension following central neuraxial blockade should be treated with vasopressors rather than fluid overloading. Specific attention is required for thromboprophylaxis, temperature control and postoperative nausea and vomiting management. Highdose opioids are not advisable to avoid side effects like sedation, respiratory depression, nausea or vomiting. Shorter-acting analgesics (like fentanyl), and anesthetics are preferred wherever possible.43,45 Postoperatively, early commencement of oral intake, including carbohydrate drinks and discontinuation of IV fluids is desirable. Early oral intake is associated with lesser wound complications, reduced rates of ileus and shorter hospital stay. Thoracic epidural analgesia is strongly recommended in open abdominal surgery. Drains and urinary catheters should be removed as soon as possible. Multimodal analgesia is used with NSAIDs, paracetamol, gabapentin or pregabalin which has opioid sparing affect and facilitates early mobilization.43

CONCLUSION Stress response to surgery encompasses complex metabolic and hormonal changes triggered by the stimulation of hypothalamus-pituitary-adrenal axis. The cumulative response is hypermetabolic and hypercatabolic, which leads to impaired wound healing and immune function, muscle wasting and organ failure. The magnitude and duration of the stress response is proportional to the surgical trauma. General anesthesia cannot abolish the metabolic hormonal responses completely. Epidural blockade using local anesthetic agents abolishes the stress response to a greater extent. Recently introduced ERAS programs aim to attenuate the body’s response to surgery by multimodal perioperative pathways aimed at achieving early recovery after surgery. For how long does the stress response to surgery last postoperatively? Do patients exhibit genetic predisposition to this response? Specific long-term studies are needed to answer these queries. Till such time, the stress response to surgery should be recognized as a definitive clinical entity which needs to be aggressively managed to ensure better patient and surgical outcome.

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ACKNOWLEDGMENT The author acknowledges the contribution of Dr Bhavna Gupta, Senior Resident, Department of Anesthesiology and Intensive Care, Maulana Azad Medical College, New Delhi, India in preparation of this chapter.

KEY POINTS • •

•

•

• • •

•

Stress response to surgery is body’s response to tissue trauma and is proportional to the extent and duration of surgery. There is activation of sympathetic system and hypothalamus-pituitaryadrenal axis leading to release of mediators and hormones like cortisol, catecholamines, glucagon, and inflammatory cytokines. Overall response of the body is hypermetabolic and hypercatabolic leading to muscle wasting, impaired wound healing, delayed recovery, morbidity and mortality. The stress response though evolved as a protective and healing process following an injury, needs to be attenuated or abolished for better surgical and patient outcome. General anesthesia in usual clinical dosages does not completely abolish the stress response. Epidural blockade with local anesthetic agents is effective in suppressing stress response to a large extent. Surgical Stress Index (SSI) is a new method of evaluation of surgical stress response besides clinical parameters like heart rate, blood pressure and measuring blood levels of stress hormones like cortisol ACTH, epinephrine, nor-epinephrine and prolactin. Interventions like use of newer shorter-acting anesthetic agents, minimallyinvasive surgery, epidural analgesia with local anesthetic agents and multimodal perioperative ERAS protocols are effective in attenuating the surgical stress response.

REFERENCES 1. Desborough JP. The stress response to trauma and surgery. Br J Anesth. 2000;85(1): 109-17. 2. Cuthbertson DP. Observations on the disturbance of metabolism produced by injury to the limbs. Q J Med. 1932;1:233-46. 3. Desborough JP. Physiological responses to surgery and trauma. In: Hemmings HC Jr, Hopkins PM (Eds). Foundations of Anesthesia. London: Mosby, 1999. pp. 713-20. 4. Kahveci K, Ornek D, Doger C, et al. The effect of anesthesia type on stress hormone response: Comparison of general versus epidural anesthesia. Niger J Clin Pract. 2014;17(4):523-7. 5. Wallace LK, Starr NJ, Leventhal MJ, et al. Hyperglycemia on ICU admission after CABG is associated with increased risk of mediastinitis or wound infection. Anesthesiology. 1996;85(Suppl):A286. 6. Lin E, Lowry SF, Calvano SE. The systemic response to injury. In: Schwartz SI, Shires GT, Spencer FC, et al (Eds). Principles of Surgery, 7th edition., International edition. Vol-1, McGrawHill Health Profession Division. 1998;1:3-52.

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7. Kehlet H. Modification of responses to surgery by neural blockade: clinical implications. In: Cousins MJ, Bridenbaugh PO (Eds). Neural Blockade in Clinical Anaesthesia and Management of Pain. Lippincott-Raven, Philadelphia, Pa, USA, 3rd edition, 1998. pp. 129-71. 8. Chrousos GP. The stress response and immune function: Clinical implications. The 1999 Novera H. Spector Lecture. Ann N Y Acad Sci. 2000;917:38-67. 9. Sheeran P, Hall GM. Cytokines in anesthesia. Br J Anesth. 1997;78(2):201-19. 10. Jameson P, Desborough JP, Bryant AE, et al. The effect of cortisol suppression on the interleukin-6 and white cell responses to surgery. Acta Anesthesiol Scand. 1997;41(2):123-6. 11. Longnecker DE. Stress free to be or not to be? Anesthesiology. 1984;61(6):643-4. 12. The adrenocortical hormones. In: Guyton AC, Hall JE (Eds). Textbook of Medical Physiology, 9th edition. Philadelphia: WB Saunders Company. 1998;77:957-70. 13. Keith I. Anesthesia and blood loss in total hip replacement. Anesthesia. 1977;32(5): 444-50. 14. Adams HA, Hempelmann G. The endocrine stress reaction in anesthesia and surgery—origin and significance. Anesthesiol Intensivmed Notfallmed Schmerzther. 1991;26(6):294-305. 15. Desborough JP, Hall GM. Modification of the hormonal and metabolic response to surgery by narcotics and general anesthesia. Clin Anesthesiol. 1989;3:317-34. 16. Bent JM, Paterson JL, Mashiter K, et al. Effects of high-dose fentanyl anesthesia on the established metabolic and endocrine response to surgery. Anesthesia. 1978;39(1): 19-23. 17. Wagner RL, White PF. Etomidate inhibits adrenocortical function in surgical patients. Anesthesiology. 1984;61(6):647-51. 18. Jung SM, Cho CK. The effects of deep and light propofol anesthesia on stress response in patients undergoing open lung surgery: a randomized controlled trial. Korean J Anesthesiol. 2015;68(3):224-31. 19. Kaushal RP, Vatal A, Pathak R. Effect of etomidate and propofol induction on hemodynamic and endocrine response in patients undergoing coronary artery bypass grafting/mitral valve and aortic valve replacement surgery on cardiopulmonary bypass. Ann Card Anesth. 2015;18(2):172-8. 20. Marana E, Colicci S, Meo F, et al. Neuroendocrine stress response in gynecological laparoscopy: TIVA with propofol versus sevoflurane anesthesia. J Clin Anesth. 2010;22(4):250-5. 21. Wang XW, Cao JB, Lv BS, et al. Effect of Perioperative dexmedetomidine on the endocrine modulators of stress response: a meta-analysis. Clin Exp Pharmacol Physiol. 2015;42(8):828-36. 22. Crozier TA, Beck D, Schlager M, et al. Endocrinological changes following etomidate, midazolam or methohexital for minor surgery. Anesthesiology. 1987;66:628-35. 23. Desborough JP, Hall GM, Hart GR, et al. Midazolam modifies pancreatic and anterior pituitary hormone secretion after upper abdominal surgery. Br J Anesth. 1991;67(4): 390-6. 24. Payne JD, Nadel L. Sleep, dreams, and memory consolidation: the role of the stress hormone cortisol. Learn Mem. 2004;11(6):671-8. 25. Paola A, Carlo L, Cinzia DR, et al. Stress response to surgery, anesthetics role and impact on cognition. J Anesth Clin. 2015;6:539. 26. Radulovic J, Rühmann A, Liepold T, et al. Modulation of learning and anxiety by corticotropin-releasing factor (CRF) and stress: differential roles of CRF receptors 1 and 2. J Neurosci. 1999;19(12):5016-25. 27. Croiset G, Nijsen MJ, Kamphuis PJ. Role of corticotropin-releasing factor, vasopressin and the autonomic nervous system in learning and memory. Eur J Pharmacol. 2000;405(1-3):225-34.

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28. Cerejeira J, Batista P, Nogueira V, et al. The stress response to surgery and postoperative delirium: evidence of hypothalamic-pituitary-adrenal axis hyperresponsiveness and decreased suppression of the GH/IGF-1 Axis. J Geriatr Psychiatry Neurol. 2013;26(3):185-94. 29. Tang JX, Mardini F, Janik LS, et al. Modulation of murine Alzheimer pathogenesis and behavior by surgery. Ann Surg. 2013;257(3):439-48. 30. Casati A, Fanelli G, Pietropaoli P, et al. Monitoring cerebral oxygen saturation in elderly patients undergoing general abdominal surgery: a prospective cohort study. Eur J Anesthesiol. 2007;24(1):59-65. 31. Casati A, Fanelli G, Pietropaoli P, et al. Continuous monitoring of cerebral oxygen saturation in elderly patients undergoing major abdominal surgery minimizes brain exposure to potential hypoxia. Anesth Analg. 2005;101(3):740-7. 32. Enquist A, Brandt MR, Fernandes A, et al. The blocking effect of epidural analgesia on the adrenocortcial and hyperglycaemic responses to surgery. Acta Anesthesiol Scand. 1977;21(4):330-5. 33. Moore CM, Cross MH, Desborough JP, et al. Hormonal effects of thoracic extradural analgesia for cardiac surgery. Br J Anesth. 1995;75(4):387-93. 34. Loick HM, Schmidt C, Van Aken H, et al. High thoracic epidural anesthesia, but not clonidine, attenuates the perioperative stress response via sympatholysis and reduces the release of troponin T in patients undergoing coronary artery bypass grafting. Anesth Analg. 1999;88(4):701-9. 35. Meissner A, Rolf N, Van Aken H. Thoracic epidural anesthesia and the patient with heart disease: Benefits, risks and controversies. Anesth Analg. 1997;85(3):598-612. 36. Aceto P, Perilli V, Lai C, et al. Update on posttraumatic stress syndrome after anesthesia. Eur Rev Med Pharmacol Sci. 2013;17(13):1730-7. 37. Ilies C, Gruenewald M, Ludwigs J, et al. Evaluation of the surgical stress index during spinal and general anesthesia. Br J Anesth. 2010;105(4):533-7 38. Lui S, Carpenter RL, Neal JM. Epidural anesthesia and analgesia. Their role in postoperative outcome. Anesthesiology. 1995;82(6):1474-506. 39. Steinbrook RA. Epidural anesthesia and gastrointestinal motility. Anesth Analg. 1998;86(4):837-44. 40. Kehlet H. Acute pain control and accelerated postoperative surgical recovery. Surg Clin N Am. 1999;79(2):431-43. 41. Widnyana IM, Senapathi TG, Aryabiantara IW, et al. Metabolic stress response attenuate by oral glucose preoperatively in patient underwent major surgery with general anesthesia. Int J Anesth Pain Med. 2017,3:1. 42. Finnerty CC, Mabvuure NT, Ali A, et al. The surgically induced stress response. JPEN J Parenter Enteral Nutr. 2013;37(5 Suppl):21-9. 43. Lassen K, Soop M, Nygren J, et al. Consensus review of optimal perioperative care in colorectal surgery (ERAS) group recommendations. Arch Surg. 2009;144(10):961-9. 44. Kakkar B. Geriatric anesthesia. Anesth Commun. 2017;101:1-7. 45. Engelman RM. Fast-track recovery in the elderly patients. Ann Thorac Surg. 1997; 63(3):606-7.

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5

Cardiac Risk Assessment Ramachandran Gopinath, Monu Yadav

INTRODUCTION Perioperative adverse cardiovascular events are one of the most common causes, which may lead to increased morbidity and mortality. With the advancement of medical science and treatment modalities, throughout the world approximately 200 million patients undergo noncardiac surgical procedures per year.1 Incidence of cardiovascular complications in these patients may vary from 0.5% to 30%.2,3 In recent years, due to advancement of anesthetic and surgical techniques, availability of newer drugs and monitoring devices, perioperative outcomes have definitely improved. Even geriatric and patients with risk factors are considered for anesthesia and surgery. Preoperative cardiovascular risk assessment is extremely important for favorable outcome.

APPROACH TO PERIOPERATIVE CARDIAC ASSESSMENT FOR CORONARY ARTERY DISEASE PATIENT Perioperative cardiac risk assessment requires a systematic approach. Depending upon the time available for evaluation, noncardiac surgical procedures can be divided into four types—emergent procedures, urgent procedures, time-sensitive procedures, and elective procedures. Emergent procedures: When minimal or no time is available for assessment and immediate limb saving or life-saving procedure needs to be done within 6 hours. Urgent procedures: When limited time is available for assessment and limb saving or life-saving procedure needs to be done within 6–24 hours. Time-sensitive procedures: For these procedures, even 1–6 weeks can be taken for assessment before the surgical procedure, and outcome can be affected by changes done in management. Oncologic surgical procedures come in this category. Elective procedures: These surgical procedures can even be postponed for up to one year. Depending upon the risk of major adverse cardiac event (MACE) associated with the surgical procedure and they can be either low-risk procedures or elevatedrisk procedures.4

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Low-risk procedures are those which are associated with risk of less than 1% for MACE of myocardial infarction (MI) or death. Elevated risk procedures are associated with a risk of more than 1% for MACE of death or MI.5 The systematic approach towards cardiac risk assessment should include assessment of functional capacity, routine investigations and specific investigations for preoperative cardiac assessment, pertaining to perioperative anticoagulant therapy or other medications, prior coronary intervention and assessment in a specific patient population associated with specific comorbidities. Step 1: Risk Stratification (a) Patient scheduled for emergency surgery: Assess clinically, explain the risk and proceed to surgery. (b) Patient scheduled for elective surgery: Proceed to step 2. Step 2: Assess for Acute Coronary Syndrome (ACS) (a) ACS present: Patient has to be treated as per the standard guidelines. (b) No ACS present: Estimate risk of MACE. Step 3: Assess for MACE Using a Validated Risk Prediction Index (a) Low risk less than 1%: It can proceed to surgical exercise without further evaluation. (b) Elevated risk more than 1%: Assess for functional capacity (step 4). Step 4: Assess for Functional Capacity (a) Moderate to greater exercise capacity metabolic equivalents (METs) more than 4–10: No further evaluation required and can proceed to surgery. (b) If unknown or poor functional capacity with less than 4 METs: Further testing (step 5—stress testing) is required to plan for surgery or preoperative care. Step 5: Stress Testing (a) Stress test normal: Proceed to surgery, no further test required. (b) Stress test positive: Coronary angiography and revascularization needs to done according to standard guidelines or alternative noninvasive surgical treatment strategies are to be followed.

ASSESSMENT OF THE RISK OF PERIOPERATIVE MACE For assessment of perioperative risk of MACE in patients scheduled to undergo noncardiac surgery, various risk prediction models are used (Table 1). Risk factors which are considered in these models may be: • Surgery-specific risk [Revised Cardiac Risk Index (RCRI) and National Surgical Quality Improvement Program (NSQIP)].1,6 • Insulin-dependent diabetes mellitus (RCRI).1,7 • Elevated serum creatinine more than or equal to 2.0 mg/dL (RCRI)1,7 or more than 1.5 mg/dL (NSQIP).6 • Advanced age (NQSIP).6,7 • American Society of Anesthesiologists (ASA) grading (NSQIP).6,7 • Preoperative functional status (NSQIP).6,7

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Table 1: Timeline for development of various cardiac risk assessment indices. ASA

1960

Goldman

1977

Detsky

1986

Larssen

1987

ACC

1996

ACP

1997

Lee RCRI

1999

ACC

2002, 2006, 2009, 2014

VSGNE

2010

Gupta MICA

2011

ACS-NSQIP, R-RCRI

2013

VQI, CCS

2016

GS-CRI

2017

(ASA: American Society of Anesthesiologists; ACC: American College of Cardiology; ACP: American College of Physicians; RCRI: Revised Cardiac Risk Index; VSGNE: Vascular Study Group of New England; MICA: Myocardial Infarction and Cardiac Arrest; ACS NSQIP: American College of Surgeons National Surgical Quality Improvement Program; VQI: Vascular Quality Initiative; CCS: Canadian Cardiovascular Society; GS-CRI: Geriatric-Sensitive Cardiac Risk Index).

Table 2: American Society of Anesthesiologists (ASA) physical status classification system.8 ASA I

A normal healthy patient

ASA II

A patient with mild systemic disease without substantive functional limitations

ASA III

A patient with severe systemic disease with substantive functional limitations; one or more moderate to severe diseases

ASA IV

A patient with severe systemic disease that is a constant threat to life

ASA V

A moribund patient who is not expected to survive without the operation

ASA VI

A declared brain-dead patient whose organs are being removed for donor purposes

American Society of Anesthesiologists (ASA) Classification In 1963, ASA proposed the classification of preoperative patients according to physical status for anesthetic risk assessment (Table 2).8 The addition of “E” to the numerical status (e.g. IE, IIE, etc.) denotes emergency surgery.

Goldman Cardiac Risk Index In 1977, first multifactorial cardiac risk index was given by Goldman, et al. Nine variables associated with high-risk of perioperative adverse cardiac events were included. This was named as the Original Cardiac Risk Index or the Goldman Index (Table 3).1 The risk factors are evaluated on a point scale. Patients with

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Table 3: Original Cardiac Risk Index or the Goldman Index.9 Risk factor

Points

1. Third heart sound (S3)

11

2. Elevated jugulovenous pressure

11

3. Myocardial infarction in past 6 months

10

4. Electrocardiogram (ECG): Premature arterial contractions or any rhythm other than sinus

7

5. ECG shows >5 premature ventricular contractions per minute

7

6. Age >70 years

5

7. Emergency procedure

4

8. Intrathoracic, intra-abdominal or aortic surgery

3

9. Poor general status, metabolic or bedridden

3

scores more than 25 had a 56% incidence of death and 22% incidence of severe cardiovascular complications. Patients with scores less than 26 had a 4% incidence of death and 17% incidence of severe cardiovascular complications. Patients with scores less than 6 had a 0.2% incidence of death and 0.7% incidence of severe cardiovascular complications.9

Modified Cardiac Risk Index (Detsky et al., 1986)10 Detsky et al., (1986) further modified and validated Goldman’s cardiac risk index. They gave the type of surgery a separate pretest probability. Congestive heart failure (CHF) variable was modified and recent or previous MI and severity of angina were included.6 Both these risk indices had limitations. Although original Cardiac Risk Index by Goldman and modification by Detsky were useful in identifying risk factors for cardiac morbidity, but they were very complicated to apply and were not efficient when applied to vascular surgery patients.

Revised Cardiac Risk Index (Lee et al., 1999)1 The RCRI is a validated risk predictor index, which was published in 1999 by Lee et al., and has been used worldwide for assessment of the perioperative risk of MACE. It was more accurate and easier to use as compared to original cardiac risk index. Patients with none or only single risk factor have a low risk of MACE, and patients with two or more risk factors have increased risk (Table 4).

American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP)6 The ACS NSQIP surgical risk calculator is a nationally validated, risk-adjusted, outcomes-based program predicts surgery-specific risk using various procedural codes.8 It uses 21 patient-specific variables and if the surgery is emergent or not and then calculates the risk of MACE along with 8 other outcomes (Table 5).

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Table 4: Revised Cardiac Risk Index.1 1. Creatinine ≥ 2 mg/dL 2. Heart failure 3. Insulin dependent diabetes mellitus 4. Intrathoracic, intra-abdominal or suprainguinal vascular surgery 5. History of cerebrovascular accident or transient ischemic attack 6. Ischemic heart disease Risk for cardiac death, nonfatal myocardial infarction, and nonfatal cardiac arrest: 0 predictors = 0.4%, 1 predictor = 0.9%, 2 predictors = 6.6%, ≥3 predictors = >11%.

Table 5: The ACS NSQIP surgical risk calculator.6 1. Age 2. Renal failure 3. Functional status, body mass index 4. Emergency case 5. Diabetes mellitus, hypertension, heart failure 6. Procedure Current Procedural Terminology code 7. American Society of Anesthesiologists physical status class 8. Wound class 9. Sex, dyspnea, smoker, ascites, ventilator dependent, disseminated cancer, steroid use 10. Systemic sepsis, previous cardiac event, chronic obstructive pulmonary disease, dialysis

The risk is estimated based upon information provided by the patient to the healthcare provider. It is a web based calculator available at www.riskcalculator.facs.org.4

American College of Surgeons National Surgical Quality Improvement Program Myocardial Infarction and Cardiac Arrest (MICA) Risk Calculator7,11 Database of NSQIP was used by Gupta et al., to recognize the risk factors leading to intraoperative or postoperative MI or cardiac arrest.11 In the year 2007, it was reported that out of nearly 200,000 postoperative patients 0.65% had perioperative MI or cardiac arrest. Data was analyzed by multivariate logistic regression analysis and five factors ASA status, age, elevated value of creatinine (>1.5 mg/dL), and type of surgery were identified as predictors of MICA (Table 6). The inguinal hernia was used as the reference group by ACS NSQIP MICA risk calculator and included adjusted odds ratio for different sites of surgery. This is also a web based calculator available at: http://www.surgicalriskcalculator.com/ miorcardiacarrest/4

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Table 6: The American College of Surgeons National Surgical Quality Improvement Program Myocardial Infarction and Cardiac Arrest Risk Calculator.11 1. Age 2. Creatinine > 1.5 mg/dL 3. Partially or totally dependent functional status 4. Type of surgery. 5. American College of Anesthesiologists (ASA) class

The target complications included are defined as follows: • Cardiac arrest is defined as chaotic cardiac rhythm requiring initiation of basic or advanced life support.4 • Myocardial infarction is defined as 1 mm ST-segment elevation in more than 1 contiguous leads, new left bundle branch block, new Q-waves in 2 or more contiguous leads, or elevation in level of troponins more than 3 times normal with suspected ischemia. Using certain patient variables as predictors, a risk index is calculated which predicts risk of perioperative MI and cardiac arrest.4 Limitations of ACS NSQIP MICA risk calculators: • They have no validity in population outside the NSQIP. • Definition of MI only considers ST-elevation or a large increase in level of troponin in symptomatic patients. • Use of ASA Classification having poor inter-rater reliability. On the basis of calculated risk of MACE, the surgical procedures can be categorized as low-risk if calculated risk of MACE is less than 1% or high-risk if calculated risk of MACE is more than 1%.

The Vascular Study Group of New England (VSGNE) Risk Index Vascular Study Group of New England (VSGNE) risk index was specifically developed for patients undergoing vascular surgery.7,12 As in vascular surgery postoperative patients (elective or urgent like lower-extremity bypass, endovascular abdominal aortic aneurysm repair, and open infrarenal abdominal aortic aneurysm) the risk for adverse cardiac events was considered to be underestimated by RCRI. Multivariate analysis was done including various predictors of adverse cardiac events (arrhythmia, MI, and cardiac failure, but not mortality) were increasing age [odds ratio (OR) 1.7 to 2.8], smoking (OR 1.3), insulin-dependent diabetes (OR 1.4), coronary artery disease (OR 1.4), coronary heart failure (OR 1.9), abnormal cardiac stress test (OR 1.2), long-term beta-blocker therapy (OR 1.4), chronic obstructive pulmonary disease (OR 1.6), and creatinine more than or equal to 1.8 mg/dL (OR 1.7). Cardiac revascularization prior to the surgery was protective (OR 0.8). The calculation for the various surgical procedures can be done online. This VSGNE risk index also has limitations: • No external validation has been done. • Adverse cardiac events did not include mortality.

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American College of Cardiology or American Heart Association (2014 ACC/AHA) Guidelines In 2014, two sets of clinical practice guidelines were published for cardiovascular assessment of patients scheduled for noncardiac surgery. One was the 2014 ACC or AHA guidelines on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery and the other was by the European Society of Cardiology and the European Society of Anaesthesiology (2014 ESC/ ESA guidelines).13,14 These guidelines consider patient’s functional capacity for assessment and to guide further management accordingly. In patients who are able to perform activity more than or equal to 4 METs, additional tests are not required. For patients with functional capacity less than 4 METs or unknown, further evaluation may be required if it will affect perioperative management.7 Both these guidelines have been compared in Flowchart 1.

The Vascular Quality Initiative Cardiac Risk Index (VQI CRI 2016) The VQI CRI is a valid and practical risk index to predict postoperative myocardial infarction after vascular surgical procedures. Procedure specific models including specific risk factors may improve accuracy.13 The availability of the VQI CRI as a smart phone medical application may help in cardiac risk assessment, procedure selection, and identifying patients requiring preoperative of optimization.

The Geriatric-Sensitive Cardiac Risk Index (GSCRI) (Alzerk et al., 2017)15 The Geriatric-Sensitive Cardiac Risk Index (GSCRI) is considered to be a better predictor of cardiac risk assessment in geriatric patients scheduled to undergo noncardiac surgery as compared to RCRI or Gupta MICA.15 In the validation cohort among geriatric patients. In the 2012, data set the area under the curve (AUC) for the GSCRI, RCRI, and Gupta MICA was compared. The AUC noted were 0.76, 0.63 and 0.70 respectively. When the Gupta MICA was tested in the validation cohort on geriatric patients, a significant underestimation of the risk was noted. Variables used were age, type of surgery, heart failure, history of stroke, ASA classification, functional status, diabetes mellitus status and creatinine level more than or equal to 1.5 mg/dL. Limitations of this risk index include lack of geriatric-specific data available, and it requires a better classification for functional status.

ASSESSMENT OF EXERCISE AND FUNCTIONAL CAPACITY Assessment of exercise and functional capacity is extremely important to predict perioperative adverse cardiac events and postoperative complications. Patients with high functional status have a low-risk of perioperative adverse cardiac event and do not require further evaluation before elective surgical procedure. The functional status of a patient can be easily assessed by assessing his daily

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Flowchart 1: Comparison of stepwise approach as per 2014 American College of Cardiology or American Heart Association (AHA/ACC) and European Society of Cardiology (ESC) or European Society of Anaesthesiology (ESA) guidelines.

(METs: metabolic equivalents; ECG: electrocardiography)

activities and is expressed as METs. One MET is defined as basal O2 consumption of a 40-year-old and 70-kg man (3.5 mL/kg/min) in sitting position. Functional capacity is classified on the basis of METs, as poor (10 METs). Patients with poor functional status or less than 4 METs are more prone for perioperative complications. Patient’s functional capacity can be determined by various activity scales with a set of questions. According to the activity, the functional status can be assessed as follows:7

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•

Can take care of him or herself, such as eat, dress, and can use the toilet (1 MET). • Can walk up a flight of steps or a hill or walk on level ground at 3–4 mph (4 METs). • Can do heavy work around the house, such as cleaning floors or moving heavy furniture, or climbing two flights of stairs (4–10 METs). • Can participate in strenuous sports such as football, basketball, swimming, tennis and skiing (>10 METs). Patients unable to climb two flights of stairs or walk four blocks indicate having poor functional status and are more prone for postoperative cardiopulmonary complications after major noncardiac surgical procedures. However, in orthopedic patients with inability to walk, it is difficult to assess cardiac functional status. In such circumstances, use of bicycle or arm ergometry stress testing may be considered. Duke Activity Status Index (DASI) and Specific Activity Scale (SAS) can also be used to assess functional status.16 Patients with METs of 4 or more need not to be investigated further and can proceed for surgery. However, patients with unknown or poor functional capacity (METs 10 METs) to good exercise tolerance (> 4 METs) scheduled for highrisk noncardiac surgery, no further stress testing is required.

Pharmacological Testing Routine stress testing is not advised in patients scheduled for low-risk noncardiac surgery. However, patients with poor functional capacity, undergoing increasedrisk noncardiac surgery, should be evaluated with either dobutamine stress echocardiogram or pharmacologic stress myocardial perfusion imaging (MPI), provided it alters further management. Patients scheduled for liver or kidney transplantation have to be evaluated as per its specific set of guidelines. In ambulatory patients, exercise ECG can be useful in detecting any underlying ischemia and functional status. Echocardiographic stress test provides important clinical information in patients with pulmonary hypertension and valvular heart disease. In patients with ECG suggestive of LV hypertrophy and left bundle branch block (LBB), either echocardiography or MPI should be done. If on exercise MPI, in patients with LBB septal perfusion defects unrelated to CAD are seen, then, pharmacological stress testing with adenosine, dipyridamole, or regadenoson is preferred.

Coronary Angiography Routine use of coronary angiography preoperatively is not recommended for patients scheduled for noncardiac surgical procedures (except for patients being assessed for liver or kidney transplantation).

CONCLUSION Preoperative cardiac risk assessment in patients scheduled for noncardiac surgery is a challenge to the anesthesiologist. A thorough history of present and past illness, complete physical examination, routine investigations and genuine ancillary tests as per the particular patient’s requirement may be used to assess and categorize them into a low-risk, intermediate-risk and high-risk for surgical procedure. Accordingly, preoperative optimization and perioperative cardiac risk reduction strategies can be planned and long-term better outcome can be achieved. Preoperative cardiovascular risk assessment and evaluation is of utmost importance, as perioperative adverse cardiovascular events are one of the most common causes, which may lead to increased morbidity and mortality. Assessment of cardiac risk requires a multidisciplinary approach involving treating physicians, surgeons and anesthesiologists. Detailed communications among the patient, family members of the patient, and all other healthcare professionals

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involved in the treatment is required. As per the existing guidelines, the best suitable approach can be used to reduce the perioperative cardiac complications.

KEY POINTS • • •

• • •

Perioperative major adverse cardiac events (MACE) are one of the most common causes which may lead to increased morbidity and mortality. At risk patients should be identified thorough history, physical examination and routine and special investigations as per existing guidelines. Associated risk should be stratified and the requirement for preoperative optimization by medical or interventional means should be determined to minimize the risk of perioperative cardiac complications. Assessment of cardiac risk requires a multidisciplinary approach involving treating physicians, surgeons and anesthesiologist. Detailed communications among the patient, family members of the patient, and all other ancillary departments of health care should be done. A combined decision can be taken as per the existing guidelines to determine the best approach to reduce the perioperative cardiac complications.

REFERENCES 1. Lee TH, Marcantonio ER, Mangione CM, et al. Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation. 1999;100(10):1043-9. 2. Weiser TG, Regenbogen SE, Thompson KD, et al. An estimation of the global volume of surgery: A modeling strategy based on available data. Lancet. 2008;372(9633):139-44. 3. Bakker EJ, Ravensbergen NJ, Poldermans D. Perioperative cardiac evaluation, monitoring, and risk reduction strategies in noncardiac surgery patients. Curr Opin Crit Care. 2011;17(5):409-15. 4. Rafiq A, Sklyar E, Bella JN, et al. Cardiac evaluation and monitoring of patients undergoing noncardiac surgery. Health Serv Insights. 2017;9:1178632916686074. 5. 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. 6. Bilimoria KY, Liu Y, Paruch JL, et al. Development and evaluation of the universal ACS NSQIP surgical risk calculator: A decision aid and informed consent tool for patients and surgeons. J Am Coll Surg. 2013;217(5):833-42. 7. Cohn SL. Evaluation of cardiac risk prior to noncardiac surgery. In: Saperia GM (Ed). Up To Date. [Online] Available from: http://www.uptodate.com/content/search. [Accessed August, 2018]. 8. Dripps RD. New classification of physical status. Anesthesiol. 1963;24:111. 9. Goldman L, Caldera DL, Nussbaum SR. Multifactorial index of cardiac risk in noncardiac surgical procedures. N Engl J Med. 1977;297(16):845-50. 10. Detsky AS, Abrams HB, Forbath N, et al. Cardiac assessment for patients undergoing noncardiac surgery. A multifactorial clinical risk index. Arch Intern Med. 1986;146(11):2131-4. 11. 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. 12. Bertges DJ, Goodney PP, Zhao Y, et al. The Vascular Study Group of New England Cardiac Risk Index (VSG-CRI) predicts cardiac complications more accurately than the Revised Cardiac Risk Index in vascular surgery patients. J Vasc Surg. 2010;52(3): 674-83.

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13. Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: Executive summary: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130(24):2215-45. 14. Kristensen SD, Knuuti J, Saraste A, et al. 2014 ESC/ESA Guidelines on non-cardiac surgery: cardiovascular assessment and management: The Joint Task Force on noncardiac surgery: Cardiovascular assessment and management of the European Society of Cardiology (ESC) and the European Society of Anaesthesiology (ESA). Eur Heart J. 2014;35(35):2383-431. 15. Alrezk R, Jackson N, Al Rezk M, et al. Derivation and validation of a geriatric‐sensitive perioperative cardiac risk index. J Am Heart Assoc. 2017;6(11):e006648. 16. Goldman L, Hashimoto B, Cook EF, et al. Comparative reproducibility and validity of systems for assessing cardiovascular functional class: Advantages of a new specific activity scale. Circulation. 1981;64(6):1227-34. 17. Payne CJ, Payne AR, Gibson SC, et al. Is there still a role for preoperative 12-lead electrocardiography? World J Surg. 2011;35(12):2611-6. 18. 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(5):505-9.

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CHAPTER

Anesthetic Implications of Pulmonary Hypertension

6

Mukul Chandra Kapoor

INTRODUCTION Pulmonary hypertension (PH) is common sequelae to disorders, such as cardiac dysfunction, pulmonary disease, and pulmonary thromboembolism. It is a clinical manifestation of an abnormal elevation in the pressures in pulmonary circulatory tree. PH is a serious ailment, with poor prognosis, and is associated with postoperative mortality rates of 1–18%.1 Noncardiac surgery, in patients with PH is associated with perioperative morbidity in 14–42% patients (heart failure, respiratory failure, acute kidney injury, arrhythmia, sepsis, and myocardial infarction).2,3 Pulmonary hypertension is an independent risk factor for perioperative complications and postoperative death, but the actual incidence of these complications are still not known.3

CLASSIFICATION Pulmonary hypertension was classified by the World Symposium on Pulmonary Hypertension 2013 into five categories (Box 1):4 1. Pulmonary arterial hypertension: Pulmonary arterial hypertension (PAH) is defined as an increase of mean pulmonary artery pressure (mPAP) to more than 25 mm Hg at rest, with normal pulmonary capillary wedge pressure (PCWP < 15 mm Hg) and pulmonary vascular resistance (PVR) more than three wood units, in the absence of pulmonary parenchymal or thromboembolic disease. There is no exercise criterion to this definition. Early diagnosis of PAH is difficult and screening programs in asymptomatic patients are feasible only in high-risk populations. Cardiac studies, such as echocardiography and right heart catheterization, are essential to confirm the diagnosis, with right heart catheterization being the gold standard. PAH involves progressive remodeling of the distal pulmonary arteries, resulting in elevated PVR, and finally leading to right ventricular (RV) failure. Idiopathic PAH is rare form of PAH with familial history or exposure to a risk factor. Heritable PAH may be associated with recognized gene mutations or be without any identified mutation. About 80% of familial PAH cases are linked to gene coding mutations for the bone morphogenetic protein

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Box 1: Classification of pulmonary hypertension based on recommendations of World Symposium on Pulmonary Hypertension (2013).13 ◆◆ Pulmonary arterial hypertension: −− Idiopathic −− Heritable −− Drug/toxin induced −− Associated with connective tissue disease, human immunodeficiency virus (HIV), portal hypertension, congenital heart disease, schistosomiasis −− Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis −− Persistent pulmonary hypertension (PH) of the newborn ◆◆ Pulmonary hypertension due to left heart disease: −− Left ventricular systolic dysfunction −− Left ventricular diastolic dysfunction −− Valvular disease −− Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies ◆◆ Pulmonary hypertension due to lung disease/hypoxia: −− Chronic obstructive pulmonary disease −− Interstitial lung disease −− Other pulmonary diseases with mixed restrictive and obstructive pattern −− Sleep-disordered breathing −− Alveolar hypoventilation disorder −− Chronic exposure to high altitude −− Developmental lung diseases ◆◆ Chronic thromboembolic pulmonary hypertension: −− Hematologic disorders: Chronic hemolytic anemia, myeloproliferative disorders, and splenectomy −− Systemic disorders: Sarcoidosis, pulmonary histiocytosis lymphangioleiomyo­ matosis −− Metabolic disorders: Glycogen storage disease, Gaucher disease, and thyroid disorders −− Others: Tumor obstruction, fibrosing mediastinitis, chronic renal failure, and segmental PH ◆◆ Pulmonary hypertension with unclear multifactorial mechanisms: −− Hematologic disorders −− Systemic disorders −− Metabolic disorders −− Others

receptor (BMPR) type II.5 A large number of drugs, such as aminorex/ fenfluramine derivatives and antileukemic drugs, are potentially associated with development of PAH.6,7 PAH due to connective tissue disorders, like systemic sclerosis and systemic lupus, accounts for 15–25% of all PAH cases in international registries.8,9 Nearly 6% of portal hypertension patients develop porto-PH. Liver transplant in these cases is associated to increased mortality with a 3-year survival of only 40%.10 With better diagnostic and therapeutic facilities most children with congenital heart disease survive to adulthood but nearly 10% still develop PAH.11 2. Pulmonary hypertension due to left heart disease: Left heart disease is the most common cause of PH presenting clinically. Elevated filling pressures of the

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left heart are reflected to the pulmonary circulation. PVR remains normal, so does the mPAP-PCWP gradient and the gradient between the diastolic PAP and the PCWP. A large number of these patients may develop severe PH despite not having severe heart disease. Most of them have pulmonary venous hypertension (PVH), with less severe pulmonary artery changes. Some patients progress to develop RV failure which correlates more closely to PAP rather than the left ventricular ejection fraction. 3. Pulmonary hypertension due to lung disease or hypoxia: Patients with parenchymal pulmonary disease (both obstructive and restrictive) or other diseases associated with hypoxia develop PH. Hypoxia causes vasoconstriction and increased PVR, which leads to thickening of the vasculature and polycythemia. The mechanisms responsible for hypoxic pulmonary vasoconstriction remain undefined. PAP in these patients correlate better with oxygen saturation than with spirometry parameters. Continuous oxygen therapy improves survival in patients hypoxemic at rest.12 These patients do not benefit from the use of targeted PAH therapies. 4. Chronic thromboembolic pulmonary hypertension: Acute pulmonary embolism may cause chronic thromboembolic PH in about 4% of all patients, as failure to fully resolve pulmonary embolism leads to raised PAP and RV failure. Although its treatment is surgical, surgical mortality is 4–5% even at experienced centers. In case, surgery is not an option or if the patient has residual PH after surgery, these patients usually benefit from medical therapy and balloon pulmonary angioplasty.13 5. Pulmonary hypertension due to unclear multifactorial origins: Other forms of PH with multiple pathophysiological mechanisms elevating PAPs.

PATHOPHYSIOLOGY In PAH small pulmonary arteries develop changes which range from medial hypertrophy, intimal proliferation and fibrosis, adventitial thickening and inflammatory infiltrates, to thrombotic lesions. There are reductions in prostacyclin (PGI2) levels while thromboxane levels are raised. Prostacyclin inhibits platelet aggregation and smooth muscle cell proliferation. Thromboxane A2 promotes vasoconstriction and platelet aggregation.14,15 Pulmonary vasoconstriction triggers the potassium-channels and endothelial dysfunction, reduced vasodilators release (nitric oxide and prostacyclin) and triggers vasoconstrictor release (endothelin-1).16 Imbalance in vasoconstriction/vasodilation, thrombosis, and arterial wall cell proliferation/remodeling causes PAH. Chemical mediators, such as proinflammatory cytokines (interleukin-1, interleukin-6, tumor necrosis factor, chemokines, serotonin, and growth factors), autoimmunity, and extracellular matrix proteolysis also contribute to the genesis of disease. Heritable PAH is due to gene mutations and these gene products influence the growth, differentiation, and apoptosis of pulmonary artery endothelium and smooth muscles.13 Heritable and idiopathic PAH predominantly afflicts females suggesting a role of additional factors, such as sexual hormones and pregnancy, in its genesis.17

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CLINICAL FEATURES The typical presenting symptoms of PH are nonspecific such as breathlessness, reduced functional status, and weakness. History suggestive of PH includes: light headedness on exertion; syncope; features of right heart failure, like anorexia, pedal edema, and abdominal distension; and presence of risk factors for PAH, like congenital heart disease, family history of PAH, connective tissue disorder, consumption of drugs causing PAH, and human immunodeficiency virus (HIV) infection. Syncope on exertion is an ominous development. Occasional patients present with hemoptysis, cough, or hoarseness (as the dilated pulmonary arteries compress the left recurrent laryngeal nerve compression). When PH is incidentally encountered on routine testing, clues suggesting its presence must be recognized and its etiology/type determined. Clinical signs of PH, like raised systolic PAP and enlarged pulmonary arteries, are only elicited by imaging modalities, like echocardiography and chest computed tomography (CT) scan. Features on clinical examination of patients with PH are summarized in Table 1. Clinical examination18 reveals: • Raised jugular venous pressure (JVP) with prominent “a” and “v” waves—due to RV stiffness and tricuspid regurgitation (TR) respectively • Kussmaul’s sign (inspiratory rise in JVP) • Parasternal heave due to RV hypertrophy • Loud second heart sound (P2)—the pulmonic valve shuts more vigorously due to high PAP • Audible third heart sound (S3 and/or S4)—right sided gallop is more common • Tricuspid regurgitation murmur • Evidence of right heart failure—peripheral edema, liver enlargement, and ascites.

DIAGNOSTIC EVALUATION (TABLE 2) Electrocardiograph shows right axis deviation (QRS axis > 110); right bundle branch block; signs of RV hypertrophy with strain pattern (tall R-wave, STTable 1: Signs and symptoms of pulmonary hypertension. Symptoms

• • • • • •

Exertional dyspnea Exertional chest pain or lightheadedness Chest pounding during exertion Exertional syncope Cough Hemoptysis

Signs

• • • • • • •

Loud second heart sound (P2) Right ventricular heave Murmurs of tricuspid regurgitation and/or pulmonic insufficiency Right-sided gallops Neck vein distention Right ventricular impulse or heave Raynaud’s phenomenon

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Table 2: Diagnostic evaluation of pulmonary hypertension. Routine

• • • • • • •

Complete blood count (CBC), sedimentation rate Liver function tests Thyroid function tests Connective tissue disorder screen Human immunodeficiency virus (HIV) antibody test Electrocardiogram Chest X-ray

Pulmonary function

• • • • •

Spirogram, lung volume, and DLCO Arterial blood gas Exercise oximetry Ventilation/perfusion lung scan Polysomnogram if features of obstructive sleep apnea

Cardiac function

• Transthoracic echocardiogram with Doppler • Transesophageal or stress echocardiogram if needed • Radionuclide or magnetic resonance imaging (MRI) scan, computed tomography (CT) scan

Functional grading

• 6-minute walk test • New York Heart Association Classification

Cardiac catheterization

• Chamber and pulmonary artery (PA) pressures • Oxygen saturation step-up or vasodilator trial • Left heart catheterization if coronary artery disease is suspected or low ejection fraction

depression and T-inversion in the precordial leads—R-wave taller than 5 mm or R:S ratio > 1 in V1); and p-pulmonale (high P-waves in leads II and V1—P wave > 2.4 mm in lead II). Chest radiography shows decreased retrosternal space in the lateral view due to RV hypertrophy; distended central pulmonary arteries; and pruning of peripheral pulmonary vasculature.18,19 Pulmonary hypertension is often first diagnosed on transthoracic echocardiography. Echocardiography examination, including Doppler and tissue Doppler imaging, is crucial to assess PH.20 The RV size, RV function and the systolic pulmonary arterial pressure (SPAP) must be evaluated by echocardiography. Doppler estimation of the velocity of the tricuspid or pulmonic regurgitant jet is done to calculate the PAP. Based on PAP, PAH is graded as mild (mPAP of 26–35 mm Hg); moderate (36–45 mm Hg); and severe (>45 mm Hg). Echocardiography should also evaluate severity of TR; volume status based on inferior vena cava dimensions; PVR; presence of pericardial effusion; and differentiate PAH from PVH.13 With advanced disease, RV hypertrophy occurs; RV dysfunction occurs; paradoxic septal motion may be seen; and pulmonic valve motion may be abnormal. In addition to evaluating the PH and its severity, echocardiogram is diagnostic of the cause of PH, such as left heart disease and shunts. Clinically it is important to determine whether patient has PAH or PH due to heart failure with preserved ejection fraction (HFpEF). Presence of pericardial effusion, right atrial (RA)

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enlargement, and reduced tricuspid annular plane systolic excursion (TAPSE), in echocardiography, predicts a poor prognosis.21 Measurement of chamber pressures, PAP, and PCWP by cardiac catheterization confirms the diagnosis of PH. Diagnosis of PVH can be confirmed after the measurement of PCWP. HFpEF may be present in a patient with a normal PCWP. Reversible element of the PAH and determination of responders to vasodilator therapy can be determined during cardiac catheterization. Vasodilator testing determines responders to calcium-channel antagonists and helps determine prognosis. Vasodilator responsiveness is usually assessed by administration of inhaled nitric oxide (iNO). A good therapeutic response is predicted if there is a decrease in mPAP to ≤ 40 mm Hg; mPAP decreases ≥ 10 mm Hg; and the cardiac output remains unchanged or increases after administration of iNO.22 Additional tests should be performed to exclude secondary factors and diagnose comorbid conditions. The recommended investigations are hemogram; arterial blood gases; pulmonary function tests; radionuclide lung scan; connective tissue disorder screen; liver function tests; thyroid function tests; and HIV testing. A polysomnogram is indicated if history is suggestive of obstructive sleep apnea. In the 6-minute walk test, the patient is made to walk for 6 minutes, on a measured course, while monitoring the oxygen saturation to determine the functional capacity and the prognosis. The distance traversed in the subsequent tests, during follow-up, helps assess response to therapy. Patients are considered to have severe exercise limitation if they walk less than 250–300 meters. The disease can be assessed by computed tomographic angiography too but its reliability is not established.

MEDICAL THERAPY Diuretics and anticoagulants are the mainstay in PH therapy. Diuretics reduce the RV preload. Targeting secondary factors: Secondary contributing factors should be identified and targeted. PH associated with severe polycythemia responds to bloodletting. PH associated with obstructive sleep apnea responds to continuous positive airway pressure. Patients with reversible airway obstruction should be administered bronchodilators. Patients with RV dysfunction and edema need salt restriction, diuretics, and digoxin. Oxygen should be supplemented in patients with chronic hypoxemia. Anticoagulation: Vitamin K antagonists (warfarin) should be administered to patients with severe primary or secondary PAH to prevent pulmonary thrombosis and venous thromboembolism. A target international normalized ratio is 1.5–2.5 is recommended.13,23 Patients with associated forms of PAH may not benefit from anticoagulation.24 Vasodilator therapy: The goal of vasodilator therapy is RV afterload reduction and reversal of pulmonary artery remodeling. Till recently, calcium channel antagonists were considered as the only category of vasodilators associated with

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improvement in survival. In patients exhibiting an acute response to vasodilator testing, calcium-channel antagonists treatment is very effective. Nifedipine, diltiazem, and amlodipine are commonly used. PAH patients have reduced prostacyclin synthase expression in endothelial cells and thus inadequate levels of vasodilator prostacyclin (which also has antiproliferative effects).25 Prostanoids (epoprostenol, treprostinil, and iloprost) are the mainstay of PAH therapy now.26,27 Nitric oxide pathway: Nitric oxide increases cyclic guanosine monophosphate (cGMP) levels which is a potent vasodilator of the pulmonary circulation. Phosphodiesterase (PDE) type 5 inhibitors, sildenafil, and tadalafil, are currently being tried in PH therapy as they inhibit cGMP degradation.28 Soluble guanylate cyclase stimulators (Riociguat) increase the sensitivity to cGMP by a directly stimulating soluble guanylate cyclase.29 Endothelin pathway: Endothelin-1 is a potent vasoconstrictor and cell proliferation stimulator. Its levels are increased in PAH and thus therapy has been directed to target it. Endothelin receptor blockers selectively block endothelin-A receptors or both A and B receptors. Bosentan is a popular nonselective endothelin-A and -B receptor antagonist which reduces PVR and slows down disease progression. 30 Ambrisentan 31 and Macitentan 32 are newer endothelin-1 antagonists approved for use in PAH.

ANESTHETIC IMPLICATIONS Perioperative Risk Factors Perioperative risk is dependent on the type of surgery. Higher risk surgeries in patients with PH include those associated with major hemorrhage; venous air/ carbon-dioxide/fat/cement embolism; systemic inflammatory response; and lung resection.33 Risk factors contributing to morbidity and mortality in PH are: New York Heart Association (NYHA) functional class > 2; 6-minute walk distance < 300 m; coronary artery disease; previous pulmonary embolism; chronic renal failure; RV hypertrophy and dysfunction; high mPAP; emergency surgery; intermediate/ high-risk surgery; anesthesia of more than 3 hours duration; and vasopressor use during surgery.3

Intraoperative Management Mild to moderate rise in PVR preoperatively may not cause RV dysfunction but an acute rise in PVR may precipitate RV failure. The RV oxygen supply-demand relationship is disturbed after the intraoperative interventions/events. Mechanical ventilation, positive end-expiratory pressure, hypercarbia, acidosis, pressor response to laryngoscopy/intubation, inadequate analgesia, patient positioning, pneumoperitoneum, and restricted diaphragm excursion significantly increase PVR and thus RV afterload.3 Inhaled anesthetics such as isoflurane, desflurane, and sevoflurane markedly reduce RV contractility.34 Isoflurane and desflurane increase the PVR but sevoflurane does not change it.35 Nitrous oxide significantly increases the PVR.36 Up to 1 MAC of all volatile anesthetic agents can be administered

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without any adverse effects on PAP and PVR.37 Supplementary oxygen must be administered to all patients. Perioperative normothermia must be ensured to prevent pulmonary vasoconstriction and V/Q mismatch due to hypothermia. Homeometric autoregulation preserves the mechanical symbiosis between RV and the pulmonary circulation and thus helps the RV adjust to the rise in afterload. Central neuraxial blockade in the upper thoracic region blocks the cardiac sympathetics causing dysfunction of the RV homeometric autoregulation, which can lead to a severe fall in cardiac output and right heart failure.38 The myocardial oxygen supply-demand balance is disturbed during anesthesia and surgery. If systemic hypotension occurs, the perfusion of the RV gets restricted by the high RV pressures and systolic wall tension.39 Hemodynamic goals: The perioperative hemodynamic goals3 are to maintain: • Systolic blood pressure ≥ 90 mm Hg and at least 40 mm Hg more than SPAP • Mean arterial pressure (MAP) ≥ 65 and at least 20 mm Hg more than mPAP • mPAP < 35 mm Hg or at least 25 mm Hg less than MAP • PVR/SVR ratio < 0.5 or maintain preoperative PVR/SVR ratio • RA pressure—lowest possible to maintain MAP > 65 mm Hg • Cardiac index ≥ 2.2 L/min/m2. Monitoring: Invasive arterial monitoring facilitates early detection of hemodynamic instability and facilitates sampling for blood gas estimation. Central venous pressure monitoring indirectly reflects RV preload and functional capacity of RV. Transesophageal echocardiography monitoring is recommended in patients with severe PH and in patients with right heart failure. Although pulmonary artery catheter monitoring is disputed, it can provide direct measurement of PAP, PVR and thus helps guide fluid management and drug therapy.3 Anesthetic management is directed toward modulation of the RV afterload, optimizing RV contractility and preload. Thus, RV dysfunction is managed with volume loading, maintaining atrioventricular rhythm, inotropes, pulmonary vasodilators, systemic vasoconstrictors, and mechanical assist devices. The selection of the therapeutic regimen depends on the PVR and the contractile state of the ventricles. Preload optimization: Volume loading benefits depend on the contractile state of the patients RV. RV output when RA pressure is increased to 10–14 mm Hg but a higher volume load reduces the output. Volume expansion is also detrimental if the afterload is high. Use of vasodilators, like nitroglycerine, to reduce the RA pressure increases the output. RV contractility augmentation: The goal of inotropic therapy is to increase RV contractility, and thereby augment LV filling and cardiac output. β-adrenergic receptors agonists used for myocardial stimulation include dopamine, epinephrine, norepinephrine, dobutamine, and isoproterenol. β-adrenergic stimulation increases cyclic adenosine monophosphate (cAMP) in the cytosol and activates cAMP-dependent protein kinase, increasing contractility by increasing calcium influx across the sarcolemma and calcium uptake by the sarcoplasmic reticulum.

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β1 selective agonists (like dobutamine, low dose adrenaline, and isoprenaline) augment RV systolic performance, vasodilate the pulmonary vasculature and maintains LV preload. Positive lusitropic effects of inotropes improve diastolic function by augmenting diastolic relaxation. PDE III isoenzyme inhibitors (amrinone, milrinone, and enoximone) exhibit positive inotropy, vasodilation of both systemic and pulmonary circulation, and positive lusitropy. PDE III isoenzyme inhibitors do not increase the heart rate. They increase dp/dt (max) of the left ventricle (LV), reduce the LV end-diastolic pressure, and increase LV stroke work. They decrease the afterload of both the ventricles and improve their diastolic filling by lusitropic effect, without significantly increasing myocardial oxygen consumption. Vasoconstrictors noradrenaline and vasopressin increase the right coronary artery perfusion, reduce the PVR/systemic vascular resistance (SVR) ratio and thus can enhance RV performance.40,41 Right ventricular afterload reduction: Sodium nitroprusside and nitroglycerine are commonly used to reduce the PVR and unload the RV. Vasodilators reduce the RV work; improve pulmonary perfusion to reduce ventilation perfusion mismatch; and inhibit hypoxic pulmonary vasoconstriction. However, decreases in LV preload and afterload with sodium nitroprusside can result in systemic hypotension. New strategies: Prostacyclin (PGI2) and prostaglandin El (PGE1), released from the vascular endothelium and smooth muscle, have pulmonary vasodilator properties and thus can effectively reduce PVR and RV afterload. However, reduction in SVR and systemic blood pressure, with their parenteral use, may decrease myocardial perfusion and cause ischemia. Aerosolized PGI2 or PGE1 have been used a more selective pulmonary vasodilation to prevent fall in SVR.42 Inhaled nitric oxide 40 ppm induces smooth muscle relaxation and is more effective in small resistance vessels, at both pre- and postcapillary levels, rather than larger capacitance vessels. iNO decreases the PVR and PAP in proportion to the level of baseline pulmonary vasoconstriction. Its response is however variable and it may be less effective in patients with a fixed increase in PVR, as in patients with valvular heart disease. Rebound PH may however be seen on discontinuation of iNO.43

Postoperative Management Patients with PH should be intensively monitored postoperatively and their pain managed actively. Postoperative morbidity and mortality may result from fluid shifts, increase in arrhythmias, PVR, and pulmonary thromboembolism. Respiratory failure and right heart failure are major contributors to morbidity. Atrial tachyarrhythmias may cause right heart failure and death. Blood lost must be replaced as cardiac output in PH is “preload-dependent”. Ongoing vasodilator therapies must be continued.

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CONCLUSION Pulmonary hypertension comprises a number of diseases, which increase pressure in the pulmonary arteries by different mechanisms. Transthoracic echocardiogram is the investigation of choice for screening, assessing suspected PH, and for grading its severity. Pulmonary hypertension is associated with perioperative morbidity and mortality in noncardiac surgery and thus a thorough knowledge of the pathobiology, disease severity, and therapeutic options available is essential to deliver optimal outcomes. The anesthetic goals are to maintain the adequate hemodynamics, modulation of the TV afterload and optimizing RV contractility and preload. During the postoperative phase, patients must be continuously monitored and adequate analgesic therapy administered.

KEY POINTS • •

•

•

Pulmonary hypertension is sequelae of a number of diseases, which increase the pulmonary artery pressure by different mechanisms. Pulmonary hypertension is associated with perioperative morbidity and mortality in noncardiac surgery. So, a thorough knowledge of the pathobiology, disease severity and therapeutic options available is essential. The anesthetic goal is to maintain the adequate hemodynamics while preventing rise in pulmonary vascular resistance, modulation of the right ventricular afterload and optimizing right ventricular contractility and preload. During the postoperative period, monitoring should be continued and good analgesia ensured.

REFERENCES 1. Ling Y, Johnson MK, Kiely DG, et al. Changing demographics, epidemiology, and survival of incident pulmonary arterial hypertension. Results from the Pulmonary Hypertension Registry of the United Kingdom and Ireland. Am J Resp Crit Care Med. 2012;186:790-6. 2. Lai HC, Lai HC, Wang KY, et al. Severe pulmonary hypertension complicates postoperative outcome of non-cardiac surgery. Br J Anaesth. 2007;99:184-90. 3. Pilkington SA, Taboada D, Martinez G. Pulmonary hypertension and its management in patients undergoing non-cardiac surgery. Anaesthesia. 2015;70:56-70. 4. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D34-41. 5. Cogan JD, Pauciulo MW, Batchman AP, et al. High frequency of BMPR2 exonic deletions/duplications in familial pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006;174:590-8. 6. Gurtner HP. Aminorex and pulmonary hypertension. A review. Cor Vasa. 1985;27: 160-71. 7. Souza R, Humbert M, Sztrymf B, et al. Pulmonary arterial hypertension associated with fenfluramine exposure: report of 109 cases. Eur Respir J. 2008;31:343-8. 8. Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest. 2010;137:376-87. 9. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006;173:1023-30.

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10. Krowka MJ, Miller DP, Barst RJ, et al. Portopulmonary hypertension: a report from the US based REVEAL Registry. Chest. 2012;141:906-15. 11. Engelfriet PM, Duffels MG, Moller T, et al. Pulmonary arterial hypertension in adults born with a heart septal defect: the Euro Heart Survey on adult congenital heart disease. Heart. 2007;93:682-7. 12. Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Ann Intern Med. 1980;93:391-8. 13. McLaughlin VV, Shah SJ, Souza S, et al. Management of Pulmonary Arterial Hypertension. J Am Coll Cardiol. 2015;65:1976-97. 14. Christman BW, McPherson CD, Newman JH, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med. 1992;327:70-5. 15. Wilkins MR. Pulmonary hypertension: the science behind the disease spectrum. Eur Respir Rev. 2012;21:19-26. 16. Humbert M, Morrell NW, Archer SL, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43:13S-24S. 17. Soubrier F, Chung WK, Machado R, et al. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol. 2013;62:D13-21. 18. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association. J Am Coll Cardiol. 2009;53:1573-619. 19. Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30:2493-537. 20. Rudski LG, Lai WW, Afilalo J, et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr. 2010;23:685-713, quiz 786-8. 21. Raymond RJ, Hinderliter AL, Willis PW, et al. Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension. J Am Coll Cardiol. 2002;39:1214-9. 22. Sitbon O, Humbert M, Jais X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005;111:3105-11. 23. Fuster V, Steele PM, Edwards WD, et al. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation. 1984;70:580-7. 24. Olsson KM, Delcroix M, Ghofrani HA, et al. Anticoagulation and survival in pulmonary arterial hypertension: results from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA). Circulation. 2014;129: 57-65. 25. Tuder RM, Cool CD, Geraci MW, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med. 1999;159:1925-32. 26. Elliot CA, Stewart P, Webster VJ, et al. The use of iloprost in early pregnancy in patients with pulmonary arterial hypertension. Eur Respir J. 2005;26:168-73. 27. Hollatz TJ, Musat A, Westphal S, et al. Treatment with sildenafil and treprostinil allows successful liver transplantation of patients with moderate to severe portopulmonary hypertension. Liver Transplant. 2012;18:686-95. 28. Galie N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009;119:2894-903.

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29. Grimminger F, Weimann G, Frey R, et al. First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J. 2009;33:785-92. 30. Galie N, Rubin L, Hoeper M, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet. 2008;371:2093-100. 31. Galie N, Olschewski H, Oudiz RJ, et al. Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies (ARIES) Group. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double blind, placebocontrolled, multicenter, efficacy (ARIES) study 1 and 2. Circulation. 2008;117:3010-9. 32. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369:809-18. 33. McGlothlin D, Ivascu N, Heerdt PM. Anesthesia and pulmonary hypertension. Prog Cardiovasc Dis. 2012;55:199-217. 34. Kerbaul F, Rondelet B, Motte S, et al. Isoflurane and desflurane impair right ventricularpulmonary arterial coupling in dogs. Anesthesiology. 2004;101:1357-62. 35. Kerbaul F, Bellezza M, Mekkaoui C, et al. Sevoflurane alters right ventricular performance but not pulmonary vascular resistance in acutely instrumented anesthetized pigs. J Cardiothorac Vasc Anesth. 2006;20:209-16. 36. Schulte-Sasse U, Hess W, Tarnow J. Pulmonary vascular responses to nitrous oxide in patients with normal and high pulmonary vascular resistance. Anesthesiology. 1982;57:9-13. 37. Preckel B, Eberl S, Fraessdorf J, et al. Management of patients with pulmonary hypertension. Anaesthesist. 2012;61:574-87. 38. Missant C, Rex S, Claus P, et al. Thoracic epidural anaesthesia disrupts the protective mechanism of homeometric autoregulation during right ventricular pressure overload by cardiac sympathetic blockade: a randomised controlled animal study. Eur J Anaesthesiol. 2011;28:535-43. 39. Van Wolferen SA, Marcus JT, Westerhof N, et al. Right coronary artery flow impairment in patients with pulmonary hypertension. Eur Heart J. 2008;29:120-7. 40. Kwak YL, Lee CS, Park YH, et al. The effect of phenylephrine and norepinephrine in patients with chronic pulmonary hypertension. Anaesthesia. 2002;57:9-14. 41. Leather HA, Segers P, Berends N, et al. Effects of vasopressin on right ventricular function in an experimental model of acute pulmonary hypertension. Crit Care Med. 2002;30:2548-52. 42. Hache M, Denault AY, Belisle S, et al. Inhaled prostacyclin (PGI2) is an effective addition to the treatment of pulmonary hypertension and hypoxia in the operating room and intensive care unit. Can J Anaesth. 2001;48:924-9. 43. Hurford WE, Bigatello LM. NO-body’s perfect. Anesthesiology. 2002;96:1285-7.

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Cerebral Oxygenation Kiran Jangra, Kajal Jain

INTRODUCTION Brain is the organ with high energy consumption that needs energy not only to maintain cellular integrity but also for the electrical activity of neurons. Brain utilizes predominantly glucose as the main substrate, and ketone bodies or lactate as alternate substrates during shortage of availability of glucose. 1,2 Under normal physiological circumstances, cerebral metabolic rate of oxygen (CMRO2) is approximately 3.5 mL/100 g tissue/min or 150–160 mmol/100 g/min. On an average, human brain tissue partial pressure of oxygen (pO2) varies from 10 mm Hg to 40 mm Hg where pO2 below 15–20 mm Hg is considered as critical for brain tissue. At mitochondrial level, pO2 as low as 1.5 mm Hg is adequate to sustain cytochrome c oxidase (CCO) reaction.3 The cerebral metabolism is deranged in various pathological states that results in the altered brain functions and neuronal death. Cerebral hypoxia is a common secondary insult that aggravates the existing brain injuries. It is vital to understand the normal cerebral oxygenation, its monitoring, and clinical utility in various pathological conditions. There are various intracranial insults that can compromise cerebral oxygenation. These include the conditions which either increase cerebral oxygen demand by increasing CMRO2 or reduce the oxygen supply to the brain by hypoxia or hypoperfusion.

APPLIED PHYSICS Cerebral Metabolism and Oxygenation In the presence of oxygen, glucose produces two adenosine triphosphate (ATP) molecules and pyruvate. Pyruvate enters in the TCA (Krebs) cycle further produces 34 ATP molecules. In the absence of oxygen, the pyruvate enters in the anaerobic glycolysis which produces only two ATP molecules, lactate, and H+ (hydrogen) ion. This results in intracellular-cellular acidosis that blocks the action of various enzymes and ion transport. Therefore, the end result of cerebral hypoxia is intracellular acidosis and cell death. Severe ischemia cuts off the supply of both oxygen as well as glucose that result in more severe and accelerated cell death.

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Consequences of Low Blood Flow When blood flow decreases beyond the autoregulation capacity, the first change to appear at tissue level is the increase in oxygen extraction and later there is a decrease in CMRO2. This concept forms the basis of monitoring oxygenation of venous blood, as increase in oxygen extraction manifests as low cerebral venous saturation. If blood flow continues to fall further, synaptic failure occurs that produces isoelectric electroencephalogram (EEG). Till this point, neurons are viable but further decrease in blood flow results in membrane failure due to inactivity of ion pumps leading to neuronal cell death.4 In this situation, cerebral venous oxygenation will remain high as there is no neuronal activity for uptake of oxygen. Hence, monitoring of cerebral oxygenation plays an important role in detection of cerebral hypoxia and timely intervention.

MONITORING OF CEREBRAL OXYGENATION Various monitors available for monitoring cerebral oxygenation include saturation of jugular venous blood [jugular venous oxygen saturation (SjVO2), measures global oxygenation], near-infrared spectroscopy (NIRS, measures regional oxygenation), and brain tissue oxygenation (PbtO2, measures local oxygenation).

Jugular Venous Oxygen Saturation Jugular venous oxygen saturation was the first bedside tool for cerebral oxygenation monitoring. Technical Aspects

Jugular venous oxygen saturation is monitored by placing a catheter in the retrograde direction (toward brain) through internal jugular vein (IJV) and tip of the catheter is located in the jugular bulb. In most of the cases, dominant internal jugular vein is chosen and usually right side is dominant. It is measured either through intermittent blood sampling or continuously by using a fiberoptic catheter. The interpretation is based on the concept of oxygen supply and demand (Fig. 1). If supply falls shorter than the demand either because of increased metabolism or decreased perfusion, results in reduced oxygen saturation of cerebral venous blood.5 Another derived variable, arterial to jugular venous oxygen concentration difference is also widely studied in the assessment of adequacy of cerebral blood flow (CBF). The samples can get contaminated by blood from the extracranial circulation when tip of the catheter is not appropriately placed. The catheter tip must lie above the lower border of the first cervical vertebra on the lateral cervical spine radiograph, as below this level facial vein joins the IJV. Care should also be taken while withdrawing the samples, as rapid aspiration of blood (>2 mL/min) can again results in contamination of blood from extracranial vessels (facial vein) even if the catheter tip is accurately placed.

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Fig. 1: Principle of measuring jugular venous oxygen saturation (SjVO2). SjVO2 is reduced in the situation with either reduced blood supply or increased demand. (CBF: cerebral blood flow; CMRO2: cerebral metabolic rate of oxygen)

Indications

Jugular venous oxygen saturation monitoring is being used in a variety of neurosurgeries and non-neurosurgeries, especially cardiac surgeries, where brain is at risk of ischemia. Its major role is in neurointensive care as a tool in multimodal monitoring, where it is used to detect impaired cerebral perfusion and guide the therapies to optimize cerebral perfusion pressure (CPP) including augmentation of blood pressure, decrease in intracranial pressure (ICP), and optimizing ventilation. Thresholds for Treatment and Evidence

The normal range of SjVO2 values is 55–75% and values below 50% (cerebral hypoperfusion), and above 85% (hyperemia) are associated with poor outcome. Although SjVO2 below 50% indicates cerebral ischemia, normal or higher values do not reliably exclude regional ischemia. Even though the Brain Trauma Foundation (BTF) cites level 3 evidence to maintain the SjVO2 more than 50% after traumatic brain injuries (TBIs), but there are no interventional trials which confirms its effect on outcome.6 Nowadays, newer techniques of monitoring cerebral oxygenation are superseding the SjVO2.

Near-infrared Spectroscopy Near-infrared spectroscopy monitors the regional cerebral oxygen saturation (rScO2) continuously. It is a noninvasive monitor with high temporal and spatial

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resolution.7,8 Although it was first described in 1977 to detect cerebral hypoxia/ ischemia but its utility is still not translated from research to clinical use. Technical Aspects

Near-infrared spectroscopy is based on the fact that the light in the NIR spectrum (700–950 nm) traverses through the biological tissues and several molecules (chromophores) have a distinct absorption spectra. When it passes through brain tissues, NIR light is transmitted and absorbed differentially by different chromophores such as oxyhemoglobin and deoxyhemoglobin. This is known as reflectance spectroscopy where light source emits light and a detecting device, placed a few centimeters apart, detects the reflected light. In adults, light source and detector are placed on the same side of brain that allows the examination of only superficial cerebral cortex (Fig. 2). The derived values detect the relative proportions of oxy- and deoxyhemoglobin within the area of evaluation and is displayed as a simple percentage value. NIR light passes through arterial, venous, and capillary blood within the area of evaluation. Hence, it derives the saturation originating from all these three components. Commercially available oximeters have incorporated a fixed ratio of arterial and venous components (A:V) into their algorithms, either 30:70 or 40:60. In addition, rScO2 is also affected by other physiological variables such as arterial oxygen saturation, partial pressure of carbon dioxide in arterial blood (PaCO2), hematocrit, systemic blood pressure, and cerebral blood volume. The signals of rScO2 are also contaminated by underlying abnormal collection of blood intracranially or extracranially and underlying sinuses.7,9 Newer NIRS technology increases the intracranial specificity. In addition to oxy-/deoxyhemoglobin, newer technology of NIRS also measures

Fig. 2: The principle of near-infrared spectroscopy (NIRS). NIRS sensor is placed over the surface. In adult patients, both light emitter and detector are on the same side kept nearly 5 cm apart.

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the other chromophores, such as CCO which is the final electron acceptor of electron transport chain during oxidative metabolism. The oxidation of CCO reflects the balance between energy supply and demand. In association with rScO2, CCO may determine the cerebral ischemic thresholds.8 Indications

Near-infrared spectroscopy-based cerebral oximetry is clinically used during neurosurgeries and non-neurosurgeries such as carotid surgery and cardiac surgery to assist cerebral protection.10 The accuracy and reproducibility of NIRS are comparable to other modalities in detecting of cerebral ischemia with added advantages of noninvasiveness, simplicity, and good temporal resolution.11 The effect of NIRS-targeted management on the outcome is yet to be determined.12 NIRS values may decrease during hypotension in beach chair position but such desaturations were not found to increase the incidence of postoperative cognitive dysfunction and serum biomarkers of brain injury.13 Thresholds for Treatment and Evidence

The “normal” values of rScO2 usually ranges between 60% and 75%, and is better used as a trend monitor rather than absolute value as there is a substantial intra- and interindividual variation. There is insufficient data to conclude that interventions targeting rScO2 are effective in preventing postoperative cognitive dysfunction or stroke. Reductions in rScO2 values vary between 5% and 25% from baseline are reported as potential ischemic thresholds.8 Current evidence is insufficient to support that NIRS-guided treatment protocols helps in improving the outcome.

Brain Tissue Oxygen Tension Brain tissue oxygenation monitoring is being increasingly incorporated into multimodal neuromonitoring in patients with raised ICP. Technical Aspects

Brain tissue oxygenation monitoring probes measures the pO2 at tissue level. There are two types of probes available commercially, one is Licox system and another is Neurotrend. The Licox system incorporates a closed polarographic (Clark-type) cell with reversible electrochemical electrodes.14 In this system, oxygen present in the brain tissues diffuses and crosses the semipermeable membrane where it is reduced by a gold polarographic cathode that produces an electrical current flow which is directly proportional to the oxygen tension in the tissues (Fig. 3).14 This process consumes oxygen and is temperature dependent. In contrast, the Neurotrend comprises of three optical sensors for measuring partial pressure of oxygen and carbon dioxide (pO2 and pCO2), and pH along with a thermocouple contained within the microporous polyethylene tube (Fig. 4). The pO2 is measured by quenching (reduction) of intensity of optical emission from a fluorescent indicator (ruthenium) in the presence of oxygen. This process does not consume oxygen or affect the local oxygen level. The pH and pCO2 sensor works on optical absorption of light transmitted through an indicator (phenol red).

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Fig. 3: Schematic representation of the brain tissue oxygen monitor by Licox system.

Fig. 4: Schematic representation of the brain tissue oxygen monitor by Neurotrend system.

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Brain tissue oxygenation probes are placed in the most vulnerable areas of brain tissue such as, tissues immediately surrounding a lesion/hematoma/ contusion, or in appropriate vascular territories in the patients of aneurysmal subarachnoid hemorrhage (aSAH). Probe placement in such precise position may be technically very challenging and sometimes it may be impossible to achieve. In such cases and cases of diffuse brain injuries, the probe is placed in the normalappearing nondominant frontal subcortical white matter. Position of the probe should be confirmed with a computed tomography (CT) scan. The initial 1-hour period after probe placement is “run-in” period during which sample is unreliable due to local trauma following insertion and defying its use during intraoperative period. The probe functioning and responsiveness should be tested immediately following insertion and daily thereafter using “oxygen challenge” (100% inspired oxygen for approximately 20 minutes). Brain tissue oxygenation measurement is affected by the interaction of various local factors affecting cerebral oxygen supply and demand, the relative proportion of vessels in the area of interest, and oxygen diffusion gradients of tissues. Hence, it is best considered as the monitor of cellular function rather than a simple monitor of cerebral oxygenation. Indications

Despite conflicting evidence, PbtO2 monitoring is used in the management of severe TBI and to detect vasospasm in aSAH along with transcranial Doppler and radiological studies.6,15,16 It has also been used to identify the optimal cerebral oxygenation targets in patients with intracranial hematoma, and also to identify of patients who may benefit from surgical decompression for refractory intracranial hypertension.17 Thresholds for Treatment and Evidence

Normal range of brain PbtO2 lies between 20 mm Hg and 35 mm Hg (2.66–4.66 kPa). There is a wide variation in the ischemic threshold for PbtO2. A few authors defined it as 10–15 mm Hg (1.33 kPa and 2.0 kPa) while BTF recommends that if PbtO2 falls below 15 mm Hg, the brain resuscitation should be instituted.6,14 A few other studies recommend that the intervention should be started if PbtO2 falls below 20 mm Hg (2.66 kPa).15,18 In addition to the exact values of PbtO2, duration of low values and chronological trends are also important parameters to predict the outcome after TBI.19 A few observational studies suggest that there is a potential benefit of using PbtO2-guided therapy along with standard ICP/ CPP-guided management of TBI while there is a limited evidence for any benefit in pathologies other than brain injury.18 The interventions to treat brain tissue hypoxia are still unclear. Brain hypoxia is influenced by systemic blood pressure, and several other physiological factors including PaO2, PaCO2, and hemoglobin concentration.20 In fact, reversal of hypoxia with a given intervention may be associated with reduced mortality.18 Its utility is limited by the fact that it reflects local tissue oxygenation, just in vicinity of the probe and may not pick up the ischemia beyond that.

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Flowchart 1: Cerebral oxygenation-targeted therapy.

(CPP: cerebral perfusion pressure; SaO2: oxygen saturation; ICP: intracranial pressure)

CONCLUSION The cerebral metabolism is highly dependent of continuous supply of the metabolic substrates. In pathological states, there is a mismatch between energy supply and demand that favors anaerobic metabolism. With the use of advanced technology, this mismatch can be identified and appropriate measures can be implemented so as to protect the brain from permanent damage. Currently, many of these monitoring tools are available but have a limited role in clinical settings. Still there are a few studies to confirm that therapeutic interventions targeting cerebral oxygenation can improve the outcome of neurological patients. The practical utility of cerebral oxygenation monitors is outlined in Flowchart 1.

KEY POINTS •

•

• • •

Brain is an organ with very high metabolic rate and requires energy not only for cellular maintenance but also for the flow of electric current in the neurones. High metabolism makes it highly vulnerable to damage during the pathological states when there is an absolute or relative deficiency of cerebral blood flow. Cerebral oxygenation monitors work on the principle of balance between cerebral supply and demand of blood flow. There are both invasive and noninvasive monitors currently available to monitor cerebral oxygenation. Strategies directing the cerebral oxygenation promise to improve patient’s outcome, but the literature till date is conflicting.

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REFERENCES 1. Magistretti PJ, Pellerin L. Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging. Phil Trans R Soc Lond B Biol Sci. 1999;354: 1155-63. 2. Larrabee MG. Lactate metabolism and its effects on glucose metabolism in an excised neural tissue. J Neurochem. 1995;64:1734-41. 3. Masamoto K, Tanishita K. Oxygen transport in brain tissue. J Biomech Eng. 2009;131: 074002. 4. Ellis JE, Yocum GT, Ornstein E, et al. Cerebral and spinal cord blood flow. In: Cottrell JE, Patel E (Eds). Cottrell and Patel’s Neuroanesthesia, 6th edition. New York: Elsevier; 2017. pp. 19-58. 5. Schell RM, Cole DJ. Cerebral monitoring: Jugular venous oximetry. Anesth Analg. 2000;90:559-66. 6. The Brain Trauma Foundation, The American Association of Neurological Surgeons. The Joint Section on Neurotrauma and Critical Care. J Neurotrauma. 2007;24:S1-106. 7. Ghosh A, Elwell C, Smith M. Review article: Cerebral near-infrared spectroscopy in adults: A work in progress. Anesth Analg. 2012;115:1373-83. 8. Smith M. Shedding light on the adult brain: A review of the clinical applications of nearinfrared spectroscopy. Philos Transact A Math Phys Eng Sci. 2011;369:4452-69. 9. Davie SN, Grocott HP. Impact of extracranial contamination on regional cerebral oxygen saturation: A comparison of three cerebral oximetry 
technologies. Anesthesiology. 2012;116:834-40. 10. Zheng F, Sheinberg R, Yee MS, et al. Cerebral near-infrared spectroscopy monitoring and neurologic outcomes in adult cardiac surgery patients: A systematic review. Anesth Analg. 2013;116:663-76. 11. Moritz S, Kasprzak P, Arlt M, et al. Accuracy of cerebral monitoring in detecting cerebral ischemia during carotid endarterectomy: A comparison of transcranial Doppler sonography, near-infrared spectroscopy, stump pressure, and somatosensory evoked potentials. Anesthesiology. 2007;107:563-9. 12. Nielsen HB. Systematic review of near-infrared spectroscopy determined cerebral oxygenation during non-cardiac surgery. Front Physiol. 2014;5:93. 13. Laflam A, Joshi B, Brady K, et al. Shoulder surgery in the beach chair position is associated with diminished cerebral autoregulation but no differences in postoperative cognition or brain injury biomarker levels compared with supine positioning: The anesthesia patient safety foundation beach chair study. Anesth Analg. 2015;120:176-85. 14. De Georgia MA. Brain tissue oxygen monitoring in neurocritical care. J Intensive Care Med. 2015;30:473-83. 15. Le Roux P, Menon DK, Citerio G, et al. Consensus summary statement of the International Multidisciplinary Consensus Conference on Multimodality Monitoring in Neurocritical Care: A statement for healthcare professionals from the Neurocritical Care Society and the European Society of Intensive Care Medicine. Intensive Care Med. 2014;40:1189-209. 16. Diringer MN, Bleck TP, Claude HJ, et al. Critical care management of patients following aneurysmal subarachnoid hemorrhage: Recommendations from the Neurocritical Care Society’s Multidisciplinary Consensus Conference. Neurocrit Care. 2011;15:211-40. 17. Kirkman MA, Smith M. Supratentorial intracerebral hemorrhage: A review of the underlying pathophysiology and its relevance for multimodality neuromonitoring in neurointensive care. J Neurosurg Anesthesiol. 2013;25:228-39. 18. Nangunoori R, Maloney-Wilensky E, Stiefel M, et al. Brain tissue oxygen-based therapy and outcome after severe traumatic brain injury: A systematic literature review. Neurocrit Care. 2012;17:131-8. 19. Oddo M, Levine JM, Mackenzie L, et al. Brain hypoxia is associated with short-term outcome after severe traumatic brain injury independently of intracranial hypertension and low cerebral perfusion pressure. Neurosurgery. 2011;69:1037-45. 20. Bohman LE, Heuer GG, Macyszyn L, et al. Medical management of compromised brain oxygen in patients with severe traumatic brain injury. Neurocrit Care. 2011;14:361-9.

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Neuroprotection under Anesthesia Krishna HM

INTRODUCTION The high requirement of glucose (5.5 mg/100 g of tissue/min) and oxygen (3.5 mL/100 g/min) by the neuronal tissue makes it prone for ischemic and hypoxic injury. Cerebral ischemia and reperfusion injury are the main causes of brain damage in the intraoperative period. Excitatory neurotransmitters (glutamate) are released during ischemia and trigger cell death. N-methyl-Daspartate (NMDA) receptors play an important role in this. Calcium influx into the cell may be the final pathway for various mechanisms of neuronal injury like nitric oxide signaling, cytoskeleton dysfunction, free radical-mediated injury, and lipase and protease activation. This suggests that there are multiple potential targets for neuroprotective agents and hence combination therapy would be more effective than monotherapy. The penumbra surrounding the core ischemic tissue is the main area of interest in neuroprotection to salvage the viable tissue and limit the necrosis. Perioperative brain damage, as a complication of anesthesia or surgery, can manifest as transient ischemic attack (TIA), stroke, postoperative cognitive decline, or even death.

SURGERIES WHERE NEUROPROTECTION IS RELEVANT Neurological complications contribute to the morbidity and mortality following several surgical procedures. Stroke is seen as a complication in up to 6% of patients undergoing cardiac surgeries. Cerebral hypoperfusion and emboli are the important causes for these. The multiorgan dysfunction seen with cardiopulmonary bypass can be attributed to gas and particulate emboli, flow abnormality, and systemic inflammatory response syndrome. Long duration of cardiopulmonary bypass, ventricular dysfunction, and advanced age make brain more susceptible to these effects. Surgeries on thoracic and thoracoabdominal aorta can injure the spinal cord resulting in paraparesis or paraplegia. Vigilant monitoring with evoked potentials can prevent this neuronal injury.1 Cerebral angiography, transluminal angioplasty for carotid stenosis, and other endovascular interventional neuroradiological procedures require neuroprotection. Neurosurgeries for arteriovenous malformations and intracranial aneurysms require multimodal neuroprotective strategies. There is the inherent

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Box 1: Current strategies for neuroprotection under anesthesia. Physiological strategies ◆◆ Blood pressure control/induced hypertension ◆◆ Temperature control ◆◆ Maintain oxygenation ◆◆ Glycemic control ◆◆ Arterial carbon dioxide control ◆◆ Hemoglobin management ◆◆ Seizure management Pharmacological strategies ◆◆ Intravenous anesthetics ◆◆ Volatile anesthetics ◆◆ Nimodipine ◆◆ Magnesium ◆◆ Hyperosmolar agents Surgical strategies ◆◆ Decompressive craniectomy ◆◆ Extraventricular drainage of cerebrospinal fluid (CSF)

risk of vascular rupture, coil embolization and occlusion, stroke, vasospasm, and occlusion of arteries. Neuroprotection during organ transplantation is complex and requires several strategies. Research in neurosurgery is taking place for several decades. But there is a translational failure of preclinical experimental studies into clinically meaningful neuroprotection. This could be because of faulty experimental design such as inappropriate hypotheses, study of drugs or doses that are inappropriate for humans, use of animals, which are not representative of human physiology, and poor control of multiple confounding factors. The currently used strategies for clinical neuroprotection under anesthesia are summarized in Box 1.

PHYSIOLOGICALLY-BASED NEUROPROTECTION Maintaining the physiological parameters as close to normal is the simplest and probably the best method of neuroprotection. This includes optimal positioning to ensure adequate cerebral venous drainage, anticipating the stimulating events (laryngoscopy, intubation, pin application, and extubation) in the intraoperative period and taking measures to prevent hemodynamic surges during these, maintenance of cerebral perfusion pressure between 60 mm Hg and 70 mm Hg, maintenance of normoxia, normocapnia, normothermia, normotension, normal hemoglobin level, and liberal normoglycemia (140–180 mg/dL).2 Both hyperglycemia and hypoglycemia are deleterious to the brain. Induced arterial hypertension (up to 20–40% of baseline values) has been found to be useful in endovascular procedures (cerebral angioplasty/stenting, cerebral aneurysms, and intra-arterial thrombolysis), during clipping of aneurysm, during carotid endarterectomy, for cerebral vasospasm after subarachnoid hemorrhage, bypass surgery (extracranial to intracranial), and in patients with deranged cerebral autoregulation (intracranial tumors, traumatic brain injury, and hypertension).3

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It is usually achieved by maintaining hypervolemia, administering alpha agonists, and by decreasing the anesthetic depth. Hyperventilation to reduce the arterial carbon dioxide tension used to be a popular practice for management of brain injury. The response to hyperventilation therapy is rapid but is not sustained as it wears off after 6–12 hours. Hypothermia was one of the earliest neuroprotective interventions tried. Theoretically, hypothermia should protect the brain by multiple mechanisms. But practically it does not. The only context where it has been found to be useful is following return of spontaneous circulation (ROSC) after cardiac arrest. Targeted temperature management (32–36°C for at least 24 hours) is now the standard of care for brain protection following ROSC after a cardiac arrest if not responding to verbal commands. However, hypothermia has no role in neuroprotection during cardiac surgery or cerebral aneurysm surgery. Benefits of hypothermia are questionable in traumatic brain injury. Therapeutic hypothermia is only used as a secondary measure in refractory increase of intracranial pressure. Hyperthermia is detrimental across all groups of patients. Intraoperative hypothermia was not found to be useful after craniotomy for aneurysmal subarachnoid bleed.4,5

PHARMACOLOGICALLY-BASED NEUROPROTECTION Pharmacological strategies aim to suppress neurotransmission, maintain energy reserves, maintain integrity of the blood–brain barrier, promote free-radical scavenging, and block the cascade involved in cell death at various levels.

Anesthetics and Neuroprotection Anesthetic drugs exhibit neuroprotective properties, which varies with the route of administration and potency of the drugs. Action of anesthetics on gammaaminobutyric acid (GABA) A receptor potentiates inhibitory neurotransmission and reduces excitotoxicity. The duration of neuroprotection provided by the anesthetics is not clear. They are unlikely to provide long-term neuroprotection. Anesthetics act as pharmacological preconditioners providing the stressor effect for ischemic preconditioning. Volatile anesthetics accelerate neurogenesis following ischemia and hasten the process of recovery. Barbiturate therapy provides brain protection from ischemia by reducing cerebral metabolism, improving regional blood flow, reducing intracranial pressure, suppression of electrical activity, membrane stabilization, free radical scavenging, and calcium channel blockade. Though currently not widely used for cerebral protection due to their long duration of action, barbiturates still have a role as neuroprotective agent in status epilepticus and selected neurosurgical procedures that cause neuronal ischemia. The disadvantages of these agents are severe hypotension at the dose used for neuroprotection and impaired glutamate uptake resulting in adenosine triphosphate (ATP) depletion. The role of barbiturates in neuroprotection had been overestimated in the past by the confounding influence of temperature in the studies. Barbiturates do provide neuroprotection but it is only to a modest degree and is not superior to other anesthetics with respect to neuroprotection.6

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Etomidate has the advantage of minimal cardiovascular effects but is not widely used for neuroprotection because of myoclonic jerks and adrenal cortical suppression. Propofol, due to its similarity to barbiturates in suppressing neuronal activity, is an interesting option for neuroprotection. Its additional mechanisms of action include its effects on dopamine release, GABA receptors, glutamate uptake, and antioxidant properties. Ketamine provides neuroprotection by blocking the NMDA receptors. S(+)-ketamine is superior to R(–)-ketamine stereoisomer and ketamine racemate with respect to neuroprotective properties.7 Combination of reduced doses of ketamine and thiopentone has been tried for neuroprotection. The neuroprotective role of alpha-2 agonists like dexmedetomidine has only been studied in animals. The neuroprotective effects of benzodiazepines are lesser than those of propofol or thiopentone. Lignocaine decreases cerebral metabolism, and hence has been tried as a neuroprotective agent. But when the toxic levels are reached, it can cause seizures and aggravate neuronal injury.6 The neuroprotective effect of volatile anesthetics is due to suppression of the cerebral metabolic activity and concomitant reduction of cerebral blood flow. Additional mechanisms include enhancement of peri-ischemic cerebral blood flow, ATP-dependent potassium channel activation, nitric oxide synthase upregulation, suppression of release of excitotoxic neurotransmitters, and upregulation of antiapoptotic factors, including mitogen-activated protein kinases. Isoflurane has been studied extensively for its neuroprotective properties. The advantage of isoflurane over barbiturates is that it is effective at anesthetic dose whereas barbiturates have to be used in the dosage required for burst suppression. The neuroprotective properties of desflurane are equivalent to that of isoflurane. The neuroprotective function of xenon can be attributed to its NMDA receptor blocking ability and activation of potassium channel TREK-1. Due to its high MAC value, subanesthetic concentrations of xenon also provide neuroprotection in contrast to other anesthetics which requires anesthetic or supra-anesthetic doses for this effect. Nitrous oxide has weak antagonism at NMDA receptors and, therefore, the neuroprotective properties of nitrous oxide are weaker than that of volatile anesthetic agents. Clinically, there is not enough data to suggest the neuroprotective effect of inhalational anesthetics as they do not show improved neurological outcome after the surgery.8 There is no data to recommend any specific anesthetic agent as the optimal neuroprotective agent.9,10

Other Drugs Nimodipine, a calcium channel blocker, is widely used in the management of subarachnoid hemorrhage as it prevents vasospasm that follows the event. It may also exert neuroprotective effects, thus improving the outcome. However, nimodipine is not useful in traumatic brain injury. Remacemide is an NMDA antagonist used for neuroprotection during cardiac surgery. NMDA antagonists like traxoprodil, dexanabinol, selfotel, aptiganel, and eliprodil have not been found to be useful. Acadesine is an adenosine regulating substance and edaravone is a free radical scavenger. Both have been tried for neuroprotection. Dexanabinol, a cannabinoid has been tried in coronary artery

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bypass graft (CABG) surgery to reduce the postoperative cognitive impairment. Erythropoietin is being considered for neuroprotection during aortic surgery due to its action on ischemic spinal cord. AMPA receptor antagonists (zonampanel monohydrate), calpain inhibitors, anatibant (B2-bradykinin antagonist), and caspase inhibitors have shown conflicting results. In humans, magnesium has demonstrated neuroprotective properties during select surgical procedures like CABG and endarterectomy.11-13 The right dose and timing of magnesium are still being evaluated. Following drugs were evaluated for perioperative neuroprotection: ketamine, S(+)-propofol, lidocaine, thiopental, nimodipine, erythropoietin, atorvastatin, magnesium sulfate, GM1 ganglioside, lexipafant, glutamate/aspartate, xenon, remacemide, piracetam, rivastigmine, pegorgotein, and 17 beta-estradiol.14 Among these drugs, atorvastatin (20 mg/day for a minimum of 15 days preoperatively and for total 45 days), and magnesium sulfate (780 mg bolus dose during induction followed by 3,169 mg as infusion over 24 hours) were associated with a lower incidence of neurological deficit in the postoperative period. The results of ketamine, lidocaine, and magnesium sulfate were controversial on postoperative cognitive dysfunction. There was no reduction of mortality rates with any of these drugs.14 Remifentanil, propofol, mannitol, and hypertonic saline have failed to demonstrate neuroprotective effects.15,16 Based on few studies, neuroprotection with drugs might be beneficial by reducing postoperative cognitive dysfunction and new postoperative neurological deficits, but not the mortality. Majority of the studies to date have been done in population undergoing cardiac surgery, and the generalization of their results is questionable.17

SURGICAL STRATEGIES FOR NEUROPROTECTION The two surgeries, which have beneficial neuroprotection, are the ones used to reduce intracranial pressure. They are: (1) external ventricular drainage (EVD) and (2) decompressive craniectomy.18

NEUROPROTECTION IN SELECT PROCEDURES The techniques for cerebral protection during cardiac surgery include identification of high-risk patients, detection of carotid stenosis, prevent rewarming temperature more than 37°C, glucose monitoring, and optimal physiological management of the hemodynamics in the intraoperative period. In addition, use of transesophageal echocardiography to detect aortic atheromas, filters to reduce emboli, and monitors like near-infrared spectroscopy and transcranial Doppler to monitor tissue oxygenation and perfusion are useful for intraoperative neuroprotection. Prevention and treatment of arrhythmias like atrial fibrillation and minimizing aortic manipulation also prove useful. Following subarachnoid hemorrhage or aneurysmal surgery, the strategies to manage cerebral vasospasm include, triple H therapy (hypervolemia, hypertension, and hemodilution), removal of blood from subarachnoid space, and

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injection of vasodilators into the affected arteries. In refractory cases, minimally invasive procedures like use of an intra-arterial balloon catheter to dilate the spasm, instillation of tissue plasminogen activator into the cisterns, intra-aortic balloon counterpulsation to improve cerebral blood flow, and cervical spinal cord stimulation can be tried. In the endovascular management of carotid stenosis, device modifications have led to better brain protection from the emboli. These include distal balloon occlusion, distal filter protection, and proximal occlusion devices. In the distal balloon occlusion device, the balloon is inflated between the brain and the lesion (distal internal carotid artery) to prevent cerebral flow. This prevents the embolus from entering the cerebral circulation. The particulate material is later flushed out. Distal filter protection devices are commonly used. Their micropores allow blood flow but capture the particulate material. At the end of the procedure, the particulate material is removed along with the filter. In the proximal occlusion systems, there are two balloons, one to inflate in the proximal common carotid artery and the other in the external carotid artery. This causes a no-flow or a reversed-flow pattern in the internal carotid artery and prevents embolization. The device does not cross the lesion. During perinatal period, agents with antiapoptotic and antiexcitotoxic properties could be useful for neuroprotection. Barbiturates do not have a role in perinatal neuroprotection.19 Much hue and cry has been raised over the effects of anesthetics on the neonatal neuronal tissue. Apoptotic neurodegeneration seen in animal models has not been observed in human beings. The role of neuroprotection in this setting needs to be studied. Research is ongoing in the field of functional rewiring of the nervous system following injury. It involves development of new synapses and circuits from the existing viable neurons. Neurotrophic growth factors involved in neuroplasticity are being identified. The model of neuronal regeneration is being probed. Induction of stem cells to generate new functional neurons is also being tried.20,21

CONCLUSION Neuroprotection under anesthesia is still poorly understood. Despite decades of research on this topic, nothing concrete has evolved to change the clinical practice. Learning from the shortcomings in the study designs of the past, we move ahead refining the research. Better understanding of the neuronal injury at the molecular level gives us the hope. Maintenance of normal body physiology is the only proven neuroprotective measure till date. The quest for the right drug, right dose, and right timing to provide neuroprotection continues.

KEY POINTS • •

There is no single recipe for intraoperative neuroprotection. Multimodal strategy is adopted for neuroprotection with several of these being empirical. Understanding the physiology of the patient and maintaining the homeostasis rigorously is the best available neuroprotection currently.

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• •

Several drugs have been tried and many more are being evaluated for their neuroprotective properties but there is no single magic bullet. The evidence for assumed neuroprotective properties of barbiturates, propofol and inhalational anesthetics is not strong.

REFERENCES 1. Augoustides JG, Stone ME, Drenger B. Novel approaches to spinal cord protection during thoracoabdominal aortic interventions. Curr Opin Anesthesiol. 2014;27:98-105. 2. El Beheiry H. Protecting the brain during neurosurgical procedures: strategies that can work. Curr Opin Anesthesiol. 2012;25:548-55. 3. Mrara B. Neuroprotection: fact and fantasy. Southern Afr J Anaesth Analg. 2015;21: 64-6. 4. Galvin IM, Levy R, Boyd JG, et al. Cooling for cerebral protection during brain surgery. Cochrane Database Syst Rev. 2015;1:CD006638. 5. Grigore AM, Mathew J, Grocott HP, et al. Prospective randomized trial of normothermic versus hypothermic cardiopulmonary bypass on cognitive function after coronary artery bypass graft surgery. Anesthesiology. 2001;95:1110-9. 6. Bilotta F, Stazi E, Zlotnik A, et al. Neuroprotective effects of intravenous anesthetics: a new critical perspective. Curr Pharm Des. 2014;20:5469-75. 7. Bell JD. In vogue: ketamine for neuroprotection in acute neurologic injury. Anesth Analg. 2017;124:1237-43. 8. Deng J, Lei C, Chen Y, et al. Neuroprotective gases—fantasy or reality for clinical use? Prog Neurobiol. 2014;115:210-45. 9. Schifilliti D, Grasso G, Conti A, et al. Anaesthetic-related neuroprotection intravenous or inhalational agents? CNS Drugs. 2010;24:893-907. 10. Mahajan C, Chouhan RS, Rath GP, et al. Effect of intraoperative brain protection with propofol on postoperative cognition in patients undergoing temporary clipping during intracranial aneurysm surgery. Neurol India. 2014;62:262-8. 11. Chang JJ, Mack WJ, Saver JL, et al. Magnesium: potential roles in neurovascular disease. Front Neurol. 2014;5:52. 12. Golan E, Vasquez DN, Ferguson ND, et al. Prophylactic magnesium for improving neurologic outcome after aneurysmal subarachnoid hemorrhage: systematic review and meta-analysis. J Crit Care. 2013;28:173-81. 13. Zwerus R, Absalom A. Update on anesthetic neuroprotection. Curr Opin Anesthesiol. 2015;28:424-30. 14. Bilotta F, Gelb AW, Stazi E, et al. Pharmacological perioperative brain neuroprotection: a qualitative review of randomized clinical trials. Br J Anaesth. 2013;110:i113-20. 15. Uchida K, Yasunaga H, Sumitani M, et al. Effects of remifentanil on in-hospital mortality and length of stay following clipping of intracranial aneurysm: a propensity scorematched analysis. J Neurosurg Anesthesiol. 2014;26:291-8. 16. Dostal P, Dostalova V, Schreiberova J, et al. A comparison of equivolume, equiosmolar solutions of hypertonic saline and mannitol for brain relaxation in patients undergoing elective intracranial tumor surgery: a randomized clinical trial. J Neurosurg Anesthesiol. 2015;27:51-6. 17. Klein KU, Engelhard K. Perioperative neuroprotection. Best Pract Res Clin Anaesthesiol. 2010;24:535-49. 18. Hutchinson PJ, Kolias AG, Timofeev IS, et al. Trial of decompressive craniectomy for traumatic intracranial hypertension. N Engl J Med. 2016;375:1119-30. 19. Sheaa KL, Palanisamy A. What can you do to protect the newborn brain? Curr Opin Anesthesiol. 2015;28:261-6. 20. Bissonnette B. Cerebral protection. Pediatr Anesth. 2004;14:403-6. 21. Sturgess J, Matta B. Brain protection: current and future options. Best Pract Res Clin Anaesthesiol. 2008;22:167-76.

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End of Life Care in India: Problems and Solutions

9

Raj Kumar Mani, Shiv Kumar Iyer

INTRODUCTION Intensive care outcomes have improved in the past three decades however mortality continues to be significant especially in septic shock and acute respiratory distress syndrome (ARDS). We are treating an increasingly aging population with comorbidities and those with acute decompensations of chronic organ dysfunction. The ever increasing interventions and new classes of medication add to the complexity of management. It is also worth noting that at least 22% of intensive care unit (ICU) patients receive disproportionate treatment in the ICU.1 This reality adds iatrogenic burdens on the patient and the family in physical, emotional and economic terms. Avoidable suffering if not addressed, could lead to moral distress and burnout among physicians and nurses, breakdown of the delicate physician-patient relationships, conflicts and litigation and indeed adds to the growing public distrust of the medical profession. The evolution of intensive care has inevitably taken us to a more holistic approach that has added a number of soft skills to our list of essential competencies.2 A whole-person management of patients facing the end of life or futile treatments is the area of end of life care (EOLC) that is integral to quality intensive care. End of life care is in principle a timely shift of the focus of treatment to palliative rather than curative treatment. This would cut-out the aggressive use of futile interventions while optimizing treatment aimed at physical comfort and emotional stability. EOLC becomes equally patient- and family-centric recognizing the agony involved in the situation. The issues involved in what is essentially a medical decision while the paradigm shifts to EOLC, are several: Ethics, recognition of futility, checks and balances and legal framework. EOLC decisions require expertise and a careful, deliberate process to ensure timeliness, adequacy and family satisfaction.3 Since EOLC decisions have considerable ethical and legal dimensions apart from a purely medical dimension, professional guidelines and legislations have been formulated in high income countries.4 Need for law and legislation has been recognized in other countries as well. In India, efforts to shape a legal framework

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are on for more than a decade, but progress has been slow. EOLC can be improved in India if the several issues around EOLC are carefully addressed in order to develop medical and legal framework for application by the bedside.

EVOLUTION OF BIOMEDICAL ETHICS Ethics of Foregoing Life Support This includes “Withdrawal and Withholding of Life Support” (WD/WH-LS) and “Do-not-resuscitate” (DNR) directive. These decisions are based on the strong foundations of biomedical ethics that has evolved over four decades. Dilemmas generated by new developments in medicine need to be brought within the ambit of by the medical and legal professional awareness in India. In the West, contemporary ethical norms have been influenced by the Belmont Report in the US5 and the bioethical works of Beauchamp and Childress.6 The “principlistic” approach proposed in these documents is reflected in the terms autonomy, beneficence, non-malfeasance and justice. In India, we now have constitutionally validated “rights to privacy” and to ‘advance will’ both rooted in the principle of autonomy.7,8 This is also fundamental to modern medical practice. Early medical training that would focus on the principlistic approach would refine medical practice and end of life care.

Autonomy The International Declaration of Human Rights and common law holds patient autonomy to be central in medical decision. Thus, informed consent is mandatory for all medical interventions. The Supreme Court in its recent judgment says “an inquiry into common law jurisdictions reveals that all adults with capacity to consent have the right of self-determination and autonomy.” The said rights pave the way for the right to refuse medical treatment which has acclaimed universal recognition. A competent person who has come of age has the right to refuse specific treatment or all treatment or opt for an alternative treatment, even if such decision entails a risk of death.8 Refusal of life-sustaining treatments likewise is universally recognized to be a patient’s right that must be respected. For an incompetent patient, the rights are exercised through their next of kin or legally appointed healthcare proxy. The surrogates of the patient, together with the care giving team arrive at beneficent decisions respecting patient’s wishes. Surrogates are advised to faithfully represent the patient’s values and wishes (substituted judgment) rather than go by their own preferences.

Beneficence and Non-malfeasance When these principles are integrated in medical decisions, the appropriateness of those decisions is evaluated. Medical decisions are thus a composite of the four cardinal principles. Life-sustaining treatments are inappropriate if the burdens outweigh the benefits and are against the wishes of the patient, either directly or through his or her surrogates. Foregoing of life support (FLS) thus indicates a decision to allow nature to take its course rather than to medically intervene

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when inappropriate. Most decisions in the ICU are on incompetent patients, worked through between caregivers and surrogates.9 Withdrawal and withholding are widely held to be ethically equivalent as both are based on the futility of interventions and patient’s right to refuse them.4,9 Withdrawal decision may be more difficult to implement as it is seen to be an act of commission. But in practice, if held to be same in principle, a trial of interventions would be possible until futility of continuing treatment becomes acceptable to all stakeholders. These principles also form the bases of the “doctrine of double effect” that justifies unintended harm when the intent was only to provide comfort.10

The Universal Declaration of Bioethics and Human Rights A landmark development in biomedical ethics has been “The Universal Declaration of Bioethics and Human Rights” (UDBHR) of the United Nations Educational, Scientific and Cultural Organization (UNESCO) that was adopted by all member countries including India on 19th October 2005.11 It was developed by an International Bioethics Committee (IBC) consisting of healthcare professionals, philosophers, bioethicists, lawyers, government officials and other laypeople from member countries. The IBC also integrated views of several religious or spiritual groups including Confucianism, Judaism, Hinduism, Islam, Buddhism and Catholicism. Salient features of the UDBHR as applied to EOLC are: Articles 3 to 7 of the UDBHR further strengthen the principles enunciated by Beauchamp and Childress. • Article 3—Human dignity and human rights: Human dignity, human rights and fundamental freedoms are to be fully respected and the interests and welfare of the individual should have priority over the sole interest of science or society.

•



Interpretation In the Common Cause versus The Union of India, the Supreme Court has stated, “right to life and liberty as envisaged under Article 21 of the constitution is meaningless unless it encompasses within its sphere individual dignity.” With the passage of time, this court has expanded the spectrum of Article 21 to include within it the right to live with dignity as component of right to life and liberty. It has to be stated without any trace of doubt that the right to live with dignity also includes the smoothening of the process of dying in case of a terminally ill patient or a person in Persistent Vegetative State (PVS0) with no hope of recovery.8 Article 4—Benefit and harm: In applying and advancing scientific knowledge, medical practice and associated technologies, direct and indirect benefits to patients, research participants and other affected individuals should be maximized and any possible harm to such individuals should be minimized. Interpretation in the Context of FLS The best interest (maximizing benefit and minimizing harm) of a terminally ill patient is usually determined at the bedside by the conscientious, explicit

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•

•



•



and judicious use of current best evidence in making decisions about the care of the individual patient. It is thus the integration of best research evidence, clinical expertise and patient values (Sackett 1996). Integration of these principles will minimize iatrogenic harm in the form of prolonging dying and suffering and also intolerable financial burdens on the family. Article 5—Autonomy and individual responsibility: The autonomy of persons to make decisions, while taking responsibility for those decisions and respecting the autonomy of others, is to be respected. Article 6—Consent: Any preventive, diagnostic and therapeutic medical intervention is only to be carried out with the prior, free and informed consent of the person concerned, based on adequate information. The consent should, where appropriate, be express and may be withdrawn by the person concerned at any time and for any reason without disadvantage or prejudice. Interpretation The right to refuse continuing life-sustaining therapy that is not likely to benefit and may cause harm in the context of terminal illness flows from both Articles 5 and 6. A competent terminally ill patient may exercise this right directly. Article 7—Persons without the capacity to consent: In accordance with domestic law, special protection is to be given to persons who do not have the capacity to consent or who are otherwise termed as incompetent. Interpretation By the bedside, the physician determines the competency of the patient. Then together with the surrogates or legally appointed healthcare proxy, due respect to the patient’s wishes is accorded in the decisions made.

NEED TO BRING ETHICAL PRINCIPLES TO THE BEDSIDE Widely held bioethical principles are thus to be integrated into bedside decisionmaking. Autonomy is not an automatic implementation of patient or family demands.12 The duty of the caregiver is to ensure that the patient or surrogate is empowered to make an informed choice. Repeated high-quality communication between caregivers and surrogates is essential.13 Sometimes a “paternalistic autonomy” may be employed if the patient or family does not wish to engage in detailed meetings.14 It is important to address the concerns of the patient or family and navigate discussions towards mutual understanding. Truth telling, empathy, patient listening and not hesitating to revisit issues are the foundations of such processes. “Shared decision-making” is currently the model advocated by professional bodies.3,4,9

SHARED DECISION-MAKING MODEL Shared decision-making model in principle provides opportunity to bring together the principles of autonomy and beneficence. It also covers for the potential

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fallibility on the part of the physician by requiring that a body of responsible persons be involved on the caregiver side. An iterative process is integrated into the decision-making.3,4 It also recommends an iterative process in determining futility, integrating second opinions if need be. A candid acknowledgment and open discussion of gray areas is also necessary. Around 95% of critically-ill patients lack decisional capacity or wish to defer it to their families.9 However, half the family members in a French study were unable to participate in EOL decision-making.14 Depression or anxiety was found in 70% of family members.15 The stresses are due to many factors: uncertainties about prognosis, poor communication by clinicians, cost burdens, unfamiliar environment and depersonalization, conflicts with physicians and within family, the burden of responsibility, sense of guilt over decisions and time pressure for making decisions.16-18 Several studies have raised doubts on the reliability of surrogate opinion.19 Surrogates’ decisions may make ill-conceived or unrealistic demands from the treating team. Therefore, the physician must use the “best interests” standards as the ultimate guide in the decisions.

NEED TO SEPARATE FOREGOING OF LIFE SUPPORT FROM EUTHANASIA Active euthanasia is distinct in all respects from FLS. It is legalized under strictly regulated conditions only in the Netherlands, Belgium, and Switzerland among a few. Euthanasia is an active intervention by the physician to end the life of the patient as an act of mercy through the administration of a lethal injection.4,20 In the above-mentioned countries, patient needs to request euthanasia himself, i.e. while he or she retains capacity; physician intends to put an end to his or her life (unlike in FLS) and actively injects a drug for the purpose or in assisted suicide enables the patient to administer it.4,20-22 The crucial distinction between “killing” and letting die has been the basis for separating the two acts.4,23 FLS, on the other hand, is a holding back active intervention when the balance of harm versus benefit is judged to be clearly with the former when the patient refuses those interventions.3,4,9 The Supreme Court of India in its recent judgment clarifies this: “There is an inherent difference between active euthanasia and passive euthanasia as the former entails a positive affirmative act, while the latter relates to withdrawal of life-support measures or withholding of medical treatment meant for artificially prolonging life. In active euthanasia, a specific overt act is done to end the patient‘s life whereas in passive euthanasia, something is not done which is necessary for preserving a patient’s life. It is due to this difference that most of the countries across the world have legalized passive euthanasia either by legislation or by judicial interpretation with certain conditions and safeguards.”8 The agency of the death of the patient is the disease and the dying process has begun already. Therefore, in refraining from intervention, the physician is deemed to be acting lawfully by the Indian Law Commission in its 196th Report.24 By a similar argument the Report has declared the suicide laws to be inapplicable in relation to FLS decisions.24 The term “passive euthanasia” used loosely to

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signify FLS is outdated as it is misleading, inappropriate and self-contradictory. This terminology has been discouraged in modern medical practice.4,20,25

CONTEMPORARY PRACTICES ACROSS THE WORLD Setting goals of care appropriate to the phase of illness and estimated prognosis is inevitable in medicine.4,12,13,26 In India, FLS decisions have been treated as exceptional situations that would require a judicial procedure. In common perception, since prognostic uncertainty exists in medicine, stringent safeguards are believed to be necessary for FLS decisions. In contrast, these decisions have been increasingly made easier in the developed world where 75–90% of dying patients in critical care units receive an FLS decision.27,28 These decisions are made between caregiver teams and surrogates with the assistance of hospital ethics committees.23,29 Judicial appeal is reserved for dispute resolution. International consensus is against a practice that favors interventions as the default practice.4,9 In the state of Oregon, Physician Orders for Life-Supporting Treatment (POLST) is an online system used to access documented decisions based on the competent patient’s wishes and values.30 However, Indian physicians like in other low income Asian countries, are reported to be reluctant to limit aggressive interventions as they perceive legal risks in such decisions.31-33

IMPROVING THE LEGAL FRAMEWORK FOR END OF LIFE CARE In India we are yet to have a comprehensive legal framework for all acute scenarios encountered in the critical care setting as opposed to the PVS scenario. Case laws in the world date back to 1976 with the Quinlan case in the US.29 Legislation to strengthen patient’s autonomy and the right to refuse life support followed in the early 90’s.34 Instruments to uphold patient autonomy in the form of advance directive (AD) and to appoint a healthcare proxy (HP) followed.35 Since then there have been legislation on EOLC around the world and evolving. Indian case laws have been few and focusing mainly on suicide and euthanasia. The Aruna Shanbaug’s case36 legalized “passive euthanasia,” requiring a court procedure, thereby rendering day-to-day EOLC difficult. The clinical situations where FLS would be applicable need to be reviewed by court.37 The fear of treatment limitation decisions leading to risks of liability as deficiency of service or as active euthanasia hampers the clinician in ethical decision-making. In a small cohort of 150 physicians the majority felt hampered by either the law or the hospital administration.33 This is corroborated by a large survey 8-year later across several countries in Asia.32 However, the amicus curiae in the Aruna Shaunbag’s case36 pointed out that “in some countries stopping (or not starting) a medically useless (futile) treatment, and stopping or not starting a treatment at the patient’s request is considered normal medical practice.” The issues of patient’s self-determination, futility, brain death, FLS, safeguarding of rights during incapacity, death in dignity, right to palliative care, and withdrawal of nutrition or hydration need to be addressed and explored fully.38 Recent landmark judgment, Common Cause versus The

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Union of India8 has validated the Right to Autonomy and AD. It lay down in detail procedural safeguards for implementing FLS decisions that involve a hospital ethics committee, jurisdictional magistrate of the first class, the district collector and the high court. However, most decisions in the ICU are required to be made within the first-week of admission39-41 as most situations concern the terminally acute stages of chronic incurable conditions.

RATIONALIZING THE CLINICAL DECISION-MAKING AND IMPLEMENTATION The joint statement of the Indian Society of Critical Care Medicine (ISCCM) and the Indian Association of Palliative Care (IAPC) developed a clinical decisionmaking algorithm in 2014.3 It is a stepwise algorithm that emphasizes early, open and repeated communication and complete documentation. Implementation of a withdrawal or withholding decision involves switching over to comprehensive palliative care. This includes adequate symptom control, psychospiritual support, open visitation, family support and bereavement care. It would also include the option of safe discharge to home care where palliative care should be facilitated. It aims to improve the quality of dying by bringing together appropriate FLS decisions in the ICU setting and palliative care principles and skills.42 As with any complex decisions in medical care a well-defined process is required for end-of-life in dementia (EOLD) with in-built safeguards to prevent misuse or inappropriate application. Declared hospital policies on EOLC exist for reputed institutions all over the world. Standard operating procedures (SOPs) are often laid down by professional bodies and individual institutions as for other medical procedures. Regular audits are also required to be conducted to measure outcomes in terms of the authenticity and quality of these decisions. Defined procedures ensure that these decisions are made by a responsible body of healthcare experts adopting contemporary evidence-based approach to EOLC.

HOW TO IDENTIFY CONTEXTS FOR END OF LIFE CARE Terminal illness is defined as an irreversible or incurable disease condition from which death is expected in the foreseeable future. Examples of these include the scenarios listed below:3 • Advanced age coupled with poor functional state due to one or more chronic debilitating organ dysfunction. For example, end-stage pulmonary, cardiac, renal or hepatic disease for which the patient has received or declined standard medical or surgical options. • Severe refractory illnesses with organ dysfunctions unresponsive to a reasonable period of aggressive treatment. • Coma (in the absence of brain death) due to acute catastrophic causes with nonreversible consequences such as traumatic brain injury, intracranial bleeding or extensive infarction. • Chronic severe neurological conditions with advanced cognitive and/or functional impairment with little or no prospects for improvement, e.g. advanced dementia, quadriplegia or chronic vegetative state.

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• • •

Progressive metastatic cancer where treatment options have failed or patient has refused treatment. Postcardiorespiratory arrest with prolonged poor neurological status. Any other comparable clinical situations coupled with a physician prediction of low probability of survival.

FOREGOING OF LIFE SUPPORT PATHWAY International consensus and professional guidelines exist for standardizing the process of FLS decisions and implementation. The Supreme Court of India in Common Cause versus The Union of India has outlined a procedure for FLS with or without advance directives. However, there are no governmental or statutory guidelines as yet. It is important to bear in mind that delays of FLS decisions impose intolerable physical, emotional and financial burdens on the patients and families, thus defeating the purpose and intent of the Supreme Court judgment. We suggest following the pathway that has been described in detail in the statement of the ISCCM and IAPC3 that is well aligned with international consensus on FLS as essential to quality EOLC. The 12-step algorithm includes the following: 1. Accurately assess the terminal nature of the medical condition and the futility or potential inappropriateness of interventions in the given situation. 2. Establish consensus among all caregivers and identify the primary communicator within the healthcare team. 3. Determine competence of the patient. If deemed competent communicate directly with the patient. 4. If the patient is incompetent, elicit and confirm the existence of AD and/or HP. If not, identify the appropriate surrogate from the family for discussion. 5. Ensure honest, accurate and early disclosure of the medical condition and the potential inappropriateness of interventions in the given situation to the competent patient or if incompetent and to the family or surrogate. 6. Use shared decision-making to establish a consensus through open and repeated discussions. Pay careful attention to the principles of good communication during this process: −− Ensure an appropriate setting for the discussion. −− Ask the patient and family what they understand. −− Discuss the general goals of care. −− Establish context for the discussion. −− Discuss specific treatment preferences—therapy that is to be withheld or withdrawn and treatment that is to be continued. −− Respond to emotions. 7. Maintain transparency and accountability through accurate documentation and appropriate informed consent. 8. Ensure consistency of information to the patient and family or next friend or appropriate surrogate. In case of lack of consensus or conflict seek independent opinion, refer to Hospital Ethics Committee and to External Review Committee and last for judicial review in that order of escalation.

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9. Establish and implement the plan for WD/WH-LS including effective and compassionate palliative care, after death care and bereavement care. 10. Effective and compassionate palliative care to patient and support to the family. 11. Postbereavement care. 12. Review the care process.

END OF LIFE CARE IMPROVEMENT INITIATIVES IN INDIA The barriers to effective EOLC in India are numerous.37,43 The ISCCM in 2005 published the first position statement on EOLC44 and later that year prevailed upon the Indian Law Commission to develop the 196th draft Bill on “Medical Treatment of Terminally-ill Patients.”16 The ISCCM guidelines were revised in 2012.45 Professional groups [ISCCM, IAPC and the Indian Academy of Neurology (IAN)] came together to form the End of Life Care in India Task Force (ELICIT). In response to the invitation on draft Bill entitled “Medical Treatment of Terminallyill Patients (for the protection of patients and medical practitioners)” published by the Ministry of Health and Family Welfare (MOHFW), ELICIT has submitted an alternative draft.46 By the joint efforts of the ISCCM and IAPC, EOLC standards have been included by the National Accreditation Board for Hospitals and Healthcare Providers (NABH) in its latest list of mandatory compliances.47

CONCLUSION AND FUTURE DIRECTIONS End of life care improvement depends on professional and societal awareness of the medical, ethical, social and legal dimensions. Reform in the medical practice within carefully constructed ethical and legal framework is the need of the hour in India. The main challenge is to prevent the institution of potentially inappropriate treatments that would add iatrogenic burdens and to shift focus to appropriate palliative care. There has been an exponential increase in research and publication on EOLC in the recent years. In India the issues relating to EOLC, particularly law and legislation are in evolution. Recent landmark Supreme Court judgments and governmental initiatives provide great opportunities for reform.

KEY POINTS • • • •

•

Appropriate foregoing of life support is integral to day-to-day critical care practice. Foregoing of life support is rooted in patient’s right to Autonomy and Privacy and in the physician’s obligation to provide beneficent care. India needs a pragmatic medicolegal framework to improve end of life care. Professional guidelines recommend a deliberate, transparent and documented process through open communication between a body of caregivers and the patient/surrogates for end-of-life decisions. In India, constitutional validity of the right to refuse life saving interventions and to execute an Advance Directive have been established through two recent Supreme Court judgments.

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• •

Presently the recommendation of a lengthy procedure by the Supreme Court is found to be problematic in implementation. Professional and societal advocacy are needed to improve the quality of end of life care in India.

REFERENCES 1. Piers RD, Azoulay E, Ricou B, et al. Inappropriate care in European ICUs: Confronting views from nurses and junior and senior physicians. Chest. 2014;146(2):267-75. 2. The CoBaTrICE collaboration, Bion JF, Barrett H. Development of core competencies for an international training program in intensive care medicine. Intensive Care Med. 2006;32(9):1371-83. 3. Myatra SN, Salins N, Iyer S, et al. End-of-life care policy: An integrated care plan for the dying. Indian J Crit Care Med. 2014;18(9):615-35. 4. Sprung CL, Truog RD, Curtis JR, et al. Seeking worldwide professional consensus on the principles of end-of-life care for the critically ill: the WELPICUS study. Am J Respir Crit Care Med. 2014;190(8):855-66. 5. The Belmont Report: Ethical Principles and guidelines for the protection of human subjects for research. (1979). The National commission for the protection of Human subjects for biomedical and behavioral research. Available from www.fda.gov/ohrms/ dockets/ac/05/briefing/2005 [Accessed on August 2018]. 6. Beauchamp TL, Childress JF, (Eds). Principles of Biomedical Ethics, 7th edition. Oxford: Oxford University Press; 2013. 7. Reportable: In: The Supreme Court of India Civil Original Jurisdiction. Writ Petition (Civil No. 494 of 2012). Justice K Puttaswamy vs. Union of India. 8. Reportable In the Supreme Court of India Civil Original Jurisdiction. Common Cause vs. The Union of India. Writ Petition (Civil) no. 215 of 2005. [Online] Available from http:// supremecourtofindia.nic.in/supremecourt/2005/9123/9123_2005_Judgement_09Mar-2018.pdf [Accessed on August 2018]. 9. Carlet J, Thijs LG, Antonelli M, et al. Challenges in end-of-life care in the ICU: Statement of the 5th International Consensus Conference in Critical Care: Brussels, Belgium, April 2003. Intensive Care Med. 2004;30(5):770-84. 10. Quill TE, Dresser R, Brock DW. The role of double effect—a critique of its role in decision-making. N Engl J Med. 1997;337(24):1768-71. 11. Have H, Michèle J. The UNESCO Universal Declaration on Bioethics and Human Rights: Background, Principles and Application; 2009. 12. Curtis JR, White DB. Practical guidance for evidence-based ICU family conferences. Chest. 2008;134(4):835-43. 13. Azoulay E, Sprung C. Family-physician interactions in the intensive care unit. Crit Care Med. 2004;32(11):2323-8. 14. Azoulay E, Pochard F, Chevret S, et al. Half the family members of intensive care unit do not want to share in decision-making process: A study in 78 French intensive care units. Crit Care Med. 2004;32(9):1832-8. 15. Pochard F, Darmon M, Fassier T, et al. Symptoms of anxiety and depression in family members of intensive care unit patients before discharge or death. A prospective multicenter study. J Crit Care. 2005;20(1):90-6. 16. Majesko A, Hong SY, Weissfeld L, et al. Identifying family members who may struggle in the role of surrogate decision maker. Crit Care Med. 2012;40(8):2281-6. 17. Azoulay E, Pochard F, Kentish-Barnes N, et al. Risk of post-traumatic stress symptoms in family members of intensive care unit patients. Am J Respir Crit Care Med. 2005;171(9):987-94. 18. Sinuff T, Giacomini M, Shaw R, et al. “Living with dying”: The evolution of family members’ experience of mechanical ventilation. Crit Care Med. 2009;37:154-8.

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19. Truog RD, Campbell ML, Curtis JR, et al. Recommendations for end-of-life care in the intensive care unit: A consensus statement by the American College [corrected] of Critical Care Medicine. Crit Care Med. 2008;36(3):953-63. 20. Definition of terms used in limitation of treatment and providing palliative care at end of life: The Indian Council of Medical Research Commission Report. Indian J Crit Med. 2018;22(4):249-62. 21. Ebrahimi N. The ethics of euthanasia. Aust Med Stud J. 2012;3:73-5. 22. Weiss M. Illinois Death with Dignity Act: A Case for Legislating Physician Assisted Suicide and Active Euthanasia. Ann Health L Advance Directive. 2014;23:13-198. 23. Airedale NHS Trust vs Bland:1993 (1) AII ER 821. 24. Law Commission of India. (2006). 196th report on Medical treatment of terminally ill patients (for the protection of patients and Medical practitioners). [Online] Available from http://lawcommissionofindia.nic.in/reports/rep196.pdf/. [Accessed on August 2018]. 25. Michalsen A, Reinhart K. “Euthanasia”: A confusing term, abused under the Nazi regime and misused in present end-of-life debate. Intensive Care Med. 2006;32(9):1304-10. 26. Kon AA. Shepard EK, Sederstrom NO, et al. Defining Futile and Potentially Inappropriate Interventions: A Policy Statement From the Society of Critical Care Medicine Ethics Committee. Crit Care Med. 2016;44(9):1769-74. 27. Prendergast TJ, Claessens MT, Luce JM. A National Survey of End-of-life Care for critically-ill patients. Am J Respir Crit Care Med. 1998;158(4):1163-7. 28. Sprung CL, Cohen SL, Sjokvist P, et al. End-of-life practices in European intensive care units: The Ethicus study. JAMA. 2003;290(6):790-7. 29. In re Quinlan, 70 N.J.10 (1976). 30. Tolle SW, Teno JM. Lessons from Oregon in Embracing Complexity in End-of-Life Care. N Engl J Med. 2017;376(11):1078-82. 31. Divatia JV, Amin PR, Ramakrishnan N, et al. Intensive Care in India: The Indian Intensive Care Case Mix and Practice Patterns Study. Indian J Crit Care Med. 2016;20(4):216-25. 32. Phua J, Joynt GM, Nishimura M, et al. ACME Study Investigators and Asian Critical Care Clinical Trials Group. Withholding and withdrawal of life‑sustaining treatments in low‑middle‑income versus high-income Asian countries and regions. Intensive Care Med. 2016;42:1118-27. 33. Barnett VT, Aurora VK. Physician beliefs and practice regarding end‑of‑life care in India. Indian J Crit Care Med. 2008;12(3):109-15. 34. Cruzan vs. Director, Missouri Department of Health, 497 US. 261 (1990). 35. The Texas Statute for Advance Directives. (2017). [Online] Available from http://tlo2. tlc.state.tx.us/statutes/docs/HS/content/htm/hs.002.00.000166.00.htm. [Accessed on August 2018]. 36. Aruna Ramachandra Shanbaug vs The Union of India & Ors. Writ petition (criminal) no. 115 of 2009 (Supreme Court of India Proceedings). 37. Gursahani R, Mani RK. India: Not a country to die in. Indian J Med Ethics. 2016;1(1): 30-5. 38. Mani RK. Constitutional and legal protection for life support limitation in India. Indian J Palliat Care. 2015;21(3):258-61. 39. Mani RK, Mandal AK, Bal S, et al. End-of-life decisions in an Indian intensive care unit. Intensive Care Med. 2009;35(10):1713-9. 40. Sinuff T, Cook DJ, Rocker GM, et al. For the level of care study investigators and the Canadian Critical Care Trials group. DNR directives are established early in mechanically ventilated intensive care patients. Can J Anesth. 2004;51(10):1034-41. 41. Le Conte P, Baron D, Trewick D, et al. Withholding and withdrawing life support therapy in an emergency department: prospective survey. Intensive Care Med. 2004;30: 2216-21. 42. Mani RK. Coming together to care for the dying in India. Ind J Crit Care Med. 2014;18:562-7. 43. Mani RK. Top ten barriers to improving end of life care in India. Crit Care Update, 2018.

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44. Mani RK, Amin P, Chawla R, et al. ISCCM position statement: Limiting life-prolonging interventions and providing palliative care towards the end of life in Indian intensive care units. Indian J Crit Care Med. 2005;9:96-107. 45. Mani RK, Amin P, Chawla R, et al. Guidelines for end-of-life and palliative care in Indian ICUs: ISCCM consensus ethical position statement. Indian J Crit Care Med. 2012;16(3):166-81. 46. Ministry of Health and Family Welfare Draft Bill on Treatment of Terminally ill patients (for the protection of patients and medical practitioners). http://india.gov.in/ministryhealth-and-family-welfare-[cited 2018 May 27]. 47. National Accreditation Board for Hospitals. (2016). [Online] Available from http://www. nabh.co/NABHStandards.aspx/. [Accessed on August 2018].

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10

Organophosphorus Poisoning Saikat Sengupta, Chandrshish Chakravarty

INTRODUCTION Organophosphates are agricultural insecticides. They inhibit acetylcholinesterase, the enzyme that degrades acetylcholine. The organophosphate compound binds to the enzyme and causes a conformational change at the binding site of acetylcholinesterase to acetylcholine. These cholinesterase inhibitors thus exert their toxicity as they block the activity of acetylcholinesterase, which results in accumulation of acetylcholine at cholinergic receptors. Organophosphates as well as carbamates bind to acetylcholinesterase forming a conjugate and that is far more stable than the acetylcholine-acetylcholinesterase conjugate. The carbamate-acetylcholinesterase bond however spontaneously hydrolyzes in minutes to hours leading to acetylcholinesterase being eventually regenerated (reversible binding). Carbamates, unlike the phosphates, penetrate the central nervous system (CNS).1 Carbamate poisoning thus spontaneously resolve within 24–48 hours and does not lead to significant morbidity or mortality. However, the phosphorylated as well as phosphonylated enzymes degrade slowly over days to weeks, making acetylcholinesterase essentially inactive (as in irreversible binding). To ensure normal return of physiologic enzyme activity, new enzyme must be generated or an antidote needs to be supplied to the system. After phosphorylation of acetylcholinesterase over 24–48 hours, “aging” occurs. The enzyme then can no longer spontaneously hydrolyze and remains permanently inactivated.2 Self-poisoning with organophosphorus is a major clinical and public health problem in rural Asia.3 The alkyl organophosphates in insecticides are mostoften responsible for cases of poisoning. Exposure occurs during manufacture, mixing, or spraying of the OP compound. However, there are several reports of deliberate suicidal ingestion of the concentrated insecticide. There have been reports of poisoning following adulteration of cooking oil or alcohol with aryl organophosphates. The organophosphate pesticide chlorpyrifos (CPF) remains in use throughout the world.

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CHEMICAL DESCRIPTION As a chemical class of compounds, organophosphates (OP) are mainly of the following types; diethyl organophosphates (DEOP), dimethyl organophosphates (DMOP) and S-alkyl compounds. They can also be classified as THIONS (inactive) and OXONS (active). The thions require hepatic activation to corresponding oxons for their systemic effect. They are absorbed from mouth, skin, conjunctiva, gastrointestinal (GI) and respiratory tract. Their metabolism occurs in the liver and they are eliminated through urine. The compounds are largely-distributed in fat tissue. Redistribution from the fat stores can lead to delayed onset of symptoms (leptophos, fenthion). All OP compounds take milliseconds (ms) for inhibition but reactivation half-time (t1/2) differs. It is 0.7 h for DMOP, 31 h for DEOP and less than 1 h for S-alkyl compounds. Aging t1/2 for DMOP compounds is 3.7 h, for DEOP compounds it is 33 h and less than 30 min for S-alkyl compounds. • Dimethyl organophosphates compounds are less toxic because they reactivate faster. However, reactivation with the antidote pralidoxime (PAM) is not possible after four t½ (12 h) leading their being labeled as less-responsive. • Diethyl organophosphates compounds are more toxic, but reactivation with antidote can occur till up to 130 h (5 days). Therefore, their response to therapy with PAM is much better. • S-alkyl compounds age faster and are less-toxic but are usually nonresponsive to antidote PAM.

PATHOPHYSIOLOGY Organophosphorus pesticides inhibit esterase enzymes, namely the acetylcholinesterase (AChE) at the synapses as well as red-cell membranes, and butyrylcholinesterase or pseudocholinesterase in plasma. The inhibition of butyrylcholinesterase or pseudocholinesterase is not symptomatic but the acetylcholinesterase inhibition leads to accumulation of acetylcholine at the receptor sites in the synapses of the autonomic nervous system (ANS), central nervous system (CNS), and neuromuscular junctions (NMJ).4 The resultant overstimulation and the subsequent autonomic, CNS, and neuromuscular features of organophosphorus poisoning are well-known.

ORGANOPHOSPHORUS POISONING To arrive at a diagnosis in a suspected patient with poisoning, the following steps are usually followed: • Detailed history (or whatever history is made available from whichever source). • Physical examination (with personal protection). • Toxidrome. • Diagnostic and ancillary tests. • Observed response to antidotes. Toxidrome (toxic syndrome) is a term coined to describe the syndrome caused by dangerous levels of toxins in the body. It is the mainstays in the diagnostic approach to a poisoned patient.

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Cholinergic The toxidrome due to the cholinergic affects is best remembered with the help of two mnemonics. Symptoms produced due to nicotinic effects are remembered by the days of the week (Monday to Sunday) and those produced due the action on the muscarinic receptors by DUMBBELLS. Cholinergic: Nicotinic toxidrome: Days of the week. Monday — Mydriasis Tuesday —Tachycardia Wednesday — Weakness Thursday — Tremor, Hypertension Friday — Fasciculation Saturday — Somnolence Cholinergic: Muscarinic toxidrome: DUMBBELLS. Diarrhea, Diaphoresis Urination Miosis Bronchorrhea, Bronchospasm, Bradycardia Emesis Lacrimation, Lethargy Salivation

Anticholinergic The usual features of poisoning due to an anticholinergic agent are: “HOT as a Hare” — Hyperthermia “RED as a Beet” — Flushed “DRY as a Bone” — Dry skin “BLIND as a Bat” — Dilated pupils “MAD as a Hatter” — Delirium, Hallucinations Tachycardia Urinary retention Several authors have also described the typical toxidrome as SLUDGE, comprising of: Salivation Lacrimation Urination Defecation Gastric cramps Emesis. The dreaded clinical course with these compounds is due to the manifestations of acute cholinergic crisis which usually starts within 3–6 hours of exposure and lasts for 24–48 hours. If symptoms present after 12-hour, the etiology is unlikely to be anticholinesterase (AChE) inhibitors. The effects may be delayed with lipophilic compounds or after prolonged dermal exposure. Onset is also delayed in OP compounds requiring hepatic activation (parathion to paraoxon).

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Table 1: Symptoms and signs of organophosphate poisoning based on receptors involved.5 Type of receptor

Receptor subtype

Nicotinic

Muscarinic

Acts on

Clinical manifestation

N1/Nm

Neuromuscular junction

Weakness, fasciculations, cramps, paralysis

N2/Nn

Autonomic ganglia, adrenal medulla

Tachycardia, hypertension

M1–M5

CNS

Anxiety, restlessness, ataxia, convulsions, insomnia Dysarthria, tremors, coma

M2

Heart

Bradycardia, hypotension

M3, M2

Pupils

Blurred vision, miosis

M3, M2

Exocrine glands

Respiratory-rhinorrhea, bronchorrhea Gastrointestinal-increased salivation, diarrhea Ocular-increased lacrimation Others-excessive sweating

M3, M2

Smooth muscles

Bronchospasm, abdominal pain, urinary incontinence

Initially the nicotinic symptoms of tachycardia, mydriasis, hypertension, fasciculations and muscle weakness are predominant. Presence of muscarinic symptoms may give a mixed picture. The muscarinic symptoms are more sustained unlike the transient nicotinic symptoms. The central nervous system (CNS) symptoms of delerium, respiratory depression, seizure and coma may present at any point of time. Organophosphate poisoning may also cause QTc prolongation, arrhythmia, pancreatitis, parkinsonism and bilateral recurrent laryngeal nerve palsy. The most frequent cause of death is respiratory failure due to a combination of bronchorrhea, bronchospasm, neuromuscular dysfunction (diaphragmatic) and respiratory depression. There has been an attempt to look at the symptoms and signs in OP poisoning by different approaches. This may possibly improve understanding of the underlying mechanism, which may help clinicians with the acute management of such patients. A group from Vellore has tried to describe these based on the receptors involved (Table 1) and time of onset (Table 2), which have been enumerated below.5

CONFIRMATION OF DIAGNOSIS Organophosphate poisoning is most often, if not always, a clinical diagnosis. Diagnosis depends on a history of exposure to the compound prior to the onset of illness which is a conglomeration of signs and symptoms of diffuse parasympathetic stimulation.

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Table 2: Symptoms and signs of organophosphate poisoning based on time of manifestation.5 Time of manifestation Acute: Minutes to 24 hours

Delayed: 24 hours to 2 weeks

Late: After 2 weeks

Mechanism

Clinical manifestation

Nicotinic action

Weakness, fasciculations, cramps, paralysis

Muscarinic

Salivation, lacrimation, urination, defecation, gastric cramps, emesis, bradycardia, hypotension, miosis, bronchospasm

Central receptors

Anxiety, restlessness, convulsions, respiratory depression

Nicotinic

Intermediate syndrome

Muscarinic

Bradycardia, miosis, salivation

Central receptors

Coma, extra pyramidal manifestations

Peripheral

Peripheral neuropathic process

Plasma cholinesterase levels are a sensitive biomarker of OP exposure. Acetylcholinesterase (AChE) is found primarily in erythrocytes and nervous tissue whereas pseudocholinesterase is found in the plasma. Pseudocholinesterase is nonspecific in its action than AChE. The activities of both these may be decreased and exposure to OP can be confirmed by laboratory measurement of erythrocyte acetylcholinesterase and plasma pseudocholinesterase activity. Inhibition of AChE is considered specific for organophosphate poisoning because a number of conditions like pregnancy, immediate postpartum period, liver dysfunction, certain exogenous compounds like echothiophate may produce low plasma pseudocholinesterase level. 6 Measurement of pseudocholinesterase level is more sensitive but less specific than the red blood cell cholinesterase level for organophosphate poisoning. The following guideline is usually used: • Between 30% to 50% of normal—exposure. • Greater than 50% inhibition—toxic manifestations occur. • Levels are 20% or less of normal—symptoms appear. In clinical scenario, confirmation of poisoning, rather than diagnosis, occurs by laboratory determinations. Baseline values of cholinesterase levels prior to exposure are very unlikely to be available. Only sequential postexposure cholinesterase determinations can confirm organophosphate poisoning.

MANAGEMENT OF ORGANOPHOSPHORUS POISONING The cornerstones of treatment of organophosphate poisoning are threefold: • Decontamination • Supportive therapy • Definitive therapy with atropine and pralidoxime (PAM).

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Decontamination involves removal of all clothing (which may act as a storage for further skin absorption) followed by thorough soap and water wash. There is limited evidence for gastric lavage or activated charcoal. They can be only useful when used early after oral intake. It is important to note here that healthcare worker (HCW) needs to use universal precautions for dermal exposure and treat these patients in well-ventilated area. Secondary poisoning in HCW though rare is a distinct possibility. Supportive care constitutes of early airway protection and maintaining adequate oxygenation with supplemental oxygen therapy. Hemodynamic stability is assured by judicious use of intravenous (IV) fluid (up to 20 mL/kg) boluses and/or vasopressors. Arrhythmias like torsades are managed with IV magnesium sulfate (MgSO4) and seizures are treated with benzodiazepines along with atropine. Gastric lavage is often the initial intervention for poisoned patients on hospital arrival. This at times is at the expense of resuscitation and giving antidotes. There is no evidence to suggest that gastric decontamination benefits patients poisoned with organophosphorus. Gastric decontamination should be done after the patient has been stabilized by treatment with oxygen, atropine, and an oxime.7 Definitive therapy: The mainstay of therapy is atropine and oximes. Atropine is used as the anticholinergic drug of choice. One of the most commonly applied regime is the doubling dose regime. 8 The initial dose of atropine is 1–3 mg IV bolus. Five minutes after giving the initial IV bolus of atropine, pulse rate, blood pressure, pupil size, sweat, and chest sounds are checked. If no improvement is seen, double the original dose of atropine is administered. The patient is continuously reviewed every 5 min and doubledose of atropine is administered if response is found to be inadequate or absent. Improvement of parameters marks cessation of dose doubling and similar or smaller doses are considered. Atropine boluses are continued until the heart rate is greater than 80 per min and the systolic blood pressure is more than 80 mm Hg. The best end point for atropinization is a chest that is free of crackles on auscultation. The other clinical end points are a dry axillae and pupils that are reasonably normal in size. This doubling dose regimen allows as far as 70 mg of atropine to be administered in stepwise fashion to a patient within 30 min, resulting in rapid stabilization. Once atropinization is complete, 10–20% of the total loading dose is infused every hour for 24–48 hours and then decreased by 1/3rd to 1/4th of previous day dose. Atropine is weaned over 3–5 days. This is authenticated by a study from South India which showed benefit from infusions of atropine compared with repeated bolus doses.9 Infusions reduce fluctuations in blood atropine concentration, and thus reduces the need for frequent patient monitoring, which in itself is a challenge in hospitals with staff shortage. While managing a patient who undergoes atropine therapy, one should be aware of the features of atropine toxicity. It is marked by agitation, fever, ileus and urinary

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retention. If suspected, atropine is withheld for 30–60 min and IV benzodiazepine is administered for sedation. If symptoms improve, one may restart atropine at 70–80% of the previous dose. If there is recurrence of similar symptoms, glycopyrrolate 7.5 mg diluted in 200 mL normal saline is to be infused over 24 hours. Oximes are AChE reactivators and when administered before aging (diethyl>dimethyl>S-alkyl), they cleave OP-AChE complex and free the enzyme to degrade acetylcholine. The most commonly used oxime is pralidoxime (PAM). PAM is administered as a loading dose of 30 mg/kg given over 20 min, followed by an infusion at the rate of 8 mg/kg/h. Essentially, in a 70 kg man, a loading dose of 2 g is followed by 500 mg per hour. The oximes are continued for 12– 24 hours after atropine is no longer required. If pseudocholinesterase levels are measured, they should show an increasing trend. Empirically they may be continued for 7 days. One needs to be careful during the administration of the loading dose. If it is given very rapidly it may cause respiratory arrest, vomiting and diastolic hypotension. Despite the beneficial effects of pralidoxime which were first noted with parathion poisoning, the overall effectiveness has been much debated, especially amongst Asian clinicians who have been unconvinced of its benefit.10,11 A couple of RCT’s from Vellore, noted that low-dose infusions of pralidoxime might actually cause harm.12,13 A very large RCT conducted by Pawar et al., in Baramati, India studied the effect of very-high-dose of pralidoxime (2 g loading dose, then 1 g either every hour or every 4 h for 48 h, followed by 1 g every 4 h until recovery) in 200 patients with moderate OP poisoning. They found that the high-dose regimen had reduced case fatality, lesser pneumonia and reduced mechanical ventilation time. The study suggested that large doses of pralidoxime could have benefit if patients are treated early and are given good supportive care.14 However, in another RCT, Eddleston et al., administered PAM as 2 g bolus followed by 0.5 mg/h as infusion and did not observe any mortality difference. There were more patients requiring ventilation in the PAM group, though for a shorter duration.15 World Health Organization recommends giving PAM loading and infusion to all symptomatic patients with OP poisoning.16 As on date, it is worthwhile to follow the WHO recommendations. Benzodiazepines: Patients poisoned with organophosphorus may frequently develop delirium. The pesticide itself, atropine toxicity, hypoxia, alcohol-intake, and other medical complications may contribute towards this. Treatment of underlying causes usually resolves delirium and agitation however some patients need pharmacological intervention. Acutely agitated patients need treatment with diazepam. Diazepam is also the first-line therapy for seizures.17 Seizures seem to be more common with organophosphorus nerve agents (such as soman and tabun).18 Other therapies: Magnesium sulfate blocks ligand-gated calcium channels, which results in reduced ACh release from presynaptic terminals, and improves function

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at the neuromuscular junction, and reduced CNS overstimulation mediated by NMDA receptor activation.19 The α-2-adrenergic receptor agonist clonidine also reduces ACh synthesis and its release from presynaptic terminals and thus can be efficacious.20 Sodium bicarbonate is sometimes used for treatment of organophosphorus poisoning in place of oximes.21

INTERMEDIATE SYNDROME Postorganophospherus poisoning intermediate syndrome has an incidence ranging from 20% to 80%. The pathophysiology of this is unclear. It has been postulated that it could be due to the following: • Prolonged AChE inhibition • Partial or inadequate oxime therapy • Muscle necrosis • Oxidative stress related myopathy • Dysregulation or desensitization of postsynaptic nicotinic receptors. Intermediate syndrome is suspected when there is sudden development of neuromuscular weakness characterized by difficulty in neck holding. This is generally seen 24–96 hours after resolution of acute symptoms of OP poisoning. Lipophilic, high-potency, DMOP (e.g. fenthion) is mostly-associated and represent either prolonged absorption and redistribution or delayed elimination from tissue depots. The classical features of intermediate syndrome comprise of: • Facial, neck and proximal muscle weakness. • Cranial nerve palsy. • Respiratory muscle weakness (often requiring mechanical ventilation). • Decreased or absent deep tendon reflexes. • It is often preceded by recurrence of cholinergic symptoms. • Electromyography showing abnormality. • Neuromuscular junction is affected. The treatment of intermediate syndrome is supportive which includes mechanical ventilation and nursing care. The syndrome being self-limiting, usually there is spontaneous resolution in 4–18 daytime.

ORGANOPHOSPHORUS-INDUCED DELAYED PERIPHERAL NEUROPATHY A long-term consequence of OP poisoning is an entity called organophosphorusinduced delayed peripheral neuropathy or Organophosphorus-induced delayed peripheral neuropathy which occurs 1–3 weeks after exposure. It is characterized by distal axonopathy, and the type of axonopathy relates to the kind of compound. Type-1 is common with phosphates, type 2 for phosphite and type 3 with phosphine. The pathophysiology of this is possibly Wallerian type degeneration of axons and myelins of long nerve fibers of CNS and peripheral nervous system. Early signs and symptoms are paresthesia and calf pain. The patients complain

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of weakness of distal limb muscle (foot drop) and small muscles of hand (claw hand). There could be ataxic gait and decreased DTR. In the later stages spasticity, hyperreflexia and clonus may develop. No definitive specific therapy for this condition is available and a permanent motor deficit is the usual outcome.

FACTORS AFFECTING OUTCOME IN ORGANOPHOSPHORUS POISONING22 The outcome after OP poisoning depends upon:

Toxicity Toxicity is usually rated according to the oral lethal dose (LD50). Parathion (LD50 13 mg/kg, WHO: Class IA) is highly toxic but temephos (LD50 8,600 mg/kg, WHO: unlikely to cause acute hazard) is rarely-known to cause death.

Impurities Pesticides which are stored in hot conditions may cause chemical reactions that have toxic products.

Formulation and Strength These are of the manufactured pesticide.

Alkyl Subgroups Either two-methyl groups are attached via oxygen atoms to the phosphate (dimethyl organophosphorus) or two ethyl groups to the phosphate (diethyl organophosphates). Acetylcholinesterase aging is faster for dimethyl poisoning and lower for diethyl poisoning. Oximes given quickly to patients with dimethyl poisoning are more effective. Some pesticides have atypical structures, with another alkyl-group (propyl in profenofos) which is attached to the phosphate group via a sulfur atom. These organophosphorus pesticides age acetylcholinesterase even faster. Oximes are not effective in such poisoning.

Need for Activation Many compounds are inactive thioates. They have a double-bonded sulfur attached to the phosphorus atom. They need to be desulphurated to make the active oxon, via cytochrome P450 enzymes in the gut wall and liver.

Duration of Effect, Fat Solubility and Half-life Fat soluble thioate OP pesticides (e.g. fenthion) distribute in large amounts to fat stores after absorption. The peak blood OP concentration and the early cholinergic features are usually mild. Subsequently redistribution and activation causes recurrent cholinergic features that last days or weeks. Peripheral respiratory failure is a feature with these OP compounds due to continuing inhibition of acetylcholinesterase. Aging starts after acetylcholinesterase

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inhibition. Theoretically prolonged oxime therapy could be beneficial. Other OP compounds (dichlorvos) do not need activation, are not fat soluble. They have a much more rapid-onset of effect and also a shorter duration of activity. Fat solubility is graded according to the Kow (logarithm octanol/water coefficient) given below. • Less than 1.0 = not fat soluble • More than 4.0 = very fat soluble23 These factors affect the speed of onset of organophosphorus poisoning after ingestion. Oxon organophosphorus inhibits acetylcholinesterase rapidly and therefore there is an early-onset of clinical features with respiratory arrest often occurring prior to hospital presentation. There is thus an increased risk of hypoxic brain damage and aspiration. The conversion of parathion, the thioate organophosphorus to paraoxon is extremely fast and patients can become unconscious in less than 20 min. However, signs and symptoms of poisoning by other thioate organophosphorus, such as dimethoate and fenthion, happen later, and the patient has more time to present to hospital.22

CONCLUSION Monocrotophos, a very toxic organophosphate had been incriminated in the Bihar midday meal school children tragedy. Following this the government has proposed banning of 18 very toxic insecticides-pesticides for domestic and agricultural use. Many more are under the scanner and may be considered for banning or restricted use soon like many other countries in the world. In the meantime it is important for us to recognize the vulnerable population, common toxidromes at presentation and early use of antidotes. It is also important to protect those who are unexposed but coming in contact with the patient. This involves avoiding latex gloves and using rubber gloves, prompt bagging of contaminated clothes and discarding leather shoes used by victim. Few more things to remember before we end the discussion are: In patients having recurrent seizures, it is prudent to rule out other toxins or head injury; liquid organophosphate ingestion may result in severe ARDS which needs to be differentiated from pulmonary edema; avoiding opioids, succinylcholine, phenothiazines and theophylline in all victims must be protocolised. Lastly, events that lead to suicidal ideation or accidental exposure needs to be discussed and sorted out with the help of social support, government agencies and psychiatric help as India is one of the world capitals in OP toxicity and death.

KEY POINTS • •

Organophosphorus (OP) poisoning is a major clinical and public health problem, especially in rural areas. Inhibition of acetylcholinesterase by organophosphates causes conformational change at its binding site with acetylcholine and leads to accumulation of acetylcholine. This results in overstimulation of acetylcholine receptors in synapses of the ANS, CNS, and NMJ.

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• • •

• • •

Toxidrome with organophosphate poisoning is SLUDGE, comprising of: Salivation, Lacrimation, Urination, Defecation, Gastric cramps, and Emesis. Plasma levels of cholinesterase are a sensitive biomarker of OP exposure. The cornerstones of treatment of organophosphate poisoning are decontamination, supportive therapy and definitive therapy with atropine and pralidoxime (PAM). The most commonly applied regime is the doubling atropine dose regime. Atropine infusions too are frequently used. WHO recommends giving PAM loading and infusion to all symptomatic patients with OP poisoning. Factors like toxicity, impurities, formulation and strength, alkyl subgroups, need for activation, fat solubility and half-life affect outcomes.

REFERENCES 1. Moriya F, Hashimoto Y. Comparative studies on tissue distribution of organophosphorus, carbamate and organochlorine pesticides in decedents intoxicated with these chemicals. J Forensic Sci. 1999;44(6):1131. 2. Peter JV, Cherian AM. Organic insecticides. Anesth Intensive Care. 2000;28(1): 11-21. 3. Eddleston M, Phillips MR. Self-poisoning with pesticides. BMJ 2004;328(7430):42-4. 4. Lotti M. Clinical toxicology of anticholinesterase agents in humans. In: Krieger R, (Ed). Handbook of pesticide toxicology. Volume 2. Agents, 2nd edition. San Diego: Academic Press; 2001. pp. 1043-85. 5. Peter JV, Sudarsan TI, Moran JL. Clinical features of organophosphate poisoning: A review of different classification systems and approaches. Indian J Crit Care Med. 2014;18(11):735-45. 6. Tafuri J, Roberts J. Organophosphate poisoning. Ann Emerg Med. 1987;16(2):193-202. 7. Eddleston M, Haggalla S, Reginald K, et al. The hazards of gastric lavage for intentional self-poisoning in a resource poor location. Clin Toxicol (Phila). 2007;45(2):136-43. 8. Aaron CK. Organophosphates and carbamates. In: Ford MD, Delaney KA, Ling LJ, (Eds). Clinical toxicology. Philadelphia: WB Saunder’s Company; 2001. pp. 819-28. 9. Ram JS, Kumar SS, Jayarajan A, et al. Continuous infusion of high doses of atropine in the management of organophosphorus compound poisoning. J Assoc Physicians India. 1991;39(2):190-3. 10. De Silva HJ, Wijewickrema R, Senanayake N. Does pralidoxime affect outcome of management in acute organophosphate poisoning? Lancet. 1992;339(8802):1136-38. 11. Singh S, Batra YK, Singh SM, et al. Is atropine alone sufficient in acute severe organophosphate poisoning?: Experience of a North West Indian Hospital. Int J Clin Pharmacol Ther. 1995;33(11):628-30. 12. Johnson S, Peter JV, Thomas K, et al. Evaluation of two treatment regimens of pralidoxime (1 g single bolus dose vs. 12 g infusion) in the management of organophosphorus poisoning. J Assoc Physicians India. 1996;44(8):529-31. 13. Cherian AM, Peter JV, Samuel J, et al. Effectiveness of P2AM (PAM —pralidoxime) in the treatment of organophosphorus poisoning. A randomized, double-blind placebo controlled trial. J Assoc Physicians India. 1997;45:22-4. 14. Pawar KS, Bhoite RR, Pillay CP, et al. Continuous pralidoxime infusion versus repeated bolus injection to treat organophosphorus pesticide poisoning: A randomized controlled trial. Lancet. 2006;368(9553):2136-41. 15. Eddleston M, Szinicz L, Eyer P, et al. Oximes in acute organophosphorus pesticide poisoning: A systematic review of clinical trials. QJM. 2002;95(5):275-83.

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16. WHO International Program on Chemical Safety. Poisons information monograph G001. Organophosphorus pesticides. Geneva: World Health Organization; 1999. 17. Murphy MR, Blick DW, Dunn MA. Diazepam as a treatment for nerve agent poisoning in primates. Aviat Space Environ Med. 1993;64(2):110-15. 18. Sidell FR. Nerve agents. In: Sidell FR, Takafuji ET, Franz DR, (Eds). Medical aspects of chemical and biological warfare. Washington, DC: Borden Institute, Walter Reed Army Medical Center; 2006. pp. 129-79. 19. Singh G, Avasthi G, Khurana D, et al. Neurophysiological monitoring of pharmacological manipulation in acute organophosphate poisoning. The effects of pralidoxime, magnesium sulfate and pancuronium. Electroencephalogr Clin Neurophysiol. 1998;107(2): 140-48. 20. Liu WF. A symptomatological assessment of organophosphate-induced lethality in mice: Comparison of atropine and clonidine protection. Toxicol Lett. 1991;56(1-2):19-32. 21. Wong A, Sandron CA, Magalhaes AS, et al. Comparative efficacy of pralidoxime vs. sodium bicarbonate in rats and humans severely poisoned with OP pesticide. J Toxicol Clin Toxicol. 2000;38:554-55. 22. Eddleston M, Buckley NA, Eyer P, et al. Management of acute organophosphorus pesticide poisoning. Lancet. 2008;371(9612):597-607. 23. Benfenati E, Gini G, Piclin N, et al. Predicting logP of pesticides using different software. Chemosphere. 2003;53(9):1155-64.

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11

Apneic Oxygenation Pradeep Bhatia, Swati Chhabra

INTRODUCTION Tracheal intubation attempts in apneic “at-risk” patients may lead to hypoxemia. Many strategies have been adopted in the clinical practice to prolong the safe apnea time. The safe apnea time is defined as the time until arterial saturation (SaO2) reaches 88–90% (critical arterial desaturation) after ventilation ceases. Beyond this point which corresponds with upper inflection point on oxygen dissociation curve, there is a rapid decline in SaO2. Healthy adults have a safe apnea time of 8–9 min when adequately preoxygenated, in contrast to about 1 min, if they have been breathing room air.1 Apneic oxygenation involves continuous delivery of oxygen in the upper airway in the absence of ventilation. This prolongs the safe apnea time, in addition to that provided by preoxygenation alone. Use of apneic oxygenation was first reported in 19592 and its current applications have expanded from operating rooms to airway management in emergency situations and intensive care units (ICU). Various other terminologies which have been used to describe the process of apneic oxygenation are aventilatory mass flow (AVMF),3 apneic diffusion oxygenation, diffusion respiration4 and mass flow ventilation.

PHYSIOLOGY OF APNEIC OXYGENATION During normal breathing in a healthy adult, oxygen (O2) is taken up in the blood from the alveoli at a rate of approximately 250 mL/min and carbon dioxide (CO2) is taken up in the alveoli at a similar rate (Fig. 1A). Owing to differences in solubility in blood, in an apneic state, O2 continues to move into blood from alveoli at an unchanged rate while only 8–20 mL/min of CO2 returns into the alveoli from the bloodstream and rest of CO2 produced is buffered in the blood and tissues (Fig. 1B).5 This phenomenon creates a negative alveolar pressure and an airflow from pharynx into the lungs, in the presence of a patent airway, even in the absence of ventilation. Apneic oxygenation provides oxygen rich mixture in pharynx and due to bulk flow of gases down a pressure gradient (and not molecular diffusion),

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A

B

Figs. 1A and B: Diagrammatic representation of gas exchange during normal breathing (A) and during apnea (B).

there is an improvement in arterial oxygen saturation and a prolonged safe apnea time. With effective preoxygenation, continuous delivery of high-flow oxygen and a patent airway, in a healthy adult PaO2 can be maintained at more than 100 mm Hg for up to 100 min without a single breath but this lack of ventilation will result in significant hypercapnia (PaCO2 increases by 5 mm Hg during the first minutes and 3 mm Hg any further min) and acidosis.6

PREOXYGENATION AND APNEIC OXYGENATION Preoxygenation is the process of utilizing 100% oxygen to replace nitrogen in the lungs while the patient is breathing spontaneously such that the functional residual capacity (FRC) can act as reservoir of oxygen. This reservoir contains 450 mL of oxygen when a healthy person is breathing room air versus 3,000 mL while breathing 100% oxygen. The adequacy of preoxygenation can be evaluated by fraction of expired oxygen (FeO2) of more than 90%.7 Preoxygenation has been instrumental in extending the safe apnea time.5,8 But the oxygen reservoir created by it is fixed and does not gets replenished once apnea sets in. Preoxygenation is thus a prerequisite for apneic oxygenation, which is a more continuous process. In the event of inadequate preoxygenation and prolonged apnea time, oxygen concentration in alveoli is rapidly reduced and desaturation ensues before apneic oxygenation takes effect.

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TECHNIQUES FOR APNEIC OXYGENATION Nasal Cannula (Prongs) The standard nasal cannula, which is a flexible tube with two protruding prongs of diameter approximately half of diameter of nares, is inserted and connected to an oxygen source at 5–15 L/min after induction of anesthesia during the apneic phase. Apneic oxygenation at these flow rates does not provide any CO2 clearance. The technique has also been termed as NO DESAT (nasal oxygen during efforts securing a tube). The nasal cannulas can be left attached to the patient during preoxygenation and ventilation with mask provided they do not cause a significant leak. The flow rates applied in clinical scenarios are highly variable probably because of the conventional teaching discouraging high flows with nasal cannula due to patient discomfort.9,10 However, a study has demonstrated that 15 L/min flow through a standard nasal cannula was well-tolerated by volunteers without any side effects.11 The mucosal drying effects might be discomforting with longterm use in awake patients which not the case in anesthetized individuals for a short time. Low-flow nasal cannulas provide a variable and limited FiO2 (24–44%), so, during intubation attempt after induction of anesthesia, flow rate can be increased to 15 L/min which will create a pharyngeal oxygen reservoir and increase the FiO2 contributing to increased delivery of oxygen to the alveoli during apneic oxygenation (Fig. 2).5 This can prolong the safe apnea time over preoxygenation alone by 2–5 min.12,13

Fig. 2: Apneic oxygenation with nasal cannula during intubation attempts. Source: With permission from McMahon Publishing, New York.

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Transnasal Humidified Rapid-Insufflation Ventilatory Exchange Although there is enough current evidence that apneic oxygenation, when employed for extending safe apnea time during intubation attempts, does not lead to clinically significant hypercapnia with cardiac or cerebral sequelae. But there is some early evidence of adverse outcomes since apneic oxygenation allows for little or no CO2 clearance.14 Transnasal humidified rapid-insufflation ventilatory exchange (THRIVE) is a technique which uses high flow (up to 70 L/min) of warmed and humidified oxygen for both preoxygenation and apneic oxygenation. This continuous insufflation at high flow rate can achieve a continuous positive airway pressure (CPAP) of about 7 cm of H2O leading to opening up of small airways and reduced shunting.15,16 Continuous insufflation of oxygen at high flow, which is the mainstay of THRIVE, not only facilitates oxygenation but also allows for some CO2 clearance such that the rate of rise in CO2 is roughly one-third of the expected values.17 THRIVE thus enhances apnea time and patient safety over “classical apneic oxygenation” by combining the benefits of apneic oxygenation and apneic ventilation through CPAP and flow-dependent dead space flushing. In a study on 25 patients with difficult airway, use of THRIVE led to prolongation of apnea time by a median of 14 minutes (5–65 min) and no patient desaturated below 90%.17 Besides difficult airway, THRIVE has been applied successfully for obese patients, rapid sequence intubation, procedural sedation for GI endoscopies, awake craniotomies, bronchoscopies and in postanesthesia care unit (PACU).18-23 High flow nasal oxygen can cause problems like mucosal drying, bleeding etc. and humidification and warming of oxygen is a solution to this. Many devices are currently available for application of THRIVE in clinical settings e.g. Optiflow (Fisher and Paykel), Comfort Flo Humidification system (Teleflex) etc. These devices deliver high flows (up to 70 L/min) of heated and humidified gases through a wide bore nasal cannula (Figs. 3 to 5).

Nasopharyngeal Catheter Their initial use dates back to World war I when the sufferers of gas poisoning were administered oxygen through rubber catheters placed in nasopharynx. Further, they were modified with a Y tube to deliver oxygen to an assembly of double nasal catheters. The distance between nares and tragus is measured to estimate the depth of insertion of a catheter in the nasopharynx and oxygen is delivered at 5–15 L/min for apneic oxygenation. Currently available nasopharyngeal airways with a port for oxygen delivery can also be used for the purpose of apneic oxygenation, although the less-invasive nasal cannulas are preferred in clinical practice worldwide.

Tracheal Catheter During the apneic phase, a catheter is inserted in the trachea and oxygen is delivered at 0.5 L/min which has reportedly permitted a safe apnea time of up to 45 min during otorhinolaryngologic procedures without any adverse events

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Fig. 3: Flow rate of 70 L/min for apneic oxygenation using THRIVE (transnasal humidified rapid-insufflation ventilatory exchange). Source: With permission from McMahon Publishing, New York.

Fig. 4: High-flow nasal cannula for THRIVE which can be used for preoxygenation as well as apneic oxygenation. Source: With permission from McMahon Publishing, New York.

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Fig. 5: Apneic oxygenation (THRIVE) with high-flow nasal cannula during intubation attempts. Source: With permission from McMahon Publishing, New York.

due to hypercapnia.24 This technique has also been used during apnea test for brain death. After cessation of mechanical ventilation, a narrow bore catheter is passed through the endotracheal tube and apneic oxygenation is provided with 4–10 L/min of flow.25 This apneic oxygenation prevents desaturation while brain death examination is being performed.

Endobronchial Catheter Catheters inserted bilaterally in main-stem bronchi can be used for administration of apneic oxygenation. This technique has limited clinical applicability. In an old prospective study without control group, two endobronchial catheters were inserted into right and left main bronchi with oxygen flow of 0.6–0.7 L/min in elective gynecological surgical patients and observed during 30 min of apnea. At the end of 30 min, no significant fall in PaO2 occurred (321 vs. 299 mm Hg) but there was a significant rise in PaCO2 (37.0 vs. 54.9 mm Hg).26

Oxygenating Laryngoscope Laryngoscopes modified for delivery of oxygen can be used for apneic oxygenation. This method has been overlooked in the clinical studies evaluating apneic oxygenation. A study which tested laryngoscope for apneic oxygenation in a manikin connected to a preoxygenated 2.5 L test lung found that over a 20min period, SpO2 remained more than 90% with both direct intratracheal and perlaryngoscope oxygen insufflation which was significantly above levels noted in either the control or nasal insufflation dummy groups. This technique needs more formal clinical studies to prove its role.

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CLINICAL APPLICATIONS OF APNEIC OXYGENATION Apneic oxygenation can be applied in all the areas where intubations are performed. A recent meta-analysis, which included 11 studies (six high qualities randomized controlled trials, four low quality level two studies and one low quality level three study) demonstrated a strong evidence for benefit of apneic oxygenation in terms of improved oxygen saturation in elective surgical patients, obese patients and critically-ill patients without respiratory failure. However, no significant benefit was found in patients with respiratory failure.27 A literature review which evaluated 18 studies revealed that majority of the studies prove that apneic oxygenation is beneficial with only 4 studies concluding that desaturation was not prevented with apneic oxygenation.28 There are also certain gaps in literature as all studies have compared apneic oxygenation with no apneic oxygenation or observed effects of apneic oxygenation without any control group. Only one study compares two different techniques of apneic oxygenation (nasal prongs vs. nasopharyngeal catheter, both at 5 L/ min) and found apneic oxygenation with nasopharyngeal catheter to be better.29 However, nasal cannulas are most-commonly used and studied in clinical practice, probably as they are less “invasive” compared to other techniques. Also, there is a wide variation in oxygen flow rate used for apneic oxygenation, the desaturation values (SpO2 90–95%) and apneic time cut offs in the study protocols. Below is a review of recent literature in various clinical settings:

Operating Room General Surgical Population

Ample literature is there to substantiate beneficial effects of apneic effects in general surgical patients. A narrative review summarized that eight comparative studies demonstrated the benefits of apneic oxygenation in the operating room administered through various techniques (nasal, nasopharyngeal, tracheal, endobronchial) by prolonging time to and reducing incidence of desaturation. No adverse events were observed due to hypercapnia. Four studies without control group also showed that SpO 2 level maintenance with prolonged apnea times.30 During thoracic surgeries, application of apneic oxygenation with a continuous positive airway pressure (CPAP) of 2–5 cm of H 2O to the nonventilated operative lung through double lumen tube (DLT) can improve arterial oxygenation. Adequacy of surgical exposure might be an issue with this technique. Obese Population

The population which is at maximal risk of desaturation is the obese. A study compared apneic oxygenation (nasopharyngeal; 5 L/min) with no apneic oxygenation and evaluated time to SpO2 less than 95% with a cut off of 4 min in obese patients. At the end of 4 min, 16 of 17 patients in apneic oxygenation group had SpO2 100% while control group desaturated to less than 95% in a mean apneic time of 145 sec.31 Another study with obese patients compared apneic oxygenation (nasal cannula; 5 L/min) with no apneic oxygenation and

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evaluated duration to SpO2 less than 95% with a cut off of 6 min. Duration for which SpO2 remained more than 95% was 5.29 min in apneic oxygenation group vs. 3.49 min in control group. Lowest SpO2 observed during the study period of 6 min was 94.3% in apneic oxygenation group and 87.7% in control group.13 Difficult Airways

Apneic oxygenation provides an unpressurised environment in a difficult airway scenario and prevents “attempt-stop to ventilate-reattempt” cycle and gives the operator a favorable apneic window.17 High-flow nasal oxygenation has been reported to be well-tolerated in awake patients for fiberoptic intubation with better oxygenation and intubating conditions.32 Pediatric Population

The practice of apneic oxygenation is less studied in pediatric population which is also the “at-risk” group for severe hypoxemia with shorter apneic times. Pediatric patients have higher oxygen consumption than adults. The most-recent study on apneic oxygenation in this group evaluated it in 149 pediatric emergency intubations. Patients in apneic oxygenation group received 100% oxygen by nasal cannula during ETI. Children up to 2-year received 4 L/min, more than 2 years to less than or equal to 12 years received 6 L/min, and more than 12 years received 8 L/min. They concluded that it is an easily-applied intervention which decreases incidence of hypoxemia. Nearly 50% of children not receiving apneic oxygenation experienced hypoxemia with a median lowest SpO2 of 93 (69,99) vs. 100 (95,99) in apneic oxygenation group.33 Using pediatric nasal cannula at high flow can achieve a CPAP of 4 cm H2O.34 However, there is much scope for comprehensive evaluation of apneic oxygenation in pediatric population. Obstetric Population

Owing to a decreased FRC and increased oxygen consumption, the pregnant females tend to desaturate faster with apnea. Also, there is an increased incidence of failed intubation in this population.35,36 The benefits of apneic oxygenation would logically fit into obstetric practice but due to ethical considerations of keeping parturient apneic for study purposes, evidence does not exist. However, a study investigated apneic oxygenation during rapid sequence intubation in parturient in simulated computational model. They found that apneic oxygenation significantly increased time to desaturation but rise in PaCO2 and fall in pH was observed with prolonged apnea time.37 Panendoscopy and Bronchoscopy

With proper patient selection, close monitoring and effective preoxygenation, panendoscopy was reported to be successfully performed in majority of patients in a retrospective study with total intravenous anesthesia under apneic oxygenation with a tracheal catheter. Apnea was safely tolerated up to 45 min without adverse consequences of hypercarbia and with better surgical visualization due to absence of an endotracheal tube.24 In an older study, bronchoscopies were safely

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performed with apnea times of up to 20 min. The resulting hypercapnia during apneic oxygenation was well tolerated.38

Outside Operating Room Intensive Care Unit and Emergency Department

Intubation is considered as a lifesaving procedure in intensive care units and emergency rooms. Critically-ill patients are more prone to hypoxemia during emergency intubations owing to underlying pathophysiology like increased oxygen demand, cardiorespiratory compromise etc. Two meta-analysis evaluating efficacy of apneic oxygenation during emergency intubations concluded that apneic oxygenation was associated with decreased hypoxemia and increased lowest peri-intubation SpO2.39,40 Preoxygenation, in this subset of patients, might be ineffective or not possible and application of apneic oxygenation while intubating has shown clear benefits in majority of the studies.5 There may exist some contradicting evidence where apneic oxygenation had little or no benefit in preventing hypoxemia in patients with hypoxic respiratory failure. However this goes down well with the physiology of apneic oxygenation as these patients are more likely to have severe pulmonary shunting making passive exchange of oxygen ineffective.41-43 There is evidence that multiple intubation attempts may lead to an increased incidence of adverse events like hypoxemia, arrhythmias, aspiration, hypotension and cardiac arrest.44,45 With apneic oxygenation increased success rate of intubation in first attempt has been reported without occurrence of hypoxemia.9,39,40 Out-of-hospital Setting

As in a controlled hospital setting, apneic oxygenation has been of proven benefit in out-of-hospital settings by decreasing the incidence of desaturation during rapid sequence intubation.46

LIMITATIONS OF APNEIC OXYGENATION In spite of all the supporting literature, apneic oxygenation has its own limitations or words of caution which have been mentioned at various instances above. To summarize, preoxygenation is an indispensable prerequisite to apneic oxygenation as it cannot cover up an ineffective preoxygenation to prolong safe apnea time. Patients undergoing apneic oxygenation need to be closely monitored for signs of hypercapnia and intervened at the earliest. Many studies have not provided data on PaCO2 or EtCO2 and no adverse event has been reported owing to hypercapnia even though mean apnea time reported range from 5.29 min to beyond 45 min. Yet it is recommended that apneic oxygenation should not be used for longer duration and should be avoided in patients with raised intracranial pressure or cardiac ailments. Maintaining a patent airway is an absolute necessity for an apneic gas flow from pharynx to alveoli. So, apneic oxygenation is difficult to achieve in rapid sequence intubation with cricoid pressure.

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STEP-BY-STEP APPROACH TO APNEIC OXYGENATION Below is a representative step-by-step approach to administer apneic oxygenation through nasal cannula which is the most-widely used interface for the purpose. This might need to be tailored to individual patient needs: • Identify the candidates for apneic oxygenation. • Attach nasal cannula and use a well-sealed mask over it to ensure adequate preoxygenation (FeO2 > 90% or when gas monitoring is not available; eight vital capacity breaths over 60 sec or tidal volume breathing for 3 min) with 100% oxygen. If there is leak in mask seal due to nasal cannula, leave them over the mask and attach just before intubation attempt. • Induce general anesthesia and administer neuromuscular blocking drug. Maintain patent airway at all times with jaw thrust, oropharyngeal or nasopharyngeal airway. • Administer oxygen through nasal cannula at 15 L/min during intubation attempts with close monitoring of vital signs. • Continue apneic oxygenation till endotracheal tube is placed and effective ventilation is confirmed.

CONCLUSION Current literature indicates that apneic oxygenation has an important role in ensuring patient safety in scenarios when increase in safe apnea time prior to successful intubation is critical to prevent desaturation. The application of apneic oxygenation should be preceded by effective preoxygenation with maintenance of a patent airway and close monitoring of circulatory parameters throughout the procedure. Use of apneic oxygenation in indicated areas of operating rooms, intensive care units and emergency rooms is must as evidence based practice and should be adopted as a standard operating procedure.

KEY POINTS •

•

•

•

The safe apnea time is defined as the time until arterial saturation (SaO2) reaches 88–90% (critical arterial desaturation) after ventilation ceases. Beyond this point which corresponds with upper inflection point on oxygen dissociation curve, there is a rapid decline in SaO2. Apneic oxygenation involves continuous delivery of oxygen in the upper airway in the absence of ventilation. This prolongs the safe apnea time, in addition to that provided by preoxygenation alone. Apneic oxygenation provides oxygen rich mixture in pharynx and with a patent airway, bulk flow of gases occurs down a pressure gradient (and not molecular diffusion) resulting in improvement in arterial oxygen saturation. Preoxygenation is a prerequisite for apneic oxygenation. With inadequate preoxygenation and prolonged apnea time, oxygen concentration in alveoli is rapidly reduced and desaturation ensues before apneic oxygenation takes effect.

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•

•

•

Nasal cannula (prongs), nasopharyngeal catheter, tracheal catheter, endobronchial catheter and oxygenating laryngoscope have been used as interfaces for application of apneic oxygenation. Besides operating rooms, apneic oxygenation has proved its merits in intensive care units and emergency scenarios including out-of-hospital settings. Since apneic oxygenation improves arterial oxygenation with concomitant hypercarbia, it is recommended that apneic oxygenation should not be used for longer duration and should be avoided in patients with raised intracranial pressure or cardiac ailments.

REFERENCES 1. Drummond GB, Park GR. Arterial oxygen saturation before intubation of the trachea— an assessment of techniques. Br J Anesth. 1984;56(9):987-93. 2. Frumin MJ, Epstein RM, Cohen G. Apneic oxygenation in man. Anesthesiology. 1959;20:789-98. 3. Bartlett RG Jr, Brubach HF, Specht H. Demonstration of aventilatory mass flow during ventilation and apnea in man. J Appl Physiol. 1959;14(1):97-101. 4. Draper WB, Whitehead RW. Diffusion respiration in the dog anesthetized with pentothal sodium. Anesthesiology. 1944;5:262-73. 5. Weingart SD, Levitan RM. Preoxygenation and prevention of desaturation during emergency airway management. Ann Emerg Med. 2012;59(3):165-75. 6. Brandt L, Rudlof B. Physiology of apnea. DAAF Refresher Course Aktuelles Wissen für Anesthesisten Nr. 2007;33:211-20. 7. Baraka AS, Salem MR. In: Hagberg CA (Ed). Benumof and Hagberg’s Airway Management. 3rd edition. Philadelphia: Elsevier Saunders; 2013. pp. 280-97. 8. Bhatia PK, Bhandari SC, Tulsiani KL, et al. End-tidal oxygraphy and safe duration of apnea in young adults and elderly patients. Anesthesia. 1997;52(2):169-78. 9. Sakles JC, Mosier JM, Patanwala AE, et al. First pass success without hypoxemia is increased with the use of apneic oxygenation during rapid sequence intubation in the emergency department. Acad Emerg Med. 2016;23(6):703-10. 10. Ward JJ. High-flow oxygen administration by nasal cannula for adult and perinatal patients. Respir Care. 2013;58(1):98-122. 11. Brainard A, Chuang D, Zeng I, et al. A randomized trial on subject tolerance and the adverse effects associated with higher- versus lower-flow oxygen through a standard nasal cannula. Ann Emerg Med. 2015;65(4):356-61. 12. Taha SK, Siddik-Sayyid SM, El-Khatib MF, et al. Nasopharyngeal oxygen insufflation following preoxygenation using the four deep breath technique. Anesthesia. 2006;61(5):427-30. 13. Ramachandran SK, Cosnowski A, Shanks A, et al. Apneic oxygenation during prolonged laryngoscopy in obese patients: a randomized, controlled trial of nasal oxygen administration. J Clin Anesth. 2010;22(3):164-8. 14. Joels N, Samueloff M. Metabolic acidosis in diffusion respiration. Journal of Physiology. 1956;133(2):347-59. 15. Ritchie JE, Williams AB, Gerard C, et al. Evaluation of a humidified nasal high-flow oxygen system, using oxygraphy, capnography and measurement of upper airway pressures. Anesth Intensive Care. 2011;39(6):1103-10. 16. Duncan SR, Mihm FG, Guilleminault C, et al. Nasal continuous positive airway pressure in atelectasis. Chest. 1987;92(4):621-4. 17. Patel A, Nouraei SA. Transnasal humidified rapid-insufflation ventilatory exchange (THRIVE): A physiological method of increasing apnea time in patients with difficult airways. Anesthesia. 2015;70(3):323-9.

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18. Heinrich S, Horbach T, Stubner B, et al. Benefits of heated and humidified high flow nasal oxygen for preoxygenation in morbidly obese patients undergoing bariatric surgery: A Randomized Controlled Study. J Obes Bariatrics. 2014;1(1):7. 19. Miguel-Montanes R, Hajage D, Messika J, et al. Use of high-flow nasal cannula oxygen therapy to prevent desaturation during tracheal intubation of intensive care patients with mild-to-moderate hypoxemia. Crit Care Med. 2015;43(3):574-83. 20. Schumann R, Natov NS, Rocuts-Martinez KA, et al. High-flow nasal oxygen availability for sedation decreases the use of general anesthesia during endoscopic retrograde cholangiopancreatography and endoscopic ultrasound. World J Gastroenterol. 2016;22(47):10398-405. 21. Kumar P, Mcginlay M, Kelly C, et al. High-flow nasal oxygenation: A new tool to increase patient safety during awake craniotomy. J Neurosurg Anesthesiol. 2017;29(3):368-9. 22. Lucangelo U, Vassallo FG, Marras E, et al. High-flow nasal interface improves oxygenation in patients undergoing bronchoscopy. Crit Care Res Pract. 2012;2012:506382. 23. Ansari BM, Hogan MP, Collier TJ, et al. A randomized controlled trial of high-flow nasal oxygen (OptiFlow) as part of an enhanced recovery program after lung resection surgery. Ann Thorac Surg. 2016;101(2):459-64. 24. Rudlof B, Hohenhorst W. Use of apneic oxygenation for the performance of panendoscopy. Otolaryngol Head Neck Surg. 2013;149(2):235-9. 25. Scott JB, Gentile MA, Bennett SN, et al. Apnea testing during brain death assessment: A review of clinical practice and published literature. Respir Care. 2013;58(3):532-8. 26. Babinski MF, Sierra OG, Smith RB, et al. Clinical application of continuous flow apneic ventilation. Acta Anesthesiol Scand. 1985;29(7):750-2. 27. White LD, Melhuish TM, White LK, et al. Apneic oxygenation during intubation: a systematic review and meta-analysis. Anesth Intensive Care. 2017;45(1):21-7. 28. Gleason JM, Christian BR, Barton ED. Nasal cannula apneic oxygenation prevents desaturation during endotracheal intubation: An Integrative Literature Review. West J Emerg Med. 2018;19(2):403-11. 29. Achar SK, Pai AJ, Shenoy UK. Apneic oxygenation during simulated prolonged difficult laryngoscopy: Comparison of nasal prongs versus nasopharyngeal catheter: A prospective randomized controlled study. Anesth Essays Res. 2014;8(1):63-7. 30. Wong DT, Yee AJ, Leong SM, et al. The effectiveness of apneic oxygenation during tracheal intubation in various clinical settings: a narrative review. Can J Anesth. 2017;64(4):416-27. 31. Baraka AS, Taha SK, Siddik-Sayyid SM, et al. Supplementation of pre-oxygenation in morbidly obese patients using nasopharyngeal oxygen insufflation. Anesthesia. 2007;62(8):769-73. 32. Badiger S, John M, Fearnley R A, et al. Optimizing oxygenation and intubating conditions during awake fiberoptic intubation using a high flow nasal oxygen delivery system. Br J Anesth. 2015;115(4):629-34. 33. Vukovic AA, Hanson HR, Murphy SL, et al. Apneic oxygenation reduces hypoxemia during endotracheal intubation in the pediatric emergency department. Am J Emerg Med. 2018. 34. Chris Nickson. (2018). Apneic Oxygenation. [Online] Available from https:// lifeinthefastlane.com/ccc/apnoeic-oxygenation/. [Accessed on September, 2018]. 35. Hawthorne L, Wilson R, Lyons G, et al. Failed intubation revisited: 17-year experience in a teaching maternity unit. Br J Anesth. 1996;76(5):680-4. 36. Barnardo PD, Jenkins JG. Failed tracheal intubation in obstetrics: A 6-year review in a UK region. Anesthesia. 2000;55(7):690-4. 37. Pillai A, Chikhani M, Hardman JG. Apneic oxygenation in pregnancy: A modeling investigation. Anesthesia. 2016;71(9):1077-80. 38. Kettler D, Sonntag H. Apneic oxygenation using Tris-buffers during bronchography. Anesthesist. 1971;20(3):94-8.

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39. Oliveira JE Silva L, Cabrera D, Barrionuevo P, et al. Effectiveness of apneic oxygenation during intubation: A systematic review and meta-analysis. Ann Emerg Med. 2017;70(4):483-94. 40. Binks MJ, Holyoak RS, Melhuish TM, et al. Apneic oxygenation during intubation in the emergency department and during retrieval: A systematic review and meta-analysis. Am J Emerg Med. 2017;35(10):1542-46 41. Semler MW, Janz DR, Lentz RJ, et al. Randomized trial of apneic oxygenation during endotracheal intubation of the critically-ill. Am J Respir Crit Care Med. 2016;193(3): 273-80. 42. Vourc’h M, Asfar P, Volteau C, et al. High-flow nasal cannula oxygen during endotracheal intubation in hypoxemic patients: A randomized controlled clinical trial. Intensive Care Med. 2015;41(9):1538-48. 43. Caputo N, Azan B, Domingues R, et al. Emergency department use of apneic oxygenation versus usual care during rapid sequence intubation: A randomized controlled trial (The ENDAO Trial). Acad Emerg Med. 2017;24(11):1387-94. 44. Hasegawa K, Shigemitsu K, Hagiwara Y, et al. Association between repeated intubation attempts and adverse events in emergency departments: An analysis of a multicenter prospective observational study. Ann Emerg Med. 2012;60(6):749-54. 45. Mort TC. Emergency tracheal intubation: complications associated with repeated laryngoscopic attempts. Anesth Analg. 2004;99(2):607-13. 46. Wimalasena Y, Burns B, Reid C, et al. Apneic oxygenation was associated with decreased desaturation rates during rapid sequence intubation by an Australian helicopter emergency medicine service. Ann Emerg Med. 2015;65(4):371-6.

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12

Noninvasive Hemodynamic Monitoring Muralidhar Kanchi

INTRODUCTION Monitoring of the cardiovascular system is necessary for all patients under anesthesia, in the intensive care units and in emergency room. Monitoring of critically-ill patients requires constant vigilance and the ultimate goal is centered on optimizing tissue perfusion, maintenance of cellular respiration and prevention of end-organ damage.1 Knowledge of hemodynamics is necessary to ensure tissue oxygenation of the peripheral organs and to dictate the clinical management outcome parameters like postoperative complications, length of intensive care stay, length of hospital stay, mortality, acute renal failure, neurological insult so on and so forth.2 The cardiovascular system can be monitored by either invasive or noninvasive means and can be continuous or intermittent (Flowchart 1). Currently, invasive hemodynamic monitoring is preferred in patients with moderate to severe cardiovascular or respiratory disease and those undergoing major surgery, in critically-ill patients and in complex surgical procedures. However, invasive monitoring such has pulmonary artery catheters suffer from inherent disadvantages such as need for training both for insertion and interpretation of data, increased risk of complications and lack of benefit in terms of improved outcomes in the critically ill. This has led to a marked momentum in the development of noninvasive techniques of monitoring the hemodynamics. Flowchart 1: Methods of hemodynamic monitoring.

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TYPES OF HEMODYNAMIC MONITORS Depending on the degree of invasiveness, the hemodynamic monitors can be loosely categorized into invasive, semi-invasive, minimally-invasive and noninvasive. However, in the literature, there is no clarity on the definition of terms “invasive” and “noninvasive.” Additionally, there is a considerable overlap of meaning conveyed by the terms “less-invasive,” “semi-invasive” and “minimallyinvasive.” The noninvasive monitoring is widespread in its use but there are no prospective trials to demonstrate that such a monitoring improves clinical outcome. Despite this, noninvasive techniques are invaluable are extremely useful in determining patients who need advanced monitoring. From the discussion point of view and to avoid confusion, we will define each of the terms as follows: • Invasive: Techniques that breach the integrity of the skin or mucous membrane for example, a pulmonary artery floatation catheter (PAFC). • Less-invasive: This terminology is industry-driven and is specially applied to arterial catheter and/or a central venous catheter and this is “less-invasive” in comparison to a PAFC. • Semi-invasive: Those that depend upon the presence of an indwelling arterial catheter and/or a catheter in central vein. • Minimally-invasive: These invade the body cavity but don’t breach the integrity of the mucous lining such as urinary catheter and tansesophageal echocardiography. • Noninvasive: In this group we have those monitors that are attached to the skin surface and don’t pierce the skin surface and, that does not require arterial or central venous cannulation typical example being the electrocardiogram (ECG). The following monitoring methods will be used in this discussion but traditional modes of monitoring such as ECG, pulse oximetry, noninvasive armcuff based blood pressure and echocardiography will not be touched upon: • Advanced modes of noninvasive blood pressure. • Noninvasive methods of determination of filling pressures. • Noninvasive cardiac output.

NONINVASIVE MEASUREMENT OF ARTERIAL BLOOD PRESSURE Photoplethysmography The engineering principles of pulse oximeter have been adapted to determine hemodynamic parameters noninvasively. The plethysmographic signal is analogous to direct arterial pressure waveform. Researchers have looked into the possibility of using this observation to derive arterial blood pressure, fluid responsiveness, systemic vascular resistance, stroke volume and continuous cardiac output.3-6

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The following photoplethysmographic devices have been designed for continuous estimation of arterial blood pressure and are commercially available: • CNAP (CNSystems, Graz, Austria) • ClearSight (formerly called Nexfin; Edwards Lifesciences, Irvine, CA) • Finometer (Finapres Medical Systems, Amsterdam, Netherlands). These monitoring devices use a volume-clamp technique that employs a quick feedback loop between an oximeter and inflatable finger cuffs (similar to traditional blood pressure cuffs) to exhibit a continuous visual display of arterial pressure. Swift increase or decrease of the pressure in one or two cuffs to a point at which photoplethysmographic waveform oscillations are maximum and the digit’s inflow arterial pressure will equalize that in the cuffs. Though these devices are useful to recognize rapidly changing hemodynamics, a meta-analysis concluded these devices produce inaccurate and imprecise readings of arterial pressures, larger than what is acceptable.7 Nevertheless, current work has highlighted the successful use of these systems to measure cardiac output.8 Photoplethysmography can be combined with ECG to estimate pulse transit time, i.e. the time from a ventricular beat until blood is delivered to the oximetry site (Figs. 1A and B). This method has been successfully used to determine evanescent changes in blood pressure in patients following induction of anesthesia.9,10 This information can be tagged to patient-specific demographics to generate a continuous estimation of cardiac output. This technology has been incorporated into esCCO monitor (Nihon Kohden, Tokyo, Japan).5 Limitations of Photoplethysmography

•

•

Considerable processing is needed to cancel out noise from the oximeter signal. Noise is generated due to changes in tone of vasculature due to autonomic nervous variations, anesthesia, surgery, or critical illness. Many of the studies have demonstrated good to high correlation of photoplethysmography with gold standards in healthy controls and stable subjects but lose reliability in unstable and critical situations.6 However, photoplethysmography is an interesting and potentially useful method for hemodynamic monitoring.

Tonometry Arterial pressure in the radial artery can be measured noninvasively and electromechanically using applanation tonometers. This is similar to estimating pressure by palpating pulse amplitude. Continuous monitoring of arterial pressure and calculated cardiac output can be performed using the T-line device (Tensys Medical Inc., San Diego, CA). This device must be placed optimally over the radial artery to obtain a high-quality arterial waveform signal which may be challenging in a conscious patient.7

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A

B Figs. 1A and B: Pulse wave transit time (PWTT) derived from surface electrocardiogram (ECG) and pulse oximetry tracing.

DETERMINATION OF FILLING PRESSURES For determination of filling pressures, many techniques have been described. Substitutes for stroke volume have been introduced to assess volume status especially during intermittent positive pressure ventilation (IPPV).

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These surrogates include stroke volume variation (SVV), systolic pressure variation (SPV) and pulse pressure variation (PPV). These methods have been developed for dynamic assessment of preload. Recently, studies have promoted less-invasive and noninvasive techniques. These methods are extremely useful when no arterial line is in place, either in the surgical suite or in the intensive care unit. The ventilation-induced changes in arterial pulse pressure may be determined by: • Photoplethysmography with volume-clamp. • Stroke volume measurement by pulse contour analysis. • The velocity time integral (VTI) of blood flow in the left ventricular outflow tract (LVOT) at echocardiography. • Thoracic aortic blood flow by esophageal Doppler. • Amplitude of the plethysmographic signal has been established as preload responsiveness indicators. There is a suggestion that the variations of the peak velocity in the carotid or brachial arteries may reflect PPV and indicate preload responsiveness. Conditions where pulse pressure and stroke volume variations are not reliable include: • Spontaneous breathing. • Cardiac arrhythmias. • Low tidal volume. • Poor lung compliance. • Open chest. • Increased intra-abdominal pressure. • Very high respiratory rate (HR/RR < 3.6). • Right heart failure. • Intra-aortic balloon pump.

DETERMINATION OF CARDIAC OUTPUT Various invasive, semi-invasive, minimally-invasive and noninvasive methods to monitor cardiac output are detailed in Flowchart 2.

Noninvasive Cardiac Output Monitors Electrical Bioimpedance

The electrical impedance across the chest varies with the changes in amount of blood contained in the thorax during a cardiac cycle. In this concept that was originally developed in the 1960s, voltage-generating sensors are applied to the bare chest and electrical bioimpedance is measured. The difference between applied and detected voltage is mathematically extrapolated to derive the stroke volume. Suggested position of leads for measurement of cardiac output using bioimpedance technique is shown in Figures 2A and B. The following of bioimpedance monitors that measure cardiac output are available in the market currently: • The BioZ (CardioDynamics, San Diego, CA)

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Flowchart 2: Methods of monitoring cardiac output.

• PhysioFlow (NeuMeDx, Inc., Bristol, PA) • NICOMON (Larsen and Toubro Ltd., Mumbai, India) • NICCOMO (Medis, Ilmenau, Germany) • CSM3000 (Cheers Sails Medical, icationvShenzhen, China) devices.11 The advantages of this technology include noninvasiveness, easy application and economy. Significant disadvantages include unreliability due to presence of extravascular lung water due to pulmonary congestion, improper electrode placement, arrhythmia, concurrent electrical interference for example, by electrocautery, unsuitability during cardiac surgery when chest is open, and abnormal or unacceptable systemic vascular resistance values.12 A recent meta-analysis found discordant cardiac output values with bioimpedance when compared to standard techniques.13 In general, these devices are not

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A

B Figs. 2A and B: Suggested position of leads for measurement of cardiac output using bioimpedance technique.

recommended for intraoperative use or long-term monitoring in a critically-ill individual, but they may provide insight into CO in a stable patient in the ward or outpatient department. Thoracic Bioreactance

Thoracic bioreactance devices have been developed to overcome the limitations of bioimpedance where the impedance signal is processed differently. The algorithm used is expanded to determine the phase shift in transthoracic voltage which depends on thoracic resistance and capacitance.13 Current models of this system include: • NICOM (Cheetah Medical, Portland, OR) • AESCULON (Osypka Medical Services, Berlin, Germany).

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Though the influence of lung water on the measurements is minimized in bioreactance technique, this method has similar limitations as bioimpedance devices.11 Nevertheless, the NICOM system in particular has been found to be highly accurate in measuring CO when compared to transthoracic thermodilution measurements,14 although some studies have not found it to be as accurate in critically-ill patients.15,16

Minimally or Semi-invasive Monitors Minimally-invasive monitoring devices consist of those that require low-risk cannulation of peripheral veins or arteries or device insertion into natural orifices. While increasing the risk of patient harm, they overcome some of the limitations of noninvasive devices. For practical purposes, they are among the most feasible options for advanced cardiovascular monitoring in the ICU. Endotracheal Cardiac Output Monitor

The ECOM system (ConMed Corp., Utica, NY) measures the intrathoracic, rather than external, impedance. This is an effort to overcome some of the limitations of traditional bioimpedance method to measure cardiac output. This method uses electrodes within a specially designed endotracheal tube (Fig. 3). The accuracy of measuring impedance from within the trachea, which lies in close proximity to the aorta, is increased by electrode placement within a patient’s chest, thus avoiding some of the noise captured otherwise. This technique has shown promise in determining fluid responsiveness but the major drawback of this system centers around inaccuracy in calculating cardiac index. Also, the ECOM system is not totally noninvasive in that it requires the presence of an arterial catheter and is therefore more appropriately considered minimally-invasive. Partial Carbon Dioxide Rebreathing

The Fick principle is the statement that is used to derive the cardiac output. This statement elucidates that the amount of an indicator taken up by an organ in

Fig. 3: Showing endotracheal tube used for endotracheal CO monitor.

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unit time equals arteriovenous concentration difference of that indicator (A-V difference) times the blood flow. The Fick method conventionally uses oxygen (O2) and cardiac output is derived by measuring the amount of O2 consumed divided by the A-V difference across the lungs. This method is cumbersome in routine practice and hence this principle is applied to other respiratory gases such as carbon dioxide (CO2). Carbon dioxide has a high diffusion capacity, is easily measurable and is consistently produced in end organs. These characteristics make it an ideal respiratory gas for replacement of O2 in the Fick equation. As the partial pressure of end-tidal CO2 approximates mixed venous CO2 tension, CO can be calculated by intermittently permitting CO2 rebreathing (for example by adding additional dead space to the ventilatory circuit) and measuring the change in end-tidal CO2 as compared to measurement at a nonrebreathing time. This approach has been shown to correlate with cardiac output derived from a PAFC under most conditions. However, this CO2 rebreathing technique is flawed in states of low tissue production of CO 2 (e.g. hypothermia), with significant shunting and very high CO. Constant minute ventilation is mandatory requirement to ensure respiratory variation does not produce large swings in PaCO2 and this method is not applicable to spontaneously breathing patients.17-19 The NICO (Respironics, Murrysville, PA) (Fig. 4) is a common device that employs the partial CO2 rebreathing technique that derives the CO using the modified Fick principle. It fits into the category of semi-invasive or minimallyinvasive hemodynamic monitor as it needs that the patient’s trachea is intubated. There are conflicting results regarding the accuracy of the estimated cardiac output some claiming good correlation where as some others found poor agreement with gold-standard.18-21 Arterial Pulse Contour Analysis

Analysis of peripheral arterial waveforms to estimate cardiac output is one of the popular approaches to advanced hemodynamic monitoring in the last few years. Examination of pulse contour provides a mechanism to derive a variety of cardiovascular parameters such as stroke volume, stroke volume-index, cardiac output, cardiac index, stroke volume variation, systemic vascular resistance and several other derived parameters. In essence, stroke volume is derived by calculation of the area under the arterial pressure waveform curve and compliance and resistance of the arterial circuit is factored in with proprietary algorithms or known physiologic data based on patient age, height, weight, and gender.22 The devices that use pulse contour analysis to measure CO are as follows: • FloTrac Vigileo (Edwards Lifesciences, Irvine, CA) • LiDCO (LiDCO Ltd., London, England) • PiCCO (PULSION Medical Systems AG, Munich, Germany) • PRAM or MostCare (Vytech Health, Padova, Italy). The FloTrac or Vigileo uses pulse contour analysis to estimate the stroke volume and has undergone several software updates to improve the precision and accuracy. It is exceptional in that it does not involve manual calibration but

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Fig. 4: Cardiac output measurement using modified Fick’s principle (NICO).

is self-calibrated using demographic data to determine vascular compliance and resistance. It uses a company proprietary algorithm based on biophysical variables and calculates CO. In a simplistic manner with FloTrac or Vigileo: CO = PR × sd (AP) × X Where PR indicates pulse rate, sd (AP) indicates pulsatility by means of the standard deviation of the arterial pressure wave over a 20-sec period, and X represents a constant that computes arterial compliance and peripheral vascular resistance.23 The most recent FloTrac or Vigileo software generation does appear to be more accurate than its predecessors. However, all versions of this device may be inaccurate in situations with low systemic vascular resistance or high CO (e.g. patients with cirrhosis undergoing liver transplant) and can have disagreement with gold-standard methods of CO estimation.24 The lithium dilution cardiac output (LiDCO) (Figs. 5A to C) system is based on dyedilution method of determination of cardiac output; lithium is used to calibrate

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the pulse contour derived CO every few hours in this method. 0.3 M lithium is injected into a central or peripheral vein and a concentration curve is plotted by a lithium-sensing electrode incorporated within an indwelling arterial cannula. Distribution of lithium is restricted to plasma alone and hence the packed cell volume (PCV) is subtracted from the area under the curve as is shown in the equation:23 LiDCO CO = (Lithium dose × 60)/(Area × (1 − PCV)) Regardless of central or peripheral venous injection of lithium, LiDCO is shown to be a precise method to evaluate the CO including in critically-ill patients, during cardiac surgery and liver transplantation.25-28 The PiCCO system (Fig. 6) depends on a pulse contour analysis to determine cardiac output which is calibrated using a transpulmonary thermodilution principle. Known quantity of cold saline at room temperature is injected through a central venous cannula and the temperature change is determined down-stream in the arterial system by a thermistor-topped arterial cannula placed in the femoral artery. Recently, software of this method has been modified to consider the shape of the arterial waveform and measure aortic compliance and peripheral vascular resistance. Cardiac output is determined using the formula: PiCCO CO = cal × HR × ∫ [P(t)/SVR + C(p) × dP/dt]dt Where cal is the patient specific thermodilution calibration value, HR is heart rate, P(t)/SVR is the area of the waveform, C(p) is arterial compliance, and dP/dt accounts for the shape of the waveform.23 This technique is considered to be less-invasive as it does not require a PAFC but an arterial and central venous cannula is needed. There have been conflicting results using this transpulmonary thermodilution calibration technique but compares favorably with CO estimation as measured by PAFC thermodilution. 24,29,30 The PRAM/MostCare device uses pulse contour analysis to measure the cardiac output continuously using a proprietary method to derive beat-to-beat stroke volume. It is exceptional that it needs no calibration and uses data from an indwelling arterial cannula but does assume values of aortic elastance. The formula used to determine cardiac output is: PRAM CO = HR × [A/(P/t × K)] Where HR is heart rate, A is the area under the systolic portion of arterial pulse curve, P/t evaluates systolic and diastolic pressure over time, and K represents instantaneous pulsatile acceleration of the arterial cross-sectional area. PRAM/ MostCare is relatively a new technique using pulse contour analysis and its accuracy is unclear.24

Doppler Ultrasound Interaction of ultrasound with moving object produces changes in frequency as perceived by a stationary transducer (Doppler shift). Devices such as the

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A

B

C Figs. 5A to C: The lithium chloride indicator dilution method of measuring cardiac output.

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Fig. 6: Configuration of PiCCO system.

ultrasound CO monitor (USCOM, Sydney, Australia), CardioQ (Deltex Medical, Chichester, UK), and the HemoSonic 100 (Arrow International, Reading, PA) use this principle of Doppler technology to determine the velocity and direction of blood flow and derive the stroke volume from the velocity time integral and the cross-sectional area. The USCOM measures flow across one of the semilunar valves, namely aortic or pulmonary valve using a handheld probe positioned on the thoracic inlet or anterior chest wall. The CardioQ and HemoSonic 100 are esophageal probes that measure flow in the descending thoracic aorta. Alterations in the velocity-time integral (VTI) indicate changes in CO, and these devices are somewhat protected from confounding caused by variations in systemic vascular resistance. They periodically need to be refocused on the outflow tract of interest and cannot be used continuously. Improper positioning can potentially lead to incorrect aortic or pulmonary outflow tract area calculations. Additionally, abnormal relationships between the thoracic inlet, chest wall, or esophagus and the aortic and pulmonic outflow tracts may lead to inaccurate velocity-time integral calculation.11,31

CONCLUSION Hemodynamic monitoring is an essential component of management of patients under anesthesia and in critical care situations. Noninvasive approach has shown considerable promise but in critical care situations and high-risk surgery, the validity of noninvasive monitoring is not yet firmly established. An algorithmic approach to select the appropriate monitor is given

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Flowchart 3: Algorithm for hemodynamic monitoring in high-risk surgery/critically ill patients.

(TEE: transesophageal echocardiography; TTE: transthoracic echocardiography; OED: esophageal Doppler; LiDCO: lithium dilution cardiac output; PiCCO: pulse contour cardiac output; ECOM: endotracheal cardiac output; CNAP: continuous noninvasive blood pressure; esCCO: estimated continuous cardiac output).

in Flowchart 3. The research is on to develop a hemodynamic monitoring that is accurate and universally applicable. A thorough understanding of the available devices is mandatory for appropriate selection of a given device to provide optimal care to patients.

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KEY POINTS • •

•

•

• • •

•

•

Hemodynamic monitoring is a key to assess the status of the cardiovascular system and can be invasive, noninvasive; continuous or intermittent. Invasive monitoring such as pulmonary artery catheters and has increased risk of complications and lack of benefit in terms of improved outcomes in the critically-ill. Currently, the focus is on the development of reliable noninvasive monitoring of CVS which is accurate, inexpensive and can be applied in a variety of situations. Photoplethysmography used to monitor blood pressure and cardiac output has high correlation in healthy controls but loses reliability in unstable, critical situations. Applanation tonometry measures arterial blood pressure and calculated cardiac output. Stroke volume variations, systolic pressure variation and pulse pressure variations are used for dynamic assessment of preload. Electrical Bioimpedance and Thoracic Bioreactance measure cardiac output noninvasively, whereas Fick principle and arterial pulse contour analysis are minimally or semi-invasive methods used to measure cardiac output. Noninvasive approach has shown considerable promise but in critical care situations and high-risk surgery, the validity of noninvasive monitoring is not yet firmly established. A thorough understanding of the available devices is mandatory for appropriate selection of a given device to provide optimal care to patients.

REFERENCES 1. Vincent JL, De Backer D. Circulatory shock. N Engl J Med. 2013;369(18):1726-34. 2. Grocott MPW, Dushianthan A, Hamilton MA, et al. Perioperative increase in global blood flow to explicit defined goals and outcomes after surgery: A Cochrane Systematic Review. Br J Anesth. 2013;111(4):535-48. 3. Young CC, Mark JB, White W, et al. Clinical evaluation of continuous noninvasive blood pressure monitoring: accuracy and tracking capabilities. J Clin Monit. 1995;11(4): 245-52. 4. Thiele RH, Colquhoun DA, Patrie J, et al. Relationship between plethysmographic waveform changes and hemodynamic variables in anesthetized, mechanically ventilated patients undergoing continuous cardiac output monitoring. J Cardiothorac Vasc Anesth. 2011;25(6):1044-50. 5. Ball TR, Tricinella AP, Alex Kimbrough B, et al. Accuracy of noninvasive estimated continuous cardiac output (esCCO) compared to thermodilution cardiac output: A pilot study in cardiac patients. J Cardiothorac Vasc Anesth. 2013;27(6):1128-32. 6. Bartels K, Thiele RH. Advances in photoplethysmography: Beyond arterial oxygen saturation. Can J Anesth. 2015;62(12):1313-28. 7. Kim SH, Sang-Hyun K, Marc L, et al. Accuracy and precision of continuous noninvasive arterial pressure monitoring compared with invasive arterial pressure: A systematic review and meta-analysis. Anesthesiology. 2014;120(5):1080-97.

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8. Wagner JY, Negulescu I, Schöfthaler M, et al. Continuous noninvasive cardiac output determination using the CNAP system: Evaluation of a cardiac output algorithm for the analysis of volume clamp method-derived pulse contour. J Clin Monit Comput. 2015;29(6)807-13. 9. Kim SH, Song JG, Park JH, et al. Beat-to-beat tracking of systolic blood pressure using noninvasive pulse transit time during anesthesia induction in hypertensive patients. Anesth Analg. 2013;116(1):94-100. 10. Sharwood-Smith G, Bruce J, Drummond G. Assessment of pulse transit time to indicate cardiovascular changes during obstetric spinal anesthesia. Br J Anesth. 2006;96(1): 100-5. 11. Critchley LA, Lee A, Ho AM. A critical review of the ability of continuous cardiac output monitors to measure trends in cardiac output. Anesth Analg. 2010;111(5):1180-92. 12. Saugel B, Cecconi M, Wagner JY, et al. Noninvasive continuous cardiac output monitoring in perioperative and intensive care medicine. Br J Anesth. 2015;114(4): 562-75. 13. Peyton PJ, Chong SW. Minimally invasive measurement of cardiac output during surgery and critical care: a meta-analysis of accuracy and precision. Anesthesiology. 2010;113(5):1220-35. 14. Raval NY, Squara P, Cleman M, et al. Multicenter evaluation of noninvasive cardiac output measurement by bioreactance technique. J Clin Monit Comput. 2008;22(2): 113-9. 15. Fagnoul D, Vincent JL, Backer DD. Cardiac output measurements using the bioreactance technique in critically-ill patients. Crit Care. 2012;16(6):460. 16. Raue W, Swierzy M, Koplin G, et al. Comparison of electrical velocimetry and transthoracic thermodilution technique for cardiac output assessment in critically ill patients. Eur J Anesthesiol. 2009;26(12):1067-71. 17. Cuschieri J, Rivers EP, Donnino MW, et al. Central venous-arterial carbon dioxide difference as an indicator of cardiac index. Intensive Care Med. 2005;31(6):818-22. 18. Marik PE. Noninvasive cardiac output monitors: a state-of-the-art review. J Cardiothorac Vasc Anesth. 2013;27(1):121-34. 19. Rocco M, Spadetta G, Morelli A, et al. A comparative evaluation of thermodilution and partial CO2 rebreathing techniques for cardiac output assessment in critically-ill patients during assisted ventilation. Intensive Care Med. 2004;30(1):82-7. 20. Odenstedt H, Stenqvist O, Lundin S. Clinical evaluation of a partial CO2 rebreathing technique for cardiac output monitoring in critically ill patients. Acta Anesthesiol Scand. 2002;46(2):152-9. 21. Nilsson LB, Eldrup N, Berthelsen PG. Lack of agreement between thermodilution and carbon dioxide-rebreathing cardiac output. Acta Anesthesiol Scand. 2001;45(6):680-5. 22. Thiele RH, Durieux ME. Arterial waveform analysis for the anesthesiologist: Past, present, and future concepts. Anesth Analg. 2011;113(4):766-76. 23. Maus TM, Lee DE. Arterial pressure-based cardiac output assessment. J Cardiothorac Vasc Anesth. 2008;22(3):468-73. 24. Schlöglhofer T, Gilly H, Schima H. Semi-invasive measurement of cardiac output based on pulse contour: A review and analysis. Can J Anesth. 2014;61(5):452-79. 25. Linton R, Band D, O’Brien T, et al. Lithium dilution cardiac output measurement: a comparison with thermodilution. Crit Care Med. 1997;25(11):1796-800. 26. Jonas MM, Kelly FE, Linton RA, et al. A comparison of lithium dilution cardiac output measurements made using central and antecubital venous injection of lithium chloride. J Clin Monit Comput. 1999;15(7-8):525-8. 27. Mora B, Ince I, Birkenberg B, et al. Validation of cardiac output measurement with the LiDCOTM pulse contour system in patients with impaired left ventricular function after cardiac surgery. Anesthesia. 2011;66(8):675-81.

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28. Costa MG, Rocca GD, Chiarandini P, et al. Continuous and intermittent cardiac output measurement in hyperdynamic conditions: pulmonary artery catheter vs. lithium dilution technique. Intensive Care Med. 2008;34(2):257-63. 29. Meier-Hellmann A, Sakka SG, Reinhart K. Comparison of pulmonary artery and arterial thermodilution cardiac output in critically-ill patients. Intensive Care Med. 1999;25(8):843-6. 30. Staier K, Wilhelm M, Wiesenack C, et al. Pulmonary artery vs. transpulmonary thermodilution for the assessment of cardiac output in mitral regurgitation: a prospective observational study. Eur J Anesthesiol. 2012;29(9):431-7. 31. Critchley LA, Huang L, Zhang J. Continuous cardiac output monitoring: What do validation studies tell us? Curr Anesthesiol Rep. 2014;4(3):242-50.

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CHAPTER

13

Role of Extraglottic Devices in Children Deepanjali Pant, Archna Koul

INTRODUCTION Management of the difficult pediatric airway has benefitted greatly from the introduction of extraglottic devices (EGDs). As the name suggests, EGD is a generic description for airways that remain outside the glottis, serving the same purpose of ventilation and oxygenation like the conventional infraglottic airway device, i.e. endotracheal tube (ETT). Following the clinical introduction of classic laryngeal mask airway (cLMATM) by Dr Archie IJ Brain in 1988, a variety of EGDs with numerous modifications to improve clinical safety and efficacy have entered the airway market. The intent of this chapter is to review the status of different EGDs currently available for pediatric airway management, based on recent evidencebased literature. Airway management is an essential skill for safe anesthesia practice in the pediatric age group, as most of the critical incidents relevant to pediatric anesthesia relate to airway and/or ventilation problems. Prior to the introduction of the LMA®, the options for airway management were either facemask or endotracheal tube. Adequate ventilation with facemask at times may be very difficult or ineffective leading to hypoxia and hypercarbia. Invention of the ETT made major and lengthy surgical procedures safe and feasible even in small babies. However, endotracheal intubation (ETI) is a critical intervention and the skill needs to be mastered well to avoid associated risks of trauma, hypoxia, etc. EGD occupies a position in between the facemask and ETT and provides a cost-effective, less-invasive and hands-free airway management in pediatric patients.

INDICATIONS Though the gold standard for safe airway control is still considered to be tracheal intubation with an endotracheal tube, the extraglottic airway device is holding its own as primary airway in routine and emergency cases, though the risk of aspiration must be taken into account.1 The EGDs are invaluable in the difficult airway scenario in the hospital and out of hospital settings.2 Apart from its use as the main airway device the EGD can also function as a conduit for guiding the endotracheal tube into the trachea, either blindly or using a bougie or fiberscope.1 They are also an integral part of neonatal resuscitation.

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TYPES OF EXTRAGLOTTIC DEVICES Extraglottic devices in contemporary use in pediatric age group are listed in Table 1. They can broadly be grouped as: • Laryngeal mask airways (LMAs) • Laryngeal masks and others: −− Laryngeal tube (LT) and laryngeal tube suction device (LTS II) −− Cobra perilaryngeal airway (CobraPLATM) and Cobra plus −− Streamlined liner of pharyngeal airway (SLIPATM) −− i-gel® −− Intubating laryngeal airway-Air Q®. There are several classifications of the EGDs mainly based on their design or functional evolution which are detailed in Table 2.3 The early versions of pediatric EGDs such as the LMA® were just smaller copies of the adult device. Even now very few EGDs have been designed keeping in mind the unique features of the pediatric airway. These include the Air-Q® with a wide curved airway tube and a ventilating orifice to prevent the epiglottic downfolding that is common in the pediatric airway. This EGD also aids in tracheal tube placement in infants and children.

SIGNIFICANCE OF ANATOMICAL DIFFERENCES FROM ADULTS Anatomical differences in the airway between children and adults are most evident in infants and smaller babies. Knowledge of these differences is critical for successful airway management with EGDs using appropriate modification in positioning and selection of type and size of equipment.4 The hypopharynx or esophagus is the seat for the distal end of a properly placed EGD, the cuff or the base of the device surround the supraglottic region, forming an effective seal. Thus, they are also known as supraglottic airway devices (SADs/SGDs). • A relatively large head and a prominent occiput in relation to body size cause slight flexion at the neck in supine position. Thus, a support under the shoulder or neck or head is required according to the age and size of the baby to facilitate the alignment of external auditory meatus-sternal notch axis for insertion of EGD. • A relatively large tongue and a large floppy acutely posteriorly angled epiglottis over the glottic inlet may affect easy insertion of EGD and cause frequent down folding of epiglottis in small babies. • Higher and anterior position of glottis (C1 in infants, C3 by age of 7, C6 in late adolescents) in smaller babies may affect positioning of a few EGDs as they are mostly downsized forms of adult equipment. • Pediatric trachea is more flexible and prone to dynamic collapse. EGDs are relatively contraindicated in tracheomalacia.5 • Most children have relatively prominent tonsillar and adenoidal tissue, which makes them prone to bleeding even with minor trauma and upper airway obstruction if not fully awake.

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Perilaryngeal

Perilaryngeal

Perilaryngeal

LMA UniqueTM 1997/polyvinyl chloride (PVC) (Fig. 2)

LMA® Flexible 1993/silicon and PVC (Fig. 3)

Sealing site

cLMA (LMA Classic) 1988/silicone (Fig. 1)

TM

Name of extraglottic devices/ year/material

3 sizes #2 10–20 kg # 2.5 20–30 kg #3 30–50 kg

Same as classic LMA

5 sizes #1 < 5 kg # 1.5 5–10 kg #2 10–20 kg # 2.5 20–30 kg #3 30–50 kg

Size (Pediatric use)

•

• •

•

• •

• •

Long, narrow, flexible wirereinforced airway tube Reusable and disposable Difficulty to insert and may require a stylet to stiffen Tube can be moved out of surgical field without loss of seal or cuff displacement

Disposable cLMATM Easy to insert

Reusable Easy to insert

Description

Table 1: Extraglottic devices in contemporary use in pediatric age group.

• •

• •

• •

Intraoral surgery Head and neck surgery

Short elective surgery Field situation

Short elective surgery Difficult or failed intubation

Clinical application

•

•

•

• •

•

•

•

• •

Contd ...

Low OSP Unsuitable for prolonged spontaneous ventilation Kink proof but does not prevent obstruction from biting Malposition less earily diagnosed as tube doesnot give clear indication of cuff orientation Acts as a barrier, prevents soiling of glottis by blood or secretions in tonsillectomy

Stiffer tube and less compliant cuff Avoid cross-contamination

Low OSP Mainly for spontaneous respiration No aspiration protective

Special feature

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Size and cuff volume same as classic LMA

Solus LMA (Fig. 7)

Same as classic LMA

Size and cuff volume same as classic LMA

Perilaryngeal

LMA® Supreme 2007/PVC (Fig. 5)

Same as classic LMA

Size (Pediatric use)

Soft Seal LMA (Portex) PVC (Fig. 6)

Perilaryngeal

Sealing site

PLMA (LMA ProSeal) 2000/silicone (Fig. 4)

TM

Name of extraglottic devices/ year/material

Contd ...

•

•

•

•

• •

• • •

• • •

Includes standard, MRI compatible and flexible tube LMA®

Similar to LMA ® unique but large oval cuff deeper bowl, no tapering at tip. No epiglottic bar, clear shaft allows easier visualization of secretion and exhaled condensation Embedded blue pilot line exits proximally, so remains out of way and less irritation

Disposable PLMATM Preformed semi rigid airway tube Easy insertion without finger or introducer

Reusable Reinforced airway tube Drain tube allows passage of gastric tube and venting of gastric gas and liquid Integrated bite-block Cup deeper, no bar Second dorsal cuff in > # 3

Description

•

•

•

• •

• • •

Disposable

Disposable, cost-effective, eliminates risk of cross-infection Easy access for flexible fibreoptic devices

Same as PLMATM Reinforced cuff prevent folding of mask

IPPV Laparoscopic procedure Difficult and failed intubation

Clinical application

•

•

•

• •

•

• •

Contd ...

MRI compatible—ferrous free option with MRI logo

Made of PVC—less permeable to N2O Pilot balloon labeled with size and maximum cuff volume

OSP less than PLMATM More stability

High OSP Softer cuff, larger proximally, better seal Aspiration protection

Special feature

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Perilaryngeal

Perilaryngeal

Ambu Aura-i laryngeal mask (Fig. 10)

Intubating LMA ILMA, Fastrach 1997/ Silicone, PVC (Fig. 11)

Perilaryngeal

Perilaryngeal

TM

Sealing site

Ambu® Aura GainTM2014 PVC (Phthalates free) (Fig. 9)

Ambu AuraOnce 2007/PVC (Fig. 8)

®

Name of extraglottic devices/ year/material

Contd ...

# 3 30–50 kg with ETT 6 mm

Size and cuff volume same as classic LMA

Size and cuff volume same as classic LMA

Size and cuff volume same as classic LMA

Size (Pediatric use)

•

• •

•

•

• • •

•

•

•

• •

Easy to use Short wide rigid tube to accommodate ETT. Integrated bite block Attached metal handle aid on handed insertion, adjustment and stabilization during ETT insertion

ETT size indication on connector black Latex-free

Shorter wide preformed airway tube Narrow drain tube Higher insertion success rate Disposable

Higher-insertion success short Rigid, curved (70°) airway tube Aligns anatomical airway, especially in smaller babies Reinforced mask tip does not bend during insertion Convenient depth marks, no aperture bar

Description

•

• •

•

• •

• •

• •

Unsuitable for MRI unit Primary use in difficult and failed intubation To aid intubation (blind/ visually guided)

High OSP, Suitable for spontaneous and controlled ventilation Difficult and failed intubation

Disposable Suitable for spontaneous ventilation short elective procedures Difficult and failed intubation Cost effective in infected cause

Clinical application

• •

•

•

•

•

• •

• • •

Contd ...

High incidence of airway morbidity No aspiration protection Reinforced high-pressure low volume cuff not for prolonged use was of importance prior to introduction of Air-Q

Conduit for intubation in difficult airway

Better protection against aspiration MR safe, phthalate free

Low OSP No aspiration protection Softer, more exible cuff than LMA® MR Safe, new versions phthalate free

Special feature

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Base of tongue

Streamlined liner of pharyngeal airway soft plastic (SLIPATM) 2002/Ethylene-vinyl acetate copolymer (Fig. 15)

#35 #39 #43

5–10 kg 10–20 kg 20–30 kg

#1 New Born (purple) #1.5 1–2 years (orange) #2 2–5 years (dark blue) #2.5 Large child (white)

Perilaryngeal

•

•

•

• •

•

•

•

Baska mask® 2012/Silicone (Fig. 14)

< 4 kg 4–7 kg 7–17 kg 17–30 kg 30–50 kg

• •

#0.5 #1.0 #1.5 #2 #2.5

Perilaryngeal

Non-cuffed, latex free, anatomically preformed, softens to body temperature to fit laryngeal structure No integrated bite block

Non-inflatable cuff, anatomic seal Membranous bowl 2 enlarged gastric drainage ports Insertion tab can increase angulation for negotiation, color coded connector

Oval mask Curved, wider and shorter airway tube An orifice designed to prevent epiglottic folding No gastric drain

Similar to ILMA, but with two built-in fiberoptic channels which emerge under epiglottic bar. One channel transmits light, the other conveys image to monitor at proximal end attached via a magnetic latch connector

Description

Air Q® Intubating laryngeal airway/2012 (Fig. 13)

Size (Pediatric use) •

Sealing site

LMA C-Trach 2005 (Fig. 12)

Name of extraglottic devices/ year/material

Contd ...

• •

•

•

• • •

•

• •

Single use Short elective surgery

Spontaneous and controlled ventilation Difficult and failed intubation

Easy insertion 99% in first attempt 2 versions for pediatric use: −− Standard-cuffed −− Self-pressurized (no in atable cuff)

Awake intubation Very useful in unstable cervical spine Indication and insertion technique same as ILMA

Clinical application

•

•

•

•

•

•

•

•

•

Contd ...

Sticks to pharynx and palate Hollow boot shaped chamber provides storage for 50 mL pharyngeal secretions—reduces risk of pulmonary aspiration

Better protection against aspiration Advanced self-sealing variable pressure cuffed

Accommodates standard cuffed ETT Can be safely removed after intubation

Battery operated, rechargeable Autoclavable up to 20 times Real-time image of glottis – improves first-attempt intubation rate

Special feature

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Base of tongue

Base of tongue

Base of tongue

LTS – II 2004/Silicone and PVC (Fig. 16)

Cobra Perilaryngeal airway (PLA) PVC 2003 (Fig. 17)

Sealing site

Laryngeal tube 1999 Silicone and PVC (Fig. 16)

Name of extraglottic devices/ year/material

Contd ...

#0.5 #1.0 #1.5 #2

2.5–7.5 kg 7.5–15 kg 16–30 kg 31–60 kg

Same sizes

6 sizes with color coded connector # 0 10 Transparent < 5 # 1 20 White 5–10 kg # 2 35 Green 12–25 kg # 2.5 60 Orange 125–150 cm

Size (Pediatric use)

•

•

•

•

• •

•

Single use single lumen airway tube Wide, tapered, flexible, distal end (cobra head design)

Most recent version of LT family High OSP. Additional esophageal lumen ends just distal to esophageal cuff for suction and gastric tube placement

Wide and curved single lumen tube Piration Two anterior facing oval shape ventilator outlets in between two low volume high pressure cuffs Large proximal oropharyngeal cuff near middle of tube, small distal esophageal cuff near blind distal tip. Single inflation tube

Description

• •

•

•

•

Short elective surgery Difficult and failed intubation

First-line device in a difficult airway

Both spontaneous and controlled Difficult airway scenario

Clinical application

•

•

•

•

• • •

•

Contd ...

Higher sealing pressure than cLMATM No aspiration protection

Better ventilation and less gastric insufflation as compared to LT

Easy atraumatic insertion Out of hospital use Low gastric inflation as distal cuff blocks esophageal inlet Protects against aspiration

OSP and aspiration protection similar to PLMATM, but better than cLMATM

Special feature

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Sealing site

Base of tongue

Perilaryngeal

Perilaryngeal

Name of extraglottic devices/ year/material

Cobra plus PLA

i-gel® 2007/SEBS (Styrene Ethylene Butadiene Styrene) (Fig. 18)

Shiley LM PVC/(Fig. 19)

Contd ...

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2–5 kg 5–12 kg 10–25 kg 25–35 kg

Greater tensile strength, easier insertion, less occlusion Less flexible, integrated inflation tube

#1.0 #1.5 #2 #2.5

Same as Cobra PLA

Size (Pediatric use)

•

• •

• •

• •

•

•

•

Disposable

Noninflating soft-gel cuff Narrow drain tube on left side (#1 has no drain tube) Epiglottis blocker present Buccal cavity stabilizer aids insertion and prevents rotation Rigid tube works as bite-block Color-coded polypropylene “protective cradle”

Low pressure, high volume oval cuff attached proximal to wide part (< 25 cm H2O). Large lumen as a conduit for ETT or fiberscope Short breathing tube allows ETT to pass below vocal cords without removing it

Description

•

• •

• •

Larger inner diameter of shaft than other devices of similar size

Disposable Both spontaneous and controlled ventilation MR safe Difficult and failed intubation

Clinical application

•

•

• • •

• •

•

•

•

More resistant to compression Curvature identical to that of ETT, does not differ across different sizes

No compression trauma as thermoplastic elastomer gets an anatomic seal Higher insertion success OSP between cLMA TM and PLMATM Reliable seal Aspiration protection Better stability

A distal curve in addition for easier placement and a thermistor on pharyngeal cuff for intraoperative temperature monitor

Serious of slots on ventilatory end prevents obstruction by epiglottic

Special feature

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Fig. 1: Classic LMA.

Fig. 2: LMA Unique.

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Fig. 3: Flexible LMA.

Fig. 4: ProSeal LMA.

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Fig. 5: LMA Supreme.

Fig. 6: Soft Seal LMA.

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Fig. 7: Solus LMA.

Fig. 8: Ambu Aura Once Mask.

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Fig. 9: Ambu Aura Gain LM.

Fig. 10: Ambu Aura I LM.

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Fig. 11: Intubating LMA.

Fig. 12: LMA C-Trach.

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Fig. 13: AirQ Intubating Laryngeal Airway.

Fig. 14: Baska Mask.

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Fig. 15: Streamlined liner of pharyngeal airway (SLIPA).

Fig. 16: Laryngeal tube-laryngeal tube suction (LT-LTS).

Fig. 17: Cobra perilaryngeal airway (Cobra-PLA).

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Fig. 18: i-gel

Fig. 19: Shiley laryngeal mask (LM).

•

Small children are usually dependent on diaphragmatic excursion for ventilation and have relatively large stomach with lower gastroesophageal sphincter tone. Thus, they are more predisposed to gastric insufflations during bag mask ventilation (BMV) attempts prior to EGD insertion or in case of improper positioning of EGD. Gastric insufflations impede diaphragmatic movement, thus compromising ventilation.

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• Reusable (cLMATM, LTS II) • Disposable (i-gel®, AAG)

• Disposable ones are cheaper and easier to maintain • Prevention of disease transmission and prion disease. • Useful in resuscitation and field situation.

• Higher OSP (first-seal) and hypopharyngeal seal (second-seal) are important safety factor • SLIPATM has a different mechanical

• Simple airway device • Improves PPV and protection against aspiration • Dynamic sealing mechanism.

Material used

Presence of gastric tube or reservoir to protect against aspiration

Single airway tube Specific design with drain tube Facilitates intubation

• 1st generation (cLMATM, Cobra PLATM, LT) • 2nd generation (PLMATM, LTS II, i-gel®, SLIPATM, AAG) • 3rd generation (Baska mask®, Elisha)

• With drain tube (PLMATM, i-gel®) or reservoir (SLIPATM) • Without drain tube (LMA®)

• Perilaryngeal sealer (LMAs and LMs) • Peripharyngeal sealer (LT, LTS-II, Cobra PLATM • Cuffless anatomically preshaped sealer (SLIPATM, i-gel®)

• Supraglottic-seal around glottic inlet and remain • Supraglottic (cLMATM, PLMA, Ambu mask) superior to larynx • Retroglottic (LT, LTS—II) • Retroglottic—distal end terminates in upper esophagus, remain posterior to glottis

Distal end location in relation to glottis

Sealing mechanization Seal perilaryngeal area or at base of the tongue

• Cuffless devices—MR compatible as pilot balloon • Cuffed (cLMATM, PLMATM) (carrying ferromagnetic material) of cuff inflation • Uncuffed (i-gel®, Baska Mask®) assembly is absent • Cuff-related morbidity absent but increased risk of leaks

Presence of inflatable cuff

Classification (Examples)

Significance

Classification criteria

Table 2: Classification of extraglottic airway devices for children.

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FACTORS AFFECTING CORRECT PLACEMENT The EGDs are usually inserted blindly always via oral route for elective as well as emergency airway control. Flexibility of shaft and dome affects ease of insertion and function. But better compliance due to malleability of shaft with patient’s anatomy comes at the price of requiring more force for device insertion. Increased flexibility of dome or cuff is associated with an effective seal but increases chance for folding during insertion. The factors for an effective EGD placement include shape of the palatopharyngeal curve, pharyngeal tone, position of the head and neck and anesthesia depth. Ventilation via the facemask is maintained till conditions are conducive to EGD placement like loss of eyelash reflex, jaw relaxation and absence of movement. Since EGD placement is a blind technique, suboptimal positioning may be a common occurrence. Multiple methods exist for insertion of LMA in children with varying success rates.6 Though a significant number of anesthesiologists routinely use the digital method of insertion, the introducer aided approach is the manufacturer’s recommended technique for PLMATM insertion in children. In contrast to standard technique, 180° rotational technique with a partially inflated cuff improved ease of insertion of CLMATM 7 whereas 90° rotation technique for PLMATM insertion demonstrated an increased ease of insertion with reduced pharyngeal trauma.8 Successful placement is clinically assessed by the ability to ventilate easily, with visual inspection of adequate chest rise without significant resistance or leak and smooth expiration, to rapidly refill the reservoir bag. In addition, the square wave capnography confirms it. Signs of displacement include: • Low-expired tidal volume • Inadequate chest expansion • Audible leak • An abrupt fall in airway pressure because of loss of seal between cuff and periglottic tissue. In case of suspected dislodgement, minor airway interventions removal of the device and replacement and if required, finally tracheal intubation is to be done. The EGDs with inflatable cuffs have a manufacturer’s recommended volume of air for inflation. Overinflation of cuff to compensate for a leak when the EGD used is too small for a child is a commonly used wrong practice.9 Overinflation of cuff beyond normal range (< 60 cm H2O) may compress the structures around the pharynx and larynx and may also cause loss of seal due to displacement. These cuff-pressure related morbidities are best minimized with the use of recent better cuff related technologies such as use of a continuous cuff pressure monitor in routine practice (Fig. 20).10 The efficacy of an EGD depends on its oropharyngeal seal pressure (OSP) or oropharyngeal leak pressure (OLP/OPLP). OSP is an effective indicator for assessing the efficacy of EGDs in protecting airway and providing positive pressure

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Fig. 20: Cuff pressure monitoring.

ventilation (PPV). OSP is assessed by closing the expiratory valve with a fresh gas flow of 3 L/min, then releasing the expiratory valve completely when gas leak is audible at the mouth or with stethoscope at the epigastrium or attainment of an equilibrium state of airway pressure. The digital readout of airway pressure on anesthesia machine is the OSP and is not permitted to exceed 30 cm of H2O. PLMA provides better PPV characteristics by allowing higher OSP with decreased rate of gastric insufflations when compared with CLMA.1 Leak pressure of EGD in children is lower than in adults, but PPV is possible even with these low leak pressures. First seal of a PLMA implies ability to ventilate and second seal is against the upper esophageal sphincter. Sometimes one seal can occur without the other if the epiglottis is trapped or mask is malpositioned. To check the second seal, viscous water-soluble sterile lubricant is applied to cover the proximal end of the drain tube. If the device is properly positioned, on manual ventilation the gel remains as such, but if it bubbles or blows off, the device needs to be positioned more deeply and checked again. Evidence-based literature is usually based on comparison of EGDs with ETT as the gold standard or amongst each other with regard to OSP, success rate of insertion at first attempt, ease of insertion, time taken for insertion, glottis-view grading on fiberscope and overall complications. Data from different studies is enumerated in Table 3.1 A fiberscope is inserted through the airway port up to the end of shaft and fiberoptic view is graded as:1 • Grade 1: Full-view of glottis • Grade 2: Partial-view of glottis

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• Prospective, randomized single center trial/palatoplasty

66/10–20 kg

90/1–6 years (10–20 kg) 60/1–12 years

1498

100/3 months to 6 years 40/2–5 kg

i-gel® #2/PLMATM#2/ cLMATM #2

i-gel®/PLMATM

LMA®/ETT

AAG/LMA® supreme TM

cLMATM #1/ i-gel® # 1

SLIPATM/LMA –U

Das B et al.,38 2012

Saran S et al.,39 2014

Luce V et al.,40 2014

Jagnnathan N,41 2016

Pant D et al.,42 2016

Zhu W et al.,43 2016 100/2 months to 12 years

Meta-analysis = 19 RCTs. 12 studies—muscle relaxant 16 studies—controlled ventilation

RCT/Paralyzed/PCV

Prospective randomized observational study/daycare surgery

RCT

• • •

RCT Elective short duration surgery (1–2 h) Paralyzed children

• •

Prospective randomized study

Randomized, crossover study 30 children Anesthetized, nonparalyzed

FLMA/RAE

•

Kundra P et al.,26 2009

Type of study

CLMA vs. PLMA

Goldmann K et al.,37 2005

2–30 months 5–12 kg

Device compared

Author/year

No of patients/ age group

Table 3: Summary of comparative studies on extraglottic devices in pediatric patients.

OSP significantly higher in i-gel® group Hemodynamic ease of insertion and postoperative complication were comparable

LMA-STM required more airway maneuver AAG useful alternative to LMA-STM in children

In LMA ® group postoperative complications like desaturation, cough laryngospasm and breath holding was less

•

•

Contd ...

Both are efficient in paralyzed children without severe complication SLIPATM—OSP significantly higher and intraoperative dislodgement significantly lower

i-gel® #1 has significant higher OSP and less prone to displacement on change of position

• •

•

i-gel® as effective as PLMATM for controlled ventilation in children

• •

In RAE group, leak fraction significantly higher until throat pack, peak airway pressure and airway resistance significantly higher at all time-intervals Smoother emergence in FLMA group

High-reliability of gastric tube placement and better P leak with PLMA makes it more suitable for infants, particularly for PPV

Significant outcome

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586

181/0–12 months

240/0–17 years (5–30 kg)

60/2–5 years

LMA-S TM/PLMATM LMA-s/i-gel

Microcuff ETT/LMA®

LMA-STM/Air-QTM/ Aura-ITM

i-gel®/LMA® supremeTM

LTS-II/ PLMATM

16 types SGDs

Bhattarcharjee et al.,45 2017

Drake-Brackman et al.,46 2017

Brueggeney et al.,47 2017

Gupta S et al.,48 2017

Chandrakar et al.,49 2017

Mihara et al.,50 2017 5823

100/2–5 years

4 RCTs 3 RCTs

60/ > 5 kg up to 12 years

i-gel®/AAO

Aquil M 44 2017

No of patients/ age group

Device compared

Author/year

Contd ...

Prospective observational study elective surgery < 4 hours Pressure controlled ventilation (PCV)

Network meta-analysis—65 RCTs

RCT/anesthetized and paralyzed in elective surgery

RCT/spontaneous breathing/different head and neck position

•

•

RCT Minor elective procedure

Meta-analysis/7 RCT

RCT No relaxant

Type of study

OLP, 1st attempt insertion success rate similar Insertion is faster with LMA-S than with i-gel

Based on 3-D MRI, both distort airway anatomy compared to native value

•

•

•

•

• • •

OLP higher in i-gel®, PLMATM, Cobra PLATM. Risk of device failure low with PLMATM, cLMATM, LMA-U but high with i-gel® i-gel® has lowest risk of blood staining

LTS II is a safe alternative with higher OSP

Neck exion caused a significant increase in OPLP and extension caused a fall with both devices Deterioration of FOB view and ventilation with both—cautions use in extreme flexion.

Leak pressure lowest with Air-Q® PPV possible with all three devices LMA-STM highest 1st attempt and overall success rate and easy to insert

LMA® associated with clinically significant Fewer PRAE and lower incidence of major PRAE (Laryngospasm and bronchospasm) Perioperative respiratory adverse events • •

• •

•

Significant outcome

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• •

Grade 3: Only epiglottic structure seen Grade 4: No glottis or epiglottic structure visible. Epiglottic down folding is also noted during fiberoptic evaluation.

SELECTION OF CORRECT SIZE OR DEVICE The selection of type of EGD invariably depends on personal choice, availability of the product and institutional protocol. The selection of correct size of EGD is usually determined by patient’s weight as per instruction of the manufacturer. However, in case of obese children, the SAD may be sized appropriately by agepredicted weight. Independent of weight or sex of a child, the perilaryngeal and oropharyngeal cavity develop in direct relation to age and height in the pediatric age group. Thus, selection by weight may not be most suitable for overweight and underweight children. Choosing the size of PLMATM according to the size of ear (mask of PLMATM approximating ear size) is a valid alternative method in case of emergency situations where the weight of the patient is not known, because the ear size depends on age rather than body size (Fig. 21).11

REMOVAL OF SUPRAGLOTTIC AIRWAY DEVICES The optimal timing for removal of EGD has not yet been defined. However, the presence of risk factors such as nocturnal cough, cold, wheezing, history of (h/o) asthma, passive smoking, etc. are well-established factors for bronchial hyperreactivity, thereby increasing the risk of perioperative respiratory adverse events (RAEs). Since the volatile anesthetics are bronchodilators and blunt airway

Fig. 21: Approximation of mask size to ear.

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reflex, removal of SAD in a deeper plane is associated with less incidence of RAE than in the awake-state where airway reflexes are re-established. In an RCT involving 290 children, Ramgolam et al., noted a 10% difference in incidence of respiratory complications between deep and awake removal groups, this may be clinically significant.12 If the commonly observed respiratory complications such as desaturation or cough require respiratory support with noninvasive ventilation (NIV) or emergency tracheal intubation, there is consequent increase in PACU stay and cost of hospitalization, the quality of recovery and, above all, dissatisfaction from patients and parents. Firstly, it is important to be aware that respiratory complications frequently occur (1 in every 2–3 children) when the child has at least one risk factor. Early recognition and prompt treatment of these events by well-trained personnel in operation room and PACU is a must. Secondly, removal of EGD in a deeper plane of anesthesia prevents reflex responses to airway removal. Though the depth of plane of anesthesia is subjective to the clinician’s discretion, the end-tidal sevoflurane concentration of 2.2 volume% achieves uncomplicated removal of LMA in 95% of children.13 Although the timing of removal of an SAD may not affect the incidence of adverse respiratory events by well-trained clinicians, the removal of SAD in deep plane of anesthesia is necessary in the subgroup of children with presumed greater risk such as infants, history of OSA, high ASA physical status.14

EXTRAGLOTTIC DEVICES IN PEDIATRIC TRAUMA In view of moderate pre hospital ETI failure rates, advanced airway interventions may not be necessary to achieve adequate ventilation and oxygenation. EGDs may provide an alternative method to achieve airway control. Hernandez et al. published a retrospective single institutional comparative study between patients with SAD (King LT) as the rescue airway vs. BMV (standard of care) patients. The SAD group had more incidences of hypoxia and inadequate ventilation at the time of hospital admission and there was increased mortality and airway control required tracheostomy. However, some multisystem pediatric trauma patients may necessitate an SGD placement during initial trauma resuscitation.15

EXTRAGLOTTIC DEVICES AND DIFFICULT AIRWAY Wide availability of plethora of EGDs led the Difficult Airway Society (DAS) to form the Airway Device Evaluation Project Team (ADEPT) for evidence-based formal evaluation of equipment associated with airway management regarding their clinical effectiveness and safety standards. 16 They concluded that EGDs have an established role in management of difficult airway especially in “cannot ventilate, cannot intubate” (CVCI) situation.2 In difficult airway situation, the role of EGDs can be either as: • First-choice as primary airway • As a rescue device • As a conduit for fiberscope-guided intubation.

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It is logical to evaluate the role of different EGDs in simulated pediatric difficult airway situations than in real situations. Simulators and manikin based training sessions provide technical and critical decision making skills and team work policy. Kulnig J et al. compared 5 commonly available EGDs and ETT in a pediatric manikin under simulated physiological and pathologic airway conditions such as tongue edema and limited cervical spine mobility involving 41 pediatricians of varying clinical experience. They inferred that the laryngeal tube, Ambu AuraGain and Air-Q proved superior to the LMA®, EasyTube as well as conventional ETI in providing fast and effective ventilation during simulated difficult airway situation.17 Since EGDs are a part of the algorithm for difficult-airway management, presently they are an integral component of almost every airway crash-cart worldwide. The All India Difficult Airway Association (AIDAA) guidelines for management of unanticipated difficult tracheal intubation in children between 1 year to 12 years of age, define the role of EGDs in their structural stepwise approach for management as follows:18 • Second generation EGDs are preferred because of a higher-seal pressure, drain tube and better fit to airway contour. • A maximum of 2 intubation attempts should be allowed in children as more frequent trials can cause hypoxia and damage mucosa and cause swelling which may lead to a difficult situation in which EGD placement may not be possible. The second attempt should be made only after attaining oxygen saturation of more than or equal to 95% and availability of additional help. A third and final attempt at laryngoscopy should only be done by an anesthesiologist with pediatric experience to analyze the anatomy and thus plan a strategy. • Recommendation for number of attempts at EGD insertion is limited to two with mask ventilation in between two attempts. • The second attempt of EGD insertion should consider the change in shape and size of EGD according to the clinical situation. • Once an EGD is successfully placed, an essential and short duration surgery may be done safely with EGD as primary ventilation device. Otherwise, EGD is used as a conduit for flexible fiberoptic bronchoscope aided ETI to proceed with surgery. If it is unsafe to proceed with EGD as primary airway device or ETI is unsuccessful, the choice remains between waking up the child in case of elective surgery or surgical tracheostomy in case of emergency surgical procedure. • Rescue mask ventilation should be resumed in case two attempts to use EGS are unsuccessful. Adequate depth of anesthesia should always be maintained with intravenous (IV) anesthetic such as propofol or an inhalational agent for proper face mask ventilation and/or insertion of EGD but the decision to use a neuromuscular blocker should be taken only by a qualified and experienced anesthesiologist, based on sound clinical judgment.

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Though EGDs such as Ambu® Aura-iTM and Air-QTM masked laryngeal airway are designed as conduits for tracheal intubation, blind intubation of anesthetized children is not recommended for elective or rescue purposes as the success of blind intubation is unacceptably low as evidenced by the RCT of Kleine M et al. Flexible fiberscopic guidance should always be used for intubation through a pediatric EGD.19 Airway management guidelines for children suggest EGDs as the immediate “Plan B,” in case of failed bag-mask ventilation and intubation. Once oxygenation is assured, tracheal intubation is still desirable in such cases.

NEONATES AND EXTRAGLOTTIC DEVICES Proficient airway management is the cornerstone of successful neonatal resuscitation. Both facemask application and ETT placement remain a huge challenge for resuscitators. Meta-analysis of seven randomized controlled trails suggest that initial respiratory management of newborns with LMA® is a safe and feasible alternative to facemask (FM) ventilation in late preterm and term infants. However, the available evidence is insufficient to recommend the LMA® instead of FM ventilation in the delivery room.20 This is especially pertinent for the defined subgroup of newborns of gestational age less than 34 weeks or weight less than 1,500 g at birth, for there is a dearth of evidence and further trials are required. Use of the LMA® in neonatal resuscitation goes back to 1994, to a study that included 21 term and near-term neonates with a 100% success rate in insertion on 1st attempt and 20 were successfully resuscitated.21 American Association of Pediatrics (AAP) and American Heart Association (AHA) guidelines included LMA® for neonatal resuscitation in the year 2000.22 The 2015 International Liaison Committee on Resuscitation (ILCOR) and European Resuscitation Council (ERC) guidelines suggest it as an alternative to ETI in late preterm (> 34-weeks gestational age), full-term and newborns with body weight greater than 2,000 g when facemask ventilation is unsuccessful or intubation not feasible.23 For newborn, all the available EGDs are of size # 1 (cLMATM, PLMATM, LMA® supremeTM, i-gel®, AAO, AAG, ShileyTM LMA®) except size # 0.5 Cobra PLATM and Air-QTM disposable LMA®. Mostly manikin-based comparative studies are available which may not be equivalent to in-vivo scenario, so more RCTs are warranted for evidence on short and long-term outcome. Gandini and Brimacombe suggested that after a 15 min educational training program, proficiency in LMA® positioning took only 5 sec and confidence in using LMA® increased from 8% to 97%, thus the LMA® can be used effectively by relatively inexperienced staff.24 Surfactant administration via LMA® (Air-Q) led to a significant reduction in FiO2 requirement.25 This therapy also decreased the proportion of newborns with moderate respiratory distress syndrome (RDS) requiring mechanical ventilation versus standard ETI with sedation. However, sufficient evidence is warranted for promoting routine use of surfactant via LMA®. Case reports supporting successful use of LMA® in isolated upper airway or craniofacial malformations in syndromic babies have been reported for transfer of babies especially with difficult airways.

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For long-term mechanical ventilation, the LMA® is usually not recommended because of potential lingual edema due to venous and capillary congestion. The usual complications associated with use of EGD in neonates are soft tissue trauma, vomiting, regurgitation, stridor, partial airway obstruction and breath-holding.20

EXTRAGLOTTIC DEVICES IN ORAL SURGERY In the past, ETT was considered the safest option for a secure and definitive airway in oral surgery. However, the concerns related to intubation such as repeated attempts, laryngeal edema due to tight fitting ETT, aspiration in case of small ETT and frequent problems of cough, breath-holding, laryngospasm during extubation and emergence with a constant threat for hypoxia existed side by side. Recently the role of flexible LMA (FLMA, Fig. 3) as a suitable alternative has been demonstrated for tonsillectomy, head and neck surgery and palatoplasty in the children weighing between 10 kg and 20 kg (as the smallest FLMA available is # 2). Contrary to the conventional prediction of probability of dislodgement of FLMA, on opening the mouth gag the FLMA rim is pushed tightly against the glottis and resulting an increase in expiratory tidal volume indicating a moreeffective seal. However, insertion of FLMA by conventional midline technique may be difficult in large palatal clefts as the cuff gets caught within the defect and/or cuff tends to fold back on itself on being pushed down after touching the posterior pharyngeal wall.26 Thus, insertion by lateral approach with a partially inflated cuff may lead to a higher success rate of insertion.27 It should be kept in mind that an abrupt fall in airway pressure indicates displacement of FLMA leading to loss of seal between cuff and periglottic tissues. On the other hand, a sudden increase in airway pressure may suggest airway obstruction after gag application. The main advantage of FLMA over RAE ETT lies in its significantly wider lumen than RAE tube leading to lower resistance and pressure in airway. Another benefit of FLMA in oral surgery is that it can be left in situ till the child is fully awake. Thus, there is no coughing or straining which may cause desaturation, laryngospasm and laryngotracheal soiling. Palatoplasty requires the child to be positioned with a hyperextended neck to keeps the oropharynx at a lower level than the glottis. This prevents trickling of blood into trachea during surgery. Thus, it is important to retain children in the same position during emergency and reposition in lateral position for extubation when the swallowing reflex returns.

NASOPHARYNGEAL AIRWAY VERSUS LARYNGEAL MASK AIRWAY® FOR BRONCHOSCOPY Diagnostic and therapeutic flexible fiberoptic bronchoscopy is often required in children on an elective basis, mostly as a day case procedure. Shoukry et al., compared use of LMA® versus nasopharyngeal airway (NPA) for ventilation in a prospective single-blinded clinical trial involving 90 children, aged 5–10 years, undergoing diagnostic fiberoptic bronchoscopy under general anesthesia. Use of NPA as supraglottic ventilating device resulted in significant reduction in

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hypoxemia and desaturation episodes together with shorter bronchoscopy time and better recovery compared with LMA® ventilation technique.28 The rationale behind this finding may be that due to unshared airway with operator, the NPA group had better oxygenation and significantly less frequency of desaturation episodes leading to shorter duration of the procedure. Use of the LMA® also requires more depth of anesthesia and longer bronchoscopy time leads to higher requirements of propofol.

ADVANTAGES AND DISADVANTAGES OF EXTRAGLOTTIC DEVICES OVER ENDOTRACHEAL TUBE These devices are easy to insert, pose less-resistance to breathing as compared to the ETT and cause less postoperative sore throat. Hemodynamic response is less than with endotracheal intubation and EGD insertion requires a lighter plane of anesthesia. Since the EGDs are placed above the glottis, the vocal cord trauma is reduced. EGD use is more economical since there is less drug requirement. The EGDs are safer in children with upper respiratory infection. These devices can be used in a wide-variety of airway control scenarios in anesthesia, the ICU, resuscitation and management of a difficult airway. Though EGDs are employed for both spontaneous and controlled ventilation, they are not foolproof against aspiration. They are not ideal for patients who have a potential for clinical deterioration in the future or patients requiring highventilatory pressure or prolonged ventilation. EGDs may not be preferred for managing airway during transfer of sick children and diagnostic studies at remote locations. Limited mouth opening is a relative contraindication for EGDs.

CURRENT OVERALL STATUS OF EXTRAGLOTTIC DEVICES In the past, the common misconceptions about LMA® use in children were: • It can be easily displaced, so unsuitable for long procedures. • They cannot be used for controlled ventilation. • LMA® cannot be used in neonates less than 5 kg. • LMA® are not suitable for head and neck surgery, oral surgery or in nonsupine positions. However, the newer EGDs have evolved so much to be uniquely innovative in various ways and have established clinical evidence of safety and efficacy in all the above-mentioned situations.29 A questionnaire survey among the practicing anesthesiologists who attended the National Pediatric Anesthesia Conference, 2016 on the current practice of SADs in pediatric anesthesia in India indicated that cLMATM (55.4%) still remains the most-commonly used SAD in routine practice, followed by secondgeneration devices such as PLMATM (30%) and i-gel® (15%).30 In contrast to this single point survey, another nationwide survey carried out one and half-year later showed a shift in the preference of EGD towards second-generation device over first-generation ones (60.74% vs. 39.26%) among Indian anesthesiologists.31 However, the trend of safe practices such as use of capnography, measurement of intracuff pressure and OSP and appropriate disinfection are lacking which

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needs to be addressed during training and continued medical education. Several meta-analysis involving many randomized controlled trials (RCT) carried out specifically in the pediatric population suggest that the second-generation devices may provide certain advantages over first-generation SADs.32 In our institution, the PLMATM is the routinely used EGD in children and the other newer devices such as AAG, i-gel®, FLMA, Baska mask® are also used as per the clinical situation, individual preference and expertise. Disposable EGDs have a huge advantage over reusable devices regarding transmission of prion diseases. Pathological prion proteins (prions), agents of transmissible spongiform encephalopathy (TSE) are extremely resistant to autoclaving and conventional sterilization and disinfection processes.33 But prion inactivation can be accomplished by STERRAD® NX system units utilizing hydrogen peroxide gas plasma technology as an alternative low temperature method with short cycle times and no toxic residue.34 Our institutional protocol utilizes STERRAD-sterilization for all reusable EGDs. Size 1 LMA® was reported to have highest complications.35 Use of EGDs in the prone position is a challenge even in adults, due to the possibility of dislodgement, obstruction, desaturation or hypercapnea. In children, especially less than 2-year old, the base of the tongue is not bulky enough to retain the SAD in place in unconventional positions such as prone positions, thus best avoided.36

CONCLUSION Choice of an EGD should be based on clinical evidence. However, preference of one EGD over another in clinical setting depends on individual experience and training with clear background knowledge of the pediatric airway and details of the device. Management of the pediatric airway with EGD is a skilled intervention and skill mastery improves with increasing experience, which can be augmented using simulated environment, or with a dedicated training in operating room. Further well-powered RCTs to ensure safety in children are still warranted.

KEY POINTS • • •

• •

Supraglottic or extraglottic devices (EGDs) have an established role in routine and emergency pediatric airway management. The selection and the type of EGD invariably depends on the personal choice, expertise and availability of the device. Easy availability of EGDs with user friendliness and short learning curve are of immense help in the difficult airway scenario, for neonatal resuscitation and when required as a conduit for fiber optic guided intubation. Proper use of EGDs avoids problems associated with endotracheal intubation like sore throat and hemodynamic instability to provide a hands free airway. The early versions of the EGDs for children, like the LMA, were scaled down versions of the adult device, but recently a few EGDs have been designed specifically for pediatric airway, such as the Air-QÒ, which is the intubating LMA of choice for infants and children.

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REFERENCES 1. Jagannathan N, Ramsey MA, White MC, et al. An update on newer pediatric supraglottic airways with recommendations for clinical use. Pediatr Anesth. 2015;25(4):334-45. 2. Jagannathan N, Sequera-Ramos L, Sohn L, et al. Elective use of supraglottic airway devices for primary airway management in children with difficult airways. Br J Anesth. 2014;112(4):742-8. 3. Sharma B, Sahai C, Sood J. Extraglottic airway devices: Technology update. Med Devices (Auckl). 2017;10:189-205. 4. Nagler J, Mick NW. Airway management for the pediatric patient. In: Walls R, Hockberger R, Gausche-Hill M, (Eds). Rosen’s Emergency Medicine: Concepts and Clinical Practice, Ninth Edition. Elsevier; 2017. pp. 1994-2004. 5. Asai T. Is it safe to use supraglottic airway in children with difficult airways? Br J Anesth. 2014;112(4):620-2. 6. Guay J, Suresh S. Airway management in children: keep your head up. EC Anesthesia. 2018;4(3):72-4. 7. Nakayama S, Osaka Y, Yamashita M. The rotational technique with a partially inflated laryngeal mask airway improves the ease of insertion in children. Pediatr Anesth. 2002;12(5):416-9. 8. Yun MJ, Hwang JW, Park SH, et al. The 90° rotation technique improves the ease of insertion of the ProSealTM laryngeal mask airway in children. Can J Anesth. 2011;58(4):379-83. 9. Stendal C, Glaisyer H, Liversedge. Pediatric supraglottic airway devices update. Rev Colomb Anesthesiol. 2017;45(S2):39-50. 10. Wong JG, Heaney M, Chambers NA, et al. Impact of laryngeal mask airway cuff pressures on the incidence of sore throat in children. Pediatr Anesth. 2009;19(5):464-9. 11. Haliloglu M, Bilgen S, Uzture N, et al. Simple method for determining the size of the ProSeal laryngeal mask airway in children: a prospective observational study. Braz J Anesthesiol. 2017;67(1):15-20. 12. Ramgolam A, Hall GL, Zhang G, et al. Deep or awake removal of laryngeal mask airway in children at risk of respiratory adverse events undergoing tonsillectomy—a randomized controlled trial. Br J Anesth. 2018;120(3):571-80. 13. Lee JR, Lee YS, Kim CS, et al. A comparison of the end-tidal sevoflurane concentration for removal of the laryngeal mask airway and laryngeal tube in anesthetized children. Anesth Analg. 2008;106(4):1122-5. 14. Jagannathan N, Asai T. Removal of a supraglottic airway in children with increased risk of respiratory complications: is timing of removal not important? Br J Anesth. 2018;120(3):440-2. 15. Hernandez MC, Antiel RM, Balakrishnan K, et al. Definitive airway management after prehospital supraglottic rescue airway in pediatric trauma. J Pediatr Surg. 2018;53(2):352-6. 16. Pandit JJ, Popat MT, Cook TM, et al. The Difficult Airway Society ‘ADEPT’ guidance on selecting airway devices: the basis of a strategy for equipment evaluation. Anesthesia. 2011;66(8):726-37. 17. Kulnig J, Füreder L, Harrison N, et al. Performance and skill retention of five supraglottic airway devices for the pediatric difficult airway in a manikin. Eur J Pediatr. 2018;177(6):871-8. 18. Pawar DK, Doctor JR, Raveendra US, et al. All India Difficult Airway Association 2016 guidelines for the management of unanticipated difficult tracheal intubation in Pediatrics. Indian J Anesth. 2016;60(12):906-14. 19. Kleine-Brueggeney M, Nicolet A, Nabecker S, et al. Blind intubation of anesthetized children with supraglottic airway devices Ambu®Aura-iTM and Air-QTM cannot be recommended: A randomized controlled trial. Eur J Anesthesiol. 2015;32(9):631-9. 20. Bansal SC, Caoci S, Dempsey E, et al. The laryngeal mask airway and its use in neonatal resuscitation: A critical review of where we are in 2017/2018. Neonatology. 2018;113(2):152-61.

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Yearbook of Anesthesiology-8 21. Alzahem AM, Aqil M, Alzahrani TA, et al. Ambu AuraOnce versus i-gel® laryngeal mask airway in infants and children undergoing surgical procedures. A randomized controlled trial. Saudi Med J. 2017;38(5):482-90. 22. Wyckoff MH, Aziz K, Escobedo MB, et al. Part 13: Neonatal Resuscitation: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132(18 Suppl 2):S543-60. 23. Wyllie J, Bruinenberg J, Roehr CC, et al. European Resuscitation Council Guidelines for Resuscitation 2015: Section 7. Resuscitation and support of transition of babies at birth. Resuscitation. 2015;95:249-63. 24. Gandini D, Brimacombe J. Manikin training for neonatal resuscitation with the laryngeal mask airway. Pediatr Anesth. 2004;14(6):493-4. 25. Vannozzi I, Ciantelli M, Moscuzza F, et al. Catheter and laryngeal mask endotracheal surfactant therapy: the CALMEST approach as a novel MIST technique. J Matern Fetal Neonatal Med. 2017;30(19):2375-7. 26. Kundra P, Supraja N, Agrawal K, et al. Flexible laryngeal mask airway for cleft palate surgery in children: A randomized clinical trial on efficacy and safety. Cleft Palate Craniofac J. 2009;46(4):368-73. 27. Kundra P, Deepak R, Ravishankar M. Laryngeal mask insertion in children: A rational approach. Pediatr Anesth. 2003;13(8):685-90 28. Shoukry AA, Sharaf AG. Nasopharyngeal airway versus laryngeal mask airway during diagnostic flexible fiberoptic bronchoscope in children. Open Anesth J. 2018;12:1-7. 29. Ramesh S, Jayanthi R. Supraglottic airway devices in children. Indian J Anesth. 2011;55(5):476-82. 30. Kaniyil S, Smithamol PB, Joseph E, et al. A survey of current practice of supraglottic airway devices in pediatric anesthesia from India. Anesth Essays Res. 2017;11(3): 578-82. 31. Jain RA, Parikh DA, Malde AD, et al. Current practice patterns of supraglottic airway device usage in pediatric patients amongst anesthesiologists: A nationwide survey. Indian J Anesth. 2018;62(4):269-79. 32. Saikia P. Use of supraglottic airway devices in pediatric patients in the Indian context —some we know, some we need to know and march ahead. Indian J Anesth. 2018;62(4):249-53. 33. Yan ZX, Stitz L, Heeg P, et al. Low-temperature inactivation of prion protein on surgical steel surfaces with hydrogen peroxide gas plasma sterilization. Infect Control Hosp Epidemiol. 2004;25(4):280-3. 34. Fichet G, Antloga K, Comoy E, et al. Prion inactivation using a new gaseous hydrogen peroxide sterilization process. J Hosp Infect. 2007;67(3):278-86. 35. Patel B, Bingham R. Laryngeal mask airway and other supraglottic airway devices in pediatric practice. Contin Educ Anesth Crit Care Pain. 2009;9(1):6-9. 36. Kundra P. Securing of supraglottic airway devices during position change and in prone position. Indian J Anesth. 2018;62(3):159-61. 37. Goldmann K, Jakob C. Size 2 ProSeal laryngeal mask airway: A randomized, crossover investigation with the standard laryngeal mask airway in pediatric patients. Br J Anesth. 2005;94(3):385-9. 38. Das B, Mitra S, Jamil SN, et al. Comparison of three supraglottic devices in anesthetized paralyzed children undergoing elective surgery. Saudi J Anesth. 2012;6(3):224-8. 39. Saran S, Mishra SK, Badhe AS, et al. Comparison of i-gel® supraglottic airway and LMA-ProSealTM in pediatric patients under controlled ventilation. J Anesthesiol Clin Pharmacol. 2014;30(2):195-8. 40. Luce V, Harkouk H, Brasher C, et al. Supraglottic airway devices vs. tracheal intubation in children: A quantitative meta-analysis of respiratory complications. Pediatr Anesth. 2014;24(10):1088-98. 41. Jagannathan N, Hajduk J, Sohn L, et al. A randomized comparison of the Ambu® AuraGainTM and the LMA® supreme in infants and children. Anesthesia. 2016;71(2): 205-12.

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42. Pant D, Koul A, Sharma B, et al. A comparative study of laryngeal mask airway size 1 vs. i-gel® size 1 in infants undergoing daycare procedures. Pediatr Anesth. 2015;25(4): 386-91. 43. Zhu W, Wei X. A randomized comparison of pediatric-sized streamlined liner of pharyngeal airway and laryngeal mask airway-unique in paralyzed children. Pediatr Anesth. 2016;26(5):557-63. 44. Aqil M, Delvi B, Abujamea A, et al. Spatial relationship of i-gel® and Ambu® AuraOnceTM on pediatric airway: A randomized comparison based on three-dimensional magnetic resonance imaging. Minerva Anestesiol. 2017;83(123-32):23-32. 45. Bhattacharjee S, Som A, Maitra S. Comparison of LMA SupremeTM with i-gelTM and LMA ProSealTM in children for airway management during general anesthesia: A metaanalysis of randomized controlled trials. J Clin Anesth. 2017;41:5-10. 46. Drake-Brockman TF, Rangolam A, Zhang G, et al. The effect of endotracheal tubes versus laryngeal mask airways on perioperative respiratory adverse events in infants: A randomized controlled trial. Lancet. 2017;389(10070):701-8. 47. Kleine-Brueggeney M, Gottfried A, Nabecker S, et al. Pediatric supraglottic airway devices in clinical practice: A prospective observational study. BMC Anesthesiol. 2017;17(1):119. 48. Gupta S, Dogra N, Chauhan K. Comparison of i-gel® and laryngeal mask airway supremeTM in different head and neck positions in spontaneously breathing pediatric population. Anesth Essays Res. 2017;11(3):647-50. 49. Chandrakar S, Sreevastava DK, Bhasin S, et al. Comparison of laryngeal tube suction II and proseal LMA in pediatric patients, undergoing elective surgery. Saudi J Anesth. 2017;11(4):432-6. 50. Mihara T, Asakura A, Owada G, et al. A network meta-analysis of the clinical properties of various types of supraglottic airway device in children. Anesthesia. 2017;72(10): 1251-64.

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CHAPTER

14

Intraoperative Fluid Management for Neonates

Ekta Rai

INTRODUCTION Neonates are defined as babies up to 28 days of postnatal period. They have smaller size, larger proportion of surface area than volume, and immature organ systems involved with homeostasis. Hence, the fluid management for this subgroup is always challenging. This chapter would be able to highlight the difference between the fluid management in the ward, intraoperatively and perioperatively.

HISTORICAL FACTS Since 1950, intravenous (IV) fluids have been accepted as a routine. Historically, the initial maintenance fluids were “four and one-fifth solutions”—4% dextrose and 0.18% sodium chloride (NaCl). The concept emerged from the composition of the breast milk which has 10–40 mmol/L Na+. In 1957, Holliday and Seger recommended the well-known “4-2-1 rule”.1

NEONATAL PHYSIOLOGY •

•

Total body water, extracellular fluid: intracellular fluid (ICF): Neonates have excess total body water (TBW) especially extracellular fluid (ECF) in comparison to adults. They not only have higher TBW but proportion of ECF to ICF is also high. Term neonates have 80% water (45% ECF) and preterm neonates have even more water (23 weeks 90% TBW: 60% ECF), whereas, adults have 60% water (20% ECF). After birth, there is efflux of fluid from ICF to ECF. This results in hypervolemia leading to salt and water diuresis by neonatal kidneys by 48–72 hours, resulting in loss of weight (10%) in first 3 days of life. Since the ECF is larger compartment in a preterm, so the weight loss (15%) is greater.2 The clinical implication is that hypovolemia will be less tolerated as the TBW is high. The water-soluble drugs are required in higher initial dosages as volume of distribution is large for them. Fluid restriction is advised on days 1–2 as hypervolemia due to fluid shift is noticed.3 Inefficient neonatal heart: Neonate heart exhibits flat Starling curve highlighting the poor responsiveness to preloading.4 Overfilling can lead

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•





•





to heart failure.5 The myocardium of neonate is a collection of disorganized myocardial cells, more noncontractile tissues, and water between the contractile tissues due to more ECF and TBW, so neonatal heart is unable to increase stroke volume.6,7 CO is maintained by increasing the heart rate (Treppe effect). Since the baseline heart rate is high, this compensatory mechanism is limited. Carbohydrate and short-chain fatty acids are the energy source for the neonatal heart. Diastolic relaxation improves in 1st month of life. Neonatal heart has reduced L-type channels and entry of ionized calcium occurs through T-type channels, proteins, and reverses Na/Ca exchange mechanism, which is associated with calcium removal from cells. Propagation of calcium is poor since the T-tubular system is poor and limited ryanodine receptors at sarcoplasmic reticulum (SR) results into limited calcium release on trigger. Relaxation is inefficient as the uptake of the calcium in SR is inadequate. Thus, cardiac contraction is extracellular calcium dependent. This immature L-type calcium channels, T-tubule, and SR matures by end of 1 month of life.8,9 The clinical implication is that both hypo- and hypervolemia are not well tolerated by the neonates. Extracellular calcium ion maintenance is essential for the proper functioning of the heart in neonates.10,11 Neonatal heart and inotrope: Fact to remember is that at birth, the sympathetic component is more dominant but in infancy, it reverses and parasympathetic system becomes more prominent. Given to flat Starling curve, heart rate stimulation by beta-agonist improves the CO but these drugs have their intrinsic effect on the neonatal. In sick neonates, downregulation of beta receptors is found.12 The current interest is in low-dose vasopressin in pediatric intensive care unit (PICU) to overcome the resistance of inotropes. Autonomic innervations are present but are immature in neonates, thus they are prone for hemodynamic fluctuations. At birth, the sympathetic component is more dominant but in infancy, it reverses and parasympathetic system becomes more prominent.13,14 This reduced autonomic response results in reduced baroreceptor sensitivity. Therefore, the hemodynamic instability is more common in neonates with limited compensatory increase in heart rate as the basal heart rate is higher in neonates (120–180/min). Neonatal kidneys: At full term, the glomerular filtration rate (GFR) is only around 20–30% of the adult value. The newborn kidney has a limited function and thus, is unable to remove excess water and sodium.3 Overload of fluid or sodium in the 1st week may result in conditions like necrotizing enterocolitis, chronic lung disease, and patent ductus arteriosus.2 The GFR reaches adult value by 1 year of age. The tubular function and, thus, sodium retaining ability develops by 32 weeks of gestation. The immaturity of kidneys also affects the metabolism and thus, the duration of various drugs are prolonged. Thus, the water-soluble drugs are required in larger quantities in relation to weight as first bolus but since the renal and hepatic functions are immature hence, the further dosing is reduced.

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FLUID LOSS Fluid loss can be categorized as: • Sensible water loss, which is the loss by kidneys and gastrointestinal (GI) system. • Insensible water loss, which occur due to evaporation from the skin (70%) and respiratory tract. Neonates loose water due to evaporation from skin and respiratory system. This water loss is higher in preterm neonates. These losses are high due to increased respiratory rate, body temperature, increased ambient temperature, and increased basal metabolic rate.

COAGULATION SYSTEM Neonates are at risk of coagulation deficiencies due to the following reasons:2 • Immaturity of the coagulation system • Presence of sepsis, frequently associated with thrombocytopenia and coagulopathy • Jaundice • Vitamin K deficiency: Vitamin K is required for production of hepatic coagulation factors like II, IV, IX, and X. It can be administered through IM (single dose) or oral route (three doses). Vitamin K should be given routinely to all neonates preoperatively. Why should we infuse fluids? When a neonate is posted for surgery, fluid is transfused to cover for the fluid deficits. These fluid deficits build up preoperatively as well as intraoperatively. • Preoperative deficit occurs due to fasting, GI losses, loss through skin, and blood loss if bleeding. Relative hypovolemia occurs in septic neonate. • Intraoperative deficit occurs due to blood loss, normal maintenance requirement of fluids, and “third space” loss. Aim of fluid therapy is to maintain tissue perfusion, metabolic function, and acid-base-electrolyte status. Fasting time should be as per ASA guidelines. Preoperative fasting should be minimum to prevent discomfort, dehydration, and hypoglycemia to the neonate. Fasting for mother’s milk is 4 hours as per ASA guidelines. European countries are moving toward more liberal fasting orders and they allow breast milk even up to 3 hours prior to elective surgery. If fasting is required for prolonged period, isotonic maintenance fluid should be initiated with dextrose. What should be our fluid? In 1957, Holliday and Segar suggested the constituent and volume of the fluid to be infused for volume maintenance in children. Based on the weight, the maintenance fluid was decided. A “4-2-1” rule was laid down for maintenance fluid based on the requirement of water against the caloric requirement (1 mL/calorie spent) of an awake healthy child. Thus, in an awake healthy child, calorie and water consumed are considered equal. Electrolyte requirements were

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Table 1: Fluid requirement for body weight. Body weight daily

Fluid requirement

0–10 kg

4 mL/kg/h

10–20 kg

40 mL/h + 2 mL/kg/h above 10 kg

>20 kg

60 mL/h + 1 mL/kg/h above 20 kg

calculated based on the composition of human milk, sodium (3 mmol/L), and potassium (2 mmol/L) which resulted in hypotonic solution. According to the “4-2-1” rule (Holliday–Segar formula), the fluid requirement is calculated as shown in Table 1. However, after 50 years of using “4-2-1” formula, it was highlighted that:15-19 • Children undergoing surgery are not healthy children, they are not necessarily in anabolic phase of metabolism, which means that the caloric requirement is less than that estimated by “4-2-1 rule”.20 • Children under anesthesia and ICU are either anesthetized or sedated, so there is further reduction in the caloric requirement and water by children. • Due to stress of surgery, nonosmotic secretion of ADH occurs, leading to increased free water absorption and reduction in urine output. So, isotonic solutions21-23 like PlasmaLyte (alkalosis on larger volume administration) and Ringer lactate are infused intraoperatively to neonates more than 3 days as maintenance fluid. For physiological reasons, on day 1, 10% dextrose can be given alone in the nursery, but electrolyte should be monitored. On day 2, hypotonic fluid with sodium can be added on as maintenance fluid.

DEXTROSE: TO GIVE OR NOT TO GIVE Glucose transporter proteins 3 (GLUT3) and phosphorylation enzymes increase five times as neonates grows into adults. Cerebral metabolic rate increases from neonatal period to 6 years of age (6.8 mg glucose/min/100 g) and then decreases to adult period (5.5 mg glucose/min/100 g). Neonatal brain can generate adenosine triphosphate (ATP) by utilizing ketone bodies, lactate, and free-fatty acids.24 Hyperglycemia reduces glucose uptake and lactate accumulation and also lactate clearance is greater. Hence, hyperglycemia is better tolerated in neonates. Risks from hyperglycemia include: increased impact of ischemic changes in brain, hyperosmotic diuresis, and resulting hypovolemia. Glucose is essential for the growth and functioning of normal brain. Hypoglycemia is less well tolerated by neonatal brain. Hypoglycemia leads to symptoms and permanent neurological damage by the following mechanism:25 • Hypoglycemia stimulates the stress response (increased cortisol, epinephrine, glucagon, and growth hormone). • It causes loss of cerebral vascular tone leading to increase in cerebral blood flow. • It shifts cerebral metabolism from glycolytic precursors to Krebs cycle intermediates.

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Blood glucose levels may be maintained by surgical stress intraoperatively but it is found that perioperatively, the blood glucose fluctuations are more if glucose is not supplemented externally.26 Situations where there is less or almost no stress responses are expected are as follows: • Working regional block prior to incision • Sick babies • Very low-birth weight babies (90, risk of infection 3.3%; GFR 60–90, risk of infection 7.0%; GFR 30–59, risk of infection 8.3%; GFR 55 years), high injury severity score (>15), high base deficit (>8 mEq/L) and high serum lactate (>2.5 mmol/L).8,9

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Flowchart 1: Pathophysiology of massive blood loss.

MASSIVE BLOOD TRANSFUSION GUIDELINES The goal of MT is preservation of tissue perfusion and oxygen delivery to prevent end-organ damage till surgical hemostasis is achieved. Most of the trauma MT guidelines are applicable in the nontrauma settings also. But till date, no algorithm has been validated for nontrauma patients.10 A retrospective study by McDaniel et al. highlighted that, application of massive transfusion protocol (MTP) in a nontrauma setting resulted in poor clinical outcomes.11 It was due to overactivation of nontrauma MTPs in more than 50% of the incidences, in which MT did not happen and this led to wastage of blood and blood products.11 Currently, two major guidelines of importance for MT are:12,13 1. European guidelines by the Task Force for Advanced Bleeding Care in Trauma (updated in 2013).12 2. Trauma Quality Improvement Program (TQIP) recommendations from the American College of Surgeons.13 These guidelines recommend early recognition of clinically significant hemorrhage and timely administration of the required blood products in a scientific manner as guided by rapid laboratory or point-of-care coagulation tests. Coagulation factor concentrates, hemostatic agents, and blood salvage techniques can also be used to minimize the need of bold transfusion.14

MASSIVE TRANSFUSION PROTOCOLS Massive transfusion protocol facilitates replacement of massive blood loss with appropriate blood products, timely fashioned to improve patient outcome.15

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Protocols are constituted in various institutes depending upon patient population and characteristics, distance between blood bank and clinical areas, availability of laboratory tests and blood products available. Components of MTP include the following:15 1. Activation criteria 2. Activation process 3. Preset leadership and communication plan 4. Preset transfusion management 5. Timing and types of laboratory testing 6. Use of hemostatic agents, prevention and management of hypothermia 7. Termination criteria. A sample MTP is given in Appendix 1.

When to Initiate Massive Transfusion Protocol Activation of MTPs is usually done by a senior clinician in response to massive bleeding. Once the patient is in the protocol, the blood bank ensures rapid and timely delivery of all blood components together to facilitate resuscitation. Many scoring systems have been developed for early identification of patients, who require massive blood transfusion for resuscitation upon arrival in the emergency department,2 since early MT in the emergency room result in increased survival compared to when done in the operating room.16 These scoring system should also be able to exclude those who do not need MT. The commonly used scoring systems for initiating MT are: • Trauma-associated severe hemorrhage (TASH)17 score which was the first MT scoring system. It has seven variables; systolic blood pressure (