Oxford Textbook of Neuroscience and Anaesthesiology 2018947871, 9780198746645

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Oxford Textbook of 

Neuroscience and Anaesthesiology Edited by

George A. Mashour Bert N. La Du Professor of Anesthesiology Research Professor of Anesthesiology and Neurosurgery Faculty, Neuroscience Graduate Program Director, Center for Consciousness Science Director, Michigan Institute for Clinical & Health Research Associate Dean for Clinical and Translational Research University of Michigan Medical School Ann Arbor, Michigan, USA

Kristin Engelhard Professor of Anesthesiology Vice-​Chair of the Department of Anesthesiology University Medical Center of the Johannes Gutenberg-​University Mainz, Germany

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Oxford Textbooks In Anaesthesia Oxford Textbook of Anaesthesia for the Elderly Patient Edited by Chris Dodds, Chandra M. Kumar, and Bernadette Th.Veering Oxford Textbook of Anaesthesia for Oral and Maxillofacial Surgery Edited by Ian Shaw, Chandra M. Kumar, and Chris Dodds Principles and Practice of Regional Anaesthesia, Fourth Edition Edited by Graeme McLeod, Colin McCartney, and Tony Wildsmith Oxford Textbook of Cardiothoracic Anaesthesia Edited by R. Peter Alston, Paul S. Myles, and Marco Ranucci Oxford Textbook of Transplant Anaesthesia and Critical Care Edited by Ernesto A. Pretto, Jr., Gianni Biancofiore, Andre DeWolf, John R. Klinck, Claus Niemann, Andrew Watts, and Peter D. Slinger Oxford Textbook of Obstetric Anaesthesia Edited by Vicki Clark, Marc Van de Velde, Roshan Fernando Oxford Textbook of Neuroscience and Anaesthesiology Edited by George A. Mashour and Kristin Engelhard

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1 Great Clarendon Street, Oxford, OX2 6DP, United Kingdom Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford is a registered trade mark of Oxford University Press in the UK and in certain other countries © Oxford University Press 2019 The moral rights of the authors have been asserted First Edition published in 2019 Impression: 1 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by licence or under terms agreed with the appropriate reprographics rights organization. Enquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above You must not circulate this work in any other form and you must impose this same condition on any acquirer Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016, United States of America British Library Cataloguing in Publication Data Data available Library of Congress Control Number: 2018947871 ISBN 978–​0–​19–​874664–​5 Printed in Great Britain by Bell & Bain Ltd., Glasgow Oxford University Press makes no representation, express or implied, that the drug dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-​to-​date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publishers do not accept responsibility or legal liability for any errors in the text or for the misuse or misapplication of material in this work. Except where otherwise stated, drug dosages and recommendations are for the non-​pregnant adult who is not breast-​feeding Links to third party websites are provided by Oxford in good faith and for information only. Oxford disclaims any responsibility for the materials contained in any third party website referenced in this work.

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Dedication

George A. Mashour Dedicated to my wonderful children, Alexander Fulgens Mashour and Anna Luise Mashour—​may they live long, healthy, and joyful lives, and reach the fullest potential of their beautiful minds.

Kristin Engelhard Dedicated to my mentors and teachers Eberhard Kochs and Christian Werner, who always encouraged and supported me throughout my academic career.

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Preface-the three pillars of Neuroanaesthesiology

While serving as the President of the Society for Neuroscience in Anesthesiology and Critical Care, I  espoused a vision for neuroanaesthesiology that was supported by three ‘pillars’. The traditional pillar of neuroanaesthesiology relates to the care of neurosurgical and neurological patients. The clinical care of individuals with neurologic compromise is incredibly rewarding and represents a true opportunity to make a positive difference in the lives of others. However, the specialty of anaesthesiology is itself a form of clinical neuroscience. On a daily basis, even as anaesthetists for non-​neurosurgical cases, we modulate peripheral nerves, the spinal cord, subcortical arousal systems, thalamocortical and corticocortical networks supporting consciousness, pain networks, memory systems in the medial temporal lobe, the neuromuscular junction, and the autonomic nervous system. From this perspective, ‘neuroanaesthesiology’ is more a compression of ‘neuroscience in anaesthesiology’ than ‘neurosurgical anaesthesiology’. The mechanistic study of our therapeutic interventions, which represents another pillar, is exciting neuroscience in its own right, and has profound implications for nervous system function. Finally, the question of how the peri-​operative period might negatively impact the brain is the new frontier of outcomes studies and has been a major priority for the field of anaesthesiology in the past decade. Questions related to anaesthetic neurotoxicity, cognitive dysfunction, stroke, and other neurologic outcomes of non-​neurosurgical interventions represent a critically important third pillar for the subspecialty.

The Oxford Textbook of Neuroscience and Anaesthesiology is the first book of its kind to comprehensively address all three pillars related to neuroscience in anaesthesiology. The first section treats the neuroscientific foundations of anaesthesiology, including the neural mechanisms of general anaesthetics, cerebral physiology, the neurobiology of pain, and more. The second section represents the traditional pillar related to the care of patients with neurologic disease in the operating room or intensive care unit, with a focus on clinical neuroanaesthesia. These chapters systematically treat the peri-​operative considerations of both brain and spine surgery, and provide introductions to neurocritical care and pediatric neuroanaesthesia. Finally, the last section examines some connections of neurology and anaesthesiology, examining how conditions such as dementia, stroke, or epilepsy interface with the peri-​operative period. This international textbook gathers the best available expertise of authors and leaders in the field from Canada, Germany, Italy, New Zealand, Spain, Switzerland, the UK, and the US. They have done an outstanding job of crafting concise yet highly informative chapters describing the cutting edge of neuroscience and neuroanaesthesia. It is my hope that this textbook is itself a ‘chapter’ in the evolution of the field, creating a lasting foundation and appreciation for the three pillars of neuroscience in anaesthesiology. George A. Mashour, M.D., Ph.D.

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Contents

Abbreviations  xi Contributors  xv Digital media accompanying the book  xvii

SECTION 1​

Neuroscience in Anaesthetic Practice  1 Neural Mechanisms of Anaesthetics  3 Andrew McKinstry-​Wu and Max B. Kelz

2 Intracranial Pressure  17 Harald Stefanits, Andrea Reinprecht, and Klaus Ulrich Klein

3 Cerebral Physiology  27 Stefan Bittner, Kerstin Göbel, and Sven G. Meuth

4 Introduction to Electroencephalography  35 Michael Avidan and Jamie Sleigh

11 Neurophysiologic Monitoring for Neurosurgery  137 Antoun Koht, Laura B. Hemmer, J. Richard Toleikis, and Tod B. Sloan

12 Brain Trauma  149 Anne Sebastiani and Kristin Engelhard

13 Supratentorial Craniotomy for Mass Lesion  161 Shaun E. Gruenbaum and Federico Bilotta

14 The Posterior Fossa  173 Tasha L. Welch and Jeffrey J. Pasternak

15 Cerebrovascular Surgery  189 Deepak Sharma and David R. Wright

16 Interventional Neuroradiology  201 Nathan Manning, Katherine M. Gelber, Michael Crimmins, Philip M. Meyers, and Eric J. Heyer

5 The Autonomic Nervous System  47

17 Pituitary and Neuroendocrine Surgery  213

6 Neuromuscular Junction: Anatomy and Physiology, Paralytics, and Reversal Agents  61

18 Hydrocephalus and Associated Surgery  225

David B. Glick, Gerald Glick†, and Erica J. Stein

Christiane G. Stäuble, Heidrun Lewald, and Manfred Blobner

7 Principles of Neuroprotection  77 Sophia C. Yi, Brian P. Lemkuil, and Piyush Patel

8 Neurotoxicity of General Anaesthetics  93 Margaret K. Menzel Ellis and Ansgar Brambrink

9 Neurobiology of Acute and Chronic Pain  111 Adrian Pichurko and Richard E. Harris

Douglas A. Colquhoun and Edward C. Nemergut Paola Hurtado and Neus Fàbregas

19 Awake Craniotomy for Tumour, Epilepsy, and Functional Neurosurgery  235 Lashmi Venkatraghavan and Pirjo Manninen

20 Anaesthesia for Complex Spine Surgeries  245 Ehab Farag and Zeyd Ebrahim

21 Spine Trauma  255 Timur M. Urakov and Michael Y. Wang

22 Paediatric Neuroanaesthesia  263

SECTION 2​

Clinical Neuroanaesthesia  10 Neurologic Emergencies  125 Ross P. Martini and Ines P. Koerner

Sulpicio G. Soriano and Craig D. McClain

23 Basics of Neurocritical Care  273 Magnus Teig and Martin Smith

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  contents

SECTION 3​

26 Epilepsy  303

Neurologic Patients Undergoing Non-​Neurologic Surgery 

27 Parkinson’s Disease  309

24 Cerebrovascular Disease  289 Corey Amlong and Robert D. Sanders

25 Peri-Operative Considerations of Dementia, Delirium, and Cognitive Decline  297 Phillip E. Vlisides and Zhongcong Xie

Adam D. Niesen, Adam K. Jacob, and Sandra L. Kopp M. Luke James and Ulrike Hoffmann

28 Treatment of Psychiatric Diseases with General Anaesthetics  315 Laszlo Vutskits

Index  323

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Abbreviations

133Xe Xenon 3D Three-​dimensional AANS American Association of Neurological Surgeons ABC Airway, breathing, circulation ABCB-​1 ATP-​binding cassette subfamily B member 1 ABI Acute brain injury ABP Arterial blood pressure ABR Auditory brain stem responses ACA Anterior cerebral artery ACC Anterior cingulate cortex ACDF Anterior cervical discectomy with fusion ACh Acetylcholine AChE acetylcholinesterase ACSNSQIP American College of Surgeons National Surgical Quality Improvement Program ACTH Adrenocorticotropic hormone ADH Antidiuretic hormone ADHD attention deficit hyperactivity disorder AED Anti-​epileptic  drug AION Anterior ischemic optic neuropathy AIS Abbreviated Injury Scale AIS Acute ischemic stroke AMPA α-​amino-​3-​hydroxy-​5-​methyl-​4-​ isoxazolepropionate ANP Atrial natriuretic peptide ANS Autonomic nervous system AQP1 Aquaporin-​1 AQP4 Aquaporin-​4 AQPs Aquaporins ARAS Ascending reticular activating system ARCTIC Acute Rapid Cooling of Traumatic Injuries of the Cord study ARDS Acute respiratory distress syndrome ASA American Society of Anesthesiologists ASA PS American Society of Anesthesiologists Physical Status ASIA American Spinal Injury Association ASICs Acid-​sensing ion channels ATP Adenosine triphosphate AV Atrioventricular AVM Arteriovenous malformations Aβ Amyloid-​beta BAC Balloon-​assisted coiling

BAER Brainstem auditory evoked response BBB Blood-​brain barrier BDNF Brain-​derived neurotrophic factor BF Basal forebrain BIS Bispectral index BIS Bispectral index BK Bradykinin BP Blood pressure BTF Brain Trauma Foundation Ca Aterial concentration cAMP Cyclic adenosine monophosphate CAS Carotid artery stenosis CAT-​1 Cationic amino-​acid transporter type 1 CBF Cerebral blood flow CBV Cerebral blood volume CBVS Cerebrovascular surgery CCS Central cord syndrome CCT Cranial computed tomography CEA Carotid endarterectomy CE-​MRC Contrast material-​enhanced MR cisternography CGRP Calcitonin gene-​related peptide CHD Congenital heart disease CHF Congestive heart failure CI Cardiac index CIC Intracerebral compliance CM Cerebral microdialysis CMAP Compound muscle action potential CMR Cerebral metabolic rate CMRO2 Cerebral metabolic oxygen consumption CMT Central medial thalamus CNAP Compound nerve action potential CNS Central nervous system CNT-​2 Concentrative nucleoside transporter type 2 COMT Catechol-O-methyl transferase COX Cycloxygenase COX-​2 Cyclooxygenase-​2 CPB Cardiopulmonary bypass CPP Cerebral perfusion pressure CPR Cardiopulmonary resuscitation CRP C-​reactive protein CRPS Chronic regional pain syndrome CSF Cerebrospinal fluid CSWS Cerebral salt wasting syndrome

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xii

a bbreviations

CT Computed tomography CTA CT angiography CTP CT-​perfusion Cv Venous concentration CVA Cerebrovascular accident CVR Cerebrovascular resistance DA1 Dopamine type 1 DA2 Dopamine type 2 DBH dopamine β-​hydroxylase DBS Deep brain stimulation/​stimulator DCI Delayed cerebral ischaemia DDAVP desmopressin acetate DIND Delayed ischemic neurological deficit DL Direct laryngoscopy DLPFC Dorsolateral prefrontal cortex DMN Default Mode Network DOAC Direct acting oral anticoagulant DOPA Dihydroxyphenylalanine DpMe Deep mesencephalic reticular formation DR Dorsal raphe DRG Dorsal root ganglion DVT Deep vein thrombosis DWI diffusion-​weighted imaging ECG Electrocardiogram ECMO Extracorporeal membrane oxygenation ECoG Electrocorticography ECT Electroconvulsive therapy ED Effective dose EEG Electroencephalography EG Endothelial glycocalyx EMG Electromyography ENS Enteric nervous system EP Evoked potentials ESL Endothelial surface layer ESO European Stroke Organization ET Endotracheal tube ETCO2 End-​tidal carbon dioxide ETV Endoscopic third ventriculostomy EVD External ventricular drain/​drainage FDA Food and Drug Administration FFP Fresh frozen plasma FiO2 Fraction of inspired oxygen FLAIR Fluid-​attenuated inversion recovery fMRI Functional magnetic resonance imaging FOUR Full outline of unresponsiveness FSH Follicle stimulating hormone FV Flow velocity GA General anaesthesia GABA Gamma-​aminobutyric  acid GCS Glasgow Coma Scale GH Growth hormone GI Gastrointestinal GLUT-​1 Glucose transporter type 1 GPi Globus pallidus internus H reflex Hoffmann’s reflex Hb Haemoglobin HCN Hyperpolarization-​activated cyclic nucleotide-​gated HD Hydrocephalus

HF Heart failure HHT Hereditary Haemorrhagic Telangiectasia HIF-​1α Hypoxia-​inducible factor 1 alpha HS Hypertonic saline Hz Hertz IADL Instrumental activities of daily living IARS International Anesthesia Research Society IBA1 Ionized calcium binding adaptor molecule 1 IBV Intracranial blood volume ICA Internal carotid artery ICH Intracranial haemorrhage ICP Intracranial pressure ICU Intensive care unit ICV Intracranial volume IHAST Intraoperative Hypothermia for Aneurysm Surgery Trial IIT Intensive insulin therapy IL-​6 Interleukin-​6 IOM Intra-operative neurophysiological monitoring ION Ischemic optic neuropathy IOM Intra-operative neurophysiological monitoring IONM Intraoperative neurophysiological monitoring IPG Internal pulse generator IPL Inferior parietal lobule IQ Intelligence quotient IV-​tPA Intravenous tissue-​type plasminogen activator K Potassium K2P Two-​pore-​domain potassium channel Kv Voltage-​gated potassium channel LA Local anaesthesia LAT-​1 Large neutral amino-​acid transporter type 1 LC Locus coeruleus LD Lumbar drain/​drainage LDF Laser Doppler flowmetry LDT Laterodorsal tegmentum LGICs Ligand-​gated ion channels LH Luteinizing hormone LMA Laryngeal mask airway LMWH Low molecular weight heparin LoRR Loss of righting reflex LOX Lipoxygenase LP Lactate:pyruvate LVH Left ventricular hypertrophy MABL Maximal allowable blood loss MAC Minimum alveolar concentration MAC Monitored anaesthesia care MADRS Montgomery-​Asberg Depression Rating Scale MAO Monoamine oxidase MAO-​B Monoamine oxidase-​B MAOIs MAO inhibitors MAP Mean arterial blood pressure MCA Middle cerebral artery MCI Mild cognitive impairment MCT-​1 Monocarboxylic acid transport type 1 MDD Major depressive disorder MDR-​1 Multidrug resistance gene MEG Magnetoencephalography MEN-​1 Multiple endocrine neoplasia type 1 MEP Motor evoked potentials

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MER MERCI

Microelectrode recordings Mechanical Embolus Removal in Cerebral Ischemia trial MH Malignant hyperthermia miRNA Micro-​RNA ml Millilitres MLS Manual-​in-​line stabilization MnPO Median preoptic nucleus MOCAIP Morphological clustering and analysis of ICP pulse mPFC Medial prefrontal cortex mps Metres per second MRI Magnetic resonance imaging mRNA Messenger RNA mRS Modified Rankin score Mx Mean flow velocity reactivity N2O Nitrous oxide nAChR Nicotinic acetylcholine receptor NANC non-​adrenergic non-​cholinergic neurotransmitter Nav Voltage-​gated  sodium NCF Nucleus cuneiformis NGF Nerve growth factor NICU Neurological intensive care unit NIHSS National Institutes of Health Stroke Scale NIRS Near infrared spectroscopy NMB Neuromuscular block NMDA N-​methyl-​D-​aspartate NMS Neuroleptic malignant syndrome NO Nitric oxide/​Nitrogen monoxide NOS Nitric oxide synthase NPH Normal pressure hydrocephalus NPPB Normal perfusion pressure breakthrough NPY Neuropeptide Y NREM Non-​REM NS Nociceptive specific NSAIDs Non-​steroidal anti-​inflammatory  drugs NSF N-​ethyl maleimide sensitive factor NSM Neurogenic stunned myocardial NSQIP National Surgical Quality Improvement Program Risk OPP Ocular perfusion pressure OR Operating room ORx Near-​infrared spectroscopy OSA Obstructive sleep apnoea OWLS Oral and written language scale PaCO2 Partial pressure of arterial carbon dioxide PACU Post-​anaesthesia care unit PAG Periaqueductal grey PaO2 Partial pressure of arterial oxygen PB Parabrachial nucleus PCA Posterior cerebral artery PCA Patient-​controlled analgesia PCC Prothrombin complex concentrate PC-​MRI Phase-​contrast  MRI PCOM Posterior communicating PD Parkinson’s disease PEEP Positive end-​expiratory pressure PET Positron emission tomography PFC Prefrontal cortex PFO Patent foramen ovale PGE2 Prostaglandin E2

PICC PIN PION PIV PKA PKC PNMT PnO PNS POCD PONV PORC

abbreviations

Peripherally inserted central catheter Pressure inside the endoscope Posterior ischemic optic neuropathy Pressure-​induced vasodilation Protein kinase A Protein kinase C Phenylethanolamine N-​methyl transferase Pontine reticular nucleus, oral part Parasympathetic nervous system Postoperative cognitive dysfunction Postoperative nausea and vomiting Postoperative residual curarization/​Postoperative residual neuromuscular block POVL Postoperative vision loss PPT Pedunculopontine tegmentum PPV Positive prediction value PRES Posterior reversible encephalopathy syndrome PRx Pressure reactivity index PSI Patient state index PtiO2 Brain tissue oxygenation PZ Parafacial zone RA Rheumatoid arthritis RBC Red blood cell RCRI Revised cardiac risk index RCT Randomized controlled trial RE Response entropy REM Rapid eye movement RLN Recurrent laryngeal nerve RN Raphe nuclei RNA Ribonucleic acid ROI Region of interest ROS Reactive oxygen/​oxidative species Rout Resistance to CSF outflow RSI Rapid sequence induction rSO2 Regional cerebral oxygenation rTPA Recombinant tissue plasminogen activator R-​type High-​voltage-​activated calcium channels RVM Rostroventralmedial medulla RVP Rapid ventricular pacing SA Sinoatrial SAH Subarachnoid haemorrhage SBP Systolic blood pressure SBT Spontaneous breathing test SCI Spinal cord injury SE State entropy SE Status epilepticus SEP Sensory evoked potentials SI Primary somatosensory cortex SIADH Syndrome of inappropriate antidiuretic hormone secretion sICH Symptomatic intracerebral haemorrhage SII Secondary somatosensory cortex SjvO2 Supra normal jugular venous oxygen saturation SMA Supplemental motor area SMT Spinomesencephalic tract SNACC Society for Neuroscience in Anesthesiology and Critical Care SNAPs Synaptosomal-​associated protein SNARE Soluble NSF receptor

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xvi

xiv

a bbreviations

SNS SPECT SRT SSEP SSRIs STAIR STN STT SVS SWS TBI TCA TCD TCS TDF TEE THx THx TIVA TMN

Sympathetic nervous system Single-​photon emission CT Spinoreticular tract Somatosensory evoked potentials Selective serotonin and norepinephrine reuptake inhibitors Stroke Therapy Academic Industry Roundtable Subthalamic nucleus Spinothalamic tract Slit ventricle syndrome Slow-​wave  sleep Traumatic brain injury Tricyclic antidepressant Transcranial Doppler sonography Transcranial stimulation Thermal diffusion flowmetry Transoesophageal echocardiogram High temporal resolution Therapeutic hypothermia Total intravenous anaesthetic Tuberomamillary nucleus

TNF-​α Tumour necrosis factor α tPA Tissue plasminogen activator TRP Transient receptor potential TRPM TRP melastatin receptor TRPV TRP vanilloid receptor TSH Thyroid stimulating hormone VAE Venous air embolism VEP Visual Evoked Potentials VIP Vasoactive intestinal protein VLPO Ventrolateral preoptic nucleus vPAG Ventral periaqueductal gray VPL Ventroposterolateral VPS Ventriculoperitoneal shunt VR-​1 Vanilloid receptor VRL-​1 Vanilloid-​like receptor  1 VTA Ventral tegmental area WDR Wide dynamic range WFNS World Federation of Neurological Surgeons ZO Zona occludens β-​ARK β-​adrenergic receptor

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Contributors

Corey Amlong, Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, USA

Gerald Glick†, Department of Medicine, Rush Medical College, USA

Michael Avidan, Department of Anesthesiology, Washington University School of Medicine, USA

David B. Glick, Department of Anesthesia & Critical Care, University of Chicago, USA

Federico Bilotta, Department of Anesthesiology, Critical Care and Pain Medicine, Sapienza University of Rome, Italy

Kerstin Göbel, Department of Neurology, University Hospital Münster, Germany

Stefan Bittner, Department of Neurology, Johannes Gutenberg University Mainz, Germany

Shaun E. Gruenbaum, Department of Anesthesiology, Yale University School of Medicine, USA

Manfred Blobner, Klinik für Anaesthesiologie der Technischen Universität München, Klinikum rechts der Isar, Germany

Richard E. Harris, Department of Anesthesiology, University of Michigan Medical School, USA

Ansgar Brambrink, Department of Anesthesiology, Columbia University, USA

Laura B. Hemmer, Department of Anesthesiology and Neurological Surgery, Northwestern University, Feinberg School of Medicine, USA

Douglas A. Colquhoun, Department of Anesthesiology, University of Michigan Medical School, USA Michael Crimmins, Walter Reed National Military Medical Center, Department of Neurology, Neurosurgery and Critical Care, USA Zeyd Ebrahim, Department of General Anesthesiology, Anesthesiology Institute, Cleveland Clinic, USA Margaret K. Menzel Ellis, Portland VA Medical Center, Assistant Professor of Anesthesiology, Oregon Health & Science University, USA Kristin Engelhard, Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-​University Mainz, Germany Neus Fàbregas, Anesthesiology Department, Hospital Clìnic de Barcelona, Spain Ehab Farag, Department of General Anesthesia and Outcomes Research, Anesthesiology Institute, Cleveland Clinic, USA Heidrun Lewald, Klinik für Anaesthesiologie der Technischen Universität München, Klinikum rechts der Isar, Germany Katherine M. Gelber, Department of Anesthesiology, Cedars-​Sinai Medical Center, USA

Eric J. Heyer, Departments of Anesthesiology and Neurology, Columbia University, USA Ulrike Hoffmann, Department of Anesthesiology, Duke University, USA Paola Hurtado, Anesthesiology Department, Hospital Clìnic de Barcelona, Spain. Adam K. Jacob, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, USA M. Luke James, Departments of Anesthesiology and Neurology, Duke University, USA Max B. Kelz, Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine, USA Klaus Ulrich Klein, Department of Anesthesia, General Intensive Care and Pain Management, Medical University of Vienna, Austria Ines P. Koerner, Department of Anesthesiology & Perioperative Medicine, Department of Neurological Surgery, Oregon Health & Science University, USA

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c ontributors

Antoun Koht, Department of Anesthesiology, Neurological Surgery, and Neurology, Northwestern University, Feinberg School of Medicine, USA Sandra L. Kopp, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, USA

Jamie Sleigh, Department of Anaesthesia and Pain Medicine, Waikato Clinical Campus, University of Auckland, New Zealand Tod B. Sloan, Department of Anesthesia, University of Colorado School of Medicine, USA

Brian P. Lemkuil, Department of Anesthesiology, University of California San Diego, USA

Martin Smith, Department of Neuroanaesthesia and Neurocritical Care, The National Hospital for Neurology and Neurosurgery, University College London Hospitals, UK

Pirjo Manninen, Department of Anesthesia, Toronto Western Hospital University Health Network, University of Toronto, Canada

Sulpicio G. Soriano, Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, USA

Nathan Manning, Departments of Neurosurgery and Radiology, Columbia University Medical Centre, New York Presbyterian, USA

Christiane G. Stäuble, Klinik für Anaesthesiologie der Technischen Universität München, Klinikum rechts der Isar, Germany

Ross P. Martini, Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, USA

Harald Stefanits, Department of Neurosurgery, Medical University of Vienna, Austria

Craig D. McClain, Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, USA

Erica J. Stein, Department of Anesthesiology, The Ohio State University, USA

Andrew McKinstry-​Wu, Department of Anesthesiology and Critical Care, University of Pennsylvania, USA Sven G. Meuth, Department of Neurology, Institute of Translational Neurology, Westfälische-​Wilhelms University Münster, Germany Philip M. Meyers, Departments of Radiology and Neurological Surgery, Columbia University, USA Edward C. Nemergut, Department of Anesthesiology, University of Virginia Health System, USA Adam D. Niesen, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, USA

Magnus Teig, Department of Anesthesiology, University of Michigan Medical School, USA J. Richard Toleikis, Department of Anesthesiology, Rush University School of Medicine, USA Timur M. Urakov, Department of Neurosurgery, University of Miami, Jackson Memorial Hospital, USA Lashmi Venkatraghavan, Department of Anesthesia, Toronto Western Hospital, University of Toronto, Canada Phillip E. Vlisides, Department of Anesthesiology, University of Michigan Medical School, USA

Jeffrey J. Pasternak, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, USA

Laszlo Vutskits, Department of Anesthesiology, Pharmacology and Intensive Care, University Hospitals of Geneva, Department of Basic Neuroscience, University of Geneva Medical School, Switzerland

Piyush Patel, VA Medical Center, University of California San Diego, USA

Michael Y. Wang, University of Miami, Miller School of Medicine, USA

Adrian Pichurko, Department of Anesthesiology, Northwestern University, Feinberg School of Medicine, USA

Tasha L. Welch, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, USA

Andrea Reinprecht, Department of Neurosurgery, Medical University of Vienna, Austria

David R. Wright, Departments of Anesthesiology & Pain Medicine and Neurological Surgery, University of Washington, USA

Robert D. Sanders, Department of Anesthesiology, University of Wisconsin, USA

Zhongcong Xie, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, USA

Anne Sebastiani, Department of Anesthesiology, University Medical Center of the Johannes Gutenberg University Mainz, Germany Deepak Sharma, Department of Anesthesiology & Pain Medicine, University of WashingtonUSA

Sophia C. Yi, Department of Anesthesiology, University of California San Diego, USA

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Digital media accompanying the book

Individual purchasers of this book are entitled to free personal access to accompanying digital media in the online edition. Please refer to the access token card for instructions on token redemption and access. These online ancillary materials, where available, are noted with iconography throughout the book. Q Cases and multiple-​choice questions

The corresponding media can be found on Oxford Medicine Online at: www.oxfordmedicine.com/otneuroanesthesiology If you are interested in access to the complete online edition, please consult with your librarian.

 1

SECTION 1

Neuroscience in Anaesthetic Practice

1 Neural Mechanisms of Anaesthetics  3 Andrew McKinstry-​Wu and Max B. Kelz

2 Intracranial Pressure  17 Harald Stefanits, Andrea Reinprecht, and Klaus Ulrich Klein

3 Cerebral Physiology  27 Stefan Bittner, Kerstin Göbel, and Sven G. Meuth

4 Introduction to Electroencephalography  35 Michael Avidan and Jamie Sleigh

5 The Autonomic Nervous System  47

David B. Glick, Gerald Glick†, and Erica J. Stein

6 Neuromuscular Junction: Anatomy and Physiology, Paralytics, and Reversal Agents  61 Christiane G. Stäuble, Heidrun Lewald, and Manfred Blobner

7 Principles of Neuroprotection  77 Sophia C. Yi, Brian P. Lemkuil, and Piyush Patel

8 Neurotoxicity of General Anaesthetics  93 Margaret K. Menzel Ellis and Ansgar Brambrink

9 Neurobiology of Acute and Chronic Pain  111 Adrian Pichurko and Richard E. Harris

 3

CHAPTER 1

Neural Mechanisms of Anaesthetics Andrew McKinstry-​Wu and Max B. Kelz

Introduction The first public demonstration of general anaesthesia took place in 1846. Over 170 years later, a majority of the estimated 234 million annual surgical procedures worldwide are performed under general anaesthesia (1). Nevertheless, general anaesthetics remain poorly understood as a unique class of drug that has infallible clinical efficacy with a narrow therapeutic window. Despite their pervasive use, there is a lack of basic knowledge of where and how anaesthetics produce both their desirable and unintended side effects. Apparent similarities in dose-​dependent behavioural effects among gaseous, volatile, and intravenous general anaesthetics led to the historical belief that all general anaesthetics shared a single molecular mechanism of action. Older theories of anaesthetic action relied on common chemical properties of the anaesthetics to explain their common effects, such as the association of lipid solubility with anaesthetic potency (the Meyer-​ Overton rule). Ultimately, these early theories fell out of favour with the realization that anaesthetics could exert their actions in lipid-​free protein preparations. Subsequently, many molecular targets of individual anaesthetics have been identified. With the discovery of each new molecular target, the fallacy of a unitary molecular mechanism of anaesthesia becomes more apparent. The past twenty years have demonstrated that knowledge of both the specific molecular targets, as well as their location in discrete neural circuits, is a prerequisite to any real understanding of anaesthetic hypnosis. Hence, the molecular, neuronal, circuit, and network targets of anaesthetics are all critical to our neuroscientific framework of how these agents produce reversible unconsciousness.

Molecular Mechanisms of Anaesthetic Hypnosis The breadth of molecular targets of general anaesthetics highlights the diversity of molecular mechanisms sufficient to produce anaesthetic hypnosis. Inhaled and intravenous anaesthetics act on diverse protein targets to exert their hypnotic effects: ion channels, G-​protein coupled receptors, and constituents of the electron transport chain, among others (Figure 1.1).

Ligand-​Gated Ion Channels Ligand-​gated ion channels (LGICs) are common targets for volatile, gaseous, and potent intravenous agents. They provide an easily understood mechanism for modulating individual neural activity and offer a plausible method for altering large-​scale neural effects. General anaesthetics variously affect multiple LGICs, the two most common being potentiation of inhibitory anionic channels and inhibition of excitatory cationic channels. In fact, the vast majority of general anaesthetics demonstrate specific actions at one or both of two LGICs:  potentiation of the anionic gamma-​aminobutyric acid (GABA)-​gated GABAA receptor, and inhibition of the cationic glutamate-​and-​glycine-​gated N-​methyl-​D-​aspartate (NMDA) receptor.

Inhibitory Ligand-​Gated Ion Channel Potentiation GABA is the most common inhibitory neurotransmitter in the central nervous system (CNS.) The GABAA-​receptor, an abundant GABA effector site, is a heteropentameric ligand-​gated chlorine-​ selective ion channel responsible for GABA’s inhibitory effects in the CNS. Importantly, it is also a crucial functional target of most potent intravenous agents and volatile anaesthetics (2–​7). Volatile and intravenous anaesthetics that affect the GABAA-​receptor enhance endogenous GABAergic signalling at pharmacologically relevant concentrations, and at higher concentrations can directly open the channel (5–​10). Synaptic potentiation of GABAA-​receptors affects size and duration of rapid, phasic, inhibitory postsynaptic potentials. Potentiation at extrasynaptic receptors, in contrast, alters baseline membrane potential through tonic chloride currents (11). The net effect of these actions is to decrease the chance that the postsynaptic neuron will fire an action potential in the presence of pharmacologically relevant concentrations of many general anaesthetics. Mounting evidence suggests that it is the extrasynaptic, tonic inhibition that is the primary method through which general anaesthetics produce their effects (12). Specific mutations in GABAA-​receptor subunits at known anaesthetic binding sites produce attenuation to anaesthetic effects of specific agents, both in vitro and in vivo. Mutations in the alpha subunit of the GABAA-​receptor reduce the effect of volatile anaesthetics and benzodiazepines, while beta subunit mutations attenuate the effects of intravenous and volatile anaesthetics (3, 5). This suggests a critical role for action at the GABAA-​receptor in producing on-​target anaesthetic effects.

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KV1

HCN

K2P

NaV

NMDA

Glycine

GABA

mAch

nAch

TTCa

RTCa

Mt Complex I

Ethers

Halothane

Propofol

Etomidate

Barbiturates

Ketamine Nitrous Oxide/ Xenon Dexmedetomidine

Figure 1.1  Summary of the effect of anaesthetic drugs on molecular targets relevant to anaesthetic hypnosis. Light blue circles represent activation or potentiation, dark blue circles indicate inhibition, and white circles indicate no effect. Circles with more than one colour are present where different agents of a single anaesthetic class have differing effects. Where interactions have not been explored in the literature, no circle is present. Kv1.1: Shaker-​related voltage-​gated potassium channel HCN: Hyperpolarization-​activated cyclic nucleotide-​gated channel, K2P: Two-​pore potassium channels, NMDA: N-​ methyl D-​aspartate receptor, Glycine: Glycine receptor, GABA: gamma-​aminobutyric acid receptor, mAch: muscarinic acetylcholine receptor, nAch: nicotinic acetylcholine receptor, TTCa: T-​type calcium channel, RTCa: R-​type calcium channel, Mt complex I: Complex I of the electron transport chain (NADH: ubiquinone oxidoreductase).

Glycine receptors are the other significant inhibitory, anionic LGICs in the CNS. This receptor family is found mostly in the brainstem and spinal cord. Like GABAA-​receptors, glycine receptors are heteropentameric chlorine channels, and are directly activated or potentiated by volatile and many intravenous anaesthetics (13–​16). Evidence for the functional importance of glycine receptors to anaesthetic action is not as robust as that for the GABAA-​receptor. Glycine receptor mutations can produce divergent responses to anaesthetic endpoints. Site-​specific mutations of the glycine receptor that alter in vitro receptor sensitivity to volatile and potent intravenous anaesthetics do not always produce associated changes in immobility or hypnotic sensitivity in vivo (6, 17). Specifically with propofol, the glycine receptor may not contribute to immobility. A structural analogue of propofol that potentiates glycine (but not GABA) receptor signalling, 2,6 di-​tert-​butylphenol, lacks any immobilizing effects in vivo (7, 18, 19). Similarly, a Q266I point mutation introduced into the α1 subunit of the glycine receptor that decreases receptor sensitivity to isoflurane unexpectedly conferred hypersensitivity to the immobilizing properties of both isoflurane and enflurane in mice. These results suggest that glycine receptors containing the α1 subunit are unlikely to mediate immobilizing properties of anaesthetics (20).

Excitatory Ligand-​Gated Ion Channel Inhibition Many general anaesthetics act to inhibit excitatory LGICs, a complementary effect to their potentiation of inhibitory LGICs. Glutamate is the primary excitatory neurotransmitter of the CNS. Among glutamate’s targets is the NMDA receptor (where it has glycine as a co-​receptor). NMDA receptors are the functional target for a significant number of general anaesthetics. Like the extrasynapic GABA receptors responsible for tonic currents, NMDA receptors do not produce the fast postsynaptic transmission responsible for excitatory postsynaptic potentials, but acts presynaptically, postsynaptically, and extrasynaptically, and can affect synaptic plasticity (21). All known noncompetitive NMDA antagonists severely disturb consciousness, with many acting as general anaesthetics at sufficient concentrations (22). The gas anaesthetics nitrous oxide and xenon, as well as the intravenous agent ketamine, all act primarily as NMDA receptor antagonists, while many of the volatile anaesthetics possess NMDA antagonist activity in addition to their effects on other putative anaesthetic targets (23–​26). The nicotinic acetylcholine receptor, a ligand-​gated nonspecific cation channel, is inhibited by volatile anaesthetics at clinically relevant concentrations. While that inhibition does not mediate anaesthetic hypnosis, it may mediate amnesia and analgesic effects of volatile anaesthetics (27–​30). Moreover, central cholinergic

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signalling via nicotinic receptors appears important for anaesthetic emergence. Although blockade of cholinergic signalling may not be sufficient to alter loss-​of-​righting-​reflex or Minimum alveolar concentration (MAC) concentration, it can still be sufficient to retard emergence from anaesthetic hypnosis (discussed later in this chapter).

Constitutively Active and Voltage-​Gated Ion Channels Members of the two-​pore-​domain potassium channel family (K2P) produce a continuous non-​inactivatable current that modifies resting membrane potential and thus affects neuronal excitability (31). Volatile and gaseous anaesthetics directly activate members of this family, including TREK-​1, TREK-​2, TASK-​1, TASK-​2, and TASK-​3. Anaesthetic activation of these K2P channels causes an increase in potassium efflux out of the cell leading to hyperpolarization. However, not every member of the K2P family is activated by anaesthetic exposure. Several members are insensitive to anaesthetics, while THIK-​1, TWIK-​2, TALK-​1, and TALK-​2 are actually closed by anaesthetic exposure. Mutations of two-​pore-​ domain potassium channels can abrogate sensitivity to activation by volatile and gaseous anaesthetics. Distinct gene mutations alter volatile sensitivity versus sensitivity to gaseous anaesthetics (32). An in vivo knockout of one K2P, TREK-​1, caused an impressive 40% resistance to halothane and more modest resistance to other inhaled anaesthetics, while leaving barbiturate sensitivity unchanged (33). Hyperpolarization-​activated cyclic nucleotide-​ gated (HCN) channels are tetrameric, relatively nonspecific cation channels that activate with cell hyperpolarization (as opposed to depolarization.) The Ih current, produced by HCN activation, is involved in producing long-​term potentiation, dendritic integration, control of working memory, and thalamocortical oscillations (34). Of the four HCN isoforms, HCN1 is both abundant in the CNS and inhibited by volatile and intravenous agents. Agents as diverse as isoflurane, ketamine, and propofol inhibit HCN1 at clinically relevant doses. In in vivo models, this HCN1 inhibition plays a direct role in the hypnotic potency of these agents (35–​38). There is even debate that NMDA receptor antagonists producing hypnosis do so not through actions at the NMDA receptor itself, but through their inhibition of HCN1 (37). The involvement of HCN channels in critical CNS processes and their inhibition by diverse anaesthetic agents suggest a significant role for this channel in anaesthetic-​induced hypnosis. Voltage-​gated potassium channels of the Kv1 family are recently identified targets of volatile anaesthetics that contribute to suppression of arousal. Flies with mutations in a gene coding for a member of the Kv1.2 family (shaker) exhibit altered sensitivity to volatile anaesthetics, requiring higher doses than wild-​type controls to cease movement (39). Sevoflurane enhances currents in members of the Kv1 family, with other clinically used volatiles also affecting Kv1 currents, suppressing firing in the central medial thalamus (40). Kv1 channel inhibitors infused into the central medial thalamus are able to reverse continuous low-​dose sevoflurane anaesthesia in animal models, as are antibodies against Kv channels (41). Voltage-​gated sodium channels are a requisite for normal excitatory neuronal function, as they are key to initiating and propagating action potentials. Their inhibition by volatile anaesthetics presynaptically results in a decreased likelihood of action potential propagation and decreased presynaptic neurotransmitter release. Several sodium channel subtypes are inhibited by volatile anaesthetics in pharmacologically relevant concentrations, though

neural mechanisms of anaesthetics

historically inhibition had only been seen at higher concentrations (42). The role of sodium channels in volatile anaesthetic hypnosis is demonstrated by hypersensitivity to isoflurane and sevoflurane in mice with reduced activity in one voltage-​gated sodium channel subtype, NaV1.6 (43). Presynaptic voltage-​gated calcium channels are critical for neurotransmitter release and inhibited by general anaesthetics, making them likely anaesthetic targets. Low-​voltage-​activated T-​type calcium channels, which modulate cellular excitability through regulating burst firing and pacemaker activity, are inhibited by clinically relevant concentrations of volatile and intravenous anaesthetics (44–​46). In vivo knockouts of T-​type calcium channels do not show changes in anaesthetic sensitivity to the loss of righting reflex (LoRR), a traditional rodent equivalent endpoint to loss of consciousness in humans, though they do have altered speed of induction and reaction to noxious stimuli (46, 47). This suggests that the effects of anaesthetics upon these channels modulate the anaesthetized state, rather than cause it. High-​voltage-​activated calcium channels (R-​type) are also sensitive to inhibition by volatile anaesthetics, and contribute to rhythmicity of thalamocortical circuits. R-​ type knockouts display less electroencephalographic suppression at 1% isoflurane than their wild-​type counterparts. This suggests that thalamic calcium channels are involved in isoflurane-​induced thalamic suppression, thought to contribute to unconsciousness (48).

G-​Protein-​Coupled Receptors G-​protein-​coupled receptors make up the largest and most diverse family of membrane receptors. They comprise 4% of the entire coding human genome and are the target for over a quarter of all current pharmaceuticals (49). Drugs that affect this receptor superfamily are an integral part of anaesthetic practice, including such diverse classes as opioids, vasopressors, and anticholinergics. So, while these receptors are known targets for producing analgesia and amnesia, there is little direct evidence that volatile-​anaesthetic-​ induced hypnosis is primarily mediated via this superfamily of receptors. This is despite the fact that volatile anaesthetics do selectively activate G-​protein-​coupled receptors at pharmacologically-​ relevant concentrations (50, 51). Ketamine very specifically interacts with a subset of olfactory receptors, which are a subgroup of G-​protein-​coupled receptors, though it is unclear if these interactions are in any way related to its anaesthetic actions (52).

Electron Transport Chain Unlike the previously discussed membrane-​bound proteins in the cell’s outer membrane, components of complex I, a multi-​subunit member of the respiratory chain, are putative anaesthetic targets located in the inner mitochondrial membrane. Animal models with mutations in specific subunits of complex I, GAS-​1 in C. elegans and Ndufs4 in mice, are hypersensitive to volatile anaesthetics. This hypersensitivity phenotype is strictly mirrored across evolution up to and including humans with complex I mutations (53–​55). The anaesthetic hypersensitivity phenotype is not present in all complex I gene mutations, nor is it present with other electron transport chain mutations, indicating a specific interaction between volatile anaesthetics and precise complex I  subunits. While halogenated ethers and alkanes inhibit complex I function though interaction with the distal portion of the complex, volatile anaesthetics do not appear to disproportionately decrease ATP production in complex I mutants. This dissociation suggests volatile anaesthetic hypnotic

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action is not solely a result of disproportionate mitochondrial energetic disruption in those mutants, begging the persistent question of how these mutations cause anaesthetic hypersensitivity (56–​58).

Systems Neuroscience and Anaesthetic Effects: Discrete Nuclei and Local Networks There is incontrovertible evidence for anaesthetic drugs interacting with multiple molecular targets to affect behaviour, but anaesthetic hypnosis is impossible to explain by mere examination of molecular binding events in isolation. The imperfect connection between molecular action and larger-​scale brain phenomena must be interpreted in light of relevant neuroanatomy. Complexities are introduced by circuit-​level interactions—​neuronal hyperpolarization that reduces firing of a presynaptic inhibitory input can increase activity for the postsynaptic neuron resulting in a net increase of circuit output. Evaluating the net contribution of anaesthetics on discrete brain regions to hypnosis provides a way to simplify the massive complexity encountered at the molecular and neuronal level without ignoring the fundamental circuitry of the CNS.

Sleep and Arousal Pathways General anaesthetics alter the activity of endogenous arousal circuits. Such actions directly contribute to their hypnotic effects (Figure 1.2). Anaesthetic-​induced unconsciousness is a non-​ arousable behavioural state that shares many commonalities with slow-​wave sleep (SWS) There is a functional loss in cortical connectivity during both NREM sleep and anaesthetic hypnosis. Moreover, over much of the anaesthetic dose response range, the cortical electroencephalography (EEG) exhibits striking similarities, such that processed EEG measures developed to assess

anaesthetic depth can also distinguish wakefulness from sleep (59–​ 65). During anaesthesia and sleep, thalamic nuclei and wake-​active nuclei, collectively known as the reticular activating system, are similarly inhibited (46, 66–​70). Parallels between the states extend to their functional effects—​in some cases anaesthesia can substitute for sleep. Sleep debt does not accrue during prolonged periods of propofol-​induced unconsciousness, while propofol hypnosis appears to relieve previously incurred sleep debt (71–​73). Conversely, sleep deprivation or administration of endogenous somnogens reduce the dose of anaesthetic required for hypnosis. In a parallel vein, induction and maintenance of anaesthesia itself alters levels of endogenous somnogens (72, 74). Together, these data support the theory that anaesthetic-​induced hypnosis stems in part from actions of anaesthetics on the neural circuits involved with endogenous sleep-​wake control.

Arousal-​Promoting Nuclei of the Reticular Activating System The ascending reticular activating system, extending rostrally from the mid pons to the hypothalamus, basal forebrain, and thalamus, was first identified more than half a century ago. Stimulation of the brain stem reticular formation causes cortical arousal during anaesthetic states (75). Subsequently, discrete interacting neuronal populations were found to be the arousal-​promoting components of the activating system, including cholinergic, histaminergic, adrenergic, serotonergic, dopaminergic, and orexinergic centres.

Laterodorsal Tegmentum (LDT) and Pedunculopontine Tegmentum (PPT) These nuclei comprise two major cholinergic populations in the brainstem with the ability to regulate arousal state and promote

Frontal cortex Mesial parietal cortex Precuneus Posterior cingulate cortex Thalamus Hippocampus Mesopontine tegmental area Amygdala Ox

TMN (HA)

VTA (DA) DpMe (Glut)

BF (Ach/Glut/GABA) POA (GABA/Gal)

RN (5-HT) vPAG (DA)

PZ (GABA)

PPT/LDT (ACh) LC (Ne)/PB (Glut) Pno

Figure 1.2  Cortical and subcortical (inset) structures affected by anaesthetic agents and potentially contributing to hypnosis. Arrows indicate the ascending reticular activating system, both the anterior branch passing through the basal forebrain before ascending to the cortex and the posterior branch extending into the cortex via the thalamus. The primary neurotransmitters associated with their respective subcortical structures are listed in parentheses.  BF: basal forebrain, Ox: orexin field, TMN: tuberomamillary nucleus, VTA: ventral tegmental area, DpMe: deep mesencephalic reticular formation, PPT/​ LDT: pedunculopontine tegmentum/​laterodorsal tegmentum, LC/​PB: locus coeruleus/​parabrachial nucleus, PnO: pontine oralis, PZ: parafacial nucleus, vPAG: ventral periaqueductal grey, RN: raphe nucleus, POA: preoptic area. HA: histamine, DA: dopamine, Glut: glutamate, Ach: acetylcholine, GABA: gamma-​aminobutyric acid, 5-​HT: serotonin, Gal: galanin.

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wakefulness or REM sleep. These cholinergic neurons densely innervate the midline and intralaminar thalamic nuclei and thalamic reticular nucleus and alter thalamic activity from bursting to spiking (76). Direct effects of these nuclei on anaesthetic-​induced hypnosis are unknown. Despite this, the PPT is in a region that is associated with pain-​induced movement, the inactivation of which leads to a significant decrease of isoflurane MAC (77).

Locus Coeruleus (LC) The Locus Coeruleus is the site of the brain’s largest collection of noradrenergic neurons. As with many of the other monoaminergic systems, the LC diffusely innervates the brain by projecting directly to the cortex, thalamus, hypothalamus, basal forebrain, amygdala, hippocampus, and other subcortical systems. State-​dependent modulation of activity within the LC has long been proposed as an essential means of regulating arousal. Changes in the activity of LC neurons occur before, and are predictive of, changes in an organism’s behavioural state (78). Through its actions on alpha1 and beta receptors, firing of LC neurons promotes wakefulness through actions on the medial septum, the medial preoptic area, and the substantia innominata within the basal forebrain. Activity in the LC modulates thalamocortical circuits, switching the tone of thalamocortical neurons from the burst pattern of slow-​wave sleep to a spiking pattern that characterizes wakefulness. Consequently, optogenetically driven LC activity causes transitions from SWS to wakefulness (79). Under deep isoflurane anaesthesia, artificially driven LC activity has been shown to cause EEG desynchronization. Similarly, artificially induced firing of the LC speeds emergence from isoflurane anaesthesia (80). However, the LC is not the sole source of adrenergically driven arousal. Noradrenergic populations outside of the LC, such as the A1 and A2 brainstem groups, also may contribute to the regulation of sleep, wakefulness, and anaesthesia (81–​83).

Pontine Reticular Nucleus, Oral Part (PnO) Neurons in this large region (which includes the sublaterodorsal nucleus) receive cholinergic, orexinergic, and GABAergic inputs and include wakefulness-​promoting and REM-​on populations. PnO activity also modifies anaesthetic action. GABAergic activity at the PnO produces resistance to induction without significant effects on emergence (84–​87). Electrical stimulation at the PnO causes an increase in functional connectivity under continuous isoflurane anaesthesia, similarly suggesting anaesthetic antagonist actions (88). This region highlights the critical importance of neuroanatomic and neurochemical compartments: unlike most other regions of brain, increased GABA levels in the PnO promote wakefulness. Other seemingly paradoxical effects occur in this region:  wakefulness is actually impaired by local delivery of adenosine or acetylcholine into PnO, or alternatively, promoted by local delivery of orexin or GABA (89–​91). Cholinergic input to the PnO originates from the LDT and PPT, while the orexinergic input arises from the hypothalamus. Divergent responses to adenosine and GABA suggest that simple disinhibition of a single population of PnO neurons is not sufficient to understand the actions of these neuromodulators. Further clouding the picture, microinjections of pentobarbital within a region that has been termed the mesopontine tegmental area, which overlaps with a significant portion of the PnO and some neighbouring structures, have been shown to induce hypnosis similar to systemic administration of a larger general anaesthetic dose, while nearby injections lack any

neural mechanisms of anaesthetics

systemic effects (92, 93). Clearly, a more complex local microcircuitry awaits discovery.

Deep Mesencephalic Reticular Formation (DpMe) Over the decades, many studies have demonstrated that electrical stimulation in the DpMe reliably induces cortical activation in anaesthetized animals. These presumptively glutamatergic neurons project to the thalamus, hypothalamus, and basal forebrain, where they increase their firing rates prior to the onset of wakefulness, and fire more slowly during SWS (94). These glutamatergic neurons are possibly part of a previously poorly recognized arm of the ascending arousal system that potentially includes the parabrachial nucleus as well.

Hypocretin/​Orexinergic Neurons The orexin signalling system exerts potent wake-​promoting and wake-​stabilizing effects, and plays an important role in modulating anaesthetic emergence. As with the monoaminergic wake-​active systems, the orexin system displays state-​dependent firing patterns with maximal activity during active wakefulness and silence during SWS (95). Anatomically, these neurons project to all of the monoaminergic groups along with extending to the basal forebrain, midline thalamic nuclei, and other regions known to participate in the regulation of arousal. When signalling of these neurons is impaired, narcolepsy with cataplexy ensues (96). Local application of orexin excites target neurons expressing either of the two orexin Gq-​ coupled neurotransmitter receptors, including the LDT, LC, RN, basal forebrain (BF), and thalamocortical neurons. Halogenated ethers, propofol, and pentobarbital inhibit orexinergic neuronal activity, and genetic knockout of these neurons results in delayed emergence from isoflurane and sevoflurane anaesthesia without affecting sensitivity to anaesthetic induction (97–​99). In the case of barbiturate anaesthesia, the pharmacologic inverse is true as well: intracerebroventricular injection of orexin speeds emergence, and orexin1-​receptor blockade negates this effect (100). The case of delayed emergence without altered induction in orexinergic deficient animals highlights the intriguing possibility that distinct populations of neurons may unilaterally and differentially impact the process of entering into or exiting from the anaesthetic state.

Wake-​Promoting Neurons of the Basal Forebrain The BF encompasses heterogeneous populations of neurons active in arousal and sleep that modify anaesthetic state and sensitivity. GABA agonists microinjected at the BF potentiate systemic intravenous and volatile anaesthetic effect and duration, as do electrolytic lesions of the medial septum within the BF (101, 102). The BF sits atop the ventral extrathalamic relay and receives integrated arousal inputs from caudal structures. Within the BF, there are wake-​active cholinergic neurons, wake-​active glutamatergic neurons, wake-​ a ctive parvalbumin-​ c ontaining GABAergic neurons, and sleep-​active somatostatin-​containing GABAergic neurons (103). The cholinergic neurons receive afferents from the LC, DpMe, Tuberomamillary nucleus (TMN), orexinergic neurons, parabrachial neurons, and glutamatergic neurons of the BF, and send widespread efferent projections to the cortex and hippocampus, as well as back to the hypothalamus. Selective lesion of cholinergic neurons within the nucleus basalis of the BF prolongs behavioural effects of propofol and pentobarbital (104). Increased cholinergic activity of the basal forebrain during wakefulness is responsible for the fluctuations in cortical acetylcholine levels. The

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cholinergic neurons stimulate cortical activation, and the resultant increased discharge frequency, along with increased activity of cortically projecting parvalbumin-​containing GABAergic neurons, underlies the desynchronized EEG that typifies wakefulness as well as REM sleep (103, 105).

Parabrachial Nucleus Neurons in the parabrachial nuclei belong to a recently identified glutamatergic arm of the anterior branch of the ascending arousal system and can themselves modify the anaesthetic state. Lesion of the parabrachial nuclei induces coma, while the sleep-​ active parafacial zone (see Sleep-​active Neurons of the Basal Forebrain and Parafacial Zone) promotes SWS through inhibition of glutamatergic parabrachial neurons that, in turn, project to the BF (106–​109). Electrical stimulation of the parabrachial nucleus is able to antagonize continuous low-​dose isoflurane administration (110). This observed direct effect on anaesthetic sensitivity, as well as the parabrachial’s known anatomic and functional connection with sleep-​active nuclei and other CNS regions that affect anaesthetic sensitivity and emergence, suggests a significant role for the parabrachial nucleus in maintaining or emerging from an anaesthetic state. However, this has yet to be fully explored.

Ventral Tegmental Area (VTA) A midbrain dopaminergic and GABAergic region associated with both arousal and reward, the VTA receives diverse inputs and has widespread outputs, including the prefrontal cortex, cingulate gyrus, hippocampus, amygdala, and nucleus acumbens. Reflecting those widespread connections, it is functionally diverse, with roles in motivation, cognition, and arousal (111). Dopaminergic neurons of the VTA do not appear to change their firing rate across sleep–​ wake. Consequently, VTA dopamine neurons have not been linked to modulation of spontaneous arousal. Nevertheless, dopaminergic neurons are suppressed by GABA, and other neurons within the VTA have circadian-​dependent activity (112–​116). Artificially driving dopamine release from the VTA, administration of methylphenidate, or more selective pharmacologic agents that act on D1-​ like receptors, will all accelerate anaesthetic emergence, and can even reverse anaesthesia produced by continuous administrations of propofol or isoflurane (117–​120).

Tuberomamillary Nucleus (TMN) The sole source for histamine in the CNS, the histaminergic neurons of the TMN have widespread projection throughout the brain and have activity tightly correlated with arousal state (121). Though centrally administered histamine causes potent arousal, and central H1 antagonists produce sedation, the role of the TMN in modifying general anaesthesia is circumscribed. Lesions of the TMN increase sensitivity to isoflurane-​induced LoRR, but leave propofol, ketamine, and barbiturate sensitivity unchanged (122). Cell-​specific knockout of GABAA receptors in histaminergic cells likewise produced no change in propofol hypnotic sensitivity. These phenomena were observed despite the fact that histaminergic neurons lacking GABAA receptors were resistant to hyperpolarization by propofol—​strong evidence that histaminergic neurons are not critical to induction or maintenance of propofol hypnosis (123).

Dorsal Raphe (DR) and Ventral Periaqueductal Gray (vPAG) The serotonergic neurons of the raphe nuclei have diffuse projections throughout the brain and comprise the largest source of

CNS serotonin. The median raphe contributes little to producing or modulating anaesthetic actions. In contrast, when the DR is silenced by calcium blockage or by lesion, sensitivity is increased to pentobarbital or halothane and cyclopropane, respectively (124, 125). The raphe nuclei (RN) do display state-​dependent firing similar to noradrenergic or histaminergic centres. Single unit recordings, however, demonstrate that firing rates of serotonergic neurons do not anticipate spontaneous changes in arousal state (126). This suggests that activity of the DR is not causally linked to changes in behavioural state. Within the vPAG, there is a population of dopaminergic neurons that are wake-​active. This is in contrast to dopaminergic neurons of the VTA or substantia nigra, which do not display state-​dependent activity. However, the vPAG dopaminergic neurons appear not to contribute to anaesthetic hypnosis. Instead, they modulate analgesia, with lesions of these neurons causing decreased reaction to noxious stimuli under general anaesthesia (127, 128).

Sleep-​Active Neurons and Nuclei When compared to the large numbers of known arousal-​ promoting, wake-​active nuclei, there are few neural populations that are predominantly active during SWS or REM sleep with decreased activity during wakeful states. Neurons with sleep-​active firing patterns are most commonly found in the preoptic area and BF (though populations do exist elsewhere, including in the pons and cortex.) These populations act as a network counterbalance to many of the arousal-​promoting populations discussed previously. Just as there are many examples of anaesthetics depressing those arousal centres, there is evidence for sleep-​active neurons being directly and indirectly activated by certain anaesthetics.

Preoptic Area: Ventrolateral Preoptic Nucleus (VLPO) and Median Preoptic Nucleus (MnPO) In the earliest attempts to identify specific populations of sleep-​ promoting neurons, a definitive role was assigned to the preoptic anterior hypothalamus. This broad region encompasses the VLPO, which lies within the anterior hypothalamus on the ventral floor at the level of the optic chiasm, as well as the MnPO, which straddles the decussation of the anterior commissure. Neurons with heightened activity during SWS are found throughout the preoptic area, with the greatest concentration found in VLPO. Neurons of the VLPO are more active during SWS and REM sleep. Changes in VLPO activity precede the changes in an organism’s behavioural state. Retrograde and anterograde labelling studies show the VLPO is reciprocally interconnected with many wake-​promoting nuclei, including the histaminergic TMN, serotonergic RN, noradrenergic LC, and the cholinergic LDT and PPT, as well as the orexinergic neurons of the hypothalamus. VLPO neurons contain the inhibitory neurotransmitters GABA and galanin and are thus ideally positioned to coordinate and reciprocally inhibit wake-​active ascending reticular activating nuclei. The role of the preoptic area in promoting and modulating the anaesthetic state appears connected to its regulation of sleep and wake. Destructive lesions of VLPO cause long-​lasting insomnia. Bilateral lesions of the VLPO also cause a biphasic change in anaesthetic sensitivity that possibly relates to insomnia:  at six days post-​destruction, animals showed resistance to isoflurane LoRR, while 24  days post-​lesion, subjects showed hypersensitivity to isoflurane LoRR. Such changes have been hypothesized to arise

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due to accumulating sleep pressure as VLPO lesioned animals fail to sleep (129, 130). Isoflurane directly depolarizes GABAergic neurons in VLPO. Acute resistance to isoflurane induction seen following VLPO lesions suggests that in normal conditions, anaesthetic activation of VLPO contributes to induction. Except for ketamine, every other general anaesthetic appears to depolarize and recruit putative sleep-​active VLPO neurons. The population of neurons throughout the preoptic area (including the VLPO, MnPO, and surrounding area) that are active during recovery SWS (after sleep deprivation) significantly overlap with the population of neurons activated with systemic administration of hypnotic doses of dexmedetomidine. This reinforces earlier findings suggesting dexmedetomidine acts on native preoptic sleep circuits to produce hypnosis (131, 132). Similar to the VLPO, MnPO sleep-​ a ctive neurons are GABAergic and fire more rapidly several seconds prior to sleep onset. Although not as broadly activated by anaesthetics as the VLPO, some inhaled anaesthetics also appear to activate putative sleep-​active MnPO neurons (133). Microinjection of benzodiazepines, propofol, and pentobarbital into the MnPO has been shown to induce SWS (72, 134, 135). Due to the state-​dependent firing pattern of MnPO neurons, they have been assigned an important role in the initiation of sleep. The MnPO is known to send inhibitory projections to multiple arousal systems, including the orexinergic neurons in the hypothalamus, in a manner similar to the VLPO.

Sleep-​active Neurons of the Basal Forebrain and Parafacial Zone (PZ) While arousal-​promoting neurons of the BF and pons are well established and their effects on anaesthetic states detailed, it is only recently that sleep-​active groups in these structures were identified. Although they interact with arousal centres known to influence anaesthetic actions, the effects of these newly detailed groups on the anaesthetic state and the effects of anaesthetics on their action remain to be investigated. Parvalbumin-​positive GABAergic neurons of the BF are wake-​active and strongly promote arousal, while another subset of GABAergic neurons expressing somatostatin in the BF comprise a sleep-​active group. Somatostatin positive, GABAergic neurons of the BF exhibit specific increases in local unit activity during SWS. Optogenetic stimulation of these neurons can induce SWS (103). The parafacial zone is a pontine region lateral to the seventh nerve containing SWS-​active GABAergic neurons. Those sleep-​active, inhibitory neurons project directly onto arousal-​promoting glutamatergic neurons of the parabrachial nucleus, which, in turn, project to arousal-​promoting neurons of the BF. Artificial stimulation of those PZ GABAergic neurons produces SWS (108). Anaesthetic effects on the PZ and sleep-​active neurons of the BF await further study.

Thalamus The thalamus is a critical structure that plays at least three major roles in wakefulness and consciousness. First, in terms of levels of consciousness, the thalamus is an important conduit for arousal pathways from the brainstem. Second, in terms of the content of consciousness, it is a major relay station for sensory information en route to the cortex. Third, in terms of the organization of conscious experience, the higher-​order nuclei of the thalamus play a critical role in facilitating corticocortical coherence and communication.

neural mechanisms of anaesthetics

The central thalamus has long been known to be critical to arousal, with small lesions of the area leading to gross disorders of consciousness (136). The anterior intralaminar nuclei, of which the central medial thalamus (CMT) is a part, receive significant ascending cholinergic innervation from the BF and brainstem. Microinjection of nicotine into the CMT is sufficient to reverse continuous systemic sevoflurane anaesthesia in animal models. This effect is replicated with an infusion of antibodies against potassium channels in the Kv1 family (41, 137). In slice recordings of neurons of the CMT, sevoflurane reduces firing, which is, in turn, reversed by administration of a Kv1 inhibitor (40). Activity of the CMT appears to be critical for both sleep and anaesthesia, as changes in high-​f requency oscillations that occur at both the onset of sleep and anaesthetic-​induced loss of consciousness occur first in the CMT, rapidly followed by cortical changes (68). More generally, thalamic inactivation as measured by reduced blood flow has been associated with anaesthetic-​induced unconsciousness, although whether this is causal or secondary to unconsciousness itself remains unclear (138).

Neocortex and Limbic Cortex The effects of anaesthetics are particularly heterogeneous across the neocortex, in stark contrast to the largely antiquated ‘wet blanket’ theory of anaesthetic action as a general neuronal depressant. The extent to which the primary sensory cortices are affected by many general anaesthetics remains unclear. These primary processing areas are still able to maintain normal or near-​normal responses to evoked potentials while longer-​latency potentials are inhibited. In contrast, the function of higher-​order association cortices and portions of the entorhinal cortex are markedly impaired by general anaesthetics. The mesial parietal cortex, the anterior and posterior cingulate cortices, and the precuneus are deactivated in sleep and anaesthesia, as measured indirectly by changes in cerebral blood flow (139–​141). Given the variability of anaesthetic effect on individual cortical areas, hypnotic effects of anaesthetics may either prove to be a result of direct actions upon the cortex or could be a result of network-​level perturbations that include cortical and subcortical interactions.

Brain Networks and Anaesthesia The specific molecular target(s) of an anaesthetic may not yield immediate insight into mechanisms by which the drug produces unconsciousness. Complete understanding requires detailed knowledge of drug effects on their molecular targets, as well as how ensuing changes in the activity of neurons and glia affect local and distant circuits in addition to the global impact on networks. The relevant actions of anaesthetics, and hence their common mechanism, may thus be their ultimate disruption of network function-​decreasing functional information integration. Understanding discrete effects of anaesthetics on receptors, individual neurons, and brain nuclei are necessary but not sufficient in isolation. To investigate anaesthetic disruption of network level processes, large-​scale brain activity studies employ functional magnetic resonance imaging (fMRI), positron emission tomography (PET), magnetoencephalography (MEG), or high-​density electroencephalography (EEG).

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Thalamocortical Network Thalamocortical networks are key to information integration, as they gate ascending sensory information, ascending arousal signals, and modulate corticocortical relays. Disruption of the system illustrates the importance of this network, which results in disorders of consciousness (136, 142). Shifting from cortically dominant to thalamus-​dominant thalamocortical circuits during anaesthetic-​ induced loss of consciousness corroborates a model of propofol hypnosis whereby GABAergic activation results in strengthened thalamocortical connections and an intrinsic thalamically-​driven alpha (8–​12 Hz) electrical rhythm (143, 144). Evidence from animal models that changes in thalamic rhythms slightly precede related cortical rhythms at the time of anaesthetic-​induced loss of consciousness also lends credence to the theory of thalamus-​ rhythm-​driven thalamocortical loop as critical to anaesthetic hypnosis (68). Other animal models using field potentials within the thalamus and cortical EEG show that ketamine/​xylazine-​induced loss of consciousness coincides with a shift in the dominant direction of information transfer from cortex-​thalamus during consciousness to thalamus-​cortex (145). Counter to the argument of a predominant thalamocortical disruption by anaesthetics, slice and chronic in vivo recordings suggest that corticocortical connections are preferentially disrupted by volatile anaesthetics, while thalamocortical connections remain intact (146), Evidence from functional connectivity studies of the thalamus and cortex, which rely on relative blood flow as measured via PET or fMRI, rather than the electrical measurements of EEG and subcortical electrodes, do not demonstrate tight association of thalamus and cortex. Instead, their functional connectivity is eliminated with the onset of anaesthetic-​induced unconsciousness, purportedly through a silencing of the thalamus (147). While this loss of functional connectivity between the cortex and thalamus was first described with isoflurane and halothane, a similar pattern was also described with dexmedetomidine-​induced loss of consciousness (148). Recent studies have further solidified the pattern of reduced thalamocortical connectivity using both ketamine and sevoflurane, making it a robust finding across multiple anaesthetic classes (149, 150). The difference in conclusions between methods using relative blood flow as a proxy for neural activity and those directly measuring electrical signatures of that activity may be a result of different temporal and spatial resolutions between the two strategies. Simultaneous measures of EEG and fMRI during a slow propofol-​ induced loss of consciousness addressed this disparity, and demonstrated a distinct phenomenon: isolation of the thalamocortical network from sensory input at the point of maximum slow-​wave activity on EEG, and the emergence of a sensory-​responsive primitive cortical network independent of the isolated thalamocortical network (151). The functional compartmentalization through thalamocortical isolation corresponds with the other EEG evidence, suggesting emergence of thalamically driven rhythms during anaesthetic-​induced unconsciousness (143, 144). Only with functional isolation would the dominant rhythm driver be thalamus rather than corticocortical connections.

Corticocortical Networks As sensory integration and processing are integral to awareness, the disruption of these functions are a predicted hallmark for

anaesthetic-​induced unconsciousness. The parietal lobe contains multiple primary sensory cortices. Executive function depends upon the frontal cortex. Consequently, effective communication between the two regions is considered necessary for consciousness. It follows that disruption of that communication would serve to produce anaesthetic-​induced unconsciousness (152, 153). However, rather than a simple complete breakdown of all frontal-​parietal communication, anaesthetic-​induced unconsciousness is associated with a specific disruption of feedback communication between the frontal and parietal cortices. Thus, although there is effective information transfer from the parietal cortex forward to the frontal cortex (feed-​forward), reciprocal information transfer from the frontal cortex to the parietal (feedback) is impaired with the onset of anaesthetic-​ induced unconsciousness (154). This pattern of feedback inhibition has proven remarkably robust over anaesthetics with varying molecular mechanisms of actions, from ketamine, to volatile agents, to propofol (155). That this pattern of feedback or top-​down processing is also impaired in vegetative states suggests that this could be a general process for unconsciousness (156, 157).

Global Distance Connectivity and Information Integration Capacity In addition to evidence that anaesthetics may exert their effects through specific networks such as those mentioned previously, anaesthetic action on large-​scale brain network organization and generalized ability for information integration may be the source of their unconsciousness-​inducing effects. Analyses of whole-​brain networks under general anaesthesia show increased local information exchange but impaired longer distance communication (158). This change from global connectedness to a more local pattern occurs for both volatile anaesthetics and propofol, and has been seen in with the distinct measurement modalities of both EEG and fMRI (159). While not all analyses have specifically found an increase of ‘small-​worldness’ of the networks (local over long-​distance), decreases in network efficiency are common, and therefore the amount of information that could be transmitted and integrated by a network is diminished in the presence of a general anaesthetic (160–​163).

Conclusions While primary anaesthetic pharmacologic effects necessarily occur at the molecular level, the diversity of both general anaesthetics’ molecular targets and their subsequent cellular-​level actions does not clearly translate into obvious behavioural commonalities observed in vivo. Only at the level of neural circuits can we begin to appreciate the common effects among the diverse array of individual anaesthetic drugs. Distinguishing the proximate cause and secondary effects culminating in anaesthetic hypnosis remains a significant challenge for the field. Identifying the critical anaesthetic induced network adaptations in both cortical and subcortical circuits truly responsible for loss of consciousness itself, as opposed to circuit level side effects of anaesthetic drug exposure, represents another significant challenge. Resolving these challenges will benefit both the field of anaesthesiology as well as neuroscience.

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Summary ◆ Anaesthetics act upon a variety of protein targets to exert their hypnotic effects. ◆ Relevant hypnotic molecular targets of general anaesthetics include ligand-​gated ion channels (examples: GABA and NMDA receptors), voltage-​gated ion channels (examples:  Kv1 and Nav1.6), constitutively active ion channels (example: K2P), G-​ protein-​coupled receptors, and respiratory complex I. ◆ Anaesthetics elicit circuit-​level effects not readily predicted by their effects on single neurons of a given circuit. ◆ Anaesthetics can affect endogenous neural systems regulating sleep and arousal, and such actions may produce or potentiate their hypnotic effects. ◆ The thalamus is part of the ascending arousal system, serves as a relay for sensory information, and facilitates corticocortical communication. While thalamic inactivation does not invariably lead to loss of consciousness, artificial stimulation can reverse hypnosis during continuous anaesthetic administration, presumably through the ascending arousal pathways. ◆ Disruption of function in cortical association areas by anaesthetics corresponds with changes of global network properties during hypnosis, where long-​range connections decline and the total capacity for information integration decreases. It is not yet clear whether direct action at those association centres directly underlies network adaptations or whether the primary change occurs elsewhere and propagates to impair cortical activity. ◆ Both thalamocortical networks as well as corticocortical patterns of connectivity are altered with anaesthetic hypnosis. Changes in both of these networks may reflect a final common marker or mediator of anaesthetic-​induced unconsciousness.

Multiple-​Choice Questions Q Interactive multiple-​choice questions to test your knowledge

on this chapter can be found in the online appendix at www. oxfordmedicine.com/​otneuroanesthesiology.

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phase of anesthesia and modulates hyperalgesia caused by sleep deprivation. European Journal of Neuroscience. 2014;40(1):2264–​73. 88. Pillay S, Liu X, Baracskay P, Hudetz A. Brainstem stimulation increases functional connectivity of basal forebrain-​paralimbic network in isoflurane-​anesthetized rats. Brain Connectivity. 2014;4(7):523–​34. 89. Watson CJ, Soto-​Calderon H, Lydic R, Baghdoyan HA. Pontine reticular formation (PnO) administration of hypocretin-​1 increases PnO GABA levels and wakefulness. Sleep. 2008;31(4):453–​64. 90. Tanase D, Baghdoyan HA, Lydic R. Dialysis delivery of an adenosine A1 receptor agonist to the pontine reticular formation decreases acetylcholine release and increases anesthesia recovery time. Anesthesiology. 2003;98(4):912–​20. 91. Coleman C, Baghdoyan H, Lydic R. Dialysis delivery of an adenosine A2A agonist into the pontine reticular formation of C57BL/​6J mouse increases pontine acetylcholine release and sleep. Journal of Neurochemistry. 2006;96(6):1750–​9. 92. Devor M, Zalkind V. Reversible analgesia, atonia, and loss of consciousness on bilateral intracerebral microinjection of pentobarbital. Pain. 2001;94(1):101–​12. 93. Abulafia R, Zalkind V, Devor M. Cerebral activity during the anesthesia-​like state induced by mesopontine microinjection of pentobarbital. The Journal of Neuroscience. 2009;29(21):7053–​64. 94. Datta S, MacLean R. Neurobiological mechanisms for the regulation of mammalian sleep–​wake behavior: Reinterpretation of historical evidence and inclusion of contemporary cellular and molecular evidence. Neuroscience & Biobehavioral Reviews. 2007;31(5):775–​824. 95. Lee M, Hassani O, Jones B. Discharge of identified orexin/​hypocretin neurons across the sleep-​waking cycle. The Journal of Neuroscience. 2005;25(28):6716–​20. 96. Kilduff TS, Peyron C. The hypocretin/​orexin ligand–​receptor system: Implications for sleep and sleep disorders. Trends in Neurosciences. 2000;23(8):359–​65. 97. Zecharia A, Franks N. General anesthesia and ascending arousal pathways. Anesthesiology. 2009;111(4):695. 98. Zhang L-​N, Li Z-​J, Tong L, Guo C, Niu J-​Y, Hou W-​G, et al. Orexin-​A facilitates emergence from propofol anesthesia in the rat. Anesthesia and Analgesia. 2012;115(4):789. 99. Kelz M, Sun Y, Chen J, Meng Q, Moore J, Veasey S, et al. An essential role for orexins in emergence from general anesthesia. Proceedings of the National Academy of Sciences. 2008;105(4):1309–​14. 100. Kushikata T, Hirota K, Yoshida H, Kudo M, Lambert DG, Smart D, et al. Orexinergic neurons and barbiturate anesthesia. Neuroscience. 2003;121(4):855–​63. 101. Ma J, Shen B, Stewart LS, Herrick IA, Leung LS. The septohippocampal system participates in general anesthesia. The Journal of Neuroscience. 2002; 22(2):RC200 102. Leung S, Ma J, Shen B, Nachim I, Luo T. Medial septal lesion enhances general anesthesia response. Experimental Neurology. 2013;247:419–​28. 103. Xu M, Chung S, Zhang S, Zhong P, Ma C, Chang W-​C, et al. Basal forebrain circuit for sleep-​wake control. Nature Neuroscience. 2015;18(11):1641–​7. 104. Leung S, Petropoulos S, Shen B, Luo T, Herrick I, Rajakumar, et al. Lesion of cholinergic neurons in nucleus basalis enhances response to general anesthetics. Experimental Neurology. 2011;228(2):259–​69. 105. Lin S-​C, Brown R, Shuler M, Petersen C, Kepecs A. Optogenetic dissection of the basal forebrain neuromodulatory control of cortical activation, plasticity, and cognition. The Journal of Neuroscience. 2015;35(41):13896–​903. 106. Fuller P, Sherman D, Pedersen N, Saper C, Lu J. Reassessment of the structural basis of the ascending arousal system. The Journal of Comparative Neurology. 2011;519(5):933–​56. 107. Anaclet C, Lin J-​S, Vetrivelan R, Krenzer M, Vong L, Fuller P, et al. Identification and characterization of a sleep-​active cell group in the rostral medullary brainstem. The Journal of Neuroscience. 2012;32(50):17970–​6.

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108. Anaclet C, Ferrari L, Arrigoni E, Bass C, Saper C, Lu J, et al. The GABAergic parafacial zone is a medullary slow wave sleep-​promoting center. Nature Neuroscience. 2014;17(9):1217–​24. 109. Kaur S, Pedersen N, Yokota S, Hur E, Fuller P, Lazarus M, et al. Glutamatergic signaling from the parabrachial nucleus plays a critical role in hypercapnic arousal. The Journal of Neuroscience. 2013;33(18):7627–​40. 110. Muindi F, Kenny J, Taylor N, Solt K, Wilson M, Brown E, et al. Electrical stimulation of the parabrachial nucleus induces reanimation from isoflurane general anesthesia. Behavioural Brain Research. 2016;306:20–​5. 111. Beier KT, Steinberg EE, DeLoach KE, Xie S, Miyamichi K, Schwarz L, et al. Circuit architecture of VTA dopamine neurons revealed by systematic input-​output mapping. Cell. 2015;162(3):622–​34. 112. Yim CY, Mogenson GJ. Electrophysiological studies of neurons in the ventral tegmental area of Tsai. Brain Research. 1980;181(2):301–​13. 113. Lee RS, Steffensen SC, Henriksen SJ. Discharge profiles of ventral tegmental area GABA neurons during movement, anesthesia, and the sleep-​wake cycle. The Journal of Neuroscience. 2001;21(5):1757–​66. 114. Luo AH, Aston-​Jones G. Circuit projection from suprachiasmatic nucleus to ventral tegmental area: a novel circadian output pathway. European Journal of Neuroscience. 2009;29(4):748–​60. 115. Luo AH, Georges FEE, Aston-​Jones GS. Novel neurons in ventral tegmental area fire selectively during the active phase of the diurnal cycle. European Journal of Neuroscience. 2008;27(2):408–​22. 116. Miller JD, Farber J, Gatz P, Roffwarg H, German DC. Activity of mesencephalic dopamine and non-​dopamine neurons across stages of sleep and waking in the rat. Brain Research. 1983;273(1):133–​41. 117. Chemali J, Dort C, Brown E, Solt K. Active emergence from propofol general anesthesia is induced by methylphenidate. Anesthesiology. 2012;116(5):998. 118. Taylor N, Chemali J, Brown E, Solt K. Activation of D1 dopamine receptors induces emergence from isoflurane general anesthesia. Anesthesiology. 2013;118(1):30. 119. Solt K, Van Dort CJ, Chemali JJ, Taylor NE, Kenny JD, Brown EN. Electrical stimulation of the ventral tegmental area induces reanimation from general anesthesia. Anesthesiology. 2014;121(2):311–​9. 120. Solt K, Cotten J, Cimenser A, Wong K, Chemali J, Brown E. Methylphenidate actively induces emergence from general anesthesia. Anesthesiology. 2011;115(4):791. 121. Takahashi K, Lin J-​S, Sakai K. Neuronal activity of histaminergic tuberomammillary neurons during wake–​sleep states in the mouse. The Journal of Neuroscience. 2006;26(40):10292–​8. 122. Luo T, Leung SL. Involvement of tuberomamillary histaminergic neurons in isoflurane anesthesia. Anesthesiology. 2011;115(1):36–​43. 123. Zecharia A, Yu X, Götz T, Ye Z, Carr D, Wulff P, et al. GABAergic inhibition of histaminergic neurons regulates active waking but not the sleep–​wake switch or propofol-​induced loss of consciousness. The Journal of Neuroscience. 2012;32(38):13062–​75. 124. Cui SY, Cui XY, Zhang J, Wang ZJ, Yu B. Diltiazem potentiates pentobarbital-​induced hypnosis via 5-​HT 1A and 5-​HT 2A/​2C receptors: Role for dorsal raphe nucleus. Pharmacology, Biochemistry, and Behavior. 2011; 99(4):556–​72. 125. Roizen MF, White PF, Eger EI, Brownstein M. Effects of ablation of serotonin or norepinephrine brain-​stem areas on halothane and cyclopropane MACs in rats. Anesthesiology. 1978;49(4):252–​5. 126. Trulson ME, Jacobs BL. Raphe unit activity in freely moving cats: correlation with level of behavioral arousal. Brain Research. 1979;163(1):135–​50. 127. Lu J, Jhou T, Saper C. Identification of wake-​active dopaminergic neurons in the ventral periaqueductal gray matter. The Journal of Neuroscience. 2006;26(1):193–​202. 128. Lu J, Nelson L, Franks N, Maze M, Chamberlin N, Saper C. Role of endogenous sleep‐wake and analgesic systems in anesthesia. Journal of Comparative Neurology. 2008;508(4):648–​62.

129. Eikermann M, Vetrivelan R, Grosse-​Sundrup M, Henry M, Hoffmann U, Yokota S, et al. The ventrolateral preoptic nucleus is not required for isoflurane general anesthesia. Brain Research. 2011;1426:30–​7. 130. Moore J, Chen J, Han B, Meng Q, Veasey S, Beck S, et al. Direct activation of sleep-​promoting VLPO neurons by volatile anesthetics contributes to anesthetic hypnosis. Current Biology. 2012;22(21). 131. Nelson LE, Lu J, Guo T, Saper CB, Franks NP, Maze M. The alpha2-​ adrenoceptor agonist dexmedetomidine converges on an endogenous sleep-​promoting pathway to exert its sedative effects. Anesthesiology. 2003;98(2):428–​36. 132. Zhang Z, Ferretti V, Güntan İ, Moro A, Steinberg EA, Ye Z, et al. Neuronal ensembles sufficient for recovery sleep and the sedative actions of α2 adrenergic agonists. Nature Neuroscience. 2015;18(4):553–​61. 133. Han B, McCarren HS, O’Neill D, Kelz MB. Distinctive recruitment of endogenous sleep-​promoting neurons by volatile anesthetics and a nonimmobilizer. Anesthesiology. 2014;121(5):999–​1009. 134. Mendelson WB. Sleep induction by microinjection of pentobarbital into the medial preoptic area in rats. Life Sciences. 1996;59(22):1821–​8. 135. Tung A, Bluhm B, Mendelson WB. Sleep-​inducing effects of propofol microinjection into the medial preoptic area are blocked by flumazenil. Brain Research. 2001;908(2):155–​60. 136. Schiff N. Central thalamic contributions to arousal regulation and neurological disorders of consciousness. Annals of the New York Academy of Sciences. 2008;1129(1):105–​18. 137. Alkire M, McReynolds J, Hahn E, Trivedi A. Thalamic microinjection of nicotine reverses sevoflurane-​induced loss of righting reflex in the rat. Anesthesiology. 2007;107(2):264. 138. Mhuircheartaigh R, Rosenorn-​Lanng D, Wise R, Jbabdi S, Rogers R, Tracey I. Cortical and subcortical connectivity changes during decreasing levels of consciousness in humans: A functional magnetic resonance imaging study using propofol. The Journal of Neuroscience. 2010;30(27):9095–​102. 139. Maquet Cyclotron Research Centre. Functional neuroimaging of normal human sleep by positron emission tomography. Journal of Sleep Research. 2000;9(3):207–​31. 140. Kaisti KK, Långsjö JW, Aalto S, Oikonen V, Sipilä H, Teräs M, et al. Effects of sevoflurane, propofol, and adjunct nitrous oxide on regional cerebral blood flow, oxygen consumption, and blood volume in humans. Anesthesiology. 2003;99(3):603–​13. 141. Långsjö J, Alkire M, Kaskinoro K, Hayama H, Maksimow A, Kaisti K, et al. Returning from oblivion: Imaging the neural core of consciousness. The Journal of Neuroscience. 2012;32(14):4935–​43. 142. Schmid M, Singer W, Fries P. Thalamic coordination of cortical communication. Neuron. 2012;75(4). 143. Ching S, Cimenser A, Purdon PL, Brown EN, Kopell NJ. Thalamocortical model for a propofol-​induced alpha-​rhythm associated with loss of consciousness. Proceedings of the National Academy of Sciences. 2010;107(52):22665–​70. 144. Vijayan S, Ching S, Purdon PL, Brown EN, Kopell NJ. Thalamocortical mechanisms for the anteriorization of α rhythms during propofol-​induced unconsciousness. The Journal of Neuroscience. 2013;33(27):11070–​5. 145. Kim S-​P, Hwang E, Kang J-​H, Kim S, Choi J. Changes in the thalamocortical connectivity during anesthesia-​induced transitions in consciousness. NeuroReport. 2012;23(5):294. 146. Raz A, Grady S, Krause B, Uhlrich D, Manning K, Banks M. Preferential effect of isoflurane on top-​down vs. bottom-​up pathways in sensory cortex. Frontiers in Systems Neuroscience. 2014;8:191. 147. White N, Alkire M. Impaired thalamocortical connectivity in humans during general-​anesthetic-​induced unconsciousness. NeuroImage. 2003;19(2):402–​11. 148. Akeju O, Loggia ML, Catana C, Pavone KJ, Vazquez R, Rhee J, et al. Disruption of thalamic functional connectivity is a neural correlate of dexmedetomidine-​induced unconsciousness. Elife. 2014;3:e04499.

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149. Bonhomme V, Vanhaudenhuyse A, Demertzi A, Bruno M-​AA, Jaquet O, Bahri MA, et al. Resting-​state network-​specific breakdown of functional connectivity during ketamine alteration of consciousness in volunteers. Anesthesiology. 2016;125(5):873–​88. 150. Ranft A, Golkowski D, Kiel T, Riedl V, Kohl P, Rohrer G, et al. Neural correlates of sevoflurane-​induced unconsciousness identified by simultaneous functional magnetic resonance imaging and electroencephalography. Anesthesiology. 2016;125:861–​72. 151. Mhuircheartaigh R, Warnaby C, Rogers R, Jbabdi S, Tracey I. Slow-​wave activity saturation and thalamocortical isolation during propofol anesthesia in humans. Science Translational Medicine. 2013;5(208):208ra148. 1 52. Imas OA, Ropella KM, Wood JD, Hudetz AG. Isoflurane disrupts anterio-​p osterior phase synchronization of flash-​ induced field potentials in the rat. Neuroscience Letters. 2006;402(3):216–​2 1. 153. Imas O, Ropella K, Ward B, Wood J, Hudetz A. Volatile anesthetics disrupt frontal-​p osterior recurrent information transfer at gamma frequencies in rat. Neuroscience Letters. 2005;387(3):145–​50. 154. Ku S-​W, Lee U, Noh G-​J, Jun I-​G, Mashour G. Preferential inhibition of frontal-​to-​parietal feedback connectivity is a neurophysiologic correlate of general anesthesia in surgical patients. PloS ONE. 2011;6(10). 155. Lee U, Ku S, Noh G, Baek S, Choi B, Mashour G. Disruption of frontal–​parietal communication by ketamine, propofol, and sevoflurane. Anesthesiology. 2013;118(6):1264.

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156. Boly M, Garrido MI, Gosseries O, Bruno M-​AA, Boveroux P, Schnakers C, et al. Preserved feedforward but impaired top-​down processes in the vegetative state. Science. 2011;332(6031):858–​62. 157. Thul A, Lechinger J, Donis J, Michitsch G, Pichler G, Kochs EF, et al. EEG entropy measures indicate decrease of cortical information processing in disorders of consciousness. Clinical Neurophysiology. 2016;127(2):1419–​27. 158. Schröter M, Spoormaker V, Schorer A, Wohlschläger A, Czisch M, Kochs E, et al. Spatiotemporal reconfiguration of large-​scale brain functional networks during propofol-​induced loss of consciousness. The Journal of Neuroscience. 2012;32(37):12832–​40. 159. Li D, Voss LJ, Sleigh JW, Li X. Effects of volatile anesthetic agents on cerebral cortical synchronization in sheep. Anesthesiology. 2013;119(1):81–​8. 160. Liang Z, King J, Zhang N. Intrinsic organization of the anesthetized brain. The Journal of Neuroscience. 2012;32(30):10183–​91. 161. Lee H, Mashour G, Noh G-​J, Kim S, Lee U. Reconfiguration of network hub structure after propofol-​induced unconsciousness. Anesthesiology. 2013;119(6):1347. 162. Monti M, Lutkenhoff E, Rubinov M, Boveroux P, Vanhaudenhuyse A, Gosseries O, et al. Dynamic change of global and local information processing in propofol-​induced loss and recovery of consciousness. PloS Computational Biology. 2013;9(10):e1003271. 163. Liu X, Ward D, Binder J, Li S-​J, Hudetz A. Scale-​free functional connectivity of the brain is maintained in anesthetized healthy participants but not in patients with unresponsive wakefulness syndrome. PLoS ONE. 2014;9(3).

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CHAPTER 2

Intracranial Pressure Harald Stefanits, Andrea Reinprecht, and Klaus Ulrich Klein

Introduction This chapter on intracranial pressure (ICP) explains the following topics: contents of the intracranial vault (brain parenchyma, cerebrospinal fluid, arterial and venous blood), ICP waveforms, intracranial elastance curve, intracranial hypertension, intracranial herniation syndromes, and monitoring of ICP. Alexander Monro (1733–​1817) first described ICP in 1783. By describing that brain tissue is nearly incompressible and surrounded by non-​expandable cranium, he suggested that intracranial blood volume (IBV) remains constant. George Kellie (1720–​1779) stated that intracranial fluid could not be added or removed without simultaneous equivalent replacement or displacement. Francois Magendie (1783–​1855) first described the circulation of cerebrospinal fluid (CSF) flowing from the ventricles to the spinal cord by discovering a small foramen in the roof of the fourth ventricle (foramen Magendie). In 1846, Sir George Burrows (1801–​ 1887) constituted a reciprocal relationship between IBV and CSF. The neurosurgeon Harvey Cushing (1869–​1939) and his co-​worker Lewis Weed endorsed the doctrine of Monro and Kellie by stating that with an intact cranium, the net sum of all intracranial vault volumes (brain tissue, blood, CSF volume) remains constant and that an increase in one component should cause a reduction in one or both of the other two components (1). Investigation of CSF started in 1891, when Heinrich Quincke (1842–​1922) published his studies on lumbar puncture and the chemical investigation of CSF. In the early twentieth century, repetitive lumbar CSF puncture was widely used as first clinical method to determine ICP. Later in 1960, the neurosurgeon pioneer Nils Lundberg published a thesis that largely influenced ICP monitoring (2), as measurements were first performed in the ventricles over a period of several hours (3). Numerous theories exist to explain why CSF surrounds the cerebrum:  a) buoyancy:  the mass of the brain is about 1400 grams, although the net weight of the brain suspended in the CSF is equivalent to a mass of 25 grams. Therefore, the brain exists in neutral buoyancy, allowing the brain to maintain its density without being impaired by its own weight. According to philosopher Rudolf Steiner (1861–​1925), this exemption of the gravity is essential for higher brain function; b) protection: CSF protects the brain to a certain extent against any impact; c) prevention of brain ischaemia: CSF can be reduced to counteract brain oedema when needed; d) chemical stability/​cooling/​clearing waste: CSF is produced in the ventricles and circulates through the ventricular

and subarachnoidal spaces, rinsing metabolic compounds from the central nervous system (CNS). It has been suggested that CSF has a ‘sink action’ by which metabolites produced in the brain during metabolic activity diffuse into CSF and thereby are removed from the brain. Also, it has been suggested that CSF flow might be able to cool the brain whenever it is needed. CSF plays an important role in flushing cerebral metabolic toxins (e.g., beta amyloid) from the interstitial fluid. This process is increased during natural sleep by opening extracellular channels controlled by glial cells allowing rapid influx of CSF into the brain. Today, indications for monitoring of ICP include traumatic brain injury, intracerebral haemorrhage, subarachnoid haemorrhage (SAH), hydrocephalus, malignant infarction, oedema, infection, and metabolic disorders (4). Measurement of ICP complements information on cerebral perfusion pressure (CPP), cerebrovascular autoregulation, and compliance of the cerebrospinal system.

Contents of the Intracranial Vault (Brain Parenchyma, CSF, Blood) To understand the dynamics of ICP regulation, anatomical considerations have to be undertaken concerning the contents of the intracranial vault. The outlined anatomical landmarks are important for the understanding of herniation syndromes and their clinical symptoms, since brainstem structures, cranial nerves, and arterial vessels are located close to the intracranial bottleneck areas and edges. The skull is the brain’s bony (stiff) hull that has only one big outlet for the medulla oblongata: the foramen magnum. It contains all relevant compartments, including the brain tissue, CSF spaces, and arterial and venous vessels (Figure 2.1 and Table 2.1).

Parenchyma The brain parenchyma including the cranial nerves makes up about 85% of total intracranial volume (ICV). The largest part of the brain is the cerebrum (or telencephalon) with its two hemispheres, separated by a vertical (sagittal) diaphragm, the falx cerebri. It is situated on top of the ‘core of the brain’, which is considered to be the relay station for higher cognitive functions: the thalamus and brainstem, parts of the diencephalon and mesencephalon, which continues caudally to the pons and the medulla oblongata. Dorsally adjacent to the brainstem is the cerebellum, which is separated from the cerebrum by an axial tent-​like diaphragm, the tentorium cerebelli. The tentorial notch allows the caudal continuation of the

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1 8

3 9

4

2

5

6 10

Figure 2.1  Schematic view of intracranial spaces and brain parenchyma. (1) telecenphalon, (2) cerebellum, (3) diencephalon, (4) mesencephalon, (5) pons, (6) medulla, (7) falx, (8) lateral ventricles, (9) tentorium cerebelli, and (10) foramen magnum.

brainstem towards the foramen magnum. The cranial nerves III to XII originate from the brainstem. The brain parenchyma has to be considered a rather static volume that is easily adaptive to chronic compression up to a certain extent (in cases of slowly growing tumours, such as meningiomas), but very sensitive to acute compression such as intracranial bleeding. Volume expansion of the parenchyma might be caused by tumour, abscess, intracranial haemorrhage (ICH), or oedema. The latter can be focal (e.g., in cases of tumour, bleeding, infection, stroke, venous stasis) or general (e.g., in SAH, global infarctions, traumatic brain injury, or associated with systemic diseases). A natural atrophy of the brain can be observed during ageing, which provides more buffer space for volume expansion in elderly people.

Cerebrospinal Fluid The CSF space makes up 10% of the ICV, equalling a total of 120–​200 ml. CSF is a low-​protein, glucose-​containing liquid that contains few cells, mostly lymphocytes (up to 4/​µl). It is mainly produced by

Table 2.1  The contents of the cranial vault are divided into three compartments. Proportions of intracranial volume are given in %. Contents of the intracranial vault Brain parenchyma

85%

Cerebrospinal fluid

10%

Blood

5%

ultrafiltration from blood in the plexus choroideus at a rate of 250–​ 500 ml/​24h. Its resorption sites are arachnoidal granulations close to the venous sinuses and the spinal nerve roots. Production and resorption are in a physiological balance. There are four major inner CSF spaces, called the ventricles, which are connected to each other and to the outer CSF space, i.e., the subarachnoid space. The lateral ventricles extend from the frontal to the occipital and to the temporal lobes, and are connected to the third ventricle by the foramen of Monro. The aqueduct extends to the fourth ventricle and thus connects supratentorial to infratentorial ventricles. The foramina of Luschka and the foramen of Magendie are the (infratentorial) pathways between inner and outer CSF spaces (Figure 2.2). Disorders of CSF circulation are called hydrocephalus, a condition that can be acute or chronic. Sudden blockade of the aforementioned foramina or the aqueduct—​the bottlenecks of CSF circulation—​lead to acute failure of CSF circulation and symptoms of herniation (Box 2.1). Aqueductal stenosis, blockade of the foramina of Monro (colloid cysts), Luschka, and Magendie may occur acutely by a tumour mass or blood clotting after intraventricular haemorrhage (within few hours) or chronically by congenital membranes or slowly growing masses. Malresorption of CSF may occur as a consequence of high CSF protein content, which can occur post-​haemorrhage (degradation of blood cells), post-​infection (meningitis/​ventriculitis), or as exudate (tumour, e.g., vestibular schwannoma), and can lead to acute, subacute, or chronic hydrocephalus. Normal pressure hydrocephalus is a chronic CSF circulation disorder, leading to typical clinical symptoms (Hakim-​Trias), i.e., cognitive and gait disorders as well as urinary incontinence (5, 6).

Blood The cerebral blood volume makes up 5% of the ICV, mainly consisting of venous vessels. Cerebral blood flow (CBF) and associated cerebral blood volume (CBV) are regulated by mechanisms influencing cerebral resistance (i.e., constriction or dilation of vessels, static autoregulation) over time (dynamic autoregulation). The pressure reactivity index (PRx) is described as a correlation coefficient between (e.g., ten-​second average) ICP and mean arterial blood pressure (MAP) over a time window (e.g., five minutes). In severe brain injury patients, impaired autoregulation contributes to unfavourable outcome. CPP is calculated as a difference between the MAP at head level and the ICP. The concept of the ‘optimal CPP’ should be followed, since values beyond the CPP level optimizing cerebral autoregulation are associated with fatal outcome or increased disability. The optimal CPP is between 50 and 95 mmHg, but it is patient-​and time-​dependent, and thus needs continuous monitoring. In cases of acutely elevated ICP, decreasing the IBV is a short-​term strategy to decrease ICP. This can be achieved by moderate (short-​term) hyperventilation leading to hypocapnia and associated cerebral vasoconstriction. Special caution has to be undertaken in patients suffering from vasospasm after SAH.

Intracranial Compliance The pressure-​volume relationship between ICP, ICV, and CPP pressure is known as the Monro-​Kellie doctrine, which states that i) the brain is enclosed in the non-​expandable cranium; ii) brain parenchyma is nearly incompressible; iii) the blood volume of the intracranial vault is nearly constant; and iv) a continuous outflow of venous blood from the intracranial vault is required to make room

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intracranial pressure

increased ICP include continued decrease in level of consciousness (stupor, coma), dilated pupils, no reaction of pupils to light, vomiting, bradycardia, hyperthermia, and papilloedema. The ability of the craniospinal space to accommodate for changes in ICV (CSV, parenchyma, blood) is defined by a non-​linear hyperbolic relationship between pressure and volume. Notably, ICP physiologically can increase or decrease in return of thoracic pressure changes (e.g., 2–​4  mmHg) during respiration. Head-​up positioning decreases ICP, as the pressure gradient between CSF and the venous blood system increases. Special procedures may increase ICP (e.g., Trendelenburg positioning).

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Cerebral Perfusion Pressure 4

Figure 2.2  Structures of the CSF space. (1) foramen of Monroi, (2) aqueduct, (3) prepontine cistern/​floor of the third ventricle, and (4) outlet of the 4th ventricle/​foramen Magendi.

for incoming arterial blood. Intracerebral compliance (CIC = ∆V/​ ∆P) reflects the ability of the intracranial system to compensate for changes in volume (∆V) per unit change in pressure (∆P). Intracerebral elastance (EIC = ∆P/​∆V) is the inverse of compliance (Figure 2.3). ICP is measured at the level of the  foramen of Monro. The normal value for ICP at rest is 10±5 mmHg for a supine adult. Mild ICP elevation is defined as 16–​20  mmHg, moderate ICP elevation as 21–​30 mmHg, and severe ICP elevation as 31–​40 mmHg (1  mmHg  =  0.133 kPa, see Table 2.2). Early clinical signs of increased ICP include decreased level of consciousness, confusion, restlessness, lethargy, cerebral and pupillary dysfunction, deterioration of motor function, headache, personality changes, and decreasing Glasgow Coma Scale score. Late clinical signs of

Box 2.1  Clinical Alert Signs Indicating Brainstem and Eloquent Cortical Area Herniation: Early Counteraction Required ◆​ Headache ◆​ Neurological dysfunction ◆​ Ipsilateral dilation of pupil ◆​ Oculomotor paresis ◆​ Hemiparesis ◆​ Contralateral dilation of pupil ◆​ Pathological breathing ◆​ Bradycardia, hypertension ◆ ​ Apnoea

Intracranial volume is regulated by the crystalloid osmotic pressure (about 5000 mmHg) gradient across the impermeable blood-​brain barrier (BBB). Whenever the BBB is severely damaged, this crystalloid osmotic gradient might be considerably small. Notably, colloid pressure (about 20 mmHg) and hydrostatic pressure also account for entry of water into brain parenchyma. It is important to maintain plasma crystalloid osmotic pressure and oncotic pressure in case of acute brain injury. ICV, and thereby ICP, is predominantly influenced by arterial partial pressure of carbon dioxide (PaCO2), as CBF increases 2–​6% per mmHg increase in PaCO2 levels. Also, CBF is tightly coupled to cerebral metabolism and increases with the increase in cerebral metabolic rate. CPP is defined as CPP = MAP–​ICP. Normal CBF remains constant and ranges from 45–​50 ml/​100g brain tissue/​min. Cerebral perfusion and autoregulation may be disturbed in acute brain injury, potentially causing an increase in CBV and ICP, thereby decreasing CPP and causing subsequent brain injury. Normal CPP values range between 70 and 90 mmHg. In neurosurgical care, the lower therapeutic thresholds are between 50 and 70 mmHg in traumatic brain injury and 80 mmHg and more in special cerebrovascular pathologies.

ICP Waveform The ICP pulse wave is a dynamic, pulsatile waveform that shows oscillating components at two different frequencies (cardiac and respiratory cycles, see Figure 2.3). Normally, patients show a low and stable ICP (20 mmHg), amplitude, and periodicity of pulsatile components might indicate reduced intracranial elastance. For example, increase in P1–​3 amplitude might represent increased CSF volume. In contrast, when a large volume of CSF is drained off, or in the case of an incompletely closed skull after craniectomy, the ICP waveform will decrease in amplitude. A prominent P1 wave may occur when the systolic blood pressure is very high. A diminished P1 wave might occur when the systolic blood pressure is too

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ICP (mmHg)

(a) 14 13 12 11 10 9 8 7 6 5 4 3

P1

0

50 100 150 200 250 300 350 400 Time (ms) P2 P1

P3

ICP (mmHg)

(b) 14 13 12 11 10 9 8 7 6 5 4 3

Pressure

0

∆p (c) 10 9 8 7 6 5 4 3

50 100 150 200 250 300 350 400 Time (ms) P1

ICP (mmHg)

20

∆p ∆V

Volume

∆V

P2

0

P3

50 100 150 200 250 300 350 400 Time (ms)

Figure 2.3  Cerebral curve (non-​linear hyperbolic relationship). Initially, an increase in the ICV results to small increase in ICP. With increasing ICP, however, the same amount of increase in volume leads to a larger increase in ICP, thus indicating reduced cerebral compliance (left). With increasing ICP there are typical changes of the ICP curve (right diagram; C, normal, P1>P2>P3; B, moderate impairment, P2>P1>P3; A, severe impairment, P2 only, no P1/​P3).

low, leaving only P2, although P2 and P3 are not changed by this. A prominent P2 wave may occur when intracerebral compliance has decreased (e.g., increasing ICP) or during inspiratory breath hold. During hyperventilation, P2 and P3 waves might diminish. A  rounded ICP waveform with reduced peaks from P1–​3 might occur when ICP is critically high. A number of pathological waves have been described so far. Modern extended ICP pulse waveform analysis (e.g., morphological clustering and analysis of ICP, or MOCAIP) potentially may allow for detection of cerebrovascular

Table 2.2  Typical ICP values during different activities and sleep in babies and adults. Activity

Baby [mmHg]

Adult [mmHg]

Lying supine

6±1

10±5

Standing up

–​5±5

–​5±5

Non-​REM-​sleep

7±2

12±5

REM-​sleep

19–​22

15–​25

Coughing, sneezing

20–​40

30–​110

changes, for example, during intracerebral vasodilation or vasoconstriction.

Lundberg A–​C Waves Lundberg A-​waves (plateau waves) are clearly pathological and defined as a sudden ICP increase up to 50–​100 mmHg lasting 5–​20 minutes (Figure 2.4). During A-​waves, it is common to develop clinical signs and symptoms of early herniation, including bradycardia and hypertension. Although the underlying mechanism remains unknown, it has been postulated that CPP cannot meet cerebral metabolic demand, thereby triggering cerebral vasodilation and subsequent increase in CBV and ICP. This, in return, causes additional CPP decrease, ultimately resulting in a vicious cycle. Atypical Lundberg A-​waves do not exceed an elevation of 50 mmHg and are an early indicator of neurological deterioration. Lundberg B-​waves are oscillating waves defined as a short modest ICP increase of 10–​20 mmHg lasting 0.5–​2 minutes. It has been postulated that B-​waves might be caused by vasomotor centre instability when CPP is unstable or at the lower limit of cerebrovascular autoregulation. Lundberg C-​waves are rapid sinusoidal fluctuations of up to 20  mmHg of ICP lasting for 7–​15 seconds (about 0.1 Hz). These waves correspond to Mayer fluctuations in

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ICP (mmHg)

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Lundberg B waves

ICP (mmHg)

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0

10

20

30

40 Time (min)

60

Lundberg C waves

ICP (mmHg)

50 40 30 20 10 0

0

10

20

30

40 Time (min)

Figure 2.4  Lundberg A waves (5–​50 mmHg, 5–​20 minutes), Lundberg B waves (10–​20 mmHg, 0.5–​2 minutes) and Lundberg C waves (several mmHg, about 0.1 Hz).

MAP that have been documented in healthy individuals and potentially are caused by cardiovascular interactions.

Cerebrovascular Pressure Reactivity CBF autoregulation describes the ability of the cerebral vasculature to maintain a stable CBF despite fluctuations in CPP. With intact autoregulation, a rise in arterial blood pressure (ABP) produces cerebral vasoconstriction, a decrease in CBV, and a fall in ICP (7, 8). A  fall in ABP produces the opposite effects. With disturbed autoregulation, a rise in ABP is transmitted to the intracranial compartment and produces a rise in ICP as a passive pressure effect. Cerebral autoregulation can be determined by investigating the moving Pearson correlation coefficient between changes in ABP and ICP, i.e., PRx. In fact, waveforms of ABP and ICP are correlated at higher temporal resolution. PRx is negative (e.g., between 0 and –​1) when cerebral vessels are pressure reactive and aim to counteract changes in ABP. Instead, PRx is positive (e.g., between 0.3 and 1) when cerebral vessels are not pressure reactive and alterations in MAP are mostly directly transmitted to ICP. PRx has been identified as a predictor of outcome after traumatic brain injury

in terms of mortality. When measured over time at different CPP thresholds, PRx demonstrates a U-​shaped curve, suggesting a specific relationship of individual autoregulation. This approach can be used to tailor individual CPP management in order to optimize the patient’s autoregulation. As ABP and ICP routinely are measured continuously in patients at risk, this index is readily available when using appropriate software. Notably, the underlying principle of PRx also works for cerebral variables other than the ICP, such as cross-​correlating MAP and CBF velocity determined by transcranial Doppler sonography (Mx) or regional frontal haemoglobin oxygen saturation determined by near-​infrared spectroscopy (ORx, THx) ideally determined at high temporal resolution.

ICP Measurement Intraventricular Catheters Direct measurement of ICP in the lateral ventricle is still considered the ‘gold standard’ for ICP measurement (Figure 2.5 and Box 2.2) (9). The measurement is performed at the level of the meatus acusticus externus corresponding to the foramen of Monro. Advantages of this measurement include the possibility of external

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Figure 2.5  Intraventricular and intraparenchymal ICP measurement.

calibration and CSF drainage. However, placement of the catheter may be difficult or even impossible in case of severe brain swelling with collapsed ventricles. Furthermore, the risk of infection is reported to be between 3.5% to more than 20% according to different larger clinical studies. Many authors report an increase of infection risk with prolonged usage (10). In clinical practice it is important to be aware that ICP recordings are representative only with a closed drainage system (4, 11, 12, 13, 14).

Intraparenchymal Probes ICP can be recorded by inserting a probe into the brain parenchyma. Usually, these probes are inserted in a non-​eloquent brain area, although the exact placement, especially in focal pathologies, is a matter of ongoing debate. Measurement of ICP is local and does not necessarily represent CSF pressure. The risk for parenchymal bleeding or infection is 50% of serum glucose