Oxford Neuro e Anestesio PDF

i
Oxford Textbook of
Neuroscience and
Anaesthesiology
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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
iii
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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1
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v
Dedication
George A. Mashour Kristin Engelhard

Dedicated to my wonderful children, Alexander Fulgens Mashour Dedicated to my mentors and teachers Eberhard Kochs and Christian
and Anna Luise Mashour—may they live long, healthy, and joyful Werner, who always encouraged and supported me throughout my
lives, and reach the fullest potential of their beautiful minds. academic career.
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Preface-the three pillars

of Neuroanaesthesiology
While serving as the President of the Society for Neuroscience The Oxford Textbook of Neuroscience and Anaesthesiology is the
in Anesthesiology and Critical Care, I espoused a vision for first book of its kind to comprehensively address all three pillars
neuroanaesthesiology that was supported by three ‘pillars’. The related to neuroscience in anaesthesiology. The first section treats
traditional pillar of neuroanaesthesiology relates to the care of the neuroscientific foundations of anaesthesiology, including the
neurosurgical and neurological patients. The clinical care of indi- neural mechanisms of general anaesthetics, cerebral physiology,
viduals with neurologic compromise is incredibly rewarding and the neurobiology of pain, and more. The second section represents
represents a true opportunity to make a positive difference in the the traditional pillar related to the care of patients with neuro-
lives of others. However, the specialty of anaesthesiology is itself a logic disease in the operating room or intensive care unit, with a
form of clinical neuroscience. On a daily basis, even as anaesthe- focus on clinical neuroanaesthesia. These chapters systematically
tists for non-neurosurgical cases, we modulate peripheral nerves, treat the peri-operative considerations of both brain and spine
the spinal cord, subcortical arousal systems, thalamocortical and surgery, and provide introductions to neurocritical care and pedi-
corticocortical networks supporting consciousness, pain networks, atric neuroanaesthesia. Finally, the last section examines some
memory systems in the medial temporal lobe, the neuromuscular connections of neurology and anaesthesiology, examining how
junction, and the autonomic nervous system. From this perspective, conditions such as dementia, stroke, or epilepsy interface with the
‘neuroanaesthesiology’ is more a compression of ‘neuroscience in peri-operative period.
anaesthesiology’ than ‘neurosurgical anaesthesiology’. The mech- This international textbook gathers the best available expertise of
anistic study of our therapeutic interventions, which represents authors and leaders in the field from Canada, Germany, Italy, New
another pillar, is exciting neuroscience in its own right, and has pro- Zealand, Spain, Switzerland, the UK, and the US. They have done an
found implications for nervous system function. Finally, the ques- outstanding job of crafting concise yet highly informative chapters
tion of how the peri-operative period might negatively impact the describing the cutting edge of neuroscience and neuroanaesthesia.
brain is the new frontier of outcomes studies and has been a major It is my hope that this textbook is itself a ‘chapter’ in the evolution
priority for the field of anaesthesiology in the past decade. Questions of the field, creating a lasting foundation and appreciation for the
related to anaesthetic neurotoxicity, cognitive dysfunction, stroke, three pillars of neuroscience in anaesthesiology.
and other neurologic outcomes of non-neurosurgical interventions
represent a critically important third pillar for the subspecialty. George A. Mashour, M.D., Ph.D.
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ix
Contents
Abbreviations xi 11 Neurophysiologic Monitoring

Contributors xv for Neurosurgery 137
Antoun Koht, Laura B. Hemmer,
Digital media accompanying the book xvii J. Richard Toleikis, and Tod B. Sloan
12 Brain Trauma 149
SECTION 1 Anne Sebastiani and Kristin Engelhard
Neuroscience in Anaesthetic Practice 13 Supratentorial Craniotomy for
1 Neural Mechanisms of Anaesthetics 3 Mass Lesion 161
Andrew McKinstry-Wu and Max B. Kelz Shaun E. Gruenbaum and Federico Bilotta
2 Intracranial Pressure 17 14 The Posterior Fossa 173

Harald Stefanits, Andrea Reinprecht, Tasha L. Welch and Jeffrey J. Pasternak
and Klaus Ulrich Klein 15 Cerebrovascular Surgery 189
3 Cerebral Physiology 27 Deepak Sharma and David R. Wright
Stefan Bittner, Kerstin Göbel, and Sven G. Meuth 16 Interventional Neuroradiology 201
4 Introduction to Electroencephalography 35 Nathan Manning, Katherine M. Gelber, Michael
Michael Avidan and Jamie Sleigh Crimmins, Philip M. Meyers, and Eric J. Heyer
5 The Autonomic Nervous System 47 17 Pituitary and Neuroendocrine Surgery 213

David B. Glick, Gerald Glick†, and Erica J. Stein Douglas A. Colquhoun and Edward C. Nemergut
6 Neuromuscular Junction: Anatomy and 18 Hydrocephalus and Associated Surgery 225

Physiology, Paralytics, and Reversal Agents 61 Paola Hurtado and Neus Fàbregas
Christiane G. Stäuble, Heidrun Lewald, and Manfred Blobner 19 Awake Craniotomy for Tumour, Epilepsy,
7 Principles of Neuroprotection 77 and Functional Neurosurgery 235
Sophia C. Yi, Brian P. Lemkuil, and Piyush Patel Lashmi Venkatraghavan and Pirjo Manninen
8 Neurotoxicity of General Anaesthetics 93 20 Anaesthesia for Complex Spine Surgeries 245

Margaret K. Menzel Ellis and Ansgar Brambrink Ehab Farag and Zeyd Ebrahim
9 Neurobiology of Acute and Chronic Pain 111 21 Spine Trauma 255

Adrian Pichurko and Richard E. Harris Timur M. Urakov and Michael Y. Wang
22 Paediatric Neuroanaesthesia 263
SECTION 2 Sulpicio G. Soriano and Craig D. McClain
Clinical Neuroanaesthesia 23 Basics of Neurocritical Care 273
Magnus Teig and Martin Smith
10 Neurologic Emergencies 125
Ross P. Martini and Ines P. Koerner
x
x contents
SECTION 3 26 Epilepsy 303

Neurologic Patients Undergoing Adam D. Niesen, Adam K. Jacob, and Sandra L. Kopp
Non-Neurologic Surgery 27 Parkinson’s Disease 309
M. Luke James and Ulrike Hoffmann
24 Cerebrovascular Disease 289
Corey Amlong and Robert D. Sanders 28 Treatment of Psychiatric Diseases
with General Anaesthetics 315
25 Peri-Operative Considerations of Dementia,
Laszlo Vutskits
Delirium, and Cognitive Decline 297
Phillip E. Vlisides and Zhongcong Xie
Index 323
xi
Abbreviations
133Xe Xenon BAER Brainstem auditory evoked response

3D Three-dimensional BBB Blood-brain barrier
AANS American Association of Neurological Surgeons BDNF Brain-derived neurotrophic factor
ABC Airway, breathing, circulation BF Basal forebrain
ABCB-1 ATP-binding cassette subfamily B member 1 BIS Bispectral index
ABI Acute brain injury BIS Bispectral index
ABP Arterial blood pressure BK Bradykinin
ABR Auditory brain stem responses BP Blood pressure
ACA Anterior cerebral artery BTF Brain Trauma Foundation
ACC Anterior cingulate cortex Ca Aterial concentration
ACDF Anterior cervical discectomy with fusion cAMP Cyclic adenosine monophosphate
ACh Acetylcholine CAS Carotid artery stenosis
AChE acetylcholinesterase CAT-1 Cationic amino-acid transporter type 1
ACSNSQIP American College of Surgeons National Surgical CBF Cerebral blood flow
Quality Improvement Program CBV Cerebral blood volume
ACTH Adrenocorticotropic hormone CBVS Cerebrovascular surgery
ADH Antidiuretic hormone CCS Central cord syndrome
ADHD attention deficit hyperactivity disorder CCT Cranial computed tomography
AED Anti-epileptic  drug CEA Carotid endarterectomy
AION Anterior ischemic optic neuropathy CE-MRC Contrast material-enhanced MR cisternography
AIS Abbreviated Injury Scale CGRP Calcitonin gene-related peptide
AIS Acute ischemic stroke CHD Congenital heart disease
AMPA α-amino-3-hydroxy-5-methyl-4- CHF Congestive heart failure
isoxazolepropionate CI Cardiac index
ANP Atrial natriuretic peptide CIC Intracerebral compliance
ANS Autonomic nervous system CM Cerebral microdialysis
AQP1 Aquaporin-1 CMAP Compound muscle action potential
AQP4 Aquaporin-4 CMR Cerebral metabolic rate
AQPs Aquaporins CMRO2 Cerebral metabolic oxygen consumption
ARAS Ascending reticular activating system CMT Central medial thalamus
ARCTIC Acute Rapid Cooling of Traumatic Injuries of the CNAP Compound nerve action potential
Cord study CNS Central nervous system
ARDS Acute respiratory distress syndrome CNT-2 Concentrative nucleoside transporter type 2
ASA American Society of Anesthesiologists COMT Catechol-O-methyl transferase
ASA PS American Society of Anesthesiologists COX Cycloxygenase
Physical Status COX-2 Cyclooxygenase-2
ASIA American Spinal Injury Association CPB Cardiopulmonary bypass
ASICs Acid-sensing ion channels CPP Cerebral perfusion pressure
ATP Adenosine triphosphate CPR Cardiopulmonary resuscitation
AV Atrioventricular CRP C-reactive protein
AVM Arteriovenous malformations CRPS Chronic regional pain syndrome
Aβ Amyloid-beta CSF Cerebrospinal fluid
BAC Balloon-assisted coiling CSWS Cerebral salt wasting syndrome
xi
xii a bbreviations
CT Computed tomography HF Heart failure

CTA CT angiography HHT Hereditary Haemorrhagic Telangiectasia
CTP CT-perfusion HIF-1α Hypoxia-inducible factor 1 alpha
Cv Venous concentration HS Hypertonic saline
CVA Cerebrovascular accident Hz Hertz
CVR Cerebrovascular resistance IADL Instrumental activities of daily living
DA1 Dopamine type 1 IARS International Anesthesia Research Society
DA2 Dopamine type 2 IBA1 Ionized calcium binding adaptor molecule 1
DBH dopamine β-hydroxylase IBV Intracranial blood volume
DBS Deep brain stimulation/stimulator ICA Internal carotid artery
DCI Delayed cerebral ischaemia ICH Intracranial haemorrhage
DDAVP desmopressin acetate ICP Intracranial pressure
DIND Delayed ischemic neurological deficit ICU Intensive care unit
DL Direct laryngoscopy ICV Intracranial volume
DLPFC Dorsolateral prefrontal cortex IHAST Intraoperative Hypothermia for Aneurysm
DMN Default Mode Network Surgery Trial
DOAC Direct acting oral anticoagulant IIT Intensive insulin therapy
DOPA Dihydroxyphenylalanine IL-6 Interleukin-6
DpMe Deep mesencephalic reticular formation IOM Intra-operative neurophysiological monitoring
DR Dorsal raphe ION Ischemic optic neuropathy
DRG Dorsal root ganglion IOM Intra-operative neurophysiological monitoring
DVT Deep vein thrombosis IONM Intraoperative neurophysiological monitoring
DWI diffusion-weighted imaging IPG Internal pulse generator
ECG Electrocardiogram IPL Inferior parietal lobule
ECMO Extracorporeal membrane oxygenation IQ Intelligence quotient
ECoG Electrocorticography IV-tPA Intravenous tissue-type plasminogen activator
ECT Electroconvulsive therapy K Potassium
ED Effective dose K2P Two-pore-domain potassium channel
EEG Electroencephalography Kv Voltage-gated potassium channel
EG Endothelial glycocalyx LA Local anaesthesia
EMG Electromyography LAT-1 Large neutral amino-acid transporter type 1
ENS Enteric nervous system LC Locus coeruleus
EP Evoked potentials LD Lumbar drain/drainage
ESL Endothelial surface layer LDF Laser Doppler flowmetry
ESO European Stroke Organization LDT Laterodorsal tegmentum
ET Endotracheal tube LGICs Ligand-gated ion channels
ETCO2 End-tidal carbon dioxide LH Luteinizing hormone
ETV Endoscopic third ventriculostomy LMA Laryngeal mask airway
EVD External ventricular drain/drainage LMWH Low molecular weight heparin
FDA Food and Drug Administration LoRR Loss of righting reflex
FFP Fresh frozen plasma LOX Lipoxygenase
FiO2 Fraction of inspired oxygen LP Lactate:pyruvate
FLAIR Fluid-attenuated inversion recovery LVH Left ventricular hypertrophy
fMRI Functional magnetic resonance imaging MABL Maximal allowable blood loss
FOUR Full outline of unresponsiveness MAC Minimum alveolar concentration
FSH Follicle stimulating hormone MAC Monitored anaesthesia care
FV Flow velocity MADRS Montgomery-Asberg Depression Rating Scale
GA General anaesthesia MAO Monoamine oxidase
GABA Gamma-aminobutyric  acid MAO-B Monoamine oxidase-B
GCS Glasgow Coma Scale MAOIs MAO inhibitors
GH Growth hormone MAP Mean arterial blood pressure
GI Gastrointestinal MCA Middle cerebral artery
GLUT-1 Glucose transporter type 1 MCI Mild cognitive impairment
GPi Globus pallidus internus MCT-1 Monocarboxylic acid transport type 1
H reflex Hoffmann’s reflex MDD Major depressive disorder
Hb Haemoglobin MDR-1 Multidrug resistance gene
HCN Hyperpolarization-activated cyclic MEG Magnetoencephalography
nucleotide-gated MEN-1 Multiple endocrine neoplasia type 1
HD Hydrocephalus MEP Motor evoked potentials
xi
abbreviations xiii
MER Microelectrode recordings PICC Peripherally inserted central catheter

MERCI Mechanical Embolus Removal in Cerebral PIN Pressure inside the endoscope
Ischemia trial PION Posterior ischemic optic neuropathy
MH Malignant hyperthermia PIV Pressure-induced vasodilation
miRNA Micro-RNA PKA Protein kinase A
ml Millilitres PKC Protein kinase C
MLS Manual-in-line stabilization PNMT Phenylethanolamine N-methyl transferase
MnPO Median preoptic nucleus PnO Pontine reticular nucleus, oral part
MOCAIP Morphological clustering and analysis of ICP pulse PNS Parasympathetic nervous system
mPFC Medial prefrontal cortex POCD Postoperative cognitive dysfunction
mps Metres per second PONV Postoperative nausea and vomiting
MRI Magnetic resonance imaging PORC Postoperative residual curarization/Postoperative
mRNA Messenger RNA residual neuromuscular block
mRS Modified Rankin score POVL Postoperative vision loss
Mx Mean flow velocity reactivity PPT Pedunculopontine tegmentum
N2O Nitrous oxide PPV Positive prediction value
nAChR Nicotinic acetylcholine receptor PRES Posterior reversible encephalopathy syndrome
NANC non-adrenergic non-cholinergic neurotransmitter PRx Pressure reactivity index
Nav Voltage-gated  sodium PSI Patient state index
NCF Nucleus cuneiformis PtiO2 Brain tissue oxygenation
NGF Nerve growth factor PZ Parafacial zone
NICU Neurological intensive care unit RA Rheumatoid arthritis
NIHSS National Institutes of Health Stroke Scale RBC Red blood cell
NIRS Near infrared spectroscopy RCRI Revised cardiac risk index
NMB Neuromuscular block RCT Randomized controlled trial
NMDA N-methyl-D-aspartate RE Response entropy
NMS Neuroleptic malignant syndrome REM Rapid eye movement
NO Nitric oxide/Nitrogen monoxide RLN Recurrent laryngeal nerve
NOS Nitric oxide synthase RN Raphe nuclei
NPH Normal pressure hydrocephalus RNA Ribonucleic acid
NPPB Normal perfusion pressure breakthrough ROI Region of interest
NPY Neuropeptide Y ROS Reactive oxygen/oxidative species
NREM Non-REM Rout Resistance to CSF outflow
NS Nociceptive specific RSI Rapid sequence induction
NSAIDs Non-steroidal anti-inflammatory  drugs rSO2 Regional cerebral oxygenation
NSF N-ethyl maleimide sensitive factor rTPA Recombinant tissue plasminogen activator
NSM Neurogenic stunned myocardial R-type High-voltage-activated calcium channels
NSQIP National Surgical Quality Improvement Program Risk RVM Rostroventralmedial medulla
OPP Ocular perfusion pressure RVP Rapid ventricular pacing
OR Operating room SA Sinoatrial
ORx Near-infrared spectroscopy SAH Subarachnoid haemorrhage
OSA Obstructive sleep apnoea SBP Systolic blood pressure
OWLS Oral and written language scale SBT Spontaneous breathing test
PaCO2 Partial pressure of arterial carbon dioxide SCI Spinal cord injury
PACU Post-anaesthesia care unit SE State entropy
PAG Periaqueductal grey SE Status epilepticus
PaO2 Partial pressure of arterial oxygen SEP Sensory evoked potentials
PB Parabrachial nucleus SI Primary somatosensory cortex
PCA Posterior cerebral artery SIADH Syndrome of inappropriate antidiuretic hormone
PCA Patient-controlled analgesia secretion
PCC Prothrombin complex concentrate sICH Symptomatic intracerebral haemorrhage
PC-MRI Phase-contrast  MRI SII Secondary somatosensory cortex
PCOM Posterior communicating SjvO2 Supra normal jugular venous oxygen saturation
PD Parkinson’s disease SMA Supplemental motor area
PEEP Positive end-expiratory pressure SMT Spinomesencephalic tract
PET Positron emission tomography SNACC Society for Neuroscience in Anesthesiology and
PFC Prefrontal cortex Critical Care
PFO Patent foramen ovale SNAPs Synaptosomal-associated protein
PGE2 Prostaglandin E2 SNARE Soluble NSF receptor
xvi
xiv a bbreviations
SNS Sympathetic nervous system TNF-α Tumour necrosis factor α

SPECT Single-photon emission CT tPA Tissue plasminogen activator
SRT Spinoreticular tract TRP Transient receptor potential
SSEP Somatosensory evoked potentials TRPM TRP melastatin receptor
SSRIs Selective serotonin and norepinephrine reuptake TRPV TRP vanilloid receptor
inhibitors TSH Thyroid stimulating hormone
STAIR Stroke Therapy Academic Industry Roundtable VAE Venous air embolism
STN Subthalamic nucleus VEP Visual Evoked Potentials
STT Spinothalamic tract VIP Vasoactive intestinal protein
SVS Slit ventricle syndrome VLPO Ventrolateral preoptic nucleus
SWS Slow-wave  sleep vPAG Ventral periaqueductal gray
TBI Traumatic brain injury VPL Ventroposterolateral
TCA Tricyclic antidepressant VPS Ventriculoperitoneal shunt
TCD Transcranial Doppler sonography VR-1 Vanilloid receptor
TCS Transcranial stimulation VRL-1 Vanilloid-like receptor  1
TDF Thermal diffusion flowmetry VTA Ventral tegmental area
TEE Transoesophageal echocardiogram WDR Wide dynamic range
THx High temporal resolution WFNS World Federation of Neurological Surgeons
THx Therapeutic hypothermia ZO Zona occludens
TIVA Total intravenous anaesthetic β-ARK β-adrenergic receptor
TMN Tuberomamillary nucleus
xv
Contributors
Corey Amlong, Department of Anesthesiology, University of Gerald Glick†, Department of Medicine, Rush Medical
Wisconsin School of Medicine and Public Health, USA College, USA
Michael Avidan, Department of Anesthesiology, Washington David B. Glick, Department of Anesthesia & Critical Care,
University School of Medicine, USA University of Chicago, USA
Federico Bilotta, Department of Anesthesiology, Critical Care and Kerstin Göbel, Department of Neurology, University Hospital
Pain Medicine, Sapienza University of Rome, Italy Münster, Germany
Stefan Bittner, Department of Neurology, Johannes Gutenberg Shaun E. Gruenbaum, Department of Anesthesiology, Yale
University Mainz, Germany University School of Medicine, USA
Manfred Blobner, Klinik für Anaesthesiologie der Technischen Richard E. Harris, Department of Anesthesiology, University of
Universität München, Klinikum rechts der Isar, Germany Michigan Medical School, USA
Ansgar Brambrink, Department of Anesthesiology, Columbia Laura B. Hemmer, Department of Anesthesiology and
University, USA Neurological Surgery, Northwestern University, Feinberg School
of Medicine, USA
Douglas A. Colquhoun, Department of Anesthesiology, University
of Michigan Medical School, USA Eric J. Heyer, Departments of Anesthesiology and Neurology,
Columbia University, USA
Michael Crimmins, Walter Reed National Military Medical Center,
Department of Neurology, Neurosurgery and Critical Care, USA Ulrike Hoffmann, Department of Anesthesiology, Duke
University, USA
Zeyd Ebrahim, Department of General Anesthesiology,
Anesthesiology Institute, Cleveland Clinic, USA Paola Hurtado, Anesthesiology Department, Hospital Clìnic de
Barcelona, Spain.
Margaret K. Menzel Ellis, Portland VA Medical Center,
Assistant Professor of Anesthesiology, Oregon Health & Science Adam K. Jacob, Department of Anesthesiology and Perioperative
University, USA Medicine, Mayo Clinic College of Medicine, USA
Kristin Engelhard, Department of Anesthesiology, University M. Luke James, Departments of Anesthesiology and Neurology,
Medical Center of the Johannes Gutenberg-University Mainz, Duke University, USA
Germany
Max B. Kelz, Department of Anesthesiology and Critical Care,
Neus Fàbregas, Anesthesiology Department, Hospital Clìnic de University of Pennsylvania Perelman School of Medicine, USA
Barcelona, Spain
Klaus Ulrich Klein, Department of Anesthesia, General Intensive
Ehab Farag, Department of General Anesthesia and Outcomes Care and Pain Management, Medical University of Vienna,
Research, Anesthesiology Institute, Cleveland Clinic, USA Austria
Heidrun Lewald, Klinik für Anaesthesiologie der Technischen Ines P. Koerner, Department of Anesthesiology & Perioperative
Universität München, Klinikum rechts der Isar, Germany Medicine, Department of Neurological Surgery, Oregon Health &
Science University, USA
Katherine M. Gelber, Department of Anesthesiology, Cedars-Sinai
Medical Center, USA
xvi
xvi c ontributors
Antoun Koht, Department of Anesthesiology, Neurological Jamie Sleigh, Department of Anaesthesia and Pain Medicine,
Surgery, and Neurology, Northwestern University, Feinberg School Waikato Clinical Campus, University of Auckland, New Zealand
of Medicine, USA
Tod B. Sloan, Department of Anesthesia, University of Colorado
Sandra L. Kopp, Department of Anesthesiology and Perioperative School of Medicine, USA
Medicine, Mayo Clinic College of Medicine, USA
Martin Smith, Department of Neuroanaesthesia and Neurocritical
Brian P. Lemkuil, Department of Anesthesiology, University of Care, The National Hospital for Neurology and Neurosurgery,
California San Diego, USA University College London Hospitals, UK
Pirjo Manninen, Department of Anesthesia, Toronto Sulpicio G. Soriano, Department of Anesthesiology, Perioperative
Western Hospital University Health Network, University of and Pain Medicine, Boston Children's Hospital, Harvard Medical
Toronto, Canada School, USA
Nathan Manning, Departments of Neurosurgery and Christiane G. Stäuble, Klinik für Anaesthesiologie der
Radiology, Columbia University Medical Centre, New York Technischen Universität München, Klinikum rechts der Isar,
Presbyterian, USA Germany
Ross P. Martini, Department of Anesthesiology and Perioperative Harald Stefanits, Department of Neurosurgery, Medical
Medicine, Oregon Health & Science University, USA University of Vienna, Austria
Craig D. McClain, Department of Anesthesiology, Perioperative Erica J. Stein, Department of Anesthesiology, The Ohio State
and Pain Medicine, Boston Children's Hospital, Harvard Medical University, USA
School, USA
Magnus Teig, Department of Anesthesiology, University of
Andrew McKinstry-Wu, Department of Anesthesiology and Michigan Medical School, USA
Critical Care, University of Pennsylvania, USA
J. Richard Toleikis, Department of Anesthesiology, Rush
Sven G. Meuth, Department of Neurology, Institute of University School of Medicine, USA
Translational Neurology, Westfälische-Wilhelms University
Münster, Germany Timur M. Urakov, Department of Neurosurgery, University of
Miami, Jackson Memorial Hospital, USA
Philip M. Meyers, Departments of Radiology and Neurological
Surgery, Columbia University, USA Lashmi Venkatraghavan, Department of Anesthesia, Toronto
Western Hospital, University of Toronto, Canada
Edward C. Nemergut, Department of Anesthesiology, University
of Virginia Health System, USA Phillip E. Vlisides, Department of Anesthesiology, University of
Michigan Medical School, USA
Adam D. Niesen, 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
Jeffrey J. Pasternak, Department of Anesthesiology and of Basic Neuroscience, University of Geneva Medical School,
Perioperative Medicine, Mayo Clinic College of Medicine, USA Switzerland
Piyush Patel, VA Medical Center, University of California San Michael Y. Wang, University of Miami, Miller School of
Diego, USA Medicine, USA
Adrian Pichurko, Department of Anesthesiology, Northwestern Tasha L. Welch, Department of Anesthesiology and Perioperative
University, Feinberg School of Medicine, USA Medicine, Mayo Clinic College of Medicine, USA
Andrea Reinprecht, Department of Neurosurgery, Medical David R. Wright, Departments of Anesthesiology & Pain Medicine
University of Vienna, Austria and Neurological Surgery, University of Washington, USA
Robert D. Sanders, Department of Anesthesiology, University of Zhongcong Xie, Department of Anesthesia, Critical Care and
Wisconsin, USA Pain Medicine, Massachusetts General Hospital, Harvard Medical
School, USA
Anne Sebastiani, Department of Anesthesiology, University
Medical Center of the Johannes Gutenberg University Mainz, Sophia C. Yi, Department of Anesthesiology, University of
Germany California San Diego, USA
Deepak Sharma, Department of Anesthesiology & Pain Medicine,

University of WashingtonUSA
xvi
Digital media
accompanying the book
Individual purchasers of this book are entitled to free personal ac- The corresponding media can be found on Oxford Medicine
cess to accompanying digital media in the online edition. Please Online at: www.oxfordmedicine.com/otneuroanesthesiology
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Q Cases and multiple-choice questions
xvi
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
2
3
CHAPTER 1
Neural Mechanisms
of Anaesthetics
Andrew McKinstry-Wu and Max B. Kelz
Introduction Ligand-Gated Ion Channels

The first public demonstration of general anaesthesia took place Ligand-gated ion channels (LGICs) are common targets for vola-
in 1846. Over 170 years later, a majority of the estimated 234 mil- tile, gaseous, and potent intravenous agents. They provide an easily
lion annual surgical procedures worldwide are performed under understood mechanism for modulating individual neural activity
general anaesthesia (1). Nevertheless, general anaesthetics remain and offer a plausible method for altering large-scale neural effects.
poorly understood as a unique class of drug that has infallible General anaesthetics variously affect multiple LGICs, the two most
clinical efficacy with a narrow therapeutic window. Despite their common being potentiation of inhibitory anionic channels and in-
pervasive use, there is a lack of basic knowledge of where and hibition of excitatory cationic channels. In fact, the vast majority
how anaesthetics produce both their desirable and unintended of general anaesthetics demonstrate specific actions at one or both
side effects. of two LGICs: potentiation of the anionic gamma-aminobutyric
Apparent similarities in dose-dependent behavioural effects acid (GABA)-gated GABAA receptor, and inhibition of the cationic
among gaseous, volatile, and intravenous general anaesthetics glutamate-and-glycine-gated N-methyl-D-aspartate (NMDA)
led to the historical belief that all general anaesthetics shared receptor.
a single molecular mechanism of action. Older theories of an- Inhibitory Ligand-Gated Ion Channel Potentiation
aesthetic action relied on common chemical properties of the GABA is the most common inhibitory neurotransmitter in the
anaesthetics to explain their common effects, such as the asso- central nervous system (CNS.) The GABAA-receptor, an abundant
ciation of lipid solubility with anaesthetic potency (the Meyer- GABA effector site, is a heteropentameric ligand-gated chlorine-
Overton rule). Ultimately, these early theories fell out of favour selective ion channel responsible for GABA’s inhibitory effects in the
with the realization that anaesthetics could exert their actions CNS. Importantly, it is also a crucial functional target of most po-
in lipid-free protein preparations. Subsequently, many molecular tent intravenous agents and volatile anaesthetics (2–7). Volatile and
targets of individual anaesthetics have been identified. With the intravenous anaesthetics that affect the GABAA-receptor enhance
discovery of each new molecular target, the fallacy of a unitary endogenous GABAergic signalling at pharmacologically relevant
molecular mechanism of anaesthesia becomes more apparent. concentrations, and at higher concentrations can directly open the
The past twenty years have demonstrated that knowledge of both channel (5–10). Synaptic potentiation of GABAA-receptors affects
the specific molecular targets, as well as their location in dis- size and duration of rapid, phasic, inhibitory postsynaptic potentials.
crete neural circuits, is a prerequisite to any real understanding Potentiation at extrasynaptic receptors, in contrast, alters baseline
of anaesthetic hypnosis. Hence, the molecular, neuronal, cir- membrane potential through tonic chloride currents (11). The net
cuit, and network targets of anaesthetics are all critical to our effect of these actions is to decrease the chance that the postsynaptic
neuroscientific framework of how these agents produce revers- neuron will fire an action potential in the presence of pharmacologic-
ible unconsciousness. ally 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
Molecular Mechanisms of Anaesthetic their effects (12). Specific mutations in GABAA-receptor subunits at
Hypnosis known anaesthetic binding sites produce attenuation to anaesthetic
The breadth of molecular targets of general anaesthetics highlights effects of specific agents, both in vitro and in vivo. Mutations in the
the diversity of molecular mechanisms sufficient to produce anaes- alpha subunit of the GABAA-receptor reduce the effect of volatile
thetic hypnosis. Inhaled and intravenous anaesthetics act on di- anaesthetics and benzodiazepines, while beta subunit mutations
verse protein targets to exert their hypnotic effects: ion channels, attenuate the effects of intravenous and volatile anaesthetics (3, 5).
G-protein coupled receptors, and constituents of the electron trans- This suggests a critical role for action at the GABAA-receptor in pro-
port chain, among others (Figure 1.1). ducing on-target anaesthetic effects.
4
4 Section 1 neuroscience in anaesthetic practice
Mt
KV1 HCN K2P NaV NMDA Glycine GABA mAch nAch TTCa RTCa Complex
I
Ethers
Halothane
Propofol
Etomidate
Barbiturates
Ketamine
Nitrous
Oxide/
Xenon
Dexmedeto-
midine
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 Excitatory Ligand-Gated Ion Channel Inhibition
LGICs in the CNS. This receptor family is found mostly in the Many general anaesthetics act to inhibit excitatory LGICs, a
brainstem and spinal cord. Like GABAA-receptors, glycine re- complementary effect to their potentiation of inhibitory LGICs.
ceptors are heteropentameric chlorine channels, and are directly Glutamate is the primary excitatory neurotransmitter of the CNS.
activated or potentiated by volatile and many intravenous anaes- Among glutamate’s targets is the NMDA receptor (where it has gly-
thetics (13–16). Evidence for the functional importance of glycine as a co-receptor). NMDA receptors are the functional target for
cine receptors to anaesthetic action is not as robust as that for the a significant number of general anaesthetics. Like the extrasynapic
GABAA-receptor. Glycine receptor mutations can produce diver- GABA receptors responsible for tonic currents, NMDA receptors
gent responses to anaesthetic endpoints. Site-specific mutations do not produce the fast postsynaptic transmission responsible
of the glycine receptor that alter in vitro receptor sensitivity to for excitatory postsynaptic potentials, but acts presynaptically,
volatile and potent intravenous anaesthetics do not always pro- postsynaptically, and extrasynaptically, and can affect synaptic plas-
duce associated changes in immobility or hypnotic sensitivity in ticity (21). All known noncompetitive NMDA antagonists severely
vivo (6, 17). Specifically with propofol, the glycine receptor may disturb consciousness, with many acting as general anaesthetics at
not contribute to immobility. A structural analogue of propofol sufficient concentrations (22). The gas anaesthetics nitrous oxide
that potentiates glycine (but not GABA) receptor signalling, 2,6 and xenon, as well as the intravenous agent ketamine, all act pri-
di-tert-butylphenol, lacks any immobilizing effects in vivo (7, marily as NMDA receptor antagonists, while many of the volatile
18, 19). Similarly, a Q266I point mutation introduced into the anaesthetics possess NMDA antagonist activity in addition to their
α1 subunit of the glycine receptor that decreases receptor sen- effects on other putative anaesthetic targets (23–26).
sitivity to isoflurane unexpectedly conferred hypersensitivity to The nicotinic acetylcholine receptor, a ligand-gated nonspecific
the immobilizing properties of both isoflurane and enflurane in cation channel, is inhibited by volatile anaesthetics at clinically
mice. These results suggest that glycine receptors containing the relevant concentrations. While that inhibition does not mediate
α1 subunit are unlikely to mediate immobilizing properties of anaesthetic hypnosis, it may mediate amnesia and analgesic ef-
anaesthetics (20). fects of volatile anaesthetics (27–30). Moreover, central cholinergic
5
Chapter 1 neural mechanisms of anaesthetics 5
signalling via nicotinic receptors appears important for anaesthetic historically inhibition had only been seen at higher concentrations
emergence. Although blockade of cholinergic signalling may not (42). The role of sodium channels in volatile anaesthetic hypnosis
be sufficient to alter loss-of-righting-reflex or Minimum alveolar is demonstrated by hypersensitivity to isoflurane and sevoflurane
concentration (MAC) concentration, it can still be sufficient to re- in mice with reduced activity in one voltage-gated sodium channel
tard emergence from anaesthetic hypnosis (discussed later in this subtype, NaV1.6 (43).
chapter). Presynaptic voltage-gated calcium channels are critical for neuro-
transmitter release and inhibited by general anaesthetics, making
Constitutively Active and Voltage-Gated Ion Channels them likely anaesthetic targets. Low-voltage-activated T-type
Members of the two-pore-domain potassium channel family calcium channels, which modulate cellular excitability through
(K2P) produce a continuous non-inactivatable current that modi- regulating burst firing and pacemaker activity, are inhibited by
fies resting membrane potential and thus affects neuronal excit- clinically relevant concentrations of volatile and intravenous anaes-
ability (31). Volatile and gaseous anaesthetics directly activate thetics (44–46). In vivo knockouts of T-type calcium channels do
members of this family, including TREK-1, TREK-2, TASK-1, not show changes in anaesthetic sensitivity to the loss of righting
TASK-2, and TASK-3. Anaesthetic activation of these K2P chan- reflex (LoRR), a traditional rodent equivalent endpoint to loss of
nels causes an increase in potassium efflux out of the cell leading to consciousness in humans, though they do have altered speed of in-
hyperpolarization. However, not every member of the K2P family duction and reaction to noxious stimuli (46, 47). This suggests that
is activated by anaesthetic exposure. Several members are insensi- the effects of anaesthetics upon these channels modulate the anaes-
tive to anaesthetics, while THIK-1, TWIK-2, TALK-1, and TALK-2 thetized state, rather than cause it. High-voltage-activated calcium
are actually closed by anaesthetic exposure. Mutations of two-pore- channels (R-type) are also sensitive to inhibition by volatile anaes-
domain potassium channels can abrogate sensitivity to activation thetics, and contribute to rhythmicity of thalamocortical circuits. R-
by volatile and gaseous anaesthetics. Distinct gene mutations alter type knockouts display less electroencephalographic suppression at
volatile sensitivity versus sensitivity to gaseous anaesthetics (32). 1% isoflurane than their wild-type counterparts. This suggests that
An in vivo knockout of one K2P, TREK-1, caused an impressive 40% thalamic calcium channels are involved in isoflurane-induced thal-
resistance to halothane and more modest resistance to other inhaled amic suppression, thought to contribute to unconsciousness (48).
anaesthetics, while leaving barbiturate sensitivity unchanged (33).
Hyperpolarization-activated cyclic nucleotide- gated (HCN) G-Protein-Coupled Receptors
channels are tetrameric, relatively nonspecific cation channels that G-protein-coupled receptors make up the largest and most di-
activate with cell hyperpolarization (as opposed to depolarization.) verse family of membrane receptors. They comprise 4% of the en-
The Ih current, produced by HCN activation, is involved in pro- tire coding human genome and are the target for over a quarter
ducing long-term potentiation, dendritic integration, control of of all current pharmaceuticals (49). Drugs that affect this receptor
working memory, and thalamocortical oscillations (34). Of the four superfamily are an integral part of anaesthetic practice, including
HCN isoforms, HCN1 is both abundant in the CNS and inhibited such diverse classes as opioids, vasopressors, and anticholinergics.
by volatile and intravenous agents. Agents as diverse as isoflurane, So, while these receptors are known targets for producing analgesia
ketamine, and propofol inhibit HCN1 at clinically relevant doses. and amnesia, there is little direct evidence that volatile-anaesthetic-
In in vivo models, this HCN1 inhibition plays a direct role in the induced hypnosis is primarily mediated via this superfamily of
hypnotic potency of these agents (35–38). There is even debate that receptors. This is despite the fact that volatile anaesthetics do select-
NMDA receptor antagonists producing hypnosis do so not through ively activate G-protein-coupled receptors at pharmacologically-
actions at the NMDA receptor itself, but through their inhibition relevant concentrations (50, 51). Ketamine very specifically
of HCN1 (37). The involvement of HCN channels in critical CNS interacts with a subset of olfactory receptors, which are a subgroup
processes and their inhibition by diverse anaesthetic agents suggest of G-protein-coupled receptors, though it is unclear if these inter-
a significant role for this channel in anaesthetic-induced hypnosis. actions are in any way related to its anaesthetic actions (52).
Voltage-gated potassium channels of the Kv1 family are recently
identified targets of volatile anaesthetics that contribute to suppres- Electron Transport Chain
sion of arousal. Flies with mutations in a gene coding for a member Unlike the previously discussed membrane-bound proteins in the
of the Kv1.2 family (shaker) exhibit altered sensitivity to volatile an- cell’s outer membrane, components of complex I, a multi-subunit
aesthetics, requiring higher doses than wild-type controls to cease member of the respiratory chain, are putative anaesthetic targets lo-
movement (39). Sevoflurane enhances currents in members of the cated in the inner mitochondrial membrane. Animal models with
Kv1 family, with other clinically used volatiles also affecting Kv1 mutations in specific subunits of complex I, GAS-1 in C. elegans
currents, suppressing firing in the central medial thalamus (40). and Ndufs4 in mice, are hypersensitive to volatile anaesthetics. This
Kv1 channel inhibitors infused into the central medial thalamus hypersensitivity phenotype is strictly mirrored across evolution up
are able to reverse continuous low-dose sevoflurane anaesthesia in to and including humans with complex I mutations (53–55). The
animal models, as are antibodies against Kv channels (41). anaesthetic hypersensitivity phenotype is not present in all com-
Voltage-gated sodium channels are a requisite for normal exci- plex I gene mutations, nor is it present with other electron transport
tatory neuronal function, as they are key to initiating and propa- chain mutations, indicating a specific interaction between volatile
gating action potentials. Their inhibition by volatile anaesthetics anaesthetics and precise complex I subunits. While halogenated
presynaptically results in a decreased likelihood of action poten- ethers and alkanes inhibit complex I function though interaction
tial propagation and decreased presynaptic neurotransmitter re- with the distal portion of the complex, volatile anaesthetics do not
lease. Several sodium channel subtypes are inhibited by volatile appear to disproportionately decrease ATP production in complex
anaesthetics in pharmacologically relevant concentrations, though I mutants. This dissociation suggests volatile anaesthetic hypnotic
6
action is not solely a result of disproportionate mitochondrial ener- anaesthetic depth can also distinguish wakefulness from sleep (59–
getic disruption in those mutants, begging the persistent question 65). During anaesthesia and sleep, thalamic nuclei and wake-active
of how these mutations cause anaesthetic hypersensitivity (56–58). nuclei, collectively known as the reticular activating system, are
similarly inhibited (46, 66–70). Parallels between the states extend
Systems Neuroscience and Anaesthetic to their functional effects—in some cases anaesthesia can substi-
tute for sleep. Sleep debt does not accrue during prolonged periods
Effects: Discrete Nuclei and Local Networks of propofol-induced unconsciousness, while propofol hypnosis ap-
There is incontrovertible evidence for anaesthetic drugs interacting pears to relieve previously incurred sleep debt (71–73). Conversely,
with multiple molecular targets to affect behaviour, but anaesthetic sleep deprivation or administration of endogenous somnogens
hypnosis is impossible to explain by mere examination of molecular reduce the dose of anaesthetic required for hypnosis. In a parallel
binding events in isolation. The imperfect connection between vein, induction and maintenance of anaesthesia itself alters levels
molecular action and larger-scale brain phenomena must be in- of endogenous somnogens (72, 74). Together, these data support
terpreted in light of relevant neuroanatomy. Complexities are intro- the theory that anaesthetic-induced hypnosis stems in part from
duced by circuit-level interactions—neuronal hyperpolarization actions of anaesthetics on the neural circuits involved with en-
that reduces firing of a presynaptic inhibitory input can increase dogenous sleep-wake control.
activity for the postsynaptic neuron resulting in a net increase of
circuit output. Evaluating the net contribution of anaesthetics on Arousal-Promoting Nuclei of the Reticular
discrete brain regions to hypnosis provides a way to simplify the Activating System
massive complexity encountered at the molecular and neuronal The ascending reticular activating system, extending rostrally from
level without ignoring the fundamental circuitry of the CNS. the mid pons to the hypothalamus, basal forebrain, and thalamus,
was first identified more than half a century ago. Stimulation of the
Sleep and Arousal Pathways brain stem reticular formation causes cortical arousal during an-
General anaesthetics alter the activity of endogenous arousal cir- aesthetic states (75). Subsequently, discrete interacting neuronal
cuits. Such actions directly contribute to their hypnotic effects populations were found to be the arousal-promoting components
(Figure 1.2). Anaesthetic-induced unconsciousness is a non- of the activating system, including cholinergic, histaminergic, ad-
arousable behavioural state that shares many commonalities with renergic, serotonergic, dopaminergic, and orexinergic centres.
slow-wave sleep (SWS) There is a functional loss in cortical con-
nectivity during both NREM sleep and anaesthetic hypnosis. Laterodorsal Tegmentum (LDT) and Pedunculopontine
Moreover, over much of the anaesthetic dose response range, the Tegmentum (PPT)
cortical electroencephalography (EEG) exhibits striking simi- These nuclei comprise two major cholinergic populations in the
larities, such that processed EEG measures developed to assess 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) PPT/LDT
RN
(ACh)
(5-HT)
POA
(GABA/Gal)
vPAG
LC (Ne)/PB
(DA)
(Glut)
PZ
(GABA) 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.
7
wakefulness or REM sleep. These cholinergic neurons densely systemic effects (92, 93). Clearly, a more complex local microcir-
innervate the midline and intralaminar thalamic nuclei and thal- cuitry awaits discovery.
amic reticular nucleus and alter thalamic activity from bursting to
Deep Mesencephalic Reticular Formation (DpMe)
spiking (76). Direct effects of these nuclei on anaesthetic-induced
hypnosis are unknown. Despite this, the PPT is in a region that is Over the decades, many studies have demonstrated that electrical
associated with pain-induced movement, the inactivation of which stimulation in the DpMe reliably induces cortical activation in an-
leads to a significant decrease of isoflurane MAC (77). aesthetized animals. These presumptively glutamatergic neurons
project to the thalamus, hypothalamus, and basal forebrain, where
Locus Coeruleus (LC) they increase their firing rates prior to the onset of wakefulness,
The Locus Coeruleus is the site of the brain’s largest collection of and fire more slowly during SWS (94). These glutamatergic neurons
noradrenergic neurons. As with many of the other monoaminergic are possibly part of a previously poorly recognized arm of the as-
systems, the LC diffusely innervates the brain by projecting directly cending arousal system that potentially includes the parabrachial
to the cortex, thalamus, hypothalamus, basal forebrain, amygdala, nucleus as well.
hippocampus, and other subcortical systems. State-dependent
modulation of activity within the LC has long been proposed as Hypocretin/Orexinergic Neurons
an essential means of regulating arousal. Changes in the activity The orexin signalling system exerts potent wake-promoting and
of LC neurons occur before, and are predictive of, changes in an wake-stabilizing effects, and plays an important role in modulating
organism’s behavioural state (78). Through its actions on alpha1 and anaesthetic emergence. As with the monoaminergic wake-active
beta receptors, firing of LC neurons promotes wakefulness through systems, the orexin system displays state-dependent firing pat-
actions on the medial septum, the medial preoptic area, and the terns with maximal activity during active wakefulness and silence
substantia innominata within the basal forebrain. Activity in the during SWS (95). Anatomically, these neurons project to all of the
LC modulates thalamocortical circuits, switching the tone of thal- monoaminergic groups along with extending to the basal forebrain,
amocortical neurons from the burst pattern of slow-wave sleep to midline thalamic nuclei, and other regions known to participate in
a spiking pattern that characterizes wakefulness. Consequently, the regulation of arousal. When signalling of these neurons is im-
optogenetically driven LC activity causes transitions from SWS to paired, narcolepsy with cataplexy ensues (96). Local application of
wakefulness (79). Under deep isoflurane anaesthesia, artificially orexin excites target neurons expressing either of the two orexin Gq-
driven LC activity has been shown to cause EEG desynchron- coupled neurotransmitter receptors, including the LDT, LC, RN,
ization. Similarly, artificially induced firing of the LC speeds emer- basal forebrain (BF), and thalamocortical neurons. Halogenated
gence from isoflurane anaesthesia (80). However, the LC is not the ethers, propofol, and pentobarbital inhibit orexinergic neuronal
sole source of adrenergically driven arousal. Noradrenergic popu- activity, and genetic knockout of these neurons results in delayed
lations outside of the LC, such as the A1 and A2 brainstem groups, emergence from isoflurane and sevoflurane anaesthesia without
also may contribute to the regulation of sleep, wakefulness, and an- affecting sensitivity to anaesthetic induction (97–99). In the case
aesthesia (81–83). of barbiturate anaesthesia, the pharmacologic inverse is true as
well: intracerebroventricular injection of orexin speeds emergence,
Pontine Reticular Nucleus, Oral Part (PnO) and orexin1-receptor blockade negates this effect (100). The case
Neurons in this large region (which includes the sublaterodorsal of delayed emergence without altered induction in orexinergic de-
nucleus) receive cholinergic, orexinergic, and GABAergic inputs ficient animals highlights the intriguing possibility that distinct
and include wakefulness-promoting and REM-on populations. populations of neurons may unilaterally and differentially impact
PnO activity also modifies anaesthetic action. GABAergic activity the process of entering into or exiting from the anaesthetic state.
at the PnO produces resistance to induction without significant
effects on emergence (84–87). Electrical stimulation at the PnO Wake-Promoting Neurons of the Basal Forebrain
causes an increase in functional connectivity under continuous The BF encompasses heterogeneous populations of neurons ac-
isoflurane anaesthesia, similarly suggesting anaesthetic antag- tive in arousal and sleep that modify anaesthetic state and sensi-
onist actions (88). This region highlights the critical importance tivity. GABA agonists microinjected at the BF potentiate systemic
of neuroanatomic and neurochemical compartments: unlike most intravenous and volatile anaesthetic effect and duration, as do
other regions of brain, increased GABA levels in the PnO pro- electrolytic lesions of the medial septum within the BF (101, 102).
mote wakefulness. Other seemingly paradoxical effects occur in The BF sits atop the ventral extrathalamic relay and receives inte-
this region: wakefulness is actually impaired by local delivery of grated arousal inputs from caudal structures. Within the BF, there
adenosine or acetylcholine into PnO, or alternatively, promoted are wake-active cholinergic neurons, wake-active glutamatergic
by local delivery of orexin or GABA (89–91). Cholinergic input to neurons, wake- a ctive parvalbumin- c ontaining GABAergic
the PnO originates from the LDT and PPT, while the orexinergic neurons, and sleep-active somatostatin-containing GABAergic
input arises from the hypothalamus. Divergent responses to adeno- neurons (103). The cholinergic neurons receive afferents from the
sine and GABA suggest that simple disinhibition of a single popu- LC, DpMe, Tuberomamillary nucleus (TMN), orexinergic neurons,
lation of PnO neurons is not sufficient to understand the actions parabrachial neurons, and glutamatergic neurons of the BF, and
of these neuromodulators. Further clouding the picture, micro- send widespread efferent projections to the cortex and hippo-
injections of pentobarbital within a region that has been termed campus, as well as back to the hypothalamus. Selective lesion of
the mesopontine tegmental area, which overlaps with a significant cholinergic neurons within the nucleus basalis of the BF prolongs
portion of the PnO and some neighbouring structures, have been behavioural effects of propofol and pentobarbital (104). Increased
shown to induce hypnosis similar to systemic administration of a cholinergic activity of the basal forebrain during wakefulness is re-
larger general anaesthetic dose, while nearby injections lack any sponsible for the fluctuations in cortical acetylcholine levels. The
8
cholinergic neurons stimulate cortical activation, and the resultant CNS serotonin. The median raphe contributes little to producing
increased discharge frequency, along with increased activity of or modulating anaesthetic actions. In contrast, when the DR is si-
cortically projecting parvalbumin-containing GABAergic neurons, lenced by calcium blockage or by lesion, sensitivity is increased to
underlies the desynchronized EEG that typifies wakefulness as well pentobarbital or halothane and cyclopropane, respectively (124,
as REM sleep (103, 105). 125). The raphe nuclei (RN) do display state-dependent firing
similar to noradrenergic or histaminergic centres. Single unit re-
Parabrachial Nucleus
cordings, however, demonstrate that firing rates of serotonergic
Neurons in the parabrachial nuclei belong to a recently identi- neurons do not anticipate spontaneous changes in arousal state
fied glutamatergic arm of the anterior branch of the ascending (126). This suggests that activity of the DR is not causally linked to
arousal system and can themselves modify the anaesthetic state. changes in behavioural state.
Lesion of the parabrachial nuclei induces coma, while the sleep- Within the vPAG, there is a population of dopaminergic neurons
active parafacial zone (see Sleep-active Neurons of the Basal that are wake-active. This is in contrast to dopaminergic neurons of
Forebrain and Parafacial Zone) promotes SWS through inhibition the VTA or substantia nigra, which do not display state-dependent
of glutamatergic parabrachial neurons that, in turn, project to the activity. However, the vPAG dopaminergic neurons appear not to
BF (106–109). Electrical stimulation of the parabrachial nucleus is contribute to anaesthetic hypnosis. Instead, they modulate anal-
able to antagonize continuous low-dose isoflurane administration gesia, with lesions of these neurons causing decreased reaction to
(110). This observed direct effect on anaesthetic sensitivity, as well noxious stimuli under general anaesthesia (127, 128).
as the parabrachial’s known anatomic and functional connection
with sleep-active nuclei and other CNS regions that affect anaes- Sleep-Active Neurons and Nuclei
thetic sensitivity and emergence, suggests a significant role for the
When compared to the large numbers of known arousal-
parabrachial nucleus in maintaining or emerging from an anaes-
promoting, wake-active nuclei, there are few neural populations
thetic state. However, this has yet to be fully explored.
that are predominantly active during SWS or REM sleep with de-
Ventral Tegmental Area (VTA) creased activity during wakeful states. Neurons with sleep-active
A midbrain dopaminergic and GABAergic region associated with firing patterns are most commonly found in the preoptic area and
both arousal and reward, the VTA receives diverse inputs and has BF (though populations do exist elsewhere, including in the pons
widespread outputs, including the prefrontal cortex, cingulate and cortex.) These populations act as a network counterbalance to
gyrus, hippocampus, amygdala, and nucleus acumbens. Reflecting many of the arousal-promoting populations discussed previously.
those widespread connections, it is functionally diverse, with roles Just as there are many examples of anaesthetics depressing those
in motivation, cognition, and arousal (111). Dopaminergic neurons arousal centres, there is evidence for sleep-active neurons being
of the VTA do not appear to change their firing rate across sleep– directly and indirectly activated by certain anaesthetics.
wake. Consequently, VTA dopamine neurons have not been linked Preoptic Area: Ventrolateral Preoptic Nucleus (VLPO) and
to modulation of spontaneous arousal. Nevertheless, dopamin- Median Preoptic Nucleus (MnPO)
ergic neurons are suppressed by GABA, and other neurons within
In the earliest attempts to identify specific populations of sleep-
the VTA have circadian-dependent activity (112–116). Artificially
promoting neurons, a definitive role was assigned to the preoptic
driving dopamine release from the VTA, administration of methyl-
anterior hypothalamus. This broad region encompasses the VLPO,
phenidate, or more selective pharmacologic agents that act on D1-
which lies within the anterior hypothalamus on the ventral floor
like receptors, will all accelerate anaesthetic emergence, and can
at the level of the optic chiasm, as well as the MnPO, which strad-
even reverse anaesthesia produced by continuous administrations
dles the decussation of the anterior commissure. Neurons with
of propofol or isoflurane (117–120).
heightened activity during SWS are found throughout the preoptic
Tuberomamillary Nucleus (TMN) area, with the greatest concentration found in VLPO. Neurons of
The sole source for histamine in the CNS, the histaminergic neurons the VLPO are more active during SWS and REM sleep. Changes
of the TMN have widespread projection throughout the brain and in VLPO activity precede the changes in an organism’s behavioural
have activity tightly correlated with arousal state (121). Though state. Retrograde and anterograde labelling studies show the VLPO
centrally administered histamine causes potent arousal, and central is reciprocally interconnected with many wake-promoting nuclei,
H1 antagonists produce sedation, the role of the TMN in modifying including the histaminergic TMN, serotonergic RN, noradrenergic
general anaesthesia is circumscribed. Lesions of the TMN increase LC, and the cholinergic LDT and PPT, as well as the orexinergic
sensitivity to isoflurane-induced LoRR, but leave propofol, keta- neurons of the hypothalamus. VLPO neurons contain the inhibi-
mine, and barbiturate sensitivity unchanged (122). Cell-specific tory neurotransmitters GABA and galanin and are thus ideally
knockout of GABAA receptors in histaminergic cells likewise positioned to coordinate and reciprocally inhibit wake-active as-
produced no change in propofol hypnotic sensitivity. These phe- cending reticular activating nuclei.
nomena were observed despite the fact that histaminergic neurons The role of the preoptic area in promoting and modulating the
lacking GABAA receptors were resistant to hyperpolarization by anaesthetic state appears connected to its regulation of sleep and
propofol—strong evidence that histaminergic neurons are not crit- wake. Destructive lesions of VLPO cause long-lasting insomnia.
ical to induction or maintenance of propofol hypnosis (123). Bilateral lesions of the VLPO also cause a biphasic change in an-
aesthetic sensitivity that possibly relates to insomnia: at six days
Dorsal Raphe (DR) and Ventral Periaqueductal Gray (vPAG) post-destruction, animals showed resistance to isoflurane LoRR,
The serotonergic neurons of the raphe nuclei have diffuse pro- while 24 days post-lesion, subjects showed hypersensitivity to
jections throughout the brain and comprise the largest source of isoflurane LoRR. Such changes have been hypothesized to arise
9
due to accumulating sleep pressure as VLPO lesioned animals The central thalamus has long been known to be critical
fail to sleep (129, 130). Isoflurane directly depolarizes GABAergic to arousal, with small lesions of the area leading to gross dis-
neurons in VLPO. Acute resistance to isoflurane induction seen orders of consciousness (136). The anterior intralaminar nuclei,
following VLPO lesions suggests that in normal conditions, an- of which the central medial thalamus (CMT) is a part, receive
aesthetic activation of VLPO contributes to induction. Except for significant ascending cholinergic innervation from the BF and
ketamine, every other general anaesthetic appears to depolarize brainstem. Microinjection of nicotine into the CMT is suffi-
and recruit putative sleep-active VLPO neurons. The population cient to reverse continuous systemic sevoflurane anaesthesia in
of neurons throughout the preoptic area (including the VLPO, animal models. This effect is replicated with an infusion of anti-
MnPO, and surrounding area) that are active during recovery SWS bodies against potassium channels in the Kv1 family (41, 137).
(after sleep deprivation) significantly overlap with the population In slice recordings of neurons of the CMT, sevoflurane reduces
of neurons activated with systemic administration of hypnotic firing, which is, in turn, reversed by administration of a Kv1 in-
doses of dexmedetomidine. This reinforces earlier findings sug- hibitor (40). Activity of the CMT appears to be critical for both
gesting dexmedetomidine acts on native preoptic sleep circuits to sleep and anaesthesia, as changes in high-f requency oscillations
produce hypnosis (131, 132). that occur at both the onset of sleep and anaesthetic-induced
Similar to the VLPO, MnPO sleep- a ctive neurons are loss of consciousness occur first in the CMT, rapidly followed
GABAergic and fire more rapidly several seconds prior to sleep by cortical changes (68). More generally, thalamic inactiva-
onset. Although not as broadly activated by anaesthetics as the tion as measured by reduced blood flow has been associated
VLPO, some inhaled anaesthetics also appear to activate putative with anaesthetic-induced unconsciousness, although whether
sleep-active MnPO neurons (133). Microinjection of benzodi- this is causal or secondary to unconsciousness itself remains
azepines, propofol, and pentobarbital into the MnPO has been unclear (138).
shown to induce SWS (72, 134, 135). Due to the state-dependent
firing pattern of MnPO neurons, they have been assigned an im- Neocortex and Limbic Cortex
portant role in the initiation of sleep. The MnPO is known to send
The effects of anaesthetics are particularly heterogeneous across the
inhibitory projections to multiple arousal systems, including the
neocortex, in stark contrast to the largely antiquated ‘wet blanket’
orexinergic neurons in the hypothalamus, in a manner similar to
theory of anaesthetic action as a general neuronal depressant. The
the VLPO.
extent to which the primary sensory cortices are affected by many
Sleep-active Neurons of the Basal Forebrain and Parafacial general anaesthetics remains unclear. These primary processing
Zone (PZ) areas are still able to maintain normal or near-normal responses
While arousal-promoting neurons of the BF and pons are well es- to evoked potentials while longer-latency potentials are inhibited.
tablished and their effects on anaesthetic states detailed, it is only In contrast, the function of higher-order association cortices and
recently that sleep-active groups in these structures were identi- portions of the entorhinal cortex are markedly impaired by general
fied. Although they interact with arousal centres known to influ- anaesthetics. The mesial parietal cortex, the anterior and posterior
ence anaesthetic actions, the effects of these newly detailed groups cingulate cortices, and the precuneus are deactivated in sleep and
on the anaesthetic state and the effects of anaesthetics on their ac- anaesthesia, as measured indirectly by changes in cerebral blood
tion remain to be investigated. Parvalbumin-positive GABAergic flow (139–141). Given the variability of anaesthetic effect on in-
neurons of the BF are wake-active and strongly promote arousal, dividual cortical areas, hypnotic effects of anaesthetics may either
while another subset of GABAergic neurons expressing somato- prove to be a result of direct actions upon the cortex or could be a
statin in the BF comprise a sleep-active group. Somatostatin posi- result of network-level perturbations that include cortical and sub-
tive, GABAergic neurons of the BF exhibit specific increases in cortical interactions.
local unit activity during SWS. Optogenetic stimulation of these
neurons can induce SWS (103). The parafacial zone is a pontine re-
gion lateral to the seventh nerve containing SWS-active GABAergic Brain Networks and Anaesthesia
neurons. Those sleep-active, inhibitory neurons project directly The specific molecular target(s) of an anaesthetic may not yield
onto arousal-promoting glutamatergic neurons of the parabrachial immediate insight into mechanisms by which the drug pro-
nucleus, which, in turn, project to arousal-promoting neurons of duces unconsciousness. Complete understanding requires de-
the BF. Artificial stimulation of those PZ GABAergic neurons pro- tailed knowledge of drug effects on their molecular targets, as
duces SWS (108). Anaesthetic effects on the PZ and sleep-active well as how ensuing changes in the activity of neurons and glia
neurons of the BF await further study. affect local and distant circuits in addition to the global impact
on networks. The relevant actions of anaesthetics, and hence their
Thalamus common mechanism, may thus be their ultimate disruption of
The thalamus is a critical structure that plays at least three major network function-decreasing functional information integration.
roles in wakefulness and consciousness. First, in terms of levels of Understanding discrete effects of anaesthetics on receptors, indi-
consciousness, the thalamus is an important conduit for arousal vidual neurons, and brain nuclei are necessary but not sufficient
pathways from the brainstem. Second, in terms of the content of in isolation. To investigate anaesthetic disruption of network level
consciousness, it is a major relay station for sensory information en processes, large-scale brain activity studies employ functional
route to the cortex. Third, in terms of the organization of conscious magnetic resonance imaging (fMRI), positron emission tomog-
experience, the higher-order nuclei of the thalamus play a critical raphy (PET), magnetoencephalography (MEG), or high-density
role in facilitating corticocortical coherence and communication. electroencephalography (EEG).
01
Thalamocortical Network anaesthetic-induced unconsciousness. The parietal lobe con-

Thalamocortical networks are key to information integration, as tains multiple primary sensory cortices. Executive function
they gate ascending sensory information, ascending arousal signals, depends upon the frontal cortex. Consequently, effective com-
and modulate corticocortical relays. Disruption of the system illus- munication between the two regions is considered necessary for
trates the importance of this network, which results in disorders consciousness. It follows that disruption of that communication
of consciousness (136, 142). Shifting from cortically dominant to would serve to produce anaesthetic-induced unconsciousness
thalamus-dominant thalamocortical circuits during anaesthetic- (152, 153). However, rather than a simple complete breakdown
induced loss of consciousness corroborates a model of propofol of all frontal-parietal communication, anaesthetic-induced un-
hypnosis whereby GABAergic activation results in strengthened consciousness is associated with a specific disruption of feed-
thalamocortical connections and an intrinsic thalamically-driven back communication between the frontal and parietal cortices.
alpha (8–12 Hz) electrical rhythm (143, 144). Evidence from Thus, although there is effective information transfer from the
animal models that changes in thalamic rhythms slightly precede parietal cortex forward to the frontal cortex (feed-forward),
related cortical rhythms at the time of anaesthetic-induced loss reciprocal information transfer from the frontal cortex to the
of consciousness also lends credence to the theory of thalamus- parietal (feedback) is impaired with the onset of anaesthetic-
rhythm-driven thalamocortical loop as critical to anaesthetic hyp- induced unconsciousness (154). This pattern of feedback in-
nosis (68). Other animal models using field potentials within the hibition has proven remarkably robust over anaesthetics with
thalamus and cortical EEG show that ketamine/xylazine-induced varying molecular mechanisms of actions, from ketamine, to
loss of consciousness coincides with a shift in the dominant dir- volatile agents, to propofol (155). That this pattern of feedback
ection of information transfer from cortex-thalamus during con- or top-down processing is also impaired in vegetative states sug-
sciousness to thalamus-cortex (145). Counter to the argument of a gests that this could be a general process for unconsciousness
predominant thalamocortical disruption by anaesthetics, slice and (156, 157).
chronic in vivo recordings suggest that corticocortical connections
are preferentially disrupted by volatile anaesthetics, while thalamo- Global Distance Connectivity and Information
cortical connections remain intact (146), Integration Capacity
Evidence from functional connectivity studies of the thal- In addition to evidence that anaesthetics may exert their effects
amus and cortex, which rely on relative blood flow as measured through specific networks such as those mentioned previously,
via PET or fMRI, rather than the electrical measurements of EEG anaesthetic action on large-scale brain network organization and
and subcortical electrodes, do not demonstrate tight association generalized ability for information integration may be the source
of thalamus and cortex. Instead, their functional connectivity is of their unconsciousness-inducing effects. Analyses of whole-brain
eliminated with the onset of anaesthetic-induced unconsciousness, networks under general anaesthesia show increased local informa-
purportedly through a silencing of the thalamus (147). While this tion exchange but impaired longer distance communication (158).
loss of functional connectivity between the cortex and thalamus This change from global connectedness to a more local pattern oc-
was first described with isoflurane and halothane, a similar pattern curs for both volatile anaesthetics and propofol, and has been seen
was also described with dexmedetomidine-induced loss of con- in with the distinct measurement modalities of both EEG and fMRI
sciousness (148). Recent studies have further solidified the pattern (159). While not all analyses have specifically found an increase
of reduced thalamocortical connectivity using both ketamine and of ‘small-worldness’ of the networks (local over long-distance),
sevoflurane, making it a robust finding across multiple anaesthetic decreases in network efficiency are common, and therefore the
classes (149, 150). amount of information that could be transmitted and integrated
The difference in conclusions between methods using rela- by a network is diminished in the presence of a general anaesthetic
tive blood flow as a proxy for neural activity and those directly (160–163).
measuring electrical signatures of that activity may be a result of dif-
ferent temporal and spatial resolutions between the two strategies.
Simultaneous measures of EEG and fMRI during a slow propofol- Conclusions
induced loss of consciousness addressed this disparity, and dem- While primary anaesthetic pharmacologic effects necessarily
onstrated a distinct phenomenon: isolation of the thalamocortical occur at the molecular level, the diversity of both general an-
network from sensory input at the point of maximum slow-wave aesthetics’ molecular targets and their subsequent cellular-level
activity on EEG, and the emergence of a sensory-responsive primi- actions does not clearly translate into obvious behavioural com-
tive cortical network independent of the isolated thalamocortical monalities observed in vivo. Only at the level of neural circuits
network (151). The functional compartmentalization through thal- can we begin to appreciate the common effects among the diverse
amocortical isolation corresponds with the other EEG evidence, array of individual anaesthetic drugs. Distinguishing the prox-
suggesting emergence of thalamically driven rhythms during imate cause and secondary effects culminating in anaesthetic hyp-
anaesthetic-induced unconsciousness (143, 144). Only with func- nosis remains a significant challenge for the field. Identifying the
tional isolation would the dominant rhythm driver be thalamus ra- critical anaesthetic induced network adaptations in both cortical
ther than corticocortical connections. and subcortical circuits truly responsible for loss of consciousness
itself, as opposed to circuit level side effects of anaesthetic drug
Corticocortical Networks exposure, represents another significant challenge. Resolving
As sensory integration and processing are integral to awareness, these challenges will benefit both the field of anaesthesiology as
the disruption of these functions are a predicted hallmark for well as neuroscience.
1
Summary 6. Mascia M, Trudell JR, Harris AR. Specific binding sites for alcohols and
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◆ Anaesthetics act upon a variety of protein targets to exert their Academy of Sciences. 2000;97(16):9305–10.
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mechanisms of general anesthetic action. Trends in Pharmacological
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clude ligand-gated ion channels (examples: GABA and NMDA 8. Jenkins A, Greenblatt EP, Faulkner HJ, Bertaccini E, Light A, Lin
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9. Li, X, Pearce, RA. Effects of halothane on GABA(A) receptor
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their effects on single neurons of a given circuit. Neuroscience. 2000;20(3):899–907.
10. Bieda M, MacIver B. Major role for tonic GABAA conductances in
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2005;6(3):215–29.
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18. Ahrens J, Haeseler G, Leuwer M, Mohammadi B, Krampfl K, Dengler
Multiple-Choice Questions R, et al. 2,6 di-tert-butylphenol, a nonanesthetic propofol analog,
modulates alpha1beta glycine receptor function in a manner distinct
Q Interactive multiple-choice questions to test your knowledge from propofol. Anesthesia and Analgesia. 2004; 99(1):91–6.
on this chapter can be found in the online appendix at www. 19. Krasowski MD, Jenkins A, Flood P, Kung AY. General anesthetic
oxfordmedicine.com/otneuroanesthesiology. potencies of a series of propofol analogs correlate with potency
for potentiation of gamma-aminobutyric acid (GABA) current at
the GABAA receptor but not with lipid solubility. The Journal of
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61
7 1
CHAPTER 2
Intracranial Pressure
Harald Stefanits, Andrea Reinprecht,
and Klaus Ulrich Klein
Introduction and subarachnoidal spaces, rinsing metabolic compounds from the

central nervous system (CNS). It has been suggested that CSF has
This chapter on intracranial pressure (ICP) explains the following a ‘sink action’ by which metabolites produced in the brain during
topics: contents of the intracranial vault (brain parenchyma, cere- metabolic activity diffuse into CSF and thereby are removed from
brospinal fluid, arterial and venous blood), ICP waveforms, intra- the brain. Also, it has been suggested that CSF flow might be able
cranial elastance curve, intracranial hypertension, intracranial to cool the brain whenever it is needed. CSF plays an important
herniation syndromes, and monitoring of ICP. role in flushing cerebral metabolic toxins (e.g., beta amyloid) from
Alexander Monro (1733–1817) first described ICP in 1783. By the interstitial fluid. This process is increased during natural sleep
describing that brain tissue is nearly incompressible and sur- by opening extracellular channels controlled by glial cells allowing
rounded by non-expandable cranium, he suggested that intra- rapid influx of CSF into the brain.
cranial blood volume (IBV) remains constant. George Kellie Today, indications for monitoring of ICP include traumatic brain
(1720–1779) stated that intracranial fluid could not be added or injury, intracerebral haemorrhage, subarachnoid haemorrhage
removed without simultaneous equivalent replacement or displace- (SAH), hydrocephalus, malignant infarction, oedema, infection,
ment. Francois Magendie (1783–1855) first described the circula- and metabolic disorders (4). Measurement of ICP complements in-
tion of cerebrospinal fluid (CSF) flowing from the ventricles to the formation on cerebral perfusion pressure (CPP), cerebrovascular
spinal cord by discovering a small foramen in the roof of the fourth autoregulation, and compliance of the cerebrospinal system.
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 Contents of the Intracranial Vault (Brain
Lewis Weed endorsed the doctrine of Monro and Kellie by stating Parenchyma, CSF, Blood)
that with an intact cranium, the net sum of all intracranial vault
To understand the dynamics of ICP regulation, anatomical con-
volumes (brain tissue, blood, CSF volume) remains constant and
siderations have to be undertaken concerning the contents of the
that an increase in one component should cause a reduction in one
intracranial vault. The outlined anatomical landmarks are im-
or both of the other two components (1).
portant for the understanding of herniation syndromes and their
Investigation of CSF started in 1891, when Heinrich Quincke
clinical symptoms, since brainstem structures, cranial nerves, and
(1842–1922) published his studies on lumbar puncture and the
arterial vessels are located close to the intracranial bottleneck areas
chemical investigation of CSF. In the early twentieth century, re-
and edges. The skull is the brain’s bony (stiff) hull that has only
petitive lumbar CSF puncture was widely used as first clinical
one big outlet for the medulla oblongata: the foramen magnum. It
method to determine ICP. Later in 1960, the neurosurgeon pioneer
contains all relevant compartments, including the brain tissue, CSF
Nils Lundberg published a thesis that largely influenced ICP moni-
spaces, and arterial and venous vessels (Figure 2.1 and Table 2.1).
toring (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 cere- Parenchyma
brum: a) buoyancy: the mass of the brain is about 1400 grams, The brain parenchyma including the cranial nerves makes up about
although the net weight of the brain suspended in the CSF is 85% of total intracranial volume (ICV). The largest part of the
equivalent to a mass of 25 grams. Therefore, the brain exists brain is the cerebrum (or telencephalon) with its two hemispheres,
in neutral buoyancy, allowing the brain to maintain its density separated by a vertical (sagittal) diaphragm, the falx cerebri. It is
without being impaired by its own weight. According to philoso- situated on top of the ‘core of the brain’, which is considered to be
pher Rudolf Steiner (1861–1925), this exemption of the gravity the relay station for higher cognitive functions: the thalamus and
is essential for higher brain function; b) protection: CSF protects brainstem, parts of the diencephalon and mesencephalon, which
the brain to a certain extent against any impact; c) prevention of continues caudally to the pons and the medulla oblongata. Dorsally
brain ischaemia: CSF can be reduced to counteract brain oedema adjacent to the brainstem is the cerebellum, which is separated
when needed; d) chemical stability/cooling/clearing waste: CSF is from the cerebrum by an axial tent-like diaphragm, the tentorium
produced in the ventricles and circulates through the ventricular cerebelli. The tentorial notch allows the caudal continuation of the
81
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 re-
7
sorption are in a physiological balance. There are four major inner
CSF spaces, called the ventricles, which are connected to each other
1 and to the outer CSF space, i.e., the subarachnoid space. The lateral
ventricles extend from the frontal to the occipital and to the tem-
8
poral 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) path-
ways between inner and outer CSF spaces (Figure 2.2). Disorders of
3 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
4 9 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
5 or blood clotting after intraventricular haemorrhage (within few
2
hours) or chronically by congenital membranes or slowly growing
6 masses. Malresorption of CSF may occur as a consequence of high
CSF protein content, which can occur post-haemorrhage (degrad-
10 ation 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 hydro-
Figure 2.1 Schematic view of intracranial spaces and brain parenchyma.
(1) telecenphalon, (2) cerebellum, (3) diencephalon, (4) mesencephalon, (5) pons,
cephalus is a chronic CSF circulation disorder, leading to typical
(6) medulla, (7) falx, (8) lateral ventricles, (9) tentorium cerebelli, and (10) foramen clinical symptoms (Hakim-Trias), i.e., cognitive and gait disorders
magnum. as well as urinary incontinence (5, 6).
Blood
brainstem towards the foramen magnum. The cranial nerves III to The cerebral blood volume makes up 5% of the ICV, mainly con-
XII originate from the brainstem. The brain parenchyma has to be sisting of venous vessels. Cerebral blood flow (CBF) and associ-
considered a rather static volume that is easily adaptive to chronic ated cerebral blood volume (CBV) are regulated by mechanisms
compression up to a certain extent (in cases of slowly growing tu- influencing cerebral resistance (i.e., constriction or dilation of ves-
mours, such as meningiomas), but very sensitive to acute com- sels, static autoregulation) over time (dynamic autoregulation). The
pression such as intracranial bleeding. Volume expansion of the pressure reactivity index (PRx) is described as a correlation coef-
parenchyma might be caused by tumour, abscess, intracranial ficient between (e.g., ten-second average) ICP and mean arterial
haemorrhage (ICH), or oedema. The latter can be focal (e.g., in blood pressure (MAP) over a time window (e.g., five minutes). In
cases of tumour, bleeding, infection, stroke, venous stasis) or gen- severe brain injury patients, impaired autoregulation contributes to
eral (e.g., in SAH, global infarctions, traumatic brain injury, or as- unfavourable outcome. CPP is calculated as a difference between
sociated with systemic diseases). A natural atrophy of the brain can the MAP at head level and the ICP. The concept of the ‘optimal
be observed during ageing, which provides more buffer space for CPP’ should be followed, since values beyond the CPP level opti-
volume expansion in elderly people. mizing cerebral autoregulation are associated with fatal outcome or
increased disability. The optimal CPP is between 50 and 95 mmHg,
Cerebrospinal Fluid
but it is patient-and time-dependent, and thus needs continuous
The CSF space makes up 10% of the ICV, equalling a total of 120–200 monitoring. In cases of acutely elevated ICP, decreasing the IBV
ml. CSF is a low-protein, glucose-containing liquid that contains is a short-term strategy to decrease ICP. This can be achieved by
few cells, mostly lymphocytes (up to 4/µl). It is mainly produced 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.
Table 2.1 The contents of the cranial vault are divided into three
compartments. Proportions of intracranial volume are given in %.
Intracranial Compliance
Contents of the intracranial vault The pressure-volume relationship between ICP, ICV, and CPP
pressure is known as the Monro-Kellie doctrine, which states that
Brain parenchyma 85% i) the brain is enclosed in the non-expandable cranium; ii) brain
Cerebrospinal fluid 10% parenchyma is nearly incompressible; iii) the blood volume of the
Blood 5% intracranial vault is nearly constant; and iv) a continuous outflow of
venous blood from the intracranial vault is required to make room
9 1
Chapter 2 intracranial pressure 19
increased ICP include continued decrease in level of conscious-

ness (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 relation-
ship 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 de-
1 creases ICP, as the pressure gradient between CSF and the venous
2 blood system increases. Special procedures may increase ICP (e.g.,
3 Trendelenburg positioning).
Cerebral Perfusion Pressure

4 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 crystal-
loid 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 main-
tain 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),
Figure 2.2 Structures of the CSF space.
(1) foramen of Monroi, (2) aqueduct, (3) prepontine cistern/floor of the third
as CBF increases 2–6% per mmHg increase in PaCO2 levels. Also,
ventricle, and (4) outlet of the 4th ventricle/foramen Magendi. 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
for incoming arterial blood. Intracerebral compliance (CIC = ∆V/ and ranges from 45–50 ml/100g brain tissue/min. Cerebral perfusion
∆P) reflects the ability of the intracranial system to compensate and autoregulation may be disturbed in acute brain injury, poten-
for changes in volume (∆V) per unit change in pressure (∆P). tially causing an increase in CBV and ICP, thereby decreasing CPP
Intracerebral elastance (EIC = ∆P/∆V) is the inverse of compliance and causing subsequent brain injury. Normal CPP values range be-
(Figure 2.3). tween 70 and 90 mmHg. In neurosurgical care, the lower therapeutic
ICP is measured at the level of the foramen of Monro. The thresholds are between 50 and 70 mmHg in traumatic brain injury
normal value for ICP at rest is 10±5 mmHg for a supine adult. Mild and 80 mmHg and more in special cerebrovascular pathologies.
ICP elevation is defined as 16–20 mmHg, moderate ICP eleva-
tion 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 in-
ICP Waveform
creased ICP include decreased level of consciousness, confu- The ICP pulse wave is a dynamic, pulsatile waveform that shows
sion, restlessness, lethargy, cerebral and pupillary dysfunction, oscillating components at two different frequencies (cardiac and
deterioration of motor function, headache, personality changes, respiratory cycles, see Figure 2.3). Normally, patients show a low
and decreasing Glasgow Coma Scale score. Late clinical signs of and stable ICP (<20 mmHg) waveform that fluctuates in response
to MAP variations. Additionally, ICP may fluctuate in response
to daily activities such as exercise or coughing (increase up to
110 mmHg). The normal ICP waveform consists of three charac-
Box 2.1 Clinical Alert Signs Indicating Brainstem and Eloquent teristic upstrokes (P1–3). The first large peak P1 (percussion wave)
Cortical Area Herniation: Early Counteraction Required is generated by pulsations of major intracranial arteries and the
choroid plexus. The second smaller peak P2 (tidal wave) depends
◆ Headache upon the intracranial elastance. The third peak P3 (dicrotic wave)
◆ Neurological dysfunction is produced by aortic valve closure. ICP overall pulse wave can be
increased by expiration (increase in central venous pressure) and
◆ Ipsilateral dilation of pupil
decreased by inspiration (decrease in central venous pressure).
◆ Oculomotor paresis Changes in mean ICP (>20 mmHg), amplitude, and periodicity of
◆ Hemiparesis pulsatile components might indicate reduced intracranial elastance.
For example, increase in P1–3 amplitude might represent increased
◆ Contralateral dilation of pupil
CSF volume. In contrast, when a large volume of CSF is drained off,
◆ Pathological breathing or in the case of an incompletely closed skull after craniectomy, the
◆ Bradycardia, hypertension ICP waveform will decrease in amplitude. A prominent P1 wave
may occur when the systolic blood pressure is very high. A dimin-
Apnoea
◆
ished P1 wave might occur when the systolic blood pressure is too
02
(a) 14 P2
13
12
11
ICP (mmHg)
10
9 P1
8
7
6
5
4
3
0 50 100 150 200 250 300 350 400
Time (ms)
(b) 14
P2
13
12
11 P1
P3
ICP (mmHg)
10
Pressure
9
8
7
6
5
4
3
0 50 100 150 200 250 300 350 400
∆p Time (ms)
(c) 10 P1
9
ICP (mmHg)
8 P2
7 P3
6
5
∆p
4
3
∆V Volume ∆V 0 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. changes, for example, during intracerebral vasodilation or
A prominent P2 wave may occur when intracerebral compliance vasoconstriction.
has decreased (e.g., increasing ICP) or during inspiratory breath
hold. During hyperventilation, P2 and P3 waves might diminish. Lundberg A–C Waves
A rounded ICP waveform with reduced peaks from P1–3 might
occur when ICP is critically high. A number of pathological waves Lundberg A-waves (plateau waves) are clearly pathological and de-
have been described so far. Modern extended ICP pulse waveform fined as a sudden ICP increase up to 50–100 mmHg lasting 5–20
analysis (e.g., morphological clustering and analysis of ICP, or minutes (Figure 2.4). During A-waves, it is common to develop
MOCAIP) potentially may allow for detection of cerebrovascular clinical signs and symptoms of early herniation, including brady-
cardia and hypertension. Although the underlying mechanism
remains unknown, it has been postulated that CPP cannot meet
cerebral metabolic demand, thereby triggering cerebral vasodila-
Table 2.2 Typical ICP values during different activities and sleep tion and subsequent increase in CBV and ICP. This, in return,
in babies and adults. causes additional CPP decrease, ultimately resulting in a vicious
cycle. Atypical Lundberg A-waves do not exceed an elevation of
Activity Baby [mmHg] Adult [mmHg] 50 mmHg and are an early indicator of neurological deterioration.
Lying supine 6±1 10±5 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
Standing up –5±5 –5±5
postulated that B-waves might be caused by vasomotor centre
Non-REM-sleep 7±2 12±5 instability when CPP is unstable or at the lower limit of cerebro-
REM-sleep 19–22 15–25 vascular autoregulation. Lundberg C-waves are rapid sinusoidal
fluctuations of up to 20 mmHg of ICP lasting for 7–15 seconds
Coughing, sneezing 20–40 30–110
(about 0.1 Hz). These waves correspond to Mayer fluctuations in
1 2
Lundberg A waves
60
50
40
ICP (mmHg)
30
20
10
0
0 10 20 30 40 50 60 70 80
Time (min)
60 Lundberg B waves
50
ICP (mmHg)
40
30
20
10
0
0 10 20 30 40 50 60 70 80
Time (min)
60
Lundberg C waves
50
ICP (mmHg)
40
30
20
10
0
0 10 20 30 40 50 60 70 80
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 poten- in terms of mortality. When measured over time at different CPP
tially are caused by cardiovascular interactions. thresholds, PRx demonstrates a U-shaped curve, suggesting a spe-
cific relationship of individual autoregulation. This approach can
be used to tailor individual CPP management in order to optimize
Cerebrovascular Pressure Reactivity the patient’s autoregulation. As ABP and ICP routinely are meas-
CBF autoregulation describes the ability of the cerebral vasculature ured continuously in patients at risk, this index is readily available
to maintain a stable CBF despite fluctuations in CPP. With intact when using appropriate software. Notably, the underlying prin-
autoregulation, a rise in arterial blood pressure (ABP) produces ciple of PRx also works for cerebral variables other than the ICP,
cerebral vasoconstriction, a decrease in CBV, and a fall in ICP (7, such as cross-correlating MAP and CBF velocity determined by
8). A fall in ABP produces the opposite effects. With disturbed transcranial Doppler sonography (Mx) or regional frontal haemo-
autoregulation, a rise in ABP is transmitted to the intracranial com- globin oxygen saturation determined by near-infrared spectros-
partment and produces a rise in ICP as a passive pressure effect. copy (ORx, THx) ideally determined at high temporal resolution.
Cerebral autoregulation can be determined by investigating the
moving Pearson correlation coefficient between changes in ABP ICP Measurement
and ICP, i.e., PRx. In fact, waveforms of ABP and ICP are correl-
ated at higher temporal resolution. PRx is negative (e.g., between Intraventricular Catheters
0 and –1) when cerebral vessels are pressure reactive and aim to Direct measurement of ICP in the lateral ventricle is still con-
counteract changes in ABP. Instead, PRx is positive (e.g., between sidered the ‘gold standard’ for ICP measurement (Figure 2.5 and
0.3 and 1) when cerebral vessels are not pressure reactive and alter- Box 2.2) (9). The measurement is performed at the level of the me-
ations in MAP are mostly directly transmitted to ICP. PRx has been atus acusticus externus corresponding to the foramen of Monro.
identified as a predictor of outcome after traumatic brain injury Advantages of this measurement include the possibility of external
2
Figure 2.5 Intraventricular and intraparenchymal ICP measurement.
calibration and CSF drainage. However, placement of the catheter ventricular drain (EVD) or a lumbar drain (LD). The latter can only
may be difficult or even impossible in case of severe brain swelling be applied in communicating hydrocephalus, and an open passage
with collapsed ventricles. Furthermore, the risk of infection is re- through the aqueduct and the outlet of the fourth ventricle is man-
ported to be between 3.5% to more than 20% according to different datory, which can be estimated by radiologic imaging (i.e., to check
larger clinical studies. Many authors report an increase of infection for mass lesions and ventricular diameter gradients). Blockage of
risk with prolonged usage (10). In clinical practice it is important to CSF pathways could lead to transtentorial or transforaminal her-
be aware that ICP recordings are representative only with a closed niation (see Herniation Syndromes).
drainage system (4, 11, 12, 13, 14). In many cases, an external ventricular drainage is the first choice.
It can be implanted in a sterile surrounding at the intensive care
Intraparenchymal Probes unit (ICU) or in the operating theatre by a neurosurgeon and com-
ICP can be recorded by inserting a probe into the brain paren- bines draining of CSF with measurement of ICP. The EVD is a sili-
chyma. Usually, these probes are inserted in a non-eloquent brain cone catheter that is inserted into the lateral ventricle, usually by a
area, although the exact placement, especially in focal pathologies, frontal and rarely by an occipital or temporal approach, through a
is a matter of ongoing debate. Measurement of ICP is local and does burr hole and a small incision of the dura (15, see Table 2.3). The
not necessarily represent CSF pressure. The risk for parenchymal most common variant is a frontal burr hole over Kocher’s point,
bleeding or infection is <1%. Microtransducers cannot be recali- which is 1 cm anterior to the coronary suture and 3 cm lateral from
brated after insertion and drift from zero might occur during long- the midline (Figure 2.6). The target point is the entrance of the for-
term measurement. amen of Monro which is situated at the crossing of virtual lines
through the medial canthus of the eye (anterior-posterior) and the
Drainage of CSF external acoustic meatus (left-right). The EVD can be attached to
the bone via a bolt system or tunnelled subcutaneously. The ven-
In cases of acute hydrocephalus, drainage of CSF has to be per- tricular catheter is secured by suturing it to the skin, although it
formed promptly. This can be done by insertion of an external may also be connected to a second distal silicone catheter with a
‘Vienna connector’ to prevent accidental removal by the patient or
during nursing procedures. The CSF drainage system includes a
Box 2.2 Reasons for Performing ICP Monitoring drip chamber that is positioned according to the patient’s head, at a
certain level above reference points such as the radix nasi or the ex-
◆ Severe brain trauma (GCS 3–8) ternal acoustic meatus (point where the tip of the ventricular cath-
eter is estimated to be, i.e. the opening of the foramen of Monro).
◆ Severe subarachnoid haemorrhage (traumatic, vascular) The level of the drip chamber can be adjusted according to a re-
◆ Severe cerebral ischaemia sistance for the drained CSF target amount (principle of commu-
nicating vessels). It is typically placed between 0 and 15 cm above
Diagnostic
◆ (hydrocephalus, shunt insufficiency)
the reference points and adapted to ICP (normal values between
3 2
Table 2.3 Step-by-step guide for the implementation of an external

ventricular drain inserted into the lateral ventricle via a burr hole
over Kocher’s point (see Figure 2.5 for anatomical landmarks).
1 Define Kocher’s point (3 cm lateral from the midline, 1 cm

anterior from the coronary suture)
2 Define skin incision for drainage outlet
3 Shaving of the head
4 Washing with disinfectant, marking of Kocher’s point, drainage
outlet, and a 3 cm incision (in the course of a possible skin
incision if microsurgical operation is planned on this side) + sterile
draping
5 Skin incision, lifting of periosteum, insertion of a spreader,
coagulation with bipolar cautery
6 Burr hole
7 Coagulation of dura
8 Incision of dura (rather small to prevent CSF fistula)
9 Coagulation of superficial cortex
10 Placement of ventricular catheter (orthogonal to the bone,
target as described); depth measured on CCT scan before hands
(mostly 5.5–6 cm from dura; should be marked on catheter);
the ependymal lining is felt as a tactile resistance; the catheter is
only inside the ventricles when CSF is flowing (catheter end can
be placed as low as possible to enhance flow); CSF probes to
bacteriology and cell count
11 Temporary clamping of catheter (bulldog clamp) as close to the Figure 2.6 Axial view of the lateral ventricles in reference to the skull.
dura as possible—marks depth The vertical bar crosses the medial angle of the eye, the horizontal bar represents
a virtual connection of both external acoustic meatus—the crossing marks the
12 Incision at skin outlet target structure for the tip of the EVD, i.e., the Foramen of Monro. The arrow tip
points towards Kocher’s point marking the entry zone of the EVD. It is situated
13 Tunnelling of catheter (still clamped)
1 cm anterior to the coronal suture, 3 cm paramedian.
14 Testing of catheter function
15 Skin closure with subcutaneous and skin sutures (bulldog clamp
removed and placed at catheter end) plastic tube. The distal drainage system may be blocked by blood
16 Fixation of catheter on skin with connector remnants and can be changed under sterile conditions. The prox-
imal catheter may be tilted or clotted. Furthermore, attached valves
17 Connection of ‘Vienna connector’ system must be checked. Aspiration of CSF can be performed in order to
18 Tube connector mobilize blood clots from inside the silicone tube. Sterile condi-
19 Testing of catheter function tions have to be guaranteed, and the ‘no-touch technique’ should
be used during the procedure. All connectors should be cleaned
20 Connection to valve and distal collection system with disinfectant before attaching a syringe. Only syringes up to
21 Skin closure 2 ml of volume should be used in order to avoid excessive negative
pressure at the tip of the silicone catheter. Plexus choroideus, epen-
NB: ICP probes and EVD probes with bolt systems should be implanted as described by
the respective manufacturers. dyma, and brain tissue could be aspirated, leading to injury of brain
tissue or intraventricular haemorrhage. Aspiration of CSF should
only be performed by experienced team members. Knowledge of
0 and 20 mmHg), flow volume (10–25 ml/hour), and ventricular the width of the lateral ventricles is mandatory for this procedure. If
size. Lowering of the drip chamber below the level of the foramen of the ventricles are totally collapsed (slit ventricles) by CSF drainage
Monro (including dropping it) may lead to serious over-drainage of or cerebral oedema, aspiration is dangerous and should not be
CSF and, if unnoticed, may result in upwards transtentorial hernia- performed.
tion. The position of the ventricular catheter may be controlled by a Flushing of the silicone catheter is an even more invasive pro-
computed tomography (CT) scan. The EVD may stop draining CSF cedure and should be performed only by experienced team mem-
due to several reasons, all of which must be checked step by step in bers after careful consideration. The risk of introducing germs into
order to prevent malfunctioning and increase of ICP. The ICP may the ventricular system is very high when not performed under
be below the counter-pressure maintained by the level of the drip sterile conditions. All connectors have to be disinfected multiple
chamber. Functioning of the EVD can easily be checked by lowering times before attachment of a syringe filled with 0.9% sodium
the drip chamber for a few seconds, when the CSF should again chloride solution or artificial CSF. No more than 1–2 ml should be
start to drain and CSF pulsation can be seen inside the transparent injected into the silicone catheter. If all these procedures fail to start
42
the EVD functioning, a cranial computed tomography (CCT) scan compression of the oculomotor nerve. This complements to the
should be considered to check for ventricular size or dislocation stretching of the nerve over the clivus (due to downward shift of
of the ventricle catheter. The ICP should only be measured by the its origination), resulting in ipsilateral mydriasis at an early stage.
transducer when the distal drainage system is closed. A lumbar CSF This is an absolute alert sign—immediate lowering of ICP has to
drain is inserted intradurally under sterile conditions between ver- be achieved.
tebrae L4/5, L3/4, or L2/3. The level of L4/5 can easily be found by ◆ Subfalcine: Parts of the hemisphere inheriting the mass lesion
connecting the palpable rims of the anterior iliac crests. The drain may herniate below the falx cerebri, possibly compressing the
is also connected to a drip chamber and a distal drainage system. pericallosal and callosomarginal arteries, leading to brain in-
However, ICP measurement is not reliable. From both types of farcts of the medial frontal lobe (gyrus cinguli, gyrus frontalis
drainages, CSF should be analysed at regular intervals (e.g., every superior) down to the precuneus. On CCT, a midline shift can
second day). The following parameters may be evaluated (Table be seen (measured at the level of the septum pellucidum or the
2.4). Additionally, microbiological cultures should be performed pineal gland). Greater than 5 mm of midline shift may lead to
regularly. stupor, and greater than 9 mm to coma.
◆ Transtentorial: When the supratentorial ICP increases, structures
Herniation Syndromes shift further downwards, leading to transtentorial herniation. It is
There are different reasons for causes of impairment of conscious- a rather late, often terminal event, leading to direct compression of
ness in neurological and neurosurgical patients, and conscious- the brainstem. The oculomotor nuclei are damaged on the contra-
ness is dependent on the functioning of the ascending reticular lateral side, resulting in mydriasis and loss of light reaction of the
activating system (ARAS), a network of neurons with connections contralateral (in addition to the ipsilateral) pupil. Bilateral mydriasis
from the pons up to the cerebral cortex. The following three terms and decerebrate posturing (flexion of upper, extension of lower ex-
are often used to describe impairment of consciousness, but all tremities) are signs of a late phase of herniation. Furthermore, the
terms used should be complemented by detailed clinical descrip- posterior cerebral artery (PCA) is at risk—its compression leads to
tions of the patient. parietooccipital brain infarcts (visual impairments, blindness).
1) Somnolence is a sleep-like state that can be disrupted easily by ◆ Tonsillar: Raised pressure in the posterior fossa leads to her-
speaking to the patient. Wakefulness and awareness are im- niation of the cerebellar tonsils through the foramen magnum.
paired and attention cannot be sustained. Compression of the medulla oblongata leads to respiratory arrest
2) Stuporous patients may be roused only by strong stimuli, such and compression of the outflow of the fourth ventricle to acute
as pain. hydrocephalus.
3) Coma is characterized by a loss of consciousness with an Besides impairment of consciousness, other signs of increasing ICP
unarousable patient, even to strong stimuli. Motor responses have to be considered, such as headache, altered brain function
are possible. (sensory or motor deficits, speech impairment, cognitive dysfunc-
tion), seizures, and visual disturbances. Conservative measures
Different grading scales such as the Glasgow Coma Scale or the Full should be undertaken before aiming at surgical interventions (Box
Outline of Unresponsiveness score are used to describe these states 2.3). There should at least be a consideration of surgical intervention
in more detail. Increase of ICP leads to compression of the struc- for intracranial lesions with mass effect leading to clinical symp-
tures relevant for the ARAS by ‘herniation’ through the tentorial toms. Extra-axial and intra-axial tumours, intracranial bleedings
notch and the foramen magnum or the facial and tentorial edges: (especially epidural and subdural haematoma, but in some cases
◆ Uncal and Central: Unilateral, supratentorial mass lesions shift also intracerebral haemorrhage), as well as large abscesses often re-
the brain downwards and towards the contralateral side, leading quire surgical intervention. Mass lesions in the posterior fossa—
to compression of the diencephalon and the brainstem in the including intraparenchymal bleeds—have to be surgically treated
tentorial notch and at the tentorial edge, thus leading to im- when compression of the fourth ventricle is suspected or expected
pairment of consciousness. Also, temporal structures, especially due to swelling. In cases of strokes, conservative management
the uncus, herniate around the tentorial edge, leading to direct should be aimed at, except from large cerebellar strokes. However,
Table 2.4 The following parameters of the cerebrospinal fluid are important for the differential diagnosis of infection and haemorrhage.
CSF Compound Normal Values Pathological Changes

Cell count 1–4/µl up to 100s + activated lymphocytes = reactive (viral) meningitis; 1000s + neutrophil
granulocytes = bacterial meningitis.
Glucose >50% of serum glucose <50% of serum glucose = bacterial growth.
Protein <100 mg/dl High protein in tumours, bacterial meningitis, SAH.
Lactate <1–2 mmol/L High lactate in SAH or bacterial growth.
Cytology Few lymphocytes, monocytes Activated lymphocytes in viral meningitis; Neutrophil granulocytes in bacterial
meningitis; siderophages (12h to >3d), erythrophages (<12h to 3d) in SAH/IVH.
5 2
4. Le Roux P, Menon DK, Citerio G, Vespa P, Bader MK, Brophy G,

Box 2.3 Management of Increased ICP et al. The International Multidisciplinary Consensus Conference
on Multimodality Monitoring in Neurocritical Care: Evidentiary
In cases of increased ICP, it is vital to optimize parameters
tables: A statement for healthcare professionals from the Neurocritical
of ventilation, haemodynamics, sedation, and positioning. Care Society and the European Society of Intensive Care Medicine.
Additionally, both conservative and surgical therapy options Neurocritical Care. 2014;Suppl 2:S297–361.
should be considered. 5. Fishman RA. Cerebrospinal fluids in diseases of the nervous system.
Philadelphia, PA: Saunders; 1992.
◆ Optimization of PaCO2 (35 mmHg), PaO2 (120 mmHg), tem-
6. Rosenberg GA. Brain fluids and metabolism. Oxford: Oxford University
perature (<37.5°C/99.5°F), serum electrolytes (Sodium), pH. Press; 1990.
Drainage
◆ of CSF, check for 30° head up and optimal cranial 7. Kety SS, Shenkin HA, Schmidt CF. The effects of increased intracranial
venous outflow. pressure on cerebral circulatory functions in man. The Journal of
Clinical Investigation. 1948;27:493–9.
◆ Identify potential causes for increased ICP, consider CCT. 8. Kirkman MA, Smith M. Intracranial pressure monitoring, cerebral
◆ Consider volume and vasopressor in case of hypotension for perfusion pressure estimation, and ICP/CPP-guided therapy: A
standard of care or optional extra after brain injury? British Journal of
individual target CPP. Anaesthesia. 2014;112:35–46.
◆ Consider osmodiuretics (e.g., mannitol 20% 125–250 ml, 9. Narayan R, Kishore P, Becker DP, Ward JD, Enas GG, Greenber RP,
cave: plasma osmolality). et al. Intracranial pressure: To monitor or not to monitor? A review of
our experience with severe head injury. The Journal of Neurosurgery.
◆ Consider temporary (5–10 min) hyperventilation (e.g., PaCO2 1982;56:650–9.
30 mmHg). 10. Pfisterer W, Mühlbauer M, Czech T, Reinprecht A. Early diagnosis
of external ventricular drainage infection: Results of a prospective
◆ Consider neurosurgical therapy (e.g., decompressive
study. The Journal of Neurology, Neurosurgery & Psychiatry.
hemicraniectomy). 2003;74:929–32.
◆ Consider barbiturate coma (e.g., thiopental bolus 5–10 mg/ 11. Chesnut R, Videtta W, Vespa P, Le Roux P; Participants in
kg or 3–5 mg/kg/h) or mild hypothermia (e.g., 33–35°C/ the International Multidisciplinary Consensus Conference
on Multimodality Monitoring. Intracranial pressure
91.4–95°F).
monitoring: Fundamental considerations and rationale for monitoring.
Neurocritical Care. 2014;Suppl 2:S64–84.
12. Citerio G, Oddo M, Taccone FS. Recommendations for the use of
when brain shift increases, decompressive hemicraniectomy within multimodal monitoring in the neurointensive care unit. Current
48 hours after onset leads to favourable outcomes in patients Opinion in Critical Care. 2015;21:113–9.
13. Czosnyka M, Miller C; Participants in the International
younger than 60 years (adapted from 16).
Multidisciplinary Consensus Conference on Multimodality
Monitoring. Neurocritical Care. 2014;Suppl 2:S95–102.
References 14. Helbok R, Olson DM, Le Roux PD, Vespa Paul; Participants in
the International Multidisciplinary Consensus Conference on
1. Cushing H. The blood-pressure reaction of acute cerebral compression,
Multimodality Monitoring. Intracranial pressure and cerebral
illustrated by cases of intracranial hemorrhage. American Journal of
perfusion pressure monitoring in non-TBI Patients: Special
Medical Sciences. 1903;125:1017–45.
considerations. Neurocritical Care. 2014;Suppl 2:S85–94.
2. Lundberg NG. Continuous recording and control of ventricular
15. Marcus HJ, Wilson MH. Videos in clinical medicine. Insertion of
fluid pressure in neurosurgical practice. [Doctoral dissertation]
an intracranial-pressure monitor. New England Journal of Medicine.
Copenhagen: Ejnar Munksgaard; 1960.
2015;373:e25.
3. Lundberg N, Troupp H, Lorin H. Continuous recordings of the ventricular-
16. Koenig M. Cerebral herniation syndromes and intracranial hypertension.
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62
7 2
CHAPTER 3
Cerebral Physiology
Stefan Bittner, Kerstin Göbel, and Sven G. Meuth
Introduction produced compounds, such as hormones, and exogenously sup-

plied substances, such as pharmacological drugs or toxins. Thus,
The central nervous system (CNS; i.e. brain and spinal cord) is a small changes in its supply lead to severe metabolic consequences.
metabolically very active organ that requires a continuous supply
of energy. Adequate cerebral circulation to the brain, despite vari- Components and Function of the Neurovascular Unit
ations in its perfusion pressure, is essential for this continuous en- Several different mechanisms ensure the transport of oxygen and
ergy supply, as cerebral tissue is very intolerant of hypoxia, due to nutrients (see Other Mechanisms of Vascular Regulation) via the
its lack of substrate storage and high metabolic rate. Cessation of blood in an organized process. The cerebral demands are accom-
the cerebral circulation to the CNS for only a few minutes can pro- plished by a group of cells of both vascular and neural origin, called
duce permanent brain damage. the neurovascular unit (1). This concept was defined by Harder as
In addition, the cerebral blood flow (CBF) determines the cere- a structure that contains specialized endothelial cells, extracellular
bral blood volume (CBV) that is the result of cerebral arterial supply matrices, pericytes, basal laminae covered with smooth muscular
and venous drainage. The CBV, a major component of the intra- cells, neurons, interneurons, and astrocytes. All components are
cranial contents, plays an important role in determining the total linked to each other, thereby establishing a functional and anatom-
volume of the brain. As the cranium, at least in adults, resembles a ical whole that results in a highly efficient system of regulating trans-
closed hard case with limited compliance, the abnormal changes in port into the CNS and CBF. Each component of the neurovascular
intracranial contents, such as the cerebral tissue, cerebrospinal fluid unit seems to play a specific role. However, the precise role has not
(CSF), and CBV, manifest in the form of a proportionate change yet been fully established.
in intracranial pressure (ICP). Therefore, precise mechanisms pro- Knowledge of the structure of the neurovascular unit is funda-
viding stable CBF are needed to avoid cerebral damage, while mean mental to understanding some aspects of cerebral metabolism and
arterial blood pressure (MAP) and cerebral perfusion pressure blood flow, as well as the pathogenesis of several neurological dis-
(CPP) are changing. orders. This knowledge is also fundamental to the interpretation
However, even today, we only have a limited understanding of of investigation methods, such as positron emission tomography
how this mechanism works at the molecular level. This chapter re- (PET) and functional magnetic resonance imaging.
views the components and physiology of the blood-brain barrier As indicated, the neurovascular unit is organized by different
(BBB), the cerebral metabolism, and the CBF, with special emphasis structural components: endothelial cells of the BBB were long
on the mechanism of anaesthetic action on the cerebral blood ves- considered to be passive components (2). However, it is currently
sels and the CBF. known that specialized high-resistance tight junctions between
cerebral endothelial cells limit the paracellular movement of sub-
Anaesthetics and Their Effects on Cerebral stances into the CNS (see Figure 3.1). The main molecular compo-
nents of the tight junctions can be separated into two classes: the
Physiology: General Aspects integral transmembrane and the adaptor cytoplasmic proteins
Blood-brain Barrier and Blood-cerebrospinal Fluid linked to the actin cytoskeleton. Occludin and claudins are the
Barrier most important membrane components, and are proteins with four
transmembrane domains and two extracellular loops (3). Occludin
The ideal function of organs requires a constant interior milieu
is a phosphoprotein with a cytoplasmic domain associated with the
of the whole organism. However, as the CNS is the most complex
integral tight junction proteins, zona occludens (ZO). Claudins are
organ of the human body, this systemic regulation is not sufficient
responsible for the regulation of permeability. At present, more
for the delicate physiological functions, and needs a constant meta-
than 20 members of this group are known, claudin-3, -5, and -12
bolic supply. Therefore, a highly specialized barrier—the BBB—
are localized at the tight junctions of the BBB, while the presence
additionally protects these structures, thereby creating a particular
of claudin-1 in the endothelial cells is under discussion. ZO-1, first
interior milieu within the organism. The entrance of cells, elec-
identified as an associated cytoplasmic tight junction protein, is a
trolytes, proteins, and drugs exerting effects on CNS functions is
phosphoprotein which acts as a central organizer of the tight junc-
tightly regulated by the structure of the BBB, although the brain
tion complex and as a nuclear factor inducing gene expression.
consumes 20% of all metabolic reserves of the body and has a
Junctional adhesion molecules are present at the junctional level
limited capacity to store energy. This is true for both endogenously
and are involved in the formation and maintenance of the tight
82
might communicate with pericytes, as gap junctions, tight, and

adherens junctions connect them.
astrocyte In mid-to larger-sized vessels, the neurovascular unit also in-
volves mural vascular muscle cells (myocytes) that are, in addition,
pericyte recognized as main effectors of diameter changes. Two basal mem-
brain tissue
basal lamina
branes, the luminal and the abluminal membranes, enlace these
structures and must be passed by molecules and cells trying to
blood enter the CNS.
brain capillary
Due to the highly sophisticated function of neurons to detect
on very small variations in the supply of oxygen and nutrients to the
ur
ne CNS, neurons can be called the pacemaker of the neurovascular
astrocyte
unit, as they immediately transform these signals into chemical
and electrical messages to interneurons or astrocytes. Via this
mechanism, vascular tone, and consequently the blood supply to
the surrounding area, can be influenced. Astrocytes completely
surround blood vessels with their processes. However, these pro-
cesses are not relevant for barrier function. Furthermore, they have
long been considered to play only a passive and secondary role in
the neurovascular unit. However, in 1990, MacVicar and Newman
showed that these cells have a great capacity to propagate calcium
occludin
waves, thereby forming a specialized network of intercommunica-
tion (5). In addition, they are responsible for induction and main-
claudin tenance of endothelial barrier properties and the maintenance of
tight vascular tone.
JAMs
junction Astrocytes seem to be the most versatile cells of the neurovascular
cadherin unit, as they can communicate with both components of the blood
vessels and neurons via connections. This organization makes it
possible to propagate electrical messages over large distances and
to transmit these electrical messages to the pericytes and myocytes.
Figure 3.1 Neurovascular unit composition. This mechanism may lead to changes in the vascular tone, not only
Brain capillaries (endothelial cells and membranes) are completely surrounded by in adjacent areas, but also in more distant regions. The signal can be
pericyte and astrocyte processes. The interspace between the astrocyte processes modified according to neuronal activity, thereby indirectly causing
is larger than between the endothelial cells. Accordingly, the tight junctions vasodilatation or vasoconstriction. Anatomically, astrocytes com-
composed of different integral transmembral and adaptor cytoplasmic proteins municate via their end-feet, which are in contact with the surface of
(e.g., occludin, claudin) of the endothelial cells limit transport to the brain, but not
smooth muscular cells and pericytes, thereby acting as an efficient
the astrocyte processes.
and fast surface for the action of neuromodulators. Despite regu-
lating CBF, astrocytes can modulate tight junction proteins, such as
junctions. Adherens junctions are located below the tight junctions, occludin or ZO-1, thereby changing transendothelial permeability.
and participate in the control of paracellular permeability and sta- Furthermore, they can induce endothelial expression of different
bilize endothelial cell–cell interactions. transporters (discussed further later in this section).
Despite their barrier function, endothelial cells produce vaso- Nonetheless, to supply the CNS, respiratory gases and nutritive
active and trophic factors (see Local Blood Flow Regulation in the substances have to pass the BBB. For this purpose, the following
Brain) that are important for controlling the vascular tone. The two mechanisms are available: lipid-mediated free diffusion, and
extracellular matrix, an environment for the diffusion of ions, ad- carrier-or receptor-mediated transport.
enosine triphosphate (ATP), and neurotransmitters, might, at least As tight junctions largely prevent paracellular movement, an al-
theoretically, influence the interplay of these substances produced ternative pathway for substances is the direct passage through the
by the endothelial cells. endothelial cells themselves by lipid-mediated diffusion. Lipid sol-
Pericytes are rounded cells that are in close contact with the uble small molecules with a molecular weight of <400 Da can pass
endothelial cells and surround the abluminal surface. Similar to the endothelial plasma membrane, as these compounds fulfil the
other components of the neurovascular unit, this contact is not dual criteria: molecular weight <400 Da, and high lipid solubility,
only anatomical, but also functional, e.g., these cells participate in which is equivalent to low hydrogen bonding. Using this mech-
the maturation and development of endothelial cells and in the me- anism, endogenous and exogenous compounds can pass the BBB
tabolism of myocytes. For a long time, pericytes were described as by transcellular diffusion, as well as the respiratory gases oxygen
simple support cells; however, it is known today that these cells con- and carbon dioxide. Ions and small solutes diffuse by the para-
tract in response to ATP, are able to control the capillary diameter, cellular route. However, most nutritive substances are hydrophilic.
secrete growth factors, and influence endothelial stability through For example, D-glucose, the main substrate of cerebral metabolism,
matrix deposition (4). Pericytes synthesize molecular components is not lipid soluble, nor are distinct amino acids that cannot be pro-
of the basement membrane, including proteoglycans, which are duced by the brain. These substances pass the BBB with the help of
important to the BBB. It has been suggested that endothelial cells specific transport systems by a transcellular pathway.
9 2
Chapter 3 cerebral physiology 29
These mechanisms are necessary to regulate the cerebral intake principle. For an experimental assessment, non-physiological gas
of compounds very carefully. For example, the BBB glucose car- (e.g., nitrous oxide [N2O] or radioactive gas) is inhaled. Thereafter,
rier that also transports other hexoses, such as galactose, mannose, the absorbed amount of gas in the CNS and its concentration in the
or deoxyglucose, was identified as the glucose transporter type 1 arterial and cerebral venous blood is recorded. The arterial concen-
(GLUT-1). The density of GLUT-1 is higher at the abluminal side tration (Ca) of foreign gas can be measured in any artery. For meas-
than at the luminal side, thereby providing a homeostatic control urement of the brain venous concentration (Cv), blood is taken
of D-glucose influx to the CNS. The expression of GLUT-1 is con- from the jugular vein by puncture or catheter.
trolled by the hypoxia-inducible factor 1 alpha (HIF-1α) and can be
modulated by astrocytes.
CBF = volume / time
The BBB phenylalanine carrier that also transports other large
and, to a lesser extent, small neutral amino acids, has been shown = absorbed amount of indicator / time * (Ca − Cv )
to be the large neutral amino-acid transporter type 1 (LAT-1). The
BBB arginine carrier that also transports other cationic amino The brain is supplied with blood by the circle of Willis. Potential
acids (ornithine, lysine), was identified as the cationic amino-acid collateral pathways exist between the internal and external ca-
transporter type 1 (CAT-1). The BBB lactate carrier that also trans- rotid arteries via the meningeal and ophthalmic vessels. Although
ports other monocarboxylic acids (ketone bodies, acetoacetate, the brain is only 2% of the total body weight, CBF is about 50 ml/
β-hydroxybutyrate and pyruvate), is the monocarboxylic acid 100 g tissue per minute under physiological conditions, which re-
transport type 1 (MCT-1). The BBB adenosine carrier that also sembles 15% of the cardiac output, and is required to maintain a
transports the pyrimidine nucleoside uridine and other purine nu- blood flow of 700–900 ml/min. However, there are large regional
cleosides (inosine, guanosine) has been shown to be the concentra- differences overall. For example, values for blood flow in the white
tive nucleoside transporter type 2 (CNT-2). matter are about 20 ml/100 g tissue per minute, while in the grey
Different receptor-mediated carriers complement this system. matter, values from 80 to 140 ml/100 g tissue per minute are meas-
For example, both transferrin and insulin can be found in the brain, ured. As the CBF hardly ever fluctuates, a constant intracranial
but there is no mRNA in the CNS. Therefore, both substances are blood volume of 100–150 ml can be measured. This relatively con-
produced outside the CNS and are transported to brain by receptor- stant blood supply is perpetuated by the so-called autoregulation.
mediated carriers. This concept includes the cerebral ability to sustain a constant CBF,
These different transport systems allow a selective extraction of despite changes in the CPP. Autoregulation is present in many vas-
compounds from the blood into the brain. In addition, there are cular beds, but is particularly well-developed in the brain, likely
carriers available to transport compounds from the brain to the due to the need for a constant blood supply and water homeostasis.
blood to protect the CNS from potentially dangerous substances. In normotensive adults, the CBF remains constant, provided the
One of these classic active efflux transporters is P-glycoprotein, CPP is in the range of 60–160 mmHg, independent of the MAP
which is a product of the multidrug resistance gene (MDR-1), also and cardiac output. Therefore, autoregulation is the mechanism
named the ATP-binding cassette subfamily B member 1 (ABCB- that protects the CBF in physiological situations, such as exercise
1) and is located on both the luminal and abluminal endothelial and in pathological conditions, such as cardiogenic shock. Below
membranes, thereby mediating rapid removal of ingested toxic and above this limit, autoregulation is lost and the CBF becomes
lipophilic metabolites and reducing drug penetration into the brain dependent on the MAP in a linear fashion. When the CPP falls
(6). The expression and functional activity can be modulated by below the lower limit of autoregulation, reduction in the CBF is first
astrocytes and pericytes. Different enzymes expressed within the compensated by an increased oxygen extraction from the blood
BBB complement the active efflux transporter system. Both systems and, subsequently, cerebral ischaemia ensues. Pressures above the
are subject to modulation. upper limit may result in oedema, haemorrhage, seizures, and pos-
terior leukoencephalopathy. The normal autoregulatory curve may
Basics Principles of the Blood-cerebrospinal Fluid Barrier
be shifted towards higher pressures in chronically hypertensive
The CSF is mainly produced at the choroid plexus of the ventricles patients.
(about 500 ml per day), moves over the surface of the brain, and is The mechanisms of autoregulation in the CNS are not completely
constantly absorbed into the general circulation across the arach- understood and likely differ with increases versus decreases in pres-
noid villi into the superior sagittal sinus of the venous bloodstream, sure. The autoregulation mechanism starts within two seconds after
so that a constant volume of 120–160 ml is constantly present. changes in the CPP. Decreasing the CPP leads to a dilatation, while
In this way, a rapid equilibrium occurs between the CSF and increasing the CPP causes a constriction of the cerebral resistance
blood. Substances that should reach brain tissue from the CSF can vessels.
diffuse. However, the differential rates create a paradox that sub- The CBF is dependent on two dimensions: the CPP, and the cere-
stances injected into the CSF distribute easily to the blood and brovascular resistance (CVR). The CPP and CVR can be calculated:
poorly to the brain. Parts of the hypothalamus and pituitary use
this process, which allows the transfer of hormones produced in
the brain to the blood. CPP = MAP − ICP
Cerebral Blood Flow and Metabolism CVR = CPP / CBF
Global Cerebral Blood Flow and Metabolism A constant blood supply is sustained by an adaptation of the CVR
Oxygen consumption and substrate absorption of the CNS can be in relation to changes in the CPP. Moreover, the ICP is a critical de-
calculated using the Kety and Schmidt method, based on the Fick terminant of the CPP. As the ICP increases above 20 mmHg, focal
03
reductions in the CBF occur. The three major components of the Functional Analyses by Determination of Local Blood Flow and
intracranial cavity are the brain tissue, CSF, and CBV. If one compo- Metabolism Parameters
nent increases its volume, it must be compensated for by a decrease Blood flow and metabolism differ in individual brain structures, but
in another to prevent the ICP from increasing. are closely interconnected. For adaptation to alternating demand
Activity of the brain and CBF has a close correlation with cere- that is preset by changing metabolism, blood flow must be adjusted.
bral metabolism. If the cerebral concentrations of oxygen and This so-called hyperaemia is the mechanism by which microscopic
metabolic substrates are measured in the arterial and cerebral blood flow is regulated at a local level, ensuring that the delivery
venous blood, oxygen consumption and substrate utilization can of nutrients and oxygen fits the changes in activity at a local level.
be calculated: Local metabolism is dependent on the function of the respective
Cerebral metabolic oxygen consumption (CMRO2) or substrate brain structure (see Figure 3.2). The hyperaemia mechanism is ac-
utilization = CBF * (Ca − Cv) tivated, for example, in physiological situations: with increasing
The physiological oxygen consumption is about 3 ml/100 g visual strain, the metabolism in the visual cortex increases. As indi-
brain tissue per minute. Oxygen consumption differs per region cated, the neurovascular unit accomplishes the coupling of changes
with the highest values in the cortex. As the brain weight is about in the blood supply. The result of this metabolism augmentation is
1400 g, the cerebral energy requirement is about 15% of the total an increase in blood flow that can be measured more simply than
organism demand. With increasing oxygen demand, the CBF in- local metabolism.
creases, while oxygen difference in the arterial and venous blood Local Blood Flow Regulation in the Brain
remains constant. Different factors can influence cerebral me-
The connection of functional activity, metabolism, and blood flow
tabolism, e.g., body temperature. An increase in body tempera-
in the brain results from a release of functional and metabolic de-
ture of 1°C leads to an enhanced oxygen consumption of about
pendent factors from cells in the interstitial space, and is regulated
10–15%.
by the neurovascular unit. With the help of this mechanism, the
Glucose is the almost exclusive substrate of cerebral metabolism.
vessel tone can be regulated. An important function-dependent
Alternatively, ketones can be metabolized in cases of high plasma
factor is potassium that is released into the cerebral extracellular
concentrations. However, ketones can cover only half of the cere-
space after the generation of an action potential. Therefore, an in-
bral energy requirement. Under physiological conditions, an appre-
crease in interstitial potassium concentration is the result of en-
ciable amount of ketones is metabolized by the brain after several
hanced neuronal activity leading to an elevated cerebral blood flow.
days of fasting. Typical pathophysiological conditions include, for
Metabolic factors are hydrogen, lactate, prostaglandins (especially
example, diabetic ketoacidosis.
prostaglandin E), nitrogen monoxide, and adenosine. Generation
Local Cerebral Blood Flow and Local Cerebral Metabolism of these factors is augmented by a discrepancy between oxygen de-
mand and offer. An increased interstitial concentration of potas-
Method for Local Measurements
sium, hydrogen, lactate, and adenosine leads to a dilatation of the
As physiological and pathophysiological changes in the metabolic
cerebral vessels. While potassium allows a fast regulation, fine ad-
state rarely affect the whole brain, but only specific anatomical re-
justment occurs by metabolic factors (see Figure 3.3).
gions, local methods for taking measurements were developed to
These local factors act on the outer surface of cerebral vessels
register regional changes in the CBF and metabolism. A common
and regulate their tone. In the blood stream, they have almost no
method for taking measurements is the application of a radioactive
physiological influence, as the BBB of endothelial cells does not
indicator by inhalation or injection. Thereafter, the indicator’s con-
allow an extensive impact of circulating substances on the muscu-
centration is determined in the arterial blood and cerebral tissue
lature of vessels. Exempt are blood gases, especially carbon dioxide,
over time. For measurement in the brain, γ-detectors that detect
that can pass the BBB. Thus, an alteration of arterial carbon dioxide
tissue radiation are placed around the head. For measurement of
pressure (e.g., hyper-and hypoventilation) leads to a change of
the regional cerebral blood flow, well-diffusible indicators, such as
133Xe, are used. The accumulation of these indicators in the brain pH value in the CSF and in the interstitial fluid that surrounds the
cerebral vessels. Modification of pH value is the triggering factor
and their elution are dependent on the level of local CBF. Local
for a constriction (by a reduction in carbon dioxide [hypocapnia],
oxygen consumption can be measured with the help of 15O. For
interstitial alkalosis) or a dilatation (by an increase in carbon di-
measurement of regional glucose consumption, the glucose ana-
oxide [hypercapnia], interstitial acidosis, see also Figure 3.3).
logue 2-deoxyglucose that is labelled with 18F is commonly used.
Physiological oxygen partial pressures have no influence on blood
Brain cells absorb and phosphorylate 2-deoxyglucose, but cannot
flow. The blood flow only increases if the oxygen partial pressure is
further metabolize this substance. Subsequently, 2-deoxyglucose ac-
below 50 mmHg.
cumulates in the cerebral tissues over time, depending on its phos-
Nitrogen monoxide is produced by cerebral endothelial cells and
phorylation rate, which is similar to that of glucose. Accumulation
by different cells in the cerebral tissue, such as astrocytes, muscle
of radioactive tracers is higher in those brain regions with a high
cells, and specific neurons. In the brain, nitrogen monoxide mostly
cerebral metabolism than in areas with low rates. 15O and 18F are
leads to a basal dilatation of the vessels and strengthens the effect of
positron-emitting substances and can be detected by PET. This nu-
other vasoactive substances (see Figure 3.3).
clear medical method can detect disturbances in the local CBF and
metabolism and is the gold standard for the measurement of cere- Other Mechanisms of Vascular Regulation
bral perfusion and oxygen metabolism. However, due to its logistic, In the brain, an innervation of vessels is less important for blood
time and personnel consuming effort, the technique is challenging flow than in other organs. The sympathetic noradrenergic con-
to implement in routine diagnostics. For this purpose, the method stricting nerve fibres in the cerebral vessels are mostly activated
of choice remains computer tomography. during rising blood pressure. They reduce a pressure-induced
1 3
Glucose metabolism in the visual cortex
thalamus
visual
cortex
Visual changing checkerboard

white light
stimulus
Eyes
OPEN/CLOSED
60%
20% 23%
Glucose
8%
metabolism
Figure 3.2 Analyses of brain function via measurement of local blood flow.

Dependency of local cerebral metabolism on stimulus intensity: with increasing intensity and complexity of a visual stimulus, cerebral metabolism rises in the visual
cortex. The complex scene was the view of a quite busy park in New York.
increase in blood flow and tighten the BBB to decrease fluid in- nitric oxide. A direct relationship of endothelial cells with astrocytes
flux to the cerebral tissue. The importance of parasympathetic is also being researched. Vessel contraction or dilatation would
cholinergic dilating innervation is not yet completely understood. then depend on numerous factors, ranging from the intensity of
The same is true for the function of vasoactive peptides. However, neuronal stimulation, the intrinsic characteristics of the endothelial
signals not only influence endothelial cells and musculature of cell, pericyte, and muscle cells. It most likely also depends on the
cerebral vessels but also indirectly act on astrocytes, neurons, or area of the CNS in which the neurovascular unit is located. Among
pericytes. Under physiological conditions with an adequate supply all the factors that seem to be relevant in the regulation of brain
of nutrients and oxygen, myocytes and pericytes remain in a state hyperaemia, intra-astrocyte calcium concentration may play an im-
of basal contractility. This tone is the result of the balance between portant role that does not seem to be only regulated by neuronal
vasodilator and vasoconstrictor signals determined by neurons. In activity. Furthermore, calcium influx can also lead to vasoconstric-
these circumstances, the neuron is able to communicate with the tion or vasodilation in the same group in different neuronal situ-
astrocytes, either directly or indirectly, through interneurons after ations. This means that astrocytes are not only influenced on the
the release of glutamate. Figure 3.3 shows one example. Following metabolic pathway but also according to the neuronal information
the release of glutamate during synaptic transmission, postsynaptic and the surrounding environment, depending on several factors,
receptors are stimulated on both the downstream neurons and the such as neuropeptides, ATP, or nitric oxide. There is evidence that
astrocytic processes localized on synapses. Activation of these re- the bipolar response of vasoconstriction versus vasodilation is de-
ceptors on astrocytic processes increases the calcium concentration pendent on the bioavailability of nitric oxide that is not only pro-
in astrocytes, thereby causing a chain reaction. This gain induces a duced by endothelial cells, but also by neurons.
release of different vasoactive substances, such as prostaglandins, Apart from astrocytes, neurons can be stimulated by glutamate,
which are released by the astrocyte end-feet directly into the muscle which leads to a release of, for example, nitrogen monoxide and
cells or pericytes, resulting in cell contraction. In the process, in- adenosine, both known vasoactive factors. Furthermore, pericytes
creases in calcium concentrations can be dispersed in a wave-like can play an important part in the regulation of blood flow as they
manner in the astrocytes and reach other astrocytes via the gap can modulate the diameter of vessels by specialized proteins, such
junctions. Through this connection, vasoactive substances reach as actin.
other distant cerebral vessels. Vasoactive substances, such as pros-
taglandins, ATP, or nitrogen monoxide released by astrocytes can Age Dependency of Cerebral Blood Flow and Metabolism
lead to a dilatation and a constriction of the vessels. The cerebral metabolism and blood flow varies considerably from
Endothelial cells may also modulate the vascular tone, as birth to old age. In the first months of life, cerebral metabolism and
they produce both a number of vasoconstrictive agents, such as blood flow rise rapidly during the period of cerebral growth and de-
endothelin and thromboxane, and vasodilator substances, such as velopment and reach a maximal level at about the time maturation
23
Figure 3.3 Local mechanisms of blood pressure regulation in brain.

Oxygen (O2) and carbon dioxide (CO2) can freely diffuse across the blood-brain barrier. A reduced amount of O2 has a direct effect on vessel musculature and leads to
vasodilatation. Furthermore, O2 concentration acts on the release of vasoactive substances, such as adenosine, prostaglandin E (PGE, indirectly), or nitric oxide (NO).
The effect of carbon dioxide is stronger and contrary to oxygen. In this line, a high CO2 content leads to a reduction in pH value. This reduction leads to vasodilatation.
A further important factor is potassium (K+) that is released in the extracellular space during each action potential. An increase in K+ concentration in the extracellular
space also leads to vasodilatation. Vasoconstriction can be initiated by contrary processes (e.g., reduced CO2 concentration with an increase in pH value).
With increasing neuronal activity, these cells release glutamate to the neuronal synapse. Postsynaptic receptors of glial cells and neurons are stimulated in this process.
This leads to an increase in calcium (Ca2+) concentration in the astrocytes. This increase leads to activation of ion channels, especially K+ channels. Furthermore,
vasoactive substances are released. Neurons can release NO and adenosine.
is completed; values (per gram of cerebral tissue) are higher in neuronal tissue, and is therefore of utmost importance during an-
children than in adults. The rate of blood flow in different cerebral aesthetic procedures. Pharmacological modulation of the CBF can
structures peaks at different times, depending on the maturation be mediated either by a direct impact on the CNS blood vessels
rate of the particular area. The peak is reached during adolescence. or indirectly by modulating the cerebral metabolism or breathing
With increasing age, CBF and probably cerebral metabolism only frequency. As described previously, arterial O2 (PaO2) and CO2
decline to the levels characteristic of adulthood. CBF and oxygen (PaCO2) concentrations have important influences on the CBF.
consumption normally remain unchanged between young adult-
hood and older age, but can distinctly decrease if arteriosclerotic
changes in the cerebral vessels or neurodegenerative disorders de-
Table 3.1 Normal values for cerebral metabolism.
velop. As plasma concentrations of ketones increase in the elderly,
they can additionally be metabolized. The increase in ketones is
Parameter Normal Value
caused by reduced utilization of ketones by the skeletal muscula-
ture that decreases with age. Brain weight 1,400 g
ICP 10–15 mmHg
Effects of Anaesthetics on Cerebral Physiology
CBF 45–60 ml/100 g/min
Anaesthetics and other peri-operative drugs have important influ-
ences on brain physiology by modulating the CMRO2, CBF, or ICP CMRO2 3.0–3.8 ml/100 g/min
(see Table 3.1 for normal values) (7). A constant regulation of the CBF, cerebral blood flow; CMRO2, cerebral metabolic rate of oxygen consumption; ICP,
CBF levels ensures a constant delivery of glucose and oxygen to the intracranial pressure.
3
In physiological and mild hypoxic conditions, the CBF is largely treatment and pretreatment with benzodiazepines or slow injec-
independent of PaO2. However, these changes during significant tion rate might reduce the incidence of this side effect. The main
hypoxemic conditions, with PaO2 levels lower than 50 mmHg advantage of etomidate is a low occurrence of cardiovascular side
strongly increasing the CBF. In contrast, small elevations of PaCO2 effects (11).
levels already have a significant effect on the CBF. Changes in the
Ketamine
ICP by anaesthetics are the secondary result of changes in the CBF
or the production and resorption of CSF. In neuroanaesthesia, con- The effect of ketamine on the respiratory and circulatory systems
siderable emphasis is placed on the manner in which anaesthetic is different from that of other anaesthetics. When used at anaes-
agents and techniques influence the CBF. The importance of the thetic doses, it stimulates, rather than depresses, the circulatory
CBF is first based on the delivery of oxygen, glucose, and other en- system. Ketamine is a potent cerebral vasodilator that is capable
ergy substrates, and small alterations can have a major impact on of raising CBF values relatively independently from the systemic
neurological outcome under vulnerable conditions with impaired arterial blood pressure (see also Table 3.2). Ketamine has no major
BBB, e.g., after cerebral ischaemia. A high CBF promotes vasogenic influence on the CMRO2, and does not increase ICP as long as the
brain oedema under these conditions. Second, the CBF correlates patient’s PaCO2 is kept constant. Ketamine has an important role
directly with the ICP over a broad range of values (8, 9, 10). during anaesthesia and at intensive care units for the treatment of
ventilated patients as it reduces the need for catecholamines, opi-
Hypnotic Drugs (Barbiturates, Etomidate, and Propofol) oids, it produces airway relaxation, and supports bowel movement.
Application of barbiturates, etomidate, and propofol reduces Its mechanism of action is mainly by noncompetitive antagonism
both the cerebral metabolism and CMRO2 (see also Table 3.2). of NMDA receptors and potential neuroprotective effects of keta-
Due to a physiological coupling of the CBF and CMRO2, a sec- mine have been proposed.
ondary cerebral vasoconstriction and a reduction in the CBF oc-
curs. This effect can be monitored first by electroencephalogram Volatile Inhalation Anaesthetics
(EEG) measurements, which show initial burst suppressions, and Volatile inhalation anaesthetics (e.g., isoflurane, sevoflurane,
later on an isoelectric EEG. From a therapeutic point of view, a desflurane) are usually combined with intravenous analgesics (e.g.,
lower CBF correlates with reduced CBV, which can be used to opioids). Volatile inhalation anaesthetics result in a dose-dependent
reduce elevated ICP values. Therefore, these drugs display fa- decoupling of the CBF and CMRO2 (see also Table 3.2). The CBF
vourable characteristics during neurosurgery and in patients with increases due to direct cerebral vasodilation, which is paralleled by
traumatic brain injury. However, sufficient cranial perfusion has a decrease in the CMRO2. This decoupling is a unique feature of
to be warranted, especially in the case of propofol and barbitur- volatile inhalation anaesthetics as the CBF and CMRO2 normally
ates, as these substances lead to a direct vasodilatation in the per- show a direct correlation. The ICP can increase due to an increase
ipheral blood vessels and to systemic hypotension. Barbiturates, in the CBV. These effects barely occur at concentrations below a
etomidate, and propofol possess no analgesic effects and are often minimal alveolar concentration (MAC) of 1.0, especially in the
combined with analgesics. Propofol is often used for the induction case of sevoflurane. Furthermore, volatile inhalation anaesthetics
and maintenance of anaesthesia. Depending on premedication, interfere with cerebral autoregulation. Importantly, the sensitivity
dosage, and injection rate, it can cause respiratory depression and towards higher CO2 concentrations remains intact, which ensures
apnoea. Myoclonic events are often observed during etomidate safe use during anaesthetic procedures.
Table 3.2 Influences of anaesthetic drugs on cerebral physiology.
Substance CBF CMRO2 ICP Burst Suppression Autoregulation CO2 Regulation

Barbiturates ↓↓ ↓↓ ↓↓ ~5 mg/kg ↔ ↓
Etomidate ↓↓ ↓↓ ↓↓ ~0.2–0.3 mg/kg ↔ ↓
Propofol ↓↓ ↓↓ ↓↓ ~2 mg/kg ↔ ↓
Opioids ↔/↓ ↔/↓ ↔/↓ ↔ ↔
Benzodiazepine ↓ ↓ ↓
Ketamine ↑ ↔ ↑ ↓
N2O ↑ ↑ ↑ ↓ ↔
Halothane ↑↑ ↓ ↑↑ ↓ ↑
Desflurane ↑ ↓ ↑ ↓ ↑
Isoflurane ↔/↑ ↓↓ ↔/↑ 1.5–2.0 MAC ↔/↓ ↑
Sevoflurane ↔ ↓↓ ↔ 1.5–2.0 MAC ↔/↓ ↑
α2-agonists ↓ ↔ ↓ ↔ ↔
↓, reduction; ↓↓, strong reduction; ↑, increase; ↑↑, strong increase; ↔, no change.

CBF, cerebral blood flow; CMRO2, cerebral metabolic rate of oxygen consumption; ICP, intracranial pressure; MAC, minimal alveolar concentration;
43
Nitrous oxide (N2O) increases cerebral metabolism, CBF, and ICP. cerebral physiology. Continuous and sufficient supply of energy to
Therefore, its use should be avoided in patients with brain trauma the CNS is essential as cerebral tissue lacks substrate storage while
or those who have CNS disorders with impaired metabolic rates. being highly metabolically active. Therefore, an adequate and stable
CBF is needed to avoid permanent brain damage, while MAP and
Opioids
CPP are changing. Under physiological conditions CBF is about 50
Opioids are widely used in the practice of anaesthesia for ml/100 g brain tissue per minute. Oxygen consumption is 3 ml/100
preanaesthetic medication, systemic and spinal analgesia, supple- g per minute. Glucose is the almost exclusive substrate of cerebral
mentation of general anaesthetic agents, and as primary anaes- metabolism. Alternatively, ketones can be metabolized in cases of
thetic. Opioids have analgesic but no hypnotic effects. Opioids used high plasma concentrations. CBF is linked to local metabolism that
for anaesthesia (e.g., fentanyl, alfentanil, sufentanil, remifentanil) differs between brain regions. Local cerebral activity leads to in-
cause respiratory depression via reduced sensitivity of the respira- creased metabolism followed by enhanced CBF. Responsible mech-
tory centre towards CO2. Thereby, decreasing the CMRO2 and CBF anisms are not completely understood.
in a dose-dependent manner, these effects are less pronounced Anaesthetic agents cause reversible and dose-dependent effects
compared with other substances, such as barbiturates, etomidate, on cerebral physiology, including ICP, CBF, and CMRO2. These
or propofol (see also Table 3.2). Physiological regulation of the changes are clinically important to avoid unwarranted side effects.
CBF is maintained. A respiratory depression can be antagonized by
opioid antagonists (e.g., naloxone) or respiratory stimulants (e.g.,
doxapram). Remifentanil has the shortest half-life (3–4 min) and is Multiple-Choice Questions
especially suitable for total intravenous anaesthesia in combination Q Interactive multiple-choice questions to test your knowledge
with propofol. on this chapter can be found in the online appendix at www.
Benzodiazepines oxfordmedicine.com/otneuroanesthesiology.
Benzodiazepines (e.g., diazepam, flunitrazepam, clorazepat,
midazolam) enhance the effect of the neurotransmitter γ- References
aminobutyric acid (GABA) resulting in sedative, hypnotic, anxio- 1. Muoio V, Persson PB, Sendeski MM. The neurovascular unit—concept
lytic, and muscle relaxant properties. Benzodiazepines are well review. Acta Physiologica (Oxford). 2014;210(4):790–8.
known for their strong muscle-relaxing properties and can be 2. Ueno M. Molecular anatomy of the brain endothelial barrier: An
useful in the treatment of muscle spasms, e.g., in patients receiving overview of the distributional features. Current Medicinal Chemistry.
mechanical ventilation. However, a too-high dosage of benzodi- 2007;14(11):1199–206.
azepines may cause peripheral respiratory depression. They lead 3. Nico B, Ribatti D. Morphofunctional aspects of the blood-brain barrier.
to a minor reduction in the CMRO2 and CBV (less than barbitur- Current Drug Metabolism. 2012;13(1):50–60.
4. Fernandez-Klett F, Priller J. Diverse functions of pericytes in cerebral
ates, etomidate, and propofol; see also Table 3.2). Benzodiazepines
blood flow regulation and ischemia. The Journal of Cerebral Blood Flow
are effective as medication given a couple of hours before surgery & Metabolism. 2015;35(6):883–7.
to relieve anxiety. Importantly, they possess a clinically relevant 5. MacVicar BA, Newman EA. Astrocyte regulation of blood flow in the
antiepileptic effect. Benzodiazepine over-dosage can be antagon- brain. Cold Spring Harbor Perspectives in Biology. 2015;7(5).
ized by the antagonist flumazenil. 6. Chaves C, Shawahna R, Jacob A, Scherrmann JM, Decleves X.
Human ABC transporters at blood-CNS interfaces as determinants
Clonidine of CNS drug penetration. Current Pharmaceutical Design.
Apart from its use to treat hypertension, the α2-agonist clonidine 2014;20(10):1450–62.
has pleiotropic clinical indications, such as attention deficit hyper- 7. Bonhomme V, Boveroux P, Hans P, Brichant JF, Vanhaudenhuyse A,
activity disorder, anxiety disorders, and alcohol or opioid with- Boly M, et al. Influence of anesthesia on cerebral blood flow, cerebral
metabolic rate, and brain functional connectivity. Current Opinions in
drawal. Clonidine is also a mild sedative, and can be used as
Anaesthesiology. 2011;24(5):474–9.
premedication before surgery or procedures. It might also be con- 8. Thiel H, Roewer N. Anästhesiologische pharmakotherapie. 3rd ed.
sidered for analgesia, e.g., in combination with sufentanil. Clonidine Stuttgart: Thieme; 2014.
reduces the CBF without altering cerebral metabolism (8). 9. Liu PL. Anästhesiologie: Grundlagen und Verfahren. Urban &
Fischer; 1996.
10. Bause H, Kochs E, Scholz J. Duale Reihe Anästhesie.
Summary Teningen: Thieme; 2011.
This chapter summarizes the physiology of cerebral metabolism 11. Miller RD, Erikson LI, Fleisher L, Wiener-Kronish JP, Young LW.
and CBF with an emphasis on the effects of anaesthetic agents on Miller’s anesthesia. Philadelphia, PA: Elsevier 2014.
5 3
CHAPTER 4
Introduction
to Electroencephalography
Michael Avidan and Jamie Sleigh
Although Richard Caton was, in 1875, the first to note electrical ac- EEG montages are typically used, including two or four frontal elec-
tivity in the brains of monkeys and rabbits, it was Hans Berger who trodes (e.g., F7, Fp1, Fp2, and F4), plus a ground and reference elec-
first recorded electrical activity from human brains in 1924 using trode. With this limited montage, important topographical features
a string galvanometer (1). Electroencephalography has since been are not appreciated (e.g., the posterior rhythm and the anterior to
used clinically, especially for investigating seizures and disorders posterior gradient) and candidate measures of connectivity be-
of consciousness (2). In 1937, Gibbs, Gibbs, and Lennox proposed tween brain regions (e.g., frontal and parietal cortex) cannot be de-
that electroencephalography should be incorporated into routine termined. By limiting the EEG to frontal electrodes, it is impossible
anaesthetic practice (3), but only in recent years has increased to determine whether EEG features are generalized, lateralized, or
adoption occurred. multifocal. Nonetheless, much of the emphasis in this chapter is on
The electroencephalogram (EEG) provides a graphic represen- EEG features seen in frontal channels. This focus reflects typical
tation of differences in voltage between cerebral locations plotted current practice, especially in the operating room with various pro-
over time. As such, the EEG can be considered as a voltmeter for prietary EEG devices.
the cerebral cortex. The EEG has good temporal resolution, but
poor spatial resolution, reflecting electrical activity from only the
outer layer of cerebral cortical neurons. Spatial resolution may Waveforms in the EEG
be improved by increasing the number of electrodes used in the The composite waveform displayed by the EEG is typically com-
EEG. Unlike heart electrical activity, which is easily detected as it is plex, appears irregular, and reflects electrical activity originating
measured in millivolts on the chest wall, cortical electrical activity from the brain, from extra-cranial sources (e.g., eye movement, fa-
is measured in microvolts on the scalp. Therefore, substantial amp- cial muscles, heart activity) and from nearby electrical devices (e.g.,
lification is required to record EEG activity, which can frequently medical equipment, monitors). It is important to attempt to obtain
introduce artefact. The amplitude, phase, and frequency of elec- the ‘cleanest’ possible EEG signal (optimal signal-to-noise ratio)
trical activity vary over time and scalp location. by ensuring that the electrodes have minimal impedance (e.g., <5
Electrodes are placed at specific positions on the scalp, and a kilo-ohms) and by minimizing external sources of electrical inter-
channel consists of a pair of electrodes from which potential difference. Applying filters appropriately (e.g., high-pass filter set at
ference or voltage is measured. The montage refers to the inclusion 0.5 Hz and low-pass filter set at 35 Hz) to the signal also helps to
and order of channels in the EEG display. With bipolar montages, enhance the visual information provided by the EEG. A high-pass
channels are comprised of adjacent electrodes, where one serves as filter allows frequencies higher than the set value to pass and at-
the reference electrode. Bipolar montages are typically displayed ei- tenuates frequencies below the specified value. A low-pass filter is
ther longitudinally from the forehead to the occiput starting on the the opposite. However, over-zealous filtration (e.g., Bispectral Index
left side of the cranium and moving sequentially to the right side, Monitor® [Covidien, Boulder, CO] high-pass filter set at 2 Hz) can
or from the left side of the cranium to the right side (transverse) result in loss of valuable low frequency (e.g., between 0.5 and 2 Hz)
starting at the forehead and moving sequentially backwards to- visual information from the EEG display. Common mode rejec-
wards the occiput. With a referential montage, a common reference tion is another mechanism to decrease ‘noise’ whereby noise that
electrode is used for all the channels. By convention, electrodes is common to both the active and reference electrode is rejected.
placed on the right side of the cranium are assigned even numbers Any waveform, no matter how complex, can be deconstructed
and on the left, odd numbers. A descriptive region (e.g., Fp, frontal into sinusoidal components through the mathematical process of
pole; F, frontal; T, temporal; C, central; z [for zero], midline; A, aur- Fourier transform. The complex EEG waveform can therefore be
icular; P, parietal; O, occipital) further delineates the position of the conceptualized as a sum of a range of sinusoidal waves of various
electrodes. So, a right-sided electrode placed on the forehead above frequencies. By convention, different frequency bands have been as-
the eye would be designated Fp2, and a midline parietal electrode signed Greek letter labels (which are typically spelled out) as follows:
would be designated Pz. The inion (posteriorly), the nasion (anteri-
◆ (Slow [delta] waves, <1 Hz)
orly), and the auricular electrodes are frequently used for reference
(see Figure 4.1). In anaesthetic and intensive care practice, limited ◆ Delta, 1 to 4 Hz (or 0 to 4 Hz)
63
These frequency bands are not based on specific neurobiological

NASION properties and the definitions vary in different sources (5).
Fp1 Fp2
F7
F3 Fz F4
F8 EEG Changes with General Anaesthesia
EEG Changes and Neurobiology
There are common EEG patterns from frontal channels that are fre-
A1 T3 C3 Cz C4 T4 A2
quently seen during general anaesthesia and that can be readily ap-
preciated from the raw EEG waveform. With the onset of sedation
and with the progression to anaesthesia, the EEG waveform typic-
P3 Pz P4
T5 T6 ally becomes less complex, there is a shift from higher to lower fre-
quencies, and the voltage (or power) of the EEG tends to increase
O1 O2 (6). An underlying pattern of slow waves or delta waves (0.1 to 4
Hz) is a reassuring, albeit non-specific, correlate of adequate anaes-
INION
thetic depth with agents having gamma aminobutyric acid (GABA)
agonist activity (see Figure 4.2). These anaesthetic agents generate
Figure 4.1 EEG electrode placement using the international 10–20 system. slow oscillations at fixed frequencies, which might be drug specific
In the public domain. https://commons.wikimedia.org/wiki/File:21_electrodes_of_ and are typically less complex than the slow-wave rhythms that
International_10-20_system_for_EEG.svg. The right to use this work is granted to anyone for occur during natural sleep (7). Steriade and colleagues described
any purpose, without any conditions, unless such conditions are required by law.
very slow waves (<1 Hz) and (other faster) delta waves during gen-
eral anaesthesia (8). Coinciding with (or riding on) the slow waves
◆ Theta, 4 to 8 Hz or delta waves there are often low frequency beta waves (12 to 15
◆ Alpha, 8 to 12 Hz Hz) or alpha waves (8 to 12 Hz), which are similar in appearance
to sleep spindles (9). The coinciding or coupled (‘spindle’) waves
◆ (Sigma, 12 to 14 Hz; often the frequency band for sleep spindles
can also occur in the theta frequency band (4 to 8 Hz), especially
during physiological sleep)
with ether-derived inhaled agents (9). As anaesthesia deepens,
◆ Beta, 12 to 30 Hz (or 14 to 30 Hz) slow waves or delta waves take up an increasingly larger compo-
◆ Gamma, >30 Hz nent of the EEG signal.7 With very deep general anaesthesia burst
Wakeful EEG
100
EEG Blinks
Amplitude (µV)
–100
0 5 10 15
Drowsy EEG
100
Beta Delta
Amplitude (µV)
–100
15 20 25 30
Anesthesia EEG
100
Amplitude (µV)
Delta and some Spindles Delta
–100
30 35 40 45
Time(s)
Figure 4.2 Examples of typical frontal EEG waveforms seen during the course of induction of anaesthesia with propofol.
In the first 15 seconds the predominant rhythm is high frequency, low amplitude beta waves with sporadic very high amplitude deflections, reflecting voltage swings
induced by eyeball movements during blinking. During the next 15 seconds (15 to 30 sec), as the patient becomes unresponsive, high amplitude deflections from blinks
are no longer apparent, there is a shift to lower frequency beta activity (outlined oval), and then slower delta waves become visible (wide arrows). During the next 15
seconds (30 to 45 sec), the dominant rhythm shifts to a high amplitude delta rhythm (wide arrows) with some higher frequency waves/spindles (probably alpha waves)
‘riding’ (phase to amplitude/power coupled) predominantly on the peaks of the delta waves.
7 3
Chapter 4 introduction to electroencephalography 37
suppression occurs, which is characterized by periods of suppres- EEG pattern, which could either indicate a plane of deep surgical
sion lasting seconds to minutes, punctuated with bursts of high anaesthesia, or simply that the patient is in a state of natural sleep.
voltage electrical activity over a few seconds (10, 11). With even Both the GABAergic intravenous induction agents (barbiturates,
deeper anaesthesia, the EEG electrical activity becomes persistently benzodiazepines, propofol, etomidate, and neurosteroids) and
suppressed until the trace appears to be isoelectric (11). Burst sup- ether-or hydrocarbon-based volatile anaesthetic drugs (isoflurane,
pression and persistent suppression are not normal EEG patterns, sevoflurane, desflurane, and halothane) will directly or indirectly
and are not seen during sleep. Apart from deep general anaesthesia, induce thalamocortical hyperpolarization (so-called ‘down’ states)
these patterns may occur with brain pathology, hypoxic injury, in and thus produce a characteristic pattern as described previously
coma, and with severe hypothermia (10). (i.e., loss of high frequencies, increase in slow waves, and increase
During sleep and general anaesthesia there are probably syn- in total power in the EEG). However, because the various drugs
chronized events in billions of synaptically coupled neurons in have different spectra of molecular actions, there are some subtle
thalamocortical systems (12). The three key oscillatory patterns de- differences between the groups. For example, propofol will tend
scribed with sleep and general anaesthesia (slow-wave oscillations, to produce an EEG with more sharply defined alpha oscillations
delta waves, and spindles) are generated by the thalamocortical than is typical with volatile agents—which in turn induce a more
system acting as a complex network (13). Spindles are generated pronounced theta peak. Drugs such as sevoflurane and etomidate
within the thalamus and then spread to the cortex (13). The main have more of a tendency to induce seizures and will often dem-
elements implicated in the genesis of spindles are the GABAergic onstrate transient EEG signs of cortical irritability. Such signs in-
thalamic reticular neurons and the glutamatergic thalamocortical clude epileptiform spikes (large amplitude waves with a duration
neurons. Spindles result from repetitive spike bursts in thalamic re- of less than 70 msec) or even short, unifocal runs of epileptiform
ticular neurons that produce rhythmic inhibitory postsynaptic po- discharges (19).
tentials in thalamocortical neurons (13). Delta oscillations appear The other large class of general anaesthetic drugs are loosely
when thalamocortical neurons are at a more hyperpolarized level of termed as ‘NMDA blockers’, or ‘dissociative anaesthetics’, which
membrane potential than when spindles are generated (13). With include ketamine, nitrous oxide, xenon, and cyclopropane. These
the onset of sleep or general anaesthesia, thalamocortical neurons drugs have some modest hyperpolarizing actions and can induce
typically generate (sleep) spindles. These spindles migrate anteri- slow waves in the EEG. However, these effects are often outweighed
orly on the surface EEG, and become apparent in frontal channels by a dramatic increase in high-frequency activity that is probably
(14). With deepening sleep or anaesthesia, different thalamocor- driven by corticothalamic depolarization as a result of activation
tical neurons generate either spindles or delta waves, and the delta of aminergic and cholinergic systems in the brain. Consonant with
waves become progressively more prominent (13). Slow-wave this, these drugs typically tend to decrease narrow-band alpha os-
oscillations were thought to be generated exclusively in the neo- cillations. Thus, the effects of nitrous oxide and ketamine on com-
cortex, but have recently been found to have an essential thalamic mercial EEG depth of anaesthesia indices tend to be minimal, or
contribution (15, 16). A single functional thalamocortical network even paradoxical. Only xenon has been shown to induce enough
is likely to be essential for the generation of this key EEG rhythm slow-wave activity that commercial indices of depth of anaesthesia
of sleep and anaesthesia (15). When thalamocortical neurons are (discussed later) can be reasonably used with this agent. These
in a hyperpolarized state, transfer of sensory information relayed drugs also show some interesting, and completely unexplained,
from environmental stimuli via the ‘thalamic gate’ to the cortex EEG effects. For example, the sudden introduction or with-
is substantially curtailed (12), which is a key feature of general drawal of nitrous oxide causes a large transient increase in delta
anaesthesia (17). waves (20).
Biophysical modelling suggests that burst suppression is a con- The EEG effects of opioids are nuanced, complex, and under-
dition in which basic cell function is preserved during states of investigated. On the one hand, these drugs tend to suppress nox-
lowered metabolism, which would be consistent with all the aeti- ious input and cause a modest increase in slow waves when given
ologies of burst suppression (10). It has recently been found that alone in large enough dose to a wakeful patient. Conversely,
burst suppression is not necessarily a homogenous global phenom- their analgesic actions are mediated in part through endogenous
enon, and bursts can occur asynchronously across the cortex.11 aminergic analgesic systems, and thus opioids have been shown to
Furthermore, burst suppression can manifest in a limited cortical decrease EEG power when given, in the presence of GABAergic
region, while electrical activity in other areas has no suppression hypnotics such as propofol, to patients in the absence of painful
(11). Interestingly, intra-operative burst suppression has been stimuli (21). However, surgical stimulation commonly causes a de-
found to be independently associated with postoperative delirium crease in alpha oscillation during light anaesthesia. This is presum-
(18). Whether this merely reflects a patient’s underlying vulner- ably due to nociceptive input disrupting the thalamic bursting state.
ability as opposed to a causal link is currently unknown. Regardless Administration of opioids in this situation will restore the alpha os-
of whether or not EEG suppression is deleterious, it usually indi- cillation, presumably because the noxious input-induced depolar-
cates that general anaesthesia is unnecessarily deep. ization has been effectively blocked.
Usually the co-administration of other drugs alters the EEG
Effects with Different Drugs patterns only in very subtle ways. Drugs such as atropine,
While the effects of the commonly used anaesthetic drugs on the dexmedetomidine, clonidine, and antihistamines—which decrease
EEG are profound, these changes must always be interpreted in the the brain stem arousal neuromodulators—will tend to open potas-
context of the patient’s pre-operative condition, the presence or ab- sium channels by various mechanisms and bias towards thalamo-
sence of surgical stimulation, and the co-administration of other cortical hyperpolarization. This has the effect of augmenting slow
medications. An obvious example is the occurrence of a slow-wave waves in the EEG. Conversely, surgical stimulation, and drugs that
83
increase the arousal neuromodulators—such as catecholamines and in individual frequency bands, decreased alpha and theta spindles,
physostigmine—will tend to close potassium channels, increase decreased inter-hemispheric coherence, and increased propensity
cyclic-AMP, and cause thalamocortical depolarization, which shifts for epochs of burst suppression. Another key constraint is that an-
the EEG towards higher frequencies. aesthesia is usually administered in the context of surgery. It has
been observed that noxious stimuli can decrease theta and alpha
EEG Changes as a Function of Patients’ Age spindles, resulting in a paradoxical ‘delta arousal’ pattern on the
The EEG pattern evolves predictably through the course of a life- EEG (24). Conceptually, this reduction in spindles could reflect a
time. The neonatal EEG is very different to that of a mature brain decrease in thalamocortical hyperpolarization, which could theor-
(22, 23), but in essence, shows a much more episodic pattern that etically permit increased (noxious and other) sensory transmission
is reminiscent of burst suppression. This pattern has been termed via the thalamus to the cortex. The spindles often return following
‘tracé alternant’ and is seen predominantly in sleep and in pre- the administration of a potent opioid analgesic. However, this re-
maturity. Wakeful neonates will show irregular prominent delta sponse pattern cannot be relied upon since many patients, like
waves. Over the course of the first few years of life the EEG develops some elderly, do not reliably develop prominent spindles during
the features that will be seen as characteristic of the adult. In the general anaesthesia.
wakeful state, these include the establishment of the occipital alpha Although there are EEG changes that typically occur with in-
rhythm and significant beta power, and loss of delta predominance. creased anaesthetic concentration, the EEG does not change pre-
These changes reflect the developmental maturation, myelination, dictably in every patient, and a generalized concentration-response
and synaptic pruning in the central nervous system (CNS). Over characterization has so far proved elusive. It is unclear whether
this time the EEG, while under general anaesthesia, starts to look beyond loss of responsiveness, anaesthesia ‘deepens’ steadily, or
similar to that seen in the adult. However, pre-pubertal children still with punctuated, quantal shifts. Furthermore, even at unchanging
display a number of dramatic and special EEG features. Examples anaesthetic concentrations, the EEG might show important and
are ‘hypnagogic’ and ‘hypnopompic hypersynchrony’, in which apparently unpredictable changes (e.g., alternate between a delta-
runs of very high amplitude slow oscillations occur as a normal spindle pattern and a burst suppressed pattern). One approach that
part of drowsiness and transitions to and from consciousness. has been advocated is to titrate the anaesthetic until the EEG shows
The most prominent age-related change in the EEG after pu- a typical pattern of general anaesthesia, like a delta-spindle pattern
berty is a general decrease in amplitude that occurs progressively (see Figure 4.3), and then to slowly decrease the concentration. The
throughout life, and which is seen in wakefulness, sleep, and while theoretical problem with this approach is that there might often
under general anaesthesia. As an example, an anaesthetized 20- be hysteresis between induction and emergence concentration-
year-old patient would typically show a frontal delta power of about response curves, such that if a patient starts to show (phenotypic
25dB, whereas that of a 70-year-old patient would be around only or EEG) arousal, a substantial increase in anaesthetic concentra-
15dB. This probably reflects an age-related decrease in grey matter tion might be required to render the patient unresponsive. An even
volume and decreased cortical synchrony, which is associated with more pernicious approach than this is the recommendation to de-
decreased density of cortical connections. This decline in EEG crease anaesthetic administration solely on the basis of a reassuring
power has important clinical consequences, because the reduction processed EEG index without determining whether the index value
in absolute delta amplitude with age will influence the calculation is concordant or discordant with the raw EEG waveform (25). This
of depth of anaesthesia indices (as explained later). The EEGs of concern was highlighted by a recent study where awake volun-
the elderly during anaesthesia are also more variable and difficult teers received neuromuscular blocking agents (succinyl choline or
to interpret because of an increased incidence of co-existing neuro- rocuronium) without receiving any anaesthetic agents (26). Despite
logical disease. On the one hand, there are the drowsy patients with remaining lucid, BIS values decreased in these volunteers to num-
impaired arousal systems who show obvious delta waves even pre- bers purportedly indicating adequate ‘depth’ of anaesthesia for sur-
induction, and have extreme sensitivity to anaesthesia. At the other gery (26). The current generation of processed EEG indices should
extreme are the agitated patients with overactive arousal systems probably not be relied upon to fine-tune anaesthetic titration when
and who do not show a slow-wave EEG pattern, even during appar- neuromuscular blocking agents are administered.
ently adequate anaesthesia.
Special Concepts
Titration of Anaesthesia
There are challenges associated with titrating anaesthesia using the Power Spectrum, Spectral Edge Frequency,
EEG for guidance. The use of simplistic formulaic approaches or and Spectrogram
the uncritical application of processed EEG-derived indices might The Fourier transform can be useful to deconstruct any (complex)
lead to inadvertent errors with potential consequences to patients, EEG waveform signal into composite sine wave components at dif-
such as unintended intra-operative awareness. Some of the chal- ferent frequencies. The information yielded through this process
lenges flow from topics previously addressed. Modern general an- can be presented in different ways, and can be clinically applicable
aesthesia is seldom achieved with the administration of a single during general anaesthesia. One of the ways of presenting the data
class of anaesthetic agent, and the various combinations of drugs is to show what percentage of the EEG power resides in each of
are expected to have different effects on the EEG. As noted, the the frequency bands of interest (e.g., delta, theta, alpha, and beta).
EEG changes with anaesthetic agents are likely to differ according This information can also be depicted graphically with a power
to patients’ age and health status. For example, compared with their spectrum, with frequency on the x-axis and power in decibels on
young, healthy counterparts, older patients with cognitive im- the y-axis. From the power spectrum, various potentially inform-
pairment can be expected to have lower EEG power overall and ative frequencies can be appreciated, such as the median frequency,
9 3
Figure 4.3 Four electroencephalogram (EEG) waveforms from a single frontal EEG channel between Fp1 and F7.
Each waveform shows the EEG at a different sweep speed, from 6.25 mm/sec to 50 mm/sec. The slower speeds are useful for appreciating the low frequency underlying
delta rhythm over time (16 to 32 seconds), and the other waves (beta, alpha, and theta) can be discerned at the faster sweep speeds. Several features consistent with
general anaesthesia are present. There is a high-amplitude low-frequency (~1 Hz) underlying delta waveform (dotted sine wave) with alpha spindles (discrete arrows at ~9
Hz) visible ‘riding’ on the underlying delta rhythm. The alpha spindles are relatively continuous (as seen in the slower sweep speeds) and are more prominent at the peaks
than the troughs of the delta waves (i.e., there appears to be phase-amplitude coupling). This EEG waveform was obtained from a Bispectral Index monitor® with the
filters turned off (to reveal the underlying slow delta pattern).
the mode frequency, and the spectral edge frequency, which is the response with increasing concentrations of intravenous or inhaled
frequency below which typically 90% or 95% of the EEG power anaesthetic agents (28). Unfortunately, no particular threshold
resides. value of this biphasic spectral edge frequency pattern is reliable in
The spectral edge frequency is an easy-to-understand, non- predicting the point of loss of responsiveness (28). Nonetheless,
proprietary processed EEG index; if burst suppression is absent, spectral edge frequencies less than 14 Hz are frequently seen with
the spectral edge frequency tends to shift towards lower numbers adequate depth of general anaesthesia (6).
corresponding to a shift to higher power in lower frequencies as The spectrogram provides a useful graphical representation of
anaesthesia deepens (6). The 90% spectral edge frequency with a the information in the power spectrum over time (29). By using
threshold of 14 Hz has been shown to have reasonable utility in colour to depict the density of power within frequency bands, time
predicting (lack of) patient movement with both isoflurane and can be shown on the x-axis and frequency on the y-axis. With this
propofol anaesthesia (27). Although anaesthetists consider absence approach, the clinician can readily appreciate how the power in
of movement as an important goal in relation to general anaesthesia each frequency changes over the course of a general anaesthetic.
as it is necessary for surgery to proceed, it is not an ideal standard As such, the spectrogram provides a big picture overview of the
for evaluation of EEG-derived indices. While the absence of move- EEG trends over the course of a general anaesthetic (see Figure 4.4).
ment in response to a surgical stimulus has historically been a The spectrogram is especially useful in illustrating how different
useful end-point for comparing and calibrating volatile anaesthetic anaesthetic agents (e.g., propofol and volatile agents) have different
agents, it is mediated predominantly by spinal cord reflexes (as op- effects on the EEG during general anaesthesia, and the spectrogram
posed to by cortical function), and therefore EEG-based metrics are is also helpful in depicting how the EEG changes under general an-
not likely to be reliable in predicting (lack of) movement. The spec- aesthesia tend to change somewhat predictably (decrease in power
tral edge frequency (along with other EEG parameters) has been in all frequency bands, especially in the alpha band) with increasing
noted to have a biphasic (initial increase followed by a decrease) age (29).
04
40
Induction Surgery Emergence Waking
30
Frequency (Hz)
Diathermy
20
10 Alpha
Delta
0
3
CeVGA
Propofol
2
Fentanyl
Ce
0
0 16 32
Time (min)
Figure 4.4 Spectrogram of the EEG during a short anaesthetic and operation.

This image shows the loss of high frequencies and the development of a strong delta and alpha (spindle) pattern for the duration of surgical anaesthesia; and also
diathermy artifacts during surgery and electromyography (EMG) effects on waking. Dark denotes low power and pale denotes high power. The lower figure shows
the estimated effect-site concentrations (Ce) of the hypnotic and opioid drugs. The concentrations are µg/ml for propofol, ng/ml for fentanyl, and minimum alveolar
concentration (MAC) units for the volatile general anesthetic agent (CeVGA).
Cross Frequency Coupling and Coherence propofol concentrations (at transitions between wakefulness and
Important information is contained in the relationships among general anaesthesia), the alpha spindles have maximum amplitude
the component frequencies of the EEG, and between EEG wave- at the trough of the slow oscillations (30. 33).
forms from different brain regions. It is important to emphasize Inter-region coherence measures the phase consistency between
that, while spectral analysis provides clinically useful insights by pairs of signals in each frequency band in different brain regions
showing which frequencies dominate the EEG waveform, it does (e.g., thalamus and frontal cortex, frontal and parietal cortex, and
not reveal how the oscillations at different frequencies are related left and right frontal cortices). A coherogram provides a graphical
to one another (30). To illustrate this point, consider two cardiac representation over time (on the x-axis) of the coherence (depicted
arrhythmias. The first is atrial fibrillation with an irregular ven- in colour density) between regions of interest over a frequency
tricular rate of 60 per minute and an atrial rate of 300 per mi- range (typically between 0 and 30 Hz) on the y-axis (9). With both
nute; there is no fixed phase relationship between the atrial and propofol and volatile-based anaesthesia (e.g., sevoflurane), there
ventricular rates. The second rhythm is atrial flutter, now with is increased alpha frequency coherence between the left and right
a regular ventricular rate of 60 per minute, and an atrial rate of frontal cortices (9). With sevoflurane, there is also cross-cortical
300 per minute; the atrial and ventricular rates are now phase coherence in theta oscillations (9). In contrast, while there is an in-
coupled with a ratio of five atrial beats to every ventricular beat. crease in slow oscillations in the EEG waveform with propofol and
A power spectrum for both of these cardiac rhythms will show sevoflurane general anaesthesia, these 0.05 to 1 Hz oscillations do
a frequency spike at 1 Hz for the ventricular rate (one beat per not appear to become increasingly coherent across the cortex with
second) and 5 Hz for the atrial rate (five beats per second); it will general anaesthesia (9, 34) (see Figure 4.6).
not reveal whether these two frequency spikes are related or not.
EEG waves in different frequency bands (e.g., alpha and delta) Proprietary pEEG Indices
can be related to each other in different ways. Such relationships Over the last 20 years many proprietary indices of anaesthesia
include phase-phase, phase-amplitude/power, phase-f requency, have been developed, usually with the aim of concatenating the
power-power, and frequency-frequency (31) (see figure 4.5). rich variety of EEG patterns seen under general anaesthesia into
The bispectral index algorithm reportedly incorporates an ana- a single number (0–100) that indicates ‘depth of anaesthesia’. It is
lysis of cross-frequency phase coupling (the ‘SynchFastSlow’ sub- hoped that this index could be used to guide titration of anaes-
parameter) in the calculation of its proprietary index. However, thetic drugs and prevent intra-operative recall from underdosage,
studies that have examined this BIS parameter have found that or aberrant recovery from overdosage. These indices quantify the
cross-frequency coupling contributes negligibly to this measure shift to slow EEG frequencies that occur with GABAergic anaes-
(30, 32). Nonetheless, the theoretical additional informational thetic drugs. None of the indices have been well validated with
value provided by (phase-amplitude) cross frequency coupling be- non-GABAergic drugs, with the possible exception of xenon.
tween slow oscillations and alpha spindles has been demonstrated None of the indices reliably correlates with loss of behavioural
studying propofol anaesthesia (30). At higher propofol concentra- response (or consciousness). There are numerous counterexam-
tions (with deep general anaesthesia), the alpha spindles have max- ples of patients that are unresponsive in the presence of a high
imum amplitude at the crest of the slow oscillations, and at lower index value, and some who are responsive in the presence of a
1 4
(a)
(b)
Power to power
Y1
X–Y1
(c)
Phase to phase
Y2
X–Y2
(d)
Phase to power
Y3
X–Y3
(e)
Phase to frequency
Y4
X–Y4
(f)
Power to frequency
Y5
X–Y5
(g)
Frequency to frequency
Y6
Y5–Y6
Figure 4.5 Diagram of the various possible modes of cross-frequency coupling.

Reproduced from Frontiers In Computational Neuroscience, 7, 78, Jirsa V, Muller V., Cross-frequency coupling in real and virtual brain networks. Copyright © 2013 Jirsa and Müller. This is an open-
access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/3.0/), which permits use, distribution, and reproduction in other
forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics, etc.
low value. Most indices rely on pre-frontal EEG only; and are by comparing a large number of candidate classifiers of the EEG
significantly distorted by EMG activity. All the indices have signal with various patient states. The resultant index is a composite
been derived phenomenologically by statistical correlations be- weighted sum of three statistical estimators—the ‘Beta Ratio’, the
tween EEG pattern and anaesthetic drug dosage, or behaviour, ‘Synch-Fast-Slow’, and the ‘Suppression Ratio’. At light levels of an-
in varying populations of patients. It is unclear as to which is aesthesia or sedation, the Beta Ratio quantifies the relative loss of
the best index, because direct comparisons between the com- high frequencies and gain in alpha power. By excluding any con-
peting systems have only been done in relatively small numbers sideration of low frequencies at this point, the manufacturers made
of patients, and the results are ambiguous. Most seem to have a the index very resistant to blinks and eye movements, which makes
predictive accuracy of between 80–95%. Nevertheless, these first- the transition to loss of responsiveness clearer. At levels of anaes-
generation devices have achieved a significant advance by being thesia approaching surgical planes the Synch-Fast-Slow estimates
engineered to be simple to operate and robust to electrical noise, the relative increase in delta power. The manufacturers claim to use
thus getting the EEG out of the confines of the epileptologist and bispectral analysis to quantify this, although Hagihira et al. (35)
the sleep laboratory, and into the considerable rough and tumble have shown that accurate estimation of the bispectrum requires
of the operating room. many minutes of EEG data, and thus it is unclear whether the use
The predominant systems in present use include the Bispectral of the bispectrum on short data segments really is making a signifi-
Index (BIS, Covidien, Dublin, Ireland), the M-entropy (RE/SE cant contribution. At higher concentrations of anaesthetic drugs,
Datex Ohmeda, GE Healthcare, Madison, WI), the Patient State the burst suppression pattern predominates, which is captured
Index (PSI, SEDline, Masimo Corp, Irvine, CA), and the Narcotrend by the Suppression Ratio (the percentage of time that the EEG is
(Arbeitsgruppe Informatik/Biometrie der Anästhesieim Klinikum suppressed). These three indices are combined in a proprietary
Region Hannover OststadtHeidehaus, Hannover, Germany). The algorithm to give the index. The weights have been refined many
BIS was developed earliest and has been investigated most exten- times over the years, thus making direct comparisons somewhat
sively over more than two decades. The algorithm was derived problematic.
24
(a)
Wakeful: Spectrum General Anaesthesia: Spectrum
20 20
10 10
Power (dB)
0 0
–10 –10
–20 –20
0 10 20 30 40 0 10 20 30 40
Wakeful: Coherence General Anaesthesia: Coherence
0.8 0.8
0.6 0.6
Coherence
0.4 0.4
0.2 0.2
0 0
0 10 20 30 40 0 10 20 30 40
Frequency (Hz) Frequency (Hz)
(b)
(c)
Figure 4.6 (Continued)
3 4
(d) algorithms makes it difficult for the clinician to interpret, or en-

F3–P3 Coherence tirely trust, the index.
40
0.9
35 0.8 Entropy
The use of various entropy measures to quantify the EEG under
30 0.7
anaesthesia is based on the appealing concept that loss of con-
0.6 sciousness might be correlated with brain activity becoming more
Frequency (Hz)
25
constrained. Entropies are mathematical measures of the freedom
0.5
20 in a system, and, as applied to the EEG, are indicators of how pre-
0.4 dictably it evolves over time.
15 The main single-channel entropies that have been shown to
0.3
be usefully related to anaesthesia administration are the spec-
10 0.2 tral entropy, the approximate entropy (and its variant, the sample
0.1
entropy), and the permutation entropy. The spectral entropy
5
applies the Shannon entropy formula to the spectral content of
the EEG signal. In essence, a high entropy value indicates the
20 40 60 80
presence of equal amounts of many different frequencies in the
Time (sec)
signal and hence high complexity of brain processes; this is seen
Figure 4.6 (a) These line diagrams illustrate the typical shift in the power when the patient is awake. Under deep anaesthesia, the EEG fre-
spectrum that occurs with propofol or ether- derived volatile agent (e.g., quency spectrum is narrow, dominated by only a few frequencies
isoflurane, sevoflurane, desflurane) general anaesthesia. Of note, there is a (usually delta and alpha oscillations), and thus has a low entropy
shift to lower frequencies with a delta peak and a peak in the theta/ alpha value. The approximate entropy does not use the power spec-
range, reflecting spindles. The coherence pattern is different. There is no
trum to capture the dynamic evolution of the EEG signal, but
marked coherence band with wakefulness. With general anaesthesia, there
is often a peak in coherence across the cortex in the alpha band. (b) Frontal
instead statistically estimates how predictable the next point in
electroencephalograph (EEG) traces at 1 MAC sevoflurane anaesthesia. The the waveform is from a short series of previous points. Irregular
EEG waveforms show a slow undulating delta wave with persistent theta/ alpha signals have a high value of approximate entropy, and regular
spindles ‘riding on’ the delta waves. The alpha waves are largely coherent across signals have a low value. The permutation entropy first converts
the frontal cortex; the peaks of the alpha waves largely coincide in the two EEG the raw EEG signal into a series of symbols that represent the
traces. This is a bipolar montage with two channels: EEG1 is between Fp1 and F7, various shapes in the waveform, and then calculates the entropy
and EEG2 is between Fp2 and F4. (c) Frontal electroencephalogram (EEG) traces
of this train of symbols. It has the advantage that it is resistant
at 1 MAC sevoflurane anaesthesia. The EEG waveforms show a slow undulating
delta wave (dashed line) with persistent theta/ alpha spindles ‘riding on’ the delta
to low-frequency high-amplitude noise (but is sensitive to high-
waves. The delta waves are largely incoherent across the frontal cortex; the peaks frequency noise). Of all the non-proprietary measures, it most
of the delta waves largely do not coincide in the two EEG traces. This is a bipolar closely approximates the BIS. However, it does not adequately
montage with two channels: EEG1 is between Fp1 and F7, and EEG2 is between capture the transition to the burst suppression pattern in deep
Fp2 and F4. (d) This cohereogram illustrates strong coherence in the alpha band anaesthesia (36).
(approximately 12 Hz.) between left sided frontal (F3) and parietal (P3) cortical In recent years there has been a lot of interest in the application
regions following induction of anaesthesia with propofol.. of numerous variants of the entropy approach to the EEG under
anaesthesia. The reasoning has been that there are probably sev-
eral different processes synchronously active in the brain at any
The M-entropy uses the spectral entropy of the EEG. The basis for one time. Proposed methods include numerous multi-scale and
the calculation of this will be discussed in more detail in Entropy. multi-channel methods, and the application of Tsallis and Renyi
However, the commercial instantiation of this has some features entropies to various wavelet, Hilbert-Huang, and symbolic de-
that deserve comment. Firstly, the success of the algorithm is largely compositions of the EEG waveform. So far, none has really shown
due to undisclosed pre-processing that makes the commercial index significant improvement in performance over the simple first-
very resistant to artefacts, in particular, low frequency blinks and generation indices.
eye movements. Secondly, the M-entropy consists of two spectral
entropies calculated over different frequency ranges, the Response
Entropy (RE, 0–47 Hz), and the State Entropy (SE, 0–32 Hz). The gap EEG Measures of Connectivity
between the RE and the SE is an indicator of facial muscle activity In the last two decades it has become apparent that many brain
(i.e., grimacing), and has been proposed as an index of nociception. functions are dependent on long-distance communication across
The PSI has also gone through a number of modifications, and is widely separated brain regions. Therefore, pathological and
also a composite index incorporating undisclosed changes in dif- pharmacologically-induced dysfunction can be mediated and
ferent frequencies and inter-and intra-hemispheric coherence. Again, manifest at the level of the network. As applied to anaesthesia, there
its main advantage is that it displays the spectrogram (also termed is increasing experimental evidence that dynamic coordination be-
the density spectral array) of the EEG, which is a very powerful and tween widely separated parts of the brain is crucial for higher-order
underused tool for the visual appreciation of the effects of anaesthesia. functions, such as consciousness and memory; thus, the primary
The Narcotrend uses various multivariate pattern recognition action of anaesthetic drugs might be to limit this spread of informa-
methods, originally derived from sleep staging, to classify the depth tion, and so impair CNS responsiveness. Excitingly, recent studies
of anaesthesia. As with all these monitors, the hidden nature of the have indicated that impaired flow of information might indeed be
4
the common factor in the action of a wide range of different classes backbones, and hence, reduction in the richness of the brain’s
of anaesthetic drugs—and even other pathological causes of coma. repertoire of responses (37).
The brain is not a random structure, so the primary routes that
constrain connectivity are the anatomical white matter fibre struc- Artefacts
tures. However, functional connectivity between regions will also The amplitude of the EEG signal is small, typically up to fifty-fold
depend on the dynamic state of the brain in each region. For ex- smaller than the ECG and the EMG signals. Artefacts are there-
ample, if the brain region is very hyperpolarized, the likelihood of fore a major problem in all EEG work. The most common sources
incoming information causing activity is much less than if the target of artefacts are the muscle (EMG and ocular) activity, and the fact
region was depolarized, and therefore is much more responsive to that the electrode and cabling systems can act as aerials and thus
input. ‘Functional connectivity’ is usually estimated by looking for induce currents from surrounding electromagnetic fields. The pre-
statistical correlations between regions. However, there is no reason cise sources of the electromagnetic radiation are often not apparent,
that information has to flow symmetrically between two regions. but can arise from various electrical devices such as IV pumps,
Some analysis methods have been developed to detect the direction heaters, ventilators, and monitors. Physical movement of electrode
of information flow. These are based on the idea that if a second leads will also cause larger artefacts. The impact of these artefacts
distant signal improves the ability to predict the future evolution of is increased if the electrode impedance is high, or there is a large
a primary signal, then it must have causative influence on that pri- difference in impedance between the electrodes in the montage.
mary signal. The strength of these causal interactions is often termed Electromagnetic radiation-induced artefacts can be most reliably
‘effective connectivity’. Functional connectivity is usually estimated diagnosed by inspection of the EEG spectrogram. They typically
by detecting synchronous changes in regional brain activity, either show absolutely regular geometric (non-biological looking) pat-
from functional magnetic resonance imaging (with a time reso- terns, often with narrow frequency bands that are harmonics of the
lution of seconds), or from EEG/magnetoencephalography (with line frequency (50 or 60 Hz). They usually will have an abrupt onset
a very fast time resolution, but poor spatial resolution). The use of and offset. The main clinical significance is that the level of noise
direct cortical (ECoG) electrodes overcomes the spatial resolution may be sufficient to prevent the burst suppression algorithm from
issue, but obviously is very invasive, and is generally restricted to detecting a suppression segment, and thus failing to give warning
studies in epileptic patients. of a state of deep anaesthesia.
There is a plethora of different mathematical methods that EMG activity typically lies in a wide frequency band from about
have been employed to estimate connectivity from high-density 10 Hz to 300 Hz, but mainly above 30 Hz (38). If there is associated
EEG montages, and it is unclear at this time as to which method patient movement or eye movement, the EMG can extend down
is best. They can be broadly classified into simple undirected into the delta waveband. This overlap in frequencies between EMG
measures of coupling between regions (such as two-point cross- and EEG makes it very difficult, perhaps even impossible, to reliably
correlation and coherence), linear directed methods (such as separate out the two signals, and it has resulted in many examples
Granger Causality and Directed Phase Lag Index), and nonlinear of potentially dangerous distortions of the commercially available
methods (such as Symbolic Transfer Entropy, and generalized indices for depth of anaesthesia. In many ways it is important that
synchronization indices). With some interesting exceptions, all the clinician should not see the EMG activity necessarily as an arte-
these methods have shown that anaesthetic-induced loss of con- fact, but it is more accurate to see this activity as an informative
sciousness seems indeed to correlate with impaired frontoparietal ‘signal’—because increase in muscle tone usually is an indicator of
coordination. Recently there have been efforts to look in more inadequate delivery of anaesthesia or analgesia. The actual source
detail at how these disturbances in interactions might occur. The of the EMG is usually from the frontalis muscle, which is surpris-
tools required for this are various, more-complex indices of the ingly resistant to neuromuscular blockade. However, the source of
structure and topology of the network. These include measures the EMG signal can also be more distant, such as from temporalis
that are historically derived from graph theory, and aimed at muscle, or even submental muscles. The ECG can also be some-
capturing the changes in the underlying ‘road map’ of the brain times seen in the EEG, especially in patients with thick necks.
function. For example, the ‘path length’ is an indicator of global However, it is not usually a problem, as it doesn’t influence indices
integration (with an inverse relationship), and the ‘clustering covery strongly and has an obvious shape and timing, making it easy
efficient’ is an indicator of local segregation. It has been shown to diagnose.
that propofol significantly increases these measures, thus pro-
viding a specific description that propofol does not simply glo-
bally reduce connectivity, but instead acts in a relatively specific Future Directions
fashion to weaken hubs in the network (as seen by an increase The uses of EEG analysis in anaesthesia are still burgeoning and
in path length, or reduction in global efficiency), and strengthen the field has not yet reached maturity. From a scientific viewpoint,
local connectivity (as seen by an increased clustering co-efficient these techniques need to be explored as paths to reaching a detailed
and modularity). The effect of this is to lose the balance between neurobiological understanding of the mechanisms that underlie
local and distant organization of information. It is also possible consciousness and analgesia. This knowledge could then be trans-
to use less abstract averaging techniques, and break the network lated into clinical benefits. In particular, there is a need for the val-
up into specific ‘backbones’ that are the underlying building idation of better EEG indices that actually correspond reliably with
blocks of it structure. Again, it has been shown that general an- conscious state. It is likely that indices that capture the anaesthetic-
aesthesia is associated with a reduction in the diversity of these induced changes in brain connectivity will be the most successful.
5 4
However, the reported EEG effects are quite subtle and it remains to 15. Crunelli V, David F, Lorincz ML, Hughes S. The thalamocortical
be seen if they can be effectively translated into the operating room. network as a single slow wave-generating unit. Current Opinion in
The EEG of a particular patient is almost as unique as their face. Neurobiology. 2015;31:72–80.
16. David F, Schmiedt JT, Taylor HL, Orban G, Di Giovanni G, Uebele VN,
In the spirit of personalized medicine, it is important that any of
et al. Essential thalamic contribution to slow waves of natural sleep. The
these putative EEG indices can be individualized for each patient, Journal of Neuroscience. 2013;33(50):19599–610.
rather than relying on a heuristic statistical average. To be useful, 17. Herd MB, Lambert JJ, Belelli D. The general anaesthetic etomidate
these indices will also need to include contextual information about inhibits the excitability of mouse thalamocortical relay neurons by
the surgical stimulation and ongoing drug dosage and be able to modulating multiple modes of GABAA receptor-mediated inhibition.
provide predictive warning of impending change in cerebral state, The European Journal of Neuroscience. 2014;40(3):2487–501.
rather than simply responding to the change in state after the event. 18. Soehle M, Dittmann A, Ellerkmann RK, Baumgarten G, Putensen
C, Guenther U. Intraoperative burst suppression is associated with
Hand in hand with this would be the development of improved
postoperative delirium following cardiac surgery: A prospective,
hardware, which is easier to use (e.g., the so-called ‘dry’ electrodes), observational study. BMC Anesthesiology. 2015;15:61.
is more resistant to noise, and is able to achieve better spatial reso- 19. Constant I, Seeman R, Murat I. Sevoflurane and epileptiform EEG
lution by source localization. changes. Paediatric Anaesthesia. 2005;15(4):266–74.
20. Foster BL, Liley DT. Nitrous oxide paradoxically modulates slow
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7 4
CHAPTER 5
The Autonomic Nervous System

David B. Glick, Gerald Glick†, and Erica J. Stein
Introduction neurons have cell bodies within the horns of the spinal grey matter.
Preganglionic nerve fibres from these cell bodies exit the vertebral
In order to provide an optimal anaesthetic, a comprehensive back- column in the anterior nerve roots and enter the ganglion at their
ground understanding of the autonomic nervous system is im- respective level through the white (myelinated) ramus and then ex-
perative. The autonomic nervous system (ANS) controls the body’s tend to three types of ganglia: i) those grouped as paired sympa-
involuntary activities, and is essential as it oversees the body’s re- thetic chains, ii) various unpaired distal plexuses, and iii) terminal
sponses to life-threatening challenges and preserves the body’s vital or collateral ganglia near the target organ.
maintenance needs including cardiovascular, gastrointestinal, and The 22-paired ganglia form the sympathetic chain and lie along
thermal homeostasis. either side of the vertebral column. Nerve trunks formed by the pre-
The ANS is classically divided into two subsystems, the sym- ganglionic fibres connect these ganglia to one another. Grey rami
pathetic nervous system (SNS) and the parasympathetic ner- communicantes, formed by the postganglionic fibres exiting from
vous system (PNS). A third subsystem, the enteric nervous system each ganglion, connect the ganglia to the spinal nerves (Figure 5.1).
(ENS), has been added to the original characterization of the ANS. Sympathetic postganglionic fibres innervate the trunk and limbs
Activation of the SNS elicits what is traditionally called the ‘fight or via the spinal nerves. The sympathetic distribution to the head
flight’ response, including redistribution of blood flow away from and neck—enabling and mediating vasomotor, pupillodilator,
the viscera to skeletal muscle, augmented cardiac function, sweating, sudomotor (sweat gland) secretory, and pilomotor functions—
and pupillary dilatation. The PNS governs activities of the body more comes from the three ganglia of the cervical sympathetic chain.
closely associated with maintenance of function, such as digestive Preganglionic fibres of these cervical structures originate in the
and genitourinary functions. Disease states, as well as the normal upper thoracic segments. In 80% of people, the stellate ganglion is
stress response, may profoundly alter autonomic activity. As a conse- formed by the fusion of the inferior cervical ganglion with the first
quence, responses to surgery, anaesthesia, and medication adminis- thoracic ganglion. The postganglionic sympathetic fibres innerv-
tration may be unexpectedly difficult to manage. Therefore, the safe ating the terminal cardiac, oesophageal, and pulmonary plexuses
administration of anaesthesia requires recognition of how the ANS have their origins in the upper thoracic paravertebral sympathetic
normally functions and how disease states can affect this function, ganglia (Figure 5.2).
thereby avoiding responses or interactions that could produce dele- In contrast to the paravertebral ganglia, the unpaired prevertebral
terious effects. Additionally, the surgical stress response can have a ganglia (coeliac, superior mesenteric, aorticorenal, and inferior
wide range of negative consequences. It can affect endocrine function mesenteric) reside in the abdomen and pelvis anterior to the ver-
leading to hyperglycaemia and poor wound healing, inflammation tebral column. Their postganglionic fibres innervate the viscera of
leading to pain, water and electrolyte management causing impaired the abdomen and pelvis. (Figure 5.2)
renal function, and sympathetic excitation leading to cardiac compli- Ganglia of the third type, the terminal or collateral ganglia, are
cations. Therefore, selecting an appropriate anaesthetic that mitigates small, few in number, and near their target organs (e.g., the adrenal
the stress response can improve peri-operative outcomes. medulla). The adrenal medulla and other chromaffin tissue are hom-
ologous to sympathetic ganglia, all being derived embryonically
Functional Anatomy from neural crest cells. Unlike sympathetic postganglionic fibres,
Each branch of the ANS exhibits a unique anatomic motif that is re- the adrenal medulla releases not only norepinephrine (NE), but
capitulated on a cellular and molecular level. The underlying theme epinephrine as well. Pheochromocytomas are rare catecholamine-
of the SNS is an amplification response, whereas that of the PNS secreting tumours. These tumours occur in the adrenal medulla in
is a discrete and narrowly targeted response. The ENS is arranged a majority of cases; however, they can originate from chromaffin
nontopographically, as would be appropriate for the viscera, and re- cells anywhere in the SNS and have been found in the chest, ab-
lies on the mechanism of chemical coding to differentiate between domen, and pelvis.
nerves serving different functions. Sympathetic preganglionic fibres are relatively short because
sympathetic ganglia are generally close to the central nervous
Sympathetic Nervous System (Thoracolumbar) system (CNS), but they are distant from the effector organs; there-
The SNS originates from the spinal cord in the thoracolumbar re- fore, postganglionic fibres run a long course before innervating ef-
gion, from T1 through L2 or L3. The preganglionic sympathetic fector organs. Preganglionic sympathetic fibres may pass through
84
Cranial nerves-
From spinal cord, III, VII, IX, X
medulla, hypothalamus
Brainstem
Pre Post
Spinal nerves
Pre T1-L3 Cranial outflow
Post
To blood vessels, Viscus

sweat glands
Sympathetic ganglion
Sacral nerves
S2–S4
Gray ramus
communicans
Pre
White
RC
Sacral outflow
Viscus Collateral ganglion Post
Sympathetic division Parasympathetic division
Figure 5.1 Autonomic nervous system.

Pre, Preganglionic neuron; Post, postganglionic neuron; RC, ramus communicans.
Reprinted from Miller’s Anesthesia, Miller, R., Eriksson, L., Fleisher, L. et al. (eds), Chapter 5, The Autonomic Nervous System, Glick, D., p. 349. Copyright (2015) with permission from Elsevier.
multiple ganglia before synapsing, and their terminal fibres may colon. Most vagal fibres do not synapse until they arrive at small
contact large numbers of postganglionic neurons. Terminal fibres ganglia on and about the thoracic and abdominal viscera (Figure
of preganglionic axons may synapse with more than 20 ganglia, 5.2). Nerve roots from S2–S4 contribute the nervi erigentes, or
and, moreover, one cell may be supplied by several preganglionic pelvic splanchnic nerves. They synapse in terminal ganglia associ-
fibres. Sympathetic response, therefore, is not confined to the seg- ated with the rectum and genitourinary organs.
ment from which the stimulus originates, allowing an amplified,
diffuse discharge. Enteric Nervous System
Given the importance of clinical phenomena such as nausea,
Parasympathetic Nervous System (Craniosacral) vomiting, and alterations in bowel and bladder function asso-
The PNS arises from cranial nerves III, VII, IX, and X, as well as S2– ciated with anaesthesia, it is surprising how little is understood
S4. Unlike the SNS, the ganglia of the PNS are in close proximity to about the third branch of the ANS. The ENS is the system of
or within the innervated organ. This location of ganglia makes the neurons and their supporting cells found within the walls of the
PNS more targeted and less robust than the SNS (Figure 5.1). gastrointestinal tract, including the neurons within the pancreas
Preganglionic fibres of the PNS originate in three areas of the and gallbladder (1).
CNS: the midbrain, the medulla oblongata, and the sacral part of One major difference between the ENS and the sympathetic and
the spinal cord. Fibres arise in the Edinger-Westphal nucleus of parasympathetic branches of the ANS is its extraordinary degree
the oculomotor nerve course in the midbrain to synapse in the cil- of local autonomy. For example, digestion and peristalsis continue
iary ganglion, thereby innervating the smooth muscles of the iris after spinal cord transection or during spinal anaesthesia, although
and ciliary muscles. In the medulla oblongata lie parasympathetic sphincter function may be impaired.
components of the facial (lacrimatory nucleus), glossopharyngeal, Although functionally discrete, the gut is influenced by sympa-
and vagus (dorsal motor nucleus) nerves. The facial nerve gives off thetic and parasympathetic activity. The sympathetic pregangli-
parasympathetic fibres to the chorda tympani, which subsequently onic fibres from T8–L3 inhibit gut action via the coeliac, superior,
synapse in the ganglia of the submaxillary or sublingual glands and inferior mesenteric ganglia. A spinal or epidural anaesthetic
and the greater superficial petrosal nerve that synapses in the covering the midthoracic levels removes this inhibition, yielding a
sphenopalatine ganglion. The glossopharyngeal nerve synapses in contracted small intestine that may afford superior surgical con-
the optic ganglion. The postganglionic fibres innervate the mucous, ditions in combination with the profound muscle relaxation of a
salivary, and lacrimal glands; they also carry vasodilator fibres. spinal anaesthetic (2). The sphincters are relaxed, and peristalsis is
The vagus nerve transmits approximately 75% of the traffic of normally active.
the PNS. It supplies the heart, tracheobronchial tree, liver, spleen, Conversely, if the contents of the upper intestine become overly
kidney, and the entire gastrointestinal tract except for the distal acidic or hypertonic, an adrenergically mediated enterogastric
9 4
Chapter 5 autonomic nervous system 49
Parasympathetic Sympathetic
innervation innervation
Pons
Eye
III
(radial muscle, iris)
Medulla
Eye Salivary gland
(circular muscles,
iris) Superior Blood vessels,
Cervical
VII Middle (head and neck)
Lacrimal glands ganglion
Inferior
Cervical
Salivary glands IX
Heart
X
Cardioaccelerator
nerve
Heart Respiratory
tract
Respiratory
Paravertebral sympathetic ganglion chain

tract Blood vessels
(trunk)
Thoracic
Sweat glands
Stomach Stomach
Splanchnic
nerve Liver
Small intestine
Spleen
Proximal Small intestine

colon
Adrenal gland
Celiac
ganglion Colon
Kidneys Rectum
Lumbar
Superior
Ureters mesenteric Kidneys
ganglion
Bladder
Distal colon Inferior Bladder

mesenteric
ganglion
Rectum
Genitals
Sacral
Genitals Hypogastric Blood vessels

Pelvic nerve lower
nerve extremities
Spinal cord
Figure 5.2 Schema of the autonomic nervous system depicting the innervation of peripheral effector organs and the anatomic origin of peripheral autonomic nerves
from the spinal cord. The roman numerals on nerves originating in the tectal region of the brainstem refer to the cranial nerves that provide parasympathetic outflow to
the effector organs of the head, neck, and trunk.
Reprinted from Miller’s Anesthesia, Miller, R., Eriksson, L., Fleisher, L., et al. (eds), Chapter 5, The Autonomic Nervous System, Glick, D., p. 349. Copyright (2015) with permission from Elsevier.
reflex may be induced that reduces the rate of gastric emptying. In Loss of parasympathetic nervous control usually decreases bowel
the unstimulated state the adrenergic neurons of the gastrointes- tone and peristalsis, but over time, the increased activity of the en-
tinal tract are usually inactive. Reflex pathways, both within and teric plexus compensates for the loss. Spinal cord lesions may re-
external to the alimentary tract, cause discharge of these neurons. move sacral parasympathetic input, but cranial parasympathetics
Thus, during abdominal surgery, when the viscera are handled, may still be carried by branches of the vagus nerve to the end-organ
reflex firing of the adrenergic nerves may inhibit the motor ac- ganglia. As a result, colonic dilation and faecal impaction (which
tivity of the intestine for an extended period and thereby produce may precipitate hypertension in autonomic hyper-reflexia) may
postoperative ileus. occur, while small intestinal dysfunction is less common.
05
Unlike the SNS and the PNS, in which geographic location con- Table 5.1 Neuropeptides and their actions.
fers selective action, in the gut an alternative pattern of chemical
coding, through a combination of amines and peptides, assumes an Peptide Action(s)
important organizational role.
Bombesin Multiple stimulatory effects (ind, gastrin
Acetylcholine is the principal excitatory trigger of the release)
nonsphincteric portion of the ENS, causing muscle contraction.
Cholinergic neurons have several roles in the ENS, including Calcitaonin gene-related peptide Gastric acid secretion, muscle constriction
excitation of external muscle, activation of motor neurons aug- CCK8 Unknown
menting water and electrolyte secretion, and stimulation of gas- Dynorphin Opiate effects
tric cells. Neural control of gastrointestinal motility is mediated
through two types of motor neurons: excitatory and inhibitory. Endothelin-1 Vasoconstriction
These neurons act in concert on the circular smooth muscle layer Galanin Muscle constriction
in sphincteric and nonsphincteric regions throughout the di- Leu-enkephalin Opiate effects
gestive tract, and they supply the muscles of the biliary tree and
the muscularis mucosae. Although excitatory motor neurons Neuromedin U Muscle constriction, vasoconstriction
supply the external longitudinal muscle, the role of inhibitory Neuropeptide Y Vasoconstriction
motor neurons is not well established in this muscular layer. Pituitary adenylate cyclase Adenylate cyclase activation
Enteric motor neurons to the circular muscle of the small and activating peptide
large intestine are activated by local reflex pathways contained
Peptide histidine methionine Muscle relaxation, secretion
within the wall of the intestine. Distention evokes polarized re-
flexes, including contraction proximally and relaxation distally, Somatostatin Multiple inhibitory effects (ind. Gastrin
which in synchrony constitute peristalsis. Nicotinic antagonists inhibition)
abolish enteric reflexes, suggesting that the sensory neurons or Substance P Vasodilation, muscle constriction
interneurons in the pathway are cholinergic. In cases of cholin-
Vasoactive intestinal polypeptide Vasodilation, muscle relaxation, secretion
ergic overload, such as insecticide poisoning or ‘overreversal’ of
muscle relaxants (in which cholinesterase is inhibited), there is a CCK8 = cholecystokinin-8
tendency for the gut to become hyper-reactive. Reproduced from Neuroscientific Foundations in Anesthesiology, Mashour GA, Lydic R (eds),
There are many neuroactive compounds other than NE and The Autonomic Nervous System, Glick D, Glick G, p. 173. Copyright (2011) with permission
acetylcholine that participate in the autonomic control of intes- from Oxford University Press.
tinal function. The predominant non-adrenergic non-cholinergic
(NANC) neurotransmitter appears to be nitric oxide (NO), which
provides the primary intrinsic inhibitory innervation to the gastro- Parasympathetic nervous input acts primarily to conserve energy,
intestinal (GI) tract. Other neuroactive chemicals and peptides maintain organ function, and to support vegetative processes.
identified in the GI tract include substance P, a variety of opiate Most organs of the body exhibit dual innervation, with input from
peptides, vasoactive intestinal protein (VIP), and a growing popu- the sympathetic and parasympathetic systems frequently mediating
lation of peptide hormones (Table 5.1). Complex interactions be- opposing effects (Table 5.2) (5). Stimulation of one system may have
tween these neurotransmitters underlie the local control of GI an excitatory effect on the end organ, whereas stimulation of the
function. In addition to the wide array of amines and peptides af- other system may have an inhibitory effect. For example, sympathetic
fecting local ENS activity recent literature has demonstrated that stimulation of the heart increases the rate and vigour of contrac-
intestinal microbes also interact with the enteric nervous system. tion and enhances conduction through the atrioventricular node,
Stressful conditions, such as surgery, alter GI permeability, motility, whereas parasympathetic stimulation decreases heart rate, atrial
immune function, and the release of hormones and other mediators contractility, and conduction through the atrioventricular node. In
in the GI tract (3). In addition, gut microbes and their by-products patients with chronic atrial fibrillation, atrial nerve densities are sig-
affect the intestinal barrier and can target intestinal sensory nerves. nificantly increased, exemplifying the potential deleterious effects
Although the mechanism is poorly understood, stress hormones, of ANS imbalances (6). One of the two systems normally domin-
such as NE and epinephrine, have been implicated in stimulating ates the organ’s function, providing its ‘resting tone’ (Table 5.3). In a
the growth of specific gut-related pathogens, such as Yersinia few organs, most notably blood vessels, the spleen, and piloerector
enterocolitica, E. coli, and various Salmonella and Shigella species muscles, the SNS alone provides innervation.
(4). The impact of the interplay between local flora and the ENS on To predict the effects of drugs, the interaction of the sympathetic
the gut’s microbial balance during the peri-operative period is not and parasympathetic systems in different organs must be under-
yet fully elucidated. stood. Blockade of sympathetic function unmasks pre-existing
parasympathetic activity, and the converse relation also is true. For
example, basal heart rate is mainly determined by parasympathetic
Function tone, but with administration of atropine, unopposed sympathetic
Organization and Integration tone causes tachycardia.
The sympathetic system, in response to internal or external chal-
lenges, acts to i) increase heart rate, arterial pressure, and car- Adrenergic Function
diac output, ii) dilate the bronchial tree, and iii) shunt blood Activation of the adrenergic neurons influences many bodily func-
away from the intestines and other viscera to voluntary muscles. tions, but the effects on circulation and respiration are among the
1 5
Table 5.2 Responses elicited in effector organs when stimulated by sympathetic and parasympathetic nerves.
Dominant Effector Organ Adrenergic Response Receptor Involved Cholinergic Response Response (A or C)
Heart–Rate of contraction Increase β1 Decrease C
Heart–Force of contraction Increase β1 Decrease C
Blood vessels, Arteries (most) Vasoconstriction α1 A
Blood vessels, Skeletal muscle Vasodilation β2 A
Blood vessels, Veins Vasoconstriction α2 A
Bronchial tree Bronchodilation β2 Bronchoconstriction C
Splenic capsule Contraction α1 A
Uterus Contraction α1 Variable A
Vas deferens Contraction α1 A
Prostatic capsule Contraction α1 A
Gastrointestinal tract Relaxation α2 Contraction C
Eye, Radial muscle, iris Contraction (mydriasis) α1 A
Eye, Circular muscle, iris Contraction (miosis) C
Eye, Ciliary muscle Relaxation β Contraction C
Kidney Renin secretion β1 (Accommodation) A
Urinary bladder, Detrusor Relaxation β Contraction C
Trigone and sphincter Contraction α1 Relaxation A, C
Ureter Contraction α1 Relaxation A
Insulin release from pancreas Decrease α2 A
Fat cells Lipolysis β1 A
Liver glycogenolysis Increase α1 A
Hair follicles, smooth Contraction α1 A
muscle (piloerection)
Nasal secretion Increase C
Salivary glands Increase secretion α1 Increase secretion C
Sweat glands Increase secretion α1 Increase secretion C
A, adrenergic; C, cholinergic
Reprinted from Human Pharmacology: Molecular to Clinical, Wingard L, Brody T, Larner J, et al. (eds), p.77. Copyright (1991), with permission from Elsevier.
most important. Ventilation is increased by a central effect on the responsible for most of the sympathetically induced smooth muscle
ventilatory centres and by bronchodilation. Heart rate and myo- contraction throughout the body, namely the vascular, bronchial,
cardial contractility are also markedly increased. Function of the and ureteral smooth muscle and the ciliary muscle of the eye (7).
gastrointestinal and genitourinary systems is decreased as a result The gastrointestinal and genitourinary sphincter mechanisms are
of the relaxation of the smooth muscle in these organs and con- stimulated by α-receptors. α-receptor agonism decreases pancreatic
traction of their sphincters. Gastrointestinal secretory activity is in- insulin secretion from the pancreatic β-cells. In the peripheral vas-
hibited, and adrenal medullary output is increased. Metabolism is culature, α1-and α2-receptors modulate vascular tone in response
stimulated to provide more fuel for bodily function in the form of to humorally borne neurotransmitters and exogenously adminis-
glucose and fatty acids. tered drugs. In particular, the pulmonary arteries have a relatively
The endogenous catecholamines, NE and epinephrine, possess high concentration of α1-receptors (8), so alpha-agonists can pro-
α-and β-receptor agonist activity. Norepinephrine has minimal foundly increase right ventricular afterload.
β2-receptor activity, whereas epinephrine stimulates the β1- and β-receptor agonism appears to be primarily responsible for sym-
β2-receptors. pathetic stimulation of the heart, relaxation of vascular and bron-
The physiologic responses mediated by α-adrenoceptors are chial smooth muscle, stimulation of renin secretion by the kidney,
wide-ranging and important. α-receptor-mediated activity is and several metabolic consequences, including lipolysis and
25
Table 5.3 Usual parasympathetic or sympathetic dominance Thus, the stress response should not be conceived of as a uniform
at specific effector site. response; it can vary in mechanism, intensity, and manifestations.
Blood Glucose
Site Predominant Tone
SNS stimulation through β- receptor activation augments
Ciliary muscle Parasympathetic glycogenolysis in the liver and muscles and liberates free fatty acids
Iris Parasympathetic from adipose tissue, ultimately increasing blood glucose levels. In
neonates, epinephrine plays an additional role in the exothermic
Sinoatrial node Parasympathetic
breakdown of brown fat to maintain body temperature (i.e.,
Arterioles Sympathetic nonshivering thermogenesis).
Veins Sympathetic α2-and β2-receptors also are present in the pancreas. As noted,
α2-receptor activation suppresses insulin secretion by pancreatic
Gastrointestinal tract Parasympathetic
islet cells. Thus, blockade of these receptors may increase insulin
Uterus Parasympathetic release and may be associated with significant lowering of blood
Urinary bladder Parasympathetic glucose levels. β2-receptor stimulation increases glucagon and in-
sulin secretion and decreases peripheral sensitivity to insulin (16).
Salivary glands Parasympathetic
Sweat glands Sympathetic (cholinergic) Potassium Shift
Plasma epinephrine also takes part in the regulation of serum po-
Reproduced from Neuroscientific Foundations in Anesthesiology, Mashour GA, Lydic R (eds), tassium concentration. Transient hyperkalaemia occurs as potas-
The Autonomic Nervous System, Glick D, Glick G, p. 175. Copyright (2011) with permission
from Oxford University Press. sium shifts out of hepatic cells with the glucose efflux produced by
β2-adrenergic stimulation. This effect is followed by a more pro-
longed hypokalaemia as the β2-adrenergic stimulation drives po-
glycogenolysis. The β1-receptor mechanism is thought to be pri- tassium into muscle and red blood cells. Exogenously administered
marily involved in the cardiac effects (9) and release of fatty acids or endogenously released epinephrine stimulates the β2-receptors
and renin, whereas the β2-receptors are primarily responsible for of red blood cells, activating adenylate cyclase and the sodium-
smooth muscle relaxation and hyperglycaemia. In specialized cir- potassium ATPase, driving potassium into the red cells.
cumstances, however, β2-receptors may also mediate cardiac ac-
tivity. Although acute changes in arterial pressure and heart rate Cholinergic Function
can be caused by NE or epinephrine, chronic hypertension does not Acetylcholine release is the hallmark of parasympathetic activa-
appear to be related solely to circulating levels of these hormones tion. The actions of acetylcholine are almost diametrically opposed
(10). In fact, 85% of resting arterial pressure is controlled by the to those of NE and epinephrine. In general, the muscarinic effects
renin-angiotensin system. of acetylcholine are qualitatively the same as the effects of vagal
Nevertheless, in hypertensive patients, sympathetic hyper- stimulation.
reactivity is common. There are consistent data suggesting that acti- The dose of exogenously administered acetylcholine determines
vation of the SNS increases as a patient becomes more hypertensive its effect. A small intravenous dose causes generalized vasodilation
(11). Hypertension also affects the PNS through impairment of car- (including the coronary and pulmonary circulation), whereas a
diac vagal modulation (11). Invasive approaches to decrease sympa- larger dose demonstrates negative chronotropic and dromotropic
thetic activity, such as continuous carotid baroreceptor stimulation effects. The vasodilation occurs because significant numbers of
and renal arterial denervation, have been used to treat patients with muscarinic receptors exist in vascular beds, despite the absence of a
drug-resistant hypertension, with mixed results (12). cholinergic nerve supply. A second mechanism of vessel relaxation
Heart failure (HF) is another condition in which activation of the by acetylcholine is inhibition of NE release from adrenergic nerve
SNS and inhibition of the PNS have been identified. Myocardial terminals.
injury or alterations in preload result in activation of the SNS, Acetylcholine decreases heart rate, the velocity of conduction
causing both increased release and decreased uptake of NE. in the sinoatrial (SA) and atrioventricular (AV) nodes, and atrial
Acutely, catecholamine-induced inotropy and dromotropy work to contractility. In the SA node, acetylcholine causes membrane
maintain cardiac output. Adrenergic activity also causes vasocon- hyperpolarization, thereby delaying attainment of the threshold
striction increasing preload. Both NE and angiotensin II stimulate potential with a resultant decrease in heart rate. The profound
sodium reabsorption in the kidney and contribute to sodium re- bradycardia or asystole seen when heart transplant patients are
tention and volume expansion that is characteristic of HF. Chronic given an anticholinesterase exemplifies an extreme example of this
SNS stimulation causes myocyte enlargement and remodelling, phenomenon (17). In the AV node, acetylcholine decreases con-
resulting in ventricular dilatation (13). Chronic HF leads to ele- duction velocity and increases the effective refractory period. This
vated levels of NE and epinephrine, leading to a chronically ele- decrease in AV nodal conduction accounts for the complete heart
vated stimulation of the cardiac B-receptor system that eventually block seen when large amounts of cholinergic agonists are given. In
results in a reduction in the cardiac B-receptor density and cardiac the ventricle, acetylcholine decreases automaticity in the Purkinje
inotropic reserve depletion (14). system, thereby increasing the fibrillation threshold.
Psychological and physical stimuli may evoke different sympa- Parasympathetic activation has many effects outside the cardio-
thetic compensatory responses. Public speaking activates the ad- vascular system. Cholinergic stimulation causes smooth muscle
renal gland with a disproportionate rise in serum epinephrine, constriction, including that of the bronchial walls. In the gastro-
whereas physical exercise elicits primarily a rise in serum NE (15). intestinal and genitourinary tracts, smooth muscle in the walls
3 5
constricts, but sphincter muscles relax, leading to incontinence. population of the neuron. In general, 1% of stored NE is released
Topically administered acetylcholine constricts the smooth muscle with each depolarization, implying a significant functional reserve.
of the iris, causing miosis. The vesicles have two fundamentally different functions: to take
Signs and symptoms of cholinergic overload reflect all these ef- up and store neurotransmitters, and to fuse with and bud from the
fects as well as nausea and vomiting, intestinal cramps, belching, presynaptic plasma terminal membrane. The proteins of vesicles
urination, and urgent defecation. All glands innervated by the can be divided into two functionally discrete classes. The first class,
PNS are stimulated to produce secretions, including the lacrimal, transport proteins, provides the channels and pumps for the up-
tracheobronchial, salivary, digestive, and exocrine glands. take and storage of neurotransmitters. The second class of proteins
directs movement and docking reactions of the vesicle membrane.
Pharmacology Release of Norepinephrine
Adrenergic Pharmacology There are several different processes by which the contents of the
vesicle enter the synaptic cleft. The dominant physiologic mech-
Synthesis of Norepinephrine anism of release is exocytosis, during which the vesicle responds
Norepinephrine is synthesized from tyrosine, which is actively to the entry of calcium by initiating the sequence of vesicular
transported into the varicosity of the postganglionic sympa- docking, fusion, release of vesicular contents, and, ultimately,
thetic nerve ending. Tyrosine is synthesized from phenylalanine. endocytosis (the process by which vesicular membrane and pro-
Precursors are taken up in greater amounts in shock and this in- teins are recaptured).
creased uptake may have beneficial effects on the efforts of the SNS Various specific soluble and membrane-bound proteins have
to maintain perfusion pressure. been identified that participate in docking, fusion, and endocytosis.
A series of steps results in the conversion of tyrosine to NE and Synaptotagmin serves as the intermediary between calcium entry
epinephrine (in the adrenal medulla). The first of these steps in- and docking.19 Although the mechanisms of docking and fusion
volves the cytoplasmic enzyme tyrosine hydroxylase. This is the rate- are still incompletely understood, it appears to be a highly differen-
limiting step in NE biosynthesis. High levels of NE inhibit tyrosine tiated process in which a pair of soluble binding proteins—soluble
hydroxylase, whereas low levels are stimulatory. During stimulation N-ethyl maleimide sensitive factor (NSF) attachment proteins
of the SNS, an increased supply of tyrosine increases synthesis of (SNAPs) and soluble NSF receptors (SNAREs)—interact (20, 21).
NE. Tyrosine hydroxylase activity is modified by phosphorylation. SNARE proteins are present on both the vesicular and neuronal
Whereas acute control of tyrosine hydroxylase occurs by altering membranes. A core complex of SNARE proteins is formed when
enzyme activity, chronic stress can elevate tyrosine hydroxylase three or four of these proteins (two reactive sites each from the
levels by stimulating synthesis of new enzyme. Influenced by tyro- vesicle and the cell membranes) are brought into close proximity.
sine hydroxylase, tyrosine is converted to dihydroxyphenylalanine The apposition of the two membranes allows them to fuse and
(DOPA), which is decarboxylated to dopamine by an aromatic the vesicular contents to be released into the synaptic cleft. Three
amino acid decarboxylase (DOPA decarboxylase). SNARE proteins involved in synaptic exocytosis have been iden-
Dopamine can and does act as a neurotransmitter in some cells, tified: synaptobrevin (on the vesicular membrane), and syntaxin-
but most of the produced dopamine is β-hydroxylated within the 1 and SNAP-25 (on the neuronal membrane). Other proteins,
vesicles to NE by the enzyme dopamine β-hydroxylase (DBH). In including synaptophysins, have been identified that can bind to
the adrenal medulla, and to a limited extent in discrete regions of synaptobrevin and inhibit SNARE complex formation and exocyt-
the brain, another enzyme, phenylethanolamine N-methyl trans- osis (Figure 5.3) (22).
ferase (PNMT), methylates about 85% of the NE to epinephrine. Evidence for the biologic relevance of these proteins is derived
Glucocorticoids from the adrenal cortex pass through the adrenal from observations that tetanus toxin and botulinum toxin block
medulla and can activate the system, and stress-induced steroid re- vesicular release by binding to the docking and fusion proteins
lease can increase epinephrine production. This local circulation (23), whereas microinjection of SNAP into neurons enhances exo-
amplifies the effects of glucocorticoid release (18). cytosis (19, 24). In vesicular docking and release, a subpopulation
of vesicles is tethered to the active zone of the prejunctional neuron.
Storage of Norepinephrine
These are the readily releasable vesicles noted previously (22, 25,
Norepinephrine is stored within large, dense-core vesicles. These 26). The short latency between excitation and vesicle release (27)
vesicles also contain calcium and a variety of peptides and ad- has functional implications, particularly in facilitating rapid trans-
enosine 5'-triphosphate (ATP). Although NE is the predominant mission in the SNS.
neurotransmitter at sympathetic nerve endings, depending on the Although chromaffin cells in the adrenal medulla synthesize epi-
nature and frequency of physiologic stimuli, the ATP can be re- nephrine and NE, the two compounds are stored in and secreted
leased selectively for an immediate postsynaptic effect through from distinct chromaffin cell subtypes. Data suggest that there may
purinoreceptors. be a preferential release from one or another form of chromaffin
The vesicles containing NE are heterogeneous and exist within cell depending on the stimulus (28). Nicotinic agonists or depolar-
functionally defined compartments. An actively recycling popula- izing agents cause the preferential release of NE, whereas histamine
tion of synaptic vesicles has been defined, together with a reserve elicits predominantly epinephrine release (29–31).
population of vesicles that is mobilized only on extensive stimu-
lation. Newly synthesized or taken up transmitters are incorpor- Inactivation
ated preferentially into the actively recycling vesicles and are the Most of the NE released is rapidly removed from the synaptic cleft
first ones released on stimulation. These readily releasable vesicles via active reuptake mechanisms in the neuron. If a transmitter is to
make up approximately 10% of the total NE containing vesicular exert fine control over an effector system its half-life in the biophase
45
Figure 5.3 Representation of the function of SNARE proteins.

(a) Vesicle is docked. SNAREs, synaptotagmins are not engaged. (b) Formation of SNARE complex. The vesicle and the plasma membrane are brought into close
proximity. (c) Ca2+ triggers the opening of the fusion pore and the release of vesicular contents.
Reproduced with permission of Annual Review of Neuroscience, 27, Südhof, T, The synaptic vesicle cycle, pp. 509–547. © 2004 by Annual Reviews, http://www.annualreviews.org.
(i.e., the extracellular space close to the receptor) must be short. The urine. This type of testing can be particularly useful when testing
active reuptake mechanism ensures that NE’s time in the synaptic for catecholamine-secreting tumours, in which a test of plasma
cleft is appropriately short. Most released NE is transported into the metanephrines, the metabolite of epinephrine by COMT, has a sen-
storage vesicle for reuse. This neurotransmitter uptake into synaptic sitivity of 96%.
vesicles is driven by an electrochemical proton gradient across the Inhibition of MAO would be expected to have a great impact on
synaptic vesicle membrane. After reuptake, the small amounts of the sympathetic function of a patient. MAO inhibitors (MAOIs) are
NE not taken up into the vesicle are deaminated by cytoplasmic generally well tolerated, but the stability of the patient belies the fact
monoamine oxidase (MAO). that amine handling is fundamentally changed.
Uptake of NE into the nerve varicosity and its return to the Other compounds can produce sympathomimetic effects by
storage vesicle, albeit efficient, is not specific for the neurotrans- acting as false transmitters. Although it is not used therapeutic-
mitter. Some compounds structurally similar to NE may enter the ally, tyramine is the prototypic drug studied. It is present in many
nerve by the same mechanism and may result in depletion of the foods, particularly aged cheese and wines. Tyramine enters the
neurotransmitter. These false transmitters can be of great clinical sympathetic nerve terminal through the reuptake mechanism,
importance. Moreover, some drugs that block reuptake into the displacing NE from the vesicles into the cytoplasm. Released NE
vesicle or into the nerve ending itself may enhance response to cat- leaks out from the cytoplasm, causing the hypertensive effect of
echolamines; that is, more NE remains available to receptors. These tyramine. However, a secondary effect can occur. In the vesicle,
drugs include cocaine and tricyclic antidepressants. tyramine is converted by DBH into octopamine, which is even-
Activity of the reuptake system varies greatly among different tually released as a false transmitter in place of NE, but without
tissues. Peripheral blood vessels have almost no reuptake of NE, the hypertensive effect, because it has only 10% of the potency of
consequently, NE must be metabolized within the synaptic cleft to NE (33).
be inactivated and rapid rates of NE synthesis within the vesicle
are necessary to modulate vascular tone. On the other hand, the Adrenergic Receptors
highest rate of reuptake is found in the heart. Adrenergic receptors have been sub-classified as α1, α2, β1, β2, or β3
Metabolism based on responses to specific drugs.
During storage and reuptake, the NE that escapes uptake into the α-Adrenergic Receptors
nerve ending enters the circulation where it is metabolized by MAO α1-adrenergic receptor subtypes α1A/D, α1B, and α1C have been char-
or catechol-O-methyl transferase (COMT) in the blood, liver, and acterized. Several α2-isoreceptors (α2A, α2B, and α2C) have also been
kidney (32). described (34). The α2-receptors are found in the peripheral nervous
Epinephrine is inactivated by the same enzymes. The final meta- system, in the CNS, and in a variety of organs, including platelets,
bolic product of inactivation is vanillylmandelic acid. The two cata- liver, pancreas, kidney, and eyes, where specific physiologic func-
bolic enzymes (MAO and COMT) and the vigorous uptake system tions have been identified (35). The predominant α2-receptor of the
account for an efficient clearance of catecholamines. Because human spinal cord has been identified as the α2A-subtype (36, 37).
of this rapid clearance, the half-life of NE (and most biogenic There is more than theoretical relevance in the subclassification
amines) in plasma is short, less than one minute. Consequently, of receptors (38). For example, the α-adrenergic receptors in the
a more ideal measure of catecholamine production may be meta- prostate gland are predominantly α1A. Therapy with selective α1A-
bolic by-products, rather than catecholamine levels in the blood or antagonists for benign prostatic hypertrophy may avoid some of the
5
postural hypotension and other deleterious effects that occur with group occupies the intracellular terminus, where phosphorylation
less specific α-antagonists. occurs. Along the cytoplasmic domains, there is interaction with
Receptors can be presynaptic as well as postsynaptic. Presynaptic G-proteins and kinases, including β-adrenergic receptor kinase.
receptors may act as heteroreceptors or autoreceptors. An The β-receptor has mechanistic and structural similarities with
autoreceptor is a presynaptic receptor that reacts to the neuro- muscarinic, but not nicotinic, acetylcholine receptors, primarily in
transmitter released from its own nerve terminal, providing feed- the transmembrane sections. Muscarinic receptors and β-receptors
back regulation. A heteroreceptor is a presynaptic receptor that are coupled to adenylate cyclase through G-proteins; both can ini-
responds to substances other than the neurotransmitter released tiate the opening of ion channels.
from that specific nerve terminal. This regulatory scheme is present β-receptors have been further divided into β1-, β2-, and β3-
throughout the nervous system but is particularly important in the subtypes, all of which increase cyclic adenosine monophosphate
SNS (39). (cAMP) catalysed by adenylate cyclase and the mediation of G
Although several presynaptic receptors have been identified, the proteins (41, 42). Traditionally, the β1-receptors were thought to
α2-receptor may be of the greatest clinical import. Presynaptic α2- be isolated to cardiac tissue, and β2-receptors were believed to be
receptors regulate the release of NE and ATP through a negative- restricted to vascular and bronchial smooth muscle. Although
feedback mechanism (40). Activation of presynaptic α2-receptors this model of distribution is useful because it reflects the primary
by NE inhibits subsequent NE release in response to nerve clinical effects of pharmacologic manipulation of the β1-and β2-
stimulation. receptor subtypes, β2-receptors are more important in cardiac
function than indicated by this model. The β2-receptor popula-
β-Adrenergic Receptors tion in human cardiac tissue is substantial, accounting for 15% of
The structure of the β-adrenergic receptor was among the first to the β-receptors in the ventricles, and 30% to 40% in the atria (43).
be ascertained and is well characterized. Like the α-receptor, the β2-receptors may help compensate for disease by maintaining
β-receptor is one of the superfamily of proteins that have seven the response to catecholamine stimulation when β1-receptors are
helices woven through the cellular membrane. These transmem- downregulated during chronic catecholamine stimulation, as is
brane domains are labelled M1 through M7; antagonists have spe- seen in heart failure (44). In fact, the β2-population is almost un-
cific binding sites, whereas agonists are more diffusely attached to affected in end-stage congestive cardiomyopathy (45). In addition
hydrophobic membrane-spanning domains (Figure 5.4). The extra- to positive inotropic effects, β2-receptors in the human atria par-
cellular portion of the receptor ends in an amino group. A carboxyl ticipate in the regulation of heart rate. In heart failure, chronic
NH2
Extracellular
domains
β-agonist
β-antagonist
Transmembrane
domains
M1 M2 M3 M4 M5 M6 M7
Cytoplasmic
domains
G protein
β-ark
COOH
Figure 5.4 Drawing of the molecular structure of the β-adrenergic receptor.The transmembrane domain acts as a ligand-binding pocket. The cytoplasmic domains can
interact with G proteins and kinases (i.e., β-adrenergic receptor (β-ARK)) which can phosphorylate and desensitize the receptor.
Adapted from Heart Physiology: From Cell to Circulation, Opie L. H., p.194. Copyright (2003) with permission from Lippincott, Williams & Wilkins. Source data from Hypertension, 15, Raymond J. R.,
Hnatowich M., Lefkowitz R. J., and Caron M.G, Adrenergic receptors: Models for regulation of signal transduction processes, pp. 119–131.
65
sympathetic stimulation results in less heart rate variability, cleft or in plasma. For β-adrenergic receptors, this response is
which has been shown to be a predictor of sudden cardiac death. fast; within 30 minutes of denervation or adrenergic blockade, the
β-blocker therapy with bisoprolol has been shown to induce a sig- number of receptors increases. This rapid adaptation can compli-
nificant increase in heart rate variability (14). Additionally, three cate peri-operative adrenergic management. One example of this
β-blockers (bisoprolol, carvedilol, and sustained-release meto- is the pronounced waxing and waning of support for the peri-
prolol succinate) have been shown to reverse ventricular remod- operative initiation of β-blockers. Current American College of
elling and reduce mortality in heart failure with reduced ejection Cardiology/American Heart Association guidelines have limited
fraction (46). the indications for initiation of β-blockade started one day or less
Localization of β3-receptors to fat cells suggests a new thera- before noncardiac surgery because while they have been shown
peutic target for obesity. Polymorphism of the β3-receptor subtype to prevent nonfatal myocardial infarctions in ‘at risk’ patients,
is associated with obesity and the potential for the development of they also increase the rates of death, hypotension, bradycardia,
diabetes (47–49). Point mutations in genes encoding β2-receptors and stroke. There is currently insufficient data regarding whether
are correlated with decreased downregulation of β-receptors and or not to continue β-blockade started more than two days before
nocturnal asthma (50, 51). noncardiac surgery (56). Many chronic conditions, such as vari-
cose veins (57) or aging, can decrease adrenergic receptor number
Dopamine Receptors (downregulation) or responsiveness.
Clinically and at the cellular level, responses to many hormones
Dopamine exists as an intermediate in NE biosynthesis and ex- and neurotransmitters wane rapidly despite continuous exposure
ogenously administered dopamine exerts predominantly α-or to adrenergic agonists (58). This phenomenon, called desensi-
β-adrenergic effects, depending on the dose administered. tization, has been particularly well studied for the stimulation of
Furthermore, Goldberg and Rajfer (52) demonstrated physiologic- cAMP levels by plasma membrane β-receptors (59). Mechanisms
ally distinct dopamine type 1 (DA1) and dopamine type 2 (DA2) re- postulated for desensitization include uncoupling (e.g., phosphor-
ceptors, and these remain the most important of the five dopamine ylation), internalization, and downregulation. The molecular mech-
receptors that have been cloned. DA1 receptors are postsynaptic and anism underlying rapid β-receptor desensitization appears to result
act on renal, mesenteric, splenic, and coronary vascular smooth from an alteration in the functioning of β-receptors themselves that
muscle to mediate vasodilation through stimulation of adenylate uncouples the receptors from the stimulatory Gs-protein.
cyclase and consequent increased cAMP production. The vaso- Agonist- i nduced desensitization involves phosphoryl-
dilatory effect tends to be strongest in the renal arteries. Renal DA1 ation of G-protein-coupled receptors by two classes of serine-
receptors located in the tubules modulate natriuresis through the threonine kinases. One of these initiates receptor-specific or
sodium-potassium ATPase pump and the sodium-hydrogen ex- homologous desensitization. The other works through second
changer (52–55). The DA2 receptors are presynaptic; they may in- messenger- dependent kinases, mediating a general cellular
hibit NE and perhaps acetylcholine release. There are also central hyporesponsiveness, called heterologous desensitization.
DA2 receptors that may mediate nausea and vomiting. Ultimately, an inhibitory arrestin protein binds to the phosphor-
ylated receptor, causing desensitization by blocking signal trans-
GTP-Binding Regulatory Proteins (G-proteins) duction. Because enzymatic phosphorylation occurs only in the
Each class of adrenergic receptor couples to a different major sub- activated state, transient β-blockade has been used in states of re-
family of G-proteins, which are linked to different secondary mes- ceptor desensitization such as heart failure or cardiopulmonary
sengers. α1-receptors are linked to phospholipase C activation. bypass to achieve a ‘receptor holiday’ (60). Regeneration of a func-
β-receptor stimulation activates Gs-proteins, enhancing adenylate tional β-receptor is contingent on internalization of the receptor,
cyclase activity and cAMP formation. The briefest encounter of with dephosphorylation and consequent recycling. Receptor
plasma membrane β-adrenergic receptors with epinephrine or NE populations can thus change rapidly through internalization and
results in profound increases in the intracellular levels of cAMP (up subsequent recycling.
to four hundredfold higher than the basal level). Increased cAMP In contrast, downregulation occurs after prolonged exposure
synthesis activates protein kinases, which phosphorylate target pro- to an agonist (as in chronic stress or heart failure). New receptors
teins, thereby eliciting various cellular responses that complete the must be synthesized before a return to a baseline state is possible.
path between β-receptor and effect. In contrast, stimulation of α2-
receptors results in Gi inhibition of adenylate cyclase. Cholinergic Pharmacology
There is a relative abundance of G-proteins, resulting in amplifi- Acetylcholine Synthesis
cation of receptor agonism at the signal transduction step; however, Acetylcholine is synthesized intraneuronally from acetyl coenzyme
the number of G-protein molecules greatly exceeds the number of A and choline through the action of the enzyme choline acetyl
β-adrenergic receptors and adenylate cyclase molecules. Thus, it transferase in the synaptosomal mitochondria (61). Sources of
is the receptor concentration and ultimately adenylate cyclase ac- choline include dietary phospholipids, hepatic synthesis of phos-
tivity, rather than G-protein availability, that limit the response to phatidylcholine from dietary precursors such as ethanolamines,
catecholamines. and choline released by hydrolysis of acetylcholine. Choline is
transported as phospholipid and is taken up by a high-affinity
Upregulation and Downregulation transport system. This system appears to be largely responsible for
β-adrenergic receptor populations are dynamic; they change sig- determining acetylcholine levels, although there is some evidence
nificantly in response to the amount of NE present in the synaptic that precursor availability may limit cholinergic activity. The level
7 5
of circulating choline can affect the release of acetylcholine when Compared with adrenergic receptors, cholinergic receptors turn
rapid firing takes place. over slowly. When a nerve to a muscle is transected, it takes be-
tween one to three days to increase the number of cholinergic re-
Storage and Release ceptors. These new receptors are no longer confined to the motor
On the presynaptic side, the nerve ending contains many vesicles end plate, and that change has important clinical ramifications.
that contain acetylcholine. When a nerve impulse arrives at the pre- For example, life-threatening hyperkalaemia can result from the
synaptic nerve terminal, it causes an influx of calcium ions across stimulation of these abundant ectopic cholinergic receptors by
the membrane. This induces 100–300 synaptic vesicles to fuse with succinylcholine.
the presynaptic membrane at specific release sites, resulting in the In contrast to the ion-gated nicotinic receptors, muscarinic re-
liberation of acetylcholine from vesicles into the synaptic cleft. ceptors belong to the superfamily of G-protein-coupled receptors.
Muscarinic receptors, therefore, have a greater homology to α-and
Inactivation β-receptors than to nicotinic receptors. Like the other members of
Acetylcholine is an ester that hydrolyses spontaneously in alka- the family of receptors with seven helices, muscarinic receptors use
line solutions into acetate and choline, yet the rate of hydrolysis is G-proteins for signal transduction. Five muscarinic receptors (i.e.,
substantially increased by enzymatic catalysis. The two most sig- M1 through M5) exist with the primary structural variability res-
nificant biologic hydrolytic enzymes are acetylcholinesterase and iding in a cytoplasmic loop between the fifth and sixth membrane-
butyrylcholinesterase. spanning domains.
Acetylcholinesterase, sometimes called tissue esterase or true es- The muscarinic receptors have diverse signal transduction mech-
terase, is a membrane-bound enzyme present in all cholinergic syn- anisms. The odd-numbered receptors (i.e., M1, M3, and M5) work
apses that functions to destroy acetylcholine released from nerve predominantly through the hydrolysis of polyphosphoinositide,
endings. Acetylcholinesterase is very efficient, terminating trans- whereas the even-numbered receptors work primarily to regulate
mission within milliseconds after acetylcholine release. The sub- adenylate cyclase (62).
strate turnover is 2500 molecules per second. The enzyme also is Muscarinic receptors are found on central and peripheral
present in tissues that are not innervated, such as erythrocytes. Its neurons; a single neuron may have muscarinic receptors with exci-
function in these tissues is unknown. tatory and inhibitory effects. Presynaptic muscarinic receptors may
Inhibition of acetylcholinesterase prevents the destruction of inhibit the release of acetylcholine from postganglionic parasym-
acetylcholine in cholinergic synapses and can activate all cholin- pathetic neurons; presynaptic nicotinic receptors may increase its
ergic systems simultaneously. In addition to their therapeutic uses, release.
cholinesterase inhibitors are also the active ingredients in insecti- Because of the complex coupling, the response of the muscar-
cides and many nerve gases. inic system is sluggish and an application of acetylcholine might
Butyrylcholinesterase, sometimes called plasma esterase or not produce a response for seconds to minutes. The effect, however,
pseudocholinesterase, is a soluble enzyme that is made pri- long outlives the presence of the agonist. Although the transmitter
marily in the liver and circulates in the blood. Its function in is destroyed rapidly, the cellular response continues for many
normal situations is not known. Individuals who are genetic- minutes. Muscarinic receptors are desensitized through agonist-
ally incapable of making the enzyme are normal in all other re- dependent phosphorylation in a mechanism similar to that de-
spects. It is important for the destruction of some cholinergic scribed earlier for β-receptors.
drugs, such as succinylcholine, which are not metabolized by
acetylcholinesterase. Non-Adrenergic, Non-Cholinergic Neurotransmission
in the Autonomic Nervous System
Cholinergic Receptors Classically, NE has been considered the moderator of vascular
Cholinergic receptors are organized into two major subdivi- tone. Beginning in the early 1960s, however, various other com-
sions: muscarinic and nicotinic. Muscarinic receptors are present pounds, including monoamines, purines, amino acids, and
mostly in peripheral visceral organs; nicotinic receptors are found polypeptides, were identified that fulfilled the criteria of func-
on parasympathetic and sympathetic ganglia and on the neuromus- tional neurotransmitters (63, 64). Other transmitter candidates
cular junctions of skeletal muscle. demonstrated in perivascular nerves using histochemical and
Although these two classes of receptors are structurally and func- immunohistochemical techniques include ATP, adenosine, VIP,
tionally distinct, having significantly different responses to acetyl- substance P, 5-hydroxytryptamine, neuropeptide Y (NPY), and
choline, the chemical itself exhibits no specificity to either receptor. calcitonin gene-related peptide (CGRP). Immunocytochemical
However, specific antagonists can exploit the difference between studies show that more than one transmitter or putative trans-
the muscarinic and nicotinic receptors. mitter may be co-localized in the same nerve. The most common
The nicotinic receptors are pentameric membrane proteins, con- combinations of transmitters in perivascular nerves are NE, ATP,
sisting of two α-units, one β-unit, one ε-unit, and one δ-unit. These and NPY in sympathetic nerves (Figure 5.5); acetylcholine and
five subunits surround an ion channel through which sodium or VIP in parasympathetic nerves; and substance P, CGRP, and ATP
calcium may enter the cell or potassium may exit. Acetylcholine in sensory-motor nerves. Many of these putative transmitters act
or nicotinic antagonists bind to the α-subunits. For the channel to through co-transmission, which is the synthesis, storage, and re-
open, acetylcholine must occupy a receptor site on each of the two lease of more than one transmitter by a nerve (65). Autonomic
α-subunits. The ion channel response to acetylcholine is instantan- nerves exhibit chemical coding—individual neurons serving a spe-
eous and usually lasts only a few milliseconds because acetylcholine cific physiologic function contain distinct combinations of trans-
is rapidly destroyed by acetylcholinesterase in the synapse. mitter substances (66).
85
The concepts of co-transmission and neuromodulation have Vas deferens

become accepted mechanisms in autonomic nervous control. To Many blood vessels
establish that transmitters coexisting in the same nerves act as co-
transmitters, it is necessary to demonstrate that, on release, each
substance acts postjunctionally on its own specific receptor to pro-
duce a response.
For many perivascular sympathetic nerves, there is evidence
that NE and ATP act as co-transmitters and are released from the Prejunctional
same nerves but act on α1-receptors and P2-purinoceptors, respect- neuromodulation (NPY)

ively, to produce vasoconstriction (67, 68) (Figure 5.5). ATP, once
thought to act only as an electrical buffer for the charged NE, is
believed to mediate contraction through P2-receptors by voltage- ATP NE NPY
dependent calcium channels (69). The fast component of contrac-
Postjunctional
tion appears to be mediated by these purinoceptors, whereas NE neuromodulation (NPY)
sustains contraction of muscle by acting on the α1-receptor through + + +
P2 α1
receptor-operated calcium channels. ATP is stored in vesicles along
nerve varicosities. It is released into the synaptic cleft via exocyt- (a) Heart
osis and then binds to postsynaptic purinergic receptors. ATP is Spleen
Brain
then degraded to adenosine by membrane-bound ATPases and 5’-
nucleotidases. Adenosine is taken up into the presynaptic neuron Sympathetic Sympathetic
where ATP is resynthesized and incorporated into vesicles for sub-
sequent release (70).
NPY is also co-localized with NE and ATP. However, in some +
Y
vessels, NPY has little or no direct action. Instead, NPY acts as NP
a neuromodulator prejunctionally to inhibit the release of NE + + +
from the nerve or postjunctionally to enhance the action of
Local NE NE NPY
neuron
NE (Figure 5.5a) (71, 72). In other vessels, notably those of the + NPY
spleen, skeletal muscle, and cerebral and coronary vasculature,
NPY has direct vasoconstrictor actions. In the heart and brain, (b) (c)
local intrinsic (nonsympathetic) neurons use NPY as the prin-
cipal transmitter (see Figure 5.5b). In the spleen, NPY appears Figure 5.5 Schematic representation of different interactions that occur between
neuropeptide Y (NPY) and adenosine triphosphate (ATP) and the norepinephrine
to act as a genuine co-transmitter with NE in perivascular sym-
(NE) released from single sympathetic nerve varicosities.
pathetic nerves (see Figure 5.5c) (73). The frequency of stimu- (a) Diagram showing what occurs in the vas deferens and many blood
lation determines which vesicles are mobilized to release their vessels, where NE and ATP, probably released from small granular vesicles, act
transmitters. synergistically to contract (+) the smooth muscle through α1 adrenoceptors and
A classic transmitter, such as acetylcholine, coexists with VIP P2 purinoceptors, respectively. (b and c) Sympathetic neurotransmission in the
in the parasympathetic nerves of many organs, but in this in- heart and brain (b) and the spleen (c).
stance, the two transmitters are stored in separate vesicles. They Reprinted from Miller’s Anesthesia, Miller, R., Eriksson, L., Fleisher, L., et al. (eds), Chapter 5, The
Autonomic Nervous System, Glick, D., p. 349. Copyright (2015) with permission from Elsevier.
can be released differentially at different stimulation frequencies,
depending on where they are located (74, 75). For example, in
the salivary gland, they can act independently on acinar cells
and glandular blood vessels (68). Cooperation is achieved by the nearly every adrenergic and dopaminergic receptor subtype. The
selective release of acetylcholine at low frequencies and of VIP genetic coding for the muscarinic receptor subtypes, on the other
at high frequencies of stimulation. Elements of prejunctional hand, is remarkably well conserved (77). In addition to variants in
and postjunctional modulation have also been described. It is the coding for the autonomic receptors, genetic mutations in the
becoming increasingly apparent that in many biologic states, codes for the proteins responsible for catecholamine synthesis, re-
including pregnancy (76), hypertension, and aging, the relation- uptake, and breakdown have also been identified as have variants
ships among co-transmitters may be an important determinant for the receptor coupled G-proteins (78). Though many poten-
of a compensatory response, allowing finer control of important tial genetic contributors to autonomic-related disease states, such
physiologic function. Additionally, the large number of dif- as essential hypertension, lipid and glucose metabolism, postural
ferent receptors may provide targets for potential pharmacologic tachycardia syndrome (79), and long-QT syndrome (80) have been
interventions. identified, no single genetic mutation has completely explained any
of the examined autonomic dysfunctions. Therefore, abnormalities
Genetic Contributors to Autonomic Function in autonomic function are likely polygenic in origin with signifi-
In recent years an explosion in the knowledge of non-Mendelian cant environmental inputs. Once the collection of genetic variants
genetic contributors to human physiologic and pathophysiologic responsible for the majority of the autonomic findings of a given
function has occurred. Genetic variations as small as a single nu- disease are identified, the impact of the combined genetic contribu-
cleotide polymorphism and, to a lesser extent, larger deletion and tion on responsiveness to a given drug or class of drugs will need to
insertion sequences have been identified in the genes that code for be assessed through directed clinical trials.
9 5
23. Schiavo G, Rossetto O, Montecucco C. Clostridial neurotoxins as

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61
CHAPTER 6
Neuromuscular Junction
Anatomy and Physiology,
Paralytics, and Reversal Agents
Christiane G. Stäuble, Heidrun Lewald,
and Manfred Blobner
Introduction: A Short History from Arrow distinct parts: the presynaptic terminal, the synaptic cleft, and the
postsynaptic membrane.
Poison to Muscle Relaxants Presynaptically, the nerve synthesizes the transmitter acetylcho-
The French physiologist Claude Bernard (1813–1878) discovered line (ACh) and stores it in small vesicles. If an action potential ar-
that curare, the arrow poison that the Amazon Indians extracted rives at the distal motor nerve ending, voltage-gated channels allow
from the plant Chondodendron tomentosum, causes paralysis activity-dependent entry of Ca2+ ions, which results in fusion of the
without interrupting nerve conductivity, leaving the muscle sus- acetylcholine vesicles with the presynaptic membrane and release of
ceptible to contraction by direct stimulation (1, 2). This finding was ACh into the synaptic cleft. The released transmitter diffuses in the
a milestone in the discovery of the neuromuscular junction, i.e., the synaptic cleft and binds to the postsynaptic nicotinic acetylcholine
interface between muscle and nerve. receptor (nAChR) resulting in muscle contraction. Subsequently,
In 1911, the German surgeon Arthur Läwen had started to acetylcholine detaches from the receptors and is degraded by the en-
administer preparations of curare intramuscularly to his an- zyme acetylcholinesterase (AChE). Neuromuscular blocking agents
esthetized patients in an attempt to paralyse their abdominal block the postsynaptic nAChRs by inhibiting the binding of ACh.
muscles and optimize his surgical conditions (3). Since curare
was not sufficiently available at that time, it took 30 years till Presynaptic Physiology and Pharmacology
Harold Griffith and Enid Johnson introduced a purified extract The presynaptic release of acetylcholine is triggered by the influx
of curare as a paralytic agent in a patient undergoing general of calcium through voltage-dependent ion channels. Certain drugs
anaesthesia in 1942 (4). By the middle of the twentieth century, inhibit the influx of calcium into the nerve terminal and the re-
neuromuscular blocking agents were routinely used in clinical lease of acetylcholine. Magnesium competitively inhibits the influx
practice and the concept of ‘balanced anaesthesia’ was estab- of calcium into the nerve terminals, whereas calcium channel ant-
lished (4, 5). agonists and aminoglycoside antibiotics block the channel. Hence,
Currently, muscle relaxants are administered in anesthetized these drugs impair neuromuscular transmission and potentiate the
patients to provide temporary muscle paralysis to facilitate endo- effect of neuromuscular blocking agents.
tracheal intubation (6) and to improve surgical conditions during a The nAChR is the key player in neuronal communication con-
procedure (7). Less commonly, muscle relaxants are used in critic- verting neurotransmitter binding into membrane electrical de-
ally ill patients in the intensive care unit (ICU) to facilitate mechan- polarization. Notably, some ACh receptors are located on the
ical ventilation, decrease oxygen consumption, and attenuate rises presynaptic terminal of the neuromuscular junction. Their subunit
in intracranial or intrathoracic pressures resulting from suctioning composition (α3β2) differs from the postsynaptic receptors. These
or coughing (8). Another indication for muscle relaxants is to pre- presynaptic ACh receptors facilitate the release of acetylcholine
vent motion during therapeutic or diagnostic manoeuvres, either to from the nerve terminal through a positive feedback mechanism
prevent self-injury or to prevent dislodgement of medical devices preventing the decrease (fade) of transmitter release during repeti-
(endotracheal tube) (8). tive nerve stimulation. It is important to note that nondepolarizing
neuromuscular blocking drugs block both the presynaptic and
the postsynaptic ACh receptors. Thus, the facilitated ACh release
Anatomy and Physiology associated with this positive feedback mechanism is impaired by
The mammalian neuromuscular junction is the prototypical and the presence of nondepolarizing neuromuscular blocking agents.
most extensively studied synapse, which is designed to enable rapid Clinically, this is detected as a ‘fade’ during repetitive nerve
transmission (9). It consists of three functionally and structurally stimulation.
62
62 Section 1 neuroscience in anaesthetic practice
Postsynaptic Physiology and Pharmacology 75% of the ACh receptors must be occupied by an antagonist before
In the healthy innervated muscle, the postsynaptic ACh receptors any effect can be seen (‘Iceberg phenomenon’). At least 95% receptor
are highly localized to the neuromuscular endplate region and are occupancy is necessary for complete neuromuscular paralysis (see
considered as ‘mature’ receptors. A mature receptor consists of Figure 6.1). The percent receptor occupancy, and not the abso-
five subunits (9–11). Four different proteins, termed α, β, ε, and lute receptor number blocked, varies with dose and therefore with
δ-subunit are present in a ratio of 2:1:1:1. The binding sites for concentrations reached at the neuromuscular junction. Therefore,
ACh and for nondepolarizing blocking agents are localized in the if the receptor number is increased, and if antagonists occupy the
α-subunit (10). However, when there is deprivation of neural influ- same percentage of receptors, the absolute number of receptors re-
ence or activity, as in the foetus or after denervation, the muscle ex- maining unblocked is still high. In these instances, a given concen-
presses ‘immature’ or ‘foetal’ acetylcholine receptors, in which the tration of muscle relaxant will produce a smaller paralytic effect,
ε-subunit is been replaced by a γ-subunit (8, 12). These immature provided that other factors, such as ACh release, are unchanged.
nAChR receptors are no longer localized at the endplate region, but Clinically, this can be described as resistance to antagonists (10).
are spread throughout the muscle membrane at the junctional and
extrajunctional area (8). This ‘ε to γ-switch’ in nAChR subunit com- Paralytics: Mechanisms of Action of Muscle
position has important physiologic and metabolic consequences for Relaxants
the receptor (10, 13). The mature ACh receptors are metabolically
Neuromuscular blocking agents inhibit the postsynaptic ACh re-
more stable, with a half-life approximating two weeks, whereas im-
ceptor leading to muscle paralysis. They are classified into two
mature ACh receptors have a metabolic half-life of around 24 hours
major groups: competitive block of the acetylcholine receptors pro-
(14). Immature receptors have a smaller single channel conduct-
duced by nondepolarizing neuromuscular blocking agents, and the
ance, but a two-to tenfold longer mean channel open time (15, 16).
non-competitive block by depolarizing neuromuscular blocking
In addition, the sensitivity and affinity to ligands differ. Agonists,
agents (see Figure 6.2).
such as ACh and succinylcholine, depolarize immature receptors
more easily; one-tenth to one-hundredth of normal doses of these
Competitive Block
agonists can effect depolarization (16, 17).
The nondepolarizing neuromuscular blocking drugs bind to the
Margin of Safety of Neurotransmission α-subunit of the ACh receptor. They do not, however, show any
intrinsic agonist activity. Since one molecule of a nondepolarizing
Paton and Waud first described the margin of safety of neurotrans-
muscle relaxant is sufficient to occupy the receptor and prevent
mission and developed the concept of the relative excess of AChRs
opening of the ion channel, ACh and the nondepolarizing muscle
that need to be blocked prior to twitch depression (muscle relax-
relaxants compete for the α-subunit binding site at the receptor.
ation) (18). After administration of neuromuscular blocking agents,
Hence, the term ‘competitive block’ indicates that the chance of
Injection
Time to 95% recovery
Time to 25% recovery
onset Recovery index (25%–75%)

100
Transmission [%]
Neuromuscular
0
Injection
95
Blocked Acetylcholine
75
Receptors [%]
Time
Figure 6.1 ‘Iceberg-phenomenon’ and definitions of neuromuscular parameters.

63
Chapter 6 neuromuscular junction 63
DRUG: Acetylcholine Succinylcholine High or repetitive Benzylisoquinolones

doses of Steroid muscle relaxants
succinylcholine
ACTION: Agonist Partial Agonist Partial antagonist Antagonist
Phase I-block +
Non-competitive Phase II-block
Competitive block
EFFECT: Contraction block and (non-competitive
with paralysis
paralysis and competitive)
with paralysis
Intrinsic agonist activity
Figure 6.2 Agonistic and antagonistic interactions at the nicotinic acetylcholine receptor.
binding is solely dependent on the concentration of each ligand pre- block is also not fully understood. If many receptors are desensi-
sent at the neuromuscular junction and its affinity for the receptor. tized, insufficient normal receptors are left to depolarize the motor
end plate and neuromuscular transmission is impaired.
Non-Competitive  Block
The neuromuscular paralysis produced by the depolarizing neuro- Channel Block
muscular blocking drug succinylcholine is non- competitive. Direct channel blocking occurs when molecules that bind to the
Succinylcholine is a partial agonist of the ACh receptor and opens ACh receptor change its conformation preventing its physiologic
the ion channel. Here, the binding of only one succinylcholine mol- function and further ACh binding to the α-subunit. Accordingly,
ecule to the α-subunit is sufficient to depolarize the receptor (phase the result either can be an open or a closed channel block, or flick-
I block) and induces muscle fasciculations followed by paralysis. ering between open and closed states. This can occur following
The other α-subunit can be occupied by either ACh or succinyl- administration of ACh or neuromuscular blocking agents. ACh re-
choline. In contrast to ACh, succinylcholine cannot be hydrolysed ceptors are also susceptible to a channel block if a deep neuromus-
by AChE. Therefore, it detaches from the receptor and repeatedly cular blockade by nondepolarizing relaxants is antagonized with
binds to other ACh receptors until it is cleared from the junctional AChE inhibitors. The increased number of ACh molecules dis-
area into the plasma where it is hydrolysed by the enzyme plasma places the muscle relaxant and prevent its binding to the α-subunit,
(pseudo-) cholinesterase. while the channel is kept open by ACh. The relaxant molecules then
can enter the open channel and block the receptor for a longer dur-
Phase II Block ation than the original block produced by binding to the α-subunit.
A Phase II block is a complex phenomenon observed not only
after high doses of succinylcholine, but also after regular doses of Acetylcholinesterase Enzyme
succinylcholine during decreased metabolism due to lack or func-
tional inefficiency of the pseudocholinesterase. Consecutively, suc- AChE hydrolyses ACh to acetate and choline within one milli-
cinylcholine is relatively overdosed in the synaptic cleft and the second after its presynaptic release. Both metabolites do not show
initial phase I (depolarization) block is converted into a phase II any intrinsic activity at the nAChR. By specific inhibition of AChE,
(nondepolarizing) block (19). The exact mechanism underlying the metabolism of ACh can be prevented, and its concentration in
a phase II block, however, remains unclear. Clinically, a phase II the synaptic cleft increased. Clinically, this is used to reverse the
block is characterized by a tetanic or train-of-four (= TOF) fade. effects of nondepolarizing neuromuscular blocking drugs (see
Importantly, a phase II block can be reversed with AChE inhibitors Reversal Agents).
in contrast to phase I block.
Chemical Structure and Specific Properties
Desensitization Block of Muscle Relaxants
If ACh receptors have been sensitized, they can still bind ACh, but
they cannot be activated to open their channels. It is likely that the Structure-Activity Relationship of Muscle Relaxants
desensitized state is a physiologic response, in which the desensi- Analogous to ACh, all muscle relaxants have at least one quaternary
tized ACh receptors are in equilibrium with the sensitive receptors amine group which is involved in binding to the nAChR α-subunit.
to prevent excessive muscle response to extreme neural stimulation Succinylcholine consists of two ACh molecules bound together to
(12). An increase in desensitized receptors can be induced by an form diacetylcholine. Therefore, it retains the depolarizing capacity
extreme concentration of agonists, high levels of ACh or succinyl- of ACh, but is not susceptible to hydrolysis by AChE. Since suc-
choline. Here, the exact mechanism that induces a desensitization cinylcholine can only be metabolized by the plasmacholinesterase,
64
degradation of succinylcholine is delayed when compared doses of nondepolarizing neuromuscular blocking drugs have
with ACh. no effect on these autonomic ganglia, with the exception of
Most nondepolarizing neuromuscular blocking drugs also pancuronium. After injection, pancuronium blocks muscarinic re-
contain two amine groups. Some of these compounds have two ceptors evidenced as tachycardia.
quaternary amines. D-tubocurarine (curare), vecuronium, and Aside from the clinical effects of compounds on the receptors of
rocuronium are mono-quaternary at a physiological pH. The the ANS, central effects are also possible, especially after prolonged
second amine group is protonated and is therefore present in an use and disrupted blood-brain barrier. Animals studies indicate
uncharged state as a tertiary amine. Steroidal muscle relaxants with that the intrathecal administration of muscle relaxants can induce
bisquaternary structure prefer to block postganglionic muscarinic seizures (22). Case reports of accidental intrathecal injection have
ACh receptors leading to vagolytic effects. In mono-quaternary confirmed these findings in humans (23).
substances (e.g. vecuronium, rocuronium), the vagolytic effects are
much weaker. Relaxant Effects on the Carotid Body
The stereochemical aspects of a compound also play a role Neuronal type nAChRs are important in signalling hypoxia from
in structure- activity relationships. Muscle relaxants of the the carotid body chemoreceptors to the CNS. Muscle relaxants were
benzylisoquinolone type (d- tubocurarine, mivacurium, and shown to inhibit these neuronal ACh receptors at the carotid body
atracurium) tend to have histaminergic side effects. Some ste- and therefore, to reduce the acute hypoxic ventilatory response,
reoisomers of atracurium have histaminergic properties, while which normally compensates for a decrease in oxygen saturation
cisatracurium does not show histaminergic side effects in by increasing the respiratory minute volume (24).
clinical doses.
The affinity to the nAChR is of major importance for the onset Relaxant Effects on Bronchial Smooth Muscle
time of a muscle relaxant (20). Muscle relaxants with a lower af- Muscle relaxants are also able to exert effects on muscarinic recep-
finity need to be administered in higher doses to achieve complete tors which are found on smooth muscles of the bronchi. The M2 and
neuromuscular block. The high initial dose, however, is associated M3 receptors, both expressed on smooth muscle subtype, inhibit
with a higher concentration gradient between the central compart- relaxation and facilitate contraction of smooth muscle, respectively.
ment and the neuromuscular junction, and this results in rapid Although muscarinic receptor control of the airway is complicated,
drug diffusion to the ACh receptor, resulting in faster onset of the muscle relaxant-induced net effects on airway tone depend on
paralysis (21). the relative block of M2 and M3 receptors. Since M3 muscarinic re-
ceptor activation is associated with contraction, potent antagonists
Intrinsic Activity of Relaxants at the Neuromuscular at the M3 muscarinic receptor should inhibit bronchoconstriction,
Junction despite the M2 muscarinic receptor block. At doses in the clinical
Ligands at the nAChR induce either agonistic, partial agonistic, or range, pancuronium, a potent M2 antagonist, is not associated with
antagonistic activity depending on their intrinsic activity (Figure bronchoconstriction, because it is a potent M3 muscarinic receptor
6.2). The classic agonist is ACh: after binding of two ACh mol- antagonist (25). Rocuronium, cisatracurium, or mivacurium also
ecules (one to each of the α-subunits), the receptor-associated ion do not potentiate vagally induced bronchoconstriction (26).
channel opens and muscle contraction follows. Succinylcholine
acts as a partial antagonist: it opens the ion channel after binding to Histamine Release and Anaphylaxis by Relaxants
the receptor; however, it elicits only an initial depolarization with Histamine release from mast cells can be induced either by an
muscle fasciculations followed by muscle paralysis. In contrast, antigen-antibody reaction as a result of anaphylaxis (mediated by
nondepolarizing muscle relaxants are antagonists of the ACh re- IgE), by activation of the complement system (IgG or IgM), or by
ceptor displaying minimal intrinsic agonist activity. direct action of molecules on the surface of mast cells. Two types
of mast cells are differentiated: mucosal (in the bronchial system
Relaxant Effects on ACh Receptors of the Central and and gastrointestinal tract), and serosal (vascular endothelium, skin,
Autonomic Nervous System connective tissue) (27).
Nicotinic acetylcholine receptors are not only located at the neuro- Direct Effects on Mast Cells
muscular junction, but are also found in the central nervous system
The quaternary ammonium structure of muscle relaxants presents a
(CNS) and in autonomic ganglia. Although these ACh receptors
weak histaminergic effect on mast cells. In clinical doses, succinyl-
differ in their subunit composition, they all contain α-subunits with
choline and benzylisoquinolones (d-tubocurarine, atracurium,
ACh-binding capacity. Therefore, it is obvious that muscle relaxants
mivacurium) can directly liberate histamine from serosal mast
that bind to the ACh receptors of the neuromuscular junction have
cells. Clinical symptoms are erythema, blistering, tachycardia,
the potential to interact with these receptors located in the central
and hypotension. The pharmacologically selective cis-atracurium
and autonomic nervous system (ANS).
and the commonly used steroidal muscle relaxants (pancuronium,
Ganglia of the ANS transduce either sympathetic or parasym-
vecuronium, rocuronium) have no direct histaminergic effects
pathetic signals, both with the transmitter ACh. Succinylcholine
(28). In clinical practice, the administration of histamine receptor
stimulates sympathetic and parasympathetic ganglia, and the post-
blockers can suppress the side effects of histamine release (29).
ganglionic parasympathetic muscarinic receptors. Thus, increased
salivary secretions and bradycardia are common after administra- Anaphylactic Reactions
tion of succinylcholine. To prevent these reactions, muscarinic re- Anaphylactic reactions to muscle relaxant are very rare and are not
ceptors can be prophylactically blocked with atropine. Therapeutic related to other drug allergies (30).
65
Pre-Clinical Pharmacology 4. Recovery index: The recovery index usually describes the speed
of the offset of the paralytic effect, and is defined as the time
and Pharmacological Variables taken for recovery from 25% to 75% twitch height.
of Neuromuscular Block 5. Total duration of action: The total duration of action is described
The neuromuscular blocking action of muscle relaxants is char- by the interval between injection of the muscle relaxant and re-
acterized by a decreased contractile response to stimulation of covery of the TOF-ratio to ³ 0.9 (31).
the respective motor nerve. To determine the clinical response
after injection of a muscle relaxant, the twitch depression of a
Pharmacokinetics
skeletal muscle (e.g., adductor pollicis muscle) in response to its
nerve stimulation (ulnar nerve) is measured following injection Muscle relaxants are usually administered intravenously to ensure
of the muscle relaxant. A twitch of 100% is the response in ab- rapid onset, fast distribution, and predictable elimination. A de-
sence of any neuromuscular block, while 0% indicates complete sired paralytic effect after subcutaneous or intra-muscular appli-
paralysis. Although there is an individual variability among pa- cation can only be achieved with high relaxant doses, while the
tients in terms of response to muscle relaxants, the compounds pharmacodynamics after intramuscular injection are unpredict-
are characterized by the following pharmacologic variables (see able. Importantly, muscle relaxants are not absorbed through the
also Figure 6.1): gastrointestinal tract.
1. Potency: The potency of a muscle relaxant is described by its
Pharmacokinetic Models and Parameters
‘effective dose’ (ED): ED95 and ED50 are the doses of muscle
relaxant necessary to suppress the twitch response by 95% (5% Pharmacokinetic models attempt to describe the relationship be-
twitch height) or 50% (50% twitch height) of baseline (100%) tween time and plasma concentration of a drug and its metabolites in
twitch height, respectively. mathematical terms. The parameters for muscle relaxants are gener-
ally calculated by using a two-compartment model. After injection,
2 Onset: Onset describes the time interval between injec- the muscle relaxant is immediately distributed in the ‘central’ com-
tion of the muscle relaxant and development of maximal partment, before it is redistributed to the ‘peripheral’ compartment
neuromuscular block. (biophase, neuromuscular junction) (Figure 6.3). Metabolism and
3. Clinical duration of action (dur25 or dur95): The clinical duration elimination of the drug begins almost instantaneously. Parameters
of action is the interval between injection of the muscle relaxant that are used to describe the pharmacokinetics of a muscle relaxant
and recovery of the twitch to 25% or 95% of baseline twitch are the initial total volume of distribution, volume of distribution at
height (i.e., 75% and 5% twitch suppression), respectively. If the steady state, plasma clearance, and elimination half-life. The term
surgical conditions require continued relaxation, re-injection of context-sensitive half-life describes the pharmacokinetics of a drug
the muscle relaxant becomes necessary at or before 25% recovery. after repeated or continuous administration.
Injection k01
1
2 k21
k0e Effect
Central Compartment Compartment
ke0
k12 (Biophase)
Peripheral Compartment
k20 k10 k10 k10
Elimination Elimination
Degradation: Renal: All
plasma cholinesterase: additionally
mivacurium, succinylcholine Hepatic: Steroids
Hoffmann degradation: Hoffmann Degradation in plasma:
cis-atracurium cis-atracurium
plasma cholinesterase:
succinylcholine
Figure 6.3 Schematic illustration of the distribution of muscle relaxants in the different compartments.
The propagated model can be used to mathematically determine pharmacokinetic parameters. kx-y describes the redistribution constants between the different
compartments.
6
Factors Influencing Pharmacokinetics of Relaxants Pregnancy

Volume of Distribution During pregnancy, the pharmacokinetics and pharmacodynamics
All muscle relaxants have a more or less positively charged qua- of muscle relaxants remain unaltered. However, increased po-
ternary ammonium group, which remains ionized independent of tency and duration of action should be considered with the use of
the pH. The positive charge makes it almost impossible for muscle nondepolarizing muscle relaxants when magnesium is adminis-
relaxants to bind to lipids. Therefore, the volume of distribution of tered for premature uterine contractions or pre-eclampsia.
muscle relaxants is almost exclusively in the extra-cellular space. Temperature
If muscle relaxants are administered for prolonged time (>24h), Hypothermia prolongs the duration of action of muscle relaxants
distribution into less perfused tissue (third compartment) such as due to a delayed metabolic breakdown and delayed hepatic and
connective tissue occurs resulting in a volume of distribution that renal clearances (40). In the case of atracurium and cis-atracurium,
can then increase up to tenfold (32). it is also related to a delayed spontaneous decay (Hofmann
Plasma Protein Binding elimination).
After injection, muscle relaxants bind to plasma proteins, particu-
larly to albumin and γ-globulins. Elimination and Metabolism of Relaxants
Pharmacologic Potency The neuromuscular effect of a single dose of a relaxant is primarily
The pharmacologic potency of a muscle relaxant is described by terminated by redistribution from the neuromuscular junction
its affinity to the acetylcholine receptor. Many relaxants exhibit and central compartment to the peripheral compartment. After
a reciprocal relationship between pharmacologic potency and repeated injections, however, the redistribution capacity becomes
onset time. If a low-affinity drug requires a high dose of muscle starved, and the relaxants and their active metabolites can be re-
relaxant (e.g., higher ED95) to achieve a defined twitch depres- distributed into the central compartment. Thus, neuromuscular
sion, the concentration gradient between the central compart- recovery is determined primarily by the elimination of the drug.
ment and neuromuscular junction will be high, resulting in
faster delivery of the drug to the receptor. In contrast, if the
Renal Elimination
drug has a high affinity for the acetylcholine receptor, it will All muscle relaxants can be eliminated through the kidneys. At
be administered in smaller doses (lower ED 95), and the gra- physiological pH, muscle relaxants are ionized as quaternary
dient for drug transfer will be lower, resulting in a slower onset amines. Patients with healthy renal function can eliminate muscle
(20, 21). relaxants at a rate of approximately 1–2 ml/kg/min. Reabsorption
from the tubules does not take place. In patients with impaired renal
Speed of Injection function, the elimination half-life of muscle relaxants excreted pri-
Fast injection of muscle relaxant generates a high concentration marily by the kidneys (pancuronium, rocuronium) is prolonged.
gradient between the central compartment and neuromuscular
junction, and therefore expedites onset time. Metabolism—Ester Hydrolysis
Perfusion Succinylcholine and mivacurium are inactivated by the
Intravenously administered muscle relaxants must be transported plasmacholinesterase after redistribution in the central
via the bloodstream to their effective compartments. If the cardiac compartment.
output is reduced, onset of the neuromuscular block is delayed (33). Atypical Plasma Cholinesterases
Obesity The incidence of individuals with heterozygous atypical plasma
At normal doses, the positive charge of the muscle relaxant pre- cholinesterase is 1:480. The duration of action of succinylcho-
vents its absorption into fat tissue. Therefore, the body weight- line and mivacurium in these cases is only minimally delayed.
related volume of distribution and clearance in obese patients is Homozygous carriers of the atypical plasma cholinesterase (inci-
markedly reduced compared to normal patients. The elimination dence: 1:3200), however, can experience prolonged neuromuscular
half–life, however, remains almost unaltered (34). block enduring up to three to six hours. The ‘dibucaine test’ uses the
local anaesthetic dibucaine to inhibit plasma cholinesterase in vitro
Age (41). Normal isoforms of plasma cholinesterase are more easily in-
The volume of distribution for muscle relaxants is larger in chil- hibited than the atypical isoforms. The percentage of inhibition of
dren compared with adults. Therefore, children require a higher plasma cholinesterase is referred to as ‘dibucaine-number’. Normal
dose of muscle relaxant to achieve a given relaxant concentra- plasma cholinesterases will be inhibited about 70% by dibucaine,
tion. The neuromuscular junction is also more sensitive in the whereas abnormal cholinesterases are less inhibited.
child compared with the adolescent (35). Thus, the higher dose
can result in a prolonged paralysis. The increased heart rate Acquired Cholinesterase Deficiency
and cardiac index in children also shortens the onset time of Different factors, e.g., renal insufficiency or pregnancy, can in-
neuromuscular block. hibit the plasma cholinesterase activity. Furthermore, various
Despite the decrease of ACh receptors with aging (36, 37), the drugs effect cholinesterase function, e.g., cholinesterase inhibitors,
sensitivity towards neuromuscular blocking drugs remains un- pancuronium and the anti-emetic metoclopramide. If the plasma
altered (36, 38, 39). However, distribution and elimination kin- cholinesterase activity is reduced to values around 500 IU/l, the
etics are often prolonged in the elderly due to impaired organ neuromuscular block induced by succinylcholine or mivacurium
function. can be prolonged up to 2.5 times (42).
67
Metabolism-Nonenzymatic Decay (Hofmann Effects and Side Effects of Succinylcholine

Elimination) By depolarizing the endplate, succinylcholine induces muscle
Atracurium and cis-atracurium are inactivated by spontaneous, fasciculations, followed by paralysis, and causes a variety of un-
temperature, and pH-dependent degradation by the so-called wanted side effects (Box 6.2). Due to its mechanism of action
Hofmann elimination. Their metabolites are inactive at the neuro- succinylcholine causes a temporary increase in serum potassium
muscular junction. Hofmann elimination takes place in the central levels, even in healthy patients. Clinically this becomes relevant
and peripheral compartment and in the synaptic cleft. In addition, in patients with neuromuscular pathologies where quantitative
atracurium is degraded via ester hydrolysis. and/or qualitative changes in the ACh receptor expression occur.
In patients with up-regulation of ACh receptors, there is a larger
Metabolism—Hepatic Elimination increase in serum potassium levels after succinylcholine admin-
Steroidal relaxants are eliminated via the kidneys and the liver. For istration. The resulting hyperkalaemia can cause dangerous dis-
vecuronium and rocuronium, hepatic elimination processes faster turbances in cardiac rhythm, including ventricular fibrillation
than renal elimination, but slower than the dissipation of action (9). (see also Neuromuscular Diseases and Muscle Relaxants)
due to redistribution. If muscle relaxants are given repetitively, after It is imperative to question the use of succinylcholine if a patient
drug redistribution is starved, the recovery from neuromuscular has a pre-existing hyperkalaemia. It is difficult, however, to provide
blockade is prolonged. an exact number above which succinylcholine should not be used.
The number 5.5mEq/l is usually referenced (46). Since the use of
rocuronium is also well established for rapid sequence induction,
Clinical Pharmacology of Depolarizing alternative approaches are currently available (47).
Relaxant Succinylcholine The mechanism for the increase in intracranial pressure (ICP)
Succinylcholine, the only depolarizing muscle relaxant in clinical is incompletely understood. It may be mediated via an increase in
use today, is given almost exclusively for rapid-sequence induction afferent spinal neural traffic originating from muscle spindle fibres,
(RSI) in patients with an increased risk for aspiration (43, 44). followed by an increase in cerebral blood flow (48).
The effects of succinylcholine on the cardiovascular system are di-
Rapid Sequence Induction verse, since it binds to the cholinergic receptors of the ANS (Box 6.2).
After intravenous injection, most of the succinylcholine is imme- Succinylcholine stimulates muscarinic receptors at the sinoatrial node
diately metabolized by the plasma cholinesterase, even before it of the heart, inducing bradycardia. These effects often are observed
reaches the synaptic cleft. Thus, only a fraction reaches the neuro- when high vagal tone is present, which is common in paediatric pa-
muscular junction and displays a depolarizing effect within 20–40 tients or after vagal stimulation induced by the laryngoscopy blade.
seconds. Clinically, this can be seen as a series of muscle fascicu- Although rare, the use of succinylcholine is associated with the
lations followed by deep neuromuscular paralysis within the first highest incidence of anaphylactic reactions among neuromus-
minute after injection. cular blocking agents. Should severe cardiopulmonary side effects
The ED95 for succinylcholine is 0.3 mg/kg bodyweight. In clinical occur after injection of succinylcholine, it is vital to consider an
practice, however, to ensure fast and complete paralysis very often allergic reaction and treat the patient accordingly. In addition,
1.0 mg/kg (3 ´ ED95) of succinylcholine is given. However, a re- succinylcholine is a strong trigger of malignant hyperthermia.
duced intubation dose (0,5–0,6mg/kg KG) can also provide accept-
able intubating conditions within 60 seconds (45). Neuromuscular Clinical Pharmacology of Nondepolarizing
recovery begins after succinylcholine diffuses into the plasma, Neuromuscular Blocking Drugs
where it is metabolized by plasma cholinesterase. Despite the devel-
opment of newer nondepolarizing neuromuscular blocking drugs Nondepolarizing neuromuscular blocking drugs can be classified in
with faster onset times (rocuronium) or shorter duration of action a number of ways (Table 6.1), but it is their chemical structure that
(mivacurium), succinylcholine remains the only muscle relaxant
that combines both properties: short onset time (<1 min) and short Box 6.2 Adverse Effects of Succinylcholine.
duration of action (5–10 min). The absolute and relative contra-
indications for use of succinylcholine are based on its side effects Stimulation of muscarinic acetylcholine receptors of the car-
(Box 6.1). diac sinus node
Bradycardia
AV-node  rhythm
Ventricular arrhythmia
Depolarization of the endplate
Box 6.1 Contraindications to Succinylcholine. Increased intracranial pressure
Neuromuscular diseases Increased intraocular pressure
Denervation (after two days) Increased intragastric pressure
Immobilization (after three days) Release of intracellular potassium
Burns (after two days) Myalgia
Disposition to malignant hyperthermia Masseter spasm
Allergy against succinylcholine Trigger for malignant hyperthermia (MH)
Homozygous for atypical plasma cholinesterase Allergic reactions
68
Table 6.1 Classification of nondepolarizing muscle relaxants.

In the literature, these muscle relaxants are classified according to their potency (ED95), duration of action, chemical structure, or chronologically,
depending on the relevance.
ED95 (mg/kg) Clinical Introduction Chemical Classification Duration of Action

Rocuronium 0.3 1992 Aminosteroid Intermediate
Vecuronium 0.05–0.06 1980 Aminosteroid Intermediate
Pancuronium 0.06–0.07 1960 Aminosteroid Long
Mivacurium 0.08 1997 Benzylisoquinolone Short
Atracurium 0.25 1980 Benzylisoquinolone Intermediate
Cis-atracurium 0.05 1995 Benzylisoquinolone Intermediate
d-Tubocurarine 0.5 1942 Dibenzyl-tetrahydro-isoquinolone Long
Alcuronium 0.2– 0.25 1964 Strychnine-derivate Long
is most relevant when considering pharmacokinetic and pharma- achieve this onset time (47). However, 1.2 mg/kg rocuronium has a
codynamic parameters and side effects. prolonged duration of neuromuscular block (47).
Priming
Standard Intubation
Two successive injections of a nondepolarizing muscle relaxant can
The major reason for using muscle relaxant for induction of an- decrease the onset of muscle paralysis. Thus, a small subparalytic
aesthesia is to facilitate endotracheal intubation. In clinical prac- (‘priming’) dose is injected about three minutes before the full
tice, little emphasis is put on neuromuscular monitoring when intubating dose. By priming, it is possible to achieve onset times in
determining the optimal time-point of intubation. Most anaes- the range of one minute.
thetists judge the time-point to be when adequate depth of anaes-
thesia and muscle relaxation is achieved by clinical assessment. Increased Intubating Dose
Others use the standard onset time provided by the manufac- By increasing the dose of the nondepolarizing muscle relaxant, the
turer. Normally, a 2 × ED95 dose of a muscle relaxant is injected, onset time for deep paralysis can be decreased, while the risk for
and an intubation attempt is started after the standard onset time unwanted cardiovascular side effects are increased and the time to
(Table 6.2). complete neuromuscular recovery is prolonged.
Rapid Sequence Induction with Nondepolarizing Neuromuscular Recovery from Nondepolarizing

Muscle Relaxants Muscle Relaxants
When there is substantial risk for aspiration, the primary goal during Although nondepolarizing muscle relaxant have very few side ef-
induction of anaesthesia is to secure the airway within 60–90 sec- fects during anaesthesia, a residual duration of action beyond the
onds after loss of the protective airway reflexes. Currently, succinyl- end of surgery is a common problem and referred to as residual
choline (1mg/kg) and rocuronium (1.2 mg/kg) are the only muscle neuromuscular block, sometimes called postoperative residual
relaxants with the appropriate pharmacologic characteristics to curarization (PORC) (49). PORC is a common sequela of muscle
Table 6.2 Onset and duration of action after 2 × ED95.
Onset (min) Dur 25 (min) Duration of Action till TOF ≥ Recovery Index (min)
0.9 (min)
Rocuronium 1.5–2.5 35–50 55–80 10–15
Vecuronium 2–3 30–40 50–80 10–20
Pancuronium 3.5–6 70–120 130–220 30–50
Mivacurium 2.5–4.5 15–20 25–40 5–9
Atracurium 2–3 35–50 55–80 10–15
Cis-atracurium 3–6 40–55 60–90 10–15
Alcuronium 3.5–6 80–120 170–240 45–60
Refer to Figure 6.1 for definitions of Onset, Dur25, TOF ≥ 0.9, and recovery index
69
relaxant use. Up to 60% of all patients receiving a muscle relaxant (12). The receptors with ε-subunits in the healthy junction are re-
have residual paralysis upon leaving the operating room depending placed by receptors containing a γ-subunit, also termed ‘immature’
on the length of surgery (49–51). If residual paralysis is unrecog- receptors (10, 12). Consecutively, the ligand sensitivity and affinity
nized and untreated, patients face postoperative cardiorespiratory of these immature receptors are altered (10). Classic theory of re-
complications (52). The clinical consequences include hypoven- ceptor control suggests that in the presence of increased receptor
tilation (53–55), atelectasis, aspiration (56, 57), pneumonia, and numbers, there is hypersensitivity to agonists such as succinylcho-
even death (58). Simple measures, such as making neuromuscular line, while the antagonist concentration to achieve a given paralysis
monitoring available and advocating the use of reversal agents (see by a nondepolarizing relaxant is increased (10). Neuromuscular
Reversal Agents) to prevent residual curarization are effective tools pathologies inducing ACh receptors upregulation include all forms
for reducing its incidence (52, 59). of denervation (60), immobilization (61), burn injury (62), and sys-
temic inflammation (63). (Figure 6.4)
Factors Confounding the Clinical Lower and Upper Motor Neuron Lesion
Pharmacology of Relaxants The potential for succinylcholine-induced hyperkalaemia after a
lower motor neuron lesion has been well established (64). An in-
Renal Insufficiency and Muscle Relaxants creased sensitivity to succinylcholine is present three to four days
If renal function is impaired, the clearance of relaxants is reduced. after denervation and reaches a critical level after seven to eight
However, since the neuromuscular effects of a single relaxant dose days. Patients demonstrating hypersensitivity to agonists usually
are mainly terminated by redistribution, the neuromuscular re- also display resistance to nondepolarizing neuromuscular blocking
covery is not prolonged after injection of a single dose. After repeti- drugs (65). Lesions such as strokes, cerebral haemorrhage (66),
tive injections, however, the decreased renal clearance of relaxants head trauma (67), multiple sclerosis (68), and paraplegia or quadri-
can prolong neuromuscular recovery. Importantly, the elimination plegia (69) also result in upregulated ACh receptors with the po-
pathways of atracurium, mivacurium, and rocuronium are inde- tential of demonstrating hypersensitivity to succinylcholine and
pendent of the renal function. resistance to nondepolarizing neuromuscular blocking drugs. The
time period over which the receptors remain upregulated is unclear
Hepatic Diseases and Muscle Relaxants (66). Since it is difficult to predict how a neurological patient will
Liver failure is often associated with secondary hyperaldosteronism, react to muscle relaxants, succinylcholine should be avoided and
which results in fluid retention and an increased volume of distri- neuromuscular function monitored when using nondepolarizing
bution of muscle relaxants. Consequently, larger doses of muscle muscle relaxants during anaesthesia.
relaxants are required to achieve a desired paralysis. Due to the im- Immobilization
paired hepatic elimination, the administered high doses may stay
The state of immobilization contrasts with denervation syndromes
in the central compartment for a longer time, which leads to a pro-
in that there is no direct damage to cord or nerve roots, and the
longed neuromuscular blockade.
muscle fibres remain innervated. However, immobilization (from
After a single dose, the clearance times are relatively insignificant
isolated limbs with plaster cast to total body immobilization in
since redistribution within the compartments is the major factor
an ICU setting) also induces an upregulation of ACh receptors
determining duration of action. However, after repetitive adminis-
(61, 70). The peak effect on ACh receptor regulation occurs after
tration of steroidal muscle relaxants accumulation occurs, because
14 days of immobilization, but the duration of these changes is un-
the elimination of these drugs is partly dependent on hepatic func-
clear in humans (61). Immobilization-induced receptor prolifer-
tion. These drugs also have metabolites that are pharmacologically
ation was shown to cause a rightward shift of the dose-response
active. In addition, plasmacholinesterase activity can also be de-
curve of nondepolarizing muscle relaxants (61) and an increased
creased in hepatic dysfunction as a result of decreased synthesis
sensitivity to succinylcholine (10).
(42). Atracurium and cis-atracurium are eliminated independently
of hepatic function.
Neuromuscular Diseases and Muscle Relaxants

Upper motor neuron lesions
The integrity and function of pre-, intra-, and postsynaptic
structures are important for the function of the neuromuscular Lower motor neuron lesions ‘Upregulation’ of AChR
Increased requirement for non-
endplate. Any neuromuscular disease that changes nerve conduc- Muscle trauma
depolarizing muscle relaxants
tion or electrical activity of the muscle membrane, therefore, influ- Burn injury (’Resistance’)
ences neuromuscular architecture, ACh receptor expression, and Immobilization Hyperkalaemia after succinylcholine
pharmacodynamics of muscle relaxants. (Figure 6.4) administration
Sepsis/Infection
Increased Expression of the ACh Receptor
Normal
When innervation and electrical conductivity are established be-
tween muscle and nerve, the mature receptors are localized at the
Myasthenia gravis ‘Downregulation’ of AChR
neuromuscular junction only. Deprivation of the neural influences
Organophosphate poisoning Decreased requirement with non-
leads to an up-regulation of ACh receptors and a spread of the recep- depolarizing muscle relaxants
tors into the peri-and extra-junctional areas of the neuromuscular Chronic cholinesterase inhibition
(Increased sensitivity)
junction (10). In addition, receptor upregulation is associated with
a change in subunit composition towards the immature isoform Figure 6.4 Diseases with altered acetylcholine receptor (nAChR) expression.
70
Burn Injury the cardiac output or muscle perfusion, the onset time to muscle
Burn injury induces an upregulation of ACh receptors in the muscle paralysis is slowed.
underneath the burn site, but not at distant muscles (71). Burn of Neuromuscular transmission can be influenced by drugs that act
a single limb (8–9% body surface area) is sufficient to cause lethal on the nerve terminal or receptor. Presynaptically, three mechan-
hyperkalaemia following succinylcholine (72). Since it takes several isms have been identified, all of which decrease the release of ACh.
days to initiate the upregulation, succinylcholine can be used for up First, cyclic adenosine monophosphate (cAMP) and adenosine
to 48–72 hours after acute burn injury. Any use beyond this time triphosphate (ATP) are necessary to synthesize ACh. Furosemide
point should be avoided (10). inhibits the synthesis of cAMP, thereby also decreasing pre-
synaptic ACh synthesis. Second, volatile anaesthetics block pre-
Infection and Systemic Inflammation
synaptic ACh receptors, which decreases the availability of ACh at
Inflammation and infections influence the dose-relationship of the presynaptic membrane during repetitive stimulation. Finally,
neuromuscular blocking agents (63). Clostridial infections such volatile anaesthetics, as well as magnesium (80, 81), calcium ant-
as botulism, present in drug-abusers (73) and patients with tissue- agonists, and aminoglycoside antibiotics (82) reduce ACh release
allografts (74), inhibit the presynaptic release of ACh and cause by blocking presynaptic calcium channels. Postsynaptically, nu-
long-term muscle weakness with ACh receptor upregulation merous drugs block the α-subunit of the ACh receptor in a dose-
up to 128 days (75). Due to the presynaptic effects of botulinum dependent fashion. These include inhalational anaesthetics (83),
toxin, there is hypersensitivity to nondepolarizing muscle re- aminoglycoside antibiotics (84), quinidine (85), tricyclic anti-
laxant e.g., atracurium despite upregulation of ACh receptors (76). depressants (86), ketamine (87), midazolam (88), and barbitur-
However, botulinum toxin mediated upregulation can also lead to ates (89). Recent data suggest that propofol also has effect at the
hyperkalaemia with succinylcholine as reported in humans (77). neuromuscular junction, since the potency of rocuronium was
In patients with systemic inflammation, resistance towards the significantly enhanced after 30 minutes of intravenous propofol
effects of nondepolarizing muscle relaxant needs to be anticipated anaesthesia (90).
after more than four days. The risk for succinylcholine-induced Dantrolene, which inhibits calcium release and re-uptake into the
hyperkalaemia occurs after more than one week (10). In critically sarcoplasmatic reticulum, is used for acute treatment of malignant
ill patients, infection and immobilization often occur simultan- hyperthermia. It can potentiate the effect of the nondepolarizing
eously, which complicates neuromuscular recovery. Both factors muscle relaxants at a muscular level without exerting an effect on
independently increase ACh receptor expression and, therefore, neuromuscular transmission (91).
pharmacodynamic effects can be potentiated (63).
Decreased Number of ACh Receptors Reversal Agents
Myasthenia Gravis A residual duration of action beyond the end of surgery, or
Myasthenia gravis is an autoimmune disease associated with muscle PORC, is a common problem since it bears a substantial risk for
weakness and fatigue. Antibodies against the ACh receptor are pre- impaired upper airway function (92), airway obstruction, and
sent in approximately 80% of the patients. These auto-antibodies muscle weakness and, consecutively, for pulmonary complications
to the ACh receptor in myasthenic patients lead to a decrease in such as hypoxia and pneumonia (52). Therefore, it is also associ-
receptor number (downregulation of acetylcholine receptors). ated with a delayed discharge from the post-anaesthesia care unit
Clinical symptoms generally start with ptosis and diplopia, and (93). To avoid PORC, the anaesthetist can antagonize the residual
proceed to bulbar paralysis. Later disease stages are marked by dys- effects with cholinesterase inhibitors or after administration of
arthria, dysphagia, and weakness of extremities and respiratory rocuronium or vecuronium with the selective relaxant binding
muscles (78). The therapeutic approach to myasthenia, aside from agent, sugammadex.
thymectomy, is the administration of cholinesterase inhibitors. Due Before reversal of residual neuromuscular block, the degree
to the downregulation of ACh receptors, patients with myasthenia of residual paralysis should be evaluated. The TOF-ratio is the
are sensitive to nondepolarizing muscle relaxants. If muscle relax- most common method of assessing muscle weakness, and a ratio
ants are used during anaesthesia, constant neuromuscular function of ≤0.9 is recommended for full recovery from paralysis (94).
monitoring for the duration of anaesthesia is advised. The reduced Prolonged muscle weakness beyond expected duration after the
number of ACh receptors, however, raises the dose requirements use of nondepolarizing muscle relaxant may be due to delayed
of succinylcholine. For rapid-sequence induction, therefore, it is elimination or increased sensitivity to the drug. After the re-
advisable to increase the dose of succinylcholine to 1.5–2 mg/kg. versal drug has been administered, the patient should be closely
Although the therapy with cholinesterase inhibitors can cause de- monitored in the recovery room, since the half-life of the reversal
layed hydrolysis of succinylcholine and prolong the neuromuscular drug might be shorter than that of the muscle relaxant, poten-
block (79), the discontinuation of cholinesterase inhibitor therapy tially causing reoccurrence of neuromuscular block, so called
is not recommended. re-curarization.
If succinylcholine or mivacurium was used, the underlying
Interaction of Relaxants with Other Drugs reason for prolonged muscle weakness could be plasma cholin-
Although some drugs have neuromuscular effects, due to the high esterase deficiency or atypical plasma cholinesterase. In both cases,
margin of safety of neuromuscular transmission these effects are antagonism with cholinesterase inhibitors will not be beneficial.
only seen as a potentiation of the muscle relaxant effect. Therefore, these patients should be mechanically ventilated until
Hemodynamic effects of drugs that are co-administered with re- spontaneous recovery occurs. In case of prolonged paralysis after
laxants can affect the onset time of muscle relaxants. This can play use of succinylcholine or mivacurium, the activity of the plasma
a major role in rapid sequence induction. If these drugs decrease cholinesterase can be determined.
71
Cholinesterase Inhibitors (Neostigmine, the neuromuscular blocker, the faster the neuromuscular recovery
Pyridostigmine) will be after administration of an antagonist.
Mechanisms of Action 5. The choice of anaesthetic drugs and depth of anaesthesia.
Cholinesterase inhibitors (neostigmine, pyridostigmine) are Since volatile anaesthetics potentiate the neuromuscular blocking
used clinically to antagonize the residual effects of neuromus- effects of nondepolarizing relaxant (104, 105), the efficacy of
cular blocking agents and to accelerate neuromuscular recovery anticholinesterase drugs is decreased in the presence of anaesthe-
at the end of surgery (95). They work indirectly by increasing the tizing concentrations of volatile anaesthetics (106). Withdrawal
ACh concentration at the neuromuscular junction. Thus, the ac- of the volatile anaesthetics at the end of surgery will speed up the
cumulated ACh at the neuromuscular junction competes with pharmacologic reversal (107). In addition, other drugs potentiating
the residual molecules of the neuromuscular blocking drug for the effects of neuromuscular blocking agents (e.g., magnesium, cal-
the available unoccupied nAChR. This increases the chance of cium) also limit the efficacy of anticholinesterase drugs (95).
displacing the muscle relaxant from the ACh receptor.
Side Effects
Pharmacokinetics and Metabolism
Inhibition of AChE not only increases the concentration of ACh
Cholinesterase inhibitors drugs are eliminated via the kidneys. at the neuromuscular junction, but also at all other synapses using
Therefore, the elimination is delayed in patients with kidney ACh as a transmitter. In the parasympathetic system, therefore,
insufficiency. cholinesterase inhibitors have numerous unwanted side effects,
Clinical Pharmacology of AChE Inhibitors including bronchoconstriction, increased airway resistance, in-
creased salivation, and increased bowel motility (95). To minimize
Antagonism of nondepolarizing neuromuscular blockade by AChE
these unwanted side effects, AChE inhibitors are typically com-
inhibitors depends primarily on five factors (95).
bined with a muscarinic antagonist (parasympatholytic drug) such
1. The depth of neuromuscular blockade when reversal is attempted. as glycopyrrolate or atropine.
Cholinesterase inhibitors have been used to antagonize the residual
effects of neuromuscular blockers for decades with the drawback Selective Relaxant Binding Agent: Sugammadex
of its limited use for deep neuromuscular blockade. Importantly, Mechanisms of Action
cholinesterase inhibitors have a ceiling effect on AChE. Once the In September 2008, a new class of reversal drug, the first selective re-
enzyme is completely inhibited, the administration of additional laxant binding agent, sugammadex, was introduced to the European
doses is not useful because the concentration of ACh at the neuro- market. It is unique in its property to rapidly (within one to three
muscular junction is finite. Hence, in a ‘cannot intubate, cannot minutes) and completely reverse the neuromuscular blocking ef-
ventilate’ situation, recovery from a deep neuromuscular blockade fects of rocuronium and eliminate the bound complex via the kid-
after administration of AChE inhibitors is not fast enough to re- neys (108). In 2008, the US Food and Drug Administration (FDA)
store patient’s spontaneous breathing. At reappearance of T2 and initially rejected the use of Sugammadex in the US, but finally ap-
T4 (second and fourth twitch of the TOF-stimulation pattern, re- proved the medication use on 15 December 2015 (109).
spectively) even complete inhibition of AChE with high doses Sugammadex, a modified γ-cyclodextrin, is a hydrophilic mol-
neostigmine (50–70µg/kg) is not able to restore neuromuscular ecule with a lipophilic core that can encapsulate other lipophilic
transmission effectively (96–98). Due to this ceiling effect, a certain molecules. γ-cyclodextrins are cyclic oligosaccharide carbohydrates
degree of recovery has to be awaited before these drugs are effective made of eight sugar molecules obtained from the degradation of
in reversing neuromuscular block. It is recommended to wait until starch (108). Although the drug was designed to bind specifically to
four twitches of TOF stimulation are visible (99, 100). rocuronium, other steroidal muscle relaxants such as vecuronium
2. Anticholinesterase  drugs. and pancuronium are also bound by sugammadex, but with a lower
affinity (110). Sugammadex exerts its effects by forming very tight
The most commonly used anticholinesterase drugs are pyridostig- complexes at a 1:1 ratio with steroidal neuromuscular blocking
mine and neostigmine (95). drugs. One molecule of sugammadex is able to noncovalently bind
3. Anticholinesterase  dose. one molecule of steroidal muscle relaxant. This binding is further
The dose depends on the depth of neuromuscular recovery, the increased by acid groups (COO-) adding an additional electrostatic
desired speed of neuromuscular recovery, and the recovery index bond interaction with the positively charged nitrogen of the muscle
of the used neuromuscular blocking agent. The maximal dose of relaxant. Importantly, no affinity is existing to other muscle relax-
neostigmine should be 70µg/kg (101). For pyridostigmine, the dose ants such as mivacurium, atracurium, and cisatracurium.
ranges between 30–70µg/kg body weight (95).
Pharmacokinetics and Metabolism
4. The rate of spontaneous clearance of the neuromuscular blocker. Recovery of neuromuscular function occurs after injection of
The plasma concentration of drugs with a short duration of action sugammadex within two steps:
decreases more quickly than those with intermediate or long dur-
Step one:
ation. Following administration of cholinesterase inhibitors, the
antagonism induced by the effect of AChE, and the decrease in After intravenous injection of sugammadex, all free intravascular
plasma concentration of the neuromuscular blocker due to redistri- molecules of rocuronium are encapsulated in the central com-
bution and elimination is crucial for the recovery of neuromuscular partment. This leads to a concentration gradient towards the
function (102, 103). Therefore, the more rapid the elimination of neuromuscular junction.
72
Step two: (113), sugammdex was further evaluated before it was licensed in

the US in December 2015 (109). In a randomized, double-blind,
Consecutively, extravasal rocuronium molecules are shifted parallel-group, repeat-dose trial, one person of the 299 participants
from the peripheral compartment (neuromuscular junc- treated with sugammadex showed an anaphylactic reaction (109).
tion) towards intravasal, in the central compartment, where Therefore, clinicians should be aware of the possibility of a hyper-
they get encapsulated. This rapidly restores neuromuscular sensitivity reaction or anaphylaxis and monitor and treat patients
transmission. accordingly.
Since the use of sugammadex can be associated with bradycardia
The elimination half-life of sugammadex is about 100 minutes. It
within minutes of its administration, patients should be closely
is nearly 100% cleared by the kidneys, with a clearance of about
monitored for haemodynamic changes during and after reversal of
75–120ml/min. In the presence of sugammadex, the hepatic bio-
neuromuscular blockade. If necessary, treatment with anticholin-
transformation and biliary excretion of rocuronium is changed to
ergic agents, such as atropine, should be started (109).
a completely liver-independent renal pathway. Although a recent
The most common adverse reactions reported in clinical trials
study indicates that sugammadex provides rapid reversal of deep
included vomiting, low blood pressure (hypotension), pain, head-
rocuronium-induced neuromuscular block in renal insufficient pa-
ache, and nausea (112). In addition, doctors should also advise
tients, current safety experience is insufficient to support recom-
women using hormonal contraceptives that sugammadex may tem-
mended use of sugammadex in this population, considering the
porarily reduce the contraceptive effect, so they must use an alter-
prolonged sugammadex-rocuronium complex exposure in patients
nate method of birth control for a period of time (109).
with severe renal impairment (111).
Clinical Pharmacology of Sugammadex Special Considerations in Neuroanaesthesia
Depending on the muscle relaxant and the depth of neuromus-
cular block at the time of attempted reversal, different doses of and Neurocritical Care
sugammdex are recommended (108) (see Table 6.3) The given doses Neuromuscular Blocking Agents in Neuroanaesthesia
should be able to accelerate the speed of recovery from a neuro- In neuroanaesthesia, muscle relaxants are required for induction of
muscular block to a TOF ratio of 0.9 in an average of three minutes anaesthesia and during surgery to inhibit involuntary movements.
(108). In contrast to cholinesterase inhibitors, sugammadex has Since nondepolarizing neuromuscular blocking agents do not af-
the capability to reverse neuromuscular block independently of its fect cerebral blood, cerebral oxygen metabolism, or ICP (95), they
depth (96). are the first choice. If a rapid sequence induction is required, it is
The affinity of sugammdex for vecuronium is less, which results important to keep in mind that injection of succinylcholine mildly
in a slightly slower speed of neuromuscular recovery. However, increases cranial pressure (114). The mechanism for this increase,
there are no dose recommendations for the immediate reversal of a however, is incompletely understood, but may be mediated via an
vecuronium-induced neuromuscular block. The sugammadex dose increase in afferent spinal neural traffic originating from muscle
to reverse a deep (post-tetanic count of 1–2) or a moderate (TOF spindle fibres, followed by an increase in cerebral blood flow (48).
count >2) vecuronium-induced neuromuscular block are the same Thus, rocuronium can be used in these patients. Rocuronium has
as for rocuronium (108). been shown to be an alternative with identical intubation condi-
tions when used in appropriate doses (1.2 mg/kg) (47).
Side Effects In patients with neuromuscular pathologies, ACh receptor
Sugammadex is biologically inactive, does not bind to plasma pro- upregulation is common following all forms of denervation
teins, and appears to be safe and well tolerated. Additionally, it (strokes, cerebral haemorrhage (66), head trauma (67), multiple
has no effect on AChE or any receptor system in the body (112). sclerosis (68), paraplegia or quadriplegia (69)), prolonged immo-
Due to concerns about the nature and frequency of anaphyl- bilization (61), and systemic inflammation (63), with the potential
axis and hypersensitivity reactions reported in the clinical trials of demonstrating resistance to nondepolarizing neuromuscular
Table 6.3 Sugammadex dosing.
Sugammadex doses for an average reversal time of three minutes in a rocuronium-induced neuromuscular block.
Dose Sugammadex Indication Mean Recovery Time to Remarks

TOF 0.9
16 mg/kg (1, 2) Immediate reversal after 1.2 mg/kg rocuronium 1.5 minutes
4 mg/kg (1, 3–5) Routine reversal of deep neuromuscular block (PTC 1-2) 3 minutes
2 mg/kg (1, 6–9) Routine reversal of moderate neuromuscular block (T2 2 minutes
appearance)
1 mg/kg (10) Reversal at reappearance of four twitches to TOF stimulation 2 minutes Data from single-centre RCT
0.22 mg/kg (11) Reversal at TOF 0.5 2 minutes Data from single-centre RCT
Abbreviations: PTC: post-tetanic count, RCT: randomized controlled trial, TOF: train-of-four count

73
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114. Minton MD, Grosslight K, Stirt JA, Bedford RF. Increases in 120. Annegers JF, Hauser WA, Coan SP, Rocca WA. A population-based
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7
CHAPTER 7
Principles of Neuroprotection
Sophia C. Yi, Brian P. Lemkuil, and Piyush Patel
Neuroprotection is a broad term that includes drug administration ranges from a few hours to several days. Cerebral ischaemia is often
or physiologic manipulation before, during, or after a neurologic divided into two broad categories: global and focal ischaemia. The
insult, in order to limit neurologic injury and optimize outcome. former is characterized by a cessation in CBF (i.e., cardiac arrest).
Energy failure resulting from cerebral ischaemia activates diffuse During global ischaemia, insufficient metabolic substrate (oxygen
biochemical and molecular cascades that are responsible for fur- and glucose) delivery results in rapid energy failure and cellular in-
ther injury and increased morbidity and mortality. Thus, ischaemia jury. Neurons considered selectively vulnerable to ischaemic energy
and its downstream effects are central elements of neuroprotection. failure are found in distinct locations such as the hippocampus (5),
The primary aetiology of central nervous system (CNS) insult may layers III, V, and VI of the cerebral cortex, the striatum, and the
be stroke, which is a leading cause of disability worldwide and the Purkinje cells of the cerebellum (6). Focal ischaemia, which occurs
second leading cause of death, or other insults such as subarachnoid during an ischaemic stroke, results from cessation of blood flow
haemorrhage, neurosurgical procedures, or traumatic brain/spinal through a cerebral artery resulting in reduced CBF to a discrete vas-
cord injury. This chapter begins by discussing cerebral metabolism cular territory. Within the ischaemic territory there is an ischaemic
and energy failure, followed by a summary of the difficulties en- core that undergoes rapid cell death, and a surrounding area known
countered with translation of preclinical neuroprotective strategies as the ischaemic penumbra. The penumbra exhibits electrical dys-
into improved clinical outcomes. It concludes by reviewing peri- function yet may remain viable and salvageable for extended
operative neuroprotective strategies and focuses on the potential periods of time if flow can be restored (7). However, in the absence
role of anaesthetic drugs and physiologic manipulation. of flow restoration, the penumbra is gradually recruited into the
core in a time-dependent fashion. Focal ischaemia is often better
Cerebral Metabolism tolerated than global ischaemia due to the potential for collateral
blood flow, through the circle of Willis and leptomeningeal vessels,
The brain is unique in that its metabolic demands are substantial which may be sufficient to stave off energy failure and cell death for
yet its capacity to store metabolic substrate is limited. As such, the a period of time until efforts to restore normal flow can be initiated.
brain is dependent upon the continual flow of blood to provide a
constant supply of both glucose and oxygen. Oxygen consumption
by the brain averages 3.5 mL of oxygen/100g of brain tissue per mi- Energy Failure and Pathophysiologic
nute. The total cerebral oxygen consumption of 50 mL per minute Mechanisms
represents nearly 20% of total body utilization. To help meet this
high metabolic demand, the brain receives approximately 15% of Severe impairment in metabolic substrate delivery to the brain causes
the total cardiac output. As a result, impairment to cerebral blood a rapid decline in cellular adenosine triphosphate (ATP) and a well-
flow and metabolic substrate delivery is poorly tolerated and results characterized energy failure cascade. Maintenance of homeostatic ion
in rapid energy failure and neurologic dysfunction. gradients across the cell membrane is an active process that requires
Global cerebral blood flow (CBF) is approximately 50 mL/100g of ATP. As ATP levels decline to critical thresholds, ionic homeostasis
brain tissue per minute. CBF is tightly regulated over a wide range cannot be maintained. As a result, the plasma membrane depolar-
of cerebral perfusion pressures (CPPs). Neuronal dysfunction, indi- izes, which is characterized by rapid efflux of K+ and influx of Na+
cated by electroencephalographic (EEG) slowing, is apparent when and Ca+ (8). Simultaneous depolarization of the presynaptic terminal
CBF is reduced to about 20 mL•100 gm•min-1. Therefore, there is releases the excitatory neurotransmitter glutamate. Glutamate acti-
substantial physiologic reserve in substrate delivery. Further reduc- vates both N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-
tion in CPP results in a gradual but progressive reduction in cere- 5-methyl-4-isoxazolepropionate (AMPA) receptors causing further
bral blood flow (Figure 7.1). As CBF approaches 15mL/100g per Ca+ and Na+ influx (9, 10, 11). Additional calcium entry occurs via
minute, the EEG becomes suppressed (1,2). Within the range of voltage-sensitive Ca+ channels on the cell membrane along with re-
6–15 ml/100g per minute, a progressive state of energy failure oc- lease from the endoplasmic reticulum via metabotropic glutamate
curs that ultimately culminates in membrane failure and cell death receptors. The result is toxic cytosolic Ca+ levels and enhanced injury
(3). The time course over which irreversible injury and cell death mediated by glutamate that is referred to as excitotoxicity.
occurs, if flow is not restored, is likely minutes when there is a com- Water passively follows the influx of Na+ and Ca+ into the
plete cessation of flow (as in cardiac arrest, 4). Within the ischaemic cell within minutes, which causes cellular oedema known as
penumbra, neurons remain viable for a variable period of time that cytotoxic edema (12). Further oedema, referred to as vasogenic
78
50 60
Ca2+
g)
mH
(m
40 VSCC
P
CP
Cerebrovascular Reserve Ca2+
CB
F (m
30
l• 1
00g
m
Dysfunction EEG Slowing

-1 •m
20
(viable) EEG Suppressed
in
-1 )
Loss of SSEP
10 Glutamate
Death
Membrane Failure
0 Na+, Ca2+ Na+, Ca2+
Figure 7.1 The effect of cerebral perfusion pressure (CPP) on cerebral blood AMPAR NMDAR
flow (CBF).
When CPP decreases below the lower limit of autoregulation, CBF declines in a Ca2+
pressure-dependent manner. EEG manifestation of reduced cerebral perfusion is
not apparent until CBF decreases to about 20 ml•100gm-1•min-1; although the VSCC mGluR
EEG is suppressed below this flow limit, somatosensory evoked potentials (SSEP)
are still recordable. Neuronal dysfunction is apparent but tissue is still viable if IP3
CBF is restored. With a CBF ~15 ml•100gm-1•min-1, SSEPs are not observed. With Ca2+
further reduction in CBF (below 6–10 ml•100gm-1•min-1), energy failure leads to ER
membrane depolarization (sodium and calcium influx and potassium efflux). Ca2+
Rapid neuronal death ensues. NOS
Lipases Endonucleases Proteases
NO
oedema, occurs over the following 24–72 hours as breakdown PG Cytoskeletal
Peroxy breakdown
of the blood-brain barrier (BBB) allows plasma proteins into LT
Energy failure nitrite
ROS
the brain substance. With severe injury to a significant cere- ROS
bral territory, post-ischaemic oedema may increase intracra- Cyt c release DNA damage
nial pressure and impair cerebral perfusion if it is not managed Caspase-9
aggressively. Caspase-3
From the initial site of injury (the ischaemic core), cellular de- Apoptosis
polarization waves spread over the surrounding tissue to the mar-
gins of the ischaemic zone (13). Spreading depolarization waves
increase metabolic demand, exacerbate energy failure, and cause
further glutamate release. This process is potentially modifiable and Figure 7.2 Excitotoxicity.
thus a target for neuroprotective strategies. Cerebral ischemia leads to massive release of glutamate from presynaptic
terminals. Glutamate subsequently leads to NMDAR, AMPAR, and mGluR
activation. Calcium influx via glutamatergic receptors, from voltage sensitive
Oxidative Stress calcium channels, and from intracellular stores (endoplasmic reticulum, ER) leads
to excessive calcium accumulation in the neuron. Downstream activation of
Calcium is a ubiquitous second messenger and cofactor required lipases, endonucleases, and proteases leads to a variety of detrimental processes
for many cellular enzymes. As a result of uncontrolled increases that all lead to membrane, cytoskeletal, and DNA damage. Activation of nitric
in cytosolic Ca+, an array of detrimental biochemical cascades is oxide synthase (NOS) causes increased nitric oxide (NO); the combination of
initiated (Figure 7.2). Activated proteases break down cytoskeletal NO and superoxide radicals generates the highly toxic peroxynitrite. Arachidonic
protein elements, while nucleases and lipases indiscriminately acid metabolism generates prostaglandins, leukotrienes, and reactive oxidative
damage DNA and cellular lipids (14). Toxic calcium levels also species (ROS), all of which exacerbate neuronal injury. Mitochondria buffer some
of the excess calcium. The consequence is increased mitochondria calcium levels,
promote reactive oxygen species (ROS) (15). Together, activated
mitochondrial injury with attendant energy failure and the release of cytochrome
lipases and ROS produce lipid peroxidation that disrupts the cel- c. The latter activates caspases causing apoptosis.
lular membranes (16). The result is further energy failure, mito-
chondrial injury, and release of cytochrome c, a prominent trigger
of apoptotic cell death (17). Calcium also promotes the synthesis neurologic deterioration (Figure 7.3). Modulation of many of
of nitric oxide, which along with superoxide anions, form the these biochemical pathways has been the target of neuroprotective
highly reactive species peroxynitrite (18). Through second mes- strategies.
senger systems and promotion of ROS, calcium initiates pro-
inflammatory processes that can impede the microcirculation Acidosis
and exacerbate the initial ischaemic insult (19). Furthermore, a
chronic inflammatory state occurs after ischaemic injury that can As oxygen delivery to the brain is reduced, neurons are forced to
persists for as long as six months and likely contributes to delayed undergo anaerobic glycolysis as the only means of ATP synthesis.
79
Chapter 7 principles of neuroprotection 79
Excitotoxicity
Injury
Inflammation
Apoptosis
Glutamate IL-1
Ca++ TNFa
ROS Caspases
Minutes Hours Days Weeks–Months

Protection - Repair
Scar formation
GABA-A IL-10 Vasculogenesis
Adenosine BCL Neurogenesis
K+-ATP EPO
Anti-inflammation Repair
Anti-excitotoxicity
Survival Regeneration
Figure 7.3 Time course of neuronal death.

Excitotoxic mediated cellular death occurs over minutes to hours following ischemic energy failure. Severely injured neurons may undergo necrotic cell death, which
causes lysis and release of cell contents that initiate an intense inflammatory response and collateral damage. Inflammation can contribute to further cell death over days
to weeks. Apoptotic cell death can occur in injured neurons that survive the initial insult. Neuronal apoptosis has been demonstrated weeks to months following the
initial ischemic insult. Thus, neuronal death from ischemic energy failure is a dynamic process during which neurons continue to die for many months following the initial
injury.
This process leads to lactate formation and reduction in tissue pH. Difficulties Encountered: Translation
An acidic environment may cause further injury to the ischaemic
brain. By providing additional substrate for anaerobic metabolism, of Neuroprotective Strategies from Animals
hyperglycaemia induces more profound reductions in tissue pH. to Humans
Indeed, hyperglycaemia is associated with increased ischaemic Neuroprotective strategies aimed at modifying injurious bio-
neurologic injury. chemical and molecular processes triggered by cell energy failure
(direct neuroprotection) have received significant attention for
Cell Death over 30 years. Well over 1000 neuroprotective agents have been in-
The energy failure cascade results in cell death by either necrosis or vestigated in the preclinical setting (21), with roughly two-thirds
apoptosis, depending on the duration or intensity of ischaemic in- showing neuroprotective efficacy. Despite so many promising pre-
sult, type of cell, and the stage of the cell life cycle. Necrosis occurs clinical studies, no direct neuroprotective strategies (except systemic
relatively early during ischaemic injury and is the predominant hypothermia for global hypoxic injury) have translated into im-
mechanism of cell death in neurons of the ischaemic core; however, proved clinical outcomes. The difficulty with translation of therapy
in areas of more mild injury, such as in the ischaemic penumbra, from the experimental to the clinical setting has been ascribed to
apoptosis contributes to neuronal loss. multiple factors that have been reviewed previously (22, 23). The
Apoptosis, or programmed cell death, is manifested by chro- factors involved can be summarized as inherent differences between
matin condensation, cell shrinkage, and membrane blebbing. study animals and humans along with profound differences between
Importantly, apoptosis occurs without inflammation and thus experimental protocols and the practical limitations of the clinical
limits collateral damage to surrounding neurons (20). In contrast, setting:
necrosis is characterized by rapid cellular swelling, lysis, and re-
◆ Rodents, a frequently used experimental model, have anatom-
lease of cellular contents, which exacerbates the local inflamma-
ically distinct brains compared to humans. Rodent brain tissue
tory state and puts surrounding cells at risk. Although apoptotic
is comprised of 90% grey matter compared to roughly 50% in
cell death can occur relatively early during ischaemic injury, it
human brains (24).
may also be delayed for months, depending on the severity of
the ischaemic insult (Figure 7.3). Modification of cellular apop- ◆ Animals selected for preclinical experiments tend to be young
totic signalling has been proposed as a potential mechanism of and healthy, whereas stroke patients are typically older and have
neuroprotection (discussed later). multiple co-morbidities, such as hypertension, diabetes, and
80
hyperlipidaemia. Specific comorbidities, such as diabetes, can in- The primary mechanism of experimental barbiturate
dependently influence stroke severity and outcome (25). neuroprotection remains unclear. However, it is apparent that CMR
◆ Animal models most frequently focus on mechanical middle reduction is unlikely. A variety of anaesthetics capable of equiva-
cerebral artery occlusion, whereas human stroke is most com- lent CMR reduction have not demonstrated neuroprotection in the
monly embolic and it occurs in diverse patterns. setting of focal ischaemia. Furthermore, neuroprotection of similar
magnitude has been demonstrated over a broad range of barbit-
◆ Experimental therapeutic interventions are often timed to be urate dosing, including doses approximately a third of that re-
given just prior to, during, or shortly after the ischaemic insult, quired to achieve EEG suppression (33, 40, 41). Finally, equivalent
which is not typically feasible in human stroke patients. electrophysiologic doses of various barbiturates do not produce
◆ Animal studies often use infarct volume as a primary outcome, similar degrees of protection. Cole et al. demonstrated that thio-
whereas human trials use functional outcome measures. pentone and methohexital, but not pentobarbitone, reduced early
focal cerebral ischaemic injury in rats (42). Therefore alternative
◆ Experimental studies frequently assess their endpoint early, such
mechanisms of neuroprotection have been hypothesized, including
as within one week, whereas human trials often use more remote
free radical scavenging (43), attenuation of glutamate excitotoxicity
endpoints that range from 6 to 12 months.
(44), reduction in depolarization (45), and inhibition of calcium
In 1999, the Stroke Therapy Academic Industry Roundtable release (46).
(STAIR) published recommendations to serve as benchmarks
to evaluate preclinical evidence, guide future experimental Volatile Anaesthetics
methodology, and better select treatment therapies for future Similarly to barbiturates, volatile anaesthetics suppress CMR, but
clinical trials (26). Evaluation of the previously published pre- uniquely cause direct cerebral vasodilation. Beyond their ability to
clinical work with STAIR criteria identified the use of hetero- reduce CMR, proposed mechanisms by which volatile agents provide
geneous methodologies that were frequently of low quality and neuroprotection include activation of ATP-dependent potassium
has raised questions about whether the most efficacious therapies channels, upregulation of nitric oxide synthase, and attenuation of
are being selected for clinical trials (21, 27). Future experimental glutamate release. A large number of animal studies have demon-
studies will require models that better approximate the clinical strated that isoflurane, sevoflurane, and desflurane can reduce focal
situation, employ more stringent methodology, and select in- ischaemic injury (47). The magnitude of protection appears compar-
vestigative therapies based upon the success and quality of the able to barbiturates with little variability between agents.
preclinical data. As previously discussed, neuronal injury after ischaemia is a pro-
cess, rather than a discrete event, that continues well beyond the
Peri-operative Neuroprotective Strategies initial insult (48). However, most experimental studies involving
volatile anaesthetics have evaluated neurologic outcome within
Anaesthetics days of the ischaemic insult. When outcome is evaluated beyond
Nearly 60% of the brain’s metabolic substrate demand is tied to two weeks in models involving moderate or severe neurologic in-
the support of electrophysiologic function, while the remaining sult, a neuroprotective benefit is no longer demonstrated (49).
40% is linked to cellular activities aimed at maintaining cell in- This suggests that volatile anaesthetics delay, but do not prevent,
tegrity and homeostasis. Given that anaesthetics can suppress the neuronal death. In contrast, with mild focal ischaemia, sustained
electrophysiologic component of cerebral metabolic rate (CMR), neuroprotection with volatile anaesthetic use is achievable (50, 51).
it was postulated that anaesthetic administration could mitigate However, long-term neuroprotection has been demonstrated in
energy failure by reducing metabolic requirements in the face of preclinical studies that have employed young animals. Short-term
impaired substrate delivery. Although many experimental studies protection is difficult to achieve in aged animals and to date, the
have suggested neuroprotective efficacy with various anaesthetics long-term efficacy of anaesthetic neuroprotection in aged animals
drugs, there has been very limited support for anaesthetic-mediated has not been shown. These data suggest that volatile agents may
neuroprotection in human trials. produce sustained neuroprotection in the young brain provided the
injury severity is very mild.
Barbiturates
Barbiturates have been extensively studied due to their ability to Etomidate
produce suppression of the EEG. In the setting of global ischaemia, Etomidate is capable of decreasing CMR up to 50% by producing
barbiturates have failed to reduce ischaemic injury in numerous burst suppression on EEG (52). Although Sano et al. (32) demon-
animal and human studies (28–31). By contrast, barbiturates do re- strated reduced ischaemic injury in the hippocampus of rats treated
duce injury in focal ischaemia models when administered before with etomidate, the effect was small and did not provide any cortical
(32–34), during (35, 36), or after (37) the ischaemic event, although protection. In a focal ischaemia model, Drummond et al. not only
long-term neuroprotection was not evaluated. Supportive human demonstrated significantly larger infarct volumes in rats treated
data remains sparse and conflicting. Nussmeier et al. demonstrated with etomidate to achieve EEG burst suppression compared to thio-
neuroprotection using thiopental during cardiopulmonary bypass pental, but also an apparent detrimental effect compared to control
surgery (38), which was not replicated in a subsequent study (39). (53). In a subsequent study, the harmful effect of etomidate com-
Given the absence of a clear neuroprotective effect in humans, bar- pared to halothane controls was subsequently re-demonstrated and
biturates are not currently recommended for the sole indication of shown to cause an adverse effect on mitochondrial function, medi-
neuroprotection. ated, at least in part, by etomidate-induced inhibition of nitric oxide
81
synthase (54). In patients undergoing intracranial vascular surgery, demonstrated improved neurologic outcome 12 days later (75). The
the administration of etomidate was associated with a greater re- initial magnitude of xenon neuroprotection appears enhanced by
duction in tissue PO2 and tissue blood flow (55). Etomidate has not the addition of hypothermia; however, the enhanced effect is not
been shown to provide any meaningful neuroprotection in animal sustained when examined at 28 days (76). Despite promising pre-
models and may in fact worsen cerebral ischaemia. clinical data, xenon use in clinical trials has been limited largely due
to limited clinical availability of the drug.
Propofol
Propofol, like barbiturates and etomidate, can maximally reduce Physiologic Management and
the electrophysiologic component of CMR (56). Its profound ef-
fect on CMR and frequent clinical use made propofol an attractive
Neuroprotection
target for evaluation as a neuroprotective agent. Propofol adminis- Management of basic physiologic parameters such as systemic
tration has been shown to increase neuronal tolerance to hypoxia temperature, arterial oxygen and carbon dioxide tension, blood
and attenuate the severity of inflammation and oxidative stress. glucose, and CPP will influence neurologic injury, although a
These effects likely extend beyond propofol-induced CMR re- neuroprotective outcome benefit has only been demonstrated with
duction. There appears to be an independent beneficial effect on induced systemic hypothermia following global hypoxic injury
lowering oxygen free radical production, increasing free radical (post-cardiac arrest or neonatal asphyxia). This section summarizes
scavenging, reducing inducible nitric oxide synthase activity, and information regarding the effect of these parameters on the acutely
attenuating glutamate release (57, 58). The magnitude of propofol’s injured CNS and, when possible, provides specific management
neuroprotective effect in focal ischaemia models is similar to that of recommendations.
barbiturates (59). However, like volatile anaesthetics, the improve-
ment in infarct volume and neurologic outcome demonstrated Systemic Temperature
early (3–7 days) after ischaemia (60, 61) is not sustained (62). In Systemic temperature elevation enhances the extent of injury in
the clinical setting, propofol administration to achieve burst sup- models of ischaemia (focal and global) and brain trauma, while
pression on the EEG was not effective in improving neurologic out- fever burden in the intensive care unit is associated with worse out-
come in open heart surgery (63). In summary, propofol does not comes in a variety of acute CNS injuries. The primary mechanism
afford sustained neuroprotection except in the setting of very mild responsible for the relationship between systemic temperature and
ischaemic injury. neurologic outcome has not been clearly defined. Temperature
does significantly influence cerebral metabolism; for every 1°C re-
Ketamine duction in temperature, CMR decreases by approximately 6–7%.
Ketamine is a N-methyl-d-aspartate (NMDA) receptor antagonist. Broadly speaking, it is prudent to avoid hyperthermia in all patients
Its pharmacologic properties include production of a dissociative who have suffered an ischaemic insult or those who are at risk for
anaesthetic state, activation of the sympathetic nervous system with CNS ischaemia. The use of induced hypothermia in specific situ-
potential increase in heart rate and blood pressure, bronchodila- ations is addressed further on.
tion (64), and analgesia with attenuation of opioid tolerance (65).
In models of focal cerebral ischaemia, neuroprotection with keta- Neonatal Hypothermia
mine use has been demonstrated in rats (59, 66); however, use of Experimental and clinical studies have demonstrated that neuronal
S (+)-ketamine in patients undergoing open heart surgery did not cell death occurs in two main stages following a severe global is-
demonstrate neuroprotection (67). Therefore, ketamine has not chaemic insult (77, 78). The first stage involves rapid cell death from
demonstrated to be neuroprotective in humans suffering an acute energy failure. The second stage occurs following a latent period of
stroke. Moreover, its use may be limited by its side-effect profile, as at least six hours. The mechanisms responsible for delayed cell death
multiple NMDA antagonists have been curtailed by their neuro- include excitotoxicity, apoptosis, and cytotoxic effects of microglia
psychiatric side effects (68–70). activation (79). The second phase involves impaired metabolism
and energy failure at least six hours after initial recovery of cerebral
Xenon oxidative metabolism in infants who sustained moderate to severe
Xenon is an inert gas that is a non-competitive antagonist of NMDA intra-partum asphyxia (80, 81). It is during the latent period that
receptors (71). Experimental data support potential cellular and early implementation of systemic hypothermia has been shown to
molecular pathways for xenon-mediated neuroprotection such as reduce mortality and major neurodevelopmental disability when
modulation of neuroapoptosis and inflammation, excitotoxicity reapplied within six hours of intrapartum asphyxia in term and late
duction, and modulation of various ion channels (KATP and TREK- preterm (>35 week gestation) neonates. Importantly, meta-analysis
1). There have been over 40 preclinical studies demonstrating of the randomized controlled trials (RCTs) has shown that the
xenon-induced neuroprotection in a variety of injury models (trau- beneficial effects of hypothermia are sustained well beyond the
matic brain injury, focal ischaemia, global ischaemia) (72). Mice peri-intervention period with observable favourable outcome dif-
exposed to xenon had improved neurologic scores and reduced ferences 18–24 months after birth (82, 83).
cerebral infarct volume 24 hours after middle cerebral artery oc-
clusion (73). Rats exposed to xenon had reduced damage to the Induced Hypothermia After Cardiac Arrest
cortex, hippocampus, basal ganglia, and thalamus one week after Cardiac arrest quickly results in global ischaemic injury and
injury from unilateral carotid artery occlusion (74). Rats exposed cell death. Upon return of spontaneous circulation, cerebral
to xenon and subsequently subjected to cardiopulmonary bypass reperfusion initiates various harmful chemical cascades that cause
82
further neurologic injury. Two prospective randomized trials have at six months (96). The results of various other studies have con-
demonstrated improved neurologic outcome at time of discharge flicted with the findings of the aforementioned study. However,
and at six months, without an observed increase in adverse events, these studies demonstrating a neuroprotective benefit were either
in patients treated with induced hypothermia (32–34°C) for 12–24 severely limited by small study size or poor methodologic quality.
hours that was initiated within 2–3 hours of return of spontaneous The largest RCT in children following severe TBI failed to dem-
circulation (84, 85). Moderate systemic hypothermia was the first onstrate an outcome benefit to hypothermia at six months with a
and only direct neuroprotective therapy that has been shown to trend towards worse outcomes in the hypothermia treated group
be efficacious in humans and has been incorporated in standard (97). In the more recent EUROTHERM study (98), induction of
clinical practice. Although the exact mechanisms responsible for hypothermia in patients with TBI did not result in better outcomes
outcome improvement are not firmly established, it is likely a than routine care alone at six months. Therefore, there is currently
combination of reductions to CMR, free radical formation, and no support for the use of hypothermic neuroprotection in children
glutamate release as well as modulation of pro-inflammatory and with severe TBI ,and insufficient evidence to support routine use
apoptosis pathways (86). Regardless of the mechanisms, the rate of of hypothermia for the sole purpose of neuroprotection in adults.
rewarming appears critical to maintaining the observed beneficial
effects of hypothermia. The optimal rate of rewarming is not well Hypothermia and Focal Ischaemic Stroke
established, but it is typically done slowly (0.1–0.25° C/hr) in a con- Experimental data suggest that body temperature during the peri-
trolled fashion. infarct period is independently related to stroke severity, infarct size,
and mortality. Similarly, a number of human studies have found the
Hypothermia and Spinal Cord Injury presence of fever to be an independent predictor of poor outcome
Spinal cord injury (SCI) affects 250,000–500,000 people world- (99, 100). Experimental data suggest that induced hypothermia
wide each year and is associated with enormous morbidity/mor- shortly after ischaemic insult (up to 2.5 hours) reduces ischaemic
tality, as well as economic burden (87). Often traumatic in nature, volume and improves functional outcomes with beneficial effects
it results in a primary irreversible injury to cell bodies and axons present well beyond the injury period (101, 102). Together, along
due to mechanical energy transfer. The primary injury initiates a with the favourable impact of hypothermia on outcome following
series of complex biochemical cascades that result in further tissue global ischaemia in humans, there has been renewed interest and
damage known as secondary injury. Currently, there is no estab- optimism for therapeutic hypothermic neuroprotection following
lished neuroprotective strategy that has proven to be efficacious acute ischaemic stroke. However, induction of hypothermia is ac-
after SCI. While the administration of steroids was initially thought companied by various challenges in this patient population. First,
to be efficacious and became common practice following the it may not be feasible due to the fact that these patients are often
National Acute Spinal Cord Injury Studies (NASCIS) II (88) and not admitted to the ICU and therefore the intensive nursing care
III (89), mounting criticism of the design, statistical analysis, and required for systemic hypothermia may not be available. There is
study endpoints brought the validity of the trials into question. As also concern that shivering may be uncomfortable and delay/pre-
of 2013, the Joint Section on Disorders of the Spine and Peripheral vent induction of hypothermia in a patient group that frequently
Nerves of the Congress of Neurological Surgeons and the American is awake and not sedated. Although protocols to address some of
Association of Neurological Surgeons (AANS) do not recommend these concerns have been established, the various concerns have
the use of steroids in acute SCI in the first 24–28 hours following likely contributed to the limited human data available regarding
injury (90). There has been significant success with the application induced hypothermia. Indeed, there have only been a handful of
of hypothermia (local spinal cord and systemic) for acute SCI in RCTs that have evaluated the induction of hypothermia in the care
the preclinical setting (91), and there is evidence indicating that of patients with acute ischaemic stroke. These studies were recently
the beneficial effects may be sustained (92, 93). Although prelim- reviewed by the European Stroke Organization (ESO) (103), who
inary human studies and reports are encouraging, there remains graded the quality of available evidence as low. Based on this evi-
a paucity of human data. At this time, the AANS and Congress of dence, the ESO does not recommend induction of hypothermia
Neurological Surgeons states there is insufficient evidence to rec- for the sole purpose of neuroprotection in patients with focal is-
ommend for or against therapeutic hypothermia as treatment for chaemic stroke. Further well-designed human investigations will
acute spinal cord injury (94). We anticipate that the Acute Rapid be needed to inform clinical management of this patient popula-
Cooling of Traumatic Injuries of the Cord (ARCTIC) study (95), tion and address questions such as the timing, duration, and degree
an ongoing prospective, multi-centre trial evaluating the effects of of hypothermia.
moderate intravascular hypothermia for treatment of acute cervical The Intraoperative Hypothermia for Aneurysm Surgery Trial
SCI will help clarify the role of systemic hypothermia in acute SCI. (IHAST) investigators evaluated intra-operative induced hypo-
thermia prior to potential ischaemic injury. Patients were random-
Hypothermia and Traumatic Brain Injury ized prior to surgery to achieve either intra-operative hypothermic
Traumatic brain injury (TBI) is major cause of death and disability (32–33°C) or normothermic (36–37°C) targets prior to potential
worldwide. Much like global ischaemic injury, TBI results in pri- intra-operative ischaemia. Unfortunately, neurologic evaluation
mary neurologic injury that initiates a myriad of processes that re- at 90 days revealed no neurologic outcome benefit attributable to
sult in further injury. The secondary injury occurs subacutely over hypothermia (104). However, it should be noted that the number
hours to days, and is the main target of various neuroprotective of patients who received temporary clips in excess of 20 minutes
strategies, including hypothermia. The largest multicentre RCT by (high risk of ischaemic injury) was quite small (five to six in each
Clifton et al. evaluating hypothermia in 392 severe adult TBI pa- group). Consequently, the argument has been advanced that mild
tients found no difference in mortality or Glasgow Outcome Score intra-operative hypothermia may well be of benefit in patients at
83
considerable risk of intra-operative ischaemia owing to the com- 100 Pressure - Passive Normal
Cerebral Blood Flow (ml•100 gm-1•min-1)

plexity of the aneurysm and the potential need for temporary Dilated Autoregulation
vascular occlusion. Importantly, the IHAST investigators demon-
strated that mild induced intra-operative hypothermia is feasible 75
and safe. Therefore, use of mild hypothermia may be considered
in operative patients deemed to be at high-risk of intra-operative
50
ischaemia if the operative team is willing to accept a delay in emer-
gence from anaesthesia to provide sufficient time for rewarming
to occur. 25 Pressure - Passive
Restricted
Arterial Oxygen Tension
Cerebral reperfusion following two minutes or more of ischaemia 0
results in formation of ROS (105–107) that are detrimental to 0 50 100 150 200
cellular lipids and can injure the blood brain barrier (108, 109). Cerebral Perfusion Pressure (mm Hg)
Concerns about exacerbating oxidative stress with supranormal
Figure 7.4 Normal (light blue) and impaired (dark blue) cerebral autoregulation
arterial oxygen tension following global cerebral ischaemia have curves.
been supported by both preclinical and human studies (110–113). Following various neurologic injuries, cerebral autoregulation is impaired and cerebral
Clinical studies have associated hyperoxia with increased neuro- blood flow becomes perfusion pressure dependent. In a restricted pressure-passive
logic deficits and mortality, primarily in patients resuscitated state, cerebral blood flow (CBF) may be subnormal despite cerebral perfusion
following cardiac arrest (114–116). In fact, a large multicentre co- pressure (CPP) within the typical autoregulatory range. This has been demonstrated
hort study demonstrated a dose-dependent association between following severe traumatic brain injury (TBI) and subarachnoid haemorrhage (SAH).
supranormal oxygen tension and risk of in-hospital mortality (115,
117). A more recent investigation involving a mixed multicentre
cohort of subarachnoid haemorrhage, ischaemic stroke, and hypercapnia. Thus, in the absence of a means to monitor the effect
intracerebral haemorrhage patients also found hyperoxia to be an of PaCO2 manipulation on cerebral tissue perfusion, normocapnia
independent predictor of in-hospital mortality (118). Although the remains standard practice.
available clinical studies do not prove causation, they support the
hypothesis that hyperoxia following global ischaemia (and perhaps Glucose Management
other acute neurologic injuries) may cause further neurologic in- Identifying the optimal glucose target for critically ill patients has
jury and underscores the need for human trials of controlled oxy- proven very difficult. In 2001, clinical care shifted towards inten-
genation following various ischaemic neurologic injuries. For now, sive insulin therapy (IIT) (glucose target 80–110 mg/dL) following
it seems prudent to rapidly titrate down inspired oxygen concentra- publication of a large single-centre RCT that reported a mortality
tion as soon as the clinical situation permits. benefit compared to conventional glucose management (134).
However, the 2009 NICE-SUGAR trial (135) shifted clinical care
Arterial Carbon Dioxide Tension back toward a more moderate glucose target of 140–180 mg/dL
Arterial carbon dioxide tension (PaCO2) plays a significant role in the after it demonstrated that IIT increased mortality in critically ill
regulation of CBF. For each mmHg change in PaCO2, CBF changes patients compared with the moderate glucose target group. The un-
by 1–2 mL/100 g of brain tissue/minute. Consequently, hyperven- expected increase in mortality has been attributed to the increased
tilation is often strategically initiated as a temporary measure to incidence of hypoglycaemia with IIT.
help manage an intracranial hypertensive crisis until more defini- The optimal glucose target for patients with acute brain injury
tive treatment measures can be employed. Hyperventilation, how- is even more difficult to define. On one side, hyperglycaemia at
ever, conveys a potential risk for ischaemia (119–123), particularly time of presentation has been associated with worse neurologic
in situations where CBF may be lower than normal (123) despite outcomes and increased mortality in a variety of acute neuro-
a ‘normal’ CPP (TBI (124–127) and high-grade SAH, Figure 7.4). logic injuries (SAH, TBI, ICH, ischaemic stroke, post-cardiac
The expert panel convened by the Brain Trauma Foundation stated arrest) (136–142). Although hyperglycaemia present upon admis-
that prophylactic hyperventilation is ‘not recommended’, and that sion may simply be an indicator of injury severity (143) resulting
‘hyperventilation should be avoided during the first 24 hours after from well-described pathways involving increased levels of cortisol
injury when CBF is often critically reduced’ (128). and plasma catecholamines, hyperglycaemia may also potentiate
Despite some support for the occurrence of a favourable so- neurologic injury during ischaemic energy failure by providing
called Robin Hood effect or inverse steal (129), hypocapnia has additional metabolic substrate for anaerobic metabolism. Indeed,
generally proven ineffective in both experimental and clinical anaerobic metabolism has been shown to increase tissue acidosis
settings involving focal ischaemia (130–132). More recently, post (144), which, in turn, increases cell death (145) and may exacer-
hoc multivariate analysis from a small retrospective study found bate neurologic injury. However, Gray et al. were unable to dem-
hypocapnia during general anaesthesia for emergent thromb- onstrate a 90-day mortality improvement with aggressive glucose
ectomy to be associated with worse neurologic outcomes (133). management following acute ischaemic stroke (146). In contrast
Meanwhile, hypercapnia has the potential to cause intracerebral to concerns regarding hyperglycaemia, there is growing concern
steal and may worsen intracellular pH. Although the available evi- that acute brain injured patients may be more sensitive to reduc-
dence is far from definitive, animal and limited human data sug- tions in systemic glucose compared to critically ill patients without
gest there may be detrimental effects from both hypocapnia and concomitant brain injury (147–149). A predisposition towards
84
detrimental effects resulting from aggressive systemic glucose man- spontaneously or from early initiation of antihypertensive drugs,
agement may occur for a variety of reasons. First, reduced glucose have been associated with increased infarct volume, early neuro-
delivery to the tissue may result from changes in CBF, which have logic deterioration, and poorer outcomes (167–169). In patients
been demonstrated in a variety of neurologic injury states (150– with severe TBI, a CPP less than 50 mmHg is routinely associated
153). Second, glucose transport across the BBB and into cells is an with tissue hypoxia (170–173), while systemic hypotension has
active process requiring specific transporters (glut 1 and 3) (154). been demonstrated to be one of the most important contributors
Brain injury is likely to influence this activity and probably does to a poor outcome (174–177). Thus, acceptable arterial blood pres-
so to a variable degree depending on both the type of injury and sure limits should be thoughtfully considered and discussed with
its severity. Third, various neurologic injuries have been shown to the surgical team prior to any procedure, particularly in the set-
cause a hyperglycolytic state due to multiple biochemical cascades ting of recent neuronal injury. Consideration should be given to the
that increase metabolic requirements (148, 155). Finally, there is patient’s baseline blood pressure, the neurologic pathology, and the
concern that insulin has direct detrimental effects on brain glucose procedure itself. In general, MAP/CPP should be maintained at or
metabolism that is independent of reductions in systemic glucose near baseline and should be adjusted based upon assessment of the
(148, 156–157). Thus, the optimal systemic glucose target following ischaemic risk. Data to provide specific guidelines are insufficient
acute neurologic injury remains ill defined at the present time. The for most neurologic injuries. However, the available data provide
present authors’ intra-operative intervention threshold occurs at support for the reduction of blood pressure to less than 180/105
systemic glucose greater than 200mg/dL with a goal of preventing in stroke patients who have been treated with tissue plasminogen
any further increase. A target systemic glucose of 140–180 mg/dL activator (tPA) to offset the risk of haemorrhagic conversion, while
is also reasonable, particularly in elective neurosurgical proced- guidelines for stroke patients who have not received tPA suggest
ures without acute brain injury, which is in alignment with various avoiding blood pressure treatment for the first 24 hours unless sys-
guidelines put forth for the management of critically ill patients tolic blood pressure (SBP) is greater than 220 mmHg or diastolic
(158–160). exceeds 120mmHg (178). A CPP goal of 60–70 mmHg is routinely
targeted following severe TBI and appears reasonable based upon
Cerebral Perfusion Pressure the available evidence (179).
Optimal blood pressure limits cannot be singularly defined nor
uniformly applied to a variety of acute neurologic injuries. Rather, Miscellaneous Medications
blood pressure goals should be tailored to the individual patient While numerous neuroprotective medications showed promising
(i.e., baseline blood pressure) and the clinical setting. In healthy results in animals, phase III trials in humans have not demon-
patients, CBF is autoregulated over a mean arterial pressure (MAP) strated efficacy. Examples of such failures include the Na channel
range of about 70–150 mmHg. Although there is wide inter-indi- blocker fosphenytoin (180), calcium channel inhibitors (168, 181–
vidual variation in the lower autoregulatory limits, maintenance of 182), the sedative clomethiazole (183), glutamate receptor antag-
CBF can be ensured for most patients with a MAP in the range onists (184), and free radical scavengers (185). In total, 46 phase
of 70–80 mmHg. However, an important theme in acute neuro- III studies as compiled by Minnerup et al. have demonstrated false
logic injury is the predisposition for ischaemia and thus an em- positive or true negative results (186). While one study, the SAINT
phasis on maintaining MAP/CPP at normal or even high-normal I trial, had positive results (187), the subsequent larger study, the
levels. This concept emanates from appreciation that biochemical SAINT II trial (187), had negative results.
cascades initiated by spinal cord injury potentiate the risk of sec- Although phase III clinical trials have not yielded statistically sig-
ondary ischaemic injury, awareness that CBF is frequently very low nificant neuroprotection in humans, it is worthwhile to note the
in some brain regions following acute insults such as TBI and SAH, positive effects of antidepressants, specifically fluoxetine, on post-
and recognition that cerebral autoregulation may be impaired fol- stroke recovery in humans and nimodipine in subarachnoid haem-
lowing various injuries (Figure 7.4) (124, 161). In addition, main- orrhage patients. While fluoxetine has not yet reached the phase
tenance of arterial pressure is also relevant to situations where the III clinical stage, multiple small RCTs studies have demonstrated
effective perfusion pressure is reduced by forces exerting pressure improvement in functional recovery (188), executive functioning
on tissue such as intracranial hypertension (CPP = MAP-ICP), (189), and survival rates (190) in depressed and non-depressed pa-
ongoing spinal cord compression, and surgical retraction of brain tients post stroke. To date, the largest and most compelling study
tissue (162). Furthermore, there is concern that acute ischaemic is the 2011 double-blinded placebo-controlled FLAME trial (191),
stroke injury may be exacerbated by reductions in MAP associ- in which 118 patients were randomized to fluoxetine or placebo
ated with delivery of anaesthesia for emergent thrombectomy by for three months starting 5–10 days after stroke onset. At 90 days,
either reducing collateral flow to the ischaemic region or by redu- there was significant motor improvement in the fluoxetine group.
cing flow past an incomplete flow-limiting lesion. Indeed, main- In addition, the calcium channel blocker nimodipine, dosed orally,
tenance of high-normal CPP can help maintain CBF and has been was found to be protective in preventing secondary ischaemia and
shown to improve various neurophysiologic parameters, including poor outcome in subarachnoid haemorrhage patients (192) and is
neurologic function (163–165). However, practitioners should be widely considered the standard of care in this patient population.
cautious about augmenting blood pressure beyond high normal
MAPs as this may increase the risk for recurrent stroke, haem- tPA
orrhagic conversion, cerebral oedema and vascular injury (166). In 1995, the National Institute of Neurological Disorders published
By contrast, hypotension can reduce CBF and exacerbate neuro- a two-part trial evaluating safety and efficacy of tPA in patients with
logic function. Reductions in blood pressure (as little as 10–20% acute ischaemic stroke. In this trial, patients with ischaemic stroke
from hypertensive levels) following acute ischaemic stroke, either treated within three hours of symptoms were 30% more likely to
85
have minimal or no disability at three months (193). In 1996, the in the EXTEND-IA (215) trial, the ESCAPE (216) trial, and most
US FDA approved the use of tPA for treatment of acute stroke and recently SWIFT PRIME (217).
its use has continued to be associated with increased odds of fa- The anaesthetic management of patients undergoing an
vourable outcome (194, 195), particularly in those who are younger endovascular intervention is currently either anaesthetist or centre
than 75 years old, have mild to moderate strokes, or were treated dependent. ‘Anaesthesia’ can range from local anaesthesia (LA)
within 90 minutes (196, 197). Adverse reactions include allergic without sedation to general anaesthesia (GA) with or without
reaction, myocardial infarction, and symptomatic intracerebral airway instrumentation. The optimal anaesthetic is debated with
haemorrhage (sICH). While sICH has been reported in most major advantages and disadvantages inherent to each technique. Minimal
studies, the incidence has remained consistently low with the sedation (LA only or conscious sedation) may potentially expedite
National Institute of Neurological Disorders and Stroke reporting procedure commencement without delays associated with anaes-
6.4% in treated groups vs. 0.6% in the placebo (198). Overall, the thetic induction and airway management, while simultaneously
use of tPA has been repeatedly demonstrated as safe even when facilitating continuous neurologic assessment and avoidance of
used in centres not accustomed to treating acute ischaemic stroke sudden hemodynamic/physiologic changes. However, the risks of
(199). The three-hour time window has been challenged. Multiple an unsecured airway, potential for patient discomfort and move-
studies have demonstrated improved outcomes with tPA up to 4.5 ment, and the need for an emergent conversion to GA should be
hours after symptom onset without significant increases in compli- considered. Conversely, GA with endotracheal intubation provides
cations or mortality (200–202). The FDA subsequently approved optimal procedural conditions that result in fewer technical fail-
the expansion of tPA use for up to 4.5 hours, although the expan- ures (218). Multiple retrospective studies, however, have implicated
sion came with additional exclusion criteria, e.g., patients could not GA as an independent predictor of poor neurologic outcome and
be older than 80, be on any anticoagulants, have a baseline NIHSS increased mortality (219–223). The adverse effects of general an-
score over 25, or have both diabetes mellitus and previous his- aesthesia have been attributed to larger haemodynamic fluctuations
tory of stroke. It is still recommended that tPA be given as soon as and greater risk of hypotension, while controlled ventilation may
possible for best outcome (203). The time window continues to be result in rapid changes to PaCO2 (hypocapnia) that physiologic-
challenged with multiple studies demonstrating improved outcome ally could influence outcome (224). The opposing view is that the
after stroke up to six hours (204–206), although its use up to six negative effects associated with GA are the result of a selection bias
hours would be considered an off-label use as it is not approved by for ‘sicker’ patients rather than a direct effect of GA itself. Despite
the FDA. the methodologic limitations of the currently available studies, the
negative outcomes associated with GA and the reasonable safety
Interventional Procedures profile associated with limited sedation suggest avoiding GA
should at least be considered in those patients without a clear in-
Mechanical Thrombectomy dication for immediate intubation (225). Furthermore, in patients
Patients who are ineligible for or fail tPA may be eligible for requiring GA, every effort should be made to avoid unnecessary
mechanical thrombectomy. There are three classes of mechanical procedural delays along with efforts to maintain normotension,
thrombectomy devices approved by the FDA. In 2004, based on the while maintaining strict normocarbia and normoxia. The target
results of two trials, the Mechanical Embolus Removal in Cerebral blood pressure during anaesthesia has not been clearly defined.
Ischemia (MERCI) (207) and subsequently the multi-MERCI The work of Davis et al. (226) suggests that the risk of increased
(208), coil retrievers became the first FDA approved mechanical morbidity and mortality increases below a systolic pressure of
thrombectomy device available. The Penumbra Pivotal Stroke Trial 140 mmHg. Based on these data, maintenance of the systolic pres-
(209) subsequently led to the FDA approval of the aspiration device sure in the range of 140–150 mmHg is a reasonable approach. After
called the Penumbra stroke system in 2007. Finally, stent retrievers thrombectomy, blood pressure management continues to be crit-
were introduced in 2012 after the SWIFT trial (210) demonstrated ical. Variables that may influence the target blood pressure include
good neurologic outcome and lower mortality rates compared the completeness of thrombus removal and the risk of haemorrhage
to MERCI retrievers. Subsequent generations of stents have also in the previously ischaemic region. If thrombus removal is incom-
shown to be more efficacious than the MERCI retrievers (211). plete and regions of the brain remain ischaemic, maintenance of
Complications and adverse events include groin complications, SBP in the range of 140–150 mmHg can maintain collateral perfu-
intracerebral haemorrhage, subarachnoid haemorrhage, thrombus sion. However, with complete thrombus retrieval, the SBP should
fragmentation, and embolization. Symptomatic intracerebral be no more than 140 mmHg to reduce the risk of haemorrhage. The
haemorrhage was highest in the coil retrievers (9–11%) and aspir- blood pressure can then be titrated to the neurologic examination
ation devices (11%), and lowest in the stent retrievers (2%). While of the patient upon recovery from anaesthesia.
multiple studies had previously failed to demonstrate mechanical
thrombectomy as being more effective than tPA alone (212, 213),
those studies were riddled with methodologic concerns such as Conclusion
the lack of baseline imaging, inclusion of patients with small vessel Neuroprotection is a broad term that includes drug administration
disease, usage of older devices, or late intervention. Most recently, or physiologic manipulation before, during, or after a neurologic in-
trials have demonstrated the superiority of mechanical thrombec- sult, in order to limit neurologic injury and optimize outcome. The
tomy in conjunction with standard of care over standard of care brain is unique in that its metabolic demands are substantial yet its
alone. In the MR CLEAN (214), 32.6% of patients in the interven- capacity to store metabolic substrate is limited. As a result, impair-
tion arm achieved functional independence compared to the 19.1% ment of CBF and metabolic substrate delivery is poorly tolerated and
in the control. This superiority in outcome was again demonstrated results in rapid energy failure and neurologic dysfunction. With the
86
exception of tPA and mechanical thrombectomy for acute stroke, peroxynitrite formation in ischemic stroke linked to neural damage.
and hypothermia for cardiac arrest and neonatal asphyxia, our cap- The Journal of Neuroscience. 1999;19(14):5910–8.
acity to protect the brain is limited. Direct evidence for anaesthetic- 19. Huang J, Upadhyay UM, Tamargo RJ. Inflammation in stroke and focal
cerebral ischemia. Surgical Neurology. 2006;66(3):232–45.
mediated neuroprotection in human trials is limited. Given the lack
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93
CHAPTER 8
Neurotoxicity of General
Anaesthetics
Margaret K. Menzel Ellis and Ansgar Brambrink
Introduction have emerged regarding the long-term cognitive and behavioural

effects of anaesthetic exposure during brain development, particu-
Since anaesthesia gained widespread acceptance in the mid- larly in patients who are exposed to anaesthesia before three years
nineteenth century, the rapid evolution of the safety and sophisti- of age (4).
cation of general anaesthesia has paved the way for revolutionary Numerous retrospective, observational studies have been under-
advances in medicine and surgery. However, a growing body of taken to assess the association of exposure to anaesthesia in in-
both preclinical and observational clinical evidence has fostered fancy and early childhood with long-term alterations in behaviour,
both scientific and public concerns regarding anaesthetic neurodevelopment, learning, memory, cognition, and language (Table
toxicity, particularly in young children. Early studies demonstrated 8.1). One retrospective birth cohort study of over 5,000 children
widespread neuronal cell death following NMDA antagonist ad- assessed the risk of learning disabilities later in life in those who re-
ministration in developing animals (1, 2). Given the known toxic ceived general anaesthesia before the age of four. When compared
effects of maternal ethanol use on human foetal development, to children who did not receive anaesthesia at a young age, a single
GABA-ergic agents were studied; again, widespread neuronal cell anaesthetic was not associated with any increased risk. However,
death was observed in neonatal rats (3). Since that time, volatile children who received two or more anaesthetics were found to have
anaesthetic, nitrous oxide, and propofol exposure have all been a twofold increased risk of developing a learning disability; there
studied in animal models, revealing similarly concerning toxic ef- was also a concomitant risk increase associated with a longer dur-
fects as well as negative effects on cognition and behaviour. ation of anaesthesia (5). Similar results from subsequent studies
The severity and consistency of this injury prompted several support these findings (6, 7); cumulative exposures to volatile an-
large, retrospective database studies, the majority of which sug- aesthetics, chloral hydrate, and midazolam in congenital cardiac
gest an association between early anaesthetic exposure in young surgery patients have been found to be independent predictors of
children and difficulties with behaviour or cognition later in life. poor performance on neurocognitive testing, despite the multiple
Ongoing prospective investigations are underway to further ex- comorbidities and risk factors for neurologic injury in that popu-
plore these implications. While the current data does not support a lation (8, 9). When a cohort of patients was analysed specifically
change in clinical practice, paediatric anaesthetists and those who for the development for attention deficit hyperactivity disorder
provide anaesthesia to paediatric patients should consider these (ADHD) by the age of 19, a significant association with repeated
concerns when discussing the risks and benefits of anaesthesia with anaesthetic exposures was again noted (10). In a study comparing
parents. unexposed children with school-aged children who were exposed
to general anaesthesia for surgical procedures in the first year of
Current Clinical Evidence life, there was no difference in mean standardized test scores, but an
During the earliest use of anaesthesia for surgical procedures in inverse relationship was observed between test score and duration
very young infants, concerns about haemodynamic safety and of anaesthetic exposure, and a higher proportion of the exposed
monitoring were paramount. As anaesthetic monitoring and children had very poor test performance (11).
medication safety have dramatically improved over the past sev- Other studies of academic performance have produced negative
eral decades, the risk of life-threatening cardiopulmonary com- results. A study in Denmark did not find any association between
plications during general anaesthesia has decreased. Furthermore, an early exposure to general anaesthesia for inguinal hernia re-
as our understanding of the physiology of neonatal pain and the pair and impaired test scores at 15 or 16 years of age (12). A recent
infant brain has evolved, the previously accepted belief that neo- Swedish study investigated a very large cohort of approximately two
nates did not feel and could not remember the pain of surgery has million children, born between 1973 and 1993, utilizing data from
now given way to a clear understanding of the detriment to young the Swedish national healthcare system and from population re-
patients who undergo surgical procedures without anaesthesia or gisters to assess whether there was an association between anaes-
analgesia. However, now that anaesthesia can be safely provided thetic exposure and school results at age 16. Each exposed child was
to an increasing number of very young surgical patients, concerns matched with five unexposed controls. Contrary to the majority of
94
Table 8.1 Summary of design, population, and findings of population-based studies of neurocognitive and behavioural outcomes following childhood exposure to general anaesthesia.
Study Design Population Number Outcome Exposure Inclusion Exclusion (n) Findings
(Surgery type) (History of
anaesthesia
exposure)
Kalkman et al. Retrospective pilot University Medical n=243 ◆ Performance on Child GA <6 yo ◆ Underwent paediatric ◆ Congenital dx other ◆ Trend toward
2009 (102) study. Center, Utrecht, (n=243) Behaviour Checklist urologic surgery in 1987, than the one requiring more behavioural
Netherlands completed by parent 1991, 1993, or 1995. surgery. issues observed in
(urologic surgery). or surrogate. ◆ Other risk factors for population exposed
cognitive impairment. at younger ages.
◆ Urgent or day surgery. ◆ No statistically
significant difference.
◆ Moved outside
Netherlands.
◆ Adopted.
◆ >19 yo at time of
analysis.
Bartels et al. 2009 Retrospective Netherlands twin n=2286 ◆ Standardized test GA <3 yo ◆ Born 1986–1995. ◆ Severe illness or ◆ Lower standardized
(103) monozygotic twin registry (n=425 <3 yo; scores age 12. or ◆ Monozygotic twins. handicap (n=50). test scores in
cohort. (any surgery). 911 <12 yo). ◆ Teacher ratings age 12. ◆ Gestational age <32 population exposed
GA <12 yo.
weeks (n=132). <3 yo.
◆ Low birth weight ◆ More cognitive
(n=670). problems in
population exposed
<3 yo.
◆ No differences within
twin pairs between
exposed and
unexposed.
DiMaggio et al. Retrospective cohort. New York State n=5433 ◆ Behavioural
or GA <3 yo. ◆ Born in NY state ◆ Behavioural or ◆ Doubled likelihood
2009 (14) Medicaid (n=383) developmental d/o dx. 1999–2001. developmental dx of developmental or
(inguinal hernia repair). ◆
IHR age <3. preceded IHR behavioural d/o in
(n not reported). exposed pts.
Wilder et al. 2009 Retrospective birth Olmstead County, MN n=5357 ◆ Reading,

written GA <4 yo. ◆ Born 1976–1982. ◆ Left Olmstead County or ◆ Single exposure not
(5) cohort. (any surgery). (n=593) language, or math LD by died <5 yo (n=2830). associated with risk
age 19. ◆
Severe MR (n=19). of LD.
◆ Non-consent (n=342). ◆ Increased risk of
LD with multiple
exposures.
◆ Increased risk of LD
with longer duration
of exposure.
95
DiMaggio et al. Retrospective sibling New York State n=10450 ◆ Behavioural or GA <3 yo. ◆ Born in NY state ◆ Behavioural or ◆ Increased likelihood
2011 (15) cohort Medicaid (n=304) developmental d/o dx. 1999–2005. developmental d/o of developmental or
(any surgery). dx preceded exposure behavioural d/o in
or was <10 months in exposed pts.
unexposed (n=1200). ◆ Increased likelihood
◆ Cardiac, ENT, or of developmental or
neurosurgery (n=59). behavioural d/o with
increased number
and duration of
exposure.
◆ No difference within
twin pairs between
exposed and
unexposed.
Flick et al. Retrospective Olmstead County, MN n=5357 ◆ Need for IEP for GA <2 yo. ◆ Born 1976–1982. ◆ Left Olmstead County or ◆ Increase in LD if
2011 (7) matched cohort. (any surgery). (n=350) emotional or died <5 yo (n=2830). multiple surgeries.
behavioural d/o. ◆ Severe MR (n=19). ◆ Decrease in school
◆ Reading, written ◆ Non-consent (n=342). group achievement
language, or math LD and cognition test
by age 19. scores in exposed pts.
◆ Score on school ◆ No difference in need
administered for IEP for emotional
achievement test and or behavioural d/o.
cognition exam.
Hansen et al. 2011 Retrospective birth Denmark national civil n=17234 ◆ Average 9th grade test GA <1 yo. ◆ Born 1986–1990. ◆ Died or migrated before ◆ No significant
(12) cohort. registry (n=2689) scores (age 15–16). ◆ IHR <1 yo. 1 June 2006 (n=1078). difference in test
(inguinal hernia repair). ◆ Proportion of children scores in exposed pts.
not attaining test ◆ Bigger effect seen
scores (special needs, from male gender,
alternative school, birth weight, parental
dropouts). education than from
anaesthetic exposure.
◆ Higher risk of test
score nonattainment
in exposed group.
Block et al. Retrospective cohort. University of Iowa n=287 Iowa state achievement GA <1 yo. ◆ At least one of three ◆ Died (n=18). ◆ Disproportionate
2012 (11) (IHR/orchiopexy, (n=287) test scores. included surgeries. ◆ Unable to locate (n=93). number of exposed
pyloromyotomy, ◆ Otherwise healthy. pts had very low state
◆ Did not return study
circumcision). achievement test
◆ Between 7–17.9 yo at mailing questionnaire
scores (<5%ile) vs.
time of search. (n=215).
population average.
◆ No Iowa test scores
◆ Association between
(n=85).
poor score and
◆ Non-consent (n=22). exposure duration.
◆
No difference in
mean test scores.
(Continued )
96
Table 8.1 Continued
anaesthesia
exposure)
Ing et al. Retrospective analysis Australian Pregnancy n=2608 Testing at age ten: GA <3 yo. ◆ Born to mothers enrolled ◆ Lost to follow up ◆ Lower scores on
2012 (16) of prospectively Cohort (Raine) (n=321) ◆ Language in pregnancy cohort (n=260). receptive and
collected pregnancy/ Study 1989–1992. expressive language
◆ Cognitive function
birth cohort data. (any surgery). testing in exposed
◆ Motor skills pts.
◆ Behavioural d/o. ◆
Lower scores on
testing of abstract
reasoning in exposed
pts.
◆ No difference on
motor or behavioural
testing.
Sprung et al. 2012 Retrospective cohort. Olmstead County, MN n=5357 ADHD by age 19. GA <2 yo. ◆ Born 1976–1982. ◆ Left Olmstead County or ◆ Association between
(10) (any surgery). (n=350) died <5 yo (n=2830). multiple exposures
◆ Severe MR (n=19). and ADHD.
◆ Non-consent (n=342).
Bong et al. Retrospective cohort. Singapore n=206 ◆ Aggregate score on Sevo GA <1 yo. ◆ Born 1998–1999. ◆ Prematurity. ◆ No difference in
2013 (6) (minor surgery (n=100) standardized test at ◆ ASA I or II. ◆ Genetic d/o. standardized testing
including IHR, age 12. scores.
◆ Minor surgery. ◆ CNS d/o.
circumcision, ◆ Formal LD dx. ◆ Increase in formal LD
◆ 30–120 minutes. ◆ Congenital cardiac
cystoscopy, in exposed pts.
defect.
pyloromyotomy).
◆ Severe renal d/o.
◆ Family hx of DD or LD
(combined n=29).
◆ Declined participation
(n=49).
Garcia Guerra et al. Retrospective cohort. A University- affiliated n=91 Testing in kindergarten: GA ≤6 weeks for ◆ Admitted to paediatric ◆ Died before kindergarten ◆ Number of days
2013 (9) paediatric hospital, (n=91) ◆ IQ testing. CHD surgery. ICU following CHD age (n=19). on chloral hydrate
Alberta, Canada surgery with CPB ◆ Chromosomal associated with lower
◆ Visual Motor
(CHD surgery). between 4/2003 and abnormalities (n=16). score on performance
Integration
12/2006. IQ testing.
developmental testing. ◆ Lost to follow up (n=8).
◆
◆ Cumulative dose
Adaptive behaviour ◆ Encephalitis (n=1).
of benzodiazepine
assessment testing.
associated with lower
score on visual motor
integration testing.
97
Andropoulos et al. Retrospective cohort. A university- affiliated 59 Bayley scale of infant and GA <30 d for ◆ Pre-op and seven-day ◆ Died before 12 months ◆ Increased cumulative
2014 (8) paediatric hospital, (n=59) toddler development CHD surgery. postoperative MRI (n=10). volatile anaesthesia
Houston, TX testing at 12 months. available. ◆ Did not return for testing exposure associated
(CHD surgery). ◆ Survival to 12 months. (n=24). with lower composite
scores on cognitive
◆ Completion of ◆ Did not meet inclusion
testing.
neurocognitive tests. criteria or met exclusion
◆ criteria (n not reported): ◆ Increased cumulative
Hypothermic (<30ºC)
volatile anaesthesia
CPB >60 minutes. ◆ Prematurity <35 weeks.
exposure associated
◆ Anatomic cardiac lesion. ◆ Low birth weight. with trend toward
◆ Known dysmorphic lower language
syndrome. section scores.
◆ Surgery not requiring ◆ New postoperative
CPB. brain injury on MRI
◆ Pre-operative hx of associated with lower
cardiac arrest. composite scores and
◆
Intra-operative factors: trend toward lower
language section
◆ No aortic
scores.
cross-clamping.
◆ Length of ICU stay
◆ CPB<60 minutes.
was most consistent
◆ Temperature nadir factor associated
>30ºC. with lower cognitive
testing scores.
Chemaly et al. Retrospective cohort. A university-affiliated n=592 ◆ Behavioural change GA <4 yo. ◆ Anaesthesia between ◆ Chronic illness (n=40). ◆ Increased rate
2014 (80) paediatric hospital, (n=292) on Eyberg Child 1/2004 and 12/2005. ◆ Complicated neonatal of behavioural
Lebanon Behavior Inventory ◆ Age. course (n=35). abnormalities in
(any surgery). questionnaire. exposed group.
◆ >1 anaesthetic exposure
(n=52). ◆ Increased rate
of behavioural
◆ Behavioural assessment
abnormalities in pts
data unavailable (n=74).
who had surgery vs. a
diagnostic procedure.
◆ Increased rate
of behavioural
abnormalities with
increased duration of
anaesthesia.
◆ Highest rate
of behavioural
abnormalities in
pts who received
anaesthesia between
0–6 months.
◆ Increased rate
of behavioural
abnormalities in
pts who received
multiple vs. a single
anaesthetic agent.
(Continued )
98
Table 8.1 Continued
anaesthesia
exposure)
Ing et al. Retrospective cohort. Pregnancy cohort n=2547 ◆ Direct GA 3–10 yo. ◆ Born to mothers enrolled ◆ Exposure before three ◆ Decreased motor
2014 (4) (Raine) study (n=375) neuropsychological in pregnancy cohort years of age (n=321). function in exposed
(any surgery). testing. 1989–1992. ◆ Lost to follow up vs. unexposed pts.
◆ McCarron Assessment (n=220). ◆ No difference in
of Neuromuscular language or cognitive
Development. function between
exposed and
unexposed pts.
Ing et al. Retrospective cohort. Pregnancy cohort n=781 ◆ Direct GA <3 yo. ◆ Born to mothers enrolled ◆ Lost to follow up ◆ Increased of language
2014 (19) (Raine) Study (n=112) neuropsychological in pregnancy cohort (n=260). deficit on neuropsych
(any surgery). testing results. 1989–1992. ◆ Incomplete data testing in exposed pts.
◆ ICD-9 code for (n=1825). ◆ Increased risk
mental, behavioural, of ICD-9 coded
neuro-developmental language, cognitive
disorder. and/or behavioural
◆ Standardized testing disorder.
academic achievement ◆ No difference
scores. in standardized
testing benchmark
score achievement
between groups.
Stratmann et al. Retrospective case Northern n=56 ◆ Object recognition GA <2 yo. ◆ Age 6–11 at time of ◆ Did not meet inclusion ◆ Decreased
2014 (104) matched cohort. California: UCSF, UC (n=28) memory test. testing. criteria or met exclusion recollection on
Davis ◆
IQ test score. ◆
ASA PS 1 or 2 criteria (n=484). object memory test
(any surgery other than ◆ ASA PS ≥3. in exposed pts.
◆ Child behaviour ◆ Anaesthetic dose of
neurosurgery or checklist scores. >120 MAC*minutes. ◆ Attention or learning ◆ No difference in
CHD surgery). impairment. familiarity on object
◆ Induction with volatile ±
memory test.
propofol. ◆ CNS dx or trauma.
◆ No difference in IQ.
◆ Maintenance with ◆ Cancer.
volatile ± N2O. ◆ No difference in child
◆ Prematurity.
behaviour checklist
◆ Low birth weight. score.
◆ Genetic syndrome.
◆ Intra-operative
haemodynamic or
respiratory instability.
◆ Colour blindness.
◆ English non-fluency.
◆ Unable to contact
(n=292).
◆ Declined participation (n=28).
◆ Inability to comply with
instructions (n=2).
9
Backeljauw et al. Retrospective case Existing language n=106 (n=53) ◆ MRI findings. GA <4 yo ◆ Volunteers 5–18 yo. ◆ Did not meet inclusion ◆ Lower IQ test scores
2015 (17) matched cohort. development ◆ Oral and written ◆ No hx neuropsych criteria. in exposed pts.
and MRI language test score. illness, head trauma, LD, ◆ Unsatisfactory MRI ◆ Lower listening
database: Cincinnati, prematurity. quality (n=1 pair). comprehension
◆ IQ test score.
OH scores in exposed
(any surgery). pts.
◆ No grey matter
differences in
thalamus or
retrosplenial cortex.
◆ Decreased IQ
associated with
decreased grey
matter volume in
anterior cerebellum,
parts of frontal
lobe, lingual gyrus,
occipital lobes.
◆ Decreased oral and
written language test
score associated with
decreased grey matter
volume in right
lingual gyrus, occipital
lobe, temporal lobe,
parahippocampal
gyrus.
Glatz et al. Retrospective cohort Swedish national n=two million ◆ Average school marks ◆ GA <4 yo. ◆ Born in Sweden ◆ Neurosurgery. ◆ Minimal difference in
2015 (13) analysis. healthcare and (n=107640 exposed, at 16 yo. ◆ Subgroups 1973–1993. ◆ Cardiac surgery. average school marks
population registers n=34480 single ◆ At least one surgical with one exposure.
◆ 0–6 months. ◆ Cancer dx.
(any surgery). exposure <4 yo). procedure before four ◆ No difference within
◆ 7–12 months. ◆ Dx of malformation
years of age. any age subgroup.
◆ 13–24 months. (abstract, n not reported).
(Continued )
10
Table 8.1 Continued
anaesthesia
exposure)
Taghon et al. 2015 Retrospective cohort. Nationwide Children’s n=30 ◆ Accuracy and GA <2 yo. ◆ 10–17 yo. ◆ Did not meet inclusion ◆ No difference in
(18) Hospital: Columbus, (n=15) response time on go/ ◆ Surgery at least one hour or met exclusion criteria. response time or task
OH no-go task testing. duration. ◆
Known or possible accuracy between
(any surgery). ◆ Whole-brain activation pregnancy. exposed pts and
◆ Cognitive capacity to
pattern on fMRI. unexposed controls.
complete go/no-go task ◆ Documented respiratory
and participate in fMRI. or haemodynamic ◆ Differences in
instability on anaesthesia activation of
◆ Right-hand dominance.
record. cingulate gyrus,
◆ English fluency. cerebellum,
◆ Prenatal ethanol
paracentral lobule
exposure.
between groups.
◆ Exposure to antiepileptic
medication.
◆
ADHD.
◆ Traumatic brain injury.
◆ Psychiatric dx.
◆ Substance abuse.
◆ Psychoactive
medications.
◆ (Screening criteria, n not
reported).
ADHD = attention deficit hyperactivity disorder; ASA PS = American Society of Anesthesiologists Physical Status; CHD = congenital heart disease; CPB = cardiopulmonary bypass; DD = developmental delay; d/o = disorder; dx = diagnosis; GA = general
anaesthesia; hx = history; ICU = intensive care unit; IEP = individualized educational plan; IHR = inguinal hernia repair; IQ = intelligence quotient; LD = learning disability; MR = mental retardation; pts = patients; sevo = sevoflurane
10
Chapter 8 neurotoxicity of general anaesthetics 101
prior studies, this group found little to no association between an- national population, possible effects of surgery itself, each patient’s
aesthetic exposure in early childhood and impairment in academic social and economic environment, and other co-morbidities, cannot
function. In fact, they found that several other factors, including be excluded. Additionally, since many of the patients in these studies
being male, being born in December vs. January, and low parental were exposed to anaesthesia decades ago, newer anaesthetic agents
education levels, were associated with a risk of poor academic per- and significantly improved monitoring make these results difficult
formance that was several orders of magnitude higher than the very to interpret in the context of recent developments in the safety of an-
small risk associated with anaesthetic exposure (13). While these aesthetic practice. Moreover, the various outcome measures studied
studies did not demonstrate an association between early anaes- in these retrospective analyses (neurocognitive testing, diagnostic
thetic exposure and learning difficulties in the school environment, codes found in medical records, standardized test results, school
they add another facet to our understanding of this relationship performance) may not be comparable. Indeed, a recent study, which
and should prompt further investigation of the possible variability compared neuropsychological testing, International Classification
of the phenotype of anaesthetic neurotoxicity between populations. of Disease (ninth revision, ICD-9) codes from medical records, and
The association between early anaesthetic exposure and later school standardized testing scores in a previously studied cohort of
diagnosis of a developmental or behavioural disorder has also been ten-year-old children with a history of anaesthetic exposure before
investigated. In one large retrospective birth cohort study, children the age of three, found that the ICD-9 codes and direct neuropsycho-
who underwent inguinal hernia repair with general anaesthesia in logical testing scores indicated cognitive deficits in the exposed pa-
the first three years of life had twice the likelihood of a develop- tients, while the standardized testing scores did not (19).
mental or behavioural disorder diagnosis when compared to those Two large, prospective studies have recently been published, and
with no anaesthetic exposures (14). A cohort of twin siblings was another is in progress. The General Anesthesia and Apoptosis (GAS)
also retrospectively assessed with similar findings in the population study, a randomized, multicentre trial comparing neurocognitive
as a whole, including an association of increased risk with cumula- outcomes at five years of age following general and regional anaes-
tive anaesthetic exposure. Interestingly, however, in sibling pairs in thesia for neonates undergoing inguinal hernia repair, is ongoing (20).
which one twin had an early anaesthetic exposure and the other did Preliminary results from the first two years of follow- up have shown
not, there was no difference observed (15). When deficits of lan- no difference in neurodevelopmental outcome (21). The multicentre
guage were specifically assessed, there was once again a significantly Pediatric Anesthesia and Neurodevelopment Assessment (PANDA)
increased relative risk of impairment in children who were exposed cohort study, which compared healthy children who underwent in-
to anaesthesia at an early age, even with a single exposure (16). guinal hernia repair under inhalational anaesthesia before 3 years of
Recently, magnetic resonance imaging (MRI) has been explored age to unexposed siblings, did not find statistically significant dif-
as a potential modality for evaluating changes in brain structure in ferences in IQ scores, memory/learning, motor/processing speed,
function in young adults with a history of exposure to anaesthesia visuospatial function, attention, executive function, language, or be-
at a young age. One study assessed performance on oral and written havior in later childhood (mean age of testing was 10-11 years). (22).
language scale (OWLS) and intelligence quotient (IQ) testing, as Most recently, the Mayo Anesthesia Safety in Kids (MASK) study,
well as regional grey matter volume on MRI in a case-matched co- which evaluated a large cohort of Minnesota children with multiple,
hort of healthy volunteers who had been exposed to general an- single, or no anaesthetic exposures before 3 years of age through
aesthesia prior to four years of age. They found that, in addition to extensive prospective neurocognitive testing during late childhood
poorer performance on both the OWLS and IQ tests, the subjects and teenage years, did not identify a statistically significant asso-
with a history of anaesthesia exposure had decreased grey matter ciation between anesthesia exposure and the primary outcome of
volume in the cerebellum, occipital lobe, temporal lobe, lingual IQ testing; however, children with multiple exposures scored lower
gyrus, and several other brain areas (17). In a retrospective ana- on measures of processing speed and fine motor abilities, and the
lysis of congenital cardiac surgery patients, a higher dose of volatile parents of multiply exposed children reported challenges with
anaesthetic administered intra-operatively was significantly associ- reading, executive function, and behavior (23).
ated with both impairment on neurocognitive testing at 12 months
of age and new white matter lesions on routine postoperative MRI Proposed Mechanisms of Anaesthetic
(8). Another study, which compared functional MRI (fMRI) find-
ings in children with and without a history of anaesthetic exposure, Neurotoxicity
found that children between ten and 17 years old who had been While it is challenging to perform prospective experiments in
exposed to general anaesthesia before the age of two had significant human subjects, there are several well-established in vitro and in
differences in the activation of the cingulate gyrus, cerebellum, and vivo animal models for studying the cellular and molecular effects
paracentral lobule while performing a task. However, there was no of exposure to anaesthetic agents (see Figure 8.1). Since brain de-
difference in response time or the accuracy of task performance be- velopment involves a complex confluence of events, anaesthesia
tween the exposed children and unexposed, age-matched controls may cause damage through various related mechanisms (Figure
(18). This early data suggests that MRI and fMRI may be useful, 8.1). Multiple animal studies have strongly associated exposure to
noninvasive tools for continuing to investigate the association be- a variety of anaesthetic agents with cognitive and developmental
tween anaesthetic exposure and structural and functional brain disorders in rodents and non-human primates. The consistent asso-
changes; further study is needed in this area. ciation of anaesthesia with neurotoxicity, and the theory that anaes-
While these findings are compelling, the retrospective nature of thetics exert their main actions through a relatively small number
the existing data prevents clear conclusions from being drawn. As of receptor interactions (GABAA potentiation, NMDA antagonism)
with any retrospective study, the presence of confounders, e.g., pa- have prompted further investigation of these specific pathways and
tient characteristics necessitating surgery, the homogeneity of any their related mechanisms.
102
Figure 8.1 This figure highlights both currently established mechanisms of anesthetic neurotoxicity as well as potential strategies for protection against such injury.
The various pathways are organized according to cell type affected and the sub-cellular structure involved (boxes 1–3). Box (1) lists several stimuli that lead to apoptosis
within the neuronal cell body, or soma. Experimental evidence from several laboratories suggest that various anesthetic agents can trigger either the intrinsic or extrinsic
apoptotic pathways. In addition, several agents that provided protection against anesthetic-induced neuronal injury in laboratory experiments are indicated according to
the specific apoptotic pathway (intrinsic or extrinsic) considered relevant to their effects (box 1). Box (2) describes several experimentally observed changes that occur
in the dendrites of neurons after exposure to anesthetic agents. Box (3) outlines anesthetic-induced damage that has been observed in neuronal axons. Boxes (4–6)
describe the deleterious effects of anesthetic exposure on several types of non-neuronal glial cells, including microglia (4), astroglia (5), and oligodendroglia (6).
‘brain growth spurt’, which is a rapid period of connection building

Synaptogenesis that peaks at birth, a pattern that is seen both in humans and in
In humans, synaptogenesis begins in the third trimester of preg- other species. When animal models are used in studies of neurotox-
nancy and continues throughout life. According to experimental icity, the developmental age of the animal model is chosen to cor-
evidence, the developing brain is most vulnerable to anaesthetic tox- respond closely to that of the infant human brain. For example, at
icity during the period of highly active synaptogenesis known as the 120 days of gestation in a rhesus macaque, the brain is in the same
103
stage of development as a term human neonate between zero and Several proposed effects of anaesthesia have been studied
six days of age. A rhesus macaque at six days of age has a similarly in relation to the activation of the intrinsic pathway. One such
developed brain as a six-month-old human infant, and at 35 days of mechanism is postsynaptic neuronal death as a consequence of
life, the macaque’s is comparable to that of a 12-month-old human a lack of stimulation due to the inhibitory nature of many an-
child (24). In rodents, the brain growth spurt is known to take place aesthetic agents on neuronal signal transmission. This theory is
during the first two weeks of life (25); however, there is evidence that, strengthened by evidence that infants spend the majority of their
for multiple reasons, this stage of rodent brain development may be sleep in a state of active brain function, and in premature infants,
more closely analogous to that of a late second-trimester or early a decreased relative active sleep time has been associated with
third-trimester human foetus and potentially an even earlier devel- worse developmental outcomes (42, 43). In an in vitro mouse
opmental stage in non-human primates (26). Thus, it is possible that cortical neuron model, enhanced firing activity was associated
a number of findings from laboratory experiments in neonatal mice with downregulation of pro-apoptotic genes (44). In particular,
and rats may simulate the effects of an intrauterine (rather than a apoptosis may be related to an interruption in the processing of
neonatal or infantile) anaesthetic exposure in humans. brain-derived neurotrophic factor (BDNF), which is normally re-
Synaptogenesis is not a homogeneous process. Research shows leased in response to neuronal activation and functions to pro-
that different areas of the brain develop at different develop- mote neuronal growth and differentiation. In a mouse model,
mental stages. For example, in the foetal rhesus macaque, rapid isoflurane exposure impaired processing of a pro-apoptotic pre-
synaptogenesis is widespread, involving the cerebral cortex, basal cursor of BDNF, leading to increased apoptosis directly through
ganglia, thalamus, amygdala, cerebellum, and brainstem. However, the p75 receptor pathway as well as a lower level of BDNF (45).
by the time the macaque is in its first days of life, the majority of These effects are particularly pronounced in the cerebral cortex
rapid synaptogenesis is limited to the grey and white matter of the and the thalamus (46). Isoflurane has also been shown to acti-
cerebral cortex and brainstem (27). This suggests that different vate the intrinsic pathway through an increase in the level of the
areas of the brain may be most vulnerable to anaesthetic neurotox- pro-apoptotic factor Bax and a decrease in the level of the anti-
icity at variable times during the brain growth spurt. In fact, there is apoptotic factor Bcl-2; interestingly, these changes did not occur
evidence that vulnerability to anaesthetic-induced neuroapoptosis with desflurane administration (47).
may vary with the age of each individual cell (28–31). Further com- When the brains of 7-day-old rat pups were examined following
plicating this picture is the fact that different anaesthetic agents a six-hour isoflurane and nitrous oxide exposure, apoptosis was
may actually have more potent toxicity during different stages of seen in glutaminergic, GABA-ergic, and dopaminergic neurons
brain development (29, 32). Finally, although it is known that mat- throughout the hippocampus, cingulate cortex, and substatia
uration of some brain areas, e.g., the frontal lobe, continues into nigra. However, when the basal forebrain was examined (in which
young adulthood, there has been no investigation of the effects of cholinergic neurons predominate in rats and humans), there was
anaesthetic toxicity on this phase of brain development. no significant difference in apoptosis between exposed and un-
exposed rats. It has been hypothesized that suppression of cho-
Neuroapoptosis linergic signalling by anaesthesia may contribute to apoptosis of
Multiple laboratory studies of multiple anaesthetic agents have glutaminergic, GABA-ergic, and dopaminergic neurons that rely
demonstrated a strong association with neuronal apoptosis in upon cholinergic stimulation to prevent atrophy and apoptosis (48).
the developing brains of animals. Ketamine, propofol, thiopental, Reactive oxygen species, formed during the metabolism of oxygen,
isoflurane, sevoflurane, benzodiazepines, and nitrous oxide (25, have also been implicated in anaesthetic-induced neuroapoptosis.
32–39) have all been shown to induce neuronal apoptosis in foetal One study found that human embryonic stem cell-derived neurons
or neonatal rodent, porcine, and non-human primate models. underwent apoptosis via the intrinsic pathway after 24 hours of
Ketamine, isoflurane, and propofol have also been shown to in- ketamine exposure. An increase in reactive oxygen species was
duce apoptosis of oligodendrocytes, which are critical for axonal also noted in the cells exposed to ketamine, which was attenu-
myelination, in foetal and neonatal rhesus macaques (29, 31, 32). ated by co-administration of the reactive oxygen species scavenger
One study also observed isoflurane and nitrous oxide-induced Trolox; Trolox also attenuated ketamine-induced neuronal apop-
neuroapoptosis in the spinal cord of neonatal rats (40). tosis in this in vitro model, suggesting a causative role for reactive
This programmed cell death process can be induced through ei- oxygen species (49). Reduced mitochondrial integrity as a result
ther an intrinsic or extrinsic pathway; there is evidence to support of upregulation of antioxidant species has been demonstrated as a
that anaesthetic agents interact with both of these pathways in com- response to midazolam/nitrous oxide/isoflurane anaesthesia in rat
plex ways. The intrinsic apoptosis pathway is initiated as a response pups (50). Antioxidants such as L-carnitine and pramipexole, which
to cellular damage or stress, which then promotes mitochondrial counteract the effects of reactive oxygen species, have also been
cytochrome C release. Cytochrome C triggers the assembly of a shown to attenuate ketamine-induced neurotoxicity in rat forebrain
caspase-activating complex, sometimes known as an ‘apoptosome’, culture (51), and to prevent neuroapoptosis and cognitive impair-
which in turn leads to a cascade of caspase protein activation, cul- ment in rats when co-administered with an isoflurane/nitrous oxide
minating in an organized, pre-programmed destruction of cellular or isoflurane/nitrous oxide/midazolam anaesthetic (52, 53).
structures, eventually resulting in cell death (41). The extrinsic Anaesthetic agents also lead to apoptosis through inflammatory
pathway is initiated when inflammatory substance, such as tumour processes that activate the extrinsic pathway. While many anaes-
necrosis factor α (TNF-α) and interleukin-6 (IL-6) bind to external thetics have anti-inflammatory properties in the adult brain (54), they
receptors on a cell, triggering intracellular signalling cascades that have been shown to promote inflammation in the developing rodent
ultimately result in a common end-point of caspase activation and brain. After neonatal mice were exposed to multiple sevoflurane an-
cell death. aesthetics, increased levels of the pro-inflammatory mediators IL-6
104
and TNF-α were measured in the lysates of harvested brain tissues had episodes of hypoxemia or hypotension, further investigation of
(55). In a separate experiment, IL-6 was found to be elevated in rat this relationship may prove particularly clinically relevant.
pup brain tissue, along with the level of cleaved caspase-3 (a marker Finally, there is some evidence that a reduction in neurogen-
of apoptosis) following a single sevoflurane anaesthetic (35). Multiple esis following early exposure to general anaesthesia may lead to
sevoflurane anaesthetic exposures also resulted in cognitive impair- memory deficits. When postnatal day 14 rats and mice were ex-
ment, which was ameliorated by concurrent treatment with the anti- posed to daily isoflurane anaesthesia for four days, they showed
inflammatory ketorolac (55). These inflammatory mediators may significant memory impairments on subsequent testing. On histo-
exert a synergistic neurotoxic effect when combined the widespread logic examination, no increase in cell death was observed; however,
inflammatory response seen after surgical stimulation. the hippocampal stem cell pool was significantly smaller, and the
Sustained excitatory stimulus in developing rodent brain has number of hippocampal neurons was lower in the young rodents
been associated with neuronal death during seizures or following who were exposed to isoflurane (63). The underlying mechanism
hypoxia-ischaemia or hypoglycaemia (excitotoxicity). Although and significance of these findings have yet to be fully elucidated.
GABA-ergic agents exert sedative-hypnotic effects in adults, GABAA
receptor activation is an excitatory phenomenon during early de- Alteration in the Neuronal Network Structure
velopment of the mammalian brain. The potassium-chloride co- Given the complex nature of brain development, processes
transporter KCC-2 establishes a membrane chloride gradient. other than induced apoptosis are likely also altered by anaes-
Activation of KCC-2 through GABA-ergic signalling in the mature thetic exposure. During neuron development, several out-
brain leads to neuronal inhibition; however, in the immature brain, growths, known as neurites, begin to extend from the neuronal
an immature form of KCC-2, known as NKCC1, is present. GABA- cell body. One of these is destined to extend, grow, and develop
ergic activation of NKCC1 causes an excitatory response (56, 57). into a signal-transmitting axon, while the others will arbourize
Thus, while GABA-ergic medications are commonly used to treat into a network of signal-receiving dendrites. Dendrite develop-
excitatory conditions such as status epilepticus in the mature brain, ment, arbourization, and the density of small dendrite projec-
it is possible that sustained paradoxical GABAA mediated excita- tions known as dendritic spines, which increase the specificity
tion may contribute to anaesthetic-induced neurotoxicity in the of dendrite signal reception, are all important parts of synapse
developing brain. However, recent evidence suggests that the KCC building. When postnatal day 16 rat pups were exposed to
switch, which may occur around birth in rodents and could con- isoflurane, sevoflurane, or desflurane, a rapid and significant in-
tribute to the anaesthetic toxicity seen experimentally in mouse and crease in synaptic spine density was observed compared to un-
rat pup models, is likely to occur before birth in humans, and even exposed controls (64). When propofol was administered to 15-,
earlier in non-human primates (26). Therefore, it is possible that this 20-, or 30-day-old rat pups in a subsequent experiment, increases
mechanism could contribute to neurotoxicity following in utero, ra- in dendritic spine density and the number of synapses were again
ther than neonatal, exposure to anaesthesia in humans. observed; however, dendritic spine density in the prefrontal
In addition to these mechanisms, there is evidence that a relatively cortex was reduced when administered to five-or ten-day-old rat
recently described class of molecules may play a significant role in pups (65). This suggests that the effects of propofol on this aspect
the apoptotic response of neuronal cells. These small ribonucleic of synapse generation may be dependent upon the developmental
acid (RNA) molecules, known as micro-RNA (miRNA), are non- stage of the brain. Interestingly, this effect was not observed with
coding RNA molecules that bind in complexes to messenger RNA midazolam (66). When immature GABA-ergic neurons were ex-
(mRNA), downregulating translation or increasing degradation of posed to low doses of ketamine in vitro, dendritic development
mRNA strands. When a group of 84 miRNAs were assayed in human was also impaired. After four hours of exposure to a sub-lethal
embryonic stem cell-derived neurons after exposure to propofol, 20 dose or a two-day exposure to a very low dose of ketamine, de-
of them were found to be downregulated (58). Of these, several had creases in dendrite length and complexity were observed (67).
already been established to have important roles in neuronal dif- Since GABA-ergic neurons often function as interneurons, which
ferentiation and the regulation of apoptosis (59, 60); however, one, form modulatory connections between other neurons, an alter-
miR-21, was of particular interest due to its well-established anti- ation in their behaviour during development could disrupt the
apoptotic activity. In order to further investigate the role of miR-21 formation and function of important neural networks.
in anaesthetic-induced apoptosis, stem cell-derived neurons were During axonal development, the establishment of axon-dendrite
altered to either upregulate or knock down levels of miR-21. When polarity, in which the axon becomes differentiated from the den-
these neurons were exposed to propofol, more apoptosis was seen in drites, is a crucial step in the development of a functional neuron
the knock-down neurons, whereas the neurons with upregulation (68). Isoflurane exposure delays this polarization process in an
of miR-21 were protected from the apoptotic effect of propofol (58). in vitro model of embryonic mouse neocortical neurons. Higher
There is also evidence that mi-RNAs play a role ketamine-induced concentrations of isoflurane and a longer exposure time were as-
neurotoxicity (61). Additional investigation into the interaction of sociated with a dose-dependent retardation of neuronal polariza-
anaesthetic exposure and miRNA activity is ongoing. tion. Similar results were seen with exposure of the same model
While there is no evidence that show hypoxic-ischaemic injury to propofol, but interestingly were not seen with the pure GABAA
plays a direct role in the development of anaesthetic neurotoxicity, agonist muscimol, arguing against a purely GABAA-mediated
a history of prior hypoxia and/or ischaemia may predispose an al- process (69).
ready vulnerable patient to a more severe degree of damage. Rats Once polarity is established, the axonal neurite forms a growth
exposed to hypoxia prior to administration of isoflurane and ni- cone, which is comprised of the flattened end of the extending
trous oxide increased apoptosis (62). Given that many neonatal pa- neurite and several small, spiky extensions of actin and microtubules
tients who will require repeat exposure to anaesthetic have often known as filopodia. The filopodia respond to attractive and repulsive
105
external guidance cues, which influence the growth cone to extend development. It has been well established in rat models that ethanol
and collapse respectively. The balance of these alternating influences exposure during late adolescence results in demyelination of pre-
and resulting morphologic changes guides the growing axon down frontal white matter structures in rats (74) and alters the integrity
a specific path. This process requires precise timing, as the elong- of white matter in human teenagers (75). Further investigation is
ation of axons toward their eventual targets requires the presence of needed to determine whether or not oligodendrocytes remain vul-
a series of time-limited signals (68). When a model of embryonic nerable to the toxic effects of anaesthesia as well during later stages
mouse neocortical neurons were exposed to isoflurane, impaired col- of brain development.
lapse of the axonal growth cone in response to a repulsive cue was
observed; once the cells were allowed to recover from isoflurane, a
normal collapse response was restored (70). Similar responses were
The Role of Surgery
seen when the cells were exposed to thiopental and midazolam, sug- Since the vast majority of anaesthetic exposures occur simultan-
gesting that this may be a GABAA-mediated phenomenon. Exposure eously with a surgical procedure, the effect of surgery itself on the
of the cells to a pure GABAA agonist, muscimol, again resulted in developing brain must also be considered. It has been well estab-
impaired growth cone collapse, and exposure to the GABAA antag- lished that exposure to pain is associated with long-term behav-
onist pictrotoxin led to a preservation of the growth cone collapse ioural changes in both animals and humans, and that analgesia is
response in the presence of isoflurane, strengthening this hypothesis necessary to address pain resulting from surgical procedures and
(70). Although these effects on the sensitivity of the growth cone to other conditions. Neonates with a history of circumcision without
repulsive cues are short lived, even a temporary alteration in axon local anaesthesia had a stronger pain response to subsequent routine
migration may be associated with a long-term change in brain devel- vaccination than neonates who were either uncircumcised or who
opment or may contribute to eventual neuroapoptosis. had been pretreated with a local anaesthetic prior to undergoing
circumcision (76). When rat pups were anaesthetized and random-
Role of Glial Cells ized to splenectomy vs. no surgery, glial cell activation, interleukin-
There is a growing body of literature implicating other types of 1 and TNF-α expression, and a proportionally higher expression of
brain cells as important targets of anaesthetic neurotoxicity. Glial pro-apoptotic factors were all observed in the pups who underwent
cells, which include microglia, astrocytes, oligodendrocytes, epen- surgery (77). While the composition and delivery of the anaesthetic
dymal cells, and Schwann cells, are the support system for neurons. used in this study (intraperitoneal fentanyl and droperidol) do not
They provide nutrients and oxygen, degrade and remove dead correspond to anaesthetic regimens commonly administered in
neuronal cells, and provide physical structural support to maintain humans, neither opioids nor neuroleptics have been implicated in
the spatial relationships between neurons. anaesthetic neurotoxicity and are unlikely to confound the study’s
In astrocytes, which are responsible for a diverse set of functions, results. In rat pups whose paws were repeatedly injected with for-
including nutrient provision, maintenance of ionic balance, and malin, prolonged neuronal excitation, increased apoptosis, and
support of the blood-brain-barrier endothelium, cytostructural subsequent cognitive dysfunction were observed; these effects were
changes have been clearly observed when rat cells were exposed attenuated by concurrent ketamine administration (78). However,
to isoflurane in vivo. Interestingly, these changes did not seem to another study found that ketamine-induced neuroapoptosis in
affect cell function or survival, suggesting that astrocytes may be young rats was actually attenuated by noxious injection of Freund’s
relatively resistant to toxicity from anaesthetics (71). In fact, astro- adjuvant into the foot pad (79). Finally, in one retrospective study
cytes may actually be instrumental to attenuate propofol-induced of children who underwent surgery or diagnostic procedures under
neuroapoptosis (72). general anaesthesia before the age of four, the children who had
Microglial cells act as macrophages in the central nervous system surgery had a significantly higher rate of behavioural abnormalities
(CNS), removing dead and injured cells and infectious agents. on testing between the ages of ten and twelve than the children who
Given the observed increase in pro-inflammatory mediators after underwent diagnostic procedures (80). This data, while conflicting,
exposure to general anaesthetics, it has been theorized that micro- suggests that the relationship between pain stimulus, anaesthetic
glial activation may be the source of these inflammatory mediators exposure, and neurotoxicity warrants systematic investigation.
and may lead to accelerated destruction of other neuronal cells.
Indeed, when six-day-old mouse pups were exposed to sevoflurane
anaesthetics on three consecutive days, the number of cells that Reducing Neurotoxicity
stained positive for ionized calcium binding adaptor molecule Several therapeutic agents have been shown to be potentially pro-
1 (IBA1), a marker of microglial cell activation, was significantly tective against anaesthetic-induced neurotoxicity (Figure 8.1). In
increased compared with unexposed controls (55). This suggests animal models, alpha-2 agonists have been shown to be protective
that stimulation of microglial cells may be an important step in the against neuroapoptosis and cognitive impairment induced by
neuroinflammatory cascade associated with anaesthetic toxicity in isoflurane, ketamine, and propofol (81–83). Dexmedetomidine, a
the developing brain. selective alpha-2 receptor agonist with sedative and analgesic prop-
Oligodendrocytes, which are necessary for myelination in the erties, has been shown to attenuate both neuroapoptosis and long-
CNS white matter, have been shown to be subject to isoflurane-, term-memory impairment when co-administered with isoflurane
ketamine-, and propofol-induced apoptosis in foetal and neonatal anaesthesia in seven-day-old rat pups. This protective effect was
rhesus macaques (29, 30, 32, 73). This apoptosis occurs at the point abolished by the addition of the alpha-2 antagonist atipamezole
of maturation when the oligodendrocytes developed the ability to (82). When dexmedetomidine was administered to embryonic day
myelinate axons, suggesting that a deficit in myelination could par- 20 foetal rats concurrently with propofol for one hour, a significant
tially explain anaesthetic-associated problems with neurobehavioral increase in apoptotic markers was seen in the brain tissue of the
106
foetal rats exposed to propofol when compared to unexposed rats, particularly in the thalamus, when compared with another group of
which was not seen in the rats co-treated with dexmedetomidine. rats that underwent sham anaesthesia. However, while all of the ex-
A separate cohort under the same experimental model had a de- posed rats displayed short-term memory impairment, the rats living
cline in neurocognitive function at 35 days of after in utero propofol in the enriched environment had a return of normal memory over
exposure, which was not seen in unexposed rats or in rats who also the next several months, while memory deficits persisted in the rats
received dexmedetomidine (81). living in the standard (deprived) environment (97). This suggests
When erythropoietin, which promotes BDNF expression, was that, in rats, an enriched environment can mitigate the cognitive
administered to rat pups immediately following sevoflurane anaes- effects of anaesthesia exposure; however, it is unclear how this will
thesia, decreases in both apoptosis and cognitive impairment were translate to human infants, the overwhelming majority of whom al-
observed (84). Bumetanide, which interferes with GABA-ergic ready grow up in an ‘enriched environment’, and are intensely tended
signalling through inhibition of NKCC1, has been shown to nearly to following anaesthesia and surgery.
eliminate the increase in levels of pro-apoptotic markers seen in rat
pups following exposure to sevoflurane (85). Neuroapoptosis was
also reduced when a single dose of lithium, which is known to sup- Conclusions
press pro-apoptotic pathways and to counteract ethanol-induced The majority of anaesthetic medications, including the volatile
apoptosis, was administered to neonatal mice prior to exposure to anaesthetics, propofol, NMDA antagonists (nitrous oxide, keta-
propofol and ketamine (86). Lithium has also been shown to protect mine), GABAA agonists (including barbiturates and benzodi-
against isoflurane-induced neuroapoptosis in non-human primates azepines), and synergistic combinations thereof (98) have been
(87, 88). NMDA-induced neuroapoptosis in rat primary cortical strongly associated with neurotoxicity and cognitive disorders in
neurons has also been shown to be prevented by pre-treatment with the developing brains of several animal species, including non-
the oestrogen receptor antagonists estradiol-17β and estriol (89). human primates. Many mechanisms of neurotoxicity have been
Pramipexole, which restores mitochondrial integrity and has described in preclinical experiments, and new mechanisms con-
antioxidant properties, was protective against cognitive impairment tinue to emerge. These data support the observed association of
when administered to seven-day-old rats alongside an anaesthetic impaired cognitive and behavioural development anaesthetic ex-
of midazolam, nitrous oxide, and isoflurane (90); similar results posure during the vulnerable period in both prospective animal
have been seen with several other antioxidant medications and sub- and retrospective human cohort studies, and concerns about
stances, including melatonin, curcumin (found in turmeric), and L- the long-term effects of anaesthesia have escalated as the body
carnitine (27, 48, 91, 92). When bone marrow stromal cells, which of evidence grows. Indeed, neurocognitive dysfunction has now
have been shown to repair CNS damage in stroke models, were in- been shown to persist for years in a cohort of non-human pri-
jected in rat pups 30 minutes after the induction of sevoflurane an- mates following even a single, albeit prolonged (24h), neonatal
aesthesia, the increase in pro-inflammatory IL-6 seen in the group ketamine anaesthetic (99). While this laboratory evidence is ro-
treated with sevoflurane alone was suppressed (35). bust, there is no direct evidence available that these effects are
Inhaled substances have also been studied as neuroprotectants. translatable to humans. Furthermore, the available human data,
Hydrogen and xenon gases are both able to quickly neutralize re- while compelling, is largely retrospective in nature. The results of
active oxygen species. When hydrogen gas was administered as a two recently published prospective studies and the preliminary
component of the anaesthetic carrier gas (0.3%, .06%, or 1.3%) in results available from a third have been mixed with regards to
a 3% sevoflurane general anaesthetic, neuroapoptosis and oxida- the association between early childhood anesthetic exposure and
tive stress were reduced and the memory and behavioural deficits neurodevelopmental consequences later in childhood (21, 22,
seen in the rats exposed to sevoflurane alone were ameliorated (93). 23). While anaesthesia for minor surgery seems to be save for
Xenon gas has been shown to be protective against neuroapoptosis children, the role of anesthesia for major surgery is unclear.
and cognitive decline in seven-day-old rats when administered for The SmartTots initiative, which is a collaborative public-private
two hours on the day before an exposure to general anaesthesia with partnership between the International Anesthesia Research
isoflurane and nitrous oxide (62). Preconditioning with isoflurane Society (IARS) and the Food and Drug Administration (FDA),
itself, when administered for a short period of time on the day works to address gaps in science regarding paediatric anaesthetic
prior to a six-hour general anaesthetic with 1.5% isoflurane, has safety and neurotoxicity. The current consensus of this expert
been shown to ameliorate isoflurane-mediated apoptosis in young group of anaesthetists and scientists is that mounting concerns
rats (94). Early evidence suggests that low concentrations of carbon about the potential for cognitive or behavioural impairment in
monoxide administered as a carrier gas component may also be the future should not prevent urgent or emergent paediatric sur-
protective, possibly through modulation of cytochrome oxidase ac- gery, as withholding a necessary surgical procedure is likely to
tivity and reduction of oxidative stress (95, 96). More research is cause patient immediate harm (100). If the need for surgery is
needed in this area, as identification of a successful, feasible mitiga- less clear, discussion of the risks, benefits, and timing of surgery
tion strategy could have profound clinical impact. should take place between the anaesthetist, the surgeon, and the
Finally, there is evidence in experimental studies that providing parents.
environmental enrichment may actually reverse the neurocognitive It is important to note that at this time, there is no recommenda-
deficits seen after exposure to anaesthesia. In one study, seven-day- tion to support a change in clinical practice based upon the current
old rat pups were randomized to either an enriched environment (soft state of the evidence (101). However, some anaesthetists choose to
bedding, running wheel, toys) or a standard environment (lacking employ putative mitigation strategies, such as regional anaesthesia
these amenities) four weeks after undergoing sevoflurane anaes- or the use of an opioid-heavy anaesthetic, to reduce the amount of
thesia. The exposed rats had significant evidence of neuroapoptosis, anaesthetic exposure; while there is no evidence to support this as
107
a neuroprotective strategy, it may be acceptable based on clinical 15. DiMaggio C, Sun LS, Li G. Early childhood exposure to anesthesia
judgment and the individual characteristics of each patient. The and risk of developmental and behavioral disorders in a sibling birth
use of a combination of regional anaesthesia, dexmedetomidine, cohort. Anesthesia & Analgesia. 2011;113(5):1143–51.
16. Ing C, DiMaggio C, Whitehouse A, Hegarty MK, Brady J, von
and opioid as a substitute for volatile anaesthetics, ketamine, or
Ungern-Sternberg BS, et al. Long-term differences in language and
benzodiazepines is currently being investigated; at this time, it is cognitive function after childhood exposure to anesthesia. Pediatrics.
unknown whether the elimination of the offending agents in paedi- 2012;130(3):e476–85.
atric practice will be feasible or will affect the potential long-term 17. Backeljauw B, Holland SK, Altaye M, Loepke AW. Cognition and brain
neurologic sequelae of anaesthesia and surgery. structure following early childhood surgery with anesthesia. Pediatrics.
Ongoing and future prospective studies may help to link these 2015;136(1):e1–2.
laboratory observations to outcomes in humans. Until that time, 18. Taghon TA, Masunga AN, Small RH, Kashou NH. A comparison of
functional magnetic resonance imaging findings in children with and
anaesthetists should counsel patients and families regarding
without a history of early exposure to general anesthesia. Paediatric
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anaesthesia. 19. Ing CH, Dimaggio C, Malacova E, Whitehouse AJ, Hegarty MK,
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10
1
CHAPTER 9
Neurobiology of Acute
and Chronic Pain
Adrian Pichurko and Richard E. Harris
Introduction Nociception vs. Pain

Treatment of pain is among the physician’s most important roles. Though nociception and pain are closely related, they are mech-
It is associated with assuaging suffering, showing care, and is per- anistically and conceptually distinct. The International Association
ceived by many as closely linked to the nobility of the profession. for the Study of Pain carefully distinguishes the two: it defines
Patients are often as or more concerned with the relief of pain than nociception as ‘the process by which noxious stimuli impinge upon
they are with their ailments themselves. It is perhaps humankind’s the body from internal or external sources and then transduces
best attempt to care for itself. into information sent through neural pathways sent through the
Chronic pain has profound societal implications. It is widely peripheral nervous system into the central and autonomic nervous
prevalent, affecting an estimated 116 million Americans as of 2011 systems’ (2). The IASP defines pain as ‘an unpleasant sensory and
(1) and poses a significant financial burden for the United States, emotional experience associated with actual or potential tissue
estimated at 500–600 billion dollars annually in terms of care, damage, or described in terms of such damage’ (2). Nociception
lost productivity, and government spending on disability. Yet the is, therefore, a signalling process that ends in the central nervous
discipline of pain management, for its many merits, is still in its system (CNS) and pain is the result of its realization in the brain,
relative infancy. The diagnosis behind a subjective complaint (‘it and thus, its perception. ‘Pain’ then includes cognitive-affective and
hurts’) may remain open-ended; not uncommonly, organic causes sensory-discriminatory components involved with higher-order
cannot be found and the legitimacy of the complaint may be ques- processing and behavioral response (2). The distinction between
tioned. Even with signs suggesting a diagnosis, therapeutic mo- nociception and pain is important, in part, because each can exist
dalities may be dangerous, fraught with side effects, or ineffective. independently of the other. Nociception is not always realized as
The process of treatment selection may be inelegant; without an pain, as in the example of patients with spinal cord transection.
objective picture, the default becomes a ‘try and see’ approach, A nociceptive stimulus applied to an area below the level of the
leading to longer-than-normal care, potential dismay, and the risk lesion will not result in perceived pain, but is recognized by the
of side effects. autonomic nervous system and may result in an exaggerated sym-
Fortunately, recent innovations suggest hope for the future. The pathetic response known as autonomic hyper-reflexia. Similar ex-
advent of imaging techniques such as functional magnetic reson- amples include autonomic responses to surgical stimulation under
ance imaging (fMRI) and connectivity mapping has helped char- general anaesthesia and in certain cases of massive trauma in which
acterize functional and anatomic patterns suggestive of specific the patient does not appear to sense pain (3).
causes of pain and this portends diagnostic use. Targeted therapies, Conversely, not all pain requires nociceptive input. While a
e.g., intrathecal infusion pumps, spinal cord and deep brain stimu- stimulus may evoke inflammatory, neuropathic, and central types
lators, allow for ever more-precise modulation of the pain neural of pain, they may also occur spontaneously without peripheral
circuitry. Organized task forces are gathering large-scale data and input (4). Central post-stroke pain is a phenomenon that occurs in
are identifying areas for further research on existing therapies, for a portion (8–46%) (5) of patients after a cerebrovascular event, usu-
example, in chronic opioid treatment. ally in those affecting the thalamus, brainstem, or cortex. Such pa-
The discipline of pain medicine is in some ways inherently tients report spontaneous pain in the absence of noxious stimulus;
frustrating for both patients and clinicians alike due to nonspecific in such cases, pain is due to abnormality of central nervous func-
complaints, potentially unclear diagnoses, and limited treatment tioning and does not require nociception.
options with results that may not be generalized. Physicians must Chronic pain can be classified by these mechanisms into three
understand and differentiate how two complaints of ‘back pain’ can main classes: nociceptive, neuropathic, and central pain. Nociceptive
differ in their nuanced pathophysiology, treatment, and overall re- pain is generally thought of as pain that originates from altered ac-
sult. Yet, this often-nebulous field remains central to the well-being tivity in peripheral nerve fibres, whether by directly evoking neural
of individuals, society, and the practice of medicine. However it un- activity or by lowering their activity threshold. This could be the
folds, our understanding of pain will be integral to the direction of result of inflammation or other factors (see Box 9.1). Neuropathic
medicine. pain refers to pain generated from nerve injury or impingement,
12
low pain sensitivity (11). This inter-individual variation also exists

Box 9.1 Inflammatory Pain has Similarities with Nociceptive Pain
with experimentally induced hyperalgesia and allodynia (12).
While some sources classify inflammatory pain separately be- The distinction between nociception and pain is important in
cause of its difference at the membrane receptor level, its neural clinical decision-making. Centrally acting medications such as
pathway is not distinct from nociceptive pain and the two will tricyclic antidepressants (TCAs) and selective serotonin and nor-
not be distinguished here. epinephrine reuptake inhibitors (SNRIs), normally used for psy-
chological benefit, appear to affect pain, at least in part, at the level
of subjective perception. Peripherally acting medications such as
such as with spinal stenosis or chemical-induced peripheral nerve non-steroidal anti-inflammatory drugs (NSAIDs) affect the process
damage, e.g., from chemotherapy or diabetic neuropathy. Central of nociception. A patient complaining of pain may have abnormal-
pain, sometimes known as functional pain, is an evolving concept ities in one or both of these processes, which would influence the
that describes abnormalities in the responsiveness or function of efficacy of these interventions. Therefore, to understand the aeti-
neural activity, resulting in amplified experience of evoked or spon- ology of a patient’s complaint and the approach to treatment, the
taneous pain. Fibromyalgia, for example, is thought to result from distinction between nociception and pain is significant.
dysregulated central modulatory systems that amplify or misinter-
pret musculoskeletal nervous signals as painful (see Box 9.2). Some
pain syndromes such as irritable bowel syndrome, some types of
Anatomy of Pain Processing
noncardiac chest pain, and tension-type headache have features Basic Pathway of Nociceptive Pain
that suggest abnormalities in central processing (6–8). Other pain Nociceptive pain refers to the experience of pain evoked by a nox-
syndromes, such as migraine, appear to have complex aetiologies ious physical or chemical stimulus, such as that evoked by a paper
with inflammatory, neuropathic, and central components. Cancer cut on the finger. Its ‘basic pathway’ from stimulus to realization
pain can also present a complex picture and may involve nocicep- involves the relay of nociceptive neurobiological information from
tive/inflammatory and neuropathic elements (9). Often patients peripheral tissues centrally, ending in the spinal cord or brain. The
with central pain disorders also have concomitant neurobiological process is divided into functional steps, referred to as transduction,
symptoms along with the pain, such as higher prevalence of fatigue, conduction, transmission, and perception, as detailed in Figure 9.1.
depression, poor sleep, and cognitive slowing (10).
Nociceptive, neuropathic, and central pain can result in hyper- Transduction
sensitivity to subsequent stimulation in the area of the ini- Transduction refers to the conversion of a noxious stimulus into
tial insult and, in some cases, generalized throughout the body. neural information. This initial step takes place when a ligand or
Exaggerated response to a normally noxious stimulus is referred to noxious force activates nociceptors, neurons that transmit noxious
as hyperalgesia, while the interpretation of non-noxious stimuli as stimuli from the peripheral site of irritation to the spinal cord.
nociceptive is known as allodynia. Both processes can occur as a re- Nociceptors contain various ionotropic receptors, known as noci-
sult of underlying peripheral and central nervous changes, known ceptor transducers, on the membranes of their peripheral terminals.
as peripheral and central sensitization. The biological changes of Each type of nociceptive transducer responds to designated stimuli
peripheral sensitization take place from the level of tissue damage like extreme hot or cold temperature, chemicals, or mechanical
to its input in the dorsal horn of the spinal cord, thus associating it shearing forces, but they share in common a high threshold of ac-
with the nociceptive process, rather than pain. Although detailed tivation. Upon opening, the channels create an inward current of
evidence for central sensitization in humans is still emerging, its sodium and sometimes other cations such as calcium, which can
purported mechanism involves changes in the CNS and can thus be act as a second messenger depending on the receptor. These in-
more closely aligned with pain perception than with nociception. ward currents, called generator potentials, depolarize the neuron,
Both will be discussed in greater detail later in this chapter. bringing it towards a threshold above which the signal propagates
It is clear that great variability in response exists between down the axon as an action potential.
healthy volunteers and patients for a given nociceptive stimulus. With the explosion of molecular biological data in the past two
Individuals report considerable variation in pain on a one-to-ten decades, various such receptors have been identified that respond
(visual analogue) scale, which can be attributed to differences in to different types of noxious stimuli: TRPV 1, 2, and 3 receptors
nociceptive apparatus or in the cognitive and emotional influ- sense noxious heat (>42 C), TRPM8 receptors sense noxious cold
ences that amount to the final experience (11). When subjected to (<10 C), acid-sensing ion channels (ASICs) sense protons or acidic
a noxious heat stimulus, fMRI in highly pain-sensitive individuals environment, and P2X receptors sense ATP that is released during
showed significantly greater activation of areas of the anterior cin- tissue damage. Other nociceptive receptors likely exist but have yet
gulate, somatosensory I, and prefrontal cortices than in those with to be fully identified or characterized.
Transient receptor potential channels, or TRP channels, are a
class of non-selective cation channels that are activated by noxious
sensory information, including pain and temperature, pressure,
Box 9.2 Central Pain is Distinct from Neuropathic Pain voltage, irritant agents, inflammatory molecules, pH, osmolality
changes, UVB radiation, and other chemicals. They are also highly
It is worth noting that some sources classify central pain as a
responsive to lipids in their environment, some of which act as
type of neuropathic pain. However, due to significant differ-
TRP agonists, modulators, or inhibitors. Because such lipids are
ences in mechanisms and implications, they will be discussed
metabolites of the cycloxygenase (COX) and lipoxygenase (LOX)
separately here.
pathways, this explains the effectiveness of COX-inhibiting drugs
13
Chapter 9 neurobiology of acute and chronic pain 113
4. Perception
Medial (affect-cognitive-evaluative)
structures:
Cerebrum Cingulate
Amygdala
Anterior insula
Third order neuron
Lateral (sensory-discriminatory)
structures:
SI
SII
Posterior insula
3. Transmission
Brainstem
Modulation:
Local
Descending
2. Conduction
Ascending
Nociceptors:
Unimodal
Polymodal
Silent Second order neuron
1. Transduction
Nociceptor transducers:
Ionotropic
Metabotropic Spinal cord
First order neuron
Figure 9.1 Basic steps in the pathway of nociceptive pain.

Transduction refers to changing a noxious stimulus into a neural signal, conduction refers to its propagation along a peripheral neuron (nociceptor) to the spinal cord,
transmission refers to central signal modification (amplification or suppression) and relay to the brain, and perception denotes its realization as experience. Interventions
against nociceptive pain may target various points along this pathway.
in decreasing the transduction of pain (13). Once activated, TRP ability to sense noxious cold, suggesting that TRPM8-independent
channels evoke ionic currents that modulate action potentials in mechanisms also exist for the detection of cold (17).
peripheral terminals and modify intracellular signal pathways ASICs are heterotrimeric, sodium-preferential cation channels
within the nociceptor. that activate on exposure to extracellular protons. Among other
TRP receptors identified as playing a role in pain transduction tissues, they are expressed in the peripheral and central nervous
include members of the TRPV (vanilloid) and TRPM (melastatin) systems, including on nociceptors, where they appear to be respon-
sub-families. TRPV receptor subtypes 1, 2, and 3 activate in response sible for acidosis-related pain from ischaemia, inflammation, and
to noxious heat at various thresholds. TRPV1, also known at the infection. ASIC subtypes 1, 2, and 3 are most closely associated
vanilloid receptor 1 (VR-1), activates in response to temperatures with nociception (18). ASIC3 also appears to be responsible for
42 degrees Celsius and above (14). It is also activated by capsaicin, pressure-induced vasodilation (PIV), a local cutaneous response to
the chemical compound responsible for the feeling of heat in spicy low pressure applied to skin, and may be protective against pressure
food, and appears to be potentiated by the presence of hydrogen ulcers (19). The ASIC-inhibiting drug amiloride is able to block
ions (14). TRPV2, also known as vanilloid-like receptor 1 (VRL- pain induced by exposure to acidic solutions and also attenuates
1, in contrast to VR-1), activates in response to temperatures 52 PIV (19–21).
Celsius and above (15). TRPV3, present in keratinocytes, activates It has long been known that ATP applied to blisters in humans
to moderate, innocuous temperatures between 22 and 40 degrees causes slow, nonsustained pain (22). An ATP-activated ionotropic
Celsius, but shows increased activation at noxious temperatures receptor family called P2X has been characterized. While subtypes
(16). Some evidence suggests that activating keratinocytes with the of these receptors exist in neural and non-neural tissue, subtypes
TRPV3 receptor signals adjacent nociceptors, possibly via direct found on nociceptors likely contribute to tissue damage-related
chemical signalling or through ATP interaction with the P2X3 re- nociception (23, 24). In rats, injection of a P2X agonist induces
ceptor. TRPM activates in response to cold temperatures (<25 de- mechanical allodynia (25). Because these receptors open in re-
grees Celsius) as well as to certain agents that produce a cooling sponse to micromolar concentrations of ATP (26), the millimolar
sensation, e.g., menthol, icilin, and eucalyptol (17). Knockout gene concentrations of intracellular ATP are likely to activate these
experiments demonstrate that TRPM-deficient mice retained some receptors when released. Extracellular nucleotidases present
14
ubiquitously in tissues remove phosphate groups from ATP (27), AMPA, kainate, and NMDA receptors, neuropeptides produce
providing a mechanism for the deactivation of the nociceptive slower, more sustained synaptic currents via G-protein-coupled
signal. The presence of ATP-specific receptors and degrading en- receptors. Trophic factors such as BDNF activate tyrosine kinase
zymes establishes this ubiquitous molecule as a plausible effector of receptor B to modify membrane excitability (4). These fast and
nociception in sufficient concentrations. slow processes together allow for immediate signalling as well
as for activity-and use-dependent synaptic plasticity to occur.
Conduction
Interestingly, some elements of the neural signal can occur in
If the summative depolarization created by generator potentials is the opposite direction, towards the peripheral terminal of the
sufficient to activate voltage-gated sodium channels on the neur- nociceptor.
onal membrane, the subsequent inflow of sodium then propagates
the depolarization down the nerve as an action potential. Typically, Transmission
the frequency and duration of the series of action potentials is dir- Transmission refers to the synaptic transfer and modulation of
ectly proportional to the intensity and duration of the noxious input from one neuron to another (4). It describes the point from
stimulus. The action potential travels to the dorsal root ganglion which the nociceptor central terminal synapses in the dorsal horn
(DRG) and ends at the nociceptor’s central terminal, where it syn- of the spinal cord (or, if from the head, in the spinal nucleus of the
apses in the dorsal horn of the spinal cord, having reached the CNS. trigeminal nerve in the medulla) to its projections into the brain. It
The presence, specificity, and threshold of nociceptor transducers involves processing at the synapse of the nociceptor in the dorsal
on a nociceptor dictate its sensory capabilities. Depending on the horn, where local modulation by interneurons takes place, as well
nociceptor transducers on its peripheral terminal, a nociceptor may as descending modulation from the brain, before ascending in the
react to only one form of stimulus, such as noxious heat, and is thus spinal cord. At this stage of the nociceptive pathway, the nocicep-
called unimodal. More commonly, nociceptors are polymodal and tive signal may undergo conditioning that can amplify or reduce its
transmit signals from multiple noxious stimuli. Some neurons have magnitude prior to reaching the brain.
transducers with high thresholds of activation and respond only to At the synapse of the peripheral nociceptor in the dorsal horn,
damaging stimulus; these are referred to as silent nociceptors. local signalling factors affect both pre-and postsynaptic aspects of
Peripheral nerve fibres are classified into three groups; A, B, and signal conduction. While the fast synaptic potential is transmitted
C, with the A group further dividing into alpha, beta, gamma, and via the neurotransmitter glutamate, other factors such as substance
delta. The A-delta and C fibres are responsible for nociceptive pain P and NGF are released into the synapse to cause slower effects that
and can be uni-or polymodal. A-fibres are of medium-large diam- sensitize the neurons to further stimuli. This process is responsible
eter (2–5 um), myelinated, and fast-conducting. A-delta fibres con- for temporal summation of stimuli that lead to an exaggerated re-
duct at 2–30 metres per second (mps) and synapse in specific areas sponse, called wind-up, as well as other forms of sensitization that
of the dorsal horn known as Rexed’s laminae I and V; due to their will be discussed later. Presynaptic receptors that modulate the
faster conduction velocity, these fibres transmit ‘first pain’, the im- signal include mu opioid, CB-1 cannabinoid, and GABAB recep-
mediate component of nociceptive pain, such as the painful slice of tors, and presynaptic voltage-gated calcium channels are pharma-
a papercut. C-fibres are thinner (0.2–1.5 um), unmyelinated, and cologically targeted for this purpose as well. Postsynaptically, mu
slower conducting at less than 2 mps. These neurons synapse at opioid and GABA receptors activate potassium and chloride cur-
Rexed’s laminae I and II and transmit the lingering component of rents, respectively, that hyperpolarize the neuron’s membrane po-
nociceptive pain, called ‘second pain’ (28, 29). This corresponds to tential and thus inhibit the creation of action potentials (34).
the burning pain of a paper cut that remains after the initial slice. In 1965, Wall and Melzack postulated the ‘Gate Control Theory’,
Action potentials propagate down an axon by a cascade effect one of the first theories about pain transmission in the spinal cord.
caused by voltage-gated sodium (Nav) and potassium (K) chan- It was proposed that a form of local inhibition, in which innocuous
nels within the axon membrane. The depolarization of membrane sensory input from A-beta fibres inhibits concurrent nociceptive
potential created by an influx of sodium through an open channel transmission, reduced afferent pain signalling. Although newer
opens nearby Nav. This feed forward mechanism, if passing a critical theories exist, this was one of the first explanations for the efficacy
cell membrane potential, can then cause a depolarization to spread of acupuncture and spinal cord stimulation (35).
throughout the neuron. The DRG expresses roughly six types of Other inhibitory and facilitatory systems descend from the
sodium channels. Nav1.8 and Nav1.9 are selectively expressed in brain to modulate the nociceptive signal in the dorsal horn. One
small-diameter DRG neurons, most of which are nociceptors (30, descending inhibitory system involved is the locus coeruleus (LC),
31) Aberrant behaviour or mutations of Nav1.7 channels on DRG which inhibits primary afferent terminals and projection neurons
neurons are implicated in nociception, erythromelalgia, and some via norepinephrine-induced activation of alpha-2 receptors (36).
types of fibromyalgia (32). Evidence now demonstrates that these The ventrolateral periaqueductal grey (PAG) is an effector site of
sodium channels are dynamic; trophic factors, injury, and post- opioids and also produces descending inhibition of spinal pro-
translational phosphorylation modify their expression and sensi- cessing (37). Other brain sites that can produce descending inhib-
tivity, and after injury they can cause aberrant, spontaneous action ition are the sensory cortex, thalamus, hypothalamus, midbrain,
potentials (32, 33). pons, and medulla (37). The rostroventralmedial medulla (RVM)
Once they reach the central terminal in the spinal cord, high- is of special interest because it appears central to all descending
frequency action potentials cause the release of glutamate, neuromodulation and because it may itself cause inhibition or facilita-
peptides such as substance P, and neuromodulators such as tion. It contains cells referred to as ‘ON’, ‘OFF’, and ‘neutral’, which
brain-derived neurotrophic factor (BDNF) into the synapse (4). produce differing patterns of tonic or phasic activity that are dis-
Whereas glutamate produces fast synaptic transmission via its rupted with nociceptive input (38). These signals are mediated by
15
excitatory neurotransmitters glutamate and neurotensin as well as, (SRT), spinomesencephalic tract (SMT, a component of the SRT),
in some cases, serotonin (38, 39). spinocervical tract, and postsynaptic dorsal columns have also
After synapsing in the dorsal horn, the nociceptive signal con- been noted to carry nociceptive information, explaining these find-
tinues to the brain. In its simplest form, this circuit is monosynaptic, ings. The latter two tracts transmit largely innocuous stimuli, but
referring to the single synapse between peripheral nociceptor and have been noted to transmit mixed and purely noxious stimuli as
central neuron; in other instances, it is polysynaptic, transmitting well (43).
signals through multiple interneurons that further modulate the
Perception
signal before ascending to the brain.
Peripheral neurons entering the dorsal horn of the spinal cord Once at the brain, the nociceptive signal is further processed and
synapse at different anatomic layers, called Rexed’s Laminae, which represented in various centres, where it ultimately manifests as per-
contain the cell bodies of second-order neurons. A-delta fibres tend ception of pain. Here, the process is no longer just ‘nociception’;
to synapse in Laminae I, II, and V, while C fibres tend to synapse cognitive, emotional, and sensory characteristics are integrated in
in Lamina I and II. A-beta fibres, which carry non-noxious sen- the experience of pain. Studies using advanced brain neuroimaging
sory neural information such as light touch, synapse in Laminae techniques such as fMRI and positron emission tomography (PET)
III through VI. have provided insight into the activity patterns that are associated
Lamina I contains mostly cell bodies of nociceptive specific (NS) with the experience of pain.
cells that transmit only nociceptive information. It contains the The various centres in the brain that are activated in response to
bodies of spinothalamic tract (STT) neurons that transmit sharp pain are known collectively by several names. Whereas the term
‘first’ pain as well as neurons that transmit various types of second ‘pain matrix’ has been used to describe these loci, the terms ‘pain
pain. The latter neurons are called HPC cells, short for ‘heat, pinch, network’ or ‘cerebral signature for pain’ are sometimes used in fa-
cold’, after the various stimuli they conduct, and are associated with vour in order to emphasize the fluid and varying nature of such
C-fibre nociceptors and ‘second’ pain (40). brain activity. There has been a realization that pain perception dif-
Cell bodies in Lamina V tend to be wide dynamic range (WDR) fers between subjects and, importantly, between different types of
neurons that transmit both innocuous and nociceptive information pain. As such, centres of brain activity that correlate with pain are
(41). They receive input from A-delta, A-beta fibres, and C fibres, described in terms of primary centres that are more consistently ac-
responding to intensity of stimulus in a graded fashion. Because tivated, and secondary or ancillary centres, where activity is more
of this graded response, these neurons demonstrate wind-up, variable (Figure 9.2).
increasing their output with rapidly repeated input (42). Primary structures of the cerebral pain signature are subdivided
From the dorsal horn, nociceptive information is carried through by function, described as ‘lateral’ and ‘medial’ structures. Lateral re-
various spinal cord tracts to the brain. The spinothalamic tract is fers to the part of the network closer to the parietal and temporal re-
typically associated with nociception, which the postsynaptic gions of the brain, which is responsible for sensory-discriminatory
neuron enters after decussating in the anterior commissure at components of pain. This includes the primary and secondary som-
the level of input into the spine. It ascends in the anterolateral atosensory cortices (SI and SII), the thalamus, and the posterior
cord and synapses in the ventroposterolateral (VPL) thalamus, insula. Medial refers to the affective-cognitive-evaluative aspects of
where it is thought to contribute to the sensori-discriminatory pain perception that take place in the medial-frontal areas of the
process of pain (43). Ablation of this tract in humans causes sig- brain, and includes the anterior insula, anterior cingulate cortex
nificant, but not always total, analgesia. The spinoreticular tract (ACC), and prefrontal cortex (PFC). Meta-analysis of PET and
Dorsal cingulate SMA
SI
Dorsolaterl prefrontal cortex
Insula/SII
Rostral anterior cingulate
Hippocampus
Amygdala
PAG
Thalamus Cerebellum
Ventral posterior RVM
Ventral medial
Figure 9.2 Associations between the experience of pain and various centres in the brain.

Areas more consistently activated and thought essential to experiencing pain are referred to as primary centres, labelled in black. Secondary structures, labelled in blue,
are less consistently activated and are likely significant in reaction to pain and other ancillary aspects of the experience.
16
fMRI studies in humans demonstrates that these centres most con- 39); the posterior cingulate cortex (~BA 30, 23, 31), and precuneus
sistently show increased activity during acute nociceptive stimuli (~BA 7); areas of the inferior, medial, and superior frontal gyri (~BA
and are modulated by activity during pharmacologically induced 8, 9, 10, 47); the hippocampal formation, and the lateral temporal
analgesia. The relationship of these centres to pain is complex and cortex (~BA 21) (46). This network is more active while the brain is
it may be premature to state that their activation is necessary and in a non-task state and is interrupted (i.e., connectivity is decreased)
sufficient for pain perception. This is especially true since fMRI and during externally focused task conditions, in disease states such
PET studies have largely only shown correlation with pain sensa- as Alzheimer’s, and with provocation of acute pain. Some states of
tions and have not definitively demonstrated causation. chronic pain have been associated with greater connectivity of the
Sensory-discriminatory (lateral) centres of pain perception ap- DMN to more traditional pain network loci, such as the insula in
pear responsible for characterizing the location and intensity of the neuropathic pain (47) and fibromyalgia (48). This, too, may repre-
stimulus. The SI on the postcentral gyrus of the parietal lobe is the sent painful sensations interfering with cognitive processes.
main receptive locus for the sense of touch represented in the dis-
tribution of the sensory homunculus. The SII is also responsible for Acute vs. Chronic Pain
the perception of peripheral sensory stimuli, located in the parietal
operculum of the lateral sulcus. fMRI studies show that SII activity Aetiologies of Acute and Chronic Pain
consistently correlates with the perceived intensity of a stimulus, By its technical definition, acute pain lasts less than three months
rather than its objective intensity, and it is a point of interest in and chronic pain lasts longer. In a broader sense, the two differ
studying central pain syndromes that involve hypersensitivity (see qualitatively and mechanistically, transitioning from one to
Mechanisms of Pain Sensitization). The thalamus relays informa- the other gradually and not necessarily in accordance with the
tion from peripheral structures to cortical areas and thus shows ac- three-month  limit.
tivity with sensory input. The posterior insula connects to the SII Acute nociceptive pain appears to have a purpose in aiding an
and collects input from the ventral posterior and ventromedial nu- organism’s survival by alerting it to danger; therefore, in biological
cleus of the thalamus, where it receives information about pain and terms, it is considered an adaptive function. Phylogenetically, pain
other homeostatic signals. The detection of exaggerated activity at tracts in primates approximate other tracts associated with homeo-
these centres in some chronic pain syndromes, such as to pin-prick static behaviours that aid in survival, such as temperature, itch,
hyperalgesia in chronic regional pain syndrome (CRPS), implicates muscle ache, and other interoceptive (relating to internal stimuli)
these regions as targets for treatment and demonstrates that sensi- sensations. These tracts synapse in Rexed’s lamina I of the dorsal
tivity to identical stimuli varies greatly between individuals. horn of the spinal cord, and project to autonomic, limbic, and other
The ‘medial’ primary structures of the pain network, the anterior homeostatic loci in the CNS. It has been thus proposed that pain is
insula, ACC, and PFC, are associated with affective and cognitive itself a ‘homeostatic emotion’ that alerts us to danger and prompts
processing of pain. The anterior insula projects to the amygdala and us to move away from the source of noxious stimulus (40).
is thus closely tied with limbic activity such as anxiety. The ACC While nociceptive pain tends to be of an acute nature, neuro-
is associated with higher cognitive functions regarding reward an- pathic and central pain tend to be of more chronic duration. As
ticipation, decision-making, and emotion, likely assigning antici- described earlier, neuropathic pain is caused by peripheral nerve
patory and reactive components to pain. The PFC is involved in damage by a lesion or other disruption of the nervous system. Pain
complex cognitive behaviour and decision-making, implicating it resulting from an abnormality in the brain or spinal cord is de-
in aspects of the pain experience involving judgment and executive scribed as central neuropathic, functional, or simply, central pain;
function. Increased activation in these areas has again been noted it is distinguished from neuropathic pain because it results in ab-
to pin-prick hyperalgesia in CRPS (44), suggesting cognitive and normal processing of sensation, rather than abnormal input. These
emotional components of the condition. types of pain are further characterized in Table 9.1. These types of
The basal ganglia, motor cortex, supplemental motor area (SMA), pain are further characterized in Table 9.1. As acute nociceptive
cerebellum, amygdala, and hippocampus are among areas con- pain is sustained, it may take on features of neuropathic and central
sidered to be secondary structures of the pain network, meaning that pain, reflecting the nervous system’s remodelling in response to the
they are activated by painful stimuli, albeit less reliably. It is thought stimulus. While the transition from acute to chronic pain does not
that their activation may reflect epiphenomena, such as pain-evoked follow a consistent timeline, some evidence exists that it occurs in
movement suppression, that vary according to the instance of pain. discrete pathophysiological and histological steps (36).
The PAG, RVM, parabrachial nucleus (PB), dorsal reticular nucleus, Neuropathic, central, and other forms of chronic pain do not ap-
and nucleus cuneiformis (NCF) have been implicated in initiation pear to have a function in survival, and perhaps may even hinder
and maintenance of central sensitization states and hyperalgesia in it; thus, they are considered maladaptive. Current models describe
humans as they play a central role in pain modulation (45). In add- chronic pain as a disease entity in itself, with its own comorbidities
ition, regions of the orbitofrontal cortex such as dorsolateral pre- that are more prevalent such as depression, impaired sleep, and
frontal cortex (DLPFC) and medial prefrontal cortex are implicated decreased function in daily activity (10). The American Pain
in higher cognitive processing of pain and aspects of its top-down Foundation (APF) estimates the prevalence of these conditions in
modulation, such as distraction. Such findings illustrate that the ex- chronic pain patients on chronic opioids: impaired enjoyment of
perience of pain has complex and varied dynamics. life (59%), depression (77%), trouble concentrating (70%), impact
It is worth mentioning another set of brain loci, collectively known on energy level (74%), and impaired sleep (86%) (49).
as the Default Mode Network (DMN), that has been helpful in char- Acute pain that persists may lead to neuroplastic changes
acterizing certain elusive types of pain. This network typically con- throughout the neuron and its connections as it evolves into chronic
sists of the inferior parietal lobule (IPL) (Brodmann Area [~BA] 40, pain. While this transition is poorly understood, mechanisms have
17
Table 9.1 Properties of pain by category.
Nociceptive Peripheral Neuropathic Central

Aetiology Inflammation or damage to tissue Damage or entrapment of peripheral Disturbance in pain processing in CNS
nerves
Symptoms Evoked pain Spontaneous and/or evoked pain Spontaneous and/or evoked pain
Sensitization Peripheral and central Peripheral* and central Central
Common Treatments NSAIDs, opioids Neuroactive (centrally acting) Neuroactive compounds
compounds
Examples Osteoarthritis, surgical incision Peripheral diabetic neuropathy, Fibromyalgia, post-stroke pain
neuropathic pain from spinal stenosis
Nociceptive, peripheral neuropathic, and central pain have different characteristics; however, any single instance of pain may include a mix of the three. For example, although osteoarthritis
causes mostly nociceptive pain, it may acquire a central component over time.
* Only demonstrated in post-herpetic neuralgia
been identified that may sensitize the nervous system to further stimulus, once developed, it may continue after the stimulus is re-
pain, even in the absence of the original stimulus. Such remodelling moved. It is characterized by increased sensitivity to stimuli both
mainly includes the processes of peripheral and central sensitiza- locally and sites remote from the injury. Cytoarchitectural changes
tion, with contribution from other forms of neural change such as occur in the dorsal horn of the spinal cord that cause amplified syn-
ectopic excitability, phenotypic switches, structural reorganization, aptic transmission from the central terminal of the nociceptor to
and decreased inhibition (4). dorsal horn neurons. These changes occur in two phases. Initially
there is an acute activity-dependent phase that depends on nocicep-
Mechanisms of Pain Sensitization tive input, followed by a transcription-dependent phase in which the
Peripheral sensitization refers to increased responsiveness and re- initial stimulus is no longer present and the process is driven by
duced threshold of nociceptive neurons in the periphery to the altered transcription within the central neuron.
stimulation of their receptive fields (2). This is triggered by noxious In the acute phase, nociceptive input triggers release of glu-
stimuli and the release of sensitizing agents around the nociceptor; tamate and substance P from the central terminal of the nociceptor
an example of this is demonstrated by a light touch on a sunburned into the dorsal horn synapse. Via various postsynaptic receptors
area, resulting in greater pain (allodynia: the non-noxious touch (NMDA glutamate, NK1, Tyrosine kinase B), intracellular kin-
stimulus is now perceived as painful). When tissue damage oc- ases in the dorsal horn neuron are activated and phosphorylate
curs, some factors released from damaged cells act as nociceptor various receptors, modifying their sensitivity and availability. In
activators, which evoke nociceptor potentials, while others act particular, NMDA glutamate receptors are phosphorylated, which
as nociceptor sensitizers, which increase a neuron’s sensitivity to increases their responsiveness and recruits them from intracellular
mechanical and thermal stimuli. Prostaglandin E2 (PGE2), brady- stores onto the cell membrane. This process happens soon after the
kinin (BK), and nerve growth factor (NGF) behave as nociceptor nociceptive stimulus and results in pain elicited by normally sub-
sensitizers and are thus responsible for peripheral sensitization. threshold stimuli, including those beyond the injured area.
PGE2 is the end-product of arachidonic acid conversion by the en- The kinase cascade also induces changes in gene expression
zyme cyclooxygenase-2 (COX-2) and binds to Prostaglandin E re- and phenotype of the neuron, leading to the late, transcription-
ceptors. BK is a peptide derived from cleaved kininogens that both dependent phase of central sensitization. This phase is charac-
activates and sensitizes nociceptors. Its constitutively expressed terized by diffuse pain hypersensitivity and a ‘sickness syndrome’
neuronal B2 receptor is responsible for this action, but B1 recep- throughout the body. Changes in sensitivity can manifest locally
tors expressed in damaged tissues may contribute to hyperalgesia as well as systemically. Rodent models of hypersensitivity demon-
as well (50). NGF binds to tyrosine kinase A receptors and also acts strate local induction of dynorphin in the dorsal horn, associated
as a nociceptor sensitizer. with local thermal and mechanical sensitivity (51, 52). Localized
Once these inflammatory mediators bind to their membrane peripheral tissue injury can induce COX-2 diffusely throughout the
receptors on peripheral nerve terminals, they activate intra- CNS via a circulating humoral factor that increases interleukin-1
cellular kinases protein kinase A (PKA) and protein kinase C beta levels in the cerebrospinal fluid (53). This, in turn, increases
(PKC). These then phosphorylate transducer channels, including PGE-2 throughout the spinal cord, causing late-onset, diffuse cen-
the nociception- specific Nav1.8 and Nav 1.9 channels (see tral sensitization. Spinal glial cells also contribute to sensitization
Conduction), lowering their activation threshold and increasing by secreting inflammatory cytokines in response to peripheral in-
excitability (4). Thus, chemical changes at the site of tissue damage flammation, chronic nerve trauma, or central infection (54).
can change the behaviour of a nociceptor from its peripheral to its Whereas peripheral and central sensitization account for much
central terminus. of the transition to chronic pain, other changes along the neural
Central sensitization refers to the increased responsiveness of pathway contribute as well. Damaged peripheral nerves alter ex-
nociceptive neurons in the CNS to their normal or sub-threshold pression of sodium channels and demonstrate ‘leaky’ sodium cur-
afferent input (2). Although it begins with the initial noxious rents that may cause ectopic discharges (55). The activity of ion
18
channels, NGFs, and inflammatory mediators on nociceptors can receptor binding, which may play a role in the pain that these pa-
alter their gene transcription and, ultimately their phenotype, al- tients experience (34).
tering their levels of receptors, ion channels, transmitters, and other
functional proteins. Basic Approach to the Chronic Pain Patient
Damage to peripheral nerves may also lead to aberrant re-
growth of nerve terminals in the spinal cord, termed structural Context
reorganization. It has been demonstrated in rats that damaged Chronic pain is a widely prevalent illness with individual and
low-threshold A-beta sensory fibres may grow central terminals public health implications. Affecting roughly a fifth of the US
in superficial laminae of the dorsal horn that are responsible population, it is the foremost reason for being on disability and
for nociception (56), although this was not reproduced in other results in missed work days and medical expenses (64). The issue
studies (57). It is known, however, that pain in response to light has thus been examined by the National Institute of Health, which
touch in a human model of neuropathic pain is due in part to aber- identified the need for more robust data, greater education, more
rant central response to low-threshold sensory fibres (58). Chronic individualized care, and greater availability of effective treatments
peripheral nerve injury that causes pain may lead to loss of local (1, 64) (summarized in Table 9.2).
GABA-and glycinergic inhibitory interneurons in the spinal cord, The contemporary biopsychosocial model of illness emphasizes that
causing increased transmission to the brain. In support of this, ad- chronic pain has societal, psychological, and functional dimensions.
ministration of GABAA and GABAB-mimetics is shown to reduce Such patients are at risk of comorbid conditions such as anxiety and
allodynia in neuropathic pain in rats (59). Thus, remodelling of decreased cardiopulmonary reserve from decreased mobility, which
cellular architecture, altered gene transcription, and cytotoxicity may impact anaesthetic care. Pre-operative anxiety correlates with
may mediate chronic pain. postoperative pain experience and is important to address where
possible. Maladaptive psychological behaviours common in this
Blood Flow and Structural Changes in Chronic Pain population are indicators of poor long-term functional outcome (65).
While our information about pain processes in the periphery and In neurosurgical patients, undertreating postoperative pain
spinal cord are quite granular, our understanding of the patho- can result in distressing patient experience and unstable haemo-
physiological process at the level of individual cells and molecules dynamics, but overtreating it can compromise the postoperative
in the brain lags behind. These studies typically involve human neurologic exam, cause respiratory depression with hypercarbia
brain neuroimaging of chemical, structural, and functional changes and increase in intracranial pressure, and inhibit brain and spine
during chronic pain. Studies involving experimentally induced perfusion from decreased adrenergic tone (65).
pain have noted increased blood flow, associated with increased re- Chronic postoperative headache after craniotomy is common,
sponsiveness, to the pain network centres and decreased flow to with an incidence as high as 65% (66). Infratentorial surgery causes
centres associated with antinociception. Studies of chronic pain more reported pain than supratentorial and a cranioplasty after
also implicate brain structures outside the typical pain network— posterior fossa surgery increases the risk of postoperative headache
such as the frontal pole, superior temporal gyrus, and the nucleus compared to without cranioplasty. Acute postoperative pain correl-
accumbens—that are involved in emotional and cognitive assess- ates with the risk of developing chronic postoperative pain and it is
ment (60). Importantly, brain responses to experimental pain believed that effective acute pain care can lower the risk (65).
stimuli share weak yet statistically significant activity seen during
some states of chronic pain. Neuroanaesthetic Care for the Chronic Pain Patient
Functional MRI studies examining aberrant functional connect- Chronic pain patients presenting for neurosurgery should be evalu-
ivity between the DMN and other pain network regions are associated with respect to its location, quality, concomitant neurologic
ated with some chronic pain states. Compared to normal controls, deficits, and provocative factors, such as sensitivity to light touch.
patients with chronic lower back pain showed decreased interrup- This information suggests the presence of central sensitization, pro-
tion of DMN centres when performing a task (61). vides insight into the ability to comply with a sensorimotor exam,
Imaging studies in chronic central pain patients note regional and also raises considerations for positioning. The clinician should
decreases in brain grey matter compared to matched controls. know the patient’s usual range of pain scores and set a realistic ex-
Irrespective of the aetiology, location, and course of the pain con- pectation for pain control. A list of pain medications and recent
dition, the most common loci affected are the cingulate cortex, administration history helps gauge the dosing of postoperative an-
orbitofrontal cortex, insula, and dorsal pons, despite some differ- algesics and identify barriers to elucidating mental status. A history
ences between pain syndromes (62). Of note, such a cross-sectional of pain procedures can identify recent steroid doses received and
study cannot differentiate effect from predisposition, nor imply the presence of any implanted pain devices in the spine, such as
causality. It has been shown, however, that grey matter density is intrathecal pumps and spinal cord stimulators.
decreased in chronic pain subjects in areas not associated with Multimodal analgesia is advocated by the American Society of
pain, namely the prefrontal cortex and right thalamus, and that the Anesthesiologists (ASA) acute pain task force and may benefit
decrease was proportional to duration of pain (63). chronic pain patients. Analgesic medicines and techniques used
Chemical neuroimaging studies using proton magnetic res- during general anaesthesia apply to neuroanaesthesia as well, with
onance imaging have also shown that central pain patients diag- some particular considerations. NSAIDs are often used with cau-
nosed with fibromyalgia display increased levels of glutamate and tion due to concerns for bleeding and impaired bone fusion, but
decreased levels of GABA within the insula, which may lead to these effects are mostly demonstrated in animal models and have
hypersensitivity of this region. Also, PET studies have shown that not been substantiated in peri-operative studies. There is concern
central pain patients also display altered mu opioid and dopamine that ketamine would cause an undesired increase in intracranial
19
Table 9.2 Proposed loci of action of pharmacological and non-pharmacological pain interventions.
Transduction Conduction Transmission Perception

Medications
Opioids X? X X
NSAIDs X X
Gabapentinoids X
Tricyclic antidepressants X? X X
SNRIs X X?
Tramadol X? X X
Local anaesthetics X X X
Clonidine X? X
Ketamine X X
Capsaicin X (topical) X (systemic)
Steroids X X
Other
Transcutaneous electrical X
stimulation
Spinal cord stimulation X X?
Peripheral nerve stimulation X X*
Intrathecal pumps X
Acupuncture X X X
Placebo X X
Exercise X X X
Cognitive behavioural therapy X X
Meditation X X
Mounting evidence explains the analgesic effect of various interventions. Opioid receptors may be expressed on peripheral nerve endings in states of inflammation, which is of uncertain
significance. Many drugs interrupt the transfer of neural signal at the synapse at the dorsal horn of the spinal cord. Interventions that affect perception of pain likely reflect changes in brain
as well as spinal cord (descending modulatory) processing.
* Peripheral stimulation increases inhibitory transmission to spinal cord
pressure in at-risk patients, although data in traumatic brain in- with chronic pain, analgesic strategies should address the blockade
jury studies has not demonstrated an increase compared to opioids. of afferent nociceptive signals and possibly the disruption of central
Lidocaine infusions show analgesic efficacy but decrease seizure sensitization with NMDA antagonists.
threshold and should be used with caution with cortical and espe-
cially temporal lobe surgery. Corticosteroids can be used for anal-
gesic effect, but may elevate blood glucose and their use has been Summary
associated with unfavourable long-term outcomes in head injury Pain is both a sensory and emotional experience that may or may
(65, 67). not involve the process of nociception, the neural response to a
Infiltration and neuraxial techniques may be used as well. Some noxious stimulus. The nociceptive pathway involves relay of infor-
evidence suggests that scalp block decreases the incidence of chronic mation from the injured tissue, through the peripheral nerve and
post-craniotomy pain. Spinal and epidural techniques have been spinal cord, to the brain; plastic changes at any step may result in
used for minor lumbar surgery with improved haemodynamics pathological pain. Chronic pain is viewed as a biopsychosocial
and pain control. Caution is advised to ensure that neuraxial tech- illness; peri-operatively, it may impact patients’ comfort, anxiety,
niques are not performed at spinal levels that interfere with im- and neurologic exam. The neuroanaesthetist caring for such patients
planted pain devices, although instrumentation at other levels is is encouraged to use a multimodal analgesic plan that minimizes
not contraindicated (65). interference with cognition and cardiorespiratory stability. The ad-
Experimental evidence suggests that maintenance of pain hyper- vent of advanced diagnostic and treatment techniques may allow
sensitivity requires ongoing afferent input and central processing; for a more precise, individualized approach to pain, with hope for
the disruption of either causes relief (68). Especially for patients greater efficacy in the future.
120
20. Jones NG, Slater R, Cadiou H, McNaughton P, McMahon SB.

Multiple-Choice Questions Acid-induced pain and its modulation in humans. The Journal of
Q Interactive multiple-choice questions to test your knowledge Neuroscience. 2004;24:10974–9.
on this chapter can be found in the online appendix at www. 21. Ugawa S, Ueda T, Ishida Y, Nishigaki M, Shibata Y, Shimada S.
oxfordmedicine.com/otneuroanesthesiology. Amiloride-blockable acid-sensing ion channels are leading acid sensors
expressed in human nociceptors. Journal of Clinical Investigation.
2002;110:1185–90.
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12
123
SECTION 2
Clinical Neuroanaesthesia
10 Neurologic Emergencies 125

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
17 Pituitary and Neuroendocrine Surgery 213
Douglas A. Colquhoun and Edward C. Nemergut
18 Hydrocephalus and Associated Surgery 225
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
Sulpicio G. Soriano and Craig D. McClain
23 Basics of Neurocritical Care 273
124
125
CHAPTER 10
Neurologic Emergencies
Introduction and bony boundaries, leading to compression or displacement

of the brainstem, cranial nerves, and cerebral vasculature. Early
Neuroanaesthetists will frequently care for patients with known identification of impending herniation and rapid intervention to
intracranial pathologies that can worsen in the peri-operative medically or surgically decompress the cranial vault are critical, as
period and cause neurologic emergencies. Neurologic emergen- brainstem compression, if not rapidly corrected, can be fatal.
cies can also develop peri-operatively in patients undergoing
non-neurosurgical procedures, emphasizing that generalist an- Common Causes of Intracranial Hypertension
aesthetists should also be prepared to manage these emergencies. Herniation is commonly the result of an expanding mass lesion
Finally, anaesthetists may be asked to assist with airway manage- such as a tumour or haemorrhage but may also occur with exten-
ment for patients experiencing neurologic emergencies in the in- sive cerebral oedema. Traumatic subdural or epidural haematoma,
tensive care unit or the emergency department. While nuances of intracranial haemorrhage, or malignant cytotoxic cerebral oedema
treatment may differ between these settings, the main principles following a hemispheric ischaemic stroke may cause elevated ICP
remain the same: time is brain and ABCs. The longer they remain progressing to herniation (3). Intracranial mass effect from tumour,
untreated, the more neurologic emergencies threaten brain and life, abscess, or surrounding vasogenic oedema can also cause elevated
so treatment must be initiated urgently; airway, breathing, and cir- ICP. Patients with hepatic encephalopathy may have elevated ICP
culation, the mainstays of any emergency treatment, are critical, as a result of intracellular osmotic oedema secondary to the me-
as hypoxia and hypotension will further damage an injured brain. tabolism of ammonia (4). Herniation in a patient who just had a
Diagnosis and appropriate treatment must be initiated as early as craniotomy is most commonly caused by mass effect from haem-
possible, if feasible in parallel to the initial stabilization of the pa- orrhage, usually a rapidly expanding epidural or intraparenchymal
tient. This chapter discusses four common neurologic emergencies haematoma. These patients need to return to the operating room
that the reader may encounter in their daily practice, herniation, for surgical decompression, evacuation of the haematoma, and
coma, stroke, and status epilepticus. It attempts to provide a gen- securing of the bleeding source. Herniation from cytotoxic (is-
eral overview of pathophysiology, diagnosis, and treatment for each chaemia) or vasogenic (tumour or abscess) oedema is more com-
emergency, with specific primers to differing approaches in each of monly seen in patients in the ICU and may develop more slowly.
the possible settings (emergency room, post-anaesthesia care unit Anaesthetists will often be called to assist with airway management
(PACU), intensive care unit (ICU)) when relevant. This chapter fo- for these patients. Severe TBI, epidural and subdural haematoma,
cuses on neurologic emergencies in the peri-operative setting and and intraparenchymal haemorrhage are the most likely causes of
is not meant to be a comprehensive discussion of all possible dif- herniation in the emergency room. Obstructive hydrocephalus
ferential diagnoses. The Neurocritical Care Society has published can cause herniation and can rapidly develop in patients with
Emergency Neurologic Life Support (ENLS) (1) recommendations intraventricular extension of subarachnoid or intraparenchymal
that provide a more in-depth discussion of neurologic emergencies haemorrhage, obstruction of the third ventricle by tumour, or com-
in the pre-hospital and emergency room setting. pression of the fourth ventricle from a cerebellar mass lesion (tu-
mour, haemorrhage, ischaemia with oedema).
Herniation Syndromes Symptoms of Herniation
Pathophysiology of Intracranial Hypertension Increased ICP in the otherwise awake patient may initially present
As the volume within the intracranial vault is fixed, the sum of as headache, nausea/vomiting, and somnolence. The progression of
the volumes of brain, blood, and CSF contained within the skull intracranial hypertension to herniation may be gradual or abrupt,
is constant (Monro-Kellie hypothesis). Small changes in volume depending on the underlying aetiology (more gradual when intra-
(<100 ml) can be accommodated by shifting blood and CSF into cranial hypertension is caused by cerebral oedema, usually abrupt
the spinal canal. If volume increases further, e.g., because of active in cases of active haemorrhage). Common sites of brain herniation
haemorrhage, compensatory mechanisms are exhausted and intra- are downward or upward across the cerebellar tentorium separ-
cranial pressure increases (Figure 10.1). Intracranial hypertension ating the anterior/middle and posterior fossae (transtentorial her-
is defined as an ICP >20 mmHg for >5 minutes (2). Further increase niation), midline across the falx cerebri (subfalcine herniation),
in volume can rapidly cause herniation of brain tissue across dural and downward across the foramen magnum (cerebello-tonsillar
126
126 Section 2 clinical neuroanaesthesia
Critical volume central stimulation. If no response is elicited by central stimu-

lation, apply peripheral stimulation next to determine whether
Intracranial pressure the patient withdraws all extremities symmetrically from the
stimulus. A new anisocoria or a dilated and fixed pupil in a
comatose patient must raise suspicion for uncal herniation, es-
pecially if the patient also exhibits new contralateral weakness
(absent or reduced withdrawal from painful stimulation). While
the diagnosis should be confirmed by non-contrast head CT,
which also allows to identify the underlying pathology, emer-
gent treatment aimed at reducing intracranial volume (and thus
Intracranial volume
ICP) must be begun without delay. Rapid reduction of elevated
ICP, and maintenance of cerebral perfusion pressure (CPP) are
Figure 10.1 Intracranial pressure increases rapidly once a critical intracranial the goals of early management of herniation syndromes. The
volume is reached and compensatory mechanisms are exhausted. pillars of treatment are summarized in Box 10.1. As with all
emergencies, it is crucial to ask for help and extra hands early,
and to maintain close communication with the patient’s pri-
herniation) (Figure 10.2). Each presents with a unique clinical syn-
mary treatment team.
drome (Table 10.1). For clinical practice, however, it is usually suffi-
cient to appreciate that rapid deterioration of level of consciousness Therapies to Reduce Intracranial Pressure and Reverse
(or failure to awaken after anaesthesia) in combination with new Herniation
cranial nerve deficit (most commonly CN III) and/or hemipar-
esis equals herniation until proven otherwise. Downward hernia- Medical and surgical interventions aim to reduce the volume
tion with compression of the brainstem triggers the Cushing triad of the intracranial components to reduce ICP. Decompressive
of hypertension, bradycardia, and irregular respirations/apnoea, hemicraniectomy or suboccipital decompression can addition-
very late signs that predict imminent death if left untreated. While ally expand the available space. ABC (airway, breathing, circula-
the most imminent threat of herniation is death from midbrain/ tion) comes first when treating patients at risk for, or with signs
brainstem compression, transtentorial and subfalcine herniation of herniation—the injured brain is even more susceptible to hyp-
also cause compression of the posterior (at the tentorium) or an- oxia/ischaemia than the healthy brain. Elevating the patient’s head
terior (at the falx) cerebral artery, which can lead to ischaemia and and maintaining it in neutral position improves jugular venous
infarction. drainage and helps reduce intracranial blood volume. Caution
should be taken to avoid coughing, which raises ICP by increasing
Clinical Management of Herniation intrathoracic pressure; laryngoscopy should only be attempted after
a sufficient plane of anaesthesia is reached.
Herniation or ‘brain code’ is a life-t hreatening emergency that
should be approached with the same urgency as a cardiac ar- Hyperventilation
rest. Symptomatic treatment must be initiated immediately,
often in parallel to diagnosis of the underlying pathology (most Hyperventilation induces hypocarbia, which alkalizes the cere-
commonly by non-contrast head CT). When assessing a coma- brospinal fluid (CSF). A decreased hydrogen ion concentration in
tose patient, check pupil size and response to light as well as the CSF causes cerebral vasoconstriction, which reduces cerebral
response to painful stimulation. A jaw thrust applied to open blood flow and (secondarily) cerebral blood volume. The initial
the patient’s airway is quite stimulating and can double as response to hyperventilation is rapid (within minutes), but short
lived. Cerebral vessels quickly accommodate to a new partial pres-
sure of arterial carbon dioxide (PaCO2) set point and return to
their baseline state over six to ten hours. Brief hyperventilation can
often sufficiently reduce intracranial pressure to provide a bridge to
more definitive medical/surgical interventions and should be ini-
tiated without delay. Patients suffering from herniation need to be
mass intubated for airway protection, but hyperventilation can already
be initiated by bag/mask ventilation while intubation is prepared.
Hyperventilation should be limited in duration (<2 h) and severity
(mild hyperventilation, PaCO2 30 mmHg) to not cause further
U
harm by restricting cerebral blood flow to injured parts of the brain.
mass Patients with parenchymal brain injury may have decreased cere-
bral blood flow already, and an impaired capacity for blood vessels
T T to respond to changes in carbon dioxide (CO2). Hyperventilation
will only be effective in areas of brain where CO2 reactivity is pre-
Figure 10.2 Different routes of herniation. served. Patients with haematomas or non-traumatic mass lesions
An expanding supratentorial mass shifts the brain across the midline and precipitating herniation are most likely to benefit from brief hyper-
causes herniation of the uncus (U) through the tentorium, stretching CNIII and ventilation. In cases of refractory ICP elevation, moderate hyper-
compressing the midbrain. A cerebellar mass causes herniation of the cerebellar ventilation (PaCO2 25 mmHg) can be employed as a third-tier
tonsils (T) through the foramen magnum, compressing the brainstem. intervention.
127
Chapter 10 neurologic emergencies 127
Table 10.1 Common Herniation Syndromes
Precipitating Event Structures Compressed Clinical Signs

Lateral (Uncal) or Supratentorial mass lesions ◆ CN III and Edinger-Westphal ◆ Ipsilateral dilated pupil unresponsive to light
Central Transtentorial force the medial part of the nucleus ◆ Contralateral hemiparesis, which may progress to bilateral
temporal lobe (uncus) or the ◆ Corticospinal tract paresis (from compression of contralateral crus cerebri
diencephalon (central) across against tentorium)
◆ Midbrain
the tentorium at the level of the
◆ Pons ◆ Coma
midbrain.
◆ Posterior cerebral arteries ◆ Decerebrate posturing
◆ Hyperventilation
◆ PCA infarction
Upward Transtentorial Posterior fossa mass causes ◆ Midbrain ◆ Small and minimally reactive pupils
cerebellum to herniate upwards ◆ Pons ◆ Conjugate downward gaze
through tentorium; can be
◆ Cerebellum ◆ Coma
iatrogenic following placement
of external ventricular drain. ◆ Superior cerebellar arteries ◆ Decerebrate posturing
◆ Abnormal respiratory pattern
Subfalcine Mass lesion of cerebral cortex ◆ Cingulate gyrus ◆ Contralateral lower extremity hemiparesis
causes lateral midline shift under ◆ Anterior cerebral arteries ◆ May have few symptoms; often diagnosed only by
falx cerebri. imaging
Cerebello-tonsillar Global, severe intracranial ◆ Medulla ◆ Hypertension, bradycardia, respiratory arrest (Cushing’s
hypertension or localized ◆ Vertebral arteries triad)
cerebellar mass effect force Arrhythmias, cardiovascular collapse
◆
◆ High spinal cord
cerebellar tonsils downward
through foramen magnum.
Osmotherapy only effective in reducing cerebral oedema associated with brain tu-
Osmotherapy creates an osmotic gradient across the blood-brain- mours and have no place in treatment of elevated ICP or herniation.
barrier (BBB) to remove excess water from the brain parenchyma,
Mannitol
thus reducing cerebral oedema and brain volume and lowering
ICP. Osmotherapy requires an intact or partially intact BBB and Mannitol is a simple sugar alcohol that acts as an osmotic diur-
may be most effective in the setting of vasogenic, rather than cyto- etic when administered intravenously. Immediately after adminis-
toxic, cerebral oedema. The osmotic agents most commonly used tration of mannitol, serum osmolality increases, driving water to
are mannitol (0.5–1 mg/kg bolus, most commonly a 20% solution) move from the interstitial to intravascular compartment. Blood
and hypertonic saline (3%–23.4% solutions, most commonly 30 volume is transiently increased and blood haematocrit and vis-
ml bolus of 23.4% solution or 250 ml of 3% solution). Steroids are cosity decreased. These effects result in a rapid decrease in cerebral
volume and ICP, and an increase in cerebral blood flow and oxygen
delivery.
Mannitol is not metabolized, does not cross the BBB, and is fil-
tered in the glomerulus but not reabsorbed. The result is a delayed
Box 10.1 Emergency Treatment of Brain Herniation
osmotic dehydration of the brain by intravascular volume con-
traction. This has a secondarily beneficial effect on ICP that may
◆ Suspect herniation in comatose patient with dilated, unre-
last several hours. Repeat dosing is associated with decreased ef-
sponsive (‘blown’) pupil and contralateral hemiparesis.
fectiveness and the development of renal failure at >320mOsm/kg.
Elevate
◆ head of bed, maintain head in neutral position to opti- Mannitol should be given as a rapid bolus, as there is no benefit of
mize venous outflow. continuous infusion.
◆ Hyperventilate (bag-mask ventilation initially; intubate for High initial doses of mannitol (1.0–1.5 g/kg body weight) may
airway protection before CT). be beneficial in patients with impending herniation, compared to
more traditional doses of 0.6–0.7 g/kg, as they are associated with
◆ Osmotherapy: (0.5–)1 g/kg mannitol or 250 (–500) ml 3% sa-
reduced cerebral oedema and improved outcomes (5). The lower
line (or equivalent volume of higher concentration).
dose range is appropriate for the management of intracranial
◆ Propofol or other anaesthetic to reduce CMRO2 after hypertension without herniation. Mannitol causes significant car-
intubation. diovascular effects that may limit its use. Patients with underlying
Rapid
◆ diagnosis of underlying pathology (non-
contrast congestive heart failure may develop pulmonary oedema after
head CT). mannitol administration, while hypovolemic patients may not tol-
erate the diuresis associated with it. Mannitol is not effective (and
◆ Urgent surgical intervention, if applicable. contraindicated) in anuric patients.
128
Hypertonic Saline treated promptly, prognosis is generally poor for those who have
Varying concentrations of sodium chloride from 3% to 23.4% are intraparenchymal pathologies severe enough to cause herniation.
also effective in the treatment of intracranial hypertension. Rapid
Intracranial Pressure Monitoring
administration of 23.4% sodium chloride can reverse transtentorial
herniation and reduce ICP (6). Hypertonic saline, unlike mannitol, Intracranial pressure monitoring has no relevance for emergency
does not appear to cause kidney injury, but may cause cardiac ar- management. Herniation is a clinical diagnosis that can occur at
rhythmias when given rapidly. Treatment goal with hypertonic sa- various levels of ICP elevation and cannot be predicted by ICP
line is to raise serum sodium by 5 mEq/L in the first hour. Serum values. It is unclear what numbers should be targeted in the acute
sodium concentrations of up to 160 mEq/L are considered safe, and management of patients that already have ICP monitoring in place.
no cases of central pontine myelinolysis have been described after For the chronic management of patients with traumatic brain in-
the use of hypertonic saline for ICP management. jury (TBI), guidelines from The Brain Trauma Foundation rec-
High concentrations of hypertonic saline (>3%) have high osmo- ommend to maintain ICP below 15–20 mmHg and CPP between
lality and are preferentially administered through a central vein. In 50–60 mmHg. It appears reasonable to use similar parameters for
an emergency, however, hypertonic saline should not be withheld acute management.
because central access is unavailable.
No large randomized studies exist that directly compare the two Coma
agents, but recent meta-analyses suggest that hypertonic saline may Coma is an absence of wakefulness and awareness of self.
be more effective in lowering elevated ICP than mannitol (7, 8). The Patients who are comatose have no eye opening, are nonverbal,
difference is likely not large enough to choose one over the other in and do not arouse to stimuli. Many different pathologies can
all circumstances. As institutional preferences may dictate which lead to the presenting symptom of reduced level of conscious-
agent is more readily available, it is appropriate to use either one. ness and coma. Not all of them are relevant in the peri-operative
The osmotic agent of choice should be stocked in the operating period, as many systemic disorders, such as bacterial meningitis
rooms and the emergency department to not delay treatment. or encephalitis, would most likely have been detected during
the pre-operative evaluation. This overview focuses on more
Decreasing Cerebral Metabolic Rate
common causes of coma that can develop during and after sur-
In the healthy brain, cerebral metabolic oxygen consumption gery, which are summarized in Box 10.2. The therapeutic goals
(CMRO2) and cerebral blood flow (CBF) are coupled. Anaesthetic of patients with coma include removal of the offending cause,
agents can be used to reduce CMRO2, which is thought to lower and supportive care.
ICP by reducing intracranial blood volume. Reduced CMRO2 may Wakefulness or alertness depends upon the ascending reticular
also increase the brain’s resilience towards ischaemia, although this activating system (ARAS), a complex neuronal network extending
is likely less relevant in a comatose patient whose neuronal activity from the brainstem to thalamic intralaminar nuclei and the basal
is already suppressed. Propofol reduces CMRO2 and CBF and is an forebrain. Broadly, coma can be the result of structural disruption
appropriate drug to use for intubation and sedation during the trip of the ARAS or cortical structures, or of a metabolic derangement
to the CT scanner. Avoid hypotension by cautious dosing and early resulting in decreased cortical function.
use of vasopressors, if needed, to not further compromise cerebral
perfusion pressure (CPP). CPP = MAP-ICP, thus CPP is already Differential Diagnoses of Postoperative Coma
reduces in the setting of elevated ICP. ICP elevation that comprom- The single most common cause of coma or delayed awakening
ises CPP usually causes sympathetic discharge that raises mean ar- in the peri-operative phase is residual effect of anaesthetic drugs.
terial blood pressure (MAP). This hypertension is an appropriate Supportive therapy and time is frequently all that is required
response and should not be aggressively treated. for this to resolve. In doubt, application of benzodiazepine
(flumazenil, 200 µg IV) or opiate (naloxone, 20-40 µg IV) antag-
Surgical Intervention onists can help establish the diagnosis. Residual neuromuscular
In the surgical patient after craniotomy, new ICP elevation and her-
niation is most likely caused by haemorrhage (epidural/subdural
or intraparenchymal). These patients need to return to the OR
emergently, once CT confirms the diagnosis, for decompression Box 10.2 Possible Causes of Coma in the Peri-operative Period
and haematoma evacuation. Other patients with significant focal
mass effect that causes herniation (e.g., from TBI, spontaneous ◆ Residual anaesthetic effect.
intraparenchymal haemorrhage, or malignant cerebral oedema ◆ Hypoglycaemia.
from hemispheric infarction) may benefit from decompressive
◆ Basilar artery thrombosis.
hemicraniectomy as a life-saving intervention. Patients with mass
lesions in the posterior fossa benefit from suboccipital decom- ◆ Subclinical status epilepticus or postictal state.
pression. Placement of an external ventricular drain is appropriate ◆ Hypothermia.
when obstructive hydrocephalus causes herniation, or as an adju-
◆ Hyponatraemia with cerebral oedema.
vant to reduce ICP by removing CSF from the intracranial vault.
The prognosis after surgical intervention for brain herniation de- ◆ Brainstem compression/herniation.
pends on the underlying pathology. While patients with extra-axial ◆ Anoxic brain injury.
(epidural and subdural) haematomas may recover quite well if
129
Table 10.2 Metabolic and toxic encephalopathies and classic findings.
Metabolic Encephalopathies Findings

Hypoglycaemia Tremor, tachycardia, sweating, seizure.
Hyperosmolar hyperglycaemia Profound dehydration from osmotic diuresis. Serum glucose and serum osmolarity elevated.
Hypoxia Cyanosis, tachycardia—early, bradycardia—late.
Hypercarbia Arrhythmias, seizure.
Uraemia Renal failure, anion gap acidosis, shallow rapid breathing, confusion/weakness.
Hyponatraemia Seizures, weakness, cerebral/pulmonary oedema.
Hypernatraemia Seizures, weakness, tremor.
Hypercalcaemia Hypotonia, confusion, short QT on ECG.
Wernicke’s disease History of alcohol use, malnutrition, ataxia/ophthalmoplegia/confusion, nystagmus.
Toxic Encephalopathies
Organophosphates Sweating, salivation, increased secretions, flaccid paralysis, miosis.
Alcohol/Methanol/Ethylene glycol Anion gap metabolic acidosis, sweet odour.
Amphetamines/cocaine Mydriasis, tachycardia/hypertension.
Aspirin overdose Respiratory alkalosis and anion gap metabolic acidosis, seizures.
Acetaminophen Hypoglycaemia, acidosis, cerebral oedema.
Selective serotonin reuptake inhibitors (SSRI) or tricyclic Flushing, diarrhoea, tachycardia/hypertension, hyperthermia mydriasis, myoclonus.
antidepressants (TCA)
Antipsychotics Somnolence without respiratory depression, hypotension, tachycardia.
Anticonvulsants Broad, depends on agent, but bradycardia/asystole, nystagmus, respiratory depression common.
blockade causes the patient to be awake and distressed, but unable basic causes of coma have been corrected or excluded, and the
to move. Careful examination should easily differentiate this pres- patient remains comatose, a more exhaustive list of differential
entation from one of coma. Hypothermia can also lead to reduced diagnoses should be considered. Tables 10.2 and 10.3 summarize
level of consciousness in the peri-operative period and should be the most relevant metabolic and toxic encephalopathies that can
treated aggressively with active warming. Hypoxia, hypercarbia, present with coma, as well as structural and neurologic reasons of
and hypoperfusion are obvious causes of coma, which will be coma. Electrolyte abnormalities, abnormal blood glucose (low or
addressed during the initial attention to the ABCs. Once these hyperosmolar states), uraemia, or hypothermia can cause coma in
the peri-operative period. The injured brain is also more sensitive
to anaesthetic, hypnotic, and analgesic drugs; patients with brain
injury may emerge from anaesthesia much more slowly. Many of
Table 10.3 Neurologic and structural aetiologies of peri-operative the neurologic causes in Table 10.3 are neurologic emergencies
coma and classic findings. in and of themselves and are discussed separately in this chapter.
Toxic encephalopathies should be considered only in patients
Aetiology Findings who were comatose before surgery (trauma patients requiring
Herniation CN III palsy, hemiparesis, Cushing’s Triad. emergent life-saving surgery before full diagnostic workup was
completed), as they are unlikely to have been exposed to toxins
Ischaemic stroke Basilar artery stroke may cause coma.
during surgery.
Anoxic-ischaemic Marked cerebral oedema on non-contrast
encephalopathy head CT.
Clinical Evaluation of the Comatose Patient
Diffuse axonal injury Acceleration/deceleration mechanism, CT
imaging may appear normal. Poor prognosis. Prompt recognition of a comatose state, identification/removal of
the cause, and supportive care are essential to a favourable patient
Meningitis, encephalitis Fever, headache, nuchal rigidity. outcome. In a patient who is unresponsive to voice and touch, a
Autoimmune encephalitis Seizures, spasticity, coma. noxious stimulus should be applied. Jaw thrust is a good choice of
Nonconvulsive status Acutely unresponsive with unexplained stimulus, as it also opens the airway. Rapid assessment of ABCs
epilepticus aetiology, history of brain injury, requires EEG should precede any detailed neurologic assessment. If cervical
to diagnose. spine injury cannot be excluded (most relevant for patients in the
ICU or emergency department), in-line mobilization should be
Postictal state Recent seizure, lethargy, confusion.
used during intubation.
130
Neurologic Assessment with patterns of breathing is challenging. Anaesthetics, opioids,

Detailed assessment and localization of neurologic deficits can pro- benzodiazepines, and neuromuscular blockade may interfere with
vide important diagnostic information for patients with structural the neural regulation of respiration and obscure a precise neuro-
aetiologies of coma, whereas metabolic/toxic aetiologies of coma logic exam. Cheyne-Stokes respirations are characterized by cres-
tend to have few localizing findings. cendo/decrescendo tidal volumes alternating with apnoeas and
The Glasgow Coma Scale (GCS) is an objective measurement of may be a sign of bilateral cortical dysfunction. Isolated lesions in
level of consciousness and evaluates motor, eye opening, and verbal the midbrain may result in rapid hyperventilation. Several peri-
responses to stimulation (Table 10.4). A GCS score of ≤ 8 is syn- operative problems may also cause hyperventilation, e.g., pain,
onymous with coma. anxiety, muscle weakness secondary to inadequate reversal of para-
lytic agents, sepsis, or acidosis, making this finding less helpful.
Brainstem and Cranial Nerve Exam Irregular, ataxic breathing may be seen with ischaemia in the me-
dullary respiratory centre.
The cranial nerve exam aids in distinguishing between brainstem
Motor function is another important component of the neuro-
and cortical unresponsiveness. Table 10.5 summarizes important
logic exam, beginning with an assessment of muscle tone.
brainstem reflexes mediated by the cranial nerves. The pupils are
Hypotonia may suggest residual neuromuscular blockade, cho-
particularly important in the diagnosis of coma. The normal pupil-
linergic crisis, or hypercalcaemia. Hypertonia may be associated
lary response to light involves afferent optic nerve (CN II) fibres,
with malignant hyperthermia, but also with serotonin syndrome or
the oculomotor (CN III) nucleus in the midbrain, and the efferent
neuroleptic malignant syndrome. Movements should be character-
CN III fibres, which control pupillary constriction. The CN III nu-
ized as involuntary, reflexic, or purposeful. Involuntary movements
cleus or pathways are easily compressed during uncal/transtentorial
may be characterized as seizure activity, myoclonus, or tremor.
herniation, resulting in an asymmetrically dilated pupil on the side
Absence of cortical inhibition of spinal cord afferents may cause
of the lesion. In the presence of unresponsiveness, this is an om-
clonus or rigidity, but this can also be the result of various meta-
inous sign of brainstem compression, and requires rapid medical
bolic disturbances.
and surgical intervention, as discussed in Clinical Management of
Stereotypical reflexes in response to a painful stimulus can also
Herniation. Bilaterally fixed and dilated pupils suggest a comprom-
localize a pathologic lesion. Flexor (decorticate) posturing, or
ised midbrain, central herniation, or drug intoxication (sympatho-
flexion/adduction of the arms and wrists with extension of the
mimetics, TCAs, anticholinergic drugs). Bilateral pinpoint pupils
lower extremities, suggests cortical dysfunction. Extensor (decere-
may suggest a lesion in the pons, but more common aetiologies
brate) posturing, or extension and pronation of the arms and ex-
would be opioid intoxication or cholinergic toxicity.
tension of the legs, is associated with brainstem injury. Metabolic
Spontaneously roving eye movements or dysconjugate resting
encephalopathies may exhibit decorticate posturing, but rarely de-
gaze suggest an intact brainstem but cortical dysfunction.
cerebrate posturing. Purposeful movements such as reaching for
Nystagmus, or other rapid horizontal eye movements may be pre-
an endotracheal tube or localization of a painful stimulus suggest
sent in patients with nonconvulsive status epilepticus, or with over-
intact cortical function.
dose of several of the antiepileptic drugs. Lateral deviation of both
eyes could be a sign of an ipsilateral hemispheric lesion, a contra- CT Imaging
lateral seizure focus, or contralateral pontine damage involving CN
VI. Downward gaze fixation may occur with dorsal midbrain or A non-contrast head computed tomography (CT) scan is the pre-
thalamic compression. Upward gaze fixation may be present with ferred imaging method in the unresponsive patient because it pro-
bilateral cortical dysfunction. vides the most amount of information in the shortest period of time.
Abnormal respiratory patterns may signify brainstem injury or CT will detect cerebral oedema, hydrocephalus, haemorrhage, an
compromise, but the correlation between specific brainstem lesions intracranial mass and related mass-effect on surround structures,
or hypodensities reflective of sub-acute ischaemic strokes, allowing
the confirmation or exclusion of most neurologic/structural causes
of coma. CT is unrevealing in patients with toxic-metabolic coma,
Table 10.4 Glasgow Coma Scale (GCS).
and is most helpful in patients with focal signs (9).
If cerebral infarction is a concern, CT angiography or perfusion
Eye Opening Verbal Response Motor Response
scans can provide information about brain areas with comprom-
6—normal ised or threatened vascular supply, as discussed in more detail in
5—normal conversation 5—localizes the section on Ischaemic Stroke.
4—eyes are open 4—disoriented 4—withdraws from Advanced Tests

pain
Magnetic resonance imaging (MRI) is much more sensitive than
3—opens eyes to voice 3—nonsensical speech 3—abnormal flexion CT for the identification of acute ischaemic stroke or diffuse axonal
2—opens eyes to 2—incomprehensible 2—abnormal injury but is an impractical test for the early evaluation of altered
pain sounds extension mental status. In patients with unclear CT imaging, or with an
unexplained coma, MRI can be useful once the patient has been
1—no response 1—no response 1—no response
stabilized. An unstable patient in the MRI scanner will be isolated
Reprinted from The Lancet, 304, 7872, Teasdale G., Jennett B., Author(s), Assessment of from critical supportive care/interventions during the prolonged
coma and impaired consciousness a practical scale, pp. 81-94., Copyright (1974), with scanning time.
permission from Elsevier.
13
Table 10.5 Localization of brainstem reflexes
Exam Technique Afferent Path Brainstem Nucleus Efferent Path Normal Response Abnormal Response
Pupillary reflex Response to light. CN II, optic tracts. Edinger-Westphal nucleus. CN III. Direct and consensual Anisocoria, no
constriction. response to light.
Oculo-cephalic Head turned from side CN VIII (vestibular Pons, medial longitudinal CN III and Eyes move conjugately Gaze fixed at
reflex to side. branch). fasciculus, parapontine CN VI. in opposite direction. midline, does not
reticular formation. shift with head
turning.
Vestibulo-oculo- Irrigate external auditory Nystagmus with fast No nystagmus.
cephalic reflex canal with cold water. component away from
stimulus
Corneal reflex Stimulation of cornea CN V. Pons, trigeminal and facial CN VII. Blink. Absent blink.
with cotton filament or nuclei.
drop of saline.
Cough reflex Stimulation of carina CN IX and CN X. Medulla CN IX and Cough. Absent cough.
(naso-tracheal or CN X.
endotracheal suction
catheter).
Gag reflex Stimulation of soft Symmetric elevation of Absent gag.
palate (tongue blade, soft palate.
cotton swab).
In an unconscious patient with a history of seizures or at risk for Ischaemic stroke in general arises from thrombotic or embolic
seizure, electroencephalography (EEG) is required for diagnosis. occlusion of a small or large blood vessel that supplies the brain.
Non-convulsive status epilepticus is discussed elsewhere in this Embolic stroke is often associated with arterial fibrillation and
chapter. thought to be caused by clots formed in the non-contracting atria.
Patients with risk factors for stroke, such as carotid stenosis, ath-
Directed Therapies erosclerosis, atrial fibrillation, a hypercoagulable state, history of
Whether the aetiology is structural or metabolic, directed therapies coronary artery disease, hypertension, diabetes, and age >65, may
to correct the aetiology of coma should be instituted as early as suffer a stroke in the peri-operative period. Additionally, peri-
feasible to mitigate ongoing brain damage. Environmental, toxin, operative stroke can be caused by embolism of plaques mobilized
or drug exposures should be treated with the appropriate antidote. by direct manipulation of atherosclerotic vessels, or by hypoten-
Coma related to residual anaesthetic or hypnotic agents should be sion or low cardiac output causing hypoperfusion and ischaemia
treated supportively unless an antagonist exists for rapid reversal. in patient with stenosis of intracranial arteries. As neurons in the
Abnormal haemodynamics, temperature, or glucose levels should ischaemic brain die at a rate of approximately two million cells per
be corrected and monitored frequently. A structural aetiology of minute, the early goal of ischaemic stroke management is to pro-
coma may require surgical intervention. Obtain the necessary vide revascularization therapy as soon as possible. Pathogenesis and
imaging, and inform the neurosurgical team of the patient’s status
as soon as possible.
Box 10.3 Diagnosis and Emergency Treatment of Stroke
Ischaemic Stroke
While management of ischaemic stroke in the emergency depart- ◆ Suspect large vessel stroke in patients with hemiparesis and
ment is guided by well-established guidelines published by the cortical signs (gaze deviation, aphasia, neglect) or with altered
American Heart Association, no guidelines exist that specific- level of consciousness and new cranial nerve deficit (basilar
ally address the management of stroke in the peri-operative set- artery occlusion).
ting. A patient presenting to the emergency department within 4.5 ◆ Emergent consult to stroke neurology.
hours of stroke onset, who is not at increased risk of bleeding, will
◆ Obtain urgent non-contrast head CT to exclude haemorrhagic
usually receive recombinant tissue plasminogen activator (rtPA)
stroke.
after haemorrhagic stroke is excluded by non-contrast head CT.
In contrast, time of onset is often poorly defined in patients with ◆ Give tPA, if no contraindications (bleeding risk).
peri-operative stroke, and most patients are at increased risk for ◆ Obtain CT angiography (CTA) of head and neck to detect
life-threatening haemorrhagic complications risk, both contraindi- large vessel occlusion.
cations for the use of rtPA. These patients thus require a slightly
Transfer
◆ patients with large vessel occlusion to interventional
different, and more individualized, approach. Box 10.3 summarizes
neuroradiology for clot retrieval.
important management aspects for peri-operative stroke.
132
treatment of peri-operative stroke are also discussed in c hapter 24, be lowered to <180/105 mmHg. Titratable intravenous agents like
Cerebrovascular Disease, in this book. labetalol, hydralazine, and nicardipine are preferred.
A stroke neurologist should be consulted as early as possible to
Diagnosis assist with diagnosis and guide treatment of the patient with a new
peri-operative stroke. If no stroke neurologist is available in house,
Any patient who has a new neurologic deficit postoperatively,
consultation by telemedicine with a stroke centre may be avail-
which is not caused by an obvious seizure, should be considered
able. Many institutions have stroke alert systems in place that are
to have suffered a stroke. Focal motor deficit (arm/leg weakness or
modelled on STEMI or cardiac arrest alert pathways, to minimize
hemiparesis, facial weakness) suggests a stroke caused by occlusion
response time to new strokes. Anaesthetists should familiarize
of a vessel in the anterior cerebral circulation (middle cerebral ar-
themselves with these pathways, and collaborate to extend them to
tery (MCA), anterior cerebral artery (ACA), or carotid artery). If
the peri-operative setting.
cortical signs are present, e.g., gaze deviation to the side of the in-
If the patient is a candidate for rtPA, coagulation studies and a
jury, aphasia (inability to speak or understand language), neglect
platelet count should be obtained to exclude a subtle coagulopathy
(reduced awareness of one side of the body, e.g., inability to vol-
that would increase the risk of haemorrhagic transformation.
untarily move an arm while briskly withdrawing it from stimula-
Serum glucose should be maintained within normal limits.
tion), or visual field deficit, they suggest occlusion of a large vessel
and possible large hemispheric infarction. Basilar artery occlusion
causes brainstem stroke, which presents as coma with cranial nerve
Imaging
deficits. A stroke in the cerebellum presents with vertigo, nausea, The purpose of early non-contrast CT imaging is to exclude haem-
ataxia, and nystagmus, all of which are easy to miss in the peri- orrhagic stroke or other obvious mass lesions that may mimic stroke
operative patient. symptoms; CT evidence of ischaemia does not begin to appear until
Stroke severity can be graded using the National Institutes of after three hours. Early signs of ischaemia on non-contrast head
Health Stroke Scale (NIHSS). NIHSS includes assessments of CT include loss of grey-white differentiation, sulcal effacement in
level of consciousness, gaze, visual fields, facial paresis, arm or early cerebral oedema, or a hyperdense blood vessel sign indicating
leg motor control, sensory loss, aphasia and dysarthria, and neg- arterial occlusion. The presence of obvious hypodensity in more
lect/inattention. The total score ranges from 0–42, with a higher than one-third of any cerebral hemisphere indicates a large area
score indicating larger strokes and predicting worse prognosis. that is already infarcted. This increases the risk of haemorrhagic
While NIHSS scores are helpful to predict outcome as well as risk transformation, and patients are therefore not candidates for rtPA.
of haemorrhagic conversion after treatment with rtPA, and facili- CT can be combined with CT-angiography (CTA), which allows
tate communication with the stroke neurologist, not all anaesthesia visualization of the vessel occlusion. Large vessel occlusion (ca-
providers are familiar with the detailed scoring. Important infor- rotid artery, basilar artery, main MCA branches) is less likely to re-
mation can easily be related without use of the NIHSS by describing solve with rtPA alone. Patients with large vessel occlusion should
the presenting symptoms. therefore be evaluated for possible clot retrieval by interventional
The most important information to obtain is the time of symptom neuroradiology. Reperfusion by rtPA or clot retrieval can only
onset because this will dictate whether a patient will be a candi- benefit ischaemic brain that is not yet infarcted, while reperfusion
date for intravenous fibrinolysis with rtPA. If the patient emerges of infarcted tissue increases the risk of haemorrhagic transform-
from anaesthesia with new symptoms, the time of onset is assumed ation/bleeding into the infarct. CT-perfusion imaging (CTP) can
to be when the patient was last awake and symptom free. After help differentiate whether ischaemic tissue is already infarcted or
short procedures, this may still leave the patient in the window for still at risk.
reperfusion by rtPA. In all other situations, imaging studies can While diffusion weighted (DWI) magnetic resonance imaging
help determine whether there is still risk of brain ischaemia that (MRI) is highly sensitive and specific for detecting ischaemia or
would benefit from reperfusion. infarction as early as minutes after symptom onset, MRI is often
not readily available and requires relatively long scanning times. All
Supportive Management information required for treatment decision can be obtained by CT,
ABCs should be addressed first. Hypoxia may be a result of airway including CTA and CTP; thus, treatment should not be delayed by
obstruction/hypoventilation related to reduced oropharyngeal attempts to obtain MRI imaging. MRI may be superior to CT for
muscle tone and loss of reflexes. Aspiration and atelectasis are the detection of brainstem strokes. However, the underlying vessel
common in patients with stroke and in the peri-operative period. occlusion (basilar artery) can reliably be diagnosed by CTA.
Oxygen should be administered to hypoxic patients, but it has not
demonstrated benefit for stroke patients in the absence of hypoxia. Intravenous Fibrinolysis with rtPA
Intubation may be required for patients with altered mental status Intravenous fibrinolysis using rtPA can break down a blood clot
or airway obstruction. and restore perfusion to the brain distal to the occlusion, improving
Blood pressure is commonly elevated in patients with acute stroke survival and long-term neurological outcome after ischaemic
in an attempt to optimize perfusion to the ischaemic brain through stroke. Current guidelines by the American Heart Association rec-
collateral flow. Hypertension should not be treated in the first 24 ommend use of rtPA as soon as possible, ideally within one hour of
hours after ischaemic stroke unless the blood pressure exceeds 220/ symptom onset, acceptably within three hours of symptom onset,
120 mmHg (permissive hypertension). If patients are candidates for and cautiously within 4.5 hours. Patients receiving rtPA in the 3–
fibrinolytic therapy with rtPA, or at increased risk of haemorrhagic 4.5-hour window should be under 80 years of age, have no history
conversion after mechanical thrombectomy, blood pressure should of anticoagulant use, no history of prior stroke or diabetes, and no
13
imaging evidence of ischaemia involving more than one-third of activity can cause excitotoxic neuronal injury. Seizure activity that
the MCA territory. lasts for more than five minutes or recurs without the patient re-
While a long list of contraindications to rtPA exists, based on gaining consciousness represents status epilepticus (SE). SE is a
early studies of the drug, the most important contraindication is an neurologic emergency that requires aggressive treatment to avoid
increased bleeding risk. This may be a risk of intracranial haemor- additional brain injury. Mortality related to SE is high, but early
rhage in patients with large areas of brain infarction or underlying successful treatment is associated with improved outcome (12).
brain pathology, or a risk of systemic haemorrhage from vessels Rapid treatment, stabilization of vital signs, and investigation for a
that cannot be compressed or in confined spaces where small bleeds reversible underlying cause are important in the early management
can cause large damage (epidural haematoma). The risk of sys- of SE. Treatment follows a tiered approach, which is summarized
temic haemorrhage excludes rtPA use in most patients with peri- in Box 10.4.
operative strokes, although its use may be considered after minor
peripheral procedures, with careful weighing of risk vs benefit. Exam Findings in Status Epilepticus
Over 1 hour, 0.9 mg/kg rtPA based on ideal body weight are ad-
Repetitive tonic/clonic movements, gaze deviation, and nystagmus
ministered to the eligible patient, with the first 10% administered
are notable positive symptoms of SE. Negative symptoms (sug-
as a bolus. ICU monitoring should continue for at least 24 hours
gesting non-convulsive SE) include lethargy/confusion, coma,
after rtPA application, to allow early detection of haemorrhagic
aphasia, and staring. A postictal state of reduced level of conscious-
complications. Placement of catheters, tubes, and lines that can
ness commonly follows convulsive seizures, and if prolonged,
cause bleeding from non-compressible sites should be delayed for
should prompt the clinician to consider non-convulsive SE. The
four hours.
focused physical exam should assess for cranial nerve and focal
A sudden decline in neurologic status in a patient receiving
motor deficits, in addition to the ABCs, as focal deficits may sug-
rtPA should be interpreted as an intracerebral haemorrhage until
gest an underlying structural aetiology.
proven otherwise. Stop the rtPA, if it is still infusing, and obtain
During a generalized tonic-clonic seizure, generalized muscle
an urgent head CT. Reversal of the coagulopathy, which may stop
contractions cause an abrupt decrease in venous capacitance and
ongoing haemorrhage, requires administration of cryoprecipitate
increase in preload, drastically increasing cardiac output and blood
and platelets.
pressure. Autonomic instability may occur and result in tachy-
Endovascular Interventions cardia/bradycardia. Serum lactate and body temperature increase
in convulsive SE. During seizure activity there are often prolonged
Newly developed stent retriever systems allow mechanical periods of apnoea and hypoxia/hypercarbia. At the same time,
thrombectomy and successful reperfusion in many cases. CMRO2 and CBF increase, putting the brain at risk for ischaemia.
A series of randomized trials demonstrated improved func- In seizures lasting longer than 30 minutes, CBF autoregulation is
tional outcome in patients treated with thrombectomy using impaired, and cerebral perfusion may be threatened. Patients with
stent retrievers, compared to rtPA alone (10). The American increased ICP and threatened brain perfusion may experience sig-
Heart Association recommends mechanical thrombectomy for nificant additional morbidity as a result of the haemodynamic ef-
patients with large vessel occlusion within six hours of symptom fects of even brief seizures.
onset, up to twelve hours in select patients. In the peri-operative
patient where time of onset is unclear, the decision to attempt Emergent Initial Therapy
thrombectomy will often be based on the size of the remaining
As with all emergencies, ABCs should be assessed and interventions
tissue at risk estimated by CTP (or MRI).
instituted if necessary. Early intubation is indicated for signs of as-
The interventional management of stroke is more fully discussed
piration, hypoxia, or in patients with elevated ICP. Vital signs may
in Chapter 16, Interventional Neuroradiology, of this book. There
has been significant recent discussion whether general anaesthesia
or monitored anaesthesia care offers better conditions for inter-
ventional thrombectomy and associate with improved patient out- Box 10.4 Diagnosis and Emergency Treatment of Status
come. The interested reader is referred to the relevant consensus Epilepticus
statement by the Society for Neuroscience in Anesthesiology and
Critical Care (11). ◆ Seizures that last longer than five minutes or recur without a
return to neurologic baseline constitute status epilepticus.
Status Epilepticus ◆ First line treatment with benzodiazepine (4 mg lorazepam iv,
repeat once if needed).
Postoperative seizures are not uncommon after craniotomy and
often represent cortical irritability. Patients with temporal lobe or ◆ If unsuccessful, add second line treatment with intravenous
cortical lesions are at elevated risk for peri-operative seizures. These phenytoin/fosphenytoin (20 mg/kg), valproic acid (20–40 mg/
seizures are usually brief (1-2 minutes) and self-limiting. Non-con- kg), or levetiracetam (1–3 g).
trast CT imaging may be obtained to exclude new intracranial path- ◆ If unsuccessful, induce general anaesthesia (propofol or high-
ologies (most commonly haemorrhage). No additional treatment is dose midazolam). Intubate for airway protection.
required acutely, other than monitoring for seizure recurrence. The
◆ If neuromuscular blockade is used, or seizures stop but patient
neurosurgical team may elect to start an anti-epileptic drug (AED)
remains comatose, obtain EEG to exclude ongoing (subclin-
such as phenytoin/fosphenytoin or levetiracetam. While a single
ical) seizure activity.
brief seizure poses little risk of patient harm, prolonged seizure
134
be challenging to assess in an actively seizing patient, but should be is not available for patients who require drug-induced coma to
maintained in the physiologic range. IV access and patency should terminate SE, consider transfer to a facility that can provide con-
be confirmed. Intraosseous access can be helpful, if IV access is lost tinuous EEG monitoring.
during the seizure, and cannot be rapidly re-established.
The most important element of therapy is termination of seiz- Nonconvulsive Status Epilepticus
ures. Not only is early seizure termination important to mitigate Nonconvulsive SE may occur immediately following generalized
neuronal damage, but the earlier medications are administered, the convulsive SE, or independently in patients with unexplained al-
more likely they will be successful. tered mental status. In patients with a prolonged postictal state, or
Benzodiazepines are the first line drug of choice to ter- unexplained altered mental status, EEG is recommended to exclude
minate SE. As GABAA receptor agonists, they block seizure ac- occult nonconvulsive status. These patients may have subtle phys-
tivity through neuronal hyperpolarization. Four mg lorazepam ical findings such as nystagmus or tonic eye deviation, in the ab-
should be administered intravenously, which can be repeated sence of motor findings consistent with seizure.
after five to ten minutes if seizures continue. While lorazepam
is the best studied benzodiazepine and should be used first, 10 Diagnostic Interventions
mg midazolam intramuscularly is similarly effective and can be Treatment of SE is the same independent of aetiology, so diagnostic
used if lorazepam is not readily available. If seizure activity ter- efforts should not delay treatment. Basic labs should be sent as
minates with benzodiazepines, supportive treatment should be soon as possible to exclude simple causes of seizure such as hypo-
initiated, with special attention to respiratory depression and glycaemia (or ketoacidosis) and hyponaetremia. CT imaging of the
hypotension. head is indicated in the peri-operative period to exclude new intra-
cranial pathology, such as haemorrhage or cerebral oedema.
Urgent Control Therapy
Ongoing seizure activity despite first line AED therapy requires the
use of additional agents. For patients who have responded to ini- Transition of Care
tial therapy, urgent control therapy may also be indicated to attain The patient with a neurologic emergency will likely require the in-
a therapeutic level of a longer-acting AED before the initial agent volvement of multiple care teams. If the patient is initially managed
wears off. Several different AEDs are commonly used as second by anaesthesia providers in the post-anaesthesia care unit, transfer
line agents. No randomized data are currently available to support to an intensive care team (ideally specializing in neurocritical care)
one specific drug, so the selection can be guided by patient circum- should occur once the patient is stabilized and after any necessary
stances and provider preference. Phenytoin/fosphenytoin (loading surgical intervention. A safe handoff to the receiving ICU team in-
dose of 20 mg/kg IV of phenytoin equivalent), valproic acid (20–40 cludes a summary of the patient’s presentation, medical and surgical
mg/kg IV loading dose), and levetiracetam (loading dose 1–3 g IV) history, their neurologic exam and imaging results, and treatments
are the most commonly used agents. Fosphenytoin is associated that have been administered so far.
with a lower rate of cardiovascular side effects (hypotension and
bradycardia) than phenytoin and can be administered more rapidly Cases and Multiple-Choice Questions
(up to 150 mg phenytoin equivalent per minute). It is therefore pre-
ferred over phenytoin, if available. Q Interactive cases and multiple-choice questions to test your
knowledge on this chapter can be found in the online appendix at
Treatment of Refractory Status Epilepticus www.oxfordmedicine.com/otneuroanesthesiology.
If seizures continue after appropriate doses of a first-line and
second-line agent have been given, the patient has refractory SE. References
Ongoing seizure activity requires the induction of a pharmacologic
1. Miller CM, Pineda J, Corry M, Brophy G, Smith WS. Emergency
coma, without losing time trying to terminate SE with additional Neurologic Life Support (ENLS): Evolution of management in the first
second-line agents. Propofol in typical anaesthetic doses and high- hour of a neurological emergency. Neurocritical Care. 2015;23 Suppl
dose midazolam (up to 2 mg/kg/hr) can be used to induce and 2:S1–4.
maintain an anaesthetic state. Patients need to be intubated at this 2. Brain Trauma Foundation, American Association of Neurological
point, if this has not been done before. If non-depolarizing neuro- Surgeons, Congress of Neurological Surgeons, Joint Section on
muscular blockers are used for intubation, tonic-clonic movements Neurotrauma and Critical Care AANS/CNS, Bratton SL, Chestnutt
RM, et al. Guidelines for the management of severe traumatic brain
will no longer be visible. This does not guarantee that electrical
injury. VII. Intracranial pressure monitoring technology. Journal of
seizure activity has stopped. EEG monitoring should be obtained Neurotrauma. 2007;24 Suppl 1:S45–54.
urgently to confirm suppression of seizure activity. Vasopressor 3. Fitch W, McDowall DG, Keaney NP, Pickerodt VW. Systemic vascular
support will often be needed to counteract the myocardial depres- responses to increased intracranial pressure. 2. The ‘Cushing’ response
sion caused by high-dose propofol. Barbiturates (pentobarbital or in the presence of intracranial space-occupying lesions: Systemic and
thiopental) are alternative agents that can be used for refractory cerebral haemodynamic studies in the dog and the baboon. Journal of
status epilepticus. Their side effects (hypotension, immunosuppres- Neurology, Neurosurgery, and Psychiatry. 1977;40(9): 843–52.
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in chronic liver disease. Lancet. 1998;351(9104): 719–21.
Once patients are haemodynamically stable after induction of 5. Cruz J, Minoja G, Okuchi K. Major clinical and physiological benefits
anaesthesia, any missing CT imaging should be obtained. Patients of early high doses of mannitol for intraparenchymal temporal lobe
should then be transferred to the (neuroscience) ICU for further hemorrhages with abnormal pupillary widening: A randomized trial.
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6. Koenig MA, Bryan M, Lewin JL 3rd, Mirski MA, Geocadin RG, 10. Chen CJ, Ding D, Starke RM, Mehndiratta P, Crowley RW, Liu KC,
Stevens RD. Reversal of transtentorial herniation with hypertonic et al. Endovascular vs medical management of acute ischemic stroke.
saline. Neurology. 2008;70(13): 1023–9. Neurology. 2015;85(22):1980–90.
7. Kamel H, Navi BB, Nakagawa K, Hemphill JC 3rd, Ko NU. Hypertonic 11. Talke PO, Sharma D, Heyer EJ, Bergese SD, Blackham KA, Stevens
saline versus mannitol for the treatment of elevated intracranial RD. Society for Neuroscience in Anesthesiology and Critical
pressure: A meta-analysis of randomized clinical trials. Critical Care Care Expert consensus statement: Anesthetic management of
Medicine. 2011;39(3): 554–9. endovascular treatment for acute ischemic stroke*: Endorsed
8. Mortazavi MM, Romeo AK, Deep A, Griessenauer CJ, Shoja MM, by the Society of NeuroInterventional Surgery and the
Tubbs RS, et al. Hypertonic saline for treating raised intracranial Neurocritical Care Society. Journal of Neurosurgical Anesthesiology.
pressure: literature review with meta-analysis. The Journal of 2014;26(2):95–108.
Neurosurgery. 2012;116(1): 210–21. 12. Legriel S, Azoulay E, Resche-Rigon M, Lemiale V, Mourvillier
9. Rafanan AL, Kakulavar P, Perl J 2nd, Andrefsky JC, Nelson DR, Arroliga B, Kouatchet A, et al. Functional outcome after convulsive status
AC. Head computed tomography in medical intensive care unit epilepticus. Critical Care Medicine. 2010;38(12):2295–303.
patients: Clinical indications. Critical Care Medicine. 2000;28(5):1306–9.
136
137
CHAPTER 11
Neurophysiologic Monitoring
for Neurosurgery
Antoun Koht, Laura B. Hemmer,
J. Richard Toleikis, and Tod B. Sloan
Introduction identified by a phase reversal of the responses; this is most likely

due to the horizontal nature of the dipole generator located in the
Neurosurgery has been expanding in range and scope fuelled by gyrus (2, 15, 16). This technique, combined with MEPs elicited by
advances in navigation, magnification, radiology and anaesthesi- monopolar cortical stimulation, has been reported to identify the
ology. This expanded scope includes more aggressive surgical pro- sensorimotor cortex in 100% of patients (13). When surgery is near
cedures that are also associated with increased neurological risk. the motor cortex or pyramidal tracts, direct stimulation also is used
Intra-operative neurophysiological monitoring (IOM) has evolved to define the motor cortex or motor pathway and thus limit undue
as a surgical tool to enhance decision making and improve outcome motor injury with tumour resection (17–19). During cortical
(1–6). Somatosensory evoked potentials (SSEPs), which were intro- stimulation, electroencephalography (EEG) can be used to identify
duced in the 1970s, were followed by auditory brain stem responses seizure activity. As such, it is an invaluable tool to recognize and
(ABRs), cranial and peripheral nerve electromyography (EMG) treat seizures following cortical stimulation. In addition, its unique
and later by motor evoked potentials (MEPs) and other innova- ability to identify a seizure focus is key to ablation procedures.
tive techniques (7–9). Understanding these techniques, early rec-
ognition of signal changes, and appropriate management of such
changes are key to the effective application of IOM. IOM During Neurovascular Surgery
The monitoring modalities discussed earlier can also be applied
during intracranial neurovascular surgery. One of the most fre-
IOM During Intracranial Surgery quent uses is during aneurysm clipping to detect cerebral ischaemia
The dynamic neurophysiology of IOM complements the structural caused by clip application, temporary parent artery occlusion, per-
neuroanatomic imaging in localizing central nervous system struc- forating artery injury, brain retraction, aneurysm trapping, vaso-
tures that require protection. This is particularly important when spasm, or relative hypotension (1, 20–22).
an intracranial tumour is near functionally important areas or crit- EEG can be employed to monitor for potential cortical ischaemia
ical vascular structures. SSEPs are one of the most commonly used (8, 23). Rapid and specific changes in the EEG occur with cerebral
evoked potential monitoring modalities. They are used to monitor blood flow reductions allowing detection of such an event before
the sensory cortex and subcortical pathways mediating proprio- irreversible neural infarction occurs (24, 25). Although EEG can
ception and vibration for the nerves stimulated (typically median evaluate a large area of the cortex, subcortical ischaemia can go un-
nerve [spinal roots C6–T1], ulnar nerve [C8–T1], and posterior detected. If pharmacologic burst suppression is used for metabolic
tibial nerve [L4–S2] see Figure 11.1) (10–12). MEPs monitor the suppression, EEG can confirm its presence but monitoring for is-
motor cortex and descending pathways of the corticospinal tract chaemia is then excluded (26).
and peripheral motor nerves (Figure 11.2). MEPs are more ef- There is a correlation between cortical SSEP changes and
fective than SSEPs for avoiding motor injuries because they directly postoperative motor deficits. This correlation occurs be-
monitor motor function, respond to neural compromise faster, and cause the primary sensory and motor cortex share a common
are more sensitive to ischaemia in areas of the cortex, brainstem, blood supply (26). However, in up to 25% of cases with a new
and spinal cord (12). postoperative motor deficit, the SSEPs were unaltered (1). In
For tumours located near the motor and sensory cortex, SSEPs such cases, MEPs can detect the occurrence of ischaemia. When
can localize the rolandic fissure. This helps minimize surgical in- stimulating the motor cortex, it is vital that the transcranial
jury to the motor cortex and provides a safe approach for removal stimulation (TCS) results in stimulation of the motor cortex,
of tumours (13, 14). Localization is accomplished by recording the and not deeper structures in the brain (20). MEP monitoring
cortical component of the contralateral median nerve SSEP using of the subcortical motor pathways is sometimes very important
multi-contact recording strips placed on the parietal cortex. The and is particularly useful during intracranial neurovascular sur-
central sulcus, which separates the motor and sensory areas, is gery because perforating arteries (which affect the functional
138
138 Section 2 clinical neuroanaesthesia
Cortex
Sensory
Cortex
Thalamus
Cervico-medullary
Junction
Cervical Spine
Spinal Cord
Spinal cord
*
Peripheral n.
Microvolts
Milliseconds
Figure 11.1 The SSEP is produced by stimulation of a peripheral nerve (arrow).

The electrical activity enters via the dorsal nerve root and ascends the spinal cord via the dorsal column pathway of proprioception and vibration. It synapses at the
cervicomedullary junction and crosses the midline ascending in the medial lemniscus to the ventral posterolateral nucleus of the thalamus where it has a second synapse.
From there it ascends to the primary sensory cortex. SSEP recordings can be made along the pathway; shown are responses from the peripheral nerve, spinal cord,
cervical spine, and cerebral cortex.
Reprinted from Anesthesiology Clinics of North America, 24, 4, Jameson LC, Sloan TB, Monitoring of the brain and spinal cord, PP. 777–791. Copyright (2006), with permission from Elsevier.
status of deep structures, including motor pathways travelling extremity SSEP and MEP monitoring should be considered so that
through the corona radiata, internal capsule, cerebral peduncle, all anatomic areas at risk are monitored (8, 21, 34, 35). However,
basis pontis, and pyramids) are sensitive to blood flow interrup- specific attention should be made to ensure that the anatomic area
tion (1, 20, 27–29). most at risk based on aneurysm location is monitored. For example,
A review of published case series involving intracranial aneurysm and very broadly, upper extremity SSEPs and MEPs should be
clipping found the positive predictive value (PPV) of a permanent monitored during aneurysm clipping when possible ischaemia of
MEP loss and a new neurological deficit to be 1.0. The PPV of a tran- the middle cerebral artery (MCA) territory can occur and lower
sient loss or signal change was 0.31, with a transient loss/deterior- extremity SSEPs and MEPs should be monitored during clip-
ation being followed by a variety of clinical findings postoperatively ping of the anterior cerebral artery with possible ischaemia in its
(20). It appears that MEPs represent a ‘semi-quantitative technique’, distribution.
and its use is able to predict severe postoperative motor deficits, but it IOM has been shown to prevent morbidity in both adults and
lacks the ability to precisely predict transient or mild deficits (30). In paediatric patients undergoing surgical and endovascular manage-
a study comparing the motor outcomes before and after institution ment of arteriovenous malformations (AVMs) (25, 36). It has been
of MEPs for unruptured anterior circulation aneurysm clippings, shown to be useful for resection or embolization near the central re-
postoperative motor deficits were reduced from 4.5% to less than 1% gion or close to the sensory-motor pathways. Test occlusion of AVM
when MEPs were utilized (comparable to or better than coiling) (22). feeders can be used to identify vessels that are critical for supplying
MEPs can also be produced by direct cortical stimulation when blood to normal tissue and avoiding iatrogenic injury (8, 9).
the dura is open (31). This increases the risk of bridging vein in- IOM is also being employed in extracranial-intracranial bypass
jury, but gives more focused stimulation with less stimulation procedures where MEPs and SSEPs provide additional useful in-
intensity. Both transcranial and direct cortical stimulation tech- formation for blood flow-oriented monitoring (i.e., intra-operative
niques are equally effective to detect motor system compromise flowometry and indocyanine green fluorescence angiography)
(32). Combined use has been reported to glean benefits of both (37). It has also been suggested that intra-operative SSEPs and
techniques (33). MEPs can complement pre-operative balloon test occlusion by
Since multiple vascular territories can be affected during intra- identifying patients needing a bypass operation during aneurysm
cranial neurovascular procedures, the use of both upper and lower surgery (38).
139
Chapter 11 neurophysiologic monitoring for neurosurgery 139
IOM During Skull Base and Brainstem

Motor Cortex Surgery
To minimize potential injury to neural structures during sur-
gery deep in the brainstem, known surgical ‘safe entry zones’ can
D I1 I2 be mapped using cranial nerve nuclei as landmarks. Mapping is
achieved by recording muscle activity after stimulation of the motor
Spinal Cord nuclei of cranial nerves VII, IX, X, and XII on the floor of the fourth
ventricle (8, 39). This mapping is important since the anatomy may
be distorted by tumour.
Cranial nerve monitoring is often used in surgery within the
CMAP brainstem to identify the location and integrity of cranial nerves
(Table 11.1). Triggered EMG can help the surgeon identify intact
nerves in the operative field by stimulation using a mono-or bi-
Arm Milliseconds Millivolts polar probe in the surgical site. A resulting polyphasic compound
muscle action potential is recorded from an innervated muscle (40).
Spontaneous free-running EMG activity of muscles innervated by
NMJ
cranial nerves can also be monitored (8). Spontaneous EMG can
Spinal Cord Muscle identify stretch or blunt mechanical trauma to motor nerves sig-
Leg
nalled by high-frequency bursts of compound muscle action po-
tentials because non-irritated/non-stimulated nerves should not
NMJ
produce any EMG activity (40, 41). The amount of EMG activity
Figure 11.2 Pathway and typical responses of the motor evoked potential. has been shown to correlate with neurological status after posterior
Motor evoked potentials (MEPs) are produced by transcranial electrical fossa tumour surgery (8, 42).
stimulation of the motor cortex using electrodes on the scalp or exposed cortex One of the earliest applications of IOM was to monitor the fa-
(arrow). The electrical activity descends following the corticospinal tract to the cial nerve during vestibular schwannoma resection. Use of IOM
anterior horn of the spinal cord. After synapsing, the response then travels via is now considered standard of care for this surgery and has been
nerve roots and peripheral nerves until it produces a muscle response. The MEP
shown to improve postoperative outcome (8, 16, 40, 43). In surgery
can be monitored in the epidural space as a D wave, or as a compound muscle
action potential (CMAP). for hemifacial spasm, stimulation of one branch of CN VII may
Reprinted from Anesthesiology Clinics of North America, 24, 4, Jameson, L. C., Sloan, T. B., cause a ‘lateral spread response’ with activation of other branches
Monitoring of the brain and spinal cord, PP. 777–791. Copyright (2006), with permission from of CN VII; neuromonitoring of its disappearance may help predict
Elsevier. success (44). These triggered EMG responses allow intermittent
Table 11.1 Muscles and evoked potentials used for cranial nerve monitoring.
Cranial Nerve EMG (muscles monitored) SEP MEP

I Olfactory No monitoring techniques
II Optic VEP
III Oculomotor Inferior rectus m.
IV Trochlear Superior oblique m.
V Trigeminal Masseter m., T-SEP
temporalis m. Trigeminal
n. Evoked
Potentials
VI Abducens Lateral rectus m.
VII Facial Orbicularis oculi m., orbicularis oris m. MEP
VIII Auditory ABR
IX Glossopharyngeal Stylopharyngeus m.
(soft palate)
X Vagus Vocalis m., MEP
(Recurrent Laryngeal n.) cricothyroid m.
XI Spinal accessory Sternocleidomastoid m., trapezius m.
XII Hypoglossal Genioglossus m.,
(tongue)
140
monitoring as a surgical tool. A more continuous form of moni- suppression is being employed during clipping, EEG is then
toring can be done using corticobulbar responses elicited by TCS only able to monitor for and confirm burst suppression. Cortical
while recording from muscles innervated by the cranial nerve (45). SSEPs can detect cerebral ischaemia, but will miss some motor
Brainstem IOM also includes ABRs, which enable monitoring of tract ischaemia due to differing blood supply territories. MEPs
the auditory pathway and which are generated by acoustic stimuli can be a better early detector of ischaemia occurring in motor
of the cochlea (46, 47) (Figure 11.3). Typically, these are monitored subcortical pathways particularly supplied by perforating ar-
using scalp and ear electrodes (Figure 11.3), but the early responses teries. However, MEPs can be more challenging to employ than
can also be monitored using electrodes in the operative field to the other monitoring modalities mentioned.
focus on the nerve and cochlear nucleus. ABRs are used in pos- 3. As the surgeons are working on surgical exposure, the
terior fossa surgeries to preserve hearing and assess brainstem in- neuromonitoring team reports a reproducible change in
tegrity (11, 48). SSEPs and ABRs together monitor the functional MEPs with decreased amplitude in bilateral upper and lower
integrity of about 20% of the brainstem (8, 49, 50). Changes in extremities. No change in SSEPs or EEG is identified. Do you
ABRs are more sensitive than changes in vital signs for detecting suspect a surgical aetiology for the change? It is unlikely that
brainstem injury (51). ABRs are particularly useful because the a global change has occurred from a surgical manoeuvre at this
vestibulocochlear nerve is frequently at risk during surgery in the point. For a global change, it would be more likely that there is a
cerebellopontine angle, posterior/middle fossa, or brain stem (52). physiological or pharmacological aetiology.
For surgery near the cerebral peduncles, ventral medulla, basal 4. For the situation described in question 3, do you suspect
pons, or vertebrobasilar arteries, MEPs can be added to the moni- a physiological or pharmacological change? A physiological
toring regimen, since injury to the pyramidal tracts is possible (8). change would be unlikely since decreased oxygen delivery (such
Multimodality monitoring with SSEPs, MEPs, EMG, and ABRs as from hypotension or anaemia) would also affect the other
have allowed surgical resection of brainstem tumours that had pre- monitoring modalities. A review of the anaesthetic record finds
viously been considered unresectable (8, 49). that a small dose of intermediate muscle relaxant had been given
by the anaesthesia provider.
Intracranial Case: A 53-year-old woman with 5 mm right
5. During temporary clipping, a change in the MEPs is re-
MCA unruptured aneurysm presents for craniotomy for an-
ported from the left upper extremity followed by a change
eurysm clipping.
in SSEPs from the same extremity. What do you suspect and
1. What neuromonitoring modalities would you employ?
what action do you take? Since this focal neuromonitoring
While there is no standard of care for neuromonitoring modal-
change anatomically corresponds to the area at risk during clip-
ities for this surgery, EEG, SSEP, and MEPs should be considered.
ping, it is likely this change is surgically related. If the surgeon
2. Give a brief description of the main benefits and draw-
is unable to remove the temporary clip at this point, the blood
backs of each type of monitoring for this surgery. EEG can be
pressure should be raised to help provide collateral perfusion.
used to assess cerebral ischaemia, but, if pharmacologic burst
1 IOM During Spine and Spinal Cord Surgery

One of the first major applications of IOM in spine surgery was
2
to reduce the risk of paralysis in young adults undergoing correc-
tion of scoliosis. Currently the risks include distraction or compres-
sion of the spinal cord from correction by instrumentation (hooks,
wires, and pedicle screws), direct spinal cord trauma, epidural
5 6 haematoma, and derotation. Risks also include ischaemia from ten-
3 sion on blood vessels, relative hypotension, anaemia, and ligation
4
of anterior segmental vessels. Corpectomy and anterior fusion in
fracture or tumour management, with or without posterior instru-
7 mentation, further increases the risk of neurological compromise
IV
V as the vascular supply of the spinal cord can be disrupted due to
direct ligation of segmental vessels. Although direct trauma to the
III
II spinal cord can produce injury, paralysis is thought to be most
I VII likely the result of an ischaemic insult to the anterior and central
VI
portions of the spinal cord. Hence, if ischaemia can be detected,
the opportunity for correction can potentially mitigate irreversible
damage. As spinal instrumentation has evolved, the nearly con-
tinuous monitoring of SSEP, MEP, and EMG assists in identifying
Figure 11.3 Pathway and peaks of the auditory brainstem response. the specific component of the procedure that needs correction to
The ABR is produced by stimulating the cochlea with ‘clicks’ via earphones reduce neurological risk.
inserted in the ear canal. The first seven peaks of the ABR recorded from the scalp
The SSEP has a long track record of use in the correction of
and ear are produced near the structures in the brainstem as described in the text.
Typically waves I, III, and V are seen during monitoring. spinal deformity of scoliosis and became a standard of care when
Reprinted from Archives of Physical Medicine & Rehabilitation, 68, 3, Aravabhumi, S., Izzo, K. L., the Scoliosis Research Society and European Spinal Deformities
Bakst, B. L., Brainstem auditory evoked potentials: Intraoperative monitoring technique in Society evaluated the outcome of 173 surgeons and 51,263 cases
surgery of posterior fossa tumors, pp. 142–146. Copyright (1987), with permission from Elsevier. (53). They noted a reduction of the rate of paralysis from 0.7–4% to
14
0.55%. Their position paper in 1992 was echoed in the British lit- Table 11.2 Peripheral nerve roots and muscles commonly monitored.
erature as indication that IOM was ‘standard of practice’ in patients
with a high risk of neurological injury (54). Level Muscle Spinal Roots MEP
Subsequent to this, IOM has become widely applied as a key
Cervical Trapezoids, C 2–4
tool for many spine procedures. The application of IOM is effective Sternocleidomastoid
during the correction of spinal deformities because it is thought to
be able to detect many, if not all, of the iatrogenic causes of neuro- Biceps, Deltoid C 5, 6
logical deterioration (55) and experience has indicated that IOM Flexor carpi radialis C 6, 7
changes usually occur in sufficient time for interventions to be
Triceps C 7–8
made so as to prevent an irreversible injury (56, 57).
Since the SSEP traverses the posterior columns, the possibility Thoracic Adductor pollicis brevis, C 8–T 1 MEP
of an isolated motor tract injury that is not reflected in the SSEP Abductor digiti minimi
is possible when the insult does not affect a wide cross-section of intercostal muscles T 1–4
the spinal cord. This occurrence was seen in the Scoliosis Research
Upper rectus abdominis T 5–6
Society evaluation (1 in 1500 cases) (53). When the transcranial
electrical motor evoked potential technique was developed, it was Middle rectus T 7–8
rapidly applied to monitoring of spinal surgery after Food and Drug abdominis
Administration approval in 1995. Studies demonstrated that moni- Lower rectus abdominis T 9–11
toring of MEPs was 100% sensitive in identifying patients who sub-
Inferior rectus T 12
sequently awoke with a transient or short-term neurologic deficit, abdominis
whereas the sensitivity of SSEPs was only 43% (56–58).
Hence, for spine surgery, the combination of SSEPs and MEPs Lumbar Iliopsoas L1
has been advocated to better detect spinal injury (56, 57, 59). Adductor longus L 2–4
Combined monitoring has a higher sensitivity to impending injury,
Vastus medialis, L 2–4
with MEPs correlating better with neurologic injury to the motor
Quadriceps
tracts (29, 56, 57, 60). Several studies have shown sensitivity and
specificity approaching 100% when combined monitoring is used Lumbosacral Tibialis anterior L 4–S 1 MEP
(e.g., SSEPs and MEPs) (58). MEPs have been seen to respond to Peroneus longus L 5–S 1
an insult 5 to 16 minutes before SSEPs and were more responsive to
Sacral Gastrocnemius L 5–S 2
spinal cord blood flow as a consequence of hypotension or vascular
insult in the grey matter (58, 60). Abductor hallicus S 1–2 MEP
SSEPs and MEPs are usually monitored during surgery cephalad Anal sphincter S 2–4
to the termination of the cord (L1–L2). Below this level, the spinal
* Monitoring methods for peripheral nerves. Shown are muscles commonly used for
nerves continue in the cauda equina, nerve roots, and peripheral
EMG monitoring of various nerve roots during surgery and for pedicle screw threshold
sensory and motor nerves. In addition, the SSEP is transmitted testing. Also indicated are the muscles typically utilized for motor evoked potential (MEP)
by several nerve roots and the individual muscle responses of the monitoring.
MEP can be activated by more than one nerve root. As such, both
SSEPs and MEPs are not specific for individual nerve roots. These
anatomic considerations give rise to some controversy regarding stimulated to determine the current necessary for stimulating the
whether the SSEP and/or MEP should be monitored on spinal nearby nerve root (‘threshold’) and activating a muscle response.
column surgery below the termination of the cord. When this is low, the screw has likely broken through the pedicle
In order to assess nerve roots, EMG techniques are used wall and, if very low, the screw may be on or near the nerve root
similar to cranial nerve monitoring. Neurotonic—that is, high- signalling the need to reconsider placement. Several studies sup-
frequency, high-amplitude—discharges in spontaneous muscle port the usefulness of pedicle screw testing for reducing nerve root
EMG (‘free run EMG’) allows identification of blunt trauma injury (62, 63).
or nerve irritation. In addition, a nerve root can be stimulated Of note, thresholds may be elevated with chronically com-
(‘triggered EMG’) to locate it or test its integrity. A variety of pressed nerve roots and some screws do not conduct electricity
muscles can be used for EMG monitoring during surgery on the such that the pilot hole should be tested (64). Threshold testing is
spine (Table 11.2). more difficult in the thoracic region since fewer muscles are avail-
The lack of ability of the SSEP or MEP to specifically monitor able for EMG. However, stimulation of a medially malpositioned
individual nerve roots was highlighted when spinal instrumenta- thoracic screw may activate the corticospinal tract within the
tion evolved utilizing pedicle screws and the risk of postoperative spinal cord. This has given rise to a testing paradigm using screw
radiculopathy from nerve root injury was as high as 10% (61). stimulation parameters similar to transcranial MEP techniques
The largest experience with pedicle screw testing has been for while recording responses from lower extremity muscles (anterior
the lumbar spine where misdirected screws that have breached tibialis, medial gastrocnemius, abductor hallucis, and quadriceps)
the medial pedicle wall have placed nerve roots at risk. This oc- (65). In the cervical region the pedicles are smaller, making place-
curs as frequently as 15–25% of the placed screws (61). To detect ment more challenging. Fortunately, a large number of muscles
the breach, the screw or screw hole (in the case of some screws are available allowing threshold testing similar to the lumbar
that are coated and not electrically conductive) can be electrically region.
142
Some surgical teams are supplementing or replacing pedicle The use of EMG for surgery on the spinal cord is particularly key
screw testing with stereotactic guidance utilizing intra-operative to untethering procedures. Surgical treatment is aimed at the most
computerized tomography (‘O arm’). This allows planning the tra- complete release of the spinal cord without iatrogenic damage to
jectory of the screw before placement, rather than testing after the critical nerve roots. In these cases, EMG allows differentiation of
pilot hole is placed. Despite the use of these techniques, cortical functional tissue from tissue that can be sacrificed, such that an im-
perforation may still occur. Thus, threshold testing remains in use provement in outcome has been seen (72–74).
in some centres (66). Preserving neural function is particularly important for motor
As with differences in pedicle anatomy, other IOM considerations and sensory function of the lower extremities, but also bowel,
are seen in different spine regions. For example, during cervical bladder, and sexual function (73). Monitoring modalities avail-
spine surgery, the use of MEPs is believed to decrease morbidity in able to achieve this include SSEP, MEPs (including those of the
part because they may allow differentiation between cervical cord anal musculature), EMG of musculature in the myotomes from L2
myelopathy and peripheral neuropathy (67). Also in the cervical to S4, and the bulbocavernosus reflex. This reflex is generated by
region, SSEP and MEP acquisition shortly after induction and be- stimulating the pudendal nerve and recording the response in the
fore positioning can be informative regarding cervical spine pos- anal sphincter. The afferent sensory path is formed by the sensory
ition and safety. With surgery on the anterior cervical spine, the C5 fibres of the pudendal nerve. These neurons synapse in the grey
nerve root has a high risk (up to 5.9%) for a postoperative deficit, matter of the spinal cord (S2–S4) and the efferent limb travels over
prompting use of routine EMG monitoring (68). Another consid- the motor fibres of the pudendal nerve to the muscles of the pelvic
eration in anterior cervical procedures is occlusion of the carotid floor, including the external anal sphincter.
artery and traction injury on the recurrent laryngeal nerve, leading The removal of intramedullary spinal cord tumours carries a signifi-
to postoperative vocal cord dysfunction (2–5%). In these cases, the cant risk for surgical damage and subsequent neurological dysfunc-
recurrent laryngeal nerve is monitored using spontaneous EMG tion. In these procedures, the use and efficacy of IOM has been well
acquired via endotracheal tubes with surface electrodes positioned documented (75). The identification of the midline is useful to define
adjacent to the vocal cords. In the thoracic spine, procedures may the safe entry pathway to minimize surgical injury. Since the SSEP
be anterior, posterior, or with a combined approach. When con- tracts follow the dorsal columns, which lie adjacent to the midline,
ducted anteriorly, spinal cord ischaemia can occur from loss of ra- stimulation of the lower extremity and recording from a series of con-
dicular segmental arteries, especially the artery of Adamkiewicz tacts across the posterior aspect of the cord allows the identification of
(located commonly at T9–T12 on the left). the dorsal median sulcus (76). The monitoring modalities during sur-
With spinal column surgery, it is thought that paralysis is the gery of intramedullary spinal cord tumours include MEPs and SSEPs.
most likely result of an ischaemic insult that IOM may be able to For recording MEPs, the epidural D wave and CMAP re-
detect. Although deliberate hypotension has been used successfully sponses from the upper and lower extremities have been used.
in some young healthy patients, a mean pressure <55 mmHg in- During tumour resection, the D wave is used as a quantitative
creases neurological risk (69). A mean of 65–75 mmHg has been indication of corticospinal tract integrity. Surgery should be
recommended prior to the corrective manoeuvre with a restoration halted when the amplitude decreases by 50% (77). MEP moni-
of the mean to >70 mmHg after spinal manipulation and correction toring has also been successfully used to locate the motor tracts
(69). It has become common to mildly increase the mean pressure using collision of the transcranially activated response with
in patients exhibiting possible ischaemia or when spinal cord in- stimulation inside the spinal cord, resulting in a loss of the usual
jury is suspected (69). Posterior procedures with an osteotomy can muscle responses (76).
cause stretching and injury to the anteriorly located blood vessels. With spinal cord AVMs, IOM has allowed provocative testing of
Despite the controversy mentioned here about the use of SSEPs the vascular supply to determine the safety of vessel sacrifice. In this
or MEPs below L1–L2, several studies have demonstrated the effi- case, test clamping or the injection of sodium amytal, which blocks
cacy of using multimodal IOM (SSEP, MEP, EMG) during lumbo- grey matter neural activity of MEPs, and lidocaine, which blocks
sacral spine surgery (55, 70). One study specifically indicated the white matter conduction pathways of SSEPs and MEPs, helps iden-
value of MEPs in reducing postoperative pain scores (55). tify blood vessels critical to normal neurological function.
As an alternative, or in some patients from whom MEPs cannot Neurosurgery for the treatment of incapacitating spasticity (often
be acquired, the Hoffmann’s reflex (H reflex) is sometimes used the result of cerebral palsy) utilizes IOM with EMG. In these chil-
(71). This is a compound muscle action potential (CMAP) that re- dren, afferent activity in the L2–S2 region results in excessive ef-
sults from electrical activation of a monosynaptic spinal cord reflex ferent muscle tone into adjacent myotomes and even contralateral
following stimulation of a peripheral nerve. In addition to moni- muscles. EMG is used to identify those nerve rootlets for sacrifice
toring the sensory and motor nerves, the H reflex also monitors the that give rise to the hyperactivity, thus allowing a selective dorsal
spinal cord grey matter at the level of the reflex and detects spinal rhizotomy (78). Similar to surgery on a tethered cord, rootlets ne-
cord injury cephalad to the reflex (‘spinal shock’). cessary for urogenital and anal sphincter tone should be preserved.
EMG has emerged as an important monitor for procedures con- These procedures have allowed an improvement in leg and foot
ducted in the lumbar and sacral region. For a lateral approach to function while reducing the incidence of urinary complications
the lumbar region, EMG has been used to reduce neural injury to from 24% to near zero (74).
the components of the lumbar plexus. EMG monitoring is helpful
with a minimally invasive approach since the surgeon has a limited Spine Case: A 14-year-old female is undergoing spinal cor-
field of view and may inadvertently injure a nerve root. When the rective surgery for scoliosis in the prone position. The curvature
surgical procedure places the cauda equina at risk (usually below to be corrected involves instrumentation with rods and pedicle
L1–L2), IOM using EMG is used to preserve nerve root function. screws from T4 to L1.
143
1. What are the typical monitoring modalities that are number needed for useful clinical function. Therefore, a clearly de-
being used and what are their roles? fined CNAP is a good prognostic indicator (81). This is in contrast
• MEP using upper extremity (adductor pollicis brevis) and to abnormal CNAPs, which are low in amplitude due to fewer func-
lower extremity (adductor hallicus, tibialis anterior) muscle tional fibres being present and of longer duration due to temporal
responses. dispersion resulting from wide variations in conduction velocities.
• SSEP using upper extremity (ulnar nerve) and lower ex- Such recordings provide information that significantly improves
tremity (posterior tibial nerve) stimulation with recording over the clinical outcomes of nerve repair.
the brachial plexus (Erb’s point), popliteal fossa, cervical spine,
and sensory cortex. Managing IOM Changes
• EMG responses of multiple lower extremity muscles as well
as those used for MEP. The lower extremity MEP and SSEP re- Establishing baseline IOM signals utilizing supportive anaesthesia
sponses are primarily to monitor for neural compromise in the and technical settings is essential. The responses are then repeat-
operative area of the spine. The upper extremity responses serve edly monitored to identify changes that may signify possible neural
to assess positioning problems in the upper extremity and serve compromise. Confirmed changes should be analysed for tech-
as controls for global effects (e.g., anaesthesia) altering the lower nical, physiological, pharmacological, positional, or surgical origin.
extremity responses that might be misinterpreted as surgical re- Each of these changes has special characteristics that can be used
lated problems. The multiple recording sites assist in identifying to establish cause and guide management (84). Physiological and
the location of neural dysfunction in the pathways. The EMG pharmacological aetiologies of evoked potential changes tend to
will monitor nerve root compromise from stretch or retrac- be global and more cortical than subcortical. By contrast, surgical,
tion, allow pedicle screw testing, and identify light anaesthesia technical, and positional causes tend to be localized.
(global increase in background activity).
The Contribution of IOM to Neurological
IOM During Peripheral Nerve Surgery Outcome
There are two primary reasons for recording from a peripheral Several older animal studies found that ischaemia to the spinal
nerve during surgery. The first of these is simply to provide an cord was associated with a clinical motor deficit; if the ischaemia
assessment of function during procedures when such function is is corrected in a timely manner, the SSEP changes were reversible
placed at risk. Examples of this would be to avoid nerve palsies as a (85–87). Changes in the SSEP and permanent deficit were related
result of patient positioning or brachial plexus compression during to the duration of ischaemia. One study found that the occurrence
a scapula-thoracic arthrodesis (79). The second reason is to proof paraplegia was zero with 15 minutes of ischaemia, 30% after 17
vide diagnostic information relating to a nerve or plexus injury. If minutes, 33% after 20 min, 38% after 25 min, and 100% after 60
a nerve is bluntly and completely transected, a delayed early repair minutes. They also found that the SSEP returned when reperfusion
of the nerve is generally planned after a period of three weeks’ time. was restarted in reverse order to the loss (86). A relationship was
However, the vast majority of peripheral nerve injuries leave the seen in animal studies between severe cord ischaemia, lack of
nerve in some degree of continuity (80, 81). In such cases, the nerve movement, and changes in SSEP. They also found localized spinal
is capable of significant regeneration if conditions are optimal (81). cord ischaemia could cause motor deficits without SSEP changes,
Electrically stimulating the nerve and recording the compound nerve consistent with the difference in vascular supply between the sen-
action potential (CNAP) that occurs beyond the site of injury can pro- sory and motor tracts (85).
vide information on the status of the fibre population within the nerve. In humans, IOM has become a frequently utilized component of
By establishing a protocol that allows for spontaneous regeneration surgical decision making despite substantial Level I evidence. SSEP
to occur, regeneration can be assessed (81). However, no activity may and MEP as a biomarker and surrogate endpoint for postoperative
be apparent immediately following an injury. In such cases, a recom- neurological deficits for both spine and intracranial surgeries was
mended protocol would be to postpone surgery for an interval of three recently examined (88). The investigators utilized a three-step
to five months to allow time for spontaneous regeneration to occur. evaluation framework recommended by the Institute of Medicine
The method of stimulating and recording CNAPs is safe, simple, (89) and assessed causal links using guidelines adopted by the
and straightforward (82). Stimulation is done using a tripolar elec- GRADE working group (90). They concluded that IOM-related
trode arrangement and the resulting activity is recorded using biomarkers comply with some of the Institute of Medicine frame-
a similar bipolar arrangement. The size of a CNAP from normal work for validating surrogate endpoints. This supports IOM’s as-
nerve (0.2–1 mV) is considerably larger than the electrical signals sociation with surgical events and contingency analysis supports
recorded from the scalp. As a result, signal averaging is not required. IOMs beneficial impact on postoperative outcomes (88).
Recordings can be acquired using standard monitoring equipment A literature review to establish evidence-based guidelines for
and anaesthetic management is not an issue. The acquisition of the use of SSEP and MEP in spinal surgery and certain aortic sur-
CNAPs from a healthy nerve requires a pulsatile stimulus intensity geries was recently conducted. Utilizing evidence-based meth-
of 4–6 mA with pulse duration less than 0.1 msec. However, an in- odology, the American Academy of Neurology sought to answer
jured nerve or one embedded in scar tissue may require stimulus the question, ‘Does IOM with SSEP and MEP predict adverse
intensities as high as 30–40 mA with pulse durations as short as surgical outcome?’ The panel found four Class I studies that
0.02 msec to elicit recordable CNAPs (83). compared complications in a group with IOM changes with the
It has been determined that the number of nerve fibres needed group that did not have IOM changes (91–94). In these studies,
to produce a large amplitude, short duration CNAP is the same 16–40% of patients who had IOM changes had an adverse
14
outcome (paraparesis, paraplegia, or quadriplegia), while no Multiple–Choice Questions

events occurred in patients who did not have IOM changes. An
additional eight Class II studies were reviewed (57–59, 95–100). Q Interactive multiple-choice questions to test your knowledge
These Class II studies were consistent with the Class I studies on this chapter can be found in the online appendix at www.
demonstrating that all paraparesis, paraplegia, and quadriplegia oxfordmedicine.com/otneuroanesthesiology.
occurred in the patients with IOM changes, and none of the ad-
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149
CHAPTER 12
Brain Trauma
Anne Sebastiani and Kristin Engelhard
Introduction has to be aware that the severity of TBI may increase over time.
Depending on the severity of the trauma, transient headaches, diz-
Traumatic brain injury (TBI) is the most common cause of per- ziness, or nausea can occur after a mild TBI and then progressively
manent disability and death in patients younger than 40 years of deteriorate leading to unconsciousness and coma. Ominous signs
age (1, 2). TBI is mainly the result of road traffic accidents, assaults, are dilated pupils, which show no reaction to light, hemiparesis,
falls, and domestic abuse. To minimize brain damage after TBI, or abnormal extension/flection to painful stimuli. Additionally,
knowledgeable and fast treatment of the patient according to cur- TBI patients can suffer from multiple severe injuries after trauma
rent guidelines is necessary. As the brain has nearly zero tolerance (polytrauma). Therefore, a careful examination has to be per-
for hypoxia, it is essential to ensure adequate oxygenation during all formed in all patients with a severe trauma. In 15% of the trauma
steps of the treatment after injury. patients, the spine is also injured. Depending on the mechanism of
the trauma, injuries of the lung, abdomen, vessels, and the bones
Epidemiology can occur. As major blood loss, hypoxia, and arterial hypotension
exacerbate neuronal injury, it is critical to detect and treat these
In the United States, TBI accounts for about 2.5 million emergency injuries as soon as possible. Additionally, the mechanism of the
department visits, hospitalizations, and deaths. Of these persons, accident, e.g., the extent of the car damage or the height of the fall,
approximately 87% were treated in and released from emergency can provide important insights into the potential severity of the
departments, another 11% were hospitalized and discharged, damage.
and approximately 2% died (in 2010 according to a report by the
Centers for Disease Control and Prevention). In Europe, the inci-
dence ranges from 47.3 up to 694 per 100,000 individuals per year. Pathophysiology
Mortality from TBI ranges from 9 per 100,000 per year to 28.10 per Brain trauma is the consequence of an external forceful impact,
100,000 per year (3). which directly leads to damage of brain tissue and often to im-
pairment of brain function (primary injury). It is not accessible
to any treatment and can only be avoided by preventive measures
Classification (e.g., helmets, airbags). Symptoms of a TBI can occur immediately
TBI can be classified by mechanism. Apart from a closed head in- or can develop slowly over time. Even if the skull is not fractured,
jury, an open and penetrating TBI is characterized by disruption the brain can hit the inside of the skull and be bruised. The head
of the skull and the dura mater. Additionally, TBI can be categor- may be intact, but problems could result from bleeding or intra-
ized by severity as mild, moderate, or severe according to acute in- cranial swelling. The mechanically induced primary injury con-
jury characteristics that suggest the extent of damage to the brain. tains an epicentre with axons, glial cells, and vascular structures
The Glasgow Coma Scale (GCS) is the most universally utilized that sustain irreversible damage. At the macroscopic level, the
level of consciousness scale worldwide, consisting of three com- primary injury may include skull fractures, extra-axial haemor-
ponents: motor response, verbal response, and eye opening—the rhage (epidural haematoma, subdural haematoma, and subarach-
worse the response, the lower the number (4) (Table 12.1). Certain noid haemorrhage), and intra-axial haemorrhage (contusions,
acute interventions can compromise accuracy of the GCS, e.g., ap- diffuse axonal injury, and brain stem injury). At the cellular level,
plication of sedatives/anaesthetics, thereby leading to misclassifica- microporation of membranes, ion channel leakage, and protein
tion of TBI severity. In clinical practice, additional criteria are used, disturbances are induced within minutes to hours after the initial
including duration of loss of consciousness, altered consciousness, injury. The traumatic penumbra surrounds this irreversibly dam-
and/or post-traumatic amnesia. Imaging techniques, such as com- aged area with cells that have sustained reversible damage. The
puted tomography (CT) scans for the identification of structural penumbra is the area where most of the deleterious secondary
damage, might contribute to the assessment of injury severity. The changes occur. These secondary changes develop within minutes,
Abbreviated Injury Scale (AIS) score for the head and neck region hours, or days after the initial impact and may further cause in-
can be used to classify TBI. The AIS ranks injuries on a six-point jury to the brain tissue. A complex series of pathologic events is
scale based on mortality risk, with ‘1’ indicating minor injury and initiated that finally converge to cerebral hypoxia and ischaemia.
‘6’ indicating a non-survivable injury. Table 12.2 summarizes the These events determine the evolution of the traumatic penumbra
measurements to classify TBI severity (5). The treating physician either into irreversible lesions (secondary injury) or complete
150
Table 12.1 Glasgow Coma Scale. ◆ the cerebrospinal fluid (CSF) contributes approximately 8%; and,
◆ blood in the vasculature contributes approximately 12% of the
Ability Score total ICV.
Motor Response The sum of these three components has to be stable. Any increase
Normal 6 in ICV of one of these compartments following TBI (such as intra-
cranial haematoma, brain oedema, or obstruction of the drainage)
Localized to pain (purposeful movement to side of pain). 5
must be compensated by volume reduction of one of the other com-
Withdraws to pain 4 partments to maintain normal intracranial pressure (ICP). The CSF
Abnormal flexion to pain (an abnormal posture that can 3 system has the greatest buffering capacity through displacement of
include rigidity, clenched fists, legs held straight out, and arms CSF from the cranium to the spinal subarachnoid space. Cerebral
bent inward toward the body with the wrists and fingers blood volume (CBV) reduction occurs first by compression of the
bent and held on the chest). low-pressure venous system, followed by capillary collapse, and
Abnormal extension to pain (an abnormal posture that can 2 then arterial compression, leading to cerebral ischaemia. The im-
include rigidity, arms and legs held straight out, toes pointed pact of ICP on outcome lies in its role in determining cerebral perfu-
downward, head and neck arched backwards). sion pressure (CPP) (CPP = mean arterial pressure [MAP]—ICP).
None 1 A rise in ICP is called intracranial hypertension. It is a secondary
insult that can result from the primary injury, vascular engorge-
Verbal Response
ment, obstruction to CSF flow, or brain oedema. It is known to be
Normal conversation 5 associated with poorer outcomes in TBI patients, which has led to
Disoriented conversation 4 considerable interest in its monitoring and manipulation. Normal
ICP in healthy adults is usually regarded as 5–15 mmHg, and in
Words, but not coherent 3
TBI an ICP of >20–25 mmHg is widely accepted as intracranial
No words, only sounds 2 hypertension (6). Intracranial hypertension for a period of more
None 1 than five minutes worsens neurologic outcome after TBI.
Brain oedema is defined as an increase in brain water content
Eye Opening
and can cause intracranial hypertension. In most cases of brain
Spontaneous 4 injury, brain oedema is a combination of the vasogenic and the
To voice 3 cytotoxic type caused by blood brain barrier disruption and is-
chaemia, respectively. Most cases of brain injury resulting in ele-
To pain 2
vated ICP begin as focal brain oedema. When pathophysiological
None 1 conditions occur in association with an intracranial hematoma,
the resultant increased ICP causes a further reduction in CPP
Reprinted from The Lancet, 304, 7872, Teasdale G., Jennett B., Author(s), Assessment of
coma and impaired consciousness a practical scale, pp. 81-94., Copyright (1974), with and exacerbation of cerebral ischaemia. Eventually, intracranial
permission from Elsevier. hypertension, if untreated, leads to herniation of the brain stem
Score: Motor Score + Verbal Score + Eye Score = 3 to 15 through the foramen magnum causing brain death. Furthermore,
the monitoring of ICP after TBI allows early detection of sec-
ondary haemorrhage.
resolution (Figure 12.1). The following sections discuss disorders
that may be initiated after primary injury. Systemic Effects
Intracranial Hypertension TBI may affect disturbances of various organ systems even in the
The contents of the cranium (intracranial volume, ICV, 1600 ml) absence of concomitant extracerebral organ injury or systemic in-
can be divided into three major components: fection. The systemic manifestation is multifactorial and involves
interferences of the autonomic nervous system (sympathetic dis-
◆ the brain or tissue compartment accounts for approximately
charge), inflammatory responses, endocrine dysfunctions, and the
80%;
Table 12.2 Classification for the severity of TBI.
Criteria Mild Moderate Severe

Structural Imaging Normal Normal or abnormal Normal or abnormal
Loss of Consciousness < 30 minutes 30 minutes to 24 hours >24 hours
Post-traumatic Amnesia 0–1 day >1 and <7 days >7 days
GCS (best available in 24 hours) 13 to 15 9 to 12 3 to 8
Abbreviated Injury Scale 1 to 2 3 4 to 6
score: Head
15
Chapter 12 brain trauma 151
Traumatic Brain Injury
Primary Injury
Contusion
Cerebral Ischemia
Diffuse Axonal Injury
Secondary Injury
Oedema
Energy Dysfunction
Impaired Oxygen Diffusion
Exitotoxicity
Neuro-inflammation
Systemic Inflammation
ARDS
Surgical Procedures
High Tidal Volume
Hypo-& Hyperventilation
Inadequate PEEP Infections
Figure 12.1 Pathologic events following TBI.
treatment modalities of TBI. Endocrine and electrolyte imbalance, have severe TBI and those suffering from multiple systemic injuries
cardiovascular and respiratory disturbances, influences on the co- with substantial blood loss may, however, develop hypotension and
agulation cascade, and a systemic immune response is common a decrease in cardiac output. Systemic hypotension (systolic blood
after TBI. Thirty-five percent of patients with brain injuries develop pressure <90 mmHg) at the time of hospital admission is associated
failure of at least one organ, and the most common non-neurologic with increased morbidity and mortality (7).
organ system failure involves the respiratory system. Respiratory responses to head trauma include apnoea and ab-
Cardiovascular responses are commonly observed in the acute normal respiratory patterns. Respiratory insufficiency, spontan-
stage of TBI including hypertension, tachycardia, and increased eous hyperventilation, and aspiration of vomitus or blood often
cardiac output. The increased blood pressure may be partially due occur. Additionally, TBI patients suffer from pulmonary injuries
to a neural response to intracranial hypertension called the Cushing including ventilator-associated pneumonia, acute respiratory
response/reflex and may indicate brain herniation. Patients who distress syndrome (ARDS), and neurogenic pulmonary oedema.
The aetiology of the neurogenic pulmonary oedema is thought
to be a surge of catecholamines that results in cardiopulmonary
Box 12.1 Management Checklist for the Treatment of Intracranial dysfunction due to an autonomic response to elevated ICP. Early
Hypertension recognition and treatment of respiratory problems are indispens-
able as respiratory failure and mechanical ventilation are risk
1. Keep physiological variables in normal range. factors for increased mortality, poor neurological outcome, and
longer intensive care unit (ICU) or hospital length of stay (8).
2. Head position (30°elevation); avoid rotation of the head. As a further consequence of TBI, neuroendocrine dysfunction
3. CPP >60 mmHg (50 mmHg lowest acceptable if massive occurs, and consists of pituitary dysfunction and water/electro-
fluid-therapy or high doses of vasoconstrictors are necessary). lyte imbalance. The pituitary gland, its vascular supply, and its
4. Arterial carbon dioxide tension (PaCO2) control (normocarbia, stalk are highly susceptible to trauma, which can result in diabetes
PaCO2 = 35–40 mmHg, if ICP >20–25 mmHg, then induce insipidus. Additionally, TBI may hamper the secretion of antidiur-
short-term hyperventilation: PaCO2 = 30–35 mmHg). etic hormone by hypothalamic neurons causing the syndrome of
inappropriate antidiuretic hormone secretion (SIADH). Diabetes
5. Provide adequate sedation. insipidus and SIADH are usually diagnosed in the first days after
6. CSF drainage if ventricles are still detectable. the trauma and present with hypotonic polyuria. Frequently, the
poor general status of most patients prevents adequate fluid intake
7. Consider mannitol or hypertonic saline.
to compensate these losses, which may result in severe dehydration
8. Consider barbiturate therapy (under EEG monitoring). and hypernatraemia (9).
9. Fever control; consider mild hypothermia. Coagulopathy is often observed after TBI (about 60% in severe TBI,
less than 1% in mild TBI), possibly due to massive release of tissue
10. Consider decompressive craniectomy. factor, altered protein C homeostasis, microparticle upregulation,
152
and platelet hyperactivity. A state of hypercoagulability can be fol- Emergency Room and Diagnostics
lowed by a haemorrhagic state and hyperfibrinolysis (10).
Temperature regulations may be disturbed after TBI and it has In the emergency room setting a head CT is frequently performed
been shown that systemic hyperthermia may induce further brain to decide whether the patient needs surgical intervention or
damage. should be transferred to the ICU. During this period, it is essen-
tial that the physiological parameters are kept constant and that
increased ICP is sufficiently treated. The wide availability, rapid
Cerebral Metabolic Disturbances imaging, and evaluation with a head CT scan support its use as
Ischaemia and metabolic crisis are frequent post-traumatic sec- the primary imaging method. The head CT identifies the pres-
ondary brain insults that negatively influence outcome. In the ence of life-threatening structural lesions caused by the primary
core area of the injury and the traumatic penumbra (the area impact. A CT should be performed in all patients with a GCS of
of hypoperfused tissue that surrounds damaged tissue) brain 14 or lower and in patients with a GCS of 15 in the presence of the
damage results in reduced cerebral blood flow (CBF) and de- following risk factors for intracranial lesions: nausea, vomiting,
creased metabolic rate. An increase in ICP additionally de- severe headache, amnesia, neurologic deficits, injury mechanism,
creases CPP and consequently aggravates hypoperfusion. The age (<4 and >65 years), and therapy with anticoagulants. CT also
autoregulation of the CBF may also be impaired. A combin- provides the detection of secondary injury processes such as brain
ation of arterial hypotension and impaired cerebrovascular oedema, infarctions, and transtentorial herniation. If the patient
autoregulation exacerbates brain ischaemia. Cerebral post- suffers from multiple traumas, a spiral CT of the body should be
traumatic metabolic disturbances have commonly been char- performed. As TBI is a dynamic process, the initial CT requires
acterized by an increase of the lactate/pyruvate ratio above 40, follow-up studies within six to nine hours after trauma (13). About
measured by intracerebral microdialysis. High lactate/pyruvate 25–45% of contusions enlarge in size and 15% of diffuse injuries
ratio is attributed to compromised cerebral perfusion and im- manifest with lesions detectable on CT (14, 15). Magnetic res-
paired oxygen delivery (11). onance imaging (MRI) is more sensitive to detect brain damage;
however, for the immediate emergency most clinics are not ad-
equately equipped to perform an MRI in severely injured and ven-
Management and Treatment tilated patients. In patients with neurological disorders without
The primary injury is not accessible to any treatment and can an adequate correlate in the CT, an MRI should be performed in
only be avoided by preventive measures (e.g., helmets, airbags). the following days, because with this method even minor lesions
Over time, the area of damage expands to the adjunct tissue can be detected.
where cells are more or less injured but can potentially be res-
cued. A cascade of pathophysiological processes trigger cell death Clinical Management
by high lactic acid concentrations due to anaerobic glycolysis, All therapeutic strategies focus on optimization of the delivery of
depleted ATP-stores, increased membrane permeability, exces- oxygen and glucose to the brain cells. This includes maintaining
sive release of excitatory neurotransmitters, increase of intra- adequate CPP, controlling ICP, optimizing the oxygen content of
cellular Ca2+ concentration, and oedema formation leading to the blood and reducing the consumption of oxygen in the brain.
self-destructive intracellular processes. These lead to the gener- There is no ‘magic bullet’ to protect the brain after trauma. While
ation of free radicals, inflammation, and proteolysis. The aim of many interventions have been shown to be protective in experi-
the neuroprotective therapy focuses on limiting secondary brain mental studies, the translation to the clinical setting has generally
injury to minimize the expansion of the primary lesion and save failed, most likely due to the complex pathophysiology of brain
as much brain tissue as possible. damage, the heterogeneous patterns of damage, and various pre-
The next sections describe the treatment of TBI patients, and dis- existing diseases of the patients. Therefore, treatment should focus
cuss pre-hospital management, treatment in the emergency room, on the control of an elevated ICP and the maintenance of a cere-
diagnostics, the operating room, and the ICU. bral homeostasis (i.e., normoxia, normocapnia, normotension,
normovolemia, normoglycaemia, normothermia). A basic aim in
Pre-Hospital Management patients with severe TBI, after addressing the surgical evacuation
The pre-hospital management of TBI can have a major influence on of intracranial mass lesions, is the insertion of an ICP probe to
outcome, which is determined by the time until help is provided, monitor the ICP.
by the type and quality of care received, by the time until the pa-
tient is transported to a hospital, and by the quality of the hospital. ICU Management
Pre-hospital trauma care has to be started as soon as possible. Poor In the critical care setting, the management of TBI patients should
outcome has been associated with hypotension (systolic blood pres- follow established protocols with a close monitoring of parameters,
sure <90 mmHg) and hypoxia/hypoxaemia (O2 saturation <90% or including CPP, ICP, and oxygenation status (16). Clinical standard
PaO2 <60 mmHg) after severe TBI as independent, but possibly assessments like blood pressure, heart rate, skin turgor, mucous
preventable, risk factors (12). At the same time, TBI patients should membrane hydration status, urine output, and GCS have to be con-
be transported to the nearest hospital (neurotrauma centre) that is stantly monitored. Depending on the severity of the trauma, tran-
CT equipped and has a neurosurgical department for a definitive sient headaches, dizziness, or nausea can occur after a mild TBI
diagnosis and for a possible decompressive craniotomy in case of and further deteriorate, leading to unconsciousness and coma.
increased ICP. All patients with multiple traumas should be treated Ominous signs include dilated pupils with no reaction to light, par-
as having a cervical spine injury and a collar should be applied. esis, or abnormal extension/flection to painful stimuli. Chapter 23
153
in this volume presents a detailed overview of ICU management of advanced airway management and concentrate on bag-valve-mask
TBI patients. ventilation.
Oxygenation and Ventilation Choice of Anaesthetic Agents

Adequate oxygenation and normoventilation have to be achieved as Anaesthesia in non-fasting patients and for emergency proced-
hypoxaemia and hypercapnia are known to further exacerbate sec- ures should be accomplished by rapid sequence induction (RSI).
ondary injuries (17). The optimal oxygen tension for TBI patients The choice of anaesthetic drugs for TBI patients should be mainly
is unclear. An inspiratory oxygen fraction of 1.0 should be avoided based on the personal experience of the practitioner and on in-
as hyperoxaemia may trigger brain injury by hyperoxic cerebral dividual circumstances (22). Traditionally, anaesthetic induction
vasoconstriction, via oxygen radical formation, and inhibition of agents and succinylcholine (alternatively rocuronium, if applic-
metabolic enzymes. Control of pulse oximetry, PaO2, and PaCO2 is able) are administered followed by a rapid intubation without
mandatory as changes will affect cerebral haemodynamics and ICP. mask ventilation (23). There is little evidence base for recom-
Patients with isolated head injury can be managed with traditional mendations when choosing drugs for TBI patients Therefore, the
ventilation strategies, but those with additional chest trauma, as- choice of anaesthetic agents and other adjunctive drugs is based
piration, or massive resuscitation after shock are at high risk for on the consideration of their effects on CBF, cerebral metabolism,
developing acute lung injury. As is more generally true, the use of and cerebral volume. In low concentrations, intravenous and vola-
a large tidal volumes could result in acute lung injury for patients tile anaesthetics suppress cerebral metabolism, which is associated
with isolated head injury and with normal lung function; a tidal with a decrease of CBF due to vasoconstriction. This leads to a
volume of 6 ml/kg BW or less is part of protective ventilation re- decrease of the intracerebral blood volume and, thereby, of ICP.
commendations. A plateau pressure of 30 cm H2O is considered as While intravenous anaesthetics linearly further decrease ICP in
a safe limit to protect from ventilator induced lung injury (18, 19). higher concentrations, volatile anaesthetics possess a direct vaso-
The use of PEEP levels up to 10–15 cmH2O and inverse ratio ven- dilatory effect, which increases CBF, increases CBV and, thereby,
tilation seem to be safe in patients with intracranial hypertension increases ICP. Desflurane shows the strongest vasodilatory effect,
and severe chest trauma (20). while sevoflurane has the least. Nevertheless, if the ICP is in-
Capnometry/-graphy is the gold standard for ensuring ad- creased in TBI patients, volatile anaesthetics should be replaced by
equate ventilation during mechanical ventilation and is effective intravenous anaesthetics such as propofol. Care should be taken
for preventing hypocapnia and hypercapnia as well as hypoven- that the MAP does not decrease during general anaesthesia; hypo-
tilation and hyperventilation. While hypocapnia (end-tidal CO2 tension should be treated using vasoconstrictors and fluid therapy.
<35 mmHg) induces cerebral vasoconstriction, reduced CBF, and Nitrous oxide should be avoided in all TBI patients. Barbiturate
hypoxia, hypercapnia results in vasodilatation, increases CBF/ application increases infection rates (24). Barbiturates decrease
volume, and ICP. Mechanical ventilation is crucial in all head-injury cerebral metabolism and reduce CBF, causing a decrease in CBV
patients with high ICP. If an acute brain stem herniation is immi- and a decrease in ICP. The administration of barbiturates is gen-
nent, hyperventilation can be a life-saving intervention. Apart from erally reserved for the refractory intracranial hypertension when
this indication, hyper-as well as hypoventilation have to be avoided other therapies have failed (6). In many countries etomidate is
as CBF can be reduced at a time when it already be compromised, avoided for anaesthesia as it has inhibitory effects on steroid gen-
risking cerebral ischaemia contributing to secondary brain injury. esis, even after a single administration. Ketamine was suggested
A pneumo-or haemothorax has to be immediately treated. to be contraindicated in TBI patients due to perceived risks of
intracranial hypertension, but in intubated and ventilated patients
Airway Management ketamine has no adverse effect on ICP. Additionally, ketamine
While an isolated brain trauma per se does not necessarily lead to stabilizes MAP and the amount of vasopressors can be decreased.
airway obstruction, severely limited levels of consciousness may It also fosters bowel movement and leads to bronchodilatation,
lead to airway obstruction due to displacement of the tongue or the which is desirable for the treatment of TBI patients in the ICU.
soft palate. Unconsciousness is also associated with compromised Furthermore, in haemodynamically unstable patients, it may be
protective airway reflexes, which put the patient at increased risk the drug of choice because of fast onset and excellent analgesic
of aspiration of gastric contents and blood. Additionally, head in- effects and duration (25). Narcotics, like sufentanil, fentanyl, and
jury can induce apnoea. Other concomitant injuries such as chest remifentanil have no negative effects on ICP as long as MAP, and
trauma can also contribute to hypoxaemia. In adult patients with thereby CPP, is maintained. Muscle relaxants can be used in TBI
severe TBI (GCS score ≤8), an endotracheal intubation via rapid patients, with a potential exception of succinylcholine, which pos-
sequence induction is indicated, when the staff is appropriately sibly increases ICP.
skilled and trained. Expected times for transportation of the pa-
tient should be considered, as oesophageal intubation, aspiration, Cardiovascular Stabilization and Fluid Management
and circulatory effects of hypnotic drugs may complicate patient Primary interventions have to include maintenance of the mean ar-
management and can result in life-threatening situations, when terial blood pressure to guarantee an optimal CPP by an adequate
performed by an inexperienced team (21). When a pre-hospital fluid resuscitation, control of active haemorrhage, and vasocon-
endotracheal intubation cannot be performed at a high standard, strictor application. Normovolemia is the intended fluid manage-
basic airway management should be the mainstay of treatment. ment goal. In poly-traumatized TBI patients the suggested benefits
A less-experienced team should be trained in using alternative of permissive hypotension and limited fluid resuscitation have to be
supraglottic devices as their first choice airway device. Lastly, res- balanced with the adverse consequences of cerebral hypoperfusion.
cuers with only occasional experience should avoid pre-hospital As blood products are not available at the pre-hospital setting,
154
isotonic or hypertonic crystalloid and colloid solutions may be ap- hematocrit and blood viscosity, and increases CBF and cerebral
plied to maintain adequate intravascular volume. oxygenation delivery. These rheologic effects might explain the
The intact blood-brain barrier (BBB) is not permeable to ions early decrease of ICP. Both osmotherapeutics increase the osmotic
and, therefore, osmotic pressure can be leveraged to avoid cerebral gradient across plasma and brain compartments due to the BBB,
oedema. In TBI patients the injured brain tissue becomes more sen- which is not permeable for ions, and thereby, withdraw water from
sitive to changes in the intravascular volume state and the plasma brain tissue.
osmolality, as the damaged BBB shows an increased permeability. ◆ Mannitol 20% should start with an intravenous bolus 0.5
Therefore, volume and the composition of intravenous solutions g–0.75g/kg BW over 15 to 30 minutes (max. 4–6 times/day).
must be considered in terms of their effect on the disrupted physi- Mannitol concentrations greater than 15% have a tendency to
ology and their likely impact on patient outcome. In addition to crystallization. It should be intravenously applied by using a
fluid resuscitation therapy in polytraumatized patients given to filter-type administration set. Mannitol may precipitate acute
stabilize MAP and CPP, TBI patients also receive osmotically ac- renal failure when serum osmolarity exceeds 320 mOSm/l
tive fluids, aiming to decrease cerebral swelling and secondary through intrarenal vasoconstriction combined with intravas-
brain injury from decreased oxygen delivery related to decreased cular volume depletion. Mannitol should be administrated
CBF. Beneficial effects on the outcome of TBI patients by hyper- as repeated boluses rather than continuously, only in patients
tonic fluid administration are controversial (26, 27). In theory, with increased ICP and serum osmolarity has to be monitored
hypertonic solutions have a positive effect on ICP by producing closely.
an osmotic gradient between the intracellular/interstitial and the
intravascular compartments. Only iso-and hypertonic solutions ◆ Hypertonic saline 7.5–10% therapy should start with an intra-
should be infused in TBI patients. Even Ringer’s lactate solution venous bolus 3 ml/kg BW up to 250 ml/day. Hypertonic saline
is slightly hypotonic and should be avoided in larger amounts. may be preferred in settings which require fast cardiovascular
Glucose solutions also become hypotonic as soon as the glucose is resuscitation of an associated haemorrhagic shock because a
metabolized. Therefore, only high concentrations of glucose solu- small-volume bolus results in volume expansion without diur-
tions (e.g., 40%) with low volume should be used for the treatment etic effects. Complications with hypertonic saline include severe
of low plasma-glucose levels. There is no outcome benefit for TBI hypernatraemia, volume overload, and osmotic demyelination
patients when treated with any colloid, and resuscitation with 4% syndrome.
albumin has been shown to increase mortality in this population Several studies have shown that hypertonic saline is equal or
(compared with 0.9% saline in the SAFE trial) (28). In regions with even superior to mannitol in reducing ICP (30, 31). One risk
an intact BBB this gradient may result in shrinkage of swollen cells. of hyperosmotic agents is the rebound effect, which might in-
Hydroxyethyl starch and dextran administration may negatively increase ICP, which might take place when the BBB is ruptured
fluence blood coagulation. to a great extent. As mannitol is entirely excreted in the urine
there is risk of acute tubular necrosis, particularly if serum
ICP Management osmolarity exceeds 320 mOsmol/l. Therefore, plasma osmolarity
Sustained intracranial hypertension, defined as an ICP >20 mmHg has to be monitored during therapy with hyperosmotic agents.
for a period of more than five mintues, worsens neurologic out- While furosemide itself has only a minimal effect on ICP, in
come in TBI and therefore should be treated promptly. Therefore, combination with mannitol it enhances the effects of mannitol
the ICP should be kept below 20–25 mmHg, as a high ICP is a on plasma osmolality, resulting in a greater reduction of brain
powerful predictor of neurological deteriorations. In TBI patients water content. Furosemide can, therefore, be recommended as
who receive mechanical ventilation and ICP monitoring, at least supplemental treatment. Diuretic effect may lead to electrolyte
one episode of ICP of more than 20 mmHg occurs in 50% (2). CPP disturbances, hypovolaemia, and hypotension which can be un-
should be kept higher than 60 mmHg by maintaining an adequate desirable in trauma patients.
MAP. All factors that aggravate or precipitate elevated ICP should Hyperventilation
be avoided. Box 12.1 provides a check list for the emergency man-
Hyperventilation (low arterial PaCO2) increases pH in the extra-
agement of intracranial hypertension.
cellular space, constricts cerebral blood vessels, decreases CBV
Head Position and CBF, and thereby rapidly reduces ICP, while it has no effect on
Head elevation at 15–30° can lower ICP without adversely affecting cerebral metabolism. In patients with increased ICP CBF might
MAP or CPP. However, elevation >40° may decrease CPP (29). already be reduced to a critical threshold of 18–20 ml/100 g/min,
When head elevation is used, the pressure transducers for blood while the metabolic demand is maintained. Hyperventilation
pressure and ICP must be zeroed at the same level (at the level of would further reduce CBF and aggravate the flow-metabolism
the foramen of Monroi) to assess CPP accurately. The head should imbalance leading to cerebral ischaemia. Furthermore, the ef-
be placed in a neutral midline position to avoid obstruction of cere- fect of hyperventilation on ICP is only transient, because the
bral venous outflow. extracellular space of the brain rapidly accommodates to the
pH change induced by hyperventilation. Therefore, the only role
Osmotic Drugs that mild hyperventilation (PaCO2=30-35 mmHg) plays is the
The administration of osmatic drugs has become first choice for management of acute elevations in ICP. Under these circum-
pharmaceutical ICP reduction and is recommended as a guideline. stances, hyperventilation can be life-saving and can temporize
The commonly used osmotherapeutics—mannitol and hypertonic until more definitive treatment of intracranial hypertension can
saline—have an immediate plasma-expanding effect that reduces be undertaken.
15
Barbiturate Therapy Neuroprotective Interventions

Barbiturates appear to exert their ICP lowering effects through Neuroprotective Drugs
vasoconstriction with reduction of CBF and CBV secondary to During the last 40 years, over 100 potential neuroprotective drugs
suppression of cerebral metabolism (32). Adversely, for every four have been tested in clinical trials including anti-inflammatory
patients treated with barbiturates, one will develop hypotension. drugs (e.g., corticosteroids), anti-excitotoxic substances (e.g.,
Additionally, barbiturate application results in a fall in body tem- NMDA-inhibitors), Ca2+-antagonists, antioxidants, anti-apoptotic
perature and is an independent risk factor of early onset pneumonia drugs, progesterone, and erythropoietin (44–46). Unfortunately, al-
after TBI (33). Barbiturates can control ICP in haemodynamically though most of these drugs were neuroprotective in experimental
stable patients when other treatments have failed, but there is no studies, these results could not be translated to clinical TBI patients
evidence that barbiturate therapy in patients is associated with re- (47). However, in retrospective analysis of cohorts, it was realized
duction in death and disability (34). that the physiological variables did influence the outcome of TBI
patients. Therefore, there is a consensus that physiological variables
Hypothermia
should be kept in a normal range.
Mild hypothermia can be used to control elevated ICP, but it
possibly has no influence on outcome of the TBI patient (35). Normoglycaemia
Hypothermia may induce more severe complications (e.g., mul- High and low blood glucose concentrations deteriorate neuro-
tiple organ failure, impairment of coagulation, arrhythmia). logical outcome after TBI. Therefore, it is reasonable to keep the
During therapeutic hypothermia, patients are especially at risk of blood glucose concentration in a range of 110–150 mg/dl. This has
impaired haemodynamics and, therefore, careful management of been suggested to be the optimal range for critical care patients
CPP is essential during hypothermia. The routine application of (48, 49).
hypothermia cannot be recommended at present. While the indi- Normotension and Normovolaemia
cation of hypothermia is unclear, it is evident that hyperthermia High amounts of fluids and vasopressors are associated with a
should be avoided. sevenfold higher risk of developing ARDS. Therefore, if such inter-
Ventricular Drains ventions are necessary to keep the lower level of CPP over 60 mmHg
Ventricular drains can drain fluid from the ventricles of the brain it is acceptable to reduce CPP to 50 mmHg. After TBI, cerebrovas-
and keep them decompressed. cular autoregulation is often impaired, and cerebral perfusion then
becomes directly dependent on the systemic pressure and resultant
Decompressive Craniectomy CPP. Therefore, CPP should be kept above 50 mmHg to avoided
Decompressive craniectomy is a surgical procedure used to con- cerebra ischaemia. If cerebrovascular autoregulation is impaired,
trol severely elevated ICP and to prevent herniation after severe a CPP above 70 mmHg might lead to hyperaemia and oedema
traumatic brain injury or stroke. Ultra-early intervention with formation. Finally, as the status of cerebrovascular autoregulation
decompressive craniectomy under ICP monitoring before neuro- cannot be easily assessed and also changes over time, it is recom-
logic conditions become worse may reduce the mortality rate, mended to keep CPP between 50–70 mmHg.
increase the rate of recovering consciousness, and improve neuro- Normocapnia and Normoxaemia
logic outcomes of malignant middle cerebral artery infarction (36). One of the main targets of the treatment of TBI patients is to avoid
In severely head injured trauma patients with a very high risk of hypoxia. Therefore, the SaO2 should be kept above 96%. As the
brain death, decompressive craniectomy allowed 25% of patients paCO2 regulates CBV, hypercapnia should be avoided as it might
to attain social rehabilitation after 1 year (37). Results of surgical elevate ICP. Hypocapnia can be initiated for a short period to con-
treatment in patients <50 years of age undergoing decompressive trol for high ICP, but should be normalized as soon as possible.
craniectomy are even more encouraging (38). Especially in chil- Normothermia
dren with severe head trauma, early decompressive craniectomy
Several clinical multicentre trials failed to prove a protective ef-
with duraplasty favourably improves outcome in all patients
fect of hypothermia in TBI patients. However, there is an associ-
after severe traumatic brain injury (39, 40). In adult TBI patients,
ation between hyperthermia and worse neurological outcome after
bifrontotemporoparietal decompressive craniectomy decreased
severe TBI. It is suggested that fever reduction improves brain
ICP and the length of stay in the ICU, but was associated with more
metabolism, but there is little direct proof in humans that the rela-
unfavourable outcome (41). As methodological problems have
tionship between fever and exacerbation of brain injury is causal.
been discussed in context with the DECRA trial, decompressive
Even though there is evidence base, targeted normothermia is a
craniectomy should be still part of the therapy when it is indi-
commonly accepted goal in clinical management of TBI patients
cated and when the patient may still have a chance of an improved
(50, 51).
functional outcome (42). Decompressive craniectomy should only
be performed in patients younger than 50 years without multiple Anticoagulation
trauma, or in patients with an age below 30 years despite major Anticoagulation therapy in TBI patients is based on practical
extracranial injuries, diffuse axonal injury, or brain stem injury. decision-making and on expert opinion. TBI patients have a
Additionally, severe brain swelling should be apparent on head high risk of thromboembolic events due to a highly activated co-
CT. A primary brainstem lesion or injury should exclude this pro- agulation pathway and immobilization of patients under deep
cedure. The craniectomy should be performed in an interval up sedation. Therefore, these patients should receive compression
to 48 hours after the accident and before irreversible brainstem stockings together with low molecular weight heparin or low dose
damage or generalized brain damage has occurred (43). unfractionated heparin. The Parkland Protocol, which is based on
156
the modified Bernwood criteria, can be used to determine the time of oral anticoagulants can be justified three days after injury.
to start anticoagulation therapy with heparin. The Bernwood cri- However, the optimal time for oral anticoagulation resumption
teria are used to estimate the probability that the initial bleeding will seems to be seven to ten days after injury. The most commonly
expand. If the Bernwood criteria are positive, no anticoagulation used measurements of coagulation are provided by prothrombin
should be initiated. If there is no progression of the bleeding in the time, activated partial thromboplastin time, and International
control head CT 24 hours after injury, then anticoagulation therapy Normalized Ratio. Viscoelastic tests like thromboelastography
can be started (see Figure 12.2). If there is a progression after 24 or thromboelastometry (e.g., ROTEM system) can be easily per-
hours, the head CT should be repeated at least after 72 hours and formed in whole blood and provide additional information about
then the start of anticoagulation therapy should be reconsidered, the steps of fibrin formation and fibrinolysis, if applicable.
assuming there is no sign of progression of the trauma (52).
Neuromonitoring
Patients with atrial fibrillation, deep venous thrombosis, arti-
ficial heart valves, stroke, and myocardial infarction and after The following parameters have to be checked continuously in treat-
stent-implantation routinely receive anticoagulation therapy. ment of TBI patients, and have to include an initial evaluation of
These patients have a higher risk of haematoma expansion after the neurologic conditions by checking:
TBI, which is associated with a higher mortality (53). In these ◆ GCS score;
patients, the oral anticoagulants have to be terminated and the ◆ Pupillary response (size, symmetry, light reflex, accommodation);
anticoagulant effect should be reversed using prothrombin com-
plex concentrates (PCCs) or fresh frozen plasma (FFP); direct ◆ Motor/sensory function.
thrombin-inhibitors or Factor Xa antagonists; when a patient is Pupillary response may have prognostic value in TBI patients.
taking antiplatelet drugs, transfusion of thrombocytes should A unilaterally dilated pupil suggests the presence of a mass le-
be performed (54). Discussions about the patient starting sion. Abnormally dilated and nonreactive pupils are strongly
anticoagulation with heparin can occur after the patient stabilizes associated with a poor neurologic outcome (but dilated pupils
and the activity of the anticoagulant drugs has declined. The re- may also be present after administration of drugs, e.g., epi-
sumption of anticoagulation therapy is a very challenging task nephrine). The initial GCS, the mechanism of the injury, and
that has to be individually balanced, because there is only a small the progression has to be noted until the patient arrives in the
range for optimal therapy. New oral anticoagulants decrease the emergency room. Additionally, a body check for injuries of other
rate of post-traumatic bleeding and are therefore recommended organs has to be immediately performed. Acute intrathoracic,
as a safer option compared with coumarins (e.g., warfarin). intraperitoneal, and intrapelvic bleeding may lead to an abrupt
In patients at high risk for thromboembolism, a resumption haemorrhagic shock.
TBI
Yes
Craniotomy/ICP monitoring?
No
Any criteria?
No - Subdural/Epidural haematoma >8 cm
- Contusion/Haemorrhage >2 cm
- Multiple contusions/lobes
- Subarachnoid with abnormal CT-angiogram
Yes
Repeat CCT-scan (24 hours) No

Moderate Risk TBI
stable?
Yes
No
Repeat CCT-scan (72 hours)
Low Risk TBI High Risk TBI
stable?
Yes
Initiate anticoagulation Initiate anticoagulation Consider

24 hours after trauma 72 hours after trauma prophylactic filter
Figure 12.2 Modified Parkland Protocol. Algorithm for anticoagulation therapy after TBI.

Adapted from Journal of Neurotrauma, 29, 10, Phelan HA. Pharmacologic venous thromboembolism prophylaxis after traumatic brain injury: A critical literature review, pp. 1821–1828. The
publisher for this copyrighted material is Mary Ann Liebert, Inc. publishers © 2012.
157
As the morbidity and mortality after TBI correlates with the Transcranial Doppler Sonography (TCD)
incidence of complications, the prognosis can be improved by Using an ultrasound probe, TCD technique is used to measure
clinical neurological examination and close neuromonitoring of the blood flow velocity of mean cerebral arteries of the base of the
adverse events. This includes the detection of factors triggering brain. It combines ultrasound and the Doppler principle to measure
hypoxic or ischaemic episodes. The monitoring of ICP seems to erythrocyte flow of basal cerebral arteries. The quality of the TCD
be the most important method to individually adapt the therapy signal is investigator-dependent and correct interpretation requires
to the TBI patient. The examining physician should take into training. TCD helps to assess cerebrovascular autoregulation and
account the effects of sedative drugs, which may markedly influ- estimate CPP. High-normal values of CBF velocity may indicate
ence neurological responses. Neurophysiologic monitoring like hyperaemia or vasospasm. Some studies have shown that cere-
electroencephalography (EEG) and evoked potentials (EP), as brovascular autoregulation may be impaired during the first days
well as control of cerebral perfusion using transcranial Doppler after TBI.
sonography (TCD) or laser Doppler flowmetry (LDF) are useful
Invasive Neuromonitoring
to assess the function and the blood supply of brain tissue. As
oxygenation of the cerebral tissue is one of the major goals of TBI ICP Monitoring
therapy, it is often useful to measure brain tissue oxygenation ICP monitoring is indicated for TBI patients at high risk for intra-
(PtiO2) directly with an intraparenchymal probe. Alternatively, cranial hypertension, i.e., patients with a GCS <8 and pathology
oxygenation of brain tissue can also be assessed by near infrared identified by neuroimaging—this includes mass lesions due to
spectroscopy (NIRS) or by measurement of the oxygen saturation haematoma, contusion, oedema, midline shift, and compressed
in the jugular bulb. However, both of these methods have their basal cisterns. In patients with a normal admission head CT, an
disadvantages and, therefore, cannot be recommended as routine ICP monitor is recommended if the patient´s age is >40 years, the
monitoring for TBI patients. Cerebral microdialysis allows the patient shows unilateral or bilateral motor posturing, or episodes of
measurement of markers or cell integrity, metabolism, and oxy- systolic blood pressure (BP) <90 mmHg. The gold standard for ICP
genation. However, due to its need for high maintenance it is not measurement is the intraventricular probe using a ventriculostomy,
often used. because of its accuracy and the possibility of therapeutic fluid
drainage. Intraparenchymal probes also deliver reliable values,
Non-Invasive Neuromonitoring while epidural probes should not be used (56). Measurement of
Pupillary Response the ICP is recommended in many guidelines for an adequate treat-
For assessment and management of ICP, the pupillary response has ment of TBI patients. Unfortunately, no randomized prospective
to be checked for size, symmetry, light reflex, and accommodation multicentre clinical trial has proven that measurement of ICP im-
in very short intervals until an ICP probe is implanted. Fixed and proved patient outcome. However, from a pathophysiological per-
dilated pupils in comatose patients that are not caused by drug ac- spective, measurement of ICP is a useful parameter for treatment
tion or a local trauma indicate compression or injury of the third decisions in order to detect herniation and brain shifts. The CPP,
cranial nerve due to an extending intracranial mass lesion or by which is necessary for an adequate cerebral perfusion, can only be
diffuse brain injury. Fixed and dilated pupils in comatose patients calculated if ICP is known. In patients with TBI the ICP should be
are well known to be related to a poor prognosis, especially when kept below 20–25 mmHg to maintain CPP between 60–70 mmHg.
present bilaterally (55).
Near Infrared Spectroscopy (NIRS) is a non-invasive technique to Brain Tissue Oxygenation (PtiO2)
determine regional cerebral tissue oxygen saturation. This tech- The partial pressure of oxygen in the cerebral interstitium is in-
nique uses principles of optical spectrophotometry that makes vasively measured by a flexible microcatheter (polarographic
use of the fact that biological material (skull) is relatively trans- Clark-type microelectrode or an optical fluorescence probe) dir-
parent in the NIR range measuring changes of oxyhaemoglobin, ectly inserted into the white matter. The catheter should be placed
deoxyhaemoglobin over the combined arterial, capillary and into non-traumatized tissue as assessed on CT scan. A PtiO2 of
venous compartments. The technique is insufficiently validated for <10 mmHg for longer than 15 minutes is an independent predictor
routine use in TBI. of worse outcome. If PtiO2 is <15 mmHg, therapeutic interventions
to optimize cerebral oxygen delivery include CPP augmentation,
Electroencephalography (EEG) red blood cell transfusion in the setting of concomitant anaemia,
The EEG is a non-invasive and continuous measurement of the and normobaric hyperoxia (57).
spontaneous electrical brain activity. The signals mainly represent
the synaptic activity of cortical neurons, and therefore can be used
for monitoring of the neuronal integrity and a surrogate parameter Summary
for cerebral metabolism. Continuous EEG monitoring also helps Severe TBI is a leading cause of death and long-term disability, with
to detect seizures. In critically ill patients, seizures are often non- a substantial public health impact. The major goal of the manage-
convulsive and may aggravate brain injury. ment of patients with TBI lies in the prevention of secondary brain
Evoked Potentials (EPs) are measured on the scalp as evoked EEG damage. Prompt and adequate therapy is necessary: appropriate
responses to an electrical stimulus. This stimulus is applied to the management of respiration, circulation, metabolism, and fluid
median or tibial nerves. EPs are less disturbed by sedative agents or replacement are essential for the long-term outcome of these pa-
hypothermia than EEG. Somatosensory EPs are very good single tients. Prolonged intracranial hypertension and decreased cerebral
prognostic indicators after TBI to predict poor or favourable prog- perfusion results in irreversible brain damage and should be imme-
nosis. Bilateral absence of EPs is often associated with poor clinical diately treated. The management of TBI starts in the pre-hospital
prognosis and outcome. setting. Anaesthetists take care of TBI patients throughout the
158
peri-operative period—in the emergency room, during operative 19. Beckers SK, Brokmann JC, Rossaint R. Airway and ventilator
procedures, and at the ICU. Therefore, they have an important role management in trauma patients. Current Opinion in Critical Care.
to improve patient outcome and prognosis. 2014;20(6):626–31.
20. McGuire G, Crossley D, Richards J, Wong D. Effects of varying levels of
positive end-expiratory pressure on intracranial pressure and cerebral
Cases perfusion pressure. Critical Care Medicine. 1997;25(6):1059–62.
21. Davis DP, Koprowicz KM, Newgard CD, Daya M, Bulger EM, Stiell I,
Q Interactive cases to test your knowledge on this chapter can
et al. The relationship between out-of-hospital airway management and
be found in the online appendix at www.oxfordmedicine.com/ outcome among trauma patients with Glasgow Coma Scale Scores of 8
otneuroanesthesiology. or less. Prehospital Emergency Care. 2011;15(2):184–92.
22. Brain Trauma Foundation, American Association of Neurological
Surgeons, Congress of Neurological Surgeons, Joint Section on
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16
CHAPTER 13
Supratentorial Craniotomy
for Mass Lesion
Shaun E. Gruenbaum and Federico Bilotta
Introduction majority of malignant brain tumours (80%). Brain tumours result

in significant morbidity and mortality, and account for approxi-
The anaesthetic management of the patient undergoing craniotomy mately 12,000 deaths per year in the United States alone. The rela-
for supratentorial mass requires an in-depth understanding of the tively limited number of craniotomy procedures for supratentorial
pharmacology of anaesthetic agents and the principles of neuro- mass requires that anaesthetists undergo subspecialty training to
pathophysiology. The peri-operative goals for craniotomy for adequately care for these patients. This fact was highlighted by re-
supratentorial tumour are to provide a smooth and haemodynam- cent large observational study, in which procedures performed in
ically stable induction and maintenance, to maintain adequate high-volume, academic centres had a lower postoperative mortality
cerebral perfusion pressure (CPP) (>70 mm Hg) and oxygenation, rate than procedures performed in small-volume centres (4).
employ techniques that will optimize surgical exposure, achieve
a rapid recovery and neurological examination upon emergence,
and achieve adequate postoperative pain control (1). Because there Pre-Operative Considerations
are few randomized clinical trials that guide the decision-making
process for these patients, a combination of applied theory and ex-
History and Physical Examination
pert consensus primarily guides anaesthetic management (2). This Planning the appropriate anaesthetic approach requires a thorough
chapter reviews the anaesthetic considerations for patients under- knowledge of the patient’s history and general state. A focused his-
going craniotomy for supratentorial mass lesion. tory and physical examination provides important information
regarding the patient’s peri-operative risk of undergoing a crani-
otomy for supratentorial mass, and is therefore an important com-
Epidemiology ponent of the pre-operative assessment (see Box 13.1).
In developing the appropriate anaesthetic plan for craniotomy for In addition to a standard pre-operative exam (cardiopulmonary,
supratentorial mass lesion, knowledge of the anatomical location, airway, etc.), special attention should be given to the neurological
size, and histology is of great importance. According to the Central history and physical. A major goal of the pre-operative assess-
Brain Tumor Registry of the United States, more than 340,000 pri- ment is to determine the suspected intracranial pressure (ICP),
mary brain and CNS tumours were reported between 2007 and 2011, and approximately how much reserve remains for ICP and cere-
with 64,000 new cases diagnosed in 2011 alone (3). Approximately bral blood flow (CBF) before cerebral ischaemia and neuro-
one-third of tumours were malignant. Men presented with 42% logical impairment ensues (5). Any pre-existing neurological
of tumours overall and 55% of malignant tumours. Of these tu- deficits should be carefully documented, and compared with any
mours, 80% were supratentorial (they occurred in the cerebral postoperative deficits to determine if they are new. Patients with a
hemispheres above the tentorium of the dura). Supratentorial tu- history of seizures should be asked about the frequency of seizure
mours are often incidental findings, or depending on anatomical and the date of the last known seizure. Patients on chronic anti-
location, may grow to a large size before they produce symptoms. epileptic medications (especially sodium valproate) often have
Infratentorial tumours involving the cerebellum and brain stem, in elevated serum liver enzymes, and some experts recommend that
contrast, typically produce symptoms at a smaller size. The annual liver enzymes be evaluated prior to surgery (6). It is particularly
incidence of primary brain and central nervous system (CNS) tu- important to ask about any auras associated with the seizures, so
mours is 28 per 100,000 adults over the age 20, and the median age it can be recognized and promptly treated if experienced in the
of diagnosis is 59 years. peri-operative period.
The most frequent tumour type is the non-malignant men- Brain perfusion and oxygenation is largely dependent on the
ingioma (36%), followed by the malignant glioblastoma (16%), pi- patient’s cardiovascular and respiratory status. Therefore, these
tuitary tumours (15%), and all other malignant gliomas (11.7%). organ systems should be carefully evaluated prior to surgery.
Both meningiomas and glioblastomas are more common in older Cardiac conduction deficits may result from increased ICP (i.e.,
ages than younger ages. Overall, while gliomas account for only bradycardia and hypotension), and should be noted. Patients with
29% of all primary brain and CNS tumours, they make up the malignant tumours often have coagulation disorders, and may
162
before or after induction of general anaesthesia should be deter-

Box 13.1 Pre-Operative Considerations in Supratentorial
Craniotomy mined on an individual basis, depending on how the patient is ex-
pected to tolerate the induction period.
◆ Planning the appropriate anaesthetic approach requires a thor- The risks of bleeding during craniotomy depend greatly on the
ough knowledge of the patient’s history and general state. depth, size, histology, and proximity of the mass to major blood
vessels. The anticipated risks of bleeding should always be discussed
◆ In addition to a standard pre-operative exam (cardiopul- with the surgeon prior to craniotomy. All patients undergoing cra-
monary, airway, etc.), special attention should be given to the niotomy for supratentorial tumour should have two large-bore
neurological history and physical. intravenous lines placed. Unanticipated blood loss to the point of
◆ The decision of whether to use anxiolytic premedication haemodynamic instability is uncommon, and therefore a central
should be considered on an individual basis depending a par- venous catheter is rarely indicated. If there is a high risk of intra-
ticular patient’s proposed risks and benefits. operative bleeding suspected, or if it is anticipated that centrally
acting vasopressors will be administered, the placement of a central
◆ The anticipated risks of bleeding should always be discussed
venous catheter should be considered.
with the surgeon prior to craniotomy.
Pre-operative placement of a central venous catheter should also
◆ Pre-operative placement of central venous catheter should be considered in patients at high risk for venous air embolism, espe-
also be considered in patients at high risk for venous air em- cially when craniotomy is performed in the sitting position. A cen-
bolism, especially when craniotomy is performed in the sitting tral venous catheter can be used to aspirate air that is entrapped in
position. the right atrium. A multi-orifice catheter is thought to be superior
to a single-orifice catheter in aspirating air, and should be placed
with the tip 2 cm below the junction of the superior vena cava and
require low molecular weight heparin after craniotomy to prevent right atrium. Some authors recommend the jugular approach as the
thromboembolism (5). first choice when placing a central venous catheter, because it has
the least potential for unintended injury (5). However, others have
Premedication argued that the internal jugular vein should be avoided because of
The decision of whether to use anxiolytic premedication should be the potential risk of impeding venous drainage of the brain and for
considered on an individual basis depending a particular patient’s presenting limited surgical positioning (2). Although a subclavian
proposed risks and benefits. In most patients, a small dose of central venous catheter may interfere less than a jugular venous
carefully titrated midazolam or fentanyl before induction can be catheter, it carries a high risk of unintended injury such as pneumo-
beneficial and safely administered. Premedication is effective in re- thorax, which can increase the CO2. Therefore, a subclavian ap-
ducing patient anxiety and preventing the negative effects of stress- proach should be considered a last-choice option.
induced tachycardia and hypertension on cerebral metabolic rate
(CMR) and CBF. Intra-Operative Management
Patients with increased ICP deserve special consideration and
caution. Sedation may result in a slowed respiratory pattern, which Induction
may lead to increased pCO2, upper airway obstruction, and hypox- A stable induction of general anaesthesia for supratentorial cra-
aemia. These effects may cause a sudden and extreme increase in ICP, niotomy should be achieved with minimal changes in heart rate
resulting in a rapid deterioration of the patient’s neurological status. and blood pressure, and avoidance of hypercarbia and hypoxaemia
Furthermore, the use of midazolam may result in postoperative de- (Box 13.2). Some anaesthetists recommend a slow and controlled
lirium and a change in the patient’s neurological exam. This is es- induction with propofol to minimize its hypotensive effects. In
pecially important in the elderly population. Therefore, in the event elderly or frail patients, etomidate may be a suitable alternative to
of a change in neurological status, it may be difficult to distinguish propofol for induction. Fentanyl or sufentanil premedication can
the effects of the medication from a worsening mass effect. When be particularly useful in reducing the amount of propofol required
sedating medications are administered, the patient should never be for induction of anaesthesia (7).
left unsupervised and the anaesthetist should always be prepared to Laryngoscopy and tracheal intubation has a profoundly stimu-
provide emergency airway management if needed. lating effect associated with increased arterial blood pressure
(ABP), heart rate, and ICP. The sympathetic response to laryngos-
Intravascular Access and Monitoring copy should be anticipated and prevented with intravenous opi-
All patients undergoing craniotomy for supratentorial mass lesion oids in the patient with supratentorial mass by providing adequate
should have standard monitoring, including electrocardiogram analgesia. Intravenous and tracheal lidocaine should also be con-
to detect abnormalities in cardiac rate, rhythm, or myocardial is- sidered. In the event of severe hypertension on laryngoscopy, the
chaemia, pulse oximetry to detect hypoxia, end-tidal carbon di- patients’ pupils should be assessed to rule out a possible brainstem
oxide (ETCO2) to detect trends in the partial pressure of dissolved herniation.
carbon dioxide (PaCO2) and detection of venous air embolism,
temperature monitoring, and monitoring of urine output. In pa- Muscle Relaxation
tients undergoing craniotomy, an arterial line should always be Patient movement during craniotomy for supratentorial mass
placed to measure continuous blood pressure, and to allow for fre- can be extremely dangerous, particularly when the patient’s head
quent arterial blood gas measurements, including PaCO2, glucose, is fixed in cranial pins. When there are no contraindications, the
and hematocrit. The decision of whether to place the arterial line use of a non-depolarizing muscle relaxant may be useful to achieve
163
Chapter 13 supratentorial craniotomy for mass lesion 163
relaxants. Remifentanil is especially useful in this context because

Box 13.2 Intra-Operative Considerations in Patients Undergoing
Supratentorial Tumour Craniotomy of its short half-life and predictable analgesic effects.
Insertion of Cranial Pins
◆ A stable induction of general anaesthesia for supratentorial
craniotomy should be achieved with minimal changes in heart Head fixation in a stereotaxic Mayfield frame is typically done prior
rate and blood pressure, and avoidance of hypercarbia and to supratentorial craniotomy for mass lesion. Between two and four
hypoxaemia. external pins are applied to the patient’s scalp at a pressure of 60–
80 pounds per square inch (psi). Head pinning has a profoundly
◆ Patient movement during craniotomy for supratentorial mass stimulating effect that is similar to that of a surgical incision. Head
can be extremely dangerous, particularly when the patient’s pinning results in a large catecholamine release, resulting in signifi-
head is fixed in cranial pins. cant hypertension and tachycardia, and should be anticipated and
◆ Head pinning results in a large catecholamine release, resulting pre-emptively treated. Furthermore, it is imperative that the patient
in significant hypertension and tachycardia, and should be an- does not move during head pinning, which could result in a signifi-
ticipated and pre-emptively treated. cant scalp laceration or cervical spine injury.
◆ The goals of anaesthetic maintenance for supratentorial sur- Head pinning is a particularly critical point in the surgery, and
gery is to maintain ideal intracerebral haemodynamics, pro- should have the anaesthetist’s attention. Communication between
vide neuroprotection, and allow for a quick awakening and the surgeon and anaesthetist is paramount at this time, and any con-
neurological recovery. cerns should be discussed. An arterial line should ideally be placed
prior to insertion of cranial pins, so that continuous blood pres-
◆ Prospective, randomized clinical trials have failed to con- sure can be accurately monitored. Prior to the application of cranial
sistently demonstrate that one anaesthetic technique is ad- pins, the patient’s scalp should be infiltrated with local anaesthetic
vantageous over another with regards to time to recovery, (8–10). The anaesthesia should be deepened and administration
extubation, or postoperative cognitive function of a muscle relaxant may be considered to maintain akinesia. An
An
◆ infusion of opioids such as fentanyl or remifentanil can opioid infusion can blunt the haemodynamic response to pinning,
dramatically reduce the amount of volatile agent or propofol and when used it should ideally be started prior to head pinning.
needed during craniotomy, and has been shown to be effective Patients typically will require additional treatment prior to head
in reducing the emergence time. pinning. Medications commonly used to blunt the hemodynamic
response to pinning include general anaesthetics (i.e., opioids
◆ An important goal of craniotomy for supratentorial mass re-
such as remifentanil, fentanyl, or sufentanil (11), and even sub-
section is the anaesthetist’s optimization of the surgical field,
anaesthetic doses of ketamine at 0.5 mcg/kg (12). Pre-operative ad-
and several techniques are employed to reduce cerebral oe-
ministration of oral gabapentin at 900 mg, which has been shown
dema, blood volume, or CSF volume during surgery.
to reduce surgical opioid requirements, decrease postoperative
The
◆ goals of fluid management for patients undergoing cra- pain, and attenuate the response to laryngoscopy and intubation,
niotomy for supratentorial management are to maintain has also been shown to effectively blunt the hypertensive effects of
normovolaemia and normotension. head pinning (13). Because the haemodynamic response from pin-
ning is typically short-lived, large doses of long-acting agents are
typically not recommended because they can result in significant
immobility. Succinylcholine is known to cause a transient increase hypotension that persists long after the head is fixed.
in ICP, and its use is generally reserved to facilitate tracheal intub- Patients with chronic, uncontrolled hypertension are at particu-
ation in patients in whom a difficult intubation is anticipated. The larly high risk of developing severe hypertension during head fix-
clinical significance of this increased ICP is unclear, however, and ation. Severe hypertension during head pinning may cause cerebral
is thought to be only of concern in patients with previously elevated haemorrhage at the surgical site, or rarely, at a remote intracra-
ICP. Rocuronium can also be used in situations where a difficult in- nial site (14, 15), and may require surgical evacuation. Patients on
tubation is anticipated, provided that sugammadex is readily avail- anticoagulants, as well as patients with vascular brain lesions (i.e.,
able to reverse the rocuronium if needed. arteriovenous malformations or cerebral aneurysm), known co-
While the non-depolarizing muscle relaxants have minimal agulation disorders, or disrupted blood-brain barrier (BBB) func-
effects on intracerebral haemodynamics, it is generally recom- tion are at high risk of haemorrhage. Severe hypertension may also
mended that long-acting muscle relaxants should be avoided be- contribute to cerebral oedema, and may significantly compromise
cause of the susceptibility of neurosurgical patients to the effects the surgical exposure.
of myorelaxant sequelae (5). However, it should be noted that the
use of older anti-epileptic medications (phenytoin, carbamazepine, Maintenance of Anaesthesia
phenobarbital, and valproic acid) may induce hepatic enzymes The goals of anaesthetic maintenance for supratentorial sur-
and result in an increased metabolism of muscle relaxants (2). gery is to maintain ideal intracerebral haemodynamics, provide
Therefore, the duration of shorter-acting muscle relaxants may be neuroprotection, and allow for a quick awakening and neurological
significantly shorter than otherwise anticipated. If motor evoked recovery. The optimal anaesthetic maintenance regimen for patients
potentials or cranial nerves will be monitored, muscle relaxants are undergoing craniotomy has been heavily debated in the literature
not administered and an alternative method of preventing patient (16). It is thought that a total intravenous anaesthetic (TIVA) is
movement should be employed. In this context, an opioid infu- advantageous because it interferes least with electrophysiological
sion can be useful for achieving akinesis without the use of muscle monitoring, and is superior with regards to its reduction of CBR
164
and cerebral blood volume (CBV). Furthermore, during crani- (31), but failed to demonstrate any differences in postoperative out-
otomy for intracranial tumour, propofol anaesthesia results in a comes. Furthermore, of all the inhalational agents, desflurane has
lower ICP and higher CPP than sevoflurane or isoflurane anaes- the strongest vasodilating effects on cerebral vessels, which may re-
thesia, suggesting improved operating conditions with TIVA (17). sult in increased ICP and an impaired surgical field.
At equipotent doses, cerebral metabolism is reduced with An infusion of opioids such as fentanyl or remifentanil can dra-
inhalational agents to the same degree as intravenous agents. At matically reduce the amount of volatile agent or propofol needed
low concentrations of inhalational agents, the reduced CMR re- during craniotomy (32, 33), and has been shown to be effective
sults in cerebral vasoconstriction. As concentrations increase, in reducing the emergence time (34, 35). Furthermore, an opioid
however, volatile agents have a dose-dependent direct vasodila- infusion may be highly effective in preventing the postoperative
tory effect, causing an increase in CBF and uncoupling of CBF hypertension that is commonly observed during emergence after
and CMR. Therefore, at higher concentrations, inhalational agents craniotomy (34).
may increase ICP and reduce surgical exposure, and impair cere- The use of remifentanil has been associated with the most rapid
brovascular autoregulation in response to decreases in mean ar- emergence and earliest cognitive recovery compared with other opi-
terial pressure. Desflurane has the highest vasodilating effect of oids (35–37), although patients may require more antihypertensive
the inhalational agents, whereas sevoflurane has the least. At con- medications to maintain the mean ABP within 20% of baseline on
centrations below 1.0 MAC, sevoflurane does not increase CBV or emergence (35). Similarly, the use dexmedetomidine may reduce
ICP, and cerebral autoregulation is maintained. For these reasons, the anaesthetic and analgesic requirements, which may facilitate a
sevoflurane may be the most appropriate inhalational agent for rapid wake-up (38). The use of desflurane has been shown to be
neuroanaesthesia. result in earlier postoperative cognitive recovery and correction
Others have argued, however, that the use of inhalational agents is of hypercarbia compared with sevoflurane and isoflurane (39, 40).
advantageous in that they may result in a more rapid postoperative This benefit of desflurane has also been demonstrated in obese pa-
recovery and optimal postoperative neurological exam. Prospective, tients, in whom a rapid emergence may be particularly challenging
randomized clinical trials have failed to consistently demonstrate due to impaired gas exchange and hypercarbia (39).
that one anaesthetic technique is advantageous over another with Prior to surgery, the anaesthetist should discuss with the sur-
regards to time to recovery, extubation, or postoperative cogni- geon whether intra-operative neurophysiological monitoring will
tive function (18–20). Furthermore, both anaesthetic techniques be used, as this will impact the choice of anaesthetic agents admin-
offered similar intra-operative and postoperative hemodynamic istered. Volatile anaesthetic agents are known to decrease the amp-
profiles, postoperative outcomes, total hospital stay, and cost litude and increase the latency of somatosensory evoked potentials
(21, 22). Therefore, there are several anaesthetic techniques that (SSEPs) in a dose-dependent manner, especially when the inhaled
may be safely employed for craniotomy for supratentorial tu- dose exceeds 0.5 the minimum alveolar concentration (MAC).
mour. Currently the most commonly employed techniques are a When CBF drops under 20 cc/min/100g, the SSEPs are altered, and
sevoflurane-opioid or propofol-opioid anaesthetic. Some authors they are lost at 15–18 cc/min/100g. An alternative anaesthetic such
recommend that the predictability and controllability of volatile as propofol should be available in these patients if the SSEP wave-
techniques are preferred in elective, uncomplicated neurosurgical form is adversely affected at doses under 0.5 MAC.
procedures, while a TIVA may be more appropriate in more com- An acute decrease in amplitude or increase in latency of neuro-
plicated patients with elevated ICP (5). physiological evoked potentials could indicate direct trauma, is-
In recent years, the alpha- 2 adrenergic receptor agonist chaemia, compression, or haematoma around a particular nerve or
dexmedetomidine has gained increasing popularity for use in brain region. In this circumstance the surgeon has to be notified,
neurosurgical procedures because of its sympatholytic properties and blood pressure should be returned to normal or 20% above
and possible neuroprotective properties (23, 24). Dexmedetomidine normal, and the surgeon should investigate what caused the change
infusion has been shown to result in stable haemodynamics during in signal. An arterial blood gas should be drawn to determine and
craniotomy without an increased incidence of bradycardia or correct any metabolic derangements.
hypotension (25–27). Furthermore, dexmedetomidine use has
been shown to reduce sevoflurane, fentanyl, and anti-emetic re- Optimization of Surgical Field
quirements, decrease ICP, and improve outcomes (28). When the An important goal of craniotomy for supratentorial mass resec-
infusion is started early, dexmedetomidine can also be useful in tion is the anaesthetist’s optimization of the surgical field. The brain
blunting the haemodynamic response to tracheal intubation (27. volume is the most significant factor that affects the surgical field,
29) and cranial pinning (30). For these reasons, dexmedetomidine and several techniques are employed to reduce cerebral oedema,
may be a useful adjunct for craniotomy for supratentorial anaes- blood volume, or CSF volume during surgery. Furthermore, proper
thesia and other neurosurgical procedures. patient positioning ensures adequate cerebral venous drainage, and
A primary goal during the maintenance of anaesthesia during is of utmost importance in optimizing the surgical field.
craniotomy is to achieve a rapid awakening at the completion of Mannitol (0.5–1 g/kg I.V.), an osmotic diuretic, is the most com-
the procedure. Desflurane is a potentially attractive volatile anaes- monly used hyperosmolar therapy (41). In areas with an intact
thetic for neurosurgical procedures because of its low solubility and BBB, mannitol shifts water from the brain to the blood, where it can
rapid recovery. However, its use in neurosurgical procedures has enter the systemic circulation. This results in a reduction in ICP and
been debated. While both animal and human studies have demon- better surgical exposure. Mannitol is typically administered over a
strated its use in patients undergoing craniotomy for supratentorial 30-minute to one-hour infusion. Mannitol takes effect in 15 min-
tumour, a prospective, randomized clinical trial demonstrated that utes from the onset of infusion, achieves its peak effect in one hour,
desflurane use resulted in shorter extubation and recovery times and its effects last from three to six hours. Rapid administration
165
of mannitol is not recommended because it can result in an acute Table 13.1 Effect of anaesthetic agents on amplitude and latency
increase in ICP due to an increase in CBV, pulmonary oedema, of somatosensory evoked potentials.
and hypotension due to mannitol’s histamine effects. The timing of
mannitol infusion is also very important in achieving its optimal ef- Drug Amplitude Latency
fects, and should be started around the time of incision. In patients
Volatile agents ↓ (dose-dependent) ↑ (dose-dependent)
who are refractory to mannitol, or in whom mannitol is contraindi-
cated, hypertonic saline (3%, 7.5%, or 23.4%) has been shown to N20 ↓ No effect
effectively reduce ICP and improve CPP (41). While some studies Etomidate ↑ ↑
have suggested that hypertonic saline offers benefits of volume ex- Midazolam ↓ No effect
pansion and improved cerebral and systemic haemodynamics over
mannitol, recent prospective data failed to establish clear guidelines Opioids Little clinical effect Little clinical effect
for its use (42). Because of the potential significant risks associated Ketamine ↑ No effect
with hypertonic saline administration, including central pontine Propofol ↓ (at high doses) ↑ (at high doses)
myelinolysis, hypertonic saline should be considered when mul-
tiple doses are needed or other therapies have failed.
Carbon dioxide (CO2) is a potent cerebral vasodilator, and an in-
crease in PaCO2 by 1 mm Hg results in an increase in CBF by 1 cc/ intravenous agents, with the exception of ketamine, decrease both
100g/min. Although chronic hyperventilation is no longer used for CBF and CMRO2. Ketamine increases both CBF and CMRO2, and
neurosurgical procedures, it is commonly employed during crani- is typically avoided in craniotomy. Nitrous oxide decreases CMRO2,
otomy for mass lesion to rapidly decrease CBF and improve surgical but its effects on CBF are unclear.
exposure. Hypocapnia shifts the plateau of the autoregulation curve
downward, resulting in lower CBF (43). The target PaCO2 is typic- Fluid Management
ally 35–40 mm Hg and unnecessary hypocapnia should be avoided While historically fluids had been restricted in neurosurgical pro-
to reduce the risk of cerebral ischaemia. The PaCO2 can be lowered cedures out of fear that fluids would promote cerebral oedema (45),
via hyperventilation to 25–30 mm Hg as a temporizing rescue fluid restriction is known to increase the likelihood of hypotension
measure in cases of severe and rapid onset to lower ICP, until other and reduced CPP. Therefore, the goals of fluid management for pa-
measures are effective. When the PaCO2 is decreased to less than tients undergoing craniotomy for supratentorial management are
25 mm Hg, this results in cerebral vasoconstriction and reduced to maintain normovolaemia and normotension. These goals may
oxygen delivery. Because the ETCO2 and PaCO2 often poorly cor- present challenges for the anaesthetist, and there is little substan-
relate, ETCO2 should not be considered an appropriate substitute tive data to guide optimal fluid management (46). Mannitol and
for frequent arterial blood sampling and PaCO2 measurements (5). other diuretic use are common in patients undergoing craniotomy
It is especially important that adequate ABP be maintained during for supratentorial mass, which may greatly contribute to fluid loss
periods of hypocapnia, and increased perfusion pressures should and hypotension. Therefore, large volumes of intra-operative fluid
be considered to minimize the risk of ischaemia (43). The concomi- may be needed in these patients to maintain adequate intravascular
tant use of other cerebral vasoconstrictors should be avoided. tone, correct dehydration, and promote haemodynamic stability.
Raising the head of the bed by 15–30 degrees rapidly promotes Hypo-osmolar solutions such as Ringer’s Lactate solution (osmo-
cerebral venous drainage and decreased jugular venous pressure, larity of 273 mOsm/kg) have long been thought to promote brain
and is one of the most rapid techniques of reducing CBV and ICP, oedema, and have historically been avoided during neurosurgical
and improving surgical exposure. When raising the head of the bed procedures. Normal saline (osmolarity 308 mOsm/kg) has there-
is considered, it should be done with close communication with fore traditionally been the preferred crystalloid solution for neuro-
the surgeon. Importantly, care should be taken that MAP is not surgical procedures. However, the use of normal saline in these
decreased by this measure, as any beneficial effect would be neg- patients has recently come under heavy scrutiny in recent years be-
ated by an overall decrease in CPP. Dexamethasone (10–20 mg cause of its tendency to cause significant hyperchloremic acidosis.
IV) is often administered during surgery to decrease postoperative As such, many have questioned whether normal saline should have
brain swelling and ICP, but has little effect on improving surgical any role in the fluid management of patients undergoing neurosur-
exposure. gical procedures (47). A Ringer solution without lactate, or isotonic
The anaesthetic management of a patient with an intracra- PlasmaLyte may be the best options for crystalloid solutions. When
nial mass requires knowledge of the effects of anaesthetic agents red blood cell transfusion is necessary, calcium-containing solu-
on CMRO2 and CBF. To reduce ICP and optimize surgical ex- tions may coagulate with citrate and should therefore not be used.
posure, anaesthetic agents are typically chosen that reduce both In this context, some authors advocate for the use of PlasmaLyte, a
CMRO2 and CBF (Table 13.1). Volatile agents are known to de- balanced solution that does not contain calcium (47). Some alterna-
crease CMRO2, but increase CBF at doses that exceed 0.6 MAC. tively advocate for Ringer solution without lactate. Hyperglycaemia
As discussed previously, sevoflurane has the fewest vasodilating may worsen outcomes after cerebral ischaemia, and glucose-
effects of the inhalational agents, whereas desflurane has the most. containing solutions should not be used (5). Furthermore, when
However, in patients undergoing supratentorial tumour resection glucose-containing solutions are used, the glucose is metabolized
without midline shift, general anaesthesia with 1 MAC of isoflurane and the hypo-osmotic free water that is left can cause cerebral oe-
or desflurane did not result in a change in ICP compared with dema. Therefore, if a patient needs a glucose infusion, one would
baseline values, whereas mean arterial pressure (MAP) and CPP have to administer a low volume, high concentration of glucose
significantly decreased compared with baseline values (44). Most (i.e., 40%). Fluids should be warmed to maintain normothermia.
16
The role of colloid oncotic pressure is unclear in cerebral oe- It is recommended that blood glucose concentrations should be
dema, and there is currently a lack of consensus regarding when controlled with carefully titrated insulin infusions, and that insulin
colloid solutions should be used, and who may benefit most from boluses be avoided because of the risk of rapid fluctuations in blood
its use (48). When administered with mannitol, studies have dem- glucose concentrations (66, 68, 69). Dextrose-containing solutions
onstrated that hetastarch results in impaired clot propagation and are typically avoided. The utility of continuous glucose monitoring
clot strength compared to when mannitol is administered with devices and automated glucose and insulin infusion pumps are cur-
lactated Ringer solution (49). Hetastarch should therefore be espe- rently being investigated, and may be useful for this patient popula-
cially avoided when impaired haemostasis is suspected. tion in the future (68, 70).
Blood Transfusion Intra-Operative Complications

Anaemia is one of the most common complications of neurosur-
gical procedures, and approximately 1.4% of patients undergoing Venous Air Embolism
craniotomy for brain tumour receive peri-operative blood trans- Venous air embolism (VAE) is a potentially catastrophic compli-
fusion (50). The brain is particularly sensitive to the effects of cation that can occur during neurosurgical procedures in which
hypoperfusion, which may increase the risk of secondary brain in- there is a pressure gradient of at least 5 cm between an open vein
jury. To date there have been no trials that have determined the at the surgical site and the right atrium of the heart. The volume of
ideal blood transfusion threshold in patients undergoing elective air and rate of entry into the venous circulation is dependent on
craniotomy for supratentorial mass lesion (51). A recent large- the pressure gradient, which is determined the location of the mass
scale study in more than 6,500 patients examined the effects of and patient position. While craniotomy for supratentorial mass is
pre-operative anaemia on early postoperative patient outcomes most commonly performed with the patient lying supine, the re-
after elective cranial surgery (52). Pre-operative anaemia, regard- verse Trendelenburg position is often employed to lower ICP and
less of the severity, was associated with an increased hospital length improve surgical exposure by facilitating cerebrospinal fluid and
of stay, but not an increased 30-day morbidity or mortality rate. cerebral venous drainage away from the surgical field. While the
A second study with more than 8,000 patients found that a pre- risk of VAE is highest for craniotomy in the sitting position, it can
operative haemoglobin concentration under 11 g/dL was associ- occur during surgery in the prone or lateral position as well if the
ated with an increased risk of 30-day postoperative morbidity and venous pressure in the surgical bed is sub-atmospheric. The risks
mortality compared with non-anaemic patients (53). In the absence are minimized with careful surgical dissection and liberal use of
of cardiac disease, it is unclear whether early and aggressive blood bone wax and saline irrigation.
transfusion protocols would improve postoperative outcomes for VAE is typically detected with end-tidal CO2, precordial Doppler,
these patients. Furthermore, the risks associated with unnecessary or transoesophageal echocardiogram (TEE), although no single
blood transfusions should not be underestimated. monitoring modality will accurately predict all cases of VAE (71).
Three to 5 cc/kg (200–300 cc) introduced into the cerebral vascu-
Glucose Control lature is considered a lethal dose. TEE, perhaps the most sensitive
In neurosurgical patients, peri-operative hypoglycaemia and hyper- diagnostic tool in the detection of VAE, can identify as little as 0.02
glycaemia are associated with an increased risk of adverse events mL of air. In VAE, the patient can rapidly develop hypoxaemia due
(54, 55). Peri-operative hyperglycaemia during craniotomy for to an increase in alveolar dead space. Significant right heart strain
supratentorial mass is common in both diabetic and non-diabetic can precipitate cardiac ischaemia, hypotension, and cardiac arrest.
patients, and may be related to several factors including the stress of Thrombocytopenia frequently accompanies VAE and increases the
surgery and peri-operative administration of corticosteroids (56). patient’s risk of bleeding (72).
While the suspected causal effects of hyperglycaemia on cerebral Paradoxical arterial embolism is thought to be a major risk
metabolism and ischaemia have not been definitively determined, of VAE, and many clinicians therefore recommend routine pre-
it is known that blood glucose concentrations >150 mg/dL are operative screening for a patent foramen ovale (PFO) with TEE.
associated with poor neurological outcomes and increased mor- Transcranial Doppler has also emerged in recent years as an in-
tality in the setting of intracranial haemorrhage (ICH) and trau- expensive, non-invasive, and easy alternative method of assessing
matic brain injury (57–60). However, the suspected adverse risks for PFO (73). For patients at increased risk of VAE, especially
in patients undergoing elective craniotomy for supratentorial mass when the craniotomy is performed in the sitting position, some
is unclear (54). A single study demonstrated that persistent out- authors recommend that the PFO be surgically closed prior to
patient hyperglycaemia is an independent risk factor for mortality craniotomy (74).
in patients undergoing resection of malignant astrocytoma, and
there have otherwise been no prospective clinical trials that have Acute Increase in Intracranial Pressure
studied the effects of blood glucose concentration in craniotomy The intracranial space includes the contents of the brain (~85–
for supratentorial mass. 90%), blood (~5%), and CSF (~5–10%). Because the cranium is a
Tight blood glucose control (target range 80–110 mg/dL) is gen- fixed, incompressible space, an increase in any of these three com-
erally not recommended because of the significantly increased risk ponents must result in a decreased volume in another component.
of hypoglycaemia and associated mortality (61–64). Although the An acute increase in ICP during craniotomy can be detrimental for
precise optimal range of blood glucose concentration has yet to be several reasons. First, as ICP rises and approaches the MAP, CBF
established (55), some authors recommend that a moderate blood may be significantly and rapidly reduced. Second, an acute increase
glucose concentration between 110 and 140 mg/dL should be main- in ICP can result in potentially catastrophic and life-threatening
tained (65–67), and all values above 150 mg/dL should be treated. brain herniation and brainstem compression.
167
An acute intra-operative increase in ICP should be rapidly iden- by an uneventful procedure (75). Postoperative ICH, because of the
tified and treated, and the causing factors should be eliminated. skull’s limited compliance and compensation mechanisms to acute
CBV reduction can be rapidly achieved through a combination increases in intracranial volume, may result in a sudden increase
of hyperventilation, intravenous anaesthetic agents, mannitol, in intracranial pressure (ICP). When this occurs, it can lead to se-
or hypothermia (41). If an external ventricular drain was placed, vere complications, including permanent neurological deficits and
draining CSF can directly lower CBV. death. When postoperative ICH develops, 50% of the time bleeding
Acute hypertensive episodes are avoided, as cerebral occurs within the first 20 hours after completion of the crani-
autoregulation is abolished at MAPs >150 mmHg. Furthermore, otomy (Figure 13.1), and in 50% of those patients (25% overall)
maintaining adequate systemic oxygenation is vital, because CBF bleeding typically occurs within the first four hours. Therefore,
exponentially and rapidly increases when the PaO2 drops below these patients require tight clinical surveillance after craniotomy
50 mm Hg. Seizure activity results in an increase in CMRO2 and for supratentorial mass, which is often done in the intensive care
CBF, should be treated immediately with benzodiazepines, anti- unit (ICU) (75).
epileptic medications, and propofol if suspected during crani- It is imperative that patients are closely monitored in the first 24
otomy. Lastly, hyperthermia results in an increase in CMRO2 and hours after craniotomy (76). If a patient does not rapidly regain
CBF, and should be avoided. consciousness or develops a focal neurological deficit, a head CT
scan should be done immediately to evaluate for a neurosurgical
Postoperative Management complication. The optimal method of detecting a new neurological
deficit after craniotomy is contingent on having a fully coopera-
Emergence tive and conscious patient. Therefore, the goals at the completion
After completion of craniotomy for supratentorial mass lesion, the of the procedure are to ensure a rapid emergence and adequate
emergence from anaesthesia, extubation, and postoperative man- neurological examination, and early extubation when indicated.
agement is a critical stage of the procedure (see Box 13.3). This Although the clinical surveillance should be extended beyond the
period may result in serious complications, even when preceded immediate postoperative period, there is no evidence to support
the need for ICU or step-down unit over a clinical ward admission,
provided that the patient is adequately monitored.
Box 13.3 Postoperative Considerations in Patients Undergoing When possible, early recovery and extubation is ideal because
Supratentorial Tumour Craniotomy it allows the clinician to perform a full clinical and neurological
evaluation, and to detect new postoperative neurological deficits
◆ After completion of craniotomy for supratentorial mass lesion, in the event that ICH should occur (77, 78). Furthermore, early
the emergence from anaesthesia, extubation, and postoperative extubation is desirable because delayed extubation is associated
management is a critical stage of the procedure. with adverse systemic effects, including increased O2 consump-
tion and release of catecholamines (79). Several considerations
◆ When postoperative ICH develops, 50% of the time bleeding
should be taken into account when planning the strategy of emer-
occurs within the first 20 hours after completion of the cra-
gence, including the timing of awakening/recovery, the deci-
niotomy, and in 50% of those patients (25% overall) bleeding
sion to extubate, the patient’s neurocognitive status, the patient’s
typically occurs within the first four hours.
◆ When possible, early recovery and extubation is ideal because
it allows the clinician to perform a full clinical and neuro-
logical evaluation, and to detect new postoperative neuro- >80h
logical deficits in the event that ICH should occur. 12%
◆ When early emergence and extubation is planned, it is im-
portant that it be accomplished with minimal haemodynamic 61–80h
and respiratory derangement. 9%
◆ The clinical management of patients after craniotomy for intra-

0–20h
cranial mass necessitates tight surveillance of several variables 41–60h 49%
of unique importance, including serial neurological exams and 13%
assessment of the patient’s neurocognitive status.
◆ Postoperative pain after craniotomy is common, and can in-
crease the risk of postoperative complications, including ar-
terial hypertension and postoperative haemorrhage. 21–40h
17%
◆ Patients after craniotomy are at high risk of PONV, possibly
due to stimulation of the chemoreceptor trigger zone and to the
area postrema, a medullary structure that controls vomiting. Figure 13.1 Percent temporal distribution of intracranial haemorrhage
After
◆ craniotomy for supratentorial mass, some patients, espe- after completion of craniotomy procedure.
cially those with limber palsy, have a substantially higher rate Almost half of patients who develop intracranial haemorrhage after craniotomy
bleed within in the first 20 hours after craniotomy. In almost half of these patients
of deep vein thrombosis (DVT) even when pharmacological
(25% overall), bleeding occurs within the first four hours after completion of
prophylaxis is administered. craniotomy (not shown).
168
haemodynamic and respiratory status, the expected postoperative of the surgical procedure (84). Patients with severe brain swelling,
pain and risk of postoperative nausea and vomiting (PONV), and and patients that have been operated on the brain stem or cranial
the risk of deep vein thrombosis (DVT). nerves (especially the cranial nerves involved with the gag reflexes,
When early emergence and extubation is planned, it is important IX through XII), deserve special attention. In these patients it is
that it be accomplished with minimal haemodynamic and respira- essential to establish a sedation plan that allows for optimal mech-
tory derangement. The importance of optimal management of the anical ventilation and minimized ICP, as well as a prompt neuro-
emergence phase is highlighted by the results of a large in which logical evaluation. Therefore, short-acting anaesthetics and the use
procedures performed in more qualified centres (high-volume, of local anaesthetics in the endotracheal tube are indicated in these
academic centres) were shown to be associated with a lower patients (85).
postoperative mortality (4).
The clinical management of patients after craniotomy for intra- Pain
cranial mass necessitates tight surveillance of several variables of Postoperative pain after craniotomy is common, and can increase
unique importance, including serial neurological exams and assess- the risk of postoperative complications including arterial hyper-
ment of the patient’s neurocognitive status (78). Arterial hyperten- tension and postoperative haemorrhage (86). Postoperative pain
sion frequently occurs during emergence, and is a strong predictor should therefore be anticipated and aggressively prevented (87,
of postoperative ICH (75). Arterial hypertension should be aggres- 88). The optimal treatment is controversial, and there are no es-
sively prevented with an agent that does not increase the CBV, such tablished guidelines to guide pain management in these patients.
as labetalol, esmolol, and nicardipine (80). Furthermore, the oc- The use of non-steroidal anti-inflammatory drugs are commonly
currence of new-onset atrial fibrillation in the early postoperative administered in postsurgical patients, they are typically avoided in
period is a strong predictor of a worsened neurological status and neurosurgical patients because of their potential effects on platelet
increased mortality (81). aggregation (89).
The occurrence of ICH should be promptly diagnosed with serial Interestingly, a recent systematic review and meta-analysis of
neurological examinations monitoring that focus on identifying the available clinical evidence demonstrated that the use of a se-
focal lesions in the anatomical area of the surgical procedure, and lective scalp block with local anaesthetics, when performed in
the presence of new neurological deficits should immediately be the pre-operative period or at the end of surgery, was effective
referred for a brain CT scan (76). In these patients the neuro- in preventing postoperative pain (4). The intra-operative use of
logical status, as measured by the Glasgow Coma Scale (GCS), is dexmedetomidine was also effective in reducing the need for an-
the strongest predictor of successful extubation. This in contrast algesics, and resulted in improved postoperative pain scores (90).
to most other ICU patients, in whom the (Fraction of inspired Intravenous cyclooxegenase-2 (COX-2) inhibitors, such parecoxib,
oxygen (FiO2)/PaO2 ratio, respiratory rate, and other variables however, were not effective in reducing opioid consumption after
are the most accurate predictors of successful extubation (82). The craniotomy (91). Despite conventional methods of pain manage-
prospective study from Namen and colleagues in 100 neurosur- ment, studies have demonstrated that postoperative pain after
gical patients demonstrated that the implementation of ‘traditional’ craniotomy is common, highlighting the need for an improved,
weaning protocol in neurosurgical patients had substantial limita- multimodal, and individualized approach to pain management
tions, due to concerns about the patients’ neurologic impairments (86, 92).
and the observation that a GCS ≥8 at extubation was associated
with a success in 75% of cases, whereas a GCS <8 resulted in only Postoperative Nausea and Vomiting
a 33% success rate (82). Cognitive recovery is also predictor of ad-
Patients after craniotomy are at high risk of PONV, possibly due
equate gas exchange including PaCO2 (39).
to stimulation of the chemoreceptor trigger zone and to the area
Postoperative fluid therapy should be preferably accomplished
postrema, a medullary structure that controls vomiting. Studies
with isotonic solutions, and dextrose-containing solutions should
have shown that more than half of patients experience PONV after
be generally avoided and used only if hypernatremia develops (46,
craniotomy (93). In these patients, pharmacological prevention of
83). The use of colloids has been associated with an increased risk
PONV should be aggressively pursued. Selective serotonin antag-
of postoperative ICH, possibly because of a dilution effect on co-
onists of serotonin type 3 receptors (5-HT3), including ondansetron
agulations factors, and should be minimized (49).
and tropisetron (94), have been effective in treating PONV after cra-
Delayed Extubation niotomy for supratentorial tumour. The use of dexmedetomidine
as an adjunct in the maintenance of general anaesthesia has been
Although early emergence and extubation should be considered
shown to reduce the requirements for sevoflurane and fentanyl, and
the standard of care whenever feasible, there are several conditions
results in less need for anti-emetic therapy in the first two hours
that would warrant a postponement of extubation. Some studies
after surgery (28, 90). Furthermore, medications that increase the
have suggested that implementing a weaning protocol that com-
risk of PONV, including volatile anaesthetics and long-acting opi-
bines both respiratory parameters and neurological assessment
oids, should be used judiciously (95).
may be useful in determining which patients can be successfully
extubated, but prospective studies are lacking (82). The patient’s
haemodynamic and respiratory status should be stable before Deep Vein Thrombosis
considering extubation, especially in the setting of arterial hyper- After craniotomy for supratentorial mass, especially those with
tension, hypoxia, or hypercarbia because of their effects on CBF limb weakness, have a substantially higher rate of DVT even when
(43). Hypothermia in the postoperative period is particularly det- pharmacological prophylaxis is administered. Interestingly, an
rimental, and should be aggressively prevented from the beginning observational study examined 4293 patients who had undergone
169
craniotomy, in which 126 patients (3%) developed DVT. In 86% 4. Momin EN, Adams H, Shinohara RT, Frangakis C, Brem H, Quinones-
of patients that developed DVT, unfractionated low molecular Hinojosa A. Postoperative mortality after surgery for brain tumors
weight heparin had been administered (96). In this cohort the by patient insurance status in the United States. Archives of Surgery.
2012;147(11):1017–24.
strongest predictors of DVT were poor functional status, older age,
5. Bruder N, Ravussin P. Supratentorial masses: Anesthetic considerations.
the presence of motor deficits, high-grade gliomas, and chronic ar- 5th ed. Philadelphia, PA: Elsevier; 2010.
terial hypertension. Recent evidence suggests that administration 6. Hussein RRS, Soliman RH, Abdelhaleem Ali AM, Tawfeik MH,
of heparin 12 hours after craniotomy is relatively safe with a low Abdelrahim MEA. Effect of antiepileptic drugs on liver enzymes. Beni-
risk of secondary haemorrhage, and some authors recommend that Suef University Journal of Basic and Applied Sciences. 2013;2:14–9.
more aggressive anticoagulation protocols may be justified (97). 7. Bansal S, Ramesh VJ, Umamaheswara Rao GS. Fentanyl co-
However, there is currently no expert consensus regarding when to administration decreases the induction dose requirement of propofol
in patients with supratentorial tumors and not in patients with spinal
start anticoagulation therapy after supratentorial craniotomy.
lesions. Journal of Neurosurgical Anesthesiology. 2012;24(4):345–9.
8. Rozet I, Vavilala MS. Risks and benefits of patient positioning during
Other Considerations neurosurgical care. Anesthesiology Clinics. 2007;25(3):631–53, x.
In the immediate postoperative period, it is vital to be aware of po- 9. Geze S, Yilmaz AA, Tuzuner F. The effect of scalp block and local
tential complications related to removal of cranial pins. Bleeding infiltration on the haemodynamic and stress response to skull-pin
is common, and can typically be stopped with the application of a placement for craniotomy. European Journal of Anaesthesiology. 2009
Apr;26(4):298–303.
pressure dressing with gauze. Occasionally however, closure with
10. Yildiz K, Madenoglu H, Dogru K, Kotanoglu MS, Akin A, Boyaci A.
sutures or staples may be required to stop the bleeding. The re- The effects of intravenous fentanyl and intravenous fentanyl combined
moval of cranial pins may also increase the risk of venous air em- with bupivacaine infiltration on the hemodynamic response to skull
bolism (VAE) (98). If the concern for VAE is high, such as when pin insertion. Journal of Neurosurgical Anesthesiology. 2005;17(1):9–12.
craniotomy is performed in the sitting position, the placement of 11. Jamali S, Archer D, Ravussin P, Bonnafous M, David P, Ecoffey C. The
antibiotic ointment on the pins is recommended to minimize the effect of skull-pin insertion on cerebrospinal fluid pressure and cerebral
risk of VAE (8). perfusion pressure: influence of sufentanil and fentanyl. Anesthesia &
Analgesia. 1997;84(6):1292–6.
12. Agarwal A, Sinha PK, Pandey CM, Gaur A, Pandey CK, Kaushik
Conclusions S. Effect of a subanesthetic dose of intravenous ketamine and/or
local anesthetic infiltration on hemodynamic responses to skull-pin
The anaesthetic management of the patient undergoing craniotomy
placement: a prospective, placebo-controlled, randomized, double-
for supratentorial mass requires that the anaesthetist has an in- blind study. Journal of Neurosurgical Anesthesiology. 2001;13(3):189–94.
depth understanding of the pharmacology of anaesthetic agents 13. Misra S, Koshy T, Unnikrishnan KP, Suneel PR, Chatterjee N.
and the principles of neuro-pathophysiology. There are several peri- Gabapentin premedication decreases the hemodynamic response
operative goals for craniotomy for supratentorial tumour. Patients to skull pin insertion in patients undergoing craniotomy. Journal of
should have a smooth and haemodynamically stable induction and Neurosurgical Anesthesiology. 2011;23(2):110–7.
maintenance of general anaesthesia, and adequate CPP (>70 mm 14. Brisman MH, Bederson JB, Sen CN, Germano IM, Moore F, Post KD.
Intracerebral hemorrhage occurring remote from the craniotomy site.
Hg) and oxygenation should be maintained. Achieving adequate
Neurosurgery. 1996;39(6):1114–21; discussion 1121–2.
surgical exposure is an important goal for the anaesthetist, and sev- 15. Koller M, Ortler M, Langmayr J, Twerdy K. Posterior-fossa
eral techniques to optimize the surgical exposure should be em- haemorrhage after supratentorial surgery--report of three
ployed. In the early postoperative period, a rapid awakening should cases and review of the literature. Acta Neurochirurgica (Wien).
be achieved to allow for an immediate neurological examination 1999;141(6):587–92.
on emergence, and patients should be given adequate analgesics 16. Gruenbaum SE, Bilotta F. Propofol versus thiopental use in patients
for postoperative pain control. More randomized clinical trials are undergoing craniotomy. Minerva Anestesiologica. 2014;80(7):753–5.
17. Petersen KD, Landsfeldt U, Cold GE, Petersen CB, Mau S, Hauerberg J,
needed to better guide the clinical decision-making process when
et al. Intracranial pressure and cerebral hemodynamic in patients with
managing these patients in the peri-operative period. cerebral tumors: a randomized prospective study of patients subjected
to craniotomy in propofol-fentanyl, isoflurane-fentanyl, or sevoflurane-
Cases fentanyl anesthesia. Anesthesiology. 2003;98(2):329–36.
18. Lauta E, Abbinante C, Del Gaudio A, Aloj F, Fanelli M, de Vivo P, et al.
Q Interactive cases to test your knowledge on this chapter can Emergence times are similar with sevoflurane and total intravenous
be found in the online appendix at www.oxfordmedicine.com/ anesthesia: results of a multicenter RCT of patients scheduled
otneuroanesthesiology. for elective supratentorial craniotomy. Journal of Neurosurgical
19. Magni G, Baisi F, La Rosa I, Imperiale C, Fabbrini V, Pennacchiotti ML,
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172
173
CHAPTER 14
The Posterior Fossa
Tasha L. Welch and Jeffrey J. Pasternak
Introduction transverse sinus that ultimately empty into the jugular veins.
A lesser route of venous drainage, especially for lower brainstem
The posterior fossa contains structures essential for life—the brain- and inferior regions of the cerebellum, occurs via small veins that
stem and cerebellum. The pathophysiology of disease states af- traverse the foramen magnum and empty into the venous plexus of
fecting the posterior fossa and surgery within the posterior fossa the cervical spinal cord.
pose several challenges distinct from those encountered during Also located within the posterior fossa is the major outflow tract
supratentorial craniotomy. This chapter discusses the unique an- for cerebrospinal fluid (CSF) contained within the ventricles of the
aesthetic implications of posterior fossa surgery. brain. CSF flows out of the lateral ventricles and into the third ven-
tricle. At the level of the upper brainstem, the CSF enters the cere-
Anatomy bral aqueduct of Sylvius and drains into the fourth ventricle located
The floor of the cranial skull base is divided into three fossae: the posterior to the pons and medulla and anterior to the cerebellum.
anterior, middle, and posterior fossae. The anterior, posterior, CSF then exits the fourth ventricle to enter the subarachnoid space
and lateral walls of the posterior fossa are comprised of cranial either by the median aperture or the lateral apertures (otherwise
bones, whereas the inferior and superior boundaries are marked known at the foramen of Magendie or foramina of Luschka, re-
by the foramen magnum and tentorium cerebelli (a reflection of spectively). Additionally, the fourth ventricle communicates caud-
dura mater), respectively. Figure 14.1 shows the the brainstem and ally with the central canal of the spinal cord.
cerebellum,which are the primary gross neurologic structures con-
tained within the posterior fossa. Indications for Surgery in the
The brainstem comprises only 4% of the total brain mass and is Posterior Fossa
divided into three primary regions: the midbrain, pons, and me-
dulla, although some include the diencephalon as a component of A variety of pathologic conditions exist involving the posterior
the brainstem. Although the brainstem is critical in regulating the fossa that may require surgical intervention. These can broadly be
function of cranial nerves III through XII, it has a variety of other divided into tumours, vascular disorders, and structural anom-
functions. The brainstem also serves as a conduit for afferent and alies. This chapter reviews some of the more common pathologies
efferent tracts connecting the spinal cord with higher centres and a that require posterior fossa craniotomy, but the reader should be
relay and integrative site for inflow into and outflow from the cere- aware that many other, less common, indications for posterior fossa
bellum. Additionally, the brainstem plays a key role in regulation surgery exist.
of the cardiovascular system, control of breathing, modulation of
pain, and level of consciousness. Tumours
The cerebellum lies posterior to the brainstem at the level of the Tumours are the most frequent indication for posterior fossa sur-
pons and medulla. Grossly, the cerebellum consists of two lateral gery. In fact, the posterior fossa is the most common location for
hemispheres and a midline region called the vermis. The primary paediatric brain tumours, although adults are not immune to pos-
role of the cerebellum is the initiation, coordination, and execu- terior fossa tumours. Table 14.1 outlines some of the key features of
tion of motor tasks as well as maintenance of postural balance. The posterior fossa tumours in children and adults. The most common
cerebellum also plays a key role in orchestration of complex motor paediatric posterior fossa tumours are cerebellar astrocytoma,
tasks with modifications based on past task completion—otherwise brainstem glioma, medulloblastoma, and ependymoma. In adults,
known as ‘motor learning’. metastases to the cerebellum are the most common posterior fossa
The neurologic structures contained in the posterior fossa receive neoplasm whereas haemangioblastoma is the most common pri-
blood supply from the vertebrobasilar arterial system, as illustrated mary posterior fossa neoplasm. Although pineal tumours are not
in Figure 14.2A. The cerebellum is supplied by three paired arteries located within the posterior fossa, surgical access to these tumours
and the brainstem receives its blood supply from small perforating generally involve access to the posterior fossa.
vessels that arise from the vertebral and basilar artery and their
branches. Figure 14.2B illustrates patterns of venous drainage of Vascular Abnormalities
the posterior fossa structures. The major routes of venous drainage Various vascular lesions can occur in the posterior fossa, including
are via tributaries of the great Vein of Galen, straight sinus, and aneurysms, arteriovenous malformations, haemorrhage, and
174
Although there is an association between cranial nerve compres-

sion syndromes and multiple sclerosis, a vascular aetiology may
be the cause in some cases. One of the cerebellar arteries (most
commonly the superior cerebellar artery) may compress the nerve
CN IV as it exits the brainstem, leading to irritation. Often, conservative
management including oral pain medications, rhizotomy, or if ap-
Midbrain propriate, radiofrequency ablation may be attempted. For patients
who fail conservative treatment, microvascular decompression via
CN III
posterior fossa approach may be offered.
Pons
Structural Anomalies
CN V A variety of structural abnormalities require posterior fossa sur-
gery. The most common indication is the treatment of a Chiari
CN VI Malformation, with Dandy Walker malformations representing a
CN VII much less common indication for surgery.
CN VIII Chiari malformations are represented by four classes of hind-
CN IX
brain disorders. Type I Chiari malformations are characterized by
CN XII the herniation of cerebellar tonsils through the foramen magnum.
CN X Patients often present in their third or fourth decade of life with
Medulla symptoms of headache worsened by neck extension or Valsalva,
CN XI ataxia, with or without weakness and numbness in the extrem-
ities. Surgical management generally consists of decompression
via suboccipital craniotomy and upper cervical vertebral lamin-
ectomy. Type II Chiari malformations often present in infancy
with lower cranial nerve dysfunction, hydrocephalus, and apnoeic
Figure 14.1 Neural components contained within the posterior fossa.
spells. In addition to caudal displacement of the cerebellar tonsils,
Used with permission of Mayo Foundation for Medical Education and Research. All rights
reserved.
the cerebellum appears hypoplastic with caudal displacement of
the cerebellar vermis, brainstem, and fourth ventricle. Obstructive
hydrocephalus, myelomeningocele, and congenital fusion of cer-
vascular compression of cranial nerves. Although most intracra- vical vertebrae (Klippel-Feil deformity) are also often present.
nial aneurysms arise in supratentorial regions, about 10% occur Surgical treatment involves suboccipital craniotomy and upper
in the posterior fossa, with the rostral segment of the basilar ar- cervical laminectomy for decompression. Type III Chiari malfor-
tery (i.e., ‘basilar tip’) and posterior inferior cerebellar artery being mations are most severe and are characterized by herniation of at
the most common sites (1). In most circumstances, management least the cerebellum, brainstem, and fourth ventricle through the
of posterior fossa aneurysms involves interventional radiology- foramen magnum into an encephalocele. These anomalies have an
based procedures to avoid surgically entering the posterior fossa. extremely high mortality. Type IV Chiari malformations are a mis-
Additionally, the management of arteriovenous malformations and nomer as they represent cerebellar hypoplasia without herniation
arteriovenous fistulas in the posterior fossa are often also managed of structures through the foramen magnum.
via interventional radiology-based procedures or via radiotherapy, Another structural anomaly that may require posterior fossa
if possible (2). However, in certain circumstances, the posterior surgery is the Dandy Walker malformation, a common congenital
fossa must be entered surgically to treat these disorders. malformation affecting the cerebellum (5). It is characterized by ab-
Ten percent of all intraparenchymal haemorrhages occur in sence of the cerebellar vermis with cystic dilatation of the fourth
the posterior fossa with the majority of these being found in the ventricle. Obstructive hydrocephalus can present with Dandy
cerebellum (3). Patients often present with headache, ataxia, or al- Walker malformations due to stenosis of the cerebral aqueduct
terations in consciousness and may require surgical evacuation. and lack of patency of the foramina of Luschka and Magendie (6).
Another major class of cerebellar haemorrhage includes those that Patients may present for placement of a shunt to decompress the
occur following a neurosurgical procedure conducted in a loca- posterior fossa cyst with or without shunting of the lateral vent-
tion other than the cerebellum (4). These ‘remote’ cerebellar haem- ricles (if aqueductal stenosis is also present).
orrhages have been reported following supratentorial and spine
surgery and are attributed to either acute CSF hypovolaemia or Signs and Symptoms of Posterior Fossa
mechanical traction on deep brain structures that impedes venous
outflow from the cerebellum.
Pathology
Cranial nerve compression syndromes, most commonly af- Presentation of pathology in the posterior fossa will depend on
fecting the trigeminal (V) and less commonly the facial (VII) and multiple factors including the location of the lesion, the rate of
glossopharyngeal (IX) nerve, may have a vascular aetiology. These growth or development of the lesion, and the impact of the lesion
cranial nerve compression syndromes often present with pain in on CSF flow and overall intracranial pressure (ICP).
the distribution of the nerve (i.e., trigeminal or glossopharyngeal Pathology involving the brain stem often presents with focal
neuralgia) or muscle spasms in the muscles innervated by that deficits related to brain stem function. This can include cranial nerve
nerve (i.e., hemifacial spasm due to facial nerve compression). dysfunction, disorders in respiratory regulation, sensory-motor
175
(a) (b) Inferior sagital sinus

Internal cerebral veins
Basal vein of Rosenthal Vein of Galen
Posterior communicating artery Posterior mesenphalic vein Precentral vein
Posterior cerebral artery Superior vermian vein
Straight sinus
Lateral mesenphalic vein
Superior cerebellar artery
Anterior pontomesenphalic vein
Petrosal (Dandy’s) vein

Basilar artery
Hemispheric vein
Anterior inferior cerebellar artery
Anterior medulary vein
Inferior vermian vein
Posterior inferior cerebellar artery
Vertebral artery Anterior spinal vein
Figure 14.2 The neurologic structures contained in the posterior fossa that receive blood supply from the vertebrobasilar arterial system.
A: Arterial supply to neural structures in the posterior fossa. The posterior fossa sturctures are supplied predominantly via the vertebrobasilar system. Blood enters the posterior fossa via paired vertebral
arteries that join at the ponto-medullary junction to give rise to a single basilar artery. At the junction of the midbrain and pons, the basilar artery bifurcates into bilateral posterior cerebral and posterior
communicating arteries. The brainstem structures are supplied by perforating arteries directly derived from the vertebrobasilar system. The cerebellum is supplied by three pairs of major arteries arising from
the vertebrobasilar system.
B: Venous drainage of posterior fossa structures.
Used with permission of Mayo Foundation for Medical Education and Research. All rights reserved.
176
Table 14.1 Characteristics of posterior fossa tumours.
Epidemiology Pathology Associations Locations Radiographic Treatment and

appearance Prognosis
Children
Astrocytoma Juvenile Pilocytic Most common Low-grade tumour Neurofibromatosis Cerebellum (60%) and Usually contain a Complete resection is
Astrocytoma paediatric brain derived from Type 1. optic nerve (25–30%). cyctic component usually curative. Five-
tumour. Usually astrocytes. and enhances with year survival >90%.
arises during first two contrast.
decades of life.
Brainstem Commonly presents Found in brainstem. Neurofibromatosis Pons (most Brainstem tumour Two-year survival of
Glioma in children ages Four major Type 1. common location), of varing appearance <10% with diffuse
7–9 years. types: diffuse, focal, mesencephalon, depending on specific type. Otherwise, good
exophytic, and and medulla (least type. or excellent long-term
cervicomedullary. common location). survival with surgery.
Medulloblastoma Second most Primitive Coffin-Siris, Cowden, In children, most Hyperdense tumours No metastases,
common paediatric neuroectodermal Gardner, Gorlin, Li- arise from the with occasional complete resection,
brain tumour. More tumour. Extremely Fraumeni, and Turcot cerebellar vermis cyctic components. and negative c-
commonly seen in cellular. syndromes. and protrude into Almost all enhance erbB-2: 5-year
males. Median age of the fourth ventricle with contrast. Can survival=100%;
diagnosis is 9 years. and brainstem. In metastesis in CNS no metastases,
adults, they often via CSF. complete resection,
arise in cerebrellar and positive c-erbB-
hemispheres. 2: 5y survival=54%;
metasteses
present: 5y-
survival=20%
Ependymoma 10% of all paediatric Glial tumours Neurofibromatosis Most arise from Heterogeneous Resection with or
brain tumors.Posterior with ependymal Type 2. the floor of the appearance with without radiation.
fossa mean age is differentiation thought fourth ventricle in heterogenous contrast Five-year survival rate
6 years whereas to arise from glial stem children. Most are enhancement. in children is 50–75%.
supratentorial cells. supratentorial (and Calcifications With recurrance,
tumours commonly often intraparencymal) and cysts can be prognosis is poor
present in third in adults. associated. (mortality up to 90%).
decade.
Pineal region tumours Rare overall. Common Most are classified None identified Pineal region. Diverse. Contoversial. Some
in children in the into either: pinealoma, Surrounding are radiosensitive
second decade of life pineoblastoma, or structures include (while others
but can also occur in germ-cell derived the third ventricle, are complely
adults. pineal tumour. True corpus callosum, and radioresistant. Due to
pathology is extremely thalamus. Proximity location, surgery may
diverse. to deep cerebral be challenging and
vein makes surgical associated with a high
approach risky. rate of complications.
17
Adults
Vestibular Most diagnosed in Benign. Derived from Neurofibromatosis Internal auditory canal Well circumstribed Treatment may
Schwannoma 4th–7th decade of Schwann cells. Dense Type 2. and cerebellopontine with some contrast include observation,
life. Acoustic neuroma cellularity and rare angle. enhancement resection, or radiation
is a misnomer as mitoses. located in the depending on
the tumour is often internal auditory symptoms and co-
derived from the canal and possibly morbidities. Prognosis
vestibular (not the cerebellopontine is excellent.
acoustic) component angle.
of cranial nerve VIII
and is derived from
Schwann cells, not
neurons.
Metastases Most arise from Well demarkated Primary non-CNS Most are Variable. Often Radiation, resection,
lung, breast, renal (except for melanoma) cancer. supratentorial but 15% have excessive and chemotherapy
cell, melanoma, and with extensive of metastases arise in peritumoral oedema. are performed for
GI adenocarcinoma. oedema. the cerebellum. Ring-enhancement palliative purposes
Thyroid and or evidence of and to minimize
choriocarcinoma can haemorrhage. symptoms in the
also metasteasize short term. One year
to brain. 50% are a mortality =50% with
solitary CNS tumour. treatment.
Haemangioblastoma Slight male Vascular low-grade von Hippel Lindau, 95% occur in the Sharply demarcated Resection is often
predominance. tumour despite the pheochromocytoma. cerebellum (especially homogeneous mass curative. Large lesions
Occurs commonly in ‘-blastoma’ suffix. the cerebellar often composed of may benefit from
4th–7th decade but hemispheres). cysts, High perfusion pre-operative partial
earlier in patients with on blood flow studies. embolization.
von Hippel Lindau
syndrome..
CNS: Central nervous system
178
deficits due to compression of afferent or efferent tracts from or to

more rostral regions of brain, or alterations in level of conscious-
ness. In addition, brain stem lesions can impact CSF flow leading
to obstructive hydrocephalus with symptoms of headache, nausea,
vomiting, papilloedema, or altered level of consciousness.
Disorders affecting the cerebellum often result in difficulty co-
ordinating motor tasks and not frank motor weakness. This can
include postural instability, difficulty initiating, coordinating, or
terminating movements, errors in smoothness of movements, or
impaired motor learning. Medial cerebellar lesions lead to difficulty
with coordination of axial musculature typically causing postural
instability. Lateral lesions result in altered motor function of the
ipsilateral appendicular muscles, including the inability to perform
rapid alternating movements (dysdiadochokinesis), inability to
target an object with a finger (dysmetria), or complex movements
that are decomposed into specific tasks.
Lesions contained within or that abut the fourth ventricle mani-
fest by obstructing the flow of CSF with or without compression
of adjacent structures in the brainstem or cerebellum. Obstruction
of CSF flow leads to dilatation of the lateral and third ventricles
and symptoms of increased ICP as discussed previously. The floor
of the fourth ventricle is formed by dorsal structures contained in
the pons and superior medulla, including various cranial nerve
tracts and nuclei (especially VII, IX, and X) and both afferent and
efferent tracts to and from rostral brain structures. Additionally,
regions responsible for the regulation of ventilation, such as the
nucleus tractus solitarius, lie near the floor of the fourth ventricle
predisposing to alterations in ventilation pattern.
The diagnosis of posterior fossa pathology depends on the pres-
ence of these signs and symptoms as well as imaging that may
include computerized tomography (CT) or magnetic resonance
imaging. Vascular abnormalities, such as aneurysms or arterio-
venous malformations, may require cerebral angiography to fur-
ther delineate anatomy and plan appropriate treatment.
Surgical Approaches
The posterior fossa is generally entered via one of two classic
routes: the midline suboccipital and lateral suboccipital approaches.
It should be noted that in some circumstances, such as in patients
with larger tumours or tumours requiring superior extension (e.g.,
pineal tumours), the craniotomy site can be extended or modified.
The midline suboccipital approach to the posterior fossa is il-
lustrated in Figure 14.3A and is often chosen for midline lesions
such as decompression of Chiari malformations, resections of
medulloblastoma or ependymoma, or resections of tumours in the
pineal region via a supracerebellar approach. In patients having a
midline approach, the most common body positions are prone or
sitting. Factors dictating the choice of body position include sur-
geon preference and need for increased neck flexion. However, for
pineal region tumours, many surgeons prefer the sitting position
A: Midline suboccipital approach.

B: Lateral suboccipital approach.
C: Temporal craniotomy. This approach can provide access to the major arteries of
the vertebrobasilar system and can be used for aneurysm clippings such as those
involving the posterior cerebral (as shown), superior cerebellar, or basilar arteries.
Used with permission of Mayo Foundation for Medical Education and Research. All rights
reserved. Figure 14.3 Surgical approaches to the posterior fossa.
179
Chapter 14 the posterior fossa 179
as it allows for inferior traction of the cerebellum by gravity, thus alert adult patients, small doses of benzodiazepines may help alle-
increasing available room to access this deep region (7). viate anxiety without significantly affecting ventilation. However,
The lateral suboccipital approach (Figure 14.3B) provides op- patients with intracranial pathology may be particularly sensitive
timal access to the cerebellopontine angle for resection of vestibular to the respiratory depressant effects of opioids and sedatives. Drug-
schwannomas, meningiomas in the cerebellopontine angle, and induced respiratory depression may lead to further increases in ICP
microvascular decompression of cranial nerves. The lateral cere- due to an increase in arterial carbon dioxide (CO2) partial pressure.
bellum can also be easily accessed via the lateral suboccipital ap- Sedation should be administered cautiously as it can mask changes
proach. The lateral suboccipital approach also offers access to the in level of consciousness that can accompany intracranial path-
pons for resection of masses, or aneurysms near the vertebrobasilar ology and intracranial hypertension.
junction, such as those involving the posterior inferior cere-
bellar artery. In addition to prone and sitting position, the lateral
suboccipital approach can also be performed with the patient in the Induction of Anaesthesia
park-bench position, frank lateral position, or even in the supine The goals for induction of anaesthesia in patients with posterior
position with the head turned. fossa lesions include maintenance of cerebral perfusion pressure
Other aneurysms in or near the posterior fossa may be more ef- (CPP), haemodynamic stability, and avoidance of increases in ICP.
fectively accessed via other approaches. For example, aneurysms of Sudden and sustained increases in systemic blood pressure (BP)
the basilar tip or of the posterior cerebral artery can be accessed by may be accompanied by increases in cerebral blood flow (CBF),
a temporal approach as shown in Figure 14.3C (8, 9). cerebral blood volume (CBV), and ICP that may precipitate cere-
bral oedema and decrease cerebral perfusion. Prolonged episodes
Pre-Operative Assessment and Management of hypotension should be avoided to prevent brain ischaemia.
Although not always required, placement of an intra-arterial cath-
Pre-operative evaluation should focus on the needs of each indi- eter prior to induction of anaesthesia may allow for tighter and
vidual patient while also considering the unique aspects of sur- more precise control of BP during periods of haemodynamic ex-
gery requiring entry into the posterior fossa. It is important to tremes, such as induction of anaesthesia and laryngoscopy or other
obtain and document a baseline gross neurologic history and per- noxious events.
form a focused neurologic examination. Knowledge of the pre- Induction of anaesthesia is usually achieved with medications
existing neurologic physical status will allow for stratification of such as propofol, etomidate, or a barbiturate. These medications
pre-existing versus new neurologic deficits upon emergence from produce a reliable onset of anaesthesia without causing increases
anaesthesia and may also help guide care following surgery. Pre- in ICP. Earlier data suggested that ketamine can increase CBF,
operative review of available radiologic imaging may reveal evi- metabolism, and ICP. However, several more recent studies have
dence of intracranial hypertension if mass effect or midline shift is demonstrated that ketamine does not significantly increase ICP
present, can help to stratify risk for intra-operative bleeding (i.e., if and may be beneficial by providing haemodynamic stability and
surgery involves or is near major vessels), and help predict risk for maintaining CPP (11).
new postoperative neurologic deficits. To facilitate tracheal intubation, a nondepolarizing neuromus-
In addition to airway evaluation, a thorough assessment of the cular blocking drug can be administered. The use of succinylcho-
patient’s cardiovascular and pulmonary status is important to de- line may be associated with a modest but transient increase in
termine if the patient will tolerate the physiologic surgical stress ICP and should be administered with caution, although it is not
and positions necessary for posterior fossa surgery, such as the absolutely contraindicated. Succinylcholine should be used with
sitting position. In patients who may have alterations in cerebral caution (if at all) in any patient with pre-existing motor deficits
autoregulation due to hypertension, cerebrovascular disease, or due to concern for hyperkalaemia. The noxious stimuli during
cardiovascular disease, this concern is particularly important. laryngoscopy can be blocked by additional doses of intravenous
This subset of patients may require special considerations in posi- anaesthetics, intravenous lidocaine, esmolol, or short-acting opi-
tioning and systemic arterial pressure goals to maintain adequate oids. Once the position of the endotracheal tube has been con-
cerebral perfusion. Also, in patients in whom the sitting position firmed, ventilation should be instituted to maintain normocapnia.
is planned, any prior echocardiography reports should be reviewed A lower target PaCO2 may be transiently required in patients with
for the presence of an intracardiac shunt, such as a patent foramen elevated ICP.
ovale (PFO). Patients without prior echocardiography exams must After induction of anaesthesia, large bore intravenous access
be screened for intracardiac shunts prior to being placed in the sit- should be obtained. Central venous lines are commonly placed,
ting position. They may be at increased risk for paradoxical air em- particularly if the sitting position is utilized and may be of benefit
bolism if a venous air embolism (VAE) occurs, and might be better in patients having posterior fossa surgery in horizontal positions.
suited for a horizontal rather than sitting position. The tip of the central venous catheter should be positioned in the
Patients with cranial nerve deficits leading to dysphagia, loss of right atrium to allow for withdrawal of air in the event of a venous
a gag reflex, and laryngeal nerve dysfunction may have decreased air embolism. Urinary catheters and gastric tubes are commonly
oral intake predisposing to hypovolaemia and electrolyte abnor- placed after induction of anaesthesia.
malities. Patients with a diminished gag reflex and laryngeal nerve
dysfunction may require continued intubation postoperatively.
Pre-operative anxiety is prevalent among patients undergoing Maintenance of Anaesthesia
neurosurgical procedures; however, administration of premedica- Maintenance of anaesthesia in patients undergoing posterior
tion is not routinely performed in this patient population (10). In fossa craniotomy can be achieved using a variety of anaesthetic
180
techniques consisting of both inhaled and intravenous anaesthetics. Table 14.2 Advantages of the sitting vs. horizontal positions.
The primary goals include maintenance of stable haemodynamics,
CPP, and allowance for rapid awakening after surgery. The choice Advantages Disadvantages
of anaesthetic for maintenance is governed by the specific needs
Sitting ◆ Improved surgical ◆ Increased risk of VAE.
of the surgery (i.e., neurophysiologic monitoring, brain relaxation). exposure. ◆ Hypotension and decreased
Inhalation anaesthetics permit for rapid titration and emergence to
◆ Enhanced cerebral cerebral perfusion pressure.
allow for prompt neurologic examination, but may not be the ideal venous and CSF ◆ Excessive neck flexion may
choice for cases requiring brain relaxation due to the cerebral vaso- drainage. lead to airway oedema
dilation associated with inhaled anaesthetics. Total intravenous ◆ Improved airway access. and stretching of the
anaesthetics are ideal for procedures involving neuromonitoring spinal cord.
◆ Improved chest wall
and requiring brain relaxation. Titratable, short-acting opioids
compliance. ◆ May require additional
(e.g., fentanyl, sufentanil, remifentanil) are usually preferred in lines and monitors due to
◆ Better access to chest
posterior fossa surgery to allow for a rapid emergence from an- risk of VAE.
and extremities for
aesthesia. Long-acting opioids (e.g., morphine, hydromorphone, line and monitor
oxymorphone, or excessive amounts of fentanyl) may contribute to placement.
a delayed emergence or postoperative hypoventilation and should
Horizontal ◆ Optimize surgical ◆ Patients with limited neck
be used with caution.
(Lateral, Prone, exposure to certain range of motion may not
The use of nitrous oxide (N2O) during intracranial surgery areas of the brain. tolerate the neck rotation
Park-bench)
is controversial. In most circumstances, it can be used safely. necessary for some of
◆ Reduced
However, N2O causes cerebral vasodilation and has the potential to haemodynamic these positions.
increase CBV and ICP and should be used with caution in patients compromise. ◆ Brachial plexus injuries
with space-occupying lesions or known elevation of ICP. Also, N2O can occur with lateral and
should be avoided in patients who potentially may harbour intra- park-bench.
cranial air, i.e., those who have undergone craniotomy or spine sur- ◆ Difficulty with ventilation
gery with dural breech within eight weeks. N2O should also be used may occur.
with caution in patients having procedures performed in the sitting ◆ Airway oedema.
position. The incidence of VAE in the sitting position is not influ- ◆ Increased risk of cranial
enced by N2O use (12). However, in the event of a VAE, N2O should nerve injuries.
be discontinued due to concern about expansion of the volume of
the air embolus and exacerbation of the physiologic sequelae.
Skeletal muscle paralysis should be maintained throughout the
Patient position is determined by surgical factors such as neuro-
procedure as movement while undergoing posterior fossa surgery
surgeon preference and the need for optimal surgical exposure.
can be detrimental. Skeletal muscle relaxation is usually achieved
Patient factors are also considered when determining positioning.
with non-depolarizing neuromuscular blocking drugs.
Comorbid diseases, musculoskeletal flexibility, and the ability of
The haemodynamic response to stimulating events, such as
the patient to tolerate the anticipated surgical position should be
laryngoscopy, pinion placement, and surgical incision, should be
assessed pre-operatively to ensure that the position can be safely
pharmacologically attenuated as significant hypertension could
achieved while the patient is anaesthetized. Table 14.2 outlines the
lead to increased CBF, worsening intracranial hypertension, or
advantages and disadvantages of sitting versus horizontal positions
increasing the risk of intracranial haemorrhage. Administration
for posterior fossa surgery.
of additional intravenous or inhaled hypnotic drugs, intravenous
lidocaine, short-acting opioids, or short-acting beta adrenergic an- Sitting Position
tagonist drugs, such as esmolol, can attenuate hypertension.
The sitting position confers many advantages for surgical proced-
Iso-osmolar intravenous fluids should be used for maintenance
ures in the posterior fossa. It offers improved surgical exposure, en-
as these solutions do not adversely cause oedema formation in the
hanced cerebral venous and CSF drainage, and minimizes blood
brain when used in modest amounts. As the blood-brain barrier
loss. Gravity-assisted caudal retraction of the cerebellum makes
does not allow for rapid transit of ions, the osmolarity of a solu-
the sitting position especially appealing for access to the pineal
tion determines the distribution of fluids between the intravascular
region (7). Advantages of the sitting position for the anaesthetist
and the extracellular compartment. Therefore, hypo-osmolar solu-
include access to the airway, lower airway pressures during mech-
tions, such as 0.45% sodium chloride, should be avoided to prevent
anical ventilation, lack of a major source of external pressure on
a shift of free water into brain tissue, leading to brain oedema. Fluid
the eyes, and access to the chest and extremities for monitoring
administration should be titrated to maintain euvolaemia. The use
and line placement. However, the sitting position is associated with
of glucose solutions should be avoided as hyperglycaemia in the
a risk of VAE due to the surgical site above the level of the heart
setting of cerebral ischaemia can exacerbate neuronal injury and
causing venous pressure at the operative site to be sub-atmospheric,
worsen outcomes (13).
requiring additional monitoring. Utilization of the sitting position
has been decreasing probably due to combination of concern for
Positioning complications specific to this position and the need for additional
Posterior fossa surgery can be performed with the patient in sev- monitoring for VAE (14). Contraindications to utilizing the sitting
eral positions: sitting, prone, lateral, park-bench, and even supine. position include, but are not limited to, a PFO or other source of
18
potential intracardiac shunt due to risk for paradoxical air em- support should be placed under the elbows to reduce risk for down-
bolism. In patients with a working ventriculoatrial shunt, neurosur- ward displacement of the upper arms and risk for stretch of the bra-
gical procedures that risk entrainment of air through the shunt are chial plexus. Finally, at least a two-finger-breath distance should be
better performed in a horizontal position, if possible. Additionally, noted between the chin and manubrium as excessive neck flexion
those with symptomatic orthostatic hypotension or musculoskel- could impede jugular venous drainage or provide excessive stretch
etal limitations may not tolerate the sitting position. to the spinal cord, limiting perfusion and increasing risk for a cer-
When patient position is changed from supine to sitting, venous vical cord injury (19).
pooling in the lower body results in reduced cardiac preload. This
change in position to sitting is also associated with a decrease in the
cardiac inotropic state and a decrease in systemic afterload (15).
Complications and Monitoring
Taken together, these effects on cardiovascular physiology predis- As stated previously, although the sitting position has many ad-
pose to systemic hypotension that can decrease cerebral perfusion. vantages, there are some complications that are very specific
Challenges arise with determining CPP in patients in the sit- to this position. These include VAE, paradoxical air embolism,
ting position. While in the sitting position, there is a hydrostatic pneumocephalus, macroglossia, cervical cord injury, and periph-
pressure gradient between the aortic root and circle of Willis. CPP eral nerve injury.
should optimally reflect correction for the hydrostatic pressure
difference between the heart and the brain (16). This is generally Venous Air Embolism and Paradoxical Air Embolism
accomplished by measuring BP via an intra-arterial catheter and VAE is probably the most common complication specifically attrib-
referencing the pressure transducer to the vertical height of the uted to the sitting position. However, it is important to note that
external auditory meatus, which approximates the position of the any position where the operative site is above the horizontal level
circle of Willis. Lack of correction for hydrostatic pressure may put of the heart potentially predisposes to a risk for VAE. This includes
the patient at undue risk of cerebral hypoperfusion (17). However, shoulder surgery in the sitting position, cervical muscular denerv-
the factors governing cerebral perfusion are not well described. ation for torticollis, or procedures performed supine but where
Specifically, some argue that in a closed circulatory circuit, a venous excessive reverse Trendelenburg position is used. Craniotomies
siphon physiology may significantly contribute to cerebral perfu- performed in the sitting position are at particularly high risk for
sion (18). As such, correction of hydrostatic gradients in the arterial VAE as the operative site is elevated above the level of the heart, and
circulation may not be necessary. Given this controversy, the most the veins in the cranium may be non-collapsible due to the attach-
conservative strategy supports correcting for the hydrostatic pres- ment to bone or dura.
sure gradient by placing the arterial transducer at the level of the The incidence of VAE during neurosurgical procedures is dif-
external auditory meatus. This would encourage a more aggressive ficult to ascertain. Overall, the reported rate in the literature is
avoidance of lower pressures as measured by the transducer and wide: 1.6–93% (20). The large range in rates can be attributed to a
potentially improved cerebral perfusion. variety of factors including the retrospective nature of many inves-
Compared to horizontal positions, the sitting position allows tigations and heterogeneity within the investigations with respect
for greater diaphragmatic excursion with mechanical ventilation to the monitors employed to detect VAE. Recent retrospective data
increasing functional residual capacity. There is less chest wall report an overall VAE rate of 5.5% in sitting neurosurgical cases
restriction during inspiration leading to lower peak and plateau with 11%, 4.7%, and 3.3% occurring in sitting craniotomies, deep
airway pressures during mechanical ventilation (15). These effects brain stimulator lead implantations, and cervical spine procedures,
on respiratory mechanics can be especially beneficial in obese pa- respectively (21). It is very likely that many mild VAE events were
tients who may be challenging to ventilate in the prone or lateral underreported in this series.
positions. The severity of VAE can vary widely. There are a variety of
To place a patient in the sitting position, induction of anaesthesia, grading scales to describe the severity of VAE based on clinical
airway management, and placement of lines and monitors are all signs or transoesophageal echocardiographic (TEE) findings (22–
performed with the patient in the supine position. Figure 14.4A il- 24). However, events can broadly be classified into mild, moderate,
lustrates a patient properly placed in sitting position. Once the head or severe events (21) defined as:
is secured to the arch frame and the arch frame is secured to the
bed, it is critical that no further changes are made in bed flexion Mild: evidence of VAE on pre-cordial Doppler sonography or TEE
between the segments of the table where the torso rests and the seg- without changes in end-expired CO2 tension or haemodynamics.
ment where the thighs rest, as this may cause injury to the cervical Moderate: evidence of VAE on pre-cordial Doppler sonography or
spine. Changes in the height and position of the head should be TEE with evidence of haemodynamic changes or a decrease in
made only by changing the overall vertical height of the bed or by end-expired CO2 tension.
changing the degree of Trendelenburg and reverse Trendelenburg
position. Severe: evidence of VAE on pre-cordial Doppler sonography or
Specific positioning details should also be considered. The TEE with haemodynamic changes necessitating return to the
patient’s lower back should rest against the bed. If there is signifi- supine position for resuscitation.
cant space between the patient’s lumbar region and the table mat- In patients without a right-to-left circulatory conduit (e.g., PFO),
tress, the majority of the patient’s weight will rest on the ischial air that is entrained into the systemic venous system passes through
tuberosities potentially increasing the risk for a pressure-related the right side of the heart to enter the pulmonary circulation. Here,
injury. The hands should be resting on the patient’s abdomen or the bubbles of air prevent forward blood flow through the pul-
secured appropriately on cushioned armrests. Blankets or other monary circulation leading to an increase in dead space ventilation,
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Figure 14.4 Illustrations of a patient properly placed in sitting position, and horizonal positions used for posterior fossa surgery.
A: The sitting position. The Mayfield head holder is placed on the patient’s head and secured to the table with an arch frame. The bed is ‘flexed’ so that the angle
between the torso and upper legs assumes an angle of a causal sitting position. The most caudal segment of the bed is also lowered to decrease the angle at the knees
as to reduce hamstring stretch. A foot board is also otimized to support the feet. The upper arms are supported either by resting on the bed or with blankets to reduce
stretch on the brachial plexus and the hands are resting on the abdomen or armboards. Finally, there is appropriate space between the chin and the manubrium.
B: Horizonal positions for posterior fossa surgery. In descending order: prone, park-bench, lateral, and supine positions.
183
pulmonary hypertension, and decreased right ventricular cardiac less-sensitive or specific techniques to monitor for VAE include
output. Local hypoxaemia induces reflex pulmonary vasoconstric- transcranial Doppler sonography (detecting the presence of air
tion that exacerbates the pulmonary hypertension. Furthermore, in the cerebral circulation after systemic entry), increases in end-
air induces an inflammatory response in the vascular endothelium expired nitrogen tension, decreases in end-expired CO2 tension,
(25–27). This cascade not only induces injury to the pulmonary the presence of a new murmur on cardiac auscultation, or the pres-
microvasculature but also serves to exacerbate systemic hypoten- ence of hypotension or decreased systemic oxygen saturation.
sion. In the setting of a rapid entrainment of a large volume of air, The incidence of PFO in the general population is 27% (28). To
pulmonary vasoconstriction will cause an increase in right ven- test for the presence of a PFO via TEE, the heart should be insonated
tricular afterload and subsequent right ventricular failure. to allow for visualization of both atria. Typically, the four-chamber
A variety of methods have been described to monitor for VAE. view is most commonly used (Figure 14.5). Approximately 30mg
In general, the most sensitive techniques are TEE and precordial H2O of Positive end-expiratory pressure (PEEP) is administered to
Doppler sonography. TEE offers the advantage of providing a quan- allow for a restriction of venous return to the right side of the heart.
titative assessment of the degree of VAE as opposed to pre-cordial Agitated saline containing a small amount of air is then injected into
Doppler sonography, which alerts only to whether or not air is a vein. When air is visualized in the right atrium, PEEP is released
present in the heart. Additionally, TEE can be used to assess for allowing for an abrupt increase in venous return to the right side
the presence of a potential right-to-left intracardiac shunt. Other of the heart, temporarily increasing right-sided heart pressures. If
Figure 14.5 The transesophageal echocardiographic four-chamber view.

A shows the four-chamber view, and B shows intracardiac air. Four-chamber transesophageal echocardiogram illustrating air opacifying the right atrium (RA) but also air
bubbles are present in left atrium (LA) in a patient with a patent foramen ovale.
184
the right atrial pressure is greater than left atrial pressure following
Box 14.1 Steps to Perform in the Event of a Venous Air Embolism
PEEP release, and a PFO is present, air may be visualized in the
left atrium (Figure 14.5). There are a few limitations of this tech-
nique worth mentioning. First, the presence of air in left atrium 1. Notify surgeon and ask them to flood the field if possible.
immediately following release of PEEP suggests the presence of a 2. Discontinue nitrous oxide if in use and initiate 100% oxygen.
PFO but a very small amount of air appearing in the left atrium
3. Aspirate from central line if present.
after approximately ten cardiac cycles may simply be air that has
transited the pulmonary circulation. Second, detection of a PFO 4. Maintain haemodynamics as necessary.
by this technique depends on an increase of right atrial pressure so 5. Jugular compression.
that it is greater than left atrial pressure to cause air to transit into
6. Reposition the patient to supine position.
the left atrium. This right-to-left pressure gradient may not occur
in those with chronically increased left-sided heart pressure, such 7. Consider hyperbaric therapy.
as those with hypertensive heart disease or left-sided valvular sten-
osis. Also, in patients who are absolutely or relatively hypovolaemic
(i.e., immediately after being placed in the sitting position, blood
pools in the lower body decreasing right ventricular preload), it inhibitors, such as milrinone, may be beneficial in decreasing pul-
may be difficult to increase right atrial pressure with PEEP release. monary artery vasoconstriction and increasing right ventricular
As such, the test should be performed while the patient is in the output (31, 32).
supine position. A catastrophic complication of air entrainment occurs when air
Pre-cordial Doppler sonography is the most sensitive non- enters the systemic arterial circulation. This paradoxical air em-
invasive monitor for VAE. The probe is placed lateral to the sternal bolism occurs when a large amount of air transits the pulmonary
border and moved superior and inferiorly until cardiac sounds circulation, but can occur in large quantities in patients with a PFO.
are auscultated. In our experience, multiple parasternal sites are Systemic air can enter the capillary network in vital organs limiting
insonated bilaterally and the probe is secured with tape over the site perfusion. Air in the brain, coronary circulation, or renal arteries
allowing for the most optimal heart sounds. Additionally, a small can predispose to stroke, myocardial infarction, and renal infarcts,
amount of air in agitated saline is injected via a vein to confirm that respectively.
a change in Doppler sounds occurs. If this does not occur, a new
site is chosen and reconfirmed with agitated saline injection again. Other Complications Associated with the Sitting
In cases at high risk for VAE, such as posterior fossa craniotomy, Position
central venous access should be considered. This can be accom- Some degree of pneumocephalus occurs following the majority of
plished with placement of either a standard central line via the intracranial procedures. However, in the sitting position, the CSF
subclavian route (as internal jugular access may impede on the op- located in the subarachnoid space and above the level of the sur-
erative site) or via an antecubital vein. Electrocardiography elec- gical incision tends to drain out following opening of the dura
trodes or TEE can be used to position the antecubital ‘long arm’ mater. This fluid can be replaced, in part, by air during the sur-
central venous line at the position of the right atrial/superior vena gical procedure. In most circumstances, this air does not cause ill
caval junction. It is important to note that, even in the setting of effects and is generally absorbed over the weeks following surgery.
a large VAE, very little air is often aspirated. Thus, acquisition of In some circumstances, the volume of air can impede cerebral
central access and aspiration of air may not significantly improve perfusion by increasing ICP. This tension pneumocephalus gener-
haemodynamic stability or modulate outcome (21, 26, 29). ally presents as delayed emergence from anaesthesia and may or
In the setting of an acute VAE, the clinician should immediately may not be associated with haemodynamic abnormalities. If ten-
notify the surgeon and discontinue N2O to prevent expansion of sion pneumocephalus is considered, diagnosis is made via a non-
the air bubbles. It is vital to be aware of iatrogenic sources of VAE, contrast CT scan of the head. Treatment involves emergent surgical
such as the small amount of air seen following intravenous injec- evacuation. N2O use has been attributed to an increased risk for
tions of medications. With true VAE, the surgeon may flood the tension pneumocephalus. However, there is no evidence other
field with saline although this is sometimes difficult to effectively than anecdotal case reports to support this association. During any
perform with the patient in the sitting position. If a site of entrain- intracranial procedure, institution of N2O use after dural closure
ment is identified, it should be closed. With continued or signifi- can increase intracranial volume and increase risk for tension
cant air entrainment, application of bilateral jugular pressure can pneumocephalus. However, if N2O is used for the duration of the
reduce further entrainment and assist the surgeon in identifying case, risk for pneumocephalus-induced intracranial hypertension
the source (30). Aspiration of air from a central line should be at- should be very low (33).
tempted. With significant and continued air entrainment, return Excessive neck flexion or the presence of a TEE probe can lead
to the supine position may not only increase venous pressure at to macroglossia due to jugular compression and impaired venous
the surgical site (reducing further entrainment) but the supine drainage from the tongue. Extubation of patients with macroglossia
position may also improve systemic haemodynamics and allow can result in acute airway obstruction and difficulty with direct
for effective cardiopulmonary resuscitation, if needed (Box 14.1). laryngoscopy. In patients with macroglossia, the TEE probe should
Haemodynamic support should be instituted if necessary. be removed and the patient should remain intubated until the
Phenylephrine may improve right coronary perfusion and norepin- macroglossia resolves.
ephrine is noted to increase systemic BP without further increasing Excessive neck flexion can also lead to stretching of the spinal
right ventricular afterload (27). In addition, phosphodiesterase cord. Patients with pre-existing cervical cord compression or
185
compromise are theoretically at increased risk. This can present as if there is a likelihood of bleeding and the need for transfusion or if
postoperative quadriplegia. Peripheral neuropathies can also de- rapid administration of fluids is anticipated. A central venous cath-
velop in the sitting position. Inadequate support of the arms can eter should be considered in patients with poor peripheral vascular
lead to brachial plexus stretch predisposing to a brachial plexus access, in patients whose medical comorbidities require a central
neuropathy. In addition, sciatic or peroneal nerve injury can occur. line, if a large degree of blood loss is expected, and if there is risk
Therefore, appropriate padding and attention to detail with patient for significant VAE.
positioning may reduce the risk of these injuries. Episodes of bradycardia are possible during posterior fossa pro-
cedures. The aetiology of these events is either direct compression
Horizontal Positions of the brainstem or traction on cranial nerves (most commonly cra-
Alternatives to the sitting position include a variety of positions nial nerve V, IX, and X) leading to increased afferent activity. In
where the patient is maintained in a relative horizontal position. these circumstances, increased vagal outflow results in increased
As illustrated in Figure 14.4, these include the prone, park-bench, cardiac parasympathetic stimulation and subsequent bradycardia.
lateral, and even supine position with the head turned. The choice These bradycardic events are generally very abrupt in onset and
of the specific position depends on the location of the pathology, can be profound, occasionally manifesting as asystole. Fortunately,
surgical approach, surgeon, preference, musculoskeletal limita- treatment generally involves release of pressure or traction on
tions, and comorbidities. For example, midline lesions can be ap- CNS structures and the heart rate will often return to normal very
proached via the prone or park-bench position, whereas lateral quickly. Transcutaneous pacing or intravenous administration of
lesions are best performed in the lateral, park-bench, or supine either atropine or epinephrine with chest compressions to facili-
positions. Patients with limited range of motion in the neck may tate drug circulation may be required if these episodes are not self-
not tolerate positions that require significant neck rotation. Also, limiting. There is very little evidence to suggest that prophylactic
patients with limited shoulder mobility may not tolerate resting on doses of anticholinergic drugs, such as atropine or glycopyrrolate,
their shoulder or the degree of shoulder flexion utilized in the lat- are of any benefit in reducing the risk for or severity of bradycardic
eral or park-bench positions. In any position, attention should be episodes.
paid to musculoskeletal flexibility and padding of appropriate pres- Other monitors that may be considered include a precordial
sure points. Ventilation may be difficult in patients with morbid Doppler ultrasound probe and TEE. These monitors are best used
obesity while in the prone position. for detection of a VAE and have been discussed previously.
The lateral and park-bench positions are both associated with an Electrophysiologic monitoring is used in select procedures to
increased risk for brachial plexus injury. An axillary roll should be help determine the integrity of various neural pathways during
placed under the shoulder and adjacent to the upper chest to reduce posterior fossa surgery. These special monitoring techniques are
stretch of the brachial plexus. The prone position is associated with usually managed by electrophysiologists with special training in
the development of dependent airway oedema. Although compres- the conduction and interpretation of these techniques. The need
sion of the eyes may be a risk in other procedures performed in the for monitoring and the specific choice of the type of monitoring
prone position, it is a very low risk in patients in whom a Mayfield often depends on the nature and location of the pathology, and sur-
headholder or other versions of pinions are utilized. If significant geon preference. Monitoring may include one or a combination
reverse Trendelenburg is utilized the patient may be at risk for VAE of brainstem auditory evoked responses (BAERs), electromyog-
and VAE should be suspected in any case involving unexplained raphy (EMG), somatosensory evoked potentials (SSEPs), or motor
hypotension and decreased end-expired CO2 tension. evoked potentials (MEPs). The specific anaesthetic implications of
these modalities are discussed in Chapter 12.
Monitoring
The aims of monitoring during posterior fossa surgery are to main-
Emergence
tain both cardiopulmonary stability and adequate CPP, and to detect The goals for emergence from anaesthesia include early awakening,
VAE. Routine monitors for posterior fossa surgery include five-lead prevention of abrupt increases in BP, and minimizing coughing and
electrocardiogram, BP monitoring, temperature, pulse oximetry, straining. Early awakening from anaesthesia will allow for assess-
and capnography. The use of an intra-arterial catheter will allow for ment of neurologic function to identify any adverse events related
continuous monitoring of systemic BP and cerebral perfusion, while to the surgical procedure. The sedative effects of general anaesthesia
allowing blood sampling as needed. Capnography monitoring will may cause an exacerbation of any pre-existing neurologic deficits
allow for continuous assessment of the end-expired CO2 tension (34). New or persistent neurologic deficits should be communi-
to aid in ventilatory adjustments to manage arterial CO2 tension. cated to the surgeon and promptly investigated. Hypertension,
Temperature monitoring is conducted with either a nasopharyn- coughing, and straining should be avoided during emergence,
geal or oesophageal temperature probe and is useful in preventing extubation, and the early postoperative period. These factors can
hyperthermia or uncontrolled hypothermia. Placement of a urinary contribute to postoperative brain oedema and an increased risk
catheter can aid in peri-operative fluid balance assessment and can of intracranial haemorrhage. Rapid onset antihypertensives such
prevent bladder distention during administration of diuretic medi- as labetalol and esmolol should be immediately available for ad-
cations or a lengthy surgical procedure. A nerve stimulator should ministration during a hypertensive episode. In patients without
be used to assess the degree of skeletal muscle paralysis if neuromus- pre-operative poorly controlled systemic hypertension, a persistent
cular blocking drugs are used during the procedure. systolic BP >160 mmHg following craniotomy may be associated
Intravenous access should be obtained prior to induction of gen- with increased risks for intracranial haemorrhage and surgical site
eral anaesthesia. Large bore intravenous catheters should be placed bleeding (35).
186
The decision to remove a tracheal tube at the end of a procedure brainstem injury, e.g., depressed level of consciousness, pupillary
in patients who underwent posterior fossa surgery must take into abnormalities, or abnormal respiratory patterns.
consideration several factors. In addition to the standard criteria
for extubation, the nature and extent of surgery and the patient Posterior Fossa Syndrome
position must also be considered. Surgery in the posterior fossa Posterior fossa syndrome is a complication of posterior fossa sur-
may include manipulation of cranial nerves and the brainstem gery commonly observed in 11–29% of all children having proced-
(36). Trauma and oedema of these structures can compromise the ures in the posterior fossa (38). It is especially common following
patient’s ability to support their airway due to decreased airway resection of medulloblastoma (39). Classically, patients will exhibit
reflexes or maintain adequate oxygenation and ventilation (37). mutism or dysarthria accompanied by other findings such as ataxia,
Airway and tongue oedema can occur following posterior fossa frank neurologic deficits, hypotonia, dysphagia, dysmetria, and
surgery in any position. Intubation should be maintained in these cognitive or behavioural changes. Signs and symptoms can occur
patients until the patient is awake, following commands, and immediately following surgery or onset can be delayed for up to a
demonstrating return of protective airway reflexes. When delaying week after surgery. Recent data suggests that injury or tumour in-
extubation, a head up position allows venous drainage and may volvement of the primary outflow tracts of the cerebellum, specific-
assist in reducing the amount of airway oedema and aid in a de- ally the dentate nucleus and cerebello-cerebral tract, may be a more
creased time to extubation. Extubation over a tube exchanger can specific cause (40). Children with posterior fossa syndrome have
be considered if there is concern that the patient may not be able to decreased cerebral cortical perfusion, which is likely due to loss of
protect their airway or that glottic oedema may be present. cerebellar afferents, thus accounting for the diffuse constellation of
symptoms of both cerebral and cerebellar origin (40). Treatment
Other Complications Associated involves pharmacologic options to manage specific symptoms,
including use of antidepressants. Overall, some patients recover
with Posterior Fossa Surgery completely. However, many are left with residual deficits including
As with any surgical procedure there are complications that can ataxia, dysarthria, and both cognitive and behavioural problems.
arise with posterior fossa craniotomy. Some of the complications
are related to the nature of the surgery, positioning for surgery, Postoperative Haemorrhage
and anaesthetic-related complications. Many of the complications Overall, the rate of postoperative intracranial haemorrhage fol-
associated with supratentorial surgery such as haemorrhage and lowing an intracranial procedure is reported to be in the range of
stroke can occur in posterior fossa surgery as well. This section re- 0.8% to 50% (41, 42). This wide range is likely due the specific diag-
views the most common complications specific to surgery in the nostic criteria used to define intracranial haemorrhage, whether or
posterior fossa. not occult haemorrhages are included, and the prevalence of risk
factors for haemorrhage in the study population. Data describing
Postoperative Neurologic Deficits Specific to Posterior the rates of postoperative posterior fossa intracranial haemor-
Fossa Procedures rhage are limited. However, in one investigation consisting of
Given that cranial nerves III–XII originate and transit through the 1074 intracranial procedures, a total of 116 postoperative intracra-
posterior fossa, surgical procedures performed in the posterior nial haemorrhages were identified and nine occurred in the pos-
fossa put the cranial nerves at risk for injury. Furthermore, posterior fossa: seven in the cerebellum, one at the cerebellopontine
terior fossa pathology may compromise cranial nerve function angle, and one in the pineal region (43). It is important to note that
pre-operatively—thus the patient may present for surgery with postoperative intracranial haemorrhage can generally be stratified
pre-existing cranial nerve deficits. The surgeon and anaesthetist into either surgical site haemorrhages (occurring at the site of sur-
may elect to monitor cranial nerve function intra-operatively via gery) or remote (occurring distant from the site of surgery). This
electrophysiologic-based techniques. distinction is critical as the risk factors and pathophysiology for
Dysfunction of any cranial nerve can have a significant impact surgical site and remote intracranial haemorrhage is believed to be
on the quality of life for any patient. Depending on the nerve that quite different.
sustained injury, manifestations can include diplopia, facial muscle Risk factors for surgical site haemorrhage are inadequate sur-
palsy, deafness, or dysphagia. Injury to nerves IX and X can place gical haemostasis, coagulopathy, and postoperative hypertension
the patient at increased risk for aspiration or cause hoarseness or (35, 44–46). The aetiology and risk factors for remote intracranial
frank airway compromise. The clinician should use caution when haemorrhage are less understood. Remote intracranial haemor-
planning to remove a tracheal tube postoperatively in a patient who rhage can occur following intracranial procedures (e.g., cerebellar
underwent a posterior fossa procedure and does not have an in- haemorrhage following supratentorial surgery) or following other
tact gag reflex as this may indicate the patient’s inability to prevent surgical procedures (e.g., spine surgery) (47–49). The cerebellum
aspiration, or worse yet, protect the airway. In this circumstance, is a common site for remote haemorrhage in the posterior fossa.
the tracheal tube should be left in place until the patient is evalu- Although an aetiology is often not always clear, mechanical trac-
ated by otolaryngology and appropriate cranial nerve function is tion or acute loss of CSF leading to ‘cerebellar sag’ may put trac-
demonstrated. tion on the deep venous system impairing venous outflow from the
Deficits other than those related to cranial nerve function can cerebellum and subsequent haemorrhage (4). Management may
also occur following posterior fossa surgery. These can include, but include observation for smaller haemorrhages without significant
are not limited to, frank sensory and motor deficits as a result of symptoms. However, patients many require decompressive cra-
injury to afferent and efferent tracts from and to the spinal cord, niotomy for severe haemorrhage. Although outcome depends on
ataxia or other evidence of cerebellar dysfunction, or evidence of haemorrhage severity and specific patient comorbidities, up to 67%
187
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neurobehavioural deficits in the Posterior Fossa Syndrome in children year survey and identification of avoidable risk factors. Neurosurgery.
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189
CHAPTER 15
Cerebrovascular Surgery
Deepak Sharma and David R. Wright
Introduction syndromes are associated with pain or spasm in the distribution of

the affected cranial nerve.
Increasing numbers of cerebrovascular conditions are being treated The general principles of pre-anaesthesia evaluation apply also
via an endovascular approach. However, with the advancements to the patients with cerebrovascular disease with special attention
in microsurgical technique and peri-operative care, there is also to the neurological disease, the resulting non-neurological sequela
increasing enthusiasm to perform open cerebrovascular surgery (e.g., stress-induced cardiomyopathy from ruptured aneurysm),
(CBVS) for complex cerebrovascular conditions. This chapter fo- and the conditions known to have established association with the
cuses on the clinical principles applicable to the anaesthetic and specific cerebrovascular disease (e.g., Ehlers-Danlos syndrome and
peri-operative management of CBVS. The science guiding many of coarctation of the aorta with aneurysms). The American Society
the principles is covered in greater detail in Section 1 of this text- of Anesthesiologists (ASA) classification of physical status is useful
book. It is impossible to envisage every situation that might be en- for stratification of the patient’s pre-existing health status. The ASA
countered in CBVS, but the guiding principles discussed in this physical status 3–5 independently predict peri-operative cardio-
chapter should be applicable in most circumstances. vascular complications and mortality in patients undergoing intra-
cranial surgery (1). A review of medications is critical because of
Pre-Anaesthesia Evaluation and significant anaesthetic implications. For example, anticonvulsant
therapy is associated with increased resistance to nondepolarizing
Management muscle relaxants (2). Yet, the prophylaxis should be continued peri-
The peri-operative management starts with a pre-anaesthesia evalu- operatively. Steroid administration may be associated with adrenal
ation aimed to assess and optimize the patient’s medical condition suppression and intra-operative hyperglycaemia (3). Beta-blocker
and to formulate a suitable anaesthesia plan. An understanding of therapy should be continued through the peri-operative period (4).
the underlying pathophysiological process and the patient’s symp- Angiotensin converting enzyme (ACE) inhibitors are often avoided
toms determines the appropriateness of various investigations and on the morning of major craniotomy to avoid intra-operative
interventions. The indications for CBVS can be broadly grouped hypotension. Patients with aneurysmal subarachnoid haemorrhage
into conditions at risk for intracranial haemorrhage (ICH) or those (SAH) will be on nimodipine for prevention of delayed ischaemic
that have already haemorrhaged (cerebral aneurysms and vascular neurological deficits (DINDS), and while it should be continued
malformations), occlusive lesions (moyamoya and atherosclerosis), peri-operatively, it should alert the anaesthetist about possible
and vascular compression syndromes. Obviously, the time available intra-operative hypotension (5).
for pre-operative evaluation and optimization is dependent on the A focused physical examination is critical for anaesthetic plan-
acuity of the clinical presentation. Patients presenting with acute ning. Evaluation of the level of consciousness serves as a baseline for
ICH and signs of cerebral herniation or Cushing’s triad (hyperten- postoperative comparison, may guide the anaesthetic requirement,
sion, bradycardia, and irregular breathing) often require rapid cere- and help decide postoperative extubation versus elective ventila-
bral decompression and may not provide enough opportunity for tion. The neurological evaluation should include a focused assess-
detailed pre-anaesthesia evaluation. In most other cases, there is ment of pupillary size and reactivity, cranial nerves, and motor and
time for adequate evaluation and necessary optimization. sensory functions. Focal neurological deficits should be recorded
The presenting symptoms should be carefully recorded. Patients for correlation to intra-operative evoked potential monitoring and
with aneurysms typically have the ‘worst headache of my life’ and postoperative comparison. The pre-operative intracranial pressure
may have associated neurological deficits, although aneurysms may (ICP) should be recorded, if being monitored. Other organ sys-
sometimes be diagnosed incidentally. Patients with arteriovenous tems, specifically cardiovascular and respiratory function, should
malformations (AVMs) may present with acute ICH, seizures, be evaluated. Recording of pre-operative vital parameters provides
headache, or neurological deficits. The only symptom in small chil- baseline values to direct haemodynamic management. Pre-opera-
dren with vein of Galen malformation or large AVMs may be high- tive correction of dehydration in patients with reduced intake of
output cardiac failure with no neurological symptoms. Patients with fluids, vomiting, or the use of diuretics and contrast agents can
moyamoya and atherosclerotic disease typically suffer from tran- prevent hypotension following induction of anaesthesia. Careful
sient ischaemic attacks (TIA), but also may have focal neurological airway assessment is mandatory to ensure the ability to adequately
deficits or intracerebral haemorrhage. The vascular compression oxygenate and ventilate under anaesthesia. Finally, laboratory
190
investigations and neuroimaging should be reviewed. Transfusion Table 15.2 The World Federation of Neurological Surgeons (WFNS)
requirement should be anticipated and blood products ordered. In grading scale for intracranial aneurysms.
addition, there are specific considerations for various cerebrovas-
cular diseases, which are described in the next section. WFNS Grade Glasgow Coma Scale (GCS) Score Motor Deficits
1 15 –
Cerebral Aneurysms
The assessment of patients with aneurysms should incorporate 2 13–14 –
clinical grading of the SAH, typically using the modified Hunt and 3 13–14 +
Hess grading system (Table 15.1) (6) or the World Federation of 4 7–12 +/–
Neurological Surgeons (WFNS) grading system (Table 15.2) (7).
These grading systems not only allow assessment of peri-operative 5 3–6 +/–
morbidity and communication between physicians, but also indi- Reproduced with permission from Critical Care Medicine, 43, 1, Zoerle, T., Lombardo, A.,
cate the severity of cerebral pathophysiology as well as extracra- Colombo, A., et al., Intracranial pressure after subarachnoid haemorrhage, pp. 168-76.
nial sequelae of SAH. Patients with worse neurological status and Copyright (2015) with permission from Wolters Kluwer Health, Inc.
higher-grade SAH are more likely to have raised ICP, impaired
cerebral autoregulation, and cerebrovascular reactivity to carbon
inversion, appearance of U-waves, and prolonged QT interval
dioxide (8–10). This implies the higher risk of cerebral ischaemia
occur commonly after SAH (17). Most often, the ECG abnor-
and hence, the need for strict haemodynamic control. Moreover,
malities are neurogenic rather than cardiogenic. While ECG ab-
higher-grade SAH also increases the risk of stress cardiomyopathy
normalities are common after SAH, myocardial dysfunction with
and cardiac arrhythmias (11, 12), as well as hyperglycaemia (13),
regional wall motion abnormality and Takotsubo cardiomyopathy
hyponatraemia, and hypovolaemia (14). While, the surgery cannot
(transient cardiac syndrome involving left ventricular (LV) ap-
be delayed in patients with ruptured aneurysms, the anaesthetists
ical akinesis mimicking acute coronary syndrome) are relatively
should initiate the correction of fluid, electrolyte, and glucose de-
uncommon (18). In fact, the ECG abnormalities in patients with
rangements. In patients with ventriculostomy (external ventricular
SAH are usually not related to LV dysfunction (19). Nevertheless,
drain, EVD), the anaesthetist should continue to monitor and treat
myocardial dysfunction may be indicated by increased circulating
the ICP. Sudden drainage of large volumes of cerebrospinal fluid
levels of cardiac Troponin I levels (20). Typically, the presence of
(CSF) can cause rebleeding of the ruptured aneurysm and should
ECG changes, especially in haemodynamically stable patients war-
be avoided. Neurogenic pulmonary oedema resulting from sympa-
rant no further investigations and should not delay urgent surgery.
thetic surge and/or inflammatory response may occur in patients
However, in patients with ECG changes suspicious of myocardial
with severe SAH, particularly in those involving the posterior cir-
ischaemia, e.g., Q-waves, ST elevations, especially in patients who
culation (15), requiring higher oxygen concentration and ventilator
are hypotensive or requiring vasopressor/inotropic support, it is
adjustments (16). Certain genetic syndromes such as autosomal-
desirable to monitor serial Troponin I levels. This may guide closer
dominant polycystic kidney disease and type IV Ehlers-Danlos
haemodynamic monitoring intra-operatively, e.g., cardiac output
syndrome may be associated with aneurysmal SAH.
monitoring to guide fluid and vasopressor/inotrope choices. Yet,
In patients with high-grade SAH, myocardial dysfunction re-
the surgery should typically not be delayed because an unsecured
sulting from sympathetic hyperactivity should be suspected. A var-
aneurysm will continue to remain at risk of rebleeding. In rare
iety of electrocardiographic (ECG) abnormalities such as sinus
cases, patients with severe cardiac dysfunction may not be deemed
bradycardia, sinus tachycardia, ST segment depression, T-wave
suitable candidates for craniotomy and may undergo endovascular
intervention to coil the aneurysm.
The Fisher grading system on computed tomography (CT) is
Table 15.1 Modified Hunt and Hess grading system for aneurysmal commonly used to assess the risk of cerebral vasospasm after an-
subarachnoid haemorrhage. eurysmal SAH (21) (see Table 15.3). The CT (Figure 15.1) should
be reviewed for additional information such as haematoma volume
Grade Neurological Status and hydrocephalus, which may predict intra-operative brain
0 Unruptured aneurysm swelling. Cerebral vasospasm sets in typically after 72 hours of SAH
and most patients undergo surgery before this. Nevertheless, a re-
1 Asymptomatic or mild headache and slight nuchal rigidity
view of the cerebral angiogram helps assess collateral cerebral cir-
2 Severe headache, stiff neck, no neurologic deficit except cranial culation in addition to examining the aneurysm itself.
nerve palsy
3 Drowsy or confused, mild focal neurologic deficit Arteriovenous Malformations
4 Stuporous, moderate or severe hemiparesis Cerebral AVMs are typically congenital but usually present with
an acute ICH in young adulthood and sometimes in pregnancy.
5 Coma, decerebrate posturing On other occasions they present with seizures, focal neuro-
Patient is assigned to 1 higher grade if cerebral vasospasm on angiogram or presence logical deficits, headache, or hydrocephalus. The presence of mul-
of serious systemic disease (hypertension, diabetes, severe atherosclerosis or chronic tiple intracranial AVMs should raise the suspicion of Hereditary
obstructive pulmonary disease). Haemorrhagic Telangiectasia (HHT), also known as Osler-Weber-
Adapted from Journal of Neurosurgery, 28, 1, Hunt, W.E., Hess, R.M., Surgical risk as related
to time of intervention in the repair of intracranial aneurysms, pp. 14-20. Copyright (1968)
Rendu syndrome. Patients with HHT may have associated pul-
American Association of Neurological Surgeon. monary, hepatic, and spinal AVMs, telangiectasia on the lips, oral
19
Chapter 15 cerebrovascular surgery 191
Table 15.3 The Fisher grading system for aneurysmal subarachnoid Table 15.4 Spetzler-Martin Grading Score for cerebral arteriovenous
haemorrhage. malformation (AVM). The scores for each characteristic are added
to assign a total score of 1–6. A score of 6 refers to an inoperable AVM.
Grade Appearance of Blood on Head Computed Tomography
(CT) AVM Characteristic Score
1 No blood detected. Size
2 Diffuse deposition or thin layer with all vertical layers (in <3 cm 1
interhemispheric fissure, insular cistern, ambient cistern).
3–6 cm 2
3 Localized clot and/or vertical layers 1 mm or more in
>6 cm 3
thickness.
Location
4 Intracerebral or intraventricular clot with diffuse or no
subarachnoid blood. Non-eloquent site 0
Reproduced from Neurosurgery, 6, 1, Fisher, C.M., Kistler, J.P., Davis, J.M., Relation of cerebral Eloquent site* 1
vasospasm to subarachnoid hemorrhage visualized by CT scanning, pp. 1-9. Copyright
Pattern of venous drainage
(1980) with permission from Oxford University Press.
Superficial only 0
Any deep venous drainage 1
mucosa, and fingertips, and often have epistaxis, gastrointestinal
bleeding, and iron-deficiency anaemia. Congestive heart failure due *Sensorimotor, language, or visual cortex, hypothalamus or thalamus; internal capsule; brain
to large shunt should be excluded particularly in younger children. stem; cerebellar peduncles; or cerebellar nuclei
Reproduced from Journal of Neurosurgery, 65, 4, Spetzler, R.F., Martin, N.A., A proposed
The AVMs are graded using the Spetzler-Martin system based
grading system for arteriovenous malformations, pp. 476-483. Copyright (1986) American
on the size, pattern of venous drainage, and neurological elo- Association of Neurological Surgeons.
quence of the adjacent brain (Table 15.4) (22). Grade I malfor-
mations are small, superficial, and located in the non-eloquent
cortex, Grade V lesions are large, deep, and situated in neuro-
logically critical areas, and Grade VI lesions are essentially inop- Another major concern is the risk of hyperaemic complications
erable (22). Permanent neurologic deficit is uncommon in grades leading to haemorrhage and oedema after resection of AVM.
I–III but occurs in about 20% of grades IV–V (22). Figure 15.2 Normal perfusion pressure breakthrough (NPPB) and /or occlu-
shows a grade IV AVM. The risk of haemorrhage with hypertensive hyperaemia are the likely mechanisms (24). The surgery for
sion may be high, particularly with small AVMs, due to higher AVM is often staged to reduce the risk of haemorrhagic compli-
perfusion pressure inside the smaller AVM (23). Although most cations (24). Importantly, the risk of hyperaemic complications
patients undergo pre-operative endovascular embolization to exists even after embolization (24). Hence, careful management
decrease the vascularity of the AVM, the anaesthetist should of blood pressure (BP) is critical.
be prepared for intra-operative bleeding requiring transfusion.
Figure 15.1 Left MCA aneurysm rupture with Fisher grade 3 subarachnoid Figure 15.2 A large left frontal AVM, Spetzler-Martin grade IV.
haemorrhage. Arterial supply arises from the orbital branches of the left anterior cerebral artery.
The image shows the most confluence area expanding the left sylvian fissure. Venous drainage is to both, the superior sagittal sinus as well as a deep cerebral
A ventriculostomy has been placed in the right lateral ventricle. vein into the straight sinus.
192
Moyamoya Disease vestibular schwannoma, meningioma, or epidermoid or other cyst.

Moyamoya disease is a chronic progressive cerebrovascular dis- Hemifacial spasm represents a segmental myoclonus of muscles in-
ease characterized by stenosis or occlusion of the arteries around nervated by the facial nerve caused by compression of the nerve by a
the circle of Willis with prominent arterial collateral circulation. vascular structure, or by a brainstem lesion. Microvascular decom-
‘Moyamoya’ is a Japanese word meaning ‘puff of smoke’ which depression involves craniotomy and separation of the compressing
scribes the angiographic appearance of the vascular collateral net- vascular structure away from the nerve. Patients with trigeminal
work in patients with this condition (Figure 15.3). Avoidance of neuralgia are usually on carbamazepine, which antagonizes the ef-
peri-operative dehydration and hypotension is critical to avoid fects of non-depolarizing muscle relaxants and hence, neuromus-
cerebral ischaemia in patients with moyamoya disease. Cerebral cular blockade should be monitored closely. Carbamazepine can
blood flow (CBF) reserve is assessed pre-operatively using per- also cause hyponatraemia, requiring monitoring of sodium levels.
fusion CT, perfusion-weighted MRI, positron emission tomog-
raphy (PET), single-photon emission CT (SPECT), or transcranial Goals of Anaesthetic Management
Doppler (TCD) ultrasonography with acetazolamide challenge. The general goal of intra-operative management is to render the
patient unconscious to facilitate surgery, to provide adequate an-
Carotid Atherosclerosis algesia, and maintain homeostasis and vital functions. The an-
Patients with carotid atherosclerosis often have associated periph- aesthetic goals specific to craniotomy for cerebrovascular surgery
eral vascular disease and coronary artery disease, as well as other are listed in Box 15.1. These goals are accomplished by selection
comorbidities such as diabetes mellitus and renal insufficiency that re-
quire pre-operative evaluation and optimization. An exercise stress test,
dobutamine echocardiography, or dipyridamole imaging may be war- Box 15.1 Summary of Anaesthetic Goals for Cerebrovascular
ranted in select patients with high suspicion of myocardial ischaemia. Surgery
Most guidelines recommend aspirin for symptomatic and asymp-
tomatic patients undergoing carotid endarterectomy (CEA) (25, 26). 1. Provide adequate amnesia, analgesia, and immobility.
Carotid endarterectomy can be performed under local/regional or gen-
eral anaesthesia (27, 28). However, the pre-operative evaluation should 2. Optimize cerebral blood flow and oxygenation.
identify the preferable technique for the individual patient. General 3. Optimize haemodynamic parameters based on cerebrovas-
anaesthesia may be preferable for patients with significant anxiety, in- cular pathology:
ability to cooperate or communicate, neurocognitive dysfunction, or
◆ Avoid hypertension prior to clipping of an aneurysm to
inability to lie supine comfortably for the duration of surgery.
prevent rebleeding; BP can be normalized post clipping.
Trigeminal Neuralgia/Hemifacial Spasm ◆
Avoid hypertension prior to resection of AVM; con-
Trigeminal neuralgia is characterized by episodic pain in the distri- sider decreasing the BP below baseline after resection
bution of one or more divisions of the trigeminal nerve, triggered to prevent hyperemic complications.
by trivial stimuli. Compression of the nerve by an aberrant loop of ◆ Avoid hypotension to prevent cerebral ischaemia prior
an artery or vein is the most common cause. Other causes include to revascularization in occlusive cerebrovascular dis-
eases; avoid hypertension after revascularization to
prevent hyperemic complications.
4. Control intracranial pressure and provide optimal brain
relaxation.
5. Avoid secondary physiological insults by:
◆ arterial hyper-/ hypotension.
◆ hypoxia.
◆ hyper-/hypoglycaemia.
◆ hyper-/excessive hypocarbia.
◆ hyperthermia.
◆ seizures.
6. Facilitate intra-operative neurophysiological monitoring.

7. Provide intra-operative neuroprotection.
8. Avoid positioning-related complications.
9. Accomplish early emergence after surgery to facilitate neuro-
logical assessment.
Figure 15.3 Moyamoya disease with stenosis of the left MCA (arrow). 10. Prevent postoperative pain, nausea/vomiting, respiratory
There is development of the collateral vasculature giving the characteristic ‘puff of
complications.
smoke’ appearance distal to the occlusion.
193
of appropriate pharmacological agents and by careful regulation of other hand, institution of hypocapnia in patients under propofol
haemodynamic and ventilation parameters. anaesthesia may lead to excessive cerebral vasoconstriction and
cerebral ischaemia (33). In patients with supratentorial tumours,
the ICP has been shown to be lower and cerebral perfusion pres-
Induction of Anaesthesia sure (CPP) higher in patients who received propofol compared to
Anaesthesia should be induced carefully and the airway should be sevoflurane or isoflurane anaesthesia (31). Although there are no
secured avoiding hypoxia, hypercarbia, and haemodynamic per- such data for patients undergoing CBVS, these findings indicate
turbations. Hypertension during laryngoscopy and intubation can potential benefit of propofol anaesthesia. However, low-dose in-
cause an increase in the transmural pressure across the wall of the haled agents as part of balanced anaesthesia can effectively provide
aneurysm and provoke a rebleed. Likewise, it may cause bleeding optimal operative conditions, particularly if ICP is not elevated
from an AVM although the risk may be lower. Hypertension during pre-operatively.
laryngoscopy and intubation can be attenuated by using one or In patents with moyamoya disease, intracerebral steal is believed
more of the following agents: opioids, lidocaine, beta-blockers, cal- to occur such that global hyperaemia indicated by supra normal
cium channel blockers, or additional bolus of propofol. Placement jugular venous oxygen saturation (SjvO2) is associated with a de-
of an arterial line prior to induction of anaesthesia allows close crease in regional CBF measured by laser Doppler flowmetry (34).
monitoring of BP and can guide rapid treatment if needed. Regional CBF levels may be decreased by inhaled anaesthesia in
In patients presenting for emergent craniotomy who may have a patients with moyamoya disease despite an increase in SjvO2 due to
full stomach and in patients with acutely increased ICP, the gastric intracerebral steal, a phenomenon not observed with intravenous
emptying may be altered, increasing the risk of aspiration during anaesthesia (35). In addition, the optimal range of carbon dioxide
intubation. In such circumstances, a rapid sequence intubation is (CO2) for isoflurane is more restricted than that for propofol, be-
desirable. The effect of succinylcholine on ICP is often debated. cause isoflurane induces hyperaemia itself (34). In fact, intravenous
However, it has been shown to have no detrimental effect on ICP anaesthesia with propofol has potential for preservation of CBF in
(29) and anaesthetists should not hesitate to use it if anticipating a the frontal lobes (36).
difficult airway. Finally, just as hypertension is detrimental for pa- Other factors such as the effect on evoked potential signal
tients with unsecured aneurysms and AVMs, hypotension is un- quality should be considered while selecting the anaesthetic agent.
desirable in patients with occlusive cerebrovascular disease and While the inhalational agents cause dose-dependent increases in
should be avoided. latency and decreases in amplitude of somatosensory evoked po-
tentials (SSEPs), less than 1.0 MAC concentration is compatible
with monitoring of cortical SSEPs, although propofol anaesthesia
Choice of Anaesthetic Agents does not affect SSEPs (37). Nevertheless, if motor evoked poten-
The ideal anaesthetic agent for CBVS would reduce the cerebral tial (MEP) monitoring is contemplated, propofol anaesthesia may
metabolic rate (CMR), avoid intracranial hypertension, maintain ad- in preferred especially in patients with pre-existing neurological
equate CBF, be haemodynamically stable, provide neuroprotection, deficits, although <0.5 MAC desflurane is also compatible with
facilitate the use of neurophysiological monitoring, and be easily MEPs (38). Monitoring MEPs also precludes the use of neuromus-
titrated to the required anaesthetic depth allowing rapid emergence cular blocking agents. Brainstem evoked potentials, on the other
and assessment of the patient’s neurological condition. Obviously, hand, are the most resistant to the effect of anaesthetic agents.
such an agent does not exist. The intravenous and inhaled an- Nitrous oxide is generally avoided not only because it increases
aesthetic agents differ substantially in their pharmacodynamics CMR and CBF, but also because of the adverse cardiorespira-
and pharmacokinetic properties and the choice is based on the tory outcomes associated with its use. Dexmedetomidine, an α2-
patient’s neurological condition, proposed procedure, co-existing adrenoceptor agonist is a suitable adjunct for craniotomy. Potential
diseases, and planned neurophysiological monitoring. Both intra- advantages include sedation and analgesia without respiratory de-
venous and inhaled anaesthetics can be safely used for CBVS. The pression, attenuation of neuroendocrine and haemodynamic re-
anaesthetic agents are typically combined with potent opioids to sponses, and reduction of anaesthetic and opioid requirements, in
provide analgesia (remifentanil, fentanyl, sufentanil, morphine, or addition to favourable pharmacokinetics facilitating rapid wash out
hydromorphone) and sometimes neuromuscular blocking agents after termination of infusion.
to provide immobility.
Most anaesthetic agents decrease the CMR. However, propofol Anaesthetic Technique for Carotid
decreases CBF and maintains the coupling between CMR and CBF,
while inhaled anaesthetics have a dose dependent effect on the CBF
Endarterectomy
(30). Inhaled anaesthetics typically decrease CBF when used in <1.0 CEA can be safely and effectively conducted under local/regional
MAC (minimum alveolar concentration) doses but tend to cause or general anaesthesia with no difference in the risk of stroke, myo-
cerebral vasodilation at higher concentrations leading to uncoup- cardial infarction, or mortality (27, 28). While the use of local an-
ling between CBF and metabolism (30). In patients with reduced aesthesia allows neurological monitoring of the conscious patient,
intracranial compliance, this ‘luxury perfusion’ can cause further some patients may be more comfortable under general anaesthesia.
increase in ICP and brain swelling (31). Moreover, isoflurane and The cerebrovascular effects of anaesthetic agents may be important
desflurane causes more cerebral vasodilation than equal concentra- in making a pharmacological choice. The cerebral vasodilatory ef-
tion of sevoflurane (32). However, the cerebral vasodilatory effect of fect of volatile anaesthetic agents causing brain swelling is less rele-
inhalational agents can be avoided by hyperventilation, which will vant to CEA. Nevertheless, maintenance of CBF and CMR coupling
decrease the partial pressure of carbon dioxide (PaCO2). On the and preservation of cerebral autoregulation make propofol an
194
attractive choice (39). Moreover, the gradient between MAP and anticipated, appropriate monitoring with transoesophageal echo-
internal carotid artery pressure (stump pressure) during carotid cardiography or precordial Doppler should be planned.
clamping has been reported to be lower with propofol than with The major neurological complications during CEA result from
sevoflurane anaesthesia, suggesting that cerebral perfusion pres- cerebral ischaemia due to carotid clamping and cerebral embolism
sure is better maintained with propofol and that sevoflurane can from the atheroma. Neuromonitoring during CEA under general an-
cause cerebral steal during CEA (40). Propofol also appears to im- aesthesia is aimed at early detection of these complications to direct
prove short term cognitive performance after CEA (41). appropriate interventions (e.g., BP augmentation, insertion of carotid
Regional anaesthesia for CEA may involve either a superficial shunt). Neuromonitoring may be performed using one or more of
cervical plexus block or combined deep and superficial cervical the following: EEG, evoked potentials, cerebral oximetry using near
plexus block. The risks associated with deep cervical plexus block infrared spectroscopy (NIRS), stump pressure, and TCD ultrason-
include injection into the CSF leading to brainstem anaesthesia, ography (46). Percent change in CBF velocity on TCD, cerebral oxy-
intra-arterial injection, and phrenic nerve paralysis. Yet another genation (rSO2) on NIRS, and stump pressure measurement provide
option is the technique of cooperative patient general anaesthesia, similarly high accuracy for the detection of cerebral ischaemia during
where the patient is anaesthetized with intravenous anaesthesia carotid surgery (46). A 40–50% decrease in CBF velocity on TCD
technique and during carotid clamping, anaesthesia is reduced and and 12%–13% reduction in rSO2 after cross clamp indicates cere-
maintained only with remifentanil, such that the patient is able bral ischaemia and the need for carotid shunting in patients under-
to respond to verbal statements and participate in neurological going CEA under general anaesthesia (46, 47). Also, TCD is the only
monitoring (42). monitor that is able to detect cerebral emboli, postoperative throm-
bosis, and hyperperfusion, but has high rate of technical difficulties.
Intra-operative SSEPs are often used to decide the need for shunting.
Intra-Operative Monitoring The SSEPs are highly specific in predicting neurological outcome fol-
Intra-operative monitoring should be tailored to the acuity of lowing CEA. Patients with peri-operative neurological deficits are 14
the cerebrovascular disease and complexity of the proposed pro- times more likely to have had changes in SSEPs during the procedure.
cedure. All patients should have the standard ASA monitors— However, the sensitivity of this modality is somewhat weak (48).
electrocardiography, BP, pulse oximetry, capnography, temperature,
and anaesthetic concentration monitoring for inhaled anaesthetics. Intracranial Pressure Management and
Arterial line should be placed for continuous BP monitoring, for
sampling PaCO2, glucose levels, and electrolytes, as well as for
Brain Relaxation
measuring pulse pressure variability to guide fluid status. A central Intracranial surgery requires the brain tissue to be relaxed to fa-
venous line may be placed to supplement vascular access and to cilitate exposure of the lesion to be treated and minimize the risk
facilitate infusion of total intravenous anaesthesia and medications
such as hypertonic saline and phenytoin. It may be useful to ad-
minister vasopressors and inotropes particularly in patients with
associated Takatsubo cardiomyopathy or pre-existing myocardial Box 15.2 Strategies for Intra-Operative Brain Relaxation and
Control of Intracranial Pressure during Intracranial Vascular
dysfunction. Patients with ruptured aneurysms frequently have a
Surgery
ventriculostomy which can be used to monitor ICP and CPP.
Anaesthetic manipulation of physiological variables, e.g.,
PaCO2, BP, ICP, CPP, and concentration of anaesthetic agents as 1. Maintenance of adequate depth of anaesthesia and analgesia.
well as the surgical technique, affect the CBF and oxygenation. 2. Selection of appropriate anaesthetic agents and doses (<1.0
While temporary clip and carotid cross clamping can cause cere- MAC inhaled anaesthestic; intravenous anaesthetics for pa-
bral ischaemia, revascularization and resection of a large AVM tients with anticipated brain swelling).
can lead to hyperaemia. Maintaining SjvO2 between 55–70% 3. Optimal positioning (slight head elevation and avoiding ex-
serves as a surrogate for adequate balance between the cerebral cessive neck flexion or rotation).
oxygen delivery and metabolic requirement. Jugular oximetry is
useful to guide determination of the minimum BP that should be 4.
Optimization of haemodynamic parameters (avoid
maintained to avoid global cerebral hypoperfusion (43). It is also hyperaemia).
helpful in accomplishing brain relaxation by titrating hyperven- 5. Controlled ventilation with normocarbia to moderate
tilation within safe limits (44, 45). Jugular oximetry allows moni- hypocarbia (PaCO2 30–35mmHg)*.
toring of global cerebral oxygenation without interfering with the
6. Mannitol.
surgical field and allows individualization of physiological param-
eters (44, 45). 7. Hypertonic saline.
Electroencephalogram (EEG) is monitored to titrate anaesthetic 8. Cerebrospinal fluid drainage.
doses to burst suppression during temporary clipping. Monitoring
SSEPs and MEPs guides surgical intervention such as reperfusing 9. Steroids for vasogenic oedema.
the brain during prolonged temporary clipping or repositioning a 10. Burst suppression with propofol/thiopental bolus.
permanent aneurysm clip by noticing decrease in signal amplitude
*Briefperiods of PaCO2 <30 mmHg should be used only in emergent
or increase in latency. Monitoring of brainstem auditory evoked
conditions or when other ICP reduction manoeuvres have failed. Strict
potentials and cranial nerves is critical during microvascular de-
normocarbia for occlusive diseases.
compression surgery. In addition, when venous air embolism is
195
of brain injury associated with retraction pressure applied to the of collateral vessels. These new vessels have impaired cerebrovas-
surface of the brain. Box 15.2 lists the strategies for ICP control and cular autoregulation and reactivity and are unable to control the
brain relaxation. Importantly, hyperventilation should be avoided increased CBF after revascularization, which can cause cerebral
in patients with moyamoya disease and carotid atherosclerosis be- hyperperfusion syndrome (52). Many factors play a role in the
cause it may worsen cerebral ischaemia. Hypercarbia could also pathophysiology of cerebral hyperperfusion syndrome after CEA,
be detrimental to these patients by contributing to cerebral steal. including impaired cerebral autoregulation, ischaemia-reperfusion
Hence, normocarbia is desirable. In patients with ruptured aneur- injury, oxygen-derived free radicals, and baroreceptor dysfunction
ysms, aggressive hyperventilation should not be instituted before (53). In order to prevent cerebral hyperaemia, BP should be care-
dural opening because the resulting decrease in the transmural fully controlled following revascularization in patients with occlu-
pressure can cause rebleeding. Administration of 3% hypertonic sive cerebrovascular disease.
saline is associated with similar brain relaxation and arteriovenous
oxygen and lactate difference as mannitol (49). Mannitol is often Temporary Clipping for Aneurysm
not needed for patients with moyamoya disease and its use should The treatment of complex aneurysms may involve the placement
be discussed with the surgeon. Finally, drainage of CSF is an ef- of a temporary clip to occlude the parent vessel proximal to the
fective method for rapid ICP reduction but should be used cau- aneurysm. The temporary clip reduces blood flow through the an-
tiously considering the potential risk of aneurysm rebleeding. eurysm which facilities the dissection and accurate placement of a
permanent clip around the neck of the aneurysm. While this tech-
nique reduces the risk of intra-operative rupture, it exposes the
Haemodynamic Management brain tissue downstream of the aneurysm to the risk of ischaemia.
Careful control of BP is essential in CBVS. The patient’s pre- A temporary clip may be applied for a brief duration of up to ten
operative baseline haemodynamic parameters should be noted. minutes without ischaemia of the middle cerebral artery terri-
Hypertensive responses to noxious stimuli such as laryngoscopy tory (54). However, it is sometimes released to allow reperfusion
and intubation, application of Mayfield pins, and surgery itself and then reapplied after a few minutes if more time is needed.
should be avoided to prevent haemorrhage from unsecured aneur- Importantly, hypotension must be avoided during temporary clip-
ysms or AVMs. In addition to adequate depth of anaesthesia and ping. Usually, the BP is increased to 10–20% above baseline during
analgesia, antihypertensive drugs may be needed. Conversely, in temporary clipping to recruit collateral blood flow to the territory
patients presenting with intracerebral bleed and in patients with at risk of ischaemia. Another strategy to avoid cerebral injury in
occlusive cerebrovascular disease, it is important to avoid hypoten- the presence of reduced cerebral blood flow is to reduce the CMR
sion. In patients with an ICP monitor, the CPP should be main- by increasing the depth of anesthesia as measured by the appear-
tained in the range of at least 50–70 mmHg with vasopressors and/ ance of burst suppression on the EEG (54, 55, 56). Boluses of ei-
or inotropes, if needed. It is critical that infusions and boluses of ther thiopentone, propofol, or etomidate may be used to induce
vasopressors, inotropes, and short-acting antihypertensive agents burst suppression, which allows time for complete dissection of
such as nicardipine and esmolol be readily available. the aneurysm neck and identification and preservation of the sur-
Specific haemodynamic goals for various CBVS procedures vary rounding vascular anatomy. Despite the fact that data are lacking
and are briefly listed in Box 15.1, but it is important to also take into on the effectiveness of supplemental protective drugs used to in-
account comorbid conditions. Briefly, hypertension is undesirable duce burst suppression on improvement of neurologic outcomes
before an aneurysm is clipped because it can precipitate rebleeding. of patients undergoing temporary clipping, it is common practice
Once, the aneurysm is secured, the BP goals can be normalized in largely because there appears to be no major disadvantage as long
communication with the surgeon. Additionally, in patients with as hypotension from the bolus drug can be avoided (56). Induced
ruptured AVMs, hypertension is undesirable. Importantly however, hypothermia to decrease the metabolic requirement of the brain
and different from aneurysms, BP needs to be actively kept below during temporary clipping has been proposed as a neuroprotective
the pre-operative baseline even after a large AVM has been re- strategy. However, a large study of 1001 patients with WFNS
sected. This is to prevent post resection hyperaemic complications grades I–III randomized to intra-operative hypothermia (target
(haemorrhage and oedema) due to NPPB or occlusive hyperaemia temperature, 33°C, with the use of surface cooling techniques) or
(50, 51). The parenchyma surrounding a high-flow AVM is chron- normothermia (target temperature, 36.5°C) observed no advan-
ically hypoperfused. As a result, it has impaired autoregulation and tage of hypothermia on improving the neurologic outcome (57).
lacks the ability to vasoconstrict in response to increased blood In fact, postoperative bacteraemia was more common in the hypo-
flow. Following removal of an AVM, the capillary beds and arteri- thermic patients (57). Hence, intra-operative hypothermia cannot
oles in the ‘normal’ parenchyma become vulnerable to hyperaemia be recommended for neuroprotection in patients with good grade
even at normal perfusion pressure (50). An alternative explanation SAH. Nevertheless, hyperthermia is detrimental and must be
is stagnant arterial flow in former AVM feeders due to increased avoided.
resistance to flow and endothelial abnormalities coupled with the
obstruction of the venous outflow of surrounding parenchyma Adenosine Induced Temporary Flow Arrest
(51). Irrespective of the mechanism, it is critical that BP be lowered Temporary clipping may not be suitable in some situations when
pharmacologically, if needed. occlusion is not possible due to either the location of the aneurysm
In patients with moyamoya disease and carotid atherosclerosis, (e.g., paraclinoid internal carotid or basilar artery), size (e.g., a giant
hypotension must be avoided prior to revascularization to prevent aneurysm interferes with the visualization of the proximal artery),
worsening of pre-existing cerebral ischaemia. Chronic cerebral is- or when atherosclerosis is severe in the proximal artery. In such
chaemia in these patients results in the compensatory development situations, transient cardiac standstill with adenosine is an option
196
for decompression of the aneurysm which aides in optimally posi- been shown to be associated with reduced odds of poor outcome in
tioning of the permanent clip (58, 59). It is also useful in the event patients with SAH (61). Higher haemoglobin level is also associated
of inadvertent intra-operative rupture of the aneurysm where it with lower risk of cerebral infarction (61). Conversely, in patients
helps to maintain a clear surgical field. Adenosine is a dromotropic undergoing surgery for aneurysms, pre-operative anaemia is inde-
and chronotropic agent that induces high-degree atrioventricular pendently associated with prolonged hospital stay, peri-operative
block, decreasing the heart rate within seconds followed by brief complications, and return to the operating room but ironically,
asystole. The duration of adenosine-induced asystole is dose-de- blood transfusion is also associated with peri-operative complica-
pendent, but can vary considerably (58, 59). Decompression of the tions (62). Intra-operative decision to transfuse blood should typ-
aneurysm develops immediately with asystole, and is maintained ically be made based on overall fluid and haemodynamic status,
during the periods of profound-moderate hypotension before re- haemoglobin value, and rapidity of blood loss, taking into account
covery of the BP. Burst suppression is usually induced before causing the patient’s cardiac comorbidity and neurological dysfunction.
cardiac standstill to reduce the CMR during the period of asystole The use of cell saver should be considered as an option in surgeries
and hypotension. Adenosine in doses of 0.29–0.44 mg/kg results in with significant blood loss.
about 57 (range 26–105) seconds of moderate hypotension (58, 59). Given the association of both hypo-and hyperglycaemia with
After the circulation has returned to baseline, additional doses of poor outcomes in neurosurgical patients, the goal of anaesthetic
adenosine can be given if needed. However, tachyphylaxis has been management is to maintain normoglycaemia. In patients at
reported, requiring dose escalation. Adenosine is not suitable for risk for ischaemic brain injury, intra-operative hyperglycaemia
patients with reactive airways disease, cardiac conduction diseases, is associated with long-term changes in cognition and gross
and coronary artery disease; it is ineffective in patients with pace- neurologic function. The definition of hyperglycaemia and the
maker devices. Cardiac arrhythmias such as transient atrial fibril- threshold for insulin treatment is often debated. In an analysis
lation, ventricular tachycardia, or atrial flutter may occur during of the Intraoperative Hypothermia for Aneurysm Surgery Trial
cardiac rhythm recovery. Occasionally, ST segment depression (IHAST), three months after surgery, patients with blood glucose
may occur. With experienced providers, adenosine induced tran- concentrations of 129 mg/dL or more were more likely to have
sient asystole is an effective and safe method to facilitate aneurysm impaired cognition and those with glucose 152 mg/dL or more
clipping. were more likely to experience deficits in gross neurologic func-
Alternatively, rapid ventricular pacing (RVP) to produce tion (63). Among patients undergoing CEA, those with operative
flow arrest has been described to safely lower the arterial BP day glucose >200 mg/dl have an increased risk of peri-operative
in a controlled and directly reversible manner during cerebro- stroke or TIA, myocardial infarction, and death (64). Nevertheless,
vascular surgery (60). In a series of 12 patients, the authors re- the benefits of tight glucose control in neurosurgical patients have
ported RVP for periods of 40 seconds with an immediate and not been demonstrated conclusively and glucose levels may fluc-
significant reduction of BP in each patient (60). The maximum tuate substantially under anaesthesia. Therefore, regular glucose
degree of hypotension was obtained 3.2 ± 0.7 seconds after the monitoring and maintaining the blood glucose level in the range
start of RVP and normal sinus rhythm returned instantaneously, of 80–150mg/dL is often recommended.
along with recovery of indexes of haemodynamic function when
RVP was terminated (60). The decrease in BPs facilitated dissec-
tion, and during clipping, the aneurysm sac felt softer and was Emergence from General Anaesthesia
easier to manipulate and no complications related to RVP oc- The goal for emergence is to have an awake patient so that neuro-
curred (60). However, this technique requires planning and add- logical examination may be performed. Patients who were in-
itional devices and may not be an option in sudden unanticipated tubated pre-operatively, those with poor neurological status, and
aneurysmal bleed. patients undergoing prolonged surgery around the brainstem are
likely to remain intubated. Emergence from anaesthesia requires
Fluid, Electrolyte, Transfusion, and Glucose diligent planning to accomplish a timely, smooth emergence with
minimal haemodynamic perturbation and straining on the tra-
Management cheal tube. Anaesthetic agents should be gradually weaned be-
Patients undergoing CBVS should be administered non-glucose fore a trial of spontaneous ventilation to determine adequate
containing, warm, isotonic intravenous fluids. Hypotonic fluids respiratory drive and minute ventilation. The adrenergic surge
like lactated Ringer’s solution are avoided since they can worsen associated with emergence may be treated with a short-acting
cerebral oedema and brain swelling. Despite the use of diuretics to opioid or an antihypertensive such as esmolol or nicardipine.
facilitate brain relaxation, the goal is to maintain normovolaemia Coughing and straining on the tracheal tube during emergence
during CBVS. Since cerebral salt wasting, diabetes insipidus, hypo- can be prevented with lidocaine or judicious use of remifentanil.
kalaemia, and hypocalcaemia are often associated with aneurysmal Dexmedetomidine has both sedative and analgesic properties,
SAH, electrolytes should be monitored regularly under anaesthesia but does not cause respiratory depression, and is also useful in
and corrected accordingly. Surgical blood loss can sometimes be facilitating timely and smooth emergence. Alternatively, some
substantial requiring blood transfusion, particularly during AVM experts prefer to use clonidine to facilitate a smooth emer-
resection, intra-operative rupture of an aneurysm, or due to in- gence, although timing and dose need to be carefully titrated.
advertent vascular injury. A haemoglobin level of 10g/dL is often Unexpected delay in emergence mandates ruling out potential
considered to be a balance between optimal oxygen-carrying confounding factors such as drug overdose, hypothermia, and
capacity and rheology of blood to facilitate perfusion of cerebral hypoglycaemia before an imaging study is performed to rule out
microvasculature. More recently, higher haemoglobin level has an intracranial cause.
197
noncardiac surgery: A report of the American college of cardiology

Immediate Postoperative Management foundation/American heart association task force on practice
In the immediate postoperative period, the patients should be guidelines. Circulation. 2009;120(21):e169–276.
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haemodynamic stability, pain control, and neurological recovery. JM. Implications of nimodipine prophylaxis of cerebral vasospasm on
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After CEA, TCD monitoring should be continued in the recovery
of Neurosurgery. 1985;62(2):200–5.
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A 100% increase in CBF velocity indicates hyperperfusion syn- in the repair of intracranial aneurysms. Journal of Neurosurgery.
drome and should be rapidly treated. 1968;28(1):14–20.
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piritramide including patient-controlled analgesia (PCA) should on a Universal Subarachnoid Hemorrhage Grading Scale. Journal of
be used judiciously for postoperative pain management, avoiding Neurosurgery. 1988;68(6):985–6.
8. Zoerle T, Lombardo A, Colombo A, Longhi L, Zanier ER, Rampini
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natives include intra-operative local anaesthetic scalp infiltration, 9. Dernbach PD, Little JR, Jones SC, Ebrahim ZY. Altered cerebral
and intravenous paracetamol. Pre-operative oral gabapentin used autoregulation and CO2 reactivity after aneurysmal subarachnoid
can decrease the postoperative pain scores and the total morphine hemorrhage. Neurosurgery. 1988;22(5):822–6.
consumption. Selective serotonin (5-HT3) receptor antagonists are 10. Carrera E, Kurtz P, Badjatia N, Fernandez L, Claassen J, Lee K, et al.
the first-choice drugs for prophylaxis of postoperative nausea and Cerebrovascular carbon dioxide reactivity and delayed cerebral
ischemia after subarachnoid hemorrhage. Archives of Neurology.
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2010;67(4):434–9.
portant to avoid PONV because retching can contribute to increase 11. Davies KR, Gelb AW, Manninen PH, Boughner DR, Bisnaire D.
in ICP. Ondansetron or granisetron administered at the time of Cardiac function in aneurysmal subarachnoid haemorrhage: a study
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Peri-operative management of CBVS requires good under- hyperglycemia as an indicator of severity of the ictus in poor-grade
patients with spontaneous subarachnoid hemorrhage. Clinical
standing of the pathophysiology of the disease process, planned
Neurology and Neurosurgery. 2000;102(2):78–83.
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Optimal anaesthetic management incorporating rational intraventricular blood predict elevated plasma atrial natriuretic factor
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tenance of physiological parameters, and preparedness to deal 15. Muroi C, Keller M, Pangalu A, Fortunati M, Yonekawa Y,
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2008;20(3):188–92.
16. Tagami T, Kuwamoto K, Watanabe A, Unemoto K, Yokobori S,
Cases and Multiple-Choice Questions Matsumoto G, et al; SAH PiCCO Study Group. Optimal range of
global end-diastolic volume for fluid management after aneurysmal
Q Interactive cases and multiple-choice questions to test your
subarachnoid hemorrhage: a multicenter prospective cohort study.
knowledge on this chapter can be found in the online appendix at Critical Care Medicine. 2014;42(6):1348–56.
www.oxfordmedicine.com/otneuroanesthesiology. 17. Manninen PH, Ayra B, Gelb AW, Pelz D. Association between
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60. Saldien V, Menovsky T, Rommens M, Van der Steen G, Van Loock K, 2008;83(4):406–17.
Vermeersch G, et al. Rapid ventricular pacing for flow arrest during 64. McGirt MJ, Woodworth GF, Brooke BS, Coon AL, Jain S, Buck D,
cerebrovascular surgery: Revival of an old concept. Neurosurgery. 2012 et al. Hyperglycemia independently increases the risk of perioperative
Jun;70(2 Suppl Operative):270–5. stroke, myocardial infarction, and death after carotid endarterectomy.
61. Naidech AM, Drescher J, Ault ML, Shaibani A, Batjer HH, Alberts MJ. Neurosurgery. 2006;58(6):1066–73.
Higher hemoglobin is associated with less cerebral infarction, poor
20
201
CHAPTER 16
Interventional Neuroradiology
Nathan Manning, Katherine M. Gelber,
Michael Crimmins, Philip M. Meyers, and Eric J. Heyer
Introduction likelihood (and safety) of needing to convert emergently from

MAC to GA should it become necessary. All personnel working in
Neuroradiology is a rapidly evolving field in the diagnosis and treat- the INR suite, including the anaesthetist, risk exposure to ionizing
ment of cerebrovascular diseases. Interventional neuroradiology radiation, both from the x-ray tube itself but also from scatter radi-
(INR), also known as neurointervention, endovascular neurosur- ation emanating from the patient (1). Radiation exposure should be
gery, and interventional neurology, benefits by new techniques and kept as low as reasonably possible for the patient and hospital per-
technologies introduced every year. These rapid developments can sonnel. This requires both protective gear for the anaesthetist and
become difficult to assimilate, even for the interventional specialist. communication with the neuro-interventionalist to limit exposure
The number, variety, and complexity of these procedures also create when the anaesthetist needs access to the patient.
challenges for the anaesthetist, who may not be a specialized neuro- The needs of the patient are primarily related to comfort and
anaesthetist. Furthermore, these procedures may be performed in safety. Some INR procedures may require that the patient can
diverse settings, ranging from the operating room to ‘remote’ sites be examined at various points during the procedure to check for
in the hospital, such as the interventional radiology department neurological deficits. This requires full understanding and cooper-
or another catheterization facility. Ultimately, the optimal anaes- ation on the part of the patient. New agents are now available to use
thetic and peri-operative plan must address the needs of the neuro- as part of a sedation regimen that will put the patient in a comfort-
interventionalist, the anaesthetist, and the patient. able state during the prolonged periods when their cooperation is
Unique aspects of neuro-interventional procedures include elab- not needed, but fully awake when the patient needs to participate
orate (often biplane) fluoroscopy equipment, the need for a co- in his/her care.
operative patient (even under monitored anaesthesia care [MAC]), This chapter reviews fundamental principles for providing care
and often the ability to perform an abbreviated neurologic examin- to patients undergoing INR procedures from the viewpoint of
ation. The neuro-interventionalist often watches the progression of the patient, the neuro-interventionalist, the anaesthetist, and the
the procedure from two directions at one time on multiple screens. neuro-intensivist. It provides a background of endovascular treat-
Three-dimensional (3D) imaging applications are most commonly ment of cerebral disorders and then focuses on the treatment of
used to depict the complex vascular anatomy of the cerebral arteries. three disorders that are treated by endovascular therapy: cerebral
Newer systems can also perform complex calculation of vessel sizes aneurysms, carotid artery stenosis, and acute ischaemic stroke. In
to a tenth (or even hundredth) of a millimetre, computational flow general, the approach for paediatrics is similar, but this chapter
dynamics, and cerebral blood flow parameters. Shielding to prevent does not specifically discuss management of paediatric patients,
injury to the radiologist and anaesthetist creates obstacles to the because, except for cerebral aneurysms, carotid artery stenosis and
usual intravenous and ventilator circuits used in the conventional acute ischaemic stroke are uncommon in this age group.
operating room. Finally, radiation is emitted over the patient’s head,
precluding easy access to the airway in an emergency.
The anaesthetist is also presented with a number of challenges
Endovascular Surgical
when providing care in the INR suite. This offsite location fre- Neuroradiology: Background
quently does not have the typical operating room (OR) set-up to The first successful endovascular surgical neuroradiology case was
which the anaesthetist is accustomed. The anaesthesia equipment, reported by Luessenhop and Spence in 1960 (2). An inoperable,
including the machine, medication, and supplies, are often in un- giant arteriovenous malformation was embolized using methyl
conventional places in the room due to the large size of the x-ray methacrylate beads introduced directly into the cervical internal ca-
equipment. The anaesthetist must also be ready to help manage the rotid artery (2). Interestingly, the authors report the patient suffered
physiological consequences of sudden and unexpected procedure- progressive weakness of the contralateral upper limb over the sub-
specific complications (e.g., intracerebral haemorrhage or vascular sequent 14 hours, which subsequently improved, then completely
occlusion), which may be problematic outside of a formal OR and resolved, highlighting the unique physiological considerations that
with a closed cranial cavity. Furthermore, the anaesthetist must are intertwined but often misunderstood in endovascular surgical
help to decide on MAC versus general anaesthesia (GA), and the neuroradiology.
20
From these early beginnings, endovascular surgical Aneurysm Patients

neuroradiology has developed from a therapy of last resort to the Patients presenting for elective treatment of unruptured intracra-
first choice in treatment of many cerebrovascular diseases and re- nial aneurysms will most often be medically optimized prior to
lated conditions. Consequently, not only have the numbers of pa- intervention. While these patients may be in their usual state of
tients undergoing these procedures increased but also the types of health, it is important to consider the associated systemic diseases
patients requiring INR. Patients may be in different states of health, that may be present. Frequently, they have a history of smoking,
either in critical extremus (such as the increasingly common hypertension, and diabetes. It is therefore important to assess and
endovascular treatment of acute ischaemic stroke patient) or alter- medically optimize each patient individually as required.
natively as outpatients in their normal state of health. It is therefore In addition to medical comorbidities, elective cerebral an-
clear that each patient will present unique challenges with regard to eurysm treatment may require the use of adjunctive devices such
their background physiology, the disease process being treated, and as endoluminal stents or flow diversion devices. In these circum-
the procedure that is being performed. stances, platelet activation, resulting in thromboembolic compli-
Endovascular procedures are performed for treatment of vas- cations or even parent vessel occlusion, is a constant risk. Such
cular lesions in the brain. The commons ones are cerebral aneur- patients will require platelet suppression prior to surgery, typically
ysms, arteriovenous malformations, cavernous malformations, with dual antiplatelet medication (i.e., aspirin and clopidogrel). In
cerebral vascular stenosis, and acute ischaemic stroke. They require the setting of a ruptured intracranial aneurysm resulting in SAH,
different anaesthetic considerations. For example, cerebral aneur- the patient’s physiology will be vastly more unstable and complex.
ysms rupture because the transmural pressure across the wall is Even small amounts of subarachnoid blood will result in elevations
increased, whereas cerebral and carotid artery vascular stenosis in intracranial pressure (ICP) and decreased cerebral compliance.
require increased systemic pressure to sustain cerebral blood flow As the volume of subarachnoid blood increases so does the like-
across a high resistance barrier and prevent cerebral ischaemia. lihood that ICP management will be required. This is particu-
Patients with acute ischaemic stroke with a proximal occlusive le- larly true if the aneurysm rupture has resulted in a parenchymal
sion have to be handled differently because they need significantly haematoma.
increased systemic blood pressure (BP) to open up collateral ar- Observation and management of ICP will require considerable
terial vessels to circumvent the stenotic/occlusive lesion. A con- resources to optimize cerebral perfusion pressure (CPP) in order
sensus publication for the treatment of acute ischaemic stroke has to prevent cerebral hypoxia, but at the same time reduce the risks
been recently published (3). of aneurysm rebleeding prior to endoluminal coiling. Cardiac and
This chapter emphasizes the endovascular treatment of cerebral pulmonary issues arise with increased frequency in part as a con-
aneurysms, carotid artery stenosis, and acute ischaemic stroke. It sequence of the intracranial bleed (7–9). Cardiac dysrhythmia and
does not cover the treatment of other disorders such as arterio- left ventricular dysfunction are particularly common, as is neuro-
venous malformations or cavernous malformations because of genic pulmonary oedema and alterations in pulmonary circulatory
their similarity to those discussed. function (10).
Endovascular Therapy for Cerebral Intracranial Pressure Monitoring and Treatment

Aneurysms Patients with intracranial hypertension can deteriorate rapidly in
the INR suite. This condition needs to be addressed prior to the
Aneurysm Background endovascular procedure, because intracranial hypertension is ex-
Relatively few people are affected by cerebral aneurysms (6–16 acerbated by the supine position, and the anaesthetist has only
per 100,000), although the high morbidity and mortality of sub- limited treatments available during the procedure. Placement of
arachnoid haemorrhage (SAH) is a source of considerable concern. an external ventricular drain (EVD) in patients with intracranial
Rupture of an intracranial saccular aneurysm accounts for only hypertension prior to ruptured aneurysm embolization is neces-
~3% of all strokes. However, more than half of these patients die sary to monitor ICP. ICP goals are not entirely based on scientific
within the first 30 days (4). Urgent intervention to avoid rerupture evidence. Typically, the ICP goal has been <20 mm Hg but this goal
has been shown to reduce the risk of permanent morbidity and was not found to be associated with improved outcome in trau-
death (5). Improvements in medical therapy have also been shown matic brain injured (TBI) patients (11). In practice, ICP goals have
to improve outcomes in SAH patients. Until the ruptured aneurysm been based on maintaining CPP at >60 mm Hg (CPP = MAP-ICP).
is secured by surgical clipping or endovascular coil occlusion, gen- CPP target can be achieved either by increasing mean arterial pres-
eral recommendations are to keep the BP low in an effort to prevent sure (MAP), or by reducing ICP.
recurrent rupture of the aneurysm. In patients with an EVD, lying flat for 15–30 minutes will reveal
The precise aetiology and pathogenesis of cerebral aneurysms re- if a patient’s ICP will rise and whether the patient can tolerate the
mains unclear. However, stresses on the arterial wall, whether they interventional procedure. If the ICP rises to >10–20 mm Hg when
are atherosclerotic, related to shear stress, or intrinsic defects, lead the head of the bed is lowered from 300 to 00, this is a sign of re-
to thinning and weakening of the normal vascular microanatomy. duced cerebral compliance. If a significant increase in ICP occurs as
Typically, there is marked attenuation or complete loss of media evidenced by clinical signs, direct pressure measurement, or radio-
at or around the aneurysm neck with a poor cellular sac wall con- graphic findings, then the procedure should be delayed if possible,
taining abnormal extracellular matrix components (6). This may or more aggressive treatment of ICP with hypertonic saline (typic-
lead to an increasingly unstable situation, with further aneurysm ally 23.4% or 3% solutions) via a central line catheter, intravenous
progression and eventual rupture. mannitol (0.25 to 1 gm/kg), dexamethasone (6–10 mg), and/or
203
Chapter 16 interventional neuroradiology 203
drainage of cerebral spinal fluid (CSF) should be initiated before cerebral aneurysms (16). The primary endpoint of this study was
and during the procedure because the patient will be supine both death or dependency using the modified Rankin scale. Enrolment
for transport to the INR suite and during the procedure. commenced in 1994 and was halted in 2003 as it became clear that
coil occlusion was superior to neurosurgical clipping in terms of
Evaluation of a Patient with Suspected Intracranial functional outcomes. Coiling had a 22.6% superiority over surgical
Hypertension clipping in terms of disability-free survival at one year. This rep-
A patient with ICP elevation with impending neurological decom- resents an absolute risk reduction of 6.9% (p = 0.0008) for coiling
pensation will typically have one of the following features: over clipping. Recurrent haemorrhages were not significantly dif-
ferent between the two groups. Recently, long-term data from the
◆ Somnolence or coma
UK arm of ISAT has been provided confirming that endovascular
◆ Cranial Nerve 3 Palsy (which would appear as a dilated pupil coiling was superior to microsurgical clipping in terms of good
early on and down and out orientation of the eye and ptosis as it functional outcomes (17). There is thus Level 1, Grade A evidence
progresses). supporting endovascular coiling over microsurgical clipping for
◆ Cranial Nerve 6 Palsy (presenting as inward deviation of the ruptured cerebral aneurysms. The Cerebral Aneurysm Rerupture
eyes, typically effecting both eyes, and signifying global intracra- After Treatment (CARAT) study supports the findings in ISAT that
nial hypertension compressing the nerves as they enter Dorello’s aneurysms treated by endovascular coil occlusion do not rerupture
canal). at a significantly greater rate than aneurysms treated by surgical
clipping. However, this is dependent upon achieving adequate an-
◆ Flexor or extensor posturing of the extremities.
eurysm occlusion (18–20).
◆ Lundberg waves on ICP monitors (a strong indicator of Not all aneurysms are suitable for simple coiling. The mechanics
impending herniation) (12). of coil embolization require the coils to be physically restrained by
◆ Cushing’s reflex (Intermittent bradycardia with hypertension). the aneurysm in order for the coils to form a basket and not pro-
lapse into the parent artery. This is the case for aneurysms which
◆ Changes in respiratory pattern such as Cheyne-Stokes (hyper- have a neck that is relatively narrow compared to the overall an-
ventilation followed by apnoea) or apneustic breathing (erratic eurysm size. However, many aneurysms are broad necked, may
breathing pattern). even incorporate the origin of one or more vessels, may have a
Management of ventilation and temperature is important prior fusiform geometry, or are a component of a larger abnormal ar-
to treatment because pCO2 >40 cm/H20 may cause cerebrovascular terial segment. Several techniques and devices are now available to
dilatation which can further increase ICP, while hyperventilation treat such aneurysms. The oldest and probably most widely used
with pCO2 <25 cm/H20 may transiently reduce ICP but can com- technique is balloon-remodeling, also known as balloon-assisted
promise CPP and lead to cerebral ischaemia. Hyperthermia can coiling (BAC). In this technique a compliant, endoluminal bal-
also raise ICP and in the presence of cerebral ischaemia may worsen loon is positioned across the aneurysm neck alongside the coiling
outcome (13–15). By contrast, hypothermia may protect the brain microcatheter. The balloon is temporarily inflated while the coils
in patients with refractory ICP both by lowering cerebral metabolic are being placed within the aneurysm, and acts as a physical barrier
demand and by reducing neuronal activity and excitotoxic effects. to coil prolapse. Once the coil is in position the balloon is deflated
However, hypothermia is clearly difficult to maintain during inter- and the coil is observed for prolapse or misplacement. If a satisfac-
ventional procedures. If a patient is on a cooling protocol in the tory position is achieved the coil is detached, otherwise it is repo-
neurological intensive care unit (NICU), plans should be made to sitioned. This process is repeated until the aneurysm is sufficiently
avoid rapid rewarming (a potentially very dangerous scenario in packed after which the microcatheter and balloon are removed.
patients with elevated ICP) and to maintain cooling during trans- There is little doubt that BAC adds a layer of complexity to any pro-
port and aneurysm treatment. During transport, icepacks under cedure. For example, inflation of the balloon applies some mechan-
the armpits and against the trunk as well as ice cold saline infu- ical stress to the arterial wall with a concomitant risk of dissection.
sion may need to be used. Once in the procedure, surface cooling Balloon inflation also reduces or arrests flow, which may increase
devices such as cooling blankets or Arctic Sun® are the most reli- the risk of thromboembolism or frank ischaemia. However, data on
able and readily available devices for maintaining iatrogenic hypo- BAC risk has been inconsistent, and the largest series to date failed
thermia. However, the neuro-interventionalist needs access to the to demonstrate significantly increased risks (21). Where more per-
groin in order to access the major arteries and veins to treat the manent scaffolding is required to achieve aneurysm packing, a
patient. Access to the groin can be a problem when these devices stent may be used (22–24). Under these circumstances the coiling
are employed. microcatheter may be placed in the aneurysm and a stent deployed
within the parent artery, crossing the aneurysm neck and ‘jailing’
Endovascular Treatment of Aneurysms the microcatheter within the aneurysm. Coiling may then be car-
The goal of both endovascular and traditional open surgical treat- ried out with the stent acting to prevent coil prolapse. Alternatively,
ments is to exclude the abnormal vascular segment from the cir- the stent may be placed beforehand and the microcatheter man-
culation while preserving normal cerebral perfusion. In 1990, the euvered through the struts of the stent and into the aneurysm.
Guglielmi Detachable Coil (GDC) was introduced, paving the way Irrespective of the order, upon completion of coiling the catheters
for successful endovascular treatment of cerebral aneurysms; for are removed and the stent remains permanently in situ. Such a tech-
the first time, a reasonable alternative to open surgical clipping was nique requires pre-and postoperative anti-platelet therapy to pre-
available. The International Subarachnoid Aneurysm Trial (ISAT) vent thromboembolic complications and because of this, is used
compared endovascular occlusion and surgical clipping of ruptured reluctantly in the setting of recent haemorrhage.
204
Recently a new paradigm has emerged for the endovascular therapy. As anti-platelet therapy is avoided, this technique may play
treatment of aneurysms. Rather than focusing on endosaccular a role in ruptured aneurysms, which would otherwise require stent-
occlusion of the aneurysm, a new range of ‘Flow Diverting’ stents assisted coiling or flow diversion.
has been introduced to allow endovascular reconstruction of the
entire diseased arterial segment (25, 26). The first such device was Endovascular Complications
the Pipeline™ (eV3, Plymouth, MN, USA), and it remains the most Aneurysm rupture is the most feared procedural complication
widely used with the greatest body of evidence behind it. Rather and typically occurs during coil deployment. The prospective
than being laser cut from nitinol, as traditional stents are, the Analysis of Treatment by Endovascular approach of Non-ruptured
Pipeline is woven from cobalt chromium and platinum strands. Aneurysms (ATENA) study demonstrated a rupture rate of 2.6%,
Previously, endovascular stents had relatively low metal coverage with the majority of the ruptures being clinically silent (31). As
(typically <10%). However, the Pipeline has 30–35% surface area, would be expected, the treatment of previously ruptured aneurysms
more than three times that of traditional stents. A flow diverter, as carries a slightly higher rupture risk of 3.7% as demonstrated by the
the name suggests, diverts flow away from the aneurysm and along CLARITY study. Again, few patients suffered permanent sequelae
the normal parent artery. This means the aneurysm’s morpho- (32). The same studies described thromboembolic complications in
logical characteristics contribute little to treatment success. Flow 7.1 and 13.3% of unruptured and ruptured aneurysms, respectively.
diversion eventually leads to haemostasis within the aneurysm and Along with device malfunction and other minor complications, in
subsequently thrombosis. There is no doubt that the introduction ATENA coiling of unruptured aneurysms had a 30-day permanent
of flow diverters has allowed successful treatment of hitherto un- morbidity and mortality rate of 1.4 and 1.7%, respectively. The per-
treatable aneurysms. It is particularly unique in its ability to treat manent treatment morbidity and mortality for ruptured aneurysms
long segment disease with a fusiform configuration, such as may in the CLARITY study was 3.7 and 1.5%, respectively.
be seen in the setting of dissection. Eventually the flow diverter
provides a scaffold for neoendothelial in growth, permanently Anaesthesia for Patients with Cerebral Aneurysm
excluding the aneurysm (27). The utility of flow diverters hinges An experienced neuro-anaesthetist will have a better understanding
on their ability to preserve flow in side branches and perforators, of what the endovascular surgeon and NICU team will want during
even if completely covered by the stent. This phenomenon is likely the periprocedural period. Most diagnostic angiograms can be per-
related to inflow and outflow differentials, leading to a constant formed on a cooperative patient with local or moderate sedation.
drawing of blood from the parent artery down a negative pressure Cooperative patients can undergo intracranial catheterization with
gradient. This preferentially maintains side branch patency but oc- administration of local anaesthetics injected in advance at the site
cludes the ‘dead-end’ aneurysm. However, there is an increased of the femoral artery catheterization.
risk of thromboembolic complications and, in particular, perfor- During treatment of intracranial vascular lesions, it is impera-
ator stroke, which is rarely seen with other techniques. A recent tive that the patient remain as motionless as possible. Clearly, this
meta-analysis demonstrated an ischaemic stroke rate of 6% with can be achieved most readily under GA with muscle relaxation.
an overall perforator infarct rate of 3% (28). Ischaemic stroke, and Relaxation can easily be monitored with a train-of-four neuro-
in particular perforator strokes, were more common when flow muscular stimulator so that patients can be extubated shortly
diversion was used in the posterior circulation. This likely reflects after the procedure is finished. In some patients the procedure can
the greater density of perforator vessels in the posterior circulation. be performed with MAC. The choice is both patient and neuro-
Two further complications are encountered with flow diversion, interventionalist dependent.
which are as yet not adequately explained: intraparenchymal haem- Frequent neurological evaluations may be important in patients
orrhage and delayed subarachnoid haemorrhage. Both may occur with neurological injury or in patients who undergo neurological
in the postoperative or delayed period. Meta-analysis demonstrates testing. Therefore, some patients need to be sedated during the INR
an intraparenchymal haemorrhage rate of 3%, with no associ- procedure but awakened for an intraprocedural evaluation. All pa-
ation to aneurysm size or location. This implies that it represents tients ideally need to be awake at the end of the INR procedure
an inherent procedural risk. Delayed subarachnoid haemorrhage to help the neuro-intensivist evaluate the patient for neurological
has a rate of 4% and is associated with large and giant aneurysms. deterioration.
These combine to give a procedure-related permanent morbidity The choice of caring for patients with MAC or GA should be dis-
and mortality of 5 and 4%, respectively. While this appears high, it cussed by the interventionalist and anaesthetist. For patients with
should be remembered that often, reconstructive flow diversion is unruptured, unprotected cerebral aneurysms, management of sys-
used to treat large or giant aneurysms, blister aneurysms, or long temic BP is of major concern, specifically systemic hypertension.
segment disease, all of which are themselves associated with in- ICP can in part be predicted by clinical signs. These signs have been
creased rates of morbidity and mortality. codified by a number of different scales, such as the Hunt-Hess
Recently, the concept of flow disruption has been introduced, scale, the Fisher scale, and the World Federation of Neurosurgical
in part from the experience with flow diversion. Flow-disrupting Societies classification (Table 16.1). For patients with a Hunt-Hess
devices are designed to achieve aneurysm thrombosis by disrup- scale score of >2, there is an increased likelihood of increased ICP.
tion of intra-aneurysmal blood flow. The first such device is called
the WEB (Sequent Medical, Palo Alto, CA, USA), which has been Motor Deficit Management of Blood
shown to be safe and effective in the treatment of wide-neck bifur-
cation aneurysms of the basilar and middle cerebral arteries in the Pressure and ICP
initial studies (25, 26, 29, 30). The device is placed within the an- Before intubation, management of increased ICP is treated by
eurysm sac and as such obviates the need for aggressive anti-platelet making sure venous drainage is optimized by raising the head of the
205
Table 16.1 WFNS Subarachnoid Haemorrhage Grading Scale While this scale was designed for extubation in the NICU, similar
criteria can be easily imagined for extubating peri-operatively in
Grade Glasgow Coma Score (GCS) Motor Deficits the INR suite. Additional considerations will need to be taken in
patients with high ICP and unsecured aneurysms, as well as in pa-
I 15 –
tients who will need another invasive procedure in the immediate/
II 14–13 – near future (e.g., failed aneurysm coiling of a ruptured aneurysm
III 14–13 + requiring surgical clipping).
IV 12–7 +/–
V 6–3 +/–
Endovascular Therapy for Carotid Artery
Stenosis
Reproduced from Journal of Neurology, Neurosurgery & Psychiatry, 51, 11, G. M.
Teasdale, C. G. Drake,W. Hunt, N. Kassell, K. Sano, B. Pertuiset, J. C. De Villiers, A universal Carotid atherosclerotic disease is estimated to be responsible for
subarachnoid hemorrhage scale: report of a committee of the World Federation of 20% of acute ischaemic strokes (40). As with atherosclerotic dis-
Neurosurgical Societies. Copyright © 1988, British Medical Journal. ease in other arterial segments, the prevalence of carotid stenosis
increases with age. Surgical carotid endarterectomy (CEA) is cur-
bed or tilting the x-ray table in reverse Trendelenberg, decreasing rently the accepted standard of treatment for revascularization of
the fullness of the parenchyma with mannitol, draining cerebro- extracranial carotid atherosclerotic disease. Surgery was demon-
spinal fluid, or hyperventilating the patient to vasoconstrict the strated to be superior to medical management by multiple random-
cerebral vasculature. ized, controlled trials around the end of the twentieth century. With
To manage BP, patients generally have a radial artery catheter the success of percutaneous stenting of atherosclerotic disease in
placed prior to induction. During induction, the BP is monitored other vascular segments such as the lower limb, renal arteries, and
carefully. Etomidate and propofol are commonly used as a part of cardiac arteries, carotid artery stenting (CAS) emerged as a new
induction (33, 34). Thiopental, etomidate, and propofol reduce ICP, alternative to surgery.
cerebral metabolic demand and induce cerebral vasoconstriction
(35). Ketamine should be avoided in patients with suspected intra- Treatment of Carotid Artery Stenosis
cranial hypertension. The proposed benefits of endovascular treatment of carotid sten-
The anaesthetist generally administers a sedative hypnotic, e.g., a osis centres on reduction of operative risks related to endarter-
narcotic like fentanyl and a muscle relaxant like succinylcholine or ectomy: concomitant cardiac morbidity, contralateral carotid
rocuronium. Using a non-depolarizing paralytic is preferred if the occlusion, and inaccessibility of the stenotic vessel behind the man-
patient appears likely to be easily intubated, but the depolarizing dible requiring more extensive surgical exposure. Largely relying on
muscle relaxant succinylcholine should be used if there is any doubt data from the Stenting and Angioplasty with Protection in Patients
that intubation may be difficult (36). Many anaesthetists perform at High Risk for Endarterectomy (SAPPHIRE) trial (~8% reduc-
a test laryngoscopy beforehand to see if the BP will increase sig- tion in composite end-point of death, stroke, or myocardial infarc-
nificantly with laryngoscopy by itself. If it does, a short-acting beta tion for CAS versus CEA and a statistically significant lower rate
blocker like esmolol may be administered in increments of 30 to of restenosis) (41), CAS found a place in patients deemed to be at
50 mg to blunt the sudden increase in systemic pressure. Esmolol increased risk for surgery. Therefore, stent angioplasty is currently
and lidocaine blunt the stimulatory effects of intubation and reduce approved for patients with medical contraindications to surgery,
ICP spikes (37). A number of different potent inhalational agents restenosis after endarterectomy, radiation-induced stenosis, high
can aid with maintenance of anaesthesia. Since most cause systemic cervical stenosis, or contralateral carotid occlusion. Importantly, a
vasodilation, they decrease the systemic pressure. If increased ICP distal embolic protection device was used in all CAS patients in
is a problem, then a total intravenous technique using an infusion SAPPHIRE, which had not been the case in previous trials. An em-
of propofol, a narcotic like fentanyl, remifentanil, or sufentanil, and bolic protection device is used to prevent embolic strokes during
a muscle relaxant like rocuronium, vecuronium, or cisatracurium angioplasty and stenting of the atherosclerotic lesion. The device
may be used. At the end of the procedure, once the patient is re- traps particles of atherosclerotic plaque or blood clots, which are
versed from the muscle relaxant, awake, and following commands, subsequently retrieved at the end of the procedure. These devices
the patient can be extubated. Rarely do patients have to remain in- have subsequently become the standard of care in CAS.
tubated unless they start out intubated before the procedure. Several randomized trials have directly compared carotid surgery
with stent angioplasty in more general patient populations. Carotid
Extubation and Brain Injury and Vertebral Artery Transluminal Angioplasty Study (CAVATAS)
Extubation is the goal at the end of an endovascular procedure. enrolled 504 patients with symptomatic carotid stenosis (at least
However, patients with depressed mental status, often measured by 30% luminal diameter reduction) and considered suitable for ei-
the Glasgow Coma Scale (GCS) (see Table 10.4, Table 12.1), can have ther endarterectomy (253 patients) or stent angioplasty (251 pa-
delayed extubation due to an inability to protect the airway. GCS <8 tients, with 26% receiving stents at the discretion of the treating
was associated with extubation failure in one study (38). Salam and physician) (16). Patients not suitable for endarterectomy were then
colleagues came up with simple criteria for extubation failure in randomized to either stent angioplasty or medical treatment. There
patients who passed a spontaneous breathing test (SBT) that in- were no significant outcome differences between endarterectomy
cluded cough peak flow, secretion volume, and ability to follow and stent angioplasty at 30 days (death, 3% stent angioplasty vs. 2%
simple commands (open eyes, follow with eyes, grasp hand, stick surgery; disabling stroke, 4% for both; and non-disabling stroke,
out tongue) with a high degree of sensitivity and specificity (39). 4% for both) (16). Analysis of long-term survival demonstrated no
206
differences between stenting and endarterectomy in the rate of ipsi- However, when patients with carotid artery stenosis are treated
lateral stroke or any disabling stroke, in up to three years of follow- endovascularly they are usually managed with very mild sedation
up examinations. However, two other European trials in France so that a clinical evaluation can be performed. Prior to performing
and Germany, EVA-3S and SPACE, failed to show the equiva- the angioplasty, a number of different protection devices are de-
lence of stenting to endarterectomy in low surgical risk patients. ployed to reduce the number of emboli that may be released from
The Carotid Revascularization Endarterectomy versus Stent Trial the site of stenosis and dispersed into the brain. The anaesthetist
(CREST) (42, 43) was a large multicentre, prospective, randomized monitors systemic BP by a radial artery catheter or measuring the
trial comparing CAS to CEA in both symptomatic and asymptom- BP off of the femoral artery catheter placed by the endovascular
atic carotid stenosis patients. It reported the results of 2502 patients physician. The goal is to maintain BP at a level wherever the pa-
followed for a mean of 2.5 years with outcomes estimated to four tient is asymptomatic, usually at his or her baseline BP. Since most
years. No difference between CAS and CEA was demonstrated with stenotic atherosclerotic lesions are located at the bifurcation of the
regard to the primary end-point of composite death, any stroke or common carotid, when the angioplasty is performed there is fre-
myocardial infarction in the periprocedural period, or ipsilateral quently stimulation of the carotid sinus with concomitant brady-
stroke within four years after randomization. However, the details cardia. This bradycardia can be prophylactically treated with an
of the data have been much debated. It seems clear that CEA carries antimuscarinic such as atropine or glycopyrrolate.
a significant risk of myocardial infarction, diagnosed by elevations
in cardiac enzymes. However, CAS carries a greater risk of stroke. Endovascular Therapy for Acute
Proponents of CEA argue that many patients classified as sustaining
myocardial infarction in CREST had asymptomatic cardiac enzyme Ischaemic Stroke
rises which have little impact on quality of life. Conversely, while In the United States, on average, a person has a stroke every 40
much of the increased stroke incidence for CAS was in ‘minor’ seconds, contributing to the estimated 6.8 million Americans
strokes, this classification included patients with NIHSS ≤8, which who have had a stroke, or around 3% of the population (4). While
may indicate significant deficits. haemorrhagic stroke often has a more aggressive clinical course,
The debate continues as to what place CAS has in extracranial ca- ischaemic stroke is by far the more common entity and accounts
rotid revascularization in the absence of contraindications to CEA, for ~87% of strokes. The introduction of intravenous thromb-
largely due to a small but significant increased stroke risk in CAS. olysis and the NINDS trial (54) was a substantial step in acute
Much of the excess stroke risk in CAS is seen in the periprocedural ischaemic stroke management. The publication in 2015 of five land-
period. This could be predicted when taking into consideration that mark trials demonstrating the superiority of adding endovascular
in CAS, the stenotic, atherosclerotic lesion must be crossed with thrombectomy to standard care (55–59) has placed interventional
a guide wire, may need balloon pre-dilatation, and then is mech- neuroradiology at the forefront of large vessel, acute ischaemic
anically trapped by the struts of the stent. This may lead both to stroke care (60).
atheromatous emboli and platelet activation, whereas in CEA the
atheromatous lesion is often removed en bloc. Medical therapy has Treatment of Acute Ischaemic Stroke
advanced since the first patients were enrolled in CREST. There Until recently guidelines only advocated the use of intravenous
is now far greater understanding of the role of dual antiplatelet tissue-type plasminogen activator (IV-tPA) within 4.5 hours from
therapy and the issues with clopidogrel non-responders, which has symptom onset in patients without evidence of haemorrhage on
come largely from the cardiology literature. CREST-2, a follow-up computed tomography (CT) scan. If given rapidly, IV-tPA can re-
study to CREST, has been designed to compare CAS and CEA with duce disability. Patients treated within three hours of symptom
modern medical management to medical management alone. It is onset have an odds ratio of 1.53 for a favourable outcome at
likely that improved antiplatelet therapy would reduce some of the three months. Clearly, the goal of acute ischaemic stroke (AIS)
stroke risk in CAS, particularly in the peri-operative period. This therapy is to achieve meaningful reperfusion of the ischaemic
has been supported with early studies demonstrating halving of penumbra, thereby halting expansion of the ischaemic core (60).
the early ischaemic events in CAS patients treated with aggressive Unfortunately, IV-tPA has limited efficacy in recanalizing proximal
antiplatelet regimens (44). Interestingly, a similar reduction in early artery occlusions in the ICA and M1 segments. As tPA affects clot
ischaemic events in CAS has been demonstrated for aggressive disruption by activation of enzymatic thrombolysis, the clot burden
statin therapy (45). Moreover, as technique, stents, and distal pro- seen in large vessel ischaemic stroke (predominantly ICA and M1)
tection devices evolve, a decreasing rate of periprocedural strokes appears to be too large to reliably achieve reperfusion in a timely
is reported (46). The current consensus is that CAS should be used fashion (61). Endovascular therapy was viewed as an alternative for
in select patients who are anticipated to have high surgical risk. It large vessel occlusions, with the promise of more reliable and de-
would be expected that as our understanding of the pathophysi- finable reperfusion. However, early techniques failed to live up to
ology of periprocedural ischaemia improves, along with evolution expectations.
in techniques and devices, CAS will have a significantly larger role Initially, endovascular stroke therapy focused on delivering fi-
to play in extracranial carotid revascularization. brinolytic drugs directly to the clot via microcatheters with or
without mechanical disruption with wires or even ultrasound.
Anaesthesiology for Patients with Carotid Artery Initial results were promising, although large randomized con-
Stenosis trolled trials, including the Interventional Management of Stroke
Patients who have carotid artery stenosis can be treated by CEA or (IMS) III trial, have shown these techniques to be no better than
carotid artery angioplasty and stenting. A number of studies have intravenous therapy (62). Early generation mechanical devices
recently been published comparing the two treatments (16, 47–53). were introduced in an attempt to perform thrombectomy. Devices
207
such as the Merci were designed to incorporate within the clot and stroke, these trials reiterate the importance of rapid intervention.
then allow the clot to be retracted into a guide catheter. However, As with all surgical and endovascular procedures, there must be
this device had limited success. Second-generation devices such workforce collaboration. This issue was examined in the Solitaire
as the Penumbra system were designed around suction thromb- FR Thrombectomy for Acute Revascularization (STAR) study (63).
ectomy, using pneumatic suction through specially designed cath- While the American Society of Anesthesiologists has recom-
eters along with mechanical clot disruption to improve aspiration. mendations regarding the pre-anaesthesia assessment of patients,
While this was an improvement on the Merci, clinical results with there are no data specific to the pre-anaesthetic evaluation of pa-
the Penumbra system were also underwhelming. tients presenting for emergency treatment of AIS. Every attempt
More recently a new generation of devices has been introduced should be made to obtain a history, perform a physical examination
called ‘stentrievers’. These devices are stents, deployed across the including a neurological examination, and obtain relevant chem-
clot and then retrieved, generally under flow reversal, retrieving istry values; however, none of these steps should delay initiation of
the clot often intact. Technical success with stentrievers has been treatment, because there is substantial evidence of the detrimental
impressive with quality reperfusion (TICI ≥2b) in around 80% effect in delaying treatment of AIS (67).
of patients in as little as half the time required with other tech- No prospective studies have been performed concerning the ad-
niques. A large single arm European registry using stent-retrievers vantage of GA over monitored anaesthesia care (MAC). However,
was published. In a severe stroke population (mean NIHSS = 17), subgroup analysis of patients receiving GA in MR CLEAN and
quality reperfusion (TICI ≥2b) was achieved in ~80%, in a mean a number of retrospective studies have now looked at this issue.
procedural time of 29 minutes. Mortality at three months was only These studies provide evidence that use of MAC may result in better
7% with a symptomatic haemorrhage rate of 1.5%. Most encour- neurologic outcomes. ‘Neurological outcome is more likely to be
agingly of all, three-month modified Rankin score (mRS) 0–2 was good (modified Rankin score ≤2) in patients who are not intub-
achieved in 58% (63). This compares very favourably to a IV-tPA ated or do not receive heavy sedation, pharmacological paralysis,
single arm study published contemporaneously with a similarly se- or GA’ (68–72). Patients not intubated for endovascular treatment
vere stroke population (mean NIHSS = 17) in which three-month of AIS have been reported to have a lower final infarct volume on
mRS 0–2 was achieved in only 35% (64). In an unusually unani- diffusion-weighted magnetic resonance imaging studies or non-
mous turn around, five multi-national randomized controlled trials contrast head CT, and shorter length of stay in the ICU (71). Yet,
were published in 2015 demonstrating the overwhelming success of some data are contradictory: patients receiving no sedation or light
endovascular mechanical thrombectomy for large vessel ischaemic sedation had higher successful angiographic reperfusion rates than
stroke in addition to standard care compared with standard care those who received heavy sedation or pharmacological paralysis in
alone (55–59). The first reported trial was the Dutch study, MR one study (71), but not in another (73). Some of the studies ad-
CLEAN (55). The presentation of the preliminary results of this dressing the type of anaesthesia care have been criticized for selec-
trial in late 2014 prompted the review and subsequent early ter- tion bias because patients with more severe strokes (i.e., presenting
mination (due to overwhelming positive results) of the Canadian with higher NIH stroke scores) were more often treated with the
ESCAPE (56), the North American and European SWIFT-PRIME general anaesthetic group (68). Therefore, the association of worse
(58), and the Australian and New Zealand EXTEND-IA trials (65). neurologic outcome is less associated with GA but more likely re-
These trials shared the common ground of identifying large vessel lated to the fact that the patients with greater pre-existing, and pos-
occlusion early using neuroradiology and achieving high rates of sibly permanent, neurological disability received GA (68). What
quality reperfusion in a timely fashion. These trials have now es- may be more relevant than the type of anaesthesia administered
tablished interventional neuroradiology as the standard of care for is careful BP control: systolic BP should be maintained >140 mm
acute ischaemic stroke due to large vessel occlusion (59). Hg during GA (72, 74). BP is likely to be lower on induction of GA
than in patients receiving MAC. The choice between GA and MAC
Anaesthesiology for Patients with Acute is ideally made jointly by the neuro-interventionalist and the an-
Ischaemic Stroke aesthetist. However, there is no conclusive evidence for increased
A task force was established by the Society for Neuroscience in incidence of intraprocedural complications, delays to the start of
Anesthesiology and Critical Care (SNACC) to develop consensus treatment, or whether one anaesthetic is better than another (66).
on peri-operative management of patients with AIS (3). The results Extubation is the goal at the end of an endovascular procedure. The
were reviewed by members of the executive boards of SNACC, criteria for extubation were discussed in the section on extubation
the Society of Neurointerventional Surgery, and the Neurocritical of patients with cerebral aneurysms.
Care Society. The task force reviewed the relevant literature up Stroke intervention is an emergency procedure that requires co-
until August 2012, and issued the statement that the ‘. . . purpose of ordination with anaesthesia services while minimizing any delays.
this consensus statement is to advise on anesthetic management of For every ten minutes of delay, outcomes are significantly worse in
endovascular treatment of AIS’ (66). At the time of publication of acute stroke intervention (75). Without question, time is essential;
this consensus statement, no randomized controlled trials (RCTs) rapid achievement of revascularization is the goal. No case should
had demonstrated benefit of endovascular treatment of AIS com- be delayed for problems associated with intravenous or intra-
pared to intravenous tissue plasminogen activator (IV-tPA) alone. arterial access. The INR physician can easily supply the anaesthetist
Since then, six RCTs have reported results that demonstrate a sig- with arterial access for BP monitoring at the time of catheter-
nificant advantage of endovascular treatment in addition to IV-tPA ization. The crucial element is that the anaesthetist must main-
(55, 61–64) for patients with AIS and large vessel occlusion within tain the systemic BP at normal to elevated values. The American
six hours of stroke onset. In addition to the importance of complete Heart Association recommendations suggest keeping the sys-
or near-complete revascularization of the occlusions causing acute tolic BP between 140–180 mmHg (76). Current guidelines for BP
208
management are still under discussion, and many experts argue the cranial cavity, protamine should be readily available to reverse
for liberalization of BP in AIS to levels as high as 220/120 mmHg the effect of heparin. Different algorithms are available regarding
until revascularization is achieved. Hypotension should be avoided the amount of protamine necessary to administer to reverse the
because it can reduce collateral blood flow to the ischaemic brain anticoagulation due to heparin, but the most reliable measure of
beyond the point of arterial occlusion. Pressure management reversal is an activated clotting time. If an aneurysm ruptures, pro-
may be changed under specific circumstances, such as treatment tamine should be administered quickly. Quick administration of
of acute ischaemic stroke, if intravenous tissue plasminogen acti- protamine frequently causes a drop in systemic BP due to hista-
vator (IV-tPA ) is given. The management of BP in patients with mine release, but also can cause a dangerous allergic anaphylactic
incomplete cerebral revascularization is less clear because there are or anaphylactoid reaction, which may be fatal. As well, an over-
conflicting needs: maintaining adequate collateral blood flow yet dose of protamine can cause weakening of the clot structure and
avoiding haemorrhagic conversion of a bland infarct, which oc- platelet dysfunction (82). Vigilance to timing of when the heparin
curs with some frequency in any event. The recommendation after was given and the dose of heparin given should be well understood
reperfusion therapy is to keep BP lower than 180/105 mmHg (77). prior to administration of protamine.
The focus on avoiding extreme hypertension in patients who have Many patients have also received IV-tPA (0.9 mg/kg). Usually,
received IV-TPA or endovascular therapy is to avoid conversion of the effect of heparin is not reversed at the end of the procedure. If a
a bland infarct to a haemorrhagic one, a possible consequence of catheter-induced intracerebral haemorrhage occurs, then rapid re-
recanalization of an occluded vessel. There is evidence that a U- versal of heparin with protamine may be helpful. The effect of tPA is
shaped relationship exists between baseline systolic BP and both more difficult to terminate, although the half-life is relatively brief.
early and late death or late dependency; too low and too high sys- Intracerebral haemorrhage is often self-limited, but more elaborate
temic BPs are deleterious (Figure 16.1) (76–78). protocols have been suggested without evidence of better efficacy.
Other physiological parameters must also be carefully controlled. Surgical evacuation may become necessary.
PaCO2 should be maintained between 35 to 45 mm Hg under general MAC has analogous haemodynamic, arterial oxygenation, and
anaesthesia. Systemic temperature should be kept between 35o–37o carbon dioxide, and glucose management standards. Sedation
C, even though a third of patients with AIS are febrile, and systemic should be tailored to treatment of anxiety and excessive motion,
cooling may provide neuroprotection under certain conditions. There but still allowing a patient to protect the airway and to cooperate
is no evidence for immediate systemic cooling in AIS patients (79). in intraprocedural testing, if required. It cannot be overemphasized
Hyperglycaemia is common in patients with AIS. Hyperglycaemia that team communication between the anaesthetist and neuro-
predicts poorer outcome, but there are no specific data on glycaemic interventionalist is extremely important for the patient is to receive
management during endovascular treatment of AIS, and there is the best care possible.
evidence that tight glucose control is associated with increased inci-
dence of hypoglycaemia and poor clinical outcomes (80).
Heparin is often administered during endovascular treatment to
Cases
reduce the incidence of catheter induced embolic and thrombotic Q Interactive cases to test your knowledge on this chapter can
events (81). Because patients with these lesions may bleed into be found in the online appendix at www.oxfordmedicine.com/
otneuroanesthesiology.
30 68
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CHAPTER 17
Pituitary and
Neuroendocrine Surgery
Douglas A. Colquhoun and Edward C. Nemergut
Introduction The anterior pituitary is a collection of five different cell types that
are responsible for the secretion of six different trophic hormones.
Surgeries on the pituitary are commonly encountered in The gonadotropes are responsible for the secretion of Luteinizing
neuroanaesthesia practice. Pituitary tumours are the third most hormone (LH) and Follicle stimulating hormone (FSH). Each other
common brain tumour, comprising about 10–15% of all primary cell type is specific to the hormone secreted: Thyrotrope—Thyroid
brain tumours (1). The incidence of pituitary tumours is rising in stimulating hormone (TSH); Corticotrope—Adrenocorticotropic
the general population, although this likely represents an increase hormone (ACTH), Somatotrope—Growth hormone (GH) and
in the diagnosis of these tumours secondary to both increased Lactotrope—Prolactin. Each trophic hormone has its own regu-
awareness and continuous improvements in intracranial imaging, latory hormone secreted from the hypothalamus that acts on the
rather than a true rise in incidence (1). Nevertheless, this patient anterior pituitary to modulate expression and is subject to feedback
population poses unique challenges to the anaesthetist caring for inhibition at the hypothalamus and at the pituitary. Disruption
them in the peri-operative period and requires the care of a multi- of the hypophyseal portal system leads to a loss of secretion of all
disciplinary team to accurately diagnose and manage their disease hormones except prolactin, secretion of which is increased (see
process as they undergo surgical resection. Table 17.1).
The posterior pituitary contains its own plexus of capillaries into
Anatomy and Physiology which its endocrine hormones are secreted. The posterior pituitary
Encased within the sella turcica of the sphenoid, the pituitary gland is composed of nerve terminals from the supraoptic and paraven-
is comprised of two distinct groups of tissues. The neurohypophysis tricular nuclei of the hypothalamus. These projections form the
(posterior pituitary) is a direct neural projection of the hypothal- hypothalamic-hypophyseal tract. The hypothalamic-hypophyseal
amus connected via the infundibulum (or pituitary stalk) and is tract along with the hypophyseal portal system form the pituitary
derived from neural ectoderm. The adenohypophysis (anterior pi- stalk. The secretion of these hormones is controlled by the hypo-
tuitary) is of epithelial origin, tracing its embryologic heritage to thalamus as they are synthesised within the hypothalamus, trans-
the endoderm of the buccal cavity. A small intermediate lobe forms ported via neurons, and secreted. The posterior pituitary secretes
a remnant in the adult human and is derived from the anterior pi- oxytocin and vasopressin (antidiuretic hormone, ADH).
tuitary. Together these parts are referred to as the pituitary gland The anatomy of those structures within the fossa and close to
and collectively weigh around 0.5 g, although this can increase to the pituitary gland must be understood in order to appreciate the
1 g during pregnancy. The pituitary gland measures approximately operative course and potential for complications. The roof of the
9 mm x 9 mm (AP x RV dimension). sphenoid sinus is formed by the sella turcica. The sella turcica is
These tissues are bound to one another by the pituitary stalk, bounded laterally by the cavernous sinuses, which are separated by
which consists of the neurones from the hypothalamus to the pos- dura and thin layer of bone. This protects the pituitary from the
terior pituitary and the hypophyseal (or pituitary) portal system pressure effects of fluctuant cerebrospinal fluid. Within the cav-
of blood vessels. These vessels allow the control of the anterior pi- ernous sinus on each side run the Oculomotor (III), Trochlear
tuitary by the hypothalamus via release of secretory or inhibitory (IV), Ophthalmic (V1), and Maxillary (V2) divisions of the trigem-
factors into this blood vessel system. Factors are secreted from the inal nerve, the Abducens (VI) cranial nerve, and the internal ca-
median eminence of the hypothalamus into capillaries that are rotid artery. The sella turcica is covered by a dural reflection—the
collectively referred to as the primary plexus. These subsequently diaphragma sella. The optic chiasm is directly above the sella tur-
converge to form the hypophyseal (or pituitary) portal vessels. The cica and is slightly anterior to the pituitary stalk. Thus, any mass
portal system supplies the anterior pituitary via a secondary plexus lesion is liable to cause compression on the optic chiasm (which
of capillaries and modulate the production of hormones by the an- would likely offer the least resistance), but additionally compression
terior pituitary. There is evidence of retrograde flow within these of either cavernous sinus, with resultant nerve palsy or obstructed
vessels, suggesting that interaction hypothalamic-pituitary may be venous flow. Violation of the boundaries of the sella put these struc-
possible in both directions (2). tures at risk during operative procedures on the pituitary.
214
Table 17.1 Hormones of the anterior pituitary and an overview of function secretion regulation.
Anterior Pituitary Hormone

Pituitary Hormone Lutenizing hormone (LH) Folicle stimulating Thyroid stimulating Growth hormone (GH) Adrenocorticotrophic Prolactin
hormone (FSH) hormone (TSH) hormone (ACTH)
Secreting Cell Type Gonadotrope Thyrotrope Somatotrope Corticotrope Lactotrope
Hypothalamic Hormone Gonadotropin-releasing Gonadotropin-releasing Thyrotropin releasing GH-releasing hormone Corticotropin-releasing Prolactin releasing factor
hormone (releasing) hormone (releasing) hormone (releasing) (releasing) hormone (releasing) (releasing)
GH release inhibiting Dopamine (inhibitory)
factor—Somatastatin
(inhibitory)
Target Tissue Testes/ovaries Testes/ovaries Thyroid Throughout the body Adrenal cortex Breast
Major Role Testosterone synthesis/ Sperm maturation/follicular Secretion of thyroid Promotion of growth and Synthesis + secretion of Milk production and
ovulation, Oestrogen + development hormones protein synthesis cortisol, Androgens and expression
progesterone synthesis aldosterone
215
Chapter 17 pituitary and neuroendocrine surgery 215
Systemic Changes Associated with Pituitary and growth. In premenopausal women this presents as a wide var-
iety of disturbances of menstrual function. In adult males the pres-
Tumours entation is usually a subtler complaint of loss of libido, impotence,
Masses within the pituitary are common findings. Autopsy series and infertility (13, 14). Galactorrhoea is rare in men (15). In adult
place the incidence of microadenoma at around 10% of the popu- males and post-menopausal women the presentation is more likely
lation (3). Similar results have been obtained in healthy volunteer to include local mass effects rather than clinical dysfunction (14).
series undergoing MRI (4). The vast majority (85–90%) of masses As a consequence, these tumours are usually macroadenomas at
undergoing surgical resection are pituitary adenomas (3). Alternate time of presentation (13, 16).
pathologies commonly include Craniopharyngiomas and Rathke’s GH is required throughout life for the maintenance and develop-
cleft cysts (3). However, a broad differential including infectious ment of many tissues. Deficiency of GH in patients with pituitary
or inflammatory causes, vascular malformations, metastases, and failure leads to reduced life expectancy (15).
gliomas are all possible. Hypersecretion of GH in the adult leads to acromegaly. Pituitary
Adenomas within the pituitary are classified into ‘micro’ or ‘macro’ cause is responsible for 95% of acromegaly (17). Acromegaly has
adenomas on the basis of size. Microadenomas are typically defined an insidious onset and patients usually present a number of years
as having size in all dimensions of less than 10 mm. Tumours can after the initial onset of the symptoms. Patient complaints include
be further classified into ‘functioning’ or ‘non-functioning’ based progressive glove/ring, shoe, or hat sizes (17). There can be a gen-
on their synthetic function (5). The clinical presentation of the pi- eralized coarsening of the facial features, enlargement of mandible
tuitary mass depends on both size and functional status. Those that leading to overbite and prognathism, and enlargement of tongue
present due to mass effect have symptoms such as headache, visual and nose. Tissue overgrowth may lead to joint disease, early osteo-
field defects, and decreases in visual acuity (due to the proximity phyte formation, ossification of ligaments, and spinal stenosis,
and vulnerability of the optic nerves). The visual deficit may mani- all which may significantly limit functional status. Fibrous tissue
fest as a progressive loss of central visual acuity and additional loss changes and expansion may lead to nerve entrapment. Children
of visual field at the temporal visual fields, particularly in the su- who develop this condition prior to fusion of the epiphyseal plate
perior areas (3). As these tumours are slow growing, this may not have continued bone growth and may present with giagantism.
prompt presentation until quite advanced. Acromegaly is characterized by generalized organomegaly.
Headache is a common finding (40–70%) in those with pituitary Cardiac disease in present in 20% of patients (18). Hypertension is
masses. The mechanism of this process is variable with possibilities present in 50% and left ventricular hypertrophy (LVH) is present in
including dural stretch, cavernous sinus involvement, or changes half of those without evidence of hypertension. This may progress
to hormonal function (particularly GH and prolactin) (6). While to cardiac failure due to chronic high output state. Systolic function
multiple headache subtypes may occur, there is a clear association is usually preserved; however, diasotolic function is often poor, es-
between a family of headaches referred to as trigeminal auto- pecially in patients with LVH. Ejection fraction may be raised. ST
nomic cephalalgia (TAC) and pituitary function (6, 7). In this type Depression, t-wave abnormalities, and arrhythmias may be seen on
of headache unilateral facial pain in the trigeminal distribution is electrocardiogram (17). Central and obstructive sleep apnoeas are
paired with an autonomic finding such as tearing or conjuctival common, the latter relating to hypertrophy of the airway tissues
injection (7). Tumours that subsequently bleed or infarct are as- (17). GH hypersecretion may lead to diabetes mellitus (17).
sociated with sudden onset headache which may be present along Patients with acromegaly have a marked increased in mortality
with visual loss, impaired extraocular movement, facial sensation by about 70% (19). Cardiovascular disease is a leading cause of
changes, and somnolence (6). death. This increased morality remains after surgical resection and
Subclinical or minimally symptomatic pituitary haemorrhage is elevated by around 30% compared with the general population
occurs in up to 25% of patients with pituitary adenomas. When (19). Dekkers and colleagues in a meta-analysis compared those
this is associated with an abrupt onset of symptoms it is referred to undergoing treatment before 1995 and after and found a marked
as pituitary apoplexy (8). This is present in 2–7% of patients with decrease in mortality, which has been thought to be attributable
adenomas and may be due to haemorrhage, infarction, or a mixed improved medical and surgical management (17, 19).
presentation (9). These patients often require immediate surgical ACTH-producing tumours are associated with the clinical pres-
management in order to improve visual deficits and may require entation of Cushing’s disease (20). These patients present with
long-term subsequent hormonal supplementation (9). weight gain and obesity, usually predominantly in the central tis-
Case series reports on patients undergoing pituitary resection sues, in fat deposits over the thoracic spine (‘buffalo hump’) and
reveal that around half of procedures are performed to resect producing a enlarged, round face (‘moon facies’). There can also
nonfunctioning adenomas (10, 11). Prolactinomas are the most be epidural fat deposition leading to neurologic deficits, although
common type of functioning pituitary tumour, followed by GH- this is rare (21). Hypertension is common alongside altered glu-
secreting, ACTH-secreting, and rarely, TSH-secreting or multi- cose handling leading to diabetes mellitus and hypercholesterol-
hormone-secreting tumours (12). emia leading to increased cardiovascular morbidity (20). There also
Prolactin hyper-secretion in pituitary tumours can result from ei- may be an increase in the propensity for thromboembolic events
ther adenomas that produce prolactin or by tumours whose growth in these patients. Loss of libido is a common complaint, alongside
impairs the tonic dopaminergic inhibition of lactotrope (as this is menstrual abnormalities and hirsutism in women. Although it is
under constant, negative inhibition). Excess prolactin production commonly noted in many medical texts, only 10–15% of patients
classically leads to galactorrhoea and disturbances in reproductive may be found to have hypokalaemic acidosis (20). Depression is a
function (13). The clinical presentation depends on the age and common psychiatric manifestation along with insomnia. Overall
gender of the patient. In children this presents as delayed puberty quality of life is reduced, despite improvements after treatment (22).
216
Tumours which secrete TSH are rare. In addition to the mass and failed or poorly tolerated medical or radiation therapy (17, 23).
effects common to pituitary disease these lead to the presentation Patients presenting with prolactin-secreting microadenomas are
of the classical features of hyperthyroidism including palpitations, usually managed medically using dopamine agonists (23). This is
weight loss, tremors, and anxiety (17). These patients may be clin- usually effective in preventing continued growth; however, women
ically treated for hyperthyroidism for a prolonged period of time, contemplating immediate pregnancy may need surgical resection
prior to the central cause of their symptomatology being recog- in order for this to be feasible (17, 23).
nized. As a consequence these tumours are often macroadenomas Radiation therapy has been offered to selected candidates who
(88%) at time of presentation (17). decline or fail operative treatment of their pituitary neoplasm. Use
Rathke’s cleft cysts are derived from a failure of invagination of of this modality for nonfunctioning pituitary adenomas (including
the embryologic cyst. They may grown and become enlarged to the macroadenomas) has been described in the literature (29). For
point of presenting as pan-hypopituitarism (17). Evidence of these functioning tumours, rates of response vary depending on the mo-
cysts can be found in up to 20% of patients at autopsy series. But dality employed and the nature of the tumour to be treated (30).
the vast majority are not clinically relevant. Craniopharyngioma is Due to the increased prevalence of cardiovascular disease in pa-
a rare tumour which presents clinically in two age groups: either in tients with acromegaly and Cushing’s disease (discussed earlier), it
childhood or adolescence, or in the over fifties (17). These tumours is appropriate to conduct a pre-operative evaluation of cardiac risk
may become large and cause significant mass effects, including ob- and function. An electrocardiogram may reveal evidence of LVH.
struction of CSF flow (17). Clinical assessment may reveal symptoms of cardiac failure. LVH
It should be noted that pituitary adenomas may present in con- can further be assessed and in particular the presence of diastolic
cert with an underlying familial or systemic disease. Multiple dysfunction via echocardiography. The increased risk of coronary
endocrine neoplasia type 1 (MEN-1) is as an autosomal dominant artery disease should be considered and if adequate functional
disorder with tumours noted in parathyroid gland, pancreas, and status is not achieved then consideration of further risk stratifica-
pituitary gland. These usually present as prolactinomas. MEN-1 tion should be considered.
is associated with dysfunction of tumour suppressor gene MEN1 The management of sleep apnoea in the peri-operative period
(17). Familial isolated pituitary adenomas are found in fewer than for this patient population is controversial. While unmanaged,
5% of cases of pituitary masses. These may present as gigantism obstructive sleep apnoea is a risk for peri-operative airway mor-
in teenagers or as a familial form of acromegaly. McCune-Albright bidity and is known have significant detrimental effects on day-
Syndrome is a rare syndrome that may include pituitary tumours time function and can contribute to both pulmonary and systemic
alongside café-au-lait spots, precocious puberty, and widespread hypertension; the use of positive pressure support in the con-
abnormal fibrous bone growth. text of endoscopic trans-sphenoidal surgery is challenging (31).
Sleep apnoea is present with high prevalence in patients with
known Cushing’s disease and acromegaly (32, 33). Case reports of
Pre-Operative Evaluation pneumocephalus in the postoperative period in patients treated
The decision to proceed to surgery should only occur after careful with positive pressure support suggest caution (34). Some im-
consideration of MRI imaging of the Sella and careful biochem- provement may be noted in patients with acromegaly in the first six
ical evaluation of pituitary function (23). Biochemical evaluation to eight postoperative weeks (31). Nevertheless, medications with
includes assessment of circulating concentrations of the anterior pi- sedative properties such as benzodiazepines and opioids should be
tuitary hormones and also assess circulating concentrations of their used cautiously in the peri-operative period.
target hormones (23). It may be indicated to determine the func- Metabolic derangements are common in patients presenting for
tion of the Hypothalamus-Pituitary-Adrenal access by provocative pituitary surgery. Diabetes mellitus, as a result of impaired carbo-
testing to determine the ACTH reserve (24). The goal is to try and hydrate handling due to acromegaly, is common. This may correct
determine the true functional status of any mass. Additional la- rapidly after biochemical control of the lesion in the postoperative
boratory investigation should include a complete blood count to period (17). Although diabetes insipidus may be associated with
evaluate for co-existing anaemia and an assessment for common the presentation of a craniopharyngioma or Rathke’s cleft cyst, it is
electrolyte abnormalities. Glucose, calcium, potassium, and so- rarely associated with pituitary adenomas. Nevertheless, if encoun-
dium may all be deranged in the settings of pituitary disease and tered, diabetes insipidus and associated hypernatremia may need to
its complications (25). be assessed and managed.
Pre-operative evaluation may be undertaken by joint pituitary
medical/surgical clinics; indeed, some advocate for the develop- Intra-Operative Management
ment of true multidisciplinary centres for the management of these Patients with acromegaly have long been known to be at signifi-
complex patients (26). The goal of any surgical intervention is to cant increased risk of difficulty in airway management (35). The en-
improve any mass-related effects that may be present and gain bio- larged tongue, presence of obstructive sleep apnoea, enlarged facial
chemical control of the endocrine disease. features, and rapid time to desaturation all contribute to challenges
Patients presenting for surgical management of their pituitary with bag mask ventilation in this patient population (36).
mass may have already undergone a period of medical manage- Repeated studies have demonstrated that a reassuring pre-
ment. While medical therapy has advanced for patients with ac- operative airway exam (by Mallampati classification) is not pre-
romegaly (27) and Cushing’s disease (28), proceeding to surgical dictive of ease of intubation in acromegalic patients (10, 37, 38).
resection remains the normal practice. Indications for proceeding Nemergut and colleagues noted that in 121 consecutive patients
to surgery include mass effects (such as visual changes, headaches), with acromegaly, 50% of those with difficult-to-manage airways
haemorrhage (discussed previously), acromegaly, Cushing’s disease, were noted to have Mallampati Class 1 or 2 scores (10). Schmitt and
217
colleagues also noted that in their series of 128 patients with acro- in a large database study that around 2% of patients required ei-
megaly, 20% of patients with a reassuring airway examination were ther transfusion or were noted to have an internal carotid artery
subsequently found to be difficult to intubate (37). The upper lip (ICA) injury (49). Involvement of the ICA is rare, but is potentially
bite test may be more sensitive than Mallampati classification; how- catastrophic (50–52). Both open and endovascular management
ever, Sharma and colleagues believe that its poor sensitivity limited strategies have been described in the literature to address this com-
its applicability (39). Even a global clinical assessment as described plication (52–54). In a large case series, Raymond and colleagues
by Friedel and colleagues still revealed high rates of unanticipated noted ICA bleeding in 17 of 1800 patients undergoing trans-
difficulty in intubation (40). sphenoidal pituitary resection (53). Other sources of bleeding in-
Given these challenges associated with airway management, it clude the sphenopalatine artery, which Raymond and colleagues
seems prudent to ensure the easy availability of advanced airway reported in four patients in their case series (51, 53). Delayed
management devices. Additionally, a low threshold should be util- bleeding from vascular injury around two weeks postoperatively
ized for consideration of an awake intubation strategy for airway has been reported (55, 56).
management. The surgical team may express a preference for an Pituitary surgery has evolved significantly in the past 30 years.
oral RAE tube to improve access to the nose. Tubes can alternately Removal of a pituitary mass by craniotomy was first described in
be taped out of the way of the surgical team. The tube should be 1887 in a ten-patient case series by Horsley (57). Later refinements
well secured, as the anaaesthesia team will not have easy access to included a trans-sphenoidal approach via a rhinotomy by Schloffer
the airway during the case. The oily skin that may be encountered (58). Cushing described a completely internal approach, using a
in patients with acromegaly may make this more challenging, and sublabial incision (58). Further work lead to the refinement of these
the use of alcohol or another cleanser may be required to allow microscopic, internal approaches (59), with Griffith and Veerapen
adhesion. describing the entirely endonasal approach in 1987 (60). Improving
No single technique has emerged as being clearly superior for endoscopic technologies allowed the refinement of these endonasal
the maintenance of general anaesthesia in patients undergoing sur- procedures to an entirely endoscopic technique by Jankowski and
gery for pituitary resection. Gemma and colleagues, when utilizing colleagues in 1992 (61).
remifentanil in addition to isoflurane compared with isoflurane Use of an endoscopic technique allows a panoramic view of the
alone, noted shorter time to following commands in the former surgical field (58). Microscopic techniques suffer as exposure is
group, but no difference in time to extubation (41). Comparisons of only limited to the area exposed by the retractors and the field of
remifentanil plus sevoflurane or propofol showed shorter recovery view narrows as the exposure becomes deeper due to the use of
times in the remifentanil-sevoflurane group in one study and no an external microscope (58). Endoscopic surgery is felt to offer ad-
difference, but improved cognitive function at five and ten minutes vantages, particularly for the resection of larger tumours (62), and
postoperatively, in the propofol-remifentanil group in another (42, it has lead to a shift in practice during the early 2000s, although
43). The use of short-acting opioids may be preferable due to the regional variations continue to exist (63). It should be noted that
risks of respiratory depression and the challenges of airway man- in selected cases transfrontal approaches may still be indicated
agement discussed earlier. Nasal packing is frequently placed in the based on tumour size, location, or surgeon preference, although
postoperative period, which means ventilation is exclusively via the there is a significantly increased risk of morbidity in this patient
oral cavity; the patient can be informed of this pre-operatively and population (64).
reminded during emergence. A succession of large case series, structured reviews, and subse-
The use of an intra-arterial catheter has potential indications in quent meta-analyses (58, 65–70) and opinion papers (71–73) have
trans-sphenoidal surgery in patients with known significant car- established the safety and efficacy of the move towards endoscopic
diac comorbidities and in the early detection of sudden hyper- practice. For many centres, an endoscopic technique has evolved
tensive episodes (5). When considering the use of a radial artery to be the standard practice, achieving at least non-inferiority com-
catheter, it should be noted that patients with acromegaly may be at pared with microscopic techniques, and potentially offering bene-
risk of ischaemia of the hand secondary to occlusion of ulnar blood fits in reported pain and time to discharge.
flow in 50% of patients as detected by abnormal Allen’s test (44). Multiple variations are described in endoscopic approaches to
Care should be exercised in positioning those with acromegaly the pituitary. Access may be obtained via one of both nares with
due to known bony and fibrous tissue overgrowth and the high varying degree of resection of the turbinates, nasal septum, and
incidence of carpal and cubital tunnel disorders (45, 46). These sphenoid rostrum (58, 62). The degree of resection can relate dir-
patients are at risk of peripheral neuropathy, which may already ectly to post-operative nasal morbidity, so a balance between ad-
established prior to the surgical procedure. equate exposure and risk should be maintained (62).
Patients undergoing trans-sphenoidal pituitary surgery are fre- In selected cases the surgical team may place a lumbar CSF drain
quently positioned in the head-up position. Venous air embolism prior to the procedure. Some clinicians advocate their use to prevent
(VAE) has been reported to be encountered in up to 10% of patients post-operative CSF leaks (74). However, for patients with extensive
undergoing trans-sphenoidal surgery (47). Monitoring, including lesions, particularly those that have a supra-sellar component, in
the use of pre-cordial Doppler, is recommended, as a case of pul- order to assist the exposure and improve surgical conditions, the
monary oedema which was attributed to repeated VAE during anaesthesia team may be asked to manipulate a lumbar drain. One
a trans-sphenoidal pituitary resection has been reported (48). method introduces 10–20 ml of air or saline into the lumbar drain
However, evidence of significant other morbidity and mortality due (with strict sterile technique) (75), which transiently increases CSF
to this complication is scant (5). pressure and causes a descent of the suprasellar structures into the
Significant haemorrhage is a known but uncommon compli- operative field (76). A similar effect can be obtained by mild hypo-
cation of trans-sphenoidal surgery. Krings and colleagues noted ventilation and consequent rise of pCO2 and cerebral vasodilation.
218
A role may exist for the management of significant CSF leaks by mixed alpha and beta adrenergic agents (i.e., epinephrine) may
regulation of CSF pressure via a lumbar drain. This may be placed cause the development of extremely high blood pressures and reflex
after the occurrence of a leak to assist in pressure regulation while bradycardia. Treatment of this bradycardia with anti-cholinergic
the defect heals (77). The development of more sophisticated flap agents may precipitate acute pulmonary oedema in setting of car-
repairs for even large dural defects has led to this practice being diac failure. Postoperative pain management regimens may include
called into question, given the 3–5% reported complication rate the use of paracetamol (acetaminophen), ketorolac, or narcotic
of the lumbar drain (78). Some studies note the utility of intra- pain medications. The latter must be used with care in patients with
thecal fluorescein administration in the localization of leak sites obstructive sleep apnoea, as noted previously.
(58, 79). The anaesthesia team may be asked to introduce this via The use of steroids in the peri-operative period is complex.
a pre-existing lumbar drain. The rate of intra-operative leak detec- Steroids are indicated for stress dosing of patients who pre-
tion was said to be 61% in a study by Jakimovski and colleagues, operatively have hypopituitarism, have documented pre-operative
although this translated into a 3% risk of significant postoperative ACTH deficiency, or are on replacement therapy (92). For those
CSF leak (80). who pre-operatively have an intact cortisol regulation mechanism
The development of intra-operative guidance techniques has as- and undergo resection of the adenoma alone, an early morning cor-
sisted the advance of endoscopic approaches (81). Utilizing high- tisol dose on the first few postoperative days may be safely used
resolution, pre-operative, cross-sectional scanning and known to guide whether supplementation is required (92, 93). Inder and
reference points, the position of the surgical instruments can be Hunt proposed hydrocortisone replacement for patients with 8
calculated (82). While the use of these techniques varies between am cortisol <3.6 μg/dL and recommended testing and considering
each reported case series, they have become standard in this type temporary dosing for those with levels <9 μg/dL, stress dose those
of surgery in many centres (83, 84). The consensus seems to be that with levels <16 μg/dL and note that those with levels above this
these techniques are particularly useful in procedures that lead to have normal pituitary-adrenal function (92). An intact stress re-
reoperation, where traditional landmarks have been markedly dis- sponse in this patient population is predictive of preservation of
rupted (85). Guidance techniques are useful in the navigation to- normal pituitary function (94).
wards the tumour, but additionally in the determination of zones For patients with Cushing’s disease, assays of cortisol levels are
of resection within the pituitary gland itself. The use of millimetre- obtained every six hours in the postoperative period. For these
level pre-operative scanning can allow for determination of zones patients, a POD 2 serum cortisol <3.5 μg/dL is predictive of long-
of resection, with some authors claiming utility in patients with re- term success of the surgical intervention (95). Failure of the serum
current adenomas or microadenomas (86). Based on an analysis cortisol level to fall indicates the possibility of incomplete resec-
of practice in the United States, it is thought that image guidance tion and need for re-exploration, or a trial of a different treat-
might contribute to lower risk of CSF leak, shorter length of patient ment modality (92, 96). Rates of recurrence are significantly lower
stay, and reduced costs (87). in patients with subnormal vs normal levels in the postoperative
More recent advances in operating room technologies have al- period: 9% vs 24%, respectively, in meta-analysis by Sughrue and
lowed the inclusion of magnetic resonance imaging (MRI) scanners colleagues (97). Patients should be monitored closely for signs of
into the operative environment. Low field scanners (< 0.5T) can adrenal insufficiency, such as malaise, nausea, tachycardia, hypo-
be integrated into traditional operating rooms, whereas high field tension, and hypothermia (96), which may present 24 to 36 hours
scanners (>1.5T) require the development of dedicated operating postoperatively. Hydrocortisone supplementation should be initi-
environments with shielding technologies. These allow the surgeon ated in those who are symptomatic or have been found to have a
to continue with surgery after an intra-operative scan revels incom- serum Cortisol < 2 μg/dL (5, 98).
plete resection. This may lead to high rates of complete resection or The methods of management described here require labora-
higher proportion of resection in tumours which cannot be com- tory assessment with a rapid turn-around time in order to decide
pletely excised (88). if intervention is required within the next few hours (5). Patients
Trans-sphenoidal surgery is not typically associated with sig- with hypopituitarism may not absorb steroids via an enteral
nificant patient discomfort. Most pain can be managed well on route in the peri-operative period and therefore will require IV
an oral pain-relief regimen by the second postoperative day, and replacement (96).
endoscopic approaches are thought to be associated with less Dexamethasone has historically been used as a peri-operative
postoperative pain than microscopic approaches (70). The use steroid as it was thought not to interfere with postoperative
of local anaesthetics such as cocaine or lidocaine before surgery Cortisol assays. Burkhardt and colleagues explored this con-
is routine at most centres; however, the short duration of these cept in a review of practice and noted that patients treated with
drugs is not thought to contribute to patient analgesia after sur- 4 mg Dexamethasone (typically as a postoperative nausea and
gery. According to Pasternak and colleagues, intranasal injection vomiting prophylaxis dose) failed to show the expected stress
is associated with increases in systemic blood pressure of 60 mm response rise in cortisol production (99). This may suggest
Hg systolic (89). This may relate to systemic absorption of epineph- the clouding of the clinical picture by using Dexamethasone
rine, given its demonstrated dose-dependent relationship in com- intra-operatively  (99).
parison of 1:400,000 and 1:200,000 injection (90), but this may be
associated with adverse outcomes (91). Some clinicians use agents Common Complications (Diabetes
with sole alpha adrenergic activity, in which systemic absorbtion
can cause hypertension and bradycardia. Patients who have pre- Insipidus)
operative beta adrenergic blockade may also be vulnerable, as the Diabetes insipidus (DI) is a common postoperative problem caused
effectively unopposed alpha adrenergic stimulation from otherwise by an interruption of the secretion of antidiuretic hormone from
219
the posterior pituitary, or by a lesion at the level of the hypothal- hyponatraemia may be related to the excessive release of ADH
amus, the posterior pituitary, or the hypophyseal portal system. in the interphase of the triphasic response discussed previously,
Practice reviews and surveys reveal an incidence of around 15% of the development of SIADH (which in turn may be related to pain,
this complication, about half of which will be permanent, although stress, infection, or CNS trauma), iatrogenic causes such as exces-
this does vary widely (100–106). Larger tumours, those under- sive desmopressin use (as mentined previously), hypotonic fluid
going repeat surgery or surgery for craniopharyngiomas, and those administration, or the development of cerebral salt wasting (rare).
whose surgery was complicated by intra-operative CSF leak are felt Assessment of volume status is crucial, as this may point to diag-
to be particularly at risk (100, 102, 106). Existing meta-analyses nosis—hypovolaemia in cerebral salt wasting vs hypervolaemia
show conflicting results as to whether there is any difference in in other hyponatraemic states. Management includes consider-
incidence between those undergoing microscopic vs endoscopic ation of the use of fluid restriction in mild cases (where serum
resection (105). Na >125mEq/L), and the use of hypertonic saline or an emerging
This complication presents polydipsia and polyuria with the therapeutic option: use of vasopressin receptor antagonists
creation of more than 30ml/kg of urine in a 24-hour period, with (‘-vaptans’) which cause free water loss in more severe cases (107).
a specific gravity of the urine <1.005. A rising serum sodium or Vasopressin receptor antagonists must be avoided in hypovolemic
a serum sodium >145 mEq/dL supports the diagnosis (107). If patients (107) and administration must be guided by serial elec-
these signs are not present, then other diagnostic possibilities, e.g., trolyte measurement. In all cases, the serum sodium must not be
hyperglycaemic-induced polyuria, which has a normal serum so- allowed to rise more than 12mEq/L in a 24hr period (107).
dium and uinary specific gravity >1.005, and post-operative diur- Violation of the dura and the development of a CSF leak either
esis, with a low or normal sodium uinary specific gravity >1.005 intra-operatively or in the postoperative period presents as CSF
and no polydipsia, should be entertained (107). Patients with ac- rhinorrhea. Rates of CSF leak of around 15% have been described
romegaly and Cushing’s disease are thought to have increased in the literature, although this varies widely (77, 109). Management
urinary output after resection due to loss of excess fluid in tissues of intra-operatively recognized CSF leaks involves the harvesting
(105, 107). Close monitoring of serum electrolytes and fluid intake of an abdominal fat graft for placement. Alternatively, newer tech-
and output in the peri-operative period is required. Should there be niques involve the use of an intranasal flap or use of injectable gel
any clinical suspicion of development of DI, then the serial meas- materials to close the defect (110, 111). Postoperative CSF leaks
urement of urine specific gravity and serum sodium concentration may be managed with lumbar drainage or repeat endoscopic sur-
is indicated (105). gical exploration; rarely transcranial repair may be required (77).
DI may present as either a transient phenomena presenting in Given the nature of the surgery, a persistent bony defect is pre-
the first one to two postoperative days and possibly lasting three sent at the operative site. It is unknown how long this area of
to five days, or permanent phenomena (or so-called ‘triphasic’ weakness persists. However, case reports showing inadvertent
phenomena), where the patient appears to have transient polyuria intracranial placement of a nasogastric tube as far as 25 days out
that self-resolves and then is followed by a recurrent permanent from surgery should be taken as an indication for care (112, 113).
phenomena (105). This triphasic presentation occurs when the As discussed, for similar reasons the use of positive pressure venti-
degenerating neurons release their remaining vasopressin stores as lation via the nasal route should be undertaken with caution in the
they are undergoing transitioning towards permanent loss. For per- peri-operative period.
manent DI to be established, >85% of hypothalamic magnocellular In their case series, Flynn and Nemergut determined the risk of
neurons must be lost (105). vomiting in the postanaesthesia care unit after trans-sphenoidal
A patient may, for at least a short period of time, be able to main- surgery to be 7.5%, and a known intra-operative CSF leak, use of
tain adequate oral free water intake to maintain a normal serum a fat graft (for repair of CSF leak), the use of a lumbar intrathecal
sodium concentration. This may be sufficient to enable patients catheter, or the resection of craniopharyngiomas all increased the
with transient DI to recover normal posterior pituitary function. risk of PONV in their patient population (114). Curiously, prophy-
However, most patients, while asleep, otherwise impaired, or who lactic administration of ondansetron or droperidol did not alter
have an abnormal thirst mechanism, will be unable to do this and the risk of emesis, but did reduce the risk of nausea. The use of
therefore will require pharmacotherapy. The use of intranasal, intra- an orogastric tube to evacuate any blood that may have entered
venous, or oral desmopressin may be required, the first of which the stomach during the surgery at the conclusion of the procedure
may not be possible in the presence of nasal packing (107). These should be considered. Additionally, nausea and vomiting in the
therapies must be tailored to the individual patient, in dosing and postoperative period may be a sign of adrenal insufficiency, which
duration of therapy (105). If desmopressin is utilized, serum sodium must be excluded (34).
should be carefully monitored as iatrogenic syndrome of inappro- Exophthalmos is a known presentation of patients with Cushing’s
priate antidiuretic hormone secretion (SIADH) from desmopressin disease (115). Care should be taken in the protection of the eyes, as
and resultant hyponatraemia can be associated with high morbidity the eyelids may not completely close in these patients and thus are
and mortality. Care should be taken to prevent fluid overload at the vulnerable to corneal exposure or abrasion injuries.
beginning of therapy if a patient maintains a high fluid intake (105). Patients may notice significant change in their sense of smell after
Patients may also experience postoperative hyponatraemia this endoscopic trans-sphenoidal surgery. While this may relate to
(107), which is 2.8 times more likely in patients with Cushing’s flap creation, all patients in a study conducted by Rotenberg and
disease; hyponatraemia peaks at the seventh postoperative day colleagues complained of change in olfaction (116). When meas-
(108). Hensen and colleagues noted this to occur in 8% of their ured quantitatively there was felt to be a 16% decrease in measures
patient population in the first ten days postoperatively; how- of olfaction (116), which is significantly detrimental to subsequent
ever, only 2% were symptomatic (108). The development of quality of life.
20
16. Colao A, Sarno AD, Cappabianca P, Briganti F, Pivonello R, Somma

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24
25
CHAPTER 18
Hydrocephalus and
Associated Surgery
Paola Hurtado and Neus Fàbregas
Introduction approximately 330–380 ml of CSF enters the venous circulation in

the same time frame. According to the traditional understanding,
The understanding and treatment of hydrocephalus (HD) is a CSF is formed inside the lateral brain ventricles, mostly by secre-
subject of extensive research in different domains. To address this tion from the choroid plexuses. It is generated at a constant rate
persistent problem, an ‘International Hydrocephalus Workshop’ of 0.4 ml.min-1.g tissue-1, similar to the cells of the renal proximal
series has been conducted with the intent to better understand the tubule and pancreatic ducts, and circulates through the third and
pathology and to set international guidelines. Noteworthy in this fourth ventricles. It then circulates through the basal cisterns and
context is Professor Marmarou, whose work intensively focused on tentorium before it exits into the subarachnoid space via the fourth
the progress of intracranial pressure dynamics and HD knowledge. ventricle foramina of Luschka and Magendie. CSF is essentially ab-
Marmarou defined the pressure volume index (PVI). This measure- sorbed by the arachnoid villi into the venous channels of the sagittal
ment represents the amount of volume that must be added to the sinus and internal jugular system, and/or via cranial and spinal
intracranial compartment to raise intracranial pressure by a factor nerves paraneural sheaths into the lymphatic system. In addition,
of 10; PVI led to an improved understanding of the various forms of absorption towards the interstitial compartment occurs via the
HD (1). The work resulted in the 2005 Guidelines for the Diagnosis Virchow-Robin spaces. The rate of absorption is dependent on the
and Management of Normal Pressure Hydrocephalus (2). pressure gradient between the subarachnoid space and the venous
Further advances have led to a new era in the diagnosis and system. CSF volume is replaced three to four times per day (3).
treatment of HD: Membrane transporters are key elements in brain water and CSF
1) Developments of techniques as magnetic resonance imaging homeostasis. Aquaporins (AQPs), which are membrane proteins
(MRI) show the actual effects of the distortion caused by that facilitate water diffusion across the blood-CSF interface, ap-
HD and by the presumed changes in the chemical milieu of pear in the developing choroid plexus epithelium and are retained
the brain. throughout life. Aquaporin-1 (AQP1) is a water channel located
mainly at the choroid plexus epithelium and plays an active role in
2) Improvement in minimally invasive neurosurgery and pro-
CSF production. AQP1 is heavily expressed at ventricular-facing
gress in neuroendoscopy devices have created the opportunity
membrane of the choroid plexus epithelium but not in blood-brain
of avoiding a permanent ventriculoperitoneal shunt (VPS) to
barrier (BBB) endothelium. AQP1 is downregulated in HD and
thousands of patients whose HD can be controlled with an
upregulated in cases of human choroid plexus tumours. Thus, by
endoscopic third ventriculostomy (ETV).
modulating AQP1, it may be possible to selectively modulate water
3) Better design of shunt valves diminishes the malfunctioning movement from blood into the cerebral ventricles.
that rendered many patients too much often to the operating Aquaporin- 4 (AQP4) is expressed at the ependymal, glia
room for shunt surgical revision. limitans, and perivascular end feet processes of astrocytes of the
The aim of this chapter is to summarize, for the neuro-anaesthetist, BBB, facilitating water movement across these tissue interfaces.
HD diagnosis and surgical approach as well as cerebrospinal (CSF) Observations obtained from animal studies, as well as a few cases in
physiology and pathology. humans, indicate an adaptive and protective role of up-regulation
of AQP4 in HD; this upregulation can decrease CSF production
and increase oedema clearance. An understanding of CSF move-
Cerebrospinal Fluid Physiology ment across the brain-barrier systems due to AQP1 and AQP4 may
be important to our understanding of the pathophysiology of HD
Synthesis, Reabsorption, and Dynamics and possible pharmacological treatments that modulate the expres-
The CSF volume is approximately 150 ml in adults; 125 ml is dis- sion of these proteins (4–6).
tributed in the cranial and spinal subarachnoid spaces and 25 The osmotic pressure change inside the central nervous system
ml in the ventricles. A volume of 500–600 ml is secreted by the (CNS) capillary network is crucial in the regulation of intersti-
choroid plexus epithelium over the course of a 24-hour day and tial fluid and CSF volumes, which are continuously mixed by
26
fluid pulsations. The pathophysiological significance of changes Table 18.1 Human cerebrospinal fluid composition.
in CSF volume is assessed from haemodynamic (choroid plexus
blood flow and pulsatility), hydrodynamics (choroidal hypo-and Parameter (Units) Normal Theoretical Pre-Neuroendoscopy
hypersecretion), and neuroendocrine factors (i.e., coordinated Values Values
regulation by atrial natriuretic peptide, arginine vasopressin, and Ph 7.28–7.32 7.44 ± 0.09
basic fibroblast growth factor).
There has been an increased focus on CSF flow, including how PO2 (mmHg) 40–44 147.80 ± 31.20
it impacts cerebral metabolism and haemodynamics, neural stem PCO2 (mmHg) 44–50 34.10 ± 22.20
cell progression in the subventricular zone, and catabolite/pep- Standard bicarbonate (mEq 20–25 23.80 ± 3.00
tide clearance from the CNS (7). Novel insights utilizing molecular L-1)
and cellular biology, as well as neuroimaging, indicate that CSF
Base excess (mmol L-1) - −1.70 ± 3.90
circulation comprises not only directed flow, but also a pulsatile
movement with a continuous bidirectional fluid exchange between Ionised calcium (mmol L-1) - 0.80 ± 0.06
blood, interstitial fluid, and CSF. Total calcium (mEq L-1) 2.1–2.7 2.12 ± 0.5
The mechanical coupling between cerebral blood flow and CSF
Glucose (g L-1) 0.5–0.8 0.67 ± 0.12
flow throughout the cardiac cycle is of great importance. Cerebral
blood volume variations cause the oscillatory bidirectional move- Sodium (mEq L-1) 135–145 148.70 ± 3.53
ment of the CSF within the craniospinal axis. Phase-contrast cine- Potassium (mEq L-1) 2.6–3 2.35 ± 0.24
matic magnetic resonance imaging (MRI) provides a noninvasive
Magnesium (mEq L-1) 3.5–4.4 3.14 ± 0.44
and rapid evaluation of CSF hydrodynamics. Using cardiac-gating,
this technique is extremely sensitive in evaluating CSF flow dy- Protein (g L-1) 15–45 26.15 ± 22.90
namics and is more accurate than conventional MRI to evaluate Chlorine (mEq L-1) 118–130 126.44 ± 1.60
CSF flow. MRI is sensitized to velocity changes in a specific dir-
Osmolality (mOsm Kg-1) 280–310 297.10 ± 20.27
ection, while signals from stationary protons and from motion in
other directions are ruled out. However, the clinical application Adapted from Minimally Invasive Neurosurgery, 50, 1, Salvador, L., Valero, R., Carrero, E., et al.,
of CSF flow dynamics analysis has been restricted due to the high Cerebrospinal fluid composition modifications after neuroendoscopic procedures, pp. 51–
55. © Georg Thieme Verlag KG.
interindividual variation of normal CSF flow values measured in
healthy volunteers (8).
clearance across capillary walls (AQ 4) and arachnoid villi when
Composition and Function CSFP and fluid retention are markedly elevated (7).
Brain capillaries (the BBB) also produce a significant amount of Moreover, one of the primary functions of CSF is to protect the
fluid and are governed by the Starling principle. Under normal cir- brain from mechanical damage and serve as a cushion for the brain;
cumstances, 20% of the CSF comes from this interstitial fluid (ISF). CSF dampens the effects of intracranial and extracranial forces.
The total volume of the interstitial fluid (ISF) is twice that of the CSF
and the chemical composition is similar. The most characteristic Hydrocephalus
feature is the low-protein concentration, which amounts to 0.4% of
the protein concentration in plasma (9). The composition of CSF Definition and Aetiology
is detailed in Table 18.1. The bulk of ion transport from blood to HD is an increase in CSF volume with dilatation of the cerebral
the CSF occurs via the transcellular route across the choroid plexus ventricles or subarachnoid spaces. It is a complex disorder with sev-
epithelium. Substance exchange occurs between the CNS extracel- eral theories regarding its pathophysiology. CSF absorption ceases
lular interstitial fluids and CSF, which is assumed to serve as a sink if venous pressure exceeds the intracranial pressure. The presence
for the removal of various metabolites out of the CNS by its unidir- of blood or adhesions within the ventricular system or subarach-
ectional pulsatile flow and absorption. Thus, distribution of water, noid space increases the resistance to CSF outflow through the
which constitutes the bulk of ISF and CSF, is very limited due to its arachnoid granulations.
rapid turnover across the microvascular walls. It is important to HD as a complex disease is divided into infantile (see Box 18.1),
emphasize that microcirculatory/microvessel hypothesis intercon- juvenile, or adult forms. It can be further divided into either high-
nects the physiology of all craniospinal fluids (plasma, intracellular, pressure or normal pressure HD. It exists in communicating or
extracellular, and cerebrospinal fluid) (11). noncommunicating forms depending on whether there is no ob-
The CSF circulation around blood vessels penetrating from the struction between the ventricles and the subarachnoid space.
subarachnoid space into the Virchow Robin spaces provides both Finally, it can also be divided into active or arrested HD depending
a drainage pathway for the clearance of waste molecules from the on the progression of the symptoms (14).
brain and a site for the interaction of the systemic immune system
with that of the brain. CSF recycling between subarachnoid space, Congenital HD can result from CNS malformations, infections,
brain, and ventricles promotes interstitial fluid convection with intraventricular haemorrhage, genetic defects, trauma, and ter-
both trophic and excretory benefits (12). It serves as a transport ve- atogens. The disorders can be grouped according to the primary
hicle for neurotransmitters and other metabolites produced in the pathogenic mechanism (obstructive versus absorptive).
brain. Finally, CSF reabsorption via multiple pathways (olfactory HD that begins in infancy before fusion of the cranial sutures, if
and spinal arachnoid bulk flow) is likely complemented by fluid untreated, typically results in marked enlargement of the head
27
Chapter 18 hydrocephalus and associated surgery 227
In aging and Alzheimer disease, the expanding CSF space reduces

Box 18.1 Common Causes of Hydrocephalus in the Infant and
Newborn the CSF turnover rate, thus compromising the CSF sink action to
clear harmful metabolites (e.g., amyloid) from the CNS.
Pure obstructive hydrocephalus: In the last decade, the most widely accepted theory for HD has been
◆ Intracranial cysts with no evidence of bleeding at diagnosis. Greitz’s hyperdynamic flow, which divides HD into two main groups,
◆ Triventricular hydrocephalus due to aqueductal stenosis. acute and chronic. Acute HD, or non-communicating type, is caused
by an intraventricular CSF obstruction. For example, approximately
◆ Asymmetrical hydrocephalus due to atresia of the foramen 30% of subarachnoid haemorrhage patients develop acute obstructive
of Monro. HD within the first three days after aneurysm rupture (see Figure
◆ Obstruction of the fourth ventricle outlets. 18.1). Acute HD can complicate the postoperative evolution of dif-
ferent neurosurgical procedures such as posterior fossa surgery (9).
Obstructive hydrocephalus with a transient minor communi-
Chronic HD is further divided into communicating and chronic
cating component:
obstructive HD. In the latter there is a structural blockage of the CSF
◆ Large arachnoid cysts circulation within the ventricular system (e.g., stenosis of aqueduct
◆ Chromosomal abnormalities, syndromic, genetic (X-linked; of Silvius) that can remain silent for some years depending on the
osteogenesis imperfecta; craniofacial syndromic disorders degree of stenosis. In young adults and children, obstructive-type
HD is the most common type due to diseases such as cystic lesions,
◆ Consequence of metabolic inherited disease (Hurler’s disease; tumours, obstructive membranes, trauma, or haemorrhagic stroke.
achondroplasia) Chronic HD is due to decreased intracranial compliance, causing
Communicating hydrocephalus: restricted arterial pulsations, and increased capillary pulsations
◆ Permanent impaired absorption. stressing the hydrodynamic origin of both types of chronic HD.
The major absorption of CSF occurs in the capillaries of the central
◆ Primary congenital hydrocephalus (malformed brain; devel- nervous system and not in the pacchionian granulations (which
opmental/genetic association). are projections of the arachnoid villi in the dural sinuses) (9). In
◆ Secondary prenatal hydrocephalus (post hemorrhagic; some instances, such as meningitis, both absorption and flow may
postinfectious). be interrupted, which is defined as complex-type HD. Rarely, HD
may be the result of excessive CSF production.
◆ Secondary Postnatal hydrocephalus (prematurity-related;
Normal pressure HD (NPH) refers to a condition of pathologically
posthaemorrhagic; postinfectious; venous congestion–
enlarged ventricular size with normal opening pressures on lumbar
craniosynostosis, achondroplasia; venous thrombosis–su-
puncture; it occurs as an idiopathic or secondary condition. When
perior vena cava obstruction after cardiac surgery).
associated with an identified aetiology, NPH can occur in all age
◆ Increased secretion: Choroid plexus papilloma/carcinoma. groups. Impaired absorption of CSF is the suspected mechanism in
Communicating hydrocephalus with an obstructive most cases. Identified underlying causes are intraventricular and/or
component: subarachnoid haemorrhage (either from aneurysm or trauma) and
prior acute or ongoing chronic meningitis (from infection, cancer,
◆ Tumours.
or inflammatory disease). Decreased CSF re-absorption leads
◆ Intraventricular haemorrhage (with a clot in the aqueduct, re- to gradual accumulation of CSF within the ventricular system.
sulting in intracranial cysts). Although increased pressure is not measured on lumbar punc-
◆ Infection, meningitis, or encephalitis, resulting in intracranial ture, a pressure effect is nonetheless believed to occur locally on
cyst or secondary obstruction.
◆ Chiari 2, Dandy Walker malformation.
◆ Encephalocele.
Adapted from Child’s Nervous System, 22, 12, Beni-Adani L, Biani N,

Ben-Sirah L, Constantini S, The occurrence of obstructive vs absorptive
hydrocephalus in newborns and infants: relevance to treatment choices,
pp. 1543–1563. Copyright (2006) with permission from Springer.
rather than frank destruction of brain tissue. The skull expands

and partially relieves ICP. If HD occurs acutely or occurs after
fusion of the cranial sutures, the head does not enlarge, ICP in-
creases, and there is more rapid destruction of brain tissue.
In children, HD is almost always associated with increased ICP and
its aetiology is typically due to obstructive disturbances of CSF
circulation. For example, a large suprasellar mass causes an ob- Figure 18.1 Tetraventricular hydrocephalus in patient with severe subarachnoid
struction to CSF flow with dilation of the lateral ventricles. haemorrhage..
28
periventricular white matter tracts, producing the observed path- pressure is similar to treatment of NPH but may also include shunting,
ology and clinical symptoms. Dilatation of the ventricular system or be managed with serial lumbar punctures, optic nerve sheath de-
may lead to loss of brain cells resulting in a variety of neurological compression, and acetazolamide to lower CSF pressure. Bariatric sur-
symptoms, stroke, and sometimes even death due to pressure ap- gery may be appropriate in those with comorbid obesity.
plied on the brain parenchyma (2).
Imaging
Benign intracranial hypertension implies increased CSF pressure
that is measurable during lumbar puncture, but there is no obvious Ventriculomegaly that appears in brain computed tomography
cause (such as a tumour or infection) and there are normal sized (CT) with aging and cortical atrophy is known as ‘ex-vacuo’. HD
ventricles. This entity is not considered HD. Other terms used for is well demonstrated using MRI. Progressive development in tech-
the same situation are pseudotumour cerebri syndrome, and idio- nology allows us to better assess CSF circulation, aid in the diag-
pathic intracranial hypertension. Benign intracranial hypertension nosis, and help determine the aetiology. The provided data are
usually occurs in young obese women (15). important for planning the management as well as follow-up of the
patients. Before MRI was available, radionucleotide cisternography
was considered an effective tool in selecting patients with NPH for
Diagnosis shunting. In this test, if the protein-bound tracer entered the vent-
Symptoms ricles quickly but flow became restricted over the convexities and
The clinical symptoms of HD are a consequence of expansion of required several days to clear, the patient would be very likely to
the ventricular system, raised ICP or decreased intracranial com- improve with a shunt (15).
pliance. The clinical expression depends on the age of the patient. Box 18.3 lists the most commonly used radiological criteria in
High ICP is the hallmark of acute obstructive HD and may cause the diagnosis of HD. Nevertheless, these criteria are not specific for
headache, nausea, vomiting, drowsiness, and decreased con- HD and their sensitivities are poor. The gold standard diagnostic
sciousness. Patients become progressively obtunded and, with a method for HD is ventriculographic studies, but this is a highly in-
worsening course, may have difficulty in protecting their airway. vasive method and may lead to serious complications. Therefore,
In communicating HD, the symptoms are mainly caused by de- new MRI techniques have been developed in order to determine
creased intracranial compliance and decreased cerebral blood flow HD aetiology and treatment. These techniques include phase-
(CBF). NPH is associated with a classic triad (‘Hakim’s triad’) of de- contrast MRI (PC-MRI), three-dimensional (3D) T2W sequences,
mentia, gait disturbance, and urinary incontinence (see Box 18.2). and contrast material-enhanced MR cisternography (CE-MRC).
This clinical syndrome is potentially reversible by the placement All three techniques have their own advantages and disadvantages.
of a ventriculoperitoneal shunt. However, there is little consensus Three-dimensional sampling perfection with application opti-
regarding the diagnosis of NPH and the selection of patients for mized contrast using the variable flip-angle evolution (3DSPACE)
shunt placement (17). Not only communicating HD but also be- technique has shown to be useful in the evaluation of patients with
nign aqueduct stenosis may cause the clinical syndrome of NPH. obstructive HD. The technique allows scanning of the whole cra-
Classic signs of benign intracranial pressure are headaches or nium in an acceptable acquisition time using isotropic voxels (with
blurred vision, possibly accompanied by pulsatile tinnitus, hearing voxel size <1 mm3), which is useful in obtaining high-resolution
loss, and dizziness. Papilloedema (swelling of the optic disk) is the multiplanar reformatted images without exceeding specific absorp-
most common examination finding. Treatment of benign intracranial tion rate limits. Other advantages are that the technique is flexible,
Box 18.2 Requirements for ‘Consensus’ Opinion Regarding

Box 18.3 Radiological Criteria in the Diagnosis of Hydrocephalus
Diagnosis of Normal Pressure Hydrocephalus
◆ Frontal horn span >5.5 cm (Evans ratio >0.4). 1. Ventriculomegaly (Evans’ index >0.3)*.
Hakim’s
◆ triad (dementia, gait disturbance, and urinary 2. Enlargement of the third ventricular recesses and lateral
incontinence). ventricular horns.
◆ Clearly defined aetiology. 3. Decreased mamillopontine distance and frontal horn angle.
◆ Predominant gait difficulties with mild or absent cognitive 4. Thinning and elevation of the corpus callosum.
impairment. 5. Normal or narrowed cortical sulci.
◆ Little or no cortical atrophy. 6. Periventricular white matter hyperintensities (interstitial
◆ Absent or moderate white matter changes. edema and acute hydrocephalus).
◆ Lumbar puncture to rule out chronic meningitis (can do ‘tap’ 7. Aqueductal flow void phenomenon in T2W images (a sign of
test at the same time). communicating hydrocephalus).
◆ Optional: 40 cc LP test (‘tap test’) or 1–5 day continuous CSF *Evans ratio (index) is the ratio of maximum width of the frontal horns to
lumbar drainage at 10 cc/hr. the maximum width of the inner table of the cranium.
Source data from Insights Imaging, 5, 4, Kartal MG, Algin O, Evaluation
Adapted from Seminars in Neurology, 27, 1, Tsakanikas D, Relkin N, Normal of hydrocephalus and other cerebrospinal fluid disorders with MRI: An
pressure hydrocephalus, pp. 58–65. ©2007 Georg Thieme Verlag KG. update, pp. 531–541, 2014.
29
allowing employment of different sequence types such as T1W, increased ICP during an infusion study is helpful in distinguishing
T2W, fluid-attenuated inversion recovery (FLAIR), proton-density between HD and predominant brain atrophy. A large amplitude is
weighted or variant flip-angle mode T2W images. Additionally, the associated with a good outcome after shunting, whereas a low amp-
3D-SPACE technique is noninvasive and less sensitive to artefacts. litude has no predictive power in outcome prognostication. Pulse
The most significant finding on MRI to discriminate between acute amplitude is reduced by a properly functioning shunt.
and chronic forms of HD is periventricular hyperintensities on This test also provides a useful measure of shunt function after
T2W or FLAIR images, which is consistent with acute interstitial surgery. Aside from its clinical utility, this technique is invasive,
oedema (15, 18, 19). poorly standardized and requires technical expertise (21, 22).
Removal of CSF Treatment
Measuring a clinical response to a ‘test’ removal of CSF is used HD is one of the more frequent neurosurgical diseases and treat-
in the diagnosis of NPH and selection of patients for surgery. ment of choice is the surgical placement of a shunt system. The
Nevertheless, the negative predictive value of these tests is low, major changes in treatment have been the use of advanced CSF valve
since patients with a negative response to this test can still improve design, broad application of endoscopic techniques, including ETV,
after shunting. and a more conservative approach given the recognition of the scale
The Fisher Test involves removing 30 to 50 ml of CSF and of CSF shunt complications. In contrast to other neurosurgical pro-
documenting patient’s gait and cognitive function before and 30 to cedures, it is frequent that neurological status improves after surgery.
60 minutes after the procedure. An improvement in one or more Medical treatment is sometimes a therapeutic option.
of the measures following the procedure suggests a better outcome Acetazolamide, a carbonic anhydrase inhibitor, has been shown to
after placement of a ventriculoperitoneal shunt. decrease CSF production in both in vivo and in vitro animal models.
A temporary catheter in the lumbar space connected to drainage This could be due to an effect on AQP-1 expression in choroid
at a rate of 5 to 10 ml h-1. may also be considered. The patient is fol- plexus tissue. The diuretic furosemide at high concentration (1 mg-
lowed and continuously evaluated over two to seven days looking 1 Kg-1 d-1) inhibits carbonic anhydrase and decreases CSF produc-
for improvement of symptoms (16). tion. Both drugs have been used alone or in combination for short
term medical management of posthaemorrhagic ventricular dilata-
Intracranial Pressure Monitoring tion in infants as well as in slowly progressive HD in patients too
Prolonged intracranial pressure monitoring via an intracranial unstable for surgery (14). In newborns with posthaemorrhagic HD,
transducer in patients with NPH reveals intermittent rhythmic treatment with diuretics is usually not effective. Treatment with fi-
pressure deviations or Lundberg B waves (0.5 to 2 per minute os- brinolytic agents is used in this population and in adult haemor-
cillations). Some clinicians use measures of basal ICP greater than rhagic strokes with intraventricular haemorrhage.
5–10 mmHg and/or the presence of predominating B-waves to
diagnose NPH. The invasive nature of this technique and lack of Pre-Operative Assessment
consensus criteria clearly limits its usefulness (16). Neurological assessment is especially important in a hydrocephalic
patient. The symptoms of intracranial space occupation and raised
Lumbar Infusion Test ICP (such as persistent headache, vomiting, and papilloedema)
‘Infusion tests’ are one of the available procedures to study CSF must be evaluated. Space-occupying lesions producing more than
circulation. In patients with clinical and radiological features of 10 mm shift of the midline structures suggest significant com-
HD, ICP is deliberately raised and disorders of CSF circulation are promise of intracranial dynamics. A history of repeated aspiration
evaluated through measurements of the resulting ICP. One or two of stomach contents reveals laryngeal incompetence.
intralumbar cannulae are inserted and normal saline is infused at Coma is a common presentation of acute HD and may be asso-
a constant rate (1.6 to 1 ml min-1) while CSF pressure is recorded ciated with hypoxia and hypercarbia, which in turn can further re-
by a transducer. This test shows the pressure level at which CSF duce responsiveness by increasing ICP. Reduced ventilation creates
absorption and infusion are balanced. The resistance to CSF out- conditions for basal pulmonary collapse and consolidation, leading
flow (Rout) is also calculated as the difference between the steady to pneumonia. Dehydration will develop rapidly as the patient is
state pressure during infusion and the baseline pressure, divided unable to eat and drink and the increased blood viscosity will pre-
by the infusion rate. RCSF values between 12 and 18 mmHg/mL dispose to venous thrombosis.
per minute are commonly the thresholds to identify patients who In the presence of HD and increased ICP, aggressive manage-
may benefit from shunting. Pulse-pressure amplitude and rate of ment of arterial hypertension should be addressed only after HD is
pressure increase are also calculated and recorded (20). treated. Take into account that hypertension may be a response to
The pulse waveform of ICP is an essential element of pressure high ICP, especially following head injury or subarachnoid haem-
recording, aside from its mean value. Czosnyka and colleagues (21) orrhage (SAH). ECG abnormalities are frequently present in pa-
reviewed their experience with the measurement and interpretation tients who have had a SAH or who have raised ICP (23).
of ICP pulse amplitude by referring to a database of recordings in HD is a common pathology in children, and neonates and in-
hydrocephalic patients. Amplitude was positively correlated with fants are at higher risk for morbidity and mortality than any other
a mean ICP and resistance to cerebrospinal fluid outflow but did age group. Respiratory and cardiac-related events account for a
not seem to be correlated with cerebrospinal elasticity, dilatation majority of these complications. A complete airway examination
of ventricles, or severity of HD (NPH score). Amplitude increases is essential. Most cardiac morbidity due to congenital heart disease
slightly with age and is significantly correlated with the ampli- occurs during the first year of life, and echocardiography can be
tude of CBF velocity as assessed using transcranial Doppler ultra- helpful in the assessment of the cardiovascular system, especially
sonography. A positive association between pulse amplitude and in the neonate (24).
230
External Ventricular Drainage Box 18.4 Predictors of Improvement After Shunting for Normal
Indications Pressure Hydrocephalus
An external ventricular drain (EVD) can be used for initial manage-
ment of acute HD and intracranial hypertension due to obstructive Unfavourable indicators:
HD (tumours, post-surgery of posterior fossa or decompressive ◆ Early appearance of dementia.
craniotomy, abscess, intraventricular haemorrhage, haematomas).
◆ Moderate to severe dementia.
An EVD permits both drainage and measurement of ICP by means
of a pressure transducer connected to a stopcock. ◆ Dementia present for more than two years.
In traumatic brain injury an EVD is often indicated to maintain Gait
◆ disorder absent or appearing after dementia.
ICP within normal range. If the ICP is normal the drainage system
can remain closed at a level of 10 cm/H2O referred to the skull base. ◆ Alcoholism.
The system must be opened if the ICP >20 cm/H2O, nevertheless ◆ MRI findings:
the system must be opened every three hours to guarantee the per- ◆ Marked white matter disease.
meability. If there is high ICP the drainage is opened and some-
times is left at 0 cm/H2O level if needed (25). ◆ Diffuse sulcal enlargement.
An EVD can be inserted after high-grade SAH, if there is ◆ Medial temporal atrophy.
intraventricular haemorrhage, HD, or brain oedema and before
Favourable indicators:
the endovascular coiling procedure is performed. An open EVD
system can be used to calculate dynamic autoregulation indices in ◆ Early appearance of gait disorder.
SAH patients with the pressure measurement from the most prox- ◆ Gait disorder as most predominant symptom.
imal part of drain (26).
◆ Duration of symptoms less than six months.
Intra-Operative Management ◆ Identified etiology of NPH.
This surgery is done by an incision at a frontal or parietal level,
insertion of a catheter through a burr hole in one lateral ventricle, Positive
◆ findings on diagnostic tests:
and connecting it to a closed sterile drainage system. The catheter is ◆ High resistance on CSF infusion test.
subcutaneously tunnelled. Monitored anaesthesia care under local ◆ Clinical response to CSF removal (tap test, lumbar drain).
anaesthesia is an appropriate technique, with the patient supine,
the shoulder elevated, and the neck and head contralaterally ro- ◆ B-
waves comprising more than 50% of tracing on con-
tated. The ventricular side of choice, if possible, is the right. If the tinuous ICP monitoring.
patient is comatose, or non-cooperative, general anaesthesia is re-
quired. The entire procedure lasts approximately 30 minutes. If the Source data from: Seminars in Neurology, 27, 1, Tsakanikas D, Relkin N.,
ventricles are not enlarged enough, the puncture can fail. Normal pressure hydrocephalus, pp. 58–65, 2007; Acta Neurochirurgica,
In the presence of HD and increased ICP, aggressive manage- 146, 4, Krauss JK, Halve B, Normal pressure hydrocephalus: survey on
contemporary diagnostic algorithms and therapeutic decision-making in
ment of arterial hypertension should be addressed only after HD is
clinical practice, pp. 379–388, 2004.
treated. If the EVD is placed after SAH there is a risk of a rerupture
of the aneurysm with rapid decompression, which has to be kept in
mind by all members of the interventional team. In some cases, patients with an EVD continue to have high drain
output (high than 100 ml d-1) several days after the injury that man-
Postoperative Care and Complications
dates the placement of a CSF shunt. It is necessary that the acute
A malfunction of the EVD can be due to a kinking of the system. phase has been finished and the CSF must be clear (no blood, no
Another frequent reason is that the distal end is not inside the vent- signs of infection). If neurologic deterioration occurs, a permanent
ricles or that the ventricles are without CSF; a brain CT is needed ventriculoperitoneal shunt is needed.
for diagnosis of the aetiology. The ventriculoperitoneal shunt is the most common interven-
If there is a haemorrhage, it is common for blood clots to ob- tion. It diverts the flow of CSF from the ventricular system to
struct the system and the external tubing, and all the system must the peritoneal cavity where it can be absorbed as part of the cir-
be changed. In order to avoid infection, extreme attention is war- culatory process. Less commonly, CSF is diverted into the heart
ranted when manipulating the system. (ventriculoatrial), or without a cranial approach from the lumbar
Overdrainage can result in a sudden emptying of the ventricles space to the peritoneum (lumboperitoneal).
and provoke an acute subdural haematoma from loss of buoyancy
for the brain and tearing of bridging veins. CSF Valves
Modern valves can be grouped into one of several categories based
Shunt Surgery: Indications on their hydrodynamic characteristics: differential-pressure valves,
Most cases of HD are progressive, meaning that neurological de- siphon-resisting valves, flow-regulating valves, and adjustable
terioration will occur or progress if it is not effectively and con- valves. In paediatric patients, closure of the sutures, attainment
tinuously treated. Treatment is surgical drainage with a shunt or a of erect posture, growth, and aging are all additional situations in
third ventriculostomy. Placing a shunt is the treatment of choice in which the opening pressure of the valve may require adjustment.
NPH (see Box 18.4). Chronic HD requiring a shunt can be also a Whatever valve is chosen, it is likely more important to understand
consequence of SAH, after brain injury, after some posterior fossa the benefits and disadvantages of each and select an appropriate
procedures, or decompressive craniotomies. management scheme (24).
231
Differential-pressure valves have been available longer than the These interventions have traditionally been performed under
other valves, and surgeons have accumulated the most experience general endotracheal anaesthesia as the standard management tech-
with this type of valve. These valves open when the pressure differ- nique since patients are placed in an extreme position of rotation
ence across the valve exceeds a predetermined threshold. The valve of the neck to facilitate subcutaneous tunnelling catheter placement
then remains open, and during this time it has a very low resistance and the head is covered with surgical fields. Accumulated clinical
to flow. When the pressure difference drops below the predeter- experience with supraglottic airway devices and ongoing design
mined threshold, the valve closes again and flow stops. When the pa- improvements have encouraged ever-widening applications, and la-
tient is in the upright position, a large differential pressure between ryngeal masks have been used successfully for airway management
the head and the abdomen develops from the long column of water even when anaesthetized patients are placed in non-supine positions
in the shunt tubing. The valve therefore opens, and fluid flows until during emergency or elective surgery. The Proseal® laryngeal mask
the pressure in the head is excessively negative. This phenomenon is has been reported to be useful for airway management in patients
called siphoning, and it is thought to be responsible for overdrainage undergoing ventriculoperitoneal shunt. Due to the forced position
and its associated complications. Differential-pressure valves are of the neck, however, it may be necessary to reposition the mask or
available with low, medium, and high opening pressures. In general, even proceed to orotracheal intubation in some cases. As is the case
low-, medium-, and high-pressure valves refer to opening pressures for other advanced uses, experience with the device is necessary.
of approximately 5, 10, and 15 cm/H2O, respectively. Unfortunately, Material for managing a difficult airway should be on hand (27).
however, there are no uniform standards for these designations, and The tunnelling phase of ventriculoperitoneal shunt insertion
the manner in which the pressure is measured is variable. is the most painful part, but patients are often given inadequate
Siphon-resisting valves contain a device that is designed to re- opioid analgesic for fear of postoperative delayed recovery and/or
duce flow as the patient assumes the upright position (i.e., when respiratory depression. This has changed after the introduction of
siphoning occurs). Similar mechanisms are available as separate remifentanil (28).
components that can be added to other shunt systems. Shunt Surgery: Postoperative Care and Complications
Flow-regulating valves consist of a flexible diaphragm that moves
There are many possible serious complications of VPS to consider,
along a piston of variable diameter, resulting in three pressure flow
including shunt malfunction, subdural haematoma, seizures, shunt
stages. In stage 1, the valve functions like a differential-pressure valve.
infection, or intracerebral haematoma. Several brainstem signs and
In stage 2, as the ventricular pressure increases, the diaphragm des-
symptoms may arise from CSF overdrainage. A midbrain upward
cends along the piston, whose diameter progressively enlarges. This
herniation into the tentorial notch can be the preliminary patho-
reduces the flow orifice and dramatically increases the resistance to
physiological event initiating a complex impairment of adjacent
flow. A very small increase in the flow rate results, despite a progres-
neuronal structures. Slit ventricle syndrome (SVS) is a serious,
sive increase in pressure. In stage 3, a high-pressure safety release
potentially suddenly life-threatening complication of long-term
mechanism results in open flow when the pressure in the ventricular
(many years) overdrainage in shunted children. When shunting oc-
catheter reaches approximately 40 cm/H2O. The diaphragm at this
curs before fontanels and suture closure, the risk can rise to 20%
point is beyond the end of the piston and resistance is very low.
according to some reports in the literature. Given low ICP due
Externally adjustable valves enable the surgeon to make
to chronic overdrainage, the driving force for head growth is in-
noninvasive alterations in the valve’s pressure-flow profile as the
adequate, which can cause scaphocephalic head deformity. The
patient’s clinical course changes. Unlike traditional valves, how-
craniospinal compliance becomes fixed and reduced such that even
ever, programmable valves may be percutaneously adjusted with
a few millilitres of CSF can decide a patient’s clinical state.
an external magnet or a special programming tool that works via
Other complications are due to the abdominal part of the pro-
a magnetic field. This may be advantageous in patients with NPH,
cedure, with potential abdominal perforation or peritonitis. Distal
in patients with arachnoid cysts, and in patients with complications
shunt failures—either due to improper placement or secondary
caused by acute or chronic overdrainage, such as subdural hygromas,
dislocation of the distal catheter out of the peritoneal cavity—have
chronic subdural haematomas, and slit-ventricle syndrome.
been reported in 10%–30% of cases of shunt failure. Some authors
Although a clear advantage to adjustability has not yet been dem-
have described a laparoscopy approach in order to have a direct
onstrated in terms of shunt survival, many surgeons find this feature
control of the final location of the distal shunt (29).
desirable in an attempt to relieve symptoms, maintain large vent-
Although most shunt complications have the highest incidence
ricles, or deal with small fluid collections. The ability to adjust the
within the first year, shunt malfunctions can appear at any time.
valve pressure noninvasively, and thus potentially minimize subse-
Shunts revisions due to malfunction and infection are complica-
quent operative manipulations of the shunt system, may warrant the
tions that can require frequent operative procedures. A VPS that is
increased expense and complexity of the programmable system.
adjustable from the outside is probably the best solution for NPH
Shunt Surgery: Intra-Operative Management as it avoids the need for shunt revision and also can be adjusted to
optimize function without more surgery (24, 30, 31).
Patients with an external ventricular drainage valve who are sched-
uled for shunt surgery typically need to have the EVD closed at least Neuroendoscopies, Endoscopic Third Ventriculostomy
from the night before the intervention in order to have enough CSF Indications
intraventricular volume to facilitate ventricular location. The surgical ETV has a high success rate and is becoming the treatment of
field comprises the head (for the burr hole ventricle puncture and in- choice for noncommunicating HD, mainly in paediatric patients.
sertion of the intraventricular catheter and connection with the valve), Neuroendoscopy has also been used to revise malfunctioning shunts
the lateral neck and anterior chest wall (for tunnelling the catheter), as well as to treat infective HD secondary to tuberculous menin-
and the abdomen (for introducing the distal part of the shunt system). gitis and intraventricular haemorrhage. Other interventions include
23
endoscopic removal of cysts, tumour biopsies, complete removal of changes in CSF composition in one study (10), which found a sig-
intra-and paraventricular tumours, intraventricular nontumoral nificant correlation between changes in CSF composition and the
lesions such as neurocysticercosis, haematomas, and hypothalamic total volume of irrigation solution used, but no correlation with the
haematomas, and choroid plexus cauterization (13, 24). duration of neuronavigation. A cut-off point of 500 ml of saline
There is probably a subset of idiopathic NPH patients with a irrigation solution was associated with a reduction in CSF pH of
high-grade stenosis at the aqueduct of Silvius and differences be- greater than 0.2. Unfortunately, similar studies have not been per-
tween the outflow resistances measured above and below the aque- formed with Ringer’s solution. Routine use of irrigating solutions is
duct that can benefit from ETV (32). not necessary in some uncomplicated ETV endoscopic procedures.
Intra-Operative Management To avoid intra-operative and postoperative complications arising
from the use of irrigating fluids, some surgeons take care to limit
The patient position for neuroendoscopy is usually supine with
the loss of CSF.
slight flexion of the neck, or with a head-up tilt ranging from 45° to
Occasionally, bleeding may occur during intraventricular endo-
90°. The cranium is fixed in a head frame. Through a coronal burr
scopic procedures. The scope must then be maintained within the
hole, the endoscope is introduced into the ventricular system via
field and continuous irrigation solution generally stops the bleeding.
the frontal horn. The endoscope has a channel for aspiration and
Cauterization may be attempted if a bleeding site can be identified
a working channel through which a variety of instruments can be
and a ventricular drain may be left in place along the endoscopic
passed. The anaesthesia goals are to ensure patient immobility, pre-
tract to allow for drainage of the intraventricular haemorrhage
vent, detect, and treat sharp increases in ICP, and plan for rapid
in rare cases where mild bleeding persists. If the bleeding is cata-
emergence for prompt neurologic assessment. Nitrous oxide is often
strophic, rapid conversion to open craniotomy might be considered.
avoided to prevent its diffusion into air trapped in the ventricles and
Hypothermia during neuroendoscopy is seen more often in small
subdural space following decompression of the ventricles (18). In
children, caused by large exchanges of irrigating fluid and ventricular
the presence of significant raised ICP, when propofol is used there
CSF and by the wetting of drapes with the returning perfusate (37).
is a greater margin of safety compared to volatile agents because
In an observational prospective study, BIS monitoring trends and
propofol reduces CBF along with cerebral metabolic depression.
values were lower in paediatric hydrocephalic patients, indicating
A ventriculocisternostomy is performed in order to achieve com-
a consistently deeper hypnotic state than in normal subjects. This
munication between the lateral ventricles and the third ventricle to
should be taken into consideration when adjusting anaesthesia levels
the cisterns and the subarachnoid spaces. By performing a hole in
entirely based upon BIS values in hydrocephalic patients (38).
the lamina quadrigemina at the floor of the third ventricle it comes
into direct communication with the interpeduncular cistern; a Postoperative Care and Complications
Fogarty catheter is passed through the hole performed in the floor Detection and diagnosis of neurological dysfunction is imperative
of the third ventricle to build a permanent communication. in order to exclude treatable causes such as intracranial haemor-
Neuroendoscopic surgery can cause intra-operative increases rhage. An acute haemorrhage after the procedure can originate from
in ICP that are associated with disturbances in cerebral perfu- an inadvertent lesion to the vascular structures at the basilar level.
sion pressure (CPP) and CBF. Continuous measurement of CPP Delayed awakening is a major concern to the anaesthetist. An
could be beneficial; ICP can be measured indirectly by measuring intra-operative increase of more than 30 mm Hg in neuroendoscopic
the pressure inside the endoscope (PIN). PIN is obtained with a ICP has been associated with greater postoperative complications,
fluid-filled catheter connected to a stop-cock connected to the the most common of which was delayed awakening (39). It can be
irrigation lumen of the neuroendoscope and attached to a pres- a direct lesion to brain structures, as an injury to the hypothalamus
sure transducer zeroed at the skull base. In patients with available may give rise to transient hypothalamic dysfunction, which can lead
transcranial Doppler ultrasound images, episodes of reduced dia- to the syndrome of inappropriate secretion of antidiuretic hormone
stolic flow rate in the middle cerebral artery during ventricular or diabetes insipidus with fluctuating serum electrolyte levels. Mild
irrigation have been reported. This situation demonstrates the im- hypoaldosteronism may be provoked by the altered physiologic flow
portance of monitoring ICP and CPP (33). of CSF across the third-ventricular floor following ETV. This flow
The anaesthetist should always be prepared for a conversion from may be misinterpreted by brain receptors as an increase in fluid
minimally invasive procedures to a major operation. This statement volume. Postoperative electrolytic changes after intraventricular
applies to procedures from ETV to tumour retrieval. Beat-to-beat neuroendoscopy have been reported in a number of studies (10, 36).
monitoring of heart rate and mean arterial pressure by an indwelling Patients undergoing ETV may be managed as outpatients, pro-
arterial catheter can be beneficial, including for children. Premature vided the procedure is short and uneventful.
babies and neonates with a low mean arterial pressure are more vul-
nerable to cerebral ischaemia even with a modest increase in ICP.
The occurrence of hypertension and tachycardia (atypical Cushing Key Points for Clinicians
reflex) has been observed as the result of an increase in ICP. Also, Magnetic Resonance Imaging
the Cushing reflex develops in almost every case when CPP dropped ◆ MRI aids in diagnosis, therapeutic planning, and postsurgery
below 15 mmHg (34). Waiting for a persistent bradycardia before follow-up of hydrocephalic patients and provides additional
alerting the surgeon of raised ICP during ETV may be too late, as physiological information.
fatal asystole can develop. However, the occurrence of bradycardia ◆ The 3D-SPACE technique seems to be the most efficient and
has not always been associated with a low CPP. rapid for evaluating HD, ETV, and the shunt catheter.
Warmed (at body temperature) lactated Ringer’s solution is the ◆ In concerning or complex cases, PC-MRI, 3D heavily-T2W,
most frequently used irrigation fluid during neuroendoscopies (35, and/or CE-MRC images may prevent false-negative or false-
36). The use of saline as irrigation solution produced significant positive results.
23
◆ A close collaboration between radiologists and peri-operative ◆ In NPH patients MRI demonstrates ventriculomegaly out of
clinicians is needed in order to better apply technological proportion to sulcal enlargement and no evidence of CSF flow
improvements. obstruction
◆ IdiopathicNPH is more common in elderly individuals and its
Acute Obstructive Hydrocephalus
pathogenesis is uncertain.
◆ Sudden increase in CSF volume with critical limitations of com-
◆ Secondary NPH is associated with SAH or meningitis, oc-
pensatory mechanisms, can happen at any age.
curs in any age group, and is associated with impaired CSF
◆ It can be secondary to congenital or acquired illness, tumours, reabsorption.
infections, and haemorrhages, or a postoperative event.
◆ ‘Infusion test’ is used to evaluate the suitability of placing a CFS
◆ It is a life-threatening event associated with an increase in intra- shunt in patients diagnosed of normal pressure HD; it can also be
cranial pressure and its effects on CBF. useful in adjusting the system for some dysfunctions.
Cerebral Perfusion Pressure and Cerebral Blood Flow CSF Shunts

◆ In the presence of HD and increased ICP, aggressive manage- ◆ Modern valves can be grouped into one of several categories
ment of arterial hypertension should be addressed only after HD based on their hydrodynamic characteristics: differential-
is treated. pressure, siphon-resisting, flow-regulating, and adjustable.
◆ Placement requires general anaesthesia, and the patient can be
External Ventricular Drainage
comatose before the surgery, but usually improves afterwards.
◆ External drainage is the initial treatment for acute obstructive  HD.
◆ In acute head trauma, placing an EVD provides the gold
standard values of ICP and allows CSF drainage as a treatment to
Cases
decrease ICP. Q Interactive cases to test your knowledge on this chapter can
be found in the online appendix at www.oxfordmedicine.com/
◆ After SAH if a dilatation of ventricular system is initially diag-
nosed, it is typical to proceed to an EVD.
◆ The EVD has to be inserted before the endovascular procedure
because the heparinization needed to deploy the coil will jeop-
References
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compliance and outflow resistance of the cerebrospinal fluid system.
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235
CHAPTER 19
Awake Craniotomy
for Tumour, Epilepsy, and
Functional Neurosurgery
Lashmi Venkatraghavan and Pirjo Manninen
Introduction not ideally suitable included those who are confused, agitated,
and with dementia. The lack of understanding of the spoken lan-
Awake craniotomy is a procedure for which the patient is almost guage may be a problem but can be remedied with the presence of a
‘fully’ awake for some period of time to allow for neurological translator. Relative contraindications include patients with morbid
testing. The goals and challenges of the anaesthetic management obesity, obstructive sleep apnoea, and difficult airway management.
are to have a patient who is comfortable, with good analgesia and The goals of the anaesthetic management are to have a comfort-
minimal anxiety, and able to participate in the neurophysiologic able patient who is able to stay immobile on an operating room
mapping. Other aims include adequate oxygenation and venti- (OR) table for the duration of the procedure, or at least during
lation, haemodynamic stability, and optimal brain conditions. the period of wakefulness, and yet be alert and cooperative with
Historically, the awake craniotomy was used for epilepsy surgery, cortical mapping. These goals can be accomplished by adequate
but now is used increasingly for patients with brain tumours as well preparation of the patient, a comfortable environment, appropriate
as for patients with functional disorders for deep brain stimula- administration of analgesic and sedative medications, ongoing
tion (DBS) procedures. The role of the anaesthetist is critical for communication and support of the patient, and rapid treatment of
the successful outcome of these procedures. This chapter covers complications.
the anaesthetic considerations and management of patients under-
going awake surgery for brain tumours, epilepsy, and functional
disorders. Awake Craniotomy for Tumour Surgery
The indications for an awake patient during intracranial surgery Awake craniotomy for tumour surgery is a well-accepted pro-
include i) cortical mapping of eloquent brain function (speech, cedure. Suitable patients are those who have a supratentorial tu-
motor, sensory, and vision); ii) intra-operative electroencephalog- mour with minimal dural involvement. Awake craniotomy is not
raphy (EEG) monitoring for the identification of an epileptogenic suitable for tumours located in the posterior fossa with extensive
focus; and iii) the localization of deep brain target nuclei using dural involvement due to excessive pain on resection, or difficulty
awake neurological testing. The most common procedures per- in positioning. The decision for an awake craniotomy is initially
formed include craniotomy for resection of a tumour, epilepsy sur- determined by the surgeon and then confirmed with consultation
gery, and insertion of a deep brain stimulator (DBS) for functional by the anaesthetist in a pre-operative anaesthesia setting or clinic.
neurological disorders (1–6).
The benefits of an awake craniotomy include neurological moni- Pre-Operative Assessment
toring, especially language mapping that cannot be performed The pre-operative assessment by the anaesthetist is similar to that of
during general anaesthesia, and the ability to help predict neuro- any patient with a neurological disorder coming for a craniotomy.
logical outcome. The anaesthetic management may involve the use All medications for ongoing medical conditions should be con-
of less-invasive monitoring and anaesthesia drugs, with prevention tinued, especially dexamethasone for treatment of oedema associ-
of postoperative nausea and vomiting. Shorter hospital stays with ated with the brain tumour and anticonvulsant drugs for seizure
fewer hospital-related complications and overall costs are possible, control. Psychological preparation is critical. The patient should be
as is day surgery (7, 8). Awake craniotomy for tumour surgery may informed of the complexities of the procedure. The establishment
also allow for a comparable extent of tumour removal while con- of good rapport between the anaesthetist and patient is crucial.
currently decreasing the incidence of new neurological deficits (9). Reassurance and warning about periods of potential discomfort
Patient selection is critical to the success of an awake procedure. and pain such as the insertion of local anaesthesia, pinning of the
The patient must be cooperative, motivated, and have an under- headframe, and the loud vibrating noise of the drill during bone
standing of the procedure and the reasons for it. Patients who are work are important. Explanations are needed for specific testing
236
of motor function, speech, or memory during intra-operative Sedation Techniques

mapping. There are essentially two different techniques used for awake crani-
otomy; conscious sedation with no or minimal manipulation of the
Preparation airway, and the ‘asleep-awake-asleep’ technique with manipulation
The concept of being awake for surgery in the OR can be terrifying of the airway for the periods of unconsciousness. The choice of the
to patients. Prior to bringing the patient in, the OR should be com- technique used depends on the preferences of the neurosurgeon,
pletely ready so that all members of the team can devote their atten- anaesthetist, and institution. The conscious sedation technique usu-
tion to the patient. The environment should be friendly and the OR ally refers to when the patient is sedated to an average level ‘3’ of the
table as comfortable as possible. Anaesthetic drugs and equipment Modified Observer’s Assessment of Alertness/Sedation scale, where
for conscious sedation, induction of general anaesthesia if needed, the patient will respond after their name is called loudly or repeat-
and treatment of complications should be available. Prevention of edly (12). There is usually no airway manipulation other than the use
unnecessary traffic and noise can be accomplished by placing a sign of a nasal airway in some situations. Commonly used drugs include
on the door informing people of the awake procedure. midazolam, propofol, fentanyl, remifentanil, and dexmedetomidine
Positioning of the patient requires extra attention. The sur- (12–16). These drugs may be administered as infusions, bolus injec-
gical position may be lateral decubitus, supine, or semi sitting. tions, target controlled, or patient controlled. The sedation is stopped
Positioning and draping of the patient’s face should allow good or decreased during mapping and then resumed for resection and
visualization of the face and airway for the anaesthetist, while closure. A well-accepted technique has been propofol infusion and
enabling the patient to participate in neurological testing. There an opioid (fentanyl, remifentanil). More recently, dexmedetomidine
should be some freedom of movement of the extremities to has been used. Dexmedetomidine is an alpha2-adrenoreceptor
allow for comfort and motor testing. Rigid skull pin-fixation agonist that provides sedation, analgesia, and anxiolysis with min-
systems are frequently used to accommodate neuronavigation imal risk of respiratory depression (15). Other agents are often added
for imaging and a still surgical field. After head fixation, the pa- to provide more analgesia (fentanyl, remifentanil) and for more am-
tient should be allowed to awaken to ensure that head and neck nesia and less alertness (propofol, midazolam).
position are comfortable and good airway access (good mouth Asleep-awake-asleep is a commonly used technique (2). General
opening) is possible in the event that manipulation of the airway anaesthesia is induced at the beginning of the procedure and main-
is needed. tained for the craniotomy. The patient’s airway is maintained with
Standard monitors include electrocardiogram, noninvasive blood an endotracheal tube or oral/nasal airway, but, most commonly, the
pressure cuff, pulse oximeter, and end-tidal carbon dioxide via nasal laryngeal mask airway (LMA). The use of the LMA is advantageous
prongs or mask used to deliver supplemental oxygen. Invasive moni- because of the ease of removal and re-insertion for the latter part of
toring with an arterial catheter or rarely central venous catheter is the procedure. General anaesthesia may be with ether intravenous or
used as indicated for selected patients or according to institutional inhalation anaesthesia, with or without controlled ventilation. Once
practices. Urinary catheter can often be avoided, but administration the dura is opened the patient is awakened completely and the airway
of fluids should be kept to a minimum. Monitoring of depth of anaes- device removed for the period of intra-operative neurologic evalu-
thesia may help in regulating doses of anaesthetic agents and allowing ation. For resection of the lesion and for closure, general anaesthesia
for shorter awakening times and patient’s capability to perform intra- is again induced with reinsertion of the airway device. The advan-
operative language testing (10). However, the role of the anaesthetist is tages of asleep-awake-asleep are better tolerance for prolonged pro-
more than just monitoring vital signs. Awake patients need additional cedures and for the less-cooperative patients. There is also a patent
vigilance to ensure well-being and rapid diagnosis of any complica- airway and the ability to ventilate/hyperventilate and control PaCO2
tion. Nonpharmacologic or social measures are very useful to help
the patient through the procedure, especially during the periods of Intra-Operative Cortical Mapping
complete wakefulness. These include frequent reassurance, warning The purpose of cortical mapping and neurological testing is to lo-
the patient in advance about loud noises and painful interventions, calize the areas of eloquent brain function. It is accomplished by
allowing the patient to move intermittently, providing ice chips and a placing a stimulating electrode directly on the cortex and asking the
cold cloth to the face, and just holding the patient’s hand. patient to perform tasks. Speech testing may be with simple counting
or naming days of the week or more complex mapping with pic-
Anaesthesia Management ture naming, verb-noun association, comprehension, or repetitive
Local Anaesthesia reading/writing tasks. Motor testing is with movement of the ex-
tremities. To ensure that the patient is fully alert for mapping, and
Adequate administration of local anaesthesia for infiltration and re-
that there are no lingering effects of sedative drugs, propofol should
gional scalp blocks is essential. Initially this is for the skull fixation
be discontinued for at least 10–20 minutes before. However, small
pin sites (11). Infiltration of local anaesthesia for the surgical inci-
doses of opioids (fentanyl, remifentanil) and dexmedetomidine may
sion site of a smaller craniotomy may be with a ‘ring block’ (11).
be administered during mapping. For some patients, continuous
Regional scalp blocks may also be used and are performed by the
monitoring is also helpful during tumour or lesion resection.
infiltration of six nerves: greater and lesser occipital, supraorbital,
supratrochlear, zygomaticotemporal, auriculotemporal, and greater
auricular nerves. Long-acting local anaesthetic agents used include Complications
bupivacaine, ropivacaine, and levobupivacaine with the addition of Intra-operative complications can occur but with good vigilance
epinephrine. Lidocaine, which has a fast onset, may be added, and these can be treated quickly. The most common complications
is also used to infiltrate areas that are still painful during the pro- and their treatments are listed in Table 19.1 (4, 11, 17). If a severe
cedure, such as the dura. complication leads to an uncooperative or unresponsive patient,
237
Chapter 19 awake craniotomy, epilepsy, and functional neurosurgery 237
Table 19.1 Complications during awake neurosurgical procedures.
Complications Causes Treatment

Respiratory: desaturation, Oversedation, loss of consciousness from an Stopping or decreasing sedation.
decrease respiratory rate, intracranial event or seizures, venous air embolism, Chin lift, jaw thrust.
hypercapnia. aggravation of pre-operative respiratory disease.
Securing of the airway: oral or nasal airway, laryngeal mask,
Airway: obstruction. Mechanical, oversedation. endotracheal tube.
Release headframe from table.
Seizures Pre-operative history of seizures, No treatment if short.
frequently during cortical stimulation, may be short, Initial treatment—small dose propofol (10–20mg) or midazolam
localized, or generalized. (1–2mg), protected from injury.
After dural opening, ice saline on cortex by surgeon.
If prolonged, or generalized:
Airway, Breathing/oxygenation, Circulatory stability
Phenytoin or levetiracetam (slowly administered)
If repeated treatments required, patient may become drowsy and need
airway support.
Pain Worse during pin fixation, dissection of the temporalis Additional local anaesthesia, and/or analgesia, and/or sedation.
muscle, traction on the dura, manipulation of the
intracerebral blood vessels.
Anxiety/Fear Anxious or poorly prepared patient, worse during Reassurance, sedation, analgesia.
painful, noisy parts.
Nausea/vomiting Patient anxiety, medications, surgical stimulation. Anti-emetics, propofol, sedation.
Worse during stripping of the dura and manipulation
of the temporal lobe and meningeal vessels.
Disinhibition, agitation. Drug reaction, anxiety. Increase sedation, change sedative drugs, or awaken patient.
Tight brain Oversedation, airway obstruction. Decrease sedation, encourage deep breathing, head elevation, mannitol.
Venous air embolism Open veins--burr hole, craniotomy, venous sinus. Warn surgeon, cover area with solution, head down if possible,
Presents with cough, shortness of breath, agitation, supportive measures.
chest pain.
Cardiovascular: blood pressure, Drug related, anxiety, pain, blood loss, intracranial Treat cause with appropriate sedation, analgesia, vasoactive agents,
heart rate changes. manipulation. fluids.
especially due to a catastrophic intracranial event such as haem- unit, intensive care unit, or step-down unit. Careful monitoring of
orrhage or continuous seizures, securing of the airway and/or the neurological status and vital signs, and rapid diagnosis and treat-
induction of general anaesthesia may be required. To do this safely, ment of any complications is critical. Postoperative analgesia needs
a plan of action is necessary. Airway assessment with the patient’s to be titrated to patients’ needs. Shorter hospital stays are often
position and headframe placement determines the best approach. possible, including day surgery (7–8).
The LMA may be used temporarily or for completion of the pro- Carefully-selected, well-informed patients are likely to tolerate
cedure. Occasionally, endotracheal intubation will be required. This an awake craniotomy well and patient satisfaction for tumour sur-
can be accomplished with the patient either on their side or supine, gery is high (8, 13, 18). Patients report this as a positive experience
from the patient’s front or in the traditional way. The surgeon needs and understand the rationale behind it. Causes of failure may be
to protect the sterile brain field. After preoxygenation, anaesthesia due to lack of intra-operative communication with patients and the
can be induced, if necessary, with a small dose of propofol (with or occurrence of complications, especially intra-operative seizures.
without opioids and muscle relaxant). Intubation may be accom-
plished with any device depending on comfort of anaesthetist, such
as direct laryngoscopy, video-laryngoscopy, fibreoptic bronchos- Awake Craniotomy for Epilepsy Surgery
copy, or intubating LMA. If any difficulty in securing the airway is Epilepsy, a common chronic disorder, is initially treated medic-
anticipated, an awake intubation with local anaesthesia should be ally; however, it is refractory in about 30% of patients with failure
performed. to obtain adequate seizure control or with unacceptable side ef-
fects associated with anti-epileptic drugs. Approximately 15–20%
Postoperative Care of these patients are candidates for surgical treatment. Benefits of
Postoperative care is the same as for any patient undergoing a surgery include the possibility of being seizure free, experiencing a
neurosurgical procedure. This may be in a postanaesthetic care significant reduction in the frequency of seizures, and/or cognitive
238
improvement due to reduction or elimination of anticonvulsive tomography (CT), magnetic resonance imaging (MRI), single-
drugs. Suitability of a patient for epilepsy surgery is assessed by a photon emission computerized tomography, and positron-
multidisciplinary evaluation. emission-tomography; ii) electrophysiology with surface EEG and/
The surgical procedures include i) resective surgery with or intracranial electrocorticography (ECoG); and iii) functional
removal of an epileptogenic focus, lobectomy (frontal or tem- assessments with neuropsychological testing, functional MRI, and
poral) with or without amygdalohippocampectomy resection; Wada testing. Many advances in neurological imaging techniques
and excision of scar tissue, ii) non-resective surgery with modi- have reduced the need for invasive evaluations. General anaes-
fication of seizures by disconnection procedures such as corpus thesia is required for invasive investigations for the placement of
callosotomy or hemispherectomy, and stimulation procedures epidural electrodes, subdural grids, and strip electrodes through
with DBS or vagal nerve stimulator. Good surgical outcome de- burr holes or a craniotomy (Figure 19.1). The considerations for
pends on the complete resection of the seizure focus without anaesthesia include the concerns of a patient with epilepsy and the
any damage to eloquent brain. In addition to the definitive pro- precautions that apply to any craniotomy. The anaesthetic agents
cedure, patients may require anaesthesia for some of the pre- used are not specific as there are no EEG recordings at this time.
surgical evaluations. The electrode plates or grids are quite bulky and might require
brain shrinkage with mannitol and hyperventilation. Intracarotid
Pre-operative Evaluation for Localization sodium amytal injection (also known as the Wada test) is used
of Epileptogenic Focus to test for the lateralization of language and memory. This test
Presurgical evaluations are required for the localization of the is usually performed done without an anaesthetist. But more re-
seizure focus and identification of areas of eloquent brain func- cently, etomidate has been used, which requires the presence of an
tion (19). These are performed by i) imaging using computerized anaesthetist.
Α1–2
Α2–3
Η1–2
Η2–3
50 µV 50 µV
1 sec 1 sec
Ν1–2
Ν2–3
Alfentanil 250 µg
Figure 19.1 Top: Medussa (or Montreal) frame for intra-operative electrocorticographic recording.

Bottom: Intra-operative electrocorticographic recordings showing background interictal activity (left) and pharmacoactivation with alfentanil (right) in a patient with left
mesial temporal lobe epilepsy.
Channels A1–2, A2–3 are from the amygdala and periamygdalar region, channels H1–2 and H2–3 are from the hippocampus and perihippocampal region, and N1–2
and N2–3 represent neocortical activity(N1–3). Data were acquired at 5 Hz and high pass filters at 70 Hz with a scale bar = 1 s (horizontal) and 50 µV (vertical).
239
Pre-Operative Assessment epileptogenic (22). The ECoG recordings are highly affected by an-
Epilepsy surgery can be performed with an awake craniotomy or aesthetic agents but complete cessation of all drugs may not always
under general anaesthesia (3, 4, 20–21). The technique of anaes- be possible and general anaesthesia is also frequently used (see Box
thesia is dependent on the location of the seizure focus, the need 19.1). Additional recordings can be obtained from microelectrodes
for intra-operative testing or localization of the seizure focus and inserted into the cortex or depth electrodes into the amygdala and
eloquent brain function, and the ability of the patient to withstand hippocampal gyrus. Stimulation of epileptogenic focus is possible
an awake procedure. This decision is usually made by the surgeon pharmacologically, if insufficient information is obtained during
in conjunction with the multidisciplinary team evaluating and as- ECoG (Figure 19.1) This can be performed by the administration
sessing the patient for their epilepsy treatment. Additionally, the of small doses of methohexital (10 to 50 mg), thiopental (25 to 50
anaesthetist plays an important role in assessing the ability of the mg), propofol (10 to 20 mg), etomidate (2 to 4 mg), and alfentanil
patient’s ability to undergo an awake craniotomy. The pre-operative (500 to 1000 µg) or remifentanil (50 to 100 µg).
anaesthetic assessment and preparation is similar to that discussed
for awake craniotomy for tumour resection. Pre-operative admin- Vagal Nerve Stimulation
istration of anticonvulsant agents is done in consultation with the Vagal nerve stimulation is used for the treatment of medically re-
neurologist and surgeon. Specific considerations in patients with fractory epilepsy and some neuropsychiatric disorders (25, 26). The
epilepsy include the associated medical problems such as psychi- procedure involves the surgical placement of an electrode wrapped
atric disorders, syndromes such as neurofibromatosis, and history around the left vagus nerve which is then tunnelled and connected
of trauma. There are many adverse effects of anti-epileptic drugs, to a generator pacemaker inserted into the chest wall. The postulated
which are dose-dependent and usually associated with long-term mechanism of action involves stimulation of afferent vagal nerve
therapy (21). Most anticonvulsants are metabolized by the liver and fibres that modulate cerebral neuronal excitability, either through
will cause liver enzyme induction, which increases the rate of me- the activation of limbic system, noradrenergic neurotransmitter
tabolism of other drugs, particularly anaesthetic agents.
Anaesthesia Management
BOX 19.1 Anaesthesia for Intra-operative
The overall anaesthetic preparation and management is similar to Electrocorticography (ECoG)
that for tumour surgery except for the additional considerations of
the effects of anaesthetic agents on ECoG. Also, the duration of the Awake Craniotomy
procedure may be longer due to a larger craniotomy and more com- Anaesthesia agents:
plex mapping. Regional scalp blocks are used to provide sufficient
◆ Avoid benzodiazepines: suppress interictal epileptiform
local anaesthesia. Table 19.1 shows complications (4, 20). Seizures
discharges.
are not unexpected in this group of patients. Short focal seizures
may not need any treatment, but when prolonged, they will need to Propofol: stop
◆ infusion 20 min before ECoG.
be treated with cold saline on the cortex (if exposed) and/or small ◆ Dexmedetomidine: least effect on epileptiform discharges,
doses of propofol (or midazolam if all ECoG and mapping is com- stop or decrease concentration during ECoG.
plete). If recurrent seizures occur, patients may become excessively
drowsy and securing of the airway and/or general anaesthesia may ◆ Opioids: fentanyl or remifentanil infusion, may use low dose
be required. Post-ictal drowsiness may also interfere with mapping. during ECoG.
Both conscious sedation and asleep-awake-asleep techniques are ◆ Inhalation agents: for the unconscious periods only.
used. Common techniques for conscious sedation include propofol ◆ Avoid other drugs that cause sedation like antihistamines.
infusion with fentanyl and/or remifentanil, and dexmedetomidine
in conjunction with other agents (23–24). However, with advances
General Anaesthesia
in pre-operative neurological imaging and testing, and use of
frameless stereotactic surgery for localization of the epileptic focus, ◆ Warn patients pre-operatively about the risk of awareness
the need for an awake patient has decreased. Some patients, espe- during ECoG.
cially children and those with developmental delay, will not tolerate
◆ Maintenance with intravenous or inhalation agents.
an awake craniotomy. The challenge for general anaesthesia is that
localization of the epileptic focus is needed to provide good con-
ditions for ECoG and for motor testing. This is achieved by using Before ECoG
the minimal amount and levels of anaesthesia during the mapping ◆ Both intravenous and inhalational agents are weaned down or
period, but also avoiding long periods of potential awareness on the stopped.
part of the patient. If no intra-operative testing is to be performed
the anaesthetic techniques and agents are at the discretion of the ◆ Low dose remifentanil or dexmedetomidine may be continued.
anaesthetist.
During ECoG
Intra-Operative Recordings and Activation ◆ Muscle relaxants may be needed to prevent movement.
Intra-operative localization of the epileptogenic focus may be
◆ Pharmacological activation may be needed for enhancement
performed with ECoG by the placement of electrodes directly
of interictal epileptiform discharges.
on the cortex over and adjacent to the area predetermined to be
240
system, or generalized brain stem arousal. The procedure is per- these target nuclei is increased with the use of neuroimaging with
formed under general anaesthesia, usually with endotracheal in- a stereotactic head frame, intra-operative neurophysiological re-
tubation. Abnormal motion of vocal cords as a result of vagal cordings, and stimulation testing of an awake patient (30, 31). The
stimulation can cause partial airway obstruction with a LMA. choice of localization techniques used varies with institutional
However, trauma to vocal cords has also been reported in patients practice, although most routinely use all three.
with an endotracheal tube as the VNS intermittently adducts the
vocal fold against the rigid endotracheal tube. The other concerns Surgical Techniques
of the anaesthetic management relate to the medical condition of The DBS system consists of three main components: i) intracra-
the patient. Possible complications during the procedure include nial electrode, a coiled wire insulated in polyurethane with four
cardiovascular events such as bradycardia or atrioventricular block. platinum iridium electrodes for implantation in the target area; ii)
Postoperative complications include lower facial paralysis, laryn- pulse generator, a battery-powered programmable single-or dual-
geal dysfunction including vocal cord paralysis, and respiratory channel internal pulse generator (IPG) encased in titanium housing
problems such as decreased respiratory effort, risk of aspiration, which sends electrical pulses to stimulate the target site; and iii) ex-
and worsening of obstructive sleep apnoea. tension cable connecting the DBS electrode to the IPG. The surgical
procedure involves two stages: i) insertion of the electrode(s) into
Anaesthesia for Functional Neurosurgery the target area of the brain, and ii) the internalization of the DBS
electrode(s) and implantation of the pulse generator.
Functional neurosurgery is performed for the treatment of dis- The procedure begins with the placement of a stereotactic
orders that have an alteration of function without gross structural headframe to establish external coordinates for electrode insertion
or anatomical changes. The aim of this procedure is to improve by imaging of the target nuclei with MRI or CT in the radiology
the quality of life of the patient. Functional neurosurgical proced- suite. The patient is then transferred to the OR, positioned in a sit-
ures include both ablative procedures and DBS (27). Advantages of ting or semi-sitting position with the headframe fixed to the OR
DBS over the traditional ablative procedures such as thalamotomy table. An incision and burr hole(s) are made for the placement of
and pallidotomy are that it is non-destructive, reversible, and an electrode guide and DBS electrode(s) into the vicinity of the
adjustable (28). planned target. The next stage is localization of the target nuclei
The initial success of DBS therapy was in patients with with the electrophysiological mapping technique of microelectrode
Parkinson’s disease (27). The indications and applications have recordings (MER). The microelectrode is inserted above the target,
now expanded to include movement disorders (dystonia, essential and then slowly advanced along its trajectory while its tip records
tremors, Tourette’s syndrome), psychiatric disorders (depression, and amplifies neuronal discharges along the path. Specific brain
obsessive-compulsive disorders), chronic pain, epilepsy, cluster structures are identified by their unique patterns of firing (Figure
headaches, Alzheimer’s disease, and anorexia nervosa (29). The 19.2). Stimulation testing is performed on the awake patient to ob-
primary target site nucleus for each DBS procedure varies with the serve for improvement of their symptoms and for any unwanted
patient’s disorder and symptoms. Table 19.2 summarizes the poten- side effects. Radiological confirmation of the electrode is also per-
tial therapeutic targets for the various disorders. The therapeutic formed. A second electrode may be inserted in the contralateral
effectiveness of DBS depends on the placement of the stimulating side for bilateral DBS. Better imaging techniques using 3 Tesla
electrodes in close proximity to the target nuclei, which are often and 7 Tesla MRI have improved the accuracy of target localiza-
deep seated and small in size. The accuracy of the localization of tion. Successful procedures have also been performed with intra-
operative MRI guidance (32).
The second stage, internalization of DBS electrodes and implant-
Table 19.2 Targets for deep brain stimulation. ation of the IPG, can be performed either immediately after inser-
tion or at a later date. The decision is dependent on the patient’s
Disease Target for DBS condition, team preference, and local hospital logistics. The ini-
tiation of stimulation of the DBS is not started until two to four
Parkinson’s disease Subthalamic nucleus, Globus pallidus internus weeks after insertion as post-operative oedema around freshly im-
Essential tremors Ventral intermediate thalamus planted electrodes may lead to a ‘microlesion effect’ that can inter-
fere with the assessment of clinical symptoms (31).
Dystonia (including Globus pallidus internus
Torticollis)
Pre-Operative Assessment
Obsessive compulsive Anterior limb of internal capsule
The selection of appropriate patients for these procedures is accom-
disease
plished by a multidisciplinary team (42). Pre-operative assessment
Epilepsy Anterior nucleus of thalamus and preparation is similar to that discussed for awake craniotomy.
Chronic pain Ventrocaudal thalamus, Periventricular grey However, these procedures are usually long in duration and require
active patient participation. Thus, patients need reassurance, psy-
Depression Subcallosal cingulate gyrus, Nucleus accumbens
chological preparation, and instructions. The pre-operative admin-
Tourette syndrome Centromedian-parafascicular nucleus of thalamus istration of disease specific drugs should be done in conjunction
Headache (cluster, Hypothalamus with neurosurgical team. Some patients need to be in ‘drug off ’ state
migraine) to facilitate intra-operative mapping and clinical testing. This poses
Alzheimer’s disease Fornix/hypothalamus additional challenges to the peri-operative care, as the ‘drug off ’
state may worsen the patient’s symptoms, especially in Parkinson’s
241
GPe
PU
Border
GPE
Gpi
STN
GPI
VP
STN under GA
STN-No sedation
Figure 19.2 Left: Basal ganglia target sites for DBS insertion; Right: Changes in neuronal discharges are shown as the electrode travels from GPe through border cells
into the GPi. High-frequency discharges are typical of Gpi. Bottom: Neuronal discharges characteristic of the STN under no sedation is shown in a 63-year-old patient
with Parkinson’s disease. The firing rate is 40 Hz. Under general anaesthesia (propofol 100mcg/kg/min and remifentanil 0.06mcg/kg/min) STN cell show a slow firing rate
(17Hz). The recordings were obtained in a 49-year-old patient with Parkinson’s disease.
Pu—Putamen; GPe—Globus Pallidus pars external; Gpi—Globus Pallidus pars internal; VP—Visual Pathway/Optic tract; STN—Subthalamic Nucleus; GA-General Anesthesia
disease and dystonia (6). If the symptoms are severe, a reduced dose during the initial part of the procedure and during mapping, to con-
of their regular medication can often be administered. scious sedation during opening and closure. During MAC the an-
aesthetist provides patient comfort and helps with clinical testing.
Anaesthetic Management After all testing is completed the patient may be sedated. For con-
The overall anaesthetic management is similar to that discussed scious sedation, propofol has been the most commonly used seda-
previously for awake craniotomy. The major challenges relate to tive agent with or without opioids (fentanyl, remifentanil) but now
specific concerns of the patient with functional disorders and con- dexmedetomidine is frequently used (43, 44). Optimal conditions
siderations of the procedure as shown in Table 19.2 (6, 33). Local are achievable if sedation is stopped prior to MER and testing. The
anaesthesia is initially infiltrated at pin sites for the headframe and use of benzodiazepines is usually avoided because they have a pro-
then at the site of incision(s) for the bur hole(s) for electrode inser- found inhibitory effect on the neuronal discharges (45). The effects
tion. Scalp nerve blocks (supraorbital and greater occipital) may of propofol on MER signals shows a short-lived decrease in spon-
also be used. Positioning and monitoring needs are similar to that taneous activity of the STN neurons (35). Low-dose infusion rates
of an awake craniotomy. Patients with severe movement disorders of dexmedetomidine may be a better choice due to its non-GABA-
and spasticity may pose difficulty in positioning as well as in moni- mediated mechanism of action allowing for MER, haemodynamic
toring due to artefacts. Positioning is important to ensure comfort stability, and analgesic properties (38, 44, 46). When treated for
and cooperativeness. The head and neck should be positioned with dystonia using combinations of dexmedetomidine and propofol,
some degree of flexion at the lower cervical spine and extension at paediatric patients have tolerated the procedures well (47–49).
the atlanto-occipital joint to make the patient’s airway patent. The General anaesthesia for DBS surgery is an alternative in patients
legs should be flexed and supported under the knees to maintain who cannot tolerate being awake due to excessive fear, anxiety, re-
stability when the head and back are elevated to a sitting position. duced cooperation, or chronic pain syndromes, with severe ‘off-
Conscious sedation and monitored anaesthesia care (MAC) are medication’ movements, severe dystonia or choreoathetosis, and
both used. The anaesthetic agents used will vary from none (MAC) paediatric patients. General anaesthesia may also provide a higher
24
level of acceptance for DBS surgery by some patients and also min- Table 19.3 Considerations for management of anaesthesia for deep
imize the need to stop medication prior to surgery, thereby min- brain stimulation.
imizing the painful ‘off-medication’ dystonia and movements (40,
50). However, intra-operative mapping and stimulation testing will 1.Patient related
be difficult under general anaesthesia. In some situations, confirm- Disease
ation of the location of implanted DBS electrode may be with only
Primary disease (Parkinson’s, dystonia, epilepsy).
MRI after the procedure (49, 51, 52).
Comorbidities (cardiac, respiratory, diabetes).
Effect of Anaesthetic Agents on Neuromonitoring Age (elderly, children).
Intra-operative MER and stimulation testing are used to confirm Psychological—anxiety.
accurate localization of the therapeutic target. The MER are the Medications
direct measurements of both spontaneous and stimulus-evoked
cellular activity, which can help to distinguish neuron cell bodies Polypharmacy, altered pharmacokinetics and dynamics.
from axonal tracts. Accurate localization of the target nuclei de- Medication ‘off state’—worsening of symptoms.
pends on the individual cellular activity as well as the background Continuation of medications.
neuronal discharges. Both are affected by anaesthetic agents (34, 2. Procedure related
35). The rate and pattern of neuronal discharges differ among the
various target cells (Figure 19.2). Similarly, the effects of anaes- General
thetic agents on the MER are different for individual target nuclei. Multiple locations for procedure and transporting
The ability to record MER from the subthalamic nucleus (STN) (radiology, OR).
in Parkinson’s disease has been more successful with various an- Considerations of anaesthesia in remote location and
aesthetic techniques, including propofol and dexmedetomidine in MRI.
sedation, and general anaesthesia with both intravenous or inhal- Long duration of surgery
ation agents (34, 36–38). In contrast, effects of anaesthetic agents Temperature control.
on globus pallidus internus nucleus (GPi) are more profound with
the firing rates in the GPi nucleus decreased significantly and long Positioning.
pauses were recorded under general anaesthesia with propofol (39, Stereotactic frame.
40). The differences in the anaesthetic effects on the various target Local anaesthesia with or without sedation.
nuclei (STN versus GPi) may be explained by the amount of their
Headframe fixed to OR table: Airway considerations.
GABA input. The GPi neurons have a higher GABA input com-
pared to the STN neurons and therefore are more suppressed by Stimulation testing of patient
most anaesthetic agents (41). Need cooperative, alert patient.
Testing efficacy of stimulation and also for
Complications complications.
Complications during DBS surgery are similar to those of an awake 3. Anaesthesia related
craniotomy (Table 19.3). Some relate more to the patient and their
Positioning
disorder, such as the inability to perform adequate testing due to
severe movements of the patient (20, 53, 54). Airway compromise Sitting, semi-sitting.
is an important consideration. A stereotactic headframe makes Complications (venous air embolism, hypovolaemia).
airway access limited, plus shifting of the body with continuous se- Monitoring
vere movements increases flexion of the neck when the headframe
Movement-related artefact on SO2, electrocardiogram
is fixed to the table. Initially talking and/or swallowing may be dif- and blood pressure monitoring.
ficult for the patient, but this may quickly proceed to complete ob-
Blood pressure control
struction of the airway. Other respiratory complications may occur
due to poor respiratory muscle function and fatigue, especially in Risk of intracranial haemorrhage with hypertension.
patients with Parkinson’s disease. Venous air embolism may also Optimal level blood pressure not well defined, systolic
occur due to the sitting or semi-sitting position, especially during blood pressure <140 mmHg or 20% of baseline.
creation of the burr holes. Cardiovascular adverse events can lead Anaesthetic effects on microelectrode recordings
to devastating complications. Hypertension is a common intra-
Varies with disease and target areas.
operative event due to poor pre-operative control, patient distress,
or anxiety during the procedure, or can be secondary to other Avoid benzodiazepines.
events. Hypertension has been associated with increased risk of Dexmedetomidine ideal.
intracerebral haemorrhages (54). Arterial blood pressure must be Stop after burr hole.
controlled before the insertion of the electrode(s) to prevent intra-
Balanced anaesthesia is preferred if under GA.
cranial haemorrhage. The optimal level of blood pressure is not well
defined; a systolic blood pressure of <140 mm Hg or a 20% increase Postoperative considerations
of the patient’s usual range is commonly used. Dexmedetomidine Slow emergence.
sedation is advantageous as this often results in lower blood pres- Postoperative cognitive problems.
sures (44). Drugs used to treat and control hypertension include
243
labetalol, hydralazine, nitroglycerine, sodium nitroprusside, and 5. Venkatraghavan L, Luciano M, Manninen P. Anesthetic management
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in patients with implanted neurostimulator devices. British Journal of
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erator is often implanted in the pectoral area, but the leads from Awake craniotomy for removal of intracranial tumor: considerations
the DBS system must be tunnelled from the site of the burr hole for early discharge. Anesthesia & Analgesia. 2001;92(1):89–94.
through the neck and this is painful. At this time there are no spe- 8. Khu KJ, Doglietto F, Radovanovic I, et al. Patients’ perceptions of
awake and outpatient craniotomy for brain tumor: a qualitative study.
cific anaesthetic drug considerations. However, as head position is
Journal of Neurosurgery. 2010;112(5):1056–60.
often manipulated during this procedure, the seal of a LMA might 9. Brown T, Shah AH, Bregy A, Shah NH, Thambuswamy M, Barbarite
be unpredictable, thus, endotracheal intubation is usually preferred. E, et al. Awake craniotomy for brain tumor resection: the rule
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12. Chernik DA, Gillings D, Laine H, Hendler J, Silver JM, Davidson AB,
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13. Manninen PH, Balki M, Lukitto K, Bernstein M. Patient satisfaction
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245
CHAPTER 20
Anaesthesia for Complex
Spine Surgeries
Ehab Farag and Zeyd Ebrahim
Introduction characteristic features are their bifid spinous processes and a for-
amen in their transverse processes. These foramina transversaria
The increased complexity of spinal surgical procedures in the last contain the vertebral artery and vein. The first cervical vertebra
two decades has led spine surgery to evolve into a multidisciplinary is known as the atlas, which has no body. It contains an anterior
specialty. This chapter aims to present the most recent evidence- tubercle instead. Its superior articular facets articulate with the
based advances in the peri-operative anaesthetic management for occipital condyles of the skull and are oriented in a roughly
complex spine surgeries. parasagittal plane. The head thus moves forward and backward
on this vertebra. The second cervical vertebra axis forms the
Anatomy pivot upon which C1 rotates. The most distinctive characteristic
The vertebral column is composed of series of 31 separate bones of this vertebra is its strong odontoid process (dens), which rises
known as vertebrae. There are seven cervical or neck vertebrae, 12 perpendicularly from the upper surface of the body. The body
thoracic vertebrae, and five lumbar vertebrae. The sacrum is com- is deeper in front than behind, and prolonged downward anteri-
posed of five fused vertebrae, and there are two coccygeal verte- orly so as to overlap the upper and front part of the third ver-
brae, which are sometimes fused. In the normal adult there are four tebra. The interval between the posterior aspect of the odontoid
curvatures in the vertebral column in an anteroposterior plane. process and the anterior aspect of the posterior ring of the atlas
These serve to align the head with a vertical line through the pelvis. is termed the posterior atlas-dens interval and contains the
In the thoracic and sacral regions, these curves are oriented con- space available for the cord. The space available for the cord at
cave anterior and each is known as a kyphosis. In the lumbar and C1 may be divided into cord, which occupies only half the space.
cervical regions, the curves are convex anterior and each is known Therefore, it allows for some encroachment of the spinal lumen
as a lordosis. These latter normal curvatures develop during child- without compromising the cord. At the lower cervical levels (be-
hood in association with lifting the head (cervical) and assuming tween C4 and C7), the spinal cord normally fills approximately
upright sitting (lumbar) and thus known as secondary curvatures. 75% of the cross-sectional area of the canal. The seventh cervical
The thoracic and sacral curvatures are the same in adults as they are vertebra has a prominent spinous process, hence the name ver-
in foetuses, and they are known as primary curvatures. Each vertebra prominens.
tebra is composed of a body anteriorly and neural arch posteriorly. Thoracic vertebrae form a transition between cervical verte-
The arch encloses an opening, the vertebral foramen, which helps brae and lumbar vertebrae below. The upper four thoracic verte-
to form a canal in which the spinal cord is housed. The neural arch brae are like cervical vertebrae, for they have vertically oriented
of each vertebra is divided into components by spinous and trans- articular facets and posteriorly directed spinous processes. The
verse processes. The parts of the neural arch between the spinous lower four thoracic vertebrae contain more lumbar features,
and the transverse processes are called the laminae and the parts of such as large bodies, robust transverse and spinous processes,
the arch between the transverse processes and the vertebral body and lateral projecting articular facets. The middle four thoracic
are called the pedicles. At the point where the laminae and ped- vertebrae have characteristics between these two regions. These
icles meet, each vertebra contains two superior articular facets and include vertically oriented articular processes and long, slender,
two inferior articular facets. The pedicle of each vertebra is notched and inferiorly inclined spinous processes. The thoracic vertebrae
at its superior and inferior edges. Together the notches from two are characterized by their articulations to the ribs. Massive bodies
contiguous vertebrae form an opening, the intervertebral foramen, and robust spinous and transverse processes characterize lumbar
through which spinal nerves pass (Figure 20.1). vertebrae. The sacrum consists of five fused vertebrae. It articu-
lates with the fifth lumbar vertebra above and the coccyx below,
and with the iliac bones on either side. In addition to its charac-
Regional Differences in Vertebral Structure teristic shape, it contains both anterior and posterior foramina
Typical cervical vertebrae have large spinal canals, oval shaped through which anterior and posterior rami of spinal nerves pass
bodies, and articular facets oriented obliquely. Their most (Figure 20.2 A, B, C).
246
Atlas (a)
Cervical Axis Superior articular process
vertebrae
Spinous process
Pedicle
Transverse process
Inferior articular process
Posterior tubercle Body
Thoracic
vertebrae Anterior tubercle
Spinous process
Lamina
Superior articular process
Lumbar
vertebrae Vertebral foramen
Pedicle
Posterior tubercle
Transverse foramen Body
Sacrum
Anterior tubercle
C4
Coccyx
Figure 20.1 The vertebral column. (b)

Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography © 2015- Superior articular process
2017. All Rights Reserved. Transverse process
Pre-Operative Assessment Pedicle

Body
Lamina
Pre-operative assessment as in other surgeries should routinely in-
clude a history and physical examination as well as optimization of Spinous process
the patient for surgery. The risk for a peri-operative cardiovascular
event should be properly assessed in the pre-operative evaluation. Inferior articular process
The better identification of the risk factors and understanding of Inferior vertebral notch
the benefit-to-risk ratio of major surgery may lead to interventions
that decrease the risk of peri-operative cardiovascular events. The
two most common risk models used in the peri-operative assess- Spinous process
ment are Revised Cardiac Risk Index (RCRI) and the American
College of Surgeons’ National Quality Improvement Program Risk Transverse process
(NSQIP) model (1).
Radiological diagnosis should be integral part in the pre- Lamina
operative evaluation before spine surgery. Radiological diagnoses
of atlanto-axial subluxation, often present in rheumatoid arth- Superior articular process
ritis patients or Down’s syndrome patients, should be considered
in the pre-operative assessment, for direct laryngoscopy in pa- Pedicle
tients with undiagnosed subluxation has been reported to cause
quadriplegia (2). Vertebral foramen
Body
Physical examination before complex spine surgery is important,
because spine disease is often generalized, affecting the whole spine
but with different degrees of severity (just as peripheral vascular
disease affects the whole vascular system, but with different degrees T6
of severity).
Figure 20.2 The anatomical differences between cervical (A), thoracic (B), and
Pre-operative examinations of a conscious nontrauma patient’s lumbar vertebrae (C).
ability to flex and extend the neck without symptoms while the patient Figures 20.2A, B, and C: Reprinted with permission, Cleveland Clinic Center for Medical Art &
conscious is a crucial step in assessing the upper airway management Photography © 2015-2017. All Rights Reserved.
247
Chapter 20 complex spine surgery 247
(c)
Superior vertebral notch
Transverse process
Pedicle Body
Lamina
Spinous process
Inferior vertebral notch
Spinous process
Lamina
Transverse process
Pedicle
Body
Vertebral foramen
L2
Figure 20.2 Continued
during surgery. The patient should be examined for the presence or was not excessive, did not result in movement of an injured cervical
absence of Lhermitte’s sign, sometimes called the ‘barber chair’ phe- spine in a cadaver model (4).
nomenon. Lhermitte’s sign is an electrical sensation that runs down Atlanto-axial instability, observed in patients with rheumatoid
the back and into the limbs caused by the posterior column’s involve- arthritis (RA) and Down’s syndrome, holds important clinical sig-
ment in the pathological process. Either flexing or extending the nificance. In atlanto-axial instability, the odontoid process is no
neck elicits this. The presence of Lhermitte’s sign suggests compres- longer firmly held against the back of the anterior arch of C1, due
sion of the spinal cord in the neck such as cervical spondylosis, disc either to disruption or laxity of the transverse ligament or to damage
herniation, tumour, or Chiari malformation. Extra caution should be of the odontoid process itself. Roughly 30% of patients with severe
taken to keep the neck in a neutral position during intubation and RA and 15% of Down’s syndrome patients may exhibit atlanto-axial
throughout the procedure. Notably, extension at the craniocervical subluxation. Therefore, it is advisable for those patients to have
junction is necessary for full mouth opening. A potential small mouth cervical dynamic radiographs before any surgical procedure that
opening should be considered a sign for difficult intubation. requires DL or extensive neck manipulation. Notably, translation
movements or angulation of adjacent vertebral bodies in flexion
Movement of the Cervical Spine With or extension during DL may result in spinal cord compression.
Maintaining neutral neck position during intubation is of utmost
Intubation importance to avoid cervical spinal cord injury, especially during
Placement of the endotracheal tube (ET) during direct laryngos- cervical spine surgery.
copy (DL) is a very complex manoeuvre. The primary force applied The primary force applied during DL is as high as 50–70 Newton
by the laryngoscope is upward lift, which results in extension of (N) (45 N is sufficient to lift 4.5 Kg or 10 lbs). The more difficult
the atlanto-occipital interspace. The lift also results in flexion at the the exposure, such as with cervical spondylosis, the greater force
lower vertebrae. The laryngoscope exerts maximal extension of the needed to be applied, causing a potentially greater likelihood of
occiput and atlas, which is counterbalanced by flexion below C2. It cervical spinal cord injury during intubation. The use of the new
was thought that manual-in-line stabilization (MLS) might reduce video scope Airtraq resulted in a 23% reduction in cervical spine
neck movement during DL in an unstable neck by applying force motion in cadaveric study; it exerted only 20% of the force by
to the head and neck equal in magnitude and opposite in direc- DL (5). Therefore, fibreoptic intubation is an ideal method for
tion to those generated by DL. However, MLS not only failed to re- intubation, especially in cases when cervical spine movement is
duce movement at the site of instability in cadaver models but also not feasible, resulting in the least degree of upper cervical spine
limited vocal cord visualization (3). Cricoid pressure, as long as it motion (6).
248
Central Cord Syndrome and Direct during general anaesthesia did not negatively affect the respiratory
mechanisms, but it did improve lung volumes and oxygenation.
Laryngoscopy However, in obese patients the abdomen should be freely moving
Schneider first described Central Cord Syndrome (CCS) in 1954. during respiration in order to achieve the beneficial effects of the
Classic CCS presents as spinal cord injury with weakness in prone position on respiration.
upper extremities greater than lower extremities in patients with
underlying cervical spondylosis. The pathological mechanism often Poisson Effect and Prone Position
involves hyperextension of the cervical spine with cord compres- Breig and colleagues showed that the spinal cord stretches with the
sion, by osteophytes anteriorly and enfolded ligamentum flavum flexion of the cervical spine and shortens and thickens with exten-
posteriorly, impinging on the central core of the spinal cord and sion: the ‘Poisson effect’ (15). Prone positioning is often associated
leading to ischaemia, oedema, or haematomyelia. Hyperextension with modest degrees of extension; therefore, the cord might sus-
may seem mild as with DL, but in the setting of cervical spondylosis tain excessive pressure induced by soft tissue encroachment on the
it can result in marked neurological injury. Younger patients with spinal canal with extension and aggravated by the pre-existing canal
congenital cervical stenosis are also at increased risk of sustaining stenosis. The clinical relevance of these findings is that a persistent
CCS as a result of hyperextension injury during DL (7, 8). malposition of an abnormal neck may result in cord ischaemia and
neurological injury (16). Prone positioning is also associated with
Pathophysiological Changes with Prone increases in vena caval pressures, which may further reduce cord
blood flow, already comprised by cord compression, by increasing
Position resistance in the venous outflow channels (21).
Cardiovascular Changes
Cardiac index (CI) and venous return decrease in the prone pos Haemodynamic and Fluid Management During Spine
ition due to a decrease in the left ventricular volume and com- Surgery in the Prone Position
pliance. These changes are attributed to inferior vena caval The aim of fluid management is to maintain normovolaemia and
compression and decreased left ventricular compliance due to inadequate tissue perfusion while avoiding interstitial tissue oedema.
creased intrathoracic pressure. The knee-chest position is associ- However, the reduction in CI and venous return in the prone pos-
ated with up to 20% reduction in CI, although CI decreases 3% only ition have made the fluid and haemodynamic management in prone
when the prone position is on pillows (one pillow under the thorax position challenging tasks, especially during lengthy and complex
and one under the iliac crests, leaving the abdomen free to move spine surgeries. It is not uncommon for hypovolaemia with inad-
like in Jackson’s table). equate fluid resuscitation to occur during complex spine surgery.
The reduction in CI in the prone position not only results in Moreover, blood loss can be difficult to quantify due to pooling
haemodynamic instability in the prone position, but also re- on drapes. The use of invasive monitoring techniques, especially
duces the metabolism of anaesthetic medications, like Propofol during complex surgeries, will aid in dynamic blood pressure
demonstrating a significant reduction in cardiac output. During monitoring and frequent evaluation of haemoglobin and hemato-
the maintenance of anaesthesia using propofol compared with crit levels to avoid the problem of underestimating blood loss.
isoflurane (9, 10). Pearce observed vena caval pressures to be 0 to Meanwhile, inappropriate or excessive resuscitation can result in
40 mm/H2O in patients in the prone position with the abdomen iatrogenic acute hypervolaemia, which is a major problem during
hanging free (11). In contrast, patients with abdominal compres- complex spine surgeries.
sion had vena caval pressures greater than 300 mm/H2O. Increased Iatrogenic hypervolaemia increases the secretion of atrial natri-
venous pressure not only increases bleeding during spine surgery uretic peptide (ANP). ANP induces shedding and disruption of
due to the congestion of vertebral veins, but also can impair spinal endothelial glycocalyx (EG) (17). The EG consists of membrane-
cord perfusion. bound proteoglycans and glycoproteins, which build a network
The use of the prone position with abdominal compression was in which plasma proteins are retained. EG plus bound fluids and
identified as a plausible cause of spinal cord ischaemia leading to plasma proteins form the endothelial surface layer (ESL) with a
neurological deficits after cervical laminectomy. The authors of this thickness of about 1 μm. The noncirculating part of the plasma
case series recommended the avoidance of abdominal compres- fixed within the ESL is approximately 700–1000 mL in humans. The
sion and hypotension, especially in myelopathic patients for whom ESL is the major barrier between the blood and interstitial tissue.
maintenance of spinal cord perfusion pressure is of paramount Therefore, the disruption of EG by hypervolaemia could induce in
importance (12). interstitial oedema and impaired tissue perfusion. In addition to its
important role in tissue perfusion, the EG plays a very important
Changes in Respiratory Physiology role in maintaining the proper functions of immune and coagula-
Near-normal ventilation-perfusion matching has been observed in tion systems. Normally, the small endothelial adhesion molecules
the prone position. Perfusion is more evenly distributed and to- are within the EG, therefore, the degradation of EG will enhance the
gether with the recruitment of dorsal airways results in an increase adherence of inflammatory cells to the endothelial cells. Moreover,
in lung units and consequently functional residual capacity. Of after shedding the EG, circulating glycocalyx components like
note, the prone position is sometimes used in patients with acute heparan sulphates have a direct chemotactic effect on leukocytes
respiratory distress syndrome to improve oxygenation and de- and increase at the site of inflammation. Consequently, the destruc-
crease shunt (13). Pelosi and colleagues confirmed similar findings tion of the EG can trigger an inflammatory cascade. The EG has an
during general anaesthesia (14). Therefore, the prone positioning important mechanosensory role by translating the sheer stress into
249
biochemical activation of endothelial cells to release nitric oxide In a recent study by our group, 116 patients undergoing com-
(NO). The EG is a crucial component for binding and regulating plex spine surgeries were randomly assigned to peri-operative IV
enzymes involved in the coagulation cascade. Furthermore, at- lidocaine (2mg·Kg-1·h-1) or placebo during surgery and the post-
tached to the EG is antithrombin III, the most important inhibitor anaesthesia care unit. Pain was evaluated with a verbal rating scale.
of thrombin and factor Xa (18–20). Quality of life at one and three months was assessed using Acute
The average insensible fluid loss is only 0.5ml/Kg/h via skin and Short-form (SF) 12 health survey. Lidocaine not only improved the
airways in a conscious adult. During abdominal surgery insens- pain scores in the postoperative period but also significantly im-
ible fluid loss increases to only 1ml/Kg/h. Avoiding hypovolaemia proved the quality of life measured by SF-12 at one to three months,
and hypervolaemia, which includes a careful indication for peri- postoperatively (26). The use of an epidural catheter inserted by the
operative fluid management, is an important element to maintain spine surgeon at the end of the procedure is another useful tech-
healthy EG and limit peri-operative fluid and proteins shifts into nique for postoperative pain management especially after complex
the interstitial space. Goal-directed fluid therapy and reduced spine surgeries. We retrospectively reviewed 245 medical records
use of crystalloid are essential to maintain normovolaemia and of adult patients undergoing major spine surgeries who received
ESL integrity. Of note, 80% of the infused crystalloids are dis- epidural analgesia or patient-controlled intravenous analgesia for
tributed into the interstitial tissues under all conditions. The use postoperative pain management. The use of epidural analgesia was
of crystalloid at the rate of 1–2 ml/Kg/h for maintenance and associated with better postoperative analgesia and reduced the
iso-oncotic colloid like albumin for the replacement of blood amount of opioid consumption postoperatively compared with
loss is likely beneficial for fluid management during spine sur- patient-controlled intravenous analgesia (27). A single dose of
gery. In our practice, we prefer to use pulse pressure variation ketorolac (60 mg) was an effective adjunct in multimodal regimens
methods for goal-directed therapy to guide the fluid manage- to reduce postoperative pain. Improved postoperative analgesia
ment during spine surgery (21). If the blood pressure remains achieved with ketorolac was also accompanied by a reduction in
lower than the required target even after fluid optimization, it is postoperative nausea and vomiting (28).
vital to administer vasopressors or inotropes to reach the target Gabapentin blocks thrombospondin-induced synapse formation
blood pressure (21). Markedly, the use of vasopressors constricts by interfering with thrombospondin-α2δ-1 interaction. Therefore,
the precapillary sphincter and decreases the perfusion pressure binding of gabapentin to α2δ-1 receptor inhibits synapse forma-
in the capillaries, thereby reducing the filtration pressure and the tion by thrombospondins. Increased levels α2δ-1 levels were shown
tissue oedema. The use of hydroxyethyl starch solutions should to lead to enhanced excitatory synaptic transmission and elevated
be used cautiously during spine surgeries, for it may impair the neuropathic pain states. Thus, gabapentin may reduce the develop-
coagulation process and induce peri-operative renal impairment ment of neuropathic pain states after spine surgery by inhibiting
(22, 23). excitatory synaptic formation. The use of α2δ-1 blockers pregabalin
and gabapentin in the dose of 75 mg and 300 mg respectively one
Intra-Operative Neurophysiologic Monitoring hour before spine surgery for lumbar discectomy and hourly after
Intra-operative neurophysiologic monitoring (IONM) refers to surgery for seven days was associated better pain relief and long
the various neurophysiologic tests used to assess functional in- term functional outcome. However, pregabalin was associated
tegrity of the central and peripheral nervous systems during sur- with less pain intensity and improved outcomes at three months
gical procedures that place these structures at risk for iatrogenic postoperatively compared with gabapentin (see Table 20.1) (29, 30).
injury. The purpose of IONM is to provide feedback regarding
changes in neural functioning before the development of irre- Peri-Operative Complications
versible neural injury, thereby permitting intervention to prevent
or minimize postoperative neurologic deficits. For the full discus- Postoperative Visual Loss After Spine Surgery
sion of the subject of IONM the reader may refer to Chapter 11 on Postoperative vision loss (POVL) or impairment after spine surgery
neurophysiologic monitoring. is devastating problem with an incidence of 0.1% to 1% (31). The
causes remain poorly understood, but appear to be multifactorial
Treatment of Surgical Pain After Spine Surgeries and may include impaired of the eyes’ venous drainage, head pos-
Successful analgesic strategies for spine surgery are very important ition, or occlusion of retinal vessels from pressure on the eye globes.
for achieving acute pain control in the postoperative period, but
also to potentially prevent the development of chronic postsurgical Ocular Perfusion Pressure
pain. Postoperative pain can be severe after posterior spine sur- Ocular perfusion pressure (OPP) is defined as the difference be-
geries. Acute pain is one of the leading causes for readmission after tween mean arterial pressure (MAP) and intra-ocular pressure
ambulatory spine surgeries (24). (32). Either decreases in MAP or elevated intra-ocular pressure
Multimodal analgesia is considered the best approach for will thus decrease OPP. Most commonly, perfusion is impaired
managing the postoperative pain after complex spine surgeries. by a combination of decreased MAP and increased intra-ocular
The multimodal approach can be defined as a combination of pressure (32). The eye has its own autoregulation, which enables
an opioid and non-opioid analgesic, with or without regional the constant flow within different perfusion pressures. However,
anaesthesia. The use of multimodal analgesia usually results in the lower limit of autoregulation usually shifts to higher levels
improving the quality of analgesia with concurrent reduction to maintain constant blood flow in hypertensive patients. The
in the incidence of some opioid side effects like postoperative eyes of hypertensive patients are more vulnerable to low blood
nausea, vomiting, constipation, and sedation through opioid pressures. In the optic nerve head, reduction in blood pressure
sparing effect (25). below the critical autoregulatory level decreases blood flow (32).
250
Table 20.1 Recommendations for peri-operative analgesia.
Type of Spine Surgery Analgesia Disposition

Minor (laminectomy, Pre-operative: Continue pre-operative analgesics. Acute care floor
foraminotomy, discectomy) Intra-operative: Paracetamol, IV opioids.
Postoperative: Oral opioid/acetaminophen combinations.
Moderate (anterior cervical Pre-operative: Continue pre-operative analgesics. Acute care floor or step-
discectomy and fusion, 1–2 Intra-operative: Ketamine bolus, lidocaine infusion, paracetamol, IV opioid. down unit
level fusion)
Postoperative: Opioid PCA, acetaminophen.
Major (multilevel fusion) Pre-operative: Continue pre-operative analgesics, consider addition of a gabapentenoid. Intensive care unit
Intra-operative: Methadone versus intrathecal opioid; ketamine, lidocaine and dexmedetomidine
infusions, paracetamol.
Postoperative: Gabapentinoid, opioid PCA, paracetamol/acetaminophen, consider ketamine and/or
lidocaine infusion if severe pain.
Reprinted with permission from Best Practice & Research Clinical Anaesthesiology, 30, 1, Dunn, L.K., Durieux, M.E., Nemergut, E.C., Non-opioid analgesics: Novel approaches to perioperative
analgesia for major spine surgery, pp. 79–89. Copyright (2016) Elsevier.
Pillunat and colleagues have shown that ocular autoregulation an independent predictor for POVL (35). The true incidence of
might be deficient in some healthy individuals, rendering them postoperative AION might be underestimated because small areas
unable to maintain normal blood flow to the optic nerve head of anterior optic nerve infarction may produce only small visual
in the presence of low OPP (33). This finding would explain why defects that pass unnoticed during the postoperative period. These
some patients with intact ocular auto-regulation would be able to patients may present low-perfusion glaucoma with multiple areas
maintain normal ocular blood flow despite low OPP. Therefore, it of optic atrophy later (36).
is better to ensure adequate OPP during complex spine surgeries Posterior ischaemic optic neuropathy (PION) is relatively rare,
to ensure normal blood flow to the optic nerve head. and presents clinically as retrobulbar optic neuropathy. It is be-
Intra-ocular pressure is another factor that determines OPP. lieved to result from infarction of the intra-orbital portion of the
Intra-ocular pressure usually increases over time in the prone optic nerve. PION can be presented postoperatively as acute deficit
pressure and can reach up to 40 mm Hg. During the prone pos- in visual acuity with ipsilateral afferent pupillary defect. PION is
ition the impaired venous return from the head due to increased characterized by visual deficit in the presence of a normal optic disc
intrathoracic pressure results in ophthalmic venous congestion. The and funduscopic examination. Optic nerve atrophy usual develops
venous congestion impairs the aqueous humour drainage and re- within four to eight weeks of the onset of visual loss.
sults in increased intra-ocular pressure. Ischaemic optic neuropathy The main causes of PION are not well identified. However, PION
(ION) caused by increased ocular venous congestion and thereby has been described after bilateral neck dissection due to bilateral
increased intra-ocular pressure has been observed in other proced- ligation of the internal jugular veins, which led to facial oedema,
ures with similar physiology such as bilateral radical neck operations venous congestion, and increased intra-orbital pressure (37, 38).
with bilateral jugular veins ligation and robotic prostatectomies
with steep Trendelenburg positions. Autoregulatory mechanisms Cortical Blindness
enable the eye to maintain constant flow over a wide range of OPP. Cortical blindness results from damage to the occipital cortex or
However, autoregulation becomes deficient in maintaining the con- optic radiation; the main causes for cortical blindness are ischaemic
stant flow when the intra-ocular pressure reaches 45 mm Hg, and at or traumatic. Clinically, loss of vision is accompanied by retention
this point blood flow becomes pressure dependent. of pupillary reaction to light and normal funduscopic examination
(39). Cortical blindness is usually best diagnosed by a CT or MRI,
Types of Visual Loss and Impairment which helps identify infarcted areas in the occipital lobe. Cortical
Associated with Spine Surgery blindness has been reported during spine surgery due to hypo-
tension, anaemia, and abnormal head position jeopardizing the
Ischaemic Optic Neuropathy vertebrobasilar circulation (40, 41).
ION occurs either in the anterior part of the optic nerve where
the nerve enters the globe or the posterior part where the nerve Central Retinal Artery and Vein Occlusion
lies within the orbit. Blood flow to the optic nerve is autoregulated The main cause of retinal artery occlusion after spine surgery is
to maintain a nearly constant supply despite changes in perfusion external ocular pressure from a headrest combined with arterial
pressure. However, autoregulation operates effectively only over a hypotension, resulting in obstructing the flow in the retinal artery.
particular range of perfusion pressures. Above or below this range, However, retinal artery occlusion could occur by atherosclerotic
blood flow depends directly on MAP, so ischaemic damage can re- emboli from the carotid artery. Central retinal occlusion typically
sult. Anterior ischaemic optic neuropathy (AION) can also result presents as a complete loss of vision in one eye that usually im-
from a low hematocrit because choroidal blood flow decreases with proves with time. Funduscopic examination reveals pallor and oe-
haemodilution (34). However, low hematocrit was not found to be dema of the retina, with a cherry-red spot at the fovea (42).
251
Central retinal vein occlusion has been reported after spine sur- increased at the rate of 2.0 mm Hg/h in patients receiving al-
gery due to external pressure on the globe from the headrest in the bumin, which was significantly slower than in patients receiving
prone position. Funduscopic findings usually include retinal haem- LR 3.1 mm Hg/h. This finding would explain why the decreased
orrhages in all quadrants, cotton-wool spots, and dilated tortuous use of colloid was an independent risk factor for POVL after com-
retinal veins (43). plex spine surgeries. Avoiding anaemia is another important factor
during spine surgeries for choroidal blood flow, which is respon-
sible for up to 70% of retinal requirements of oxygen and glucose,
Factors Contributing to Vision Loss and decreases during experimental isovolemic haemodilution to hem-
Impairment After Spine Surgery atocrit levels of 20–22% (34). Despite the recent case control study
for POVL after spine surgeries did not identify hypotension and
Head Position and Compartment Syndrome
anemia as independent risk factors for POVL (35). It is prudent to
In a French survey of ophthalmic complications after spine sur- follow the recent practice advisory for POVL associated with spine
gery, the authors proposed two preventive measures to avoid surgery that recommends keeping haemoglobin or hematocrit
measures to avoid vision loss after spine surgery in the prone levels at approximately 9g/dL or 28%, respectively (46), in addition
position. The first was to avoid eye compression when using a to avoid hypotension to maintain adequate OPP.
horseshoe-shaped headrest, and the second was to avoid lateral In summation, maintaining adequate OPP during spine surgeries
rotation of the head in patients with suspected carotid atheroma in prone position is crucial to avoid POVL.
(44). Therefore, turning the head to one side in prone position Nandyala and colleagues have identified 105 cases of POVL after
during hour L3–4 decompression with fusion was the cause of spine surgeries using Nationwide Inpatient Sample Database over
ION and POVL (45). the period between 2002 and 2009 (46). The authors identified
the incidence of POVL after spine surgery of 1.9 events per 10,000
Other Contributing Factors for POVL cases. The rates of POVL were highest among patients having thor-
In a recently published multicentre case control study the authors acic (19.7 cases per 10,000) and posterior lumbar (1.9 cases per
compared 80 adult patients with ION from American Society of 10,000) fusions. However, fewer than 10 cases of POVL were iden-
Anesthesiologists POVL registry with 315 adult control subjects tified following anterior cervical, anterior lumbar, or posterior cer-
after spinal fusion surgery from 17 centres. The risk factors for ION vical fusions. The authors identified spinal deformity, diabetes with
were identified as obesity, male sex, Wilson frame use, longer an- end-organ damage, and pre-existing neurological disorder to be the
aesthetic duration, greater estimated blood loss, and decreased col- only risk factors for POVL. However, the authors used a very con-
loid administration (35). servative P-value (P< 0.0005) that may increase the risk of a false-
The results of our study could explain to a great extent the re- negative conclusion.
sults for POVL after spine fusion surgeries. In our study we fac-
torially randomized patients undergoing complex spine surgeries The Relation Between Body Mass Index (BMI) and
in prone position into four groups: albumin and topical α-2 agonist Postoperative Complications
brimonidine; albumin and topical placebo; lactated Ringer’s solu- Marquez-Lara and colleagues and McClendon J Jr. and colleagues
tion and topical placebo; and lactated Ringer’s solution and topical identified an increase in the rates of complications even up to two
brimonidine. IOP was measured with a pneumotonometer (7, 21). years after lumbar spine surgery in obese patients (BMI >30 Kg/
The prone position increased IOP on average by 12±6 mm Hg. IOP m2) (47, 48). Furthermore, the morbidly obese patients were three
was 38 ± 10 mm Hg at the end of the procedure (approximately 5.5 times more likely than the underweight patients (BMI <19 Kg/m2)
h). In twelve patients intraocular pressure exceeded 50 mm Hg after and eight times more likely than the patients of normal weight (19
five hours of surgery. The increase in intraocular pressure during Kg/m2 to 24.9 Kg/m2) to have complications within two years.
surgery and consequently decreased OPP would explain why pro-
longed anaesthesia time was identified a risk factor for POVL after
spine fusion surgeries. Large blood loss usually accompanies pro-
Prolonged Intubation After Complex Spine Surgeries
longed surgeries followed by periods of haemodynamic instability, Factors independently associated with persistent tracheal intub-
which further jeopardizes OPP. ation after major spine surgery were greater age, higher ASA phys-
The use of the Wilson frame was identified as a risk factor for ical status classification, longer case duration, greater estimated
POVL due to its effect on decreasing the head venous return and blood loss, and considerable IV fluid requirements, including crys-
thus increasing intra-ocular pressure with reducing OPP. Obesity talloid, colloid, or transfused red blood cell (49). Products reported
is the third risk factor for POVL. In our study we did not find a that greater age, more comorbidities, longer operating times, and
relation between body mass index with either pre-operative or higher red blood cell transfusion requirements were associated
intra-operative intra-ocular pressure. However, obese patients with an increased risk for prolonged tracheal intubation (>48 h) in
had a lower cardiac index than non-obese patients in the prone patients who had cervical spine surgery (50).
position, and it was difficult to keep their MAP within the target
values during surgery. Therefore, obese patients had a lower OPP Complications Associated with Cervical Spine Surgery
than non-obese patients, making them more vulnerable to develop Immediate postoperative care after cervical spine surgeries, espe-
POVL than non-obese ones. The other important risk factor for cially the extensive ones, is crucial as emergency re-intubation or
POVL was reduced percentage of colloid administration. In our tracheostomy can lead to graft-related neurologic complications,
study using goal-directed fluid administration to guide crystal- hypoxia, and death. Risk factors for delayed extubation after cervical
loid or colloid fluid management, we found intra-ocular pressure spine procedures include obesity, operative time greater than ten
25
hours, anterior cervical discectomy with fusion (ACDF) including of the plexus across the coracoid process and glenohumeral joint
C2 level, and asthma. Additional rare risk factors include recurrent (7). Notably, turning the head to one side can cause brachial
laryngeal nerve (RLN) palsy (<1% with left -sided approaches), oe- plexus injury as it can exert addition stretch on the brachial plexus.
sophageal perforation, and new postoperative spinal cord deficits Therefore, positioning the shoulders at no more than 90° of abduc-
(7, 51). When these risk factors are present, it is preferable to post- tion with the arms pronated (palms down) with the head in neural
pone immediate postoperative extubation and instead to extubate position is recommended to avoid brachial plexus injury in prone
over a tube exchanger with fibreoptic examination in order to iden- position (7).
tify residual postoperative tracheal and /or vocal swelling.
The development of postoperative wound haematoma is a po- Cases
tentially catastrophic complication. It can present as a neck mass
associated with dysphagia and occasionally as respiratory dis- Q Interactive cases to test your knowledge on this chapter can
tress. Its incidence varies between 1% and 11% (52). The man- be found in the online appendix at www.oxfordmedicine.com/
agement of this complication can sometimes require immediate otneuroanesthesiology.
awake fibreoptic intubation and re-operation to evacuate the
neck haematoma. In the setting of a significantly deviated tra- References
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25
CHAPTER 21
Spine Trauma
Timur M. Urakov and Michael Y. Wang
Introduction Intercostal muscles are supplied by the thoracic nerves. The ac-
cessory muscles include sternocleidomastoid, supplied by cranial
Estimated global incidence of spinal cord injury (SCI) is 250 000 nerve XI, and scalene muscles, supplied by the cervical plexus.
to 500 000 people a year (1). North America tends to have higher The brachial plexus controls the movement of the upper ex-
rates of incidence of SCI than Europe. In countries like the US, tremity and originates from nerves C5, C6, C7, C8, and T1. Lower
Finland, and Australia, the rates of traumatic SCI have been extremity musculature is supplied by the nerve roots originating at
dropping reflecting the drop in road traffic crashes. While the L2, L3, L4, L5, and S1. The pudendal nerve is essential in the control
incidence has been increasing in Norway, it still remains one of of pelvic organs and bowel and urinary functions, and it originates
the lowest in the world. SCI is more prevalent in males, with up from S2, S3, and S4 nerve roots.
to 82% reported in the United States. Statistically, young adults The spinal cord usually ends between lumbar vertebral bodies
and the elderly are more likely to be injured. Motor vehicle acci- one and two. Nuclei of lumbar and sacral nerves are located in the
dents are the leading cause of SCI in the world, followed by falls, distal portion of the cord.
violence, sports, recreational activities, and iatrogenic sources. The autonomic nervous system includes sympathetic and para-
In the first year after high cervical injury, the costs associated sympathetic tracts. The sympathetic system originates in the hypo-
with the care of an SCI patient can be over a million US dollars, thalamus of the brain and travels down the cord in intermediolateral
with each subsequent year’s cost coming close to 200,000 USD (2). grey column. The preganglionic sympathetic fibres exit the spinal
These costs include medical care, equipment, assisted accommoda- cord from the anterior horn together with spinal nerves between
tion, and loss of productivity. the levels of T1 and L2. They synapse in the associated ganglia lo-
SCI process can be divided into three stages. The primary mech- cated in paravertebral, and para-aortic areas. Postganglionic sym-
anism involves the actual damaging event. The secondary mech- pathetic fibres supply vasculature and secretory organs of the head
anism shortly after is the result of the systemic compromise from and body. The superior cervical ganglion is responsible for the
the injury involving cardiovascular, pulmonary, haematologic, and sympathetic supply of head while the middle and inferior cervical
other responses that may result in ischaemia, hypoxia, or oedema, ganglia project to cardiac and pulmonary systems.
further damaging the injured cord. The third mechanism is related The parasympathetic system also travels down the
to the healing process ongoing for years after the injury and results intermediolateral grey column of the cord and exits with the sacral
in further deterioration of the neurological status due to fibrosis plexus controlling the function of distal intestinal, reproductive,
and scar formation. and excretory systems. Proximal gastrointestinal, cardiac, and pul-
Caring for SCI patients is challenging in both acute and chronic monary parasympathetic control is achieved via the vagus nerve.
settings. Understanding the anatomy and physiology of the injury Anatomical considerations define the physiological changes in
is key in providing the anaesthesia and managing systemic compli- the body systems depending on the level of the SCI. Lesions above
cations associated with it. C4 affect the phrenic nerve and result in severe respiratory com-
promise. Cardiac function is dependent on the balance between the
Anatomy
parasympathetic supply from the vagal nerve and postganglionic
The spinal cord carries the motor, sensory, and autonomic informa- sympathetic supply from lower cervical and thoracic paravertebral
tion between brain and systemic organs. The severity of injury and ganglia. Injuries above T7 reduce sympathetic output and disturb
the degree of long-term complications is in direct relationship with this balance. Vascular tone is highly dependent on the sympathetic
the level of injury. system, therefore dehydration, hypoperfusion, and hypothermia
Motor fibres originate in the cortex of the brain and combine into become a constant threat to spinal cord patients. The distal gastro-
the tracts as they descend. The motor tracts travel in the antero- intestinal system is dependent on sacral parasympathetic output
lateral areas of the spinal cord with the nuclei of the lower motor and is affected by injury at any level, making constipation and
neurons located in the anterior horn. Sensory information is car- urinary retention the most common chronic problem (Figure 21.1).
ried along the same peripheral nerves and in the dorsal aspect of
the spinal cord towards the thalamus and sensory cortex of the Classification of Spinal Cord Injury
brain. Respiration in healthy adults is a coordinated function of the SCI is classified into complete and incomplete. American Spinal
diaphragm and intercostal and accessory muscles. The diaphragm Injury Association (ASIA) classifies SCI in five categories (Table
is supplied by the phrenic nerve from nerve roots C3, C4, and C5. 21.1). Where a classification of ASIA A is complete and ASIA E is
256
unstable or on the brink of instability when one of the following

conditions are met: (i) all the anterior or all the posterior elements
are destroyed; (ii) there is >3.5 mm horizontal displacement of one
vertebra in relation to an adjacent one on a lateral x‐ray; or (iii)
there is more than 11° of rotation of one vertebra to an adjacent one
(4). Above the level of C2, examples of unstable injuries include dis-
ruption of the transverse ligament of the axis and a Jefferson burst
fracture of the atlas following axial loading, which causes atlanto-
axial instability. Disruption of the tectorial and alar ligaments and
some occipital condylar fractures also causes atlanto‐occipital
instability.
Rigid collar immobilization in prehospital evaluation is the
standard of care for all patients with potential cervical spine in-
jury. Recently there has been a move away from such practise with
soft or semirigid collars falling into consideration (5). 2013 joint
AANS/CNS guidelines on cervical spine trauma management rec-
ommend rigid spinal immobilization with rapid C-spine clearance
to avoid unnecessary collar immobilization.
During direct or indirect laryngoscopy manual in-line stabiliza-
tion is recommended to oppose the forces on the head and neck
Figure 21.1 Sagittal CT scan (A) and MRI (B) of the spine representing T9 during the airway establishment (5). While the use of cricoid pres-
burst fracture and T8 on T9 listhesis with canal compromise and severe cord sure has not been associated with significant cervical movement in
compression. a cadaver study, it still should be used in moderation in patients
with SCI (6). Similarly, jaw thrust and chin lift manoeuvres should
be used cautiously during mask ventilation (7). Gum elastic bougie,
assigned to intact patients, categories ASIA B, C, and D describe the laryngeal mask airway, and oesophageal-tracheal combitube have
level of incomplete injury based on sensory and motor involvement. been proven to be useful alternatives (8, 9). Endotracheal intub-
ation carries a significant risk of failure in trauma setting and
Anaesthesia Care for Acute Cervical Spine tracheostomy set-up should be readily accessible (10).
Cord Injury There is a variety of techniques available for less urgent peri-
operative intubation. The patient’s comorbidities have to be kept
Airway Management in mind as the pre-existing spine pathology can complicate the
SCI is present in up to 5% of major trauma cases, 14% of which are intubation. Klippel-Feil anomaly, ankylosing spondylitis, previous
unstable injuries (3). It is imperative to minimize cervical move- surgical instrumentation, and rheumatoid arthritis may all limit the
ment during airway management to reduce the risk of further SCI range of cervical motion. Awake intubation has been proven safe in
especially in unconscious patients with brain trauma. cervical trauma patients but may not feasible in uncooperative pa-
The stability of the cervical spine is dependent on ligamentous tients (11). Nasotracheal intubation is generally not recommended
and vertebral elements. Damage to these elements may not be de- due its risk of airway bleeding, limited visibility, and especially in a
tectable by plain x‐rays alone. The adult cervical spine below C2 is setting of basilar skull fractures as may be evident by raccoon eyes
and Battle’s signs. Video-assisted intubation may be a preferred
safe choice. Fibreoptic intubation appears to cause least amount of
Table 21.1. American Spine Injury Association grading of the spinal cervical spine manipulation, although several small-scale studies
injury. imply that videolaryngoscopy may lead to shorter intubation time
while carrying similar risk profile (12, 13, 14). This issue remains
ASIA grade Description controversial and current guidelines allude to the choice of the de-
Grade A Complete lack of motor and sensory function below the level vice to anaesthetist’s experience and training (13).
of injury including the sacral area. Autonomic dysregulation may result in hyperactive response
Grade B Some sensation below the level of the injury (including anal
with airway stimulation, which may result in significant hypoten-
sensation). sion, bradycardia, and cardiac arrest (15). Positive pressure ventila-
tion increases the intrathoracic ventilation and may cause further
Grade C Some muscle movement is spared below the level of injury, but
hypotension since the usual response to increase the venous return
more than 50% of the muscles below the level of injury cannot
is not present.
move against gravity.
In cases where airway management proves to be more difficult or
Grade D More than 50% of the muscles that are spared below the level a rapid intubation is required, complete neuromuscular block is re-
of injury are strong enough to move against gravity. commended (13). Succinylcholine is known to cause hyperkalaemia
Grade E All neurologic function is intact. due to denervation hypersensitivity and should be avoided from
day three for up to nine months in SCI patients. Generally, if the pa-
Reproduced from American Spinal Injury Association: International Standards for
Neurological Classification of Spinal Cord Injury, revised 2011; Atlanta, GA, Revised 2011, tient remains paralyzed, succinylcholine use is avoided altogether
Updated 2015. even in chronic patients. Non-depolarizing agents like rocuronium
257
Chapter 21 spine trauma 257
are a safe alternative as its actions can be readily reversed with been shown to improve early survival in haemorrhagic trauma
an acetylcholinesterase inhibitor such as neostigmine or physo- patients, although its high cost currently precludes it from being
stigmine (16). Sugammadex was recently approved for paralysis widely popular (25).
reversal in Europe in 2009 and the United States in 2015. Its ac- Fluid administration is an inevitable component of any surgery
tions include direct binding and inhibition of rocuronium and it and especially so in traumatic spine injury patients. While permis-
is believed to produce fewer cholinergic side effects compared to sive hypovolaemia is not recommended for SCI patients, fluid over-
stigmine family drugs (13). load becomes a pertinent issue contributing to pulmonary oedema,
congestive heart disorder, and worsening of injured cord oedema.
Blood Pressure Management In view of blood loss and continuous efforts of fluid resuscitation
Damage to the sympathetic outflow to the heart and vasculature the coagulation factors and platelet count become more diluted and
in the setting of SCI contributes to systemic hypotension due to should be closely monitored for the need of specialized transfusion.
unopposed vagal tone, commonly referred as neurogenic shock. Hypotonic solutions, such as 5% dextrose in water and half saline,
Secondary ischaemic injury to the cord should be avoided by are not used in SCI patients due to the risk of worsening cord oe-
maintaining mean arterial pressure (MAP) above 85 mmHg for the dema. Albumin is also contraindicated following the recommenda-
first seven days after injury (17). Injuries above T7 have an 85% tions from SAFE-TBI study (26). Using cardiac output monitoring
risk of serious cardiovascular instability (18). Elevated intracranial devices may allow a more controlled fluid administration reducing
pressure either related to brain injury or ventilation hypercapnia the risks of fluid overload (27).
provides an opposing force in brain and spinal cord perfusion and
should be included in the consideration of blood pressure (BP) Hypothermia
maintenance. Neuroprotective properties of hypothermia have been long recog-
Since the usual sympathetic input may be compromised, the nized. However, lowering the body temperature also has an effect
pharmacological agents for the control of BP should include on its systemic functions. BP control is complicated during hypo-
inotropic, chronotropic, and vasoconstrictive properties. Drugs thermia and the coagulation profile may change in prolonged re-
that are α1-and β1-agonist include dopamine, norepinephrine, duction of body temperature.
and epinephrine, and are usually the first choice in BP manage- Moderate therapeutic hypothermia at 33° C has been shown to
ment. Phenylephrine has minimal effect on β 1 receptors and positively affect the mechanisms that have a potential for redu-
strong α1 response making it useful in peripheral vasodilation cing the secondary damage to the injured cord. Such mechanisms
without the effects on heart contractility. Its downside is that it influence apoptotic cascade, reduce mitochondrial dysfunction,
can cause reflex bradycardia (19). Dobutamine is generally not decrease vascular permeability and capillary leakage, reduce cell
used in SCI patients due to its effect on β2 receptors and vaso- membrane and DNA injury, improve intracellular acidosis, reduce
dilation. Anticholinergic agents may be further considered in pa- metabolic demand, and decrease deleterious pro-inflammatory
tients with sustained bradycardia. In cases of pharmacologically cytokine and free radical release (28).
resistant bradycardia early use of a cardiac pacemaker has been Interest in hypothermia for SCI patients skyrocketed after a
advocated (20). dramatic case where a professional American football player who
sustained a cervical injury was immediately cooled on the playing
Fluid Management field, with subsequent slightly better outcome than usually ex-
Systemic hypotension and blood loss related to initial trauma or pected in such injuries. Soon after, Levi and colleagues demon-
intra-operative haemorrhage present additional challenges in the strated the safety and potential benefits of systemic hypothermia in
maintenance of fluid and electrolyte balance. Spine procedures SCI patients with an intravascular cooling device initiated within
involving transpedicular osteotomy or instrumentation have a an average of nine hours for 48 hours (29). Six out of fourteen ASIA
greater blood loss profile more often requiring blood transfusions A patients showed some form of improvement at one-year follow
(21). Haemoglobin levels below 7–8 g/dl are considered to be the up, which was a significantly higher percentage compared to other
indication for blood transfusion (22). reports at the time (30).
Blood transfusion carries a significant risk in itself (23). The The usual body response to hypothermia involves hypothalamic
adverse reactions include haemolysis due to mismatched blood modulation of adrenergic output. This in response causes blood di-
groups, fever, bacterial, viral, and rare prion infections, graft versus version away from the extremities and hence may increase epidural
host disease, transfusion-related acute lung injury, and the de- venous blood volume and peri-operative blood loss. Depressed
rangements in acid-base and electrolyte profiles. core temperatures induce coagulopathy and decrease platelet func-
Several strategies exist to reduce the intra-operative blood loss. tion, further contributing to blood loss.
Specialized operating tables like the Jackson table are used for op- Adrenergic response in view of hypothermia and lighter sed-
erations in prone position. They are designed to alleviate the pres- ation may result in increased shivering and increased muscle
sure on the abdominal content and vena cava thus reducing the tissue oxygen consumption. Hypothermia creates a left shift on the
pressure in the epidural venous complex. Meticulous use of intra- haemoglobin curve, making it more difficult to release oxygen. This
operative cautery to eliminate the bleeders as soon as they appear puts vital organs, including the spinal cord, at increased risk of an-
and use of the Cell Saver machine to salvage lost blood reduces the oxic injury. Hypoxia may further induce anaerobic metabolism and
need for transfusions. Intra-operative antifibrinolytic agents, such lactic acid build up with transient hypoglycaemia (31).
as aminocaproic and tranexamic acids, have been successfully tried Hypoxia is worsened by reduced bronchial arterial blood
and showed decrease in surgical blood loss with no increased risk flow delaying the uptake of oxygen and release of carbon di-
in thromboembolic events (24). Recombinant factor VII use has oxide. Coronary vasculature resistance increases in hypothermia
258
reducing coronary perfusion. If myocardial demand increases due Surgeons (CNS) medical evidence-based Guideline on acute cer-
to afterload change, the heart is at risk for damage and reduced car- vical spine injury management, the use of steroids is not recom-
diac output. mended. Previous reports from the National Acute Spinal Cord
Renal, hepatic, and pancreatic functions are also reduced in Injury Studies (NASCIS) multicentre, double-blinded, random-
hypothermia. This affects the rate of metabolism of anaesthetic ized trials showed positive effects of steroids. However, recently
agents and may produce longer emergence and recovery periods. these reports have been discredited to level III evidence due to
The complication involved with hypothermia in SCI patients in- lack of appropriate placebo controls and low statistical power.
clude pulmonary atelectasis, pneumonia, deep venous thrombosis Meanwhile, the evidence for the harmful effects of steroids such as
(DVT), and pulmonary embolus (29, 32). Other reported compli- wound infection, hyperglycaemia, GI haemorrhage, and possible
cations associated with hypothermia applied for non-SCI reasons involvement in sepsis, pneumonia, and death due to respiratory
include increased risk of morbid myocardial outcomes, surgical failure remained strong, making steroids contraindicated in SCI
wound infection, increased blood loss, and prolonged recovery in patients (17).
hospitalization (33). Nonetheless, many experts believe the benefit
of hypothermic neuroprotection outweighs these risks in the set- Anaesthesia Care for Chronic Spinal
ting of SCI (34). To date, there have been no high-quality random-
ized control trials to test the efficacy of hypothermia in SCI patients Cord Injury
and the latest guidelines on management of SCI patients do not Advancements in understanding and management of patients
include any recommendations for its use. with SCI resulted in a dramatic increase in the number of older
people living with SCI. Affected patients survive longer and chronic
Monitoring medical conditions become apparent, and there has also been an
Multimodal intra-operative monitoring is an essential compo- increase in the need for elective surgeries and obstetric services.
nent of modern spine surgery. It provides continues surveil- Understanding the pathophysiology of such patients is important
lance of motor and sensory evoked potentials and spontaneous in peri-operative assessment and anaesthesia management. Hambly
electromyography (EMG). and Martin deserve credit for putting together a comprehensive re-
Motor evoked potentials (MEP) are elicited by stimulation of view on the topic that laid a solid ground for many subsequent re-
the motor cortex with scalp electrodes and output measured at views and will form the base for the remainder of the chapter (16).
each muscle group. Somatosensory evoked potentials (SSEP) are
obtained by peripheral dermatomal stimulation and recorded over Autonomic Dysreflexia
the sensory cortex on the scalp. Baseline readings are obtained be- The healing process after the cord injury results in aberrant con-
fore surgery commences and are compared to intermittent intra- nections between ascending and descending fibres of sympathetic
operative stimulations for changes in latency and amplitude of pathways. With the lack of inhibitory descending signals from
the response. SSEPs can be continuously monitored, but MEPs higher centres this results in diffuse inappropriate sympathetic re-
require the surgeon to pause as the motor stimulation may pro- sponse from an unrelated stimulus and usually leads to profound
duce a muscle jerk that shifts the patient. When the neuronal signal vasoconstriction. Such response is termed autonomic dysreflexia
pathway is disrupted the latency of the response increases and the and can lead to hypertensive crisis and subsequent intracranial or
amplitude falls. retinal haemorrhage, seizures, myocardial ischaemia, pulmonary
EMG activity is continuously recorded by placing electrodes into oedema, and death (37).
the appropriate muscle. Intra-operatively increase in activity indi- Common features of autonomic dysreflexia included headache,
cates that the nerve supplying it is being irritated, and alerts the sweating, flushing above the level of injury, and reflex bradycardia.
surgeon to make necessary adjustments. Some patients may present with pupillary changes, Horner’s syn-
Monitoring is useful in early detection of potential damage to the drome, nausea, anxiety, and penile erection. The incidence is higher
nerves during surgery, allowing for appropriate adjustments. Other in patients with the lesion above T7 vertebral level. Response is be-
factors that may affect the electrical activity and quality of the lieved to be via the adrenergic pathways and while the total circu-
monitoring modality, include patient position, hypotension, degree lating adrenaline levels are lower in the SCI patients it appears that
of anaesthesia, presence of paralytic agents, and hypothermia. the sensitivity to catecholamines is increased.
Volatile agents and nitrous oxide reduce the amplitude of MEPs A range of stimuli, usually below the level of injury, can trigger
even at low concentrations and should be avoided. Any form of the response. Bladder distension is the most common culprit, fol-
muscle relaxation is also not desirable if motor potentials are moni- lowed by bowel distention, uterine contraction, acute abdominal
tored, making intravenous anaesthesia with propofol preferable pathology, urinary tract infection (UTI), and even anal fissure. Less
in monitored surgical cases (35). Dexmedetomidine can be used prevalent but significant stimuli also include ingrown toenails, de-
intravenously to reduce propofol infusion. Dexmedetomidine, cubitus pressure ulcers, and sunburn. Removal of the triggering
opioids, and ketamine have no effect on MEP activity (36). If only stimulus is usually sufficient in controlling the BP hike from auto-
SSEPs and EMGs are monitored, the volatiles can be used in some nomic dysregulation. Upright position may further help with BP
cases, but should not exceed 1 MAC. management.
The attacks tend to be short lasting and if pharmacological agents
Steroids are used they should have a property of rapid onset and short dur-
Currently, according to the 2013 Joint Section on Disorders of ation. The Consortium for Spinal Cord Medicine recommends use
the Spine and Peripheral Nerves of the American Association of of antihypertensive pharmacologic agents if, after attempted con-
Neurological Surgeons (AANS) and the Congress of Neurological servative measures involving upright posture, loosened clothes, and
259
reduced irritation to the bladder and bowel, the BP remains above Three to four months after the injury spinal shock subsides, spas-
150 mmHg in an adult, 140 mmHg in an adolescent, 130 mmHg in ticity develops below the level of injury. Just like smooth muscles of
a child 6–12 years old, or 120 mmHg in a child under five years old the vasculature react in autonomic dysreflexia, the skeletal muscles
(38). Many drugs have been proposed for the management of acute can have a severe spastic response to the slightest stimuli. Spasms
dysreflexia with no definitive guidelines to date (39). can cause injury to the extremities and over a period of time so can
Nifedipine is a calcium-channel blocker that has a negative ino- contractures in the digits and limbs. However, some degree of spas-
tropic effect as well as causes peripheral vascular relaxation. It is ticity is beneficial as well. Spastic muscle contractions stimulate cir-
given as a 10mg dose in a sublingual or bite and swallow fashion. culation and venous return, maintain bone health, prevent muscle
While nifedipine is known to be highly effective at BP control in wasting, and can be beneficial in daily activities, like bed trans-
acute episodes of autonomic dysreflexia, the report on its use in fers. Medical management includes oral or intrathecal baclofen, a
hypertensive emergencies not specific to SCI has identified ser- gamma-amino butyric acid (GABA) agonist. Incomplete injuries
ious adverse effects, including stroke, myocardial infarction, severe result in asymmetric muscle recruitment and can lead to scoliosis
hypotension, and death, and therefore its use has been cautioned requiring corrective surgery.
and even discouraged (40). Bone density significantly falls after the sixteen month after
Nitroglycerine and other nitrates acts to relax vascular smooth injury. Resorption is greatest in the pelvis, making it prone
muscle of peripheral arteries and veins. Venous dilation promotes to fractures. Large joints start to deposit bone, forming para-
peripheral pooling and reduces venous return, while arterial re- articular heterotopic ossification that limits range of motion
laxation directly reduces pressure. Use of other vasodilators, like and may present as a warm painful swelling over the joint. It is
sildenafil, should be considered in SCI patients. If sildenafil is taken treated with passive physiotherapy, etidronate, and occasionally
within 24 hours nitrates should not be administered. According to surgery.
clinical consensus nitrates are safe in use for acute BP management High SCI disrupts hypothalamic pathways controlling body
of autonomic dysregulation. temperature. The patient becomes poikilothermic with the body
Adrenergic α-1 blocking agents like terazosin, prazosin, and temperatures reflecting the environment. Hyperthermia may con-
phenoxybenzamine counteract arterial vasoconstrictive response. tribute to dehydration and unintended hypothermia is a constant
Their regular use has been deemed appropriate as a prophy- threat presenting with delirium or depressed consciousness.
lactic management of autonomic dysreflexia. Alpha-1 inhib- Skin is also affected in patients with SCI. It becomes atrophic
ition also facilitates urinary sphincter contraction and alleviates and hyperaesthetic with reduced blood flow. Decubitus ulcers are
incontinence. common due to lack of sensation at pressure points, decreased
Captopril was shown to effectively reduce the BP in 80% of acute padding from atrophied underlying muscle, and altered blood
autonomic dysreflexia episodes in a small pilot study of 26 patients supply. Ulcers are often complicated with infection and can lead
(41). It is a competitive inhibitor of angiotensin I-converting en- to osteomyelitis, septicaemia, amyloidosis, and can also trigger
zyme (ACE) with no reports of hypotensive complications, making spasms and autonomic dysreflexia.
it a more favourable first-choice option according to some experts. Risk of DVT is elevated in the first eight to twelve weeks after
Other drugs that have been tested in autonomic dysreflexia in- injury with documented incidence greater than 50% and incidence
clude prostaglandins, phenozopyridine, magnesium sulphate, of fatal pulmonary embolism as high as 5% (42). Early prophylaxis
diazoxide, beta-blockers, mecamylamine, and hydralazine, with is highly recommended. Mechanical prophylaxis is generally in-
little evidence to support their use. Sildenafil has not been con- sufficient and different pharmacologic agents are used including
firmed to be effective. coumadin, unfractionated heparin, and low molecular weight
heparin like enoxaparin and dalteparin. Level 1 data suggests that
Physiological Changes in Chronic SCI Patients enoxaparin is more effective than standard subcutaneous heparin
Multiple cardiovascular changes occur in chronic SCI patients. at reducing venous thromboembolic events with seemingly less
Changes in the autonomic nervous system lead to continuous fall risk of bleeding complication (43). In the event of heparin-induced
in BP during Valsalva manoeuvre with no tendency to plateau. thrombocytopenia, an alternative agent like danaparoid sodium
Venous return is impaired and blood pools in lower limbs. Reduced can be used.
renal perfusion results in higher levels of renin, angiotensin II, and Novel therapeutic anticoagulants include the oral form of direct
aldosterone, leading to salt and water retention. thrombin inhibitor, dabigatran, and direct factor Xa inhibitor,
Respiratory reserve is decreased due to malfunction of affected rivaroxaban. The oral form is much more appealing than injections
respiratory muscles. Depending on the level of injury a combin- and the drugs have been successfully used in the prevention of
ation of the four respiratory muscle groups can be affected: dia- stroke in patients with atrial fibrillation and DVT in patients after
phragm, intercostals, abdominal wall, and accessory muscles. hip or knee replacement surgery (44). There is no antidote to the
Injuries above C4 are nearly incompatible with life without arti- new oral anticoagulants and no current studies evaluating their use
ficial ventilation. Lesions of the lower cervical spine eliminate in chronic SCI patients exist.
intercostal involvement and over time accessory muscles may con- Renal failure used to be the leading cause of death in SCI patients
tribute up to 90% of ventilation. Lung volume initially may be as (45). Cord injury results in detrusor-sphincter dyssynergia, where
low as 30% of normal but then doubles in six months. Expiratory bladder and the sphincter both contract at the same time leading
reserve volume is close to absent due to loss of active expiration. to incomplete voiding, high intravesical pressure, and vesico-
Paralysis of abdominal muscles also impairs coughing ability, to ureteric reflux. Patients rely on self-catheterization and are pre-
which tetraplegic patients adapt by contracting clavicular portion disposed to UTI and urinary stone formation. Renal amyloidosis
of pectoralis major muscle. used to be common and was related to chronic osteomyelitis and
260
decubitus ulcers. Postural effects on BP can stimulate the release anaesthetist of a possible increased sensitivity to anaesthetics and
of atrial natriuretic peptide and nocturnal diuresis causing severe prepare for abrupt hypotension. Delayed emergence from anaes-
hyponatraemia in some patients. thesia related to the use of an intrathecal baclofen pump has also
Gastric emptying is delayed in SCI patients. It can take up to five been reported (48). However, it is still not recommended to dis-
times longer than usual and caution needs to be applied with the continue baclofen infusion acutely before the operation due to the
use of oral fluids and medications. Length of nothing-by-mouth risk of rebound spasticity. Hyperexcitability-related intra-operative
status may need to be adjusted in pre-operative planning (16). events, like spasms, autonomic dysreflexia, or penile erections, can
be managed by deepening the anaesthesia.
Obstetrics
It is estimated that SCI from all causes affect 52,000 women in the
United States, with approximately 2,400 new cases occurring each
Conclusion
year (45). Following an SCI, women’s menstrual cycle is interrupted Advances in medical care have resulted in prolonged survival of
for 6–18 months. Eventually it returns and fertility normalizes (46). men and women with SCI of various degrees. These patients live on
UTIs are common and may precipitate premature labour in preg- to develop chronic medical conditions, require elective surgeries,
nant patients. The risk of anaemia, pressure sores, and thrombo- and reproduce. In providing the anaesthesia, special consideration
embolic events is also increased during pregnancy. for the changes in the pathophysiology of these patients needs to
During labour, women with lesions between T5 and T10 may feel be taken in to account. Acute and chronic recovery of SCI may be
the contractions and below T10 level will experience pain. Uterine complicated by such specific events as spinal shock, autonomic
contractions can trigger autonomic dysreflexia and hypertensive dysreflexia, spasticity, and temporal systemic changes.
episodes, for which epidural analgesia is the most common pre-
ventive measure. Epidural catheter may remain for up to two days Cases and Multiple-Choice questions
after delivery to prevent post-partum autonomic dysreflexia. The
headache and hypertension of pre-eclampsia may be mistaken for
autonomic dysreflexia and require a separate evaluation. If epi-
www.oxfordmedicine.com/otneuroanesthesiology.
dural analgesia fails to control BP, medications like nifedipine,
hydralazine, or verapamil are considered safe and carry no adverse
effects on the uterus, while nitroprusside is relatively contraindi- References
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26
263
CHAPTER 22
Paediatric Neuroanaesthesia
Sulpicio G. Soriano and Craig D. McClain
Introduction and Background idealized autoregulatory range of blood pressure in an infant is

lower than an adult, reflecting the relatively low cerebral metabolic
The anaesthetic management of infants and children undergoing requirements and blood pressure during infancy, recent evidence
neurosurgical procedures should be based on the developmental demonstrates heterogeneity of the lower limits of autoregulation in
stage of the patient. The evolving maturational changes of the paediatric patients (6). Although cerebral autoregulation is intact
various organ systems have a significant impact of the drugs and in healthy full-term neonates (4), it may be absent in critically ill
techniques used for the safe conduct of anaesthesia. Subspecialty premature neonates (7). Cerebral blood flow pressure-passivity is
training in paediatric neurosurgery has driven advances in intra- common in premature neonates with low gestational age and birth
cranial surgery in infants and children, prompting calls for simi- weight and systemic hypotension. Systolic arterial blood pressure
larly trained anaesthetists and intensivists for the management of is a poor indicator of cerebral perfusion pressure in these patients,
these infants and children (1). Age-dependent differences in cra- while the diastolic closing pressure may be a better surrogate of
nial bone development, cerebrovascular physiology, and neuro- cerebral perfusion in this population (8). Extremes in blood pres-
logic lesions distinguish neonates, infants, and children from their sure can lead to cerebral ischaemia and intraventricular haem-
adult counterparts. In particular, the central nervous system (CNS) orrhage and dictates rigorous control of haemodynamics in this
undergoes a tremendous amount of structural and physiological vulnerable population.
change during the first two years of life. The goal of this chapter is Children have high cerebral metabolic requirement for oxygen
to highlight these age-dependent differences and their effect on the and glucose (CMRO2 and CMRGlu) relative to adult values
anaesthetic management of the paediatric neurosurgical patient. (CMRO2 5.8 vs. 3.5 mL/100g/m and CMRGlu 6.8 vs. 5.5mL/100g/
m, respectively) (9). At birth, CMRGlu is approximately 13–25
Developmental Aspects μmol/100g/min and rises to 49–65 μmol/100g/min at three to four
years. It remains at this rate until nine years and subsequently settles
The genesis of the CNS takes place early in gestation and is orches- at 19–33 μmol/100g/m) (10). These ontological changes in CRMO2
trated by a combination transcriptional and mechanical factors (2). and CMRGlu are reflected in CBF values derived from brain per-
A basic understanding of normal and abnormal development of the fusion computerized tomography scans (5). Cerebrovascular re-
CNS is essential for understanding the pathology of congenital le- activity to carbon dioxide appears to be normal in newborns, but
sions of the CNS (3). may be deranged in setting of perinatal asphyxia (11). Fraction of
The primitive CNS is derived from the neural plate, which folds inspired oxygen (FIO2) has an impact on CBF. Decreasing FIO2
and fuses dorsally. Primary neurulation occurs when the neural from 1.0 to 0.21 decreases CBF by 33% (12). Premature neonates
plate folds to form the neural tube. The walls of neural tube give are also vulnerable to the detrimental effects of high FIO2 due to
rise to the brain and spinal cord, while the canal develops into the liberation of reactive oxygen species leading to bronchopulmonary
ventricles and central canal of the brain and spinal cord, respect- dysplasia and retinopathy of prematurity (13).
ively. Fusion of the cranial neural folds and closure of the cranial Neonates and infant initially have compliant intracranial space
neuropore give rise to the forebrain, midbrain, and hindbrain. due to open fontanelles, which close from four months to one year.
Failure of the anterior neuropore to close by 24 days results in Therefore, gradual increases in intracranial mass due to a tumour,
anencephaly. Secondary neurulation ensues when the neuroepi- chronic hydrocephalus, and haemorrhage are undetectable due to
thelium caudal to the posterior neuropore closes. Derangements compensatory distension of the fontanelles and widening of the
in this progression can lead to spinal dysraphism (spinal bifida, cranial sutures. However, given the diminutive neonate and infant
myelomeningocele, and tethered cord). intracranial volume, acute increases in cranial content due to blood
After birth, the CNS is essentially fully developed with some or cerebrospinal fluid often result in life-threatening intracranial
fine tuning that occurs between the neonatal and toddler period hypertension (14).
(4). Cerebral blood flow (CBF) varies with the age of the patient,
which peaks between two and four years and settles to adult
levels at seven to eight years (5). Prematurity, traumatic brain in- Pre-Operative Assessment and Planning
jury, neurovascular anomalies, hypoxic brain injuries, intracranial Neonates and infants have the highest risk for perioperative re-
haemorrhage, inflammatory processes, and congenital heart de- spiratory and cardiovascular morbidity and mortality than any age
fects have an impact on cerebral haemodynamics. Although the group (15). Since the systemic effects of general anaesthesia and the
264
physiological stress of surgery impact this vulnerable group, a thor- Pre-operative fasting guidelines have evolved and are frequently
ough review of the patient’s history can reveal conditions that may dictated by regional practices (16). The most commonly utilized
increase the risk of adverse reactions and identify patients who re- guideline is fasting from solids for eight hours, breast milk for four
quire more extensive evaluation or whose medical condition needs hours, and clear liquids for two hours. The purpose of limiting oral
to be optimized before surgery. If a cardiac defect is suspected (loud intake is to minimize the risk of aspiration of gastric contents during
cardiac murmur, low room air oxygen saturation, cyanosis, or re- induction of anaesthesia. However, prolonged fasting periods and
spiratory distress) it is necessary to obtain an echocardiogram and vomiting may induce hypovolaemia and hypoglycaemia, which
an assessment by a paediatric cardiologist in order to optimize car- can exacerbate haemodynamic and metabolic instability under
diac function prior to surgery. There are also specific peri-opera- anaesthesia.
tive concerns for paediatric patients (Table 22.1). Congestive heart
failure can occur in neonates with large cerebrovascular malforma- Intra-Operative Management
tions and requires aggressive haemodynamic support. Right to left
shunting can occur through a patent ductus arteriosus or foramen Induction of Anaesthesia
ovale. Management of the neonatal respiratory system may be dif- A smooth transition into the operating suite depends on the level
ficult because of the diminutive size of the airway, neonatal pul- of anxiety and the cognitive development and age of the child (17).
monary physiology, craniofacial anomalies, laryngotracheal lesions, Children between the ages of 9 months and six years may have sep-
and acute (hyaline membrane disease, retained amniotic fluid) or aration anxiety. Midazolam, administered orally or intravenously,
chronic (bronchopulmonary dysplasia) pulmonary disease. Since is effective in relieving anxiety and producing amnesia. Parental
these conditions are in a state of flux, they should be addressed involvement during induction of anaesthesia is common in paedi-
preoperatively in order to minimize perioperative morbidity. atric operating rooms and requires full engagement of the surgical
team. Obtunded and lethargic patients do not require premedica-
tion with sedatives and should have an anaesthetic induction per-
formed in an expeditious manner.
The patient’s comorbidities and neurologic status should dictate
Table 22.1 Coexisting conditions that impact anaesthetic induction of anaesthesia. If the patient does not have intravenous
management. access, anaesthesia can be induced with sevoflurane and oxygen by
mask followed by an immediate placement of an intravenous access.
Condition Anesthetic Implications If this is not possible, an intraosseous access should be considered.
Congenital heart disease Hypoxia In patients with intravenous access, anaesthesia can be induced
arrhythmias, with propofol. It should be noted that significant hypotension and
cardiovascular instability, possible cerebral ischaemia may occur after an induction dose of
paradoxical air emboli.
propofol (18), due to the lack of surgical stimulation or in the setting
of hypovolaemia. This can be minimized by reducing the dosage of
Prematurity Postoperative apnoea. anaesthesia and the use of a volume bolus or vasoconstrictors.
Gastrointestinal reflux Aspiration pneumonia. Intracranial hypertension may be exacerbated due to hypercapnia
Upper respiratory tract Laryngospasm, bronchospasm,
if the airway becomes obstructed during induction. Maintenance
of a patent airway with mild hyperventilation will alleviate this
infection hypoxia, pneumonia.
problem.
Craniofacial abnormality Difficult tracheal intubation. Some patients presenting for neurosurgical procedures may
Denervation injuries Hyperkalaemia after succinylcholine, be at higher risk for aspiration of gastric contents. Aspiration in
resistance to non-depolarizing muscle infants is very rare, while the occurrence of hypoxemia is quite
relaxants, common. Therefore, it is recommended to ventilate children after
abnormal response to nerve stimulation. a non-depolarizing relaxant has been given with a maximal pres-
sure of 1–12 cm/H2O instead of a rapid-sequence induction with
Epilepsy Hepatic and haematological abnormalities,
succinylcholine. If it is necessary to give succinylcholine, its contra-
increased metabolism of anaesthetic indications, malignant hyperthermia susceptibility, muscular dys-
agents,
trophies, and recent denervation injuries, should be considered.
ketogenic diet.
Arteriovenous malformation Congestive heart failure. Vascular Access and Positioning
Neuromuscular disease Malignant hyperthermia, Given the diminutive size of paediatric patients in relation to
respiratory failure, equipment used during neurosurgical procedures (table, micro-
scopes, navigational systems, and intra-operative imaging detects),
Sudden cardiac death.
limited access to the patient during neurosurgical procedures re-
Chiari malformation Apnoea, quires secure intravenous access prior to the start of surgery. Large
aspiration pneumonia. peripheral venous cannulae are sufficient for most craniotomies.
Hypothalamic/pituitary Diabetes insipidus, Should initial attempts fail, central venous cannulation may be ne-
lesions hypothyroidism, cessary. Femoral vein catheterization avoids the risk of pneumo-
adrenal insufficiency.
thorax and does not interfere with cerebral venous drainage.
Furthermore, femoral catheters are easily accessible. The routine
265
Chapter 22 paediatric neurosurgery 265
use of central venous catheters was not effective in reducing hypo- Maintenance of Anaesthesia
tension in craniofacial surgeries in paediatric patients (19). Given Given the possibility of iatrogenic cerebral hypoperfusion during
the small calibre of infant cerebral venous catheters, its use as a con- surgery (25), judicious dosing of anaesthetic drugs is obligatory.
duit for aspiration of venous air emboli (VAE) is questionable (20). Immature neonatal organ systems are highly sensitive to anaes-
Cannulation of the radial artery provides direct blood pressure thetic agents. Neonatal myocardial function is particularly sus-
monitoring and sampling for blood gas analysis. The dorsalis pedis ceptible to the depressant effects of both inhaled and intravenous
and posterior tibial artery are more accessible should attempts at anaesthetics, and these agents need to be administered judiciously
radial artery cannulation fail. to any block surgical stress response without causing myocardial
Patient positioning requires careful preoperative planning to depression. As mentioned previously, appropriate management
allow adequate access to the patient for both the neurosurgeon and of intraoperative blood pressure is hampered by the assumptions
anaesthetist. Children have relatively thin skulls and are at risk for on a range of blood pressures that maintain adequate cerebral
depressed skull fractures and perforation of underlying blood ves- blood flow and cerebral autoregulation in paediatric patients (26).
sels with cranial fixation devices (21, 22). Should a depressed skull This hypothetical range of blood pressure is simplified and not
fracture or intracranial haemorrhage be suspected, urgent imaging necessarily supported by the original reports (27). This requires
with CT or MRI scanning can detect the extent and location of the vigilant monitoring of the blood pressure and adjusting the an-
injury and prompt immediate evacuation of the haematoma (23). aesthetic dosing, fluid administration, and vasopressor support
Modifications of these standard fixation devices and headrests if needed. Since the exclusive use of specific anaesthetic drugs
should be utilized to minimize this preventable and potentially le- and technique has no impact on outcome (28), an opioid (i.e.,
thal complication (24). fentanyl, sufentanil, or remifentanil) combined with low-dose
Surgical positioning affects the physiologic status of the patient isoflurane or sevoflurane are frequency utilized in these patients.
(Table 22.2). The prone position can increase intra-abdominal Dexmedetomidine can be used as an adjunct and does not sig-
pressure and lead to impaired ventilation, venocaval compres- nificantly affect most intraoperative neurophysiologic moni-
sion, and bleeding due to increased epidural venous pressure. Soft toring and reduces opioid requirements (29). Patients on chronic
rolls are generally used to elevate and support the lateral chest wall anticonvulsant therapy usually require a larger dose of neuro-
and hips in order to minimize abdominal and thoracic pressure. muscular blocking agents and opioids because of induced enzym-
Neurosurgical procedures are performed with the head slightly ele- atic metabolism of these agents (30). The use of neuromuscular
vated, which facilitates venous and CSF drainage from the surgical blocking agents should be discussed with the surgical and moni-
site. However, this increases the likelihood of VAE. Significant ro- toring teams if assessment of motor function during seizure and
tation of the head can also impede venous return via compression spinal cord surgery is planned. Infants and children are especially
of the jugular veins and can lead to impaired cerebral perfusion, in- susceptible to hypothermia during any surgical procedure be-
creased ICP, and venous bleeding. Vigilant assessment of the airway cause of their large surface area-to-weight ratio. Active heating of
is critical in prone patients throughout the case because of the pro- the patient by increasing ambient temperature and use of radiant
pensity for the tongue to slide out of the mouth and kinking of the light warmers during induction of anaesthesia, catheter insertion,
endotracheal tube. Nasotracheal intubation and placement of an and preparation and positioning of the patient are prophylactic
oral bite/tongue may prevent these complications. Obese patients measures against hypothermia. Forced hot air blankets, mattress,
may be difficult to ventilate in the prone position and may benefit and intravenous fluid warmers can also prevent intraoperative
from the sitting position. In addition to the physiological sequelae temperature loss and postoperative shivering
of the sitting position, a whole spectrum of neurovascular compres-
sion and stretch injuries can occur.
Management of Fluids and Blood Loss
Haemodynamic stability during intracranial surgery requires
careful maintenance of the patient’s fluids and electrolytes to pre-
Table 22.2 Physiologic effects of patient positioning serve neurological function. Since the lower limit of cerebral
autoregulation for paediatric patients is unknown, they are at
Position Physiological Effect
risk for cerebral hypoperfusion especially when they are deeply
anaesthetized during periods of massive blood loss (26, 31, 32).
Head up/sitting Increased cerebral venous drainage, Meticulous fluid and blood administration is essential in order to
decreased cerebral blood flow, minimize haemodynamic instability, especially in the paediatric
increased venous pooling in lower extremities, patient. Stroke volume is relatively fixed in the neonate and in-
postural hypotension. fant, so the patient should be kept euvolaemic. Balanced electro-
lyte solutions or normal saline are generally chosen because they
Head down Increased cerebral venous and intracranial pressure,
are mildly hyperosmolar and should minimize cerebral oedema.
decreased functional residual capacity (lung function),
However, rapid infusion of more than 60 ml/kg of normal saline
decreased lung compliance. may cause hyperchloremic acidosis (33). The routine administra-
Prone Venous congestion of face, tongue, and neck, tion of glucose-containing solutions is generally avoided during
decreased lung compliance, neurosurgical procedures except to patients who are at risk for
venocaval compression. hypoglycaemia, such as premature and term neonates and in-
fants on supplemental glucose or total parenteral nutrition infu-
Lateral decubitus Decreased compliance of downside lung.
sions. Patients with diabetes mellitus, total parental alimentation,
26
and premature and small new-born infants may require glucose- closure. Tracheal intubation of a neonate with a myelomeningocele
containing intravenous fluids. or encephalocele can be challenging depending on the size and lo-
Maintaining euvolaemia is crucial during craniotomies in in- cation of the defect. The supine patient may be elevated on rolled-
fants and children by preserving the circulating blood volume with up towels in order to minimize direct pressure on the lesion. Blood
intravenous fluids and blood products. Premature neonates have and fluid loss depends upon the size of the lesion and the amount
a circulating blood volume of approximately 100 ml/kg total body of tissue dissection required to repair the defect. In some cases,
weight; full-term newborns have a volume of 90 ml/kg; infants have the neural tissue may need to be identified during exploration of
a blood volume of 80 ml/kg. Maximal allowable blood loss (MABL) the defect and an electromyography (EMG) requires discontinu-
can be estimated using a simple formula: MABL = Estimated cir- ation of neuromuscular blockade. It should be noted that this le-
culating blood volume * (starting hematocrit-minimum acceptable sion has been associated with disordered breathing and apnoea and
hematocrit)/starting hematocrit. obliges careful respiratory monitoring during the postoperative
Transfusion of 10 ml/kg of packed red blood cells increases period (37).
haemoglobin concentration by 2 g/dl. Paediatric patients are suscep- A recent multicentre randomized trial demonstrated effi-
tible to dilutional thrombocytopenia in the setting of massive blood cacy in reduction of shunt placement for hydrocephalus in
loss and multiple red blood cell transfusions (34). Administration myelomeningocele closures during the prenatal period (38). This
of 5–10 ml/kg of platelets increases the platelet count by 50,000 to procedure requires specialized techniques in foetal surgery and
100,000/mm3. The routine use of the antifibrinolytic tranexemic anaesthesia (39).
acid in surgical procedures with excessive blood loss such as pos-
terior spine fusions, cardiac surgery, and craniofacial reconstructive Tethered Cord
procedures has been shown to decrease blood loss in paediatric Malformations of the spinal result from abnormal development of
patients (35). the spinal cord. These include myelomeningocele, tight filum ter-
Haemodynamic collapse due to massive blood loss or VAE looms minal, lipomeningocele, and split cord. The underlying functional
as a catastrophic complication for any major craniotomy. Large- pathology with these lesions is nerve impingement leading to in-
bore intravenous access and arterial blood pressure monitoring are continence (urinary and faecal), lower extremity weakness, and
therefore essential for these procedures. Massive blood loss should pain. Surgical management is directed at identification and release
be aggressively treated with crystalloid and blood replacement and of the affected nerve roots. This is complicated by the homoge-
vasopressor therapy (e.g., dopamine, epinephrine, norepinephrine). neous appearance of the surrounding tissue and neural elements.
VAE commonly occurs during the surgery. Maintaining euvolaemia Since these surgeries are performed in the prone position, they
minimizes this risk. Early detection of a VAE with continuous pre- require careful padding of vulnerable pressure points (eyes, ears,
cordial Doppler ultrasound may allow treatment to be instituted and ulnar and peroneal nerves). These surgical procedures are as-
before large amounts of air are entrained. Should a VAE produce sociated with minimal blood loss, with spinal cord haemangiomas
haemodynamic instability, the operating table must be placed in as an exception. Functional nerve roots may be difficult to dissect
the Trendelenburg position in order to improve cerebral perfu- from the surrounding tissue and may result in an inadvertent in-
sion and prevent further entrainment of intravascular air. Special jury during the surgical dissection. Therefore, nerve root surgery
risks exist in neonates and young infants, since right-to-left cardiac requires EMG with detection of corresponding muscle movement
mixing lesions can result in paradoxical emboli. In the case of se- as an end-point. EMG of the anal sphincter and muscles of the
vere cardiovascular collapse, some paediatric centres have rapid re- lower extremities identifies and minimizes inadvertent injury to
sponse extracorporeal membrane oxygenation (ECMO) teams that nerves innervating these muscle groups. Therefore, muscle relax-
can provide cardiopulmonary support when the crisis is refractory ation should be avoided or discontinued after tracheal intubation
to standard cardiopulmonary resuscitation algorithms (36). to facilitate monitoring.
Hydrocephalus
Anaesthetic Management of Specific Hydrocephalus is the most common affliction of paediatric neuro-
Neurosurgical Procedures: Congenital surgical patients (40). It has been defined as, ‘an active distension of
Disorders the ventricular system of the brain related to inadequate passage of
CSF from its point of production within the ventricular system to
Myelomeningocele/Encephalocele its point of absorption into the systemic circulation’ (41). This can
Neonatal neurosurgery is commonly performed on an emergent be due primarily to build-up of CSF within the ventricular system
basis in order to minimize the impact of the congenital lesion. of the CNS by congenital lesions, tumours, or extrinsic factors.
This is especially relevant for newborns with a myelomeningocele Communicating hydrocephalus occurs when the blockage of CSF
or encephalocele, where rupture of the lesion’s membrane can flow is downstream of the ventricles, while non-communicating
lead to system infections and insensible fluid losses. Since the ur- hydrocephalus occurs when the flow of CSF is blocked along one
gent nature of these neurosurgical procedures may hasten the of the passages connecting the ventricles. Pathological increases
preoperative evaluation of the patient, a thorough neonatal and in CSF production or decreases in reabsorption are less common
cardiovascular evaluation is essential to minimize intraoperative causes of hydrocephalus. The common symptoms of hydrocephalus
morbidity. Newborns with myelomeningoceles have a propensity include a rapid increase in head circumference, irritability, sleepi-
to develop hydrocephalus due to abnormal development of the pos- ness, nausea and vomiting, and downward deviation of the eyes.
terior fossa. Severe cases of hydrocephalus may require placement Acute obstruction of a ventricular shunt requires urgent treatment
of a ventricular peritoneal shunt (VPS) after the myelomeningocele because an acute increase in intracranial pressure in the relatively
267
small cranial vault of the infant and child can have devastating Choroid plexus tumours or papillomas are extremely vascular and
consequences. are associated with massive blood loss and transfusions (50).
The anaesthetic management of these patients depends on the Craniopharyngiomas may be associated with hypothalamic and
acuity of the patient’s symptoms. In a patient with an intact mental pituitary dysfunction. Steroid replacement therapy with either
status or one in whom intravenous access cannot be established, an dexamethasone or hydrocortisone may be required because the
inhalation induction with sevoflurane and gentle cricoid pressure integrity of the hypothalamic-pituitary-adrenal axis may be un-
may be used. If the patient is obtunded, is at risk for herniation, or certain. Perioperative diabetes insipidus (DI) can lead to electro-
has a full stomach, intravenous or intraosseous access should be lyte and haemodynamic derangements. Laboratory studies should
established in order to perform an intravenous/intraosseous induc- therefore include serum electrolytes and osmolality, urine-specific
tion followed by tracheal intubation (42). VAE may occur during gravity, and urine output. DI is marked by a sudden polyuria (>4
placement of the distal end of a ventriculo-atrial shunt if the opera- mL/kg/hr), hypernatraemia, and hyperosmolarity. Initial manage-
tive site is above the heart. ment consists of infusion of aqueous vasopressin (1–10 mU/kg/
Premature neonates are likely candidates for hydrocephalus sec- hr) and judicious fluid administration that matches urine output
ondary to intraventricular haemorrhages (43, 44). The severity of and estimated insensible losses (51). There are several operative
posthaemorrhagic hydrocephalus is assessed by serial head ultra- approaches to craniopharyngiomas in children. Subfrontal crani-
sounds. Accumulated CSF can be temporarily drained by place- otomies are common in infants and smaller children because of
ment of a ventricular reservoir or ventriculosubgaleal shunt. difficulties with diminutive anatomy and limitations of endoscopic
Diversion of CSF is the permanent treatment for hydrocephalus. equipment. This approach increases the risk of VAE due to the bony
However, placement of a ventriculoperitoneal shunt is limited by sinuses and venous sinuses. Standard transnasal approaches are
the size and increased risk of shunt failure. Recent advancements commonly used for older children. Postoperative derangements in
in endoscopic techniques are being utilized to perform endoscopic sodium and fluid homeostasis should prompt serial measurements
third ventriculostomies (ETV) with the option of cauterization of of serum sodium to guide fluid therapy.
the choroid plexus in premature neonates (45, 46).
Epilepsy
Neoplasms: Posterior Fossa Tumours Epilepsy surgery in children has become a viable approach to the
Posterior fossa tumours may impinge upon brain stem structures treatment of medically intractable seizures. Given the wide spec-
vital to the control of respiration, heart rate, and blood pressure, trum of medical conditions that cause epilepsy, a thorough evalu-
complicating the intra-operative management of these patients. ation is needed to identify processes that have an impact on the
The mass effect of the tumour may obstruct CSF flow and cause conduct of anaesthesia (Table 22.3). These pose several anaesthetic
hydrocephalus with intracranial hypertension. Placement of an ex- management issues (52). A subpopulation of epilepsy patients
ternal ventricular drain (EVD), VPS, or ETV has been proposed to will be on a ketogenic, (high-fat, low-carbohydrate) diet that pro-
temporize symptoms and may require emergent surgery (47, 48). motes ketosis and metabolic acidosis, which can be exacerbated
However, a preoperative course of dose steroids may be efficacious by the use of carbohydrate-containing solutions (53). Lactated
in less symptomatic patients (49). Ringer’s solution and glucose-containing intravenous fluid should
Medulloblastomas, cerebellar astrocytomas, and ependymomas be avoided. Arterial blood gases and plasma glucose levels should
are sequentially the most common paediatric brain tumours. The also be measured frequently to avoid severe metabolic derange-
respiratory control centres and cranial nerve nuclei can be dam- ments during the intraoperative period. Patients on chronic
aged during surgical dissection. Stimulation of the nucleus of cra- anticonvulsant therapy with phenytoin, carbamazepine, or pheno-
nial nerve V can cause hypertension and tachycardia. Irritation of barbital will have increased requirements for nondepolarizing
the nucleus of the vagus nerve (X) may result in bradycardia or muscular relaxants and opioids due to increased activity of P450
postoperative vocal cord paralysis. Continuous observation of the hepatic enzymes (30).
blood pressure, electrocardiogram, and electromyography (for Resection of a seizure focus requires a team approach. The mo-
monitoring cranial nerve VII) are essential to detect encroach- dality of the intraoperative monitoring will have an impact on the
ment upon these vital structures. During the elevation of the conduct of the anaesthetic. A two-stage procedure entails place-
bone flap, inadvertent entry into the straight and transverse sinus ment of grids and strips of invasive electrocorticography (ECoG)
can precipitate massive VAE. Rapid treatment of VAE (flood the
surgical field, head down, fluid and vasopressor administration)
should be instituted. Since the respiratory control centres and Table 22.3 Medical conditions associated with intractable seizures
cranial nerve nuclei are vulnerable during surgical procedures on
the brainstem, the possibility of apneusis or airway obstruction Condition Anesthetic Implications
should be considered. Furthermore, the upper airway may be oe-
Tuberous sclerosis Cardiac conduction defects,
dematous due to large fluid shifts and the dependent nature the
arrhythmias,
prone position.
intracardiac rhabdomyomas,
Neoplasms: Supratentorial Tumours renal insufficiency,
Supratentorial are more common than posterior tumours in pa- pulmonary insufficiency.
tients less than two years of age. These include embryonic derived Struge Weber Disseminated intravascular coagulopathy,
tumours (primitive neuroectodermal tumours, pineoblastoma, and increased intra-operative blood loss.
ependymoma), gliomas, choroid plexus tumours, and teratomas.
268
for identification and mapping of the seizure focus. These patients Cerebrovascular Disease
will have their anticonvulsants reduced after the first craniotomy The primary goal of the anaesthetist during cerebrovascular sur-
and are at risk for postoperative seizures. After a week or more of gery is to optimize cerebral perfusion while minimizing the risk
continuous monitoring, these patients will return for removal of of bleeding. Large arteriovenous malformation (AVM) in neo-
the grids and strips and, if detected, resection of the seizure focus. nates may be associated with high output congestive heart failure
Nitrous oxide can precipitate pneumocephalus after a recent crani- requiring vasoactive support. These patients have their lesions
otomy (three weeks) and should be avoided until after the dura is embolized in the interventional radiology suites prior to the sur-
opened in the second craniotomy. gical resections. Hypertensive crisis after embolization or surgical
General anaesthetics can compromise the effectiveness of intra- resection of the AVM should be rapidly treated with vasodilators.
operative neurophysiologic monitors that guide the resection of the Microsurgical resections of these AVMs and aneurysms requires
epileptogenic focus. High levels of volatile anaesthetics and neuro- rigorous blood pressure control in order to enhance cerebral perfu-
muscular blockade may also suppress cortical stimulation. In order sion of vulnerable downstream regions of the lesions. Arterial blood
to optimize the electrocorticographic signal, localization of the pressure should be closely monitored and the level of anaesthetics
focus with surface electrodes requires low inspired concentration and vasopressor support should be adjusted accordingly. The use of
of a volatile anaesthetic. Supplemental boluses or infusions of opi- induced hypothermia has not demonstrated any clinical efficacy in
oids are ideal in this situation. Cortical stimulation may be neces- adult trials and is not indicated in paediatric patients (55). Intra-
sary to identify vulnerable areas on the motor strip and will require operative rupture of large intracerebral aneurysms may occur and
discontinuation of neuromuscular blockade. blood may obscure the operative field. Transient flow arrest with
In situations where the seizure focus lay in functional areas of adenosine has been reported in adults and should be considered
the brain (language and motor/sensory centres), an awake child as a last resort in paediatric patients (56). Meticulous control of
will be the optimal guide for the resection. A variety of techniques blood pressure should be continued in the postoperative period.
have been advocated to facilitate intraoperative assessment of Postoperative hyponatraemia due to either cerebral salt wasting
motor-sensory function and speech. In the ‘sleep-awake-asleep’ or the syndrome of inappropriate anti-diuretic hormone (SIADH)
technique the patient undergoes general anaesthesia for the sur- have been reported and result in hypovolaemic hyponatraemia or
gical exposure. The patient is then awakened for functional testing hypervolaemic hyponatraemia, respectively. It is essential to dif-
and general anaesthesia is reinstituted when patient cooperation is ferentiate between the two, because of divergent therapeutic inter-
no longer needed. Most cooperative patients will tolerate sedation ventions (replacement of isotonic fluids versus fluid restriction,
with propofol or dexmedetomidine. Propofol does not interfere respectively).
with the ECoG if it is discontinued 20 minutes before monitoring The goal of anaesthetic management of patients with moyamoya
in children undergoing an awake craniotomy (54). Supplemental syndrome is to optimize cerebral perfusion with aggressive
opioids are administered to provide analgesia. It is, however, im- pre-operative hydration and maintain normotension or mild
perative that candidates for craniotomy under local anaesthesia or hypertension during surgery and the postoperative period (57).
sedation be mature and psychologically prepared to participate in Intra-operative normocapnia is essential, because both hyper-and
this procedure. hypocapnia can lead to steal phenomenon from the ischaemic re-
Medically intractable generalized seizures may not have discrete gion. Intra-operative EEG monitoring may be utilized during
foci to resect and disconnection procedures to isolate epileptogenic surgery to detect cerebral ischaemia. Optimization of cerebral per-
regions of the brain have been developed. These include subpial fusion should be extended into the postoperative period to main-
transection, corpus callosotomy, and functional hemispherectomy. tain euvolaemia and the use of sedatives and opioids is indicated to
Corpus callosotomy places the child at risk for bleeding and VAE prevent hyperventilation induced by pain and crying.
due to the frontal surgical approach and proximity of the sagittal
sinus. These patients tend to be lethargic and somnolent after com-
Neuroendoscopy
plete division of the corpus callosum, placing the patient at risk
for aspiration pneumonitis and airway obstruction. Therefore, Technological advances in endoscopic surgery have provided less-
the patient should be fully awake prior to extubation of their tra- invasive approaches to the surgical management of CNS lesions
chea. Functional hemispherectomy was evolved from anatomic (58). These include ETV for hydrocephalus, tumour biopsies, and
hemispherectomy. The later was associated with having the highest insertion of ventricular shunt catheters. Despite the relative safety
morbidity and mortality of surgical procedures for intractable epi- of this procedure, hypertension, arrhythmias, and neurogenic pul-
lepsy. Indications for hemispherectomy include Sturge-Weber syn- monary oedema have been reported in conjunction with acute
drome, cortical dysplasia, hemimegaloencephaly, and Rasmussen intracranial hypertension due to lack of egress of irrigation fluids
syndrome. Functional hemispherectomy preserves the bulk of and/or manipulation of the floor of the third ventricle (59). These
the hemisphere with selective temporal lobectomy, resection of minimally invasive techniques have been applied to the treatment
the central region, and disconnection of the frontal, parietal, and of craniosynostosis, which have resulted in reduction of blood loss,
occipital lobes. This modification has resulted in a significant re- VAE, and morbidity (60, 61).
duction in blood loss, haemodynamic collapse, and postoperative
morbidity. The use of antifibrinolytics to optimize coagulation and Neuroradiology
supplement transfusion of platelets and fresh frozen plasma are in- Advances in diagnostic and therapeutic imaging technology have
dicated to counter anticipated massive bleeding in these proced- provided less invasive procedures to diagnose and treat CNS
ures. Aggressive fluid administration and vasopressor support is lesions in paediatric patients (62). Most neuroradiological studies
vital to preserve cerebral perfusion and cardiac output. such as CT scans and MRIs can often be accomplished with light
269
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27
273
CHAPTER 23
Basics of Neurocritical Care
Introduction post-hoc analysis of 391 TBI patients in the original NICE-SUGAR

study found no significant outcome differences in patients treated
Neurocritical care is a subspecialty of intensive care medicine dedi- with intensive compared to conventional glucose control des-
cated to the treatment of critically ill neurological patients. It has pite a higher incidence of hypoglycaemia in the intensive control
matured over the last decade through new knowledge, advances group (5).
in imaging and monitoring techniques and the introduction of The optimal blood glucose target after ABI therefore remains un-
neurointensivists and neurocritical care units (1). This chapter re- certain, although moderate level control, aiming to maintain serum
views the general principles of neurocritical care, and the critical glucose between 6.0–10.0 mmol/l, while avoiding large swings in
care management of acute brain injury (ABI) and associated non- glucose levels, is usually recommended (6).
neurological complications.
Anaemia
General Principles of Neurocritical Care Anaemia activates hypoxic cell signalling pathways and adversely
Critically ill neurological patients require meticulous general inten- affects cerebral oxygen delivery. Optimal haemoglobin (Hb) thresh-
sive care support as well as interventions targeted to their neuro- olds during neurocritical care are undefined, but it seems unlikely
logical disorder. The management of ABI focuses on prevention of that the restrictive transfusion practices in general critical care can
intracranial complications, optimization of systemic physiological be extrapolated because of the increased susceptibility of the in-
variables to maintain cerebral perfusion and substrate delivery, and jured brain to ischaemia. After subarachnoid haemorrhage (SAH),
management of non-neurological complications (Table 23.1). consensus guidelines recommend that Hb concentration should be
maintained between 80–100 g/L, although higher thresholds might
Cardiorespiratory Management be appropriate in patients at high risk of delayed cerebral ischaemia
A single episode of hypoxaemia (PaO2 <8kPa or SpO2 <90%) or (DCI) (7). It has been recommended that Hb concentration should
hypotension (systolic blood pressure (BP) <90 mmHg) is strongly be maintained >90 g/L in the acute phase after TBI. However, a
associated with poor outcomes after severe traumatic brain injury randomized controlled trial of erythropoietin and two transfusion
(TBI) (2), and all management guidelines emphasize the preven- thresholds (Hb concentration 70 g/l and 100 g/L) found that nei-
tion or rapid reversal of hypoxaemia and hypotension. ther administration of erythropoietin nor maintenance of Hb >100
Aggressive fluid resuscitation leading to hypervolaemia is det- g/L improved neurological outcomes at six months after TBI, but
rimental after ABI, and maintenance of euvolaemia with isotonic the latter was associated with more adverse events, particularly
crystalloids is recommended (3). Hypertonic saline (HS) solutions thromboembolism (8).
have no outcome benefits over isotonic crystalloids, and albumin
is associated with increased mortality after TBI. A vasoactive agent Temperature
is required if adequate BP and cerebral perfusion pressure (CPP) Fever (variably defined as core body temperature exceeding 37.5oC
cannot be achieved with fluid resuscitation. Norepinephrine has to 38.5oC) occurs in more than 50% and 70% of critically ill TBI
a predictable and consistent effect on systemic BP and cerebral and SAH patients, respectively, and is independently associated
haemodynamics (see Box 23.1). with worse outcomes. An infective cause of a pyrexia should always
be excluded and treated (pneumonia is particularly common), but
Glycaemic Control fever may be related to non-infective causes such as hypothalamic
Brain injury-induced hyperglycaemia is common, and likely re- dysfunction secondary to the effects of subarachnoid blood or is-
lated to a stress response leading to increased cortisol secretion and chaemia. Targeted normothermia is increasingly used during the
gluconeogenesis (4). Hyperglycaemia has multiple adverse effects neurocritical care management of ABI, despite the absence of high-
on the injured brain and is associated with worsened outcomes quality evidence of benefit (9).
after ABI. Randomized controlled trials of tight glycaemic control
with intensive insulin therapy (IIT) during neurocritical care have Seizures
been inconclusive, but all have shown that it is associated with a Seizures should be treated aggressively, but the routine use of
high incidence of hypoglycaemia (4). This was presumed to be a prophylactic anticonvulsants for primary or secondary seizure
major factor explaining the lack of efficacy of IIT after ABI, but prevention is not recommended. There is some evidence that
274
Table 23.1 General principles of the neurocritical care management TBI, graduation compression stockings or intermittent pneumatic
of acute brain injury. compression stockings are applied until the patient is ambulatory,
whereas compression stockings may confer a non-significantly
Ventilation ◆ PaO
2 >13 kPa higher risk of death after acute ischaemic stroke (AIS) where inter-
◆ PaCO
2 4.5–5.0 kPa mittent calf compression alone is recommended. Low molecular
◆ Lung protective ventilation strategies (tidal weight heparin (LMWH) reduces the rates of deep vein thrombosis
volume 6 ml/kg ideal body weight, PEEP (DVT) after TBI, but the timing of chemoprophylaxis is contro-
6–12 cm/H2O and recruitment manoeuvres) as versial and should balance the risks of DVT against that of intra-
brain-directed therapy allows cranial bleeding. LMWH to prevent DVT after AIS is supported
◆ PEEP to maintain oxygenation (PEEP (<12– by class I evidence, but it should be withheld for at least 24 hours
15 cm/H2O does not have adverse effects on ICP after thrombolysis therapy to minimize the risk of intracranial
and may reduce ICP if oxygenation is improved) haemorrhage.
◆ Ventilator ‘care bundle’ to minimize risk of
pneumonia Nutritional Support
◆ Head-up positioning TBI is associated with a hypermetabolic state and excessive ni-
◆ Oral hygiene trogen wasting. Early enteral feeding (within 48 hours of admis-
◆ Peptic ulcer prophylaxis
sion) is associated with a significant reduction in mortality, poor
outcomes, and infectious complications.
◆ Daily sedation holds if ICP allows
Cardiovascular ◆ Maintain MAP >90 mmHg

Neuromonitoring
◆ Target euvolaemia with isotonic crystalloids
Advances in monitoring and imaging techniques in association
◆ Vasopressors/inotropes if insufficient response to with improved understanding of the pathophysiology of ABI have
fluid led to the introduction of more effective and individualized treat-
ICP and CPP targets ◆ CPP 50–70 mmHg ment strategies that have translated into improved outcomes for
after TBI ◆ ICP <20 mmHg patients. As well as close monitoring and assessment of cardiac and
respiratory variables, a range of neuromonitoring techniques are
Other ◆ Normoglycaemia glucose 6.9–10.0 mmol/l
commonly used during neurocritical care (10, 11).
◆ Normothermia
◆ Seizure control Clinical Assessment

◆ Enteral
nutrition to begin within 48 hours Serial clinical assessment of a patient’s neurological status remains
◆ Thromboembolic prophylaxis the cornerstone of neuromonitoring. The Glasgow Coma Scale
(GCS) is a standardized, internationally recognized method for
CPP, cerebral perfusion pressure; ICP, intracranial pressure; MAP, mean arterial pressure; PEEP,
positive end-expiratory pressure; TBI, traumatic brain injury. evaluating global neurological status by recording best eye opening,
motor, and verbal responses to physical and verbal stimuli (table
23.2). In association with identification and documentation of lo-
calizing signs, such as pupil responses and limb weaknesses, the
phenytoin might be detrimental after ABI. Whether newer anti- GCS remains the standard for clinical assessment fifty years since
convulsants such as levetiracetam are more effective or safer is yet its first description (12). The main limitations of the GCS are that
to be confirmed. verbal responses are not assessable in intubated patients and brain-
stem function is not directly considered. The full outline of unre-
Venous Thromboembolism sponsiveness (FOUR) score provides additional information not
captured by the GCS, including details about brainstem reflexes
ABI is a significant risk factor for venous thromboembolism, but
and respiratory drive, and is able to recognize the locked-in syn-
guidelines for prophylaxis vary between brain injury types. After
drome (13). Clinical assessment is limited in sedated patients, when
reliance is placed on other neuromonitoring techniques.
Box 23.1 Brain injury outcomes are dependent on timely action Intracranial and Cerebral Perfusion Pressures
The monitoring and management of intracranial pressure (ICP) is

◆ Time is brain; even a single, short period of physiological upset
a standard of care in many centres during the critical care manage-
may cause permanent damage.
ment of TBI, and increasingly used in other brain injury types. In
◆ Systemic complications are common after a brain injury and addition to measuring absolute ICP, ICP monitoring permits the
may worsen it. calculation of CPP, a therapeutic target in itself, identification of
◆ Manage the whole patient, not just their brain. Solely brain- pathological ICP waveforms, and derivation of indices of cerebro-
focused treatments may cause iatrogenic harm. vascular pressure reactivity.
ICP is most commonly measured using an intraventricular cath-
◆ Experience matters; higher-volume centres may achieve better eter or parenchymal monitoring device (14). Ventricular cath-
outcomes; consider early referral to a specialist neurosciences eters measure pressure in the CSF of the lateral ventricles, which
centre. is an assessment of global ICP. They allow in vivo calibration and
275
Chapter 23 basics of neurocritical care 275
Table 23.2 The Glasgow Coma Score Scale. Box 23.2 Indications for Intracranial Pressure Monitoring
in Traumatic Brain Injury
Response Score
Brain Trauma Foundation guidelines
Eye opening Spontaneous 4
To loud voice 3 ◆ Salvageable patients with severe TBI and an abnormal cranial
To pain 2 CT scan.
None 1 Salvageable
◆ patients with severe TBI and a normal scan and
Verbal response Orientated 5
two or more of the following:
Confused, disorientated 4 ◆ age >40 years.
Inappropriate words 3 ◆ unilateral or bilateral motor posturing.
Incomprehensible sounds 2
◆ systolic BP <90 mmHg.
None 1 Milan consensus conference recommendations
Motor response Obeys commands 6 ◆ Comatose TBI patients with initial CT scan showing minimal
Localizes 5 abnormality that subsequently worsens (e.g., development of
Withdraws (flexion) 4 contusions or signs of raised ICP).
Abnormal flexion posturing 3
Comatose
◆ TBI patients with cerebral contusions when inter-
Extension posturing 2 ruption of sedation to check neurological status is dangerous,
None 1 or clinical examination unreliable.
Glasgow coma score <8 indicates unconsciousness. ◆ Comatose TBI patients with large bifrontal contusions and/or
Reprinted from The Lancet, 304, 7872, Teasdale, G., Jennett, B., Author(s), Assessment of haemorrhagic mass lesions close to the brainstem, irrespective
coma and impaired consciousness a practical scale, pp. 81–94. Copyright (1974), with of initial GCS.
permission from Elsevier.
◆ Following secondary decompressive craniectomy.
◆ Following evacuation of acute supratentorial intracranial
therapeutic drainage of CSF, but are associated with relatively haematoma in salvageable patients with:
high complication rates, including catheter-related ventriculitis.
Microtransducer (strain gauge) or fibreoptic ICP monitoring de- ◆ GCS motor score ≤5.
vices are sited in brain parenchyma usually via a cranial access de- ◆ pupillary abnormalities.
vice. They are easy to insert and have minimal complication rates,
◆ prolonged/severe hypoxaemia and/or hypotension.
but in vivo recalibration is not possible. Although parenchymal
ICP monitoring devices measure localized pressure, they provide ◆ compressed or obliterated basal cisterns.
equivalent pressure measurements to ventricular catheters in most ◆ midline shift >5 mm or exceeding thickness of an
circumstances. Several non-invasive ICP monitoring techniques extra-axial  clot.
are available, including ultrasound or computed tomography (CT)-
measured optic nerve sheath diameter, but none are sufficiently ◆ new extra-axial haematomas, parenchymal contusions or
accurate for routine clinical use and most are unable to monitor brain swelling.
intracranial dynamics continuously (15). ◆ intra-operative brain swelling.
The 2007 Brain Trauma Foundation (BTF) recommendations
for ICP monitoring (16) have recently been supplemented by a ICP, intracranial pressure; CPP, cerebral perfusion pressure; CT, computed
tomography; GCS, Glasgow coma scale; TBI, traumatic brain injury.
European expert statement (Box 23.2) (17). While guidelines focus
on treating ICP above a certain threshold (usually >20 mmHg), Adapted from: Neurosurgery, 80, 1, Carney N, Totten AM, O’Reilly C et al,
it is the overall burden of intracranial hypertension (i.e., the Guidelines for the Management of Severe Traumatic Brain Injury, Fourth
time spent above a defined ICP threshold as well as absolute ICP Edition, pp. 6-15, 2017; Acta Neurochirurgica, 156, 8, Stocchetti N, Picetti E,
values) which is the important determinant of outcome. Changes Berardino M et al, Clinical applications of intracranial pressure monitoring
in the ICP waveform are observed as ICP increases, and wave- in traumatic brain injury, pp. 1615-1622, 2014.
form analysis has been utilized to predict the onset of intracranial
hypertension.
CPP is calculated as the difference between mean arterial pres-
sure (MAP) and ICP. Accurate calculation requires that the zero reactivity index (PRx) can be calculated as the moving correl-
reference points for both MAP and ICP should be the same, i.e., ation coefficient of consecutive time averaged data points of ICP
at the level of the brain using the tragus of the ear as the external and ABP over a four-minute period, and measured continuously
landmark (18). as a marker of autoregulatory status. A negative value for PRx in-
dicates an inverse correlation between ABP and ICP and normal
Cerebrovascular Autoregulation cerebrovascular reactivity, whereas a positive PRx defines a non-
The pressure reactivity of cerebral vessels determines the ICP re- reactive cerebrovascular circulation when changes in ABP and
sponse to changes in arterial blood pressure (ABP), with disturbed ICP are in phase. PRx can be used to identify optimal CPP tar-
reactivity indicating disturbed pressure autoregulation. A pressure gets (19). Cerebrovascular reactivity can also be assessed using an
276
oxygen reactivity index, defined as the moving correlation between derived variables, have been studied extensively as an assessment of
brain tissue partial pressure of oxygen (PtiO2) and ABP. Similarly, the adequacy of CBF. A major drawback of SjvO2 monitoring is that
the correlation between ABP and transcranial Doppler (TCD) it is unable to detect regional ischaemia. Although of considerable
ultrasonography-derived blood flow velocity (FV) and several near historical interest, SjvO2 monitoring is being superseded by other
infrared spectroscopy (NIRS)-derived variables have also been de- bedside techniques such as PtiO2 monitoring.
scribed (see Near Infrared Spectroscopy).
Brain Tissue Oxygen Monitoring
The attraction of indices such as PRx is that they use information
that is already collected, but in a more intelligent manner. However, PtiO2 is now considered the ‘gold standard’ bedside measure of
novel analytical techniques of multimodal monitoring may quan- cerebral oxygenation (22). PtiO2 is a complex and dynamic vari-
tify CA more robustly than signal processing techniques such as able that represents the interaction between cerebral oxygen de-
PRx (20). livery and demand, as well as tissue oxygen diffusion gradients. As
such, PtiO2 is best considered a biomarker of cellular function as
Cerebral Blood Flow opposed to a simple monitor of hypoxia/ischaemia.
Normal brain PtiO2 lies between 2.66 and 4.66 kPa, and clinical
TCD is a non-invasive technique for assessing cerebral haemo-
studies suggest that PtiO2 values less than 1.3 kPa are indicative
dynamics in real time. It uses a low-frequency pulsed wave ultra-
of severe brain hypoxia. Treatment to increase brain oxygenation
sound probe to measure blood FV through basal cerebral vessels
is usually recommended when PtiO2 falls below 2.0 kPa. When
from the Doppler shift caused by red blood cells moving through
interpreting PtiO2, the duration and chronological trend of cere-
the field of view. It measures relative blood flow changes rather than
bral hypoxia as well as its severity should be considered since it
actual cerebral blood flow (CBF). The TCD FV waveform resembles
is the overall burden of hypoxia/ischaemia that is the key deter-
an arterial pulse wave and may be quantified into peak systolic, end
minant of outcome.
diastolic, and mean FVs. The pulsatility index provides an assess-
PtiO2 is a focal measure and probe location is therefore crucial.
ment of distal cerebrovascular resistance. TCD is most commonly
Placement in peri-lesional but viable brain tissue allows monitoring
used in the diagnosis and management of cerebral vasospasm after
of ‘at risk’ brain regions and is considered optimal by many. An
SAH, and to assess CA after TBI.
alternative approach recommends placement in normal appearing
Thermal diffusion flowmetry (TDF) is an invasive, continuous,
white matter, when PtiO2 effectively acts as a global measure of
and quantitative monitor of regional CBF, but clinical data using
cerebral oxygenation. Satisfactory probe location must always be
this technology are limited (see Box 23.3).
confirmed with a cranial CT scan to allow appropriate interpret-
Cerebral Oxygenation ation of PtiO2 readings.
PtiO2 is strongly influenced by systemic BP and CPP, and also by
Brain hypoxia can occur despite ICP and CPP being within ac- other systemic physiological variables including PaO2, PaCO2, and
cepted thresholds for normality. Monitors of the adequacy of cere- Hb concentration.
bral perfusion, such as brain tissue oxygen partial pressure (PtiO2), Which intervention (or combination of interventions) to reverse
provide a more complete picture of the injured brain and its re- brain hypoxia is most effective in improving outcome remains un-
sponse to treatment (21). clear. In fact, it appears that it is the responsiveness of the hypoxic
Jugular Venous Saturation brain to a given intervention that is the prognostic factor, with re-
Jugular venous oxygen saturation (SjvO2), the first bedside monitor versal of hypoxia being associated with reduced mortality (23).
of cerebral oxygenation, is a flow-weighted, global measure which Near Infrared Spectroscopy
provides a non-quantitative estimate of the adequacy of cerebral NIRS-derived cerebral oximetry offers non-invasive, bedside
perfusion. The normal range of SvjO2 is 55% to 70%. Low SvjO2 monitoring of cerebral oxygenation. Commercial devices measure
values indicate cerebral hypoperfusion or increased oxygen demand regional cerebral oxygen saturation (rScO2) with high temporal
that is not matched by increased supply, whereas high values indi- and spatial resolution over multiple regions of interest. While
cate relative hyperaemia or arterio-venous shunting. The arterial to rScO2 is able to assess the balance between cerebral oxygen supply
jugular venous oxygen content concentration difference, and other and demand, its determination is influenced by several physio-
logical variables as well as by technological limitations (24). There
has been rapid expansion of the clinical use of NIRS-based cere-
Box 23.3 The Ideal Monitor of Brain Injury Does Not Yet Exist bral oximetry during cardiac surgery following studies suggesting
an association between intra-operative cerebral desaturation and
Monitoring
◆ brain injury is best achieved by following con- an increased risk of peri-operative cognitive decline. However,
scious level and motor exam; commonly they may be affected there has been limited investigation of the utility of NIRS during
as a consequence of the brain injury or necessary therapies. neurocritical care. There are several concerns during the clinical
application of NIRS, particularly ‘contamination’ of the signal by
◆ At this time, no perfect objective monitor of brain injury exists. extracranial tissue. Furthermore, the application of commercial
◆ ICP monitoring alone driven care does not appear to improve NIRS devices is potentially confounded by the optical complexity
outcome. of the injured brain.
◆ Many new technologies are being developed to assess brain Emerging applications for NIRS include the non-invasive moni-
oxygenation, metabolism and cerebral autoregulation; the best toring of indices of CA using signal processing techniques similar
monitor may well be an integration of these. to those for PRx (25), as well as novel analytical methods of multi-
modal monitoring of slow wave oscillations (20). In the research
27
setting, NIRS-monitored changes in the oxidation status of oxidized as the specialty has developed, its case mix has broadened to include
cytochrome c oxidase, the final electron acceptor in the mitochon- comprehensive management for all life-threatening disorders of the
drial electron transport chain responsible for over 95% of oxygen central nervous system (CNS) and their complications. Although
metabolism, provides additional information about cellular energy TBI, SAH and intracerebral haemorrhage (ICH) continue to make
status which may aid in the determination of ischaemic thresholds up a large proportion of cases, the admission of patients with other
in the injured brain (26). diagnoses, such as AIS, neuromuscular disorders, status epilep-
ticus, and CNS infection, is increasingly common.
Cerebral Microdialysis
Cerebral microdialysis (MD) allows bedside analysis of biochemical Traumatic Brain Injury
substances in brain tissue extracellular fluid (ECF) (27). Glucose, Patients with severe TBI should be managed in an ICU offering
lactate, pyruvate, and glycerol are commonly measured variables immediate access to multidisciplinary clinical neuroscience teams
in the clinical setting, and each is a marker of a particular cellular and other relevant specialties, supported by appropriate imaging
process associated with glucose metabolism, hypoxia/ischaemia, and investigational facilities. The critical care management of TBI
or cellular energy failure. The lactate:pyruvate (LP) ratio, in com- requires a coordinated and comprehensive approach to treatment,
bination with ECF glucose levels, provides information about the including strategies to prevent secondary brain injury by avoidance
brain’s metabolic state, and the ability to assess glucose metab- of systemic physiological insults, such as hypotension, hypoxaemia
olism is a particular strength of cerebral MD monitoring. MD is and disturbances of glucose and temperature homeostasis, and
also able to identify both ischaemic and non-ischaemic causes of maintenance of cerebral perfusion and oxygenation.
cellular energy dysfunction and the ensuing metabolic crisis (28).
ICP-and CPP-Guided Therapy
Recommended values to prompt clinical intervention include brain
glucose <0.8 mmol/L, LP ratio >40 and lactate concentration > The sole goal of identifying and treating ICH has been superseded
4 mmol/L (27). In the research setting, cerebral MD can be used to by a focus on the prevention of secondary brain insults using a
measure a multitude of other substances including cytokines. multi-faceted approach to maintenance of cerebral perfusion and
While cerebral MD has contributed substantially to the under- oxygenation (32). The recommendations for CPP thresholds after
standing of the pathophysiology of brain injury, its clinical utility TBI have changed over time, following recognition that both high
is still debated. and low CPP is associated with adverse outcomes. The most re-
cent guidelines from the BTF recommend that CPP be maintained
Electroencephalography between 50–70 mmHg after TBI, and that excessive CPP should
be avoided because of the risk of acute respiratory distress syn-
Electroencephalography (EEG) has established indications in
drome (ARDS) related to excessive administration of fluids and
the diagnosis and management of seizures or status epileptics.
vasopressors (16).
Continuous EEG monitoring is increasingly employed in the
ICH is associated with worse outcomes, and treatment is usu-
neurocritical care unit following evidence that nonconvulsive seiz-
ally recommended if ICP exceeds 20mmHg (16). The only ran-
ures are common after brain injury. EEG monitoring should be
domized controlled trial of ICP-guided management after TBI
undertaken in all patients with unexplained and/or persistently al-
(Benchmark Evidence from South American Trials: Treatment of
tered consciousness to exclude seizures as the cause of the altered
Intracranial Pressure, BEST:TRIP) found similar three-and six-
neurological state (29).
month outcomes in patients in whom treatment was guided by ICP
Multimodal Monitoring and Informatics monitoring compared to treatment guided by imaging and clin-
ical examination in the absence of ICP monitoring (33). A meta-
A single neuromonitor is unable to detect all episodes of cerebral analysis incorporating 24,792 patients with severe TBI also found
compromise, and recent guidance highlights the importance of that ICP monitoring-guided management of ICH was not associ-
multimodal neuromonitoring to guide an individualized approach ated with significant mortality benefit overall compared to treat-
to patient management based on monitored physiologic variables ment without ICP monitoring, although mortality rates were lower
rather than generic, often empirical, thresholds (30). in those who underwent ICP monitoring in studies published after
Multimodality neuromonitoring produces large and complex 2012 (34).
datasets, and systems have been developed to analyze and present
clinically relevant data in a user-friendly and timely manner at the Treatment of Intracranial Hypertension
bedside (31). Incorporation of advanced algorithms permits auto- ICP-lowering strategies are administered in a stepwise manner,
matic recognition and rejection of anticipated and expected fluctu- starting with first-line, safer interventions, and reserving higher-
ations in data. The inclusion of computational models of cerebral risk options for patients with neuroimaging or monitoring evi-
oxygenation, haemodynamics, and metabolism has potential to fa- dence of brain hypoxia or cerebral metabolic distress, or those at
cilitate interpretation of complex datasets and provision of timely imminent risk of cerebral herniation (Figure 23.1).
summary outputs at the bedside, as well as provide patient-specific
simulations of clinically important but unmeasured physiological Sedation
variables such as cerebral metabolism. Most sedatives have beneficial effects on ICP and CPP, but there
is no evidence that one agent is superior to another (35). Propofol
reduces cerebral metabolic rate and ICP and is widely used, often
Neurocritical Care Case Mix in combination with infusion of a short-acting opioid. The alpha-
The earliest neurocritical care units were established to coordinate 2 agonist dexmedetomidine has shown some promise for sedation
the postoperative management of complex neurosurgical cases but, after brain injury but there is no high-quality evidence of efficacy.
278
Second-line treatment options

First-line treatment options
ICP sustained
• ventriculostomy
• 30° head-up tilt >20–25 mmHg
• optimize CPP
• neck in neutral position Evidence of cerebral
• mannitol
• avoid neck compression hypoxia/ischaemia
• hypertonic saline
ICP • avoid hypoxaemia
• loop diuretics
>20–25 mmHg • maintain normocapnea
• therapeutic hypothermia
• avoid hypotension
• sedation
• analgesia
• surgical removal of
intracranial mass lesions
ICP sustained
>20–25 mmHg
Evidence of cerebral
hypoxia/ischaemia
Risk of brain
herniation
Third-line treatment options

• barbiturates
• decompressive craniectomy
Figure 23.1 Management of raised intracranial pressure.

First-line treatment options are followed by second-and third-line therapies if ICP remains high or there is other evidence of brain ischaemia/hypoxia and/or imminent
risk of cerebral herniation.
CPP, cerebral perfusion pressure; ICP, intracranial pressure
Barbiturates are often used in the treatment of refractory ICH, but TH also has many potential neuroprotective actions including
they do not reduce mortality after TBI and substantially increase stabilization of the blood-brain barrier and inhibition of inflam-
the risk of hypotension. mation and intracellular calcium overload. Compelling preclinical
evidence of benefit has failed to translate into positive outcomes
Hyperventilation
in large-scale randomized clinical trials. The EUROTHERM3235
Hyperventilation was previously routinely used as an ICP lowering trial was terminated early because hypothermia (32–35°C) was
intervention, but it can precipitate or worsen global and regional equivalent to standard care for the reduction of raised ICP in se-
cerebral ischaemia because of critical reductions in CBF. As such, vere TBI, but associated with higher mortality and worse functional
hyperventilation should be used only as a temporizing measure, outcome (37).
and avoided in the first 24 hours (when CBF is often significantly
reduced) or as a prophylactic intervention. Neurosurgery
The role of neurosurgery in the management of TBI is discussed in
Osmotic Therapy
detail in Chapter 13. Decompressive craniectomy involves removal
Mannitol (0.25–1.0 g/kg) is a standard of care for the acute treat- of a large area of the skull vault and opening of the dura to reduce
ment of elevated ICP, but has never been subject to a random- ICP, but there is divided opinion on its relative benefits and risks.
ized comparison against placebo. HS may have a more profound The Decompressive Craniectomy (DECRA) trial has increased ra-
and long-lasting effect on ICP compared with mannitol, but out- ther than resolved the controversy about the indications, technique,
come benefits over mannitol have not been demonstrated (36). timing, and selection of patients for decompressive craniectomy
Although previously believed to be a dangerous by-product of after TBI (38). Given the dismal outcome of patients with high ICP
anaerobic metabolism, it is now clear that lactate can act as a refractory to other therapies, decompressive craniectomy is often
preferential fuel in the injured brain. There is preliminary evi- included in the management strategy of patients who may have a
dence that hypertonic lactate solutions spare cerebral glucose, chance of a reasonable functional outcome when other measures
improve cerebral energy metabolism, and effectively reduce have failed to control ICP.
elevated ICP.
Therapeutic Hypothermia Subarachnoid Haemorrhage
Moderate therapeutic hypothermia (TH) effectively reduces raised Aggressive resuscitation and multidisciplinary management aimed
ICP in some patients. Rewarming is the most dangerous phase of at reducing early and late complications is associated with improved
TH, and must be carried out in a controlled manner (0.1–0.25˚C outcomes after aneurysmal SAH (39). Following securing of the an-
per hour) to minimize the risk of rebound intracranial hyperten- eurysm, the critical care management of SAH involves treatment
sion and hyperkalaemia. of intracranial complications such as hydrocephalus, optimization
279
of systemic physiology, and prevention and treatment of DCI and Recent guidelines emphasize euvolaemia as the target for both pre-
non-neurological complications (7). vention and treatment of DCI, with no place for haemodilution
(7). Once the aneurysm is secured induced hypertension is the
Rebleeding
most effective treatment of DCI. BP should be increased step-
Rebleeding was historically the major cause of death following poor wise in response to improvement in neurological function or
grade SAH, but rebleeding rates have dramatically reduced fol- neuromonitoring variables, or radiological evidence of improved
lowing the shift towards early securing of the ruptured aneurysm. cerebral perfusion (40). In the presence of adequate volume status,
Endovascular coiling of intracranial aneurysms represents a major norepinephrine is widely used to augment BP. The higher BP
advance in the treatment of SAH and allows minimally invasive and should be maintained for two to three days and gradually weaned
effective treatment. Extreme hypertension is a risk for rebleeding while monitoring for deterioration in clinical and neuromonitoring
prior to aneurysm repair. Tranexamic acid reduces the risk by as status. There is preliminary evidence that early goal-directed
much as 40% but it is not routinely used because it does not im- haemodynamic therapy might reduce the risk of DCI and improve
prove outcome, possibly because of micro-thrombosis related cere- outcome after SAH.
bral ischaemia and increased risk of venous thromboembolism. Endovascular interventions, including balloon angioplasty and
Blood Pressure Management intra-arterial infusion of vasodilating agents, are indicated in pa-
Hypertension is a normal response to SAH, but excessively high BP tients with symptomatic vasospasm resistant to BP augmenta-
increases the risk of re-bleeding. Prior to securing the aneurysm, tion. Several pharmacological agents which target the diverse
the patient’s usual BP can be used to refine targets, although MAP pathophysiology of DCI have been investigated, but only oral
is often empirically maintained between 90–110 mmHg. Modest nimodipine, a specific antagonist of the L-type voltage-gated cal-
BP elevations (MAP <110 mmHg) do not require intervention, but cium channel, has been shown to improve outcome. Multicentre
extreme hypertension should be treated cautiously with infusion randomized phase 3 trials have found no benefits of statins, mag-
of short-acting anti-hypertensive agents such as esmolol, labetalol, nesium, endothelin-A antagonists, or anti-thrombotic agents on
or nicardipine. Vasodilating agents such as sodium nitroprusside short-or long-term outcomes after SAH (42).
should be avoided because of the risk of secondary increases in ICP.
Once the aneurysm is secured, BP should be maintained approxi- Intracerebral Haemorrhage
mately 20% higher than baseline to minimize the risk of DCI. The treatment of ICH remains largely supportive, but recent evi-
dence indicates that early aggressive treatment, including inten-
Intracranial Pressure sive BP control, correction of coagulopathy and admission to a
Intracranial hypertension is common after SAH, particularly early neurocritical care unit, is associated with improved outcomes
after the ictus and in comatose patients. The indications for ICP (43). ICH was previously considered a single haemorrhagic
monitoring are often inter-related with the need to treat obstructive event, but is now recognized as a complex, dynamic process
hydrocephalus, so a ventricular catheter, being both a diagnostic involving three distinct phases –initial haemorrhage, haema-
and therapeutic modality, is usually preferred (40). Transmural toma expansion, and perihaematoma oedema. Seventy-three
pressure changes are as important as absolute levels of BP as a percent of patients develop expansion of the haematoma in the
risk for aneurysm re-bleeding, and rapidly lowering ICP with first 24 h, and this is an important cause of early neurological
ventriculostomy may increase this risk. The CSF drainage pressure deterioration.
should therefore initially be set at 10-20 cmH2O.
Acute Blood Pressure Lowering
Delayed Cerebral Ischaemia BP is elevated in 75% of patients with acute ICH, and strongly as-
DCI is the term applied to any neurological deterioration, including sociated with haematoma expansion and poor outcome. A recent
focal neurological deficits and altered consciousness, persisting for randomized clinical trial (the Intensive Blood Pressure Reduction
more than one hour and when other neurological and systemic in Acute Cerebral Haemorrhage Trial–INTERACT-2) confirmed
causes for the deterioration have been excluded (41). It is second that acute BP lowering to systolic BP (SBP) <140 mmHg is safe, and
only to the initial haemorrhage in terms of morbidity and mor- may improve functional outcome after ICH (44).
tality. DCI has been attributed to cerebral vasospasm but the exact
relationship between the two is unclear. DCI can occur in the ab- Anticoagulation-Related  ICH
sence of vasospasm and vice versa, and ischaemia often involves Warfarin anticoagulation not only increases the risk of ICH, but
more than one vascular territory. Other mechanisms contributing also doubles the mortality rate compared to spontaneous ICH. Even
to DCI include vascular dysautoregulation, micro-thrombi, direct small haematomas can transform into a catastrophic haemorrhage
neurotoxic effects, and cortical spreading depolarizations (41). within minutes in the presence of anticoagulation. Urgent reversal
The diagnosis of DCI can be made on clinical and radiological of warfarin anticoagulation to an INR less than 1.3 is recommended
grounds. Patients may present with a spectrum of impaired con- in the presence of ICH. The direct acting oral anticoagulants
sciousness and/or focal neurological deficits, but the clinical diag- (DOACs) are associated with a lower risk of ICH compared to war-
nosis is difficult or impossible in poor grade or sedated patients farin, but the mortality rate in those who do develop intracranial
when reliance is placed on serial TCD supplemented by other bleeding is similar to that of warfarin-related ICH. The difficulties
neuromonitoring modalities and neuroimaging (40). of managing DAOCs in bleeding patients, including lack of specific
A combination of hypervolaemia, haemodilution, and hyperten- measures of anticoagulant action and limited reversal strategies,
sion (triple H therapy) was previously the mainstay of treatment to bring particular challenges to the management of DOAC-related
prevent and treat DCI, but the focus is now on hypertension only. ICH (45).
280
Neurosurgery brain-directed therapies. The ICU management of non-neurologic

Neurosurgical interventions after ICH remain controversial. organ dysfunction and failure presents significant challenges be-
Evacuation of a spontaneous superficial ICH within 12 hours of cause optimum treatment for the failing systemic organ system may
ictus in a patient without intraventricular haemorrhage does not conflict with brain-directed therapies, and vice versa (49).
increase the rate of death or disability at six months, and might have
a small but clinically relevant survival advantage in some patients. Cardiac Complications
Decompression of cerebellar haematomas producing mass effect on The neurogenic stunned myocardial (NSM) syndrome is a revers-
the brainstem can be life saving, and external ventricular drainage ible neurologically mediated cardiac injury characterized by ECG
is indicated in patients with acute hydrocephalus. Minimally inva- changes, elevated cardiac troponin, and a spectrum of ventricular
sive surgery, including needle aspiration of the haematoma with or dysfunction (50). It is related to excessive norepinephrine release
without local administration of recombinant tissue plasminogen from myocardial sympathetic nerve terminals which leads to pro-
activator to dissolve clots or intraventricular haemorrhage, is cur- longed opening of β1-adrenergic receptor-controlled calcium
rently being investigated. channels, rapid depletion of adenosine triphosphate, and subse-
quent mitochondrial dysfunction and cell death. NSM may be as-
Acute Ischaemic Stroke sociated with minimal clinical effects but, in severe cases, can lead
Increasing numbers of patients with AIS are being admitted to the to cardiogenic shock and pulmonary oedema. ABI-related cardio-
ICU for physiological optimization, management of post-stroke vascular dysfunction often resolves spontaneously, emphasizing
complications (including those related to thrombolytic therapy) the importance of general supportive critical care during periods
and for novel therapy (46). In 2015, five studies reported positive of instability.
outcomes after endovascular intervention (intra-arterial thromb- ECG abnormalities are particularly common and reported
olysis and/or mechanical clot retrieval) compared to best medical in 49% to 100% of patients after SAH. Abnormalities include
therapy in AIS patients with large artery occlusion (47). cardiac arrhythmias, ST segment morphological changes, flat-
Neurosurgery tened or inverted T waves, and prolongation of the QTc interval.
Repolarization normalizes as the neurological insult resolves so
Decompressive hemicraniectomy performed within 48 hours of
ECG abnormalities are often transient. No specific treatment is re-
symptom onset reduces mortality from 78% to 29% and signifi-
quired, but drugs that prolong the QTc interval should be avoided.
cantly improves favourable outcomes in patients with malignant
Cardiac troponin I abnormalities are identified in 20% to 68% of
middle cerebral artery infarction aged between 18 and 60 years
SAH patients, peaking within 24–36 hours of ictus. These can be
(48). In older patients (over 60 years), surgery also confers substan-
associated with characteristic ventricular regional wall motion ab-
tial mortality benefits but at the cost of more survivors with poor
normalities reflecting the distribution of sympathetic nerves rather
neurological function.
than specific vascular territories, in line with the aetiology of NSM.
LV dysfunction occurs in around 15% of patients after SAH, but the
Non-Neurological Complications degree of dysfunction is often mild and transient.
Non-neurological organ dysfunction and failure, particularly car- Modification of sympathetic responses has been suggested as
diorespiratory complications, are common after ABI and independ- a way to limit cardiac dysfunction after ABI. Patients on chronic
ently associated with adverse outcomes. Systemic complications antihypertensive therapy have a lower incidence of SAH-associated
may develop secondary to brain injury-related catecholamine and cardiac injury, and small observational studies have shown that
neuroinflammatory responses (Figure 23.2), or as complications of patients already taking beta blockers have improved outcomes
ECG changes
Cardiac
Hypotension
dysfunction
LV dysfunction
Brain Injury related

sympathetic and Hypertension Acute lung injury
neuroinflammatory
responses
Systemic
NPO
inflammatory
Pneumonia
response
Figure 23.2 Causes of non-neurological complications after acute brain injury.

LV, left ventricular; NPO, neurogenic pulmonary oedema
281
after TBI. However, there is no evidence that the introduction of deterioration is anticipated because of likely progression of the
sympatholysis in the acute phase after ABI improves outcome, and underlying brain injury.
the risk of hypotension would be a cause for concern. Inotropic High tidal volume ventilation and high respiratory rate are in-
support with dobutamine is beneficial in the setting of low car- dependent predictors of ARDS in patients with ABI in the same
diac output after NSM, but pure vasopressors are often necessary way as in the general ICU population (51). While many patients
to maintain cerebral perfusion despite their potential adverse ef- can be safely managed using standard lung protection ventilation
fects on cardiac work. Echocardiography and continuous cardiac strategies, in others there can be a conflict between the at-risk
output monitoring may be useful in guiding therapy in patients lungs and injured brain. Permissive hypoxaemia and hypercapnia
with symptomatic NSM. are contraindicated in the early phase after ABI, and those with
refractory ICH and ARDS present the greatest challenge. A ven-
Pulmonary Complications tilation strategy that maximizes cerebral oxygenation and con-
Brain injury-induced pulmonary dysfunction includes neurogenic trols CO2 while balancing the risks to the lungs and impact on
pulmonary oedema (NPO), pulmonary aspiration, ventilator- brain-directed therapy should be identified for each patient
associated pneumonia, ventilator-induced lung injury, ARDS, and individually (52).
pulmonary embolism. A substantial proportion of neurocritical care patients re-
quire a tracheostomy, but the optimal timing remains unset-
Neurogenic Pulmonary Oedema tled. While it has previously been suggested that tracheostomy
NPO is a brain injury-related pulmonary oedema in the ab- should be considered after one week of mechanical ventila-
sence of primary cardiac failure or significant volume overload. tion in patient in whom a reasonable neurological outcome is
It is likely related to catecholamine-related hydrostatic and per- predicted, a strategy of early tracheostomy may be associated
meability oedema, and a systemic inflammatory response (51). with better overall clinical outcome compared to delayed (be-
Positive end expiratory pressure may be used to optimize oxy- yond day seven) tracheostomy.
genation and reduce extravascular lung water acutely after NPO.
Catecholamine-induced redistribution of blood into the pul- Dysnatraemia
monary circulation results in an under-filled systemic circu- Disorders of sodium homeostasis are common after ABI, and both
lation, so fluid restriction and the use of diuretics to treat the hypo-and hypernatraemia have adverse effects on the injured
oedema are contraindicated since they may exacerbate this acute brain. A systematic approach to diagnosis and treatment is essen-
hypovolaemic state tial (see Table 23.3).
Neurogenic Ventilation-Perfusion Mismatch Hyponatraemia
Moderate to severe hypoxaemia can occur in the absence of Hyponatraemia can be related to the syndrome of inappropriate
interstitial or alveolar oedema. The aetiology of this neurogenic antidiuretic hormone secretion (SIADH) or the cerebral salt
ventilation-perfusion mismatch is incompletely understood but wasting syndrome (CSWS). It is important to distinguish between
is likely to include hypothalamic-mediated redistribution of pul- the two because the treatment approaches are different, although a
monary blood flow, increase in dead-space secondary to pul- mixed picture is not uncommon (53). Biochemical criteria may fail
monary microembolism, and depletion of lung surfactant because to differentiate CSWS from SIADH, so diagnosis is often reliant on
of excessive sympathetic stimulation. clinical examination; the key clinical diagnostic factor is the pres-
ence of volume depletion in CSWS.
Complications of Brain-Directed Therapy
Electrolyte-f ree water restriction is the standard treatment of
Brain-directed therapies may themselves cause or worsen pul- SIADH but may worsen cardiovascular instability and increase
monary dysfunction. Induced hypertension with fluid and vaso- the risk of cerebral hypoperfusion after ABI. Consideration
pressors/inotropes to increase CPP is associated with ARDS, and should be given to the use of 1.8% saline in hyponatraemic
TH and barbiturates with higher rates of pneumonia. brain-injured patients, particularly those at high risk of DCI
Pneumonia after SAH. Pharmacological therapies such as demeclocycline
Pneumonia is the most common non-neurological complication and ADH-receptor antagonists may have a place. The primary
on the neurocritical care unit. Risk factors include more severe treatment of CSWS is volume and sodium resuscitation, and
brain injury, poor bulbar function, pulmonary aspiration, mechan- fludrocortisone or hydrocortisone may also be used to limit the
ical ventilation, and age greater than 65 years. The risk of ventilator- natriuresis.
associated pneumonia can be minimized by the use of ventilation The correction of hyponatraemia can itself lead to neurological
‘care bundles’ (Table 23.1). sequelae, particularly central pontine myelinolysis. Gradual cor-
rection of sodium deficits can minimize this risk. In most cir-
Mechanical Ventilation Strategies cumstances, serum sodium should be increased by no more than
Comatose brain injured patients or those with altered mental 0.5–1.0 mmol/L/h to a maximum of 8–10 mmol/L/24 h. Treatment
status or impaired bulbar function are at risk of airway obstruc- should always be targeted to the point of alleviation of symptoms
tion and pulmonary aspiration. Brain injury may also cause rather than to an arbitrary serum sodium value.
dysregulation of respiratory drive and alteration of pulmonary
mechanical function. Intubation and mechanical ventilation is re- Hypernatraemia
quired in comatose patients or those with deteriorating conscious Brain injury-
related hypernatraemia is most commonly
level, but should also be considered in those in whom neurologic caused by central diabetes insipidus (DI) secondary to failure
28
Table 23.3 Features and treatment of sodium disturbances after acute brain injury.
SIADH CSW DI
Plasma volume Increased Reduced Reduced
Sodium balance Positive/neutral Negative Neutral
Water balance Positive Negative Negative
Serum sodium Low Low High
Serum osmolality Low High/normal High
Urine sodium High High Normal
Urine osmolality High Normal/high Low
Management ◆ Electrolyte-free water restriction to 1000-1500ml/day if cardiovascular ◆ volume and sodium ◆ replace fluids
status allows resuscitation to maintain
1.8% saline if fluid restriction contraindicated (e.g. risk of DCI after SAH)
◆ fludrocortisone—may limit
◆ normovolaemia
◆ Demeclocycline—inhibits renal response to ADH sodium loss ◆ DDAVP if urine
output >250 ml/h
◆ ADH-receptor antagonists—inhibit binding of ADH to renal receptors
ADH, antidiuretic hormone; CSW, cerebral salt wasting syndrome; DCI, delayed cerebral ischaemia; DDAVP, 1-deamnio-8-D-arginine vasopressin; DI, central diabetes insipidus; SAH, subarachnoid
haemorrhage; SIADH, syndrome of inappropriate ADH secretion.
Normal values: plasma osmolality 278–305 mmol/kg; plasma sodium 135–145 mmol/l; urine osmolality 350–1000 mmol/kg; urine sodium 20–60 mmol/l or 100–250 mmol/24hr.
of antidiuretic hormone (ADH) release from the hypothalamic- and may be supplemented with a mineralocorticoid in the presence
pituitary axis (HPA). This results in inability to concentrate of hyponatraemia (54).
urine, and the production of large volumes of dilute urine. The
incidence of DI can be as high as 35% after TBI. The classic
symptoms of polyuria, polydipsia, and thirst are absent in un- Brain Death
conscious patients in whom the following criteria confirm the Death has historically been defined by cessation of cardiorespira-
diagnosis of DI: tory function, but this became complicated by the introduction of
◆ increased urine volume (usually >3000 ml per 24 hours). mechanical ventilation during the 1950s and 1960s. There is broad
consensus that human death is ultimately death of the brain, and
◆ high serum sodium (>145 mmol/L). that this crucially involves the irreversible loss of the capacity for
◆ high serum osmolality (>305 mmol/kg). consciousness, combined with the irreversible loss of the capacity
to breathe. The development and publication of the first widely
◆ abnormally low urine osmolality (<350 mmol/kg).
accepted standard for the confirmation of brain death came from
Confirmation of low urine specific gravity (<1.005) in the presence an ad hoc Committee of the Harvard Medical School in the US in
of high urine output and high serum sodium is suggestive (but not 1968, followed by comprehensive guidance in the UK in 1976 (55).
diagnostic) of DI. While there is an inevitable link between brain death and organ
The management of DI involves replacement and retention of donation, the primary reason for confirming brain death is to allow
water and replacement of ADH. Conscious patients are able to in- the withdrawal of life-sustaining therapies, including mechanical
crease their own water intake and this is often sufficient if the DI ventilation, from an individual who can no longer derive benefit
is self-limiting. In unconscious patients, fluid replacement is best from them.
achieved with water via a nasogastric tube, and urine output con- Confusingly, brain death is defined in two different ways based
trolled with synthetic ADH usually using small titrated doses of on ‘whole’ brain (US) and ‘brainstem’ (UK) formulations. The
1-deamnio-8-D-arginine vasopressin (DDAVP). central role of the brainstem in the state of irreversible coma that
constitutes brain death was incorporated into UK guidelines from
Endocrine Disorders the outset, whereas other jurisdictions preferred a whole brain ap-
Endocrine failure after ABI is related to direct injury to the HPA, proach. These apparent differences have little practical relevance
intracranial hypertension-related hypothalamic ischaemia, and because the clinical diagnosis of both is identical. Furthermore,
inflammation-related primary gland failure. HPA dysfunction death is not a single event but a process that leads progressively to
leading to adrenal insufficiency occurs in up to 50% of severe TBI the failure of all functions that constitute the life of a human being.
patients, and the effects can be long lasting. Acute screening for Once a threshold of irreversibility has been reached, and brain
pituitary insufficiency with standard hormone stimulation/re- death (whether whole brain or brainstem) is such a point, it is not
sponse tests should be considered in all at risk patients and those necessary to wait for the death of the whole organism for the inev-
with unexplained hyponatraemia or hypoglycaemia or persisting itable consequence of its biological death to be certain (55).
requirement for high-dose vasopressors. The effect of hormone There are international differences in the diagnosis of brain death
replacement on outcome is not well studied, but hydrocortisone but these are generally inconsequential. Importantly there are key
should be considered in the presence of refractory hypotension, areas of consistency (56):
283
◆ unresponsive coma with an established aetiology; Summary

◆ absence of reversible conditions; Neurocritical care is a subspecialty of intensive care medicine dedi-
◆ absent cortical or brainstem mediated motor reflexes; cated to the treatment of critically ill neurological patients. It has
◆ absent brainstem reflexes; matured over the last decade through new knowledge, advances
in imaging and monitoring techniques, and the introduction of
◆ loss of the capacity to breathe. neurointensivists and neuroscience critical care units. Critically
A clinical diagnosis of brain death is sufficient in many countries ill neurological patients require meticulous general intensive care
to confirm death. Crucially this incorporates three sequential but support as well as interventions targeted to their neurological dis-
inter-dependent steps. There must be no doubt that the patient’s co- order. The management of ABI is particularly complex and focuses
matose condition is due to irreversible brain damage of known aeti- on prevention of intracranial complications, optimization of sys-
ology, and potentially reversible causes of coma and apnoea, such as temic physiological variables to maintain cerebral perfusion and
drug effects, metabolic or endocrine disturbances, or hypothermia, substrate delivery, and management of non-neurological compli-
must be excluded. A clinical examination of brainstem reflexes and cations. Advances in monitoring and imaging techniques in associ-
apnoea test is then undertaken. Most national guidelines specify ation with improved understanding of the pathophysiology of ABI
the qualification as well as level of experience of the physicians have led to the introduction of more effective and individualized
determining brain death, the number of clinical examinations re- treatment strategies that have translated into improved outcomes
quired (usually two), and any mandated time interval between the for patients.
examinations. It is usual to wait 24 hours after hypoxic-ischaemic Management of critically ill brain- injured patients in a
brain injury before a determination of brain death is made, but there neurocritical care unit is associated with lower risk of mortality and
is generally less specific guidance for other clinical circumstances. poor neurological outcome compared to management in a general
A comprehensive clinical examination when performed by com- ICU. Early aggressive intervention can result in excellent outcomes
petent examiners has perfect diagnostic accuracy for the diagnosis in some patients who would previously have been deemed unsal-
of brain death, but confirmatory tests are required in addition to vageable, and clinicians must avoid unjustified early therapeutic ni-
clinical testing in some countries. In most they are optional and hilism while maintaining realistic expectations.
reserved for circumstances where some doubt exists about the clin-
ical diagnosis (e.g., following infusion of long-acting sedative drugs Cases and Multiple-Choice Questions
such as thiopental) or because the patient might be too unstable to
undergo an apnoea test. Confirmatory investigations generally fall
into two general categories that either demonstrate the loss of cere-
www.oxfordmedicine.com/otneuroanesthesiology.
bral electrical activity or confirm absence of intracerebral blood
flow (57).
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286
287
SECTION 3
Neurologic Patients
Undergoing
Non-Neurologic Surgery
24 Cerebrovascular Disease 289

Corey Amlong and Robert D. Sanders
25 Peri-Operative Considerations of Dementia, Delirium, and Cognitive Decline 297
26 Epilepsy 303
Adam D. Niesen, Adam K. Jacob, and Sandra L. Kopp
27 Parkinson’s Disease 309
28 Treatment of Psychiatric Diseases with General Anaesthetics 315
Laszlo Vutskits
28
289
CHAPTER 24
Cerebrovascular Disease
Corey Amlong and Robert D. Sanders
Introduction It should be noted that incidence and mortality have significant

geographic variability. In the United States, for example, a dispro-
Cerebrovascular disease and stroke account for nearly one in twenty portionately high incidence of strokes occur in the eight southern
deaths in the United States and have an estimated prevalence of states of North Carolina, South Carolina, Tennessee, Alabama,
2.6% in the American population (1). Nearly 800,000 people in the Georgia, Mississippi, Louisiana, and Arkansas, with an even more
US suffer a new or recurrent stroke annually, with 75% of these focused area within these states being responsible for a dispropor-
being a first attack; this equates to a stroke every 40 seconds (1). tionately high mortality rate (1, 7). In contrast, people residing in
Eighty-seven percent of these strokes are ischaemic in origin, 10% Mediterranean countries have a relatively low incidence of stroke
result from intracerebral haemorrhage, and 3% from subarachnoid (14), presumably related to diet and lifestyle, indicating that these
haemorrhage (1). two factors play a major role in the development of cerebrovascular
Peri-operative stroke is a rare consequence of surgical inter- disease.
vention and anaesthesia that has profound effect on patient out- As already mentioned, the majority of strokes are ischaemic in
comes; incurring a cerebrovascular accident (CVA) in the setting of origin. This ischaemia, however, may be born of many different
noncardiac, non-neurologic surgery is associated with an adjusted aetiologies. In cardiac surgery where historically there has been
eightfold increase in mortality (2). Incidence in this population is much attention paid to hypoperfusion from anaesthetic-induced
between 0.05–0.7% (2–4). Extrapolated to a global population this hypotension or cardiopulmonary bypass, embolism is actually
represents nearly two million strokes annually. The overall inci- been shown to be the most prevalent cause (15, 16). It is certainly
dence of postoperative stroke varies with type of surgery and patient possible that hypotension contributes to the frequency of embolic
characteristics; incidence after cardiac surgery is 4.6% with double occlusion; Caplan and colleagues (17) postulate that decreased
or triple valve surgery incurring an incidence of 9.7% (5). Table perfusion decreases clearance of microemboli, thereby leading
24.1 lists the incidence of stroke after various surgical procedures. to blockage of vessels and extension of the hypoperfused area
Mortality associated with stroke is high. All comers who suffer of brain. The direct mechanism of peri-operative stroke in non-
a stroke have a 30-day mortality of 9–13% (1, 6, 7). Those who cardiac cases is less well defined but may be more related to cere-
survive outside of this 30-day window have been shown to have a brovascular thrombosis than emboli (18). Regardless of the direct
higher than expected mortality rate compared to the general popu- cause of the stroke, there is a growing body of literature describing
lation, with a 20-year mortality of 26.8% (8). Patients presenting the contributory role of inflammation in stroke pathogenesis.
with stroke after undergoing general surgery have an in-hospital Specific inflammatory biomarkers have been linked to prediction
mortality rate of up to 26% (4,9). of occurrence and severity of stroke (19), and future preventative
Perhaps even more concerning than the high mortality is the therapy may be aimed in part at reducing some of these inflamma-
degree of disability associated with a cerebrovascular event. tory biomarkers in an effort to decrease stroke occurrence. Several
Disability from stroke is broad in scope, ranging from mild deficits inflammatory cytokines are increased following surgery (20), and
in cognition or mobility to complete dependence on others for ac- the body’s systemic inflammatory response to surgery and peri-
tivities of daily living. Some form of cognitive dysfunction has operative stress is widely accepted. With this in mind, it is not sur-
been shown to be present in half of patients six months after acute prising that many have theorized the increased incidence of and
stroke (10) and 22% of patients five years after acute stroke (11), mortality from peri-operative stroke is linked to amplification of
highlighting the pervasive nature of stroke sequelae. The 2013 inflammatory pathways seen in the peri-operative state.
Global Burden of Disease Study (12) calculated a global preva- Multiple attempts to identify the populations at greater risk for peri-
lence of ischaemic stroke of 3.17%. Despite this relatively low operative cerebrovascular events in an effort to aid prevention have
prevalence, however, ischaemic stroke was found to be responsible been made. Mashour and colleagues (2), using data from 523,059
for 11.89% of all years lost due to intellectual disability. A separate patients in the American College of Surgeons National Surgical
study using similar metrics projects cerebrovascular disease to be Quality Improvement Program (ACSNSQIP) database, identified
the number four contributor worldwide to disability-adjusted life nine pre-operative factors that were present more often in patients
years lost by the year 2020. In developing countries, it is projected who suffered peri-operative stroke during or after noncardiac, non-
to be the second-highest contributor behind only ischaemic car- neurologic surgery. These factors are listed in Box 24.1.
diac disease (13).
290
290 Section 3 neurologic patients undergoing non-neurologic surgery
Table 24.1 Incidence of stroke based on type of surgery. mainly by predisposing patients to atrial fibrillation, but in them-
selves carry an increased risk of stroke as well (22).
Type of Surgery Incidence (Reference) The peri-operative risk of stroke in patients with carotid dis-
ease is somewhat controversial, especially when patients are
Isolated CABG 3.8% (5)
asymptomatic from their carotid disease. As stated previously,
Combined CABG and valve surgery 7.4% (5) most peri-operative strokes are embolic in nature and not the
Double or triple valve surgery 9.7% (5) result of hypoperfusion. Bucerius and colleagues (5) identified
pre-existing cerebrovascular disease (including stenosis of one or
Isolated mitral valve 8.8% (5)
both carotid arteries) as a significant risk factor for peri-operative
Isolated aortic valve 4.4% (5) stroke in patients undergoing cardiac surgery. However, when
Beating-heart CABG 1.6%–2.5% (5) patients with carotid disease suffer a stroke after cardiac sur-
gery, the lesion is often on the side contralateral to the affected
Hip arthroplasty 0.4% (4)
carotid (23), indicating that the carotid disease cannot solely be
Colectomy 0.4% (4) held responsible. Delayed strokes occurring outside of the im-
Appendectomy 0.0% (2) mediate postoperative period may be precipitated by inadequate
peri-operative resuscitation and dehydration (15). Unfortunately,
Hernia repair 0.1% (2)
there is a paucity of data regarding the relationship between ca-
Hysterectomy 0.1% (2) rotid disease and stroke in patients undergoing noncardiac, non-
Abdominal exploration 0.5% (2) neurologic surgery.
Not surprisingly, having incurred a cerebrovascular event is in
Limb amputation 0.8% (2)
itself a major risk factor for another such event. Rutten-Jacobs and
Spine surgery 0.1% (2) colleagues (8), in a prospective cohort of 724 patients aged 18–50
Pancreatic surgery 0.3% (2) followed on average 9.1 years after first-ever stroke, transient is-
chaemic attack (TIA), or intracerebral haemorrhage found that cu-
mulative 20-year risk of recurrent stroke was 19.4%. Prior stroke
or TIA has consistently been identified as a risk factor for peri-
Atrial fibrillation and valvular disease are not ACS NSQIP vari-
operative stroke in patients undergoing cardiac and aortic surgery
ables and thus were not included in the aforementioned study; how-
(5), carotid endarterectomy (24) and general surgery (2, 9, 18).
ever, both have long been known to be a significant risk factor in
The aforementioned statistics on the epidemiology of stroke
developing stroke in the general population. Atrial fibrillation is as-
refer strictly to overt strokes, or acute cerebral ischaemic attacks
sociated with a fivefold increase in stroke risk across all ages (1) and
that have clear clinically apparent sequelae. These statistics do not
has been found to be a contributing factor in nearly a quarter of all
include covert strokes, which may be defined as acute cerebral is-
strokes in patients aged 80–89 years (21), due largely to the propen-
chaemic attacks without clear clinical manifestations. Vermeer and
sity for left atrial thrombus formation in this arrhythmia. Cardiac
colleagues (25) found that 18.4% of unselected adults aged 60 to
dysrhythmias have also been shown to be associated with stroke in
90 years had magnetic resonance imaging (MRI) evidence of covert
the peri-operative setting (9). Disease of the mitral valve, in par-
stroke, while only 3.3% had evidence of symptomatic stroke. The
ticular mitral stenosis, increases the risk of systemic embolism
same study, at a five-year follow-up interval, found a 9% incidence
of new covert stroke in patients without imaging evidence of prior
cerebral ischaemia, and a 30% incidence in patients with prior evi-
dence of cerebral ischaemia. Patients with MRI evidence of covert
Box 24.1 Independent Predictors of Stroke stroke have nearly double the risk of the general population of
developing dementia and have a steeper decline in global cognitive
◆ Age ≥62 years. function with impaired performance on neuropsychological testing
Myocardial
◆ infarction in previous six months. (26), indicating a significant impact on the daily lives of these pa-
tients. A recent pilot study (27) showed an 11.4% incidence of covert
Acute
◆ renal failure. stroke in patients undergoing noncardiac, non-neurologic surgery.
◆ History of stroke with or without neurologic deficits. The significance of this is yet unknown, but if the decreased cogni-
◆ Pre-existing dialysis. tive function after covert stroke in the non-surgical population (26)
is extrapolated to the surgical population, these findings are indeed
◆ Hypertension requiring medications. concerning.
◆ History of transient ischaemic attack.
◆ Chronic obstructive pulmonary disease. Peri-Operative Considerations to Minimize
◆ Current smoker. Risk of Stroke
The increased risk of stroke associated with anaesthesia and surgery
Reproduced from Anesthesiology, 114, 6, Mashour G, Shanks A and compared to non-surgical controls (28) demands that providers be
Kheterpal S. Perioperative stroke and associated mortality after noncardiac, cognizant of several considerations when taking care of the patient
nonneurologic surgery, pp. 1289–1296. Copyright (2011) with permission with cerebrovascular disease. Given the increased morbidity and
from Wolters Kluwer Health, Inc.
mortality associated with peri-operative stroke it is imperative that
291
Chapter 24 cerebrovascular disease 291
providers take steps to minimize risk when taking care of these nature (15, 16). Other literature suggests that thromboembolism is
complicated patients. the underlying cause of peri-operative stroke in patients who have
undergone general surgery (18).
Timing of Elective Surgery Findings of the POISE trial (38) illustrate a link between high-
It is clear that patients who have a history of cerebrovascular dis- dose metoprolol use and peri-operative stroke in patients under-
ease are at an increased risk of stroke in the peri-operative period; going noncardiac surgery. Metoprolol use was associated both with
pre-existing cerebrovascular disease has consistently been shown to increased rates of clinically significant hypotension and increased
be a risk factor for peri-operative stroke (2, 5, 9, 18, 24). What is less rates of peri-operative stroke and death, thus suggesting a possible
clear is the temporal relation between prior stroke and risk during correlation between peri-operative hypotension and peri-operative
and after elective surgery. While it has been shown that cerebral stroke. This in part led to a large retrospective case control study
autoregulation is impaired after stroke (29), it is unclear how clin- (39) that found a significant association with the duration of time
ically significant this is in the setting of surgery where other factors that a patient’s blood pressure was decreased 30% from baseline
such as blood loss, dehydration, and anaesthesia may all contribute and the incidence of postoperative stroke. Another retrospective
to cerebral hypoperfusion. Relatively early studies examining the study by Mashour and colleagues (40) examining the effects of
temporal correlation of stroke and surgical interventions yielded more clinically relevant doses of metoprolol on stroke found an in-
no evidence that recent or remote stroke influences the risk of peri- creased risk of peri-operative stroke in patients who received either
operative stroke (30, 31). On the contrary, a more recent study by pre-operative or intra-operative metoprolol compared to patients
Jorgensen and colleagues (32) found that history of stroke was as- who received other beta-blockers. The same study also found in-
sociated with adverse outcomes after surgery, especially in patients creased stroke risk in patients who had periods of intra-operative
who suffered a cerebrovascular event within nine months of sur- hypotension, but there was no collinearity between hypotension
gery. Certainly, more studies are needed to further clarify if timing and pre-operative metoprolol use.
of elective surgery after cerebrovascular event is important in risk Patients with existing cerebrovascular disease must be considered
mitigation. The most recent guidelines regarding this topic from separately from those simply at risk. Although carotid disease does
the Society for Neuroscience in Anesthesiology and Critical Care not in itself seem to increase the risk of stroke due to hypoperfusion
(SNACC) (33), published prior to the Jorgensen study, suggest a (15), it is important to keep in mind that patients who have suf-
case-by-case approach and involvement of the patient’s neurologist fered a recent cerebrovascular event have altered autoregulation
when discussing timing of elective surgery. (29) and may be more dependent on systemic pressure for cerebral
perfusion.
Type of Anaesthetic It remains unclear just how clinically significant the associ-
No data currently exist examining stroke risk in a broad surgical ation is between intra-operative hypotension and postoperative
patient population as related to anaesthetic technique. However, stroke. Nevertheless, it seems prudent to attempt to maintain
evidence does exist showing that the use of regional anaesthesia in intra-operative patient blood pressure within 30% of their base-
patients undergoing knee and hip arthroplasty is associated with line, especially in patients who are high risk for peri-operative
a reduced risk of stroke compared to general anaesthesia (34, 35). cerebral infarct. Permissive hypertension should be allowed in
A large multicentre randomized control trial performed by Lewis patients who have had acute stroke to maximize collateral per-
and colleagues (36) showed no difference in stroke incidence in fusion until intervention is achieved. Intra-operative blood
patients undergoing carotid endarterectomy under general versus pressure goals should be determined based upon the patient’s
local anaesthesia. baseline blood pressure as opposed to predetermined mean ar-
The potential for neuroprotection from anaesthetic agents has terial or systolic pressures or attempts to estimate autoregulation
long been studied. Many studies on this matter yield inconclusive limits (39, 41).
results or data that may not be clinically applicable. A recent review
of qualifying randomized control trials by Bilotta and colleagues Anaemia
(37) found no evidence of improved mortality in patients receiving Surgery and blood loss frequently go hand in hand. Blood loss,
studied drugs with neuroprotective properties. However, the au- of course, leads to decreased levels of haemoglobin, which in
thors do suggest that data from several studies points towards de- turn reduces the oxygen-carrying capacity of blood. Significant
creased post-operative cognitive decline. See Chapter 8 for more intra-operative bleeding has been found to be an independent
detail on the subject of neuroprotection. predictor of postoperative stroke in high-risk patients under-
going noncardiac surgery (38). In cardiac surgery requiring by-
Blood Pressure pass, both the post-bypass haemoglobin and the volume of blood
Hypotension in the peri-operative period is common and is fre- transfused are independent predictors of stroke with the number
quently implicated as the culprit when stroke occurs. Until recently of units transfused directly associated with risk of stroke (42).
there has been very little evidence to support this assumption. Lower haemoglobin levels, in the absence of hypotension, cor-
Complicating the examination of the relationship between peri- relate with larger cerebral infarct area in patients outside of the
operative hypotension and stroke is the multitude of definitions surgical arena who have suffered a stroke (43). It seems apparent
used for the term ‘hypotension,’ making study-to-study compari- that there exists a correlation between anaemia and stroke. As
sons difficult. such, SNACC guidelines suggest that haemoglobin levels should
Cardiac surgery has classically been associated with periods be kept above 9 gm/dl in patients already on a beta-blocker to
of hypotension, be it from long bypass runs or cardiac dysfunc- minimize the risk of stroke in patients undergoing noncardiac,
tion. However, most strokes after cardiac surgeries are embolic in non-neurologic surgery (33).
29
Glycaemic Control and continued not longer than 21 days, may have some benefit in
The optimal blood glucose level for patients having surgery is a reducing risk of recurrence (50).
long-studied and long-debated topic. Risk of end-organ damage Vitamin K antagonist therapy is often prescribed to patients with
and other deleterious effects of hyperglycaemia must be balanced atrial fibrillation with the occasional patient with atrial fibrillation
with the risk of over-treatment resulting in hypoglycaemia. and coronary artery disease receiving both a vitamin K antagonist
Hyperglycaemia has long been known to have deleterious effects and antiplatelet agent. Given that vitamin K antagonists are at least
on neurologic outcome (44). Studies in animals using models of as effective as antiplatelet agents for prevention of acute coronary
cerebral ischaemia suggest that hyperglycaemia exacerbates intra- syndrome, this double therapy likely puts patients at an increased
cellular acidosis, causes accumulation of extracellular glutamate, risk of bleeding unnecessarily (50). The exception, of course, is pa-
worsens brain oedema formation and blood-brain barrier disrup- tients who have received recent cardiac stents.
tion, and increases the tendency for haemorrhagic transforma The dilemma occurs when the anticoagulated patient presents
tion (44). In carotid endarterectomy (45) and cerebral aneurysm for surgery. The risk of intra-operative bleeding must be weighed
surgery (46) where ischaemia is predictable, hyperglycaemia against the risk for peri-operative stroke. This is certainly true for
increases the risk of poor neurologic outcomes. Rosso and col- patients with atrial fibrillation, which is a major risk factor for peri-
leagues (47) showed that, in patients with ischaemic stroke, those operative stroke. Studies to guide management of these patients,
without hyperglycaemia had MRI evidence of reduced infarct in terms of mitigating risk of peri-operative stroke, are lacking.
size and had better outcomes compared to patients with hyper- Most patients with atrial fibrillation who are being treated with
glycaemia. This finding was independent of the mode of insulin an oral vitamin K antagonist can safely discontinue the drug prior
therapy. to surgery without need for bridging therapy. In patients with a
Similar to hyperglycaemia, hypoglycaemia carries risks of poor higher risk of thromboembolism, bridging with heparin should be
outcomes. The NICE-SUGAR trial (48) demonstrated that critic- considered (51).
ally ill patients had increased rates of hypoglycaemia and increased Patients with a history of stroke or TIA who develop atrial fib-
risk of death when receiving intensive insulin therapy. The same rillation after cardiac surgery should be considered for therapy
therapy in patients with traumatic brain injury is associated with with heparin (52). Also, in the cardiac surgery population, ob-
decreased levels of extracellular cerebral glucose, abnormal cere- servational studies have shown protective effect of aspirin against
bral glucose metabolism, and increased mortality (49). Given the peri-operative stroke (53, 54). There is little evidence to guide man-
limited ability of the central nervous system to compensate for low agement of patients taking antiplatelet agents for stroke prevention
glucose availability, it is no surprise that hypoglycaemia is detri- who are undergoing noncardiac procedures. The recent POISE-2
mental to the injured or ischaemic brain. trial suggested that patients who continued aspirin had no differ-
The ideal blood glucose range in any surgical patient, especially ence in incidence of peri-operative stroke compared to placebo,
in the patient with cerebrovascular disease undergoing surgery, is although this study brought to light the risk of aspirin use on peri-
a controversial subject. In the patient at high risk for stroke under- operative bleeding (55). It should be noted that stroke was not a
going noncardiac surgery, a blood glucose of 180mg/dL has been primary outcome in this study. Interestingly, patients who initiated
suggested as the upper limit (33). Common sense dictates that aspirin during the course of the study were found to have a lower
if treatment is required, blood glucose should be monitored fre- incidence of peri-operative stroke, although the authors admit
quently to avoid episodes of hypoglycaemia. this finding may have been coincidental. Nevertheless, the sugges-
tion remains that aspirin use in the peri-operative period may re-
duce stroke risk, although this is at the cost of increased bleeding
Anticoagulation
risk (55).
It is increasingly common for patients to present for surgery who
have been on some sort of anticoagulation regimen either for atrial
fibrillation or cardiac stents. Patients who have suffered an is- Care of the Patient with Peri-Operative CVA
chaemic stroke or TIA, regardless of the cause, are also frequently Despite the best intentions of peri-operative providers and the
placed on some sort of anticoagulant to mitigate risk of recurrent many steps they may take to minimize risk of stroke, the occa-
stroke. Recommendations from the American Heart Association sional peri-operative stroke will surely still occur. Quick and effi-
are for treatment with antiplatelet agents after noncardioembolic cient management of these patients is key in minimizing sequelae.
ischaemic stroke to reduce risk of recurrence (50). This recommen- The old adage ‘time is brain’ certainly applies in the peri-operative
dation is based on evidence suggesting no significant difference be- setting. Quick recognition, good communication, and fluid man-
tween antiplatelet agents and vitamin K antagonists in this regard, agement of the patient with acute stroke will lead to more effi-
with the vitamin K antagonists putting patients at greater risk for cient therapeutic interventions. Assessment and treatment of acute
bleeding complications (50). The specific antiplatelet agent chosen peri-operative strokes should follow the guidelines set forth by
should be tailored to the individual patient. The most common the American Heart Association Guidelines for management of
choice, of course, is aspirin, but other antiplatelet agents are in- Patients with Acute Ischemic Stroke in 2013 (56) as well as the up-
creasingly in use. Evidence suggests the combination of aspirin dated 2015 guidelines that focus on endovascular treatment (57).
and clopidogrel for reducing risk of recurrent stroke when con-
tinued for two to three years after stroke occurrence may increase Timing: When Do Strokes Occur?
risk of bleeding compared to either agent on their own. However, Most peri-operative strokes occur on or after postoperative day 2
there also exists evidence that aspirin and clopidogrel combination (9, 18), suggesting that direct insults from surgery and anaesthesia
therapy, when initiated within 24 hours of a minor stroke or TIA may be less important than postoperative events. Furthermore,
293
studies examining details of peri-operative stroke in noncardiac Table 24.2 National Institute of Health stroke scale.
surgery report only 5.8% occur during the operation (18).
A direct causal agent behind this delay in stroke occurrence has Test Response and Score
not been identified; it is most likely that many factors contribute.
Consciousness Alert–0
Inflammatory markers may be increased long after surgery (19,
Drowsy–1
20) and the link between inflammation and stroke is established
(19). The postsurgical patient might also be at risk for intravascular Obtunded–2
dehydration due to under-resuscitation, fluid shifts, and nil-per-os Comatose/unresponsive–3
status, possibly creating a cerebrovascular environment favourable Orientation (two questions— Answers both questions correctly–0
for microemboli formation (17). Postoperative vascular endothe- month and age) Answers one question correctly–1
lial dysfunction may play a role as well, as anaesthetics have been Answers neither question correctly–2
shown to disrupt normal endothelial actions (58). The disrupted
endothelium may lead to plaque rupture, thrombus formation, or Response to commands Performs both tasks correctly–0
(two tasks –open/close eyes, Performs one task correctly–1
vasospasm. Lastly, the propensity for hypercoagulability seen with
squeeze hand)
surgery coupled with delayed re-initiation of patients’ anticoagu- Performs neither task correctly–2
lants after surgery may also predispose them to stroke. Gaze Normal horizontal movement–0
Partial palsy–1
Assessment/Diagnosis
Complete palsy –2
Diagnosis of a stroke in the peri-operative setting may be more
difficult for several reasons. Obviously, an intra-operative stroke Visual fields No defect–0
will not be diagnosed until the patient emerges from anaesthesia. Partial hemianopia–1
Clinical signs of cerebral ischaemia postoperatively may be masked Complex hemianopia–2
by residual anaesthetic, paralytic, narcotic pain medication, or a Bilateral hemianopia–3
milieu of several other pharmacologic agents administered in the Facial movement Normal–0
peri-operative setting. Presence of residual volatile anaesthetic is Minor weakness–1
easily measured in the operating room; however, residual effects of
Partial weakness–2
propofol and dexmedetomidine are less easily quantified. Reversal
Complete unilateral palsy–3
of some anaesthetic drugs may be useful in facilitating a neurologic
exam but may also lead to haemodynamic instability from pain or Motor function (both arms) No drift–0
direct effects of the reversal agent. In the patient with delayed emer- Drift before five seconds–1
gence, altered mental status, or neurologic deficit where pharmaco- Falls before five seconds–2
logic cause has been ruled out or made less likely, stroke should be No effort against gravity–3
considered. No movement–4
Assessment of acute stroke should start with physical examin-
ation of the patient and evaluation of vital signs including blood Motor function (both legs) No drift–0
pressure, oxygen saturation, and temperature. A detailed neuro- Drift before five seconds–1
logic exam utilizing the National Institutes of Health Stroke Scale Falls before five seconds–2
should also be performed (Table 24.2). Laboratory studies including No effort against gravity–3
serum glucose, electrolytes, complete blood count, and coagulation No movement–4
studies may also help identify causes of altered neurologic function. Ataxia None–0
When initial evaluation leads the provider to strongly suggest
Ataxia in one limb–1
stroke as the cause of deficits, imaging should be used to determine
Ataxia in two limbs–2
if the stroke is ischaemic or haemorrhagic. MRI provides more ac-
curate diagnostic information but the duration of the scan limits Sensory No  loss–0
its usefulness. Non-contrast computed tomography (CT) is a much Mild sensory loss–1
more rapid means of imaging and generally provides adequate Severe sensory loss–2
diagnostic information. CT perfusion imaging or angiography may
Language Normal–0
be added to the scan to help determine which patients may benefit
Mild aphasia–1
from prompt endovascular intervention.
Severe aphasia–2
Management of Peri-Operative Stroke Mute/global aphasia–3
Management of acute peri-operative stroke mirrors that of out-of- Articulation Normal–0
hospital stroke. The first and most important divergence point in Mild dysarthria–1
management is dictated by the type of stroke: ischaemic or haem- Severe dysarthria–2
orrhagic. Haemorrhagic strokes are the minority and the provider
Extinction/inattention None–0
will be led down a pathway of strict blood pressure control, reversal
of coagulation defects, and possible surgical correction as out- Mild/one sensory modality lost–1
lined in recommendations from the American Heart Association/ Severe/two sensory modalities lost–2
American Stroke Association (59, 60). Source data from NIH Stroke Scale (https://stroke.nih.gov/resources/scale.htm).
294
Ischaemic strokes are far more common in the peri-operative and providers should take care to thoroughly prepare patients in a
period and treatment is generally aimed at restoring blood fashion that minimizes risk in the peri-operative period.
flow to affected brain. A common intervention is recombinant
tissue plasminogen activator (rTPA), although administration References
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297
CHAPTER 25
Peri-Operative Considerations
of Dementia, Delirium,
and Cognitive Decline
Introduction go undiagnosed for a period of time. Thus, epidemiologic metrics

such as prevalence and incidence may not accurately reflect true
Dementia is a deeply distressing experience for patients, families, disease influence within a population.
and caregivers. Symptoms that characterize dementia often include
personality changes, impaired memory, and decline in thinking
and learning. Ultimately, patients often become unable to perform Peri-Operative Considerations
instrumental activities of daily living (IADLs) and become reliant Unfortunately, there are very few data available to guide peri-
on caregivers. This burden may become more salient in the peri- operative decision-making for those with dementia and cognitive
operative setting, which salience has led many to question whether impairment. Some studies implicate certain anaesthetic agents in
surgery and anaesthesia lead to either accelerated cognitive decline promoting AD pathophysiology, although most available data come
or the precipitation of new-onset cognitive impairment. Indeed, from the laboratory. Large database studies have found conflicting
postoperative alterations in cognition have been observed over results as to the association between anaesthesia and postoperative
many years, and the question remains as to whether or not sur- cognitive impairment. This chapter reviews the preclinical and
gery and anaesthesia affect postoperative cognitive trajectory. This clinical evidence that possibly link anaesthesia and postoperative
question is especially pertinent in vulnerable patients, such as those cognitive impairment, though presently, no firm conclusions can
with dementia. Postoperative delirium and postoperative cognitive be drawn.
dysfunction (POCD) are also growing public health concerns, al- In 2004, Eckenhoff and colleagues first reported that, in cultured
though evidence-based management guidelines are in their infancy. cells, the anaesthetic isoflurane induces amyloid-beta (Aβ) oligo-
With an aging population and ever-increasing surgical volume, any merization, which is one of hallmarks of AD pathophysiology (4).
deleterious effects on cognition could have an enormous impact. Similar findings have since been demonstrated by other labora-
Thus, further research into the effects of anaesthesia and surgery tories (5). Isoflurane has also been found to induce tau protein
on postoperative cognitive function is both timely and critical. This phosphorylation, another hallmark of AD pathophysiology (6);
chapter reviews peri-operative considerations for neurologically sevoflurane has demonstrated similar findings in the laboratory (7,
vulnerable patients, such as those with pre-existing cognitive im- 8). Interestingly, desflurane was recently shown not to induce Aβ
pairment and dementia. Additionally, it discusses postoperative de- production unless accompanied by hypoxia (9). Desflurane may
lirium, POCD, and cognitive trajectory after surgery. also induce less metabolic stress (i.e., mitochondria-associated
cellular apoptosis) and less learning impairment compared to
isoflurane (10). Similarly, propofol has been shown to inhibit
Epidemiology isoflurane-induced Aβ aggregation and caspase activation (11) and
The estimated global prevalence of dementia is approximately enhance cognitive function in mice (12). Thus, each of these anaes-
5–7%, and the overall number of people with dementia worldwide thetics seemingly has a different preclinical neurobiological signa-
is expected to double every 20 years (1) (Figure 25.1). Alzheimer’s ture with regard to AD pathophysiology. In particular, desflurane
disease (AD) is the most common form of dementia, affecting an and propofol may be associated with less neurologic harm com-
estimated 5.3 million Americans in 2015 (2). Furthermore, approxi- pared to other agents, although further clinical exploration is re-
mately 11% of Americans age 65 and older have AD (2), and with an quired. These findings are summarized in Table 25.1.
estimated 19 million patients age 65 and older requiring inpatient Clinical investigation has not been nearly as robust as the labora-
procedures annually (3), up to nearly two million AD patients per tory research on this topic. A small pilot study demonstrated po-
year may require anaesthesia services in US acute care hospitals tentially less decline in postoperative cognitive function in patients
alone. Because AD evaluation and diagnosis is often a gradual, pro- who received desflurane compared to isoflurane (13), although
tracted process, many patients with AD pathophysiology may often the study was limited by sample size and follow-up duration.
298
140 anaesthesia group was older and had a higher comorbidity burden
compared to controls. Furthermore, the highest risk groups under-
120 went non-cardiovascular surgery and were not exposed to general
115.4
Dementia Patients (millions)
Projected Global Number of
100
anaesthesia, which appears counterintuitive. Thus, factors other
than surgery and anaesthesia likely contribute to the development
80 of dementia. In fact, prediction models have largely demonstrated
65.7 that clinical characteristics—such as age, baseline cognitive impair-
60 ment, and level of education—predict postoperative cognitive im-
pairment (18). In contrast to the mentioned study, a retrospective
40
35.6 case-control study from the Mayo Clinic found no association be-
20 tween procedures requiring general anaesthesia and the risk for
subsequent dementia (19). Ultimately, population-based, obser-
0 vational studies should be interpreted with caution, as causation
2010 2030 2050
cannot be directly inferred and unaccounted for variables are
Figure 25.1 Global prevalence of dementia. Prevalence is expected to present.
approximately double every 20 years based on recent projections. Currently, there are no guidelines for the peri-operative man-
Reprinted from Alzheimer’s & Dementia, 9, 1, Prince, M., Bryce, R., Albanese, E., Wimo, A., agement of patients with dementia. Despite the growing body of
Ribeiro, W., Ferri, C. P. The global prevalence of dementia: a systematic review and metaanalysis,
preclinical evidence suggesting a link between exposure of cer-
pp. 63–75. Copyright (2013) adapted with permission from Elsevier.
tain anaesthetics and neurotoxicity, further clinical confirmation
is needed. The pilot studies described previously represent a good
foundation for future prospective clinical investigation. Pre-
Accelerated progression of mild cognitive impairment (MCI) was operative biomarkers and specific anaesthetics (i.e., desflurane and
recently demonstrated with sevoflurane anaesthesia compared to propofol) may offer a tailored approach for minimizing neurologic
propofol and epidural anaesthesia (14). Additional preliminary harm for those at risk, pending further investigation. The efficacy of
data have demonstrated that differences in human cerebrospinal such a strategy, however, requires further clinical validation. Large
fluid Aβ and tau protein concentrations may predict postoperative database studies demonstrate conflicting findings with regards to
cognitive impairment, and isoflurane and desflurane may differ- the link between surgery and dementia, and large epidemiologic
entially affect these proteins (15, 16). It is hoped that this line of studies have to be interpreted with caution. At present, no definitive
investigation will lead to a novel method by which patients at risk clinical conclusions can be drawn with regards to anaesthesia and
for postoperative cognitive impairment can be identified. Various dementia risk. Well-designed, multicentre trials are required before
anaesthetic agents may then differentially modulate this risk, but clinical recommendations can be made.
further work is needed to clarify these preliminary findings. From a
population-based standpoint, multiple epidemiologic studies have
examined the associations between anaesthesia and surgery and
Postoperative Delirium
subsequent dementia risk. Recently, a retrospective longitudinal Patients with dementia and other forms of cognitive impairment
study demonstrated an association between dementia risk and ex- are at considerably increased risk for postoperative delirium (20).
posure to general anaesthesia (adjusted hazard ratio 1.75 [95% con- The Diagnostic and Statistical Manual of Mental Disorders, Fifth
fidence interval 1.59–1.92]) (17). There are significant limitations Edition (DSM-5) defines delirium as disturbances in attention,
to consider, however. The study was retrospective in design, and the awareness, and cognition that tend to fluctuate and develop over a
short period of time (21). Surgical patients are particularly prone to
the development of delirium, with incidences ranging from 6.7% in
Table 25.1. Anaesthetic neurodegeneration—laboratory findings elective general cases to approximately 70% in trauma and surgical
intensive care units (22, 23) (Figure 25.2). Across epidemiologic
Anaesthetic Laboratory Findings Implications studies, age, pre-operative cognitive impairment, urgent surgery,
and higher comorbidity burden have all been consistently iden-
Isoflurane Increased Aβ production (4, 5), Promotion of AD
tau protein phosphorylation (6). pathophysiology in the
tified as risk factors associated with postoperative delirium (20,
laboratory setting. 24–26). Hospitalized patients with these risk factors may be more
susceptible to peri-operative brain insult.
Sevoflurane Increased Aβ production (7, 49), Promotion of AD
The pathophysiology of delirium is likely multifactorial and
tau protein phosphorylation (8). pathophysiology in the
manifests on a number of neuroscientific levels. In vulnerable
laboratory setting.
brain regions, neurotransmitter imbalances—specifically between
Desflurane No increase in Aβ production May not promote AD acetylcholine and dopamine—have been associated with delirium
unless accompanied by hypoxia pathophysiology to the (27). Adverse inflammatory responses have also been posited to
(9). same degree as isoflurane,
play a role in delirium pathogenesis. Specific proinflammatory
sevoflurane.
cytokines—especially interleukin-6 (IL-6)—have been found to
Propofol Inhibition of isoflurane-induced May help alleviate be elevated in delirious patients compared to controls (28, 29). In
Aβ aggregation and caspase isoflurane-induced a recent pilot clinical trial, ketamine attenuated the incidence of
activiation (11). propagation of AD
postoperative delirium, and patients treated with ketamine had re-
pathophysiology.
duced levels of c-reactive protein (CRP) compared to the placebo
29
Chapter 25 dementia 299
80 in elderly patients after anaesthesia and surgery, Moller and col-

70%
70 leagues used a neuropsychological testing battery to test for POCD in
60 the landmark 1998 International Study of Post-Operative Cognitive
Incidence (%)
50
40%
Dysfunction (ISPOCD1) multicentre study (40). Cognitive decline
40 36% was indeed noted in elderly patients up to 3 months after major
30%
30 surgery, and this decline occurred independently of peri-operative
20 18%
physiologic derangements studied (i.e., hypotension and hypox-
10 7%
aemia). Interestingly, patients’ self-reported insights into cognitive
0
function did not correlate with testing results in the study, indicating
s
iac
lar
re
nt
ive
CU
that patients may not be objectively aware of cognitive performance.
tu
ge
cu
rd
ct
aI
ac
er
Ele
as
Ca
Fr
um
Em
Follow-up data from the same group demonstrated that only 0.9%
rV
l,
p
ra
ra
ajo
l,
Hi
ne
ra
l/T
of patients who completed all testing demonstrated POCD at one to

M
c,
ne
Ge
di
ica
Ge
ae
two years after surgery (41); however, the true incidence of POCD
rg
op
Su
rth
may have been underestimated, as patients who did not complete

O
all testing possibly had a lower functional status and higher disease
Figure 25.2 Delirium incidence across various surgical populations. Individual
percentages were extracted from representative studies in the literature (22, 23, burden. Alternatively, POCD may have been overestimated given the
35, 50–57), and composite averages were calculated for cardiac (35, 50, 51), major lack of long-term, rigorous baseline testing. Nonetheless, this also
vascular (52–54), and hip fracture surgery (55, 56). suggested that POCD for most patients may have been a transient,
reversible phenomenon. Along these lines, a 2007 systematic review
found that POCD may indeed occur in noncardiac surgery patients
group (30). Thus, inflammation may be closely involved with de- soon after surgery, although most studies reported either no decline
lirium pathophysiology, and cytokine-mediated blood-brain bar- in cognitive function or improved cognitive function six months or
rier (BBB) disruption could be another potential mechanism by later after surgery (42). A number of methodological issues were
which this occurs (31). Lastly, an additional recent finding is the present in many of these studies, including lack of pre-operative cog-
link between AD neuropathogenesis (e.g., reduced Aβ/Tau ratio in nitive trajectory. In 2009, Avidan and colleagues were able to retro-
cerebrospinal fluid) and postoperative delirium (32). These physio- spectively track long-term cognitive function prior to surgery using
logic insults that lead to delirium might manifest as network-level the Washington University Alzheimer’s Disease Research Center
brain disturbances. Recent data have demonstrated loss of func- (43). In doing so, they identified three cohorts—surgical, medical
tional connectivity among brain regions in delirious cardiac sur- illness, and control—for tracking cognitive trajectory. No associ-
gery patients (33). These findings may ultimately reflect a lack of ation was found for any long-term effects of noncardiac surgery or
information processing during delirium, but further work remains medical illness on cognition. Patients with dementia declined more
to be done. quickly than nondemented patients, though neither noncardiac sur-
Prevention and treatment are paramount, as postoperative de- gery nor medical illness were associated with accelerated cognitive
lirium has been associated with prolonged hospital admission, decline compared to controls.
cognitive decline, functional disability, and increased mortality Nonetheless, even if cognitive dysfunction after surgery is a tran-
(34–37). Cognitive decline is a particular concern, as recent data sient phenomenon, it may represent a vulnerable period for pa-
demonstrate that patients who experience postoperative delirium tients, as POCD has been associated with increased mortality within
may be at risk for immediate cognitive decline after surgery and the first year after surgery (18). Recently, various neuromonitoring
delayed cognitive recovery postoperatively (35) (Figure 25.3). The strategies—such as cerebral oximetry and electroencephalography
American Geriatrics Society released guidelines for the preven- (EEG)-guided anaesthesia—have been tested to examine the effi-
tion of postoperative delirium (38), and such efforts could ultim- cacy of minimizing postoperative delirium and POCD shortly after
ately help reduce postoperative delirium-associated morbidity and surgery. Preliminary results have been encouraging, as EEG-and
mortality. cerebral oximetry-guided protocols have demonstrated early suc-
cess at minimizing cognitive dysfunction after surgery (44–46). This
may represent an impactful strategy through which anaesthetists
Cognitive Decline may reduce neurologic morbidity and mortality postoperatively,
The idea of cognitive decline after anaesthesia and surgery has been though larger multicentre trials are needed.
considered for many years. Postoperative cognitive changes have Ultimately, controversy exists as to as to the reality of POCD. This
been appreciated since the 1950s, when a case series from Cowley might stem, in part, from the lack of standardized POCD defin-
Road Hospital in Oxford documented postoperative changes in ition and testing. Current neuropsychometric testing batteries vary,
personality and cognition (39). Cognitive decline after anaes- and while there is considerable overlap in testing strategies among
thesia and surgery, known as postoperative cognitive dysfunction studies, cognitive testing strategies have not been identical. As men-
(POCD), lacks a standardized definition, although it generally re- tioned, investigators are also faced with many confounders when
fers to the decline in various domains of cognitive function after studying cognitive trajectory after surgery. Pre-operative cognitive
anaesthesia and surgery. This decline may last for days, weeks, or mapping, various peri-operative factors (e.g., type of anaesthesia,
even years in certain circumstances, as described in more detail in type of surgery, medications received, complications during admis-
the following sections. sion), and medical comorbidities may all independently contribute
Much of the available data come from the previous two decades of to postoperative cognitive course. Cognitive decline after cardiac
research. After accumulating reports of early cognitive dysfunction surgery, for example, seems much more pronounced compared to
30
(a) Unmatched Analysis

30
25
Estimated Score
20
No delirium
15 Delirium
0
Before 2 5 30 183 365
Surgery Days after Surgery
(b) Sensitivity Analysis with Matched Baseline Score

30
25
Estimated Score
20
No delirium
15 Delirium
0
Before 2 5 30 183 365
(c) Sensitivity Analysis with Duartion of Delirium

30
25
Estimated Score
20
No delirium
<3 Days delirium
15 ≥3 Days delirium
0
Before 2 5 30 183 365
Figure 25.3 Cognitive trajectory by mini mental status exam (MMSE) score depicted after cardiac surgery. Panel A displays the main (unmatched) analysis of all 225
patients in this study. Patients with delirium had a more significant decrease in MMSE score compared to those without delirium (7.7 points vs. 2.1, respectively, p<0.001).
Of note, however, patients with delirium had a lower MMSE at baseline compared to those without delirium (25.8 vs. 26.9, p<0.001). Panel B shows cognitive trajectory
in patients after matching for baseline MMSE scores in delirious and non-delirious patients. After this adjustment, mean MMSE scores did not differ significantly
between groups at 6 and 12 months (p=0.06). Panel C demonstrates the relationship between duration of delirium and cognitive trajectory. Delirium lasting ≥3 days was
associated with a greater decrease in MMSE score and slower recovery time compared to patients with delirium lasting <3 days.
Reproduced from The New England Journal of Medicine, Saczynski, J. S., Marcantonio, E. R., Quach, L., et al. Cognitive trajectories after postoperative delirium, 367, 1, pp. 30–39. Copyright © 2012
Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
301
Chapter 25 dementia 301
noncardiac surgery (47). This should highlight the challenges as- and increases beta-amyloid protein levels. Archives of Neurology.
sociated with trying to study the effects of individual variables on 2009;66(5):620–31.
POCD. Updated consensus statements and recommendations may 8. Le Freche H, Brouillette J, Fernandez-Gomez FJ, Patin P, Caillierez R,
Zommer N, et al. Tau phosphorylation and sevoflurane anesthesia: An
be a reasonable start towards a unified approach for studying cog-
association to postoperative cognitive impairment. Anesthesiology.
nitive trajectory after anaesthesia and surgery. 2012;116(4):779–87.
9. Zhang B, Dong Y, Zhang G, Moir RD, Xia W, Yue Y, et al. The
Summary inhalation anesthetic desflurane induces caspase activation and
increases amyloid beta-protein levels under hypoxic conditions.
Surgical patients with cognitive disorders such as dementia Journal of Biological Chemistry. 2008;283(18):11866–75.
and postoperative delirium may be particularly vulnerable to 10. Zhang Y, Xu Z, Wang H, Dong Y, Shi HN, Culley DJ, et al. Anesthetics
poor outcomes peri-operatively. The prevalence of patients isoflurane and desflurane differently affect mitochondrial function,
with dementia seems to be increasing, and the number of sur- learning, and memory. Annals of Neurology. 2012;71(5):687–98.
gical patients with dementia will likely increase as well over 11. Zhang Y, Zhen Y, Dong Y, Xu Z, Yue Y, Golde TE, et al. Anesthetic
propofol attenuates the isoflurane-induced caspase-3 activation and
the coming decades. Although there are robust laboratory data Abeta oligomerization. PLoS ONE. 2011;6(11):e27019.
characterizing the effects of various anaesthetic agents on AD 12. Shao H, Zhang Y, Dong Y, Yu B, Xia W, Xie Z. Chronic treatment with
pathophysiology, the clinical relevance of these findings has anesthetic propofol improves cognitive function and attenuates caspase
yet to be determined. Pilot clinical data indicate that different activation in both aged and Alzheimer’s disease transgenic mice.
anaesthetics may lead to different cognitive outcomes, though Journal of Alzheimers Disease. 2014;41(2):499–513.
results are preliminary, and further study is needed. Early clin- 13. Zhang B, Tian M, Zhen Y, Yue Y, Sherman J, Zheng H, et al. The
ical studies have also examined cerebrospinal fluid biomarkers effects of isoflurane and desflurane on cognitive function in humans.
for predicting peri-operative cognitive vulnerability, which 14. Liu Y, Pan N, Ma Y, Zhang S, Guo W, Li H, et al. Inhaled sevoflurane
could hold promise for identifying patients at high-risk for may promote progression of amnestic mild cognitive impairment: A
postoperative cognitive impairment. Postoperative delirium has prospective, randomized parallel-group study. American Journal of the
been associated with significant morbidity and mortality, and Medical Sciences. 2013;345(5):355–60.
prevention and management strategies are urgently needed. 15. Zhang B, Tian M, Zheng H, Zhen Y, Yue Y, Li T, et al. Effects of
Lastly, cognitive decline after surgery—b oth in patients with anesthetic isoflurane and desflurane on human cerebrospinal fluid
and without pre-existing cognitive impairment—continues to Abeta and tau level. Anesthesiology. 2013;119(1):52–60.
16. Xie Z, McAuliffe S, Swain CA, Ward SA, Crosby CA, Zheng H, et al.
be a major public health concern. Large strides need to be made
Cerebrospinal fluid abeta to tau ratio and postoperative cognitive
in terms of POCD definition and unified study methodology, change. Annals of Surgery. 2013;258(2):364–9.
which could help to resolve controversies related to the exist- 17. Chen PL, Yang CW, Tseng YK, Sun WZ, Wang JL, Wang SJ, et al. Risk
ence and nature of cognitive decline after surgery. With an aging of dementia after anaesthesia and surgery. British Journal of Psychiatry.
surgical population, these issues need to be urgently addressed, 2014;204(3):188–93.
both for individuals and populations at large. 18. Monk TG, Weldon BC, Garvan CW, Dede DE, van der Aa MT,
Heilman KM, et al. Predictors of cognitive dysfunction after major
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Cases and Multiple-Choice Questions 19. Sprung J, Jankowski CJ, Roberts RO, Weingarten TN, Aguilar AL,
Runkle KJ, et al. Anesthesia and incident dementia: a population-
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30
CHAPTER 26
Epilepsy
Adam D. Niesen, Adam K. Jacob, and Sandra L. Kopp
Introduction neurosurgical procedures, a specific type of surgical procedure

has not been associated with peri-operative seizures (7). However,
Postoperative seizures are uncommon events that are frequently seizures following cardiac surgery are well-known, serious compli-
challenging to evaluate, diagnose, and manage. Due to the wide cations and the incidence is probably underestimated (8). Seizure
differential diagnosis and importance of early intervention to op- activity during or after cardiac surgery is likely a marker of both
timize outcomes, it is critical to recognize and respond to neuro- focal and global cerebral ischaemic events. In infants and children,
logic changes that occur in the peri-operative period. Specifically, early seizures following cardiac surgery are indicative of central
peri-operative physicians should have a clear comprehension of nervous system injury and have been linked to adverse neuro-
the pathophysiology of and risk factors for seizures as well as the logical outcomes (9). Non-convulsive seizures may be frequently
common treatments. Neurosurgical patients represent a unique missed due to the lack of outward manifestation of seizure activity.
subset of peri-operative patients with distinctive characteristics and This can lead to prolonged depression of consciousness, and poten-
challenges that usually do not apply to the general peri-operative tially increased morbidity and mortality.
population in regards to peri-operative seizures. Therefore, this
chapter will not discuss seizure activity in neurosurgical patients.
By definition, a seizure is the clinical manifestation of abnor- Incidence, Prevalence, and Outcomes
mally hyperexcitable cortical neurons. Although seizures are com- As previously mentioned, there is an estimated 8–10% lifetime risk
monly thought of in the context of epilepsy syndromes, a variety of of experiencing a single seizure and a 3% risk of developing a per-
acute conditions throughout a person’s lifetime (e.g., fever, trauma, sistent seizure disorder (1, 2). The intellectually and developmen-
electrolyte disturbances, infection, alcohol withdrawal) may result tally disabled population has a higher incidence of epilepsy, and
in isolated seizure activity in an otherwise normal individual. In the there is increased morbidity and mortality in children with seizures
general population, there is an 8–10% lifetime risk of experiencing and neurological deficits (10, 11). In addition, this group of pa-
a single seizure and a 3% risk of developing a persistent seizure dis- tients tends to have more frequent seizures and undergoes a greater
order (1, 2). Therefore, a significant number of patients presenting number of anaesthetics, as they often require anaesthesia for rou-
for anaesthesia and surgery will have experienced a seizure at some tine procedures (e.g., radiology exams, dental exams, and treat-
time in their lives. ment) or procedures related to trauma sustained during a seizure
There are two types of seizures, which are classified based on that a healthy patient otherwise would not require (12).
clinical and electroencephalography (EEG) data: partial and gen- A multicentre prospective cohort study in Thailand was the
eralized (Table 26.1). Partial, or focal, seizures originate and re- first large-scale study to estimate the incidence of peri-operative
main in a limited area of the brain, with the initial classification seizures in the general population. They reported an incidence of
based upon level of consciousness during seizure activity. During postoperative seizure of 3.1 per 10,000 for all patients undergoing
simple partial seizures, the patient maintains consciousness, while all surgical and anaesthesia types, including neurosurgical proced-
consciousness is impaired during complex partial seizures. Further ures. Unfortunately, the incidence of postoperative seizure in pa-
subclassification is based on the clinical signs and symptoms of the tients with an underlying seizure disorder was not reported (13).
partial seizure. Generalized seizures involve both cerebral hemi- Two subsequent cohort studies have evaluated the risk of peri-
spheres and typically do not present with focal features. A gener- operative seizures among patients with a known seizure disorder.
alized seizure may manifest with motor symptoms (convulsive) or The first, a population-based study, examined the incidence of seiz-
without motor symptoms (nonconvulsive); however, consciousness ures in patients with epilepsy undergoing general anaesthesia for
is always impaired. procedures other than neurosurgical or invasive neurodiagnostic
There are many factors that may contribute to a change in procedures (14). Seizures were observed in 2% of patients and they
seizure threshold. Some of these include anti-epileptic medication reported no adverse effect after receiving general anaesthesia. Of
noncompliance, altered timing of anti-epileptic medication admin- the six identified seizures, five occurred in children under 13 years
istration, distorted gastrointestinal absorption of these medications, of age. Thus, the occurrence rate in adults was 0.8% and the occur-
electrolyte disturbances, exposure to anaesthetic agents, metabolic rence rate in children was 3%. A subsequent retrospective cohort
derangements, drug and alcohol withdrawal, and sleep depriv- study examined the postoperative seizure occurrence rate among
ation (2–6). These conditions commonly occur during the peri- patients with a pre-existing seizure disorder who received sedation
operative period or while patients are hospitalized. Not including or anaesthesia of any type. This study identified an overall incidence
304
304 Section 3 neurologic patients undergoing non-neurologic surgery
Table 26.1 Seizure classification.
Seizure Type Features

Generalized
Absence Brief episodes of staring, unawareness, unresponsiveness. May occur anytime, often with hyperventilation. No warning before seizure,
completely alert immediately after seizure.
Atypical absence Brief episodes of staring, often somewhat responsive. Hard to distinguish from the person’s usual behaviour. Unlike other absence
seizures, cannot be produced by hyperventilation.
Myoclonic Brief, sudden, involuntary, shock-like muscle contraction arising from the CNS that causes either generalized or focal clonic jerks. Occur
in variety of epilepsy syndromes with different characteristics.
Atonic Very brief sudden loss of tone, which may be limited to eye blinks or head drops but can involve the entire body. A myoclonic jerk
may precede or accompany the seizure.
Tonic Episodes of increased muscle tone/stiffening movements in the body, arms, or legs. Consciousness is usually preserved. Often occur
during sleep, affecting both sides of the body.
Clonic Rapidly alternating contraction and relaxation of a muscle(s). Movements cannot be stopped by restraining or repositioning the arms
or legs.
Tonic-clonic Formerly known as ‘grand mal’ seizure. Often idiopathic. Usually preceded by an aura, then progresses to the tonic and clonic phases,
followed by postictal period with somnolence, confusion, and amnesia.
Partial
Simple partial Brief episodes of varying symptoms (motor, sensory, autonomic, psychic), depending which specific region of the brain is affected.
Often, the focus is located in the temporal lobe and/or hippocampus. Often a subjective experience (auras, sensory hallucinations).
Consciousness is retained. Often a precursor to larger seizures.
Complex partial Usually preceded by an aura (e.g., simple partial seizure), larger portion of the brain is affected causing loss of consciousness. Person
may display automatisms such as lip smacking, chewing, or swallowing. Most commonly originates in the temporal lobe.
Secondary generalized Begins as a simple partial or complex partial seizure, abnormal electrical activity spreads to both cerebral hemispheres. Commonly
results in generalized seizure with tonic-clonic features.
of peri-operative seizures of 3.4% (95% confidence interval, 2.2%– characteristic of their usual seizure, and while local anaesthetic
5.2%), with the peri-operative period defined as operating room toxicity could not be absolutely excluded as a contributing factor,
entry until three days after the end of the anaesthetic or hospital dis- it was felt to be unlikely. Comparable to the findings in patients
missal, whichever time period was longer (7). More frequent pre- receiving all types of anaesthesia, the timing of the most recent
operative seizures (p <0.001) and a shorter time between the last pre-operative seizure was found to be significantly related to the
pre-operative seizure episode and surgery (p <0.001) were found to likelihood of experiencing a postoperative seizure (p <0.001). The
be significantly associated with the chance of experiencing a peri- authors came to a similar conclusion: patients who have more fre-
operative seizure. In addition, as the number of outpatient anti-epi- quent seizures at baseline are more likely to experience a seizure in
leptic medications required for adequate seizure control increased, the postoperative period.
so did the frequency of peri-operative seizures (p <0.001). Neither Postoperative neurologic deficit, including seizure, is a well-
the type of surgery nor the type of anaesthesia (general anaesthesia, known complication after cardiac surgery. When considering
regional anaesthesia, or monitored anaesthesia care) affected the all patients presenting for cardiac surgery (i.e., with or without
frequency of peri-operative seizures in this patient population. The a known history of seizure disorder), the estimated incidence of
authors concluded that in patients with a pre-existing seizure dis- seizures following cardiac surgery ranges from 0.4% to 3.8% (8,
order, the majority of peri-operative seizures are likely related to 16–18). Contributing factors and outcomes in this patient popu-
the patient’s underlying condition. lation were investigated in a review of 2,578 consecutive cardiac
The association of anaesthesia type and peri-operative seizure surgery patients at a single institution (8). Postoperative seizure
risk was further evaluated in a group of patients with a history of was documented in 31 (1.2%) of patients. These seizures were fur-
a seizure disorder undergoing regional anaesthesia (15). In this ther categorized, with 71% classified as generalized tonic-clonic,
retrospective review of patients with a history of a seizure disorder 26% simple/complex partial, and 3% status epilepticus. Procedure
receiving regional anaesthesia, 24 patients (5.8%) experienced type was a significant contributing factor in the occurrence of
seizure activity during the postoperative hospital course. None of postoperative seizure (coronary bypass 0.1%, isolated valve 1%,
the identified seizures could be conclusively linked to the regional valve/coronary bypass 3%, aorta 5%; p <0.001). In addition, pa-
technique. Based on the time interval between local anaesthetic tients with postoperative seizure activity suffered a nearly fivefold
injection and/or termination of the infusion and the event, it was higher operative mortality compared to those that did not experi-
determined that the regional anaesthetic was neither the primary ence a seizure. Based on this information, postoperative seizure ac-
aetiology nor a contributing factor for the seizure in 19/24 patients. tivity in adult patients undergoing cardiac surgery is a predictor
In the remaining five patients, peri-operative seizure activity was of permanent neurologic deficit and increased operative mortality
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Chapter 26 epilepsy 305
(8). Heart transplant patients have an even higher incidence of (5). This can be particularly difficult to avoid in patients who re-
postoperative seizures at approximately 4.8%. quire anti-epileptic medications that do not have parenteral
formulations.
Risk Factors In patients with a pre-existing seizure disorder undergoing an-
aesthesia, altered anti-epileptic medication levels were felt to be
There are a number of conditions that may contribute to seizure a contributing factor in greater than 40% of patients who experi-
activity in patients with or without an underlying seizure dis- enced seizure activity in the peri-operative period (7). One of the
order. Common provocative conditions include fever, head in- clinical challenges of caring for the patient with a seizure disorder
jury, excessive alcohol intake, withdrawal from alcohol or drugs, is that the therapeutic level for anti-epileptic medications must be
hypoglycaemia, electrolyte disturbances, intracranial infection interpreted with caution. An effective therapeutic level may vary
or haemorrhage, ischaemic stroke, and drugs that may lower the from patient to patient as well as the timing of the blood draw.
seizure threshold (e.g., tramadol, theophylline, baclofen, ketamine, Indeed, it is commonplace for an individual patient’s therapeutic
meperidine) (19). In addition, there are several factors that may level to lie outside of the laboratory reported standard therapeutic
increase the risk for seizure activity in patients with a seizure dis- range. Moreover, anti-epileptic drug levels are affected by frequent
order (Table 26.2), including changes in anti-epileptic drug levels, drug-drug interactions. Interestingly, substitution of generic anti-
fatigue, stress, sleep deprivation, menstruation, and excessive al- epileptics for brand name or substitution of a generic formula-
cohol intake (3, 4, 20). Routinely, hospitalized patients experience tion from one manufacturer for the same generic drug produced
high levels of stress and sleep interruption/deprivation. In add- by a different manufacturer can also affect blood levels and thus
ition to the stress and sleep deprivation of hospitalization, there the risk of having a seizure (23). Conversely, cytochrome P450 ac-
are additional factors in the peri-operative period that can affect tivation by a number of anti-epileptic drugs, such as phenytoin,
anti-epileptic drug levels. These include but are not limited to pre- phenobarbital, and carbamazepine, alters the hepatic metabolism
operative medication noncompliance, changes in dosing schedule, of many drugs. Anti-epileptic medications may also reduce the re-
interaction with other peri-operative medications, anaesthetic ex- quired anaesthetic concentration for induction, maintenance, and
posure, and changes in gastrointestinal motility leading to delayed emergence (24).
absorption and reduced bioavailability (4, 6). For example, patients A number of medications routinely used in the peri-operative
may skip their usual dosing of anti-epileptic medications in order period can affect the seizure threshold or have significant inter-
to comply with nil-by-mouth (NPO) instructions or are not admin- actions with anti-epileptic drugs (25). Caring for patients who re-
istered their medications on schedule (21, 22). Postoperatively, this quire multiple medications for seizure control at baseline present a
is exacerbated in patients who are not allowed to take oral medica- particular clinical challenge, as they carry a greater risk of seizure
tions due to their surgical procedure or are unable to tolerate oral recurrence when their usual medications are withdrawn or dosage
intake due to nausea, vomiting, or ileus. Decreased anti-epileptic reduced (26). Predictably, as the number of baseline anti-epileptic
drug serum levels may contribute to peri-operative seizure activity medications increases, the occurrence of peri-operative seizure ac-
tivity also increases (7, 15). Formulating the most effective plan
for peri-operative anti-epileptic medication management may be
Table 26.2. Risk factors associated with peri-operative seizure activity. quite complex and often requires consultation with a neurologist.
Patients with more frequent seizure activity at baseline and those
Factors Associated With Increased Factors Not Associated With with a seizure event close to the time of admission carry a greater
Frequency of Postoperative Seizures Increased Frequency of risk of seizure occurrence in the peri-operative period.
Postoperative Seizures Focal or global ischaemia following hypoperfusion, emboli (par-
ticulate or air), metabolic derangements, and drug reactions are
Patients with pre-existing seizure ◆ Anaesthetic technique
contributing factors for seizure activity following cardiac surgery
disorder: (general, regional, monitored
anaesthesia care).
(8). Deep hypothermic circulatory arrest, aortic calcification or ath-
◆ More frequent seizure activity at
eroma, critically ill peri-operative state, and tranexamic usage have
baseline. ◆ Type of surgery (not including
neurologic or cardiac surgery).
been identified as risk factors as well (8, 16–18, 27). The proposed
◆ Increasing number of anti-epileptic
underlying mechanism for seizures related to tranexamic acid use is
medications.
competitive binding of tranexamic acid to GABA, yielding reduced
◆ Short time between last seizure and
inhibitory activity and increased neuronal excitation (27). Seizure
surgery.
activity associated with tranexamic acid use appears to occur early
◆ Younger age.
in the postoperative period, is usually generalized tonic-clonic, and
Patients undergoing cardiac surgery: is typically easily treated. Posterior reversible encephalopathy syn-
◆ Cerebral ischaemic event. drome (PRES) caused by therapeutic cyclosporine is an additional
◆ Pre-operative cardiac arrest. cause of seizures in patients undergoing cardiac transplantation
◆ Open chamber procedure. (28). Changing the immunosuppressant regimen typically allevi-
◆ Deep hypothermic circulatory arrest. ates this problem.
◆ Bypass time >150 minutes.
◆ Aortic calcification or atheroma.

Preventive Strategies and Treatment
◆ Critically ill peri-operative state.
The most effective strategy to prevent peri-operative seizure is to
◆ Tranexamic acid use.
optimize the patient’s pre-operative condition and avoid known
306
peri-operative risk factors that might lower the patient’s seizure are clustered together without full recovery of consciousness be-
threshold. This largely depends on the patient’s baseline health tween seizures. At this point, neuronal injury may have already oc-
status and the procedure he or she is undergoing. Efforts should curred and spontaneous termination of the seizure is unlikely (30).
be made to correct electrolyte or metabolic derangements pre- Continued supportive therapy combined with efforts to terminate
operatively. If the procedure is urgent or emergent, such electrolyte the seizure with pharmacologic treatment should be made with a
or metabolic issues should be addressed as soon as possible in the goal of minimizing the severity of the neurologic injury.
scope of the overall anaesthetic care. In patients with a pre-existing
seizure disorder taking anti-epileptic medications, pre-operative
medication noncompliance or missed doses due to NPO status
Current Guidelines or Recommendations
may result in decreased anti-epileptic drug levels and subsequent Patients with a new diagnosis of seizures or increasing difficulty
seizure activity. Therefore, the patient’s usual anti-epileptic medi- of seizure control require evaluation to attempt to determine the
cation regimen should be followed as closely as possible leading underlying cause as well as adjust medications. This should ideally
up to and including the day of surgery, particularly for those pa- occur prior to the patient presenting for an anaesthetic. The anaes-
tients with frequent or recent seizures and patients requiring mul- thetic management of a patient with a history of seizures is influ-
tiple medications for seizure control. Maintenance of an inpatient enced more by the underlying cause of the seizure than the fact that
dosing regimen that is as close as possible to the outpatient regimen the patient has had a seizure. Seizures that occur intra-operatively
is of critical importance. This can be particularly challenging, as may be related to the anaesthetic technique or an acute neuro-
a number of anti-epileptics do not have a parenteral formulation logic insult, whereas seizures that occur postoperatively are typ-
and the interpretation of blood levels may be challenging for prac- ically due to the patient’s underlying seizure disorder. Anaesthetic
titioners unfamiliar with these medications. Pre-operative and agents such as propofol, thiopental, benzodiazepines, and volatile
inpatient consultation with a neurologist is frequently helpful in anaesthetics (excluding enflurane and sevoflurane) cause a dose-
managing complex cases. dependent increase in the seizure threshold. Medications such as
Preventative strategies aimed at optimizing intra-operative cere- alfentanil, remifentanil, and methohexital have been shown to re-
bral protection play a role in improving outcomes in patients who duce the seizure threshold.
are at risk, particularly in the cardiac surgical population (8). Intra- Several different types of anti-epileptic drugs are routinely used
operative use of drugs known to induce epileptiform EEG activity to control patient’s seizures. Most anticonvulsants (phenytoin,
(e.g., etomidate, sevoflurane) should be avoided unless there is phenobarbital, and carbamazepine) induce the cytochrome P450
strong indication of their superiority versus alternative anaesthetic system which can lead to resistance to neuromuscular blocking
options. Prophylactic administration of agents that help suppress agents. Pre-operative laboratory testing will depend on the specific
neuronal excitatory activity (e.g., benzodiazepines, gabapentin) side effects of individual anti-epileptic agents. A complete blood
should be considered (29). count and platelet count in addition to an electrolyte panel are the
The anaesthetist should be prepared to treat seizure activity in most commonly obtained pre-operative tests in order to optimize
the peri-operative setting, with the understanding that patients conditions prior to anaesthetic administration. Pre-operative co-
who have frequent seizures at baseline and those whose last seizure agulation profiles are recommended in patients taking valproic
was close to the time of admission are more likely to have a seizure. acid, as it has been shown to interfere with platelet count and func-
Postoperative seizure activity treatment is focused on administration in addition to reducing fibrinogen and von Willebrand factor,
tion of oxygen, management of haemodynamics, and seizure ter- thus interfering with haemostasis (31).
mination. In addition to treatment with GABAergic agents like Despite potential interactions with anaesthetic and other peri-
benzodiazepines or propofol, the sodium channel blocker pheny- operative medications, most authorities believe that it is essential to
toin and the mixed action agent valproate are recommended for continue patients on their usual anti-epileptic medication regimen.
treatment of peri-operative seizures. Phenytoin is not recom- This includes educating patients to take their usual morning dose
mended for acute termination of peri-operative seizure, as it is less with a sip of water in the pre-operative period. For those patients
likely to be effective and rapid administration may lead to hypo- unable to take oral medications peri-operatively or with altered GI
tension and cardiac arrhythmias. These effects are due to the pres- tract absorption, there are several parenteral options (e.g., pheny-
ence of propylene glycol diluent to enhance water solubility. In the toin, valproate, levetiracetam, phenobarbital). In addition, some
particular situation of suspected local anaesthetic systemic toxicity, medications are available as a suspension for nasogastric tube ad-
administration of phenytoin should be avoided due to a common ministration. These medication adjustments should ideally be dir-
site of action at the sodium channel. Valproic acid can be infused ected by a neurologist familiar with the patient’s underlying seizure
rapidly and rarely causes hypotension; it also has very little seda- disorder.
tive effect and is long acting. The newer intravenous, anticonvulsant
drugs (valproic acid, levetiracetam) have helped to reduce the un-
desired side-effects (hypotension, bradycardia, cardiac arrest) asso- Summary
ciated with phenytoin and fosphenytoin. For the majority of patients in the peri-operative period, seiz-
In the event of peri-operative seizure activity, early head com- ures are uncommon events. However, patients with a pre-existing
puted tomography scan has been indicated to identify any readily seizure disorder and cardiac surgical patients are at higher risk for
treatable pathology. In the event such a lesion is identified and developing peri-operative seizures. Of the patients with an existing
promptly treated, the outcome is generally good, with little residual seizure disorder, those that experience more frequent seizures at
neurologic impairment. In status epilepticus, continuous seizure baseline, require multiple medications for daily seizure control,
activity occurs for five minutes or longer, or two or more seizures and whose most recent seizure is in close proximity to the date of
307
Chapter 26 epilepsy 307
surgery are at higher risk for postoperative seizure activity. Cerebral 13. Akavipat P, Rungreungvanich M, Lekprasert V, Srisawasdi S. The Thai
ischaemia, long bypass times, deep hypothermic circulatory arrest, Anesthesia Incidents Study (THAI Study) of perioperative convulsion.
aortic calcification or atheroma, critically ill peri-operative state, Journal of the Medical Association of Thailand. 2005;88(Suppl. 7).
14. Benish SM, Cascino GD, Warner ME, Worrell GA, Wass CT. Effect of
and the use of tranexamic acid are all risk factors for seizure activity
general anesthesia in patients with epilepsy: A population-based study.
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activity, including but not limited to sleep deprivation, stress, elec- blockade in patients with a history of a seizure disorder. Anesthesia &
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epileptic regimen. Close attention to maintenance of the patient’s 16. Martin K, Wiesner G, Breuer T, Lange R, Tassani P. The risks
home anti-epileptic regimen, replacement of oral medications with of aprotinin and tranexamic acid in cardiac surgery: a one-year
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Cases and Multiple-Choice Questions 18. Roach GW, Kanchuger M, Mangano CM, Newman M, Nussmeier N,
Wolman R, et al. Adverse cerebral outcomes after coronary bypass
Q Interactive cases and multiple-choice questions to test your surgery. Multicenter Study of Perioperative Ischemia Research Group
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19. Pohlmann-Eden B, Beghi E, Camfield C, Camfield P. The first seizure
and its management in adults and children. British Medical Journal.
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CHAPTER 27
Parkinson’s Disease
Introduction to set appropriate expectations will often prevent unnecessary con-

fusion and anxiety-related problems in the peri-operative period.
Parkinson’s disease (PD) is a chronically progressive neurodegenerative Due to their age profile and associated comorbidities, patients
disease defined by the classic clinical symptom triad of resting tremor, with PD will often present to the operating suites for interventions
muscle rigidity, and bradykinesia. The first formal description of the other than neurosurgery, including ophthalmological procedures
‘shaking palsy’ was made by James Parkinson in 1817, although the such as cataract surgeries, urological procedures such as prostate
syndrome has been known since biblical times. In 1879 Jean-Marie and incontinency surgeries, and orthopaedic surgeries due to their
Charcot noted additional features including the autonomic dysfunc- increased risk of falls and fractures. All of these surgeries require a
tion and renamed the ‘shaking palsy’ after James Parkinson. Fourteen dedicated personal approach and sufficient tremor control, espe-
years later, the association between the substantia nigra and PD was cially when performed with local or regional anaesthetic regimens.
made, although the aetiology of the disease is still unknown. In the
second half of the twentieth century, neuropathological and neuro-
chemical characteristics of the disease were elucidated and treatment Pathophysiology and Clinically Relevant
strategies began to be developed.
This chapter discusses PD epidemiology, pathophysiology, and
Staging
disease staging, and particular organ system involvement will be The degeneration of dopaminergic cells within the pars compacta
examined with specific attention placed on relevant information for of the substantia nigra and the resulting deficiency of dopamine
anaesthetists. are the underlying mechanisms for the development of parkin-
sonian symptoms. The basal ganglia, which include the striatum
(caudate nucleus and putamen), the globus pallidus, subthalamic
Epidemiology and General Considerations nucleus, and the substantia nigra, create clinically important motor
PD is one of the most common neurodegenerative diseases in circuits, which balance excitatory cholinergic neurons and in-
the United States, second only to Alzheimer’s disease. It affects all hibitory dopaminergic neurons (3, 4). Notably, acetylcholine in
ethnic groups with a slight male preponderance. With an overall PD is present in normal amounts; however, dopamine deficiency
prevalence of about 0.3% in the general population, PD increases to results in an imbalance in the dopamine-acetylcholine ratio and,
include approximately 1% of people over 60 years of age. Further, thereby, increased activity of inhibitory nuclei. This excessive in-
the incidence of PD is increasing exponentially among people aged hibition of the thalamic and brainstem nuclei receiving outflow
65 to 90 years (1); thus, with the increasing size of the US aging from the basal ganglia results in akinesia, rigidity, and tremor.
population, the number of patients with PD undergoing surgical This shifted and uneven balance should be kept in mind when
procedures is likely to increase substantially in the near future. considering parasympathomimetic (i.e., neostigmine) as well
Caring for patients with PD is a complex and challenging task for as parasympatholytic (i.e., atropine) drugs in the peri-operative
the anaesthetist. It requires not only a thorough understanding of period. In PD patients whose antiparkinsonian drug regimens in-
the underlying pathology and current medical treatment, but also a cludes anticholinergic medications, possible side effects and ad-
sensitive and receptive personal approach and attitude. In the often verse reactions may be unpredictable.
time-compacted and intense surgical environment, these tasks may There are different scales and staging systems that classify the se-
be particularly difficult. In addition to the classical symptom triad, verity of PD. The Hoehn and Yahr (HY) Stage (Box 27.1) has been
patients with PD are more likely to suffer from comorbidities like used frequently (5) to characterize broad descriptive categories of
depression, anxiety, and speech problems than the average surgical PD patients and allow the anaesthetist to get a quick measure of the
patient (2). Furthermore, bradykinesia presenting as ‘masked fa- impairment severity their patient has to endure.
cies’ and cognitive impairment may result in the inability to ac- Mild or early PD has generally been defined as HY stage 1 and 2,
curately demonstrate and articulate emotions and needs. It is, when symptoms might be subtle and go unrecognized. Advanced
therefore, necessary to establish an empathetic working relation- disease is classified as HY stage 4 and 5. Despite the availability of
ship with patients and their families, create a calm and organized medical and surgical treatments that improve motor symptoms, PD
atmosphere, and minimize interruptions and noise. A few minutes leads to progressive disabilities and eventual death in most patients.
310
stomach despite fasting, aspiration on induction, impaired swal-

BOX 27.1 Hoehn and Yahr (HY) Stage
lowing capability and silent aspiration, reduced protein binding,
and altered bioavailability of drugs.
1. Unilateral involvement only, usually with minimal or no
functional disability. Urogenital System
2. Bilateral or midline involvement without impairment of Parkinsonism is often accompanied by lower urinary tract symp-
balance. toms (7). Urinary urgency and frequency with or without urinary
3. Bilateral disease: mild to moderate disability with impaired incontinence, i.e., overactive bladder, occurs in up to 70% of pa-
postural reflexes; physically independent. tients with PD. Overactive bladder in PD is thought to reflect al-
tered frontal–basal ganglia circuits that normally suppresses the
4. Severely disabling disease; still able to walk or stand micturition reflex. Finally, patients may suffer from erectile dys-
unassisted. function and decreased sexual activity.
5. Confinement to bed or wheelchair unless aided.
Cognitive System and Psyche
Adapted from Movement Disorders, 19, 9, Goetz CG, Poewe W, Rascol O Nonmotor symptoms of PD can be evident early in the disease,
et al., Movement Disorder Society Task Force report on the Hoehn and sometimes presenting symptoms. Most commonly patients may
Yahr staging scale: status and recommendations, pp. 1020-1028. Copyright initially suffer from depression, fatigue, and disorders of sleep (2).
(2004) with permission from the Movement Disorder Society. These impairments may result in delayed return to baseline neuro-
logical examination or prolonged awakening from general anaes-
thesia. Eventually cognitive decline and psychosis often appear
in late stages of PD. Postoperative confusion, delirium, and drug-
General Considerations for the induced psychosis may further complicate PD and may be diffi-
Anaesthetist: Organ Systems and Their cult to treat due to interactions with PD pathophysiology and drug
regimen.
Specifics
Respiratory System Drug Treatment
Upper airway dysfunction is common in PD and was previously
Antiparkinsonian drug therapy (Table 27.1) is started for clin-
described by James Parkinson. In fact, respiratory complications,
ical symptoms and if the patient desires treatment (8, 9). Current
in particular aspiration pneumonia, are the most common causes
therapy is designed to enable good quality of life as long as possible
of death in these patients. Involvement of laryngeal muscles in
since no definitive treatment is currently available. Dopaminergic
PD-related involuntary movements may result in failure of proper
drugs are often the initial therapy recommended for treatment of
swallowing (dysphagia) or coughing, retaining of secretions, atel-
motor symptoms (10), as they are more potent than anticholinergic
ectasis, and aspiration. Thus, pre-operative assessment of venti-
agents, amantadine, and selective MAO-B inhibitors.
lation, swallowing, and coughing in patients with PD is critical
to avoid respiratory failure after extubation and during recovery. Dopamine
Neuromuscular monitoring is strongly advised, and extubation
should not be performed until neuromuscular blockade is fully Levodopa, a dopamine precursor, is considered the most effective
reversed. antiparkinsonian agent. Taken orally, as a prodrug, it is metabol-
ized to dopamine, which effectively addresses all cardinal symp-
toms. However, with a half-life of 30–60 minutes, levodopa is
Cardiovascular System generally combined with a peripheral decarboxylase inhibitor such
The most prevalent cardiovascular symptom in PD is orthostatic as carbidopa to reduce the decarboxylation of levodopa before it
dysregulation and hypotension (6). However, medications that reaches the brain. Another preparation designed to prolong the
treat PD symptoms may complicate evaluations of orthostasis. action of levodopa is carbidopa plus levodopa plus catechol-O-
Levodopa can cause hypotension by facilitating peripheral vaso- methyltransferase (COMT) inhibitor, e.g., entacapone. Treatment
dilation, as can bromocriptine or pergolide. These side effects may with levodopa is limited by increasing side effects (nausea, vomiting,
be especially true during anaesthesia with inhalational anaesthetics. dizziness, and hypotension) and most predominantly by the loss of
Cardiac arrhythmias and defective cardiovascular reflex control effectiveness after five to seven years. The majority of patients will
may also occur. Thus, invasive intra-operative monitoring should achieve sufficient symptom control with levodopa doses between
be considered in cases that may not otherwise warrant it. 300–600 mg/d for the first few years after initiation. Patients then
begin to develop complications like end-of-dose akinesia and dys-
Gastrointestinal System kinesia as the action of the drug is shortened to under four hours,
Disturbances in gastrointestinal (GI) function greatly impact the requiring more frequent dosing intervals.
quality of life of patients with PD, including sialorrhoea, dysphagia,
gastroparesis, constipation, and reduced appetite. These symptoms Dopamine Agonists
are exacerbated by nearly all pharmacological therapies for PD, and Dopamine agonists are alternative first-line agents for PD with
PD treatment might result in substantial weight loss and malnour- various compounds having similar efficacy but different side ef-
ishment. The anaesthetist should carefully assess the severity of im- fect profiles. They directly stimulate striatal postsynaptic dopa-
paired GI dysfunction and plan for related complications, e.g., full mine receptors and are associated with a lower risk of dyskinesia
31
Chapter 27 parkinson’s disease 311
Table 27.1 Common antiparkinsonian drugs.
Drug Class Example Halftime Peak Usual dose Side effects Interactions
Plasma
Time
Levodopa/Decarboxylase
Inhibitor
Levodopa plus Carbidopa Sinemet 1.5 h 0.5 h 100 mg Levodopa/25 Anorexia, nausea, Effect of:
(immediate mg Carbidopa vomiting, dizziness, antihypertensive drugs↑
release) q3–three times/d motor fluctuations,
catecholamines ↑
dyskinesia, confusion,
Levodopa plus Carbidopa Sinemet 1.5 h 2h 100 mg Levodopa/25 Opioids → effect of
hallucinations
(controlled mg Carbidopa Levodopa↓
release) q3–three times/d
Levodopa plus Stalevo 1.7 h 0.6–2.4  h 50 mg Levodopa/ All of the above plus
Carbidopa plus 1.6–2  h 2.5–3.4  h 12.5 mg diarrhoea
Carbidopa/200
Entacapone 0.8–1 h 1–1.2 h
mg Entacapone
q3–three times/d
Dopamine Agonists
Ergot-derivatives
Bromocriptin Parlodel 6–12 h 1–3 h 1.25mg Nausea, hypotension, Effect of:
q12- two times/d dizziness, headache antihypertensive drugs↑
Non-ergot-derivatives
Pramipexole Mirapex 8.5 h 2h (IR), 6 h 0.5–1.5  mg Nausea, vomiting, Effect of:
(ER) q3–three times/d hypotension, ankle antihypertensive drugs↑
oedema, excessive
Ropinirole ReQip 6 h (ER) 1–2h (IR), 1 mg daytime sleepiness,
6–10 h q3–three times/d confusion, compulsive
(ER)
behaviour and
hallucinations
Anticholinergic Agents
Trihexyphenidyl Artane 6–12 h 1.3 h 2 mg Confusion, impaired Tachycardia
q3–three times/d memory, constipation,
urinary retention,
Benztropine Cogentin 6–48 h Onset PO 1 mg blurred vison, angle close
1h q2–two times/d glaucoma
Selective MAO-B Inhibitors
Selegiline Eldepryl Irreversible Onset PO 5 mg Dyskinesia, nausea Potential for interaction
blockade 1h q2–two times/d depression, dizziness, with SSRIs, Pethidine
sleep disorder postural (Meperidine), Tramadol
Rasagiline Azilect Irreversible 1h 1 mg hypotension, peripheral
blockade q1–one time/d oedemas, anxiety and
hallucinations
NMDA Antagonists
Amantidine Symmetrel 16 h 2–4 h 100 mg Confusion, hallucinations, NO combined treatment
q2–two times/d nervousness, dizziness, with neuroleptics
insomnia
and motor fluctuations in their first four to five years of treatment; dose-titration over several weeks. This pharmacokinetic profile
however, they are slightly less effective, and levodopa is commonly has the advantage of decreased drug fluctuations but increased
needed as an adjuvant. Dopamine agonists are divided into two difficulty of symptom management. Due to peripheral dopamin-
major groups: the older ergot derivatives, i.e., bromocriptine, and ergic stimulation, dopamine agonists may cause nausea and ortho-
the newer non-ergot derivatives, i.e., ropinirole and pramipexole. static hypotension, which can be decreased by slow in-titration of
Dopamine agonists may have very long half- lives requiring the drug. Further, dopamine agonists have the potential to induce
312
hallucinations and should be avoided in patients with dementia. Treatment of Parkinson-Associated Depression,
Finally, older ergot derivatives have been rarely associated with Fatigue, Dementia, and Psychosis
retroperitoneal, pleural, or pericardial fibrosis, as well as thickening
SSRIs and TCAs are currently considered the first choice to treat
and dysfunction of the cardiac valves. For this reason, non-ergot
depression in PD patients. Most experts in the field use traditional
derived agonists are preferred.
SSRIs, serotonin and norepinephrine reuptake inhibitors, or TCAs
Caveat: Drugs with dopamine antagonist properties like
with follow-up in four to six weeks and therapy adjustment as
phenothiazines, butyrophenones (e.g., droperidol), and
needed. In exceptionally severe cases, transcranial magnetic stimu-
metoclopramide can enhance motor symptoms of PD. Thus, they
lation or electroconvulsive therapy is used to treat depression.
are contraindicated.
Drugs to treat fatigue include methylphenidate and modafinil, but
these are considered investigational. Rivastigmine and memantine
Monoamine Oxidase-B Inhibitors
can be taken by PD patients to address dementia. Newer atyp-
Selegiline and the newer agent rasagiline block the degradation ical antipsychotic drugs, which have much reduced parkinsonian
of dopamine via MAO-B inhibition, thus increasing dopamine side effects, allow psychosis treatment without exacerbating PD.
availability. Rasagiline inhibits MAO-B with potency five-to ten- Clozapine has been shown to be particularly effective but can cause
fold higher than that of selegiline; however, rasagiline is not me- severe agranulocytosis in 1–2% of patients. Olazapine, risperidone,
tabolized to amphetamines and, therefore, does not display the and quetiapine are also options with fewer parkinsonian side ef-
sympathomimetic and neurological effects seen with selegiline. fects. Classical neuroleptic drugs are dopamine antagonists and are
All MAO-B inhibitors decrease the amount of levodopa needed contraindicated in PD. Overall, PD patients, especially in advanced
by 20–30%. MAO-B inhibitors have fewer side effects than dopa- disease states, can have a long and complex list of medications
mine agonists, require little titration, yet have potential for serious taken, making it very difficult to determine the cause of possible
interactions with selective serotonin reuptake inhibitors (SSRIs), side effects and symptoms of drug interactions in the peri-operative
tramadol, and meperidine. period.
Caveat: The MAO-B inhibitors selegiline and rasagiline given
together with serotonergic substances, e.g., SSRIs or tricyclic anti-
depressants (TCAs) like imipramine, can induce serotonin syndrome. Neuroleptic Malignant Syndrome
Their combined use is contraindicated. Also, the combination of NMS is a life-threatening, neurological disorder most often caused
selegiline and meperidine can induce delirium, muscle rigidity, and by an adverse reaction to neuroleptic or antipsychotic drugs.
hyperthermia. Symptoms include high fever, sweating, unstable blood pressure,
stupor, muscular rigidity, and autonomic dysfunction. It can be ac-
Anticholinergic Agents companied in severe cases with rhabdomyolysis, metabolic acidosis,
Anticholinergic agents act on muscarinic acetylcholine receptors to renal failure, and disseminated intravascular coagulopathy. In most
modulate striatal dopamine and acetylcholine imbalance. With al- cases, the disorder develops within the first weeks of treatment with
most no effect on akinesia, their use is limited based on their side the offending drug; however, NMS may develop any time during the
effects (typically anticholinergic side effects on autonomic func- therapy period. Abrupt discontinuation of antiparkinsonism drugs
tion). Anticholinergic agents should be used with caution in the (levodopa) may also result in NMS; therefore, the anaesthetist must
elderly due to delirium and are contraindicated in patients with de- ensure continuous application of the patient’s medication through
mentia as they can cause memory deterioration and disorientation. the entire peri-operative period. In addition, drugs with anti-
dopaminergic activity, such as the anti-emetic metoclopramide, can
NMDA Antagonists induce NMS. Diagnosis can be difficult, especially in differentiating
Used as adjunct therapy, amantadine is the drug of choice to treat NMS from malignant hyperthermia and the serotonin syndrome,
akinetic crisis and can be administered parenterally. Amantadine as all share similar initial symptoms.
may induce changes in the sleep-awake cycles, causing insomnia Caveat: Care should be taken to avoid deleterious medication com-
at night. The drug is excreted as an active product in the urine, binations, physical stress, starvation, and dehydration, all of which
and patients with renal impairment should be carefully monitored, can precipitate NMS.
as higher concentrations may result in myoclonus, agitation, and
psychosis. Anaesthesia Management
Pre-operative assessment of the patient’s disease stage, with ex-
Catechol-O-Methyl-Transferase Inhibitors plicit respect to the organ systems and their particular problems
COMT inhibitors decrease the degradation of levodopa, leading (dysphagia, aspiration, pneumonia, hypotension, infections of the
to higher bioavailability of levodopa with the added benefit urinary tract, gastroparesis) should be thorough.
of ‘smoothing’ fluctuations in dopamine concentration. Used Of utmost importance is the continued and uninterrupted appli-
largely as adjunct therapy in the late stage of the disease, COMT cation of the antiparkinsonism medications. Frequent dosing and
inhibitors must be administered with levodopa due to their short half-lives should be taken into account. Medications should
very short half-lives. Concomitant administration leads to side be taken as long as possible before surgery and should be restarted
effects reflective of excess levodopa availability, e.g., hallucin- as soon as possible in the postoperative period. If necessary, levo-
ations, nausea, involuntary movements. The most common side dopa is available in specific formulations that can be given via naso-
effect is diarrhoea, which often leads to discontinuation of the gastric tube. Since levodopa is exclusively absorbed in the proximal
therapy. small intestine, rectal application is not useful.
31
Chapter 27 parkinson’s disease 313
isoflurane and sevoflurane are considered safe in PD patients.

BOX 27.2 Pre-Induction Considerations
In contrast, halothane can sensitize the heart to arrhythmogenic
effects of catecholamines. In addition, desflurane can dose-
1. Patients may be difficult to intubate due to reduced mouth dependently induce activation of the sympatho-adrenergic
opening and neck extension. system and induce tachyarrhythmia, but has been reported safe
2. Patients can display an excessive reaction to catecholamines. (11) if used in doses <1 MAC.
Catecholamine administration may require slow titration of Intravenous anaesthetics are used safely and on a regular basis
continuous infusion with initially low dosages until the de- in surgery for patients with PD. Although divergent case reports
sired effect has been achieved. Bolus doses should be avoided. exist, no large randomized studies have been published. As men-
3. Due to possible severe hypotension, estimation of volume tioned before, the key in caring for patients with PD is thoughtful
status is important and effects of inhalational or intravenous planning, slow and considerate application of any drug, and con-
anaesthetic agents should be anticipated. stant re-evaluation of the patient’s situation. Propofol can either
induce (12) or abolish (13) dyskinesia. Ketamine is theoretically
4. Depending on the degree of dysautonomia, invasive arterial contraindicated in PD because of an anticipated exaggerated
blood pressure monitoring should be considered with close sympathetic response but has been safely administered (14, 15).
attention to continuous electrocardiogram monitoring and However, ketamine’s hallucinogenic potential should be con-
should be continued in the postoperative setting. sidered carefully given the side effects of some antiparkinsonism
5. Emergence from anaesthesia might be prolonged and medications.
extubation should occur only after confirmed (neuromus- Opioid use in patients with PD is somewhat controversial.
cular monitoring) full reversal of neuromuscular blockade. Opioids may cause or increase muscle rigidity and, in particular,
thorax rigidity. Clinical practice suggests that this complication is
6. Special emphasis should be placed on sufficient recovery of
strongly dependent on concentration and speed of administration;
swallowing and coughing capacity in these patients.
therefore, the recommendation is to use low and careful dosing,
7. Postoperative shivering is common in PD patients and should if necessary. While alfentanil can cause acute dystonia (16) and,
always be distinguished from parkinsonian symptoms. thus, is relatively contraindicated, fentanyl and remifentanil are
8. PD patients are more prone to develop postoperative confu- generally considered safe and well tolerated if given in an appro-
sion and hallucinations, which can be very difficult to distin- priate manner. Furthermore, some evidence points to dose require-
guish from drug withdrawal and drug interactions. ments for fentanyl (17). While rapid remifentanil boluses should be
avoided, due to possible muscle rigidity, infusions that are slowly
titrated have been shown to almost completely abolish tremor and
have been used in ophthalmologic surgery with great success.
Furthermore, patients with PD should be scheduled first in the
Nondepolarizing neuromuscular blocking agents should
morning to avoid long fasting periods and dehydration. Finally,
be used with neuromuscular monitoring in place, and short-
a warm and reliable professional relationship must be established
acting agents may be preferred. There are no reported cases of
with the patient and their loved ones. In the setting of regional an-
nondepolarizing blocking drugs worsening the symptoms of PD.
aesthesia or monitored care, unnecessary frequent variation in an-
Succinylcholine may not be the first choice for neuromuscular
aesthesia providers should be avoided in order to reduce additional
blockade, as anecdotal reports of hyperkalaemia in PD patients
confusion and anxiety.
exists. However, these reports have not been reproduced in larger
Regional anaesthesia may be preferable in PD patients if applic-
studies.
able, as it avoids neuromuscular blockade and side effects of gen-
eral anaesthetics, e.g., postoperative nausea and vomiting. There
is the added benefit of early oral application of antiparkinsonian Implantation of Deep Brain Stimulators
medication. Deep brain stimulator (DBS) placement is a surgery specific to
patients with PD. As an alternative treatment for essential tremor
General Anaesthesia and dystonia, patients presenting for DBS placement are usually
All general anaesthetics have the potential to interfere with any asked not to take their current antiparkinsonian medications.
parkinsonian medication and aggravate potential side effects, es- Absence of pharmacological therapy allows neurophysiologists to
pecially systemic blood pressure. Thus, anaesthetics should be used measure the effect of microelectrode recording and stimulation in
with caution with anticipation of common side effects, such as the basal ganglia on the predominant symptom, i.e., tremor, intra-
hypotension, and precautions should be taken. Box 27.2 highlights operatively. This voluntary pharmacological ‘off-period’ results in
anesthetic considerations. the aggravation of symptoms (tremor, dystonia, depression) prior
Inhalational anaesthetics have manifold effects on different to surgery and adds to the complexity of these cases for the anaes-
receptors in the brain, and side effects are often tied to dosing. thesia provider. Thankfully rare, the most common complications
Most inhalational anaesthetics produce dose-d ependent de- include intracranial haemorrhage (approximately 3%), seizures,
crease in blood pressure and reduce baroreflex modulation of and psychological/psychiatric deterioration with age >64 years
heart rate and blood pressure—all of which may already be im- being an independent risk factor (18). Systemic blood pressure
paired in PD patients. Furthermore, inhalational anaesthetics should be well controlled through the peri-operative period. High
have the potential to inhibit synaptic re-uptake of dopamine, doses of dexmedetomidine, remifentanil, and propofol can com-
which occurs at clinically relevant concentrations. However, pletely suppress the tremor in PD, significantly influence neuronal
314
spiking (19), and alter mental status for prolonged periods of time. References
With reasonable dosing dexmedetomidine can be an excellent drug
1. Moghal S, Rajput AH, D’Arcy C, Rajput R. Prevalence of movement
to provide moderate sedation, but it is important to allow suffi-
disorders in elderly community residents. Neuroepidemiology.
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315
CHAPTER 28
Treatment of Psychiatric Diseases

with General Anaesthetics
Laszlo Vutskits
Introduction should also be granted as powerful, context-dependent modulators

of neural plasticity. In this context, an intriguing possibility is that
Psychiatric disorders are defined as mental or behavioural patterns anaesthetics-induced modulation of neural plasticity might repre-
causing either suffering or a poor ability to function in ordinary life sent a therapeutic value in the treatment of some psychiatric con-
(1). These conditions are generally characterized by a combination ditions. In line with this possibility, an increasing number of both
of abnormal thoughts, perceptions, emotions, behaviour, and rela- experimental and clinical observations suggests a therapeutic role
tionships with others. The burden of mental disorders continues to for general anaesthetics in major depressive disorders. This chapter
grow and the estimated global lifetime prevalence of these patho- aims to provide insights into this possibility.
logical states is estimated to reach over one-third of the population
worldwide with important regional differences (2). In fact, while
approximately 25% of Europeans present meeting criteria at some Major Depressive Disorder—Epidemiology
point in their life for DSM-IV-defined mental disorders, this preva-
lence is close to 50% in the United States (3, 4). Anxiety and mood and Treatments
disorders are by far the leading causes of these pathologies in all con- Major depressive disorder (MDD) is a seriously debilitating condi-
tinents followed by impulse-control and substance use disorders. tion with a lifetime prevalence of approximately 17% (7). It is among
Mental illnesses are the leading causes of disability-adjusted life the leading causes of disability worldwide with enormous personal
years worldwide (5). According to the World Health Organization, suffering and economic loss (8). The diagnosis of MDD is based on
the global cost of mental illness is estimated to exceed 2.5 trillion a series of well-defined symptoms, many of which might reflect a
US dollars every year in the world and is projected to double during diverse array of underlying pathophysiological mechanisms (9, 10).
the next decade (5). Major depressive disorder is the leading cause This, in turn, complicates the design of a unified approach to treat
of these expenses followed by direct and indirect costs linked to the this disorder. Accordingly, currently available pharmacological
management of schizophrenia (5). Understanding the pathophysi- treatments have serious limitations. They might need several weeks
ology of these diseases and thereby developing efficient therapeutic to provide therapeutic effects and suicidal behavioural patterns can
approaches is therefore of high priority public health importance. even increase during this period (11). Additionally, they operate
General anaesthetics comprise a family of largely heterogenous with a relatively row rate of efficacy and this is often accompanied
substances with the common capacity of rapidly inducing transient by a high incidence of relapse (12, 13). Development of new drugs
loss of consciousness and amnesia upon administration. Therefore, with faster action and more efficacy is therefore strongly warranted.
these drugs are indispensable components of the pharmacological Before the advent of psychopharmacological revolution in the
armamentarium aimed to provide optimal surgical conditions, 1950s, electroconvulsive therapy (ECT) was the mainstream thera-
both for patients and surgeons, during the peri-operative period. peutic option to treat psychiatric disorders (14). As early as the
Given the seemingly on/off effects of general anaesthetics on con- sixteenth century, the Swiss physician Paracelsus described orally
sciousness, it has been initially considered that exposure to these taken camphor to produce seizures in order to treat psychiatric con-
drugs does not induce long-term interference with central nervous ditions. This method was reintroduced in the early 1930s by Von
system function. However, observations accumulating over the past Meduna, who used intramuscular injection of camphor and, later,
few decades argue against this conception. It is now well established intravenous infusion of pentylenetetrazol to treat catatonic stupor
that general anaesthetics are potent modulators of major neuro- in schizophrenic patients by convulsions (15). The use of electricity
transmitter systems, and that even short-term pharmacological for seizure induction was first reported by the Italian psychiatrist
interference with neurotransmitter-driven neural activity patterns and neurophysiologist Cerletti and Bini, who successfully treated
can have long-term consequences on brain physiology (6). This im- a young mute catatonic patient in 1938 (16), and this method has
plies that general anaesthetics cannot simply be acknowledged as rapidly gained widespread use in the psychiatric community (14).
drugs inducing a rapidly reversible state of unconsciousness but Since these early days, ECT has undergone continuous refinements
316
and a recent meta-analytic review demonstrates that it is indeed a anaesthesia when compared with a similar simulated ECT protocol
valid therapeutic tool for treatment of depression, including severe where only thiopentone was administered (27). These trials thus
and resistant forms (17). Despite decades of use, the therapeutic brought convincing arguments in favour of the beneficial impact of
mechanism of action of ECT remains unsolved. This does not general anaesthesia in depressive states, and raised the intriguing
mean that we do not know what ECT does, but it is rather diffi- possibility that an anaesthetic-induced decrease in neural activity
cult to identify which one(s) among its many effects on the brain might be an important component accounting for these effects. To
is needed for the therapeutic action (18). An emerging view is that further test this hypothesis, in two subsequent trials, Langer and
ECT increases brain plasticity (19). Indeed, in addition to its potent colleagues demonstrated that six sessions of isoflurane anaesthesia-
facilitating action on serotonin-, norepinephrine-, and dopamine- induced brief burst suppression over two weeks had comparable
mediated neurotransmission, it also increases the expression of effects with the delivery of six bitemporal ECT under general an-
several neurotrophic factors, including brain-derived neurotrophic aesthesia in terms of both objective and subjective mood scales for
factor (BDNF) (20, 21). Moreover, ECT induces structural changes up to five weeks (28, 29). Importantly, the capacity for sustained
in the brain, including angio-, glio-, and neurogenesis, along with concentration was significantly better in patients having received
increased dendritic arborization and synaptogenesis (19). As de- isoflurane compared to the ECT group (29). The antidepressant and
pression is associated with decreased neuroplasticity (9), it is thus neurocognitive effects of isoflurane anaesthesia were subsequently
tempting to speculate that the ensemble of these aforementioned reconfirmed in a group of 20 patients with medication-refractory
highly complex effects, aimed to promote neuroplasticity, might be depression (30). In this study, ECT had modestly better effect at
required for the therapeutic action of ECT. follow-up in severity-matched patients, while the isoflurane group
showed better neurocognitive score improvement (30). More re-
cently, a prospective pilot study demonstrated antidepressant prop-
Clinical Trials Suggesting a Therapeutic Role erties of 50% nitrous oxide inhalation in patients with treatment
for Anaesthesia in Patients with Depressive resistant MDD (31).
Disorders
In most cases, ECT is performed under general anaesthesia. Since Rapid Antidepressant Effects of Ketamine
general anaesthesia, in itself, is a robust modulator of brain states, A growing number of randomized clinical studies, accumulating
an important question is to determine whether the therapeutic over the past 15 years, suggests an antidepressant role for the com-
value of ECT is indeed linked to the passage of electrode-delivered petitive NMDA receptor antagonist ketamine in patients with
electricity or to the impact of general anaesthetics on neural net- mood disorders (32). It is interesting to note that the idea to use this
works. To elucidate this issue, active ECT should be compared with particular anaesthetic to treat depression is not based on the afore-
a simulated procedure in which shocks are not delivered. Results mentioned putative link between the anaesthesia component of
from early studies aimed to address this problem were conflicting ECT and the therapeutic effect. Rather, it stems from the so-called
and open to important methodological criticism due to very low ‘initiation and adaptation’ hypothesis, which assumes that the de-
sample size and to the lack of adequate comparison groups. In layed effects of currently used classic pharmacological antidepres-
1953, Miller and colleagues found a comparable improvement in sants are primarily due to the delayed adaptive effects of these drugs
social performance of 30 patients presenting with chronic cata- on glutamatergic neurotransmission systems, which stand in the
tonic schizophrenia following treatment with either ECT, non- centre of the therapeutic response (33). In line with this postulate,
convulsive stimulation under thiopental anaesthesia, or thiopental preclinical studies demonstrate the prompt efficacy of NMDA ant-
anaesthesia alone (22). Similar observations were made in a group agonists in various animal models of depression (34, 35). Further
of patients with mixed diagnoses of depressive states, where no stat- indications on the role of glutamatergic systems in the pathophysi-
istically significant difference was found in outcome with straight ology of depressive disorders came from human studies where
ECT, ECT plus succinylcholine, ECT plus thiopentone, thiopen- proton magnetic resonance imaging (MRI) revealed increased glu-
tone alone, and nitrous oxide anaesthesia alone (23). In contrast tamate levels in the cerebral cortex of medication-free subjects with
to these observations, another study suggested a slight superiority unipolar major depression when compared with a matched popu-
of ECT compared to simulated ECT under thiopentone, but it is lation of healthy controls (36). Last but not least, the glutamate
important to note that while 12 patients in this work received ECT, release inhibitors lamotrigine and riluzole were found to exert anti-
only four subjects comprised the simulated group (24). depressant properties in clinical trials (37, 38). Altogether, these
Following these initial observational studies, randomized trials laboratory and clinical observations strongly suggest that drugs
were designed and conducted to compare anaesthesia alone with acting directly to decrease the efficacy of glutamatergic signalling
ECT under anaesthesia in terms of therapeutic efficacy. In a co- are expected to demonstrate rapid onset of action to relieve symp-
hort of 32 patients suffering depressive psychosis, six brief sessions toms in depressed patients.
of unilateral ECT under methohexitone anaesthesia over a period Rapid therapeutic actions of ketamine were first demonstrated in
of two weeks showed comparable improvement on the Hamilton a small group of seven patients with major depression by Berman
Rating Scale for Depression (25) with a simulated procedure and colleagues (39). In this randomized, double-blinded, and
where study subjects received only anaesthesia (26). In line with placebo-controlled trial, intravenous administration of 0.5 mg/kg
these observations, in a six-month follow-up of 70 patients with ketamine over a period of 40 minutes was associated with robust
severe depression, the Northwick Park Electroconvulsive Therapy decreases in depressive symptoms, emerging progressively within
trial demonstrated equivalent therapeutic value of eight succes- three days. These initial observations were subsequently confirmed
sive ECT sessions over a period of four weeks under thiopentone in a cohort of 18 patients with DMS-IV major depression, using
317
Chapter 28 major psychiatric disease 317
an elegant cross-over design (40). Compared to the placebo group, to negative stimuli in the anterior cingulate cortex, amygdala,
patients receiving ketamine showed significant improvement in de- and paralimbic regions while reduced responses were detected
pression as early as two hours following drug administration, and, to positive stimuli and reward-related information in the pre-
most importantly, this effect remained significant for at least one frontal cortex and the striatum (48, 49). These findings indicate
week. These pioneering studies were followed by a large number that dysfunction of neuronal systems involved in the processing
of clinical trials, and several meta-analyses are now available sup- of the rewarding potential of emotive stimuli might be central to
porting unanimously the therapeutic potential of ketamine in symptoms of MDD such as anhedonia or anxiety (50). Therefore,
MDD both in drug-free patients and in those who were under pharmacological treatment strategies that lead to improvement of
classic antidepressant medications (41, 42, 43, 44). Among the clinical symptoms are expected to normalize pathological network
various symptom clusters characterizing MDD, ketamine appears activity.
to rapidly and robustly relieve anhedonia (i.e., the reduced cap- Administration of ketamine to healthy volunteers acutely in-
acity to experience pleasure), suggesting its action on the reward creases metabolic activity in the prefrontal and anterior cingulate
system in the brain (44). Relatedly, ketamine administration has cortices (51, 52, 53). The findings are consistent with preclinical
been shown to rapidly reduce suicidal ideation, a feature that makes data showing that ketamine injection rapidly leads to glutamate
this drug uniquely suited to treat suicidal ideation in hospitalized release in these brain regions as well as with proton MRI in hu-
patients (45, 46). Importantly, administration of ketamine, 0.5 mans demonstrating an association between ketamine adminis-
mg/kg over 40 minutes intravenously in the majority of trials, ap- tration and acute increases in cortical glutamate levels (53, 54, 55,
peared safe with no life-threatening effects reported. Nevertheless, 56). Recent investigations shed light on how ketamine may affect
mild psychotomimetic symptoms, including unpleasant dissocia- specific brain regions in MDD. (18F)-fluorodeoxyglucose PET
tive effects, were frequently reported, but these resolved rapidly revealed no significant change in whole brain metabolism two
following the end of administration. Transient hypertension and hours following ketamine injection in unmedicated treatment-
tachycardia were also reported but rarely required pharmacological resistant patients with MDD (57). However, a priori region of
intervention. interest (ROI) analysis of candidate structures showed decreased
metabolism in the right habenula and the extended medial and
Mechanisms of Actions Underlying orbital prefrontal networks while increased activity was detected
in sensory association cortices when compared to baseline ac-
Therapeutic Effects of Anaesthetics tivity levels in these same subjects (57). Subsequent works from
Understanding the mechanisms through which anaesthetics can the same investigators demonstrated that ketamine but not pla-
exert therapeutic effects in MDD is a major challenge for several cebo administration increased metabolism in the right striatum
reasons. First, elucidating pharmacokinetic and pharmacodynamic and in the subgenual anterior cingulate cortex, and revealed a
drug properties that are required for therapeutic effects will pro- positive correlation between the extent of increase in metabolism
vide valuable information to design better targeted clinical studies in these ROI and the improvement in the Montgomery-Asberg
in the future. Second, identification of anaesthetic-triggered mo- Depression Rating Scale (MADRS) (58). Specifically, the ketamine
lecular cascades involved in the antidepressant effects could give infusion-induced reduction in anhedonia levels positively correl-
rise to designing new drugs specifically targeting these pathways. ated with increased glucose metabolism in the dorsal anterior cin-
Third, research in this field will contribute to widen comprehension gulate cortex and putamen as well as with decreased metabolism
of the mechanisms through which anaesthetics modulate neural in the orbitofrontal cortex (59, 60). A very recent fMRI study
plasticity. This, in turn, might provide useful information for future using emotion perception tasks showed reduced neural responses
studies focused on the protective effects of these drugs following to positive faces in the right caudate in treatment-resistant MDD
brain injury. Finally, these studies will continue to improve under- patients and these responses were selectively increased when
standing on the highly complex neurobiology of mood disorders. evaluated one day following ketamine administration (61). While
The neurobiology of MDD, although far from being completely these aforementioned studies provide highly valuable informa-
elucidated, appears to comprise a highly complex series of subtle tion on neural systems involved in the antidepressant effects of
cellular and molecular alterations that will ultimately lead to dys- ketamine, several important questions remain open. Among
function of complex neural networks (reviewed in 9, 10). Hence, them, a particularly relevant issue is whether and to what extent
one straightforward approach to study the mechanisms through the ketamine-induced changes in network activities persist over
which anaesthetics might improve depressive symptoms is to ask time. Indeed, while the beneficial effect of ketamine on depres-
how exposure to these drugs impacts already identified pathways sive symptoms is detectable for an extended period, there are
involved in the neurobiology of depression. This can be achieved currently no studies available addressing the long-term effect of a
by focusing on the network, on the individual cell, or on molecular single dose ketamine injection on brain circuitry in MDD. In light
cascades. of the potentially important role of the brain reward system in
In terms of neuronal network functions, an emerging concept the pathophysiology of MDD, another important series of as yet
is that brain region-specific functional disconnections are major unexplored questions concern the impact of ketamine on reward
contributors to the pathophysiology of MDD (47). This altered and emotional processing in these patients.
connectivity does not necessarily mean a reduction in the number The molecular and cellular mechanisms underlying the neural
of synaptic contact and circuitry function, but can also translate substrate-specific changes of brain circuitry in MDD following
into increased activity and function in certain brain areas. For ex- ketamine administration is an intense field of research. It is be-
ample, functional MRI and positron emission tomography (PET) coming increasingly clear that depression is associated with loss of
in human subjects revealed increased neuronal network activity neurotrophic support which, in turn, may lead to reduced synaptic
318
connectivity in neuronal networks (9, 62). In postmortem tissue antagonist ketamine. This drug has repeatedly shown rapid efficacy
from patients with MDD, microarray gene profiling and electron in depressive states and some of the mechanisms underlying this
microscopic stereology revealed lower expression of synaptic effect have been elucidated. Several important questions, however,
function-related genes along with lower number of synapses when remain open. Among them, since the effects of single bolus keta-
compared with matched controls (63). In line with these human ob- mine appear transient, one important issue is to elucidate whether
servations, several stress models of depression in rodents have been repeated injections of ketamine can maintain sustained remis-
shown to induce brain region-specific changes in neuronal arbour sion in patients with MDD. While several case reports describe
architecture and synapses (for review see 64). In general, chronic repeated ketamine injection with variable outcome, there is cur-
stress induces reduction in the number of dendritic spines, small rently no study available to specifically address this question. Dose-
protrusions of the dendritic surface representing the postsynaptic response studies to determine the concentration-dependent effects
sites of excitatory synaptic contacts onto neurons (64). There is now of ketamine in MDD are also lacking. This line of research will be
extensive genetic evidence suggesting that brain-derived neuro- of utmost interest to determine the pharmacokinetic aspects of
trophic factor (BDNF) plays a key role in these processes and the antidepressant properties. Identifying which particular modalities
downstream signalling pathways that mediate the actions of this characterizing MDD are prone to positively respond to ketamine
neurotrophin have been identified (64). Among them, the mech- needs to be addressed in the future. In fact, new data suggest the
anistic target of rapamycin complex 1 (mTOTRC1) is of central efficacy of ketamine in rapidly reducing suicidality and in allevi-
importance since it regulates activity-dependent protein synthesis ating post-traumatic stress disorder symptoms (71, 72). Whether
implicated in synaptic plasticity (65). Chronic stress-related re- other psychiatric pathologies, such as obsessive-compulsive dis-
duced mTORC1 signalling is associated with decreased expression orders or cocaine dependence, can also be treated with ketamine
of synaptic proteins along with a decreased number and function of is an intense field of current research (73, 74, 75). Importantly,
dendritic spine synapses (66). safety issues related to toxicity associated with repeated ketamine
Recent experimental observations reveal that administra- administration should definitely be elucidated especially in light of
tion of a single low dose of ketamine to young rodents leads to a abuse liability to this drug (76). Last but not least, and with par-
rapid increase in the number of dendritic spine synapses in the ticular relevance to peri-operative care, implementing low-dose
medial prefrontal cortex (mPFC) and this is accompanied by in- ketamine administration into routine anaesthesia management is
creased synaptic function (66). Ketamine-induced activation of the an intriguing possibility. Indeed, in addition to the large number
mTORC1 pathway and the concomitant increase in the expression of subjects with MDD requiring surgery, approximately 20% of pa-
of synaptic proteins appear central to this effect (66). In animal tients without the diagnosis of depressive disorders experience de-
models of chronic stress, both the behavioural and synaptic deficits pressed mood during the peri-operative period, and this has been
were rapidly reversed by a single dose of ketamine via activation of shown to affect recovery and prognosis (77). Initial reports sug-
mTORC1 (67). A role for BDNF in the synaptic and behavioural gest that implementing small-dose ketamine into the anaesthesia
effects of ketamine has also been identified. Indeed, the antidepres- regimen improves postoperative mood both in patients with and
sant behavioural properties of ketamine were blocked in condi- without the diagnosis of MDD (78, 79). Further studies are needed
tional BDNF deletion mutant mice as well as following the infusion to gain insights into this issue.
of a function blocking anti-BDN antibody into the mPFC (68, 69). Although ketamine is emerging as the drug of choice to rapidly
Similarly, both the ketamine-induced induction of spine synapses treat symptoms of MDD, it is important to remember that other
and the antidepressant effects are absent in the BDNF Met allele general anaesthetics might also exert similar effects. Indeed, early
knock-in mice (70). The ensemble of these observations provides studies repeatedly revealed therapeutic effects of general anaes-
a mechanistic explanation of how decreased levels of BDNF and thesia and this line of research should be actively pursued (27, 28,
downstream mTORC signalling, associated with depressive states, 29, 30). In line with these clinical data, laboratory observations also
can be reversed via rapid acting antidepressants such as ketamine suggest that general anaesthetics are powerful modulators of syn-
(64). According to this hypothesis, ketamine rapidly reverses spine aptic plasticity via the modulation of neurotransmitter release and
synapse deficits in the mPFC via a burst of glutamate via disinhib- growth factor signalling (6). Importantly, similar to ketamine, these
ition of GABAergic interneurons that control glutamate transmis- drugs can rapidly induce the formation of new synapses (6, 80, 81).
sion. The consequent increase in AMPA receptor signalling triggers It will, therefore, be important to determine whether or not, and in
activity-dependent release of BDNF and its signalling via the TrkB what dosing and administration regimens, currently used general
receptor. This, in turn, will stimulate mTORC1 signalling, leading anaesthetics can have equivalent therapeutic efficacy in depressive
thereby to increased synthesis of synaptic proteins required for new states when compared to ketamine. Research in this direction will
excitatory synapse formation. Interestingly, both in humans and ro- not only lead to an increased understanding of the effects of general
dents, the antidepressant response to ketamine is maintained for anaesthetics on the central nervous system, but might open new av-
approximately seven days and ketamine-induced increases in spine enues for anaesthesiology as a discipline to administer general an-
densities persist for the same duration (64). aesthesia with a therapeutic goal of improving pathology in mood
disorders and, potentially, other psychopathologies.
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32
32
Index
Tables, figures, and boxes are indicated by an italic t, f, and b following the page number.
A antiparkinsonian drugs 310–12 awake craniotomy 235–43

Abbreviated Injury Scale (AIS) 149 apoptosis 79, 102–3 asleep-awake-asleep technique  236
acetazolamide 229 approximate entropy 43 benefits 235
acetylcholine 50, 52, 56–7, 58, 61 aquaporins 225 complications  236–7
acetylcholine receptors ARCTIC trial 82 conscious sedation 236, 239
decreased number 70 arousal  6–8 contraindications 235
immature/mature  62 arterial carbon dioxide tension 83 cortical mapping 236
increased expression 69–70 arterial oxygen tension 83 epilepsy surgery 237–9
muscarinic 4f, 57 arteriovenous malformations 138, 142, 189, indications 235
muscle relaxants 64 190–1, 195, 268 patient selection 235
nicotinic 4–5, 4f, 57, 61, 62, 64 ASA status 189 tumour surgery 235–7
acetylcholinesterase 57, 61 ascending reticular activating systems 6–8, 24 axon-dendrite polarity  103–4
acetylcholinesterase enzyme 63 ASIA classification 255–6
inhibitors 70 ASICS 112, 113 B
acidosis  78–9 asleep-awake-asleep technique 236, 268 balloon-assisted coiling 203
acquired cholinesterase deficiency 66 astrocytes 28, 31, 104 barbiturates
acromegaly 215, 216–17, 219 astrocytoma 180t, 267 cerebral physiology 33, 33t
action potential 114 ATENA trial 204 ICP 155
A-delta fibres 114, 115 atlanto-axial subluxation 246, 247 molecular targets 4f
adenosine, temporary flow arrest 195–6 ATP 58, 77, 112, 113–14 neuroprotection 80
adherens junctions 28 atracurium 68t posterior fossa surgery 177–8
adrenal insufficiency 282 atrial natriuretic peptide 248 refractory status epilepticus 134
adrenergic receptors 54–6 auditory brainstem responses 140 traumatic brain injury 153
adrenocorticotrophic hormone 214t autonomic dysreflexia 258–9 basal forebrain 7–8, 9
age autonomic nervous system 47–58 benign intracranial hypertension 228
cerebral blood flow and metabolism 31–2 adrenergic function 50–2 benzodiazepines
EEG changes 38 adrenergic receptors 54–6 cerebral physiology 33t, 34
muscle relaxants 66 anatomy  47–50 status epilepticus 134
Airtraq 247 cholinergic function 52–3 benztropine 311t
alcuronium 68t cholinergic receptors 57 Bernwood criteria 156
allodynia 112 co-transmission  58 BEST:TRIP trial 277
Alzheimer’s disease 297 dopamine receptors 56 β-blockers  56
amantadine 311t, 312 downregulation 56 biopsychosocial model of illness 118
anaemia enteric nervous system 47, 48–50 bispectral index (BIS) 40, 41
neurocritical care 273 function  50–3 blood-brain barrier 19, 27–9
non-neurologic surgery with cerebrovascular genetic contributors 58 blood-CSF barrier 29
disease 291 G-proteins  56 blood glucose, see glucose control
aneurysms, see cerebral aneurysms integration 50 brachial plexus injury 185, 252
anterior cingulate cortex 116 muscle relaxant effects 64 bradykinin 117
anterior ischaemic optic neuropathy 250 non-adrenergic, non-cholinergic brain
anticholinergic agents 311t, 312 neurotransmission  57–8 blood-brain barrier 19, 27–9
anticoagulation organization 50 death  282–3
intracerebral haemorrhage 279 parasympathetic nervous system 47, 48, 255 networks  9–10
non-neurologic surgery with cerebrovascular pharmacology  53–8 oedema 150
disease 292 sympathetic nervous system 47–8, 255 parenchyma  17–18
traumatic brain injury 155–6 upregulation 56 relaxation  194–5
anti-epileptic drugs 133, 134, 189, 239, 265, 267, autoreceptor 55 tissue oxygenation 157, 276
305, 306 autoregulation 29 trauma, see traumatic brain injury
324
324 index
brain-derived neurotrophic factor (BDNF) cerebral salt wasting syndrome 268, 281, 282t supratentorial tumours 267
103, 114, 318 cerebrospinal fluid (CSF) tethered cord 266
brainstem blood-CSF barrier 29 choline 56
anatomy 173 cerebral blood flow and 226 cholinergic receptors 57
death 282 composition 226t chromaffin cells 53
glioma 176t differential diagnosis of infection and cis-atracurium  68t
intra-operative monitoring  139–40 haemorrhage 24t CLARITY trial 204
reflexes 130, 131t drainage 22–4, 173 claudins 27
signs and symptoms of pathology 174, 178 draining pre-pituitary surgery 217–18 clonidine 33t, 34, 196
bromocriptine 311t historical background 17 CNT-2  29
bulbocavernosus reflex 142 physiology  225–6 cognitive decline
bumetanide 106 shunts 230–1, 233, 267 Parkinson’s disease 310
burn injury 70 spaces 18 postoperative 299–301
burst suppression 36–7, 195 synthesis 18, 225 coherogram 40
butyrylcholinesterase 57 theories 17 coil embolization 203
valves  230–1 coma 24, 128–31, 229
C volume 18, 225 competitive block 62–3
calcium 77, 78 cerebrovascular disease, non-neurologic complex I of electron transport chain 4f,  5–6
voltage-gated channels 4f, 5 surgery  289–94 compound nerve action potential 143
captopril 259 cerebrovascular oxygen reactivity index 275–6 computed tomography (CT)
CARAT trial 203 cerebrovascular resistance 29 coma 130
carbamazepine 192 cerebrovascular surgery 189–97 Fisher grading system for SAH 190
carbon dioxide 30, 165 anaesthetic choice 193 hydrocephalus 228
cardiac arrest, hypothermia 81–2 anaesthetic management 192–3 ischaemic stroke 132
carotid atherosclerosis 189, 192, 195, 205–6 blood transfusion 196 traumatic brain injury 152
carotid body 64 brain relaxation 194–5 COMT inhibitors 310, 312
carotid endarterectomy 192, 193–4 children 268 concentrative nucleoside transporter type 2
cerebral hyperperfusion syndrome 195 electrolytes 196 (CNT-2)  29
cationic amino-acid transporter type 1 emergence from anaesthesia 196 conscious sedation 236, 239, 241
(CAT-1)  29 fluids 196 context-sensitive half-life  65
CAVATAS trial 205–6 glucose management 196 cooperative patient general anaesthesia 194
cell death 79 haemodynamic management 195–6 corneal reflex 131t
central cord syndrome 248 ICP management 194–5 corpus callosotomy 268
central medial thalamus 9 induction of anaesthesia 193 cortical blindness 250
central nervous system intra-operative monitoring 194 cortical mapping 236
development 263 postoperative management 197 corticocortical networks 10
muscle relaxants 64 pre-anaesthesia evaluation and corticosteroids, see steroids
central pain 112, 116, 117t management  189–92 co-transmission  58
central post-stroke pain 111 cervical collar 256 cough reflex 131t
central retinal artery/vein occlusion 250–1 C-fibres 114, 115 cranial nerves
central sensitization 112, 117 channel block 63 compression syndromes 174
cerebellum 173, 178 Cheyne-Stokes respiration 130 injury 186
cerebral aneurysms 189, 190 Chiari malformation 174 monitoring 139
endovascular therapy 202–5 children craniopharyngioma 216, 267
intra-operative monitoring during clipping blood loss 265–6 CREST-2 trial 206
137, 138 cerebrovascular surgery 268 cross frequency coupling 40
temporary clipping 195 CNS development 263 Cushing reflex 151, 232
cerebral blood flow (CBF) 18, 19, 27, 29–32, 77 decompressive craniectomy 155 Cushing’s disease 215, 216, 218, 219
CSF and 226 EEG 38 Cushing triad 126
neurocritical care 276 encephalocele 266 cytotoxic oedema 77
cerebral blood volume (CBV) 18, 27, 150 epilepsy surgery 267–8
cerebral hyperperfusion syndrome 195 fluids  265–6 D
cerebral ischaemia 77 hydrocephalus 226–7, 229, 266–7 Dandy Walker malformation 174
cerebral metabolic oxygen consumption induction of anaesthesia 264 dantrolene 70
(CMRO2) 30, 128 intra-operative management  264–6 decompressive craniectomy 155, 278, 280
cerebral metabolism 29–32, 77 maintenance of anaesthesia 265 DECRA trial 278
children 263 muscle relaxants 66 deep brain stimulation 240–3, 313–14
normal values 32t myelomeningocele 266 deep mesencephalic reticular formation 7
traumatic brain injury 152 neuroanaesthesia  263–9 deep vein thrombosis 168–9, 259
cerebral microdialysis 277 neuroendoscopy 268 default mode network 116
cerebral oxygenation 276–7 neuroradiology  268–9 delayed cerebral ischaemia 279
cerebral perfusion pressure (CPP) 19, 77, 128, neurotoxicity of general anaesthetics 93–101 delirium, postoperative 162, 298–9
150, 275 positioning 265 dementia 297–8, 312
calculation 18, 29 posterior fossa syndrome 186 dendrites 104
definition 19 posterior fossa tumours 173, 176t, 267 depolarizing neuromuscular blocking
neuroprotection 84 postoperative care 269 drugs 63, 67
normal value 19 postoperative pain 269 depressive disorders 315–18
optimal 18 pre-operative assessment and descending modulation 114
traumatic brain injury 155 planning  263–4 desensitization 56
cerebral physiology 27–34 sedation 269 desensitization block 63
325
index 325
desflurane proprietary pEEG indices 40–2 Fisher grading system 190

cerebral physiology 33, 33t referential montage 35 Fisher test 229
dementia 297, 298t slow waves 36, 37 FLAME trial 84
Parkinson’s disease 313 spectral edge frequency 39 flow disrupting devices 204
supratentorial craniotomy 164 spectral entropy 43 flow diverting stents 204
traumatic brain injury 153 spectrogram 39 fluoxetine 84
desmopressin 219 spindles 36, 37 focal ischaemia 77
dexamethasone 165, 218 system 36f follicle-stimulating hormone 214t
dexmedetomidine thalamocortical network 10 fosphenytoin 133, 134
awake craniotomy 236 titration of anaesthesia 38 Fourier transform 35, 38
cerebrovascular surgery 193, 196 tracé alternant 38 FOUR score 274
children 265, 269 traumatic brain injury 157 fourth ventricle lesions 178
deep brain stimulation 241 waveforms  35–6 frontal cortex 10
molecular targets 4f electromyography (EMG) functional MRI
neuroprotection 105 artefact on EEG 44 information integration 10
supratentorial craniotomy 164, 168 intra-operative monitoring 139–40, 141, neurotoxicity of anaesthetics 101
traumatic brain injury 277 142, 266 pain 118
diabetes insipidus 151, 216, 218–19, 267, 281–2 spinal cord injury 258 thalamocortical network 10
dibucaine-number  66 electron transport chain 4f,  5–6 functional neurosurgery 240–3
dibucaine test 66 encephalocele 266 functional pain 112
dopamine 53 endoscopic surgery furosemide 154, 229
dopamine agonists 310–12, 311t children 268
dopamine β-hydroxylase 53 hydrocephalus 231–2, 233, 267 G
dopamine receptors 56 pituitary 217 GABAA-receptor 3, 4f, 104
dorsal raphe 8 endothelial cells 27–8, 31 gabapentin 163, 249
Down’s syndrome 247 endothelial glycocalyx 248–9 gag reflex 131t
D wave 142 endothelial surface layer 248 gamma-aminobutyric acid-gated GABAA
endovascular neurosurgery, see interventional receptor 3
E neuroradiology GAS trial 101
elderly enteric nervous system 47, 48–50 gate control theory 114
EEG 38 entropy 43 generator potentials 112
ketones 32 environmental enrichment 106 Glasgow Coma Scale (GCS) 130, 130t, 149,
muscle relaxants 66 ependymoma 176t, 267 150t, 168, 274
electrocardiogram (ECG) epilepsy glial cells 105
artefact on EEG 44 awake craniotomy 237–9 global ischaemia 77
subarachnoid haemorrhage 190, 280 corpus callosotomy 268 globus pallidus internus nucleus 242
electroconvulsive therapy (ECT) 315–16 electrocorticography 238, 239, 267–8 glucose control
electrocorticography 238, 239, 267–8 hemispherectomy 268 autonomic nervous system 52
electroencephalography (EEG) 35–45 non-neurologic surgery  303–7 cerebrovascular surgery 196
age changes 38 paediatric surgery 267–8 neurocritical care 273
approximate entropy 43 epinephrine 51, 52 neuroprotection  83–4
artefacts 44 erythropoietin 106 non-neurologic surgery with
bipolar montage 35 ESCAPE trial 207 cerebrovascular disease 292
bispectral index (BIS) 40, 41 ethers, molecular targets 4f supratentorial craniotomy 166
burst suppression 36–7, 195 etomidate traumatic brain injury 155
cerebral blood flow 77 cerebral physiology 33, 33t glucose transporter type 1 (GLUT-1) 29
cerebrovascular surgery 194 EEG effects 37 glutamate 4, 31, 77, 114
coherogram 40 molecular targets 4f glycaemic control, see glucose control
common mode rejection 35 neuroprotection  80–1 glycine receptors 4, 4f
cross frequency coupling 40 posterior fossa surgery 179 G-protein-coupled receptors  5
delta waves 36, 37 supratentorial craniotomy 162 G-proteins  56
elderly 38 traumatic brain injury 153 growth hormone 214t, 215
electrode montage 35 EUROTHERM trial 82 GTP-binding regulatory proteins 56
entropy 43 EVA-3S trial 206
filters 35 evoked potentials
motor (MEPs) 137–8, 140, 141, 142, 143, 193,
H
Fourier transform 35, 38 haemangioblastoma 177t
functional connectivity measures 43–4 194, 258
Hakim’s triad 228
general anaesthesia 36–8 somatosensory (SSEPs) 137, 138, 140–1, 142,
halothane
historical background 35 143, 157, 164, 193, 194, 258
cerebral physiology 33t
information integration 10 excitatory ligand-gated ion channels 4–5
molecular targets 4f
international  10–20 excitotoxicity 77, 104
Parkinson’s disease 313
intra-operative monitoring 137 EXTEND-IA trial 207
HCN1 5
M-entropy 41, 42 external ventricular drain 22–4, 230, 233
headache
Narcotrend 41, 42 extracellular matrix 28
pituitary tumours 215
neonates 38 extracranial–intracranial bypass procedures 138
postoperative 118
neurocritical care 277 eye movements 130
heart failure 52
paradoxical delta arousal 38 heart rate 52
Patient State Index 41, 42 F hemifacial spasm 192
permutation entropy 43 fibreoptic intubation 247, 256 hemispherectomy 268
power spectrum 38–9 filopodia 104 hereditary haemorrhagic telangiectasia 190–1
326
326 index
herniation syndromes 18, 24–5, 125–8 IHAST trial 82–3, 196 anaesthetist’s contribution 144

clinical management 126 immobilization 69 brainstem surgery 139–40
clinical signs 19b IMS III trial 206 cerebrovascular surgery 194
emergency treatment 127b inflammation evidence-based guidelines  143–4
surgical intervention 128 delirium  298–9 intracranial surgery 137
symptoms  125–6 muscle relaxants 70 managing changes 143
therapies to reverse 126–8 neurotoxicity of anaesthetics 104 multimodality 140, 142
types 24, 127t stroke 289 neurological outcome 143–4
heteroreceptor 55 information integration 10 neurovascular surgery 137–8
Hoehn and Yahr staging 309, 310b infusion test 229 peripheral nerve surgery 143
Hoffmann’s reflex 142 inhalational anaesthetics posterior fossa surgery 185
Hofmann elimination 67 cerebral physiology 33t,  33–4 skull base surgery 139–40
horizontal position 180t, 182f, 185 cerebrovascular surgery 193 spine and spinal cord surgery 140–3, 249,
HPC cells 115 coherogram 40 258, 266
H reflex 142 EEG effects 37 intraparenchymal probes 22, 157
Hunt and Hess grading system 190 neuroprotection 80, 106 intravenous anaesthesia
hydrocephalus 18, 225–33 Parkinson’s disease 313 cerebrovascular surgery 193
acute 227, 233 posterior fossa surgery 179 Parkinson’s disease 313
aetiology  226–8 supratentorial craniotomy 164, 165 total intravenous anaesthesia 163–4, 180, 205
aquaporins 225 traumatic brain injury 153 traumatic brain injury 153
children 226–7, 229, 266–7 inhibitory ligand-gated ion channels 3–4 intraventricular catheters 21–2, 157
chronic 227, 233 insula 116 inverse steal 83
chronic obstructive 227 intensive insulin therapy 83 ISAT trial 203
communicating 227, 228 INTERACT-2 trial 279 ischaemic core 78, 79
complex-type  227 interventional neuroradiology 201–8 ischaemic optic neuropathy 250
congenital 226 carotid artery stenosis 205–6 ischaemic penumbra 77
CSF valves 230–1 cerebral aneurysms 202–5 ischaemic stroke
definition 226, 266 historical background 201–2 emergency care 131–3
diagnosis  228–9 ischaemic stroke 206–8 endovascular therapy 206–8
endoscopic surgery 231–2, 233, 267 radiation exposure 201 hypertension 132
external ventricular drain 22–4, 230, 233 intracerebral haemorrhage, neurocritical hypothermia  82–3
Greitz’s hyperdynamic flow theory 227 care  279–80 mechanical thrombectomy 133, 206–7
ICP monitoring 229 intracerebral steal 193 neurocritical care 280
imaging 228–9,  232–3 intracranial compliance 18–19 NIHSS 132
lumbar drains 22, 24 intracranial hypertension recombinant tissue plasminogen activator
lumbar infusion test 229 benign (idiopathic) 228 132–3, 206, 208
medical treatment 229 causes 125 isoflurane
non-communicating  227 pathophysiology 125 cerebral physiology 33, 33t
normal pressure 18, 227–8, 233 patient evaluation 203 dementia 297, 298t
pre-operative assessment 229 subarachnoid haemorrhage 279 Parkinson’s disease 313
removal of CSF (Fisher test) 229 supratentorial craniotomy 167, 168 ISPOCD1 trial 299
shunt surgery 230–1, 233, 267 traumatic brain injury 150, 151b, 277
symptoms 228, 266 intracranial pressure (ICP) 17–25 J
treatment  229–32 arterial blood pressure and 21 jugular venous oxygen saturation 276
hydrogen, neuroprotection 106 cerebrovascular surgery 194–5 junctional adhesion molecules 27–8
hyperaemia 30 clinical signs of increase 19 juvenile pilocytic astrocytoma 176t
hyperalgesia 112 endovascular therapy for cerebral
hyperpolarization-activated cyclic aneurysms  202–3
nucleotide-gated (HCN) channels 4f, 5 head-up positioning 19, 154
K
K2P channels 4f, 5
hypertension historical background 17
KCC-2  104
autonomic nervous system 52 Lundberg A–C waves 20–1
ketamine
head fixation 163 management of increase 25b
analgesia 118, 119t
ischaemic stroke 132 measurement methods 21–2
antidepressant effects 316–18
hyperthyroidism 216 measurement site 19
cerebral physiology 33, 33t
hypertonic saline 127, 128, 154, 165, 278 mild elevation 19
cranial pin insertion 163
hyperventilation moderate elevation 19
EEG effects 37
ICP 126, 154, 278 monitoring 128, 157, 229
molecular targets 4, 4f, 5
neuroprotection 83 neurocritical care 274–5
neuroprotection 81
hypocretin neurons 7 normal value 19
Parkinson’s disease 313
hypothermia pulse amplitude 229
posterior fossa surgery 179
cardiac arrest 81–2 severe elevation 19
supratentorial craniotomy 165
ICP 155, 203 subarachnoid haemorrhage 279
traumatic brain injury 153
ischaemic stroke 82–3 supratentorial craniotomy 166–7
ketones 30, 32
muscle relaxants 66 therapy to reduce 126–8
Klippel–Feil deformity 174
neonatal 81 thoracic pressure and 19
Kv1 family 4f, 5
spinal cord injury 82, 257–8 traumatic brain injury 154–5, 275b
kyphosis 245
traumatic brain injury 82, 278 typical values 20t
hypoxic-ischaemic injury 104 waveform (P1–3)  19–20
intracranial vault 17–18 L
intra-ocular pressure 250 lactate:pyruvate 277
I
intra-operative neurophysiological large neutral amino-acid transporter type 1
iceberg phenomenon 62
monitoring  137–44 (LAT-1)  29
idiopathic intracranial hypertension 228
327
index 327
laterodorsal tegmentum 6–7 muscle relaxants nerve root assessment 141

levodopa 310, 311t acetylcholine receptors 64 neurocritical care 273–83
Lhermitte’s sign 247 age 66 acute ischaemic stroke 280
lidocaine 119 anaphylaxis 64 anaemia 273
ligand-gated ion channels 3–5 autonomic nervous system 64 brain death 282–3
limbic cortex 9 bronchial smooth muscle 64 cardiorespiratory management 273
lipid-mediate diffusion 28 burn injury 70 case mix 277–80
lithium 106 carotid body 64 cerebral blood flow 276
local modulation 114 central nervous system 64 cerebral microdialysis 277
locus coeruleus 7, 114 chemical structure 63–4 cerebral oxygenation 276–7
lordosis 245 clinical duration of action 65 cerebrovascular autoregulation 275–6
lower motor neuron lesion 69 clinical response to (twitch depression) 65 EEG 277
lumbar drains 22, 24 depolarizing 63, 67 fever 273
lumbar infusion test 229 drug interactions 70 fluids 273
Lundberg A–C waves 20–1 elimination  66–7 glucose control 273
luteinizing hormone 214t endotracheal intubation 68 ICP  274–5
endovascular aneurysm therapy 206 informatics 277
M histamine release 64 intracerebral haemorrhage 279–80
McCune-Albright syndrome 216 hypothermia 66 multimodal monitoring 277
macroglossia 184 immobilization 69 neuromonitoring  274–7
magnetic resonance imaging (MRI) infection 70 neuromuscular blockade 73
coma 130 inflammation 70 non-neurological complications  280–2
CSF flow 226 liver failure 69 nutritional support 274
hydrocephalus 228–9,  232–3 lower motor neuron lesion 69 outcome 283
ischaemic stroke 132 mechanisms of action 62–3 seizures  273–4
neurotoxicity of anaesthetics 101 metabolism  66–7 subarachnoid haemorrhage 278–9
pituitary surgery 218 myasthenia gravis 70 traumatic brain injury 277–8
traumatic brain injury 152 neuroanaesthesia  72–3 venous thromboembolism 274
see also functional MRI neurocritical care 73 neuroendoscopy, see endoscopic surgery
major depressive disorder 315–18 neuromuscular disease 69–70 neurogenic pulmonary oedema 151, 190, 281
mannitol 127, 154, 164–5, 195, 278 neuromuscular junction 64 neurogenic shock 257
manual-in-line stabilization  247 non-depolarizing 62–3,  67–9 neurogenic stunned myocardium 280
margin of safety of neurotransmission 62 obesity 66 neurogenic ventilation–perfusion mismatch 281
MASK trial 101 onset 65 neurointervention, see interventional
mast cells 64 perfusion 66 neuroradiology
maximal allowable blood loss 266 pharmacokinetics  65–6 neuroleptic malignant syndrome 312
MCT-1  29 pharmacologic potency 66 neurologic emergencies 125–34
mechanical thrombectomy 85, 133, 206–7 plasma protein binding 66 neuromuscular blockade
mechanical ventilation 281 posterior fossa surgery 178 channel block 63
mechanistic target of rapamycin complex 1 potency 65 competitive block 62–3
(mTORC1) 318 pregnancy 66 desensitization block 63
median preoptic nucleus 8, 9 quaternary amine group 63, 64, 66 neuroanaesthesia  72–3
medulloblastoma 176t, 267 rapid sequence induction 68, 69, 73 neurocritical care 73
memory deficits 104 recovery index 65 non-competitive block 63
M-entropy 41, 42 renal insufficiency 69 Parkinson’s disease 313
metabolic encephalopathies 129t reversal  70–2 pharmacology  65–6
microelectrode recordings 240, 241, 242 speed of injection 66 phase II block 63
microglial cells 105 supratentorial craniotomy 162–3 spinal cord injury 256–7
micro-RNA  104 total duration of action 65 see also muscle relaxants
midazolam traumatic brain injury 153 neuromuscular junction 61–2, 64
paediatrics 264 upper motor neuron lesion 69 neuronal networks 104–5
postoperative delirium 162 uses 61 neuropathic pain 111–12, 116, 117t
status epilepticus 134 volume of distribution 66 neuropeptide Y 58
mivacurium 68t see also neuromuscular blockade neurophysiologic monitoring, see
molecular targets 3–6 myasthenia gravis 70 intra-operative neurophysiological
monitored anaesthesia care 207, 208, 241 myelomeningocele 266 monitoring
monoamine oxidase-B inhibitors myocytes 28, 31 neuroprotection  77–86
311t, 312 anaesthetics  80–1
monocarboxylic acid transporter type 1 N arterial carbon dioxide tension 83
(MCT-1)  29 Narcotrend 41, 42 arterial oxygen tension 83
monosynaptic circuits 115 NASCIS II/III trials 82 cerebral perfusion pressure 84
Monro-Kellie doctrine 18, 125 National Institutes of Health Stroke Scale glucose management 83–4
motor evoked potentials (MEPs) 137–8, 140, (NIHSS) 132, 293t hyperventilation 83
141, 142, 143, 193, 194, 258 near infrared spectroscopy 157, 276–7 hypocapnia 83
moyamoya disease 189, 192, 193, 195, 268 necrosis 79 mechanical thrombectomy 85
MR CLEAN trial 207 neocortex 9 medical management 84
multimodal analgesia 118–19, 249 neonates physiologic management 81–5
multimodal monitoring 140, 142, 277 EEG 38 temperature  81–3
multiple endocrine neoplasia type 1 hypothermia 81 tissue plasminogen activator 84–5
(MEN-1)  216 neostigmine 71 translation from animals to humans 79–80
muscarinic acetylcholine receptor 4f, 57 nerve growth factor 117 traumatic brain injury 155
328
328 index
neurotoxicity  93–107 blood loss 265–6 peripheral nerve fibres 114

evidence for 93–101 fluids  265–6 peripheral nerve surgery, monitoring 143
mechanisms  101–5 induction of anaesthesia 264 peripheral sensitization 112, 117
reducing  105–6 intra-operative management  264–6 permutation entropy 43
surgery 105 maintenance of anaesthesia 265 peroxynitrite 78
neurovascular unit 27–9 positioning 265 P-glycoprotein  29
NICE-SUGAR trial 83, 273, 292 postoperative care 269 phase II block 63
nicotinic acetylcholine receptor 4–5, 4f, 57, postoperative pain 269 phenylephrine 257
61, 62, 64 pre-operative assessment and planning 263–4 phenylethanolamine N-methyl transferase 53
nifedipine 259 sedation 269 phenytoin 133, 134, 306
nimodipine 189 vascular access 264–5 pineal region tumours 176t
nitric oxide 50 see also children Pipeline™ 204
nitrogen monoxide 30 pain  111–19 pituitary apoplexy 215
nitroglycerine 259 acute  116–18 pituitary gland
nitrous oxide aetiologies  116–17 anatomy and physiology 213
cerebral physiology 33t, 34 biopsychosocial model 118 trauma 151
cerebrovascular surgery 193 blood flow 118 tumours  215–16
EEG effects 37 central 112, 116, 117t pituitary hormones 213, 214t
molecular targets 4, 4f central post-stroke 111 pituitary surgery
neuroendoscopy 232 chronic  116–18 intra-operative management  216–18
posterior fossa surgery 179 chronic pain patient 118–19 postoperative complications 218–19
supratentorial craniotomy 165 conduction 114 pre-operative evaluation 216
traumatic brain injury 153 functional 112 pneumonia 281
NKCC1 104 gate control theory 114 POISE trials 291, 292
NMDA antagonists 311t, 312 homeostatic emotion 116 Poisson effect 248
EEG effects 37 hypersensitivity 117 polysynaptic circuits 115
NMDA receptor 4, 4f neuroanaesthetic care 118–19 pontine reticular nucleus, oral part 7
nociceptive pain 111, 112–16, 117t neuropathic 111–12, 116, 117t positioning
nociceptive specific cells 115 nociception and 111–12 children 265
nociceptors 112 nociceptive 111, 112–16, 117t horizontal 180t, 182f, 185
activators 117 perception  115–16 prone 248–9, 265
sensitizers 117 postoperative 118, 168, 197, 218, 249, 269 sitting 178–81, 180t, 182f,  184–5
silent 114 primary and secondary brain centres posterior fossa 173–87
transducers 112 115–16 anatomy 173
unimodal and polymodal 114 reflexes 130 complications of surgery 181, 183–5, 186–7
non-competitive block 63 second 114 cranial nerve compression syndromes 174
nonconvulsive status epilepticus 134 sensitization 117–18 CSF outflow 173
non-depolarizing neuromuscular blocking structural changes 118 emergence from anaesthesia 185–6
drugs 62–3,  67–9 transduction  112–14 indications for surgery 173–4
non-steroidal anti-inflammatory drugs transmission  114–15 induction of anaesthesia 179
(NSAIDs) 118, 119t, 168 pancuronium 68t intra-operative monitoring 185
norepinephrine 51, 52, 53–4, 58 PANDA trial 101 maintenance of anaesthesia 179–80
normal pressure hydrocephalus 18, 227–8, 233 parabrachial nucleus 8 positioning for surgery 179–81
paradoxical air embolism 184 posterior fossa syndrome 186
O parafacial zone 9 postoperative intracranial
O arm 142 parasympathetic nervous system 47, 48, 255 haemorrhage  186–7
obesity parietal lobe 10 postoperative neurologic deficits 186
muscle relaxants 66 Parkinson’s disease 309–14 pre-operative assessment and
postoperative visual loss 251 anaesthesia management 312–13 management 179
obstructive sleep apnoea 216 cardiovascular system 310 signs and symptoms of pathology 174, 178
occludin 27 cognitive decline 310 structural anomalies 174
ocular perfusion pressure 249–50 deep brain stimulators 313–14 surgical approaches 178–9
oculo-cephalic reflex 131t dementia 312 tumours 173, 176–7t, 267
oligodendrocytes 105 depression 312 vascular lesions 173–4
opioids drug treatment 310–12 posterior ischaemic optic neuropathy 250
analgesia 119t, 197, 269 epidemiology 309 postoperative problems
cerebral physiology 33t, 34 fatigue 312 cognitive dysfunction 299–301
cranial pin insertion 163 gastrointestinal system 310 delirium 162, 298–9
EEG effects 37 Hoehn and Yahr staging 309, 310b nausea and vomiting 168, 197, 219
Parkinson’s disease 313 neuroleptic malignant syndrome 312 pain 118, 168, 197, 218, 249, 269
posterior fossa surgery 179 pathophysiology 309 residual curarization 68–9
supratentorial craniotomy 164 psychosis 312 seizures 133, 303–7
orexinergic neurons 7 respiratory system 310 visual loss 249–51
Osler–Weber–Rendu syndrome  190–1 urogenital system 310 wound haematoma 252
osmotic therapy 127–8, 154, 278 Parkland Protocol 155–6 postsynaptic neuronal death 103
oxidative stress 78 patent foramen ovale 166, 179, 181, 183–4 potassium
Patient State Index 41, 42 cerebral blood flow 30
pedicle screw testing 141–2 channels 4f, 5, 114
P pedunculopontine tegmentum 6–7 epinephrine and 52
P2X 113
periaqueductal grey 8, 114 power spectrum 38–9
paediatric neuroanaesthesia 263–9
pericytes 28, 31 pramipexole 106, 311t
329
index 329
pre-cordial Doppler sonography 184 children 269 spinothalamic tract 115

prefrontal cortex 116 deep brain stimulation 241 STAIR criteria 80
pregnancy supratentorial craniotomy 162 STAR trial 207
muscle relaxants 66 traumatic brain injury 277–8 status epilepticus 133–4, 306
spinal cord injury 260 seizures stentrievers 207
prematurity 263, 267 classification 304t steroids
preoptic area 8–9 isolated 303 analgesia 119
pressure reactivity index (PRx) 18, 21, 275 neurocritical care 273–4 cervical spinal injury 258
pressure volume index 225 peri-operative 133,  303–7 pituitary surgery 218
primary somatosensory cortex (SI) 116 selegiline 311t, 312 supratentorial tumours 267
prolactin 214t sella turcica 213 stroke
prolactinoma 215, 216 serotonin syndrome 312 central post-stroke pain 111
prone positioning 248–9, 265 sevoflurane peri-operative  289–93
propofol cerebral physiology 33, 33t see also ischaemic stroke
bispectral index 40 coherogram 40 stunned myocardium 280
carotid endarterectomy 193–4 dementia 297, 298t stupor 24
cerebral physiology 33, 33t, 128 EEG effects 37 Sturge Weber syndrome 267t
cerebrovascular surgery 193 Parkinson’s disease 313 subarachnoid haemorrhage
coherogram 40 traumatic brain injury 153 blood pressure 279
dementia 297, 298t Shaker-related voltage-gated potassium delayed cerebral ischaemia 279
EEG effects 37 channels 4f, 5 ECG 190, 280
functional connectivity 44 shunt surgery 230–1, 233, 267 external ventricular drain 230
microelectrode recordings 241 sildenafil 259 fever 273
molecular targets 4, 4f siphoning 231 grading 190
neuroendoscopy 232 sitting position 179–81, 180t, 182f,  184–5 haemoglobin 273
neuroprotection 81 sleep 6, 8–9 hydrocephalus 227
paediatrics 264, 269 sleep apnoea 216 ICP 279
Parkinson’s disease 313 sleep-awake-sleep 236,  268 morbidity and mortality 202
posterior fossa surgery 179 slit ventricle syndrome 231 neurocritical care 278–9
refractory status epilepticus 134 SmartTots 106 neurogenic pulmonary oedema 190
supratentorial craniotomy 162 SNAPs 53 nimodipine 189
traumatic brain injury 277 SNARE proteins 53 rebleeding 279
prostaglandin E2 117 sodium channels 5, 114 troponins 280
proton magnetic resonance imaging 118 somatosensory cortex (SI/SII) 116 subthalamic nucleus 242
pseudotumour cerebri syndrome 228 somatosensory evoked potentials (SSEPs) succinylcholine
psychiatric disease 315–18 137, 138, 140–1, 142, 143, 157, 164, 193, adverse effects 67b
pulmonary oedema, neurogenic 151, 190, 281 194, 258 cerebrovascular surgery 193
pupils 130, 131t, 156, 157 somnolence 24 clinical pharmacology 67
pyridostigmine 71 SPACE trial 206 contraindications 67b, 264
spasticity 142, 259 mechanisms of action 63
R spectral edge frequency 39 Parkinson’s disease 313
rapid sequence induction 67, 68 spectral entropy 43 partial antagonist action 64
traumatic brain injury 73, 153 spectrogram 39 posterior fossa surgery 179
rapid ventricular pacing 196 Spetzler–Martin score 191 spinal cord injury 256
rasagiline 311t, 312 spinal cord supratentorial craniotomy 163
Rathke’s cleft cysts 216 anatomy 255 traumatic brain injury 153
reactive oxygen species 78, 103 congenital malformations 266 sugammadex 71–2, 257
recombinant tissue plasminogen activator 84–5, spinal cord injury 255–60 supratentorial craniotomy 161–9
132–3, 206, 208, 294 acute cervical 256–8 blood transfusion 166
recurrent laryngeal nerve palsy 252 ASIA classification 255–6 cranial pin insertion 163
refractory status epilepticus 134 autonomic dysreflexia 258–9 cranial pin removal 169
Rexed’s laminae 115 chronic  258–60 deep vein thrombosis 168–9
rheumatoid arthritis 247 epidemiology 255 delayed extubation 168
Robin Hood effect 83 hypothermia 82, 257–8 early extubation 167–8
rocuronium 68t neurogenic shock 257 emergence from anaesthesia 167–8
supratentorial craniotomy 163 pregnancy 260 epidemiology 161
traumatic brain injury 153 stages 255 fluid management 165–6, 168
ropinirole 311t spine surgery 245–52 glucose control 166
rostroventralmedial medulla 114–15 central cord syndrome 248 history-taking  161
R-type calcium channels 4f, 5 cervical spine 251–2 ICP increase 166–7
iatrogenic acute hypervolaemia 248–9 induction of anaesthesia 162
intra-operative monitoring 140–3, 249, intracranial hypertension 167, 168
S 258, 266 intra-operative complications  166–7
saline, hypertonic 127, 128, 154, 165, 278
intubation 247 intra-operative management  162–6
SAPPHIRE trial 205
postoperative complications 249–52 maintenance of anaesthesia 163–4
scalp block 168, 197, 236
postoperative pain 249 muscle relaxation 162–3
scoliosis surgery 140–1
pre-operative assessment  246–7 optimization of surgical field 164–5
secondary somatosensory cortex (SII) 116
prone positioning 248–9 pain control 168
second pain 114
visual loss after 249–51 physical examination 161–2
sedation
spine trauma, see spinal cord injury postoperative management 167–9
awake craniotomy 236, 239
30
330 index
supratentorial craniotomy (cont.) haemoglobin 273 vanilloid receptor 1 (VR-1) 113

postoperative nausea and vomiting 168 hypothermia 82, 278 vascular compression syndromes 189
premedication 162 ICP management 154–5 vasoactive intestinal protein (VIP) 58
pre-operative considerations  161–2 ICP monitoring 157, 275b vasogenic oedema 77–8
total intravenous anaesthesia 163–4 ICU management 152–3 vecuronium 68t
vascular access 162 imaging 152 venous air embolism 166, 169, 179, 181, 183–4,
venous air embolism 166, 169 increase in severity 149 217, 266
supratentorial tumours 267 intracranial hypertension 150, 151b, 277 venous thromboembolism 274
SWIFT-PRIME trial 207 neurocritical care 277–8 ventilation–perfusion mismatch,
sympathetic nervous system 47–8, 255 neuromonitoring  156–7 neurogenic 281
synaptogenesis  102–3 neuroprotection 155 ventral periaqueductal grey 8
syndrome of inappropriate antidiuretic neurosurgery 278 ventral tegmental are 8
hormone secretion (SIADH) 151, 268, nutritional support 274 ventricles 18
281, 282t osmotic therapy 154, 278 ventriculocisternostomy 232
oxygenation 153 ventriculoperitoneal shunt 230, 231, 267
T pathophysiology  149–50 ventrolateral preoptic nucleus 8–9
temperature polytrauma 149 vertebrae 245
muscle relaxants 66 pre-hospital management 152 vestibular schwannoma 177t
neuroprotection  81–3 rapid sequence induction 73, 153 vestibulo-oculo-cephalic reflex  131t
tension pneumocephalus 184 secondary injury 149–50 visual loss, postoperative 249–51
tethered cord 266 sedation  277–8 volatile agents
thalamocortical network 10 systemic effects 150–2 cerebral physiology 33t,  33–4
thalamus 9, 116 traumatic penumbra 149 cerebrovascular surgery 193
thyroid-stimulating hormone 214t treatment 152 coherogram 40
tight junctions 27–8 ventilation 153 EEG effects 37
tissue plasminogen activator 84–5, 132–3, 206, trigeminal neuralgia 192 neuroprotection 80, 106
208, 294 trihexyphenidyl 311t Parkinson’s disease 313
TOF-ratio  70 triphasic phenomena 219 posterior fossa surgery 179
total intravenous anaesthesia 163–4, 180, 205 troponins 190, 280 supratentorial craniotomy 164, 165
toxic encephalopathies 129t TRP channels 112–13 traumatic brain injury 153
tranexamic acid 279 TRPM8 receptors 112, 113 voltage-gated ion channels 5, 114
transcranial Doppler sonography 157, 183, 276 TRP receptors 112, 113 VR-1  113
transient receptors potential channels 112–13 TRPV receptors 112, 113 VRL-1  113
transition of care 134 T-type calcium channels 4f, 5
traumatic brain injury 149–58 tuberomamillary nucleus 8 W
adrenal insufficiency 282 tuberous sclerosis 267t Wada test 238
airway management 153 d-tubocurarine  68t whole brain death 282
anaesthetic agent choice 153 two-compartment model 65 wide dynamic range neurons 115
anticoagulation  155–6 two-pore-domain potassium family (K2P) 4f, 5 wind-up  114
cardiovascular stabilization 153–4 tyramine 54 World Federation of Neurological Surgeons
cerebral metabolism 152 tyrosine (hydroxylase) 53 (WFNS) grading system 190
classification 149, 150t
clinical management 152 U X
decompressive craniectomy 155, 278 upper motor neuron lesion 69 xenon
DVT prophylaxis 274 EEG effects 37
emergency room 152 V molecular targets 4, 4f
epidemiology 149 vagal nerve stimulation 239–40 neuroprotection 81, 106
external ventricular drain 230 vagus nerve 48
fever 273 valproic acid 134, 306
fluids  153–4
Z
vanilloid-like receptor 1 (VRL-1) 113 ZO-1  27

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i

Oxford Textbook of

Oxford Textbooks In Anaesthesia

Oxford Textbook of Anaesthesia for the Elderly Patient

Oxford Textbook of

George A. Mashour Kristin Engelhard

Preface-the three pillars

Abbreviations xi 11 Neurophysiologic Monitoring

2 Intracranial Pressure 17 14 The Posterior Fossa 173

5 The Autonomic Nervous System 47 17 Pituitary and Neuroendocrine Surgery 213

6 Neuromuscular Junction: Anatomy and 18 Hydrocephalus and Associated Surgery 225

8 Neurotoxicity of General Anaesthetics 93 20 Anaesthesia for Complex Spine Surgeries 245

9 Neurobiology of Acute and Chronic Pain 111 21 Spine Trauma 255

SECTION 3​ 26 Epilepsy 303

133Xe Xenon BAER Brainstem auditory evoked response

CT Computed tomography HF Heart failure

MER Microelectrode recordings PICC Peripherally inserted central catheter

SNS Sympathetic nervous system TNF-​α Tumour necrosis factor α

Deepak Sharma, Department of Anesthesiology & Pain Medicine,

1 Neural Mechanisms of Anaesthetics 3

Introduction Ligand-​Gated Ion Channels

4 Section 1 neuroscience in anaesthetic practice

Chapter 1 neural mechanisms of anaesthetics 5

6 Section 1 neuroscience in anaesthetic practice

Chapter 1 neural mechanisms of anaesthetics 7

8 Section 1 neuroscience in anaesthetic practice

Chapter 1 neural mechanisms of anaesthetics 9

10 Section 1 neuroscience in anaesthetic practice

Thalamocortical Network anaesthetic-​induced unconsciousness. The parietal lobe con-

Chapter 1 neural mechanisms of anaesthetics 11

12 Section 1 neuroscience in anaesthetic practice

Chapter 1 neural mechanisms of anaesthetics 13

14 Section 1 neuroscience in anaesthetic practice

Chapter 1 neural mechanisms of anaesthetics 15

Introduction and subarachnoidal spaces, rinsing metabolic compounds from the

18 Section 1 neuroscience in anaesthetic practice

ultrafiltration from blood in the plexus choroideus at a rate of 250–​

Chapter 2 intracranial pressure 19

increased ICP include continued decrease in level of conscious-

Cerebral Perfusion Pressure

20 Section 1 neuroscience in anaesthetic practice

Figure 2.3 Cerebral curve (non-​linear hyperbolic relationship).

Chapter 2 intracranial pressure 21

22 Section 1 neuroscience in anaesthetic practice

Figure 2.5 Intraventricular and intraparenchymal ICP measurement.

Chapter 2 intracranial pressure 23

Table 2.3 Step-​by-​step guide for the implementation of an external

1 Define Kocher’s point (3 cm lateral from the midline, 1 cm

24 Section 1 neuroscience in anaesthetic practice

CSF Compound Normal Values Pathological Changes

Chapter 2 intracranial pressure 25

4. Le Roux P, Menon DK, Citerio G, Vespa P, Bader MK, Brophy G,

Introduction produced compounds, such as hormones, and exogenously sup-

28 Section 1 neuroscience in anaesthetic practice

might communicate with pericytes, as gap junctions, tight, and

Chapter 3 cerebral physiology 29

Cerebral Blood Flow and Metabolism CVR = CPP / CBF

30 Section 1 neuroscience in anaesthetic practice

Chapter 3 cerebral physiology 31

Glucose metabolism in the visual cortex

Visual changing checkerboard

Figure 3.2 Analyses of brain function via measurement of local blood flow.

32 Section 1 neuroscience in anaesthetic practice

SECTION 3 26 Epilepsy 303

SNS Sympathetic nervous system TNF-α Tumour necrosis factor α

Introduction Ligand-Gated Ion Channels

4 Section 1 neuroscience in anaesthetic practice

6 Section 1 neuroscience in anaesthetic practice

8 Section 1 neuroscience in anaesthetic practice

10 Section 1 neuroscience in anaesthetic practice

Thalamocortical Network anaesthetic-induced unconsciousness. The parietal lobe con-

12 Section 1 neuroscience in anaesthetic practice

14 Section 1 neuroscience in anaesthetic practice

18 Section 1 neuroscience in anaesthetic practice

ultrafiltration from blood in the plexus choroideus at a rate of 250–

20 Section 1 neuroscience in anaesthetic practice

Figure 2.3 Cerebral curve (non-linear hyperbolic relationship).

22 Section 1 neuroscience in anaesthetic practice

Table 2.3 Step-by-step guide for the implementation of an external

24 Section 1 neuroscience in anaesthetic practice

28 Section 1 neuroscience in anaesthetic practice

30 Section 1 neuroscience in anaesthetic practice

32 Section 1 neuroscience in anaesthetic practice

34 Section 1 neuroscience in anaesthetic practice

36 Section 1 neuroscience in anaesthetic practice

38 Section 1 neuroscience in anaesthetic practice

40 Section 1 neuroscience in anaesthetic practice

Figure 4.5 Diagram of the various possible modes of cross-frequency coupling.

42 Section 1 neuroscience in anaesthetic practice

44 Section 1 neuroscience in anaesthetic practice

46 Section 1 neuroscience in anaesthetic practice

The Autonomic Nervous System

48 Section 1 neuroscience in anaesthetic practice

Chapter 5 autonomic nervous system 49

50 Section 1 neuroscience in anaesthetic practice

Chapter 5 autonomic nervous system 51

52 Section 1 neuroscience in anaesthetic practice

Chapter 5 autonomic nervous system 53

54 Section 1 neuroscience in anaesthetic practice

Chapter 5 autonomic nervous system 55

56 Section 1 neuroscience in anaesthetic practice

Chapter 5 autonomic nervous system 57

58 Section 1 neuroscience in anaesthetic practice

The concepts of co-transmission and neuromodulation have Vas deferens

Chapter 5 autonomic nervous system 59

60 Section 1 neuroscience in anaesthetic practice

function in humans. Journal of Cardiovascular Pharmacology. pharmacology: Molecular-to-clinical. St. Louis: Mosby Year

Figure 6.1 ‘Iceberg-phenomenon’ and definitions of neuromuscular parameters.

Metabolism-Nonenzymatic Decay (Hofmann Effects and Side Effects of Succinylcholine

ED95 (mg/kg) Clinical Introduction Chemical Classification Duration of Action

Table 6.2 Onset and duration of action after 2 × ED95.