Essentials of Evidence-Based Practice of Neuroanesthesia and Neurocritical Care [1 ed.] 0128217766, 9780128217764

Table of contents :
Dedication
Contents
Contributors
Acknowledgments
Section A: Introduction
1. Introduction to evidence-based practice • Indu Kapoor, Charu Mahajan, and Hemanshu Prabhakar
Section B: Neurophysiology
2. ICP or CPP thresholds • Judith Dinsmore and Mazen Elwishi
3. Role of hypothermia • Franziska Herpich, Theresa Human, and Mehrnaz Pajoumand
4. Mechanical ventilation—PEEP • Chiara Riforgiato, Denise Battaglini, Chiara Robba, and Paolo Pelosi
Section C: Neuropharmacology
5. Intravenous or inhalational anesthetics? • Rajeeb Kumar Mishra
6. Hyperosmolar therapy • Tomer Kotek, Alexander Zlotnik, and Irene Rozet
7. Role of nitrous oxide • Indu Kapoor, Charu Mahajan, and Hemanshu Prabhakar
8. Antimicrobial prophylaxis • Jason M. Makii, Jessica Traeger, and Justin Delic
9. Role of antiepileptics • Rohan Mathur and Jose I. Suarez
10. Treatment of hypertension • Ashish Khanna and Abhay Tyagi
11. Role of statins for neuroprotection • Micheal Strein, Megan Barra, Veronica Taylor, and Gretchen Brophy
12. Role of stem cell therapy inneurosciences • Shilpa Sharma, Madhan Jeyaraman, and Sathish Muthu
Section D: Neuromonitoring
13. ICP monitoring • Matthew A. Kirkman
14. Type of ICP monitor • Pasquale Anania, Denise Battaglini, Paolo Pelosi, and Chiara Robba
15. Newer brain monitoring techniques • Nuno Veloso Gomes, Patrick Mark Wanner, and Nicolai Goettel
16. Intraoperative neuromonitoring • Laura Hemmer, Amanda Katherine Knutson, and Jamie Uejima
Section E: Neuromonitoring
17. Blood transfusion triggers • Maria J. Colomina, Laura Contreras, and Laura Pariente
18. Reversal of anticoagulation in neurosurgical and neurocritical care settings • Massimo Lamperti, Amit Jain, and Vinay Byrappa
19. Role of decompressive craniectomy • Mayank Tyagi, Charu Mahajan, and Indu Kapoor
20. Strategies for brain protection • Hossam El Beheiry
21. Anesthesia for carotid endarterectomy • Nidhi Gupta
22. Anesthesia for acute stroke • Sarang Biel and Ines P. Koerner
23. Anesthesia for spine surgery • Andres Zorrilla-Vaca
Section F: Neurointensive care
24. Choice of sedation in neurointensive care • Hugues Marechal, Aline Defresne, Javier Montupil, and Vincent Bonhomme
25. DVT prophylaxis • Ritesh Lamsal and Navindra R. Bista
26. Role of steroids • Walter Videtta and Gustavo Domeniconi
27. Initiation of nutrition • Swagata Tripathy and Dona Saha
28. Glycemic control • Shaun E. Gruenbaum, Raphael A.O. Bertasi, Tais G.O. Bertasi, Benjamin F. Gruenbaum, and Federico Bilotta
29. Anesthetics for status epilepticus • Mariangela Panebianco
Section G: Ethical issues
30. Diagnosing brain death • Christopher R. Barnes and Michael J. Souter
Section H: Recent advances
31. Simulations in clinical neurosciences • Ljuba Stojiljkovic, Kan Ma, and Jamie Uejima
Section I: Webliography
32. Webliography • Vanitha Rajagopalan and Hemanshu Prabhakar
Index

Citation preview

Essentials of Evidence-Based Practice of Neuroanesthesia and Neurocritical Care

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Essentials of Evidence-Based Practice of Neuroanesthesia and Neurocritical Care

Edited by Hemanshu Prabhakar

Professor, Department of Neuroanaesthesiology and Critical Care, All India Institute of Medical Sciences (AIIMS), New Delhi, India

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright © 2022 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN 978-0-12-821776-4 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Nikki P Levy Acquisitions Editor: Melanie Tucker Editorial Project Manager: Susan Ikeda Production Project Manager: Selvaraj Raviraj Cover Designer: Christian J Bilbow Typeset by STRAIVE, India

Dedication To my parents, my family, and my patients. To Professor Prathap Tharyan, who taught me the basics of evidence-based practice.

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Contents Contributors xv Acknowledgments xix

Section A Introduction 1. Introduction to evidence-based practice Indu Kapoor, Charu Mahajan, and Hemanshu Prabhakar Introduction 3 Evidence-based practice in neuroanesthesia 3 References 4

Section B Neurophysiology 2. ICP or CPP thresholds Judith Dinsmore and Mazen Elwishi Introduction 9 Question 10 What ICP threshold should we target and what is the optimal CPP range? 10 Controversy 10 Should ICP and CPP thresholds be protocolized according to consensus guidelines or individualized to achieve better outcomes? 10 Evidence 10 Consensus 13 Conclusion 13 References 13

3. Role of hypothermia Franziska Herpich, Theresa Human, and Mehrnaz Pajoumand Introduction 15

What disease states should target temperature management be considered? 16 Cardiac arrest 16 Acute ischemic stroke 16 Intracerebral hemorrhage 16 Aneurysmal subarachnoid hemorrhage 16 Traumatic brain injury 17 Spinal cord injury 17 Status epilepticus 18 Bacterial meningitis 18 Acute liver failure 18 Is one method of cooling superior? 18 What is the optimal target temperature? 18 Cardiac arrest 18 Traumatic brain injury 21 Does time to TTM implementation change outcomes? 21 What is the optimal duration of TTM to improve outcomes? 21 What is the optimal rate of rewarming to improve patient outcomes and prevent complications? 22 Is there an optimal method/protocol to detect and treat shivering? 22 The Columbia antishivering protocol 22 Non-pharmacologic management of shivering 23 Pharmacologic management of shivering 23 What are the important complications to evaluate during TTM? 24 Cardiovascular 24 Infections 25 Bleeding 25 Laboratory 25 Skin integrity 25 Consensus statement 25 What disease states should target temperature management be considered? 25 Is one method of cooling superior? 25 What is the optimal target temperature? 26 Does time to TTM implementation change outcomes? 26 What is the optimal duration of TTM to improve outcomes? 26

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What is the optimal rate of rewarming to improve patient outcomes and prevent complications? 26 Is there an optimal method/protocol to detect and treat shivering associated with TTM? 26 What are the important complications to evaluate during TTM? 26 Conclusion 26 References 26

4. Mechanical ventilation—PEEP Chiara Riforgiato, Denise Battaglini, Chiara Robba, and Paolo Pelosi Introduction 33 The questions/controversy: The brain-lung crosstalk 33 From the brain to the lung 34 From the lung to the brain 34 PEEP effects on lung, cardiovascular, and brain pathophysiology 35 PEEP and oxygenation improvement 35 PEEP, intrathoracic pressure, and cerebral blood flow (CBF) 36 PEEP and arterial PaCO2 increase, from dynamic hyperinflation to alveolar overdistension 36 Laboratory evidence 37 Clinical evidence 37 Mechanical ventilation strategies in ABI patients 37 Consensus statement 39 Conclusions 39 References 40

Section C Neuropharmacology 5. Intravenous or inhalational anesthetics? Rajeeb Kumar Mishra Introduction 45 Controversies 45 Intracranial pressure and cerebral perfusion pressure 46 Cerebral blood flow and cerebrovascular resistance 46 The cerebral metabolic rate of oxygen consumption 46 Brain volume and relaxation 46 Cerebral autoregulation 46 Cerebral oxygenation 47

Neuroprotection 47 Epileptogenesis 47 Intraoperative neurophysiologic monitoring and anesthesia 48 Systemic hemodynamics 48 Recovery and emergence and postoperative complications 48 Consensus statement 49 Cerebral hemodynamics 49 Intraoperative brain relaxation 49 Cerebrovascular resistance 49 Cerebral metabolic rate of oxygen consumption 49 Cerebral autoregulation 49 Cerebral oxygenation 49 Neuroprotection 50 Epileptogenesis 50 Intraoperative neurophysiologic monitoring and anesthesia 50 Systemic hemodynamics 50 Recovery and emergence and postoperative complications 50 Conclusion 50 References 50

6. Hyperosmolar therapy Tomer Kotek, Alexander Zlotnik, and Irene Rozet Introduction 53 Effect of intravenous hyperosmolar fluids on the brain 53 Background, mechanism, dosing, clinical use, and adverse effects of common hyperosmotic fluids 54 The question/controversy 58 Comparison between mannitol and hypertonic saline 58 Clinical and practical considerations 58 General practical considerations 58 Mannitol 59 Hypertonic saline (HTS) 59 Consensus statement 60 TBI guidelines 4th edition 60 Review of recent literature 60 Neuroanesthesia: Elective supratentorial tumors 60 Traumatic brain injury (TBI) 61 Intracerebral hemorrhage (ICH) and acute ischemic stroke (AIS) 62 Subarachnoid hemorrhage (SAH) 62 Conclusion 63 References 63

Contents  ix

7. Role of nitrous oxide Indu Kapoor, Charu Mahajan, and Hemanshu Prabhakar Introduction 67 The question: Is it safe to use N2O in neurosurgical cases? 67 Laboratory evidence 67 Clinical evidence 68 The question: Is it safe to use N2O in spine surgeries? 70 Laboratory evidence 70 Clinical evidence 71 The question: Is N2O safe to be used in interventional neuroradiology? 71 Laboratory evidence 71 Clinical evidence 71 The question: What is the current status of the use of N2O in pediatric patients undergoing neurosurgical procedures under general anesthesia? 72 Laboratory evidence 72 Clinical evidence 72 The question: Is it safe to use N2O in the geriatric patient population who are scheduled for neurosurgical procedures under general anesthesia? 72 Laboratory evidence 72 Clinical evidence 73 Conclusion 73 References 73

8. Antimicrobial prophylaxis Jason M. Makii, Jessica Traeger, and Justin Delic Introduction/background 77 Clinical evidence 78 Classification of neurosurgical procedures and evidence 78 Pharmacotherapy 80 General principles 80 Drug classes 81 Conclusion/consensus statement 85 References 85

9. Role of antiepileptics Rohan Mathur and Jose I. Suarez Introduction 89 Questions and controversies 89 Laboratory evidence 90 Clinical evidence 90

What is the definition of and recommended early management strategy for SE? 90 Does administration of benzodiazepines early in the course of SE, increase the risk of intubation? 93 If SE resolves with early benzodiazepine treatment, should an ASD be started to prevent recurrence of seizures? 93 If SE does not resolve with benzodiazepines, what is the next line of antiseizure drugs? Is there any evidence to support the use of a particular ASD over another? 93 What is the role of newer ASDs in the management of SE? 93 When is SE considered refractory and what ASDs should be used in the management of refractory SE? 94 What treatment strategy should be pursued in the management of super-refractory SE? What treatment strategy should be pursued in the management of newonset refractory SE (NORSE)? 94 What is the role of ASDs in the prevention of seizures after spontaneous ICH? 94 What is the role of ASDs in the prevention of seizures after SAH? 95 What is the role of ASDs in the prevention of seizures after TBI? 95 What is the role of ASDs in the prevention of seizures in postcraniotomy patients? 95 What is the role of ASDs in the prevention of seizures after HII? 96 Consensus statements 96 Conclusion 96 References 97

10. Treatment of hypertension Ashish Khanna and Abhay Tyagi Introduction 99 Definition and classification 99 Secondary hypertension 100 Hypertension and cerebral autoregulation 100 Clinical evidence 101 Hypertensive crises 101 Traumatic brain injury 104 Intracerebral hemorrhage 105 Acute ischemic stroke 105 Subarachnoid hemorrhage (SAH) 105 Postoperative hypertension 107 Conclusion 108 References 108

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11. Role of statins for neuroprotection Micheal Strein, Megan Barra, Veronica Taylor, and Gretchen Brophy Introduction 111 Traumatic brain injury 112 Laboratory evidence 112 Clinical evidence 116 Acute ischemic stroke 124 Laboratory evidence 124 Clinical evidence 125 Intracerebral hemorrhage 136 Laboratory evidence 136 Clinical evidence 136 Aneurysmal subarachnoid hemorrhage 137 Laboratory evidence 137 Clinical evidence 146 Summary of on-going trials 155 Conclusion 155 References 155

12. Role of stem cell therapy in neurosciences Shilpa Sharma, Madhan Jeyaraman, and Sathish Muthu, Introduction 163 Properties, sources, and characterization of stem cells 164 Immunomodulation by stem cells 164 Lymphocyte system 164 HLA-G5 system 165 Neurogenic signaling of stem cells 165 Wnt pathway 166 Notch pathway 166 Sonic Hedgehog (SHH) pathway 166 Neurotrophic factors 166 Growth factors 166 Bone morphogenetic factors (BMPs) 167 Neurotransmitters 167 Transcription factors 167 Epigenetic regulators 168 Role in neurological disorders 168 Alzheimer’s disease 168 Parkinson’s disease 169 Huntington’s disease 170 Cerebral palsy 170 Stroke 170 Traumatic spinal cord injury 171 Multiple sclerosis 171 Amyotrophic lateral sclerosis 172 Polio 172 Meningomyelocele 173

Conclusion 174 References 174

Section D Neuromonitoring 13. ICP monitoring Matthew A. Kirkman Introduction 183 Intracranial pressure 183 ICP monitoring techniques (covered in detail in Chapter 14) 183 Question: What are the indications for ICP monitoring? 184 Clinical evidence 184 Consensus statement 185 Question: What is the ICP threshold for treatment? 185 Clinical evidence 185 Consensus statement 186 Question: How should raised intracranial pressure be managed? 186 Sedation 187 Hyperventilation 187 Osmotic therapy 187 Targeted temperature management 187 Barbiturates 188 Surgery 188 Question: Does ICP monitoring improve outcomes? 188 Clinical evidence 188 Consensus statement 189 Question: What is the optimal cerebral perfusion pressure target? 189 Laboratory evidence 189 Clinical evidence 189 Consensus statement 190 Conclusion 190 References 190

14. Type of ICP monitor Pasquale Anania, Denise Battaglini, Paolo Pelosi, and Chiara Robba Introduction 193 The controversy 193 Laboratory and clinical evidence 194 Consensus statement 194 Type of invasive ICP monitoring 194 Intraventricular device 194 Intraparenchymal, subdural and epidural device 195

Contents  xi

Non-invasive ICP monitoring 196 Transcranial doppler 197 Optic nerve sheath diameter 198 Pupillometry 198 Conclusion 199 References 199

15. Newer brain monitoring techniques Nuno Veloso Gomes, Patrick Mark Wanner, and Nicolai Goettel Introduction 203 Why do we need new neuromonitoring technologies? 204 The move from reactive to proactive medicine and from protocolized to individualized medicine 204 The need for noninvasive neuromonitoring modalities in patients with or at risk for acute brain injury 204 The need for invasive neuromonitoring modalities in patients with or at risk for acute brain injury 204 Novel neuromonitoring technologies 204 Automated infrared pupillometry 204 Optic nerve sheath ultrasound 207 Cerebrovascular reactivity monitoring and personalized medicine 208 Multimodal neuromonitoring and future directions 212 Conclusion 213 References 213

16. Intraoperative neuromonitoring Laura Hemmer, Amanda Katherine Knutson, and Jamie Uejima Introduction 217 Somatosensory evoked potential 217 Motor evoked potentials 217 Evoked potential assessment 218 Electromyography 218 The question/controversy 218 Laboratory evidence 218 Clinical evidence 219 Spine deformity correction 219 Intramedullary spinal cord tumor resection 220 EMG/pedicle screw placement 220 Cervical spine surgery 221 Minimally invasive surgery 221 Tethered cord surgery 221 Non-surgical applications 221 Cost-effectiveness 222

Consensus statement 222 Conclusion 222 References 223

Section E Neuromonitoring 17. Blood transfusion triggers Maria J. Colomina, Laura Contreras, and Laura Pariente Key points 229 Introduction 229 Red blood cells transfusion. Optimal transfusion trigger 230 What are the transfusion requirements for red blood cells in neurosurgery? 230 Can the presence of preoperative anemia influence the need for red blood cells transfusion? 230 Red blood cells transfusion trigger 231 Transfusion and coagulation factors. Optimal transfusion trigger 231 Should a standard coagulation test be performed before any surgery? 231 To neurosurgery, what are the minimum acceptable values of the standard coagulation tests? 232 When would it be indicated the administration of coagulation factors? Recommended triggers 234 Platelet transfusion. Optimal transfusion trigger 234 Do we still think that the minimum platelet count for neurosurgery is 100×109/L? 234 In the pediatric population, do we need to consider the same values to indicate a platelet transfusion? 235 Conclusion 236 References 236

18. Reversal of anticoagulation in neurosurgical and neurocritical care settings Massimo Lamperti, Amit Jain, and Vinay Byrappa Introduction 239 Questions/controversy 240 What are the common indications for chronic anticoagulation therapy? 240 What are the common therapeutic agents used for chronic anticoagulation therapy? 240

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What is the bleeding risk involved with chronic anticoagulation therapy? 242 What medical factors are associated with higher bleeding risk? 243 What is the incidence and outcome of spontaneous intracranial hemorrhage in patients on chronic anticoagulation therapy? 247 Do we have multivariate composite bleeding risk prediction models? 248 Are there any specific factors for intracranial bleeding? 248 What neurosurgical or neurocritical care situations warrant urgent reversal of anticoagulation? 251 What are the general considerations while managing critical intracranial bleeding in patients on anticoagulation therapy? 251 Laboratory tests for the measurement of anticoagulation activity 256 What are the risks of interruptions of chronic anticoagulation therapy? 258 Composite scores predicting the risk of thromboembolic complications and the need for long-term anticoagulation therapy 258 What are the key considerations for restarting anticoagulation following neurosurgical procedure or spontaneous intracranial hemorrhage? 259 Evidence-based recommendations 260 Conclusion 261 References 261

19. Role of decompressive craniectomy Mayank Tyagi, Charu Mahajan, and Indu Kapoor Introduction 267 Controversy 268 DC in TBI 268 DC in stroke 269 DC in aSAH 269 Controversies related to cranioplasty 269 Laboratory evidence 269 Clinical evidence 270 DC for patients having TBI 270 DC for patients having a stroke 271 DC in other conditions 272 Consensus statement 272 DC in TBI 272 DC in AIS 273

Conclusion 274 References 274

20. Strategies for brain protection Hossam El Beheiry Introduction 279 Question/controversy 279 Laboratory evidence 280 Preconditioning 280 Postconditioning 280 Clinical evidence 281 Consensus statement 283 Conclusion 283 References 283 Further reading 285

21. Anesthesia for carotid endarterectomy Nidhi Gupta Introduction 287 Anesthetic considerations during carotid endarterectomy 287 Neuromonitoring during carotid endarterectomy 288 The controversy 289 Clinical evidence 289 Local or regional anesthesia 289 General anesthesia 290 Evidence-based literature on anesthesia for carotid endarterectomy 291 Conclusion 295 References 295 Further reading 297

22. Anesthesia for acute stroke Sarang Biel and Ines P. Koerner Introduction 299 The controversy 300 Preclinical evidence 300 Clinical evidence 301 Early retrospective reports 301 2014 SNACC consensus statement 302 Randomized controlled trials 303 SIESTA 303 AnStroke 303 GOLIATH 303 Comparison 304 Consensus statement 305 Conclusion 305 References 306

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23. Anesthesia for spine surgery Andres Zorrilla-Vaca Overview 309 Questions/controversies 309 Preoperative phase 309 Intraoperative phase 312 Evidence-based anesthetic approach for spine surgeries 315 Conclusions 316 References 316

Controversy 361 Specific disease conditions 361 Brain tumors 361 Traumatic brain injury 362 Aneurysmal subarachnoid hemorrhage 362 Acute ischemic stroke 362 Spinal cord injury 363 Miscellaneous neuromuscular diseases 363 Conclusion 363 References 364

26. Role of steroids Walter Videtta and Gustavo Domeniconi

Section F Neurointensive care 24. Choice of sedation in neurointensive care Hugues Marechal, Aline Defresne, Javier Montupil, and Vincent Bonhomme Introduction 321 The question/controversy 322 Laboratory evidence 327 Propofol 327 Benzodiazepines 329 Alpha2-adrenergic agonists 331 Inhaled anesthetic agents 333 Opioids 336 Barbiturates 338 Ketamine 339 Other agents 341 Clinical evidence 341 Propofol 341 Benzodiazepines 342 Alpha2-adrenergic agonists 343 Inhaled anesthetic agents 344 Opioids 345 Barbiturates 345 Ketamine 346 Consensus statement and conclusions 346 References 348

25. DVT prophylaxis Ritesh Lamsal and Navindra R. Bista Introduction/background 359 Causes 359 Clinical presentation 360 Diagnosis 360 Imaging 360

Introduction 367 Controversy 367 Laboratory evidence 367 Clinical evidence 368 Traumatic brain injury (TBI) 368 Chronic subdural hematoma (CSDH) 369 Central nervous system infections 369 Bacterial meningitis (BM) 369 Tuberculous meningitis (TB) 370 Intracerebral hemorrhage (ICH) 370 Consensus statement 371 Conclusions 371 References 371

27. Initiation of nutrition Swagata Tripathy and Dona Saha Introduction 375 The question/controversy 376 How important is timely, appropriate initiation of nutrition in the critically ill patients? 376 Is it possible to overnourish a patient? 376 Nutrition-risk stratification—Why and how? 376 Estimating calorie requirement while initiating nutrition in the ICU 376 What should be the caloric goal, best route, and time to initiate nutrition? 377 Ancillary controversies in initiating nutrition in the ICU 377 Laboratory evidence 377 How important is timely, appropriate initiation of nutrition in a critically ill patient? 377 Is it possible to overnourish a patient? 377 Nutrition-risk stratification—Why and how? 378 Clinical evidence 379 How important is timely, appropriate initiation of nutrition in a critically ill patient? 379

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Is it possible to overnourish a patient? 379 Nutrition-risk stratification—Why and how? 379 Estimating calorie requirement while initiating nutrition in the ICU 379 What should be the caloric goal, best route, and time to initiate nutrition 380 Ancillary controversies in initiating nutrition in the ICU 380 Consensus statement 381 How important is timely, appropriate initiation of nutrition in a critically ill patient? 381 Is it possible to overnourish a patient? 381 Nutrition-risk stratification—Why and how? 381 Estimating calorie requirement while initiating nutrition in the ICU 381 What should be the caloric goal, best route, and time to initiate nutrition 382 Ancillary controversies in initiating nutrition in the ICU 383 Special consideration in neurological patients 383 Conclusion 384 References 385

28. Glycemic control Shaun E. Gruenbaum, Raphael A.O. Bertasi, Tais G.O. Bertasi, Benjamin F. Gruenbaum, and Federico Bilotta Introduction 389 Pathophysiology 389 Controversy 390 Clinical evidence 391 Subarachnoid hemorrhage 391 Acute ischemic stroke 392 Traumatic brain injury 392 Consensus statement 392 Conclusion 393 References 393

29. Anesthetics for status epilepticus Mariangela Panebianco Introduction 395 The question/controversy 395 Clinical evidence 396 Consensus statement 399 Conclusions 399 References 400

Section G Ethical issues 30. Diagnosing brain death Christopher R. Barnes and Michael J. Souter Introduction 403 The controversy 403 Clinical evidence for diagnosing death by neurologic criteria 404 Consensus statement 405 Prerequisites of clinical testing 405 Conclusion with clinical scenarios 408 References 411

Section H Recent advances 31. Simulations in clinical neurosciences Ljuba Stojiljkovic, Kan Ma, and Jamie Uejima Introduction 417 The question/controversy 417 Evidence from simulation education research 418 Simulation education research evidence: Assessment tools and debriefing techniques to improve education 418 Evidence from clinical sciences 419 Simulation skill training in neurosurgical anesthesia 419 Basics in neurophysiological monitoring simulation training 421 High-fidelity simulation in management of critical events 422 Training in anesthesia nontechnical skills 423 Consensus statement 424 Conclusion 424 References 424

Section I Webliography 32. Webliography Vanitha Rajagopalan and Hemanshu Prabhakar Index 433

Contributors Numbers in parenthesis indicate the pages on which the authors’ contributions begin.

Vinay Byrappa (239), Anesthesiology Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates

Pasquale Anania (193), Department of Neurosurgery, San Martino Policlinico Hospital, IRCCS for Oncology and Neurosciences, Genoa, Italy

Maria J. Colomina (229), Department of Anaesthesiology, Critical Care and Pain Clinic, Bellvitge University Hospital; University of Barcelona, Barcelona, Spain

Christopher R. Barnes  (403), Department of Anesthesiology and Pain Medicine, University of Washington, Harborview Medical Center, Seattle, WA, United States

Laura Contreras  (229), Department of Anaesthesiology, Critical Care and Pain Clinic, Bellvitge University Hospital; University of Barcelona, Barcelona, Spain

Megan Barra (111), Department of Pharmacy, Massachusetts General Hospital, Boston, MA, United States Denise Battaglini  (33,193), Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neurosciences, Genoa, Italy; Department of Medicine, University of Barcelona, Barcelona, Spain Raphael A.O. Bertasi (389), Department of Anesthesiology and Perioperative Medicine, Mayo Clinic-Florida, Jacksonville, FL, United States Tais G.O. Bertasi  (389), Department of Anesthesiology and Perioperative Medicine, Mayo Clinic-Florida, Jacksonville, FL, United States Sarang Biel  (299), Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, OR, United States Federico Bilotta  (389), Department of Anesthesiology, Critical Care and Pain Medicine, Sapienza University of Rome, Rome, Italy Navindra R. Bista (359), Department of Anaesthesiology, Tribhuvan University Teaching Hospital, Institute of Medicine, Tribhuvan University, Kathmandu, Nepal Vincent Bonhomme  (321), University Department of Anesthesia and Intensive Care Medicine, Centre Hospitalier Regional de la Citadelle; Department of Anesthesia and Intensive Care Medicine, University Hospital of Liege; Anesthesia and Intensive Care Laboratory, GIGA-Consciousness Thematic Unit, GIGA-Research, Liege University, Liege, Belgium Gretchen Brophy (111), Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, Richmond, VA, United States

Aline Defresne (321), University Department of Anesthesia and Intensive Care Medicine, Centre Hospitalier Regional de la Citadelle; Department of Anesthesia and Intensive Care Medicine, University Hospital of Liege; Anesthesia and Intensive Care Laboratory, GIGAConsciousness Thematic Unit, GIGA-Research, Liege University, Liege, Belgium Justin Delic  (77), Department of Pharmacy, Cooper University Hospital, Camden, NJ, United States Judith Dinsmore  (9), Department of Anaesthesia, St. Georges University Hospital, London, United Kingdom Gustavo Domeniconi (367), Sanatorio de la Trinidad San Isidro, Buenos Aires, Argentina Hossam El Beheiry (279), Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto; Department of Anesthesia, Trillium Health Partners, Mississauga, ON, Canada Mazen Elwishi  (9), Neuroanaesthesia & Critical Care, St George’s University Hospital, London, United Kingdom Nicolai Goettel  (203), University of Basel, Department of Clinical Research, Basel, Switzerland; University of Florida College of Medicine, Department of Anesthesiology, Gainesville, FL, United States Nuno Veloso Gomes (203), University of Basel, Department of Clinical Research; University Hospital Basel, Department of Anesthesia, Prehospital Emergency Medicine and Pain Therapy, Basel, Switzerland Benjamin F. Gruenbaum  (389), Department of Anesthesiology and Perioperative Medicine, Mayo Clinic-Florida, Jacksonville, FL, United States

xv

xvi  Contributors

Shaun E. Gruenbaum (389), Department of Anesthesiology and Perioperative Medicine, Mayo Clinic-Florida, Jacksonville, FL, United States

Charu Mahajan  (3,67,267), Department of Neuroanaesthesiology and Critical Care, All India Institute of Medical Sciences (AIIMS), New Delhi, India

Nidhi Gupta  (287), Indraprastha Apollo Hospitals, New Delhi, Delhi, India

Jason M. Makii  (77), Department of Pharmacy Services, University Hospitals Cleveland Medical Center; Case Western Reserve University School of Medicine, Cleveland, OH, United States

Laura Hemmer  (217), Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States Franziska Herpich  (15), Departments of Neurology and Neurological Surgeries, Thomas Jefferson University Hospitals, Philadelphia, PA, United States Theresa Human (15), Barnes-Jewish Hospital, Washington University, St. Louis, MO, United States Amit Jain (239), Anesthesiology Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates Madhan Jeyaraman  (163), Indian Stem Cell Study Group, Lucknow; Department of Biotechnology, School of Engineering and Technology; Department of Orthopaedics, School of Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, India Indu Kapoor  (3,67,267), Department of Neuroanaesthesiology and Critical Care, All India Institute of Medical Sciences (AIIMS), New Delhi, India Ashish Khanna  (99), Department of Anesthesiology, Section on Critical Care Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States

Hugues Marechal  (321), Department of Anesthesia and Intensive Care Medicine, Centre Hospitalier Regional de la Citadelle, Liege, Belgium Rohan Mathur  (89), Division of Neurocritical Care, Departments of Anesthesiology and Critical Care Medicine, Neurology, and Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, United States Rajeeb Kumar Mishra (45), Department of Neuroanesthesia and Neurocritical Care, National Institute of Mental Health and Neurosciences, Bengaluru, India Javier Montupil  (321), University Department of Anesthesia and Intensive Care Medicine, Centre Hospitalier Regional de la Citadelle; Department of Anesthesia and Intensive Care Medicine, University Hospital of Liege; Anesthesia and Intensive Care Laboratory, GIGA-Consciousness Thematic Unit, GIGA-Research, Liege University, Liege, Belgium

Matthew A. Kirkman (183), Department of Neurosurgery, Queen’s Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom

Sathish Muthu  (163), Indian Stem Cell Study Group, Lucknow; Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh; Department of Orthopaedics, Government Medical College & Hospital, Dindigul, Tamil Nadu, India

Amanda Katherine Knutson  (217), Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States

Mehrnaz Pajoumand  (15), Department of Pharmacy, University of Maryland Medical Center, Baltimore, MD, United States

Ines P. Koerner  (299), Anesthesiology & Perioperative Medicine and Neurological Surgery, Oregon Health & Science University, Portland, OR, United States Tomer Kotek  (53), Ben Gurion University of the Negev, Beersheba, Israel

Mariangela Panebianco (395), Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Clinical Sciences Centre for Research and Education, Liverpool, United Kingdom

Massimo Lamperti  (239), Anesthesiology Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates

Laura Pariente  (229), Department of Anaesthesiology, Critical Care and Pain Clinic, Bellvitge University Hospital; University of Barcelona, Barcelona, Spain

Ritesh Lamsal  (359), Department of Anaesthesiology, Tribhuvan University Teaching Hospital, Institute of Medicine, Tribhuvan University, Kathmandu, Nepal

Paolo Pelosi  (33,193), Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neuroscience; Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy

Kan Ma  (417), Department of Anesthesiology and Pain Medicine, St. Michael's Hospital, University of Toronto, Canada

Hemanshu Prabhakar  (3,67,431), Department of Neuroanaesthesiology and Critical Care, All India Institute of Medical Sciences (AIIMS), New Delhi, India

Contributors  xvii

Vanitha Rajagopalan  (431), Department of Neuroanaesthesiology and Critical Care, All India Institute of Medical Sciences, New Delhi, India Chiara Riforgiato  (33), Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neuroscience; Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy Chiara Robba  (33,193), Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neuroscience; Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy Irene Rozet (53), Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, United States Dona Saha  (375), Department of Anaesthesiology and Critical Care, All India Institute of Medical Sciences Bhubaneswar, Bhubaneswar, Odisha, India Shilpa Sharma  (163), Department of Paediatric Surgery, All India Institute of Medical Sciences, New Delhi, Delhi; Indian Stem Cell Study Group, Lucknow, Uttar Pradesh, India Michael J. Souter (403), Department of Anesthesiology and Pain Medicine, University of Washington, Harborview Medical Center, Seattle, WA, United States Ljuba Stojiljkovic  (417), Department of Anesthesiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States Micheal Strein (111), Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, Richmond, VA, United States Jose I. Suarez  (89), Division of Neurocritical Care, Departments of Anesthesiology and Critical Care Medicine, Neurology, and Neurosurgery, The Johns

Hopkins University School of Medicine, Baltimore, MD, United States Veronica Taylor (111), Virginia Commonwealth University School of Pharmacy, Richmond, VA, United States Jessica Traeger  (77), Department of Pharmacy Services, University Hospitals Cleveland Medical Center, Cleveland, OH, United States Swagata Tripathy  (375), Department of Anaesthesiology and Critical Care, All India Institute of Medical Sciences Bhubaneswar, Bhubaneswar, Odisha, India Abhay Tyagi  (99), Department of Anesthesiology, St. Elizabeth’s Medical Center, Tufts University, Boston, MA, United States Mayank Tyagi (267), Department of Neuroanaesthesiology and Critical Care, All India Institute of Medical Sciences (AIIMS), New Delhi, India Jamie Uejima  (217,417), Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States; Department of Anesthesiology and Pain Medicine, St. Michael’s Hospital, University of Toronto, Canada Walter Videtta (367), Hospital Nacional Prof. A. Posadas, Buenos Aires, Argentina Patrick Mark Wanner  (203), University Hospital Basel, Department of Anesthesia, Prehospital Emergency Medicine and Pain Therapy, Basel, Switzerland Alexander Zlotnik  (53), Ben Gurion University of the Negev, Beersheba, Israel Andres Zorrilla-Vaca (309), Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, TX; Department of Anesthesiology, Universidad Del Valle, Cali, Colombia; Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States

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Acknowledgments I thank the administration of the All India Institute of Medical Sciences (AIIMS), New Delhi (India), for allowing me to carry out this academic task. I also thank the faculty and staff of the Department of Neuroanaesthesiology and Critical Care at AIIMS, New Delhi, for their support. I specially thank Dr. Charu Mahajan and Dr. Indu Kapoor for their constructive criticism and inputs in this academic endeavor. Special thanks are due to the team of Elsevier—Melanie Tucker, Kristi Anderson, Susan Ikeda, Selvaraj Raviraj, and all those involved in this project.

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Section A

Introduction

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Chapter 1

Introduction to evidence-based practice Indu Kapoor, Charu Mahajan, and Hemanshu Prabhakar Department of Neuroanaesthesiology and Critical Care, All India Institute of Medical Sciences (AIIMS), New Delhi, India

Chapter outline Introduction Evidence-based practice in neuroanesthesia

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References

4

Introduction Evidence-based medicine (EBM) is defined as “explicit and judicious use of current best evidence in making decisions about the care of individual patients” (Sackett, Rosenberg, Gray, Haynes, & Richardson, 1996). David M. Eddy first use the term “evidence-based” in 1987 in a manual commissioned by the Council of Medical Specialty Societies which was eventually published by the American College of Physicians (Eddy & American College of Physicians, 1992). He further discussed “evidence-based” policies in several other papers published in medical journals (Eddy, 1990a, 1990b). EBM requires the integration of the best research evidence, clinical expertise, and the patient’s distinctive conditions. The need for EBM is growing rapidly in health care practice because of many factors which include: increasing patient expectations, increased number of publications, information overload, and introduction of new technologies. The evidence obtained from research can be used either to improve clinical practice or to improve health service management. In situations where there is good quality evidence, the health care provider can give the best to the patient with minimal complications. However, in conditions where the evidence is poor, the decision-maker will have to depend on his/her experience, available resources, and patient’s expectations. Thus, evidence-based medicine is the backbone of health care facilities that provides a structured approach towards patient management.

Evidence-based practice in neuroanesthesia Recent times have witnessed a remarkable growth in the field of neuro-anesthesia techniques and monitoring with evolving research and publications. The good quality research which is on the top of the evidence pyramid including systematic reviews, meta-analysis, and randomized controlled trials (RCTs) is still very low on the list. On literature search, the data reveals a small fraction of work that has direct implications on clinical practice with little clinical significance. The majority of trials in neuro-anesthesia provide results with a low level of evidence. In the future, well-designed RCTs with large sample sizes may influence the neuro-anesthesia practice worldwide. Cerebral perfusion pressure (CPP) and intracranial pressure (ICP) are the two main pillars in the treatment of neurosurgical patients who undergo anesthesia for surgery. As per current clinical evidence, the target ICP should be maintained  70 mmHg (Level III) (Carney et  al., 2017). The treatment of intracranial hypertension is either CPP targeted (Rosner’s concept) or ICP targeted or volume targeted (Lund’s concept) (Bullock et al., 1996; Eker, Asgeirsson, Grände, Schalén, & Nordström, 1998; Rosner, Rosner, & Johnson, 1995). At present there is a lack of evidence supporting the superiority of one approach over another. Among anesthetic agents, inhalational agents have vasodilatory effects on central nervous system vasculature in dose-dependent manner (Holmström & Akeson, 2004). Despite using it for many years, the use of nitrous oxide (N2O) is still debatable in neuro-anesthesia practice. The landmark trials-ENIGMA I and ENIGMA II had widely studied the effect of N2O on a large number of patients expected to undergo major surgery (Myles et al., 2007, 2014). In ENIGMA I trial authors concluded that the avoidance of N2O does not significantly affect the duration of hospiEssentials of Evidence-Based Practice of Neuroanesthesia and Neurocritical Care. https://doi.org/10.1016/B978-0-12-821776-4.00001-9 Copyright © 2022 Elsevier Inc. All rights reserved.

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tal stay. Authors in the ENIGMA II trial supported the safety profile of N2O use in major non-cardiac surgery and did not show an increase in the risk of death and cardiovascular complications or surgical-site infection with its use (Myles et al., 2014). Neurosurgical cases in these trials contributed to a very small percentage of the study population. Thus, the result of these studies can’t be simply applied to neurosurgical patients. Further large RCTs would be required to find out the exact place of N2O in neuro-anesthesia field. The intravenous anesthetic agents have vasoconstrictive effects on the cerebral vasculature (Alkire et al., 1995). According to the Intraoperative Hypothermia For Aneurysm Surgery Trial (IHAST) data, thiopental or etomidate administration do not have any clinically significant demonstrable effect on postoperative neurologic outcomes in patients undergoing temporary clipping (Hindman, Bayman, Pfisterer, Torner, & Todd, 2010). Regarding the effect of hyperosmolar therapy, that is, mannitol or hypertonic saline on ICP, there is no conclusive evidence at present to support the superiority of one over another at reducing intracranial pressure in patients undergoing craniotomy for brain tumors (Prabhakar, Singh, Anand, & Kalaivani, 2014). Hyperventilation is one of the intraoperative strategies to provide a relaxed brain to the surgeon during craniotomy (Gelb et al., 2008). It has a short-term or temporary, but profound effect on cerebral blood flow (CBF). However, if used for a prolonged period, it has been shown to have a significantly worse outcomes than those were at the normal ventilatory rates (Muizelaar et al., 1991). Decompressive craniectomy (DC) is a neurosurgical procedure done to treat raised intracranial pressure (ICP) in patients with traumatic brain injury. DECRA trial (Decompressive Craniectomy in Diffuse Traumatic Brain Injury) showed that early DC is found to decrease ICP and the length of stay in intensive care unit (ICU), but is associated with more unfavorable functional outcomes (Cooper et al., 2011). At present, there is no evidence that DC can improve overall outcomes in adults. Regarding fluid resuscitation, the Saline versus Albumin Fluid Evaluation (SAFE) study was the first large multicentric RCT that showed no difference in the 28-day mortality rate between the saline and albumin groups (Finfer et al., 2004). The recommendation by the European Society of Intensive Care Medicine suggests that the colloids should not be used in patients with traumatic brain injury (TBI) (Reinhart et al., 2012). Regarding different neuroprotective strategies used in neurosurgical patients which include hypothermia, glycemic control, maintenance of mean arterial pressure, different anesthetic agents, and various other drugs, have no strong guidelines based on relevant clinical evidence. Most of the clinical evidence is weak due to the lack of large RCTs. According to Brain Trauma Foundation (BTF) 2016 guidelines, out of 15 parameters discussed, only steroids have level 1 recommendation against their use in TBI patients since their use in TBI patients leads to an increase in the mortality rate (Carney et al., 2017). Many unresolved issues still exist in neuro-anesthesia practice worldwide. Though many trials have been done in recent times which show results that are of minimal clinical importance, an improved approach and methodology towards good research would be an answer to controversies revolving around inconclusive topics.

References Alkire, M. T., Haier, R. J., Barker, S. J., Shah, N. K., Wu, J. C., & Kao, Y. J. (1995). Cerebral metabolism during propofol anesthesia in humans studied with positron emission tomography. Anesthesiology, 82(2), 393–403. discussion 27A. Bullock, R., Chesnut, R. M., Clifton, G., Ghajar, J., Marion, D. W., Narayan, R. K., et al. (1996). Guidelines for the management of severe head injury. Brain Trauma Foundation. European Journal of Emergency Medicine: Official Journal of the European Society for Emergency Medicine, 3(2), 109–127. Carney, N., Totten, A. M., O’Reilly, C., Ullman, J. S., Hawryluk, G. W. J., Bell, M. J., et al. (2017). Guidelines for the management of severe traumatic brain injury, fourth edition. Neurosurgery, 80(1), 6–15. https://doi.org/10.1227/NEU.0000000000001432. Cooper, D. J., Rosenfeld, J. V., Murray, L., Arabi, Y. M., Davies, A. R., D’Urso, P., et al. (2011). Decompressive craniectomy in diffuse traumatic brain injury. The New England Journal of Medicine, 364(16), 1493–1502. https://doi.org/10.1056/NEJMoa1102077. Eddy, D. M. (1990a). Clinical decision making: From theory to practice. Practice policies- -guidelines for methods. JAMA, 263(13), 1839–1841. Eddy, D. M. (1990b). Clinical decision making: From theory to practice. Guidelines for policy statements: The explicit approach. JAMA, 263(16), 2239–2240. 2243. Eddy, D. M., & American College of Physicians. (1992). In D. M. David (Ed.), A manual for assessing health practices & designing practice policies: The explicit approach American College of Physicians. Eker, C., Asgeirsson, B., Grände, P. O., Schalén, W., & Nordström, C. H. (1998). Improved outcome after severe head injury with a new therapy based on principles for brain volume regulation and preserved microcirculation. Critical Care Medicine, 26(11), 1881–1886. Finfer, S., Bellomo, R., Boyce, N., French, J., Myburgh, J., & Norton, R. (2004). A comparison of albumin and saline for fluid resuscitation in the intensive care unit. The New England Journal of Medicine, 350(22), 2247–2256. Gelb, A. W., Craen, R. A., Rao, G. S. U., Reddy, K. R. M., Megyesi, J., Mohanty, B., et al. (2008). Does hyperventilation improve operating condition during supratentorial craniotomy? A multicenter randomized crossover trial. Anesthesia and Analgesia, 106(2), 585–594. table of contents https:// doi.org/10.1213/01.ane.0000295804.41688.8a. Hindman, B. J., Bayman, E. O., Pfisterer, W. K., Torner, J. C., & Todd, M. M. (2010). No association between intraoperative hypothermia or supplemental protective drug and neurologic outcomes in patients undergoing temporary clipping during cerebral aneurysm surgery: Findings from the Intraoperative Hypothermia for Aneurysm Surgery Trial. Anesthesiology, 112(1), 86–101. https://doi.org/10.1097/ALN.0b013e3181c5e28f.

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Holmström, A., & Akeson, J. (2004). Desflurane increases intracranial pressure more and sevoflurane less than isoflurane in pigs subjected to intracranial hypertension. Journal of Neurosurgical Anesthesiology, 16(2), 136–143. Muizelaar, J. P., Marmarou, A., Ward, J. D., Kontos, H. A., Choi, S. C., Becker, D. P., et al. (1991). Adverse effects of prolonged hyperventilation in patients with severe head injury: A randomized clinical trial. Journal of Neurosurgery, 75(5), 731–739. Myles, P. S., Leslie, K., Chan, M. T. V., Forbes, A., Paech, M. J., Peyton, P., et al. (2007). Avoidance of nitrous oxide for patients undergoing major surgery: A randomized controlled trial. Anesthesiology, 107(2), 221–231. Myles, P. S., Leslie, K., Chan, M. T. V., Forbes, A., Peyton, P. J., Paech, M. J., et al. (2014). The safety of addition of nitrous oxide to general anaesthesia in at-risk patients having major non-cardiac surgery (ENIGMA-II): A randomised, single-blind trial. Lancet (London, England), 384(9952), 1446–1454. Prabhakar, H., Singh, G. P., Anand, V., & Kalaivani, M. (2014). Mannitol versus hypertonic saline for brain relaxation in patients undergoing craniotomy. The Cochrane Database of Systematic Reviews, 7. https://doi.org/10.1002/14651858.CD010026.pub2, CD010026. Reinhart, K., Perner, A., Sprung, C. L., Jaeschke, R., Schortgen, F., Johan Groeneveld, A. B., et al. (2012). Consensus statement of the ESICM task force on colloid volume therapy in critically ill patients. Intensive Care Medicine, 38(3), 368–383. https://doi.org/10.1007/s00134-012-2472-9. Rosner, M. J., Rosner, S. D., & Johnson, A. H. (1995). Cerebral perfusion pressure: management protocol and clinical results. Journal of Neurosurgery, 83(6), 949–962. Sackett, D. L., Rosenberg, W. M., Gray, J. A., Haynes, R. B., & Richardson, W. S. (1996). Evidence based medicine: What it is and what it isn’t. BMJ (Clinical Research Ed.), 312(7023), 71–72.

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Section B

Neurophysiology

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Chapter 2

ICP or CPP thresholds Judith Dinsmorea and Mazen Elwishib a

Department of Anaesthesia, St. Georges University Hospital, London, United Kingdom, bNeuroanaesthesia & Critical Care, St George’s University Hospital, London, United Kingdom

Chapter Outline Introduction Question What ICP threshold should we target and what is the optimal CPP range? Controversy Should ICP and CPP thresholds be protocolized according to consensus guidelines or individualized to achieve better outcomes?

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Evidence Consensus Conclusion References

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Introduction Monitoring the brain after injury plays a crucial role in the early detection of secondary adverse events, assessing response to treatment, and optimizing cerebral function. Intracranial pressure and cerebral perfusion pressure are the most commonly used modalities in neurocritical care. The cranium is a rigid structure with a fixed internal volume containing the brain, cerebral blood, and cerebrospinal fluid (CSF). Under normal physiological conditions, the volume of the brain parenchyma is relatively constant and intracranial pressure (ICP) is derived primarily from the circulation of cerebral blood and CSF. The presence of a space-occupying lesion or an increase in the volume of any of the individual constituents necessitates the displacement of the others or an increase in ICP (the Monro-Kellie doctrine). Intracranial pressure has physiological values of 3–4 mmHg up to one year of age, and 10–15 mmHg in adults. However, the threshold for what is considered raised ICP or intracranial hypertension is dependent upon the individual pathology. In hydrocephalus, values over 15 mmHg are considered elevated whereas in traumatic brain injury (TBI) the threshold for intervention is typically 20–25 mmHg. Intracranial hypertension can have devastating complications. As ICP increases, cerebral perfusion begins to decrease with a reduction in cerebral blood flow (CBF). Eventually, compression of brain tissue against the tentorium, falx, and foramen magnum and ultimately herniation can occur. In addition to TBI, intracranial hypertension may complicate a range of other neurological conditions such as subarachnoid or intracerebral hemorrhage, ischemic stroke, meningitis, and hepatic encephalopathy. Intracranial hypotension can also occur usually secondary to CSF leakage. Different methods are available to monitor ICP, but the two most commonly used methods are the use of an intraventricular catheter or an intraparenchymal micro-transducer device. The intraventricular catheter is considered the gold standard method as it measures global ICP in addition to allowing therapeutic drainage of CSF. Although the use of ICP monitoring varies between countries and centers, there are well-established indications and recommendations for its use in patients with TBI (Brain Trauma Foundation, 2020). Along with the direct measurement of pressure, ICP monitors are also used to guide clinical management and to calculate cerebral perfusion pressure (CPP). Additional information can be gained from analysis of the ICP waveform including the assessment of pressure-volume compensatory reserve and cerebrovascular pressure reactivity. Cerebral perfusion pressure describes the pressure driving blood through the cerebrovascular bed and is calculated according to the equation: CPP = mean arterial pressure (MAP) − mean ICP. It is important to note that for accurate calculation the transducers measuring both MAP and ICP should be zeroed at the level of the foramen of Monro (Thomas, Czosnyka, & Hutchinson, 2015). The primary goal of an adequate CPP is to maintain CBF and tissue oxygenation. Recommendations for the optimal CPP threshold have changed over time. Current guidelines target a CPP between 60 and 70 mmHg with Essentials of Evidence-Based Practice of Neuroanesthesia and Neurocritical Care. https://doi.org/10.1016/B978-0-12-821776-4.00002-0 Crown Copyright © 2022, Published by Elsevier Inc. All rights reserved.

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evidence of adverse outcomes at higher and lower values (Smith, 2015). When the CPP falls below 50 mmHg there is a risk of cerebral ischemia and aggravation of secondary brain injury. An individualized target for each patient has been proposed taking into account variables including age, sex, underlying pathology (Kirkman & Smith, 2014). Calculation of an optimal CPP for individual patients will need to consider cerebral autoregulation and cerebrovascular pressure reactivity. Cerebral autoregulation is an important mechanism that allows the cerebral vascular system to maintain a relatively constant CBF despite changes in MAP and CPP. However, it is frequently impaired in brain injury. It is now possible to continuously monitor autoregulation using derived indices such as the cerebrovascular pressure reactivity index (PRx). This is a key component of cerebral autoregulation and determines the ICP response to changes in arterial blood pressure (ABP). When cerebrovascular pressure reactivity is defective such as in cases of TBI, a rise in MAP will lead to a passive increase in CBV and eventually a rise in ICP, whereas a drop in MAP will cause an opposite effect. PRx is calculated as a correlation coefficient between the slow waves of MAP and ICP at sequential time-averaged points over a defined period. Negative values, where ABP is negatively correlated with ICP, or values around zero, indicate intact autoregulation. Positive values suggest disturbed reactivity or impaired autoregulation. The concept of an individualized or optimum CPP (CPPopt) is based on the observation that PRx and CPP exhibit a U-shaped relationship with time. The PRx is at its lowest value where cerebrovascular reactivity is best preserved, and this corresponds to the CPPopt (Fig.  2.1). Continuous cerebrovascular reactivity monitoring could therefore be used to derive individualized targets such as optimum CPP (CPPopt) and patientspecific ICP thresholds (Zeiler et al., 2020).

Question What ICP threshold should we target and what is the optimal CPP range? Setting physiological parameters and treatment thresholds is part of good critical care and protocol-based treatment strategies appear to improve morbidity and mortality outcomes (Helmy, Vizcaychipi, & Gupta, 2007). Most current treatment strategies aim to maintain a single target threshold for ICP or a range for CPP; thresholds are based on analysis of data derived from populations of patients with TBI (Brain Trauma Foundation, 2020). The Brain Trauma Foundation (BTF) guidelines for the management of severe TBI have been widely adopted across the globe. In the 4th edition, the ICP treatment threshold was set at 22 mmHg based on the available evidence which indicated increased mortality with sustained higher ICP levels. The CPP threshold was set at 60–70 mmHg with evidence of significant harm with CPP  70 mmHg (Table 2.1).

Controversy Should ICP and CPP thresholds be protocolized according to consensus guidelines or individualized to achieve better outcomes? Although the use of single target thresholds provides a useful starting point for patient management, the evidence for this approach is inconsistent (Helbok, Meyfroidt, & Beer, 2018; Kirkman & Smith, 2014; Smith, 2018). In addition, single target thresholds fail to account for either heterogeneity of injury type or individual patient response to treatment (Younsi et al., 2017). An individualized approach using multimodality monitoring to target each patient could be used in other types of acute brain injury such as intracerebral and subarachnoid hemorrhage in addition to TBI. As the technology has evolved, clinicians now can personalize patient care using models for predicting optimal CPP and ICP thresholds. There is some evidence that these individual targets may be associated with better outcomes than existing consensus guidelines (Zeiler et al., 2020). However, these prediction models currently come from single center studies, albeit with multicenter validation studies, and large-scale prospective validation is still required. In addition, global adoption of such individualized approaches will require major investments in monitoring equipment and software packages that may not be widely available.

Evidence Despite the widespread use of ICP and CPP guided therapy, there is no high-quality evidence for outcome benefit. Most studies have investigated patients with TBI and results are inconsistent (Bragge et al., 2016). This is in part due to the difficulties involved in conducting prospective randomized controlled trials (RCT) in this area but also to the fact that TBI is not a single pathophysiological entity; rather it represents a heterogeneous set of disease processes each requiring different approaches to both diagnosis and management. In the absence of robust evidence, consensus guidelines dictate practice

FIG. 2.1  Illustration of CPPopt determination with the upper and lower ends of autoregulation. Illustration of CPPopt determination with the upper and lower ends of autoregulation. Curve a: U-shaped PRx -CPP curve showing automated CPPopt. The PRx threshold is set for 0.3 for impaired autoregulation (white line). The intersection with the U-shaped curve marks both the upper and lower reactivity CPP values. Curve b: PRx-CPP curve with PRx threshold set at 0.0 for impaired autoregulation. The result is a smaller CPP range for upper and lower reactivity CPP values. (With thanks to Zeiler, F. A., Ercole, A., Czosnyka, M., Smielewski, P., Hawryluk, G., Hutchinson, P. J. A., Menon, D. K., & Aries, M. (2020). Continuous cerebrovascular reactivity monitoring in moderate/ severe traumatic brain injury: A narrative review of advances in neurocritical care. British Journal of Anaesthesia, 124(4), 440–453. https://doi:10.1016/j. bja.2019.11.031.)

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TABLE 2.1  Brain Trauma Foundation (BTF) recommendations for ICP and CPP. Brain Trauma Foundation Guidelines—4th Edition Recommendations for ICP and CPP Intracranial pressure thresholds

Treating ICP above 22 mmHg is recommended because values above this level are associated with increased mortality (Level IIb evidence). A combination of ICP values and clinical and brain CT findings may be used to make management decisions (Level III evidence).

Cerebral perfusion pressure thresholds

The recommended target CPP value for survival and favorable outcomes is between 60 and 70 mmHg (Level IIb evidence). Avoid aggressive attempts to maintain CPP above 70 mmHg with fluids and pressors because of the risk of adult respiratory failure (Level III evidence).

Brain Trauma Foundation Guidelines (BTF)—4th Edition showing recommendations for intracranial pressure (ICP) and cerebral perfusion pressure (CPP) with the level of evidence.

and of these, the BTF guidelines are considered the gold standard. There is evidence of adverse outcomes, specifically excess mortality in those patients with refractory intracranial hypertension (Badri et al., 2012). However, there is insufficient evidence to provide Level I or Level IIa recommendations for ICP thresholds. The current BTF recommendation is to treat ICP > 22 mmHg (Level IIb). Although some meta-analyses of ICP targeted care have reported treatment benefits (Stein, Georgoff, Meghan, Mirza, & El Falaky, 2010; Zhao et al., 2016), others have suggested it might be associated with a worse outcome (Su & Wang, 2014; Yuan et al., 2015). The only prospective RCT, the BEST-TRIP trial, came from South America (Chesnut et al., 2012). This showed no difference in 3-6-month outcome between those patients who had ICP targeted therapy when compared to patients whose management was based on clinical assessment and imaging. However, differences in patient care before hospital admission and after discharge were not reported and there have been concerns about the generalizability to routine practice in higher-income countries. There is also little evidence from RCTs to support a specific CPP threshold or range and recommendations have changed over time. The BTF recommends using CPP to decrease 2-week mortality in severe TBI and current guidelines set the CPP threshold at 60-70 mmHg. There is evidence of significant harm with CPP  70 mmHg. Higher CPP values (> 70 mmHg) had been previously advocated due to the perceived physiological advantages of increased perfusion. However, outcomes were not improved and there appeared to be a potential to cause harm with the increased fluid volumes and vasopressor or inotrope use required to maintain CPP linked to a fivefold increase in the frequency of acute lung injury (Robertson et al., 1999). In the absence of high-quality evidence for single ICP and CPP targets, the use of more dynamic, individualized CPP and ICP thresholds have been proposed. To determine optimal CPP and ICP at an individual level both cerebral autoregulation and cerebral vascular reactivity need to be considered. Various studies have evaluated the use of continuously monitored PRx. As described previously, the U-shaped curve obtained by plotting the PRx index against CPP forms the basis for individualized or optimal CPP targets. It appears that individual CPPopt thresholds can be identified in about 65% of TBI patients with both the upper (hyperperfusion) and lower extremes (hypoperfusion) associated with worse cerebral vascular reactivity (Steiner et al., 2002). A 24-h period of dynamic monitoring seems sufficient to determine the optimal CPP. Importantly, the optimal CPP threshold appears to be dynamic; specific for individual patients but also varying at different time points in response to changing physiology. Retrospective data support a strong association between failure to achieve CPPopt and unfavorable outcomes (Aries et al., 2015). It was also noted that hypoperfusion was associated with higher mortality and hyperperfusion with more severe disability. Prospective evaluation of CPPopt guided therapy is still awaited although a recommendation for its use has been made albeit with only moderate quality of evidence (Puppo et al., 2014). A feasibility study (COGiTATE) to assess the use of CPPopt guided management is currently ongoing. The concept of an individual ICP treatment threshold, using continuously monitored cerebrovascular reactivity with PRx, has also been proposed. Although work is in its early stages, two studies appear to demonstrate a stronger association between outcome and time spent above individual ICP thresholds when compared to the existing BTF ICP thresholds. In the first of these studies, individual ICP thresholds were identified by plotting PRx against ICP. The ICP threshold is determined as the ICP value that corresponds to a PRx value of + 0.20 and where all subsequent higher ICP values have persistent PRx values > + 0.20. There was a statistically significant correlation between hourly ICP dose above the individual threshold and outcome at 6 and 12 months when compared to hourly ICP dose above 20 and 22 mmHg (BTF thresholds) (Christos et  al., 2014). The prospective multicenter CENTER TBI High-Resolution ICU sub-study used semi-automated algorithmic detection of individual ICP thresholds using similar criteria to the above

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study (Steiner et al., 2002; Zeiler et al., 2019). The mean hourly dose of ICP above a patient’s individual ICP threshold was more strongly associated with mortality compared to the dose above the BTF threshold of 22 mmHg. However, this work is very much in its infancy and currently remains a research tool. A moving correlation coefficient named RAP indicates the relationship between ICP and amplitude of ICP pulse waveforms. RAP has values close to 0 when compensatory reserve is good, increasing to values closer to + 1 when the compensatory mechanisms are exhausted such as in severe TBI. A weighted ICP can then be derived as wICP = (1 − RAP) × ICP. A CENTER TBI validation study reported that wICP displayed a better association with outcome and mortality rates when compared to mean ICP. This provides a promising scope for research but is currently an experimental concept and further studies are needed to identify wICP treatment thresholds.

Consensus In the current absence of high-quality evidence, expert recommendations and consensus statements are considered valuable tools to guide clinical practice. The latest edition of the BTF reviewed all the available evidence and advised thresholds for blood pressure, ICP and CPP. These thresholds may be considered values to avoid to reduce the possibility of adverse outcomes or values to achieve to improve the likelihood of a positive outcome or a value that triggers a change in treatment. See Table 2.1. Recommendations for the use of ICP monitoring and management options for treatment of elevated ICP guidelines have also been produced by other expert groups but these do not specify ICP thresholds (Christos et al., 2014; Koskinen et al., 2014). The Neurocritical Care Society and the European Society of Intensive Care Medicine have produced recommendations for multimodality monitoring in neurocritical Care which include the use of ICP and CPP. These do not support the use of a single threshold for ICP (Puppo et al., 2014).

Conclusion There remains a lack of evidence to support ICP and CPP monitoring but despite this, their use remains fundamental to the care of patients with acute brain injury. Increased ICP and in particular refractory increased ICP and its burden—­duration and intensity, is linked to adverse outcomes. Although most commonly used for the management of TBI, monitoring provides useful information in other conditions such as subarachnoid and intracerebral hemorrhage. Despite existing consensus guidelines, thresholds for intervention are uncertain. It is increasingly recognized that reliance on single thresholds for all patients is an oversimplification. Targets and thresholds will vary both within and between patients depending upon time, specific pathology, and individual response to injury. Advances in monitoring have led to the possibility of personalized medicine with individual targets such as CPPopt. Although prospective validation is lacking it appears that these individualized targets may have a stronger association with the outcome than current consensus-based thresholds. The future management of acute brain injury will rely on an individual approach with continuous input from multiple monitors better predicting imminent secondary injury rather than ICP and CPP in isolation.

References Aries, M. J. H., Van Der Naalt, J., van den Bergh, W. B., van Dijk, M., Elting, J. W. J., Czosnyka, M., et al. (2015). Neuromonitoring of patients with severe traumatic brain injury at the bedside. Netherlands Journal of Critical Care, 20(2), 6–12. http://njcc.nl/sites/default/files/pdf/review_10.pdf. Badri, S., Chen, J., Barber, J., Temkin, N. R., Dikmen, S. S., Chesnut, R. M., et al. (2012). Mortality and long-term functional outcome associated with intracranial pressure after traumatic brain injury. Intensive Care Medicine, 38(11), 1800–1809. https://doi.org/10.1007/s00134-012-2655-4. Bragge, P., Synnot, A., Maas, A. I., Menon, D. K., Cooper, D. J., Rosenfeld, J. V., et al. (2016). A state-of-the-science overview of randomized controlled trials evaluating acute management of moderate-to-severe traumatic brain injury. Journal of Neurotrauma, 33(16), 1461–1478. https://doi. org/10.1089/neu.2015.4233. Brain Trauma Foundation. (2020). Guidelines for the management of severe TBI (4th Ed.). Brain Trauma Foundation. Retrieved from https://braintrauma. org/guidelines/guidelines-for-tthe-management-of-severe-tbi-4th-ed#/. (Accessed 18 May 2020). Chesnut, R. M., Temkin, N., Carney, N., Dikmen, S., Rondina, C., Videtta, W., et al. (2012). A trial of intracranial-pressure monitoring in traumatic brain injury. New England Journal of Medicine, 367, 2471–2481. https://doi.org/10.1056/nejmoa1207363. Christos, L., De Santis, S. M., Smielewski, P., Menon, D. K., Hutchinson, P., Pickard, J. D., et al. (2014). Patient-specific thresholds of intracranial pressure in severe traumatic brain injury. Journal of Neurosurgery, 120, 893–900. https://doi.org/10.3171/2014.1.jns131292. Helbok, R., Meyfroidt, G., & Beer, R. (2018). Intracranial pressure thresholds in severe traumatic brain injury: Con: The injured brain is not aware of ICP thresholds! Intensive Care Medicine, 44(8), 1318–1320. https://doi.org/10.1007/s00134-018-5249-y. Helmy, A., Vizcaychipi, M., & Gupta, A. K. (2007). Traumatic brain injury: Intensive care management. British Journal of Anaesthesia, 99(1), 32–42. https://doi.org/10.1093/bja/aem139.

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Kirkman, M. A., & Smith, M. (2014). Intracranial pressure monitoring, cerebral perfusion pressure estimation, and ICP/CPP-guided therapy: A standard of care or optional extra after brain injury? British Journal of Anaesthesia, 112(1), 35–46. https://doi.org/10.1093/bja/aet418. Koskinen, L. O., Latronico, N., Maas, A. I. R., Payen, J. F., Rosenthal, G., Sahuquillo, J., et al. (2014). Clinical applications of intracranial pressure monitoring in traumatic brain injury: Report of the Milan consensus conference. In Vol. 156. Acta neurochirurgica (pp. 1615–1622). Springer-Verlag Wien. https://doi.org/10.1007/s00701-014-2127-4. Puppo, C., Riker, R., Robertson, C., Schmidt, M., Taccone, F., Naidech, A., et  al. (2014). 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 Medicine, 40(9), 1189–1209. https://doi.org/10.1007/ s00134-014-3369-6. Robertson, C. S., Valadka, A. B., Hannay, H. J., Contant, C. F., Gopinath, S. P., Cormio, M., et al. (1999). Prevention of secondary ischemic insults after severe head injury. Critical Care Medicine, 27(10), 2086–2095. https://doi.org/10.1097/00003246-199910000-00002. Smith, M. (2015). Cerebral perfusion pressure. British Journal of Anaesthesia, 115(4), 488–490. https://doi.org/10.1093/bja/aev230. Smith, M. (2018). Multimodality Neuromonitoring in adult traumatic brain injury: A narrative review. Anesthesiology, 128(2), 401–415. https://doi. org/10.1097/ALN.0000000000001885. Stein, S. C., Georgoff, P., Meghan, S., Mirza, K. L., & El Falaky, O. M. (2010). Relationship of aggressive monitoring and treatment to improved outcomes in severe traumatic brain injury. Journal of Neurosurgery, 112(5), 1105–1112. https://doi.org/10.3171/2009.8.JNS09738. Steiner, L. A., Czosnyka, M., Piechnik, S. K., Smielewski, P., Chatfield, D., Menon, D. K., et al. (2002). Continuous monitoring of cerebrovascular pressure reactivity allows determination of optimal cerebral perfusion pressure in patients with traumatic brain injury. Critical Care Medicine, 30(4), 733–738. https://doi.org/10.1097/00003246-200204000-00002. Su, H., & Wang, F. (2014). The effects of intracranial pressure monitoring in patients with traumatic brain injury. PLoS One, 9(2), e87432. Thomas, E., Czosnyka, M., & Hutchinson, P. (2015). Calculation of cerebral perfusion pressure in the management of traumatic brain injury: Joint position statement by the councils of the Neuroanaesthesia and Critical Care Society of Great Britain and Ireland (NACCS) and the Society of British Neurological Surgeons (SBNS). British Journal of Anaesthesia, 115(4), 487–488. https://doi.org/10.1093/bja/aev233. Younsi, A., Zaaroor, M., Zelinkova, V., Zemek, R., Zumbo, F., Winkler, M. K. L., et al. (2017). Traumatic brain injury: Integrated approaches to improve prevention, clinical care, and research. The Lancet Neurology, 16(12), 987–1048. https://doi.org/10.1016/S1474-4422(17)30371-X. Yuan, Q., Wu, X., Sun, Y., Yu, J., Li, Z., Du, Z., et al. (2015). Impact of intracranial pressure monitoring on mortality in patients with traumatic brain injury: A systematic review and meta-analysis. Journal of Neurosurgery, 122(3), 574–587. https://doi.org/10.3171/2014.10.JNS1460. Zeiler, F. A., Ercole, A., Cabeleira, M., Beqiri, E., Zoerle, T., Carbonara, M., et al. (2019). Patient-specific ICP epidemiologic thresholds in adult traumatic brain injury. Journal of Neurosurgical Anesthesiology, 33, 28–38. https://doi.org/10.1097/ANA.0000000000000616. Zeiler, F. A., Ercole, A., Czosnyka, M., Smielewski, P., Hawryluk, G., Hutchinson, P. J. A., et al. (2020). Continuous cerebrovascular reactivity monitoring in moderate/severe traumatic brain injury: A narrative review of advances in neurocritical care. British Journal of Anaesthesia, 124(4), 440–453. https://doi.org/10.1016/j.bja.2019.11.031. Zhao, S., Yan, R., Su, Z., Qiu, S., Xu, J., Zhou, Y., et al. (2016). Effects of intracranial pressure monitoring on mortality in patients with severe traumatic brain injury: A meta-analysis. PLoS One, 11(12). https://doi.org/10.1371/journal.pone.0168901.

Chapter 3

Role of hypothermia Franziska Herpicha, Theresa Humanb, and Mehrnaz Pajoumandc a

Departments of Neurology and Neurological Surgeries, Thomas Jefferson University Hospitals, Philadelphia, PA, United States, bBarnes-Jewish Hospital, Washington University, St. Louis, MO, United States, cDepartment of Pharmacy, University of Maryland Medical Center, Baltimore, MD, United States

Chapter outline Introduction What disease states should target temperature management be considered? Cardiac arrest Acute ischemic stroke Intracerebral hemorrhage Aneurysmal subarachnoid hemorrhage Traumatic brain injury Spinal cord injury Status epilepticus Bacterial meningitis Acute liver failure Is one method of cooling superior? What is the optimal target temperature? Cardiac arrest Traumatic brain injury Does time to TTM implementation change outcomes? What is the optimal duration of TTM to improve outcomes? What is the optimal rate of rewarming to improve patient outcomes and prevent complications? Is there an optimal method/protocol to detect and treat shivering? The Columbia antishivering protocol Non-pharmacologic management of shivering Pharmacologic management of shivering

15 16 16 16 16 16 17 17 18 18 18 18 18 18 21 21 21 22 22 22 23 23

What are the important complications to evaluate during TTM? Cardiovascular Infections Bleeding Laboratory Skin integrity Consensus statement What disease states should target temperature management be considered? Is one method of cooling superior? What is the optimal target temperature? Does time to TTM implementation change outcomes? What is the optimal duration of TTM to improve outcomes? What is the optimal rate of rewarming to improve patient outcomes and prevent complications? Is there an optimal method/protocol to detect and treat shivering associated with TTM? What are the important complications to evaluate during TTM? Conclusion References

24 24 25 25 25 25 25 25 25 26 26 26 26 26 26 26 26

Introduction The origins of targeted temperature management (TTM) date back to 1940 and renewed interest in the modern era has produced data in various neurologic conditions, becoming a cornerstone for neuroprotective strategies (Benson, Williams Jr., Spencer, & Yates, 1959; Fay, 1945). Despite conflicting results from clinical trials, TTM is still used as an intervention to treat secondary brain damage and remains a critical intervention in patients experiencing an acute neurologic injury. Controversy still exists as to what diseases TTM should be considered, what temperature should be targeted, what devices are most effective with the least complications, and what duration is most effective.

Essentials of Evidence-Based Practice of Neuroanesthesia and Neurocritical Care. https://doi.org/10.1016/B978-0-12-821776-4.00003-2 Copyright © 2022 Elsevier Inc. All rights reserved.

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What disease states should target temperature management be considered? Cardiac arrest Early investigations established that hyperthermia after cardiac arrest (CA) is associated with poor outcomes (Bro-Jeppesen, Hassager, Wanscher, et al., 2013; Leary, Grossestreuer, Iannacone, et al., 2013; Zeiner, Holzer, Sterz, et al., 2001). Two landmark trials published in the early 2000s demonstrated the neuroprotective effects of therapeutic hypothermia (TH) after CA, thereby informing the use of TTM in this patient population for years to come. In the Hypothermia after Cardiac Arrest (HACA) trial, 275 comatose survivors of out-of-hospital ventricular fibrillation CA were randomized to mild hypothermia (target temperature 32°C–34°C) for 24 h(Hypothermia after Cardiac Arrest Study Group, 2002). Results demonstrated that 55% of patients in the hypothermia group had a favorable neurologic outcome at 6 months, defined as independence with moderate to no disability, as compared to 39% in the normothermia group (RR 1.40; 95% CI, 1.08–1.81; p = 0.009). Furthermore, the hypothermia group had lower mortality compared to normothermia, 41% compared to 55% respectively (RR 0.74; 95% CI, 0.58–0.95; p = 0.02). Bernard et al. randomized 77 comatose survivors of out-of-hospital ventricular fibrillation cardiac arrest to hypothermia (33°C) or normothermia (Bernard, Gray, Buist, et al., 2002). 49% (21 of 43) of patients in the hypothermia group had a good outcome and were either discharged home or to a rehab facility as compared to 26% (9 of 34) of patients in the normothermia group (p = 0.046). A limitation of both trials is that temperature was not tightly maintained in the control groups.

Acute ischemic stroke The effects of hyperthermia after acute ischemic stroke (AIS) have been investigated and have consistently been associated with poor clinical outcomes (Greer, Funk, Reaven, Ouzounelli, & Uman, 2008; Saini, Saqqur, Kamruzzaman, Lees, & Shuaib, 2009). Su et al. randomized patients with massive cerebral hemispheric infarction to hypothermia (33°C or 34°C) or normothermia (Su, Fan, Zhang, et  al., 2016). Although underpowered, the results demonstrated no difference in the primary mortality outcome however mild hypothermia may improve neurologic outcomes at 6 months, as evaluated by modified Rankin score. The more recent randomized open-label clinical trial (EuroHYP-I) compared 3-month functional outcomes of patients with AIS when randomized to hypothermia (34°C or 35°C) or standard treatment alone (van der Worp, Macleod, Bath, et al., 2014). The results did not demonstrate any difference in outcomes although only 98 of the originally intended 1500 patients were included as the trial was discontinued due to slow recruitment and termination of funding. A prospective randomized study comparing the safety and clinical outcome of hemicraniectomy alone with combination therapy (hemicraniectomy and hypothermia of 35°C) in malignant brain infarction, suggested an improvement in functional outcome with combination therapy (Els et al., 2006). Therefore, the Decompressive surgery plus hypothermia for space-occupying stroke (DEPTH-SOS) trial was conducted to evaluate the effects and safety of moderate hypothermia (33°C ± 1°C) for at least 72 h compared to standard care after hemicraniectomy in patients with malignant stroke (Neugebauer, Schneider, Bosel, et al., 2019). The trial was stopped for safety reasons after enrollment of 50 patients as there was a trend toward a higher rate of significant adverse events within 14 days in the hypothermia group, that persisted at 12 months follow-up. In fact, the combination may be potentially harmful.

Intracerebral hemorrhage Hyperthermia in intracerebral hemorrhage (ICH) has been associated with hematoma growth and poor outcome at 90 days (Rincon, Lyden, & Mayer, 2013). Several small studies examined the effects of mild hypothermia compared to controls and found perihematomal edema volume remained stable in the hypothermia group, while it significantly increased in the control group (Kollmar et al., 2010; Staykov et al., 2013). A retrospective case-control study evaluating normothermia to treat fever after ICH was associated with increased duration of sedation, mechanical ventilation, and ICU stay and not associated with improved discharge functional outcome (Lord, Karinja, Lantigua, et al., 2014). These results bring into question the benefit of fever control with TTM in ICH, which introduces its own set of risks.

Aneurysmal subarachnoid hemorrhage Fever is associated with an increased risk of death, vasospasm, and poor outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH) (Gowda, Jaffa, & Badjatia, 2018; Oliveira-Filho, Ezzeddine, Segal, et al., 2001). Intraoperative

Role of hypothermia Chapter | 3  17

hypothermia was investigated as early as 1955 as adjunctive therapy during surgery to secure a ruptured aneurysm. The Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) was a multicenter, prospective, randomized trial, that evaluated outcomes in those that underwent intraoperative hypothermia (33°C) compared to normothermia (36.5°C) (Todd, Hindman, Clarke, & Torner, 2005). The study failed to demonstrate significant differences between the groups to duration of ICU and hospital stay, rates of death, discharge disposition, or functional outcome. However, the incidence of postoperative bacteremia was significantly higher in the hypothermia group. A case-control study in 40 consecutive febrile patients compared to 80 historical controls evaluated the impact of induced normothermia (37°C) on outcome following aSAH. A multivariable linear regression model showed that induced normothermia was associated with improved outcomes at 1 year. Few retrospective case series have investigated the effect of TTM during the acute phase of aSAH with poor grade WFNS (Anei, Sakai, Iihara, & Nagata, 2010; Nagao, Irie, Kawai, et al., 2000; Nakamura, Tatara, Morisaki, Kawakita, & Nagao, 2002; Yasui, Kawamura, Suzuki, Hadeishi, & Hatazawa, 2002). Overall outcomes results were unsatisfactory with mortality rates of 47%–67% and favorable outcomes as low as 5%–44%. Anei et al. compared outcomes before and after the introduction of HT at their institution and found no difference in mortality between groups (Anei et al., 2010). Gasser et al. however showed more promising results in patients with aSAH WFNS 4 to 5 who received TH after developing refractory intracranial hypertension (Gasser, Khan, Yonekawa, Imhof, & Keller, 2003). TH was initiated on day 4.2 ± 3.3 and continued for 4.3 ± 3.9 days. 47.6% (10 of 21) had favorable GOS (4, 5), however, cooling for more than 72 h was associated with more complications. Seule et al. evaluated 100 aSAH patients that received TH, of which 28 patients had symptomatic vasospasm refractory to hypertensive and endovascular therapies (Seule, Muroi, Mink, Yonekawa, & Keller, 2009). The mean duration of TH was 5.7 ± 3.3 days. Although 57% of the patients had a poor-grade aSAH, a favorable outcome (GOS 4–5) was achieved in 57% of patients. Of patients with refractory intracranial hypertension, a favorable outcome was obtained in 25%. Of note, 23 of the 28 patients with vasospasm were treated concomitantly with TH and barbiturate coma which could skew the results significantly.

Traumatic brain injury The use of prophylactic hypothermia to prevent secondary brain injury after traumatic brain injury (TBI) has been evaluated in multiple studies. While earlier trials demonstrated the benefit of prophylactic hypothermia, larger trials failed to do so (Clifton, Allen, Barrodale, et al., 1993; Clifton, Miller, Choi, et al., 2001; Clifton, Valadka, Zygun, et al., 2011; Maekawa, Yamashita, Nagao, Hayashi, & Ohashi, 2015; Polderman et al., 2002; Smrcka, Vidlak, Maca, Smrcka, & Gal, 2005). The Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury-Randomized Clinical Trial (POLAR-RCT) compared prophylactic hypothermia (33°C–35°C sustained for at least 72 h and up to 7 days) to normothermia and found no difference in neurological outcomes and mortality at six months (Cooper, Nichol, Bailey, et al., 2018). Of note, 13% of patients in the hypothermia group failed to reach the target temperature (TT) and 19% were withdrawn early. TT for refractory intracranial cerebral pressure (ICP) management was evaluated in a small randomized trial which resulted in significant reductions in cerebral blood flow and cerebral metabolic rate of oxygen (Shiozaki, Sugimoto, Taneda, et  al., 1993). The European Study of Therapeutic Hypothermia (32°C–35°C) for Intracranial Pressure Reduction after Traumatic Brain Injury (the EUROTHERM3235 Trial) was stopped early due to safety concerns, demonstrating worse outcomes with hypothermia compared to normothermia (Andrews, Sinclair, Rodriguez, et al., 2015).

Spinal cord injury Two approaches to TH in acute spinal cord injury (SCI) include local and systemic cooling. Local hypothermia focuses on cooling only the region of the injury or spinal cord, whereas systemic hypothermia focuses on cooling the core temperature of the body. A series of 20 patients with complete acute spinal cord injury who received corticosteroids, decompressive surgery, and localized cord cooling (dural temperature 6°C) demonstrated that 80% of patients achieved some sensory and motor functional recovery (Hansebout & Hansebout, 2014). Levi and colleagues conducted a retrospective analysis of 14 patients with acute cervical SCI who underwent endovascular cooling (33°C for 48 h) compared to controls. At final follow-up (50.2 weeks), almost 43% of patients were incomplete (Levi, Casella, Green, et al., 2010). Nevertheless, there is a paucity of prospective investigations evaluating the neuroprotective outcomes of TH in acute SCI. Consensus Statement: Systemic hypothermia is not recommended at this time in acute SCI until prospective clinical trials address the safety and efficacy of this intervention.

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Status epilepticus Few studies have evaluated TH in patients with highly refractory clinical and/or electrographic epileptic activity that remained uncontrolled despite pharmacological treatment. In these trials, TH was initiated 1–60 days following status epilepticus (SE) onset, with a TT ranging from 30°C to 35°C, and duration varied from 20 to 240 h (Corry, Dhar, Murphy, & Diringer, 2008; Elting, Naalt, & Fock, 2010; Guilliams, Rosen, Buttram, et al., 2013; Lin, Lin, Hsia, Wang, & Group, 2012; Ren, Su, Tian, et al., 2015). Hypothermia was deemed effective in controlling seizure activity in 82% of cases, but rewarming lead to recurrence in 49% of cases. The HYBERNATUS trial evaluated TH (32°C–34°C for 24 h) in patients with convulsive SE (Legriel, Lemiale, Schenck, et al., 2016). No statistical difference in functional outcome was noted however hypothermia group had a lower rate of progression to electroencephalograph-confirmed SE on the first day when compared to the control group (11% vs 22%; OR, 0.40; 95% CI, 0.20–0.79; p = 0.009).

Bacterial meningitis A multicenter, randomized clinical trial compared hypothermia (32°C–34°C for 48 h) to the standard of care in 98 comatose patients with severe community-acquired bacterial meningitis to evaluate differences in functional outcome at 3 months (Mourvillier, Tubach, van de Beek, et al., 2013). The trial was stopped early due to concerns over excess mortality in the hypothermia group (25 of 49 patients [51%]) compared with the control group (15 of 49 patients [31%]; (RR, 1.991; 95% CI, 0.05–3.77; p = 0.04).

Acute liver failure In patients with acute liver failure (ALF) being bridged to orthotopic liver transplantation, moderate hypothermia (32°C–33°C) has been shown to safely prevent increases in ICP (Jalan, Olde Damink, Deutz, et al., 2003; Jalan & Rose, 2004). A retrospective cohort trial in 97 patients (compared to 1135 normothermic controls) with grade III or IV hepatic encephalopathy at high risk for cerebral edema compared TH (32°C–35°C) on 21-day survival and complications (Karvellas, Todd Stravitz, Battenhouse, Lee, & Schilsky, 2015). The unadjusted 21-day survival and transplant-free survival rates were similar for both groups (p > 0.4) and TH was not associated with increased risk for complications. While the aforementioned study was retrospective in nature, Bernal et al. conducted a multicenter, randomized, controlled trial in Europe to determine whether induced moderate hypothermia for 72 h at 33°C–34°C (compared to control at 36°C–37°C) could prevent or delay clinically significant elevations in ICP (Bernal, Murphy, Brown, et al., 2016). There was no significant difference between the groups for the primary outcome (TH 35% vs. control 27%; RR 1.31; 95% CI, 0.53–3.2; p = 0.56) mortality and adverse events.

Is one method of cooling superior? Currently, there are numerous types of cooling techniques available (Hoedemaekers, Ezzahti, Gerritsen, & van der Hoeven, 2007; Polderman & Herold, 2009; Sonder, Janssens, Beishuizen, et  al., 2018; Vaity, Al-Subaie, & Cecconi, 2015). See Table  3.1 for a comparison of various cooling strategies. A recent meta-analysis compared cooling methods to determine if one improved neurological outcome or mortality over another after CA (Calabro, Bougouin, Cariou, et al., 2019). Overarching results showed core cooling devices (endovascular catheters, infusion of cold saline, ECMO, esophageal or trans-nasal) had a probability of a better neurological outcome, but not survival when compared to surface cooling devices (ice packs, cooling pads, air or water circulating blankets). Additionally, invasive devices (endovascular catheters, ECMO, dialysis) and devices with a temperature feedback loop were associated with favorable outcomes and survival when compared to other methods. Endovascular catheters had better outcomes when compared to air or water circulating blankets and blankets had better outcomes than other surface cooling devices. Although this data has been acknowledged in many studies, most of the data included in this meta-analysis came from non-RCTs.

What is the optimal target temperature? Cardiac arrest Fray and Benson observed that hypothermia for patients with severe TBI or anoxic brain injury (ABI) could lead to improved outcomes. However, hypothermia was often deep with temperatures of 30°C or below. This resulted in a poor riskbenefit ratio due to increased incidence of arrhythmias, infections, and coagulopathies.

Role of hypothermia Chapter | 3  19

TABLE 3.1  Cooling techniques. Method

Auto-feedback loop

Clinical pearls

Ice packs

No

Infusion of cold saline

No

Effective to induce hypothermia but not effective to maintain TT. Readily available. Low cost can be used adjunctively with other methods

Conventional cooling methods

Surface cooling devices Cooling blankets (water or air circulation)

Typically no

CritiCool

Yes

InnerCool STX

Yes

Flexipads

No

ArticSun

Yes

Hydrogel-coated water-circulating pads are superior to water-circulating blankets for fever control in critically ill neurologic patients. Ease of application. High risk for skin breakdown and injury. Time to goal temperature ranges from 2 to 8 h. Shivering is more common with surface cooling than with other therapies

Intravascular cooling devices Thermoguard XP

Yes

InnerCool RTx

Yes

Less failure to reach TT and less overcooling. Increased risk for bloodstream infection and venous thrombosis due to catheter

Other Extracorporeal

Yes

Must have trained personnel

Esophageal

Yes

Not encompassing to the patient. MRI compatible. Ease of insertion and TT initiation. Gastric port is not approved for enteral feeding or medication administration although case reports of success have been published

RhinoChil (trans-nasal)

No

Ease of application. Studied primarily in the prehospital setting

In the 1990s multiple animal studies confirmed the initial positive results with fewer adverse events, using only mild hypothermia (32–34°C) (Coimbra & Wieloch, 1994; Colbourne, Sutherland, & Corbett, 1997; Ginsberg, Sternau, Globus, Dietrich, & Busto, 1992). About a decade later, the first two RCTs demonstrated the neuroprotective properties of TH in ventricular fibrillation CA, leading to improved survival and better neurological function (Bernard et al., 2002; Hypothermia after Cardiac Arrest Study Group, 2002). As discussed previously, the two RCTs in 2002 used mild hypothermia with a target temperature (TT) of 32–34°C. Bernard et al. randomized comatose CA survival patients into hypothermia group cooled to 33°C and maintained at that temperature for 12 h or normothermia (Bernard et al., 2002). 49% in the treatment arm had a good outcome, compared to 26% in the normothermia group (P = 0.046). After adjustment for baseline differences in age and time from collapse to return of spontaneous circulation (ROSC), the odds ratio for a good outcome in the hypothermia group compared with normothermia was 5.25 (95% CI, 1.47–18.76; P = 0.011). The difference in mortality between the hypothermia group (51%) and the normothermia group (68%) had a trend toward improved survival in the treatment arm but did not reach statistical significance. The European HACA trial included 275 patients of which 136 were cooled to a TT of 32–34°C and remained at that temperature for 24 h (Hypothermia after Cardiac Arrest Study Group, 2002). The treatment arm had a favorable neurologic outcome at 6 months in 55% (cerebral performance category [CPC] 1 or 2; see Table 3.2) compared to 39% in the normothermia group (RR 1.4; 95% CI, 1.08–1.81). As a result of its relatively large sample size, the study also showed the hypothermia group had significantly improved mortality (41%) compared to the normothermia group (55%) (RR, 0.74; 95% CI, 0.58–0.95). These results revolutionized the care of ABI and in 2003 the International Liaison Committee on Resuscitation (ILCOR) recommended a TT of 32–34°C for comatose CA survivors (Nolan, Morley, Vanden Hoek, et al., 2003). In 2019, the first trial investigating TTM for survivors of CA with non-shockable rhythms compared mortality and clinical outcome after TTM with a TT of 33°C versus 37°C (Lascarrou, Merdji, Le Gouge, et al., 2019). 581 patients were included and at 90 days, 10.2% (29 of 284) of patients in the hypothermia group were alive with a good clinical outcome (CPC 1–2) versus 5.7% (17 of 297) in the normothermia group (difference, 4.5 percentage points; 95% CI, 0.1 to 8.9; P = 0.04). Mortality did not differ significantly between the hypothermia and the normothermia groups (81.3% versus 83.2%).

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TABLE 3.2  Cerebral performance category scale. Scale 1

Good cerebral performance: conscious, alert, able to work and lead a normal life. May have a mild neurologic or psychologic deficit.

2

Moderate cerebral performance: conscious, sufficient cerebral function for independent activities of daily life. Able to work in a sheltered environment.

3

Severe cerebral disability: conscious, dependent on others for activities of daily life because of impaired brain function (in an institution or at home with profound family support). Ranges from ambulatory state to severe dementia or paralysis.

4

Coma or vegetative state. Unconscious, no interaction with the environment.

5

Brain death

CPC 1 and 2 are considered good neurologic outcomes while CPC 3–5 are considered poor neurologic outcomes. Adapted from Safar, P. (1981). Cerebral resuscitation. Mount Sinai Journal of Medicine, 48(4), 385–388.

In an earlier 2013 study, Nielsen et al. attempted to address this limitation and compared 33 versus 36°C in comatose CA survivors of presumed cardiac etiology (Nielsen, Wetterslev, Cronberg, et al., 2013). 473 patients were randomized to the 33°C group and 466 patients to the 36°C group. There was no difference in mortality between the 33°C group and the 36°C group (50% vs. 48%; P = 0.51). There was also no significant difference at the 180-day follow up, at which 54% of the patients in the 33°C group had either died or had poor neurologic outcomes (CPC 3–5 and modified ranking scale 4–6) compared to 52% of patients in the 36°C group (P = 0.78). When adjusted for known prognostic factors, the results remained similar. Thus, no benefit was found for 33°C over 36°C in comatose CA survivors. Based on these results, the guidelines were adjusted in 2015, and the recommended TT after cardiac arrest was changed to a constant temperature within the range of 32–36°C (see Table  3.3 for an overview of cardiac arrest trials) (Donnino, Andersen, Berg, et  al., 2015). It remains uncertain if there are subgroups of comatose CA survivors who benefit from a lower versus a higher TT.

TABLE 3.3  Overview of postcardiac arrest trials. Bernard et al. (2002)

HACA (2002)

Nielsen et al. (2013)

Lascarrou et al. (2019)

Population

OHCA with VF as initial rhythm

OHCA with VF and pulseless VT

OHCA with presumed cardiac etiology

OHCA with initial nonshockable rhythm

Total number of patients

77

273

939

584

Type of trial

Australian single-center trial

Multicenter trial including 9 European ICUs

Multicenter trial including 36 ICUs in Europe and Australia

Multicenter trial in 25 ICUs in France

TT

33°C vs normothermia

32–34°C vs normothermia

33°C vs 36°C

33°C vs normothermia

Duration of hypothermia

12 h

24 h

28 h followed by strict normothermia for 72 h post-ROSC

24 h followed by 24 h of strict normothermia

Rate of rewarming

0.5°C/h

0.3–0.6°C/h (Rewarmed over 8 h)

0.5°C/h

0.25–0.5°C/h

Mortality outcome

At discharge: 51% (hypothermia) vs 68% (normothermia) (NS)

At 6 months: 41% (hypothermia) vs 55% (normothermia) P = 0.02

At end of trial: 50% (33°C) vs 48% (36°C) (NS)

At 90 days: 81.3% (33°C) vs 83.2% (normothermia) (NS)

Good neurological outcome

49% (hypothermia) vs 26% (normothermia) P = 0.046

55% (hypothermia) vs 39% (normothermia) P = 0.009

46% (33°C) vs 48% (36°C) (NS)

10.2% vs 5.7% P = 0.04

HACA, The Hypothermia after Cardiac Arrest Study Group; OHCA, out of hospital cardiac arrest; VF, ventricular fibrillation; VT, ventricular tachycardia; ROSC, the return of spontaneous circulation; NS, not significant.

Role of hypothermia Chapter | 3  21

For instance, if a patient is at increased risk for seizures or worsening cerebral edema, it is reasonable to choose a lower temperature. On the other hand, a higher TT might be beneficial if the patient is at risk for significant bleeding. Additionally, the patient’s baseline temperature could guide the depth of the treatment. If a patient presents with an initial body temperature closer to the lower end of the TH range, it is sensible to maintain them at that lower temperature. Of note, active or rapid rewarming to a higher temperature is never advised (Callaway, Donnino, Fink, et al., 2015).

Traumatic brain injury The use of hypothermia in TBI has lost importance after multiple trials showed either no or a harmful effect when hypothermia was administered early after the injury as a prophylactic measure. The only potential remaining indication of hypothermia in TBI is as a therapeutic tool, when patients develop elevated ICP, refractory to conventional treatments like hyperosmolar therapy and sedation (Clifton et al., 2001; Clifton, Valadka, Aisuku, & Okonkwo, 2011; Clifton, Valadka, Zygun, et al., 2011; Lazaridis, 2016). Clifton et al. showed favorable effects on ICP in the treatment group, in which patients were cooled to 33°C and the EUROTHERM3235 trial improved ICP by cooling their hypothermia arm to maintain an ICP ice packs).

What is the optimal target temperature? In CA survivors, 36°C appears to be as effective as 33°C, however, 36°C is still considered to be hypothermia and therefore does not fully resolve this controversy. Since hyperthermia is an independent risk factor for poor outcomes in neurologically injured patients, the avoidance of pyrexia should always be sought (Hajat, Hajat, & Sharma, 2000; Takino & Okada, 1991; Zeiner et al., 2001).

Does time to TTM implementation change outcomes? TTM should be implemented as quickly as possible after ROSC in CA survivors. We currently do not recommend prehospital cooling with cold saline infusion (Callaway et al., 2015).

What is the optimal duration of TTM to improve outcomes? For comatose survivors after CA, TTM should occur for at least 24 h followed by another 24 h of strict normothermia (Callaway et al., 2015; Donnino et al., 2015). In other disease states, the cooling intervals should be minimized to reduce complications.

What is the optimal rate of rewarming to improve patient outcomes and prevent complications? Patients undergoing TTM should be rewarmed at a rate of 0.25°C/h to normothermia. Aggressive forced rewarming is highly discouraged.

Is there an optimal method/protocol to detect and treat shivering associated with TTM? Shivering should be vigilantly evaluated using the bedside shiver assessment score by the bedside clinician. Scores > 1 should be managed using a combination of non-pharmacological and pharmacological interventions in a stepwise approach.

What are the important complications to evaluate during TTM? Although numerous complications have been identified with TTM, monitoring and treating hemodynamic alterations, volume status, and shivering is imperative. Understanding the limitations in laboratory values, including potassium and arterial blood gases, and how to correct for these alterations. And lasting close evaluation for infection and skin breakdown, specifically among those with surface cooling methods is vital.

Conclusion Although many controversies still exist in the target temperature management realm, several good practice statements can be made based on the available literature. Future prospective studies are needed to flush out the true answers to these controversies, however, in the meantime, we have guidance on how to administer TTM and to whom.

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D., Casella, G., Green, B. A., et al. (2010). Clinical outcomes using modest intravascular hypothermia after acute cervical spinal cord injury. Neurosurgery, 66(4), 670–677. https://doi.org/10.1227/01.NEU.0000367557.77973.5F. Lin, J. J., Lin, K. L., Hsia, S. H., Wang, H. S., & Group, C. S. (2012). Therapeutic hypothermia for febrile infection-related epilepsy syndrome in two patients. Pediatric Neurology, 47(6), 448–450. https://doi.org/10.1016/j.pediatrneurol.2012.08.013. Liou, A. K., Clark, R. S., Henshall, D. C., Yin, X. M., & Chen, J. (2003). To die or not to die for neurons in ischemia, traumatic brain injury and epilepsy: A review on the stress-activated signaling pathways and apoptotic pathways. Progress in Neurobiology, 69(2), 103–142. https://doi.org/10.1016/ s0301-0082(03)00005-4. Lord, A. S., Karinja, S., Lantigua, H., et al. (2014). Therapeutic temperature modulation for fever after intracerebral hemorrhage. 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(2001). Buspirone and meperidine synergistically reduce the shivering threshold. Anesthesia and Analgesia, 93(5), 1233–1239. https://doi.org/10.1097/00000539-200111000-00038. Mongardon, N., Perbet, S., Lemiale, V., et al. (2011). Infectious complications in out-of-hospital cardiac arrest patients in the therapeutic hypothermia era. Critical Care Medicine, 39(6), 1359–1364. https://doi.org/10.1097/CCM.0b013e3182120b56. Mooney, M. R., Unger, B. T., Boland, L. L., et al. (2011). Therapeutic hypothermia after out-of-hospital cardiac arrest: Evaluation of a regional system to increase access to cooling. Circulation, 124(2), 206–214. https://doi.org/10.1161/CIRCULATIONAHA.110.986257. Mort, T. C., Rintel, T. D., & Altman, F. (1996). The effects of forced-air warming on postbypass central and skin temperatures and shivering activity. Journal of Clinical Anesthesia, 8(5), 361–370. https://doi.org/10.1016/0952-8180(96)00081-5. Mourvillier, B., Tubach, F., van de Beek, D., et al. (2013). Induced hypothermia in severe bacterial meningitis: a randomized clinical trial. JAMA, 310(20), 2174–2183. https://doi.org/10.1001/jama.2013.280506. Nagao, S., Irie, K., Kawai, N., et al. (2000). Protective effect of mild hypothermia on symptomatic vasospasm: A preliminary report. Acta Neurochirurgica. Supplement, 76, 547–550. https://doi.org/10.1007/978-3-7091-6346-7_114. Naito, H., Isotani, E., Callaway, C. W., Hagioka, S., & Morimoto, N. (2016). Intracranial pressure increases during rewarming period after mild therapeutic hypothermia in postcardiac arrest patients. Therapeutic Hypothermia and Temperature Management, 6(4), 189–193. https://doi.org/10.1089/ther.2016.0009. Nakajima, Y., Takamata, A., Ito, T., et al. (2002). Upright posture reduces thermogenesis and augments core hypothermia. Anesthesia and Analgesia, 94(6), 1646–1651. table of contents https://doi.org/10.1097/00000539-200206000-00053. Nakamura, T., Tatara, N., Morisaki, K., Kawakita, K., & Nagao, S. (2002). Cerebral oxygen metabolism monitoring under hypothermia for severe subarachnoid hemorrhage: Report of eight cases. Acta Neurologica Scandinavica, 106(5), 314–318. https://doi.org/10.1034/j.1600-0404.2002.01300.x. Neugebauer, H., Schneider, H., Bosel, J., et al. (2019). Outcomes of hypothermia in addition to decompressive hemicraniectomy in treatment of malignant middle cerebral artery stroke: a randomized clinical trial. JAMA Neurology, 76(5), 571–579. https://doi.org/10.1001/jamaneurol.2018.4822. Nicolaou, G., Chen, A. A., Johnston, C. E., Kenny, G. P., Bristow, G. K., & Giesbrecht, G. G. (1997). Clonidine decreases vasoconstriction and shivering thresholds, without affecting the sweating threshold. Canadian Journal of Anaesthesia, 44(6), 636–642. https://doi.org/10.1007/BF03015448. Nielsen, N., Wetterslev, J., Cronberg, T., et al. (2013). Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest. The New England Journal of Medicine, 369(23), 2197–2206. https://doi.org/10.1056/NEJMoa1310519. Nolan, J. P., Morley, P. T., Vanden Hoek, T. L., et  al. (2003). Therapeutic hypothermia after cardiac arrest: an advisory statement by the advanced life support task force of the International Liaison Committee on Resuscitation. Circulation, 108(1), 118–121. https://doi.org/10.1161/01. CIR.0000079019.02601.90.

30  SECTION | B Neurophysiology

Nolan, J. P., Soar, J., Cariou, A., et al. (2015). European resuscitation council and European Society of Intensive Care Medicine 2015 guidelines for postresuscitation care. Intensive Care Medicine, 41(12), 2039–2056. https://doi.org/10.1007/s00134-015-4051-3. Oliveira-Filho, J., Ezzeddine, M. A., Segal, A. Z., et al. (2001). Fever in subarachnoid hemorrhage: relationship to vasospasm and outcome. Neurology, 56(10), 1299–1304. https://doi.org/10.1212/wnl.56.10.1299. Olson, D. M., Grissom, J. L., Williamson, R. A., Bennett, S. N., Bellows, S. T., & James, M. L. (2013). Interrater reliability of the bedside shivering assessment scale. American Journal of Critical Care, 22(1), 70–74. https://doi.org/10.4037/ajcc2013907. Park, B., Lee, T., Berger, K., et al. (2015). Efficacy of nonpharmacological antishivering interventions: A systematic analysis. Critical Care Medicine, 43(8), 1757–1766. https://doi.org/10.1097/ccm.0000000000001014. Park, S. M., Mangat, H. S., Berger, K., & Rosengart, A. J. (2012). Efficacy spectrum of antishivering medications: meta-analysis of randomized controlled trials. Critical Care Medicine, 40(11), 3070–3082. https://doi.org/10.1097/CCM.0b013e31825b931e. Polderman, K. H. (2004a). Keeping a cool head: How to induce and maintain hypothermia. Critical Care Medicine, 32(12), 2558–2560. https://doi. org/10.1097/01.ccm.0000148087.41418.0a. Polderman, K. H. (2004b). Application of therapeutic hypothermia in the ICU: Opportunities and pitfalls of a promising treatment modality. Part  1: Indications and evidence. Intensive Care Medicine, 30(4), 556–575. https://doi.org/10.1007/s00134-003-2152-x. Polderman, K. H. (2008). Induced hypothermia and fever control for prevention and treatment of neurological injuries. Lancet, 371(9628), 1955–1969. https://doi.org/10.1016/S0140-6736(08)60837-5. Polderman, K. H. (2009). Mechanisms of action, physiological effects, and complications of hypothermia. Critical Care Medicine, 37(7 Suppl), S186– S202. https://doi.org/10.1097/CCM.0b013e3181aa5241. Polderman, K. H. (2018). Cooling after cardiac arrest-the longer the better? Journal of Thoracic Disease, 10(Suppl 26), S3300–S3304. https://doi. org/10.21037/jtd.2018.07.96. Polderman, K. H., & Herold, I. (2009). Therapeutic hypothermia and controlled normothermia in the intensive care unit: Practical considerations, side effects, and cooling methods. Critical Care Medicine, 37(3), 1101–1120. https://doi.org/10.1097/CCM.0b013e3181962ad5. Polderman, K. H., Tjin, T., Joe, R., Peerdeman, S. M., Vandertop, W. P., & Girbes, A. R. (2002). Effects of therapeutic hypothermia on intracranial pressure and outcome in patients with severe head injury. Intensive Care Medicine, 28(11), 1563–1573. https://doi.org/10.1007/s00134-002-1511-3. Raghupathi, R., Graham, D. I., & McIntosh, T. K. (2000). Apoptosis after traumatic brain injury. Journal of Neurotrauma, 17(10), 927–938. https://doi. org/10.1089/neu.2000.17.927. Ren, G. P., Su, Y. Y., Tian, F., et al. (2015). Early hypothermia for refractory status epilepticus. Chinese Medical Journal, 128(12), 1679–1682. https://doi. org/10.4103/0366-6999.158378. Rincon, F., Lyden, P., & Mayer, S. A. (2013). Relationship between temperature, hematoma growth, and functional outcome after intracerebral hemorrhage. Neurocritical Care, 18(1), 45–53. https://doi.org/10.1007/s12028-012-9779-9. Rosa, G., Pinto, G., Orsi, P., et al. (1995). Control of post anaesthetic shivering with nefopam hydrochloride in mildly hypothermic patients after neurosurgery. Acta Anaesthesiologica Scandinavica, 39(1), 90–95. https://doi.org/10.1111/j.1399-6576.1995.tb05598.x. Saini, M., Saqqur, M., Kamruzzaman, A., Lees, K. R., & Shuaib, A. (2009). Effect of hyperthermia on prognosis after acute ischemic stroke. Stroke, 40(9), 3051–3059. https://doi.org/10.1161/strokeaha.109.556134. Scirica, B. M. (2013). Therapeutic hypothermia after cardiac arrest. Circulation, 127(2), 244–250. https://doi.org/10.1161/CIRCULATIONAHA.111.076851. Sessler, D. I. (2009). Thermoregulatory defense mechanisms. Critical Care Medicine, 37(7 Suppl), S203–S210. https://doi.org/10.1097/ CCM.0b013e3181aa5568. Seule, M. A., Muroi, C., Mink, S., Yonekawa, Y., & Keller, E. (2009). Therapeutic hypothermia in patients with aneurysmal subarachnoid hemorrhage, refractory intracranial hypertension, or cerebral vasospasm. Neurosurgery, 64(1), 86–92. discussion 92-3 https://doi.org/10.1227/01. NEU.0000336312.32773.A0. Shankaran, S., Laptook, A. R., Ehrenkranz, R. A., et al. (2005). Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. The New England Journal of Medicine, 353(15), 1574–1584. https://doi.org/10.1056/NEJMcps050929. Shankaran, S., Laptook, A. R., Pappas, A., et al. (2014). Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy: A randomized clinical trial. JAMA, 312(24), 2629–2639. https://doi.org/10.1001/jama.2014.16058. Sharma, D. R., & Thakur, J. R. (1990). Ketamine and shivering. Anaesthesia, 45(3), 252–253. https://doi.org/10.1111/j.1365-2044.1990.tb14709.x. Shiozaki, T., Sugimoto, H., Taneda, M., et al. (1993). Effect of mild hypothermia on uncontrollable intracranial hypertension after severe head injury. Journal of Neurosurgery, 79(3), 363–368. https://doi.org/10.3171/jns.1993.79.3.0363. Smrcka, M., Vidlak, M., Maca, K., Smrcka, V., & Gal, R. (2005). The influence of mild hypothermia on ICP, CPP and outcome in patients with primary and secondary brain injury. Acta Neurochirurgica. Supplement, 95, 273–275. https://doi.org/10.1007/3-211-32318-x_56. Sonder, P., Janssens, G. N., Beishuizen, A., et al. (2018). Efficacy of different cooling technologies for therapeutic temperature management: A prospective intervention study. Resuscitation, 124, 14–20. https://doi.org/10.1016/j.resuscitation.2017.12.026. Staykov, D., Wagner, I., Volbers, B., Doerfler, A., Schwab, S., & Kollmar, R. (2013). Mild prolonged hypothermia for large intracerebral hemorrhage. Neurocritical Care, 18(2), 178–183. https://doi.org/10.1007/s12028-012-9762-5. Steiner, T., Friede, T., Aschoff, A., Schellinger, P. D., Schwab, S., & Hacke, W. (2001). Effect and feasibility of controlled rewarming after moderate hypothermia in stroke patients with malignant infarction of the middle cerebral artery. Stroke, 32(12), 2833–2835. https://doi.org/10.1161/hs1201.99511. Stockmann, H., Krannich, A., Schroeder, T., & Storm, C. (2014). Therapeutic temperature management after cardiac arrest and the risk of bleeding: Systematic review and meta-analysis. Resuscitation, 85(11), 1494–1503. https://doi.org/10.1016/j.resuscitation.2014.07.018. Su, Y., Fan, L., Zhang, Y., et al. (2016). Improved neurological outcome with mild hypothermia in surviving patients with massive cerebral hemispheric infarction. Stroke, 47(2), 457–463. https://doi.org/10.1161/STROKEAHA.115.009789.

Role of hypothermia Chapter | 3  31

Suehiro, E., Singleton, R. H., Stone, J. R., & Povlishock, J. T. (2001). The immunophilin ligand FK506 attenuates the axonal damage associated with rapid rewarming following posttraumatic hypothermia. Experimental Neurology, 172(1), 199–210. https://doi.org/10.1006/exnr.2001.7765. Suehiro, E., Ueda, Y., Wei, E. P., Kontos, H. A., & Povlishock, J. T. (2003). Posttraumatic hypothermia followed by slow rewarming protects the cerebral microcirculation. Journal of Neurotrauma, 20(4), 381–390. https://doi.org/10.1089/089771503765172336. Sweney, M. T., Sigg, D. C., Tahvildari, S., & Iaizzo, P. A. (2001). Shiver suppression using focal hand warming in unanesthetized normal subjects. Anesthesiology, 95(5), 1089–1095. https://doi.org/10.1097/00000542-200111000-00011. Taccone, F. S., Picetti, E., & Vincent, J. L. (2020). High quality targeted temperature management (TTM) after cardiac arrest. Critical Care, 24(1), 6. https://doi.org/10.1186/s13054-019-2721-1. Takino, M., & Okada, Y. (1991). Hyperthermia following cardiopulmonary resuscitation. Intensive Care Medicine, 17(7), 419–420. https://doi.org/10.1007/ BF01720680. Talke, P., Tayefeh, F., Sessler, D. I., Jeffrey, R., Noursalehi, M., & Richardson, C. (1997). Dexmedetomidine does not alter the sweating threshold, but comparably and linearly decreases the vasoconstriction and shivering thresholds. Anesthesiology, 87(4), 835–841. https://doi. org/10.1097/00000542-199710000-00017. Taniguchi, Y., Lenhardt, R., Sessler, D. I., & Kurz, A. (2011). The effect of altering skin-surface cooling speeds on vasoconstriction and shivering thresholds. Anesthesia and Analgesia, 113(3), 540–544. https://doi.org/10.1213/ANE.0b013e3182273b19. Thompson, H. J., Kirkness, C. J., & Mitchell, P. H. (2010). Hypothermia and rapid rewarming is associated with worse outcome following traumatic brain injury. Journal of Trauma Nursing, 17(4), 173–177. https://doi.org/10.1097/JTN.0b013e3181ff272e. Todd, M. M., Hindman, B. J., Clarke, W. R., & Torner, J. C. (2005). Mild intraoperative hypothermia during surgery for intracranial aneurysm. The New England Journal of Medicine, 352(2), 135–145. https://doi.org/10.1056/NEJMoa040975. Vaity, C., Al-Subaie, N., & Cecconi, M. (2015). Cooling techniques for targeted temperature management post-cardiac arrest. Critical Care, 19, 103. https://doi.org/10.1186/s13054-015-0804-1. van der Worp, H. B., Macleod, M. R., Bath, P. M., et al. (2014). EuroHYP-1: European multicenter, randomized, phase III clinical trial of therapeutic hypothermia plus best medical treatment vs. best medical treatment alone for acute ischemic stroke. International Journal of Stroke, 9(5), 642–645. https://doi.org/10.1111/ijs.12294. Wadhwa, A., Sengupta, P., Durrani, J., et al. (2005). Magnesium sulphate only slightly reduces the shivering threshold in humans. British Journal of Anaesthesia, 94(6), 756–762. https://doi.org/10.1093/bja/aei105. Wang, C. H., Chen, N. C., Tsai, M. S., et al. (2015). Therapeutic hypothermia and the risk of hemorrhage: A systematic review and Meta-analysis of randomized controlled trials. Medicine (Baltimore), 94(47). https://doi.org/10.1097/MD.0000000000002152, e2152. Wu, T. C., & Grotta, J. C. (2013). Hypothermia for acute ischaemic stroke. Lancet Neurology, 12(3), 275–284. https://doi.org/10.1016/ S1474-4422(13)70013-9. Yasui, N., Kawamura, S., Suzuki, A., Hadeishi, H., & Hatazawa, J. (2002). Role of hypothermia in the management of severe cases of subarachnoid hemorrhage. Acta Neurochirurgica. Supplement, 82, 93–98. https://doi.org/10.1007/978-3-7091-6736-6_17. Zeiner, A., Holzer, M., Sterz, F., et al. (2001). Hyperthermia after cardiac arrest is associated with an unfavorable neurologic outcome. Archives of Internal Medicine, 161(16), 2007–2012. https://doi.org/10.1001/archinte.161.16.2007. Zweifler, R. M., Voorhees, M. E., Mahmood, M. A., & Parnell, M. (2004). Magnesium sulfate increases the rate of hypothermia via surface cooling and improves comfort. Stroke, 35(10), 2331–2334. https://doi.org/10.1161/01.STR.0000141161.63181.f1.

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Chapter 4

Mechanical ventilation—PEEP Chiara Riforgiatoa,b, Denise Battaglinia, Chiara Robbaa,b, and Paolo Pelosia,b a

Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neuroscience, Genoa, Italy, bDepartment of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy

Chapter outline Introduction The questions/controversy: The brain-lung crosstalk From the brain to the lung From the lung to the brain Peep effects on lung, cardiovascular, and brain pathophysiology Peep and oxygenation improvement Peep, intrathoracic pressure, and cerebral blood flow (CBF)

33 33 34 34 35 35

Peep and arterial PaCO2 increase, from dynamic hyperinflation to alveolar overdistension Laboratory evidence Clinical evidence Mechanical ventilation strategies in ABI patients Consensus statement Conclusions References

36 37 37 37 39 39 40

36

Introduction Patients who develop acute brain injury (ABI) often require admission to intensive care unit (ICU) ward for mechanical ventilation (MV) support due to their inability to maintain airway patency or an adequate gas exchange (Backhaus et al., 2015). ABI can be the result of many conditions (i.e., traumatic brain injury (TBI), acute ischemic stroke (AIS), subarachnoid hemorrhage (SAH), etc.). The need for artificial ventilation may depend on which brain areas are damaged. A pathological involvement of the respiratory centers (located in the pons, medulla, and cortex), consciousness areas (in the thalami, limbic system, and reticular formation of the brain stem), and swallowing control (in the medulla and brain stem connection) may make MV urgently necessary (Bösel, 2017). MV plays a relevant role in the maintenance of adequate gas exchange to minimize the risk of secondary brain damage and represents one of the main therapeutic strategies to face ABI by modulating MV on patient and brain needed. Over the past decades, MV strategies have changed in favor of low tidal volume (VT 6–8 mL/kg of predicted body weight, PBW), positive end-expiratory pressure (PEEP), driving pressure (P), Plateau pressure  45 mL/cmH2O, and the second with respiratory system compliance  15 mmHg, and in three studies ICP > 25 mmHg. Two primary outcomes were defined as: (1) mortality and (2) a favorable outcome defined as Glasgow Outcome Scale (GOS) ≥ 4, or extended Glasgow Outcome Scale (GOSE) ≥ 5. Secondary outcomes included ICP, time of elevated ICP, cerebral perfusion pressure, and brain tissue oxygen partial pressure. Overall, Schwimmbeck et al. concluded that although there was no statistically significant difference in mortality or outcomes between mannitol and HTS groups, there was a tendency to lower mortality with HS, comparing to mannitol. There was no difference in favorable outcomes or physiological brain parameters between mannitol and HTS. And, adverse effects of hyperosmolar therapy (e.g., electrolyte imbalance) have not been sufficiently reported. Taken heterogeneity of the studies by the severity of TBI, nature of injury (e.g., some studies included non-TBI patients), treatment regimen (e.g., precraniectomy vs postcraniectomy), etc., the definite conclusion on the particular hyperosmolar agent and its’ regimen in TBI could not be made. A recent analysis of prospective trials comparing continuous infusion of HTS versus boluses in patients with TBI by Asehnoune et al. (2017) concluded that continuous infusion may have survival and 90-day functional outcome benefits comparing to intermittent boluses. Interestingly, no adverse events (e.g., renal failure) of continuous therapy were reported and analyzed. Hopefully, two currently ongoing European studies: COBI (continuous hyperosmolar therapy for traumatic brain-­ injured patients) trial (Roquilly et al., 2017) and SOS (Sugar or Salt) trial (Rowland, Veenith, Scomparin, et al., 2019) will provide valuable data clarifying the right regimen and application of HTS versus mannitol for treatment in TBI. In summary, the results of recent studies comparing mannitol to HTS do not offer a specific recommendation to select one of them as a first-line agent in TBI patients with elevated ICP, however, for refractory intracranial hypertension, the use of HTS seems to be a priority.

62  SECTION | C  Neuropharmacology

Intracerebral hemorrhage (ICH) and acute ischemic stroke (AIS) Hyperosmolar fluids are the mainstem medical treatment in patients with large and/or hemispheric stroke suffering neurologic deterioration, cerebral edema and/or signs of increased ICP regardless of the nature of the stroke. The same is true for the treatment of patients with intracerebral hemorrhage suffering perihematomal edema and an increased ICP. Guidelines for the Management of Spontaneous Intracerebral Hemorrhage published in 2015, suggested hyperosmolar therapy to be beneficial in symptomatic patients with perihilar edema, and/or increased ICP (Hemphill 3rd et al., 2015). Based on the limited data, Evidence-Based Guidelines for the Management of Large Hemispheric Infarction, A Statement for Health Care Professionals from the Neurocritical Care Society and the German Society for Neuro-Intensive Care and Emergency Medicine recommended following: (1) use of “mannitol or HTS for reducing brain edema and tissue shifts in LHI only when there is clinical evidence of cerebral edema” (strong recommendation, moderate quality of evidence); (2) “suggest using osmolar gap instead of serum osmolality to guide mannitol dosing and treatment duration” (weak recommendation, low quality of evidence); (3) hypertonic saline dosing should be guided by serum osmolality and serum sodium (strong recommendation, moderate quality of evidence); (4) use of mannitol cautiously in patients with acute renal impairment (strong recommendation, moderate quality of evidence); (5) use of HTS cautiously in patients with volume overload state (i.e., heart failure, cirrhosis, etc.) since this agent will expand intravascular volume (strong recommendation, high quality of evidence) (Torbey et al., 2015). In 2018, the American Heart Association/American Stroke Association (AHA/ASA) in the Guidelines for the early management of patients with acute ischemic stroke in 2018, considered the use of hyperosmolar fluids in case of clinical deterioration in patients with hemispheric strokes (Class IIa, Level of Evidence C-LD) (Powers et al., 2019). However, in cases of malignant hemispheric edema, medical treatment alone was proven to be inferior to surgical treatment: decompressive craniotomy had unequivocal mortality benefits over medical treatment. The role and value of hyperosmotic therapy in preventing parenchymal shifts (lateral or transtentorial) in patients with large strokes are unclear. Patho-physiologically, hyperosmolar fluids may potentially aggravate the ICP gradient between ischemic or edematous parenchyma and preserved one by their debulking effect on the preserved brain parenchyma. This may be especially detrimental in cases of large brain lesions such as stroke or large supratentorial mass (e.g., tumor or intracerebral hemorrhage), potentially causing lateral parenchymal shifts. Early animal and small human studies utilizing both mannitol and HTS, suggested that hyperosmotic fluids in large brain lesions like hemispheric stroke, are either ineffective in improving lateral tissue shift or even detrimental, worsening brain edema in the lesion area. A recent review undertaken by Mohney and colleagues analyzed available literature to clarify the effect of hyperosmotic therapy on lateral brain shifts and survival in patients with hemispheric strokes (Mohney, Alkhatib, Koch, O'Phelan, & Merenda, 2020). Besides animal studies, authors analyzed eight human studies of various designs and various intracranial pathology describing an effect of hyperosmolar therapy on radiologic and clinical outcomes. Only two studies (Misra, Kalita, Ranjan, & Mandal, 2005; Santambrogio, Martinotti, Sardella, Porro, & Randazzo, 1978) out of eight were randomized control trials. Both studies reported no difference in neurologic outcome and mortality in patients with hemispheric stroke or supratentorial intracranial hemorrhage if mannitol was used as a hyperosmolar treatment. However, early therapy with hyperosmolar fluids in patients with large strokes and radiologic worsening such as lateral parenchymal shifts only, but without clinical deterioration, is not justified and may be detrimental. In one recent pilot study (Riha et al., 2017) an increase in in-hospital mortality was associated with hyperchloremia in patients with the intracerebral hemorrhage who received a continuous infusion of 3% HTS. In summary, currently, in patients with ICH or AIS, therapy with hyperosmolar fluids should be utilized in patients with clinical neurologic deterioration and signs of increased ICP only.

Subarachnoid hemorrhage (SAH) Both mannitol and HTS have been similarly used in the treatment of patients with SAH. However, high-quality RCTs comparing mannitol to HTS efficacy in SAH are largely lacking. A recent systematic review of Pasarikovski et al. (Pasarikovski, Alotaibi, Al-Mufti, & Macdonald, 2017) intended to analyze the role and efficacy of HTS in the treatment of severe SAH. Pasarikovski et al. included 5 small studies with total of 175 patients, but only three of them had a prospective design, and only two studies (a total of 47 patients) pursued randomization, but one of them applied an alternating protocol of mannitol and HTS. Studies varied in the concentration of HTS (range 3%–23.5%), regimen, the severity of SAH, and were lacking to report appropriate outcomes. Therefore, the authors performed only a qualitative analysis, but could not perform a quantitative analysis. The authors concluded that HTS reduces ICP in patients with SAH similarly to mannitol and that there is no evidence to conclude on the superiority of the specific hyperosmolar agent and regimen in the treatment of severe SAH with increased ICP.

Hyperosmolar therapy Chapter | 6  63

Conclusion Current evidence suggests that both mannitol and hypertonic saline are effective agents for managing acute intracranial hypertension especially in the setting of traumatic brain injury, yet Class I evidence for this therapy is sparse. The difficulty of acquiring sufficient data to prove Class 1 evidence includes variability of treatment protocols along with the insufficient magnitude of the studied population. Clinical practice utilizing both mannitol and hypertonic saline should be guided by patients’ clinical status and monitoring of osmolality, osmolal gap, and serum sodium. Research of the recent decade suggests that both mannitol and hypertonic saline are efficient hyperosmotic treatment tools in patients with increased ICP regardless of etiology. There has been a suggestion that hypertonic saline might be beneficial in patients with traumatic brain injury, particularly, if given as a continuous infusion. Further research is warranted to support this suggestion. The timing and regimen of both mannitol and hypertonic saline in critically ill patients with brain pathology are under the discretion of the treating physician and is usually limited to the treatment of increased ICP. Further research is warranted to elucidate the role and choice of hyperosmolar therapy in early or preventive treatment in acute brain insults.

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Chapter 7

Role of nitrous oxide Indu Kapoor, Charu Mahajan, and Hemanshu Prabhakar Department of Neuroanaesthesiology and Critical Care, All India Institute of Medical Sciences (AIIMS), New Delhi, India

Chapter Outline Introduction The question: Is it safe to use N2O in neurosurgical cases? Laboratory evidence Clinical evidence The question: Is it safe to use N2O in spine surgeries? Laboratory evidence Clinical evidence The question: Is N2O safe to be used in interventional neuroradiology? Laboratory evidence Clinical evidence

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The question: What is the current status of the use of N2O in pediatric patients undergoing neurosurgical procedures under general anesthesia? Laboratory evidence Clinical evidence The question: Is it safe to use N2O in the geriatric patient population who are scheduled for neurosurgical procedures under general anesthesia? Laboratory evidence Clinical evidence Conclusion References

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Introduction Nitrous oxide, commonly known as “laughing gas,” was coined by Humphry Davy due to its euphoric effect. It is a colorless, noninflammable gas with the formula “N2O.” Since 1844, N2O has been used in dentistry and surgery, as an analgesic and anesthetic agent (Sneader, 2005). N2O is a weak anesthetic agent and so used as a carrier gas for other inhalational agents such as isoflurane, sevoflurane, desflurane, etc. It has a minimum alveolar concentration of 105% and a blood/gas partition coefficient of 0.46. Because of its poor blood solubility, alveolar and brain concentrations are achieved very rapidly. Its mechanism of action includes partial blockade of N-methyl-d-aspartate [NMDA] receptors, acetylcholine [nAch] receptors, gamma-aminobutyric acid [GABA] receptors, and histamine receptors, and partial potentiation of GABA and glycine receptors. N2O is no longer an inert gas as it has a significant cerebral effect. When administered alone or with minimal background inhalational anesthetic agent it causes increases in cerebral blood flow [CBF]. However, when administered with a certain intravenous anesthetic agent, its effect on CBF may be reduced. The CBF is higher with 1 MAC combination of 0.5 MAC volatile agent and 0.5 MAC N2O, compared to 1 MAC of volatile agent alone. N2O may increase or produce no change in the cerebral metabolic rate of oxygen consumption [CMRO2]. It might cause an increase in intracranial pressure [ICP] in patients with mass lesions. This increase in ICP can be reduced by intravenous drugs like barbiturates or propofol. N2O can impair cerebral autoregulation but preserves CO2 reactivity and has no effect on the rate of CSF formation and resistance to CSF resorption. N2O increases the spinal cord’s utilization of glucose similar to the effect in the brain (approximately 25%). Both neurotoxic and neuroprotective properties have been demonstrated with N2O use (Ganjoo & Kapoor, 2017).

The question: Is it safe to use N2O in neurosurgical cases? Laboratory evidence In recent years, the safety and efficacy of N2O have been questioned several times. While many studies have shown adverse effects of N2O anesthesia, there is still no consensus as to whether N2O is dangerous enough to warrant discontinuation as Essentials of Evidence-Based Practice of Neuroanesthesia and Neurocritical Care. https://doi.org/10.1016/B978-0-12-821776-4.00007-X Copyright © 2022 Elsevier Inc. All rights reserved.

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an anesthetic or analgesic (Maze, Sanders, & Weimann, 2008). Sakabe et al. studied the cerebral effect of N2O in 27 dogs. They observed that N2O cause an increase in canine cerebral metabolism accompanied by an increase in cerebral blood flow [CBF] and slowing of electroencephalographic [EEG] activity. The cerebrospinal fluid [CSF] pressure paralleled the change in CBF. However, these circulatory, metabolic, and EEG responses were found to be modified with background anesthetic agents (Sakabe, Kuramoto, Inoue, & Takeshita, 1978). Another study on rodents observed that N2O exposure in combination with other clinical anesthetic agents after birth and from postnatal day 0–7 have shown a consistent, excessive increase in apoptosis in various brain regions, most notably the retrosplenial cortex (RSC) and thalamus (Lu, Yon, Carter, & Jevtovic-Todorovic, 2006). It has also been found that animals exposed to N2O anesthesia, have long-term impairment of cognitive function (Jevtovic-Todorovic et al., 2003; Shu et al., 2010). A data from a recent study suggest that a neuroinflammatory response to surgery may also be responsible for POCD in an animal model (Wan et al., 2007). N2O also seem to provoke seizures in animals, but this has not been replicated in humans. In mice, withdrawal seizures have been seen after short exposures to N2O (Vaughn & Pruhs, 1995). There have been contradictory animal reports on the effect of N2O on ICP. Saidman and Eger showed no change in ICP with 70%–75% N2O (Saidman & Eger, 1965), whereas Sakabe and colleagues found an increase in ICP in dogs (Sakabe et al., 1978).

Clinical evidence N2O has been used continuously and safely for many years in this patient population. Regarding the central nervous system effect of N2O in humans, N2O tend to increases cerebral metabolic rate [CMR], CBF, and ICP, all theoretically undesirable effects in the setting of intracranial neurosurgery (Culley & Crosby, 2008). Though in nonneurosurgical patients, several well-controlled studies found no clinically significant differences between patients receiving or not receiving N2O during surgery (Arellano et al., 2000; Myles et al., 2007; Schricker et al., 2014; Tang et al., 1999). The landmark trials-ENIGMA I and ENIGMA II had widely studied the effect of N2O on a large number of patients expected to undergo major surgery (Myles et al., 2007; Schricker et al., 2014). In ENIGMA I trial, patients were randomly assigned to N2O-free (80% oxygen, 20% nitrogen) or N2O-based (70% N2O, 30% oxygen) anesthesia. Out of 3187 eligible patients, 2050 consenting patients were recruited. Their result showed that the patients in the N2O-free group had significantly lower rates of major complications (odds ratio, 0.71; 95% confidence interval, 0.56–0.89; P = .003) and severe nausea and vomiting (odds ratio, 0.40; 95% confidence interval, 0.31–0.51; P  100 × 109/L for patients undergoing neurosurgical surgery or neuraxial axis bleeding. Viscoelastic tests such as thromboelastometry and thromboelastography are useful to detect platelet dysfunction, especially in patients with intracranial bleeding.

Introduction Transfusion is a common practice in neurosurgical surgical procedures, both in the red blood cells (RBC) use, coagulation, and platelet factors. But, despite the different studies that have been incorporated into the literature, there is no evidencebased consensus on what should be the best transfusion practice in neurosurgery. This same introduction has been repeated in two important reviews carried out 10 years ago (Feng, Charchaflieh, Wang, & Meng, 2019; McEwen & Huttunen, 2009). One of the main reasons that would justify this assessment resides in the scarce high-quality evidence based on results in relation to transfusion practice and its best indication in neurosurgery (Feng et al., 2019; Vlaar, Oczkowski, & de Bruin, Essentials of Evidence-Based Practice of Neuroanesthesia and Neurocritical Care. https://doi.org/10.1016/B978-0-12-821776-4.00017-2 Copyright © 2022 Elsevier Inc. All rights reserved.

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230  SECTION |E  Neuromonitoring

2020). However, the absence of quality transfusion practice evidence in neurosurgery should be based on an understanding of the complex pathophysiology related to anemia, coagulopathy, and balance between risks and benefits associated with transfusion of all allogeneic blood products (Goebel, 2018; Kisilevsky, Gelb, Bustillo, & Flexman, 2018a, 2018b). We agree that the decision to transfuse any blood component should not be based on numerical aspects as widely used as the hemoglobin (Hb) concentration for RBC, as well as for other blood components (Kisilevsky et al., 2018a). In neurosurgery, the question of the best trigger for optimal transfusion remains a controversial issue (Kisilevsky et al., 2018a, 2018b; Linsler et al., 2012). In addition, neurosurgery includes different entities that can influence and determine the practice. For example, some surgeries in the skull base (which do not compromise the carotid territory) and epilepsy, usually do not require emergency surgery and therefore will be associated with a lower transfusion risk, while traumatic brain injuries (TBI), aneurysm surgeries, or subarachnoid hemorrhages (SAH) often require quick surgery, shorter preparation of the patients and an elevated transfusion risk (Goebel, 2018; Linsler et al., 2012). Recent research examples Bagwe, Chung, Lagman, et al. (2017), who performed an extensive review of intracranial surgery concluding that, currently, there is no sufficient evidence to recommend a transfusion threshold due to the inhomogeneity among the variety of types of surgery included in the analyzed studies. This same situation applies to the TBI scene. Lelubre et al (Lelubre, Bouzat, Crippa, & Taccone, 2016) on the effect of anemia and transfusion in patients with TBI concluded that the optimal level of Hb to indicate a transfusion RBC is not yet clearly defined. Among other items, the authors demonstrate using a logistic regression model, that a transfusion trigger with Hb > 9.0 g/dL was associated with higher hospital mortality, while the presence of anemia wasn’t. There was a beneficial factor in patients with Hb  9.0 g/dL. An important conclusion for the authors was to recommend one restrictive transfusion trigger widely (Lelubre et al., 2016). Trying to explain the current situation regarding transfusion triggers in neurosurgery can be difficult. But all the authors who have contributed to the realization of this chapter and, as the main objective of this review, we are going to try to explain this reason by asking questions related to routine clinical practice and answering them with the available evidence so far.

Red blood cells transfusion. Optimal transfusion trigger What are the transfusion requirements for red blood cells in neurosurgery? Although classically neurosurgical surgeries have been associated with higher transfusion requirements, the current evidence seems to contradict this clinical impression. In a retrospective study of 3026 patients, Linsler et al. (2012) included all the performed neurosurgical procedures and analyzed the RBC units administered intraoperatively or on the two postoperative days, using a Hb transfusion trigger of 9 g/dL. They concluded that the probability of transfusion was well below 10 g/dL, being acute subdural hematomas and spinal cord tumors the interventions with the highest transfusion probability. In another prospective study with 152 patients Crawford-Sykes, Ehikhametalor, Tennant, et al. (2014) assessed transfusion threshold with an 8 g/dL Hb. They presented a transfusion rate of 13.2%. Predictive factors, such as a preoperative Hb  7 g/dL, which is the recommended and accepted transfusion trigger in other types of critical patients (A Brain Trauma Foundation, 2007; Bagwe et al., 2017;

Blood transfusion triggers Chapter | 17  231

Couture et al., 2002; Crawford-Sykes et al., 2014; Feng et al., 2019; Griesdale, Sekhon, Menon, et al., 2015; Kisilevsky et al., 2018a; Kozek-Langenecker, Ahmed, Afshari, et al., 2017). There is a paradox associated with transfusion, on the one hand, the presence of anemia has been associated with increased mortality and poor results, on the other hand, transfusion is also associated with poor results. Therefore, the decision to transfuse neurosurgical patients should be the consequence of weighing the improvement in oxygen transport capacity against the risks of the blood products administration. The absence of defined thresholds generates a wide variability in transfusion practices between centers, between procedures, and according to the doctors who care for the patient. The exact level at which anemia threatens tissue oxygenation is unknown and probably varies by tissue, pathology, and individual (Kisilevsky et al., 2018a; Lelubre et al., 2016; Vincent, 2020).

Red blood cells transfusion trigger The critical Hb level in neurosurgery remains unclear (Bagwe et al., 2017; Feng et al., 2019; McEwen & Huttunen, 2009). Historically, Hb levels below 10 g/dL were considered reasonable as a trigger for RBC transfusion, especially in patients with TBI. However, this trigger is not based on evidence. We start from the basis that, the acceptable Hb levels in healthy patients cannot be extrapolated to the neurocritical patient in whom the compensatory mechanisms may be altered or antagonized by other pathophysiological responses, which may contribute to a reduction in the supply of cerebral Hb oxygen levels below 8–9 g/dL (Colomina & Guilabert, 2016; Lelubre et al., 2016). A randomized controlled trial (RCT) performed in patients with TBI found that a threshold of Hb 10 g/dL had no improvement in neurologic results compared to 7 g/dL and, by contrast, was associated with a higher incidence of thromboembolic events (Robertson, Hannay, Yamal, et al., 2014). The secondary analysis of this study showed that the transfusion threshold of 10 g/dL increased intracranial bleeding risk by 2.3 times (Vedantam, Yamal, Rubin, Robertson, & Gopinath, 2016). Oddo et al (Oddo, Milby, et al., 2009) found that a Hb level  40 in patients with HSA, and compromised brain tissue oxygen tension in patients with TBI. In patients with severe TBI, Griesdale et al (Griesdale et al., 2015) showed that, an increased area under the curve (product of Hb concentration and duration when Hb  50% stenosis and highly selected asymptomatic patients with > 60% stenosis can be considered for additional interventional management [either CEA or carotid stenting (CAS)], within 14 days of symptom onset if possible, and if the estimated periprocedural complication rate is 5-10 minutes

YES

Early Status Epilepticus

First line medication

Seizures > 10-30 minutes

YES

YES

YES

IV diazepam or IV midazolam

IV phenytoin/ fosphenytoin Alternative treatment

IV phenobarbital or IV valproate/ levetiracetam/ lacosamide/ brivaracetam

Refractory Status Epilepticus

Third line medication

Seizures > 24 h

Alternative treatment

Established Status Epilepticus

Second line medication

Seizures > 30-60 minutes

IV lorazepam

midazolam infusion Alternative treatment

propofol infusion or thiopental/ pentobarbital infusions

Super-Refractory Status Epilepticus

Continue with third line medication

Alternative treatment

ketamine isoflurane

FIG. 29.1  Algorithm for the treatment of status epilepticus.

infusion rates. Fosphenytoin is entirely eliminated through metabolism to phenytoin by blood and tissue phosphatases. The half-life for conversion of fosphenytoin to phenytoin ranges from 7 to 15 min. The pharmacokinetic properties of fosphenytoin permit the drug to serve as a well-tolerated and effective alternative to parenteral phenytoin in the emergency and nonemergency management of acute seizures in children and adults. Other medications that could possibly be used in the treatment of SE include valproic acid, levetiracetam, and lacosamide. Valproic acid or valproate is a short-chain fatty acid that decreases seizure activity by prolonging the recovery of voltage-gated sodium channels and through effects on GABA metabolism. Intravenous loading doses of 25–45 mg/kg have been given at a maximum rate of 6 mg/kg/min without hemodynamic compromise. Since valproate appears to have few cardiovascular effects, it may serve as a second-line drug that could be administered in recalcitrant SE before giving phenobarbital or initiating treatment for RSE. Levetiracetam inhibits the burst firing of neurons without affecting normal neural excitability. It appears to act via an unknown specific binding site in the brain. This novel binding site is the synaptic vesicle protein, SV2A, which is an integral membrane protein present on synaptic vesicles and some neuroendocrine cells. It appears to have few cardiovascular side effects. Side effects are primarily neuropsychiatric, with both agitation and sedation being noted. Doses of 2500 mg have been shown to be safe and effective when used as an additional drug to treat SE. Lacosamide is another potential alternative to phenytoin and phenobarbital, but current evidence is too sparse to give recommendations. A dose of 200–400 over 3–5 min appears to be effective in add-on to treat SE. Brivaracetam is a high-affinity synaptic vesicle glycoprotein 2A ligand with high brain permeability and rapid onset of action. The initial brivaracetam dose ranged from 50 to 400 mg. Phenobarbital is a barbiturate with similar properties as

398  SECTION | F  Neurointensive care

the benzodiazepines but is believed to activate a varying isoform of the GABAA receptor. Phenobarbital is used less often due to its long half-life and significant cardiorespiratory depressant effects. Dosing is similar to phenytoin, with initial i.v. a bolus of 20–40 mg/kg. Refractory status epilepticus (stage III): Midazolam is a short-acting benzodiazepine that is considered the first drug of choice of treatment for RSE. It is rapidly inducible and has cardiorespiratory side effects that are significant but considerably less than encountered with propofol or the short-acting barbiturates. Effective initial i.v. dose of midazolam is 0.01– 0.2 mg/kg. A loading dose ranging between 0.05 and 2.0 mg/kg/h. With prolonged use of midazolam at the doses typically required for seizure control, patients develop tachyphylaxis to the drug, significant volume accumulation, and prolonged sedation due to drug accumulation, and prolonged sedation due to drug accumulation, particularly in the setting of obesity or renal failure. Propofol is an alternative to midazolam. It is a short-acting nonbarbiturate hypnotic used for induction. It has the advantages of rapid induction and elimination. Since propofol is commonly used for sedation, it is usually immediately available in most emergency rooms or intensive care units. Loading dose is 2–3 mg/kg with maintenance of 2–12 mg/ kg/h. However, its prolonged use is limited by the development of hypertriglyceridemia because of its formulation in a lipid emulsion. Another rare but fatal adverse event of propofol seen with high doses and prolonged use is propofol-related infusion syndrome (PRIS), which manifests as cardiac arrhythmias, rhabdomyolysis, metabolic acidosis, and shock. Therefore, its use should be limited to doses