Neurocritical Care

Second Edition
Neurocritical Care
Second Edition

Edited by
Michel T. Torbey
Department of Neurology, University of New Mexico
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Library of Congress Cataloging-in-Publication Data
Names: Torbey, Michel T., editor.
Title: Neurocritical care / edited by Michel T. Torbey.
Other titles: Neurocritical care (Torbey)
Description: Second edition. | Cambridge, United Kingdom ; New York, NY :
Cambridge University Press, 2019. | Includes bibliographical references
and index.
Identifiers: LCCN 2018059107 | ISBN 9781107064959 (hardback : alk. paper)
Subjects: | MESH: Nervous System Diseases–therapy | Critical Care–methods |
Intensive Care Units
Classification: LCC RC86.7 | NLM WL 140 | DDC 616.02/8–dc23
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ISBN 978-1-107-06495-9 Hardback
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Nevertheless, the authors, editors, and publishers can make no warranties that
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Contents
List of Contributors vii
Preface xi
1 The Neurological Assessment of the Critically Ill
Patient 1
Abdo Barakat and Diana Greene-Chandos
2 Cerebral Blood Flow Physiology and Metabolism in
the Neurocritical Care Unit 11
Rajat Dhar and Michael Diringer
3 Cerebral Edema and Intracranial Pressure in the
Neurocritical Care Unit 19
Shivani Ghosal and Kevin N. Sheth
4 Hypothermia in the Neurocritical Care Unit:
Physiology and Applications 28
Karina Woodling, Archana Hinduja, and Michel
T. Torbey
5 Analgesia, Sedation, and Paralysis in the Neurocritical
Care Unit 33
Yousef Hannawi and Wendy C. Ziai
6 Airway Management and Mechanical Ventilation in
the Neurocritical Care Unit 50
David B. Seder and Julian Bösel
7 Neuropharmacology in the Neurocritical Care
Unit 62
Sarah M. Adriance
8 Intracranial Monitoring in the Neurocritical Care
Unit 78
Chad M. Miller
9 Electrophysiologic Monitoring in the Neurocritical
Care Unit 86
Anh T. Nguyen and Asma Zakaria
10 The Role of Transcranial Doppler as a Monitoring
Tool in the Neurocritical Care Unit 92
Maher Saqqur, David Zygun, and Andrew Demchuk
11 Ischemic Stroke in the Neurocritical Care Unit 103
Julian Bösel
12 Intracerebral Hemorrhage in the Neurocritical Care
Unit 129
Xuemei Cai and Jonathan Rosand
13 Management of Cerebral Venous Thrombosis in the
Neurocritical Care Unit 146
Xiaomeng Xu, Xiaoying Yao, and Magdy Selim
14 Subarachnoid Hemorrhage in the Neurocritical Care
Unit 154
Katja E. Wartenberg and Stephan A. Mayer
15 Status Epilepticus in the Neurocritical Care Unit 176
Fawaz Al-Mufti and Jan Claassen
16 Neuromuscular Disorders in the Neurocritical Care
Unit 188
Christopher L. Kramer, Edward M. Manno, and Alejandro
A. Rabinstein
17 Management of Head Trauma in the Neurocritical
Care Unit 199
Peter Le Roux
18 Management of Autoimmune Encephalitis in the
Neurocritical Care Unit 233
Murat Sari, Diana Greene-Chandos, and Michel T. Torbey
19 Management of Cerebral Salt-Wasting Syndrome and
Syndrome of Inappropriate Antidiuresis in the
Neurocritical Care Unit 238
Wendy Wright
20 Brain Death in the Neurocritical Care Unit 247
Mark M. Landreneau and David M. Greer
21 Neuroterrorism and Drug Overdose in the
Neurocritical Care Unit 254
John J. Lewin III, Mohit Datta, and Geoffrey S. F. Ling
22 Infections of the Central Nervous System in the
Neurocritical Care Unit 269
Mohamed Sharaby and Barnett R. Nathan
23 Management of the Spinal Cord Injury in the
Neurocritical Care Unit 290
Kristine O’Phelan and Indira De Jesus
24 Postoperative Management in the Neurocritical Care
Unit 299
Ryan A. Grant, Andy J. Redmond, and Veronica L. Chiang
v
 Contents
25 Ethical Considerations in the Neurocritical Care
Unit 314
Fred Rincon
26 Pulmonary Consult: Management of Severe Hypoxia in
the Neurocritical Care Unit 324
Rafael A. Calderón Candelario, Matthew C. Exline, and
Naeem A. Ali
27 Management of Refractory Arrhythmias in the
Neurocritical Care Unit 335
Mahmoud Houmsse and Dilesh Patel
28 An Infectious Diseases Consult in the Neurocritical
Care Unit 351
Michael Frank and Mary Beth Graham
29 A Nephrology Consult in the Neurocritical Care
Unit 359
Jason Prosek and Nabil Haddad
30 Management of Hepatic Encephalopathy in the
Neurocritical Care Unit 370
Stephen M. Riordan and Roger Williams
31 Hypoxic Encephalopathy in the Neurocritical Care
Unit 382
Maximilian Mulder and Romergryko G. Geocadin
vi
32 Management of Delirium in the Neurocritical Care
Unit 392
Diana Greene-Chandos and Michel T. Torbey
33 Generalized Weakness in the Neurocritical Care
Unit 397
Farrukh S. Chaudhry and Edward M. Manno
34 Management of Severely Brain-Injured Patients
Recovering from Coma in the Neurocritical Care
Unit 404
Caroline Schnakers and Martin M. Monti
35 Acute Demyelinating Disorders in the Neurocritical
Care Unit 414
Lauren Koffman and Joao A. Gomes
36 Building a Case for a Neurocritical Care Unit 421
Panayiotis N. Varelas and Efstathios Papavassiliou
37 Neurointensive (NCCU) Care Business Planning 430
Sara Widing and Noah Grose
Index 442
Color plates are to be found between pp. 228 and 229
Contributors

Sarah M. Adriance, PharmD, BCPS Mohit Datta, MD

Specialty Practice Pharmacist, Neurocritical Care, Department
of Pharmacy, The Ohio State University Wexner Medical
Center, Columbus, OH, USA
Naeem A. Ali, MD
The Ohio State University Wexner Medical Center, Columbus,
OH, USA
Fawaz Al-Mufti, MD
Department of Neurology, Robert Wood Johnson University
Hospital, New Brunswick, NJ, USA
Abdo Barakat, MD
University of Minnesota, Anesthesiology Department, MN, USA
Julian Bösel, MD
Department of Neurology, Klinikum Kassel, Kassel, Germany
Xuemei Cai, MD
Massachusetts General Hospital, Boston, MA, USA
Palmetto Health USC, Columbia, SC, USA
Indira De Jesus, MD
Neurology, Christiana Care Health System, De, USA
Andrew Demchuk, MD, FRCPC
Department of Clinical Neurosciences, University of Calgary,
Calgary, Alberta, Canada
Rajat Dhar, MD
Department of Neurology (Division of Neurocritical Care),
Washington University in St. Louis, Saint Louis, MO, USA
Michael Diringer, MD
Department of Neurology (Division of Neurocritical Care),
Washington University in St. Louis, Saint Louis, MO, USA
Matthew C. Exline, MD
The Ohio State University Wexner Medical Center, Columbus,
OH, USA

Rafael A. Calderón Candelario, MD, MSc Michael Frank, MD

University of Miami, Miller School of Medicine, Miami,
FL, USA
Farrukh S. Chaudhry, MD
Department of Neurology and Rehabilitation, The University
of Illinois College of Medicine, Chicago, IL, USA
Veronica L. Chiang, MD
Yale-New Haven Hospital, Yale University, New Haven,
CT, USA
Jan Claassen, MD, PhD, FNCS
Neurological Intensive Care Unit, Columbia University
College of Physicians and Surgeons, New York, NY, USA
Medical College of Wisconsin, Milwaukee, WI, USA
Romergryko G. Geocadin, MD
Johns Hopkins Medical Institutions, Baltimore, MD, USA
Shivani Ghosal, MD
New York-Presbyterian Hospital, New York, NY, USA
Joao A. Gomes, MD
Lerner College of Medicine, Cerebrovascular Center,
Cleveland Clinic, Cleveland, OH, USA
Mary Beth Graham, MD
Medical College of Wisconsin, Milwaukee, WI, USA

vii
 List of Contributors

Ryan A. Grant, MD, MS John J. Lewin III, PharmD, MBA, FASHP, FCCM
Yale-New Haven Hospital, Yale University, New Haven, Departments of Pharmacy, Anesthesiology and Critical Care
CT, USA Medicine, Johns Hopkins Medical Institutions, Baltimore,
MD, USA
Diana Greene-Chandos, MD
Department of Neurology and Neurosurgery, Geoffrey S. F. Ling, MD, PhD, FAAN, FANA
Cerebrovascular and Neurocritical Care Division, Departments of Anesthesiology and Critical Care Medicine
The Ohio State University, College of Medicine, Columbus, and Neurology, Johns Hopkins Medical Institutions,
OH, USA Baltimore, Department of Neurology, Uniformed Services
University of the Health Sciences, Bethesda, MD, USA
David M. Greer, MD, MA, FCCM, FAHA, FNCS
Boston University, Boston, MA, USA Edward M. Manno, MD
Department of Neurology, Feinberg School of Medicine,
Noah Grose, RN, BSN, MSN, ACNP-BC Northwestern University, IL, USA
The Ohio State University Wexner Medical Center, Columbus,
OH, USA Stephan A. Mayer, MD, FCCM
Department of Neurology, Henry Ford Health System, Detroit,
Nabil Haddad, MD MI, USA
The Ohio State University Wexner Medical Center, Columbus,
OH, USA Chad M. Miller, MD
Neurocritical Care, Riverside Methodist Hospital, Columbus,
Yousef Hannawi, MD OH, USA
Division of Cerebrovascular Diseases and Neurocritical Care,
Department of Neurology, The Ohio State University, Martin M. Monti, PhD
Columbus, OH, USA Department of Psychology, University of California Los
Angeles, Department of Neurosurgery, David Geffen School
Archana Hinduja, MD of Medicine at University of California Los Angeles,
Department of Neurology, Cerebrovascular and Neurocritical CA, USA
Care Division, The Ohio State University, College of Medicine,
Columbus, OH, USA Maximilian Mulder, MD
Abbott Northwestern Hospital, Minneapolis, MN, USA
Mahmoud Houmsse, MD, FACP, FACC
The Ohio State University Wexner Medical Center, Columbus, Barnett R. Nathan, MD
OH, USA Departments of Neurology and Internal Medicine, University
of Virginia, Charlottesville, VA, USA
Lauren Koffman, DO
Department of Neurology, Rush University Medical Center, Anh T. Nguyen, MD
Chicago, IL, USA Neurologic Institute, Houston Methodist Hospital, Houston,
TX, USA
Christopher L. Kramer, MD
Department of Neurology and Surgery Kristine O’Phelan, MD
(Neurosurgery), University of Chicago Medical Center, University of Miami Hospital, Miami, FL, USA
Chicago, IL, USA
Efstathios Papavassiliou, MD
Mark M. Landreneau, MD Department of Neurosurgery, Beth Israel Deaconess Hospital,
Yale University School of Medicine, New Haven, CT, USA Boston, MA, USA

Peter Le Roux, MD, FACS Dilesh Patel, MD

Brain and Spine Center, Lankenau Medical Center, Ohio State University Wexner Medical Center, Columbus,
Wynnewood, PA, USA OH, USA

viii

Jason Prosek, MD
Ohio State University Wexner Medical Center, Columbus,
OH, USA
Alejandro A. Rabinstein, MD
Mayo Clinic, Rochester, MN, USA
Andy J. Redmond, MD
Christus Mother Frances Hospital-Tyler, Tyler, TX, USA
Fred Rincon, MD, MSc, MBEthics, FACP, FCCP, FCCM, FNCS
Thomas Jefferson University, Philadelphia, PA, USA
Stephen M. Riordan, MBBS (Hons), MD, FRACP, FRCP
Gastrointestinal and Liver Unit, Prince of Wales Hospital and
Prince of Wales Clinical School, University of New South
Wales, Sydney, Australia
Jonathan Rosand, MD, MSc
Neuroscience and Intensive Care Unit, Massachusetts General
Hospital, Boston, MA, USA
Maher Saqqur, MD, MPH, FRCPC
Department of Medicine, Division of Neurology, University of
Alberta, Edmonton, Alberta, Canada
Murat Sari, MD
Department of Neurology, Cerebrovascular and Neurocritical
Care Division, The Ohio State University, College of Medicine,
Colombus, OH, USA
Caroline Schnakers, PhD
Department of Psychology, University of California Los
Angeles, Department of Neurosurgery, David Geffen School
of Medicine at University of California, Los Angeles, CA, USA
David B. Seder, MD, FCCP, FCCM
Department of Critical Care Services, Maine Medical Center,
Portland, ME, USA
Magdy Selim, MD, PhD
Beth Israel Deaconess Medical Center / Harvard Medical
School, Boston, MA, USA
Mohamed Sharaby, MD
Neurocritical Care, University of Virginia Health System,
Charlottesville, VA, USA
Kevin N. Sheth, MD, FAHA, FCCM, FNCS, FAAN, FANA
Department of Neurology, Yale New Haven Hospital, New
Haven, CT, USA
List of Contributors
Michel T. Torbey, MD, MPH, FCCM, FAHA
Department of Neurology, The University of New Mexico,
Albuquerque, NM, USA
Panayiotis N. Varelas, MD, PhD
Departments of Neurology and Neurosurgery, Henry Ford
Hospital, Detroit, MI, USA
Katja E. Wartenberg, MD, PhD
University of Leipzig, Leipzig, Germany
Sara T. R. Widing, MHA
Joe DiMaggio Children’s Hospital, Orlando, FL, USA
Roger Williams CBE, MD, FRCP, FRCS, FRCPE, FRACP,
F Med Sci, FRCPI (Hon), FACP (Hon)
Institute of Hepatology, Foundation for Liver Research,
London, and Faculty of Life Sciences and Medicine, King’s
College, London, UK
Karina Woodling, MD
Department of Neurology, Cerebrovascular and Neurocritical
Care Division, Ohio State University, College of Medicine,
Columbus, OH, USA
Wendy Wright, MD, FCCM, FNCS
Emory University School of Medicine, Atlanta, GA, USA
Xiaomeng Xu, PhD
Beth Israel Deaconess Medical Center, Boston, MA, USA
Xiaoying Yao, MD
El Camino Hospital, Mountain View, CA, USA
Asma Zakaria, MD
Division of Medical Critical Care Services,
Department of Medicine, Inova Fairfax Hospital, Falls Church,
VA, USA
Wendy C. Ziai, MD, MPH
Division of Neurosciences Intensive Care, Department of
Anesthesiology and Critical Care Medicine and
Department of Neurology, Johns Hopkins University,
Baltimore, MD, USA
David Zygun, MD, MSc, FRCPC
Departments of Critical Care Medicine, Clinical Neurosciences
and Community Health Sciences, University of Calgary,
Calgary, Alberta, Canada
ix
Preface
Management of critically ill neurologic and neurosurgical
patients can be challenging. The complexity of the brain and
how it reacts to different physiological stressors continues to
present itself as a black box, even to the seasoned intensivist.
The “Neurocritical Care” book has been produced to provide
all healthcare professionals caring for critically ill neurologic
and neurosurgical patients with a straightforward, concise, and
practical reference to assist them with management decisions.
A lot of changes in the field of neurocritical care have
happened since the first edition of the book. Neurocritical care
units exist now in most academic centers. Quality practice
parameters are being defined. Board certification in neurocri-
tical care is more common. Nonetheless, education needs
continue to be in high demand.
The book is intentionally limited in depth, but comprehen-
sive in scope. The emphasis has been placed on discussing day-
to-day management issues that are commonly seen in the
neurocritical care unit addressing both medical and neuro-
specific management issues.
Upon completion of this book, the reader should be able to
understand the nuances in neurocritical care patients and
determine the most effective therapy to limit secondary brain
injury.
I would like to express my deepest gratitude to the authors,
neurocritical nurses and fellows, families, and particularly
the patients who continue to stimulate my passion for
neurocritical care.
xi
 Chapter
The Neurological Assessment of the
1 Critically Ill Patient
Abdo Barakat and Diana Greene-Chandos
Critically ill patients admitted to the intensive care unit (ICU)
may exhibit signs and symptoms of primary or secondary neuro-
logical disorders. Factors such as altered mental status, agitation,
pain, sedation, neuromuscular blockade, hypothermia, metabolic
disturbances, intubation/mechanical ventilation, and surgical or
traumatic lesions of the extremities may complicate the inter-
pretation of the neurological assessment in the ICU. Neverthe-
less, neurological signs in the critically ill have been established as
prognostic indicators and markers of severity. Subsequently, a
proper neurological assessment of the critically ill patient
remains a central aspect of care, diagnosis, and prognosis [1].
General Approach to the Neurological
Assessment
1. History: Obtaining a history from the patient, family,
friends, or witnesses is invaluable. Investigate the context of
the presenting illness, the chronological sequence of events,
any past medical history, medications, or allergies.
2. General medical exam: A general medical exam and
assessment of vital signs should always precede the
neurological exam.
3. Level of consciousness: The level of consciousness can be
described using three parameters: awake, alert, and aware.
Albeit simplistic, this approach is a valid method of
evaluating the level of consciousness, and subsequently
guiding the neurological exam. Table 1.1 offers definitions
of various states of altered consciousness.
• Conscious patient:
• Proceed with the traditional neurological examination
including cognition, cranial nerves, motor and
sensory function, reflexes, and coordination.
• Adapt the exam to the underlying neurological
process [1].
• Serial examinations offer insight into potential
trends of improvement or worsening [1].
• Sedated patient:
• Assess the feasibility of interrupting sedation.
• Score delirium, coma, and muscular strength using
validated scales following interruption[1,2,3].
• Comatose patient:
• Assess the level of arousal, brainstem function,
motor responses, and respiratory pattern [2].
• This can be achieved by means of validated scoring
systems, mainly the Glasgow Coma Scale (GCS) [4]
or the Full Outline of UnResponsiveness (FOUR)
scale [5] (Table 1.2).
4. Every patient admitted to the ICU should receive a
baseline neurological assessment, followed by serial exams
on a daily basis at a minimum. A higher frequency can
be tailored to the individual needs of every critically ill
patient [1].
Sedation
Sedation can mask certain neurological signs of progression
or deterioration towards life-threatening events, especially in
patients with primary neurological injury [6]. Accordingly,
continued sedation is not only a potential confounding factor
in the neurological assessment, but also a risk for missing
certain neurological complications of other systemic diseases
such as ischemia, leukoencephalopathy, or hemorrhage sec-
ondary to septic shock[7,8]. Moreover, sedation was found to
be an independently modifiable risk factor in terms of time-to-
extubation and mortality [8]. Studies have shown that in the
case of mechanically ventilated patients, routine interruption
of continuous sedation (ICS) is recommended and leads to
reductions in the amount of time spent in the ICU and in the
risk of developing complications secondary to prolonged
mechanical ventilation[1,8,9–11].
Critically ill patients with elevated intracranial pressure
(ICP) are the exception to the above recommendation, and
routine ICS should be deferred [1]. Nevertheless, a focused
neurological exam could still offer meaningful information, as
brainstem reflexes can still be assessed in the context of sed-
ation and any abnormalities carry prognostic significance [12].
Delirium
Delirious states can be commonly found in patients suffering
from diffuse toxic, metabolic, or multifocal injuries to the
central nervous system[2]. Its manifestations are the result
1
 Chapter 1: The Neurological Assessment of the Critically Ill Patient

Table 1.1 States of altered consciousness

States of acutely altered consciousness States of subacute or chronic alterations in consciousness

Clouding of consciousness: a state with reduced wakefulness,
awareness, or attention
Delirium: a floridly abnormal mental state characterized by
disorientation, fear, irritability, misperception of sensory stimuli, and
often, visual hallucinations
Obtundation: a state of mental blunting and torpidity, characterized
by reduction in alertness, slower psychological responses to
stimulation, and increased sleep time
Stupor: a condition of deep sleep or behaviorally similar
unresponsiveness from which the subject can be aroused only by
vigorous stimuli
Coma: a state of unarousable unresponsiveness in which the subject
lies with eyes closed
Adapted from reference [2].
Dementia: not accompanied by reduction in arousal
Hypersomnia; a state characterized by excessive but normal-
appearing sleep from which the subject readily, even if briefly,
awakens when stimulated
Vegetative state: a return of wakefulness after severe brain injury
accompanied by an apparent total lack of cognitive function
Brain death: a state in which all functions of the brain, including
cortical, subcortical, and brainstem functions, are permanently lost
Others; akinetic mutism, apallic syndrome, locked-in syndrome

Table 1.2 Glasgow Coma Scale (GCS) and Full Outline of UnResponsiveness (FOUR) scores

Glasgow Coma Scale FOUR score

Eye response 4 = eyes open spontaneously 4= eyelids open or opened, tracking, or blinking to command
3 = eyes opening to verbal command 3= eyelids open but not tracking
2 = eyes opening to pain 2= eyelids closed but open to loud voice
1 = no eyes opening 1= eyelids closed but open to pain
0= eyelids remain closed with pain
Motor response 6 = obeys commands 4= thumbs-up, fist, or peace sign
5 = localizing pain 3= localizing to pain
4 = withdrawal from pain 2= flexion response to pain
3 = flexion response to pain 1= extension response to pain
2 = extension response to pain 0= no response to pain or generalized myoclonus status
1 = no motor response
Verbal response 5 = oriented
4 = confused
3 = inappropriate words
2 = incomprehensible sounds
1 = no verbal response
Brainstem reflexes 4= pupil and corneal reflexes present
3= one pupil wide and fixed
2= pupil or corneal reflexes absent
1= pupil and corneal reflexes absent
0= absent pupil, corneal and cough reflex
Respiration 4= not intubated, regular breathing pattern
3= not intubated, Cheyne–Stokes breathing pattern
2= not intubated, irregular breathing
1= breathes above ventilator rate
0= breathes at ventilator rate or apnea
Max–min 15–3 16–0

of depression in overall brain functioning or bilateral involve- Delirium is a common problem in the intensive care
ment of the limbic structures [2]. Delirium is associated with a unit (ICU). Accurate diagnosis is limited by the difficulty
number of risk factors, as well as certain outcomes that make of communicating with mechanically ventilated patients
its timely diagnosis clinically important. [13]. Nevertheless, a number of studies have shown

2
 Chapter 1: The Neurological Assessment of the Critically Ill Patient

Figure 1.1 Richmond Agitation-Sedation Scale (RASS)

Scale Label Description (reproduced with permission).

+4 COMBATIVE Combative, violent, immediate danger to staff

+3 VERY AGITATED Pulls to remove tubes or catheters; aggressive
+2 AGITATED Frequent non-purposeful movement, fights ventilator
+1 RESTLESS Anxious, apprehensive, movements not aggressive
0 ALERT & CALM Spontaneously pays attention to caregiver
-1 DROWSY Not fully alert, but has sustained awakening to voice V
(eye opening & contact >10 sec) O
-2 LIGHT SEDATION Briefly awakens to voice (eyes open & contact <10 sec) I
C
-3 MODERATE SEDATION Movement or eye opening to voice (no eye contact) E

If RASS is ≥ -3 proceed to CAM-ICU (Is patient CAM-ICU positive or negative?)

T
-4 DEEP SEDATION No response to voice, but movement or eye opening O
to physical stimulation
U
-5 UNAROUSABLE No response to voice or physical stimulation C
H
If RASS is -4 or -5 Æ STOP (patient unconscious), RECHECK later

Sessler, et al., Am J Repir Crit Care Med 2002, 166: 1338-1344 Ely, et al., JAMA 2003; 286. 2983-2991

CAM-ICU Worksheet Figure 1.2 CAM-ICU worksheet (reproduced with permission).

Check here
Feature 1: Acute Onset or Fluctuating Course Score if Present
Is the patient different than his/her baseline mental status?
OR Either
Has the patient had any fluctuation in mental status in the past 24 hours as question Yes
evidenced by fluctuation on a sedation/level of consciousness scale (i.e., →
RASS/SAS), GCS, or previous delirium assessment?
Feature 2: Inattention
Letters Attention Test (See training manual for alternate Pictures)
Directions: Say to the patient, “ I am going to read you a series of 10 letters.
Whenever you hear the letter ‘A,’ indicate by squeezing my hand.” Read Number of
letters from the following letter list in a normal tone 3 seconds apart. Errors >2 →

S A V E A H A A R T or CASABLANCA o r A B A D B A D A AY
Errors are counted when patient fails to squeeze on the letter “A” and
when the patient squeezes on any letter other than “A.”
Feature 3: Altered Level of Consciousness
RASS
Present if the Actual RASS score is anything other than alert and calm (zero) anything other
than zero →

Feature 4: Disorganized Thinking

Yes/No Questions (See training manual for alternate set of questions)

1. Will a stone float on water?

2. Are there fish in the sea?
3. Does one pound weigh more than two pounds?
4. Can you use a hammer to pound a nail?
Combined
Errors are counted when the patient incorrectly answers a question. number of
Command errors >1®
Say to patient: “Hold up this many fingers” (Hold 2 fingers in front of patient)
“Now do the same thing with the other hand” (Do not repeat number of
nd
fingers) *If the patient is unable to move both arms, for 2 part of command
ask patient to “Add one more finger”
An error is counted if patient is unable to complete the entire command.

Criteria Met →
CAM-ICU
Positive
Overall CAM-ICU
(Delirium Present)
Feature 1 plus 2 and either 3 or 4 present = CAM-ICU positive Criteria Not Met →
CAM-ICU
Negative
(No Delirium)

Copyright © 2002, E. Wesley Ely, MD, MPH and Vanderbilt University, all rights reserved

that an accurate diagnosis is still feasible in the ICU care unit recommend that all adult ICU patients be regularly
setting [13,14] assessed for delirium using either the Confusion Assessment
Recent clinical practice guidelines for the management of method for the ICU (CAM-ICU) or the Intensive Care Delir-
pain, agitation, and delirium in adult patients in the intensive ium Screening Checklist (ICDSC) [14]. It is recommended to

3
 Chapter 1: The Neurological Assessment of the Critically Ill Patient
assess for delirium at repeated intervals in order to improve
diagnostic sensitivity and monitor response to interventions
[1]. The suggested assessment includes two steps:
• Step 1: Sedation assessment using the Richmond Agitation-
Sedation Scale [15] (Figure 1.1)
• Step 2: Delirium assessment using the CAM-ICU [13] or
the ICDSC [16]. Delirium should only be assessed after the
interruption of sedation in order to distinguish it from
persistent sedation [16] (Figure 1.2).
Stupor and Coma
Assessing a critically ill patient with impaired consciousness
is no simple feat. Stupor and coma can be manifestations
of a wide array of disturbances, and a systematic approach
to assessment and diagnosis is crucial, especially in the case
of reversible causes [17]. To note, the priority before obtaining
any answers is to evaluate for and secure neuro-protection
by stabilizing the patient [2,17]. The pathophysiology of
impaired consciousness can be divided into two broad mechan-
isms [2,18]:
1. Depressed functioning of the cerebral hemispheres (+/– some
brainstem structures); diffuse bilateral hemisphere damage
2. Injury to brainstem (reticular) activating mechanisms.
These mechanisms can alternatively be explained by disturb-
ances that either cause structural brain lesions or diffuse neur-
onal dysfunction [17]. A rare group of conditions can mimic
coma, such as psychogenic unresponsiveness secondary to cata-
tonia or conversion reactions [2]. Those conditions still deserve
a full medical and neurological assessment to rule out the
presence of a structural or organic disturbance that might
present with psychogenic features. For instance, a bilateral thal-
amic stroke can be misdiagnosed as a conversion reaction [17].
Assessing a Patient with Impaired Consciousness
A structured and systematic approach to the assessment of a
comatose patient (or any patient with impaired consciousness)
can prove useful.
1. Initial Stabilization
The initial stabilization of a critically ill patient presenting
with impaired consciousness should be the primary objective
of the ICU team. Patient stabilization includes the following
[2,17,19]:
• Ensuring patent airways
• Supporting breathing and ventilation (oxygen saturation
96%)
• Aspiration prevention
• Maintaining circulation: IV access, blood pressure
management
• Drawing blood for analysis and cultures (if febrile)
• Immobilizing the cervical spine until it is cleared
• Empiric treatment for infection if suspected on admission
4
• Lowering intracranial pressure: elevate the head of the bed
to 30° if increasing ICP; flatten it if suspecting a posterior
circulation stroke
• Seizure control if clinically indicated
• Administering thiamine and giving glucose pending
lab tests
• Adjusting body temperature
• Restoring acid–base and electrolyte balance
• Considering antidotes if a drug overdose is suspected
(routine administration of antidotes is not recommended;
supportive care is superior)
2. Initial Assessment
• History: Obtain a history from relatives, friends, witnesses,
or even law enforcement officials
• Physical exam:
• Vital signs: any abnormality in vital signs is significant
to the diagnosis and/or management
• General physical exam: signs of nuchal rigidity, trauma,
acute or chronic systemic illness, drug or poison
ingestion [2,17,18]
• Focused neurological exam (detailed in Section
3. below)
• Laboratory tests and ECG [17,20]. Some initial tests may
include some or all of the following depending on the
clinical setting [20]:
• Complete blood count with differential, erythrocyte
sedimentation rate (ESR), and C-reactive protein (CRP)
• Serum electrolytes, blood urea nitrogen (BUN),
creatinine, glucose
• Thyroid, parathyroid, and adrenal function tests
• Liver function tests, amylase, lipase, ammonia
• Troponin levels
• Arterial blood gases with lactate level
• Cerebrospinal fluid evaluation, including cytology
• Body fluid cultures (blood, urine, stool, sputum, CSF)
• Culture of indwelling catheters
• Serum and urine toxicology
• Antiepileptic drug levels
• Heavy metals.
3. Focused Neurological Exam
Critically ill patients with impaired consciousness have limited
to no ability to cooperate with the examiner. Given techno-
logical advances, it might be tempting to resort prematurely to
neuroimaging or neurophysiologic testing. However, a focused
neurological exam remains the cornerstone of the initial
assessment, guides the choice of advanced testing, and most
importantly, allows the proper interpretation of findings on
those more sophisticated tests [18]. In the ICU setting, such an
exam aims at localizing the anatomy and depth of coma by
unveiling certain lateralizing or focal signs, as well as high-
lighting any brainstem dysfunction [17].
 Chapter 1: The Neurological Assessment of the Critically Ill Patient
GCS and FOUR Score
One way to proceed with the examination is to quantify the
depth of coma by using validated scoring systems that evaluate
some or all of the following: the level of consciousness, motor
responses, brainstem function, and respiratory patterns [2].
The Glasgow Coma Scale (GCS) and the Full Outline Of
UnResponsiveness (FOUR) score have been the most widely
used [4,5]. The GCS has been utilized in intensive care settings
for decades. It measures verbal responses, motor responses,
and eye opening by scoring the best responses to graded
stimuli, with the aim of defining the depth and duration of
impaired consciousness and coma [2,4]. Two main limitations
to that system are the inability to properly assess intubated or
aphasic patients, and the fact that the score does not include a
component to score brainstem functioning[5]. The FOUR
score was subsequently designed to account for those limita-
tions by incorporating breathing patterns and brainstem
testing[5]. The FOUR score also allows further assessment of
patients with the lowest GCS score (GCS = 3), and is able to
identify locked-in syndrome as well as herniation processes
[5,21]. Multiple prospective studies showed that both scores
had good overall performance, and both remain valid methods
to be used in the ICU [1,20,22]. The added benefit of the
FOUR score is its robust predictive value in the prognosis of
poor outcome [20].
Table 1.2 illustrates both scoring systems. Documenting
the score of every component separately offers added clinical
value compared to a total sum of scored components [17].
Respiratory Patterns
An abnormal respiratory status can lead to hypoxemia, acid–
base disturbances, and electrolyte imbalances, all of which
can contribute to the progression of neurological damage.
The breathing pattern can also offer some localizing infor-
mation, but it has to be interpreted in the context of other
signs, as there can be overlap (Table 1.3).
The Eye Exam
• Observe the resting position of the eyes, and note any
conjugate or disconjugate deviation (Table 1.4).
• Note any spontaneous eye movements (Table 1.5)
• Inspect both pupils in terms of size, shape, and symmetry.
Note the presence of anisocoria, if any (i.e. difference in
pupil size >1 mm).
• Perform a fundoscopy to assess for subhyaloid
hemorrhages, hypertensive retinopathy, and papilledema
[17,18]. The absence of papilledema does not rule out
elevated ICP [18]. The presence of venous pulsations is
characteristic of a normal ICP, but their absence is less
meaningful [17].
• Ocular ultrasonography of the optic nerve sheath with a
high-frequency probe can offer accurate measurement of
ICP when fundoscopy is not revealing, but suspicion is
high [17].
Brainstem Reflexes
Brainstem reflexes not only help localize lesions, but also help
guide the need for supportive care in the critically ill patient.
Compared to abnormal motor responses, brainstem reflexes
are more useful in localization as they can be traced back to the
location of the cranial nerve nuclei involved [17] (Table 1.6).
Of note, abnormal brainstem reflexes need not solely arise
from intrinsic brainstem pathologies, but also from extrinsic
processes exerting a mass effect on the brainstem, as in the case
of herniation syndromes[17]. The main reflexes discussed in
this section are: pupillary responses, eyelid and corneal
reflexes, oculocephalic and oculovestibular reflexes, and gag
and cough reflexes.
Pupillary Responses – – In addition to inspecting pupil size,
shape, and symmetry, pupillary responses (Afferent: CN II –
Efferent: CN III) should be assessed to evaluate the functioning
of CN II and III, the presence of central autonomic disturb-
ances such as Horner’s syndrome, and to distinguish structural
from metabolic causes [18]. Shine a light into one pupil, and
also into the other pupil. Note if the pupils are equally reactive
or unreactive, if the response is brisk or sluggish, and if it is
consensual (Figure 1.3). Confounding factors that should be
noted include: previous ocular injury and recent use of
mydriatics or other drugs, such as atropine or dopamine [18].
Eyelid and Corneal Reflexes
• Observe the position of the eyelids. In most cases of
impaired consciousness, the eyes will be closed. Open
the eyes by lifting the eyelids and release them.
A normal response would be a gradual return to
baseline position. Failure to close back to baseline on
either side points towards an ipsilateral facial nerve
dysfunction [2].
• Observe blinking. Spontaneous blinking is suggestive of an
intact pontine reticular formation. Unilateral absence of
blinking is suggestive of ipsilateral facial nerve dysfunction.
The complete absence of blinking points towards a structural
or metabolic process affecting the reticular formation [2].
• The corneal reflex (Afferent: CN V – Efferent: CN VII) is
tested by touching the edge of the eye (not over the iris)
with a cotton wisp, a tissue, or other soft material. Brushing
the eyelashes or tickling the inside of the nose can also elicit
a sensorimotor reflex. The following responses can be
observed [2]:
• Eyelid closure; suggestive of an intact facial nerve and
CN VII nucleus
• Bell’s phenomenon; a conjugate upward deviation of
the eyes indicating intact brainstem pathways from the
CN III nucleus in the midbrain to the CN VII nucleus
in the lower pons
• Contralateral jaw deviation (corneal pterygoid reflex); a
phenomenon that may occur when a lesion injures the
trigeminal nucleus above the mid-pons. In this case,
Bell’s phenomenon disappears.
5
 Chapter 1: The Neurological Assessment of the Critically Ill Patient

Table 1.3 Respiratory patterns in brain injury [2,17]

Respiratory pattern Area of concern

Normal Patient awake Small and unilateral lesion

Cheyne–Stokes Hyperpneic phase lasts Large bilateral hemispheric; metabolic

longer than the apneic brain dysfunction
phase
Cheyne–Stokes Shorter apneic phase Large unilateral injuries
variant

Central neurogenic Sustained, regular, rapid,
hyperventilation fairly deep hyperpnea
Apneustic Prolonged inspiratory phase
or pauses alternative with
expiratory pauses
Cluster Clusters of breath separated
by irregular pauses
Lower midbrain; upper pons; systemic
hypoxia; metabolic acidosis; often
associated with brainstem tumors
Bilateral, mid- or lower pons, very poor
prognosis
Lower pons, medulla

Ataxic Completely irregular, deep Medulla; very poor prognosis

breaths, shallow breaths
Hiccups Medulla
Sighs or yawns Rapidly increasing ICP

Table 1.4 Eye deviation corresponding to brain injury [17,18]

Oculocephalic Reflex – –The oculocephalic reflex is also known
as the doll’s head eye phenomenon or the proprioceptive head- Conjugate deviation
turning reflex. The afferent pathway of this test is debated to Frontal lobe Eyes look towards the lesion
either arise from the vestibular system or the proprioceptive
Medial thalamus, pons, seizures Eyes look away from the
afferents from the neck [2]. The excitatory stimuli to the extrao- lesion or focus
cular muscles appear to travel via the medial longitudinal fas-
ciculus [2]. Before performing this maneuver, ascertain that the Thalamus, midbrain pretectum, Downward deviation
cervical spine is cleared [2,18]. To perform this maneuver, keep or metabolic causes
the eyelids open and briskly turn the patient’s head from side to Brainstem, sleep, seizures Upward deviation
side with a brief pause at endpoints [2]. In a comatose patient Disconjugate deviation
with intact brainstem and cranial nerves, the normal response is
a contraversive conjugate eye deviation [2,18]. This means that (Right) CN III palsy (Right) Eye “down and out,”
(Right) pupil dilated
the eyes turn to the left, laterally, when the head is turned to the
right. Flexing and extending the neck can be performed as well (Right) CN VI palsy (Right) Eye inwardly deviated
[2]. Similarly, a normal response would be a conjugate upward Posterior fossa Skew deviation, vertical
eye deviation with neck flexion. An absent oculocephalic reflex displacement
means that the eyes follow the head movement [2].

Oculovestibular (Caloric) Reflex • Cold-water calorics: Slowly infuse water, 50 cm3 at 30 °C or

• Oculovestibular testing affects similar pathways to those
involved in the oculocephalic reflex. The test utilizes a
stronger stimulus, calorics, to stimulate convection
currents in the endolymph, which in turn activate
vestibular receptors and subsequently eye deviation [2].
Before the test is done, use an otoscope to ensure that the
ear canal and tympanic membrane are intact [2,17].
1 cm3 of ice water, into the ear canal using a syringe, with
the head of the bed elevated at 30° [2,17].
• In a conscious patient, ice-cold water into the right ear,
for example, induces nystagmus with the slow
component towards the right (the irrigated ear) and the
fast component contralaterally [2]. This can also be
observed in psychogenic coma [17].

6
 Chapter 1: The Neurological Assessment of the Critically Ill Patient

Table 1.5 Spontaneous eye movements in unresponsive patients [2,18] • In a comatose patient with an intact brainstem, the eyes
should tonically deviate away from the irrigated ear [2].
Purposeful eye movements Consider locked-in syndrome,
catatonic, pseudo-coma • To test for vertical eye movements, both canals have to
be irrigated simultaneously with warm water. A normal
Roving eye movements Nonspecific (toxic, metabolic, response involves an upward gaze [2].
(slow, conjugate) bilateral hemispheric); CN III
and VI intact Gag and Cough Reflexes – – CN IX constitutes the afferent
Nystagmus: component of both gag and cough reflexes, while CN
1. Spontaneous nystagmus 1. Uncommon in coma; X constitutes its efferent component. Both their nuclei are
2. Refractory nystagmus consider pseudo-coma located in the medulla, a part of the brainstem not well tested
(irregular jerks of the eyes 2. Mesencephalic tegmental by scoring systems such as the GCS or the FOUR score [24].
backward into the orbit) lesions
Testing both reflexes is relatively easy to do. It allows the
3. Convergence nystagmus 3. Mesencephalic lesions
4. Severe mid-pontine to
examiner to assess the integrity of the lower brainstem, and
(slow divergent phase,
quick convergent phase) lower pontine damage also guide airway protection and mechanical ventilation proto-
4. Nystagmoid jerking of a cols in patients with impaired gag or cough reflexes [24].
single eye Neurocritical care patients on mechanical ventilation are at
high risk of developing acute lung injury, and the absence of
Ocular bobbing (rapid Acute pontine lesions
either gag or cough reflexes is strongly predictive of that [24].
conjugate downward
movement, slow recovery to
Patients receiving neuromuscular blockers or therapeutic over-
mid-position) dose of sedatives may have absent gag and cough reflexes, and
therefore the examiner should always be aware of pitfalls in the
interpretation of findings [2].
Table 1.6 Neurological findings that help to localize site of structural brain
disease by location of lesion • The pharyngeal or gag reflex: If a patient is not intubated,
test by stimulating the posterior pharynx with a tongue
Cortical Variable motor response depressor, a cotton swab, or suction device [25]. The gag
Spontaneous eye movements (roving, dipping)
reflex is more difficult to test for in an intubated patient. If
Upward or downward eye movement
such a situation, jiggle the endotracheal (ET) tube gently
Brainstem Anisocoria back and forth, and observe for a response. The gag reflex
Mid-position fixed pupil may be suppressed in patients who have been intubated for
Occupation bobbing a while, and consequently, testing the cough reflex is of
Skew deviation
value [26].
Internuclear opthalmoplegia
Extensor or flexor posturing • The tracheal or cough reflex: This test is performed by
advancing a suctioning catheter into the ET tube down to
the level of the carina [25]. A cough response should be
elicited following one or two suctioning passes if the
• In a comatose patient, the eyes should tonically deviate
medulla is intact [25].
towards the side of cold irrigation if the brainstem is
intact [17]. Limited irregular beats of nystagmus may Motor Responses
be observed initially, but the eyes should ultimately and
The goal is to be able to assess motor function in the setting of
tonically deviate towards the irrigated side for up to 2–3
impaired consciousness. Motor responses are thus evaluated
minutes. Therefore, hold off for 5 minutes before
by observation and graded stimuli. Spontaneous movements
testing the opposite ear [2].
or posturing should be noted [17]. The nature of responses to
• To test for vertical eye movements, both canals have to further verbal and noxious stimuli can help localize the anat-
be irrigated simultaneously with ice water. In a comatose omy of the brain insult [18,19].
patient, a normal response involves downward gaze [2]. Stimuli should be administered on both sides of the
• The absence of response should be interpreted with body to assess for asymmetry. Noxious stimuli elicit pain,
caution as this may be the result of various etiologies, but should not cause injury [18]. This can be done by apply-
such as brain death, brainstem lesions, pre-existing ing pressure over the supraorbital ridge or the temporoman-
vestibular disease, ototoxic drugs such as gentamicin, dibular joint, rubbing the sternum, compressing the nail bed,
vestibulosuppressant drugs such as sedatives, or pinching the Achilles tendon [17,18]. A normal response
phenytoin, or tricyclic antidepressants, neuromuscular would be to fend off the examiner’s hand or at least localizing
blockade, and other metabolic causes. where the pain is coming from. The other thing to observe is
• Warm-water calorics: The same sequence as described the presence or absence of a cortico-sensory response [27].
above can be performed by irrigating with warm water, no Grimacing of the face is such a cortical response [27], and
more than 44 °C [2]. may be present in the absence of limb movements [18].

7
 Chapter 1: The Neurological Assessment of the Critically Ill Patient

Pupillary response to
light

Non-reactive Reactive

Small (miotic) Large (mydriatic) Small (miotic) Large (mydriatic)

Pontine lesion, Argyll Mydriatic drops,

Old age, Horner's
Robinson pupils atropine, overdose Childhood, anxiety
syndrome, anisocoria
(usually irregular), (amphetamine, cocaine, states, physiological
(physiologically
opiates, pilocarpine or derivatives), brain anisocoria
smaller)
drops death

Figure 1.3 Pupillary abnormalities (adapted from reference [23])

• A patient with a diffuse metabolic encephalopathy might Assessing Neuromuscular Complications

withdraw away from the stimulus, and this response may
• Patients admitted to the ICU may have motor weakness
be asymmetric if one hemisphere is affected more than the
that is pre-existing or undiagnosed, newly acquired, or
other [28].
associated with their critical illness [29,30].
• When the insult affects the upper midbrain, the motor
• Nevertheless, the complexity of the intensive care setting
response to noxious stimuli may translate into decorticate
poses limitations on the assessment and diagnosis of motor
posturing, which can be unilateral or bilateral depending
weakness. Patients may be sedated, noncooperative, or
on the anatomy of the lesion: arms are flexed, legs are
unable to communicate, which makes the performance and
extended, and toes extend downward [18,28].
interpretation of the neurological exam challenging [29].
• When the insult affects the lower midbrain or upper pons,
Accordingly, the primary step to approach a case of motor
the motor response to noxious stimuli may translate into
weakness is understanding its clinical setting by
decerebrate posturing: arms, legs, and toes are extended [28].
investigating the patient’s history and charts, list of
Decerebrate rigidity describes a bilateral process, whereas a
medications received in the ICU, and precipitating factors,
decerebrate posture describes a unilateral process [18].
such as electrolyte disturbances, drugs, infections, trauma,
• When the insult affects anywhere along the or prolonged immobility [29].
medullopontine reticular formation or the acute motor
• The motor exam should be complete and systematic in
phase of a spinal cord transection, the motor response is
order to highlight the etiology of weakness. As discussed
either flaccid or absent [2].
earlier, consider routine interruption of continuous

8
 Chapter 1: The Neurological Assessment of the Critically Ill Patient

sedation in order to limit its confounding effects on
the exam, and to increase the chance of patient
cooperation [31].
• In the presence of fixed or focal signs, or impaired
consciousness despite the interruption of sedation,
neuroimaging and/or neurophysiologic testing should be
considered [31].
• The motor exam should help distinguish the various
etiologies of weakness [29]:
• Central nervous lesions
• Spinal cord lesions
• Neuromuscular disorders
• Neuropathic causes of weakness such as compression/
entrapment neuropathies, critical illness
polyneuropathy (CIP), Guillain–Barré syndrome, etc.
• Myopathic causes of weakness such as critical illness
myopathy (CIM) or rhabdomyolysis.
• ICU-acquired weakness (ICU-AW) is a potential
complication of critical illness that should be investigated in
a patient presenting with diffuse symmetrical weakness,
respiratory muscle weakness, and facial muscle sparing [32].
• This complication is largely explained by CIP or CIM [32].
• The neurological exam helps distinguish ICU-AW from
other neuromuscular disturbances. In ICU-AW, upper
motor neuron signs are absent, facial and extraocular
muscles are spared, weakness is symmetric and diffuse,
and it does not fluctuate or progress in ascending or
descending patterns [1,32].
• The following features should be noted on the motor
exam[2,23]:
• Symmetry in every aspect of the exam
• Facial or extraocular muscle involvement
• Proximal or distal muscle involvement
• Respiratory muscle involvement
• Progression of muscle weakness: rapid, slow,
fluctuating, ascending, descending
• Muscle tone: normal, rigid, spastic, paratonic,
hypotonic, flaccid
• Deep tendon reflexes: increased, normal, decreased, or
absent
• Superficial and plantar reflexes
• Muscle atrophy
• Other motor signs such as fasciculation, fatigability, or
myalgia
• Other neurological signs such as dysautonomia or
sensory loss.
Conclusion
The take home message of this chapter revolves around five
recommendations with regards to the neurological assessment
of the critically ill [1]:
(1) Every critically ill patient in the ICU should receive a
proper neurological assessment.
(2) Every neurological assessment should evaluate
consciousness and cognition, brainstem function, and
motor function. The level of consciousness guides the
subsequent exam.
(3) The confounding effect of sedation on the interpretation of
the neurological assessment should be managed by
interrupting sedation, unless the risks of interruption
outweigh the benefits of minimizing the confounding
potential, such as in patients with reduced intracranial
compliance.
(4) The neurological assessment should precede and guide any
subsequent testing or imaging.
(5) Certain aspects of the neurological assessment carry a
prognostic significance in well-defined patient populations,
and should help guide goals of care.

4. Teasdale G, Jennett B Assessment of neuropathology of septic shock. Brain

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 Chapter
Cerebral Blood Flow Physiology and Metabolism
2 in the Neurocritical Care Unit
Rajat Dhar and Michael Diringer
The brain has high energy requirements combined with an
inability to store substrates critical for this tissue metabolism.
This precarious balance results in a vital organ that is highly
dependent on constant blood flow, providing oxygen and
glucose via tissue perfusion. Although the brain only com-
prises 2% of total body weight, it receives 15% of cardiac
output (700 ml/min) at rest, and accounts for 20% of oxygen
consumption, and an even greater proportion of glucose util-
ization. Even brief interruptions in blood flow can trigger
acute cerebral dysfunction, whether loss of consciousness from
global hypoperfusion (e.g. syncope from non-perfusing cardiac
arrhythmias or hypotension) or focal neurological deficits
relating to ischemia from thromboembolism or vasospasm.
Normal Physiology of Cerebral Blood Flow
Cerebral blood flow (CBF) is the primary measure of brain
perfusion, and thus serves as a vital parameter in assessing
the adequacy of substrate delivery and viability of brain tissues.
It is expressed in volume of blood reaching a defined mass of
brain tissue in a given time period (typically ml/100 g/minute).
Normal CBF is approx. 50 ml/100 g/min, but may decrease
slightly with age [1]. This whole-brain value averages more
metabolically active gray matter (70–80 ml/100 g/min) and
the white matter (20 ml/100 g/min). Flow must be adequate
to deliver sufficient glucose and oxygen to meet cerebral
metabolic demands, primarily required to maintain neuronal
ion gradients and support synaptic transmission. To ensure
this critical balance in the absence of significant storage
capacity, flow and metabolism are usually tightly coupled,
whereby increases in metabolism (expressed, for oxygen
utilization, as CMRO2, cerebral metabolic rate of oxygen)
are matched by increases in CBF and hence greater oxygen
delivery (DO2 = CBF
CaO2, the arterial oxygen content).
Nonetheless, CBF normally delivers 2–3 times the required
oxygen (DO2 approx. 8 ml O2/100 g/min, compared to a
CMRO2 of approx. 3 ml/100 g/min), allowing for some reserve
in cases of reduced CBF and/or DO2. The proportion of
oxygen extracted (expressed as OEF, oxygen extraction frac-
tion) remains around 30–35% in normal conditions, rising
only if DO2 falls out of proportion to CMRO2. This is usually
due to global or regional hypoperfusion (i.e. reduction in
CBF), but can also occur due to arterial desaturation (i.e.
systemic hypoxemia) or anemia. The Fick principle describes
the relationship between metabolism, delivery, and extraction
of oxygen:
CMRO2 ¼ DO2
OEF ¼ CBF
AVDO2
ðarteriovenous difference in oxygen contentÞ
Autoregulation
Given the importance of perfusion to neuronal function
and integrity, homeostatic mechanisms actively maintain
stable and adequate levels of CBF in the face of physiologic
perturbations, largely through adaptive vascular reactivity.
A fundamental instance of this is the ability of the brain to
regulate its own perfusion, independent of changes in systemic
blood pressure and cardiac output, a process termed cerebral
pressure autoregulation. As systemic and hence cerebral per-
fusion pressure changes, cerebral precapillary arterioles
respond with changes in tone [2]. The resultant change in
vessel diameter impacts flow through these resistance vessels,
as governed by the Hagen–Poiseuille law of laminar fluid
dynamics, which states that:
QðflowÞ¼ perfusion pressure=resistance
In the case of cerebral circulation: CBF = CPP/CVR; where
cerebrovascular resistance (CVR) is determined by the fourth-
power of the vessel radius, and to a lesser extent by blood
viscosity. This relationship means that small changes in vessel
diameter can result in significant changes in flow. Without
pressure autoregulation, a fall in systemic blood pressure and
hence cerebral perfusion pressure (CPP = MAP, mean arterial
pressure minus ICP, intracranial pressure) would precipitate a
potentially dangerous drop in CBF. Instead, resistance vessels
increase their diameter in response to lower CPP. This reduc-
tion in CVR balances the fall in CPP and maintains constant
CBF. However, such vasodilatation will also increase cerebral
blood volume (CBV), which, in the setting of reduced intra-
cranial compliance, can increase ICP. Conversely, vasocon-
striction protects against hyperemia when CPP is increased,
preventing hydrostatic cerebral edema as MAP rises. CBF
remains maintained at constant levels despite the vagaries of
systemic circulation along this autoregulatory plateau
(Figure 2.1).
11
 Chapter 2: Cerebral Blood Flow Physiology and Metabolism
Cerebral blood flow
Active changes in vessel diameter
Autoregulatory plateau
Passive
collapse
Lower limit
Cerebral perfusion pressure
Figure 2.1 Cerebral pressure autoregulation: cerebral blood flow is preserved
within limits of autoregulation by changes in vessel diameter.
However, there is a limit to the extent of this autoregula-
tory compensation. Once a vessel is maximally dilated or
constricted (i.e. exhaustion of autoregulatory reserve), further
changes in CPP will result in altered CBF. At perfusion pres-
sures beyond these limits (typically below 50–60 mmHg at the
lower end and above 150 mmHg at the upper end), CBF will
fall or rise in parallel with changes in MAP and CPP. These
limits are shifted to the right in patients with chronic, espe-
cially untreated, hypertension [3], making such patients more
vulnerable to hypoperfusion if blood pressure is lowered even
to relatively normal levels. As pressure rises above the upper
threshold of autoregulation, CBF will rise, and hypertensive
encephalopathy and endothelial damage associated with
hydrostatic cerebral edema can occur [4].
Relationship Between CBF and PaCO2
The cerebral circulation is not only responsive to changes
in pressure, but also to a number of other physiologic param-
eters. Partial pressure of carbon dioxide (PaCO2) is one of the
most powerful such modulators. Between PaCO2 levels of
20–80 mmHg, a rise of even 1 mmHg can result in an increase
in CBF of 3–4% [5]. Such changes in CBF are the result of
changes in arteriolar tone, in this case occurring in response
to changes in local pH. When PaCO2 rises, acidosis causes
vasodilatation and higher CBF, while with hyperventilation,
PaCO2 falls, vessels constrict, and CBF falls. This is the basis by
which hyperventilation lowers CBV and thereby can reduce
ICP, albeit at the expense of lower CBF and potentially even
ischemia in susceptible patients. The onset of this effect is
rapid but not durable. pH adapts and normalizes over a few
hours, meaning vessel diameter and CBF return to baseline.
Changes in PaO2 within the normal range do not affect
CBF in the same way. Only when PaO2 falls below 50–60 mm
Hg, such that arterial desaturation occurs, does the resultant
drop in oxygen saturation (SaO2) and hence artertial oxygen
concentration (CaO2) lead to reduced DO2 and compensatory
vasodilatation; this in turn raises CBF and restores DO2 to
12
normal levels. A similar homeostatic response occurs in
the face of anemia, as lower hemoglobin also reduces CaO2,
resulting in vasodilatation, higher CBF, and restored DO2 [6].
The effects of reduced blood viscosity at lower hematocrit
levels may (through the Hagen–Poiseuille law) further
improve CBF in those with anemia.
Passive
vasodilatation These regulatory vasomotor responses do not occur in
isolation and so are not independent of one another. If vessels
are maximally dilated (for example, in response to hypotension
or proximal stenosis/occlusion – reducing perfusion pressure),
the ability to compensate for reductions in hematocrit or
further drops in MAP will be attenuated or lost [7]. The
Upper limit residual ability to respond to such threats and maintain CBF/
DO2 by vasodilatation is captured in the concept of cerebro-
vascular reserve. Degree of reserve can be assessed by response
to changes in pH or PaCO2 (e.g. administration of acetazola-
mide, which induces acidemia and should trigger cerebral
vasodilatation if reserve is present). This may be an important
marker of future stroke risk, as validated in those with carotid
stenosis, where stroke risk was highest in those with impaired
vasodilatory reserve [8].
Vascular reactivity and the ability to regulate CBF may be
impaired in certain disease states, either globally (e.g. after
severe head trauma) or regionally (in the territory of acute
focal ischemia or vasospasm [9,10]). Similarly, autoregulation
may be impaired in the hemisphere ipsilateral to severe carotid
stenosis, leading to hyperemia and hyperperfusion syndrome
in some patients after revascularization [11]. Conversely,
autoregulation appears to be preserved even within the peri-
hematomal region around intracerebral hemorrhage (ICH)
[12]. This means that careful reductions in MAP may be
tolerated in such patients without inducing a fall in CBF.
Conversely, in situations where autoregulation is impaired,
CBF will vary passively with perfusion pressure. In this setting,
drops in MAP even within the normal range (especially in
chronically hypertensive patients) can reduce CBF further
[13]; blood pressure may need to be monitored and main-
tained scrupulously in such patients to avoid worsening or
inducing ischemia.
Cerebral Ischemia
Ischemia occurs when flow is inadequate to supply adequate
oxygen to support cellular metabolism such that energy failure
occurs (i.e. CMRO2 falls). Critical CBF thresholds may vary
depending on the metabolic activity of particular regions/
tissues (e.g. gray versus white matter), and systemic oxygen
content [14]. Severity of ischemia as well as its duration may
determine progression to infarction, as does ability to compen-
sate for reduced CBF and DO2, mediated by cerebrovascular
reserve and elevations in OEF. In general, as CBF falls to half its
baseline level (approx. 25 ml/100 g/min), electroencephalogram
(EEG) activity slows and neurological function may become
altered [15]. Protein synthesis may be inhibited at even higher
levels [16]. Once CBF falls below 20 ml/100 g/min, electrical

failure develops (EEG may become isoelectric), and a shift to
anaerobic metabolism leads to increased lactate production.
With CBF below 10–12 ml/100 g/min, there is loss of synaptic
transmission and failure of ion pumps [17]. In such tissues, cell
death and cytotoxic edema (i.e. ischemic infarction) will rapidly
ensue if flow is not promptly restored. An ischemic penumbra
may exist, wherein flow is below the threshold for electrical
failure and neurological deficits to emerge, but above that of
energy failure and inevitable infarction. Ischemia may be revers-
ible in such a region if flow is restored, otherwise tissue may be
recruited into the infarct without reperfusion [18].
Three stages of hemodynamic impairment have been
proposed to encapsulate the vascular and metabolic changes
seen with falling cerebral perfusion [19]. Initial drops in CPP
lead to autoregulatory vasodilatation, which serves to maintain
CBF at or just below baseline levels, while increasing CBV and
mean transit time (MTT) (Figure 2.2). Once this cerebrovas-
cular reserve has been exhausted, CBF falls with any further
reduction in CPP. This in turn lowers DO2, necessitating a
compensatory increase in OEF to maintain a steady supply of
oxygen to the tissues for cellular metabolism. This stage is
termed, oligemia (or “misery perfusion”) and the increase in
oxygen extraction can be seen in lower saturation of the
effluent venous blood leaving the brain capillaries (i.e. reduced
jugular venous oxygen saturation, assuming hypoperfusion is
sufficiently diffuse). This high-risk state may overlap somewhat
the “penumbra” concept of abnormal but viable tissue, where
metabolism is preserved despite constrained flow. OEF can
only increase up to a maximal level (70–80%) and once tissue
cannot extract more oxygen, but CBF and DO2 continue to
fall, now insufficient oxygen is available and CMRO2 will
CBV Maximal
vasodilatation –
reserve exhausted
CBF
Maximal OEF
OEF (around 70-80%)
CMRO2
Autoregulation Oligemia Ischemia Infarction
Decreasing Cerebral Perfusion Pressure
Figure 2.2 Stages of worsening hemodynamic impairment and
compensatory mechanisms as cerebral perfusion pressure falls (modified after
Powers et al. Ann Int Med 1987;106:27–34, Derdeyn et al. Brain
2002;125:595–607.)
Chapter 2: Cerebral Blood Flow Physiology and Metabolism
decrease (i.e. frank ischemia). CBF and CMRO2 now fall in
parallel, as energy and ion pump failure develops. Infarction
will ensue without restoration of flow, wherein OEF again falls
to normal or even below normal levels.
Prevention of ischemic injury is the rationale for monitor-
ing CBF in patients with acute brain injuries such as traumatic
brain injury (TBI) or stroke. However, it must be noted that
CBF alone has a number of limitations as the sole marker of
tissue viability. There appears significant variability in defining
CBF thresholds for ischemia, likely due to the importance
of metabolic factors and the contribution of oxygen content
in blood (as determined by oxygen saturation and hemoglobin
levels) to net DO2. An isolated CBF value may not provide
adequate information about the presence or risk of ischemia
because:
1. Reduced CBF implies impaired perfusion, but does not
inform on the balance between flow and metabolism, the
critical determinant of ischemia [20]. OEF may rise to
maintain metabolism even in the face of reduced CBF and
DO2, and the point at which CBF is insufficient depends on
the extent that such compensation can occur. In this sense,
jugular venous saturation is a better marker of (global)
flow–metabolism mismatch than CBF alone.
2. If metabolic demands are reduced (as in hypothermia, with
sedative drugs such as barbiturates, or in brain regions
around intracerebral hematoma or after diffuse brain
injuries such as TBI or subarachnoid hemorrhage), then
CBF may be appropriately reduced as a result of intact
flow–metabolism coupling [21]. In spite of a low CBF
measurement, in this situation OEF would be normal or
even reduced, and ischemia would not be a primary
concern. A similar effect may be seen in regions with
diaschisis, whereby sites remote from the primary injury
exhibit reduced metabolic demands and concordant
reductions in CBF, again without imminent risk of
ischemia.
3. Ischemia can occur despite a relatively normal CBF, in
cases of profound anemia or systemic hypoxemia (in both,
CaO2 and so DO2 is low), or in carbon monoxide
poisoning. Hypoglycemia can similarly threaten neuronal
viability despite normal CBF.
4. CBF may be normal distal to an occluded or stenosed
intracranial vessel if collaterals are adequate to maintain
tissue perfusion, and/or if vasodilatory reserve is able to
compensate for the reduction in distal perfusion pressure.
Therefore, without testing of CVR, CBF measurement
alone will not inform on the extent of vascular impairment
and may underestimate the risk of imminent ischemia in
such circumstances.
5. Duration of ischemia may be as important as level of CBF
reduction in some circumstances. Moderately reduced CBF
for prolonged durations can cause similar injury to total
cessation of flow for short durations. There are also
populations of neurons that are selectively more vulnerable
13
 Chapter 2: Cerebral Blood Flow Physiology and Metabolism
to ischemia than others, despite the same degree of
hypoperfusion. For example, neocortical pyramidal
neurons, Purkinje cells of the cerebellum, and CA1
neurons in the hippocampus appear to preferentially suffer
ischemic cell death with reversible global hypoxic-ischemic
injury.
6. Global measures of CBF (or jugular venous saturation)
may miss small ischemic regions, as seen in focal processes
such as vasospasm or small strokes.
In sum, cerebral ischemia clearly occurs not as a simple
dichotomy evaluated by CBF, but along a continuum with
dynamic boundaries and multiple layers. While CBF is a
central component of assessing risk of ischemia, it must be
placed in the proper context.
CBF in Acute Ischemic Stroke
Alterations in CBF and oxidative metabolism evolve from time
of vessel occlusion in stroke, through to stages of irreversible
infarction and eventually reperfusion. CBF decreases acutely
after stroke onset, usually associated with increased CBV as
vessels try to vasodilate and compensate. OEF rises to compen-
sate and try to maintain oxygen delivery. CMRO2 will be
relatively preserved at first, but falls progressively over the next
few hours in the core of the affected vascular territory as tissue
moves from oligemia to ischemia [22]. With persistent ische-
mia, infarction develops and tissue neither requires nor is able
to extract oxygen, so OEF will fall. However, OEF remains
elevated in the penumbra, where salvageable tissue may remain
viable for many hours [23]. As reperfusion occurs, CBF
increases above the level required to support metabolism in
injured tissue, and OEF falls below normal (i.e. supply is in
excess of demand), a stage termed luxury perfusion. In the
delayed subacute period, flow–metabolism coupling may be
restored, and CBF declines to negligible values in the infarcted
core, while OEF normalizes.
Promptly restoring flow to penumbral regions forms the
rationale for attempts at early reperfusion and otherwise aug-
menting CBF in the face of acute ischemia. As autoregulation
may be impaired, maintaining blood pressure (i.e. permissive
hypertension) may be important in avoiding extension of the
infarct due to a fall in CBF in the vulnerable zone. A clue to the
presence of pressure-dependent penumbra is fluctuation in
neurological deficits, with worsening as blood pressure falls
[24]. Inducing hypertension to improve CBF and reduce
infarct burden may be considered when (pressure-dependent)
penumbra is still present, as identified clinically and/or by
imaging [25].
CBF in Intracerebral Hemorrhage
A number of studies have demonstrated that CBF is reduced
both globally and in the zone of tissue around acute intracer-
ebral hematoma [26,27]. While this hypoperfusion was
initially thought to represent ischemia this may not, in fact,
be the case. In a study of 19 patients who underwent positron
14
emission tomography (PET) imaging within 24 hours of ICH
onset, CMRO2 was reduced to an even greater extent than CBF
in the peri-hematomal region [21]. OEF was decreased rather
than increased, suggesting that rather than a zone of ischemia,
the reduced CBF (and CMRO2) represented primary metabolic
down-regulation with secondary and appropriate reduction
in CBF. This hypothesis was further supported by finding
mitochondrial dysfunction in pathologic specimens from the
peri-hematomal tissue [28]. In the absence of ischemia, there
should be less concern about treating severe hypertension in
acute ICH. The status of autoregulation was specifically tested
by lowering MAP from a mean of 145 mmHg to 119 mmHg in
14 patients with small to moderate-sized ICH [12]. This 17%
reduction in MAP was not associated with any fall in CBF,
globally or in the peri-hematomal region, suggesting that auto-
regulation is preserved within these bounds, at least for small
to moderate-sized hematomas. Clinical trials have suggested
that early blood pressure reduction is safe after ICH and may
result in some clinical improvement [29].
CBF in Subarachnoid Hemorrhage
Studies have documented reductions in CBF in patients with
subarachnoid hemorrhage (SAH), even prior to development
of vasospasm, more so in those with severe hemorrhage
[30,31]. However, this appears matched by reduced CMRO2,
suggesting primary metabolic suppression coupled with lower
CBF requirement, rather than true ischemia [32]. Aneurysmal
rupture, with rapid intense rise in ICP to arterial levels, often
leads to cerebral circulatory arrest, transient global ischemic
injury, and may induce a transient reversible state of metabolic
“hibernation.” The presence of blood in the subarachnoid
space around the brainstem may also directly modulate cere-
bral metabolic activity.
Cerebral vasospasm, a narrowing of the intracranial arter-
ies at the base of the brain, that lie in apposition to the clot
burden, is a common radiographic finding that peaks 4–14
days after SAH [33]. This process is often paralleled by a
further reduction in CBF that occurs globally, but more
in certain regions. While the magnitude of CBF reduction
correlates roughly with severity of vasospasm, it may not be
restricted or even concordant with the territory of affected
vessels [34]. If CBF is reduced sufficiently, OEF rises and
symptoms of ischemia may develop [35]. If CBF is not restored
(traditionally by hemodynamic interventions such as induced
hypertension, or by endovascular attempts to reverse vaso-
spasm, such as angioplasty or intra-arterial vasodilators), then
these ischemic deficits may become irreversible, as CMRO2
falls and infarction develops. Whilst the time course over
which ischemia progresses to infarction is more variable in
delayed cerebral ischemia after SAH than in acute stroke,
infarction remains a major source of disability for those sur-
viving the initial aneurysm rupture. Recently the role of arter-
ial vasospasm as the primary contributor to ischemia and
infarction is increasingly being questioned. Not only does

angiographic narrowing not correlate well with hypoperfusion
and oligemia [34], but infarction is sometimes seen in territor-
ies without any vasospasm [36].
Surprisingly, the ability of hemodynamic therapies such
as induced hypertension, hypervolemia, and hemodilution (com-
bined under the rubric of “triple-H Therapy”) to raise CBF is
also not clear. In a PET study of SAH patients with presumed
symptomatic ischemia, a fluid bolus did not improve CBF over-
all, although it did augment flow to some extent in regions with
CBF below 25 ml/100 g/min [37]. Induced hypertension appears
to have the most robust effect, both clinically in terms of reversal
of symptoms [38] and in terms of augmenting perfusion [39].
Notably, the ability of hypertensive therapy to improve CBF rests
on whether pressure autoregulation is impaired or lost in these
patients. Without loss of autoregulatory function in vulnerable
regions, raising MAP would not improve CBF. Finally, hemo-
dilution has largely fallen out of favor, with the realization that
CBF alone is not the outcome of interest, and even if reducing
hematocrit marginally improves flow, by concomitantly redu-
cing oxygen carrying capacity it actually reduces oxygen delivery
and may worsen ischemia [40]. Recent studies have attempted to
delineate whether blood transfusion may actually improve
oxygen delivery to vulnerable brain regions after SAH [41] and
whether such an intervention could provide comparable or
greater benefit than fluid alone [42].
CBF in Traumatic Brain Injury
Reductions in CBF have also been documented early after
severe TBI. However, it seems, as in acute ICH and SAH, the
majority of this hypoperfusion is appropriate to a hibernating
brain with reduced CMRO2 [43]. True ischemia has been
harder to characterize and quantify, with PET measures of
regionally elevated OEF providing estimates that up to 16%
of the brain after TBI is at least at high risk for ischemia [44].
This coupled with an association between CPP and outcomes
has led to the widespread adoption of CPP targets (maintain-
ing CPP above 55–60 mmHg) as a primary means of mitigat-
ing secondary ischemic injury. Of course, elevations in ICP, as
may be seen after TBI, are additional contributors to lower
CPP, reductions in CBF, and ischemia after TBI [45].
Depending on autoregulatory status, lower CPP may either
lower CBF and threaten ischemia, or (if autoregulation is
functional), then a drop in CPP will induce compensatory
vasodilation, which while maintaining CBF will also increase
CBV, which can lead to higher ICP [46]. While CPP-targeted
therapy is recommended, the optimal targets have yet to be
elucidated and may require individualization. The use of cere-
brovascular pressure reactivity-guided targets (i.e. finding the
CPP which optimizes indices of dynamic autoregulation) is
currently being evaluated as one such approach [47].
Techniques for CBF Measurement
CBF as a marker of perfusion and risk of ischemia is an
important parameter in those with varying acute brain insults.
Chapter 2: Cerebral Blood Flow Physiology and Metabolism
Detecting ischemia by the neurologic examination alone is
insensitive, given the confounders of sedation and the possi-
bility of silent or subclinical ischemia going undetected (or
detected only when severe and too late to be easily reversed).
The ideal CBF monitor would provide accurate and quantita-
tive regional (not just global) real-time assessments at the
bedside, whilst being easily available, noninvasive, and repro-
ducible – allowing monitoring of trends and response to inter-
ventions. Ideally such a monitor would also allow some
estimation of metabolic or functional integrity of brain tissue
to place flow in the context of demands and reserve. Such a
monitor does not currently exist, but various modalities allow
some portion of these goals to be achieved.
CBF may be measured in a cross-sectional manner by
imaging techniques such as PET, computed tomography
(CT) or magnetic resonance imaging (MRI), or with continu-
ous bedside devices such as trancranial Doppler (TCD) or the
invasive thermal diffusion probe. EEG also provides a marker
of neuronal dysfunction in the face of worsening ischemia,
although quantitative analysis of waveforms is required to
detect subtle changes. The most commonly utilized imaging
measurements of CBF are based on one of two principles: the
Fick principle and the central volume principle.
Fick Principle
The amount of a substance taken up by a tissue is equal to the
amount of that substance delivered minus the amount
removed in the venous system (applying the law of conser-
vation of matter). Kety and Schmidt applied this principle to
measuring whole-brain CBF, using the inert diffusible gas
nitrous oxide as the tracer, whereby amount of the gas taken
up by the brain should equal CBF times arteriovenous differ-
ence in tracer concentration [48]. The latter can be determined
by measuring gas concentrations in a peripheral artery (repre-
sentative of cerebral arterial blood) and the internal jugular
vein, after a period of gas inhalation. Further refinements of
the Kety–Schmidt technique incorporated xenon-133, the
brain activity of which could be measured in various regions
by external detectors positioned around the head. This tech-
nique forms the basis of SPECT imaging. With xenon, end-
tidal radioactivity could be used to estimate arterial levels,
obviating the need for invasive arterial access. However, to
truly obtain quantitative reproducible measurement of CBF,
PET techniques with measurement of arterial radioactivity are
required. These utilize an injection of 15O labeled water, with
positron emission measured by gamma-ray detectors, allowing
regional measurement of CBF [49]. Another major advantage
of PET is that other tracers (15O labeled oxygen and carbon
monoxide) can be introduced to also measure CBV, OEF, and
CMRO2. The major disadvantages of PET lie in its complexity,
requirement for invasive arterial monitoring, and limited
availability.
Stable xenon CT relies on the fact that xenon is a radio-
dense, lipid-soluble gas that can be administered by inhalation
15
 Chapter 2: Cerebral Blood Flow Physiology and Metabolism
and visualized by CT imaging. Brain uptake can be measured
with serial CT images taken over time, and CBF quantified
using the Kety–Schmidt principle, knowing the partition coef-
ficient for xenon and estimating arterial levels by end-tidal
concentration [50]. Reliable quantitative regional values for
CBF can be obtained and the study repeated, if necessary, after
about 20 minutes (once the xenon has washed out). However,
quality of xenon CT is degraded by patient motion and incurs
relatively high radiation exposures if repeat studies are per-
formed. End-tidal xenon levels may not be accurate in patients
with pulmonary disease, leading to underestimation of CBF by
as much as 20% [51]. Although compared to PET, xenon CT is
relatively simple and inexpensive; medical-grade xenon is not
FDA-approved and requires an IND (investigational new drug
status). Nonetheless, xenon CT has been used in experienced
centers for quantitative assessment of regional CBF in patients
at risk for ischemia [52]. It has also been used to assess
cerebrovascular reactivity and response to interventions such
as angioplasty and induced hypertension [53,54].
Central Volume Principle
Techniques that track a nondiffusible intravascular tracer
(such as CT and MR perfusion) can measure MTT, CBV,
and CBF. Serial scans are taken as the tracer (e.g. iodinated
CT contrast) passes through the cerebral vasculature and then
washes out. The change in tissue density or susceptibility is
proportional to the serum concentration of the agent, allowing
a time–density curve to be constructed for each voxel, and
MTT calculated [55]. MTT is then related to CBF and CBV by
the central volume principle: MTT = CBV/CBF, which states
that MTT is prolonged if CBF is reduced or CBV is increased.
Deconvolution allows further teasing out of the contribution
of CBF and CBV to MTT measurements, by comparing pixel
density to that in a selected artery (i.e. arterial input function).
Limitations of techniques utilizing intravascular tracers
include the fact that they measure vascular perfusion (i.e. flow
in vessels) not true tissue perfusion, and timing of scans with
bolus arrival and selection of proper arterial input function are
both important determinants of study quality and accuracy.
Major advantages to such approaches are that CT and MR
scanners are widely available, and CT perfusion can be carried
out along with routine CT scanning in acute stroke patients or
other scenarios (as well as CT angiography to visualize the
vasculature). Moderate agreement has been found between
CBF measurements by CT perfusion (CTP) or MR perfusion
with xenon CT as the reference standard.
Arterial spin-labeling is a relatively new technique that
applies a magnetic pulse to a slab of brain below the area of
interest, thereby labeling the water molecules in the inflowing
blood. This allows flow to be determined without need for
exogenous contrast, especially useful in patients with renal
failure (in whom even gadolinium exposure is contraindi-
cated). It has low signal:noise ratio and so requires a longer
acquisition time, is sensitive to motion artifact and may exhibit
16
poor signal detection in low flow regions. Its application to
acute stroke is only recently expanding as technology and
techniques have improved [56,57].
Thermal Diffusion
The Hemedex™ probe is a small catheter that can be placed in
the subcortical white matter through a burr hole, allowing
focal measurement of perfusion. It accomplishes this by gen-
erating heat at its distal end and measuring the temperature
field reaching a proximal sensor. As heat dissipation is propor-
tional to local blood flow, temperature change between the two
probes allows an estimation of CBF to be derived. This moni-
tor allows for real-time continuous and quantitative measure-
ment of CBF without requiring patient transport. However,
not only is the probe invasive, it is highly focal, only measuring
perfusion in a small region around its location, and it may not
be reliable in the setting of fever. Nonetheless, some early
studies have suggested promise as a monitor for detection of
delayed cerebral ischemia after SAH [58].
Transcranial Doppler (TCD)
TCD allows noninvasive real-time measurement of blood flow
velocities in basal cerebral arteries, as long as adequate tem-
poral bone windows are available. Measurements can be
repeated at regular intervals to follow trends (for example, in
monitoring for vasospasm after SAH). However, TCD is sus-
ceptible to a number of caveats. It is highly operator-
dependent; for example, if angle of insonation varies, flow
velocity will not correlate linearly with CBF. It only measures
flow velocity in large proximal vessels (e.g. middle cerebral
artery), as an estimate of perfusion to an entire vascular terri-
tory or hemisphere. Correlation of blood flow velocity and
CBF depends on the assumption that vessel diameter remains
constant. This assumption may be violated in the setting of
vasospasm, where changes in velocity reflect more changes in
vessel caliber, rather than alterations in perfusion. In such
settings, TCD velocities correlate poorly with actual hemi-
spheric CBF [59]. Given these limitations, TCD is better suited
to look at trends or changes with maneuvers, such as required
in testing cerebrovascular reactivity, or for monitoring for
development of vasospasm or vessel reopening over time.
Near-infrared Spectroscopy (NIRS)
By detecting reflectance of near-infrared light through the
scalp to the brain, relative amounts of cerebral oxy- and
deoxyhemoglobin in the cortex can be derived. This can be
used to assess relative oxygen supply versus demand and hence
adequacy of CBF (rather than absolute CBF, itself ). NIRS
provides a noninvasive, real-time bedside monitor, but has as
of yet undergone limited validation against quantitative CBF
measurements or utilization in the clinical detection of ische-
mia outside of the OR setting [60]. It may be best suited to
monitor trends in tissue oxygenation parameters and assess
status of dynamic autoregulation [61].

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 Chapter
Cerebral Edema and Intracranial Pressure
3 in the Neurocritical Care Unit
Shivani Ghosal and Kevin N. Sheth
Cerebral edema is a common challenge in the intensive care
unit, and often occurs during trauma, malignant ischemic
stroke, or hemorrhage. The condition describes a relative
increase in the brain’s water content, as a result of pathologic
fluid and solute movement between intracranial compart-
ments. The brain’s four intracranial compartments are intra-
cellular, extracellular, intravascular, and cerebrospinal fluid.
Barriers separate each of these compartments, and allow each
to maintain their own electrochemical environments. In acute
brain injury, disruptions of these barriers may lead to cerebral
edema formation [1,2].
Cerebral edema, vascular congestion, and hydrocephalus
may all cause swelling. Swelling, within the finite space of
the cranial vault, can lead to increased intracranial pressures,
herniation syndromes, and compromised blood delivery –
further worsening cerebral edema and increasing intracranial
pressure. Neurocritical care management of these conditions
requires solid understanding of cerebral edema mechanisms,
treatment strategies, and future research targets.
Cerebral ischemia can create all forms of cerebral edema.
Given its relatively high prevalence, cerebral ischemia has been
a popular target of research. For the purposes of the following
section, cerebral ischemia will be the model for discussion of
cerebral edema formation.
Though cerebral edema has traditionally been classified
into cytotoxic and vasogenic classes, this system oversimplifies
the complexity of the underlying pathophysiology.
Starling’s equation is a framework for understanding
cerebral edema and its basic classes [3].To apply the equation,
for the net fluid movement between compartments that creates
edema, there are two forces in edema formation: (1) a “driving
force” and (2) a permeability pore. The “driving force” is the
sum of hydrostatic and osmotic pressure gradients; both
deliver solute to the brain. Hydrostatic pressure is the pressure
difference between the precapillary arterioles and postcapillary
venules. This difference is directly affected by blood and tissue
pressure. Osmotic pressure is the concentration difference
between osmotically active particles in the blood and the
extracellular tissues. In a healthy brain, hydrostatic pressure
plays less of a role because of the tight junctions between
endothelial cells created by the blood–brain barrier. In an
injured brain where the blood–brain barrier is compromised,
both hydrostatic and osmotic pressures can have critical roles.
The second component of edema formation, the permeability
pore, is the capillary permeability that allows for transcapillary
passage of substances between intravascular and extracellular
spaces [4].
From these two forces, edema fluid moves by bulk
flow [1]. The driving forces are the concentration gradients
of the moving constituents – sodium, chloride, and water are
common driving forces. The degree of insult to the permeabil-
ity pore, by ischemia, trauma, or other forces, determines the
spaces involved.
The type of space, in combination with the type of driving
force, gives the classes of cerebral edema: cytotoxic, ionic,
vasogenic, and hemorrhagic conversion. Though the classes
are distinct, each are related step-wise in their pathophysiology.
For cytotoxic edema, the involved spaces are the extracellular
and intracellular compartments; the blood–brain barrier
remains intact. With the movement of ions and water into
cells, the extracellular space is depleted and shrinks. This deple-
tion creates a new sodium gradient between the extracellular
and intravascular spaces. The remaining classes of cerebral
edema arise from this new gradient, along with the degree of
capillary permeability.
Each of these classes will now be discussed within the
framework of their driving forces and involved spaces.
Cytotoxic edema is a fluid shift from extracellular into
intracellular space. The driving forces are altered osmotic
gradients across the cell membrane. Cytotoxic edema often
results from ischemia, which leads to energy depletion. Energy
depletion in turn causes failure of active transport processes
such as the Na/K ATPase pump, and loss of transmembrane
ionic gradients [5]. Cytotoxic edema begins as an inflow of
sodium down its concentration gradient, followed by an inflow
of both chloride and water as secondary participants. Involved
cells depolarize and bleb due to increased intracellular charge
and volume. Depolarization from sodium and calcium further
alters cell permeability, to both sodium and calcium. The
overall redistribution expands the intracellular and shrinks
the extracellular spaces. As there are no new contributions
from the intravascular space, tissue swelling itself does
not occur [6]. On imaging, this edema involves both grey
and white matter; the grey–white junction on brain computed
19
 Chapter 3: Cerebral Edema and Intracranial Pressure
tomography (CT) and magnetic resonance imaging (MRI)
is not preserved. Signal will be increased on MRI T2 and
diffusion-weighted imaging (DWI) sequences, and decreased
on apparent diffusion coefficient (ADC). Cytotoxic edema is
conventionally thought to be resistant to known medical
treatment [7].
The shrinkage of the extracellular space sets the stage for the
next class of cerebral edema: ionic edema. The extracellular
space is depleted of sodium, calcium, and water. Ionic edema
is a fluid shift from the intravascular space of the blood–brain
barrier to the extracellular space; the driving forces are osmotic
pressure gradients between the two spaces. For ionic edema,
hydrostatic pressure gradients have minimal contribution.
Sodium first flows down its concentration gradient from the
intravascular to the depleted extracellular space, in order to
replenish solute lost during formation of cytotoxic edema.
The transport of sodium then creates an electrical gradient for
chloride inflow, and an osmotic gradient for water inflow. The
overall redistribution expands the extracellular space. Tissue
swells from the intravascular space contribution. Of note, ionic
edema is distinct from vasogenic edema due to maintained
exclusion of protein from the blood–brain barrier [2,4].
Vasogenic edema, closely related to ionic edema, is the
next class of cerebral edema. Vasogenic edema is also a fluid
shift from the intravascular space of the blood–brain barrier
to the extracellular space. Here however, due to a complete
disruption of the blood–brain barrier, the driving forces are
both oncotic and hydrostatic pressures. The disruption is
likely to be multifactorial, due to increased inflammatory
mediators, thrombin-induced endothelial cell retraction,
and ischemia-induced release of matrix metalloproteinases.
In this state, the brain’s capillaries are no longer protected by
tight junctions, and act as fenestrated capillaries. Plasma
proteins such as albumin, IgG, and dextran leak through,
along with water into the extracellular space. Increases in
blood pressure lead to increased driving forces for proteins,
water, and ions across a compromised permeability pore. The
overall redistribution, as with ionic edema, expands the extra-
cellular space and causes tissue swelling. On imaging, the
grey-white junction is preserved. MRI T2, DWI, and ADC
scans show increased signal, mainly involving white matter.
Vasogenic edema can be responsive to both steroids and
osmotherapy.
Hemorrhagic conversion is sometimes conceptualized as
the final phase of cerebral edema [8,9]. The conversion is a
catastrophic failure of capillary integrity, resulting in a com-
plete fluid shift from the capillary intravascular space into the
brain parenchyma. Here, all constituents of blood, including
erythrocytes, are involved. Prolonged ischemia followed by
reperfusion through dead capillary endothelial cells is likely
to be a large part of this multifactorial process. Like the
preceding classes, hemorrhage adds volume to the paren-
chyma, and causes swelling. The addition of the toxic oxidant
hemoglobin kindles a strong inflammatory response, further
promoting all three aforementioned classes of edema.
20
The tissue swelling and associated increased volume of
cerebral edema create challenges for volume management. The
Monroe–Kellie doctrine states the normal skull is a rigid, fixed
volume of space that holds the intracranial contents of brain
(1300–1500 ml), blood (approx. 75 ml), and cerebral spinal fluid
(CSF; approx. 75 ml). Given the fixed space of the skull, and
the noncompressible nature of its contents, an increase in the
volume of one compartment gives only two options. One is a
compensatory decrease in the volume of another compartment.
The other option is an increased intracranial pressure to main-
tain more mass within a fixed volume [1,10].
The compensatory mechanisms for increased intracranial
volume are unfortunately limited. An early compensation is
CSF displacement from the intracranial compartment into the
spinal thecal sac. After this measure is maximized, the next
step is a decrease of cerebral blood volume, preferentially
venous blood, into the jugular veins. The arterial system can
compensate by shunting intracranial arterial blood into the
extracranial carotid arteries, though this may endanger the
brain with further ischemia. Unfortunately, these efforts
overall involve small changes in already small volume com-
ponents of the intracranial vault; brain parenchyma is the
main occupant. To manage increased volume while maintain-
ing intracranial pressure, the parenchyma itself must move –
this is cerebral herniation [3,7].
In order to maintain adequate delivery of oxygen
and nutrients, healthy brain tissue needs a constant level of
perfusion. Cerebral perfusion is determined by the difference
between mean arterial pressure (MAP) and intracranial pres-
sure (ICP). Normal cerebral perfusion pressures range from
50–70 mmHg.
In the setting of normal ICP, the brain can autoregulate its
cerebral vascular resistance to keep normal perfusion pressures
over a wide range of MAPs. For instance, for low MAP, tissue
perfusion is preserved by cerebral arterial vasodilation to
lower arterial resistance. For high MAP, tissue is protected
by cerebral arteriolar vasoconstriction to increase resistance,
prevent blood–brain barrier damage, and protect tissue from
hyperperfusion. The mechanisms required for successful cere-
bral autoregulation are complex, and are often compromised
in the setting of brain injury. Brain injury on its own can lead
to a variety of cerebral edema classes. Management of the
added volume of edema is limited due to the fixed volume of
the skull. Outcomes may lead to herniation, increased intra-
cranial pressure, or a combination of the two [11,12].
In the setting of isolated herniation, displacement of tissue
can lead to obstruction of CSF outflow or venous return,
leading to increased intracranial pressure. In the setting of
isolated intracranial hypertension, compression of brain tissue
can lead to mechanical injury and vascular compromise. Even
if normal ranges for cerebral perfusion pressures are main-
tained, continued increased intracranial pressures greater than
20 cmH20 are independently associated with brain injury and
poor outcome. In the common setting of combined herniation
and increased intracranial pressure, elevated intracranial

pressure from compromised blood or CSF outflow leads to
decreased perfusion, increased ischemic burden, and com-
promised energy. Ischemia can lead to autoregulatory vaso-
dilation. With vasodilation, the volume of the intracranial
vault is again increased, leading to increased intracranial
pressure and decreased cerebral perfusion. This vicious cycle
is a common challenge in neurointensive care.
Though increased intracranial pressure can be lethal for
intensive care unit (ICU) patients, the signs and symptoms
of the condition have poor specificity and sensitivity. The
commonly taught classic Cushing triad of bradycardia, hyper-
tension, and abnormal respirations is found in only half of
increased ICP patients, and more often during terminal her-
niation. Cushing’s component of bradycardia can be mislead-
ingly masked by tachycardic responses to pain or agitation.
Early symptoms of increased ICP are more often nonspecific
new-onset hypertension and headache. Increased ICP manage-
ment requires a high degree of clinical suspicion and assess-
ment of risk factors [1,10].
Somnolence or decreased level of consciousness can often
be the first sign of cerebral edema or increased ICP. Focal
cerebral edema can displace the thalamus and brainstem,
compromising major components of the ascending arousal
system. Widespread cerebral edema or increased intracranial
pressure can lead to global hypoperfusion, or blockage of
cerebrospinal fluid flow due to displacement of periventricular
tissue; both these end-states form a vicious cycle of worsening
increased intracranial pressure. Increased intracranial pressure
is a harbinger of early neurologic deterioration [10].
This section reviews herniation syndromes, their involved
structures, and clinical exam findings. It is important to
remember that although cerebral edema, intracranial hyper-
tension, and herniation are often closely linked, the entities
are still distinct. Increased intracranial pressure can arise not
only from tissue swelling, but also impaired vascular or
CSF flow. Cerebral edema can lead to increased intracranial
pressure in the absence of loss of compensatory mechanisms
for increased tissue volume within the intracranial vault; her-
niation occurs in the absence of increased intracranial pressure
in one-third of patients.
Central herniation, typically seen with centrally located
masses, is downward displacement of the cerebral hemispheres
through the tentorial notch. The displaced tissue can compress
the diencephalon and midbrain. Clinically, patients show
altered Edinger–Westphal nucleus activity by bilateral pupil-
lary dilation, and altered reticular activating system and red
nucleus activity by decreased mental status and extensor pos-
turing. Central herniation can lead to posterior cerebral artery
compression, cerebral aqueduct compression, leading to
obstructive hydrocephalus, and brainstem Duret hemorrhage.
Subfalcine herniation, seen in a variety of conditions, is
displacement of the cingulate gyrus under the falx cerebri.
Here, the displaced tissue can compress the involved hemi-
sphere’s anterior cerebral artery – ipsilateral, contralateral, or
both. Clinically, patients show altered frontal lobe function by
Chapter 3: Cerebral Edema and Intracranial Pressure
hyperactive or hypoactive delirium. Involvement of the motor
cortex will manifest as contralateral lower-extremity paresis.
Lateral transtentorial herniation is the most common form
of herniation. Often seen with laterally located masses, the
extra volume displaces the mesial temporal lobe, uncus, and
hippocampal gyrus through the tentorial incisura. This dis-
placement can compress the midbrain, oculomotor nerve,
and posterior cerebral artery. Clinical signs are similar to those
seen in central herniation, due to displacement through the
tentorial incisura – common elements are depressed level of
consciousness and pupillary dilation. Along with these signs,
compression onto cerebral peduncles can cause contralateral
hemiparesis, and midbrain involvement can manifest as
neurogenic hyperventilation. The complications of lateral
transtentorial herniation and central herniation are similar.
Tonsillar herniation, often due to mass lesions in the
posterior fossa, is cerebellar tonsil displacement through the
foramen magnum, with compression of the medulla. With
this insult to the medulla and its associated regulatory
pathways, clinical signs can include ataxic breathing, cardiac
dysrhythmias, autonomic instability, pontine (pinpoint) pupils,
episodic extensor posturing, and a depressed level of conscious-
ness. Medullary compression and resulting compromised circu-
lation may eventually lead to brainstem stroke.
Upward herniation, somewhat uncommon and usually due
to excessive ventricular CSF drainage, is an upward displace-
ment of posterior fossa contents through the tentorial notch.
On CT scan, this displacement has a characteristic “spinning
top” appearance of the midbrain, with the quadrigeminal plate
compromised by protruding cerebellar tissue. Clinical findings
with upward herniation can include bilateral pupillary dilation,
extensor posturing, and depressed mental status. Further
compromise of the posterior circulation with ensuing stroke
is possible.
The last class of cerebral herniation, external herniation, is
due to injury and compromise of the skull. This class is often
accompanied by loss of CSF and brain tissue; intracranial
pressure may not be raised due to injuries creating an open
system for intracranial contents. In severe cases, patients can
have herniation of parenchyma through skull breach. Clinical
findings depend on the damaged location.
Despite efforts to describe and monitor clinical signs of
increased ICP or cerebral edema, there are very few validated
examination findings that are sensitive as well as specific; early
changes in level of consciousness are especially difficult to
detect. Neuroimaging can be a useful adjunct tool for following
cerebral edema or other intracranial structural changes in
patients in danger of increased ICP development. Though the
optimal imaging modality for monitoring malignant edema
continues to be a topic of discussion, each modality can contrib-
ute to clinical assessment and decision-making [7,13].
CT scans are useful for first-line diagnostic imaging – the
modality is usually fast and readily available. The scan can
easily help differentiate between ischemia and hemorrhage to
guide immediate intervention. Structural changes associated
21
 Chapter 3: Cerebral Edema and Intracranial Pressure
with cerebral edema, such as mass effect, compression of the
ventricular system, and shift of midline structures can also
be visualized on CT imaging, and can help assess risk for
increased ICP. Currently, a dense middle cerebral artery
(MCA) sign or the degree of midline shift at the level of the
septum pellucidum are the most commonly used metrics for
radiographic deterioration. Due to their speed and availability,
CT scans are useful for serial screens to grossly monitor
evolution of cerebral edema and CSF dynamics [14].
The weaknesses of CT scans are poor specificity for distin-
guishing swelling from tissue infarction, and poor sensitivity
for actual quantification or classes of edema. Here, MRI scan-
ning can have a distinct advantage. Cytotoxic edema reduces
extracellular water content, thereby reducing the overall
diffusability of water molecules. On MRI, this is initially char-
acterized by a reduced ADC signal, and increased DWI
signal, without change in T1 or T2 images. Vasogenic edema
causes increased extracellular water content, reflected on
MRI by increased T2 and fluid-attenuated inversion recovery
(FLAIR) signals, with decreased T1 signal. For cases of further
blood–brain barrier breakdown, MRI scans are both useful for
detecting early stages of vasogenic edema that may predispose
patients to hemorrhagic transformation, as well as early con-
trast enhancement. Recent studies found MRI DWI lesion
volumes >82 ml at six hours from symptom onset had 98%
specificity for neurologic deterioration from cerebral edema,
although sensitivity was low at 52%. While MRI can be useful
in giving a more detailed assessment of both class and amount
of cerebral edema, the scans are lengthy and less widely avail-
able. Contraindications such as clinical instability, cardiac
pacemakers, or metal implants – as well as expense – preclude
MRI as a universal radiographic screening tool [14,15].
Perfusion CT has recently also been found to be an accur-
ate predictor for cerebral edema development in the context of
malignant MCA infarction. In a 2011 study, in 52 patients,
the cerebral blood volume to cerebrospinal fluid volume ratio
had sensitivity, specificity, and positive and negative predictive
values >95% for malignant edema formation after stroke.
Although perfusion CT has similar availability to MRI with
fewer contraindications, it too is not without its pitfalls.
Perfusion CT has a high false-negative rate in smaller-volume
ischemic stroke, and has poor precision differentiating
between stroke and stroke mimics such as tumors [13–15].
Neurocritical patients commonly have depressed levels of
consciousness, whether by diffuse, toxic metabolic or by focal,
structural processes. Management decisions depend on clinical
assessment of the patient’s trajectory and the contributing
processes.
Patients at risk of cerebral edema and increased intracra-
nial pressure can have dynamic trajectories, and require
close monitoring. The bedside exam, with neuroimaging, elec-
troencephalography (EEG), and lumbar puncture if pertinent,
are mainstays. The clinical exam should focus on the patient’s
level of consciousness and developing focal neurologic def-
icits – these help localize the parenchymal damage. Overall,
22
however, for neurocritical care patients, these assessment
measures for level of consciousness can be limited, especially
in the setting of pharmacologic sedation or neuromuscular
paralysis. Serial neuroimaging can be helpful to confirm clin-
ical localization, as well as to monitor for worsening cerebral
edema – findings such as sulcal effacement, or loss of the basal
cisterns. For certain patients, EEG to screen for nonconvulsive
seizures, or lumbar puncture to exclude infectious processes,
can also be helpful [16].
For a percentage of patients, in addition to the aforemen-
tioned monitoring methods, ICP monitoring can be useful for
assessment and management. The Brain Trauma Foundation
guidelines suggest ICP monitoring in traumatic brain injury
patients with a Glasgow Coma Scale score of <8 and an
abnormal CT head scan. ICP monitoring can also be con-
sidered with brain injury patients with normal head CT and
two of the following three conditions: (1) age greater than 40,
(2) unilateral or bilateral motor posturing, and (3) systolic
blood pressure <90 mmHg. These guidelines are advisory,
however, not strict criteria. Clinical suspicions for patients at
significant risk for secondary injury from elevated ICP or poor
cerebral perfusion pressure are the best selection markers for
ICP monitoring [12,17].
Though clinical management directed by ICP monitoring
has not consistently shown improved outcomes, given the wide
variety and unpredictable courses of these patients, creating
a generalized statement regarding the harms or benefits of
ICP monitoring is difficult. In general, for patients with rapidly
evolving intracranial disease, where elevated ICP and com-
promised cerebral perfusion are likely, ICP monitoring can
help guide a patient’s management and overall outcome [17].
For monitoring, the ICP waveform is a three-part tracing
created by transient increases in pressure from arterial blood
delivery to the brain. The first two waveforms, P1 and P2, are
during systole, and the last, P3, is during closure of the aortic
valve. P1 is the percussion wave; arterial flow to the choroid
plexus creates CSF production and a transient increase in ICP.
P2 is the elastance wave; increased CSF and restriction of
ventricular expansion by the fixed volume of the skull con-
tinues the increased ICP of P1. P3 is a dicrotic wave caused by
closure of the aortic valve. In normal physiology, P1 will be the
peak value, which then decreases for P2 and P3. With patients
with increased ICP, P2 will be higher than P1. This indicates
limited intracranial space, where small increases in intracranial
volume now cause dramatic increases in intracranial pressure.
There are many options and potential sites for ICP
monitoring. The remainder of this section will briefly review
options for ICP monitoring, along with their benefits
and risks.
External ventricular drains (EVDs) are the gold standard
for ICP monitoring [12,17]. The drain is inserted through the
nondominant hemisphere, and into the lateral ventricle.
A fluid-coupled transducer at the tip of the device is positioned
at the foramen of Monroe. The transducer allows for continu-
ous ICP monitoring, and the drain allows for intermittent

release of CSF when intracranial pressures are elevated. Con-
traindications to EVD placement include collapsed ventricles,
coagulopathy, or infections over the insertion site. Collapsed
ventricles make insertion difficult, and coagulopathies increase
the risk of hemorrhage into the catheter tract. Infection, injury
to eloquent tissue, and CSF overdrainage are additional pos-
sible risks with EVD insertion.
Solid-state ICP monitors are fiberoptic or microwire ICP
transducers placed in brain parenchyma or other intracranial
compartments. The monitors have greater flexibility for place-
ment and can be coupled with tissue oximeters, thermometers,
or microdialysis catheters. The advantage of the solid-state ICP
monitor is the smaller risk of hemorrhage due to smaller
craniotomy. Though the risk of infection is lower without a
drain, the solid-state monitor is not therapeutic and cannot
drain CSF. ICP measurements may also drift with time, with
limited ability for rezeroing after insertion.
The subarachnoid “bolt” is a fluid-coupled ICP monitor,
placed through a ventriculostomy into the epidural space. This
is followed by a durotomy to allow CSF communication. Given
the small incisions and lack of drain, the risk for infection or
hemorrhage is again lower; the bolt can also be placed in
the setting of collapsed ventricles. The limitations of the bolt
are similar to those of solid-state monitors – it cannot drain
CSF, and ICP measurements may become inaccurate and drift
with time.
The lumbar catheter is a fluid-coupled monitor inserted
into the lumbar thecal sac by lumbar puncture. With a patient
in lateral decubitus position, the lumbar pressures should be
equivalent to ventricular pressures; with the patient upright,
the ventricular pressure will be the difference between the
lumbar pressure and distance from the drain to the foramen
of Monroe (approximated by the tragus). The advantage of the
lumbar catheter is avoidance of a craniotomy. The device can
drain CSF, while also monitoring ICP. However, because the
catheter preferentially drains the subarachnoid space rather
than the intraventricular component, it can be ineffective in
cases of ventriculomegaly, and harmful for patients with sig-
nificant shift of midline structures.
The previous sections of this chapter have discussed types
of cerebral edema, the relationship between edema, herniation,
and intracranial pressure, and methods for ICP measurement.
Management of increased intracranial pressure targets the
underlying altered pathophysiology at work. In this final
section, we will now discuss methods for ICP management.
Although each method tackles a different element of ICP
pathophysiology, the general goals with each are: (1) to opti-
mize cerebral perfusion and oxygenation, and (2) to minimize
cerebral metabolic demands. These, in turn, minimize disrup-
tion of ionic or osmolar gradients between the parenchyma
and intravascular space, and thereby lessen cerebral edema.
Head and neck positioning is a simple maneuver to
decrease intracranial pressure. As the head of the bed is raised,
intrathoracic pressure decreases, and jugular venous drainage
improves. The decrease in cerebral blood volume decreases
Chapter 3: Cerebral Edema and Intracranial Pressure
intracranial pressure, though drops in cerebral blood volume
may come at a cost. In hypotensive patients, head elevation can
compromise cerebral blood delivery and worsen ischemia.
In clinical practice, head of the bed elevation should be indi-
vidualized to each patient, with close monitoring of ICP
and CPP [12].
Ventilation and oxygenation are major concerns in patients
with cerebral edema, not only for adequate oxygenation
of compromised tissue, but also for intracranial pressure man-
agement. Intubation should be considered early for airway
protection in patients with poor mental status. This helps to
maintain airway control and PaCO2 levels, without limiting
necessary sedation or pain management.
Both hypoxia and hypercapnea work to dilate cerebral
vasculature. This increase in cerebral blood volume can be
harmful for patients with already increased ICP or cerebral
edema. Controlled hyperventilation promotes reflex cerebral
vasoconstriction, and can reduce ICP with a peak effect in
20–40 minutes. With this method, a balance needs to be
maintained between ICP management and adequate regional
cerebral blood flow. In a healthy brain, 35 mmHg is a normal
target for PaCO2. In the presence of increased ICP or cerebral
edema, target PaCO2 should be 28–32 mmHg. Reflex vasocon-
striction can dangerously compromise blood flow below these
values, especially in the setting of an edematous brain [18].
Though hyperventilation can be effective in an acute setting
for lowering ICP, vasoconstriction caused by respiratory alkal-
osis will last only 10–20 hours, after which patients can have
rebound vascular dilation and intracranial hypertension due to
CSF buffering. Hyperventilation is best utilized as a bridging
therapy. After longer-term therapies have started, hyperventi-
lation should be slowly tapered over 6–24 hours to avoid quick
re-equilibration and spikes in cerebral blood volume.
Osmotherapy and hypertonic therapy can be powerful
interventions in patients with cerebral edema and increased
intracranial pressure. The rationales for both these therapies
trace back to the mechanisms for cerebral edema formation.
Osmotherapy dehydrates brain tissue by creating an
osmotic gradient that draws water from a swollen interstitium
back into intravascular space. As vasogenic edema is caused by
egress of fluid from the intravascular to the extracellular space,
osmotic therapy can be very effective in reversing vasogenic
edema. For cytotoxic edema, where displaced fluid is not
extracellular but intracellular, osmotherapy is less effective.
Of note, if osmotic agents are infused for prolonged periods
of time, the agents can further damage the blood–brain
barrier, leak into the extracellular space, and worsen cytotoxic
edema.
An ideal osmotic agent should be nontoxic, with a high
reflection coefficient against the blood–brain barrier – solute
particles should not be able to pass through the membrane,
nor should they damage it. Mannitol has been the most widely
used osmotic agent, by virtue of these criteria [19].
Mannitol works in two stages: first, an osmotic dehydration
of the brain; second, a diuretic effect at the renal tubules. At the
23
 Chapter 3: Cerebral Edema and Intracranial Pressure
level of the brain, the reflection coefficient for mannitol of
0.9 allows for strong oncotic pull from the extracellular to
the intravascular space. At the level of the renal tubules, the high
osmotic load of mannitol causes a large, rapid diuresis. This is
somewhat dangerous, as it causes volume contraction and
lowered mean arterial pressures, leading to poor cerebral perfu-
sion pressures and ischemia. To maintain cerebral perfusion,
urine output after mannitol administration should be closely
monitored and matched so that the patient remains euvolemic.
Mannitol administration is at 0.25–1.5 g/kg by IV bolus.
Its effects are usually maximal 20–40 minutes after adminis-
tration, and the bolus can be repeated every six hours. The
decision to repeat mannitol dosing is guided by serum
osmolality. In practice, at serum osmolality greater than
320 mOsm/L, mannitol is felt to be more harmful, especially
due to renal tubular injury and possible damage to the blood–
brain barrier. In some cases, mannitol therapy has been
given at higher serum osmoles with minimal worsening of
outcome. Decisions to give repeat mannitol can also be guided
by the serum osmole gap, the difference bween calculated
serum osmoles and measured serum osmoles. Mannitol dosing
should be held for a serum osmolar gap greater than
10 mOsm/L. The decision to give mannitol is, in the end,
dependent on each individual patient’s course.
Mannitol has its side effects, along with its advantages.
Hypotension secondary to dehydration, hemolysis and renal
injury from the oncotic load, and electrolyte disturbances such
as hypokalemia, hypomagnesemia, and hypernatremia
through large volume diuresis are all common complications
of this osmotic therapy [19,20].
Hypertonic solutions are similar in principle to
osmotherapy [21]. Hypertonic therapy removes fluid from
the extracellular space by drawing water towards the higher
sodium concentration of the intravascular space. The therapy
has similar osmotic effects as mannitol, but instead of achiev-
ing an end effect of diuresis, hypertonic solutions increase
both blood volume and mean arterial pressure by the increased
serum osmotic load. The decrease in intracranial pressure,
coupled with an increase in mean arterial pressure, improves
cerebral perfusion pressure – a particular benefit for tissue in
ischemic danger [23].
With a reflection coefficient of 1.0 in the presence of an
intact blood–brain barrier, hypertonic saline can be remark-
ably effective in drawing fluid from the interstitium. Hyper-
tonic saline is administered in a variety of concentrations, and
the rate of infusion can be variable, with both continuous
and staggered options [22,23]. IV bolus injections of 23.4%
hypertonic saline, a 30 mL “bullet” can be used in cases of
severe intracranial hypertension. Like mannitol, the bolus can
be given every six hours. The decision to repeat saline “bullet”
dosing is guided by serum sodium concentration. In practice,
the goal serum sodium range is 145–155 mEq/L to be main-
tained for up to 48–72 hours, though higher values and longer
durations can be targeted [21]. Again, as with mannitol, the
decision should be individualized for each patient.
24
Hypertonic saline is not without its side effects. Starting
with its infusion, hypertonic saline can cause hemolysis due to
serum osmotic disequilibrium, and coagulation abnormalities
from the hemolysis. The extra fluid load may exacerbate
congestive heart failure and pulmonary edema; the added
cardiopulmonary strain and increased mean arterial pressure
can lead to arrhythmias and myocardial ischemia. Electrolyte
derangements with hypertonic saline are common; hypo-
kalemia, hypomagnesemia, and hypocalcemia are common
offenders. With the cholermic load of hypertonic saline,
hypercholeremia can lead to metabolic acidemia, further
worsening electrolyte disturbances. Sodium acetate in place of
sodium chloride lessens the risk of metabolic acidemia [22,23].
Hypertonic saline can be dangerous to the brain as well.
Hyperosmolar dehydration and shrinkage of the brain may
lead to sheared bridging veins and subdural hematomas. The
high sodium load can cause overly quick osmotic changes,
leading to myelinolysis, encephalopathy, seizures, and coma.
Serial labs are important to ensure a safe, graded change in
serum sodium. In the same way, withdrawal of hypertonic
saline may cause rebound hyponatremia – with osmotic shifts
leading to new cytotoxic, ionic, or vasogenic edema.
There are few discriminating factors in choosing between
mannitol and hypertonic saline for ICP management; most
often, the two are given together in alternation. In patients
with congestive heart failure, mannitol is preferred due to its
role as a diuretic. By similar logic, for dehydrated or hypoten-
sive patients, hypertonic saline is a useful volume expander,
and increases mean arterial pressure and cerebral perfusion.
Because hypertonic saline can cause hemolysis and damage to
smaller vessels, it requires central access for prolonged therapy.
Mannitol can be given by peripheral IV, and can be given
before central access is established. Patients suffering from
alcoholism, malnutrition, or chronic hyponatremia are poor
candidates for hypertonic saline due to risk of myelinolysis,
and may have better outcomes with mannitol therapy [21].
Another method to protect an at-risk edematous brain is
reduction of energy demands. With poor blood delivery,
energy-dependent mechanisms for maintaining electro-
chemical gradients fail; cytotoxic edema develops as a result.
Vascular metabolic coupling attempts to reduce brain meta-
bolic needs and prevent cytotoxic and other classes of edema.
With decreased metabolic demands, blood flow requirements
may also decrease, thereby reducing the contribution of cere-
bral blood volume to the patient’s intracranial vault.
Hypothermia and barbiturates are currently the management
mainstays for cerebral metabolic activity reduction, although
the latter is less used due to its own potential dangers [24].
While hyperthermia has been a well-established harm to
brain tissue, hypothermia’s specific benefits and respective
underlying mechanisms remain unclear. Patients are cooled
to 32 °C for about 48 to 72 hours, and then rewarmed slowly to
prevent a rebound of neuroinflammation. Shivering during
cooling is suppressed, as it can increase metabolism and CO2
production, thereby increasing intracranial pressure [25].

It should be noted that hypothermia so far shows limited
neuroprotection in clinical trials for traumatic brain injury
patients. The largest neuroprotective effects for hypothermia
have been in cardiac arrest survivors. Current hypotheses are
that hypothermia helps to lessen the inflammatory cascades,
apoptotic pathways, matrix metalloproteinases, and free radicals
of brain injury – and thus lessens all classes of edema [26,27].
Though therapeutic hypothermia is currently being studied
for its possible benefits in cerebral edema and ICP manage-
ment, as with most methods of ICP control, it has associated
risks. Most importantly, hypothermia can mask fever response
to infection – chilled patients require close surveillance for
infection by lab and microbiology testing. Coagulopathies, with
or without thrombocytopenia, arise from poor functioning of
clotting cascade enzymes. Cardiac arrhythmias, hypotension,
and cardiac failure are also serious associated morbidities [26].
Barbiturates have been seen to be neuroprotective in
experimental studies, though their effects in clinical practice
have been mixed – barbiturate therapy is controversial. Despite
lower ICPs with barbiturate therapy, no improvement in clin-
ical outcome has been demonstrated in clinical trials. The
chemicals work, as is suspected with therapeutic hypothermia,
by cutting cerebral metabolic activity. This allocates more
energy to homeostatic energy-dependent systems and lessens
the risk of edema formation. However, the potential risks of
barbiturates are high and life-threatening. As a result, they are
often saved as a last-resort medical therapy for reducing cere-
bral edema.
Of the barbiturates, pentobarbital and propofol are more
commonly used. Pentobarbital can be infused for 48–72 hours,
after which the drug can be discontinued without weaning
due to its long half-life of 20 hours. While patients are
on barbiturate therapy, they often undergo continuous EEG
monitoring as the medication is titrated to electrographic
burst-suppression [24]. The degree of suppression is somewhat
arbitrary – the goal is rather to control ICP. Due to EEG
suppression and associated barbiturate coma, the neurologic
exam is compromised. Subtle changes in neurologic status are
masked, especially with the long half-life of pentobarbital. The
shorter half-life of propofol has made it a popular alternative
to pentobarbital.
Both drugs can have lethal side effects. Propofol and pento-
barbital are associated with severe hypotension – leading to
decreased cerebral perfusion, renal failure, and cardiovascular
collapse – immune suppression, and generalized edema from
third-spacing [7,24]. Propofol itself can also cause hypertrigly-
ceridemia and increased CO2 production from the lipid carrier
vehicle – with resultant pancreatitis and cerebral vasodilation.
Propofol infusion syndrome, with refractory metabolic acidosis
with or without elevated lactate, is rare but can be fatal [24].
In severe cases of malignant edema with or without associ-
ated increased ICP, surgical decompression by craniectomy
and duroplasty can be used as rescue therapy. Craniectomy
and duroplasty effectively change the rigid intracranial vault
of the Monroe–Kellie doctrine to an open, flexible volume for
Chapter 3: Cerebral Edema and Intracranial Pressure
edematous tissue to expand. Dural grafting is usually recom-
mended. The bone flap is saved in a bone bank or peritoneal
cavity, and replaced in three months.
The timing of the surgery from time of brain insult, as
well as the patient’s age and preoperative medical morbidities,
must be carefully taken into account for risk–benefit analysis
of surgical intervention. Decompressive measures should be
undertaken early in the disease process, ideally prior to cere-
bral herniation and associated tissue damage. Clinical trials
have shown mortality and functional outcome benefit for
malignant MCA stroke patients under 60 years of age, treated
within 24–48 hours of stroke onset. Debate still continues for
these patients’s long-term functional outcomes, though meta-
analysis has been positive. The role of surgical intervention in
traumatic brain injury, or intraparenchymal or subarachnoid
hemorrhage, remains unclear [28].
As with all salvage therapies, the decision to pursue
hemicraniectomy does not guarantee a patient’s ability to live
independently without severe neurologic deficits. The risks, as
well as realistic expectations regarding the surgery, should be
discussed fully with a patient’s surrogate decision-makers.
Complications from surgery include hemorrhage at craniect-
omy borders, infection, persistent subdural hygromas, and
hydrocephalus.
This last section of the chapter looks to the new frontier of
neuroprotection in cerebral edema and ICP management, and
recalls the underlying mechanisms of cerebral edema classes.
As cerebral edema and intracranial hypertension can have such
high rates of morbidity and mortality, more research is being
targeted at understanding the pathophysiology behind edema
formation, and prevention rather than damage control.
Tissue injury, with compromised blood delivery and
energy-dependent processes, leads to a cascade of biochem-
ical and vascular changes. Trials of neuroprotective agents
have had mixed results, with success in experimental models,
but so far limited benefit in clinical practice. Although there
are currently no well-established pharmacologic therapies for
edema prevention, some promising targets for intervention
have been discovered.
Matrix metalloproteinase-9 (MMP-9) is an enzyme acti-
vated in acute stroke. MMP-9 works to disrupt the blood–
brain barrier; it has an active role in ionic and vasogenic edema
formation, as well as hemorrhagic transformation. Some stud-
ies have used MMP-9 titers as a prognostic factor during the
first 24 hours after acute stroke, with higher values associated
with more negative outcome. Promising animal stroke
models with inhibition of MMP-9 have shown reduced stroke
volumes. Regarding MMP-9 antagonists, two agents, minocy-
cline and edaravone, show potential. Minocycline, a tetracyc-
line antibiotic, works to inhibit MMP-9. The drug has been
shown to lower MMP-9 levels in stroke patients without com-
promising patient safety in two small clinical trials. Edaravone,
a free radical scavenger, also works to inhibit MMP-9; the
agent is commonly given in China and Japan in combination
with thrombolytic therapy for acute ischemic stroke patients.
25
 Chapter 3: Cerebral Edema and Intracranial Pressure

For both agents, although their effect on MMP-9 levels is
known, their effect on edema prevention remains to be seen
[27,29].
The SUR1 sulfonylurea receptor has emerged as another
possible target for cerebral edema prevention [30]. The SUR1
receptor is more commonly known at the level of pancreatic
beta-islet cells; in diabetic patients, SUR1 antagonism by select-
ive inhibitors such as glyburide eventually leads to insulin
release. Interestingly, SUR1 is also found in the capillary endo-
thelium of the central nervous system. In the setting of acute
stroke, SUR1 up-regulates a nonselective cation channel NC
(Ca-ATP), resulting in inflow of cations to the extracellular
space, bulk movement of water, and subsequent edema forma-
tion. Glyburide, as a known selective antagonist of SUR1, is
currently under investigation as a possible neuroprotective
agent against cerebral edema. The SUR1/TRPM4 channel
antagonism may also lead to decreased activation of MMP-9
[27,30,31]. The Glyburide Advantage in Malignant Edema and
Stroke (GAMES-RP) trial is a randomized, multicenter, pro-
spective double-blind trial that studies glyburide’s effects on
cerebral edema for patients with large acute anterior circula-
tion ischemic stroke, with the need for decompressive surgery
and 90-day functional status as primary outcomes [32,33].
The aquaporin-4 (AQP4) channel is a possible target for
cerebral edema prevention. The channel is highly concentrated
within the blood–brain barrier, along capillaries and adjacent
to cell surfaces. Its high water permeability helps worsen ionic
and vasogenic edema. Interestingly, in knockout mouse
models lacking AQP4, both cytotoxic edema and vasogenic
edema were lessened. Antagonists for the AQP4 channel are
still under development. Bumetanide, NSAIDs, astragaloside,
and Lycium barbarum have all been shown to suppress AQP4
in rats and reduce postischemic cerebral edema, though clin-
ical efficacy in humans has not yet been formally established
[34,35].
Progesterone may help to rebuild the blood–brain barrier,
and thus reduce edema formation. Its role in an acute pre-
ventative setting has yet to be determined. Although in a phase
2 randomized trial, progesterone was shown to decrease 30-
day mortality, stroke and cerebral edema data has been limited
to animal models [36].
Cerebral edema and elevated intracranial pressure are
common challenges in the neurocritical care unit, and can
impart major morbidity and mortality to its patients. The
causes of these conditions are varied, although they are most
commonly seen in acute brain injury from trauma or stroke.
With edema formation, swelling tissue can compromise cere-
bral blood flow. This causes worse ischemia, further edema,
and increased compression of vital brain structures.
Management of cerebral edema works to prevent second-
ary neuronal injury from cerebral ischemia. Management of
increased intracranial pressure similarly attempts to limit
intracranial pressure, while maximizing cerebral perfusion.
Methods are varied, and include head position, directed hyper-
ventilation, osmotic and hypertonic therapy, and cerebral-
vascular coupling with hypothermia or barbiturate therapy.
Decompressive surgery can be effective at reducing poor out-
come in malignant stroke, though patient selection is limited,
and postsurgery mortality is still high.
New approaches to cerebral edema and intracranial hyper-
tension focus on the pathophysiology underlying each condi-
tion, and its prevention. Early detection and protection may
help optimize patient outcomes. Both are exciting frontiers in
neurocritical care.

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27
 Chapter
Hypothermia in the Neurocritical Care Unit:
4 Physiology and Applications
Karina Woodling, Archana Hinduja, and Michel T. Torbey
Introduction
Therapeutic hypothermia (TH) is defined as the active lowering
of core body temperature with the purpose of preserving organ
function. Despite ample animal and clinical data demonstrating
a neuroprotective effect from induced hypothermia after cardiac
arrest, stroke, and traumatic brain injury, the use of TH in
clinical practice remains limited due to side effects, lack of
consensus on the ideal duration and goal targeted temperature,
and major limitations in infrastructure. The term TH is being
replaced by a more specific term “targeted temperature manage-
ment” (TTM) to represent a range of temperature goals defined
as mild (34.5–36.5 °C), moderate (34.5–32 °C), marked (28–32 °C),
and profound hypothermia (<28 °C). In this chapter, we will
review the different mechanisms, technology, and clinical indica-
tions for TH.
Mechanism of Neuroprotection
Several potential TH neuroprotection mechanisms have been
reported including [1,2]:
• Reduction of cerebral metabolic rate resulting in reduction
in cellular oxygen and glucose requirements
• Reduced mitochondrial dysfunction leading to
improvement in energy homeostasis
• Reduction of inflammatory markers such as tumor
necrosis factor alpha (TNF-⍺), interleukin 6 (IL-6), and
interleukin 1β (IL-1β)
• Attenuation of neuronal apoptosis, by reducing pro-death
signals, preventing caspase activation
• Stabilization of the blood–brain barrier.
Approach to Hypothermia
Therapeutic hypothermia (TH) can be achieved through
different approaches, endovascular cooling or ice cold saline
being the most commonly used:
External surface cooling: Ice packs on key areas in the body
are used in order to decrease whole body temperature: head,
neck, chest, and lower extremities. Usually rewarming is
achieved with a heated-air blanket [3]. Cold air has also been
used to achieve hypothermia, with a slow rate of 0.3–0.5 °C
per hour, which is often too long, and not as efficient [4].
28
Ice cold saline: Intravenous cold saline has been shown to
effectively reduce body temperature. Rapid infusion of 4 °C
cold saline over 30 minutes usually results in a 2.5 °C drop in
temperature [5,6]. Weight-based infusion (30 mL/kg) over
12 to 24 hours has been associated with fewer side effects [5].
An infusion of lactated Ringer solution at 50 mL/min has
shown comparable results to ice cold saline infusion [7].
Endovascular cooling: This is by far the most promising
cooling technique and considered the standard approach in
many institutions. Assessing the safety and feasibility of this
technique has been studied using a closed-loop endovascular
system placed in the inferior vena cava to achieve moderate
hypothermia. In cardiac arrest the median time to reach
33°C was 210 minutes, with a cooling average between
0.5–0.11 °C/h [8]. In acute ischemic stroke, moderate
hypothermia was achieved in 180 ± 60 minutes, with a
mean duration of 67 ± 13 hours, with a rate of 1.4 °C/h [9].
No significant complications were reported, making this a
safe, feasible method to achieve rapid cooling.
Clinical Applications of Hypothermia
Hypothermia and Cardiac Arrest
The documented use of TH in cardiac arrest (CA) dates back
to the 1800s, when initial efforts consisted of covering the body
with snow, hoping for return of spontaneous circulation
(ROSC) [10]. In the last decade, a significant amount of evi-
dence emerged in support of use of TH in CA patients.
For patients with ventricular fibrillation (VF) out-of-
hospital CA, data from two clinical trials reported improved
survival and increased functional recovery with a temperature
of 32–34°C for 12–24 hours [3,11]. In an attempt to better
define the optimal temperature goal, the Targeted Tempera-
ture Management (TTM) Trial was designed to compare 33 °C
or 36 °C in out-of-hospital CA patients irrespective of the
initial rhythm [12]. No significant difference in mortality at
six months was observed between the groups. A subsequent
substudy of the TTM Trial, demonstrated increased mortality
from prolonged time to ROSC with a hazard ratio of 1.02 per
minute (95% CI 1.01–1.02), but lack of association with the
level of TTM (p = 0.85) [13]. Although TH is widely used to
provide neuroprotection to comatose patients resuscitated

from cardiac arrest from shockable rhythms, its use in cardiac
arrest from nonshockable rhythms remains controversial. Sev-
eral observational studies have demonstrated favorable neuro-
logical outcome and survival from use of TH in post-CA
patients with initial nonshockable rhythm, while others have
demonstrated conflicting studies[14–16].
The American Heart Association (AHA) recommendations
are summarized below [17]:
• After ROSC, TTM should be used in comatose patient after
nonshockable CA.
• Select and maintain a constant temperature between 32 °C
and 36 °C during TTM.
• Specific features of the patient may favor selection of one
temperature over another for TTM.
• Higher temperatures might be preferred in patients for
whom lower temperatures convey some risk (e.g.
bleeding).
• Lower temperatures might be preferred when patients
have clinical features that are worsened at higher
temperatures (e.g. seizures, cerebral edema).
• It is reasonable that TTM be maintained for at least
24 hours after achieving target temperature.
• It is recommended against the routine prehospital cooling
of patients after ROSC with rapid infusion of cold
intravenous fluids.
• It may be reasonable to actively prevent fever in comatose
patients after TTM.
Hypothermia and Ischemic Stroke
Hyperthermia in ischemic stroke patients has been associated
with worsening stroke severity, infarct size, mortality, and
poor outcomes [18]. While data on the appropriate depth of
TH in ischemic stroke patients is lacking, animal data has
demonstrated reduction in infarct size, cerebral edema, and
improved functional outcomes at 34 °C [19].
The Copenhagen Stroke Study applied surface cooling in
awake ischemic stroke patients with 12 hours of last being
known well. The goal was to maintain a targeted temperature
of 35 °C for 6 hours and compared to controls [20]. No
significant differences in mortality and neurological outcome
at six months were observed. The COOLAID (Cooling for
Acute Ischemic Brain Damage) and COOLAID II trials
demonstrated the feasibility of hypothermia with a target tem-
perature of 32 °C using surface cooling and endovascular
cooling, respectively. Neither study showed any significant
benefit of hypothermia in ischemic stroke patients [21,22].
Subsequently, several other feasibility trials have looked at
the different applications of hypothermia in ischemic stroke
without success [23,24]. The evidence for the role of TH in
large hemispherical infarction (LHI) has been more justified.
Moderate TH in LHI was associated with significant reduction
in intracranial pressure (ICP) [25]. When compared to hemi-
craniectomy though, mortality was significantly higher in
those treated with TH compared to hemicraniectomy
Chapter 4: Hypothermia: Physiology and Applications
(47 versus 12%, p = 0.02) [9]. In elderly patients who were
not eligible for hemicraniectomy, TH was found to be a valid
alternative to surgery [26].
Although hypothermia may be a promising neuroprotec-
tive strategy, its benefit in treating acute ischemic stroke
patients is not well established. In the recent AHA guidelines
for management of acute ischemic stroke, the recommenda-
tion is to offer hypothermia only in the context of ongoing
clinical trials [27].
Hypothermia and Intracerebral Hemorrhage
Although fever has been identified as an independent predictor
of poor clinical outcome after spontaneous intracerebral
hemorrhage (sICH), the role of TH in sICH remains contro-
versial. One pilot clinical trial compared patients with sICH
>25 mL and targeted temperature of 35 °C for 10 days to
controls [28,29]. No significant difference was found between
absolute hematoma size in the TH group and controls.
A significant increase in size of peri-hematoma edema was
observed in controls compared to TH group at day 14 com-
pared to baseline. In addition, progressive improvement in
functional outcomes was noted in the TH group at 3 months
and 12 months. In addition, a meta-analysis of preclinical
studies demonstrated significant reduction in edema, blood–
brain barrier leakage and improved behavioral outcomes from
use of TH compared to normothermia [30]. Hypothermia
could have a potentially neuroprotective effective therapy in
acute ICH and warrants further study.
Hypothermia and Subarachnoid Hemorrhage
The use of TH in SAH dates back to 1954, when it was used
as a neuroprotectant to minimize the effect of anoxia during
surgical repair of the aneurysm [31]. The Intraoperative Hypo-
thermia for Aneurysm Surgery Trial evaluated the impact
of TH during acute aneurysmal SAH clipping procedures
and found no significant differences in mortality, discharge
destination, and Glasgow Outcome Scores (GOS) at three
months [32]. A pilot study among patients with aneurysmal
SAH demonstrated no significant difference in survival or
functional outcome from use of TH with or without decom-
pressive hemicraniectomy (DHC) when compared to DHC
alone for management of global cerebral edema and refractory
ICP, thus it may be less promising for refractory ICP in these
patients [33].
Hypothermia and Traumatic Brain Injury
The positive effect of TH in closed head injury was first
demonstrated by Rosomoff in the 1950s. Cooling induces a
reduction in brain metabolism by 5% per 1 °C reduction in
core temperature, leading to vasoconstriction and reduction in
brain volume, thus decreasing ICP. Based on these mechan-
isms, several clinical studies have been undertaken to deter-
mine its benefit in patients with traumatic brain injury.
29
 Chapter 4: Hypothermia: Physiology and Applications
The National Acute Brain Injury: Hypothermia (NABIS:H)
study, a prospective, multicenter, randomized trial compared
the benefits of TH with a target temperature of 33 °C, initiated
by surface cooling within six hours after injury for 48 hours
followed by gradual rewarming with normothermic patients
[34]. No significant difference in clinical outcome at six
months was observed between cohorts. In subgroup analysis,
weak evidence for improved outcomes in hypothermic patients
on admission subject to TH, compared to those in the nor-
mothermia group was found, which led to the NABIS:H II trial
[35]. This study was terminated early for futility, given the lack
of difference in clinical outcome at six months. A similar multi-
center randomized controlled trial in Japan found no beneficial
effects from the use of TH for 48 hours among severe TBI
patients with low ICPs [36]. The Cool Kids Trial demonstrated
lack of improvement from use of TH in the pediatric popula-
tion, further justifying the conclusion that short-term hypother-
mia for 48 hours might not beneficial in patients with TBI.
The use of TH in management of raised ICP was evaluated
in the Eurotherm trial [37]. TBI patients with refractory ICP
who failed Tier 1 treatments (mechanical ventilation, sedation)
were randomly assigned to TH versus standard of care
(osmotherapy) as Tier 2 treatments. Upon failure to control
ICP, Tier 3 treatments (barbiturates, decompressive craniect-
omy) were used. TH with a target temperature of 32–35 °C was
maintained for at least 48 hours, following which treatment
was continued if necessary to control raised ICP or rewarming.
This trial was suspended early due to worse clinical outcomes
at six months in the TH group. Despite these results, there
were fewer occurrences of failure in controlling ICP in the TH
group compared to controls. Similarly, the Brain-Hypothermia
Study Group (B-HYPO) randomized severe TBI patients
(Glasgow Coma Score (GCS) 4–8) to either prolonged TH
(32–34 °C) for  72 hours followed by gradual rewarming or
fever control [38]. No significant differences in outcome were
observed between the groups. In severe TBI patients (GCS 
8), TH of 33–35 °C from 3–14 days demonstrated marked
reduction in ICP and mortality, with an increased rate of
favorable outcome [39]. The same group demonstrated
improved outcome from long-term TH (average of five days)
compared to short-term TH amongst TBI with mass effect and
midline shift >1 cm.
Hypothermia and Spinal Cord Injury
Although used for several neurological conditions, the use of
TH in spinal cord injury (SCI) only came into the spotlight
when it was used when the Buffalo Bills’ tight end Kevin Everett
2. Frietsch T, Krafft P, Piepgras A, et al.
References (2000). Relationship between local
1. Polderman K.H (2008). Induced cerebral blood flow and metabolism
hypothermia and fever control for during mild and moderate
prevention and treatment of hypothermia in rats. Anesthesiology
neurological injuries. Lancet 371(9628): 92(3): 754–763.
1955–1969.
30
sustained a severe, incomplete cervical spinal cord injury. Levi
reported the feasibility and safety of TH initiated, in a case series
of SCI patients, for 48 hours with a target temperature of 33 °C
followed by gradually controlled rewarming. Improved out-
comes were subsequently demonstrated in 35.5–42.8% of
patients with the use of systemic TH [40,41]. In another pro-
spective series of SCI patients subjected to local TH (deep cord
cooling with a dural temperature of 36 °C within eight hours of
injury, in addition to surgical decompression and steroids), 80%
of patients with complete cord injury made some recovery in
motor or sensory function [42]. Further clinical trials are needed
to establish the clinical role of TH in SCI.
Hypothermia and Status Epilepticus
TH has demonstrated antiepileptic and neuroprotective prop-
erties in animal models and clinical case series in seizure
patients [43,44]. Based on these promising results, the HYPER-
NATUS (Hypothermia for Neuroprotection in Convulsive
Status Epilepticus), a large multicenter trial, randomized critic-
ally ill patients with convulsive status epilepticus to TH with
standard care or standard care alone [45]. Although the rates of
progression to electroencephalogram (EEG)-confirmed status
epilepticus on the first day was lower with the use of TH (11%
versus 22%; OR, 0.40; 95% CI, 0.20–0.79; p = 0.009), no signifi-
cant difference in the functional outcome using the Glasgow
Outcome Score (GOS) with the use of TH was observed.
Although no major significant differences between the subgroup
analyses were observed, a trend towards improvement in func-
tional outcome in patients aged 65 years was observed with
TH. The outcomes of patients with seizures is highly variable
and dependent on the etiology, thus despite the lack of impact in
outcome, it might be used as a temporary measure to control
further neuronal injury from ongoing seizures.
Conclusions
The use of TH has emerged as a major breakthrough in the
treatment of neurological injuries. While several challenges in
safe and effective application, patient comfort, management of
shivering, and complications have been overcome in the last
decade, many questions still remain unanswered. Currently,
the highest level of evidence in the use of TH is amongst
comatose patients with ROSC after VF/pVT (pulseless ven-
tricular tachycardia) CA. Several studies to evaluate the opti-
mal age group, depth, duration, and rate of achievement of TH
specific to various disease conditions are required to validate
its clinical use.
3. Bernard SA, Gray TW, Buist MD,
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32
therapeutic hypothermia versus fever
control with tight hemodynamic
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 Chapter
Analgesia, Sedation, and Paralysis in the Neurocritical
5 Care Unit
Yousef Hannawi and Wendy C. Ziai
An intensive care unit (ICU) stay is often a stressful and
painful experience. Recent surveys indicate that 50–80% of
patients experience pain during their ICU stay [1]. Critically
ill patients experience pain more readily than healthy subjects;
a phenomenon known as hypernociception. The most painful
experiences for ICU patients are endotracheal suctioning and
being turned in bed. In addition, many patients have pain at
rest without a noxious stimulus [1]. This decreased threshold
of pain in the ICU has been attributed to immobility and
systemic inflammation. In addition to pain, ICU patients often
suffer from stress, which has been frequently attributed to
painful procedures. Other factors that may play a role in ICU
stress include inability to communicate due to endotracheal
intubation, interruption of sleep, hallucinations, and night-
mares. This stressful experience is not without complications,
as one retrospective study found that 25% of ICU patients with
self-reported stressful experiences during their ICU stay, such
as nightmares, anxiety, respiratory distress, or pain, showed
symptoms of post-traumatic stress disorder four years later
[2], thus, the importance of adequate analgesia and sedation to
achieve patient comfort.
The importance of providing such comfort has to be
balanced with the need to minimize continuous deep sedation
and paralysis, as the latter has been shown to improve out-
come and decrease length of stay[3]. Sedatives have been
questionably attributed to long-term cognitive decline as well.
However, a recent large prospective cohort study of medical
and surgical ICU patients who suffered respiratory failure or
shock found no correlation between the use of sedatives and
decline in neuropsychological examination at 3 and 12
months after an ICU stay [4]. In neurologically injured
patients, one of the primary tenets of care is the capacity to
perform repeated neurologic exams as the optimal means of
assessing the patients’ condition. With respect to bedside
evaluation and titration of sedation, the neurologically
injured patient may indeed be the most difficult ICU popula-
tion to manage [5]. Cognitive dysfunction leads to increased
fear, restlessness, and agitation from the inability to under-
stand one’s predicament. Yet even modest sedation may mask
subtle neurologic deterioration, hence the need for close
nursing, physician support and observation, and titrating
medications as needed without impairing neurologic evalu-
ation [6].
Patients with traumatic brain injury (TBI) constitute the
hallmark brain disorder when discussing difficult sedation
paradigms. They are often agitated and at risk of injury to self
or the medical staff caring for them. Many TBI patients are
also withdrawing from chronic alcohol and drug use, and this
must be factored into the choice and duration of sedation [6].
Sedation
Indications for Sedation
As discussed above, ICU patients often experience anxiety due
to stressful events. Anxiety may coincide with motor signs
known as agitation. This is often associated with alteration in
mental status, known as delirium [1,7]. The latter is important
to recognize, as it may be a sign of an underlying systemic
condition or neurologic dysfunction, including hypoxemia,
hypercapnia, metabolic disturbances, infection, cerebral hypo-
perfusion or ischemia, and concomitant administration of
psycho-active medications such as antidepressants, anticonvul-
sants, peptic ulcer prophylactics, and interactions with promo-
tility agents or corticosteroids. In such a situation, the
underlying pathology should be addressed first [7].
After ruling out other etiologies, sedation may be initiated
for goals of [1]:
• Treating anxiety
• Facilitating mechanical ventilation
• Facilitating neurological exams
• Avoiding deleterious changes in intracranial and cerebral
perfusion pressures.
Sedation consists of anxiolysis, hypnosis, and amnesia [5,6].
The amnestic effect of the sedative regimen likely decreases
long-term unpleasant psychiatric events. In neurologically ill
patients, an ideal sedation regimen will either preserve the
neurologic examination as required for constant clinical moni-
toring or has the potential to be discontinued with rapid return
for an uncompromised examination. Preferred agents there-
fore should have rapid onset, short duration of action, and a
large therapeutic window without significant hemodynamic
effects [5,6,8]. Periodic interruption of sedative infusions and
titration to the lowest effective dose are associated with shorter
duration on mechanical ventilation, fewer tracheostomies, and
shortened ICU stay [3].
33
 Chapter 5: Analgesia, Sedation, and Paralysis

Sedation Assessment Pharmacology of Selected Sedatives

Subjective Assessment of Sedation and Agitation
Frequent assessment of the degree of sedation or agitation may
facilitate the titration of sedatives to predetermined endpoints.
An ideal sedation scale should provide data that are simple to
compute and record, accurately describe the degree of sedation
or agitation within well-defined categories, guide the titration
of therapy, and have validity and reliability in ICU patients
[5,6] (see Figure 5.1).
A sedation goal or endpoint should be established and
regularly redefined for each patient. Regular assessment and
response to therapy should be systematically documented. The
use of a validated sedation assessment scale is recommended
(Table 5.1). The most commonly used sedation score is the
RASS. The NICS is another score that may be easier to apply
and communicate (Table 5.1)[6,9]. Objective measures of sed-
ation using, for example, a bispectral index (BIS) monitor are
not routinely used in the ICU.
Benzodiazepines and propofol are commonly administered
sedative agents in the neuro-ICU [5,6,10,11].
Benzodiazepines
• Mechanism of action: interact at specific binding site on
neuronal γ-aminobutyric acid A (GABAA) receptors that
contain specific α-subunits [12]
• Possess sedative, hypnotic, but lack intrinsic analgesic
benefits
• Potentiate effects of narcotics when given together
• Induce anterograde amnesia, not retrograde
• In addition to their sedative and anxiolytic effect,
benzodiazepines (BZs) have other central nervous system
(CNS) advantages, such as anticonvulsant, decreasing
cerebral blood flow (CBF), decreasing cerebral metabolic
rate of oxygen demand (CMRO2), no change in
intracranial pressure (ICP), and central muscle relaxation

Is the patient comfortable and at goal?

No Yes

Rule out and correct reversible causes Reassess goal daily;

Titrate and taper therapy to maintain goal;
Consider daily wake-up; IVP
Taper if >1 wk high-dose therapy and doses more
1
Use nonpharmacologic treatment, monitor for withdrawal often than
optimize the environment every 2
Hemodynamically unstable hr?
Fentanyl: 25–100 μg IVP q 5–15 min or
2 Use pain scale to Hydromorphone: 0.25–0.75 mg IVP q 5–15 min
Set goal for Hemodynamically stable
assess for paina analgesia
Morphine: 2–5 mg IVP q 5–15 min
Repeat until pain controlled, then scheduled Consider continuous
doses + p.r.n infusion opioid or
sedative

Acute agitation
Midazolam: 2–5 mg IVP q 5–15 min
until acute event controlled
Use sedation scale
3 Set goal for Lorazepam
to assess for via infusion?
sedation
agitation/anxietyb Use a low rate and
Ongoing sedation IVP loading
≥3 days doses
propofol? Lorazepam: 1–4 mg IVP q 10–20 min until
(except at goal, then q 2–6 hr scheduled + p.r.n. or
neurosurgery Propofol: start 5 ug/kg/min, titrate q 5 min
pts) until at goal

Convert to
yes
lorazepam Benzodiazepine or
opioid: taper infusion rate
by 10–25% per day
4 Use delirium scale Set goal for
to assess for control of Haloperidol: 2–10 mg IVP q 20–30 min,
deliriumc delirium then 25% of loading dose q 6 hr
aNumeric rating scale or other pain scale.
bRiker Sedation-Agitation Scale or other sedation scale.
cConfusion Assessment Methord for the ICU.

Figure 5.1 Algorithm for the sedation and analgesia of mechanically ventilated patients. This algorithm is a general guideline for the use of analgesics and
sedatives. Refer to the text for clinical and pharmacologic issues that dictate optimal drug selection, recommended assessment scales, and precautions for patient
monitoring. Doses are approximate for a 70 kg adult. IVP = intravenous push [8].

34
 Chapter 5: Analgesia, Sedation, and Paralysis

Table 5.1 Sedation assessment scales

Score description Definition

Richmond Agitation Sedation Scale (RASS) [7]
+4 Combative Overtly combative, violent, immediate danger to staff
+3 Very agitated Pulls, removes tubes or catheters, aggressive
+2 Agitated Frequent nonpurposeful movements, fights ventilator
+1 Restless Anxious, but movements not aggressive
0 Alert and Calm
–1 Drowsy Not fully alert, but has sustained awakening (eye opening, eye contact to voice >10 seconds)
–2 Light sedation Briefly awakens with eye contact to voice (<10 seconds)
–3 Moderate sedation Movement and eye opening but no eye contact
–4 Deep sedation No response to voice, but movement or eye opening to physical stimulation
–5 Unarousable No response to voice or physical stimulation
Nursing Instrument for Communication of Sedation (NICS) [9]
+3 Dangerously agitated Physical risk to patient or others
+2 Agitated Frequent or constant motor activity requiring restraints not controlled with verbal reminders
+1 Anxious, fidgety Calms with reassurances and instruction
0 Awake, cooperative, calm
–1 Lethargic Arouses easily to voice or gentle tactile stimulation
Attentive, purposeful stimulation motor examination, eyes closed when not stimulated
–2 Deeply sedated Requires loud voice or deep stimulation to arouse
Will follow commands briefly only when stimulated
–3 Unresponsive No command-following or purposeful motor activity
Riker Sedation-Agitation Scale (SAS)[8]
7 Dangerous agitation Pulling at endotracheal tube (ETT), trying to remove catheters, climbing over bed rail, striking at
staff, thrashing side-to-side
6 Very agitated Does not calm despite frequent verbal reminding of limits, requires physical restraints, biting ETT
5 Agitated Anxious or mildly agitated, attempts to sit up, calms down to verbal instructions
4 Calm and cooperative Calm, awakens easily, follows commands
3 Sedated Difficult to arouse, awakens to verbal stimuli or gentle shaking but drifts off again, follows simple
commands
2 Very sedated Arouses to physical stimuli, but does not communicate or follow commands, may move
spontaneously
1 Unarousable Minimal or no response to noxious stimuli, does not communicate or follow commands
Motor Activity Assessment Scale (MAAS) [8]
6 Dangerously agitated No external stimulus is required to elicit movement and patient is uncooperative, pulling at tubes or
catheters or thrashing side-to-side or striking at staff or trying to climb out of bed and does not
calm down when asked
5 Agitated No external stimulus is required to elicit movement and attempting to sit up or moves limbs out of
bed and does not consistently follow commands (e.g. will lie down when asked but soon reverts
back to attempts to sit up or move limbs out of bed)
4 Restless and cooperative No external stimulus is required to elicit movement and patient is picking at sheets or tubes or
uncovering self and follows commands
3 Calm and cooperative No external stimulus is required to elicit movement and patient is adjusting sheets or clothes
purposefully and follows commands

35
 Chapter 5: Analgesia, Sedation, and Paralysis

Table 5.1 (cont.)

Score description Definition

2 Responsive to touch or name Opens eyes or raises eyebrows or turns head toward stimulus or moves limbs when touched or
name is loudly spoken
1 Responsive only to noxious Opens eyes or raises eyebrows or turns head toward stimulus or moves limbs with noxious stimulus
stimulus
0 Unresponsive Does not move with noxious stimulus
Ramsay Scale[8]
1 Patient anxious and agitated or restless or both
2 Patient cooperative, oriented and tranquil
3 Patient responds to commands only
4 A brisk response to a light glabellar tap or loud auditory stimulus
5 A sluggish response to a light glabellar tap or loud auditory stimulus
6 No response to a light glabellar tap or loud auditory stimulus
AVRIPAS – Revised Sedation Scale [13]
Agitation/ Alertness
1 Unresponsive to command/difficult to arouse, eyes remain closed, physical stimulation
2 Appropriate response to physical/mostly sleeping, eyes closed to stimuli, calm
3 Mild anxiety, delirium, agitation/dozing intermittently, arouses easily (calms easily)
4 Moderate anxiety, delirium, agitation/awake, calm.
5 Severe anxiety, delirium, agitation/wide awake, hyperalert
Respiration
1 Intubated, no spontaneous effort
2 Respirations even, synchronized with ventilator
3 Mild dyspnea/tachypnea, occasional asynchrony
4 Frequent dyspnea/tachypnea, ventilator asynchrony
5 Sustained, severe dyspnea/tachypnea

• Reversible with flumazenil (0.2–1.0 mg; maximum dose • Decreases tidal volume, compensated by increase in
3 mg), a BZ antagonist that acts at the BZ binding site on respiratory rate
the GABA receptor with: • Blunts response to hypoxia and hypercarbia [11].
• Onset of action: 5 minutes
Midazolam (Versed)
• Elimination half-life: 60 minutes
• Duration of action: 0.5–3.5 hours • Most commonly used BZ in the ICU for sedation and
also the drug of choice for acute and short-term
• May require continuous infusion or alternative airway
sedation; three to four times more potent than
support
diazepam, shortest half-life of all BZs, no significant
• Precipitates withdrawal in benzodiazepine-dependent
active metabolites, water soluble [5,6,11]
patients
• Highly lipophilic; therefore, crosses the blood–brain
• May precipitate seizures or status epilepticus
barrier quickly, resulting in a rapid onset of action, 2–5
• With prolonged use: tachyphylaxis, reversible
minutes
encephalopathy
• Prescribed dose for maintenance of sedation in critically ill
• Withdrawal syndrome, possible seizures on acute cessation
adult patients: 2–5 mg/h (0.02–0.1 mg/kg/h)
• Paradoxical reactions causing increased agitation and
• Short duration of action (2–6 hours) due to rapid
delirium in patients with pre-existing CNS pathology can
metabolism by the liver to an inactive metabolite
occur due to altered sensory perception

36

• Distribution half-life: 7–10 minutes
• Elimination half-life: 2–2.5 hours
• Half-life (time for drug plasma concentration to decrease
by 50% after cessation of a continuous infusion) depends
on infusion duration.
Table 5.1 lists commonly used scales for assessment of sedation
in the intensive care unit (ICU).
• Special precautions:
• Elderly and patients with liver disease: increased
volume of distribution and decreased elimination
• Increased effect in patients with renal failure due to
increase in active unbound portion
• Repeated doses or continuous IV can lead to prolonged
sedation despite its short half-life, due to sequestration
in fat stores and its slower release from these stores
later. Respiratory and cardiovascular depression are
minimal with continuous infusion due to lower peak
plasma concentration than with bolus dosing [11].
Lorazepam (Ativan)
• Five to six times more potent than diazepam; most potent
BZ in ICU
• Slower onset of action, 5–10 minutes due to lower lipid
solubility; therefore, less appealing for acute agitation
• Prescribed dose: 0.044 mg/kg every 2–4 hours; infusion
rates up to 10 mg/h safe and effective in ICU patients
• Greater water solubility, which prolongs its serum half-life:
• Distribution half-life: 3–10 minutes
• Elimination half-life: 10–20 hours
• No active metabolite; therefore resistant to drug
interactions except valproic acid, which inhibits lorazepam
metabolism
• Lorazepam is carried in a solvent solution (propylene
glycol) to increase its solubility in the plasma. Excess doses
of lorazepam infusion may lead to propylene glycol
toxicity. Propylene glycol is converted in the liver to lactic
acid. Toxicity is characterized by lactic acidosis, delirium,
hallucinations, hypotension, and in severe cases multiorgan
failure. This toxidrome has been reported in patients
receiving high doses of intravenous lorazepam for more
than two days. Thus, an unexplained metabolic acidosis in
patients receiving high-dose lorazepam for more than
24 hours must bring attention to this complication [11].
Diazepam (Valium)
• Rapid onset, 2–5 minutes, but long-acting lipophilic BZ
• Prescribed dose: 0.1–0.2 mg/kg every 2–4 hours
• Distribution half life: 50–120 minutes
• Elimination half-life: 20–40 hours. Active metabolite,
desmethyl-diazepam, with elimination half-life of 96 hours,
results in accumulation of both the parent diazepam and
metabolite with repeated doses; further converted to
oxazepam (t1/2 = 10 hours)
Chapter 5: Analgesia, Sedation, and Paralysis
• This BZ has a long half-life due to its potent active
metabolites, which limits its use in the ICU, where a
titratable short-acting drug with rapid reversal of effect is
often required
• Resedation occurs after reversal with flumazenil because of
its long duration of action
• Formulated in sterile fat emulsion (previously in propylene
glycol), which has reduced complications
(thrombophlebitis, thrombosis, metabolic acidosis)
• Minimal cardiovascular depressant effects on blood
pressure and respiratory drive [11].
Synergistic Sedation Regimens with Benzodiazepines
BZs may be used synergistically with other drugs to lower the
side effect profile and decrease toxicity. Examples include the
combination of haloperidol and BZ. In this case, lower doses of
BZ and haloperidol may result in lower risk of impaired
respiratory drive and decreased risk of extrapyramidal symp-
toms, respectively.
Another example is the combination of propofol and BZ.
This combination may result in better hemodynamic stability
due to lowering the dose of propofol [6,11].
Propofol (2,6-Diisopropyl Phenol)
• Mechanism of action: enhances γ-aminobutyric acid
(GABA) transmission; antagonist at N-methyl-d-aspartate
(NMDA) receptors. Its GABA receptor site is different
from the BZ GABA site [14].
• Pure sedative-hypnotic, little analgesic action, some
antegrade amnesia
• Usual dosage in the ICU is 1–3 mg/kg/h
• Produces general anesthesia at induction dose of 2 mg/kg
• Onset of action: 1–2 minutes
• Ultra-short-acting due to:
• Highly lipophilic structure and extensive tissue
redistribution
• Extrahepatic metabolism
• After cessation of continuous infusion, recovery from
unconsciousness to awake, responsive state occurs within
10–15 minutes without withdrawal or tolerance; more
reliable weaning from mechanical ventilation than
midazolam infusion.
• Predictable kinetics, even in the presence of hepatic and
renal failure
• Three half-lives:
• Distribution half-life: 2–4 minutes
• Elimination half-life: 30–60 minutes
• Terminal half-life, during which propofol is eliminated
from tissue fat, 300–700 minutes
• Hemodynamic effects: decreases all cardiac indices
including: mean arterial pressure (MAP), systemic vascular
resistance (SVR), central venous pressure (CVP), cardiac
output (CO) and heart rate (HR).
37
 Chapter 5: Analgesia, Sedation, and Paralysis
• CNS effects: decreases ICP, CMRO2, and potentially
cerebral perfusion pressure (CPP) and cerebral blood flow
(CBF) because of its effects on MAP. Thus, pressors are
often required to maintain CPP. However, this effect is
rarely seen with the lower infusion doses used for sedation.
This effect on ICP makes it a good treatment option in
patients with elevated ICP. It also may be used for
treatment of status epilepticus. Its role as a neuroprotective
agent, found in animals, has not been well demonstrated in
human studies [10].
• Given its short half-life, titrability, and quick systemic
clearance, it is an appealing sedative agent in the neuro-
ICU, especially in mechanically ventilated patients [10].
• There is a spectrum of abnormal movements associated
with peri-operative propofol infusion, including
myoclonus, seizure-like events, and possibly seizures.
Propofol at low doses or at the beginning of infusion may
have potential pro-convulsant activity [5,6].
• Unfavorable characteristics:
• Hypotension, especially in hypovolemic patients;
however, better cardiovascular stability compared with
barbiturate therapy
• Respiratory depressant: infusions increase respiratory
rate and reduce ventilation response to hypercarbia,
impair upper airway reflexes, bronchodilator effects in
patients with reactive airways disease, increases CO2
production – requires increased minute ventilation to
maintain normal acid–base status
• Hypertriglyceridemia and pancreatitis because it is
mixed as an emulsion in a phospholipid vehicle
• Potential for infection and drug incompatibility
requiring a dedicated IV catheter
• Pain with peripheral injection necessitating central
access; consider lidocaine before administration
• Tonic–clonic seizures when abruptly stopped after days
of infusion
• Rarely, urine, hair, and nail beds turn green [10].
Propofol Infusion Syndrome (PRIS)
• Syndrome of metabolic acidosis, rhabdomyolysis, elevated
creatine kinase (CK), renal failure, myocardial failure,
cardiac arrhythmias, and hyperlipidemia [14–16]
• Pathogenesis related to propofol-induced blockade of
mitochondrial fatty oxidation and accumulation of free
fatty acids with pro-arrhythmic effects
• Most cases reported in children, resulting in part from
reduced energy stores and higher sympathetic tone
• Approximately 20 adult cases reported, usually in settings
of head injury or other brain injury, including status
epilepticus
• Mortality is about 30%
• Recommended to avoid prolonged propofol infusion (>48
hours) at rates >5 mg/kg/h in adults
38
• Patients on long-term propofol infusions (>72 hours)
should be monitored for signs of this syndrome, including
elevated CK, hypertriglyceridemia, and liver profile [10].
α2-Agonists
Dexmedetomidine (Precedex)
• Mechanism of action: highly selective α2-adrenergic
agonist, decreases sympathetic activity [6]
• It has unique properties by providing sedation and
analgesia without affecting the arousal system as BZs and
propofol do. The electroencephalogram (EEG) pattern of
these patients is similar to sleep EEG. Thus, patients can be
deeply sedated, but they still arouse well.
Dexmedetomidine does not have amnestic effect and it
does not cause respiratory depression. It is an appealing
agent for the neuro-ICU as it facilitates neurologic exams
without clinically significant changes in ICP or CPP.
• Recommended for short-term sedation <24 hours
• Decrease in ICP reported in experimental studies and may
be due to α2-receptor-induced arteriolar vasoconstriction
causing decreased CBV
• Usual dosage: load at 0.1 μg/kg IV for 10 minutes, then
0.2–0.7 μg/kg per hour; avoid bolus dose to minimize
hypotension
• Elimination half-life: 2 hours; duration of action: 2–6 hours
• Route of elimination: 95% renal
• Side effects: hypotension and bradycardia, agitation
• Multicenter studies revealed that dexmedetomidine
recipients required no additional supplements for sedation;
however, due to lack of amnestic properties,
benzodiazepines and narcotics may be required to improve
amnesia and analgesia. Compared to midazolam,
dexmedetomidine is associated with a lower risk of
delirium, hypotension and decreased mechanical
ventilation times [6]. Dexmedetomidine also has the
potential to become a novel therapeutic option for the
management of alcohol withdrawal syndrome-associated
agitation and autonomic hyper-reactivity and may reduce
benzodiazepine requirements and improve the
hemodynamic profile and alcohol withdrawal severity [17].
Further study is required to answer this clinical question.
Overall, dexmedetomidine appears to be a good sedative
agent in the neuro-ICU [18]. However, at this time its high
price limits its use to selected cases.
Clonidine (Catapres)
• Mechanism of action: central α2-agonist
• Uses: sedative, analgesic, hypertension, blunt
manifestations of substance abuse withdrawal,
postoperative shivering
• CNS: decreases CBF; decreases CPP, no clear effect on
CMRO2
• Distribution half-life: 6–14 minutes
• Elimination half-life: 7–10 hours

• Side effects: sedation, dry mouth, rebound hypertension
approximately 18 hours after clonidine is discontinued,
decreased MAP
• Usual dose: 0.1 mg q8–24h; up to 0.6 mg/day; duration of
action: 12–48 hours
• Studied as adjuvant to morphine patient-controlled
analgesia (PCA): bolus of clonidine at end of operation
improved analgesia for first 12 hours postoperatively and
addition of clonidine to PCA (20 μg; lockout interval (LI):
5 minutes) significantly reduced nausea and vomiting in
females undergoing lower abdominal surgery [14].
Neuroleptics
Haloperidol (Butyrophenone)
• Mechanism of action: central postsynaptic dopamine
antagonist
• It is used mainly for treatment of hallucinations, psychosis
and agitation associated with delirium. It does not have
analgesic or amnestic properties and it is not
recommended as a first-line drug for sedation
• Usual dose (for delirium): 1–5 mg increments IV, q hourly;
infusions of approximately 300 mg/24 h shown to provide
sedation without respiratory depression
• Distribution half-life: 5–17 minutes
• Elimination half-life: 10–19 hours
• Metabolized by liver and excreted by kidneys
• Contraindication: allergy to droperidol, Parkinson’s
disease, pregnancy, seizures (decreases seizure threshold)
• Complications:
• Extrapyramidal symptoms (acute dystonic reaction)
treated with diphenhydramine
• Hypotension due to α-blocking property
• Neuroleptic malignant syndrome (NMS)
• Symptoms and signs: hyperthermia, muscle rigidity,
autonomic instability, increased creatine
phosphokinase (CPK), granulocytosis, hyperglycemia
• Pathophysiology: dysautonomia due to dopamine
antagonism
• Treatment: discontinue the drug and start dantrolene
and/or bromocriptine
• Prolongation of QT interval – potentially lethal torsades de
pointes. Thus, QTc should be monitored daily in patients
receiving high doses of the drug
• Haloperidol should be used with caution in neurosurgical
conditions or patients with brain injury due to its effects on
decreasing seizure threshold [7,12].
Droperidol (Inapsine)
• Mechanism of action: central postsynaptic dopamine
antagonist
• Like haloperidol, useful for decreasing anxiety associated
with psychosis, but less effective for situational anxiety;
antiemetic effect
Chapter 5: Analgesia, Sedation, and Paralysis
• Usual sedative dose: 0.625–2.5 mg IV q4–24 h; up to 5 mg
in 24 hours
• Duration of action: 2–12 hours
• Side effects: extrapyramidal reactions, hypotension,
dysphoria, akathisia, depressed carotid body drive to
ventilate [14,19].
Other Sedatives
Etomidate
• Mechanism of action: pharmacologically active component
is dextroisomer, which produces sedation through
stimulation of GABA receptor
• Usual dose for induction of anesthesia: 0.3 mg/kg
• Elimination half-life: approximately 30 minutes
• Metabolized by liver to inactive carboxylic acid ester
• CNS: decreases CBF, decreases CMRO2, decreases ICP,
increases CPP
• CVS: unchanged CO and HR. No initial hypotension, but,
it can induce prolonged hypotension due to adrenal
suppression
• Side effects: nausea, vomiting, thrombophlebitis (due to
propylene glycol formulation), generalized seizures,
myoclonus, adrenal suppression, increased intraocular
pressure
• Contraindications: acute intermittent porphyria, seizures
• Prolonged infusions for sedation in critically ill patients
have been terminated due to increased mortality likely
related to adrenal suppression. On the other hand, the use
of single-dose etomidate for rapid sequence intubation is
controversial, as some studies have linked it to worse
outcomes in cases of sepsis and trauma due to adrenal
suppression [20]. Another large retrospective analysis did
not find any association with worse outcomes [21]. These
findings have decreased the use of etomidate for intubation
in the ICU [22].
Ketamine
• Mechanism of action: phencyclidine (angel dust)
derivative; interacts with the following receptors: NMDA,
opioid, monoaminergic, muscarinic, and voltage-sensitive
calcium channels and sodium channels
• Short-acting IV anesthetic, hypnotic, profound amnestic,
excellent analgesic
• Stimulates the limbic system, such as the hippocampus and
suppresses thalamocortical region, leading to a
dissociative state
• Most useful in ICU to facilitate brief but painful
procedures; considered promising as treatment for
refractory status epilepticus (SE)
• Usual dose: subanesthetic: 0.2–0.5 mg/kg IV or
1.5–2.0 mg/kg IM; induction of anesthesia: 1–2 mg/kg
IV or 5–10 mg/kg IM
• Elimination half-life: 2–3 hours
39
 Chapter 5: Analgesia, Sedation, and Paralysis
• Metabolized by hepatic microsomal enzymes to active
metabolite norketamine, then hydrolyzed to inactive
glucuronide metabolite
• Beneficial effects of ketamine include patient’s ability to
maintain spontaneous ventilation, bronchodilation, and
cardiovascular stimulation by activation of the sympathetic
nervous system; potentially useful for induction of
anesthesia in patients with acute hypovolemia and asthma
• CNS: increases CBF, increases CMRO2, increases ICP, and
decreases CPP
• CVS: Increases MAP, increases SVR, increases HR,
unchanged CO
• Contraindications: increased ICP, seizure disorder,
ischemic heart disease
• Side effects: epileptogenic, nightmares and hallucinations
(attenuated by cotreatment with benzodiazepines),
delirium, excessive salivation and lacrimation (limited by
use of anticholinergic-glycopyrrolate), increased ICP; rapid
tolerance [5,6].
Barbiturates
• Mechanism of action: interacts at specific barbiturate
receptor on neuronal GABA receptor complex; also acts on
chloride channels at high concentrations
• Generally not used for sedation in ICU patients
• Primary uses in the ICU: treatment of seizures and
intractable intracranial hypertension
• Progressive increase in dose results in sedation, hypnosis,
and then anesthesia
• Thiopental (Pentothal):
• Usual dose: Induction of anesthesia – thiopental: 5 mg/
kg IV; rapid short-term treatment for increased ICP:
25–50 mg IV while awaiting effect of longer-acting
agents; significant hypotension may occur
• Elimination half-life: 5–12 hours, but duration of action
short (after single bolus injection) due to rapid
diffusion from brain back to inactive peripheral sites
• Thiopental was taken off the market in 2011 after its
manufacturing company decided to stop producing the
drug because of its use in lethal injections
• Phenobarbitol (Luminal):
• Usual dose (sedation): phenobarbital: 1–3 mg/kg IV or
IM; up to 200 mg in 24 hours
• Duration of action: 10–24 hours (elimination may take
up to 120 hours)
• Pentobarbital (Nembutal):
• Usual dose (drug-induced coma): pentobarbital: 10 mg/
kg IV loading dose, followed by infusion of 1–2 mg/kg
per hour.
• Metabolism: hepatic; enzyme inducer; affects
metabolism of other drugs
• CNS: decreases CBF, decreases CMRO2, decreases ICP,
decreases CPP
40
• CVS: decreases MAP, decreases SVR, tachycardia in
hypovolemic patients with hypotension
• Side effects: central respiratory depression, apnea,
hypersalivation, bronchospasm, laryngeal spasm, renal
artery constriction, and decreased urine output;
potential lethal withdrawal syndrome; allergic reaction
in 2%; depression of gastrointestinal motility; cardiac
contractility and white blood cell function
• Patients in barbiturate coma require mechanical
ventilation, vasoactive agents, nasogastric
decompression, often with parenteral nutrition, and
surveillance cultures due to high risk of infection.
• EEG monitoring recommended to ensure optimal
dosing [5,6].
Diphenhydramine (Benadryl)
• Mechanism of action: first-generation H-1 receptor
antagonist
• Extensive hepatic metabolism
• Clinical ICU uses: sleeping aid in insomnia, can be used for
sedation, but not as first line, treatment for haloperidol/
droperidol-induced extrapyramidal reactions, allergic
dermatitis (pruritis, urticaria)
• Usual sedative dose: 25–50 mg IV q6–8 h; up to 400 mg in
24 hours
• Duration of action: 6–24 hours
• Side effects: overdose can produce flushed face, fever,
mydriasis, and seizures [14].
Recommendations
• Due to their rapid onset of action midazolam or diazepam
should be used for rapid sedation of acutely agitated
patients. However, diazepam has a longer half-life and its
effect may be more prolonged.
• Propofol and dexmedetomidine are preferred when rapid
awakening (e.g. for neurologic assessment or extubation) is
important.
• Midazolam is recommended for short-term use only, as it
produces unpredictable awakening and time to extubation
when infusions continue longer than 48–72 hours.
• Lorazepam is recommended for the sedation of most
patients via intermittent IV administration or continuous
infusion. The use of lorazepam has been declining in the
USA in the last few years.
• The titration of the sedative dose to a defined endpoint is
recommended with systematic tapering of the dose or daily
interruption with retitration to minimize prolonged
sedative effects.
• Triglyceride concentrations should be monitored after two
days of propofol infusion, and total caloric intake from lipids
should be included in the nutrition support prescription.
• The use of sedation guidelines, an algorithm, or a protocol
is recommended.

Delirium
As many as 75% of ICU patients have delirium, characterized
by an acutely changing or fluctuating mental status, inatten-
tion, disorganized thinking, and an altered level of conscious-
ness that may or may not be accompanied by agitation [7].
Delirium is associated with increased mortality and increased
length of stay of ICU patients [7]. A recent large prospective
study showed direct correlation between the length of delirium
and cognitive outcome at 3 and 12 months post ICU discharge
[4]. Screening for delirium through systematic assessment is
recommended as a practice in the ICU. Interestingly, although
BZs are used to treat agitation in the ICU, they are associated
with higher risk for delirium. Risk factors for delirium include
hypertension, pre-existing dementia, alcoholism, and increased
disease severity at admission [7].
The Confusion Assessment Method for Diagnosis of Delirium
in the ICU (CAM-ICU) scale is the most reliable available scoring
system that can be used in the routine monitoring of delirium
onset in the ICU [7]. This score consists of four variables:
1. Acute onset of mental status changes or a fluctuating
course over the previous 24 hours
2. Inattention: this can be assessed by using the letter
attention test where more than two errors are considered
abnormal
3. Altered level of consciousness (any level of consciousness
other than alert, such as lethargic, stupor or coma; or any
score other than 0 on the RASS).
4. Disorganized thinking: this is assessed by a two-step test
including four questions to be answered and command-
following tasks. An abnormality is present when any
question is answered incorrectly and the patient is not able
to complete the command test. The four questions are:
a. Will a stone float on water?
b. Are there fish in the sea?
c. Does one pound weigh more than two pounds?
d. Can you use a hammer to pound a nail?
The command part consists of:
a. “Hold up this many fingers.” (Examiner holds two
fingers in front of patient.)
b. “Now do the same thing with the other hand.”
(Not repeating the number of fingers)
Patients are diagnosed with delirium if they have both
features 1 and 2 and either features 3 or 4.
Treatment of Delirium
Treatment of delirium should be directed towards the under-
lying systemic or neurologic etiology that is believed to play a
role in the onset of delirium. Delirium is often multifactorial,
which makes correcting the underlying etiologies quite chal-
lenging [7]. Antipsychotics can be used to treat symptoms
associated with delirium, including agitation, hallucinations,
and psychosis. Haloperidol is a common agent that can be
Chapter 5: Analgesia, Sedation, and Paralysis
used since it is available in intravenous form [7]. QT interval
should be monitored when the patient is receiving this medi-
cine. However, this drug is not associated with shortening the
length of delirium. Atypical antipsychotics such as risperidone,
olanzapine, and quetiapine may decrease the length of delir-
ium. Drug intervention is not recommended for prevention of
delirium.
Nonpharmacologic Strategies
Nonpharmacologic strategies are important methods for pre-
vention of delirium. Early mobilization has been shown to
decrease the incidence of delirium, decrease length of stay,
and increase ventilation-free days in large clinical trials. Early
mobilization should be implemented in these patients as soon
as possible [7].
Sleep is another important physiological phenomenon that
is believed to be important to recover from illness. The
patient’s own report is the best measure of sleep adequacy.
Environmental modulation to promote sleep is recommended
in the ICU, including minimizing noise, lighting mimicking
the 24-hour day cycle (bright light should be avoided at night),
relaxation, music therapy by selecting the patient’s personal
preference, massage therapy, and the use of earplugs [7].
Analgesia
Pain control in the neurocritical care unit is important in the
management of postoperative neurosurgical conditions and
critical conditions where concern arises that opioids may
adversely affect the neurologic examination, and nonsteroidal
anti-inflammatory medications may be associated with
increased risk of bleeding in the peri-operative period [23].
Thus, pain may not be adequately controlled postoperatively in
the neuro-ICU. After craniotomy, moderate to severe pain
occurs in 60–84% of patients. Frontal craniotomy appears
to be associated with lower pain scores, and posterior fossa
procedures with the greatest percentage of patients reporting
moderate and severe pain (85%) and the highest use of
analgesics. Procedures involving greater degrees of muscle
and tissue damage are associated with a higher incidence of
severe pain. This includes subtemporal and suboccipital
approaches [24].
Pain Assessment
Pain is defined according to the International Association for
the Study of Pain as an “unpleasant sensory and emotional
experience associated with actual or potential tissue damage, or
described in terms of such damage.” Based on this definition,
pain is a subjective personal experience for the most part, and
the most reliable and valid indicator of pain is self-reporting by
the patient [25]. ICU patients frequently experience pain and
the hypernociception phenomenon is common, as many
patients report pain at rest. The most frequent sources of pain
in the ICU are minor procedures such as endotracheal suction-
ing and turning in bed. Rest pain is most commonly reported
41
 Chapter 5: Analgesia, Sedation, and Paralysis
in the back and legs and it is similar to myalgia. These facts
combined with communication difficulty in many ICU
patients due to mechanical ventilation or cognitive dysfunction
make assessment of pain a real challenge [1].
Given these challenges, systematic and consistent routine
assessment of pain among ICU patients is recommended [7].
The most appropriate pain assessment tool will depend on
the patient involved, his/her ability to communicate, and the
caregiver’s skill in interpreting pain behaviors or physiologic
indicators [7].
In general, a numeric rating scale (NRS) of pain based
on the patient’s response is considered the gold standard.
In patients who are not able to communicate, a scale based
on the patient’s behavioral responses to pain is the best
methodology of assessment. The Behavioral Pain Scale, a
12-point scale based on limb movement, facial expression,
and mechanical ventilation synchrony is a well-validated
method for assessment in pain patients without brain injury
[26]. However, patients with brain injury may have focal
weakness that may interfere with the behavioral response to
pain. Rating of pain based on physiologic parameters such as
heart rate, blood pressure, and respiratory rate is no longer
recommended [7].
Analgesic Agents
Opiates are recommended as the first-line treatment option for
control of non-neuropathic pain in the ICU. Nonopiates
should be used as adjunctive treatment to decrease pain sever-
ity [7]. Gabapentin or carbamazepine in combination with
opioids is considered first-line treatment for neuropathic pain
in an ICU setting. Postoperative craniotomy patients are fre-
quently monitored in the neuro-ICU [27]. There are concerns
for increased bleeding risk with the use of nonsteroidal anti-
inflammatory drugs (NSAIDs) in addition to the priority of
monitoring neurologic exams in the acute postoperative
period, which limits the use of PCA [28]. Postcraniotomy pain
has been typically managed with acetaminophen, oxycodone,
and intravenous fentanyl on an as-needed schedule. More
recently, studies have been published including randomized
clinical trials evaluating the use of PCA with fentanyl and
NSAIDs, which gave encouraging results. Pain was better
controlled with a PCA regimen compared to an as-needed
bolus schedule [29]. There was no increase in side effects,
and blood oxygenation indices were not significantly different
[30,31]. However, there are still many questions to be
answered in terms of safe dosing, frequency, and type of
surgery, as patients with suboccipital craniotomy have higher
pain scores and may need more frequent neurologic monitor-
ing [32]. Thus, a more careful evaluation of PCA is needed in
these patients. Local anesthetics are not routinely recom-
mended for pain control in the ICU setting. However, a few
studies have reported that bupivacaine improved pain assess-
ment, reduced requirement for morphine, and may have
reduced nausea and vomiting after supratentorial craniotomy.
42
Opiates
• Mechanism of action: interact with opioid μ-receptors
• Primarily analgesic, sedative, and anxiolytic, but no
appreciable amnesia
• CNS: decreases CBF, CMRO2, ICP, centrally mediated
thoracoabdominal (wooden chest syndrome)/laryngeal/
pharyngeal, muscle rigidity attributed to rapid
administration, attenuated by neuromuscular blockers
• CVS: decreases MAP due to venodilation, decreased
sympathetic tone, and histamine release, dose-dependent
vagal-mediated bradycardia attenuated by atropine
• Respiratory: depresses ventilation; hence, any increase in
PaCO2 can lead to increased CBF and ICP. Caution should
be exercised in nonmechanically ventilated patients with
impaired intracranial pressure dynamics
• Other effects: delayed gastric emptying, ileus, sphincter of
Oddi spasm, urinary retention
• Metabolized by the liver, excreted renally
• Reversible with use of a pure opioid antagonist, naloxone,
and agonist-antagonist, nalbuphine
• Naloxone: onset time 1–2 minutes, elimination half-life 60
minutes, short duration of action results to renarcotization,
which can be prevented by repeated boluses. Pain,
hypertension, dysrhythmias, pulmonary edema, cardiac
arrest, or withdrawal in opioid-dependent patients are
some complications to be kept in mind [5].
Fentanyl (Sublimaze)
• A synthetic opiate with 75–100 times the potency of morphine
• Single dose of fentanyl has more rapid onset and shorter
duration than morphine because of its greater solubility
and rapid redistribution
• With continuous infusion, fentanyl accumulates in fat
stores, resulting in markedly prolonged duration
• The elimination half-life of fentanyl, 5 hours, is longer than
that of morphine, 4 hours, due to its large volume of
distribution, 4 L/kg.
• Does not cause histamine release like morphine; hence, less
hemodynamic instability, making it suitable for patients in shock
• Metabolized to norfentanyl in liver, which has its own
analgesic power
• Usual dose: PCA: demand: 10–50 μg; LI: 5–10 minutes;
basal rate: 50 μg/h
• Usual dose: sedation: 25–50 μg/h with or without bolus; up
to 200–300 μg/h
• Duration of action: 30–60 minutes (increases with higher
cumulative doses)
• Most commonly used analgesic in the ICU setting; it is
often given as continuous infusion in patients on
mechanical ventilation
• Sufentanil: analogue of fentanyl with 5–10 times the potency
• Not often used for PCA. Dose: demand: 4–6 μg; LI:
5–10 minutes; basal rate: 5 μg/h [19].

Remifentanil (Ultiva)
• Selective μ-receptor agonist; analgesic potency similar to
fentanyl
• Rapid clearance because it is rapidly hydrolyzed by
the nonspecific esterases in tissue and blood, does
not accumulate and rapid recovery after
discontinuation
• Not a good analgesic for postoperative use, but used
commonly for analgesia for craniotomy due to these
properties
• Usual dose (sedation): bolus 0.5–1.0 μg/kg IV; infusion:
0.025–0.2 μg/kg/min
• Duration of action: 5–10 minutes after discontinuation of
infusion [5,19].
Morphine Sulfate
• Lowest lipid solubility causing slow CNS entry
• Has a long distribution half-life, 4–11 minutes, because it is
relatively water soluble
• Metabolized by conjugation with glucuronic acid in
hepatic and extrahepatic sites, especially kidneys. Morphine
6-glucuronide, a hepatic metabolite excreted in the urine,
can accumulate in renal failure
• Releases histamine
• Usual dose (analgesia): 2–10 mg IV q4h; PCA: demand:
1–2 mg; LI: 5–10 minutes; basal rate: 0.5 mg/h
• Duration of action: 4–12 hours [5].
Hydromorphone (Dilaudid)
• Morphine derivative
• 6–8 times the potency of morphine (1.3 mg of
dilaudid = 10 mg IM morphine)
• Metabolized as inactive glucuronide; no active
metabolite, therefore good choice for patients with renal
dysfunction
• Used for moderate to severe pain in opioid-tolerant
patients who require larger than usual doses of opioids to
provide adequate pain relief; especially useful in spinal
surgery patients with a history of narcotic use
• Available in IV, IM, and SC preparations.
• Usual PCA dose: demand: 0.20–0.5 mg; LI: 5–10 minutes;
basal infusion rate: 0.4 mg/h [5].
Oxycodone (Percocet, Percodan)
• Mechanism of action: semisynthetic narcotic with
multiple actions qualitatively similar to those of
morphine
• Used for moderate to moderately severe postoperative
pain
• Usual dose: 10–30 mg PO q4–6 h
• Side effects: constipation, dry mouth, confusion, sedation,
light-headedness, respiratory depression, nausea, vomiting,
headache, sweating [19].
Chapter 5: Analgesia, Sedation, and Paralysis
Codeine (Empirin #2,3,4; Tylenol #2,3,4)
• Mechanism of action: acts on μ-opiate receptors
predominantly via its metabolite morphine
• Metabolized by the highly polymorphic enzyme
cytochrome P450 (CYP)2D6. Patients with different
CYP2D6 genotypes may respond differently in terms of
pain relief and adverse events (poor metabolizers and
ultrafast metabolizers)[33]
• Available alone or in combination with aspirin or
acetaminophen
• Usual dose: 15–60 mg PO/IM q4 h
• Compared to morphine, codeine produces less analgesia,
sedation, and respiratory depression [34].
Tramadol (Ultram)
• Synthetic opioid; aminocyclohexanol group
• Opioid mechanism: acts centrally; weak opioid receptor
agonist
• Binding to μ-receptor 6000-fold less than morphine;
weaker affinity for δ- and κ-receptors
• Nonopioid mechanism: inhibits central uptake of
monoamines: norepinephrine and serotonin
• Metabolized by O- and N-demethylation; O-
demethyltramadol is the active metabolite
• Slow metabolism in humans with a large amount of
unchanged renal excretion
• High oral bioavailability of 70%
• Oral form available in United States; intravenous PCA
available in Europe
• Used for moderate to moderately severe chronic pain not
requiring rapid onset of analgesic effect
• Oral dosing: 50–100 mg PO q4–6h, up to 400 mg/day; start
at 25 mg/day dose and titrate up by 25 mg/day over three
days to 100 mg, then by 50 mg/day over three days to 200
mg/day
• PCA dosing: demand dose: 10–20 mg; 5–10 minutes LI; 4-
hour limit.
• Side effects: sweating, dry mouth, drowsiness, nausea,
vomiting, headache, dizziness. Tramadol also may decrease
seizure threshold, so it should be given with caution in
postcraniotomy patients, especially those with a history of
seizure disorder. In addition, tramadol may cause
serotonin syndrome when it is combined with other
serotonergic drugs, such as selective serotonin reuptake
inhibitors (SSRIs), monoamine oxidase inhibitors
(MAO), etc.
• Tramadol is a less effective analgesic than other opioids [19,34].
Narcotics with Active Metabolites
1. Codeine – morphine
2. Hydrocodone – hydromorphone
3. Morphine sulfate – morphine 3-glucuronide, morphine 6-
glucuronide
43
 Chapter 5: Analgesia, Sedation, and Paralysis
4. Oxycodone – weak metabolites, oxymorphone and
noroxycodone.
Significance: active metabolites accumulate in renal and liver
disease, further extending the duration of action of narcotics.
Nonopiates
Ketamine
• Potent NMDA receptor antagonist
• Counteracts development of tolerance in peri-operative
pain management. Thus, it will be an option in a low
infusion dose for patients with peri-operative pain and a
history of opioid dependence
• Studies of systemic combination of ketamine and
morphine PCA suggest no clear benefit due to
psychomimetic effects and cognitive impairment [5].
Local Anesthetics (Lidocaine, Bupivacaine, Others)
• Local anesthetic: produces reversible conduction block of
impulses along central and peripheral nerves after regional
anesthesia; reduces inflammatory mediators and pain
perception
• Central effects: modifies neuronal responses in dorsal horn
• Little evidence for postoperative morphine-sparing
analgesic effect when lidocaine used systemically with
morphine PCA [35]
• Rarely used for pain control in the ICU setting
• Intercostals or thoracic paravertebral nerve block with
long-acting local anesthetics can be used to control
postoperative pain after thoracotomy for certain spine
procedures and for managing pain in patients with lumbar
spine injury and multiple rib fractures [36]
• Scalp nerve block after cranial surgery provides analgesia
similar to morphine for first 24 hours [35,37–40].
Acetaminophen (Tylenol)
• Nonopiate, nonsalicylate analgesic and antipyretic
• Effective for moderate pain, but no anti-inflammatory
action
• Present in many oral analgesics used for postoperative pain
(its main use in the ICU setting): Percocet, Vicodin
(hydrocodone bitartrate and acetaminophen), and
Darvocet (propoxyphene napsylate)
• Usual dose: 325, 500, and 650 mg PO, 1–2 tablets
q4–6h
• Hepatic metabolism. Dose should be limited to 4 g daily to
avoid hepatic toxicity [19].
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
• Mechanism of action: inhibit production of prostanoids via
reduced activity of two cyclo-oxygenases (COX-1 and
COX-2). COX-2 is an isoform predominantly expressed
during the inflammatory process. With the exception of
selective COX-2 inhibitors, all other NSAIDs have few or
no selective properties
44
• Primary effect is pain relief, but also has antipyretic and
anti-inflammatory effects
• The major advantage is lack of respiratory depression
• Risk of hemorrhage in patients undergoing intracranial or
spinal surgery due to platelet inhibition limits use in this
population, although current exposure to NSAIDs is not a
risk factor for intracerebral hemorrhage or subarachnoid
hemorrhage [19].
Ketoralac (Toradol)
• Hepatic metabolism (with renal clearance)
• Usual dose: 15–60 mg IV or IM q6h; up to 120 mg/day;
decrease dose by one-half in patients >65 years
• Duration of action: 4–12 hours.
Ibuprofen (Motrin)
• Renal metabolism
• Usual dose: 400–800 mg PO q6–8h; up to 1200–3200 mg/day
• Higher doses have increased risk of bleeding
• Duration of action: 6–8 hours
• Side effects: symptomatic gastroduodenal ulcers, digestive
bleeding, perforation and renal injury are the most
common serious adverse effects [19].
Selective COX-2 Inhibitors
• Mechanism of action: selective COX-2 inhibition
• Major advantage over other NSAIDs is no adverse effect on
platelet function (COX-2 is not expressed by platelets)
• Celecoxib (Celebrex):
• Hepatic metabolism
• Usual dose: 100–200 mg PO q12–24h; up to 400 mg in
24 hours
• Duration of action: 12–33 hours
Drugs for Neuropathic Pain
Medications that are commonly used for neuropathic pain
include tricyclic antidepressants, serotonergic antidepressants,
and antiepileptics. These medications are rarely used alone for
pain management in an ICU setting [41]. Gabapentin is briefly
discussed here.
Gabapentin
• Gabapentin is structurally similar to GABA. Its mechanism
of action is thought to be related to modulation of calcium
channels
• It is used as initial or adjunctive therapy for neuropathic pain
• It does not bind to plasma proteins and it is entirely
secreted through the kidneys. Thus, the dose must be
reduced in patients with renal failure
• The effective dose for neuropathic pain ranges from
1800–3600 mg/day, which should be divided on a three to
four times a day schedule
• Side effects include nausea, dizziness, sedation, and
behavioral changes [41].

Neuromuscular Blockade
Neuromuscular blockade drugs are divided in two categories
based on their mechanism of action on the postsynaptic end
plate; depolarizing and nondepolarizing. Succinylcholine is the
only available depolarizing agent. Succinylcholine has a very
short half-life and is primarily used during anesthesia for
general surgeries. Its multiple side effects, especially its inter-
action with potassium, make it an undesirable medication for
use in the ICU, although it is still sometimes used to facilitate
intubation [42]. Thus, nondepolarizing neuromuscular blockers
are considered the drugs of choice to achieve muscular relax-
ation in the ICU. Overall, the use of neuromuscular blocking
agents (NMBAs) has been steadily declining over time, other
than to facilitate intubation. In general, all other resources must
be exhausted before application of these drugs [43].
Indications
• The most common indications for long-term
administration of NMBAs include facilitation of
mechanical ventilation, control of ICP, ablation of muscle
spasms associated with tetanus, and decreasing oxygen
consumption. NMBAs are often used to facilitate
ventilation and ablate muscular activity in patients with
elevated ICP or seizures, but have no direct effect on either
condition. Patients who are being treated for seizures who
also take NMBAs should have EEG monitoring to ensure
that they are not actively seizing while paralyzed.
• The majority of patients in an ICU who are prescribed an
NMBA can be managed effectively with pancuronium.
• For patients for whom vagolysis is contraindicated (e.g.
those with cardiovascular disease), NMBAs other than
pancuronium may be used.
• Because of their unique metabolism, cisatracurium or
atracurium are recommended for patients with significant
hepatic or renal disease.
• Patients receiving NMBAs should be assessed both
clinically and by train of four (TOF) monitoring with a
goal of adjusting the degree of neuromuscular blockade to
achieve one or two twitches.
• Before initiating neuromuscular blockade, patients should
be medicated with sedative and analgesic drugs to provide
adequate sedation and analgesia in accordance with the
physician’s clinical judgment to optimize therapy.
• For patients receiving NMBAs and corticosteroids, every
effort should be made to discontinue NMBAs as soon as
possible.
• Drug holidays (i.e. stopping NMBAs daily until forced to
restart them based on the patient’s condition) may decrease
the incidence of acute quadriplegic myopathy
syndrome (AQMS).
• Patients receiving NMBAs should have prophylactic eye
care therapy and deep venous thrombosis (DVT)
prophylaxis.
Chapter 5: Analgesia, Sedation, and Paralysis
• Patients who develop tachyphylaxis to one NMBA should
try another drug if neuromuscular blockade is still required.
• Institutions should perform an economic analysis using
their own data when choosing NMBAs for use in an ICU.
Pharmacology of Neuromuscular-Receptor Blockers
The discussion will be limited to nondepolarizing neuromus-
cular blockers as they are most commonly used in the ICU.
Aminosteroidal Compounds
The aminosteroidal compounds include pancuronium, pipe-
curonium, vecuronium, and rocuronium.
Pancuronium
• A long-acting, nondepolarizing compound
• Intravenous bolus dose of 0.06–0.1 mg/kg for up to 90
minutes; continuous infusion by adjusting the dose to the
degree of neuromuscular blockade that is desired
• Side effects
• Vagolytic (more than 90% of ICU patients will have an
increase in heart rate of 10 beats/min)
• In patients with renal failure or cirrhosis, the
neuromuscular blocking effects of pancuronium are
prolonged because of its increased elimination half-life
and the decreased clearance of its 3-
hydroxypancuronium metabolite that has one-third to
one-half the activity of pancuronium [19].
Pipecuronium
• Long-acting NMBA with an elimination half-life of about
2h
• The administration of 8 mg of the drug followed by
intermittent boluses of 4–6 mg when needed result in
optimal paralysis [19].
Vecuronium
• Vecuronium is an intermediate-acting NMBA that
is a structural analogue of pancuronium and is not vagolytic
• An IV bolus dose of vecuronium 0.08–0.1 mg/kg, produces
blockade within 60–90 seconds that typically lasts 25–30
minutes. After an IV bolus dose, vecuronium is given as a
0.8–1.2 μg/kg/min of continuous infusion, adjusting the
rate to the degree of blockade desired
• 35% of a dose is renally excreted; patients with renal failure
will have decreased drug requirements
• 50% of an injected dose is excreted in bile, patients with
hepatic insufficiency will also have decreased drug
requirements to maintain adequate blockade
• Vecuronium has been reported to be more commonly
associated with prolonged blockade once discontinued,
compared with other NMBAs
• Recovery time averages 1–2 hours but ranges from
30 minutes to more than 48 hours [19].
45
 Chapter 5: Analgesia, Sedation, and Paralysis
Rocuronium
• Rocuronium is a newer nondepolarizing NMBA with a
monoquaternary steroidal chemistry that has an
intermediate duration of action and a very rapid onset
• When given as a bolus dose of 0.6–1.0 mg/kg, blockade is
almost always achieved within 2 minutes, with maximum
blockade occurring within 3 minutes. Continuous
infusions are begun at 10 mg/kg/min
• The rocuronium metabolite 17-desacetylrocuronium has
only 5–10% activity compared with the parent
compound [19].
Benzylisoquinolinium Compounds
The benzylisoquinolinium compounds include d-tubocuranine,
atracurium, cisatracurium, doxacurium, and mivacurium.
D -Tubocurarine
• Tubocurarine was the first nondepolarizing NMBA to gain
acceptance and use in the ICU
• It induces histamine release and autonomic ganglionic
blockade. Hypotension is rare, however, when the agent is
administered slowly in appropriate dosages (e.g. 0.1–0.2
mg/kg). Metabolism and elimination are affected by both
renal and hepatic dysfunction.
Atracurium
• Atracurium is an intermediate-acting NMBA with minimal
cardiovascular adverse effects and is associated with
histamine release at higher doses
• It is inactivated in plasma by ester hydrolysis and Hofmann
elimination so that renal or hepatic dysfunction does not
affect the duration of blockade. Thus, it will be an option
for patient with hepatic or renal failure
• Laudanosine is a breakdown product of Hofmann
elimination of atracurium and has been associated with
central nervous system excitation
• Seizures in patients who have received extremely high
doses of atracurium or who are in hepatic failure
• 10–20 g/kg/min with doses adjusted to clinical
endpoints or by TOF monitoring. Infusion durations
range from 24 to 200 hours. Recovery of normal
neuromuscular activity usually occurs within 1–2 hours
after stopping the infusions and is independent of organ
function
• Long-term infusions have been associated with the
development of tolerance, necessitating significant dose
increases or conversion to other NMBAs
• Atracurium has been associated with persistent
neuromuscular weakness, as have other NMBAs [19].
Cisatracurium
• Cisatracurium, an isomer of atracurium, is an
intermediate-acting NMBA that is increasingly used in lieu
of atracurium
46
• It produces few, if any, cardiovascular effects and has a
lesser tendency to produce mast cell degranulation than
atracurium
• Bolus doses of 0.1–0.2 mg/kg result in paralysis in an
average of 2.5 minutes, and recovery begins at
approximately 25 minutes; maintenance infusions should
be started at 2.5–3 μg/kg per minute
• Cisatracurium is also metabolized by ester hydrolysis
and Hofmann elimination, so the duration of
blockade should not be affected by renal or hepatic
dysfunction
• Prolonged weakness has been reported after the use of
cisatracurium [19].
Doxacurium
• Doxacurium, a long-acting agent, is the most potent
NMBA currently available
• Doxacurium is essentially free of hemodynamic adverse
effects
• Initial doses of doxacurium 0.05–0.1 mg/kg may be given
with maintenance infusions of 0.3–0.5 μg/kg/min and
adjusted to the degree of blockade desired. An initial bolus
dose lasts an average of 60–80 minutes
• Doxacurium is primarily eliminated by renal excretion. In
elderly patients and patients with renal dysfunction, a
significant prolongation of effect may occur.
Mivacurium
• Mivacurium is one of the shortest-acting NMBAs currently
available
• It consists of multiple stereoisomers and has a half-life of
approximately 2 minutes, allowing for rapid reversal of the
blockade.
Recommendations for Monitoring Degree of
Blockade
Even though the patient may appear quiet and “comfortable,”
experienced clinicians understand the indications and thera-
peutic limits of NMBAs. Despite multiple admonitions that
NMBAs have no analgesic or amnestic effects, it is not uncom-
mon to find a patient’s degree of sedation or comfort signifi-
cantly overestimated or even ignored. It is difficult to assess
pain and sedation in a patient receiving NMBAs, but patients
must be medicated for pain and anxiety, despite the lack of
obvious symptoms or signs. In common practice, sedative and
analgesic drugs are adjusted until the patient does not appear
to be conscious and then NMBAs are administered.
• Monitoring neuromuscular blockade is recommended.
Monitoring the depth of neuromuscular blockade may
allow use of the lowest NMBA dose and may minimize
adverse events
• Visual, tactile, or electronic assessment of the patient’s
muscle tone or some combination of these three is

commonly used to monitor the depth of neuromuscular
blockade
• Observation of skeletal muscle movement and respiratory
effort forms the foundation of clinical assessment;
electronic methods include the use of ventilator software
allowing plethysmographic recording of pulmonary
function to detect spontaneous ventilatory efforts and
“twitch monitoring,” i.e. the assessment of the muscular
response by visual, tactile, or electronic means to a
transcutaneous delivery of electric current meant to induce
peripheral nerve stimulation (PNS)
• TOF monitoring (with a goal of three or four twitches)
• Implementation of a protocol using PNS to monitor the
level of blockade in patients receiving a variety of NMBAs
found a reduction in the incidence of persistent
neuromuscular weakness [43]
• Currently, there is no universal standard for twitch
monitoring. The choice of the number of twitches
necessary for “optimal” blockade is influenced by the
patient’s overall condition and level of sedation. The
choice of the “best” nerve for monitoring may be
influenced by site accessibility, risk of false positives,
considerations for the effect of stimulation on patient
visitors, and whether faint twitches should be included in
the assessment of blockade. The low correlation of
blockade measured peripherally compared with that of the
phrenic nerve and diaphragm underscores the importance
of three issues:
1. More than one method of monitoring should be
utilized
2. Poor technique in using any device will invariably
produce inaccurate results
3. More clinical studies are necessary to determine the
best techniques.
• Patients receiving NMBAs should be assessed both
clinically and by TOF monitoring with a goal of adjusting
the degree of neuromuscular blockade to achieve one or
two twitches.
Potential Complications of Neuromuscular Blockade
Use in the ICU
• Anxiety in the awake, paralyzed patients
• Plasma pseudocholinesterase autonomic and
cardiovascular effects (i.e. vagolytic)
• Decreased lymphatic flow
• Risk of generalized deconditioning
• Skin breakdown
• Peripheral nerve injury
• Corneal abrasion and keratitis. Prophylactic eye care is
highly variable and recommendations may include
methylcellulose drops, ophthalmic ointment, taping the
eyelids shut to ensure complete closure, or eye patches
• Myositis ossificans
Chapter 5: Analgesia, Sedation, and Paralysis
• Risk of prolonged muscle weakness, acute quadriplegic
myopathy syndrome (AQMS)
• Potential central nervous system toxicity.
Skeletal muscle weakness in ICU patients is multifactorial,
producing a confusing list of names and syndromes, includ-
ing AQMS, floppy man syndrome, critical illness polyneuro-
pathy (CIP), acute myopathy of intensive care, rapidly
evolving myopathy, acute myopathy with selective lysis of
myosin filaments, acute steroid myopathy and prolonged
neurogenic weakness.
Prolonged Recovery from NMBAs
• The steroid-based NMBAs are associated with reports of
prolonged recovery and myopathy. This association may
reflect an increased risk conferred by these NMBAs or may
reflect past practice patterns in which these drugs may have
been more commonly used [43]
• Steroid-based NMBAs undergo extensive hepatic
metabolism, producing active drug metabolites
• The 3-desacetyl vecuronium metabolite is poorly dialyzed,
minimally ultrafiltrated, and accumulates in patients with
renal failure because hepatic elimination is decreased in
patients with uremia. Thus, the accumulation of both
3-desacetyl vecuronium and its parent compound,
vecuronium, in patients with renal failure contributes to a
prolonged recovery by this ICU subpopulation.
Acute Quadriplegic Myopathy Syndrome
• AQMS consists of a clinical triad of:
• Acute paresis
• Myonecrosis with increased CPK concentration
• Abnormal electromyography (EMG), characterized by
severely reduced compound motor action potential
(CMAP) amplitudes and evidence of acute denervation.
• AQMS, also referred to as postparalytic quadriparesis, is
one of the most devastating complications of NMBA
therapy and one of the reasons that indiscriminate use of
NMBAs is discouraged
• Neurologic examination reveals a global motor deficit
affecting muscles in both the upper and lower extremities,
and decreased motor reflexes. However, extraocular muscle
function is usually preserved. This myopathy is
characterized by low amplitude CMAPs, and muscle
fibrillations, but normal (or nearly normal) sensory nerve
conduction studies
• Muscle biopsy shows prominent vacuolization of
muscle fibers without inflammatory infiltrate, patchy
type 2 muscle fiber atrophy, and sporadic myofiber
necrosis
• Modest CPK increases (0 to 15-fold above normal range)
are noted in approximately 50% of patients and are
probably dependent on the timing of enzyme
47
 Chapter 5: Analgesia, Sedation, and Paralysis

measurements and the initiation of the myopathic process.
Thus, there may be some justification in screening patients
with serial CPK determinations during infusion of
NMBAs, particularly if the patients are concurrently
treated with corticosteroids
• Also, since AQMS develops after prolonged exposure to
NMBAs, there may be some rationale to daily “drug holidays”
• Other factors that may contribute to the development of
the syndrome include nutritional deficiencies, concurrent
drug administration with aminoglycosides or cyclosporine,
hyperglycemia, renal and hepatic dysfunction, fever, and
severe metabolic or electrolyte disorders
• The incidence of myopathy may be as high as 30% in
patients who receive corticosteroids and NMBAs
• Acute myopathy in ICU patients is also reported after
administration of the benzylisoquinolinium NMBAs (i.e.
atracurium, cisatracurium, doxacurium) [43].
Drug–Drug Interactions of NMBAs
Medications that affect neuromuscular transmission likely will
interact with NMBAs through different mechanisms. A few are
mentioned here:
• Phenytoin causes resistance to NMBAs by up-regulating
acetylcholine receptors
• Magnesium has a marked inhibitory effect on
acetylcholine release by competing with calcium
presynaptically
• Corticosteroids may decrease the sensitivity of the end
plate to the receptor
• Calcium channel blockers theoretically depress muscle
contractility
• Most antimicrobials affect synaptic transmission
• Antiarrhythmics: (procainamide, quinidine) block
nicotininc receptor channels.

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49
 Chapter
Airway Management and Mechanical Ventilation
6 in the Neurocritical Care Unit
David B. Seder and Julian Bösel
Introduction
The airway management and mechanical ventilation of
patients with neurological disease requires continuous atten-
tion to the effects of respiration on neurophysiology. Brain-
injured patients frequently lack compensatory reserves and are
therefore vulnerable to “minor” physiologic changes to which
we may pay little attention – an intubation during which the
bed is left flat, ventilation interrupted, light analgosedation
administered, and prolonged direct laryngoscopy performed
may precipitate brain herniation in a patient with a mass lesion
or elevated intracranial pressure (ICP). Yet it takes little effort
to minimize the time the head is down, to see that ventilation
is not interrupted, and to provide adequate analgosedation –
possibly leading to a very different outcome.
Airway and ventilation concerns in neurocritical care can
be considered in terms of those general to all patients with
critical illness, and those specific to patients with neurological
diseases. This chapter will describe fundamental concerns
related to airway management and mechanical ventilation in
patients with acute neurological disease.
General Airway and Ventilation Management
Concerns
Airway management is conceived in terms of indications
for intubation, extubation, or a surgical airway, prediction of
difficult bag-mask ventilation or intubation, preparation for
intubation, the intubation procedure itself, including use of
specialized airway adjunct devices, peri-intubation patient
management, and general criteria for extubation.
Ventilation concerns include maintenance of acid–base
status and systemic oxygenation, lung-protective ventilation in
patients at risk of ventilator-associated lung injury, and ventila-
tory management of respiratory pathophysiology, such as
obstructive airway disease, severe hypoxemia, or pneumothorax.
Airway Management
Airway management issues specific to neurocritical care
include intubation of patients with known or suspected ele-
vated ICP, an unstable cervical spine, threatened cerebral per-
fusion, and management of neuromuscular respiratory failure.
The extubation or tracheostomy of patients with neurological
50
injury is increasingly acknowledged as an area of wide vari-
ability in practice, and will be discussed in detail.
Ventilation concerns specific to neurocritical care include
the effects of ventilation on cerebral blood flow, including
intentional hyperventilation for elevated ICP, the effects of
airway pressure on ICP and cerebral perfusion pressure
(CPP), and effects of oxygen and pH on reperfusion injury.
Indications for Intubation
Common indications for intubation of patients with neuro-
logical diseases are failure to oxygenate, failure to ventilate,
failure to protect the airway, anticipated neurological or
cardiopulmonary decline, and prevention of ischemia or sec-
ondary neurological injury related to anxiety, pain, work of
breathing, or aspiration.
Because of the potential for respiratory arrest, large-volume
aspiration, or unsafe hemodynamic fluctuations, intubation and
the initiation of mechanical ventilation are critical to protect
patients in a period of neurological decline. In particular,
patients that will require transport, neuroimaging, and medical
or surgical procedures to maintain clinical stability should be
intubated to ensure a stable airway and adequate oxygenation
and ventilation. It should be noted that “failure to protect the
airway” is a grossly subjective measure but involves two primary
components – adequate airway clearance involving oropharyn-
geal coordination, cough reflexes, and respiratory muscle
strength, and the ability to maintain a patent upper airway.
Contraindications to (Elective) Intubation
Except for a “Do Not Intubate” order, there are no absolute
contraindications to intubation – that is to say contraindica-
tions must be weighed against the benefits of intubation for
patients in a period of rapid decompensation. Relative contra-
indications include the need to preserve the neurological
examination without the interfering effects of sedative and
analgesic agents, the presence of critical brain ischemia, such
as in an acute cerebrovascular flow-failure event, in which a
large ischemic penumbra is perfused by maximally dilated
collateral vasculature, significant cervical spine instability,
and an anticipated difficult airway (such as mechanical upper
airway obstruction) with inadequate resources present. Each of
these relative contraindications will be discussed further in this

chapter, but clinicians must recognize these circumstances
require special attention, and should not be attempted without
a risk–benefit assessment and maximal preparation.
Alternatives to Intubation
Intubation and postintubation management often require
analgesia and sedation, at times muscle relaxants, and vasocon-
strictor agents and/or intravascular fluids to counteract the
effects of those vasodilators. Intubation is extremely uncomfort-
able, activates the sympathetic nervous system, and requires
frequent analysis of the adequacy of ventilation by arterial blood
gas or end-tidal carbon dioxide measurement. Alternatively,
high-flow oxygen delivery by a standard or high-flow nasal
cannula or face mask device can provide close to 100% inspired
oxygen, provide a small amount of positive end expiratory
pressure (PEEP), and may be better tolerated than noninvasive
positive pressure ventilation (NPPV) with a pressure mask.
Technology to provide NPPV has dramatically improved in
recent years – including the development of portable ventilators
specifically designed for noninvasive ventilation that can com-
pensate for mask leaks and typically provide excellent patient–
ventilator synchrony [1,2]. Hundreds of different pressure masks,
including full hoods, face masks, oronasal masks, nasal masks,
and tight-fitting nasal cannulas make patient comfort during
mask ventilation less of an issue than ever before. Using modern
equipment, the practical limitations to NPPV are that it provides
partial, not complete, ventilatory support, and it offers no lower
airway protection or maintenance of an open upper airway.
Finally, tracheostomy should be viewed as an alternative to
intubation. Many patients with neurological disease and espe-
cially those with brain injury lack adequate airway protective
reflexes, but ventilate and oxygenate perfectly well. In such
cases, early tracheostomy can provide a reliable and patent
upper airway, facilitate suctioning of the lower airways, allow
patients to breathe spontaneously, therefore preserving
respiratory muscle function, and eliminate the need for anal-
gesia and sedation that may slow neurological recovery by
interfering with the return of consciousness [3,4]. Tracheos-
tomy will be discussed later in this chapter.
Table 6.1 ATS/ERS guidelines to contraindications of NPPV [5]
• Cardiac or respiratory arrest
• Non-respiratory organ failure
• Hemodynamic instability or unstable cardiac arrhythmia
• Severe encephalopathy (GCS <10)
• Severe upper gastrointestinal bleeding
• Facial trauma, surgery or deformity
• Upper airway obstruction
• Inability to cooperate or protect airway
• Inability to clear respiratory secretions
• High risk for aspiration
Chapter 6: Airway Management and Mechanical Ventilation
Preparation for Intubation
Preparation for intubation of the neurological patient should
include a presedation neurological assessment, assessment of
factors associated with difficult bag-mask ventilation and diffi-
cult intubation, and selection of induction agents, as well as
fluids and vasopressors to maintain hemodynamic stability.
Anticipatory of intubation, clinicians should assess and con-
sider five categories of risk:
• Is this a difficult airway or difficult mask-ventilation scenario?
• What medications or maneuvers should be avoided?
• Is this intubation high risk due to elevated intracranial
pressure?
• Is this intubation high risk due to threatened cerebral
perfusion?
• Is the cervical spine unstable?
Preparation for Difficult Mask Ventilation and
Difficult Airway Scenarios
Difficult bag-mask ventilation is usually a more dangerous
situation than difficult intubation – a sedated or paralyzed
patient may arrest if they cannot be oxygenated or ventilated,
while a difficult intubation can typically be bag-mask ventilated
indefinitely – long enough for neuromuscular blockade to wear
off or help to arrive. The “MOANS” pneumonic can be used to
predict difficulty of bag-mask ventilation:
M = Mask seal (beard, unusual anatomy)
O = Obesity/obstruction
A = Age >55
N = No teeth
S = Stiff lungs
The “LEMON” pneumonic helps to predict a difficult airway:
L = Look (at the face, mouth, and neck)
E = Evaluate the mouth opening and airway position
M = Mallampati score
O = Obstruction
N = Neck mobility
The airways of patients with risk factors for either difficult
mask ventilation or difficult intubation should be approached
with caution. The urgency of the intubation, as well as the skill
level of the intubating clinician must be considered. Because
not every difficult intubation can be predicted, clinicians
should enter into every intubation situation with a “backup”
plan. Patients anticipated to be difficult to ventilate or intubate
should prompt preparation with appropriate back-up in terms
of skilled individuals (e.g. anesthesiology assistance) and
special equipment. Adjunct airway devices such as laryngeal
mask airways, special blades, video scopes, intubating stylets,
fiberoptic intubating equipment, and surgical airway equip-
ment should be immediately available. In modern airway
management, the availability of basic airway adjunct devices
such as laryngeal mask airways (LMAs), videoscopes, and
intubating stylets should be considered mandatory.
51
 Chapter 6: Airway Management and Mechanical Ventilation
Induction Medication Issues to Consider in the
Neurocritically Ill
As a neuromuscular blockade agent, succinylcholine should be
withheld in patients with hyperkalemia, as well as those with
normal potassium levels, but at risk for a surge in serum
potassium due to prolonged immobility. Examples of such
patients in the neurological population include those with
upper motor neuron lesions resulting from stroke, brain or
spinal cord tumors, other intracerebral or spinal cord masses,
closed head injury, spinal cord injury, or encephalitis. Keta-
mine, a dissociative agent that maintains blood pressure was
suspected to increase ICP by older reports, but according to
more recent studies is safe if coadministered with a sedative.
Especially in a dehydrated patient, propofol and opioids may
cause excessive vasodilation and blood pressure drop unless
counteracted with vasopressors or fluids.
Intubation in the Setting of Elevated Intracranial
Pressure
Patients with intracranial hypertension are at risk for ICP or
inadequate cerebral perfusion during intubation. Clinicians
should pay special attention to the adequacy of sedation and
analgesia during laryngoscopy, to head-of-the-bed up pos-
itioning, and to the adequacy of blood pressure and ventila-
tion. Direct laryngoscopy causes sympathetic stimulation,
potentially triggering tachycardia, hypertension, broncho-
spasm, and increased ICP. When preparing for intubation,
leave the head of the bed up at 30° to 45°, briefly bring the
bed flat during the procedure, then return the bed to its
original position. If necessary, the patient can be maintained
in reverse Trendelenburg positioning throughout the intub-
ation. Medications that blunt the ICP rise associated with
laryngoscopy include intravenous lidocaine, analgesics such
as fentanyl, and sympatholytics like esmolol. Hypotension,
hypoxemia, and hypercarbia cause vasodilation and an
increase in cerebral blood volume, leading to a rise in ICP.
Preoxygenation is vital as it washes out nitrogen in the lungs
and prolongs the time to oxyhemoglobin desaturation. The
patient’s minute ventilation should be maintained throughout
the procedure to avoid CO2 retention – a matter of urgency in
patients with central nervous system mass lesions and elevated
ICP. Adequate intravenous access is critically important to
manage hemodynamic changes during intubation, and we
suggest routine infusion of isotonic crystalloid during the
procedure. Vasopressors should be readily available in the
event of hypotension to maintain adequate CPP.
Intubation in the Setting of Impaired Cerebral
Perfusion
In suspected or proven ischemic stroke, one should proceed
with intubation as with elevated ICP by avoiding hypotension
during induction and postintubation, and taking special
52
precautions to avoid hypotension-inducing drugs, especially
in hypotensive patients. When an ischemic stroke is suspected
or known to be occurring, or a state of inadequate cerebral
blood flow (CBF) exists for other reasons, brain ischemia
should be presumed to be present.
The cerebrovascular circulation is ordinarily well collat-
eralized, and many patients presenting with stroke symptoms
can be seen to have an infarct core and an ischemic penumbra
on perfusion computed tomography (CT) or magnetic reson-
ance imaging (MRI). Under these circumstances, the ischemic
penumbra may be conceptualized as a region of maximally
vasodilated vessels, receiving maximal shunting of the cerebro-
vascular circulation, yet CBF is severely compromised and
maximally compensated. Hypertension and tachycardia in
such patients may reflect a physiologic, not pathophysiologic,
response to this ischemia and may be necessary to maintain
perfusion of the ischemic territory [6,7].
Further, even vasoactive agents that do not perceptibly
drop the systemic blood pressure or alter CPP may reverse
physiological regional shunting of blood to the region of
ischemia, and should be avoided in conditions of active ische-
mia. An episode of relative or actual hypotension, such as
would be precipitated by the administration of a vasodilator
sedative medication like propofol to a volume-depleted patient,
can dramatically worsen infarction size by “stealing” blood
flow from maximally dilated watershed territories between
vascular distributions.
Brain ischemia is not limited to ischemic stroke, but can
also be variably present in patients with cerebral vasospasm,
traumatic brain injury (TBI), intracranial and extracranial
cerebrovascular stenosis, intracerebral hemorrhage, and
hypoxic-ischemic encephalopathy following resuscitation from
cardiac arrest. Strong associations between episodic hypotension
in the critical hours following resuscitation and poor neuro-
logical outcome have been noted in TBI and hypoxic-ischemic
encephalopathy after cardiac arrest [8,9] The intubating clin-
ician should be aware of the risks of even a transient decrease in
cerebral blood flow, and strive to maintain both cerebral and
systemic vascular tone during airway management.
Brain ischemia is also worsened by hyperventilation – an
association clearly demonstrated in TBI [10] and explained in
the laboratory by a dramatic and immediate decrease in CBF
and increase in the volume of ischemic brain tissue when
hyperventilation is performed [11]. Clinicians should attempt
to maintain normocapnea during this period, and early correl-
ation of an arterial CO2 sample with end-tidal CO2 (ETCO2) is
suggested, so that continuous capnography can be used to
verify normocarbia.
Intubation of a Patient with an Unstable
Cervical Spine
When spinal column or ligamentous injury to the neck is
suspected due to the mechanism of injury – such as any blunt
head trauma resulting in loss of consciousness – all measures
 Chapter 6: Airway Management and Mechanical Ventilation

must be taken to protect the spinal cord during any move-

ments or procedures. Preintubation airway maneuvers, includ-
ing jaw tilt, bag-mask ventilation, cricoid pressure, and direct
laryngoscopy can all injure the spinal cord when cervical
instability is present.
Any patient with a confirmed or suspected unstable cer-
vical spine should be immediately placed in a rigid cervical
collar or other stabilization device. During intubation, manual
in-line axial stabilization and gentle traction of the head and
neck by an assistant are mandatory if the patient requires any
manipulation of the head or neck. During airway manage-
ment, cervical subluxation occurs during chin lift, jaw thrust,
bag-mask ventilation, and tracheal intubation, as well as man-
euvers such as cricoid pressure and head turning. Mask venti-
lation was found in one study to cause more cervical spine
displacement than any other method used for tracheal intub-
ation [12]. These maneuvers must not be used.
The basic principles of cervical spine stabilization have
been developed and refined over decades, though no modifica-
tions to the algorithm mapped out by the American College of
Surgeons’ Advanced Trauma Life Support (ATLS) course are
recommended. In urgent circumstances in the field, endotra-
cheal intubation is preferred to bag-mask ventilation or cri-
cothyrotomy and should be performed with in-line spinal
stabilization. Although cricoid pressure is no longer recom-
mended during intubation, it definitely should not be used in Figure 6.1 “Ramping up” an obese patient. In panel A, the usual supine
patients with cervical spine injury, since it may cause posterior alignment in obesity is shown. In panel B, the patient is “ramped up” with
blankets, bringing the external auditory meatus to the level of the sternal notch.
displacement of the cervical spine.
Hypoxia, hypoventilation, and large-volume aspiration are
larger risks to trauma patients than complications of endotra- inability to meet ventilatory demands. Alternatively, some
cheal intubation; in-line spinal stabilization helps ensure safe rapidly progressive forms of neuromuscular respiratory failure
intubating conditions when direct laryngoscopy is performed cause severe bulbar dysfunction and loss of cough reflexes.
[13], and is the standard of care. The minimum amount of When bulbar dysfunction is predominant, intubation is typic-
anterior–posterior displacement of the cervical spine occurs ally required. But when respiratory muscle weakness is the
with flexible fiberoptic intubation, however [14], and is pre- dominant problem, patients with preserved bulbar function
ferred when time and circumstances allow, and when severe and dyspnea or increased work of breathing should undergo
instability is present. a trial of noninvasive ventilation combined with airway clear-
ance by the frequent use of chest physiotherapy and a cough-
assist device. Such interventions can prevent the need for
Reducing Peri-Intubation Risk intubation and improve outcomes, particularly in patients with
Backup plans for oxygenation and ventilation, and for securing myasthenia gravis [15].
the airway under difficult circumstances, should include Any patient with neuromuscular weakness and dyspnea
airway adjuncts and special equipment, and routine “ramping should undergo an assessment of respiratory function that
up” of obese patients prior to administration of muscle relax- includes:
ants. Clinicians should use medications best suited to an indi- • Arterial blood gas measurement
vidual patient’s pathophysiology, including intravascular • Serial pulmonary function testing to include negative
volume expansion, prevention of episodic hypotension with inspiratory force (NIF) and vital capacity (FVC)
vasopressors and hemodynamically neutral intubating agents,
• Assessment of bulbar function, neck strength, and cough.
blunting of the ICP response to direct laryngoscopy with
Patients with a rapidly progressive course and those who
analgesics, and minimizing time with the head of the bed flat.
do not rapidly stabilize gas exchange and work of breathing
with noninvasive ventilation should be intubated [15]. Because
Neuromuscular Respiratory Failure of the potential for exacerbating weakness and prolonged
Respiratory failure in patients with neuromuscular disease is effects of the medications, the administration of corticoster-
often associated with a weak cough and failure to clear secre- oids, muscle relaxants, or neuromuscular blocking agents is
tions, leading to atelectasis, shunting, pneumonia, and the discouraged.

53
 Chapter 6: Airway Management and Mechanical Ventilation
In myasthenia gravis, succinylcholine may require approxi-
mately 2.5 times the dose to produce the same effects, and the
action may be prolonged. Nondepolarizing agents such as
rocuronium are also safe, but will have a prolonged duration
[16]. In conditions such as Guillain–Barré, succinylcholine can
precipitate life-threatening hyperkalemia, and only nondepo-
larizing agents should be used. Rocuronium, a short-acting
nondepolarizing agent is a safe and almost identically effective
induction agent in cases of neuromuscular weakness, often
administered at a dose of 0.6–1.2 mg/kg.
Preintubation Neurological Evaluation
Urgent management of the airway should coincide with a
rapid, but detailed, neurological assessment [7]. The preseda-
tion/preintubation neurologic exam is crucial to subsequent
triage decisions, and can typically be conducted in a few
minutes. It establishes a baseline that is used to assess thera-
peutic interventions or may identify injuries that are at risk of
progressing (e.g. unstable cervical spine fractures). The assess-
ment identifies the most appropriate testing and helps to avoid
unnecessary, uncomfortable interventions, such as cervical
spine immobilization. The preintubation neurological assess-
ment is the responsibility of the team leader who is coordin-
ating resuscitation efforts; findings should be documented and
communicated directly to the treatment team that assumes
care of the patient.
The preintubation neurological examination should rou-
tinely include assessment of:
• Level of arousal, interaction, and orientation, as well as an
assessment of simple cortical functions such as vision,
attention, and speech comprehension and fluency
• Cranial nerve function
• Motor function of each individual extremity
• Tone and reflexes
• Comment on subtle or gross seizure activity
• Cervical spine tenderness, when appropriate
• Sensory level in patients with suspected spinal cord injury.
Intubation
Rapid sequence intubation may provide protection against the
reflex responses to laryngoscopy and rises in ICP [17]. The
presence of coma should not be interpreted as an indication to
proceed without appropriate analgesia and sedation. Although
the patient may seem unresponsive, laryngoscopy and intub-
ation trigger elevates ICP unless appropriate pretreatment and
induction agents are used.
Outcomes in patients with intracranial catastrophes are
related to the maintenance of brain perfusion and oxygenation;
consequently, tight control of these two parameters is critical.
Cerebral perfusion pressure (CPP) is the physiologic correlate
for blood flow to the brain and is calculated as the difference
between the mean arterial pressure (MAP) and ICP. It is
generally recommended that the ICP be maintained below
54
20 mmHg, MAP at 80–110 mmHg, and CPP at a minimum
of 60 mmHg. Because the intracranial pressure may not be
known at the time of urgent intubation, clinicians should
anticipate elevated ICP in patients with a mass lesion such as
hematoma, hydrocephalus, tumor, or cerebral edema, and
choose an appropriate BP target accordingly. Although some
authors have postulated that ICP may be unimportant in the
setting of a preserved CPP [18], there are data suggesting
ICP >30 is independently associated with injury [19], and a
CPP-only ICP management strategy is not recommended.
Many neurologically impaired patients have compromised
CBF, even with a normal ICP. For example, patients with
ischemic stroke, vasospasm, and hypoxic-ischemic brain injury
often have impaired cerebrovascular autoregulation and are
each critically sensitive to decreases in blood pressure and
CBF. In these patients, the goal is to maintain MAP and
CPP, as for the patients with known or suspected elevation of
ICP. Vasodilators, which reverse physiological shunting,
should be avoided. Common induction agents are described
in Table 6.2.
Approach to the Difficult Airway
A stylet is a smooth malleable plastic or metal rod that is
placed through the endotracheal tube to facilitate intubation –
a “J” or “hockey stick” shape allowing the tube to be directed
anterior towards the vocal cords is preferred. Another
common technique is bimanual laryngoscopy. The laryngos-
copist uses his or her right hand to apply either cricoid pres-
sure or the “BURP” maneuver (backward, upward, rightward
pressure on thyroid cartilage) to attempt to obtain a better
view of the airway. An assistant then holds this position as the
laryngoscopist intubates.
Airway adjuncts can facilitate intubation. The gum-elastic
bougie is a common choice. It is a 60 cm malleable intubating
stylet with a 40° angled tip that is placed through the visualized
vocal cords. Alternatively, a bougie can be placed blindly
through the vocal cords by “feeling” the tracheal rings upon
appropriate placement. The endotracheal tube is then
advanced and the bougie removed.
A lighted stylet, or light wand, is placed blindly. When the
lighted tip enters the glottis, the anterior neck displays a bright
red light, and when it enters the esophagus, there is a diffuse
dull glow. The endotracheal tube is then advanced over the
stylet into the trachea.
Video intubation has revolutionized airway management,
in part because there does not need to be a direct line of vision
between the eye and the vocal cords – a video camera at the
curved tip of an intubating blade allows for an intubating stylet
or endotracheal tube to be passed between the vocal cords
without a direct line of vision – making difficult anterior
airways accessible. Flexible bronchoscopy facilitates nasal or
oral intubation, though oral intubation is preferred unless
absolute spinal neutrality is demanded. Except in unusual
circumstances, the video laryngoscope is preferred over the
 Chapter 6: Airway Management and Mechanical Ventilation

Table 6.2 Induction agents

Drug Dose Onset of Duration of Indications Precautions

action effect
Fentanyl 1–3 μ/kg IV push Within 2–3 min 30–60 min Pre-induction, blunts ICP rise Respiratory depression,
over 1–2 min hypotension, rare muscle
rigidity
Lidocaine 1.5 mg/kg IV 45–90 s 10–20 min Pre-induction, blunts ICP rise Avoid if allergic or high
2–3 min grade heart block if no
before intubation pacemaker
Esmolol 2 mg/kg IV 2–10 min 10–30 min Pre-induction, blunts ICP rise Bradycardia, hypotension,
increased airway reactivity
Etomidate 0.3–0.5 mg/kg IV 30–60 s 3–5 min Induction, sedation; does not Decreases seizure
push cause hypotension. Decreases threshold, fasciculations
CBF, ICP, preserves CPP mimicking seizures,
decreases cortisol synthesis
Propofol 1–2 mg/kg IV push 9–50 s 3–10 min Induction, sedation, reduces Hypotension, myocardial
ICP and airway resistance, depression
anticonvulsive effects
Ketamine 2 mg/kg IV push 1–2 min 5–15 min Induction, analgesia, sedation, Catecholamine surge,
amnesia, bronchodilatory tachycardia, hypertension
effects; good in hypotension
Thiopental 3 mg/kg IV push 30–60 s 5–30 min Good for normotensive, Hypotension,
normovolemic pts with status bronchospasm
epilepticus or "ICP
Succinylcholine 1.5–2 mg/kg IV 30–60 s 5–15 min Preferred paralytic unless Caution in hyperkalemia,
contraindicated myopathy, neuropathy/
denervation; avoid if
history of malignant
hyperthermia
Rocuronium 1 mg/kg 45–60 s 30–50 min Paralysis when Long acting, avoid in renal
succinylcholine failure
contraindicated
Vecuronium 0.1 mg/kg Within 3 min 25–40 min Long acting, avoid in renal
failure, slower onset than
rocuronium

fiberoptic bronchoscope due to its ease of use and utility in
anterior displacement of the tongue, improving laryngeal
visualization.
The most commonly used superglottic device is the laryn-
geal mask airway (LMA). The LMA is a small, inflatable latex
mask mounted on the end of a hollow tube. The deflated
device is placed blindly into the hypopharynx with the opening
of the mask projected anteriorly. Once positioned, the mask is
inflated, the opening positioned over the glottis, and the device
is secured by tape like an endotracheal tube. The intubating
LMA (ILMA) has a more rigid and wider tube with a handle
for insertion. This device allows for blind placement of a
modified endotracheal tube through the ILMA. The Combi-
tube® is an esophageal-tracheal double-lumen airway that is
also placed blindly. If the tracheal lumen is placed into the
trachea, ventilation is achieved through the distal lumen. If it is
placed into the esophagus (more common), ventilation is
achieved through the proximal apertures above the distal cuff.
A true emergency arises when a patient cannot be intub-
ated or ventilated. In this situation, a surgical airway is neces-
sary. A needle, wire-guided, or surgical cricothyroidotomy
should be performed; tracheostomy is a more complex and
time-consuming procedure and should be reserved for non-
emergent situations. In a needle cricothyroidotomy, a small
catheter over a needle is passed percutaneously in a caudad
direction through the cricothyroid membrane. When air
bubbles are seen in the syringe, the catheter is advanced over
the needle and the syringe and needle are removed. The cath-
eter is then connected to high-pressure oxygen tubing and
transtracheal jet ventilation is performed. The guide-wire tech-
nique is performed similarly, with the exception that a guide-
wire is placed through the needle and the needle and syringe

55
 Chapter 6: Airway Management and Mechanical Ventilation
are removed with only the guide-wire left behind. A dilator-
airway catheter is passed over the guide-wire, the guide-wire is
removed, and the catheter cuff is inflated. A surgical airway
using a scalpel can be performed quickly and successfully by
nonsurgeons.
Overview of Ventilation
Many types of neurological injury are exacerbated by respira-
tory compromise. Carbon dioxide and pH are powerful deter-
minants of cerebral vascular tone, and the intended or
unintended effects of hyperventilation (decreased cerebral
blood flow, decreased intracranial blood volume, and decreased
ICP) should be anticipated, monitored, and manipulated by
clinicians. Conversely, hypoventilation and hypercapnea cause
cerebral vasodilation and increased ICP. Hyperoxia is a potent
exacerbant of reperfusion injury, while hypoxia is strongly
associated with worse outcomes in stroke, hypoxic-ischemic
encephalopathy, and traumatic brain injury. Finally, when
work of breathing is markedly increased, up to 50% of the
cardiac output may be diverted to the respiratory muscles,
potentially “stealing” blood flow from the ischemic brain or
spinal cord. This metabolic stressor can be effectively managed
by sedation, intubation, and initiation of full mechanical venti-
latory support.
Effects of Hyperventilation and Hypoventilation on
Brain Physiology
Hyperventilation causes cerebral vasoconstriction and
decreased CBF [20], while hypoventilation causes cerebral
vasodilation and increased ICP. Accordingly, dysventilation
is associated with poor outcomes in TBI [10]. The Brain
Trauma Foundation recommends targeting eucapnea in
patients with brain trauma [21]. This should be understood
as a PaCO2 of 30–45, and ideally 35–40.
However, the relationship between arterial and central pH
and pCO2 is complex and incompletely understood. When
underlying metabolic acidosis is concurrent with acute brain
injury, such as in diabetic ketoacidosis [22], it is likely
that because of the blood–brain barrier and central nervous
system (CNS) buffering capacity, CNS pH and CBF are often
preserved, despite a severely acidic systemic pH and very
low pCO2.
Alternatively, in patients with chronic respiratory acidosis
due to chronic obstructive pulmonary disease (COPD), sleep
apnea/obesity hypoventilation syndrome, chronic neuromus-
cular disease, or other etiologies, the set point of cerebral CO2
reactivity changes. It is therefore recommended that mechan-
ical ventilation be adjusted to correct the pH and not the pCO2,
or that the estimated “premorbid” pCO2 target be used (the
pCO2 that achieves a normal pH). This is recommended on
both physiological and practical grounds, since ventilating
patients with obstructive lung disease to “normal” pCO2
targets may be extremely difficult. Because a great deal of
physiologic uncertainty exists in these cases, CBF and/or
56
metabolic monitoring are recommended whenever available
to guide the titration of pH and pCO2 targets, with attention
paid to how changes in ventilation affect CBF and metabolism.
Under these circumstances, surrogates for CBF and metab-
olism may include jugular venous oximetry, direct intracranial
monitoring of CBF or brain tissue oxygen tension, or meas-
urement of lactate and pyruvate levels in the CNS by micro-
dialysis techniques. It should be understood that these
recommendations are based on physiologic knowledge as well
as observational human and experimental animal data, and
that little prospective experimental human data has been
gathered in this area [23–25].
Acidemic and Alkalemic Hypocarbia: Potential for
Suppression of Spontaneous Hyperventilation
There are two circumstances that should be considered in
patients with spontaneous hypocarbia: those whose response
to systemic metabolic acidosis accounts for their high ventila-
tory demand, and those (alkalemic) patients in whom ventila-
tion exceeds systemic metabolic needs.
In patients whose ventilation is driven by metabolic acid-
osis, suppression of the respiratory drive with sedation or
neuromuscular blockade is not recommended, unless direct
measurement of brain chemistry suggests that hyperventilation
is linked directly to cerebral metabolic crisis. Under these
circumstances, clinicians must find another means to buffer
pH. When a patient with metabolic acidosis is ventilated to a
normal pCO2, acidemia may cause biochemical stress.
It has been observed in TBI that while intubated and
mechanically ventilated patients presenting with hypocarbia
(due to excessive prehospital ventilation) have worse out-
comes than their normocarbic peers, nonintubated patients
presenting with hypocarbia do not – suggesting that such
hypocarbia may be a physiologic response and should not
be suppressed [10].
Little is known about alkalemic hypocarbia in patients with
an acute brain injury. Spontaneous alkalemic hypocarbia
following brain injury may be theoretically explained by a
variety of physiologic and pathophysiologic mechanisms,
more than one of which may be present in an individual
patient:
• Brain tissue acidosis requiring acute hyperventilation as a
buffer until CNS bicarbonate-generating compensatory
mechanisms can “catch up”
• Inadequately treated pain, anxiety, fear, or agitation
• Autoregulation of elevated ICP
• Heme breakdown products or increased acidity of the
ventricular system
• Mechanical compression of chemoreceptors in the floor of
the 4th ventricle
• Physiologic dysregulation of the medullary respiratory
rhythm generator, which has afferent inputs from the pons,
mesencephalon, and higher cortical centers.

A single recent trial of patients with severe brain injury moni-
tored for brain tissue oxygen showed brain tissue hypoxia
worsened when ETCO2 values were reduced by spontaneous
alkalemic hyperventilation, suggesting possible harm [24].
There is a critical deficiency of scientific knowledge in this
area, and since it is rarely known whether alkalemic hypocap-
nia is a physiologic or pathophysiologic process, suppression
of this respiratory activity is not recommended unless there is
evidence of hyperventilation causing direct harm, either by
inducing cerebral ischemia or indirectly by increased systemic
metabolic demands and work of breathing.
Purposeful Hyperventilation to Control Elevated ICP
When a patient develops brain herniation with elevated intra-
cranial pressure, hyperventilation is an appropriate interven-
tion to acutely decrease ICP and prevent widespread infarction
of neuronal tissues and death. Maximal cerebral vasoconstric-
tion is achieved at a pCO2 of 20 mmHg, so ventilation below
this level will be ineffective and may further impede venous
return to the heart, decrease blood pressure, and exacerbate
cerebral hypoperfusion.
During hyperventilation, ETCO2 monitoring (quantitative
capnography) is suggested. As soon as other treatments to
control ICP are in place (e.g. blood pressure support,
osmotherapy, surgical decompression, hypothermia, metabolic
therapy), hyperventilation should be rapidly weaned to restore
brain perfusion [26].
Hyperventilation for increased ICP is not safe or effective
when employed for a prolonged period [27,28]. Hyperventi-
lation severely reduces CBF, increases the volume of ischemic
tissue, and, when the patient is weaned off, may result in
rebound elevation of ICP [29,30]. When prolonged (mild)
hyperventilation must be employed, it is strongly recom-
mended that both ETCO2 and cerebral metabolic monitoring
(jugular oximetry, CBF, brain tissue oxygen, or cerebral micro-
dialysis) be used together with ICP monitoring to verify the
adequacy of tissue perfusion.
Effects of Hyperoxia and Hypoxia on Brain Physiology
Supra-physiologic levels of oxygen provided to acutely ill
patients can worsen reperfusion injury and outcomes [31,32].
Hyperoxia causes the formation of reactive oxygen species in
postischemic tissue beds, impairing mitochondrial function
[33]. Conversely, hypoxia is an important cause of secondary
brain injury [34], and the injured and ischemic brain is par-
ticularly vulnerable to low oxygen levels.
Hyperoxia at a level of PaO2 >300 mmHg on the first
arterial blood gas following resuscitation is independently
associated with poor outcomes following TBI [33] and cardiac
arrest [32,34,35], although not all published data agree [36,37].
Hyperoxia drives the formation of reactive oxygen species,
overwhelming antioxidants at sites of tissue injury, directly
injures respiratory epithelium and alveoli, inducing inflamma-
tion, drives hypercarbia, and leads to reabsorption atelectasis
Chapter 6: Airway Management and Mechanical Ventilation
in the lung. In addition to oxidative stress to the brain, it may, at
least theoretically, be associated with the ill-understood phe-
nomenon of hyperoxemia-induced cerebral vasoconstriction.
It is recommended that 100% oxygen be provided for
preoxygenation immediately prior to intubation, but that
oxygen be immediately weaned following intubation to 50%,
or the lowest FiO2 that will support an oxyhemoglobin satur-
ation of 95–100%. This normoxic resuscitation strategy is
recommended in American Heart Association Guidelines for
postresuscitation care after cardiac arrest [38].
Noninvasive Ventilation
If airway protection is adequate and the patient cooperative,
noninvasive positive pressure ventilation (NPPV) adminis-
tered via a snug-fitting oronasal, nasal, or full-face mask
should be considered. In medical patients with an acute exacer-
bation of COPD or congestive heart failure, NPPV has fewer
complications than invasive mechanical ventilation, and is
associated with better outcomes. In neurologic patients, NPPV
is increasingly recognized as an effective initial intervention for
early neuromuscular respiratory failure from myasthenia
gravis [15], and in patients with acute respiratory disease and
underlying chronic neuromuscular weakness. Its use in
Guillan–Barré syndrome is suspect, however, with highly vari-
able results and major concerns about safety due to the poten-
tial for respiratory arrest.
In patients with neuromuscular weakness, early use of
NPPV maintains lung expansion, reduces the work of
breathing, and decreases the risk of intubation. Only patients
with adequate airway protective reflexes should be treated, and
NPPV should not be used as a substitute for endotracheal
intubation when acute respiratory failure is severe or complete
elimination of the work of breathing is desirable. NPPV
requires close observation in a monitored setting and the
availability of rapid intubation in the event of respiratory
decompensation. Many clinicians prefer the security of inva-
sive mechanical ventilation with an endotracheal tube (ETT)
or tracheostomy, but neurointensivists should be aware that in
ICUs where high-quality, safe NPPV can be provided, it is
often strongly preferred by patients and can reduce mortality,
the incidence of hospital-acquired infections, the need for
sedation and analgesia, and the length of ICU stay [1,39,40].
NPPV should be used in conjunction with mechanical cough-
assist devices to aid in airway clearance – a combination that
effectively treats mucus plugging and atelectasis, and prevents
many patients from requiring intubation.
Acute Respiratory Distress Syndrome
Many modes and techniques of ventilation have been proposed
to manage the severe gas exchange abnormalities associated
with acute respiratory distress syndrome (ARDS), though only
a few important issues are covered here. The fundamental
principle behind management of ARDS is that patients are at
high risk of developing ventilator-induced lung injury, due to
57
 Chapter 6: Airway Management and Mechanical Ventilation
both the vulnerable, inflamed condition of the lungs, and the high
pressures and levels of inhaled oxygen required to achieve sys-
temic oxygenation. Lung-protective ventilation must be provided.
Lung-protective ventilation can be conceived as a strategy of
low tidal volumes, low distending pressures, adequate PEEP to
prevent cyclic alveolar collapse, minimization of inflammation
(biotrauma), and avoidance of very high FiO2. This combination
target can be achieved through a variety of ventilatory modes,
but requires close attention and frequent ventilator adjustment.
Generally speaking, patients with ARDS should be ventilated
using a strategy of low tidal volumes (4–6 mL/kg), low plateau
pressures (<30 mmHg), PEEP adequate to prevent cyclic col-
lapse of alveolar units, and inhaled oxygen fraction rapidly
weaned to 0.6 or less, using PEEP [41], neuromuscular blockade
agents [42], and body positioning [43] to best advantage.
Although the landmark study of low tidal volume mechan-
ical ventilation [44] emphasizes permissive hypercarbia, fluc-
tuations of carbon dioxide levels are potent mediators of CBF
and ICP, and must be carefully considered in patients with
elevated ICP or compromised CBF. Several very small investi-
gations suggest that lung-protective ventilation strategies caus-
ing mild hypercarbia in patients with elevated ICP may be well
tolerated [45,46], but more data are needed before this may be
considered safe in routine practice. Prone positioning seems to
increase ICP [47], although several studies show that a small
increase in ICP may be more than offset by dramatic improve-
ments in oxygenation [48]. Neurological patients with ICP
elevation or cerebral edema should not be maintained acide-
mic or proned unless continuous monitoring of ICP and
cerebral metabolism are available to verify safety.
Airway Pressure and Intracranial Pressure
When lung compliance is high, increased intrathoracic pres-
sure may reduce venous return from the brain and increase
ICP. Additionally, high PEEP decreases venous return to the
heart, decreasing cardiac output and MAP, reducing CPP, and
leading indirectly to increased ICP via reflex cerebral vasodila-
tion. However the individual response to increased PEEP varies
greatly, probably according to lung and ventricular compliance,
and patients with normal or poor pulmonary compliance usu-
ally do not demonstrate PEEP-associated ICP increases [49]. In
patients with severe stroke, raised PEEP did not produce signifi-
cant increase in ICP, but MAP and thus CPP were reduced [50].
In clinical practice, PEEP may be of paramount value to achieve
adequate oxygenation, and should not be routinely reduced to
prevent increased ICP, yet the relationship of PEEP and mean
airway pressure to ICP, CPP, and cerebral perfusion is of
concern, and should be monitored and individually considered
based on an individual patient’s physiology.
Liberation from Mechanical Ventilation
Ventilator Weaning
Weaning from mechanical ventilation is a continuous process
that should begin as soon as a moderate level of medical and
58
Table 6.3 Contraindications to spontaneous breathing trials in
neurological patients
• FiO2 >80%, PEEP >10 cmH2O, or high risk of lung de-
recruitment in severe ARDS
• Deep sedation or paralysis for control of seizures, ICP, or
shivering
• Active neurological or myocardial ischemia
• Symptomatic cerebral vasospasm
• Inadequate respiratory muscle strength to support even high-
pressure support weaning
• Central apnea
respiratory stability is achieved. While excessive work of
breathing should be avoided as a stressor in patients with
ongoing neurologic or cardiac ischemia, respiratory work is
necessary to prevent muscle atrophy, and increased duration of
mechanical ventilation is strongly correlated with the develop-
ment of ventilator-associated pneumonia (VAP) and other med-
ical complications. Ventilator weaning should proceed unless a
strong contraindication exists, such as described in Table 6.3.
Weaning of mechanical ventilation begins with the down-
ward titration of FiO2 and mean airway pressures, typically to
an FiO2 of 50% and PEEP of 5–8 cmH2O. Compared to
gradually reducing the respiratory rate using synchronized
mandatory ventilation or the level of pressure support trig-
gered by each breath, the best results are obtained through the
use of spontaneous breathing trials (SBTs). SBTs vary widely
in design, but reflect periods of breathing during which
most or all of the work of breathing is performed by the
patient, and after which a protocolized assessment is per-
formed to determine suitability for the discontinuation of
mechanical ventilation. The most common types of SBTs
involve placing the patient on continuous positive airway
pressure (CPAP) with a low-level pressure support sufficient
to overcome ETT resistance, and T-piece trials, in which the
patient breathes spontaneously for a predetermined duration
through the endotracheal tube with oxygen flow-by.
The ability of the patient to tolerate a T-piece or CPAP trial
for 30–60 minutes, while maintaining a respiratory rate <30
and (during pressure support weans) RR/Vt ratio <105), is a
useful predictor of successful extubation. In patients with a
depressed level of consciousness or neuromuscular respiratory
weakness, the ability to tolerate a T-piece or CPAP ventilation
overnight offers additional reassurance that the patient has
adequate stamina to tolerate breathing off the ventilator indef-
initely. Indications of tiring during a SBT include an increas-
ing respiratory rate with decreasing tidal volumes, a drop in
arterial oxygen saturation, diaphoresis, the progressive use of
accessory muscles of respiration, or hemodynamic instability.
Failure of a weaning trial is a physiologic stressor, and patients
with these signs should be returned to mechanical ventilation.
Successful SBTs do not predict the ability to protect the
airway. Finally, SBT performed “too early” in conjunction with
 Chapter 6: Airway Management and Mechanical Ventilation

“wake-up” trials have led to ICP increases, compromised cere-
bral oxygenation, and release of stress hormones in some
patients with severe brain injury – caution is warranted [51].
In patients with tracheostomy or receiving NPPV, detachment
from and reconnection to the ventilator is uneventful and easy to
perform. Extubation and reintubation, however, always entail risk.
Before a planned extubation, the patient’s volume status, airway
reactivity, secretions, and cardiac function should be optimized.
Even with careful patient selection and medical optimization, as
many as 20% of extubated patients are reintubated within 48
hours. Of all critically ill patients, the extubation success of those
with neurological diseases is the most difficult to predict.
Tracheostomy
Traditionally, tracheostomy is performed for comfort, oral
care, secretions management, and to assist in ventilator
weaning when mechanical ventilation is required for more
than 14 days. In comatose patients or those with profound
neuromuscular weakness for whom a prolonged period of
ventilator dependence is anticipated, early tracheostomy
within three to five days of intubation extends these benefits.
A recent pilot study of early tracheostomy versus prolonged
endotracheal intubation with attempted extubation showed a
mortality benefit to early tracheostomy[3], and recent retro-
spective data support this approach [52]. Most patients with
significant bulbar dysfunction following an acute brain injury
will require tracheostomy for secretions management,
although they can often be weaned rapidly from mechanical
ventilation, and most will be decannulated when cough
strength and airway protective reflexes have recovered.
Percutaneous tracheostomy creates a temporary stoma
that is easily and rapidly reversible upon decannulation,
while surgical tracheostomy creates a more durable and per-
manent stoma that typically requires surgical closure. In some
patients with severe persistent oropharyngeal muscle weakness,
a tracheostomy is necessary to manage secretions and prevent
aspiration, even though respiratory muscle function is adequate.
Long-Term Ventilation
In chronic respiratory failure, patients and clinicians should
work together to determine the best interface for mechanical
ventilatory support. Patients with good bulbar function and a
normal level of consciousness can often tolerate intermittent
daytime and continuous nocturnal NPPV by nasal or face
mask, while those at high risk of aspiration, or with a low or
waxing and waning level of arousal, are more safely ventilated
by tracheostomy. Patients with chronic respiratory failure may
have an improved quality of life with NPPV, and are at lower
risk of developing respiratory infections than patients with a
permanent tracheostomy – this has been dramatically demon-
strated in patients with respiratory failure due to progressive
Duchenne muscular dystrophy [53]. Yet patients with a trache-
ostomy can sometimes speak and eat; an experienced speech
therapist can determine the safety of and capacity for these
activities. Adjustments in tidal volume and tracheostomy size
may be important in facilitating speech, and cuff deflation
dramatically improves the ability to speak and swallow, but
leaves the airway open and at risk of large-volume aspiration.
For patients requiring ventilatory support for months or
years, small suitcase- or laptop-sized ventilators are available
for home use. Battery-powered portable ventilators allow
wheelchair-bound patients to travel out of the home. For
patients with respiratory failure after brainstem or high cer-
vical cord lesions, an implantable phrenic nerve pacemaker can
sometimes be used to stimulate diaphragmatic contraction,
liberating the patient from connection to a ventilator.
Summary
The neurological and respiratory systems are intricately con-
nected, and high-quality neurocritical care requires meticulous
attention to how these organ systems interact. Attentive respira-
tory care minimizes secondary brain injury and facilitates neuro-
rehabilitation, while inattention to respiratory concerns can lead
to dramatically worse neurological and functional outcomes.

by neurointensivists. Neurocrit Care 10 neurological life support: airway,

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61
 Chapter
Neuropharmacology in the Neurocritical Care Unit
7 Sarah M. Adriance
Introduction
From protein binding alterations to frequent drug–drug inter-
actions, from hypermetabolic states to anuria, there exists a
multitude of reasons that the therapeutic interventions of
choice must be individualized in a critically ill patient. The
principles of clinical pharmacology provide the basis of opti-
mizing a safe and effective drug regimen. The four major
subdivisions of pharmacology include pharmacokinetics,
pharmacodynamics, pharmacotherapeutics, and toxicology.
Simply stated, pharmacokinetics and pharmacodynamics focus
on what the body does to the drug and what the drug does to
the body, respectively. The following pharmacokinetic and
pharmacodynamics factors must be taken into consideration
to optimize effectiveness and to minimize toxicity.
• Pharmacokinetics (PK)
: Drug absorption
: Drug distribution
: Drug metabolism
: Drug elimination
: Drug dosing
: Mediation compliance
: Medication adverse drug events
: Body weight
: Body fluid volume
• Pharmacodynamics (PD)
: Drug interactions
: Drug tolerance
: Drug receptor availability
: Genetic factors.
The key component to the subdivision of pharmacotherapeu-
tics is monitoring for a clinical or therapeutic response to
ensure maintenance of the desired outcome. This may include
targeting adequate drug level concentrations in the serum.
Overall this chapter aims to provide the clinician with the
pharmacologic knowledge to select an appropriate drug regi-
men for the neurocritically ill adult patient. This chapter is not
inclusive of all medications used in the course of care, but
highlights common medications in the following classes: seda-
tives, analgesics, antiepileptics, osmotics, antishivering agents,
and medications used to prevent and treat cerebral vasospasm.
62
Some fundamental pharmacology terms used in this
chapter:
Elimination half-life – The time necessary to reduce drug
concentration in the blood, plasma, or serum to one-half
after steady state has been reached. Elimination half-life of a
drug refers to the elimination of the parent drug molecule
and not any metabolites, if present.
Enzyme induction – Faster metabolism of a compound due
to an increase in either enzyme content or rate of enzymatic
process. An inducer increases clearance and decreases
steady-state concentrations of other substrates.
Enzyme inhibition – Slower metabolism of a compound,
usually due to competition for an enzyme system. An
inhibitor decreases clearance and increases steady-state
concentrations of other substrates.
Linear pharmacokinetics – Serum concentrations of drug
change proportionally with an increase in dose (most drugs
follow).
Nonlinear pharmacokinetics – Serum concentrations of drug
change disproportionally (greater increase) with an increase
in dose (e.g. phenytoin).
Sedatives
Sedation is a broad term used in critical care that can encom-
pass the administration of various pharmaceutical classes of
medications that are general central nervous system (CNS)
depressants. These include benzodiazepines and other benzo-
diazepine receptor agonists, opioid analgesics, barbiturates,
sedative-hypnotics, α2-agonists, and neuroleptics, which are
all of diverse chemical structures. The underlying needs of
the patient must be carefully assessed so an appropriate medi-
cation can be selected and therapy can be optimized.
It has been documented in critically ill patients that con-
tinuous infusion analgesic and sedative agents can contribute
to increased duration of mechanical ventilation and longer
lengths of stay in the intensive care unit (ICU) and hospital
[1]. Likewise, complications can arise with undersedation, such
as agitation, anxiety, increased intracranial pressure (ICP),
patient harm, removal of lines and devices, and ventilator
dysynchrony [2,3]. While balancing sedation in any critical ill
patient is important, the neurocritically ill patient presents

unique challenges. Because the bedside clinician in the neuro-
sciences critical care unit (NCCU) relies on an accurate neu-
rologic exam as the principal means of assessing patient status,
including improvement and deterioration, many drugs used in
the course of managing sedation have the potential to also alter
consciousness and interfere with this ever-important exam.
Sedation requirements, including agent selection, must be
considered carefully when a high-quality neurologic assess-
ment is also necessary.
Common sedation indications in the NCCU include the
following:
• Patient comfort
: Agitation
: Anxiety
: Fear
: Pain
• Increased ICP
• Ventilator dysynchrony.
In the NCCU, general treatment principles to keep in mind
during the provision of sedation are:
1. Analgesia is not provided by the majority of agents used to
help manage sedation in the ICU and therefore one must
consider pain as a source of agitation, anxiety or delirium,
and treat it first.
2. A short-acting agent may allow for frequent interruption of
therapy for an accurate neurologic exam.
Thoughtful sedation decisions also incorporate the following
drug factors: route of administration, pharmacokinetics, on
and off effects, and tolerability. With respect to the manage-
ment of intracranial hypertension specifically, adequate sed-
ation is important to control pain, autonomic stress, and
agitation, which are factors that can negatively affect ICP.
When surveyed, practice in the NCCU revealed that the
most common analgesic and sedative used were fentanyl and
propofol, respectively [4], although it is important to note that
no specific agent has evidence of superiority over another and
safety and efficacy data specific to the neurocritically ill patient
population are lacking. Additionally, patients may display a
variable physiologic response due to genetic differences in the
µ-opioid receptor. A brief discussion of the major analgesic
and sedative classes used in a neurocritically ill patient follows.
Refer to Table 7.1 for more specific pharmacologic and phar-
macotherapeutic information for commonly used agents to
manage sedation in the NCCU.
Opioid Analgesics
Opioids are a core component of pain management in the ICU
and can also provide mild sedative effects. Opioids exert their
effects through interaction with three opioid receptors (δ, μ, κ).
These receptors are widely distributed in CNS and peripheral
tissues, including vascular, cardiac, airway, and gastrointestinal
systems, leading to their diverse effects. Advantages of the
commonly used opioids in the ICU include a rapid onset of
Chapter 7: Neuropharmacology
action and short duration of action (especially with fentanyl
and remifentanil) and reversibility with naloxone, an opioid
receptor antagonist. Note naloxone should not be used to
reverse opioid effects in order to perform a routine neurologic
assessment due to potential precipitation of hypertension,
tachycardia, and agitation. Lower doses of naloxone are rec-
ommended in critically ill patients. For example, 0.4 mg of
naloxone may be diluted in 10 mL of normal saline to a final
concentration of 40 μg/mL. Initial dosing of 40–80 μg aliquots
may be used. Patients who have received longer-acting
opioids may experience return of respiratory depression or
sedation after the effects of naloxone dissipate, which can
range from 30 to 60 minutes. Respiratory depression should
be anticipated with opioids, especially at higher doses. Be
aware that opioids can cause miosis and potentially interfere
with an exam, signaling neurological deterioration with ele-
vated ICP. Opioids as a class can also cause pruritus, chest wall
or muscle rigidity (high doses), nausea/vomiting, and gastro-
intestinal dysmotility. The drug–drug interactions of major
concern are those involving coadministration of other CNS
and respiratory depressants, which may lead to exaggerated
effects on these organ systems. The hepatic metabolism of
fentanyl specifically involves the cytochrome P450 (CYP)
enzymes, mainly 3A4. Administration of inducers of CYP450
3A4 (e.g. carbamazepine, dexamethasone, phenobarbital, phe-
nytoin, rifampin) may increase the clearance of fentanyl, and
inhibitors of CYP450 3A4 (e.g. antidepressants, azole antifun-
gals, clarithromycin, diltiazem, erythromycin, protease inhibi-
tors) can decrease its clearance. Hydromorphone undergoes
hepatic metabolism via glucuronidation, and morphine via
conjugation and therefore have fewer drug–drug interactions.
Benzodiazepines
The activity of the major inhibitory neurotransmitter γ–
aminobutryic acid (GABA) is enhanced following administra-
tion of benzodiazepines. This class of medications binds to
various subunits of the GABAA-gated chloride channel to
modulate the effects of GABA and produce in varying degrees:
anxiolysis, sedation, hypnosis, muscle relaxation, anterograde
amnesia, and anticonvulsant activity. Benzodiazepines do not
provide analgesia. Advantages of the commonly used benzodi-
azepines in the ICU (midazolam, lorazepam) include a rapid
onset of action and reversibility with flumazenil, a GABAA
receptor antagonist. Note that flumazenil should not be used
to reverse benzodiazepine effects in order to perform a routine
neurologic assessment. Caution with its use must be used in
the neurocritically ill patient or in chronic users of benzodi-
azepines as its administration may lead to increase in ICP,
hypertension, and lowering of the seizure threshold. Patients
who have received longer-acting benzodiazepines may experi-
ence return of sedation after the effects of flumazenil dissipate,
which can range from 20 to 60 minutes. Lower doses of
benzodiazepines normally do not effect respiration in normal
adults, but caution should be taken in those with impaired
63
 Chapter 7: Neuropharmacology

Table 7.1 Common IV sedation agents

Agent, Class IV Dosinga Key pharmacologyb Therapeutic considerations

Fentanyl Intermittent Onset: 1–2 min • Reduce dose in severe renal impairment and
Analgesic, opioid 25–50 μg q 0.5–1 h Elimination t½: 0.5–1 h; moderate hepatic impairment. Avoid in severe
Continuous 2–4 h repeated dosing hepatic impairment
25–100 μg/kg/h, Metabolism: Hepatic • Hypercarbia may occur due to respiratory
titrate by Excretion: Renal depression and lead to cerebral vasodilation and
25 μg/h q 15–30 min increased ICP
Hydromorphone Intermittent Onset: 5–15 min • Reduce dose in severe renal and hepatic
Analgesic, opioid 0.4–0.8 mg q 2–3 h Elimination t½: 2–3 h impairment
Metabolism: Hepatic, active metabolite • Accumulation of active metabolites in renal
(H3G) impairment can lead to neuroexcitation
Excretion: Renal • Hypercarbia may occur due to respiratory
depression and lead to cerebral vasodilation and
increased ICP
Morphine Intermittent Onset: 5–10 min • Reduce dose in moderate and severe renal
Analgesic, opioid 2.5–5 mg q 3–4 h Elimination t½: 3–4 h impairment and severe hepatic impairment
Metabolism: Hepatic, active • Accumulation of active metabolites in renal
metabolites (M3G, M6G) impairment can lead to neuroexcitation
Excretion: Renal • Hypotension may occur secondary to histamine
release
• Hypercarbia may occur due to respiratory
depression and lead to cerebral vasodilation and
increased ICP
Remifentanil Continuous Onset: 1–3 min • Base dose on IBW in obese patients (>30% over
Analgesic, opioid Load 0.5–1 μg/kg Elimination t½: 3–10 min IBW)
Maintenance Metabolism: Plasma esterases • Dose reduce in elderly
0.05–0.2 μg/kg/min, Excretion: Renal
titrate by 0.05 μg/kg/
min q 5 min
Dexmedetomidine Continuous Onset: 5–10 min • Reduce dose in severe hepatic impairment
Sedative, Load not Elimination t½: 2–3 h • Systemic hypotension adverse effect may impair
α2-agonist recommended in Metabolism: Hepatic CPP
critically ill Excretion: Renal • Bradycardia occurs commonly
Maintenance
0.2–1.5 μg/kg/h,
titrate by 0.2 μg/kg/h
q 30 min
Lorazepam Intermittent Onset: 2–10min • Avoid in severe renal and hepatic impairment
Sedative, 0.25–1 mg q 5–30min Elimination t½: 12–14 h • Hypercarbia may occur due to respiratory
benzodiazepine Continuous Metabolism: Hepatic depression and may cause cerebral vasodilation
0.5–2 mg/h, titrate by Excretion: Renal and increased ICP (high doses)
0.5 mg/h q 0.5mg q • Systemic hypotension may impair CPP (high
30min doses)
• IV formulation contains propylene glycol. High
doses (
1 mg/kg/day or
10 mg/h) may lead to
accumulation and toxicity
Midazolam Intermittent Onset: 3–5 min • Prolonged sedation with prolonged infusion,
Sedative, 0.5–2 mg q 5–30 min Elimination t½: 2–6 h especially in severe renal impairment
benzodiazepine Continuous Metabolism: Hepatic, active metabolite • Accumulation of active metabolite in renal
1–4 mg/h, titrate by 1 (1- hydroxymidazolam) impairment can lead to increased sedation and
mg/h q 30 min Excretion: Renal adverse effects
• Hypercarbia may occur due to respiratory
depression and lead to cerebral vasodilation and
increased ICP (high doses)
• Systemic hypotension may impair CPP (high doses)

64

Table 7.1 (cont.)
Agent, Class IV Dosinga Key pharmacologyb
Propofol Continuous Onset: 1–2 min
Sedative, hypnotic 5–100 μg/kg/min, Elimination t½: 30–60 min (wake-up
titrate by 5–10 μg/kg/ time, however, is 15 min in infusions
min q 5–10 min 72 h in duration)
Metabolism: Hepatic
Excretion: Renal
a
Intermittent doses provided are initial starting doses and are based on approximate equipotent doses of medications in the same class.
b
Values based on normal organ function
CPP cerebral perfusion pressure; GI gastrointestinal; h hour; H3G hydromorphone-3-glucuronide; IBW ideal body weight; ICP intracranial pressure; IV intravenous;
kcal kilocalorie; kg kilogram; M3G morphine-3-glucuronide; M6G morphine-6-glucuronide; μg microgram; mg milligram; min minute; ICP intracranial pressure; N/V
nausea, vomiting; PRIS propofol-related infusion syndrome; t½ half-life; q every
hepatic function (e.g. alcoholics, cirrhotics) or when other
CNS depressants are present. Higher doses of benzodiazepines
will decrease blood pressure and increase heart rate. These
effects are more pronounced in patients with underlying car-
diac disease. The drug–drug interactions of major concern are
those involving coadministration of other CNS, cardiac, and
respiratory depressants, which may lead to exaggerated effects
on these organ systems. The hepatic metabolism of midazolam
specifically involves the CYP enzymes, mainly 3A4. Adminis-
tration of inducers of CYP450 3A4 (e.g. carbamazepine, dex-
amethasone, phenobarbital, phenytoin, rifampin) may increase
the clearance of midazolam and inhibitors of CYP450 3A4 (e.g.
antidepressants, azole antifungals, clarithromycin, diltiazem,
erythromycin, protease inhibitors) can decrease its clearance.
Lorazepam undergoes hepatic metabolism via glucuronidation
and therefore has fewer drug–drug interactions.
Propofol
Propofol is thought to act primarily at the GABAA receptors in
the CNS, although its exact mechanism is unknown. In add-
ition to its sedative and hypnotic effects, propofol can also
suppress electroencephalography (EEG) activity and therefore
may be used as an anticonvulsant in higher doses. Propofol
decreases cerebral oxygen utilization with subsequent reduc-
tions in arterial cerebral blood flow requirements, which leads
to cerebral vasoconstriction. Propofol may be used to manage
ICP second to this effect. Like the benzodiazepines, propofol
does not provide analgesia. Advantages of this agent in the
ICU include a rapid onset of action, an ultra-short duration of
action, and rapidly titratable properties. Hypotension should
be anticipated with propofol administration, which is more
pronounced in patients with underlying cardiac disease or
hypovolemia, in the elderly, or when other cardiac depressants
are present. The drug–drug interactions of major concern are
those involving coadministration of other CNS and cardiac
depressants, which may lead to exaggerated effects on
Chapter 7: Neuropharmacology
Therapeutic considerations
• Can decrease ICP via effects on cerebral
metabolism
• Systemic hypotension may impair CPP
• Risk of PRIS increases at high doses (
80 μg/kg/
min), monitor for acidosis and creatinine kinase
when used
48 h.
• Provides considerable IV lipid load, monitor
triglycerides, and caloric intake (1.1 kcal/mL).
• Contraindicated in patients with severe allergy to
egg and soy proteins
these organ systems. Respiratory depression is a common
adverse effect.
Dexmedetomidine
Dexmedetomidine is a selective α2-agonist with sedative and
mild analgesic properties. It primarily acts in the locus coer-
uleus to decrease sympathetic outflow and modulate pain
pathways. Additional peripheral effects (vasoconstriction
and hypertension) can occur at the α2b-receptor, which are
observed when high doses are administered, such as loading
doses. Dexmedetomidine may also be used in the NCCU for
its antishivering effects, which are discussed further in
another section of this chapter, and for the treatment of
autonomic instability that may occur following neurologic
injury. Comparative to the benzodiazepines or propofol,
dexmedetomidine does not cause as much CNS depression
and is devoid of respiratory depression at usual doses. The
major advantage of this agent in the NCCU is related to its
lighter sedative effects compared to other agents, which can
preserve the neurological assessment. Hypotension and
bradycardia are common with dexmedetomidine adminis-
tration. Generally this agent is not well tolerated in hypovo-
lemic patients or in the setting of hemodynamic instability.
The drug–drug interactions of major concern are those
involving coadministration of other CNS and cardiac
depressants, which may lead to exaggerated effects on these
organ systems.
Antiepileptics
Seizures and status epilepticus (SE) etiologies in the NCCU are
numerous and commonly occur as a complication of neuro-
logical disease (e.g. stroke, anoxic brain injury, CNS infection,
brain tumor, head trauma), antiepileptic drug (AED) discon-
tinuation or noncompliance, metabolic derangements, and
side effects of medications. Following immediate diagnosis,
65
 Chapter 7: Neuropharmacology
the timely administration (5 to 10 minutes) and the selection
of an effective AED have proven crucial in prevention of
neuronal damage and permanent brain injury. An EEG is used
to confirm or exclude the diagnosis and to monitor the
response to AEDs.
This section of the chapter will focus on the recommended
pharmacologic treatments specifically for SE, as well as seizure
prophylaxis in specific neurologic injuries. Following is a
section on therapeutic drug level monitoring and key drug–
drug interactions. The less frequently used agents such as
ketamine, corticosteroids, and immunomodulation with intra-
venous immunoglobulin (IVIG) or plasma exchange are not
highlighted here, but more information may be obtained from
recent guidelines [5].
Current treatment recommendations for the management
of SE are characterized as emergent, urgent or refractory
treatments [5]. To summarize the clinical approach outlined
in the recent guidelines, every patient that presents with SE
needs the following, regardless of whether immediate control
of SE was achieved:
1. An emergent treatment medication (i.e. benzodiazepine)
2. A second AED added for urgent treatment
3. An AED for maintenance therapy, which may be a
scheduled dosing regimen of the urgent treatment AED
selected.
If 20 minutes from the time of seizure onset has passed
and SE is not controlled, refractory SE treatments (RSE)
must be considered. The overall goal of treatment is to
obtain control of SE within 60 minutes of seizure onset.
While the treatment of SE focuses greatly on early and
effective medication intervention, there are nonpharmaco-
logical measures that are standards of care and should not
be missed [5].
It is important to emphasize that emergent treatment
with a benzodiazepine is supported by randomized con-
trolled trial data. In a pivotal trial, lorazepam successfully
stopped more SE within 20 minutes of initiation and sus-
tained control for at least 40 minutes when compared to
phenobarbital, phenytoin, or combination therapy of pheny-
toin with diazepam [6]. Benzodiazepines exert their antiepi-
leptic activity by increasing the major CNS inhibitory
neurotransmitter GABA by binding to the GABAA receptor.
From a pharmacologic perspective, their greater effectiveness
in terminating SE can be explained by a more lipid-solubility
compared to other AEDs, which allows the drug to enter the
CNS more quickly. When IV access is not available for loraze-
pam, frequently used for in-hospital SE, midazolam and diaze-
pam offer alternative routes of administration. However, the
duration of antiepileptic action is shorter with these agents,
which can translate into earlier seizure recurrence. Dose-related
respiratory depression and systemic hypotension have been
described as the most common adverse effects of benzodiazep-
ines in SE trials. There are no definitive data for which AED
should be added next. Due to overlapping mechanisms of action
66
of many AEDs, selection may be based on minimizing side
effects while optimizing efficacy. Guidelines also provide a
graded recommendation based on available evidence and expert
opinion. Refer to Table 7.2 for pharmacologic and therapeutic
considerations of all the recommended agents, including those
for RSE.
Seizure Prophylaxis
The administration of AEDs for seizure prophylaxis is a
highly variable practice depending on the disease state, extent
of injury, location of injury, and surgical interventions.
Prophylaxis has specifically been studied in patients with
aneurysmal subarachnoid hemorrhage, craniotomy, intracer-
ebral hemorrhage, intracerebral tumor, ischemic stroke, and
traumatic brain injury. The reader is referred to a newly
published comprehensive review of the evidence for seizure
prophylaxis in various subpopulations of neurocritically ill
patients [7]. Below is a discussion on two noteworthy
populations.
Traumatic Brain Injury (TBI)
Phenytoin has been shown to significantly reduce early-onset
seizures following severe TBI, defined as seizures occurring
within first seven days post injury [8]. Its use in this setting is
supported by different guidelines [9,10]. A loading dose of
20 mg/kg should be used, with maintenance doses adjusted
based on therapeutic concentration targets discussed
above under TDM. Phenytoin should not be used beyond
the first seven days for prophylaxis, however, due to negative
effects on functional outcome at one month [11]. Sodium
valproate has been shown to be effective in also reducing
early-onset seizures, but due to an increase in mortality rates
in patients studied, it is not recommended for prophylaxis with
this patient population [12]. It is unclear if levetiracetam is as
effective as phenytoin for seizure prophylaxis due to underpow-
ered trials. When compared to phenytoin, levetiracetam has
demonstrated higher functional outcomes scores at three and
six months [13].
Aneurysmal Subarachnoid Hemorrhage (aSAH)
There is no clear evidence that the administration of AED
prophylaxis significantly reduces the incidences of seizures in
patients with aSAH. According to guidelines, prophylaxis may
be considered in this patient population in the immediate
posthemorrhagic period or for a three- to seven-day course,
depending on which guideline is referenced (no specific agent
is suggested) [14,15]. A negative association with phenytoin on
functional and cognitive outcomes has been described at three
months when used for prophylaxis in uncontrolled trials
[16,17]. Thus, some providers for this indication may avoid
phenytoin. When compared to phenytoin, levetiracetam-
treated patients had higher incidence of seizures, but a trend
toward a lower incidence of poor outcome in terms of death or
discharge to nursing home.
 Chapter 7: Neuropharmacology
Table 7.2 Antiepileptics for status epilepticus
Agent Timing Initial dosing Key pharmacology
Lorazepam Emergent 0.1 mg/kg IVP up to 2 mg/min MOA: Binds to GABAA receptor,
(max 4 mg/dose); may repeat in allows entry of Cl– and results in
5–10 min decreased neuronal firing
Protein binding: >90%
Onset: 2–10 min
Metabolism: Hepatic,
glucuronidation
Elimination t½: 12–14 h
Excretion: Renal
Midazolam Emergent 0.2 mg/kg IM (max 10 mg) MOA: Binds to GABAA receptor,
0.2 mg/kg intranasal allows entry of Cl– and results in
0.5 mg/kg buccal decreased neuronal firing
Protein binding: >90%
Onset: 3–5 min
Metabolism: Hepatic, CYP3A4,
(1- hydroxymidazolam)
Elimination t½: 2–6 h
Excretion: Renal
Diazepam Emergent 0.15 mg/kg IVP up to 5 mg/min MOA: Binds to GABAA receptor,
(max 10 mg/dose); may repeat in allows entry of Cl– resulting in
5 min decreased neuronal firing
0.2mg/kg rectal gel Protein binding: >90%
Onset: <1 min (IV)
Metabolism: Hepatic, CYP3A4,
2C19 active metabolites
Elimination t½: 20–50 h
Excretion: Renal
Phenytoin, Emergent Load 20 mg/kg IV up to 50 mg/min MOA: Prolongs recovery of
Fosphenytoin Urgent (fosphenytoin 20mg/kg PE up activated voltage-gated Na+
Refractory to 150 mg PE/min); may give channels in neuron to stabilize
additional 5–10 mg/kg against repetitive neuronal firing
(5–10 mg/kg PE) in 10 min Protein binding: >90%
Use TBW unless obese (>125% IBW) Onset: 0.5–1 h
Obese: adjusted weight = IBW + Metabolism: Hepatic, CYP2C9, 2C19
(1.33)(TBW – IBW) Elimination t½: 12–29 h (dose and
Maintenance empiric 5–7 mg/kg/ hepatic function dependent)
day divided two to three doses Excretion: Renal
See text for therapeutic drug
monitoring
Notable AEs and therapeutic
considerations
AEs: Hypotension and
respiratory depression (dose
dependent)
• IV formulation contains
propylene glycol. High doses
(
1mg/kg/day or
10mg/h)
may lead to accumulation
and toxicity
AEs: Hypotension and
respiratory depression (dose
dependent)
• Accumulation of active
metabolite in renal
impairment can lead to
increased sedation and
adverse effects
• Shorter duration of action
(<2 h, dose dependent)
AEs: Hypotension and
respiratory depression (dose
dependent)
• Anticonvulsant duration is
20–30 minutes, but drug
elimination is much longer so
sedation may linger,
especially with rectal gel
• IV formulation contains
propylene glycol ;
accumulation and toxicity
may occur
• Shorter duration of action
(20–30 min)
AEs: Arrhythmias, hypotension
(especially rapid IV
administration) injection site
pain, phlebitis, purple glove
syndrome, tissue necrosis,
hepatotoxicity (routinely
monitor transaminases),
various dermatologic
conditions
• Fosphenytoin conversion to
phenytoin in 15 min
• Lack of propylene glycol and
ethanol diluents in
fosphenytoin and a more
physiologic pH may cause
less local and systemic effects.
• IV formulation contains
propylene glycol ;
accumulation and toxicity
may occur
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 Chapter 7: Neuropharmacology

Table 7.2 (cont.)

Agent Timing Initial dosing Key pharmacology Notable AEs and therapeutic
considerations
Sodium Emergent 20–40 mg/kg IV; may give MOA: Exact mechanism unknown, AEs: Hepatoxocity,
valproate Urgent additional 20 mg/kg in 10 min but thought to be involved in encephalopathy
Refractory Maintenance empiric 5–10 mg/kg/ increasing concentrations of GABA hyperammonemia,
day in three divided doses ideally Protein binding: 80–90% pancreatitis, rash,
usual 15 mg/kg/day (concentration dependent) thrombocytopenia, elevation
(max 60 mg/kg/day) Onset: 1 h of hepatic transaminases
See text for therapeutic drug Metabolism: Extensive hepatic • Routinely monitor
monitoring (primarily glucuronidation and transaminases
mitochondrial β-oxidation; minor • Not recommended in
CYP450 2C9, 2C19) with many significant hepatic
active metabolites impairment
Elimination t½: 15 h (increased in
elderly and liver disease, decreased
with other AEDs)
Excretion: Renal
Phenobarbital Emergent Initial 20 mg/kg IV over 50 mg/min; MOA: Binds to GABAA receptor, AEs: Hypotension, respiratory
Urgent may give additional 5–10 mg/kg in allows entry of Cl– and results in depression, various
Refractory 10 min decreased neuronal firing dermatologic conditions,
Maintenance 1–3 mg/kg/day in Protein binding: 20–40 % injection site pain,
two to three divided doses Onset: 5 min thrombophlebitis
See text for therapeutic drug Metabolism: Hepatic, CYP2C9, 2C19 • IV formulation contains
monitoring Elimination t½: 53–140 h propylene glycol;
Excretion: Renal accumulation and toxicity
may occur
Levetiracetam Emergent 1000–3000 mg IV over 15 min MOA: Exact mechanism unknown; AEs: Somnolence
Urgent thought to involve regulation of • Minimal drug–drug
Refractory presynpatic neurotransmitter interactions
release
Protein binding: <10%
Onset: Rapid
Metabolism: Small amount of
enzymatic hydrolysis
Elimination t½: 6–8 h
Excretion: Renal
Midazolam Urgent Load 0.2 mg/kg IV over 2 mg/min See above See above
continuous Refractory Maintenance 0.05–2 mg/kg/h • Tachyphylaxis with prolonged
infusion infusion; titrate to CEEG infusion use
Breakthrough seizure 0.1–0.2 mg/kg
bolus and increase by 0.05–0.1 mg/
kg/h q3–4 h
Propofol Refractory Load 1–2 mg/kg IV MOA: GABAA receptor agonist AEs: Hypotension, respiratory
continuous Maintenance 20–200 μg/kg/min (exact MOA unknown) depression, cardiac failure,
infusion infusion; titrate to CEEG Protein binding: 97–99% rhabdomyolysis, metabolic
Breakthrough seizure may bolus Onset: 1–2 min acidosis, PRIS
1mg/kg and increase by 5–10 μg/ Metabolism: Hepatic • Risk of PRIS increases at high
kg/min q5min Elimination t½: 30–60 min (wake-up doses (
80 μg/kg/min);
time, however, is 15 min in monitor for acidosis and
infusions 72 h in duration) creatinine kinase when used
Excretion: Renal
48 h
• Provides considerable IV lipid
load; monitor triglycerides and
caloric intake (1.1kcal/mL)
• Contraindicated in patients
with severe allergy to egg and
soy proteins

68
 Chapter 7: Neuropharmacology

Table 7.2 (cont.)

Agent Timing Initial dosing Key pharmacology Notable AEs and therapeutic
considerations
Pentobarbital Refractory Load 5–15 mg/kg IV over MOA: Binds to GABAA receptor, AEs: Hypotension frequently
continuous 50 mg/min; may give additional allows entry of Cl– and results in requiring vasopressor support,
infusion 5–10 mg/kg decreased neuronal firing respiratory depression,
Maintenance 0.5–5 mg/kg/h Protein binding: 45–70% myocardial depression,
infusion; titrate to CEEG Onset: Immediate paralytic ileus
Breakthrough seizure 5mg/kg Metabolism: Hepatic • IV formulation contains
bolus, increase infusion by Elimination t½: 15–50 h propylene glycol ;
0.5–1 mg/kg/h q 12 h (dose dependent) accumulation and toxicity
Excretion : Renal may occur

Lacosamide Refractory 200–400 mg IV over 30 min MOA: Exact mechanism AEs: PR interval prolongation,
unknown, but may decrease hypotension
neuronal firing by enhancement
of slow inactivation of Na channels
Protein binding: <15%
Onset: 1–4 h
Metabolism: Hepatic, CYP3A4, 2C9,
2C19
Elimination t½: 13 h
Excretion: Renal
Topiramate Refractory 200–400 mg enterally MOA: Blocks voltage-gated Na AEs: Metabolic acidosis
300–16000 mg/day divided two to channels in neuron, enhances
four times daily GABAA receptor activity,
antagonizes AMPA/kainite of
glutamate receptor, weakly inhibits
carbonic anhydrase all of which
may play a role in its anticonvulsant
activity
Protein binding: 15–41%
Onset: 1–4 h
Metabolism: Small hepatic, CYP3A4,
2C19
Elimination t½: 21 h
Excretion: Renal
AEs adverse effects; Cl– chloride; CEEG continuous electroencephalogram; GABA γ-aminobutyric acid; GI gastrointestinal; h hour; IBW ideal body weight; IV
intravenous; IVP intravenous push; kg kilogram; mg milligram; min minute; MOA mechanism of action; N/V nausea, vomiting; PE phenytoin equivalents; PRIS
propofol-related infusion syndrome; t½ half-life; TBW total body weight; q every

AED Therapeutic Drug Monitoring and Drug–Drug
Interactions
Therapeutic drug-level monitoring (TDM) may be indicated
for AEDs that have a narrow therapeutic range, including
some AEDs discussed above in the management of seizures.
The therapeutic range is determined by the PK and PD prop-
erties of the AED. In the ICU the primary goal of TDM is to
optimize the therapeutic effects and clinical outcome, while
minimizing side effects. Drug levels in this setting are generally
obtained after AED initiation, with ongoing seizure activity,
and when seizure control has been achieved to set a reference
serum concentration for the patient. Interpretation of drug
levels should never be in isolation, as all patients should be
evaluated for a clinical response as well. If an unsatisfactory
clinical response is achieved, there are dose-related side effects
or drug toxicity, then the drug regimen should be adjusted or
an alternate therapy considered.
Adjusting the drug regimen based on a drug level should be
done when steady-state concentrations have been reached,
whenever possible. Steady-state concentrations are generally
assumed if the medication has been dosed for at least three
to five half-lives of the drug. Ideally, a steady-state trough drug
level is used for interpretation and adjustment. Trough con-
centrations should be obtained as close to but before the
next scheduled dose. Following dose adjustment, a steady-state
concentration is attained on the new dose when three to five

69
 Chapter 7: Neuropharmacology
half-lives of the drug have passed. Patients with SE may require
more intensive monitoring. The TDM principles provided
below are general guidelines. Some patients may require levels
above therapeutic range for adequate seizure control; however,
an increase in adverse effects may occur.
When new therapy is added to an existing AED, pharma-
cokinetic changes, including enzyme induction or enzyme
inhibition, can result. A comprehensive review of all medica-
tions in the patient’s profile should be conducted to identify
and anticipate the presence of drug–drug interactions.
A clinical pharmacist can be consulted for assistance with dose
modification involving pharmacokinetic calculations and pro-
vide more detail regarding drug–drug interactions.
Fosphenytoin and Phenytoin TDM Targets
Total Concentrations of 10–20 μg/mL
• Adjust for low serum albumin using:
Corrected phenytoinðmg=LÞ ¼ Observed phenytoinðmg=LÞ
ðO:2 albumin½g=dLÞþ 0:1
• In end-stage renal disease binding to albumin is impaired.
Use:
Corrected phenytoinðmg=LÞ ¼ Observed phenytoinðmg=LÞ
ðO:1 albumin½g=dLÞ þ 0:1
Free (unbound) Concentrations of 1–2 μg/mL
• Useful in altered plasma protein binding states, including
hepatic or renal dysfunction, cystic fibrosis, burn, trauma,
malnourished, and in the elderly.
Fosphenytoin and Phenytoin TDM Principles
• Obtain first level 2 h postload (IV therapy)
• If concentration is subtherapeutic, mini-loads are
commonly used in clinical practice to immediately place
patient in therapeutic range and before a new maintenance
dose is initiated
: Mini-load dose = [(Vd)  (Css desired – Css measured)]
/SF
: Use the following definitions and parameters for the
calculation
– Steady-state concentration (Css)
– Bioavailability (F) = 1.0
– Salt factor (S) = 0.92
– Volume of distribution (Vd) = 0.7 L/kg adults
• Steady-state concentration is achieved in 7–10 days (can
vary greatly due to nonlinear kinetics)
• Modest changes in dose can more easily cause toxicity due
to nonlinear kinetics
• Conservative dose changes are especially warranted in
altered protein binding states
• Suspect toxicity if nystagmus, ataxia, lethargy, or other
altered mental status or motor signs are present. Phenytoin
70
can also induce seizures, usually at total levels >30 μg/mL
(unbound >3 μg/mL)
• In addition to altered plasma protein binding states, obesity
will affect phenytoin disposition (see Table 7.2 for dose
adjustments).
Fosphenytoin and Phenytoin Drug–Drug Interactions
• Many potential interactions exist, as fosphenytoin/
phenytoin induces most CYP450 enzymes
• Metabolism of fosphenytoin/phenytoin is susceptible to
inhibition by CYP2C9, 2C19
• Other highly protein-bound drugs can interfere with
fosphenytoin/phenytoin
• Selected interactions between AEDs:
: Pentobarbital: fosphenytoin/phenytoin concentrations
can decrease due to induction of metabolism
: Phenobarbital: fosphenytoin/phenytoin
concentrations can increase or decrease due to changes
in metabolism
: Topiramate: fosphenytoin/phenytoin concentrations
can increase due to decreased metabolism
: Valproate sodium (and derivatives): fosphenytoin/
phenytoin total concentrations can decrease and
unbound concentrations can increase due to
displacement from binding site (complex mechanism);
concomitant use of valproate can also increase
hypersensitivity reactions
• Selected interactions between non-AEDs:
: Oral anticoagulants: fosphenytoin/phenytoin
concentrations can increase; anticoagulant effects can
increase or decrease
: Folic acid: phenytoin concentrations can decrease
: Nimodipine: phenytoin concentrations may increase;
nimodipine therapeutic effects can be reduced with
concomitant phenytoin use
: Trimethoprim: phenytoin concentrations can increase
due to inhibition of metabolism.
Phenobarbital TDM Target
Total Concentrations of 15–40 μg/mL
TDM principles:
• Loading doses are used to rapidly place patient in
therapeutic range, given long half-life of drug
• A level may be obtained prior to steady state to evaluate the
trajectory towards steady-state concentrations
• Steady-state concentration achieved in three to five weeks
• Suspect toxicity if nystagmus, ataxia, lethargy, coma,
stupor, or reduced respiratory function. Life-threatening
toxicity at concentrations >100 μg/mL
• Phenobarbital disposition is affected by liver disease.
TDM drug–drug interactions
• Many potential interactions exist, as this AED induces
most CYP450 enzymes

• Metabolism of this AED is susceptible to inhibition by
CYP2C9, 2C19
• Other highly protein-bound drugs can interfere with
phenobarbital
• Selected interactions between AEDs:
: Fosphenytoin/phenytoin: phenobarbital concentrations
can increase due to competition for hepatic metabolism
: Sodium valproate (and derivatives): phenobarbital
concentrations can increase due to competition for
hepatic metabolism; empirically adjust phenobarbital
dose downward by 50%.
Sodium Valproate and Derivatives TDM Targets
Total concentrations of 40–100 (150) μg/mL (upper end of
serum concentration range is not definitively established).
Free (unbound) Concentrations of 1–2 μg/mL
• Useful in altered plasma protein binding states, including
hepatic or renal dysfunction, cystic fibrosis, burn, trauma,
malnourished, and in the elderly.
TDM principles:
• Obtain level immediately following loading dose
• Steady-state concentration usually achieved in 2 to
4 days
• Dose and total valproate concentrations follow
nonlinear kinetics due to interplay with plasma protein
binding
• Unbound concentrations follow linear kinetics
• Suspect toxicity if CNS depression, lethargy,
encephalopathy, respiratory depression, and myoclonus
• Drug disposition may be affected by altered protein
binding states.
TDM drug–drug interactions:
• Many potential interactions exist as this AED induces most
CYP450 enzymes
• Metabolism of this AED is susceptible to inhibition by
CYP2C9, 2C19.
• Other highly protein-bound drugs can interfere with
this AED.
• Selected interactions between AEDs:
: Fosphenytoin/phenytoin: sodium valproate (and
derivatives) concentration can decrease due to increase
in metabolism. Concomitant use of phenytoin can also
increase hypersensitivity reactions
: Phenobarbital: sodium valproate (and derivatives)
concentration can decrease due to competition for
hepatic metabolism.
• Selected interactions between non-AEDs:
: Carbapenems (imipenem, meropenem, ertapenem):
sodium valproate (and derivatives) concentration
can decrease markedly due to increase in
metabolism.
Chapter 7: Neuropharmacology
Hyperosmolar Solutions
Osmotic agents, mannitol and hypertonic saline (HTS), are
commonly used in the management of intracranial hyperten-
sion and cerebral edema that may develop following brain
insults such as TBI, malignant ischemic stroke, and hemor-
rhagic strokes. These hyperosmolar solutions can rapidly
reduce ICP in the emergency setting, which can temporarily
stabilize the patient while other diagnostic or therapeutic
treatment strategies such as neurosurgery are being con-
sidered. Hypertonic saline may also be indicated for patients
with symptomatic hyponatremia, cerebral salt wasting, or syn-
drome of inappropriate secretion of antidiuretic hormone. The
focus here will be their use to treat cerebral edema and elevated
intracranial pressures. Mannitol is the current recommended
agent for this purpose in adult guidelines for the management
of TBI [18]. In general, there are limited studies of hyperos-
molar agents in other brain injuries to provide consensus. In a
meta-analysis it was suggested that HTS was more efficacious
at ICP reduction [19]. Either agent’s impact on clinical out-
comes, however, has not been determined.
Successful osmotic agents must be hyperosmolar to the
serum osmolarity range of approximately 280–310 mOsm/L
and have a high osmotic reflection coefficient. The reflection
coefficient refers to a substance’s permeability across the
blood–brain barrier (BBB). A value of 1 means the substance
is excluded from transport across the BBB and is osmotically
most active (range 0–1). In the setting of an intact BBB,
mannitol and HTS primarily reduce cerebral edema and ICP
by extracting water from the parenchyma into the intravascu-
lar compartment by creation of an osmotic gradient. Due to a
reflection coefficient of <1, mannitol, however, has been
shown to be less effective in regions of injured brain where
cerebral autoregulation is lost and the BBB has been disrupted.
This can contribute to a rebound in ICP or edema. Additional
mechanisms of action for these agents involve plasma volume
expansion and subsequent cerebral autoregulatory vasocon-
striction, to which initial reductions in cerebral edema and
ICP are attributed, and a decrease in serum viscosity to
improve cerebral blood flow. Hypertonic saline additionally
may attenuate the inflammatory response to brain injury.
Further information regarding pharmacology, dosing and
therapeutic management are included in Table 7.3. Of note,
clinical practice can vary surrounding the use of osmotics.
Hypertonic saline is more suitable for patients with volume
depletion, renal failure, hypotension, or those with intracranial
hypertension refractory to mannitol.
Antishivering Agents
Shivering is commonly encountered in a patient whose body
temperature is being aggressively modulated for an out-of-
hospital cardiac arrest or for an acute brain injury with subse-
quent refractory intracranial hypertension or fever. It is an
involuntary, defensive response of increased heat production
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 Chapter 7: Neuropharmacology

Table 7.3 Osmotic therapies for cerebral edema and increased ICP

Mannitol Hypertonic saline

U.S. product 20% mannitol (1100 mOsm/L) 3% (1027 mOsmol/L)
availability 25% mannitol (1375 mOsm/L) 5% (1711 mOmsmol/L)
(osmolarity) 23.4% (8008 mOsmol/L)
Suggested 20% or 25% 3% or 5%
dosing and  Bolus dose as needed for ICP >20 mm Hg,  Bolus dose as needed for ICP >20 mm Hg, >5–10 min,
administration >5–10 min, e.g. 0.5–1.5 g/kg IV over 15–30 min e.g. 250 mL over 10–20 min
 May schedule doses for maintenance, e.g. 0.25–0.5 g/kg IV  Continuous infusion may be used to maintain serum Na
every 4–8 h (e.g. Na 145–155 mEq/kg), e.g. 0.1–2 mg/kg/h titrated to
 Higher bolus dose typically used in crisis, brain herniation, goal Na
e.g. 1–1.5 g/kg IV over 5–15 min
 Contraindicated in anuria. 23.4%
 In-line 5-micron filter required. Peripheral administration  30mL over 10 min typically in crisis, brain herniation
permitted  Central line only with all concentrations
Drug Onset: 15 min (ICP); 1–3 h (diuresis) Onset: ~15 min
properties Duration: 2–6 h (ICP) Duration: ~1.5–10 h
Elimination t½: 0.5–2.5 h Excretion: Renal (primarily), saliva, sweat, tears
Metabolism: Hepatic (minimal) to glycogen Reflection coefficient: 1.0
Excretion: Renal Limited PK data available
Reflection coefficient: 0.9
Adverse  Hypovolemia, hypernatremia, hypokalemia  Hypernatremia, hypokalemia, hyperchloremic metabolic
effects  Nephrotoxicity including acute tubular necrosis acidosis
 Circulatory overload (CHF, pulmonary edema)  Risk of central pontine myelinolysis; reported in cases of
chronic hyponatremia and rapid correction, especially in
alcoholic and malnourished patients
 Circulatory overload (CHF, pulmonary edema)
 Local tissue phlebitis
 Hypotension with too rapid infusion
Monitoring  Routine electrolytes  Routine electrolytes, including serum Na q 6 h
 Strict intake and output monitoring to maintain adequate • Traditional therapy goal Na 150–155 mEq/L
intravascular volume  Rebound cerebral edema or ICP, especially during
 Systemic hypotension may occur due to rapid diuresis tapering (cautious wean advised)
before adequate amounts of replacement fluids  Central pontine myelinolysis (avoid increases in serum
 Serum osmolality q 6 h Na >10–12 mEq/L/day)
• Traditional therapy goal 300–320 mOsm/kg
• Threshold of 320 mOsm/kg challenged
• Osmolar gapa may be used as surrogate marker to assess
drug clearance in between dosing (calculate gap prior to
mannitol dose)
• Osmolar gap of 15–20 indicates incomplete clearance of
mannitol and could predispose the patient to rebound
edema and nephrotoxicity
• If the osmolal gap is elevated, the dose of mannitol may
be held and the dose should be reduced or the dosing
interval extended to allow for complete removal of the
drug prior to repeat dosing
 Rebound cerebral edema or ICP, especially during tapering
and disruption of BBB (cautious wean advised)
BBB blood–brain barrier; CHF congestive heart failure; CSW cerebral salt wasting; h hour; ICP intracranial pressure; IV intravenous; L liter; mEq milliequivalents;
mg/kg/h milligrams per kilogram per hour; mOsm/kg osmolality; mOsm/L osmolarity; PK pharmacokinetics; Na sodium; q every; SIADH syndrome of inappropriate
antidiuretic hormone
a
Osmolar gap = measured serum osmolality – calculated osmolality

72

to maintain the body’s core temperature. However, shivering
can negatively impact the metabolic benefits we hope to
achieve with therapeutic hypothermia or normothermia. Add-
itionally, it may increase intracranial pressure and metabolic
demand. It is therefore essential that the shivering response be
controlled.
The pharmacologic agents that may be used to counter
shivering target various receptors and are proposed to modu-
late thermoregulation in different ways (see Table 7.4). Gener-
ally, pharmacologic management begins with analgesics and
sedatives, and neuromuscular blockers are reserved if the pre-
vious interventions do not reduce shivering. No specific drug
or regimen is universally accepted. Much of the data published
is in healthy volunteers or in the peri-operative period where it
is important to keep in mind the effects of general anesthesia
on thermoregulation [20]. Note, there are studies in healthy
volunteers that show combining antishivering agents may
result in synergistic or additive effects, such as buspirone with
meperidine, or dexmedetomidine with meperidine [21,22].
Physiologic affects and subsequent specific dose reductions
have not been delineated in this patient population, but the
clinician should be aware that the hypothermic slowing effects
on hepatic enzymes can affect drug metabolism in hepatically
metabolized medications. Common antishivering agents pre-
sented in Table 7.4 are affected [23]. At 34 °C, propofol
clearance was decreased with subsequent increases in serum
concentration by nearly 30%. Vecuronium clearance was
decreased by 11% for every 1 °C reduction, leading to a
doubling of duration of action. At 32 °C, fentanyl plasma
concentrations increased by 25%. Other NMBs such as rocur-
onium and pancuronium would be expected to have an effect.
The drug therapies highlighted in Table 7.4 are the agents
utilized in a well-cited protocol designed for the prophylaxis
and treatment of shivering, known as the Columbia Anti-
Shivering Protocol [24]. With the use of this protocol, 18%
of patients required prophylactic interventions only (see
Table 7.4). One additional agent was required by 29% of
patients, two additional agents by 35%, and three additional
agents by 15%. A small percentage (<3%) required four add-
itional agents. In clinical practice, drug therapy may be
guided by the Bedside Shivering Assessment Scale (BSAS),
with a goal to achieve no to minimal shivering or a BSAS score
of 1 [24,25].
Cerebral Vasospasm and Delayed Cerebral
Ischemia
The development of cerebral vasospasm or narrowing of the
cerebral arteries following aSAH may occur between 3 and 21
days after aneurysm rupture, most frequently occurring at days
7 to 10. Delayed cerebral ischemia (DCI) may or may not be
associated with the development of cerebral vasospasm and,
like vasospasm, is a significant contributor to morbidity and
mortality in aSAH. No therapy has been shown to improve
mortality in aSAH patients who develop cerebral vasospasm or
Chapter 7: Neuropharmacology
DCI. Universal recommendations to prevent DCI include
maintenance of euvolemia in the SAH patient and the prophy-
lactic use of oral nimodipine and are standard of care [26,27].
A smaller amount of literature currently exists for other sys-
temic therapies and locally administered medications to the
cerebral vasculature.
Systemic Therapies
Triple-H Therapy
Triple-H therapy (hypervolemia, hemodilution, hypertension)
is considered the traditional treatment approach for active
cerebral vasospasm and DCI. In clinical practice, application
of triple-H therapy is highly variable. Generally hypervolemia
is achieved with administration of 0.9% sodium chloride and
may also include 5% or 25% albumin to maintain circulating
blood volume. Fluid balance is monitored closely and clin-
icians may also target a specific central venous pressure or
pulmonary artery occlusion pressure. The theoretical advan-
tage of hemodilution and targeting a reduced hematocrit while
maintaining hypervolemia is to reduce blood viscosity and
increase cerebral flood flow (CBF) and oxygen delivery. Meas-
ures of CBF, however, are not maintained with this strategy
and oxygen delivery capacity is reduced [28]. Another
approach that has been evaluated is the administration of
packed red blood cells (PRBCs) to improve oxygen delivery
to ischemic areas. Anemia is a common occurrence following
aSAH. Some experts recommend PRBC transfusions to main-
tain hemoglobin at 8–10 g/dL and in some cases a higher
hemoglobin target may be appropriate [26]. Lastly, the
principle of hypertension in triple-H therapy includes increas-
ing or maintaining a blood pressure to improve cerebral per-
fusion pressure and CBF. This therapy is recommended by
current guidelines, unless blood pressure is elevated at baseline
or the cardiac status of the patient prevents it [27]. Some
clinicians may target a systolic blood pressure or a mean
arterial pressure, but hemodynamic targets for the treatment
of vasospasm or DCI have not been studied. There are no
comparative vasopressor trial data. Commonly, phenylephrine
or norepinephrine, and to a lesser extent dopamine, may be
used in the management for induction of hypertension [26].
There are randomized controlled trial data that show prophy-
lactic triple-H therapy is not beneficial and its use is currently
not recommended [26,27,29,30].
Nimodipine
Nimodipine is a calcium channel blocker that inhibits the
entry of calcium into smooth muscle cells, thereby inhibiting
vasoconstriction. Although the exact mechanism of nimodi-
pine’s effectiveness in aSAH outcomes has not been fully
elucidated, it may attenuate the increases in calcium that lead
to cellular ischemia and cause cellular death. Compared to
other calcium channel blockers, nimodipine has increased
lipophilicity and greater effect on cerebral arteries. Nimodipine
administered prophylactically has been shown to decrease the
73
 Chapter 7: Neuropharmacology
Table 7.4 Antishivering agents
Agent Dosing Key pharmacology
Step 0 [Prophylaxis] – Implement all baseline interventions listed in section belowa
Acetaminophen 650–1000 mg Elimination t½: 2–3 h
(APAP) PO q 4–6 h (prolonged in hepatic
insufficiency)
Metabolism: Hepatic with
toxic intermediate; NAPQI
(can accumulate with as
little as 4 g/day APAP)
Excretion: Renal
Buspirone 30 mg PO q 8 h Elimination t½: 2–3 h
(prolonged in severe
hepatic or renal
impairment)
Metabolism: Hepatic with
active metabolite
Excretion: Renal
Magnesium 0.5–1 mg/h IV Excretion: Renal
sulfate to maintain
serum level of
3–4 mg/dL
Step 1 [Mild Sedation] – Select an opioid or dexmedetomidine for BSAS score 2–3 and maximize therapy
Step 2 [Moderate Sedation] – Select an opioid and dexmedetomidine if inadequate control with Step 1 and maximize therapy
Meperidine 50–100 mg Elimination t½: 3 h
IM/IV (prolonged in cirrhosis)
Half-life: 15–20 h for
normeperidine
(prolonged in cirrhosis)
Metabolism: Hepatic with
active metabolite
(normeperidine)
Excretion: Renal
Fentanyl Initiate Elimination t½: 2–4 h
continuous (prolonged with
infusion at continuous infusion)
25 μg/h Metabolism: Hepatic
Excretion: Renal
Dexmedetomidine Initiate Elimination t½: 2–3 h
continuous Metabolism: Hepatic
infusion at Excretion: Renal
0.2 μg/kg/h
(max 1.5
μg/kg/h)
74
AEs and therapeutic
considerations
AEs: Increased serum alkaline
phosphatase, nausea, hepatic cell
necrosis (dose related)
Contraindicated in severe hepatic
impairment or severe active liver
disease
AEs: Dizziness, headache, nausea,
sedation
Reduce dose or avoid in severe hepatic
or renal impairment
AEs: Electrolyte disturbances and
toxicities, which progress with
increasing serum levels; nausea,
flushing, hyporeflexia, CNS
depression, respiratory and muscle
paralysis, cardiac toxicity including
arrest
Avoid or monitor serum levels
frequently in severe renal failure
AEs: CNS excitation including
tremors, muscle twitches, seizures
(accumulation of normeperidine),
hypotension, N/V, respiratory
depression sedation, slowed gastric
emptying
Reduce dose or avoid in severe hepatic
or renal impairment due to risk of
neurotoxicity
AEs: As listed for meperidine with
exception of less hypotension (lack of
histamine release) and no CNS
excitation
Reduce dose in severe renal
impairment and moderate hepatic
impairment; avoid in severe hepatic
impairment.
AEs: Bradycardia, hypotension,
sedation
Reduce dose in severe hepatic
impairment
Mechanism of effect in
thermoregulation
Inhibits cyclooxygenase-
mediated prostaglandin
synthesis, which lowers the
hypothalamic set point
5-HT1A partial agonist, which
lowers the shivering
threshold
Vasodilator, which
counteracts normal adaptive
response of vasoconstriction
during surface cooling
process
Antagonist activity at NMDA
receptor also impairs
thermoregulatory control
Reduces time to target
temperature and increases
patient comfort
Agonist at α2B-receptor,
which lowers the shivering
threshold
Agonist activity at opioid
receptors (μ, κ) and
antagonist activity at NMDA
receptor also impair
thermoregulatory control
Agonist activity at μ-opioid
receptor impairs
thermoregulatory control
Agonist at central
α2A-receptors, which reduces
both vasoconstriction and
shivering thresholds
 Chapter 7: Neuropharmacology

Table 7.4 (cont.)

Agent Dosing Key pharmacology AEs and therapeutic Mechanism of effect in

considerations thermoregulation
Step 3 [Deep Sedation] – If inadequate control with Steps 0–2 with BSAS score 1
Propofol 50–75 μg/kg/min Elimination t½: 4–7 h AEs: Bradycardia, hypotension, PRIS, Peripheral vasodilatory
continuous (prolonged with respiratory depression, sedation effects reduce primarily
infusion continuous infusion) Risk of PRIS increases at high doses vasoconstriction, but also
Metabolism: Hepatic (
80 μg/kg/min), monitor for acidosis shivering thresholds
Excretion: Renal and creatinine kinase when used
48
h
Provides considerable IV lipid load,
monitor triglycerides and caloric intake
(1.1 kcal/mL).
Contraindicated in patients with severe
allergy to egg and soy proteins
Step 4 [Neuromuscular blockade] – If inadequate control with Steps 0 – 3
Vecuronium 0.1 mg/kg IV Elimination t½: 60–80 min AEs: Muscle atrophy and weakness Control involuntary muscle
bolus Metabolism: Hepatic Loss of neurologic exam (masks contractions involved in
Excretion: Renal, fecal insufficient sedation and seizure shivering
activity)
Prolonged paralysis may occur in
severe hepatic or renal failure
a
Baseline intervention per protocol should also include skin counterwarming at a maximum temperature of 43 °C
5-HT serotonin; AEs adverse effects; BSAS Bedside Shivering Assessment Scale; CNS central nervous system; dL deciliter; h hour; IM
intramuscular; IV intravenous; kg kilogram; mg milligram; μg microgram; min minutes; NAPQI N-acetyl-p-benzoquinone imine; NMDA N-
methyl-d-aspartate; N/V nausea and vomiting; PO by mouth; q every; PRIS propofol-related infusion syndrome
Bedside Shivering Assessment Scale (BSAS)
Score Definition
0 None: no shivering noted on palpation
1 Mild: shivering localized to the neck and/or thorax
2 Moderate: shivering also involves gross movement of upper extremities
3 Severe: shivering involves gross movement of the trunk and upper and lower extremities

risk of secondary ischemia and poor neurological outcome,
and is the only FDA-approved therapy for aSAH patients
[31,32]. Only oral preparations of nimodipine are available in
the USA The labeled dosing is 60 mg orally every four hours
for 21 consecutive days started within 96 hours from SAH
onset. Product labeling recommends dose adjustment to 30 mg
every four hours in patients with cirrhosis [33]. Clinically,
nimodipine may also be adjusted to 30 mg every two hours
secondary to hypotension. This practice has been suggested by
some experts rather than withholding therapy [26]. Nimodi-
pine undergoes extensive hepatic metabolism via CYP3A4.
A small percentage of the drug is eliminated renally. The major
adverse effect is hypotension.
Nicardipine
Nicardipine is also a calcium channel blocker used for its
vasodilation properties. As a continuous infusion it has been
shown to significantly reduce symptomatic vasospasm com-
pared to placebo, but not neurologic outcome at three months
[34]. Significantly more patients tolerated a target dose of
0.075 mg/kg/hour compared to 0.15 mg/kg/hour over 14 days,
and dose titrations were protocolized in this study [35].
Common adverse effects reported were hypotension, pulmon-
ary edema, and azotemia. Nicardipine may also cause periph-
eral venous irritation and product labeling suggests changing
the site of infusion every 12 hours. Nicardipine is metabolized
by the liver primarily via CYP3A4. Renal elimination accounts
for approximately 50% of total elimination. While dose adjust-
ments may be warranted in liver or renal disease, no specific
recommendations are available.
Magnesium
Magnesium causes smooth muscle relaxation and vasodilation
through inhibition of calcium. Early trial data reported prom-
ising effects on cerebral vasospasm prevention with high-dose
magnesium administered intravenously. However, in the larg-
est randomized, placebo-controlled trial to date, magnesium
failed to improve outcomes in SAH [36]. Targeting elevated

75
 Chapter 7: Neuropharmacology

serum magnesium is not recommended, but avoiding hypo-
magnesemia in SAH patients is [26,27].
Locally Administered Therapies
Alteplase
Alteplase is a thrombolytic that has been evaluated for intrathecal
(IT) administration to accelerate the clearance of blood from the
basal cisterns and ventricles in SAH. A meta-analysis reported
significant reduction of poor neurologic recovery, delayed neuro-
logic deficits, angiographic vasospasm, and chronic hydrocepha-
lus among patients treated with IT thrombolytics (both alteplase
and urokinase studied) [37]. The authors recognize that the trials
lack standardization and that more robust data are needed.
Dosing for alteplase in two trials was 8 mg or 10 mg, adminis-
tered once to the basal cisterns using various techniques.
Nicardipine
Intra-arterial (IA), intraventricular (IVT) and IT routes of
administration have been used for cerebral vasospasm treat-
ment with nicardipine. The IV formulation of the branded
product (Cardene®) is preservative-free and was used in all
data currently published. Nicardipine has been shown to cause
sustainable effects on cerebral vasodilation and reductions in
cerebral flow velocities [38–42]. Dosing varies throughout
available studies and includes a max of 5 mg for IA therapy
per vessel and 4 mg for IVT/IT every 8–12 hours with a
recommendation to clamp drains for 30 minutes following
each administration. The side effects that may be anticipated
with these routes of administration are increases in ICP, and
reductions in blood pressure and increases in heart rate in
which vasopressor therapy may be required. Additionally,
one must consider the risk of ventricular catheter-related
infections for IVT administration.
Verapamil
Verapamil is a calcium channel blocker that may be used as an
IA injection for cerebral vasospasm. It has been shown to be
effective in reversing refractory vasospasm, yet its dosing has
varied considerably, from 25 to 360 mg per vessel [43,44].
Compared to locally administered nicardipine, a smaller
amount of literature on verapamil exists. Like nicardipine,
increases in ICP, and reductions in blood pressure and
increases in heart rate have been associated with its treatment.
Papaverine
Papaverine is a phosphodiesterase inhibitor that, when admin-
istered into a cerebral artery, causes vasodilation through
actions on smooth muscle. Papaverine has been the most
widely studied among the locally administered therapies, but
has considerable side effects, including hemodynamic com-
promise, increased ICP, seizures, and worsening of spasms.
Its use is not routinely employed and acquisition of the
drug may be difficult with national backorder issues (see
www.ashp.org/DrugShortages for up-to-date information).

status epilepticus. Verterans Affairs Neurobehavioral effects of phenytoin

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 Chapter
Intracranial Monitoring in the Neurocritical Care Unit
8 Chad M. Miller
Introduction
Invasive neuromonitoring is fast becoming an integral part of
neurocritical care due to its capability and role in identifying
risk for secondary injury and patient deterioration. Care of the
brain-injured patient that utilizes only systemic therapeutic
parameters and generalized patient goals has been shown
to result in unacceptable rates of delayed brain injury [1].
Traditional signs of injury, such as examination changes and
hemodynamic variation, are important but insensitive and
late markers of irreversible damage, and are preceded by
subclinical edema, inflammation, ischemia, and free radical
production by hours and sometimes days [2]. Current neuro-
monitoring devices are capable of assessing risks for deterior-
ation by measurement of the uptake, delivery, or utilization
of brain metabolites at a time when therapeutic intervention
is possible.
Monitors may be categorized into two basic types. Regional
monitors provide information specific to a localized area of the
brain near the detection probe. They provide data unique to a
small portion of the brain that may or may not have relevance
to the health of the entire brain or a region remote from the
detection device. Probes for these monitors are often inserted
into areas of specific interest or risk for secondary injury.
Global monitors provide an averaged assessment of the condi-
tion of the entire brain. While these monitors are effective in
identifying diffuse injury or impairment resulting from com-
promised substrate delivery, they may lack sensitivity for
injury that is specific to a focal brain lesion. The concept of
multimodal monitoring addresses the spatial and etiologic
diversity of secondary injury by utilizing various complemen-
tary monitors.
This chapter will discuss the most commonly used brain
monitors in the neurocritical care unit. The type of injury and
brain physiology relevant to each monitor will be discussed, as
well as the complications of placement, desired timing, dur-
ation, and ideal location for probe placement. The best clinical
data supporting use of each monitor will be described, and the
integration of each monitor into a comprehensive clinical
monitoring algorithm will be considered. The importance of
systemic parameters, such as temperature and blood pressure,
are reviewed elsewhere in this book. Two of the most com-
monly used noninvasive multimodal monitors, transcranial
78
Doppler ultrasonography and electroencephalography, are
described in separate chapters.
Intracranial Pressure Monitoring
Intracranial pressure (ICP) monitoring is the most widely
used invasive monitor in the brain-injured patient. Its value
derives from a preponderance of data across several diag-
noses correlating adverse short- and long-term outcomes
with intracranial hypertension. The pressure in the cranial
vault is a product of the collective volumes of brain, cerebro-
spinal fluid (CSF), blood, and, occasionally, foreign matter.
Shifts in the relative volumes of blood and CSF attempt to
maintain normal ICP. When brain compliance decreases and
compensatory changes in volume are exhausted, pressure
increases and brain mass is displaced. ICP is most often
measured via an extraventricular catheter (EVD) coupled
to a fluid pressure transducer or an intraparenchymal
fiberoptic catheter. Both may be placed through a burr hole
or the lumen of a cranial bolt. Normal ICP ranges between
2 and 10 mmHg. ICP can alternatively be expressed in
cmH2O (1 cmH2O = 0.74 mmHg). ICP is reactive and can
be elevated during pain, straining, or other transient
events. Sustained elevations in ICP (>5 minutes) in excess
of 20–25 mmHg are considered worthy of intervention,
though thresholds for damage are likely to be patient specific
[3]. In addition to the extent of pressure elevation, the dur-
ation of sustained ICP contributes to subsequent injury.
In the most broad sense, ICP monitoring is indicated when
intracranial hypertension is suspected or when it is unknown
in a comatose patient (Glasgow Coma Scale (GCS) <9). The
most directive recommendations for ICP monitoring are
included in the 2007 Brain Trauma Foundation Guidelines
for the management of severe traumatic brain injury (TBI).
Patients should receive an ICP monitor when a salvageable
patient with an abnormal head CT (computed tomography)
has a GCS between 3–8 following resuscitation. Alternatively,
monitoring should be considered in patients with a normal
head CT when they exhibit unilateral or bilateral motor pos-
turing, cerebral perfusion is compromised (systolic blood
pressure (SBP) <90 mmHg), or age is >40 years [3]. Nontrau-
matic indications for ICP monitoring are similarly based
upon level of alertness and suspicion of intracranial

hypertension. In most circumstances, treatment directed
toward lowering ICP should be guided by ICP monitoring.
The gold standard for ICP assessment is transduction of
pressure through a fluid-coupled EVD. This approach also
allows for therapeutic CSF drainage for elevated pressures
and evacuation of intraventricular hemorrhage. ICP can only
be accurately measured when drainage has stopped and the
fluid column is directed to the transducer. As a result, it is not
possible to continuously drain CSF and concomitantly meas-
ure pressure. When an EVD is used in this capacity, it is
prudent to have a second monitor to continuously measure
pressure during drainage or utilize an EVD that assesses ICP
via a second method. In addition to quantitative pressure
assessment, analysis of the ICP waveform can provide warning
of worsening cranial compliance and pending decompensa-
tion. In a characteristic three-wavelet ICP tracing, a P2 tidal
wave greater in amplitude than the P1 percussion wave is
concerning for impending intracranial hypertension.
Due to vascular resistance, intracranial hypertension may
result in secondary ischemic damage by lowering cerebral
perfusion pressures (CPP = mean arterial pressure – ICP).
This phenomenon is likely one of the many reasons why
isolated targeting of ICP thresholds is inadequate as a thera-
peutic aim.
The chief risks in placement of an intracranial pressure
monitor are hematoma formation in the catheter track or
catheter-associated infection. Symptomatic hemorrhage after
EVD placement occurs in less than 2% of placements [4]. This
incidence is generally considered lower with placement of
smaller caliber fiberoptic probes. The risk of hemorrhage can
be minimized for either device by reducing the number of
catheter passes into the brain parenchyma and assuring cor-
rection of coagulopathies and thrombocytopenia. The rate of
CNS infection attributable to ICP monitoring devices is
dependent upon the device used and the criteria and method
for defining infection. The rate of EVD infection marked by a
positive CSF culture is considered to be 8–9% [5]. The pres-
ence of intraventricular blood, subarachnoid hemorrhage, cra-
niotomy, systemic infection, catheter irrigation, and CSF leak
all predispose to infection. The risk for ventriculitis related to
EVD placement is time dependent and increases sharply after
5 days [6]. Despite this fact, infectious risks are not lessened by
routine catheter exchange. The rate of infection related to
fiberoptic catheters is likely less, but is difficult to determine
due to lack of routine CSF sampling. The role of prophylactic
antibiotics prior to and after placement of an ICP monitor is
controversial, though one large series did not show benefit [7].
Similarly, the use of antibiotic-coated catheters has been
shown to dramatically reduce infection and catheter coloniza-
tion in some studies [8], while failing to demonstrate benefit in
others [9]. Implementation of EVD placement bundles that
incorporated hand hygiene, prophylactic antibiotic use, mul-
tiple sterile glove exchanges, hair clipping, use of full body
drapes and surgical attire, antimicrobial catheters, and use of
both iodine povacrylex (0.7%) and isopropyl alcohol (74%),
Chapter 8: Intracranial Monitoring
have demonstrated dramatic reductions in infection rates
(9.2% to 0%) [10].
Although ICP monitoring has been central to the care of
brain-injured patients with intracranial hypertension for years,
its value in achieving improved patient outcomes is debatably
unproven. This controversy rose again after the results of the
BEST-TRIPS trial failed to demonstrate benefit for ICP-guided
therapy after severe TBI [11]. This South American trial of
324 severely brain-injured patients randomized subjects to
receive therapy guided by either early placement of an ICP
monitor or empiric ICP-lowering therapies based upon radio-
logic and clinical suspicion of intracranial hypertension. The
six-month composite outcome of survival, level of conscious-
ness, extended Glasgow Outcome Scale (eGOS), and neuro-
psychiatric testing failed to reveal a difference between the
groups. While lauded for its randomized investigation of an
unsubstantiated common practice, the generalizability of the
study has drawn criticism due to poor prehospital care, short
durations of ICP monitoring, absence of standard rehabili-
tation, and aggressive ICP reduction measures in the control
group. The study has caused the monitoring community to
consider the legitimacy of the established thresholds for ICP
monitoring and question the reliance upon sole ICP-directed
care. While randomized studies have not shown direct treat-
ment benefit from ICP monitoring, use of guideline treatment
protocols that include ICP monitoring have consistently
resulted in superior outcomes [12]. The summation of current
data suggests that there is a clear role for ICP monitoring, but
it is best interpreted with the consideration of physical exams,
radiologic findings, cerebral perfusing pressures, and comple-
mentary neuromonitoring data.
Brain Tissue Oxygen Monitoring
A brain tissue oxygen probe measures regional brain oxygen
content utilizing a polarographic Clark electrode or optical
luminescence. The probe is inserted through a bolt system or
independently through a burr hole with the tip of the probes
situated in cerebral white matter. In vivo experiments have
demonstrated outstanding accuracy within physiologic ranges
of oxygenation with minimal drift over time [13]. While the
probe provides data regarding brain oxygen content (PbtO2),
delivery and utilization can be inferred. There is uncertainty
regarding whether the catheter actually measures arteriolar,
venous, or capillary oxygenation. PbtO2 values most closely
approximate the product of CBF and cerebral arteriovenous
oxygen tension difference, suggesting that it represents diffu-
sion of dissolved oxygen across the blood–brain barrier [14].
Common treatment thresholds for the Clark electrode system
are 15–20 mmHg (Licox; Integra Life Sciences, Plainsboro,
NJ). PbtO2 values acquired within an hour of catheter place-
ment often reflect artifacts from placement and should not be
used to make clinical decisions [15].
The risks associated with probe insertion are minimal.
Radiographic hematomas occur after 1.7–2.9% of placements
79
 Chapter 8: Intracranial Monitoring
[16,17] and cases of infection have rarely been reported. The
timing and location of probe insertion should consider the
characteristics of secondary injury that are being monitored.
In a study of delayed cerebral infarction after aneurysmal
subarachnoid hemorrhage (aSAH), infarction occurred ipsilat-
eral to the ruptured aneurysm in 91% of cases. DCI occurred
in the same vascular territory as the parent vessel in 86% of
cases. A monitor with perfect sensitivity for ischemic risk
placed in the ipsilateral middle cerebral artery territory will
identify 71% of DCIs [18]. As a result, it is reasonable to place
a PbtO2 probe in the ipsilateral MCA territory three to four
days after aSAH to best monitor ischemic risk. In a study of
405 severe TBI patients, probes placed in normal but vulner-
able brain tissue yielded values that were predictive of three-
and six-month clinical outcome, whereas probes placed in
radiographic normal brain generally demonstrated normal
oxygen content without correlation to outcome [19]. After
resuscitation from severe TBI, low PbtO2 values occur in
68% of patients with normal ICP and CPP parameters [20].
As a result, probes should be placed in normal white matter
adjacent to brain at risk early after resuscitation from TBI.
PbtO2 values correlate closely with outcome and survival
after a variety of primary brain injuries. In a study of
43 severely injured TBI patients, the likelihood of death was
related to increasing duration of time below a PbtO2 of
15 mmHg or any time <6 mmHg [21]. These low values are
amenable to therapy [22]. Numerous single-center studies have
reported improved outcomes attributable to PbtO2-guided
protocols. In one such study, mortality was reduced from
44 to 25%, compared to historical controls matched for age,
GCS, and Injury Severity Scores (ISS) [23]. In a similar study
of 139 severe TBI patients, PbtO2-directed care versus histor-
ically matched CPP-driven therapy resulted in lower six-
month GOS (3.55 ± 1.75 versus 2.71 ± 1.65; p <0.01) [24].
Mortality was also improved (25.9% versus 41.5%), despite
higher ISS in the CPP-managed cohort. The ongoing BOOST
II trial is exploring these benefits in a randomized multicenter
designed trial.
Brain tissue oxygen monitors have also been used to assess
ischemic risks after aSAH. The number of PbtO2-defined hyp-
oxic episodes after aSAH correlates with one-month mortality
[25]. The mean daily PbtO2 is higher among survivors despite
similar ICP in both groups (33.94 ± 2.74 versus 28.14 ± 2.59;
p = 0.05). Episodes of low PbtO2 are amenable to therapy that
augments cerebral flow [26]. In a study comparing brain
oxygenation to CT perfusion scans, mean transit time best
correlated with oxygen content (R = –0.50, p = 0.017) [27].
Cerebral Microdialysis
Cerebral microdialysis is a monitoring technique that provides
a real-time assay of the biochemical health of the brain. A thin
(0.9 mm) probe with low tensile strength is guided into cere-
bral white matter through a burr hole or bolt mechanism. The
catheter consists of input and output tubing connected by a
80
semipermeable membrane at its distal tip. Artificial CSF is
infused by a battery operated pump (0.3 µL/min) through
the input tubing to the distal membrane. Fluid is retained
within the catheter system. However, analytes in the brain
interstitium pass down their concentration gradients and are
collected through the membranous tip of the catheter. Fluid
then passes through the output tubing and is collected hourly
in small microvials. This fluid is analyzed within the intensive
care unit by a portable point-of-care device yielding real-time
brain chemistry data. Commonly measured analytes include
glucose, lactate, pyruvate, glutamate, and glycerol. The first
three provide insight regarding brain metabolism and fuel
availability. Glutamate is a general measure of cellular distress,
and plays important roles in the development of brain edema
and electrochemical cell stability. Glycerol is a key constituent
of the lipid neuronal membrane. Elevations of this analyte
signify cellular loss. Other analytes may be collected and quan-
tified by the microdialysis technique. Recovery of the desired
molecule is dependent upon the perfusate rate, length, and
pore size of the catheter tip, and the size and electrical charge
of the analyte.
Normal analyte values have been defined for the five most
commonly assayed molecules. However, intrasubject trends in
concentrations often carry as much or more clinical signifi-
cance than absolute values.
Considering the size and delicate characteristics of
the catheter, brain injury related to placement is typically
minimal. Most data reporting complications from placement
derive from secondary outcomes of clinical trials and
report the risk of hemorrhage and infection comparable
to or less than fiberoptic ICP monitors. As with other
regional monitors, the optimal timing and placement of
microdialysis catheters should reflect the purpose of its
placement. Catheters remain functional for five to seven days
after placement.
Cerebral microdialysis has proven to be a sensitive indica-
tor of secondary injury after aSAH. In a prospective trial of
microdialysis monitoring after aneurysm rupture, lactate:
pyruvate ratio (LPR) elevations of 20% followed by a 20% rise
in glycerol identified DCI in 17 of 18 patients when the
catheter was placed in the vascular territory at risk [28]. These
changes were noted nearly 12 hours prior to clinical deterior-
ation. In another single-center study, glutamate elevations
were the earliest predictors of impending ischemia and pre-
ceded DCI in 87% of patients [29]. The neurochemical changes
related to ischemia are modifiable and have been shown to
improve and correlate with clinical recovery following inter-
ventional restoration of blood flow [30]. The relationship
between cerebral and serum blood glucose levels has been
shown to be inconsistent after aSAH. Furthermore, measures
to tighten glycemic control may result in critically low brain
glucose levels and resultant metabolic distress [31]. The role of
cerebral microdialysis in management of glycemic control in
brain-injured patients is an area of great interest and
opportunity.

In a study of 223 severe TBI patients, elevated LPR and
glutamate concentrations were predictive of mortality [32].
Similarly, Stein and colleagues showed that metabolic crisis
persisting beyond 72 hours after trauma predicted poor out-
come, even among fully resuscitated patients [33]. Six-month
frontal atrophy after severe TBI corresponds to the duration
of time with LPR elevation [34]. During impaired cerebral
autoregulation, low perfusing pressures are more likely to
affect pericontusional neurochemistry than that in radiologi-
cally normal brain [35]. As in aSAH, aggressive glycemic
control has been shown to have adverse biochemical effects
(elevated LPR and glutamate) despite reasonable serologic
glucose control [36]. While the correlation of analyte con-
centrations to outcome is compelling, there is less evidence
supporting the clinically modifiable nature of microdialysis
findings.
Cerebral microdialysis has been utilized in the study of
several other patient populations in the neurocritical care unit.
Our understanding of the nonischemic nature of secondary
injury after intraparenchymal hemorrhage was furthered
by microdialysis characterization of peri-hematomal neuro-
chemistry. Predictive models of malignant edema have been
reported after ischemic stroke [37]. These findings may even-
tually prove helpful when weighing the clinical need and bene-
fits of early decompressive craniectomy. Peri-tumor and
cerebral assays of chemotherapeutic drugs, antiepileptics, and
antibiotics have provided insight regarding the central nervous
system penetration of therapies whose concentrations are vital
to their efficacy [38–40]. Given the diversity of applications for
this monitoring device, its clinical growth would appear to
be limitless.
Regional Cerebral Blood Flow Monitoring
Among the multiple mechanisms of secondary injury affecting
neurocritically ill patients, ischemia is pervasive and compli-
cates the course of trauma, aSAH, ischemic stroke, and other
types of primary injury. Regional cerebral blood flow monitors
have been created for the purpose of identifying brain hypo-
perfusion and ischemia. They have risen in popularity in part
due to recognition that therapies are available to reverse
impaired blood flow. Two different types of regional cerebral
blood flow (rCBF) monitors are available for clinical use;
thermal diffusion flowmetry (TDF) (QFlow 500 Probe, Heme-
dex Inc., Cambridge, MA) and laser Doppler flowmetry (LDF).
TDF utilizes a probe fitted with two thermistors, one that emits
heat, and one that records ambient temperature change. Based
upon the conductive and convective properties of the brain,
the clearance and propagation of heat can be mathematically
transformed into cerebral blood flow approximations. This
technology has been validated with Xenon-CBF comparisons,
and the data is expressed in typical CBF units of mL/100 g/min
[41]. The LDF method determines blood flow using a laser to
detect red blood cell mass and velocity in the microcirculation.
Red blood cell flux, which correlates with CBF is computed
Chapter 8: Intracranial Monitoring
and displayed as a linear integral output. This method is
sensitive to changes in CBF, but is also limited by movement
artifacts. LDF devices are not currently available in the United
States [42].
The TDF probe is flexible and approximately 1 mm in
diameter. It can be placed in a burr hole or bolt system, though
the latter is often preferable to minimize probe movement in
the brain white matter. Limited data exists regarding the infec-
tious risks or placement complications related to the catheter.
Given the catheter dimensions, the risks are assumed to be on
par with that of a fiberoptic ICP monitor. Both CBF monitors
are regional and reflect perfusion in the specific vascular dis-
tribution of their placement. This feature makes them favored
for monitoring of focal ischemic processes such as vasospasm,
compression vascular injury, and progression of stroke. Since
TDF values correlate well with Xenon-derived CBF, and ische-
mic thresholds are well defined via this technique, it is reasonable
to use a minimum treatment threshold of 15–18 mL/100 g/min
to guide therapy. The probe remains viable and accurate for a
mean of 10 days. Timing of location of placement should coin-
cide with anticipated ischemic risks. After aSAH, the mean onset
of transcranial Doppler recorded vasospasm is five days [43].
The limited clinical experience with TDF has been confined
to monitoring situations where vascular compromise is likely.
Interventional restoration of impaired blood flow due to cere-
bral vasospasm is demonstrable by rCBF monitoring [44].
Intraoperative arterial occlusion is reflected by rapid changes
in TDF blood flow [45]. Similar reactivity has been seen
following changes in systemic blood pressure and PCO2 in
autoregulation-impaired patients [46]. Low TDF values have
also been shown to be predictive of poor clinical outcome after
head injury [47]. However, despite their apparent instinctive
value, the benefits and therapeutic impact of rCBF remain
unproven.
Jugular Bulb Saturation
Jugular bulb saturation monitoring provides a continuous
assessment of the percentage of oxygenated hemoglobin in
the jugular bulb of the brain. Monitoring requires annulation
of the jugular vein and advancement of a flexible catheter
whose tip possesses a distal continuous oximeter that rests in
the region of the jugular bulb. The oximeter is typically cali-
brated with mixed venous blood gases drawn from the distal
tip of the catheter on a routine basis (every eight hours).
Venous blood in the jugular bulb contains very little contam-
ination from the extracranial circulation. As a result, the dif-
ference between the systemic arterial oxygenation (SaO2) and
the jugular venous saturation (SjO2) reveals the percentage
extracted by the brain. This difference is termed the cerebral
oxygen extraction rate and ranges between 20 and 40% in
normal physiologic conditions [48]. Assuming arterial oxygen
saturation rates remain near 100%, SjO2 values between
55–80% are considered normal. Since jugular blood on each
side of the neck originates from a mixed sample of superficial
81
 Chapter 8: Intracranial Monitoring
and deep drainage from each side of the brain, jugular bulb
monitoring is theoretically a global monitor. Some reports
have raised concern regarding this assumption [49]. Low
SjO2 can result from increased oxygen extraction or poor
oxygen delivery. Impaired cardiac output, anemia, severe dif-
fuse vasoconstriction, systemic hypoxia, or increased oxygen
utilization (e.g. seizures) may result in this finding. Alterna-
tively, high SjO2 values may represent hyperemia, metabolic
depression related to sedation, neuronal hypometabolism or
loss, or high cardiac output. Caudal displacement of the jugu-
lar catheter allows facial venous contamination, which can
spuriously elevate SjO2.
Risks for jugular bulb placement include carotid artery
puncture and hematoma, insertion site infection, and venous
thrombosis around the catheter tip [50]. Ultrasound guidance
and sterile technique mitigate some of these risks. Heparinized
saline at low rate (5 mL/hour) has also been used to minimize
thrombotic complications. Placement of the SjO2 catheter
through an introducer allows for ease of replacement and
removal during magnetic resonance imaging. Proper place-
ment of the jugular bulb can be confirmed with a lateral
skull film.
The prevalence of SjO2 desaturations correlates with mor-
tality after severe TBI (threshold = 50% saturation for 10
minutes) [51]. Multiple hypoxic episodes predicted a poor
outcome in 90% of individuals, while a similar outcome was
observed in 55% of subjects without desaturations. In a small
study of aSAH patients, the arteriovenous difference in
oxygen content (AVDO2) rose above normal range one day
prior to onset of neurological deficits related to vasospasm.
These findings were reversible, with institution of triple-H
therapy [52]. The hypoxia identified by SjO2 monitoring
appears to be distinct and complementary to that detected
by brain tissue oxygen probes [53]. Jugular bulb monitoring
appears to be more sensitive to hypoxia related to hyperventi-
lation, whereas PbtO2 more commonly detects changes
attributable to systemic hypoxemia. Therefore, it is reason-
able to use both monitoring devices for patients at risk for
ischemic injury. While still used as a global monitor in the
neurocritical care unit, most recent literature describing
jugular bulb use originates from the cardiac bypass and
intraoperative settings.
Advanced Neuroimaging as a Neuromonitor
Neuroimaging is often used in the neurocritical care unit
to monitor radiologic changes in injury or confirm risks
suspected by continuous monitoring. Patients suffering trau-
matic contusions or spontaneous intraparenchymal hemor-
rhages (IPHs) are at risk for hemorrhagic expansion in the
early course of their care. Noncontrast CT scans and con-
trasted studies are valuable in assessing both growth and
potential for further bleeding until hemostasis has been
confirmed. Early contrast extravasation (CT within six
hours) after traumatic IPH occurs in 41% of patients and
82
is predictive of hemorrhage progression and clinical
deterioration [54]. In another series, hemorrhagic expansion
occurred in 42% of patients with closed and penetrating
injuries and abnormal presenting head CTs. Rates of expan-
sion were greater for the elderly and those presenting sooner
after injury [55]. Findings of radiologic worsening were clin-
ically relevant and accounted for surgical treatment in 25%
of the cohort demonstrating expansion. Similar associations
and impact have been reported after spontaneous nontrau-
matic hemorrhages [56]. Routine imaging every four to six
hours is advisable until radiologic stability is noted after acute
hemorrhagic brain injury.
CT angiography and CT perfusion techniques have been
accurately used to diagnose and confirm suspicion of cerebral
vasospasm after aSAH. This tool is valuable to establish the
causal relationship of deterioration prior to pursuing blood
pressure augmentation, catheter angiography, or other treat-
ments with potential risk.
Acute neuroimaging also has beneficial diagnostic and
prognostic indications. In patients with acute stroke symp-
toms, gradient recalled echo (GRE) magnetic resonance (MR)
sequences have proven to be as accurate as noncontrast CT in
the identification of acute blood [57]. Furthermore, this MR
technique is superior in the identification of microbleeds and
differentiation of chronic hemorrhage. MR identification of
diffuse axonal injury after TBI holds prognostic value, particu-
larly when the location of the lesions are considered [58].
Cerebrovascular injury occurs in 1–2% of patients after blunt
trauma and results in infarction in one-quarter of these cases
[59]. The EAST guidelines for TBI management recommend
CT angiography for patients with elevated risk of vascular
injury (skull-based fracture, cervical spine injury, displaced
facial fracture, mandibular fracture, significant flexion injury,
focal neurological deficits, GCS <9, or hard signs of neck
vascular injury). The Marshall CT classification of traumatic
injury provides prognostic information based upon the status
of the mesencephalic cisterns, degree of midline shift, and
presence of surgical masses [60]. The predictive value for
discharge survival is enhanced when age, GCS motor score,
and presence of SAH or intraventricular blood are included in
the assessment model [61].
The convenient availability of acute neuroimaging has been
implicated as a cause of unnecessary and excessive costs. In a
trial of 301 mild TBI patients (GCS 13–15), radiologic progres-
sion was present in only 6% of patients and only four patients
in total required nonemergent neurosurgical intervention
based upon the scan findings [62]. The authors suggest that
repetitive CT scanning is overused in the mild TBI population.
In a similar study, a six-month evaluation of all CT scans
acquired on an academic neurosurgical service revealed that
scans acquired on patients without neurological changes were
unlikely to demonstrate significant findings and unlikely to
require an intervention [63]. The probability of clinical value
was related to imaging indication and scans obtained for
“reconnaissance,” were seldom revealing.
 Chapter 8: Intracranial Monitoring

Clinical Algorithms for Monitoring in the
Neurocritical Care Unit
The lack of studies comparing types of monitors or demon-
strating benefit of neuromonitoring-directed care limit con-
sensus opinion regarding the role and indication for each
monitor. That considered, the wealth of data demonstrating
the rate and impact of secondary disability despite conven-
tional management suggests that there is much to be gained by
utilizing the enhanced and pre-emptive detection provided by
neuromonitoring devices. The forthcoming guidelines released
by the Consensus International Conference on Multimodality
Monitoring should provide consistency and direction to some
of these unknowns.
When monitoring is utilized within a neurocritical care
unit, there are fundamental principles that should be followed
that increase the likelihood of successful implementation and
improved clinical outcomes.
Criteria for monitoring should be determined by consen-
sus opinion of all members of the neurocritical care team and
clearly expressed within the monitoring policy. When the
indications are well defined, there is less of a chance of missing
a monitoring opportunity or subjecting a patient to unneces-
sary monitoring risks. In a multidisciplinary setting, where
participants have varying comfort and experience with neuro-
monitoring, it is always best to have a prespecified and physio-
logically sound approach that is uniform for each patient.
While further research is needed to define the best
approaches to multimodal monitoring, it is reasonable to
follow a protocol that implements complementary global and
regional monitors. Furthermore, monitors should be chosen
that have a track record for being useful in identifying the
types of secondary injury most common for patient diagnosis
and condition (e.g. hyperventilating, hypoxemic, suspicion of
intracranial hypertension).
Changes in brain physiology and chemistry occur on a
minute-to-minute time frame. Therefore, it is crucial that the
neurocritical care team orchestrate a call panel of surgeons and
intensivists who are capable of placing the invasive monitors in
a timely fashion. Likewise, order sets should be drafted to
provide nursing guidance for monitor care and expectations
for reporting of abnormal monitoring data. The display of
monitoring data must be of a scale and format that allows
graphical identification of irregularities and temporal com-
parison with monitoring parameters to examine causality.
Finally, expectations for monitoring devices should be rea-
sonable. Similar to physical examination and radiographic
imaging, no neuromonitor has the capacity to identify all
mechanisms of potential deterioration, nor does any monitor
possess perfect sensitivity and specificity for any single risk.
Neuromonitoring data must be analyzed in concert with other
patient data and tied to therapeutic interventions that have
proven efficacy.
Conclusion
Patients experience physiologic change that precedes neuro-
logical deterioration. These processes can be measured and
used to anticipate and prevent permanent sequelae. Neuro-
monitoring allows provision of critical care that is both brain
and patient specific. Though promising, implementation
and execution of a neuromonitoring program requires a well-
organized team approach. The continued growth of neuro-
monitoring will be determined by its successful incorporation
into monitoring-directed therapies that yield improved clinical
outcomes.

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85
 Chapter
Electrophysiologic Monitoring in the
9 Neurocritical Care Unit
Anh T. Nguyen and Asma Zakaria
The last two decades have witnessed a remarkable reinvention
of the role of the neurologist, from an outpatient consultant to
a critical presence in the inpatient setting. Spotting a neurolo-
gist in an emergency room or intensive care unit is no longer
incongruous, rather an expectation of their relatively new roles
as acute stroke doctors and neurointensivists. With this shift in
patient care setting came a shift in research and many ques-
tions that have plagued the neurologic community for decades
have resurfaced. The groundbreaking neurophysiologic dis-
coveries of the previous century have armed us with an under-
standing of how the normal neuron functions. Now, in the
inpatient, critically ill population, we once again find ourselves
wondering what is happening within the shroud of the skull.
Continuous monitoring of cardiovascular physiology is
routinely employed in all ICUs. This is due to the relative
simplicity of a largely mechanical system, as well as the ability
to detect objective parameters of cardiac function distal to the
primary organ. Primary organ dysfunction has predictable and
identifiable repercussions. In contrast, dysfunction in the ner-
vous system is difficult to quantify in less than gross terms in
comatose, encephalopathic, or sedated ICU patients. Hourly
neurologic examinations in most neurocritical care units pro-
vide a fragmented and subjective functional assessment. Tech-
nological innovations now allow us to monitor cerebral oxygen
tension and metabolism, as well as quantifiable surrogates of
cellular metabolism via multimodal monitoring tools. Unfor-
tunately these are invasive and the information obtained is
localized to a small radius of tissue around the probe.
Electrophysiologic studies, and electroencephalography (EEG)
in particular, are increasingly being utilized for their ability to
reveal a global picture of cerebral activity in patients with impaired
functional states. These studies provide not only a continuous
assessment of cortical pathophysiology, but can also guide treat-
ment and prognosticate functional outcome. Unfortunately, they
can be limited by the dampening effect of the skull, wounds and
bandages, motion and electrical artifacts, and the availability of
equipment, technicians, and trained electroencephalographers.
Continuous Electroencephalography (CEEG) in
the ICU
Neurophysiology literature is teeming with descriptions of
changes in electrical potentials in patients with an altered state
86
of consciousness, coma, and brain death. In 1976 the Atlas of
Electroencephalography in Coma and Cerebral Death was
compiled [1] as a follow-up to the NINDS supported Collab-
orative Study of Cerebral Death [2] establishing that the crit-
ically ill EEG is different from that of other neurologic
patients. With more widespread use, the field of ICU EEG
monitoring has matured. More data and prolonged studies,
with the ability to review and quantify long-term trends, have
redirected focus on EEG findings that were historically con-
sidered benign or lumped into the all encompassing diagnosis
of “encephalopathy.” We now find ourselves questioning the
significance of EEG findings and the indications for treat-
ment – queries that may only be answered with pooled
resources and prospective data. Inter-reader subjectivity in
reporting has been reduced by a standardized nomenclature
for critical care EEG compiled by the American Clinical
Neurophysiology Society (ACNS)[3]. In conjunction with the
Neurocritical Care Society (NCS), the ACNS has formulated
its guidelines for the indications of CEEG monitoring in the
ICU. Some of the common indications for CEEG monitoring
are discussed below.
Detection of Nonconvulsive Seizures and Status
Epilepticus
Nonconvulsive seizures (NCSz) and nonconvulsive status epi-
lepticus (NCSE) have been recognized in 8–48% [4] of coma-
tose patients in any adult or pediatric ICU, depending on the
primary etiology of altered consciousness (Figure 9.1).
CEEG can provide essential information in the detection
and management of patients with altered mental status, espe-
cially in the setting of recent convulsive status epilepticus (SE),
a history of epilepsy, recent brain injury, fluctuating level of
consciousness, and stereotypical or paroxysmal activity,
including, but not limited to, myoclonus, twitching, dysauto-
nomia, nystagmus and hippus [5].
Convulsive Status Epilepticus
Cessation of convulsive activity in patients with SE can be a
symptom of electro-mechanical dissociation, with up to 48%
continuing to have NCSz including 14% with NCSE [6], the
latter having significantly worse outcomes compared to
patients who stopped seizing when convulsive activity stopped.

Toxic Metabolic [5,6]
Hypoxic Ischemic Injury [7]
Ischemic Stroke [8]
ICH [9,10]
SAH [7]
Blunt TBI [11]
Penetrating TBI [11]
Post Generalized Status [12]
0 10 20 30 40 50
Figure 9.1 Incidence of seizures detected by CEEG based on underlying etiology. References are marked in parentheses.
CEEG is therefore warranted in all patients who do not quickly
regain consciousness after treatment for a clinical seizure; not
only to detect ongoing seizure activity, but to monitor therapy
and minimize treatment-related complications in patients who
remain on prolonged sedation.
Subarachnoid Hemorrhage
Approximately one-fifth of patients experience clinical seizures
after subarachnoid hemorrhage (SAH), of which half occur in
the peri-operative period [7]. The occurrence of peri-operative
seizures does not portend a higher risk of delayed epilepsy.
None of these patients had CEEG monitoring and it is possible
that the burden of nonconvulsive seizures is much higher.
Claassen et al., in their retrospective review of 570 consecutive
patients who underwent CEEG monitoring, recorded seizures
in 19% of their 108 SAH patients; 95% of the seizures were
nonconvulsive and 70% of patients with NCSz had NCSE [7,8].
Intracerebral Hemorrhage
Seizures occurred in 14–28% of patients with intracerebral
hemorrhage (ICH) in two prospective trials [9,10]. While
Vespa et al. found that seizures were more common in lobar
hemorrhages, De Hurdt’s group, with their much larger
sample size, found a cortical location to be the only predictor
of early seizures (<7 days from ictus) in this population.
Younger patients, with cortical involvement, a history of prior
ICH and higher NIHSS values were more likely to have
seizures at ictus. Seizures were associated with progressive
midline shift [10] and hematoma expansion [11], whereas
periodic discharges were more commonly seen in cortical
hemorrhages and were independently associated with worse
outcomes [11]. While patients with seizures had higher Glas-
gow Outcome Scores at discharge in Vespa’s cohort, no differ-
ences in outcomes were seen at six months in De Hurdt’s
group.
Chapter 9: Electrophysiologic Monitoring
Average % incidence of
seizures in cited medical
literature
60
Ischemic Stroke
Clinical seizures occur in 8.6% of ischemic stroke patients [12]
and can be classified into early (<2 weeks after stroke) and late
(>2 weeks) onset; the latter being an independent risk factor for
developing epilepsy. Cortical location of stroke is the only risk
factor for early-onset seizures, with a fourfold higher incidence
among watershed infarctions [13]. CEEG in acute stroke patients
revealed seizures in 2% and epileptiform activity in 17% [14],
however, there is no evidence to support a benefit from prophy-
lactic antiepileptic treatment in this patient population.
Traumatic Brain injury (TBI)
Seizures occur in 12–22% of blunt head trauma and 35–50% of
penetrating brain injuries [15]. Ten percent of prospectively
followed moderate to severe TBI patients develop late-onset
seizures, with the highest risk in patients with biparietal
contusions and dural penetration by bone or metal fragments
(Table 9.1) [16]. In 1990 Temkin et al. [19] showed a 73%
reduction in early post-traumatic seizures (<1 week from
injury) in patients given phenytoin versus placebo. However,
a similar effect was not seen in patients with late post-
traumatic seizures. CEEG of 94 patients with moderate to
severe TBI revealed seizures in 21%, half of which were non-
convulsive [18]. All six patients diagnosed with post-traumatic
status epilepticus died. Interestingly, prophylactic therapeutic
phenytoin did not protect against the occurrence of seizures.
In a follow-up study, Vespa et al. showed that patients with
post-traumatic NCSz and NCSE had higher intracranial pres-
sures and lactate:pyruvate ratios compared to patients without
seizures, indicating a possibly treatable cause of metabolic
crisis and secondary brain injury.
Toxic Metabolic Encephalopathy
Medical and surgical critical care patients are susceptible to
metabolic abnormalities, which may cause alterations in
87
 Chapter 9: Electrophysiologic Monitoring

Table 9.1 Risk factors for late post-traumatic seizures in 647 prospectively
100 98% 100%
followed patients [16] 93%
88%
82%
Risk factors for late post-traumatic seizures % 80 77%
Biparietal contusions 66 56%
60

[%]
Dural penetration with bone or metal 62.5
40
Multiple intracranial operations 36.5
Convulsive seizures (N = 9)*
Multiple subcortical contusions 33.4 20 15% Nonconvulsive seizures (N = 101)

Subdural hematoma with evacuation 27.8 0

At start 1 1- 6 6 - 12 12 - 24 24 - 48 48 - 168 >168
Midline shift greater than 5 mm 25.8 of CEEG
Multiple or bilateral cortical contusions 25 Time of CEEG monitoring to record first seizure [h]

Risk for late post-TBI seizures by GCS Figure 9.2 Time elapsed between start of continuous EEG monitoring and
detection of the first seizure (N = 110). *Three of these nine patients had
GCS 3–8 in first 24 hours 16.8 nonconvulsive seizures as well. (Copied with permission from: Claassen J, Mayer SA,
Kowalski RG, et al. Detection of electrographic seizures with continuous EEG monitoring in
GCS 9–12 in first 24 hours 24.3 critically ill patients. Neurology 2004; 62:1743–1748.)

GCS 13–15 in first 24 hours 8.0

100
98 100 100100
95 96
91
consciousness and lower the seizure threshold. In a study of 80 86 87
80
201 medical ICU patients without known neurological disease
67 70
[20] who underwent CEEG for altered mental status or pos- 60
61
[%]
sible seizures, 22% had periodic discharges (PDs) or seizures,
50
and had significantly higher death or severe disability rates at 40
discharge. Two-thirds of the seizures were nonconvulsive, with
Noncomatose (N = 56)
a fourfold higher seizure frequency in patients with sepsis. 20
17 Comatose (N = 54)
A retrospective review of SICU [21] patients had similar 13
results (16% NCSz, 29% PD) with NCSE only occurring in 0
At start 1 1- 6 6 - 12 12 - 24 24 - 48 48 - 168 >168
septic patients. of CEEG
Transplant patients are another high-risk group with Time of CEEG monitoring to record first seizure [h]
seizures reported after liver, kidney, pancreas, cardiac, lung,
Figure 9.3 Time to record the first seizure, comparing noncomatose and
and bone marrow transplants, especially in the early post- comatose patients. (Copied with permission from: Claassen J, Mayer SA, Kowalski RG,
operative period [5]. et al. Detection of electrographic seizures with continuous EEG monitoring in critically ill
patients. Neurology 2004; 62:1743–1748.)

Hypoxic-Ischemic Injury
Seizures are detected in 5–40% of survivors of cardiac arrest
[14]. In the Columbia study, 20% of patients with hypoxic-
ischemic injury had seizures, the majority of which were non-
convulsive [7]. The role of CEEG in post-cardiac-arrest
patients is not limited to seizure or artifact detection, but
rather it serves an important role in prognostication of mean-
ingful neurologic recovery, as described later in this chapter.
Duration of Monitoring
Adequate duration of monitoring has been a matter of debate
given the cost, and often limitation of resources and personnel.
In a retrospective review by Claassen et al. [7], 19% of the
570 patients were found to have seizures, the vast majority
(>90%) of which were nonconvulsive. Of the patients who
were found to have seizures, 56% had one within the first hour
of recording, with a yield of 88% in 24 hours and 93% at 48
hours. While 98% of noncomatose patients had manifested
within 48 hours, comatose patients showed a slight delay in
the first seizure, with 87% seizures detected at 48 hours
(Figures 9.2 and 9.3) The study concluded that CEEG moni-
toring could be discontinued in noncomatose patients if no
ictal activity was seen in the first 24 hours, whereas longer
durations may be required for comatose patients. In the setting
of ictal or periodic patterns, monitoring can be prolonged,
depending on the clinical setting.
In patients with aneurysmal SAH, CEEG monitoring is not
only applicable in investigating the presence of nonconvulsive
seizures, but can also be expanded to aid in detection of
delayed cerebral ischemia (DCI), a major cause of morbidity
and mortality after SAH. The obvious goal is to recognize
patients who are prone to DCI and treat these patients with
volume resuscitation, vasopressors, and angioplasty before
infarction occurs. Certain EEG patterns such as relative α-
variability can detect ischemia from vasospasm up to two days
before clinical changes. The exact duration of monitoring has
yet to be fully elucidated, but from a study by Claassen,
monitoring of these patients should begin as soon as possible
and be continued for up to 14 days [22],

88

Monitoring of Ongoing Therapy
The use of CEEG has found utility in monitoring patients where
the clinical examination is lost or no longer reliable. These
instances are many and include patients undergoing induced
coma for refractory SE, patients receiving neuromuscular block-
ade, and in the management of elevated intracranial pressure.
Numerous IV medications, including propofol, barbitur-
ates, and benzodiazepines, are employed for the management
of refractory SE and elevated intracranial pressure. These
medications, however, are not without limitations as they
harbor significant potential side effects. CEEG allows the prac-
titioner to achieve the desired suppression using the smallest
required amount of medications, which in turn will limit the
side effects of these coma-inducing drugs.
Furthermore, CEEG is paramount in the diagnosis of NCSE,
a condition that is difficult to diagnose and often missed with
initial routine EEGs. In the benzodiazepine trial for the diagnosis
of NCSE, Jirsch and Hirsch proposed utilizing a short-acting
benzodiazepine such as midazolam in incremental doses in
patients with neurologic impairment and EEG findings of rhyth-
mic, periodic, or generalized epileptiform discharges. Doses of
1 mg of midazolam were given to patients, with monitoring for
EEG changes and the patient’s vital signs between doses. The trial
was stopped when a maximum dose of 0.2 mg/kg of midazolam
was given, adverse effects such as respiratory depression were
noted, or if there was a definite improvement, either clinically or
with resolution of the aforementioned EEG pattern. This test was
considered positive for NCSE if there was a resolution of the
EEG pattern in combination with improvement in the patient’s
clinical state or the appearance of previously absent normal EEG
patterns such as a posterior-dominant rhythm [23].
Ischemia Detection
Vasospasm and its resultant DCI is a common and life-
threatening complication of aneurysmal SAH. Despite new
advances in medicine, vasospasm has remained a major cause
of morbidity and mortality in this patient population [24].
Currently, digital subtraction angiography (DSA) remains the
gold standard in the diagnosis of vasospasm, but it does harbor
multiple limitations. These include the inability to be per-
formed consistently or continuously, or in the ICU, and, given
the invasiveness of the procedure, its own complications,
including embolic strokes.
CEEG offers a continuous and noninvasive means for
detecting cerebral vasospasm in SAH patients. In fact, by
carefully analyzing the CEEG data for specific patterns such
as relative α-variability and poststimulation α:δ ratio, CEEG
can help uncover ischemia due to vasospasm up to two days
before any change in neurologic exam is seen. In Claassen’s
study of 34 patients, DCI was more likely to develop in patients
with an α:δ ratio more than 50% below baseline, with a sensi-
tivity of 89% and specificity of 84% [22]. Moreover, given the
sensitivity of EEG in detecting ischemia, its use can be easily
expanded to other patients at high risk for stroke.
Chapter 9: Electrophysiologic Monitoring
The utility of CEEG for ischemia detection is not free from
limitations. There can be significant artifacts despite the use of
filters, especially in noncomatose patients. The labor-intensive
task of removing and then reapplying electrodes for imaging
modalities such as CT, MRI, or angiography can be tedious,
and often delays the necessary studies. Although efforts are
being made to circumvent some of these issues, the routine use
of CEEG for this application is currently limited to only a few
centers in the USA.
Prognosis
Early prognostication of irreversible brain injury can help phys-
icians determine the feasibility of continuing aggressive medical
measures in the comatose patient. The possible role of CEEG as
an aid in this determination has led to numerous studies.
Following Cardiac Arrest
The American Academy of Neurology (AAN) has compiled
guidelines to predict neurologic outcomes in comatose post-
cardiac-arrest patients [25]. Unfortunately, these do not provide
much insight into the prognostic challenges faced once patients
have been treated with moderate hypothermia. In the work done
by Cloostermans et al., 43% of patients with a good neurologic
outcome after hypothermia had continuous, diffusely slow EEG
patterns 12 hours postresuscitation, whereas this pattern was
not seen in patients with poor outcomes. Alternately, a low
voltage or isoelectric EEG observed 24 hours postresuscitation,
had a 40% sensitivity and 100% specificity for predicting poor
neurological outcome compared to 24% and 100%, respectively,
for somatosensory evoked potentials (SSEPs) [26]. Early EEG
reactivity may therefore portend a favorable recovery, while lack
of this finding at 24 hours may signify a more sinister outcome
earlier than other, more routinely used modalities.
Burst suppression, seen in EEG, is generally associated with
poor outcome. In prior studies by Cloostermans et al., how-
ever, 18% of patients with burst suppression at 12 or 24 hours
post cardiac arrest had a good functional outcome. More
recently, Hofmeijer et al. described a more specific pattern of
“burst suppression with identical bursts” as being a distinct
pathological EEG pattern only occurring in patients with dif-
fuse cerebral ischemia, but not in patients with other causes of
burst suppression. In fact, Hofmeijer’s study observed “burst
suppression with identical bursts” in 20% of comatose patients
between 12 and 36 hours post cardiac arrest with a universally
poor outcome [27].
Following Other Causes of Acute Brain Injury
Prognostic implications of various causes of acute brain injury
are listed in Table 9.2.
What Should Be Treated?
There is still great debate as to which neurological entities
should be treated with an anticonvulsant. In their review of
ICH patients, Reddig et al. did not see a significant difference
89
 Chapter 9: Electrophysiologic Monitoring

Table 9.2 Prognostic significance of CEEG after acute brain injury

Causes of acute brain Prognostic implications

injury
Generalized status Patients with NCSE after cessation of convulsive activity had worse outcomes [6]
epilepticus
Subarachnoid hemorrhage All patients without EEG reactivity or state changes within 24 hours and generalized periodic discharge (GPD)
(HH 3) or bilateral independent periodic discharge (BiPD) at any point during hospitalization had poor outcomes at
three months. Lateralized periodic discharges (LPDs) and absence of sleep architecture were associated with
poor outcomes [28]
Intracerebral hemorrhage Posthemorrhagic seizures were associated with worsening NIHSS, worsening midline shift, and worse
outcomes [10]. PD were independently associated with worse outcomes [11]
Ischemic stroke Late-onset seizures have a higher risk of epilepsy [12]
Traumatic brain injury Status epilepticus is associated with 100% mortality in moderate–severe TBI [18]
Sepsis NCSz and PD are associated with higher disability and death [20]
Coma EEG suppression and lack of reactivity associated with worse outcomes [29]

in outcomes between those that were prescribed prophylactic
anticonvulsants versus those that were not [30]. In fact, Nai-
dech et al. found that prophylactic phenytoin treatment was
associated with more fever and worse outcomes in this patient
population [31]. This has been extended to patients with
aneurysmal SAH in a double-blind randomized controlled trial
by Rosengart et al., revealing prophylactic anticonvulsant
treatment to be associated with worse outcomes and more
in-hospital complications [32].
Other Electrophysiologic Studies in the ICU
Neurophysiologic studies such as SSEP, visual evoked potentials
(VEPs), and brainstem auditory evoked responses (BAERs) have
numerous applications in the ICU setting. These evoked
potentials differ in the stimulus and sensory pathway being
assessed and are not infrequently used for the diagnosis of
demyelinating diseases, as prognosticating tools after anoxic
brain injury, and for monitoring the integrity of neuronal tracts
and structures that are at risk for damage with ongoing cerebral
injury.
Differing from EEG, in which the signal perceived is con-
tinuous and generated from the outer layers of the cortex,
evoked potentials are a measure of the brain’s response to
repetitive stimuli involving a specific pathway [33].
It has been well established that the absence of bilateral
SSEP is associated with poor outcome in comatose patients
post cardiac arrest. The inverse situation, relating the presence
of SSEP to good prognosis in cases where the EEG pattern is
flat, however, does not necessarily hold true [26,34].

nontonic-clonic status epilepticus in prospective multicenter study. Arch

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AR (1998). Persistent nonconvulsive
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(2007). Electrographic seizures and
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20. Vespa PM, Nuwer MR, Nenov V, et al.
(1999). Increased incidence and impact
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21. Vespa PM, Miller C, McArthur D, et al.
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Prediction of outcome in comatose
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(2011). The prophylactic use of an
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(2009). Anticonvulsant use and
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 Chapter
The Role of Transcranial Doppler as a Monitoring
10 Tool in the Neurocritical Care Unit
Maher Saqqur, David Zygun, and Andrew Demchuk
Introduction
Transcranial Doppler (TCD) has been increasingly utilized as a
monitoring tool in the neurocritical care unit (NCCU) since it
is a noninvasive tool and can be brought to the bedside.
The purpose of this chapter is to provide an account of
the common indications for TCD in the NCCU. The number
one indication is the detection and monitoring of vasospasm
in patients with aneurysmal and traumatic subarachnoid
hemorrhage (SAH). In addition, TCD is being studied as a
noninvasive estimator of intracranial pressure (ICP) and cere-
bral perfusion pressure (CPP) in patients with severe traumatic
brain injury. In addition, it has been utilized as a monitoring
tool for detection of microembolic signals in the presence of
acute ischemic stroke. Finally, TCD has been extensively stud-
ied in the setting of clinical brain death.
Over the past decade, Power M-mode TCD, transcranial
color coded duplex, and the use of contrast agents have
extended the utility of TCD in the NCCU to include indica-
tions such as monitoring of arterial occlusion in acute ische-
mic stroke and detection of microembolic signals in carotid
stenosis and cardioembolic disease [1].
Subarachnoid Hemorrhage: Detection
of Vasospasm
Cerebral vasospasm is a delayed narrowing of the cerebral
vessels, that is induced by blood products that remain in
contact with the cerebral vessel wall following SAH [2]. Vaso-
spasm usually begins about day 3 after onset of SAH and is
maximal by day 6–8. It is often responsible for delayed cerebral
ischemia (DCI) seen in SAH patients [3]. In addition, patients
with severe vasospasm have a significantly higher mortality
than those without vasospasm. The most common cause of
SAH is the spontaneous rupture of a cerebral aneurysm [4].
Other causes include head injury and neurosurgical proced-
ures like brain tumor resection. Vasospasm resulting from
aneurysmal SAH is a well-known complication occurring in
up to 40% of patients after an aneurysmal SAH, and carries a
15–20% risk of stroke or death [5].
Vasospasm was first demonstrated angiographically by
Ecker and Riemenschneider as cerebral arterial narrowing
following SAH [6]. Cerebral angiography of the brain is
92
considered the gold standard for detection of vasospasm.
However, this procedure is invasive, and carries the risk of
complications such as stroke due to cerebral embolus, dissec-
tion, or rupture of cerebral arteries [7]. Almost 20 years ago,
TCD was proposed for the diagnosis of cerebral vasospasm [8].
The diagnosis of spasm with a TCD device is based on the
hemodynamic principle that the velocity of blood flow in an
artery is inversely related to the area of the lumen of that
artery. In theory, TCD may serve as a relatively simple
screening method of cerebral vasospasm, and some investi-
gators have advocated the replacement of angiography by TCD
[9–11].
While TCD is effective in identifying vasospasm, several
studies have demonstrated that the isolated use of TCD flow
velocity numbers cannot accurately assess the presence of
vasospasm, whereas, repeated series of TCD measurements
may enhance the diagnostic accuracy of this tool [12].
Technical Aspects of TCD
TCD is a noninvasive, bedside, transcranial ultrasound method
of determining flow velocities in the basal cerebral arteries.
When using a range-gated Doppler ultrasound instrument,
placement of the probe in the temporal area just above the
zygomatic arch allows the velocities in the middle cerebral
artery (MCA) to be determined from the Doppler signals.
The flow velocities in the proximal anterior (ACA), terminal
ICA (tICA) and posterior (PCA) cerebral arteries can be
recorded at steady state and during test compression of the
common carotid arteries.
TCD monitoring often begins by obtaining a baseline TCD
study on day 2 or 3 post SAH onset, with adherence to a
comprehensive isonation protocol that examines all proximal
intracranial arteries. TCD studies are then continued daily
from day 4 to day 14 after SAH onset. The TCD examination
begins with temporal window isonation of the proximal MCA
on the affected side; usually 50 to 60 mm, and then distal
MCA, at a depth 40 to 50 mm. The examination then returns
proximally to the MCA/ACA bifurcation where a bidirectional
flow signal is located at 60 to 80 mm depth. The temporal
window isonation continues with more caudal angulation of
the probe to evaluate the terminal ICA at 60 to 70 mm depth.
The temporal window isonation is completed by posterior

angulation to evaluate the PCA at depth 55–75 mm. The
protocol is then repeated for the opposite hemisphere. The
ICA siphon can also be isonated via the transorbital window at
depths of 60 to 70 mm. This is preferable if no temporal ICA
signal can be obtained.
The transforaminal window isonation occurs via the fora-
men magnum and is first performed at 75 mm depth to locate
the terminal vertebral artery (VA) and proximal basilar artery
(BA). Isonation of the BA is performed distally along its course
(range 80 to 100 mm depth), followed by assessment of the
more proximal left and right VAs at depths of 50 to 80 mm by
lateral probe positioning. Finally, submandibular window iso-
nation is performed to obtain reference velocities from the
cervical internal carotid artery (cICA) for calculation of the
Lindegaard ratio. The Lindegaard ratio or hemispheric index
compares the highest velocity recorded in an intracranial vessel
divided by the highest velocity recorded in the ipsilateral
extracranial ICA.
TCD technology called Power M-mode TCD (PMD/TCD)
is now available and simplifies the operator dependence of
TCD by providing multigate flow information simultaneously
in the Power M-mode display [1]. PMD/TCD is attractive as a
rapid bedside technology, since PMD facilitates temporal
window location and alignment of the US beam to enable
assessment of multiple vessels simultaneously, without sound
or spectral clues. The presence of signal dropoff with PMD as a
result of excess turbulence can indicate flow disturbance
resulting from vasospasm (VSP) (Figure 10.1) [13].
The degree of vasospasm in the basal vessels is correlated
with the amount of acceleration of blood flow velocities through
the vessels as they become narrowed [11]. The greatest correl-
ation between TCD MFV and angiographic vessel narrowing
occurs in the MCA. Lindegaard et al. [11] showed that the
vasospastic MCA usually demonstrates velocities greater than
120 cm/s on TCD, with the velocities being inversely related to
Left ACA
Cerebral Angiography
Spectrogram
Left MCA
Chapter 10: The Role of Transcranial Doppler
arterial diameter. In addition, velocities greater than 200 cm/s
are predictive of a residual MCA lumen diameter of 1 mm or
less. The normal MCA diameter is approximately 3 mm.
Unfortunately, TCD mean flow velocities (MFVs) do not
allow calculation of cerebral blood flow volume and cannot be
substituted for CBF measurements [14–16]. The TCD MFV
provides us with a predictive assessment of the degree of vessel
narrowing, spasm progression or regression, and compensa-
tory vasodilatation.
TCD has been used as a monitoring tool for the develop-
ment of cerebral vasospasm in different drug trials [17,18]. It
has also been utilized to monitor the efficacy of interventional
angioplasty treatment [19] and detect the recurrence of arterial
narrowing [20].
While elevated TCD MFVs can suggest cerebral vasospasm,
the velocities alone cannot determine if a patient has symp-
tomatic cerebral vasospasm [21]. In addition, different intra-
cranial vessels have different velocity criteria for diagnosing
vasospasm. In the next few sections, we will review the litera-
ture for TCD criteria for different intracranial vessels.
A recent study by Kantelhardt et al. showed that CT angi-
ography can be easily and efficiently compared to TCD. It can
provide anatomic orientation of the trajectory of the artery and
may help to standardize investigation protocols and reduce
interinvestigator variability. In addition, image guidance may
also allow extension of the use of TCD to situations of a
pathological or variant vascular anatomy [22].
Middle Cerebral Artery Vasospasm
TCD has a well-documented and established value in detecting
middle cerebral artery vasospasm (MCA-VSP) [23–29]. The
TCD sensitivity varies from 38 to 91% and the specificity varies
from 94 to 100% (see Figure 10.1 as an example of a patient
with severe proximal MCA- and ACA-VSP).
Figure 10.1 Example of a patient with severe left
MCA and moderate ACA-VSP. The highest MFVs
were obtained at the dropoff signals in both MCA
and ACA vessels. (Bottom) Left MCA MFV =
212 cm/s is an indicative of severe vasospasm.
(Top) Left ACA MFV = 127 cm/s is an indicative of
moderate vasospasm. A black and white version of
this figure will appear in some formats. For the color
version, please refer to the plate section.
PMD
93
 Chapter 10: The Role of Transcranial Doppler
Vora et al. [28] studied the correlation between proximal
MCA MFV and angiographic vasospasm after SAH. They
explored three different parameters: highest MCA MFV at
three depths (5, 5.5, and 6 cm), the largest MFV increase in
one day before digital subtraction cerebral angiography (DSA),
and ipsilateral MCA/contralateral MCA MFV difference. For
MCA MFV
120 cm/s, the sensitivity of TCD for detecting
moderate or severe MCA-VSP is 88% and the specificity is
72%, whereas for MCA MFV
200 cm/s, the sensitivity of
TCD for detecting moderate or severe MCA-VSP was 27% and
the specificity 98%. So, for individual patients, only low or very
high middle cerebral artery flow velocities (i.e. <120 or

200 cm/s) reliably predicted the absence or presence of
clinically significant angiographic vasospasm (moderate or
severe vasospasm). Intermediate velocities, which were
observed in approximately one-half of the patients, were not
dependable and should be interpreted with caution. Interest-
ingly, all patients with an MCA MFV of 160–199 cm/s and
right to left MFV difference >40 cm/s had significant
vasospasm.
Burch et al. [23] found TCD had low sensitivity (43%), but
good specificity (93.7%) for detecting moderate or severe
vasospasm (>50%) when an MCA MFV of 120 cm/s was used
as the cut-off. When the diagnostic criterion was changed to at
least 130 cm/s, specificities were 100% (tICA) and 96% (MCA)
and positive predictive values were 100% (tICA) and 87%
(MCA). The authors conclude that TCD accurately detects
tICA and MCA-VSP when flow velocities are at least 130 cm/s.
However, its sensitivity may be underestimated and the import-
ance of operator error overestimated.
B C
A MFV ratio = 1.4), showing aMCA/cMCA MFV ratio
G the plate section.
D E
94
Finally, increased blood flow velocities (FVs) may not
necessarily denote arterial narrowing. Both increasing flow
and reduced vessel diameter may lead to high flow velocities.
Consequently, cerebral vasospasm may not be differentiated
from cerebral hyperemia by the mere assessment of FV in the
basal arteries [27,28]. To account for this diagnostic shortcom-
ing of TCD, Lindegaard et al. [10] suggested defined use of
ratios of FVs between intracranial arteries and cervical internal
carotid artery. The normal value for this ratio is 1.7 ± 0.4 [30].
It is recommended to use each patient as his/her own control
since there are anatomical differences among individuals. The
presence of an MCA/cervical ICA MFV ratio >3 is indicative
of moderate proximal MCA-VSP, whereas a ratio >6 is an
indicative of severe vasospasm.
MCA-VSP detection is influenced by multiple factors:
improper vessel identification (TICA, PCA), increased collat-
eral flow, hyperemia/hyperperfusion, proximal hemodynamic
lesion (cervical ICA stenosis or occlusion), operator inexperi-
ence, and aberrant vessel course.
Recently, our group derived TCD criteria for detecting
MCA-VSP to facilitate more accurate detection of VSP based
on angiographic proven MCA-VSP. On the basis of our find-
ings [31], we proposed a TCD scoring system for the detection
of MCA-VSP. Using a single criterion, only moderate sensitiv-
ity and specificity for vasospasm detection can be achieved.
In our study, we showed that combining multiple criteria
(baseline MCA MFV
120, preangio MCA MFV
150, and
the ratio of preangio MCA MFV to baseline MCA MFV
1.5)
resulted in better accuracy for MCA-VSP detection
(Figure 10.2) [31].
Figure 10.2 52-year-old patient who underwent
endovascular coil embolization for left ICA saccular
aneurysm. (A) Day 2: baseline TCD showing left
MCAMFV of 136 cm/s. (bMCA MFV
120). (B) Day 6:
preangio left MCA MFV 210 cm/s (aMCA/bMCA
MFV ratio = 1.55 ), showing preangio MCA MFV
>150 and aMCA/ bMCA MFV ratio
1.5. (C) Day 6:
preangio right MCA MFV 99 cm/s (aMCA/cMCA

1.25. (D) Day 6: preangio left ACA MFV of 168 cm/s
(aMCA/(i)ACA MFV ratio = 1.5). (E) Day 6: preangio
left PCA MFV of 32 cm/s (aMCA/ iPCA MFV ratio = 8),
showing aMCA/iPCA MFV ratio
2.5. (F) Day 6:
preangio left ICA (extracranial) MFV of 30 cm/s
(aMCA Lindegaard ratio = 8.6), showing aMCA
Lindegaard ratio
3. (G) Day 6: cerebral
angiography showing left MCA severe vasospasm.
A black and white version of this figure will appear in
some formats. For the color version, please refer to
F

Anterior Cerebral Artery Vasospasm
The ability of TCD to detect anterior cerebral artery vasospasm
(ACA-VSP) has been examined in different studies
[8,24,26,32,33]. In general, TCD has low sensitivity (13–83%)
and moderate specificity (65–100%) for detecting ACA-VSP.
Wozniak et al. [33] found that TCD has very low sensitivity
(18%), but good specificity (65%) for detecting any degree of
ACA-VSP. She used an ACA MFV >120 cm/s as criteria for
vasospasm. For moderate and severe vasospasm (>50% sten-
osis), the sensitivity increased to 35%. Grollmund and colleagues
[32], using the FV criteria of a 50% increase in ACA-FV, accur-
ately detected vasospasm in 10 out of 14 subjects (sensitivity
71%). ACA-VSP could not be detected when it was present in
the more distal pericallosal portions of the ACA. In contrast,
Lennihan and coworkers [26] used a FV criteria of at least
140 cm/s and detected vasospasm in only 2 out of 15 ACAs
(sensitivity 13%). Vasospasm was present in a portion of five
ACAs not insonated by TCD. Doppler signals could not be
isonated from nine ACAs (false-positive occlusion), including
three ACAs with angiographic vasospasm. Aaslid and coauthors
found that FVs in ACAs correlated poorly with residual lumen
diameter.
ACA-VSP detection can be limited by the presence of
collateral flow (patient with one ACA-VSP might not have
high MFV in that affected vessel since flow will be diverted
to the contralateral ACA through the Acomm), difficulty iso-
nating the more distal A2 segment (pericallosal artery), and
poor angle of isonation in the temporal window.
Internal Carotid Artery Vasospasm
There are few studies that examined the role of TCD in
detecting internal carotid artery vasospasm (ICA-VSP) [23,34].
Burch et al. [23] found that when a MFV of at least 90 cm/s
was used to indicate terminal ICA (TICA) vasospasm, the
sensitivity was 25% and specificity was 93%. When the diag-
nostic criterion was changed to at least 130 cm/s, specificities
were 100% (IICA) and 96% (MCA), and positive predictive
values were 100% (IICA) and 87% (MCA). The authors con-
clude that TCD accurately detects TICA and MCA-VSP when
flow velocities are at least 130 cm/s. However, its sensitivity
may be underestimated and the importance of operator error
overestimated.
ICA-VSP detection is affected by several factors: increased
collateral flow, hyperemia/hyperperfusion, and anatomical
factors (angle of insonation between the trajectories of OA
and VSP ICA >30°).
Vertebral and Basilar Arteries Vasospasm
The ability of TCD to detect vertebral basilar artery VSP (VB-
VSP) has been examined in numerous studies [35–37].
Sloan and coworkers [36] found that MFV
60 cm/s was
indicative of both VB- and BA-VSP. For the vertebral artery,
the sensitivity was 44% and specificity was 87.5%. For the
Chapter 10: The Role of Transcranial Doppler
basilar artery, the sensitivity was 76.9% and specificity was
79.3%. When the diagnostic criterion was changed to

80 cm/s (vertebral artery) and
95 cm/s (basilar artery), all
false-positive results were eliminated (specificity and positive
predictive value, 100%). They concluded that TCD has good
specificity for the detection of vertebral artery vasospasm, and
good sensitivity and specificity for the detection of basilar
artery vasospasm. Transcranial Doppler is highly specific
(100%) for vertebral and basilar artery vasospasm when flow
velocities are
80 and
95 cm/s, respectively.
Soustiel et al. [37] found that the BA:extracranial vertebral
artery (eVA) ratio may contribute to an improved discrimin-
ation between BA-VSP and vertebrobasilar hyperemia while
enhancing the accuracy and reliability of TCD in the diagnosis
of BA-VSP. A BA:eVA threshold value of 3 accurately delin-
eates patients suffering from high-grade BA-VSP (
50% diam-
eter reduction).
The difficulty in detecting VB-VSP can be caused by mul-
tiple factors which include severe bilateral PCA-VSP, increased
collateral flow, hyperperfusion, and anatomical variations
(horizontal course of VA, tortuous course of BA).
Complete TCD Examination with Lindegaard
Ratio Determination
Although, TCD identificaton of MCA-VSP is most accurate,
an isonation protocol studying all basilar vessels demonstrates
greater diagnostic impact than sole MCA isonation[34]. Naval
et al. [12] performed a two-part study designed to compare
the reliability of relative increases in flow velocities with
conventionally used absolute flow velocity indices and to
correct for hyperemia-induced flow velocity change. Relative
changes in flow velocities in patients with aneurysmal SAH
correlated better with clinically significant vasospasm than
absolute flow velocity indices. Correction for hyperemia (Lin-
degaard ratio) improved the predictive value of TCD in vaso-
spasm. All 10 patients who developed symptomatic vasospasm
exhibited a twofold increase in flow velocities prior to
developing symptomatic vasospasm. Five patients had a three-
fold increase.
Distal Vasospasm Detection by TCD
Vasospasm can be limited to a distal vascular pattern in a small
percentage of cases. Distal vasospasm is often not detected by
TCD [38]. Its occurrence can be anticipated by distal distribu-
tion of blood on posthemorrhage head CT. In some circum-
stances, reduced flow in the M2 segment can be picked up on
TCD and is suggestive of distal narrowing. Fortunately, isol-
ated distal vasospasm is a rare entity [38], and cerebral blood
flow methods such as xenon CT or SPECT are useful in
confirming the diagnosis. Newer CT angiography bolus tech-
niques provide better delineation of the distal vasculature.
TCD monitoring is advantageous since it is portable, inex-
pensive, easily repeatable, and noninvasive. However, there are
95
 Chapter 10: The Role of Transcranial Doppler
some limitations with operator dependence and insensitivity
for detecting distal vasospasm. TCD appears to have the
greatest value in detecting MCA-VSP, although a complete
intracranial artery evaluation should be performed with use
of the Lindegaard ratio to correct for hyperemia-induced flow
velocity change. In addition, trending and day-to-day compari-
son of blood flow velocities are critical in identifying vaso-
spasm. An MFV increase of 50 cm/s or more during the first
24-hour period is indicative of a high risk of delayed cerebral
ischemia due to vasospasm [39].
TCD in Traumatic Brain Injury: Intracranial
Pressure and Cerebral Perfusion Pressure
The measurement and management of ICP, in conjunction
with cerebral perfusion pressure (CPP), is recommended in
patients following severe traumatic brain injury [40,41]. Con-
ventionally, intracranial pressure measurement has required
placement of an invasive monitor. These monitors carry the
risk of infection, hemorrhage, malfunction, obstruction, or
malposition. Consequently, TCD has been suggested as a
potential noninvasive assessment of ICP and CPP.
A number of different approaches have been employed to
describe the relationship between TCD parameters, CPP, and
ICP. Chan and colleagues studied 41 patients with severe
traumatic brain injury [42]. As ICP increased and CPP
decreased, flow velocity fell. This fall preferentially affected
diastolic values initially. Below a CPP threshold of 70 mmHg,
they found a progressive increase in the TCD pulsatility index
(r = –0.942, P< 0.0001):
peak systolic velocity  end diastolic velocity
PI ¼
timed mean velocity
This occurred whether the CPP decrease was due to an
increase in ICP or a decrease in arterial blood pressure. Klin-
gelhofer et al. showed that increasing intracranial pressures are
reflected in changes in the mean flow velocity and Pourcelot
index [43]:
peak systolic velocity  end diastolic velocity
Pourcelot index ¼
peak systolic velocity
In a subsequent study, the same group demonstrated a good
correlation between ICP and mean systemic arterial pressure 
Pourcelot index/mean flow velocity in a select group of
13 patients with cerebral disease (r = 0.873; P<0.001) [44].
Homberg et al. found PI changes 2.4% per mmHg ICP [45].
Although the aforementioned evidence suggests TCD par-
ameters are correlated with ICP and CPP in certain instances,
acceptance into clinical practice requires analysis of agreement
of noninvasive estimation methods with measured values. Ini-
tial proposed formulas for the prediction of absolute CPP have
proved disappointing, with large 95% confidence intervals for
predictors [46,47]. Schmidt and colleagues showed that a
prototype bilateral TCD machine with a built-in algorithm to
assess CPP and externally measured values for arterial blood
96
pressure has improved correlation with invasively measured
perfusion [48]. They used the formula:
mean arterial pressure  diastolic flow velocity
CPP ¼
mean flow velocity
þ 14 mmHg
and found absolute difference between measured CPP and
estimated CPP was less than 10 mmHg in 89% of measure-
ments and less than 13 mmHg in 92% of measurements. The
95% confidence range for predictors was ±12 mmHg for the
CPP; varying from 70 to 95 mmHg. Attempts at estimation of
ICP have demonstrated similar confidence intervals [49].
Unfortunately, these values are still unacceptable for clinical
purposes. Bellner and colleagues determined PI correlation
with ICP (>20 mmHg) to have a sensitivity of 89% and
specificity of 92% [50]. They concluded that PI may provide
guidance in those patients with suspected intracranial hyper-
tension and repeated measurements may be of use in the
neurocritical care unit.
Finally, TCD has role as a monitoring tool for cerebral
vasospasm after TBI. Its occurrence is variable and can be seen
in 19 to 68% of cases. However, the clinical course tends to be
milder, with earlier onset and shorter duration in comparison
to aneurysmal SAH [51]. In a recent study by Razumovsky
et al., in wartime TBI, he found TCD signs of mild, moderate,
and severe vasospasms were observed in 37%, 22%, and 12% of
patients, respectively. TCD signs of intracranial hypertension
were recorded in 62.2%, of which 5 patients (4.5%) underwent
transluminal angioplasty for post-traumatic clinical vasospasm
treatment and 16 (14.4%) had a craniectomy. He concluded
that cerebral arterial spasm and intracranial hypertension are
frequent and significant complications of combat TBI. There-
fore, daily TCD monitoring is recommended for their recog-
nition and subsequent management [52].
Brain Death
TCD findings compatible with the diagnosis of brain death
include: (1) brief systolic forward flow or systolic spikes with
diastolic reversed flow, (2) brief systolic forward flow or
systolic spikes and no diastolic flow or (3) no demonstrable
flow in a patient in whom flow had been clearly documented
on a previous TCD examination. Recently, de Freitas and
Andre performed a systematic review of 16 previous studies
examining the use of TCD in patients with the clinical diag-
nosis of brain death [53]. The overall sensitivity was 88% with
the most common cause of false negatives being a lack of
signal in 7% and persistence of flow in 5%. The overall speci-
ficity was 98%. Importantly, the criteria for brain death was
variable, with only seven groups assessing the vertebrobasilar
artery and some authors accepting the absence of flow in only
one artery. The same authors performed the largest study to
date, including 206 patients with the clinical diagnosis of
brain death in Brazil. TCD had a sensitivity of 75% for
confirming brain death. Multivariable analysis revealed that

absence of sympathomimetic drug use and female gender
were associated with false-negative results. The validity of
TCD-diagnosed brain death depends on the time lapse
between brain death and the performance of TCD [54], as
some patients require repeated examinations before TCD
criteria are met [55].
Assessment of CO2 Reactivity and Pressure
Autoregulation
TCD has been utilized for the assessment of cerebral carbon
dioxide reactivity and pressure autoregulation [56,57], given
that changes in middle cerebral artery velocity reliably correl-
ate with changes in cerebral blood flow [58]. Impairment of
CO2 reactivity and pressure autoregulation has been associated
with poor neurological outcome following head injury
[59–63]. In addition to the valuable prognostic information
provided by these examinations, it has been suggested that
TCD-identified disturbances of pressure autoregulation and
CO2 reactivity may be used for optimization of cerebral hemo-
dynamics following brain injury [57,64]. However, the utility
of such an approach has yet to be tested with respect to effect
on neurological outcome in clinical trials.
Acute Ischemic Stroke and Monitoring
of Recanalization
Ultra-early neuroimaging may provide crucial information for
the individual patient by determining the status of arterial
occlusion and collateral perfusion, as well as the extent and
Right MCA MFV 58 cm/sec
Figure 10.3 Left MCA M1 occlusion. Affected MCA high resistance PMD signature (small arrows showing no flow in diastole). Flow diversion to ACA with ACA MFV
> MCA MFV. Affected MCA MFV/unaffected MCA MFV ratio = 0.24 (<0.5). Black arrows correspond to artery on subsequent angiogram. A black and white version of
this figure will appear in some formats. For the color version, please refer to the plate section.
Chapter 10: The Role of Transcranial Doppler
severity of ischemia in the earliest stages of treatment [65].
Noncontrast computed tomography (NCCT) can provide
information regarding the extent and severity of ischemic
injury by visualization of early ischemic changes. Hyperdense
MCA stem and the M2 MCA “dot” sign [66] give some clues to
location of occlusion and clot burden. CT angiography (CTA)
and magnetic resonance angiography (MRA) are available
modalities to assess vessel patency in acute stroke [67,68].
However, both imaging methods are “snap shots in time” that
aren’t able to provide continuous information about arterial
patency during or after intravenous tissue plasminogen activa-
tor (tPA) treatment. TCD is ideal for such bedside monitoring.
It is inexpensive, portable, noninvasive, and requires minimal
patient cooperation. TCD has not been widely accepted for use
in acute stroke because of the belief that TCD is too operator
dependent to be applied to acute stroke decision-making.
Several studies have compared TCD with DSA, contrast-
enhanced CTA, and MRA in the acute stroke setting with
variable accuracy [69–71]. Utilization of detailed diagnostic
TCD criteria using specific flow findings demonstrate that
accuracy can be improved. TCD accuracy for detection of
MCA occlusion is superior to other intracranial locations, such
as vertebral and basilar artery occlusion [72,73].
PMD/TCD appears to improve window detection and sim-
plifies the operator dependence of TCD by providing multigate
flow information simultaneously in the Power M-mode display
[1]. PMD/TCD facilitates temporal window location and align-
ment of the US beam to view blood flow from multiple vessels
simultaneously, without sound or spectral clues [74] (see
Figure 10.3 as an example of MCA occlusion on PMD/TCD).
Left MCA MFV 14 cm/sec
97
 Chapter 10: The Role of Transcranial Doppler

Prolonged TCD monitoring has been performed for years. Monitoring for Emboli
No adverse biological effects have ever been documented for
TCD is able to detect high-intensity transient signals (HITS),
the frequencies and power ranges used in diagnostic ultra-
otherwise referred to as microembolic signals (MES), which
sound if applied according to safety guidelines [75]. Recent
represent emboli traversing through the major intracranial
work has demonstrated a role for TCD monitoring in acute
vessels (Figure 10.4). MES correspond to true emboli in animal
stroke to follow the evolution of the MCA occlusion in real
models [84]. TCD can monitor for emboli by continuous
time [76] and to determine the speed of clot lysis [77].
isonation of the middle cerebral arteries bilaterally. These
Obtaining continuous information about the status of an
MES are frequent early following an acute stroke [85]. Micro-
arterial occlusion in acute stroke has the potential to be very
embolic signals represent an independent predictor of early
helpful in further decision-making with thrombolytic therapy
ischemic recurrence when the cause appears related to large
[78]. Some sites of arterial occlusion have been demonstrated
artery atherosclerosis such as carotid or middle cerebral artery
to have a limited response to tPA. Terminal ICA or tandem
stenosis [86–88]. Emboli detection has also be shown to opti-
ICA/MCA arterial occlusions are less likely to recanalize com-
mize management of carotid endarterectomy with reduced
pletely [79].
emboli counts after postoperative dextran therapy [89]. Simi-
The timing of arterial recanalization after IV recombinant
larly, emboli monitoring during carotid stenting demonstrated
tPA (rtPA) therapy as determined with TCD correlates with
lower emboli counts with a proximal endovascular clamping
clinical recovery from stroke and demonstrates a 300-minute
when compared to a filter device [90].
window to achieve early complete recovery [80]. Rapid arterial
Acetylsalicylic acid [91,92], clopidogrel [93], and tirofiban/
recanalization is associated with better short-term improve-
heparin [94] all appear effective in reducing MES counts and
ment, whereas slow (>30 minutes) flow improvement and
have shown trends to reductions in clinical ischemic events
dampened flow signal are associated with a less favorable
(TIA/stroke). Combinations of these therapies seem most
prognosis [77]. Overall, the degree of recanalization by TCD
effective at abolishing microembolization. Large-scale trials
is an independent predictor of outcome. When combined with
are needed with clinical outcomes as the primary endpoint.
stroke severity and early CT ischemic change, it is most pre-
dictive of early outcome after intravenous tPA administration
[81]. Early reocclusion is another common finding of TCD
Carotid Endarterectomy and Carotid
monitoring during thrombolysis, which complicates systemic Artery Stenting
tPA therapy. Up to 34% of tPA-treated patients with recanali- TCD monitoring during carotid endarterectomy can provide
zation develop reocclusion. This accounts for two-thirds of information regarding the flow velocities in the MCA segment
patients who deteriorate clinically after initial improvement that correlate with the stump pressure during surgical cross
[82,83]. clamping [95,96]. In addition, TCD can provide real-time

Figure 10.4 Two microembolic signals displaying

high intensity, brief duration and unidirection on
spectrogram (white thick arrows) and movement
over time across space on M-mode (white thin
arrows). A black and white version of this figure will
appear in some formats. For the color version, please
refer to the plate section.

98
 Chapter 10: The Role of Transcranial Doppler

monitoring of MES during CEA and carotid stenting, and
these results have been correlated with the occurrence of new
ischemic stroke [97–99].
Summary
TCD is an established monitoring modality in the NCCU. It
is a validated screening test for the diagnosis of vasospasm
in patients with SAH and may be used to follow therapy.
Recent evidence suggests TCD holds promise for the detec-
tion of critical elevations of ICP and decreases in CPP. TCD
findings of brain death are well described and its use may
allow for the most favorable timing of a confirmatory test
such as angiography. Finally, TCD has a defined role in
acute ischemic stroke as both a diagnostic and a monitoring
tool.

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 Chapter
Ischemic Stroke in the Neurocritical Care Unit
11 Julian Bösel
Introduction
Severe acute ischemic stroke (AIS) has been recognized as
deserving management in the neurocritical care unit (NCCU)
and considerable progress in its understanding and manage-
ment has been made over the last 10 years. The results of older
studies had put into question the usefulness of giving patients
with severe AIS access to NCCU treatment and mechanical
ventilation, based on a very poor reported prognosis with
mortality rates between 50 and 80% [1–4]. Today, however,
treatment options such as endovascular thrombectomy, decom-
pressive surgery, or targeted temperature management have
changed the perspective of these patients, and they require
rapid, adequately aggressive, and consequent emergency and
critical care. This chapter addresses, in fairly chronological
order, the step-wise management of severe ischemic stroke, i.e.
the acute assessment, stabilization, and recanalizing treatment in
the emergency room (ER), the general aspects of care for ische-
mic stroke patients in the NCCU, and finally specific treatment
aspects associated with different types of ischemic stroke. Other
features of stroke care, such as recognition and prehospital
management, general stroke unit management, and secondary
stroke prophylaxis, will not be covered.
What is a “Severe” Ischemic Stroke?
Most forms of ischemic stroke can and should be managed on
stroke units. However, if the main stem of a brain-supplying
vessel such as the distal internal carotid artery (ICA), the
proximal middle cerebral artery (MCA) or the basilar artery
(BA) is occluded, the affected brain territory is large and the
resulting deficit substantial. Vertebrobasilar stroke can also
result in impairment of vital functions such as circulation,
breathing, and airway protection. Finally, ischemic stroke can
have cerebral (e.g. edema) or systemic (e.g. cardiac arrhyth-
mias) sequelae that cannot be sufficiently handled on stroke
units. There is no official definition of “severe” stroke, but the
following criteria might characterize this dimension (one or
more): substantially disabling deficit (National Institute of
Health Stroke Scale (NIHSS) >15), immediate near-complete
or complete dependence (modified Rankin Scale (mRS) 4–5),
compromise of vital functions, association with extra-cerebral
complications, features of space-occupying effect or brainstem
involvement on computed tomography (CT).
When Should a Patient with AIS be Placed in
the NCCU?
Patients with ischemic stroke that display the above-named
features may at first be managed in the ER or on the stroke unit,
or be admitted to the NCCU for prophylactic close monitoring.
While it is customary in some centers to admit all patients to the
NCCU who received thrombolysis, many centers manage these
patients very successfully on the stroke unit. The key point is that
AIS patients must never be without a monitor in the acute phase.
If AIS patients develop the following features, however, they
should certainly be transferred to the NCCU (Table 11.1).
Types of ischemic stroke often requiring NCCU care are
given in Table 11.2.
Acute Assessment in the Emergency Room
Concerning the early management of acute ischemic stroke,
new guidelines from the American Heart Association/
American Stroke Association have been very recently pub-
lished [5]. Reference to these guidelines will be made through-
out the chapter. Stroke has to be recognized as an absolute
emergency and treated with at least the same priority as a
myocardial infarction. Although certain aspects of the ische-
mic stroke patient must under no circumstances be neglected
during ER assessment, this has to be achieved rapidly. “TIME
IS BRAIN” is not only a very true pathophysiological rationale
but has been demonstrated in early stroke trials [6,7] and
confirmed in countless more recent studies. An organized
approach (Table 11.3, Figure 11.1), ideally involving a proto-
col, code, and dedicated team, has proved beneficial and is
recommended in current guidelines [5].
Time frames have been suggested by panels of stroke experts
(National Symposium on Rapid Identification and Treatment of
Acute Stroke) (Table 11.4) to achieve thrombolysis in an eligible
AIS patient within 60 min of entering the hospital.
Vital Functions
Heart rate, blood pressure, and systemic oxygen saturation
have to assessed immediately in all patients suspected for AIS
upon arrival in the ER. Should any of these vital functions be
unstable, they need to be stabilized first. Although rarely
necessary, this might even include intubation and ventilation
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 Chapter 11: Ischemic Stroke
Table 11.1 Indications for transfer of AIS patients to the NCCU
• Large infarction with signs of swelling and/or mass effect on
cerebral imaging
• Postendovascular treatment if this involved intubation and
mechanical ventilation
• Need for neurosurgical operations (e.g. decompression) or
invasive interventions
• Instability during thrombolysis or thrombolysis-related bleeding
• Compromise in airway protection with risk of aspiration
• Respiratory failure and need of intubation
• Substantial hemodynamic instability
• Progressive decline of level of consciousness
Table 11.2 Types of AIS usually requiring management in the NCCU
• Any stroke treated endovascularly requiring
postinterventional intensive care
• Large hemispheric stroke (“malignant” middle cerebral artery
infarction)
• Space-occupying cerebellar stroke
• Basilar occlusion
• Stroke from large-vessel arterial dissection
• Stroke from bacterial endocarditis
Table 11.3 Stroke chain of survival (“The Eight Ds”)
Detection Prehospital recognition of stroke signs and
symptoms
Dispatch Prehospital immediate 911-activation emergency
medical system (EMS) dispatch
Delivery Prehospital immediate transport to and
notification of stroke hospital
Door Immediate ER triage to high-acuity area
Data Rapid ER evaluation, monitoring, laboratory tests,
imaging
Decision Diagnosis, choice of acute treatment, discussion
with patient/family
Drug Application of drugs/interventions
Disposition Timely transfer to stroke unit or NCCU
Adapted from [5]
of the patient before further assessment can be continued.
A quick general examination of systems should follow, as well
as assessment of the Glasgow Coma Scale (GCS).
Relevant History
Taking a brief history from the patient has to be attempted,
particularly with regard to the main present complaint, the
104
dynamics of its development and the point in time of the insult.
The latter is the most important aspect in AIS history. If the exact
time of onset cannot be clarified, it has to be estimated and the
last point in time that the patient was without symptoms (“last
seen well”) be taken for the time of onset to define the time-
window. Often, however, patients with severe AIS are not able to
provide a history themselves, either due to aphasia/anarthria or
decline in level of consciousness and the key elements of the
history have to be obtained from the emergency personnel or the
family, if present. In addition to the aspects named above, further
information should be obtained on past medical diseases and
comorbidities (especially recent bleeding, trauma, or operations),
current medication (especially anticoagulants), and the prehospi-
tal condition of the patient. All of these may influence the
decision on acute treatment. Usually, the typical constellation in
the history will be that of a sudden neurological deficit with a
syndrome correlating to a brain vessel territory, with the symp-
toms remaining unchanged or gradually resolving. However,
some types of ischemic stroke may present with stuttering or
step-wise worsening symptoms, such as in basilar thrombosis,
sinus/venous thrombosis, or arterial dissection.
Neurological Exam
A five-minute neurological examination of the suspected
stroke patient has to include testing of the level of conscious-
ness, speech, response to simple commands, cranial nerves II/
III/IV/VI/VII, the main tendon reflexes, Babinski´s sign, limb
power, and localizing response to (painful) stimuli. At times,
orienting testing of coordination may by feasible, too. ER
personnel may use a well-validated tool for initial examination
or triage of the patient suspected for AIS, the Recognition of
Stroke in the Emergency Room (ROSIER) scale. This tool
comprises seven items: loss of consciousness/syncope, seizures,
new asymmetric facial weakness, asymmetric arm weakness,
asymmetric leg weakness, speech disturbance, and visual field
defect. In the validating study, it had a sensitivity of 92%, a
specificity of 86%, a positive predictive value (PPV) of 88%,
and negative predictive value of 91% [8].
From the history and the neurological examination, one
should try to rule out so called “stroke mimics,” such as seizures,
migraine attacks, or hypoglycemia. However, if there remains
suspicion that the patient may suffer from AIS, consideration of
these mimics should not lead to withholding stroke treatment.
Grading the Deficit
The most common way to score the severity of ischemic stroke
is by the National Institutes of Health Stroke Scale (NIHSS).
This score has not only been the best validated and most
widespread score in all large relevant stroke trials, it has also
proved very helpful in monitoring the clinical course and
informing treatment decisions in everyday stroke care, and
its use is recommended in current guidelines [5] (Table 11.5).
Certain NIHSS “cut-off values” have been used as a basis
for treatment decisions. While it had been suggested in the
 Chapter 11: Ischemic Stroke

Rapid assessment in the ER

• History from patient, EMS or family: Deficit, time of onset, anticoagulation drugs, etc.
• Assessment/stabilization of vital functions, bedside monitoring of EKG, HR, BP, SpO2
• Quick general and neurologic examination, assessment of GCS and NIHSS

Anterior circulation stroke Posterior circulation stroke

Onset <4.5 (3) h Onset >4.5 h/ Onset <12 h/coma <6 h,
unknown pupils reactive to light
Yes
NIHSS >10?

No

NECCT Stroke MRI with MRA or advanced CCT with CTA

No Yes No
Yes ICH? Intravenous Small infarct core?
IVT contra-
indications? Thrombolysis Relevant Mismatch?

No
Large vessel
occlusion?

Yes Consider
combined

Endovascular
Recanalization

Standardized care in the SU/NCU

Regular reassessment for transfer to/management in the NCCU

• Neurological/general examination, bedside monitoring, repeated cerebral imaging, adjunctive tests

Large Hemispheric Cerebellar Brainstem

Stroke Stroke Stroke
No No No
Decreased LOC, anisocoria, Decreased LOC,
Dysphagia?
Increased ICP? Increased ICP?

Stabilize ICP, CPP Stabilize ICP,CPP Consider

Consider EVD +
Consider hemicraniectomy Decompression Tracheostomy
Figure 11.1 Suggested approach to acute and critical care of ischemic stroke

105
 Chapter 11: Ischemic Stroke

Table 11.4 Time goals in ER-based stroke care

8. Sensory 0 – No sensory loss
Action Time (min) 1 – Mild sensory loss
Door to physician <10 2 – Severe sensory loss
Door to stroke team <15 9. Language 0 – Normal
Door to CT initiation <25 1 – Mild aphasia
Door to CT interpretation <45 2 – Severe aphasia
3 – Mute or global aphasia
Door to drug (“needle”) <60
10. Articulation 0 – Normal
Door to stroke unit (SU)/NCCU admission <180
1 – Mild dysarthria
Adapted from(5)
2 – Severe dysarthria
Table 11.5 National Institutes of Health Stroke Scale (NIHSS) 11. Extinction or 0 – Absent
inattention 2 – Mild (loss, one sensory modality
1A. Level of 0 – Alert
lost)
consciousness 1 – Drowsy
3 – Severe (loss, two modalities lost)
2 – Obtunded
3 – Coma/unresponsive
1B. Orientation 0 – Answers both correctly
questions (2) 1 – Answers one correctly past to consider an NIHSS of at least 4, reflecting a stroke
2 – Answers neither correctly relevant enough to deserve thrombolysis and to consider an
1C. Response to 0 – Performs both tasks correctly NIHSS >25 a devastating stroke in which thrombolysis should
commands (2) 1 – Performs one task correctly be withheld, these traditions have to be regarded with great
caution today. Minor strokes with an NIHSS <4 can still be
2 – Performs neither
disabling for some patients, may well progress later in the
2. Gaze 0 – Normal horizontal movements course, and can be quite safely thrombolyzed. Furthermore,
1 – Partial gaze palsy stroke patients with an NIHSS >25 may be identified by MRI
2 – Complete gaze palsy imaging as being severely hypoperfused, but not yet infarcted
in a large brain territory, or may have a small infarction area in
3. Visual fields 0 – No visual field defect
a strategically important area. The NIHSS appears very helpful,
1 – Partial gaze palsy however, in identifying patients with a large vessel occlusion
2 – Complete gaze palsy (LVO). In a very interesting study, Fischer et al. correlated the
4. Facial movements 0 – Normal NIHSS of 226 consecutive AIS patients with arteriographic
1 – Minor facial weakness findings and found that an NIHSS of 12 or more predicted a
central occlusion (BA, ICA, M1, M2) with a PPV of 91% [9].
2 – Partial facial weakness
This might influence decisions on advanced imaging and/or
3 – Complete unilateral palsy recanalizing treatment methods.
5. Motor function (arm) 0 – No drift
a. Left
b. Right
1 – Drift before 5 seconds Diagnostic Tests
2 – Falls before 5 seconds Laboratory
3 – No effort against gravity Blood sampling on admission should always include blood
4 – No movement glucose, electrolytes, renal function studies, complete blood
6. Motor function (leg) 0 – No drift
count with platelet count, and the basic coagulation param-
a. Left eters prothrombin time (PT), activated partial thromboplastin
1 – Drift before 5 seconds
b. Right time (aPTT), and the international normalized ratio (INR).
2 – Falls before 5 seconds Other parameters such as troponin T, thyroid stimulating
3 – No effort against gravity hormone, liver function tests, pregnancy test, toxicology
4 – No movement screen, or D-dimer test may be desirable in some patients,
7. Limb ataxia 0 – No ataxia
but should not delay overall assessment. Troponin T may be
elevated in AIS and often does not indicate myocardial infarc-
1 – Ataxia in one limb
tion. It should therefore be interpreted in the context of the
2 – Ataxia in two limbs electrocardiogram (ECG) and kidney function.

106

Assessment of coagulation is most important in this set-
ting, as it directly affects treatment decisions on recanalization.
In patients on heparin, the aPTT, and on warfarin, the INR,
respectively, will demonstrate therapeutic activity. Point-of-
care devices, especially for coagulation testing (possibly the
most important laboratory tests in acute ischemic stroke),
can save valuable time [10]. For patients on new oral anti-
coagulants (NOACs), reliable tests of drug activity may not be
available in the ER. The ecarin clotting time (ECT) has a
robust and linear relationship with levels of direct thrombin
inhibitors, such as dabigatran. The thrombin time (TT) is also
a sensitive indicator of the presence of these drugs, but may be
influenced by other anticoagulants. A normal TT excludes the
presence of significant dabigatran acitivity, while the PT/INR is
not helpful. Assessment of the activity of direct factor Xa inhibi-
tors, such as rivaroxaban or apixaban, afford specific factor Xa
assays [5]. It has to be stressed that this is an area of considerable
uncertainty, and if the history suggests that the patient has taken
NOACs within a time frame compatible with persisting thera-
peutic action and no tests to determine the latter are rapidly
available, intravenous thrombolyis has to be refrained from and/
or other ways of recanalization be considered.
Imaging
Timely cerebral imaging is paramount in AIS. Recommenda-
tions for the ideal choice and sequence of imaging methods are
currently under development [11]. Although a large variety of
imaging techniques are theoretically available, it is important
for a given center to focus on and improve the locally estab-
lished methods and keep in mind both practicability and time-
pressure when handling AIS.
Noncontrast-enhanced computed tomography (CT) is not
only widely available, quickly performed, and allows access to
an unstable patient, but is excellent for ruling out intracranial
hemorrhage, the main contraindication to intravenous throm-
bolysis (IVT). CT may also demonstrate other causes of neu-
rologic deficits or seizures, such as large enough brain tumors,
brain edema, hydrocephalus, or indirect signs of sinus and
venous thrombosis. Hypodensity indicating AIS may be seen
within 3–6 hours of onset [12], but earlier, small, or posterior
circulation strokes may not be displayed. So-called early signs
A B C right 6 h from onset. (A) MRA displaying M1
Chapter 11: Ischemic Stroke
of AIS, such as loss of gray-white-matter differentiation, loss of
basal ganglia distinction, cortical and insular blending, swell-
ing of gyri with sulcal effacement, may be detected by up to
70% of observers [13]. They are not longer regarded as contra-
indications to thrombolysis. Structured scoring systems for
hypodensities, such as the Alberta Stroke Program Early CT
Score (ASPECTS) may improve detection of AIS [14,15]. The
hyperdense middle cerebral artery (MCA) sign, reflecting the
thrombus, indicates LVO. The latter is a stronger predictor of
severe stroke (PPV, 91%) than >50% hypodensity of the MCA
territory (PPV, 75%). If frank hypodensity in more than one-
third of the MCA territory is seen, thrombolysis should be
withheld, since the risk of hemorrhage is high and the chance
of benefits are low. Adding contrast medium for CT angiog-
raphy (CTA) will display vessel occlusions and stenoses within
3–5 minutes in a quality close to conventional angiography
[16,17], and may well influence treatment decisions. CTA is
less often associated with nephropathy (2–3%) than feared in
the past [18] and offers further information on stroke age,
extent, and etiology by use of source images, in combination
with ASPECTS [19], or by thrombus evaluation [20], if these
methods are established in the given center. Perfusion CT is
another option to enhance information on potentially salvage-
able tissue and is easy to quantify. It has the disadvantages of
more ionizing radiation and reduced brain coverage if scan-
ners with a 4-cm-thick slab per contrast bolus are used. Last
generation 256/320-slice scanners allow for rapid whole-brain
coverage in perfusion imaging, but availability is limited.
Magnetic resonance imaging (MRI), including diffusion-
weighted imaging (DWI), perfusion-weighted imaging (PWI),
fluid-attenuated inverse recovery (FLAIR) sequences, and MR
angiography (MRA), may be the most sensitive way to confirm
ischemic stroke as early as possible, show the extent of
fresh and older infarction parts, help to clarify etiology, display
differential diagnoses, and, above all, display potentially
salvageable tissue, all without exposing the patient to ionized
radiation (Figure 11.2). It is certainly the best method of
imaging for suspected brainstem stroke, in which CT is very
insensitive. MRI incorporating T2*-weighted sequences is
as accurate as CT in detecting cerebral hemorrhage (21).
Noncontrast-enhanced MR time-of-flight (TOF) angiography
Figure 11.2 Stroke MRI in MCA occlusion on the
occlusion; (B) DWI displaying small infarcted
area; (C) PWI displaying larger underperfused
area (= mismatch). A black and white version of this
figure will appear in some formats. For the color
version, please refer to the plate section.
107
 Chapter 11: Ischemic Stroke
demonstrates vessel stenosis with a sensitivity of 60–85% and
vessel occlusion with a sensitivity of 80–90% when compared
to CTA and digitial subtraction angiography (DSA), and is
thus reasonably useful in severe stroke, without exposing the
patient to contrast medium (22). Disadvantages of MRI are
limited availability, relatively long duration of image acquisi-
tion (15–20 min), vulnerability to patient motion artifact,
patient contraindications (pacemaker, claustrophobia, agita-
tion), limited access to a potentially unstable patient during
imaging, and the (low) risk of potentially dangerous nephro-
genic reactions to the contrast medium gadolinium(23) if used
to enhance MRA.
MRI can be recommended if the time since insult is
unknown, such as in wake-up stroke. Furthermore, it is often
the only way to confirm brainstem stroke and may influence
treatment decisions in basilar occlusion (BAO). Most interest
in MRI for AIS comes from the “mismatch” concept, i.e. the
overlay of DWI and PWI sequences to delineate the penumbra,
the tissue around the infarct core that is underperfused and
dysfunctional, but not yet irreversibly destroyed. Many stroke
centers base individiual recanalizing efforts on that concept
beyond the time window. The mismatch concept for selection
of well-collateralized patients for IVT within an extended time
window was investigated in several studies and trials [5,24],
which raised hopes for this approach. However, the results of
two pivotal clinical trials testing the mismatch concept for IVT
within the 3–9-hour window (DIAS 1 and 2) showed favorable
trends, but no significant clinical benefits (25). Still, many
stroke experts believe in the mismatch concept, which is con-
sidered an option for selected patients in the current guidelines
[5], and new studies on this concept are currently being per-
formed, indicating possible design problems in the previous
trials. Finally, MRI has been proposed for prognostication of
severe stroke such as malignant hemispheric stroke with stud-
ies yielding robust results (26).
Cerebral DSA is still considered the “gold-standard” of
vascular imaging, but is an invasive procedure with potential
risks, such as groin vessel aneurysm, bleeding, cerebral vaso-
spasm, stroke, or even death, and considering the excellent
quality of noninvasive methods such as MRA and CTA, it no
longer plays a major role in early AIS assessment, unless it is
used not only for diagnosis but also for subsequent endovas-
cular recanalization [5].
Transcranial Doppler/duplex (TCD) ultrasound can dis-
play vessel stenoses, occlusions, and collateral flow, and thus
help to understand the etiology and degree of compensation in
AIS. However, TCD demands a good bony window in the
patient, is quite investigator-dependent, time-consuming,
and, compared to other means of intracranial vascular
imaging, of less than optimal accuracy [27], particularly with
regard to the posterior circulation. Its use should not delay
imaging in early AIS assessment. Secondary application of
extracranial ultrasound after CT may help to detect stroke
sources such as carotid stenosis or carotid/vertebral dissection,
108
though. TCD has been suggested for enhancement of throm-
bolysis (sonothrombolysis), and initial studies were promising
[28], but some authors reported cerebral hemorrhage when
low frequencies were used [29], and since more evidence has
been gathered in newer trials [30,31], TCD for sonothrombo-
lysis cannot be routinely recommended.
Bedside Monitoring
Monitoring installed immediately on admission and
remaining on the patient during acute stroke care and for at
least the first 24 h has to include ECG for assessing cardiac
rhythm and rate, blood pressure (BP) monitoring, and pulse
oximetry for arterial oxygen saturation (SpO2). Temperature
should be taken at least once on admission, and, if abnormal,
periodically thereafter.
Acute Treatment of Early Ischemic Stroke
Supplementary Oxygen, Airway and Ventilation
Management
About 50–60% of patients with AIS might present with hyp-
oxia or at least desaturation episodes (SpO2 <95% for >5 min)
[32], but the remaining patients are normoxemic. Still, the
great majority of AIS patients receive supplementary oxygen
in the prehospital phase and in the ER. Although it may seem
intuitive that a patient with acute occlusion of a major brain
artery, i.e. shutting off of oxygen from the respective brain
region, should be supplied with extra oxygen, this is actually
questionable. It is important to aim for tissue oxygenation and
not for arbitrary levels of oxygen in the blood. Toxic levels of
oxygen in patients that are not hypoxemic may cause tissue
damage resulting from oxygen free radical formation, lipid
peroxidation, and other mechanisms. Hyperoxia might also
impede brain perfusion by a not completely understood pro-
cess called hyperoxia-related cerebral vasoconstriction that
may counterbalance and thus abolish the gain in blood oxy-
genation or might theoretically even lead to worsening of
ischemia [33–35]. A large, quasi-randomized controlled trial
resulted in no benefits from the application of 3 L oxygen
within the first 24 h of AIS [36]. It therefore seems reasonable
to follow the guidelines at present [5], i.e. to aim for no more
than normoxemia and only administer oxygen noninvasively
(e.g. by nasal pronges or face mask) to patients with an SpO2
below 95%. Respiration can often be supported by positioning
the patient with the head of bed elevated to 15–30°. For some
AIS patients who can tolerate it, the supine position might be
preferrable [37,38].
No clinical trial or prospective study has clarified the role
of orotracheal intubation and early mechanical ventilation in
AIS, although retrospective studies have suggested little benefit
by these measures in the context of severe stroke [39,40].
However, if a patient has the perspective of potentially
beneficial therapies such as endovascular recanalization,

decompressive surgery, or critical care for treatable transient
complications such as pneumonia, and the premorbid state
and patient’s/family’s wishes do not preclude this, initiation of
invasive ventilation should not be delayed if signs of respira-
tory decompensation or loss of airway protection are present.
Blood Pressure
Most AIS patients will present with high BP, either reflecting
their underlying pathogenesis of a long-standing un- or under-
treated arterial hypertension or an acute reaction of the body
to raise cerebral perfusion, or both. In many cases, BP will
decrease spontaneously within 90 min of onset. Since rapid
reduction of BP may theoretically worsen penumbra perfusion
in patients with compromised cerebral autoregulation or an
(often unknown) hemodynamically relevant proximal artery
stenosis, acute high BP should most often be tolerated. Despite
several large studies on acute BP lowering in AIS, the data are
very inconsistent and do not favor a particular regime or drug.
Studies suggested a worse outcome if substantial BP variation
was present in the first 24 h [41,42]. A retrospective study in
>10,000 AIS patients receiving IVT suggested that the best
outcomes are associated with a systolic BP between 140 and
150 mmHg [43]. At present, it is advisable to tolerate acute
high BP, if it does not exceed 220/120 mmHg. The latter is
assumed to promote secondary hemorrhage, brain edema, or
systemic end-organ damage. Furthermore, high BP must be
lowered if IVT is planned. Some medical comorbidities, such
as myocardial infarction, aortic dissection, or congestive heart
failure, might also call for BP to be lowered and might result in
a trade-off for optimal brain perfusion. BP management in
these situations has not been clarified, and has to be handled
individually and guided by close neurological monitoring to
avoid deterioration. Oral premorbid antihypertensive drugs
can be paused, since AIS patients may have impaired swallow-
ing and the longer duration of pharmacologic action may
Table 11.6 Suggested approach to arterial hypertension in AIS patients planned for recanalization
Patient eligible for IVT, except if BP >185/110 mmHg
If BP cannot be lowered to <185/100 mmHg. . .
Management of BP during and after recanalizing therapy to
maintain BP <180/105 mmHg
If systolic BP >180–230 or diastolic BP >105–120 mmHg
If BP not controlled by above-named drugs or diastolic BP
>140 mmHg
Adapted from [5].
Chapter 11: Ischemic Stroke
compromise steering of BP in the acute phase. They may be
restarted within the first few days, but when exactly is not clear
and has to be decided individually. Table 11.6 shows the
approach to hypertension in early AIS currently recommended
in the guidelines [5].
Arterial hypotension is very rare in AIS and may indicate
hypovolemia, heart failure, myocardial infarction, or sepsis
[44], and should be treated adequately either by fluid adminis-
tration or the use of vasopressors. Drug-induced hypertension
for AIS outside these situations is not well supported by
conclusive data. Hemodilution is not recommended.
Blood Glucose
There is ample evidence that acute hyperglycemia in AIS is
associated with infarct growth and worse outcome [45–47].
However, it is still unclear, despite considerable research effort,
whether targeting glucose to a particular level in this acute
phase is beneficial. GIST-UK, the only randomized trial on
hyperglycemia treatment by insulin/potassium/glucose infusion
yielded neutral results, was stopped prematurely, and had
numerous methodological shortcomings [48]. In particular,
the achieved difference in glucose levels was only ca. 10 mg/dL
between the groups, quite possibly too little to achieve clinical
significance. Hypoglycemia, although rare in AIS, may be
equally if not more detrimental for the brain. Therefore, it is
reasonable not to apply intensive glucose lowering, but to try to
adjust the level between 140 and 180 mg/dL by subcutaneous
insulin, and to treat hypoglycemia below 60 mg/dL vigorously,
such as with a slow IV push of 25 mL of 50% dextrose [5].
Anticoagulation and Antiaggregation
Past traditions of administering heparin or low molecular
weight (LMW) heparinoids to AIS patients in the acute phase
in order to promote perfusion have no convincing base of
Labetalol 10–20 mg IV over 3 min, may repeat once; or
Nicardipine 5 mg/h IV, titrate up by 2.5 mg/h every 5–15 min, maximum 15
mg/h, adjust to maintain BP limits; or
Other appropriate agents (e.g. hydralazin, enalapril)
. . .do NOT administer recombinant tissue-type prothrombin activator (rtPA)!
Monitor BP every 15 min for 2 h from start of therapy, then every 30 min for
6 h, then every hour for 16 h
Labetalol 10 mg IV followed by continuous IV infusion 2–8 mg/min; or
Nicardipine 5 mg/h IV, titrate up to desired effect by 2.5 mg/h every 5–15
min, maximum 15 mg/h
Consider IV sodium nitroprusside
Monitor and do not allow ICP to increase in a severe stroke
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 Chapter 11: Ischemic Stroke
evidence. In addition, administration of direct thrombin
inhibitors, other oral anticoagulants, IV glycoprotein IIb/IIIa
antagonists, carries the risk of cerebral hemorrhage, is not estab-
lished by data, and cannot be recommended, particularly not
within the first 24 h after IVT. Oral aspirin within 48 h of stroke
onset is recommended for most patients, but again not until 24 h
after IVT [5]. Withholding aspirin should be considered in patients
with severe stroke if early decompressive surgery is planned.
It is of great importance, however, to clarify the coagula-
tion status and the presence of premorbidly administered
anticoagulants on admission, since this may influence deci-
sions regading recanalization. In most cases, acute adminis-
tration of anticoagulants or antagonization of previously taken
anticoagulants will not be warranted in severe AIS.
Recanalization
Decision-Making According to Guidelines, Approval and Beyond
To reverse acute vessel occlusion, i.e. to recanalize, as soon as
possible is not only a plausible principle, but was clearly
associated with better outcome in several studies [49], and
may be the paramount aim in acute stroke care. However,
recanalization often has a limited time window and may even-
tually cause reperfusion trauma (relevant intracerebral hemor-
rhage, ICH). The slogan “TIME IS BRAIN” cannot be
overemphasized. The time window, however, is highly individ-
ual and depends on the particular patient´s collateralization via
adjacent vessels. In some patients, the penumbra (the brain area
around the infarct core that is underperfused but potentially
salvageable) may be lost within 2 h, while in others it may still
be saved after 12 h or more. Therefore, larger stroke centers
equipped with MRI or advanced CTA technology have turned
to a more individual recanalization policy, as opposed to a rigid
time window regime. Furthermore, since IVT will only lead to
30% recanalization in large-vessel (proximal main stem arteries)
occlusion [50], endovascular interventions may be chosen instead
or in addition. Also, although guideline-based recanalization by
IVT include a great number of official contraindications, some of
these (age over 80 years, diabetes, seizures, etc.) have been recog-
nized to relate to design aspects of the approval studies for IVT,
have been shown or suggested to be irrelevant by numerous
other studies, and are ignored in many stroke centers, if the
alternative (i.e. a large, severely disabling or life-threatening def-
icit) appears to outweigh the risks of treatment [51] (Table 11.7).
Furthermore, it was recently shown that patients with so-called
minor strokes (NIHSS <4), but that still constitute an individu-
ally relevant deficit, should not be denied recanalization treat-
ment. A considerable number of these will otherwise progress to
a larger stroke and showed a favorable clinical course in several
studies [52,53]. Finally, IVT in stroke mimics (such as seizures or
migraine attacks) seems to be quite safe and is only very rarely
associated with symptomatic ICH [54–57].
It has to be emphasized, however, that IVT by rtPA is
only approved by the US FDA within 3 h and by the European
110
EMA within 4.5 h of onset, according to the official indications
and contraindications. All other approaches employing rtPA are
off-label, individual attempts to save the patient and should ideally
involve the patient’s or family’s written informed consent. If the
patient is unable to provide this and the family or a legal proxy are
not present, it is reasonable to proceed with the treatment regarded
optimal in this emergency situation, but somebody bearing and
constating witness to the physician´s decision is advisable.
Intravenous Thrombolysis
The benefits of the current gold standard of recanalization
were suggested by several observational studies before they
were eventually confirmed in the NINDS milestone trial of
1995, which enrolled 624 patients and showed that AIS
patients randomized to rtPA at a dose of 0.9mg/kg body
weight within 3 h of stroke onset had an almost doubled
chance of a favorable three-month outcome (complete or
nearly complete recovery) when compared to placebo-treated
patients [58]. Several other degrees of deficits and measures of
outcome were in favor of IVT, too. Interestingly, even patients
with severe stroke (NIHSS >20, signs of brain edema and mass
effect on CT), despite having an overall worse outcome, did
better if they received IVT. The rate of (any, not necessarily
symptomatic) ICH was 6.4% under rtPA and 0.6% under
placebo, but mortality after two months was similar. These
findings led to FDA and EMA approval of rtPA for IVT within
3 h of onset. The results were not only confirmed in several
large subsequent trials, but also in the prospective community-
based registry SITS-ISTR in almost 12,000 patients, i.e. in “real
life” settings outside controlled trials [59]. Over the following
20 years, more pivotal trials have investigated extending IVT.
After trials like ECASS I/II or ATLANTIS A/B had suggested
that IVT up to 4.5 h from onset may be safe and beneficial, it
was the second milestone trial, ECASS III in 2008, that pro-
vided proof. Of 418 AIS patients randomized to rtPA between
3 h and 4.5 h from onset, 52% had an excellent outcome (mRS
0–1) at three months compared to 45% of 403 placebo-treated
patients (OR 1.34, p = 0.04) [60]. Despite a rate of symptom-
atic ICH of 2.4% in rtPA-treated patients compared to 0.2% in
those treated with placebo, mortality was higher in the latter
group. In 2012, a meta-analysis of 12 trials on IVT (over 7000
patients, including results from the Third International Stroke
Trial (IST-3), to date the largest RCT on IVT in 3035 patients),
confirmed the previous findings, suggested benefits, even after
up to 6 h, and in all age categories, and reinforced once more
the importance of timely treatment [61]. Based on data from
these trials, the EMA approved rtPA for AIS up to 4.5 h after
onset, while the FDA declined to do so, for reasons difficult to
understand. US stroke experts from the AHA/ASA regard IVT
within 4.5 h reasonable, but recommend following the ECASS
III exclusion criteria (age >80 years, intake of oral anticoagu-
lants, baseline NIHSS >25, CT hypodensities >1/3 of MCA
territory, and the combination of previous stroke and diabetes
mellitus) [5]. Further extension of the time window, such as in
 Chapter 11: Ischemic Stroke

Table 11.7 Inclusion and exclusion criteria for IVT within 3 h

Inclusion criteria Meaningful neurological deficit caused by ischemic stroke

Onset of symptoms <3 h (USA) before start of therapy
Age >18 years
Exclusion criteria Frank hypodensities on CT being multilobar or involving >1/3 of the cerebral hemisphere
Prior stroke in previous three months
History or presence of intracranial hemorrhage
Suspicion of subarachnoid hemorrhage
Significant head trauma in previous three months
Intracranial neoplasm, arteriovenous malformation (AVM), or aneurysm
Recent intracranial or intraspinal surgery
Active internal bleeding
Acute bleeding diathesis, including but not limited to a platelet count of <100000/mm3
Heparin within the last 48 h raising aPTT above normal levels
Oral anticoagulation with INR >1.7 or PT >15 seconds
Current use of direct thrombin inhibitors or direct factor Xa inhibitors with elevated sensitive laboratory tests (such as
aPTT, INR, platelet count, and ECT, TT, or appropriate factor Xa activity assays)
Highly elevated blood pressure (>185/100 mmHg)
Blood glucose concentration <50 mg/dL (2.7 mmol/L)
Relative exclusion Minor or rapidly improving symptoms
criteriaa Age >80 years
Pregnancy
Seizures at onset with postictal residual neurological symptoms
Major surgery or serious trauma in previous 14 days
Gastrointestinal or urinary tract hemorrhage in previous 21 days
Acute myocardial infarction in previous three months
a
Note: Recent evidence suggests that under some circumstances, with very careful consideration and weighting of risks and benefits, patients may receive IVT
despite one or more of these contraindications! This policy should be restricted to experienced stroke centers. Adapted from [5].

wake-up stroke after selecting patients by stroke MRI (exclu-
sion of advanced stroke by normal FLAIR sequence) has just
been proven efficacious in the WAKE-UP trial [62].
In summary, there is no doubt that timely IVT works and
improves the outcome of thousands of patients (Table 11.8).
That benefits are achievable within a time window extending
to 3 h does not mean that emergency physicians and neuro-
intensivists may slow down. Treatment success remains clearly
time dependent [63,64]. The establishment of quick transport
and access to recanalization by IVT in as many hospitals
equipped with CT and basic stroke expertise as possible is
certainly the most important action to improve stroke care
world-wide. The employment of trained emergency personnel,
the role of telemedicine, and even the option of CT-equipped
stroke ambulances are currently under investigation to fulfill
this goal. Emergency and critical care neurologists are key
players in this scenario.
Application of rtPA via a well-secured IV access under
continuous monitoring and controlled BP can be started in
the ER and continued on the SU or the NCCU, or even in an
ambulance, if transport to another center is decided. Close
neurological assessment is paramount to detect deterioration
as a possible sign of thrombolysis-related ICH. Another note-
worthy side effect of IVT is orolingual angioedema, occurring
in 1–5% of IVTs as swelling of lips, tongue, or oropharynx,
usually contralateral to the affected hemisphere. Although
most often mild and transient, it can rarely be life-threatening
and may call for treatment interruption and antiallergic ther-
apy (e.g. by ranitidine, methylprednisolone).
Intra-Arterial Thrombolyis, Mechanical
Thrombectomy
Since large brain vessel occlusion (i.e. distal internal carotid
artery (ICA), proximal middle cerebral artery (MCA, segments
M1 or more than one M2), basilar artery (BA), or dominant
vertebral artery (VA)) will respond to IVT in only 30% of the
cases, alternative or additional endovascular local treatment

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 Chapter 11: Ischemic Stroke

Table 11.8 Intravenous thrombolysis for AIS

Infuse 0.9 mg/kg rtPA (maximum 90 mg) over 60 minutes, with 10% of the dose given as a bolus over 1 min
Monitor patient on a stroke unit or a neurocritical care unit
Monitor BP and neurological state every 15 min for 2 h, then every 30 min for 6 h, then hourly for 24 h after start of rtPA infusion
Increase frequency of BP measurements if BP is >180/105 mmHg and administer antihypertensives to keep BP below this level
If the patient develops severe headache, acute hypertension, nausea or vomiting, neurological deterioration, assume ICH, stop rtPA infusion, obtain
CT scan
Delay or avoid nasogastric tubes, indwelling bladder catheters, and central venous or arterial lines if the patient can be managed without
Obtain a follow-up CT or MRI 24 h after IVT before starting anticoagulants or antiplatelet drugs
Adapted from [5].

(intra-arterial thrombolysis, IAT) may be chosen. Very differ-
ent catheter devices, local therapies and adjunctive drug treat-
ments have been tried over recent decades, and employed as
IVT rescue strategies, replaced IVT in the case of contraindi-
cations, or combined with IVT (“bridging”) (for a review see
[65]). For bridging, prior IV rtPA is often reduced in dose,
although it appears safe to use the full dose in bridging as well
[66]. Despite impressive recanalization rates when combining
IVT and IAT, a favorable outcome has only been achieved in
up to 50% of cases [67]. Notwithstanding this lack of sufficient
evidence of clinical efficacy, two devices, (MERCI and PEN-
UMBRA) have been FDA approved. Today, mechanical
thrombectomy (MT) using stent retrievers may be the most
widespread and preferred technique, achieving recanalization
rates of 80–100% [68]. In February 2013, three randomized
controlled trials (RCTs) on endovascular stroke treatment
were published in the New England Journal of Medicine; none
showed superiority over IVT [69–71]. The largest of these,
IMS3, was planned to randomize 900 patients to endovascular
treatment (IAT or MT) added to IVT within 3 h versus IVT
alone. After 656 patients the trial was stopped for futility and
showed no difference in Modified Rankin Scale (mRS) or
mortality at three months [71]. Since these trials hardly
employed stent retrievers and were quite heterogeneous with
regard to their design, their results were not regarded as
settling the issue. Indeed, in 2014 the Dutch MR CLEAN trial
was the first RCT to prove efficacy of endovascular AIS treat-
ment. Of 500 patients with anterior circulation AIS, 190 were
randomized for MT by stent retrievers within 6 h of onset in
addition to IVT, 32.6% of which reached an mRS of 0–2 at
90 days compared to 19.1% in the IVT-only group [72]. Soon,
two more highly positive RCTs on MT with stent retrievers
were published: ESCAPE, demonstrating favorable long-term
outcome in 53% (IVT+) IAT patients versus 29.3% IVT
patients out of 316 anterior circulation AIS [73], and
EXTEND-IA, showing highly significant benefits of IAT com-
bined with IVT in only 70 AIS patients as compared to IVT
only, i.e. early neurological improvement and better reperfu-
sion in 80% and 100% versus 37% and 37%, respectively [74].
Both trials employed stent retrievers, multimodal CT imaging,
and short treatment windows. More RCTs from independent
groups all over the world that were stopped early or completed
thereafter, all showed consistently that the combination of MT
with IVT was more efficacious than IVT alone for AIS caused
by LVO [75–77]. These results substantially affected acute
stroke care and influenced guidelines [78]. The newest devel-
opment at the time of writing is that selected stroke patients
with LVO and good collaterals can even be selected neuro-
radiologically to benefit from MT as late as 16–24 h from
stroke onset [79]. Currently, MT for mild and more severe
strokes and patients with poorer imaging status is being
investigated. A number of questions remain to be answered,
such as how to best manage the patients peri- and postpro-
cedurally. At present, key elements for success appear to be
the use of stent retrievers, detection of salvageable brain
tissue by rapid and simply interpretable imaging, and a lean
flow of action.
Peri-Interventional Care
Neurointensivists, neuroanesthesists, and emergency phys-
icians may be involved in stabilizing the patient before, during,
and after endovascular stroke. A standardized protocol for the
procedure can help to save valuable time [80]. It appears
reasonable, although not sufficiently backed up by studies, to
keep oxygenation and circulation parameters within certain
limits during the procedure. Examples from the Heidelberg
stroke center are SpO2 >95%, ETCO2 35–45 mmHg, SBP
140–160 mmHg. Great variations of blood pressure and espe-
cially hypotension should be avoided [41,42,81]. In addition,
hyperventilation associated with hypocarbia may theoretically
lead to cerebral vasoconstriction and hypoperfusion of the
penumbra and may be deleterious. Both events may occur
during intubation and mechanical ventilation [82]. Although
most interventionalists prefer general anesthesia and intub-
ation for the procedure [83], a number of retrospective studies
suggest that the nonintubated state under so-called “conscious
sedation” may be advantageous and even result in better out-
comes [84–86]. This, however, was contradicted by three
single-center randomized trials comparing general anesthesia
with conscious sedation. In all three, general anesthesia was
not inferior, and in some regards better, compared to

112

conscious sedation [87–89]. Many other open questions on
peri- and postinterventional care exist, such as those on
adjunctive anticoagulation, temperature management, timing
of extubation, timing of control CT scan, etc. At present, it
may be reasonable to avoid adjunctive anticoagulants, to keep
the patient normothermic, apply immediate close NCCU
monitoring, strive for early extubation, and perform a CT scan
12 h after the procedure or earlier, if the patient does not wake
up for extubation or displays neurological deterioration [90].
General Aspects of Ischemic Stroke
Management in the NCCU
Since high-quality data on many aspects of general critical care
specific for ischemic stroke are scarce, the reader will be
referred to general stroke guidelines [5,91] and general inten-
sive care guidelines (on specific topics of ICU or NCCU care,
as published by the SCCM, the ESICM, and the NCS) through-
out this part of the chapter. Careful adaptation of these may
often be appropriate for the NCCU patient with ischemic
stroke as well.
Airway Management
Impaired level of consciousness, decreased respiratory drive,
loss of protective reflexes and dysphagia may lead to life-
threatening respiratory situations in patients with severe AIS
on admission or during the later course. In the past, numerous
studies suggested that AIS patients so severely affected that
they required invasive airway securing and mechanical venti-
lation [3,4,92–95] would have mortality rates between 40 and
80%. The relative value of intubating AIS patients, considering
the high use of ICU resources and the bad prognosis despite
ICU care, was challenged by these reports. However, these
studies may have been influenced by a nihilistic or self-
fulfilling prophecy in the absence of a proven effective treat-
ment option. Advanced options for therapies of severe AIS,
including the potential perspective of decompressive surgery,
support that life-saving intubation and initiation of mechan-
ical ventilation should not be withheld or delayed. Certainly,
this should take into account the wishes of the patient or the
family and the overall clinical situation, but initating invasive
ventilation in an acute and possibly unclear emergency situ-
ation when such statements cannot be obtained does not
constitute an ethical obstacle to later withdrawing treatment
efforts, if appropriate.
The need for mechanical ventilation in the large hemi-
spherical infarction (LHI) patient may often be driven by the
need for airway protection in a conscious adult, and may
therefore be different from other populations. One prospective
observational study addressed mechanical ventilation and
intubation in LHI [40], reporting a GCS score of <10 or
respiratory failure as indications for intubation. In another
prospective study, 54 of 218 AIS patients required mechanical
ventilation; of these, 90% were intubated due to neurological
deterioration and 10% due to cardiopulmonary compromise
Chapter 11: Ischemic Stroke
[92]. Independent predictors of mechanical ventilation (MV)
were history of hypertension and infarct size >2/3 of MCA
territory. In AIS patients with – at times even relatively small –
vertebrobasilar strokes, intubation is frequently necessary if
the brainstem is involved and decline of level of consciousness,
dysphagia, or loss of protective reflexes ensue. The decision to
intubate should be made using features such as: (a) a GCS 8
or progressive decline in level of consciousness, (b) clinical or
monitoring signs of respiratory failure, (c) loss of protective
reflexes, (d) signs of increased intracranial presure, (e ) infarct
size >2/3 of MCA territory on imaging [4], (f) coexistence of
pulmonary edema or pneumonia, or (g) imminent surgical or
invasive procedure.
Principally, early extubation should be a primary goal.
Extubation can be difficult, as impaired level of consciousness
and a high prevalence of dysphagia may lead to extubation
failure and reintubation, which is associated with increased
morbidity and mortality in ICU patients [96]. NCCU patients
often experience postextubation dysphagia [97], and reintuba-
tion rates can be as high as 35% [98,99]. Classical predictors of
successful extubation from general critical care are unreliable
in the brain-injured ICU patient [100,101] and this certainly
applies to most AIS patients in the NCCU as well. For instance,
cooperation is often not achievable simply due to aphasia or
apraxia, and dysphagia is much more frequent. As such, clas-
sical extubation triggers can only be used for cautious orienta-
tion in LHI patients. Only one recent retrospective study in
47 intubated MCA stroke patients suggested that a composite
GCS score 8 trends towards extubation success (with a mean
eye score of 4 in those who could be extubated versus 2.5 in
those who could not) [102]. Prospective studies focused on
extubation success in AIS NCCU patients do not exist.
A recent prospective study, PRINCIPLE, only reported in
abstract so far, investigated predictors of reintubation in
93 critically ill AIS patients planned for extubation. Of these,
36% needed reintubation, and the predictors were reduced
level of consciousness for initial intubation, a higher Airway
Care Score, episodes of raised ICP, length of NCCU stay, and
need for antibiotic treatment. Obviously, extubation must not
be attempted if sufficient respiratory and airway protection
criteria [103] are not present, but if they are, it often can be
achieved even though cooperation is not established. On the
other hand, failure to detect dysphagia might result in
unnecessary reintubation. It appears reasonable to attempt
extubation after successful spontaneous breathing trials, in
the absence of relevant oropharyngeal saliva collections and
absence of relevant demand for suctioning, together with the
presence of a cough reflex and tube intolerance, if the patient is
free of analgesia and sedation, even if communication and
cooperation cannot be established. Stand-by reintubation
measures should be provided, and the patient remain under
monitored observation for at least 24 h postextubation.
Tracheostomy is frequently necessary in the ICU patient if
timely extubation is not feasible. While the procedure has to be
applied to ca. 10–15% in the general ICU, the rate is 20–30% in
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 Chapter 11: Ischemic Stroke
the NCCU [104,105]. Tracheostomy and particularly early
tracheostomy, reportedly beneficial in selected ICU patients
[106], has seldom been studied in AIS patients specifically
[107,108]. A retrospective study in ICU stroke patients
(including AIS) surviving ICU care after prolonged ventilation
and tracheostomy suggested good outcomes in about 25% of
tracheostomized patients, as well as reductions in ventilation
duration, ICU stay, and costs from earlier tracheostomy [109].
A more recent randomized trial on early tracheostomy in
mixed cerebrovascular ICU patients including 20 patients with
large ischemic hemispheric stroke did not confirm the latter
two advantages but demonstrated safety, feasibility, and reduc-
tion in the need for sedation [110]. Predictors for tracheos-
tomy need in patients with severe AIS have not been defined
and there is currently insufficient evidence on potential out-
come benefits of tracheostomy in general or early tracheos-
tomy in particular. As there is some evidence and also
experience-based reasons to assume tracheostomy is a rela-
tively safe and feasible bedside-procedure in the NCCU
[110,111], this should be done as early as the need for long-
term airway protection or mechanical ventilation becomes
clear to the treating physican. This remains a clinical, individ-
ual decision and general customs for tracheostomy in ICU
patients should be applied. It appears reasonable to consider
tracheostomy in AIS patients failing extubation or if extuba-
tion is not feasible by 7–14 days after intubation.
Ventilation
Modern ventilation of the ICU patient follows lung-protective
principles. One of these is the application of low tidal volume
at higher respiratory frequencies. The associated benefits were
first shown in acute respiratory distress syndrome (ARDS)
patients and then extended to other ICU populations [112].
Another principle is that of the “open lung,” meaning to keep
alveoli open by principal application of positive end expiratory
pressure (PEEP) and that of PEEP escalation in the treatment
of ARDS [113]. Superiority of any specific mode of mechanical
ventilation has not been established in the ICU, so far.
Although the above-named principles of ventilation have not
been studied sufficiently in NCCU-dependent AIS patients, it
appears reasonable to apply them, until such data support
other modes. Goals of ventilation should be optimal arterial
oxygenation (arterial partial pressure of oxygen (PaO2) >70
mmHg) and normalization of the arterial partial pressure of
carbon dioxide (PaCO2) to between 35 and 40 mmHg, as a
drop in the latter may lead to cerebral vasoconstriction and
risk of secondary ischemia, while a rise may cause cerebral
vasodilation and a subsequent increase in ICP. It appears
desirable to strive for early adoption of patient-controlled
modes of ventilation to achieve training of respiratory muscles,
and to apply standardized respirator weaning as soon as the
patient allows this.
Two small prospective observational studies have
addressed ventilation settings in LHI patients. The fear of
114
increased venous return resulting in increased ICP when PEEP
escalation is used to treat LHI patients was first examined in a
study in 13 LHI patients equipped with ICP neuromonitoring.
Increasing PEEP to 12 mmHg did not lead to relevant rises in
ICP [114]. Further, intensifying ventilation using alterations of
the inspiration:expiration (I:E) ratio from 1:2 to 1:1 in 13 LHI
patients did not influence ICP or cerebral perfusion pressure
(CPP) [115]. Thus, these forms of ventilation escalation to
improve oxygenation may be safe in LHI patients, provided
neuromonitoring (ICP and CPP) is in place. In the only
prospective study on mechanical ventilation in 37 patients
with AIS, including LHI, subjects were ventilated using a
volume-controlled mode and an I:E ratio of 1:2, the PaO2
was adjusted to >90 mmHg and the PaCO2 to about 35
mmHg. In this population, no patient received hemicraniect-
omy, and mortality was 70%, irrespective of the cause for
intubation (“respiratory” versus “neurological”). No further
focus on the method of ventilation or subgroup analysis was
chosen in this study [40].
Until new data suggests otherwise, patients with severe AIS
should be ventilated according to general principles of modern
ICU ventilation with the goals of normoxemia and avoidance
of hypo- and hypercapnia. Escalation of PEEP or alteration of
I:E ratio can be considered to achieve optimal oxygenation,
preferrably if ICP/CPP monitoring is in place.
Analgesia and Sedation
Patients with large AIS, in the acute phase of their disease,
often need analgesia and sedation to achieve freedom from
pain, anxiety, and agitation. Addtionally, sedation and anal-
gesia may facilitate medical goals such as lowering ICP, enab-
ling procedures and operations, or terminating seizures. The
way to optimally use analgesia and sedation has rarely been
studied in NCCU patients, including those with AIS. Although
common analgesics and sedatives such as different opioids,
midazolam, propofol, ketamine, etc. have been subject to small
studies on brain-injured patients (mainly traumatic brain
injury (TBI) or subarachnoid hemorrhage (SAH)), but this
was largely limited to physiologic rather than outcome effects.
There are currently no data to allow for preference of any
analgesic or sedative agent over another in neurocritical care
[116,117]. Likewise, the application of sedation and pain
scores, sedation and analgesia protocols [118,119], or sedation
monitoring devices such as bispectral index (BIS) have been
addressed in small studies on brain-injured ICU patients
[120,121], but not in AIS patients, specifically. Daily wake-up
trials were reported to be beneficial for reduction of ventilation
duration [122] and outcome [123,124] in earlier ICU studies.
A large recent RCT failed to confirm a benefit associated with
daily wake-up protocols [125]. Furthermore, sedation inter-
ruption in NCCU populations (TBI and SAH) was associated
with potentially negative effects, such as transient rises in ICP
and stress hormone levels [126,127] and cerebral deoxygen-
ation [128], and this might apply to AIS patients as well.

Aiming for the lowest level of analgesia and sedation that
still provides systemic and cerebral hemodynamic stability, as
well as patient comfort, seems desirable. Overall, the goal
should be to free the patient from sedation as soon as appropri-
ate. Neuromonitoring of at least ICP and CPP is recommended
to guide sedation. Daily wake-up trials should be abandoned or
postponed at clinical or monitoring signs of physiological com-
promise or discomfort. Intensivists should use the agents cus-
tomary in their units, choosing them according to patient
comorbidities and agent-specific side effects, and pay particular
attention to avoidance of hypotension.
Gastrointestinal Tract
Dysphagia as a result of stroke lesions compromising the
swallowing act at different stages affects 30–50% of stroke
patients in the acute phase. The strongest impairment is caused
by brainstem stroke. Screening for dysphagia has been
reported to decrease pneumonia in the general stroke popula-
tion [129]. Dysphagia screening tests such as the gugging
swallowing test (GUSS) have been studied and found useful
in AIS patients, but patients with large or multiple strokes or
rapid decline in level of consciousness were not included [130].
The swallowing provocation test (SPT), testing the involuntary
part of swallowing by means of a thin oropharyngeal catheter,
might overcome problems with vigilance or cooperation [131].
After initial screening, dysphagia can be confirmed and differ-
entiated by endoscopic swallowing tests that do not necessarily
demand patient cooperation. In particular, the fiberoptic endo-
scopic evaluation of swallowing (FEES) can be done in severely
affected and uncooperative patients, and it has been found
reliable and predictive in studies on acute stroke patients
[132,133]. A recent study of over 300,000 stroke patients found
that less than one-third received dysphagia screen and 1 in 17
experienced a hospital-associated pneumonia [134].
Studies on the best timing for nasogastric tube (NGT)
placement [135] in critically ill AIS patients are lacking. Simi-
larly, predictors of the need for percutaneous endoscopic gastro-
stomy (PEG) tube placement have only been studied in mixed
ischemic stroke populations. Two retrospective analyses have
found a high NIHSS score to be most predictive of PEG need
[136,137]. In a recent Cochrane analysis of the general acute and
subacute stroke population, NGT and PEG did not differ in
terms of case fatality, but PEG was more secure and resulted in
fewer treatment failures and reduced gastrointestinal bleeding,
as well as higher feed delivery [138]. In terms of gastric ulcer
prophylaxis, recent data support ranitidine use in reduction of
nosocomial pneumonia versus proton pump inhibitors.
With this lack of studies focusing on food intake, delivery,
and gastrointestinal function in NCCU patients with AIS, it
may be best to carefully transfer insights from general ICU
care. It is often possible to assess swallowing by standard
screening tests in the very early phase (days 1 and 2; patients
might still be in the emergency room or the stroke unit) to
guide NGT placement. Once level of consciousness starts to
Chapter 11: Ischemic Stroke
decline, however, the patient should be kept nil by mouth and
the NGT be placed at a very low threshold to avoid aspiration.
The NGT can then be used for feeding over the next few weeks
of NCCU treatment. During this time, gastrointestinal trans-
port stimulation and gastric ulcer prophylaxis following prin-
ciples from general critical care can be applied. In the later
phase of the disease, i.e. after termination of sedation and
weaning from the respirator, swallowing capacity can be
reassessed, preferrably by use of an endoscopic method such
as the FEES and the results incorporated into the decision to
place a PEG.
Fluid Status and Nutrition
AIS patients in the NCCU should be kept euvolemic, since
hypovolemia may compromise cerebral perfusion by hypoten-
sion and high blood viscosity, while hypervolemia may pro-
mote brain edema. The average demand for an adult patient is
2–3 L/day (1 mL/kg/h), but individual factors such as higher
perspiration under invasive ventilation and fever, as well as
cardiac and renal function have to be taken into account. After
decades of ICU controversy regarding colloidals and crystal-
loidals in volume management, more recent studies have cast
doubt on the benefits of colloids in many situations and
populations. ALIAS, a large RCT on albumin versus crystal-
loids in AIS was stopped early for futility after 841 patients,
since no outcome benefits in either group were found [139].
Hypotonic fluids may promote edema and should be avoided.
In essence, crystalloids (normal saline) should be chosen for
fluid management of the AIS patient in most situations.
In terms of nutrition, one study addressed the energy
demand of 21 LHI patients in a group of 35 stroke patients
[140]. In these sedated and ventilated patients, the total energy
expenditure (TEE) was assessed by indirect calometry during
the first five days after admission. A strong correlation was
found between the TEE and the basal energy expenditure
(BEE), as estimated by the Harris–Benedict equation. The
study showed a lower energy expenditure in these LHI patients
than in other ICU populations.
The guiding principle in general ICU nutrition is towards a
preference for enteral over parenteral nutrition. A recent meta-
analysis demonstrated benefits of early (<24 h) initiation of
enteral nutrition [141]. Nutrition should be tailored to meeting
caloric demand while avoiding overfeeding and hyperglycemia
in AIS patients, using the Harris–Benedict equation to predict
basal energy demand. However, this formula does not provide
information on the composition or delivery method of nutri-
tion. It is probably advisable to follow general ICU principles
in AIS patients, i.e. to: (a) calculate energy (caloric) demand
and standardize caloric requirements based on height, weight,
age, and sex, (b) balance nutrition to represent the components
carbohydrate, protein, and fat (taking into account “nutri-
tional” components of some infused drugs) and supplement,
(c) start nutrition on day 2 from admission, (d) use enteral
over parenteral nutrition whenever possible.
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 Chapter 11: Ischemic Stroke
Glucose Control
Both hyperglycemia and hypoglycemia are associated with
increased morbidity and mortality in severe AIS and many
other neurocritical care conditions. So far, it remains unclear
whether systemic glucose itself is the decisive pathophysiologic
factor in these observations or just an indicator of other
compromising mechanisms. Likewise, the impact of control-
ling glucose and the best method to do so have remained
controversial in stroke patients [48] in the brain-injured ICU
population. A recent large retrospective analysis of more than
1900 mixed NCCU patients showed no benefits of tight glu-
cose control, but rather a higher rate of hypoglycemia and
higher mortality [142]. Furthermore, a recent systematic
review and meta-analysis on 16 RCTs in more than 1200 mixed
NICU patients found no mortality benefits of intensive insulin
therapy, but the association with a higher risk of hypogly-
cemia, particularly jeopardizing in the ischemic brain. How-
ever, very loose glycemic control was also associated with
worse neurologic recovery. The authors concluded that inter-
mediate glucose control (insulin therapy aiming for 140–180
mg/dL) may be most appropriate for this patient population
[143] and is also recommended in current stroke guidelines[5].
Hemoglobin Control
Anemia is associated with worse outcome in ischemic stroke, if
it is present in either the acute [144] or the subacute [145]
phase. Anemia, found in the majority of ICU patients from the
third day of admission, has also been associated with worse
outcome in brain diseases such as SAH, TBI, and ICH (for a
review see [146]). A very recent retrospective study on critic-
ally ill AIS patients revealed that almost all of these acquire
marked anemia during their NCCU course, which is then
associated with longer ICU stay and duration of ventilation
[147]. However, the optimal hemoglobin level in critically ill
AIS patients is unclear, as is the optimal red blood cell (RBC)
transfusion policy. A recent systemic review and meta-analysis
found six RCTs concerning hemoglobin levels and transfusion
in the NICU and came to the conclusion that insufficient
evidence exists to currently recommend either a restrictive or
a liberal transfusion strategy in these patients [148]. However,
AIS patients were not the subject of the trials analyzed.
Theoretically, optimizing the oxygen carrying capacity
should play a decisive role in ischemia and oligemia. The
physiological benefits of RBC transfusion suggested in neuro-
monitoring studies in TBI and SAH patients [149,150] should
be assumed for LHI patients as well. It is thus questionable if
7 g/dL hemoglobin, (a widely accepted level in general ICU
patients), is also optimal for LHI patients. However, transfu-
sion was more often found to be associated with worse out-
come in neurocritical care patients, either by being an
indicator of higher disease severity or indeed causing
harm [146]. In anemic NCCU patients with AIS, RBC trans-
fusion did not improve the situation [147]. Until more
research clarifies optimal (individual?) hemoglobin levels and
116
transfusion strategies, it is probably reasonable to use RBC
transfusion below a hemoglobin level of 7 g/dL or if systemic
or cerebral monitoring – if available – suggests a compromised
arteriovenous oxygen extraction. RBC transfusion should also
be triggered by specific situations such as planned surgery,
hemodynamic status, and bleeding. Anemia or the progression
thereof should be avoided by reducing blood sampling to the
minimum necessary, treating infection and renal disease early,
and preventing volume overload and promoting appropriate
diuresis, etc.
Deep Vein Thrombosis Prophylaxis
In a study exploring nearly 150,000 stroke patients, the inci-
dence of deep vein thrombosis (DVT) was approximately 3%,
despite a median DVT prophylaxis rate of 97% [151]. The
recent CLOTS1 trial on the prevention of DVT and pulmonary
embolism (PE) in 5632 acute stroke patients, screening sys-
tematically for DVT and PE revealed an incidence of 11.4% of
DVT in the early (7–10 days) and an additional 3.1% in the late
(25–30 days) phases of the hospital stay [152]. Of the stroke
patients with DVT, 35% were symptomatic and 5% developed
PE. The authors concluded that DVT prophylaxis has to be
started early and continued for at least four weeks. This study
confirmed and extended previous studies on this subject, but
contained only a difficult to determine portion of patients with
severe stroke (probably less than 20%). CLOTS1 showed that
thigh-length graduated compression stockings are not benefi-
cial with regard to prevention of DVT or PE when compared
to patients for whom stockings were avoided [153]. Further-
more, more skin ulcers, necrosis, and even leg ischemia were
found in the stocking group. Below-knee stockings resulted in
more DVTs than thigh-length stockings in the follow-up trial
[154]. Intermittent pneumatic compression (IPC) has recently
been investigated in CLOTS3, enrolling almost 3000 immobile
AIS patients, and was found to reduce the risk of DVT effect-
ively at the price of significantly more skin breaks, and showed a
trend to better survival [155]. Heparin is an effective preventive
strategy for DVT in patients with acute stroke and the conco-
mittant bleeding risk is outweighed by the benefits of throm-
boembolic prevention [156]. Low molecular weight heparin
appears to be superior to unfractionated heparin [157–159].
A small study in patients with ICH found that heparin could
be started safely within two days of onset without augmenting
cerebral bleeding [160], which appears reassuring with regard to
early start of low-dose heparin or LMWH in AIS patients too.
If AIS patients in general are at considerable risk of DVT
and PE, the extremely immobile, ventilated, and unconscious
LHI patient in the ICU should be at a much higher risk, even if
this has not been systematically investigated. A form of DVT
prophylaxis, installed early and continued for at least as long as
immobilization is present, appears warranted. As stockings are
of no proven benefit in stroke patients, as opposed to surgical
patients, and as patients in the ICU are more prone to skin
problems and often need access to their legs for nursing care,

positioning, or application of devices, stockings should be
avoided and IPC only very carefully considered. Although
these patients certainly have a higher bleeding risk than the
general ischemic stroke patient, this does not outweigh the
benefits of DVT and PE prophylaxis. Therfore, these patients
should receive DVT prophylaxis from admission to the ICU
and for the time of immobilization. LMWH should be used for
DVT prophylaxis. Early mobilization should be strived for in
NCCU-dependent AIS patients with a stable systemic and
cerebral physiology.
Anticoagulation
Patients with increased thromboembolic risk, e.g. due to atrial
fibrillation (AF) or a prosthetic heart valve, need reinitiation of
their oral anticoagulation, which is usually paused in the event
of a large ischemic stroke. The best point in time for this
reinstatement is highly controversial, however, as prevention
of embolism has an accompanying risk of intracerebral hemor-
rhage. Guideline recommendations on the same dilemma in
anticoagulated patients suffering an intracerebral hemorrhage
range from two days to four weeks [5,91]. In ICH patients with
prosthetic valves and withheld anticoagulation, thromboembo-
lism occurred in 3% during the first 30 days [161] and in 0% in
the first 15 days [162]. The HAEST study showed an incidence
of recurrent stroke after an initial stroke, including secondary
to atrial fibrillation, of 8.5% within 14 days in spite of LMWH
[163]. A first study on the question of heparin bridging before
oral anticoagulation in the general stroke population (4082 AF
patients with ischemic stroke or TIA) showed that heparin
bridging did not result in benefits, but prolonged hospital stay
[164]. Ischemic or hemorrhagic events were rare (2%) in this
study, in which oral anticoagulation was reinitiated early (days
4–5), but the number of patients with severe stroke in that
population can only be estimated and was likely below 20.
There is no conclusive evidence to solve this very challen-
ging problem. Recommendations regarding the best timing
differ considerably, as do the customs in different ICUs. Rein-
itiation after 7, 14, 21, or more days, bridging with heparin or
not, very different aPPT/aPTT targets when using heparin and
reanticoagulation with warfarin or new oral anticiagulants
have all been chosen and make the situation quite confusing.
These considerations may serve as a strategy: (a) the throm-
boembolic risk is low in the first two weeks, even in AF patients
with a prior stroke or a patient with a prosthetic valve, (b) the
risk of bleeding is quite high in a large stroke, (c) oral intake will
be compromised for weeks, (d) invasive procedures such as
hemicraniectomy, tracheostomy, or PEG placement do not
comply well with anticoagulation. Hence, it appears reasonable
that oral anticoagulation should be reinitiated after at most four
weeks in patients with large AIS, provided all invasive proced-
ures are completed. In selected patients with an extraordinarily
high thromboembolic risk (e.g. prosthetic valve with TEE evi-
dence of intracardiac thrombus), earlier individual therapy (e.g.
with a modest aPPT/aPTT heparin strategy) may be chosen.
Chapter 11: Ischemic Stroke
Infectious Disease Management
As in the majority of ICU patients, pneumonia is the
most common infection in intubated and ventilated stroke
patients. A single study on 236 acute ischemic stroke
patients admitted to an ICU revealed an NIHSS equal to
or greater than 10, dysphagia, or any other infection on
admission as independent risk factors for stroke-associated
pneumonia. Another risk factor, albeit not independent, was
stroke size larger than 66% of the MCA territory [165]. The
PANTHERIS trial in 80 patients with severe MCA stroke
randomized patients to either prophylactic moxifloxacin
within 36 h of onset or to placebo. The trial not only
demonstrated the prominent role of immunosuppression
in poststroke infections, but also showed a significantly
reduced infection rate in the per-protocol analysis and a
strong trend in the intention-to-treat analysis. Neurological
outcome and survival were not influenced, however [166].
The general principles for infection control and prevention,
such as line and Foley care, should be followed. The use of
an indwelling urinary catheter was associated with worse
clinical outcome at three months in nonselective ischemic
stroke patients [167], but these can hardly be avoided in
the NCCU.
The majority of patients with severe AIS, known to be
associated with stroke-associated immunosuppression [168],
will present with risk factors for pneumonia on admission or
shortly therafter. Given the high risk and association with
morbidity, early initiation of preventive strategies, such as
early intubation and/or NG tube placement, bundles of
ventilation-associated pneumonia prevention and standard
hygienic measures – even if high-quality evidence behind these
measures is scarce – seems prudent. Any infection must be
treated early, aggressively, and according to modern standards
of ICU infection control. Although the results of PANTHERIS
are intriguing, one trial is certainly not enough to justify
prophylactic antibiotics yet.
Blood Pressure Management
BP mangement in the NCCU should follow similar principles
to those applied in the ER for early stroke treatment [5].
Patients may have disturbed cerebral autoregulation, and
thus systemic alterations in blood pressure might passively
be transduced to cerebral perfusion, which has to be kept in
mind. Systemic hypotension may lead to secondary ischemia,
and hypertension to secondary hemorrhagic transformation
or edema promotion. Only neuromonitoring, e.g. ICP and
CPP, or measures of autoregulation, might help to guide
systemic blood pressure treatment. However, actualization
of this process remains theoretical and largely unresolved.
Often in the sedated AIS patient, preventing hypotension by
vasopressors and volume will dominate the early phase, while
antihypertensive measures might have to be applied later
when the patient is allowed to wake up and is weaned from
the ventilator.
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 Chapter 11: Ischemic Stroke
Temperature Management
About one-third of patients presenting with AIS will be hyper-
thermic. Fever has been associated with worse outcome in
numerous studies, and the putative effects involve increase in
metabolic demand, relase of excitatory neurotransmitters, for-
mation of free radicals, promotion of apoptosis, etc. [169,170].
Fever can be part of a nonspecific stress response, or be caused
by central hypothalamic dysregulation or infection (e.g. pneu-
monia, urinary tract infection, infective endocarditis). Obvi-
ously, infections should be searched for and treated vigorously
with antibiotics. Pharmacological measures to lower temperature
to achieve normothermia, have been neither very efficient nor
produced convincing outcome benefits. The largest randomized
trial on high-dose acetaminophen for normothermia in AIS had
to be abandoned due to lack of funding after 1400 patients. It
found no significant differences in prespecified outcomes
between the groups, which had a mean body temperature differ-
ence of 0.26 °C; in a post-hoc analysis there was a beneficial effect
for patients with a baseline temperature between 37 and 39 °C
[171]. Possibly, application of a consequent step-wise nor-
mothermia protocol involving not only acetaminophen or meta-
mizol, but also convection methods, ice-packs, ice-cold saline
infusions, or surface and endovascular cooling devices, might
achieve benefits, but that remains to be proven. Since measures
to achieve normothermia appear fairly safe, their application to
keep AIS patients at a target tempereture of 36.5–37.0 °C in the
acute phase of their NCCU stay may be reasonable.
Hypothermia as a long-standing neuroprotective principle
has been backed up by countless experimental studies and is
thought to work by reduction of metabolic and oxygen
demand, decrease in excitotoxic neurotransmitter release,
inhibition of free radical formation, and stabilization of the
blood–brain barrier, and antiedematous, anti-inflammatory,
and many other mechanisms. It can be subdivided into mild
(up to 33 °C), moderate (29–33 °C) and deep (below 29 °C)
hypothermia. It can be maintained by different surface and
endovascular, systemic, and regional cooling devices and
induced by very diverse methods, such as cooling packs, ice-
cold saline infusions, nasal and sinus cooling, etc. Established
in open heart and thoracic surgery, the only evidence-based
place for hypothermia in critical care is in cardiac arrest
patients. Even this, however, has recently been challenged by
the TTM trial, showing no significant advantages with 33 °C
hypothermia, if consequent normothermia (36 °C) was
achieved in the control group [172], possibly pointing to the
primary importance of the latter. Small clinical studies on
hypothermia in severe AIS have had mixed, at times encour-
aging, results, but a recent Cochrane analysis comes to the
conclusion that there is at present too little evidence to rou-
tinely advocate therapeutic hypothermia in AIS [173]. Poten-
tial side effects of hypothermia are cardiac arrhythmias,
electrolyte derangents, impaired coagulation, immunosuppres-
sion and infection, and rebound edema/raised ICP on rewarm-
ing. All of these appear to be less frequent under mild
compared to moderate hypothermia. Shivering, the
118
physiological response to cooling, is associated with high sys-
temic and cerebral energy demand, and has to be fought by the
wrapping of hands and feet, and drugs such as meperidine,
buspirone, or clonidine. Rewarming should not be faster than
0.1 °C/h. Current randomized trials are investigating hypother-
mia in AIS further, and will hopefully produce evidence on its
impact, indication, patient selection, target temperature and
duration, and optimal technical application over the next years.
Seizures
Seizures can occur as part of stroke onset (“immediate
seizures”) or, in the course of severe stroke, can be triggered
by hemorrhagic transformation or edema formation. Overall,
the incidence is probably around 10%. There is no data sup-
porting prophylactic anticonvulsants. Manifest seizures or
status epilepticus have to be treated as is customary in other
fields of neurology and neurocritical care [5,174].
Management of Brain Edema and Raised Intracranial
Pressure
Large AIS leads to the generation of at first cytotoxic and later
vasogenic edema, however with considerable differences in
extent and dynamics between individual patients [175]. On
average, clinically relevant edema builds up at day 2 or 3 from
onset. In posterior circulation stroke, relatively little edema can
cause dangerous tissue compression and CSF flow blockage
due to limited space in the posterior fossa of the skull. Basic
measures to prevent brain edema comprise the restriction of
free water, avoidance of hypo-osmolar fluids, avoidance of
excess glucose administration, avoidance of hypertension after
reperfusion therapies, minimization of hypoxenia and hyper-
carbia, caution in application of drugs causing cerebral vaso-
dilation, and treatment of hyperthermia. Recently, edema-
inhibitory effects of oral antidiabetics have been described in
experimental studies [176] and made the subject of a currently
ongoing trial (GAMES [177]). Another theoretical approach to
edema prevention, hypothermia, awaits further prospective
research. If clinically relevant edema occurs and is detected
by clinical signs (decline in level of consciousness, worsening
of neurological deficit, nausea and vomiting, anisocoria), ICP
monitoring, or cerebral imaging, pharmacological treatment
should be applied. Steroids are not efficient in AIS-related
edema and may have deleterious side effects for the NCCU
patient [178]. Osmotherapy, following the principle of osmot-
ically drawing fluids from the brain tissue into the blood for
removal, has been applied for more than 50 years. The two
substances with the most supportive data are mannitol and
hypertonic saline. Many other substances have been used, but
are probably dispensable. Some authors have criticized
osmotherapy for AIS-related edema therapy, postulating that
in the context of a damaged blood–brain barrier, the sub-
stances may actually collect in the tissue rather than the blood,
draw fluids from healthy tissue to infarcted tissue, and thus
increase mass effect and midline shift. Data on this theory are

inconsistent [179,180], however, and there are decades of
experience with osmotherapy in space-occupying stroke show-
ing its ICP-decreasing effect, if osmotherapeutics are applied in
a pulsatile fashion. Osmotherapy alone is very often not suffi-
cient to treat brain edema, however [181].
Every NCCU patient with severe AIS who is prone to
edema formation and particularly if clinical observation is
limited by ventilation and sedation, should have ICP measured
by parenchymal probe or external ventricular drain (if hydro-
cephalus is feared or present), and CPP calculated (CPP =
mean arterial pressure (MAP) – ICP). If ICP exceeds 25 mmHg
for more than five minutes, immediate measures to lower it
(and/or raise CPP by augmentation of MAP) should be under-
taken and cerebral imaging realized to detect the cause of the
ICP increase. Causes will be edema with mass effect and
midline shift (hemispheric stroke) or consequent hydrocepha-
lus (cerebellar stroke) in most of the cases, but may also be
secondary hemorrhage, seizures, reduced venous return, etc.
There are no specific data on optimal ICP-lowering therapy in
severe stroke, so it is recommended to follow a step-wise
approach common in other brain injuries (Table 11.9).
Management of Specific Types of Ischemic
Stroke
Large Hemispheric Infarction
Occlusion of the distal ICA or proximal MCA that has
persisted for too long or cannot be successfully recanalized
leads to infarction of the total or subtotal MCA territory,
possibly combined with infarction of the adjacent ACA
and/or PCA territory. This type of stroke is called an LHI
or “malignant” MCA infarction, because of the very poor
prognosis associated with its natural course. Patients initially
present with a severe hemisyndrome combined with aphasia
or neglect, depending on the hemisphere, and show quite
stereotypical deterioration over the first few days, such as
decline in level of consciousness and anisocoria, reflecting
swelling of the affected hemisphere. Despite maximal conser-
vative critical care efforts, the mortality rate of LHI is between
70 and 80% [1,2,182], due to massive swelling of the infarcted
area leading to horizontal displacement of the brainstem and
ICP increases within the rigid skull. Medical options to pre-
vent or reduce brain edema have been disappointing so far.
Classical osmotherapy is not sufficient to improve clinical
outcome in LHI [181].
The previously bleak perspective for these patients has
changed over the last 10 years, since recent evidence has been
obtained on the benefits of decompressive hemicraniectomy
(DHC). This surgical measure, by which a large (>12 cm)
bone flap is removed over the affected hemisphere, combined
with duroplasty, allows for outside swelling of the affected
tissue, leaving the healthy parts of the brain uncompromised
(Figure 11.3). The bone flap is stored frozen or subcutane-
ously, and reinserted after rehabilitation and shrinking of the
affected hemisphere, usually after three weeks to three months.
Chapter 11: Ischemic Stroke
Table 11.9 Suggested step-wise approach to lowering ICP in severe AIS
• Elevate head of bed to about 20°, keep neck straight to
support venous return
• Initiate or augment analgesia and sedation
• Initiate mechanical ventilation
• Consider hyperventilation, but only transiently
: Regard as short-term measure to gain time for more
definite solution
: Raise ventilation rate, aim for a PaCO2 of 30–35 mmHg
(not less!)
: Keep CPP >70 mmHg by raising MAP
• Treat conditions such as seizures, fever, hyperglycemia,
respiratory distress, etc.
• Apply osmotherapy
: Mannitol, e.g. 20%, 0.25 g/kg to 0.5 g/kg
: Hypertonic saline, e.g. 3% in 250 mL
: Pulsatile administration, guided by ICP measurements
: Monitor osmolar gap, serum sodium, renal function
• Apply barbiturates
: Pentobarbital, e.g. 10 mg/kg
: Thiopental, e.g. 1.5 mg/kg to 3.5 mg/kg
: Use continuous EEG for maintenance of burst
suppression pattern
: Anticipate hypotension, skin lesions, infections, sepsis,
coagulopathies
• Apply muscle relaxation
: Vecuronium 0.1 mg/kg
: Pancuronium 0.1 mg/kg
• Consider surgical methods
: Decompressive hemicraniectomy for large hemispheric
stroke
: Decompressive occipital trepanation for large cerebellar
stroke
: External ventricular drain for hydrocephalus (e.g. in large
cerebellar stroke)
: Hematoma evacuation for IVT-related cerebral bleeding
with mass effect
• Consider mild to moderate hypothermia
The order of steps may vary individually. Hyperventilation and barbiturate
administration can be deleterious and should be cautiously considered.
After the initial encouraging results from observational
studies [183], the pooled data on 93 patients from three Euro-
pean RCTs showed that DHC for patients <60 years suffering
from LHI leads to a reduction in mortality rate from 70 to 20%
(number needed to treat (NNT) = 2), a 40% risk reduction
for severe disability (NNT = 2), a doubled chance (20%) of
surviving with mild disability, but a risk of surviving with
moderate to severe disability of about 30% [184]. This mile-
stone evidence of survival and outcome benefits from the
procedure led to international recognition of DHC and to its
implementation into guidelines for LHI patients under 60 years
of age. Very recently, the DESTINYII trial on DHC for LHI in
112 patients >60 years confirmed a highly significant survival
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 Chapter 11: Ischemic Stroke

Figure 11.3 Large hemispheric infarction on

A B the left. (A) CCT, axial, without
hemicraniectomy, note midline shift. (B) MRI,
frontal, after hemicraniectomy, note outward
protrusion.

A B C D

12 h 24 h 40 h
Figure 11.4 Large cerebellar infarction on the left. CCTs, axial, (A) 12 h from onset, (B) 24 h from onset, (C) 40 h from onset, note compression of 4th ventricle,
(D) after decompressive occipital trepanation.

beneftit (33% versus 70%, NNT = 4) that was mainly respon- Space-Occupying Cerebellar Stroke
sible for an “outcome benefit” (mRS = 0–4, 38% versus 18%),
Large cerebellar stroke can initially present with surprisingly few
but showed survival after six months with moderate to severe
clinical cerebellar signs. With progressive swelling of infarcted
disability (mRS = 4) in 32% and with severe disability (mRS
tissue within the small posterior fossa of the rigid skull leading
= 5) in 28% of the surgical patients [185]. These data provide
to compression of the aqueduct and subsequent hydrocephalus,
fairly solid grounds for patient and family counselling on the
the patient may decline in level of consciousness, often around
option of DHC, which is a very important element of care in
the third day after onset. This situation is life-threatening and
this type of stroke. Surgical treatment of LHI involves opti-
requires rapid measures. CT score has been suggested to moni-
mal and maximal neurocritical care before and after the
tor and recognize this development [194], as well as serial
operation.
acoustic evoked potential measurements, but neither has been
Another option to reduce or prevent swelling might be
employed routinely to a noteworthy degree. Clinical monitoring
therapeutic hypothermia. Small studies have suggested that
for change in level of consciousness remains the preferred
cooling the LHI patient is safe, feasible, reduces ICP, and
approach. Data are scarce, but the mortality rate for space-
may reduce mortality to 38–50%, i.e. not as effectively as
occupying cerebellar stroke is probably at least 40%, and higher
DHC [186–189]. Whether the addition of hypothermia to
age, early decline in level of consciousness, and brainstem
DHC may further improve outcome [190] is currently being
involvement predict a poor course. Mortality may be reduced
investigated in the DEPTH-SOS trial [191]. The rewarming
by decompressive occipital trepanation (DOT) and insertion of
phase can be critical in LHI [192].
an external ventricular drain (EVD) to 25%, as far as a few small
New NCS guidelines on the critical care aspects
studies suggest [194–197] (Figure 11.4). Details of this approach
of treating patients with LHI have very recently been
remain open questions, such as optimal timing and trigger,
published [193].

120
 Chapter 11: Ischemic Stroke

extent of trepanation, coremoval of part of the atlas, coremoval
of infarcted brain tissue, order of DOT and EVD, etc. If decom-
pressive surgery is combined with maximal neurocritical care
and patients survive the acute phase, they can have a surpris-
ingly favorable clinical course with early respirator weaning and
extubation and a good eventual clinical outcome.
display the extent of brainstem involvement and evoked poten-
tials (auditory (AEP) and somatosensory (SSEP)) to show
brainstem conductivity are recommended as a basis for deci-
sions on treatment or treatment withdrawal, together with
clinical reaction of the patient to cessation of sedation.

Basilar Occlusion Ischemic Stroke from Infective Endocarditis

Occlusion of the basilar artery (BA) resulting from emboli or
local thrombosis of a BA stenosis may be detected late due to
the often stuttering and prolonged development of symptoms
as nonspecific as an unsteady gait, dizziness, or slurred speech.
Eventually, the patient may develop tetraparesis, oculomotor
deficits, and coma. Because of the very bad prognosis of this
acutely life-threatening situation, recanalization is often aimed
for by a combined approach of IVT and IAT (“bridging”
[198,199) and a longer time window for this approach
accepted (up to 12 h from onset). The use of advanced MRI
selection of patients [200] and the use of stent retrievers for
recanalization of BAO may have improved the situation [201].
Overall, however, current data does not allow for routine
preference of endovascular BAO recanalization over rapid
IVT, as the BASICs registry study has shown [202]. The acute
phase of BAO, the IAT procedure, and the ensuing NCCU
phase very often require intubation and mechanical ventilation
for disturbed consciousness and dysphagia. Early tracheos-
tomy may be warranted for the same reasons. Early MRI to
Bacterial endocarditis, much more frequent in patients with
artificial valves, immunosuppression and IV drug abuse, may
lead to septic embolic infarctions in 10–40% of cases and has to
be suspected in the ER if stroke patients present with fever, a
murmur, and suggestive skin lesions (nail splinter hemor-
rhages, petechial bleeds, Osler nodes) [203]. If these infarctions
are large or the endocarditis involved in severe sepsis, these
patients should be treated on the NCCU rather than on the
stroke unit. It is of paramount importance to rapidly establish
the diagnosis and the correct antibiotic treatment according to
current cardiology guidelines. Cardiosurgical cooperation for
valve replacement is mandated if echocardiography reveals
progressive valve destruction, very large vegetations, or uncon-
trollable systemic infection. Cardiac surgery is limited by the
cerebral situation, however, and should be postponed by two
to six weeks, if tolerable, because of the high risk of cerebral
hemorrhage [204]. Above all, IVT and anticoagulation must be
avoided since these infective ischemic infarctions tend to trans-
form hemorrhagically and may lead to fatal bleeding.

Stroke Association. Stroke 44(3): thrombolysis in patients with acute

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 Chapter
Intracerebral Hemorrhage in the Neurocritical
12 Care Unit
Xuemei Cai and Jonathan Rosand
Intracerebral hemorrhage (ICH) is nontraumatic spontaneous
bleeding into the brain parenchyma. Annually, approximately
75,000 people in the United States suffer an ICH, which
accounts for 10–30% of all stroke cases across different ethnic
groups [1–3]. ICH is the most fatal and least treatable form of
stroke with one month mortality exceeding 40% [4]. In addition,
survivors suffer severe disability [5,6]. Patients with ICH require
ICU management and patients cared for in specialized neuro-
logic intensive care units are less likely to die as a result of their
ICH [7,8]. Although, compared to ischemic stroke and sub-
arachnoid hemorrhage, the pace of advances in management
of ICH has been slow, ongoing trials in minimally invasive
surgery and optimal medical management are underway [9,10].
ICH is classified as either primary or secondary, based on
the underlying vascular pathology that causes the bleeding.
The majority (78–88%) of primary ICHs result from a rup-
tured vessel as a consequence of chronic injury to the small
cerebral vessels by sustained hypertension (hypertensive vas-
culopathy) [11–13] or abnormal protein deposition (cerebral
amyloid angiopathy) [14,15]. Secondary causes of ICH include
underlying vascular malformations, ruptured saccular aneur-
ysms, coagulation disorders, use of anticoagulants and throm-
bolytic agents, drug abuse, and hemorrhage into existing
infarction (venous or arterial), brain tumor, or infectious focus
(Table 12.1) [5,16,17].
Table 12.1 Etiology of secondary ICH
• Aneurysm
• Arteriovenous malformation
• Anticoagulant and thrombolytic use
• Cavernous angioma
• Coagulation disorder
• CNS vasculitis
• Cocaine
• Dural arteriovenous fistula
• Dural sinus thrombosis
• Hemorrhagic conversion of ischemic stroke
• Intracranial neoplasm or infection
• Moyamoya disease
Epidemiology and Risk Factors
ICH is a common disorder that occurs in all populations.
Estimates of overall incidence are 24.6 cases per 100,000 people
per year [4], slightly higher among men, young and middle-
aged African-Americans, and Asians [2]. Advanced age and
hypertension are the most prevalent ICH risk factors, account-
ing for up to 50% of cases [1,16].
Hypertensive vasculopathy is usually the result of under-
lying arteriolosclerosis (thickening and damage to the arterio-
lar wall, also referred to as fibrohyalinosis or lipohyalinosis)
[12]. The most commonly affected arteries are the deep pene-
trators (medium-small arterioles, 100–600 μm in diameter) in
the basal ganglia (putamen, caudate nucleus, or thalamus),
pons, or cerebellum [12,13,16]. Their spontaneous rupture
causes a typical pathologic and neuroimaging pattern of deep
ICH (Figure 12.1 a–d). Hypertensive vasculopathy can also
affect more superficial vessels, leading to lobar hemorrhage
(Figure 12.1e).
Cerebral amyloid angiopathy (CAA) is the second most
common cause of primary ICH, and may account for up to
35% of cases [1,15]. This angiopathy results from dynamic
deposition of β-amyloid peptide within the walls of small-to-
medium size vessels of the brain and leptomeninges [18–20].
Amyloid deposits contribute to vessel fragility and lead to spon-
taneous rupture, causing distinct pathological and neuro-
imaging patterns of lobar hemorrhages [20], as well as
microhemorrhages identified by MRI (Figure 12.2) [20–22].
CAA-associated ICH carries a high risk of recurrence (10–20%
per year) [20–22]. In contrast, the risk of recurrent hypertensive
ICH can be less than 2% per year, provided that hypertension
is well controlled [23,24]. Other risk factors for ICH
include age, antithrombotic/anticoagulant use, liver disease,
excessive alcohol consumption, sympathomimetic use, and
hypocholesterolemia [1,4,5,25].
Accumulated evidence now convincingly demonstrates
that inherited genetic variation substantially influences the risk
of ICH [26]. Only a fraction of the genetic variants that affect
ICH have been discovered thus far, but those that have been
identified appear to render their effects in multiple different
ways. There are those that appear to influence ICH risk by
acting on blood pressure, or on risk of CAA, while there are
those that appear to act through different, yet to be elucidated
pathways [27–29].
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 Chapter 12: Intracerebral Hemorrhage
Pathophysiology
Intracerebral hemorrhage is a dynamic multistep process
involving cerebral vessel rupture, secondary hematoma expan-
sion, and subacute inflammation [17]. The precise mechan-
isms of early hematoma expansion are still poorly understood.
Following initial vessel rupture, the accumulating volume of
extravasated blood contributes to sudden rise in intracranial
pressure (ICP), associated tissue distortion, and breakdown in
blood–brain barrier leading, possibly, to secondary foci of
hemorrhage at the periphery of the initial hematoma [30]. In
addition, early tissue ischemia and poor venous outflow, as
well as propensity for local coagulopathy due to the role of
plasmin and fibrin degradation products, along with continued
bleeding from the primary ruptured vessel have been suggested
as possible contributors to expansion of the initial clot [31–33].
Early hematoma growth is a common and deleterious event
associated with high neurologic morbidity and poor clinical
130
Figure 12.1 Intracerebral hemorrhage. Axial CT
scans from five patients demonstrate ICH in the
basal ganglia (a), thalamus (b), pons (c), cerebellum
(d), and the lobar brain regions (e).
Figure 12.2 MRI characteristics of cerebral
amyloid angiopathy. This patient’s head CT
revealed a left frontoparietal lobar hemorrhage (left
panel). Follow-up gradient-echo (susceptibility)
sequenced MRI revealed numerous punctate
microhemorrhages (right panel), suggesting
underlying cerebral amyloid angiopathy. (Adapted
from Goldstein JN, Greenberg SM, Rosand J. Emergency
management of intracerebral hemorrhage. Continuum
2006;12(1):13–29.)
outcome [34,35] (Figure 12.3). For each 10% increase in hema-
toma growth in ICH patients, there is a 5% increased hazard of
death and a 16% greater likelihood of worse functional outcome
[35]. Based on computed tomography (CT) data, more than
one-third of ICH patients whose initial CT scan is obtained
within three hours of symptom onset, develop a clinically
significant increase in hematoma volume (>33%) [35,36].
Hematoma expansion is also detected in those who present
beyond three hours, although with reduced frequency [37].
The primary mechanism of injury due to ICH appears to be
mass effect from the hematoma itself [34,35]. As measured by
poor functional outcome, the neurologic damage is propor-
tional to the volume of hematoma, i.e. the amount of blood
that extravasates from the ruptured vessel intraparenchymally
[34–36). When ICH occurs in patients receiving anticoagula-
tion, hematoma expansion has been observed in half of
patients, regardless of time of presentation [36]. This expansion
 Chapter 12: Intracerebral Hemorrhage

appears to be an important contributor to the high mortality of Table 12.2 The ICH score
warfarin-related ICH [33,37]. Component of ICH score Points
The significance of perihematomal hypodensity often
observed on CT remains poorly understood [38,39]. This GCS score
hypodensity, often referred to as edema, appears as early as 3–4 2
one hour after the bleeding event and can persist up to two 5–12 1
weeks or more [38,40]. It may result from the extrusion of
plasma that results from clot formation [41] and/or the inflam- 13–15 0
3
matory response to cerebral clot formation, when thrombin- ICH volume, cm
rich plasma permeates brain parenchyma and triggers an 30 1
inflammatory cascade with activation and expression of cyto-
toxins, inflammatory mediators, induction of matrix metallo- <30 0
proteases [42,43], leukocyte recruitment [43], and disruption IVH
of the blood–brain barrier [44,45]. Yes 1
No 0
Prognosis Infratentorial origin of ICH
ICH is one of the deadliest acute neurologic disorders, with
Yes 1
one-year mortality rates approaching 50% [5,46]. The majority
of patients who survive have some degree of residual neurolo- No 0
gic disability, with only 20% regaining independence within six Age, years
months [46].
80 1
Hematoma volume and expansion, Glasgow Coma Score
(GCS) or National Institutes of Health Stroke Scale (NIHSS) <80 0
on presentation, intraventricular extension, anticoagulant use, Total ICH score 0–6:
advanced age, and infratentorial location of the hemorrhage
Score 30-day mortality
appear to predict 30-day and one-year mortalities [37,47,48].
The ICH score comprises GCS, ICH volume, presence of IVH 0 0%
and/or infratentorial blood, and age to grade ICH and to 1 13%
predict 30-day mortality (Table 12.2) [48]. However, because
2 26%
withdrawal of aggressive measures is commonly sought by
family members and physicians in the setting of ICH, clinical 3 72%
care withdrawn from patients within the first 24 hours 4 97%
becomes the single most important predictor of survival after
5 100%
ICH [7]. This last point requires careful consideration because
No patient, in this study or others, has received a score of 6. This likely reflects
physicians’ judgment of poor prognosis remains imprecise, the fact that infratentorial hematomas have a limited space in which to
raising the possibility that bias introduced by “self-fulfilling expand to >60 mL of blood. (Adapted from Hemphill JC 3rd, Bonovich DC,
prophecies” probably affects most studies of ICH outcome Besmertis L, et al. The ICH score: a simple, reliable grading scale for
intracerebral hemorrhage. Stroke. 2001;32:891–7.)
[49,50]. Current guidelines from the American Stroke

Figure 12.3 Early hematoma expansion. Initial CT

scan taken 50 minutes after symptom onset (a)
showing right-sided cerebral hematoma, which is
significantly increased on repeat head CT at
160 minutes (b), including intraventricular
extension.

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 Chapter 12: Intracerebral Hemorrhage

Association recommend that new care-limiting orders such as that total to a score value corresponding to the percentage
do-not-resuscitate orders be considered only once the second probability of achieving functional independence (GCS greater
full day of care is provided and should not limit appropriate than or equal to 4) at 90 days [51]. Furthermore, to remove
medical and surgical interventions. Note these guidelines do the care-withdrawal bias, the score was also validated in ICH
not cover patients with pre-existing limitation-of-care orders. survivors after 90 days. More recently published data on
Furthermore, the key question for most patients and their the ICH score also shows that it stratifies patients based on
family members is not the likelihood of death, but the likeli- functional outcome based on modified Rankin scale up to
hood of long-term disability should the patient survive. The 12 months posthemorrhage [52].
FUNC score is a clinical assessment tool designed to predict at
admission which patients with ICH are likely to attain func- Diagnosis
tional independence at 90 days following ICH (Table 12.3)
ICH should be considered in any patient with acute and rapidly
[51]. The components of the FUNC score include age, GCS,
developing focal neurologic deficits, particularly when there are
ICH location, ICH volume, and pre-ICH cognitive impairment
signs or symptoms of rising ICP (headache, decreased levels of
arousal, nausea and vomiting) [1,5,53]. Emergent evaluation
Table 12.3 The FUNC score with head CT should be initiated immediately.
Noncontrast head CT scan is a highly sensitive and specific
Component of FUNC score Points
neuroimaging tool in diagnosis of ICH [54–56].
3
ICH volume (cm ) Hematoma location, size, intraventricular extension, pres-
<30 4 ence of hydrocephalus, and/or mass effect can be quickly and
reliably assessed on CT alone. ICH volume can be estimated by
30–60 2 using the ABC/2 method [57,58], where A is the greatest
>60 0 hemorrhage diameter by CT, B is the diameter 90° to A, and
Age, years C is the approximate number of CT slices with hemorrhage
multiplied by slice thickness in cm (Figure 12.4). The 2018
<70 2 AHA/ASA ICH Performance Measures outline recommenda-
70–79 1 tions that an established method such as ABC/2 be used to
80 0 establish baseline severity score (such as ICH score) [59].
ICH location
Lobar 2
Deep 1
Infratentorial 0
GCS
9 2
8 0
Pre-ICH cognitive impairment
No 1
Yes 0
Total FUNC score 0–11:
Score % Functionally independent at 90 days
Entire cohort Survivors only
0–4 0 0
5–7 13 29
8 42 48
9–10 66 75
11 82 95 Figure 12.4 Using the ABC/2 method for ICH volume measurement. On axial
(Adapted from Rost NS, Smith EE, Chang Y, et al. Prediction of functional head CT, multiply A = largest hematoma diameter (curved left arrow), B =
outcome in patients with primary intracerebral hemorrhage: the FUNC score. largest diameter perpendicular to A (thin arrow), and C = number of slices
Stroke. 2008;39:2304–2309.) containing ICH (each is usually 0.5 cm) and divide total by 2. Volume is
expressed in milliliters.

132

If an underlying aneurysm or arteriovenous malformation
(AVM) is suspected, CT angiography (CTA) or catheter angi-
ography will provide diagnostic information [56,59,60]. In
recent years, CTA has emerged as a well-tolerated, noninvasive,
rapid, and widely available diagnostic test for the detection of
underlying structural abnormalities in ICH. For these reasons,
CT angiography is now frequency performed prior to conven-
tional angiography.
Recent literature shows that CT angiography has high accur-
acy in detecting intracranial aneurysms larger than 4 mm in size
(92–100% sensitivity); however, even with higher-resolution
multidetector CT scanners, the sensitivity for smaller aneurysms
(<4 mm) is lower, in the range of 74–92% [61].
As a general rule, angiography should be especially con-
sidered in those patients <55 years old without chronic hyper-
tension or whose neuroimaging characteristics of the hematoma
include atypical topographical and morphometric features [62].
For example, peri-sylvian fissure hemorrhage may frequently
Chapter 12: Intracerebral Hemorrhage
Figure 12.5 Left Sylvian fissure hemorrhage (left
panel) obscuring left middle cerebral artery
aneurysm diagnosed by angiography (right panel).
(Adapted from Goldstein JN, Greenberg SM, Rosand
J. Emergency management of intracerebral hemorrhage.
Continuum 2006;12(1):13–29.)
Figure 12.6 Right Sylvian fissure hemorrhage (left
panel) obscuring right lenticulostriate artery
aneurysm (white arrow) shown on a 3D
reconstruction based on conventional angiography
(right panel).
obscure MCA aneurysm (Figure 12.5) or lenticulostriate artery
aneurysm as an underlying etiology (Figure 12.6).
Vascular anomalies producing ICH may be small and can
be missed on the initial angiogram if the ruptured aneurysm is
thrombosed or if the feeding vessel develops vasopasm. Repeat
angiography may be beneficial in establishing the presence of
an underlying vascular malformation [63].
MRI can be as sensitive as CT in detecting blood products
without loss of specificity [59]; however, its role in ICH is
currently limited to the nonacute setting since it seldom offers
information unavailable from CT that can assist with acute
decision-making.
MRI is most frequently used as an adjunct tool to elucidate
an underlying etiology (e.g. evidence of microhemorrhages
consistent with CAA, presence of AVM or venous cavernoma,
evidence of hemorrhagic conversion of ischemic infarction, or
potentially, causal hemorrhagic neoplasm) [56,64,65]. MRI
may frequently be delayed to allow for better visualization of
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brain parenchyma, as the blood products continue to be Table 12.4 Sample rapid sequence intubation (RSI) for patients at risk for
elevated intracranial pressure
reabsorbed for up to 8–12 weeks after the acute ICH.
Time Step
Management Zero minus 10 minutes Preparation
Current management of ICH focuses on urgent support of
vital function, prevention of hematoma expansion, reduction Zero minus 5 minutes Preoxygenation (100% O2 for 5
of mass effect, minimizing of secondary neurologic injury, and minutes)
prevention of nosocomial complications [66]. This approach is Zero minus 3 minutes Pretreatment
usually taken in several integrated steps: Vecuronium 0.01 mg/kga
• Urgent clinical and radiographic evaluation, leading to a Lidocaine 1.5 mg/kg
diagnosis of ICH Fentanyl 3 μg/kg (slowly)
• Airway and circulation support Zero Paralysis with induction
• Reversing coagulopathy and consideration of acute Etomidate 0.3 mg/kgb
hemostatic therapy, should it become available
Succinylcholine 1.5mg/kga
• Controlling blood pressure
• Preventing hyperglycemia, hypotension, and pyrexia Zero plus 45 seconds Placement
• Management of elevated ICP Sellick’s maneuver
• Seizure prophylaxis Laryngoscopy with intubation
• Neurosurgical evaluation End-tidal CO2 confirmation
• Admission to an intensive care unit or dedicated stroke Zero plus 2 minutes Postintubation management
unit with physician and nursing neuroscience acute care Ventilation
expertise. a
May substitute rocuronium 1.0 mg/kg or vecuronium 0.15 mg/kg for
1. Assess vital functions. Any patient arriving to the succinylcholine. If so, omit vecuronium during pretreatment.
b
hospital with suspected cerebral hemorrhage constitutes an May substitute thiopental 3.0 mg/kg for etomidate in patients who are
hemodynamically stable or hypertensive.
emergency. Initial management includes a swift clinical evalu- (Reprinted with permission from Walls RM. Airway. In: Marx JA, ed. Rosen’s
ation, including assessment of the patient’s ability to protect Emergency Medicine: Concepts and Clinical Practice. 5th edition. St. Lois: C.V.
his or her airway. Early intubation is essential for patients with Mosby, 2002: 2–21. Copyright Elsevier (2002).)
impaired arousal, which raises risk of aspiration, hypoxemia,
and hypercarbia [67]. For this purpose, ultra-short-acting
neuromuscular blockade or sedative-hypnotics agents are pre-
ferred to allow for rapid return of motor control and assess-
ment of neurologic deficits (Table 12.4) [68]. 4. STAT laboratory investigation. Prothrombin time/
Since the act of endotracheal intubation may cause transient international normalized ratio (PT/INR), partial thrombo-
ICP elevation and, as such, contribute to worsening of plastin time (PTT), complete blood count (CBC) with plate-
mass effect or development of cerebral ischemia due to reduction lets, D-dimer, fibrinogen, electrolytes, blood urea nitrogen/
in cerebral blood flow (CBF), special care should be taken to creatinine (BUN/Cr), glucose, liver function tests, type and
choose medications that will minimize this effect (Table 12.5) screen to blood bank, toxicology screen for young patients or
[69]. those with history of substance abuse. Each of these labora-
Etomidate is known to have the least impact on blood pressure tory values may have an impact on diagnosis or management
and should be used for induction. Although thiopental has of ICH.
cerebroprotective and anticonvulsant properties, its use should 5. Arrange for STAT head CT scan. Topographic and
be limited in patients with ICH due to its tendency to cause morphologic properties of the hematoma (volume, location,
hypotension because of its venodilatory and myocardial mass effect, midline shift, associated abnormalities within the
depressor effects. If paralysis is used with induction, pretreat- brain suggestive of secondary ICH) will alert the viewer to the
ment with a defasciculating dose of a competitive neuromus- etiology of the ICH and its further management [53–56]. The
cular blocker (e.g., pancuronium or vecuronium) should be ABC/2 method can rapidly and reliably estimate ICH volume
administered before succinylcholine dose. (Figure 12.4) [57].
2. Measure GCS, FUNC score, and ICH score (Tables 12.2, Consider performing CT angiography, which may be
12.3, and 12.6). 2018 AHA/ASA Performance Measure for helpful in identifying an underlying vascular lesion. Further-
ICH include measuring a baseline severity score within six more, contrast extravasation on CT angiography (“spot sign”)
hours of hospital arrival [59]. can help predict hematoma expansion in ICH (Figure 12.7)
3. Establish acute comorbidities (acute myocardial injury, [70,71].
hypertensive emergency, arrhythmia, blood dyscrasia, etc.) 6. Neurosurgical evaluation. Cerebellar ICH is a neuro-
based on initial clinical exam and vital signs monitoring. surgical emergency [72]. Indications for surgery include ICH

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Table 12.5 Sedating agents for the mechanically ventilated patient

Agent Class Dose Frequency of dosing

Propofol Alkylphenol 5–80 µg/kg/min Continuous infusion
Fentanyl Opioid 2–3 µg/kg q0.5–1 h
Morphine Opioid 0.01–0.15 mg/kg q1–2 h
Hydromorphone Opioid 10–30 µg/kg q1–2 h
Midazolam Benzodiazepine 0.02–0.1 mg/kg q0.5–2 h
Diazepam Benzodiazepine 0.03–0.1 mg/kg q0.5–6 h
Lorazepam Benzodiazepine 0.02–0.06 mg/kg q2–6 h
(Adapted from Goldstein JN, Greenberg SM, Rosand J.Emergency management of intracerebral hemorrhage. Continuum. 2006;12(1):13–29.)

Table 12.6 Glasgow Coma Scale

Best motor Best verbal Best eye-opening

response response response
Obeys Oriented (5) Spontaneously
commands (6) open (4)
Localizes to Confused (4) Opens to speech (3)
pain (5)
Withdraws to Inappropriate Opens to pain (2)
pain (4) words (3)
Flexion to Incomprehensible (2) None (1)
pain (3)
Extension to None (1)
pain (2)
None (1)
Points are in parentheses. (Adapted from Teasdale G, Jennet B. Assessment
of coma and impaired consciousness: a practical scale. Lancet. 1974;2:81–84.)

>3 cm in diameter, brainstem compression, and hydrocepha-

lus [73]. External ventricular drain placement alone is usually
insufficient in cerebellar hematoma with 4th ventricle com-
pression. While there is no randomized controlled trial data
suggesting cerebellar ICH evacuation is beneficial, case series
data suggests improved outcomes and mortality with surgery
compared to medical management [74,75].
For patients with supratentorial ICH, indications for sur-
gery are less clear. For ICH in a superficial lobar distribution
without intraventricular extension, there may be a small sur-
vival benefit to early surgical evacuation according to the
STICH II (Surgical Trial in IntraCerebral Hemorrhage II) trial
when compared to standard conservative management [76].
Previous randomized studies have not demonstrated signifi-
cant benefit to hematoma evacuation, particularly in those
with ICH >1 cm from cortical surface or GSC >8, who had
worsened outcomes with surgery [80]. In select patients,
neurosurgical intervention is worth considering; in particular,
young patients with large lobar hematomas, who deteriorate
Figure 12.7 CT angiogram with spot sign (arrows).
rapidly due to mass effect, are likely to benefit from craniot-
omy with hematoma evacuation and duraplasty to follow.
Also on the horizon are new minimally invasive techniques
for hematoma evacuation including endoscopic-enhanced
aspiration or thrombolytic-enhanced aspiration. Some of these
procedures make use of CT-stereotactic guidance. Small
numbers of trials have demonstrated improved clot evacuation
and decreased mortality without improvement in functional
outcomes [78–79]. Larger clinical trials are underway to fur-
ther study these minimally invasive techniques as an effective
treatment option for ICH [80].
External ventricular drains (EVDs) are frequently used in
patients with intraventricular hemorrhage, as well as in those

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Table 12.7 Differential diagnosis of ICH

Spontaneous (primary) ICH • No suspicion for underlying lesion

ICH secondary to aneurysmal rupture
ICH secondary to underlying tumor, AVM, cavernous
malformation, or venous sinus thrombosis
Hemorrhagic conversion of ischemic infarction
(Adapted from the MGH Acute Stroke Service Guidelines for Emergency Department Management of Brain Hemorrhage (www.stopstroke.org).)
• No further radiologic studies may be necessary
• Likely etiology: HTN versus CAA
• Considered when the hematoma is situated in the peri-sylvian region or extends
down to a vessel of the circle of Willis or has an unusual morphology
• CTA or other vascular imaging should be performed
• If an aneurysm is confirmed, contact neurosurgery immediately and follow SAH
guidelines for BP and airway control
• Additional brain imaging is necessary to exclude an underlying lesion
• Both contrast CT or contrast MRI may be useful initially and several weeks later
once hemorrhage products have begun to be reabsorbed
• Management of each condition will depend on underlying etiology
• Additional brain imaging with MRI (and diffusion-weighted imaging (DWI) if
available) may be needed to confirm the underlying ischemic etiology in regions
that were not subject to hemorrhagic transformation
• Regions of subtle petechial hemorrhage that are not visible on unenhanced CT,
but easily seen on MR gradient echo susceptibility sequences, have an unclear
significance with respect to initiation of antithrombotic therapy
• If acute ischemic stroke is suspected (onset <12 hours), contact acute stroke
team immediately

with suspected elevated ICP, deteriorating levels of conscious-
ness, CT evidence of mass effect or hydrocephalus, and in
patients in whom neurologic examination cannot be followed.
Patients with intraventricular blood may benefit from direct
application of thrombolytic agents through indwelling ven-
tricular catheters [81].
7. Consider the differential diagnosis based on the pre-
liminary evaluation (Table 12.7). Based on the ICH etiology,
specific management guidelines will apply.
8. Correct coagulopathy. There are multiple sources of
coagulopathy that may contribute to hemorrhage and hema-
toma expansion, including blood dyscrasias (thrombocyto-
penia, prolonged PT/PTT associated with liver failure,
platelet dysfunction from chronic kidney disease, and poor
nutritional status) as well as anticoagulation with heparin,
heparinoids, warfarin, or other oral anticoagulants. Antiplate-
let agents increase the risk of ICH slightly [82], but their effect
on outcome appears to be limited [37]. Management of these
conditions is addressed separately.
Anticoagulation with warfarin increases the risk of ICH and
worsens the severity of disease, approximately doubling its
mortality [33,83]. This mortality appears to be related to hema-
toma expansion due to prolonged bleeding, which is commonly
observed in patients with anticoagulation-related ICH [32,33,84].
Therefore, early reversal of coagulopathy, although of unproven
benefit, is critical [85] and 2018 AHA/ASA Performance Metrics
for ICH includes patients with INR >1.4 from warfarin treat-
ment receiving therapy to replace vitamin-K-dependent clotting
factors (PCC or FFP) within 90 minutes of ED presentation in
addition to IV vitamin K. Reversal of anticoagulation is usually
achieved by concomitant administration of clotting factor
replacement therapy and vitamin K, since clotting factors have
a limited half-life (Table 12.8).
Currently no widespread formal practice guidelines exist
for the emergent management of warfarin-related ICH due
to lack of clinical trial data. Most authors recommend fresh
frozen plasma (FFP) or a concentrate of specific clotting factors
as a means of early repletion of vitamin-K-dependent clotting
factors [86,87]. Prothrombin complex concentrate (PCC) is a
combination of clotting factors whose production is normally
inhibited by warfarin – including factors II, VII, IX, and
X. Prothrombin complex concentrate has been shown to rapidly
reverse the effects of vitamin K antagonists, as measured by
INR, and factor levels in patients with major bleeding [88].
Administration of FFP at 10 mL/kg is very rarely associated
with a risk of transfusion reaction, volume overload, and
congestive heart failure. Depending on the clinical condition
of the patient, however, judicious administration of diuretics
may be indicated [89]. If FFP is administered without con-
comitant vitamin K, the effect will dissipate in 6–8 hours. FFP
should therefore never be used without concomitant vitamin
K for ICH.
Intravenous vitamin K is the preferred route of adminis-
tration, due to its accelerated absorption, and oral vitamin
K should always be administered when the intravenous route
is unavailable [87]. When administered at a rate not exceeding

136

Table 12.8 Sample guidelines for emergent reversal of coagulopathy
in ICH
Patients on warfarin:
1. Administer fresh frozen plasma (FFP) 10 mL/kg over 90
minutes.
a. Each unit of FFP contains 200 mL
b. Prothrombin complex concentrate (dosed by INR) can be
substituted:
If INR <4, 25 units/kg (max 2500 units)
If INR 4–6, 35 units/kg (max 3500 units)
If INR >6, 50 units/kg (max 5000 units)
2. Administer vitamin K 10 mg IV over 10 minutes
3. Repeat INR at 4 hours:
a. If INR is >1.3, administer a second dose of FFP (10 mL/kg over
90 minutes)
b. Otherwise, check INR every 6 hours for 24 hours
4. Repeat INR at 8 hours:
a. If INR is still >1.3, evaluate for disseminated intravascular
coagulation (DIC)
b. Otherwise, check INR every 6 hours for 24 hours
Patients on heparin:
Administer protamine 10–50 mg IVP over 1–3 minutes
Patients with platelet disorders:
1. Thrombocytopenia (platelet count <100,000/µL):
a. Consider platelet transfusion depending upon severity
2. Von Willebrand syndromes:
a. Administer 0.3 µg/kg DDAVP IV over 30 minutes
b. Consider VWF factor concentrate
3. Recent antiplatelet agent use such as ASA or clopidogrel:
a. Consider 1 dose (6 unit equivalent) of platelets.
Current guidelines for our institution can be found at www.stopstroke.org.
1 mg/min, it is associated with a very small risk of severe
allergic reaction [86,87,89].
Reversal of anticoagulation by any means (vitamin K, FFP,
or PCC) is associated with a risk of thrombosis depending on
the patient’s underlying indication for anticoagulation.
Regardless of the choice of agent and protocol used, frequent
re-evaluation of the INR is critical to guide continued correc-
tion of coagulopathy [87,89]. Follow-up therapy should
include a STAT PT/INR every 4 hours during the first 24 hours
of hospitalization, then every 6 hours up to 36 hours of
hospitalization, and then as needed.
If the INR is more than 1.4 at four hours, a second dose of
vitamin K 10 mg IV can be given, as well as a second dose of
FFP (10 ml/kg over 90 minutes). If the INR remains above 1.4
at eight hours, the possibility of disseminated intravascular
coagulation should be considered.
Anticoagulation with standard (unfractionated) heparin
may similarly increase risk of continued bleeding and
Chapter 12: Intracerebral Hemorrhage
hematoma expansion and it is prudent to initiate its immediate
reversal with protamine sulfate, a specific antidote, which is
administered at a dose of 1.0–1.5 mg per 100 units/h of
heparin, if administered within 30 minutes of cessation of
heparin infusion, or 0.5 mg of protamine sulfate for every
100 units/h of heparin, if administered between 30 and
45 minutes of cessation of heparin infusion. There is a risk
of anaphylactic reaction to protamine, especially in diabetic
patients who have been exposed to insulin. Of note, FFP is
equally effective for temporary reversal of heparin effects but
its use is nonspecific and inefficient due to heparin’s short half-
life [86,87,89].
The plasma half-life of heparin averages 1–2 hours in
healthy adults. However, the half-life of the drug increases
with increasing doses. After IV administration of heparin
sodium 100, 200, or 400 units/kg, the plasma half-life of the
drug averages 56, 96, and 152 minutes, respectively. The
plasma half-life of the drug is decreased in patients with liver
impairment, but may be prolonged in cirrhotic patients. In
anephric patients or patients with severe renal impairment, the
half-life of heparin may be slightly prolonged.
Thus, to follow up initial treatment, STAT PTT every hour
for the next four hours, and then every four hours through
12 hours of hospitalization, and then at least every 24 hours for
three days of hospitalization is required [90].
9. Other anticoagulation agents. Strategies for reversal
of low molecular weight heparin (LMWH) should include
protamine sulfate, although it only negates about 60% of
the antifactor Xa activity of LMWH. Protamine, however, has
negligible effects on danaparoid (a mixture of anticoagulant
glycosaminoglycans used to treat heparin-induced thrombo-
cytopenia) and fondaparinux (a synthetic antithrombin-binding
pentasaccharide with exclusive antifactor Xa activity). For
patients who have received enoxaparin, use 1 mg of protamine
for each milligram of enoxaparin; if PTT is prolonged 2–4 hours
after the first dose, consider additional dose of 0.5 mg for each
milligram of enoxaparin. With dalteparin or tinzaparin: 1 mg of
protamine for each 100 anti-Xa IU of dalteparin or tinzaparin; if
the PTT is prolonged 2–4 hours after first dose, consider add-
itional dose of 0.5 mg for each 100 anti-Xa IU of dalteparin or
tinzaparin [86,87,89,90].
Darcuizumab now has been approved to reverse dabiga-
tran. Antifibrinolytic agents, such as ε-aminocaproic acid
(Amicar) can also be considered [91]. Dabigatran is an oral
direct thrombin inhibitor which in the Re-LY study (at both
150 mg BID and 110 mg BID dosing) had a third of the risk of
ICH compared to warfarin when used for primary prevention
of ischemic stroke in atrial fibrillation [92]. The serum half-life
of dabigatran is 12–17 hours (up to 34 hours in cases of severe
renal impairment); 80% of the dose is renally excreted [92].
A possible but invasive method of reversal is dialysis, although
one-third of dabigatran is plasma protein bound and therefore
cannot be dialyzed [93]. No other specific antedote for dabiga-
tran currently exists. Recombinant factor VIIa has been studied
137
 Chapter 12: Intracerebral Hemorrhage
in animal models with reduction in bleeding time, but failed to
prevent hematoma expansion in a mouse model of ICH [94].
PCC does not appear to be effective in reversing the anticoagu-
lant action of dabigatran [95].
Andexanet alpha is a modified recombinant factor Xa
molecule that reverses oral direct and injectable indirect
factor Xa inhibitors. Rivaroxaban and apixaban are highly
protein bound, thus dialysis is ineffective in removing both
drugs [96,97). There is no human data available for efficacy
of recombinant activated factor VII in this setting [98].
There is limited human data showing 50 IU/kg dose of
PCC product restores thrombin potential and normalizes
prothrombin time in healthy subjects who were adminis-
tered rivaroxaban [95], although reversing the actual bleed-
ing tendency of patients on rivaroxaban remains to be
studied. There is no human data available for treatment of
the coagulant effect of apixaban [99]. However, in the ARIS-
TOTLE study comparing warfarin to apixaban for primary
stroke prevention in atrial fibrillation, there was a 49%
reduction in ICH risk in patients on apixaban compared to
warfarin (100).
Platelet disorders are managed based on the underlying
etiology. Our practice is to reserve platelet transfusion for
patients who are taking acetylsalicylic acid (ASA) in addition
to warfarin [90]. There are no data to suggest whether platelet
repletion is required, if patients are using other agents with
antiplatelet action (ADP inhibitors such as clopidogrel and
ticlopidine, PDE III inhibitors such as cilostazol, IIb/IIIa
inhibitors such as abciximab, ebtifibatide, and tirofiban, and
adenosine reuptake inhibitors such as dipyridamole).
Among noniatrogenic platelet disorders, thrombocytopenia
(platelet count <100,000/µL) is treated with repeated platelet
transfusion until the platelet count exceeds 100,000/µL [90].
Patients with von Willebrand syndrome should be given 0.3
μg/kg DDAVP as an intravenous infusion over 30 minutes.
Transfusion of von Willebrand factor concentrate should then
be administered, in consultation with a transfusion medicine
or hematology specialist. DDAVP is also known to benefit
patients with uremic platelet dysfunction [101], congenital
platelet function disorders, and recent ingestion of antiplatelet
agent combination (e.g. ASA and clopidogrel).
The mechanism of action of DDAVP is thought to be of a
general endothelial stimulant for factor VIII, prostaglandin I2, and
plasminogen-activated release. This direct and local effect on vessel
walls may produce an increase in platelet adhesion, and thus
decrease the bleeding time in patients with platelet dysfunction.
Resuming anticoagulation and timing of resumption are still
debated. A recent meta-analysis of observational studies in
VKA-associated found that resuming anticoagulation in the
setting of atrial fibrillation in ICH survivors protects against
future ischemic events better than antiplatelet agents without
concurrent increased risk of recurrent ICH [91]. In the absence
of randomized trials that include the newer oral anticoagulants,
decision-making must balance the risk of rebleeding from ICH
and the benefit of anticoagulation on an individual basis.
138
10. Management of hypertension. Controversy surrounds
the initial treatment of hypertension in patients with acute
ICH, due in part to conflicting data suggesting both decrease
and increase in mortality associated with such treatment [102–
104]. Acute ICH patients commonly have elevated blood pres-
sure (BP) [105]. BP elevation has, in some studies, been shown
to be associated with increased risk of neurologic deterioration
and poor outcome [105,106], leading to long-standing recom-
mendations for BP reduction in acute ICH. High BP has also
been observed in patients with hematoma expansion; however,
there is no conclusive evidence of whether this raised BP is a
cause or consequence of this expansion [102].
While lowering of blood pressure in acute ICH is hypo-
thetically aimed at minimizing risk of hematoma expansion,
this BP reduction may also reduce cerebral blood flow (CBF)
and, consequently, contribute to ischemia in already com-
promised cerebral parenchyma [103,104,107]. Aggressive BP
management can be associated with simultaneous DWI lesions
on MRI and possible increase in ischemic lesions both peri-
hematoma and distant to the hematoma [108,109].
Recent trials exploring BP reduction in ICH include
INTERACT II (Intensive Blood Pressure Reduction in Acute
Cerebral Hemorrhage Trial 2) and ATACH II (Antihypertensive
Treatment in Acute Cerebral Hemorrhage 2). INTERACT II is a
Phase 3 clinical trial of early aggressive SBP goal <140 mmHg
versus conservative SBP control <180 mmHg. INTERACT II
suggests aggressive SBP control led to a 13% reduction in bad
outcome (defined as Modified Rankin Scale (mRS) of 3–6) and a
trend towards decrease in hematoma growth although neither of
these outcomes reached clinical significance [110]. There was no
increase in adverse events in the treatment group randomized to
aggressive BP control. ATACH II was a multicenter, randomized
Phase 3 trial to determine the efficacy of early, intensive, anti-
hypertensive treatment using intravenous (IV) nicardipine initi-
ated within three hours of onset of ICH and continued for the
next 24 hours in subjects with spontaneous supratentorial ICH.
The primary hypothesis is that SBP reduction to 110–139 mmHg
reduces the likelihood of death or disability at three months after
ICH, defined by an mRS of 4–6, by at least 10% absolute
compared to standard SBP reduction to 140–179 mmHg [111].
The two arms in ATACHII showed no difference in mortality or
disability, but increased renal adverse events in the more inten-
sive BP cohort (9% versus 4%) [112]. A standard approach to BP
management in patients with severely elevated pressures has
been proposed and is currently summarized in the American
Heart Association/American Stroke Association 2015 Guidelines
(Table 12.9), although these guidelines were published prior
to publication of ATACHII. Currently in practice, most neuro-
intensivists favor lowering blood pressure to a target of 140–160
mmHg in those presenting with initial SBP <220 mmHg.
An ideal antihypertensive agent in acute ICH would min-
imize cerebral vasodilatation in order to prevent increase in
cerebral blood volume (CBV), ICP increase, and CBF decrease
(Table 12.10) [90]. Among widely available medications, labe-
talol carries the fewest cerebrovascular side effects and is the

Table 12.9 American Heart Association/American Stroke Association
recommendations for blood pressure management in spontaneous ICH
• If SBP 150–220 mmHg and no contraindications to acute BP
treatment, acute lowering of SBP to 140 mmHg is safe
• If SBP >220 mmHg, consider aggressive reduction of BP with
continuous intravenous infusion and frequent blood pressure
monitoring every five minutes
(Adapted from Hemphill JC, Greenberg SM, Anderson C, et al. Guidelines for
the management of spontaneous intracerebral hemorrhage in adults: 2015/6
update. A Guideline from the American Heart Association/American Stroke
Association Stroke Council. Stroke. 2015;46: 2032–2060.)
Table 12.10 Blood pressure management in ICH (suggested IV
medications)
Labetalol Up to 100 mg/h by intermittent bolus doses of
5–20 mg or continuous drip (2–8 mg/min,
maximum 300 mg/day)
Esmolol 250 μg/kg as a load; then continuous infusion of
25–300 μg/kg per minute
Nitroprusside 0.1–10 μg/kg/min (continuous infusion only)
Nicardipine 5 mg/h increased by 2.5 mg/h q 15 min to max
15 mg/h (continuous infusion)
Hydralazine 5–20 mg q 30 min as an IV load, or 1.5–5.0 μg/
kg/min continuously
Enalapril 1.25–5 mg IV bolus q 6 h (first test dose should
be 0.625 mg to avoid the risk of precipitous
blood pressure lowering)
(Adapted from Broderick JP, Connoly S, Feldman E, et al. Guidelines for the
management of spontaneous intracerebral hemorrhage in adults: 2007
update. A Guideline from the American Heart Association/American Stroke
Association Stroke Council, High Blood Pressure Research Council, and the
Quality of Care and Outcomes in Research Interdisciplinary Working Group.
Stroke. 2007;38:2001–2023.)
most commonly used in the emergency setting. It can be
administered in repeated bolus doses or continuous intraven-
ous infusion. Other agents such as nicardipine or esmolol can
also be used; however, hydralazine and sodium nitroprusside
should be avoided, at first, due to their propensity to cause
cerebral vasodilation and increased ICP. In all cases of ICH,
systolic BP should be maintained above 90 mmHg to avoid
decrease in CBF and additional cerebral ischemia of the peri-
hematomal zone. Alternatively, mean arterial pressure (MAP)
or cerebral perfusion pressure (CPP) may be selected as a
target variable to follow in monitoring of the effective anti-
hypertensive therapy.
2018 AHA/ASA ICH Performance Measures now include
treatment for long-term blood pressure elevation for modifi-
able long-term secondary prevention at hospital discharge
[59,60].
11. Management of hypotension. Low systemic blood
pressure may carry equal, and possibly worse, neurologic risks
in patients with ICH. Etiology of hypotension must be
Chapter 12: Intracerebral Hemorrhage
Table 12.11 Management of hypotension in ICH
Some suggested medications:
Phenylephrine 2–10 μg/kg/min
Dopamine 2–20 μg/kg/min
Norepinephrine 0.05–0.2 μg/kg/min
(Adapted from the MGH Acute Stroke Service Guidelines for Emergency
Department Management of Brain Hemorrhage (www.stopstroke.org).)
Table 12.12 Insulin titration in critical care setting
Blood glucose Action
<60 mg/dL Stop insulin. Give 50 mL of dextrose 50%
water (D50W). Recheck BG every 30 minutes.
When BG reaches >150 mg/dL, restart at 50%
of previous rate
60–70 mg/dL Stop insulin. Give 25 mL of dextrose 50%
water (D50W). Recheck BG every 30 minutes.
When levels reach >150 mg/dL, restart at
50% of previous rate unless the dose is
<0.25 U/h
70–110 mg/dL Stop insulin
110–140 mg/dL Decrease insulin rate by 50%
140–180 mg/dL No change in insulin rate
180–240 mg/dL Insulin infusion rate of 2 units/h
240–300 mg/dL Insulin infusion rate of 3 units/h
>300 mg/dL Insulin infusion rate of 4 units/h
established and treated aggressively to prevent impairment of
CBF and worsening of cerebral ischemia. Volume repletion
with isotonic crystalloid boluses or colloids is the first
approach, and requires monitoring of central venous pressure
(CVP) for effectiveness. If hypotension persists after correction
of volume deficit, continuous infusion of vasopressors should
be considered, particularly for low systolic blood pressure such
as <90 mmHg (Table 12.11) [90]. If CVP is normal or elevated
in the setting of hypotension, then further evaluation of car-
diac function using a pulmonary artery catheter or noninva-
sive measures is indicated.
12. Glycemic control. Hyperglycemia and hypoglycemia
may worsen outcome in ICH [107,112]. Patients should there-
fore be monitored and treated several times daily for any
elevation in blood sugar [113]. In monitored settings, continu-
ous insulin infusions are ideal for maintaining normoglyce-
mia, although the optimum target glucose level remains to be
clarified in ICH (Table 12.12).
13. Pyrexia control. Sustained fever after ICH is likely to
be associated with poor outcome [14]. Potential sources of
infection have to be investigated thoroughly at fever onset
[114]. Several sources recommend antipyretics (such as acet-
aminophen 650 mg every six hours) for sustained fever in
excess of 38 °C (101.4 °F) or external cooling procedures
139
 Chapter 12: Intracerebral Hemorrhage
[25,90,115]; however, evidence to support efficacy of these
interventions in patients with ICH is lacking.
14. Management of elevated ICP. Increased ICP is
common in patients with ICH [116,117]. Elevated ICP is
usually recognized by progressively worsening level of arousal,
or development of worsening or new neurologic deficit accom-
panied by evidence of mass effect (“midline shift,” edema,
hydrocephalus, or herniation) on neuroimaging.
Emergent management of elevated ICP in a rapidly deterior-
ating patient includes:
1. Proper head positioning (elevated to 30°)
2. Rapid infusion of 20% mannitol at 1.0–1.5 g/kg
3. Hyperventilation (increase in ventilation rate with constant
tidal volume) of the patient to a PCO2 of 30–35 mmHg
[116,117]
These are temporary measures designed to lower ICP quickly
and effectively, until a definitive treatment can be instituted. In
this case, a neurosurgical intervention such as EVD or crani-
otomy may prove life-saving [16,66,107] (Table 12.13).
For patients in whom the neurologic exam cannot be
followed, and elevated ICP is suspected, early invasive ICP
monitoring offers additional diagnostic and therapeutic advan-
tages [118]. Early neurosurgical consultation is essential to
prevent cerebral herniation, the most detrimental of ICH
complications.
The goal ICP is <20 mmHg, while CPP is optimal when
maintained above 70 mmHg. Options for continued medical
therapy in patients who are not deemed to be surgical candidates
or in whom CSF drainage with EVD is insufficient include:
1. Osmotherapy (20% mannitol 0.25–0.5 g/kg every four
hours or hypertonic saline (NaCl), 30 mL of 23% or
continuous infusion of 3% NaCl)
2. Use of barbiturates (pentobarbital 10 mg/kg over
30 minutes or thiopental 1.5 mg/kg to 3.5 mg/kg)
3. Pharmacologic paralysis with vercuronium or
pancuronium (both 0.1 mg/kg) (90,119)
There is no indication for corticosteroid use for elevated ICP
in ICH [59].
15. Seizure prophylaxis. Patients with ICH have an esti-
mated 30-day risk of clinically evident seizure activity of 8%,
with lobar ICH being an independent predictor of early seizure
onset [120]. Up to 2% of ICH patients will develop convulsive
status epilepticus after their index event, and up to 28% of
continuously monitored stuporous or comatose ICH patients
will develop some sort of epileptiform activity during the first
72 hours after admission [120–122].
Seizure activity is associated with neurologic deterioration,
progressive mass effect, and worse clinical outcomes in these
patients [120]; however, the benefit of primary prophylactic
use of anticonvulsive therapies has not been demonstrated.
The American Stroke Association guidelines no longer
recommend the use of prophylactic anticonvulsants due to
several studies showing worsened outcomes in patients treated
140
Table 12.13 Emergency management of elevated ICP
1. Elevation of the head of the bed at 30 degrees
2. Osmotherapy
a. Mannitol 20% 0.25–0.5 g/kg every 4 hours
b. Hypertonic saline
3. Barbiturates
a. Pentobarbital 10 mg/kg over 30 minutes
b. Thiopental 1.5–3.5 mg/kg
4. Paralysis
a. Vecuronium 0.1 mg/kg
b. Pancuronium 0.1 mg/kg
5. Hyperventilation (temporary measure only)
a. Raise ventilation rate with a constant tidal volume
b. Goal PCO2 30–35
6. ICP monitor placement in patients with hydrocephalus or clinical
deterioration secondary to elevated ICP
a. Goal ICP <20 mmHg
7. External ventricular drain may be indicated in patients with or at
risk for hydrocephalus
with prophylactic phenytoin for seizure prevention in ICH
(123,124). Continuous EEG monitoring should be considered
for ICH patients with depressed or fluctuating mental
status. Clinical seizures should be treated with antiepileptic
agents. Electrographical seizures accompanied by change in
mental status should also be treated [107]. Multiple antiepi-
leptics are available for use in the intensive care setting
(Table 12.14).
16. Role of hemostatic therapy. The FAST (Factor Seven
for Acute Hemorrhagic Stroke Treatment) trial was under-
taken to evaluate whether a potent initiator of hemostasis
could reduce mortality in ICH. However, while higher doses
of recombinant FVIIa led to reduction in hematoma expansion
at 24 hours, there was no change in primary outcome of death
or severe disability; furthermore, there was a significantly
increased risk of thromboembolic events [125]. Antifibrinoly-
tic agents such as ε-aminocaproic acid and tranexamic acid
have also been studied in pilot studies, but results were not
promising [91].
17. Venous thromboembolism prophylaxis. Pulmonary
embolism from DVT accounts for nearly 10% of deaths after
stroke. Pharmacological prophylaxis does not contribute to
hematoma expansion and is more efficacious in combination
with pneumatic compression devices. 2018 AHA/ASA Per-
formance Metrics include documentation of VTE prophylaxis
using lower-limb pneumatic compression on day of admission
or day after admission [59].
18. Dysphagia screening. Dysphagia after ICH leads to
aspiration pneumonia. Formal evaluation of dysphagia is asso-
ciated with reduced risk and should be conducted within 24 h
of admission [59].

Table 12.14 Anticonvulsant agents commonly used for seizure treatment
Agent Initial dose
Phenytoin 20 mg/kg IV
Fosphenytoin 20 mg PE/kg IV
Phenobarbital 20 mg/kg IV
Valproate 15–20 mg/kg IV
Levetiracetam 500–1000 mg IV
Lacosamide 200–300mg IV
Conclusion
From its onset, ICH is a dynamic illness that requires frequent
and thorough reassessment. Once the diagnosis of ICH is made,
urgent intervention to reduce hematoma volume or prevent its
expansion can be life-saving. These patients require early inten-
sive care provided through the collaborative effort of emergency
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 Chapter
Management of Cerebral Venous Thrombosis in the
13 Neurocritical Care Unit
Xiaomeng Xu, Xiaoying Yao, and Magdy Selim
Definition and Epidemiology
Definition
Cerebral venous thrombosis (CVT) refers to clot formation
within the dural venous sinuses or the cerebral venous drain-
age system. The most commonly affected sinuses are the
superior sagittal sinus, transverse sinuses, straight sinus, cor-
tical veins, internal jagular veins, and deep veins.
Incidence
Cerebral venous thrombosis is a rare but important cause of
stroke, especially among young individuals. The reported inci-
dence of CVT in different studies varies greatly. It was trad-
itionally estimated to be 2 to 4 cases per million per year, but
recent studies reported a much higher incidence of 13 cases [1]
to 15 cases [2] per million each year, as a result of improved
diagnosis by advanced imaging techniques [2,3].
Age and Sex
CVT occurs predominantly in young and middle-aged
patients, of whom >90% are less than 65 years old [4]. The
male to female ratio is 1:3, and the prevalence in women is
likely due to sex-specific risk factors such as the use of oral
contraceptives, pregnancy, and postpartum [5,6]. However,
despite previous CVT, pregnancy caused a low absolute risk
for recurrent CVT. Therefore, prior CVT should not be a
contraindication for pregnancy [7].
Risk Factors
There are several risk factors that predispose to CVT. In
women, oral contraceptives, pregnancy, and postpartum are
predominant risk factors. In addition, hereditary and acquired
prothrombotic conditions can increase the risk for CVT.
Table 13.1 lists many of these risk factors. A thorough history
and exam will often identify acquired factors.
Diagnosis
The diagnosis of CVT requires: (1) Clinical suspicion based on
the presenting symptoms and signs, (2) using brain imaging to
confirm CVT, and (3) additional laboratory tests and imaging
to determine the underlying cause of CVT.
146
Clinical Manifestations of CVT
The clinical features of CVT are usually diverse and unspecific,
which adds to the difficulty in making a timely diagnosis.
Clinical manifestations of CVT are attributed to two mechan-
isms: (1) elevation of overall intracranial pressure (ICP) and
brain edema resulting from the obstruction of the cerebral
venous sinus and cerebral blood outflow, and (2) focal brain
injury due to the local effects of the clot and venous infarction.
Compared with other forms of stroke, the symptoms of CVT
are usually slow in the onset, progressive, and may be bilateral.
Abrupt onset is rare, and is mostly seen in obstetrical and
infectious cases.
Headache is the most common and earliest symptom of
CVT affecting about 90% of cases, and may be the only
symptom in up to 25% of patients [8]. The headache is usually
progressive over days to weeks, but thunderclap headache has
been reported in some cases. Other symptoms and signs of
increased ICP, such as papilledema and transient visual
obscurations, may manifest themselves later on. Seizures, focal
or generalized, occur in ~40% patients, and are usually second-
ary to a venous infarct. Altered level of consciousness may be
seen in ~5% of cases, and may be postictal or attributed to
increased ICP. In addition, venous infarct(s) may result in
focal neurological deficit in affected regions. These are vari-
able, but hemiparesis is most common. Rare presentations of
CVT include tinnitus, vertigo, cranial nerve palsies, and cere-
bellar symptoms/signs. Coma, stupor, extensor spasms, or
abulia may be seen with deep CVT leading to involvement of
the basal ganglia and thalami.
Imaging of the Brain and Venous Sinuses
Imaging studies are key to establish the diagnosis of CVT in
suspected cases.
Computed Tomography
Noncontrast computed tomography (CT) is usually the first
imaging examination in these clinical scenarios, due to its
readiness in emergent settings and value in excluding other
neurological conditions with similar signs and symptoms.
However, radiological changes on noncontrast CT scans are
too subtle to be diagnostic in most cases of CVT. Therefore, a
negative CT result cannot entirely rule out the possibility of
 Chapter 13: Management of Cerebral Venous Thrombosis

Table 13.1 Risk factors for CVT CVT. Indeed, an initial CT scan is interpreted as “normal” in
RISK CATEGORY RISK FACTOR Prevalence 25% to 40% of patients with CVT.
CT findings may include: changes in the mastoid or middle
INFECTIOUS ear structures in patients with septic lateral sinus thrombosis,
Infection of head and neck 8% venous infarctions, which tend to be hemorrhagic and located
Central nervous system 2% in nonarterial or subcortical locations, and effacement of the
sulci or slit-like ventricles due to brain edema or high ICP. The
Other 4% most straightforward and direct evidence of CVT is to directly
NONINFECTIOUS visualize the thrombus in the vein or sinus. On plain CT scans,
GENETIC Antithrombin deficiency an acute clot can appear as homogeneous hyperdensity of a
cortical vein or a cerebral sinus, mimicking a subarachnoid
Protein C deficiency hemorrhage. In the cases of superior sagittal sinus CVT, the
Protein S deficiency clot may emerge as a dense triangle due to the anatomic
Factor V Leiden 22% structure of the superior sagittal sinus, which is referred to as
thrombophilia the filled delta sign (Figure 13.1). One of the drawbacks of
plain CT scans is that an acute clot can only be seen in the first
Prothrombin G20210A
7–14 days. After that, the clot becomes isodense or hypodense,
mutation
and difficult to visualize.
ACQUIRED: Therefore, in subacute and chronic cases, contrast-
a enhanced CT scan and CT venography are recommended.
SEX-SPECIFIC Pregnancy and postpartum 21%
On contrast-enhanced CT scans, the filling defect sign and
Oral contraceptives 54%
empty delta sign are equivalent to the above findings on plain
Hormone replacement 4% CT scans.
therapy
DISEASE-RELATED: Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) is the imaging modality of
MALIGNANCY Cancer 5%
choice in CVT. Compared with CT, MRI is more sensitive in
Myeloproliferative 3%
neoplasms
AUTOIMMUNE Systemic lupus 1%
DISEASE erythematosus
Antiphospholipid syndrome 6%
Behçet's disease 1%
Inflammatory bowel disease 2%
Sarcoidosis 0%
OTHER DISEASE Thyroid disease 2%
Nephrotic syndrome 1%
Anemia 9%
Hyperhomocysteinemia 5%
Dehydration 2%
Central nervous system 2%
malformation
MECHANICAL Head trauma 1%
INJURY
Lumbar puncture 2%
Neurosurgical operation 1%
Jugular vein catheterization 1%
NONE IDENTIFIED 13%
Prevalence per ISCVT cohort study [1].
a
Prevalences of sex-specific risk factors were calculated. Figure 13.1 Filled delta sign on plain CT (arrow). The clot in superior sagittal
sinus causes increased density than normal.

147
 Chapter 13: Management of Cerebral Venous Thrombosis
Figure 13.3. Gradient echo T2* MRI showing susceptibility artifact within the
left transverse sinus (arrow) consistent with sinus thrombosis.
detecting parenchymal abnormalities, such as focal edema and
infarctions, and the thrombus during the acute, subacute, and
chronic stages. The clot appears isointense on T1- and hypo-
intense on T2-weighted images during the acute phase, and
gradually becomes hyperintense on both T1- and T2-weighted
images by the second week.
The main direct sign of thrombus on MRI is the absence of
flow void within the affected venous sinus (Figure 13.1), which
is equivalent to a hyperdensity sign on plain CT and filling
defect sign on contrast-enhanced CT. However, T1- and T2-
weighted images have limitations, and false positives due to
148
Figure 13.2 MRI T1-weighted images. The clot in
the superior sagittal sinus (arrows) appears
isointense during the acute phase (A), and
hyperintense during the chronic phase (B).
Figure 13.4 A left transverse and sigmoid sinuses thrombosis (arrow)
confirmed by MRV.
slow blood flow are not uncommon. While susceptibility-
weighted MRI may allow direct visualization of deoxyhemo-
globin in the thrombus as an area of signal loss/darkening
within the affected sinus (Figure 13.2), contrast-enhanced
MRI and MR venography are always recommended.
Venography
Plain CT or MRI can be entirely normal in about 30% of cases.
Therefore, CT or MR venography is recommended when CVT
is suspected, even when plain CT or MRI are negative [8,9].
Although the diagnostic value of CTV and MRV is equivalent,
due to concerns about radiation and iodine contrast, MRV is
the most widely used modality (Figure 13.3). The 2D time-of-
flight (TOF) is the most commonly used MRV technique
(Figure 13.5A). However, TOF MRV has limitations because

flow gaps are not uncommon. The use of gadolinium-
enhanced MRV is less likely to be affected by flow artifacts,
and when combined with a 3D magnetization-prepared rapid
gradient-echo (MP-RAGE) sequence (Figure 13.5B) is superior
to TOF MRV, particularly in complicated cases with anatomic
variants [8].
The use of invasive digital subtraction angiography (DSA),
the historical gold standard for diagnosing CVT, is declining
due to improvement in the sensitivity and specificity of non-
invasive CT/MR venography. Nowadays, DSA use is often
limited to patients in whom MRV/CTV is inconclusive, or
equivocal cases where it is difficult to ascertain if CVT detected
on CTV/MRV is attributable to sinus hypoplasia or filling
defects due to arachnoid granulations.
Blood Tests and Other Imaging Studies
The use of D-dimer as an alternative to imaging to exclude
CVT diagnosis in low-risk patients has been debatable. Serum
levels >500 μg/L have 91% specificity, 97% sensitivity, and 55%
positive predictive value. However, there are many causes for
elevated D-dimer, and false-negative results may be seen in
subacute or chronic cases, small clot burden, and cases pre-
senting with isolated headache.
Laboratory tests are mostly helpful in determining the
etiology of CVT (Table 13.1), including underlying infection,
malignancy, hematological and inflammatory disorders, or
prothrombotic conditions. Recommended initial tests include:
complete blood count, chemistry, sedimentation rate, and
coagulation studies. In cases where the cause of CVT remains
undetermined after careful history and initial tests, testing for
an inherited thrombophilia, including factor V Leiden, pro-
thrombin gene mutation, antithrombin III deficiency, and
protein C and S deficiencies, should be considered. Ideally,
testing should be done before initiation of anticoagulation
and repeated four to six weeks later, particularly in patients
whose initial work-up is negative. Work-up for an occult
malignancy should be undertaken in those whose evaluation
and thrombophilia testing are unrevealing.
Chapter 13: Management of Cerebral Venous Thrombosis
Figure 13.5 (A) TOF-MRV shows lack of flow in
right transverse sinus (arrow). (B) MP-RAGE with
gadolinium shows patency of the sinus (arrow).
Triage and Prognosis
Triage
Because of the diversity of causes and presenting symptoms,
patients with CVT commonly encounter many specialists in
different healthcare settings. Patients presenting with isolated
headaches or nonlocalizing symptoms/signs of increased ICP
are often encountered by family practitioners or internists as
the first primary providers. This may prompt referral to a
neurologist or local emergency department. Those presenting
with neurological symptoms or signs are encountered by
neurologists or emergency medicine physicians. Intensivists
often encounter patients with CVT whose level of conscious-
ness is impaired or are in a coma, and those who develop
seizures or significant complications related to large hemor-
rhagic infarction, high ICP, and brain edema. Other specialists,
such as hematologists, oncologists, and neurosurgeons may be
involved at different stages of hospitalization and evaluation
on a case-by-case basis.
Prognosis
Approximately one-quarter of patients deteriorate within sev-
eral days of the diagnosis of CVT. Patients with depressed level
of consciousness upon presentation are more likely to deterior-
ate. Early mortality is often attributed to herniation due to a
large hemorrhagic infarct or massive brain edema, pulmonary
embolism, or refractory status epilepticus. Predictors of mor-
tality include: altered consciousness, thrombosis of the deep
venous system, and posterior fossa lesions. Observational stud-
ies report complete recovery in ~79% of patients, ~8% death
rate, and 5% dependency rate (i.e. modified Rankin Scale score
3) after a median follow-up of 16 months [7].
Risk stratification scores have been developed to inform
patients of their individual prognosis and to select those who
might benefit most from aggressive treatments. In one model,
2 points were assigned for the presence of malignancy, coma,
or thrombosis of the deep venous system, and 1 point for male
sex, presence of decreased level of consciousness, or ICH.
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 Chapter 13: Management of Cerebral Venous Thrombosis
A cut-off of score 3 points indicated a higher risk of death or
dependency at six months (c-statistics ~85%)[11]. Another
study developed a risk score model incorporating two more
predictive variables, age >37 and infection. In this model,
5 points were assigned to male sex, 6 points for ICH, 7 points
for mental status disorder, 7 points for age >37, 10 points for
Glasgow Coma Score <9, 11 points for cancer, 11 points for
deep CVT, and 12 points for central nervous system infection.
The predictive value of a score <14 for good outcome (modi-
fied Rankin Scale score 2) was 0.96, whereas the predictive
value of a score 14 for poor outcome was 0.39 [12].
Treatment
Acute Management
Anticoagulation
Acute anticoagulation is recommended, even in the presence
of hemorrhagic infarctions, to prevent thrombus growth, pul-
monary embolism, and deep vein thrombosis. This is based on
the results of two randomized trials of intravenous unfractio-
nated heparin (UFH) and subcutaneous low-molecular-weight
heparin (LMWH), which included a total of 79 patients with
CVT [13,14], and showed no increase in the risk of intracer-
ebral hemorrhage and a reduction in poor outcome and death
with anticoagulation (RR = 0.46; 95% confidence interval
0.16–1.3) [15]. A randomized trial comparing UFH and
LMWH showed that LMWH was associated with better clinical
outcome at three months [16]. However, intravenous UFH
might still be preferable in the acute setting if neurosurgical
intervention is anticipated and rapid reversal of coagulopathy
is needed.
Thrombolysis and Thrombectomy
There is insufficient evidence to recommend mechanical
thrombectomy with or without intrasinus thrombolysis as a
first-line treatment for CVT. The Thrombolysis or Anticoagula-
tion for Cerebral Venous Thrombosis (TOACT) Trial found
that endovascular treatment (EVT) did not improve clinical
outcomes and was recently terminated [3]. Furthermore,
although the spontaneous recanalization rates of CVT
approaches 85% after a few months, recanalization does not
seem to be related to long-term outcomes. Therefore, EVT
should not be routinely applied in cases with low risk for poor
outcome, and should be reserved for situations where significant
neurological deterioration occurs despite intensive anticoagula-
tion to facilitate recanalization and to reduce fatalities [17,18].
Symptom Management
Intracranial Hypertension
Isolated intracranial hypertension occurs in ~40% CVT cases
[19]. The elevation of ICP is mainly due to CSF malabsorption.
Thrombus in the superior sagittal and lateral dural sinuses
may impair arachnoid granulations, which leads to reduced
CSF absorption. Meanwhile, hemorrhage into the ventricles
150
and severe brain edema may also lead to increased ICP by
causing obstructive hydrocephalus. Intracranial hypertension
may cause papilledema and visual field loss. Therefore, close
monitoring of vision is necessary, and urgent therapeutic
measures should be taken immediately when visual alteration
is observed [20].
Although the optimal treatment for intracranial hyperten-
sion in CVT is inconclusive, acetazolamide 500–1000 mg/day
can be considered, and therapeutic lumbar puncture, serial
lumbar puncture, or a lumbo-peritoneal shunt may be neces-
sary [21,22]. In life-threatening cases with intractable intracra-
nial hypertension, decompressive hemicraniectomy may be
considered [23]. Steroids are not recommended [24].
Seizures
Seizures occur in ~40% of patients with CVT, and are associ-
ated with worse prognosis [25,26]. Although prophylactic anti-
epileptic drugs are not recommended, early initiation of
antiepileptic drugs is warranted after the first onset of a single
seizure.
Treatment of Specific Conditions
Heparin-induced thrombocytopenia (HIT) may predispose to
CVT. HIT is a complication of UFH, and typically occurs 4 to
10 days after exposure to UFH. It must be suspected when a
patient who is receiving UFH is noted to have a decrease in
platelet count, particularly if the fall is >50% of the baseline
count. Confirming the diagnosis of HIT requires immuno-
assays to identify antibodies against heparin/platelet factor-4
(PF4) complexes and/or functional assays measuring the
platelet-activating capacity of PF4/heparin-antibody com-
plexes. If HIT is suspected, all heparin products, including
the use of UFH in flush catheters, must be discontinued
immediately. Alternative anticoagulants, typically a direct
thrombin inhibitor such as argatroban, should be used instead.
In HIT patients, warfarin may cause microthrombosis, and
in these patients international normalized ratio (INR) usually
exceeds 4.0. Therefore, initiation of warfarin should be post-
poned until platelet count exceeds 150  109/L [27,28]. Vita-
min K should be given immediately if warfarin has already
been given [29].
Long-Term Management
Oral Anticoagulation
Transition to oral anticoagulation is recommended for long-
term management in order to prevent recurrent CVT or other
venous thromboses. Traditionally, vitamin K antagonists, i.e.
warfarin, with target INR of 2.0–3.0 is often recommended.
Novel oral anticoagulants (NOACs) present new options for
long-term anticoagulation. Two case series including a total of
22 patients who received NOACs after heparin therapy in the
acute phase reported similar clinical benefits to warfarin
[30,31]. Given the nature and size of these studies, the use of
NOACs for routine treatment of CVT requires further study
 Chapter 13: Management of Cerebral Venous Thrombosis

Figure 13.6 Flow chart for suggested

Clinical suspicion of CVT management of patients with suspected CVT.
(e.g. headache, seizure, focal symptoms, etc.)

Imaging
(MRI + gadolinium-enhanced MRV with 3D
MP-RAGE is the optimal imaging strategy)

No
Confirmed diagnosis of CVT Consider other diagnoses
Yes

Start acute anti-coagulation

(LWMH may be preferred over heparin)
ICH/hydrocephalus/severe
Yes intracranial hypertension:
Complications
May consider hemicraniotomy
No
as a lifesaving method
Oral anticoagulation, preferably warfarin
(target INR: 2-3) for long-term
management (generally 3-12 months)

and its use to treat CVT should be cautiously considered,
especially as an alternative to UFH or LMWH during the acute
phase [32].
The optimal duration for oral anticoagulation after CVT is
uncertain. The American Heart Association/American Stroke
Association guidelines recommend continuing anticoagulation
for 3 to 6 months in patients whose CVT was provoked and
related to reversible risk factors (for example, due to side
effects of medical therapy), 6 to 12 months for those with
idiopathic CVT, and life-long for patients with recurrent
CVT or irreversible severe prothrombotic conditions with
high thrombotic risk, such as homozygous factor V Leiden
or prothrombin gene mutation, and antithrombin III or pro-
tein C or S deficiencies [8].
Figure 13.6 summarizes a suggested flow chart for manage-
ment of patients with suspected CVT.
Pregnancy
Women with a history of CVT are at increased risk of recur-
rence during future pregnancies. The risk of CVT recurrence
with pregnancy is ~1.2%, and is highest during the third
trimester and first four puerperium weeks. Therefore, prophy-
laxis with LMWH throughout future pregnancies and at least
six weeks postpartum is recommended [7,33,34].
Pharmacology
Heparin
Dose: bolus 80 units/kg (maximum 5000 units) + infusion
12 units/kg/h (maximum 1200 units/h) for normal body
habitus or 1800 units/h for morbid obesity.
Monitoring Schedule
1. PTT should be checked at baseline, 6 hours after bolus or
any rate change and then daily, with a therapeutic target of
50–70 seconds
2. Platelets counts should be checked daily to monitor for HIT
3. Hemoglobin and hematocrit should be checked every other
day to monitor for bleeding.
Precautions
1. Heparin should be discontinued immediately with
suspicion of HIT
2. Heparin should be prescribed with caution during pregnancy
because it increases the risk of maternal hemorrhage.
Therefore in pregnancy and postpartum LMWH is preferred.
LMWH (enoxaparin)
Dose: 1.5mg/kg per day or 1mg/kg every 12 hours, subcutaneously.
Monitoring Schedule
1. Platelet counts should be checked daily to detect
thrombocytopenia
2. Anti-Factor Xa level may be used to monitor the effect of
enoxaparin in patients with severe renal impairment or
underlying bleeding.
Precautions
1. Warfarin should be initiated in conjunction with
enoxaparin. Enoxaparin therapy should continue for at
least five days and until therapeutic effects of warfarin have
been achieved (INR 2.0 to 3.0)

151
 Chapter 13: Management of Cerebral Venous Thrombosis

2. In patients with severe renal impairment (creatinine clearance Precautions

<30 mL/min), the dosage regimen is 1 mg/kg daily
3. Enoxaparin must not be administered by intramuscular
injection
4. Lumbar puncture or other procedures should be
performed at least 24 hours after the last dose, and the next
dose should be delayed for at least four hours. In patients
with creatinine clearance <30 mL/min, the procedure
should be performed at least 48 hours after the last dose.
Warfarin
Dose: titrated from 2–5 mg/d to the therapeutic dosage that
maintains the INR between 2.0 to 3.0.
Monitoring Schedule
INR should be monitored daily until stable in the therapeutic
range. Subsequent INR should be obtained every one to
four weeks.
1. INR should be monitored regularly
2. Warfarin can infrequently cause tissue necrosis; in this
situation, warfarin should be discontinued and replaced by
alternative anticoagulants
3. Warfarin is teratogenic and is contraindicated during
pregnancy. If the benefit of taking warfarin outweighs the
risk in pregnant women, the decision should be reviewed
on a case-by-case basis
4. Acute kidney injury may occur in patients with previous
renal insufficiency
5. Warfarin may cause systemic atheroemboli and cholesterol
microemboli; once the phenomena are observed, warfarin
should be discontinued and alternative anticoagulants
should be considered
6. Warfarin should not be used as initial therapy in patients
with HIT, but can be considered when the platelet count
returns to normal.

Thrombosis)-2 PREGNANCY Study. 14. de Bruijn SF, Stam J (1999).

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 Chapter
Subarachnoid Hemorrhage in the Neurocritical

14 Care Unit
Katja E. Wartenberg and Stephan A. Mayer

Epidemiology
Subarachnoid hemorrhage (SAH) is an acute cerebrovascular
event with profound effects on the central nervous system
and several other organs, and is defined by bleeding into the
subarachnoid space between the arachnoid layer and pia
mater. SAH occurs with an incidence of 2–22.5 per 100,000
[1,2]. The highest reported incidences of aneurysmal SAH
(aSAH) come from Japan and Finland and occur at a rate of
16–22.5 per 100,000 per year. In the United States, SAH
occurs at approximately 6 per 100,000, or a total of 18,000
events per year. The incidence of aSAH peaks in the 55–60-
year-old age group. Additionally, subarachnoid hemorrhage
is a consequence of traumatic brain injury in 12–53%, which
corresponds to approximately 240,000 persons per year in the
United States.
The etiology of spontaneous SAH is quite diverse:
• Ruptured intracranial aneurysm (75–80%)
• “Angiogram negative SAH” (7–10%)
• Cerebral arteriovenous malformations (AVMs; 4–5%)
• Vasculitis
• Intracerebral carotid or vertebral artery dissection
• Ruptured arterial infundibulum (rare)
• Coagulation disorders (rare)
• Cerebral venous thrombosis
• Spinal arteriovenous malformations
• Cocaine use
• Sickle cell disease
• Pituitary apoplexy
• Tumor.
The poor-grade patients (Hunt Hess or World Federation of
Neurological Surgeons (WFNS) scale grade IV and V), 18–24%
of the entire SAH population, present the greatest challenge to
the neurointensivist. They have worse long-term functional
outcomes and higher mortality rates [3–5]. However, early
and aggressive treatment of patients with severe SAH has
resulted in unexpected improvements in long-term outcome
[6–10]. Of 26 patients with poor-grade SAH with neurocogni-
tive testing at one year, half of the patients, mainly young and
highly educated individuals, all employed in full-time jobs
prior to SAH, had mild cognitive deficits and were able to live
normal lives [5].
Between 10 and 12% of patients die before they get medical
attention.
Of equal importance is that mortality rates are substantially
higher and good long-term functional outcomes less common
at centers that treat less than 18 patients with SAH per year
[11–14].
Risk Factors
Risk factors include:
• Age 50 years (most common 40–60 years)
• Female sex [15,16] depending on hormonal status [17]
• African-American race [18]
• Arterial hypertension
• Cigarette smoking: relative risk is 3.0 for men, 4.7
for women
• Moderate or excessive alcohol consumption
• Cocaine or any other sympathomimetic agents
• Prior SAH from a separate aneurysm or family history of
SAH or cerebral aneurysms
• Multiple aneurysms
• Arteriovenous malformations
• Coarctation of the aorta
• Moya Moya disease
• Pituitary gland tumors
• Osler–Weber–Rendu syndrome
• Bacterial endocarditis
• Connective tissue disease associated with intracranial
aneurysms such as autosomal dominant polycystic kidney
disease, Ehlers–Danlos syndrome (type IV), Marfan
syndrome, pseudoxanthoma elasticum, and fibromuscular
dysplasia [15–32].
Clinical Presentation
Patients with SAH present with an explosive generalized head-
ache as well as neck stiffness and back pain, photophobia,
nausea and vomiting, loss of consciousness, and seizures.
About 80% of patients describe the pain as “the worst headache
of my life.” More than 20% of patients experience “sentinel
headaches” lasting for minutes or hours, from 14 days up to
8 weeks before SAH, accompanied by nausea and vomiting.

154
 Chapter 14: Subarachnoid Hemorrhage

These symptoms originate from minor leaking of blood from

an aneurysm [33,34]. In the primary care setting, studies have
shown that 25% of patients who complain of an acute, severe,
paroxysmal headache will have an aSAH.
Preretinal or subhyaloid hemorrhages – large, smooth-
bordered, and on the retinal surface – occur in up to 25% of
patients [35]. Seizures may be the presenting symptom in up to
20% of patients, mostly within the first 24 hours after SAH
[36]. An oculomotor nerve palsy often accompanies a poster-
ior communicating artery aneurysm. An abducens nerve palsy
may accompany a posterior cerebral artery aneurysm.

Diagnosis
SAH is misdiagnosed in about 12% of cases. Reasons for initial
misdiagnosis encompass not obtaining an imaging study in
73% and/or not performing or falsely interpreting a lumbar
puncture in 23%. This often leads to delayed treatment until
rebleeding or neurological deterioration has occurred, with
increased morbidity and mortality [16,37].
The clinical condition upon admission of a patient is most
commonly rated using the Glasgow Coma Scale (GCS) [38],
Hunt and Hess scale [39], or the World Federation of Neuro-
surgical Societies (WFNS) scale [40]. Reports of intra- and
interobserver agreements are sparse and highly variable. How-
ever, obtaining a score with either the Hunt and Hess or
WFNS scales on admission is recommended as these are the
single most useful predictors of long-term outcome [41].
Noncontrast computed tomography (CT) remains the single
most important test for the diagnosis of SAH (Figure 14.1). In
the first 24 hours, the sensitivity of a CT for SAH is 92–95%
[42–46]. As time passes, the sensitivity to detect blood on a head
CT declines to 57–85% on days 5 and 6 and to 50% after one
week [44,47]. With the newer generation of CT scanners, the
sensitivity amounts to 100% within the first six hours and 87%
six hours or more after symptom onset [48].
The Fisher scale is a radiological scale based on the amount
and distribution of blood on CT, which is set into relation with
occurrence of delayed cerebral ischemia (DCI; Figure 14.2)
[49]. A modification of the original Fisher scale with particular
attention to thick cisternal and ventricular blood resulted in a
more accurate prediction of symptomatic vasospasm through
a linear relationship between the amount of cerebral blood and
risk of DCI (Figure 14.3) [50,51].
Magnetic resonance tomography (MRI) with proton-dens-
ity-weighted, fluid-attenuated inversion recovery, diffusion-
weighted imaging, and gradient echo sequences can also be
used to make the initial diagnosis of SAH or to detect a
completely thrombosed aneurysm when the initial angiogram
is negative [52]. However, the usefulness of MRI in the acute
setting is often limited by logistics, the need for acute resusci-
tation and critical care management of the patient, and motion
artifacts [41].
If the CT does not reveal subarachnoid blood, but SAH is
strongly suspected, a lumbar puncture should be performed.
Figure 14.1 Computed tomography showing subarachnoid hemorrhage as
thick blood clots in all basal and cisterns, interhemispheric and sylvian fissures.
SAH can be determined by demonstrating xanthochromia (a
yellow-tinged appearance) after centrifugation, which differen-
tiates SAH from a traumatic tap. Xanthochromia may take up
to 12 hours to appear after aneurysm rupture. Within 12
hours, the erythrocyte count is elevated and does not diminish
from tube 1 through 4. Red blood cells and xanthochromia
disappear within about two weeks, unless hemorrhage recurs.
Spectrophotometry is another method to evaluate CSF for
subarachnoid blood with a sensitivity of 100% and a specificity
of 29–92% [53,54].
Two- or three-dimensional selective catheter cerebral
angiography remains the gold standard for detecting intracra-
nial aneurysms and delineating their anatomy (Figure 14.4a)
[41]. With increasing availability and improving image
quality of CT angiography (CTA) and magnetic resonance
angiography (MRA) the need to perform an urgent catheter
angiography has reduced over past decades. The sensitivity of a
three-dimensional time-of-flight MRA ranges between
55–93%, and for aneurysms 5 mm between 85–100%. MRA
assessment of the aneurysm neck and of the relationship to the
originating artery is limited [55–59]. CTA is more readily
obtainable and faster than MRA. This imaging modality
carries a sensitivity of 77–100% for all aneurysms and
95–100% for aneurysms 5 mm (Figure 14.4b). Vessel tortu-
osity and lack of experience restrict its usefulness [60–64].
Additional information, such as aneurysm wall calcification,
intraluminal thrombosis, and relationships to bony landmarks
and intraparenchymal hemorrhage may be revealed by CTA.

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 Chapter 14: Subarachnoid Hemorrhage

Figure 14.2 Fisher scale [49] on noncontrast computed tomography: (A) Grade I: no subarachnoid blood, risk of symptomatic vasospasm 21%. (B) Grade II: diffuse,
thin subarachnoid blood <1 mm thick, risk of symptomatic vasospasm 25%. (C) Grade III: diffuse or focal, thick subarachnoid blood >1 mm, risk of symptomatic
vasospasm 37%. (D) Grade IV: no or diffuse, thin subarachnoid blood with ventricular hemorrhage, risk of symptomatic vasospasm 31%.

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Figure 14.3 Modified Fisher scale [50,51] on noncontrast computed tomography: (A) Grade I: no or minimal subarachnoid blood, no intraventricular hemorrhage,
risk of symptomatic vasospasm 24%. (B) Grade II: minimal subarachnoid blood with intraventricular hemorrhage, risk of symptomatic vasospasm 33%. (C) Grade III:
diffuse or focal, thick subarachnoid blood, no intraventricular hemorrhage, risk of symptomatic vasospasm 33%. (D) Grade IV: diffuse or focal, thick subarachnoid
blood with intraventricular hemorrhage, risk of symptomatic vasospasm 40%.
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 Chapter 14: Subarachnoid Hemorrhage
Figure 14.4 Selective catheter cerebral angiography with injection of the left internal carotid artery (A) and computed tomography angiography (B) demonstrating
an aneurysm of the anterior communicating artery (arrow). A black and white version of this figure will appear in some formats. For the color version, please refer to the
plate section.
Decisions about the repair mode of the ruptured aneurysm
may be solely based on information obtained by CTA [65–68].
Newer techniques, including dual energy CTA at lower radi-
ation dosages and multisection CTA combined with matched
mask bone elimination are precise in diagnosing intracranial
aneurysms [69,70].
However, a four-vessel (bilateral internal carotid and verte-
bral artery injections) is mandatory when these imaging tests
are negative for aneurysms. Furthermore, with cerebral
angiography the adequacy of aneurysm repair is assessed during
coiling or after surgical clipping. Vasospasm, local thrombosis,
or poor technique can lead to a false-negative angiogram. For
this reason, patients with a negative angiogram should receive a
follow-up study one to two weeks later. An aneurysm will be
demonstrated in about 1–2% of these cases [71].
Prognostic Indicators
The severity of the hemorrhage, determined by the Hunt and
Hess or WFNS scales on admission, is the most useful pre-
dictor of long-term outcome. The scales have a strong associ-
ation to mortality (Table 14.1).
In 1981, a committee was formed by the WFNS to create a
universal subarachnoid hemorrhage grading scale which is
strongly predictive of functional outcome after SAH (Table 14.2).
Current developments in neurocritical care including
advanced continuous neuromonitoring, a shift of focus to imme-
diate real-time normalization of pathophysiological states, and
158
better recognition and management of complications following
SAH have improved the level of care and clinical outcome.
The mortality rate was reduced from 50% to 25–35%
[10,73,74]. Mortality rates are higher in women than in men
[75–77]. Of the two-thirds of patients who survive, approxi-
mately 50% are permanently disabled, mainly due to neuro-
cognitive deficits (20%), and anxiety and depression, which
occur in up to 80%. Many patients do not return to work or
retire early, and their relationships are affected [78,79]. Older
age, poor clinical grade upon presentation, rebleeding, larger
aneurysm size, global cerebral edema, delayed cerebral ische-
mia, and medical complications impact functional outcome
after SAH. Of all these factors, the clinical condition upon
arrival in the hospital appears to be the single most important
risk factor for poor outcome [4,80–82].
Pathophysiology/Etiology
Saccular aneurysms most often occur at the circle of Willis or
its major branches, especially at bifurcations. They arise where
the arterial elastic lamina and tunica media are defective, and
tend to enlarge with age. The typical aneurysm wall is com-
posed only of intima and adventitia and can become paper-
thin. Many aneurysms, particularly those that rupture, are
irregular and multilobulated, and larger aneurysms may be
partially or completely filled with an organized clot, which
occasionally is calcified. The point of rupture is usually
through the dome of the aneurysm. In the International
 Chapter 14: Subarachnoid Hemorrhage

Table 14.1 Modified Hunt and Hess SAH grading scale and mortality Table 14.2 World Federation of Neurosurgical Societies (WFNS) SAH
grading scale and correlation with outcome at one month by Glasgow
Grade Signs and symptoms Hospital Hospital Outcome Scale (GOS)
mortality as mortality
originally 1991–2009 Grade GCS Presence of % Patients with
reported by score aphasia, poor outcome
Hunt and Hess hemiparesis, or one month after
hemiplegia discharge (GOS
0 Unruptured aneurysm 1–3), N = 294
1 Asymptomatic or mild 11% 5.8% 0 20
HA or mild nuchal (intact
rigidity aneurysm)
2 Cranial nerve palsy, 26% 7.2% 1 15 53
moderate to severe HA,
nuchal rigidity 2 13 14 70

3 Drowsiness, confusion, 37% 15.9% 3 13 14 + 85

or mild focal
neurologic deficit
4 Stupor, moderate or 71% 30.5%
severe hemiparesis,
early decerebrate
5 Deep coma, 100% 64.8%
decerebrate, moribund
appearance
Data from 275 patients reported by Hunt and Hess in 1968 [39], and
1134 patients reported by Naval et al. in 2013 [72].
Subarachnoid Aneurysm Trial (ISAT) 15–33.5% of patients
had multiple aneurysms (16% of patients had two aneurysms,
3–4% had three aneurysms, and 1–2% had four aneurysms).
Many of these are “mirror” aneurysms on the same vessel
contralaterally. To determine which aneurysm actually rup-
tured the following features can be considered:
• Distribution of blood on CT
• Area of vasospasm on angiography
• Irregularities in the shape of the aneurysm
• Size of the aneurysm.
Between 85 and 90% of intracranial aneurysms are located in
the anterior circulation (Figure 14.5). Posterior circulation
aneurysms most often occur at the apex of the basilar artery
or at the junction of the vertebral and posterior inferior cere-
bellar artery. Saccular aneurysms of the distal cerebral arterial
tree are rare.
Congenital aneurysms are the most common cause of
spontaneous SAH. Other causes of spontaneous SAH include:
• Traumatic aneurysm – pseudoaneurysm at site of vessel
wall injury
• Giant aneurysm – aneurysm >2.5 cm diameter
• Vein of Galen aneurysm/malformation – typically presents
as heart failure in an infant in the first few weeks of life
• Mycotic aneurysm – infectious cause of aneurysm (usually
bacterial), commonly occurring at distal MCA sites and in
the vertebrobasilar system
4 7 12 +/ 93
5 3 6 +/
(From Drake CG. Progress in cerebrovascular disease: management of
cerebral aneurysm. Stroke 1981;12:273–83 and Teasdale GM, Drake CG, Hunt
W, et al. A universal subarachnoid hemorrhage scale: report of a committee
of the World Federation of Neurosurgical Societies. J Neurol Neurosurg
Psychiatry. 1988; 51:1457.)
• AVM – intranidal aneurysms or arterialized venous
channels are usually the source of hemorrhage
• Dural AV-fistula – risk of hemorrhage is highest when
blood flow is retrograde to cortical vessels
• Perimesencephalic/prepontine nonaneurysmal SAH.
In 7–10% of cases, no aneurysm is found on the cerebral
angiogram. These cases are classified as “angiogram-negative
SAH”. Most commonly, the diagnosis is a perimesencephalic
or prepontine nonaneurysmal SAH, which is associated with
excellent functional outcome.
Management and Treatment of SAH and its
Complications
General Emergency and Critical Care Management
In acute SAH, the sudden rise of intracranial pressure (ICP) up
to the level of the mean arterial pressure (MAP) leads to
cessation of cerebral circulation, resulting in loss of conscious-
ness [83], and development of global cerebral edema, as well
as acute ischemic injury on neuroimaging (Figure 14.6)
[80,84–86].
Initial care should focus on:
• Optimal oxygenation and hemodynamics to ensure
cerebral perfusion and oxygen supply
• Control of intracranial pressure caused by hydrocephalus
and/or global cerebral edema
• Blood pressure control
• Seizure control
• Antifibrinolytic agents to prevent aneurysm rebleeding.
The resuscitation goals for SAH are presented in Table 14.3.

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 Chapter 14: Subarachnoid Hemorrhage

Figure 14.5 Distribution of the most common

locations of cerebral aneurysms.

30% anterior communicating artery

20% middle
cerebral
artery

15% internal
carotid artery 25% posterior
communicating
artery
1% posterior
cerebral
artery

10% basilar artery

including junctions
with vertebral arteries,
AICAs and SCAs

5% vertebral artery

Recurrent Hemorrhage
Recurrent hemorrhage occurs in 9–17% of patients in the first
72 hours, 40–87% of those within the first six hours. The risk
is 4% in the first 24 hours and 1.5% per day for the following
13 days. In the long term, rebleeding occurs at 3% per year
and its associated mortality is 2% per year. Patients with
high-grade SAH, loss of consciousness at index bleed, larger
aneurysms, sentinel bleeds, angiography within three to six
hours of symptom onset, delay to treatment, and incomplete
aneurysm repair are at higher risk for recurrent hemorrhage
[7,87–89].
The literature reports available are not sufficient for specific
recommendations regarding blood pressure reduction, adm-
inistration of antifibrinolytic therapy with tranexamic acid or
aminocaproic acid prior to cerebral angiography or aneurysm
repair. Lowering blood pressure to a systolic value of 140–160
mmHg with a titratable agent is recommended [41]. A MAP of
110 mmHg can be tolerated. However, the MAP and CPP
should be adjusted carefully to maintain cerebral blood flow
[41,68]. A short course of antifibrinolytic therapy may be
undertaken until aneurysm repair for a maximum of 72 hours.
This therapy should be discontinued two hours prior to

160

Figure 14.6 Diffusion-weighted imaging of a patient with Hunt and Hess
5 subarachnoid hemorrhage, obtained with admission, showing acute ischemic
injury in the distribution of the bilateral anterior cerebral artery territory.
endovascular aneurysm repair. Thrombembolic events present
a contraindication, and patients should be monitored closely
for deep venous thrombosis [41,68,89]. The use of steroids is
not supported by any controlled trials.
Patients diagnosed with SAH should be treated at high-
volume centers (>35 cases per year) with appropriate specialty
neurointensive care units, neurointensivists, vascular neuro-
surgeons, and interventional neuroradiologists [11–13,41].
Treatment of Increased Intracranial Pressure
Subarachnoid hemorrhage is associated with intracranial hyper-
tension caused by hydrocephalus, space-occupying intracerebral
hemorrhage, and global and focal cerebral edema. Hydrocepha-
lus occurs in 20–30% after SAH through reduced reabsorption
of cerebrospinal fluid at the arachnoid granulations and pial
surface or obstruction of the fourth ventricle by blood [90–92].
The treatment of choice is insertion of an EVD [41], which may
result in a prompt clinical response, such as improvement of
consciousness [93]. The drain chamber should be kept at higher
pressure levels (15–20 cmH2O) to prevent shear stress in the
presence of an unprotected aneurysm. The infection risk is up
to 15%. If there is no improvement in 36–48 hours and the ICP
is low, a poor neurological state is likely due to primary brain
injury related to the acute effects of hemorrhage. Weaning of
Chapter 14: Subarachnoid Hemorrhage
the EVD should begin after ICP has been controlled for 48 hours
either by trials of intermittent clamping or raising the EVD level
with ICP monitoring. Serial lumbar puncture [94] or placement
of a lumbar drain [95] present alternatives to prolonged or
repeated EVD placement if the basal cisterns are open. About
18–26% of all SAH patients require a ventriculoperitoneal shunt
for persistent hydrocephalus [91,96].
Space-occupying intraparenchymal hemorrhages should be
treated by craniotomy and surgical decompression. Decompres-
sive craniectomy is indicated in patients with life-threatening
cerebral edema, with or without intracerebral hemorrhage, due
to infarction or recurrent hemorrhage and should be performed
rapidly to avoid herniation [97].
Apart from head-of-bed elevation, sedation, temperature
control, administration of isotonic fluids, maintaining CPP
>60 mmHg and an arterial partial pressure of carbon dioxide
of 35 mmHg, bolus administration of hypertonic saline may be
the preferred treatment for ICP crisis. Hypertonic saline given
for ICP control resulted in an increase in cerebral blood flow
in ischemic regions and in brain tissue oxygenation, as well as
in a decrease in ICP [98,99].
Multimodal monitoring including ICP, MAP, CPP, partial
pressure of cerebral tissue oxygen (pbtO2), cerebral lactate,
pyruvate, glucose, glycerol, and glutamate by microdialysis
and reactivity indices may help to determine the optimal
CPP threshold. The pressure reactivity index is calculated as
the correlation coefficient between ICP and MAP to reflect
cerebral autoregulation states. If autoregulation is disturbed,
MAP changes are transmitted passively to ICP through a
nonreactive vasculature. The optimal CPP is defined as the
CPP at the lowest pressure reactivity index observed within a
range of CPP (usually 50–90 mmHg) [100].
Volume Status
Intravascular volume status should be monitored closely as
reduced intravascular volume may cause cerebral ischemia
and infarction [101–104]. Assessment of fluid status should
not be based solely on central venous pressure, but include
clinical examination of the patient, records of in- and output,
hourly urine output, and stroke volume variation in intubated
patients. Routine placement of pulmonary artery catheters is
not recommended [68]. Intravenous fluid management for
patients with SAH should aim at euvolemia [41,68]. Prophy-
lactic hypervolemia may be harmful [105–108]. Isotonic fluids
such as 0.9% saline at 1–1.5 ml/kg/h can be used. Supplemental
250 ml boluses of crystalloid (0.9% saline) or colloid (5%
albumin) solution can be given every two hours. However,
crystalloids are preferred [68]. Hypertonic saline solutions
are an alternative to normal saline for patients suffering from
refractory intracranial hypertension or symptomatic intracra-
nial mass effect. Hypotonic fluids should be avoided [41].
Treatment of Seizures
The frequency of seizures in SAH has been reported to be
1–7% at onset. Approximately 5% experience seizures during
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Table 14.3 Acute management and resuscitation goals of subarachnoid hemorrhage

Blood pressure Invasive monitoring

Goal: Systolic <140 mmHg, diastolic <110 mmHg, mean blood pressure <110 mmHg, CPP >60 mmHg until
aneurysm repair
Drugs: IV urapidil 5–40 mg/h, IV labetalol 5–150 mg/h, IV nicardipine 5–15 mg/h, IV clevidipine
1–32 mg/h, IV esmolol 50–100 μg/kg/min, IV metoprolol 1–5 mg/h, IV hydralazine 1.5–7.5 mg/h, IV
clonidine 0.03–0.12 mg/h
Prevention Aneurysm repair through coiling or clipping
of rebleeding Option: Epsilon aminocaproic acid 4 g IV, followed by 1 g/h for a maximum of 72 hours, up to 4 hours prior to
angiogram
Fluid balance Monitoring through cardiac output monitor measuring stroke volume variation (most accurate, only in fully
mechanically ventilated patients), internal jugular or subclavian central line (CVP – less reliable), urine output,
and clinical
Isotonic fluids only: 0.9% NaCl at 1.0–1.5 mL/kg/h
Oxygenation Goal: Oxygen saturation >95%
Intubation and mechanical ventilation if GCS <8
Fever control Goal: Temperature 37 °C
Methods: IV or PO acetaminophen or metamizol 500–1000 mg, if not successful ice packs, cold wraps, surface
or endovascular temperature control systems with management of shivering
Glucose control Goal: 4.5–7.0 mmol/L (81–126 mg/dL)
Methods: Continuous insulin infusion
Caution: Avoid hypoglycemia
Option: Adjust to cerebral glucose level if microdialysis is used
Nutrition Enteral nutrition should be started and be at goal (25–30 kcal/kg/day) within 48 hours of admission
DVT prophylaxis Sequential compression devices
Heparin 5000 U SC every 8 hours or enoxaparin 30–40 mg SC daily within 24 hours after aneurysm repair,
withhold 24 hours before and after intracranial procedures
Aspiration prophylaxis Head of bed elevation 30°
Gastric protection Pantoprazole 20–40 mg IV or PO daily
Laboratory Admission: Electrolytes, CBC, coagulation, D-dimer, troponin I, creatine kinase, type and cross blood, urine
analysis, toxicology screening
Daily: CBC, electrolytes, creatinine, blood gas
Other tests Electrocardiogram
Chest radiograph
Option: Transthoracic echocardiography
Hyponatremia Isotonic fluids: 0.9% NaCl at 1.0–1.5 mL/kg/h
Limit free water intake
Options: 2–20% hypertonic saline solutions, NaCl tablets, fludrocortisone or hydrocortisone for negative fluid
balance
Seizure prophylaxis Antiepileptic treatment for patients with initial seizure, focal intracerebral clot or focal cerebral edema prior to
aneurysm clipping with levetiracetam 500–2000 mg IV daily divided into two dosages
Maximum 3–7 days without evidence of seizures
EEG monitoring of patients with Hunt and Hess grades 4 and 5
Extraventricular drainage Emergent EVD placement for all patients with Hunt and Hess grades 4 and 5 and patients with decreased
mental status and hydrocephalus
Raising the EVD level or clamping dependent on EVD output as soon as possible
No antibiotic prophylaxis
CSF for cell count and differential, glucose, lactate, protein every other day; culture if cell count increases
Caution: CSF drawings increase the risk of infections; sterile conditions should be applied

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Table 14.3 (cont.)

Neurogenic stunned Hemodynamic monitoring (PiCCO, Pulsion Medical Systems, Munich, Germany; Flo Trac, Edwards Lifesciences,
myocardium with Irvine, California, United States of America; pulmonary artery catheter)
pulmonary edema Goal MAP: 70–90 mmHg
Inotropic support: Milrinone 0.25–0.75 μg/kg/min or dobutamine 3–15 μg/kg/min
Vasopressors: Norepinephrine 0.03–0.6 μg/kg/min (first choice), phenylephrine 2–10 μg/kg/min, dopamine
5–30 μg/kg/min
Diuresis
Increase FiO2 and PEEP
Transthoracic echocardiography
Vasospasm Nimodipine 60 mg PO every four hours until SAH day 21
prophylaxis and diagnosis Avoid hypomagnesemia
Daily transcranial Doppler sonography including Lindegaard index (see Table 14.4)
Option: CT angiography, CT perfusion, or MR perfusion imaging on SAH days 4–12 (mean day 9) in high-risk
patients (Hunt and Hess grade 4,5; modified Fisher grade 3,4)
Vasospasm therapy Consider Trendelenburg position (head down), caution: increased rates of ventilator-associated pneumonia
Infusion of 500–1000 ml 0.9% saline or 5% albumin over 15 min
Start vasopressors (norepinephrine, phenylephrine, dopamine) to raise systolic blood pressure to 160–220 mm
Hg (20 mmHg above current) until deficits resolve
Consider milrinone or dobutamine in patients with congestive heart failure or myocardial ischemia
Refractory vasospasm:
Angiographic angioplasty and/or intra-arterial papaverine, verapamil, or nicardipine
Hemodynamic monitoring with PICCO or Flowtrac, augmentation for goal cardiac index 4.0 L/min/m2 and
diastolic pulmonary artery pressure >14 mmHg with dobutamine or milrinone
Abbreviations: CPP: cerebral perfusion pressure, CVP: central venous pressure, DVT: deep vein thrombosis, CBC: complete blood count, EEG:
electroencephalography, EVD: extraventricular drainage, FiO2: inspired fraction of oxygen, PEEP: positive end expiratory pressure, NaCl: sodium chloride.
(Modified from Future Neurology 2013 with permission.)

hospitalization, and 7% will develop epilepsy during the first year
after discharge [109,110]. The most important trigger for seizure
is focal pathology such as large subarachnoid clots, intracerebral
or subdural hematoma, and cerebral infarction. A seizure at the
onset of SAH does not predict an increased risk for epilepsy
[109]. Routine use of phenytoin or fosphenytoin may worsen
functional and cognitive outcome after SAH [111,112] and is no
longer recommended [41,68]. If seizure prophylaxis with other
antiepileptic drugs is warranted to prevent rebleeding, they
should be administered for three to seven days only [68].
Comatose patients may have nonconvulsive seizures or status
epilepticus (8–19%) [113–115]. Therefore, continuous electroen-
cephalographic monitoring (CEEG) is recommended in poor-
grade SAH patients in stupor or coma. The effect of treatment
of nonconvulsive seizures in these patients is not clear [68].
Aneurysm Repair
Clipping within 48–72 hours of ictus and safer microsurgical
techniques result in permanent aneurysm obliteration in over
90% confirmed by intra- or postoperative angiograms, as well
as in low morbidity and mortality (5–15%), excluding giant
aneurysms [29,42,116,117]. The complication rate of clipping
is highest during the repair of large or basilar artery aneurysms
[118–120]. Aneurysms on the middle cerebral artery may be
more amenable to surgery [121,122].
With the introduction of Guglielmi detachable coils
(soft thrombogenic detachable platinum coils, GDC, Target
Therapeutics, Fremont, CA) for endovascular therapy of aneur-
ysms in 1991 [123,124] coil embolization became an important
alternative to craniotomy and aneurysm clipping. Obliteration
of small-necked aneurysms is achieved in 80–90%. The compli-
cation rate is up to 9%, including perforation and cerebral
ischemia [125]. The International Subarachnoid Hemorrhage
Aneurysm Trial (ISAT) enrolled 2134 good-grade patients with
mostly small aneurysms <10 mm in the anterior circulation in a
randomized fashion to undergo aneurysm clipping or coiling.
At one year, death and dependency was 23.5% after coiling and
30.9% after clipping (absolute risk reduction of death and
dependence at one year was 7.4% with coiling), which may be
attributed to decreased rates of brain retraction injury or intra-
procedural rebleeding with coiling compared to clipping. The
risk of epilepsy is decreased with coiling after one year (14%
versus 24%). The main concern about endovascular therapy is
an increased rate of rebleeding after several years due to coil
compaction and aneurysm regrowth at the residual neck (recur-
rent hemorrhage 7% with coiling versus 2% with clipping after
one year) [110,126].
The decision between surgical clipping and endovascular
coiling should be made by a team of neurological, surgical, and
interventional cerebrovascular experts and based on clinical
and radiological characteristics such as:
• Clinical status of the patient
• Anatomical location in regards to surgical access
• Anatomy of the access vessels (tortuosity, atherosclerosis)

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 Chapter 14: Subarachnoid Hemorrhage
• Width of aneurysm neck in comparison to the dome and the
parent artery (wide neck aneurysms are difficult to completely
obliterate with coils, coils may migrate and be a source for emboli)
• Presence of an intracerebral hematoma with mass effect
[41,119].
Recent advances in technique, including the balloon remod-
eling technique that holds the coils in the aneurysm cavity,
liquid polymer coils, and embolic agents make treatment of
broad neck aneurysm feasible. The skills of the neurointerven-
tionalist or neurosurgeon, as well as the institution, may have a
great impact on the decision on treatment modality. Regardless
of the methods, aneurysms should be treated as early as possible
to prevent rebleeding. Delayed follow-up imaging to determine
the status of the aneurysm over time should be performed [41].
Delayed Cerebral Ischemia
DCI is defined as development of new focal neurological deficit
and/or deterioration in level of consciousness, lasting for more
than one hour, or the appearance of new infarctions on CT or
MRI. The underlying pathophysiology is thought to be vaso-
spasm, and other causes have been excluded [127,128]. This
definition has been found to be more meaningful than symp-
tomatic vasospasm (new focal deficit and/or decrease in level
of consciousness due to vasospasm), especially in patients with
severe SAH whose neurological deterioration may be unrecog-
nized. Arterial narrowing can be demonstrated angiographi-
cally in 50–70% and leads to delayed ischemia in 19–46%
after SAH (angiographic vasospasm, see Figure 14.7). The
Figure 14.7 Cerebral angiogram demonstrates vasospasm of branches of the
anterior and middle cerebral arteries (see arrows).
164
development of DCI starts on day 3 after SAH, is maximal at
5 through day 14, and resolves on day 21. Presence of thick
subarachnoid blood seen on admission CT and severe intra-
ventricular hemorrhage are strongly associated with higher
risk for vasospasm (Figures 14.2 and 14.3) [49–51,129,130].
Prevention and management of DCI is listed in Table 14.3.
Monitoring for Delayed Cerebral Ischemia
Observation in a neurointensive care unit with expertise in
performing frequent neurological examinations (GCS exam
hourly, National Institute of Health Stroke Scale (NIHSS)
[131] six-hourly) and daily transcranial Doppler ultrasonogra-
phy (TCD) are simple and helpful monitoring tools [41,68].
Decreased level of consciousness and focal signs such as apha-
sia or hemiparesis in a good-grade SAH patient should prompt
the clinician to take immediate action [41,68].
TCD is a noninvasive method that can diagnose vasospasm
noninvasively in the larger cerebral arteries with high specifi-
city and variable sensitivity, dependent on the operator and
other systemic conditions [132,133]. A mean flow velocity
(Vm) of greater than 120 cm/s in the middle cerebral artery
(MCA) is concerning for vasospasm, Vm above 200 cm/s is
considered to be predictive, but dynamic changes in the mean
flow velocities, such as a twofold increase might be more
sensitive for the diagnosis of vasospasm [132,134].
A Lindegaard index (Vm of the middle cerebral artery in
relation to Vm in the extracranial internal carotid artery, see
Table 14.4) above 6 also indicates the presence of arterial
vasospasm [134–136].
A high suspicion for DCI should trigger an imaging study,
such as CT with CTA and/or CT perfusion (CTP), MRI with
MRA, or the gold standard, a cerebral angiogram [41,68]. CTA
has been found to have a high negative predictive value of
95–100%, a good correlation with cerebral angiography, and a
tendency to overestimate the degree of arterial narrowing
[137,138]. CTP gives additional information on cerebral per-
fusion status with mean transit time (MTT) and cerebral blood
flow (CBF). Both correlate well with cerebral angiography,
MTT >6.4 s is more sensitive, and CBF more specific for
vasospasm [139,140]. These imaging tests should be repeated
if the clinician is uncertain about the change in clinical status
being caused by DCI, if an endovascular intervention is con-
sidered, and if the risks of the planned therapy may outweigh
the benefits [68].
Poor-grade patients in stupor or coma require different
monitoring techniques to identify DCI. Multimodal
Table 14.4 Lindegaard ratio [136]
Mean MCA MCA:ICA Interpretation
velocity (cm/s) ratio
<120 <3 Normal
120–200 3–6 Mild vasospasm
>200 >6 Severe vasospasm

monitoring may be helpful in these patients by providing
direct and real-time information about partial brain tissue
oxygen pressure (pbtO2; by polarographic technique through
a Clark electrode) and metabolism (cerebral lactate, pyruvate,
glucose, glycerol, and glutamate by microdialysis), cerebral
perfusion (MAP – ICP = CPP, cerebral blood flow by thermal
diffusion microprobe), and depression of brain activity by
cEEG or intracortical electrodes. Quantitative cEEG analysis
demonstrated sensitive and specific detection of DCI by reduc-
tions in α-variability or α/δ ratio [141,142]. Clusters of spread-
ing depolarizations seen on cortical EEG have been associated
with DCI [143]. These are currently being investigated in the
DISCHARGE-1 phase III study. PbtO2 monitoring allows for
early detection of DCI showing a decrease in cerebral oxygen-
ation [144]. Elevations of glycerol, glutamate, and lactate/pyru-
vate ratios as markers of ischemia have been correlated with
reductions of cerebral blood flow on positron emission tom-
ography and DCI [145–147]. When used, these parameters
should be interpreted with caution, given their limited region
of capture and their location in relation to blood clots and
other pathologies. Moreover, screening for perfusion deficits
and arterial narrowing with CTA and CTP may be reasonable
in poor-grade patients [68].
Prevention of Delayed Cerebral Ischemia
Aside from high vigilance for symptoms of DCI, it may be
prevented by pharmacological interventions.
Nimodipine, a dihydropyridine calcium channel blocker,
was found to improve neurological outcome after SAH based
on neuroprotection rather than its effect on the vasculature.
Oral nimodipine (60 mg every four hours) should be adminis-
tered from day 1 through 21 [41,68,148].
Magnesium, a physiologic calcium antagonist, blocks
voltage-gated calcium channels, reduces release of glutamate
and calcium entry into cells. Its vasodilatative effect and safety
in SAH was repeatedly confirmed. The IMASH trial enrolled
327 patients to be randomized to receive magnesium or placebo
within 48 hours of symptom onset for 10–14 days. A difference
in primary outcome, defined as favorable outcome at six
months according to the extended GOS could not be demon-
strated [149]. Only one trial with 107 patients showed a reduc-
tion of DCI defined as ischemic infarction by 29% in the
magnesium group (64 mmol/day for 14 days), which did not
result in better long-term outcome or reduced mortality at six
months [150]. These findings were confirmed by a meta-
analysis including a total of 875 patients [151]. Therefore,
administration of additional magnesium is not recommended;
however, hypomagnesemia should be treated [68].
Statins have been evaluated in small randomized, con-
trolled trials for safety, their neuroprotective effect, and their
potential to decrease the incidence of DCI after SAH. In a
meta-analysis, a reduction of DCI and a small effect on
mortality could be demonstrated, but the results were other-
wise heterogeneous [152]. A multicenter trial studying the
effect of simvastatin 40 mg daily for 21 days on DCI versus
Chapter 14: Subarachnoid Hemorrhage
placebo, STASH, did not show any statin-related effect on
outcome. As the use of statins is safe in SAH, if patients are
already taking statins prior to SAH they should be continued
and starting statins may be considered in patients presenting
with SAH [68].
Clot removal and intrathecal administration of recombin-
ant tissue plasminogen activator (rtPA) or urokinase during
craniotomy to promote fibrinolysis, as well as head shaking
aimed at clot dissolution, are still under investigation
[153,154]. Another approach to reduce the incidence of DCI
are nimodipine microparticles in a sustained-release formula-
tion administered via EVD (NEWTON trial). Endothelin
receptor antagonists such as clazosentan did not succeed in
reducing DCI [155].
Management of Delayed Cerebral Ischemia
The treatment of DCI encompasses hemodynamic and endo-
vascular management.
Hemodynamic augmentation involves volume expansion
with crystalloid or colloid solutions, as well as elevation of
blood pressure and cardiac output in order to improve cerebral
blood flow through arteries in spasm and without autoregula-
tory capacity. This management strategy is often referred to as
“triple-H therapy” – hypervolemia, hypertension, hemodilu-
tion – and is considered the standard therapy for DCI. How-
ever, only limited data are available about its effects [156–161].
Most of these small studies report hypervolemia and/or
administration of vasopressors such as dopamine or norepin-
ephrine to be safe with variable effects on cerebral blood flow
and DCI. Phenylephrine was found to be safe to elevate the
MAP by 20–35% in the setting of DCI [162]. In the presence of
cardiac dysfunction, dobutamine or milrinone infusions are
alternatives to increase cardiac output as measured by cardiac
index [163–165]. However, dobutamine may lower the MAP
and require an increased vasopressor dosage [68]. Hemodilu-
tion is not recommended because of a reduction of oxygen
delivery to the brain [166]. If DCI is suspected, saline bolus
administration and a trial of step-wise-induced hypertension
with a vasopressor or inotropic drug should be undertaken
with periodic neurological assessments of the patient to define
the MAP target. If nimodipine administration leads to hypo-
tension, the dose may be reduced or the drug discontinued
[41,68]. If DCI is refractory to maximized induced hyperten-
sion and hypervolemia or limited by complications, such as
congestive heart failure, myocardial ischemia, or pulmonary
edema, cerebral balloon angioplasty and/or administration of
intra-arterial papaverine, nicardipine, or verapamil may lead
to reversal of neurological deterioration. Intracranial pressure
and arterial blood pressure should be monitored during
administration of intra-arterial vasodilators. The timing of
endovascular therapy should take into account the level and
tolerance of hemodynamic augmentation, prior evidence of
vasospasm, and the availability of endovascular procedures.
Studies report 70% sustained clinical improvement if intra-
arterial balloon angioplasty is performed within two hours of
165
 Chapter 14: Subarachnoid Hemorrhage
symptom onset, and 40% sustained clinical improvement
when performed more than two hours after symptom onset.
However, a more recent study reports worse clinical outcome
six months after SAH in patients with suspected vasospasm
based on a diffusion/perfusion mismatch on MRI who under-
went interventional management of DCI [41,68,167–170].
Electrolyte Disturbances
Hyponatremia occurs in 20–40% of SAH patients. Hypomag-
nesemia (40%), hypokalemia (25%), and hypernatremia (20%)
are also common after SAH [4,171–173]. Hyponatremia is
usually caused by the syndrome of inappropriate antidiuretic
hormone secretion (SIADH) and free-water retention and/or
excessive renal sodium excretion due to increased brain and
atrial natriuretic factor, so-called “cerebral salt-wasting syn-
drome” [4,174]. Intravascular volume depletion and sodium
loss may increase the risk of DCI and infarction [101,102]. In
124 WFNS grade 4 and 5 patients, hyponatremia (serum
sodium <135 mmol/L) developed in 63%, caused by cerebral
salt-wasting syndrome in 55%. Late-onset hyponatremia
(between SAH days 4 and 9) correlated with a higher occur-
rence of cerebral infarction in this patient population. Never-
theless, hyponatremia did not have an association with poor
outcome at three months (GOS 1–3) [175].
Fludrocortisone and hydrocortisone have been studied for
prevention of hyponatremia in SAH [176–180]. If started early,
the corticosteroids are effective in prevention of natriuresis
and hyponatremia. However, their use was complicated by
hyperglycemia and hypokalemia.
Administration of large-volume isotonic crystalloids and
restriction of free-water intake should be applied to counteract
potential hypovolemia and to prevent inappropriate water
retention. Hypertonic saline (3%) may be used to correct
hyponatremia [68,181].
Conivaptan is an arginine vasopressin receptor antagonist
(V1A/V2) approved for the treatment of euvolemic and hyper-
volemic hyponatremia [182]. Initial reports of its use in neuro-
critical care patients with hyponatremia have indicated
promising results [183]. Caution should be taken to avoid
hypovolemia with the use of conivaptan [68].
Treatment of Medical Complications
In addition to the direct effects of the initial hemorrhage and
secondary neurological complications, SAH also predisposes
to medical complications that may be associated with poor
long-term outcome [4] and increase the length of stay in the
neurocritical care unit (NCCU) and in the hospital [184].
Fever
Fever (38.3 °C) is the most common medical complication in
SAH patients (41–72%) [4,185–190]. It has been linked with an
increased risk of symptomatic vasospasm [187], an increased
length of NCCU and hospital stay [184] and with poor outcome
(mRS 4–6), dependence in activities of daily living, and
166
cognitive impairment at three months [4,187,188]. In SAH
patients, the temperature should be monitored at short intervals.
Normothermia should be the target in every SAH patient (see
Table 14.3). In a case control study of advanced fever control
with surface or endovascular cooling devices in 40 SAH patients,
advanced fever control resulted in a lower daily fever burden
and in better outcomes at 12 months (mRS 4–6 in 21%) com-
pared to conventional fever management of 80 SAH patients
(mRS 4–6 in 46%, P = 0.03) [190]. With every new occurrence
of fever, infections need to be screened for and treated. Fever
control should be attempted with antipyretics as first-line ther-
apy, followed by cold IV fluids, surface cooling or intravascular
devices, along with treatment for shivering [41,68].
Hyperglycemia
Admission or persistent hyperglycemia was associated with
DCI as well as poor short- and long-term outcomes (GOS
1–3, mRS 4–6) after SAH in several studies [4,146,191–195].
Depending on the definition, hyperglycemia occurs in
30–100% of SAH patients [4,192,193,196].
A small trial of 55 patients with SAH confirmed feasibility
and safety of continuous insulin infusion for glucose values
exceeding 7 mmol/L (126 mg/dL) with glucose assessments
performed every two hours [197]. The first randomized trial
of intensive glucose control (target glucose 80–120 mg/dL =
4.4–6.7 mmol/L) versus standard insulin therapy (target glu-
cose 80–220 mg/dL = 4.4–12.2 mmol/L) in 78 SAH patients
demonstrated a decreased rate of infection from 42% to 27% in
the intensive glucose control group. Mortality at six months
and the frequency of vasospasm were comparable in the two
groups [198]. Retrospective studies reflecting changes in clin-
ical practice, such as the introduction of insulin protocols,
demonstrated that good glycemic control (mean glucose
burden above 7.8 mmol/L (140 mg/dL) <1.1 mmol/L
(20 mg/dL)) significantly reduced the likelihood of poor out-
come at three to six months [199]. Hypoglycemia (<60 mg/
dL = 3.3 mmol/L) was identified as a powerful independent
predictor of mortality at discharge [200]. Furthermore, hypo-
glycemia resulting from tight glycemic control was linked to an
increased risk of DCI and infarction [201]. This may be seen as
a decrease in cerebral glucose, as well as an increase in lactate/
pyruvate ratio and glycerol as a marker for cell stress when
utilizing microdialysis [194,202–204]. Clinical signs of sys-
temic and cerebral hypoglycemia may not be obvious in
poor-grade SAH patients. Therefore, hypoglycemia should be
avoided while applying tight glucose control. If microdialysis is
used, the serum glucose level can be titrated according to the
cerebral glucose measurements [41,68].
Anemia
Anemia treated with blood transfusions is associated with an
increased risk of delayed infarction, mortality, and poor func-
tional outcome at three months after SAH [4,205], as well
as brain tissue hypoxia (pbtO2 15 mmHg) and metabolic
distress (lactate/pyruvate ratio 40) [206]. In a safety study,

44 SAH patients were randomized to hemoglobin targets of 10
g/dL (6.2 mmol/L) or 11.5 g/dL (7.1 mmol/L). Achieving the
higher hemoglobin target by transfusion of packed red blood
cells was found to be safe and feasible [207]. It remains uncer-
tain whether anemia after SAH reflects general illness severity,
impacts outcome directly, or whether the treatment for
anemia – blood transfusions – contributes to poor outcome
by triggering inflammatory responses [205,208,209]. To min-
imize the frequency of anemia, the number of blood drawings
should be reduced. Maintenance of hemoglobin levels between
8 and 10 g/dL (5.0–6.2 mmol/L) is recommended [68]. The
optimal hemoglobin level in SAH patients still needs to be
determined [41].
Neurogenic Stunned Myocardium and Pulmonary Edema
Subarachnoid hemorrhage may be complicated by cardiac
dysfunction and pulmonary edema due to a catecholamine
surge, resulting in neurogenic “stunned myocardium” or
“neurogenic stress cardiomyopathy” and neurogenic pulmon-
ary edema. Cardiac dysfunction is accompanied by transient
electrocardiographic abnormalities, troponin leaks, reversible
wall motion abnormalities on echocardiogram, hypotension,
and reduction of cardiac output. Neurogenic pulmonary
edema is caused by increased permeability of the pulmonary
vasculature and may be isolated or occur in conjunction with
neurogenic cardiac injury. Hypotension, reduced cardiac
output, and impaired oxygenation may impair cerebral perfu-
sion in the setting of increased ICP or DCI [210–212]. Tropo-
nin I elevations are found in about 35% of SAH patients
[213,214] and cardiac arrhythmias in 35% [4]. A meta-analysis
showed that cardiac abnormalities in electrocardiogram, echo-
cardiography, and troponin measurements are linked to DCI,
poor outcome, and mortality after SAH (discharge to six
months follow-up period) [215]. Thus, baseline evaluation
with serial cardiac enzymes and electrocardiogram is recom-
mended. Patients with evidence of depressed myocardial func-
tion and pulmonary edema should receive echocardiography
and monitoring of cardiac output. Standard management for
heart failure is applied with particular focus on cerebral perfu-
sion status. In pulmonary edema, lung-protective ventilation
and euvolemia are the targets of therapy [68].
Special Considerations for Angiogram-
Negative Subarachnoid Hemorrhage
Angiogram-negative SAH is defined as SAH not caused by
congenital aneurysm. The possible etiologies are discussed
below.
Trauma
In traumatic SAH the blood is confined to the ambient cistern,
usually unilateral and located at the tentorial margin. There is
a history of trauma. The hemorrhage is typically due to injury
of a vein through compression to the tentorial edge. If it is
unclear whether the traumatic event occurred prior to the loss
Chapter 14: Subarachnoid Hemorrhage
of consciousness, a CTA should be performed to rule out
aneurysmal SAH, which may have circumstantially caused
the traumatic brain injury.
Vertebral Artery Dissection
Dissection should be suspected in patients with recent history
of neck trauma or unusual neck movements (such as chiro-
practic manipulation). The diagnosis is confirmed by CTA or
angiography showing luminal narrowing (string sign), intimal
flap, or double lumen. Clinical signs that point to arterial
dissection include:
• Lower cranial nerve palsies
• Horner’s syndrome
• Lateral medullary syndrome.
Rebleeding occurs in 30% of patients and may be fatal in 50%.
Missed Aneurysms
Ruptured posterior circulation aneurysms may only show
hemorrhage in the fourth ventricle in up to 85% and occlusion
of the third ventricle to a lesser extent. Visualization of both
vertebral arteries including both posterior-inferior cerebellar
arteries by four-vessel cerebral angiography is crucial.
Anterior communicating-artery aneurysms may be over-
looked if they are very small (<3 mm). In a series of 130
patients, one 2-mm aneurysm at the anterior communicating
artery was not seen on initial review of CTA, but was seen on
cerebral angiography. Three-dimensional reconstruction aided
in post hoc recognition of the aneurysm on CTA.
Aneurysms may be obscured by vasospasm, thrombosis of
the aneurysm, or a poor-quality study, but should be suspected
in patients with extensive extravasation of blood into the
anterior interhemispheric fissure, the lateral sylvian fissure,
or the ventricles. Repeated angiography is diagnostic in 16%
of cases.
Dural and Spinal Arteriovenous Malformations
Tentorial-based dural AVMs may hemorrhage into the basal
cisterns, mimicking aneurysmal SAH. Angiography of the
external carotid arteries is important, as feeding vessels may
arise exclusively from this artery.
High cervical spinal AVMs can present with SAH into the
basal cisterns and ventricles in 10%. History of severe arm,
shoulder, or lower neck pain is suggestive of the diagnosis.
MRI may be used for screening if this etiology is suspected.
Mycotic Aneurysms
Endocarditis may cause aneurysms of the distal middle cere-
bral artery through septic embolization. However, 10% of
mycotic aneurysms also involve the proximal MCA. Hemor-
rhage of proximally located aneurysms may appear similar to a
ruptured saccular aneurysm. Mycotic aneurysms of the MCA
are typically treated with long courses of IV antibiotics, and
may be clipped or coiled later in the course of the disease.
167
 Chapter 14: Subarachnoid Hemorrhage

Mycotic aneurysms caused by aspergillosis are usually

located on the proximal vertebrobasilar or internal carotid
arteries. Rupture of these aneurysms causes hemorrhage into
the basilar cisterns and is frequently fatal.

Pituitary Apoplexy
Patients with pituitary apoplexy present with headache,
nausea, vomiting, meningismus, and decreased visual acuity
or diplopia. Endocrine derangements may occur, with corti-
costeroid deficiency being the most life-threatening compli-
cation. The CT scan demonstrates hemorrhage into the
pituitary fossa. A pituitary adenoma is also usually seen
on MRI.

Perimesencephalic/Prepontine SAH
This entity is termed prepontine or perimesencephalic non-
aneurysmal subarachnoid hemorrhage for the anatomic
localization of blood in the prepontine cistern (Figure 14.8).
The subarachnoid blood is restricted to the perimesencephalic
cisterns, which include the interpeduncular, crural, ambient,
and quadrigeminal cisterns, and does not extend significantly
into the lateral sylvian fissures or the anterior interhemispheric
fissure. An estimated 50–75% of aneurysm-negative SAH cases
are attributed to perimesencephalic SAH. The etiology is sus-
pected to involve rupture of a small perimesencephalic vein or
capillary. The entity of SAH carries a good prognosis, with no
incidence of rebleeding in 37 patients followed for a mean of Figure 14.8 Computed tomography demonstrating prepontine/
perimesencephalic subarachnoid hemorrhage.
45 months. Another study showed no rebleeding in
169 patients with 8–51-month follow-up.

introduced for DCI management. Current prevention of DCI

Future Perspectives
The majority of the recommendations for management of
patients with SAH are based on consensus opinions of experts
in the field [41,68]. There are many open questions, such as
the efficacy of antifibrinolytic therapy and the optimal blood
pressure goal to prevent rebleeding prior to aneurysm repair,
the efficacy of intensive glucose control and its target range,
the impact of maintained normothermia on outcome after
SAH, the optimal hemoglobin target after SAH and during
DCI, and the optimal therapy regimen for neurogenic
stunned myocardium. New endovascular techniques such as
intra-aortic balloon pumps and counterpulsation have been
and neuroprotection trials include intracisternal application
of thrombolytic therapy to decrease the clot burden, early
placement of lumbar drainage, intrathecal application of
magnesium sulfate, intraoperative implantation or intraven-
tricular use of nicardipine or nimodipine prolonged-release
formulations, as well as intravenous administration of human
albumin. The best monitoring technique and triggers for
neuroimaging and intervention for DCI in poor-grade SAH
patients, as well as the role of spreading depolarizations in
DCI and potential therapy targets for physiological derange-
ments detected by multimodality monitoring, need to be
defined.

hemorrhage epidemiology in the WHO 4. Wartenberg KE, Schmidt JM, Claassen

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Chapter 14: Subarachnoid Hemorrhage
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175
 Chapter
Status Epilepticus in the Neurocritical Care Unit

15 Fawaz Al-Mufti and Jan Claassen

Introduction antiepileptic drug (AED) noncompliance or withdrawal is by

far the most common precipitating cause of SE in adults with
Status epilepticus (SE) is defined as continuous or repetitive
pre-existing epilepsy accounting for 22–26% of all cases
seizure activity persisting for at least five minutes without
[13,18]. In older adults, SE due to remote stroke accounts for
recovery to baseline between attacks [1,2]. SE may be classified
36–61% [13] of cases. The leading causes of SE in children
into convulsive and nonconvulsive, based on the presence of
include prolonged febrile seizures [19], CNS infection, inborn
rhythmic jerking of the extremities. Refractory status epilepti-
errors of metabolism [20,21] congenital malformation, anoxia
cus (RSE) is defined as ongoing seizures failing to respond to
brain injuries, and tapering or discontinuation of AEDs.
first- and second-line anticonvulsant drug therapy. Among
these patients, 10 to 15% [3] fail to respond to third-line
therapy, and are considered to have super-refractory SE Classification of Status Epilepticus
(SRSE) [4]. Generalized Convulsive Status Epilepticus
The clinical presentation of generalized convulsive status epi-
Epidemiology leticus (GCSE) is relatively characteristic and hence rarely
SE accounts for 20% of emergency department (ED) visits for poses diagnostic challenges. Patients may initially present with
neurologic problems and 1% of all ED visits, [5–7] with a alteration in their mental status ranging from decreased
9–27% 30-day mortality rate [8]. In neurologic intensive care
units up to a third of patients will have nonconvulsive seizures
and most of these patients will be in nonconvulsive SE. The Table 15.1 Etiology of status epilepticus
prevalence of nonconvulsive seizures has also been studied in Etiology Lowenstein Towne et al.
medical and surgical intensive care units and was found to be et al. Patients (%)
between 10% and 16% for patients with impaired mental status Patients (%)
undergoing continuous electroencephalography after exclud- Discontinuation of AED 26 22.5
ing those with convulsions or neurological diagnoses [9–12].
Within this population, seizures were particularly common in Cerebral vascular disease 4 22.5
those with sepsis. After cessation of clonic movements in Ethyl alcohol consumption 10 14.2
patients with convulsive SE, nonconvulsive electrographic Idiopathic 4 14.2
seizures (NCSz) persist in 20–48%, and 14% are in NCSE
[13,14]. RSE occurs in 30–43% of patients with SE [15]. Anoxia 4 11.9
Metabolic 4 11.5
Etiology Hemorrhage – 5.1
SE may be due to acute or chronic processes (see Table 15.1). Infection 8 5.1
Approximately 44% of adults admitted with SE have no history
Tumor 6 4.4
of seizures [2]. Acute symptomatic causes are the most
common etiology, accounting for 48–63% of all SE cases Trauma 5 4.0
[16,17]. In these patients, stroke accounts for 19–20% and is Drugs 10 2.4
the most frequent cause among adults [13]. Acute electrolyte
Central nervous system infection 8 0.8
disturbances, renal failure, sepsis, central nervous system
infections (meningitis, encephalitis, or brain abscess), Congenital disorder – 0.8
medication-induced toxicity, hypoxic conditions, and head (Adapted from Lowenstein DH. Status epilepticus: An overview of the clinical
trauma (with or without epidural, subdural hematomas or problem. Epilepsia. 1999:40 (suppl 1):S3–S8 and Towne AR, et al. Determinant
of mortality of status epilepticus. Epilepsia 1994;35(1):27–34.)
contusions), are common causes of SE. Among chronic causes,

176

attentiveness and impaired responsiveness to a deeply coma-
tose state between convulsions. Simultaneously or shortly
thereafter patients begin to illustrate continuous or repeated
generalized tonic-clonic movements or rhythmic jerking of the
extremities. After convulsions have ceased, focal findings such
as focal motor impairment, also known as Todd paralysis, may
persist. A typical secondarily generalized tonic-clonic seizure
generally stops within three minutes and almost always within
five minutes [22].
Nonconvulsive Status Epilepticus
Patients in nonconvulsive status epilepticus (NCSE) are in a
phase of electro-clinical dissociation whereby seizure activity is
seen on the electroencephalogram (EEG) without convulsive
movements of the extremities and with or without subtle motor
movements. Clinical features of NCSE range from negative
symptoms (anorexia, aphasia, mutism, amnesia, catatonia,
coma, confusion, lethargy, staring) to positive symptoms (agi-
tation, aggression, automatism, repetitive blinking, nystagmus,
forced gaze deviation, crying or laughter, delusions, delirium,
echolalia, nausea or vomiting, facial twitching, and persever-
ation). This large spectrum of indistinct clinical presentations
can easily lead to misdiagnosis and delayed treatment. Con-
firmation of the diagnosis mandates electroencephalographic
monitoring.
Diagnostic criteria for NCSE are:
1. A period of behavioral change from baseline
2. EEG evidence of epileptic activity fulfilling one of the three
primary electrographic criteria (see below) lasting for at
least 10 seconds.
3. Clinical response to an AED.
Significant acute clinical improvement coupled with resolution
of epileptiform discharges in response to administration of a
rapidly acting antiepileptic drug would be diagnostic.
Electrographically NCSE is characterized by frequent
seizures or continuous ictal activity corresponding to any of
the following patterns [1,23–26]:
1. Focal or generalized spikes, sharp waves, or sharp-and-slow
complexes at frequencies >3 Hz
2. Focal or generalized spikes, sharp waves, or sharp-and-slow
complexes at frequencies <3 Hz or rhythmic activity
>0.5Hz and one of the following:
a. EEG and clinical improvement after an IV trial of
an AED
b. Subtle clinical ictal phenomena during the EEG pattern
c. Typical spatio-temporal evolution, including
incrementing onset (increase in voltage and change in
frequency), or evolution in pattern (change in
frequency >1 Hz or change in location), or
decrementing termination (voltage or frequency).
It should be mentioned that, in patients with chronic epilepsy
or epileptic encephalopathy syndromes, an EEG with frequent
or continuous generalized spike wave discharges (more than
Chapter 15: Status Epilepticus
30 total minutes of ictal EEG activity in any given hour of
recording), that is significantly different from their baseline
EEGs may be sufficient to diagnose NCSE.
Refractory Status Epilepticus
Rapid diagnosis of SE is crucial since untreated SE rapidly
becomes refractory to therapy and carries a significant mor-
bidity and mortality. RSE is defined by most experts as SE that
persists despite first- and second-line AEDs, regardless of the
elapsed time. Most commonly, patients with RSE are comatose
with no clinical manifestations of seizures [27] or they may
have subtle focal twitches in the extremities or the face, apha-
sia, amnesia, automatisms, ongoing staring, blinking, forced
gaze deviation, or nystagmoid eye movements [28,29]. Due to
the lack of population-based studies with continuous EEG
monitoring, the exact incidence and prevalence is unclear
and likely underestimated. In the Veterans Administration
(VA) cooperative study, 38% of patients with overt SE and
82% with subtle SE continued seizing after receiving full doses
of two AEDs.
The exact mechanisms underlying the development
of refractoriness are incompletely understood. Evidence has
accumulated that impairment of γ-aminobutyric acid (GABA)-
mediated inhibition related to internalization of GABA receptors
[30–34] and up-regulation of excitatory AMPA (α-amino-
3-hydroxy-5-methyl-4-isoxazolepropionate) and NMDA (N-
methyl-d-aspartate) receptors [34] may play a role in the
development of increasing refractoriness to treatment.
Diagnostic Workup
The diagnostic workup should be conducted in parallel with
treatment. Following guidelines published by the Neurocritical
Care Society for the evaluation and management of SE all
patients should receive the care detailed in Table 15.2.
Routine Workup
Telemetry
Head CT scan: To rule out intracranial hemorrhages
(subarachnoid, subdural, intraparenchymal), fractures,
masses, strokes; CT scans are appropriate for most cases
Laboratory tests: The reasons for breakthrough and
persistent seizures should be established by determining
blood glucose level and obtaining a complete blood count,
basic metabolic panel, calcium (total and ionized),
magnesium, antiepileptic drug (AED) level, routine urine
toxicology, pregnancy test, troponin, and an arterial
blood gas.
Continuous EEG monitoring: Continuous EEG must be
considered in all patients that do not return to clinical
baseline (see Table 15.3). Monitoring for 24 hours detects
95% of seizures in noncomatose patients and 80% in
comatose patients, therefore comatose patients should
undergo a minimum of 48 hours of EEG monitoring in
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 Chapter 15: Status Epilepticus

Table 15.2 Critical care intervention sequence outline for SE

Critical care intervention Suggested timing of Goals

intervention
Vital signs: O2 saturation, BP, HR Immediate (0–2 min) Establish and support baseline vital signs
Noninvasive airway protection and gas Immediate (0–2 min) Maintain airway patency, administer O2
exchange with head positioning
Intubation (if airway/gas exchange Immediate (0–10 min) Establish secure oxygenation and ventilation
compromised or elevated ICP suspected)
Finger stick blood glucose Immediate (0–2 min) Diagnose hypoglycemia
Vasopressor support if mean arterial pressure Immediate (5–15 min) Support organ perfusion and cerebral perfusion pressure
<70 mmHg
Triage lab test panel Immediate (0–5 min) Diagnose life-threatening metabolic condition
(CBC, BMP, UA)
Urgent SE control therapy with AED Immediate after initial Stop seizure
AED given (5–10 min)
Neurologic exam to assess subtle movements Urgent (5–10 min) Evaluate for focal neurologic deficits to mass lesion, acute
and focal neurologic deficits intracranial process
Continuous EEG Urgent (15–60 min) Evaluate for NCSE if not waking up after clinically obvious
seizures cease
Refractory SE treatment Urgent (20–60 min after Arrest seizures; Strategies tailored to individual patient
second AED is given) response and AED concentrations (if applicable)
Diagnostic testing: CT, lumbar puncture, MRI Urgent (0–60 min) Evaluate for mass lesions, meningitis or encephalitis.
(depending on clinical presentation)
ICP monitoring Urgent (0–60 min of Measure and control ICP
(depending on clinical presentation) imaging diagnosis)
Abbreviations: BP: blood pressure; HR: heart rate; ICP: intracranial pressure; CBC: complete blood count; BMP: basic metabolic panel; UA: uric acid; EEG:
electroencephalogram; CT: computed tomography; MRI: magnetic resonance imaging. (Adapted from Guidelines for the Evaluation and Management of Status
Epilepticus Gretchen M. Brophy et al Neurocritical Care Society Status Epilepticus Guideline Writing Committee Neurocrit Care. Aug 2012;17(1):3–23.)

Table 15.3 Indications for continuous EEG monitoring

Recent clinical seizure or SE without return to baseline >10 min 18–50% may have ongoing NCSE despite
cessation of motor activity
Coma, including post cardiac arrest Nonconvulsive seizures seen in 20–60%
Epileptiform activity or periodic discharges on initial 30 min EEG Nonconvulsive seizures seen in 40–60%
Acute brain injury or intracranial hemorrhage including traumatic brain injury (TBI) and Nonconvulsive seizures seen in 20–35%
subarachnoid hemorrhage (SAH)
Suspected nonconvulsive seizures in patients with altered mental status Nonconvulsive seizures seen in 10–30%
(Adapted from Guidelines for the Evaluation and Management of Status Epilepticus GM Brophy et al. Neurocritical Care Society Status Epilepticus Guideline Writing
Committee Neurocrit Care. 2012;17(1):3–23.)

order to rule out nonconvulsive seizures. In patients
undergoing EEG monitoring, 58% of patients who
progress to develop seizures do so within 30 minutes of the
recording [35]. EEG monitoring may demonstrate
generalized periodic discharges (GPEDs), lateralized
periodic discharges (PLEDs), or bilateral but independent
periodic discharges (BIPLEDs), which in the setting of SE
may be considered on an ictal/interictal continuum since
they do not meet formal seizure criteria and their exact
nature and significance are not well understood. Of patients
who demonstrate some of these epileptiform abnormalities
early in the EEG recording, 25% eventually demonstrated
seizures on EEG, whereas only 4% experienced a seizure
without preceding epileptiform abnormalities. Hence

178

patients with normal EEGs may not need prolonged EEG
monitoring to rule out seizures or SE [35].
Selective workup
In certain circumstances the workup should be tailored to
the clinical scenario (see Table 15.4).
Brain MRI: MRI findings in patients with SE are complex to
interpret, as both underlying causes for SE and seizure-
related changes may be observed. On MRI a seizure focus
may show up as restricted diffusion on diffusion-weighted
imaging (DWI)/apparent diffusion coefficient (ADC) in a
nonvascular territory, possibly with leptomeningeal
enhancement. Brain regions frequently affected by this
include the pulvinar of the thalamus, the hippocampus, and
cortical regions [36]. MRI may reveal areas of increased
signal intensity on FLAIR, T2, or DWI in the presence of SE.
This pattern may mimic acute infarction. These findings are
believed to represent seizure-induced cellular edema and are
seen in cortical and limbic structures, particularly the
hippocampus [37] . They may persist for days to weeks,
especially if seizures are prolonged, and either ultimately
resolve or evolve into focal atrophy and sclerosis [38]. These
lesions are nonspecific and can be associated with many
other processes. Neuronal death can occur under certain
circumstances after as little as 30 to 60 minutes of
continuous seizure activity[39,40]. The pathologic hallmark
of this phenomenon, cortical laminar necrosis, may also be
seen on brain MRI as a persistent, high-intensity lesion on
T2 or DWI, which follows the gyral anatomy of the cerebral
cortex [39,40].
Lumbar puncture (LP): The presence of fever at presentation
should raise suspicion for central nervous system (CNS)
infection, and empiric treatment with bacterial and viral
coverage should be started until the results from the
lumbar puncture and imaging ancillary testing are
available.
Table 15.4 Differential diagnosis of status epilepticus
• Movement disorders (myoclonus, asterixis, tremor, chorea,
tics, dystonia)
• Herniation (decerebrate or decorticate posturing)
• Limb-shaking transient ischemic attacks (TIAs), most
commonly associated with perfusion failure due to severe
carotid stenosis
• Psychiatric disorders (psychogenic nonepileptic seizures,
conversion disorder, acute psychosis, catatonia)
• Postanoxic myoclonus
• Any condition that may lead to decreased level of
consciousness (e.g. toxic-metabolic encephalopathies,
including hypoglycemia and delirium, anoxia, and CNS
infections), transient global amnesia, sleep disorders (e.g.
parasomnias), syncope.
Chapter 15: Status Epilepticus
Comprehensive laboratory and toxicology panel: including
toxins that frequently cause seizures (i.e. isoniazid, tricyclic
antidepressants, theophylline, cocaine, sympathomimetics,
alcohol, organophosphates, and cyclosporine).
Other laboratory tests: liver function tests, serial troponins,
type and hold, coagulation studies, arterial blood gas, AED
levels, and special serum and cerebrospinal fluid (CSF) tests
for inborn errors of metabolism.
Benzodiazepine trial: In some patients with clinically
suspected SE or questionable EEG findings, the diagnosis
may be supported by the benzodiazepine trial test, which
includes administration of sequential small doses of rapidly
acting, short-duration benzodiazepines (e.g. midazolam 1
mg). Although rarely helpful in the intensive care unit (ICU)
setting, resolution of the potentially ictal EEG pattern and
either an improvement in the clinical state or the appearance
of previously absent normal EEG patterns is diagnostic for
status epilepticus. If the EEG improves, but the patient does
not (e.g. due to marked sedation), the result is considered
equivocal.
Management
Prehospital Treatment
The most important modifiable element of therapy determin-
ing successful termination of seizures is time elapsed before
initiating benzodiazepines. When treatment with IV agents was
begun within 30 minutes of seizure onset, the initial AED was
successful in terminating SE patients’ seizures in 80% of cases,
whereas only 40% responded to therapy started beyond the
two-hour window [10,41]. Furthermore, mortality doubles with
a 24-hour delay in treatment of nonconvulsive status.
The Pre-Hospital Treatment of Status Epilepticus (PHTSE)
trial randomized SE patients to paramedic treatment with IV
diazepam, lorazepam, or placebo. PHTSE demonstrated that
emergency medical services (EMS)-delivered benzodiazepines
resulted in a higher rate of cessation of seizures before arrival
in the ED compared to placebo and was also associated with
better clinical outcomes [8]. More recently, the Rapid Anticon-
vulsant Medication Prior to Arrival Trial (RAMPART) com-
pared IM administration of midazolam to IV administration
of lorazepam. This was a randomized, double-blind, prospect-
ive, noninferiority prehospital clinical trial [42], and showed
that IM midazolam was at least as good as IV lorazepam in
terminating SE.
First responders should be ready to treat respiratory
depression in patients with SE. Apart from airway support,
other important considerations for the prehospital manage-
ment of SE include assuring stable circulation, if possible
obtaining IV access, and excluding hypoglycemia as a potential
cause of SE. Importantly, it was demonstrated that respiratory
compromise was more commonly seen in patients who
received placebo than those who were given benzodiazepines,
suggesting that administering AEDs as soon as possible is not
179
 Chapter 15: Status Epilepticus
only more efficacious, but also safer than waiting [8]. It is of
paramount importance not to withhold seizure medications
for fear of respiratory suppression as the need for intubation
from ongoing seizure activity is higher than that from benzo-
diazepine administration. As a side note, lorazepam needs to
be refrigerated and for this reason it is often impractical for
EMS use and diazepam or midazolam are used as alternatives.
Initial In-Hospital Treatment of Status Epilepticus
and Prevention of Recurrence of Seizures
Initial treatment of SE in the ED continues or complements
the elements that should have been initiated by EMS. Airway,
breathing, and circulation should be re-evaluated and support-
ive care continued. Intravenous access should be established if
access has not already been obtained. If hypoglycemia has not
been excluded, D50W 50 ml IV and thiamine 100 mg IV
should be given to all unresponsive patients. SE due to hypo-
glycemia will only respond to glucose administration and
delayed treatment will result in permanent damage if not
corrected rapidly.
Most patients with ongoing seizures are not able to secure
their airways and therefore require early intubation. Paralytics
for intubation should be avoided whenever possible since they
may mask ongoing convulsions.
Hemodynamic monitoring is mandatory since SE, as well
as antiepileptics used to treat SE, have been associated with
arrhythmias and hypotension. Early establishment of IV access
should be attempted. A suggested clinical approach is demon-
strated in Table 15.2.
First-Line Therapeutic Agents:
Benzodiazepines
In patients who continue to convulse or do not regain con-
sciousness and have electrographic seizures, additional benzo-
diazepines may be administered. Lorazepam is the preferred
first drug because of its relative longer duration of action
(12–24 h for lorazepam versus 15–30 min for diazepam).
The VA cooperative trial identified 4 mg of IV lorazepam
as the preferred initial AED, but IV diazepam was also effica-
cious in terminating seizures. Lorazepam given as the initial
AED is associated with a success rate between 59% and 65%
[43]. The recommended lorazepam dose is 0.1mg/kg in two
divided doses, which amounts to 4 mg IV to be given over two
minutes; if seizures persist after five minutes, another 4 mg can
be given.
Initial treatment failure is often a result of using inadequate
initial doses of IV benzodiazepines and then waiting too long
to repeat benzodiazepine doses and advance to second-line
agents or general anesthesia and induced coma [5].
If IV access cannot be rapidly established, diazepam 20 mg
per rectum or midazolam 10 mg administered intranasally,
buccally, or intramuscularly [8,43,44] may be chosen as
alternatives.
180
Second-Line Agents
All patients with SE should be given a second-line AED since
although the initial benzodiazepine may stop the seizures they
do not offer long-term control and seizure recurrence may
occur if longer-acting antiepileptics are not started. The pre-
ferred top-tier agents that are generally used for urgent control
of SE are IV fosphenytoin/phenytoin and valproic acid,
although phenobarbital and levetiracetam may be alternatives.
Phenytoin
Phenytoin or fosphenytoin loading should be weight based,
hence fosphenytoin must be given at a dose of 20 mg/kg IV at
150 mg/min. If seizures persist an additional 10 mg/kg IV at 150
mg/min may be given. Hypotension may be seen with loading
phenytoin or fosphenytoin in 28–50%, hence loading should be
performed with blood pressure and electrocardiogram (ECG)
monitoring. Loading doses should not be adjusted for renal or
hepatic insufficiency. Phenytoin levels should be drawn two
hours after the infusion of fosphenytoin or phenytoin.
Valproic Acid
Valproic acid is administered as 20–40 mg/kg IV over 10 min
with an additional 20 mg/kg given subsequently over five
minutes if the patient is still seizing. Valproic acid serum levels
may be obtained immediately following the loading dose infu-
sion. Recent evidence has emerged from small prospective,
randomized, open-label trials to suggest that IV valproate is
an efficacious and safe first- or second-line treatment [45].
Levetiracetam
Levetiracetam, loaded as 2.5 g intravenously over five minutes
at 1–4 g over 15 minutes, is often used off-label as a second-
line agent, but data are limited so far. A retrospective review of
36 patients receiving IV levetiracetam after failing at least one
AED showed resolution of status epilepticus in 69% [46].
Phenobarbital
IV phenobarbital is Food and Drug Administration (FDA)
labeled for the treatment of SE, but it is less commonly chosen
in adults unless other agents are contraindicated or unavail-
able. Phenobarbital 20 mg/kg is loaded intravenously at a rate
of up to 50–100 mg/min with an additional 5–10 mg/kg given
if needed. Phenobarbital prolongs and potentiates the action of
GABA on GABAA receptors and at higher concentrations
directly activates the receptors, hence it may be a less rational
choice in those who have not responded to benzodiazepines,
although there are few data to address this concern.
Lacosamide
Recent case series suggest that lacosamide given intravenously
as a bolus dose of 200–400 mg over three to five minutes may
have some efficacy as an adjunctive agent in the treatment of

status epilepticus [47,48], however this is still controversial at
this point in time [49].
Advanced Management of Refractory
Status Epilepticus
Typically SE terminates with the first- and second-line drugs
described above. SE not responding to the initial two or more
anticonvulsants should be considered to be in RSE, regardless
of the elapsed time, and an aggressive approach is required.
These patients are generally in a coma, have respiratory and
cardiovascular compromise, and have associated systemic com-
plications. Hence, these individuals are best managed in an ICU
setting, as these therapies, although effective in controlling
seizures, frequently are associated with significant cardiovascu-
lar and respiratory compromise, and risk of infections.
Recommendations for the preferred therapy for RSE are
primarily based on case series and expert opinion, hence
practices vary widely. The VA cooperative trial showed that
the treatment success rate with the first drug was 55% in the
overt status group and 15% in the subtle status group. Success-
ful termination of SE becomes progressively difficult, dropping
to 10% for second and third agents (see Table 15.5). Hence it is
not advisable to delay advanced therapy with repeated trials of
alternative second-tier AEDs.
Most experts would recommend treatment with general
anesthesia in order to induce coma with a continuous IV
AED such as midazolam or propofol as the initial step, but
valproic acid may be a reasonable alternative particularly in
patients that have an active do-not-intubate order. It is import-
ant to make the determination of refractoriness early (30–60
minutes) because delayed attempts to control status epilepticus
with antiepileptic agents are frequently ineffective.
There is some controversy regarding the benefit from anes-
thetic doses of antiepileptics based on a retrospective uncon-
trolled series of patients [50,51], but most experts would treat
the vast majority of patients with RSE with anesthetic drips [1].
Endotracheal intubation is necessary for safe induction of coma
and should be quickly performed when seizures continue.
Particularly in patients that have received long-acting paralytics
for intubation, there should be a low threshold to obtain EEG
monitoring, as convulsions may not be seen. The agents most
commonly used to induce a general anesthesic state of coma are
continuous infusions of midazolam or propofol [33,52,53].
A systematic review of studies on the treatment of RSE found
no difference in mortality (48%) comparing 193 RSE patients
treated with continuous IV propofol, continuous IV midazo-
lam, or continuous IV pentobarbital [33].
Midazolam
Midazolam is administered as 0.2 mg/kg followed by 0.2–0.4
mg/kg boluses every five minutes until seizures stop, up to a
maximum total loading dose of 2 mg/kg. This is followed by a
maintenance dose of 0.05–2.9 mg/kg/h. Advantages of
Chapter 15: Status Epilepticus
Table 15.5 Treatment of refractory status epilepticus
Midazolam Load: 0.2 mg/kg IV over 2–5 min; repeat 0.2–0.4
mg/kg boluses every 5 minutes until seizures
stop, up to a maximum loading dose of
2 mg/kg
Initial rate: 0.1 mg/kg/h. Bolus and increase rate
until seizure control
Maintenance: 0.05–2.9 mg/kg/h
Propofol Load: 1–2 mg/kg IV over 3–5 min; repeat
boluses every 3–5 minutes until seizures stop,
up to maximum total loading dose of 10 mg/kg
Initial rate: 20 μg/kg/min. Bolus and increase
rate until seizure control
Maintenance: 30–200 μg/kg/min titrated to EEG
with 5–10 μg/kg/min every 5 min or 1 mg/kg
bolus for breakthrough SE
Valproic acid 20–40 mg/kg IV over 10 min (may give
additional 20 mg/kg over 5 min if still seizing)
Pentobarbital Load: 5–15 mg/kg (5–10 mg/kg in patients with
pre-existing hypotension) infused over one
hour. May repeat 5 mg/kg boluses until seizures
stop
Initial rate: 1 mg/kg/h
Maintenance: 0.5–5 mg/kg/hour; titrated to
maintain seizure suppression pattern on EEG
and a serum level of 30–45 µg/mL. For
breakthrough SE, a 5 mg/kg bolus must be
given and the continuous infusion rate should
be increased by 0.5–1 mg/kg/h every 12 hours
Ketamine The optimum dose in refractory SE is uncertain,
but has been extrapolated from the anesthesia
literature (1–4.5 mg/kg with supplements of
0.5–2.5 mg/kg every 30–45 min or 10–50 µg/
kg/min)
Load: 1.5mg/kg every 3–5 minutes until seizure
stops, up to a max of 4.5 mg/kg
Initial rate: 20 μg/kg/min (1.2 mg/kg/h). Bolus
and increase rate by 10–20 μg/kg/min until
seizure control is established
Maintenance: 5–125 μg/kg/min (0.3–7.5mg/
kg/h)
midazolam are its rapid onset, easy titration, greater water
solubility, and circumvention of the metabolic acidosis associ-
ated with the propylene glycol vehicle of other benzodiazepines
and barbiturates [33]. A recent retrospective observational
study compared adults with RSE treated with high-dose cIV
midazolam with those treated with the previous lower-dose
cIV midazolam. Compared with the low-dose group, high-
dose cIV midazolam treatment of RSE was associated with a
lower seizure rate after midazolam discontinuation (15%
versus 64%), and may be associated with lower mortality than
traditional lower-dose protocols. Hypotension was more fre-
quent with higher cIV midalozam doses, but was not associ-
ated with worse outcome [54]. Patients with refractory NCSE
181
 Chapter 15: Status Epilepticus
treated with continuous infusions of midazolam were found to
have acute treatment failure and breakthrough seizure in 18%
and 56%, respectively [55]. The major disadvantages of mid-
azolam include the short half-life, requiring a continuous infu-
sion and the development of tachyphylaxis with prolonged
infusions [56]. Furthermore the pharmacokinetics may be
altered in critically ill patients causing a wide range of clearance
and volume of distribution inconsistencies for midazolam [57].
Propofol
The Neurocritical Care Society guidelines on SE recommend
starting a propofol drip at 20 μg/kg/min, with a 1–2 mg/kg
loading dose followed by continuous infusion dosing at 30–200
μg/kg/min titrated to EEG with 5–10 μg/kg/min every five
minutes or 1 mg/kg bolus for breakthrough SE [1]. Onset of
action is within 3–5 min and activity persists only for 5–10 min
after the drip is discontinued. Rapid discontinuation should be
avoided, as it may precipitate withdrawal seizures [58].
Significant concerns when using propofol include respira-
tory suppression, hypotension, infections with prolonged infu-
sions and propofol infusion syndrome (PRIS). PRIS is a rare
but potentially lethal complication seen more frequently with
sepsis, serious cerebral injury, and the administration of high
doses of propofol (usually doses >83 μg/kg/min or >5 mg/kg/h
for >48 h), but has also been reported following large-dose,
short-term infusions and lower-dose infusions. It is associated
with a high mortality rate (up to 33%) and is clinically charac-
terized by dysrhythmia (e.g. bradycardia or tachycardia), heart
failure, hyperkalemia, hypertriglyceridemia, metabolic acid-
osis, and rhabdomyolysis or myoglobinuria with subsequent
renal failure [59] and death. Onset is typically within four days
of initiation. The mechanism of the syndrome has yet to be
determined [53,59]. Since propofol is delivered in a lipid
vehicle, some advocate adjusting dietary calories so as to avoid
overfeeding. Advantages of propofol include less tachyphylaxis
than midazolam, and less hypotension than phenobarbital
[60]. Both midazolam and propofol are more expensive than
high-dose barbiturates. There does not seem to be significant
cost differences between the two drugs.
Barbiturates
Continuous IV infusions of barbiturates (in the USA typically
pentobarbital, in Europe thiopental), a mainstay of RSE treat-
ment for the past 50 years, has been used less frequently as
third-line therapy in favor of midazolam or propofol. Pento-
barbital is administered with a loading dose of 5–15 mg/kg
(5–10 mg/kg in patients with pre-existing hypotension)
infused over one hour, followed by an initial maintenance
continuous infusion at a rate of 0.5–5 mg/kg/h, titrated to
maintain seizure suppression pattern on EEG, which corres-
ponds typically with a serum level of 30–45 µg/mL. For break-
through SE, a 5 mg/kg bolus must be given and the continuous
infusion rate should be increased by 0.5–1 mg/kg/h every
12 hours [1,61].
182
When comparing treatment of RSE with continuous infu-
sions of propofol, midazolam, or pentobarbital, there was not
difference in mortality at discharge [33]. In contrast, pentobar-
bital had a lower frequency of acute treatment failure and
breakthrough seizures. In the only randomized controlled trial
(RCT) of RSE treatments, propofol was compared with barbit-
urates. This trial was terminated early due to insufficient
recruitment and was hence underpowered. Mortality, func-
tional outcome, and complications were similar between the
groups except the barbiturate group had longer periods of
mechanical ventilation [52]. A recent paper on super-refractory
SE showed that pentobarbital drips controlled seizures in 90%
of patients. Although seizures recurred in 48% while weaning,
80% of those patients were eventually weaned successfully,
many with the addition of phenobarbital given per mouth or
feeding tube. This retrospective analysis also found fewer side
effects (ventilator-associated pneumonia, hypotension, urinary
tract infections) compared with previously published data [62].
The main limitations of its use are related to the side-effect
profile that includes hypotension requiring pressors [63], pro-
longed mechanical ventilation [52], very long half-life (15–50
hours), blood dyscrasias, and allergic reactions ranging from
angioedema to Stevens–Johnson syndrome; furthermore it
must be used with caution in patients with hepatic or renal
impairment. In addition, high-dose barbiturates are potentially
immunosuppressive, and extra care is needed to prevent and
treat nosocomial infections [64].
Ketamine
As excitatory N-methyl-d-aspartate (NMDA) receptors are up-
regulated with prolonged SE, NMDA receptor (NMDAR) antag-
onists such as ketamine are attractive as a potential treatment
for refractory SE [65]. However, there is little clinical data to
support their administration. The optimum dose in refractory
SE is uncertain, but has been extrapolated from the anesthesia
literature. An initial 1.5 mg/kg loading dose is given every three
to five minutes until seizures stop, up to a max of 4.5 mg/kg.
The initial infusion rate is 20 μg/kg/min (1.2 mg/kg/h), but if
seizure control is not established, a bolus should be given and
the rate increased by 10–20 μg/kg/min. Patients are kept on
maintenance rate of 5–125 μg/kg/min (0.3–7.5 mg/kg/h).
A multicenter retrospective review showed that permanent
control of RSE was achieved in 57% of cases [66]. Another
recently published systematic literature review regarding the
use of NMDAR antagonists for RSE described 110 adult
patients, and showed electroencephalographic seizure control
in 56.5%, with a 63.5% response in the 52 pediatric patients
described [67]. Moreover, ketamine appears to have a syner-
gistic effect when combined with benzodiazepines [68,69].
Adverse events were rare and overall ketamine appears to be
a relatively effective and safe drug for the treatment of RSE.
However, unlike most of the other agents used for RSE, it
causes elevation of blood pressure. Caution is warranted in
patients with elevated ICP, TBI, ocular injuries, hypertension,

chronic congestive heart failure (CHF), myocardial infarction
(MI), tachyarrhythmias, and history of alcohol abuse [70].
Other Antiepileptic Drugs
If not tried earlier, one should consider adding levetiracetam,
lacosamide, phenobarbital, or pregabalin. In a study of
23 patients with brain tumors who developed RSE, 70% of
patients receiving combination therapy of phenytoin, levetir-
acetam, and pregabalin (median daily dose of 375 mg) had
control of SE within an average of 24 hours after the addition
of the third AED [71].
Ketogenic Diet
Fasting has been used to treat epilepsy since at least 500 BC and
the use of the ketogenic diet for RSE has shown some promise
as an SE treatment [72]. A retrospective case series on the use of
ketogenic diet for RSE described 10 patients with a median
duration of SE before initiation of the diet of 21.5 days and a
median number of antiepileptic medications used before the
change in diet of seven. Of the patients who achieved ketosis in
a median of three days, 90% also achieved seizure control [73].
Inhaled Anesthetics
There are few studies on the use of inhaled anesthetics for the
treatment of RSE [74,75]. Isoflurane is a volatile anesthetic,
with minimal risk of hepatotoxicity, less cardiac suppression,
and relatively safe to use in patients with porphyria, where
most other medications are contraindicated. A case series of
isofluorane use in nine patients with RSE reported seizure
control in all patients, but six of the nine patients died [76].
In another case series of seven patients treated with isofluorane
for RSE, again seizure control was achieved in all patients with
good outcome in four and mortality in three patients [74].
There are case reports of patients with prolonged refractory
status epilepticus treated with isoflurane who developed pro-
gressive T2 signal hyperintensity involving the thalamus and
cerebellum on MRI, suggesting that isoflurane may be neuro-
toxic when used in high doses for long time periods [75].
Although inhaled anesthetics seem to be efficacious in termin-
ating RSE, hypotension, poorly understood side-effect profiles,
and logistical issues, as well as the high rate of recurrence after
discontinuation of the therapy, make it a less attractive choice.
Steroids/Immunotherapy
Immunomodulatory agents such as steroids, immunoglobu-
lins, or plasmapheresis may be helpful; in selected cases of
immunologic syndromes, such as Rasmussen encephalitis,
antivoltage-gated potassium channel-related limbic encephal-
itis, acute disseminated encephalomyelitis, and paraneoplastic
disorders, seizure control was established. However, the role of
these agents outside of identified autoimmune processes is
unclear. A recent article reviewed the use of steroids and
immunotherapy in patients with highly refractory status
Chapter 15: Status Epilepticus
epilepticus, the authors considered that its increased use has
been due to the recognition of antibody-mediated causes of
RSE including NMDA and the increasing evidence of the role
of inflammation on epileptogenesis [77]. Medication resistance
in RSE is thought to result, in part, from internalization of
synaptic GABA receptors, making them unavailable for modu-
lation. Recently, NCSz were identified as possibly mediating
the established negative impact of the inflammatory response
following acute brain injury such as subarachnoid hemorrhage
[78], suggesting that immunomodulation may constitute a
novel therapeutic route to stop the negative impact of NCSz.
Nonpharmacological Therapies
Hypothermia
A small pilot study described four patients who received thera-
peutic hypothermia for RSE after failing treatment with cIV
AEDs. Therapeutic hypothermia was successful in aborting
seizure activity in all four patients, allowing midazolam infu-
sions to be discontinued; three achieved a burst-suppression
pattern on EEG. After controlled rewarming, two patients
remained seizure-free, and all four demonstrated a marked
reduction in seizure frequency [79]. A potentially beneficial
side effect of hypothermia are its neuroprotective properties.
Disadvantages include shivering, electrolyte abnormalities,
immunosuppression, and potential coagulopathy.
Electroconvulsive Therapy
Electroconvulsive therapy (ECT), which is frequently used to
treat psychiatric disorders, is known to raise the seizure thresh-
old. Based on that principle there are some case reports and
case series about using ECT in refractory SE. In a review of
eight cases, RSE cessation was noted in 80% of cases, with
complete recovery in 27% of patients [80]. This potential
indication highlights the need for clinical trials that assess the
usefulness of ECT in refractory SE. Another small case series
reported three patients with RSE treated with ECT. Two of the
three patients achieved seizure control and good outcomes and
one had persistent RSE despite ECT [81].
Surgery
Surgical approaches as a therapeutic option for RSE include
focal cortical resections, hemispherectomies, multiple subpial
transections, and, rarely, corpus callosotomy and vagal nerve
stimulator implantation. Resective surgery has shown imme-
diate and long-term benefits in cases of definite localization of
the epileptogenic focus by electrographic and imaging data
[82]. Case reports have described the use of vagal nerve stimu-
lator implantation to control prolonged RSE in adults [83].
Treatment Duration and Intensity
Controversy exists regarding the electrographic target of con-
tinuous drips. Some advocate for seizure suppression, others
183
 Chapter 15: Status Epilepticus

prefer burst suppression or even complete background
suppression.
Once control of SE is achieved with one or more of the
above medications, many experts continue cIV AED therapy
for 24–48 h of complete seizure control before gradually with-
drawing the antiepileptic/anesthetic drug infusions, but this is
based mostly on expert consensus. Weaning should be done
while the patient is under EEG monitoring.
Simultaneously, maintenance doses of traditional anticon-
vulsants should be continued to facilitate withdrawal of anes-
thetic drug infusions.
Withdrawal seizures may be seen in approximately half of
the patients and should be treated promptly. Some advocate
restarting the continuous intravenous AED at the rate that the
patient was on prior to the taper, others opt to add some of the
second-line AEDs that were not used earlier and then repeat
tapering after 24 hours without seizures. Alternatively patients
may be switched to a different cIV AED.
Complications
SE is a multisystem disease affecting most organs of the body,
requiring ICU level of care. Most organs can be secondarily
affected by ongoing seizure activity or as a consequence of
treatment. However, in practice it is difficult to differentiate
the effects of the underlying cause for SE, SE itself, and the
treatment of SE.
Prolonged or repetitive seizures reach a point when they are
unlikely to end spontaneously and hence, in addition to causing
brain injury, are associated with higher mortality and worse
clinical outcomes [55,84–86]. Continuous seizures lasting more
than 20–30 minutes have been associated with irreversible
cerebral injury [87] and pharmacoresistance [88,89]. The pres-
ence of cortical laminar necrosis, representing neuronal death,
apparent on MRI has been correlated clinically with increasing
neurologic morbidity and increasing seizure duration, even
after the effects of etiology are eliminated [86,90].
Cardiac arrhythmias are frequently seen in ongoing SE.
Stress cardiomyopathy with contraction band necrosis pre-
sumably secondary to massive catecholamine release has been
associated with death during SE.
Many patients with SE and most with RSE may be unable
to protect their airways and hence warrant intubation. Hyp-
oxia, pulmonary edema, and aspiration are frequently seen.
Infections may precipitate SE (meningitis, encephalitis)
and may develop secondary to SE, as with pneumonias. Any
fever in a patient with SE should be worked up expeditiously.
Blood, urine, and cerebrospinal fluid cultures, as well as a chest
X-ray, may be necessary. It should be noted that a mild eleva-
tion in white blood cell count may be seen in the serum and
CSF as a consequence of ongoing seizure activity.
Metabolic derangements (glucose, sodium, phosphate, cal-
cium, pH ) can be the underlying cause or the effect of SE.
These should be corrected aggressively as outlined above, since
seizures may be very difficult to control with persistent meta-
bolic abnormalities. Metabolic acidosis is also commonly seen
following seizures and this generally resolves with control of
seizures, however, in extreme situations, sodium bicarbonate
can be used [91].
Prognosis and Outcome
SE has immense potential for considerable mortality and mor-
bidity; despite medical interventions, in-hospital mortality
associated with SE ranges between 9.4 and 21% [3,8,92] and
the 30-day mortality rate is 19–27% [13,45,93]. Prolonged SE
beyond one hour, myoclonic SE, and those with symptomatic
SE have higher mortality rates [94]. RSE carries a poor out-
come with mortality rates between 23% and 61%
[3,33,55,95,96] and it appears to be rather independent of the
chosen therapeutic strategy. In a large retrospective case series,
patients with RSE had a longer hospital stay, lower return to
baseline, and increased mortality [97]. In a large retrospective
case series on super-refractory SE, patients were found to a
have a mortality rate of 42%, which is higher than previously
described for SE [62]. In-hospital mortality of patients with
NCSE is 18–52% and goes up to 65% at one month follow-up.
While etiology is the most important predictor of outcome,
older age, medical comorbidity, and high initial APACHE-II
scores are also independent risk factors for mortality
[34,98,99]. SE secondary to noncompliance or abrupt discon-
tinuation of antiepileptics, head trauma, and alcohol with-
drawal has a good outcome in 90% of patients, whereas older
age, impairment of consciousness, duration of SE, the presence
of medical complications and etiologies such as stroke, acute
metabolic dysfunction, and anoxia have a poorer outcome
[2,86,92,100]. Survivors of SE are at significant risk for recur-
rent seizures, and in some series, 10–50% are left with disab-
ling neurologic deficits; additionally, cognitive impairment is
frequent [85,92,101]. Status epilepticus will recur in approxi-
mately one-third of patients, according to one population-
based study that followed patients for 10 years [102].

hospital in the 1980s. Neurology and management. Neurol Clin 30:

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187
 Chapter
Neuromuscular Disorders in the Neurocritical
16 Care Unit
Christopher L. Kramer, Edward M. Manno, and Alejandro A. Rabinstein
Neuromuscular diseases and respiratory failure are common
problems encountered in both neurologic and medical inten-
sive care units. Neuromuscular respiratory failure can be
caused by diseases of the motor neuron, peripheral nerve,
neuromuscular junction, or muscle. Thus, localization of the
disorder is essential for adequate management.
This chapter provides a broad overview of the clinical
presentation of neuromuscular respiratory failure and reviews
key features of the most common neuromuscular diseases
encountered in the intensive care unit.
Neuromuscular Respiratory Failure
Clinical Features
The range of clinical presentation varies according to the
features of the primary diagnosis and the degree of respiratory
muscle weakness. Features include [1,2]:
• Interrupted or “staccato” speech
• Supine dyspnea or frequent nocturnal awakenings
• Anxiety or restless
• Tachycardia, tachypnea, and diaphoresis
• Accessory muscle use, which may be obvious or may only
be detected through palpation (the “respiratory pulse”)
• Paradoxical breathing pattern (i.e. inward movement of the
abdomen during inspiration)
• Oropharyngeal weakness and diminished cough causing
difficulty managing secretions and protecting the patency
of the airway
• Appendicular weakness.
Anatomical Localization
Neurological causes of respiratory failure can span the entire
neuroaxis and localization is instrumental to sort out the
differential diagnosis. The key anatomical components of res-
piration and their function are [3]:
• Cortex – voluntary control of respiration
• Medulla – automatic control of respiration from the
primary ventilatory nuclei within the pontomedullary region
• Spinal cord – anterior horn cells of C3–C5 for the phrenic
nerve, which controls the diaphragm (principal inspiratory
muscle)
188
• Cervical roots – innervate the intercostal and scalene
muscles
• Accessory muscles – the sternocleidomastoid, pectoralis
major and minor, and latissimus dorsi are recruited when
respiratory demand is high
• Neuromuscular junction – communication between the
nerves and muscles of respiration
• Muscles – effectors of respiratory effort.
Localization can be accomplished through a structured neuro-
logic examination. Attention should be paid to signs of bulbar
weakness, symmetry and proximal versus distal distribution of
limb weakness, presence or absence of sensory abnormalities,
and upper or lower motor neuron findings. Four main semio-
logical patterns, hemiparesis, quadriparesis/paraparesis +/–
sensory level, proximal weakness, and distal weakness, are
summarized in Table 16.1 [4].
Differential Diagnosis
A focused differential diagnosis can be formulated based on
localization. Examples of differential diagnoses for neurologic
respiratory failure according to the suspected portion of the
nervous system involved are listed in Table 16.2 [4].
Although during the initial evaluation the clinician should
consider all neurologic causes of respiratory failure, this chapter
will focus specifically on neuromuscular causes. In approaching
the patient with neuromuscular respiratory failure it is helpful to
first distinguish whether the condition is primary or secondary:
• Primary neuromuscular failure – patients with a new or
prior diagnosis of a neuromuscular condition, such as
myasthenia gravis (MG), Guillain–Barré syndrome (GBS),
and amyotrophic lateral sclerosis (ALS).
• Secondary neuromuscular respiratory failure – patients
admitted for a non-neurological condition who
subsequently develop weakness in the hospital, as in critical
illness neuromyopathy.
In a large study at our tertiary referral center, the most
common final etiologies for neuromuscular respiratory failure
were MG, GBS, myopathies, and ALS [5]. Approximately half of
the patients in the study did not have a prior neuromuscular
diagnosis. Not having a prior diagnosis of neuromuscular
disease was associated with longer duration of mechanical ven-
tilation, longer ICU stay, and worse outcome upon discharge,
 Chapter 16: Neuromuscular Disorders

Table 16.1 Physical exam findings for each anatomic localization of weakness

Localization Pattern of weakness Sensory loss Reflexes

Cerebral cortex, Distal > proximal Variable, depending on whether sensory Increased in the subacute to
brainstem, or spinal Extensors > flexors in arms cortex or tracks affected chronic phase; may be reduced
cord Flexors > extensors in legs acutely
Hemiparesis or single limb
Spinal cord Distal > proximal Variable, depending on whether Increased in the subacute to
Paraparesis, quadriparesis, rarely sensory tracts involved; sensory level chronic phase; may be reduced
hemiparesis diagnostic acutely
Anterior horn cell Proximal and distal Absent Decreased if muscle bulk is
severely decreased; increased in
ALS
Peripheral nerve In the distribution of the nerve, Present Decreased
or distal > proximal in arms and (ascending, stocking/glove pattern)
legs
Neuromuscular Eye muscles, bulbar muscles, Absent Normal, decreased if muscle
junction and proximal > distal weakness is severe
Fatigability
Muscle Proximal Absent Normal unless severely weak
Abbreviations: ALS: amyotrophic lateral sclerosis (Adapted and modified from [4].)

Table 16.2 Differential diagnosis for acute weakness in the critically ill patient by localization within the neuraxis

Brain/brainstem Trauma, infarction, abscess, hemorrhage, central pontine myelinolysis, sedative overdose, seizure, tumor, hypercapnia,
hypothermia, hypothyroidism
Spinal cord Trauma, infarction, transverse myelitis, epidural abscess
Anterior horn cell ALS, West Nile virus, polio and postpolio syndrome, Kennedy disease
Peripheral nerve GBS, CIDP (acute onset), vasculitic neuropathy, paraneoplastic, critical illness polyneuropathy, periodic paralysis,
porphyria, amyloid, phrenic nerve injury, heavy metal toxicity
Neuromuscular MG, prolonged neuromuscular junction blockade, botulism, organophosphate poisoning, Lambert–Eaton myasthenic
junction syndrome, hypermagnesemia, pseudocholinesterase deficiency, tick paralysis, envenomation
Muscle Critical illness myopathy, rhabdomyolysis, cachectic myopathy, toxic myopathies, acid maltase deficiency,
inflammatory myopathies, metabolic myopathies (hypo- and hyperkalemia, hypophosphatemia, hypernatremia), toxic
necrotizing myopathies (statin, colchicine), muscular dystrophy
Abbreviations: ALS: amyotrophic lateral sclerosis; GBS: Guillain–Barré syndrome; CIDP: chronic inflammatory demyelinating polyradiculoneuropathy;
MG: myasthenia gravis. (Adapted and modified from [4].)

possibly related to the higher proportion of patients in this
group with a diagnosis of GBS and delay in treatment. Patients
in whom the neuromuscular diagnosis could not be established
after thorough investigations had worse functional prognosis,
suggesting the importance of establishing a primary etiology to
deliver effective treatment.
Basic Principles of Management
The initial management of a patient with neuromuscular
respiratory failure should first focus on airway stability. Para-
doxical breathing, severe oropharyngeal weakness, and absent
or ineffective cough can portend imminent need for
ventilatory support [6]. Chest X-ray should be performed to
assess for coexisting pulmonary disease and/or acute pneumo-
nia. Arterial blood gases (ABGs) can be useful in the initial
evaluation as an indirect marker for disease severity; however,
normal ABGs or oxygen saturations do not rule out the pres-
ence of respiratory involvement in neuromuscular disease.
Chronic respiratory acidosis (low pH, high PCO2, and high
HCO3) prior to mechanical intubation, regardless of the cause
of respiratory failure, has been found to be associated with in-
hospital death and poorer outcome in survivors [7].
Patients with neuromuscular respiratory weakness need to
be closely followed with bedside pulmonary function tests.
These should include forced vital capacities (FVC), maximal

189
 Chapter 16: Neuromuscular Disorders

inspiratory pressure (MIP), and maximal expiratory pressure these readings by >30% being associated with progression to
(MEP). These measurements are important because the clinical respiratory failure and the need for intubation [8]. Rapid
exam may be insufficiently sensitive to detect and track pro- sequence intubation is recommended if endotracheal intubation
gression of respiratory muscle weakness. is performed. The use of succinylcholine should generally be
Normal tidal volumes are approximately 65–70 mL/kg. An avoided due to the possibility of provoking hyperkalemia.
initial decrease in tidal volumes may not be clinically apparent. After initial stabilization, further management is dictated
Effective cough is lost with vital capacities below 30 mL/kg. by the primary etiology. The rest of this chapter will focus on
Decreasing tidal volumes at this point will lead to progressive the most common etiologies of primary and secondary neuro-
atelectasis. Arterial blood gases at this stage of respiratory muscular respiratory failure in the intensive care unit.
failure will reveal only a subtle drop in the PO2. Hypercapnia
is a late sign of neuromuscular respiratory insufficiency, Specific Neuromuscular Diseases Encountered
developing as vital capacities drop below 20–10 mL/kg. Pul-
monary shunting occurs at vital capacities below 15 mL/kg and in the Intensive Care Unit
causes a notable decrease in oxygenation. Amyotrophic Lateral Sclerosis
Difficulties with patient compliance, oropharyngeal seal,
ALS is a progressive degenerative disease of unknown etiology
and variable effort may complicate the interpretation of vital
that leads to loss of motor neurons in the cortex, brainstem,
capacities. The flow volume loops of patients with neuromus-
and spinal cord. Clinically both upper and lower motor
cular respiratory failure appear similar to patients with
neurons are affected. A progressive muscle weakness with
chronic obstructive pulmonary disease. A prolonged tail at
fasciculations, atrophy, and spasticity is the typical presenta-
the end of exhalation may contribute significantly to the
tion. Electromyography reveals diffuse fasciculations and
volume of the vital capacity. If the respiratory technician is
motor involvement. The disease needs to be differentiated
unaware of these technicalities, the actual vital capacity may
from cervical spondylosis, thyroid disease, vitamin deficien-
be underestimated.
cies, benign fasciculations, enzyme deficiencies, multifocal
It is difficult to quantify respiratory strength on the clinical
motor neuropathy with conduction block, polymyositis, and
exam; however, a rough estimate of a vital capacity can be
other motor neuron diseases.
elicited by having the patient take a deep breath and count to
The diagnosis is usually well established before admission
the highest number they can during exhalation. A count of
to an intensive care unit; however, on rare occasions respira-
30 approximates a vital capacity of 2 L. Some coaching may
tory insufficiency is the presenting symptomatology [7].
need to occur to assure proper technique.
A variant form of ALS can present with predominantly bulbar
MIP (also known as negative inspiratory force) is probably
symptoms leading to progressive difficulties with swallowing.
the best measure of respiratory strength [7]. It is less likely to
Aspiration pneumonia under these circumstances may be the
be misinterpreted, easier to perform, and more reproducible.
initial presentation to an intensive care unit.
Adequate assessment of MIP requires that the patient be able
The mean survival after diagnosis is approximately four
to make a tight seal with his/her lips around the testing device.
years. There is no known cure and only one drug has been
A supine positioning can negatively affect values. Pre-existing
shown to afford modest slowing of the disease. Riluzole is best
pulmonary diseases must also be taken into account when
used early in the course of the disease. It is, however, expensive
interpreting the measurements.
and has many side effects. Liver function tests need to be
The decision to proceed with endotracheal intubation
monitored every three months for the first year and every six
should be based upon the entire clinical picture, including
months after that.
clinical symptoms and signs, suspected primary etiology, chest
If a patient needs and elects to continue mechanical ventila-
radiograph, laboratory findings, and pulmonary function tests.
tion after the diagnosis is secured, plans for tracheostomy and
However, it is important to recognize that a patient with a
home ventilation can be made. These patients may also need
rapidly ascending paralysis, acute dysautonomia, or neuro-
placement of a percutaneous gastrostomy tube, if the degree of
muscular junction failure may not be able to manifest the signs
dysphagia warrants placement and it is consistent with goals of
and symptoms typically encountered in a patient with
care.
impending respiratory arrest secondary to primary pulmonary
disease. Patients with some forms of acute neuromuscular
respiratory failure may appear to be doing fairly well until Guillain–Barré Syndrome
shortly before they need urgent intubation. GBS remains the most common cause of acute paralysis [9]. This
Noninvasive ventilation can be considered in patients who syndrome encompasses various subtypes; the most common
are neurologically stable with a normal PaCO2 and rapid form in the United States and Europe is acute inflammatory
anticipated improvement, such as MG. Interpretation of pul- demyelinating polyradiculoneuropathy (AIDP). The axonal vari-
monary function tests have been studied most extensively in ants, acute motor axonal neuropathy (AMAN) and acute motor
GBS, with FVC <20 mL/kg, MIP <30 cmH2O, and MEP and sensory axonal neuropathy (AMSAN) are more common in
<40 cmH2O (the “20/30/40 rule”) or a reduction in any of China, Japan, and perhaps Central America. Atypical forms with

190

more localized clinical expressions, such as the Miller–Fisher
syndrome, are also rarely encountered.
Epidemiology
Population-based studies report an incidence between 1.2 and
1.9 cases of GBS per 100,000 individuals per year [10]. The
incidence increases with age and men are affected slightly more
often than women. Epidemic outbreaks of GBS have been
reported, most notably in China, linked to contamination of
water by Campylobacter jejuni. Nearly two-thirds of patients
with GBS report a preceding infection. Speculated causative
microorganisms include Campylobacter jejuni, cytomegalo-
virus, Epstein–Barr virus, and Mycoplasma pneumoniae.
Immunizations with vaccines have been linked with the occur-
rence of GBS. Although the overall risk for most vaccines is
extremely small (<1:1,000,000) [11], brain material present in
the rabies vaccine may provoke the development of GBS as
frequently as 1:1000 immunizations. Additionally, cases of
GBS have been reported after surgeries, in patients with cancer,
after transplantations, and in patients with HIV infection.
Pathophysiology
The pathogenesis of GBS varies across subtypes, though in
general the disease is mediated by an autoimmune attack on
a wide range of myelin glycolipids in the peripheral nerves,
causing demyelination in the AIDP and Miller–Fisher variants
and axonal damage in the AMAN and AMSAN variants. The
predominant mechanism responsible for demyelination in
AIDP appears to be a CD4 T-cell-mediated response against
myelin proteins (P2, P0, or PMP22) [9,12]. No antibodies have
been found to have a pathogenic role in AIDP. In AMAN and
AMSAN, antibodies directed against specific antigens on the
axolemma are responsible for the activation of macrophages,
which in turn attack the nodes of Ranvier leading to axonal
damage with relative preservation of the myelin sheath [13].
Although the associations are not exclusive, GM1 and
GM1b antibodies have been found in patients with AMAN,
GD1a antibodies have been seen in patients with acute motor
sensory neuronopathy, and GQ1b antibodies are associated
with the Miller–Fisher variant (though this disorder appears
to be demyelinating). Molecular mimicry between microbial or
other antigens and nerve gangliosides explains the association
of GBS with other infections and malignancy, and is epitom-
ized by the association of AMAN with C. jejuni infection.
Clinical Features
Ascending weakness and areflexia is the classical clinical pre-
sentation of GBS, though its presentation is far from uniform
[9]. Distal symmetric dysesthesias are often the first manifest-
ations of the disease and can be refractory to treatment. Pain is
commonly experienced and is often described as deep with
neuropathic features, and can be localized to the back and
lower limbs, or generalized. Weakness then begins to develop
within the next one to two days and is commonly proximal
and ascending (i.e. affects the legs first). The speed of
Chapter 16: Neuromuscular Disorders
progression of the weakness can be predictive of disease sever-
ity and correlates with the risk of severe paralysis and respira-
tory failure [14]. The severity of weakness reaches its peak in
less than four weeks [15]; progression or recurrences beyond
this time should raise suspicion for chronic inflammatory
demyelinating polyradiculoneuropathy (CIDP).
Facial diplegia can be present and is often accompanied by
dysarthria and dysphagia, which increases the risk of aspiration.
Ophthalmoplegia and ptosis can be seen in severe cases and
also classically is present in the Miller–Fisher variant, where
they are accompanied by ataxia and areflexia. While normore-
flexia or hyper-reflexia may be present initially due to disrupted
spinal inhibitory mechanisms, progression to hyporeflexia or
areflexia is uniform. Neuromuscular respiratory failure occurs
in up to 25% of patients. Autonomic disturbances include
postural hypotension, diaphoresis, tachycardia, ileus, bladder
retention, hypertension, and potentially life-threatening cardiac
arrhythmias [16].
Diagnosis
Nerve conduction study (NCS) and electromyography (EMG)
are the most important studies to confirm the diagnosis of
GBS in all its forms. NCS/EMG should be performed shortly
after presentation and may be repeated to confirm the diagno-
sis and for prognostic purposes (including the distinction of
demyelinating versus axonal forms). Slowing of the motor
nerve conduction velocity is an early and characteristic finding
of patients with AIDP [17]. Prolonged F ways and H reflexes,
which assess the integrity of the roots, can be the earliest
electrophysiologic abnormality. Sensory conduction is typic-
ally normal in the sural nerve (the so-called “sural-sparing”
phenomenon) and abnormal in other nerves. The presence of
early motor nerve inexcitability represents a reliable marker of
axonal polyradiculoneuropathy. Conduction blocks can appear
later in demyelinating cases.
Lumbar puncture is also a useful test in patients with GBS, as
a pleocytosis of >50 cells/microliter can suggest an alternative
etiology. However, the typical finding in GBS is albumino-
cytological dissociation (i.e. increased protein concentration
without accompanying pleocytosis). The sensitivity of the test is
lower early in the disease course. Testing for ganglioside anti-
bodies or markers of associated microorganisms has no proven
practical value.
Treatment
Indications for admission to the intensive care unit (ICU) for
patients with GBS include neuromuscular respiratory failure,
rapidly progressive symptoms, prominent dysautonomia, or
complicating medical conditions, such as sepsis, pulmonary
embolism, or aspiration pneumonia (see Table 16.3 for man-
agement of GBS in the ICU).
Nonintubated patients should be monitored with serial
neurological examinations and pulmonary function tests at
frequent intervals to detect progression of neuromuscular fail-
ure that may require intubation [18].
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 Chapter 16: Neuromuscular Disorders
Table 16.3 ICU management of Guillain-Barré syndrome
1. Admit to ICU for progressive appendicular weakness,
dysautonomia, or respiratory weakness for observation
2. Check ECG, CXR, and baseline laboratory values
3. Follow vital capacities and negative and positive expiratory
forces every 3–8 hours
4. Place an arterial line and follow arterial blood gases
a. If dysautonomia is present:
i. Liberalize intravenous fluids as tolerated
ii. Aggressive electrolyte replacement for hypokalemia,
hypocalcemia, or hypomagnesemia
iii. Vasopressors or intravenous antihypertensive
medications should only be used if indispensable and
always with caution
iv. Antiarrhythmic medications as needed
v. Consider placement of a temporary pacemaker if
severe bradycardia
5. Intubate electively for signs of respiratory failure, inability to
control secretions, severely abnormal or rapidly worsening
pulmonary function tests, development of hypercapnia, or
severe dysautonomia
6. Start IVIG or place central access and start plasma exchange
7. Supportive care measures:
a. Place nasogastric tube and initiate enteral feeding
i. Initiate bowel regimen to ensure regular bowel
movements
ii. Observe for any abdominal distention
iii. If ileus occurs, stop enteral feedings and initiate
intermittent nasogastric suctioning and/or rectal tube
placement. Use pro-motility agents only in most
severe cases and with caution
b. Start measures for gastrointestinal and deep venous
thrombosis prophylaxis
c. Initiate chest physiotherapy and physical therapy regimen
d. Assess for pain regularly
e. Psychological support. Encourage regularly, consider
notifying Guillain–Barré support groups
8. Attempt weaning regimen when appendicular strength,
dysautonomia, and respiratory muscle strength start to improve
9. Check pulmonary function tests 12 days after intubation.
Consider elective tracheostomy for long-term ventilatory
support if pulmonary function tests are worse than on the
day of intubation.
(Adapted and modified from “Nerve and Muscle Disorders” chapter in
Torbey: Neurocritical Care 1st edition.)
In addition to the 20/30/40 rule, a forced vital capacity
below 15 ml/kg indicates the need for intubation and mechan-
ical ventilation [8]. Bulbar weakness, diminished cough, and
signs of dysautonomia should prompt strong consideration of
mechanical ventilation. Noninvasive ventilation with a bilevel
positive airway pressure (BiPAP) mask is not a safe or effective
option for patients with GBS [19].
Mechanical ventilation should be initiated using assist-
control or synchronized intermittent mandatory ventilation
192
(SIMV) modes with adequate pressure support, positive
end-expiratory pressure, and tidal volumes to prevent further
atelectasis and achieve adequate lung expansion. We recom-
mend full mechanical ventilatory support for at least the first
24–48 hours to allow adequate rest. Aggressive pulmonary
toilet is mandatory as pulmonary complications, such as pneu-
monia, are the most commonly encountered systemic compli-
cation in GBS. Patients may need to remain intubated and
mechanically ventilated for several weeks, depending on the
extent of peripheral nerve involvement.
A pulmonary function score obtained 12 days after intub-
ation can be helpful in predicting which patient will need
long-term mechanical ventilation. This score is obtained by
summating the scores of the patients’ vital capacity and nega-
tive and expiratory pressures. The score obtained at the time of
intubation is compared to a score obtained at 12 days after
intubation: if the score is improved it is likely that the patient
will be extubated within two weeks [20].
Weaning can be achieved first by reducing the rate on the
SIMV mode and then reducing pressure support. Extubation
success can be predicted when a patient can generate tidal
volumes >12–15 mL/kg or if a T-piece trial is tolerated for
30 minutes. When long-term mechanical ventilation will likely
be needed, tracheostomy should be considered as it allows
better suctioning of airway secretions and pulmonary toilet.
Patients with severe GBS may present with various compli-
cations from dysautonomia, including potentially fatal cardiac
arrhythmias, labile blood pressure, sudomotor dysfunction,
and urinary and bowel issues [21].
Cardiac telemetry surveillance is essential in all patients with
severe GBS to monitor for arrhythmias. Sudden bradycardia and
asystole can result from exaggerated vagal activity and patients
with severe and/or recurrent episodes may require pacemaker
placement. Reduced variation in the RR interval and severe hyper-
tension are predictors of increased risk for serious arrhythmias.
Hypertensive spells tend to predominate in GBS and can
generally be observed if not severe. If lowering of blood pres-
sure is necessary, short-acting agents such as captopril and
hydralazine should be used. Caution should be exercised when
using beta blockers as they may precipitate sudden hypoten-
sion and bradycardia.
Hypotensive spells can be triggered by tracheal suctioning,
bladder manipulation, or ocular pressure. Transient drops in
blood pressure should be left untreated to minimize blood
pressure fluctuations. Persistent hypotension, unless severe,
should be treated conservatively with positioning and volume
expansion. Vasoactive drugs should be used with caution
because of the possibility of exaggerated response secondary
to underlying denervation hypersensitivity.
Gastroparesis and ileus are common gastrointestinal mani-
festations of dysautonomia in GBS. Adynamic ileus can occur in
up to 15% of patients with severe GBS and may be triggered by
the concomitant administration of opiates for pain. Stool soft-
eners should be routinely prescribed to all patients with GBS.
Most cases of gastroparesis and adynamic ileus can be
treated with intermittent nasogastric suctioning and/or rectal

tube placement. Pro-motility agents such as metoclopramide
and neostigmine should be used with extreme caution as they
may precipitate severe bradycardia or sinus arrest. Severe cases
of ileus should be closely monitored with abdominal films
because they may produce massive colonic distension and even
necessitate temporary colostomy for decompression. In refrac-
tory cases, parenteral nutrition may be needed to sustain
caloric needs.
Plasma exchange (PLEX) and intravenous immunoglobu-
lin treatments (IVIG) are employed as disease-modifying
immunotherapy in GBS. Both PLEX and IVIG have been
shown to be equally effective treatments for GBS [21,22]. The
clinical endpoints in the studies evaluating patients with GBS
were the time when mechanical ventilation was no longer
required and the day of ambulation. Both occurred earlier with
IVIG and PLEX.
Plasma exchange of 2–4 L is a standardized treatment. Five
treatments provided every other day is the usual regimen,
although some advocate more aggressive plasma exchanges
early in the course of the disease (e.g. every day or more than
five sessions). Treatment is more effective when started within
two weeks of the onset of symptoms in patients with mild to
moderate disease and within four weeks of symptom onset for
patients with severe disease.
The rate of complications with PLEX is relatively low, and
most are related to problems with venous access. Other poten-
tial adverse events include hypotension, line-related bactere-
mia, and hypocalcemia. It may be preferable to avoid plasma
exchange in patients with severe dysautonomia due to the risk
of provoking blood pressure fluctuations.
IVIG is given in doses of 0.4 g/kg daily for five days and is
more commonly available and easier to administer. Unlike
PLEX, it does not require the placement of a central venous
catheter. Although IVIG can be safely administered to most
patients, one should be cautious when treating patients with
congestive heart failure because of the risk of fluid overload.
Other potential side effects include: aseptic meningitis, pseudo-
hyponatremia, renal failure, and thromboembolic complications
(related to hyperviscosity). In rare cases an anaphylactic reaction
can occur in patients who are IgA deficient.
Overall, both therapies are relatively safe and the choice of
which one to use depends primarily on the experience of each
particular center.
There is no evidence that combining plasma exchange and
IVIG improves long-term outcome compared with PLEX or
IVIG alone [23], yet additional treatments are often employed
in patients who do not show any improvement. Variations in
pharmacokinetics of IVIG may explain why some patients fail
to respond to the initial course of IVIG and it has been
suggested that patients with smaller changes in serum IgG
concentration after a course of IVIG might benefit from a
second course [24]. In fact, repeated courses of IVIG have
been reported to improve the clinical course of refractory
patients [25] and the usefulness of this strategy is being tested
in an ongoing trial.
Chapter 16: Neuromuscular Disorders
Corticosteroids are not helpful in the treatment of GBS and
limited evidence suggests that they may even be harmful [26].
However, a careful history must be obtained to differentiate
GBS from CIDP as this entity is responsive to corticosteroids.
Clues in the history suggesting CIDP include subtle paraesthe-
sias or weakness that may have preceded the current illness by
a few weeks or months.
Clinical improvement or a decrease in the progression of
the disease is usually seen after a week of treatment. The long-
term prognosis and the rate of recovery depend on the extent
and degree of demyelination and axonal damage. Demyelina-
tion, even if severe, will usually recover completely if the
underlying axonal structure remains intact. Incomplete recov-
ery can be expected if there is severe axonal damage. Fatigue is
the most common residual symptom after GBS.
Myasthenia Gravis
Myasthenia gravis (MG) is an autoimmune condition charac-
terized by dysfunction of neuromuscular junction transmission
due to an auto-antibody attack on components of the postsy-
naptic terminal [27]. This process results in fatigable weakness
of the appendicular, bulbar, ocular, and respiratory muscles.
Myasthenic crisis is defined by the presence of respiratory
failure and the need for mechanical ventilation. About one-
fifth of these patients will have at least one episode of myasthe-
nic crisis, which occurs on average eight to twelve months after
initial symptoms [28]. In up to 20% of MG patients a crisis will
be the presenting manifestation. MG can be diagnosed at all
ages, but has a bimodal distribution with predominance in
young women and older men. A genetic predisposition for
HLA, A1, DRW3, and B12 genotypes has been reported.
Pathophysiology
A T-cell-mediated attack against postsynaptic components of
the neuromuscular junction is the cause of the disruption in
neuromuscular transmission in MG. In up to 85% of patients,
antibodies are directed against the nicotinic receptor (AChR).
Receptor attack ultimately results in distortion and simplifica-
tion of the postsynaptic muscle membrane. As a result, a
progressive decrease in the end-plate potential of the post-
synaptic membrane occurs, causing decreased effectiveness of
the ACh released from the presynaptic terminal. This makes it
more difficult for muscle contraction to occur (the reason for
weakness), which is worsened with sustained contraction as
ACh from the presynaptic terminal is depleted (the reason for
fatigability) [29].
Up to 50% of “seronegative” myasthenics (i.e. patients who
do not have detectable serum anti-AChR antibodies) have anti-
bodies against the postsynaptic protein muscle-specific tyrosine
kinase (MuSK). MuSK is speculated to be responsible for clus-
tering AChRs on the postsynaptic muscle membrane and is
crucial for proper neuromuscular transmission. Antibody bind-
ing to MuSK alters its function and results in reduced numbers
of functional AChRs on the postsynaptic endplate [29].
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 Chapter 16: Neuromuscular Disorders
Excessive activity of the thymus may contribute to the
pathophysiology of MG, at least in some cases. Nearly 70%
of myasthenic patients have thymic hyperplasia, and up to 15%
have thymic neoplasia. In in-vitro studies, thymic tissue has
been shown to spontaneously generate AChR antibodies. This
provides a rationale for the disease improvement often seen
after thymectomy in patients with thymic abnormalities.
Clinical Features
The hallmark feature of MG is fatigable weakness, though the
severity and location of symptoms can vary [27]. The limb,
ocular, bulbar, and respiratory muscles can all be affected.
Limb weakness is greater proximally and can be accentuated
with sustained or repetitive muscle contraction. Ptosis exacer-
bated by sustained upgaze and ophthalmoparesis are common
in patients with bulbar weakness. Flaccid dysarthria, facial
weakness, and dysphagia may also be present. The gag reflex
is often depressed and cough strength may be reduced; these
should be tested in myasthenics. Signs of respiratory weakness,
the defining feature of myasthenic crisis, were previously dis-
cussed in the section on neuromuscular respiratory failure.
The Myasthenia Gravis Foundation of America has developed
a grading scale of 1–5 for worsening disease. Patients requiring
mechanical ventilation are considered grade 5. MuSK antibody-
positive myasthenics typically have bulbar and respiratory muscle
involvement, resulting in higher rates of myasthenic crisis.
While exceedingly rare in its purest form, the clinician
should monitor for signs of cholinergic toxicity in MG patients
taking anticholinesterase inhibitors (AChEIs). Self-medication
with increasing doses of AChEIs as myasthenic symptoms
worsen does occur and can result in a mixed clinical picture
of MG exacerbation and cholinergic crisis.
Cholinergic crisis manifests with miosis, excessive pulmon-
ary secretions, fasciculations, abdominal cramping, diarrhea,
sweating, and excessive tearing. Excessive pulmonary secretions
can cause mucous plugging, bronchiolar spasm, and hypoxia.
The reasons for MG exacerbation are many and include
preceding respiratory illnesses, medications, or surgery. For
this latter cause, many authors advocate prophylactic plasma
exchange in patients with MG before any major surgery. In
about one-third of patients, however, no definable reasons can
be found.
There are a number of pharmacologic agents that should be
avoided in patients with disease of the neuromuscular junction.
A list can usually be obtained through the hospital pharmacist,
but general aminoglycosides and quinolones should be avoided.
Other drugs with relative contraindications include the calcium
channel blockers, lithium, and chlorpromazine. The cephalo-
sporins and penicillins decrease calcium entry into the presy-
naptic terminal and thus limit acetylcholine release into the
synaptic junction.
Diagnosis
In classical cases, the distinct clinical presentation of MG
allows for rapid diagnosis. However, supplementary tests can
194
offer confirmation. Many patients will display improvement in
muscle strength when tested with edrophonium. The testing,
however, is often unreliable and needs to be performed by a
skilled observer. Electrodiagnostic studies, particularly repeti-
tive nerve stimulation and single-fiber EMG, remain a corner-
stone in the diagnosis of MG [30]. A compound muscle action
potential (CMAP) decrement of at least 10% upon repetitive
stimulation is diagnostic. Single-fiber EMG records single-
fiber action potentials and has the highest sensitivity for the
diagnosis of MG. Findings include jitter and blocking, both of
which stem from dysfunction of the neuromuscular transmis-
sion [30]. In the ICU, decremental responses can be reliably
identified, but single-fiber EMG is much more difficult to
interpret because of electrical interferences.
Testing for serum antibodies is a simple and reliable diag-
nostic method:
• AChR antibodies are most commonly observed
• MuSK antibodies should be tested when AChR antibodies
are negative, particularly among patients with prominent
bulbar and respiratory muscle weakness
• Anti-striational muscle antibodies are identified in 90% of
myasthenics with thymoma
• A CT scan of the chest should be performed in all patients
with MG to evaluate for thymic abnormality.
Pulmonary function tests, while useful, have additional limita-
tions in MG patients due to facial weakness and the fluctuating
nature of the disease. As a consequence, in MG there are no
cut-off values to guide the need for ventilatory assistance.
Treatment
The most common reason for a patient with MG to be admit-
ted to an ICU is for respiratory monitoring during a myasthe-
nic exacerbation and ventilatory support in myasthenic crisis.
The initial assessment and close monitoring of bulbar and
respiratory weakness is crucial in determining the need for
ventilatory support. If the degree of bulbar and respiratory
weakness is modest, careful monitoring, frequent suctioning,
maintenance of an erect position, incentive spirometry,
assisted cough, and early initiation of immunomodulatory
therapy can avoid the need for mechanical ventilation. If more
severe signs of bulbar and respiratory weakness are present, an
ABG should be performed to assist in determining the mode of
ventilatory support. In patients without hypercapnia, the early
utilization of BiPAP can avert intubation, translating into
marked reductions in length of ICU stay and duration of
ventilatory assistance and the incidence of pneumonia and
atelectasis [31,32]. Noninvasive ventilation should be imple-
mented early, as success declines once the patient has
developed hypercapnia.
Elective endotracheal intubation should be considered in
patients with severe bulbar and respiratory weakness with
hypercapnia. When intubation is necessary, it is preferable to
administer a lower dose of a nondepolarizing blocking agent
(e.g. 0.5 mg/kg of rocuronium instead of the usual 1 mg/kg) to

Myasthenia exacerbation
Severe weakness Mild to moderate weakness
Severe bulbar No severe bulbar Immunotherapy and
dysfunction dysfunction monitoring on the ward
Aspiration Respiratory distress
Yes No Yes No
Intubate in ICU and
Hypercapnia
start immunotherapy
Yes No
BiPAP in ICU
Start immunotherapy
prevent prolonged blockade [4]. Our practice is to rest patients
on mechanical ventilation for 24 to 48 hours prior to
attempting weaning of ventilatory support.
The pharmacological treatment of myasthenic crisis should
include cholinesterase inhibitors, immunomodulatory agents,
and anti-inflammatory/immunosuppressant medications. Cho-
linesterase inhibitors should always be continued in patients
undergoing noninvasive mechanical ventilation. However, they
can be transiently discontinued after endotracheal intubation to
minimize respiratory secretions. Cholinesterase inhibitors
should be restarted before ventilator weaning is initiated. Low
doses of atropine, glycopyrrolate, or scopolamine can be safely
administered if oral and respiratory secretions are excessive.
Immunotherapy for MG can be provided with either IVIG
or plasma exchange. There is no convincing evidence that
either option is superior, or that the combination of IVIG
and plasma exchange confers additional benefit [33–37]. IVIG
is typically administered at a dose of 0.4 g/kg for five consecu-
tive days, while plasma exchange is performed every other day
(or every day if tolerated) for a total of five or six sessions.
All myasthenics should receive corticosteroids; however,
ideal dose and route of administration in myasthenic exacerba-
tion/crisis is not well established. Daily prednisone dosing with
1 mg/kg ideal body weight during hospitalization while receiv-
ing concomitant immunomodulatory therapy is reasonable.
Caution should be exercised if high-dose intravenous methyl-
prednisolone is used in nonintubated patients as one-third to
one-half of patients will experience clinically meaningful
exacerbation of weakness within days of initiation. It is also
reasonable to start a steroid-sparing immunosuppressant (such
as azathioprine or mycophenolate mofetil) during the acute or
Chapter 16: Neuromuscular Disorders
Figure 16.1 Algorithm for the early
management of myasthenia gravis exacerbation.
(Adapted with permission from Wiley-Blackwell, “The
Practical Management of Guillain Barré Syndrome and
myasthenic crisis” in Emergency Management in
Neurocritical Care.)
subacute phase. All patients receiving high-dose corticoster-
oids should also receive gastric protection to avoid peptic
ulcers, and calcium supplementation.
Rituximab has emerged as a promising treatment for myas-
thenia. Studies have demonstrated its effectiveness in both
nonrefractory myasthenics as monotherapy and refractory
myasthenics as a steroid-sparing agent [38]. However, it
appears to have more profound and long-lasting effects in
patients with MuSK antibodies. Its use in current clinical
practice should be considered in patients with refractory MG,
when conventional treatments are contraindicated, and par-
ticularly in patients with MuSK antibodies [39].
The ICU treatment of MG has been one of the neurocritical
care success stories, with mortality dropping from about 30%
to 5% over the last few decades. Prompter diagnosis of exacer-
bation, better respiratory care and ventilatory assistance, faster
recognition and treatment of systemic complications, and
improved management of the inflammatory disorder may
have all contributed to this decline in mortality (Figure 16.1).
Botulism
Botulism is caused by a toxin produced by the anaerobic
bacterium Clostridium botulinum. It is most commonly
encountered as wound botulism in the United States among
intravenous drug abusers. Botulism is also found in improp-
erly sterilized foods (usually canned). The diagnosis is usually
based on a history of an ingested food or purulent wound. This
is followed by nausea and vomiting.
Weakness and anticholinergic symptoms start 6–24 hours
later. Anticholinergic symptoms include dry mouth, urinary
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 Chapter 16: Neuromuscular Disorders
retention, pupillary dilation, and a dysautonomia that is
followed by the development of bulbar weakness and a des-
cending paralysis. Respiratory failure can develop rapidly.
The toxin is believed to interfere presynaptically with the
release of acetylcholine into the neuromuscular junction,
although the exact mechanism is unknown. EMG findings
may not be present early, but evolve over time. They include
decreased CMAPs in at least two muscles, a 20% facilitation of
CMAP with stimulation that is prolonged for at least two
minutes, and no postactivation exhaustion. Single-fiber EMG
shows increased jitter.
Treatment is primarily supportive. Diaminopyridine,
which facilitates the presynaptic release of acetylcholine, is
helpful but will not affect the underlying disease process. An
antitoxin is available from the Centers for Disease Control and
Prevention (CDC) but must be given within 24 hours of the
onset of symptoms to be effective.
Critical Illness Neuromyopathy
Critical illness neuromyopathy (CINM), and the more recently
proposed nomenclature of ICU-acquired weakness (ICUAW),
are terms that have been coined to represent the common
co-occurrence of both critical illness myopathy (CIM) and
critical illness polyneuropathy (CIP) in the weak critically ill
patient [40].
CINM is extremely common in critically ill patients and
can occur in up to 56–100% of patients afflicted with the two
most prominent risk factors: systemic inflammatory response
syndrome (SIRS)/sepsis and multiorgan failure. Other risk
factors for CINM include prolonged mechanical ventilation
and ICU stay, corticosteroid administration, hyperglycemia,
poor nutrition, neuromuscular junction blocking-agent use,
and renal failure [40, 41].
CIP and CIM present with varying degrees of limb and
diaphragmatic weakness. Though, due to the common co-
occurrence of encephalopathy or sedation and paralysis, symp-
toms may not become apparent until the initiation of physical
therapy or extubation failure.
Clinical features specific to CIP include distal weakness, sens-
ory loss, and areflexia, with sparing of the face and extraocular
muscles [42], while those specific to CIM include proximal
weakness with occasional facial involvement and, rarely, extra-
ocular muscle weakness. Sensation is intact and deep tendon
reflexes are relatively preserved. The clinical presentation is rarely
that of pure CIM or CIP reflecting their frequent co-existence.
CIP manifests as a length-dependent axonal sensorimotor
polyneuropathy, the etiology of which remains speculative.
The leading theory is that sepsis leads to impairment of the
nerve microcirculation. Cytokines released during sepsis can
lead to endoneural edema, which is worsened by hypoalbumi-
nemia and hyperglycemia. This edema increases the distance
oxygen must diffuse to provide energy for the peripheral nerve.
The reduction in energy reserves needed for axonal transport
196
of nutrients is thought to result in the dying-back axonopathy
that constitutes CINM [43].
In CIM, thick filament (myosin) loss and focal loss of
ATPase reactivity in type I fibers is seen. Importantly, muscle
fibers functionally become inexcitable from the development
of a sodium channelopathy. Necrosis is extremely uncommon,
but can occur in cases of acute necrotizing myopathy of inten-
sive care – a rare, malignant form that is associated with
profound quadriparesis, hyperCKemia, and myoglobinuria.
Treatment options are currently limited in CINM, and
therefore, the importance of excluding other causes of weak-
ness, including a pre-existing neuromuscular disorder, cannot
be understated [40]. First, proper localization using history,
examination, and, if necessary, neuroimaging should occur,
and central nervous system causes for the weakness should
be ruled out. Laboratory studies, including an electrolyte panel
with magnesium, calcium, and phosphorus, should be ordered
to rule out a metabolic myopathy. Serum creatine kinase is
usually normal or mildly elevated in CINM and significant
elevation should prompt consideration of an inflammatory
myopathy, toxic myopathy, muscular dystrophy, or acid mal-
tase deficiency.
NCS and EMG can be extremely helpful in confirming the
diagnosis and ruling out other causes [44]. Severe reduction in
CMAP amplitude and prolongation of CMAP duration are
frequent findings in CINM [45]. Repetitive nerve stimulation
is normal in CINM, but should be performed to rule out
neuromuscular transmission disorders, such as myasthenia
gravis. Sensory nerve action potentials can be abnormal in
CIP. Neuropathic, myopathic, or mixed motor unit potentials
can be found, depending on the timing of the study and
predominance of CIM or CIP.
Direct muscle stimulation is often difficult to perform in
clinical practice due to coexisting edema and other confoun-
ders, but can be utilized to differentiate CIM from CIP by
showing muscle inexcitability in the former. Neuroimaging
and lumbar puncture are unremarkable in CINM, but these
tests may be useful to exclude other conditions. Muscle and
nerve biopsies establish the definitive diagnosis, but are rarely
utilized in contemporary clinical practice.
Aggressive risk factor management is essential to reduce
the incidence of CINM, though no definitive treatment for the
disease currently exists. A recent Cochrane meta-analysis
found an association between intensive insulin therapy and a
reduction in the incidence of CINM, duration of mechanical
ventilation, and 180-day mortality, though at the cost of a
higher incidence of hypoglycemic events. The study also dem-
onstrated that early rehabilitation in CINM was associated
with shorter time on the ventilator, though there was no effect
on ICU length of stay [46].
Mortality is high amongst patients with sepsis and CINM,
yet survivors do improve to a variable extent. While conflicting
evidence exists in the literature, CIM appears to have a better
prognosis than CIP.

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 Chapter
Management of Head Trauma in the

17 Neurocritical Care Unit

Peter Le Roux

Introduction injuries, may not require critical care. However TBI causes
more deaths in men <35 years old than all other diseases
Traumatic brain injury (TBI) is common and a major health
combined and a third of all injury-related deaths include a
and socioeconomic problem worldwide. In the United States it
diagnosis of TBI. This is important because worldwide 1 out
is estimated that someone suffers a TBI every 15 seconds and
of every 10 deaths result from injuries [19]. Furthermore >5
that >2% of the population lives with TBI-associated disability.
million US residents are living with TBI-related disabilities,
TBI is a heterogeneous disease in cause, pathology, severity,
including long-term and psychological impairments. This rep-
clinical presentation and prognosis that may occur in isolation
resents a great cost to society, including a high financial burden.
or be associated with other extracranial injuries. Despite much
In 2010, the economic cost, including direct and indirect costs,
research and success in animal studies, effective drug therapies
of TBI was estimated at $76.5 billion dollars [20].
are missing in clinical trials [1–3]. Instead TBI management is
The incidence of TBI is increasing globally because of more
centered on the early identification and removal of mass
motor vehicle use in low-income and middle-income coun-
lesions and on the detection, prevention, and management of
tries, such that by 2020, the World Health Organization has
secondary brain insults such as hypotension, hypoxia, seizures,
estimated that road traffic accidents will be the third leading
and elevated intracranial pressure (ICP), among others, that
global burden of disease and injury. In high-income countries
evolve over time following the primary injury. Hence manage-
the incidence of TBI associated with road traffic accidents has
ment in the neurocritical care unit (NCCU) can have a signifi-
decreased because of preventive measures, car design, and
cant impact on patient outcome. Much of this care has been
safety regulations. However as the population ages, more TBIs
codified in various guidelines published by organizations such
associated with falls are observed. This has had several conse-
as the National Institute for Health and Clinical Excellence in
quences, including an increase in the median age and number
the United Kingdom or the Brain Trauma Foundation and
of females in TBI populations and a shift in pathology, i.e.
Neurocritical Care Society in the United States [4–8]. In this
contusions or anticoagulation-associated bleeds from falls in
chapter we will briefly review the classification, pathology, and
older patients rather than diffuse injuries that occur in younger
pathophysiology of TBI, provide indications for surgical inter-
patients involved in road traffic accidents [21]. There also been
vention, and discuss important aspects of critical care. Several
an increase in TBIs associated with violence that in civilian
topics, e.g. cerebral blood flow (CBF), ICP, monitoring, venti-
practice now may account for up to 10% of TBIs. In the United
lation, sedation, and brain death, are also enlarged upon in
States, firearm use is frequent in violence-associated injury.
other chapters in this book. We will concentrate on moderate
This is important because gunshot wounds to the head are
and severe TBI in adults since it is these patients who usually
associated with far worse outcome than other types of TBI.
require intensive care. The reader is referred elsewhere for
recent reviews on concussion, mild TBI, and care of pediatric
TBI [9–17]. Classification
TBI may be isolated, but in a third of cases is associated with
Epidemiology extracranial injuries, i.e. polytrauma, such as intra-abdominal
The incidence and type of head injury differs between coun- or thoracic injuries or fractures. The severity or type of extra-
tries, e.g. high- versus middle- or low-income countries. Epi- cranial injury depends in part on the mechanism of injury, but
demiological data is well described in the USA through Centers its presence can affect care, both the logistics and type of care,
for Disease Control and Prevention monitoring, which and may often adversely affect outcome.
recorded that there are 403 per 100,000 emergency room (ER) There are several methods by which TBI can be classified.
visits and 85 per 100,000 hospital admission each year [18]. First, it may be broadly classified according to mechanism, as
This represents about 7% of all ER visits and more admissions blunt (closed or nonpenetrating) or penetrating. In turn these
to hospital than new cases of breast cancer. The vast majority are subdivided into low- or high-velocity injuries. In recent
(80%) of TBIs are mild and, unless associated with other years, blast injury (bTBI) has evolved as a third distinct

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 Chapter 17: Management of Head Trauma

Table 17.1 Classification of traumatic brain injury based on injury severity Table 17.2 Classification of traumatic brain injury based on admission CT
findings
GCS PTA LOC
Marshall CT classification of TBI [23]
Mild 13–15 <1 day 0–30 minutes
Category CT findings
Moderate 9–12 >1 to <7 days >30 min to <24 hours
Diffuse injury I (no No visible intracranial pathology seen
Severe 3–8 >7 days >24 hours
visible pathology) on CT scan
Abbreviations: GCS: Glasgow Coma Scale [16]; PTA: post-traumatic amnesia;
LOC: loss of consciousness Diffuse injury II Cisterns are present with midline shift of
0–5 mm; no high or mixed density
lesion >25 cm3 may include bone
fragments and foreign bodies
mechanism of injury, particularly in the military environment.
Second, TBI is classified most frequently according to clinical Diffuse injury III Cisterns compressed or absent with
severity into mild, moderate, or severe TBI (Table 17.1) using (swelling) midline shift 0–5 mm; no high or mixed
the Glasgow Coma Scale (GCS) [22] and less frequently with density lesion >25 cm3
the injury severity score (ISS). In modern clinical practice, Diffuse injury IV (shift) Midline shift >5 mm; no high or mixed
however, it is now recognized that classification according to density lesion >25 cm3
the GCS has several limitations; for example, the level of Evacuated mass Any lesion surgically evacuated
consciousness may be obscured by sedation used in clinical lesion V
care or by drug or alcohol intoxication. Third, TBI may be
Nonevacuated mass High or mixed density lesion >25 cm3;
classified according to the structural damage identified on
lesion VI not surgically evacuated
neuroimaging. Two descriptive computed tomography (CT)
classification systems, the Marshall Score [23] and the Rotter- Rotterdam CT classification of TBI [24]
dam Score [24] are most frequently used. These CT-based Variable Score
systems emphasize the presence or absence of a mass lesion
and try to differentiate diffuse injuries according to radiologic Basal cisterns
evidence for increased ICP (e.g. midline shift or status of the Normal 0
Compressed 1
basal cisterns). This CT-based classification can be useful, since
Absent 2
confounders such as sedation or intoxication do not affect
them, but are perhaps best applicable for research studies Epidural mass lesion
(Table 17.2). Finally, TBI may be classified according to Present 0
expected prognosis, e.g. the IMPACT or CRASH models that Absent 1
can be useful in comparing clinical trials or assessing quality of Midline shift
care [25,26]. Whether these prognostic techniques can be used No shift or shift <5 mm 0
in routine clinical practice is unclear since the existing Shift >5 mm 1
methods lack accuracy in select patients [27]. Intraventricular blood or SAH
Today it is recognized that TBI classification is suboptimal Absent 0
and that each of the current classification methods has limita- Present 1
tions that in part may contribute to the limited success of Sum Score Total + 1
many clinical trials. In particular these classification systems
do not adequately capture the dynamic nature of TBI path-
ology, identify important consequences of TBI that occur at
the microscopic level or allow personalized care. Technologic Table 17.3 Pathoanatomic classification of traumatic brain injury
advances in magnetic resonance imaging (MRI) and biomar-
• Skull fracture
ker development are likely to provide new insights into TBI : linear, depressed, basilar
classification and novel disease classifications in the near future
[28–30]. • Epidural hemorrhage
• Subdural hemorrhage
Pathology and Pathophysiology : acute, subacute, chronic
TBI is a heterogeneous disorder with several different forms of • Subarachnoid hemorrhage
pathology (Table 17.3). What unifies these pathologies is that • Brain contusion
brain injury results from an external force that includes direct • Intraparenchymal hemorrhage
impact (blunt or penetrating), acceleration or deceleration, or
blast waves. The pathology that results is determined by the • Intraventricular hemorrhage
nature of the external force, the area over which the force is • Traumatic axonal injury

200

exerted, the duration of the force, and the direction and
amount of subsequent head movement. Primary injury (from
the impact) and secondary injury that evolves over time then
result. Primary injury is broadly divided into blunt or pene-
trating injury and more recently blast injury.
Primary Brain Injury
Blunt TBI
In blunt injury, primary injury is caused by impact to the head
or rapid acceleration/deceleration, resulting in mechanical
forces that cause tissue distortion, compression, shearing,
and swelling. Injury to the scalp, skull, or brain may occur.
Primary brain injury may be broadly classified as: (1) cerebral
contusions, (2) extra-axial hematomas, i.e. epidural and sub-
dural, (3) subarachnoid hemorrhage (SAH), (4) intracerebral
hemorrhage (ICH), and (5) diffuse axonal injury (DAI) or
traumatic axonal injury.
Figure 17.1 CT scan findings of common intracranial hemorrhages: (A) contusions, (B) epidural hematoma, (C) acute subdural hematoma, (D) chronic subdural
hematoma, (E) traumatic subarachnoid hemorrhage, and (F) diffuse axonal injury.
Chapter 17: Management of Head Trauma
Contusions
Focal cerebral contusions are the most common lesion identi-
fied in severe TBI and are more frequent in older patients.
They represent areas of hemorrhagic necrosis associated with
acceleration and deceleration, and are most frequently seen in
the gyral crests of the orbitofrontal and anterior temporal
regions (Figure 17.1). Cerebral edema is frequent and about
a third of contusions expand during the first 24 hours after
injury, i.e. patients may deteriorate clinically. In addition mul-
tiple small contusions may coalesce into a larger ICH. On head
CT, contusions appear as hypodense regions without macro-
scopic hemorrhage, or as mixed high-density lesions when
hemorrhage is present.
Intracranial Hemorrhage
Traumatic intracranial hematomas are observed in about a
third of patients with severe TBI, 5–10% with moderate TBI
and very rarely in mild TBI.
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 Chapter 17: Management of Head Trauma
Epidural hematomas usually are associated with a skull
fracture, and in most instances involve arterial bleeding, typic-
ally from the middle meningeal artery, that distorts and com-
presses the brain. Injury to the middle meningeal vein, the
diploic veins, or the venous sinuses also may cause epidural
hematomas. Patients may present with a loss of consciousness,
a lucid interval, and then deteriorate. On CT the hemorrhage is
typically hyperdense, lens-shaped, and does not cross suture
lines (Figure 17.1). There usually is little evidence for structural
damage to the underlying brain on CT and hence outcome
often can be good when the hematoma is promptly treated.
Subdural hematomas (SDHs) typically are caused by rup-
ture of bridging veins and usually occur over the cerebral
hemispheres. They may be bilateral in up to 15% of patients.
However, SDHs also may occur in the posterior fossa or along
the falx, i.e. interhemispheric, the presence of which suggests a
coagulopathy or anticoagulation use. How the SDH develops
depends in part on age: greater than 50% of SDH are caused by
high-speed road traffic accidents (>35 mph) in young patients
(<40 years old), whereas falls are the more likely mechanism
of injury in older patients (>65 years). A lucid interval is very
rare in SDH and on head CT SDHs usually are crescent-shaped
(concave) and can cross skull suture lines (Figure 17.1).
Underlying brain injury is frequent and mortality is high
(30–90%, depending on the mechanism of injury and patient
age). Subdural hematomas also may develop over time, i.e. a
chronic SDH (Figure 17.1) and hence patients, particularly
elderly patients or those taking antiplatelet or anticoagulation
agents, may present in a delayed fashion or not recover in the
expected manner.
Subarachnoid hemorrhage results from tearing of small pial
vessels. Trauma is the commonest cause of SAH, but it
remains important to differentiate traumatic SAH from other
causes (e.g. an aneurysm) because this has significant manage-
ment implications. Furthermore while a patient’s presentation
is of a fall or road traffic accident, a preictal event, e.g. aneur-
ysm rupture, may have led to the trauma. Traumatic SAH
typically is located over the cerebral convexities, where it
may be confined to a few sulci or fissures or diffusely distrib-
uted over the cortical surface (Figure 17.1). It is less frequently
seen in the basal cisterns or ventricles (intraventricular hem-
orrhage; IVH). When there is doubt on the mechanism of
injury, vascular imaging, e.g. a CT-angiogram should be
obtained. The presence of SAH or IVH often can aggravate
outcome through the development of hydrocephalus, vaso-
spasm, and delayed ischemia, and may also indicate diffuse
axonal injury [29,31].
Diffuse Axonal Injury
DAI, also called traumatic axonal injury (TAI), is character-
ized by multiple small lesions in white-matter tracts and
occurs after rapid acceleration and deceleration of the head
[32]. On histologic analysis, axonal swellings that result from
accumulated material associated with interrupted axonal
transport are observed. These swellings may be seen
202
periodically along the axon (axonal varicosities) or manifest
as a single axon lesion (axon bulb or retraction ball) that likely
represents axon disconnection. In severe TBI, axonal injury
may represent immediate mechanical damage to axonal struc-
tural elements when there is tearing of tissue, or evolve over
time, i.e. represent a form of secondary injury. Patients with
DAI present with a depressed level of arousal that appears out
of proportion to the injury observed on CT scan. CT imaging
frequently is unremarkable or may show small punctate foci of
hemorrhage typically in the junction between cortex and white
matter, white matter structures close to the midline (corpus
callosum, internal capsule), the brainstem, cerebellum, and the
corona radiate (Figure 17.1). MRI is more sensitive and may
display abnormalities on diffusion-weighted, gradient-echo,
susceptibilty-weighted and diffusion-tensor sequences.
Traditionally, DAI was thought to be associated with
immediate mechanical axonal injury and that the axons were
not able to repair themselves or regenerate, i.e. DAI was diffi-
cult to treat and the outcome inevitably poor. Recent research
shows that DAI may result from mitochondrial dysfunction
and hence cellular energy failure, and that axons can regener-
ate. Consistent with this, laboratory studies of DAI show that it
may take up to 48 hours to become established [33], i.e. DAI
can be amenable to therapy. Today select patients with severe
DAI may recover with modern neurocritical care techniques.
Penetrating TBI
Penetrating TBI is defined as a wound in which the cranium is
breached by a projectile that is either missile (usually gun-
related) or nonmissile (e.g. knife-related). It is less prevalent
than blunt TBI, but outcome, particularly that from a gunshot
wound (GSW), often is poor. Indeed the victim of a GSW to the
head is 35 times more likely to die than is a patient with a blunt
TBI, particularly when the projectile path crosses the midline
(i.e. involves both hemispheres) or involves the brainstem [34]
(Table 17.4). In penetrating TBI the pathology depends on the
physical properties of the projectile (and weapon), its ballistics,
the location and characteristics of the intracranial trajectory,
and whether there are secondary projectiles, e.g. bullet or bone
Table 17.4 Scoring system to predict outcome from GSWs to the head
(modified from [29])
Variable Score
Age >35 years +1
GCS Score 3 or 4 +1
Nonreactive pupils +1
Missile trajectory – posterior fossa or bihemispheric +2
Points are summed for all variables. A score of 0 is assigned if the factor is not
present. The total score has prognostic significance for both survival and
functional outcome. Possible total scores range from 0 to 5. Mortality is
approximately 25% when scores are 0–1; 50% when 2, and 75% or greater
when 3–4. Functional outcome also is associated with the score: a score of
0 is associated with a 50% chance of good outcome, 1 with a 30% good
outcome, and 2 with approximately 10% chance of good outcome.

fragments. As the projectile penetrates the brain it causes tissue
crushing, laceration, and cavitation in which the brain is com-
pressed, collapses, and re-expands in a repeating wave-like
pattern. Temporary cavitation can be as much as 30 times
larger than the missile diameter and so causes injury to struc-
tures distant from the missile tract. Ultimately the amount of
brain injury depends on the amount of kinetic energy that a
missile imparts; this is defined by E = ½mv2; where m = missile
mass and v = velocity. Hence more injury is associated with a
high-velocity projectile injury.
Blast Injury
Blast injuries of the brain are now recognized as a specific
entity that occurs when acoustic, electromagnetic, light, and
thermal energy (blast wave) that emanates from an explosion
are transferred to the brain directly through the cranium, and
indirectly through oscillating pressures in fluid-containing
structures, e.g. blood vessels. This type of TBI has become a
signature injury of recent global armed conflicts and terrorist
activities, where many of the injuries result from improvised
explosive devices (IDEs), but it is less common in the civilian
environment [35]. Blast injury has several unique characteris-
tics, including: (1) rapid development of malignant cerebral
edema (<1 hour), (2) a form of dose-dependent DAI that is
different from DAI associated with blunt TBI, (3) frequent and
prolonged cerebral vasospasm and (4) concomitant injury to
the eyes, and the auditory and vestibular systems [36]. The
injury magnitude depends on several factors and in particular
blast energy and the patient’s distance from the blast epicenter.
The clinical course and outcome of blast injury is still being
elucidated, but military experience suggests that favorable out-
come is feasible after severe blast injury with early decompres-
sive craniectomy (DC) and aggressive ICP control [37,38].
Secondary Brain Injury
In patients who survive their initial trauma, each type of TBI
described above may initiate a cascade of molecular, biochem-
ical, and cellular processes that can exacerbate the primary
injury, i.e. secondary brain injury (SBI). These processes may
begin immediately and then evolve over the ensuing hours and
days; the extent and duration of which may depend on the
primary pathology. The prevention and management of SBI is
fundamental to TBI care and is the rationale behind critical
care of TBI [39].
There are a variety of mechanisms for SBI that often act
concurrently and synergistically. First are those that occur at the
microscopic (or cellular) level in the brain, e.g. neuronal
depolarization, disturbance of ionic homeostasis, glutamate
excitotoxicity, generation of nitric oxide and oxygen free rad-
icals, release of proapoptotic molecules (e.g. caspases), lipid
peroxidation, mitochondrial dysfunction, and inflammation.
In turn these processes can contribute to cellular edema and
altered cellular metabolism. Second are disturbances at the
macroscopic level in the brain, e.g. blood–brain barrier
Chapter 17: Management of Head Trauma
disruption, secondary hemorrhage or delayed hemorrhage,
ischemia, cerebral edema, and intracranial hypertension, among
others. Finally secondary brain injury may result from systemic
(or extracerebral) disturbances, e.g. systemic hypotension, hyp-
oxia, fever, hypocapnia, and altered glucose metabolism, among
others, that each can adversely affect TBI outcome [40].
Cerebral Hemodynamics
While the underlying pathophysiology is complex, ischemia,
hypoxia, and energy dysfunction are important contributors to
SBI. Consequently, providing the injured brain with adequate
CBF and delivery of oxygen and energy substrate is central to
TBI therapy. Conceptually the pathophysiology may be con-
sidered as: (1) intracranial hypertension, (2) macrovascular
dysfunction, (3) microvascular dysfunction, and (4) energy
dysfunction.
Intracranial Hypertension
The Monro–Kellie doctrine (intracranial volume [v; constant] =
v.brain + v.CSF + v.blood + v.mass lesion) provides the concep-
tual framework for current severe TBI and ICP management.
The cranial compartment can accommodate about 150 mL of
additional volume before ICP increases, since the brain is
able to compensate for a volume increase in one of the
compartments with volume changes in the others, initially
with collapse of low-pressure veins (i.e. change in cerebral
blood volume (CBV)) and then CSF egress. Once these com-
pensatory mechanisms fail or are maximized, a further
volume increase (e.g. cerebral swelling or hematoma) causes
ICP to increase. This compensatory reserve is known as
cerebral compliance, defined as the change in cerebral volume
per unit change in pressure or elastance, which is the reverse
of compliance. The compliance curve is not linear, but loga-
rithmic. In many patients with severe TBI, compliance is
poor (i.e. they are on the “steep” part of the curve) and hence
small changes in volume can cause a large increase in ICP or
even herniation. Cerebral perfusion pressure (CPP), calcu-
lated as mean arterial blood pressure (MAP) – ICP, is used as
a surrogate for CBF. Hence an increase in ICP can decrease
CPP and so cause or exacerbate ischemia. In large part,
however, this depends on cerebral autoregulation (CAR).
Macrovascular Dysfunction
Management of TBI in the ICU and in particular management
of ICP is presently focused on two main goals: to prevent
herniation and to preserve CBF, i.e. prevent ischemia. The
noninjured brain maintains a constant CBF when MAP is
between 40 and 160 mmHg through CAR. Following TBI,
however, CAR may be preserved, partially intact, or absent,
and there often is regional heterogeneity of CAR within the
brain. When CAR is impaired, CBF can become dependent on
CPP and may be inadequate, even when CPP is in the normal
range (50–70 mmHg) [41]. Indeed observational studies dem-
onstrate that brain hypoxia is common, even when CPP is
normal after severe TBI [42].
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A decrease in CBF is well described after TBI and there
often is regional heterogeneity [43]. However, a reduction in
CBF does not necessarily mean ischemia. Instead the balance
between CBF and cerebral metabolic rate of oxygen (CMRO2)
determines whether the tissue is ischemic or not. For example,
when CMRO2 is decreased, e.g. sedation, metabolic AR can
cause a matched reduction in CBF that does not imply ische-
mia. But if the CBF decrease is greater than the CMRO2
decrease then the tissue is ischemic. Hence, knowledge about
CBF alone may be inadequate to determine if there is ischemia
or not. Furthermore, ischemia may be present when CPP is
normal, i.e. bedside CPP is not a reliable measure of the
adequacy of CBF in all patients [44]. Consistent with this,
observational studies show an association between poor out-
come and compromised CAR [45].
Microvascular Dysfunction
Ischemia, i.e. macrovascular dysfunction, is not the only reason
for brain injury. Experimental and clinical evidence show that
microcirculatory changes also occur in TBI, e.g. astroglial
swelling, microthrombi in the cerebral microcirculation or
heterogeneity of red blood cell transit time into capillaries
[46,47] that in turn contribute to diffusion abnormalities as a
barrier to cellular oxygen delivery rather than ischemia [48].
Cell Energy Dysfunction
Brain activation and increased energy demand are followed by
an increase in CBF and oxygen extraction fraction (OEF).
Neuronal activation, given the brain’s appetite for glucose,
can also be accompanied by an increase in CBF and glucose
utilization without a similar increase in OEF and CMRO2 [49],
i.e. metabolic uncoupling. Several lines of evidence also show
increased glucose utilization after TBI without an oxygen or
CBF limitation (cerebral hyperglycolysis) [50]. Mitochondrial
dysfunction may also be observed leading to reduced metabol-
ism and adenosine triphosphate (ATP) production [51]. The
implication of these findings is that simply understanding ICP,
CPP, and CBF alone may miss significant cellular dysfunction
in some patients and that there is not one simple treatment for
all TBI patients. Indeed, microdialysis studies demonstrate an
elevation of the lactate/pyruvate ratio (a marker of cell energy
dysfunction) independent of CPP or that cellular metabolic
failure often precedes an increase in ICP [52–54].
Clinical Evaluation and Diagnosis
The diagnosis of a TBI is usually made by the history provided
by the patient, bystanders, or by emergency medical personnel.
An understanding of injury mechanism (e.g. fall >20 feet or
motor vehicle accident >30 mph), are important historical
findings. When no history is available, the diagnosis depends
on a physical examination that shows external signs of trauma
and neuroimaging studies. External or superficial evidence of
trauma includes abrasions, lacerations, and soft tissue swelling,
particularly of the head. Signs such as retroauricular
204
ecchymosis (Battle’s sign), periorbital ecchymosis (raccoon’s
eyes), hemotympanum, and CSF otorrhea or rhinorrhea indi-
cate a basilar skull fracture.
Clinical Evaluation
Primary Survey
Patients with TBI require prompt evaluation and management
after ensuring a secure airway with adequate oxygenation and
circulation (ABCs). During the primary survey a focused
neurological assessment is made to determine the severity of
the TBI, through the GCS [22], whether all extremities are
moving and if the pupils are equal and reactive. Pupils are an
important component in evaluation of a TBI patient. For
example, a unilateral dilated pupil that does not react to light
suggests uncal herniation and hence the likelihood of a mass
lesion that requires surgery. The GCS score may be deter-
mined quickly, and is a widely used standard score that has
good inter- and intrarater reliability and prognostic value that
allows effective communication between caregivers about a
patient’s condition. In addition it can be repeated to provide
follow-up and trends. The postresuscitation GCS, and ideally
before administration of sedatives and/or paralytics, is vital to
guide subsequent management and outcome prediction.
A GCS of 8 indicates coma, and airway intubation and
ventilation should be considered early. If necessary, an emer-
gency surgical airway (cricothyroidotomy, tracheostomy) may
be required. The GCS includes evaluation of eye opening,
verbal response, and motor response. When there is asym-
metry in either eye opening or motor scores, the best score is
used. The GCS, however, has limitations, particularly for use
in patients who are intubated or aphasic. These limitations are
addressed in other scales, e.g. the Full Outline of UnRespon-
siveness (FOUR) score [55], although the role of this scale in
TBI is still being elucidated.
Secondary Survey
Once the primary survey is completed and immediate life-
threatening injuries are excluded or managed, a secondary
survey is performed to complete the physical examination
and determine the presence and extent of non-nervous-system
injuries. A detailed neurologic examination to evaluate motor
and sensory deficits, reflexes, cranial nerves, and rectal tone is
needed. This should include assessment of spinal cord and
peripheral nerve function, since brain, spinal cord, and nerve
injuries may coexist. Baseline patient characteristics (e.g. pre-
existing brain injury), type of TBI (e.g. contusion versus extra-
axial hematoma), injury severity, and location of the lesion
determine each patient’s clinical features.
Laboratory Evaluation
Bedside testing for blood glucose is recommended in all
patients and if blood glucose is reduced it should be corrected.
Important parameters to check include: arterial blood gases
(ABGs), blood glucose, electrolytes, coagulation profile (at the

least platelet count, prothrombin time (PT), and partial throm-
boplastin time (PTT)), hematocrit and hemoglobin. Drug and
alcohol screening often is necessary.
Imaging
CT of the Head
A head CT scan without contrast is the emergency imaging
technique of choice for mild, moderate, or severe TBI [56].
The goal is to identify as early as possible any lesion that can be
corrected by neurosurgical intervention. Repeat CT assessment
is indicated when there is neurologic deterioration, but judi-
cious use is required in pediatrics. MRI has a limited role in the
acute phase and generally is only indicated in the subacute
phase if neurologic findings are not explained by the CT
findings or to further evaluate DAI. In addition, advanced
MRI techniques combined with clinical evaluation performed
in a delayed fashion in those who remain in a coma after seven
days can enhance outcome prediction [27,57].
Nearly all patients with moderate or severe TBI require
imaging, i.e. a head CT should be performed in all patients
with declining level of consciousness, prolonged loss of con-
sciousness, persistent alteration in consciousness, focal neuro-
logical signs, seizures, penetrating injury, signs of depressed or
basilar skull fracture, confusion, or agitation. Factors that
suggest a surgical intracranial hematoma are listed in
Table 17.5. Some patients with mild TBI may not warrant
imaging. Evidence-based decision algorithms have been
described to decide the need for a CT head scan in mild TBI
[58] (Table 17.6).
Table 17.5 Features suggesting an intracranial hemorrhage may be
present
• GCS <8
• Decline in GCS by >2
• Loss of consciousness and skull fracture
• Persistent drowsiness
• Children with refractory vomiting
• ICP >25
Table 17.6 Canadian rule on when to perform a head CT scan on patients
with a mild TBI [58]
High risk for neurosurgical intervention
• GCS score lower than 15 at two hours after injury
• Suspected open or depressed skull fracture
• Any sign of basal skull fracture
• Two or more episodes of vomiting
• 65 years or older
Medium risk for brain injury detection by CT
• Amnesia before impact of 30 or more minutes
• Dangerous mechanism
Chapter 17: Management of Head Trauma
The rule is not applicable if the patient did not experience a
trauma, has a GCS score lower than 13, is younger than 16
years, is taking warfarin or has a bleeding disorder, or has an
obvious open skull fracture.
On CT, acute blood is hyperdense. In some patients blood
may be isodense or hypodense when imaging is obtained very
early after the injury or if the patient is coagulopathic or
anemic. Contusions can be hyperdense, hypodense, or may
have a “salt and pepper” appearance, whereas air that indicates
an open skull fracture or craniofacial trauma is hypodense. It is
important to determine whether the perimesencephalic cis-
terns are open, compromised, or closed and the degree of
midline shift at the level of the third ventricle. These factors
are useful in surgical decision-making or in estimating ICP. In
general if the perimesencephalic cisterns are patent, ICP is
normal. CT also allows the skull and facial bones to be assessed
for fractures, displacement of bone fragments, or penetrating
objects.
Neck Imaging
Cervical spine trauma is common in TBI patients and all
patients who undergo a head CT should also have neck
imaging, including X-rays and a CT scan. An MRI may be
appropriate to exclude neck trauma in a delayed fashion.
Vascular Imaging
The incidence of blunt cerebrovascular injury (BCVI) is not
well defined after trauma, since vascular imaging is usually
performed only when vessel injury is suspected. Vascular
injury from disruption of arterial and venous structures may
include arterial dissection, aneurysms, fistulae, thrombosis,
and hemorrhage, and can be identified in 0.5–1% of patients.
Blunt injuries to the carotid or vertebral arteries may present
with late-onset ischemic strokes. In addition, vascular imaging
should be considered when the head CT scan does not fully
explain the neurologic condition. Table 17.7 describes clinical
findings that should prompt vascular imaging [59]. Diagnostic
Table 17.7 Vascular imaging: when?
• Penetrating injury:
: CT evidence for tSAH
: Pterional, transorbital, posterior fossa
• Fracture over a venous sinus
• A neurologic deficit not explained by head CT scan
• Petrous bone fracture
• Lefort II or III facial fractures
• A suspected cause for the injury (e.g. aneurysm rupture)
• Selected C-spine injuries (e.g., severe flexion or extension
injury or a fracture through the transverse foramen)
• Patients with seat-belt abrasions of the neck, or soft tissue
swelling of the anterior neck
• Epistaxis
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four-vessel subtraction angiography (DSA) is the gold stand-
ard, but multislice (eight or greater) multidetector CT angiog-
raphy (CTA) or magnetic resonance angiography (MRA) are
reasonable screening studies. Duplex ultrasound is not
adequate for BCVI screening. Similarly, CTA with a four (or
less)-slice multidetector array is not sensitive or specific
enough for BCVI screening.
Management
An organized team approach is essential to successful TBI
management and may be divided by phase: prehospital, emer-
gency department (ED), and subsequent care that includes
both surgical treatment and intensive care unit (ICU) treat-
ment. Prehospital, ED and surgical care wil be briefly dis-
cussed. In this chapter the focus is on adults with TBI [4–8].
The reader is referred elsewhere for guidelines that apply to
infants, children, and adolescents [15,17,60].
Prehospital Care
Prehospital care includes simultaneous assessment, stabiliza-
tion, and therapeutic interventions. The primary goals of ther-
apy during this phase are spine protection, a patent airway,
maintenance of adequate ventilation and oxygenation, correc-
tion and prevention of hypotension (SBP <90 mmHg)
(Table 17.8), and rapid transport to hospital, ideally a trauma
center [4–8]. Hypoxia and hypotension during transport
adversely affect outcome. Interestingly hypertension (SBP
>150 mmHg) and hyperoxia that occur early in the course
of TBI also may be associated with increased mortality [61–
63]. Consistent with other physiologic findings, these variables
demonstrate a U-shaped association with outcome in a bivari-
ate analysis, with increasing mortality at both lower and higher
values [63]. In general, endotracheal intubation in the field is
considered for patients with a GCS <8. However, the benefit of
advanced life support (ALS) over simple first aid and basic life
support (BLS) measures is not well defined and so only para-
medic personnel with expertise should perform endotracheal
intubation [64]. Indeed, prehospital intubation may aggravate
outcome if not properly performed [65,66]. Similarly, the role
Table 17.8 Prehospital care goals in adults with TBI [7,71]
• C-spine precautions
• Basic and advanced airway management to maintain:
: Oxygen saturation greater than 90%
: ETCO2 35–40 mmHg
: Hyperventilation (ETCO2 <35 mmHg) may be used as a
temporary measure if signs of herniation are present
• Obtain intravenous (IV) access
• Maintain systolic BP >90 mmHg with isotonic fluids
• Diagnose hypoglycemia and treat
• Assess GCS and pupil size
• Monitor pulse oximetry and blood pressure
206
of alternative airway devices, e.g. supraglottic devices, requires
further evaluation. Appropriate fluid administration is import-
ant to maintain a systolic blood pressure (SBP) >90 mmHg
[67]. Hypotension is corrected with isotonic crystalloid, and
hypotonic fluids should be avoided. Hypertonic saline (HTS) is
theoretically an ideal resuscitation fluid for TBI patients with
multiple injuries and shock since, unlike mannitol, it can
decrease brain edema while acting as a volume expander.
However, a benefit to HTS use has yet to be demonstrated
[68]. Albumin use during resuscitation has been associated
with increased mortality [69]. Similarly, a decision to use
plasma or packed red blood cells (pRBCs) also may influence
outcome [70].
Emergency Department Management
The management priorities in the ED are unchanged from the
prehospital goals, and the primary goals remain: (1) ensuring
adequate cerebral perfusion, (2) prevention of SBI, (3) preven-
tion and management of brain herniation. Advanced trauma life
support (ATLS) [71] and emergency neurological life support
(ENLS) guidelines form a framework for this management [7].
Table 17.9 outlines the physiologic goals that should be main-
tained as part of the goal-directed therapy in the context of
injury severity in the ED and in the ICU. For example, ICP
and CPP are specific to patients with severe TBI in the ED and
ICU once an ICP monitor is inserted, whereas systolic BP and
O2 saturation apply to both severe and moderate TBI patients.
The patient is assessed for systemic trauma. Coagulation abnor-
malities should be rapidly corrected. Vital signs are monitored
and therapy is adjusted to maintain cardiopulmonary homeo-
stasis. Neurological assessment includes an initial and then serial
determinations of GCS score.
Table 17.9 Physiologic goals for TBI critical care
• Pulse oximetry 90%
• PaO2 100 mmHg
• PaCO2 ~35–45 mmHg
• SBP 90 mmHg
• pH ~7.35–7.45
• ICP <20 mmHg
• Brain tissue oxygen pressure (PbtO2) 15 mmHg
• CPP 60 mmHg
• Temperature ~36.0–38.3 °C
• Glucose ~80–180 mg/dL
• Physiologic Na+ 135–145mmol/L; if using hypertonic saline
(HTS) 145–160 mmol/L
• INR 1.4
• Platelets 75  103
• Hgb 8 gm/dL

Table 17.10 Herniation: clinical features and management
Clinical features
• Dilated and nonreactive pupils
• Asymmetric pupils
• Motor exam that demonstrates extensor posturing or no
response
• Progressive decline in neurologic condition (decrease in GCS
>2 points) that are not associated with non-TBI causes
• Cushing’s response (increased BP, decreased pulse and
irregular respirations)
Management
• Mannitol or hypertonic saline:
: Administer 20% mannitol 0.25–1g/kg IV as a rapid (5
minutes) IV infusion
• If BP (systolic) <90 mmHg in adults hypertonic saline rather
than mannitol should be used – administer 5% NaCl 150ml IV
over 10 minutes
• Hyperventilation:
: Target a pCO2 of 28–35 mmHg (20 breaths a minute
in adult)
• Goal CPP is ~60 mmHg
• If MAP <80 mmHg:
: Consider colloid (fresh frozen plasma (FFP) if INR >1.3)
: Additional crystalloid if ICP allows
: If lactate not elevated, phenylephrine 10–100 μg/min,
other pressors prn
: Transfuse RBCs if active bleeding or Hgb <7 g%
Herniation: Identify and Treat
Mass lesions or edema can lead to herniation. Diffuse cerebral
edema typically occurs hours to days after the insult, but may
occur within the first hour, particularly in blast TBI. Signs and
symptoms are that of intracranial hypertension and the her-
niation syndromes (Table 17.10). These include agitation,
bradycardia, hypertension, progressive decrease in level of
arousal culminating in coma, abnormalities of the pupillary
light reflex, loss of other brainstem reflexes, abnormal
breathing patterns, and abnormal motor posturing. CT
imaging reveals sulcal effacement, loss of differentiation
between gray and white matter, compression of the ventricles,
and effacement of the basal cisterns. Prompt empiric treatment
with head-of-bed elevation, hyperventilation (HV), and an
osmolar agent (e.g. mannitol or HTS), and even sedation
may be given before a head CT and en route to the CT scanner.
In patients who are also hemodynamically unstable, HTS may
be particularly useful for suspected herniation, e.g. a 30 mL
bolus of 23.4% saline that can be repeated can lead to a 50%
reduction in ICP [72].
Surgical Intervention
There are many factors, including patient, clinical, and radio-
logical findings, family expectations, and expected outcome
that influence a decision for surgery. Table 17.11 lists some
Chapter 17: Management of Head Trauma
Table 17.11 General indications for surgery for traumatic intracranial
lesions
• Extra-axial mass lesion >1 cm thick
• Midline shift >5 mm
• ICH >3 cm in diameter
• Midline shift <5 mm but ICP >20 mmHg
• Penetrating injury
• Compound depressed skull fracture
• Intracranial hypertension refractory to medical management
very basic indications for surgery. Recommendations for sur-
gical intervention are detailed elsewhere [73–77]. Diffuse or
disseminated injuries, such as DAI and contusions, typically
are not managed surgically, but in select patients surgery may
be needed. Surgical intervention is generally indicated when
there is a calvarial breach and a scalp injury, a depressed skull
fracture that is indented beyond the inner table, an expanding
intracranial hematoma, or a malignant cerebral edema. Surgi-
cal intervention needs to be performed in a timely fashion.
Coagulopathy needs to be corrected and if needs be this can be
done in the operating room, i.e. waiting for blood products
should not delay surgery. Ideally the international normalized
ratio (INR) should be <1.6 and platelets >100,000; qualitative
abnormalities also need to be considered. Surgery may be
needed in a delayed fashion – e.g. repair of a frontal sinus
once cerebral swelling has decreased, a shunt for hydrocepha-
lus or treatment of a chronic subdural hematoma (CSDH).
Decision analysis suggests a burr hole, preferably with a drain
as well, is the most efficient choice for surgical drainage of
uncomplicated CSDH [78,79].
Surgery for Increased ICP
Placement of a ventriculostomy, i.e. external ventricular drain
(EVD), can help decrease ICP, particularly when there is hydro-
cephalus; a significant improvement in craniospinal compen-
sation (RAP index), CPP, and brain oxygen (PbtO2) is often
observed [80–84]. Decompressive craniectomy (DCC), either a
unilateral hemicraniectomy or bilateral frontal craniectomy,
can be used to treat intracranial hypertension. There is strong
evidence that DCC in selected patients leads to a sustained
reduction in ICP, and improvement in cerebral compliance
and ischemic burden [81–83]. Military surgeons describe very
favorable outcomes with DCC for bTBI [84] and in civilian
practice favorable outcomes can be observed in up to 60% of
patients when DCC is used as part of a protocol-driven strategy
for refractory intracranial hypertension. However, the effect on
patient outcome is still being elucidated [85,86,87], in part
because the DECRA trial in which early bifrontal DCC was
performed for cerebral edema suggested little outcome benefit
[86]. However, the DECRA trial applies to very few patients
and its definition of intracranial hypertension differs from
usual practice. This highlights the difficulty in interpreting the
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available data, since there is a lack of agreement about surgical
technique (release the dura or not and how opened), timing of
surgery, cut-off age, and TBI severity on presentation. The
results from the RESCUEicp trial suggest a benefit to DCC
when performed for medically refractory ICP, but as with every
surgical procedure, outcome ultimately may depend on why
and when the procedure was performed [87].
Intensive Care Unit Management
Organization of Care
Effective organization of care remains central to improving
TBI outcomes [88]. In the United States, critically ill TBI
patients should be managed in trauma centers that are
equipped and staffed to provide comprehensive care to trau-
matic injuries. The first trauma center was opened in the
United States in 1966 following publication of a white paper
on injury: Accidental Death and Disability: The Neglected Dis-
ease of Modern Society [89] and grew out of the realization
that traumatic injury is a disease process in itself. Early efforts
to organize trauma care focused on individual patients and
emphasized hospital-based acute care, the organization of
which was associated with improved outcomes [90,91]. The
next major step occurred in 1992 with the development of the
Model Trauma Care System Plan (MTCSP) [92], a preplanned,
comprehensive, and co-ordinated statewide and local injury
response network that included all facilities with the capability
to care for trauma. In such a system, trauma management is
organized through and encompasses the entire spectrum of
care, from injury prevention to prehospital, hospital, and
rehabilitative care for injured persons, including community
reintegration plans. These systems are still in evolution and
large areas of the United States (particularly rural) continue to
lack access to high-level trauma care within the golden hour
after injury [93].
The complexity of trauma care prompted the American
College of Surgeons (ACS) to develop the Trauma Center
Verification program. This program, which started in 1987,
has resulted in an organized approach to patient care in desig-
nated trauma centers [94]. It is recognized that resources may
not be available in all areas and so trauma centers are desig-
nated by levels using the ACS standards that indicate capability
and range from the most comprehensive patient care levels
(Levels 1 and 2) to the basic capability of immediate care for
trauma patients and transport to higher levels of designation
(Level 3 or higher). When a patient cannot be delivered to a
trauma center within one hour of injury, the ACS recom-
mends transporting the patient to a closer facility for stabiliza-
tion, before transfer to a trauma center [95]. Transfer from
nontrauma centers after adequate resuscitation does not
appear to adversely affect outcome [96]. The ACS Committee
on Trauma’s Resources for Optimal Care of the Injured Patient
continues to provide detailed descriptions of the organization,
staffing, facilities, and equipment to provide state-of-the-art
care to trauma patients at every level of the trauma system
208
[95]. In large part this is based on the belief that care can be
improved if a hospital develops an organized trauma system
and has a coordinated response to the arrival of an injured
patient. Survival rates of severely injured patients appear to be
better at higher-volume trauma centers. It is suggested that
between 600 and 650 annual trauma admissions are needed to
provide an optimal level of care. Similarly high volume (>40
severe TBI patients per quarter) is also associated with reduced
mortality and, probably, improved quality of life in severe TBI
[97]. However, very high volumes may also compromise care if
hospital resources are overwhelmed. An association between
patient volume and outcome is not always observed. Indeed
this may be an oversimplification of a complex problem and
depend more on process, structure, and geographic variation
rather than being a causal relationship [98].
Traumatic Brain Injury Guidelines
Under the sponsorship of the Brain Trauma Foundation (BTF),
the Joint Section of Neurotrauma of the American Association
of Neurological Surgeons (AANS) and the Congress of Neuro-
logical Surgeons (CNS) Guidelines for the Management of
Severe TBI were first published in 1995. These guidelines have
been revised on several occasions to reflect medical advances,
e.g. the third edition in 2007 [5,6] and most recently the fourth
edition, released in 2016 [8]. The fourth edition does not
provide a complete management protocol since it only provides
recommendations where there is “evidence” to support them.
There also is no expressed intent to produce a fifth edition.
Rather the authors propose to continuously monitor the litera-
ture and rapidly revise recommendations when new evidence is
available, i.e. a “Living Guidelines” model. The complete docu-
ment is available at: www.braintrauma.org/coma/guidelines.
The AANS and CNS have published companion guidelines
for pediatric TBI, prehospital management, penetrating TBI,
and surgical management [73–77,100]. In addition, a variety of
other professional organizations and government agencies, e.g.
the Neurocritical Care Society [7], Eastern Association for the
Surgery of Trauma (EAST) [99], or the National Institute for
Health and Care Excellence [4] in the UK, among others, have
published TBI guidelines. Early, small single-center studies in
the United States and Eastern Europe suggest that adherence to
a protocol based on the BTF guidelines, including in commu-
nity hospital settings, is associated with a reduction in mortal-
ity and poor outcome [101–103]. More recent studies in
mature, statewide trauma systems similarly indicate that use
of standardized trauma protocols (STPs) are associated with
reduced inhospital mortality [104]. The effects are also seen
when implemented in low- and middle-income countries where
resources may be fewer [105]. Guidelines offer the possibility of
conformity with best standards of clinical practice, but there
appears to be a ceiling effect in that the odds of mortality are
decreased as compliance increases up to 75%; thereafter the
effect is reversed [106]. In part this may be associated with
guidelines being based on population-derived targets rather

than titration for individual patients. Today precision medi-
cine, i.e. individualized targeted care is an emerging concept in
TBI care [107–111].
Neurocritical Care
Neurocritical care has evolved as a distinct subspeciality in the
last 10–15 years and accumulating evidence suggests that out-
comes after acute brain injury in general and TBI specifically
may be improved in dedicated NCCUs or when specialized
neurologic intensive care teams or algorithms are present to
guide management [112–115]. Nevertheless there remains sub-
stantial variation in ICU care of TBI patients [116,117]. The
presence of other traumatic injuries may require a broad
multidisciplinary approach for these patients, including input
not only from neurosurgeons and neurointensivists but also
from trauma, orthopedic, maxillofacial, otolaryngology, and
ophthalmologic surgeons, among other physicians. In patients
with polytrauma, care may be best in a trauma ICU with
neurosurgical and neurocrticial care involvement [118]. These
findings may be considered surprising since few interventions
in neurocritical care have been demonstrated to be beneficial
in randomized trials. In addition, whether the relationship is
causal is still being elucidated and there are studies that suggest
patients with severe TBI can be safely managed in nonspecia-
list units when there is efficient telephone and image consult-
ation with neurosurgeons [119]. Nevertheless there are many
potential advantages to TBI care in dedicated NCCUs over
nonspecialist care, including: higher patient volume and hence,
greater clinician experience, more emphasis on and adherence
to TBI protocols, multimodal monitoring-guided treatment
strategies, use and interpretation of neuroimaging and neuro-
monitoring data, availability of specialist allied health profes-
sionals, and practice differences associated with withdrawal of
life-sustaining interventions [114]. In addition, one in five TBI
patients suffer hospital non-neurological complications that in
turn are associated with increased mortality [120]. An organ-
ized critical care process can help prevent this. It does remain
difficult to accurately identify patients in need of specialized
intensive care using baseline characteristics [121] and hence it
is recommended that patients with severe TBI be managed
either in a dedicated neurocritical care (or trauma) unit or by
clinical teams with expertise in neurocritical care [122]. Fur-
thermore, implementation of and monitoring adherence to
evidence-based protocols is recommended. However, there
are insufficient data to support a treatment standard or a
treatment guideline that is applicable to all patients and so
care should ideally be targeted and individualized to the spe-
cific patient and pathology, based on the best available
evidence.
Goals of Care
There are several goals in the critical care of TBI: (1) outcome
prediction to select patients for appropriate treatment, (2)
prevention, identification, and management of SBIs, (3) early
Chapter 17: Management of Head Trauma
Table 17.12 General critical care strategies for TBI
Similar to other patients in intensive care, TBI victims should
receive the usual daily care as follows:
• Raising head of bed to 30°–45°: this will reduce ICP and
improve CPP, and lower the risk of ventilator-associated
pneumonia (VAP)
• Keeping the head and neck of the patient in a neutral
position: this will improve cerebral venous drainage and
reduce ICP
• Avoiding compression of internal or external jugular veins
with tight cervical collar or tight tape fixation of the
endotracheal tube that would impede cerebral venous
drainage and result in an increase in the ICP
• Turning the patient regularly and frequently with careful
observation of the ICP
• Providing eye care, and mouth and skin hygiene
• Implementing all evidence-based bundles for prevention of
infection including VAP and central line bundle
• Administrating a bowel regimen to avoid constipation and
increase in intra-abdominal pressure and ICP
• Performing physiotherapy
identification of surgical pathology, (4) balance of extracereb-
ral and intracerebral physiology, and (5) prevention of sys-
temic complications. This can be achieved in part through care
targeted at basic physiologic goals outlined in Table 17.9. In
general, CPP may be considered the most important physio-
logical parameter to follow. However, it is important to recog-
nize that simple correction of CPP alone does not mean
improved outcome, since adverse effects on lung function
can result [123,124]. In addition, normal CPP also does not
always mean normal brain metabolism [42]. General critical
care strategies are listed in Table 17.12; these measures are
important since even simple changes in position can influence
intracranial physiology [125].
Monitoring
Ongoing management of the TBI patient in the ICU relies on
five key systemic principles: normotension, normoxia, normo-
capnia, normothermia, and normoglycemia. In addition, care-
ful and repeated (or continuous) patient monitoring using a
variety of techniques, including clinical and laboratory evalu-
ation, bedside physiological monitoring with continuous or
noncontinuous techniques, and imaging is fundamental to
the care of TBI patients who require neurocritical care [129].
Clinical evaluation of neurologic function is central to moni-
toring and is best achieved with the use of objective reprodu-
cible scales, e.g. the GCS or the FOUR score [127,128]. The
GCS is rapid and readily reproducible by multiple personnel
and has been incorporated into many other critical care scales,
e.g. the APACHE II, the Simplified Acute Physiology Score
(SAPS) and SAPSII, and the Revised Trauma Score (RTS),
among others. More recently, the FOUR score, which includes
information not assessed by the GCS, including brainstem
reflexes, visual tracking, breathing patterns, and respiratory
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 Chapter 17: Management of Head Trauma
drive, has been described. The FOUR score may be useful for
the intubated patient since it does not rely on a verbal
response. Using either the GCS or FOUR score for initial
neurological assessment and follow-up neurologic checks is
acceptable and both are comparable for outcome prediction
[129]. Other scales, e.g. the Numeric Rating Scale 0–10, revised
Nociceptive Coma Scale (NCS-R), Richmond Agitation Sed-
ation Scale (RASS), the Sedation-Agitation Scale (SAS), the
Confusion Assessment Method for the ICU (CAM-ICU), or
the Intensive Care Delirium Screening Checklist (ICDSC) can
be used to assess factors such as pain, sedation, and delirium
during a TBI patient’s stay in the NCCU [122,127].
Clinical evaluation can and should complement other
monitoring techniques, including laboratory analysis and bed-
side physiologic devices [122,126,130]. For example, with
active therapy for elevated ICP, serum sodium levels and
osmolality should be tracked frequently. General parameters
that are regularly monitored in patients with severe TBI
include electrocardiography (ECG), arterial oxygen saturation
(pulse oxymetry, SpO2), capnography (end-tidal CO2,
PetCO2), arterial blood pressure (arterial catheter), central
venous pressure (CVP), systemic temperature, urine output,
arterial blood gases (ABGs), and serum electrolytes and osmol-
ality. Invasive or noninvasive cardiac output monitoring may
be required in hemodynamically unstable patients who do not
respond to fluid resuscitation and vasopressors. Finally,
follow-up imaging plays an important role and, ideally, port-
able CT, i.e. point-of-care imaging, is preferable since it
reduces the likelihood of physiologic insults associated with
transport [131–133]. Delayed sophisticated MRI imaging also
can enhance outcome prediction for patients who remain in a
coma at one week and so select appropriate patients for
ongoing care [27,57]. The role of imaging in critical care is
beyond the scope of this chapter and the reader is referred
elsewhere [134–136].
Airway Management
Patients with a GCS 8 and those unable to protect their
airway should be intubated for airway protection. Rapid
sequence intubation is the preferred method. Sedative and
analgesic agents should include short-acting agents since
assessment of neurological status over time is central to care.
Propofol is recommended for sedation, since it allows for rapid
titration and has a short half-life, so permitting frequent
reassessment of neurological function. Mouth care is necessary
to prevent VAP, however the VAP should not be regarded as a
quality indicator in the neurocritical care population [122].
Tracheostomy should be considered in ventilator-dependent
patients to reduce total days of intubation. Relative contraindi-
cations to tracheotomy include increased ICP, hemodynamic
instability, and severe respiratory failure (required FiO2 >50%
and PEEP >10 cmH2O). However the optimal timing of
tracheostomy in severe TBI patients is controversial and data
from observational studies have been challenged through
210
confounding by indication. Furthermore factors such as insur-
ance rather than medical factors may drive tracheotomy place-
ment [137]. It does appear that early tracheotomy (<5–8 days)
is associated with a shorter duration of mechanical ventilation,
intensive care unit stay, and hospital stay, but not with
hospital-acquired pneumonia or mortality, i.e. tracheotomy
may improve the process of care, but not outcome [138–140].
This, however, can be important, since TBI patients are par-
ticularly vulnerable to readmission to the ICU after discharge
and this is often as a result of respiratory compromise [141].
Oxygenation and Ventilation
Oxygen
There is a significant and independent association between
hypoxemia (and duration of hypoxia) and increased morbidity
and mortality after TBI [142–145]. Hence, efforts should be
made to avoid hypoxia (PaO2 <60 mmHg or O2 saturation
<90%), with a target oxygen status of PaO2 100 mmHg and
O2 saturation 90%. Oxygen saturation should be monitored
continuously and monitoring through an arterial line, and
serial ABG testing is indicated in patients who are mechanic-
ally ventilated or who have an ICP monitor in place. Normo-
baric hyperoxia can correct metabolic abnormalities in the
injured brain [146] and hyperoxia may be useful in select
patients [147,148]. In some studies early hyperoxia is associ-
ated with favorable neurological outcomes [149]. However,
hyperoxemia also can be associated with adverse outcomes
[62,150] and hence oxygen levels need to be patient-specific.
In patients with combined head and chest trauma, a com-
promise may be needed to provide the best possible conditions
for the brain, potentially at the sacrifice of a “protective lung
strategy” for ventilation. In addition, maintenance of oxygen-
ation needs to be balanced against the cardiovascular effects of
positive end expiratory pressure (PEEP) since PEEP increases
intrathoracic pressure and so can decrease cerebral venous
drainage and consequently increase CBV and ICP. However,
the effect of PEEP on ICP is significant only when the level of
PEEP is >15 cmH2O and usually only in hypovolemic patients
[151]. Nevertheless, in TBI patients the lowest level of PEEP
that maintains adequate oxygenation and prevents end-
expiratory collapse (5–8 cmH2O), should be used.
Carbon Dioxide
Elevated carbon dioxide dilates the cerebral blood vessels,
increasing CBV and therefore increasing ICP. By contrast,
hypocarbia (PaCO2 <25 mmHg) leads to cerebral vasocon-
striction, and while it may decrease ICP, it can result in
cerebral ischemia. The target PaCO2 in TBI therefore is eucap-
nia (35–45 mmHg). In patients with chronic CO2 retention,
such as COPD patients, CO2 should be maintained close to
their baseline CO2 and normal pH. A CO2 monitor and other
devices to assist in the prevention of hypocarbia or hypercarbia
should be considered. There is no role for prophylactic hyper-
ventilation [152]. However, therapeutic hyperventilation (HV)

can be used for brief periods when there is acute neurological
deterioration, including cerebral herniation, or for refractory
ICP elevations. Advanced cerebral monitoring (pbtO2 or jugu-
lar venous oxygen saturation) is indicated when therapeutic
HV is used to detect any adverse effect on CBF or metabolism.
When HV is continued for >12 hours, metabolic compen-
sation negates any potential benefit of respiratory alkalosis
caused by a hypocapnic state and continued HV may be
harmful. Hyperventilation ideally should be avoided in the
first 24 hours after TBI, since CBF often is reduced to approxi-
mately half that of normal during the first 24 hours, and so
aggressive HV may result in further cerebral ischemia.
Acute Lung Injury and Acute Respiratory Distress Syndrome
The incidence of acute lung injury (ALI) and acute respiratory
distress syndrome (ARDS) in TBI is between 10 and 30% [153]
and may result from aspiration, pneumonia, pulmonary con-
tusion, massive blood transfusion, transfusion-related ALI
(TRALI), sepsis, or neurogenic pulmonary edema. Manage-
ment of ALI/ARDS requires low tidal volumes, higher PEEP,
and permissive hypercapnea; a balance has to be struck in TBI
patients, particularly those with elevated ICP. Protective venti-
lation with low tidal volume and moderate PEEP has been
recommended to prevent ventilator-associated lung injury
and increased ICP [154].
Blood Pressure and Fluid Status
Both prehospital and inhospital hypotension, including even a
single episode of SBP <90 mmHg, are independently associated
with worse outcome after severe TBI [143,155]. For patients
whose only hypotensive episode occurred in the ICU, 66% die
or are vegetative compared with 17% of patients who never
have a hypotensive episode [156]. Hypotension usually does not
result from the head injury itself but from intravascular volume
depletion associated with other injuries, polyuria secondary to
diabetes insipidus, myocardial contusion that may cause pri-
mary pump failure, or from spinal cord injury. Interestingly
early findings from the Excellence in Prehospital Injury Care
(EPIC) study suggest that a ubiquitous recommendation in TBI
guidelines, i.e. maintain SBP >90 mmHg may be an oversim-
plification and that several thresholds may exist that are patient
dependent and patient specific [157].
SBP and mean arterial pressure (MAP) should be recorded
from a functioning arterial line or from a noninvasive blood
pressure (NIBP) cuff. Invasive hemodynamic monitoring with
a CVP catheter and an arterial catheter may be placed and can
help guide fluid therapy, particularly in patients who are intub-
ated and have an ICP monitor in place. Noninvasive monitors
also may be useful to measure surrogates of intravascular
volume and hemodynamics, e.g. stroke volume index variation.
The primary target is euvolemia and avoidance of SBP
<90 mmHg (i.e. maintain SBP between 90 mmHg and 180
mmHg). Recent studies, particularly those using automated
continuously recorded vital signs, suggest that a higher SBP
Chapter 17: Management of Head Trauma
(110–120 mmHg) may be more effective in reducing secondary
insults and may be particularly useful when invasive intracra-
nial monitoring is not available, since lower blood pressures
can represent a “relative” hypotensive state in TBI patients
(especially with elevated ICP) [156,158]. It should be recog-
nized that hypertension can aggravate cerebral edema in some
patients and that hypertension may also be a physiologic
response to increased ICP. Vasoactive drugs should be con-
sidered to treat hypotension once the patient is volume resusci-
tated. Norepinephrine or phenylephrine are the preferred
agents since they have minimal effects on cerebral vasomotor
tone. Dopamine causes cerebral vasodilatation and can increase
ICP. Phenylephrine, a pure α-agonist vasoactive agent, is rec-
ommended in TBI patients with tachycardia. Vasopressin also
may be used when other pressors are not feasible.
Fluids
Negative fluid balance is associated with an adverse effect on
outcome, independent of its relationship to ICP, MAP, or CPP
[159]. Hence intravenous fluid is a fundamental component of
TBI care. The goals of fluid resuscitation in TBI are the rapid
reversal of hypovolemia by restoration of intravascular
volume, avoidance of hypotension to maintain CBF, and to
limit cerebral ischemia-hypoxia, but at the same time avoid
intracranial hypertension. A CVP goal of 5–7 mmHg correl-
ates with euvolemia. Key questions about the optimal compos-
ition and volume of IV fluid in TBI still are being elucidated
and so intravenous fluid should be administered after con-
sidering its physiological rationale and potential adverse
effects. This latter variable, i.e. a safety concern, often drives
the choice of fluid. The initial resuscitation fluid should be
normal saline (NS), i.e. isotonic crystalloid. Volume resusci-
tation to achieve euvolemia should not be withheld to prevent
cerebral edema. However aggressive fluid resuscitation with
NS may result in hyperchloremic metabolic acidosis, and
excess fluid administration (i.e. hypervolemia) to increase
CPP can cause ARDS [123]. Hypotonic solutions, e.g. 0.5 NS
or 5% dextrose in water should be avoided unless required to
correct sodium balance abnormalities, whereas glucose-
containing solutions should be avoided, particularly in the first
24 to 48 hours, unless the patient develops hypoglycemia in the
absence of nutritional support. Resuscitation with 4% albumin
in TBI patients in the ICU increases mortality [69] since it may
increase ICP specifically in the first week following injury
[160]. Similarly there is a limited role for use of hydroxyethyl
starch (HES) [161,162]. Although the data is less robust, there
is an association between cumulative HES 200/0.5 volume and
mortality [139]. Hypertonic saline has been used for resusci-
tation, but ideally may be best used as a secondary osmotic
agent in ICP control, particularly when there is associated
hypotension [163,164]. Continuous HTS appears to be associ-
ated with a higher percentage of patients that achieve goal
osmolality, but other outcome measures, including ICP, CPP,
development of kidney injury, and outcome are similar when
compared with bolus administration [165].
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 Chapter 17: Management of Head Trauma
Although usually considered a byproduct of anaerobic
metabolism and a marker of organ hypoperfusion, lactate
infusion has recently been used in TBI. It seems that in
select patients IV sodium lactate may be protective and
may act as a preferential energy substrate over glucose
[166]. Early clinical data support the use of intravenous
lactate infusions and that it can help reduce ICP [167].
However successful use of this may depend on microdialysis
to identify who will benefit [168].
Hemoglobin Management
Replacement of blood products depends, in part, on hemo-
globin (Hgb). However, this is a controversial area in TBI
with limited data for evidence-based guidelines [169–171]
and there is great practice variation that often has more to
do with nonpatient factors [172]. The decision to transfuse
frequently is explained by the presence of extracerebral injur-
ies [173]. Furthermore, in TBI, transfusion may be better
guided by measures other than Hgb. For example Oddo
et al. [174] observed that anemia alone had no adverse effect
on outcome, whereas anemia coupled with brain hypoxia
aggravated outcome.
Anemia is observed in about 50% of severe TBI patients
and the vast majority of observational studies summarized in
recent reviews describe an association between reduced Hgb
concentrations and worse outcomes, i.e. anemia can cause or
exacerbate secondary brain injury [168–171]. In large studies
including the CRASH trial and the IMPACT study, a rela-
tionship between lower admission Hgb concentration and
worse outcome was observed [25,26]. In CRASH an admis-
sion Hgb concentration <9 g/dL was an independent factor
associated with poor outcome. Interestingly, this Hgb con-
centration is similar to the Hgb level associated with meta-
bolic distress in microdialysis and PbtO2 studies [175,176].
Perhaps more relevant to critical care than admission Hgb
values, studies with repeated Hgb measures also show a
relationship between anemia and poor outcome [169]. For
example, Sekhon et al. [177], in a retrospective cohort study
of 169 patients with severe TBI, observed that a mean seven-
day Hgb concentration <9 g/dL was independently associated
with increased risk mortality.
On the other hand, transfusion is associated with a variety
of deleterious effects in trauma patients and may aggravate TBI
outcome [178,179]. This creates a therapeutic dilemma, i.e.
under- or overtransfuse. In general, critical care, a restrictive
transfusion trigger (Hgb ~7 g/dL) is recommended in patients
who are free of serious cardiac disease [180]. Cogent argu-
ments can be made for both a restrictive (Hgb ~7g/dL) and
more liberal transfusion strategy in TBI. However, data accu-
mulating from several sources and summarized in recent
reviews and consensus statements suggest that Hgb targets in
general critical care may not apply to patients with acute brain
injury [169–171]. Instead, select patients may benefit from a
higher transfusion threshold, particularly when there is evi-
dence for limited cerebrovascular reserve, i.e. other measures
212
than Hgb alone may better guide transfusion [174]. Consistent
with this, surveys suggest more than 50% of these physicians
use higher Hb thresholds in patients with acute brain injury
[181]. The ratio of plasma to packed red blood cells and
platelets transfused also may influence outcome [182]. The
role of erythropoietin in TBI is still being elucidated [183];
however, it remains to be defined whether anemia and trans-
fusion are simply markers of disease severity or are independ-
ent factors associated with outcome.
Coagulation
Coagulopathy, including disseminated intravascular coagula-
tion (DIC) and increased fibrinolysis occurs in up to 50% of
severe TBI patients and its presence is an independent factor
associated with poor outcome and evolution of intracranial
bleeding [184–188]. In addition, the presence of a hypocoagul-
able state will affect the appearance of an acute intracranial
hemorrhage on head CT scan, i.e. it may appear hypo- or
isodense rather than hyperdense, or a fluid level will be pre-
sent. The coagulopathy after TBI also comprises a hypercoa-
gulable state which may lead to cerebral microthrombi that in
turn are associated with worse outcome [189].
There are several possible mechanisms for coagulopathy
after TBI, e.g. hemorrhagic shock, hypothermia, and massive
resuscitation, among others. In addition, coagulopathy can be
seen in isolated TBI associated with release of brain tissue
factor (TF), i.e. the coagulopathy of TBI is discrete from the
coagulopathy of systemic trauma [184,187]. Risk factors for
coagulopathy include: preinjury conditions, e.g. end-stage hep-
atic or renal disease, advanced age, hypotension at the scene of
injury, GCS <8, ISS >16, severity of TBI reflected by the head
abbreviated injury score (AIS), intraparenchymal lesions,
penetrating injury, and base deficit [184,190]. In addition
about 1% of the population in industrialized countries takes
an oral anticoagulant, e.g. coumadin and many others take
antiplatelet agents. Preinjury coumadin use, in particular,
increases mortality [191,192].
Laboratory measures of PT/INR, partial PTT, and platelet
counts should be followed closely. Platelet count appears to be
the strongest predictor for progression of an initial insult on
repeat head CT [193]. A target INR 1.4–1.6 is recommended
and platelets should be transfused for a platelet count
<75  103/mm3. Both the INR and platelet count should be
corrected before intracranial surgery or intracranial pressure
monitor (ICPM) or EVD placement, where an INR <1.6 and
platelet count >100,000 are preferable. FFP, vitamin K, Factor
VII, desmopressin (DDAVP), or prothrombin complex con-
centrate (PCC) should be administered, as clinically indicated,
to correct coagulopathy. Increasingly novel oral anticoagulants
(NOACs) are used in the elderly (e.g. rivaroxaban, dabigatran,
and apixaban). NOACS can be corrected using tranexamic
acid and hemodialysis (dabigatran) or with PCCs for rivarox-
aban and apixaban and more recently specific antagonists, e.g.
idarucizumab [194,195]. Institutional protocols should be
established to help manage these patients [195,196].

Intracranial Pressure
The brain is particularly vulnerable to physiological derange-
ments after TBI; increased ICP (>20 mmHg) is independently
associated with mortality. The relationship with morbidity is
less certain. The relationship between increased ICP and mor-
tality becomes proportionally greater as ICP increases; there is
a sixfold increased risk of death when ICP is >40 mmHg
[197]. While short elevations of increased ICP are associated
with worse outcome [198], the relationship between outcome
and ICP is more robust when the ICP course (early versus late,
first two days), dose, or burden of ICP (total duration), and
ICP refractory to treatment are analyzed [110,143,197,199].
Recent studies suggest that individualized or patient-specific
ICP targets may provide a more robust relationship than those
derived from population-based targets [107].
Indications for Invasive ICP Monitoring
The most recent TBI guidelines, the fourth edition, make no
Level I or IIa recommendations on ICP monitoring since there
are no randomized controlled trials (RCTs) on this topic [8].
The third edition of the guidelines published in 2007 included
indications for ICP monitoring. Meta-analytic studies that
include 25,229 patients show improved survival in patients
who receive an ICP monitor in studies published since 2007,
i.e. after the third edition was published [200]. In comatose
TBI patients with an abnormal CT scan, the incidence of
intracranial hypertension is >50%. Therefore ICP should be
monitored in TBI patients when the GCS is 8 following
initial resuscitation, and the admission head CT scan is abnor-
mal (hematomas, contusions, edema, or compressed cisterns).
An ICP monitor also should be considered for patients with
normal CT scans who have two or more of the following
features: age >40 years, posturing, systolic blood pressure
<90 mmHg. The indications for an ICP monitor remain
debated in several circumstances, including: (1) comatose
patients with an initial normal CT scan or only minimal
findings, e.g., traumatic SAH, (2) DAI, (3) bifrontal contusions
in the noncomatose patient, and (4) following surgery, such as
a decompressive craniectomy or evacuation of a mass lesion.
These topics were addressed in a recent consensus conference
on ICP [201]. An ICP monitor should also be considered in
patients undergoing other emergent surgical procedures and in
whom a TBI is suspected (GCS 3–12) to guide intraoperative
CPP management.
Type of Monitor
ICP is best monitored with an EVD or an intraparenchymal
probe [202]. An EVD may be added to a parenchymal ICP
monitor when there is hydrocephalus and when ICP does not
respond to treatment. Procedure risks and infection are greater
with EVDs and they can be more difficult to insert. Catheters
in the subdural or epidural space are less accurate and are not
recommended. Noninvasive ICP monitors are not yet ready
for routine use, although techniques such as ultrasound
Chapter 17: Management of Head Trauma
assessment of optic nerve sheath diameter (ONSD) or tran-
scranial Doppler evaluation of pulsatility index are feasible and
can be useful in select patients [203,204]. With adequate
training, trauma surgeons or intensivists can place ICP moni-
tors, provided there is neurosurgical backup, but this proced-
ure is best performed by neurosurgeons.
Management of Increased ICP
Several studies have shown that patients who do not have
intracranial hypertension or who respond to ICP-lowering
therapies have a lower mortality than those who do not
respond to therapy [e.g. 104,197,205–208]. The 2007 Brain
Trauma Foundation Guidelines recommend treatment when
ICP is >20 mmHg. The fourth edition of the BTF guidelines
recommends a new ICP threshold (22 mmHg) [8]. This new
threshold and the rationale for it have been questioned [209–
211]. In addition, compliance with guidelines even in Level
I centers is low and there remains wide variation in the treat-
ment for elevated ICP, despite these guidelines [117,212].
Initial ICU care is largely preventative and includes: (1)
appropriate head-of-bed elevation, (2) maintenance of the neck
in a neutral position, (3) avoidance of neck constriction (e.g.
loosening endotracheal tube ties), (4) prevention of hypercar-
bia, and (5) adequate treatment of pain, agitation, fever, and
seizures. When ICP remains >20 mmHg, a series of tiered
therapies can then be used (Table 17.13). Items within a tier
are not necessarily listed in order of completion and many
interventions may occur simultaneously or be difficult to
achieve (e.g. EVD insertion when there are slit ventricles).
The tiers represent increased levels of intensity for the treat-
ment of elevated ICP, and patients should be initiated in tier
I and then staged through tier 3 if no response is observed
within 120 minutes in a tier.
There are a variety of therapies for increased ICP:
CSF drainage: CSF drainage through an EVD should be
considered. The optimal method of drainage (continuous
versus intermittent) has not been established.
Osmotherapy: Typically mannitol or HTS, are adminis-
tered. While both are effective, there are insufficient data to
suggest superiority of one agent over the other and the optimal
dose, mode of administration (e.g. bolus versus continuous
infusion) and concentration are still being elucidated. Some
studies suggest HTS may be more effective [163,164,213] but
to choose the appropriate hyperosmolar agent, patient charac-
teristics such as volume status, renal function, hemodynamic
status, and sodium levels, among others, should be considered.
Mannitol treatment protocols vary from center to center,
and the dose–response relationship is not understood; often
the ICP decrease depends more on the administration protocol
or the ICP level at the time the dose is given [214]. Initial use
for increased ICP is a single bolus (not infusion) of a 20–25%
solution of 0.5–1g/kg, IV, over 10–15 minutes and repeated
every two to six hours (although ideal dosing is not well
described). ICP decreases may be greatest shortly after the
dose is given because of its effect on viscosity and vessel caliber,
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 Chapter 17: Management of Head Trauma

Table 17.13 Tiered approach to ICP management

General measures
• Ventilation: keep O2 Sat >90%, and PaO2>100 mmHg, and PCO2 ~35–45 mmHg
• Monitor systolic BP and MAP: avoid hypotension, systolic >100 mmHg
• Normothermia goal <38.3 °C: treat fever with acetaminophen and/or cooling blankets
• Adjust cervical collar placement if applicable
• Consider repeat CT: a repeat CT scan of the brain should be considered to rule out the development of a surgical mass or unexpected
intracranial lesion
• Craniotomy for surgical lesions
Tier 1
• Head of patient’s bed to be placed at 30°
• Sedation and analgesia using recommended agents (propofol, fentanyl, and versed) in intubated patients. Pain relief and sedation are
appropriate initial modalities for treatment of intracranial hypertension
• Mannitol: 0.25–1.0 g/kg; IV bolus  1 dose
• Ventriculostomy: extraventricular drain – drain to 10 cmH2O for ICP 20 mmHg sustained for 5 min. The preferred method for ICP
monitoring and drainage is to leave the ICP device to the transducer for continuous monitoring and to drain only for elevations above
the threshold (20 mmHg). When ICP is 20, the drain should be opened and allowed to drain to 10 cmH2O, then returned to the
transducer
Tier 1 completed within 120 minutes, if ICP 20 mmHg/27.2 cmH2O proceed to Tier 2
Tier 2
• Hyperosmolar therapy
: Mannitol: intermittent boluses of mannitol (0.25–1 g/kg body weight) should be administered. Attention must be paid to
maintaining a euvolemic state when osmotic diuresis is instituted with mannitol. The serum sodium and osmolality must be assessed
frequently (every 6 h) and additional doses should be held if the serum osmolality exceeds 320 mOsm/L. Maintain a serum OSM
<320 mOsm or alternative osmolar gap <20. Mannitol may be held if there is evidence of hypovolemia
: Hypertonic saline: boluses of 3% sodium chloride solution (250 mL over 6 h) or other concentrations (e.g. 23.4% – 30 mL) may be
used. Serum sodium and osmolality must be assessed frequently (every 6 h) and additional doses should be held if the serum sodium
exceeds 160 mEq/L
• PCO2 goal is 30–35 mmHg, as long as brain hypoxia is not encountered
• Neuromuscular paralysis: pharmacologic paralysis with a continuous infusion of a neuromuscular blocking agent should be employed if
the above measures fail to adequately lower the ICP and restore CPP. The infusion should be titrated to maintain at least two twitches
(out of a train of four) using a peripheral nerve stimulator. Adequate sedation must be utilized if pharmacologic paralysis is employed
Tier II completed within 120 minutes, if ICP 20 cmH2O/14.7 mmHg proceed to Tier 3.
Tier 3 (includes potential salvage therapies)
• Decompressive hemicraniectomy or bilateral craniectomy should only be performed if Tiers 1 and 2 are not sufficient
• Barbiturate or propofol (anesthesia dosage) coma: an induced coma is an option for those patients who have failed to respond to
aggressive measures to control malignant intracranial hypertension, however it should only be instituted if a test-dose of barbituates or
propofol results in a decrease in ICP, thereby identifying the patient as a “responder.” Hypotension is a frequent side effect of high-dose
therapy. Therefore, meticulous volume resuscitation (measured with a pulmonary artery (PA) catheter) should be ensured
A neosynephrine infusion may also be required
• Hypothermia: <36 °C is not currently recommended as an early TBI treatment. Hypothermia should be reserved for “rescue” or salvage
therapy after reasonable attempts at ICP control from the tier treatments above have failed

i.e., vasoconstriction [215]. Unnecessarily large doses or
prophylactic doses could lead to more mannitol being required
later [216]. In addition, when CAR or the blood–brain barrier
is impaired, aggressive mannitol use can increase ICP since it
will draw fluid into the brain. Hence it is important to measure
serum osmolarity or osmolar gap (measured – calculated
serum osmolarity) before infusing mannitol. Mannitol should
not be given if serum osmolarity is >320 mOsm/kg H2O or
osmolar gap >10 or in patients with acute kidney injury (AKI)
or renal failure. Side effects of mannitol include hypotension,
hypovolemia, hypokalemia, hyperkalemia, and acute kidney
injury (AKI).
Hypertonic saline (HTS) increases serum osmolarity dir-
ectly rather than by inducing osmotic diuresis. Hence it can
reduce ICP and simultaneously maintain or even expand intra-
vascular volume. Therefore HTS may be preferable when MAP
is reduced or patient volume status dictates caution with large
infusions. There are several different concentrations that range
from 3% to 23.4% NaCl solutions. Hypertonic saline should
not be given if serum sodium is >160 mmol/L. To administer
HTS (>3%), central venous access is required and a 50%
chloride/50% acetate mix is recommended to reduce the risk
of hyperchloremia. There are a variety of protocols for HTS
administration, but therapy can be initiated with 3% saline at

214

75 mL/h (or greater if requiring fluid resuscitation). Serum
sodium should be checked frequently and infusion continued
to a goal sodium of 150 mmol/L or a maximum of 160 mmol/L
if ICP remains refractory. Once the goal sodium or ICP is
achieved, or ICP controlled, HTS can be continued as a 0.9%
saline infusion or 2% if sodium drifts downward.
Hyperventilation: Hyperventilation causes blood and CSF
alkalosis; this causes vasoconstriction and hence reduces CBV
and ICP. Sustained or prophylactic HV can be deleterious
since it may cause cerebral ischemia. However when hernia-
tion is present, transient HV may be lifesaving. In select
patients, e.g. those with hyperemia and increased ICP, opti-
mized HV can be useful. Jugular bulb oximetry, or monitors of
CBF or PbtO2, should be used to allow for safer HV titration.
For acute ICP management, HV should begin with a PaCO2
goal of 34–36 mmHg and be advanced to a PaCO2 goal of
25–30 mmHg if there is no treatment response.
Metabolic therapy: The goal of metabolic therapy is to
suppress CMRO2. This in turn should decrease CBF and,
because CBV is reduced, ICP should decrease. In addition,
vulnerable brain tissue may be preserved since CMRO2 is
reduced in the face of decreased fuel delivery. CMRO2 may
be reduced through pharmacological means or temperature
modulation.
Pharmacologic suppression. Agents such as barbiturates,
benzodiazepines, or propofol may be administered to induce
coma (burst suppression). There is insufficient data to guide
the choice of these agents. It should be remembered that
barbiturates and propofol are myocardial depressants and per-
ipheral vasodilators, and invasive hemodynamic monitoring
and support are often needed when pharmacologic coma is
induced. Barbiturates effectively treat increased ICP and are
best indicated in patients who have adequate cardiovascular
function and intact CAR. The most commonly used agent,
pentobarbital, can be administered IV at a loading dose of 5
mg/kg, followed by an infusion of 1 to 3 mg/kg/h; a high-dose
regimen may also be used with an IV bolus dose of 10 mg/kg
over 30 minutes followed by 5 mg/kg/h infusion for three
hours, followed by 1 mg/kg/h titrated to either burst suppres-
sion on continuous electroencephalogram monitoring or an
ICP reduction. Whether barbiturate use improves outcome is
unclear, since side effects such as immune suppression, hypo-
tension (especially in volume-depleted patients), and decreased
mucocilliary clearance can mitigate any benefit on ICP.
Another option for pharmacologic coma is propofol, which
is given in an IV loading dose of 2 mg/kg, followed by a
titrated infusion of up to 200 mg/kg/min. Propofol should be
avoided in hypotensive or hypovolemic patients, and pro-
longed infusions or high doses have been associated with the
development of a ‘‘propofol infusion syndrome’’ of renal fail-
ure, hyperkalemia, myocardial failure, and metabolic acidosis,
often resulting in death. The mechanism for this is not fully
understood.
Temperature modulation. Mild to moderate hypothermia
(32–34 °C) can reduce ICP [217,218]. Most single-center
Chapter 17: Management of Head Trauma
studies suggest that induced hypothermia is associated with
better outcome. However, this outcome benefit is not observed
in large randomized multicenter studies in adults or children
with severe TBI [219,220] and may even be harmful in patients
with a lower injury severity [218]. In part, this lack of outcome
benefit may have to do with shivering, which can adversely
affect brain metabolism [221], or the rate of posthypothermic
rewarming, which if too rapid can exacerbate neuronal injury
[222]. Hence when hypothermia is used, rewarming should be
considered if the patient’s ICP is stable and <20 mmHg for at
least 48 hours, and implemented at a rate not faster than
0.1–0.25 °C/h.
Surgery: Surgery, e.g. evacuation of a mass lesion or an
EVD for hydrocephalus, plays an important role in ICP con-
trol. In addition, DCC, either unilateral or bilateral, and when
correctly performed, is the most effective way to reduce ICP,
particularly when ICP is resistant to osmotic agents [81]. In
addition other favorable effects on brain metabolism are
observed [83]. Both intra-abdominal and intrathoracic hyper-
tension can increase ICP or aggravate increased ICP. In select
patients, decompressive laparotomy (DL), even if intra-
abdominal pressure is normal, can reduce elevated ICP [223].
These procedures (DCC and DL) often make care easier and
eliminate the need for other therapies that may have deleteri-
ous effects; however, the relationship between DCC or DL and
outcome remains unclear.
DECRA, a randomized clinical trial, attempted to under-
stand the role of bifrontal DCC as an early treatment for
cerebral edema. Outcome was similar to patients who received
medical management, despite better ICP control [86]. How-
ever the definition of intractable hypertension was very differ-
ent from that usually used in clinical practice and the inclusion
criteria for DECRA apply to very few TBI patients. RES-
CUEicp [87] began before DECRA was published; 408 patients
with refractory elevated ICP (>25 mmHg) were randomized at
52 centers to DCC or medical care. Surgical patients had
significantly fewer hours than medical patients with elevated
ICP, shorter time to discharge among survivors, lower mortal-
ity, and at 12 months, outcome was better in surgical patients;
more patients (13.4% versus 3.9%) achieved upper severe dis-
ability (independent at home, but dependent outside). How-
ever moderate disability and good recovery were similar.
There are many differences in the DECRA and RESCUEicp
trials that help explain the disparate results. Population-based
studies also show that less than 20% of patients who undergo
DCC in clinical practice are eligible for the DECRA and
RESCUEicp trials [224]. There continue to be unresolved
controversies about who is an “optimal” surgical candidate,
specific timing, techniques, postoperative management of TBI
patients who undergo DCC, and timing of bone flap replace-
ment, among others. Nevertheless DCC remains an effective
treatment of increased ICP in carefully selected patients.
Lund therapy: The optimal therapy for a sustained ICP
increase remains poorly defined. The Lund concept [225],
which emphasizes a reduction in microvascular pressures to
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 Chapter 17: Management of Head Trauma
minimize cerebral edema formation represents an alternative
to ICP- or CPP-targeted therapies [226]. The goals of Lund
therapy are to preserve a normal colloid osmotic pressure (by
infusion of albumin, or blood, if there is anemia), to reduce
capillary hydrostatic pressure with blood pressure control
(metoprolol and clonidine) and to decrease CBV by vasocon-
striction of precapillary resistance vessels with low-dose thio-
pental and dihydroergotamine. The patient is also nursed flat
and neuromuscular blockade, HV, osmotherapy, and barbit-
urates are avoided. The therapy may work best when the
blood–brain barrier is disrupted and more appropriate if pres-
sure autoregulation is lost. Lund therapy has been evaluated in
experimental and clinical series or compared with historical
controls, but there is no clinical trial that has demonstrated a
benefit to this therapy in TBI [227,228]. When microdialysis is
used to guide therapy, a modified Lund approach may help
some patients with secondary brain ischemia [229]. However
the Lund concept is contrary to a common TBI treatment goal,
i.e. CBF optimization. In addition, there is evidence that some
of the individual components of Lund therapy can be deleteri-
ous in TBI. Hence, further research is required to determine if
there is a role for this therapy.
Cerebral Perfusion Pressure
Retrospective studies show that there is 20% increased mortal-
ity for each incremental CPP decrease of 10 mmHg and that
when CPP is <60 mmHg greater than 33% of the time,
mortality is inevitable. Hence CPP is an integral physiological
parameter used in TBI care. However, the scientific basis for a
preferred endpoint, i.e. ICP or CPP, when to trigger interven-
tion, and how best to treat CPP is still being elucidated.
According to Poiseuille’s law, CBF is proportional to CPP
and to vessel radius to the 4th power, and inversely propor-
tional to blood viscosity. When CAR is intact, the primary
determinant of CBF is vessel radius and CPP has little impact.
By contrast, when CAR is disturbed or absent, CPP changes
affect CBF and blood flow becomes “pressure passive.” Hence,
ensuring adequate CPP to prevent cerebral ischemia is import-
ant. The Brain Trauma Foundation currently recommends
maintaining CPP between 50 and 70 mmHg. Optimization of
CPP in the normotensive patient should begin with lowering
ICP. Increased CPP can decrease evidence for ischemia in the
brain, but clinical outcome is not improved since intravenous
fluids and vasopressors used to increase CPP can cause lung
injury [123,124]. In addition there is considerable variability in
how CPP, specifically MAP, is derived [230]. This is particu-
larly problematic in patients who are nursed with head-of-bed
elevation to >30° for ICP control, since the discrepancy
between CPP measured at the phlebostatic axis versus the
tragus could be as high as 20 mmHg. Recent research also
suggests that rather than applying a population-based target
(CPP 50–70), CPP should be individualized i.e. optimal
patient-specific CPP (CPPopt). This value, CPPopt, can vary
between patients and over time in the same patient and may
216
range between 50 and 100 mmHg. However, when patients are
managed at or close to the CPPopt, better outcomes are
observed [231–233]. Similarly the type of therapy provided,
ICP- or CPP-based, may depend on pressure reactivity with a
CPP-targeted approach being more successful when pressure
reactivity is intact, while an ICP-based strategy is better when
pressure reactivity is impaired [234].
Multimodality Neuromonitoring and New
Strategies of Care
Monitoring and treating ICP and CPP represents the standard
of care for TBI patients in the NCCU. However, whether
treating increased ICP makes a difference to outcome remains
poorly defined in large part because studies that examine the
question are confounded by many variables, some of which are
methodological. The vast majority of studies that are primarily
studies of “aggressiveness of care” or “guideline adherence”
rather than ICP treatment per se suggest that there is a signifi-
cant outcome benefit to ICP treatment [101,104,205–208,235–
239]. Since increased ICP is associated with mortality, no
randomized trial that compares ICP management with no
management has been or will be performed for obvious ethical
reasons. The recent BEST TRIPS trial attempted to examine
ICP management. Patients in general ICUs in Bolivia and
Ecuador were randomized to management strategies for severe
TBI, one of which was triggered by an ICP monitor [240].
Outcome was similar in the two groups, which is to be
expected, since there is no control group. However, the trial
has been (mis)interpreted by many as suggesting there is no
need to treat ICP. This is far from the truth and despite its title,
BEST TRIPS is not a trial of ICP care per se and not a trial of
ICP monitoring. Indeed, a recent consensus meeting on the
trial indicated that for those who currently monitor ICP, there
is no reason to change practice and that the trial itself raises
more research questions rather than answers any clinical ques-
tions [241]. In particular, it is important to define what consti-
tutes intracranial hypertension and whether ICP as a numeric
threshold is simply a marker for underlying pathophysiologic
processes or an independent target before any discussion about
treatment, and its outcome benefit, can be formulated.
ICP and CPP treatment remain central and critical to
severe TBI care. However, converging evidence from several
different lines of research suggest that care based on only ICP
and CPP thresholds may be an oversimplification of a complex
problem [108–110]. First, BTF guidelines focus primarily on
ICP and CPP control to avoid preventable secondary injury.
These decisions are based on population-derived targets rather
than titration for individual patients. Second, the pathophy-
siology of SBI represents a complex interplay between CBF,
oxygen delivery and utilization, and supply of brain energy
substrates (glucose). This interplay varies between patients,
according to pathology, and within patients over time such
that standard ICP and CPP monitoring and management
may not detect significant changes or detect them too late

[42,48,52]. Third, neuroprotection trials have failed. Fourth,
the vast majority of TBI treatments are empiric or phenomo-
nologic rather than mechanistic. Finally, the BEST TRIPS trial
[240] has refocused research efforts in TBI management. The
implications of this are as follows: (1) it is important to
understand what is happening in individual patients after
TBI and better define the phenotype of injury [30], (2) rather
than single agents, strategies of care (or combination therap-
ies) and personalized targeted approaches are needed, and (3)
to do this, high-tech monitoring is necessary to better under-
stand what is happening in a patient and essential to targeted
and mechanistic therapy.
A variety of techniques, including clinical examination,
imaging, and bedside physiologic tools, both invasive and
noninvasive, are available to monitor TBI patients
[122,126,130]. No single technique can provide complete
information about the brain’s health, and hence a combination
of monitors is needed. This approach, often called multimod-
ality monitoring (M3), has evolved in recent years along with
the growth of bioinformatics. In reality, M3 is practiced in
every ICU on every patient. For example combining the clin-
ical exam with laboratory data and a CT scan is M3. What has
emerged is the realization that more sophisticated and inte-
grated M3 can better define patient pathophysiology, identify
energy dysfunction in the brain before or in the absence of
changes in ICP and CPP, and guide optimal use of several
therapies including HV, osmotherapy, glycemic control, trans-
fusion, CPP augmentation, therapeutic temperature modula-
tion, and oxygen-based therapies, among others, in part
through identification of patient-specific thresholds, the
targeting of care to a patient’s optimal range of physiological
resilience, avoidance of potential deleterious side effects asso-
ciated with a particular therapy, enhanced outcome prediction,
and identification of mechanistic differences in patient path-
ology [126,242,243].
A variety of monitors are now available that permit
bedside assessment of advanced physiology in real time or
near real time, including: CBF, continuous electroencephalog-
raphy (EEG), brain oxygen, microdialysis, autoregulation, and
near-infrared spectroscopy, among others. Furthermore bio-
informatics better allows these signals to be integrated. These
monitors alone or in combination cannot be expected to alter
outcome. Instead, it is hoped that therapies resulting from
information provided by these tools will improve outcome by
facilitating patient- and pathophysiologic-specific targets.
Ongoing research aims to better understand how the infor-
mation provided by M3 can help guide care and the optimal
therapeutic responses. Early clinical experience, however, sug-
gests that this approach may benefit select patients, and
enhance current care [109,110,167,242–245]. For example, in
a recent phase II trial, goal-directed therapy guided by brain
oxygen, ICP, and CPP monitoring appears to be superior to
standard ICP- and CPP-guided therapy [245]. A phase III trial
to examine this question is now underway. This targeted
management may be particularly important in the elderly
Chapter 17: Management of Head Trauma
TBI patient, who now represents a larger proportion of TBI
ICU admissions [246].
Pharmacology in TBI Critical Care
Seizure Prophylaxis
Seizures occur in 10–30% of TBI patients, particularly those
with severe TBI, intracranial pathology, and depressed skull
fractures [247] (Table 17.14). In comatose patients, up to 25%
may have nonconvulsive seizures. Theoretically, seizures may
worsen outcome by increasing CMRO2 and ICP, and so con-
tribute to cerebral ischemia. Post-traumatic seizures are classi-
fied as early (<7 days) or late (>7 days). Ideally both should be
prevented. However, prophylactic antiepileptic drugs (AEDs)
reduce the incidence of early post-traumatic seizures, but do
not lessen the odds of developing post-traumatic epilepsy.
Furthermore, AEDs are associated with side effects and in
particular neurobehavorial side effects. Hence BTF guidelines
recommend the use of anticonvulsant medication (phenytoin)
for one week following TBI and recommend against longer
durations of prophylactic therapy [248]. Many centers now
use alternative agents, such as leviteracitam. AEDs are indicated
when: (1) seizures accompany presentation, (2) there is a
depressed level of consciousness (GCS 10), or (3) there is an
abnormal CT scan. In these patients phenytoin 1 g IV infusion
at 25 mg/min and not more than 50 mg/min should be admin-
istered and then followed with a maintenance dose of 100 mg q
8 h, but titrated to achieve adequate serum levels (10–20 μg/
mL). Lorazepam or diazepam should be administered in add-
ition to phenytoin for patients with prolonged seizures. Anti-
convulsant medication is stopped after seven days if there is no
seizure activity. The treatment of seizures and in particular
status epilepticus is discussed further in Chapter 16.
Sedation, Analgesia and Paralytic Agents
In severe TBI patients, endotracheal intubation, mechanical
ventilation, trauma, surgical interventions (if any), nursing care,
and ICU procedures can cause pain. Narcotics, such as mor-
phine, fentanyl and remifentanil, should be considered first-line
therapy since they provide analgesia, mild sedation, and depres-
sion of airway reflexes (cough). High bolus doses of opioids can
have potentially deleterious effects on ICP and CPP.
Table 17.14 Risk factors for seizures (modified from [247])
• Glasgow Coma Scale (GCS) score <10
• Cortical contusion
• Depressed skull fracture
• Subdural hematoma
• Epidural hematoma
• Intracerebral hematoma
• Penetrating head wound
• Seizure within 24 h of injury
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 Chapter 17: Management of Head Trauma
Sedative agents are commonly administered to adult
patients with severe TBI to prevent agitation, facilitate mech-
anical ventilation, and help control ICP and CPP, in part by
reducing cerebral metabolic rate and, in turn, cerebral blood
flow and volume. The ideal sedative for TBI patients would be
rapid in onset and offset, easily titrated to effect, able to lower
ICP and CMRO2 yet preserve the neurologic examination, and
lack active metabolites and deleterious cardiovascular effects.
Many different agents have been tried, including propofol,
ketamine, etomidate, and agents from the opioid, benzodiazep-
ine, α2-agonist (i.e. clonidine and dexmedetomidine), and anti-
psychotic drug classes. There is no convincing evidence that
one sedative agent (or administration method) is more effica-
cious than another for improvement of patient-centered out-
comes, ICP, or CPP in adults with severe TBI [249].
Neuromuscular blocking agents (NMBAs) to paralyze
patients with TBI are not recommended. NMBAs reduce ele-
vated ICP and should be considered as second-line therapy for
refractory intracranial hypertension. However, the use of an
NMBA is associated with increased risk of pneumonia and ICU
length of stay (LOS), and with neuromuscular complications.
If the TBI patient is agitated, evaluation must be made to
determine whether the patient is in pain, hypoxic, delirious, or
poorly tolerating mechanical ventilation. If pain is a concern,
then a narcotic analgesic, such as fentanyl or other short-acting
medication, should be administered. Administration of nalox-
one should not be done routinely to facilitate a neurologic
examination. Preferably, a short-acting narcotic infusion is
held for a brief time, which allows reassessment of neurologic
status. However, holding sedation in the face of unstable ICP
may be deleterious [127].
Glucocorticoids
Glucocorticoid use does not improve outcome or reduce intra-
cranial hypertension. Indeed steroids are associated with
increased mortality. For example, in the CRASH trial, a large
(10,008 adults), international, multicenter placebo-controlled
trial of methylprednisolone after TBI (GCS <14), the group
treated with steroids had an increased likelihood of death
(relative risk of 1.15), regardless of injury severity [250]. The
reason for this increased mortality is uncertain.
Stress Ulcer Prophylaxis
Severe TBI is a risk factor for stress ulcers (Cushing’s ulcer).
Hence stress ulcer prophylaxis with an intravenous H-2
blocking agent, proton pump inhibitor, or sucralfate should
be administered to patients with moderate or severe TBI who
require mechanical ventilation, and those with coagulopathies
or a history of gastric or duodenal ulcers.
Prophylaxis Against Venous Thromoembolic Events
Severe TBI patients are at risk for venous thromoembolic
events (VTEs), including deep vein thrombosis (DVT) and
pulmonary embolism (PE). Traditionally PE is considered an
endpoint of DVT, however the two may be independent
218
thrombotic entities rather than different stages of a single
pathophysiologic process [251]. Without prophylaxis, the risk
of DVT is at least 20–30% (depending on how it is diagnosed)
and PE can complicate up to 3% of patients. Factors that
increase the risk of VTE in TBI include older age, greater body
mass, lower extremity injury, pelvic fractures, ISS >15,
increased length of ICU stay, and more severe TBI [252–254].
All TBI patients who require mechanical ventilation and
sedation should receive DVT prophylaxis in the form of
sequential compression stockings upon admission and until
ambulatory. Intermittent pneumatic compression (IPC) is
effective, but graduated compression stockings (GCS) less so.
In trauma, Cochrane analysis shows that pharmacological
prophylaxis, and in particular low molecular weight heparin
(LMWH) is more effective than mechanical methods at redu-
cing the risk of DVT [255]. The risk is further reduced when
patients receive both mechanical and pharmacological prophy-
laxis. However, thromboprophylaxis may not alter the mortal-
ity associated with PE.
Although clinical practice guidelines have been developed
by the American College of Chest Physicians, the Eastern
Association for the Surgery of Trauma, and the Neurocritical
Care Society, among others, there are no clear recommenda-
tions about the timing, dose, or duration of VTE pharmaco-
logical prophylaxis after TBI, and consequently there is wide
variability in care [256]. Traditionally, pharmacological
prophylaxis has been withheld or delayed to prevent the pro-
gression of intracranial hemorrhage. The challenge is to decide
when the risk of hematoma progression is low, since withhold-
ing prophylaxis for more than four days significantly increases
the VTE risk. Intracranial hematoma expansion usually occurs
before 72 hours and even when prophylaxis is initiated before
then, the expansion may have more to do with the natural
history of the pathology rather than VTE prophylaxis in hemo-
dynamically stable patients [257]. Several principles can help
guide when pharmacological VTE prophylaxis is started
(summarized in Table 17.15), including: (1) patients are not
expected to go to the operating room in the next 24 hours for
Table 17.15 Modified Berne–Norwood criteria for pharmacolgical VTE
prophylaxis after TBI (modified from 261 and 264)
Low risk Moderate risk High risk
No moderate- or SDH or EDH >8 mm ICP monitor
high-risk features Contusion >2 cm EVD
IVH Craniotomy
Multiple contusion Progression on
SAH and abnormal CT at 72 h
CTA
Progression on CT at
24 h
Initiate Initiate Consider
pharmacological pharmacological inferior vena
prophylaxis if follow- prophylaxis if follow- cava (IVC) filter
up CT stable at 24 h up CT stable at 72 h placement

an intracranial procedure, (2) there is no systemic coagulopa-
thy and (3) there are two stable CT scans or improved CT scan
after 24 hours [214–217]. Hence, pharmacological VTE
prophylaxis may be started as early as 24 hours after TBI, if a
follow-up CT is stable, and particularly if there is no hemor-
rhage seen on the initial CT [258–264]. In other patients,
subcutaneous low-dose heparin may be initiated within
72 hours of admission, unless contraindicated due to evidence
of bleeding, need for surgery, or an indwelling intracranial
monitor. Interestingly, recent animal and clinical studies sug-
gest that early administration of unfractionated heparin (UFH)
after TBI may reduce secondary brain injury and enhance
cognitive recovery [265].
The most difficult to manage are the high-risk patients
(Table 17.15), i.e. have had a craniotomy, have an intracranial
monitor in place, and there is evidence for hematoma expan-
sion at 72 hours. In these patients an IVC filter should be
considered, particularly for those who are at high risk for VTE,
e.g. have long-bone or pelvic fractures. Limited data, mostly in
the form of case series, support a reduction in PE and PE-
related mortality. There has been increasing use of retrievable
filters, as well as the ability to safely retrieve them at longer
intervals [266]. The routine placement of IVC filters is contro-
versial, and placement is currently supported only by level III
recommendations when there are contraindications to any
anticoagulants [267].
Venous Thrombolic Event Treatment
There are published guidelines for treatment of VTE in critical
care [268], but how best to apply this to TBI and specifically to
TBI with ICH is still being elucidated. For acute DVT or PE,
initial parenteral anticoagulant therapy or anticoagulation with
rivaroxaban is recommended. When PE is accompanied by
hypotension, thrombolytic therapy is suggested. In each case
risks and benefits need to be balanced.
Fever and Temperature Control
Fever (body temperature >38.3 °C) is common after TBI and
usually is not an isolated event. Instead, fever often is a sus-
tained response during the first two weeks after injury. Only
half of the febrile episodes are from infection, with nosocomial
pulmonary infections representing the largest contributor. In
one-fifth to one-third of cases, fever remains unexplained, even
after extensive diagnostic workup [269]. Fever early after TBI
is associated with a poor GCS on presentation, the presence of
DAI, cerebral edema on the initial head CT, systolic hypoten-
sion, hyperglycemia, and leukocytosis [270]. Fever after TBI is
associated with increased oxygen utilization, increased ICP,
and worse outcome [271]. While in experimental models there
is a clear causal relationship, in humans it remains unclear
whether fever exacerbates or is merely a marker of brain
injury. However, it is generally agreed that fever should be
treated. There are several options, including: antipyretic medi-
cations such as acetaminophen, aspirin, and other nonsteroidal
Chapter 17: Management of Head Trauma
anti-inflammatory drugs, ice packs, surface cooling devices, or
intravascular cooling devices. The impact of fever control on
outcome is still being elucidated. However, there does not
appear to be a role for therapeutic hypothermia after TBI
[219,220]. On the other hand, induced normothermia attenu-
ates metabolic distress and so fever control, or more specific-
ally “targeted temperature management” is important
[272,273]. There does not appear to be a role for induced
hypothermia unless as a part of a clinical trial, although it
may still have a role in patients with refractory intracranial
hypertension [274,275].
Fever is not only a cardinal sign of infection, but also an
adaptive response that enhances the ability to fight infection,
and inducing normothermia may impair this adaptive
response. Routine infection surveillance is important [276].
Lowering body temperature to <37 °C has several known
adverse effects, including cardiac dysrhythmias, coagulopathy,
electrolyte abnormalities, and hypovolemia. These adverse
effects do not present as a problem until core body tempera-
tures are <35 °C. In contrast, shivering and vasoconstriction
responses are dependent on a temperature set point, which is
mediated via the preoptic nucleus of the anterior hypothal-
amus. In normal conditions, the hypothalamus coordinates a
response to maintain core body temperature at normothermia
(37 °C), and the shivering/vasoconstriction response begins
once temperatures are <36 °C. In brain-injured patients, the
set point is believed to be elevated and as a result the thermo-
regulatory response can be seen when lowering body tempera-
tures to normothermic levels. In fact, the incidence of
shivering has been reported to occur in up to 40% of patients
undergoing therapeutic normothermia. Shivering results in
increases in resting energy expenditure and in the systemic
rate of oxygen consumption (VO2) and in patients with severe
brain injury treated with induced normothermia, shivering is
associated with a decrease in PbtO2 [221], which correlated
with the intensity of cooling. Monitoring of therapeutic
cooling with computerized thermoregulatory systems may
help prevent shivering and optimize the management of
induced normothermia [272]. Hourly measurements using
the Bedside Shivering Assessment Scale (BSAS) are a reliable
method by which to adjust antishivering therapy [276,277].
The most effective antishivering pharmacologic agent is
meperidine, although not without potential side effects [278];
refer to Chapter 4 for details on temperature modulation and
how to control shivering.
Glucose Control
Hyperglycemia and glucose variability are associated with
worse clinical outcomes after severe TBI [279–282]. However,
the brain is an obligate glucose consumer and hypoglycemia
and in particular low brain glucose also are associated with
unfavorable outcome [282]. Consistent with this, intensive
insulin therapy, when it leads to reduced brain glucose also
can be injurious to the brain [283,284]. Hence avoidance of
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 Chapter 17: Management of Head Trauma
both systemic hyper- and hypoglycemia is recommended. This
can be facilitated with careful protocol adherence and point-of-
care testing [285]. In addition, since low brain glucose is
associated with adverse outcome, there is accumulating evi-
dence that cerebral microdialysis may be used to guide glucose
treatment, i.e. if brain glucose is low (<0.2 mM), a trial of
increasing serum glucose (by IV or enteral administration and/
or loosening glycemic control) should be considered [286].
There are, however, a variety of factors to consider whether
this is an appropriate intervention.
Microdialysis and PET studies demonstrate increased
“anaerobic” glucose metabolism after TBI that is attributed
to increased glycolysis. In addition, increased cerebral lactate
delivery is observed when glucose availability is reduced and in
the absence of brain hypoxia, suggesting that in some patients
lactate may act as an alternative fuel [287]. There also is
evidence that the pentose phosphate pathway (PPP) may gen-
erate lactate when brain oxygen decreases [288]. This has
raised the question of using intravenous exogenous lactate
supplementation in TBI. Early studies suggest a beneficial
effect in select patients, including a reduction in ICP and
excitotoxicity, and an improvement in brain glucose
[167,289]. Since energy metabolism is increasingly identified
as a factor in brain injury, further research is required to define
whether lactate supplementation and management of brain
glucose are rational therapeutic options in TBI.
Sodium and Electrolytes
Serum electrolyte disturbances are common complications
after TBI. Injury to the hypothalamic-pituitary system is a
major contributing factor. The most common causes for
hypernatremia (Na+ >150 mmol/L) in TBI patients are central
or neurogenic diabetes insipidus, osmotic diuresis (mannitol),
and the use of HTS. A serum sodium level Na+ up to 150–155
mEq/L may be acceptable in patients with increased ICP or
brain edema [290]. Correction of severe hypernatremia (Na+
>160 mmol/L) should be gradual, since abrupt changes in
serum osmolarity and rapid descrease of serum sodium con-
centration can aggravate cerebral edema. Fluid resuscitation of
hypovolemic hypernatremic TBI patients should be initially
only with NS. Management of electrolyte disturbances should
follow complete volume restoration. Hyponatremia is detri-
mental and major secondary systemic brain insult in patients
with severe TBI, since it can exacerbate brain edema and
increase ICP. It is usually secondary to cerebral salt-wasting
syndrome, or to the syndrome of inappropriate antidiuretic
hormone (SIADH) secretion. Hypophosphatemia and hypo-
magnesemia are common complications in head-injured
patients and they lower the seizure threshold [291].
Blunt Cerebrovascular Injury
Blunt cerebrovascular injury (BCVI) is diagnosed in approxi-
mately 1/1000 (0.1%) patients hospitalized for trauma in the
United States. However, most of these injuries are diagnosed
220
Table 17.16 Grading scale for blunt cerebrovascular injury [293] and
management options
Grade Pathology Management
I Intimal irregularity; Antiplatelet agents
<25% narrowing
II Dissection or intramural Anticoagulation (or
hematoma; >25% antiplatelet)
narrowing
III Pseudoaneurysm Surgical or endovascular
occlusion (observation on
anti-thrombotic agents also
is an option but rarely
resolve on their own)
IV Occlusion If neurologic deficit and
symptomatic consider repair
V Transection with If neurologic deficit and
extravasation symptomatic consider repair
following symptom development, including: arterial hemor-
rhage, cervical bruit, expanding cervical hematoma, focal
neurological deficit, neurologic examination incongruous with
imaging, ischemic stroke on follow-up imaging or symptoms
of secondary cerebral ischemia. When asymptomatic patients
are screened for BCVI the incidence rises to 1% of all blunt
trauma patients. The approach to management of BCVI is
beyond the scope of this chapter and the reader is referred
elsewhere [59,292]. Treatment is based on grading scale pro-
posed by Biffl [293] and is very briefly summarized in
Table 17.16. Careful risk assessment is required before anti-
thrombotic therapy is started. Follow-up imaging is required.
Although firm recommendations are lacking, antithrombotic
therapy, in general is administered for three to six months.
Vasospasm and Traumatic Aneurysms
Penetrating TBI and bTBI are associated with traumatic aneur-
ysm formation, and therefore vascular imaging is needed.
However, the accuracy of noninvasive vascular imaging, e.g.
MRA or CTA, can be limited, since traumatic aneurysms may
be small and on more distal vessels. When identified these
aneurysms require treatment because they can rapidly grow
and rupture with devastating consequences. In addition, if an
initial study is negative it should be repeated one week later.
Vasospasm is a common finding after bTBI and can develop
within 48 hours [294]. Vasospasm should also be considered in
other TBI patients, particularly those with extensive SAH who
deteriorate during their ICU course.
Autonomic Dysregulation Syndrome
Hypertension, tachycardia, fever, and dystonia may be a sign
of autonomic dysregulation syndrome, frequently seen in TBI,
although alternative explanations must be considered before
accepting this diagnosis of exclusion. Early fever may signal

impending autonomic dysfunction. Bromocriptine, propano-
lol, and opioids can be used to treat this condition.
Nutritional Support
Severe TBI can cause increased metabolism and create a hyper-
catabolic state. In the first two weeks, severe TBI patients may
lose 15% of their body weight a week from nitrogen loss. In
turn this may alter immune function. An increase in mortality
is observed when >30% body mass is lost [295].
Ideally, nutritional support should be initiated within
72 hours of injury. Nonparalyzed patients should receive
140% of basal energy (caloric) expenditure. Paralyzed patients
should receive 100% of basal energy expenditure. At least 15%
of the calories should be provided as protein. Full caloric needs
should be administered by day 7 post injury. Adequate nutri-
tion that is started early after injury is associated with
enhanced immunity, decreased infectious morbidity,
shortened length of hospitalization, improved neurological
recovery, and reduced mortality [296]. The role of calorie
restriction and high amino-acid supplementation in brain
recovery has not been defined [297,298].
Enteral feeding is preferred [299,300] since the risk of
infection and hyperglycemia is less than with total parenteral
nutrition (TPN), which should be used cautiously in TBI
patients because of the high glucose concentrations in hyper-
alimentation solutions. However, early enteral nutrition may
not always be feasible, e.g. in a patient with upper GI bleeding,
high gastric aspirate (>500 mL/6 h), abdominal compartment
syndrome, or shock. Severe TBI patients also may have gastric
feeding intolerance, including abnormal gastric emptying and
altered gastric function that puts them at risk for emesis and
aspiration. Residual volumes of gastric nutrition should be
assessed frequently. Prokinetic agents such as metoclopramide
improve tolerance, but if gastric intolerance is present post-
pyloric (jejunal) feeding avoids gastric intolerance and allows
higher caloric and nitrogen intake.
Secondary Surgical Procedures
During emergency surgeries for other injuries, a priority
should be to maintain target physiological parameters, e.g.
systolic blood pressure >90 mmHg (or higher if ICP is ele-
vated), and oxygenation (PaO2 100 mmHg and Pulse Ox
90%) in all patients suspected of having a TBI. Insertion of
an ICP monitor should be considered.
Patients with severe TBI, particularly those with multiple
trauma, often require other surgical procedures, e.g. ortho-
pedic procedures and plastic surgery. This may place the
patient at risk for secondary brain injury since hypoxia or
hypotension may occur during the procedure [301]. There
are no prospective studies that define the optimal timing of
secondary procedures after TBI. However, when certain prin-
ciples are followed, the timing of surgery after TBI may not
exacerbate brain injury [302]. First, nonemergent surgeries
that require general anesthesia, such as orthopedic procedures
Chapter 17: Management of Head Trauma
and plastic surgery, should be avoided in moderate and severe
TBI patients until it is evident that the brain injury has stabil-
ized. Second, in patients with elevated ICP, surgery should be
delayed. Third, close monitoring is required during surgery
and an ICP monitor should be considered in all moderate to
severe TBI patients who undergo general anesthesia for sec-
ondary procedures. Third, regional anesthetic procedures and
laparoscopic procedures should be avoided. Finally, for certain
orthopedic injuries, early damage-control surgery with delayed
definitive surgery may be considered [303].
Outcome and Outcome Prediction
Outcome for TBI patients who require critical care ranges
from death and vegetative state to full recovery. Among
patients discharged from hospital, at least half require ongoing
outpatient care, mostly for behavioral and cognitive impair-
ments at one year post injury. Three quarters have cognitive
impairment and 50–60% physical impairments [303]. In gen-
eral, traumatic coma has a better prognosis than coma from
hypoxia-ischemia, and coma from blunt trauma has a better
prognosis than coma from penetrating TBI, particularly
GSWs. There are many factors that predict poor outcome in
large populations. In particular the IMPACT (International
Mission on Prognosis and Analysis of Clinical Trials) and the
CRASH (Corticosteroid Randomization after Significant Head
Injury) scores are externally validated models derived from
large datasets that help predict 14-day mortality and six-month
outcome after TBI [25,305–307]. However, functional recovery
may continue for at least 18 months, and these scores have less
use in predicting individual patient outcome.
Early outcome prediction is important in TBI care to direct
efforts at those who will make a meaningful recovery, allow
appropriate withdrawal of care in cases of futility, and facilitate
family counseling. The IMPACT models validly predict 14-day
mortality [306] and can help guide decisions. The lower the
initial GCS score, the less likely a patient will have a meaningful
or functional outcome, but this does vary according to
resources. For example, advanced age is most associated with
poor outcome in high-income countries, and low GCS is most
associated with poor outcome in low–middle-income countries.
The relationship between advanced age and outcome is
changing as the population ages and the type of injury changes
[21,308]. In addition, aggressive care is associated with
improved outcome in all decades of life, including for people
in their 80s [239]. Accordingly, geriatric-specific prediction
tools may be more useful in geriatric patients [309]. The absence
of pupil reactivity is a strong predictor of poor outcome, par-
ticularly when a patient also is hypotensive. CT findings, such as
obliteration of the third ventricle and midline shift, predicts
early mortality (14 days), whereas a nonevacuated hematoma
is associated with poor outcome at six months [306]. Predictive
models that include baseline characteristics: age, GCS motor
score, pupillary reactivity, hypoxia, hypotension, computed
tomography classification, and traumatic SAH help predict
221
 Chapter 17: Management of Head Trauma

six-month outcome in patients with severe or moderate TBI
[260,261]. The presence of other injuries and development of
other complications adversely affects outcome, particularly in
moderate TBI and less so in severe TBI [40,310–315].
Withdrawal of Care and Futility
Many TBI deaths are associated with the withdrawal of life-
sustaining therapy. This varies across regions and across
centers, and about one-half of these deaths occur within the
first three days of care [316]. Relatives and medical teams must
frequently estimate patients’ preferences for treatment, includ-
ing life support, and these decisions are often based on per-
ceptions of a meaningful neurologic recovery. Studies show
there are communication differences about prognostic infor-
mation between patient surrogates and physicians that have
implications in goal-of-care discussions [317]. There is a pau-
city of study on treatment-limiting decisions (TLDs) in severe
TBI, but in general when initiated, the median time from the
decision to death is two days [318].
There still is much work to be done to better define accur-
ate predictors of outcome. Early levels of biomarkers measured
in CSF within 24 hours of severe TBI may help in outcome
prediction. In particular, levels of MAP-2 in combination with
clinical data provide enhanced prognostic capabilities for mor-
tality at six months [319]. Other biomarkers such as serum S-
100B or NSE are less useful or lack a defined threshold
[320,321]. A promising line of investigation involves the use
of advanced MRI (functional and diffusion-tensor sequences)
to improve prognostic accuracy. This may be particularly
useful for patients who remain in a coma seven days after
TBI, and recognizing which patients will permanently stay
severely impaired remains a key issue for neurointensive care
[27,57,322]. In general, every patient with a bilateral lesion of
the brainstem, the hypothalamus, or the thalamus has a poor
outcome.
When a decision is made to withdraw care, end-of-life care
guidelines should be followed to facilitate patient care. The
following medications can be used to enhance patient comfort:
(1) continue medications that may promote comfort (respira-
tory medications, antihypertensive), (2) administer morphine
sulfate 2–20 mg IV every 10 minutes for pain or dyspnea, and
increase or use drip titration as needed, (3) lorazepam 1–2 mg
IV every hour for anxiety and agitation, and (4) a scopolamine
patch or glycopyrolate 0.1–0.2 mg IV every four hours for
secretion management.

management of severe traumatic brain Concussion in Sport held in Zurich,

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prediction in adult traumatic brain
injury. J Neurotrauma, 24:
1558–1569.
 Chapter
Management of Autoimmune Encephalitis

18 in the Neurocritical Care Unit

Murat Sari, Diana Greene-Chandos, and Michel T. Torbey

Antibody-associated disorders of the central nervous system Table 18.1 Antibody-associated disorders of the CNS
(CNS) are divided into two broad categories: classic paraneo-
Paraneoplastic Autoimmune
plastic disorders and autoimmune disorders (i.e. autoimmune disorders encephalitis
encephalitis) [1]. Autoimmune encephalitis is associated with
antibodies that bind to cell surface determinants of membrane- Incidence Rare Common
associated proteins on neuronal cells (neuronal surface anti- Cancer Almost always Can be present
body syndrome –NSAb), whereas paraneoplastic syndromes Age Older adults Across the age
are associated with intracellular neuronal antigens. It can be continuum
challenging at times to differentiate between the two syn-
dromes. Patients with NSAb usually present with an acute or Ab target Intracellular Neuronal cell-surface
neuronal antigens or synaptic receptors
subacute symptom onset, with short duration to nadir, and a
very good response to immunotherapy [2]. Table 18.1 sum- Pathology T-cell mediated B-cell mediated
marizes some of the characteristics of each. In this chapter, we Clinical course Monophasic Relapsing
will focus on the diagnosis and management of autoimmune
Response to Limited response Responds well
encephalitis (AE).
treatment

Diagnostic Approach
The following criteria usually support the diagnosis of an
autoimmune disorder associated with NSAb [2]:
1. Acute or subacute (<12 weeks) onset of symptoms
2. Evidence of CNS inflammation (at least one):
a. CSF (lymphocytic pleocytosis, CSF oligoclonal bands,
or elevated IgG index)
b. Magnetic resonance imaging (MRI) (FLAIR/T2
hyperintensities otherwise unexplained or
enhancement of cerebellar sulci), or functional imaging
showing hypermetabolism or hyperperfusion
c. Inflammatory neuropathology on biopsy
3. Exclusion of other causes (infective, trauma, toxic).
Although additional supportive features would strengthen the
diagnosis, they are not mandatory These features include: (1)
history of other antibody-mediated disorders or organ-specific
autoimmunity and (2) preceding infectious, febrile illness or
viral disease like prodromes.
The NSAb syndrome can be further classified into definite,
probable, or possible depending on a defined list of criteria [2].
• Definite NSAb syndrome: A diagnosis can be made in
patients with known NSAb present in serum or CSF and a
response to immunotherapy. A sustained improvement in
the modified Rankin score (mRS) of at least 1 point is
defined as immunotherapy responsive [3].
• Probable NSAb syndrome: A diagnosis can be made if the
following criteria are met:
: NSAb present, OR
: There are other neuronal antibody markers of an
immune process, OR
: There is at least one clinical supportive feature, AND
: There is a response to immunotherapy.
• Possible NSAb syndrome: A diagnosis can be made if the
following criteria are met:
: NSAb negative
: There are other neuronal antibody markers of an
immune process, OR
: There is at least one supportive feature present, OR
: There is a response to immunotherapy.
Autoimmune Encephalitis Syndrome
Table 18.2 summarizes the different NSAb syndromes and
their characteristics.
Specific Autoimmune Encephalitis Syndromes
Anti-N-methyl-D -Aspartate Receptor Encephalitis
Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is
one of the most common and best-characterized subtypes of

233
 Chapter 18: Management of Autoimmune Encephalitis

Table 18.2 NSAb syndromes and their characteristics

Receptor Clinical syndrome Associated cancer Clinical notes

Neurotransmitter NMDA Neuropsychiatric Ovarian teratoma • Predominantly affects young adults, adolescents,
receptors symptoms and children
Movement disorders • 80% female
Seizures • CSF abnormalities (90%)
Autonomic dysfunction • MRI abnormalities noted in only 50%, usually
medial temporal lobe flair high signal
AMPA Limbic encephalitis Lung • Predominantly affects females (90%)
Psychosis Breast • Age distribution 40–90
Thymus (70%) • Median age: 60 years
• CSF abnormalities (90%)
• MRI abnormalities (90%)
• Frequent coexisting autoimmunities
GABAA Status epilepticus None • Predominantly affects males (83%)
Encephalitis Possible HL • Median age: 60
• Multifocal MRI abnormalities
• Frequent coexisting autoimmunities
• 20% have comorbid myasthenia gravis
GABAB Limbic encephalitis SCLC or • More common in males (60%)
Early severe seizures neuroendocrine tumor • Mean age 62 years
(50%) • Age distribution 25–75 years
• CSF abnormalities (80–90%)
• MRI abnormalities (65%)
• Frequent coexisting autoimmunities
Glycine Stiff-person Rarely HL • Age distribution: 5–69 years of age
Hyperekplexia • More common in females (55%)
PERM progressive • Coexisting GAD65 antibodies
encephalomyelitis • CSF variable
• MRI usually normal
mGluR1 Cerebellar ataxia HL • Affects both males and females
• Age distribution: 16–69 years
mGluR5 Limbic encephalitis HL • Associated with Ophelia syndrome
Secreted protein LGI1 Limbic encephalitis Thymoma <10% • Predominantly affects males (65%)
Seizures • Median age 60 years
Hyponatremia • Age distribution 30–80 years
Myoclonus • Frequent tonic seizures misdiagnosed as startle or
Faciobrachial dystonic myoclonus
seizures • CSF abnormalities (40%)
• MRI abnormalities noted in 85%, usually medial
temporal lobe
Transmembrane Caspr2 Encephalitis Thymoma • Predominantly affects males (85%)
protein Peripheral nerve (20–40%) • Median age 60
hyperexcitability • Age distribution: 45–80 years
• CSF abnormalities (25%)
• MRI abnormalities noted in 40%, usually medial
temporal lobe
DNER Paraneoplastic None • 50% males
receptor cerebellar • Age distribution: 12–73 years of age
degeneration • Notch ligand on cerebellar purkinje neurons
Abbreviations: LGI1: leucine-rich, glioma inactivated 1; Caspr2: contactin-associated protein-like 2; DPPX: dipeptidyl-peptidase-like protein 6; HL: Hodgkin
lymphoma; DNER: delta/notchlike epidermal growth factor-related

234

autoimmune encephalitis. Since the earlier case reports, the
incidence of NMDA receptor encephalitis has been on the rise
until it is now greater than any single viral etiology [4]. The
syndrome is more common in young women and children, but
men and older patients can be affected. Although, in younger
patients the presenting symptoms are often neurologic, 40% will
later develop psychiatric manifestations [5]. Older patients tend to
present with memory changes, making the diagnosis a bit more
challenging to differentiate from age-related memory disorders.
In the majority of the patients, a viral-like prodrome often
precedes the development of symptoms. Although the initial
clinical symptoms can be subtle, they are subdivided into eight
categories [6].
1. Psychiatric and cognitive changes
2. Memory problems
3. Speech deficits
4. Seizures
5. Movement disorders
6. Loss of consciousness
7. Autonomic dysfunction
8. Central hypoventilation.
Patients usually progress within days to a few weeks to develop
autonomic and respiratory changes, coma, and ultimately
requiring ICU admission [1]. About 75% of the patients are
admitted to the ICU [7].
Diagnostic Workup
Serum and CSF Markers
All patients have IgG antibodies (Abs) against the GluN1
subunit of the NMDA receptor [8]. It is essential to obtain a
CSF sample since a serum sample can be negative in 13% of
patients [9]. Lymphocytic pleocytosis, increased protein, and
oligoclonal bands are usually present in CSF.
Electroencephalography
Electroencephalography (EEG) usually shows diffuse back-
ground slowing. Extreme delta brush pattern is usually reported
in 30% of the patients. This pattern is a continuous combination
of delta activity with fast activity in the beta range. It is symmet-
ric and predominant in the frontal regions. The delta brush
pattern is associated with longer hospitalization [10].
Imaging
It is very unlikely to have any imaging abnormalities on presenta-
tion. Increased signal on MRI fluid-attenuated inversion recovery
(FLAIR) or T2 sequences is reported in 35% of patients, and faint
or transient contrast enhancement of the cerebral cortex, overlying
meninges, basal ganglia, or brainstem. Brain fluorodeoxyglucose-
positron emission tomography (FDG-PET) imaging may be indi-
cated in high clinical suspicion and negative MRI since it is more
sensitive for detecting temporal lobe abnormalities.
Tumor Screening
A tumor is identified in a significant proportion of patients; 45%
of adult females have uni- or bilateral ovarian teratomas. Ovarian
Chapter 18: Management of Autoimmune Encephalitis
carcinoma is more common in older women (>45 years old)
[11] and teratomas are more common in girls (<14 years old)
[1]. In patients with no known history of tumor, a periodic pelvic
MRI or transvaginal ultrasound (US) should be considered.
Clinical Outcome
The majority of the patients (86%) initially have a poor out-
come (mRS of 5) upon hospital discharge [7]. A significant
proportion improve with time and 81% have a favorable out-
come (mRS 0–2) at 24 months. It is important to avoid early
discussions about withdrawal of care and the chance of recov-
ery must be considered. Some early good prognosticators
include no ICU admission and early start of immunotherapy.
Relapse rates vary between 12% and 25%. Clinical relapses are
better monitored in CSF than in serum [7].
Anti-α-Amino-3-Hydroxy-5-Methyl-4-
Isoxazolepropionic Acid Receptor Encephalitis
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)
receptor antibodies target the GluR1 or GluR2 subunits
of the glutamate receptor [12]. Patients usually present with
classic symptoms of limbic encephalitis, including confusion
and memory disturbances [12]. Psychiatric symptoms and
seizures may be present. The disease usually affects middle-
aged woman. It is paraneoplastic in about 70%. The common
associated tumors include thymus, lung, or breast [1]. The CSF
laboratory profile is similar to NMDA receptor encephalitis.
Anti-γ-Aminobutyric Acid A Receptor Encephalitis
The γ-aminobutyric acid A (GABAA) receptor is a ligand-
gated chloride channel that mediates fast inhibitory transmis-
sion in the CNS. Pharmacologic or genetic alteration of this
receptor is often associated with seizures. Patients are typically
in their 40s and often present with seizures (88%), alterations
of cognition (67%), behavior (46%), or consciousness (42%),
and/or abnormal movement (35%) [13,14]. Patients can
quickly deteriorate and develop rapidly progressive encephal-
opathy, refractory seizures, and status epilepticus requiring
admission to the neurocritical care unit. Changes in behavior
typically precede seizures [13,14]. Refractory seizures should
always trigger a high level of clinical suspicion of GABAA Abs.
CSF shows lymphocytic pleocytosis, increased proteins, and
possible oligoclonal bands. MRI findings are often characteris-
tic and multifocal with extensive FLAIR/T2 changes. The dis-
ease is rarely linked to an underlying tumor and responds well
to immunotherapy.
Anti-GABAB Receptor Encephalitis
Characteristic presentation includes early prominent seizures
and limbic encephalitis-related symptoms. Rarely these
patients develop ataxia or opsoclonus-myoclonus [1]. The
syndrome is common in both men and women. Half of the
patients have an associated tumor, including small-cell
235
 Chapter 18: Management of Autoimmune Encephalitis
lung cancer or a neuroendocrine lung tumor. On average,
patients with a tumor are in their 60s compared to no-tumor
patients who are often younger. Several antibodies have
been reported including thyroid peroxidase, antinuclear anti-
bodies, and GAD65 [15]. Anti-GABAB usually responds well
to immunotherapy.
Anti-LGI1 Limbic Encephalitis
LGI1 is not a receptor itself. It is a secreted synaptic protein
that binds to two membrane proteins, disintegrin and metal-
loproteinase domain-containing protein 22 (ADAM22), and
disintegrin and metalloproteinase domain-containing protein
23 (ADAM23) [16]. It usually affects older patients, with a male
preponderance. Thymoma is present in <10% of patients.
Patients typically present with classic picture of limbic
encephalitis and seizures [1]. Faciobrachial dystonic seizures
are the most characteristic. They are described as a rapid
unilateral movement of the face, shoulder, and upper extrem-
ities [14]. Seizure control may be difficult and will require
immunotherapy for better control. Around 60% of patients
will develop hyponatremia and REM sleep disorders.
Steroids may be particularly effective in LGI1 autoimmun-
ity, requiring several months of therapy. Rate of steroid
taper is very important since relapses are observed with rapid
taper. Patients with anti-LG1 encephalitis have a relapse rate of
35% [17].
Metabotropic Glutamate Receptor 5 (mGluR5)
Antibody Syndrome
Metabotropic glutamate receptor 5 (mGluR5) Ab syndrome is
associated with Ophelia syndrome, characterized by [14]:
1. Mild encephalitis with confusion and dissociation
2. New diagnosis of Hodgkin lymphoma at the onset of
encephalitis
3. Marked improvement of the encephalitis after treatment of
lymphoma.
Neurologic symptoms improve dramatically with tumor
treatment.
Overlap with Other Disorders
There are several case reports of positive NMDA receptor
antibodies in serum and CSF from herpes simplex encephalitis
(HSE) patients during relapsing symptoms in the weeks
between diagnosis and new symptom recurrence [18]. These
patients are usually very responsive to immunotherapy [19].
Cancer Investigation Workup
Given the common association of cancer with NSAb syn-
drome, it is imperative an appropriate cancer workup is done.
European Federation of Neurological Societies Guidelines rec-
ommend the following tests:
236
• US
• Computed tomography (CT) of the thorax/abdomen
• FDG-PET
• MRI of pelvis/breast.
If the initial screen is negative, screening should be
repeated after 3–6 months. If no tumor is found, follow-up
should be repeated in four years [20]. Since anti-GABAA
receptor encephalitis has not been associated with cancer
screening, once should be sufficient. In anti-NMDA receptor
encephalitis, given its association with ovarian teratoma,
abdominal imaging should be performed every six months
until four years after the first event. In the case of relapse,
new cancer screening is recommended. For the screening of
ovarian teratoma, both CT and MRI have good sensitivities,
93–98% and 93–96%, respectively. MRI is preferred to avoid
radiation. FDG-PET is not recommended because ovarian
teratomas show little FDG uptake [20].
General and Critical Care Management
As the patient’s clinical status deteriorates they will need
admission and management in the neurocritical care unit.
Most common reasons for admission to the ICU are status
epilepticus (26%), delirium (15%), respiratory failure (15%),
coma (7%), hemiparesis (4%), and sepsis (4%) [21]. Critical
care needs to include management of mechanical ventilation,
sedation, dysautonomia, and hyperthermia.
The therapeutic goals are removal of antibodies and man-
agement of the clinical symptoms. Removal of antibodies is
achieved by either halting the trigger of the immune response,
i.e the tumor, or attacking the overactive immune system.
Although no class 1 evidence exists regarding immunotherapy
for anti-NMDA receptor encephalitis or other NSAb syn-
dromes, corticosteroids, IV immunoglobulin, plasma
exchange, or a combination of these are often used as first
line in treatment of NSAb syndrome. In the case of LGI1
antibodies, steroids may be particularly effective. Over half of
anti-NMDA receptor encephalitis patients have a good out-
come at 24 months following first-line immunotherapy and
tumor treatment within the first four weeks [7]. Patients who
do not respond to first-line therapy should receive second-line
therapy, including rituximab, cyclophosphamide, or both.
Rituximab is increasingly used as a first-line agent in severely
ill patients. Repeated doses can be used in patients with
relapses.
With cyclophosphamide there is a fear of potential adverse
effects, including premature gonadal failure, infertility, and
long-term malignancy [6]. Gonadotropin-releasing hormone
(GNRH) agonist treatment should be considered in young
women receiving cyclophosphamide to decrease the risk of
infertility [22]. Azathioprine, and/or mycophenolate mofetil
can be used as chronic immunotherapy, but due to their slow
effects they are often less useful in acute phases.

First-line therapy should be started once diagnostic
samples have been obtained before a specific Ab has been
identified. Even in patients with negative NSAbs, a trial with
steroids and IV immunoglobulin or plasma exchange can be
considered if there are no contraindications, particularly if
infectious diseases have been ruled out.
References
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Chapter 18: Management of Autoimmune Encephalitis
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237
 Chapter
Management of Cerebral Salt-Wasting Syndrome and
19 Syndrome of Inappropriate Antidiuresis in the
Neurocritical Care Unit
Wendy Wright
Introduction
Hyponatremia is the most common electrolyte disorder in
hospitalized patients. A wide range of causes are implicated,
some of which may have particular treatment strategies [1].
Hyponatremia in neurocritical care patients may be from a
variety of causes, such as cerebral salt-wasting syndrome
(CSWS), the syndrome of inappropriate antidiuresis (SIAD, also
known as the syndrome of inappropriate antidiuretic hormone,
or SIADH), or it may be multifactorial. Neurocritical care
patients have a variety of risk factors for hyponatremia, and
are more likely to develop symptoms if underlying central
nervous system pathology is present. Therefore, in the neuro-
critical care population hyponatremia should be prevented
when possible and promptly treated once identified [2]. Due
to the need to maintain cerebral perfusion pressure, when
treating hyponatremia the goals should be to maintain normal
intravascular volume and normal salt concentration [3].
Sodium and Fluid Regulation
The balance of sodium and water is mainly regulated by thirst
and arginine vasopressin (AVP, also known as antidiuretic
hormone, or ADH) [4]. Osmotic and nonosmotic stimuli
induce thirst and release of AVP [5], which lead to renal
sodium absorption or excretion, with water volume then
adjusted to maintain tonicity [6]. Osmoregulation and baro-
regulation are interdependent [4].
Osmoregulation is primarily dependent on the serum
osmolality [4], which is normally 285–295 mOsm/kg [7].
Changes in serum osmolality are largely determined by changes
in serum sodium [4]. An increase in tonicity of as little as 1–2%
is detected by osmoreceptors in the hypothalamus, causing
release of AVP from the posterior pituitary. AVP will then allow
water reabsorption from the kidney via aquaporin channels in
the distal tubule and collecting duct [6,8]. Increased tonicity will
also cause thirst, but the osmotic threshold for AVP release is
lower than the threshold for triggering thirst [9,10]. There are
osmoreceptors in the subfornical organ and the organ vascu-
larum of the lamina terminalis that lie outside of the blood–
brain barrier, allowing integration of osmotic information with
endocrine signals such as circulating natriuretic peptides [4].
Baroregulation depends on detection of circulating blood
volume by stretch-sensitive receptors in the left atrium, carotid
238
sinus, and aortic arch [4]. Reduction in blood pressure of as
little as 5–10% will cause an increase in AVP concentration
[11]. There is an exponential association between the AVP
concentration and the percentage decline in mean arterial
blood pressure, with faster increases in AVP levels as blood
pressure progressively decreases [4].
A variety of other nonosmotic stimuli can cause AVP
release. Nausea, emesis, stress, pain, fear, anxiety [8,12], and
the postoperative state [5] can all lead to AVP release, causing
water retention by the kidney, which can lead to a mild
dilutional hyponatremia. Though release of vasopressin from
the posterior pituitary is generally regulated [4], there are
pathological conditions under which the pituitary and other
cells may synthesize and secrete AVP, independent of serum
osmolality and circulating blood volume. Additionally, there
are pharmacologic and genetic factors that increase the per-
meability of the collecting duct in the absence of vasopressin.
This collection of disorders, characterized by euvolemic hypo-
natremia, had previously been called the syndrome of inappro-
priate antidiuretic hormone (SIADH), but the term syndrome
of inappropriate antidiuresis (SIAD) may more fully encom-
pass the clinical spectrum [4].
Patients with neurologic and neurosurgical diseases are
at risk for disorders of sodium and fluid balance from a variety
of causes. This dysregulation can lead to hyponatremia, which
is a relative increase in water concentration over sodium
concentration [13].
Hyponatremia
Definition
Sodium levels defining hyponatremia vary, but in general the
accepted definition of hyponatremia in the neurocritical care
setting is serum sodium concentration of less than 135 mmol/L
[14]. Hyponatremia is the most common electrolyte disorder.
The incidence depends on the sodium cut-off used, but studies
have shown hyponatremia in about 15–30% of hospitalized
patients [15]. An estimated 40–75% of these cases may be
iatrogenic or hospital acquired [16]. Hyponatremia is often
multifactorial, but the most common cause is SIAD [1]. Yearly
treatment costs in the United States are approximately $1.6 to
3.6 billion [17].

Significance
Though opinions vary, there is evidence that hyponatremia
increases morbidity and mortality [1,18]. One study of critic-
ally ill patients indicates that even slightly decreased sodium
levels are a risk factor for increased mortality [19], suggesting
that even mild hyponatremia should be treated [1]. Others
point out that in the era of aggressive fluid replacement,
there are no data to support an increase in mortality due to
hyponatremia [14]. One concern is that overly rapid correction
of sodium levels can lead to severe neurologic impairment
or even death due to osmotic demyelination syndrome
(ODS) [18].
Symptoms
In general medical patients, symptom development is related
to the severity of the hyponatremia and the rapidity with which
it develops [2,20]. However, even mild hyponatremia can
result in neurologic deterioration [2], especially in patients
with underlying central nervous system pathology [20].
Furthermore, patients with “asymptomatic” chronic hypo-
natremia are at higher risk of gait instability, falls, and bone
fractures. Early symptoms of hyponatremia include confusion,
weakness, lethargy, headache, disorientation, nausea, and
vomiting. If the condition worsens then seizures, coma, and
even death may ensue [18].
Neurologic symptoms of hyponatremia are generally due
to osmotically induced brain edema [18]. Since sodium is the
major determinant of serum osmolality and therefore neuron
size, even a small fall in serum sodium can aggravate vasogenic
cerebral edema and increase intracranial pressure [2], possibly
resulting in death [18], The brain does have protective mech-
anisms to adapt to hyponatremia. Over the first few hours in
which hyponatremia develops, small molecules such as sodium,
potassium, and chloride leave the neurons, and water follows. In
a later phase, which occurs around 48 hours into the course of
hyponatremia, larger organic osmoles are generated and then
transported out of the neuron, allowing for further water egress
[5,8]. Thus, intracranial volume is normalized. Patients with
neurologic disease [20] or postmenopausal women [1] may have
an impairment in this autoregulatory mechanism, making them
more susceptible to brain swelling from smaller changes in
sodium [20]. The presence of cerebral edema requires careful
maintenance of intravascular volume, such that the mean arter-
ial pressure can overcome intracranial pressure and maintain
cerebral perfusion pressure [21].
Efforts to try to correct the hyponatremia by increasing
sodium lead to the reverse process, as osmoles re-enter the
neuron and water follows. Due to the later part of the regulatory
phase, if trying to correct hyponatremia that has been present
for more than 48 hours, the sodium must be corrected slowly.
Otherwise, the patient will be at risk for ODS. Though the
mechanism is not fully understood, ODS may occur when large
organic osmoles generated in the later autoregulatory phase re-
enter neurons too rapidly or in too high a concentration [13].
Chapter 19: Management of Cerebral Salt-Wasting Syndrome
Classification and Differential Diagnosis of
Hyponatremia
Several classification systems for hyponatremia exist to aid
the clinician during diagnostic workup. Some authors will
first classify hyponatremia based on body fluid osmolality
and then look to volume status. Hyponatremia can be hyper-
tonic, isotonic, or hypotonic [13]. Hyperglycemia can cause
an isotonic or hypertonic hypernatremia. Pseudohyponatre-
mia can occur when a marked elevation of either plasma
lipids or proteins occupy a relatively larger portion of
plasma volume, artifactually decreasing measured sodium
levels [1,13].
Since sodium is the major effective plasma solute, hypo-
natremia is usually seen in the setting of hypo-osmolality
[13]. Some authors propose looking directly to volume status
to categorize hyponatremia [1]. Hyponatremia can occur in
the setting of hypervolemia, euvolemia, or hypovolemia.
Causes of hypervolemic hyponatremia include heart failure,
cirrhosis, and kidney disease. Causes of euvolemic hypo-
natremia include SIAD, glucocorticoid deficiency, hypothy-
roidism, low solute intake (including infusion of hypotonic
intravenous fluids), and primary polydipsia. Causes of hypo-
volemic hyponatremia include CSWS, gastrointestinal losses
(such as vomiting and diarrhea), diuretic use, and mineralo-
corticoid deficiency [13].
Workup
Once a low sodium is detected, immediately assess the patient
for serious signs and symptoms, indicating the need for
emergent treatment. The diagnostic phase is often guided
by the clinical picture. Some clinicians will check plasma
osmolality to exclude isotonic or hypertonic hyponatremia
[13,22]. Hypotonic hyponatremia is much more common, so
the diagnostic testing should depend on the volume status of
the patient. Volume status may not be readily apparent and
multiple parameters may need to be assessed in order to
obtain a clearer clinical picture. If clinically hypervolemic,
an investigation into cardiac, renal, and hepatic function
should follow. If clinically hypovolemic, one may be able to
distinguish intrarenal (CSWS, mineralocorticoid deficiency,
diuretics) from renal (gastrointestinal, vomiting, sweating)
causes by checking urinary sodium and osmolality. Urine
osmolality >200 mOsm/kg and sodium <25 mmol/L, indi-
cates an extrarenal cause, while urine osmolality >200
mOsm/kg and sodium >25 mmol/L indicates an intrarenal
cause such as CSWS [22].
If the patient is clinically euvolemic, SIAD is the most likely
cause. However, one should assess cortisol, thyroid function
tests, and urinary sodium and osmolality to look for other
treatable causes. Urine osmolarity >200 mOsm/L and urine
sodium >25 mmol/L is consistent with SIAD. If urinary
osmolality is <100 mOsm/L then psychogenic polydipsia
should be considered as a causative factor [22].
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 Chapter 19: Management of Cerebral Salt-Wasting Syndrome
Important Considerations in the Differential
Diagnosis
Euvolemic hyponatremia can have several important causes in
the neurocritical care unit other than SIAD, which will be
discussed in more detail in a later section. First, hypotonic
saline infusion is a common practice in the peri-operative
period [1]. Offending agents include 0.45% saline and lactated
Ringer’s solution, with sodium concentrations of 77 mmol/L
and 130 mmol/L, respectively. In order to prevent hyponatre-
mia, 0.9% saline is preferred as a maintenance IV fluid [13].
Adrenocorticotropic hormone (ACTH) deficiency is fairly
common in patients with subarachnoid hemorrhage and trau-
matic brain injury. Symptoms occur due to insufficient levels
of cortisol, which is necessary for efficient excretion of free
water. Patients will often have elevated AVP, but may have
lower serum bicarbonate and aldosterone levels than patients
with SIAD. Additionally, hypotension and hypoglycemia may
raise clinical suspicion. Symptoms of cortisol deficiency can
persist for some time past the inciting neurosurgical illness [1].
In the neurocritical care unit, CSWS, discussed further
below, should be considered as a leading diagnosis on the
differential of hyponatremic hypovolemia. Initial steps while
diagnostic workup is in progress should include restoration of
intravascular volume, including elimination of any diuretics.
Mineralocorticoid deficiency should be considered promptly
in case steroid replacement is required [1].
Cerebral Salt-Wasting Syndrome
Definition and Causes
CSWS is a syndrome of inappropriate natriuresis that leads to
volume depletion. It is primarily but not exclusively associated
with central nervous system diseases such as subarachnoid
hemorrhage [2]. The existence of CSWS is still doubted in
some publications, with some feeling that there is an alterna-
tive explanation for hyponatremia and others that the evidence
of volume depletion (upon which the diagnosis hinges) is
inconclusive [23,24]. Hyponatremia is not a necessary feature
of the syndrome, and it may only be mild. Other causes of
urine salt loss, such as mineralocorticoid deficiency and diur-
etic administration, should be excluded [2].
Pathophysiology
Patients with CSWS have both a water deficit and a sodium
deficit [4], thought to be due to increased secretion of natriure-
tic peptides [3,25]. In response to volume depletion, patients
also have an appropriate secretion of AVP, leading to dimin-
ished electrolyte-free water clearance and a simultaneous dilu-
tional hyponatremia. It is unclear whether brain natriuretic
peptide (BNP) or atrial natriuretic peptide (ANP) are primar-
ily responsible for CSWS. Both may be involved, as may other
natriuretic peptides. Both BNP and ANP levels are elevated in
CSWS, but BNP elevation is more consistent. BNP is primarily
240
released from the cardiac ventricles in response to an increase
in extracellular fluid volume, but it can be released by the brain
[26]. Regardless, the effect of natriuretic peptides is increased
urinary excretion of sodium due to decreased renal absorption,
probably in the proximal tubule [26], and inhibition of renin
and angiotensin release [26].
An additional proposed mechanism of CSWS is disruption
of sympathetic neural input to the kidney, causing downstream
inhibition of the renin–angiotensin–aldosterone system. Sym-
pathetic stimulation normally causes proximal tubule absorp-
tion of sodium, so depression of sympathetic input to the
kidney results in less sodium resorption in the proximal tubule
and an increase in sodium delivery to the distal tubule. This
leads to decreased effective arterial blood volume, triggering
baroreceptors to release AVP to help maintain intravascular
volume [26].
Syndrome of Inappropriate Antidiuresis
Definition and Causes
SIAD is hyponatremia generally due to oversecretion of AVP,
either in the absence of or out of proportion to physiologic
stimuli [25]. Specific diagnostic criteria for SIAD [1] include:
• Hypo-osmolality (plasma osmolality <280 mOsmol/kg)
• Inappropriate urine concentration (urine osmolality >100
mOsmol/kg) considering hyponatremia
• Clinical euvolemia
• Elevated urinary sodium (>40 mmol/L) in the setting of
normal dietary salt and water intake
• Exclusion of glucocorticoid deficiency, hypothyroidism,
diuretic administration.
SIAD is labeled “euvolemic” hyponatremia because even
though the plasma volume is slightly expanded, the extracellu-
lar volume is not clinically detectable [1]. Excess AVP increases
water permeability in the collecting duct leading to subclinical
volume expansion of about 7–10% of total body water [27].
This volume expansion triggers a release of natriuretic pep-
tides in order to regulate plasma volume, but at the expense of
sodium [28]. Like most hyponatremic syndromes, the symp-
toms depend on severity of hyponatremia and rate of develop-
ment, but in SIAD the neurologic symptoms can be worse in
the setting of other medical conditions such as fever, hypoxia, or
hypercapnia [1]. SIAD is the most common cause of hyponatre-
mia [1,29], but it is actually a heterogeneous disorder [30], itself
having many causes [1], including malignancy, pulmonary dis-
ease, and infection. Many drugs cause increased AVP secretion,
including desmopressin, selective serotonin reuptake inhibitors,
carbamazepine, tricyclic antidepressants, phenothiazines, halo-
peridol, 3,4-methylenedioxymethamphetamine (MDMA) [1],
oxcarbamazepine, and sodium valproate [29]. Neurologic and
neurosurgical causes include brain tumors, meningitis, encephal-
itis, abscess, vasculitis, subarachnoid hemorrhage, subdural hem-
orrhage, traumatic brain injury, Guillain–Barré syndrome,
multiple sclerosis [1], and stroke [29].

Pathophysiology
Hyponatremia in SIAD is presumably dilutional, due to a
relative excess of free water and not sodium deficiency. During
resting states, AVP is stored in the posterior pituitary. One
trigger for AVP release is osmoreceptor detection of an
increase in serum osmolality. Limbic system activation in
response to fear, nausea, pain, surgery, and trauma also lead
to increased AVP production [29].
Robertson describes four patterns of AVP secretion associ-
ated with antidiuresis. Type A consists of excessive, random
secretion of AVP that is not related to serum osmolality. In
Type B, AVP is released in a slow, constant manner, described
as a “leak,” and cannot be maximally suppressed, even when
osmolality is normal or falls below normal. Type C is described
as a “reset osmostat” in that AVP secretion occurs at lower
osmolality than usual. Type D is thought to be uncommon,
and is characterized by low or undetectable levels of AVP
without any obvious AVP dysregulation [30]. It is unclear if
decisions about treatment modality and timing could be opti-
mized based on the pattern of AVP secretion. There is some
speculation that the type B pattern may actually represent or
overlap with CSWS [2].
A protective homeostatic mechanism called “escape from
antidiuresis” occurs as the kidney begins to increase the clear-
ance of free water despite an inappropriately high concentra-
tion of AVP [31]. Escape from antidiuresis should limit the
extent of hyponatremia, as plasma sodium levels will stabilize
before severe hyponatremia develops [1].
Differentiating CSW from SIAD
There are no consistent criteria to distinguish SIAD from
CSWS and the two conditions can be nearly identical at pre-
sentation [2]. Both SIAD and CSWS manifest as hypotonic
hyponatremia with inappropriately high urine sodium concen-
trations [3], reduced blood urea nitrogen, and reduced uric
acid levels [18].
Differences in urate clearance have been reported to be a
distinguishing factor between SIAD and CSWS [32,33,34].
Initially, both SIAD and CSWS have low serum uric acid levels
(<4 mg/dL) and high fractional excretion of uric acid (frac-
tional excretion of uric acid (FEUA) levels >12%). When
retested after the correction of hyponatremia, SIAD patients
are reported to have normalized uric acid levels and FEUA
(<10%) [34]. In CSWS, some authors indicate that uric acid
level remains low and FEUA remains elevated after the correc-
tion of hyponatremia [32]. However, in one study of traumatic
brain injury patients, FEUA was not found to be a reliable
measure to distinguish SIAD from CSWS [35].
The key factor to differentiating SIAD from CSWS is
volume status [2, 3,18,25]. However, volume status is difficult
to assess and a large number of patients have some features
consistent with euvolemia (indicating SIAD) and some fea-
tures consistent with hypovolemia (indicating CSWS) [35]. It
is usually necessary to look at multiple parameters in order to
Chapter 19: Management of Cerebral Salt-Wasting Syndrome
assess the overall clinical picture, including things like blood
pressure, central venous pressure (CVP, less than 5 mmHg indi-
cating hypovolemia) [22], urine output (less than 0.5 mL/kg/h
indicating hypovolemia), intake and output (I/O) balance,
body weight, and skin turgor [13]. A water loading test
(administering oral water 20mL/kg up to 1500 mL, then meas-
uring the percentage of the bolus excreted; less than 80%
excretion in four hours is expected in SAID) should not be
used in the diagnostic workup of neurocritical care patients
because hyponatremia can be exacerbated [4].
Further complicating the issue of telling them apart, CSWS
and SIAD may coexist in the same patient [36,37], may happen
at different times in the same patient, or may represent a range
of diseases on the same clinical spectrum [22]. Considering the
potential for overlap of SIAD and CSWS, treatment of hypo-
natremia in the neurocritical care unit tends to focus on
restoring and retaining intravascular volume and sodium
levels [3,13]. Distinguishing between SIAD and CSWS is
required before consideration of vasopressin receptor antagon-
ists, discussed further below, which are absolutely contraindi-
cated in hypovolemic hyponatremia [38].
Treatment
General Principles
Considering the serious implications of cerebral edema in
neurocritical care patients, preventing hyponatremia is an
important goal of supportive management. Intravenous fluids
that are hypotonic to 0.9% NaCl should be avoided to prevent
the development of hospital-acquired hyponatremia. However,
even 0.9% saline may be insufficient for neurologic patients
with SIAD or CSWS. Fluid restriction should not be attempted
to prevent hyponatremia as there is too great a risk of develop-
ing volume depletion [2].
Sodium concentration can be increased by the addition or
retention of sodium or by the restriction or elimination of free
water [13] (Tables 19.1 and 19.2). Additional sodium can come
in the form of salt tablets or hypertonic saline. Fludrocortisone
will promote sodium reabsorption by the kidney. One protocol
tested in the treatment of hyponatremia via oral salt tablets and
sliding-scale hypertonic saline infusion was published by Woo
et al. [20]. One formula to estimate by how much one liter of
an infusate will increase serum sodium [5] is as follows1:
change in serum sodium
infusate sodium concentration  serum sodium
¼
total body water
1
Sodium concentration of common infusates: 23.4% NaCl has 4004
mmol/L, 3% NaCl has 513 mmol/L, 2% NaCl has 342 mmol/L, 0.9%
NaCl has 154 mmol/L. Total body water is estimated to be 60% of
total body weight in adult men, 50% of total body weight in adult
women, 50% of total body weight in elderly men, 45% of total body
weight in elderly women, 60% of total body weight in children.
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 Chapter 19: Management of Cerebral Salt-Wasting Syndrome

Table 19.1 Common hyponatremia therapies

Treatment Mechanism Typical dose range Cautions

of action
Hypertonic fluids, Direct salt 2–3% NaCl 150–500 mL IV Hypertonic saline can cause phlebitis,
usually NaCl augmentation bolus over 20 min hyperchloremic acidosis and volume overload
Can use admixture of NaCl and 2–3% NaCl 0.25–1 mL/kg/h 3% NaCl should be administered via central line
NaHCO3 (50%/50% or 75%/25%) 23.4% 30–60 mL IV bolus 23.4% saline must be administered via central line
if hyperchloremia develops over 20 min
NaCl tablets Direct salt 1–2 g po/NGT q 6–8 h Can cause nausea
augmentation
Fludrocortisone Renal salt 0.1–0.2 mg po/NGT q 12 h Can cause volume overload
retention
Conivaptan Vasopressin 20 or 40 mg IV bolus Can cause phlebitis
receptor Q 24–48 h as needed to
antagonist meet sodium goal
Tolvaptan Vasopressin 15– 30 mg po QD (can be
receptor given daily)
antagonist

Table 19.2 Hyponatremia treatment principles
• Choose a goal sodium level, based on current sodium level,
symptoms of hyponatremia and whether hyponatremia is
acute (developed within 48 h) or chronic (developed more
than 48 h ago)
• For serious signs and symptoms, consider initial goal increase
of 5 mmol/L
• Goal should not exceed 10–12 mmol/L in a 24-hour period or
18 mmol/L in a 48-hour period
• Decide how quickly this level should be achieved
• Choose a goal fluid status (usually euvolemia)
• Monitor serum sodium q 4–6 h and adjust sodium therapies
(hypertonic saline, salt tablets, maintenance IV fluids,
fludrocortisone) based on patient response
• Monitor input and output closely, adjust fluid and
medications as necessary to maintain fluid balance goal
• If sodium goal is exceeded, stop active treatment for
hyponatremia
• If goal is exceeded by more than 10–12 mmol/L in a 24-hour
period or more than 18 mmol/L in a 48-hour period and the
patient is at risk of osmotic demyelination syndrome, consider
lowering sodium to within goal range
This formula may be used, for example, to estimate that in
a 70 kg adult man, 1 L of 3% saline would theoretically increase
serum sodium by approximately 8.69 mmol/L. This formula
does not take any ongoing sodium or fluid losses into account,
so fluid amounts administered should be adjusted based on the
patient’s response to the infusion [5].
When attempting to remove free water to increase the
relative concentration of sodium, it is important to take steps
to keep neurocritical care patients in a euvolemic fluid balance.
Again, fluid restriction is not recommended, especially if there
is any possibility that the patient has CSWS [2,39]. One poten-
tial treatment strategy is to use vasopressin receptor antagon-
ists (VRAs), such as conivaptan and tolvaptan. VRA
administration requires a significant amount of monitoring
and thought in the neurocritical care population [18]. Indu-
cing a negative fluid balance might compromise cerebral per-
fusion pressure, therefore intravascular volume must be
maintained [21]. Any suspicion, however remote, of CSWS
or hypovolemia should be considered a strict contraindication
to VRA use [38,40]. Prior to administration, one must decide
what the sodium goal is, the time frame over which the goal
sodium should be achieved, and the fluid balance goal (gener-
ally euvolemia). Once the VRA is administered, sodium levels
and I/O balance must be carefully monitored. A developing
negative fluid balance, usually clinically evident by a large
amount of urine output, can herald an impending overcorrec-
tion of sodium [38] and fluid replacement to maintain euvo-
lemia can help prevent any neurologic consequences of sodium
correction.
Timing of correction should be incorporated into all treat-
ment strategies. Serum sodium concentration should be cor-
rected at a rate of no more than 10–12 mmol/L over 24 hours
and no more than a total of 18 mmol/L over 48 hours. Serious
signs and symptoms such as seizure and coma usually improve
after a 3–7 mmol/L correction [5]. If the sodium is corrected
too rapidly, ODS, which is very difficult to treat and potentially
fatal, can develop. Therefore, prevention of ODS is of utmost
importance. Symptoms include para- or quadraparesis, dysar-
thria, confusion, and coma. Bilateral pontine ODS can lead to
locked-in syndrome [29]. Patients at higher risk for ODS
include those with chronic hyponatremia (<48 h), sodium
concentration less than 105 mmol/L, hypokalemia, alcoholism,

242

malnutrition, and advanced liver disease [18]. Some authors
propose that if the maximum recommended rates of correc-
tion are exceeded, then sodium lowering should commence to
re-establish a 10–12 mmol/L within 24 hour and 18 mmol/48
hour maximum. Sometimes, sodium relowering can be
achieved by discontinuation of active treatment. However,
administration of electrolyte-free water and even intravenous
desmopressin administration should be considered in high-
risk patients [4].
When initiating treatment, the most important factors to
evaluate are the presence of serious signs and symptoms, and
whether the hyponatremia is acute (developed within the last
48 hours) or chronic (developed more than 48 hours ago). If
the hyponatremia is chronic and no serious signs or symptoms
are present, it is generally recommended to correct sodium no
more than 0.5–1 mmol/L/h, and the maximum limits stated
above should be strictly adhered to since there is a higher risk
of ODS. If the hyponatremia is acute, there is less risk for ODS,
and the sodium can be corrected at a faster hourly rate, with
the goal of staying within the maximum recommended limits
of 10–12 mmol/L in 24 hours and 18 mmol/L in 48 hours. If
serious signs or symptoms are present, then the sodium needs
to be increased more quickly initially [4].
No strong evidence exists to establish the risks and benefits
of urea, demeclocycline, lithium, mannitol, loop diuretics,
phenytoin, or fluid restriction. A recent clinical practice guide-
line recommends against demeclocycline due to the risk of
acute kidney injury [4].
Specific Treatment of CSWS
It is important to correct volume depletion in patients with
CSWS (Table 19.3). Repleting fluids with isotonic saline will
add back salt and water, but with a large amount of chloride.
This may result in impairment in renal function and hyper-
chloremic metabolic acidosis. A “balanced” crystalloid solution
might be preferable, but there is no published research to
support this [4]. Some examples of balanced crystalloids
include admixtures of sodium chloride and sodium bicarbon-
ate, at 50%/50% or 75%/25% admixtures [41]. Restore
Table 19.3 Key treatment points for neurocritical care patients with CSWS
• Replete intravascular volume with NaCl (or NaCl/NaHCO3
admixture) at a rate of 0.5–1 mL/kg/h
• Consider fludrocortisone 0.1–0.2 mg po/NGT q 12 h
• Consider salt tablets 1–2 gm po/NGT q 6–8 h
• Closely monitor sodium (q 4–6 h) and assure that sodium is
not corrected more than 10–12 mmol/L in 24 hours or more
than 18 mmol/L in a 48-hour period
• Do not consider fluid restriction or vasopressin receptor
antagonists
• 3% saline bolus (ex. 150 mL over 20 min) or infusion (0.5–1
mL/kg/h) for serious signs or symptoms of hyponatremia
Chapter 19: Management of Cerebral Salt-Wasting Syndrome
extracellular volume in patients with CSWS with 0.9% saline
or balanced crystalloid at 0.5–1.0 mL/kg/h [4] until patients are
clinically euvolemic, including stabilization of blood pressure
[18]. If the patient is hemodynamically unstable, the need for
fluid resuscitation should be considered a priority over the risk
of overly rapid correction of sodium concentration [4]. Salt tablets
and hypertonic saline may be used to restore overall sodium
content [4,13,18]. Fludrocortisone can be used to promote reten-
tion of both sodium and fluid [38]. Neither fluid restriction [39]
nor vasopressin receptor antagonists should be implemented [38].
CSWS is usually transient; as it tends to resolve in 3–4 weeks,
long-term treatment will likely not be necessary [26].
Specific Treatment of SIAD
Traditional treatment of SIAD is fluid restriction [6,8]. How-
ever, as previously stated, fluid restriction is not usually rec-
ommended in the neurocritical care unit. In addition to the
concern for compromised cerebral perfusion pressure, it is
very hard to achieve effective fluid restriction (500 mL/day
below urine output) [18], because of the need for intravenous
medications such as antibiotics and electrolyte repletion solu-
tions that are commonly used in the intensive care unit. Fur-
thermore, stringent fluid restriction will typically only lead to an
increase in sodium of about 1.5 mmol/L per day, which is
impractical for the needs of most neurocritical care patients [6].
Acute symptomatic hyponatremia is best corrected with
hypertonic saline either as bolus or infusion (Table 19.4).
A rough estimate for the infusion rate of 3% saline is to
multiply the patient’s body weight by the desired hourly
increase in sodium. For example, if the goal in a 70 kg patient
is to increase serum sodium by 0.5 mmol/L/h, the infusion rate
of 3% saline should be 35 mL/h. If the goal is 1 mmol/L/h
increase, the infusion rate should be 70 mL/h. After this initial
estimate, the infusion rate will need to be adjusted based on the
patient’s actual response to 3% saline infusion [18].
Table 19.4 Key treatment points for neurocritical care patients with SIAD
Do not fluid restrict
•
• Maintain clinical euvolemia, especially in patients with risk for
diminished cerebral perfusion pressure
• Consider fludrocortisone 0.1–0.2 mg po/NGT 12 h
• Closely monitor sodium (q 4–6 h) to help prevent sodium
correction of more than 10–12 mmol/L in 24 hours or more
than 18 mmol/L in 48 hours
• 3% saline bolus (ex. 150 mL over 20 min) or infusion
(0.5–1 mL/kg/h) for serious signs or symptoms of
hyponatremia
• Consider salt tablets 1–2 g po/per NGT q 6–8 h
• Vasopressin receptor antagonists such as conivaptan
(20–40 mg IV, repeat q 24–48 h if needed) and tolvaptan
(15–30 mg po, daily if needed) have been used in
neurocritical care patients with SIAD
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 Chapter 19: Management of Cerebral Salt-Wasting Syndrome
The response to hypertonic saline may dissipate over time.
Similarly, isotonic saline may transiently increase serum
sodium [6,29]. However, the underlying pathophysiology of
SIAD is that of water excess, not sodium deficit since aldoster-
one is usually unaffected. If isotonic saline is infused, water will
be retained and sodium will be excreted in the urine,
worsening hyponatremia [5,29]. Fludrocortisone may reduce
this natriuretic effect and help maintain sodium levels [22]. It
is not uncommon that patients are administered salt tablets in
response to hyponatremia [6]. Even if oral or intravenous
supplementation of salt does increase serum sodium levels,
the underlying pathophysiology of excess AVP is not being
addressed in these treatment strategies [22].
Vasopressin receptor antagonists are an attractive therapy
for clinicians who wish to address the underlying mechanisms
of SIAD [38]. When considering VRAs such as conivaptan or
tolvaptan, it is important to remember that these should not be
used in hypovolemic patients. Severe symptomatic hyponatre-
mia should be treated with hypertonic saline (such as 3% saline
bolus or infusion) because sodium increase will happen more
quickly. After VRA administration, close monitoring of I/O
balance will help guide the need for fluid replacement to avoid
hypovolemia. Serum sodium levels should be checked at least
every four to six hours. If overcorrection of sodium occurs, do
not give any further VRA doses and consider relowering
sodium so that it falls within recommended limits. Concerns
about VRAs include safety risks (specifically overcorrection of
sodium), lack of proven clinical benefit to sodium lowering
[18], and cost. Recent European consensus guidelines do not
recommend the use of VRAs based on the relative risk–benefit
ratio. Nor do these guidelines recommend lithium or deme-
clocycline to treat hyponatremia in the setting of SIAD [4].
Special Patient Populations
Subarachnoid Hemorrhage
Subarachnoid hemorrhage (SAH) patients have a high inci-
dence of hyponatremia and volume contraction. Most studies
report an incidence of hyponatremia of 30–50% [36,42], but
incidence rates as high as 80% have been reported. Hypo-
natremia can be due to SIAD, CSWS [43], both SIAD and
CSWS [36], or other factors can contribute. As in other disease
states, the only way to differentiate SIAD from CSWS is by
volume status. Assessing volume status may be especially diffi-
cult in SAH patients due to IV fluid administration and other
drugs that alter clinical parameters and laboratory measure-
ments [43]. The relative incidence of SIAD compared to CSWS
is heavily debated. Most authors feel that SIAD is far more
common than CSWS, with the former being the underlying
cause of low sodium in 70% of hyponatremic SAH patients [1].
One study of 326 SAH patients with hyponatremia attributed
SIAD to 69% of cases and CSWS to 6.5% of cases [44].
SAH patients generally have elevated baseline BNP levels
but normal ANP levels compared with healthy individuals.
244
This aspect of SAH contributes to the growing sense that BNP
may be the primary natriuretic peptide that causes CSWS. Urine
output and urinary excretion of sodium are greater in SAH
patients compared to craniotomy patients and healthy controls;
aldosterone levels are lower in SAH patients [26].
Causes of hyponatremia should be investigated in SAH
patients, but those who are in the time window for vasospasm
risk and have a high urine output should be treated as if they
have CSWS. Typically, this would include volume repletion to
maintain euvolemia and a combination of hypertonic saline and
fludrocortisone to address hyponatremia [43]. Of note, nimodi-
pine can worsen hyponatremia by activating release of atrial
natriuretic peptide and inhibition of aldosterone. Additionally,
a normal response to norepinephrine (often given to maintain
CPP or induce hypertension as part of vasospasm treatment in
SAH) is pressure-diuresis and natriuresis in response to
increased mean arterial pressure. This may counterproductively
cause a decrease in blood volume and serum sodium concen-
tration (inducing hypovolemic hyponatremia) [22]. When SIAD
and CSWS coexist in the same patient, excessive urinary output
with simultaneous free water retention can occur [14,36].
Endocrinology and nephrology literature may recommend
fluid restriction for euvolemic hyponatremia [43], but this is
not appropriate in SAH patients [14]. Rather, patients tend to
get generous amounts of isotonic and hypertonic fluids to
maintain CPP and prevent cerebral vasospasm [43]. The treat-
ment target should be euvolemia, and prophylactic hypervole-
mia should be avoided. Isotonic crystalloid is the preferred
agent for volume replacement. Fludrocortisone or hydrocorti-
sone should be considered in patients with a persistent nega-
tive fluid balance and as early treatment for hyponatremia to
limit natriuresis. Sodium concentrations should be carefully
monitored to prevent or avoid hyponatremia. If sodium con-
centration is below 135 mmol/L or if neurologic deterioration
is attributed to falling serum sodium concentration, hyper-
tonic saline solutions can be used to correct hyponatremia. If
vasopressin receptor antagonists are used to treat hyponatre-
mia, extreme caution must be used to avoid hypovolemia [14].
A recent study reports that hyponatremia is not associated
with poor outcome in most patents with aneurysmal SAH, but
an association with cerebral infarction was found in patients
with late-onset hyponatremia (defined as three days post-
hemorrhage) in patients with a poor clinical grade [45]. Prog-
nosis of SAH patients with hyponatremia may be improving in
the era of aggressive fluid administration [14]. Overall treat-
ment goals should focus on maintaining normal volume status
and normal sodium concentration [3].
Traumatic Brain Injury
Sodium dysregulation is common in patients who have
suffered traumatic brain injury (TBI). The incidence of dia-
betes insipidus is approximately 26% and the incidence of
SIAD is as high as 33%. DI and SIAD may occur in the same
patient over his or her clinical course, manifested as a triphasic
response (DI followed by SIAD and then a return to DI) [43].
 Chapter 19: Management of Cerebral Salt-Wasting Syndrome

The mean incidence of hyponatremia in one study was 27.7%, Conclusions

with a mean duration of 1.78 days. CVP readings in this study
Hyponatremia is common in the neurocritical care unit, yet
indicated that of nine patients, five had SIAD and three had
poorly tolerated by this patient population. Two leading causes
CSWS; the remaining patient could not be determined because
of hyponatremia are CSWS and SIAD. It can be difficult to
CVP offered inconclusive information [35]. Another cause of
distinguish between these two clinical entities, and differenti-
hyponatremia to consider after TBI is adrenal insufficiency,
ation generally depends on volume status, since CSWS causes
since as many as 50% of patients have at least transient adrenal
hypovolemic hyponatremia (likely due to circulating natriure-
insufficiency. Studies have not shown benefit with empiric
tic peptides such as BNP) and SIAD causes a euvolemic hypo-
treatment of adrenal insufficiency [43], and one large random-
natremia (due to elevated levels of AVP). In the neurocritical
ized placebo-controlled trial of empiric hydrocortisone showed
care unit, CSWS and SIAD patients are often treated to main-
an increased risk of death [46]. Hyponatremia does not seem
tain normal sodium levels and normal intravascular volume.
to correlate with Glasgow Coma Score on admission. With
Preventing hyponatremia in the neurocritical care population
prompt identification and treatment, hyponatremia need not
is an important part of overall supportive measures.
confer additional morbidity [35].

Neuroendocrine control of body 19. Stelfox HT, Ahmed SB, Khandwala F,

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 Chapter
Brain Death in the Neurocritical Care Unit

20 Mark M. Landreneau and David M. Greer

History The Harvard Report had profound influence on the wide-

spread adoption of brain death as an accepted medical defin-
The concept of brain death presupposes the viability of the
ition. By 1981, a Presidential commission [8] was formed to
body in the absence of brain and brainstem function. Until the
define death, and led to the United States legal system recog-
invention of effective positive pressure mechanical ventilation
nizing brain death as equivalent to death of the person under
by Bjorn Ibsen in the mid-twentieth century, brain death – as
the Uniform Determination of Death Act (UDDA) [9]. How-
distinguished from mere coma – was not conceivable in broad
ever, practices for the determination of brain death remained
understanding. Circulatory arrest had long been the sole cri-
and still remain heterogeneous on the state and local levels [10].
terion of death, but medical scientists at the turn of the twen-
The American Academy of Neurology (AAN) has made valiant
tieth century, such as Horsley [1], Duckworth [2], and Cushing
strides to counteract less rigorous or conflicting practices, first
[3], observed in cases of severe neurological injury the cessa-
forming a committee in 1995 and more recently in 2010 [11], in
tion of respiration prior to circulatory arrest. Apnea in some of
order to promulgate strict, consistent, and evidence-based cri-
these cases was reversible if the brain was decompressed or the
teria for the determination of death by brain criteria.
offending injury removed. The idea began to form that the
The importance of brain death as an ontological and legal
brain could die prior to cardiac arrest, but until the advent of
definition of death cannot be overstated. In an era of wide-
mechanical ventilation, death remained defined as the moment
spread and sophisticated critical care technology, the preserva-
the heart permanently stopped functioning [4].
tion of the systemic organs for several days to weeks after brain
As the implementation of positive pressure mechanical
death is not only conceivable, but in some cases easily practic-
ventilation disseminated in the 1950s, neurologists became
able if resources are mobilized to this end. Mechanical ventila-
aware of a new phenomenon, described by Wertheimer as
tion, renal replacement therapy, extracorporeal membrane
“death of the nervous system” [5] and by Mollaret and Goulon
oxygenation (ECMO), and transfusions can replace or supple-
as “coma dépassé” [6], a state of irreversible coma and apnea
ment almost any organ to maintain homeostasis with absent
that occurred to catastrophically brain-injured patients on ven-
brain function. In such situations, the strain on families, prac-
tilators. Mollaret and Goulon went as far as to suggest mechan-
titioners, and finite medical resources can be intense. Further-
ical ventilation should be stopped in these cases due to futility,
more, brain-dead donors are a common source of organs for
but no broadly codified practice emerged at the time. Further-
donation. However, it should be emphasized that brain death
more, diagnostic practices remained determined by institu-
determination is a medical diagnosis, entirely separate from
tions, if not individualized by practitioners. In the United
organ donation.
States, it was not until 1968 when the Ad Hoc Committee of
As mentioned above, United States law, the American
Harvard Medical School established seven criteria for irrevers-
Medical Association (AMA), and the AAN recognize brain
ible coma or brain death, as seen in Table 20.1 [7].
death as a form of death, completely equivalent to circulatory
death. Some ultraconservative critics of this formulation argue
Table 20.1 Harvard criteria for brain death (1968)
for a vitalist interpretation of organ function, namely that the
1. Unresponsive coma brain has no special privilege as an organ, using as support a
2. Apnea number of cases in which a body was sustained for many
3. Absence of cephalic reflexes months after being declared brain dead [12]. Nonetheless, the
opinion that death is exclusively circulatory death is held by a
4. Absence of spinal reflexes (this has since been noted to be small minority and has not had significant influence on public
allowable in brain death)
policy. Ironically, in the era of successful resuscitation after
5. Isoelectric electroencephalogram prolonged cardiac arrest with aids such as therapeutic hypo-
6. Persistence of conditions for at least 24 hours thermia, there exists more disagreement about the moment of
circulatory death than brain death. In fact, the definition of
7. Absence of drug intoxication
brain death has been considered by some to be a highly

247
 Chapter 20: Brain Death
conservative position [13] because brain death represents the
point at which the brain irreversibly ceases to function rather
than in a more fluid definition, the point at which an inevitable
process of death has begun.
Definition
The UDDA outlines a concise definition of brain death,
namely, the irreversible “cessation of all functions of the entire
brain, including the brain stem.” As mentioned above, brain-
stem death remains a controversial issue and is not included in
these criteria, even though it has been accepted as equating to
brain death in the United Kingdom [14]. In the United States,
the authoritative definition of brain death in adults is provided
by the 2010 AAN evidence-based guidelines [11]. These clinical
criteria for establishing brain death are found in Table 20.2.
Clinical Evaluation
Etiology of Injury
The most important initial step in the evaluation of brain death is
a careful and exacting history. The cause of brain injury must be a
known irreversible structural lesion or metabolic disease. Con-
founding variables are present in many cases (e.g. traumatic brain
injury in the setting of depressant drug use), and can obscure the
diagnosis. Therefore, it is imperative that all potentially reversible
metabolic or structural causes be assiduously investigated. In
adults, the most common causes of brain death [15] include:
traumatic brain injury, aneurysmal subarachnoid hemorrhage,
intracerebral hemorrhage, ischemic stroke with cerebral edema
and herniation, hypoxic-ischemic encephalopathy, and fulmin-
ant hepatic encephalopathy with cerebral edema.
Table 20.2 AAN criteria for brain death
1. Coma of sufficient and established cause. Coma is defined as a
state of unresponsiveness in which the patient lies with his or
her eyes closed and cannot be aroused, even if vigorous and
noxious stimulation are applied. Coma must be secondary to
irreversible structural disease or irreversible metabolic disease.
There can be no potentially confounding variables such as
hypothermia, toxins, sedating medications, or reversible
metabolic disorders
2. Absence of motor response
3. Absence of corneal reflexes
4. Absence of pupillary responses to light
5. Absence of oculocephalic reflexes
6. Absence of oculovestibular reflexes with caloric testing
7. Absence of gag reflex
8. Absence of cough reflex
9. Absence of sucking and rooting reflexes
10. Absence of respiratory drive at a PaCO2 of 60 mmHg or
20 mmHg above baseline
248
Drugs and Toxins
A thorough drug and toxicology screen should be performed
on every patient with possible exposures, and this includes
without exception all patients who arrive from outside the
hospital. Hospitalized patients should generally not be
excluded, as they may have been administered medications or
toxins by staff, family, or even themselves, some of which may
not appear in the medical record. There should be a time lapse
of at least five half-lives from the administration of any poten-
tial psychoactive medications or toxins, noting that hypother-
mia, renal impairment, and hepatic impairment can greatly
prolong the half-life of many drugs. There should also be no
recent administration of paralytics, which can be proven by a
train of four twitches with maximal ulnar nerve stimulation.
Metabolic Derangements
Confounding metabolic causes should be accounted for as well.
There should be no severe electrolyte abnormalities, acid–base
disturbances, or endocrine abnormalities. Laboratory values
markedly deviated from the norm should be corrected. Con-
founding medical illnesses, such as hyperammonemia and
severe acidemia, are common in patients who progress to brain
death, and must be corrected before diagnosis.
Temperature
Many patients require warming to achieve and maintain nor-
mothermia (>36 °C) .
Blood Pressure
Hypotension occurs commonly in brain death due to loss of
vascular tone and volume depletion from diabetes insipidus.
The systolic blood pressure must be equal to or greater than
100 mmHg, and if the systolic blood pressure falls to less than
90 mmHg during apnea testing, the test must be aborted (see
below).
Neurological Examination
There must be at least one neurological examination at the
appropriate time interval. Some states and hospitals require
two examinations. Any physician is qualified to perform
a brain death evaluation, but the declaring clinician should
be intimately familiar with the brain death criteria. He
or she should have demonstrated competence in the detailed
neurological examination and brain death determination.
Some states and institutions require the examiner to
have specific expertise as a neurologist, neurosurgeon, or
intensivist.
Coma
The patient should be completely unresponsive to all stimula-
tion, including noxious stimulation, and the eyes should

remain closed with no grimacing observed. Noxious stimula-
tion can be applied with a cotton wisp to the nares, a cotton-
tipped applicator inserted into the nasopharynx, supraorbital
ridge pressure, and temporomandibular joint pressure at the
level of the condyles. Spinally mediated reflexes are allowed
and will be discussed in the motor examination below.
Brainstem Reflexes
Pupillary Light Response
A bright light should be directed at each eye separately with no
pupillary response. A magnifying glass can be helpful to detect
subtle pupillary constriction. Typically, the eyes are mid-
position and the pupils midsize (4–9 mm). Early in the course
of injury, sympathetic activation can cause pupils to be dilated,
and very rarely, unusual pupillary movements, such as slowly
fluctuating pupil size, independent of light or other stimula-
tion, have been observed in an otherwise brain-dead patient
[16]. Small, miotic pupils should alert the clinician to the
possible influence of drug intoxication (e.g. narcotics).
Oculocephalic Reflex
After ensuring that there is no cervical spine injury/instability,
the oculocephalic reflex can be tested by rapidly rotating the
head in a horizontal plane and, in a separate movement, verti-
cally by flexing and extending the neck in the mid-position.
The eyes should not move within the orbits relative to head
movement.
Oculovestibular Reflex
The external auditory canal should be inspected first to ensure
there is no obstruction and the tympanum is intact. With the
head elevated to 30°, one ear at time should be irrigated with
approximately 50 mL of ice water (0 °C) and the eyes observed
for one minute. An intact reflex demonstrates tonic deviation
of the eyes toward the side of cold water administration;
however, in brain death there should be no eye movements
whatsoever. The contralateral ear should be tested after at least
a five-minute interval. Pen marks on the inferior eyelid at the
level of the pupil can be helpful as a reference point.
Corneal Reflex
A cotton tip applicator should be applied to edge of the iris
for maximal stimulation. No eyelid movement should be
observed.
Gag and Cough Reflex
A gag reflex can be tested with a tongue depressor or suction
device applied to posterior oropharynx. Deep bronchial suc-
tioning to the level of the carina should be performed one to
two times.
Other Reflexes
Jaw jerk and cutaneous frontal release reflexes, such as the
snout and root reflexes, must be absent.
Chapter 20: Brain Death
Motor Response
There must be no spontaneous or responsive motor activity.
Noxious stimulation should be applied to all four limbs in
multiple places on each limb. Spinally mediated reflexes are
still consistent with brain death, and may appear in a variety of
unusual forms. Occasionally, spontaneous movements in
coordination with ventilation appear, as do stepping move-
ments, and lower body reflexes [17–19]. One unusual group of
movements, the “Lazarus sign,” can involve slow flexion at the
waist to a sitting position, head turning, neck flexion, back
arching, and arm flexion across the body, and are spinally
mediated. Interestingly, extensor plantar responses of the foot
are not found in brain-dead patients [20]. Mittal and col-
leagues [21] have identified a list of characteristics of move-
ments after brain death that can help distinguish spinal from
postural responses, which are found in Table 20.3.
Apnea Testing
Apnea testing determines the absence of respiratory drive in
response to a CO2 and acidemic challenge. Prior to the test, the
patient must have normothermia, euvolemia, and normoten-
sion, defined as systolic blood pressure greater than or equal to
100 mmHg. The test must be aborted if the blood pressure
drops below 90 mmHg. The patient cannot be hypoxic, and
there can be no acute hypercapnia. In patients with chronic
obstructive pulmonary disease, they must show laboratory signs
of metabolic compensation, and the baseline PCO2 should be
known; otherwise, the target PCO2 value is uncertain.
Table 20.3 Distinguishing characteristics of spinal reflexes
1. There is no resemblance of a spinal response to the classic
postural motor responses. These responses are recognized by
synchronized decorticate (thumb folded under flexed fingers in
a fist, pronated forearm, flexed elbow, and extended lower
extremity with inverted foot) or decerebrate responses
(pronated and extended upper and lower extremity)
2. Most often, the spinal responses are slow and short in duration.
However, there can be some exceptions as follows: finger
flexion can be seen as quick jerks with minimal excursions and
lower extremity responses are often more complex and can be
wavy or shock-like
3. The most common spinal response is triple flexion response
(flexion in foot, knee, and hip) that may have variations such as
an undulating toe sign or a Babinski sign
4. Most movements are provoked and not spontaneous. The
provocation can be movement during nursing care of the
patient, such as turning or transfer from the bed to a
transport cart
5. In some patients, spinal reflexes can be elicited by forceful neck
flexion and by noxious stimuli below the cervico-medullary
junction. They are not seen with pressure at the supraorbital
ridge or temporomandibular joint
249
 Chapter 20: Brain Death
The steps for the apnea test are as follows:
1. Preoxygenate for at least 10 minutes with 100% oxygen to a
PaO2 >200 mmHg
2. Reduce the minute ventilation to establish eucapnia
3. Positive end expiratory pressure (PEEP) should be set to
5 cmH2O. If the patient develops hypoxia with this maneuver,
this suggests there may be difficulty with apnea testing
4. If oxygen saturation remains above 95%, obtain a baseline
arterial blood gas
5. Disconnect the patient from the ventilator. Automated
ventilators can falsely trigger breaths, particularly when
chest wall pressure is affected by chest tubes
6. Maintain oxygenation with continuous delivery of 100% at
6 L/min via a catheter at the level of the carina
7. Observe closely for respiratory excursions of the chest wall
or abdomen for 8–10 minutes, while closely monitoring
systolic blood pressure and oxygenation. The test must be
aborted if systolic blood pressure decreases below
90 mmHg or if the oxygen saturation decreases below 85%
for greater than 30 seconds.
8. If no respiratory excursions are observed, repeat an arterial
blood gas. If the PaCO2 is greater than 60 mmHg, or
greater than 20 mmHg above the known baseline for a
known CO2 retainer, the apnea test is positive and supports
a diagnosis of brain death. If inconclusive, the test can be
repeated (after correction of hypercarbia and acidosis and
again preoxygenating the patient) with a longer interval
between blood gases, even 10–15 minutes, as long as the
systolic blood pressure and oxygen saturation remain
within protocol parameters.
Ancillary Testing
An unequivocal clinical examination is sufficient to diagnose
brain death and is accepted as standard practice in the United
States. Ancillary testing is not required in most hospital policies,
and it should be kept in mind that some ancillary tests carry a
false positive and/or negative rate in certain circumstances.
However, situations may arise in which ancillary testing may
be essential for diagnosis, such as in patients with severe head
trauma, in whom certain aspects of the clinical examination
cannot be performed, or patients with severe pulmonary disease
or hemodynamic instability, in whom apnea testing may not be
performed safely. Furthermore, some countries in Europe, Cen-
tral and South America, as well as Asia, require confirmatory
testing by law. Ancillary modalities available today include
conventional angiography, electroencephalography (EEG), tran-
scranial Doppler sonography (TCD), and cerebral scintigraphy.
Computed tomography angiography (CTA) and magnetic res-
onance angiography (MRA) are not validated (see below).
Angiography
Two mechanisms may lead to the absence of cerebral blood
flow in brain death. Severe increases in intracranial pressure,
250
such as in subarachnoid hemorrhage, may lead to equilibration
of the intracranial pressure and arterial perfusion pressure,
arresting cerebral perfusion. Another mechanism is wide-
spread perivascular cytotoxic edema that compresses capillary
beds, at which point the systolic blood pressure may not be
sufficient for anterograde flow into the cerebrovascular tree
[22]. Angiography may be particularly helpful when the cause
of injury is not known, as the complete absence of cerebral
blood flow establishes sufficient cause for brain death.
Conventional Angiography
Cerebral angiography can be effective at demonstrating the
absence of intracranial blood flow. Contrast should be injected
under high pressure in both anterior and posterior cerebral
circulations. There should be no intravascular filling at the
level of intracranial entry for the vertebral and carotid arteries
[23]. However, the external carotid arteries should be patent so
as to indicate effective contrast delivery. Although conven-
tional angiography is a widely accepted ancillary test, it is
invasive and iodinated contrast material can cause end-organ
dysfunction, which can be a relevant consideration for possible
organ donation.
Computed Tomography Angiography
CTA has the advantage of being rapid and noninvasive com-
pared to conventional angiography. However, it lacks the sen-
sitivity and specificity as yet to be used as a reliable method for
confirming brain death. An investigation of 30 patients by
Combes et al. [24] showed a 30% false-negative rate compared
to conventional angiography, which are similar to rates seen in
other case series [25]. Greer et al. [26] have shown that false
positives can occur as well, most likely due to hemodynamic
instability and failure of adequate delivery of contrast to the
arterial circulation. In light of these findings, CTA is not a
validated test for determination of brain death.
Magnetic Resonance Angiography
Like CTA, MRA is a noninvasive test, and with the advent of
MRI compatible ventilators, it is becoming a more utilizable
modality. However, it suffers from poor reliability, even com-
pared to CTA. MRA may fail to show slow flow in cerebral
vasculature, even when extracranial vessels are demonstrably
patent [27]. There have been no randomized trials comparing
MRA to accepted ancillary tests, and its use in brain death
determination cannot be recommended.
Transcranial Doppler Ultrasound (TCD)
Intracranial arterial flow can also be investigated by Doppler
insonation. A 2 MHz pulsed Doppler ultrasonograph can be
used to insonate the middle cerebral arteries via a temporal
window, although anatomical variations render this window
unusable in a small percentage of patients. The posterior
circulation can be insonated via a suboccipital window. Two
signal characteristics are indicative of brain death:

1. A systolic spike pattern that shows small systolic peaks very
early in systole, indicative of high resistance due to the
intracranial pressure being greater than the systolic blood
pressure. In this case, there is an absence of diastolic or
reverberating flow.
2. Oscillating flow: equal forward and reverse flow indicates
no net forward flow. This is seen when the intracranial
pressure equals or exceeds the systolic blood pressure.
The reliability of TCD depends greatly on the equipment and
operator, but the sensitivity is 90–99%. Because of the risk of
false positives, the absence of flow signal in any circulation
cannot be used on its own as a diagnosis of cerebral circula-
tory arrest. However, if a systolic spike pattern or oscillating
flow is clearly demonstrated in the anterior and posterior
circulation, the specificity for brain death approaches 100%
[28,29].
Cerebral Scintigraphy
99m Tc-hexamethyl-propylamineoxime single photon emis-
sion tomography (HMPAO SPECT) is a noninvasive tech-
nique that measures the cerebral uptake of a radioisotope by
brain parenchyma and is highly specific for brain death.
A portable gamma camera can allow this test to be performed
at the bedside to take static images 30, 60, and 120 minutes
after injection of the radiotracer. In a prospective comparison
[30] with the invasive gold standard, conventional angiog-
raphy, 100% of patients with an “empty skull” pattern on
SPECT also had cerebral circulatory arrest on conventional
angiography. Although the “empty skull” pattern is highly
specific for brain death, its sensitivity lags behind the clinical
diagnosis of brain death, making it more of a useful test in
difficult cases. The Society of Nuclear Medicine has published
detailed procedural guidelines for the application of scintig-
raphy in brain death [31].
Electroencephalography
There is a long history of the use of EEG as an aid to the
determination of brain death, and there are consensus criteria
for its application. Prerequisites to testing include normother-
mia and the absence of toxic-metabolic encephalopathy. The
EEG must be set up with the following parameters [32]:
1. A minimum of eight scalp electrodes
2. Interelectrode impedance should be between 100 and
10,000 Ω
3. The integrity of the recording system should be tested by
deliberate creation of electrode artifact
4. There should be at least 10 cm between each electrode
5. The sensitivity should be increased to at least 2 μV for
30 minutes with the inclusion of appropriate calibrations
6. The high frequency filter should not be set below 30 Hz,
and the low frequency filter should not be set above 1 Hz
7. There should be a demonstrable lack of reactivity to intense
stimulation with pain, loud noises, and light.
Chapter 20: Brain Death
Even with rigorous standards of application, the EEG is often
not a reliable method of diagnosing brain death. Patients with
depressant drug intoxication can have isoelectric EEGs, neces-
sitating prolonged monitoring in many cases. Furthermore,
patients with isoelectric EEGs may have intact brainstem func-
tion, including spontaneous breathing, as demonstrated by
Heckman et al. [33] in a postcardiac-arrest patient. In addition
to relatively poor specificity, EEG also can show electrical
activity long after clinical criteria for brain death have been
met. Technical challenges abound as well, as the high sensitiv-
ity required often captures substantial artifact from the
environs of the ICU.
Potential Misdiagnoses
Locked-in syndrome, drug intoxication, and hypothermia can
all be mistaken for brain death. As mentioned above, a careful
and exacting history and examination are essential to avoid
misdiagnosis and potential harm. Clinical signs suggesting a
confounding diagnosis include normal brain imaging, absence
of diabetes insipidus, significant heart rate variation, fever or
shock, myoclonus (lithium and selective seratonin reuptake
inhibitor (SSRI) intoxication) or rigidity (antidopaminergic
or SSRI toxicity).
Locked-in Syndrome
Locked-in syndrome is most commonly due to a destructive
lesion at the base of the pons causing quadriplegia and paraly-
sis of the facial musculature. Blinking and vertical eye move-
ments remain intact. Consciousness remains intact due to
preservation of the reticular activating system and cortex,
and in an otherwise healthy patient, EEG will demonstrate a
reactive pattern with a posterior dominant rhythm. Most com-
monly, locked-in syndrome occurs due to occlusion of the
basilar artery, but pontine hemorrhages, tumors, and demye-
linating lesions can also cause the syndrome.
Acute Inflammatory Demyelinating
Polyneuropathy (Guillain–Barré)
Similar to a locked-in state caused by a pontine lesion, an
inflammatory polyneuropathy affecting all the peripheral and
cranial nerves can cause complete unresponsiveness and the
absence of any discernible brainstem reflexes that can be
mistaken for brain death [34]. A carefully obtained history of
progressive weakness with appropriate diagnostic laboratory
tests and nerve conduction studies can prevent mistaking this
diagnosis for brain death.
Hypothermia
Environmental exposure causing severe hypothermia can
cause the temporary depression of brain and brainstem func-
tion, mimicking brain death. At core temperatures below 32°C,
the pupillary light response is lost, and other brainstem
reflexes are impaired below 28 °C [35]. A brain death
251
 Chapter 20: Brain Death

examination should always be performed at normal body
temperature to avoid this potentially reversible condition.
Drug Intoxication
Perhaps the most common mimic of brain death is drug
intoxication. Central nervous system depressants such as bar-
biturates [36], antidepressants, and analgesics, can suppress
brain and brainstem function. Not only can patients appear
clinically brain dead, but the deep coma induced by these
agents can also correspond to an isoelectric EEG recording.
Paralytic agents [37] can also cause a clinical syndrome mim-
icking brain death, and a peripheral nerve stimulator should be
used to demonstrate a train of four twitches to rule out this
cause. Other clinical signs should urge caution as well. Myo-
clonus suggests possible lithium or SSRI intoxication. Rigidity
can be indicative of antidopaminergic, antipsychotic, or SSRI
toxicity. Prominent miosis may be indicative of opiate or
organophosphate toxicity. As a general principle, an observa-
tion period of five times the half-life of suspected ingestion
should be observed. Once a drug is at a subtherapeutic level,
the clinical evaluation of brain death can occur. If there is a
high clinical suspicion for an untestable drug or metabolite,
the patient should be observed until there is certainty of no
lingering drug effect, or an ancillary test performed.
Organ Donation
As Machado and others [4] have persuasively argued, the
concept of brain death did not emerge or evolve to benefit
organ transplants. Brain death is a medical diagnosis, a legal
definition of death, and is completely independent of organ
donation. Nevertheless, transplants often follow organ retrieval
from brain-dead donors. After brain death has been declared
and the patient has been identified as a potential donor, atten-
tive care must be made for the preservation of organ function,
should the family elect to pursue donation as consistent with
the wishes of the patient. Early involvement of organ procure-
ment organizations can help to guide care through the wide-
spread physiologic changes that occur during the time around
brain death.
Brain death is associated with well-known physiologic fea-
tures [38,39]. In early severe brain injury, catecholamine
release causes severe hypertension and “autonomic storming”
to maintain cerebral perfusion. In some causes, this can lead to
neurogenic pulmonary edema due to the spike in cardiac after-
load. After a significant loss of central nervous systemic auto-
nomic control, hypotension and vasodilation may occur and
will often require treatment with vasopressors. Furthermore,
destruction of the posterior pituitary gland leads to central
diabetes insipidus in up to 90% of brain-dead patients. Because
of the scarcity of transplantable organs and the wide variation
in management, the United Network for Organ Sharing
created a Critical Pathway for the Organ Donor with eight
common donor management goals, including mean airway
pressure, central venous pressure, pH, central venous pressure,
PaO2, sodium, glucose, single vasopressor use, and urine
output. Adherence to these goals was associated with increased
rates of transplantation [40].

7. [No authors listed]. (1968). A definition Subcommittee of the American

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253
 Chapter
Neuroterrorism and Drug Overdose in
21 the Neurocritical Care Unit
John J. Lewin III, Mohit Datta, and Geoffrey S. F. Ling
Introduction
Knowledge of proper clinical management of drug overdose
and chemical and biological toxin exposure is important for
the neurocritical care specialist. Many of the common offend-
ers principally affect the central nervous system (CNS). Even
those that do not will lead to a severely incapacitated state
when overdosed such that the afflicted patient will require
critical care in an intensive care unit (ICU).
Typically, drug overdose that occurs outside of the hospital
is first managed in the emergency department and then, if
critical care is needed, in the medical ICU. However, there
are medications that are used in the neurocritical care unit
(NCCU) that may lead to toxic overdose either through inad-
vertent provider error or because of changes in a patient’s drug
elimination. The most common offending medications are anal-
gesics, antipyretics, mood stabilizers, and sedative hypnotics.
Sadly, there is another circumstance in which the neuro-
intensivist may be called on to treat patients suffering from
toxic overdose: a chemical or biological terrorist act. In this
situation, emergency medicine and medical critical care phys-
icians will be quickly overwhelmed, and it is certain that the
neurocritical care specialist will be called upon to assist. Thus, a
discussion of the clinical management of patients suffering from
exposure to the leading known chemical weapons is warranted.
The opinions presented herein belong solely to those of the
authors. They do not nor do they imply belonging to or endorse-
ment by the Uniformed Services University of the Health Sci-
ences, U.S. Army, Department of Defense, or U.S. Government.
General Management of Drug Overdose
The most common medications leading to overdose are anal-
gesics, antipyretics, sedative hypnotics, anticonvulsants, anticoagu-
lants, antidepressants, bronchodilators, and antiarrhythmics. All
are common medications used in the NCCU.
General clinical management begins with the ABCs:
airway, breathing, and circulation. For patients with com-
promised mental status, adequacy of the airway in terms of
both patency and patient’s ability to protect it must be deter-
mined. If the patient has a Glasgow Coma Scale (GCS) score
<8, then an artificial airway should be placed, such as by
endotracheal intubation. Mechanical ventilation and supple-
mental oxygen in such circumstances is not always needed, but
254
may be if the patient has aspirated. Appropriate hemodynamic
management, consisting of fluid resuscitation, vasopressors,
and/or inotropes may also be required in cases resulting in
myocardial depression and/or vasodilation.
After ensuring the above, the clinician will need to recog-
nize if the patient’s condition is caused by a pharmacologic
agent. The optimal way to identify the offending agent is to
execute a careful and systematic approach beginning with
taking a good history and culminating with laboratory tests.
History and review of systems are especially useful. During
overdose, the patient may not be able to provide details, but
the medical record and witness accounts may be illuminating.
The physical exam may also reveal specific clinical clues such
as pinpoint pupils in narcotic overdose or nystagmus in anti-
convulsant excess. Laboratory testing may provide the critical
evidence, such as metabolic acidosis in aspirin toxicity or
excessive drug levels in barbiturate overdose.
After ascertaining that the patient is suffering from an
overdose, pharmacokinetic-directed interventions should be
initiated. Further drug absorption needs to be abated. Acti-
vated charcoal is the most commonly used agent for this
purpose. Owing to its extensive surface area, activated charcoal
binds many drugs that have not yet been absorbed across the
gastrointestinal tract. Once bound, the charcoal–drug mixture
is excreted fecally. There is also evidence that activated char-
coal interferes with enteroenteric, enterogastric, and entero-
hepatic recirculation of absorbed drug. The most common side
effect is emesis, which has largely been controlled by removing
sorbitol from preparations. It should be noted that rigorous
scientific evidence is lacking that supports activated charcoal
efficacy. In vitro adsorption studies are not always predictive of
the drug’s effects in vivo. Therefore, human studies are neces-
sary to determine efficacy of activated charcoal for any given
drug or chemical [1].
In accordance with recent American Academy of Clinical
Toxicologists and the European Association of Poison Centres
and Clinical Toxicologists (AACT/EAPCCT) guidelines, if the
drug was ingested within one hour, then activated charcoal can
be given. If not, activated charcoal will have minimal impact.
Before treatment, it is critical that airway protection is estab-
lished to minimize aspiration of charcoal or emesis. Once
airway protection is accomplished, activated charcoal can be
administered via a nasogastric tube. The recommended dose

for adults is 25–100 g (1–2 g/kg). Dilute with a minimum of
240 mL of water for each 20–30 g of activated charcoal as an
aqueous slurry. After the initial dose, charcoal can be adminis-
tered every hour, every two hours, or every four hours at doses
equivalent to 12.5 g/h. Activated charcoal should be continued
until relevant laboratory parameters (i.e. drug concentrations)
improve. There is no recommended maximum dose [1,2].
For some agents, elimination may need to be enhanced
through optimizing elimination conditions, such as alkalizing
the urine. Urine alkalinization can be considered when the
drug is a weak acid and is water soluble, such as barbiturates,
salicylates, methotrexate, and lithium. Urinary alkalinization
can be achieved in a number of ways. The suggested clinical
approach is to dilute 150 mEq of sodium bicarbonate in 1 L of
D5W or sterile water. Close monitoring and supplementation
of serum potassium should be performed, so as to minimize
development of hypokalemia. The infusion rate should be two
to four times higher than the usual IV fluid maintenance rate,
which results in 200–400 mL/h for most adults.
The goal urine pH is 7.5–8.5 with additional boluses and/or
adjustments to the infusion rate as needed. Urine pH should be
monitored every 15–30 minutes until the goal urine pH is
achieved, and then every hour thereafter. At the beginning,
baseline serum potassium and other electrolytes, creatinine,
glucose, and arterial pH are needed. Abnormalities should be
corrected. Although reported complications are rare, there is the
potential for causing hypokalemia, hypocalcemia, reduced
oxygen delivery to tissue as the oxyhemoglobin dissociation
curve is shifted to the left, cerebral vasoconstriction, and fluid
overload/pulmonary edema. Every hour thereafter, serum potas-
sium and arterial pH should be checked. Arterial pH should not
exceed 7.50. Urine output should not exceed 200 mL/h [3].
Recreational Drug Abuse and Overdose
Recreational drug abuse continues to be a major health con-
cern all over the world and has reached epic proportions in
certain metropolitan cities in developed countries. Drug abuse
and its associated risk-taking behavior makes this population
especially vulnerable to HIV, hepatitis C, and hepatitis B, and
these comorbidities can make their clinical presentation and
subsequent management particularly challenging. The common
offenders are cocaine, heroin, amphetamines, marijuana, lysergic
acid diethylamide (LSD), 3,4-methylenedioxy methamphetamine
(MDMA), morphine, codeine, various inhalants, and derivatives
of the above-mentioned compounds. A detailed description of all
these agents and their toxicities are beyond the scope of this
chapter; however, we would like to highlight a few points in
reference to cocaine and heroin overdose, and alcohol abuse.
Cocaine
Cocaine is a stimulant derived from the leaves of Erythroxylon
coca. It inhibits presynaptic uptake of excitatory catechol-
amines, dopamine, and norepinephrine. Its euphoric and cen-
tral excitatory effect is mainly due to the accumulation of these
Chapter 21: Neuroterrorism and Drug Overdose
excitatory neurotransmitters and subsequent up-regulation of
their receptors. The neurotoxic and cardiotoxic effects of
cocaine are mostly due to downstream effects of norepineph-
rine, up-regulation of endothelin receptors in vessel walls,
platelet activation and aggregation, and sodium channel block-
ade (responsible for its local anesthetic effect). Patients with an
acute overdose usually present with an acute cerebrovascular
accident or coronary syndrome, or both. The clinical presen-
tation may be that of acute stroke or myocardial infarction
(MI), but often the patient is agitated, confused, or comatose
secondary to the intracranial pathology or due to concomitant
drugs in the system. Pupils are large and the patient is usually
flushed and diaphoretic due to sympathetic overstimulation.
Blood pressure is often very high and not uncommonly the
patient presents with hypertensive urgency/emergency. The
electrocardiogram (ECG) may show changes consistent with
an acute coronary syndrome and/or left ventricular failure.
A prolonged QTc interval is often seen secondary to its sodium
channel blocking effects.
CNS syndromes include ischemic and hemorrhagic stroke.
Etiology for thrombosis may be intracranial dissection second-
ary to uninhibited α-agonist action of norepinephrine, in situ
thrombosis due to platelet activation and platelet-rich thrombi.
Hemorrhagic stroke is usually secondary to elevated blood
pressures or underlying vasculitis due to chronic cocaine use.
Chronic cocaine use is associated with vasculopathy, which
may predispose to the above stroke syndromes. Subarachnoid
hemorrhage is a rare but serious presentation associated with
cocaine use.
Management of these stroke syndromes is essentially the
same as standard American Heart Association guidelines for
acute stroke management. Cocaine use is not a contraindi-
cation for IV tissue plasminogen activator. Management of
known cocaine-associated coronary vasospasm is largely
symptomatic with oxygen, aspirin, and nitroglycerine. Rare
cases may need angioplasty and stenting. If the cardiac enzymes
continue to trend up, the patient should be referred for emer-
gent angiography to rule out coronary thrombus. β-1-specific β-
blockers (e.g. esmolol, metoprolol) are contraindicated in the
acute blood pressure management of cocaine overdose as they
may lead to unopposed α-1 receptor-mediated coronary vaso-
spasm and/or a paradoxical increase in blood pressure.
Coconsumption of alcohol and cocaine (seen in >80%
cocaine abusers) leads to altered cocaine metabolism. Trans-
esterification leads to an active metabolite cocaethylene, which
has similar pharmacodynamic properties to cocaine in the
CNS and acts on the same receptors, thereby potentiating the
stimulant and euphoric effects of cocaine. Cocaethylene has
independent myocardial and CNS toxic effects.
Heroin
Heroin is an opioid, and overdose leads to similar clinical
presentation as outlined in the opioid section of this chapter.
Heroin is chemically the diacetylated form of morphine and
255
 Chapter 21: Neuroterrorism and Drug Overdose

was first synthesized in the late nineteenth century. Bayer
marketed the drug as “Heroin” and ever since then that has
become the common street name for the drug. The acetylated
form of morphine is more lipid-soluble and hence easily
crosses the blood–brain barrier, leading to that instant “rush”
experienced by IV heroin abusers. Heroin is metabolized by
deacetylation and 6-acetyl morphine is the breakdown product
that may be detected in urine and indicates heroin use. Heroin
use can also lead to noncardiogenic pulmonary edema in rare
cases and may require ICU management for ventilator sup-
port. Treatment is largely supportive.
Alcohol
Alcohol is a widely abused drug, and as such patients are
routinely admitted to the NCCU for nonalcohol-related prob-
lems, but are concurrently in various stages of inebriation or
withdrawal.
Alcohol is a sedative hypnotic drug. Like barbiturates, it is a
global depressant. At low doses, inhibitory pathways are sup-
pressed leading to net excitation. At progressively higher doses,
drowsiness to lethargy to stupor and ultimately coma will ensue.
Most inebriated patients can usually be managed conservatively
and do not require intensive care monitoring. However, severely
inebriated patients who present in stupor or coma may need
airway protection. All patients should be hydrated to maintain
euvolemia. Thiamine, 100 mg, IV/IM daily for five days is given
to mitigate Wernicke–Korsakoff syndrome. Wernicke’s enceph-
alopathy is due to acute thiamine deficiency, whereas Korsakoff
psychosis is the long-term sequel.
In Wernicke’s encephalopathy, patients present with con-
fusion, ataxia, ophthalmoplegia, and nystagmus. This syn-
drome leads to Korsakoff’s psychosis, which manifests as
worsening confusion, confabulation, and amnesia. It is a result
of lack of vitamin B1, which is thiamine. The classic lesions are
mammillary body and thalamic degeneration. It is important
to administer thiamine before glucose. During aerobic respir-
ation, glucose is metabolized to pyruvate, which then enters
the Krebs or citric acid cycle. However, this process requires
thiamine. If glucose is administered when thiamine is deficient,
Wernicke’s syndrome can be precipitated.
As these patients are typically malnourished, they should
also receive folate, magnesium, multiple vitamins, and electro-
lyte replacement. If there is concern of ethanol withdrawal,
then a benzodiazepine such as lorazepam may be given.
Longer-acting benzodiazepines such as chlordiazepoxide or
diazepam are effective but are often used less in the NCCU
owing to their prolonged duration of action and potential for
depressing mental status.
Opioid Analgesics
Morphine is the prototypic drug of the opioid class of drugs.
Derived from opium, it is an alkaloid. Most of the clinically
used narcotic analgesics are derivatives of morphine or are
chemically closely related. Collectively, these are known as
opioids and include drugs such as codeine, oxycodone, meperi-
dine, fentanyl, methadone, buprenorphine, heroin, and hydro-
morphone. As such, the therapeutic strategy for managing
morphine overdose can be applied to these other opioids [5].
The typical clinical presentation of narcotic analgesic over-
dose is a triad of “coma, respiratory depression, and pinpoint
pupils.” The primary mechanism leading to death from over-
dose is respiratory arrest. Although morphine and its congeners
can lead to peripheral vascular dilation via histamine release,
severe hypotension is not characteristic of opioid overdose.
Thus, cardiac and cardiovascular compromise is uncommon
until profound hypoxia occurs. Seizures are more typically
related to meperidine and propoxyphene toxicity [5,6].
The therapy of choice for emergent reversal of opioid
overdose is immediate administration of naloxone, an opioid
antagonist, at 0.4 mg, IV or 0.8 mg, IM. In nonemergent
situations, 0.4 mg can be diluted in 9 mL of 0.9% NaCl to
make a 40 μg/mL solution. Between 40 and 80 μg (1–2 mL) IV
is given every two minutes until the opioid effects are
adequately reversed. Giving naloxone in this manner ensures
the minimally effective reversal dose, to allow for better pain
control and minimization of withdrawal phenomenon. This is
particularly relevant for patients with chronic pain on long-
term opioid therapy. The ideal route of administration is
intravenous but it can be given via an endotracheal tube as
well (the dose is 2 to 2.5 times the IV dose). Naloxone should
not be given orally because it is rapidly degraded via first-pass
effect through the liver.
Naloxone is effective for reversing all opioid effects. The
response is within a minute or two and lasts for up to an hour.
If recovery is incomplete, higher doses may be used, but one
should consider also the possibility that another class of drug
may be contributing as well [6,7]. An important aspect of
naloxone therapy is the short duration of action. Thus,
repeated doses of naloxone may be needed until the causative
agent is completely eliminated. In the ICU setting, this can be
via an IV infusion or periodic dosing [7].
Untoward effects of naloxone are uncommon. However,
naloxone can precipitate an acute opioid withdrawal syndrome
because it causes agonists such as morphine to vacate opioid
receptors. Rarely, when given in very high doses, naloxone can
result in pulmonary edema, agitation, and cardiac arrhythmia [7].
Chronic use of opioids leads to physical dependence. Thus,
abrupt cessation or reversal of dosing will lead to withdrawal.
Controlled withdrawal from opioid dependence and manage-
ment of symptoms are achieved differently from acute intoxi-
cation and are beyond the scope of this chapter.
Commonly Used Therapeutics in the NCCU
Phenytoin and Fosphenytoin
Phenytoin and fosphenytoin (a pro-drug of phenytoin) are
more commonly used drugs in the NCCU. Overdose is
uncommon, but has significant potential consequences should
this occur. At blood concentrations exceeding therapeutic

256

levels, >20 μg/mL, the most common clinical findings are
nystagmus, ataxia, diplopia, and vertigo. This is related to the
excitatory effect in the cerebellum. As blood levels further
increase, to >40 μg/mL, patients may experience hyperactivity,
hallucinations, and confusion. At severely toxic levels, >40 μg/
mL, patients become lethargic and, at >50 μg/mL, may pro-
gress to decerebrate rigidity and coma.
Cardiac complications of arrhythmias and hypotension are
more commonly associated with intravenously administering
the drug too rapidly. However, at toxic levels, these cardiovas-
cular effects can be seen.
Phenytoin is eliminated via a saturable hepatic microsomal
enzyme system. Thus, elimination follows zero-order kinetics,
which means a certain amount of drug is metabolized over
time, as opposed to a certain percentage. As the blood concen-
tration becomes higher, the time to eliminate the drug fully
becomes progressively longer.
Medical care is primarily supportive. If the overdose was
oral, then activated charcoal may be given. Hepatic function
will need to be determined and carefully monitored as an
untoward sequel may be hepatic failure.
Heparin
Unfractionated heparin (UFH) is a glycosaminoglycan with a
molecular weight ranging from 3000 to 30,000 daltons. UFH is
an antithrombotic agent that acts indirectly through anti-
thrombin (AT) to inhibit several clotting factors: XIIa, XIa,
IXa, Xa, IIa, and XIIIa. Blood clotting is fully inhibited in vitro
at a concentration of 1 unit/mL of whole blood. A 10,000-unit
bolus to a 70-kg male will lead to a blood concentration of 3
units/mL. The effect of this dose begins almost immediately
and will last about 1.5 hours [8–10].
For UFH, partial thromboplastin times (PTTs) are meas-
ured at regular intervals. If the PTT is excessively high or there
has been inadvertent overdose, then further administration is
stopped. Usually, no further intervention is needed. However,
if there is evidence of hemorrhage, then protamine sulfate, a
heparin antagonist, may be given. Protamine acts by binding
ionically to heparin to form an inactive complex.
The dose of protamine sulfate needed to reverse heparin
effects fully is 1 mg/100 units of heparin with a maximum of
50 mg. Given heparin’s short half-life, only the last 2–3 hours
of drug administered via a continuous infusion needs to be
reversed. This is administered by slow IV bolus at a rate of <20
mg/min. Side effects of protamine sulfate are related to hista-
mine release and are thus dyspnea, flushing, bradycardia, and
hypotension. These are largely avoided by slow administration.
There have been reports of hypersensitivity and are usually
associated with patients allergic to fish [9,10].
When compared to UFH, subcutaneous administration of
low molecular weight heparins (LMWHs) produces a more
linear and reliable degree of anticoagulation. LMWHs have a
higher ratio of antifactor Xa to antifactor IIa activity. This is
relevant to toxicity as PTT cannot be used as a measure of
Chapter 21: Neuroterrorism and Drug Overdose
LMWH anticoagulation, as the PTT is mediated via inhibition
of thrombin (factor IIa). Antifactor Xa levels can be used as
this is a pharmacodynamics measure of the anticoagulant
effects of LMWHs. Many different LMWHs are available, and
each possesses a different half-life, all of which are longer than
UFH. The effects of UFH may last hours whereas LMWHs
effects may last for hours to days. Also, unlike UFH, most
LMWHs are primarily cleared via the kidneys, so renal dys-
function may prolong the half-life substantially [9–11].
There is no well-established method for reversing the
effects of LMWH. Protamine will only partially neutralize
LMWH, about 60% of its effects. The dose is 1 mg of protam-
ine for every 100 units of antifactor Xa activity. For enoxa-
parin, this is approximately 1 mg of protamine per milligram
of enoxaparin to be reversed [8,9].
Warfarin
Warfarin is a congener of dicumarol, which is derived from
sweet clover. It is an antithrombotic agent that interferes with
blood clotting by inhibiting the vitamin-K-dependent clotting
cascade of factors II, VII, IX, and X.
The international normalized ratio (INR) of the prothrom-
bin time (PT) is used to monitor the antithrombotic effects of
warfarin. The management of warfarin therapy and elevated
INR can be complex, and is beyond the scope of this chapter.
The reader is referred to the American College of Chest Phys-
icians’ Guidelines for more information [12].
In the event of serious bleeding, further warfarin adminis-
tration is stopped and a prothrombin complex concentrate
(PCC) should be administered. PCCs come in a variety of
formulations carrying differing amounts of clotting factors.
The one PCC that is FDA-approved to reverse the effects of
vitamin K antagonists is Kcentra®, which contains the vita-
min-K-dependent clotting factors II, VII, IX and X in the
inactivated form as well as protein C and protein S.
Dosing of all PCCs is based on the Factor IX component.
In the case of warfarin reversal, the recommended dosing of
Kcentra® is based on the INR (INR 2–3.9 = 25 units/kg, INR
4–6 = 35 units/kg, and INR >6 = 50 units/kg) [13]. The reader is
referred to the specific PCC product information for compre-
hensive dosing instructions and administration information. In
addition, one can consider giving 1–10 mg of vitamin K by slow
IV infusion. If needed, vitamin K can be repeated every 12
hours. In the event of life-threatening bleeding, both a PCC
and 10 mg of IV vitamin K should be administered.
Direct Thrombin Inhibitors
Direct thrombin inhibitors, such as argatroban and bivaliru-
din, are a newer class of anticoagulants used in the settings
of heparin-induced thrombocytopenia, and acute coronary
syndromes. There are no well-studied reversal agents for this
class of drug. Aside from stopping the infusion, consideration
may be given to activated prothrombin complex concentrate
(aPCC) or PCC [14].
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 Chapter 21: Neuroterrorism and Drug Overdose
Barbiturates
The barbiturates are classic sedative hypnotic drugs. All
share common chemical features, for example, the barbituric
acid core. As such they have similar spectrums of action,
such as inducing drowsiness and suppressing central venti-
latory control centers. Pentobarbital may be considered the
prototype of this class of drugs. However, more commonly
used agents are thiopental, phenobarbital, amobarbital, and
secobarbital [5].
All are global CNS depressants. At therapeutic doses, they
have minimal effect on the peripheral nervous system and
tissue such as skeletal, cardiac, or smooth muscle. At toxic
doses, these drugs have a depressant effect on the medullary
vasomotor area and lead to cardiovascular compromise. Clinic-
ally, patients become increasingly lethargic with increasing
dosage. An ECG will show slowing that progresses to burst
suppression at high doses. At toxic doses, patients will be coma-
tose, in respiratory arrest, hypotensive, and hypothermic [5].
Medical management is primarily supportive, involving
airway, mechanical ventilation, and cardiovascular care. If the
drug was administered orally, activated charcoal should be
given and to facilitate elimination, the urine may be alkali-
nized. Urinary alkalinization is more useful for long-acting
agents such as phenobarbital which has a pKa of 7.2 and is
water soluble. Extracorporeal removal via hemoperfusion may
be considered. However, this is usually reserved for patients
who are in extremis and are worsening in spite of conventional
therapy [3,15].
Benzodiazepines
Benzodiazepines are also sedative hypnotics. However, they are
chemically distinct from barbiturates. Benzodiazepines contain
a benzene ring fused to a seven-membered diazepine ring.
Diazepam is the prototype of this class of drugs. Other com-
monly used congeners are midazolam, lorazepam, alprazolam,
and clonazepam [5].
These therapeutic agents share common clinical features.
At low therapeutic doses, they cause sedation and muscle
relaxation, and do not cause myocardial or ventilatory depres-
sion. At higher doses, there is increasing CNS depression from
hypnosis to stupor. However, even at very high doses, none of
these agents will cause true general anesthesia. To achieve
surgical anesthesia, they must be used in combination with
other drugs [5].
Medical management is primarily supportive. If the only
overdose drug is a benzodiazepine, then conservative manage-
ment is best. Typically, even with very high doses, patients do
not require airway protection, mechanical ventilation, or car-
diovascular support. If this is their only medical problem, they
do not require ICU care. When combined with other CNS
depressants, such as alcohol or opioids, high levels of benzodi-
azepines can contribute to a patient’s comatose state. In such
cases, more aggressive medical management is indicated,
including advanced critical care [5,16].
258
Another therapeutic option is flumazenil, a benzodiazepine
antagonist. For management of known or suspected benzodi-
azepine overdose, the initial dose of flumazenil is 0.2 mg given
intravenously over 30 seconds. If the desired response is not
obtained after waiting 30 additional seconds, a dose of 0.3 mg
can be administered over 30 seconds. Additional doses of
0.5 mg can be given over 30 seconds at one-minute intervals
up to a total cumulative dose of 3 mg. The onset of action is
rapid, often within one or two minutes. It can reverse any
effects of benzodiazepines. The duration of action is about 45
minutes. Thus, when treating an overdose of long-acting agon-
ists, additional doses of flumazenil may be needed. As this
drug blocks GABA/benzodiazepine receptors, it has the poten-
tial to lower seizure threshold. As such, flumazenil can precipi-
tate withdrawal (including refractory seizures and status
epilepticus) in patients who chronically take benzodiazepines.
This agent is generally reserved for patients who are comatose
and have ventilatory and cardiovascular compromise in which
benzodiazepine overdose is thought to contribute [5,16].
Tricyclic Antidepressants
Tricyclic antidepressants (TCAs) are widely used medications.
The prototypes of this drug class are imipramine and amitrip-
tyline. Other TCAs are nortriptyline, desipramine, doxepine,
amoxapine, and others. Their therapeutic mechanisms of
action are serotonin and norepinephrine reuptake inhibition.
These agents also have anticholinergic effects that contribute to
their toxicity [5].
The classic “TCA triad” of toxicity is Tonic–clonic seizures,
Cardiovascular, and Anticholinergic. In addition to seizures,
patients can develop delirium, agitation, and confusion, but
will progress with increasing doses to obtundation and coma.
Cardiovascular effects are described as “quinidine-like,” as
conduction is slowed. The ECG changes include widened QRS
complexes, prolonged PR intervals, AV conduction blocks, and,
if severe, ventricular arrhythmias. Vasodilation and decreased
myocardial contractility can lead to fatal hypotension and dys-
rhythmia. The ECG has prognostic value. If QRS is >100 ms,
there is an increased risk of seizure and >160 ms, increased
risk of dysrhythmia. Anticholinergic effects are delirium, hyper-
thermia, flushing, anhydrosis, dry mouth, anuria, ileus, and
mydriasis. The clinical course of TCA toxicity is typically
48 hours [5,17].
Therapy is mainly conservative. For seizures, lorazepam
(1–4 mg, IV) can be used. Phenytoin should be avoided as it
can exacerbate TCA cardiovascular effects. If hypotension
occurs, fluid resuscitation and vasopressor therapy should be
initiated. Vasopressors that can be considered are epinephrine
and norepinephrine, whereas dopamine is not recommended
as it requires release of endogenous norepinephrine to be
effective, which may be blocked by TCAs. In the event of
arrhythmias, sodium bicarbonate (1–2 mEq/kg) should be
given with a goal of arterial pH 7.45–7.55. Class 1a and 1c
antiarrhythmics are contraindicated [17].

Chemical and Biological Terrorism
Chemical and biological terrorism is a serious domestic
concern. In 1984, a Salmonella attack was perpetuated in
Oregon by the Rajneeshee cult and more recently, in 2001,
the Amerithrax letter attacks. Outside of the United States,
there have been many attacks on civilians. One particularly
successive attack was the sarin attack in Tokyo. These
and others underscore the importance of vigilance for both
civilian and military medical systems worldwide. Awareness
of this potential threat is important to the neurocritical
care practitioner to ensure proper clinical management of
patients [18].
In 1984, the Rajneeshee cult deposited a strain of Salmon-
ella typhimurium on doorknobs, urinal handles, supermarket
produce, and salad bars throughout an Oregon community.
This resulted in 751 cases of severe gastroenteritis. Nearly
1000 patients sought treatment, which overwhelmed the local
medical care system. Fortunately, there were no fatalities. This
attack had followed the Tylenol® cyanide poisonings in the
Chicago area in 1982, where seven fatalities were reported
related to product tampering and placement of potassium
cyanide into medication capsules. Similar attacks, possibly
related to the intense media coverage of the Tylenol® scare,
occurred subsequent to the original Tylenol® tampering case.
The original case remains unsolved [19].
Internationally, one of the most striking cases of biological
warfare-related civilian disasters is the Sverdlovsk (now Yekat-
erinburg) anthrax infections beginning in April of 1979. An
apparent accidental release of aerosol containing weapons-
grade Bacillus anthracis spores occurred in this region of the
former Soviet Union. Exposed civilians over a 4-km area
developed symptoms consistent with inhalation anthrax. There
were 77 patients identified with inhalation anthrax, and of
these, only 11 survived. To date, this is the most deadly anthrax
event [20,21].
Perhaps the most illustrative episode is the Tokyo subway
sarin gas poisonings in 1995 perpetuated by the Aum Shinri-
kyo cult. This is a good example of what can happen to a
modern medical care system when encountering a terrorist
attack. Initially, within the first few hours, a few hundred
patients were brought to the hospital. However, ultimately,
more than 5500 patients sought medical treatment. Among
the casualties were unprotected healthcare providers who
developed secondary contamination when treating victims.
There were 12 deaths from the attacks, and at least 50 were
seriously injured from organophosphate poisoning, including
seizures. One important finding is that the vast majority of
patients, about 80%, did not have evidence of nerve-agent
exposure. Instead, they had a wide variety of complaints that
were largely not attributable to sarin exposure. This very large
category of patients has been called “the worried well.” How-
ever, their impact of significantly burdening a very busy
medical care system during a critical period cannot be under-
estimated. This attack serves as a case study for the potential
Chapter 21: Neuroterrorism and Drug Overdose
for modern biological and chemical terrorism, and the med-
ical, social, and political consequences of such [18,22,23].
In a terrorist attack, the demands placed on the individual
provider and local medical care system can be overwhelming.
Traditional approaches to triage and care delivery will be
inadequate. Thus, it is crucial that preparation for such events
is done in advance and that the system as a whole practices. In
the event of a terrorist attack in which many casualties result,
neurocritical care specialists may find themselves assisting
outside of the NCCU, such as in a triage area, emergency
department, or decontamination lane.
Biological Agents
Biological agents are attractive weapons to terrorists as these
agents are inexpensive, relatively easy to procure, and present a
time delay to onset of action that allows for successful deploy-
ment and escape from authorities. It has long been held that
these agents are difficult to refine to a weapons grade, that is, in
a size and form that is easily disseminated to cause maximal
effect. In reality, weaponization of biological agents is within
the ability of terrorists. From the Amerithrax letters case, FBI
and other experts concluded that a very high grade of refined
anthrax spores were used. The terrorist was able to achieve a
particle size of 1–5 pm in diameter, which is ideal to cause
pulmonary anthrax, the most lethal manifestation of this
disease [24].
Anthrax
Bacillus anthracis is the bacteria responsible for anthrax. It has
been manufactured in a weaponized form by the United States
and several other nations, including the former USSR. Several
days after the events of September 11, 2001, the anthrax mail
attacks commenced, resulting in at least 22 cases of anthrax
and five deaths. The historical potential for anthrax to present
as a hemorrhagic meningoencephalitis makes this agent of
particular interest to the neurocritical care physician [25].
Inhalation anthrax is especially rare. Thus, it is advised that
even a single case of inhalation anthrax should prompt local
health officials to suspect a terrorist attack. Historically, this
has been referred to as “wool sorter’s disease,” owing to its
association with processing of hides, furs, and wool in
industrial mills.
Clinical symptoms present after an incubation period of one
to six days, although there are reports of cases of inhalational
anthrax that presented up to six weeks after exposure. Initial
symptoms are nonspecific, such as fever, malaise, headache, and
respiratory complaints. Patients with inhalational anthrax do
not show typical signs of routine upper respiratory infections,
and pneumonia is uncommon. Physical examination findings
are limited, but often patients present with tachycardia.
The diagnosis is based on epidemiologic data and chest
radiographic findings of widened mediastinum and pleural
effusions. This is likely due to a hemorrhagic mediastinitis.
Chest radiography or chest computed tomography (CT)
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 Chapter 21: Neuroterrorism and Drug Overdose

should be performed in all suspected cases. In the 2001 attack, Table 21.1 Antimicrobial treatment for various forms of Bacillus anthracis
(adult doses) [24]
these were abnormal in every patient with inhalational
anthrax. Organisms are not usually isolated from the sputum Manifestation of Preferred Alternative
of patients. Instead, the majority of cases have been confirmed disease therapy therapy
by blood culture, which can detect anthrax in its early stage. Inhalational anthrax Ciprofloxacin Doxycycline
Other laboratory abnormalities include elevated transami- 400 mg IV q 12 h 200 mg IV load
nases, elevated white blood cell count with a polymorphonuc- followed by
lear leukocyte (PMN) predominance (average of 9800 cells/dL 100 mg IV q 12 h
in the 2001 Amerithrax attacks).
Cutaneous anthrax Ciprofloxacin Doxycycline
As the disease progresses, subsequent symptoms include 500 mg PO q 12 h 100 mg PO q 12 h
respiratory distress and the development of septic shock. Death or amoxicillin
may follow severe pulmonary symptoms in one to two days 500 mg PO q8h
unless intensive care support and proper antimicrobial man-
Gastrointestinal Ciprofloxacin Doxycycline
agement is instituted.
anthrax 400 mg IV q 12 h 200 mg IV load
Mortality reports vary widely from 45% to 99%, likely the followed by
result of modern intensive care management of the inhalation 100 mg IV q 12 h
form of the disease. Evidence of this was taken from the
Anthrax-associated Ciprofloxacin Doxycycline
Amerithrax letters of 2001 in the United States, which were
meningoencephalitis 400 mg IV q 8 h + 200 mg IV load
associated with the lower end of this mortality spectrum owing
rifampin (CNS followed by
to aggressive treatment and recognition of the disease [24]. penetration) 100 mg IV q 12 h
Cutaneous anthrax is the most common naturally occur-
ring form of the disease. The most salient feature of cutaneous
anthrax is a painless skin lesion that, over the course of days,
can progress to a vesicle, ulcer, and then eschar with surround- Treatment of anthrax is dependent on the mode of bacter-
ing edema. These lesions can be cultured unless the patient has ial inoculation. With inhalational anthrax, the emphasis is on
begun systemic antibiotic treatment. Gram stain will often ventilatory support and intravenous antimicrobials
show Gram-positive bacilli. Mortality from the cutaneous (Table 21.1). With early institution of antibiotics, survival
form of anthrax is approximately 20%. may approach >50%. In adults, initial therapy should begin
Gastrointestinal anthrax is another highly fatal form of this with ciprofloxacin 400 mg IV q 12 h or doxycycline 200 mg IV
disease and occurs after eating infected meat. This is another followed by 100 mg IV q 12 h. In children, the doses are
possible mode of terrorist attack. Gastrointestinal anthrax can ciprofloxacin 10–15 mg/kg (maximum 400 mg) IV q 12 h, or
present as an acute gastroenteritis, acute abdomen with peri- doxycycline (100 mg IV q 12 h for children >8 years and >45
toneal signs, or diarrheal illness. Stool culture is not very kg, and 2.2 mg/kg IV q 12 h for children <8 years or <45 kg).
sensitive for anthrax and the diagnosis is usually made via The use of tetracyclines in children is generally discouraged.
polymerase chain reaction (PCR) and immunostaining of The addition of one or two other antibiotics with activity
either peritoneal or ascetic fluid. Mortality from gastrointest- against Bacillus anthracis may be considered until suscepti-
inal anthrax ranges from 60% to 80% [24,26]. bilities return. The bacterium has shown genomic evidence for
Anthrax-associated hemorrhagic meningoencephalitis is encoding of both constitutive and inducible β-lactamases and
seen in approximately 50% of cases of inhalational anthrax thus single agent use of β-lactam antibiotics is not advised.
and can present after either the inhalational or cutaneous route Owing to poor penetration of the CNS with several of these
of infection. This usually manifests as multifocal intracerebral antimicrobials, therapy of anthrax infection with any neurolo-
hemorrhage well visualized on head CT. If the patient has severe gic manifestation must include ciprofloxacin (at a higher dose
pulmonary symptoms or cutaneous manifestations concerning of 400mg IV q 8 h) and rifampin.
for anthrax, prompt sampling of the cerebrospinal fluid (CSF) A pre-exposure vaccine is available, which is completed
should be performed. Often the organism can be seen on Gram through a series of six doses over 18 months, followed by
stain of the CSF, as Bacillus anthracis appears as large Gram- yearly booster vaccination. Patients with anthrax in any form
positive bacilli singly or in short chains, with squared-off ends. of the disease require standard precautions. Person-to-person
Other CSF findings are low glucose level, elevated protein, red spread has not been documented [24,26].
blood cells, and a leukocytosis >500 cells/mL. Hemorrhagic While antimicrobials may reduce the incidence or progres-
meningoencephalitis from anthrax is an ominous condition, as sion of disease after exposure to aerosolized anthrax, delayed
death usually ensues within one week of diagnosis. initiation of treatment results in increased mortality as the
Other neurologic manifestations of anthrax include head- disease progresses to the toxemic phase. As such, two anthrax
ache, mental status changes, visual field deficits, and changes in antitoxins have been recently developed:
®
acuity. These symptoms can present with any mode of infec- • Anthrax immune globulin (Anthrivig ) is derived from
tion [25,26]. pooled human plasma from humans who have previously

260

received the anthrax vaccine. It contains polyclonal anthrax
toxin-neutralizing antibodies against protective antigen (a
component of the cytotoxic lethal toxin and edema toxin)
and is being developed as a countermeasure for the
treatment of anthrax-induced toxemia in combination with
antimicrobial treatment. It is not currently FDA approved,
but could be made available under an Emergency Use
Authorization during a declared emergency [27].
• Raxibacumab (Abthrax®) is a human IgG monoclonal
antibody against the anthrax protective antigen. It is
indicated for the treatment of inhalation anthrax in
combination with appropriate antibiotics, and for
prophylaxis of inhalation anthrax when alternative
therapies are not appropriate. It was approved by the FDA
in 2012 based on animal studies (under the FDA’s Animal
Efficacy Rule) in addition to safety data in healthy human
volunteers [28]. Dosing of raxibacumab for adults and
pediatric patients over 50 kg is 40mg/kg IV (pediatric dose
for 15–50 kg = 60 mg/kg, and for <15 kg = 80 mg/kg),
administered in 250 mL of 0.9% sodium chloride and
infused over 2 hours and 15 minutes. Premedication with
diphenhydramine one hour before infusion is required to
mitigate infusion-related reactions [29]. Raxibacumab is
stocked as part of the US national strategic stockpile as a
medical countermeasure that could be deployed in the
event of an attack [30].
Botulinum Toxin
The toxin produced by the Gram-positive bacillus Clostridium
botulinum is widely known as the deadliest toxin. It is esti-
mated that a gram of botulinum toxin could kill more than
1 million people. Ethical uses of botulinum toxin are for the
treatment of spasticity, dystonia, blepharospasm, strabismus,
cervical torticollis, and others [26,31].
Botulism is most often acquired via the gastrointestinal
route after ingestion of spores in contaminated food. Skin
contact with botulinum toxin does not produce clinical infec-
tion or toxicity. There are three distinct forms of the disease:
gastrointestinal, wound, and infant botulism. There are about
200 cases annually in the United States. An inhalational form of
botulism has been produced experimentally in primates [26,31].
The toxin has proven difficult to weaponize in an effective
manner. Thus, it has not been developed as a conventional
battlefield weapon. However, its potential use as a terrorist
weapon is not inconceivable. Contamination of water supplies,
food, and aerosol spraying are likely modes of dissemination for
terrorist purposes. The Aum Shinrikyo cult attempted to deploy
botulinum toxin without success. This was believed to be due to
inadequate understanding of technical factors, as well as poor
overall microbiology of Clostridium botulinum [31].
Botulism as a disease is well known to neurologists, produ-
cing an acute, descending paralysis that begins in the bulbar
musculature. The toxin acts via cleavage of the N-ethylmalei-
mide-sensitive factor attachment protein receptor (SNARE
protein), which prevents fusion of the acetylcholine-containing
Chapter 21: Neuroterrorism and Drug Overdose
vesicles with the presynaptic membrane at the neuromuscular
junction. This produces a paucity of acetylcholine in the syn-
aptic cleft and results in clinical weakness. There are seven
known types of botulinum toxin, all with similar clinical effects
[18,26,31].
The disease presentation is similar regardless of the type of
toxin or the way in which it is contracted. An acute descending
paralysis, beginning in the cranial nerves, precedes systemic
weakness, including respiratory musculature. The initial mani-
festations of clinical botulism are ptosis, poorly reactive dilated
pupils, and the development of ocular misalignment with
diplopia and disconjugate gaze. This can progress to facial
weakness, dysarthria, and dysphagia. Some of these signs or
symptoms may be confused with other forms of acute des-
cending weakness with cranial nerve palsies, including tick
paralysis, the Miller–Fisher variant of Guillain-Barré, myasthe-
nia gravis, pontine infarction, or diphtheria infection [32]. One
particular clinical clue to the diagnosis of botulism is the
involvement of the pupils, which is unlikely in more common
conditions such as myasthenia gravis.
The diagnosis can be confirmed with serology available at
the Centers for Disease Control and Prevention, but electro-
physiologic studies, including nerve conduction testing and
repetitive stimulation at 50 Hz showing an incremental
response is diagnostic. CSF analysis and neuroimaging studies
are typically normal. This disease can be rapidly fatal unless
patients are treated aggressively with botulinum antitoxin and
supportive measures, including mechanical ventilator support.
Mechanical ventilation should be instituted when negative
inspiratory flow declines below 30 to 20 cmH2O or vital
capacity falls below 15 mL/kg. Convalescence from botulinum
intoxication can take up to one year for a complete recovery [32].
In 2013 the FDA approved Botulism Antitoxin Heptava-
lent, which neutralizes all known botulinum nerve toxin sero-
types (types A, B, C, D, E, F, and G) for use in adults and
children over the age of 1. It is an equine immunoglobulin and
is available from the Centers for Disease Control and Preven-
tion. This immunoglobulin can stabilize a deteriorating
patient, but may not result in clinical improvement of motor
weakness. If given right at the onset of neurological symptoms
it has been shown to reduce time on the ventilator and length
of ICU stay [31]. Clinicians suspecting a diagnosis of botulism
should immediately call their state health department’s 24-
hour phone number, who in turn contacts the Center for
Disease Control for a clinical consult and release of antitoxin.
The dose for adults is one vial starting at 0.5 mL/min
titrating up to a maximum infusion rate of 2 mL/min (the
pediatric dosing is a percentage of the vial, based on body
weight). It is available through the Center for Disease Control
or as part of the national Strategic Stockpile as a medical
countermeasure in the event of an attack [33]. Botulism
immunoglobulin is also available for cases of infant botulism
caused by toxins A and B only. It is available through the
California Department of Health’s Infant Botulism Treatment
and Prevention Program [34].
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 Chapter 21: Neuroterrorism and Drug Overdose
Q Fever
Coxiella burnetii is the causative organism of Q fever. Its use as
a terrorist weapon is based on the organism’s ability to exist
in a spore-like form. As a spore, it is resistant to inactivation
from heat or desiccation, allowing it to survive in most envir-
onments for months. It is highly potent. This is a zoonotic
illness, as the bacterial reservoirs are in sheep, cattle, cats,
rodents, and goats. The organism is concentrated in the mam-
mary glands and uteri of infected animals. Thus natural infec-
tion of humans usually occurs during contact with products of
conception or by eating infected milk or cheese.
Q fever typically produces a self-limited respiratory infec-
tion, pneumonia, and/or hepatitis. Less frequently, meningo-
encephalitis can occur, along with cardiac manifestations,
including myocarditis and pericarditis. The hallmark of the
disease is the onset of high fevers, up to 105 °F, presenting a
mean of 15 days after exposure. Chest radiographs typically
show multifocal infiltrates. Serum studies show elevated trans-
aminases, although fulminant hepatic failure is quite rare. Infec-
tions of pregnant women can lead to undesirable outcomes of
pregnancy, such as miscarriage and low birth weight [24,26].
Neurologic manifestations of Q fever occur in up to 23% of
cases. These include psychosis, expressive aphasia, facial pain
resembling tic douloureux, ocular misalignment with diplopia,
and dysarthria. In the acute phase of this disease, optic neuritis
can occur. In the latter stages, if untreated, this condition can
progress to encephalitis, encephalomyelitis, and myelopathy.
The diagnosis is made via serology, as culturing this organism
is difficult and dangerous to laboratory personnel [35].
Infection control measures with known cases of Q fever
involve standard precautions. Postmortem infections of
healthcare workers during autopsy have been documented.
The earlier treatment is initiated, the more effective antibiotics
may be at preventing development of a chronic infection.
Initial treatment is with doxycycline 100 mg every 12 hours
for 15–21 days. Other options include fluoroquinolones such
as ciprofloxacin for three weeks. For patients with neurologic
symptoms, the quinolones are preferred because of better CNS
penetration than doxycycline [18,24].
Smallpox
Variola virus, the causative agent of smallpox, has been used to
deliberately infect civilians since the British used this as a
weapon against the Native Americans in the French and
Indian War in the mid-1700s. The naturally occurring form
of the disease was declared eradicated in 1980, and the last
known case occurred in 1977.
Initial infection with variola virus occurs through the
respiratory tract. Over the first four days, the virus is usually
asymptomatic, but a blood-borne infection ensues. The char-
acteristic skin lesion occurs on about day 6–8 of infection. The
viral infectivity is high at this stage from exposure to droplets
or environmental agents [26,36,37]. The clinical presentation
of the virus begins with headache, backache, malaise, and in
262
some cases, delirium. This can precede the emergence of the
rash, which develops on the face and upper extremities before
appearance of skin lesions on the trunk. This is helpful in
distinguishing the rash from other more common viral
exanthems such as varicella virus. There is currently a vaccine
in use by the military and certain healthcare providers.
The virus is especially important to the NCCU physician
because of an uncommon side effect of the renewed vaccin-
ation program. An estimated 1:300,000 of persons vaccinated
with smallpox can develop postvaccination encephalitis, which
occurs one to two weeks after vaccine administration, and has
a mortality of 25%. The encephalitis presents with headache,
meningeal signs, fever, lethargy, vomiting, and, rarely, spastic
paralysis that can progress to seizures, coma, and death. Treat-
ment of the encephalitis is supportive [36].
Venezuelan Equine Encephalitis
Venezuelan equine encephalitis (VEE) is the best-characterized
and studied member of the alphavirus family as a bioweapon
owing to its place in the United States offensive biological
weapons program in the 1950s and 1960s. This virus occurs
naturally in the United States, and is often associated with
horse outbreaks of encephalitis that usually precede human
illness in the community. It is spread by infected mosquitoes,
and is quite virulent in the equine population, resulting in a
30–90% mortality. The main cycle of transmission is via
infected mosquitoes and wild birds. In humans, the mortality
estimates are much lower, although an outbreak in Venezuela
and Columbia in 1995 killed approximately 300 persons, with
>75,000 cases reported [24,38].
The most common presentation for VEE is that of an acute
febrile, incapacitating illness, which rarely results in clinical
encephalitis in humans. Approximately 1 in 10 of those
infected with VEE will require hospitalization. Symptoms
occur within a week of inoculation, and include sudden com-
plaints of high fever, malaise, chills, rigors, profound head-
ache, photophobia, and lower extremity and back muscle
soreness. The illness can take up to two weeks for convales-
cence, and often relapses can be seen clinically after apparent
resolution. Pregnant females, children younger than 15 years
of age, and the elderly population are more susceptible to
serious neurologic manifestations of the illness, with attack
rates ranging from 1% to 4% of these populations and mortal-
ity ranging from 10% to 35%. Seizures, ataxia, and mental
status changes can be seen, and the likelihood of such neuro-
logic manifestations is theoretically greater after an intentional,
likely aerosolized viral agent attack, via transmission of the
virus directly into the CNS and the olfactory nerve [24].
The diagnosis of VEE is based on epidemiologic data,
sentinel herd data from equine surveillance, and serological
studies and PCR analysis. IgM antibodies are produced within
about five days after clinical symptoms appear. PCR is avail-
able commercially and at the Centers for Disease Control and
Prevention. Treatment is supportive as no specific treatment is
available for VEE [38].

Tetrodotoxin
Tetrodotoxin (TTX) is produced by the puffer fish, or fugu,
which is commonly found in the tropics. TTX is a sodium
channel blocker, which can cause paralysis of respiratory mus-
culature, generalized weakness, alteration of vasomotor tone,
and sensory deficits. There have been three reported cases of
toxicity since 1996, all of which were caused by eating poorly
prepared fugu [39].
Clinical manifestations of TTX toxicity can appear rapidly
or up to four hours after ingestion of contaminated food or
water, although delayed cases occurring up to 20 hours after
ingestion have been reported. Facial or oral numbness and
mild peripheral generalized weakness may be the initial com-
plaint, but hypotension, seizures, generalized paralysis, cardiac
arrhythmias, and respiratory failure may follow quickly. The
patient may progress to a locked-in state, with preservation of
consciousness, but no motor function. Eventual loss of all
brainstem reflexes precedes death [26,39].
The diagnosis is made clinically, especially a history of
eating fugu. Other animal species, including amphibians, are
known to produce this toxin, but a vast majority of cases are
due to ingestion of the puffer fish. Treatment currently is
supportive. There are animal data to support the use of mono-
clonal antibodies to TTX to reverse the effects of this toxin.
Other studies show benefit of 4-aminopyridine when used in
guinea pigs. However, no human studies with TTX antitoxins
are currently underway. Treatment with charcoal and gastric
lavage may be helpful if given early in the course, and is a safe
option in the case of suspected toxicity after eating exotic
cooked or uncooked fish [39].
Other Agents
There are many other agents that have either been weaponized
for use as a biological weapon or have theoretical potential for
use as such. However, many of these agents do not typically
present with neurologic symptoms that would prompt admis-
sion to the NCCU. Familiarity with these organisms or agents
is nevertheless prudent and has been advocated in the United
States, given the current threat of bioterrorism that is prevalent
for society as a whole. The United States Army Medical
Research Institute of Infectious Diseases considers Brucella
spp., Burkholderia mallei (glanders), Burkholderia pseudomal-
lei (melioidosis), Yersinia pestis (plague), Francisella tularensis
(tularemia), yellow fever, and Filoviridae (Ebola and Marburg
virus) as potential threats, in addition to those described
above. Further information regarding these agents is readily
available [24,40].
Standard precautions practiced in the general care of ICU
patients will provide adequate protection to the healthcare
team for a majority of bioterrorism agents, which include the
toxin-mediated diseases, anthrax, VEE, and Q fever. Suspected
smallpox infection warrants special mention in that airborne
transmission is likely. These patients should be isolated at the
highest possible level, with airborne precautions requiring the
Chapter 21: Neuroterrorism and Drug Overdose
wearing of a HEPA-filter mask by all members of the treat-
ment team while caring for the patient.
Chemical Agents
As a result of the wartime experience gained during World
War I, and the subsequent development of more potent agents
in World War II, more is known regarding the use of chemical
agents than biological. Iranian military physicians serving
during the Iran–Iraq war also provided first-hand accounts
on the treatment of nerve-agent casualties. The Aum Shinrikyo
attack as described in the preceding text provides a good case
study of terrorist use. In addition, the relevance of this threat is
underscored by the likely ease of obtaining some of these
chemicals, either through small laboratory production or
diversion of some of the many tons of chemical agents used
for legitimate industrial purposes. Accidental chemical spills or
natural disaster are another source of casualties. In 1984, the
accidental release of tons of methyl isocyanate into a large
urban area in Bhopal, India is widely considered to be the
world’s worst industrial accident. It resulted in approximately
3800 deaths and subsequently 15,000 to 20,000 premature
deaths. Those who were killed early were in close proximity
to the chemical plant that released the gas, but adverse health
effects from the exposure extended to populations who lived
anywhere in the area. Other accidents with industrial chemical
spills have occurred domestically, and in any Western city the
likelihood of treating victims of a chemical exposure is pos-
sible. Thus, familiarity with the manifestations of the chem-
ical- or nerve-agent civilian casualty is important for the
neurocritical care physician [41,42].
Organophosphates
Nerve agents, commonly referred to as organophosphates, are
the most toxic of the weaponized chemical agents (Table 21.2).
As a class, these agents act at the neuromuscular junction with
inhibition of acetylcholinesterase, thereby producing clinical
manifestations of cholinergic crisis, which can lead to incapaci-
tation and death. They have a record of successful deployment,
both on the battlefield, as well as in the civilian setting, as
discussed above. The only well-documented use of nerve
agents occurred during the Iran–Iraq war, when as many as
45,000 casualties were inflicted on the Iranian army by Iraqi
Table 21.2 Nerve agent and relative toxicity for LD50 from skin exposure
[43]
Designator Common name LD50 (in mg)
GB Sarin 1700
GA Tabun 1000
GD Soman 50
GF 30
VX 10
263
 Chapter 21: Neuroterrorism and Drug Overdose
deployment of nerve agents sarin (GB), tabum (GA), and a
mustard agent [42].
These compounds were developed first in Germany in
World War II, after more legitimate research on materials
for use as pesticides identified significant human toxicity.
These agents were stockpiled by the Nazis during the war,
but were never used. They are liquids at room temperature,
but have variable volatility. There are two generations of nerve
agents, commonly referred to as the “G” and “V” series. The
G series were developed first and are more volatile than the
V series, which are more refined, far more potent, and less
volatile at room temperature [43].
As stated in the preceding text, organophosphates are
anticholinesterases as they inhibit acetylcholinesterase, pre-
venting hydrolysis of acetylcholine leading to acetylcholine
accumulation. This results in overstimulation and desensitiza-
tion of both nicotinic and muscarinic receptor sites. These
agents bind irreversibly to acetylcholinesterases. They are
much more toxic than ethical preparations of anticholines-
terases such as commercially available pesticides, for example,
malathion and sarin, and medications, e.g., pyridostigmine,
neostigmine, and physostigmine.
Clinical manifestations of organophosphate toxicity are well
characterized. The earliest symptom may be the development of
miosis and other eye complaints, including eye pain and findings
of hyperemia, which results from direct contact of vapor with the
eye. This is followed by excessive secretions, muscle fascicula-
tions, involuntary urination and defecation, bronchoconstriction,
mental status changes, confusion, seizures, changes in muscle
tone, and eventually cardiopulmonary collapse and death, if
untreated. The agent is readily absorbed by the skin or pulmon-
ary system, and onset of symptoms after exposure is rapid.
Physical signs are evident as discussed above, but other
findings may include wheezing of bilateral lung fields, cardiac
arrhythmias, and other abnormalities of the electrocardio-
gram, including heart block.
The differential diagnosis of a patient with mild symptoms
includes nonspecific upper respiratory infection or allergic
response. However, the presence of miosis should increase
suspicion of nerve-agent exposure. This distinction is more
evident with severe intoxication, and these patients are of most
concern and in need of prompt treatment. The diagnosis is
likely to be made based on epidemiological data and presenta-
tion, although laboratory studies of acetylcholinesterase activ-
ity are available [32,43,44].
Other neurologic manifestations of a large vaporized dose
include rapid loss of consciousness, development of seizures,
and apnea, likely of a central origin and not purely from motor
weakness. Respiratory and circulatory support is crucial with
severe exposures presenting with neurologic deficits.
A concerning presentation is delayed development of the
above symptoms after a mild bare skin exposure. There may
be up to a 30-minute period of limited to no symptoms, but
then an acute decompensation to neurologic compromise and
death [44].
264
Recognition of nerve-agent exposure is vital, as it is para-
mount to begin decontamination and treatment early. Neuro-
logic damage suffered by surviving organophosphate victims is
due in large part to prolonged seizure activity, including status
epilepticus. It is this complication that results in long-term
cognitive and behavioral dysfunction. After exposure and
seizures, lesions are found in the cortex, hippocampus, and
thalamus [32,44,45].
Treatments recommended here are based on U.S. Army
algorithms developed for battlefield exposure to nerve agents.
However, it is reasonable to generalize this approach to any
civilian population that has been similarly exposed. The man-
agement of the nerve-agent casualty consists initially of decon-
tamination. Depending on the severity of symptoms, patients
with severe bronchoconstriction and profuse pulmonary secre-
tions will require early endotracheal intubation, ventilatory
support, and aggressive pulmonary toilet. Once the airway is
secured, the next step is institution of specific therapy for the
cholinergic crisis and seizures:
1. Atropine, an antimuscarinic medication, is the initial
therapy of choice for nerve-agent exposure. This will
attenuate the effects of acetylcholine at muscarinic
receptors, especially on heart rate. Other ameliorative
effects are to decrease secretions, reduce sweating, slow
gastrointestinal motility, and pupillary dilation.
a. The U.S. military use atropine auto injectors containing
2 mg of active drug and are trained to administer this
medication intramuscularly in the case of a nerve-agent
attack.
b. Doses are administered until the patient is breathing
comfortably.
c. Miosis and drying of secretions are not guidelines for
therapy.
d. Toxicity from atropine, including delirium and
hyperthermia, can occur at doses of 20 mg or more.
Iranian physicians reported that several nerve-agent
patients required heroic atropine doses, up to 200 mg
[42,44].
2. The second agent used in the U.S. Army’s algorithm of
nerve-agent treatment is pralidoxime chloride, or 2-PAM.
This oxime attaches to the organophosphate that has
effectively bound the acetylcholinesterase and can restore
normal activity to the enzyme. The most notable clinical
effect of 2-PAM is stopping fasciculations in skeletal
muscle and restoration of motor function.
a. Auto injectors of 600 mg of 2-PAM are packaged with
atropine auto injector in the U.S. military’s MARK-
1 kit.
b. Other therapeutic approaches are 1–2 g of 2-PAM via
intravenous delivery in 100 mL of normal saline over
15–30 minutes. Further dosing is based on ameliorating
persistent weakness.
c. For severe toxicity, continuous infusions of 2-PAM can
be given at a rate of 4–20 mg/kg/h. A continuous

infusion might be useful for a number of reasons,
including: slow absorption of organophosphates,
unknown quantity ingested, and delayed nicotinic
effects due to redistribution of lipid-soluble
organophosphates. There is a lack of stability data for
the infusion, and as such, it is recommended that the
infusion be prepared immediately before
administration, and changed every four hours
[32,43,44].
3. Diazepam should be used to treat seizures after nerve-agent
exposure. The U.S. Food and Drug Administration has
approved diazepam for this specific use.
a. The U.S. military packages 10 mg of diazepam under
the name Convulsive Antidote Nerve Agent, or CANA.
b. Soldiers are taught that if the nerve-agent casualty
requires the use of the three MARK-1 kits then a single
dose of CANA should be administered.
c. It is understood that, in civilian practice, diazepam is
not the agent of choice for aborting seizure. Thus the
NCCU physician can consider any appropriate
benzodiazepine for this setting. If status epilepticus
develops, treatment of the underlying condition should
continue while separate, established algorithms for
treatment of status are begun.
Pretreatment or prophylactic treatment with the acetylcholi-
nesterase pyridostigmine bromide is also supported in the U.S.
Army treatment algorithm. While this seems counterintuitive,
the mechanism of such treatment is the temporary occupation
of the cholinesterase with pyridostigmine, in order to deny
access of the active site to a nonreversible organophosphate on
subsequent exposure [32,44].
Cyanide
Cyanide has been successfully used by terrorists domestically
during the Tylenol incident in the Chicago area. It is reported
that cyanide may have also been used on Iranian army units by
Iraq during the Iran–Iraq war, although this remains uncon-
firmed. Cyanide is an unlikely agent for use on the battlefield
due to the difficulties in deploying the high concentration of
agent required to produce illness. However, terrorist use is
considered possible with deployment of the agent indoors or
in a confined space in a mass population setting. It is a highly
toxic agent with a very rapid time to incapacitation. This agent
has been used historically on the battlefields of World War I, in
German Nazi death camps during World War II, and by the
Japanese on Chinese civilians during the same period. It has
also been used for mass suicides, such as the Jones’ cult in
Jonestown, Guyana in 1978, where more than 900 followers
died after drinking cyanide [42,43].
The ionic form of cyanide is the toxic moiety, which blocks
electron transfer from cytochrome oxidase to molecular
oxygen in the mitochondria, arresting oxidative phosphoryl-
ation. Lactic acidosis ensues, as well as loss of critical metabolic
functions of the cardiovascular, respiratory, and central
Chapter 21: Neuroterrorism and Drug Overdose
nervous systems. Three different chemical agents that readily
ionize to CN– have been produced, including hydrogen cyan-
ide (AC), cyanogen bromide, and cyanogen chloride (CK).
Cyanide is found naturally in many fruits, including the pits
of cherries, peaches, apricots, and apples. Poisoning by these
food sources is possible. Other causes of cyanide poisoning are
from residential and motor-vehicle accident fires. Cyanide is
relatively easy to procure because it is manufactured in large
quantities for industrial use in production or processing of
paper, dyeing, printing, mineral extraction, photography, tex-
tiles, and is important in the plastics industry [44].
Cyanide vapor is often described as having the particular
odor of bitter almonds, although approximately one-half of the
population is unable to appreciate this odor, or the olfactory
organs may accommodate to the odor rapidly on exposure.
Onset of symptoms is rapid and predictable after a large dose
of cyanide. Within 15 seconds after inhalation of concentrated
cyanide, patients will begin to hyperventilate and quickly lose
consciousness. This is followed in less than one minute with
the onset of seizures, with cessation of all motor, respiratory,
and cardiac activity approximately six to eight minutes after
exposure. With lower concentrations, as might be encountered
after smoke inhalation or via ingestion or percutaneous
administration, the effects are much slower to develop,
although the time period may still be on the order of minutes,
during which time the patent is potentially treatable with
antidote [18,43,44].
The clinical presentation of a cyanide victim has classically
been reported to show “cherry red” skin and fundus in the
setting of respiratory distress. This is not specific for cyanide
poisoning, however, and can also be seen with carbon monox-
ide poisoning. Other findings or complaints seen with cyanide
toxicity include headache, anxiety, mental status changes, and
agitation. There are specific laboratory tests for cyanide metab-
olites. Measurement of blood cyanide concentration is helpful
in confirming the diagnosis, and can be used by forensic investi-
gators to establish a cause of death. Clinical effects are seen at
concentrations of 0.5–1 μg/mL, and concentrations exceeding
2.5 μg/mL are often not consistent with survival. Arterial blood
gases show an early decreased arteriovenous difference in PO2
with a progressive lactic acidosis. A metabolic acidosis with a
high anion gap can be present. Venous blood gas measurements
show an elevated venous PO2 due to failure of the cellular
respiratory chain and failure to off-load oxygen in the arterial
circulation [18,43].
Due to the rapid onset of action of this chemical, treatment
of a suspected cyanide victim must begin as soon as possible,
including by first responders:
• First, the victim should be removed from the source of
exposure and administered 100% oxygen.
• If any liquid exposure is suspected, removal and
decontamination must be performed before transport to
avoid secondary contamination.
• Activated charcoal can be beneficial after cyanide ingestion.
265
 Chapter 21: Neuroterrorism and Drug Overdose
• Mechanical ventilation, vasopressor support, intravenous
hydration, seizure control with benzodiazepines, and
correction of metabolic acidosis are vital measures [43].
Specific cyanide poisoning antidote therapy is a two-step pro-
cess consisting of methemoglobin formation and administra-
tion of a sulfur donor. The first step is administering sodium
nitrite or a related drug. The goal of this methemoglobin
therapy is to dissociate the bound cyanide from cytochrome a3,
which frees this enzyme to participate again in production of
ATP. Methemoglobin has a stronger affinity for cyanide than
does cytochrome a3. Other than sodium nitrite, one can use amyl
nitrite, 4-dimethylaminophenol (4-DMAP), p-aminopropiophe-
none (PAPP), p-aminoheptanoylphenone (PAHP), or p-amino-
octanoylphenone (PAOP) to form methemoglobin. Because
nitrites cause vasodilation, blood pressure and, if appropriate,
intracranial pressure (ICP) must be monitored. The dose of
sodium nitrite, the preferred antidote used by the U.S. Army, is
300 mg or 10 mL of a 30 mg/mL solution intravenously over
5–15 minutes. This may raise the percentage of methemoglobin
up to 20%, and a second dose of 5 mL or 150 mg can sub-
sequently be given. Pediatric dosing is 0.33 mL/kg, given over
10 minutes.
It is important to remember that methemoglobin is also
toxic and can itself interfere with oxygen transport. Levels of
methemoglobin should not exceed 40%. Methemoglobin-
forming compounds should not be given in smoke-inhalation
patients, due to the effects of carboxyhemoglobin, formed by
carbon monoxide, on oxygen transport. Smoke inhalation is not
a contraindication to treatment with sulfur donor drugs [18,43].
Thiosulfate, a sulfur donor drug, should be given soon after
sodium nitrate. The goal of thiosulfate administration is to
provide substrate for the enzyme rhodanese, which catalyzes
the breakdown of cyanide to thiocyanate and sulfite. These
breakdown products are then excreted by the kidneys. The adult
dose of sodium thiosulfate is 12.5 g IV, which is 50 mL of a 250
mg/mL solution; the pediatric dose is 1.65 mL/kg IV. Two
further treatments with half-doses of sodium thiosulfate can
be given if needed. Other sulfur donors such as hydroxycobala-
min appear to be useful under certain conditions, such as when
treating smoke-inhalation victims [18,43,44].
Subsequent to the incident in Bhopal, India, it has become
clear that delayed effects of cyanide toxicity exist. Postcyanide-
exposure victims can develop clinical parkinsonism, dystonia,
and other neurologic conditions, such as eye movement abnor-
malities, dysarthria, and ataxia. Delayed-onset cognitive dys-
function after apparent convalescence has been reported.
These may be related to hypoxic-ischemic lesions in the brain,
particularly in vulnerable areas of deep gray matter with sym-
metric bilateral basal ganglia lesions. Neuroimaging reveals
findings similar to anoxia-ischemia or profound metabolic
derangement. Magnetic resonance imaging (MRI) may show
cavitations in the lentiform nucleus [32,47].
Differentiating cyanide toxicity from organophosphate tox-
icity can be difficult initially. However, several of the signs seen
266
with organophosphate poisoning are not seen clinically with
cyanide toxicity. There can be some increase in secretions with
cyanide; however, it is not as profound as the hypersecretion
seen with a nerve agent. Miosis is a rare and late complication
with cyanide, but an early finding following organophosphate
poisoning. Fasciculations, a hallmark of organophosphate tox-
icity, are not seen with cyanide poisoning, although seizure
activity may be confused with fasciculations by less experi-
enced providers. Interestingly, cyanide victims are less likely to
present as cyanotic than organophosphate patients [42,43].
Decontamination Principles after Known Chemical Agent Exposure
Decontamination should ensure patient safety, as well as main-
tain a safe and contaminant-free treatment environment. This
can be difficult early in the course of a suspected chemical
exposure, but the concept can be generalized from current
standard isolation procedures well known to hospital staff
currently used for antibiotic-resistant organisms. This involves
the separation of exposed and unexposed equipment, as well as
an isolation line where those who have not yet been contamin-
ated are initially treated before being declared safe to enter the
definitive treatment facility. This process is most vital to
patients exposed to a liquid, aerosol, or dry solid chemical
agent. Vapor exposure is less likely to benefit from skin decon-
tamination owing to the high volatility of vaporized agents.
The process begins with casualty isolation and demarcation
of decontamination areas, with completed decontamination
sites, in-progress decontamination sites, and contaminated
triage areas. Windage must be taken into account in setting
up these sites. Properly trained and equipped medical person-
nel begin by removing clothing from victims, followed by
removal of chemical agents from the skin with a solution of
0.5% hypochlorite solution, which is household bleach. The
mixture used for skin decontamination is nine parts water to
one part 0.5% hypochlorite solution. This can effectively
decontaminate most chemical agents. An alternative is wash-
ing with nonfat-based soap and copious water irrigation. Thus,
this latter method requires a good supply of water. If cases of
eye contamination, eye flushes should be done with normal
saline or water. The irrigation of abdominal or other cavity
wounds with hypochlorite is contraindicated. Higher concen-
trations of hypochlorite can be used to decontaminate equip-
ment, if needed [43].
Conclusion
Toxins are ubiquitous in modern society. They may lead to
patient injury from accidental, intentional, or malicious ter-
rorist causes. The neurocritical care specialist should be famil-
iar with these threats as he or she may be called on to care for
afflicted patients. Also, vigilance for the index case of a bio-
logical or chemical attack, as well as institutional planning for
civilian mass casualty occurrences, must be developed for both
civilian and governmental agencies in all moderate- to large-
sized population centers.

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 Chapter
Infections of the Central Nervous System in the
22 Neurocritical Care Unit
Mohamed Sharaby and Barnett R. Nathan
Central nervous system (CNS) infections are not uncommon
in the neurocritical care unit (NCCU). This chapter reviews
the most common causes of CNS infections and discusses the
diagnosis and management of these life-threatening illnesses.
Encephalitis
The constellation of symptoms, including altered mental
status, focal neurological deficits, and seizures, are often sug-
gestive of cerebral dysfunction that can be referred to as
“encephalitis.” Encephalitis corresponds to an inflammation
of the brain parenchyma that can be caused by both infectious
and noninfectious diseases [1].
Coma and bulbar weakness occurring in a subset of these
patients may require respiratory intubation with admission to
the NCCU. The same is also true of patients that develop either
clinical or electrographic status epilepticus, necessitating
admission to the unit for 24- to 48-hour continuous electro-
graphic monitoring.
According to the California Encephalitis Project, the clin-
ical definition of infectious encephalitis involves the following
two criteria [2]:
1. Encephalopathy marked by >24 hours of depressed or
altered mental status, lethargy, or personality change
necessitating hospitalization.
2. One of the following findings: fever, seizures, focal
neurologic deficits, cerebrospinal fluid (CSF) pleocytosis,
abnormal electroencephalogram (EEG), or abnormal CNS
imaging.
The estimated annual incidence of encephalitis based on
extrapolation from different studies ranges between 3.5 and
7.5 cases per 100,000 persons. Despite the advances in molecu-
lar diagnostic techniques such as polymerase chain reaction
(PCR), a specific cause is found in less than half the cases [3].
Viral Causes of Encephalitis
Herpes Simplex Virus Type 1
Background
Herpes simplex virus type 1 (HSV-1) is by far the most
common etiology of acute sporadic encephalitis, ranging from
10% to 20% of all annual cases of encephalitis in the USA.
HSV-1 gains access in the CNS either via the trigeminal nerve
or the olfactory tract following a primary oropharyngeal infec-
tion. The virus can then remain dormant, but a reactivation
can cause viral spread into the CNS tissue. After CNS invasion,
focal inflammation ensues due to the host immune response
causing tissue damage and necrosis. These focal inflammatory
and necrotizing lesions have a predilection to the temporal
lobes, orbital frontal cortex, and the limbic structures. In most
instances patients present within one week of symptoms onset,
as will be discussed below [4].
Signs and Symptoms
• Patients with herpes simplex encephalitis (HSE) will have
some form of altered consciousness. Cases have been
reported with presentations ranging from lethargy and
coma to manic behavior, as well as focal neurological
disturbances.
• Fever is the most reliable physical finding in HSE,
occurring in 95% of patients.
• Headache is also a common feature while meningeal signs
are uncommon.
• Seizures can be the main presenting symptom in HSE,
reported in two-thirds of the cases seen, and are more
common in younger patients. Seizures are an independent
predictor of worst outcomes, with chronic epilepsy being a
potential complication after recovery.
• Due to the lesions involved, patients often have CNS
dysfunction attributable to the frontal and temporal
lobes such as aphasia, visual field cuts, or
hallucinations.
Diagnostic Workup
Laboratory
Lumbar Puncture (LP)
• CSF pressure is not characteristically elevated.
• CSF mononuclear pleocytosis is usually present (around
40 white blood cells (WBC)/mm3), at times with a
neutrophil predominance very early in the course.
• CSF erythrocytes are present in a majority of patients, but
this finding is not a diagnostic criterion.
• CSF protein is usually elevated as well, with a median of
70 mg/dL. CSF glucose should be normal.
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 Chapter 22: Infections of the Central Nervous System
• CSF HSV-1 polymerase chain reaction (PCR) has >95%
sensitivity and specificity. It has replaced CNS biopsy as the
gold standard diagnostic measure for HSE.
• CSF PCR negativity if the LP was done too early may also
necessitate a repeat LP within 72 hours if the suspicion is
still present.
• CSF sampling from a repeat LP after two weeks of
treatment has been recommended by recent literature, in
order to decide whether or not to continue antimicrobial
therapy for a longer duration.
Imaging
• Computed tomography (CT) of the brain without contrast
is often normal until several days into the course when
hypodensities within the temporal lobes, usually
asymmetric, appear. These signal a graver prognosis.
Hemorrhages apparent on CT are possible, but unusual.
• Magnetic resonance imaging (MRI, with and without
contrast) is far more sensitive in detecting changes
associated with HSE, but a normal MRI does not exclude
the diagnosis. Lesions caused by HSV-1 will appear as
hyperintensities on T2-weighted sequences, including
diffusion-weighted imaging (DWI). These sequences show
cytotoxic edema that is commonly misinterpreted as acute
stroke. These changes are frequently reversible. Gradient
echo sequences may show evidence of hemorrhagic
necrosis. Lesions of HSE will typically enhance with
gadolinium.
Other Testing –– Electroencephalography (EEG) is abnormal
in a high proportion (up to 80%) of patients suffering from
HSE. The findings of periodic lateralizing epileptic discharges
(PLEDs) are commonly seen, though not particularly specific.
Therapy
Antivirals
• Immediate infusion of acyclovir is the mainstay of therapy,
and can reduce mortality by more than 70%. Favorable
outcomes have been shown in patients that are younger
than age 30.
: A regimen of acyclovir 10mg/kg IV q 8 h for 14–21
days should be used with attention to nephrotoxicity.
Resistance to acyclovir has been reported, but only in
immunocompromised patients.
: If a second LP is performed at the two-week mark with
evidence of HSV DNA being present, the treatment
should be continued.
• Foscarnet 40 mg/kg IV q 8 h for 14–21 days is available as a
salvage regimen.
Adjunct Therapies
Antiepileptics –– No recommendation exists for prophylactic
administration. Patients presenting with seizures should be
started on an antiepileptic drug (AED), and those having
abnormal EEGs should be considered for AEDs.
270
Other Therapies –– The risk of hemorrhage due to HSV-1
infection is not a contraindication for subcutaneous adminis-
tration of heparin for prophylaxis of deep vein thrombosis.
Prognosis
Prognosis of patients with HSE has been shown to depend on
the extent of neurologic deficits at presentation and the
amount of time between onset of symptoms and initiation of
treatment. Even with treatment, six-month mortality is 15%,
and a long-term disability rate of 20% has been reported.
Varicella Zoster Virus
Background
Varicella zoster virus (VZV) is the most common cause of
encephalitis in immunocompromised patients, occurring as a
complication of HIV/AIDS, and patients undergoing organ
or stem-cell transplant. The mechanism is secondary to
inflammation of cerebrovascular endothelial vessels and/or
infection of the choroidal cells. Both primary VZV and
reactivation may produce CNS disease in the immunocom-
promised patient [5].
In immunocompetent patients a vasculopathy presents
acutely with focal deficits due to involvement of the large
cerebral arteries following the trigeminal distribution by weeks
to months. However, in immunocompromised patients the
presentation is that of vasculopathy of small- to medium-sized
arteries, resulting in mental status changes, focal deficits, and
CSF pleocytosis.
Following an acute infection with VZV (chickenpox), the
virus remains dormant in ganglia throughout the nervous
system. With the decline in cell-mediated immunity that
occurs with aging, or with acquired immunosuppression,
VZV may reactivate resulting in the zoster eruptions known
as shingles. By age 85 about 50% of the population will have
experienced zoster. Most VZV encephalitis cases occur in the
adult population, especially the elderly after an episode of
zoster.
Signs and Symptoms
• Patients with CNS involvement may present with
encephalitis. VZV encephalitis may or may not be
temporally related to the VZV rash and the onset of CNS
symptoms. The severity and distribution of CNS symptoms
also varies. In the majority of cases, VZV encephalitis is
concomitant with VZV meningitis, which is normally
benign and self-limiting.
• VZV can also cause myelitis. Immunocompromised
patients are at greater risk for VZV myelitis. These patients
present with paraparesis, sensory loss, or bowel and
bladder dysfunction. An outbreak of VZV rash precedes
these symptoms, but days or weeks may separate them.
• The worst prognosis and the most common cause of
encephalitis attributable to VZV is vasculitis. VZV
vasculitis affects either large or small vessels.

• Large-vessel vasculitis occurs from 2 to 10 weeks after
ophthalmic zoster. Patients present with acute, focal
neurologic deficits in stroke distributions. Some patients
develop large-vessel vasculopathy, called granulomatous
arteritis, which may also result in ischemic stroke, the
formation of aneurysms, or arterial dissection.
• Small-vessel vasculitis is more of a subacute presentation
occurring weeks or even months after a zoster outbreak. It
is much more common in immunocompromised patients.
Diagnostic Workup
Laboratory
Lumbar Puncture
• CSF typically shows a mild lymphocytic pleocytosis,
ranging from 7 to 260 WBS/mm3.
• CSF protein may be normal or slightly elevated (maximum
76 mg/dL). CSF glucose should be normal.
• Oligoclonal bands can detected in 30% of the cases a week
or more after symptom onset.
• Detection of anti-VZV IgG antibodies is more sensitive in
the diagnosis of zoster cerebral vasculopathy.
• CSF polymerase chain reaction (PCR) for VZV has a high
sensitivity and specificity.
Imaging
• CT of the brain with and without contrast is most often
normal in VZV encephalitis. Subcortical infarcts ipsilateral
to prior VZV infection sites (eye or rash) signal vasculitis.
• MRI of the brain with and without contrast should be
performed with both magnetic resonance angiography
(MRA) and DWI and an apparent diffusion coefficient map
(ADC) to detect infarcts and large-vessel changes
associated with vasculitis. Typically, the MRI will reveal
areas of increased T2 signal without restricted diffusion on
DWI, indicating no infarction.
• Cerebral angiography may be performed. An abnormal
angiogram is more common in large-vessel vasculitis and
may demonstrate a diffuse vasculitis. Particularly severe
cases with critical narrowing of the carotid artery have been
reported.
Therapy
Antivirals
• Despite the lack of trials to support its use in VZV, a
regimen of acyclovir 10–15 mg/kg IV q 8h for 14–21 days
should be used with attention to nephrotoxicity.
Adjunct Therapies
• For suspected or established vasculitis, methylprednisolone
1000 mg IV per day or its equivalent should be
administered for three to five days and tapered down
thereafter.
• Prophylactic antiepileptics have not been shown to play an
important role in management of patients with VZV.
Chapter 22: Infections of the Central Nervous System
Epstein–Barr Virus
Background
Infectious mononucleosis is what we think of when we think of
Epstein–Barr virus (EBV), with characteristic lymphadeno-
pathy, pharyngitis, and splenomegaly. Involvement of the CNS
with EBV occurs in 1% of cases, and can present as meningitis,
encephalitis, cerebellitis, transverse myelitis, optic neuritis, cra-
nial neuropathy, Guillain–Barré syndrome (GBS), and as small-
fiber sensory or autonomic neuropathy syndrome [5].
Signs and Symptoms
EBV encephalitis may present with frank encephalopathy with
altered mental status, coma, seizures, and focal neurologic
deficits. It can occur before, during, or after infectious mono-
nucleosis, or even in its absence. Some patients may exhibit an
encephalomyeloradiculitis, and some cases may mimic HSE,
with EBV accounting for about 8% of HSV-1-negative cases.
Some patients might present with an encephalomyeloradi-
culitis picture marked by headache, cough, malaise, fever,
somnolence, and mild lower extremity numbness and
weakness.
Diagnostic Workup
Laboratory
• EBV DNA amplification from CSF or serologic studies is
indicative of acute infection.
• Viral capsid antigen (VCA) IgM antibody in the serum is
indicative of active EBV but does not confirm CNS disease.
Imaging
• In encephalomyeloradiculitis, gadolinium-contrast MRI
may show nerve root signal enhancement.
Therapy
Antivirals
Acyclovir and ganciclovir may be of benefit in the treatment
of EBV.
Epstein–Barr Human Herpes Virus Type 6
Background
Epstein–Barr human herpes virus type 6 (HHV-6) is a T-
lymphotropic virus that causes a spectrum of diseases, such
as exanthema subitum, lymphadenopathy syndromes, and
meningoencephalitis. Approximately 6% of non-HSV enceph-
alitis are attributed to HHV-6 infection. HHV-6 encephalitis is
generally rare, except in the immunocompromised patient
population [5].
Signs and Symptoms
• HHV-6 can cause encephalitis in both immunocompetent
and immunocompromised patients.
• Many patients can present with temporal lobe epilepsy, and
cranial nerve palsies.
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 Chapter 22: Infections of the Central Nervous System
• The virus is also recognized as an agent in some cases
of limbic encephalitis in bone marrow transplant
recipients.
• Patients may present with behavior disturbances.
Diagnostic Workup
Laboratory
Lumbar Puncture
• HHV-6 DNA can be detected in CSF and serum with PCR
testing.
Cytomegalovirus
Background
Cytomegalovirus (CMV) encephalitis is extremely uncommon
in immunocompetent patients. However, immunosuppressed
patients may be afflicted with the condition. This is true in
HIV/AIDS and bone marrow transplant patients. CMV
encephalitis occurs due to reactivation of a previously latent
viral infection [5].
Signs and Symptoms
CMV encephalitis is characterized by nonspecific febrile
encephalopathy that can be with or without focal neuro-
logical deficits. The acute form of CMV encephalitis has been
referred to as microglial nodular encephalitis, characterized
by delirium and confusion. The subacute form is referred to
as ventriculoencephalitis, characterized by confusion and
cranial nerve dysfunction. In one-quarter of the patients
there is involvement of the brainstem with either horizontal
or vertical nystagmus, internuclear ophthalmoplegia, and
cranial nerve neuropathies. CMV encephalitis should be sus-
pected in the setting of CMV retinitis or CMV gastrointest-
inal disease.
Diagnostic Workup
Laboratory
Lumbar Puncture
• CSF pleocytosis will be observed with a
polymorphonuclear predominance.
• CSF protein is typically elevated, with depressed or normal
glucose levels.
• CSF PCR for CMV has a sensitivity of 82% and a specificity
of 99% in patients with AIDS.
Imaging
• On MRI, periventricular T2 hyperintensities are indicative
of CMV infection, and accompany ependymal gadolinium
enhancement on T1 sequences.
Therapy
• Ganciclovir 5 mg/kg IV q 12 h for 14–21 days.
• Following the acute stage of treatment, a daily maintenance
regimen of 5 mg/kg/day is started. Oral valganciclovir has
also been used for daily maintenance therapy.
272
Enteroviruses
Background
As a group, enteroviruses (EVs) are collectively the third
most common cause of sporadic viral encephalitis. It occurs
in 2% to 25% of confirmed viral encephalitis, especially in the
immunodeficient patient population with hypogammaglobu-
linemia [3].
EV is transmitted via the fecal–oral route. The EV71 sero-
type is highly virulent and has been associated with more cases
of encephalitis associated with brainstem dysfunction.
Signs and Symptoms
• The presentation of patients with enterovirus
encephalitis is typically less severe than other viral
etiologies, with less than 10% of patients presenting
with coma.
• EV71-related encephalitis affects children and younger
adults with associated fever, myoclonus, ataxia, nystagmus,
and cranial nerve palsies. In most cases the patients recover
fully. However, in approximately 20% of cases the patient is
left with residual neurological sequelae.
• EV71 is unique in causing rhombencephalitis with a more
fulminant course.
• Rapidly progressive neurogenic pulmonary edema may be
observed in some cases, which carries a mortality rate of 80%.
Diagnostic Workup
Laboratory
Lumbar Puncture
• CSF analysis in EV encephalitis usually reveals a
lymphocytic pleocytosis (median 100 WBC/mm3)
• CSF protein levels are slightly elevated (median 54 mg/dL),
with a normal glucose level (median 54 mg/dL)
• Viral PCR is very sensitive in diagnosing the disease.
Imaging
MRI of the brain is abnormal in half the number of cases seen.
There is not a specific area of the brain that EV has a predilec-
tion for. A lot of cases seem to mimic HSV with a temporal
lobe distribution of inflammation.
Therapy
There is no specific treatment. However, pleconaril and IVIG
has been tried.
Arboviruses
Arthropod-borne viruses are a vast group of viruses that are
transmitted to humans by mosquito and tick vectors. Three
family groups make up arboiruses, namely togaviruses, reo-
viruses, and bunyaviruses [3].
Several of the pathogens causing encephalitis belong to the
Flavivirus genus, including Japanese encephalitis virus (JEV),
West Nile virus, tick-borne encephalitis virus (TBEV), and

S. Louis encephalitis virus (SLEV). Each of the aforemen-
tioned pathogens are zoonotic, with primary transmission
amongst animals; however, humans are also affected, which
causes viral amplification. Most flaviviruses are transmitted
by mosquitoes as a vector, and predominantly between birds
as the main reservoir in less temperate environments. How-
ever, TBEV is transmitted by hard ticks, primarily amongst
small rodents.
St. Louis Virus
Background
SLEV is endemic in the western United States, with large
periodic outbreaks in the eastern United States, affecting pre-
dominantly patients above the age of 50, although it is particu-
larly severe in elderly patients.
Signs and Symptoms
• Subacute presentation with headache and fever, tremors,
nausea, vomiting, seizures, stupor, and paresis, marked by
generalized weakness rather than focal abnormalities.
• Urinary symptoms, including dysuria, urgency, and
incontinence may be early features.
• In one-third of all patients syndrome of inappropriate anti-
diuretic hormone (SIADH) may be present.
Diagnostic Workup
Laboratory
Lumbar Puncture
• CSF pressure is normal or mildly elevated.
• CSF IgM SLEV-capture ELISA yields 100% positivity by
the seventh day of the patient’s illness.
Serum Testing
• Serum IgM is typically positive, but is not a very specific
test, as there can be cross-reactivity with other flaviviruses.
Imaging
• MRI may show hyperintense lesions in the substantia
nigra, basal ganglia, and thalami.
Therapy
Therapy is purely supportive. There is a risk of patients
developing cerebral edema as well as seizures. Interferon α-
2b may be considered.
West Nile Virus
Background
WNV is another one of more than 70 viruses in the family
Flaviviridae of the genus Flavivirus. It is classified into five
phylogenetic lineages, with only the first two lineages being
associated with significant human outbreaks [5,6].
Mosquitoes are the main vectors, with birds serving as the
main reservoir. It is endemic to north and central America and
there is increased incidence in patients greater than 50 years of
Chapter 22: Infections of the Central Nervous System
age and immunocompromised patients. Transmission through
transfusion and transplantation has also been reported. The
initial cells infected are skin keratinocytes and dendritic cells,
which migrate to the lymphatic system, causing serum viremia
and eventually end-organ infection.
The neuroinvasive mechanism of WNV has been postu-
lated to be through: (1) viral crossing of the blood–brain
barrier (BBB) due to cytokine-mediated increased vascular
permeability, (2) passage through the BBB endothelium, (3)
infected macrophages crossing the BBB through a Trojan
horse mechanism, (4) retrograde axonal viral transport into
the CNS via peripheral and olfactory neurons.
WNV can present as West Nile fever (WNF), West Nile
meningitis (WNM), and West Nile encephalitis (WNE), with
variable presentations. The incubation period for clinical ill-
ness ranges from 2 to 14 days. However, the incubation could
take up to 21 days in immunocompromised patients. WNV
can range from a mild fever lasting a few days to a debilitating
illness lasting weeks to months.
Signs and Symptoms
• WNE ranges in severity from a mild self-limiting
confusional state to severe encephalopathy, coma,
and death.
• Extrapyramidal disorders are frequently seen, and
parkinsonism features may be observed.
• Patients with WNE may frequently develop a coarse upper
extremity tremor. The tremors are postural and have a
kinetic component.
• Myoclonus may be seen in the upper extremities and facial
muscles, particularly during sleep.
• Cerebellar ataxia, increased intracranial pressure (ICP),
cerebral edema, and seizures have been described but are
rarely seen.
• West Nile “poliomyelitis” occurs less frequently, and may
prove the initial symptom rather than following WNF.
This condition is marked by weakness in a pattern
characteristic of anterior horn cell dysfunction.
Patients may also develop bulbar weakness with
dysarthria and dysphagia ominous for impending
respiratory failure.
Diagnostic Workup
Laboratory
Lumbar Puncture
• WNV-specific IgM antibodies can be detected in the CSF.
However, the development of IgM antibodies may be
delayed or absent.
• CSF pressure is normal, with pleocytosis, normal glucose,
and mildly elevated CSF protein.
• CSF PCR for WNV is available, and although not sensitive
enough to rule out disease, its specificity allows for
diagnosis when positive.
• CSF WNV IgM antibodies also secure a firm diagnosis.
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 Chapter 22: Infections of the Central Nervous System
Serum Testing
• A rising titer of serum WNV IgG or IgM antibodies can
also assist in securing a diagnosis. However, as with IgM
antibodies in the CSF, their presence may be delayed in
immunocompromised patients.
Imaging
• T2-weighted and fluid-attenuated inversion recovery
(FLAIR) MRI findings may be seen in approximately 30%
of cases. These include hyperintense lesions in the
substantia nigra, basal ganglia, and bilateral thalami.
Similar lesions can also be seen in the spinal cord.
Therapy
Treatment of patients with neurologic complications of WNV
is purely supportive at this time. Ribavirin is not recom-
mended as a therapy.
Prognosis
West Nile encephalitis has a reported mortality as high as
12–14%. Patients with West Nile poliomyelitis most often do
not recover full motor function.
Tick-Borne Encephalitis Virus
Background
In TBEV, hard ticks are the vector, with rodents being the
typical reservoir. The virus could also be found in unpasteur-
ized milk. It is endemic to Russia, Central Europe and the Far
East, but rarely seen in the USA, with most cases being
involved in travel to the aforementioned regions [5].
Signs and Symptoms
• The presentation is that of acute encephalitis with
headache, fever, and poliomyelitis-like paralysis.
Diagnostic Workup
Laboratory
Lumbar Puncture
• TBEV IgM in the CSF is usually diagnostic.
Serum Testing
• Serum IgM antibodies can also be tested. The virus can also
be cultured from the blood in the early viremic phase.
Imaging Nonspecific.
Therapy Therapy is typically supportive.
Influenza Virus
Background
Encephalitis is a very uncommon complication of seasonal
influenza. However, influenza itself is common, and most
recently there have been several influenza pandemics. The
encephalitis associated with influenza is not typically due to
direct CNS invasion, but rather due to complications of
274
baseline neurologic conditions [5]. The most common compli-
cation is exacerbation of seizures in an epileptic patient.
Signs and Symptoms
• The occurrence of prior or concomitant respiratory tract
symptoms.
• Acute encephalitis of influenza is characterized by altered
mental status, somnolence, behavioral changes, and coma
in rare cases.
• Postinfluenza encephalitis may occur two to three weeks
after recovery from influenza.
• Parkinsonian signs have been described, and as previously
mentioned there is worsening of seizures.
Diagnostic Workup
Laboratory
Lumbar Puncture
• CSF may show elevated protein levels or a mild pleocytosis.
However, in the majority of cases the CSF studies are
normal.
Imaging
• MRI of the brain may show nonspecific T2 signal
abnormalities in the splenium of the corpus callosum, focal
or generalized cerebral edema, or a posterior reversible
encephalopathy picture. Some literature describes a finding
of necrotic lesions in the bilateral thalami.
Therapy
The patient should receive a five- to ten-day course of oselta-
mivir 75 mg PO BID.
Prognosis
The overall prognosis is typically good, with full recovery.
JC Virus
Background
Progressive multifocal leukoencephalopathy (PML) is an
encephalitis-like presentation caused by JC virus and should
be considered in patients with impaired cell-mediated immun-
ity, especially those with advanced HIV, hematologic malig-
nancies, and patients on immunomodulating therapy such as
the humanized monoclonal antibody (natalizumab).
Signs and Symptoms
• The patient may present with cognitive dysfunction.
• There may be focal neurological findings such as limb
weakness, visual cuts, and visual blindness.
Diagnostic Workup
Laboratory
Lumbar Puncture
• CSF PCR is diagnostic and is 50–75% sensitive, and
98–100% specific.

• Where CSF results are equivocal, there may be a need to
biopsy the brain to confirm the diagnosis.
Imaging
• MRI shows one or more nonenhancing, confluent
subcortical white matter hyperintensities on T2-weighted
and FLAIR imaging.
Therapy
All immunosuppressive medication should discontinued. An
HIV patient should resume or be started on highly active
antiretroviral therapy (HAART).
Bacterial Causes of Encephalitis
Bartonella
Background
Bartonella henselae, a curved Gram-negative rod, is commonly
acquired from cats, however the bacteria can also be transmit-
ted by rodents and dogs, as well as fleas, and leads to a systemic
disease marked by high fever, painful adenopathy, and hyper-
pigmented plaques and ulcerated nodules, known as cat
scratch disease. Independent of this manifestation, however,
some patients develop encephalitis with onset approximately
two to three weeks after exposure [7].
Signs and Symptoms
• As with cat scratch disease, high fever marks Bartonella
encephalitis, along with regional lymphadenopathy at the
bite or scratch site.
• Seizures and status epilepticus occur in more than 50% of
patients with Bartonella encephalitis.
• Cranial nerve deficits such as Bell’s palsy are observed, in
addition to visual deficits such as neuroretinitis.
Diagnostic Workup
Laboratory
Lumbar Puncture
• CSF pleocytosis is expected, but CSF glucose and protein
should be normal.
• CSF and lymph node cultures are of low yield.
• CSF Bartonella PCR is available, but is also of low yield.
Serum Testing
• As with CSF cultures, serum cultures are of low yield.
• Rising titer of Bartonella antibody secures a diagnosis.
Other Testing
• If the diagnosis is equivocal, a biopsy of the inflamed
lymph node for silver staining.
• Bartonella endocarditis is a serious mortality risk, and in
patients with systemic disease, obtaining an
echocardiogram is necessary.
Chapter 22: Infections of the Central Nervous System
Therapy
• Erythromycin 500 mg IV q 6 h for several months is
required for full treatment. This may be substituted with
azithromycin.
• If there is no improvement in symptoms after two to three
weeks, the patient should be tried on doxycycline 100 mg
PO daily, and rifampin 600 mg PO daily for three to six
months.
Prognosis
With adequate support, patients with treated Bartonella
encephalitis recover completely.
Legionella
Background
Legionella pneumophila is a cause of pneumonia. It can prove
to be deadly in the elderly patient population, especially in
patients who are both smokers and alcohol drinkers, or are
immunosuppressed. In the younger patient population Legion-
ella pneumophila can cause encephalitis.
Signs and Symptoms
• Legionella should be considered a possible culprit in a
patient with an atypical pneumonia along with
encephalopathy.
• Patients may present with headache and delirium or
lethargy.
• In some cases more focal deficits such as ataxia or cranial
nerve palsies have been reported.
• The patient may develop an SIADH picture.
Diagnostic Workup
Laboratory
Lumbar Puncture
• CSF is usually normal.
• Legionella is not cultured or identified from CSF.
Imaging
• CNS imaging is typically normal.
Other Testing
• Sputum or nasopharynx PCR swab is available. It is highly
specific, but has poor sensitivity.
Therapy
• Therapy consists of a high-dose, intravenous
fluoroquinolone such as levofloxacin 750 mg/day or
moxifloxacin 400 mg/day.
• Rifampin 300 mg IV q 12 h should be added to the
fluoroquinolone.
• Therapy should continue for 10 days.
• Patients able to tolerate PO medications may be
converted to oral formulations once symptoms have
resolved.
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Mycoplasma
Background
Mycoplasma pneumoniae is another atypical bacterium that
causes high fever and a lengthy, unproductive cough, and can
also lead to a variety of neurologic diseases including trans-
verse myelitis, GBS, and a marked encephalitis [8].
Signs and Symptoms
• Seizures or nonconvulsive status epilepticus can be seen in
up to 10% of cases.
• Mycoplasma more often causes meningoencephalitis.
• Cases with cranial nerve palsies have also been reported.
Diagnostic Workup
Laboratory
Lumbar Puncture
• CSF pressure is typically elevated.
• A significant pleocytosis is evident. Neutrophils may
predominate early, but a monocytic pleocytosis is expected.
• CSF PCR for Mycoplasma is available, but is not sensitivite
enough to be able to rule out the disease.
• Mycoplasma antibodies, with attention to titer trends, are
usually required for diagnosis.
Serum Testing
• The WBC count is typically normal, prompting
consideration of atypical pneumonia in patients with a
prodrome of cough and fever. Cold agglutinins, the classic
finding of Mycoplasma pneumonia, will also be evident in
encephalitis patients.
• Mycoplasma IgM could secure a diagnosis, though this test
is often negative for up to two weeks into the course of the
disease.
Imaging
• CNS imaging is usually unremarkable in Mycoplasma
encephalitis.
Therapy
• Standard therapy consists of erythromycin 500 mg IV q 6 h
for 21 days. Patients with resolution of symptoms may be
converted to oral erythromycin after 10 days.
Prognosis
Full recovery is typically achieved in a patient who is promptly
started on the correct antibiotic therapy.
Meningitis
Delineating between viral meningitis and encephalitis can at
times be a hard endeavor. In contrast to encephalitis, patients
with meningitis do not have primary deficits of brain function.
The pathology of viral meningitis is that of inflammation of
the leptomeninges. However, just because the pathology differs
from that of encephalitis, that doesn’t mean that patients do
276
not present with similar signs and symptoms. Indeed, patients
requiring neurocritical care for bacterial meningitis usually
require a high level of care to manage complications from a
secondary cerebritis or encephalitis.
Viral Causes of Meningitis
Viruses cause a self-limiting meningitis. CSF samples from
patients with viral meningitis show a relatively modest pleocy-
tosis, normal to moderately elevated protein, and normal glu-
cose. Viruses involved include enteroviruses such as coxsackie
and echovirus, HSV-2, Epstein–Barr virus, CMV and VZV.
These are typically self-limiting diseases often defying attempts
at diagnosis and requiring little in the way of supportive care.
Viruses such as HSV-2 may cause recurring meningitis,
though these are again unlikely to require critical care. When
viral CNS infection requires more acute care, the disease
typically begins or rapidly progresses into encephalitis.
Bacterial Causes of Meningitis
Background
The presentation of bacterial meningitis varies by age group.
The typical signs and symptoms suggestive of bacterial men-
ingitis include headache, fever, neck stiffness, and altered
mental status (AMS) [9]. Adults may not manifest all four
signs, and typically one or two signs are evident at presenta-
tion. In the elderly patient population, focal neurological
findings, along with AMS, is the usual presentation. Neck
stiffness and headaches are notably less frequent in that
age group.
In younger adults the most common causative agents of
community-acquired meningitis are Streptococcus pneumoniae
and Neisseria meningitides. In the elderly population the most
common causative agents are S. pneumoniae and Listeria
monocytogenes. However, in the elderly group a wide variety
of other pathogens can be found, depending on the patients’
coexisting conditions and associated immunocompromise.
Other groups that warrant mentioning include alcoholics,
patients with HIV, diabetics, patients on immunosuppression,
asplenic patients, and those with cancer. This group can be
referred to collectively as patients with immunocompromised
status, and presentation of bacterial meningitis may be atyp-
ical. Whereas the patient may present with headache, fever,
neck stiffness, and AMS, there are reports of patients present-
ing with just seizure as the manifestation of bacterial meningi-
tis. The most common pathogens causing bacterial meningitis
in this group include S. pneumoniae, L. monocytogenes, Escher-
ichia coli, Salmonella species, and Staphylococcus aureus.
Some surgical or trauma patients may have recurrent men-
ingitis. These include patients that have had traumatic head
and brain injury, or patients that have had previous head and
neck surgery by specialties such as neurosurgery or otolaryn-
gology presenting with a CSF leak causing recurrent episodes
of bacterial meningitis. Once more the manifestation of symp-
toms may be typical or atypical. The most common pathogens

causing bacterial meningitis in this group include S. pneumo-
niae, Neisseria meningitides, and Haemophillus influenza non-
B serotypes.
Finally, adults with nosocomial meningitis make up a group
by themselves. This is a rare diagnosis and in this group the
causative pathogens are different from the community-acquired
group. They may be neurosurgical or neurological patients that
have undergone challenging neurosurgical interventions or
patients that have had prolonged neuro ICU stays. In this
group, fever and AMS is the typical presentation. For this group
staphylococci and Gram-negative bacilli (such as Pseudomonas
aeruginosa) are the most common causative agents.
The key with bacterial meningitis is to keep a low threshold
of suspicion and to act fast once any of the signs and symp-
toms are noticed to avoid falling behind in the treatment of
these patients. Untreated, bacterial meningitis can be fatal. The
outcome depends on the particular group the patient falls into
and on how rapidly therapy is initiated. The emphasis in the
treatment of this disease is focused on rapid, empiric antibiotic
coverage with little or no delay for diagnostic measures [10].
Signs and Symptoms
• As mentioned above, the signs and symptoms can be
typical or atypical. However, most patients present with
only one or two of the previously mentioned signs of
headache, fever, neck stiffness, and AMS.
• Kernig’s and Brudzinski’s signs have only 50% sensitivity.
• A significant proportion (10%) of patients with bacterial
meningitis present with seizures.
• Between 10% and 20% of patients also have cranial nerve
palsies, especially III, VI, and VII.
Diagnostic Workup
Laboratory
Lumbar Puncture
• CSF pressure is typically elevated.
• A significant pleocytosis with neutrophil predominance is
present.
• CSF WBC >100 and up to 2000 WBC/mm have been
3 key feature of the disease. MRI is also more sensitive for
observed.
• CSF glucose is <40 mg/dL or <40% of serum glucose.
• CSF protein is elevated >45 mg/dL.
• CSF culture is the gold standard for the diagnosis of
bacterial meningitis.
• Gram stain often, but not always, gives an initial indication
of pathogen. It has been found helpful in culture-negative
patients.
• CSF latex agglutination can also be utilized in culture-
negative, and Gram-stain-negative patients. The test
provides serum containing bacterial antibodies or
commercially available antisera directed against the
capsular polysaccharides of meningeal pathogens.
• CSF PCR has also been used to identify causative
pathogens in culture-negative patients.
Chapter 22: Infections of the Central Nervous System
• Soluble triggering receptor expressed on myeloid cells 1
(STREM-1) has been found to be a biomarker for the
presence of bacterial meningitis but has not been widely
used in clinical practice.
• Empiric antibiotic therapy should not be delayed prior to
obtaining a CSF sample by performing a lumbar puncture,
even in an anatomically difficult patient.
Serum Testing
• Blood cultures can prove vital in determining the causative
organism and in establishing susceptibility patterns,
especially in cases where the CSF cultures are negative. For
example, Listeria is more commonly cultured from blood
than CSF.
• Serum inflammatory markers can help in distinguishing
between bacterial and viral meningitis. Increased serum
procalcitonin (>0.5 ng/ml) and C reactive protein levels
(>20 mg/L) are strongly suggestive of bacterial meningitis.
Other Testing
• Skin biopsy with Gram stain and cultures can be of value,
particularly in patients with meningococcal meningitis.
Imaging
• An effort should be made to obtain a CT scan of the
patient’s brain if this will not delay therapy, especially
before attempting an LP.
• In certain patient populations, a CT of the head prior to LP
is a must. These include the elderly, the
immunocompromised, and patients presenting with or
known to have a history of seizures or epilepsy. A CT scan
of the brain prior to LP should also be obtained in patients
with AMS, cranial nerve palsies or motor weakness, and
aphasia.
• Noncontrast CTs are preferred in the interest of time and
may show edema due to cerebritis or signs of abscess.
• MRI may also be used in the diagnosis of meningitis,
although it can prove to be time consuming. Meningeal
enhancement, especially apparent in coronal sections, is a
detecting abscesses that require an alternative therapeutic
approach. In addition, MRI is also a sensitive means of
discovering a source of bacterial invasion such as
osteomyelitis or sinusitis.
Specific Pathogens [10]
Streptococcus pneumoniae
• Streptococcus pneumoniae is a Gram-positive coccus
responsible for the majority of adult cases of bacterial
meningitis, particularly in patients over the age of 50.
• Asplenic patients, the immunocompromised, those with
multiple myeloma, hypogammaglobulinemia, alcoholism,
chronic liver or kidney disease, malignancy, diabetes, or
basilar skull fractures with leakage of CSF are more
susceptible to S. pneumoniae infection.
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• Patients with defects in their innate immunity, and those
with complement system defects are more susceptible to S.
pneumoniae meningitis.
• S. pneumoniae meningitis can be brought about by another
focus of infection, whether continguous or distant, such as
pneumonia, otitis media, mastoiditis, sinusitis, and
endocarditis.
• High rates of S. pneumoniae resistance to penicillin of up to
35% in some regions of the United States complicate
selection of empiric antibiotics for bacterial meningitis.
This necessitates the use of synergistic antibiotic
combinations (e.g. cephalosporins, vancomycin, and
rifampin). Additionally, decreasing the antibiotic-induced
release of immunostimulatory cell wall components may
prove to be an efficient new therapeutic strategy.
• Group B streptococci account for another 4% of bacterial
meningitis cases.
Haemophilus influenza
• Haemophilus influenza is a Gram-negative, coccobacillary,
facultatively anaerobic bacterium. It is the main cause of
meningitis in patients with diabetes mellitus, alcoholism,
asplenic patients, immune-deficient patients, multiple
myeloma patients, and those with head trauma with
resultant CSF leak.
• The majority of patients with H. influenza meningitis have
a focus of infections such as sinusitis, otitis media,
epiglottitis, and pneumonia, suggesting a contiguous or
hematogenous pathway that leads to spread into the CNS.
• Expanded spectrum cephalosporins have become standard
therapy of H. influenza meningitis since the emergence of
β-lactamase-producing H. influenza strains.
Neisseria meningitides
• Neisseria meningitides is a Gram-negative diplococcus
responsible for another 20% of cases, and is considered a
leading cause of meningitis in younger adults.
Meningococcal disease is associated with smoking, living in
the same household as a patient, and nursing.
• Notably, there is an increase in invasive meningococcal
meningitis that was observed in patients with deficiencies
in the terminal complement components (C5, C6, C7, C8,
and C9). This suggests that one should screen for
complement function in patients with recurrent disease.
• The clinical manifestation of meningococcal disease can
vary considerably, ranging from transient fever and
bacteremia to fulminant disease. There have been four
distinct syndromes described in the literature: (1)
bacteremia without sepsis, (2) meningococcemia without
meningitis, (3) meningitis with or without
meningococcemia, and (4) meningoencephalitis.
• This bacteria leads to disease marked by very rapid
progression. In addition, this bacterium leads to a petechial
rash or ecchymoses that signal onset of necrotizing
278
vasculitis and gangrene of the extremities found in 60% of
adult cases. Vasculitis may also manifest as profound
adrenal insufficiency, known as Waterhouse–Friderichsen
syndrome.
• Meningococcal meningitis is frequently complicated by
arthritis and hearing loss. The arthritis is immune-
mediated with immune complex deposition in the joints,
but can also be caused by hematogenous bacterial seeding
of the joints. This is typically on day five of the illness or
during the recovery phase.
• Although a meningococcal vaccine is available, living
contacts and healthcare providers exposed to a patient
diagnosed with N. meningitides infection should take
prophylactic antibiotics (four 600 mg doses of PO rifampin
q 12 h or a single 500-mg dose of ciprofloxacin).
Listeria monocytogenes
• Listeria monocytogenes, a Gram-negative rod, accounts for
about 6% of cases in adults, but up to 20% of cases in the
elderly. It is spread by contaminated food, but is also found
in soil, water, and sewage.
• Risk factors for listeria infection include adults older than
50 years of age, alcoholism, malignancy, the use of
corticosteroid therapy, immunosuppression, diabetes
mellitus, liver and chronic kidney disease, collagen vascular
disease, and conditions associated with iron overload.
• Listeria meningitis cases have been reported after the
administration of antitumor necrosis alpha (TNF-α) agents
such as infliximab and etanercept. This bacterium may
result in a rather benign CSF profile.
• Hyponatremia is a major complication that occurs in a
large percentage of patient with listeriosis. This should be
closely monitored in patients who are being treated in the
neuro ICU setting.
Streptococcus agalactiae
• Streptococcus agalactiae is a β-hemolytic Gram-positive
streptococcus. It causes meningitis most often with severe
underlying conditions.
• The risk factors for S. agalactiae meningitis include age
over 60, diabetes mellitus, pregnancy or the postpartum
state, cardiac disease, collagen vascular disorders,
malignancy, alcoholism, hepatic and kidney failure,
previous stroke, neurogenic bladder, decubitus ulcers, and
corticosteroid therapy.
• There is a slight female predominance, with 63% of the
cases occurring in women that had predisposing factors
found to have a distant focus of infection such as
endocarditis, endometriosis, or sinusitis.
Streptococcus pyogenes
• Streptococcus pyogenes is a spherical Gram-positive
bacterium that can cause meningitis with sinusitis, otitis
media, pneumonia, recent head injury, recent

neurosurgery, or in the presence of a neurosurgical device
or instrumentation.
Staphylococcus aureus
• Staphylococcus aureus, a Gram-positive coccus, is acquired
nosocomially and occurs predominantly after
neurosurgical procedures, or following the placement of a
CSF shunt. It may also be acquired in the community
setting in association with endocarditis,
immunocompromised state, or IV drug abuse.
Concomitant infections such as endocarditis, pneumonia,
or osteomyelitis could cause S. aureus meningitis.
Other Pathogens
• Aerobic Gram-negative species such as Klebsiella species,
Acinetobacter baumannii, Escherichia coli, and
Pseudomonas aeruginosa can cause meningitis in the
setting of head trauma or neurosurgical procedures.
Postneurosurgical meningitis secondary to aerobic Gram-
negative bacteria can occur several weeks after surgery.
• Anaerobic species, such as Bacteroides, Actinomyces, or
anaerobic Streptococci species often occur in mixed
infections associated with abscess, and diagnostic measures
should be directed appropriately.
Therapy
Patient characteristics direct the coverage spectrum of empiric
antibiotics. Therapy should only be narrowed on culture data
and susceptibility data.
Empiric Antibiotics
• Patients 18–50 years of age:
: Vancomycin 1 g IV q 12 h for coverage of methicillin-
resistant S. aureus (MRSA) and β-lactam resistant
S. pneumoniae
: Third-generation cephalosporin such as ceftriaxone
50 mg/kg IV q 12 h or cefotaxime 150 mg/kg IV q 8 h
for broad coverage
: This regimen does not cover Listeria or Pseudomonas
• Patients older than 50 years of age:
: Vancomycin 1 g IV q 12 h
: Third-generation cephalosporin
: Ampicillin 2 g IV q 4 h for coverage of Listeria
• Patients with a history of recent trauma:
: Vancomycin 1 g IV q 12 h
: Ceftazidime 6 g IV q 8 h or cefepime 4 g IV q 8 h for
broader Gram-negative bacilli coverage
• Patients with trauma or recent surgery and a wound
infection:
: Vancomycin 1 g IV q 12 h
: Ceftazidime 6 g IV q 8 h or cefepime 4 g IV q 8h
: Metronidazole 500 mg IV q 6 h for coverage of
anaerobes
Chapter 22: Infections of the Central Nervous System
• Patients with a CSF shunt or CSF leak:
: Vancomycin 1 g IV q 12 h
: Ceftazidime 6 g IV q 8 h or cefepime 4 g IV q 8 h
Adjunct Therapies
Bacterial meningitis is characterized by leptomeningeal
inflammation resulting from infection of the pia, the arach-
noid, and the CSF. It is rapidly progressive disorder where two
distinct, but related pathophysiological processes are involved.
On the one hand there is bacterial invasion of the subarach-
noid space and on the other there is the host’s inflammatory
response to the infection.
The rationale behind using corticosteroids in meningitis
is that the treatment will attenuate the inflammatory
process of the subarachnoid space, and reduce the resultant
vasogenic edema.
The use of corticosteroids has historically been a contro-
versial topic. However, current guidelines suggest that early
administration of corticosteroid before or right at the time of
starting antibiotic therapy and continuation for up to four
days is associated with improved survival and outcome. The
recommended dose is dexamethasone, 10 mg q 6 h for four
days and started before or with the first dose of antibiotics
[11]. There is no apparent benefit in corticosteroid adminis-
tration with meningitis caused by Gram-negative agents.
Prognosis
Mortality for bacterial meningitis depends on the pathogen.
Meningococcal and H. influenzae meningitis carry a mortal-
ity of about 5%, although pneumococcal meningitis has a
mortality around 15–30%. Meningococcal meningitis com-
plicated by sepsis, gangrene, or adrenal failure also has a high
mortality. Adults who survive do so without remnant deficits,
although in up to 30% of complicated cases, hydrocephalus
and cranial nerve deficits such as deafness and optic nerve
dysfunction may result from the high CSF content of pro-
teinaceous material during acute illness and well into
recovery.
Fungal Causes of Meningitis
Fungal meningitis is the result of yeasts gaining access to the
microcirculation from where they seed the subarachnoid space
[12]. Fungal meningitis can occur after neurosurgical proced-
ures. This typically occurs via direct inoculation of the fungus
into the CNS. The usual course of disease is that of subacute or
even chronic meningitis. Fungal meningitis is characteristically
a disease of immunocompromised patients. Sources of
immune dysfunction include HIV and medical immune sup-
pression, but also include lymphoma, leukemia, and other
severe systemic stress. In addition, diabetics are more prone
to fungal infection, as are patients with collagen vascular
disease. Finally, patients receiving total parenteral nutrition
are also at heightened risk for fungemia and therefore fungal
meningitis.
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 Chapter 22: Infections of the Central Nervous System
Cryptococcus
Background
Cryptococcus neoformans can be divided into two disease-
causing species and five serotypes: Cryptococcus neoformans
(serotypes A, D, and AD) and Cryptococcus gattii (serotypes
B and C); most clinical isolates are serotype A. C. neoformans
is a ubiquitous fungus found in soil and is often associated
with bird droppings, particularly pigeons. C. gatti is associated
with certain eucalyptus tree species. C. neoformans causes
infection in immunocompromised individuals and C. gatti
causes infection predominantly in apparently immunocompe-
tent individuals. The primary focus of infection is in the lungs
and the organism may disseminate either acutely or after a
period of latency to extrapulmonary sites, with a particular
predilection for the brain.
Cryptococcal meningitis is the most common CNS fungal
infection [12]. With the HIV infection pandemic, the inci-
dence of cryptococcal infection has emerged as an important
opportunistic infection in persons with HIV infection. Cryp-
tococcal meningitis is one of the AIDS defining illnesses.
Signs and Symptoms
• Cryptococcal meningitis usually has a subacute or chronic
course. Patients usually present with an unrelenting
headache, with or without fever, and malaise. A very small
percentage may present with altered mental status.
• Clinical examination may be normal or may include
meningism, papilledema, cranial nerve palsies and other
focal neurologic deficits, and altered mental state.
• Elevated ICP in the absence of ventricular dilatation may
cause profound visual and hearing loss, and, less
commonly, patients may develop cognitive impairment
and gait ataxia due to obstructive hydrocephalus.
• Patients who are immunocompromised may have much
more subtle presentation, but may also present with severe
headache rapidly progressing to cranial nerve dysfunction
and coma.
Diagnostic Workup
Laboratory
Lumbar Puncture
• Highly elevated CSF pressure, sometimes beyond the range
of manometers is a distinctive finding.
• CSF pleocytosis is often moderate.
• CSF protein is typically highly elevated and glucose is
depressed.
• CSF India ink stain is rarely performed anymore due to a
high occurrence of false positives and negatives.
• A latex agglutination assay for cryptococcal antigen has
high specificity and sensitivity.
Imaging
• CT of the brain without contrast is useful for evaluation of
hydrocephalus.
280
• MRI of the brain with and without contrast is useful for
detection of abscess formation. Elevated ICP and
meningovascular disease are detectable by evaluating DWI
and ADC sequences for new infarcts.
Therapy
Antifungals
• Induction therapy including amphotericin B deoxycholate
(AmBd) (0.7–1.0 mg/kg/day IV) plus flucytosine (100 mg/
kg/day orally in four divided doses) for two weeks, followed
by fluconazole (400 mg (6 mg/day) orally) for a minimum
of eight weeks is the treatment of choice.
• Lipid-based amphotericin B formulations, liposomal
amphotericin B lipid complex (ABLC) (3–6 mg/kg/day IV)
and ABLC (5 mg/kg/day IV) for at least two weeks could be
substituted for amphotericin B deoxycholate among
patients with, or predisposed to, renal dysfunction.
• Amphotericin requires close monitoring for
nephrotoxicity.
• Fluconazole 400 mg PO per day should follow IV
medications for at least 10 weeks. Higher doses of 800 mg
PO per day are preferred.
• Immunocompromised patients require oral fluconazole
until the resolution of immunosuppression.
• Consider discontinuing suppressive therapy during
HAART in patients with a CD4 cell count of 1100 cells/mL
and an undetectable or very low HIV RNA level
sustained for three months (minimum of 12 months
of antifungal therapy); consider reinstitution of
maintenance therapy if the CD4 cell count decreases to
<100 cells/μL.
Adjunct Therapies
• Routine lumbar puncture is often required with a goal of
normal closing CSF pressures.
• Some patients may require lumbar catheter to maintain
acceptable cerebral perfusion pressures.
• Patients with persistently elevated pressures, especially
those who presented with high CSF protein may require
surgical placement of long-term CSF shunts.
• Patients with visual loss due to elevated ICP may benefit
from optic nerve sheath fenestration.
Prognosis
• Mortality can reach up to 40% in patients with AIDS.
• Up to 50% of patients experience relapses.
Candidiasis
Background
Candida species form part of normal human microbial flora
and rarely cause invasive disease unless the host defenses have
been compromised. Most cases are due to Candida albicans,
with very few reports of Candida glabrata and other species

causing infection. Patients with AIDS or neutropenia are at
risk for candidal infections.
Burns, critical illness, those on broad-spectrum antibiotics,
and the use of central venous catheters may allow systemic
disease to develop in otherwise immunocompetent individuals.
CNS infection usually occurs as a manifestation of dissem-
inated candidiasis and can also occur as a complication of a
neurosurgical procedure, CSF shunt placement, or by direct
inoculation during surgery, and rarely following head trauma
[12]. Candida seeding the CNS may lead to meningitis or
abscesses, most commonly microabscesses throughout the
brain parenchyma. C. glabrata causes a more insidious form
of meningitis.
Signs and Symptoms
• Candidal meningitis can cause either acute or chronic
meningitis. Candidal endophthalmitis often leads to
candidal meningitis.
• Patients with meningeal symptoms complaining of blurred
vision or visual loss should undergo funduscopic
examination, which may reveal cotton exudates or small
hemorrhages indicative of the disease.
Diagnostic Workup
Laboratory
Lumbar Puncture
• CSF pressure is normal or modestly elevated.
• CSF adenosine deaminase levels may also be elevated.
• CSF protein is elevated and glucose moderately depressed.
• Isolation of budding yeasts in CSF secures diagnosis.
• Candida is identified by culture in most of the patients.
Imaging
• Neuroimaging is helpful in demonstrating meningeal
enhancement, microabscess, or hydrocephalus.
• Candidal meningitis may also lead to vasculitis and the
resultant infarcts are detectable with DWI and ADC
sequences.
• Mycotic aneurysm rupture is detectable with gradient echo
sequences.
Therapy
• The primary treatment of CNS candidiasis includes
liposomal amphotericin B (3–5 mg/kg/day) with or
without flucytosine (25 mg/kg four times a day) for
several weeks.
• The initial therapy should be followed by fluconazole
400–800 mg (6–12 mg/kg) daily.
• Alternative therapy for patients unable to tolerate
liposomal amphotericin B includes fluconazole 400–800
mg (6–12 mg/kg) daily.
• Treatment should continue for at least four weeks or until
all signs and symptoms, CSF abnormalities, and radiologic
abnormalities have resolved.
Chapter 22: Infections of the Central Nervous System
• The removal of intraventricular devices is recommended.
• Candida lusitaniae, though uncommon, is resistant to
amphotericin.
Aspergillosis
Background
Aspergillus, a genus of filamentous fungi, is ubiquitous
throughout the world and can be found in the air of most
buildings, including hospitals. Aspergillus fumigatus is the most
common pathogen; other identified pathogenic species include
Aspergillus flavus, Aspergillus terreus, and Aspergillus niger.
Invasive CNS aspergillus infection is primarily seen in
immunocompromised individuals, mostly neutropenic
patients, and occurs by hematogenous spread, usually from a
focus in the respiratory tract. CNS involvement may also occur
by direct extension of the infection from sinuses, nose, and ear
canals and rarely by direct inoculation after head trauma or
surgery [12].
The sinocranial form of CNS aspergillosis is often reported
from countries with a temperate climate, often in immuno-
competent individuals. The pathology of hematogenous dis-
semination to the CNS, because of the angioinvasive character
of Aspergillus, includes ischemic infarction and hemorrhage,
and the pathology in sinocranial aspergillosis is characterized
by well-formed granulomas.
Signs and Symptoms
• The clinical presentation of CNS invasive aspergillosis is
characterized by the angioinvasive predilection of the
Aspergillus species, stroke-like syndromes: cerebral
infarction, hemorrhage, and mycotic aneurysm. Meningitis
and meningoencephalitis can also occur.
• Rarely spinal syndromes can be the presenting feature.
Patients with sinocranial aspergillosis may present with
features of intracranial focal mass lesions, skull-base
syndromes: orbital apex syndrome, cavernous sinus
syndrome, proptosis with or without ocular nerve palsies,
polyneuritis cranialis, and orbitocranial syndromes.
Diagnostic Workup
Laboratory
Lumbar Puncture
• CSF cultures can be diagnostic.
• CSF polymerase chain reaction and galactomannan antigen
tests may be of help in establishing the diagnosis.
Neuroimaging, particularly in patients with sinocranial
aspergillosis, may be diagnostic.
• A definitive diagnosis may require brain tissue for
histopathologic examination.
Imaging
Cerebral aspergillosis presents three principal MRI findings:
areas consistent with infarction, ring lesions consistent with
abscess formation following infarction, and dural or vascular
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infiltration originating from paranasal sinusitis or orbital
infiltration.
Therapy
• Voriconazole (6 mg/kg IV every 12 hours for one day
followed by 4 mg/kg IV every 12 hours, oral dosage 200 mg
twice a day) is recommended for the primary treatment of
invasive aspergillosis, both pulmonary and
extrapulmonary.
• Liposomal amphotericin B (3–5 mg/kg/day IV) could be
considered as alternative primary therapy in some patients.
• Salvage therapy for patients refractory to or intolerant of
primary antifungal therapy: liposomal amphotericin B (3–4
mg/kg/day IV), ABLC (5 mg/kg/day IV), posaconazole
(initially 200 mg/day oral then 400 mg twice a day oral), or
micagungin (100–150 mg/day IV).
• Refractory infection may respond to a change to another
drug or to a combination of agents.
• Continue therapy until resolution.
• Preoperative administration of intraconazole for a week
has been shown to improve outcome in patients with
intracranial aspergillosis. The pathology of Aspergillus
granulomas in otherwise immunocompetent individuals
shows dense fibrosis. To achieve maximum cure, radical
resection of the lesion followed by postoperative
voriconazole may be the treatment of choice in patients
with intracranial aspergillomas.
Zygomycosis
Background
Zygomycetes species are found in the soil and are commonly
found in decaying organic matter, such as fruit and bread. The
most important pathogenic molds include Mucor, Rhizopus,
Rhzomucor, Absidia, and Cunninghamella species. The most
common presentation of zygomycosis is rhinocerebral disease
in the setting of patients with diabetic ketoacidosis, renal
failure, and IV drug abuse. It is predominantly spread hema-
togenously [12].
Signs and Symptoms
• The disease has a predilection for the sinuses, nasal
mucosa, eyes, and brain, manifesting as internal carotid
artery thrombosis, causing contralateral hemiplegia.
• Patients may complain for paranasal sinus symptoms,
diplopia, or acute onset of blurred vision in a diabetic or a
immunocompromised individual.
Diagnostic Workup
Laboratory
Lumbar Puncture
• CSF fungal cultures are diagnostic up to 70% of the time.
• Molecular techniques such as nucleic acid amplification are
currently being investigated to aid in the diagnosis.
282
Imaging
• Lesions associated with zygomycosis show as hyperintense
T2-weighted lesions on MRI.
Therapy
• Zygomycosis treatment requires aggressive surgical
debridement of necrotic tissue and antifungal
therapy.
• Antifungal therapy includes high-dose IV amphotericin B,
1.2–1.5 mg/kg/day of the conventional formulation or 3–10
mg/kg/day of the lipid formulation.
• Dosages as high as 2–4 g of amphotericin B can be
administered.
• As an alternative, posaconazole has been shown to be an
effective therapy in zygomycosis, including CNS
zygomycosis. The typical oral daily dosage of posaconazole
is 800 mg, given as two or four divided doses and therapy
tends to be protracted.
Prognosis
Surgical debridement is key in the treatment of zygomycosis
and survival rates are much better in patients treated with
combined medical and surgical therapy than in patients treated
with medical therapy.
Without aggressive therapy the mortality rate associated
with cerebral zygomycosis is very high, especially in dissemin-
ated infections with CNS involvement.
Coccidioidomycosis
Background
Coccidioides immitis is native to the southwestern region of the
United States and in parts of Mexico and South America.
Coccidioides species are the most common etiologic agents of
chronic meningitis in regions endemic for coccidioidomycosis.
Even a short-term trip to endemic regions can result in the
acquisition of meningeal disease.
Risk factors that increase the likelihood of contracting the
disease include immunocompromised states, most commonly
HIV/AIDS, and chronic steroid therapy increase risk, but
diabetes is also a risk factor. There is also a male preponder-
ance in cases of the disease [12].
Signs and Symptoms
• The main feature of CNS dissemination is chronic basilar
meningitis, with hydrocephalus and vasculitic infarcts
being complications.
Diagnostic Workup
Laboratory
Lumbar Puncture
• CSF anticoccidioidal antibody and culture are frequently
negative on presentation, but the serum antibody test is
usually positive.

Imaging
• MRI studies are helpful in establishing the diagnosis, and
most commonly demonstrate basilar meningitis or
hydrocephalus.
Therapy
• Fluconazole (400 mg per day) is the current preferred
treatment.
• Itraconazole, administered in dosage of 400–600 mg per
day is an effective alternative.
• Nonresponders to fluconazole or itraconazole treatment
can try intrathecal amphotericin B, 0.1 mg and 1.5 mg per
dose administered at intervals ranging from daily to
weekly, with or without continuation of azole treatment.
• Hydrocephalus most often requires ventriculoperitoneal
shunting.
Prognosis
The prognosis in patients where the disease is identified early
and who remain on lifelong treatment with azoles is typically
good.
Histoplasmosis
Background
Patients susceptible to Histoplasma capsulatum meningitis live
in the temperate climate of the Mississippi and Ohio River
valleys. One-tenth to one-quarter of patients with disseminated
histoplasmosis develop CNS histoplasmosis [12]. Patients with
AIDS are at higher risk of developing disseminated disease.
However, it can also occur in apparently normal hosts with
primary pulmonary disease.
Signs and Symptoms
• CNS histoplasmosis includes meningitis, parenchymal
lesions of the brain and/or spinal cord, or both.
Diagnostic Workup
Laboratory
Lumbar Puncture
• CSF pleocytosis with lymphocyte predominance is
expected.
• CSF protein is elevated, CSF glucose is low.
• CSF culture is possible but demands high volumes for
detection.
• Detection of Histoplasma antibody in CSF by complement
fixation is diagnostic.
• A Histoplasma antigen enzyme-linked immunosorbent
assay (ELISA) is also available.
Serum Testing
• Testing for antihistoplasmal antibodies is available
although not entirely reliable.
• Serum culture for Histoplasma is time-consuming but
often diagnostic.
Chapter 22: Infections of the Central Nervous System
Other Testing
• Urine antigen detection and antigen detection from
alveolar lavage in patients with lung disease are other
avenues of detection.
Imaging
• MRI with and without gadolinium may detect
microabscess formation.
Therapy
• The drug treatment of CNS histoplasmosis includes
liposomal amphotericin B (5.0 mg/kg daily to a total of 175
mg/kg given over four to six weeks) followed by
itraconazole (200 mg, two or three times daily) for at least
one year and until resolution of CSF abnormalities,
including Histoplasma antigen levels.
• Amphotericin requires close monitoring for
nephrotoxicity.
• Blood levels of itraconazole should be obtained to ensure
adequate drug exposure.
• CNS histoplasmosis has lower response and higher relapse
rates with the available therapies than other forms of
Histoplasma infections (CNS).
• Resection of brain or spinal cord lesions has been reported.
However, surgery is rarely needed and should be
performed only with progressive clinical findings, despite
receipt of antifungal therapy.
: Immunocompromised patients require ongoing
fluconazole therapy.
Prognosis
Mortality in Histoplasma meningitis is between 20% and 40%,
although this may reflect the mortality of systemic disease.
Almost half of patients will relapse.
Mycobacterial Causes Of Meningitis
Background
Meningitis caused by Mycobacterium tuberculosis (TB) is a
disease that is difficult to diagnosis and can have a very poor
prognosis.. Untreated, TB meningitis is fatal. Two-thirds of
patients with TB meningitis have evidence of infection else-
where. Patients with normal immune systems are prone to TB
meningitis, though patients with AIDS have been shown to
have accelerated courses [13].
Signs and Symptoms
Tuberculous meningitis moves through three clinical stages:
• In stage 1, patients are lucid but complain of fever,
headache, and neck stiffness.
• In stage 2, patients exhibit cognitive impairment coupled
with cranial nerve palsies, and often seizures.
• In stage 3, patients have hydrocephalus leading to stupor
and coma. Multiple cranial nerve palsies and motor deficits
are defining signs.
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Diagnostic Workup
Laboratory
Lumbar Puncture
• Because TB meningitis can lead to tuberculoma formation,
careful examination of CT images should precede lumbar
puncture.
• Opening pressures are most often elevated.
• CSF protein is significantly elevated, with up to 75% having
levels from 100 to 500 mg/dL. Higher protein indicates CSF
blockage.
• CSF glucose is low, sometimes markedly so.
• CSF acid-fast bacillus culture is very slow and treatment
should not be delayed. Culture offers data regarding
antibiotic sensitivities.
• CSF TB PCR offers a confirmation of diagnosis.
Imaging
• TB typically leads to basilar meningitis, readily
observed as pachymeningeal enhancement on coronal
sequences on MRI. Diagnosis of tuberculomas, which
appear as space-occupying hyperintense lesions on
T2 sequences that enhance with gadolinium, is rarer
in the United States, but affects management and
prognosis.
• Chest X-ray may also assist diagnosis, and patients with
evidence of pulmonary TB should be in respiratory
isolation.
Other Testing
• Purified protein derivative (PPD) is positive in patients
without immunocompromise, but may give a false negative
in immunosuppressed patients.
• When other measures fail, meningeal biopsy may be
required.
Therapy
Antibiotics
• Mycobacterium tuberculosis requires prolonged
combination therapy including:
: Isoniazid 300 mg PO/IM per day
: Rifampin 600 mg PO/IV per day
: Pyrazinamide 15–30 PO mg/kg per day (2 g maximum)
: Ethambutol 15–25 PO mg/kg
• Isoniazid is by far the most effective drug, but carries risk
of neuropathy (especially optic) and hepatotoxicity.
Pyridoxine 50 mg PO per day is a necessary addition to
drug regimens containing isoniazid.
• Ethambutol has poor CNS penetration. If culture results
become available showing good sensitivity to rifampin and
isoniazid, this drug may be discontinued.
• Multidrug-resistant (MDR) TB requires alternate
medications and is best managed by experts in MDR TB.
• In TB and MDR TB meningitis, antibiotic therapy usually
lasts for 9–12 months.
284
Adjunct Therapies
• Patients presenting past stage 1 usually require
corticosteroid therapy (dexamethasone 2–3 mg PO/IV q
6 h) for 1–2 months, followed by a long taper.
Prognosis
Mortality for immunocompetent patients is 21% for patients
presenting past stage 1. For immunocompromised patients at
the same stage, mortality reaches 33%. Chronic hydrocephalus
is a common complication, often requiring CSF shunt
placement.
Central Nervous System Abscess
A CNS abscess is collection of pus that can occur anywhere
along the neuraxis [14–16]. In the brain the abscess is usually
intraparenchymal, located at the grey–white interface or within
the deep white matter tissue. They typically begin as a localized
area of pus enclosed by a well-vascularized collagen capsule
with surrounding granulation tissue.
Treatment of CNS abscesses demands a multidisciplinary
approach that requires input from the neurointensivist,
neurologist, infectious disease specialist, and otolaryngologist,
with a neurosurgeon being the nucleus of the group.
The typical predisposing factors to developing an abscess
include age, immunocompromised status, having a primary
infectious source that is either contiguous (such as paranasal
sinsuses) or has reached the CNS through hematogenous
spread from a distant focus (such as endocarditis and right-
to-left cardiac shunts), or cyanotic heart disease conditions
resulting in increased blood viscosity causing microinfarcts
in the middle cerebral artery distribution. An abscess can also
be a complication of brain trauma, direct inoculation during
surgical procedures, especially ones that involve instrumenta-
tion. Another source is IV drug abuse.
Signs and Symptoms
Independent of etiology, cerebral abscesses present a common
collection of symptoms:
• Progressive headache
• Fever
• Altered mental status
• Seizures
• Focal neurologic deficit
• Increased ICP
Bacterial Causes of Cerebral Abscess
Background
Bacterial abscesses development can be divided into four stages
[15, 16]:
• Early cerebritis (days 1–4)
• Late cerebritis (days 4–10)
• Early encapsulation (days 11–14)
• Late encapsulation (day 14 onwards)

Diagnostic Workup
Laboratory
• Lumbar puncture is contraindicated in cerebral abscess
and in cases where the procedure was performed before
diagnosis, CSF was unremarkable, and cultures were
negative. In serum, elevated peripheral white blood cell
(WBC) count, erythrocyte sedimentation rate (ESR) and
C-reactive protein (CRP) indicate infection, but cultures
are usually negative [14].
• Laboratory specimens obtained from stereotactic
CT-guided aspiration or surgery should be sent for Gram
staining, and aerobic, anaerobic, mycobacterial, and fungal
cultures.
• Additionally, special stains including acid-fast stain for
mycobacteria and modified acid-fast stain for Nocardia, as
well as fungal stains, should be sent.
• Serologic specimens may help in the diagnosis of
Toxoplasma gondii or neurocysticercosis.
• PCR is at times an excellent tool to detect hardy and
obligate organisms that require stringent growth
conditions such as Fusobacterium species and Aspergillus.
Imaging
• CT with and without contrast should be performed as early
as possible in the diagnosis of abscess as discovery of a
mass-occupying lesion will determine therapeutic
options [17].
• Cerebritis stages appear as hypodense areas with
surrounding edema.
• Encapsulation stages appear as ring-enhancing lesions
surrounded by hypodense edema.
• MRI with and without gadolinium is far more sensitive
than CT in discovering areas of cerebritis and encephalitis.
• Cerebritis appears as hyperintensities in T2 sequences.
• Encapsulation leads to ring enhancement of these lesions.
Chest CT or Chest Radiograph
• Lung abscess, empyema and simple pneumonia are a
common source of bacteremia leading to cerebral abscess.
Other Testing
• Surgical specimens are available from a variety of
interventions (see later), but cultures are negative in up to
25% of cases.
Specific Pathogens
Mixed infections are very common in bacterial abscess, and
obtaining positive cultures can prove difficult [14–16]. Hence,
therapy most often centers on empiric antibiotic coverage.
However, specific risk factors have been shown to predispose
patients to particular pathogens.
In general, Staphylococcus aureus, Streptococci species and
anaerobes cause the majority of bacterial cerebral abscesses.
Patients with a history of trauma or surgery tend to have
abscesses composed of aerobic Streptococci species, S. aureus,
Chapter 22: Infections of the Central Nervous System
Clostridium species, and Enterobacteriaceae (such as Proteus
and E. coli).
Abscesses may form via direct invasion from an adjacent
infection. Middle ear infections and mastoiditis can lead to
cerebellar and temporal lobe abscesses. Nasal sinusitis can lead
to frontal lobe abscesses. The sphenoid sinus is rarely infected,
but carries a high risk of ensuing cerebral abscess. Bacteria
involved in such cases are most often Streptococci species, S.
aureus, anaerobic Gram-negative species (such as Bacteroides),
and Enterobacteriaceae. Fungal abscesses are also suspected
with such presentations.
Patients with bacteremia or endocarditis leading to cerebral
abscess typically have aerobic S. aureus or Streptococci species
infection. Patients with immune suppression (including
patients after organ transplant, patients with leukemia or
lymphoma, patients with AIDS, and patients on chronic corti-
costeroids) are susceptible to Norcardia species, Actinomyces
species and Listeria abscess, in addition to the species discussed
above. These patients also have a greater risk for
fungal abscess. Patients with AIDS with ring-enhancing lesions
are a topic of particular interest, as more than 20% of these
patients have more than one CNS opportunistic infection at a
time.
Therapy
Antibiotics
Most initial antibiotic coverage is, by necessity, empiric and
includes the following agents [17]:
• Vancomycin 30mg/kg IV q 12 h for coverage of MRSA.
• Third-generation cephalosporin such as ceftriaxone 50 mg/
kg IV q 12 h or cefotaxime 150 mg/kg IV q 8 h for broad
coverage.
• Metronidazole 15mg/kg IV loading dose, followed
by 7.5 mg/kg IV every eight hours; not to exceed 4 g/day
• Duration of therapy is uncertain, but general guidelines
include a total of six to eight weeks with four weeks of IV
therapy.
• Imaging serves as a useful guide for terminating therapy.
Adjunct Therapies
• Dexamethasone is generally recommended for patients
with a significant mass effect on imaging.
• Antiepileptic medications should certainly be prescribed
for any patient presenting with seizure.
• As 35–80% of patients with cerebral abscess eventually
have a seizure, prophylactic antiepileptics are warranted. If
the patient is seizure-free for two years then prophylactic
antiepileptic agents can be discontinued.
Surgical Intervention
• Surgical intervention is required for patients with lesions
>2.5 cm or causing mass effect. Several interventions are
available [16,18].
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• Aspiration serves as the mainstay of bacterial abscess
management. It is best for deep abscesses or patients with
multiple lesions. Repeated aspiration is often required.
• Excision reduces the risk of recurrence and can reduce the
length of required antibiotic coverage. It is performed for
abscesses only in the late encapsulated phase that can be
removed intact.
Fungal Causes of Cerebral Abscess
As discussed in the preceding text, fungal meningitis can lead
to abscess formation. In addition, direct invasion from infec-
tions of sinuses or mastoid air cells can result in fungal abscess
as well. Diagnosis is made much the same way as it is with
bacterial causes of brain abscess, with neuroimaging such as
MRI and with direct debridement and culture of the abscess.
Treatment regimens require surgical drainage and then anti-
fungal therapy, much like the treatment of fungal meningitis.
Spinal Epidural Abscess
Background
Spinal epidural abscess (SEA) is a suppurative collection in the
space surrounding the spinal cord located between the dura
mater and the vertebral periosteum [14].
Spinal epidural infections are rare, with an incidence of
0.2–2 cases per 10,000 hospital admissions. Most cases of SEA
occur in patients aged 30 to 60 years. The most common risk
factors for SEA are diabetes mellitus, followed by trauma,
intravenous drug abuse, and alcoholism.
Signs and Symptoms
• Back pain is the most common initial complaint.
• Fever/chills, paresthesias, weakness, and difficulty
ambulating are also common.
• There is an established staging system:
: stage 1, back pain at the level of the affected spine
: stage 2, nerve-root pain radiating from the involved
spinal area
: stage 3, motor weakness, sensory deficit, and bladder
and bowel dysfunction
: and stage 4, paralysis.
Diagnostic Workup
Laboratory
Lumbar Puncture
• Lumbar puncture is contraindicated if spinal epidural
abscess is suspected due to the risk of introducing purulent
material into the subarachnoid space.
Serum Testing
• Most patients have an elevated erythrocyte sedimentation
rate (ESR) on admission.
• An increased peripheral white blood cell count with a left
shift is common.
286
Imaging
• The diagnostic imaging of choice is contrast-
enhanced MRI.
• This imaging modality is highly sensitive, highly specific,
and can accurately delineate the extent and location of the
abscess.
• On T2-weighted images, the hyperintense signal of the
epidural mass can be differentiated from the nonenhancing
thecal sac and neural elements.
• On MRI, epidural abscesses have isosignal on T1-weighted
images and high signal on T2-weighted images, with
enhancement of the thickened dural surface.
• On CT, epidural abscess typically appears as a low
attenuation extra-axial mass.
Etiologies
• Because most predisposing conditions allow for invasion
by skin flora, S. aureus causes about two-thirds of cases.
• Less common causative pathogens include coagulase-
negative staphylococci, such as S. epidermidis and Gram-
negative bacteria, particularly E. coli and P. aeruginosa.
Therapy
Surgery
• Spinal epidural abscess is a neurosurgical emergency due to
the potential for rapid deterioration to severe spinal cord
dysfunction. The goal of surgery is immediate
decompression and drainage [14].
• Posterior epidural abscesses are usually treated with
decompressive laminectomy followed by irrigation through
extradural drains for several days.
• In cases of anterior SEAs, anterior decompression is
usually performed along with a partial or complete anterior
or anterolateral corpectomy, because the infection usually
extends to the vertebral column.
Antibiotics
• Broad-spectrum coverage should be initiated.
• Vancomycin 1 g IV q 12 h.
• Ceftazidime 6 g IV q 8 h or cefepime 4 g IV q 8 h.
• Metronidazole 500 mg IV q 6 h for coverage of anaerobes.
Prognosis
Patients diagnosed before the development of significant neuro-
logic deficits fare better than those with weakness or paralysis for
greater than 36 to 48 hours at the time of diagnosis. Other
factors such as older age, septicemia, and greater degree of thecal
sac compression are also associated with a worse outcome.
Subdural Empyema
Background
Subdural empyema (SDE) is a collection of suppurative mater-
ial between the dura mater and arachnoid surrounding the

brain. It accounts for approximately 15–25% of intracranial
infections and is most often a complication of infections such
as sinusitis, otitis media, or mastoiditis [14]. Less often, organ-
isms may spread inward as a complication of osteomyelitis.
Subdural empyema may also occur as a complication of neuro-
surgical procedures or, occasionally, after head trauma. It
rarely occurs from hematogenous spread.
Intracranial subdural empyema predominantly affects chil-
dren and young adults, with 70% of cases occurring in the
second and third decades of life. It is significantly more
common in men than in women.
Signs and Symptoms
High index of suspicion and rapid diagnosis of subdural
empyema are essential for a good clinical outcome. Frequently,
patients report a nonspecific illness for a few days to weeks
prior to presenting to the hospital:
• Headache, fever, and stiff neck.
• If present, focal neurological signs may help to localize the
empyema.
• Given the often nonspecific presenting symptoms,
intraparenchymal abscess, epidural abscess, meningitis,
meningoencephalitis, and subdural hematoma should be
included in the differential diagnosis.
Diagnostic Workup
Laboratory
Lumbar Puncture
• Lumbar puncture is of little value as it is neither sensitive
nor specific for subdural empyema.
• CSF studies are unpredictable and it is rare to identify the
causative organism by Gram stain or culture. Additionally,
neurological deterioration and transtentorial herniation
after lumbar puncture are well described.
Serum Testing
• Blood cultures can be positive and can assist in narrowing
antibiotic coverage.
Imaging
• Noncontrast CT scan typically demonstrates a crescent-
shaped extra-axial hypodense collection over one or both
cerebral convexities.
• The study of choice is MRI.
• Iso-intense signal on T1-weighted imaging, likely
secondary to increased protein content and high signal on
T2-weighted imaging.
• May be able to differentiate subdural empyemas from other
extra-RI maxial fluid collections, such as sterile effusions
(usually low signal on T1-weighted imaging ) and chronic
subdural hematomas (usually high signal on T1-weighted
imaging). A thin rim of enhancement may be seen,
which is usually more prominent along the inner table of
the skull.
Chapter 22: Infections of the Central Nervous System
Other Testing/Culture
• Gram stain and culture of evacuated pus from the subdural
space after surgical drainage.
• Infections are often polymicrobial.
• Anaerobic Gram-positive cocci, Streptococcus species,
Staphylococcus species, and anaerobic Gram-negative
bacilli are the most commonly isolated organisms from
empyema material.
Therapy
Surgery
• Surgical drainage of a subdural empyema is essential. The
advantage of craniotomy is that it allows for greater
exposure and ease of removing pus from a larger area.
• Stereotatic burr hole placement is less favorable due to
decreased exposure and difficulty obtaining complete
evacuation of the purulent material.
Antibiotics
• Clinical suspicion of a subdural empyema requires prompt
institution of parenteral antibiotic therapy.
• Choice of antibiotics should be based on the suspected
source of infection and on the organisms known to
commonly cause SDE.
• Otorhinogenic subdural empyemas are most commonly
due to aerobic and anaerobic streptococci and less often
due to coagulase-positive staphylococci and other
anaerobes. Infections following head trauma or surgery are
caused by coagulase-positive and coagulase-negative
staphylococci and Gram-negative bacilli.
• An acceptable empirical antibiotic regimen includes a β-
lactamase-stable penicillin, a third-generation
cephalosporin, and metronidazole. If there is concern for
MRSA or coagulase-negative staphylococci, vancomycin
should be used instead of β-lactamase-stable penicillin.
Currently, there is no evidence to support irrigation of the
subdural space with antibiotics.
• The optimal duration of antimicrobial therapy is uncertain.
• Until further studies confirm the value of shorter antibiotic
courses, parenteral antimicrobial therapy should continue
for at least three weeks after surgical intervention to be
followed by at least three weeks of oral therapy, to be
guided by culture results.
Prognosis
Several factors, such as age of patient, source of infection,
organisms involved, time from presentation to surgery, level
of consciousness at presentation, and surgical technique seem
to play a role in predicting patient mortality. There are some
reports of less overall mortality in subdural empyemas second-
ary to paranasal sinusitis compared to other primary sources
of infection. Patients who are awake and alert at presentation
have the greatest chance of survival and those unresponsive at
presentation are the least likely to survive.
287
 Chapter 22: Infections of the Central Nervous System
Ventricular Catheter Infections
Extraventricular Drain Infections
Background
Many conditions treated in the neurocritical care setting even-
tually require placement of an external ventricular drain
(EVD) for measurement and control of ICP. However, any-
where from 0–20% (with an average of about 8%) of these
catheters result in ventriculitis [19]. Several risk factors have
been identified in the development of CNS infections after
implantation of an EVD. Factors leading to an increased risk
for infection include [20]:
• Intraparenchymal hemorrhage, especially with
intraventricular extension
• Repeated sampling or irrigation of the system
• A number of attempts needed to pass the catheter into the
ventricular system
• Systemic infection
• Although it is clear that the longer a catheter remains in place
the higher chance there is of an infection, it is also evident
that prophylactic changing of the catheter is of no benefit.
Signs and Symptoms
• Alteration in mental status
• Fever
Diagnostic Workup
Laboratory
Lumbar Puncture
• CSF collected from the EVD should periodically be sent for
testing, as this is the working basis for diagnosis of EVD-
related infections. Routine sampling of CSF has not been
shown to “catch” infection any sooner than monitoring for
signs and an increase in serum WBC.
• CSF pleocytosis is not a reliable marker for infection,
though an upward trend is highly suggestive.
• CSF glucose below 2.5 mmol/L or a ratio to serum glucose
<0.4 strongly signals infection.
• CSF lactate may also rise in the face of infection.
• CSF Gram stain and culture are the standard means of
diagnosis.
Serum Testing
• Upward trend in serum WBC
Imaging
• There is little evidence supporting the use of neuroimaging
to aid in the diagnosis of ventriculitis. In extreme cases
there may be layering of debris in defendant portions of the
ventricles.
• MRI will typically show contrast enhancement of the
ventricles and the meninges, though, in light of the many
diagnoses for which EVDs are placed, this ventriculitis may
pre-date the insertion of the EVD.
288
Pathogens
The organisms typically responsible for EVD-related infections
include:
• Coagulate-negative Staphylococcus
• S. aureus
• Klebsiella
• Acinetobacter
• Pseudomonas
Therapy
Surgery
• The offending catheter should be removed as soon as
possible. If an EVD is absolutely required, replacing the
catheter should be considered.
Antibiotics
• Vancomycin 1 g IV q 12 h serves as adequate empiric
therapy for most EVD infections.
• A third-generation cephalosporin such as ceftriaxone 50
mg/kg IV q 12 h or cefotaxime 150 mg/kg IV q 8 h for
broad coverage. An antipseudomonal cephalosporin may
be necessary to cover Pseudomonas.
• Attention to trough vancomycin levels (high therapeutic
range) is required to reach adequate CNS penetration.
• Therapy should be tailored as soon as culture data and
sensitivities are available.
• Guidelines for use of intrathecal vancomycin are not
available.
CSF Shunt Infections
Background
Large population studies are not available, but the rate of CSF
shunt infection for ventriculoperitoneal and ventriculoatrial
shunts in adults is on the order of 2.5%. Shunt infections occur
in two phases [21]:
• Early shunt infections are most likely the result of surgical
contamination with bacteria from the skin of the patient.
These are most commonly infections caused by
Staphylococcus epidermidis, S. aureus, and Gram-negative
bacilli.
• Late shunt infections are most often caused by S.
epidermidis and are likely due to indolent infection or
colonization of the hardware after meningitis [21].
These patients require careful scrutiny for the possibility of
other etiologies of shunt malfunction or systemic
symptoms.
Signs and Symptoms
• Shunt infection may present as shunt malfunction without
headache or meningeal signs.
• Shunt infection may also present with symptoms of acute
bacterial meningitis.
 Chapter 22: Infections of the Central Nervous System

• Shunt malfunction may lead to headache and altered • CT of the brain without contrast is also helpful in diagnosis
mental status secondary to worsening hydrocephalus and of shunt malfunction with the demonstration of worsening
increased intracranial pressure. hydrocephalus.

Diagnostic Workup Therapy

Laboratory Surgery
Lumbar Puncture • Removal or externalization of the distal portion of the
• CSF pleocytosis is usually present, but rarely above 100 shunt is usually required.
cells/μL.
• CSF protein may be elevated and glucose is low or normal. Antibiotics
• CSF Gram stain and culture are required, but negative in • Vancomycin 1 g IV q 12 h for coverage of MRSA.
almost half of cases. • Attention to peak and trough vancomycin levels is required
to reach adequate CNS penetration.
Serum Testing
• When culture and sensitivity data become available,
• Peripheral blood cultures may also secure a diagnosis. antibiotic coverage should be narrowed, as these infections
• ESR and CRP are elevated. are not the result of multiple organisms.
Imaging • Antibiotics should be continued for 10–14 days after
• CT of the brain with contrast may demonstrate ependymal normalization of the CSF profile.
enhancement associated with ventriculitis. • After the full course of antibiotics, CSF shunt hardware
may be replaced.

the United States, 1998–2007. N Engl Handbook of Neurosurgery. Stuttgart,

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17. Simpson D. (2013). Management of
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19. Beer R, Lackner P, Pfausler B,
Schmutzhard E. (2008). Nosocomial
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255(11): 1617–1624.
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(2016). The insertion and management
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 Chapter
Management of the Spinal Cord Injury

23 in the Neurocritical Care Unit

Kristine O’Phelan and Indira De Jesus

Epidemiology Nontraumatic
Traumatic Many etiologies would be appropriately classified under this
category, such as genetic and metabolic disorders, as well as
According to recent studies, the incidence of traumatic spinal
degenerative, autoimmune, and inflammatory diseases, which
cord injury (TSCI) is higher than previously reported with a
are beyond the scope of this chapter. For the purposes of this
progressive increase among older adults. Additionally, adults
review, we will focus on complications secondary to acute
older than 65 years of age had increased mortality rates in the
spinal cord compression (SCC) associated with neoplastic,
emergency department and during hospitalization in compari-
radiation-induced, vascular, and infectious disorders.
son to adults age 18–64 years [1].
In patients with neoplastic nontraumatic spinal cord injury
Selvarajah et al. describe falls as the leading cause
(NTSCI), metastatic disease is the most common etiology
of TSCI (41.5%), followed by motor vehicle accidents
associated with extradural cord lesions. Up to 10% of patients
(MVAs) (35.5%) [1]. This is in contrast to prior studies
with cancer can develop this complication. The thoracic spine
that consistently report MVAs as the main cause of TSCI
is the most frequently affected level in these cases (60%),
[2,3]. Their analysis states that the cumulative incidence
followed by the lumbosacral (30%) and cervical (10%) areas.
among younger adults (18–64 years) remained fairly steady,
Lung, breast, and prostate cancers, lymphomas, and renal cell
but the incidence among adults over 65 years has
carcinoma are the most common primary neoplasms causing
increased. Firearm-induced TSCI, the incidence of which
metastatic NTSCI. Only 10% of extradural spinal cord neo-
has declined since its peak in the 1990s, occurred in 11.6%
plasms are primary and include multiple myeloma, chordo-
of adults aged 18–30 years, compared to 0.4% in adults
mas, chondrosarcomas, Ewing’s sarcomas, and osteogenic
aged 65 years.
sarcomas. Meningiomas and nerve sheath tumors are the
Cervical injuries are the most common, as this is the most
most common intradural extramedullary lesions causing com-
movable part of the spinal column. Thoracic and lumbosacral
pressing syndromes, and ependymomas and astrocytomas
injuries occur more commonly in younger adults, resulting
are the most common intramedullary tumors. Up to 8% of
from falls from height, gunshot wounds and MVAs, which
cancer patients may develop leptomeningeal metastatic disease
occur more frequently in this population [1].
manifested by multiple cranial or spinal nerve dysfunction,
On average, $1.6 billion was charged annually between
which is associated with a poor prognosis. There is a one-
2007–2009 for treatment of acute TSCI seen in emergency
year survival rate of only 30% in patients presenting with
departments in the USA [1].
metastatic SCC [4].
In addition, life expectancies are significantly reduced
Infectious lesions should always be suspected, especially if
for survivors of TSCI, and there is an interaction between
the patient’s clinical scenario is suggestive of this. Epidural
the severity of injury and age at injury that affects this
abscesses are an uncommon condition with an estimated inci-
estimate. For example, an individual with a high-level tetra-
dence of 0.2–2/10,000 hospital admissions [5,6]. Peak inci-
plegia that was injured at 20 years old has a lower reduction
dence is in the sixth and seventh decades of life and
in percentage of life expectancy than another individual
conditions associated with these are diabetes mellitus, intra-
sustaining the same injury at age 75 years. Although med-
venous drug misuse, chronic renal failure, alcoholism, and
ical and rehabilitative care have significantly improved lon-
cancer [5–7]. Approximately 80% occur in the posterior canal
gevity for people with TSCI compared with that observed
due to hematogenous spread and the presence of the venous
50–70 years ago, recent data indicate a relative plateauing of
plexus, fat, and small arteries in this space [4,7,8]. Staphylococ-
life expectancies for many people with TSCI; there is an
cus aureus is the most commonly reported organism. Gram-
improvement in mortality seen during the first two years
negative organisms should be suspected in patients with a
after injury (40%), however, life expectancy after that has
history of a recent neurosurgical procedure and Mycobacter-
remained the same [2].
ium tuberculosis is suggested by a subacute presentation [4].

290

Haemophilus parainfluenzae, Brucella species, and Actino-
myces israelii are amongst the many other isolates described.
Disseminated fungal infections such as cryptococcosis, asper-
gillosis, and blastomycosis are rare causes and usually arise in
immunocompromised patients. Aspergillus species are known to
cause spinal epidural abscess in patients with HIV/AIDS. Prog-
nosis depends on the clinical and neurological status at the time
of presentation and any delay in the diagnosis and treatment can
substantially impact the patient’s neurologic outcome. Mortality
has been reported consistently as high as 15–30%, depending on
study design, for the past several decades [7].
Diagnosis
Physical Exam
The cornerstone of diagnosis of an acute spinal cord injury
(SCI) is the clinical exam. Acute onset of bilateral leg and/or
arm weakness with or without bowel or bladder dysfunction
suggests the diagnosis. Unfortunately, the neurological exam-
ination has limitations and is susceptible to subjectivity that is
affected by the level of training of the clinician [9]. Addition-
ally, in multisystem trauma, the neurological examination is
further complicated by concomitant head injury, fractures and
casts, peripheral nerve injury, pre-existing neurological dis-
ease, and obtunding medications or drugs [10].
Currently, the only practical real-time method to detect
worsening injury is by repeated clinical examination. The phys-
ician treating SCI primarily manages a patient based on vital signs,
careful and frequent neurological examination, and imaging stud-
ies. Then, a determination of injury level and severity is made
based on motor strength in key muscles (see Table 23.1), pinprick
and light touch sensory perception at selected dermatomal points
in accordance with the International Standards for Neurological
Classification of Spinal Cord Injury (ISNCSCI) [10], and the ASIA
scale (see Figure 23.1 and Table 23.2).
The prognostic significance of the neurological level on the
pinprick exam is greater than that for the light touch exam and
Table 23.1 Muscle strength grading
Muscle grading
0 Total paralysis
1 Palpable or visual contraction
2 Active movement, full range of motion, gravity
eliminated
3 Active movement, full range of motion, antigravity
4 Active movement, full range of motion, and
provides some resistance
5 Active movement, full range of motion, provides
normal resistance
Not Patient unable to reliably exert effort or muscle
testable unavailable for testing due to factors such as
immobilization, pain on effort, or contraction
Chapter 23: Management of Spinal Cord Injury
may be a more sensitive indicator of the severity of SCI. The
motor exam does not include trunk muscle assessment so
assessments of thoracic injury levels are based only on sensory
scores and abdominal reflex [11].
Quadriplegia/tetraplegia represents the most serious pre-
sentation of SCI. In an alert and responsive patient, quadriple-
gia indicates a cervical lesion. Depending on the level of the
cervical lesion, there may also be respiratory failure. Pulmon-
ary function tests such as negative inspiratory force (NIF) or
vital capacity (VC) may be helpful in assessing this status [4].
Imaging
The initial imaging studies should be oriented to begin at least
two spinal segments above the level of the clinical deficit and
continue down to the conus. Many patients will present with
back pain without signs of a clear motor or sensory level or
sphincter dysfunction. Simple radiography (X-rays), computed
tomography (CT), and magnetic resonance imaging (MRI) are
among the most widely used imaging techniques used to assess
the extent of SCI. MRI is the best method for assessing acute
spinal cord injury. It facilitates longitudinally extensive seg-
ments of the spinal canal content and enables the determin-
ation of the severity and extent of spinal cord, vascular, and
disk injuries, as well as epidural hematomas. MRI is the gold
standard and should be used to image every acute spinal cord
injury case as long as the patient is stable [5]. MRI is particu-
larly helpful in the following: cases of incomplete neurological
injuries, a lack of correlation between the levels of bone injury
and neurological impairment, persistent pain with no radio-
graphic findings, the presence of disks before reduction of
dislocation, spinal cord injuries without radiologic abnormal-
ities (SCIWORA), differentiation of pathological fractures,
neoplasm infiltration, infection, and in the prognostic assess-
ment of spinal cord injury [12]. Some authors insist that CT
must be used in the initial assessments of high-risk patients, as
it can be done quickly with reliable evaluation of bony
Table 23.2 ASIA impairment scale
A Complete No motor or sensory function is preserved in
the sacral segments S4–S5
B Incomplete Sensory but no motor function is preserved
below the neurological level and includes
the sacral segments S4–S5
C Incomplete Motor function is preserved below the
neurological level, and more than half of key
muscles below the neurological level have a
muscle strength less than 3
D Incomplete Motor function is preserved below the
neurological level, and at least half of key
muscles below the neurological level have a
muscle strength of 3 or more
E Normal Motor and sensory function are normal
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 Chapter 23: Management of Spinal Cord Injury

Figure 23.1 Clinical syndromes. A black and

Spinal Cord Injury white version of this figure will appear in some
formats. For the color version, please refer to the
Paraplegia Tetraplegia plate section.
Incomplete complete Incomplete complete

Common Types of Incomplete Spinal Cord Injury

Brown–Séquard Syndrome Central Cord Syndrome

Posterior Cord Syndrome Anterior Cord Syndrome

Normal function
Impaired motor function
Impaired sensory function

structures, to prevent complications and reduce costs [13].
However, it cannot exclude spinal cord injury.
Contrast enhancement is beneficial in the detection and
characterization of epidural, intradural, and intramedullary
processes, and is useful to detect infectious and neoplastic
diseases when suspected. Contrast-enhanced CT scanning is
not as effective as MRI [14].
Guidelines have been established by the Eastern Associ-
ation for the Surgery of Trauma to assist the clinician with the
determination of which patients would benefit from full-spine
imaging following blunt trauma. These data encourage the
selective use of full-spine imaging in screening of all patients
with known or suspected high-velocity mechanisms. Low-
velocity trauma consists of ground-level falls and assaults.
High-velocity trauma includes transportation vehicle-related
accidents, explosions, and multilevel falls [15].
Myelography is useful in patients in whom MRI is contra-
indicated (i.e. those with metallic foreign bodies or cardiac
pacemakers), although these might not be contraindications
in the future. It is an invasive study and generally should be
used as a secondary imaging modality to answer questions not
addressed by MRI or CT [14].
Pathophysiology
The basis for spontaneous neurological recovery is the
preservation of functional neural tissue after SCI. The primary
mechanism comprises the initial cord lesion that results
from physical trauma to the tissue caused by a displacement
of surrounding spinal structures. This in turn initiates a
cascade of secondary injury mechanisms including ischemia,
edema, increased excitatory amino acids, and lipid

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 Chapter 23: Management of Spinal Cord Injury

Figure 23.2 Spinal roots and innervation.

C1 Diaphragm
C2 Deltoids
Biceps
C3
C4
Cervical Wrist extensors rotates arm
C5 Triceps
C6 Bends fingers
C7
T1
T2
T3
T4
T5
Spread fingers
T6
Thoracic Chest muscles
T7 Abdominal muscles
T8 Back muscles
T9
T10
T11
T12

L1

L2
Hip muscles
L3 Lumbar Thigh muscles
Knee muscles
Foot muscles
L4

L5

S1
S2
S3 Bladder and bowel
S4 Sacral Sexual function
S5

peroxidation [16] (see Figure 23.3). Autoregulation of blood Traumatic SCI

flow is lost immediately after SCI and either hyperemia or low
Studies have described a 60% increased risk of sustaining a
flow may occur, depending on injury severity. The lack of a
multiregional noncontiguous fracture of the spine following
viable clinical technique to measure spinal cord blood flow
high-velocity mechanism of injury compared with low-velocity
(SCBF) in the acute SCI setting has led to clinical practice
mechanisms. Blunt trauma sustained from vehicle-related acci-
recommendations of maintaining mean arterial pressure
dents is associated with an 83% increased risk of noncontig-
(MAP) at a level consistent with reasonable SCBF (MAP above
uous fractures of the spine, cervicothoracic being the most
80–85 mmHg) for a duration of seven days, which has been
frequent fracture pattern, followed by thoracolumbar fractures
proven to be safe and may improve neurological outcome [17].
[15]. In a series by Korres et al. [19] of 81 patients with
Current clinical measures emphasize spinal immobilization,
multiple-level noncontiguous spinal fractures, the most
and expeditious decompression [10]. There is strong evidence
common combination of fractures included thoracolumbar
from animal models that decompression of the spinal cord
(25%), followed by cervicothoracic and cervicolumbar at 17%
improves functional recovery and minimizes the secondary
and 10%, respectively. Similar studies have replicated these
injury after SCI [18].

293
 Chapter 23: Management of Spinal Cord Injury

Figure 23.3 Spinal cord injury pathophysiology.

A black and white version of this figure will appear in
axons some formats. For the color version, please refer to the
plate section.
myelin sheath
macrophages
glutamate toxicity primary injury

secondary injury
inflammation and lipid peroxidation

demyelinated axon

results [15]. Severely unstable cervical fractures must be
treated immediately, even in polytrauma patients. STASCIS
(Surgical Timing in Acute Spinal Cord Injury Study), a large,
multicenter, international, prospective cohort study, con-
cluded that decompression within the first 24 hours after SCI
can be performed safely and is associated with improved
neurologic outcome, defined as at least a two-grade AIS
improvement at six months follow-up [20]. Laminectomy for
decompression without fixation is mostly followed by severe
kyphosis. This treatment has been frequently performed in
emergency in the past to reduce post-traumatic stenosis, but
even in an emergency a posterior fixation should be performed
in addition to the decompression to provide stability [21].
Methylprednisolone (MP) is the most prescribed drug in
the setting of acute SCI in clinical practice. However, it is
simultaneously the most controversial. The American Associ-
ation of Neurological Surgeons/Congress of Neurological Sur-
geons (AANS/CNS) states: ‘‘Methylprednisolone for either
24 or 48 h is recommended as an option in the treatment of
patients with acute spinal cord injuries that should be under-
taken only with the knowledge that the evidence suggesting
harmful side effects is more consistent than any suggestion of
clinical benefit’’ (AANS/CNS, 2002). MP is a corticosteroid
that acts by inhibiting lipid peroxidation (acts as a free radical
scavenger), maintaining the blood–spinal cord barrier, enhan-
cing spinal cord blood flow, inhibiting endorphin release, and
limiting the inflammatory response. However, all NASCIS
studies reported a statistically significant increase in wound
infections, gastrointestinal hemorrhages, sepsis, pulmonary
embolism, severe pneumonia, and death [22]. Methylpredni-
solone infusions are not routinely used after TSCI in most
large academic neurosurgical practices [23].
Hypothermia has also been proposed as an option
following acute traumatic SCI. The first clinical trial using
hypothermia in human SCI was conducted in 2010 and con-
sisted of 14 patients who were treated with therapeutic hypo-
thermia with a target temperature of 33 °C for 48 hours post
injury. This study demonstrated that therapeutic hypothermia
was safe and did not increase the incidence of secondary
complications when compared to the complication rate of
normothermic patients. The authors reported that 42.8% of
the patients recovered from a complete to an incomplete SCI
stage [24]. Due to these promising findings, a large-scale trial
of systemic hypothermia is currently recruiting patients.
Nontraumatic SCI
The most common cause of nontraumatic SCI is compression
of the dural sac and its contents by an extradural tumor or
mass arising from vertebral metastases. Occasionally, it results
from subdural or intramedullary metastases or from direct
extension of a local tumor such as lung cancer. Approximately
60% of lesions occur in the thoracic, 30% in the lumbosacral,
and 10% in the cervical vertebrae [25].

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 Chapter 23: Management of Spinal Cord Injury

Although palliative radiotherapy remains the main modal- margin of health. This accelerated aging for people with SCI is
ity for treatment of metastatic spinal cord compression likely caused by physiologic changes associated with the neu-
(MSCC) in most patients, there is increasing evidence that rologic injury and impairment that lead to immediate and
direct decompressive surgical resection followed by radiother- long-term effects on body systems [28,29]. This may be the
apy is superior to radiotherapy alone [26]. main contributing factor to the increasing gap observed between
Spinal epidural abscesses (ESAs) are another important life expectancy for individuals with SCI and the general popula-
consideration in the diagnosis of patients presenting with tion. Older age in individuals with SCI is associated with mul-
nontraumatic SCI. The primary mechanism for spinal cord tiple systemic complications, such as diminished renal function,
tissue injury is unknown. Some theories include ischemia from increased cardiovascular disease, higher rates of ventilator use,
direct compression or disruption of vascular supply from and increased rates of hospitalization leading to greater disabil-
septic thrombophlebitis. While emergent surgical decompres- ity that significantly impairs quality of life [30].
sion and IV antibiotic therapy are the practice of choice for
SEA, ideal management of this condition remains controver- Cardiovascular
sial. While it is largely accepted that decline in neurologic
People with SCI have recently been shown to be at a greater
function is an indication for surgical decompression of epi-
risk of systemic inflammation, possibly because of heightened
dural abscess, the majority of clinical decisions for medical
fat stores, pressure ulcers, and frequent infections. Because
versus surgical management of this condition are based on
atherosclerosis has been identified as having an inflammatory
anecdotal evidence. Risk factors have been identified for devel-
basis, this may put people with SCI at an even greater risk of
opment of SEA (elevated erythrocyte sedimentation rate, leu-
cardiovascular conditions [2].
kocytosis, intravenous drug use, diabetes mellitus, and prior
Neurogenic shock occurs when component neurons and
spine surgery), but the prognostic value of these risk factors is
pathways of the autonomic system are damaged after SCI.
unknown. Patel et al. concluded that surgical intervention for
Acute hypotension and bradycardia are seen in injuries above
SEA results in improved motor scores compared to medical
the T6 level. This is frequently followed by chronic positional
management. The recommendation is to perform surgery as
hypotension [10]. This should not be confused with hemor-
soon as possible, as delayed surgical intervention results in
rhagic shock, which may present with acute hypotension due
lower postoperative motor scores than early surgery [26]. Four
to internal organ damage, if high-velocity trauma was the
to six weeks of intravenous antibiotics covering the most
mechanism of the acute SCI. The typical tachycardia associated
common organisms (S. aureus) broadened further in special
with hemorrhagic shock may be absent in this population as
populations as needed (see epidemiology section), followed by
they will be bradycardic due to lack of sympathetic tone.
two to four weeks of oral use is usually enough to eradicate the
Autonomic dysreflexia is seen in subacute and chronic stages
disease; unless there is evidence of associated osteomyelitis,
of spinal cord injury and manifests as episodes of reactive
which requires extended antibiotic therapy for at least eight
severe hypertension, bradycardia, diaphoresis, and headache,
weeks [27].
and is associated with unregulated sympathetic nervous system
Vascular malformations, coagulopathies, spinal tumors,
response. Visceral dilatation and surgical manipulation are
and/or radiotherapy-induced telangectasias can present as acute
common precipitants and it usually resolves with vasodilators
spinal hemorrhages causing acute onset of para- or tetraplegia,
such as nitrates [31].
accompanied by pain. This can be identified on imaging, and
The AANS 2013 SCI treatment guidelines recommend to
therapy focuses on decompression when appropriate and rever-
keep a MAP between 85 and 90 mmHg for the first seven days
sal of coagulopathy and/or thrombocytopenia [4].
following acute SCI. Vasopressors should be chosen depending
Noncompressive myelopathies such as syringomyelia and
on the level of the SCI. SCI guidelines and reviews recommend
inflammatory myelitis should always be considered as part of
dopamine as the vasopressor of choice for injuries above T6 as
the differential diagnosis of acute spinal cord dysfunction. MRI
it has both alpha and beta effects. Studies have shown that all
is a useful tool to differentiate these, less urgent scenarios, from
vasopressors are associated with an increased rate of compli-
the conditions mentioned above that would require immediate
cations, dopamine being associated with higher rates of cardiac
intervention in order to be able to make the difference in
arrhythmias and ischemia, requiring changes in the vasopres-
patient outcomes.
sor. Norepinephrine and phenylephrine are also commonly
used in this scenario as alternatives to dopamine [32] (see
Complications Table 23.3).
Some data suggest that SCI alters the trajectory of aging such
that both the rate and characteristics of aging are affected. The Respiratory
term “accelerated aging” has been used to describe this altered The diaphragm, intercostals, accessory muscles, and abdom-
aging trajectory in people with physical disability in the con- inal muscles comprise the respiratory muscles. VC and max-
text of health conditions occurring earlier and/or more fre- imum NIF, as overall pulmonary function indicators, can be
quently than would otherwise be observed, leading to a narrow used to stratify risk when assessing which patients would

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benefit from assisted ventilation before they develop respira-
tory distress. Vital capacity below 15 mL/kg and NIF below –
20 cmH2O are indicators of the need for intubation [33].
Lower admission ASIA motor score, “complete” SCI, and
more rostral injuries (usually above C5) are significantly asso-
ciated with the need for intubation and may benefit from early
tracheostomies [34]. Other factors that may lead to increased
pulmonary complications are advanced age, pre-existing med-
ical illnesses, and associated major traumatic injuries [33].
Pneumonia, atelectasis, and inability to cough in patients
with acute quadriplegia can also lead to respiratory failure even
if SCI level is caudal to the innervation of the respiratory
muscles. Bronchial mucus hypersecretion has been described
in some patients, possibly due to unopposed vagal activity
resulting from interruption of the sympathetic nervous system
in the acute injury period [33].
Assisted, pressure-controlled ventilation mode with tidal
volumes of 10 to 12 mL/kg and PEEP of 5–7 cmH2O, with
plateau pressures always below 30 is recommended to maintain
healthy lungs and prevent atelectasis. Patients should be assessed
every day for possible mechanical ventilation weaning to avoid
complications related to prolonged, unnecessary mechanical
ventilation and tracheostomy placement. The best modality
described for weaning is progressive ventilator-free breathing
(PVFB), but pressure support (PS) and synchronized intermit-
tent mandatory ventilation (SIMV) can be used as well, when
appropriate for the patient evaluated. PVFB weaning consists of
respirator-free time that can be initiated with only five minutes
of disconnection per hour and is gradually increased throughout
the day depending on the patient’s tolerance. A patient is con-
sidered to be ready for withdrawal of mechanical ventilation
when 48 hours without respiratory support is tolerated [33].
Studies have shown that regardless of the weaning modality
chosen, this process can take from weeks to months, depending
on the level of injury and the patient’s characteristics.
Genitourinary
Approximately 70–85% of individuals suffering SCI will have
some degree of bladder dysfunction leading to urinary incontin-
ence, retention, and/or urinary tract-associated infections that
can lead to complications such as kidney damage and sepsis.
Repeated infections (particularly of the bladder) are common
and related to the need for urinary catheterization [2].
If the SCI level is proximal to the sacral spinal cord, an
upper motor neuron lesion and detrusor overactivity with
incomplete bladder emptiness is expected (spastic bladder);
on the other hand, if the sacral spinal cord or the cauda equina
are involved in the injury, a lower motor neuron and detrusor
areflexia can be observed with mostly urinary retention (flaccid
bladder). Detrusor-external sphincter dyssynergia can also lead
to incomplete bladder emptying in patients with complete SCI,
and urodynamic evaluation, as well as postvoid residuals
(PVRs), are essential to accurately diagnose the bladder dys-
function and be able to provide the best treatment [35].
Clean, intermittent, time-scheduled catheterizations, and
pharmacotherapy such as antimuscarinic drugs (oxybutynin
and tolterodine tartrate), tricyclic antidepressants (TCAs), α-1
and -2 agonists (clonidine, tamsulosin, terazosin), benzodi-
azepines (diazepam), GABAB agonists (baclofen), and regular
detrusor muscle botox injection in patients not responding to
the traditional drugs mentioned, are options available for
neurogenic bladder therapy. More specialized surgical inter-
ventions and neuromodulation therapies can be considered in
cases refractory to medical therapy [36].
Gastrointestinal
Most of these complications are more frequent during the first
month after the injury. Loss of sympathetic regulation and
release of external anal sphincter from central nervous system
control results in unchecked parasympathetic activity that
leads to glandular hypersecretion and sphincter relaxation.
Transient reflex ileus with gastric dilatation can be seen in up
to 10% of patients following cervical- and thoracic-level injur-
ies. According to studies, most of the cases resolve with med-
ical management after one week of symptoms onset [37].
Fecal impactions have been the most described complica-
tion related to any SCI level (up to 45% of patients), which can
become a chronic complaint as well. A regular bowel regimen
and direct manual disimpaction maneuvers should be con-
ducted to treat this complication [37].
Peptic ulcers have been described in 2–6% of SCI cases and
can be observed as an acute or a chronic complication.
Prophylaxis with proton pump inhibitors or H2-receptor
blockers has been shown to decrease the incidence of this
complication, and the recommendation is to initiate prophy-
laxis from day 1 of admission. Endogenous corticosteroid
release secondary to trauma suffered or therapeutic adminis-
tration to reduce cord edema have been proposed as the major
mechanism of this complication [37].
Although not as common, pancreatitis should be suspected
in a patient with abdominal distention, persistent fever, ileus,
nausea, and vomiting that cannot be otherwise explained.
Parasympathetic–sympathetic imbalance and corticosteroids also
play an important role in the etiology of this potentially lethal
problem. Body CT should be done if this is a concern [37].
Enteral feeding is better than parenteral feeding and a
nasogastric tube followed by nasojejunal followed by percutan-
eous gastrostomies are the preferred options. Overfeeding must
be avoided as these patients are in a hypometabolic state [38].
Hematological
Deep vein thrombosis (DVT) rates after SCI can be as high as
100%, depending on the screening tool. Virchow’s triad of
stasis, hypercoagulability, and vessel intimal injury are the
proposed mechanisms for such a high vulnerability. SCI
patients have a 500-fold increased risk of pulmonary embolism
(PE)-related death compared to uninjured patients [39]. Some
studies have not shown a difference in DVT incidence in

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traumatic versus nontraumatic SCI, but the incidence of DVT
is definitely higher in patients treated with only mechanical
prophylaxis in comparison with patients that also had pharma-
cological prophylaxis [40]. Low molecular weight heparin
(LMWH) has been described as the preferred pharmacological
management due to its longer half-life, lower risk of bleeding
complications, and more predictable dose effect when com-
pared to unfractionated heparin. This prophylaxis should be
initiated within the first 72 hours post injury or when con-
sidered to be safe in patients with multiple body trauma, and
should be held in the morning of surgery and resumed within
24 hours following surgery, when possible [39].
Acute DVT treatment requires therapeutic dosages of
unfractionated heparin, usually intravenously, subcutaneous
LMWH (preferred), rivaroxaban, or fondaparinux, and the
duration of therapy will vary depending on the patient’s char-
acteristics, three months being the shortest recommended
period of time. Diagnostic tools should be repeated three to
six months after initiation of therapy to reassess the need for
continuation when comparing benefits and risks related to
each case [41].
Prophylactic inferior vena cava (IVC) filter placement is
controversial. This procedure should be done in high-risk
patients that have failed DVT prophylaxis or have contraindi-
cations to anticoagulation. Prophylactic IVC filter placement
can also be considered in patients with concomitant long-bone
fractures who seemed to be at extreme risk of developing DVT,
given that 80% of PE originates from clots in the legs or pelvis
[42]. To prevent long-term complications seen with permanent
IVC filters, which can include filter malposition, migration,
vena cava occlusion or perforation, retrievable filters should be
considered as these will offer the protection needed and can be
removed safely when appropriate anticoagulation can be
initiated [43].
Integument
About 30–40% of SCI patients will develop a pressure ulcer
during hospitalization and rehabilitation course. Prevention
plays a major role and includes regular monitoring for skin
breakdown and pressure relief, although the recommended
frequency for these preventive therapies varies [2].
Once the patient has developed a pressure ulcer, treatment
can be medical or surgical. Medical treatment includes local
wound care with solutions, ointments, creams, dressings, top-
ical and/or mechanical debridement, and electrical stimula-
tion. On the other hand, surgical debridement, direct wound
closure, skin grafts, and skin flaps, fasciocutaneous or myo-
cutaneous, are among the surgical treatment options
depending on the ulcer stage and severity [44].
Conclusion
Acute spinal cord dysfunction is a medical emergency and
must be attended to in an urgent fashion. Although spinal
cord injury can be a devastating event, many patients may
have reversible lesions. There are multiple potential underlying
mechanisms for acute presentations of spinal cord dysfunction
and appropriate triage, timely assessment, and appropriate
therapy can provide many patients with a favorable outcome.
Acknowledgement
We would like to thank Ryan O’Phelan for creating original
artwork for chapter figures.

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 Chapter
Postoperative Management in the Neurocritical
24 Care Unit
Ryan A. Grant, Andy J. Redmond, and Veronica L. Chiang
Advances in neurosurgery and anesthesia have dramatically
reduced intraoperative morbidity and mortality rates over the
past several years. A significant part of the care of the neuro-
surgical patient, however, occurs postoperatively in the neuro-
intensive care unit (NICU). The goal of care in a monitored
environment during this time is to prevent and treat, in a
timely fashion, potential early and often fatal complications
of both surgery and anesthesia. This requires a team of highly
trained specialists that include neurosurgeons, anesthesiologists,
neurointensivists, consultants, nurses, and key roles played by
family members. In this chapter we will discuss general concepts
that pertain to the neurosurgical patient, as well as particular
postoperative intensive care unit (ICU) guidelines for subarach-
noid hemorrhage, carotid endarterectomy, craniotomy for
tumor, craniotomy for arteriovenous malformation (AVM),
epilepsy surgery, and deep brain stimulation.
General Considerations
The majority of postoperative patients admitted to NICUs pass
through uneventfully and in general spend less than 24 hours
in this monitored setting. Most complications occur within the
first 24–48 hours after surgery and early detection can lead to
quick and efficient remedies. Postoperative complications can
be divided into those related to the effects of anesthesia in the
context of the patient’s premorbid medical conditions and
those related to their neurosurgical disease. The most critical
part of NICU care is the ability to recognize and differentiate
expected postoperative changes in clinical condition from
those that are unexpected. To achieve this, there needs to be
a clear understanding of the patient’s baseline medical condi-
tion, neurosurgical disease, and operative procedure.
Admission to NICU and Peri-operative Handoff
A thorough medical and surgical history should be obtained by
the admitting team, including a review of the medical record,
especially if the patient is slow to recover from anesthesia.
Many times family members are a reliable source of infor-
mation. Communication between the neurointensivist, the
neurosurgeon, and the anesthesiologist involved in the oper-
ation is critical in clarifying peri-operative details, including
which surgical approach was used, unexpected or problematic
events during surgery, and postoperative expectations.
Information regarding medications and fluids administered
intraoperatively, estimated blood loss, and urine output must
be conveyed.
A baseline postoperative neurologic exam must be
obtained on arrival in the NICU and any neurologic deficits
clearly documented. Routine postoperative monitoring,
including cardiac telemetry, oxygen saturation, blood pressure
(usually via arterial line), urine output, and intracranial pres-
sure (if required) should be implemented. A full set of baseline
laboratory studies, including an electrolyte panel, complete
blood count (CBC), coagulation studies, cardiac enzymes (as
needed), an arterial blood gas (if ventilated or on oxygen), and
relevant anticonvulsant levels should be obtained.
In some cases, patients may require continued post-
operative ventilatory support, intracranial monitoring, or con-
tinuous electroencephalography (CEEG) and there should be
a clear discussion clarifying the goals of management. Add-
itional tests such as computed tomography (CT) and/or mag-
netic resonance imaging (MRI) scans, as well as chest
radiographs, may also need to be performed.
Neurological Assessment
After completion of the initial baseline patient assessment,
continued neurologic and physiologic monitoring should be
performed at regular intervals. Any neurologic deficits (new or
pre-existing) may be accentuated by the persistence of halo-
genated anesthetic agents, including isoflurane. Neurologic
examinations should therefore ideally be repeated at least every
hour, looking for the expected progressive improvement in
any immediate postoperative deficit, as well as assessing for
any new deficits.
Consciousness is typically graded using the Glasgow Coma
Scale (GCS), as it is an internationally recognized standard
(Table 24.1). Strength is graded on a five-point scale: 0 being
no movement, 1 being a muscle flicker, 2 being movement, but
not against gravity, 3 being antigravity movement, but not
against resistance, 4 being some movement against partial
resistance, with the resistance subdivided into 4–, 4, 4+, and
5 being full power, with each individual muscle group tested in
isolation following a spinal surgery or spinal cord injury. Just
as important, is the sensory examination to assess function of
the dorsal columns and spinothalamic tracts.
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 Chapter 24: Postoperative Management
Table 24.1 Glasgow Coma Scale
Best eye response (E) Spontaneous opening
Opens to verbal command or
speech
Opens to pain (not applied to face)
None
Best verbal response (V) Oriented
Confused conversation, but
answers questions
Inappropriate responses, but
speech understood
Incomprehensible speech
None
Best motor response (M) Obeys commands
Purposeful movement to
noxious stimuli
Withdraws to noxious stimuli
Decorticate posturing
Decerebrate posturing
None
Any change in the patient’s GCS, pupils, or motor or
sensory examinations requires immediate notification of the
neurosurgical team, with repeat imaging often acquired to
determine if a return to the operating room (OR) is required.
Similarly, a new or ascending sensory level is a neurosurgical
emergency until proven otherwise.
Intracranial Pressure Control and Multimodal
Monitoring
Intracranial hypertension can present as focal or nonspecific
symptoms depending on its etiology. In the postoperative
setting, raised intracranial pressure (ICP) can be secondary
to the development of a progressively increasing intracranial
mass (for example a postoperative hematoma or worsening
edema) that may present with worsening focal deficits, or it
can be secondary to obstructive hydrocephalus, which may
present with decreasing level of consciousness or sixth nerve
paresis. The absolute treatment for an increasing mass is
return to the OR for evacuation, with some of the outlined
measures employed below to mitigate the situation while the
OR is mobilized. Postoperative edema usually can be con-
trolled solely with medical management, including steroids
and induction of hypernatremia. Failure of medical manage-
ment, resulting in uncontrolled ICPs, mandates surgery in the
form of a decompressive craniectomy and/or lobectomy. The
treatment for obstructive hydrocephalus is placement of a
ventriculostomy for cerebrospinal fluid (CSF) drainage and
subsequent treatment of the underlying obstruction.
Acute and persistent elevation of ICP above 20 mmHg
carries a poor prognosis, while the ability to control ICP at
300
<20 mmHg carries an improved prognosis. ICP monitoring
4 can be performed using fluid coupled systems (ventriculo-
3 stomy) or intraparenchymal fiber systems.
Additional forms of intracranial monitoring include
2 microdialysis and brain tissue oxygenation (PbtO2) via LICOX
1 monitoring. Some preliminary evidence from the trauma lit-
erature suggests that a PbtO2 <20 mmHg should be con-
5
sidered indicative of cerebral hypoxia that requires treatment
4
[1], even in the face of a normal ICP. This has resulted in the
development of algorithms in some centers to treat decreased
3
brain oxygenation by increasing cerebral perfusion pressure
2
(CPP) >70 mmHg, and correcting hypoxemia with increased
1
fraction of inspired oxygen (FiO2)/positive end expiratory
pressure (PEEP).
6 First-line treatments of ICP include:
5
• Ensure the head of bed is 30° and the head is midline to aid
in jugular venous drainage
4
3 • If a cervical collar is in place from potential trauma, make
2
sure it is not too constrictive
1 • Control fever
• Treat agitation and pain
• Hyperventilation is only a temporarily effective measure as
the pH of the CSF causing cerebral vasoconstriction will re-
equilibrate. We recommend a PCO2 range of 30–35 mmHg
in the setting of sustained elevated ICP. A PCO2 <28 mm
Hg can result in sufficient vasoconstriction to cause
ischemia, leading to potential infarction and secondary
cerebral edema. Once re-equilibration of the CSF pH has
occurred (typically within about six hours after initiation of
hyperventilation), then normalizing the PCO2 can result in
rebound intracranial hypertension and should be avoided
until the cause of the raised ICP is resolved. Regardless,
when the PCO2 is corrected after a state of equilibrium has
been reached, it needs to be corrected slowly to prevent
rebound intracranial hypertension.
Second-line treatments of ICP:
• CSF drainage is a very effective method for lowering ICP,
based on the Monro–Kelley doctrine. Placement of a
ventriculostomy allows for both drainage and ICP
monitoring. However, leaving a ventriculostomy in place
has about a 20% rate of infection, with the risk increasing
steadily for the first seven days and potentially reaching a
plateau at that time [2]. Many practitioners will keep
standing antibiotics in place to help decrease the potential
risk of infection while the ventriculostomy is in place, but
some authors find no risk reduction with antibiotic use [2].
• If ICP control is inadequate with CSF drainage alone, the
patient should be started on hypertonic saline and serum
sodium should be allowed to rise up to the 150 mEq/L
range, not to typically exceed 160 mEq/L. This is usually
done with 3% hypertonic saline, with up to 30 mL/h able to
be run through a peripheral IV, but, as it is quite caustic to
the peripheral veins, any faster rate should be infused

through a central line. Electrolytes and serum osmolality
should be checked every six hours, with hypertonic saline
held for a serum osmolality >320 mOsmol/L or a serum
osmolar gap >10 mOsmol/L, to prevent renal failure.
• Weight-based mannitol (0.5–1 mg/kg) can also be started
as a standing dose every six hours to aid in dehydration of
the brain. Electrolytes and serum osmolality should be
checked every six hours, with mannitol again held for a
serum osmolality >320 mOsmol/L or a serum osmolar gap
>10 mOsmol/L, to prevent renal failure.
• If ICP continues to be problematic, a 23.4% saline
hypertonic saline bolus can be given through a central line,
similar to a 1 mg/kg mannitol bolus infusion for
immediate ICP lowering. The effect usually occurs within
15–30 minutes, with the limits of use based on the serum
sodium, serum osmolality, and serum osmolar gap, given
the potential induction of renal insufficiency.
Third-line treatments of ICP (if ICP remains refractory to the
above):
• Trial of neuromuscular blockage
• Therapeutic hypothermia
• Barbiturate coma with EEG burst suppression
• Decompressive craniectomy
• Consideration of xenon CT to assess for hyperemia
• Consideration for decompressive laparotomy.
Hemodynamic Control
Strict blood pressure control is recommended in all patients
after intracranial surgery. The target blood pressure depends
on the surgery that was performed, the patient’s baseline blood
pressure, and the patient’s underlying cardiovascular and renal
status. As a rule of thumb, many practitioners seek a sytolic
blood pressure (SBP) of <140–150 mmHg in the postoperative
period to prevent hemorrhage; however, there are no random-
ized controlled trials to confirm this.
The indications for blood pressure control include a
reduced risk of myocardial infarction, cerebral hemorrhage,
and stroke. Concurrent with starting judicious medical therapy
for hypertension, the physician should seek and treat other
contributing causes such as pain, delirium, hypoxemia, and
volume expansion.
Intermittent doses of intravenous labetalol (5–20 mg IV
q 1 h) or hydralazine (5–10 mg IV q 1 h) can be used to treat
the hypertension. Other medications available for treating
hypertension include nitroprusside, nicardipine, esmolol, ena-
lapril, and nitroglycerin. Nitroprusside used as an infusion is
an extremely effective antihypertensive agent, but as a vaso-
dilator it is thought to worsen cerebral edema and therefore is
not used as a first-line agent. It additionally is metabolized into
the toxic metabolite cyanide, which limits its long-term use.
Therefore, for continuous infusion, nicardipine has become
the agent of choice.
Chapter 24: Postoperative Management
Fluid Balance
Restoration and maintenance of normovolemia is important.
The goal of postoperative fluid management is to provide
maintenance fluids, to replete preoperative fluid deficits, and
replace intraoperative blood and fluid losses. Additionally,
neurosurgical patients may have significant fluid and electro-
lyte shifts as a consequence of the intraoperative use of diuret-
ics, such as mannitol and furosemide, for reduction of
intraoperative brain swelling. Therefore, intra- and postopera-
tive urine output may not be the most reliable indicator of
fluid balance. Total fluid intake and output, and hemodynamic
parameters such as central venous pressure (CVP), may need
to be followed serially to guide intravenous fluid management
if required. However, we do not advocate for the placement of
a central line just for CVP monitoring.
Maintenance Fluids
Any patients who are not receiving oral nutrition should be
started on intravenous fluids. To avoid cerebral edema, patients’
status post intracranial procedures or with intracranial pathology
should be maintained on isotonic or hypertonic fluids. Hypotonic
fluids should not be used initially in patients with intracranial
pathology because of the tendency of many neurosurgical patients
to develop hyponatremia, which could exacerbate cerebral edema
or seizures. Hyperglycemic patients, especially those with brain
tumors being treated with steroids, should receive isotonic solu-
tions without dextrose. Patients with spinal pathology can be
maintained on hypotonic fluids or isotonic fluids.
Electrolytes
Serum electrolytes including sodium, blood urea nitrogen
(BUN), creatinine, and glucose should be checked before
deciding on maintenance fluids for the next 24 hours. In the
setting of persistent hyponatremia, the goals of management
are to restore normal serum sodium levels as well as to correct
the cause of the metabolic abnormality.
Serum sodium levels of <130 mEq/L alone can account for
focal neurologic deficits, alterations in level of consciousness,
or postoperative seizures. The two most common neurosurgi-
cal causes of hyponatremia are syndrome of inappropriate
antidiuretic hormone secretion (SIADH; common in most
cases of tumor and trauma) and cerebral salt wasting (CSW;
more common in vascular cases). While urine electrolytes and
osmolalities can help differentiate the two conditions, in the
postoperative patient the predominant difference is the
patient’s intravascular volume.
In SIADH, patients are usually intravascularly overloaded
and therefore the treatment for hypervolemia is diuresis and
fluid restriction to 1000–1800 mL of free water per 24 hours.
Diuresis is, however, relatively contraindicated in ruptured
intracranial vascular lesions (i.e. aneurysmal rupture) at risk
for or symptomatic of vasospasm, given concern of
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hypovolemia potentiating ischemia. In this patient population,
despite the overall fluid overload, hypertonic saline is used to
restore sodium levels. Otherwise, fluid restriction is acceptable
in most neurosurgical patients.
In patients with CSW, patients are intravascularly depleted
and hypertonic saline solutions are required to replete body
sodium and water. In the elderly, hypertonic solutions can
precipitate congestive cardiac failure and placement of a central
venous catheter could assist in hypertonic solution delivery, as
well as CVP monitoring. In addition, if a fluid concentration
greater than 1.5% hypertonic saline is to be used, such as 3%
hypertonic saline, usually a central line is preferred, given how
caustic the salt solution is to the peripheral veins.
In patients with serum sodium levels <125 mEq/L, it is
important to raise serum sodium slowly (no more than
0.5 mEq/h and 12 mEq/24 h) to avoid central pontine
myelinolysis.
Glucose Control
Blood glucose levels should be kept <180 mg/dL. Standing
sliding scales are used routinely in most ICUs. For patients
with difficult to control blood sugar levels, insulin drips can be
started, followed by the introduction of long-acting insulins
(i.e. Lantus) if required.
ICU Prophylaxis
As neurosurgical patients in general are prone to develop
certain preventable complications, the timely use of several
prophylactic agents has become standard. These include:
• H2 blockers or proton pump inhibitors to protect against
gastric ulcers caused by neurological injury and steroid use
• Subcutaneous heparin and intermittent pneumatic
compression stockings for deep venous thrombosis and
pulmonary embolism should be employed in all patients.
Prophylaxis-dose heparin is usually started 24 hours
postoperatively
• The routine use of antibiotics, such as cefazolin, for
24 hours postoperatively has been shown to reduce the
incidence of wound infections in clean neurosurgical
operations [3]. Some practitioners will then continue
antibiotics as long as a drain is in place.
Postoperative Fever
Low-grade temperatures of less than 101.5 °F, arising within
24 hours of surgery, are usually not concerning. The most
common cause of low-grade fevers is pulmonary atelectasis and
standard pulmonary therapy should be initiated in all extubated
patients if possible until they are independently ambulatory.
Fever of central origin is rare in our experience and there-
fore all cases of persistent or high-grade fever should be fully
investigated. The use of steroids significantly increases the risk
of systemic infections and the usual suspects including
sputum, urine, and blood should be cultured. When available,
302
CSF should also be obtained. Evidence of wound infection or
meningitis should also be sought via neurological exam, CT
scans of the head with and without contrast, and/or lumbar
puncture. Spinal fluid interpretation after intracranial surgery
is often difficult, as surgery itself can commonly result in
pleocytosis and a low glucose level.
Empiric antibiotics such as vancomycin and a later gener-
ation cephalosporin (e.g. ceftriaxone or ceftazidime) should be
started after obtaining CSF if there are clinical indications of
meningitis, such as a CSF leak, meningismus, or unexpected
lethargy, until culture results are available. These antibiotics can
then be discontinued or narrowed according to culture results.
The continuing workup or treatment of fever will not be
detailed here, with the exception of the one concern that
persistent undetected or inadequately treated thromboembolic
disease can also present as fever and occurs not infrequently in
this postoperative population.
Subarachnoid Hemorrhage
Spontaneous subarachnoid hemorrhage (SAH) accounts for
1–7% of strokes and is usually secondary to an underlying
aneurysm [4]. If the patient survives the acute event and is
admitted to the NICU, the risk of rebleeding is estimated at
8–23% in the first 72 hours, and thus early aneurysm treatment
should be facilitated whenever possible to prevent rebleeding
[5]. This chapter will not go into the merits of open clipping
versus endovascular coiling, but the points below should help
guide and frame management.
Patient Grading
Fisher grade (Table 24.2) is determined based on the amount
and location of hemorrhage on the CT scan and predicts the
risk of vasospasm [6]. It should be noted that Fisher 3 had the
highest risk of vasospasm in the original study, but a modified
Fisher scale now has Fisher 4 with the highest risk [7].
The Hunt and Hess grade (Table 24.3) reflects the neuro-
logical examination of the SAH patient and has been shown to
reflect patient morbidity and mortality. Hunt and Hess grade can
help decide timing for and approach to securing the aneurysm.
Table 24.2 Fisher and modified Fisher grade in subarachnoid hemorrhage
Traditional Fisher Modified Fisher
Grade Appearance of Grade Appearance of
Hemorrhage Hemorrhage
0 None
1 None 1 Minimal without IVH
2 <1 mm thick 2 Minimal SAH with IVH
3 >1 mm thick 3 Thick SAH without IVH
4 Diffuse or no SAH, with 4 Thick SAH with IVH
IVH or parenchymal
extension

Table 24.3 Hunt and Hess grade
Grade Presentation Survival
1 Asymptomatic, mild headache, slight neck 70%
stiffness
2 Moderate to severe headache, nuchal 60%
rigidity, possible cranial nerve palsy
3 Drowsy/confused, mild focal neurologic 50%
deficit
4 Stupor, moderate to severe hemiparesis, 20%
possible early decerebrate posturing
5 Deep coma, decerebrate posturing, 10%
moribund appearance
A noncontrast head CT showing acute blood in the supra-
sellar cistern is the diagnostic test in most patients and will be
positive in 90% of patients within 24 hours of rupture [8]. The
remainder is usually diagnosed by lumbar puncture and the
CSF finding of an elevated red cell count that does not clear on
subsequent tubes (to differentiate with traumatic tap) or
xanthochromia. In conjunction, an MRI with FLAIR can help
assess for subtle subarachnoid hemorrhage, especially in the
sulci, with additional sequences added to assess particularly for
blood:gradient echo (GRE), susceptibility weighted imaging
(SWI), or T2*, which are all similar in nature and depend on
the institution scanners and algorithms. Angiographic imaging
either as CT angiography (CTA), MR angiography (MRA), or
traditional digital subtraction angiography (DSA) would then
be required to demonstrate the underlying lesion.
Decreasing the Risk of Rerupture of the Aneurysm
Reverse any coagulopathies or antiplatelet effects if present.
Rarely, a short course of antifibrinolytic therapy (e.g. amino-
caproic acid; Amicar) prior to definitive aneurysm treatment
could be considered if unavoidable treatment delays are
likely in patients with a significant risk of rebleeding; if
employed, it should be used for <3 days (preferably <24
hours) given the risk of ischemic events [9]. If patients are
treated with antifibrinolytic therapy, they should have few risk
factors for thromboembolic disease, and should have close
screening for DVT.
In patients with altered mental status, a right frontal ven-
triculostomy (external ventricular drain; EVD) is often placed
upon initial presentation. CSF is not drained, however, unless
the ICP is sustained over 20 mmHg based on the concern for
aneurysmal rerupture if the extramural pressure around the
aneurysm is decreased.
Prior to securing the aneurysm, it is important to control
SBP to prevent rerupture. While our institution aims to main-
tain SBP <140 mmHg, others have reported a safe cut-off of
SBP <160 mmHg [10].
Goal hemoglobin should be above 8–10 g/dL, though it
is unclear if higher hemoglobin concentrations are helpful.
Chapter 24: Postoperative Management
It is thought that at this hematocrit the oxygen carrying cap-
acity and viscosity of the blood is optimal for patients in
vasospasm [9,10].
Routine use of antiepileptic drug (AED) prophylaxis is not
mandated for those who do not present with seizure [10]. If
chosen for use, some recent advisory guidelines no longer
recommend phenytoin given concern for worsened outcomes
[9]. Our institution employs levetiracetam for a three- to
seven- day course on average in all patients. We recommend
continuous EEG in all high-grade subarachnoid patients and
for patients with poor neurological examinations, as the rate of
seizure in this population is up to 20% [11], with the majority
(>95%) of these seizures being nonconvulsive [11]. In our
institution, we also connect our patients postaneurysm secur-
ing to help assess for vasospasm using the alpha/delta ratio and
to assess for seizures. The alpha/delta ratio allows for reliable
detection of ischemia from vasospasm and often preceeds
clinical examination and other multimodality changes by
>24 hours [11,12]. If the examination is poor upon presenta-
tion, we will connect to EEG that same day to help assess for
nonconvulsive status.
Regarding fluid balance and electrolytes, the goal is to
maintain euvolemia prior to securing the aneurysm and in
the vasospasm period. In the case of pulmonary edema exces-
sive fluid intake is avoided and diuretics can be considered to
maintain euvolemia [9,10]. Placement of a central line for
CVP monitoring can be helpful for assessment of fluid bal-
ance, but placement of pulmonary artery catheters are no
longer recommended given lack of evidence of benefit [9].
There is no evidence that hypervolemia is beneficial at this
stage [13].
Hyponatremia should be avoided and fluid restric-
tion should not be used to treat hyponatremia given
concern of worsening potential ischemia during the vaso-
spasm period. Fludrocortisone can be started to limit
natriuresis, and hypertonic saline started for refractory
hyponatremia.
For temperature control, while a standard workup for
fever should be initiated, it is possible that the fever could
be of central nervous system (CNS) origin. While it remains
controversial whether or not cooling of the brain is protective
against injury, attempts should be made to maintain
normothermia.
Hypermagnesemia is not recommended at this time [14];
hypomagnesemia should be avoided given potential ailments,
including fatigue, seizures, muscle spasms, numbness, and
muscle weakness.
There is some evidence that statins may reduce delayed
cerebral ischemia during vasospasm, but this remains contro-
versial [15]. Nevertheless, we start all our patients on pravas-
tatin 40 mg daily or equivalent, given the limited risk profile of
statins.
Oral nimodipine (60 mg q 4 h) is administered as standard
at our institution for 21 days, unless it causes prohibitive
hypotension.
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NICU Management after Endovascular
Aneurysm Coiling
The main differences between traditional craniotomy for
aneurysm clipping and endovascular coiling of an aneurysm
are that coiling patients have a minimally invasive procedure,
thus decreasing the risk of cerebral injury and edema related to
approach to the aneurysm. The tenets of clipping versus
coiling and the algorithm involved in deciding when to pursue
each are beyond the scope of this chapter. While the inherent
procedural risks of stroke and aneurysm rupture are the same
in both procedures, what one needs to know is how the post-
operative management differs, with complications resulting
from groin access (potential dissection or retroperitoneal
hematoma), as well as endovascular dissection of the extra-
or intracranial circulation. Lastly, placement of a ventriculo-
stomy is recommended, if not already in place, prior to endo-
vascular treatment of the aneurysm in case of potential
aneurysmal rupture.
The main differences in postprocedural management for
coiling are:
• Coiling patients need anticoagulation in the form of
continuous heparin infusion to reduce the risk of
thromboemboli. Our institution employs a partial
thromboplastin time (PTT) of 1.5–2.0 times the patient’s
baseline for 24 hours.
• Aspirin (81 mg or 325 mg) is started on postprocedure day
1. This is to reduce the risk of emboli formation from the
coil mass. At our institution, we have a mixed practice
dependent on the operator, with aspirin started usually in all
patients, except one clinician will not start it if the coil mass
is contained entirely within the aneurysm, with no potential
coils immediately next to or just within the parent vessel.
• Dual antiplatelet agents, usually aspirin combined with Plavix
(75 mg), are employed when intracranial stenting is
completed (i.e. flow-diverters and stent-assisted coiling). How
long to maintain aspirin and Plavix is a topic of controversy,
but most practitioners continue Plavix for at least six weeks
during re-endothelialization of the parent vessel.
• The patient needs their groin assessed at the time of each
neurological examination for at least the first six hours to
assess for a developing groin hematoma.
• Distal pulses (dorsalis pedis and tibialis posterior) also
need to be assessed with each neurological check to help
exclude a femoral artery dissection. If pulses become
diminished or lost, then vascular surgery needs to be
consulted and an arterial groin ultrasound obtained to
assess for a pseudoaneurysm. An angiogram of the
extremity in question might also become warranted.
• A postoperative hematocrit and next day hematocrit
should be obtained to rule out a retroperitoneal bleed. If
there is any clinical concern for a postoperative
hemorrhage, then serial hematocrits q 6 h are required to
make sure the hematocrit remains stable. If the hematocrit
304
starts to fall, a CT of the abdomen/pelvis is warranted and
general surgery consulted.
Vasospasm Assessment and Treatment
The biggest complication from SAH is vasospasm, which
is thought to result from irritation of the intracranial vessels
in the basal cisterns from blood breakdown products. Radio-
graphically and/or clinically evident vasospasm can occur
typically between days 3 and 21 post-SAH and the risk of
developing symptomatology from the vasospasm is directly
related to the amount of hemorrhage in the subarachnoid
space (Fisher 3 or modified Fisher 4 have the highest risk).
Transcranial dopplers (TCDs) should be used daily (in
ICUs where available) to monitor and detect vasospasm, with
normal mean blood flow velocities of <120 cm/s and vaso-
spasm indicated by velocities of >200 cm/s or a Lindergaard
ratio in the middle cerebral artery (MCA)/internal carotid
artery (ICA) >6 [16].
Vasospasm typically presents as an acute change in neuro-
logical examination, which can either be focal (e.g. new motor or
speech deficit) or global (e.g. confusion and/or a significant
change in TCD velocities). These changes should warrant a
vascular anatomy scan (i.e. CTA or formal angiogram; the latter
if there is potentially an intention to treat) to confirm vasospasm.
If vasospasm is suspected clinically, a trial of induced
hypertension should be instituted rapidly to see if it results in
clinical improvement [9,10]. Systolic blood pressure is raised
to 200 mmHg usually with phenylephrine as a first-line agent,
but norepinephrine can also be a good alternative. If induced
hypertension is started, cardiac functioning should be watched
with daily cardiac enzymes, ECGs, and echocardiograms as
needed, given the risk of Takotsubo’s cardiomyopathy (stress
cardiomyopathy that involves left ventricular apical akinesis
and mimics acute coronary syndrome), as well as cardiac
ischemia [17]. If nimodipine counteracts the goal blood pres-
sure, dosing can be changed to 30 mg q 2 h and if that does not
help, nimodipine should be discontinued.
As discussed previously, the hypervolemia and hemodilu-
tion parts of the traditional “triple H” therapy are no longer
recommended. Endovascular therapy with intra-arterial vaso-
dilators and/or angioplasty is the next step for symptomatic
vasospasm treatment not responding to blood pressure aug-
mentation, with timing being surgeon dependent. Prophylactic
angioplasty is not recommended [9,10].
After the aneurysm is secured, the ventriculostomy can be
left open to drain continuously, if needed. In the setting of
vasospasm, the ventriculostomy is left open at lower levels for
additional CSF drainage to allow for augmented blood flow.
For example, we will keep the EVD open at 0 cmH2O, or
5 cmH2O in the setting of significant vasospasm.
If the patient develops communicating hydrocephalus
after resolution of SAH then CSF diversion can be continued
using a lumbar drain, which carries less risk of infection and
dislodgement.
 Chapter 24: Postoperative Management

Carotid Endarterectomy and Carotid Stenting over 24 hours rules out myocardial infarction. If the ECG or
cardiac enzymes suggest myocardial ischemia or infarction, the
The postoperative examination in patients’ status post carotid
patient’s pain should be adequately treated with narcotics,
endarterectomy (CEA) and carotid stenting should focus on
supplemental oxygen, and a β-blocker should be used to con-
the patient’s cardiac function, neurologic examination, and
trol the heart rate and blood pressure. A cardiologist should be
include regular inspection of the surgical site (mostly for
consulted for further management.
CEA assessment for hematoma). In addition to the standard
neurological examination, close attention should be paid to the
patient’s strength (i.e. pronator drift to assess for weakness), a Ischemic and Hemorrhagic Stroke
thorough bedside language assessment to rule out aphasia/dys- A decreased level of consciousness and/or evidence of motor
phasia (i.e able to name, repeat, follow complex commands, asymmetry on physical examination in the postoperative
fluency), anosicoria (stroke versus Horner’s versus physiologic), patient raises concern for intracranial ischemia or hemor-
hypoglossal nerve injury, marginal mandibular facial branch rhage. An emergent CT scan of the head will help differentiate
function (differentiate from potential facial palsy), hoarseness between the two. Cerebral thromboembolism accounts for the
(recurrent laryngeal nerve injury), as well as potential hema- majority of strokes associated with CEA, with an incidence of
toma at the operative site (i.e. dysphagia could be any early 5% in the peri-operative period [18]. Its management depends
sign). Carotid stenting avoids these complications, but has on the extent of the patient’s deficit, whether it is progressing or
potential complications that are similar to aneurysmal coiling. resolving, and the timing of the event post procedure [19]. Some
cerebrovascular accidents (CVAs) may be asymptomatic, but
Antiplatelet Agents the majority of the major postoperative CVAs are caused by
Aspirin is usually held for 24–48 hours postoperatively to postoperative ICA occlusion or embolism from the surgical site.
prevent oozing of the surgical wound, but for patients at high If the patient has a major neurologic deficit on awakening
risk for stroke, some clinicians will operate through it. In our in the operating room and there is suspicion for an ischemic
facility, aspirin is routinely started on all postoperative CEA neurologic deficit, urgent surgical re-exploration is recom-
patients within 24 hours of surgery to decrease the rate of mended without delay for imaging (time is of the essence).
embolic complications, as well as to continue cardiac protection. The endarterectomy surface is highly thrombogenic in the
immediate postoperative period or acute dissection of the
Blood Pressure Management and Cardiac Function carotid wall may have occurred.
If the neurologic deficit evolves in the early postoperative
CEA patients should be monitored postoperatively with telem-
period while the patient is in the NICU and an emergent CT
etry and arterial catheter blood pressure tracings. Although
scan of the brain rules out intracerebral hemorrhage, a diag-
some patients may continue to be persistently hypertensive,
nostic cerebral angiogram or at least a CTA should be
especially when exacerbated by anxiety and pain, many
arranged. If the internal carotid artery is occluded on angiog-
patients may in fact become hypotensive. This is due either
raphy, prompt surgical re-exploration is required. On the
to the persistence of iatrogenically induced intraoperative
other hand, if the vessel is patent, examination of the major
baroreceptor blockade or the exposure of the carotid receptor
arterial branches may show occlusions or diffusion-weighted
to markedly increased postoperative blood flow.
MRI may show evidence of embolic phenomenon
Intravenous fluids should be used to keep patients euvole-
(Figure 24.1). In these scenarios, there are few management
mic (usually at least 100 mL/h). Systolic blood pressure should
be maintained between 110 and 150 mmHg to ensure adequate
cerebral perfusion, with higher pressures permitted in patients Figure 24.1 Diffusion-weighted
with chronic severe hypertension. It should be noted that MRI showing an acute ischemic
blood pressure lability is very common in the first 24 hours stroke in the left frontal region.
postprocedure, given the greatly increased perfusion of the
carotid bulb. Thus, long-acting agents should be avoided, and
nicardipine remains the agent of choice.
Mild hypotension may be treated with boluses of normal
saline. Hypotension that is not responsive to fluid boluses may
require pressors, such as phenylephrine.
A routine ECG should be obtained to assess for postopera-
tive myocardial ischemia, especially in the elderly or diabetic
patients who may not manifest any symptoms. Creatine kinase
(CK), CK-MB, and troponin I should also be tested every six to
eight hours during the first 24 hours after the operation.
Troponin I can detect myocardial infarction within four to
six hours of the initial stress. Three negative sets of enzymes

305
 Chapter 24: Postoperative Management
Figure 24.2 Noncontrast CT of the brain showing intracerebral hemorrhage in
the left basal ganglia.
options as anticoagulation or thrombolytic therapies are not
feasible. In a patient with recurrent embolic strokes, surgical
re-exploration may be required.
Intracerebral hemorrhage occurs in <1% of patients after
carotid endarterectomy in the first two weeks [20]. It is usually
secondary to hyperperfusion (cerebral hyperperfusion syn-
drome; CHS) and often localizes to the basal ganglia following
a hypertensive episode (Figure 24.2). Evacuation of intracer-
ebral hematomas is not usually indicated unless there is sig-
nificant mass effect.
Cerebral Hyperperfusion Syndrome (Normal
Pressure Hyperperfusion Breakthrough)
Hypertension subsequent to the restoration of normal perfu-
sion to the previously chronically ischemic cerebral hemi-
sphere is thought to be associated with the development of
CHS. It has been proposed that chronic stenosis of the internal
carotid artery leads to a loss of autoregulation in the distal
arterial system and restoration of blood flow leads to a hyper-
emic state. Many cases are mild, but if untreated, some patients
progress to intracerebral hemorrhage or death.
It usually presents with persistent headaches and/or nausea
and vomiting, and can be associated with seizures, as well as
cause focal neurological deficits, such as hemiparesis and dys-
phasia. A diagnosis of CHS can be confirmed by TCDs of the
306
middle cerebral arteries, and is defined as an increase in cere-
bral perfusion to >100% of the preoperative level [21].
Tight blood pressure control using intravenous infusion of
labetalol, nicardipine, or nitroprusside may be necessary for
the treatment of CHS, but with the careful avoidance of hypo-
tension [22].
Nerve Injury
Most cranial nerve injuries after CEA are a result of traction,
which usually will resolve spontaneously and can be managed
conservatively. Examples include:
• Pupillary asymmetry due to injury to the sympathetic fibers
surrounding the carotid artery, resulting in Horner’s
syndrome
• Asymmetry of the mouth suggesting retraction injury of
the marginal mandibular branch of the facial nerve
• Tongue deviation representing injury to the hypoglossal
nerve causing speech difficulty
• Shoulder weakness or pain due to spinal accessory nerve
injury.
These findings, however, can indicate more serious situations
and need to be closely monitored:
• Pupillary asymmetry associated with blindness suggests the
presence of an embolus lodging in the ophthalmic artery,
which likely is originating from the endarterectomy site.
Radiological investigation using MRI diffusion studies
along with carotid ultrasound is needed to determine if
ongoing emboli are occurring, requiring reoperation.
• Facial droop associated with a decreased level of
consciousness or evolving hemiparesis suggests an evolving
stroke and an emergent CT scan and carotid ultrasound
should be performed to determine if the stroke etiology is
hemorrhagic or ischemic, and again whether reoperation is
required.
• Lastly, hoarseness can be a sign of recurrent laryngeal nerve
injury. Unilateral injury is unlikely to cause significant
morbidity, but if the patient fails to recover after 12 weeks
of conservative management, he or she can be referred to
an otolaryngologist. The diagnosis can then be made
definitively by laryngoscopic visualization of an immobile
vocal cord. Laryngoscopy must be performed before
considering performing surgery on the contralateral neck.
Wound Hematoma
The development of a hematoma in the surgical wound can
occur either from slow persistent oozing along the carotid
endarterectomy site or acutely due to arterial rupture (the
latter is rare). The former presents as increasing agitation in
an otherwise neurologically intact patient associated with no
output from the surgical drain.
As CEAs are being performed in older patients, the unwary
house officer may mistake this agitation for sundowning and
prescribe a sedative. This usually precipitates acute respiratory

insufficiency and it is only when a difficult intubation scenario
is encountered due to a significantly deviated trachea that the
diagnosis becomes obvious.
In the event that acute arterial rupture occurs, priority
should be given to securing the airway, while local pressure is
applied to occlude the carotid. Carotid blowout causes rapid
neck expansion and acute respiratory compromise. If the OR is
not already set up, then bedside intubation along with bedside
clot evacuation are mandatory and must proceed simultan-
eously. It is recommended that the most experienced team
member secure the airway and the patient needs to be taken
emergently back to the operating room to explore the wound
and to repair the arteriotomy.
To avoid this situation, serial hourly measurements of neck
circumference along with serial examinations of the patient for
stridor and tracheal deviation should be performed. Output
from the surgical drain, respiratory rate, and oxygen saturation
should also be measured regularly. New-onset respiratory dif-
ficulty after CEA always requires urgent attention, and wound
hematoma must be ruled out before more common causes are
considered.
The main differences in postprocedural management of
stenting patients are:
• Dual antiplatelet agents, usually aspirin combined with
Plavix (75 mg), are employed when intracranial stenting is
completed, with both drugs given prior to the procedure in
order for them to have their maximal effect. How long to
maintain the aspirin and Plavix is a topic of controversy,
but most practitioners keep Plavix on board for at least six
weeks during endothelialization.
• On postoperative check, the patient needs their groin
assessed during each neurological check for at least the first
six hours to assess for a developing groin hematoma.
• Distal pulses (dorsalis pedis and tibialis posterior) need to
be assessed with each neurological check to help exclude a
femoral artery dissection. If pulses become diminished or
lost, then vascular surgery needs to be consulted and an
arterial groin ultrasound obtained to assess for a
pseudoaneurysm. An angiogram of the extremity in
question might also become warranted.
• A postoperative hematocrit and next day hematocrit need
to be assessed to rule out a retroperitoneal bleed. If there is
any clinical concern for a postoperative hemorrhage, then
serial hematocrits q 6 h are required to make sure the
hematocrit remains stable. If the hematocrit starts to fall, a
CT of the abdomen/pelvis is warranted and general surgery
should be consulted.
• A carotid duplex is obtained the following day to reassess
velocities.
Craniotomy for Supratentorial Tumors
Brain tumors most commonly present with a progressive neu-
rologic deficit, dependent on tumor location (weakness, sens-
ory changes, aphasia, visual spatial dysfunction), headaches in
Chapter 24: Postoperative Management
up to 50% of patients, and seizures [23]. This symptomatology
is more common for supratentorial tumors, whereas infraten-
torial tumors rarely induce seizures and instead present with
signs and symptoms of increased intracranial pressure from
hydrocephalus, with resultant headache, nausea/vomiting,
cerebellar dysfunction, and diplopia (trochlear and/or abdu-
cens nerve palsies). Morbidity and mortality has greatly
improved over the past several decades and is directly correl-
ated to tumor location, with the more common complications
including hemorrhage, cerebral edema, infarction, seizures,
and pneumocephalus.
Postoperative Edema
Postoperative edema is most commonly related to intraopera-
tive retraction. Occasionally partial resection of a glioblastoma
can result in the development of malignant edema that
requires completion of tumor resection for edema control,
but in the majority of cases, postoperative edema is self-
limited. Because of this, in our facility postoperative tumor
patients are given a four-day tapering dose of dexamethasone
starting at 10 mg q 6 h to limit postoperative edema. Concur-
rent gastric prophylaxis and glycemic control measures are
essential. Depending on the amount of edema and residual
tumor, the patient may be kept on an extended course.
Antiepileptics
Prophylactic AEDs are not needed routinely in patients with
newly diagnosed brain tumors [24]. Patients who present with
seizures, however, should be treated with AEDs throughout the
peri-operative period and serum levels should be maintained
within a therapeutic range [24]. If there is a concern for peri-
operative seizures, an anticonvulsant may be started intrao-
peratively and tapered one-week postoperatively [24]. The
most common anticonvulsants being used in our patients
today are levetiracetam and phenytoin.
Postoperative Imaging
If a patient is found to have a neurologic deficit that was not
present preoperatively or was not expected from the neurosur-
gical procedure, an emergent CT scan should be obtained to
rule out hemorrhage, edema, or hydrocephalus. For those with
an uncomplicated postoperative course, a noncontrast head CT
can be performed safely overnight after craniotomy for most
patients to facilitate early transfer of patients out of the NICU.
If an MRI scan is planned postoperatively, it is recom-
mended that it be done within 24–48 hours since after 48
hours, postoperative inflammatory vascular changes make dif-
ferentiating residual tumor from postoperative inflammation
much more difficult [25].
Based on the intraoperative diagnosis, patients may need
additional imaging. For example, spinal imaging in pediatric
posterior fossa tumors to assess for drop metastatic lesions and
a CT scan of the body in the setting of metastatic tumors to
assess for a primary lesion.
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 Chapter 24: Postoperative Management
Hemorrhage
Postoperative hemorrhage occurs in approximately 1% of cases
[26], and represents the most severe and fatal complication of
this procedure. While hemorrhage is more common with
metastatic tumors, such as renal cell carcinoma, melanoma,
and certain primary tumors such as gliomas, they can occur in
the setting of unexpected coagulopathy or as part of an evolv-
ing cerebral infarction. Residual tumor can also hemorrhage.
Platelet counts and coagulation profiles need to be checked
when postoperative hemorrhaging is discovered. MRI with dif-
fusion may need to be performed in scenarios where infarction
is suspected. In the NCCU, blood pressure can rise secondary to
intracranial hemorrhage and should be judiciously controlled
using standard antihypertensives to prevent further hemorrha-
ging, while not compromising perfusion to the brain surround-
ing the hemorrhage. It is generally believed that hemorrhage is
less likely to occur or progress if the systolic blood pressure is
maintained at <150 mmHg for at least the first 24 hours after
surgery. Any hemorrhage that causes significant neurologic
compromise is an indication for urgent surgical decompression.
Smaller hematomas may be managed conservatively.
Cerebral Edema
The development of cerebral edema can lead to worsening
neurologic function. Cerebral edema may occur as a conse-
quence of the presence of residual tumor, especially in glio-
blastoma (Figure 24.3), venous infarct, or the inflammatory
response to surgical manipulation. More commonly, however,
edema occurring at 48–72 hours postoperatively is secondary
to tissue retraction during surgery.
In general, maintaining or increasing steroid therapy along
with judicious fluid management and serum sodium monitor-
ing should allow most patients to recover without event. Cere-
bral edema can be exacerbated by the onset of SIADH and
diuresis is often required to attain mild hypovolemia.
Figure 24.3 Noncontrast head CT showing right frontal edema with
pneumocephalus after tumor resection.
308
Hyponatremia commonly occurs in this setting and should
be treated with fluid intake restriction. Hypertonic saline solu-
tions are classically used if serum sodium levels fall below 125
mEq/L to avoid seizure onset or if the hyponatremia is other-
wise symptomatic. If a patient has worsening cerebral edema
based on clinical examination in conjunction with radio-
graphic imaging, hypertonic saline (1.5% or 3%) can be started
to push the sodium to >145 mEq/L.
A less common cause of cerebral edema is delayed venous
infarction. This occurs especially in surgery where an inter-
hemispheric approach is used or when surgery is performed on
tumors adjacent to or involving large dural venous sinuses or a
major draining vein. Venous infarction can be a difficult diag-
nosis to make. An MR venogram should be performed to look
for a large venous sinus obstruction if suspected. Even if
imaging is unable to demonstrate venous thrombosis, if this
clinical entity is suspected, especially if there is hemorrhagic
change on the head CT distant to the surgical site, the man-
agement is different from the above in that fluid restriction
must be avoided in order to assist in the development of
venous collaterals. Slow continuous infusions of mannitol have
been used in these cases as it is thought to decrease the viscos-
ity of the blood and therefore improve its rheology. Anti-
coagulation will be contraindicated in the initial
postoperative period, but can be considered earlier if there is
progressive venous thrombosis. Occlusion of the superior sag-
ittal sinus may require treatment with placement of a ventri-
culostomy for communicating hydrocephalus and in some
cases endovascular treatment, if appropriate.
Pneumocephalus
Air within the cranial vault may be a cause of postoperative
neurologic decline. Simple pneumocephalus that is not under
tension may cause lethargy, confusion, headache, nausea and
vomiting, and seizures. Air may be located in the ventricles,
over the convexities, or in the posterior fossa.
Treatment is supportive, along with the use of inhaled
100% oxygen via a nonrebreather mask [27]. It is thought that
by allowing oxygen to replace nitrogen in the trapped air
space, gaseous resorption can be accelerated. Simple pneumo-
cephalus usually resolves over one to three days.
Tension pneumocephalus rarely develops. It can occur if
nitrous oxide anesthesia is not discontinued prior to closure of
the dura, or if a “ball-valve” effect develops within the intra-
cranial cavity such that soft tissue allows the entry of air, but
prevents the exit of CSF or air, or in the presence of an
infection from gas-producing organisms. The consequence is
increased intracranial pressure that may be associated with
mass effect on the brain. Symptomatic tension pneumocepha-
lus is treated by urgent surgical evacuation.
Seizures
Postoperative seizures can be of any type and result from
direct surgical cortical irritation, electrolyte imbalance, low

anticonvulsant levels, or intracerebral hemorrhage and edema.
Airway assessment is paramount – that is, if the patient fails to
regain consciousness or has labored breathing, then the patient
should be intubated to protect the airway.
Ativan 4 mg IV should be administered if seizures do not
resolve spontaneously or occur repetitively and can be repeated
every 20 minutes unless the patient develops hypotension. If
the patient is not on an anticonvulsant, they should be given a
concurrent loading dose of levetiracetam (15–20 mg/kg) or
phenytoin (15–20 mg/kg). Electrolyte and anticonvulsant
levels should be obtained and a CT scan of the head should
be performed to rule out surgically amenable pathology. If the
patient was previously on anticonvulsant therapy, it is safe to
deliver a bolus dose of the patient’s anticonvulsant medication
before the return of the serum anticonvulsant levels.
Posterior Fossa Craniectomy for Tumor
Postoperative care for patients undergoing surgery for tumors
in the posterior fossa requires an awareness of all the potential
complications seen in supratentorial tumor surgery with two
major differences:
1. The first is that seizures are not known to arise from
posterior fossa structures
2. The second is related to the specific contents of the region.
The cerebellum, brainstem, and CSF outflow tracts are
located in a confined space. Therefore, a lesser increase in
edema or bleeding can significantly worsen brainstem
function and/or hydrocephalus, with resultant severe
neurologic consequences: cranial neuropathies, and long
tract motor and sensory deficits, as well as coma and death.
Moreover, the centers for cardiac and respiratory function
are located in the pons and medulla and may be affected by the
tumor or by the surgical procedure. Irritation of the lower
brainstem may cause unpredictable episodes of cardiac or
respiratory arrest or distress in the first 72 hours after surgery.
Cranial Nerve Injuries
Injury to the fifth or seventh cranial nerves may occur during
posterior fossa surgery. Injury to the fifth cranial nerve can
cause corneal anesthesia and injury to the seventh cranial
nerve results in an inability of the patient to close the eyelid
from a resultant facial palsy. Both of these predispose the
patient to the development of corneal abrasions, or desiccation
and ulceration. Facial nerve dysfunction is most common
following resection of a vestibular schwannoma. The cornea
needs to be protected with isotonic saline eye drops during the
day and Lubriderm ointment overnight. Additionally, an eye
patch or taping the eyelid shut at night can be helpful.
Many of the lower cranial nerves responsible for swallow-
ing, speech, and coughing can be injured directly or from
retraction, with resultant severe morbidity. After surgery adja-
cent to the pons and medulla, great care must be taken in
watching for airway patency after extubation, especially if there
Chapter 24: Postoperative Management
are concurrent concerns about airway injury and edema, mar-
ginal pulmonary status, or decreased level of consciousness. If
these issues are identified as extubation risks even before
surgery, then it is usually advised that patients be allowed to
be fully awake from the effects of anesthesia before considering
extubation. If the patient is able to be extubated successfully,
then it would also be advisable to examine the swallowing
apparatus before feeding the patient, especially if there is a
significant degree of speech hoarseness or difficulty with
coughing effectively. Clearly, if the patient fails extubation,
tracheostomy and percutaneous enteral gastrostomy place-
ment should be considered.
Hydrocephalus
Critically located edema or hemorrhage in the cerebellum near
the CSF drainage pathways or within the fourth ventricle can
be rapidly fatal due to the development of acute obstructive
hydrocephalus. An abrupt increase in systolic blood pressure,
bradycardia, or change in respiratory pattern (Cushing’s triad)
may signal increased pressure in the posterior fossa.
Pupillary changes, increases in intracranial pressure, and
decreasing levels of consciousness are late findings, but this is
most commonly when the diagnosis is in fact recognized.
Rapid intubation is required in patients in this condition,
followed by rapid placement of a ventricular catheter. At this
point, the NICU physician must decide, usually clinically,
along with the help of a CT scan of the head, whether the
hydrocephalus is due to a focal clot or edema around the
drainage pathways, or if the outflow obstruction is due to
elevated pressure throughout the posterior fossa secondary to
massive hemorrhaging or edema.
In the first scenario of focal abnormality, standard drainage
of CSF via a ventriculostomy is all that is required until the
focal abnormality resolves or it is determined that permanent
CSF diversion is required. In the second scenario, however,
care must be taken to slowly drain a minimum amount of CSF
from the ventriculostomy. Rapid decompression of supraten-
torial pressure could cause the contents of the posterior fossa
to upwardly herniate through the tentorial incisura, thus per-
manently injuring the midbrain. After intubation, the patient
should be taken emergently to the operating room where
placement of the ventriculostomy should occur immediately
before surgical decompression of the tight posterior fossa.
Once surgical decompression has been achieved, then CSF
drainage can proceed as needed.
Cerebrospinal Fluid Fistula
The persistence of a CSF fistula resulting in the formation of a
pseudomeningocele after posterior fossa tumor removal has an
incidence of 5–17% [28]. Unlike supratentorial surgery, dural
defects may not be covered postoperatively with bone, espe-
cially in the setting of possible intracranial hypertension. In
this situation, even in the face of immaculate dural closure, the
risk of CSF fistula formation is high. Fistula formation is more
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 Chapter 24: Postoperative Management
likely in patients with poor wound healing secondary to previ-
ous radiation and/or chemotherapy or poor nutritional status,
and in patients with pre-existing hydrocephalus (increased
pressure on wound).
The leak of CSF comes from the skin incision and initial
treatment includes elevation of the head of bed and oversewing
the entire length of the incision with a running 3–0 nylon
suture. If the leak persists beyond 24 hours, a lumbar drain
should be placed. If this fails, then the defect should be
explored and reclosed surgically.
Less commonly, mastoid air cells are entered during pos-
terior fossa surgery and CSF may then leak through the middle
ear into the nose and throat. Conservative management with a
lumbar drain should again be tried first, but often surgical
wound re-exploration and closure of the air cells is ultimately
required.
Craniotomy for Resection of an Arteriovenous
Malformation
AVMs are developmental vascular anomalies in which there is
direct shunting of blood from arterioles to dilated medium-
sized veins without intervening capillaries, causing ischemia in
the surrounding brain. Prolonged ischemia results in persist-
ent maximal dilatation and therefore loss of autoregulatory
capacity of the vessels supplying these ischemic areas. AVMs
typically present with hemorrhage (50%), seizures, ischemia
from steal, and rarely headaches [29]. Surgical resection
remains the definitive treatment of many of these lesions,
however, endovascular embolization and gamma-knife stereo-
tactic radiotherapy (for lesions <3 cm) is gaining traction,
with good results [13,30].
The predominant aim of postoperative care is to prevent
normal perfusion pressure breakthrough bleeding, which is
thought to be secondary to the restoration of normal blood
flow in the chronically dilated blood vessels supplying ischemic
areas that have had loss of autoregulation. With the increased
blood flow or the elevation of blood pressure above what is
normally seen by the dysautoregulated vessels, cerebral edema
and hemorrhage can result.
Postoperative care in the NICU consists of strict minute-
to-minute blood pressure monitoring with an arterial catheter,
maintenance of euvolemia and use of titratable medications for
strict blood pressure control. Some clinicians prophylactically
also treat the patient with three days of β-blockade to minimize
the risk of hyperperfusion [31].
The systolic blood pressure should be maintained close to
the patient’s baseline range of blood pressures, aiming for SBP
<140 mmHg following treatment and <120 mmHg if there is
concern for hemorrhage. Patients should be treated prophy-
lactically with AEDs. Cerebral angiograms are often obtained
during the postoperative period to assess the extent of resec-
tion of the AVM.
Any change in neurologic status should prompt an urgent
CT scan to rule out cerebral hemorrhage or hydrocephalus. An
310
MRI of the brain with diffusion-weighted images should be
obtained if cerebral infarctions are suspected. If good blood
pressure control is achieved, intracerebral hemorrhage
following AVM surgery is rare. Large bleeds may occur from
breakthrough bleeding as well as from residual AVM, both of
which may require surgical evacuation.
Trans-Sphenoidal Pituitary Resection
Pituitary tumors may be removed via several approaches,
however, the trans-sphenoidal approach (TSTSRPT) is most
commonly used . This procedure is well tolerated and provides
a good cosmetic outcome. Postoperative care involves the
management and treatment of endocrine, surgical, and med-
ical complications. The most common postoperative problems
include hormonal imbalance and CSF rhinorrhea.
The more concerning problems, however, include visual
disturbances and complications arising from carotid artery
injury within the cavernous sinus. Examination of the patient
status post TSTSRPT should specifically include a thorough
examination of the visual acuity, visual fields, and extraocular
movements with each neurological examination.
Strict measurement of hourly fluid intake, output, and
urine specific gravities are essential for the detection of
diabetes insipidus. As prophylaxis for acute adreno-cortical
insufficiency, hydrocortisone 50 mg IV q 6 h is started post-
operatively and tapered by 10 mg/dose per day. If the patient
has adrenal insufficiency, then stress dose steroids are started
preoperatively at 100 mg q 8 h. After the hydrocortisone has
been discontinued, a 6–7 a.m. cortisol level is drawn. If the
cortisol level is low (<5–10 mg/dL), hydrocortisone 50 mg PO
q a.m. and 25 mg PO q p.m. should be given until adrenal
reserve recovers. If the patient remains hospitalized, the corti-
sol can be rechecked during the first week postoperatively to
determine if a lower steroid regimen can be employed or no
steroids at all. Lastly, for patients with Cushing’s disease,
depending on the extent of normal pituitary resection, no
steroids postoperatively may be required at all, given that the
primary disease process results in hypercortisolemia.
If the patient’s course is prolonged in the NICU, the entire
pituitary hormone axis should be checked to see if any other
hormonal replacements are required.
Diabetes Insipidus
Diabetes insipidus (DI) is very common after TSTSRPT. It
develops after injury to the pituitary stalk or from manipula-
tion of the posterior pituitary gland. A diagnosis of DI requires
a triad of a high urine output exceeding 250 mL/h for one to
two hours, a persistent urine specific gravity of 1.005 or less,
and a serum sodium level >145 mEq/L, or a level that is
progressively rising.
After surgery the patient should be allowed to drink to
thirst, and serum sodium levels, renal profile, and serum
osmolality should be obtained every six hours. It should be
noted that in the first 24 hours after surgery, it is common for

patients to demonstrate brisk urine output with borderline
specific gravities and a normal or slightly low serum sodium
level. The most common explanation of this is diuresis of
intraoperative fluid load.
Patients who have difficulty with oral fluid intake need to
be supplemented with intravenous fluids, such as D5W ½ NS +
20 mEq K+. If the patient is hypernatremic, 0.225% normal
saline or even D5W could be considered temporarily to help
correct the sodium. In the patient who is not tolerating PO
intake, but has urine outputs that are persistently >300 mL/h,
it is suggested that the hourly urine output be replaced by 0.5
mL/mL of 0.45% normal saline prior to the confirmation of the
diagnosis of DI so that the free water deficit is not so profound.
The free water deficit can be estimated by the formula:
0:6
weightðkgÞ
½ðserumNa=140Þ  1
If the patient is unable to tolerate oral intake, D5W 0.45% or
0.225% NaCl solution may be used to replace the free water
deficit and the patient should be given desmopressin
(DDAVP) 0.5–1 mL (2–4 μg) on an “as necessary” (PRN) basis
until the fluid balance status of the patient stabilizes over the
ensuing 3–5 days.
DI can occur in one of three patterns: transient (lasting
12–36 hours postop), prolonged (lasting months or greater),
and the least common being the “triphasic response” in which
there is first DI followed by SIADH secondary to massive
release of antidiuretic hormone (ADH) from dying pars ner-
vosa terminals followed by DI again when ADH release is
complete.
If long-term DDAVP therapy is needed, a daily dose of
10 mg intranasally is usually sufficient.
Cerebrospinal Fluid Rhinorrhea
CSF rhinorrhea is a common problem that occurs after trans-
sphenoidal surgery. It is a result of a tear in the arachnoid
above the diaphragma sella during tumor curettage and occurs
in approximately 1–3% of cases [32]. Evidence of CSF leak is
usually recognized at the time of surgery and either fat is
packed into the sphenoid sinus or a watertight cement closure
is performed to try to avoid further leakage. In cases where
nasal splints are placed at the end of surgery, it is almost
impossible to tell if there is a CSF leak postoperatively until
the splints are removed. At this time, it is important to try to
elicit evidence of a leak.
CSF rhinorrhea increases the risk of meningitis and the
development of intracranial abscesses. Lumbar drainage of
10 mL of CSF per hour over three to five days will stop CSF
rhinorrhea in most cases. Persistent CSF leakage will, however,
require surgical repair of the defect.
Visual Deterioration and Ophthalmoplegia
Visual deficits that are noted to be new after surgery may be
secondary to damage to the optic nerves, suprasellar hema-
toma formation, or herniation of the chiasm into the empty
Chapter 24: Postoperative Management
sella. A patient reporting a change in vision should be exam-
ined and taken to the CT scanner to rule out the presence of a
hematoma at the surgical site. Urgent surgical decompression
of a hematoma would be necessary to preserve vision. In cases
of chiasmal herniation, a trans-sphenoidal chiasmaplexy and
elevation of the diaphragm can rarely be performed to prevent
further visual deterioration [33]. During trans-sphenoidal sur-
gery, the third, fourth, and sixth cranial nerves may also be
injured as they course through the cavernous sinus lateral to
the pituitary gland, resulting in a nonprogressive ophthalmo-
plegia that usually improves with time.
Vascular Injury
Injury to the carotid artery or the cavernous sinus is a signifi-
cant cause of morbidity and mortality in trans-sphenoidal
surgery. Bleeding from overt rupture of the cavernous carotid
artery during surgery is usually tamponaded by placing a sig-
nificant amount of packing material (or fat) into the sella to
occlude the vessel. The operation is then halted and an emergent
postoperative cerebral angiogram must be performed.
As arterial and central venous monitoring lines are already
in place from surgery, pressors and intravenous fluids are used
to keep the systolic blood pressure at least 160–180 mmHg and
the CVP >10 mmHg or a pulmonary capillary wedge pressure
(PCWP) >14 mmHg to maintain cerebral perfusion through
collateral circulation and minimize the region of hemispheric
infarction.
Serial neurologic examinations, as well as CT scans, are
used to monitor the patient’s progress and stroke volume. The
latter may go on to require decompressive craniectomy.
Cerebral edema from a resultant stroke can be managed
with hypertonic saline to help decrease cerebral edema, and
serum sodium can be increased to the 150–160 mEq/L range.
Very rarely, carotid artery bleeding manifests as severe
epistaxis in the NICU requiring angiography to identify
the site of bleeding or to identify a pseudoaneurysm or
carotid-cavernous fistula. Reoperation may then be required
or therapeutic stenting with occlusion of the involved vessels
angiographically to achieve hemostasis. If a pseudoaneurysm is
identified, it must be treated, as this is a very unstable lesion
that is prone to hemorrhage.
Epilepsy Surgery
There are many procedures for intractable epilepsy, in-
cluding anterior temporal lobectomy (ATL), selective amygdalo-
hippocampectomy, corpus callosotomy, subtotal corpus
callosotomy, and hemispherectomy. Many of the surgical com-
plications are similar to those outlined for craniotomy; how-
ever, there are numerous functional outcomes, some transient
and others permanent, which need to be identified early.
Postoperative epilepsy patients arriving to the NICU
should have their anticonvulsant levels and electrolytes meas-
ured, and any missed doses of anticonvulsants during surgery
should be replaced to ensure that the full 24-hour dose of
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 Chapter 24: Postoperative Management

medication is received. These patients should also be main-
tained on their antiepileptic medications throughout their
hospital stay.
Anterior Temporal Lobectomy
Postoperative patients should be examined closely to rule out
language and memory disorders, visual field deficits, and
hemiparesis. Visual field deficits can be expected in patients
secondary to the extent of resection of the temporal lobe with
resultant damage to Meyer’s loop, ischemia of the lateral
geniculate body, and manipulation of the anterior choroidal
vessels. Hemiparesis may occur secondary to manipulation of
the middle cerebral artery or the anterior choroidal artery,
particularly if surgery extended into the temporal horn of the
lateral ventricle.
Both transitory and permanent language deficits may occur
after ATL. Cortical retraction and edema in essential language
areas can cause anomic dysphasia, which usually resolves
within one week [34]. Permanent language disorders occur
when more than 5–6 cm of the dominant temporal lobe is
resected and in situations in which anatomical criteria alone
are used to localize cortical language areas. Anatomical criteria
for dominant temporal lobe resection leads to variable lan-
guage outcomes post ATL; therefore, preoperative Wada
testing is helpful in localizing language function. Diminished
postoperative, nondisabling, verbal memory performance has
been noted in patients that had dominant temporal lobe
lesions, with deficits correlating with both the extent of mesial
and lateral resection of the temporal lobe [35].
Corpus Callosotomy
This procedure provides benefit for major motor seizures, but
is the preferential treatment for atonic seizures, which are also
known as drop attacks. Division of the anterior two-thirds of
the corpus callosum can result in a patient who is left-
hemisphere dominant, being lethargic with left tactile anomia,
left dyspraxia, decreased speech spontaneity or mutism, and
nondominant forced grasping and Babinski reflexes, as well as
incontinence postoperatively [36]. Sensory (posterior) discon-
nection syndrome may occur after splenial section [36].
Generally these syndromes resolve over a 7–10-day period,
starting with speech and proximal limb motor recovery and by
two to three months, patients mostly show full resolution of
their deficits in terms of daily living (neuropsychological
testing may demonstrate deficits). As these postoperative
changes are transient, all efforts must be made to protect the
patient from the complications of immobility.
Rarely, left hemiplegia and death associated with frontal
lobe swelling after commissurotomies has been reported [36].
It is thought that the brain retraction during surgery com-
promises the parasagittal bridging veins during callosal expos-
ure. Superior sagittal sinus thrombosis as a cause for swelling
should also be excluded.
Deep Brain Stimulation
Deep brain stimulation (DBS) is an effective therapy for
medication-resistant Parkinson disease. DBS of the globus
pallidus internus (GPi) and subthalamus can relieve Parkinson
symptoms such as rigidity, bradykinesia, and levodopa-
induced dyskinesia without irreversibly destroying tissue.
Patients with tremor as the predominant symptom may have
stimulation of the ventralis intermedius (VIM) instead.
Unilateral DBS of the VIM is associated with paresthesia
and pain, while bilateral DBS may cause dysarthria and bal-
ance difficulty in some patients [37]. In DBS of the GPi, 2.5%
of cases develop visual deficit due to the proximity of the optic
tract to the globus pallidus [37]. Hemiparesis may also occur,
as the internal capsule is also close to the globus pallidus.
DBS of the subthalamic nucleus is associated with intracer-
ebral hemorrhage (3.9%), seizures (1.5%), and infection (1.7%)
[2]. Stimulation-associated complications include dysarthria,
weight gain, depression, and dyskinesia.
Conclusion
Postoperative care in the NICU is aimed at detection and/or
avoidance of secondary complications. Patients’ comorbid
conditions, as well as the types of surgical procedures con-
ducted, predispose them to certain complications that must be
anticipated. A clear understanding of the patients’ past medical
history and the expected outcomes from neurosurgical proced-
ures can prepare the NICU staff for optimally caring for their
patients. Serial neurologic examinations are essential for early
detection and treatment of problems that may arise. These
guidelines provide a broad overview of management of
patients in the NICU after some of the more common proced-
ures. The principles outlined here should serve as a foundation
for the management of patients in situations other than those
that were discussed here.

deep brain stimulation: summary and review of epidemiological studies.

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 Chapter
Ethical Considerations in the Neurocritical Care Unit
25 Fred Rincon
Introduction
Medical ethics deals with moral issues related to the daily
practice of medicine [1]. Questions about the behaviors of
physicians and healthcare providers, the decision-making pro-
cess, values, rights, and responsibilities, generate ethical reflec-
tion that requires a thorough understanding of philosophical
concepts, religion, and jurisdictional laws.
In the neuroscience ICU (Neuro-ICU), treatments and
participation in research require an informed consent process.
In certain circumstances, like in the setting of life-threatening
conditions, the process of obtaining informed consent may be
waived. Several ethical ways to perform research in critically ill
populations can be implemented to protect subjects when
consent is not available.
When addressing issues relating to end-of-life, withholding
and withdrawing life-supportive therapy, clinical prognostic
questions require specific answers so care-takers should
attempt to achieve the highest level of certainty regarding the
diagnosis and prognosis, with the patient’s wishes in mind.
Medical Ethics
The field of medical ethics has evolved substantially over the
last three decades, shaped by the application of modern moral
theories and the influence of the human rights movement.
According to the World Medical Association (WMA), ethics
is “the study of morality, careful and systematic reflection on,
and analysis of moral decisions and behavior” [1]. In other
words, morality tells us what is good or bad and ethics teaches
us why.
Medical ethics is also closely related to jurisprudence. Most
jurisdictions possess laws that may specify how physicians and
healthcare providers are required to deal with ethical issues.
Medical licensing authorities and the legislature of each juris-
diction determine practice rules, and can punish physicians
and healthcare providers for ethical violations.
Medical ethics and jurisprudence are not identical, but
interact rather closely. As medical ethics can prescribe a higher
standard of behavior than does the law, sometimes physicians
and healthcare providers may encounter situations in which
they may be in violation of their jurisdiction’s pertinent laws,
so a basic knowledge of one’s practice jurisdiction laws will
help guide decisions when ethical dilemmas arise.
314
With this in mind, care of critically ill neurological
patients, as in any other field, demands the application of basic
ethical principles. Ethical principles classically associated with
the ethical decision-making process are: autonomy, benefi-
cence, nonmaleficence, and distributive justice [2].
What’s Ethical?
This is a difficult question and every individual is ultimately
responsible for making their own morally correct decisions
and implementing them. To this end, ethical dilemmas emerge
because of a conflict between the moral values and their
interpretation among the agents involved in the decision-
making process. There are several “rational” ways of approach-
ing ethical dilemmas, which are characterized by a systematic
and reflective use of reason in the decision-making process:
principlism, deontology, consequentialism and utilitarianism,
and virtue ethics [1,3] (Table 25.1).
Assessing Decision-Making Capacity in the
Neuro-ICU
In time-critical situations, physicians and healthcare providers
have the duty to preserve life. In very few conditions, patients
can be involved in the consent process. In patients who lack
decision-making capacity and without surrogates, physicians
often use an “implied consent” principle to perform life-saving
interventions. The emergency doctrine of “implied consent”
allows providers to deliver certain interventions that if not
performed in a timely basis could potentially lead to increased
morbidity and mortality (Table 25.2).
Informed Consent
Informed consent is defined as “an autonomous authorization
of individuals of a medical intervention or of involvement in
research” [3]. The concept of informed consent stems from a
principle of personal autonomy, which allows for self-
determination and is based on five important elements: (a)
decision-making capacity, (b) disclosure, (c) understanding,
(d) voluntary choice, and (e) formal authorization to be treated
or included in research [3]. This means that rational individ-
uals with decisional capacity, or competency in legal terms, are
uniquely qualified to decide what is best for themselves. It also
 Chapter 25: Ethical Considerations

Table 25.1 “Rational” ways for approaching ethical dilemmas

Moral theory Comments

Principlism As its name implies, this moral theory uses known ethical principles as the basis for making moral decisions.
It applies the principles of autonomy, justice, beneficence, and nonmaleficence [3] to particular cases in
order to determine what is right or wrong and why.
Deontology A moral theory promoted by Immanuel Kant, preaches a theory of “duty.” Kant defined the demands of the
moral law as “categorical imperatives.” Categorical imperatives are principles that are intrinsically valid; they
are good in and of themselves; they must be obeyed in all, and by all, situations and circumstances if our
behavior is to observe the moral law. In deontology, the means justify the end [1,3].
Consequentialism and Consequentialism is a label affixed to theories holding that actions are right or wrong according to the
utilitarianism balance of their good and bad consequences. In other words, it denotes theories that take the promotion of
value to determine what is right or wrong. A right act therefore, is that which produces the best overall
result as determined by a relevant theory of value. In consequentialism, the ends justify the means.
Virtue ethics This moral theory is rooted in ancient Greek philosophical principles preached by Plato and Aristotle. Virtue
ethics focuses less on decision-making (rules) and more on the character of the decision-makers as reflected
on their behavior (virtues). A virtue is a type of moral excellence. Such virtues could be compassion, honesty,
prudence, and dedication, among others. Physicians that possess these virtues are more likely to make good
decisions and to implement them in a good way [1].

Table 25.2 Components of the “implied consent” principle [4]
• The treatment in question represents the usual and
customary standard of care for the condition being treated
• It would be clearly harmful to the patient to delay treatment
awaiting explicit consent
• Patients ordinarily would be expected to consent for the
treatment in question if they had the capacity to do so
means that people should be allowed to do whatever they want,
even if doing so involves considerable risk or would be deemed
foolish by others, provided that their decision does not
infringe on the autonomy of another. Ethically, the principle
of informed consent is also supported by concepts of benefi-
cence related to professional duty to promote well-being, non-
maleficence related to the duty of not inflicting harm, and
justice by providing fair and equitable access to healthcare
and research.
English and American common laws also support the
principle of informed consent. To this end, jurisprudence has
also held that physicians and healthcare providers in general
have a duty to the patient to treat and to avoid harm, and
failure to fulfill these duties may be considered as a breach of
law, known as tort, which may result in punishment under civil
or penal law. The legal obligation of physicians to obtain their
patient’s consent before any indicated procedure has been
upheld by several landmark court rulings (Schloendorff
v. Society of New York Hospitals, Salgo v. Leland Stanford Jr.
University Board of Trustees, Cobbs v. Grant, Bouvia v. Superior
Court, among others) [5–8]. In Schloendorff v. Society of New
York Hospitals, the New York Court of Appeals ruled that
“every being of adult years and sound mind has the right to
determine what shall be done with his own body; and a surgeon
that performs an operation without the patient’s consent com-
mits an assault, for which he is liable for damages, except in
cases of emergency where the patient is unconscious, and where
it is necessary to operate before consent can be obtained” [5]. In
Salgo v. Leland Stanford Jr. University Board of Trustees, the
California Court of Appeal extended the provisions of Schloen-
dorff v. Society of New York Hospitals to include other interven-
tions ruling that it “is the duty of the physician to disclose to the
patient all the facts which mutually affect his rights and interests”
[6]. The courts have generally upheld that physicians who do not
meet their duty might be subject to liability, not only under the
principles of battery (contact without permission), but also
under the principles of negligence (injury without permission,
in violation of professional standards of care). In 1972, Cobbs
v. Grant established the legal standard of informed consent. In
this landmark case, the Supreme Court of California clarified
that the principle of battery “should be reserved for those
circumstances where a doctor performs an operation to which
the patient has not consented” and that other actions may
constitute negligence if physicians apply interventions without
“reasonable disclosure of the available choices with respect to
the proposed therapy and the dangers inherently and poten-
tially involved in each” [7]. The last case, Bouvia v. Superior
Court, established the principle of refusal of any medical ther-
apy, including those that may be potentially life-saving [8].
Decision-Making and Competency
These are terms that may be used interchangeably. Technically,
medical professionals can determine decision-making capacity,
but lack the legal authority to determine competence. How-
ever, their assessment of decision-making capacity serves not
only as a guide for many legal determinations, but also as the
functional equivalent of such determinations in the absence of
legal proceedings [3]. Competency is defined as the ability to

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perform certain tasks and the ability to make a decision.
A competent individual must be able to perform well in the
following capacities: (a) understand the information, (b)
understand the current situation and its consequences, (c)
rationally consider information in light of one individual’s
values, and (d) make an informed decision [9]. It is the phys-
ician’s finding of incapacity that causes alternative forms of
consent to be sought and a patient’s legal rights to be tempor-
arily suspended without the involvement of the court.
Disclosure
In the United States and its jurisdictions, the legal doctrine of
informed consent incorporates a third element, the disclosure
of information. Without disclosure, voluntary choice and
competence cannot be properly exercised. In clinical practice
and research, excessive emphasis on the disclosure require-
ment may undermine the implementation of informed consent
[3]. A frequently expressed issue in the consenting process is
that too much disclosure may produce anxiety in the patient
and undue influence to agree to a particular therapy or to
participate in research [9]. This may be particularly true in
critically ill patients whose decisions made under duress may
be clouded with misinformation. Nevertheless, the Declar-
ation of Helsinki [10], the most widely recognized code of
ethics related to human research, explains that subjects must
receive information concerning the objectives, methods,
benefits, and potential harms of the study at hand. The main
problem with the enforcement of disclosure in research is
that although internal review boards (IRBs) monitor the
inclusion of relevant information pertaining to the study,
there is no oversight of what investigators tell prospective
research subjects [11]. Finally, other types of information,
such as financial relationships between industry practitioners
and clinical investigators, or financial incentives to enroll
subjects and maintain them in the study [12], present an
opportunity for a conflict of interest and if such information
is pertinent to the patient’s decision to participate in the
study, may need to be scrutinized by the IRB.
Understanding
This refers to the ability to comprehend propositions related to
the intervention or treatment being sought, or participation in
research in the setting of one’s condition (objectives, risks,
benefits, alternatives, and potential outcomes) [13]. Appropri-
ate understanding depends on several factors, including level
of intelligence, language skills, attention, orientation, recall,
and memory. When healthcare professionals approach their
patients to obtain consent for procedures or participation in
research, it is important to determine the level of education to
appropriately convey the necessary information. Similarly, dis-
closure of information related to the proposed intervention in
the form of statistics may be helpful. Patients with appropriate
understanding can discuss the differences between proposed
interventions and alternatives.
316
Voluntariness
The universal right of respect for a patient’s autonomy is
rooted in the rulings from the proceedings of the Nuremberg
trials of 1947 (Nuremberg Code) [14,15]. These are the basis of
modern statements of human rights [2,10] and serve as
guidance to the basic requirements of voluntary informed
consent and the individual’s right to refuse treatment or par-
ticipate in research. The informed consent process should be
guided by the freedom to act voluntarily, without coercive
forces or undue influence. There are several issues during the
delivery of care or when consent for research may impede
voluntariness in critically ill patients. First, the natural setting
of critical illness that leads to inability to evaluate the concepts
of risk–benefit ratios, confused states, and delirium, among
others, which may impede the appropriate consent process for
clinical care and research. Second, the frightening setting of the
Neuro-ICU may impose coercive forces in these subjects based
on the need for emergency treatments or terminal illnesses
when patients may feel they have little choice but to get treated
or to participate in the proposed research. Third, the enthusi-
asm of the practitioner or investigator could lead to undue
influences by manipulation of the information or incomplete
disclosure [16].
Alternative Methods to Obtain Consent in
Critically Ill Patients without Decision-Making
Capacity
When a patient in the Neuro-ICU is deemed not to have
decision-making capacity, the physician or healthcare provider
must seek an alternate way to obtain consent. The options in
these cases are: (a) to seek a written advance directive such as a
living will or durable power of attorney (DPA) (for health-
care), or (b) in the absence of an advance directive, the phys-
ician must seek the substituted judgment of a proxy or
surrogate authorized by the jurisdictional law.
When physicians or healthcare providers are unable to find
any of the above, they can choose to invoke the emergency
situation as justification for treatment using the doctrine of
“implied consent” or “best interest” standard, but these may
apply only to emergency situations (see Assessing Decision-
Making Capacity in the Neuro-ICU). Similarly, in many juris-
dictions, if there is no advance directive or surrogate for
an incapacitated patient, a third party such as a group of
physicians not caring for the patient (alternative physician
consent), ethics team, or risk management (hospital’s legal
office) are options to obtain consent. The ethics team can serve
in the role of representing the patient’s interests by hearing the
recommendations of the treating physicians and then deciding
whether their recommended treatment plan is ethically per-
missible and in the patient’s interests, and this is usually done
with a representative of the hospital’s law office.
In the absence of surrogate decision-makers, physicians
and healthcare providers must seek the representation of the

patient’s interests in the decision-making process through a
court-appointed guardian ad litem [17]. Emergency guardian-
ship may be requested through consultation with the hospital’s
legal team (risk management, hospital counsel, etc.) and the
ethics committee. One problem with this system is that court-
appointed guardians are often unfamiliar with the patient and
have little contact with the medical professionals treating the
patients and often require some time to be appointed.
Advance Directive or Living Will
Probably this is the best tool to direct care in the event of
incapacity, usually helpful in situations related to terminal
conditions, futile care, and multiorgan dysfunction. Shortcom-
ings of these documents are: (a) that the physician may
not find instructions that clearly guide certain treatment deci-
sions, and (b) the ethical argument cannot predict a person’s
own reaction when faced with disability [18]. Studies have
demonstrated a tendency among the nondisabled to view dis-
ability as equivalent to death [19,20] and historically, investi-
gators frequently dump death in with the severe disability
group [21]. In this sense, advance directives or living wills,
even if legally valid, are suboptimal to find treatment direc-
tions in critical illness, particularly when goals of self-
determination and perceptions that guide one’s chosen moral
course may change [18].
Substituted Judgment Standard
Obtaining informed consent by an authorized surrogate
decision-maker is an alternative to direct informed consent.
Appointees by advance directive, or living will, or DPA (for
healthcare decisions), or a family member identified by juris-
dictional law are expected to make the same decisions as the
patient would if the patient’s capacity were intact. This idea of
substituted judgment is widely accepted as a valid means of
respecting patient preferences [22]. The basis of this standard
is framed by landmark court rulings such as in the matter of
Quinlan, an alleged incompetent, 70 NJ 10, 1976. In this case,
the Supreme Court of New Jersey established the concept of
substituted judgment standard. The court determined that a
guardian ad litem (appointed by court order) was not neces-
sary to represent a patient independently in a particular case
and allowed family members to make decisions on their behalf.
The ruling is rooted in an individual’s legal right to privacy
and the notion that a family member could make the assertion
based on the family’s best judgment (substituted judgment
standard). The decision included legal immunity for the phys-
icians and the suggestion to involve ethics committees in such
cases [23]. Shortcomings of the substituted judgment standard
are related to the poor accuracy of the proxy’s ability to predict
the patient’s will, which some studies have found to be no
better than random chance [22,24, the inherent difficulty of
making therapeutic decisions for other people, which may
make proxies reluctant to participate in a consent process
and make them more likely to defer to the physician’s expertise
Chapter 25: Ethical Considerations
without even considering the full disclosure of risks and bene-
fits associated with the intervention [20,25].
Best Interest Standard
When available sources for consent are lacking, a legal exception
may be invoked in emergency situations, in which case
the consent of a reasonable person to appropriate treatment
is implied [3], so the best interest standard may be applied
in these circumstances. The basis of this standard is framed
by the landmark court decision in the matter of Conroy (In
re Conroy, 486 A.2d 1209 NJ 1985). In this case, the Supreme
Court of New Jersey permitted the use of the best interest
standard, to allow the guidance of therapy for an incapacitated
patient whose guardian did not know the explicit wishes for
a particular situation. This principle is also applicable in
those cases when the burden of a therapy outweighs the benefits,
and the pain of interventions would make them inhumane [23].
One of the shortcomings of using the best interest standard is
the possibility of the physician being judged as paternalistic [26],
based on the inherent role of physicians to prevent evil or harm
by promoting good and welfare for others (beneficence)[3].
Ethical dilemmas cannot be addressed successfully unless
the probability of outcomes is entertained. In this case, the
physician should make every effort to acquire the highest level
of certainty regarding the diagnosis and prognosis with the
patient’s wishes in mind. The effort will require knowledge of
the literature and a multidisciplinary team approach to attain a
balanced view of the impact of therapeutic decisions and the
expected disability to the patient. In addressing issues related
to advance directives, and withholding and withdrawing life-
supportive therapy, clinical prognostic questions that require
specific answers include the following: (a) what is the prob-
ability of death during the next month and next year (and what
are the confidence intervals around that probability)?, (b) what
are the likely causes of death during the first and subsequent
months?, (c) if the patient survives, what level of disability and
handicap will she/he suffer?, and (d) what impact will the
intervention have on survival and/or disability? [27].
The Principle of “Clear And Convincing Evidence”
In some jurisdictions of the United States, the principle of
“clear and convincing evidence” may be used in lieu of the
substituted judgment standard. This is one of the legal prin-
ciples used in the U.S. legal system (the other two being
beyond reasonable doubt and preponderance of evidence).
This principle can be used by physicians in certain jurisdic-
tions of the United States (Missouri, New York, Florida) to
withdraw life support or any other intervention when there is
“clear and convincing evidence” of previous patient’s state-
ments and in the absence of a “declaration” such as a living
will, advance directive, or DPA. This principle is valid in many
places in the world, however the practicalities, the paperwork,
and whether or not courts of law have to be consulted are
rather country specific.
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 Chapter 25: Ethical Considerations
In the U.S. and its jurisdictions, this principle is based on
the Cruzan v. Director, Missouri Department of Health, 497 US
261 case, when the court endorsed the right of a competent
person to refuse medical therapy even if this results in the
patient’s death and is based on the liberty interest set forth by
the Fourth Amendment. The case of Terry Schiavo (Schindler
v. Schiavo, 866 So2d 140 Fl Dist Ct App, 2004) was ruled
following the same principle and endorsed Cruzan’s historic
court decision [23]. In 2010, the New York State Legislature
enacted the Family Health Care Decisions Act (FHCDA). The
enacted law covers treatment decisions, including decisions to
forgo life-sustaining therapies, in those adult patients who lack
decision-making capacity and have not signed an advance
directive. For adults who lack decision-making capacity and
have no one available to vouch for them, the FHCDA author-
izes physicians to approve medical treatments, creating a
much-needed alternative to a court-appointed guardian for
decisions to provide treatment for this patient population.
The FHCDA overcomes long-standing case law in New York
State that severely limited the authority of family members and
others close to the patient to withdraw or withhold life-
sustaining measures in the absence of a healthcare proxy or
living will [28].
End-of-Life
End-of-life conversations are routine in the Neuro-ICU. Dis-
cussions related to the goals of care are balanced by the known
ethical principles of patients, autonomy, beneficence, nonmalefi-
cence, and distributive justice. The different values and expect-
ations of the parties involved always generate ethical
conundrums. In this setting, one of the most ethically controver-
sial issues in the Neuro-ICU is how to deal with demands from
family members to administer interventions that healthcare pro-
viders may feel are inappropriate, inadvisable, or “futile.”
When facing withdrawal or withholding of medical inter-
ventions, ethical questions can’t be addressed successfully
unless the probability of outcomes is entertained. To attain a
balanced view of the impact of therapeutic decisions and the
expected disability to the patient, the effort will require a
thorough knowledge of the literature and a multidisciplinary
team approach. In addressing these issues, clinical prognostic
questions that require specific answers include: (a) what is the
probability of death during the next month and next year (and
what are the confidence intervals around that probability?, (b)
what are the likely causes of death during the first month and
subsequently?, (c) if the patient survives, what level of disabil-
ity and handicap will the patient suffer?, and( d) what impact
will the intervention have on survival or disability? [27].
Is There a Difference between Withdrawing and
Withholding?
Generally, the ethical principles of beneficence, nonmalefi-
cence, and distributive justice, the legal implications of due
care and negligence, and orthodox religious views form the
318
basis for this question [23]. Patients, family members, phys-
icians, and healthcare providers may have strong and divergent
views. Some may feel comfortable with both situations, some
may feel comfortable only when deciding not to start a ther-
apy, but some may feel uncomfortable deciding when to stop
that therapy [23].
In practice, when physicians and healthcare providers
encounter these situations, some feel morally responsible
for the effects of withdrawing care, others may find that there
is no difference, and therefore will feel no moral responsi-
bility for the end results. According to Miller and Truog,
“what distinguishes withdrawing from withholding, is that
in the former, the agent initiates the fatal consequence, as
distinct from merely permitting it to continue without inter-
vention to stop it” [29]. According to Beauchamp and Child-
ress, “feelings of reluctance about withdrawing treatments are
understandable, but the distinction between withdrawing and
withholding is morally irrelevant and can be dangerous” [3].
In regard to life-sustaining therapies, courts in the United
States have upheld the concept that there is no difference
between withdrawing and withholding [2,30]. Both are med-
ical decisions with a duty to inform the patient, and his or her
representative. For both, consent and disclosure should
always be attempted.
Very frequently in the Neuro-ICU, physicians and health-
care providers don’t know whether a therapy will be
effective. In this case, it would be better to attempt a trial of
medical therapy, by setting-up “goals” of care, determining
whether those goals can be achieved by ongoing reassessment,
and allowing the Neuro-ICU team to find if the therapy is
ineffective, while maintaining good communication with the
patient’s families, friends, and surrogates [23]. This approach
would allow the physician or healthcare team to withdraw an
ineffective therapy rather than withhold a potentially beneficial
treatment, limiting the chance for undertreatment and
avoiding ethical dilemmas.
Some treatments may be considered inappropriate or inad-
visable. Such treatments are characterized by: (a) extremely
low likelihood of achieving the intended goal, (b) minimally or
potentially beneficial but extremely expensive, and (c) uncer-
tain or controversial benefit. There is still controversy about
the medical definition of futility. Futile medical interventions
serve no meaningful purpose, no matter how often they are
repeated. Therefore, a futile medical intervention is one that
will not accomplish its intended goal. Characteristics of this
definition are that: (a) the intervention has no pathophysiolo-
gical rationale, (b) the intervention has already failed in the
patient, and (c) the unintended effect occurs despite maximal
treatment.
Futility, inappropriate, or inadvisable cases are fortunately
rare but very complicated from the ethical perspective as they
bring the values of the patient, surrogates, healthcare pro-
viders, and the society at odds. For this reason, resolution of
these conflicts requires conscientious ethical analysis and a fair
process.

Open dialogue for conflict resolution is perhaps the most
important tool when facing these situations. Conflicts in
regard to goals of care usually arise from lack of communi-
cation or misunderstandings between the parties involved. To
this end, a useful approach is to involve consultants in pallia-
tive care medicine, and ethics. The goal of bilateral discussions
is to first understand what would be the expectations of the
patient, and to decide on an accepted treatment plan that
would be most compatible with the patient’s expressed or
perceived values. It is very important that during these meet-
ings, healthcare providers strive in achieving the highest level
of certainty regarding the diagnosis and prognosis with the
patient’s values in mind.
Applying Ethical Principles for Human
Research in the ICU
The assessment of the individual’s decision-making capacity in
the setting of human research has been studied before
[16,31,32]. The results of these studies showed that a subject’s
understanding of the information provided or their clinical
situation may be suboptimal [16,31,32]. Similarly, the studies
showed that some subjects did not recognize or understand
that they were giving consent for a research project or that they
could withdraw from it if they wished [31,32].
The Nuremberg Code [14,15] of 1947 provides the ethical
framework of how to conduct human research. This docu-
ment describes the necessary conditions for clinical research
after the provisions of its solid statement that “the voluntary
consent of the human subject is absolutely essential.” In
1964, the WMA described in greater detail the ethical prin-
ciples for medical research that involved human subjects in
their landmark proclamation “The Declaration of Helsinki”
[10,15]. The American Medical Association (AMA) code of
ethics was also revised to include the concepts of informed
consent for both clinical and research procedures [33].
Some erudites of medical ethics defend the view that no
research is permissible in the absence of the subject’s voluntary
informed consent by stressing that scientific progress is mor-
ally optional, while respect for human subjects and principle of
autonomy is not. Others support experimentation in human
subjects in the absence of a consent process, as long as certain
conditions designed to protect subjects are entertained [34].
Despite this controvery, research in minors and other vulner-
able populations has continued to grow, even after the pro-
mulgation of the Nuremberg Code [34]. These practices have
been justified by the use of alternate ways of obtaining what
many believe would be the moral equivalent of the subject’s
consent, including parental consent and assent, the notion
that significant benefits of the research endeavor would be
foregone if the consent requirement were strictly interpreted,
and the use of conditions to the research such as the use of
IRBs, special study designs, op-out mechanisms, retrospective
and prospective consent processes, and independent moni-
toring [34–36].
Chapter 25: Ethical Considerations
Consent for Research by the Patient’s Legally
Authorized Representative
According to the 1981 version of the Code of Federal Regula-
tions (CFR) for the Protection of Human Subjects, “no investi-
gator may involve a human being as a subject in research
covered by this policy unless the investigator has obtained
the legally effective informed consent of the subject or the
subject’s legally authorized representative” [37]. An authorized
legal representative is defined as an individual or judicial body
authorized under applicable law to consent on behalf of a
prospective subject to the subject’s participation in the proced-
ures(s) involved in the said research.
Many patients appoint family members, friends, and others
to make pertinent decisions on their behalf during periods of
incapacity (DPA for healthcare). Many advocate to extend this
legal right to enable the DPA to make research participation
decisions. A critical difference between delegating decisions to
DPAs in the clinical setting and the research setting is that
recognizing the authority to decide about someone else’s care
seems more justifiable when there is potential that the inter-
vention will be in the patient’s best interest [34]. In contrast,
experimental procedures are not undertaken with the primary
goal of the subject’s best interest, but rather are intended to
improve general knowledge and advance science, so as
explained by Jonathan Moreno, “allowing other persons to
decide about making someone an experimental subject, even
when the individual in question has authorized them to do so,
is a qualitative departure from ordinary DPA arrangements.
Such decisions may entail considerable risks with little likeli-
hood of substantial benefit” [34]. In certain situations, the
consent process may be waived by an IRB (Table 25.3).
Even though the political system of the USA enables agents
to autonomously appoint DPAs for healthcare-related deci-
sions, there seems to be a societal interest when such private
agreements represent a potential harm to the patient themself,
in the absence of potential benefits, particularly related to
participation in high-risk research[34]. On the other hand,
the possibility of potential greater benefit for society as a whole
may argue in favor of such agreements to go forward, despite
their potential risks, particularly in circumstances when the
rejection of those individuals that have made themselves
Table 25.3 Situations in which an IRB may waive consent for research
according to the 1981 CFR [37]
• The research involves no more than minimal risk to the
subjects
• The waiver or alteration will not adversely affect the rights
and welfare of the subjects
• The research could not practicably be carried out without the
waiver or alteration
• Whenever appropriate, the subjects will be provided with
additional pertinent information after participation
319
 Chapter 25: Ethical Considerations
available to participate in research through a DPA would
significantly hinder studies of the condition that led to the
patient’s incapacity [34]. A balanced approach may be
achieved by limiting the circumstances in which the DPA’s
authority would be valid. Studies that present no prospect of
direct benefit to the patient, but entail a significant risk, could
be ineligible for participation through a DPA. However, stud-
ies that entail minimal risk could be regarded as consistent
with the patient’s best interest and therefore eligible, even if
they do not advance those interests [34]. Minimal risk is
defined in the 1981 CFR as “the probability and magnitude
of harm or discomfort anticipated in the research are not
greater in and of themselves than those ordinarily encountered
in daily life or during the performance of routine physical or
psychological examinations or tests ” [37].
Consent for Research by the Patient’s Legally
Authorized Surrogate
Usually, individuals that lose decision-making capacity have
not made an advanced directive or identified a designee in a
DPA. The law allows for family members, friends, or surro-
gates to provide consent for treatment in the clinical setting,
but whether they can grant permission for participation in
research carries an uncertain legal basis [34]. Jurisdictions
could potentially recognize “natural” surrogates (family
members or close friends) as enablers to participate in clinical
research; however, an objection to such legal arrangements is
that, unlike a legally appointed representative by advanced
directive or DPA, the surrogate’s standing as a substitute
decision-maker may arise only from the law [34]. The moral
basis for the surrogate’s authority to decide participation in
research may appear inadequate for the following reasons: the
patient has not selected the surrogate a priori, surrogates are
supposed to act on behalf of the patient’s best interest or in
accordance to the patient’s “substituted judgment,” and there
is no guarantee that even the closest relative is aware of the
patient’s values toward research or that the surrogate would act
on the basis of those preferences, even if they are known [34].
To this end, the medical best interest standard could not apply
to studies that offer no prospect of direct benefit to the patient
[34]. Knowing the dubious legality of these arrangements,
several studies and a large number of subjects have been
enrolled on the basis of surrogate decisions, so restrictions in
this pathway could minimize advances in research achieved by
prior clinical trials and their investigators.
An alternative would be to recognize in regulation the role
of surrogates in research and allow for participation in those
studies in which procedures may be potentially beneficial or
offer minimal risk [34], but even with this approach, surrogates
may not provide adequate assessment of the patient’s values in
regard to research [24,38,39]. Strikingly, even competent
patients and surrogates are unable to fully understand the main
objectives of clinical trials, and most of these patients and
families consent to research on the basis of patient–physician
320
relationships, trust, and hope for some benefits, even when
researchers have indicated the unlikely event of beneficial out-
comes [40,41]. So if the discussions during the process of
informed consent among critically ill patients, surrogates, and
others are clouded with misunderstanding or misinformation, it
is possible that the informed consent process for participation in
research in these patients may not be entirely valid.
Deferred and Waiver of Consent for Research in
Emergency Situations
The 1981 CFR provides some flexibility to enroll subjects
without decision-making capacity and without DPAs or
surrogates, but the definition of “minimal risk” may exclude
some individuals from emergency research, such as cardio-
pulmonary resuscitation and stroke interventions, among
others, which may be potentially harmful and not routine in
“daily life.” Based on this hurdle, some investigators used a
procedure called deferred consent under which patients could
be enrolled into clinical research without their informed con-
sent and then they or their surrogates were informed about the
procedures later or when the patient regained decision-making
capacity [42]. This procedure was heavily criticized on the
basis that there was no legal definition of consent for proced-
ures that have occurred previously [35]. As the practice of
deferred consent declined in the 1990s, the members of the
Coalition Conference of Acute Resuscitation and Critical Care
Researchers argued that potential risks of not allowing the
practice of deferred consent in vulnerable patients would be
equivalent to being denied the potential beneficial therapy
in the absence of known effective treatment for their life-
threatening condition [43]. The members of the coalition also
proposed that the term “minimal risk” would be changed to
one of an “appropriate incremental risk,” which is defined as
“any potential risk associated with participating in the
research protocol relative to the natural consequences of the
medical condition, or any potential risk associated with
receiving the experimental intervention relative to receiving
the standard treatment for the medical condition” [43]
(Table 25.4).
Some international guidelines also recognize that research
in emergency situations may be performed after a waiver of the
individual’s consent [45,46]. Nevertheless, few clinical research
studies have been conducted under this waiver without some
criticisms from the scientific community [47]. The PAD Trial
for example, a clinical study designed to compare two modal-
ities of care for out-of-hospital cardiac arrest, was conducted
under the new regulations [48], and is an example of the
cumbersome yet morally acceptable process to perform
research in critically ill populations. Though the authors of
the PAD Trial concluded that the process to obtain approval
for their research protocol “required significant and persistent
effort” and was “feasible,” the mean time from submission to
protocol approval was 138 days, with 51 requests and revi-
sions, the community required 1030 meetings, which were

Table 25.4 Situations in which an IRB may allow research to be conducted
in emergency settings without patient, DPA, or surrogate consent based on
the 1981 CFR, modified in 1996 [44]
• The human subjects are in a life-threatening situation,
available treatments are unproven or unsatisfactory, and the
collection of valid scientific evidence, which may include
evidence obtained through randomized placebo-controlled
investigations, is necessary to determine the safety and
effectiveness of particular interventions
• Obtaining informed consent is not feasible
• Participation in the research holds out the prospect of direct
benefit to the subjects
• The clinical investigation could not practicably be carried out
without the waiver
• The proposed investigational plan defines the length of the
potential therapeutic window based on scientific evidence,
and the investigator has committed to attempt to contact a
legally authorized representative for each subject within that
window of time and, if feasible, to asking the legally
authorized representative contacted for consent within that
window rather than proceeding without consent. The
investigator will summarize efforts made to contact the
legally authorized representatives and make this information
available to the IRB at the time of continuing review.
• The IRB has reviewed and approved informed consent
procedures and an informed consent document
• Additional protections of the rights and welfare of the
subjects will be provided, including, at least: consultation with
representatives of the communities in which the clinical
investigation will be conducted and from which the subjects
will be drawn, public disclosure to the communities in which
the clinical investigation will be conducted
attended by 8169 individuals, and there were 475 press releases
and 231 radio, television, or print commentaries [49].
Should We Require Consent for Research in Critically
Ill Patients?
Though the process of informed consent may be difficult in
critically ill populations, it may not be impossible. Truog et al.
note that many clinical interventions in the ICU can be per-
formed without informed consent, particularly those interven-
tions that carry a “tacit consent” or an implied consent in cases
of emergencies, but clinical research may definitely not [50].
When clinical procedures carry higher than minimal risk or
are defined as high-risk procedures, the clinician must obtain
informed consent from the patient or surrogate [50]. This is
particularly important when procedures or treatments do not
have an established safety track record or have not been
designed for the indication for which they are being proposed
(off-label use). Similarly, quality improvement studies may be
performed without informed consent, but these may carry
similar risks to those of clinical research; however, only clinical
Chapter 25: Ethical Considerations
research may require informed consent [51]. To this end,
Truog et al. [50] argue that a double standard may be applied
when one considers informed consent for clinical research
only, but not for quality improvement studies or certain pro-
cedures indicated on clinical grounds.
Another view in support of waiving informed consent in
clinical research is that in this instance, consent may be con-
sidered tacit or implied as well [51], as certain interventions
may potentially be life-saving so patients or surrogates
may not be allowed to refuse them because doing so would
not be in the patient’s best interest [52]. This approach may be
in conflict with the principles of autonomy and self-
determination; however, if safeguards are implemented, it
may still be a practical alternative to allow critically ill popula-
tions to be included in research that may have potential impli-
cations for future studies and improving patients’ outcomes.
Should We Exclude Critically Ill Patients Who Lack
Decision-Making Capacity from Clinical Research?
In general, clinical research in populations that cannot consent
has been done, especially under the safeguards of advanced
directives, DPAs, surrogates, or some other monitoring entity.
The exclusion of vulnerable populations, including critically ill
patients who are at risk of decisional incapacity or who lack
decisional capacity, will avoid philosophical and ethical prob-
lems inherent to clinical research by resonating with the state-
ments of the Nuremberg Code, but not go well with modern
research practices or principles of justice and equality, even in
the decades after the code was promulgated [34]. More recent
codes of ethics, such as the Declaration of Helsinki [10] and
guidelines in the United States [44] and other parts of the
world, have endorsed clinical research involving those unable
to consent, under certain conditions and safeguards [34].
Recent scholarship indicates that the Nuremberg Code was
implemented, given the events of the time, to condemn uneth-
ical practices in human research, but was intended to refer to
clinical research in normal populations and not in those who
were ill [34]. As previously explained, the recently authorized
exemption to informed consent in clinical research for emer-
gency research [44] is a greater departure from the Nuremberg
Code’s requirements. A moral justification for this narrow
exemption is the need for improvements in life-saving inter-
ventions and life-threatening conditions. To this end, a similar
approach could be entertained on behalf of those who lack or
are at risk of losing their decision-making capacity [34].
The informed consent process is one of the steps that
makes research ethically acceptable [53]. Additional require-
ments of ethically acceptable clinical research include: (a)
value, related to improvements in health or knowledge, (b)
scientific validity, meaning that research must be methodologic-
ally rigorous, (c) fair subject selection, the objectives of the
research are based on balanced distribution of risks and benefits
and appropriate selection of those needed for the research
question, (d) favorable risk-to-benefit ratio, minimizing risks
321
 Chapter 25: Ethical Considerations

and maximizing benefits, and (e) respect for the subjects. In
addition, clinical equipoise is perhaps the most important
requirement for ethical clinical research [54].
Opt-Out Approach
If consent is considered an indication of willingness rather
than refusal, and if the research entails a minimal risk, an
opt-out arrangement or passive consent is an acceptable pro-
cedure without violating the gold standard of consent and
choice [55,56]. In the opt-out approach, individuals agree not
to participate in a study. The opt-out approach has been
associated with less selection bias and higher recruitment rates
[55]. Recruiting unbiased subjects for clinical research is also
vital for the adequacy of the scientific method. The traditional
means of subject recruitment for clinical research assumes that
subjects are potentially willing to be enrolled, and a nonre-
sponse to an initial approach can be followed-up with add-
itional communication. IRBs are prompt to encourage
investigators to refrain from repeated contact with potential
candidates for research, unless the subjects actively signal
willingness to consider enrollment, in other words, to follow
the opt-in approach.

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323
 Chapter
Pulmonary Consult: Management of Severe Hypoxia in
26 the Neurocritical Care Unit
Rafael A. Calderón Candelario, Matthew C. Exline, and Naeem A. Ali
Introduction
Acute respiratory dysfunction is one of the most frequent
medical complications of critically ill patients, including those
suffering from neurological diseases. It contributes the highest
percentage of mortality from non-neurologic causes in neuro-
critically ill patients [1–3]. This chapter will focus on the
mechanisms, diagnostic criteria, stratification of severity, and
management of hypoxemia with attention to acute respiratory
distress syndrome (ARDS) in the context of the neurocritically
ill. Special consideration will be provided as well to other
commonly encountered diseases in the intensive care unit
(ICU) such as chronic obstructive pulmonary disease (COPD),
and venous thromboembolism.
As illustrated in Figure 26.1, each of the mechanisms
contributing to hypoxemia must be considered, as the treat-
ment approach varies for each disease state. Of these mechan-
isms, the most common and central to all the processes is
ventilation perfusion mismatch. While altered mental status
or respiratory muscle insufficiency may be manifestations of
neurologic diseases that contribute to the development of acute
respiratory failure, in the absence of significant hypoxemia, the
treatment approach involves respiratory support, but remains
focused on treating the underlying disease. Because the prin-
ciples of treatment are basic in the case of pure respiratory
failure caused by alveolar hypoventilation (due to altered men-
tation or respiratory muscle weakness), we do not comment on
it directly here. In contrast, because of the need to integrate the
principles of respiratory support for significant hypoxemia
with that of support for acute neurologic disease, we focus
most of our discussion on the neurologic patient with respira-
tory failure and significant cardiopulmonary disease.
Pulmonary Vascular Disease
Pulmonary vascular disease (PVD) primarily causes hypox-
emia by an impaired diffusion capacity due to pulmonary
vascular remodeling with increase in arterial thickness. With
time, increased pressures in the pulmonary circulation can
lead to a pressure overload in the right heart that combines
decreased diffusion from abnormal vasculature with low right
cardiac output. Pulmonary fibrosis with architectural changes
in the lung with increased interstitial fibrous deposits also
causes impaired diffusion.
324
Patent Foramen Ovale/Shunt
Extrapulmonary shunts such as a patent foramen ovale of
atrial septal defect (ASD) can lead to development of neurolo-
gic pathology, i.e. paradoxical emboli with stroke, and can be a
cause of hypoxemia. Systemic venous return can bypass the
pulmonary circulation by crossing the defect and causing
deoxygenated blood to mix with the return from the pulmonary
circulation and decrease oxygen concentration to the tissues. In
cases of complete atelectasis within the lung secondary to
mucous plug or severe alveolar filling processes, the same
rationale occurs within the pulmonary circulation with areas
where deoxygenated blood (coursing through atelectatic/col-
lapsed parenchyma) mixes with oxygenated blood from aerated
parts of the lung. Clinical examples of this can be pneumonia,
cardiogenic pulmonary edema, and ARDS, among others.
Venous thromboembolisms provide the opposite scenario
to shunting. With pulmonary embolism, there are ventilated
areas of the lung with no blood supply to them, increasing
dead space and in turn causing hypoxemia. Acutely, depending
on clot burden, this can also lead to right ventricular failure,
with a low forward flow/cardiac output state also contributing.
Obstructive Lung Disease
Obstructive lung diseases, such as COPD and asthma, contrib-
ute to hypoxemia in multiple ways. Mucus hypersecretion
provides for an alveolar filling process causing a low V/Q
mismatch. Lung hyperinflation seen in both of these diseases
may lead to a state of overdistension of the alveoli with
increased airway pressures causing a high V/Q state by collaps-
ing the adjacent vasculature. In emphysematous COPD, the
architectural distortion and air trapping can lead to extrinsic
compression of adjacent unaffected alveoli causing a state of
hypoventilation and atelectasis in adjacent “normal” lung.
Acute Lung Injury and Acute Respiratory
Distress Syndrome
The incidence of ARDS is 150,000/year, with mortality from
10–90% [4]. ARDS is an acute onset syndrome characterized by
nonhydrostatic pulmonary edema and hypoxemia associated
with inflammation and increased permeability, with a constella-
tion of clinical radiologic and physiologic abnormalities that
 Chapter 26: Management of Severe Hypoxia

Mechanisms of Hypoxemia
Shunt Low V/Q Mismatch Normal Ventilation/Perfussion High (V/Q) Mismatch Impaired Diffusion
(V/Q) Mismatch
O2

O2 O2
O2
CO2 O2 O2

O2 CO2
CO2 CO2
CO2 O2 O2 CO2
CO2 O2
CO2 O2 CO2 O2 O2 O2

CO2 O2 CO2 CO2 O2 CO2 O2 CO2 CO2 CO2 O2

Perfussion with no ventilation
Extrapulmonary shunt
Complete Atelectasis
Preserved Perfussion with Preserved Perfussion Preserved ventilation with low Normal to low ventilation and
decreased ventilation Preserved ventilation or absent perfussion preserved perfussion with decreased
Normal diffusion diffusing capacity
Alveolar Hypoventilation (No alveolar filling) Pulmonary Embolism
Pulmonary Fibrosis
Alveolar Filling Processes: Low Cardiac Output
Pulmonary Hypertension
ARDS High Airway Pressures

CHF Increase in dead space

Pneumonia

Figure 26.1 Mechanisms of hypoxemia with major disease categories.

Figure 26.2 Antero-posterior (AP) chest X-ray

(CXR) and computed tomography (CT) showing
bilateral patchy infiltrates in two patients with
ARDS due to H1N1 influenza.

cannot be explained by, but may coexist with, left atrial hyper-
tension (Figure 26.2) [4].
Berlin Criteria (Emphasis on Staging of Severity)
This new definition emphasizes severity stages that are associ-
ated with clinically meaningful differences in outcome
(Table 26.1). The scale has been shown to have direct relation-
ships with mortality (mild 27%, moderate 32%, severe 45%),
median ventilator-free days (mild 20, moderate 16, severe 1),
and median duration of mechanical ventilation in survivors
(mild 5, moderate 7, severe 9). The proposition is that the new
definition has better clinical validity [5].
The Implications of Clinical Management on the Berlin Definition
The amount of ventilator support was not a routine part of the
initial AECC definition of ARDS. The Berlin definition pro-
posed measuring all values of PaO2/FiO2 (PF) ratio on a
minimum threshold of respiratory support. However, the
amount of that support is a residual point of controversy.
A standard ventilatory setting (PEEP and FiO2) applied within
the first 24 hours could lead to phenotypic classification and
risk stratification. In one validation study of 459 patients, only
when the PEEP level was 10 cmH2O and FiO2 was greater
than or equal to 50% was the severity of ARDS defined in the
Berlin definition associated with increase in mortality (mild

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 Chapter 26: Management of Severe Hypoxia

Table 26.1 Severity of hypoxemia and definitions of ARDS Table 26.2 Components and individual values of the lung injury score [7]

AECC Hypoxemic ratio Chest roentgenogram Score

1994
PaO2/FiO2 PaO2/FiO2 No alveolar consolidation 0
definition
 300 200
[4] Alveolar consolidation confined to one quadrant 1
ALI ARDS
Alveolar consolidation confined to two quadrants 2
Additional criteria: Acute onset, bilateral infiltrates
Alveolar consolidation confined to three quadrants 3
on frontal chest radiograph and PAWP <18
Alveolar consolidation in all four quadrants 4
Berlin Hypoxemic ratio
2012 Hypoxemia score (PaO2/FiO2)
PaO2/FiO2 PaO2/FiO2 PaO2/FiO2
definition 300
300–>200 200–> 100 0
[5]
mmHg 100 mmHg mmHg 225–299 1
With 5 of PEEP With 5 of With 5 of
or CPAP PEEP PEEP 175–224 2
ARDS 100–174 3
Mild Moderate Severe <100 4

Additional Criteria: Within 1 week of a known PEEP score (when ventilated)

clinical insult or new or worsening respiratory 5 0
symptoms. Bilateral opacities (CXR or CT).
Respiratory failure not fully explained by cardiac 6–8 1
failure or fluid overload. Need objective 9–11 2
measurement (e.g. Echo) to exclude hydrostatic
edema if no risk factor present 12–14 3
15 4
Respiratory system compliance score (when
16.9%, moderate 41.4% and severe 55.2%). This association
available)
was diminished when respiratory support was kept at only at a
PEEP 5 cmH2O. This suggested there was a need to increase 80 mL/cmH2O 0
the minimum PEEP requirement to establish severity at 60–79 mL/cmH2O 1
10 cmH2O or more, with an accompanying FiO2 of 50%. It
40–59 mL/cmH2O 2
was reported that, at the time PaO2 was measured for the
purposes of the Berlin definition, there was no standardization 20–39 mL/cmH2O 3
of ventilator settings, and that the basis for selecting PEEP 19 mL/cmH2O 4
5 cmH2O is not well supported [6].
Final score is the average of all measured values available:
No lung injury 0
Lung Injury Score
The lung injury score (LSI) was modified to apply to ARDS Mild-to-moderate lung injury 0.1–2.5
around 1988 to characterize the presence and extent of a Severe lung injury (ARDS) >2.5
particular patient’s manifestations of acute pulmonary
damage. It has four components: CXR findings, hypoxemic
ratio, PEEP, and respiratory compliance (Table 26.2) [7]. It is Epidemiology of ARDS in Acute Stroke
not routinely used in clinical practice, but appears in many Estimates of the incidence of ARDS in acute stroke patients
clinical trials discussing ARDS. vary widely. This complication has been best studied in SAH,
where the incidence of ARDS ranges from 4–27% [2,9]. In
193,209 patients with SAH in the National Inpatient Sample
Epidemiology of Severe Hypoxemia in General ICU (NIS) database, the incidence of ARDS was more than a third
Populations (Table 26.3) [5] of all patients. In fact, the incidence increased across the years
Sepsis is the most common cause of ARDS. Patients with sepsis- of observation from 35.5% in 1993 to 37.6% in 2008. Factors
related ARDS have worse hypoxemic ratio and clinical out- that appeared to be associated with increased risk of ARDS
comes (higher overall mortality rate, fewer ICU-free days, and were treatment in an urban hospital, and associated cardiovas-
fewer ventilator-free days) compared with those with nonsepsis- cular or metabolic dysfunction [10]. Emphasizing the devas-
related ARDS [8]. ARDS has been reported to occur in 19.4% of tating implications of this non-neurologic complication in
patients with subarachnoid hemorrhage (SAH), and it is the hemorrhagic stroke, ARDS was an independent predictor of
most frequent non-neurologic organ system failure [1]. mortality and had the highest independent incremental risk

326

Table 26.3 Risk factors associated with the development of ARDS
Direct injury Indirect injury
a
• Pneumonia • Sepsis
• Bacterial • Trauma
• Viral • Burns
• Fungal • Pancreatitis
• Aspiration of gastric • Gynecologic
contents complications
• Toxic inhalation • Acute liver failure
• Near-drowning • Sickle cell disease crisis
• Pulmonary contusion • Multiple blood
transfusions
• Medication or drug
effect
a
Pneumonia can contribute directly and indirectly with development of
sepsis
with an odds ratio (OR) of 9 in multivariable analysis. The
mechanisms were speculated to be related to the deleterious
effects on neurologic function of hypoxemia and metabolic
abnormalities, as well as the impact on cerebral perfusion pres-
sure. Given this strong outcome relationship, consensus on how
to best manage the balance of metabolic demands and known
physiologic effects of ventilation in acute lung injury is required.
Epidemiology of ARDS in Traumatic Brain Injury
The prospective estimate of the incidence of ARDS in patients
who experience acute traumatic brain injury (TBI) appears to
be increasing [11]. Between 1988 and 2008, the incidence of
ARDS in TBI patients identified in the NIS increased from 2%
to 22%. ARDS appeared more common in younger age males
and Caucasians. In addition, multiple comorbidities like sepsis
or multiple organ dysfunction syndrome also increased risk.
Usual Care Management of Severe Hypoxemia
Low tidal volume ventilation with PEEP has been established
as the standard of care for ARDS with documented reduction
in mortality and increase in ventilator-free days. The intent is
to minimize excessive distention of the aerated lung to reduce
the release of inflammatory mediators that could increase lung
inflammation and the risk of nonpulmonary organ or system
failure[12].
Current Standards
Mechanical ventilator strategies are shown in Table 26.4.
Low Tidal Volume
A meta-analysis published in JAMA in 2010 evaluated treat-
ment with higher versus lower levels of PEEP in patients with
ALI and ARDS. No change in survival was noted in this group.
The subgroup that had ARDS seemed to benefit from higher
levels of PEEP (mean PEEP 15 versus 9 cmH2O in the lower-
level group) primarily in terms of survival and the number of
days with unassisted breathing [14]. Increasing PEEP beyond
Chapter 26: Management of Severe Hypoxia
recommended levels should be considered in patients with
moderate to severe ARDS, per Berlin criteria, that do not seem
to respond to the usual settings. This should be done while
maintaining plateau pressure goals.
Alternative Ventilator Modes
Pressure control ventilation (PCV) has been studied in com-
parison to volume controlled ventilation (VCV) in ARDS.
When targeted to maintain the same plateau pressure goals
(in this study less than 35) there was no evidence that one
modality is better than the other. In a study from 2000, no
significant difference was found in independent influence on
mortality between these two groups, and mean tidal volumes,
FiO2, PEEP, and respiratory rate in each group were compar-
able [15]. This was a small study of 79 patients and therefore
we cannot suggest the routine use of PCV over the more-
studied low tidal volume, lung-protective VCV.
The reported advantages of airway pressure release ventila-
tion (APRV) over VCV include an increase in mean alveolar
pressure with alveolar recruitment, and improved alveolar
ventilation, with improved ventilation/perfusion (V/Q) mis-
matching, as well as the hemodynamic and ventilator benefits
associated with spontaneous breathing and the reduced
requirement for sedation [16].
Sedative Approaches [10]
Propofol
Propofol is used extensively in neurocritical care due to its
pharmacologic properties allowing for facilitation of serial
neurologic examinations [17]. Its use has been associated with
development of hypotension. Hypotension has been shown to
convey higher mortality and poor functional outcome in
neurocritical patients [18,19]. A recent study set out to estab-
lish the risk factors for the development of hypotension in
patients receiving propofol. The study analyzed 237 patients
at two academic centers and found that the average mean
arterial pressure (MAP) was reduced by 28% and severe hypo-
tension defined as a MAP of less than 60 mmHg was found in
26.2% of the patients. The only factors associated with
increased risk of development of severe hypotension were the
presence of lower baseline MAP (60–70 mmHg), renal replace-
ment therapy, and the median number of rate changes in
propofol infusion (the maximum doses and duration were
not statistically significant) [17]. However, previous studies
have shown that the use of propofol leads to a faster time to
extubation compared to midazolam, while acknowledging the
risk of hypotension [20]. To date, propofol, with appropriate
monitoring, continues to be one of the first-line sedative medi-
cations recommended to manage critically ill patients [21].
Dexmedetomidine
Dexmedetomidine has been used in clinical practice for the
treatment of patients with respiratory failure, including those
patients with ARDS. Dexmedetomidine has shown favorable
efficacy, with some increase in the number of delirium- and
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 Chapter 26: Management of Severe Hypoxia

Table 26.4 Standardized ventilator management protocol [13]

Initial Parameters
Ventilator mode: assist control volume cycled (AC/VC)
Tidal volume (Vt): Calculate predicted body weight (PBW) in kg
• Men: 50 + 2.3 [(height in inches) – 60] or 50 + 0.91 [(height in cm) – 152.4]
• Women: 45.5 + 2.3 [(height in inches) – 60] 45.5 + 0.91[(height in cm) – 152.4]
Initial Vt = 6 mL/kg (PBW)
Respiratory rate (RR): set an initial RR to approximate minute ventilation
I:E ratio: >1:1
PEEP: 5 mmH2O
Adjustments
Vt:
• Measure Pplat every four hours and after each change in PEEP or Vt
• Adjust Vt in steps of 1 mL/kg PBW every 1–2 hours:
: If Pplat >30 cmH2O, decrease Vt to 4–5 mL/kg PBW
: If Pplat <25 cmH2O and Vt <6 mL/kg PBW, increase Vt by 1 mL/kg PBW
RR: make subsequent adjustments to RR to maintain pH of 7.30–7.45, but do not exceed an RR of 35/min and do not increase set rate if
PaCO 2 <25 mmHg
Fio2, PEEP, and arterial oxygenation:
Maintain PaO2 at 55–80 mmHg or oxygen saturation by pulse oximetry (SpO 2) at 88–95%.
Use the following combinations of PEEP/FiO 2:
FiO 2 (mmH2O) 0.3–0.4 0.4–0.5 0.5–0.7 0.7 0.7–0.9 0.9 1.0
PEEP (mmH2O) 5 8 10 12 14 16–18 18–24
Acidosis management:
• If pH <7.30, increase RR until pH = 7.30 or RR = 35/min
• If pH remains <7.30 with RR = 35, consider bicarbonate infusion
• If pH <7.15, Vt may be increased (Pplat, may exceed 30 cmH2O)
Alkalosis management: if pH >7.45 and patient is not triggering ventilator, decrease set RR, but not below 6/min

coma-free days while on ventilation. Meta-analyses have not Fluid Management

suggested a true difference in delirium when compared to
In 2006, the ARDS Clinical Trials Network studied a com-
propofol, but some advantage when compared to a benzodi-
parison of fluid management strategies and their impact on
azepine approach [22]. This is balanced against several other
outcomes in patients with ALI. No difference was found
studies that suggest there is a neuroprotective effect to patients
in mortality. However, the use of a conservative fluid-
undergoing craniotomy for tumor resection when a dexmede-
management strategy targeted at a maximum central venous
tomidine approach is used. In one series of patients undergo-
pressure (CVP) of 13 mmHg or pulmonary artery occlusion
ing spinal surgery, serum brain-derived neurotrophic factor
pressure (PAOP) of 18 mmHg (compared to 15 and 24
was reduced in patients who received standard induction anes-
mmHg, respectively) showed a significant reduction in dur-
thesia plus dexmedetomidine compared to those receiving
ation of mechanical ventilation, length of stay (LOS) in the
standard treatment alone [23]. Several follow-up randomized
ICU and increased days free of central nervous system (CNS)
trials have suggested that for patients undergoing craniotomy
failure. This was accomplished without significant changes in
for supratentorial tumor resection, overall fentanyl require-
adverse effects or increase in other organ system failures [26].
ments and intracranial pressures are improved with use of
intraoperative dexmedetomidine [24,25]. These outcomes
included the time to routine postoperative extubation. Despite Bronchoscopic and Procedural Considerations
this data, there are no large trials suggesting improved out- Fiberoptic bronchoscopy has been shown to increase transi-
comes for patients with neurologic disease and respiratory ently the intracranial pressure (ICP) of patients with and
failure when using dexmedetomidine; however, the trend without pre-existing intracranial pathology [27,28], particu-
appears to be favorable. larly in those with coughing and gagging behaviors. In fact,

328
 Chapter 26: Management of Severe Hypoxia

this effect is also seen in percutaneous dilatational tracheos-
tomy procedures that do not involve access to the upper
respiratory tree [29]. Hyperventilation as a prophylactic inter-
vention did not appear to have a major mitigating effect on this
increase in ICP [30]. In total, patients with increased ICP
should only have bronchoscopy performed after a careful
risk–benefit analysis.
The beneficial effect of prone positioning on cerebral tissue
oxygenation by increasing arterial oxygenation appears to out-
weigh the expected adverse effect of prone positioning on
cerebral tissue oxygenation by decreasing cerebral perfusion
pressure in patients with ARDS [1]. For patients with elevated
ICP who may benefit from prone positioning, heavier sedation
and ICP monitoring may be necessary.

The Role of Neuromuscular Blockers

Severe Hypoxemia Management Strategies
(Figure 26.3) [15]
Prone Positioning
A recent study of around 230 patients showed that in
patients with severe ARDS, defined in the study as a hypoxe-
mic ratio of less than 150, early application of prone position-
ing for approximately 17 hours a day significantly reduced
mortality [31].
Neuromuscular blockers (NMBs) have been proven beneficial
when provided early in ARDS. In a recent multicenter double-
blind trial of 340 patients, early administration (48 hours after
diagnosis) of an NMB (cisatracurium) improved the adjusted
90-day survival and increased the time off the ventilator, with-
out increasing muscle weakness [32]. In this study, the defin-
ition for severe ARDS was a hypoxemic ratio of 150 with a
PEEP >5 mmH2O and the duration of paralysis was two days.

Refractory
hypoxemia

Attempt increased PEEP Continue current therapy

Success
(consider short course paralysis)

Failure

Eligible for prone Yes Attempt prone

Inhaled epoprostenol* Success Continue current therapy
ventilation? ventilation

Failure
No

Success Continue current therapy

*inhaled epoprostenol can be Failure

readily administered and therefore
could be considered concurrently
Alternative approaches
with prone or other interventions. (Pressure regulated ventilation, Success Continue current therapy
No RCT support primary use of pulmonary vasodilators, RMs)
pulmonary vasodilators in favor of
lung-protective ventilation;
however, it can be effective in Failure
allowing the time to implement
prone or other approaches without Yes
added risk. Epoprostenol has not Eligible for ECMO? Consult for ECMO
been studied against prone
ventilation so this concurrent use
should not be construed as
equivalance.
No

Consider goals of care and palliative consult

Figure 26.3 Refractory hypoxemia management strategies. An example clinical treatment decision tree for general patients with severe ARDS-related
hypoxemia. All intervention benefits (improved hypoxemia) should be weighed against the potential condition-specific risks for worsened neurologic recovery.
Paralysis will prevent neurologic monitoring by peripheral exam, prone ventilation may be impracticable in patients with increased ICP managed with invasive
monitors, and anticoagulation used during ECLS may be contraindicated.

329
 Chapter 26: Management of Severe Hypoxia
A risk–benefit analysis needs to be carried out when con-
sidering NMBs in patients that require frequent neuro checks.
A trial of holding paralytics at least daily is being advocated;
however, this usually means that the patient will remain deeply
sedated with limitations in neurologic assessment as well.
High-Frequency Oscillatory Ventilation
High-frequency oscillatory ventilation (HFOV) has been
studied for patients with ARDS, as initial therapy as well as
as rescue therapy in cases of refractory hypoxemia. The ration-
ale for its use is that it can provide higher mean airway
pressures (maintaining continuous recruitment) with very
low tidal volumes (around 1–4 mL/kg) with minimal dynamic
collapse of airways, as the respiratory rate is usually between
3 and 12 breaths per second. Older studies comparing HFOV
to standard ventilation practices of the time showed a statistic-
ally significant difference in outcomes that favored the use of
HFOV [33]. However, some of the conventional ventilation
groups, to which HFOV was compared, used higher ranges of
tidal volumes (up to 10 mL/kg) or did not report the tidal
volume targets. Given that we know that low tidal volume
management provides for decreased mortality, the improved
outcomes seen with HFOV could be due to comparison with
outdated strategies. Studies reported in early 2013 showed
no difference in 30-day mortality when comparing HFOV
to a low tidal volume conventional ventilation strategy [34].
Furthermore, a trial reported in February of 2013 had to be
stopped before the end of recruitment due to increased mor-
tality in the HFOV group, as compared to conventional low
tidal volume ventilation, when used early in ARDS [35].
At this time, the appropriate timing for HFOV, if used at
all, remains uncertain. We advise its consideration as one of
multiple rescue treatments for cases that fail to respond appro-
priately to conventional lung-protective ventilation and are not
candidates for prone ventilation.
Inhaled Vasodilators
The hypothesis for the use of vasodilators in ARDS stems from
direct delivery via inhalation to ventilated areas of the lung to
provide selective vasodilation with resultant improved perfu-
sion and improvement in V/Q matching. Both nitric oxide and
inhaled prostacyclin analogue use have been reported as strat-
egies to improve hypoxemia. Their application, timing, and
patient population continue to remain controversial.
A Cochrane review conducted in 2010 included 14 ran-
domized controlled trials (RCTs) that evaluated the use of
inhaled nitric oxide (iNO) in acute hypoxemic respiratory
failure (AHRF). The review did not find any statistically sig-
nificant effect on mortality. Limited data showed early
improvements in hypoxemic ratio, ventilator-free days, and
ICU and hospital LOS. However, these improvements came
with an increased risk of development of kidney injury in
adults [36]. As discussed previously, the development of organ
system failure, particularly renal failure, is associated with
increased mortality in ARDS, and therefore given that there
330
is no evidence of improvement in mortality and the increased
likelihood of kidney injury with nitric oxide, we cannot rec-
ommend its use.
Inhaled epoprostenol (iEPO; Flolan®/Veletri®), prosta-
glandin I-2, does not require a specialized delivery system.
The rationale for its use is the same as that of iNO, selective
vasodilation, with additional theoretical anti-inflammatory
properties [37]. It has been proven an effective selective pul-
monary vasodilator with dose-related response in oxygenation
without significant systemic arterial pressure effects [38]. Some
studies have suggested up to 62.5% response rate for improve-
ment in oxygenation [39]. However, studies suggesting signifi-
cant changes in mortality are lacking, and therefore its use
continues to be controversial.
Small studies have compared iNO to iEPO. There have
been no significant differences between them in terms of
hypoxemic ratio, ventilator-free days, LOS, or adverse events.
iNO has been associated with increased costs, 4.5 to 17 times
that of inhaled epoprostenol, depending on contract price [40].
Steroids
Despite the fact that an inflammatory process characterizes
ARDS, the current evidence does not support the routine
use of corticosteroids. Their use 7–14 days after the onset of
ARDS has been associated in small trials with improvement in
oxygenation, ventilator-free days, and pulmonary compliance,
and decreased vasopressor requirements, but with an increase
in rate of neuromuscular weakness. Studies of short courses
of high-dose steroids instituted early have failed to show
improvement in survival. Starting steroids more than 14 days
after the onset of ARDS seems to increase 60- and 180-day
mortality [41].
Extracorporeal Life Support
Limited studies have shown a potential for benefit for the use
of extracorporeal life support (ECLS) in neurocritical care
patients. One retrospective evaluation reviewed adult trauma
patients who required mechanical ventilation, all of whom had
traumatic brain injury, and analyzed those that did and did not
receive veno-venous (VV) ECLS. This analysis showed after
adjustment for trauma severity and other factors, survival was
significantly reduced for those patients with VV ECLS treat-
ment [42]. However, as with all studies of the use of ECLS,
indication bias and lack of universal availability make this
therapy difficult to truly evaluate, particularly with the high
intensity of services required. It is likely that there would be
benefit with ECLS, as ventilator pressures and PaCO2 levels can
be held very low in this type of support.
Concerns for NCC Patients
ICP Elevation
There is a theoretical concern that a low-tidal volume lung-
protective strategy may be poorly tolerated in patients with neu-
rologic injuries as the associated hypercarbia increases ICP [16].

A retrospective study of 12 patients with SAH undergoing
continuous intracerebral pressure measurements with EVD,
who were mechanically ventilated and developed ARDS, showed
that a lung-protective strategy with Vt in the 5–8 mL/kg range
and PEEP at 10–15 cmH2O, with resultant PCO2 of 50–60
mmH2O did not show a significant increase in ICP [43].
A case report of a switch from PCV to APRV in an SAH
patient with EVD showed neurogenic pulmonary edema and
atelectasis, but no ARDS. There was an increase in mean
airway pressure from 10 to 22 mmH2O with the switch to
APRV without a significant effect on ICP, as measured via
EVD. Accompanying this, an increase in cerebral blood flow,
as measured by carotid Doppler, of 18% was also seen. The
conclusion was that APRV may be safely applied to neurocri-
tically ill patients, with a possible increase in cerebral blood
flow without an increase in ICP [16].
Neurogenic Pulmonary Edema
Neurogenic pulmonary edema (NPE) is defined as acute pul-
monary edema after intracranial insult that cannot be attrib-
uted to other causes of ALI/ARDS [44]. Its pathophysiology
remains unclear and there is a reported incidence of around
25% carrying an overall worse clinical prognosis [9,45,46].
A recent study evaluating its frequency and predictors utilized
two main criteria for diagnosis: (1) bilateral, symmetric,
smooth, and diffuse alveolar edema-like infiltrates on CXR
with (2) hypoxemic ratio less than 300 mmHg on the same
day. From a pool of nontraumatic hemorrhage patients,
108 were analyzed and NPE was found in 35%. Of these, 36%
were diagnosed in patients with SAH/intraventricular hemor-
rhage (IVH) and 33% in those who had intracranial hemor-
rhage (ICH)/IVH. Independent predictors for development of
NPE as per multivariate analysis were severity of disease per
APACHE II score and higher IL6 levels. Patients that
developed NPE had higher one-year mortality without
affecting one-year functional outcome [44]. The authors pro-
posed that these findings suggest a possible contribution of
inflammation in the pathophysiology of NPE development.
However, these findings have also been seen in ARDS, and
the differentiation between these entities remains elusive. For
this reason, the recommendations for management of NPE are
indistinct from those for ARDS.
Special Considerations for COPD
A COPD exacerbation is characterized by an acute change in
dyspnea, cough, or sputum production from the patient’s
baseline variability that warrants a change in medication.
The severity of an exacerbation is attributed clinically to
use of accessory muscles, paradoxical chest wall movement,
cyanosis, peripheral edema, hemodynamic instability, and
worsened mentation, suggesting increased severity [47].
Inpatient treatment focuses on providing respiratory support:
supplemental oxygen, and/or positive pressure ventilation, along
with pharmacologic treatment with bronchodilators, antibiotics,
Chapter 26: Management of Severe Hypoxia
and corticosteroids. Short-acting β-agonists (albuterol) with or
without short-acting muscarinic antagonists (ipratropium) are
the main modality of bronchodilators used.
Antibiotics are recommended when there is clinical evi-
dence of infection, characterized by increased purulence of
sputum, or the patient requires mechanical ventilation. An
initial recommendation for antibiotics includes amoxicillin-
clavulanate, macrolides, or tetracycline [47]. Fluoroquinolones
are also used and the final choice of antibiotic should be based
on local bacterial resistance patterns and previous cultures that
may be available. If amenable, cultures should be drawn and
antibiotics adjusted appropriately.
The use of corticosteroids in COPD exacerbations shortens
recovery time, improves lung function and hypoxemia, and
reduces treatment failure and hospital stay. The current rec-
ommended dose is 40 mg of prednisone daily for five days,
although there is still some debate in terms of optimal dose
and length of course [47].
When an exacerbation is severe and shows decompensated
respiratory acidosis with acidemia and signs suggestive of
increased work of breathing (accessory muscle use, retractions,
paradoxical abdominal motion), mechanical ventilation should
be instituted. Noninvasive ventilation is preferred as long as
the patient remains conscious, able to tolerate the interface and
clear secretions with adequate oxygenation. In neurocritically
ill patients with changes in consciousness and limitations in
maintaining airway protection or weakness limiting the man-
agement of secretions, this may not be feasible and invasive
mechanical ventilation may need to be instituted.
Special Considerations for Venous
Thromboembolism [7]
Venous thromboembolism (VTE) is a frequently reported
complication. Approximately 200,000 new cases occur in the
United States every year, with close to half of those developing
pulmonary embolism [48]. The main categories of risk factors
are summarized in what is known as Virchow’s triad: (1)
endothelial injury (inflammation or trauma), (2) venous stasis
(immobility), and (3) hypercoagulable state (inherited or
acquired). Most episodes of venous thromboembolism seen in
the ICU setting occur in the presence of more than one of these.
In several studies, acquired hypercoagulable state secondary to
malignancy has been associated with increased risk of VTE by a
factor greater than 3. The diagnosis of VTE starts with a thorough
clinical assessment followed by risk stratification prior to imaging
evaluation. The clinical diagnosis of deep vein thrombosis (DVT)
of the lower extremities cannot be established with certainty
without objective testing [49]. Clinical symptoms of lower
extremity DVT are nonspecific and in up to 50% of patients,
they are absent. When present, symptoms include leg swelling,
pain upon palpation of calf or thigh, and a positive Homan’s sign
(calf pain with dorsiflexion of the foot). For pulmonary embol-
ism, symptoms are also nonspecific and include dyspnea, cough,
pleuritic chest pain, tachypnea, and tachycardia [48].
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 Chapter 26: Management of Severe Hypoxia

Recommendations for the Prevention of VTE
Estimates of postoperative VTE in patients undergoing brain
surgery range from 3 to 20% [50]. Low molecular weight
heparin (LMWH) or unfractionated heparin (UFH) have been
proven superior to mechanical thromboprophylaxis alone
[50]. At present, there is no indication for thromboprophylaxis
beyond the postoperative period in patients with brain tumors.
Primary prophylaxis studies have been inconclusive [50].
The following recommendations are from the 9th edition
of Antithrombotic Therapy and Prevention of Thrombosis
Evidence-Based Clinical Practice Guidelines from the American
College of Chest Physicians:
• Neurosurgical patients:
: For craniotomy patients, the recommendation is for
mechanical prophylaxis, preferably with intermittent
pneumatic compression (IPC) be used over no
prophylaxis (Grade 2C) or pharmacologic prophylaxis
(Grade 2C) [51]
: For craniotomy patients at very high risk for VTE, e.g.
those undergoing craniotomy for malignant disease,
pharmacologic prophylaxis should be added to
mechanical prophylaxis once adequate hemostasis is
established and the risk of bleeding decreases (Grade
2C) [51]
: For patients undergoing spinal surgery, mechanical
prophylaxis, preferably with IPC over no prophylaxis
:
(Grade 2C), UFH (Grade 2C) or LMWH (Grade 2C) [51]
For patients undergoing spinal surgery at high risk for
VTE (including those with malignant disease or those
undergoing surgery with a combined anterior-posterior
approach), pharmacologic prophylaxis should be added
to mechanical prophylaxis once adequate hemostasis
is established and the risk of bleeding decreases
(Grade 2C) [51]
• Trauma patients:
: For major trauma patients, use of low-dose
unfractioned heparin (LDUH) (Grade 2C), LMWH
(Grade 2C), or mechanical prophylaxis, preferably with
IPC (Grade 2C), over no prophylaxis is recommended
[51]
: For major trauma patients at high risk for VTE
(including those with acute spinal cord injury,
traumatic brain injury, and spinal surgery for
trauma), mechanical prophylaxis should be
added to pharmacologic prophylaxis (Grade 2C)
when not contraindicated by lower extremity
injury [51]
: For major trauma patients in whom LMWH and
LDUH are contraindicated, mechanical prophylaxis,
preferably with IPC, over no prophylaxis should be
used (Grade 2C) when not contraindicated by lower
extremity injury. Pharmacologic prophylaxis
with either LMWH or LDUH should be added when
the risk of bleeding diminishes or the contraindication
to heparin resolves (Grade 2C) [51]
: For major trauma patients, an IVC filter should not be
used for primary VTE prevention (Grade 2C) [51]
: For major trauma patients, periodic surveillance with
venous compression ultrasound (VCU) should not be
performed (Grade 2C) [51].

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 Chapter
Management of Refractory Arrhythmias in the
27 Neurocritical Care Unit
Mahmoud Houmsse and Dilesh Patel
Introduction
Patients with strokes and other neurological insults in the
neurocritical care unit share similar risk factors as those in
the cardiac care unit. These factors include coronary artery
disease, vascular disease, diabetes, hypertension, smoking, and
dyslipidemia. These patients often have prior history of myo-
cardial infarction, underlying cardiomyopathy or valvular
heart disease. As a result, cardiac abnormalities are common
in the neurocritical care unit. These findings can vary from
electrocardiographic (ECG) changes to biomarker abnormal-
ities (troponin elevation) to severe hemodynamic collapse in
the setting of arrhythmias and profound myocardial dysfunc-
tion. In a large study looking at patients with ischemic stroke,
cardiac etiologies were the second most common cause of
death after neurologic processes. High-risk ECG findings are
predictive of cardiac death after stroke in addition to well-
established clinical factors, such as congestive heart failure,
poor renal function, diabetes, and severity of stroke [1].
ECG changes are very common early in the poststroke
period and can include QT prolongation, abnormal T waves,
ST segment depression or elevation, pathologic Q waves, the
presence of abnormal U waves and premature ventricular
beats. ECG changes have an overall reported incidence as high
as 81% with intracerebral hemorrhage (ICH), >90% with
subarachnoid hemorrhage (SAH) in some case series, and as
high as 90% in the setting of ischemic or embolic stroke [2].
In the setting of cardiac repolarization abnormalities on
ECG, arrhythmias are also common in the face of acute neu-
rologic events. The incidence of arrhythmias in this population
is dependent on the underlying cardiovascular disease, and the
type and location of cerebral insult. In a study of 361 patients,
27% of acute stroke patients had arrhythmias [2]. A majority
of the patients with arrhythmias (59%) had no prior history of
cardiovascular disease [2]. In another study, of 580 patients
with SAH, 4.3% had clinically significant verified arrhythmias,
excluding sinus bradycardia and sinus tachycardia, during the
hospital stay [3]. A more recent study looking at outpatient
dysrhythmias after ischemic stroke documented paroxysms of
atrial fibrillation in 44% of the patients randomized to event
monitoring [4].
These rhythm and ECG abnormalities need to be carefully
monitored and assessed as they can often lead to a change in
the clinical management decisions during the hospital stay and
at discharge.
Presentation
In the neurocritical care setting, the clinical presentation of
ECG changes and arrhythmias can be quite varied. Most often
ECG changes and arrhythmias are usually identified on routine
admission ECGs or on telemetry as alarms for rhythm changes
and ST segment changes. However, these findings can also be
associated with symptoms of palpitations, lightheadedness, or
dyspnea. Hemodynamic changes can also be a direct conse-
quence of arrhythmias. A 12-lead ECG is the first step to
clarifying the underlying cardiac rhythm disturbance. The
acute management of any arrhythmia includes prompt support
to help stabilize hemodynamic parameters. If possible, sinus
rhythm should be restored. A thorough understanding of the
underlying cardiac substrate will help decide the next steps;
often, this involves balancing the benefits and the side effects of
different therapeutic agents.
Pathophysiology
Under normal physiologic circumstances, the cardiac electrical
system is controlled by the sinus node. The sinus node is the
dominant cardiac pacemaker directing atrial depolarization
across the atria from right to left and top to bottom. Thus
during sinus rhythm on the 12-lead ECG, the P waves are
always positive (upright) in leads II, III, and AVF, and always
negative (inverted) in lead AVR. Electrical activity spreads to
the ventricles via the AV node and His bundle and then
through the right and left bundles generating a narrow QRS
complex. It is followed by repolarization of the ventricles,
which is represented as an positive (upright) T wave in all
leads except for lead V1, where it is expected to be negative
(inverted) in a normal ECG.
In the setting of neurological insults, there are several
pathologic mechanisms that lead to arrhythmias. Deregu-
lation of the normal autonomic control, hypothalamic and
cortical changes, including the insular cortex, neuroinflam-
mation due to diffuse injury, and myocyte dysfunction all
play a role in the arrhythmogenesis seen in patients in the
neurocritical care unit. The location of the neurologic injury
is also important.
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 Chapter 27: Management of Refractory Arrhythmias

Evaluating for autonomic dysfunction has demonstrated a In addition to intracranial insults, spinal cord injury has
predominance of sympathetic activity. Serum concentrations also been shown to affect cardiac function. In patients with
of catecholamines are higher in patients with cerebrovascular severe cervical spinal cord injury, supraspinal sympathetic tone
events compared to controls. Excessive norepinephrine release is reduced and patients often have bradycardia as their primary
from sympathetic cardiac nerve terminals and high levels of arrhythmia [9]. Additionally, atrioventricular (AV) block has
catecholamines in cardiac tissue have been demonstrated on been seen in patients with spinal cord injury due to a relative
pathologic studies. Subendocardial damage has been shown in increase in their vagal tone. This is often in combination with
patients with SAH who have normal coronary arteries on left autonomic dysfunction of the vascular system that presents as
heart catheterization. This damage includes lesions known as labile blood pressures or orthostatic hypotension [10].
contraction band necrosis or myofibrillar degeneration [5].
Similar lesions have also been described in patients with cat- Onset and Predictors of Arrhythmias
echolamine excess in settings such as pheochromocytoma.
The onset of ECG changes is not well established in the
However, in animal studies of stroke, these lesions and ECG
neurocritical care setting. Changes are usually noted on admis-
changes continue to be present, even in the setting of prior
sion ECGs and few serial ECGs are performed to monitor
adrenalectomy [6]. Additional support of neurologically medi-
resolution. Arrhythmias can be more clinically impactful,
ated cardiac injury comes from patients and animal studies with
and a prospective 500-patient study looking at cardiac arrhyth-
denervated hearts (cardiac transplantation or stellate ganglio-
mias in a dedicated stroke unit identified atrial fibrillation to
nectomy or bilateral vagotomy) who show fewer ECG changes
be the most common arrhythmia, both with rapid ventricular
and arrhythmias in the setting of cerebrovascular events [6].
rate and bradycardic presentations [11]. In this study the
In addition to electrical abnormalities, various studies have
number of arrhythmias detected per monitoring hour was
reported echocardiographic evidence of regional wall motion
highest during the first 12 hours of monitoring at admission
abnormalities and reduced left ventricular ejection fraction in
[11]. Another study evaluating serious cardiac events, includ-
11–41% of patients with SAH [5]. The term “neurogenic
ing nonfatal ventricular tachycardia and ventricular fibrilla-
stunned myocardium” has been used to describe the left ven-
tion, reported a peak incidence of cardiac complications
tricle (LV) dysfunction seen with apical and mid-ventricular
between days 2 and 3 of hospital stay in patients with ischemic
wall motion abnormalities, despite having no obstructive cor-
stroke [1]. In the presence of arrhythmias, pharmacotherapy
onary artery lesions. This cardiomyopathy has been described
decisions alter, and the patient may require additional invasive
as Takotsubo cardiomyopathy, among many other names.
procedures such as left heart catheterization or implantation of
Additionally, there have been both animal and human
a pacemaker or defibrillator. Identifying the group of patients
studies that have described specific cortical changes that have
high at risk for arrhythmias would help with management
correlated with impaired control of blood pressure and ECG
decisions in the critical care unit. Age, NIHSS (National Insti-
changes, including cardiac arrhythmias. Intraoperative insular
tute of Health Stroke Scale) on admission, hypertension, dia-
cortex stimulation before temporal lobectomy in epileptic
betes, prestroke modified Rankin Scale, structural heart
patients led to heart rate and blood pressure changes. The left
disease, and the presence of troponin elevation were all associ-
insular cortex more frequently produced bradycardia and
ated with significant arrhythmias in a prospective trial involv-
vasodepressor response in blood pressure, and the right insular
ing 500 stroke patients (92% ischemic stroke) [11]. In this
cortex stimulation more frequently led to tachycardia and
study, a multivariable logistic regression model revealed that
blood pressure increase [7]. Functional magnetic resonance
older age and higher NIHSS on admission were the best
imaging (MRI) studies have correlated similar findings that
predictors for those at high risk for arrhythmias.
demonstrate the importance of the insular cortex in elderly
In patients with subarachnoid hemorrhage QTc prolonga-
patients who were hypertensive [8]. Moreover, studies demon-
tion is common and can lead to ventricular arrhythmias.
strated that stroke with right insular cortex involvement was
Ventricular arrhythmias were the second most common type
associated with a prolonged QT interval, atrial fibrillation, and
of arrhythmias in a study of 200 SAH patients [12]. In this
left bundle branch blocks, and these findings correlated with
study, older age, a slower heart rate, absence of angiotensin-
increased risk of all-cause death and vascular death at two
converting enzyme inhibitors or angiotensin receptor blocker
years, even after adjustment for age, gender, and cardiovascu-
at SAH onset, and a higher stroke severity were all associated
lar history [6].
with developing ventricular arrhythmias.
With prolonged QT interval and increase in automatic
behavior of myocytes due to sympathetic overdrive, both ven-
tricular and atrial arrhythmias have been reported. Addition- Specific Rhythm Abnormalities
ally, electrolyte disturbances, specifically hypokalemia and In this section, we describe the many different rhythm abnor-
hypomagnesemia, are not uncommon in patients with neuro- malities that can be encountered in a neurocritical care patient.
logical insults, specifically SAH. This can lead to a perfect Narrow complex arrhythmias are described first and the focus
storm with life-threatening ventricular arrhythmias such as is then switched to wide complex tachycardias. Lastly, we
torsades de pointes (TdP). discuss the different conduction blocks.

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 Chapter 27: Management of Refractory Arrhythmias

Table 27.1 CHADS2 stroke risk prediction model in patients with atrial
Narrow Complex Arrhythmias fibrillation.
In general, arrhythmias originating from the atria have a
CHADS2 score Points Score Annual risk of
narrow QRS as the impulse travels down the specialized con-
stroke by points
duction system including the His bundle and Purkinje fibers.
These rhythm disorders are described below, starting with Congestive heart 1 0 1.9%
atrial fibrillation, the most commonly encountered arrhyth- failure history
mias in the neurocritical care setting. The management strat- Hypertension 1 1 2.8%
egy for these rhythm disturbances is also listed below. Age 75 years 1 2 4.0%
Atrial Fibrillation Diabetes mellitus 1 3 5.9%
Atrial fibrillation occurs in 2–4% of the general population in Stroke or transient 2 4 8.5%
the United States. It independently increases the risk of stroke ischemic attack history
approximately fivefold throughout all ages [13,14]. In the 5 12.5%
neurocritical care unit, atrial fibrillation is commonly seen in
two clinical scenarios: (1) as the cause of a major embolic 6 18.2%
stroke or (2) as a complicating hemodynamic issue in a critic- Annual risk of stroke as listed in the original study. Predicting power
(C statistic) of 0.66 in a large registry [18].
ally ill neurologic patient. In patients with acute ischemic
stroke, the prevalence of atrial fibrillation is approximately
8% in those 51–60 years of age, and with each additional
decade of life, the prevalence increases by approximately 10% Table 27.2 CHAD2S2-VASc stroke prediction model in patients with atrial
such that approximately 38% of patients 81–90 years of age fibrillation
with ischemic stroke have atrial fibrillation [15]. CHAD2S2-VASc score Points Score Annual risk
of stroke by
Etiology points
The atria of most patients with atrial fibrillation have struc- Congestive heart failure 1 0 0
tural abnormalities, ranging from fibrosis to dilatation. history
Common cardiac syndromes such as hypertension, valve dis-
Hypertension 1 1 1.3%
orders, coronary disease, and ventricular dysfunction enhance
changes in atrial tissue refractoriness that can support atrial Age 65–74 years 1 2 2.2%
fibrillation. In addition, several noncardiac conditions are Age 75 years 2 3 3.2%
associated with atrial fibrillation:
Diabetes mellitus 1 4 4.0%
• Hyperthyroidism leads to a hyperadrenergic state
Stroke or transient ischemic 2 5 6.7%
• Holiday heart refers to atrial fibrillation that occurs attack history
24 hours after an episode of binge drinking
• Pulmonary diseases including pneumonia, pulmonary Vascular disease (prior MI, 1 6 9.8%
emboli, chronic lung diseases, and acute respiratory failure peripheral arterial disease,
aortic rupture)
likely via hypoxia can lead to changes in atrial tissue
refractoriness that may facilitate atrial fibrillation. Sex category – female 1 7 9.6%
8 6.7%
Clinical Manifestations
9 15.2%
Patients with atrial fibrillation can present with a variety of
symptoms, from asymptomatic or minimally symptomatic to Annual risk of stroke as listed in the original study by Lip et al [17]. Predicting
power (C statistic) of 0.67 in a large registry [18].
those with a severe ischemic stroke. In a single patient with
paroxysmal atrial fibrillation, approximately two-thirds of the
episodes are asymptomatic. During atrial fibrillation, stasis can
lead to thrombus formation in the left atrial appendage. The The loss of the atrial contraction during atrial fibrillation
stroke risk in atrial fibrillation can be calculated by the CHADS2 can lead to a variety of hemodynamic and arrhythmic issues,
score [16] or the CHA2DS2VASc score (Tables 27.1 and 27.2) particularly in patients with diastolic heart disease. Patients
[17]. History of congestive heart failure, hypertension, age, with diastolic heart disease (left ventricular hypertrophy, aortic
diabetes, prior stroke, vascular disease, and sex of the patient stenosis, cardiac amyloid, etc.) can decompensate with the
all play a role in determining the annual risk of stroke with atrial onset of atrial fibrillation, as these conditions are very preload
fibrillation. In a patient with a stroke, the absence of cardiac dependent. From an arrhythmic standpoint, patients in atrial
symptoms does not exclude the possibility of an embolic stroke fibrillation can develop tachycardia, bradycardia, or pauses
secondary to “asymptomatic” paroxysmal atrial fibrillation. (Figure 27.1) depending on AV node conduction.

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 Chapter 27: Management of Refractory Arrhythmias
Figure 27.1 Atrial fibrillation with pause and junctional escape beat prior to sinus beat (last QRS on the strips). Pauses are common when atrial fibrillation terminates
spontaneously and it takes time for the sinus node to recover normal impulse. The term conversion pause has been used to describe this phenomenon.
Diagnosis
All patients with atrial fibrillation require a thorough history
and physical examination. Classically, the heart beat is irregu-
larly irregular. The pulse will vary in intensity due to the
changes in preload and in the diastolic interval. An ECG
documents no discrete atrial electrical activity. An echocardio-
gram can determine the presence of valvular disease or LV
dysfunction. Laboratory work should include thyroid-
stimulating hormone (TSH) to exclude hyperthyroidism.
Acute Treatment
The patient presenting with a stroke in the context of atrial
fibrillation needs prompt evaluation to facilitate the best neuro-
logic outcome. The assumption that the stroke is embolic in
the setting of atrial fibrillation is logical, but a definitive etiology
is often difficult to make, given the overlap of comorbidities
in most patients with atrial fibrillation. Regardless, prompt
imaging in the setting of an in-hospital care pathway is usually
necessary to start thrombolytic therapy if within the guideline-
driven window. This decision algorithm is discussed below.
A common scenario is the management of new onset or
chronic atrial fibrillation in the context of an acute neurologic
syndrome. The acute treatment is dictated by the clinical condi-
tion of the patient. The loss of atrial systole and the shortening
of the diastole can lead to a decrease in cardiac output.
If the patient is hemodynamically unstable with rapid ven-
tricular rate, acute electrical synchronized cardioversion is
often necessary. In the absence of acute hemodynamic com-
promise, control of the rapid ventricular response is initially
indicated. This strategy is called rate control.
Administration of an intravenous (IV) calcium channel
blocker is commonly used for the acute control of the rapid
ventricular response during atrial fibrillation. IV diltiazem
often successfully controls the ventricular response in atrial
fibrillation. The average time to a therapeutic response is
<7 minutes from the beginning of the IV infusion. Diltiazem
may be associated with hypotension; however, usually blood
338
pressure improves with the control of the rapid ventricular
response as the diastolic filling period for the LV increases with
slow ventricular rate.
IV metoprolol is an acceptable option also for those with
cardiac conditions that may benefit from β-blockers. Esmolol,
an ultra-fast-acting β-blocker, has also been used to acutely
control the rapid ventricular response.
Classically, digoxin has been used acutely to control the
rapid ventricular response. However, the therapeutic use of
digoxin is inconsistent and often ineffective. The median time
until adequate control of the ventricular response is 11.6
hours. Thus, the use of digoxin for the acute control of ven-
tricular response in atrial fibrillation has been relegated to a
secondary position. Digoxin may have a role as an adjunct to
other AV-node blocking agents, especially in patients with
concomitant congestive heart failure. In those patients that
cannot tolerate higher doses of β-blockers or calcium channel
blockers due to hypotension, digoxin can be used as an
adjunct. Amiodarone, a class III antiarrhythmic, can be used
as well to pharmacologically convert the patient back into
sinus rhythm. Note, amiodarone is a poor AV-node blocking
agent and should not be used as the primary choice for rate
control strategy.
In the acute setting, if the patient is able to tolerate systemic
anticoagulation, it should be initiated in the first 24–48 hours.
In patients with acute ischemic stroke, the possibility for
hemorrhagic conversion exists; therefore, systemic anticoagu-
lation is delayed until deemed safe from a neurologic stand-
point, usually 48 hours after the onset of the stroke. If a patient
cannot tolerate systemic anticoagulation with heparin, aspirin
should be considered as a substitute to reduce the risk of
embolic stroke.
Long-Term Treatment
When the patient’s rapid ventricular response has been con-
trolled, a decision must be made regarding the restoration of
sinus rhythm versus simply continuing to control the

ventricular response. The decision whether or not to cardiovert
a patient with atrial fibrillation is complicated. The decision
hinges on the initiation and duration of the episode of atrial
fibrillation. In patients with paroxysmal atrial fibrillation,
asymptomatic episodes occur more frequently than symptom-
atic episodes. Thus, determining the onset of atrial fibrillation
by using the patient’s appreciation of symptoms may be haz-
ardous. If the onset of atrial fibrillation can be confidently
identified to be <48 hours, the usual clinical practice is to
perform the cardioversion independent of the state of anti-
coagulation. This recommendation is based on the assumption
that a thrombus usually takes >48 hours to form.
If the onset of atrial fibrillation cannot be determined, or is
>48 hours, there are two strategies for attempting cardiover-
sion to sinus rhythm.
• The first strategy requires systemic anticoagulation for a
four-week period before elective electrical or
pharmacologic cardioversion. This period of
anticoagulation reduces the risk of embolization after
cardioversion from 5% to 1%.
• The second strategy permits cardioversion without an
antecedent four-week period of systemic anticoagulation if
an atrial thrombus is not documented by transesophageal
echocardiography.
Atrial stunning (evidence of sinus rhythm electrically, but
without effective mechanical contraction) can exist for several
weeks after a cardioversion and predisposes to blood stasis in
the atria; therefore systemic anticoagulation with heparin
transitioning to warfarin must be initiated before and con-
tinued after the cardioversion for at least four weeks. In the
second strategy, if an atrial thrombus is documented by
transesophageal echocardiography, systemic anticoagulation
should occur for four weeks before cardioversion. Cardiover-
sion is then safe and the patient is treated for at least four
more weeks after cardioversion with systemic anticoagulation
therapy.
The rate of recurrence of atrial fibrillation after cardiover-
sion is dependent on the chronicity of the atrial fibrillation and
the acute illness. In the critical care unit, the recurrence of
atrial fibrillation is usually high, given the acute neurologic
syndrome and high catecholamine state. Thus, antiarrhythmic
agents are usually initiated just before or just after cardiover-
sion in most patients.
The decision to use antiarrhythmic drug therapy is com-
plex. The benefits of sinus rhythm with the restoration of
atrial-ventricular synchrony, improved cardiac output, and
physiologic heart rate control, are clear. These benefits must
be weighed against the risks of antiarrhythmic drug therapy.
Class IC and Class III agents have been used to maintain sinus
rhythm. Several studies have demonstrated an increase in
mortality over the long term in patients who received anti-
arrhythmic drugs, presumably due to proarrhythmia. Seem-
ingly paradoxical, the greatest risk of proarrhythmia appears
immediately after cardioversion when sinus rhythm emerges.
Chapter 27: Management of Refractory Arrhythmias
Class III antiarrhythmic drugs such as dofetilide and sota-
lol prolong repolarization to a greater extent at slower heart
rates, thereby enhancing the possibility of QT interval pro-
longation and a ventricular arrhythmia. In contrast, amiodar-
one has an extremely low proarrhythmic risk and remains the
antiarrhythmic agent of choice in patients with structural heart
disease. In patients with neurologic insults, amiodarone is
likely the safest choice in the short term.
Nonpharmacologic treatments such as catheter ablation,
surgical MAZE, or rate control with AV nodal ablation and
pacing are acceptable options in the long term. Consideration
of these treatments may take place when the patient is able to
leave the neurosurgical intensive care unit.
Anticoagulation
Many studies have shown that warfarin (vitamin K antagonist
oral anticoagulant) or one of the newer oral anticoagulants
(NOAC; also known as direct oral anticoagulant: DOAC) for
atrial fibrillation reduce the risk of stroke. The decision to
initiate warfarin can be guided by the CHADS2 or
CHA2DS2-VASc scores. At a score of 2 or higher, warfarin
is a recommended choice to reduce the risk of stroke. Below a
score of 2 on either scale, aspirin may be an acceptable choice
due to the bleeding risk with warfarin. These scores are
modestly predictive of stroke risk in the long-term setting
and help facilitate the long-term anticoagulation decision
[14]. In the acute care setting, the tolerability and risk of
bleeding will dictate if anticoagulation should be initiated with
atrial fibrillation.
Summary
Overall, in a critically ill neurologic patient, atrial fibrillation
can be the etiologic factor causing a stroke or can complicate
the management of the critically ill patient. Therapy can be
algorithmically driven (Figure 27.2). The management of the
hemodynamic issues is driven by the patient’s clinical condi-
tion. Usually rate control with IV diltiazem or esmolol can
acutely stabilize the patient and then allow thorough consider-
ation of longer-term issues such as chronic anticoagulation
and the use of antiarrhythmic drugs. Nonpharmacologic ther-
apies are evolving and are not at this time appropriate to
employ in the ICU setting.
Atrial Flutter
Atrial flutter is a common arrhythmia and brief episodes may
occur during any acute illness (e.g. thyrotoxicosis, acute pul-
monary embolism, ischemic stroke, intracerebal hemorrhage).
The ECG in typical atrial flutter demonstrates a “saw-
tooth” flutter pattern with (F) waves occurring regularly at
300 beats/min. The undulating F waves are best appreciated
in inferior leads (II, III, and aVF) and lead V1. Most com-
monly, 2:1 AV conduction occurs, resulting in a ventricular
rate of 150 beats/min. With 2:1 AV conduction, the QRS or
T waves may obscure the alternate flutter waves. In these
instances, carotid sinus massage or intravenous adenosine
339
 Chapter 27: Management of Refractory Arrhythmias

Figure 27.2 Practical algorithm for management

Atrial of atrial fibrillation with rapid ventricular rate. Note,
fibrillation anticoagulation should be considered in all
patients to reduce stroke risk. (HR: heart rate, RVR:
rapid ventricular rate, BPM: beats per minute).

HR > 100 bpm

(A fib with RVR)

Unstable Stable
(hypoperfusion) (adequate perfusion)

Synchronized
cardioversion at
bedside Rhythm
Rate control
control

Full anticoagulation
recommended for 4
weeks minimum
Beta blockers Calcium channel
Rule out atrial
(metoprolol, blockers
thrombus
esmolol) (diltiazem)

Anti-arrhythmic
drugs (AADs) Anticoagulate as
“amiodarone” Digoxin (if
tolerated to reduce
hypotensive)
stroke risk

Electrical
cardioversion
If HR >110 bpm,
switch to rhythm
control

Full anticoagulation
recommended for 4
weeks minimum

may help diagnostically by increasing the degree of AV block,
unmasking the otherwise obscured F waves. Note, adenosine is
not expected to terminate atrial flutter as the typical atrial
flutter circuit is not dependent on the AV node.
Overall, the acute treatment of atrial flutter is similar to
that of atrial fibrillation in the neurocritical care unit. Both
rhythms increase the risk of stroke, and may lead to hemody-
namic consequences. The algorithm for atrial fibrillation with
rapid ventricular rate (Figure 27.2) can be used to help guide
treatment.
Rate control can be achieved with an AV nodal blocker.
Control of the ventricular response, unlike in atrial fibrillation,
is not as easily achieved as there is a macro re-entrant circuit in
the atria leading to regular activation of the AV node. Catheter
ablation of a vulnerable portion of the flutter circuit in the
right atria is curative; a lesion is placed from the tricuspid valve
annulus to the ridge of the inferior vena cava.
Anticoagulation is generally indicated in atrial flutter as the
risk of atrial thrombi is similar to that of atrial fibrillation.
A significant proportion of patients with atrial flutter, even
after ablation, will have episodes of atrial fibrillation. Thus
anticoagulation therapy should be continued while monitoring
for recurrence of atrial flutter or atrial fibrillation.
Sinus Tachycardia and Bradycardia
Sinus rhythm with a rate >100 beats/min is termed sinus
tachycardia. A large number of stresses (both physiologic –
exercise, anxiety, pregnancy – and pathologic – fever, infec-
tion, hypoxia, heart failure, hypovolemia, and sympatho-
mimetic drugs) – can precipitate this arrhythmia. In the
neurocritical care unit, sinus tachycardia may be the result of
the increased catecholamine state from an intracranial insult
or autonomic dysfunction with poor vascular tone from a
spinal injury.
Sinus rhythm with a rate <60 beats/min is termed sinus
bradycardia. Sinus bradycardia can occur in well-conditioned
athletes with enhanced vagal tone. Pharmacologic agents (e.g.
β-blockers, calcium channel blockers, and α-blockers), vagal
maneuvers (e.g. eyeball manipulation, Valsalva maneuver,
carotid sinus massage, suctioning via endotracheal tube), and
various disease states (e.g. hypothyroidism, sinus node dys-
function) may underlie sinus bradycardia. In patients with

340

acute neurologic syndromes, sinus bradycardia can be a part of
the Cushing reflex, and evaluation for elevated intracranial
pressures should be considered. Sinus bradycardia can also
be present in the setting of an acute spinal cord injury due to
changes in autonomic tone (Figure 27.3).
Management of sinus tachycardia involves searching for
secondary causes as mentioned above and treating the under-
lying illness. Medications that have anticholinergic properties
can also lead to sinus tachycardia, and these should be avoided
if possible. Once all primary causes of sinus tachycardia have
been excluded, low dose β-blockers can be considered if the
patient continues to be persistently tachycardic despite no
identifiable cause.
For sinus bradycardia, the primary question is the clinical
impact of the slower heart rate on hemodynamics. If a given
patient has acceptable perfusion and is asymptomatic in the
face of sinus bradycardia, no specific treatment is required
Figure 27.3 Sinus arrhythmia, the R to R interval varies with changes in autonomic tone. This rhythm is often present at night time.
Figure 27.4 Rhythm strip seen in a patient with vaso-vagal response on the tilt table test. Similar response may occur in the critical care unit with endotracheal tube
suction or other maneuvers that can lead to excess vagal discharge.
Chapter 27: Management of Refractory Arrhythmias
besides ongoing monitoring. However, in the presence of
symptoms or hypotension, the quickest therapy is a trial of
atropine. The second step is to search for the cause of the
bradycardia. In the setting of cerebral injury, reducing the
intracranial pressure can be not only therapeutic but diagnos-
tic. Sinus bradycardia encountered during vagal maneuvers is
generally considered benign and the particular activity leading
to vagal stimulation should be avoided. However, depending
on the degree of cardio-inhibitory response due to excess vagal
discharge, prolonged pauses may be encountered (Figure 27.4).
If the patient has bradycardia from sick sinus syndrome (unre-
liable generation of sinus node activity), then electrical pacing
should be considered. In the acute setting, this is addressed by
a transvenous temporary pacer. If necessary, an electrophysi-
ology study can be performed to assess the reliability of the
conduction system. A permanent pacemaker would be placed
prior to discharge from the hospital.
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 Chapter 27: Management of Refractory Arrhythmias
Atrial Tachycardia
Atrial tachycardia refers to an arrhythmia that is housed
entirely in the atria and does not require participation of the
AV node. Similar to premature atrial complexes (PACs), atrial
tachycardia is usually triggered by activity from an automatic
focus. As a result of the underlying autonomic dysfunction
these arrhythmias are not uncommon in patients requiring the
neurocritical care unit. Most episodes of atrial tachycardia are
paroxysmal, but incessant episodes can lead to a tachycardia-
mediated cardiomyopathy over time. The standard way to
determine the presence of an atrial tachycardia is to demon-
strate that with AV block the arrhythmia continues.
In the acute setting, β-blockers or calcium channel blockers
are the first-line therapy for management. Amiodarone can
also be safely used as the second line of therapy. For hemo-
dynamically unstable patients, synchronized cardioversion is
an acceptable option to restore sinus rhythm. Catheter ablation
has become the primary therapy in the nonurgent setting.
AV Nodal Re-Entry Tachycardia
AV nodal re-entry tachycardia (AVNRT) is characterized by a
regular, narrow complex tachycardia at a rate of 150–250
342
beats/min. Dual AV nodal pathways are necessary. A second
pathway in the AV node is present in approximately 1/100
people. Retrograde conduction to the atria commonly results
in the P wave being buried in the QRS complex. The terminal
portion of the QRS complex can house the retrograde P wave
producing a “pseudo R pattern.”
Vagal maneuvers or IV adenosine can terminate AVNRT,
as this arrhythmia is AV-node dependent. Catheter ablation of
the slow pathway in the AV node is the preferred treatment in
symptomatic patients. In hemodynamically unstable patients,
AVNRT can also be treated with a synchronized cardioversion.
Orthodromic AVRT
A bypass tract (also termed an accessory AV connection)
consists of aberrant muscle fibers that cross the fibrous AV
annulus and can electrically connect the atrium and the ven-
tricle. This provides the necessary substrate for a re-entrant
tachycardia, orthodromic AVRT. The re-entrant circuit in
orthodromic AVRT consists of normal antegrade conduction
through the AV node (resulting in a normal-appearing QRS
complex) and retrograde conduction from the ventricle to the
atria via the bypass tract. In this instance, the retrograde
P wave usually distorts the ST segments (Figure 27.5). With
Figure 27.5 AVRT with the characteristic P wave
noted as a notch in the ST segment – easily
notable in V5–V6.

orthodromic AVRT, the tachycardia is terminated by blocking
conduction in one of the limbs of the circuits.
Vagal maneuvers, such as carotid sinus massage, or a Valsalva
maneuver, may be successful by blocking conduction through the
AV node and should be tried initially. If these maneuvers fail,
adenosine (6–12 mg IV) virtually always results in transient AV-
node block and will terminate this arrhythmia. Catheter ablation of
the bypass tract has become the preferred therapy for orthodromic
AVRT. If AVRT leads to hemodynamic instability, synchronized
cardioversion should be considered.
Wolff–Parkinson–White Syndrome
Wolff–Parkinson–White (WPW) syndrome is seen when
patients have palpitation, usually from orthodromic AVRT,
and also have a delta wave on their ECG during sinus rhythm.
The prevalence of WPW syndrome in the general population is
about 0.15%, with a 2:1 preponderance for men. Patients are at
risk for developing very rapid ventricular rates, when atrial
arrhythmias, such as atrial fibrillation or flutter, occur because
the bypass tract can also conduct in an antegrade fashion.
Rapid ventricular rates, faster than 200 beats/min, during atrial
fibrillation can cascade to ischemia, ventricular fibrillation,
Chapter 27: Management of Refractory Arrhythmias
and death. Sudden cardiac death can rarely be the presenting
symptom in patients with WPW syndrome.
First-line therapy for symptomatic patients (WPW syn-
drome) is radiofrequency catheter ablation of the bypass tract.
Patients with hemodynamic compromise during atrial fibrilla-
tion require immediate synchronized cardioversion.
Digitalis, β-blockers, and calcium channel blockers are
contraindicated during atrial fibrillation in patients with
WPW syndrome.
These agents block conduction of AF impulses down the AV
node, which indirectly facilitates conduction of AF impulses
down the bypass tract. This facilitation is indirect, as elimination
of impulse conduction down the AV node eliminates the subse-
quent retrograde penetration of these impulses into the bypass
tract. This occasional retrograde penetration into the bypass
tract results in collision with other AF impulses conducting in
an antegrade fashion down the bypass tract. These ongoing
collisions result in fewer antegrade impulses depolarizing the
ventricles and therefore a slower ventricular response during
atrial fibrillation. With AV nodal block, there is unopposed
ventricular activation, which can degenerate into ventricular
fibrillation and sudden cardiac death (Figure 27.6).
Figure 27.6 ECGs of a patient with WPW
syndrome who presented with palpitations. The
top panel shows ECG with sinus rhythm. Note the
short PR and the “delta” wave – up-slurring of the
QRS after the P wave. Bottom panel shows ECG
while in atrial fibrillation. Note the different
morphologies of the QRS with different degrees of
pre-excitation (conduction via accessory pathway)
with the underlying rhythm of atrial fibrillation.
Atrial rhythm is between the long R to R interval
(prior to the last two beats).
343
 Chapter 27: Management of Refractory Arrhythmias
Multifocal Atrial Tachycardia
Multifocal atrial tachycardia (MAT) remains a descriptive
entity diagnosed by ECG criteria: an atrial rate of >100
beats/min with P waves of at least three distinct morphologies.
The chaotic nature of its P-wave morphology with varying AV
intervals may cause confusion with atrial fibrillation (no dis-
cernible P wave present). MAT is usually observed in patients
with acute pulmonary disorders and associated hypoxia.
The treatment for rapid ventricular rates with MAT is AV-
node blockade with β-blockers and calcium channel blockers;
this is similar to atrial fibrillation with rapid ventricular rate, as
discussed previously.
Premature Atrial Complexes
A premature atrial complex (PAC) usually appears on the ECG
as a premature QRS complex preceded with either a morpho-
logically abnormal P wave or no identifiable P wave (atrial
activity occurring during the QRS or T wave). PACs may
rarely be aberrantly conducted (a right or left bundle branch
block), or not at all as the AV node is refractory (usually noted
as a pause). PACs are common and usually benign events.
They may be associated with hypoxia or other adrenergic
stimuli in the neurocritical care unit. PACs may trigger sus-
tained re-entrant tachycardias. An infrequent cause of PACs,
in the intensive care unit, is the presence of a central venous
catheter with the tip in contact with the right atrial myocar-
dium, leading to intermittent atrial activation.
Most commonly, the management strategy for PACs is to
optimize electrolytes and monitor for additional arrhythmias.
As most PACs are due to an automatic focus, β-blockers can
be beneficial in reducing their frequency.
AV Junctional Tachycardia
In AV junctional tachycardia, the AV junction, rather than
remaining the default pacemaker, usurps control from the
sinoatrial (SA) node. The mechanism is thought to be auto-
matic. The usual rate is 100–130 beats/min. Retrograde P waves
may be present or AV dissociation may occur. Digitalis toxicity,
myocardial ischemia, or myocarditis usually underlies this
arrhythmia. Treatment is directed at the underlying cause.
Summary of Narrow Complex Tachycardias
During a narrow QRS tachycardia, ventricular depolarization
occurs via the AV node–His–Purkinje network. Key consider-
ations are summarized as follows:
• 12-lead ECG tracings, rather than single-lead tracings, are
preferable for the analysis of an arrhythmia
• If there is a 1:1 AV conduction, the location of the P wave
relative to the QRS complex (before, within, or after) can
help identify the arrhythmia. In general:
: atrial tachycardia – P wave before the QRS
: AV nodal re-entrant tachycardia – P wave within
the QRS
: orthodromic-AVRT – P wave follows the QRS
344
• Adenosine can be used to produce brief, high-grade block
of the AV node and reveal the underlying atrial rhythm.
AV block terminates AV nodal-dependent rhythms, such
as AV nodal re-entrant tachycardia, or orthodromic-
AVRT. AV block in general does not terminate an atrial
tachycardia, flutter, or fibrillation
• Vagal maneuvers can help in the differential diagnosis of
tachyarrhythmias. By increasing vagal tone:
: a slight transient decrease of rates will occur in sinus
tachycardia, atrial tachycardia, and atrial flutter
: abrupt termination of AV nodal re-entrant tachycardia
or orthodromic-AVRT can occur if AV block occurs
• In hemodynamically unstable patients with a narrow
complex tachycardia, synchronized cardioversion can be an
option to immediately restore sinus rhythm and improve
stability
• In hemodynamically stable patients with a narrow complex
tachycardia, utilization or avoidance of specific
antiarrhythmic therapy (AAD), including β-blockers,
calcium channel blockers, and digoxin, is based on the type
of tachycardia.
Wide Complex Tachycardias
Ventricular rhythm disorders are less common than atrial
fibrillation in the neurocritical care unit, but in general these
disorders have a greater impact on hemodynamics. Below is a
brief description of the different ventricular rhythm abnormal-
ities followed by management strategy.
Ventricular Tachycardia
Ventricular tachycardia (VT) arises from the ventricular
myocardium. The QRS complex is wide (>120 ms in duration)
as the spread of depolarization is slow due to cell-to-cell
propagation. AV dissociation is often present, but retrograde
activation of the atria from the ventricles (ventriculo-atrial
association) can be present. Retrograde P waves can sometimes
be identifiable on a 12-lead ECG or rhythm strip. If the QRS
complexes do not vary in morphology, the ventricular tachy-
cardia is monomorphic; if the QRS complexes vary in morph-
ology, the ventricular tachycardia is polymorphic. Ventricular
tachycardia is further classified as sustained (lasting >30
seconds or associated with hemodynamic compromise) or
nonsustained (>3 consecutive beats but lasting <30 seconds).
The spectrum of symptoms observed in patients with ven-
tricular tachycardia can range from none to hemodynamic
collapse. Monomorphic ventricular tachycardia (MMVT) usu-
ally implies structural heart disease. Polymorphic ventricular
tachycardia (PMVT) usually results from proarrhythmia due
to QT interval prolongation. Myocardial ischemia is the most
common etiology for ventricular tachycardia, and it should
always be considered when formulating the treatment strategy.
Short-coupled premature ventricular complexes (PVCs)
followed by a long RR interval can also initiate and maintain
polymorphic ventricular tachycardia as portions of the

ventricular myocardium are still repolarizing when the short-
coupled PVC occurs. This is also known as pause dependent
PMVT (Figure 27.7) [19].
The differential diagnosis in a wide QRS complex tachycar-
dia is either ventricular tachycardia or a supraventricular
tachycardia conducted to the ventricles with aberration due
to a functional block in the right bundle branch or left bundle
branch. Historical, clinical, and ECG variables are helpful
diagnostically to determine if the arrhythmia is ventricular or
supraventricular with aberration. Any wide QRS complex
tachycardia should be assumed to be ventricular in origin in
the presence of structural heart disease.
Torsades de Pointes
Torsades de pointes (TdP; twisting of points) refers to a PMVT
that occurs in the presence of a prolonged QT interval. Mor-
phologically, this ventricular tachycardia is characterized by
the gradual oscillation of the peaks of successive QRS com-
plexes around the baseline. TdP occurs at a rapid rate and may
self-terminate. Deterioration to ventricular fibrillation is not
uncommon.
The syndrome may be congenital or acquired. The
acquired form may be caused by a variety of medications that
can lengthen action potential duration by blocking potassium
current (Table 27.3). It can also be found in the setting of other
conditions such as intracranial hemorrhage, stroke, and liver
disease.
Often, combinations of drugs are “partners” in the
acquired syndrome, one typically a weak potassium current
blocker, and one that interferes with the metabolism of the first
drug resulting in higher systemic concentrations and enhanced
potassium current blocking effects. Treatment of this arrhyth-
mia involves removing the causative drug.
Electrolyte abnormalities, specifically low potassium and
low calcium, and low magnesium can also lengthen the action
potential duration leading to QT prolongation. Intravenous
magnesium (regardless of the actual serum magnesium levels)
should be administered in the presence of this rhythm and this
may suppress the arrhythmia.
In patients with stroke, prolonged QT interval is a common
finding, and hypokalemia should be avoided to reduce the risk
of TdP. The treatment for TdP may include intravenous
Chapter 27: Management of Refractory Arrhythmias
Figure 27.7 Polymorphic VT after a long–short
sequence. Note the long RR interval (solid arrows)
preceding the short-coupled PVC (dashed arrow)
that initiates the polymorphic ventricular
tachycardia. Prior to the PVC, there are still portions
of the myocardium that are in the process of
repolarizing. The next therapeutic step would be
atrial pacing to manage this arrhythmia.
pacing to increase the heart rate and shorten the QT interval
to reduce the risk of recurrence.
In the congenital form, at least seven culprit gene abnor-
malities have been identified. Chronic treatment may involve
oral β-blockers, cervicothoracic sympathetic ganglionectomy,
or implantable cardioverter defibrillator (ICD) implantation.
Premature Ventricular Complexes
PVCs are a common ventricular rhythm disturbance. PVCs
are single wide QRS complexes that originate in the ventricles.
Two successive PVCs are termed a couplet and three successive
PVCs, a triplet. A series of PVCs at a rate of >100 beats/min is
termed nonsustained ventricular tachycardia (NSVT). PVCs of
similar morphology are termed monomorphic, but if the
morphology varies, they are described as multifocal or poly-
morphic. If PVCs successively alternate with a sinus beat, the
rhythm is termed bigeminy.
PVCs may manifest with or be exacerbated by alcohol,
emotional stress, sympathomimetic agents, hypoxia, or other
conditions, including any type of heart disease or intracranial
process. Antiarrhythmic therapy of PVCs has never been
shown to improve outcome and can increase mortality owing
to proarrhythmic mechanisms. Thus, in patients with PVCs,
reversible factors should be sought and corrected. Underlying
heart disease requires evidence-based therapy.
Accelerated Idioventricular Rhythm
Three or more ventricular complexes occurring at a rate of
60–100 beats/min constitute an accelerated idioventricular
rhythm (AIVR). This is commonly observed in spontaneous
coronary reperfusion or after percutaneous coronary interven-
tions. Episodes of AIVR are brief and often asymptomatic.
Treatment is not necessary; however, this arrhythmia usually
requires an evaluation to exclude ischemia.
Ventricular Fibrillation
Ventricular fibrillation (VF) is characterized electrocardiogra-
phically by baseline undulations of variable amplitude and
periodicity. No definitive QRS complexes or T waves are
evident. Effective cardiac contraction is absent. Loss of con-
sciousness ensues followed by death within three to five min-
utes, unless a durable rhythm is restored. VF is usually seen
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 Chapter 27: Management of Refractory Arrhythmias

Table 27.3 Common medications that are known to prolong the QT interval

Generic name Brand name Class/clinical use Comments

Amiodarone Cordarone Antiarrhythmic/abnormal heart rhythm Females > males, TdP risk regarded as low
Pacerone
Arsenic trioxide Trisenox Anticancer/leukemia
Astemizole Hismanal Antihistamine/allergic rhinitis No longer available in the United States
Bepridil Vascor Antianginal/heart pain Females > males
Chloroquine Aralen Antimalarial/malaria infection
Chlorpromazine Thorazine Antipsychotic/antiemetic/
schizophrenia/nausea
Cisapride Propulsid GI stimulant/heartburn Restricted availability; females > males
Clarithromycin Biaxin Antibiotic/bacterial infection
Disopyramide Norpace Antiarrhythmic/abnormal heart rhythm Females > males
Dofetilide Tikosyn Antiarrhythmic/abnormal heart rhythm
Domperidone Motilium Antinausea/nausea Not available in the United States
Droperidol Inapsine Sedative, antinausea/anesthesia adjunct,
nausea
Erythromycin Erythrocin Antibiotic, GI stimulant/bacterial infection, Females > males
increase GI motility
Erythromycin E.E.S. Antibiotic, GI stimulant/bacterial infection, Females > males
increase GI motility
Halofantrine Halfan Antimalarial/malaria infection Females > males
Haloperidol Haldol Antipsychotic/schizophrenia, agitation When given intravenously or at higher-than-
recommended doses, risk of sudden death, QT
prolongation and TdP increases
Ibutilide Corvert Antiarrhythmic/abnormal heart rhythm Females > males
Levomethadyl Orlaam Opiate agonist/pain control, narcotic
dependence
Mesoridazine Serentil Antipsychotic/schizophrenia
Methadone Methadose Opiate agonist/pain control, narcotic Females > males
dependence
Methadone Dolophine Opiate agonist/pain control, narcotic Females > males
dependence
Moxifloxacin Avelox Antibiotic
Ondansetron Zofran Antiemetic
Paroxetine Paxil Antidepressant
Pentamidine NebuPent Anti-infective /Pneumocystis pneumonia Females > males
Pentamidine Pentam Anti-infective /Pneumocystis pneumonia Females > males
Pimozide Orap Antipsychotic/Tourette’s tics Females > males
Probucol Lorelco Antilipemic hypercholesterolemia No longer available in the United States
Procainamide Pronestyl Antiarrhythmic/abnormal heart rhythm
Procainamide Procan Antiarrhythmic/abnormal heart rhythm
Quinidine Cardioquin Antiarrhythmic/abnormal heart rhythm Females > males
Quinidine Quinaglute Antiarrhythmic/abnormal heart rhythm Females > males

346
 Chapter 27: Management of Refractory Arrhythmias

Table 27.3 (cont.)

Generic name Brand name Class/clinical use Comments

Sotalol Betapace Antiarrhythmic/abnormal heart rhythm Females > males
Sparfloxacin Zagam Antibiotic/bacterial infection
Terfenadine Seldane Antihistamine/allergic rhinitis No longer available in the United States
Thioridazine Mellaril Antipsychotic/schizophrenia
Tizanidine Zanaflex Muscle relaxant
Venlafaxine Effexor Antidepressant
Ziprasidone Geodon Antipsychotic/schizophrenia
Zolmitriptan Zomig Migraine treatment

Figure 27.8 Management strategy for wide

Wide complex complex tachycardia. (VT: ventricular tachycardia,
tachycardia QTc: corrected QT interval, SVT: supraventricular
tachycardia, TdP: Torsades de pointes)

Unstable Stable (adequate

(hypoperfusion) perfusion)

Congenital QT
Synchronized SVT with
VT syndrome
cardioversion aberrancy
+ TdP

QTc Short- Non-selective

AV node Ischemia
prolongation coupled β-blockers
blockade mediated
+ TdP PVC

IV Magensium,
β-blockers Atrial
IV
(metoprolol) pacing
Isoproterenol

Atrial
Lidocaine Amiodarone Lidocaine
pacing

Eliminate
offending
drug(s)

after active ischemia, after VT causing ischemia, or after atrial
fibrillation with a rapid ventricular response causing ischemia.
Secondary prevention with an ICD should be considered
in those with an episode of documented VF and cardiac
arrest. The risk of ventricular tachycardia or ventricular
fibrillation in patients is predicted by the extent of LV dys-
function. In the long term, if LV dysfunction persists
despite adequate therapy, primary prevention with ICD is
recommended.
Management of Wide Complex Tachycardia
In addressing wide complex tachycardia (WCT), the goal is to
restore or maintain adequate perfusion. The therapy is driven
by the likely underlying cause, and multiple different etiologies
need to be considered. A practical algorithm for management
is shown in Figure 27.8.
If the patient is hemodynamically unstable, prompt restor-
ation of sinus rhythm by electrical cardioversion is necessary.
For acute treatment, IV lidocaine or IV amiodarone are usu-
ally the initial agents of choice for ischemia-mediated sus-
tained VT. Patients with the potential for recurrent sustained
ventricular tachycardia often require an ICD. Underlying car-
diac conditions like ischemia, drug-induced QT prolongation,
and electrolyte imbalance must always be considered and
treated. Temporary atrial pacing should be used for pause-
dependent PMVT and drug-induced TdP. A permanent pace-
maker is needed in patients with recurrent pause-dependent
PMVT, regardless of baseline QT intervals [20].

347
 Chapter 27: Management of Refractory Arrhythmias
Conduction Blocks
Optimal cardiac performance depends on an orderly sequence
of events occurring in the cardiac conduction system: pace-
maker impulses arising in the SA node initially depolarize the
atrial myocardium, propagate slowly through the AV node,
and finally spread through the His–Purkinje network to the
ventricular myocardium. Failure of the conduction can occur
anywhere in this electrical network and is manifested as
a pause.
First-Degree AV Block
First-degree AV block is a misnomer as block is not present.
Delay in conduction from the sinus node to the ventricles
results in a PR interval longer than 0.20 seconds (200 ms).
Slow conduction through the AV node is usually due to high
vagal tone, to intrinsic AV nodal disease, or to a drug effect.
The majority of the time, no specific intervention needs to
be performed for first-degree AV block, which is considered a
benign finding.
Second-Degree AV Block
Second-degree AV block is characterized by intermittent fail-
ure of AV conduction. Type I second-degree AV block (also
termed Mobitz type I or Wenckebach) is the more common
type and is characterized by a progressive lengthening of the
PR interval and shortening of the RR interval until a P wave
fails to conduct. Typically, the P wave following the noncon-
ducted P wave has the shortest PR interval.
The most common site of type I second-degree AV block is
the AV node. In such patients, the QRS complex is narrow and
the prognosis is benign. Type I block may occur in normal
individuals as a manifestation of enhanced vagal tone, but it
also occurs in a wide variety of medical conditions, such as
acute inferior wall myocardial infarction, and congenital or
acquired diseases of the AV node, or with medications that
slow AV conduction.
In most cases, type I second-degree AV block is considered
benign and requires no specific therapy. However, in patients
who develop type I second-degree block in the absence of an
identifiable acute process, particularly the elderly with severe
coronary artery disease or calcific aortic disease, electrophy-
siologic testing should be considered to identify the site of the
block. If the block is not the AV node but within or below the
His bundle, permanent pacing is indicated.
Type II second-degree AV block (Mobitz type II) differs
from type I second-degree block in that abrupt failure of AV
conduction occurs without the preceding gradual PR pro-
longation. The location of type II second-degree block is
always within or below the His bundle, and therefore conduc-
tion down to the ventricles is not reliable. Type II second-
degree block is not considered benign and prompt action is
required to prevent hemodynamic instability with long pauses
or asystole. In the ICU, this means securing a transcutaneous
348
pacing method as the first step while preparations for trans-
venous pacing are arranged.
Most patients with type II second-degree AV block have
broad QRS complexes indicative of conduction system disease
and are commonly symptomatic (dizziness and syncope).
Causes include degenerative diseases of the conduction system,
anterior wall myocardial infarction, calcific aortic valve dis-
ease, hypertensive heart disease, and cardiomyopathy. Per-
manent pacing is indicated in all patients with type II
second-degree AV block.
Complete AV Block
Complete or third-degree AV block features total independ-
ence of the atrial and ventricular activity, due to the complete
failure of the atrial impulses to be conducted to the ventricles.
The atrial rate exceeds the ventricular rate. Third-degree AV
block exhibits total dissociation between P waves and QRS
complexes; with the ventricles being controlled by a subsidiary
pacemaker site. The site of the conduction defect may be at the
AV node or infranodal (within or below the His bundle). The
site of the block has prognostic value.
If the QRS complexes are narrow and the ventricular rate
exceeds 50 beats/min, then the block is likely at the AV node,
with a usually favorable prognosis. These patients are usually
asymptomatic, and their heart rate can increase with exercise.
If the QRS complexes are wide and the ventricular rate is
30–40 beats/min, then the site of the block is likely infranodal.
Such blocks account for the vast majority of episodes of com-
plete heart block, causing slow heart rates that are unrespon-
sive to autonomic influence. Symptoms and hemodynamic
decline are frequent. Reversible causes being infrequent, per-
manent pacing is usually indicated.
Overall, management of a bradycardic presentation
requires a search for the underlying cause and the identifica-
tion of any conduction blocks. Additionally, understanding the
reliability of the conduction system is crucial in management
decisions. The management strategy for bradycardia is shown
in Figure 27.9.
Permanent Pacemakers
A permanent pacemaker consists of an electrode lead (or leads)
and a pulse generator. In most circumstances two electrode
leads are inserted transvenously, one into the right atrial
appendage and one into the right ventricle (RV) apex. The
generator is placed in a subcutaneous pocket below the clav-
icle. The power source is a lithium battery with a life expect-
ancy of 5–10 years.
A four-letter code designation is used to describe the com-
plex function of pacemakers. The first letter indicates the cham-
ber paced, the second letter, the sensed chamber, the third, the
mode of the pacemaker response to a spontaneous cardiac
impulse, and the fourth letter indicates that the pacemaker has
the property of rate modulation (i.e. the unit can increase its
pacing rate in response to increased physiologic need).

Bradycardia
Sinus
AV block
bradycardia
PR prolongation,
Atropine Isoproterenol Wenckebach
(Mobitz Type I)
Benign,
Atrial pacing ongoing
monitoring
Common indications for permanent pacing include symp-
tomatic bradycardia experienced in patients with sinus node
dysfunction and/or with heart block. Most patients requiring a
permanent pacemaker should be considered for dual-chamber
pacing. Pacemaker systems that include atrial pacing, as
opposed to a simple VVI system which paces and senses only
the ventricle, have the advantage of maintaining AV synchrony.
Complications of permanent pacing include infection of
the leads, possible infection at the site of the generator implant,
failure to pace the ventricular or atrial myocardium, and failure
to appropriately sense underlying cardiac electrical activity.
Patients with permanent pacemakers should be monitored
regularly. The need for battery replacement is often heralded
by a spontaneous, automatic slowing of the pacing rate, a
property built into the pacemaker to alert the physician to
the need for battery replacement.
Outcomes with Rhythm Disturbances
Besides the immediate complications and changes in clinical
decision-making in the presence of ECG changes and arrhyth-
mias in the intensive care unit, many studies have documented
the long-term clinical impact of these findings in stroke
patients. In one retrospective study looking at ischemic stroke
patients, prolonged QTc interval and premature ventricular
beats have been associated with serious cardiac adverse events,
including cardiac death in the first three months [1]. In a
prospective study looking at admission QTc in the emergency
room, prolonged QTc interval was associated with a worse
survival rate (70.5% survival rate) compared to those with no
QTc prolongation (87.1% survival rate) in the first 90 days
after acute ischemic stroke [21]. In a study looking at func-
tional outcome after ischemic stroke, decreased heart rate
Chapter 27: Management of Refractory Arrhythmias
Figure 27.9 Acute management strategy for
bradycardia.
Mobitz Type II,
Third-degree
heart block
Ventricular
pacing
variability (measured as the standard deviation of all normal
to normal RR intervals) was an independent predictor of
dependency after a 60-day rehabilitation program in addition
to the patient’s age and stroke severity [22].
In addition to the ECG changes, the presence of arrhyth-
mias has also been associated with clinical outcomes in
patients with ischemic strokes. In a large registry dataset of
the Canadian Stroke Network, atrial fibrillation (the most
commonly seen arrhythmia in the setting of a stroke) was
associated with higher risk of death at 30 days and death
disability at discharge compared to patients without atrial
fibrillation in a group of 12,686 patients presenting with ische-
mic stroke [23]. In this dataset, patients with AF also had a
modest increase in intracerebral hemorrhage with thromboly-
sis compared to those without AF [23].
Looking at patients with SAH, ECG changes and arrhyth-
mias are also associated with poor outcomes. In a meta-
analysis involving 25 studies and 2690 patients with SAH, ST
depression, T wave abnormalities, and tachycardia were asso-
ciated with higher mortality [24]. The occurrence of delayed
cerebral ischemia (associated with SAH and vasospasms) was
associated with ST depressions in this meta-analysis [24]. In
another study, ventricular arrhythmias, including nonsus-
tained ventricular tachycardia have been associated with worse
mortality in SAH patients [12]. Other studies have reported
prolonged hospital stay in SAH patients who develop arrhyth-
mias, most often atrial fibrillation or flutter [25].
Overall, it appears that ECG changes and arrhythmias in
the stroke unit are likely associated with worse outcomes.
However, it is unclear if these cardiovascular findings are truly
independent makers of morbidity and mortality in stroke
patients. There are only a few studies that have developed
robust multivariate models that take stroke severity into
349
 Chapter 27: Management of Refractory Arrhythmias

account. Plus, the underlying mechanism behind higher mor-
tality associated with these cardiac abnormalities is not yet well
understood.
Summary
Cardiac arrhythmias are ubiquitous and range in a clinical
spectrum from benign to lethal. Identification of the
arrhythmia and the underlying cause prior to treatment is
important to a successful outcome. Clinical risk stratification
is often accomplished by examining the severity of the cerebral
insult and the underlying structural heart disease. Manage-
ment includes optimizing electrolytes, avoiding offending
medications, ongoing cardiac monitoring, and specific
arrhythmia-targeted pharmacotherapy.

management. Neurosurg Focus, 25(5): clinical risk stratification for predicting

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 An Infectious Diseases Consult in the Neurocritical
Chapter

28 Care Unit
Michael Frank and Mary Beth Graham

Intensive care unit (ICU) patients represent 5–10% of all Table 28.1 Causes of fever in the ICU
hospitalized patients, yet the incidence of infections in this Noninfectious Infectious
patient population is 5- to 10-fold higher than in general
hospital wards and some studies estimate that up to 25% of Drug fever Pneumonia/lung abscess/empyema
all nosocomial infections occur in the ICU setting [1,2]. The Reaction to blood Bloodstream infection with either
majority of infections in critically ill patients are related to products bacteria or fungi
device utilization, including catheter-related urinary tract DVT/PE IV line-related infection
infections (UTIs), ventilator-associated pneumonia (VAP),
Hemorrhage, especially Other prosthetic device infection, e.g.
and catheter-related bloodstream infections. Many studies
CNS CNS shunt infection
have shown that these nosocomial infections not only increase
morbidity and mortality, but also add significantly to the cost Alcohol withdrawal Clostridium difficile colitis
and duration of hospitalization [3,4]. In this chapter we review Pancreatitis Intra-abdominal abscess
the workup of fever in the ICU, management of common
Autoimmune/ Cholangitis/cholecystitis
infections encountered in the ICU, and infection control
inflammatory diseases
guidelines to prevent the spread of nosocomial infections
among patients and caregivers. Adrenal insufficiency Sinusitis
Hyperthyroidism Pyelonephritis
Workup of Fever in the ICU Heat stroke Surgical or traumatic wound infection
The definition of fever is variable, but it is generally agreed Malignant Cellulitis
on that a core temperature >38.3 °C (or hypothermia, hyperthermia
T <36.0 °C without known cause) warrants investigation in a
Neuroleptic malignant
hospitalized patient [5,6]. In patients in the neurological/
syndrome
neurosurgical ICU (NICU), fever can be an important sign
of a potential complication or can be a consequence of the Malignancy, especially
primary process requiring admission to the unit, as seen with lymphoma
subarachnoid hemorrhage. Abbreviations: DVT: deep venous thrombosis; PE: pulmonary embolism; CNS:
The development of fever is associated with a worse prog- central nervous system
nosis in the NICU, as is hypothermia [7–10]. Fever is often a
physiologic and appropriate response, and may have beneficial
effects, therefore fever itself should not necessarily be treated syndrome, and malignant hyperthermia secondary to anesthet-
except in cases of primary ischemic or traumatic brain injury. ics. The most significant infectious causes include infections of
In fact, aggressive treatment of fever may actually lead to the lung, bloodstream, urinary tract, sinuses, abdomen, and
increased mortality [11–15]. It is important to remember that wounds.
many patients in the NICU are on high-dose steroids that will The workup of fever in the ICU can be broken down into
suppress the normal febrile response, so a normal temperature historical factors, physical examination considerations, and
should not be taken as evidence of lack of infection. diagnostic testing [6]:
The potential causes of fever in the ICU are listed in • A thorough history should also include careful review of
Table 28.1. The most significant noninfectious causes include past and current medical records, noting past infections,
drug fever (usually presenting without rash or eosinophilia) past interventions, including surgery (note, benign
[16], deep venous thrombosis, blood products, adrenal insuffi- postoperative fever usually occurs within 48 hours of
ciency, “central” fever, subarachnoid hemorrhage, alcohol surgery and patient evaluation is otherwise negative),
withdrawal, malignancy, thyroid storm, neuroleptic malignant intravascular and other catheters placed, medications and

351
 Chapter 28: Infectious Diseases Consult
Table 28.2 Laboratory and radiologic testing for fever in the ICU
• CBC with differential, looking for left shift or eosinophilia
• Urinalysis and urine culture
• Blood cultures: three to four draws of 20–30 mL (including
one through line) within 24 hours, before initiation of
antibiotics if possible
• Sputum/endotracheal suction/bronchoalveolar lavage Gram
stain and culture if evidence for pneumonia (new infiltrate,
worsening pulmonary status), including stains for
Pneumocystis jiroveci and viral, AFB, and fungal stains and
cultures if immunocompromised
• Clostridium difficile testing if diarrhea is present
• Quantitative/semiquantitative cultures of catheter tips from
any lines removed
• Cultures of other fluids as indicated: CSF, pleural, joint, ascites,
abscess
• Chest radiograph and/or chest CT
• Lower extremity ultrasound/helical chest CT or ventilation–
perfusion scan
• CT or MRI of head, spine, or sinuses if indicated by clinical
suspicion
Abbreviations: CBC: complete blood count; AFB acid-fast bacillus; PCR:
polymerase chain reaction; EIA: enzyme-linked immunosorbent assay; CSF:
cerebrospinal fluid; CT: computed tomography; MRI: magnetic resonance
imaging
allergies, changes in sputum production, bowel
movements, or wound drainage, and changes in ventilator
requirements.
• A complete physical examination should be performed
with special attention to the vital signs, ventilator settings
and oxygenation, skin, IV and other catheter sites, wounds,
fundi, oral cavity, heart murmurs or rubs, lung percussion
and auscultation, abdomen for rigidity, mass, tenderness,
or peritoneal signs, and any focality or change in neuro
exam.
• Laboratory and radiologic testing is shown in Table 28.2.
Because ICU patients are usually colonized with hospital
flora, sputum or other respiratory cultures should be
obtained only if there is evidence for pneumonia, because
they are otherwise meaningless. Likewise, chronic wounds
should not be cultured because they will only show
colonization, which is unimportant.
Management of Common Infections
Pneumonia
Nosocomial pneumonia, whether ventilator-associated (VAP)
or not, is extremely common in the ICU, comprising about
25% of all ICU infections. In fact, up to one-quarter of
352
intubated patients will develop VAP. An algorithm for man-
agement is shown in Figure 28.1. Principles of management
include [17,18]:
• Diagnosis is based on the presence of fever or other
changes in vital signs, worsening in ventilation or
oxygenation parameters, and new or worsening infiltrate
on chest radiograph or CT.
• If pneumonia is present, samples for Gram stain and
culture should be sent from sputum, endotracheal suction,
or bronchoalveolar lavage. Sputum Gram-stain results are
more specific than cultures, and quantitative
bronchoalveolar lavage cultures are more helpful than
qualitative. Blood cultures should also be sent before
antibiotics are started. Depending on risk factors, urinary
antigen testing for Legionella, along with stains and
cultures for viruses, AFB, and fungi may also be sent.
Diagnostic thoracentesis with cultures should be
performed if a large pleural effusion is present.
• Empiric antibiotic therapy should be started pending these
results. The choice of specific drug(s) should take into
account local unit flora and that VAP is usually caused by
Gram-negative bacilli such as Pseudomonas or methicillin-
resistant Staphylococcus aureus, and not anaerobes. Thus,
appropriate initial empiric therapy usually consists of
linezolid or vancomycin, plus either cefepime or imipenem
or piperacillin-tazobactam, plus a quinolone such as
ciprofloxacin. “Double coverage” for Gram-negatives may
be important initially to improve chances that empiric
coverage includes an active agent, while awaiting culture
results. However, there is no evidence that double coverage
of known sensitive organisms improves treatment, and
may add toxicity.
• Therapy should be adjusted within 48–72 hours, based on
results of Gram stains and cultures, and antibiotics should
either be discontinued or modified to the most narrow-
spectrum agents that will cover the microorganisms of
concern.
• The duration of antibiotics should be limited to 7–8 days
if uncomplicated [19].
Intravascular Catheter-Related Infections
Because almost all ICU patients have central venous access,
catheter-related infections are a common complication. The
key principles in management are [20, 21]:
• Line infection needs to be considered in all patients with
fever, because localizing evidence for infection at the line
site is often absent. Empiric changes of lines should be
considered as part of the management of continued fever
without a source in the ICU patient.
• If exit site pus is present, it can be cultured. Blood cultures
drawn both through the line and peripherally are crucial,
and differential time to positivity can be an important clue
to the presence of a line infection. A blood culture drawn

Pneumonia suspected
Obtain sample for Gram stain and culture
Begin initial empiric antimicrobial therapy
Days 2 and 3: Check culture results and assess clinical response.
Clinical improvement?
No Yes
Culture results? Culture results?
Negative: Positive: Negative:
Search for Adjust antibiotics Consider d/c
other causes and search for antibiotics
other causes
through a line turning positive >120 minutes before a
simultaneous blood culture drawn peripherally is
highly suggestive of the line as the source [21].
Cultures of catheter tips should be quantitative or
semiquantitative, and only performed if infection is
suspected; catheters should not be cultured routinely when
removed [22].
• Central venous catheter infections are most often due to
staphylococci, Gram-negative bacilli or candida. In patients
with blood cultures positive for S. aureus, a
transesophageal echocardiogram (TEE) should be
performed, if not contraindicated, to rule out vegetations,
due to the high rates of complicating endocarditis.
• Follow-up blood cultures should be obtained to assess
clearance.
• Infected peripheral venous catheters should be removed.
• Central venous catheters should be removed and placed in
a new site if there is evidence of exit site infection or sepsis,
or if positive blood cultures or fever persist after initiation
of antibiotics. If the catheter was exchanged over a
guidewire and the catheter culture shows significant
colonization, the line should be removed and a new line
inserted in a new site. If blood cultures still remain positive
Chapter 28: Infectious Diseases Consult
Figure 28.1 Management of pneumonia in
the ICU.(Adapted from the American Thoracic Society
and the Infectious Diseases Society of America
guidelines [11].)
Positive:
Narrow anti-
biotics, treat
for 7-8 days
even after removal of the line, a thorough search for
another source should be performed.
• Empiric antimicrobial therapy should include vancomycin
for staphylococci and coverage for Gram-negative
organisms, dependent on local antimicrobial susceptibility
data. The duration of antibiotic therapy is dependent on
the situation and is pathogen-specific. After catheter
removal in uncomplicated cases, coagulase-negative
staphylococcal infections should be treated for five to seven
days, S. aureus infections for 14 days, only if a TEE is
performed and is negative for endocarditis, and for four to
six weeks otherwise, most Gram-negative bacilli for 10–14
days, and candida for 14 days after the first negative blood
culture.
Clostridium difficile Colitis
With the widespread use of antibiotics in hospitals and espe-
cially in ICUs, C. difficile infection is an increasingly common
complication; certain strains are associated with especially
severe disease [23]. Probiotics may reduce the incidence of
antibiotic-associated diarrhea and C. difficile disease, but
should not be given to immunocompromised patients
[24,25]. The key principles of management include [26]:
353
 Chapter 28: Infectious Diseases Consult
• Diarrhea is a common side effect of antibiotics; only
10–25% of antibiotic-associated diarrhea is actually due to
C. difficile. In addition, ICU patients often have other
reasons for diarrhea, such as tube feeding and other drugs.
• Additional manifestations of C. difficile disease include
fever, abdominal pain and cramping, and leukocytosis.
• Diagnosis depends on detection of toxigenic C. difficile.
The gold standard cell culture toxin assay has been
replaced by faster assays. Enzyme immunoassays have
excellent specificity, but their sensitivity is lower
(75–90%). Nucleic acid amplification (PCR) testing is
rapid and highly sensitive, but is plagued by false positive
results, so that a combination of assays is increasingly
being used for more accurate diagnosis of C. difficile
colitis. Because 10–30% of asymptomatic hospital patients
are colonized with C. difficile, cultures of stool are not
helpful.
• Antibiotics should be stopped if at all possible. This may be
the only treatment that is necessary for mild cases.
Rehydration, correction of electrolytes, and proper
infection control also should be addressed.
• Treatment for mild disease can be oral metronidazole
500 mg tid for 10–14 days. Oral vancomycin 125 mg qid
for 10–14 days is now preferred for most cases and is the
drug of choice for moderate to severe disease [27].
Markers for severe disease include age >60, white blood
cells (WBC) >15,000, albumin <2.5, or serum creatinine
>1.5 baseline, and are often present in ICU patients.
• Improvement should be seen within two to three days, with
resolution by six days. Lack of improvement should
prompt a search for complications, such as toxic
megacolon. The above regimens are both associated with
success rates of 90–97%, although about 20% of patients
will relapse later. Relapses usually respond to a repeat
course of oral vancomycin, sometimes used in a prolonged
tapering or pulsed-dosing regimen.
Urinary Tract Infections
Urinary tract infections (UTIs) are the most common type of
healthcare-associated infection reported to the National
Healthcare Safety Network (NHSN). Among UTIs acquired
in the hospital, approximately 75% are associated with a urin-
ary catheter and it is estimated that 15–25% of hospitalized
patients receive urinary catheters during their hospital stay
[28]. A catheter-associated UTI (CAUTI) is defined by the
presence of symptoms or signs compatible with UTI with no
other identified source of infection along with >103 colony-
forming units of one or more bacterial species in a single
catheter urinary specimen or in a midstream voided urine
specimen from a patient whose urethral, suprapubic, or
condom catheter has been removed within the previous 48
hours. Signs and symptoms compatible with a UTI include
new onset or worsening of fever, rigors, altered mental status,
malaise, or lethargy with no other identified cause, flank pain,
354
costovertebral angle tenderness, acute hematuria, pelvic dis-
comfort, and in those whose catheters have been removed,
dysuria, urgent or frequent urination, or suprapubic pain or
tenderness [29].
Although multiple risk factors have been determined, the
five most likely to be associated with the development of a
CAUTI include: (1) duration of catheterization, (2) catheter
care violations, (3) absence of systemic antibiotics, (4) female
gender, and (5) older age [30]. Strategies that have been used to
reduce the incidence of catheter-associated bacteriuria and
possible CAUTI include the following [29,31]:
• Reduce the use of urinary catheterization by restricting its
use to patients who have clear indications
• Have an established infection control program
• Insert urethral catheters using aseptic technique and sterile
equipment by trained personnel
• Indwelling catheters should not be routinely used for the
management of urinary incontinence
• Maintain a closed sterile drainage system; do not
disconnect the catheter and drainage tubing unless
absolutely necessary
• Remove the catheter as soon as possible
• Ensure adherence to hand hygiene and proper care of
catheters.
Strategies that have not been shown to decrease the inci-
dence of catheter-associated bacteriuria and CAUTI include:
• Prophylaxis with systemic antibiotics
• Prophylaxis with cranberry products or methenamine salts
• Routine catheter change
• Antimicrobials in the drainage bag
• Catheter irrigation with antimicrobials or normal saline
• Enhanced meatal care
• Routine culturing to screen for asymptomatic bacteriuria.
Studies on CAUTIs suggest that most episodes of low
colony count bacteriuria (102–104 cfu/mL) can rapidly pro-
gress to high (105cfu/mL) colony counts within 24–48 hours
[32]. CAUTIs are often polymicrobial. Urine cultures are
recommended prior to treatment to confirm that an empiric
regimen provides appropriate coverage and to allow de-
escalation of the regimen on the basis of antimicrobial suscep-
tibility data. Seven days is the recommended duration of anti-
microbial treatment for patients with a CAUTI who have
prompt resolution of symptoms, and 10–14 days of treatment
is recommended for those with a delayed response [29]. The
most frequent pathogens associated with CAUTIs in hospitals
reporting to NHSN between 2006–2007 were Escherichia coli
and Candida spp. accounting for almost 50% of the isolates
recovered, followed by Enterococcus spp., Pseudomonas aeru-
ginosa, Klebsiella pneumoniae, and Enterobacter spp. A smaller
proportion was caused by other Gram-negative bacteria and
Staphylococcus spp. Fluoroquinolone resistance among urinary
pathogens is increasing with a quarter of E. coli isolates and

one-third of P. aeruginosa isolates exhibiting resistance and
resistance of Gram-negative pathogens to other agents, includ-
ing third-generation cephalosporins and carbapenems, is
increasing in some reported series [33].
Treatment of a CAUTI depends on the clinical circum-
stances. In an asymptomatic patient, therapy should be post-
poned until the catheter can be removed. Symptomatic
patients (e.g. those with fever, chills, flank pain, dyspnea, and
hypotension) require immediate antibiotic therapy with
broad-spectrum antibiotics covering nosocomial Gram-
positive and Gram-negative organisms. In general, treatment
of CAUTI often requires removal of the catheter along with
systemic antimicrobial therapy. Despite reports of emerging
resistance, the most recently published guidelines suggest
empiric therapy with levofloxacin in patients with CAUTI
who are not severely ill [29]. For patients with candiduria,
removal of the urinary catheter can result in resolution in as
many as one-third of cases. If candiduria persists after removal
of the catheter, oral fluconazole 200 mg daily for 14 days is the
recommended treatment [34].
Sepsis
In the United States, sepsis is a leading cause of death in
noncoronary ICU patients, and the tenth most common cause
of death overall, killing 20–50% of severely affected patients
[35]. Sepsis is considered present if infection is highly sus-
pected or proven, and two or more of the following systemic
inflammatory response syndrome (SIRS) criteria are met [26]:
• Heart rate >90 beats/min
• Body temperature <36 °C or >38 °C (<96.8 °F or >100.4 °F)
• Respiratory rate >20 breaths/min; or PaCO2 <32 mmHg
• WBC count <4000 cells/mm or >12,000 cells/mm ; or
3 3
>10% band forms.
Sepsis has been defined as a systemic inflammatory response
syndrome of infectious origin. The failure of one or more
organ systems or the occurrence of hypoperfusion in conjunc-
tion with sepsis is considered to be severe sepsis. Severe sepsis
accompanied by hypotension is septic shock. The initial ther-
apy of sepsis includes fluid replacement/resuscitation, admin-
istration of effective intravenous antibiotics within the first
hour of recognition of sepsis, source control (including drain-
age of infected fluid collections, removal of intravascular
devices thought to be a source), and appropriate support for
organ dysfunction (e.g. hemodialysis, mechanical ventilation,
transfusion of blood products, and vasoactive agents for hypo-
tension) [36].
Before 1987, Gram-negative bacteria were the predominant
pathogens in severe sepsis. Among the organisms reported to
have caused sepsis in 2000, Gram-positive bacteria accounted
for over half of the cases, with Gram-negative bacteria account-
ing for a third, and polymicrobial, anaerobic, and fungal infec-
tions accounting for the remainder [27]. Combination
antimicrobial therapy is indicated in the initial empiric therapy
of severe sepsis. Empiric antimicrobial combinations should
Chapter 28: Infectious Diseases Consult
include vancomycin or linezolid to cover potentially resistant
Gram-positive organisms and an antipseudomonal β-lactam
(e.g. cefepime, ceftazidime, piperacillintazobactam) combined
with either an aminoglycoside (e.g. gentamicin or tobramycin)
or an antipseudomonal fluoroquinolone (e.g. levofloxacin or
ciprofloxacin) to cover Gram-negative pathogens. Additional
coverage for anaerobic organisms should be included when the
sepsis source is an intra-abdominal/pelvic infection or a necrotiz-
ing skin and soft tissue infection [28]. Once culture results are
available, antibiotics should be de-escalated or discontinued to
prevent the emergence of multidrug-resistant pathogens.
Procalcitonin (PCT) is a peptide precursor of the thyroid
hormone calcitonin that has been used as a biomarker to
monitor and diagnose infections [37]. Recently, the accuracy
and clinical value of PCT for diagnosis of sepsis in critically
ill patients was reviewed [38]. The results of this meta-
analysis concluded that PCT can differentiate effectively
between sepsis and SIRS of noninfectious origin. However,
the authors cautioned that the test could not be recom-
mended as a single definitive test for sepsis diagnosis, but
that it could play an adjunctive role in making the diagnosis
in combination with careful medical history, physical exam-
ination, and review of available laboratory and microbiologic
data.
Infection Control
Infection control is the discipline concerned with preventing the
spread of infections within the healthcare setting. Transmission
of infection within a hospital requires three elements [39,40]:
1. A source of infecting microorganisms
• Human sources include patients, staff, or visitors
2. A susceptible host
• Host factors include age, comorbid diseases, degree of
immunosuppression, and breaks in the first line of
defense mechanisms (e.g. indwelling catheters or other
devices, breaks in skin)
3. A means of transmission for the microorganism
• Five main routes of transmission: contact, droplet,
airborne, common vehicle, and vector-borne.
There are two tiers of isolation precautions: standard pre-
cautions and transmission-based precautions. Standard pre-
cautions are used for all patients, regardless of diagnosis or
presumed infection, and stress the need for hand hygiene and
use of personal protective equipment (e.g. gloves, gowns,
masks, face shields, and eye protection) when contact with
blood or body fluids is expected. The Centers for Disease
Control and Prevention (CDC) has recommended three spe-
cific categories of transmission-based precautions that are
always to be used in addition to standard precautions: contact,
droplet, and airborne. There are a number of infectious agents
included in each category with a brief listing outlined in
Table 28.3.
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 Chapter 28: Infectious Diseases Consult

Table 28.3 Organisms requiring isolation precautions in hospitals
Contact MRSA: methicillin-resistant Staphylococcus
isolation aureus
VRE: vancomycin-resistant enterococcus
Multidrug-resistant Gram-negative bacteria
Clostridium difficile
Droplet Influenza
isolation Neisseria meningitidis: pneumonia or meningitis
Pertussis
Parvovirus B19
Airborne Mycobacterium tuberculosis: pulmonary or
isolation laryngeal disease
Varicella: primary or reactivation
Adapted from [39] and [40].
Contact precautions are designed to prevent transmission
of infectious agents, including epidemiologically important
microorganisms by direct or indirect contact with the
patient or the patient’s environment. The CDC recommends
implementation of contact precautions for all patients infected
with multidrug-resistant organisms (MDROs) and for patients
that have previously been identified as being colonized with
target MDROs.
Droplet precautions are used for patients known or sus-
pected to have serious illnesses transmitted by large particle
droplets (>5 μm in size). Duration of isolation for the organ-
isms included in this group varies:
• For bacterial pathogens, isolation can usually be
discontinued after 24 hours of appropriate antibiotic
therapy
• For the viral pathogens listed, the duration of isolation is
less defined, but the usual recommendation is to maintain
isolation for the duration of illness.
Airborne precautions are used for patients known or sus-
pected to have illnesses transmitted by small particle droplets
(<5 μm in size). Patients should be placed in a private room
with negative pressure and high-efficiency particulate air
(HEPA) filtration. Everyone entering the room should wear
an N95 respirator or equivalent.
Patients presenting with an unknown generalized rash or
exanthema should be placed in airborne and contact isolation
while the evaluation for the specific cause ensues. For the
majority of infections listed in Table 28.3, isolation is con-
tinued for the duration of hospitalization. Isolation for vari-
cella can be discontinued when all lesions are crusted. For
Mycobacterium tuberculosis, only pulmonary and laryngeal
disease requires airborne precautions. Patients with extrapul-
monary tuberculous disease, including meningitis, require
only standard precautions.
Several studies have evaluated the efficacy of personal pro-
tective equipment (PPE) (e.g. gloves or gloves and gown) alone
to reduce the incidence and transmission of resistant bacteria,
specifically MRSA and VRE, in the intensive care setting [42,
43, 44]. Although the use of PPE alone has not been shown to
significantly reduce the incidence of multidrug-resistant
organisms in the ICU setting, some studies have pointed out
that compliance with hand hygiene before patient contact
decreases when gloves are required.
A promising intervention that has been shown to decrease
rates of MRSA is “universal decolonization” [45]. Universal
decolonization involves contact isolation for all patients with a
known history of colonization or infection with a multidrug-
resistant organism (standard precautions for all other
patients), twice daily intranasal mupirocin for five days, plus
daily bathing with chlorhexidine-impregnated cloths for the
entire ICU stay. Nasal swabs to screen for MRSA were not
done as a part of this intervention. In the study cited, universal
decolonization of patients in the ICU reduced MRSA-positive
clinical cultures by 37% and also decreased bloodstream infec-
tions from any pathogen by 44% when compared to the rates
seen in patients who underwent standard MRSA screening by
nasal swab and isolation for patients testing positive for
MRSA. Adverse events related to universal screening were rare
and included rash or pruritis related to the use of chlorhex-
idine, and costs were estimated to be approximately $40 per
patient. A smaller, but similar, study published in 2009 also
showed that daily bathing with chlorhexidine, in addition to
use of contact precautions, reduced acquisition of MRSA by
32% and VRE by 50% [46]. Overall, these studies suggest that a
combination of adherence to infection control practices,
including hand hygiene and use of PPE, for patients known
to be colonized or infected with resistant bacteria, along with
the use of chlorhexidine bathing may lead to reduced acquisi-
tion of VRE and MRSA and the subsequent development of
healthcare-associated infections in the intensive care setting.

3. Chastre J, Fagon JY. (2002). Ventilator- issued October 2004. Am J Infect

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 Chapter
A Nephrology Consult in the Neurocritical Care Unit
29 Jason Prosek and Nabil Haddad
This chapter will address the broad range of issues pertaining to
kidney disease that may be encountered in the neurointensive
care unit. It will focus on the diagnosis and management of both
acute and chronic renal dysfunction, as well as the fluid and
electrolyte disturbances that frequently accompany kidney dis-
ease. Early consultation with nephrology for acute kidney injury
in the ICU setting has been associated with improved outcomes,
even when dialysis is not performed [1]. Thus, the goals of the
following sections are to discuss the diagnosis and management
strategies of renal dysfunction from a nephrologist’s perspective.
Acute Kidney Injury
Acute renal failure, or the updated nomenclature acute kidney
injury (AKI), is a serious disorder and is associated with
significant increase in both morbidity and mortality. An
increase in serum creatinine of
0.5 mg/dL is associated with
a 6.5-fold (95% confidence interval 5.0 to 8.5) increase in the
odds of death, a 3.5 day increase in the length of hospital stay,
and nearly 7500 dollars in excess hospital costs [2]. AKI is
associated with a 5.5-fold increase in mortality after adjusting
for comorbidity in patients undergoing radiocontrast procedures
[3]. Patients who develop AKI requiring dialysis have 35.7%
in-hospital mortality and 18.8% two-year survival [4].
Definition of Acute Kidney Injury
The Acute Kidney Injury Network (AKIN) and the RIFLE
criteria (which is an acronym of Risk, Injury, Failure, Loss and
End-stage kidney disease) by the Acute Dialysis Quality Initiative
(ADQI) endorse the diagnosis of AKI in the presence of absolute
rise in serum creatinine of
0.3 mg/dL from baseline within 48
hours, or increase in serum creatinine of
50%, and/or decrease
in urine output of <0.5 mL/kg/h for more than six hours.
Below is the staging of AKI by both groups.
AKIN Criteria for AKI [5]
Stage 1. Increase in serum creatinine of more than or equal
to 0.3 mg/dL or increase to more than or equal to 1.5- to 2-
fold from baseline and/or urine output of less than 0.5 mL/
kg/h for more than six hours
Stage 2. Increase of serum creatinine of more than two- to
threefold from baseline and/or urine output of less than
0.5 mL/kg per hour for more than 12 hours
Stage 3. Increase of serum creatinine of more than threefold
from baseline, or more than or equal to 4.0 mg/dL with an
acute increase of at least 0.5 mg/dL (44 μmol/L) or on
dialysis and/or urine output of less than 0.3 mL/kg/h for
24 hours or anuria for 12 hours.
RIFLE Criteria for AKI [6]
Risk: Increased serum creatinine of 1.5 and/or urine
output of less than 0.5 mL/kg/h for more than six hours
Injury: Increased serum creatinine of 2 and/or urine
output of less than 0.5 mL/kg/h for more than 12 hours
Failure: Increased serum creatinine 3 or decreased
glomerular filtration rate (GFR) above 75%, or serum
creatinine of more than 4 mg/dL with an acute rise >0.5 mg/
dL and/or urine output of less than 0.3 mL/kg/h for 24 hours
or anuria for 12 hours
Loss: Persistent acute renal failure: complete loss of kidney
function for more than four weeks
End-stage renal disease (ESRD): Complete loss of kidney
function for more than three months
(To convert serum creatinine from mg/dL to μmol/L, multiply
by 88.4.)
KDIGO, Kidney Disease: Improving Global Outcomes
guidelines define AKI as any of:
1. Increase in serum creatinine of
0.3 mg/dL within
48 hours or
2. Increase
1.5 times from baseline within the last 7 days or
3. Decreased urine output to <0.5 mL/kg/hr for 6 hours.
Chronic Kidney Disease
Chronic kidney disease (CKD) is defined as abnormalities in
kidney function and/or structure for the duration of at least
three months. The presence of any of the following confirms
the presence of CKD:
• Decreased estimated glomerular filtration rate (eGFR) of
less than 60 mL/min/1.73 m2
• Presence of renal pathologic abnormality
• Abnormality in urine, blood studies
• Abnormality in renal imaging.
According to the level of eGFR, chronic kidney disease is classi-
fied into five stages according to the eGFR [7] (Table 29.1).
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Table 29.1 CKD classification according to eGFR
Stage 1 GFR >89
Stage 2 GFR 60–89
Stage 3a GFR 45–59
Stage 3b GFR 30–44
Stage 4 GFR 15–29
Stage 5 GFR <15
CKD may result in multiple complications, including fluid
retention, hypertension, electrolyte imbalances like hyperkale-
mia, hyponatremia, and hyperphosphatemia, metabolic acidosis,
and bone disease. It is a risk factor for acute kidney injury and an
independent risk factor for cardiovascular disease. Both morbid-
ity and mortality increase with worsening renal function. CKD
may be asymptomatic and detected incidentally by routine
laboratory tests. The severity of signs and symptoms depends
on the severity and rate of progression of CKD, in addition to
the symptomatology of the causative disease. It may include
fatigue, dyspnea from fluid overload, gastrointestinal (GI) symp-
toms like anorexia, nausea, and vomiting, itching, and bone pain
related to secondary hyperparathyroidism.
Renal replacement therapy is usually started in patients
with symptomatic stage 5 CKD and in the majority of patients
with eGFR of less than 10 mL/min. It is important to maintain
renal protective measures to slow or halt the progression of
disease in all stages of CKD, which include [8]:
1. Blood pressure control with a goal of less than 130/80
2. Glucose control with a goal for hemoglobin A1c of less than 7
3. Treatment with angiotensin-converting enzyme inhibitor/
angiotensin-receptor blocker with close monitoring of
serum potassium and creatinine
4. Lipid control with a goal for low-density lipoprotein (LDL)
cholesterol of less than 100 mg/dL and triglycerides of less
than 150 mg/dL
5. Lifestyle modifications including 4–5 g of salt intake a day
and 0.8 g/kg/day of protein
6. Avoid nephrotoxins including nonsteroidal anti-
inflammatory drugs (NSAIDs)
7. Goal for serum uric acid of less than 7 mg/dL and serum
bicarbonate above 21 mEq/L.
AKI Etiology
Acute renal failure may develop de novo or can be superimposed
on chronic kidney disease. It may result from one or several
factors, including: renal hypoperfusion from hemodynamic
factors such as volume depletion, impaired cardiac function,
and hypotension; intrinsic insults including sepsis; nephrotoxic
agents including intravenous contrast, NSAIDs, aminoglyco-
sides, and others; liver dysfunction, renovascular disorders,
obstruction and primary renal disease. In general, the etiologic
factors of AKI may be categorized into three major groups:
prerenal, renal, and postrenal causes (Table 29.2).
360
Table 29.2 Etiology of AKI
Prerenal AKI
Volume depletion: GI losses, poor oral intake, blood loss, early
sepsis, aggressive diuresis, acute abdominal compartment
syndrome, and ultrafiltration therapy CHF
Decreased effective arterial filling: Liver cirrhosis with hepatorenal
syndrome, heart failure, and nephrotic syndrome
Other causes: Renal hypoperfusion in the presence of impaired
renal autoregulation by ACE inhibitors/ARBs, NSAIDs, calcineurin
inhibitors, hypercalcemia
Renal/intrinsic AKI
Acute tubular necrosis: Renal ischemia from protracted and severe
prerenal etiology, tubular toxicity from IV contrast, gadolinium,
medications like aminoglycosides, rhabdomyolysis, intravascular
hemolysis, light chain injury
Glomerulolar injury: RPGN related to SLE, ANCA-associated renal
vasculitis, anti-GBM disease, Henoch–Schonlein purpura, acute,
infection-associated glomerulonephritis and postinfectious
glomerulonephritis
Vascular disease: HUS/TTP, cholesterol emboli (atheroembolic
disease), HELLP syndrome, postpartum AKI, renal artery
thrombosis/dissection, aortic dissection, and renal vein
thrombosis
Interstitial disease: acute interstitial nephritis, autoimmune
disorders, pyelonephritis, malignant/lymphomatous infiltration,
monoclonal protein deposition
Postrenal AKI
Bladder outlet obstruction from prostate disorders,
malignancy, stones, papillary necrosis, retroperitoneal fibrosis,
traumatic/surgical injury, strictures, neurogenic bladder, aberrant
vessels
Abbreviations: CHF: congestive heart failure; ACE: angiotensin-converting
enzyme; ARB: angiotensin II receptor blocker; RPGN: rapidly progressive
glomerulonephritis; SLE: systemic lupus erythematosus; ANCA:
antineutrophil cytoplasmic antibodies; GBM: glomerular basement
membrane; HUS: hemolytic uremic syndrome; TTP: thrombotic
thrombocytopenic purpura; HELLP: hemolysis, elevated liver enzyme levels,
low platelet levels
Symptoms of AKI
AKI may be asymptomatic and incidentally found by rou-
tine laboratory testing, or associated with multiple symp-
toms and signs related to uremia, fluid overload, acid–base
disorders, and multiple electrolytes imbalance. Symptoms
of AKI may include fatigue, dyspnea from volume over-
load, anorexia, nausea, vomiting, pruritus, and mental
status changes. Physical examination may reveal high
blood pressure, fluid overload with lung rales and periph-
eral edema, skin rash related to allergic reactions, vasculitis
or atheroemboli, flapping tremor, and other signs of sys-
temic disease including lung, liver, heart, GI, and malig-
nant disorders.
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Diagnostic Approach to AKI
Appropriate care of patients with AKI starts with obtaining a
detailed history of present illness, including any hemodynamic
insult, exposure to nephrotoxic medications, both prescription
and over-the-counter remedies, procedures, intravenous con-
trast exposure, and social and family history. It is important to
look for signs and symptoms of volume depletion, heart and
liver disease, allergic reactions, and voiding problems suggest-
ive of bladder outlet obstruction to differentiate between the
different etiologies of AKI. The presence of frothy or foamy
urine is highly suggestive of significant proteinuria. In general,
prerenal AKI and acute tubular necrosis related to hemody-
namic factors with renal hypoperfusion and/or toxic tubular
injury are common causes of AKI in the ICU settings, but it is
of crucial importance to distinguish between prerenal, renal,
and postrenal etiologic factors.
Urinalysis with microscopic examination is important
(Table 29.3). For example, the finding of more than four white
blood cells (WBCs) per high power field (HPF) and bacteria
are suggestive of infection; muddy brown or granular casts are
the hallmark of acute tubular necrosis; dysmorphic red blood
cells (RBCs) and RBC/WBC casts point to the presence of
active glomerulonephritis; urine eosinophils are present in
approximately one-third of patients with allergic interstitial
nephritis and in patients with cholesterol emboli; a urine
protein to creatinine ratio greater than 3 in patients with
proteinuria suggests a glomerular disease.
Measurement of the urine electrolytes sodium, potassium,
and chloride, and urine creatinine are helpful in identifying a
prerenal state. In an oliguric patient, which is defined by the
presence of 100–400 mL of urine in a 24-hour period, the
findings of urine osmolality above 500 mOsmol/kg, urine
sodium of less than 20 mEq/L and fractional excretion of
sodium (FENa) less than 1% are suggestive of a prerenal state.
FENa is calculated by the formula:
FENa ¼ ½ðuNa=sNaÞ=ðuCr=sCrÞ  100%
where uNa is urine sodium, sNa is serum sodium, uCr is urine
creatinine and sCr is serum creatinine. Of note, FENa is a valid
criterion only in the presence of impotent nephrons with
decreased GFR.
A renal ultrasound is important to rule out obstruction. The
presence of hydronephrosis requires immediate intervention to
Table 29.3 Urine findings in AKI
relieve the obstruction and at least partially reverse the renal
insult. Other tests include blood chemistry, complete blood
count (CBC) and serological testing, depending on the clinical
presentation. A renal biopsy for definitive diagnosis may be
indicated at times. It is important to seek a nephrology consult-
ation to assist in the management of these patients.
Initial Management of AKI
The treatment of AKI is directed at correction of electrolytes
imbalance, acid–base disorders, volume overload, and uremia,
in addition to eliminating or ameliorating the triggering
factors, if possible. Individual volume and electrolyte consider-
ations will be discussed separately, but in all patients with
compromised renal function it is important to implement
renal protective measures and supportive care, which include:
• Low salt, potassium, phosphorus, and protein diet
• Adjusting all medications for diminished GFR
• Avoiding all nephrotoxic medications, including iodinated
IV contrast, gadolinium, NSAIDs, aminoglycosides etc,. if
possible
• Monitoring volume status closely with strict intake and
output
• The use of diuretics for volume control
• Correcting electrolyte imbalance and acid–base disorders
(see below)
• Initiation of renal replacement therapy (RRT) if needed
Ongoing Management of AKI
Blood Pressure/Intravascular Volume
In the case of oliguric AKI the risk of fluid accumulation is
great and is associated with poor outcomes [9]. There is no
evidence that diuretics have any role in preventing AKI, in
fact prophylactic use increases AKI incidence. The role of
diuretics in AKI is limited, but may offer some benefit in
achieving a negative fluid balance in the setting of fluid
overload and a lung-protective strategy in patients with
acute lung injury. It may also have possible benefit in the
setting of hyperkalemia and hypercalcemia. The clinician
should be cautious with high-dose furosemide (>1 g/day),
which has been associated with ototoxicity [10]. Mannitol is
not recommended for treatment or prevention of AKI. Nor
does it have a role in the setting of radiocontrast-induced
nephropathy.

Prerenal AKI/obstruction Bland urine with no significant Nutrition/Uremic Toxin Generation

Acute tubular necrosis
Acute interstitial nephritis
Glomerulonephritis
proteinuria or hematuria
Muddy brown granular casts, 1–2+
proteinuria
WBC, WBC casts, and urine
eosinophils
Dysmorphic RBC, RBC/WBC casts,
significant proteinuria, hematuria
During AKI, hyperglycemia is common due to peripheral
insulin resistance [11,12] and protein catabolism [13]. As such,
total energy intake of 20–30 kcal/kg/day is recommended in all
cases of AKI. This is seen as a near optimal energy-to-nitrogen
balance, where higher levels of energy intake lead to more
hyperglycemia without a more positive nitrogen balance [14].
As critically ill patients are catabolic, it was once felt beneficial
to limit protein intake (and thus nitrogen) to limit the

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progression of laboratory azotemia. However, since malnutri-
tion is associated with increased mortality in critically ill
patients, management is aimed at supplying enough protein
to maintain metabolic balance. This is estimated to be 0.8–1.0
g/kg/day of protein in noncatabolic patients and up to 1.7 g/
kg/day for patients on continuous RRT [15–17]. Enteric feed-
ing is encouraged if oral feeding is not possible, offering
benefits of reduced stress ulcers and bleeding [18].
Nephrotoxin Avoidance/Pharmacologic Monitoring
In the cases of both CKD and reversible AKI, preservation of
existing renal function and enabling of renal healing is depend-
ent upon elimination of further renal insults. The use of diur-
etics in AKI carry the risk of prerenal injury, should the drug
impart intravascular volume depletion. This is difficult to
predict and can occur when the rate of diuresis exceeds the
plasma refill rate from the interstitium. In general, diuretics
should be cautiously used and only if there is adequate blood
pressure and the patient is fluid overloaded.
All medications that invoke direct toxicity to the kidneys
should be avoided whenever possible. This list includes, but is
not limited to, aminoglycosides, amphotericin, and platinum-
based chemotherapies. In the event a potentially toxic medica-
tion must be used, frequent measurement of drug levels should
be employed, if available. Measurable levels of nontoxic drugs
should also be monitored to prevent toxic accumulation. The
true GFR of the patient with AKI cannot be reliably measured
and is typically overestimated by the laboratory-generated
eGFR. Thus all medications should be dosed for a GFR of
15–30 mL/min during AKI [19].
Several medication classes without direct toxic impact to
the kidneys can impart kidney injury by disrupting auto-
regulation of renal blood flow. NSAIDs disrupt prostaglandin
synthesis, thereby leading to afferent arteriolar vasoconstriction
and decreased glomerular filtration. They should be avoided in
all cases of CKD and AKI. Drugs that antagonize the renin–
angiotensin–aldosterone system (RAAS) inhibit efferent arter-
iolar vasoconstriction, as well as decreasing sodium retention,
both of which effectively decrease glomerular filtration. Thus
ACE inhibitors, ARBs, mineralcorticoid receptor blockers, and
direct renin inhibitors should all be avoided in incident AKI. It
is reasonable to continue RAAS blockade in the setting of stable
CKD, provided the patient is hemodynamically stable and
impending kidney toxins are not anticipated (radiocontrast
dye, aminoglycosides, vancomycin, etc.).
Electrolyte Disorders
Potassium Disorders
Potassium is a major intracellular cation with a concentration
of about 130 mEq/L in the intracellular fluid. Of the total body
potassium, which is about 3500 mEq, 98% is in the intracellu-
lar compartment and 2% in the extracellular fluid. Insulin and
catecholamines via β2-adrenergic receptors are the two major
agents that result in potassium entry into cells. Renal handling
of potassium occurs mainly at the level of cortical collecting
362
ducts and most disorders of renal potassium secretion can be
explained by the principal cell function. The interaction between
potassium intake, cell shifts, and renal and gastrointestinal
excretion determine the serum potassium level. Potassium dis-
orders result from imbalance between these three factors.
Hypokalemia
The differential diagnosis of hypokalemia includes pseudohypo-
kalemia, decreased oral intake, intracellular shifts, and gastro-
intestinal and renal losses. Pseudohypokalemia results from
potassium reabsorption by metabolically active cells after
blood is drawn, as in acute leukemia, and can be avoided by
rapid separation of plasma from the cells or storage of the
drawn blood at low temperature. Increased cell entry may
result from alkalosis, insulin, catecholamines, anabolic states,
and tumors with rapid cell growth, hypothermia, chloroquine
intoxication, hypokalemic periodic paralysis, and barium
chloride intoxication. Gastrointestinal losses may result from
diarrhea, malabsorption, fistulas, laxative abuse, and villous
adenoma. Increased urine potassium excretion results from
an increase in both mineralocorticoid activity and distal deliv-
ery of water and salt to the cortical collecting ducts.
Approach to Hypokalemia
A 24-hour urine potassium of
20 mEq/L is consistent with
renal potassium loss. In the presence of high blood pressure it
is appropriate to check plasma renin and aldosterone to rule
out hyperaldosteronism. High urine potassium with low blood
pressure may result from increased distal delivery of potas-
sium. In this situation, if the serum bicarbonate is low it is
appropriate to consider renal tubular acidosis. If the serum
bicarbonate is elevated it is appropriate to check urine chlor-
ide. High urine chloride with high serum bicarbonate may
result from diuretics, magnesium deficiency, and Bartter’s
and Gitelman’s syndromes. Low urine chloride with high
serum bicarbonate suggests the appearance of nonreabsorbable
anions in the urine, as is seen in therapy with nafcillin.
Principles of Therapy
Oral potassium is the preferred route. Intravenous potassium
chloride may be given at a rate of 10–20 mEq/h. Several hundred
mEq of potassium chloride may be required to correct the
potassium deficit in the absence of renal dysfunction, and fre-
quent serum potassium and cardiac monitoring is recommended
for urgent situations. Of note in a patient with hypokalemic
acidosis, it is important to correct hypokalemia before bicarbon-
ate therapy as sodium bicarbonate may worsen the hypokalemia.
Hyperkalemia
The differential diagnosis of hyperkalemia includes pseudohy-
perkalemia from hemolysis, high platelets and WBC counts,
repeated fist clenching, prolonged application of tourniquets,
lower ambient temperature, increased potassium intake (typ-
ically via IV infusions), cell shifts from cell damage, inorganic
acidosis, insulin deficiency, cell ischemia, succinylcholine,
hyperosmolality, arginine hydrochloride and hyperkalemic

periodic paralysis. Renal potassium retention can result from
mineralocorticoid deficiency, decreased distal delivery of
sodium, and cortical collecting duct (CCD) abnormality. In
the ICU setting, cellular shifting of potassium from the intra-
cellular space is a common cause of hyperkalemia.
Approach to Hyperkalemia
In acutely ill patients it is important to look for the different
causes of potassium cell shifts and acute kidney injury. In a stable
patient, abnormal CCD function, mineralocorticoid deficiency,
and inhibitors of the renin–angiotension–aldosterone axis are
common causes. In the presence of hyperkalemia, a low trans-
tubular potassium gradient (TTKG) points to a renal disorder,
but does not differentiate between the different causes of renal
hyperkalemia. More recent data has shown that TTKG may not
be a reliable test for the diagnosis of hyperkalemia [20]. The basis
of TTKG in assessing hyperkalemia has been challenged but it
may still enforce the presence of a renal tubular disorder.
TTKG ¼ ½uK=ðuOsm=sOsmÞ=sK
where uK is urine potassium, uOsm is urine osmolality, sOsm is
serum osmolality, and sK is serum potassium. Notably the TTKG
has no units. In order for TTKG to be a valid measurement urine
osmolality (uOsm) must be more than or equal to serum Osm
(sOsm) and urine sodium (uNa) more than 25 mmol/L.
In the setting of hyperkalemia, a TTKG of <6 points
toward a renal cause of hyperkalemia and TTKG of
10
indicates proper renal handling and thus suggests a nonrenal
cause of hyperkalemia.
Treatment of Hyperkalemia
It is important to eliminate the causative factor of hyperkale-
mia, if possible. Symptomatic hyperkalemia in the presence of
ECG hyperkalemic changes requires immediate therapy
including antagonizing the effects of hyperkalemia on the cell
membranes by IV calcium, intracellular shifting of potassium
by insulin and dextrose and beta 2 agonists, and potassium
removal by loop diuretics and cation exchangers like sodium
polystyrene sulfonate, patiromer, and zirconium cyclosilicate.
In the presence of true hyperkalemia, treatment options are
listed in Table 29.4. In patients with ESRD, RRT is the main
therapy for hyperkalemia.
Table 29.4 Medical treatment of hyperkalemia
Treatment Mechanism Onset Duration
Calcium gluconate/ Membrane 1–3 min 30–60 min
chloride
Insulin (with Cell shifts 20–30 min 4–6 h
glucose)
β2-agonists Cell shifts 30 min 2–4 h
Sodium polystyrene GI excretion 1–2 h 4–6 h
sulfonate
(Kayexalate)
Diuretics Renal excretion min–h 4–6 h
Chapter 29: Nephrology Consult
Caveats are that:
• Sodium bicarbonate does not cause cell shifts of K, but
dilutes the serum, primarily effective when a metabolic
acidosis is present
• Sodium chloride causes water shifts as NaHCO3 and
K shift out of cells
• In a patient with hypokalemic acidosis first correct the
hypokalemia as bicarbonate therapy may worsen the
hypokalemia.
Hypercalcemia
True hypercalcemia is defined as an increase in the plasma ionized
calcium concentration. False hypocalcemia can result from an
increase in plasma proteins, which bind calcium and raise meas-
urable total serum calcium, but only an excess of ionized calcium
will lead to clinically relevant symptoms. These symptoms include
fatigue, weakness, gastrointestinal distress, somnolence, and can
lead to coma. An increase in ionized calcium can occur from any
combination of increased intestinal absorption, increased bone
resorption, or decreased urinary excretion. Common causes
include primary hyperparathyroidism, granulomatous diseases,
malignancy, vitamin D excess, and immobility.
Most incidences of hypercalcemia are associated with intra-
vascular volume depletion. Thus, the initial treatment is
aggressive isotonic fluid infusions up to 250 ml/h, which both
replenishes the patient’s volume status and forces urinary
calcium excretion. In the setting of AKI, CKD, and CHF, the
fluid resuscitation rate may need to be adjusted for potential
fluid accumulation. The use of loop diuretics is controversial
and should only be considered once it is clear that euvolemia
has been restored. Calcitonin has theoretical benefits for all
cases of hypercalcemia, whereas bisphosphonates are helpful in
cases related to malignancies and corticosteroids are useful in
cases of hypervitaminosis D. Hemodialysis can be considered
in the instances where AKI or CKD do not allow for the
correction of calcium with fluids and medications alone.
Hypocalcemia
As with hypercalcemia, clinically relevant hypocalcemia refers
to a fall in plasma ionized calcium. Low serum protein levels
will lead to falsely low total serum calcium. Symptoms associ-
ated with hypocalcemia include paresthesias, tetany, myocar-
dial dysfunction, QT prolongation, and papilladema. Physical
exam findings include Trousseau’s and Chvostek’s signs. The
common occurrence of this electrolyte disorder in the ICU
may be related to calcium precipitation into tissues, complex-
ing with citrate in blood products, and sporadic hypopara-
thryoidism, as well as low vitamin D activation resulting
from AKI.
Acute treatment in the ICU setting is best accomplished
with intravenous replacement in the form of calcium gluconate
and calcium chloride. Calcium gluconate is better clinically
tolerated, while calcium chloride contains more elemental
calcium on a volume basis, but can lead to skin necrosis if
extravasation occurs. In more chronic settings, treatment is
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oral replacement with calcium salts and vitamin D, with the
goal to correct measurable deficiencies.
Hypermagnesemia
Magnesium physiology is perhaps more simple than calcium’s
complex bone/ hormone interplay. As a result, hypermagnesemia
is typically caused by a combination of exogenous administration
and renal failure. Anticipation is the most effective strategy, as
magnesium-containing medications during AKI should be
avoided. The challenge is that magnesium is commonly found
in over-the-counter medications for gastrointestinal distress. Ces-
sation of magnesium supplements will allow for restoration of
normal levels in the absence of kidney injury. In refractory cases,
hemodialysis may be required to normalize levels, and these are
more likely instances of severe kidney dysfunction.
Hypomagnesemia
Low levels of serum magnesium are encountered frequently in the
ICU setting and are associated with poor outcomes. In addition,
the hypomagnesemia is encountered frequently with hypokalemia
and hypocalcemia. The transmembrane channels that control
potassium and calcium movement are often dependent upon
magnesium to function properly. Thus, the correction of serum
potassium and calcium levels frequently requires prior correction
of serum magnesium. Clinically, hypomagnesemia may manifest
as neuromuscular hyperexcitability, weakness, coma, QRS
widening, and PR prolongation. In the setting of unstable
arrhythmias, 1 to 2 g of magnesium sulfate should be given
rapidly. This same dose can be given as a slow infusion in the
case of symptomatic hypomagnesemia but hemodynamic stabil-
ity. Oral preparations can also be used in asymptomatic patients,
although these preparations are associated with GI intolerance. In
either setting, when magnesium is given to the patient with AKI,
close monitoring to avoid hypermagnesemia is required, since
renal excretion is the major regulator of serum magnesium.
time, primary changes in bicarbonate are called metabolic acid-
osis when low, and metabolic alkalosis when elevated. Evalu-
ation of acid–base status begins with the arterial pH, which is
defined as the negative log of free hydrogen ion concentration
(normal is 40 nmol/L). Low arterial pH (less than 7.36) is called
acidemia and high arterial pH (above 7.44) is called alkalemia.
Of note acidemia and alkalemia refer to changes in blood pH,
while acidosis and alkalosis refer to the clinical processes that
are driving a change in the blood pH. Low serum bicarbonate
suggests primary metabolic acidosis and high serum bicarbon-
ate suggests primary metabolic alkalosis. At the same time low
pCO2 suggests primary respiratory alkalosis and high arterial
pCO2 suggests primary respiratory acidosis. In a patient with
blood pH above 7.44 (alkalemia) the primary disorder/s may be
metabolic or respiratory alkalosis or both combined; vice versa
in the presence of acidemia, (arterial pH less than 7.36) the
primary disorder may be a respiratory acidosis versus metabolic
acidosis versus both respiratory and metabolic acidosis.
Metabolic Acidosis
Metabolism of carbohydrates and fat produces 15,000 mmol/
day of volatile acid in the form of CO2, while metabolism of
amino acids, hydrolysis of dietary phosphate, and incomplete
metabolism of glucose and fatty acids produce 50 to 100 mEq/
day of nonvolatile acid. Almost all the CO2 is removed as a gas
by the lungs, while the kidneys dispose of nonvolatile acids.
The serum anion gap (AG) differentiates between anion-
gap and nongap (hyperchloremic) metabolic acidosis. It is
calculated by the formula:
Serum anion gap ¼serum sodium  ðserum chloride
þserum bicarbonateÞ þ 10  2
High anion gap metabolic acidosis (AG above 12) results from
the retention of organic acids and toxin-induced acidosis
(Table 29.5).

Table 29.5
Acid–Base Disorders
Maintenance of blood pH within a narrow range is vital to the Anion gap acidosis Added unmeasured anions
function of all body organs. Normal arterial blood pH is 7.36 to Lactic acidosis Lactate.
7.44 and a prolonged pH below 6.9 or above 7.9 is usually fatal.
Diabetic ketoacidosis Beta hydroxybutyrate,
Hydrogen ions are extremely reactive and affect many molecules,
acetoacetate
which regulate physiological processes. Buffers are the first line
of defense and minimize changes in pH by binding with or Alcoholic (ethanol) Beta hydroxybutyrate
yielding free hydrogen ions. Bicarbonate/pCO2 is the primary ketoacidosis
extracellular fluid buffer. It acts as an acid, donating hydrogen Starvation ketoacidosis Beta hydroxybutyrate
ions by forming carbonic acid, and a base by binding hydrogen
Ethylene glycol ingestion Glycolate, oxalate
ions when there is a surplus. HCO3/CO2 can be rapidly regener-
ated in the presence of an alkalosis and acidosis. Methanol ingestion Formate
Salicylate poisoning Salicylate, lactate, ketones
CO2 þ H2 O $ H2 CO3 $ Hþ þ HCO
3
Chronic acetaminophen 5-Oxoproline (pyroglutamic
While bicarbonate is the base, pCO– is the acid, and combines ingestion acid)
with water in the presence of carbonic anhydrase to form H2CO3.
Uremic acidosis Sulfate, phosphate, urate,
Primary changes in pCO2 are called respiratory acidosis
hippurate
when elevated, and respiratory alkalosis when low. At the same

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Hyperchloremic (nongap) metabolic acidosis is caused by
the retention of HCl production or loss of serum bicarbonate
(Table 29.6). The loss of bicarbonate is associated with an
equivalent increase of chloride. The sum of HCO3– + Cl– is
normal and therefore the anion gap is normal. HCl + NaHCO3
! NaCl +H2O +CO2.
The delta AG/delta serum bicarbonate (ΔAG/ΔHCO3–),
which is the ratio between the change in the AG to the change
in serum bicarbonate, helps to identify the different primary
processes. For instance, in pure anion gap metabolic acidosis the
ΔAG/ΔHCO3– is 1, while in hyperchloremic (nongap) meta-
bolic acidosis a ΔAG/ΔHCO3– <1 is suggestive of combined
gap and nongap metabolic acidosis (Table 29.7). ΔAG/ΔHCO3–
>2 is suggestive of the presence of metabolic alkalosis.
Compensatory response in acid–base disorder goes in the
same direction as the primary disorder (Table 29.8). Response
to metabolic disorders is by respiratory means and vice versa.
Normal Compensation in Metabolic Disorders
In metabolic acidosis there is a 1.2 mmHg decrease in pCO2
for each 1 mEq/L drop in serum bicarbonate or ΔpCO2 = 1.2 
ΔHCO3–. Usually the expected pCO2 can be calculated by
Winter’s formula:
 
expected pCO2 ¼ 1:5  HCO 3 þ 8ðÞ2
In metabolic alkalosis there is a 0.7 mmHg increase in pCO2
for every 1 mEq/L increase in serum bicarbonate and can be
calculated by the formula:
 
expected pCO2 ¼ 0:7  HCO 3 þ 20ðÞ5
In acute respiratory acidosis there is a 1 mEq/L increase in
serum bicarbonate for each 10 mmHg increase in pCO2. In
Table 29.6 Causes of hyperchloremic (nongap) metabolic acidosis.
• Increase in hydrochloric acid production (HCl): ammonium
chloride (NH4Cl), cationic amino acids (arginine, lysine), total
parenteral nutrition (TPN)
• Gastrointestinal loss of bicarbonate (diarrhea)
• Posthypocapneic acidosis
• Diabetic ketoacidosis (DKA) (50% of DKA patients have
nongap metabolic acidosis due to loss of ketoacids in
the urine)
• Uretero-gastrointestinal diversions or fistulas
• Renal tubular acidosis
chronic respiratory acidosis there is a 3.5 mEq/L increase in
serum bicarbonate for every 10 mmHg increase in pCO2.
In acute respiratory alkalosis there is 2 mEq/L decrease in the
serum bicarbonate for every 10 mmHg increase in pCO2, while
in chronic respiratory alkalosis there is a 4 meq/L decrease in
serum bicarbonate for every 10 mmHg decrease in pCO2.
Treatment of metabolic acidosis should focus on correction
of the causative factors. Symptomatic therapy with bicarbonate
should be monitored closely with special attention to volume
overload and overcorrection. Also, concentrated sodium bicar-
bonate IV solutions may lead to hypernatremia. Renal replace-
ment therapy may be indicated in the presence of renal
dysfunction and intoxications, especially with the presence of
a high osmolar gap, which is created by an ingestion of a toxic
alcohol.
Metabolic Alkalosis
Metabolic alkalosis results from an increase of serum bicar-
bonate. The elevated serum bicarbonate may be a consequence
of loss of hydrogen ions and/or the generation of bicarbonate.
How the patient responds to volume expansion with normal
saline separates metabolic alkalosis into chloride-responsive
and chloride-resistant alkalosis.
Chloride-responsive (urine chloride is less than 25 mEq/L):
1. Loss of hydrogen ions:
i. Gastrointestinal losses:
a. Vomiting
b. Gastrointestinal suction
c. Villous adenoma
d. Congenital chloridorrhea
ii. Renal loss
a. Postdiuretics effect
2. Posthypercapneic alkalosis
3. Contraction alkalosis
4. Cystic fibrosis.
Chloride-resistant (urine chloride is more than 40 mEq/L):
1. High blood pressure:
i. Primary hyperaldosteronism
ii. Congenital adrenal hyperplasia
iii. Glucocorticoid responsive hyperaldosteronism.

Table 29.7 Types of metabolic acidosis

Na K Cl HCO3 AG ΔAG ΔHCO3 ΔAG/ΔHCO3

Normal 138 4 104 24 10 0 0 –
Pure high anion gap metabolic acidosis 138 4 104 14 20 10 10 1.0
Pure hyperchloremic metabolic acidosis 138 4 114 14 10 0 10 0
Mixed 138 4 110 12 16 6 12 <1

365
 Chapter 29: Nephrology Consult

Table 29.8 Body’s response to metabolic and respiratory disorders require RRT to correct the adverse metabolic and volume
Primary disorder Body’s response consequences of AKI [21].

Metabolic Retention of acid or loss Loss of pCO2

acidosis of bicarbonate Description of the Procedure
Metabolic Loss of acid or retention Retention of pCO2 RRT is a broad term that encompasses all modalities in
alkalosis of bicarbonate which the function of the native kidneys are replaced or
Respiratory Retention of CO2 Retention of HCO3– augmented by other means, including intermittent hemodi-
acidosis alysis (iHD), continuous renal replacement therapy (CRRT),
and peritoneal dialysis (PD), as well as renal transplantation.
Respiratory Loss of CO2 Loss of HCO3–
This text will discuss only the first two methods to achieve
alkalosis
RRT since they are the only means to broadly deliver this
therapy emergently. PD can be delivered acutely by using low
volume PD exchanges in some facilities and this RRT modal-
iv. Apparent mineralocorticoid activity (licorice ity is gaining momentum.
ingestion). In common with the acute RRT modalities (iHD, CRRT)
v. Exogenous steroids are the ways in which the clearance of toxins, solutes, ions,
vi. Cushing syndrome and water is achieved. Both modalities feature a semiperme-
vii. Ectopic ACTH production able membrane through which water and solutes pass to be
viii. Liddle’s syndrome carried away from the patient in a waste stream. This mem-
ix. Renovascular hypertension with secondary brane comes in the form of a cartridge made up of hollow
hyperaldosteronism synthetic polymer fibers through which blood is pumped.
2. Low blood pressure: The dialysate fluid flows in the opposite direction around
the outside of these fibers. In iHD, clearance is achieved by
i. Bartter’s syndrome
diffusion, as solutes travel down their concentration gradient
ii. Gitelman’s dyndrome
into the dialysate and are carried away from the patient. The
iii. Severe potassium depletion electrolyte concentrations in the dialysate can be adjusted to
3. Active diuretic therapy control the rate at which these different ions are cleared. For
4. Hypomagnesemia example, the dialysate contains no urea to maximize the
5. Increased delivery of unabsorbable anions to the clearance of uremic toxins, whereas dialysate potassium can
collecting ducts, as in treatment with nafcillin and other be adjusted from 0 to 4 mEq/L to control the rate of potas-
penicillins. sium clearance.
In CRRT, clearance via the convective drag of solutes
Treatment of metabolic alkalosis should be directed at
(hemofiltration or HF) across the semipermeable membrane
elimination of the causative factors. In patients with chloride-
can be added to or performed in isolation from diffusive
sensitive metabolic alkalosis, volume repletion with normal
clearance (hemodialysis or HD). In comparison to diffusive
saline is usually very effective. Treatment with normal saline
clearance, which most efficiently accomplishes small molecule
will not correct chloride-resistant metabolic alkalosis and
clearance (urea, potassium, hydrogen ions), convective clear-
therapy in these cases is directed at elimination of the causative
ance augments “middle molecule” clearance (inorganic phos-
factors, if possible, and/or blocking its effects. For instance,
phate, β2-microglobulin, potentially inflammatory cytokines).
in patients with primary hyperaldosteronism from adrenal
Regardless of modality, larger proteins (immunoglobulins,
hyperplasia, treatment with mineralocorticoid receptor
myoglobin, albumin) are not removed in any meaningful
blockers (spironolactone, eplerenone) may result in significant
quantity and need not be replaced.
improvement. Blockade of the cortical collecting duct sodium
The fluid used to achieve convective clearance in CRRT is
channels by amiloride or triamterene is an effective therapy in
delivered directly to the patient, either upstream of the dialysis
patients with Liddle’s syndrome, which is caused by an activat-
filter (prefilter), immediately downstream of the filter (post-
ing mutation of the epithelial sodium channel (ENaC). The
filter), or any combination of the two. The contents of this
carbonic anhydrase inhibitor acetazolamide, which causes
fluid can also be manipulated in order to control the rate of
bicarbonaturia, is an effective therapy in patients with volume
clearance of one solute versus another. The modality the
overload.
nephrologist chooses can be communicated by its associated
acronym. For example, continuous veno-venous hemofiltra-
Renal Replacement Therapy tion (CVVHF) uses only convective clearance. Continuous
AKI is encountered in more than 35% of critically ill veno-venous hemodialysis (CVVHD) uses only diffusive clear-
patients. The majority of these patients are successfully man- ance. Continuous veno-venous hemodiafiltration (CVVHDF)
aged medically, but ultimately 5–6% of critically ill patients employs both modalities.

366

Choice of Modality
In the setting of AKI requiring RRT the nephrologist must
choose between iHD and CRRT. This clinical question has not
been settled in the literature and at this time CRRT has not been
proven to exhibit either a survival or a renal recovery advantage
over iHD. The benefits of CRRT, however, have been shown to
cause fewer episodes of hypotension and overall improved
volume management compared to intermittent strategies [22].
Thus, CRRT is typically favored in the critically ill and hemo-
dynamically unstable patient. Particular considerations for the
Neuro ICU patient will be discussed in its own section.
Vascular Access for Dialysis
In occurrences of AKI requiring RRT and any utilization of
CRRT, a central venous dialysis catheter is required to access
the central circulation, as well as deliver the blood flow rates
necessary for adequate clearance. The right internal jugular
vein is the preferable location for this catheter as this location
minimizes catheter dysfunction, infection risk, and blood recir-
culation. Femoral veins are the next most preferable location as
the infection risk in this location has been shown to be equiva-
lent to the rate of jugular access within the first seven days of use
[23]. Catheters in the left internal jugular vein are associated
with more dysfunction and central venous stenosis in part
because of their increased angulations and vessel wall contact.
Subclavian veins should be considered a rescue option because
of catheter dysfunction and central venous stenosis encountered
with this location. Subclavian venous catheters should be placed
on the patient’s dominant side especially when long-term dialy-
sis is anticipated, in order to preserve the nondominant arm for
future dialysis access creation. A tunneled cuffed dialysis cath-
eter can also be employed for iHD and CRRT. It offers the
advantage of decreased catheter dysfunction and decreased
infections. However the expertise required to place such a cath-
eter precludes its use in most instances requiring acute initiation
of RRT. Tunneled cuffed catheters are typically reserved in
instances where a prolonged duration of dialysis is anticipated
(greater than one week) or recurrent dysfunction of temporary
dialysis catheters is encountered.
When caring for the chronic dialysis patient in the ICU,
iHD can be performed through their existing vascular access,
which will exist in the form of a tunneled cuffed catheter,
arteriovenous fistula (AVF), or arteriovenous graft (AVG).
Limb precautions should be enacted for the limb featuring this
access, which preserves the access from trauma associated with
venipuncture and blood pressure cuff insufflation.
Indications for Dialysis
There are five indications for initiation of emergent dialysis:
hyperkalemia, volume overload, clinical uremic syndrome,
toxic overdoses, and metabolic acidosis. The medical manage-
ment of each has been addressed individually, and the use of
dialysis for each indication is typically reserved for medically
intractable cases.
Chapter 29: Nephrology Consult
Hyperkalemia
Elevation of serum potassium becomes life-threatening via its
impact on nerve conduction, in particular through the myo-
cardium. This manifests as ECG changes with peaked T-waves
being an earlier manifestation, whereas a widened QRS and a
sinusoidal tracing is a later manifestation that will result in
asystole if left untreated.
Volume Overload
The consequences of excess volume is most commonly
observed objectively with regard to respiratory status. In the
nonventilated patient, the resultant pulmonary edema can
manifest as respiratory distress and increasing supplemental
oxygen requirement. In the ventilated patient this may mani-
fest as the necessity to increase positive end expiratory pressure
(PEEP) or fraction of inspired oxygen (FiO2). However, there
is increasing evidence that all organ systems are negatively
impacted by volume overload. Retrospective data suggest that
a fluid accumulation in excess of 10% of the patient’s initial
weight should be a consideration to initiate RRT.
Uremic Syndrome
Uremia is a clinical diagnosis and should be differentiated
from the laboratory finding of azotemia. It should also be
noted that blood urea nitrogen (BUN) levels are poorly pre-
dictive of clinical uremia, and tools to predict GFR in the
setting of AKI are unreliable. Mild uremia may manifest with
nausea, vomiting, anorexia, slowed mentation, and confusion.
Encephalopathy, seizures, and coma can be more severe mani-
festations of the uremic syndrome. These symptoms are all
nonspecific and require exclusion of other causes prior to
initiation of RRT. However, uremic pericarditis, which may
manifest as a pericardial effusion, friction rub, or suggestive
ECG changes, is immediately life-threatening and requires
emergent dialysis.
Toxic Ingestions
Ethylene glycol and methanol poisoning can be managed
acutely with a competitor for the alcohol dehydrogenase
enzyme. However, if the metabolism of the ingested alcohol
has progressed, competitive enzyme inhibition will be inef-
fective and RRT is suggested to reverse the resultant AKI and
metabolic acidosis, as well as potentially prevent irreversible
sequelae of the ingested material and its metabolic products.
Select medications that can reach toxic levels are dialyzable,
the most common of which is lithium. The dialyzability
of individual drugs is quite variable, based on the drug’s
chemical size, ionic charge, and degree of protein binding.
This data are readily available and are published in several
resources.
Metabolic Acidosis
An accumulation of organic acids such as lactate, as well as a
disruption of acid excretion, as in AKI can lead to an overall
excess of hydrogen ions and lead to hemodynamic instability
367
 Chapter 29: Nephrology Consult
of the patient. In cases of severe acidosis with pH <7.1, the
hypotensive patient may be less responsive to positive inotro-
pic agents and refractory hypotension may result. However, it
is unusual to encounter severe metabolic acidosis in the
absence of volume overload or uremia. In the case of isolated
metabolic acidosis, temporary correction of the acidosis by
replacing buffer in the form of bicarbonate is typically
adequate. However, in situations where this correction is
limited by hypernatremia (by use of a hypertonic sodium
bicarbonate solution), then RRT may be indicated. It should
be reinforced that the underlying source of the acid generation
needs to be sought and reversed. As highlighted by the case of
lactic acidosis, this molecule is not removed via dialysis in
meaningful amounts and will be constantly generated until
the cause of tissue hypoperfusion is reversed.
Special Considerations for Renal Failure in the
Neurocritical Care Patient
Intracranial Hypertension
Elevated intracranial pressure (ICP) may be in encountered in
a patient with a space-occupying lesion such as a stroke,
hemorrhage, or diffuse cerebral edema. From this fragile pos-
ition, in a patient who is also in need of RRT, the impact of the
dialysis procedure itself must be considered. Cerebral perfu-
sion pressure (CPP) is the difference between the mean arterial
pressure (MAP) and the ICP. Thus care must be taken to
minimize any changes in MAP and ICP during the dialysis
procedure to minimize fluctuations in CPP. Intermittent
hemodialysis compared to CRRT is associated with greater
fluctuation in MAP due to rapid shifts of solutes and water.
In addition, the rapid clearance of urea and other osmotically
active solutes during iHD is also associated with increased ICP.
This is termed dialysis disequilibrium syndrome and is
believed to be caused by the osmotic movement of water into
brain cells following rapid removal of urea from the serum.
The slower, more gradual removal of solutes and water as is
delivered by CRRT is more effective in minimizing systemic
hypotension and avoiding increases in ICP during the proced-
ure. As such, CRRT is the recommended modality for AKI
patients with acute brain injury, other causes of increased ICP,
or generalized brain edema [24–27]. In the event that CRRT
cannot be delivered, iHD operational parameters can be con-
trolled to minimize shifts. This includes slowing the blood flow
rate, slowing the dialysate rate, using a dialysis filter with a
smaller surface area, and arranging the blood/dialysate circuit
in a concurrent flow configuration.
Sodium Management
During the management of increased ICP during AKI, the
serum sodium level needs close monitoring. The spectrum of
sodium disorders that includes the syndrome of inappropriate
antidiuretic hormone (SIADH) and cerebral salt wasting (CSW)
can both lead to hyponatremia, which may lead to worsening
mental status, seizures, and further contribute to cerebral edema.
368
In the AKI patient not requiring dialysis, traditional manage-
ment strategies should be employed. Fluid restriction is the first-
line treatment for SIADH, a disorder defined by a euvolemic
status, whereas supplemental sodium via tablets or intravenous
saline administration is the appropriate strategy for CSW, a
disorder defined by volume depletion. Other medical therapies
available to achieve a target serum sodium level include fludro-
cortisone (mineralcorticoid) and tolvaptan (vasopressin antagon-
ist). Once again the patient’s fluid status will define the
appropriate strategy, as fludrocortisone will drive sodium and
water retention, while tolvaptan will induce a free water diuresis.
In the AKI patient requiring RRT, sodium management
requires an additional level of tailoring of the dialysis prescription.
This is because the typical serum sodium goal for most patients
undergoing hemodialysis does not exceed 140 mEq/L. However,
the target sodium in a patient with increased ICP or cerebral
edema is higher. In iHD, the dialysate sodium can be adjusted
to a maximum of 155 mEq/L. However, the dialysate sodium does
not dictate the patient’s final serum sodium, so regular monitoring
is necessary. With CRRT, the replacement fluid content must be
adjusted to achieve higher than normal serum sodium levels. Most
commercially prepared replacement fluids are isotonic and their
contents cannot be adjusted by the pharmacy, so custom fluids
must be used. Traditional formulations of saline and additives
(sodium bicarbonate most commonly), are used by the pharmacy
to create hypertonic replacement fluids to help achieve the target
serum sodium. Again, continuous monitoring of serum sodium
remains crucial, as this concentration is influenced by several
operational and patient variables. For either modality, a separate
infusion of hypertonic saline outside of the dialysis circuit may be
used and titrated to achieve the desired serum sodium level.
Coagulopathy
Uremic platelet dysfunction is a clinical manifestation of the
metabolic syndrome. It is not a disorder readily quantifiable
and its likelihood does not correlate with degree of azotemia.
But in the setting of AKI and hemorrhage stroke, the role of
platelet dysfunction is worthy of consideration. If a clinical
suspicion exists that platelet dysfunction is contributing to the
patient’s bleeding risk, then RRT should be delivered. Dialysis
is believed to reverse platelet dysfunction by removal of uremic
toxins and restoration of platelet-endothelial function. Add-
itionally, supportive care with cryoprecipitate, correction of
anemia, and desmopressin (dDAVP) has been demonstrated
to reduce bleeding time in cases of renal failure.
Radiocontrast Imaging
The presence of renal failure during the care of the neurocri-
tical care patient will impact the safety and appropriateness of
central nervous system (CNS) imaging. Iodinated radiocon-
trast as used in computed tomography (CT) imaging and
angiography can cause contrast induced nephropathy (CIN)
in at-risk patients. Chronic kidney disease, diabetes, and
volume contraction are all associated with increased risk of
CIN. There are institutional protocols in place at most health

centers to deliver isotonic saline prior to iodinated contrast
exposure to prevent CIN. There is no benefit of hemodialysis
or hemofiltration in the prevention of CIN. Further exposure
to iodinated contrast during an occurrence of AKI is not
recommended and will prolong renal recovery.
Magnetic resonance imaging (MRI) with gadolinium
should also be avoided in the setting of both acute and chronic
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 Chapter
Management of Hepatic Encephalopathy in the

30 Neurocritical Care Unit

Stephen M. Riordan and Roger Williams

Introduction life-threatening, with risk of intracranial hypertension and

Hepatic encephalopathy (HE) is a complex neuropsychiatric
disorder, manifestations of which range from subtle abnormal-
ities demonstrable only on neuropsychometric testing, such as
mild cognitive impairment, psychomotor slowing, and
impaired bimanual and visuomotor coordination (referred to
as minimal HE or MHE), through to overt manifestations such
as disruption of the sleep cycle, disturbed attention span,
change in personality, confusion, disorientation, and coma.
Aside from the uncommon patient with HE due to a congeni-
tal deficiency of an urea cycle enzyme, in whom liver function
is otherwise normal, HE occurs as a consequence of severe
acute or chronic liver disease or in the setting of porto-
systemic venous shunting, the latter arising either spontan-
eously, usually in the presence of portal venous hypertension
complicating cirrhosis, or iatrogenically, following portal
venous hypertension-decompressive shunt procedures, both
surgical and radiologically placed. Irrespective of the clinical
setting in which it arises, the severity of overt HE is tradition-
ally graded using systems such as the West Haven criteria [1]
(Table 30.1).
HE is the defining feature of the uncommon but devastat-
ing clinical entity of acute liver failure (ALF), in which severe
liver damage occurs in a patient without underlying chronic
liver disease due to etiologies that include, among others,
hepatitis virus infection, and paracetamol and other drug
toxicities. Advanced grades of HE complicating ALF are
Table 30.1 West Haven criteria for grading the severity of hepatic
encephalopathy [1]
Grade Manifestations
1 Trivial lack of awareness; euphoria; anxiety; shortened
attention span; impaired performance in basic
arithmetic
2 Lethargy; apathy; minimal disorientation in time and
space; subtle changes in personality; inappropriate
behavior
3 Somnolence but responsiveness to verbal stimuli;
confusion; gross disorientation; bizarre behavior
4 Coma
cerebral herniation from marked cerebral edema. HE is highly
prevalent in the more frequently encountered chronic liver
disease setting, occurring in up to 80% of patients with cirrho-
sis when those with MHE are included [2]. Overt HE occurring
in patients with cirrhosis is a debilitating disorder that greatly
adversely impacts quality of life and portends an increased
mortality rate. Even those with MHE experience substantial
impairments to their daily functioning, including the ability to
safely drive motor vehicles.
HE is also a common presenting manifestation of the
important clinical entity of acute on chronic liver failure
(ACLF), the precise definition of which is currently the subject
of much debate, but in which an acute decompensation of
hepatic function in a patient with pre-existing, clinically stable
chronic liver disease follows a precipitating insult, often infec-
tion or hepatotoxin-related, and is usually associated with the
induction of a marked inflammatory response. ACLF differs
from decompensated cirrhosis in terms of both its propensity
to rapidly progress to multiorgan failure and its very high 90-
day mortality rate of up to 79% [3].
Pathophysiological Considerations
Increasing experimental and some clinical data indicate
that it is the accumulation of unmetabolised ammonia pro-
duced in the intestine, in concert with inflammation, that
plays a key role in the pathogenesis of HE, consequent
to effects on the astrocyte, astrocyte-neuronal cross-talk,
neuronal transmission, blood–brain barrier permeability,
cerebral blood flow, and cerebral energy production. Mani-
festations and the clinical courses of HE arising in ALF
and ACLF differ from those in cirrhosis and chronic porto-
systemic shunting, likely due to, firstly, differences in the
rapidity and extent of ammonia-generated glutamine and
lactate accumulation within astrocytes, and the extent to
which this can be effectively counterbalanced by regulatory
osmotic processes; secondly, the disparate effects of chronic
as opposed to acute increased ammonia exposure on astro-
cytes, astrocyte-neuronal cross-talk, and neuronal transmis-
sion and, thirdly, the varying degrees of activation of pro-
inflammatory pathways that occur in these various clinical
contexts, as described below.

370
 Chapter 30: Management of Hepatic Encephalopathy

HE in Acute Liver Failure oxidative and nitrosative stress, consequent to the production
of reactive oxygen species and reactive nitrogen species,
In ALF, HE is so characteristically rapid in progression and
respectively [6]. Large quantities of glutamate are subsequently
frequently associated with the development of marked cerebral
released from the astrocyte and activate neuronal glutamate/N-
edema and intracranial hypertension, especially at advanced
methyl-D-aspartate (NMDA) receptors [7], leading to
encephalopathy grades (grades 3 and 4). This cerebral edema,
increased function of the glutamate-nitric oxide (NO)–cyclic
both intracellular (due to osmotic, oxidative, and nitrosative
guanosine monophosphate (cGMP) pathway and excitatory
stress) and extracellular (due to increased blood–brain barrier
neurotransmission that likely accounts for clinical manifest-
permeability, increased cerebral blood flow, and changes in
ations such as agitation and seizures [5]. The latter, especially
cerebral metabolism) in nature but with a substantially pre-
subclinical and detectable only by continuous electroencepha-
dominant intracellular component, and a profound disturb-
lographic monitoring, is common in ALF patients with
ance in astrocyte-neuronal cross-talk ultimately leading to
advanced HE grade and would exacerbate cerebral edema [8].
neuroexcitation are the key pathophysiological processes
Systemic inflammation, as recognized clinically by the sys-
responsible for HE in ALF (Figure 30.1).
temic inflammatory response syndrome (SIRS) [9] (Table 30.2)
Ammonia has long been postulated to be central to the
and resulting from the production of pro-inflammatory cyto-
development of cerebral edema in patients with ALF and
kines consequent to either severe underlying liver injury or
clinical data confirm a significant correlation between arterial
complicating bacterial or fungal infection, occurs commonly
ammonia levels and risk of cerebral herniation in this group
in ALF, and inflammation plays an important role in promot-
[4]. Ammonia is metabolized in astrocytes to glutamine, the
ing the encephalopathic effects of ammonia in this setting.
very rapid accumulation of which to high levels in ALF over-
Blood levels of the pro-inflammatory cytokine, tumour necro-
whelms the compensatory capacity of astrocytes to lose osmo-
sis factor-α (TNF-α), correlate significantly with HE grade in
lytes, such as myoinositol, and results in increased intracellular
ALF [10], while reduced TNF-α production consequent to
osmolarity and cerebral edema due to osmotic stress [5]. The
gene polymorphisms protects against the development of
markedly increased glutamine levels that occur in astrocytes in
severe HE [11]. Findings in rodent models suggest that circu-
ALF cause cytotoxic cerebral edema not only by this osmotic
lating blood levels of TNF-α produced during systemic inflam-
effect, but also via the conversion of glutamine back to ammo-
mation, as occurs clinically as a result of liver injury and
nia and glutamate in mitochondria, and by ammonia-induced
complicating bacterial or fungal infection, activate astrocytes

NEURO-EXCITATORY STATE
NEURON
ACTIVATION OF INCREASED ACTIVITY OF
GLUTAMATE/NMDA GLUTAMATE-NO-cGMP
DECREASED RECEPTORS PATHWAY
CEREBRAL
ENERGY
PRODUCTION RELEASE
OF GLUTAMATE
CIRCULATING PRO-
PRO-INFLAMMATORY INFLAMMATORY
INCREASED BLOOD– ACUTE
LACTATE CYTOKINE CYTOKINES, due to:
BRAIN BARRIER AMMONIA Liver injury
PERMEABILITY PRODUCTION
Bacterial/fungal
infection
INCREASED
CBF ACCUMULATION
OF GLUTAMINE OXIDATIVE/NITROSATIVE
STRESS
Osmotic ACTIVATION OF
regulation BRAIN ENDOTHELIAL
overwhelmed
CELLS
OSMOTIC
STRESS INTRACELLULAR
CEREBRAL EDEMA
+/- INTRACRANIAL HYPER-
EXTRACELLULAR AMMONEMIA
HYPERTENSION
CEREBRAL EDEMA
ASTROCYTE

Figure 30.1 Current concepts of the pathophysiology of hepatic encephalopathy in acute liver failure, demonstrating the key roles of ammonia (yellow arrows) and
inflammation (green arrows). CBF: cerebral blood flow; cGMP: cyclic guanosine monophosphate; NO: nitric oxide. A black and white version of this figure will appear in
some formats. For the color version, please refer to the plate section.

371
 Chapter 30: Management of Hepatic Encephalopathy
Table 30.2 Components of the systemic inflammatory response syndrome
• Temperature >38 °C or <36 °C
• Heart rate >90 beats per minute
• Respiratory rate >20 breaths per minute or PaCO2 <4.3 kPa
• White blood cell count >12  109/L or <4  109/L or >10%
immature neutrophils
SIRS may be infective or non-infective in etiology. The syndrome is defined
by the presence of two or more of these components [9].
to secrete pro-inflammatory interleukin-1 (IL-1) and IL-6 [12].
Pro-inflammatory cytokines produced outside the brain may
also contribute to the pathogenesis of HE, even without direct
cerebral entry, via activation of receptor-mediated signal trans-
duction pathways in cerebral sinusoidal endothelial cells that
result in astrocyte and microglial cell activation and intracer-
ebral pro-inflammatory cytokine production [13].
Hyperammonemia also activates sinusoidal endothelial
cells to result in increased intracerebral pro-inflammatory
cytokine production by activated astrocytes and microglial
cells. Increased brain synthesis of lactate, the cause of which
is incompletely understood, but which may relate at least in
part to ammonia-induced inhibition of α-ketoglutarate dehy-
drogenase and is correlated with elevated intracranial pressure,
likely due to both osmotic effects on the astrocyte and via the
production of extracellular water, also contributes to astrocyte
activation and resultant pro-inflammatory cytokine production
in ALF [14]. Animal models suggest that pro-inflammatory
cytokine production by astrocytes, as well as by microglial cells,
occurs early in the natural history of ALF and increases as HE
severity progresses and cerebral oedema ensues [15].
Pro-inflammatory cytokines produced by activated
astrocyte and microglial cells act in concert with ammonia
to increase oxidative and nitrosative stress in astrocytes, via
increased expression of hemoxygenase-1 and inducible nitric
oxide synthase, respectively [16]. Oxidative stress, so generated,
in turn amplifies the inflammatory response within the brain, as
an additional stimulus for astrocyte and microglial cell activation
and the production by them of pro-inflammatory cytokines [16].
Inflammation has also been implicated in the development of the
increased cerebral blood flow (CBF) that is often evident in ALF
at the time that high-grade HE and cerebral edema develop [17].
Notably, this increased CBF occurs despite markedly reduced
cerebral energy production, the latter attributed to a toxic effect
of ammonia on cellular metabolism [18].
Autoregulation of CBF, by which cerebral perfusion is
maintained as a result of reactive dilatation or constriction of
cerebral resistance vessels in response to changes in systemic
arterial pressure, is often impaired or absent in ALF patents at
that stage [19]. Increased permeability of the blood–brain
barrier has also been demonstrated experimentally in response
to pro-inflammatory cytokines, potentially allowing the free
movement of water and plasma components, such as ammo-
nia, to extracellular areas of the brain [20] and, in turn,
372
allowing increased ammonia diffusion from the extracellular
space into astrocytes, thereby exacerbating the intracellular
accumulation of ammonia and its related effects [21].
HE in Cirrhosis and Chronic Porto-Systemic Shunting
In cirrhosis and chronic porto-systemic shunting (Figure 30.2),
the clinical course of HE is usually less rapidly progressive than
in ALF. Responsible pathogenetic processes for HE differ from
those operative in ALF in three key ways. Firstly, cerebral
edema, although generally present, is typically only low-grade,
not clinically apparent, and predominantly extracellular in
nature (as opposed to the often marked degree of predomin-
antly intracellular cerebral edema that can lead to intracranial
hypertension and cerebral herniation in HE associated with
ALF); secondly, the pattern of neurotransmission is inhibitory
(as opposed to the excitatory neurotransmission that occurs in
HE associated with ALF) and, thirdly, CBF is substantially
reduced, at least in those with overt HE (as opposed to the
typically increased CBF that occurs by the time that advanced
grades of HE ensue in ALF).
As in ALF, important interactions between ammonia and
inflammation in promoting HE have been demonstrated in
cirrhosis and chronic porto-systemic shunting. Significant
deterioration in neuropsychometric test scores in cirrhotic
patients following induced hyperammonemia has been dem-
onstrated in the setting of inflammation related to superim-
posed infection, but not when hyperammonemia was induced
in the noninflammatory state, suggesting that pro-
inflammatory mediators are important in modulating the cere-
bral effects of ammonia in cirrhosis [22]. In addition to release
as a consequence of liver injury and complicating bacterial or
fungal infection, as in ALF, increased circulating pro-
inflammatory cytokines are also produced by a disturbed gut
micobiome in cirrhotic patients, resulting in a systemic inflam-
matory state, even in the absence of infection, as discussed later
[23]. The ability of cirrhotic patients to detoxify ammonia in
alternative sites to the damaged or bypassed liver, such as in
skeletal muscle, is limited by the often marked degree of
muscle wasting associated with protein catabolism that occurs
in chronic liver disease. In addition, enzymatic activity of the
urea cycle in both the liver and skeletal muscle is reduced in
zinc deficiency, which is common in cirrhotic patients, espe-
cially those with an alcohol etiology, further promoting hyper-
ammonemia in this group.
The effects on the astrocyte of a more gradual, chronic
elevation in intracellular ammonia, as occurs in cirrhosis and
chronic porto-systemic shunting, differ in several important
respects from those that occur acutely in ALF. The slower rates
of glutamine accumulation in astrocytes in the former settings
allows for more effective osmotic regulation, achieved by both
the compensatory loss of osmolytes such as myoinositol and
up-regulation of water channels such as aquaporin-4, generally
preventing or at least greatly limiting osmotic stress of astro-
cytes and, hence, intracellular cerebral edema [4,24]. In keep-
ing with this, cerebral edema of sufficient extent to be
 Chapter 30: Management of Hepatic Encephalopathy

NEURO-INHIBITORY STATE
REDUCED SEROTONERGIC TONE NEURON DECREASED
DOWN-REGULATION CEREBRAL ENERGY
REDUCED ACTIVITY OF ENHANCED PRODUCTION AND
(BUT TONIC ACTIVATION)
GLUTAMATE-NO-cGMP GABAergic TONE CBF
OF GLUTAMATE/NMDA
PATHWAY
RECEPTORS
NEUROSTEROID
INACTIVATION OF SYNTHESIS
GLUTAMATE
DECREASED TRANSPORTERS/REDUCED
CEREBRAL UP-REGULATION AND ACTIVATION
ENERGY
GLUTAMATE RELEASE
OF PERIPHERAL-TYPE CIRCULATING PRO-
PRODUCTION BENZODIAZEPINE RECEPTORS INFLAMMATORY
AND CBF CYTOKINES, due to:
Liver injury
CHRONIC LACTATE PRO-INFLAMMATORY Bacterial/fungal
INCREASED BLOOD– AMMONIA CYTOKINE infecon
BRAIN BARRIER Disturbed gut
PRODUCTION microbiome
PERMEABILITY
ACCUMULATION
OF GLUTAMINE
Osmoc
regulaon OXIDATIVE/NITROSATIVE ACTIVATION OF
effecve STRESS BRAIN ENDOTHELIAL
OSMOTIC STRESS CELLS
LIMITED INTRACELLULAR
EXTRACELLULAR Compensatory osmolyte shi
CEREBRAL EDEMA
Up-regulaon of aquaporin-4
CEREBRAL EDEMA HYPER-
(typically only minor if
AMMONEMIA
(typically low grade) ASTROCYTE detectable at all)
Figure 30.2 Current concepts of the pathophysiology of hepatic encephalopathy in cirrhosis and chronic porto-systemic shunting, demonstrating the key roles of
ammonia (yellow arrows) and inflammation (green arrows), but highlighting some important differences in end-effects compared to those in acute liver failure. CBF:
cerebral blood flow; cGMP: cyclic guanosine monophosphate; GABA: γ-amino-butyric acid; NO: nitric oxide. A black and white version of this figure will appear in some
formats. For the color version, please refer to the plate section.

detectable by computed tomography (CT) is generally not
apparent in encephalopathic cirrhotic patients, even those in
grade 3 or 4 HE [25]. Nonetheless, sensitive imaging modal-
ities, such as diffusion tensor magnetic resonance imaging
(MRI), demonstrate that cerebral edema, predominantly extra-
cellular in nature and typically only low-grade, does occur in
cirrhotic patients, even those with MHE [26]. Recent findings
in an animal model suggest that increased brain lactate pro-
duced from ammonia is more important than ammonia-
derived glutamine in the pathogenesis of the cerebral edema
that occurs in cirrhosis [27]. As well as extracellular water
produced in association with lactate synthesis and as a result
of pro-inflammatory cytokine-induced increased blood–
brain barrier permeability, as in the ALF setting, the compen-
satory mechanisms that are so critical in limiting osmotic
stress on astrocytes, namely counter-regulatory osmolyte
shift and up-regulation of water channels, likely contribute
to the development of the extracellular cerebral edema of
cirrhosis [28]. Astrocytes develop a type II Alzheimer morph-
ology when chronically exposed to increased ammonia and
this disturbance may contribute to increased blood–brain
barrier permeability, since astrocytes are a critical component
of the blood–brain barrier. Nonetheless, recent data suggest
that low-grade cerebral edema is unlikely the predominant
mechanism for HE in cirrhosis and chronic porto-systemic
shunting [29].
Disturbed neurotransmission resulting in neuroinhibition
has been described, induced by a combination of ammonia-
and pro-inflammatory cytokine-mediated steps impacting
astrocyte-neuronal cross-talk and neuronal transmission. Pro-
longed exposure of astrocytes to increased ammonia levels
leads, firstly, to inactivation of cell membrane glutamate trans-
porters, resulting in decreased glutamate release, and, sec-
ondly, to down-regulation of expression (but increased tonic
activation) of neuronal glutamate/NMDA receptor expression,
reducing the function of the glutamate-NO-cGMP pathway
and promoting a neuroinhibitory state [30]. Ammonia-
induced reduction in excitatory serotonergic neurotransmis-
sion has also been demonstrated, consequent to activation of
histamine 3 receptors and an increased serotonin turnover rate
[31]. At the same time, inhibitory γ-aminobutyric acid
(GABA)ergic tone is enhanced, consequent to up-regulation
and activation of peripheral-type benzodiazepine receptors in
astrocytes by inflammation [5] and ammonia [32], respect-
ively, leading to increased astrocyte synthesis of neurosteroids
that are positive allosteric modulators of the GABAA receptor
[5]. Binding of increased gut-derived GABA to GABA recep-
tors also contributes to the increased GABAergic tone [31].
Manganese, levels of which in the globus pallidus and putamen
are suggested by hyperintensity on T1-weighted MRI to be
increased in patients with HE complicating cirrhosis and
porto-systemic shunting, also promotes increased GABAergic

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 Chapter 30: Management of Hepatic Encephalopathy
tone by activating the peripheral-type benzodiazepine receptor
pathway [32], although no direct correlation between HE grade
and degree of pallidal hyperintensity has been demonstrated [22].
CBF is substantially reduced in cirrhotic patients with clinic-
ally overt HE, but not in cirrhotic patients with MHE or cirrhotic
patients without HE, compared to healthy subjects [33]. This
reduced CBF is coupled to, and presumably the consequence
of, reduced cerebral energy production, with both phenomena
significantly correlated with increased blood ammonia levels
[34]. Although the exact mechanisms are currently uncertain,
increased ammonia-mediated GABAergic tone, leading to inhib-
ition of neuronal activity, and ammonia-induced inhibition of
cellular metabolism have been postulated to be important [34].
Other mechanisms for the pathogenesis of HE in cirrhosis
have been proposed. Of these, the false neurotransmitter con-
cept holds that increased aromatic amino acid levels promote
increased octopamine production at the expense of dopamine
and noradrenaline [35]. Findings that the branched chain
amino acid/aromatic amino acid ratio in peripheral blood does
not correlate with HE grade, intraventricular administration of
even large amounts of octopamine does not reliably induce
coma, and low brain concentrations of dopamine and nor-
adrenaline are not necessarily associated with coma argue
against this mechanism being solely responsible for HE patho-
genesis [36]. Nonetheless, disturbances in noradrenaline- and
dopamine-related neurotransmission may contribute to
depressive/anxiety episodes and motor disturbances of HE,
respectively [31], and this false neurotransmitter concept
underlies the rationale for treatment with branched chain
amino acid solutions, as discussed below.
HE in Acute on Chronic Liver Failure
HE in ACLF can be rapidly progressive. Clinical data suggest
that both intracellular and extracellular mechanisms of cere-
bral edema are operative, with the superimposed acute insult,
often inflammatory in nature, responsible for both compon-
ents. As in HE associated with cirrhosis and chronic porto-
systemic shunting, extracellular cerebral oedema predominates
[37]. Similar findings were apparent in an animal model of
ACLF, in which superimposed endotoxin administration on a
background of cirrhosis was required for cerebral edema to
become apparent. A two-phase explanation for the occurrence
of both intracellular and extracellular cerebral edema in ACLF
has been proposed, in which an initial intracellular component
due to sudden and rapid accumulation of ammonia-derived
glutamine is followed by an increase in blood–brain barrier
permeability mediated by pro-inflammatory cytokines that pro-
motes increased extracellular water [28]. Nonetheless, cerebral
edema generally develops to a lesser extent in ACLF than in ALF
[38] and a recent analysis found cerebral edema of sufficient
extent to be detectable by CT in only 4% of ACLF patients with
grade 3 or 4 HE, although this was invariably fatal when present
[25]. Taken together, these findings suggest that other ammo-
nia- and inflammation-induced processes, such as reduction in
374
cerebral energy production and disturbed neuronal transmis-
sion [38], are likely more important than cerebral edema in the
pathogenesis of HE in ACLF in most patients. Circulatory
failure, due at least in part to hypoalbuminemia, may contribute
to the pathogenesis of HE in ACLF [38], while a disturbed
antioxidant function of albumin has also been found in ACLF
[39] and may also be relevant to HE pathogenesis.
Diagnosis
HE is a clinical diagnosis. Nonetheless, none of the clinical
manifestations of HE are specific for this disorder and it is
essential to exclude alternative diagnoses by appropriate clinical
assessment and further investigations, including cerebral
imaging, electroencephalography, and various laboratory
indices (Figure 30.3). The presence of a “flapping tremor”
(asterixis) is often a very striking clinical finding at a relatively
early stage (grade 2), on which a diagnosis of HE can be firmly
made, provided that other metabolic causes are excluded [36].
Unlike in the ALF setting, the blood ammonia level is of rela-
tively little clinical value for establishing the diagnosis of HE in
cirrhosis or chronic porto-systemic shunting, as levels do not
reliably correlate with HE grade [36]. Practical bedside tests
such as the number connection and other trail-making tests
are easily administered and generally provide useful information
in patients with low-grade HE who are able to cooperate. The
“Psychometric HE Score,” derived from the results of “paper
and pencil” neuropsychometric tests designed to diagnose subtle
cognitive changes, but which must be adjusted for age and
educational level, was endorsed as the “gold standard” test for
MHE by the working party at the 1998 World Congresses of
Gastroenterology [40]. Computerised psychometric tests such as
the “inhibitory control test” and neurophysiological tests such as
the critical flicker frequency and various evoked potentials are
alternatively widely used to diagnose MHE [5].
Approach to Management
Effective treatment of HE is focused on reversing hyperammo-
nemia and neuro-inflammation, while adopting measures to
reverse or at least limit the degree of underlying liver damage,
manage complicating cerebral edema and, in the settings of
cirrhosis and ACLF, identify and correct precipitants. The man-
agement of HE complicating ALF and ACLF must be con-
sidered separately from that occurring in other clinical
contexts, given the differing clinical courses of HE, as well as
rates of progression of underlying liver injury and risk of failure
of other organ systems, in these distinct clinical contexts.
Nonetheless, in each of these settings, careful assessment
for SIRS and an high index of suspicion for complicating
bacterial or fungal infection must be maintained. Some centers
favor the implementation of prophylactic broad-spectrum
antibiotics while awaiting results of a septic screen. There
may be a particular role for ciprofloxacin in such antibiotic
protocols on the basis of its anti-GABAergic properties [41].
Enteral nutrition is preferable to the parenteral route in order

TOXIC
- Alcohol intoxication
- Alcohol withdrawal
- Psychoactive drugs
- Salicylates
- Heavy metals
- Wernicke–Korsakoff syndrome
METABOLIC
- Electrolyte imbalance
- Hypoxia ENCEPHALOPATHY
- Carbon dioxide narcosis
- Hypoglycemia
- Uremia
- Ketoacidosis
HEPATIC
Figure 30.3 Differential diagnosis of hepatic encephalopathy.
to limit the likelihood of septic complications. Nonsteroidal
anti-inflammatory drug therapy to limit neuro-inflammation
has been proposed based on results of experimental studies
[42], but such agents can have a catastrophic effect on renal
perfusion and precipitate renal failure in both liver failure
patients and even those with well-compensated cirrhosis,
and, in our view, should be avoided. A potential role for N-
acteylcysteine in limiting or reversing oxidative stress in astro-
cytes and attenuating neuroinflammation has also recently
been proposed, given both its anti-oxidant and anti-
inflammatory properties and proven ability to cross the
blood–brain barrier [15]. Hyponatremia should be appropri-
ately corrected in view of its potential to exacerbate cerebral
edema due to osmotic stress.
HE in Acute Liver Failure
Along with the institution of specific therapies to limit the
degree of liver damage in those with treatable etiologies, consid-
eration for emergency liver transplantation based on prognostic
criteria [43] and careful assessment for and effective manage-
ment of cerebral edema are of paramount importance in the
encephalopathic ALF patient (Figure 30.4). Potential transplant
candidates should be urgently transferred to a liver transplant
unit at an early HE stage, ideally before cerebral edema has
developed and definitely before intracranial hypertension has
complicated the clinical course. Such transfer requires expert
management to minimize risk of cerebral herniation.
Neurologic support of the ALF patient in grade 3 or 4 HE is
aimed at preventing or treating cerebral edema and optimizing
cerebral perfusion. Patients should be nursed in the 20–30°
Chapter 30: Management of Hepatic Encephalopathy
INTRACRANIAL PATHOLOGY
- Hemorrhage
- Infarction
- Tumor
- Abscess
- Meningitis
- Encephalitis
- Epilepsy/postseizure encephalopathy
NEUROPSYCHIATRIC
- Organic brain syndromes
head-up position. Elective mechanical ventilation, with sed-
ation and paralysis using agents such as propofol and atracur-
ium, along with minimization of endotracheal suctioning,
patient turning and other tactile stimulation, prevent surges
in intracranial pressure, which may provoke or exacerbate
cerebral edema. Extradural pressure monitoring, with suffi-
cient clotting factor support to achieve an international nor-
malised ratio 2 and platelet transfusions to achieve a count
50 109/L at the time of insertion of the transducer, is of
value in guiding further therapy in ventilated ALF patients
with grade 3 or 4 HE. Such monitoring does carry some risk
of hemorrhage at the time of insertion of the transducer or
later, while the transducer should be removed no longer than
five days after insertion in view of the risk of infection. A fall in
cerebral perfusion pressure, the difference between mean arter-
ial pressure and intracranial pressure, to <50 mmHg due to
arterial hypotension in ALF should be managed with vasopres-
sor agents, provided intravascular volume status is adequate.
Conversely, when cerebral perfusion pressure is reduced as a
consequence of an increase in intracranial pressure, or when
the latter exceeds 25 mmHg, bolus intravenous injection of
mannitol (0.5g/kg body weight) is first-line treatment [44].
Renal replacement therapy, aiming to remove two to three
times the volume of infused mannitol and using continuous
veno-venous hemodiafiltration rather than intermittent hemo-
dialysis in order to reduce the likelihood of systemic arterial
hypotension that might result in a fall in cerebral perfusion
pressure [45], is required in patients in oliguric renal failure.
Repeated doses may be given as necessary, provided that the
plasma osmolarity does not exceed 320 mOsmol/L.
375
 Chapter 30: Management of Hepatic Encephalopathy
CONSIDERATION OF EMERGENCY
LIVER TRANSPLANTATION ACCORDING
TO PROGNOSTIC KING’S COLLEGE CRITERIA (43)
Aetiology Criteria
Paracetamol Arterial pH <7.3, irrespective of HE grade
OR
Prothrombin time >100 s + serum creatinine
>300 mmol/L in patients in grade 3 or 4 HE
Non-paracetamol Prothrombin time >100 s, irrespective of HE grade
Any three of the following, irrespective of HE grade
Non-A, non-B hepatitis or drug effect
Age <10 y or >40 y
Jaundice to HE interval >7 d
Prothrombin time >50 s
Serum bilirubin > 300 mmol/L
INSTITUTION OF SPECIFIC THERAPIES FOR TREATABLE
AETIOLOGIES OF ALF
Aetiology Intervention
Paracetamol N-acetylcysteine
Hepatitis B virus Entecavir, tenofovir
Herpes simplex virus Acyclovir
Autoimmune Corticosteroids
Budd–Chiari syndrome Thrombolysis; decompressive therapies
Lymphoma Chemotherapy
Pregnancy-associated Delivery
Figure 30.4 Schematic approach to the management of hepatic encephalopathy in acute liver failure.
Thiopentone may be beneficial in cases of otherwise intractable
cerebral edema, although may result in further hemodynamic
instability. Hyperventilation to reduce cerebral blood flow is
appropriate in the subgroup with cerebral hyperaemia, as
reflected by an increased reverse jugular venous oxygen satur-
ation (>75%). Prophylactic phenytoin has been found to
reduce the incidence of subclinical epilepsy and associated
cerebral edema [8]. The simple procedure of induction of
moderate hypothermia (32–33 oC) is beneficial in ALF patients
with otherwise uncontrolled increases in intracranial pressure
[46], while artificial liver support using plasmapheresis with
plasma exchange and extracorporeal albumin dialysis with the
molecular adsorbent recirculating system (MARS) may also
have roles in reducing cerebral edema in this group [47,48].
Notably, a recent report highlights that the prevalence of
intracranial hypertension complicating ALF at admission to a
large dedicated liver intensive care unit has fallen significantly
from 76% during the period from 1984 to 1988 to 20% during
the period from 2004 to 2008, while the mortality rate in those
with intracranial hypertension also was reduced significantly
from 95% to 55% during this time, likely consequent to earlier
disease recognition, improvements in modern liver intensive
care, better control of infection, and use of emergency liver
transplantation [49].
HE in Cirrhosis
Most episodes of HE complicating cirrhosis (Figure 30.5) are
secondary to a clinically apparent precipitating event that
requires appropriate additional treatment. Several factors
376
MONITORING OF INTRACRANIAL
PRESSURE AND STRATEGIES TO PREVENT
OR REVERSE CEREBRAL EDEMA IN
PATIENTS IN GRADE 3 OR 4 HE
- See text
MANAGEMENT OF
HE IN ALF
STRATEGIES TO PREVENT OR REVERSE
NEUROINFLAMMATION
- High index of suspicion for and aggressive
treatment of complicating bacterial or
fungal infection
- ? Prophylactic, broad-spectrum antibiotics
- ? N-acetylcysteine
may be operative in a given patient at the same time. For
example, spontaneous bacterial peritonitis or septicemia, typ-
ically with bacterial species translocated from the intestine,
ensue in a substantial proportion of cirrhotic patients with
advanced decompensation of hepatic function following gas-
trointestinal haemorrhage. Systemic alkalosis and hypokalemia
complicating treatment of ascites with diuretics lead to
increased diffusion of ammonia across the blood–brain barrier
and increased renal ammoniagenesis, respectively [36]. Every
effort should be made to identify and correct the precipitating
factor for HE in those with cirrhosis. The medical manage-
ment of HE complicating cirrhosis is set out below. Most
manifestations of overt HE complicating cirrhosis improve
with medical treatment, although refractory overt and debili-
tating syndromes such as dementia, spastic paraparesis, cere-
bellar degeneration, and extrapyramidal movement disorders
are well recognised. The latter may gradually improve
following successful liver transplantation. MHE, manifest as
persistent and cumulative deficits in working memory,
response inhibition, and learning, commonly persists in cir-
rhotic patients after resolution of overt HE and requires
ongoing medical therapy [50].
Reduction of Intestinal Production and Systemic Absorption
of Ammonia
Ammonia is produced in the intestine from dietary and
endogenous protein substrates by both bacterial metabolism
in the intestinal lumen and glutaminase activity in enterocytes.
Intestinal ammonia production can be reduced by restricting

CORRECTION OF PRECIPITATING FACTORS
- Gastrointestinal hemorrhage
- Infection
- Excess dietary protein
- Constipation
- Uremia
- Hypokalemia
- Hyponatremia
- Systemic alkalosis
- Dehydration
- Use of benzodiazepines
- Porto-systemic shunting
- Progressive liver damage
- Development of hepatocellular carcinoma
ANTI-AMMONIA STRATEGIES
Reduce Both Intestinal Production and Systemic Absorption
- Non-absorbable disaccharides (lactulose, lactitol)
- Probiotics, synbiotics
Reduce Intestinal Production but not Systemic Absorption
- Prevention of excessive dietary protein intake
- Rifaximin
Increase Systemic Metabolism
- L-ornithine-L-aspartate
- Sodium benzoate
- Zinc
- ? Glycerol phenylbutyrate
Figure 30.5 Schematic approach to the management of hepatic encephalopathy in cirrhosis.
dietary protein intake and inhibiting ammoniagenic colonic
bacteria, while systemic absorption of ammonia produced in
the intestine is reduced by acidifying the intestinal lumen.
Although dietary protein restriction is an effective form of
treatment, protein energy malnutrition is often already present
in cirrhotic patients and associated with an increased preva-
lence of complications and mortality rate. Cirrhotics require
daily protein intakes of 1.2–1.5 g/kg body weight to maintain
nitrogen balance and long-term restriction to below this range
should be avoided. Supplementation with vegetable, rather
than animal, source protein may be advantageous in patients
whose total daily dietary protein tolerance is <1 g/kg body
weight, since a significant improvement in nitrogen balance
may be achieved without precipitating or worsening hepatic
encephalopathy, possibly due to the increased fibre content of
vegetable protein [51].
The physiologic shedding of gut epithelial cells provides
additional luminal protein for metabolism to ammonia. Both
dietary and endogenous ammoniagenic substrates are removed
from the intestinal lumen by the osmotic cathartic action of
non-absorbable disaccharides. In addition to the cathartic
effect, the lowered colonic pH due to production of acetic
and lactic acids by bacterial fermentation is both hostile to
the survival of urease-producing intestinal bacteria and
reduces ammonia absorption by nonionic diffusion. Nonab-
sorbable disaccharides are considered first-line therapy for
reducing the intestinal production and systemic absorption
Chapter 30: Management of Hepatic Encephalopathy
LIVER TRANSPLANTATION
- Failed medical therapy
- Particular role in HE occurring in
association with other manifestations of
severe hepatic functional decompensation
REDUCTION IN FALSE
NEUROTRANSMITTERS
- Oral branched chain amino acids
MANAGEMENT OF INHIBITION OF
HE IN CIRRHOSIS BENZODIAZEPINE RECEPTORS
- Flumazenil
STRATEGIES TO PREVENT OR REVERSE
NEUROINFLAMMATION
- High index of suspicion for and aggressive
treatment of complicating bacterial or
fungal infection
- ? Prophylactic, broad-spectrum antibiotics
- Reduction in systemic inflammation related
to disturbed gut microbiome
- Lactulose, rifaximin, probiotics, ?synbiotics
- ? N-acetylcysteine
of ammonia in cirrhotic patients with overt HE and lactulose
(galactosidofructose) is the most commonly used of these [36].
The daily dose of lactulose should be titrated to result in two to
four soft, acidic stools (pH <6) daily and ranges from 30–60 g
in most patients. Meta-analyses suggest that oral lactitol (galac-
tosidosorbitol) at a dose of 30–45 g daily is as effective as
lactulose for treating overt HE in cirrhosis and has the advan-
tage of being more palatable, aiding compliance [52]. Disac-
charide enemas can be used if oral or nasogastric
administration is impossible [53]. A meta-analysis of 22 pub-
lished clinical trials indicated that, compared to placebo or no
intervention, treatment of cirrhotic patients with overt HE
with oral lactulose or lactitol significantly reduced the likeli-
hood of no improvement (relative risk 0.62; 95% confidence
interval 0.46 to 0.84) [54]. Predictors of nonresponse to lactu-
lose therapy include more advanced degrees of hepatic func-
tional decompensation (as reflected by the Model for End-
Stage Liver Disease Score), additional hyponatremia, high
white cell count, low mean arterial blood pressure, and pres-
ence of hepatocellular carcinoma [55]. Recent guidelines also
suggest lactulose as first-line therapy for MHE [56]. In a recent
meta-analysis comparing lactulose with placebo or no inter-
vention, the likelihood of no improvement in neuropsychiatric
test scores (relative risk 0.52; 95% confidence interval 0.44 to
0.62) was significantly reduced by lactulose therapy [57]. How-
ever, as with overt HE, not all patients with MHE treated with
lactulose improve, with hyponatraemia along with higher
377
 Chapter 30: Management of Hepatic Encephalopathy
venous ammonia levels in excess of 93.5 μmol/L shown to be
predictive of nonresponse [58].
Antibiotics with activity against colonic bacteria, such as
neomycin, metronidazole, vancomycin, and rifaximin, also
reduce intestinal ammonia production and have proven value
in the treatment of overt HE in cirrhosis [36]. Adverse effects
of neomycin (ototoxicity and renal toxicity), metronidazole
(peripheral neuropathy), and vancomycin (emergence of
resistant enterococcus strains) limit their clinical applicability.
Rifaximin is a poorly absorbed, broad-spectrum, well-tolerated
antimicrobial agent with low risk of inducing bacterial resist-
ance. Meta-analyses indicate that the efficacy of rifaximin for
treating overt HE in cirrhosis is comparable to that of non-
absorbable disaccharides [59,60]. A recent randomized,
double-blind, controlled trial suggests that the combination
of rifaximin and lactulose is more effective than lactulose alone
in cirrhotic patients with overt HE [61]. Rifaximin is also of
proven value for the management of MHE in cirrhosis, with
significant improvements demonstrated in cognition, health-
related quality of life, and simulated driving performance
[62,63].
The idea of populating the colonic lumen with urease-
negative, probiotic bacteria as a possible treatment for HE
complicating cirrhosis was first suggested over 40 years ago.
Recent meta-analyses indicate significant improvement in
MHE with both probiotic and synbiotic (probiotic plus fer-
mentable fiber) treatment, with relative risks of no improve-
ment of 0.41 (95% confidence interval 0.26 to 0.65) and 0.51
(95% confidence interval 0.32 to 0.80), respectively. Probiotic
and synbiotic treatments were better tolerated than lactulose
[64].
Increased Systemic Metabolism of Ammonia
Ornithine and aspartate are important substrates involved in
the systemic metabolism of ammonia to urea and glutamine,
respectively. L-ornithine-L-aspartate thus provides substrates
for each of these ammonia detoxification pathways. Recent
meta-analyses have confirmed significant beneficial effects of
treatment compared to placebo or no intervention in cirrhotic
patients with both overt HE and MHE (relative risk for
improvement 1.32, 95% confidence interval 1.04 to 1.69 for
overt HE; relative risk for improvement 2.25; 95% confidence
interval 1.33 to 3.82 for MHE). The efficacy of L-ornithine-L-
aspartate therapy was comparable to that of lactulose [65].
Treatment with sodium benzoate, which reduces systemic
ammonia levels by the formation of hippurate, is also of
proven value [66]. Whether there is benefit in combining these
strategies to increase the systemic metabolism of ammonia
with therapies that reduce ammonia production, such as non-
absorbable disaccharides and/or rifaximin, remains to be
properly assessed. A controlled trial of oral zinc supplemen-
tation in addition to other therapies, including lactulose, found
significant improvement in psychometric test scores in the
group receiving zinc [67]. A recent randomized, double-blind,
placebo-controlled study of glycerol phenylbutyrate, which
378
acts by promoting ammonia removal via the kidney in the
form of urinary phenylacetylglutamine, has demonstrated a
significantly beneficial effect in preventing recurrent episodes
of overt HE in patients with cirrhosis [68]. Its possible role in
the management of acute HE episodes remains to be assessed.
Inhibition of Benzodiazepine Receptors
Controlled trials of the efficacy of treatment with the benzodi-
azepine receptor antagonist, flumazenil, have been performed
in only small numbers of cirrhotic patients with HE, demon-
strating typically incomplete improvement in HE grade in
some [36]. Whether efficacy is improved in those patients with
more marked neuroinflammation has not been specifically
assessed, but may be a relevant consideration given the role
of inflammation in up-regulating the expression of benzodi-
azepine receptors in the brain [5].
Reduction of False Neurotransmitter Levels
A recent meta-analysis indicated a beneficial effect of oral, but
not intravenous, branched chain amino acid formulas in cir-
rhotic patients with recurrent HE (relative risk for benefit 1.44;
95% confidence interval 1.07 to 1.94) [69]. Branched chain
amino acid therapy does have a specific role in improving
nitrogen balance without precipitating HE in malnourished
cirrhotic subjects otherwise intolerant of protein supplementa-
tion. Controlled trials have failed to demonstrate any beneficial
effect of treatment with either L-dopa or bromocriptine [36].
HE in Chronic Portal-Systemic Shunting
HE complicating spontaneous or surgically created portal-
systemic anastomoses or transjugular intrahepatic portal-systemic
shunt (TIPSS) procedures is usually successfully managed as in
cirrhosis, as discussed above. Transhepatic embolization or surgi-
cal ligation of portal-systemic shunts is occasionally of benefit in
such patients when HE is refractory to other modalities, provided
hepatic functional reserve is satisfactory [70]. Refractory HE
complicating TIPSS may be successfully managed by the implant-
ation of a reducing stent, especially in patients in whom hepatic
function is well maintained [71].
HE in Acute on Chronic Liver Failure (ACLF)
Reversal of the precipitating factor and support of all failing
organ systems are crucial to the management of patients with
HE complicating ACLF. The use of liver transplantation is
hampered by the high frequency of concomitant conditions
that contraindicate the procedure, such as unresolved infection
and circulatory failure. Given the low incidence of intracranial
hypertension recently demonstrated in patients with even
advanced HE grades in this syndrome [25], invasive intracra-
nial pressure monitoring is generally not required. The med-
ical management of HE in ACLF currently relies on those
measures outlined above for patients with overt HE compli-
cating cirrhosis, such as nonabsorbed disaccharides and rifax-
imin, although efficacies have not been assessed in clinical
 Chapter 30: Management of Hepatic Encephalopathy

trials specific to this syndrome. In addition, it is uncertain if
rifaximin would be of any additional value in those patients
already receiving broad-spectrum parenteral antibiotics for
precipitating infection.
Much recent interest has centered on the possible role of
extracorporeal albumin dialysis using the molecular adsorbent
recirculating system (MARS) to improve HE refractory to
medical treatments in ACLF. Two multicenter, randomized,
controlled trials of MARS therapy have been performed in
ACLF patients with HE [72,73]. In the first of these, conducted
in 70 cirrhotic patients in grade 3 or 4 HE, most with ACLF,
significantly more frequent improvement and faster reduction
in HE grade were apparent in patients managed with MARS
and standard medical treatment compared to patients man-
aged with standard medical treatment alone [72]. In a subse-
quent, larger analysis of 189 patients with ACLF, the
combination of MARS and standard medical treatment was
also associated with more frequent improvement in HE grade
from 2–4 to 0–1, than in patients managed with standard
medical treatment alone (62.5% versus 38.2%), although this
difference did not reach statistical significance (P = 0.07) [73].
Therapeutic Implications of the Emerging
Concept of a Disturbed Gut Microbiome as a
Contributor to Ammonia-Modulating Systemic
Inflammation in Cirrhosis
Disturbances in the colonic mucosal microbiome have been
demonstrated in cirrhotic patients with an history of HE
compared to cirrhotic patients with no prior history of HE.
In those with a history of HE, significantly lower levels of
Roseburia species and increased abundance of Enterococcus,
Veillonella, Megasphaera, and Burkholderia are evident.
Genera overexpressed in the colonic mucosa in the HE group
were found on network analysis to be significantly associated
with both poor cognition and systemic inflammation, as
reflected by serum levels of pro-inflammatory cytokines [74].
Taken together, the findings suggest that a disturbed gut
microbiome in cirrhotic patients with a history of HE, detected
at the colonic mucosal level, may contribute significantly to
systemic inflammation, which, in turn, adversely affects cogni-
tion. Furthermore, the findings provide rationale to investigate
the use of gut-flora-altering therapies in the treatment of
cirrhotic patients with HE as potential modulators of systemic
inflammation, beyond their conventional role in reducing the
intestinal production of ammonia.
To date, assessment of this new therapeutic concept has
been conducted in two analyses of cirrhotic patients with
MHE. In one of these, treatment with lactulose led to a signifi-
cant reduction in systemic levels of the pro-inflammatory
cytokines, TNF-α, IL-6 and IL-18 that correlated significantly
with improvement in psychometric test scores [75]. Lactulose
withdrawal is accompanied by only minor change in the gut
microbiome [23], suggesting that modulation of gut microbial
function rather than microbial composition may be respon-
sible for the anti-inflammatory effects of lactulose in cirrhotic
patients with MHE. In another study conducted in this group,
treatment with rifaximin that led to significant improvement
in driving simulator performance was found to be associated
with a significant reduction in serum levels of the anti-
inflammatory cytokine, IL-10 [62]. A significant reduction in
serum levels of pro-inflammatory IL-6 occurring in association
with a significantly reduced need for hospitalisation for HE has
also been demonstrated in cirrhotic patients receiving a pro-
biotic formulation in a secondary prophylaxis study [76].
Further delineation of the anti-inflammatory effects of gut-
flora-altering therapies, along with their full impact on HE
management in various clinical contexts, are awaited.

risk factors for encephalopathy acute liver failure; a controlled clinical

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381
 Chapter
Hypoxic Encephalopathy in the Neurocritical Care Unit
31 Maximilian Mulder and Romergryko G. Geocadin
The term hypoxic encephalopathy (HE) refers to a syndrome
of global brain injury resulting from critical reduction or loss
of blood flow and supply of oxygen and nutrients to the brain.
Synonyms used to describe this clinical entity include hypoxic-
ischemic or anoxic encephalopathy and postcardiac-arrest
brain injury, among others. Most cases of HE can be attributed
to complications during the perinatal period in children, and
in adults HE mostly results from cardiac arrest or asphyxia,
with approximately half a million cases per year of HE in the
United States [1]. Hypoxic encephalopathy is one of the most
important and devastating clinical manifestations of the
postcardiac-arrest syndrome (PCAS) characterized mainly by
postcardiac-arrest brain injury, myocardial dysfunction, and a
systemic ischemia-reperfusion response [2]. This chapter will
cover the initial postresuscitation care, therapeutic hypother-
mia, and critical care management, as well as prognostication
of neurologic outcomes of hypoxic encephalopathy in adults.
Pathophysiology
The different conditions and situations that may cause HE
share a common pathophysiologic mechanism where global
brain injury results from a critical reduction in oxygen supply.
This decrease in metabolic substrate sets in motion a chain
reaction of harmful biochemical reactions that result in an
immediate primary brain injury. Secondary brain injury is a
delayed phenomenon, and is mediated by reperfusion injury/
reflow phenomena, and results and manifests with cerebral
edema, elevated intracranial pressure, nonconvulsive seizures,
and blood–brain barrier disruption, all of which may
Table 31.1 The postcardiac-arrest syndrome (PCAS)
• Postcardiac-arrest brain injury
• Postcardiac-arrest myocardial dysfunction
• Systemic ischemia/reperfusion response
: Acute kidney injury
: Ischemic hepatitis
: Systemic inflammatory response syndrome (SIRS)
: Acute respiratory distress syndrome (ARDS)
: Adrenal suppression
: Hypercoagulability
382
ultimately result in additional focal cerebral infarction and
occasionally brain death. Primary brain injury in HE is char-
acterized by the following cellular processes:
• Global cerebral hypoxia leads to cellular oxygen starvation
with a subsequent decrease of adenosine triphosphate
(ATP) production resulting in cellular energy starvation
• This results in uncontrolled glutamate release, which leads
to N-methyl-D-aspartate (NMDA) receptor-induced
excitotoxicity. Glutamate–NMDA- mediated excitotoxicity
results in intracellular calcium influx that activates a
number of secondary messengers that amplify cellular
injury and lead to a vicious cycle of calcium glutamate
excitotoxic damage
• There is a concomitant decrease in inhibitory
neurotransmitters that normally counter glutamate
excitotoxicity such as γ-aminobutyric acid (GABA) and
glycine
• Intracellular calcium overload rapidly activates neuronal
nitric oxide synthase with production of oxygen free
radicals that compound cellular injury by direct DNA
fragmentation, protein and lipid oxidation, and disruption
of the mitochondrial respiratory chain
• Oxidative stress results in complement activation, cytokine
production (interleukin-1 (IL-1), IL-6, IL-8 and tissue
necrosis factor-α (TNF-α)), and microvascular
dysfunction.
Cytotoxic edema occurs after excitotoxic injury and ionic pump
failure, as well as cellular water shift across cell membranes with
impaired aquaporin function. Matrix metalloprotease dysfunc-
tion is mainly responsible for disruptions in blood–brain barrier
integrity. Additional oxidative DNA damage incurred during
reperfusion following ischemia, induces both necrotic and
apoptotic processes in the brain at the cellular level.
Clinical Features and Diagnosis
The diagnosis of hypoxic encephalopathy is made on clinical
grounds, and is to be suspected when the patient is “found
down” and unresponsive. Evidence of cardiac arrest, asphyxia,
drowning, hanging, or carbon monoxide poisoning should be
sought at the scene and conveyed to the receiving physicians.
The neurologic clinical manifestations of HE, as well as their

frequency, are closely related to the structures that are most
commonly and readily injured. Disorders of consciousness and
arousal are the most common clinical manifestations, and, not
surprisingly, the most vulnerable areas of the brain are related
to consciousness and arousal: the cortical projection neurons,
the posterior cingulate and medial prefrontal cortex, the bilat-
eral temporoparietal junctions, cerebellar Purkinje cells, and
the hippocampus. Damage to the basal ganglia and cerebellum
is occasionally noted and commonly results in the movement
disorders and ataxia seen occasionally following HE. The
brainstem appears to be somewhat more resistant to hypoxic
injury, and therefore fewer patients present with complete
absence of brainstem activity.
A focused yet thorough neurologic assessment is essential in
the immediate management of the resuscitated cardiac arrest
patient, as clues from the exam may provide clues to the cause
of the arrest and may have implications for treatment and
prognosis. The neurologic examination should be taken in the
context of the ongoing systemic processes, pharmacologic
agents used, and the presence of hypothermia. The majority of
patients will have a nonlocalizing neurologic exam. However,
findings of focal neurologic abnormalities on examination may
direct diagnostic efforts to specific etiologies such as stroke or
hemorrhage, whereas observations of spontaneous motor activ-
ity may also require early electrophysiologic testing to differen-
tiate seizures from movement disorders and myoclonus.
Postcardiac-arrest myocardial dysfunction is common, and
may be related to the cause of the arrest, as in the case of
myocardial ischemia or a primary arrhythmia, or simply a
result of cardiac arrest secondary to neurologic, respiratory,
Table 31.2 Diagnosis and manifestations of hypoxic encephalopathy
History and Presentation:
Unresponsiveness and evidence • Cardiopulmonary arrest
of one of the following: • Asphyxia
• Drowning
• Carbon monoxide
poisoning
Clinical Findings:
• Coma
• Seizures (convulsive or
nonconvulsive)
• Myoclonus
• Parkinsonism and other
movement disorders
• Stroke with focal findings
• Dysautonomia
• Minimally conscious states
• Brain death
• Post-traumatic stress
disorder
• Depression
• Cognitive impairment
Chapter 31: Hypoxic Encephalopathy
metabolic, or other causes of arrest. This injury is often com-
pounded by defibrillation attempts and mechanical trauma
from chest compressions. Myocardial dysfunction may mani-
fest as cardiogenic shock or stress-induced cardiomyopathy.
Respiratory problems encountered in conjunction with HE
after cardiac arrest may also be the cause of arrest or simply a
result thereof, and may range from pulmonary contusions
as well as costal and sternal fractures from CPR, aspiration
pneumonia or pneumonitis due to loss of airway reflexes, and
pneumothoraces, all of which may lead to respiratory failure
with or without ARDS. Bowel ischemia, as well as renal and
hepatic dysfunction of varying degrees resulting from
ischemia-reperfusion or low-flow states can also complicate
the postresuscitation. Hematologic and coagulation dis-
orders, including activation of coagulation factors, as well as
hyperfibrinolysis, have been described and can be com-
pounded by the effects of therapeutic hypothermia if they
are not promptly recognized.
As mentioned previously, HE is a clinical diagnosis and to
date there are no tests or procedures specific for the diagnosis
of HE. Diagnostic work-up using laboratory tests, imaging and
neuro-electrophysiologic studies are secondary to the history
and physical exam in determining the cause of HE. Ancillary
studies are necessary for the critical care management of
patients with HE and to determine their prognosis, and will
be discussed in the remainder of this chapter.
Management
Prehospital and Initial Management
After a successful resuscitation with return of spontaneous
circulation per advanced cardiac life support (ACLS) guide-
lines, patients who remain unresponsive and are presumed to
have HE should be rapidly evaluated for therapeutic hypother-
mia and ongoing care, with all reasonable efforts made to
ascertain patient advance directives and do-not-resuscitate
orders, if at all possible to do expediently and with certainty
[3]. Once the patient has been resuscitated and is transferred
from the field to an emergency department or from an in-
patient setting to a critical care unit, the patient should be
quickly re-evaluated for potential contraindications and modi-
fying factors for the use of therapeutic hypothermia (TH).
If there are no contraindications for ongoing care and the
resuscitated patient has maintained return of spontaneous
circulation (ROSC), a secondary assessment should be per-
formed. At this point, the airway should be definitively secured
with endotracheal intubation if not already done, and mech-
anical ventilation instituted. All patients should have a rapid
point-of-care blood glucose test and a 12-lead electrocardio-
gram (ECG) performed immediately after resuscitation.
Hemodynamic stability must to be maintained to the extent
possible, and all appropriate patients should be considered for
cardiac reperfusion therapy based on ECG, cardiac biomar-
kers, if results are already available, and emergent bedside
383
 Chapter 31: Hypoxic Encephalopathy
echocardiography. Patients should be kept nil-per-os (NPO)
and enteral access should be obtained, urinary catheters should
be inserted in all patients, for close monitoring of urinary
output and temperature. After adequate peripheral intraven-
ous access, central venous access should be considered, based
on evaluation of the following needs: administration of vaso-
pressors, additional access, hemodynamic monitoring and
endovascular temperature management when available and
applicable. Arterial access should also be obtained exped-
itiously to enable hemodynamic monitoring and serial arterial
blood gas measurements. Once patients are deemed to have
been stabilized hemodynamically, all should have an initial
emergency cranial computed tomography (CT) to rule out
complicating conditions with potential to alter immediate
management, such as subarachnoid or intraparenchymal hem-
orrhage, ischemic stroke, and cerebral herniation. It must be
noted that depending on the initial exam and presentation, this
can be deferred if emergent coronary reperfusion is deemed
imperative or required to establish hemodynamic stability
through mechanical means.
Induction of Therapeutic Hypothermia
Therapeutic hypothermia (TH) is the only neuroprotective
strategy for HE to have proven clinical benefit, the early clin-
ical trials from 2002 showing that TH of 32–34 °C for 12–24
hours improved both survival and the neurologic outcomes of
comatose survivors of ventricular tachycardia/fibrillation (VT/
VF) arrests [4,5]. Subsequent studies showed likely survival
and quality-of-life benefits for victims of cardiac arrest with
initial rhythms of asystole or pulseless electrical activity (PEA)
with TH [6]. The largest and most recent clinical trial (TTM
trial) of TH, including comatose VT/VF and PEA/asystole
survivors, showed no difference in neurologic outcomes or
complications when comparing TH for 24 hours at 33 °C or
36 °C [7]. The International Liaison Committee on Resusci-
tation (ILCOR) issued a statement in December 2013 clarifying
the implications of the TTM trial. We fully agree with their
conclusions and recommendations, where it is clearly stated
that 36 °C does not equate to not employing TH, and that there
is no difference between TH at 33 °C and 36 °C. Finally, the
importance of avoiding hyperthermia post rewarming cannot
be overstated [8]. It is currently recommended to treat all
comatose cardiac arrest victims with TH, regardless of present-
ing ECG rhythm, in accordance with the ILCOR guidelines
(AHA class I recommendation for out-of-hospital arrest with
VT/VF as the initial rhythm, and IIB for those with PEA and
asystole as initial rhythm) [3]. There have been a number of
studies that have aimed to determine the optimal timing for
initiation of TH for treatment and prevention of HE, and
although starting sooner makes intuitive sense and is sup-
ported by preclinical studies, large studies of prehospital
induction of TH have failed to consistently demonstrate a
significant outcome benefit [9–11]. Regardless of the location,
384
initiation of cooling should happen rapidly as outlined in
Figure 31.1, with the use of chilled intravenous fluids and cool
packs, and definitive cooling measures instituted as soon as
feasible and deemed safe [12]. There is a wide variety of methods
to induce and maintain hypothermia, including surface and
internal cooling with varying degrees of invasiveness, complex-
ity, and cost. We recommend the use of automated closed-loop
systems, which are ideal to maintain target temperature, control
rewarming, and subsequently maintain normothermia.
Management in the Intensive Care Unit
Management of Rewarming, Shivering, Sedation, and Analgesia
At the time of intubation, or prior to induction of TH, it is
recommended to use a nondepolarizing paralytic agent of
short to intermediate duration, such as rocuronium, vecuro-
nium, or cisatracurium, to facilitate induction of hypothermia
by inhibiting shivering. Ongoing sedation and analgesia play a
vital role in the management of HE by facilitating induction of
hypothermia by decreasing shivering, ensuring ease, and safety
of mechanical ventilation, and ensuring patient comfort, des-
pite their effect on consciousness and potential to confound
evidence of encephalopathy. Factors such as age, weight, and
obesity, hemodynamic status, renal and hepatic function,
pharmacokinetics and dynamics, hypothermia, and the need
to accurately and quickly assess neurologic function complicate
the choice of sedatives and analgesics. Fentanyl or remifentanyl
infusions with adjuvant propofol or midazolam infusions have
been studied the most and are generally accepted to provide
adequate sedoanalgesia that is quickly titratable. Dexmedetomi-
dine has also received some interest due to its relative hemody-
namic, respiratory, and cognitive neutrality, in addition to
recently described and poorly understood neuroprotective prop-
erties and the ability to decrease shivering [13–15]. Shivering is a
significant clinical concern, as it can significantly counteract
efforts to induce and maintain TH. A clinical scale to quantify
and assess shivering has been developed and can be used to
document shivering and to effectively titrate efforts to suppress
it [16]. Additional agents and measures that may be employed
to suppress shivering include:
• A 4–6 g load of intravenous magnesium sulfate to achieve
serum magnesium levels of 3–4 mg/dL is recommended to
correct potential hypomagnesemia and to facilitate
hypothermia.
• Buspirone has been shown to be an effective adjunct in the
management of shivering.
• Skin counterwarming measures with forced air devices
applied to hands and extremities in particular are also
helpful.
After maintaining TH of 32–36 °C for 24 hours, active, con-
trolled rewarming at a rate of 0.25–0.5 °C per hour is recom-
mended until a core temperature of 36.5–37.5 °C is achieved.
However, prior to the commencement of rewarming, the
 Chapter 31: Hypoxic Encephalopathy

Cardiac Arrest
• Initiate advanced resuscitative measures per institutional protocol.
• Rapid ambulance transport to emergency department, inpatient resuscitation area or
critical care unit.

Exclusion Criteria Inclusion Criteria

• GCS >8. • ROSC achieved.
• Non survivable injury. • GCS <8 and/or
mGCS<5.
• Absence of a
limited care plan.

Not Eligible
• Standard management
without TH, limited care
plan or withdrawal of life- Emergent Intervention
sustaining therapies. • PCI +/- mechanical
circulatory support.
Stabilization & Secondary Assessment
• Airway procedures, monitoring, • Cardiac electrophysiologic
vascular access, initial cooling intervention; device
reprogramming.
measures (chilled saline, cold packs),
Care Planning Discussions: • Catheter
• Review of advanced
placement of enteric and urinary
catheters. thrombectomy/lysis, CPB
directives.
• Discussion with patient's
• Rapid diagnostic workup (ECG, CXR with surgical
thrombectomy.
TTE/EFAST, noncontrast head CT
friends/relatives.
and initial laboratory tests). • Emergent CRRT.

Relative Contraindications/Modifying
Factors
• Trauma/hemorrhagic shock or
intracranial hemorrhage?
• Pregnancy?
• Significant coagulopathy?
• Sepsis?
• Poor functional status/terminal
condition?

Induction of Therapeutic Hypothermia

• After initial cooling measures have been performed, and decision has been made to
proceed with TH, definitive cooling measures should be initiated.
• Continue TH to goal temperature and maintain for 24 hours.

Rewarming and Maintenance of Normothermia

• Rewarm at 0.25°C/hr until 37°C, and maintain strict normothermia 36-38°C for 72hr.

ROSC: return of spontaneous circulation; GCS: Glasgow Coma Scale; mGCS: motor Glasgow Coma Scale; TH: therapeutic hypothermia; ECG:
electrocardiogram; CXR: chest x-ray; TTE: transthoracic echocardiogram; EFAST: extended focused assessment in trauma; CT: computed
tomography; PCI: percutaneous coronary intervention; CPB: cardiopulmonary bypass; CRRT: continuous renal-replacement therapy.
Figure 31.1 Hypoxic encephalopathy management and therapeutic hypothermia algorithm.

385
 Chapter 31: Hypoxic Encephalopathy
following parameters must be carefully measured and taken
into account to prevent potential complications:
• Careful determination of the patient’s volume status is
important, as rewarming is accompanied with peripheral
vasodilation and increased vascular capacitance with
resulting hypotension that can be quite significant and
potentially detrimental. Volume loading may be necessary
prior to rewarming.
• Judicious determination of serum potassium levels are
important, and limitation of potassium replacement should
be considered prior to rewarming, when extracellular
shifting of potassium results in increased serum
concentrations.
• Strict, hourly glucose measurements are recommended
during rewarming as insulin sensitivity returns to normal.
Insulin administration should decrease prior to and during
rewarming to avoid potentially harmful hypoglycemia.
• As body core temperature rises, patients may begin
shivering again once temperature approaches 36°C and
measures to counter this response should be pursued
aggressively.
After completion of rewarming, the therapeutic temperature
management system should remain in place to ensure nor-
mothermia for the following 48–72 hours. Rebound hyper-
thermia is a common phenomenon occurring in about 40%
of patients post therapeutic hypothermia. It must be noted that
only temperatures >38.7 °C appear to be associated with worse
neurologic outcomes in patients who survive to discharge [17].
Organ-Specific Management Strategies
Central Nervous System
After the initial insult previously described as the primary
brain injury, secondary brain injury ensues due to reflow
phenomena and oxidative injuries, which are then com-
pounded by cerebral edema, seizures, and systemic factors.
Cerebral edema is thought to play an active role in the patho-
physiology of brain injury following cardiac arrest. Cerebral
edema seems to be apparent on the initial cranial CT in
approximately 30% of patients following cardiac arrest [18].
Scant published research is available regarding invasive intra-
cranial pressure (ICP) measurements in HE patients, and to
date there is no evidence supporting the invasive measurement
of ICP to manage patients following a global hypoxic event
[19]. Simple yet crucial measures, such as maintaining the
head of the bed elevated to 30° and in a neutral midline
position, should be maintained at all times to improve cerebral
venous drainage and avoid elevations in ICP.
Therapeutic hypothermia has some effect in decreasing
cerebral edema; however, additional measures such as
osmotherapy and barbiturate coma have not been well studied,
and at this time are not recommended for routine use. In cases
of clinical cerebral herniation, the use of hypertonic saline and
mannitol are indicated [20]. In HE secondary to cardiac arrest,
the incidence of nonconvulsive status epilepticus (NCSE) is
386
estimated to be as high as 24% [21,22], and is associated with
worse outcomes [23,24]. Acute posthypoxic myoclonus (PHM)
occurs in about 20% of patients with HE [25]. Following
hypoxic encephalopathy, the presence of convulsive or non-
convulsive seizures, or myoclonus were traditionally regarded
as sine qua non for poor neurologic outcomes; however,
advances in critical care management and therapeutic hypo-
thermia in particular have demonstrated that this is by no
means the case [26,27]. There is insufficient evidence to rec-
ommend prophylactic use of antiepileptic drugs in patients
with HE; however, the following agents and measures should
be considered:
• In the initial and emergent treatment of status epilepticus
and clinical seizures, benzodiazepines are the
recommended first-line agents, with lorazepam and
midazolam being preferred.
• For the subsequent treatment of seizures or status
epilepticus following the use of benzodiazepines,
fosphenytoin, midazolam, valproic acid, or levetiracetam
are recommended. Their short half-lives and less sedating
effects should be sought whenever possible.
• The treatment of acute PHM should be made in
consideration of its origin. Cortical myoclonus seems to
respond to levetiracetam, whereas subcortical myoclonus
seems to respond better to clonazepam. In cases of
refractory myoclonus, propofol may be useful in
terminating activity when added as a second-line agent.
• Although many centers routinely employ continuous
electroencephalography for all HE patients, the value, cost
effectiveness, and impact of this intervention has not been
well studied. If feasible, we would recommend its routine
use, as the finding of nonconvulsive status epilepticus
provides a potential therapeutic target that might represent
an opportunity to improve outcomes.
Cardiovascular Management
Given that the majority of patients who suffer HE are patients
who have had a cardiac arrest, it is not at all uncommon for
them to have significant cardiovascular compromise. This can
range from myocardial dysfunction as part of the postcardiac-
arrest syndrome, to cardiogenic shock following a myocardial
infarction, to electrical instability following a cardiac “electrical
storm.” In-depth discussion of the cardiovascular management
of myocardial reperfusion, mechanical circulatory support,
and electrophysiologic and device therapies are well beyond
the scope of this chapter. In cases of ST elevation and myocar-
dial infarction, prompt reperfusion is key to hemodynamic
stability, short- and long-term survival, and quality of life;
therefore definitively addressing myocardial infarction (some-
times even before ROSC is achieved) is imperative. In cases of
refractory electrical instability, electrophysiologic intervention
may be required on an emergent basis. Once ongoing ischemia
and electrical instability have been addressed, ongoing circula-
tory support measures need to be considered. Adequate blood

supply to the brain is critical, and should be the primary
endpoint of circulatory support with myocardial perfusion in
close second place, followed by renal, hepatic, and splanchnic
perfusion. Initially volume resuscitation with careful consider-
ation to left ventricular function may suffice. Incremental
interventions include pharmacologic vasopressor, and inotro-
pic and occasionally chronotropic support. If this proves insuf-
ficient, mechanical support may be considered, with a number
of options depending on local availability and experience,
including intra-aortic balloon counterpulsation, cardiopul-
monary bypass, percutaneous ventricular support devices,
and external arteriovenous support systems. Circulatory sup-
port for patients with HE should target the following goals:
• Euvolemia, unless otherwise clinically contraindicated. The
assessment of volume status should be based on dynamic
indices of volume, fluid responsiveness, and organ
perfusion, including cardiac ultrasonography, as well as
measurements of cardiac output, stroke volume variation,
pulse pressure variation, global end-diastolic volume, and
other hemodynamic variables, as well as physiologic
measures such as urine output.
• Mean arterial pressure (MAP) goals should be
individualized based on cardiac function, cerebral
perfusion pressure, systemic perfusion, and an
approximation of the status of cerebral autoregulation.
Usually a MAP of 60 mmHg is targeted; however, a MAP
of 70–100 mmHg may be considered, particularly to
augment CPP in cases of cerebral edema and elevated ICP.
• In cases where infection with resulting sepsis is considered,
prompt and appropriate antibiotic therapy is crucial until
microbiologic confirmation is obtained and the clinical
picture is clarified.
Mechanical Ventilation
In the management of HE, mechanical ventilation should be
aimed at maintaining tissue normoxia and normocapnea.
Although specific arterial oxygen concentration or saturation
goals have not been established for the management of HE,
there are indications that supranormal values are potentially
harmful [28,29]. Current postresuscitation guidelines recom-
mend discontinuing 100% FiO2 after ROSC and titrating down
oxygen to maintain an arterial oxygen saturation of 94–98% as
soon as possible. Normocapnea with PCO2 values between
40–45 mmHg should be targeted, as hyperventilation may
decrease cardiac output by elevating intrathoracic pressure,
decrease cerebral blood flow, and decrease seizure thresholds.
Though low tidal volume lung-protective ventilation strategies
are standard of care for patients with ARDS, we also recom-
mend ventilation with tidal volumes of 6 mL/kg of ideal body
weight in patients without evidence of ARDS. In cases of
severely impaired oxygenation and ARDS, the standard man-
agement tenets of lung-protective ventilation and permissive
hypercapnea need to be carefully considered and tailored to the
patient with HE, cerebral edema, and elevated ICP. Though no
Chapter 31: Hypoxic Encephalopathy
good-quality studies on the management of ARDS in patients
with HE and elevated intracranial pressures exist, the results of
studies on other types of brain injury can be considered.
Though there is no compelling evidence to recommend the
routine use of the following [30–35], they may be considered
with great care:
• Prone positioning ventilation may be considered in cases of
significant atelectasis and hypoxemia, though it requires
significant experience and personnel.
• The benefits and safety of high-frequency oscillation
ventilation (HFOV) may still be debated in specific patient
subgroups, but there is some evidence for its use in brain-
injured patients, and tracheal gas insufflation has regained
interest as a means to control hypercapnea during HFOV
in head-injured patients.
• The use of nitric oxide has not been shown to improve
outcomes, but may be considered in specific circumstances
when other options result in unacceptable hemodynamic
consequences or increases in intracranial pressure.
• Airway pressure release ventilation (APRV) has also been
proposed as a means to improve hypoxemia, and may
improve oxygenation without significantly affecting
cerebral venous drainage and intracranial pressure.
• The use of alveolar recruitment maneuvers may also
provide transient improvements in oxygenation with
relative safety in brain-injured patients.
Renal, Endocrine, Hematologic, and Gastrointestinal Management
Patients with HE are vulnerable to a variety of renal, endo-
crine, hematologic, and gastrointestinal disorders secondary to
critical illness, their underlying conditions, or secondary to
their brain injury. Additionally, the use of therapeutic hypo-
thermia causes significant changes in metabolism and homeo-
stasis, resulting in changes to urine output (cold diuresis) with
alterations in potassium, magnesium, and phosphate. Potas-
sium and magnesium homeostasis is vital due to its import-
ance in cardiac conduction and roles in arrhythmogenesis.
Potassium levels of >4 mEq/L and magnesium levels
>2.0 mEq/L should be maintained, with levels of 3–4 mEq/L
having been found to reduce shivering. Serum sodium levels
and volume status should be carefully monitored and main-
tained in the normal range whenever possible. These patients
can have a variety of sodium and water balance disturbances,
such as the syndrome of inappropriate antidiuretic hormone
release, and cerebral salt wasting of central diabetes insipidus.
Patients with HE with clinical herniation or signs of cerebral
edema, elevated ICP, and herniation, increased sodium goals
must be individualized, and the use of hypotonic intravenous
fluids should be avoided. Critical illness is well known to
induce or exacerbate pre-existing hyperglycemia, with the use
of therapeutic hypothermia further complicating the picture.
Hypothermia decreases endogenous insulin release, as well as
decreasing insulin sensitivity, therefore great care must be
taken to avoid hypoglycemia during rewarming as insulin
387
 Chapter 31: Hypoxic Encephalopathy
sensitivity increases to baseline. As with other forms of brain
injury, normoglycemia should be maintained with insulin
infusions to avoid the potentially erratic absorption of sub-
cutaneous insulin secondary to peripheral vasoconstriction
with changes in temperature, as well as the fluctuations of
glycemia during therapeutic hypothermia. Current evidence
suggests maintaining blood glucose levels between 144 and
180 mg/dL, as well as aggressively correcting hypoglycemia
<80 mg/dL [3]. Thyroid and adrenal endocrinopathies may
occur and should be managed the same way as in other
critically ill individuals.
Patients with HE are at very high risk for developing stress
ulcers due to many of the following conditions: mechanical
ventilation greater than 48 hours, brain injury, coagulopathy,
hypotension, and vasopressor use. With this in mind, it is
common practice to initiate pharmacologic prophylaxis and
early enteral nutrition; however, the choice of agents and the
necessity of chemoprophylaxis if enteral feeding is instituted
remains unclear [36]. Regardless of the measures chosen, it
must be considered in light of potential side effects and inter-
actions with antiplatelet agents, risk of pneumonia and Clos-
tridium difficile infection, and thrombocytopenia. With
regards to the hematological management of patients with
HE, there are a few main issues to consider including anemia,
thrombocytopenia, and coagulopathy. These may result from
an interplay in baseline patient characteristics, the use of anti-
platelet agents or anticoagulants, systemic responses such as
disseminated intravascular coagulation or consumptive coagu-
lopathies, or the use of TH. There is no clear evidence regarding
optimal hemoglobin goals or transfusion thresholds for patients
with HE. Although the subject is often controversial, it is prob-
ably best to transfuse to a goal hematocrit >30% in patients with
acute coronary syndromes and cerebral ischemia, pending
definitive prospective data, as the most recent systematic litera-
ture reviews and transfusion guidelines specifically state that
restrictive transfusions cannot be recommended in high-risk
Table 31.3 Postresuscitation goal-directed therapy
Physiologic Value or indication
parameter
Target 32–36 °C
temperature
Cooling duration 24 hours
Volume status Euvolemia
Mean arterial 60 mmHg, may consider 70–100 mmHg in
pressure individual cases if concerns for CPP
Oxygenation ABG PaO2 of 80–100 mmHg with 94–98%
saturation
Ventilation ABG PCO2 40–45 mmHg.
Glycemia Serum glucose 144–180 mg/dL
Hemoglobin 7–10 g/dL
388
patients [37,38] such as these. Deep venous thrombosis prophy-
laxis is indicated with graduated compression stockings, pneu-
matic compression devices, and appropriately weight-based
subcutaneous heparin administration, with consideration to
renal function.
Prognostication
At this time, neuroprognostication of hypoxic encephalopathy
is making a slow transition from art to science, especially in the
advent of therapeutic hypothermia for resuscitated cardiac
arrest. The 2006 practice parameters of the American Acad-
emy of Neurology provide specific recommendations for
the prognostication of neurologic outcomes for cardiac arrest
survivors not treated with TH [39], however there is
no adequate prognostic paradigm for HE treated with TH.
Clinical examination including the presence or absence
of brainstem reflexes, motor responses, and the absence of
myoclonus traditionally portended a favorable prognosis. Elec-
trophysiologic testing, serum biomarkers, and neuroimaging
have been evaluated to improve the accuracy of prognostica-
tion. However, what limited certainty these tests and param-
eters provided has become even more questionable in the
setting of therapeutic hypothermia.
Our inability to accurately predict the outcomes of patients
with HE in this day and age, despite the use of clinical and
ancillary studies, as well as the need to allow patients appro-
priate amounts of time to recover awareness and function is
dramatically highlighted in a study by Howell et al. [40]. In this
study conducted in a German neurorehabilitation center, as
many as 6.2% of 113 patients admitted with HE achieved good
functional outcomes (GOS 4–5) with improvements first being
noted 8–12 weeks post anoxic event, and despite initial poor
prognostic markers such as absent somatosensory-evoked
potentials (SSEPs). Although the mechanism for these delays
is unclear, it seems likely that medications play a role in this
process due to inadequate sedative holidays, clearance, and
timing of examinations [41]. Mounting evidence and recent
guidelines are taking these factors into account and recom-
mending that prognostic testing and decisions regarding with-
drawal of life-sustaining therapies be deferred until at least
72 hours after rewarming in cases of HE treated with thera-
peutic hypothermia [42].
The clinical neurologic examination has traditionally been
the cornerstone of neuroprognostication. However, in the
post-therapeutic hypothermia setting, several studies have
challenged the reliability of clinical testing [26,43–45], as well
as the prognostic significance of early postanoxic myoclonus
[26,27]. The use of biomarkers, though conceptually an attract-
ive option, is fraught with some important limitations including
cost and timely availability of results, but most importantly their
reliability in prognosticating poor outcomes after the applica-
tion of therapeutic hypothermia is quite poor [43,46,47]. Neu-
rophysiologic testing with electroencephalography (EEG) and
testing SSEP responses are the most commonly used modalities;
 Chapter 31: Hypoxic Encephalopathy

with SSEP previously believed to be one of the most accurate however, it is unclear whether finding and treating NCSE
and definitive ancillary prognostication methods. The utility of improves outcomes in the HE population. The predictive accur-
EEG currently lies in its ability to diagnose NCSE, which is acy of SSEP post TH is unfortunately inferior to its performance
found in approximately 30% of patients post cardiac arrest [48]; in patients not treated with hypothermia [43,49]. There has been

Comatose Cardiac Arrest Survivor

Yes No
TH

Confounders excluded
AND
Confounders excluded
>3 Days post rewarming with
no improvement and mGCS <6

Complete Absent
absence brainstem brainstem reflexes at any
reflexes time

Yes Yes
Brain death testing
No with confirmatory No
ancillary testing

Burst Day 1 Yes

suppression or agonal pattern Myoclonus status Poor
on EEG epilepticus outcome

Yes to all
Absent Day 1-3
Poor Yes Poor
N20 responses Absent N20 responses
outcome outcome
bilaterally bilaterally

DWI MRI
showing damage to any Day 1-3 Yes Poor
of the following: bilateral cortex, Serum NSE >33µg/L outcome
thalami, or brainstem

Day 3
Absent pupil or Yes Poor
corneal reflex; absent or extensor outcome
motor response

Indeterminate neurologic prognosis

Figure 31.2 Prognostication algorithm.

Abbreviations: TH: therapeutic hypothermia; mGCS: motor Glasgow Coma Scale; EEG: electroencephalography; N20: median nerve somatosensory evoked potentials;
DWI: diffusion-weighted imaging; MRI: magnetic resonance imaging; NSE: neuron specific enolase.

389
 Chapter 31: Hypoxic Encephalopathy

much enthusiasm for the use of imaging in the prognostication
of outcomes in HE, however no well-designed studies have been
conducted, even in the case of computed tomography and
magnetic resonance imaging, which are commonly used modal-
ities in clinical practice [50]. The lack of quality data on the use
of imaging as well as its conspicuous absence in any guidelines
renders its use limited to providing supporting evidence in a
multimodal prognostication strategy.
In light of the aforementioned shortcomings in neurologic
prognostication with clinical examination and ancillary stud-
ies, about the only firm recommendation that can be made at
this point is to allow patients at least 72 hours post rewarming
before attempting to prognosticate and make decisions
regarding end-of-life in HE patients treated with hypothermia.
Taking into account the uncertainties in this crucial matter we
propose the following algorithm (Figure 31.2) when making
prognostic assessments in patients with HE treated with thera-
peutic hypothermia; note that in patients treated with TH, at
least all three tests and clinical criteria must be met before
venturing to prognosticate a poor outcome. As has been men-
tioned earlier, the optimal timing of when to prognosticate is
as uncertain as the ideal paradigm; however, it must be stressed
that it should occur no sooner than 72 hours post rewarming.

8. Ian J, Nadkarni V. (2013). Targeted 15. Schoeler M, Loetscher PD, Rossaint R,

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391
 Chapter
Management of Delirium in the Neurocritical

32 Care Unit
Diana Greene-Chandos and Michel T. Torbey

Acute confusional state (ACS) is very common in the inten-

sive care unit (ICU) setting. Most often, it is one of the main
Epidemiology of Delirium
reasons a neurology consult is requested in the surgical or Hospital-acquired delirium is seen in up to 15% of general
medical ICU. Acute confusional states are often used inter- medical admissions with incidence rising in mechanically venti-
changeably when describing metabolic encephalopathy, lated patients up to 80% [1,2]. It is the most common surgical
delirium, ICU psychosis, or septic encephalopathy. Enceph- complication among older adults, with incidence varying
alopathy is defined as a subacute global brain dysfunction between 15–50% depending on the type of surgery [3]. Delirium
that is gradual in onset with very broad clinical symptoms, often persists following hospital discharge. A systemic review
whereas delirium is often described as an acute process. The found persistent delirium present in 44.7%, 25.6%, and 21% of
list of potential causes (Table 32.1) of ACS could be sum- patients at one, three, and six months post discharge, respect-
marized using “Vitamin E” as a mnemonic. In this chapter, ively [4]. It is an independent predictor of prolonged hospital
we will only focus on management of delirium and toxic stay, worsened functional status, and mortality [5,6].
metabolic encephalopathy.
Definition of Delirium
DSM-5 Diagnostic Criteria for Delirium requires all the
following criteria to be met [7]:
Table 32.1 Causes of acute confusional state 1. Disturbance in attention and awareness
2. Disturbance develops acutely (hours to few days) and tends
Major etiology Specific causes
to fluctuate in severity during the course of the day
Vascular Stroke 3. At least one additional disturbance in cognition
Vasculitis 4. Disturbances do not occur in the context of a severely
Posterior reversible encephalopathy
reduced level of arousal or coma
Infectious Sepsis 5. There is evidence of an underlying organic cause or causes.
Encephalitis/meningitis
Traumatic Diffuse axonal injury
Delirium Subtypes
Toxic Alcohol withdrawal Delirium can be expressed in the context of distinct subtypes,
Drugs
typically referred to as hypoactive, hyperactive, and mixed
Autoimmune Acute disseminated encephalitis [8,9]. Although physicians in general associate delirium with
Metabolic Electrolyte abnormalities agitation, hyperactive delirium represents only 25% of cases,
Uremia with the others having hypoactive delirium [2,3]. Hypoactive
Acute adrenal failure delirium is associated with poorer prognosis because it is
Thiamine deficiency usually less frequently recognized.
Liver failure
Hashimoto encephalopathy
Screening for Delirium
Iatrogenic Pain Although many cases of delirium are easy to identify in agi-
Loss of day/night cycle tated patients, several are undetected, especially in nonagitated
Neoplastic Primary CNS tumor patients. Several screening tools have been used in the diagno-
Carcinomatous meningitis sis of delirium, such as the Intensive Care Delirium Screening
Neurodegenerative Lewy body dementia Checklist (ICDSC) [10] and the confusion assessment method
for the ICU (CAM-ICU)[11]. These tools can be used by
Epileptic Nonconvulsive status epilepticus
nonspecialists to quickly screen and identify delirium. The

392
 Chapter 32: Management of Delirium

ICDSC is a highly predictive tool with a sensitivity of 99% and to be used in intubated patients. The test has a high sensitivity
a specificity of 64%. It has a total score of 8, with delirium (93–100%) and specificity (89–100%). The CAM-ICU consists
defined as a score of 4 or more. The CAM-ICU was designed of four features that parallel the DSM-related criteria: (1) acute
change or fluctuation in mental status, (2) inattention, (3)
Table 32.2 Richmond Agitation Sedation Scale (RASS)
disorganized thinking, or (4) altered level of consciousness.
Level of consciousness is typically assessed via the Richmond
Scale Label Agitation Sedation Scale (RASS) [12,13]. Patients with RASS
+4 Combative scores of –4 or –5 are comatose and hence could not be
assessed. The complete training manual for CAM-ICU is
+3 Very agitated
available on www.icudelirium.org. The first step in screening
+2 Agitated for delirium is assessment of level of consciousness using
+1 Restless RASS (Table 32.2). If RASS is –3 then proceed to CAM-
ICU. If the patient is unconscious (RASS <–3), suggest
0 Alert and calm
reassessing later. The second step is to assess the content of
–1 Drowsy consciousness using the CAM-ICU tool. Figure 32.1 describes
–2 Light sedation the CAM-ICU assessment flowsheet.
–3 Moderate sedation
–4 Deep sedation
Pathophysiology of Delirium
The pathophysiology of delirium remains unclear and multifac-
–5 Unarousable torial. Inflammation and sepsis, genetics, and neurotransmitters

Figure 32.1 CAM-ICU flowchart.

Acute Change of Fluctuating Course of
Mental Status

No
Yes

Inattention

No Delirium
>2 errors 0-2 errors

Altered Level of
Consciousness

RASS =0 RASS ≠0

Disorganized
Thinking

>1 error
0-1 error

Delirium Present

No Delirium

393
 Chapter 32: Management of Delirium
interactions all play a role. Sepsis may trigger an inflammatory
cascade that may negatively impact the delivery of oxygen and
nutrients to cells [14]. Multiple neurotransmitters play a role in
delirium, including monoamines (serotonin, dopamine), acetyl-
choline, glutamate, and γ-aminobutyric acid (GABA) [15–17].
The APO-E gene has also been implicated in delirium. APO-E4
carriers were delirious for two more days in medical ICU patients
compared to those without the APO-E gene [18].
Diagnostic Evaluation
It is very important to make sure a clear etiology was established
for the delirium. Additional historical, clinical, laboratory, and
imaging data are almost always required for differential diagnosis:
1. History: a detailed history is very valuable particularly in
cases of drug intoxication. The medication list should also
be reviewed. Knowledge of the past medical history is
important. Presence of dementia is particularly relevant,
because it can predispose to delirium and can be associated
with increased risk of infections or seizures.
2. Clinical examination: a thorough general and neurologic
clinical examination should always be performed. A few
clinical signs are more common in certain disorders:
• Asterexis: uremia and hyperammonemia
• Myoclonus: serotonin syndrome
• Muscle rigidity: neuroleptic malignant syndrome
• Chvostek and Trousseau signs: hypocalcemia.
• Diffuse ascending weakness: Hypophosphatemia
• Nystagmus, ataxia, and ophthalmoplegia: acute
thiamine deficiency (Wernicke’s encephalopathy).
3. Laboratory investigations: laboratory tests must include a
complete blood count (CBC) with differential, erythrocyte
sedimentation rate (ESR) and C-reactive protein (CRP),
serum electrolytes, blood urea nitrogen (BUN), glucose,
thyroid hormone evaluation, liver function tests, amylase,
lipase, ammonia, troponin levels, HIV, arterial blood gases,
and blood and urine cultures. Serum and urine toxicology
may reveal the presence of many drugs of abuse, as well as
toxic levels of tricyclic antidepressants, antiepileptics,
anticholinergics, digoxin, and other medications.
Cerebrospinal fluid evaluation should be performed if
there is high suspicion for any central nervous system
infection.
4. Electroencephalogram (EEG): a continuous EEG is
reasonable for assessment of an encephalopathic patient.
The goal is to identify nonconvulsive seizures. These were
identified 16% of the time in surgical ICU, 10% in medical
ICU, and 7% on the general inpatient floor [19–21]. EEG
typically shows nonspecific diffuse slowing in the theta
(3–7 Hz) or delta ranges (1–3 Hz) [22]. Increased beta
activity is associated with use of sedating medications,
particularly benzodiazepines. Triphasic waves are observed
in metabolic encephalopathies, particularly of hepatic or
uremic etiology.
394
5. Neuroimaging: Computed tomography (CT) is useful as the
initial screening to rule out mass lesions. Magnetic
resonance imaging (MRI) can provide significantly more
information than CT such as:
• Hypoglycemic encephalopathy: diffuse cortical and
white matter hyperintensities on T2 images with
sparing of the thalamus
• Carbon monoxide poisoning: necrosis of bilateral globi
pallidi
• Wernicke’s encephalopathy: intense T2 signal involving
the medial thalami, dorsal medulla, tectal plate, and the
periaqueductal gray matter.
Management of Delirium
Management of delirium in the ICU is very challenging. Often,
it is a balance between necessary procedures, postoperative
pain control, and medications versus dealing with delirium
as a side effect. The multifactorial nature of delirium requires
an intervention that will attempt to address as many risk
factors as possible. To date, no specific interventions have been
developed for the ICU setting. The Hospital Elder Life Pro-
gram (HELP) assessed the value of a multicomponent
approach to delirium treatment for hospitalized patients [23].
The study was aimed at six delirium risk factors: (1) cognitive
impairment, (2) sleep deprivation, (3) immobilization, (4)
psychoactive medications, (5) vision and hearing impairment,
and (6) dehydration. Delirium incidence was reduced from
15% to 10% in the intervention group [23].
Primary Prevention of Delirium
A multicomponent protocol should be implemented: the
patient, if awake, should be frequently oriented to time and
place, sleep hygiene such as dim lighting at night, or avoiding
sensory overload by making sure the patients wear their eye-
glasses and hearing aids. If continuous iatrogenic sedation is
required, daily awakening trials should be attempted to facilitate
timely ventilator weaning, mobilization, and clinical monitoring
[24]. It is also important to avoid Foley placement unless
needed. Constipation should also be prevented. Reduction of
restraints and early mobility is very important as a primary tool
for delirium prevention. Nonpharmacological interventions are
the cornerstone of managing behavioral problems in delirium.
Nurses should be trained in de-escalation techniques and when
necessary, sitters can be employed [3].
Identification of Patients at High Risk of
Developing Delirium
Risk factors are divided into two categories: predisposing and
precipitating factors.
Predisposing factors include:
• Older age
• Dementia
 Chapter 32: Management of Delirium

Table 32.3 Drugs associated with delirium Table 32.4 Management of delirium

• Benzodiazepines • Antispasmodics Assessment Assess delirium every shift and as necessary

• Opioid analgesics • Lithium Delirium is present if:
• Nonbenzodiazepine sedative • SSRI A. CAM-ICU is positive or
hypnotics • Digoxin B. ICDSC score is 4
• Antihistamines • Fluoroquinolones
Treatment Treat pain as needed
• Alcohol • Antipsychotics
Reorient the patient
• Anticholinergics • Barbiturates
Avoid benzodiazepines (except for alcohol
• Anticonvulsants • Antiparkinsonian
withdrawal)
• Tricyclic antidepressants agents
Avoid rivastigmine
• Histamine H2-receptor blockers
Avoid antipsychotics
Prevention Identify risk factors (e.g. dementia, alcohol abuse)
• Functional disabilities Avoid benzodiazepines in patients with
dementia
• High burden of coexisting conditions
Mobilize and exercise patients daily
• Male sex Promote sleep
• Poor vision and hearing Restart baseline psychiatric medications
• Depressive symptoms From Clinical Practice Guidelines for the Management of Pain, Agitation, and
• Mild cognitive impairment Delirium in Adult Patients in the Intensive Care Unit 2013 [24].
• Lab abnormalities
• Alcohol abuse.
Precipitating factors include:
• Drugs
ICU patients, but atypical antipyschotics may do so. Possible
• Surgery suggested drugs include:
• Anesthesia
1. Haloperidol: 2–5 mg IV followed by double repeated doses
• Pain
every 15–20 min if agitation persists up to a maximum of
• Infections 20 mg/d
• Acute illness 2. Olanzepine starting dose 5 mg (2.5 mg over 65 years) and
• Acute exacerbation of chronic illness. titrated on clinical judgment
The more predisposing factors are present, the fewer precipitat- 3. Risperidone starting dose 0.5 mg twice a day, up to a
ing factors are needed [25]. The acronym ICUDELIRIUM(S) maximum of 2.5 mg/d
can be used to easily remember the main risk factors associated
4. Benzodiazepine could be considered in alcohol-related
with delirium: Iatrogenic exposure, Cognitive impairment,
delirium.
Drugs, Elderly, Laboratory abnormalities, Infection, Respira-
Extreme agitation can be associated with significant side
tory, Intracranial perfusion, Urinary retention and constipation,
effects, including cardiovascular instability and hypoxia, in
Myocardial, and Sleep-sensory deprivation [26].
the critical care setting. If such symptoms are not effectively
controlled with medication, mechanical ventilation with sed-
Delirium Prevention ation and even muscle paralysis becomes an option, until
The use of medications in the treatment of delirium is underlying etiologies are identified and reversed. Propofol
common. Haloperidol is the drug of choice for the treatment infusion up to 75 μg/kg per minute has been recommended
of delirium, as indicated by the Society of Critical Care Medi- because of its immediate onset and fast elimination. In add-
cine (SCCM) guidelines [27] and the American Psychiatry ition, dexmedetomidine for delirium unrelated to alcohol or
Association [28], although its efficacy has not been tested in benzodiazipine withdrawal should be entertained to a max-
a placebo-controlled trial. In surgical patients, haloperidol imum dose of 1.5 μg/kg per hour.
could be considered at a dose of 0.5 mg three times a day,
starting at admission and continued until three days after Conclusion
surgery. A review of current patient medications is also an
Delirium is often underdiagnosed in ICU patients. It is very
important step in prevention of delirium. Table 32.3 reviews
important that ICU teams implement formal education of the
the list of medications associated with delirium [3].
staff to recognize delirium early and implement multicompo-
nent intervention programs to prevent it. Table 32.4 summar-
Pharmacological Treatment of Delirium izes the SCCM approach to the management of delirium.
Current guidelines provide no published evidence that treat- Quality metrics could be established in different ICUs to track
ment with haloperidol reduces duration of delirium in adult these efforts.

395
 Chapter 32: Management of Delirium
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 Chapter
Generalized Weakness in the Neurocritical Care Unit

33 Farrukh S. Chaudhry and Edward M. Manno

Introduction Evaluation of Generalized Weakness in the ICU

One of the most frequent neurological consultations in A systematic approach to the patient with generalized weak-
any medical or surgical intensive care unit (ICU) is for ness in the ICU should focus on taking a thorough history,
generalized weakness. Patients admitted to ICUs may have and performing both general and neurological assessments of
a number of factors leading to neuromuscular problems, the patient.
including metabolic derangements, nutritional deficiencies,
acquired diseases, and structural problems of the neuro- History
muscular system. Weakness in the setting of a critically ill
Obtaining a thorough and accurate history is crucial in identi-
patient can have profound effects on patient morbidity and
fying the source of weakness. It is important to determine the
mortality with increased length of hospital stay, medical
exact onset of symptoms, clinical course, and distribution of
complications, and cost [1]. In this chapter we have high-
the weakness. If there are associated neurologic findings, such
lighted the various causes of generalized weakness in ICU
as cranial or other peripheral neuropathies, they should be
patients, and the diagnostic approach and management of
highlighted. Exposure to new medications, prior history of
these illnesses.
weakness, family history of neuromuscular diseases, and recent
hospital course should be evaluated [7]. Recent camping trips
Causes of Generalized Weakness in the ICU
The causes of weakness in the ICU are best classified Table 33.1 Differential diagnosis of generalized weakness in intensive
according to the localization of the primary neuromuscular care units
source (Table 33.1). Difficulties can arise anywhere along the
Disorders of the central nervous Disorders of the
neuraxis, but for the purpose of this chapter we will primarily
system neuromuscular junction
focus on problems from the spinal cord to innervation of the 1. Traumatic brain or spinal cord 1. Myasthenia gravis (MG)
muscles. injury 2. Lambert–Eaton
Previously, the most common cause of generalized and 2. Structural lesions myasthenic
respiratory weakness leading to admission to ICU were dis- syndrome (LEMS)
orders related to anterior motor neuron disease, demyelinating Disorders of the anterior motor horn 3. Botulism
polyneuropathies, or neuromuscular junction (NMJ) diseases. 1. Amyotrophic lateral 4. Prolonged
In recent decades, there have been a number of other entities sclerosis (ALS) neuromuscular
described in ICU patients. This includes critical illness poly- 2. Poliomyelitis blockade
neuropathy (CIP), critical illness myopathy (CIM), and pro- 3. West Nile virus
Disorders of the muscle
4. Hopkins syndrome
longed neuromuscular blockade [2–6]. These specific entities 1. Critical illness myopathy
will be discussed in more detail in the subsequent sections. 2. Rhabdomyolysis
Disorders of the peripheral nerves
The differential diagnosis of generalized weakness in 3. Congenital or hereditary
1. Gullain–Barré syndrome (GBS)
the ICU can be extensive, as many of these patients have muscle diseases
2. Chronic inflammatory
overlapping laboratory findings, unreliable neurological demyelinating polyneuropathy
examinations, and mixed presentations. In addition, pre- (CIDP)
existing conditions may be exacerbated by critical illness. 3. Critical illness
Disease processes may include acute demyelinating poly- polyneuropathy (CIP)
neuropathy, amyotrophic lateral sclerosis (ALS), myelopa- 4. Multifocal motor
thies, prior stroke, NMJ disorders, and myopathies. In other neuropathy (MMN)
circumstances, critical illness itself or the use of various 5. Compressive neuropathies
6. Porphyria
medications may precipitate a disease process such as rhab-
7. Vasculitic neuropathies
domyolysis, CIP, CIM, etc.

397
 Chapter 33: Generalized Weakness
or tick bites etc. may point toward Lyme disease as a likely
culprit. Likewise, a recent trip to a tropical country may point
towards a tropical spastic paraparesis or human T-cell leuke-
mia virus type 1 (HTLV-1)-associated myelopathy. It is note-
worthy that often the documented histories in the ICU reflect a
limited attempt to gain insight into these questions.
Clinical Examination
The clinical examination is often difficult and in some cases
misleading in the accurate diagnosis of neuromuscular weakness
in critically ill patients. A limited ability to participate in the exam
due to sedation, an underlying encephalopathy, or other reasons
can impair the physical and neurological exam. The clinical
evaluation should start with a thorough general examination.
General Examination
An examination of the skin may bear important clues to an
underlying diagnosis, such as dermatomyositis (Gottron’s
papules, heliptrope rash) or other connective tissue diseases.
The thyroid should be palpated for enlargement or tenderness
and may be associated with disease processes such as a thyroid-
induced myopathy or an underlying NMJ disorder. Special
attention should also focus on the examination of respiratory
function, including measures of forced vital capacities, nega-
tive inspiratory force, and the use of accessory musculature [7].
Neurological Examination
The neurologic examination should be systematic and com-
prehensive and may require a consultation from a neurologist.
In general, upper motor neuron lesions can be distinguished
from lower motor neuron lesions by the presence of spasticity,
increased muscle tone, hyper-reflexia, and plantar extensor
responses. These findings can be detected in upper motor
neuron disorders such as stroke, myelopathy, and anterior
horn cell disease. In lower motor neuron disease, the exam
may show flaccid paresis, with loss of muscle bulk, and hypo-
to areflexia. In acute spinal cord injury, the initial presentation
is a flaccid paresis, rather than an upper motor neuron presen-
tation, which will develop over time. In addition, muscle bulk
may be reduced in patients with chronic NMJ disorders or
myopathies, but may be normal in the acute phases of such
diseases [7].
Attention should also be focused on the distribution of
weakness. Symmetric proximal muscle weakness is associated
with primary muscular diseases such as polymyositis, derma-
tomyositis, mitochondrial myopathies, or muscular dystro-
phies. An asymmetric pattern of muscular weakness may be
seen in nerve or nerve root injuries, or injury to the brachial or
lumbosacral nerve plexus. The presence of pain may lead to
diagnosis of Parsonage–Turner syndrome (acute brachial plex-
itis) or thoracic outlet syndrome. An ascending pattern of
weakness is often associated with GBS. Distal symmetric weak-
ness may be seen in subacute onset of CIDP or inclusion body
myositis. Mononeuropathies such as compression injury to the
peroneal nerve or radial nerve in the spiral grove can result in
398
an asymmetric distal pattern of weakness. Mononeuritis multi-
plex can have a similar presentation. Involvement of the neck
flexors or hip flexors are often more prominent in myasthenia
gravis and polymyositis. Involvement of facial muscles, ptosis,
and fatigability would be important clues towards the diagno-
sis of myasthenia gravis [7].
Patterns of sensory involvement may be able to differen-
tiate pure motor disease such as ALS, multifocal motor neur-
opathy, NMJ disorders, or other myopathies from GBS and
other neuropathies, myelopathies, or myeloneuropathies.
Sensory loss in a peripheral nerve distribution should be dif-
ferentiated from a dermatomal pattern. This can help differen-
tiate distal versus proximal sites of injury. The involvement of
the perineal area, with loss of anal sphincter tone, may point
towards cauda equina syndrome [7]. This examination is often
difficult, since many patients may not be awake enough to
participate in the examination.
Differential Diagnosis
The differential diagnosis (Table 33.1) of generalized weakness
in the ICU is broad. In this section we will briefly review some
of these causes .
Disorders of the Central Nervous System
Spinal Cord Injury
The most common cause of acute spinal cord injury is trauma.
However, spinal cord injury can be secondary to nontraumatic
causes such as cancer, infection, intervertebral disc disease,
vertebral injury, and vascular disease [8]. Another source of
spinal cord injury may be convulsive status epilepticus leading
to hyperextension injury [9]. The clinical presentation is vari-
able and depends upon the site of injury. Cervical injury may
lead to quadriparesis and respiratory compromise, while thor-
acic injuries may result in paraparesis. The distribution of
sensory loss and identification of a sensory level can help with
localization. Bladder and bowel function is commonly affected
in spinal cord injury. The diagnosis can be made readily with
the aid of neuroimaging modalities such as computed tomog-
raphy (CT) or magnetic resonance imaging (MRI). Manage-
ment is supportive in most cases; however, surgery may be
needed to stabilize the spine and extract bone fragments.
Inflammation can cause further damage to the spinal cord,
and patients are sometimes treated with drugs to reduce swell-
ing. The use of high-dose methylprednisolone has been
reported to improve outcome in spinal cord injury if given
within six hours of injury [10]. This improvement is, however,
offset by an increased risk of infections and sepsis, and thus
methylprednisolone is no longer recommended in the treat-
ment of acute spinal cord injury [11].
Structural Lesions in the Central Nervous System
This a very broad category and may include strokes (ischemic
or hemorrhagic), demyelinating disease (multiple sclerosis,
neuromyelitis optica, acute disseminated encephalomyelitis),

congential or acquired leukodystrophies, spinal muscular atro-
phies, spinal cord infarction, Brown–Sequard syndrome, trans-
verse myelitis, or other infectious or nutritional myelopathies.
Diagnosis is made based on neuroimaging, cerebrospinal fluid
(CSF) analysis, and serologies. Treatment depends on the under-
lying cause.
Disorders of the Anterior Horn Cells
Amyotrophic Lateral Sclerosis
ALS is a severely debilitating disease characterized by rapidly
progressive weakness that presents with both upper and lower
motor signs, including muscle atrophy, fasciculations (lower
motor), spasticity, and hyper-reflexia (upper motor) as well as
dysarthria, dysphagia, and dyspnea. In a study of 92 ICU
patients referred for weakness, five had underlying ALS based
on electrophysiological evidence [12]. Failure to wean from the
ventilator is the most common presentation of ALS in ICU
patients. Diagnosis may be established by electromyography
(EMG) and nerve conduction velocities (NCVs), which may
show acute denervation, chronic renervation, and fascicula-
tions. In addition, MRI of the spine may identify atrophy of
the anterior horn of the spinal cord [13].
Acute Poliomyelitis
Poliomyelitis is caused by the poliovirus and is spread by the
fecal–oral route. Spinal polio affects the anterior horn cells,
resulting in muscle weakness and acute flaccid paralysis of the
lower extremities. Polio may also affect the cranial nerves alone
or in combination with spinal polio. Due to modern vaccin-
ations, polio has been largely eradicated and would be an
extremely rare cause of ICU weakness, unless the patient was
exposed to an endemic area of the world where the virus still
exists [14].
West Nile Virus
West Nile virus (WNV) infection is more frequent than polio
in the ICU setting. The initial presentation may be similar to
any infectious encephalopathy. Initially patients may present
with nausea, vomiting, headache, fever, myalgias, signs of
meningeal irritation, and/or altered sensorium. Subsequently,
patients may develop an acute asymmetric flaccid paralysis,
with respiratory failure requiring mechanical ventilation and/
or bladder dysfunction. CSF analysis typically has an increased
white blood cell (WBC) count, increased level of protein, the
presence of immunoglobulin M (IgM) to WNV, or positive
WNV findings by polymerase chain reaction (PCR) [15]. The
CSF profile is differentiated from GBS by a CSF pleocytosis.
EMG findings are consistent with ventral motor neuron dis-
ease. In rare instances there may be demyelinating features
similar to GBS [13].
Hopkin’s Syndrome
Acute postasthmatic amyotrophy, or Hopkin’s syndrome, is a
rarely described entity in which an acute flaccid paralysis
Chapter 33: Generalized Weakness
develops after an asthmatic attack [16]. There is a report of a
similar case after Mycoplasma pneumoniae infection [17]. EMG
findings point toward anterior horn cell involvement [17].
Muscle biopsy in one case is reported to show scattered atrophic
fibers, suggestive of lesions in the anterior horn cells of the
spinal cord [18]. Prognosis may vary, with recovery reported
in one patient treated with intravenous immunoglobulins [19].
Disorders of the Peripheral Nerves
Guillain–Barré Syndrome
GBS or acquired inflammatory demyelinating polyradiculo-
neuropathy (AIDP) is a common cause of admission to an
ICU for neuromuscular weakness. The syndrome is character-
ized by acute to subacute onset of paralysis, typically in a
symmetric ascending fashion, with sensory loss and general-
ized areflexia. Diagnosis is based on the typical clinical presen-
tation, with the aid of ancillary investigations including CSF
protein >45 mg/dL and NCV with demyelinating features
showing conduction block, conduction velocities less than
80% of normal, and absent or prolonged F-waves [20]. Treat-
ment options include administration of intravenous immuno-
globulin (IVIG) or plasma exchange (PLEX) and should start
when the diagnosis is suspected. The typical dose of IVIG is 2
g/kg divided into five equal doses, given daily. It is important
to determine IgA levels prior to administering IVIG, due to the
potential risk of anaphylaxis in IgA-deficient patients. PLEX is
typically done with four or five cycles of 50 mL/kg exchanges
over 10–14 days. In head-to-head trials comparing IVIG to
PLEX, the cumulative risk of recurrence of GBS was 10.8% versus
4.3% for PLEX (p <0.001). For recurrence, the common practice
is to repeat treatment or switch to another treatment [20].
GBS leading to respiratory failure requiring mechanical
ventilation occurs in about 30% of patients. Neck flexor weak-
ness directly correlates to diaphragmatic weakness and may be
a marker of impending respiratory failure. The criteria for
elective intubation in patients with GBS include clinical
fatigue, aspiration, vital capacity (VC) <15–20 mL/kg, PO2
<70 mmHg on room air, negative inspiratory force (NIF) less
than –30 cmH2O, or a rapid decline in VC or NIF >30% in
24 hours [20]. Intubation should occur prior to impending
respiratory collapse, based on declining NIF and VC.
Chronic Inflammatory Demyelinating Polyneuropathy
CIDP is characterized by an increasing symmetric distal-to-
proximal muscular weakness that progresses for more than
two months. It can be accompanied by sensory disturbance
and reduced or absent deep tendon reflexes. The CSF analysis
reveals elevated protein and EMG/NCV studies report partial
conduction block, reduced motor conduction velocities, pro-
longed distal latency, and prolonged or absent F-waves [21].
Nerve biopsy is essential to make the clinical diagnosis of
CIDP and shows evidence of demyelination and remyelination
[21]. MRI can show enlargement and enhancement of the
nerve plexus and nerve roots. Since the pathogenesis is
399
 Chapter 33: Generalized Weakness
immune mediated, treatment options include corticosteroid use,
PLEX, or IVIG alone, or in combination. Second-line agents are
azathioprine, cyclophosphamide, and cyclosporine [21].
Critical Illness Polyneuropathy
CIP was first described in 1984 by Bolton et al., as a syndrome
of generalized weakness, and the inability to wean off the
ventilator after a prolonged critical illness [2]. CIP occurs in
25–50% of ICU patients admitted with sepsis and multiorgan
failure and can occur as early as three days after the onset of
sepsis [20]. Clinically, patients appear awake, but have minimal
withdrawal to noxious stimulation. Weakness ranges from
moderate paresis with hyporeflexia to complete areflexia and
quadriparesis. Weakness is generally symmetric and affects
nerves in a distal-to-proximal fashion [13]. Cranial nerves
are often spared but facial weakness may be present; 50% of
patients may have some sensory impairment as well. Deep
tendon reflexes vary greatly, but most patients are hyporeflexic
to normoreflexic [13,20]. NCV provide evidence of an axonal
polyneuropathy, including reduced amplitudes of both com-
pound muscle action potentials (CMAPs), and sensory nerve
action potentials (SNAPs), with normal latencies and conduc-
tion velocities [20]. On muscle biopsy myopathic changes can
be seen as CIP and CIM often coexist. The etiology of CIP/
CIM is not entirely clear and is associated with a number of
factors including the use of neuromuscular blocking agents,
hyperglycemia, corticosteroid use, aminoglycoside antibiotics,
catecholamines, parenteral nutrition, and multiorgan failure
[20]. The treatment of CIP is mainly supportive. IVIG has not
been proven to alter outcomes. Aggressive treatment for sepsis,
avoidance of neuromuscular blocking drugs, corticosteroids,
and aminoglycosides, and maintaining strict blood glucose
control may decrease the risk of developing CIP [20].
Multifocal Motor Neuropathy
MMN is an infrequent cause of weakness in the ICU setting;
however, this diagnosis should be considered in patients with a
diagnosis of ALS. It is characterized by subacute onset of
progressive asymmetric motor weakness and atrophy without
sensory abnormalities [22]. The weakness may start in one
limb (usually upper) and progress to involve other extremities.
Muscle atrophy is noted later. Deep tendon reflexes may vary.
Cranial nerves are mostly spared. NCV show focal demyelina-
tion and conduction block in motor nerves and normal sens-
ory nerves [23]. Elevated titers of anti-GM1 antibodies may be
present [22]. MMN is treatable with IVIG; however it is not
responsive to corticosteroids or PLEX [22,24].
Compressive Neuropathies
Compressive neuropathies may present as an isolated weak-
ness and/or sensory loss in a single nerve distribution and are
readily identified based on history and neurological examin-
ation. The most common compressive neuropathy in an ICU
setting is a peroneal neuropathy. This is caused by compres-
sion of the peroneal nerve at the fibular head resulting in foot
400
drop and sensory loss in the peroneal distribution. The radial
nerve may get stretched during a long operation, or prolonged
tourniquet use and this presents with wrist drop. Femoral
neuropathy after hip surgery or due to a retroperitoneal hema-
toma can occur. Ulnar neuropathy can result rarely from
placement of an arteriovenous fistula for hemodialysis. Like-
wise any nerve can be affected by direct trauma or prolonged
pressure. The prognosis depends on the type and severity of
injury. Neuropraxia (focal demyelination without axonal
damage) carries a better prognosis than axonotemesis (axonal
damage with intact perineureum and epineurium) and neuro-
temesis (severing of entire nerve sheath). EMG seven to ten days
after injury is helpful in distinguishing the severity of injury [25].
Porphyria
Acute intermittent porphyria is an autosomal dominant dis-
order resulting in an enzymatic deficiency of porphobilinogen
deaminase [26]. Most commonly it presents with a sensory
neuropathy. Extremity, back, and chest pain occur and usually
precedes the characteristic abdominal pain. A motor neur-
opathy is a late manifestation of a prolonged attack. Weakness
progresses from proximal to distal, may involve the cranial
nerves, and may be severe enough to lead to quadriplegia and
respiratory paralysis. Diagnosis is made by elevated levels of
urine porphobilinogen. NCV show reduced amplitude of sens-
ory and motor nerve action potentials with preserved conduc-
tion velocities and F-waves. EMG may show axonal loss [7].
Treatment is intravenous hemin [27].
Vasculitic Neuropathy
Acute sensorimotor polyneuropathy may be seen in associ-
ation with vasculitis. Mononeuritis multiplex, defined as
damage to two or more motor nerves in separate parts of the
body, is the most common presentation of a peripheral nerve
vasculitis. A polyradiculopathy or plexopathy may also occur
in relation to this vasculitis. Diagnosis is confirmed by careful
neurologic examination, EMG/NCV testing, and appropriate
serologic tests for vasculitis. NCV may show low SNAP and
CMAP amplitudes with or without decreased conduction vel-
ocities. EMG may show denervation with fibrillations and posi-
tive sharp waves. Although not necessary, a combined nerve and
muscle biopsy may be helpful. Treatment involves steroids for
nonsystemic vasculitis. Cyclophosphamide is reserved for
patients with evidence of systemic vasculitis. Maintenance ther-
apy includes azathioprine or methotrexate [7,28,29].
Disorders of the Neuromuscular Junction
Myasthenia Gravis
MG is an autoimmune disorder caused by antibodies against
the postsynaptic acetylcholine receptor. The disease is character-
ized by fatigability, diplopia, generalized weakness, and respira-
tory muscle compromise. It is one of the most frequent causes of
admission to the ICU for generalized respiratory weakness.
Patients with pre-existing MG may have exacerbations secondary

to infections, reduction of anticholinesterase medications, stress,
corticosteroid use, or from medications that interfere with
neuromuscular transmission. Workup includes antibody evalu-
ation, CT of the chest to evaluate for the presence of a thymoma,
and electrophysiological testing revealing impaired postsynaptic
transmission. Acetylcholine receptor antibodies are present in
85% of patients [30]. Muscle-specific tyrosine kinase (MuSK)
antibodies can be identified in up to one-third of patients with
negative acetylcholine receptor antibodies [31]. NCV with repeti-
tive nerve stimulation shows a decremental response in CMAPs
of greater than 10% and may be positive in up to 77% of patients
[32]. Single nerve fiber EMG is the most sensitive test and is
positive in up to 92% of patients with generalized MG, however,
it is more cumbersome and technically difficult to obtain [32].
Patients with decreased VC (less than 15 mL/kg), excessive
respiratory muscle fatigue, or inability to clear secretions should
be intubated electively [20]. Once intubated, anticholinergic
medication should be stopped as it results in excessive respira-
tory secretions. It can be resumed at half the original dosage after
weaning off the ventilator [20]. PLEX is the first-line treatment
for myasthenic crisis and shows rapid improvement in about
75% of the patients. IVIG is less effective than PLEX in these
situations [20]. Following improvement from PLEX or IVIG,
patients may be started on immunosuppressant medications
such as corticosteroid or azathioprine [20].
Lambert–Eaton Myasthenic Syndrome
LEMS is a presynaptic NMJ disorder with a similar clinical
presentation as MG. The defect in this process is in the
release of acetylcholine from the presynaptic nerve endings.
This is due to antibodies directed to voltage-gated calcium
channels (VGCCs), which allow calcium entry into the pre-
synaptic terminal. Calcium entry is required for the release
of acetylcholine into the synaptic cleft [33]. LEMS is a para-
neoplastic disease associated with small cell lung cancer;
however, autoimmune LEMS without cancer has been
reported. Diagnosis is made by the presence of antibodies
against VGCC, reduced CMAP on NCV and >100% incre-
ment after high frequency repetitive nerve stimulation. In
contrast to MG, response to PLEX or IVIG is transient, and
patients often benefit from treatment of the underlying
malignancy. Immunosuppressant therapy, including cortico-
steroids, azathioprine, or cyclophosphamide has had variable
results [33].
Botulism
Botulism is a food-borne illness caused by ingesting toxins
produced by Clostridium botulinum, and presents with cra-
nial nerve palsy and a symmetric descending paralysis, with
or without respiratory muscle failure. NCV are usually
normal, with repetitive nerve stimulation at higher frequency
showing an incremental response [7]. Treatment is with
botulinum antitoxin and supportive care. Early identification
is important, since the antitoxin must be administered within
24 hours.
Chapter 33: Generalized Weakness
Prolonged Neuromuscular Blockade
ICU patients with underlying hepatic or renal failure, or other
metabolic derangements, may be prone to developing pro-
longed neuromuscular blockade. Nondepolarizing neuromus-
cular blocking agents such as vecuronium and pancuronium
have been reported to cause prolonged muscle blockade several
days after their discontinuation [6,13,34]. Clinically, patients pre-
sent with generalized weakness and hyporeflexia. The process is
usually self-limiting and improves with time. NCV may show
decrease CMAPs, which improve one or two weeks after stopping
neuromuscular blockade. Some cases may progress to CIM [13].
Disorders of the Muscle
Critical Illness Myopathy
CIM is also a common acquired disorder in the ICU [13]. The
earliest description of an acquired myopathy was reported in a
patient admitted with status asthmaticus that was treated with
steroids and neuromuscular blockade [4]. Since this early
description, the entity has been described abundantly. CIM
can occur alone or in combination with CIP. It may also occur
as a sequela of prolonged neuromuscular blockade [5,13]. Risk
factors include sepsis, severe pulmonary disease, liver trans-
plant, high-dose corticosteroid administration, and prolonged
use of neuromuscular blocking agents [35]. Clinical examin-
ation shows predominantly proximal diffuse muscle weakness,
with muscle wasting and failure to wean [35]. Creatinine
kinase (CK) is elevated [13]. Electrophysiologic findings are
consistent with a necrotizing myopathy. Muscle biopsy shows
myopathy with loss of thick filaments, and atrophy of types
I and II fibers [35]. The disease is reversible, but may prolong
the duration of artificial ventilation [36]. There is no definitive
treatment, and as with CIP, avoidance of predisposing factors
is warranted.
Rhabdomyolysis
Rhabdomyolysis is characterized by myalgias, urine discolor-
ation due to myoglobinuria, and elevated serum muscle
enzymes (CK, aldolase, lactate dehydrogenase, aspartate ami-
notransferase). The causes of rhabdomyolysis may include
crush injury, strenuous exercise, prolonged convulsive
seizures, alcohol withdrawal, prolonged immobilization, gen-
etic defects, infections, heat stroke, malignant hyperthermia,
neuroleptic malignant syndrome, metabolic derangements,
diabetic ketoacidosis, toxins, steroid use, or it can be idio-
pathic. Acute renal failure is a common complication of rhab-
domyolysis [37]. The diagnosis is based on clinical
presentation, elevated CK, and the presence of urine myoglo-
bin. Ancillary data may show elevated creatinine, as well as a
high anion gap metabolic acidosis. NCV/EMG and neuroima-
ging is not necessary. The mainstay of treatment is aggressive
fluid resuscitation with normal saline to achieve urine output
of 3 mL/kg/h. Patients often require 10 L of fluid per day [37].
Electrolytes should be monitored frequently during resuscita-
tion and metabolic abnormalities corrected as soon as possible.
401
 Chapter 33: Generalized Weakness

Other Muscle Diseases Conclusion

Generalized weakness in the ICU can occur as a result of a pre-
existing congenital or hereditary myopathy. These may include
mitochondrial myopathies, acid-maltase deficiency, muscular
dystrophies, or myotonic dystrophies, etc. Inflammatory myo-
pathies such as polymyositis or dematomyositis are additional
sources of proximal muscle weakness often discovered in the
ICU. A careful history, clinical examination, with additional
ancillary testing usually can identify the diagnosis. The final
diagnosis is confirmed with a muscle biopsy or genetic testing.
Treatment is dependent on the underlying cause.
Generalized muscular weakness in the ICU can be due to a
number of causes, which may include disorders of the central
nervous system, anterior motor horn, neuropathies, myopa-
thies, or NMJ disorders. A detailed history and recognizing the
pattern of weakness may facilitate diagnosis in a number of
situations. It is important to establish the underlying diagnosis,
as treatment and outcome are disease specific.

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 Chapter
Management of Severely Brain-Injured Patients
34 Recovering from Coma in the Neurocritical Care Unit
Caroline Schnakers and Martin M. Monti
Introduction
Disorders of consciousness, as conceived today, are a
relatively recent phenomenon. Indeed, until about 60 years
ago, individuals who suffered from a brain injury of
the severity that typically leads to a disorder of conscious-
ness rarely survived. In the fifties, the introduction of
mechanical ventilation radically changed our ability to
extend the life of these patients. This revolutionary
advance in critical care, however, confronted clinicians
with an almost unprecedented, and highly perplexing,
neurological condition in which patients are alive but not
responsive to their surroundings. In the past 30 years, and
particularly since the introduction of noninvasive brain
imaging techniques, patients suffering from this neuro-
logical condition have been at the center of flourishing
clinical research, aimed at developing a full understanding
of loss and recovery of cognitive function after severe brain
injury, and scientific interest, aimed at understanding
one of the most central aspects of the human brain:
consciousness.
In this chapter, we will focus on disorders of conscious-
ness acquired after severe brain injury, including coma, the
vegetative state, and the minimally conscious state. We will
first characterize and define these clinical entities, and focus
on the clinical techniques employed to determine whether a
patient who survives severe brain injury is conscious.
Following, we will overview a growing literature addressing
the extent to which brain function can remain in conscious
versus unconscious patients. We will then discuss the factors
that should be taken into consideration when formulating a
prognosis, and the issue of potential treatments available.
Finally, we will introduce what is now considered a new
dilemma for clinicians in this context: behaviorally unrespon-
sive patients who retain, nonetheless, aspects of covert cogni-
tion. This chapter aims at including all the information
needed to optimize the care that could be provided to patients
in an acute setting, but also to optimize the feedback that
could be given to families with a relative who recovers from
coma. Indeed, accurate information early in the recovery path
is crucial for improving the way in which families can
cope with such a dramatic, and emotionally and financially
straining, situation.
404
Disorders of Consciousness
Definition
Patients who survive a severe brain injury can stay unconscious
for several weeks, being neither awake (i.e. demonstrating no eye
opening even in response to noxious stimulation), nor conscious
(i.e. demonstrating no awareness of themselves or their environ-
ment). These patients are thus in a coma, a condition defined as
“a pathological state marked by severe and prolonged dysfunc-
tion of vigilance and consciousness” [1]. Patients usually emerge
from this state within two to four weeks to evolve into a vegeta-
tive state or a minimally conscious state (see Figure 34.1).
In 1972, the term “vegetative state” (VS) was first intro-
duced by Jennet and Plum to describe “an organic body
capable of growth and development, but devoid of sensation
and thought” [2]. Patients in VS open their eyes spontaneously
or in response to stimulation, present preserved autonomic
functions (e.g. cardio-vascular regulation, thermoregulation),
but are not conscious and only show reflexive behaviors [3].
The return of eye opening, however, does not necessarily imply
the recovery of sleep–wake cycles, as shown by recent findings
reporting no electroencephalographical (EEG) changes and no
common stages of sleep (such as slow wave sleep or rapid eye
movements) during prolonged periods of eye-closing in VS
patients [4]. Patients may also display an array of spontaneous
behavior, such as moaning, smiling, crying, or grimacing.
However, these behaviors are typically produced out of con-
text, or inappropriately, and are therefore interpreted as auto-
matic and not indicative of a state of consciousness (i.e. they
are consistent with a VS diagnosis). When patients remain in
this condition for at least three weeks, they are said to be in a
persistent vegetative state. When the condition lasts longer
than three months (for patients with nontraumatic brain
injury) or one year (for patients with traumatic brain injury),
a prognosis of permanent vegetative state is made. Note that,
given the perceived negative connotation of the term “vegeta-
tive state,” The European Task Force on Disorders of Con-
sciousness has recently proposed using the more neutral and
descriptive term “unresponsive wakefulness syndrome” [5].
Some patients may remain in a vegetative state indefinitely;
others, however, might regain some level of consciousness
and are thus said to enter a “minimally conscious state”
 Chapter 34: Management of Severely Brain-Injured Patients

Conscious

Nonconscious
Behaviorally indistinguishable Conscious
patients wake
Behavioral Drowsiness

Light
Ability to produce sleep MCS
motor behavior
Deep
sleep

Nonbehavioral General
Anesthesia
Coma Aware
Content of
consciousness
VS
(awareness)
Nonawake Nonaware

Level of Awake
consciousness
(wakefulness)
Figure 34.1 The conundrum of consciousness. Disorders of consciousness are defined by two main components: the level of consciousness and the content of
consciousness. This figure illustrates where different states (i.e. coma, VS, MCS, but also states related to sleep and anesthesia) are placed on both continuums. It also
represents where patients with covert cognition would be placed. Indeed, if a conscious patient is unable to perform voluntary motor behaviors (like an MCS patient),
he/she would be indistinguishable from a VS patient, based on behavioral assessments, but could be detected using paramedical tools such as neuroimaging or
electrophysiology. (Adapted from [53]). A black and white version of this figure will appear in some formats. For the color version, please refer to the plate section.

(MCS). In 2002, the Aspen Workgroup defined the minimally

conscious state as a condition in which patients show the
Differential Brain Activity
In VS patients, metabolic dysfunctions have been observed
presence of inconsistent but clearly discernible behavioral
bilaterally in several brain regions, including polymodal associa-
signs of consciousness [6]. Patients evolving from a VS to an
tive cortices such as medial and lateral frontal regions, parieto-
MCS are thus not only awake, but also start showing simple
temporal and posterior parietal areas, posterior cingulate, and
oriented behaviors such as visual pursuit. Signs of conscious-
precuneal cortices [8]. These regions are all involved in a net-
ness in these patients may be subtle and can be hard to observe
work of areas, typically referred to as the “default mode
because of their characteristic inconsistency and fluctuations
network,” which are believed to be implicated in cognitive
in vigilance. Nevertheless, to meet diagnostic criteria for MCS,
processes such as daydreaming, mind-wandering, and thus,
observed behaviors must be replicated within a given examin-
more generally, in stimulus-independent or self-related
ation. As they progress, MCS patients may also start presenting
thoughts. Recent studies have shown that these regions are not
more complex voluntary behaviors such as response to com-
just metabolically dysfunctional, they also exhibit decreased
mands (e.g. “shake my hand”), thereby also demonstrating the
connectivity with each other in VS patients, as compared to
understanding of language. Recently, in consideration of the
conscious patients (see Figure 34.2). More specifically, the pre-
wide array of behavioral presentation of MCS patients, this
cuneus, an area in the medial parietal cortex believed to be
category has been subdivided into MCS+ and MCS–, based on
crucial in conscious processing, has been found to be signifi-
whether they can demonstrate, or not, response to command
cantly less connected to the other areas of the network in VS
[7]. Patients in an MCS may also show appropriate emotional
patients as compared to MCS patients [9]. Similar findings have
responses (cries or laughs occurring in contingent relation to
been reported when studying brain activity in response to
appropriate environmental triggers), inappropriate object
stimulation. Activation studies using auditory stimulation (i.e.
manipulation or intelligible verbalizations without being able
tones) have shown preserved functioning in the primary audi-
to functionally communicate either verbally or gesturally. The
tory cortex without, however, extending to “higher-level” inte-
recovery from MCS is defined by the re-emergence of func-
gration areas (such as the temporoparietal junction) [10].
tional communication and/or functional object use [6].

405
 Chapter 34: Management of Severely Brain-Injured Patients

Figure 34.2 Residual brain activity in disorders of consciousness. Residual brain activity at rest (within the default network) (A) and in response to noxious
stimulation (B) in patients in VS versus MCS (adapted from [9,18]). Panel C illustrates the deficit in connectivity (particularly long-distance backward connectivity) in
VS versus MCS patients (adapted from [12]). Panel D illustrates the thalamic atrophy linked to patients’ outcome at six months post injury (adapted from [14]). A black
and white version of this figure will appear in some formats. For the color version, please refer to the plate section.

Similarly, noxious stimulation (i.e. electrical stimulation of the
median nerve) activated in VS patients only a part of the
network involved in the low-level sensory-discriminative pro-
cessing of pain (i.e. midbrain, contralateral thalamus, and pri-
mary somatosensory cortex) (see Figure 34.2) [11]. In both
activation studies, low-level primary cortical activity seems to
be isolated from higher-level associative cortical activity [10,11].
More exactly, recent findings suggest that long-distance con-
nectivity (e.g. between frontal and temporal areas) is more
affected than short-distance connectivity (e.g. areas within the
temporal gyrus) and may therefore be crucial for integrative
brain processes leading to consciousness (see Figure 34.2) [12].
There is not only a disruption in the way the information is
processed at a cortical level, but also in the way it is transmitted
from a subcortical to a cortical level. Indeed, a re-establishment of
the connections between the thalamus and associative areas has
been found in a single patient recovering from a VS [13]. This is
particularly important since the thalamus constitutes a relay in
transmitting sensory/motor signals from subcortical to cortical
areas, and has a key role in conscious processing. In fact, Monti
and coworkers have recently shown that the extent of atrophy
observed in the anterior and medio-dorsal thalamic nuclei is
predictive of the patient’s recovery at six months post injury [14].
These results suggest the presence of an impaired and
disconnected residual brain activity in VS patients which, most
likely, does not lead to integrated conscious perception. In
MCS patients, however, an activity in the precuneus and the
posterior cingulate cortex (the most active regions in
awakening and the least active ones under general anesthesia
or during deep slow wave sleep) appears to be superior to the
activity observed in VS patients. In contrast to the limited
brain activation found in VS, functional imaging studies using
auditory stimulation show a larger recruitment of “higher-
level” integrative brain regions in the temporal cortex (includ-
ing the temporoparietal junction) [15–17]. In these patients,
the valence of an auditory stimulation can also lead to a
difference in brain activity. Indeed, MCS patients seem to
activate a broader part of the temporal lobe and the amygdala
in response to emotional, as compared to neutral, auditory
stimulation [16]. With respect to noxious stimulation, Boly
and coworkers showed that brain activation in MCS patients
can be similar to that observed in healthy controls, spanning
higher-level regions in the anterior cingulate cortex (known to
be related to pain unpleasantness; see Figure 34.2) [18]. In
parallel, a longitudinal case report described by Bekinschtein
and coworkers showed that, in a patient progressing from VS

406

to MCS, linguistic stimuli elicited activation across a wide
fronto-temporo-parietal well beyond the primary temporal
auditory cortex [19]. Activation in the thalamus has also been
observed to be greater in MCS versus VS patients [20]. Fur-
thermore, MCS patients also exhibit higher cortico-cortical
and thalamo-cortical connectivity, as compared to VS patients
[13,17,18,21]. These data suggest that, in contrast to VS
patients, MCS patients may retain sufficient cortical integra-
tion and access to afferent information to allow conscious
perception. Casali and coworkers have suggested the use of
an index reflecting such cortical integration (i.e. the perturba-
tional complexity index) after successfully differentiating indi-
viduals in VS from those in MCS. Such an index will
nevertheless need further validation before being integrated
into clinical daily practice [22].
Diagnosis and Consciousness Assessment
Behavioral assessment remains the gold standard to detect the
presence of consciousness in severely brain-injured patients,
but requires thorough expertise. Differentiating MCS from VS
can be particularly challenging considering that voluntary and
reflexive behaviors can be difficult to distinguish from each
other, and that behavioral signs of consciousness may be very
subtle and easily missed. Previous studies have shown that
around 40% of patients diagnosed as being in a VS were
misdiagnosed and were in fact conscious [23–25]. Using valid
and sensitive behavioral scales to detect the presence of signs of
consciousness, even subtle ones, therefore represents a real
necessity.
The Glasgow Coma Scale
The Glasgow Coma Scale (GCS) is the first behavioral scale
ever widely used. This scale has been the first validated rating
scale developed to monitor levels of consciousness in the
intensive care unit [26]. It includes three subscales that address
arousal level, motor function, and verbal abilities. The GCS has
been extensively investigated, particularly for its prognostic
value. Nevertheless, despite its widespread use, the GCS has
been criticized for its low inter-rater agreement and its use in
patients with ocular trauma, tracheostomy, or mechanical
ventilation [27]. Moreover, a previous study has shown that
using such a scale could lead to a misdiagnosis rate of 50%,
suggesting that using a standardized scale is not sufficient; the
scale has also to be a sensitive diagnostic tool [28].
The Full Outline of UnResponsiveness Scale
The Full Outline of UnResponsiveness Scale (FOUR) has
recently been developed to replace the GCS to assess severely
brain-injured patients in intensive care [29]. The scale includes
four subscales assessing motor and ocular responses, brain-
stem reflexes, and breathing. The total score ranges from 0 to
16. Unlike the GCS, the FOUR does not assess verbal functions
to accommodate the high number of intubated patients in
intensive care. It also assesses brainstem reflexes and breathing
and, therefore, helps to better monitor comatose and VS
Chapter 34: Management of Severely Brain-Injured Patients
patients. The scale also tracks emergence from VS, as it
includes the assessment of early signs of consciousness, such
as visual pursuit. The scale is globally more sensitive than the
GCS for diagnosing an MCS, but still leads to 30% misdiag-
nosis when compared to other scales such as the Coma Recov-
ery Scale-Revised (CRS-R) [28].
The Coma Recovery Scale
The CRS-R aims to improve differential diagnosis in patients
with disorders of consciousness [30]. The scale consists of
23 items that comprise six subscales addressing auditory,
visual, motor, oromotor, communication, and arousal func-
tions. Scoring is standardized and based on the presence or
absence of operationally defined behavioral responses to spe-
cific sensory stimuli. Psychometric studies indicate that the
CRS-R meets high standards for measurement and evaluation
tools designed for use in interdisciplinary acute rehabilitation.
The CRS-R can be administered reliably by trained examiners
and produces reasonably stable scores over repeated assess-
ments. Validity analyses have shown that the CRS-R is capable
of discriminating patients in MCS from those in VS even
better than other consciousness scales (such as the GCS or
the FOUR) (see Table 34.1) [28,31].
The Nociception Coma Scale
The Nociception Coma Scale (NCS) does not assess conscious-
ness, but is the first tool ever developed to assess nociceptive
pain in VS and MCS patients, which is of importance when
monitoring those patients in an acute setting. The NCS [32]
consists of four subscales assessing motor, verbal, and visual
responses, as well as facial expression. It has been validated in
patients from intensive care, neurology/neurosurgery units,
rehabilitation centers, and nursing homes. The scale has dem-
onstrated good inter-rater reliability and good concurrent val-
idity. As compared to other pain scales developed for
noncommunicative patients, the NCS shows a broader score
range and a better sensitivity to clinical diagnosis (i.e. VS
versus MCS), suggesting it constitutes a more adapted tool
for this population. The motor, verbal, and facial subscores
included in the revised version of the scale (NCS-R) have also
been found to be significantly higher in response to noxious
stimuli than non-noxious stimuli, reflecting the good sensitiv-
ity of the scale [33]. Finally, recent findings have shown a
correlation between NCS-R total scores and the activity in
the anterior cingulate cortex (related to pain unpleasantness),
reflecting further the relevance of this scale when monitoring
pain in patients with disorders of consciousness [34]. Based on
the NCS-R, a cut-off score of 4 (sensitivity of 73% and specifi-
city of 97%) has been defined as a potential clinical threshold
for detecting pain in these patients [33].
Prognosis
Several variables have to be considered when formulating a
prognosis. Among the most important are the etiology and the
407
 Chapter 34: Management of Severely Brain-Injured Patients

Table 34.1 Coma Recovery Scale-Revised record sheet patients (48–60% versus 26% attaining moderate disability)
Auditory function scale [36]. The time spent in a VS is also important to consider as
it has been negatively correlated with functional outcome. The
4 – Consistent movement to command* chance of regaining independence at one year after injury
3 – Reproducible movement to command* decreased with time from 18% (one month in VS), to 12%
2 – Localization to sound (three months in VS), and 3% (six months in VS) [35]. It also
differs according to the etiology. Patients are usually con-
1 – Auditory startle sidered in a permanent VS when they are in such state for
0 – None more than a year in case of traumatic etiologies and for more
Visual function scale than three months [3] (or six months) [37] for nontraumatic
etiologies, as they have almost no chance of recovery (less than
5 – Object recognition* 5%). Only then can the ethical and legal issues around with-
4 – Object localization: reaching* drawal of treatment be discussed. Recovery of consciousness
3 – Pursuit eye movements* may be observed in a minority of patients diagnosed as being
in a permanent VS (of traumatic and nontraumatic etiologies).
2 – Fixation* However, those patients remain severely disabled and entirely
1 – Visual startle dependent for daily support [38].
0 – None The transition from VS to MCS, as well as the amount of
behavioral changes that occur within eight weeks after injury,
Motor function scale is strongly related to the patient’s functional outcome. MCS
6 – Functional object use** patients have a better functional recovery than VS patients at
5 – Automatic motor response* one year post injury (50% versus 3% attaining moderate dis-
ability) [39]. In contrast to patients in VS, a third of patients in
4 – Object manipulation * MCS improved more than one year after injury [40]. Even
3 – Localization to noxious stimulation* though the probability of functional recovery in MCS is more
2 – Flexion withdrawal favorable relative to VS (for either traumatic or nontraumatic
etiologies), prognosis remains very difficult because of the
1 – Abnormal posturing huge heterogeneity of recovery in chronic patients. Some
0 – None/flaccid patients in MCS progress slowly, while others remain in this
Oromotor/verbal function scale condition permanently [36,40]. The duration of MCS never-
theless seems to be a strong predictor of the length of confu-
3 – Intelligible verbalization* sional state/post-traumatic amnesia [41]. Besides the level of
2 – Vocalization/oral movement consciousness, early recovery (within eight weeks) of target
1 – Oral reflexive movement conscious behaviors, such as visual pursuit and response to
command, have been linked to good functional outcome sev-
0 – None eral years after the injury [42,43]. Notice that, even though the
Communication scale presence of visual pursuit is an indicator of good prognosis, it
2 – Functional: accurate** is also one of the most difficult signs of consciousness to detect
and requires the use of sensitive diagnostic tools (such as the
1 – Non-functional: intentional* CRS-R; see previous section) [23].
0 – None Finally, a last variable to consider is the age. Indeed, an
Arousal scale advanced age leads to poor outcome [3]. Independent living at
one year may decrease from 21% for patients below 20 years
3 – Attention* old to 9% for patients between 20 and 39 years old, and almost
2 – Eye opening w/o stimulation 0% for patients above 40 years old [35]. Children between five
1 – Eye opening with stimulation and six years old are more likely to present a favorable prog-
nosis than adults [36].
0 – Unarousable
*Denotes MCS; ** Denotes emergence from MCS
Treatment
There are only a few treatments that have been showing
time since injury. VS patients with traumatic etiologies present some effect on the recovery of patients with disorders of
a better outcome at one year post injury than nontraumatic consciousness. The sensory stimulation program (SSP) is the
etiologies (10–30% versus 0–3% attaining moderate disability) most widely known and has been used in severely brain-injured
[3,35,36]. Similar observations have been made for MCS patients since the seventies. The assumption is that providing

408

structured stimulation (such as visual, auditory, tactile, olfac-
tory, and gustatory) could avoid sensory deprivation, promote
neuroplasticity, and therefore optimize the recovery from coma.
Numerous studies have investigated sensory stimulation in
patients with disorders of consciousness. However, most of
those studies were either descriptive case reports or were
affected by various methodological biases, the most important
being spontaneous recovery, making any inference as regards
the efficiency of SSP impossible [44].
Among other nonpharmacological treatments, neurosti-
mulation has been increasingly studied in the past 10 years.
Schiff and coworkers have observed treatment-related behavioral
improvements in a chronic post-traumatic MCS patient treated
with deep brain stimulation (DBS) of thalamic intralaminar
nuclei [45]. Behavioral changes such as response to command,
oral feeding, and functional communication have been observed.
Contrary to previous DBS studies, the authors have been able to
relate with certainty improvements with the treatment, as they
used a double-blind time-series design in a highly chronic
patient (six years post-injury; showed no improvements during
previous rehabilitation programs), decreasing chances of bias
due to spontaneous recovery. Even though this study shows the
effect of DBS on consciousness recovery, it has to be reproduced
in a larger sample. Moreover, DBS remains a very invasive
technique requesting the intervention of neurosurgery, which
may be risky for such a vulnerable population.
Alternative noninvasive neurostimulation techniques have
been tested, such as transcranial magnetic stimulation (TMS)
and transcranial direct current stimulation (tDCS). TMS of the
primary motor cortex has been applied in a traumatic MCS
patient five years after injury using a time-series design in
which the examiner was blinded to the stimulation received
(either TMS or median nerve stimulation as placebo). Behav-
ioral changes such as response to command, object reaching
and object manipulation were only observed after TMS ses-
sions (within the following six hours) [46]. More recently,
Thibaut and coworkers have investigated the effect of tDCS
in 55 patients with disorders of consciousness (i.e. VS and
MCS) using a double-blind sham-controlled crossover design
[47]. In each patient, one single tDCS and one sham session
were applied over the dorsolateral prefrontal cortex. Patients
showed behavioral changes (e.g. response to command and
visual pursuit) only after tDCS, but those changes were mainly
presented by MCS patients. The authors also did not find a
difference in functional outcome at one year between respond-
ers and nonresponders and concluded that short-duration
tDCS (i.e. one session) transiently improves consciousness.
Even though further investigations will be needed to show, in
a large sample, the long-lasting effect of neurostimulation on
consciousness recovery and the impact of such treatments on
patients’ long-term outcomes, those preliminary findings are
promising and may open the therapeutic choices currently
available for severely brain-injured patients.
Indeed, until now, only one treatment, amantadine, has
demonstrated its efficacy in a large sample (n = 182) using a
Chapter 34: Management of Severely Brain-Injured Patients
double-blind placebo-controlled design [48]. This pharmaco-
logical treatment facilitates the release of dopamine and delays
its recapture, resulting in an increase in synaptic dopamine
concentration. The treatment was administered to patients 4 to
16 weeks after traumatic brain injury. Giacino and coworkers
randomly assigned patients to receive amantadine or placebo
for four weeks [48]. Recovery was significantly faster in the
amantadine group than in the placebo group. This effect has
been observed in both VS and MCS patients. Amantadine
seems therefore to accelerate the functional recovery of
patients with disorders of consciousness. Other pharmaco-
logical treatments have been tested, but have not shown the
same efficacy. Two studies in, respectively, 60 and 84 patients
[49,50] have investigated the effect of zolpidem (Ambien or
Stilnox), a selective γ-aminobutyric acid (GABA) receptor
agonist, which is usually recommended in cases of insomnia
and shows sedative, anticonvulsive, anxiolytic, and myorelax-
ant effects. Those placebo-controlled double-blind single-dose
studies have shown treatment-related transient behavioral
changes (response to command, nonfunctional communica-
tion, and functional object use, one to two hours after intake)
in, respectively, 2% and 5% of their sample [49,50].
Patients with Covert Cognition
For almost ten years now, clinicians have faced a new group of
patients who are unable to show any behavioral sign of con-
sciousness but are able to respond mentally to active neuro-
imaging or electrophysiological paradigms (see Figure 34.1).
In 2006, Owen and coworkers reported the case of a young
woman considered to be in a VS. When performing a mental
imagery task, her brain activity was similar to that observed in
healthy controls [51]. Activation in the supplementary motor
area was observed when imagining playing tennis (motor
imagery), whereas activation in the premotor cortex, the para-
hippocampal gyrus, and the posterior parietal cortex was
observed when imagining moving around her home (spatial
imagery). As it is well documented that words may elicit
automatic neural responses in the absence of consciousness,
some have argued that the words “tennis” and “house” may
have automatically triggered the patterns of activation
observed. However, such activation typically lasts for a few
seconds and occurs in regions of the brain that are associated
with word processing. In this case, the activation lasted the
entire task and persisted until the patient was asked to rest.
Further, the activation was not observed in brain regions that
are known to be involved in word processing [51]. In this
sense, the decision to follow the instruction “imagine playing
tennis” rather than simply “rest” is a willful action which
clearly reflects consciousness. Following this study, Monti
and coworkers tested 54 patients using the same paradigm.
Only two patients diagnosed as being in a VS and three
patients diagnosed as being in an MCS performed the task
(9% of the group) [52]. One of these patients was asked to
answer “yes” or “no” to autobiographical questions by using
409
 Chapter 34: Management of Severely Brain-Injured Patients
Motor Imagery: Answer “YES”
Control
Patient
Figure 34.3 Willful communication in a patient diagnosed as being in a VS (adapted from [52]). A black and white version of this figure will appear in some formats.
For the color version, please refer to the plate section.
either motor or spatial imagery. Interestingly, even if this
patient did only show very fluctuating behavioral signs of
consciousness, he performed the task correctly, suggesting
a high level of cognitive functioning (see Figure 34.3) [52].
Since then, a series of studies have been published about the
detection of willful brain activity in patients diagnosed as being
in a VS, confirming the existence of patients with covert
cognition [53].
It is tempting to think that those patients are misdiagnosed
patients with locked-in syndrome (LIS). Misdiagnosis is very
frequent in LIS patients as the patients cannot move or talk
due to quadriplegia and anarthria [54]. They are nevertheless
usually able to use vertical eye movements and eye blinking to
communicate with their environment. Moreover, this syn-
drome is often due to a basilar thrombosis (60% of cases)
and, more exactly, to a selective ventropontine lesion produ-
cing a paralysis of all four limbs without interfering with
consciousness or cognition. Functional neuroimaging typically
shows preserved supra-tentorial areas (with hypometabolism
in the cerebellum). Interestingly, significant hyperactivity has
been observed bilaterally in the amygdala of acute LIS patients,
likely reflecting anxiety generated by the inability to move or
speak (stressing the importance of appropriate anxiety treat-
ment soon after diagnosis) [54].
Conversely, patients with covert cognition do not show
such preserved brain activity. A “mesocircuit” model, suggest-
ing the presence of a disconnection between subcortical and
cortical pathways (or, more exactly, an interruption in the
cortico-striato-pallido-thalamo-cortical circuit), has been
developed to explain, in the most extreme cases, the discrep-
ancy observed between motor and cognitive functions in some
410
Spatial Imagery: Answer “NO”
severely brain-injured patients [55]. This hypothesis has never-
theless to be verified at a group level. As covert cognition
seems rare (9% of cases), it is difficult to collect enough infor-
mation regarding the characteristics of such a group. Cruse
and coworkers have observed more traumatic than nontrau-
matic etiologies in MCS patients responding to motor imagery
[56]. They have not found this difference in responsive VS
patients [57]. These studies reported positive results in only
five and three patients, respectively. Future studies will have to
be multicentric in order to gather a sufficient amount of data
to establish the profile of this new clinical entity.
As previous findings have shown the presence of commu-
nication in some patients with covert cognition, recent studies
have been trying to investigate the interest of brain–computer
interfaces (BCIs) in severely brain-injured patients [58]. In
Monti’s study, patients had to use mental imagery (i.e. imagine
playing tennis or moving around their home) to respond “yes”
or “no” to autobiographical questions [52]. It is nevertheless a
complex task to perform. Sellers and Donchin have developed
a simpler electrophysiological P3-based BCI paradigm (includ-
ing four auditory stimuli: yes, no, stop, go) during which
participants have to count the appropriate answer (yes or no)
to a series of questions [59]. The authors have validated their
paradigm in paralyzed brain-injured patients without dis-
orders of consciousness, such as patients with amyotrophic
lateral sclerosis (ALS; i.e. motor neurone disease causing
muscle atrophy and dysarthria, but also, in the most extreme
cases, dysphagia and dyspnea). Appropriate P3 responses have
clearly been observed in five out of six patients. Four of them
have used this system afterwards in order to communicate
with their surroundings. Lulé and coworkers have used this
 Chapter 34: Management of Severely Brain-Injured Patients

paradigm in 16 patients with disorders of consciousness [60]. conscious from unconscious individuals in various settings
One MCS patient was able to communicate while no response (i.e. healthy subjects during sleep and anesthesia as well as
to command had been detected at the bedside. In parallel, brain-injured patients with disorders of consciousness and
Owen and coworkers have adapted this paradigm to neuro- locked-in syndrome) [22]. Such an index for the detection of
imaging and have been able to show reliable communication patients with covert cognition will nevertheless have to be
in two patients (one MCS and one VS), despite their failure to investigated in the near future.
show such ability during repeated behavioral assessments [61].
For patients who can respond to these tasks and appropri- Conclusion
ately use computerized communication devices, more options
Even though brain activity clearly differs among disorders of
have to be investigated. Indeed, the BCI paradigms described
consciousness, the detection of behavioral signs of conscious-
above only permit the use of dichotomous responses. The use
ness can be challenging at the bedside and the use of sensitive
of matrices with the alphabet has already been validated in LIS
standardized scales (such as the CRS-R) is crucial. In the
patients and has shown good results in more than 70% of cases
future, the development of classifiers based on residual brain
(for the visual modality) [62]. Such an alternative could offer
activity or residual brain connectivity could substantially help
more complex communication as it would allow the spelling of
clinicians to detect consciousness and constitute an automated
words and even sentences. Those BCI paradigms should not be
diagnostic and prognostic tool. Finally, even though pharma-
used for diagnostic purpose. The tasks used to communicate
cological treatment (such as amantadine) seems to have an
are complex and could lead some patients to be unable to
effect on consciousness recovery, further research is warranted
respond even though they are conscious. As these patients
to develop a panel of therapeutics that will optimize the man-
are severely brain-injured, it is possible that a part of them
agement of severely brain-injured patients recovering from
may present cognitive deficits compromising the accomplish-
coma.
ment of demanding active tasks. The development of a diag-
nostic technique that could detect patients with covert
cognition at rest is therefore more than needed. The perturba- Acknowledgments
tional complexity index used by Casali and coworkers could be This research is funded by the James S. McDonnell Foundation
promising in this context as it has successfully differentiated “Scholar Award”.

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413
 Chapter
Acute Demyelinating Disorders in the
35 Neurocritical Care Unit
Lauren Koffman and Joao A. Gomes
Introduction
While central nervous system demyelinating disorders are
more often than not chronic, in a small minority of patients,
acute, often life-threatening entities are well recognized. These
disorders can pose a threat either directly through inflamma-
tion and destruction of brain and spinal cord tissue, or indir-
ectly due to systemic complications (i.e. respiratory failure,
aspiration, etc.).
In this chapter we review acute inflammatory demyelinating
disorders and discuss common conditions that can pose as
mimics. Finally, we briefly review the management of emergency
complications that can be encountered with these disorders.
Acute Inflammatory Demyelinating Diseases
In this section we review the five well-characterized entities
with proven acute inflammation-mediated demyelination of
the central nervous system. Noninflammatory leukoencepha-
lopathies are discussed elsewhere.
Acute Disseminated Encephalomyelitis
Acute disseminated encephalomyelitis (ADEM) is an inflam-
matory demyelinating, monophasic process of the central ner-
vous system that is characterized histopathologically by
perivenular inflammation and demyelination [1]. While
lesions occur predominantly in the cerebral white matter, the
brainstem, and spinal cord, the gray matter may also be
affected. It typically occurs after a viral illness (i.e. influenza,
Epstein–Barr, cytomegalovirus, herpes simplex, varicella zos-
ter, mumps, HIV, and rubella) or vaccination exposure (i.e.
rabies, polio, diphtheria-tetanus, influenza, and varicella), and
is most commonly seen in children.
Clinical Presentation
Obtaining a thorough history is important in differentiation of
ADEM from alternative demyelinating processes. Symptom
onset from viral prodrome or vaccine exposure is typically
one to two weeks and includes fever, headache, and changes
in level of consciousness. Then, within a shorter time span,
seizures, focal neurologic deficits, and speech changes may be
observed [2]. There have been five different clinical patterns
described; encephalitis (20%), encephalomyelitis (13.3%),
414
myelitis (23.3%), encephalomyeloradiculitis (26.7%), and mye-
loradiculitis (16.7%) [3].
It may be noted that the onset of symptoms in postmeasles
ADEM occurs more rapidly, usually less than a week after
appearance of skin exanthema. The temporal progression of
postrabies vaccine is also abrupt, with onset of symptoms as
quickly as after the first injection [2].
There is usually a monophasic course, but relapses may
occur in 5–25% of patients, although their distinction from
multiple sclerosis remains controversial. Within cases
described as “relapsing,” the majority are described as recur-
rent (80%), and the remaining are multiphasic (20%) [3].
Acute hemorrhagic leukoencephalitis (AHLE) is thought to
be a severe form of ADEM that characteristically appears after
an upper respiratory tract infection. Aside from nonspecific
cerebrospinal fluid (CSF) pleocytosis, AHLE also courses with
an elevated red blood cell count in CSF [1]. Radiographic
findings (i.e. AHLE spares gray matter, is associated with edema
and hemorrhage, and is less often contrast enhancing) help
differentiate AHLE from ADEM [4].
Diagnosis
ADEM is a diagnosis of exclusion, with CSF analysis and
magnetic resonance imaging (MRI) comprising the diagnostic
modalities. CSF is rather nonspecific, possibly with a mild
lymphocytic pleocytosis and elevated protein [1,2]. CSF studies
are useful in ruling out infectious pathogens, with appropriate
microbiologic testing. Oligoclonal bands are also rarely seen
in ADEM, which is an important differentiating factor from
multiple sclerosis (MS) [2].
Lesions on MRI are described as T2 and FLAIR hyperinten-
sities. When compared to classic MS lesions, ADEM lesions are
confluent and may affect the deep gray structures (Figure 35.1).
During the acute phase there may also be restricted diffusion,
with a varying degree of apparent diffusion coefficient (ADC)
changes [1].
Treatment and Management
There have not been any randomized controlled trials that have
investigated therapeutic interventions. Despite this, high-dose
intravenous steroids (i.e. methylprednisolone 1000 mg/d for
three to five days) followed by a prednisone taper have become
the first line of therapy [1,5]. For steroid-refractory ADEM,

Figure 35.1 MRI demonstrating confluent white matter hyperintensities on
FLAIR in a patient with acute disseminated encephalomyelitis.
there have been reports of using both plasmapheresis and
intravenous immunoglobulin (IVIG) therapy. Given the results
of a randomized clinical trial of plasma exchange (PLEX)
in acute CNS inflammatory demyelinating disease, it is reason-
able to attempt PLEX first and reserve IVIG therapy for non-
responders [6,7].
Aside from immune modulatory therapy, supportive meas-
ures are often required. One study reported 70% of patients
requiring mechanical ventilation [5]. Patients must also be
closely monitored for signs of elevated intracranial pressure,
with appropriate treatment of cerebral edema.
Mortality rates in adults are higher than in children. For
instance, adult patients requiring ICU care have a mortality
rate that is reported to be as high as 25%, and 35% of these
patients develop long-term neurologic sequelae [5].
Acute Multiple Sclerosis (Marburg Variant)
In 1906 Otto Marburg described three cases of encephalomy-
elitis periaxialis scleroticans, an entity that shared some clinical
features with multiple sclerosis, but with a monophasic, ful-
minant, and ultimately fatal course [8]. Its greater tendency to
present with focal neurologic findings, lesser incidence of
encephalopathy, and greater asymmetry of lesions help distin-
guish it from ADEM. Pathologically, lesions in acute Marburg
variant are large, more destructive, and lack perivenous
demyelination [9].
Fortunately, this condition is only rarely encountered. Sug-
gested treatments include high-dose corticosteroid therapy,
immunosuppressants, such as cyclophosphamide, and even
plasma exchange in more severe, rapidly progressing cases [10].
Chapter 35: Acute Demyelinating Disorders
Figure 35.2 Sagittal T2-weighted
MR imaging of the upper cervical
cord and lower brainstem showing
extensive spinal cord and brainstem
involvement in a patient with
neuromyelitis optica.
Neuromyelitis Optica (Devic Disease)
Neuromyelitis optica (NMO) is an autoimmune process charac-
terized by the presence of antibodies (i.e. NMO-IgG) against
aquaporin 4 on astrocyte foot processes, which lead to an inflam-
matory demyelinating disease often coursing with optic neuritis
and transverse myelitis [11]. Interestingly, NMO spectrum dis-
orders (i.e. recurrent optic neuritis, recurrent longitudinally
extensive transverse myelitis, and hypothalamic involvement
with narcolepsy) are being more commonly recognized [10].
Clinical Presentation
Clinical manifestations include visual loss, paraplegia, tetra-
plegia, or even coma. When lesions are present in the brain,
patients may present with a spectrum of disturbances ranging
from encephalopathy to brainstem dysfunction [12]. It typically
follows a relapsing course and spinal cord involvement usually
spans three or more vertebral segments. Occasionally, neuro-
genic respiratory failure and reversible posterior leuokoence-
phalopathy syndrome (RPLS) can be presenting symptoms [13].
Diagnosis
Analysis of CSF may show pleocytosis and elevated protein, as
well as a transient presence of oligoclonal bands [12]. More
importantly, serum NMO IgG antibody may be used to distin-
guish NMO from other demyelinating processes.
Radiographic findings include possible optic nerve contrast
enhancement with edema and longitudinally extensive (three
or more vertebral segments) spinal cord lesions, with or with-
out brainstem involvement (Figure 35.2) [14]. Alternatively,
there may also be periaqueductal lesions, longitudinally exten-
sive corticospinal tract lesions, dorsal medullary lesions with
extension into the cervical cord, hypothalamic and/or thalamic
lesions, or large hemispheric lesions [12,14].
Treatment and Management
Acute NMO exacerbations are typically treated with high-dose
intravenous steroids (i.e. methylprednisolone 1 g IV QD for
five days) followed by a prednisone taper, while plasma
exchange is usually reserved for refractory cases [12]. For the
long-term management of NMO, azathioprine, mycopheno-
late mofetil, and rituximab can be considered [10].
415
 Chapter 35: Acute Demyelinating Disorders
Tumefactive Multiple Sclerosis
While multiple sclerosis is typically a disease that does
not require admission to the intensive care unit, tumefactive
MS may produce large demyelinating lesions with edema
and mass effect. Subacute onset of symptoms is common,
and atypical radiological features, such as mass effect, vaso-
genic edema, partially open ring enhancement, and diameter
greater than 2 cm should raise the index of suspicion
(Figure 35.3) [15]. Careful evaluation needs to be undertaken
in these cases, as differentiation from CNS malignancy can
be challenging.
Diagnosis
A thorough clinical history is important to identify prior
episodes of demyelination. Imaging helps rule out other poten-
tial diagnoses such as central nervous system (CNS) malig-
nancy, abscess, vasculitis, and granulomatous disease.
Radiographic features are useful in differentiating tumefactive
lesions. While it has been reported that 95–100% of lesions
enhance with contrast, the pattern may be variable (closed
rings, open rings, diffuse, homogeneous, punctate, or concen-
tric) [15]. It may also be useful to image the spinal cord, as
asymptomatic plaques may be identified and can further solid-
ify a diagnosis of MS.
Aside from imaging studies, supportive CSF findings
include elevated IgG synthesis index and the presence of oligo-
clonal bands. Evoked potentials may also be helpful, as approxi-
mately one-third of patients have abnormal visual-evoked
Figure 35.3 Coronal T2-weighted MR image showing large demyelinating
lesion with surrounding edema and mass effect in a case of tumefactive
multiple sclerosis.
416
potentials and 60% of patients have abnormal sensory-evoked
potentials [15].
If imaging, CSF, and other ancillary diagnostic tests do not
yield a definitive diagnosis, or the patient is refractory to
therapy, brain biopsy should be strongly considered.
Treatment and Management
Treatment with high-dose intravenous steroids (methylpred-
nisolone 1000 mg) for three to five days is the accepted stand-
ard therapy [15]. For those who fail to respond to steroid
therapy, plasma exchange can be considered [16]. Intracranial
pressure may need to be monitored and managed accordingly,
given the known occurrence of mass effect with midline shift
and transtentorial herniation.
Balo Concentric Sclerosis
Balo concentric sclerosis is also a monophasic, rapidly pro-
gressive acute demyelinating disease that affects primarily
young adults and is characterized by onion-like concentric
rings of demyelination and myelination. It typically presents
as a solitary tumor-like lesion that can involve the brainstem or
cerebral hemispheres and can lead to death within months.
MRI can reveal the typical lesion with concentric rings of
demyelination and surrounding edema with mass effect [10].
Treatment strategies usually suggested for acute multiple
sclerosis can also be considered for patients with the concen-
tric demyelinating lesions typical of the Balo variant.
Differential Diagnosis
While an extensive discussion of all the possible mimics of
acute demyelinating lesions is beyond the scope of this chapter,
Table 35.1 provides a comprehensive list of differential diag-
noses. We also provide a brief discussion of entities that are
either commonly encountered in critically ill patients, or that
can be easily confused with acute inflammatory demyelination.
Heroin-Associated Spongiform
Leukoencephalopathy
Heroin-associated spongiform leukoencephalopathy (HASL),
otherwise known as “Chasing the Dragon,” was first reported
in the Netherlands in 1982 after a group of patients were
admitted with a distinct constellation of neurologic symptoms
attributed to heroin ingestion while heated from a foil. The
exact toxin or additive that produces this syndrome has yet to
be identified [17].
Clinical Presentation
Based on the initial case series, three distinct stages have been
described (Table 35.2).
Diagnosis
Toxicology studies confirm the use of heroin, while MRI
demonstrates diffuse T2 hyperintensities in the cerebellar and
 Chapter 35: Acute Demyelinating Disorders

Table 35.1 Differential diagnosis of acute leukoencephalopathy Table 35.2 Clinical course of heroin-associated spongiform
leukoencephalopathy [17]
1. Vascular
a. Vasculopathy Stage Time Symptoms Percentage
i. Cerebral autosomal dominant arteriopathy (CADASIL) Initial Onset Akathisia, apathy, 100%
ii. Moya Moya bradyphrenia,
iii. Susac syndrome ataxia
b. Vasculitis
i. Drug-induced Intermediate 2–4 Pseudobulbar 55%
ii. Reversible cerebral vasoconstriction (RCVS) weeks reflexes, spastic
iii. Systemic paresis, abnormal
iv. Primary CNS movements
v. Infectious (tremors,
c. Cerebral venous thrombosis myoclonus,
d. Thromboembolic disease choreoathetoid)

2. Toxic-metabolic/nutritional Terminal >4 weeks Fever, hypotonia, 23%

a. Vitamin B12 deficiency areflexia, akinetic
b. Mitochondrial disorders mutism, respiratory
c. Central pontine myelinolysis failure
d. Carbon monoxide
e. Lead
f. Chemotherapy (i.e. methotrexate)
3. Infectious Treatment and Management
a. Viral encephalitis Patients that do not progress past the initial stage typically
b. Whipple disease stabilize and have some improvement. Despite aggressive man-
c. Progressive multifocal leukoencephalopathy agement with corticosteroid and hypertonic agents, patients
d. Cerebritis/abscess
that progress to the terminal stage have a poor prognosis [17].
e. Neurosyphilis
f. Subacute sclerosing panencephalitis (SSPE)
There is no definitive treatment and supportive care remains
g. HIV (primary or opportunistic infections) the mainstay of therapy.
h. Postinfectious
4. Radiation-related Central Pontine Myelinolysis
Central pontine myelinolysis (CPM) is classically described as
5. Inflammatory
a. Behcet syndrome
a symmetric demyelinating lesion of the pons seen in a variety
b. Hashimoto encephalopathy of patient populations, although classically associated with
c. Neurosarcoidosis rapid correction of hyponatremia. Since the first description,
d. Drug-induced a plethora of high-risk patient populations have been identi-
e. Other (neurolupus, Sjogren syndrome, etc.) fied, including those with sepsis, HIV, post-transplant, dia-
6. Neoplasia
betes, chronic alcoholics, burn injuries, liver disease, renal
a. CNS glioma failure, and end-stage cancer [19]. In addition to CPM, lesions
b. Primary CNS lymphoma may occur in the cerebellar and neocortical gray/white junc-
c. Neoplastic angioendotheliomatosis tion, thalamus, globus pallidus, putamen, caudate, lateral gen-
d. Gliomatosis cerebri iculate nucleus, and amygdala. Extrapontine myelinolysis
7. Paraneoplastic syndromes
(EPM) may occur independently, or in combination with
CPM in approximately 10% of cases [19].
8. Other (reversible posterior leukoencephalopathy syndrome,
chronic lymphocytic inflammation with pontine perivascular Clinical Presentation
enhancement, etc.)
Usually, there is a biphasic presentation, with an initial
Modified from [10] encephalopathic stage [19]. Other symptoms associated with
hyponatremia include seizures, hyporeflexia, and myalgias,
which can improve as sodium is corrected. The second
stage occurs between days 2 and 7 from the time of sodium
brainstem white matter tracts and DWI/ADC patterns consist- correction. In this phase symptoms may develop over days
ent with subacute ischemia secondary to vacuolization [18]. and range from obtundation to coma, dysarthria, ataxia,
Similarly, postmortem examination of patients shows spongi- locked-in syndrome, and death [20]. Extrapontine involve-
form degeneration of the white matter, with an accompanying ment may be distinguished from CPM by the presence of
vacuolating myelinopathy [17]. extrapyramidal signs.

417
 Chapter 35: Acute Demyelinating Disorders
Diagnosis
MRI typically demonstrates a symmetric triangular-shaped T2/
FLAIR hyperintensity within the central pons with tegmental
and ventrolateral sparing. It is important to note that there may
be a delay in the development of MRI lesions and therefore
normal imaging does not exclude the possibility of CPM [19].
Treatment and Management
Patients at high risk for osmotic myelinosis should be closely
monitoring during fluid and electrolyte repletion to avoid
precipitating CPM. Guidelines suggest an initial correction
rate of 1 mmol (mEq)/L/h with the daily total not greater than
8 mmol/L/d for acute symptomatic hyponatremia. When
sodium levels are corrected more than 10 mmol/L/d there is
increased risk of CPM. Acute hypernatremia may be corrected
at a rate of 1 mmol/L/h, whereas chronic hypernatremia
should be corrected at a slower rate (i.e. 0.5 mmol/L/h) [19].
In addition to slow correction of hyponatremia, some have
reported success using plasmapheresis and intravenous
immunoglobulins. It is hypothesized that these therapies antag-
onize myelinotoxic compounds and therefore reduce irrevers-
ible demyelination and improve functional outcomes [21].
Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) is typically
seen in patients with the acquired immunodeficiency syn-
drome (AIDS) and in those with exposure to specific mono-
clonal immunosuppressive therapies (mAbs). Polyoma virus
(i.e. JC virus) causes this viral opportunistic infection [22].
This virus is rather pervasive, with some studies citing up to
80% seropositivity in the adult population [23].
While highly active antiretroviral therapy (HAART) has
reduced the incidence of PML in AIDS patients, it still remains
one of the most common CNS opportunistic infections in this
population [24]. Natalizumab and efalizumab are most com-
monly associated with PML, although increased risk with use
of rituximab is being recognized [25].
Clinical Presentation
It is important to obtain a thorough history regarding the
above risk factors, especially HIV history, as PML may be the
presenting manifestation. Symptoms will vary based on loca-
tion of white matter changes, but one series noted that most
common initial symptoms were weakness, altered mental
status, and changes in vision [26].
Diagnosis
CSF testing for the JC virus with polymerase chain reaction
(PCR) is the gold standard. Brain biopsy may also be con-
sidered, with testing for tissue DNA, viral antigens and
expected histopathologic changes. Radiographic changes are
described as white matter lesions that do not follow a pattern
of vascular territories. Furthermore, PML lesions typically do
418
not have mass effect, edema, or enhance with contrast [27].
One caveat is that natalizumab-related PML lesions may be
more likely to have contrast enhancement [28].
Treatment and Management
There is no effective antiviral agent against JC virus. Cidofovir
was initially thought to be an effective therapy, but subsequent
experience failed to show improved mortality or residual dis-
ability [28]. Treatment focuses on supportive care and restor-
ation of the immune system.
Emergency Complications
Although infrequent, life-threatening complications of acute
demyelinating disorders can be classified into three broad
categories:
1. Related to severe inflammation:
• Malignant edema, elevated intracranial pressure (ICP)
and cerebral herniation is most frequently encountered
in the setting of ADEM, acute (Marburg variant) MS, or
tumefactive MS. Along with the acute treatment
discussed above, general measures directed towards ICP
control include head-of-bed elevation, fever control,
sedation, use of hyperosmolar therapy (mannitol or
hypertonic saline infusion), hyperventilation,
pentobarbital coma and/or hypothermia. Even
decompressive hemicraniectomy has been reported in
patients with uncontrolled demyelination and mass
effect [29].
2. Secondary to lesion location within the CNS:
• Hypothermia is rarely seen in the acute setting, and is
usually secondary to extensive hypothalamic
involvement. It is often associated with bradycardia,
thrombocytopenia, coagulopathy, and encephalopathy.
Some patients can respond to steroid therapy alone, but
more effective means of rewarming are usually required
[30].
• Neurogenic pulmonary edema is usually seen with
medullary involvement, particularly of the nucleus
tractus solitarius. Other signs and symptoms of
brainstem involvement are usually present and help
establish the diagnosis. The pathophysiology is
unclear, and likely includes altered vascular
permeability, altered sympathetic output, and pro-
inflammatory cytokines and chemokines [31]. This
entity is usually self-limited and improves as the CNS
process subsides. Mechanical ventilation is typically
required during the acute period.
• Stress cardiomyopathy rarely complicates acute
multiple sclerosis, but can lead to cardiogenic shock
and subsequent pulmonary edema. It is usually a self-
limited process, and improvement or even
normalization of left-ventricular function is frequently
seen after a few days. Supportive care, including use of
 Chapter 35: Acute Demyelinating Disorders

inotropic agents, vasopressors, and even ventricular 3. Aquaporin-4 (AQP4) depletion:

assistive devices should be considered during the acute
phase [32].
• Respiratory failure, either as a consequence of high
cervical cord involvement and diaphragmatic
weakness, as seen in patients with NMO or secondary
to aspiration of oral secretions into the airway due to
bulbar involvement, can frequently be encountered in
acute demyelinating disorders. While aggressive
treatment of inflammation is underway in the
acute setting, mechanical ventilation and even
tracheostomy should be instituted to help improve
survival [10].
• Reversible posterior leukoencephalopathy syndrome
(RPLS) involves the classic constellation of headache,
encephalopathy, visual disturbances, and seizures with
accompanying areas of subcortical edema affecting
primarily the posterior areas of the brain on MRI and
has been described in a series of patients with NMO. It
has been postulated that AQP4 depletion predisposes
to the development of vasogenic edema and RPLS.
Treatment is usually supportive, and blood pressure
control and plasma exchange typically advocated [33].

9. Mendez MF, Pogacar S. (1988). 18. Kass-Hout T, Kass-Hout O, Ziad

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 Chapter
Building a Case for a Neurocritical Care Unit
36 Panayiotis N. Varelas and Efstathios Papavassiliou
Introduction
The birth of neurocritical care (NCC) can be traced to
Harvey Cushing’s “anesthesia chart” and to Walter Dandy,
who opened the first three-bed unit in the USA for post-
operative neurosurgical patients at Johns Hopkins Hospital
in Baltimore, Maryland [1]. Modern NCC is a new field that
began in the early 1980s in a few isolated hospitals in the
USA and Europe. This new area of expertise was needed to
provide specialized care for patients with neurological and
neurosurgical problems, which until that time was only
offered in general intensive care units (ICUs) or in units of
less acuity, such as stroke units. In fact, acute neurologic
disorders were estimated to occur in 45% of medical ICU
patients and neurologic complications to occur in 33%
of patients admitted for non-neurological reasons [2].
Because enlightened neurosurgeons, neurologists, and gen-
eral intensivists realized that a substantial number of ICU
patients could be better served by specialists, Neuro-ICUs
(NICUs) were gradually established throughout the USA
and Europe during the 1990s, often directed and staffed by
neurologists with special interest in internal medicine or
anesthesiology. Then in 2002, the Neurocritical Care Society
(NCS) was formed, with close to 200 members. In 2005, the
United Council for Neurological Subspecialties (UCNS)
recognized NCC as a new neurological subspecialty and a
process was created to accredit US NCC programs and
develop an NCC physician certification. In 2008, Leapfrog
recognized neurointensivists (NIs) as part of the critical care
pool of physicians – an important development since, except
for UCNS certification, no American Board of Medical
Specialties (ABMS) critical care certification path had
existed for NIs. This boosted the subspecialty to new
heights, and the NCS grew to over 2500 members (please
visit www.neurocriticalcare.org/practitioners/physicians for
more information).
The spread of NICUs across two continents and beyond
occurred because these units addressed two fundamental issues
of care: (1) they improved patient outcomes through special-
ized and efficient care delivery, and (2) they improved the
financial state of both patients and health care systems. In this
chapter we will examine the data supporting the improved
quality of care delivery of NICUs.
ICU and NICU models
Various types of ICUs and NICUs have been described based
on geographic localization, staffing organization models, type
of care administered (“direct” or “consultative”) and 24-hour
versus daytime-only coverage. In addition, the patient popula-
tion admitted to an NICU is variable and ranges from mech-
anically ventilated patients in a specialized stroke unit to an
ICU admitting mixed neurological and neurosurgical critically
ill patients.
Despite patient variability, attempts have been made
to adjust for differences. A standardization concept for
intensivist-physician staffing has been championed by the
Leapfrog Group. It recommended that all ICU patients be
managed or comanaged by intensivists and that intensivist
coverage should meet the following standards: intensivist(s)
are present in the ICU during daytime hours seven days per
week, with no other clinical duties during this time, they return
95% of pages within five minutes, and they can rely on a
physician (e.g. fellow or resident) or nonphysician extender
who is in the hospital and is able to reach ICU patients in five
minutes during nondaylight hours (www.leapfroggroup.org/
media/file/Leapfrog-ICU_Physician_Staffing_Fact_Sheet.pdf).
Initially this mandate was not easy to follow in the NICU
world, because of the shortage of trained NIs. The situation
has improved over the years and NICUs led by trained NIs
have multiplied across the USA and Europe.
Dedicated staffing by intensivists also separates NICUs
into different models, similarly to general ICUs [3] such
as: (1) a closed NICU (where an NI admits and manages
all patients, but then discharges to a different neurology
or neurosurgery (NS) attending’s service), (2) a semi-open
NICU (where the primary attending is different from the
NI, who is consulted mandatorily for every patient and
comanages together with the primary attending who makes
admission-discharge decisions), and (3) an open NICU
(where either there is no NI involved in the care of patients
or the NI is electively consulted on a case-by-case basis,
providing guidance to the primary attending regarding
specific critical care issues). A closed or semi-open ICU with
mandatory intensivist consultation is also called a high-
intensity staffing unit, as compared to a low-intensity staffing
unit, which comprises elective or no intensivist consultation.
421
 Chapter 36: Building a Case for a Neurocritical Care Unit
In North America, the majority of ICUs have low-intensity
staffing (open ICUs), and of those, 5% do not have an intensi-
vist, while two-thirds have an intensivist available for consult-
ation [4,5]. In a study published in 2006, it was estimated that
there were 5980 ICUs in the United States, caring for approxi-
mately 55,000 patients per day. One in four ICUs were high-
intensity (26%), half had no intensivist coverage (53%), and the
remainder had at least some intensivist presence (20%). High-
intensity units were more common in larger and teaching
hospitals and more likely to be surgical or trauma ICUs [4].
There are several studies that have shown that a closed ICU or
high-intensity staffing model is associated with lower hospital
and ICU length of stay (LOS), fewer days of mechanical
ventilation, and lower hospital and ICU mortality [6, 7]. How-
ever, this is not uniformly accepted. For example, in a retro-
spective analysis of a large, prospectively collected database of
critically ill patients in 123 ICUs across 100 U.S. hospitals,
comprising 101,832 critically ill adult patients, those who
received critical care management by intensivists were gener-
ally sicker, received more procedures, and had higher hospital
mortality rates, even after adjustment for severity of illness and
propensity score, than those who did not receive care by
intensivists [8]. Most recently, in a large meta-analysis
reviewing 16,774 citations and including 52 observational
studies examining intensivist-staffing patterns, Wilcox et al.
reported that high-intensity staffing, compared to low-
intensity staffing, was associated with lower hospital (risk ratio,
0.83; 95% CI, 0.70–0.99) and ICU mortalities (pooled risk
ratio, 0.81, 0.68–0.96). The in-hospital and ICU LOS were also
lower with high-intensity staffing (–0.17, –0.31 to –0.03 days
and –0.38, –0.55 to –0.20 days, respectively). The benefit of
high-intensity staffing on hospital mortality was concentrated
in surgical (risk ratio, 0.84, 0.44–1.6) and combined medical-
surgical (risk ratio, 0.76, 0.66–0.83) ICUs, as compared to
medical (risk ratio, 1.1, 0.83–1.5) ICUs. A similar trend was
also observed on ICU mortality, with the effect only significant
in surgical and combined surgical-medical units [9].
Many NICUs do not have identical and specific locations
within a hospital, and they function as a cluster of beds or
randomly assigned beds within a larger general or surgical/
medical ICU environment. However, most modern NICUs
function as a separate entity, with a specific number of beds
dedicated only to patients with neurological or neurosurgical
disorders, usually close to the operating room or to the neurol-
ogy or neurosurgery general ward beds of the hospital.
There are other differences between general ICUs and
NICUs beyond staffing and separate bed allocation. Care and
specific ICU practices may also differ. Based on a 24-hour (one
day) prevalence survey of 143 ICUs in 69 hospitals in New
York, 1906 patients were admitted to an ICU and of those, 231
(12.1%) had a primary neurological diagnosis. Of the 231, 52
(22%) were admitted to one of nine NICUs and 179 (78%) to a
medical or surgical ICU. Neurological patients in NICUs were
more likely to have been transferred from an outside hospital
(37% versus 11%). Hemorrhagic stroke was more frequent in
422
NICUs (46% versus 16%), whereas traumatic brain injury
(TBI) (2% versus 24%) and ischemic stroke (0% versus 19%)
were less common. Despite a lower rate of mechanical ventila-
tion (39% versus 50%), ICU LOS was longer in NICU patients
(for 10 days, 40% versus 17%). More NICU patients had
undergone tracheostomy (35% versus 15%, P = 0.04), invasive
hemodynamic monitoring (40% versus 20%), and invasive
intracranial pressure monitoring (29% versus 9%) than
patients cared for in general ICUs. Intravenous sedation was
less prevalent in NICUs (12% versus 30%) and nutritional
support more prevalent compared to general ICUs (67% versus
39%) [10]. To what extent these data from a large metropolitan
area can be generalized is unclear.
Full-day versus daytime-only coverage also separates ICUs
[3]. A small minority of ICUs (12%) have night coverage by
trainees or mid-level providers (dedicated to the ICU or having
other non-ICU responsibilities) and an even smaller, but
increasing minority (7%), have 24-hour intensivist coverage
extending to after hours [4]. To our knowledge only one
NICU in the USA has adopted 24-hour NI coverage.
Regarding outcome improvement with 24-hour intensivist
presence in-house, the ICU data are sparse and disappointing.
In a retrospective analysis of the Acute Physiology and
Chronic Health Evaluation (APACHE) database that included
65,752 patients admitted to 49 ICUs in 25 hospitals in the
USA, night-time intensivist staffing was associated with a
reduction in risk-adjusted in-hospital mortality (adjusted odds
ratio for death, 0.62; P = 0.04) only in ICUs with low-intensity
daytime staffing. Among ICUs with high-intensity daytime
staffing, night-time intensivist staffing conferred no benefit
with respect to risk-adjusted in-hospital mortality (odds ratio,
1.08; P = 0.78) [11]. Similarly, in the study by Wilcox et al., 24-
hour in-hospital intensivist coverage, compared to daytime-
only coverage, did not improve hospital or ICU mortality (risk
ratio, 0.97; 95% CI, 0.89–1.1 and 0.88, 0.70–1.1, respectively)
within high-intensity staffing models [9]. No data exist about
24-hour staffing-related outcomes in NICUs.
Outcomes in NICU Patient Populations
Several studies over the last 10–15 years have published out-
comes from newly established NICUs. Most of these studies
use historical controls to compare outcomes between periods
without a NICU or with non-NI-staffed NICUs and when a NI
is present.
In an observational cohort with historical controls, Varelas
et al. compared outcomes of all patients admitted to a ten-bed
NICU in Milwaukee, WI in two, 19-month periods, before and
after the appointment of an NI. 1087 patients were analyzed in
the before-NI period and 1279 were analyzed in the after-NI
period. The unadjusted in-hospital mortality rate decreased
from 10.1% to 9.1%, respectively, in the after period, but
this decrease was significantly different from the expected
increase of 1.4% based on the University Hospitals Consor-
tium calculated mortality during the same period (P = 0.048).

The unadjusted mortality in the NICU decreased from 8% to
6.3% and the mean NICU LOS from 3.5 to 2.9 days.
A significant 42% reduction of the risk of death during the
first three days of NICU admission and a 12% greater risk for
NICU discharge (i.e. decreased LOS) were found in the after
period in multivariate Cox proportional hazard models. Dis-
charge home increased from 51.7% in the before period to
59.7% in the after period and discharge to a nursing home
decreased from 8.1% to 6.8%. Although a higher total number
of complications occurred in the after period, fewer of them
occurred in the NICU in the after period [12].
In the same issue of Critical Care Medicine, Suarez et al.
published a similar analysis from their hospital in Cleveland,
OH, using admission APACHE III score for severity adjust-
ment of the 2381 adult patients admitted to their NICU. The
analysis period extended from January 1997 to April 2000,
with the introduction of a neurocritical care team in Septem-
ber 1998. The presence of a neurocritical care team was asso-
ciated with reduced LOS in both the NICU (by an average 0.5
days) and the hospital (by an average of 1.5 days). There was
no difference in readmission rates to the NICU or discharge
disposition to home before and after the neurocritical care
team was established. The availability of the neurocritical
care team was not associated with significant changes
in long-term mortality. Factors independently associated with
long-term mortality included female gender, admission from
another intensive care unit, APACHE III score, and being
moderately disabled before admission [13].
In another study from Innsbruck, Austria, Broessner et al.
reported on the patient population admitted to an NICU over
a period of 36 months. After exclusion of neurosurgical acute
cases, 1155 patients were included. The major admission diag-
noses were cerebrovascular diseases, such as intracerebral
hemorrhage (20%), subarachnoid hemorrhage (SAH) (16%),
and complicated malignant ischemic stroke (15%), while TBI
comprised 19% and status epilepticus 6% of the cases. The
mean NICU LOS was 9.1 days, mortality 18% and mean
Therapeutic Intervention Scoring System (TISS-28) was
31 on admission and 24 at discharge. This study also reported
long-term outcomes. In a mean follow-up of 2.5 years of the
662 patients available for a telephone interview, factors associ-
ated with unfavorable functional long-term outcome (Glasgow
Outcome Scale (GOS) 1–3 or modified Rankin Score (mRS)
2–6) were admission diagnosis, sex, age >70 y, TISS-28 >40
points at admission, TISS-28 >40 points at discharge from the
NICU and LOS [14].
Apparently, these improved outcomes are derived from the
presence of a senior physician and NI, and the institution of
protocols that standardize health care delivery. Enhanced edu-
cation at nursing and resident-fellow levels may also play a
role, but the specific contribution of each of these variables has
not been studied. Data from a 2008 Taiwanese study are
revealing. In a retrospective comparison of outcomes from a
mixed SICU and NICU (eight beds each sector), two groups of
patients, one managed by junior surgical residents and one by
Chapter 36: Building a Case for a Neurocritical Care Unit
senior surgical residents were compared. The authors reported
that the mortality was 24.7% in the former group and 17.7% in
the latter. The major difference in mortality was in the neuro-
surgical patients (26.6% versus 19.2%, respectively). Interest-
ingly, patients stayed longer in the ICU when the senior
residents were managing them (median LOS was 3.0 days for
the junior-managed patients versus 3.5 days for the senior-
managed patients) [15]. These data suggest that physician
experience plays a positive role in reducing mortality, but also
a negative role in early discharge of critically ill patients.
Another possibility for the decreased mortality noticed
when an NI was present is that this is due to a faster turnover
of patients in the NICU (supported by the decreased LOS) and
to an earlier discharge to the ward, where they die instead. This
hypothesis was refuted by another study that did not find any
association between the presence of an NI in the NICU and
withdrawal of life support or ward mortality rate. Therefore
the improved NICU mortality and shorter LOS do not reflect a
“hidden” increased ward mortality and should be related to
better care delivery [16].
Lastly, another possibility of improved outcomes over an
extensive period of time is improved technology and new
therapies rather than the presence of an NI per se. This
hypothesis was refuted in a recent Canadian study. Using
prospectively collected data, Kramer and Zygun identified
patients admitted to regional ICUs in South Alberta over a
>11-year period (June 2001–July 2012). Four sequential time
periods of 2.8 years were compared, as were periods before and
after various practice modifications were introduced. Neuro-
critical care fellowship-trained specialists became available
at the end of 2003. In this large cohort of 4097 patients the
odds of death were lowest in the most recent time quartile (OR
0.70, 95% CI 0.56 to 0.88) and the odds of being discharged
home without the need for support services increased over
time (OR 1.45, 95% CI 1.38 to 1.85). Improvements were
statistically significant, however, for patients with a diagnosis
of TBI and SAH only. After adjustment for age, diagnostic case
mix and admission GCS, the three variables associated with
improved outcomes were neurocritical care consultative services,
evidence-based protocols, and clustering of patients within a
multidisciplinary ICU. Length of stay in an ICU increased
among hospital survivors (4.6 versus 3.8 days), possibly because
intensivists were making increasingly delayed decisions about
withdrawing life-sustaining interventions [17].
NICU and Ischemic or Hemorrhagic Stroke
Stroke units improve patient outcomes [18, 19], but the data
regarding NICU-admitted patients with stroke were limited
until recently, and the reasoning for admitting these patients
in the higher acuity unit is weak. Admission to an NICU was
considered optional even for comprehensive stroke centers [20],
despite the argument for the opposite [21]. With more NICU
outcome data becoming available, opinions became more posi-
tive for the NICU. Currently there is general agreement that
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 Chapter 36: Building a Case for a Neurocritical Care Unit
hemorrhagic strokes and large or brainstem ischemic strokes
requiring ventilatory support should be admitted to an NICU
[22]. The most recent 2012 Joint Commission Comprehensive
Stroke Center Certification requirements includes a provision
for dedicated NICU beds for complex stroke patients that
include staff and licensed independent practitioners with the
expertise and experience to provide neurocritical care 24 hours/
day, seven days/week (www.jointcommission.org/certification/
advanced_certification_comprehensive_stroke_centers.aspx).
Some of the studies examine stroke outcomes in general
and some specific stroke subpopulations admitted to a NICU.
Using prospectively collected data by Project Impact over three
years from 42 participating ICUs across the country (including
one NICU) and merging them with those from a second
NICU, Diringer et al. examined the factors associated with
hospital mortality in patients with ICH. The authors included
266 patients with ICH admitted to two NICUs and 772 admit-
ted to general ICUs. One-third of the NICU-admitted patients
were listed under neurology and the rest under neurosurgery,
which contrasted with only 59% under these two services in the
general ICUs (and the rest under internal medicine). Despite
the admission GCS score being higher and the APACHE II
score being lower in the NICU-admitted patients, the ICU and
hospital LOS was longer compared to the general ICUs. After
adjustment for patient demographics, severity of ICH, and
ICU and institutional characteristics, however, admission to a
general ICU (instead of a NICU) was associated with an
increased in-hospital mortality rate (OR 3.4, 95% CI
1.65–7.6). Interestingly, the presence of a full-time intensivist
was also independently associated with decreased mortality
after ICH [23].
During the same year, another study was published by
Mirski et al. from a NICU in Hawaii with a newly appointed
NI. ICD-9 and DRG codes for ICH admissions were used to
identify the patients. The authors compared the NICU out-
comes during the year 1995 (before the appointment of an NI)
with those during the year 1997 (after the appointment of an
NI) using a hospital database. They reported that mortality
decreased significantly during the after period (from 36% to
19%) and discharge to home or rehab increased significantly
(from 48% to 69%). Total hospital LOS also decreased in the
after period, but not significantly. Additional subspecialty
consultation was significantly lower in the NICU compared
to the other hospital ICUs during the period when the NI was
present. The authors also compared same-year financial and
resource use in their NICU with national benchmarks from
similar general ICUs found in an external database (HBSI
EXPLORE database). The database did not include any other
NICU with NI coverage. Adjusting for severity of illness, the
LOS in the NI-staffed NICU in Hawaii was 25–45% lower than
the non-NI-staffed ICUs in the database [24].
In a retrospective study from Zurich, Lerch et al. compared
198 patients with aneurysmal SAH treated with early aneurysm
clipping between two periods, one before and one after the
establishment of a new standardized protocol of neurointensive
424
care management. During the after period, significantly more
patients with severe SAH (i.e. World Federation of Neurological
Surgeons (WFNS) grades 4 and 5) underwent further treatment
(47.0% versus 15.3%). The outcomes were also significantly
different, with 43.5% of patients with WFNS 4 recovering in a
good functional state (GOS 4 and 5) in the before period,
whereas 63.9% had similar outcomes in the after period.
Patients with the worst admission state (WFNS grade 5) also
differed regarding outcome, with all patients in the before
period dying or surviving in a vegetative state, whereas 35.1%
of those surviving had a good outcome in the after period [25].
In another subsequent study Varelas et al. reported
433 stroke patients (acute ischemic stroke, ICH, or SAH)
admitted to a 10-bed university hospital NICU over two 19-
month periods, before and after the appointment of a NI. This
study is limited to data during the duration of hospitalization,
lacking long-term outcomes after discharge. Observed mortal-
ity did not differ between the two periods. Significantly more
patients were discharged home in the after period (75% versus
54% in the before period) and fewer to a nursing home (21%
versus 36%). After adjusting for covariates, the NICU LOS
were significantly shorter for all strokes and for each specific
type of stroke separately in the after period, with the largest
effect for ischemic strokes, followed by ICH and SAH (Cox
proportional hazard ratios were 2.37, 1.98 and 1.6, respect-
ively). Additionally, the hospital LOS was decreased for the
entire cohort in the after period, but only for the first 12 days
of stay (HR 1.7). Hospital LOS decrease in the after period was
different among the stroke subtypes: it was significantly
shorter for ischemic strokes (HR 1.8) and SAH (HR 1.4), but
not for ICH (HR 1.2) [26].
In a similar retrospective study by Bershad et al., 189
patients with acute ischemic stroke were admitted to the NICU
before the appointment of a NICU team and were compared to
211 patients after the appointment of a specialized NICU team
managing them. This study differs from the previous one due
to inclusion of long-term outcomes and because it used logistic
regression models to determine independent association
between outcome and availability of a NICU team. Similarly
to the previous study, it demonstrated that the presence of a
NICU team was associated with a significant decrease in the
NICU and hospital LOS, and a significant increase in home
discharges (47% versus 36%). Comparably to the study by
Varelas et al., the authors did not find any difference in mortal-
ity between the two periods and this absence of benefit extended
to one-year mortality comparisons. Interestingly, the only inde-
pendent predictor of in-hospital and long-term mortality was
the underlying severity of disease, as determined by the
APACHE III score. Independent predictors for NICU LOS were
the admission NIHSS and the presence of symptomatic hemor-
rhagic transformation, as well as the presence of a NI [27].
In a study reporting only SAH outcomes during two-year
periods before and after the initiation of a mandatory NI c-
management service at UCSF, Josephson et al., included
512 patients total (216 before and 296 after). This intervention

occurred only in neurosurgical-service-admitted patients.
A parallel group of 326 SAH patients were admitted and
managed under the NIs during both periods and considered
as controls. This study lacks severity adjustment and only used
Hunt and Hess score on admission for outcome adjustment.
The authors found that ICU LOS was significantly decreased in
the after period in the comanaged neurosurgical patient group
by a mean of 1.3 days, even after adjusting for demographic
characteristics and admission Hunt and Hess grade. The per-
centage of patients requiring a ventriculoperitoneal shunt
(VPS) in the after period also decreased significantly (from
23% to 11.5%), but the in-house mortality was unaffected in
this group. Interestingly, “control” patients who were admitted
under the NI service during both periods did not show the
same benefit. In fact, there was a significant increase during the
after period in the ICU LOS (by a mean of 2.4 days) and in
hospital mortality (by 8.2%) and no difference in VPS place-
ments. There was no difference in the Hunt and Hess grade
between the two periods in these control patients, but the
authors suggest that this negative trend might be explained
by a higher severity of illness in their institution, which would
imply that the comanagement strategy might have provided
even more robust benefits with such adjustment [28].
One solution for better utilization of limited health care
resources has been to stratify ICU care based on age and
severity. The very old patients with severe insults may not have
reasonable chances for survival or independent living, but this
opinion is not shared by all. In a study of 99 patients with SAH
from Sweden, Ryttlefors et al. stratified their six-month out-
comes based on age (cut-off 65 years between young and
elderly patients). Severe SAH (Hunt and Hess grade IV or V)
comprised 68/99 (69%) of patients and one-third of them were
elderly. Good recovery or moderate disability was achieved in
24.1% of the elderly and in 42.9% of the younger patients. The
frequency of severe disability was 41.4% in the elderly and
37.1% in the younger patients. Based on these results the
authors concluded that NICU care is also justified for elderly
patients with severe SAH [29].
Lastly, in a study of 2096 patients with stroke who were
admitted either to a NICU or another unit, spanning a period
of eight years before and after the appointment of an NI and
after the departure of the NI, Knopf et al. reported three- and
12-month outcomes. For acute ischemic stroke patients, com-
pared to the time interval with an NI present, the departure of
the NI predicted a worse rate of return to prestroke function at
three months, as measured by the modified Barthel Index. For
ICH, NICU treatment predicted shorter ICU and hospital LOS
but had no effect on short- or long-term outcomes. No effect of
an NI was seen in ICH patients. For SAH, availability of an NI
(but not an NICU) predicted improved outcomes, but longer
ICU LOS. Disposition and in-hospital mortality improved
when an NI was present, but continued improvement did not
occur after the departure of the NI. The authors explain the
differential effect of an NI on the three types of stroke by
suggesting the NI improves coordination and collaboration
Chapter 36: Building a Case for a Neurocritical Care Unit
among the various healthcare teams, primarily in patients with
SAH, which represents a disease at the intersection between
neurology and neurosurgery [30].
NICU Outcomes in Traumatic Brain Injury (TBI)
The first outcome data in TBI patients after the establishment
of an organized NICU are derived from Uppsala, Sweden. In
the period before the NICU, 49 patients with severe head
trauma were treated (period 1980–1981) and their outcomes
were compared with 72 patients in the after period
(1987–1988). In the after period there was a specific TBI
protocol that was followed in a specific location of the Univer-
sity hospital (NICU) by specially trained staff. The number of
“good recoveries” increased significantly after the establish-
ment of the NICU (from 12% to 31%) even after adjustment
for covariates. Interestingly, the most striking improvement
was found in patients with a GCS motor score 4 on admis-
sion. In this subgroup of patients the “good recoveries”
increased from 15% to 52% [31]. In a subsequent study from
the same institution, a third period was compared (1996–1997)
to the other two. During this period a similar standardized
protocol was used with the addition of an organized secondary
insult prevention program with objective to avoid secondary
insults via an immediate response of the team. One hundred
and fifty four patients were included and good recovery was
reported in 44% of them. Mortality decreased from 40% to
27% and then to 2.8% in the three periods in those patients
with a GCS motor score 4 on admission. In this subgroup,
good outcomes increased to 84% in the last period [32].
Data from NICUs in North America were also published
shortly after. In a survey of neurotrauma specialists of
261 American hospitals, published in 1995, Ghajar et al.
reported that 34% of all hospitals had a designated NICU
and 24% of all units a neurologist or neurosurgeon as a
director of the ICU. Only 49% of the responders were Level
I Trauma Centers and in these hospitals intracranial pressure
was monitored significantly more often than in the others [33].
In a study from Cambridge, UK by Patel et al., 285 patients
with TBI were admitted before (1991–1993) and after
(1994–1997) the establishment of an NICU and the utilization
of protocol-driven therapy with ICP and CPP clear targets.
Mortality and favorable outcomes were not different between
the two periods in the entire cohort. In patients with severe TBI,
however, favorable outcomes based on GOS at six months or
more after injury were increased significantly in the after period
(40.4% versus 59.6%). Mortality also decreased nonsignificantly
during the after period (from 27.7% to 21.9%) [34].
In a study spanning 38 months, which compared
328 patients with severe TBI admitted to a Level I Trauma
tertiary hospital before the institution of a NICU to
264 patients admitted after the development of an organized
NICU following TBI protocols, Varelas et al. reported that the
unadjusted mean in-hospital mortality rate increased 1.1% in
the after period. Nevertheless, this increase was significantly
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 Chapter 36: Building a Case for a Neurocritical Care Unit
lower compared with the University Hospital Consortium-
based expected increase of 8.1% in the mortality rate during
the same period (p <0.0001). The unadjusted mean mortality
rate in the NICU decreased from 13.4 to 12.9% (relative
mortality rate reduction 4%) and the mean NICU LOS
increased from 3.1 to 3.6 days (relative NICU LOS increase
16%), both nonsignificantly. In multivariate models, after con-
trolling for baseline differences between the two time periods,
however, the authors reported a 51% reduction in the NICU-
associated mortality rate (p = 0.01), a 12% shorter hospital
LOS (p = 0.026), and 57% greater odds of being discharged to
home or to rehabilitation (p = 0.009) in the after period [35].
Despite the fact that these results are derived from single-
center NICUs in Europe and the USA, with the possibility of
a suboptimal management in the before period (thus aug-
menting the difference seen in the after period), they are still
equal or better to any of specific, single-intervention measures
that have been published in the TBI literature.
NICU and Status Epilepticus
One of the most important factors affecting the outcome of
these patients is the duration of status epilepticus (SE), imply-
ing that a timely intervention may improve SE control or abort
the seizures. Because most NICUs are staffed by NIs primarily
trained in neurology, who have been exposed to management
of seizures and who are able to interpret electroencephalo-
grams, it was easy to hypothesize that patients with SE will
be served better in NICUs than in general ICUs. In a single-
center study Varelas et al. retrospectively evaluated 168 admis-
sions in 151 patients for definite or probable SE, 46 (27%) of
which were in the NICU and 122 (73%) in the MICU. Admis-
sions were based on bed availability between the two ICUs.
More continuous EEGs were ordered in the NICU (85% versus
30%, p <0.001), where fewer patients were intubated, but more
eventually were tracheostomized. The NICU had a higher rate
of complex partial SE and more alert or somnolent patients,
whereas the MICU had a higher rate of generalized SE and
more stuporous or comatose patients. Contributing admission
diagnoses also differed, with the NICU having higher rate of
strokes and the MICU higher rate of toxometabolic etiologies
(39% versus 12% and 11% versus 21%). After adjustment for
age, etiology, APACHE II score, admission Status Epilepticus
Severity Score (STESS), convulsive state, time to ventilator
freedom, and level of consciousness on admission, no differ-
ences were found in mortality, the ICU or hospital LOS and
modified Rankin Score at discharge. Based on these limited
data, the authors have refuted the hypothesis that NICUs offer
better care for patients with SE and could not recommend
preferential admission to a NICU for treatment of SE, when
an MICU bed is available [36].
NICU Documentation
Medical documentation is important for communication
among health care professionals, research, legal defense, and
426
reimbursement. There have been reports of insufficient docu-
mentation and resistance of physicians to comply with these
requirements.
For example, brain death documentation is deficient, even
in large teaching hospitals, with many variables and parts of
the clinical exam, explicitly mandated by the American Acad-
emy of Neurology published guidelines, missing. Documenta-
tion by the neurological and neurosurgical teams has been
reported to be more complete than documentation by other
services [37, 38]. In these studies there was no specific mention
of NICU versus other ICU documentation rate, however.
Varelas et al. examined documentation in the medical
records of an NICU after the appointment of an NI. In this
study, medical records of NICU-admitted patients with three
specific diagnoses (TBI, ICH, and SAH) were sampled and the
documentation of important prognostic variables in two time
periods, before and after the appointment of a NI, was
reported. Overall documentation improved significantly from
32.5 to 57.5% in the after period when an NI was present.
Documentation using Glasgow Coma Scale, intracerebral
hemorrhage volume, Hunt and Hess scale, and Fisher’s grade
also improved significantly in each of these diagnoses during
the after period [39].
In a separate study comparing GCS documentation in
328 patients admitted with severe TBI during a period when
no NI was present to 364 patients managed after appointment
of an NI, it was shown that documentation by the NICU team
increased significantly in the after period (from 60.4 to 82%)
[35]. These results suggest that the mere presence of a NI,
through development of protocols and peer pressure, improves
documentation of important prognostic variables.
NICU Financial Cost–Benefit
ICUs are expensive places to be. In a study analyzing the cost
of critical care medicine in the USA between 1985–2000,
Halpern et al. reported that during that period, critical care
medicine (CCM) bed costs per day increased by 126% ($1185
to $2674). Overall CCM costs increased by 190.4% ($19.1
billion to $55.5 billion) and in 2000 CCM costs represented
13.3% of hospital costs, 4.2% of national health expenditures,
and 0.56% of the gross domestic product [40]. In a subsequent
study analyzing the period 2000–2005, the same authors
reported that during that period CCM costs per day increased
by an additional 30.4% (from $2698 to $3518), in parallel with
an annual CCM costs increase of 44.2% (from $56.6 to $81.7
billion). In 2005, critical care medicine costs represented 13.4%
of hospital costs, 4.1% of national health expenditures, and
0.66% of the gross domestic product [41].
There are not much data for NICUs. In a study from
Hawaii, Mirski et al. compared same-year financial and
resource use in a newly established NICU with a national
benchmark of similar ICUs based on an external database
(HBSI EXPLORE database). The database did not include
any NICU with NI coverage (such as the authors’ NICU).
 Chapter 36: Building a Case for a Neurocritical Care Unit

They used ICD-9 and DRG codes for ICH admissions and
reported that there was a significant decrease in LOS in their
NICU (25–45% below the HBSI benchmark in a similar ICU
admission), which reflected average cost savings exceeding
$5,900 per case [24].
Subsequently, in a study from a single hospital, Varelas
et al. compared the financial data from a 16-bed NICU
between two three-year periods, before and after the appoint-
ment of an NI. The average number of admissions increased
by 24% during the period when the NI was present, the
number of patient-days by 25% and the average LOS by 2%.
In the second period, when the NI was present, the combined
mean net revenue (i.e. gross revenue minus deductions) for
both Hospital and Medical Group increased by 54.6%, the
combined direct expenses (i.e. expenses directly related to
patient care) by 42.2% and the combined contribution margin
(net revenue minus total direct expenses) by 91.2%. This was
reflected in a combined mean contribution margin per admis-
sion increase of 56.4% in the after period. Cumulatively, the
hospital benefited from an additional $3.8 million during the
first three years when a NI was present [42].
In addition to NIs, the use of robotic telepresence may
improve costs in a NICU. In a study comparing two 12-month
periods, before and after the use of robots to conduct rounds,
Vespa et al. reported that faster responses to emergencies were
observed: the response latencies were significantly shorter for
brain ischemia and elevated ICP. A decrease in the LOS for
patients with SAH of two days, and with brain trauma by one
day, was accompanied by an increase in ICU occupancy by
11% compared with the prerobot era. All these reflected an
ICU cost savings of $1.1 million attributable to the use of
robotic telepresence in one year [43].
Conclusion
During the last two decades, the new subspecialty of neurocri-
tical care has emerged and increasing numbers of NICUs have
sprung up across the Western World. This has led to signifi-
cant improvement in patient outcome for those admitted to
NICUs compared to previous periods when such entities were
either non-existent or understaffed. Although these improve-
ments may not be evenly distributed across all subgroups of
NICU-admitted patients, this may be due to paucity of data or
small sample size. In addition to short- or long-term outcome
improvement, there are indications that NIs in NICUs also
improve other metrics, such as documentation and number of
complications, with decreased cost and higher net revenue for
hospitals. Factors that may play a role in these results include
better education, communication, and integration between
teams, adoption of protocolized management based on evi-
dence instead of preferences, and increased use and familiarity
with new technologies, all achieved by the mere presence of
NIs in these ICUs. However the exact contribution of each
factor to these improvements is unknown and the most prob-
able explanation is a combination of all the above.
Despite these promising results invigorating the existence
of neurocritical care as an independent and useful entity, the
perception of NICUs by patients and families may differ from
physicians and administrators. In a study from Germany,
Kiphuth et al. retrospectively evaluated the satisfaction (inde-
pendent of functional outcome) of 704 consecutive patients
and families from their stay in the NICU, as well as their
retrospective consent (approval) for the applied life-saving
emergency procedures on admission to the NICU. These data
were collected via mailed questionnaire or structured tele-
phone interview 12 months after discharge. The authors found
that high consent and satisfaction after NICU care (91% and
90%, respectively) was observed by those patients who reached
an independent life one year after their stay. Least satisfied
patients were those with epilepsy. However, only 19% of sur-
viving patients who were functionally dependent retrospect-
ively agreed to NICU care. Unfavorable functional outcome
and the diagnosis of ischemic stroke, ICH, and cerebral neo-
plasm were independent predictors for missing a retrospective
consent. These results challenge the notion that initiation of
neurocritical care should be assumed in all patients and may be
particularly important for NIs when faced with patients with-
out families, advance directives, or the ability to state their
preferences. These results may also suggest that in some cases
palliative care instead of NICU care may be more appropriate
[44].
Questions to be answered in the future about NICUs and
NIs remain aplenty. Based on the aforementioned data, how-
ever, we strongly believe that the background for their exist-
ence has been inexorably set.

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 Chapter
Neurointensive (NCCU) Care Business Planning
37 Sara Widing and Noah Grose
Introduction
Historically, neurology has been primarily an outpatient
specialty. The advent of modern neurosurgical techniques,
as well as more elegant means of artificial ventilation in the
1960s, brought increasing numbers of neurologic patients to
the intensive care units (ICUs). Although these patients were
primarily managed by medical and surgical-anesthesiologist
intensivists, occasional consults for neurophysiologic
testing, management of neuromuscular failure, and, more
commonly, prognostication, would bring a neurologist to
the ICU. In the 1980s and 1990s, the surge in new neurosur-
gical procedures created an interest by some neurologists in
cerebrovascular disease, while others ventured into the
ICUs and carved a niche for a new subspecialty: neurocri-
tical care [1].
Changes in education and accreditation often happen after
changes in practice have already occurred. Neurocritical care
has emerged as a new subspecialty over the past 30 years based
on perceptions and evidence that neurologists with expertise in
this area improve patient care [2]. The American Board of
Psychiatry and Neurology (ABPN) first issued certifications in
vascular neurology in 2005 and the United Council of Neuro-
logic Subspecialties (UCNS) began issuing neurocritical care
certifications in 2007. Through 2011, 1098 ABPN Vascular
Neurology certifications have been issued and publically listed,
almost twice as many as the 554 UCNS Neurocritical Care
certifications [2].
Most healthcare professionals would agree hospital
administrators and physicians both have a vested interest in
adopting new services and implementing new lines of busi-
ness, such as creating and implementing a neurocritical care
program. Working together is paramount for effective busi-
ness planning, implementation, and ongoing evaluation of
services. Ultimately, the patient and “market” should be the
beneficiaries of such planning and innovation. Coming to
consensus, while perhaps challenging, may take time and
patience. Understanding how the new service being proposed
aligns with the organization’s strategic plan, outlining and
completing a business plan, vetting the proposal through the
organization’s defined approval process, and consistent
review of performance are all critical aspects of the business
planning cycle.
430
Developing a Business Plan
Overview
Business plans and financial planning should be aligned and
generally integrated into the institution’s strategic planning
process. Having said this, understanding the organization’s
strategic planning process is usually the first step in the pursuit
of developing a business plan. Strategic plans generally include
three basic elements: defining the mission or vision statement
to provide guidance to the organization that is often aspiring
in nature, distinguishing a set of initiatives or programs for
which the institution will commit resources to aid in meeting
the said mission and vision statements, and the third aspect is
the financial plan [3]. Assuming the organization’s strategic
planning process is defined and has identified your program as
an area of priority for further resource allocation, the creation
of a business plan is likely the next logical step.
While formal definitions of a business plan may vary
slightly, it can be viewed as a roadmap for the program and
subsequent business needs of the project. In the simplest form,
the business plan will outline the particulars of how you plan
to meet these goals [4]. Generally, the business plan will serve
as the operations manual for the project, and serve as a way of
communicating to the organization the details and methods of
actualizing the initiative [5].
Business plan sections generally include the following:
• Executive summary
• Mission and/or vision statement
• Description of initiative/program/product/service
• Strategic rationale
• Market analysis
• Resource requirements
• Financial plan
• Milestones and metrics
• Risks and contingencies
• Summary
• Appendix.
Business plans should be designed to be dynamic in nature and
span a period of three to five years. A multidisciplinary team
should be created to assist with the completion of the business
plan and to bring key stakeholders together in the initial stages

of the project to assist with generating support for the project
from the beginning. The success of the business plan is often
not only predicated on the financial implications, but on the
partnerships and collaborations established at the very begin-
ning. Experience lends itself to stress the importance and value
of forming an integrated planning team and forging relation-
ships with interested parties to include other physician special-
ists, nursing, ancillary services, such as pharmacy, rehabilitation,
nutrition, and information technology, biomedical engineering,
and administration.
Business Plan Details
The required sections of the business plan may vary slightly,
depending on your institutional requirements, which are usu-
ally established by the senior leadership team to include such
positions as the chief strategy officer, chief executive officer, or
chief operations officer.
Definitions of each section of most business plans can be
found below. Generally, your administrator or strategy and
business planning department can assist with completion of
the details.
Executive Summary
The executive summary is typically a one-page, concise narra-
tive that is a high-level summary of the business plan, includ-
ing key elements from each section of the plan.
Description of Initiative/Program/Product/Service
This is a summary of the current state of the program and
organizational state of affairs surrounding the proposed business
plan. It may include the current program structure, a brief
description of the customers and competition, and the most recent
performance over the past three to five years. This section can also
be viewed as synopsis of the current state of the program and the
direction being proposed during the next three to five years.
Mission and/or Vision Statement
The mission, vision, values, and goals should describe why the
program exists, also known as the mission, and include the
definition of the program’s future desired state, generally
labeled as the vision. The primary values of the program can
be included, as well as measureable goals and objectives to be
achieved over the duration of the plan.
Strategic Rationale
The strategic rationale is simply why the program is being pro-
posed. While some involved in the planning of the project may
feel this is stating the obvious, it is imperative to clearly state why
the program being proposed is needed. The strategic rationale
may be a simple one or it may be more complex. Either way
articulating “why” will help solidify and “sell” the plan ultimately.
Market Analysis
The market analysis is often a large portion of the plan, where
all facets of the existing market and competition are analyzed.
Chapter 37: Neurointensive Care Business Planning
Components to consider when completing this portion may
include:
• Defining the current market and analyzing the immediate
future market (three to five years) and long-term trends
(five to ten years and beyond). The state of affairs in the
market is important to note. Consider items such as if the
industry is expecting to shift in the immediate future or
decade. One example may include that many surgical
procedures that once were inpatient with long recoveries
are now being completed with laser ablation and
considered outpatient in nature.
• Understanding the competition is imperative. Who is the
competition? What observations can be made related to the
competition’s strategy?
• Identify the risks. In any business decision, healthcare or
not, risk-taking is often part of the equation. Knowing the
risks and articulating them helps all parties to be
transparent from the beginning. It also helps to identify a
proper exit strategy in the event this is needed.
• Target market and market segmentation. What is the target
market for such services and do segments of the identified
population exist? If so, how does the segmentation impact
the business plan, if at all?
• Accreditation and compliance requirements. Is the
program striving to achieve a certain designation, such as
Comprehensive Stroke Center designation by The Joint
Commission (TJC)? If so, are other programs already
designated in your market? If so, will this impact your
ability to apply for certification?
Resource Requirements
Recognizing the resources needed to carry out the business plan
is commonly perceived as simple; however, when operational-
izing the plan it is common for unanticipated resources to
surface. When identifying a potential resource need, it may be
helpful to outline the process of the service or how the patient
may be “cycled” through the care continuum. Resources should
include such aspects as labor/manpower (physicians, advanced
practice nurses, nursing, pharmacy, fellows, etc.), supplies, edu-
cation and training, space, any administrative considerations,
such as management, billing, coding assistance, financial analy-
sis, accreditation needs, capital equipment, information technol-
ogy to include the creation of electronic medical records,
additional computers, etc., and marketing support, to name
a few.
When identifying resource requirements it may also be
pertinent to differentiate when the implementation may occur.
For example, year 1 may include colocation of patients into one
pod within a defined intensive care unit. In this instance, it may
not be necessary to purchase all new capital equipment
(Table 37.1) or hire additional staff (Table 37.2) since the
neurocritical care patients are just being colocated with no
incremental bed capacity. Year 2 may include adding bed cap-
acity and thus require the addition of new nursing positions.
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 Chapter 37: Neurointensive Care Business Planning

Table 37.1 Sample capital requests

Equipment Year 1 Year 2 Year 3 Total

Transcranial Doppler $125,000 $125,000
Microdialysis system $60,000 $60,000
Cerebral blood flow monitor(s) $31,500 $31,500 $63,000
Catheter-based hypothermia unit(s) $47,500 $47,500 $95,000
Telemedicine cart $125,000 $125,000
Data acquisition system $25,000 $25,000
vEEG monitors $50,000 $50,000
TOTAL $264,000 $231,500 $47,500 $543,000

Table 37.2 Sample recruitment grid

Recruit Start date Year 1 Year 2 Year 3 Year 4 Year 5

Neurointensivists
Dr. Smith N/A
Neurointensivist 1 7/1/2015 X
Neurointensivist 2 7/1/2015 X
Neurointensivist 3 3/1/2016 X
Neurointensivist 4 7/1/2016 X
Neurointensivist 5 7/1/2017 X
Advanced Practice Nurses
ARNP 1 N/A
ARNP 2 7/1/2015 X
ARNP 3 1/1/2016 X
ARNP 4 1/1/2016 X
ARNP 5 7/1/2016 X
ARNP 6 7/1/2017 X

Financial Plan
The financial plan brings together resource requirements and
market projections to ultimately define and describe the finan-
cial forecast of the initiative: it is not an accounting exercise.
Until this is completed a business plan is truly only conceptual.
Being able to justify the plan with solid figures, assumptions,
and realistic projections is essential. What the plan does need
to reflect is achievable volumes and financials, since you will
most likely be held to what is being presented. Generally, one
could state there are two main reasons a business plan includes
a financial plan: to assist when seeking support, and to under-
stand and guide how the NCCU will perform financially [6].
As part of your financial analysis, remember to include
internal and external funding sources, such as grants and
outside contracts, to help support the financial picture. Some
institutions may require multiple facets of a financial plan,
such as income statement, balance sheet, and cash flow
statement. Most of the time experience has shown that a very
simple proforma outlining the revenues, expenses, and gain/
loss over a three- to five-year period of time is sufficient. An
example outline of projecting incremental, or new cases, as
well as a proforma template can be found in Figure 37.1.
Milestones and Metrics
Key milestones and metrics must be identified and will assist
with assessing how the business plan is progressing. The mile-
stones and metrics should be aligned with the program goals
set forth in an earlier section. It is reasonable to expect admin-
istration to request deliverables and progress updates through-
out the duration of the plan. Similar to any “investor,”
administration will not only seek to understand how the program
is developing, but also how they may be able to help further the
plan, if needed. The advent of the balanced scorecard implemen-
tation in the late 1990s to 2000s brings together metrics,

432
 Chapter 37: Neurointensive Care Business Planning

Neurointesive Care Business Planning

Proforma

EXAMPLE

Inpatient Volume Base Year Year 1 Year 2 Year 3 Year 4 Year 5 Total Incremental
Medical 1000 32 95 205 255 300 887
Surgical 400 200 325 425 500 625 2075
Total Incremental IP Cases 232 420 630 755 925 2962
CLINICAL
Gross Charges $40,215,196 $7,323,659 $14,647,318 $23,435,709 $28,122,851 $34,309,878 $ 107,839,414
Net Revenue $28,725,140 $ 5,231,185 $ 10,462,370 $ 16,739,792.0 $ 20,087,750.40 $ 24,507,055.49 $ 77,028,153
Direct Expense - Volume Related $ 12,342,188 $ 2,615,473 $ 5,230,946 $ 8,369,514 $ 10,043,416 $ 12,252,968 $ 38,512,317
New Direct Clinical Expense $ 162,350 $ 487,050 $ 633,165 $ 886,431 $ 1,373,968 $ 3,542,964
Cost of New Captial $ 264,000 $ 231,500 $ 47,500 $ 543,000
Incremental Margin $16,382,952 $ 2,189,362 $ 4,512,874 $ 7,689,613 $ 9,157,903 $ 10,880,120 $ 34,429,872

PROFESSIONAL
Gross Charges $ 893,077 $ 822,310 $ 1,644,619 $ 2,631,391 $ 3,157,669 $ 3,852,356 $ 12,108,344
Net Revenue - Neurology $ 637,912 $ 587,364 $ 1,174,728 $ 1,879,564.80 $ 2,255,477.76 $ 2,751,682.87 $ 8,648,817
Operating Expense (Includes New Recruits) $ 1,021,035 $ 824,000 $ 1,648,000 $ 2,636,800.00 $ 3,164,160.00 $ 3,860,275.20 $ 12,133,235
Incremental Margin $ (383,123) $ (236,636) $ (473,272) $ (757,235) $ (908,682) $ (1,108,592) $ (3,484,418)
Net Income/ (Loss) $ 15,999,829 $ 1,952,726 $ 4,039,602 $ 6,932,378 $ 8,249,221 $ 9,771,527 $ 30,945,454

Figure 37.1 Sample incremental volume projections and proforma.

milestones, and program performance in one summary. Most
healthcare organizations continue to use this concept, albeit it
may look somewhat different at each institution, to provide simple
summaries of the overall performance of the business plan.
Risks and Contingencies
As stated earlier, understanding any risks related to the business
plan implementation and market entry is crucial. If there are
opportunities to mitigate the risks, obviously one should take
action as appropriate. Additional risks or contingencies may
also be present with governing agencies such as TJC or Centers
for Medicare and Medicaid (CMS). Understanding compliance
and accreditation requirements is imperative. One such example
may be the Comprehensive Stroke Center designation by TJC.
Summary
The summary is simply just that – a summary of the above items
in a succinct, cohesive manor that “wraps” up the key points.
Appendix
Any detailed items, such as market share and financial state-
ments can usually be found in the appendix.
Financial Commitment
The amount of investment and financial support needed to create
a neurocritical care unit is dependent on the resources identified
in the resource requirement section. This often includes:
• Current manpower and future recruitment needs
• Existing space and obtainable space, if needed
• Capital equipment already present and its remaining
useful life
• Additional training and subspecialty education needed for
those caring for the neurocritically ill
• Supplies unique to the new program and service
• Information technology infrastructure.
It should be no surprise the most expensive portion of the
financial commitment will be in the salary and wages.
Depending on the staffing model being proposed, hiring nurse
practitioners can be a good way to help manage the patient
care efficiently under the direction of the attending physician.
Salary ranges vary by region and state, and will also be depend-
ent on education, years of experience, and tenure at the organ-
ization. Guidelines and approximate range of salaries (not
including benefits, which can be estimated to be about
20–30% of the salary) can be found in Table 37.3.
In an academic environment where research is routinely
conducted and supported it will be critical to identify any
research funding support to help offset salary or other items.
Recruitment packages and offers often include additional
funds to help support the recruit’s research and clinical inter-
ests. Make sure it is understood if such commitments made to
new recruits will be allocated back to the plan.
Capital investment can easily require $1.0M, not including
a portable computed tomography (CT) scanner to be used at
the bedside. As stated before, what capital equipment is already
available will dictate the future asks of the program.
Presenting to Administration
Earlier in the chapter it was noted how creating a multidisci-
plinary team may help to create engagement, buy-in, and build
relationships that will be vital when ready to present for
approval. As stated in a recent article in Becker’s Hospital

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 Chapter 37: Neurointensive Care Business Planning

Table 37.3 Sample salary and additional budgeting

Position Salary Training and education allocation

Advanced practice nurse $85k–$130k $2500 annually for continuing medical education (CME)
Bachelor’s prepared nurse $55k–$100k Generally included in nursing unit operations budget or nursing education budget at hospital
level. Many hospitals will support conference travel if nurse is presenting.
Fellow $70k–$85k Fellows may receive a yearly stipend for books, travel and CME. Depends on institution.
Nurse manager $110k–$140k Generally included in nursing unit operations budget or nursing education budget at hospital
level. Many hospitals will support conference travel if nurse is presenting.
Clinical nurse specialist/ $110k–$140k Generally included in nursing unit operations budget or nursing education budget at hospital
educator level. Many hospitals will support conference travel if nurse is presenting.
Respiratory therapist $47k–$65k Generally included in home department operations budget, if included at all.
Pharmacist $90k–$150k Generally included in home department budget.
Note the above training and education guidelines are often unique to each organization and region. The stated training and education funding should be
considered separate from routine competency and training for each professional as part of their yearly performance evaluations.

Review by Lisa Goren [7], it has become increasingly clear that
physicians and administrators no longer have a choice about
whether to work together. Goren states that it is vital to the
future of healthcare that they do, melding medical acumen
with strategic insight in order to save a flailing industry. This
insight reinforces the importance of building a collaborative,
cross-functional team of all stakeholders when the business
plan is being developed.
As the plan is developed it can often be helpful to review the
various reiterations of the proposal with administrators for
validation, gaps in planning and for “real-time” feedback. Use
this time to build rapport, solicit ideas, and to gauge the man-
agement’s engagement for such a proposal. Understanding what
metrics and “tolerance” for new investments by hospital leaders
will be important prior to presenting for approval. Allowing and
inviting joint decision-making can help build trust between you
and your administrator(s).
Six strategies that help build the connection between physicians
and hospital decision-makers, as identified by Goren, include:
1. Create rules for engagement – joint decision-making,
problem-solving, and strategic planning. Examples that
have been proven to be successful include shared
governance councils and team agreements.
2. Measure and define data sets – clearly articulate what is
being defined and how. Jointly agree the measures,
routinely measure, and discuss opportunities.
3. Patient-care-centered meetings – patient care should be the
focus of the meeting, not individual preference or a
precedence that may have been established years ago.
4. Start small with quick wins – take appropriate time to build
programs and establish cross-functional teams. Achieving small
successes helps to build trust and further the collaboration.
5. Celebrate! – health care can be a taxing profession and
acknowledging the hard work and dedication of all team
members is critical. Celebrate those small victories and
recognize achievements.
6. Create champions – positive energy is contagious. By
sharing the successes and positive stories, an environment
of healthy energy and excitement will be generated. Use
this as a time to create champions for future initiatives.
Billing and Revenue Models
Traditional billing models include the neurointensivist
“dropping” the charges in the neurocritical care unit (NCCU)
setting. As the use of acute care nurse practitioners (ACNPs)
and physician assistants (PAs) continues to grow, billing
models may shift. Each institution and professional practice
likely has their own “rules of engagement” as to how the
advanced practice providers may be utilized. Keep in mind,
when using an ACNP or PA, Medicare and Medicaid only
reimburse at 85% of the physicians fee schedule. While this is
a discounted rate, in some instances it is more prudent for
efficiency to have the ACNP or PA drop the charge. Third-
party reimbursement (commercial payers) usually varies by
contractual arrangement and must typically be billed under a
collaborating or supervising physician at 100% of the phys-
ician fee schedule.
To bill under their license, the ACNP and PA must be
credentialed with the various payers and obviously must have
the appropriate documentation to support such charges. In
some states or institutions, the collaborating or supervising
physician must also sign the documentation. If the ACNP and
physician see the patient in the hospital on the same day, the
documentation may be combined and billed at 100% under the
physician’s number for noncritical care evaluation and man-
agement services.
Consult with your department and institution as to how
best to utilize the ACNPs and PAs in the delivery of care. Most
likely, this will not be a new inquiry and practices will have
already been established. Medical records or health informa-
tion management departments can also likely guide on proper
documentation and coding practices.

434

Research Integration
Integrating research projects and using money from funded
grants is possible in conjunction with hospital and professional
revenues. Most hospitals and institutions do have a research
department that helps to govern, manage, and set guidelines as
to how to best incorporate research into the clinical enterprise.
Neurointensive Care Unit Models
The NCCU consult service model: This involves a team of
neurointensivists who provide consultation services to
neurosurgical and medical ICU patients. The primary team
manages ventilator and invasive monitoring procedures [1].
The open NCCU model: This involves a neurointensivist who
has admitting privileges in the NCCU, but is not responsible
for all patients in the NCCU and consults other medical
intensivists to care for ventilated patients [1].
The closed NCCU model: A model in which all patients
admitted to the NCCU are primarily managed by the
neurointensivist. Upon discharge from the NCCU, they are
attended to by the neurology or neurosurgical ward teams.
Most procedures are handled by the NCCU team [1].
The closed-cooperative NCCU model: A model in which the
neurology/neurosurgery service continues to have an active
role in the management of patients in the NCCU (particularly
in regard to family discussions and longer-term management
decisions). The NCCU team handles day-to-day issues,
however, and is responsible for most procedure [1].
Greater than 30 studies have compared outcomes in open
versus closed ICUs. Most were single ICUs, and most evalu-
ated outcomes after changing from open to closed units.
A meta-analysis of 27 studies involving 27,000 patients
addressed the organizational diversity of ICUs by classifying
intensivist involvement into high versus low “intensity.”
Patients in the high intensity (open or closed ICUs with man-
datory intensivist consultation) involvement was associated
with lower ICU and hospital mortality, shorter ICU and hos-
pital length of stay (LOS), and lower costs.
The Joint Commission’s Comprehensive Stroke
Certification
The recently released TJC Comprehensive Stroke Certification
has placed the value of specialty NCCU in hospitals across the
country. With this certification comes the responsibility to the
complex neurovascular population across the continuum of
care, including the ICU. Obtaining this certification demon-
strates support from the hospital in the care of the complex
neurovascular stroke patient.
The recent (July 1st, 2017) published comprehensive stroke
center (CSC) requirements for obtaining certification are:
• Standard DSPR.3 – d: The comprehensive stroke center has
dedicated neurointensive care beds for complex stroke
patients that are available 24 hours a day, seven days a week.
Chapter 37: Neurointensive Care Business Planning
• Standard DSPR.5 –7: The program provides the number
and types of practitioners needed to deliver or facilitate the
delivery of care, treatment, and services.
• The comprehensive stroke center has a written call
schedule for attending physicians with expertise in critical
care and cerebrovascular disease providing availability
24 hours a day, seven days a week.
• The comprehensive stroke center demonstrates there are
attending physicians or residents with expertise in critical
care and cerebrovascular disease available 24 hours a day,
seven days a week.
• The comprehensive stroke center director or designee is
available 24 hours a day, seven days a week.
• The comprehensive stroke center is required to have the
following practitioners and staff members providing care,
as indicated:
: The comprehensive stroke center has the following
physicians available 24 hours a day, seven days a week:
– Physicians with neurocritical care privileges provide
on-site, 24-hour care to patients in the dedicated
neurointensive care beds.
: Note 1: Fellows with neurocritical care and
cerebrovascular experience are acceptable for meeting
this requirement. Additionally, residents with
neurocritical care and cerebrovascular experiences, as
determined and documented by the residency program,
are acceptable for meeting this requirement.
: Note 2: Advanced practice nurses (APNs) or PAs with
neurocritical care and cerebrovascular experience are
acceptable for meeting this requirement as an alternative
to physicians, when the following conditions are met:
– APN or PA has additional education in
neurocritical care or cerebrovascular care and has a
minimum level of experience determined by the
organization.
– Physicians with neurology and critical care
experience are available for clinical back-up
24 hours a day, 7 days a week.
– Physicians with endovascular and critical care
experience are available for clinical back-up
24 hours a day, 7 days a week.
– Standard DSDF.1 – 1: Practitioners have education,
experience, training, and/or certification consistent
with the program’s scope of services, goals and
objectives, and the care provided.
• The medical director for the comprehensive stroke center
program is a physician with extensive experience and
expertise in neurology and cerebrovascular disease.
Examples include the following:
: Stroke or vascular neurologist
: Critical care neurologist
: Vascular neurosurgeon
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Table 37.4 Characteristics of typical inpatient stroke facilities [8]

Hospital type
Characteristics Nonstroke ASRH PSC CSC
center
Typical bed count 20–50 30–100 100–400 400–1500
Annual stroke 10–50 25–50 50–300 >300
admissions
Rapid neuroimaging No Performed and read within Performed and read within Performed and read within
24/7 45 mins of order 45 mins of order 45 mins of order
IV tPA capability 24/7 No 60-min door-to-needle time 60-min door-to-needle time 60-min door-to-needle time
Acute stroke team No At bedside within 15 mins At bedside within 15 mins At bedside within 15 mins
available
Stroke unit No No Yes Yes
Neurocritical care No No No Yes
unit
Access to No Yes, within 3 h or by transfer Yes, within 2 h, in-house or by Yes, 24/7 coverage and call
neurosurgical transfer schedule
services
Abbreviations: ASRH: acute stroke-ready hospital; PSC: primary stroke center; CSC comprehensice stroke center; IV tPA: intravenous tissue plasminogen activator

Building an Advanced Practice Provider
Intensive Care Model
For more than two decades, nurse practitioners (NPs) and PAs
have been utilized successfully in critical care medicine [9].
Use of advanced practice providers (APPs), including NPs and
PAs, is increasingly being adopted as a strategy to augment
staffing and promote continuity and quality care in the intensive
care unit [10]. The growth of APPs in the ICU has been multi-
factorial: the incorporation of the Accreditations Council for
Graduate Medicine Education (ACGME) resident work hour
restriction in 2003, followed by additional restrictions in 2011, a
shortage of physican intensivists, the aging baby boomer popu-
lation, increasing demand for ICU utilization, and the higher
acuity and complexity of the critically ill and injured patient.
The APP has been advocated as a resource to help mitigate the
physician workforce shortage in critical care. Such utilization in
critical care has evolved and expanded as a result of these
changes, both within the United States and in other countries.
APPs are two separate types of providers with differing
educational backgrounds and training, but often assume simi-
lar roles in the ICU. In ICUs and acute care units, general roles
and responsibilities of NPs and PAs include assessing patients,
obtaining patient histories, and doing physical examinations,
making rounds with the multidisciplinary team, and, for NPs
and PAs who have credentials and privileges, performing inva-
sive procedures (i.e. suturing, placing central and arterial lines,
lumbar punctures) and assisting in surgery under the supervi-
sion of a physician [10]. Other roles include serving as first
responders for institutional rapid response teams and cardiac
arrest teams, doing evaluation and triage for patients outside
of the ICU, acting as a preceptor for medical and nursing
students, providing support and education to the clinical nurs-
ing staff, and communicating with patients and families [10].
There are many varieties of NPs. The differences in certifi-
cations vary based on type of education, and pathways are
determined by primary or acute care population focus. In July
2008, a collaborative effort of the Advanced Practice Registered
Nurse (APRN) Consensus Work Group and the national
Council of State Boards of Nursing, the Consensus Model for
APRN Regulation: Licensure, Accreditation, Certification and
Education was developed. This document attempts to regulate
these variances and defines the practice, describes the APRN
regulatory model, suggests titles to be used, defines specialty,
labels the rise of new roles and population foci, and presents
plans for implementation [11].
The adult gerontology primary care nurse practitioner
(PCNP) practices within the patient population that includes
the entire spectrum of adults, including young adults, adults,
and older adults. The PCNP is a provider of direct health care
services [12]. Within this role, the PCNP synthesizes theoret-
ical, scientific, and contemporary clinical knowledge for the
assessment and management of both health and illness states.
The PCNP incorporates health promotion, health protection,
disease prevention, and management focus of adult gerontol-
ogy PCNP practice [12]. The PCNP employs evidence-based
clinical practice guidelines for screening activities, identifies
health promotion needs, provides anticipatory guidance and
counseling to address environmental, lifestyle, and develop-
mental issues [12].

436

The family nurse practitioner (FNP) practices within a
patient population in primary care family practice, including
newborns, infants, children, adolescents, adults, pregnant and
postpartum women, and older adults [13]. The FNP cares for
individuals and families across their lifespan [14]. The FNP role
includes preventative healthcare, as well as the assessment, diag-
nosis, and treatment of acute and chronic illness, and preventa-
tive healthcare for individuals and families [14]. The focus of
care is the family unit, as well as the individuals belonging to the
family, however the family chooses to define itself [13]. FNPs
primarily practice in the ambulatory care setting [13].
The ACNP is a registered nurse who has completed an
accredited graduate-level educational program that prepares
him or her as a nurse practitioner with supervised clinical
practice to acquire advanced knowledge, skills, and abilities
[15]. The core body of knowledge and competencies for adult
gerontology ACNP preparation and practice is derived from
the full spectrum of needs of high acuity patient care along the
wellness-to-illness continuum. The ACNP assesses patients
with acute, critical, and/or complex chronic illnesses through
their health history, physical, and mental status examinations,
and health risk appraisals [15]. The ACNP acknowledges and
incorporates the dynamic nature of acute, critical, and/or
complex chronic illnesses in the provision of care [15]. The
ACNP focus is the provision of restorative, curative, rehabili-
tative, palliative, and/or supportive end-of-life care, as deter-
mined by the patient’s needs. Goals include patient
stabilization for acute and life-threatening conditions, minim-
izing or preventing complications, attending to comorbidities,
and promoting physical and psychological well-being [15].
Although NPs with other educational preparation, such as
specialized training in family, adult, or gerontology care also
practice in hospital settings, only ACNPs have been educated
and trained, and have a scope of practice to manage critically ill
patients in ICUs [10]. Similarly for PAs, critical care training or
fellowships in critical care help ensure that essential skills for
managing acute and critically ill patients are mastered beyond
the primary-care-focused training of the majority of PA
Table 37.5 Differences in advanced practice providers educational backgrounds
Nurse practitioner
Education/background BSN and licensure as a registered nurse
Degree Master’s or doctorate in nurse practice
Program length 18 months–5 years
Specialty focus Yes
National certification Yes
Practice agreement State regulated – most do not require physician collaboration or
supervision
Recertification 2000 patient contact hours every 5 years, plus 75 CEUs every
requirements 5 years
Abbreviations: BSN: Bachelor of science in nursing; CEU: continuing education units
Chapter 37: Neurointensive Care Business Planning
programs. However, unlike NPs, PAs do not have a designated
scope of practice based on education, national certification, or
state board regulations [10]. Ensuring appropriate scope of prac-
tice is an essential aspect of utilizing NPs and PAs in the ICU
[10].
It is important to know the differences in the training and
education of the APP candidates when hiring for the open
positions (Table 37.6). Certification, although not required in
all states, should reflect the population of patients for which the
NP or PA has been trained [16]. Prior nurse experience with a
specific population does not qualify an NP to practice without
the population-focused education and certification [17].
There is increasing recommendations on the type of certi-
fication that is expected for NPs in ICU settings. Ensure that
you know the state laws that you are practicing in to better
know the right applicant to hire for the position.
Staffing
When you have decided to add APPs to your NCCU, the
organization will likely require you to make a business case
to support what may be perceived as an expensive endeavor
[18]. The proposal should include the potential impact on
quality, patient satisfaction, length of stay, and finances [18].
Before considering staffing numbers, it is important to
determine the role of APPs within the structure of the unit.
Will the APPs cover the NCCU full-time, during the day or at
night, or on weekdays and/or weekends [19]? What percentage
of ICU patients and concomitant critical care responsibilities
outside the ICU will be overseen by the APPs? Will they work
independently or as part of a NCCU APP team [19]? Will they
function in coordination with non-APP providers (e.g. house
staff, fellows, intensivists, or hospitalists), and how will their
workloads mesh with the availabilities and responsibilities of
the non-APPs [19]?
When creating the recruitment and staffing process it is
important to have the ability to retain staff during the on-
loading process; this rests on three basic tenets. First, the team
must have sufficient manpower to meet its responsibilities
Physician assistant
Bachelor’s in college-level course work
Master’s degree
2 years
No
Yes
Supervisory agreement with MD
100 hours of CME every 2 years, and exam
every 6 years
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 Chapter 37: Neurointensive Care Business Planning

Table 37.6 Educational differences and nurse practitioner certifications [16]

Patient population Education Certification/credential Previous nursing experience

Critically ill adults in a variety
of units: medical, surgical,
cardiovascular, trauma, or
emergency department
Adults admitted to inpatient
general medical surgical units
Adult gerontology acute care nurse
practitioner program
Adult gerontology acute care nurse
practitioner program: focus on
trauma/ critical care or focus on
emergency care
Adult gerontology acute care nurse
practitioner program
American Association of Critical
Care Nurse Certification
Corporation/ACNPC
American Nurses Credentialing
Corporation/AGACNP-BC
American Association of Critical
Care Nurse Certification
Corporation/ACNPC
American Nurses Credentialing
Corporation/AGACNP-BC
Adult intensive care unit
Cardiac intensive care unit
Trauma intensive care unit
Neuroscience intensive care
unit
Emergency department
General medical or surgical
nursing
Intensive care nursing

Table 37.7 Sample coverage schedule with 12-hour shifts

Days
APP Monday Tuesday Wednesday Thursday Friday Saturday Sunday
1 x x x
2 x x x
3 x x x
4 x x x
5 x x x
6 x x x
7 x x x
Nights
8 x x x
9 x x x
10 x x x
11 x x x
12 x x x

[19]. Second, scheduling must be consistent and fair regarding
vacation, weekend, and holiday assignments, and granting
requests for time off [19]. Third, the use of unconventional
shifts, such as rotating schedules, should be explored [19]; this
typically allows the recruitment of APPs who would have
rejected a nights-only position.
The staffing model should including filling positions with
emphasis on fully staffing Monday–Friday first, with expan-
sion to Saturday–Sunday day shift. Then the additional staff
should be hired and trained with an emphasis on expanding
coverage to 24/7 when fully staffed. When planning to hire and
staff a unit correctly for the needs of the neurocritical care
population one must remember that staffing must include
vacation request, sick time, short-term disability, and mater-
nity or paternity leave. Overstaffing with an additional one or
two APPs is reasonable to maintain safe patient ratios.
The importance of matching staffing models in the ICU to
ensure patient safety for acute and critically ill patients is well
recognized [10].
Several factors influence APP patient ratios, including the
number of ICU beds, number of shifts per day, desired ICU
occupancy rate, number of days each professional is working
per week, patient’s severity of illness, the level of care, and the
clinical, research, and teaching workload [10]. Kleinpell et al.
[10] completed a national survey on APP to patient ratios and
found that the mean provider-to-patient ratio in the ICU was
1 to 5 (range 1 to 3–1 to 8) for both NPs and PAs.
The models shown in Tables 37.7 and 37.8 are designed on
the Memorial Sloan-Kettering [19] staffing model’s recom-
mendation for staffing of APPs. This is a ratio of one APP to
every eight ICU patients during the day, and one APP to every
twelve ICU patients at night. In this model, we’ve elected to

438
 Chapter 37: Neurointensive Care Business Planning

Table 37.8 Sample coverage schedule with 24-hour shifts

M T W Th F S Su M T W Th F S Su
1 x x x x
2 x x x x
3 x x x x
4 x x x x
5 x x x x
6 x x x x
7 x x x x
8 x x x x
9 x x x
10 x x x
11 x x x x
12 x x x x

have the 1:12 ratio continue on the weekend days and nights as
well. In addition, this model is for a 24-bed NCCU.
Summary
Creating a business plan for NCCUs can be a daunting task, but
knowing the general principles and integral parts of the planning
will help in creating a successful model. Working collaboratively
with colleagues, administrators, and others will help in ensuring
the business plan meets your institutional guidelines and frame-
work for new product development. When in doubt – ask. Most
hospitals and academic centers have proven practices and tem-
plates that will help you formulate the plan.

7. Goren L. (2014). Integration and education. https://www.ncsbn.org/

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441
 Index
Locators in bold refer to tables; those in italic to figures
ABC see airway, breathing, and
circulation mnemonic
ABC/2 method, ICH volume
measurement 132, 132
abscesses see cerebral abscesses
accelerated aging, spinal cord
injury 295
accelerated idioventricular
rhythm (AIVR) 345
Accidental Death and Disability
(US government white
paper) 208
accidents see road traffic
accidents
acetaminophen 44, 73–74
acid–base disturbances
nephrology 364–66
stabilization of the patient 4
see also metabolic acidosis
acidemic hypocarbia, respiratory
physiology 56–57
activated charcoal, use in drug
intoxication 254–55
Acute Care Nurse Practitioners
(ACNPs) 437
acute confusional state (ACS)
392, 392; see also delirium
Acute Dialysis Quality Initiative
(ADQI) 359
acute disseminated
encephalomyelitis (ADEM)
414
diagnostic work-up 414, 415
management 414–15
symptoms 414
acute hemorrhagic
leukoencephalitis (AHLE)
414
acute inflammatory
demyelinating disorders 414
acute disseminated
encephalomyelitis 414–15
acute multiple sclerosis 415
Balo concentric sclerosis 416
central pontine myelinolysis
417–18
complications 418–19
442
differential diagnosis 416, 417
heroin-associated spongiform
leukoencephalopathy
416–17, 417
neuromyelitis optica 415
progressive multifocal
leukoencephalopathy
417–18
tumefactive multiple sclerosis
415–16, 416
acute inflammatory
demyelinating
polyneuropathy (AIDP)
251
acute ischemic stroke
see ischemic stroke
acute kidney injury (AKI)
359
diagnostic criteria 359
etiology 360–61, 360
management 368–69
renal replacement therapy
366–68
urinalysis findings 361–62
acute leukoencephalopathy
see acute inflammatory
demyelinating disorders
acute liver failure (ALF), hepatic
encephalopathy 370–76,
371–72, 371, 375–76
acute lung injury (ALI)
hypoxemia 324–26
Lung Injury Score 326, 326
traumatic brain injury 211
acute multiple sclerosis (Marburg
variant) 415
acute on chronic liver failure
(ACLF), hepatic
encephalopathy 374,
378–79
acute quadriplegic myopathy
syndrome (AQMS) 47–48
acute respiratory distress
syndrome (ARDS) 324–25,
325–28
definitions 326
epidemiology 326–27
grading severity 325–26, 326
management 327–30, 328, 329
neurogenic pulmonary edema
331
raised ICP 330–31
risk factors for developing
327
traumatic brain injury 211
ventilation 57–58
adaptive response, fever as 351
ADEM see acute disseminated
encephalomyelitis
adrenocorticotrophic hormone
(ACTH) 240
Adult Gerontology Primary Care
Nurse Practitioners 436
advance directives, medical
ethics 317
advanced practice provider
(APP) model 436–37,
436–38
AEDs see antiepileptic drugs
agitation
assessment 34, 35–37
ICU experience for patients 33
postoperative management
300
traumatic brain injury 218
and undersedation 62–63
airway, breathing, and
circulation (ABC)
mnemonic
drug intoxication 254
stabilization of the patient 4
traumatic brain injury 204
airways 50
alternatives to intubation 51
difficult airway scenarios/
solutions 51, 54–56
drug intoxication 254
ICP management 23
ischemic stroke 108–9, 113–14
neurological assessment prior
to intubation 54
neuromuscular respiratory
failure 53–54
stabilization of the patient 4
surgical airways 55–56
traumatic brain injury 204, 210
see also intubation;
tracheostomy
airway pressure release
ventilation (APRV), acute
respiratory distress
syndrome 327
AKI see acute kidney injury
Alberta Stroke Program Early CT
Score (ASPECTS) 107
alcohol consumption
coconsumption with cocaine
255
intoxication 256
role in delirium 395
status epilepticus 176
ALF see acute liver failure
ALI see acute lung injury
alkalemic hypocarbia 56–57
alpha-2-agonists,
neuropharmacology 38–39
ALS see amyotrophic lateral
sclerosis
alteplase, neuropharmacology 76
amantadine, consciousness
disorders 409
American Academy of
Neurology, brain death
criteria 248
American Association of
Neurological Surgeons
(AANS) guidelines, spinal
cord injury 294–95
American College of Surgeons
(ACS), Trauma Center
Verification Program 208
American Heart
Recommendations,
therapeutic hypothermia 29
American Spinal Injury
Association (ASIA)
impairment scale 291
American Stroke Association
guidelines, intracerebral
hemorrhage 131–32,
138–39, 140

aminoglycosides,
contraindications 194
aminosteroidal neuromuscular
blockers 45–47
amiodarone 339, 346–47
ammonia metabolism 370
gut microbiome disturbances
379
increasing metabolism 378
reducing ammonia
production/absorption
376–78
see also hepatic
encephalopathy
AMPA encephalitis 233–34, 235
amyotrophic lateral sclerosis
(ALS)
generalized weakness 397, 399
respiratory failure 188, 189, 190
anaerobic metabolism, cerebral
blood flow 13
analgesia 41
algorithm for mechanically
ventilated patients 34
analgesic agents, general
42
ischemic stroke 114–15
neuropharmacology of
selected agents 42–44
pain as a source of agitation/
anxiety/delirium 63
pain assessment 41–42
anemia
cerebral blood flow 13
ischemic stroke 116
subarachnoid hemorrhage
166–67
traumatic brain injury 212
anesthetic induction 52, 54–55
aneurysm 167, 220–21
aneurysmal subarachnoid
hemorrhage (aSAH) 158–59
aneurysm coiling 304
aneurysm repair 163–64
aneurysm reruptures 303
angiogram negative 167–68
epidemiology/risk factors 154
invasive neuromonitoring 80,
82
NICU outcome studies 424–25
postoperative management
303–4
seizure prophylaxis 66
angiogram negative
subarachnoid hemorrhage
167–68
angiography, brain death
evaluation 250; see also
CT-angiography
anion gap metabolic acidosis 364
anterior cerebral arteries
(ACAs), TCD monitoring
92, 93, 95
anterior motor horn disorders,
generalized weakness 397,
399; see also amyotrophic
lateral sclerosis
anterior temporal lobectomy,
epilepsy surgery 312
anthrax infection 259–61,
260–61
anti-AMPA receptor encephalitis
233–34, 235
antiarrhythmic medication
atrial fibrillation 48, 339
drug–drug interactions 48
antibiotics see antimicrobial
agents
anticholinergic medication, role
in delirium 395
anticoagulant medication
atrial fibrillation 338–39
cerebral venous thrombosis
150–51
hypoxic encephalopathy 388
intoxication/overdose 257
ischemic stroke 107, 109–10,
117
subarachnoid hemorrhage 304
antidiuretic hormone (ADH),
sodium regulation 238
antiepileptic drugs (AEDs)
brain tumor patients 307
neuropharmacology 65–71
role in delirium 395
seizure prophylaxis 66
status epilepticus 67–69
therapeutic monitoring/
drug–drug interactions 66–71
anti-GABA receptor encephalitis
233–34, 235–36
antihistamines, role in delirium
395
antimicrobial agents
anthrax infections 260
drug–drug interactions 48
hepatic encephalopathy 378
postoperative management 302
anti-NMDA receptor
encephalitis 233–35, 233–34
antipsychotic medication, role in
delirium 395
antishivering medication 65,
71–73, 73–74
antithrombotic agents see
anticoagulant medication
APACHE III (Acute Physiology
and Chronic Health
Evaluation) scores, NICU
outcomes 423
apnea testing, brain death
evaluation 249–50
APO-E gene, role in delirium
393–94
apoptosis reduction, therapeutic
hypothermia 28
aquaporin-4 (AQP4) channel
acute inflammatory
demyelinating disorders 419
cerebral edema 26
arbovirus (arthropod-borne)
encephalitis 272–74
ARDS see acute respiratory
distress syndrome
arginine vasopressin (AVP),
sodium regulation 238
arousal disorders, hypoxic
encephalopathy 382–83; see
also consciousness disorders
arrhythmias 335, 350
conduction blocks 348, 349
medications affecting QT
interval 346–47
onset/predictors 336
pacemakers 348–49
pathophysiology 335–36
prognosis 349–50
symptoms 335
see also narrow complex
arrhythmias; wide complex
tachycardias
arterial recanalization, TCD
monitoring 97
arterial spin-labeling, cerebral
blood flow measures 16
arteriovenous malformations
(AVMs) 167, 310
aSAH see aneurysmal
subarachnoid hemorrhage
aspartate therapy, hepatic
encephalopathy 378
ASPECTS see Alberta Stroke
Program Early CT Score
aspergillosis 281
diagnostic work-up 281–82
management 282
symptoms 281
aspiration
stabilization of the patient 4
subarachnoid hemorrhage
162–63
aspirin, subarachnoid
hemorrhage 304
asthma, hypoxemia 324, 331
ATACH II (Antihypertensive
Treatment in Acute Cerebral
Hemorrhage) trial 138
atracurium, neuropharmacology
46
atrial fibrillation 339
conversion pause 338
diagnostic work-up 338
epidemiology 337
etiology 337
management 338–39, 340
stroke risk prediction model
337–38
symptoms 337
atrial flutter 339–40
atrial tachycardia 342
atrioventricular junctional
tachycardia 344
atrioventricular nodal re-entry
tachycardia 342
atropine 264
Index
autoimmune diseases,
respiratory failure 191,
193–94; see also
Guillain–Barré syndrome;
myasthenia gravis
autoimmune encephalitis 233,
233, 237
cancer investigation workup
235–36
classification of types 233–34,
233–36
diagnostic criteria 233
differential diagnosis 236
management 236–37
autonomic dysregulation
syndrome 220–21
autonomy principle, ethics
314–15, 314–15
autoregulation
cerebral blood flow 11–12, 12
intracranial pressure 20–21, 97
sodium regulation 239
traumatic brain injury patients
203–4
vasodilation, cerebral edema
21
AVRIPAS - Revised Sedation
Scale 35–36
Bacillus anthracis see anthrax
bacterial abscesses 284
diagnostic work-up 285
management 285–86
specific pathogens 285
bacterial diseases requiring
patient isolation 356
bacterial encephalitis 275–76
bacterial endocarditis, ischemic
stroke 121
bacterial meningitis 276–77
diagnostic work-up 277
management 279
prognosis 279
specific pathogens 277–79
symptoms 277
bag-mask ventilation (BMV) 51
balloon remodeling technique,
aneurysm repair 164
Balo concentric sclerosis 416
barbiturates
ICP management 25, 140–45
intoxication/overdose 258
neuropharmacology 40
status epilepticus 182
traumatic brain injury 215
baroregulation 238; see also
blood pressure
Bartonella henselae, bacterial
encephalitis 275
basilar artery (BA)
ischemic stroke 103
TCD monitoring 93, 95
basilar occlusion (BAO),
ischemic stroke 108, 121
beneficence, medical ethics 314–15
443
 Index
benzodiazepine receptor
inhibitors, hepatic
encephalopathy 378
benzodiazepine trial test, status
epilepticus 179
benzodiazepines
contraindications 63–65
delirium treatment 395
drug–drug interactions 65
intoxication/overdose 258
neuropharmacology 34–37,
63–65, 64–65
role in delirium causation
395
status epilepticus 179–80
synergistic sedation regimes
37–39
traumatic brain injury 215
benzylisoquinolinium
compounds 46
Berlin criteria, acute respiratory
distress syndrome 326
Berne–Norwood criteria, VTE
prophylaxis 218
best interest standards, medical
ethics 317
BEST-TRIPS trial 79, 216
beta-blockers, contraindications
255
biological terrorism 259, 263, 266
anthrax infections 259–61,
260–61
botulinum toxin 261
Q fever 262
Salmonella typhimurium 259
smallpox 262
tetrodotoxin 263
Venezuelan equine
encephalitis 262
bladder dysfunction, spinal cord
injury 296
blast injuries, traumatic brain
injury 203
blood–brain barrier (BBB)
cerebral edema 19–20, 25–26
hepatic encephalopathy 373
neuroprotective agents 26
therapeutic hypothermia 28
blood coagulation testing see
coagulation testing
blood cultures
bacterial meningitis 277
intravascular catheter-related
infections 352–53
stabilization of the patient 4
blood pressure homeostasis
arrhythmias 336
assessment 103–4
atrial fibrillation 337–38
brain death evaluation 248
carotid endarterectomy 305
Guillain–Barré syndrome
192
hypotension-inducing drugs
52
444
intracerebral hemorrhage
138–39
ischemic stroke 52, 103–4,
108–9, 109, 117
management 138–39
physiology 238
postoperative management
301, 303, 305
subarachnoid hemorrhage
162–63
traumatic brain injury 211–12
blood transfusions
brain oxygen delivery 15
hypoxic encephalopathy 388
traumatic brain injury 212
blunt cerebrovascular injury
(BCVI) 220, 220
blunt traumatic brain injury 201–2
BMV (bag-mask ventilation) 51
body temperature
acute inflammatory
demyelinating disorders
418
brain death evaluation 248,
251–52
cerebral blood flow 13
ischemic stroke 118
stabilization of the patient 4
see also fever; therapeutic
hypothermia
BOOST II trial, brain tissue
oxygen monitoring 80
botulism
biological terrorism 261
generalized weakness 397, 401
neuromuscular respiratory
failure 195–96
brain–computer interfaces
(BCIs) 410
brain death
ancillary tests 250–51
clinical evaluation 248
definition 248
diagnostic criteria 247–48
differential diagnosis 251–52
historical perspectives 247–48
as legal definition of death 247
neurological assessment
248–51
organ donation 247, 252
spinal reflexes 249
TCD monitoring 96–97, 250–51
Brain-Hypothermia Study Group
(B-HYPO) 30
brain metabolism, microdialysis
monitoring 80
brain perfusion see cerebral
blood flow
brainstem reflexes 5–7, 249
brain tissue oxygen monitoring
79–80, 300
Brain Trauma Foundation
guidelines 22, 78–79, 208–9,
213; see also traumatic brain
injury
brain tumors, postoperative
management 307–13, 308
breathing problems see
neuromuscular respiratory
failure; respiratory disorders
bronchoscopy, acute respiratory
distress syndrome 328–30
bupivacaine, neuropharmacology
44
burst-suppression, EEG findings
cardiac arrest 89
ICP management 25
therapeutic hypothermia 183
business plans, NICUs 430–31,
439
advanced practice model
436–37, 436–38
billing models 434
Comprehensive Stroke
Certification 435, 436
executive summary 431
financial commitment/
investment 433, 434
financial planning 431–32,
433
market analysis 431
milestones and metrics
432–33
Neurointensive Care Unit
consult service model 435
presenting the case 433–34
rationale and mission
statements 431
research integration 435
risks/contingency planning
433
staffing 431, 432, 434,
437–39
buspirone 73–74, 384
CA1 neurons, hippocampal cell
death 13–14
calcium-channel blockers
atrial fibrillation 338
contraindications 194
drug–drug interactions 48
calcium-glutamate excitotoxic
damage, hypoxic
encephalopathy 382
calcium homeostasis 363–64
caloric reflex 6–7, 249
calorific needs see energy
demand reductions
CAM-ICU Worksheet 3
Canadian head CT rule,
traumatic brain injury 205
cancer see neoplasms
Candida spp. meningitis 280–81
diagnostic work-up 281–87
management 280–81
symptoms 281
carbon dioxide homeostasis
brain physiology 56
controlled hyperventilation
therapy 23
neuromuscular respiratory
failure 190, 194–95
partial pressure, and cerebral
blood flow 12
respiratory physiology 56–57
TCD monitoring 97
traumatic brain injury 210–11
cardiac arrest
CEEG monitoring 89
therapeutic hypothermia
28–29
cardiac telemetry 177–79, 192
cardiomyopathy, arrhythmias
336
cardiovascular system
hypoxic encephalopathy
386–87
spinal cord injury 295–98
cardioversion, for atrial
fibrillation 339
carotid artery injury, iatrogenic
311
carotid endarterectomy/carotid
artery stenting
cerebral hyperfusion
syndrome 306
intracerebral hemorrhage
303–6, 305–6
ischemic stroke 305–6, 305
nerve injury 306
postoperative management
305–7
TCD monitoring 98–99
wound hematoma 306–7
cat scratch disease 275
catecholamines, arrhythmias
336
catheter-related infections 351
intravascular 352–53
urinary tract 351, 354–55
CBF see cerebral blood flow
cell death, and cerebral blood
flow 13–14
cell energy dysfunction,
traumatic brain injury 204
central herniation 21
central pontine myelinolysis
(CPM) 417–18
central volume principle,
cerebral blood flow 16
cephalosporins, myasthenia
gravis 194
cerebral abscesses 284
bacterial 284–86
fungal 286
symptoms 284
cerebral amyloid angiopathy
(CAA) 129, 130
cerebral blood flow (CBF)
11–12
cerebral ischemia 12–14, 13
intracerebral hemorrhage 14
intracranial monitoring 81
measurement techniques
15–16

narrow complex arrhythmias
344
normal physiology of 11–12,
12
stages of impairment 13, 13
subarachnoid hemorrhage
14–15
traumatic brain injury 15,
203–4
see also cerebral perfusion
pressure; intracranial
pressure
cerebral compliance 203
cerebral contusions, traumatic
brain injury 201
cerebral edema 19, 26
acute respiratory distress
syndrome 331
and cerebral ischemia 19
cerebral perfusion 20–21
cerebral venous thrombosis 146
classification of types 19–20
compensatory mechanisms 20
hepatic encephalopathy 370
herniation syndromes 20–21
hyponatremia 239, 241
hypoxic encephalopathy 386
ICP management 19–21,
23–25
indications for dialysis 367
ischemic stroke 118–19
monitoring methods 22–23
neuroimaging 21–22
novel therapeutics/new
treatment frontiers 25–26
postoperative management
300, 307–8
signs and symptoms 21
swelling 19
see also cytotoxic edema;
intracranial pressure;
neurogenic pulmonary
edema
cerebral hemodynamics,
traumatic brain injury
203–4
cerebral herniation see herniation
syndromes
cerebral hyperfusion syndrome
(CHS) 306
cerebral ischemia see delayed
cerebral ischemia; ischemia
cerebral metabolism,
microdialysis monitoring 80
cerebral microdialysis
monitoring 80–81
cerebral perfusion pressure
(CPP) 11–12, 13
cerebral edema 20–21
intracranial pressure
monitoring 79
intubation 52, 54
TCD monitoring 96
traumatic brain injury
203, 216
cerebral salt-wasting syndrome
(CSWS) 238, 240
differential diagnosis 241
management 243, 243
cerebral scintigraphy, brain death
evaluation 251
cerebral vasospasm see
vasospasm
cerebral venous thrombosis
(CVT)
definitions/terminology 146
diagnostic work-up 146–49
epidemiology/risk factors 146,
147
management 150–51, 151
neuroimaging 146–49, 147–48
pharmacology 151–52
prognosis 149–50
raised ICP 150
triage 149
cerebrospinal fluid see CSF
cerebrovascular disease, status
epilepticus 176
cerebrovascular reserve 12–13
cervical internal carotid artery,
TCD monitoring 93, 94
CHADS2 (Congestive heart
failure, Hypertension, Age,
Diabetes, and Stroke) stroke
risk prediction model
337–38, 339
“chasing the dragon” 416–17, 417
chemical agent exposure 263, 266
cyanide 265–66
decontamination 266
organophosphates/nerve
agents 259, 263–65, 263 see
also terrorism
chloride-resistant metabolic
alkalosis 365–66
chloride-responsive metabolic
alkalosis 365–66
chlorpromazine 194, 346–47
cholinergic crisis, myasthenia
gravis 194
cholinesterase inhibitors,
myasthenia gravis 195
chronic inflammatory
demyelinating
polyneuropathy, generalized
weakness 397–400, 397
chronic kidney disease (CKD)
359–60
classification of stages 360
management 368–69
chronic obstructive pulmonary
disease (COPD), hypoxemia
324, 331
CIM see critical illness myopathy
CINM see critical illness
neuromyopathy
cingulate cortex, severe brain
injury 406
CIP see critical illness
polyneuropathy
cirrhosis, hepatic encephalopathy
372–74, 373, 376, 377
gut microbiome disturbances 379
protein restriction 376–78
cisatracurium,
neuropharmacology 46
CKD see chronic kidney disease
clear and convincing evidence
principle, ethics 317
clonidine, neuropharmacology
38–39
Clostridium botulinum see
botulism
Clostridium difficile infection
353–54
organisms requiring patient
isolation 356
CLOTS (Clots in Legs Or
sTockings after Stroke) trial
116–17
clouding of consciousness,
neurological assessment 2–9
CMAP see compound muscle
action potentials
CMV see cytomegalovirus
coagulation testing, ischemic
stroke 106–7
coagulation therapy 136–38,
137
coagulopathy
renal failure management 368
traumatic brain injury 212–28
cocaine, drug intoxication 255
codeine, neuropharmacology 43
coma
after severe brain injury 404
brain death evaluation 248–49
CEEG monitoring 89–90
definitions 404–5
management 408–9
neurological assessment
1, 2–9, 407 see also Glasgow
Coma Scale
Coma Recovery Scale (CRS-R)
407, 408
competency, medical ethics
315–16
complete heart blocks 348
compound muscle action
potentials (CMAPs) 196
Comprehensive Stroke
Certification 435, 436
compressive neuropathies 397,
400
computed tomography (CT)
scanning
bacterial cerebral abscesses 285
cerebral edema 21–22
cerebral venous thrombosis
146–47, 147
classification of TBI 82, 200
CSF shunt infections 289
delayed cerebral ischemia 168
intracerebral hemorrhage
130–31, 134
Index
ischemic stroke 97, 107–8
status epilepticus 177
subarachnoid hemorrhage 155,
155, 156–57
traumatic brain injury 205,
205–6
use in intracranial monitoring
82
viral encephalitis 269–70 see
also CT-angiography
conduction blocks, arrhythmias
348, 349
Confusion Assessment Method
for Diagnosis of Delirium in
the ICU (CAM-ICU) scale
41, 392–93, 393
congenital status epilepticus
176
congestive heart failure
337–38
conscious sedation, ischemic
stroke 104–13
consciousness disorders,
postinjury 404, 411
covert cognition 409–11, 410
definitions 404–5, 405
management 408–9
neurological assessment 407,
408
prognosis 407–8
residual brain activity 405–6,
406
consciousness levels
hypoxic encephalopathy
382–83
neurological assessment 1
states of altered consciousness
2–9
Consensus International
Conference on
Multimodality Monitoring
83
consequentialism, medical ethics
314–15
continuous
electroencephalography
(CEEG) 86–88, 86–91
acute brain injury 89–90
decision to treat data 89–90
delayed cerebral ischemia
88–89
duration of monitoring
88, 88
hypoxic-ischemic injury 88
intracerebral hemorrhage 87
ongoing therapy monitoring
89
prognostic uses 89–90, 89
status epilepticus 177–79, 178
subarachnoid hemorrhage
87–88
toxic metabolic
encephalopathy 87–88
traumatic brain injury 87–88,
87–90
445
 Index
continuous renal replacement
therapy (CRRT) 366–68
indications 367–68
vascular access 367
contrast induced nephropathy
(CIN) 368–69
controlled hyperventilation
therapy 23
contusions, cerebral 201
conversion pause, atrial
fibrillation 338
Cool Kids Trial 30
COOLAID (Cooling for Acute
Ischemic Brain Damage)
trials, therapeutic
hypothermia 29
Copenhagen Stroke Study 29
corneal reflexes 5, 249
coronary vasospasm, drug
intoxication 255
corpus callosotomy, epilepsy
surgery 312
corticosteroids
acute respiratory distress
syndrome 330
bacterial meningitis 279–80
brain tumors 307
drug–drug interactions 48
fever 351
Guillain–Barré syndrome 193
myasthenia gravis 195
postoperative management,
tumor surgery 307
status epilepticus 183
traumatic brain injury 218
cost–benefit studies,
Neurocritical Care Units
426–27
costs, computed tomography
scanning 82
cough reflexes 7, 249
covert cognition 409–11, 410
cox-2 inhibitors,
neuropharmacology 44
Coxiella burnetii, Q fever 262
CPP see cerebral perfusion
pressure
cranial nerve injuries 306, 309
craniectomy/craniotomy
arteriovenous malformations
310
ICP management 25
postoperative management
309–10
supratentorial tumors 307–9,
308
venous thromboembolism 332
CRASH (Corticosteroid
Randomization after
Significant Head Injury)
trial 212, 218, 221
critical illness myopathy (CIM)
196, 397, 401
critical illness neuromyopathy
(CINM) 196
446
critical illness neuropathy 397,
397
critical illness polyneuropathy
196, 397, 400
CRRT see continuous renal
replacement therapy
cryptococcal meningitis 280–86
diagnostic work-up 280–86
management 280–86
prognosis 280
symptoms 280
CSF (cerebrospinal fluid)
drainage 213, 300
CSF fistula, posterior fossa tumor
surgery 309–10
CSF rhinorrhea 311
CSF shunt infections 288
diagnostic work-up 289
management 289
symptoms 288–89 see also
lumbar puncture
CT-angiography (CTA)
brain death evaluation 250
delayed cerebral ischemia 164
intracerebral hemorrhage
133–34, 133, 135
ischemic stroke 107
subarachnoid hemorrhage 92,
155–58
traumatic brain injury 205–6,
205
use in intracranial monitoring
82
Cushing triad (bradycardia,
hypertension, and abnormal
respirations), raised ICP 21
CVT see cerebral venous
thrombosis
cyanide, toxicity 265–66
cytomegalovirus (CMV)
encephalitis 272
diagnostic work-up 272
management 272
symptoms 272
cytotoxic edema 13, 19–20,
22–23, 26
brain death 250
herpes simplex encephalitis
270
hypoxic encephalopathy 382
D-tubocuranine,
neuropharmacology 46
DCI see delayed cerebral
ischemia
decision-making, ethics
314–16
end-of-life decisions 318–19
informed consent in critically
ill patients 316–17 see also
medical ethics
decision to treat, CEEG data
89–90
decompressive surgery 25,
213–14, 300
DECRA clinical trial, traumatic
brain injury 215
deep brain stimulation (DBS)
consciousness disorders 409
postoperative management
312
deep vein thrombosis (DVT) see
venous thromboembolism
default mode brain network, 405
deferred consent, medical ethics
320–21
delayed cerebral ischemia (DCI)
164
brain tissue oxygen
monitoring 80
CEEG monitoring 88–89
CT-angiography 164
CT scanning 168
management 165–66
monitoring 164–65, 164
neuropharmacology of
selected agents 73–76
prevention 165
TCD monitoring 92
delirium 392, 395
diagnostic criteria 392
diagnostic work-up 394
epidemiology 392
etiology 392
ICU experience for patients 33
management 394–95, 395, 395
neurological assessment 1–4,
2–9, 41
pathophysiology 393–94
prevention 394–95, 395
risk factors for developing
394–95
screening tools 392–93, 393,
393
subtypes 392
treatment 41
demyelination, Guillain–Barré
syndrome 191; see also acute
inflammatory
demyelinating disorders
deontology, medical ethics
314–15
depolarizing agents,
neuromuscular blockade 45
Devic disease 415
dexamethasone 307; see also
corticosteroids
dexmedetomidine
acute respiratory distress
syndrome 327–28
as antishivering agent
73–74
drug–drug interactions 65
neuropharmacology 38
sedative effects 40, 64–65, 65
diabetes insipidus (DI), following
trans-sphenoidal pituitary
resection 310–11
diabetes mellitus, atrial
fibrillation 337–38
diabetic ketoacidosis 56–57; see
also metabolic acidosis
dialysis
indications for 367–68
vascular access 367
diaschisis, cerebral blood flow 13
diazepam
neuropharmacology 37
sedative effects 40
status epilepticus 67–69
use for chemical toxicity
265
diffuse axonal injury (DAI) 202
diffusion-weighted imaging
(DWI) 107–8, 161
digital subtraction angiography
(DSA) 108, 149
digoxin
atrial fibrillation 338
role in delirium 395
diphenhydramine,
neuropharmacology 40
direct thrombin inhibitors
intoxication/overdose 257
and intracerebral hemorrhage
137–38
disclosure, medical ethics 314–16
distributive justice, medical
ethics 314–15
do-not-resuscitate orders
intracerebral hemorrhage
131–32
medical ethics 318–19
traumatic brain injury 222
documentation, NICU outcome
studies 426
doll’s head eye phenomenon 6,
249
doxacurium,
neuropharmacology 46
droperidol 39, 346–47
drug–drug interactions
benzodiazepines 65
dexmedetomidine 65
neuromuscular blocking
agents 48
opiates 63
phenobarbital 70–71
phenytoin 70
propofol 65
valproate 71
drug intoxication/overdose 254,
266
commonly used medications
in the ICU 256–58
confusion with brain death
252
management 254–55
opioid analgesics 256
recreational drugs 255–56
see also pharmacotherapeutics
durable power of attorney, ethics
317, 319–20
duroplasty, ICP management 25
dysphagia 115, 140

Eastern Association for the
Surgery of Trauma, spinal
cord injury guidelines 292
ECG (electrocardiography)
arrhythmias 335–36
atrial flutter 339
multifocal atrial tachycardia
344
Wolff–Parkinson–White
syndrome 343
echocardiography, arrhythmias
336
edaravone, neuroprotective
agents 25–26
edema see cerebral edema
EEG (electroencephalography)
autoimmune encephalitis 235
brain death evaluation 251
cardiac arrest 89
delirium 394
hypoxic encephalopathy
388–89
ICP management 25
monitoring 86, 90
subarachnoid hemorrhage 303
therapeutic hypothermia 183
viral encephalitis 270
see also continuous
electroencephalography
electroconvulsive therapy (ECT),
status epilepticus 183
electrolyte disturbances 362–64
postoperative management
301–2
stabilization of the patient 4
subarachnoid hemorrhage 166,
303
torsades de pointes 345
traumatic brain injury 220
see also specific electrolytes
electromyography (EMG),
Guillain–Barré syndrome
191
elimination half-life, definitions
62
emboli detection, TCD
monitoring 98
“empty skull” pattern, SPECT
251
encephalitis, infectious 269
bacterial 275–76
viral 269–75
encephalomyelitis periaxialis
scleroticans 415
encephalopathy 392; see also
delirium; hepatic
encephalopathy; hypoxic
encephalopathy
end-of-life decisions 318–19; see
also do-not-resuscitate
orders
endocrine management, hypoxic
encephalopathy 387–88
endotracheal intubation see
intubation
endovascular aneurysm coiling 304
endovascular cooling,
therapeutic hypothermia 28
energy demand reductions
ischemic stroke 115
therapeutic hypothermia 28
enteral nutrition
hypoxic encephalopathy 388
ischemic stroke 115
spinal cord injury 296
traumatic brain injury 221
enteroviruses (EVs), viral
encephalitis 272
diagnostic work-up 272
symptoms 272
enzyme induction, definitions 62
enzyme inhibition, definitions 62
epidemiology
atrial fibrillation 337
cerebral venous thrombosis
146
delirium 392
Guillain–Barré syndrome 191
hypoxemia 326–27
intracerebral hemorrhage 129
spinal cord injury 290–91
status epilepticus 176
subarachnoid hemorrhage
154
traumatic brain injury 199
epidural abscesses see spinal
epidural abscess
epidural hematoma, traumatic
brain injury 202
epilepsy surgery, postoperative
management 311–12
epileptic causes, acute
confusional states 392
epoprostenol/iEPO, inhaled
vasodilators 330
Epstein–Barr virus (EBV)
encephalitis 271–72
diagnostic work-up 271
management 271
symptoms 271
esmolol, induction of anesthesia
54–55
ethical dilemmas see medical
ethics
etomidate
induction of anesthesia 54–55
intracerebral hemorrhage 134
neuropharmacology 39
Eurotherm trial 30
external herniation 21
external ventricular drains
(EVDs)
ICP monitoring 22–23,
78–79
intracerebral hemorrhage
135–36
traumatic brain injury 213
external ventricular drain
infections 288
management 288
specific pathogens 288
symptoms 288
extra-axial hematomas, traumatic
brain injury 201–2
extracorporeal membrane
oxygenation (ECMO) 330
eye exam 5
eye deviation corresponding to
brain injury 6
eyelid and corneal reflexes 5
oculocephalic reflex 6
oculovestibular (caloric) reflex
6–7
pupillary responses 5, 8–10
spontaneous movements,
unresponsive patients 7
eyelid reflexes 5
face mask devices, ventilation 51
facial droop, nerve injury 306
factor-Xa inhibitors, and
intracerebral hemorrhage
138
false neurotransmitter concept
374, 378
Family Nurse Practitioners
(FNPs) 437
FAST (Factor Seven for Acute
Hemorrhagic Stroke
Treatment) trial 140
fecal impaction, spinal cord
injury 296
fentanyl
as antishivering agent 73–74
drug–drug interactions 63
induction of anesthesia
54–55
neuropharmacology 42
sedative effects 64–65
traumatic brain injury 217
fever
as adaptive response 351
etiology 351
intracerebral hemorrhage
139–40
postoperative management
302–3
subarachnoid hemorrhage
162–63, 166
traumatic brain injury 219
workup 351–52, 352
see also body temperature;
infectious diseases
Fick principle, oxygen
metabolism 11, 15–16
financial planning 431–32, 433
firearms wounds 199, 202–3,
202–3
first-degree atrioventricular
blocks 348
Fisher scale, subarachnoid
hemorrhage 155, 156–57,
302, 302–3
fluid-attenuated inversion
recovery (FLAIR) 107–8
Index
fluid management
acute respiratory distress
syndrome 328
ischemic stroke 115
postoperative 301–2
sodium regulation 238, 242
subarachnoid hemorrhage 161,
162–63, 303
traumatic brain injury 211–12
flumazenil, hepatic
encephalopathy 378
fluoroquinolones, role in
delirium 395
focal cerebral contusions,
traumatic brain injury 201
forced vital capacities (FVC),
respiratory failure 189–90
fosphenytoin
drug–drug interactions 70
intoxication/overdose 256–57
intracerebral hemorrhage
140–41
status epilepticus 67–69, 180
therapeutic drug level
monitoring 70
fresh frozen plasma (FFP)
136–37
Full Outline of
UnResponsiveness scale
(FOUR) score
consciousness disorders 407
neurological assessment 2–5, 5
traumatic brain injury
209–10
FUNC (functional outcomes)
score 132, 132, 134
fungal infections
aneurysms 167–68
cerebral abscesses 286
meningitis 283–86
futile medical interventions,
medical ethics 318
GABA (gamma-aminobutyric
acid) receptor encephalitis
233–34, 235–36
gabapentin, neuropharmacology
44
gadolinium, contrast induced
nephropathy 369
gag reflexes 7, 249
gastric ulcers 218, 296
gastrointestinal complications,
spinal cord injury 296
gastroparesis, Guillain–Barré
syndrome 192–93
generalized convulsive status
epilepticus (CSE) 176–77,
178
generalized weakness 397, 402
diagnostic work-up 397–98
differential diagnosis 397,
398–402
etiology 397
neurological assessment 8–9
447
 Index
genetics, intracerebral
hemorrhage 129
genito-urinary impacts, spinal
cord injury 296
Glasgow Coma Scale (GCS)
2–5, 5
consciousness disorders 407
intracerebral hemorrhage 134,
135
postoperative management
299–300, 300
traumatic brain injury 204,
209–10
glucocorticoids see
corticosteroids
glucose homeostasis
hypoxic encephalopathy
387–88
intracerebral hemorrhage
139–40, 139
ischemic stroke 109, 116
microdialysis monitoring 80
postoperative management
302
stabilization of the patient 4
subarachnoid hemorrhage
162–63, 166
traumatic brain injury
219–20
glutamate
hypoxic encephalopathy 382
microdialysis monitoring
technique 80
Glyburide Advantage in
Malignant Edema and
Stroke (GAMES-RP) trial
26
glyburide, neuroprotective agents
26
glycemic control see glucose
homeostasis
guardianship 316–17; see also
substituted judgment
standard
Guglielmi detachable coils,
aneurysm repair 163
Guillain-Barré syndrome (GBS)
190–91
clinical features 191
diagnostic work-up 191
epidemiology 191
generalized weakness 397–99,
397
management 191–93, 192
pathophysiology 191
respiratory failure 188, 189,
190–93, 192
succinylcholine
contraindications 54
gunshot wounds (GSWs) 199,
202–3, 202–3
gut flora disturbances, hepatic
encephalopathy 379
glycerol, microdialysis
monitoring techniques 80
448
Haemophilus influenza, bacterial
meningitis 278
haloperidol
delirium 395
medications affecting QT
interval 39, 346–47
neuropharmacology 39
Harris–Benedict equation,
energy demand 115
Harvard criteria, brain death 247
head positioning see patient
positioning
headache, cerebral venous
thrombosis 146
heart rate assessment, ischemic
stroke 103–4
hematological impacts, spinal
cord injury 296–97
hematoma
intracerebral hemorrhage
130–31, 131
intracranial monitoring 79–80,
82
intracranial pressure
monitoring 79
minimally invasive techniques
135
traumatic brain injury
201–2
Hemedex™ probes, cerebral blood
flow measures 16
hemispheric index, TCD
monitoring 93
hemodilution see triple-H
therapy
hemodynamics, cerebral see
cerebral blood flow
hemoglobin control
ischemic stroke 116
subarachnoid hemorrhage 303
traumatic brain injury 212
hemorrhage, cerebral
intracranial monitoring 79–80
postoperative management
308
raised ICP 79
recurrent 160–61
status epilepticus 176
traumatic brain injury 201–2,
205
hemorrhagic conversion 20
hemorrhagic stroke see
intracerebral hemorrhage;
subarachnoid hemorrhage
hemostatic therapy, intracerebral
hemorrhage 140
heparin
cerebral venous thrombosis
150–51
intoxication/overdose 257
intracerebral hemorrhage 137,
137
postoperative management 302
see also low molecular weight
heparin
heparin-induced
thrombocytopenia (HIT)
150
hepatic encephalopathy (HE)
370
acute liver failure 370–76,
371–72, 371, 375–76
acute on chronic liver failure
374, 378–79
benzodiazepine receptor
inhibitors 378
cirrhosis/chronic porto-
systemic shunting 372–74,
373, 376, 377, 378
diagnostic work-up 374
differential diagnosis 370–75
false neurotransmitter concept
374, 378
grading severity 370
gut microbiome disturbances
379
increasing ammonia
metabolism 378
management 370–76, 374–75,
377
pathophysiology 370, 371, 373
reducing ammonia production
376–78
systemic inflammatory
response 371–72, 372
herniation syndromes
cerebral edema 20–21
traumatic brain injury 207, 207
heroin intoxication 255–56; see
also opiates
heroin-associated spongiform
leukoencephalopathy
(HASL) 416–17, 417
Herpes simplex encephalitis
(HSE) 269
diagnostic work-up 269–70
management 270
prognosis 270
symptoms 269–70
hexamethyl-propylamineoxime
single photon emission
tomography (HMPAO
SPECT) 251
high-frequency oscillatory
ventilation (HFOV) 330
high-intensity staffing units
421–22
histoplasmosis 283
diagnostic work-up 283
management 283
prognosis 283
symptoms 283
history-taking
brain death evaluation 248
delirium 394
drug intoxication 254
fever 351–52
generalized weakness 397–98
ischemic stroke 104
neurological assessment 1, 4
postoperative management
299
hoarseness, nerve injury 306,
309
homeostatic mechanisms see
autoregulation
Hopkins syndrome 397, 399
HSE see Herpes simplex
encephalitis
human research, medical ethics
319–22, 319
Hunt–Hess scale 155, 159, 302,
303
hydromorphone 43, 64–65
hydrostatic pressure, cerebral
edema 19
hyperammonemia see ammonia
metabolism
hypercalcemia see calcium
homeostasis
hypercapnia see carbon dioxide
homeostasis
hyperchloremic (nongap)
metabolic acidosis 365
hyperglycemia see glucose
homeostasis
hyperkalemia see potassium
homeostasis
hypermagnesemia see
magnesium homeostasis
HYPERNATUS (Hypothermia
for Neuroprotection in
Convulsive Status
Epilepticus) trial 30
hyperosmolar therapy 71, 72,
213–14
hyperoxia, brain physiology 56–57
hypertension see blood pressure
homeostasis
hypertension, hypervolemia, and
hemodilution see triple-H
therapy
hypertonic saline (HTS),
neuropharmacology 72
hypertonic saline therapy 71
hyponatremia 241–42, 241,
241–42
ICP management 24, 140–45
postoperative management
301
traumatic brain injury 214–15
see also osmotherapy
hyperventilation, brain
physiology 56, 110–12
hyperventilation therapy
brain ischemia 52
ICP management 23, 57
postoperative management
300
traumatic brain injury 215
hypervolemia see triple-H
therapy
hypoactive delirium 392
hypocalcemia see calcium
homeostasis

hypocarbia see carbon dioxide
homeostasis
hypokalemia see potassium
homeostasis
hypomagnesemia see magnesium
homeostasis
hyponatremia see sodium
homeostasis
hypotension-inducing drugs 52;
see also blood pressure
homeostasis
hypothermia see body
temperature; therapeutic
hypothermia
hypoventilation, brain
physiology 56
hypoxia/hypoxemia 324
acute lung injury 324–26
brain physiology 56–57
CEEG monitoring 88
cerebral blood flow 13–14
controlled hyperventilation
therapy 23
epidemiology 326–27, 327
grading severity 326
management 327–30, 328, 329
mechanisms 325
neurogenic pulmonary edema
331
obstructive lung disease 324,
331
patent foramen ovale shunts
324
pulmonary vascular disease
324
raised ICP 330–31
status epilepticus 176
traumatic brain injury 210–11
venous thromboembolism
331–32
see also acute respiratory
distress syndrome
hypoxic encephalopathy (HE)
382
diagnostic work-up 382–83
management 386–88, 388
pathophysiology 382
postcardiac arrest syndrome
382, 382
prehospital care 383–84
prognosis 388–90, 389
symptoms 383
therapeutic hypothermia
384–86, 385
iatrogenic causes
acute confusional states 392
acute quadriplegic myopathy
syndrome 47–48
carotid artery injury 311
drug intoxication/overdose
256–58
ICH score 131, 131–32, 134; see
also intracerebral
hemorrhage
ICU-acquired weakness
(ICU-AW) 9, 196
ICU models, developing
Neurocritical Care Units
421–22
ICU psychosis 392
ICUDELIRIUM(S) acronym
(Iatrogenic exposure,
Cognitive impairment,
Drugs, Elderly, Laboratory
abnormalities, Infection,
Respiratory, Intracranial
perfusion, Urinary retention
and constipation,
Myocardial, and
Sleep-sensory deprivation)
395
ileus, Guillain–Barré syndrome
192–93
imaging see neuroimaging
immobility, ICU experience for
patients 33
immunosuppression,
stroke-associated 117
immunotherapy, status
epilepticus 183
IMPACT (International Mission
on Prognosis and Analysis of
Clinical Trials) study 212, 221
implied consent, ethics 314,
314–15, 316
induction of anesthesia 52, 54–55
industrial accidents, chemical
agents, toxicity 263
infection, CNS 269
acute confusional states 392
acute inflammatory
demyelinating disorders 417
intracranial monitoring 79–80,
82
status epilepticus 176
subdural empyema 286–87
see also cerebral abscesses;
encephalitis; meningitis;
ventriculitis
infectious diseases 351
Clostridium difficile 353–54
intravascular catheter-related
infections 352–53
isolation of patients 355–56,
356
managing secondary infections
117
pneumonia 352, 353
sepsis 355
stabilization of the patient 4
urinary tract infections 351,
354–55
workup 351–52 see also fever
infective endocarditis, ischemic
stroke 121
inferior vena cava (IVC) filters
297
inflammation, systemic see
systemic inflammation
inflammatory demyelinating
disorders see acute
inflammatory
demyelinating disorders
influenza virus 274, 356
informed consent 314–17, 321
inhalant anesthetics, status
epilepticus 183
inhaled vasodilators 330
insular cortex, arrhythmias 336
insulin therapy, critical illness
neuromyopathy 196
Intensive Care Delirium
Screening Checklist 392–93
Intensive Care Unit (ICU)
experience for patients 33
INTERACT II (Intensive Blood
Pressure Reduction in Acute
Cerebral Hemorrhage Trial)
138
interleukins 28; see also systemic
inflammation
intermittent hemodialysis
366–68
internal carotid artery (ICA) 93,
94, 95, 103
Internal Review Boards (IRBs)
316, 319, 319, 320–21
International Subarachnoid
Aneurysm Trial (ISAT)
158–59, 163
interruption of continuous
sedation (ICS) 1
intra-arterial thrombolysis (IAT),
ischemic stroke 111–12
intracerebral hemorrhage (ICH)
129, 141
ABC/2 method 132, 132
assessment instruments
131–32, 131–32, 135
blood pressure management
138–39, 138–39
carotid endarterectomy 303–6,
305–6
CEEG monitoring 87, 89–90
cerebral blood flow 14
clinical trials 138
coagulation therapy 136–38,
137
diagnostic work-up 132–33,
132–34
differential diagnosis 136
drug intoxication 255
epidemiology/risk factors 129
glycemic control 139–40, 139
management 134–40
neuroimaging 130–31, 134,
135
neurosurgery 134–35, 140
NICU outcome studies 423–25
pathophysiology/etiology
129–30, 130–31
prognosis 89–90, 131–32
raised ICP 134, 134, 140, 140
rapid sequence intubation 134
Index
sedation 135
seizure control 140–41, 140
therapeutic hypothermia 29
vital functions 134
intracranial compartments,
disruptions 19
intracranial hemorrhage 201–2,
205
intracranial monitoring see
invasive neuromonitoring
intracranial pressure (ICP)
autoregulation 12, 20–21
cerebral edema 19–21
cerebral perfusion 20–21
cerebral venous thrombosis
146, 150
hyperventilation therapy 23,
57
hypoxemia 330–31
intracerebral hemorrhage 134,
134, 140, 140
intubation 52, 54
ischemic stroke 118–19, 119
management 23–25
monitoring 22–23, 25, 78–79
neuroimaging 21–22
neurological assessment 1, 4
postoperative management
300–1
renal failure management 368
signs and symptoms 21
subarachnoid hemorrhage 161
surgical interventions 208–13
therapeutic hypothermia
24–25, 30
tiered approach to ICP
management 213–14
TCD monitoring 96
traumatic brain injury 203–4,
208–16, 213–14
ventilation, mechanical 58 see
also cerebral blood flow
Intraoperative Hypothermia for
Aneurysm Surgery Trial 29
intravascular catheter-related
infections 352–53
intravenous fluids see fluid
management
intravenous immunoglobulin
treatment (IVIG) 193
intravenous thrombolysis (IVT)
110–11, 111–12
intubation 54
alternatives to intubation 51
difficult airway scenarios and
solutions 54–56
impaired cerebral perfusion
patients 52
indications/contraindications
50–51
ischemic stroke 110–14
neurological assessment prior
to intubation 54
neuromuscular respiratory
failure 190
449
 Index
intubation (cont.)
preparation for intubation
51
raised ICP patients 52
ramping up of obese patients
53, 53
reduction of peri-intubation
risks 53
unstable cervical spine patients
52–53
see also airways
invasive neuromonitoring 78, 83,
86
brain tissue oxygen
monitoring 79–80
cerebral blood flow
monitoring 81
cerebral microdialysis
monitoring 80–81
clinical algorithms 83
intracranial pressure
monitoring 78–79
jugular bulb saturation
monitoring 81–82
neuroimaging 82
traumatic brain injury 213
ion pumps, cerebral blood flow
13
ionic edema 20
ischemia, cerebral 19
CEEG monitoring 88
cerebral blood flow 12–14,
13
intracranial pressure
monitoring 79
intubation 52
traumatic brain injury 204
see also delayed cerebral
ischemia
ischemic stroke
airway management 108–9,
113–14
analgesia/sedation 114–15
anticoagulant medication
109–10, 117
blood pressure management
108–9, 109, 117
body temperature 118
carotid endarterectomy 305–6,
305
CEEG monitoring 87,
89–90
cerebral blood flow 14
deep vein thrombosis
prophylaxis 116–17
definitions 103
diagnostic work-up 106–8
drug intoxication 255
dysphagia 115
eight Ds of survival 104
fluid status/nutrition 115
glucose control 116
hemoglobin control/anemia
116
history-taking 104
450
hyperglycemia 109
indications for NCCU referral
103–4, 103
infection management 117
intra-arterial thrombolysis
111–12
intravenous thrombolysis
110–11, 111–12
intubation 52
management guidelines 103
monitoring 108
neuroimaging 107–8
neurological assessment
104–6, 106
NICU outcome studies 423–25
peri-interventional care
112–13
prognosis 89–90
raised ICP/edema
management 118–19, 119
recanalization 107, 110–12
seizure control 118
therapeutic hypothermia 29
time-related goals 103, 106,
110
TCD monitoring 97–98
types 119–21
ventilation, mechanical 110–14
vital functions 103–4
isolation of patients, infection
control 355–56, 356
JC virus 274–75
Joint Commission (TJC)
Comprehensive Stroke
Certification 435, 436
jugular bulb saturation (SjO2)
monitoring 81–82
jurisprudence 314; see also
medical ethics
ketamine
induction of anesthesia 52,
54–55
neuropharmacology 39–40, 44
status epilepticus 181, 182–83
ketoacidosis 56–57; see also
metabolic acidosis
ketogenic diet, status epilepticus
183
kidney problems see nephrology
Korsakoff’s psychosis 256
L-ornithine-L-aspartate therapy
378
laboratory-based diagnostic tests
autoimmune encephalitis 235
bacterial cerebral abscesses 285
brain death evaluation 248
cerebral venous thrombosis
147, 149
delirium 394
drug intoxication 254
fever 352
intracerebral hemorrhage 134
ischemic stroke 106–7
neurological assessment 4
spinal epidural abscesses 286
status epilepticus 177, 179
subarachnoid hemorrhage
162–63
traumatic brain injury 204–5
viral encephalitis 269–70 see
also blood cultures; lumbar
puncture
lacosamide 67–69, 140–41,
180–81
lactulose therapy 376–81
Lambert–Eaton Myasthenic
Syndrome (LEMS) 401
large cerebellar stroke 120–21
large hemispherical infarction
(LHI) 29, 119–20
laser Doppler flowmetry (LDF)
81
lateral transtentorial herniation
21
Lazarus sign, brain death
evaluation 249
legal perspectives, medical ethics
315, 317
Legionella pneumophila
encephalitis 275
LEMON mnemonic (Look,
Evaluate, Mallampati score,
Obstruction, Neck mobility)
51
leucine-rich, glioma-inactivated
encephalitis 233–34, 236
levetiracetam 67–69, 140–41, 180
lidocaine 44, 54–55
Lindegaard ratio 93, 95, 164
linear pharmacokinetics 62;
see also neuropharmacology
Listeria monocytogenes, bacterial
meningitis 278
lithium 194, 395
liver cirrhosis see cirrhosis
living wills, medical ethics 317
local anesthetics,
neuropharmacology 44
locally administered therapies,
neuropharmacology 76
locked-in syndrome (LIS) 251,
410
lorazepam
neuropharmacology 37
sedative effects 40, 64–65
status epilepticus 67–69
low-intensity staffing (open
ICUs) 421–22
low molecular weight heparin
(LMWH)
cerebral venous thrombosis
150–52
intoxication/overdose 257
and intracerebral hemorrhage
137
low tidal volumes, lung-
protective ventilation 57–58
lumbar catheters, ICP
monitoring 23
lumbar puncture
bacterial encephalitis 275
bacterial meningitis 277
fungal meningitis 280–86
spinal epidural abscesses 286
status epilepticus 179
subarachnoid hemorrhage 155
tuberculous meningitis 284
viral encephalitis 269–74
Lund therapy, raised ICP 215–16
Lung Injury Score (LIS) 326, 326;
see also acute lung injury;
respiratory disorders
lung-protective ventilation 57–58,
114
magnesium 48, 73–74, 75–76
magnesium homeostasis 364
delayed cerebral ischemia 165
hypoxic encephalopathy 384,
387
magnetic resonance angiography
(MRA) 107–8, 250
magnetic resonance (MRI)
imaging
acute disseminated
encephalomyelitis 415
aspergillosis 281–82
bacterial cerebral abscesses 285
cerebral amyloid angiopathy
130
cerebral edema 22
cerebral venous thrombosis
148, 148
contraindications 369
delirium 394
intracerebral hemorrhage
133–34
ischemic stroke 107–8
spinal cord injury 291–92
spinal epidural abscesses 286
status epilepticus 179
subarachnoid hemorrhage
155
tumefactive multiple sclerosis
415–16
use in intracranial monitoring
82
viral encephalitis 269–71
see also MR-angiography
magnetization-prepared rapid
gradient-echo (MP-RAGE)
sequences, venography
148–49, 148
malignant MCA-infarction see
large hemispheric infarction
mannitol 23–24, 71
ICP management 140–45
neuropharmacology 72
postoperative management
301
traumatic brain injury 213–15
see also osmotherapy

Marburg variant, acute multiple
sclerosis 415
market analysis, NICU business
plans 431
Marshall CT classification,
traumatic injury 82, 200
mask ventilation 51; see also
noninvasive positive
pressure ventilation
matrix metalloproteinase-9
(MMP-9) 25–26
maximal inspiratory pressure
(MIP) 189–90
mean arterial pressure (MAP)
cerebral perfusion 20–21
spinal cord injury 294–95
traumatic brain injury 211
see also blood pressure
homeostasis
mechanical thrombectomy
(MT), ischemic stroke
111–12
medical ethics 314
deferred consent 320–21
definitions 314
end-of-life decisions 318–19
ethical dilemmas 314,
314–15
human research 319–22, 319
implied consent 314, 314–15,
316
informed consent 314–16,
321
Internal Review Boards 316,
319, 319, 320–21
legal perspectives 315, 317
ways to obtain consent in
critically ill patients 316–17
medication see drug intoxication;
pharmacotherapeutics
meningitis 276
bacterial 276–79
fungal 283–86
tuberculous 283–84
viral 276
meperidine, as antishivering
agent 73–74
metabolic acidosis 364–65
bodily responses 365–66
indications for dialysis 367–68
respiratory physiology 56–57
types 364–65
see also acid–base disturbances
metabolic activity reduction see
energy demand reductions
metabolic alkalosis 365–66
metabolic causes, acute
confusional states 392
metabolic encephalopathy 392;
see also delirium
metabolic status epilepticus 176
metabolic therapy, traumatic
brain injury 215
metabolism, brain, microdialysis
monitoring 80
metabotropic glutamate receptor
(mGluR5) antibody
syndrome 233–34, 236
metastatic spinal cord
compression (MSCC)
294–95
methylprednisolone (MP), spinal
cord injury 294
metoprolol, atrial fibrillation 338
microdialysis intracranial
monitoring 80–81
microembolic signals (MES),
TCD monitoring 98
microglial nodular encephalitis
272
midazolam
neuropharmacology 36–37
sedative effects 40, 64–65
status epilepticus 67–69, 181,
181–82
middle cerebral artery (MCA)
severe ischemic stroke 103
surgery 25
TCD monitoring 92–94, 93
minimally conscious state (MCS)
definitions 404–5
residual brain activity 405–6
minocycline, neuroprotective
agents 25–26
“misery” perfusion 13; see also
cerebral blood flow
mismatch concept, ischemic
stroke 108
mitochondrial dysfunction,
therapeutic hypothermia
28
mivacurium,
neuropharmacology 46
MOANS mnemonic (Mask seal,
Obesity, Age, No teeth, Stiff
lungs), difficult airway
scenarios 51
mobilization of patients, delirium
prevention 41
Model Trauma Care System Plan
(MTCSP) 208
molecular adsorbent
recirculating system
(MARS) 376, 379
monitoring
cerebral blood flow 15–16
cerebral edema 22–23
delayed cerebral ischemia
164–65
intracranial pressure 22–23, 25
ischemic stroke 108
traumatic brain injury 209–10
see also EEG; invasive
neuromonitoring;
multimodal monitoring;
transcranial Doppler
monitoring
Monro–Kellie doctrine,
hemodynamics 20, 203
moral issues see medical ethics
morphine
intoxication/overdose 256
neuropharmacology 43
sedative effects 64–65
traumatic brain injury 217
mortality rates see prognostics
Motor Activity Assessment Scale
(MAAS) 35–37
motor responses 7–9
brain death evaluation 249
neuromuscular complications
8–9
MRA (magnetic resonance
angiography) 107–8, 250
MR CLEAN trial, ischemic
stroke 112
MRI scanning see magnetic
resonance imaging
MRSA (methicillin-resistant
Staphylococcus aureus) 356,
356
multifocal atrial tachycardia
(MAT) 344
multifocal motor neuropathy
(MMN) 397, 400
multimodal monitoring
delayed cerebral ischemia
164–65
intracranial monitoring 78, 83
postoperative management
300–1
traumatic brain injury 216–17
multiple sclerosis (Marburg
Variant) 415; see also
tumefactive multiple
sclerosis
muscle disorders 397, 401–2;
see also critical illness
myopathy; critical illness
neuromyopathy
muscle strength grading scale,
spinal cord injury 291
myasthenia gravis 193
clinical features 194
diagnostic work-up 194
generalized weakness 397,
400–1
grading scale 194
management 194–95
management algorithm 195
pathophysiology 193–94
respiratory failure 188, 189,
190, 193–95
succinylcholine dosage 54
Mycobacterium tuberculosis
infection control 356
organisms requiring patient
isolation 356
see also tuberculous meningitis
Mycoplasma pneumoniae,
bacterial encephalitis 275
mycotic aneurysms 167–68;
see also fungal infections
myelography, spinal cord injury
292
Index
myoclonus, hypoxic
encephalopathy 386
myopathy see critical illness
myopathy; critical illness
neuromyopathy
naloxone, contraindications 63
narcotic medication,
contraindications 52
narrow complex arrhythmias
337, 344
atrial fibrillation 337–39, 340
atrial flutter 339–40
atrial tachycardia 342
AV junctional tachycardia 344
AV nodal re-entry tachycardia
342
multifocal atrial tachycardia
344
orthodromic AVRT 342,
342–43
premature atrial complexes
344
sinus tachycardia/bradycardia
340–41, 341
Wolff–Parkinson–White
syndrome 343, 343
nasal cannulae, alternatives to
intubation 51
nasogastric tube (NGT)
placement, ischemic stroke
115; see also enteral
nutrition
National Acute Brain Injury:
Hypothermia study 30
National Institutes of Health
Stroke Scale (NIHSS)
104–6, 106
naxolone 256
near-infrared spectroscopy
(NIRS) 16
neck positioning see patient
positioning
needle cricothyroidotomy,
surgical airways 55–56
Neisseria meningitides
meningococcal meningitis
278
organisms requiring patient
isolation 356
neocortical pyramidal neurons,
cell death 13–14
neoplasms
acute confusional states 392
acute inflammatory
demyelinating disorders
417
autoimmune encephalitis
235–36
status epilepticus 176
neoplastic nontraumatic spinal
cord injury (NTSCI)
290–91, 294–95
nephrogenic systemic fibrosis
(NSF) 369
451
 Index
nephrology 359
acid–base disturbances 364–66
chronic kidney disease 359–60
electrolyte disturbances
362–64
raised ICP 368
renal failure management
368–69
renal replacement therapy
366–68
see also acute kidney injury;
chronic kidney disease
nerve agents, terrorism 259,
263–65, 263
nerve conduction studies (NCS)
191
Neurocritical Care Units,
developing 421, 427
cost–benefit studies 426–27
documentation 426
ischemic/hemorrhagic stroke
outcomes 423–25
models of care 421–22
outcome studies 422–23
status epilepticus outcomes
426
traumatic brain injury
outcomes 425–26
see also business plans
neurogenic pulmonary edema
(NPE)
acute inflammatory
demyelinating disorders 418
acute respiratory distress
syndrome 331
subarachnoid hemorrhage 167
neurogenic stunned myocardium
167, 336
neuroimaging
aspergillosis 281–82
autoimmune encephalitis 235
bacterial cerebral abscesses 285
bacterial meningitis 277
cerebral edema 21–22
cerebral venous thrombosis
146–49, 147–48
delirium 394
fungal meningitis 280
intracerebral hemorrhage
130–31, 134, 135
ischemic stroke 107–8
postoperative management of
surgery patients 307
renal failure management
368–69
spinal cord injury 291–92
spinal epidural abscesses 286
subdural empyema 287
traumatic brain injury 205,
205–6
tuberculous meningitis 284
use in intracranial monitoring
82
viral encephalitis 270–74
see also specific modalities
452
Neurointensive Care Unit
(NCCU) consult service
model 435; see also business
plans
neuroleptic medication,
neuropharmacology 39
neurological assessment 1, 9
brain death 248–51
brainstem reflexes 5–7, 8–10
consciousness disorders 407,
408
delirium 1–4, 2–9, 392–93,
393, 393
eye exam 5, 6–7
focused neurological exam 4
intracerebral hemorrhage
131–32, 131–32, 135
ischemic stroke 104
location of structural brain
disease 7–8, 7
medical exam, general 1, 4
motor responses 7–9
postoperative management
299–300, 300
prior to intubation 54
respiratory patterns 5, 6
scales/screening tools 2–5, 3, 5
sedated patients 1
and sedation 62–63
stabilization of the patient 4
states of altered consciousness
2–9
stupor/coma 1, 2–9
traumatic brain injury 204
neuromonitoring see invasive
neuromonitoring
neuromuscular blockade/
blocking agents (NMBAs)
acute quadriplegic myopathy
syndrome 47–48
acute respiratory distress
syndrome 329–30
drug–drug interactions 48
indications 45
generalized weakness 397, 401
intracerebral hemorrhage 134
monitoring degree of blockade
46–47
neuropharmacology of
selected agents 45–46
potential complications 47–48
prolonged recovery from 47
traumatic brain injury 218
neuromuscular junction
disorders, generalized
weakness 397, 400–1; see
also botulism; myasthenia
gravis
neuromuscular respiratory
failure 188, 190
acute inflammatory
demyelinating disorders 419
airway management 53–54
amyotrophic lateral sclerosis
188, 189, 190
anatomic localization of
weakness 188, 189–97
botulism 195–96
clinical features 188
differential diagnosis 188–89,
189
Guillain–Barré syndrome 188,
189, 190–93, 192
long-term ventilation 59
management 189–90
myasthenia gravis 188, 189,
190, 193–95
spinal cord injury 296
neuromuscular weakness
see generalized weakness
neuromyelitis optica (NMO)
415
neuronal surface antibodies
syndrome 233, 237
cancer investigation workup
235–36
classification of types 233–34,
233–36
diagnostic criteria 233
differential diagnosis 236
management 236–37
neuropathic pain, analgesia 44
neuropharmacology see
pharmacotherapeutics
neuroprotective agents, cerebral
edema 25–26
Neurosciences Critical Care Unit
(NCCU) indications for
referral 103–4, 103
neurostimulation, consciousness
disorders 409; see also deep
brain stimulation
neurosurgery see surgical
interventions
neurotransmitters, role in
delirium 393–94
new oral anticoagulants
(NOACs), ischemic stroke
107
nicardipine, neuropharmacology
75–76
nimopidine
delayed cerebral ischemia
165–66
neuropharmacology 73–75
subarachnoid hemorrhage
303
nitric oxide, inhaled vasodilators
330
NMBAs see neuromuscular
blockade/blocking agents
NMDA (N-methyl-D-aspartate)
receptors 233–35, 233–34,
382
Nociception Coma Scale (NCS) 407
nonconvulsive status epilepticus
(NCSE) 177, 178
noninvasive positive pressure
ventilation (NPPV) 57
alternatives to intubation 51
contraindications 51
long-term ventilation 59
neuromuscular respiratory
failure 190
nonlinear pharmacokinetics 62;
see also
pharmacotherapeutics
nonmaleficence, medical ethics
314–15
nonsteroidal anti-inflammatory
drugs (NSAIDs),
neuropharmacology 44
nontraumatic spinal cord injury
epidemiology 290–91
pathophysiology 294–95 see
also spinal cord injury
norepinephrine, arrhythmias
336
nosocomial meningitis 277
nurse practitioners (NPs)
436–37, 436–38
Nursing Instrument for
Communication of Sedation
(NICS) 34, 35–36
nutrition
ischemic stroke 115
subarachnoid hemorrhage
162–63
traumatic brain injury 221
see also enteral nutrition
obese patients, intubation
53, 53
obstructive lung disease,
hypoxemia 324, 331
obtundation, neurological
assessment 2–9
oculocephalic reflex 6, 249
oculovestibular reflex 6–7, 249
olanzepine, delirium 395
oligemia 13; see also cerebral
blood flow
ophthalmoplegia, following
pituitary resection 311
opiates
intoxication/overdose 256
neuropharmacology 42–44
role in delirium 395
sedative effects 63, 64–65
see also morphine
opt-out approach, medical ethics
322
organ donation, brain death 247,
252
organophosphates, terrorism
259, 263–65, 263
ornithine therapy, hepatic
encephalopathy 378
orthodromic atrioventricular
re-entrant tachycardia 342,
342–43
osmoregulation 238
osmotherapy
ICP management 24, 140–45
neuropharmacology 71, 72

postoperative management
301
traumatic brain injury 213–15
osmotic pressure, cerebral edema
19
outcomes see prognostics
overdose of drugs see drug
intoxication/overdose
oxycodone, neuropharmacology
43
oxygen metabolism, Fick
principle 11, 15–16
oxygenation/oxygen delivery
blood transfusion 15
ischemic stroke 103–4, 108–9
jugular bulb saturation
monitoring 81–82
subarachnoid hemorrhage
162–63
traumatic brain injury 210–11
see also hypoxia/hypoxemia;
ventilation
pacemakers, permanent 348–49
pain
assessment 41–42
as cause of agitation, anxiety,
or delirium 63
ICU experience for patients
33
postoperative management 300
see also analgesia
pancreatitis, spinal cord injury
296
pancuronium,
neuropharmacology 45
PANTHERIS (Preventive
Antibacterial Therapy in
Acute Ischemic Stroke)
trial 117
papaverine, neuropharmacology
76
paralytic agents 54–55
induced hypothermia 384–86
intoxication/toxicity 248, 252
seizures/status epilepticus,
180–81
traumatic brain injury 218–28
paraneoplastic disorders 233, 233
Parsonage–Turner syndrome 398
partial thromboplastin times
(PTTs), heparin 257
parvovirus, organisms requiring
patient isolation 356
patent foramen ovale (PFO)
shunts, hypoxemia 324
patient isolation, infection
control 355–56, 356
patient positioning
acute respiratory distress
syndrome 329
ICP management 23, 140
intubation 53, 53
postoperative management 300
traumatic brain injury 213–14
penetrating traumatic brain
injury 202–3, 202–3
penicillin, myasthenia gravis 194
pentobarbital
ICP management 25
intoxication/overdose 258
status epilepticus 181
“penumbra” concept, cerebral
ischemia 13–14, 52
peptic ulcers 218, 296
perfusion see cerebral blood flow;
cerebral perfusion pressure
perfusion CT scanning
cerebral edema 22
ischemic stroke 107
perfusion-weighted imaging
(PWI), ischemic stroke
107–8
perimesencephalic subarachnoid
hemorrhage 168
periodic lateralizing epileptic
discharges (PLEDs), viral
encephalitis 270
peripheral nerve disorders,
generalized weakness 397,
399–400; see also critical
illness neuromyopathy;
Guillain–Barré syndrome
permanent pacemakers 348–49
permanent vegetative states,
definitions 404
permeability pore, cerebral
edema 19
persistent vegetative states,
definitions 404
pertussis, organisms requiring
patient isolation 356
pharmacodynamics/
pharmacokinetics 62
pharmacotherapeutics 62
anesthetic induction 52, 54–55
antishivering medication 65,
71–73, 73–74
CEEG monitoring to achieve
correct dosage 89
definitions 62
delayed cerebral ischemia
73–76, 165
delirium 395
hyperosmolar solutions 71, 72
locally administered therapies
76
medications affecting QT
interval 346–47
status epilepticus 67–69,
180–83
traumatic brain injury 215,
217–19, 218–19
see also analgesia; antiepileptic
drugs; benzodiazepines;
drug intoxication/overdose;
neuromuscular blockade/
blocking agents; sedation/
sedatives and other specific
drugs
phenobarbital
drug–drug interactions 70–71
intracerebral hemorrhage 140–41
status epilepticus 67–69, 180
therapeutic drug level
monitoring 70
phenytoin
drug–drug interactions 48, 70
intoxication/overdose 256–57
intracerebral hemorrhage
140–41
seizure prophylaxis 66
status epilepticus 67–69, 180
therapeutic drug level
monitoring 70
physical examination
delirium 394
fever 351–52
generalized weakness 398
neurological assessment 1, 4
spinal cord injury 291
physician assistants (PAs)
436–37, 436–37
pipecuronium,
neuropharmacology 45
pituitary apoplexy, subarachnoid
hemorrhage 168
pituitary tumors, postoperative
management 311–13
plasma exchange (PLEX),
Guillain–Barré syndrome
192–93
platelet disorders
carotid endarterectomy 305
and intracerebral hemorrhage
138
subarachnoid hemorrhage 304
traumatic brain injury 212–28
pneumocephalus, postoperative
management 308
pneumonia
Legionella pneumophila
encephalitis 275
management 352, 353
organisms requiring patient
isolation 356
Poiseuille law, laminar fluid
dynamics 11
poliomyelitis, generalized
weakness 397, 399
pollution, toxicity 263
polymorphic ventricular
tachycardia (PMVT) 345
porphyria, generalized weakness
397, 400
porto-systemic shunt, hepatic
encephalopathy 372–74,
373, 378
positioning see patient
positioning
positive end expiratory pressure
(PEEP) 51
acute respiratory distress
syndrome 327
lung-protective ventilation 58
Index
postcardiac arrest syndrome
(PCAS) 382, 382; see also
hypoxic encephalopathy
posterior fossa tumors,
postoperative management
309–10
postoperative management 299,
312
admissions/handover 299
arteriovenous malformation
resection 310
blood pressure control 301,
303, 305
carotid endarterectomy/
stenting 305–7
cerebral edema 300, 307–8
deep brain stimulation 312
epilepsy surgery 311–12
fever control 302–3
fluid balance 301–3
glucose control 302
ICP control/multimodal
monitoring 300–1
neurological assessment
299–300, 300
posterior fossa tumor surgery
309–10
prognostics 300
prophylactic agents 302
seizures 303, 307–9
subarachnoid hemorrhage
302–4
supratentorial tumor surgery
307–9, 308
trans-sphenoidal pituitary
resection 311–13
postparalytic quadriparesis 47–48
potassium homeostasis 362–63
hypoxic encephalopathy 387
indications for dialysis 367
management 362–63, 363
succinylcholine
contraindications 52, 54
power M-mode TCD monitoring
93, 97
pralidoxime chloride (2-PAM)
264–65
prehospital care
hypoxic encephalopathy
383–84
traumatic brain injury 206,
206
prehospital treatment of status
epilepticus (PHTSE) trial
179–80
precuneus, consciousness
disorders 405–6
pregnancy, cerebral venous
thrombosis 146, 151
premature atrial complexes
(PACs) 344
premature ventricular complexes
(PVCs) 345
prepontine subarachnoid
hemorrhage 168
453
 Index
pressure control ventilation
(PCV) 327
pressure ulcers, spinal cord
injury 297
primary brain injury, hypoxic
encephalopathy 382
PRINCIPLE study, ischemic
stroke 113
principlism, medical ethics
314–15
pro-inflammatory cytokines
acute liver failure 371–72
hepatic encephalopathy 379
see also systemic
inflammation
probiotic bacteria, hepatic
encephalopathy 378
procainamide 48, 346–47
procalcitonin (PCT) biomarkers,
sepsis 355
progesterone, neuroprotective
agents 26
prognostics
anthrax infections 260
arrhythmias 349–50
bacterial meningitis 279
cerebral venous thrombosis
149–50
consciousness disorders
407–8
electrophysiologic monitoring
89–90, 89–90
fungal meningitis 280, 282–83
gunshot wounds 202–3
hyponatremia 239
hypoxic encephalopathy
388–90, 389
intracerebral hemorrhage
131–32
ischemic stroke 113
NICU outcome studies 422–23
postoperative management
300
spinal cord injury 291
spinal epidural abscesses 286
status epilepticus 176, 184
subarachnoid hemorrhage 154,
158
subdural empyema 287
traumatic brain injury 66,
221–22
tuberculous meningitis 284
viral encephalitis 270, 274
progressive multifocal
leukoencephalopathy
(PML) 274–75, 417–18
prone positioning see patient
positioning
propofol
acute respiratory distress
syndrome 327
as antishivering agent 73–74
contraindications 52
drug–drug interactions 65
ICP management 25
454
induction of anesthesia 54–55
sedative effects 40, 64–65, 65
status epilepticus 67–69, 181,
182
synergistic sedation regimes
37–38
traumatic brain injury 215
propofol infusion syndrome
(PRIS) 38
proprioceptive head-turning
reflex 6, 249
protamine sulfate 257
protein restriction,
hyperammonemia 376–78
prothrombin complex
concentrate (PCC) 257
proton pump inhibitors
postoperative management
302
spinal cord injury 296
traumatic brain injury 218
pulmonary problems see
neurogenic pulmonary
edema; respiratory
disorders
pupillary asymmetry, nerve
injury 306
pupillary responses 5, 8–10, 249
Purkinje cells, cell death 13–14
pyrexia see fever
Q fever 262
QRS complex
arrhythmias 335
conduction blocks 348
narrow complex arrhythmias
342, 344
tricyclic antidepressants 258
wide complex tachycardias
344–45
QT intervals
arrhythmias 336, 345, 347
medications affecting 39,
346–47
quadriplegia 291; see also spinal
cord injury
quinidine, drug–drug
interactions 48
quinolones, contraindications
194
radio-contrast imaging, contrast
induced nephropathy
368–69
ramp patient positioning 53, 53
Ramsay Scale, agitation and
sedation 35–37
rapid sequence intubation (RSI),
intracerebral hemorrhage
134
raxibacumab, use in anthrax
infections 261
recanalization, arterial
ischemic stroke 107, 110–12
TCD monitoring 98
recreational drugs, drug
intoxication 255–56
reflexes, brainstem 5–7, 249
refractory status epilepticus
(RSE) 177, 178
management 181–84, 181
regional cerebral blood flow
(rCBF), monitoring 81
remifentanyl
neuropharmacology 43
sedative effects 64–65
traumatic brain injury 217
renal problems see nephrology
renal replacement therapy (RRT)
366–68
indications 367–68
vascular access 367
RESCUEicp clinical trial,
traumatic brain injury 215
research, medical ethics 319–22, 319
respiratory care 59; see also
airways; ventilation
respiratory depression 63, 65
respiratory disorders
bodily responses 365–66
pulmonary vascular disease,
hypoxemia 324
spinal cord injury 295–96
see also neurogenic pulmonary
edema; neuromuscular
respiratory failure
respiratory patterns, neurological
assessment 5, 6
respiratory physiology 56
hyperoxia/hypoxia 57
hyperventilation/
hyperventilation 56
spontaneous hypocarbia 56–57
resuscitation, subarachnoid
hemorrhage 162–63
rewarming, therapeutic
hypothermia 384–86
rhabdomyolysis, generalized
weakness 397, 401
Richmond Agitation Sedation
Scale (RASS) 3, 34, 35–37,
392–93, 393
rifaximin, hepatic
encephalopathy 378–79
RIFLE diagnostic criteria (Risk,
Injury, Failure, Loss and
End-stage) kidney disease
359
Riker Sedation-Agitation Scale
35–37
risperidone, delirium 395
rituximab, myasthenia gravis 195
road traffic accidents
spinal cord injury 293–94
traumatic brain injury 199
rocuronium
induction of anesthesia 54–55
neuromuscular respiratory
failure 54
neuropharmacology 46
Rotterdam CT classification,
traumatic brain injury 200
SAH see subarachnoid
hemorrhage
St. Louis encephalitis virus
(SLEV) 273
salaries, staff 434
Salmonella typhimurium,
biological terrorism 259
sarin, chemical terrorism 259,
263–65, 263
scales/screening tools see
neurological assessment
second-degree atrioventricular
blocks 348
secondary brain injury (SBI) 203
sedation/sedatives 33, 40
acute respiratory distress
syndrome 327–28
algorithm for mechanically
ventilated patients 34
assessment for 34, 35–37
cerebral blood flow 13
confounding factors in
assessment 1
hypoxic encephalopathy
384–86
indications 33, 63
intracerebral hemorrhage 135
ischemic stroke 114–15
neuropharmacology 34–40,
62–65, 64–65
role in delirium 395
traumatic brain injury 218–28
seizures 66
brain tumors 307
cerebral venous thrombosis
146, 150
hypoxic encephalopathy 386
intracerebral hemorrhage
140–41, 140
ischemic stroke 118
postoperative management
303, 307–9
stabilization of the patient 4
subarachnoid hemorrhage
161–63, 162–63, 303
traumatic brain injury 217, 217
see also antiepileptic drugs;
status epilepticus
sensory stimulation program
(SSP) 408–9
sepsis
CEEG monitoring 89–90
infectious diseases 355
prognosis 89–90
septic encephalopathy 392
severe ischemic stroke, definition
103; see also ischemic stroke
shivering
antishivering medication 65,
71–73, 73–74
hypoxic encephalopathy 384–86
traumatic brain injury 219

single photon emission
tomography (SPECT), brain
death evaluation 251
sinus tachycardia/bradycardia
340–41, 341, 349
skin problems, spinal cord injury
297
sleep quality, delirium
prevention 41
smallpox, biological terrorism
262
sodium homeostasis 220, 238,
245
cerebral salt-wasting
syndrome 238, 240
classification of disturbances
239–41
definitions 238
differential diagnosis 240–41
hypoxic encephalopathy 387
management 241–44, 241–44,
241–44
mortality/morbidity 239
physiology 238
postoperative management
301–2
renal failure management 368
subarachnoid hemorrhage 166,
240, 244, 303
symptoms 239
traumatic brain injury 240,
244–45
workup 239
see also syndrome of
inappropriate antidiuresis
sodium nitrite therapy, chemical
toxicity 266
solid-state ICP monitoring 23
somatosensory evoked potentials
(SSEPs) 89
hypoxic encephalopathy
388–89
space-occupying cerebellar
stroke 120–21
spinal cord injuries
without radiologic
abnormalities (SCIWORA)
291
spinal cord injury 297
American Spinal Injury
Association scale 291
arrhythmias 336
clinical syndromes 292–93
complications/long-term
sequelae 295–97
diagnostic work-up 291–97
epidemiology 290–91
generalized weakness 397,
398–99
muscle strength grading scale
291
nontraumatic 290–91, 294–95
pathophysiology 292–95, 293–94
prognosis 291
spinal roots/innervation 293
therapeutic hypothermia 30,
294
traumatic 290, 293–94
spinal epidural abscess (SEA) 286
diagnostic work-up 286
epidemiology 290–91
management 286
pathophysiology 295
prognosis 286
specific pathogens 286, 290–91
spinal reflexes, brain death
evaluation 249
SSRIs (selective serotonin
reuptake inhibitors), role in
delirium 395
stabilization, for patient
assessment 4
staff training, advanced practice
model 437–38, 437
staffing requirements, NICUs
432, 434, 437–39, 438
Staphylococcus aureus
bacterial cerebral abscesses 285
bacterial meningitis 278–79
spinal epidural abscess 290–91
Starling’s equation, cerebral
edema 19
STASCIS (Surgical Timing in
Acute Spinal Cord Injury
Study) 294
statins
delayed cerebral ischemia 165
subarachnoid hemorrhage 303
status epilepticus (SE) 176
CEEG monitoring 86–87,
86–91, 89–90, 89–90, 89
classification of types 176–77
clinical trials 179–80
complications 184
critical care interventions 178
diagnostic work-up 177–79,
178
differential diagnosis 179
duration and intensity of
treatment 183–84
electroconvulsive therapy 183
epidemiology 176
etiology 176, 176–84
hypoxic encephalopathy 386
immunomodulatory agents
183
inhalant anesthetics 183
ketogenic diet 183
management 178–79, 181–84,
181
medication recommendations
67–69, 180–83
NICU outcome studies 426
prognosis 89–90, 184
surgery 183
therapeutic hypothermia 30,
183
steroidal neuromuscular
blocking agents 45–47
steroids see corticosteroids
Streptococcus agalactiae, bacterial
meningitis 277–78
Streptococcus pneumoniae,
bacterial meningitis, 277–78
Streptococcus pyogenes, bacterial
meningitis 278–79
Streptococcus spp., bacterial
cerebral abscesses 285
stress, ICU experience for
patients 33
stress cardiomyopathy 418–19
stress ulcers 218, 296
stroke see cerebral venous
thrombosis; hemorrhagic
stroke; intracerebral
hemorrhage; ischemic
stroke
stroke-associated
immunosuppression 117
Stroke Certification (Joint
Commission) 435, 436
stroke risk prediction model,
atrial fibrillation
337–38
structural brain disease, locating
7–8, 7
stupor, neurological assessment
1, 2–9
stylets, difficult airway scenarios
and solutions 54–56
subarachnoid bolts, ICP
monitoring 23
subarachnoid hemorrhage (SAH)
arrhythmias 336
assessment instruments 155,
159
brain tissue oxygen
monitoring 80
CEEG monitoring 87–88,
89–90
cerebral blood flow 14–15
clinical presentation 154–55
common locations 160
complications 166–67
delayed cerebral ischemia
164–66
diagnostic work-up 155–58,
155, 156–57
diffusion-weighted imaging
161
drug intoxication 255
electrolyte disturbances 166,
303
emergency management
159–63, 162–63
epidemiology/risk factors 154
future perspectives 168
grading 155, 156–57, 302–3,
302–3
hyponatremia 166, 240, 244,
303
locally administered therapies
76
NICU outcome studies 423–25
pathophysiology/etiology 158–59
Index
postoperative management
302–4
prognosis 89–90, 158
raised ICP 161
seizure control 161–63,
162–63, 303
therapeutic hypothermia 29
traumatic brain injury 202
vasospasm 14–15, 92–93, 93,
162–63, 304
see also aneurysmal
subarachnoid hemorrhage
subdural empyema (SDE)
286–87
diagnostic work-up 287
management 287
prognosis 287
symptoms 287
subdural hematoma (SDH),
traumatic brain injury 202
subfalcine herniation 21
substituted judgment standard,
ethics 316–17
succinylcholine
contraindications 52, 54, 190
induction of anesthesia
54–55
neuromuscular blockade 45
super-refractory status
epilepticus (SRSE) 176
supratentorial tumors,
postoperative management
307–9, 308
supraventricular tachycardia
(SVT) 345, 347
SUR1 sulfonylurea receptor,
cerebral edema 26
surgical airways 51, 55–56;
see also tracheostomy
surgical interventions
aneurysm repair 163–64
bacterial cerebral abscesses
285–86
external ventricular drain
infections 288
ICP management 25
intracerebral hemorrhage
134–35, 140
status epilepticus 183
subdural empyema 287
traumatic brain injury 207,
207–8, 215, 221
venous thromboembolism 332
see also postoperative
management
surrogate decision-makers, ethics
317, 320
Sylvian fissure hemorrhage 133
syndrome of inappropriate
antidiuretic hormone
(SIADH) 238, 240–41
differential diagnosis 241
management 243–44, 243–44
systemic effects, spinal cord
injury 295–97
455
 Index
systemic inflammation
hepatic encephalopathy
371–72, 372, 379
pain 33
sepsis 355
spinal cord injury 295–98
therapeutic hypothermia 28
systolic blood pressure (SBP),
traumatic brain injury 211;
see also blood pressure
homeostasis
tachycardia, ischemic stroke 52
Takotsubo cardiomyopathy 336
Targeted Temperature
Management (TTM) trial 28
TBI see traumatic brain injury
temperature see body
temperature; therapeutic
hypothermia
terrorism 254, 259, 266; see also
biological terrorism;
chemical agent exposure
tetraplegia 291; see also spinal
cord injury
tetrodotoxin (TTX), biological
terrorism 263
thalamus, consciousness
disorders 406–9
therapeutic drug level
monitoring (TDM)
antiepileptic medication 66–71
neuromuscular blocking
agents 46–47
therapeutic hypothermia (TH)
28, 30
clinical applications 28–30
hypoxic encephalopathy
384–86, 385
ICP management 24–25, 30
methods of achieving 28
neuroprotective mechanism 28
spinal cord injury 30, 294
status epilepticus 183
traumatic brain injury 215
thermal diffusion, cerebral blood
flow monitoring 16, 81
thiamine deficiency alcohol
consumption 256
thiopental 54–55, 134
third-degree atrioventricular
blocks 348
thrombectomy, cerebral venous
thrombosis 150
tick-borne encephalitis virus
(TBEV) 274
tilt table test, sinus tachycardia/
bradycardia 341
TIME IS BRAIN principle,
ischemic stroke 103, 106, 110
time-of-flight (TOF)
angiography
cerebral venous thrombosis
148–49, 148
ischemic stroke 107
456
Tokyo, sarin gas poisonings 259
tonsillar herniation 21
topiramate, status epilepticus
67–69
torsades de pointes (TdP) 39,
336, 345, 347
total parenteral nutrition (TPN),
traumatic brain injury 221
toxic ingestions
acute confusional states 392
acute inflammatory
demyelinating disorders 417
indications for dialysis 367
metabolic encephalopathy
87–88
see also drug intoxication/
overdose
toxicology screening, brain death
evaluation 248
tracheostomy 51, 55, 59
ischemic stroke 113–14
spinal cord injury 296
traumatic brain injury 210
traffic accidents see road traffic
accidents
training, advanced practice
model 437–38, 437
tramadol, neuropharmacology
43
transcranial direct current
stimulation (tDCS),
consciousness disorders 409
transcranial Doppler (TCD)
monitoring 92–100
brain death evaluation 96–97,
250–51
carotid endarterectomy/
carotid artery stenting
98–99
cerebral blood flow measures 16
cerebral carbon dioxide
autoregulation 97
delayed cerebral ischemia
164–65, 164
emboli 98
establishing brain death
96–97
ischemic stroke 97–98, 108
Lindegaard ratio 95, 164
technical aspects 92–93
traumatic brain injury 96 see
also vasospasm detection
transcranial magnetic
stimulation (TMS),
consciousness disorders 409
transient ischemic attacks, atrial
fibrillation 337–38
trans-sphenoidal pituitary
resection (TSTSRPT),
postoperative management
311–13
Trauma Center Verification
program, American College
of Surgeons 208
traumatic axonal injury 202
traumatic brain injury (TBI) 199
airway management 210
biomarkers 222
blast injuries 203
blood pressure management
211–12
blunt cerebrovascular injury
220, 220
blunt TBI 201–2
Canadian head CT rule 205
CEEG monitoring 87–90
cerebral blood flow 15
cerebral hemodynamics 203–4
cerebral microdialysis
monitoring technique 81
cerebral perfusion pressure
203, 216
cerebral vasospasm 96
classification of types 199–200,
200
diagnostic work-up 204–6
electrolyte disturbances 220
epidemiology 199
fever control 219
generalized weakness 397
glucose control 219–20
herniation 207
hyponatremia 240, 244–45
ICU management goals and
guidelines 208–10
intracranial hemorrhage
201–2, 205
jugular bulb saturation
monitoring 82
management, general
principles 206, 208–9
Marshall CT classification 82
medication recommendations
215, 217–19
monitoring, general principles
209–10
multimodal monitoring/
treatment 216–17
neurocritical care 209
NICU outcome studies 425–26
nutritional support 221
oxygen monitoring 80, 210–11
pathophysiology 200–1, 203–4
penetrating TBI/gunshot
wounds 202–3, 202–3
physiological management
goals 206–7
prehospital care 206, 206
prognosis 89–90, 221–22
raised ICP 203–4, 208–13,
213–14, 213–16
respiratory physiology 56–57
secondary brain injury 203
sedation 33
seizure control 66, 217, 217
status epilepticus 176
subarachnoid hemorrhage 167
surgery 207, 207–8, 215, 221
therapeutic hypothermia 29–30
TCD monitoring 96
vascular imaging 205–6, 205
vasospasm 220–21
venous thromboembolism 332
ventilation, mechanical
210–11 see also
consciousness disorders,
postinjury
traumatic causes, acute
confusional states 392
traumatic spinal cord injury
(TSCI)
epidemiology 290
pathophysiology 293–94 see
also spinal cord injury
triage
cerebral venous thrombosis 149
intubation 54
spinal cord injury 297
status epilepticus 178
stroke 104
tricyclic antidepressants (TCAs)
intoxication/overdose 258
role in delirium 395
triple-H therapy (hypervolemia,
hemodilution,
hypertension)
aneurysmal subarachnoid
hemorrhage (aSAH) 82
cerebral blood flow 15
delayed cerebral ischemia 73,
165–66
tuberculous meningitis 283
diagnostic work-up 284
management 284
prognosis 284
symptoms 283
tumefactive multiple sclerosis 416
diagnostic work-up 415–16,
416
management 416
tumor necrosis factor-alpha
(TNF)
acute liver failure 371–72
therapeutic hypothermia 28
see also systemic
inflammation
Tylenol 259
understanding, medical ethics
314–16
unfractionated heparin (UFH)
150, 219, 257
universal decolonization, MRSA
356
unresponsive wakefulness
syndrome, definitions 404
upward herniation 21
uremic syndrome, indications for
dialysis 367
urinary alkalinization, drug
intoxication 255
urinary tract infections,
catheter-related 351, 354–55
utilitarianism, medical ethics
314–15

vaccine-related risks,
Guillain–Barré syndrome
191
valproate
drug–drug interactions 71
intracerebral hemorrhage
140–41
seizure prophylaxis 66
status epilepticus 67–69
therapeutic drug level
monitoring 71
valproic acid, status epilepticus
180, 181
vancomycin-resistant
enterococcus (VRE) 356
varicella zoster virus (VZV) 356,
356
varicella zoster virus (VZV)
encephalitis 270
diagnostic work-up 271
management 271
symptoms 270–71
variola virus, biological terrorism
262
vascular access, dialysis patients
367
vascular causes
acute confusional states 392
acute inflammatory
demyelinating disorders
417
vascular imaging, traumatic
brain injury 205–6, 205,
220–21
vascular injury, trans-sphenoidal
pituitary resection 311
vasculitic neuropathy 397, 400
vasodilation
acute respiratory distress
syndrome 330
cerebral edema 21
vasodilatory reserve 12–13
vasogenic edema 20
vasospasm, cerebral
locally administered therapies
76
neuropharmacology of
selected agents 73–76
subarachnoid hemorrhage
14–15, 162–63, 304
traumatic brain injury
220–21
vasospasm, coronary 255
vasospasm detection, TCD
monitoring 96
anterior cerebral arteries 95
distal vasospasm detection
95–96
internal carotid artery 95
middle cerebral artery 93–94,
94
subarachnoid hemorrhage
92–93, 93
vertebral and basilar arteries
95
vecuronium
as antishivering agent 73–74
induction of anesthesia
54–55
neuropharmacology 45
vegetative state (VS)
definitions 404–5
patient communications 410
residual brain activity 405–6
vehicle accidents see road traffic
accidents
Venezuelan equine encephalitis
(VEE), biological terrorism
262
venography, cerebral venous
thrombosis 148–49, 148
venous thromboembolism
hypoxemia 331–32
hypoxic encephalopathy
388
intracerebral hemorrhage 140
ischemic stroke 116–17
spinal cord injury 296–97
subarachnoid hemorrhage
162–63
traumatic brain injury 218–19,
218–19
see also cerebral venous
thrombosis
ventilation, mechanical 50, 57
acute respiratory distress
syndrome 327–30
brain death 247
critical illness neuromyopathy
196
Guillain–Barré syndrome 192
hypoxic encephalopathy 387
ischemic stroke 108–14
long-term 59
lung-protective ventilation
57–58
management protocols 328
myasthenia gravis 194–95
raised ICP 58
and sedation 62–63, 135
spinal cord injury 295–96
traumatic brain injury
210–11
weaning from 58, 58–59, 113,
192, 296 see also
hyperventilation therapy;
intubation; noninvasive
positive pressure ventilation
ventilator-associated pneumonia
(VAP) 351
ventricular fibrillation (VF)
345–47
ventricular tachycardia (VT)
344–45, 345, 347
ventriculitis 288–89
ventriculoencephalitis 272
verapamil, neuropharmacology
76
vertebral artery (VA)
dissection, subarachnoid
hemorrhage 167
TCD monitoring 93, 95
viral diseases, organisms
requiring patient isolation
356
viral encephalitis 269–75
viral meningitis 276
virtue ethics 314–15
visual defects, following pituitary
resection 311
Vitamin E mnemonic, acute
confusional states 392
vitamin K
intracerebral hemorrhage
136–37
warfarin overdose 257
volume overload, indications for
dialysis 367
voluntariness, medical ethics
314–16
waiver of consent, medical ethics
319, 320
warfarin
atrial fibrillation 339
cerebral venous thrombosis 152
Index
intoxication/overdose 257
intracerebral hemorrhage
136–38, 137
weakness see generalized
weakness
Wernicke–Korsakoff syndrome
256
Wernicke’s encephalopathy
256
West Haven criteria, hepatic
encephalopathy 370
West Nile virus, generalized
weakness 397, 399
West Nile virus (WNV)
encephalitis 273
diagnostic work-up
273–74
management 274
prognosis 274
symptoms 273
wide complex tachycardias
(WCTs) 344
accelerated idioventricular
rhythm 345
management 347, 347
medications affecting QT
interval 346–47
premature ventricular
complexes 345
torsades de pointes 336, 345,
347
ventricular fibrillation 345–47
ventricular tachycardia
344–45, 345, 347
withdrawing/withholding care,
medical ethics 318–19; see
also do-not-resuscitate
orders
Wolff–Parkinson–White (WPW)
syndrome 343, 343
World Federation of
Neurological Surgeons
(WFNS), subarachnoid
hemorrhage grading scale
155, 159
wound hematoma, carotid
endarterectomy 306–7
xenon-CT, cerebral blood flow
measures 15–16
zygomycosis 282
457