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i

Oxford Textbook of

Neuroscience and
Anaesthesiology
ii

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

1
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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.
vi
vi
Preface-the three pillars
of Neuroanaesthesiology
While serving as the President of the Society for Neuroscience
in Anesthesiology and Critical Care, I espoused a vision for
neuroanaesthesiology that was supported by three ‘pillars’. The
traditional pillar of neuroanaesthesiology relates to the care of
neurosurgical and neurological patients. The clinical care of indi-
viduals with neurologic compromise is incredibly rewarding and
represents a true opportunity to make a positive difference in the
lives of others. However, the specialty of anaesthesiology is itself a
form of clinical neuroscience. On a daily basis, even as anaesthe-
tists for non-​neurosurgical cases, we modulate peripheral nerves,
the spinal cord, subcortical arousal systems, thalamocortical and
corticocortical networks supporting consciousness, pain networks,
memory systems in the medial temporal lobe, the neuromuscular
junction, and the autonomic nervous system. From this perspective,
‘neuroanaesthesiology’ is more a compression of ‘neuroscience in
anaesthesiology’ than ‘neurosurgical anaesthesiology’. The mech-
anistic study of our therapeutic interventions, which represents
another pillar, is exciting neuroscience in its own right, and has pro-
found implications for nervous system function. Finally, the ques-
tion of how the peri-​operative period might negatively impact the
brain is the new frontier of outcomes studies and has been a major
priority for the field of anaesthesiology in the past decade. Questions
related to anaesthetic neurotoxicity, cognitive dysfunction, stroke,
and other neurologic outcomes of non-​neurosurgical interventions
represent a critically important third pillar for the subspecialty.
The Oxford Textbook of Neuroscience and Anaesthesiology is the
first book of its kind to comprehensively address all three pillars
related to neuroscience in anaesthesiology. The first section treats
the neuroscientific foundations of anaesthesiology, including the
neural mechanisms of general anaesthetics, cerebral physiology,
the neurobiology of pain, and more. The second section represents
the traditional pillar related to the care of patients with neuro-
logic disease in the operating room or intensive care unit, with a
focus on clinical neuroanaesthesia. These chapters systematically
treat the peri-​operative considerations of both brain and spine
surgery, and provide introductions to neurocritical care and pedi-
atric neuroanaesthesia. Finally, the last section examines some
connections of neurology and anaesthesiology, examining how
conditions such as dementia, stroke, or epilepsy interface with the
peri-​operative period.
This international textbook gathers the best available expertise of
authors and leaders in the field from Canada, Germany, Italy, New
Zealand, Spain, Switzerland, the UK, and the US. They have done an
outstanding job of crafting concise yet highly informative chapters
describing the cutting edge of neuroscience and neuroanaesthesia.
It is my hope that this textbook is itself a ‘chapter’ in the evolution
of the field, creating a lasting foundation and appreciation for the
three pillars of neuroscience in anaesthesiology.
George A. Mashour, M.D., Ph.D.
vi
ix
Contents
Abbreviations xi
Contributors xv
Digital media accompanying the book
SECTION 1​
Neuroscience in Anaesthetic Practice
1 Neural Mechanisms of Anaesthetics
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
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
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
Margaret K. Menzel Ellis and Ansgar Brambrink
9 Neurobiology of Acute and Chronic Pain
Adrian Pichurko and Richard E. Harris
SECTION 2​
Clinical Neuroanaesthesia
10 Neurologic Emergencies 125
Ross P. Martini and Ines P. Koerner
11 Neurophysiologic Monitoring
for Neurosurgery 137
Antoun Koht, Laura B. Hemmer,
xvii J. Richard Toleikis, and Tod B. Sloan
12 Brain Trauma 149
Anne Sebastiani and Kristin Engelhard
13 Supratentorial Craniotomy for
3 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
35 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
61 Paola Hurtado and Neus Fàbregas
19 Awake Craniotomy for Tumour, Epilepsy,
and Functional Neurosurgery 235
Lashmi Venkatraghavan and Pirjo Manninen
93 20 Anaesthesia for Complex Spine Surgeries 245
Ehab Farag and Zeyd Ebrahim
111 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
Magnus Teig and Martin Smith
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
Wisconsin School of Medicine and Public Health, USA
Michael Avidan, Department of Anesthesiology, Washington
University School of Medicine, USA
Federico Bilotta, Department of Anesthesiology, Critical Care and
Pain Medicine, Sapienza University of Rome, Italy
Stefan Bittner, Department of Neurology, Johannes Gutenberg
University Mainz, Germany
Manfred Blobner, Klinik für Anaesthesiologie der Technischen
Universität München, Klinikum rechts der Isar, Germany
Ansgar Brambrink, Department of Anesthesiology, Columbia
University, USA
Douglas A. Colquhoun, Department of Anesthesiology, University
of Michigan Medical School, USA
Michael Crimmins, Walter Reed National Military Medical Center,
Department of Neurology, Neurosurgery and Critical Care, USA
Zeyd Ebrahim, Department of General Anesthesiology,
Anesthesiology Institute, Cleveland Clinic, USA
Margaret K. Menzel Ellis, Portland VA Medical Center,
Assistant Professor of Anesthesiology, Oregon Health & Science
University, USA
Kristin Engelhard, Department of Anesthesiology, University
Medical Center of the Johannes Gutenberg-​University Mainz,
Germany
Neus Fàbregas, Anesthesiology Department, Hospital Clìnic de
Barcelona, Spain
Ehab Farag, Department of General Anesthesia and Outcomes
Research, Anesthesiology Institute, Cleveland Clinic, USA
Heidrun Lewald, Klinik für Anaesthesiologie der Technischen
Universität München, Klinikum rechts der Isar, Germany
Katherine M. Gelber, Department of Anesthesiology, Cedars-​Sinai
Medical Center, USA
Gerald Glick†, Department of Medicine, Rush Medical
College, USA
David B. Glick, Department of Anesthesia & Critical Care,
University of Chicago, USA
Kerstin Göbel, Department of Neurology, University Hospital
Münster, Germany
Shaun E. Gruenbaum, Department of Anesthesiology, Yale
University School of Medicine, USA
Richard E. Harris, Department of Anesthesiology, University of
Michigan Medical School, USA
Laura B. Hemmer, Department of Anesthesiology and
Neurological Surgery, Northwestern University, Feinberg School
of Medicine, USA
Eric J. Heyer, Departments of Anesthesiology and Neurology,
Columbia University, USA
Ulrike Hoffmann, Department of Anesthesiology, Duke
University, USA
Paola Hurtado, Anesthesiology Department, Hospital Clìnic de
Barcelona, Spain.
Adam K. Jacob, Department of Anesthesiology and Perioperative
Medicine, Mayo Clinic College of Medicine, USA
M. Luke James, Departments of Anesthesiology and Neurology,
Duke University, USA
Max B. Kelz, Department of Anesthesiology and Critical Care,
University of Pennsylvania Perelman School of Medicine, USA
Klaus Ulrich Klein, Department of Anesthesia, General Intensive
Care and Pain Management, Medical University of Vienna,
Austria
Ines P. Koerner, Department of Anesthesiology & Perioperative
Medicine, Department of Neurological Surgery, Oregon Health &
Science University, USA
xvi
xvi c ontributors
Antoun Koht, Department of Anesthesiology, Neurological
Surgery, and Neurology, Northwestern University, Feinberg School
of Medicine, USA
Sandra L. Kopp, Department of Anesthesiology and Perioperative
Medicine, Mayo Clinic College of Medicine, USA
Brian P. Lemkuil, Department of Anesthesiology, University of
California San Diego, USA
Pirjo Manninen, Department of Anesthesia, Toronto
Western Hospital University Health Network, University of
Toronto, Canada
Nathan Manning, Departments of Neurosurgery and
Radiology, Columbia University Medical Centre, New York
Presbyterian, USA
Ross P. Martini, Department of Anesthesiology and Perioperative
Medicine, Oregon Health & Science University, USA
Craig D. McClain, Department of Anesthesiology, Perioperative
and Pain Medicine, Boston Children's Hospital, Harvard Medical
School, USA
Andrew McKinstry-​Wu, Department of Anesthesiology and
Critical Care, University of Pennsylvania, USA
Sven G. Meuth, Department of Neurology, Institute of
Translational Neurology, Westfälische-​Wilhelms University
Münster, Germany
Philip M. Meyers, Departments of Radiology and Neurological
Surgery, Columbia University, USA
Edward C. Nemergut, Department of Anesthesiology, University
of Virginia Health System, USA
Adam D. Niesen, Department of Anesthesiology and Perioperative
Medicine, Mayo Clinic College of Medicine, USA
Jeffrey J. Pasternak, Department of Anesthesiology and
Perioperative Medicine, Mayo Clinic College of Medicine, USA
Piyush Patel, VA Medical Center, University of California San
Diego, USA
Adrian Pichurko, Department of Anesthesiology, Northwestern
University, Feinberg School of Medicine, USA
Andrea Reinprecht, Department of Neurosurgery, Medical
University of Vienna, Austria
Robert D. Sanders, Department of Anesthesiology, University of
Wisconsin, USA
Anne Sebastiani, Department of Anesthesiology, University
Medical Center of the Johannes Gutenberg University Mainz,
Germany
Deepak Sharma, Department of Anesthesiology & Pain Medicine,
University of WashingtonUSA
Jamie Sleigh, Department of Anaesthesia and Pain Medicine,
Waikato Clinical Campus, University of Auckland, New Zealand
Tod B. Sloan, Department of Anesthesia, University of Colorado
School of Medicine, USA
Martin Smith, Department of Neuroanaesthesia and Neurocritical
Care, The National Hospital for Neurology and Neurosurgery,
University College London Hospitals, UK
Sulpicio G. Soriano, Department of Anesthesiology, Perioperative
and Pain Medicine, Boston Children's Hospital, Harvard Medical
School, USA
Christiane G. Stäuble, Klinik für Anaesthesiologie der
Technischen Universität München, Klinikum rechts der Isar,
Germany
Harald Stefanits, Department of Neurosurgery, Medical
University of Vienna, Austria
Erica J. Stein, Department of Anesthesiology, The Ohio State
University, USA
Magnus Teig, Department of Anesthesiology, University of
Michigan Medical School, USA
J. Richard Toleikis, Department of Anesthesiology, Rush
University School of Medicine, USA
Timur M. Urakov, Department of Neurosurgery, University of
Miami, Jackson Memorial Hospital, USA
Lashmi Venkatraghavan, Department of Anesthesia, Toronto
Western Hospital, University of Toronto, Canada
Phillip E. Vlisides, Department of Anesthesiology, University of
Michigan Medical School, USA
Laszlo Vutskits, Department of Anesthesiology, Pharmacology
and Intensive Care, University Hospitals of Geneva, Department
of Basic Neuroscience, University of Geneva Medical School,
Switzerland
Michael Y. Wang, University of Miami, Miller School of
Medicine, USA
Tasha L. Welch, Department of Anesthesiology and Perioperative
Medicine, Mayo Clinic College of Medicine, USA
David R. Wright, Departments of Anesthesiology & Pain Medicine
and Neurological Surgery, University of Washington, USA
Zhongcong Xie, Department of Anesthesia, Critical Care and
Pain Medicine, Massachusetts General Hospital, Harvard Medical
School, USA
Sophia C. Yi, Department of Anesthesiology, University of
California San Diego, USA
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
refer to the access token card for instructions on token redemption If you are interested in access to the complete online edition,
and access. please consult with your librarian.
These online ancillary materials, where available, are noted with
iconography throughout the book.
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
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CHAPTER 1
Neural Mechanisms
of Anaesthetics
Andrew McKinstry-​Wu and Max B. Kelz
Introduction
The first public demonstration of general anaesthesia took place
in 1846. Over 170 years later, a majority of the estimated 234 mil-
lion annual surgical procedures worldwide are performed under
general anaesthesia (1). Nevertheless, general anaesthetics remain
poorly understood as a unique class of drug that has infallible
clinical efficacy with a narrow therapeutic window. Despite their
pervasive use, there is a lack of basic knowledge of where and
how anaesthetics produce both their desirable and unintended
side effects.
Apparent similarities in dose-​dependent behavioural effects
among gaseous, volatile, and intravenous general anaesthetics
led to the historical belief that all general anaesthetics shared
a single molecular mechanism of action. Older theories of an-
aesthetic action relied on common chemical properties of the
anaesthetics to explain their common effects, such as the asso-
ciation of lipid solubility with anaesthetic potency (the Meyer-​
Overton rule). Ultimately, these early theories fell out of favour
with the realization that anaesthetics could exert their actions
in lipid-​free protein preparations. Subsequently, many molecular
targets of individual anaesthetics have been identified. With the
discovery of each new molecular target, the fallacy of a unitary
molecular mechanism of anaesthesia becomes more apparent.
The past twenty years have demonstrated that knowledge of both
the specific molecular targets, as well as their location in dis-
crete neural circuits, is a prerequisite to any real understanding
of anaesthetic hypnosis. Hence, the molecular, neuronal, cir-
cuit, and network targets of anaesthetics are all critical to our
neuroscientific framework of how these agents produce revers-
ible unconsciousness.
Molecular Mechanisms of Anaesthetic
Hypnosis
The breadth of molecular targets of general anaesthetics highlights
the diversity of molecular mechanisms sufficient to produce anaes-
thetic hypnosis. Inhaled and intravenous anaesthetics act on di-
verse protein targets to exert their hypnotic effects: ion channels,
G-​protein coupled receptors, and constituents of the electron trans-
port chain, among others (Figure 1.1).
Ligand-​Gated Ion Channels
Ligand-​gated ion channels (LGICs) are common targets for vola-
tile, gaseous, and potent intravenous agents. They provide an easily
understood mechanism for modulating individual neural activity
and offer a plausible method for altering large-​scale neural effects.
General anaesthetics variously affect multiple LGICs, the two most
common being potentiation of inhibitory anionic channels and in-
hibition of excitatory cationic channels. In fact, the vast majority
of general anaesthetics demonstrate specific actions at one or both
of two LGICs: potentiation of the anionic gamma-​aminobutyric
acid (GABA)-​gated GABAA receptor, and inhibition of the cationic
glutamate-​and-​glycine-​gated N-​methyl-​D-​aspartate (NMDA)
receptor.
Inhibitory Ligand-​Gated Ion Channel Potentiation
GABA is the most common inhibitory neurotransmitter in the
central nervous system (CNS.) The GABAA-​receptor, an abundant
GABA effector site, is a heteropentameric ligand-​gated chlorine-​
selective ion channel responsible for GABA’s inhibitory effects in the
CNS. Importantly, it is also a crucial functional target of most po-
tent intravenous agents and volatile anaesthetics (2–​7). Volatile and
intravenous anaesthetics that affect the GABAA-​receptor enhance
endogenous GABAergic signalling at pharmacologically relevant
concentrations, and at higher concentrations can directly open the
channel (5–​10). Synaptic potentiation of GABAA-​receptors affects
size and duration of rapid, phasic, inhibitory postsynaptic potentials.
Potentiation at extrasynaptic receptors, in contrast, alters baseline
membrane potential through tonic chloride currents (11). The net
effect of these actions is to decrease the chance that the postsynaptic
neuron will fire an action potential in the presence of pharmacologic-
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
their effects (12). Specific mutations in GABAA-​receptor subunits at
known anaesthetic binding sites produce attenuation to anaesthetic
effects of specific agents, both in vitro and in vivo. Mutations in the
alpha subunit of the GABAA-​receptor reduce the effect of volatile
anaesthetics and benzodiazepines, while beta subunit mutations
attenuate the effects of intravenous and volatile anaesthetics (3, 5).
This suggests a critical role for action at the GABAA-​receptor in pro-
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
LGICs in the CNS. This receptor family is found mostly in the
brainstem and spinal cord. Like GABAA-​receptors, glycine re-
ceptors are heteropentameric chlorine channels, and are directly
activated or potentiated by volatile and many intravenous anaes-
thetics (13–​16). Evidence for the functional importance of gly-
cine receptors to anaesthetic action is not as robust as that for the
GABAA-​receptor. Glycine receptor mutations can produce diver-
gent responses to anaesthetic endpoints. Site-​specific mutations
of the glycine receptor that alter in vitro receptor sensitivity to
volatile and potent intravenous anaesthetics do not always pro-
duce associated changes in immobility or hypnotic sensitivity in
vivo (6, 17). Specifically with propofol, the glycine receptor may
not contribute to immobility. A structural analogue of propofol
that potentiates glycine (but not GABA) receptor signalling, 2,6
di-​tert-​butylphenol, lacks any immobilizing effects in vivo (7,
18, 19). Similarly, a Q266I point mutation introduced into the
α1 subunit of the glycine receptor that decreases receptor sen-
sitivity to isoflurane unexpectedly conferred hypersensitivity to
the immobilizing properties of both isoflurane and enflurane in
mice. These results suggest that glycine receptors containing the
α1 subunit are unlikely to mediate immobilizing properties of
anaesthetics (20).
Excitatory Ligand-​Gated Ion Channel Inhibition
Many general anaesthetics act to inhibit excitatory LGICs, a
complementary effect to their potentiation of inhibitory LGICs.
Glutamate is the primary excitatory neurotransmitter of the CNS.
Among glutamate’s targets is the NMDA receptor (where it has gly-
cine as a co-​receptor). NMDA receptors are the functional target for
a significant number of general anaesthetics. Like the extrasynapic
GABA receptors responsible for tonic currents, NMDA receptors
do not produce the fast postsynaptic transmission responsible
for excitatory postsynaptic potentials, but acts presynaptically,
postsynaptically, and extrasynaptically, and can affect synaptic plas-
ticity (21). All known noncompetitive NMDA antagonists severely
disturb consciousness, with many acting as general anaesthetics at
sufficient concentrations (22). The gas anaesthetics nitrous oxide
and xenon, as well as the intravenous agent ketamine, all act pri-
marily as NMDA receptor antagonists, while many of the volatile
anaesthetics possess NMDA antagonist activity in addition to their
effects on other putative anaesthetic targets (23–​26).
The nicotinic acetylcholine receptor, a ligand-​gated nonspecific
cation channel, is inhibited by volatile anaesthetics at clinically
relevant concentrations. While that inhibition does not mediate
anaesthetic hypnosis, it may mediate amnesia and analgesic ef-
fects of volatile anaesthetics (27–​30). Moreover, central cholinergic
5
signalling via nicotinic receptors appears important for anaesthetic
emergence. Although blockade of cholinergic signalling may not
be sufficient to alter loss-​of-​righting-​reflex or Minimum alveolar
concentration (MAC) concentration, it can still be sufficient to re-
tard emergence from anaesthetic hypnosis (discussed later in this
chapter).
Constitutively Active and Voltage-​Gated Ion Channels
Members of the two-​pore-​domain potassium channel family
(K2P) produce a continuous non-​inactivatable current that modi-
fies resting membrane potential and thus affects neuronal excit-
ability (31). Volatile and gaseous anaesthetics directly activate
members of this family, including TREK-​1, TREK-​2, TASK-​1,
TASK-​2, and TASK-​3. Anaesthetic activation of these K2P chan-
nels causes an increase in potassium efflux out of the cell leading to
hyperpolarization. However, not every member of the K2P family
is activated by anaesthetic exposure. Several members are insensi-
tive to anaesthetics, while THIK-​1, TWIK-​2, TALK-​1, and TALK-​2
are actually closed by anaesthetic exposure. Mutations of two-​pore-​
domain potassium channels can abrogate sensitivity to activation
by volatile and gaseous anaesthetics. Distinct gene mutations alter
volatile sensitivity versus sensitivity to gaseous anaesthetics (32).
An in vivo knockout of one K2P, TREK-​1, caused an impressive 40%
resistance to halothane and more modest resistance to other inhaled
anaesthetics, while leaving barbiturate sensitivity unchanged (33).
Hyperpolarization-​activated cyclic nucleotide-​ gated (HCN)
channels are tetrameric, relatively nonspecific cation channels that
activate with cell hyperpolarization (as opposed to depolarization.)
The Ih current, produced by HCN activation, is involved in pro-
ducing long-​term potentiation, dendritic integration, control of
working memory, and thalamocortical oscillations (34). Of the four
HCN isoforms, HCN1 is both abundant in the CNS and inhibited
by volatile and intravenous agents. Agents as diverse as isoflurane,
ketamine, and propofol inhibit HCN1 at clinically relevant doses.
In in vivo models, this HCN1 inhibition plays a direct role in the
hypnotic potency of these agents (35–​38). There is even debate that
NMDA receptor antagonists producing hypnosis do so not through
actions at the NMDA receptor itself, but through their inhibition
of HCN1 (37). The involvement of HCN channels in critical CNS
processes and their inhibition by diverse anaesthetic agents suggest
a significant role for this channel in anaesthetic-​induced hypnosis.
Voltage-​gated potassium channels of the Kv1 family are recently
identified targets of volatile anaesthetics that contribute to suppres-
sion of arousal. Flies with mutations in a gene coding for a member
of the Kv1.2 family (shaker) exhibit altered sensitivity to volatile an-
aesthetics, requiring higher doses than wild-​type controls to cease
movement (39). Sevoflurane enhances currents in members of the
Kv1 family, with other clinically used volatiles also affecting Kv1
currents, suppressing firing in the central medial thalamus (40).
Kv1 channel inhibitors infused into the central medial thalamus
are able to reverse continuous low-​dose sevoflurane anaesthesia in
animal models, as are antibodies against Kv channels (41).
Voltage-​gated sodium channels are a requisite for normal exci-
tatory neuronal function, as they are key to initiating and propa-
gating action potentials. Their inhibition by volatile anaesthetics
presynaptically results in a decreased likelihood of action poten-
tial propagation and decreased presynaptic neurotransmitter re-
lease. Several sodium channel subtypes are inhibited by volatile
anaesthetics in pharmacologically relevant concentrations, though
Chapter 1 neural mechanisms of anaesthetics 5
historically inhibition had only been seen at higher concentrations
(42). The role of sodium channels in volatile anaesthetic hypnosis
is demonstrated by hypersensitivity to isoflurane and sevoflurane
in mice with reduced activity in one voltage-​gated sodium channel
subtype, NaV1.6 (43).
Presynaptic voltage-​gated calcium channels are critical for neuro-
transmitter release and inhibited by general anaesthetics, making
them likely anaesthetic targets. Low-​voltage-​activated T-​type
calcium channels, which modulate cellular excitability through
regulating burst firing and pacemaker activity, are inhibited by
clinically relevant concentrations of volatile and intravenous anaes-
thetics (44–​46). In vivo knockouts of T-​type calcium channels do
not show changes in anaesthetic sensitivity to the loss of righting
reflex (LoRR), a traditional rodent equivalent endpoint to loss of
consciousness in humans, though they do have altered speed of in-
duction and reaction to noxious stimuli (46, 47). This suggests that
the effects of anaesthetics upon these channels modulate the anaes-
thetized state, rather than cause it. High-​voltage-​activated calcium
channels (R-​type) are also sensitive to inhibition by volatile anaes-
thetics, and contribute to rhythmicity of thalamocortical circuits. R-​
type knockouts display less electroencephalographic suppression at
1% isoflurane than their wild-​type counterparts. This suggests that
thalamic calcium channels are involved in isoflurane-​induced thal-
amic suppression, thought to contribute to unconsciousness (48).
G-​Protein-​Coupled Receptors
G-​protein-​coupled receptors make up the largest and most di-
verse family of membrane receptors. They comprise 4% of the en-
tire coding human genome and are the target for over a quarter
of all current pharmaceuticals (49). Drugs that affect this receptor
superfamily are an integral part of anaesthetic practice, including
such diverse classes as opioids, vasopressors, and anticholinergics.
So, while these receptors are known targets for producing analgesia
and amnesia, there is little direct evidence that volatile-​anaesthetic-​
induced hypnosis is primarily mediated via this superfamily of
receptors. This is despite the fact that volatile anaesthetics do select-
ively activate G-​protein-​coupled receptors at pharmacologically-​
relevant concentrations (50, 51). Ketamine very specifically
interacts with a subset of olfactory receptors, which are a subgroup
of G-​protein-​coupled receptors, though it is unclear if these inter-
actions are in any way related to its anaesthetic actions (52).
Electron Transport Chain
Unlike the previously discussed membrane-​bound proteins in the
cell’s outer membrane, components of complex I, a multi-​subunit
member of the respiratory chain, are putative anaesthetic targets lo-
cated in the inner mitochondrial membrane. Animal models with
mutations in specific subunits of complex I, GAS-​1 in C. elegans
and Ndufs4 in mice, are hypersensitive to volatile anaesthetics. This
hypersensitivity phenotype is strictly mirrored across evolution up
to and including humans with complex I mutations (53–​55). The
anaesthetic hypersensitivity phenotype is not present in all com-
plex I gene mutations, nor is it present with other electron transport
chain mutations, indicating a specific interaction between volatile
anaesthetics and precise complex I subunits. While halogenated
ethers and alkanes inhibit complex I function though interaction
with the distal portion of the complex, volatile anaesthetics do not
appear to disproportionately decrease ATP production in complex
I mutants. This dissociation suggests volatile anaesthetic hypnotic
6

6 Section 1 neuroscience in anaesthetic practice

action is not solely a result of disproportionate mitochondrial ener-
getic disruption in those mutants, begging the persistent question
of how these mutations cause anaesthetic hypersensitivity (56–​58).
Systems Neuroscience and Anaesthetic
Effects: Discrete Nuclei and Local Networks
There is incontrovertible evidence for anaesthetic drugs interacting
with multiple molecular targets to affect behaviour, but anaesthetic
hypnosis is impossible to explain by mere examination of molecular
binding events in isolation. The imperfect connection between
molecular action and larger-​scale brain phenomena must be in-
terpreted in light of relevant neuroanatomy. Complexities are intro-
duced by circuit-​level interactions—​neuronal hyperpolarization
that reduces firing of a presynaptic inhibitory input can increase
activity for the postsynaptic neuron resulting in a net increase of
circuit output. Evaluating the net contribution of anaesthetics on
discrete brain regions to hypnosis provides a way to simplify the
massive complexity encountered at the molecular and neuronal
level without ignoring the fundamental circuitry of the CNS.
Sleep and Arousal Pathways
General anaesthetics alter the activity of endogenous arousal cir-
cuits. Such actions directly contribute to their hypnotic effects
(Figure 1.2). Anaesthetic-​induced unconsciousness is a non-​
arousable behavioural state that shares many commonalities with
slow-​wave sleep (SWS) There is a functional loss in cortical con-
nectivity during both NREM sleep and anaesthetic hypnosis.
Moreover, over much of the anaesthetic dose response range, the
cortical electroencephalography (EEG) exhibits striking simi-
larities, such that processed EEG measures developed to assess
anaesthetic depth can also distinguish wakefulness from sleep (59–​
65). During anaesthesia and sleep, thalamic nuclei and wake-​active
nuclei, collectively known as the reticular activating system, are
similarly inhibited (46, 66–​70). Parallels between the states extend
to their functional effects—​in some cases anaesthesia can substi-
tute for sleep. Sleep debt does not accrue during prolonged periods
of propofol-​induced unconsciousness, while propofol hypnosis ap-
pears to relieve previously incurred sleep debt (71–​73). Conversely,
sleep deprivation or administration of endogenous somnogens
reduce the dose of anaesthetic required for hypnosis. In a parallel
vein, induction and maintenance of anaesthesia itself alters levels
of endogenous somnogens (72, 74). Together, these data support
the theory that anaesthetic-​induced hypnosis stems in part from
actions of anaesthetics on the neural circuits involved with en-
dogenous sleep-​wake control.
Arousal-​Promoting Nuclei of the Reticular
Activating System
The ascending reticular activating system, extending rostrally from
the mid pons to the hypothalamus, basal forebrain, and thalamus,
was first identified more than half a century ago. Stimulation of the
brain stem reticular formation causes cortical arousal during an-
aesthetic states (75). Subsequently, discrete interacting neuronal
populations were found to be the arousal-​promoting components
of the activating system, including cholinergic, histaminergic, ad-
renergic, serotonergic, dopaminergic, and orexinergic centres.
Laterodorsal Tegmentum (LDT) and Pedunculopontine
Tegmentum (PPT)
These nuclei comprise two major cholinergic populations in the
brainstem with the ability to regulate arousal state and promote

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

Amygdala
Ox
TMN
(HA) VTA
(DA)

DpMe
(Glut)
BF
(Ach/Glut/GABA) 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
innervate the midline and intralaminar thalamic nuclei and thal-
amic reticular nucleus and alter thalamic activity from bursting to
spiking (76). Direct effects of these nuclei on anaesthetic-​induced
hypnosis are unknown. Despite this, the PPT is in a region that is
associated with pain-​induced movement, the inactivation of which
leads to a significant decrease of isoflurane MAC (77).
Locus Coeruleus (LC)
The Locus Coeruleus is the site of the brain’s largest collection of
noradrenergic neurons. As with many of the other monoaminergic
systems, the LC diffusely innervates the brain by projecting directly
to the cortex, thalamus, hypothalamus, basal forebrain, amygdala,
hippocampus, and other subcortical systems. State-​dependent
modulation of activity within the LC has long been proposed as
an essential means of regulating arousal. Changes in the activity
of LC neurons occur before, and are predictive of, changes in an
organism’s behavioural state (78). Through its actions on alpha1 and
beta receptors, firing of LC neurons promotes wakefulness through
actions on the medial septum, the medial preoptic area, and the
substantia innominata within the basal forebrain. Activity in the
LC modulates thalamocortical circuits, switching the tone of thal-
amocortical neurons from the burst pattern of slow-​wave sleep to
a spiking pattern that characterizes wakefulness. Consequently,
optogenetically driven LC activity causes transitions from SWS to
wakefulness (79). Under deep isoflurane anaesthesia, artificially
driven LC activity has been shown to cause EEG desynchron-
ization. Similarly, artificially induced firing of the LC speeds emer-
gence from isoflurane anaesthesia (80). However, the LC is not the
sole source of adrenergically driven arousal. Noradrenergic popu-
lations outside of the LC, such as the A1 and A2 brainstem groups,
also may contribute to the regulation of sleep, wakefulness, and an-
aesthesia (81–​83).
Pontine Reticular Nucleus, Oral Part (PnO)
Neurons in this large region (which includes the sublaterodorsal
nucleus) receive cholinergic, orexinergic, and GABAergic inputs
and include wakefulness-​promoting and REM-​on populations.
PnO activity also modifies anaesthetic action. GABAergic activity
at the PnO produces resistance to induction without significant
effects on emergence (84–​87). Electrical stimulation at the PnO
causes an increase in functional connectivity under continuous
isoflurane anaesthesia, similarly suggesting anaesthetic antag-
onist actions (88). This region highlights the critical importance
of neuroanatomic and neurochemical compartments: unlike most
other regions of brain, increased GABA levels in the PnO pro-
mote wakefulness. Other seemingly paradoxical effects occur in
this region: wakefulness is actually impaired by local delivery of
adenosine or acetylcholine into PnO, or alternatively, promoted
by local delivery of orexin or GABA (89–​91). Cholinergic input to
the PnO originates from the LDT and PPT, while the orexinergic
input arises from the hypothalamus. Divergent responses to adeno-
sine and GABA suggest that simple disinhibition of a single popu-
lation of PnO neurons is not sufficient to understand the actions
of these neuromodulators. Further clouding the picture, micro-
injections of pentobarbital within a region that has been termed
the mesopontine tegmental area, which overlaps with a significant
portion of the PnO and some neighbouring structures, have been
shown to induce hypnosis similar to systemic administration of a
larger general anaesthetic dose, while nearby injections lack any
Chapter 1 neural mechanisms of anaesthetics 7
systemic effects (92, 93). Clearly, a more complex local microcir-
cuitry awaits discovery.
Deep Mesencephalic Reticular Formation (DpMe)
Over the decades, many studies have demonstrated that electrical
stimulation in the DpMe reliably induces cortical activation in an-
aesthetized animals. These presumptively glutamatergic neurons
project to the thalamus, hypothalamus, and basal forebrain, where
they increase their firing rates prior to the onset of wakefulness,
and fire more slowly during SWS (94). These glutamatergic neurons
are possibly part of a previously poorly recognized arm of the as-
cending arousal system that potentially includes the parabrachial
nucleus as well.
Hypocretin/​Orexinergic Neurons
The orexin signalling system exerts potent wake-​promoting and
wake-​stabilizing effects, and plays an important role in modulating
anaesthetic emergence. As with the monoaminergic wake-​active
systems, the orexin system displays state-​dependent firing pat-
terns with maximal activity during active wakefulness and silence
during SWS (95). Anatomically, these neurons project to all of the
monoaminergic groups along with extending to the basal forebrain,
midline thalamic nuclei, and other regions known to participate in
the regulation of arousal. When signalling of these neurons is im-
paired, narcolepsy with cataplexy ensues (96). Local application of
orexin excites target neurons expressing either of the two orexin Gq-​
coupled neurotransmitter receptors, including the LDT, LC, RN,
basal forebrain (BF), and thalamocortical neurons. Halogenated
ethers, propofol, and pentobarbital inhibit orexinergic neuronal
activity, and genetic knockout of these neurons results in delayed
emergence from isoflurane and sevoflurane anaesthesia without
affecting sensitivity to anaesthetic induction (97–​99). In the case
of barbiturate anaesthesia, the pharmacologic inverse is true as
well: intracerebroventricular injection of orexin speeds emergence,
and orexin1-​receptor blockade negates this effect (100). The case
of delayed emergence without altered induction in orexinergic de-
ficient animals highlights the intriguing possibility that distinct
populations of neurons may unilaterally and differentially impact
the process of entering into or exiting from the anaesthetic state.
Wake-​Promoting Neurons of the Basal Forebrain
The BF encompasses heterogeneous populations of neurons ac-
tive in arousal and sleep that modify anaesthetic state and sensi-
tivity. GABA agonists microinjected at the BF potentiate systemic
intravenous and volatile anaesthetic effect and duration, as do
electrolytic lesions of the medial septum within the BF (101, 102).
The BF sits atop the ventral extrathalamic relay and receives inte-
grated arousal inputs from caudal structures. Within the BF, there
are wake-​active cholinergic neurons, wake-​active glutamatergic
neurons, wake-​ a ctive parvalbumin-​ c ontaining GABAergic
neurons, and sleep-​active somatostatin-​containing GABAergic
neurons (103). The cholinergic neurons receive afferents from the
LC, DpMe, Tuberomamillary nucleus (TMN), orexinergic neurons,
parabrachial neurons, and glutamatergic neurons of the BF, and
send widespread efferent projections to the cortex and hippo-
campus, as well as back to the hypothalamus. Selective lesion of
cholinergic neurons within the nucleus basalis of the BF prolongs
behavioural effects of propofol and pentobarbital (104). Increased
cholinergic activity of the basal forebrain during wakefulness is re-
sponsible for the fluctuations in cortical acetylcholine levels. The
8
8 Section 1 neuroscience in anaesthetic practice
cholinergic neurons stimulate cortical activation, and the resultant
increased discharge frequency, along with increased activity of
cortically projecting parvalbumin-​containing GABAergic neurons,
underlies the desynchronized EEG that typifies wakefulness as well
as REM sleep (103, 105).
Parabrachial Nucleus
Neurons in the parabrachial nuclei belong to a recently identi-
fied glutamatergic arm of the anterior branch of the ascending
arousal system and can themselves modify the anaesthetic state.
Lesion of the parabrachial nuclei induces coma, while the sleep-​
active parafacial zone (see Sleep-​active Neurons of the Basal
Forebrain and Parafacial Zone) promotes SWS through inhibition
of glutamatergic parabrachial neurons that, in turn, project to the
BF (106–​109). Electrical stimulation of the parabrachial nucleus is
able to antagonize continuous low-​dose isoflurane administration
(110). This observed direct effect on anaesthetic sensitivity, as well
as the parabrachial’s known anatomic and functional connection
with sleep-​active nuclei and other CNS regions that affect anaes-
thetic sensitivity and emergence, suggests a significant role for the
parabrachial nucleus in maintaining or emerging from an anaes-
thetic state. However, this has yet to be fully explored.
Ventral Tegmental Area (VTA)
A midbrain dopaminergic and GABAergic region associated with
both arousal and reward, the VTA receives diverse inputs and has
widespread outputs, including the prefrontal cortex, cingulate
gyrus, hippocampus, amygdala, and nucleus acumbens. Reflecting
those widespread connections, it is functionally diverse, with roles
in motivation, cognition, and arousal (111). Dopaminergic neurons
of the VTA do not appear to change their firing rate across sleep–​
wake. Consequently, VTA dopamine neurons have not been linked
to modulation of spontaneous arousal. Nevertheless, dopamin-
ergic neurons are suppressed by GABA, and other neurons within
the VTA have circadian-​dependent activity (112–​116). Artificially
driving dopamine release from the VTA, administration of methyl-
phenidate, or more selective pharmacologic agents that act on D1-​
like receptors, will all accelerate anaesthetic emergence, and can
even reverse anaesthesia produced by continuous administrations
of propofol or isoflurane (117–​120).
Tuberomamillary Nucleus (TMN)
The sole source for histamine in the CNS, the histaminergic neurons
of the TMN have widespread projection throughout the brain and
have activity tightly correlated with arousal state (121). Though
centrally administered histamine causes potent arousal, and central
H1 antagonists produce sedation, the role of the TMN in modifying
general anaesthesia is circumscribed. Lesions of the TMN increase
sensitivity to isoflurane-​induced LoRR, but leave propofol, keta-
mine, and barbiturate sensitivity unchanged (122). Cell-​specific
knockout of GABAA receptors in histaminergic cells likewise
produced no change in propofol hypnotic sensitivity. These phe-
nomena were observed despite the fact that histaminergic neurons
lacking GABAA receptors were resistant to hyperpolarization by
propofol—​strong evidence that histaminergic neurons are not crit-
ical to induction or maintenance of propofol hypnosis (123).
Dorsal Raphe (DR) and Ventral Periaqueductal Gray (vPAG)
The serotonergic neurons of the raphe nuclei have diffuse pro-
jections throughout the brain and comprise the largest source of
CNS serotonin. The median raphe contributes little to producing
or modulating anaesthetic actions. In contrast, when the DR is si-
lenced by calcium blockage or by lesion, sensitivity is increased to
pentobarbital or halothane and cyclopropane, respectively (124,
125). The raphe nuclei (RN) do display state-​dependent firing
similar to noradrenergic or histaminergic centres. Single unit re-
cordings, however, demonstrate that firing rates of serotonergic
neurons do not anticipate spontaneous changes in arousal state
(126). This suggests that activity of the DR is not causally linked to
changes in behavioural state.
Within the vPAG, there is a population of dopaminergic neurons
that are wake-​active. This is in contrast to dopaminergic neurons of
the VTA or substantia nigra, which do not display state-​dependent
activity. However, the vPAG dopaminergic neurons appear not to
contribute to anaesthetic hypnosis. Instead, they modulate anal-
gesia, with lesions of these neurons causing decreased reaction to
noxious stimuli under general anaesthesia (127, 128).
Sleep-​Active Neurons and Nuclei
When compared to the large numbers of known arousal-​
promoting, wake-​active nuclei, there are few neural populations
that are predominantly active during SWS or REM sleep with de-
creased activity during wakeful states. Neurons with sleep-​active
firing patterns are most commonly found in the preoptic area and
BF (though populations do exist elsewhere, including in the pons
and cortex.) These populations act as a network counterbalance to
many of the arousal-​promoting populations discussed previously.
Just as there are many examples of anaesthetics depressing those
arousal centres, there is evidence for sleep-​active neurons being
directly and indirectly activated by certain anaesthetics.
Preoptic Area: Ventrolateral Preoptic Nucleus (VLPO) and
Median Preoptic Nucleus (MnPO)
In the earliest attempts to identify specific populations of sleep-​
promoting neurons, a definitive role was assigned to the preoptic
anterior hypothalamus. This broad region encompasses the VLPO,
which lies within the anterior hypothalamus on the ventral floor
at the level of the optic chiasm, as well as the MnPO, which strad-
dles the decussation of the anterior commissure. Neurons with
heightened activity during SWS are found throughout the preoptic
area, with the greatest concentration found in VLPO. Neurons of
the VLPO are more active during SWS and REM sleep. Changes
in VLPO activity precede the changes in an organism’s behavioural
state. Retrograde and anterograde labelling studies show the VLPO
is reciprocally interconnected with many wake-​promoting nuclei,
including the histaminergic TMN, serotonergic RN, noradrenergic
LC, and the cholinergic LDT and PPT, as well as the orexinergic
neurons of the hypothalamus. VLPO neurons contain the inhibi-
tory neurotransmitters GABA and galanin and are thus ideally
positioned to coordinate and reciprocally inhibit wake-​active as-
cending reticular activating nuclei.
The role of the preoptic area in promoting and modulating the
anaesthetic state appears connected to its regulation of sleep and
wake. Destructive lesions of VLPO cause long-​lasting insomnia.
Bilateral lesions of the VLPO also cause a biphasic change in an-
aesthetic sensitivity that possibly relates to insomnia: at six days
post-​destruction, animals showed resistance to isoflurane LoRR,
while 24 days post-​lesion, subjects showed hypersensitivity to
isoflurane LoRR. Such changes have been hypothesized to arise
9
due to accumulating sleep pressure as VLPO lesioned animals
fail to sleep (129, 130). Isoflurane directly depolarizes GABAergic
neurons in VLPO. Acute resistance to isoflurane induction seen
following VLPO lesions suggests that in normal conditions, an-
aesthetic activation of VLPO contributes to induction. Except for
ketamine, every other general anaesthetic appears to depolarize
and recruit putative sleep-​active VLPO neurons. The population
of neurons throughout the preoptic area (including the VLPO,
MnPO, and surrounding area) that are active during recovery SWS
(after sleep deprivation) significantly overlap with the population
of neurons activated with systemic administration of hypnotic
doses of dexmedetomidine. This reinforces earlier findings sug-
gesting dexmedetomidine acts on native preoptic sleep circuits to
produce hypnosis (131, 132).
Similar to the VLPO, MnPO sleep-​ a ctive neurons are
GABAergic and fire more rapidly several seconds prior to sleep
onset. Although not as broadly activated by anaesthetics as the
VLPO, some inhaled anaesthetics also appear to activate putative
sleep-​active MnPO neurons (133). Microinjection of benzodi-
azepines, propofol, and pentobarbital into the MnPO has been
shown to induce SWS (72, 134, 135). Due to the state-​dependent
firing pattern of MnPO neurons, they have been assigned an im-
portant role in the initiation of sleep. The MnPO is known to send
inhibitory projections to multiple arousal systems, including the
orexinergic neurons in the hypothalamus, in a manner similar to
the VLPO.
Sleep-​active Neurons of the Basal Forebrain and Parafacial
Zone (PZ)
While arousal-​promoting neurons of the BF and pons are well es-
tablished and their effects on anaesthetic states detailed, it is only
recently that sleep-​active groups in these structures were identi-
fied. Although they interact with arousal centres known to influ-
ence anaesthetic actions, the effects of these newly detailed groups
on the anaesthetic state and the effects of anaesthetics on their ac-
tion remain to be investigated. Parvalbumin-​positive GABAergic
neurons of the BF are wake-​active and strongly promote arousal,
while another subset of GABAergic neurons expressing somato-
statin in the BF comprise a sleep-​active group. Somatostatin posi-
tive, GABAergic neurons of the BF exhibit specific increases in
local unit activity during SWS. Optogenetic stimulation of these
neurons can induce SWS (103). The parafacial zone is a pontine re-
gion lateral to the seventh nerve containing SWS-​active GABAergic
neurons. Those sleep-​active, inhibitory neurons project directly
onto arousal-​promoting glutamatergic neurons of the parabrachial
nucleus, which, in turn, project to arousal-​promoting neurons of
the BF. Artificial stimulation of those PZ GABAergic neurons pro-
duces SWS (108). Anaesthetic effects on the PZ and sleep-​active
neurons of the BF await further study.
Thalamus
The thalamus is a critical structure that plays at least three major
roles in wakefulness and consciousness. First, in terms of levels of
consciousness, the thalamus is an important conduit for arousal
pathways from the brainstem. Second, in terms of the content of
consciousness, it is a major relay station for sensory information en
route to the cortex. Third, in terms of the organization of conscious
experience, the higher-​order nuclei of the thalamus play a critical
role in facilitating corticocortical coherence and communication.
Chapter 1 neural mechanisms of anaesthetics 9
The central thalamus has long been known to be critical
to arousal, with small lesions of the area leading to gross dis-
orders of consciousness (136). The anterior intralaminar nuclei,
of which the central medial thalamus (CMT) is a part, receive
significant ascending cholinergic innervation from the BF and
brainstem. Microinjection of nicotine into the CMT is suffi-
cient to reverse continuous systemic sevoflurane anaesthesia in
animal models. This effect is replicated with an infusion of anti-
bodies against potassium channels in the Kv1 family (41, 137).
In slice recordings of neurons of the CMT, sevoflurane reduces
firing, which is, in turn, reversed by administration of a Kv1 in-
hibitor (40). Activity of the CMT appears to be critical for both
sleep and anaesthesia, as changes in high-​f requency oscillations
that occur at both the onset of sleep and anaesthetic-​induced
loss of consciousness occur first in the CMT, rapidly followed
by cortical changes (68). More generally, thalamic inactiva-
tion as measured by reduced blood flow has been associated
with anaesthetic-​induced unconsciousness, although whether
this is causal or secondary to unconsciousness itself remains
unclear (138).
Neocortex and Limbic Cortex
The effects of anaesthetics are particularly heterogeneous across the
neocortex, in stark contrast to the largely antiquated ‘wet blanket’
theory of anaesthetic action as a general neuronal depressant. The
extent to which the primary sensory cortices are affected by many
general anaesthetics remains unclear. These primary processing
areas are still able to maintain normal or near-​normal responses
to evoked potentials while longer-​latency potentials are inhibited.
In contrast, the function of higher-​order association cortices and
portions of the entorhinal cortex are markedly impaired by general
anaesthetics. The mesial parietal cortex, the anterior and posterior
cingulate cortices, and the precuneus are deactivated in sleep and
anaesthesia, as measured indirectly by changes in cerebral blood
flow (139–​141). Given the variability of anaesthetic effect on in-
dividual cortical areas, hypnotic effects of anaesthetics may either
prove to be a result of direct actions upon the cortex or could be a
result of network-​level perturbations that include cortical and sub-
cortical interactions.
Brain Networks and Anaesthesia
The specific molecular target(s) of an anaesthetic may not yield
immediate insight into mechanisms by which the drug pro-
duces unconsciousness. Complete understanding requires de-
tailed knowledge of drug effects on their molecular targets, as
well as how ensuing changes in the activity of neurons and glia
affect local and distant circuits in addition to the global impact
on networks. The relevant actions of anaesthetics, and hence their
common mechanism, may thus be their ultimate disruption of
network function-​decreasing functional information integration.
Understanding discrete effects of anaesthetics on receptors, indi-
vidual neurons, and brain nuclei are necessary but not sufficient
in isolation. To investigate anaesthetic disruption of network level
processes, large-​scale brain activity studies employ functional
magnetic resonance imaging (fMRI), positron emission tomog-
raphy (PET), magnetoencephalography (MEG), or high-​density
electroencephalography (EEG).
01
10 Section 1 neuroscience in anaesthetic practice
Thalamocortical Network
Thalamocortical networks are key to information integration, as
they gate ascending sensory information, ascending arousal signals,
and modulate corticocortical relays. Disruption of the system illus-
trates the importance of this network, which results in disorders
of consciousness (136, 142). Shifting from cortically dominant to
thalamus-​dominant thalamocortical circuits during anaesthetic-​
induced loss of consciousness corroborates a model of propofol
hypnosis whereby GABAergic activation results in strengthened
thalamocortical connections and an intrinsic thalamically-​driven
alpha (8–​12 Hz) electrical rhythm (143, 144). Evidence from
animal models that changes in thalamic rhythms slightly precede
related cortical rhythms at the time of anaesthetic-​induced loss
of consciousness also lends credence to the theory of thalamus-​
rhythm-​driven thalamocortical loop as critical to anaesthetic hyp-
nosis (68). Other animal models using field potentials within the
thalamus and cortical EEG show that ketamine/​xylazine-​induced
loss of consciousness coincides with a shift in the dominant dir-
ection of information transfer from cortex-​thalamus during con-
sciousness to thalamus-​cortex (145). Counter to the argument of a
predominant thalamocortical disruption by anaesthetics, slice and
chronic in vivo recordings suggest that corticocortical connections
are preferentially disrupted by volatile anaesthetics, while thalamo-
cortical connections remain intact (146),
Evidence from functional connectivity studies of the thal-
amus and cortex, which rely on relative blood flow as measured
via PET or fMRI, rather than the electrical measurements of EEG
and subcortical electrodes, do not demonstrate tight association
of thalamus and cortex. Instead, their functional connectivity is
eliminated with the onset of anaesthetic-​induced unconsciousness,
purportedly through a silencing of the thalamus (147). While this
loss of functional connectivity between the cortex and thalamus
was first described with isoflurane and halothane, a similar pattern
was also described with dexmedetomidine-​induced loss of con-
sciousness (148). Recent studies have further solidified the pattern
of reduced thalamocortical connectivity using both ketamine and
sevoflurane, making it a robust finding across multiple anaesthetic
classes (149, 150).
The difference in conclusions between methods using rela-
tive blood flow as a proxy for neural activity and those directly
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-​
induced loss of consciousness addressed this disparity, and dem-
onstrated a distinct phenomenon: isolation of the thalamocortical
network from sensory input at the point of maximum slow-​wave
activity on EEG, and the emergence of a sensory-​responsive primi-
tive cortical network independent of the isolated thalamocortical
network (151). The functional compartmentalization through thal-
amocortical isolation corresponds with the other EEG evidence,
suggesting emergence of thalamically driven rhythms during
anaesthetic-​induced unconsciousness (143, 144). Only with func-
tional isolation would the dominant rhythm driver be thalamus ra-
ther than corticocortical connections.
Corticocortical Networks
As sensory integration and processing are integral to awareness,
the disruption of these functions are a predicted hallmark for
anaesthetic-​induced unconsciousness. The parietal lobe con-
tains multiple primary sensory cortices. Executive function
depends upon the frontal cortex. Consequently, effective com-
munication between the two regions is considered necessary for
consciousness. It follows that disruption of that communication
would serve to produce anaesthetic-​induced unconsciousness
(152, 153). However, rather than a simple complete breakdown
of all frontal-​parietal communication, anaesthetic-​induced un-
consciousness is associated with a specific disruption of feed-
back communication between the frontal and parietal cortices.
Thus, although there is effective information transfer from the
parietal cortex forward to the frontal cortex (feed-​forward),
reciprocal information transfer from the frontal cortex to the
parietal (feedback) is impaired with the onset of anaesthetic-​
induced unconsciousness (154). This pattern of feedback in-
hibition has proven remarkably robust over anaesthetics with
varying molecular mechanisms of actions, from ketamine, to
volatile agents, to propofol (155). That this pattern of feedback
or top-​down processing is also impaired in vegetative states sug-
gests that this could be a general process for unconsciousness
(156, 157).
Global Distance Connectivity and Information
Integration Capacity
In addition to evidence that anaesthetics may exert their effects
through specific networks such as those mentioned previously,
anaesthetic action on large-​scale brain network organization and
generalized ability for information integration may be the source
of their unconsciousness-​inducing effects. Analyses of whole-​brain
networks under general anaesthesia show increased local informa-
tion exchange but impaired longer distance communication (158).
This change from global connectedness to a more local pattern oc-
curs for both volatile anaesthetics and propofol, and has been seen
in with the distinct measurement modalities of both EEG and fMRI
(159). While not all analyses have specifically found an increase
of ‘small-​worldness’ of the networks (local over long-​distance),
decreases in network efficiency are common, and therefore the
amount of information that could be transmitted and integrated
by a network is diminished in the presence of a general anaesthetic
(160–​163).
Conclusions
While primary anaesthetic pharmacologic effects necessarily
occur at the molecular level, the diversity of both general an-
aesthetics’ molecular targets and their subsequent cellular-​level
actions does not clearly translate into obvious behavioural com-
monalities observed in vivo. Only at the level of neural circuits
can we begin to appreciate the common effects among the diverse
array of individual anaesthetic drugs. Distinguishing the prox-
imate cause and secondary effects culminating in anaesthetic hyp-
nosis remains a significant challenge for the field. Identifying the
critical anaesthetic induced network adaptations in both cortical
and subcortical circuits truly responsible for loss of consciousness
itself, as opposed to circuit level side effects of anaesthetic drug
exposure, represents another significant challenge. Resolving
these challenges will benefit both the field of anaesthesiology as
well as neuroscience.
1
Summary
◆ Anaesthetics act upon a variety of protein targets to exert their
hypnotic effects.
◆ Relevant hypnotic molecular targets of general anaesthetics in-
clude ligand-​gated ion channels (examples: GABA and NMDA
receptors), voltage-​gated ion channels (examples: Kv1 and
Nav1.6), constitutively active ion channels (example: K2P), G-​
protein-​coupled receptors, and respiratory complex I.
◆ Anaesthetics elicit circuit-​level effects not readily predicted by
their effects on single neurons of a given circuit.
◆ Anaesthetics can affect endogenous neural systems regulating
sleep and arousal, and such actions may produce or potentiate
their hypnotic effects.
◆ The thalamus is part of the ascending arousal system, serves as a
relay for sensory information, and facilitates corticocortical com-
munication. While thalamic inactivation does not invariably lead
to loss of consciousness, artificial stimulation can reverse hyp-
nosis during continuous anaesthetic administration, presumably
through the ascending arousal pathways.
◆ Disruption of function in cortical association areas by anaes-
thetics corresponds with changes of global network properties
during hypnosis, where long-​range connections decline and
the total capacity for information integration decreases. It is
not yet clear whether direct action at those association centres
directly underlies network adaptations or whether the primary
change occurs elsewhere and propagates to impair cortical
activity.
◆ Both thalamocortical networks as well as corticocortical patterns
of connectivity are altered with anaesthetic hypnosis. Changes in
both of these networks may reflect a final common marker or
mediator of anaesthetic-​induced unconsciousness.
Multiple-​Choice Questions
Q Interactive multiple-​choice questions to test your knowledge
on this chapter can be found in the online appendix at www.
oxfordmedicine.com/​otneuroanesthesiology.
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CHAPTER 2
Intracranial Pressure
Harald Stefanits, Andrea Reinprecht,
and Klaus Ulrich Klein
Introduction
This chapter on intracranial pressure (ICP) explains the following
topics: contents of the intracranial vault (brain parenchyma, cere-
brospinal fluid, arterial and venous blood), ICP waveforms, intra-
cranial elastance curve, intracranial hypertension, intracranial
herniation syndromes, and monitoring of ICP.
Alexander Monro (1733–​1817) first described ICP in 1783. By
describing that brain tissue is nearly incompressible and sur-
rounded by non-​expandable cranium, he suggested that intra-
cranial blood volume (IBV) remains constant. George Kellie
(1720–​1779) stated that intracranial fluid could not be added or
removed without simultaneous equivalent replacement or displace-
ment. Francois Magendie (1783–​1855) first described the circula-
tion of cerebrospinal fluid (CSF) flowing from the ventricles to the
spinal cord by discovering a small foramen in the roof of the fourth
ventricle (foramen Magendie). In 1846, Sir George Burrows (1801–​
1887) constituted a reciprocal relationship between IBV and CSF.
The neurosurgeon Harvey Cushing (1869–​1939) and his co-​worker
Lewis Weed endorsed the doctrine of Monro and Kellie by stating
that with an intact cranium, the net sum of all intracranial vault
volumes (brain tissue, blood, CSF volume) remains constant and
that an increase in one component should cause a reduction in one
or both of the other two components (1).
Investigation of CSF started in 1891, when Heinrich Quincke
(1842–​1922) published his studies on lumbar puncture and the
chemical investigation of CSF. In the early twentieth century, re-
petitive lumbar CSF puncture was widely used as first clinical
method to determine ICP. Later in 1960, the neurosurgeon pioneer
Nils Lundberg published a thesis that largely influenced ICP moni-
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-
brum: a) buoyancy: the mass of the brain is about 1400 grams,
although the net weight of the brain suspended in the CSF is
equivalent to a mass of 25 grams. Therefore, the brain exists
in neutral buoyancy, allowing the brain to maintain its density
without being impaired by its own weight. According to philoso-
pher Rudolf Steiner (1861–​1925), this exemption of the gravity
is essential for higher brain function; b) protection: CSF protects
the brain to a certain extent against any impact; c) prevention of
brain ischaemia: CSF can be reduced to counteract brain oedema
when needed; d) chemical stability/​cooling/​clearing waste: CSF is
produced in the ventricles and circulates through the ventricular
and subarachnoidal spaces, rinsing metabolic compounds from the
central nervous system (CNS). It has been suggested that CSF has
a ‘sink action’ by which metabolites produced in the brain during
metabolic activity diffuse into CSF and thereby are removed from
the brain. Also, it has been suggested that CSF flow might be able
to cool the brain whenever it is needed. CSF plays an important
role in flushing cerebral metabolic toxins (e.g., beta amyloid) from
the interstitial fluid. This process is increased during natural sleep
by opening extracellular channels controlled by glial cells allowing
rapid influx of CSF into the brain.
Today, indications for monitoring of ICP include traumatic brain
injury, intracerebral haemorrhage, subarachnoid haemorrhage
(SAH), hydrocephalus, malignant infarction, oedema, infection,
and metabolic disorders (4). Measurement of ICP complements in-
formation on cerebral perfusion pressure (CPP), cerebrovascular
autoregulation, and compliance of the cerebrospinal system.
Contents of the Intracranial Vault (Brain
Parenchyma, CSF, Blood)
To understand the dynamics of ICP regulation, anatomical con-
siderations have to be undertaken concerning the contents of the
intracranial vault. The outlined anatomical landmarks are im-
portant for the understanding of herniation syndromes and their
clinical symptoms, since brainstem structures, cranial nerves, and
arterial vessels are located close to the intracranial bottleneck areas
and edges. The skull is the brain’s bony (stiff) hull that has only
one big outlet for the medulla oblongata: the foramen magnum. It
contains all relevant compartments, including the brain tissue, CSF
spaces, and arterial and venous vessels (Figure 2.1 and Table 2.1).
Parenchyma
The brain parenchyma including the cranial nerves makes up about
85% of total intracranial volume (ICV). The largest part of the
brain is the cerebrum (or telencephalon) with its two hemispheres,
separated by a vertical (sagittal) diaphragm, the falx cerebri. It is
situated on top of the ‘core of the brain’, which is considered to be
the relay station for higher cognitive functions: the thalamus and
brainstem, parts of the diencephalon and mesencephalon, which
continues caudally to the pons and the medulla oblongata. Dorsally
adjacent to the brainstem is the cerebellum, which is separated
from the cerebrum by an axial tent-​like diaphragm, the tentorium
cerebelli. The tentorial notch allows the caudal continuation of the
81
18 Section 1 neuroscience in anaesthetic practice
7
1 and to the outer CSF space, i.e., the subarachnoid space. The lateral
8
3 CSF circulation are called hydrocephalus, a condition that can be
4 9
5 or blood clotting after intraventricular haemorrhage (within few
2
6 masses. Malresorption of CSF may occur as a consequence of high
10
Figure 2.1 Schematic view of intracranial spaces and brain parenchyma.
(1) telecenphalon, (2) cerebellum, (3) diencephalon, (4) mesencephalon, (5) pons,
(6) medulla, (7) falx, (8) lateral ventricles, (9) tentorium cerebelli, and (10) foramen
magnum.
brainstem towards the foramen magnum. The cranial nerves III to
XII originate from the brainstem. The brain parenchyma has to be
considered a rather static volume that is easily adaptive to chronic
compression up to a certain extent (in cases of slowly growing tu-
mours, such as meningiomas), but very sensitive to acute com-
pression such as intracranial bleeding. Volume expansion of the
parenchyma might be caused by tumour, abscess, intracranial
haemorrhage (ICH), or oedema. The latter can be focal (e.g., in
cases of tumour, bleeding, infection, stroke, venous stasis) or gen-
eral (e.g., in SAH, global infarctions, traumatic brain injury, or as-
sociated with systemic diseases). A natural atrophy of the brain can
be observed during ageing, which provides more buffer space for
volume expansion in elderly people.
Cerebrospinal Fluid
The CSF space makes up 10% of the ICV, equalling a total of 120–​200
ml. CSF is a low-​protein, glucose-​containing liquid that contains
few cells, mostly lymphocytes (up to 4/​µl). It is mainly produced by
Table 2.1 The contents of the cranial vault are divided into three
compartments. Proportions of intracranial volume are given in %.
Contents of the intracranial vault
Brain parenchyma 85%
Cerebrospinal fluid 10%
Blood 5%
ultrafiltration from blood in the plexus choroideus at a rate of 250–​
500 ml/​24h. Its resorption sites are arachnoidal granulations close
to the venous sinuses and the spinal nerve roots. Production and re-
sorption are in a physiological balance. There are four major inner
CSF spaces, called the ventricles, which are connected to each other
ventricles extend from the frontal to the occipital and to the tem-
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
acute or chronic. Sudden blockade of the aforementioned foramina
or the aqueduct—​the bottlenecks of CSF circulation—​lead to acute
failure of CSF circulation and symptoms of herniation (Box 2.1).
Aqueductal stenosis, blockade of the foramina of Monro (colloid
cysts), Luschka, and Magendie may occur acutely by a tumour mass
hours) or chronically by congenital membranes or slowly growing
CSF protein content, which can occur post-​haemorrhage (degrad-
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-
cephalus is a chronic CSF circulation disorder, leading to typical
clinical symptoms (Hakim-​Trias), i.e., cognitive and gait disorders
as well as urinary incontinence (5, 6).
Blood
The cerebral blood volume makes up 5% of the ICV, mainly con-
sisting of venous vessels. Cerebral blood flow (CBF) and associ-
ated cerebral blood volume (CBV) are regulated by mechanisms
influencing cerebral resistance (i.e., constriction or dilation of ves-
sels, static autoregulation) over time (dynamic autoregulation). The
pressure reactivity index (PRx) is described as a correlation coef-
ficient between (e.g., ten-​second average) ICP and mean arterial
blood pressure (MAP) over a time window (e.g., five minutes). In
severe brain injury patients, impaired autoregulation contributes to
unfavourable outcome. CPP is calculated as a difference between
the MAP at head level and the ICP. The concept of the ‘optimal
CPP’ should be followed, since values beyond the CPP level opti-
mizing cerebral autoregulation are associated with fatal outcome or
increased disability. The optimal CPP is between 50 and 95 mmHg,
but it is patient-​and time-​dependent, and thus needs continuous
monitoring. In cases of acutely elevated ICP, decreasing the IBV
is a short-​term strategy to decrease ICP. This can be achieved by
moderate (short-​term) hyperventilation leading to hypocapnia
and associated cerebral vasoconstriction. Special caution has to be
undertaken in patients suffering from vasospasm after SAH.
Intracranial Compliance
The pressure-​volume relationship between ICP, ICV, and CPP
pressure is known as the Monro-​Kellie doctrine, which states that
i) the brain is enclosed in the non-​expandable cranium; ii) brain
parenchyma is nearly incompressible; iii) the blood volume of the
intracranial vault is nearly constant; and iv) a continuous outflow of
venous blood from the intracranial vault is required to make room
91

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

20 Section 1 neuroscience in anaesthetic practice

(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
12

Chapter 2 intracranial pressure 21

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-
tially are caused by cardiovascular interactions.
Cerebrovascular Pressure Reactivity
CBF autoregulation describes the ability of the cerebral vasculature
to maintain a stable CBF despite fluctuations in CPP. With intact
autoregulation, a rise in arterial blood pressure (ABP) produces
cerebral vasoconstriction, a decrease in CBV, and a fall in ICP (7,
8). A fall in ABP produces the opposite effects. With disturbed
autoregulation, a rise in ABP is transmitted to the intracranial com-
partment and produces a rise in ICP as a passive pressure effect.
Cerebral autoregulation can be determined by investigating the
moving Pearson correlation coefficient between changes in ABP
and ICP, i.e., PRx. In fact, waveforms of ABP and ICP are correl-
ated at higher temporal resolution. PRx is negative (e.g., between
0 and –​1) when cerebral vessels are pressure reactive and aim to
counteract changes in ABP. Instead, PRx is positive (e.g., between
0.3 and 1) when cerebral vessels are not pressure reactive and alter-
ations in MAP are mostly directly transmitted to ICP. PRx has been
identified as a predictor of outcome after traumatic brain injury
in terms of mortality. When measured over time at different CPP
thresholds, PRx demonstrates a U-​shaped curve, suggesting a spe-
cific relationship of individual autoregulation. This approach can
be used to tailor individual CPP management in order to optimize
the patient’s autoregulation. As ABP and ICP routinely are meas-
ured continuously in patients at risk, this index is readily available
when using appropriate software. Notably, the underlying prin-
ciple of PRx also works for cerebral variables other than the ICP,
such as cross-​correlating MAP and CBF velocity determined by
transcranial Doppler sonography (Mx) or regional frontal haemo-
globin oxygen saturation determined by near-​infrared spectros-
copy (ORx, THx) ideally determined at high temporal resolution.
ICP Measurement
Intraventricular Catheters
Direct measurement of ICP in the lateral ventricle is still con-
sidered the ‘gold standard’ for ICP measurement (Figure 2.5 and
Box 2.2) (9). The measurement is performed at the level of the me-
atus acusticus externus corresponding to the foramen of Monro.
Advantages of this measurement include the possibility of external
2
22 Section 1 neuroscience in anaesthetic practice
Figure 2.5 Intraventricular and intraparenchymal ICP measurement.
calibration and CSF drainage. However, placement of the catheter
may be difficult or even impossible in case of severe brain swelling
with collapsed ventricles. Furthermore, the risk of infection is re-
ported to be between 3.5% to more than 20% according to different
larger clinical studies. Many authors report an increase of infection
risk with prolonged usage (10). In clinical practice it is important to
be aware that ICP recordings are representative only with a closed
drainage system (4, 11, 12, 13, 14).
Intraparenchymal Probes
ICP can be recorded by inserting a probe into the brain paren-
chyma. Usually, these probes are inserted in a non-​eloquent brain
area, although the exact placement, especially in focal pathologies,
is a matter of ongoing debate. Measurement of ICP is local and does
not necessarily represent CSF pressure. The risk for parenchymal
bleeding or infection is <1%. Microtransducers cannot be recali-
brated after insertion and drift from zero might occur during long-​
term measurement.
Drainage of CSF
In cases of acute hydrocephalus, drainage of CSF has to be per-
formed promptly. This can be done by insertion of an external
Box 2.2 Reasons for Performing ICP Monitoring
◆​ Severe brain trauma (GCS 3–​8)
◆​ Severe subarachnoid haemorrhage (traumatic, vascular)
◆​ Severe cerebral ischaemia
◆​ Diagnostic (hydrocephalus, shunt insufficiency)
ventricular drain (EVD) or a lumbar drain (LD). The latter can only
be applied in communicating hydrocephalus, and an open passage
through the aqueduct and the outlet of the fourth ventricle is man-
datory, which can be estimated by radiologic imaging (i.e., to check
for mass lesions and ventricular diameter gradients). Blockage of
CSF pathways could lead to transtentorial or transforaminal her-
niation (see Herniation Syndromes).
In many cases, an external ventricular drainage is the first choice.
It can be implanted in a sterile surrounding at the intensive care
unit (ICU) or in the operating theatre by a neurosurgeon and com-
bines draining of CSF with measurement of ICP. The EVD is a sili-
cone catheter that is inserted into the lateral ventricle, usually by a
frontal and rarely by an occipital or temporal approach, through a
burr hole and a small incision of the dura (15, see Table 2.3). The
most common variant is a frontal burr hole over Kocher’s point,
which is 1 cm anterior to the coronary suture and 3 cm lateral from
the midline (Figure 2.6). The target point is the entrance of the for-
amen of Monro which is situated at the crossing of virtual lines
through the medial canthus of the eye (anterior-​posterior) and the
external acoustic meatus (left-​right). The EVD can be attached to
the bone via a bolt system or tunnelled subcutaneously. The ven-
tricular catheter is secured by suturing it to the skin, although it
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
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-
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).
The level of the drip chamber can be adjusted according to a re-
sistance for the drained CSF target amount (principle of commu-
nicating vessels). It is typically placed between 0 and 15 cm above
the reference points and adapted to ICP (normal values between
32

Chapter 2 intracranial pressure 23

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

24 Section 1 neuroscience in anaesthetic practice

the EVD functioning, a cranial computed tomography (CCT) scan
should be considered to check for ventricular size or dislocation
of the ventricle catheter. The ICP should only be measured by the
transducer when the distal drainage system is closed. A lumbar CSF
drain is inserted intradurally under sterile conditions between ver-
tebrae L4/​5, L3/​4, or L2/​3. The level of L4/​5 can easily be found by
connecting the palpable rims of the anterior iliac crests. The drain
is also connected to a drip chamber and a distal drainage system.
However, ICP measurement is not reliable. From both types of
drainages, CSF should be analysed at regular intervals (e.g., every
second day). The following parameters may be evaluated (Table
2.4). Additionally, microbiological cultures should be performed
regularly.
Herniation Syndromes
There are different reasons for causes of impairment of conscious-
ness in neurological and neurosurgical patients, and conscious-
ness is dependent on the functioning of the ascending reticular
activating system (ARAS), a network of neurons with connections
from the pons up to the cerebral cortex. The following three terms
are often used to describe impairment of consciousness, but all
terms used should be complemented by detailed clinical descrip-
tions of the patient.
1) Somnolence is a sleep-​like state that can be disrupted easily by
speaking to the patient. Wakefulness and awareness are im-
paired and attention cannot be sustained.
2) Stuporous patients may be roused only by strong stimuli, such
as pain.
compression of the oculomotor nerve. This complements to the
stretching of the nerve over the clivus (due to downward shift of
its origination), resulting in ipsilateral mydriasis at an early stage.
This is an absolute alert sign—​immediate lowering of ICP has to
be achieved.
◆ Subfalcine: Parts of the hemisphere inheriting the mass lesion
may herniate below the falx cerebri, possibly compressing the
pericallosal and callosomarginal arteries, leading to brain in-
farcts of the medial frontal lobe (gyrus cinguli, gyrus frontalis
superior) down to the precuneus. On CCT, a midline shift can
be seen (measured at the level of the septum pellucidum or the
pineal gland). Greater than 5 mm of midline shift may lead to
stupor, and greater than 9 mm to coma.
Transtentorial: When the supratentorial ICP increases, structures
◆
shift further downwards, leading to transtentorial herniation. It is
a rather late, often terminal event, leading to direct compression of
the brainstem. The oculomotor nuclei are damaged on the contra-
lateral side, resulting in mydriasis and loss of light reaction of the
contralateral (in addition to the ipsilateral) pupil. Bilateral mydriasis
and decerebrate posturing (flexion of upper, extension of lower ex-
tremities) are signs of a late phase of herniation. Furthermore, the
posterior cerebral artery (PCA) is at risk—​its compression leads to
parietooccipital brain infarcts (visual impairments, blindness).
◆ Tonsillar: Raised pressure in the posterior fossa leads to her-
niation of the cerebellar tonsils through the foramen magnum.
Compression of the medulla oblongata leads to respiratory arrest
and compression of the outflow of the fourth ventricle to acute
hydrocephalus.

3) Coma is characterized by a loss of consciousness with an
unarousable patient, even to strong stimuli. Motor responses
are possible.
Different grading scales such as the Glasgow Coma Scale or the Full
Outline of Unresponsiveness score are used to describe these states
in more detail. Increase of ICP leads to compression of the struc-
tures relevant for the ARAS by ‘herniation’ through the tentorial
notch and the foramen magnum or the facial and tentorial edges:
◆ Uncal and Central: Unilateral, supratentorial mass lesions shift
the brain downwards and towards the contralateral side, leading
to compression of the diencephalon and the brainstem in the
tentorial notch and at the tentorial edge, thus leading to im-
pairment of consciousness. Also, temporal structures, especially
the uncus, herniate around the tentorial edge, leading to direct
Besides impairment of consciousness, other signs of increasing ICP
have to be considered, such as headache, altered brain function
(sensory or motor deficits, speech impairment, cognitive dysfunc-
tion), seizures, and visual disturbances. Conservative measures
should be undertaken before aiming at surgical interventions (Box
2.3). There should at least be a consideration of surgical intervention
for intracranial lesions with mass effect leading to clinical symp-
toms. Extra-​axial and intra-​axial tumours, intracranial bleedings
(especially epidural and subdural haematoma, but in some cases
also intracerebral haemorrhage), as well as large abscesses often re-
quire surgical intervention. Mass lesions in the posterior fossa—​
including intraparenchymal bleeds—​have to be surgically treated
when compression of the fourth ventricle is suspected or expected
due to swelling. In cases of strokes, conservative management
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.
52
Box 2.3 Management of Increased ICP
In cases of increased ICP, it is vital to optimize parameters
of ventilation, haemodynamics, sedation, and positioning.
Additionally, both conservative and surgical therapy options
should be considered.
◆​ Optimization of PaCO2 (35 mmHg), PaO2 (120 mmHg), tem-
perature (<37.5°C/​99.5°F), serum electrolytes (Sodium), pH.
◆​ Drainage of CSF, check for 30° head up and optimal cranial
venous outflow.
◆​ Identify potential causes for increased ICP, consider CCT.
◆​ Consider volume and vasopressor in case of hypotension for
individual target CPP.
◆​ Consider osmodiuretics (e.g., mannitol 20% 125–​250 ml,
cave: plasma osmolality).
◆​ Consider temporary (5–​10 min) hyperventilation (e.g., PaCO2
30 mmHg).
◆​ Consider neurosurgical therapy (e.g., decompressive
hemicraniectomy).
◆​ Consider barbiturate coma (e.g., thiopental bolus 5–​10 mg/​
kg or 3–​5 mg/​kg/​h) or mild hypothermia (e.g., 33–​35°C/​
91.4–​95°F).
when brain shift increases, decompressive hemicraniectomy within
48 hours after onset leads to favourable outcomes in patients
younger than 60 years (adapted from 16).
References
1. Cushing H. The blood-​pressure reaction of acute cerebral compression,
illustrated by cases of intracranial hemorrhage. American Journal of
Medical Sciences. 1903;125:1017–​45.
2. Lundberg NG. Continuous recording and control of ventricular
fluid pressure in neurosurgical practice. [Doctoral dissertation]
Copenhagen: Ejnar Munksgaard; 1960.
3. Lundberg N, Troupp H, Lorin H. Continuous recordings of the ventricular-​
fluid pressure in patients with severe acute traumatic brain injury.
A preliminary report. The Journal of Neurosurgery. 1965;22:581–​90.
Chapter 2 intracranial pressure 25
4. Le Roux P, Menon DK, Citerio G, Vespa P, Bader MK, Brophy G,
et al. The International Multidisciplinary Consensus Conference
on Multimodality Monitoring in Neurocritical Care: Evidentiary
tables: A statement for healthcare professionals from the Neurocritical
Care Society and the European Society of Intensive Care Medicine.
Neurocritical Care. 2014;Suppl 2:S297–​361.
5. Fishman RA. Cerebrospinal fluids in diseases of the nervous system.
Philadelphia, PA: Saunders; 1992.
6. Rosenberg GA. Brain fluids and metabolism. Oxford: Oxford University
Press; 1990.
7. Kety SS, Shenkin HA, Schmidt CF. The effects of increased intracranial
pressure on cerebral circulatory functions in man. The Journal of
Clinical Investigation. 1948;27:493–​9.
8. Kirkman MA, Smith M. Intracranial pressure monitoring, cerebral
perfusion pressure estimation, and ICP/​CPP-​guided therapy: A
standard of care or optional extra after brain injury? British Journal of
Anaesthesia. 2014;112:35–​46.
9. Narayan R, Kishore P, Becker DP, Ward JD, Enas GG, Greenber RP,
et al. Intracranial pressure: To monitor or not to monitor? A review of
our experience with severe head injury. The Journal of Neurosurgery.
1982;56:650–​9.
10. Pfisterer W, Mühlbauer M, Czech T, Reinprecht A. Early diagnosis
of external ventricular drainage infection: Results of a prospective
study. The Journal of Neurology, Neurosurgery & Psychiatry.
2003;74:929–​32.
11. Chesnut R, Videtta W, Vespa P, Le Roux P; Participants in
the International Multidisciplinary Consensus Conference
on Multimodality Monitoring. Intracranial pressure
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
multimodal monitoring in the neurointensive care unit. Current
Opinion in Critical Care. 2015;21:113–​9.
13. Czosnyka M, Miller C; Participants in the International
Multidisciplinary Consensus Conference on Multimodality
Monitoring. Neurocritical Care. 2014;Suppl 2:S95–​102.
14. Helbok R, Olson DM, Le Roux PD, Vespa Paul; Participants in
the International Multidisciplinary Consensus Conference on
Multimodality Monitoring. Intracranial pressure and cerebral
perfusion pressure monitoring in non-​TBI Patients: Special
considerations. Neurocritical Care. 2014;Suppl 2:S85–​94.
15. Marcus HJ, Wilson MH. Videos in clinical medicine. Insertion of
an intracranial-​pressure monitor. New England Journal of Medicine.
2015;373:e25.
16. Koenig M. Cerebral herniation syndromes and intracranial hypertension.
Updates in neurocritical care. New Brunswick, NJ: Rutgers University
Press; 2016.
62
Another random document with
no related content on Scribd:
 120 Tab. X, 4–6 (Schädel); id. 1893 III, 78; W e b e r 1894 ib.
474.
Mus chrysocomus („n. sp. 3o“ J e n t i n k 1879 T. Ned. D. Ver. IV
p. LVI); B. H o f f m a n n 1887 Abh. Ber. Dresd. 1886/7 Nr. 3 p.
20, Tafel Fig. 1 a–f (Schädel); T h o m a s 1895 AMNH. (6) XVI,
163 und 1896 XVIII, 247; T r o u e s s a r t 1897 Cat. Mam. 485;
T h o m a s 1898 TZS. XIV, 403.
Mus fratrorum T h o m a s 1896 AMNH. (6) XVIII, 246;
Trouessart 1897 Cat. Mam. 485.
fem.,
a, b.
in Spiritus, Tomohon, Minahassa, Nord Celébes, III
und IV 94.
mas juv.,
c. in Spiritus, Tomohon, III 94.
fem.
d, e.
juv., in Spiritus, Tomohon, III 94.

Als H o f f m a n n 1887 M. chrysocomus beschrieb, besass das

Dresdner Museum kein Exemplar von callitrichus, er war auf
J e n t i n k s Beschreibung angewiesen. 1894 trafen aber 4
Exemplare ein, die Dr. J e n t i n k die Güte hatte, mit seinen Typen
zu vergleichen und als solche zu bestimmen, man kann daher an
ihrer Identität nicht zweifeln, trotzdem die Beschreibung der Art
(NLM. 1879 I, 12) nicht so zutreffend und genügend ist, dass sie
danach allein sicher erkannt werden könnte. Zwischen dem einzig
vorhandenen Typus von chrysocomus und den mir nun vorliegenden
Exemplaren von callitrichus kann ich aber keine irgendwie
wesentlichen Unterschiede constatiren, sowenig wie zwischen M.
fratrorum Thos. (wovon das Dresdner Museum 2 von T h o m a s
bestimmte Exemplare besitzt) und callitrichus. Dieser sagt (AMNH.
XVIII, 247), dass fratrorum M. chrysocomus sehr nahe stehe, aber
durch Grösse, geperlte Supraorbitalränder und mächtigere Molaren
unterschieden sei, allein die Schädel der zwei mir vorliegenden
Exemplare zeigen diese Perlung nicht, sondern haben scharfe
Ränder wie gewöhnlich; Grösse und mächtigere Molaren können als
Artunterschiede, in Ansehung der bedeutenden Differenzen der
Exemplare nach Alter und Geschlecht, nicht angesehen werden.

J e n t i n k identificirte ferner einen Schädel ohne Unterkiefer von

Parepare, Süd Celébes (Webers Zool. Erg. I, 120) mit callitrichus
und sagt, dass es sehr leicht sei, die Art nur nach dem Schädel zu
unterscheiden, unterlässt es aber die unterscheidenden Charaktere
anzugeben; er verweist nur auf einige Abbildungen zum Vergleiche
(Cat. MPB. IX Pl. 7, Zool. Erg. I Tab. X), die aber hierfür, in
Ansehung der beträchtlichen Unterschiede nach Alter und
Geschlecht und wegen der nicht hinlänglich deutlichen Details an
den Zähnen, nicht genügen. Ich halte eine solche Identificirung für
unsicher und möchte erst weiteres Material von Süd Celébes
abwarten, so wenig ich die Möglichkeit des Vorkommens von M.
callitrichus in Süd Celébes in Abrede stellen will. [25]

Endlich hat T h o m a s neuerdings (TZS. XIV, 403) M. chrysocomus

vom Berge Data, Lepanto, Nord Luzon, von 8000 Fuss Höhe
aufgeführt und bemerkt, dass die Art von fast allen anderen der
Gattung durch das völlige Fehlen der scharfen Supraorbitalränder
unterschieden sei. Ein von T h o m a s bestimmtes, ebenfalls
männliches, ziemlich adultes Exemplar im Dresdner Museum von
demselben Fundorte zeigt am Schädel ebensowenig scharfe
Supraorbitalränder, während der Typus von chrysocomus von Nord
Celébes, ein noch junges Exemplar, diese deutlich markirt hat, wie
auch aus der H o f f m a n n schen Abbildung ersichtlich ist, und wie
es der von mir angenommenen Identität mit callitrichus entspricht.
Da nun ausserdem das Exemplar von Luzon einen viel weicheren
und nicht so lebhaft gefärbten Pelz hat wie callitrichus (und
chrysocomus) und noch andere kleine Unterschiede aufweist, so
möchte ich, auch unter Berücksichtigung des entlegenen und hohen
Fundortes, trotz notorisch vorhandener Ähnlichkeiten, die Identität
nicht vertreten und nenne die Exemplare vom Berge Data: Mus
datae. Erst bei einer weit besseren Kenntniss der Mäuse dieser
Gegenden, die wohl noch lange auf sich warten lassen wird, kann
man zu einer klareren Einsicht, als es jetzt möglich ist, gelangen.

Was die speciellen Fundorte von M. callitrichus auf Celébes angeht,

so ist die Art im Norden aus der Minahassa registrirt von Manado,
Langowan, Kakas (Mus. Leid.), Tomohon (Sarasins), Lotta (Mus.
Dresd.), Rurukan 3500 Fuss hoch („fratrorum“ Brit. Mus. und Mus.
Dresd.), Amurang („chrysocomus“ Mus. Dresd.); im Süden von
Parepare, welcher letztere Fundort aber meiner Ansicht nach noch
der Bestätigung bedarf.

[Inhalt]

36. Mus hellwaldi Jent.

Tafel VII Fig. 2–10

J e1879
n t i n k T. Ned. D. Ver. IV p. LV („5o“); id. NLM. I, 11
id.1883
ibid. V, 176
id.1887
Cat. MPB. IX, 212
id.1888
ibid. XII, 65
W1894
e b e r Zool. Erg. III, 474
T 1896
h o m a s AMNH. (6) XVIII, 246
T r1897
o u e s s a r t Cat. Mam. 479.
mas,a. in Spiritus, Minahassa, Nord Celébes, 8. V.

Bis jetzt nur von der Minahassa bekannt: Manado, Langowan,

Amurang (Mus. Leid.), denn die Angabe, dass die Art auch auf
Bórneo und Bunguran (Natuna Ins.) vorkäme, hat T h o m a s
(AMNH. 6. s. XIV, 455 1894) zurückgezogen (vgl. auch H o s e Mam.
Borneo 1893, 59, Nov. Zool. I, 658 1894 und NLM. XIX, 160 1897).

Der Färbung und weichen Beschaffenheit des Pelzes nach eine sehr
schöne Art. Der Schwanz ist (nach dem S a r a s i n schen Spiritus-
Exemplar) unten gelblich, oben im basalen Drittel grau, im mittleren
zu gelblich übergehend, im distalen gelblich wie unten (dies zur
Ergänzung der J e n t i n k schen Beschreibung). Die schöne braune
Farbe der Oberseite ist scharf von der weissen Unterseite abgesetzt,
auch an den Beinen.

Bezüglich der einzelnen Figuren siehe die Tafelerklärung.

[Inhalt]

37. Mus xanthurus Gr.

Tafel VI Fig. 2–10

J.1867
E. G r a y PZS. 598
G1879
ü n t h e r ib. 75 (Mus everetti); J e n t i n k T. Ned. D.
Ver. IV p. LV („4o“) und p. LVI („2o“); id. NLM. I, 10
J e1883
n t i n k NLM. V, 177
H 1887
o f f m a n n Abh. Ber. Dresd. 1886/7 Nr. 3 p. 1, 4, 13;
T h o m a s PZS. 514 (Mus xanthurus und everetti);
J e n t i n k Cat. MPB. IX, 212
J e1888
n t i n k Cat. MPB. XII, 66
H 1893
i c k s o n Nat. N. Cel. 229 [26]
W1894
e b e r Zool. Erg. III, 474
T 1895
h o m a s AMNH. (6) XVI, 163 (Mus everetti)
id.1896
ibid. XVIII, 246
 T r1897
o u e s s a r t Cat. Mam. 472
T 1898
h o m a s TZS. XIV, 400 (Mus everetti).
Bälge
a, b.mit Schädel, mares, Tomohon, Minahassa, Nord
Celébes, 11. VII 94 und 30. III 95.
Balg c.mit Schädel, fem. juv., Makassar, Süd Celébes. 26.
XI 95.
2 mares,
d–f. 1 fem., in Spiritus, Tomohon, Minahassa, Nord
Celébes, III und IV 94.
1 mas,
g, h. 1 fem., in Spiritus, Minahassa.
fem. juv.,
i. in Spiritus, Matinang Südspitze, 29. VIII 94.

An manchen Exemplaren ist das Schwanzende behaarter als bei

anderen, ein behaarteres ist Tafel VI, 2 abgebildet.

G ü n t h e r beschrieb M. everetti von Mindanao oder einer kleinen

Insel der Nachbarschaft; er hat zwar keinen Fundort angegeben,
während solche bei allen anderen Arten, die in der Abhandlung
vorkommen, nicht fehlen, allein da sie sich nur über Mindanao-
Thiere oder Thiere der nächsten Nachbarschaft verbreitet, so scheint
der Fundort nicht zweifelhaft; ebensowenig sagt T h o m a s (TZS.
XIV, 400), woher das Exemplar stammte, er erwähnt aber die Art
vom Berge Data, Nord Luzon, 7500 Fuss hoch, von wo auch das
Dresdner Museum ein Exemplar von derselben Ausbeute und
demselben Fundort erhielt. An diesem allein kann ich die Identität
feststellen, denn G ü n t h e r s Beschreibung ist ungenügend. Da
nun aber keine wesentlichen Unterschiede zwischen diesem
Exemplar und denen von M. xanthurus von Celébes vorhanden zu
sein scheinen und Mindanao (oder Nachbarschaft) die Brücke
zwischen Celébes und Luzon bildet, so ziehe ich sie zusammen bis
eventuell eine bessere Kenntniss mir Unrecht giebt.

Die Fundorte auf Celébes sind bis jetzt in der Minahassa: Tondano
(Brit. Mus.), Manado, Langowan, Tondano, Kakas, Amurang (Mus.
Leid.), Manado, Amurang, Lotta, Rurukan 3500 Fuss hoch, Berg
Masarang 3500 Fuss hoch (Mus. Dresd.), Berg Kelelonde 4000 Fuss
hoch (Hickson), Tomohon (Sarasins); ausserhalb der Minahassa:
Matinangkette, westlich vom Gorontaloschen (Sarasins); im Süden:
Makassar (Mus. Dresd. und Sarasins).

Die Art muss sehr zahlreich vorkommen nach der relativ grossen
Zahl von Exemplaren im Leidener und Dresdner Museum und in der
Ausbeute der Herren Sarasin zu urtheilen (in Dresden 17).
H i c k s o n erwähnt dies auch für den Berg Kelelonde und sagt,
dass diese Ratten die saftigen Stiele der Kaffeebeeren besonders
lieben und daher den Plantagen sehr schaden. Ratten sind in der
Minahassa eine gesuchte Zuspeise zum Reise, 3 Arten Rattenfallen
von dort befinden sich im Museum der Bataviaasch Genootschap
(Not. XXV, 145 1897 und LIV [1898]), was beides für die Häufigkeit
der Thiere spricht.

Bezüglich der einzelnen Figuren siehe die Tafelerklärung.

[Inhalt]

38. Lenomys meyeri (Jent.)

Tafel VIII. Nat. Grösse

J e1879
n t i n k T. Ned. D. Ver. IV p. LV („7o“) und LVI („5o“, J.
verwies hier irrthümlich auf 6o p. LV = M. callitrichus); id.
NLM. I, 12
H 1887
o f f m a n n Abb. Ber. Dresd. 1886/7 Nr. 3 p. 12, 17, 21,
Tafel Fig. 2 a und b (Zähne); T h o m a s PZS. 514;
J e n t i n k Cat. MPB. IX, 211 pl. VII, 5–8 (Schädel)
 J e1888
n t i n k Cat. MPB. XII, 65
W1894
e b e r Zool. Erg. III, 474
T 1896
h o m a s AMNH. (6) XVIII, 246
T r1897
o u e s s a r t Cat. Mam. 472
T 1898
h o m a s TZS. XIV, 409 Anm., pl. XXXVI, 1 (Zähne).
Lenomys, von den früheren Autoren zu Mus gestellt.
Bälge
a, b.mit Schädel, fem., Tomohon, Minahassa, Nord
Celébes, 6. und 18. III 94.
Skelette,
c, d. mas, fem., Tomohon III 94. [27]
Skelet, e. mas, Kema, Minahassa, Nord Celébes, VIII 93.
mares,
f, g. in Spiritus, Tomohon, III 94.

Die Individuen variiren in der Färbung zwischen mehr Grau und

mehr Braun, auf Tafel VIII ist ein graueres Exemplar abgebildet.

J e n t i n k (NLM. I, 13) sagt, dass die braunen Schnurrhaare weiss

gespitzt seien, allein dies ist bei den mir vorliegenden 8 Exemplaren
(ausser den obigen noch 4 des Dresdner Museums) nicht der Fall,
höchstens dass man bei dem einen oder andern vielleicht eine
schwache Andeutung davon sehen könnte; keinenfalls ist diese
Angabe für die Art charakteristisch.

Bis jetzt nur aus der Minahassa und dem Gorontaloschen bekannt,
aus letzterem von Bone (Mus. Leid.), aus ersterer von Manado-
Langowan (Mus. Leid.), Lotta, Rurukan 3600 Fuss hoch, Berg
Masarang 3500 Fuss hoch, Amurang (Mus. Dresd.) und Tomohon
(Sarasins). Vielleicht ist der Verbreitungsbezirk der Art über Celébes
ein viel grösserer. Wenn man bedenkt, wie lange dieses relativ
grosse Thier aus der Minahassa, wo so viel gesammelt worden ist,
unbekannt blieb, so dürfte diese Vermuthung nicht ungerechtfertigt
erscheinen.
[Inhalt]

39. Craurothrix leucura (Gr.)

Tafel IX. Nat. Grösse

J.1867
E. G r a y PZS. 599 Echiothrix (Schädel abgebildet)
J e1879
n t i n k T. Ned. D. Ver. IV p. LVI. Echiothrix
id.1880
NLM. II, 12. Echiothrix
id.1883
ibid. V, 177. Echiothrix
id.1888
Cat. MPB. XII, 73. Echiothrix
F 1891
l o w e r & L y d e k k e r Intr. Mam. 477 Echinothrix
W1894
e b e r Zool. Erg. III, 474 Echiothrix
T 1896
h o m a s AMNH. (6) XVIII, 246 Craurothrix
T r1897
o u e s s a r t Cat. Mam. 502 Echiothrix.
Balg a. mit Schädel, fem., Tomohon, Minahassa, Nord
Celébes, 11. VII 94
2 fem.,
b–d. 1 mas juv., in Spiritus, Tomohon, IV 94 und IV 95.

Bis jetzt nur von der Minahassa, Nord Celébes, bekannt, und zwar
von den Localitäten Amurang (Mus. Dresd. und Mus. Leid.), Berg
Masarang 3500 Fuss hoch (Mus. Dresd.), Tomohon (Sarasins).
G r a y hatte zwar die Art von Australien beschrieben, aber
T h o m a s desavouirte diesen Fundort. Ob sie auf Celébes eine
grössere Verbreitung hat, wird die Zukunft lehren.

L y d e k k e r (Intr. Mam. 1891, 477) sagt anmerkungsweise, dass er

Echimys Gray in Echinothrix (PZS. 1867, 59) verbessere, allein
G r a y hat Echiothrix, nicht Echimys. T h o m a s schlug 1896 vor,
Craurothrix für Echinothrix zu gebrauchen, da letzterer Name bereits
vergeben sei.
1 Die Farbe der nackten Theile (Füsse etc.) der Ratten auf dieser, wie den
folgenden 3 Tafeln ist mehr oder weniger nach Gutdünken gewählt, da Angaben
darüber nicht vorliegen. ↑
2 Die goldige Ringelung der einzelnen Haare konnte auf der Abbildung (mit
Handkolorit) nicht wiedergegeben werden. ↑
[Inhalt]
Ungulata
 Suidae

[Inhalt]

40. Sus verrucosus celebensis (Müll. Schl.)

Eine a.Kopfhaut mit Schädel eines alten Männchens von

Kalimba am Pik von Bonthain, Süd-Celébes, 26. X 95.
Haut b.eines Weibchens, in Spiritus, aus der Gegend von
Makassar, Süd Celébes.
2 Häute
c, d. mit Schädeln, in Spiritus, von Frischlingen,
l ä n g s g e s t r e i f t , von Kema, Nord-Celébes, XII 94.

Weitere Schädel sind noch in den Händen des Hrn. Dr. S t e h l i n in

Basel, um zusammen mit den Babirusaschädeln der Herren
S a r a s i n (s. unten) bearbeitet zu werden. [28]

Ich weise auf N e h r i n g s Besprechung von Sus celebensis (Abb.

Ber. Dresd. 1888/9 Nr. 2 S. 5–14, Taf. I–II) und bemerke nur, dass
die Sau eine gelbliche Querbinde an der Schnauze und der alte Eber
nur éine Gesichtswarze jederseits besitzt. Im Übrigen scheint mir
F o r s y t h M a j o r ’ s Benennung (AMNH. 6 s. 1897 XIX, 527) die
zweckentsprechendste zu sein. Da das Dresdner Museum
inzwischen ein grösseres Material von Wildschweinen von Nord und
Ost Celébes (im Ganzen jetzt 14 Bälge, 12 Skelette, 4 Schädel, 1
juv. in Spiritus), sowie von den Philippinen erhielt, so hoffe ich darauf
zurückkommen oder das Material Anderen zur Verfügung stellen zu
können.

Die Herren S a r a s i n brachten auch den jungen Schädel mit

Milchgebiss eines Hausschweines von Tomohon, Nord Celébes, mit,
das eventuell vom Wildschwein abstammen könnte.

[Inhalt]

41. Babirusa alfurus Less.

Die Herren S a r a s i n erbeuteten 16 (oder mehr) Babirusa-Schädel

in Celébes, die Hr. Dr. S t e h l i n in Basel zur speciellen Bearbeitung
übernommen hat. Ich benutze aber diese Gelegenheit, indem ich
zugleich auf meine früheren Auseinandersetzungen über Babirusa
alfurus (Abh. Ber. 1896/7 Nr. 6 S. 15–25 Taf. IX) verweise, folgende
Bemerkungen über inzwischen erhaltenes Schädelmaterial zu
machen:

Der (l. c. p. 17) von mir erwähnte angebliche Babirusa-Schädel aus

dem Museum Godeffroy in Hamburg von den Salomo Inseln ist
nunmehr im Leipziger Museum für Völkerkunde aufgefunden
worden, und meine Vermuthung, dass es nur ein Sus-Schädel mit
abnorm gewachsenen unteren Hauern sei, hat sich als richtig
erwiesen (er figurirt im Leipziger Museum jedoch noch als Babirusa-
Schädel). Die oberen Hauer sind frühzeitig entfernt worden, so dass
sich die unteren unbeschränkt entwickeln konnten, allein sie sind in
dieser Entwicklung noch nicht weit vorgeschritten, und die
oberflächliche Ähnlichkeit mit einem Babirusa-Schädel, wenn man
überhaupt von einer solchen reden kann, ist nur im Stand einen
Laien zu täuschen. Übrigens sehe ich nachträglich, dass F i n s c h
dies bereits 1888 (Ethn. Erf. I, 148) richtig gestellt hat. Einen
kreisförmigen Schweinezahn bildete schon E. R o u s s e a u : Anat.
comp. du syst. dent. Paris 1839 T. 20 f. 2 ab.
Hinsichtlich der Frage der o b e r e n E c k z ä h n e b e i d e r
a d u l t e n S a u bemerkte ich l. c. p. 25: „Ob die Normalformel für
den weiblichen Babirusa bezüglich der Eckzähne 0/1 oder 1/1 zu
lauten habe, lässt sich erst sagen, wenn mehr authentische
weibliche Schädel in den Sammlungen sein werden, um zu
erkennen, ob 0/1 oder 1/1 die Ausnahme ist.“ Das Museum erhielt
von der Insel Lembeh bei Nord Celébes einen adulten weiblichen
Schädel (B 3452) von 286 mm Länge, der beiderseits einen mehr
oder weniger horizontal nach vorn und auswärts gerichteten, links
11, rechts 9 mm aus der Alveole hervorragenden, ziemlich spitzen,
oberen Eckzahn hat. Die Alveolarkrämpe (aileron), in der er wurzelt,
ist nicht stärker ausgebildet als bei dem l. c. Taf. IX, 3 von mir
abgebildeten Exemplar ohne oberen Eckzahn. Die Eckzähne des
Unterkiefers ragen links 11, rechts 12 mm aus der Alveole hervor.
Weibliche Schädel sind selten in Museen. Hr. Dr. S t e h l i n theilte
mir mit, dass ihm unter c 80 Schädeln, die er an verschiedenen
Orten gesehen, nur 5 weibliche vorgekommen seien. Sie werden
ihrer Unscheinbarkeit wegen eben an Ort und Stelle nicht
aufbewahrt, während die auffallenden Eckzähne des Männchens
jeden Laien zum Sammeln anregen. Das von mir l. c. p. 24 erwähnte
Leidener semiadulte Exemplar ist nach Dr. S t e h l i n s Ansicht völlig
adult und zeigt auch rechts eine Spur des oberen Eckzahnes in
Form eines Rudimentes; der linke ist zugespitzt. Ein dritter junger
weiblicher Schädel in Leiden, von 177 mm Länge, habe auch keine
Spur eines oberen Eckzahnes, so wenig wie das von mir erwähnte.
Die Herren S a r a s i n hätten aber auch einen alten weiblichen
Schädel mitgebracht mit oberem Eckzahne beiderseits von nicht
ganz 1 cm Länge, ziemlich stumpf, mit einem auf eine sehr mässige
Kante reducirten Alveolarvorsprung.

Ich bin an der Hand dieser Daten jetzt mehr geneigt, c 1/1 für die
Norm und c 0/1 für abnorm anzusehen. Bei seiner Gracilität kann der
Zahn unter Umständen früh ausbrechen oder ist überhaupt deciduös
und sein Fehlen daher, wie in dem von mir l. c. p. 24 beschriebenen
Falle, möglicherweise besser so zu erklären, als durch die Annahme,
dass er nie vorhanden gewesen sei; denn sein Nichtvorhandensein
bei j u n g e n Schädeln mit Milchgebiss oder Resten davon beweist
nicht, dass er nicht schon vorhanden gewesen sein konnte. [29]

In Bezug auf die Z a h n f o r m e l d e s a d u l t e n E b e r s meinte

ich l. c. p. 22, dass es noch sicher gestellt werden müsste, ob in
allen Fällen im definitiven Gebisse 3 Praemolaren auftreten. Das
Dresdner Museum erhielt inzwischen ebenfalls von der Insel
Lembeh bei Nord Celébes einen jungen männlichen Schädel (B
3453) von 249 mm Länge, der in dieser Beziehung lehrreich ist: m 3
überall noch nicht durchgebrochen; im Unterkiefer jederseits 3
Praemolaren, p 3 (der vorderste) aber beiderseits deciduös;
Eckzähne c 22 mm aus der Alveole hervorragend, ihre Wurzeln
reichen aber bereits bis ans hintere Ende von m 2; im Oberkiefer
beiderseits nur 2 Praemolaren, p 3 ist schon ausgefallen, die
Alveolenreste sind jedoch noch vorhanden, und man erkennt hier
deutlich den Grund des Ausfallens: die Wurzeln der Hauer, die c 27
mm aus der Alveole hervorragen, reichen bis an die vordere Wurzel
von p 2 und sind über den alveolaren Löchern der ausgefallenen p 3
sichtbar, sie haben zweifellos das Ausfallen von p 3 mechanisch
bewirkt; p 2 dex. bietet noch die Anomalie, dass er quer steht, die
Längsaxe der Krone ist nicht von vorn nach hinten gerichtet, sondern
von aussen nach innen; der Grund davon liegt zu Tage, indem ein
Praemolar des Milchgebisses zwischen den Alveolen von p 3 und p
2 stehen geblieben ist und noch so fest sitzt, dass man ihn nicht
bewegen kann; p 2 war nicht im Stand ihn hinauszudrängen und hat
sich daher quer stellen müssen. Legt man die Zahnreihen beider
Kiefer aufeinander, so passen sie rechts normal, links aber findet
sich zwischen p 2 und p 1 sup. eine Lücke, da p 2 nicht längs,
sondern quer steht.
Dieser Befund von 3 Praemolaren im Unterkiefer und der sichere
Beweis, dass auch p 3 im Oberkiefer vorhanden gewesen ist, lässt
mich, zusammen mit dem Umstande, dass Hr. Dr. S t e h l i n mir
mittheilt, er habe Spuren von p 3 oder die Zähne selbst öfters
angetroffen, nunmehr annehmen, dass das Vorhandensein von p 3
im Dauergebiss als die Norm zu gelten habe, wenn dieser Zahn
auch meistens früh ausfällt; im Oberkiefer treibt ihn die Wurzel des
Eckzahns mechanisch heraus, im Unterkiefer ist dies bei dem
vorliegenden Schädel (B 3453) nicht der Fall, die Wurzel verläuft im
basalen Theile des Knochens und berührt die Knochen von p 3
nicht.

Endlich bemerke ich über einen auch neuerdings erhaltenen alten

männlichen Schädel (B 3556) von 302 mm Länge aus dem
Gorontaloschen (wo der Babirusa tualangio heisst), dass ihm p 2
sup. sin. fehlt und dass dessen Alveole vollkommen verstrichen ist;
in Folge davon hat sich p 2 inf. sin. abnorm entwickelt, er überragt
mit seiner Spitze die Kaufläche von p 2 um 6 mm, während diese bei
p 2 inf. dex. unter der von p 1 bleibt, und stösst fast an den Rand
des Oberkiefers; p 2 inf. sin. steht mit seiner Basis auch höher als p
1, was wohl ebenfalls eine Folge des fehlenden Antagonisten ist;
denn dass die Wurzel des unteren Hauers die Basis in die Höhe
getrieben haben sollte, ist nicht anzunehmen, weil der
Zwischenraum zwischen ihrer Alveole und dem Kieferrande zu gross
ist. In diesem Fall hat aber auch die Wurzel des oberen Hauers p 2
sup. sin. nicht etwa ausgetrieben, denn ihre Alveole berührt dessen
Basis nicht. Wenn schon, wie wir oben und l. c. p. 22 sahen, p 3
Wechselfällen in höherem Maass ausgesetzt ist, so scheint sich
doch auch p 2 mehr oder weniger, wenn auch seltener, anomal zu
entwickeln, und steht auch dies wohl in Correlation zu dem
aussergewöhnlichen Wachsthume des Eckzahnes.
Bei einem schon länger im Museum aufbewahrten adulten Schädel
von Buru (Nr. 1993), von 284 mm Länge, liegt p 2 sup. sin. nicht
hinter p 2 inf., wie normal, sondern sie stehen übereinander und in
Folge dessen haben sich die Spitzen gegenseitig platt geschliffen.

Was die V e r b r e i t u n g d e s B a b i r u s a anlangt (l. c. p. 15), so

erfuhr ich inzwischen, dass er bei Tolitoli (Nordküste von Celébes)
ganz ausserordentlich häufig vorkomme.
[Inhalt]
 Cervidae

[Inhalt]

42. Cervus moluccensis Q. G.

Schädel,
a, b. mas und fem., von Tomohon, Minahassa, Nord
Celébes, III 94.
Schädel,
c. fem., von der Insel Djampea im Süden von
Celébes.
20d–x.
Geweihe: 1 von Kema (Nord Celébes), 3 von
Tomohon (Nord Celébes), 1 aus der Minahassa, 3 von
der Insel Djampea, 12 ohne nähere Bezeichnung aus der
Umgebung des Tominigolfes (in Gorontalo gekauft).

[30]

R ö r i g (Geweihslg. 1896, 49) hat neuerdings den Hirsch von

Celébes nach einem Geweih artlich als „C. celebensis?“ abgetrennt
und (l. c. Fig. 19) abgebildet; er sagt: „Die Geweihform dieser
Species unterscheidet sich insofern von den eben beschriebenen
(equinus), als die von der Hauptstange abgehende Sprosse nicht
hinten oder innen, sondern an der Aussenseite sich abzweigt, so
dass die dadurch entstehende Gabel nicht seitlich, sondern v o r n
offen ist. Die Träger dieser Geweihe bilden in Bezug hierauf somit
den Übergang zu denjenigen Hirschen, bei denen jene Sprosse auf
der Vorderseite der Stange entspringt und auch nach vorn gerichtet
ist, wie wir es z. B. bei den Molukkenhirschen wahrnehmen“ (vgl.
auch seine schematische Tafel zu S. 16). L y d e k k e r (Deer of all
Lands 1898, 166) nennt den Celébeshirsch C. hippelaphus
moluccensis (Q. G.) und nimmt auf R ö r i g keine Rücksicht.
W e b e r (Zool. Erg. I, 112 1890) führte nach Geweihen den
Celébeshirsch als Russa russa S. Müll. ausser von Süd Celébes von
der Insel Saleyer auf, H i c k s o n (Nat. Cel. 1893, 69) von der Insel
Talisse im Norden von Celébes.

Das S a r a s i n sche Material zusammen mit dem des Dresdner

Museums zeigt, dass R ö r i g s Abtrennung der Celébesform von
moluccensis nicht gerechtfertigt ist. Auch ich erbeutete in Süd
Celébes ein grosses Geweih, das die von R ö r i g namhaft
gemachten Charaktere exquisit zeigt, dagegen andere vom Norden
und Süden, die moluccensis entsprechen. Unter den
S a r a s i n schen sind solche, die sich als Übergänge erweisen. Es
ist nicht möglich, die von R ö r i g beschriebene Geweihform als
Altersform anzusehen, da z. B. ein junges Exemplar von
moluccensis, das ich von Ternate mitbrachte, den Charakter bereits
vorzüglich aufweist. Es giebt auch Geweihe, deren eine Stange
mehr zu moluccensis, die andere mehr zu „celebensis“ hinneigt. Das
Geweih dieses Hirsches variirt jedenfalls stark. Ein Fell aber, das
das Dresdner Museum von Nord Celébes besitzt, stimmt sehr gut
mit der Abbildung von Q u o y & G a i m a r d (Voy. Astr. 1833 I pl. 24,
Text 1830 I, 133), die einen Hirsch von Buru darstellt, so dass ich an
der Artzusammengehörigkeit nicht zweifle.

Die Herren S a r a s i n hatten den Eindruck, als ob, nach dem

Geweih zu urtheilen, der nördliche Celébeshirsch grösser sei als der
südliche, das Dresdner grosse Geweih vom Süden bestätigt dies
nicht, allein Endgültiges lässt sich jetzt noch nicht sagen. Wie
G r a a f l a n d (Minahassa 2. Aufl. 1898 App. p. V) mittheilt, wurde
der Hirsch erst Anfang der dreissiger Jahre dieses Jahrhunderts in
die Minahassa eingeführt, die Sprachen dieser Gegend haben daher
auch keine ursprüngliche Bezeichnung für ihn. Man wird ihn wohl
von den Ländern der Tominibucht angebracht haben. Im Süden ist er
sehr häufig, wie ich gelegentlich einer grossen Treibjagd im Jahr