Neurocritical Care (Pittsburgh Critical Care Medicine) 9780199375363

Table of contents :
Cover......Page 1
Series......Page 3
Neurocritical Care......Page 4
Copyright......Page 5
Dedication......Page 6
Contents......Page 8
Preface......Page 12
Contributors......Page 14
Section 1......Page 22
1 Coma and Low Arousal States ......Page 24
2 Encephalopathy and Delirium ......Page 36
3 Acute Ischemic Stroke ......Page 44
4 Intracerebral Hemorrhage ......Page 58
5 Subarachnoid Hemorrhage ......Page 65
6 Reversible Cerebral Vasoconstriction Syndrome ......Page 75
7 Anoxic Brain Injury ......Page 79
8 Seizures and Status Epilepticus ......Page 89
9 The Management of Traumatic Brain Injury ......Page 104
10 The Management of Traumatic Spinal Cord Injury ......Page 118
11 Meningitis and Encephalitis ......Page 126
12 Inflammation and Demyelination ......Page 140
13 Neuromuscular Conditions ......Page 152
14 Movement Disorder Emergencies and Movement
Disorders in the ICU......Page 162
Section 2......Page 174
15 Multimodality Monitoring ......Page 176
16 External Ventricular Drainage: Clinical Indications,
Surgical Technique, and Management......Page 186
17 Neuroimaging and Neurointerventional Procedures ......Page 194
18 Hypothermia and Fever Control in Neurocritical Care ......Page 206
19 Neuropharmacotherapy ......Page 216
Section 3......Page 232
20 General ICU Care of the Neurological Patient ......Page 234
21 Managing the Postoperative Neurosurgical Patient ......Page 245
22 Pediatric Neurocritical Care ......Page 254
23 Neurocritical Care in Pregnancy ......Page 268
24 Management of Intracranial Hypertension in Fulminant
Hepatic Failure......Page 277
25 Prognostication and Ethics ......Page 286
26 Brain Death, Organ Donation, and Transplantation ......Page 297
27 Rehabilitation in Neurocritical Care ......Page 307
Index......Page 318

Citation preview

Neurocritical Care

Pittsburgh Critical Care Medicine Series Published and Forthcoming Titles in the Pittsburgh Critical Care Medicine Series Continuous Renal Replacement Therapy edited by John A. Kellum, Rinaldo Bellomo, and Claudio Ronco Renal and Metabolic Disorders edited by John A. Kellum and Jorge Cerdá Emergency Department Critical Care edited by Donald Yealy and Clifton Callaway Trauma Intensive Care edited by Samuel Tisherman and Racquel Forsythe Abdominal Organ Transplant Patients edited by Ali Al-​Khafaji Infection and Sepsis edited by Peter Linden Pediatric Intensive Care edited by Scott Watson and Ann Thompson Mechanical Ventilation by John W. Kreit Rapid Response System edited by Raghavan Murugan and Joseph M. Darby Neurocritical Care edited by Lori A. Shutter and Bradley J. Molyneaux Cardiac Problems edited by Thomas Smitherman ICU Procedures by Scott Gunn and Holt Murray

Neurocritical Care Edited by

Lori A. Shutter, MD, FNCS, FCCM

Vice Chair of Education, Critical Care Medicine Professor, Critical Care Medicine, Neurology & Neurosurgery Director, Neurocritical Care Fellowship Training Program Medical Director, Neurovascular & Neurotrauma ICUs Pittsburgh, PA

Bradley J. Molyneaux, MD, PhD

Assistant Professor, Neurology and Critical Care Medicine University of Pittsburgh Pittsburgh, PA

1

1 Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford is a registered trade mark of Oxford University Press in the UK and certain other countries. Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016, United States of America. © Oxford University Press 2018 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by license, or under terms agreed with the appropriate reproduction rights organization. Inquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above. You must not circulate this work in any other form and you must impose this same condition on any acquirer. Library of Congress Cataloging-​in-​Publication Data Names: Shutter, Lori, editor. | Molyneaux, Bradley J., editor. Title: Neurocritical care / edited by Lori Shutter, Bradley J. Molyneaux. Other titles: Neurocritical care (Shutter) | Pittsburgh critical care medicine. Description: Oxford; New York: Oxford University Press, [2018] | Series: Pittsburgh critical care medicine series | Includes bibliographical references. Identifiers: LCCN 2018003488 | ISBN 9780199375349 (pbk.) Subjects: | MESH: Central Nervous System Diseases–therapy | Critical Care–methods | Trauma, Nervous System—therapy Classification: LCC RC350.N49 | NLM WL 301 | DDC 616.8/0428–dc23 LC record available at https://lccn.loc.gov/2018003488 This material is not intended to be, and should not be considered, a substitute for medical or other professional advice. Treatment for the conditions described in this material is highly dependent on the individual circumstances. And, while this material is designed to offer accurate information with respect to the subject matter covered and to be current as of the time it was written, research and knowledge about medical and health issues is constantly evolving and dose schedules for medications are being revised continually, with new side effects recognized and accounted for regularly. Readers must therefore always check the product information and clinical procedures with the most up-​to-​date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulation. The publisher and the authors make no representations or warranties to readers, express or implied, as to the accuracy or completeness of this material. Without limiting the foregoing, the publisher and the authors make no representations or warranties as to the accuracy or efficacy of the drug dosages mentioned in the material. The authors and the publisher do not accept, and expressly disclaim, any responsibility for any liability, loss or risk that may be claimed or incurred as a consequence of the use and/​or application of any of the contents of this material. 9 8 7 6 5 4 3 2 1 Printed by WebCom, Inc., Canada

We dedicate this book to our patients and their families—​they are the reason we come to work every day, stay at work later than our families like, and constantly strive to learn more. We also must acknowledge the advance practice providers, nurses, pharmacists, and respiratory therapists who actually run every ICU—​nothing gets accomplished without you.

Contents Preface  xi Contributors  xiii Section 1:  Neurological Conditions







1 Coma and Low Arousal States Namir Khandker and Lori A. Shutter

 3

2 Encephalopathy and Delirium Joshua Keegan and Colleen Moran

 15

3 Acute Ischemic Stroke Cynthia L. Kenmuir and Tudor G. Jovin

 23

4 Intracerebral Hemorrhage Opeolu Adeoye

 37

5 Subarachnoid Hemorrhage Sherry Hsiang-​Yi Chou

 44

6 Reversible Cerebral Vasoconstriction Syndrome Krystle Shafer and Bradley J. Molyneaux

 54

7 Anoxic Brain Injury Jonathan Elmer and Jon C. Rittenberger

 58

8 Seizures and Status Epilepticus Michael E. Reznik and Jan Claassen

 68

9 The Management of Traumatic Brain Injury Jeremy G. Stone, David M. Panczykowski, and David O. Okonkwo 10 The Management of Traumatic Spinal Cord Injury David M. Panczykowski, Jeremy G. Stone, and David O. Okonkwo

 

83

 

97

11 Meningitis and Encephalitis Ruchira Jha

 105

12 Inflammation and Demyelination Daniel B. Rubin and Henrikas Vaitkevicius

 119

 Contents



13 Neuromuscular Conditions Deepa Malaiyandi and Saša A. Živković

 131

14 Movement Disorder Emergencies and Movement Disorders in the ICU Mihai C. Sandulescu and Edward A. Burton

  141

Section 2:  Interventions and Monitoring



15 Multimodality Monitoring Maranatha Ayodele and Kristine O’Phelan

 155



16 External Ventricular Drainage: Clinical Indications, Surgical Technique, and Management Nitin Agarwal and Andrew F. Ducruet

  165



17 Neuroimaging and Neurointerventional Procedures Cynthia L. Kenmuir and Ashutosh P. Jadhav

 173

18 Hypothermia and Fever Control in Neurocritical Care Kees H. Polderman

 185

viii



19 Neuropharmacotherapy Gretchen M. Brophy and Theresa Human

 195

Section 3:  General Management and Special Populations



20 General ICU Care of the Neurological Patient Samuel A. Tisherman and Sara Hefton

 213

21 Managing the Postoperative Neurosurgical Patient Daniel Ripepi and Colleen Moran

 224

22 Pediatric Neurocritical Care Dennis W. Simon and Ericka L. Fink

 233

23 Neurocritical Care in Pregnancy Krystle Shafer and Marie R. Baldisseri

 247



24 Management of Intracranial Hypertension in Fulminant Hepatic Failure Sajid Kadir and Raghavan Murugan

  256



25 Prognostication and Ethics David Y. Hwang and Douglas B. White

 265





26 Brain Death, Organ Donation, and Transplantation Hilary H. Wang and David M. Greer

 276

27 Rehabilitation in Neurocritical Care Michael E. Reznik and Amy K. Wagner

 286

Index  297

We are pleased to provide this book to those health care providers involved in the care of critically ill patients with neurological conditions. Our goal in developing this book is to provide a foundation of knowledge to help guide the identification, understanding, medical decision-​making, and management of this unique group of patients. The critically ill neurology patient poses a challenge to many providers as standard critical care management may not be applicable. In addition, the field of neurocritical care has grown significantly in the past few years. We have more knowledge and understanding of the physiology of patients with neur­ ological conditions presenting in the intensive care unit (ICU), diagnostic and monitoring technology has advanced, and treatment options have expanded. These changes allow us to impact significantly on the care of these patients. This text strives to provide a simple, straightforward guide to these complex patients. This is meant to be a quick reference that provides focused information regarding the presentation and management of specific neurological conditions often seen in the ICU. The authors of these chapters are experts in this field, and we have been privileged to work with them in completion of this handbook. We hope you will find it to be a useful tool in your care of these patients. Lori A. Shutter and Bradley J. Molyneaux

xi

Preface

Contributors

Vice Chair, Research Co-​Director, UC Stroke Team Associate Professor Department of Emergency Medicine University of Cincinnati Cincinnati, OH

Nitin Agarwal, MD Resident Department of Neurological Surgery University of Pittsburgh School of Medicine Pittsburgh, PA

Maranatha Ayodele, MD Assistant Professor of Clinical Neurology Neurocritical Care Division University of Miami Miller School of Medicine Miami, FL

Marie R. Baldisseri, MD, MPH, FCCM Professor of Critical Care Medicine, Medicine, and Health Promotion & Development Department of Critical Care Medicine University of Pittsburgh School of Medicine Pittsburgh, PA

Gretchen M. Brophy, PharmD, BCPS, FCCP, FCCM, FNCS Professor of Pharmacotherapy & Outcomes Science and Neurosurgery Virginia Commonwealth University Medical College of Virginia Campus Richmond, VA

Edward A. Burton, MD, DPhil, FRCP Associate Professor of Neurology and UPMC Endowed Chair in Movement Disorders University of Pittsburgh School of Medicine Pittsburgh, PA

Jan Claassen, MD, PhD, FNCS Associate Professor of Neurology Head of Neurocritical Care Medical Director, Neurological Intensive Care Unit Columbia University College of Physicians & Surgeons New York, NY

Andrew F. Ducruet, MD Endovascular Neurosurgeon Barrow Neurological Institute Phoenix, AZ

xiii

Opeolu Adeoye, MD, MS, FACEP, FAHA

Contributors 

Jonathan Elmer, MD, MS Assistant Professor Departments of Emergency Medicine and Critical Care Medicine University of Pittsburgh School of Medicine Pittsburgh, PA

xiv

Ericka L. Fink, MD, MS Associate Professor, Critical Care Medicine, Pediatrics, and Clinical & Translational Science Institute Department of Critical Care Medicine Children’s Hospital of Pittsburgh Safar Center for Resuscitation Research University of Pittsburgh School of Medicine Pittsburgh, PA

David M. Greer, MD, MA, FCCM, FAHA, FNCS, FAAN, FANA Professor and Chairman Department of Neurology Boston University School of Medicine Boston, MA

Sara Hefton, MD Assistant Professor Departments of Neurology and Neurological Surgery Division of Neurotrauma and Critical Care Thomas Jefferson University Philadelphia, PA

Sherry Hsiang-​Yi Chou, MD, MSc, FNCS, FCCM Associate Professor Department of Critical Care Medicine, Neurology, and Neurosurgery University of Pittsburgh School of Medicine Pittsburgh, PA

Theresa Human, PharmD, BCPS, FNCS Neuroscience Clinical Specialist Barnes-​Jewish Hospital Washington University St.Louis, MO

David Y. Hwang, MD, FCCM, FNCS Assistant Professor of Neurology Division of Neurocritical Care and Emergency Neurology Yale School of Medicine New Haven, CT

Ashutosh P. Jadhav, MD, PhD Assistant Professor of Neurology and Neurological Surgery Director, Vascular Neurology Fellowship University of Pittsburgh School of Medicine Pittsburgh, PA

Ruchira Jha, MD, MS Assistant Professor Departments of Critical Care Medicine, Neurology, Neurological Surgery, and Clinical & Translational Science Institute Scientist-​Safar Center for Resuscitation Research University of Pittsburgh School of Medicine Pittsburgh, PA

Colleen Moran, MD

Professor of Neurology and Neurosurgery Director, Stroke Institute Co-​Director, Center for Endovascular Therapy University of Pittsburgh School of Medicine Pittsburgh, PA

Assistant Professor Department of Anesthesiology Duke University School of Medicine Durham, NC

Intensivist, Geisinger Health System Department of Medicine Danville, PA

Joshua Keegan, MD Clinical Assistant Professor Co-Director, Neurovascular ICU—UPMC Altoona Department of Critical Care Medicine University of Pittsburgh School of Medicine Pittsburgh, PA

Cynthia L. Kenmuir, MD, PhD Fellow, Departments of Neurology and Neurological Surgery University of Pittsburgh School of Medicine Pittsburgh, PA

Raghavan Murugan, MD, MS, FRCP Associate Professor of Critical Care Medicine and Clinical & Translational Science Center for Critical Care Nephrology Clinical Research Investigation and Systems Modeling of Acute Illness Department of Critical Care Medicine University of Pittsburgh School of Medicine Pittsburgh, PA

Kristine O’Phelan, MD Associate Professor of Clinical Neurology Department of Neurology University of Miami Miller School of Medicine Miami, FL

David O. Okonkwo, MD, PhD

Adult Fellow, Neurocritical Care Department of Critical Care Medicine University of Pittsburgh School of Medicine Pittsburgh, PA

Executive Vice Chair, Clinical Operations Clinical Director, Brain Trauma Research Center Department of Neurological Surgery University of Pittsburgh School of Medicine Pittsburgh, PA

Deepa Malaiyandi, MD

David M. Panczykowski, MD

Assistant Professor Co-​Director, Neurovascular ICU—​UPMC Altoona Department of Critical Care Medicine University of Pittsburgh School of Medicine Pittsburgh, PA

Chief Resident Department of Neurological Surgery University of Pittsburgh School of Medicine Pittsburgh, PA

Namir Khandker, MD

xv

Sajid Kadir, MD

 Contributors

Tudor G. Jovin, MD

Contributors 

Kees H. Polderman, MD, PhD

Krystle Shafer, MD

Professor of Critical Care Medicine Department of Critical Care Medicine University of Pittsburgh School of Medicine Pittsburgh, PA

Chief Fellow, Adult Critical Care Medicine—​Emergency Medicine Department of Critical Care Medicine University of Pittsburgh School of Medicine Pittsburgh, PA

Michael E. Reznik, MD Assistant Professor of Neurology and Neurosurgery Division of Neurocritical Care Alpert Medical School, Brown University Providence, RI

Resident Department of Anesthesiology University of Pittsburgh School of Medicine Pittsburgh, PA

Assistant Professor Director, Pediatric Neurocritical Care Department of Critical Care Medicine Children’s Hospital of Pittsburgh Safar Center for Resuscitation Research University of Pittsburgh School of Medicine Pittsburgh, PA

Jon C. Rittenberger, MD, MS

Jeremy G. Stone, MD

Associate Professor Department of Emergency Medicine, Occupational Therapy, and Clinical & Translational Science Institute University of Pittsburgh School of Medicine Pittsburgh, PA

Resident Department of Neurological Surgery University of Pittsburgh School of Medicine Pittsburgh, PA

Daniel B. Rubin, MD, PhD

Professor of Surgery, Program in Trauma University of Maryland School of Medicine Director, Center for Critical Care and Trauma Education Director, Surgical Intensive Care Unit University of Maryland Medical Center RA Cowley Shock Trauma Center Baltimore, MD

Daniel Ripepi, MD

xvi

Dennis W. Simon, MD

Fellow, Neurocritical Care Massachusetts General Hospital Brigham and Women’s Hospital Harvard Medical School Boston, MA

Mihai C. Sandulescu, MD Clinical Assistant Professor of Neurology Geisinger Commonwealth School of Medicine Scranton, PA

Samuel A. Tisherman, MD, FACS, FCCM

Douglas B. White, MD, MAS

Assistant Professor Neurology Brigham and Women’s Hospital Harvard Medical School Boston, MA

Professor of Critical Care Medicine UPMC Endowed Chair of Ethics in Critical Care Medicine Director, Program on Ethics and Decision Making in Critical Illness University of Pittsburgh School of Medicine Pittsburgh, PA

Amy K. Wagner, MD Professor, Physical Medicine & Rehabilitation and Neuroscience UPMC Endowed Chair Translational Research Associate Director Safar Center for Resuscitation Research University of Pittsburgh School of Medicine Pittsburgh, PA

 Contributors

Henrikas Vaitkevicius, MD

Saša A. Živković, MD, PhD Associate Professor of Neurology Department of Neurology University of Pittsburgh School of Medicine Pittsburgh, PA

Resident Department of Neurology & Neurological Sciences Stanford Medicine Stanford, CA

xvii

Hilary H. Wang, MD, MBA

Neurocritical Care

Section 1

Neurological Conditions

Chapter 1

Coma and Low Arousal States Namir Khandker and Lori A. Shutter

Introduction

Definitions and Physiology of Consciousness Plum and Posner presented the most accepted definition of consciousness as “the state of full awareness of the self and one’s relationship to the environment.” Control of consciousness is complex and involves a myriad of structures, pathways, and neurotransmitters. A basic understanding of these mechanisms helps clarify the etiology of altered consciousness and guide directed assessment and management.

Consciousness A simple schematic divides consciousness into two components: content and arousal. Content refers to all cognitive and affective mental functions of the brain and is generated by the cortex. Arousal refers to behavior consistent with alertness and responsiveness to the environment and is regulated by connections between the brainstem (upper pons and midbrain), diencephalon (thalamus and hypothalamus), and cortex. Some level of arousal is required for cognition. Dysfunction of these structures or connections will manifest as an alteration of mental status. Consciousness represents a continuum from coma to normal arousal with sleep being the only normal alteration. Imprecise terms such as lethargy, obtundation, and stupor represent different points on the continuum of arousal. Use of these terms are easily misinterpreted. Better communication between care teams can be achieved using behavioral descriptions (“patient will not open eyes to voice but will localize with vigorous sternal rub”) or using coma scales (described later in this chapter).

3

In the intensive care unit (ICU), coma and other low arousal states are common enough that physicians of every specialty will encounter them. They can present as a medical emergency, and all cases require a thoughtful and organized approach. The differential diagnosis is broad, with prognosis and management varying widely depending on etiology. Rapid initial assessment with a thorough history and physical examination is crucial for timely and appropriate live-​saving management.

Neurological Conditions Section 1

Coma Coma is a failure of neuronal systems responsible for arousal and awareness resulting in complete unresponsiveness to environmental stimuli. Eyes remain closed and will not open spontaneously or reactively. Reflexive movements may remain intact, but often brainstem reflexes will be depressed. Coma is typically transient, and patients will progress to different arousal states, each of which has a different prognosis for recovery.

Vegetative State After a coma, patients may begin to exhibit normal sleep/​wake cycles while otherwise remaining unresponsive, which defines a vegetative state. A patient may open his or her eyes spontaneously but will not track or fixate. Reflexive movements may become prominent, and random movements of limbs, trunk, and even vocalizations with tears or smiles may occur. No reproducible purposeful responses will be seen. These findings are consistent with diffuse or multifocal grey and white matter injury. Lower brainstem function typically remains intact.

4

Minimally Conscious State Patients who show evidence of awareness of external stimuli have entered a minimally conscious state. Patients continue to have significantly altered consciousness with variable levels of arousal and inconsistent responsiveness but demonstrate one or more reproducible behaviors consistent with awareness. Examples of responsive behaviors include following simple commands, appropriate yes/​no (verbal or gesture) responses, or other purposeful behavior. Patients who consistently demonstrate awareness have progressed out of a low arousal state.

Etiology of Coma All etiologies of coma result in neuronal dysfunction involving bilateral cerebral hemispheres or the arousal pathways. During the evaluation, it is crucial to identify readily reversible causes before permanent damage occurs. Localization of the structures involved can give clues to the underlying etiology, which can be divided into structural and nonstructural. Some etiologies can encompass features of both structural and nonstructural mechanisms, and mechanisms can evolve over time. An example would be a tumor with cerebral edema and mass effect causing generalized nonconvulsive seizures. More than one process can be active simultaneously, leading to multifactorial etiology of coma. Table 1.1 summarizes common causes of coma and coma mimics.

Structural Etiologies of Coma Structural etiologies of coma cause neuronal dysfunction by mechanical force. Causes can include but are not limited to bihemispheric or brainstem injury, mass effect, hematoma, interruption of cerebral blood flow, and trauma.

Trauma  subdural hematoma, epidural hematoma, contusion, diffuse axonal injury Neurovascular  intracerebral hemorrhage, subarachnoid hemorrhage, basilar artery occlusion, cerebral venous thrombosis, posterior reversible encephalopathy syndrome Neuroinflammatory Disorders  acute disseminated encephalomyelitis, autoimmune encephalitis Hydrocephalus intraventricular hemorrhage, Chiari malformation, colloid cyst, ependymal inflammation Central nervous system infection  meningitis, viral encephalitis, cerebral abscess Oncologic process  neoplasia with edema and mass effect, cerebral metastases

falls, multiple injuries

Headache, sudden onset, hypertension, progressive neurologic symptoms, cranial nerve deficits, papilledema Subacute onset, preceding viral illness, comorbid autoimmune disease, preceding new psychiatric diagnoses Lethargy, headache, nausea/​vomiting

Subacute onset, fever, altered mental status, nuchal rigidity, petechial rash, photophobia/​phonophobia Cachexia, history of malignancy, seizure

Metabolic  non-​convulsive status epilepticus post-​anoxic injury from cardiac or respiratory arrest septic encephalopathy fever electrolyte derangement hypercapnea endocrine derangement (dysglycemia, Addisonian crisis, thyroid dysfunction) hyperammonemia uremia nutritional deficiency

Coma and Low Arousal States

Associated Findings

Structural 

history of epilepsy, abolished motor activity, sepsis hemodynamic instability at presentation sepsis

cushingoid appearance, hypotension, pendular reflexes liver failure, valproic acid use, urea cycle metabolic disorders kidney failure substance abuse, alcohol abuse, history of gastric bypass (continued)

5

Etiology

Chapter 1

Table 1.1  Common Etiologies of Coma and Associated Findings

Neurological Conditions Section 1

Table 1.1 Continued Etiology

Associated Findings

Toxins  ethanol, toxic alcohols tricyclic antidepressants SSRI, antipsychotics benzodiazepines, opioids cyanide antiepileptic drugs carbon monoxide aspirin acetaminophen

osmolal gap, metabolic acidosis, renal failure wide QRS complex, cholinergic toxidrome rigidity, fever, myoclonus bradypnea, hypotension, miosis acidosis, high cardiac output, almond odor nystagmus, hyperammonemia headache, hypoxia, flushed skin metabolic acidosis, respiratory alkalosis hepatic failure

6

SSRI = selective serotonin reuptake inhibitors.

Several exam features can help identify a structural lesion. Often, the depth of coma will be more severe, particularly if the change is abrupt. Focal neurologic symptoms, such as anisocoria, cranial nerve deficits, or asymmetric limb movements, are highly suggestive of a structural lesion. Funduscopic examination can reveal signs of increased intracranial pressure from cerebral herniation, acute hydrocephalus, or subhyaloid hemorrhages which can be seen with acute subarachnoid hemorrhage. No focal findings need to be present to have a structurally mediated coma.

Toxic/​Metabolic Etiologies of Coma Nonstructural etiologies of coma cause neuronal dysfunction by derangements at the cellular level. The variety of metabolic causes is vast and commonly include all manner of electrolyte derangements, endocrine dysfunction including thyroid and adrenal glands, and vitamin deficiencies. Energy crises from hypoglycemia, hypoxia, fever, or seizure can precipitate coma, particularly in patients with abnormal cerebral function at baseline. Exogenous substances including opioids, alcohol, and other drugs can often cause coma via a secondary metabolic derangement and organ failure (hypoglycemia, hypoxia, seizure, hyperammonemia, uremia), or structural insult (intracerebral hemorrhage or diffuse leukoencephalopathy). Onset is typically gradual and examination shows diffuse findings, roving eye movements, and fluctuating symptoms. Myoclonic jerking is typically metabolic in origin and most commonly seen with anoxic brain injury. Muscle rigidity and fever may indicate toxic effects of neuroleptics or selective serotonin release inhibitors. A thorough general exam including vital signs is also paramount to identifying features of infection, liver failure, chronic endocrine dysfunction,

Locked-​In Syndrome Damage to the ventral pons affecting motor pathways can lead to a state where cognition and awareness are completely intact with extremely limited motor function, typically with only vertical eye movements and blinking preserved. The most common cause is occlusion of the basilar artery. Other etiologies are rare and include brainstem hemorrhage, botulism and neuromuscular diseases such as end stage amyotrophic lateral sclerosis, fulminant acute demyelinating inflammatory polyneuropathy, tick paralysis, and fulminant critical illness polyneuropathy/​myopathy. Prognosis for motor recovery depends on etiology. However, several studies suggest that quality of life can be preserved despite severe motor impairment. Physicians should not limit care solely on the idea that severe motor impairment would represent an unacceptable quality of life.

Catatonia Catatonia has a wide variety of presentations with both organic and psychiatric causes. Immobility, mutism, and refusal to eat are the most common signs, and severe forms may be confused with coma. Patients retain awareness and will often report remembering a catatonic episode in its entirety. As catatonia can be a manifestation of delirium from a general medical cause, a thorough evaluation for etiology, including medicine reconciliation, electroencephalogram (EEG), neuroimaging, and laboratory investigations should be undertaken prior to diagnosis of psychiatric disease.

Abulia and Akinetic Mutism Bilateral medial frontal lesions can affect motivation. In severe forms, apathy can be so extreme that the patient will not speak or move spontaneously even to eat or drink water. Patients remain alert and aware and may take several minutes to respond to an examiner. Etiologies can be varied and include stroke, inflammatory white matter disease, and infections. A slow and thorough neurologic exam can usually differentiate this syndrome from a true coma.

Psychogenic Unresponsiveness Patients with psychogenic coma may exhibit a profound unresponsive state but have no identifiable structural, metabolic, or toxic disorder. These

Coma and Low Arousal States

Pathophysiology affecting behavioral responses outside of the mechanisms for arousal can be frequently mistaken for coma. It is important to distinguish these states as management and prognosis can vary drastically.

Chapter 1

Coma Mimics

7

stigma of chronic heavy metal poisoning or vitamin deficiency, and cardiopulmonary collapse among other causes.

Neurological Conditions Section 1

episodes are often precipitated by stress and when witnessed may show efforts to avoid injury while suddenly becoming comatose. Neurologic exam of reflexes and cranial nerves should be normal, while other aspects may be inconsistent with repeated exam. Several exam maneuvers can help distinguish poor effort and unmask awareness. Examiners may note forcible eye closing when attempting to examine pupils with a Bell’s phenomenon (eyes rolling up with intentional eye closure). Behaviors that avoid injury, such as not allowing a hand to drop on the face or bracing for a fall, are usually present. These features are not pathognomonic for psychogenic coma, and an initial thorough workup should be performed to rule out a true coma or other low arousal state.

Coma Scales Coma scales are useful tools for communicating depth of coma. The most common scales in use are the Glasgow Coma Scale (GCS) and the Full Outline of Unresponsiveness (FOUR) score. See Table 1.2 for grading of these scales.

8

Glasgow Coma Scale The GCS was developed to improve the care of traumatic brain injury in 1974 and remains an easy-​to-​use adjunct to the physical exam that has been incorporated into many clinical guidelines. The GCS is the sum of three assessments:  motor, verbal, and eye movement. Although it is tempting to simplify the GCS into a single summed score, doing so may mask changes as the same score can be attained even with a significant change in individual components of the exam. Components of the GCS may be difficult to test when a patient is intubated or sedated, which also limits the value of GCS as a stand-​alone assessment. Reliability among GCS scores in a patient can suffer when performed by inexperienced members of care team, particularly in regards to the motor score. Observing the motion of the elbow to central stimulation is crucial. Elbows typically move away from the body with purposeful movements and withdrawal compared to the elbow moving toward the trunk in abnormal flexion or extension responses.

Full Outline of Unresponsiveness The FOUR score was developed at Mayo Clinic and addresses some of the issues encountered with GCS scoring. The scale has been validated for use in emergency departments and ICUs with nurses and physicians alike. There are four testable components: eye movement, motor response, respiration, and brainstem reflexes. The FOUR score is distinguished from the GCS by the inclusion of items that assess nonverbal cues of consciousness such as voluntary eye movements and assessments for the intubated patient.

Brainstem reflexes 0 absent pupil, corneal, and cough 1 absent pupil and corneal 2 absent pupil or corneal 3 one pupil wide and fixed 4 pupil and corneal reflexes present

Initial Evaluation of Coma Coma is a medical emergency. As such, steps for assessment and management should occur simultaneously rather than in a step-​wise fashion (Figure 1.1).

Airway, Breathing, Circulation, and Cervical Spine Precautions As with any other medical emergencies, rapid assessment of a patient’s circulatory system, airway, and respiration is a crucial first step to preventing long-​term morbidity. Obtaining adequate intravenous access, appropriate resuscitation, and correction of other readily reversible electrolyte derangements are the initial steps of caring for the comatose patient. Implementation of Advanced Cardiac Life Support (ACLS) protocols take priority.

Coma and Low Arousal States

Verbal Response 1 None 2 Sounds 3 Words 4 Confused speech 5 Oriented Best Motor Response 1 None 2 Extension 3 Abnormal flexion 4 Withdrawal 5 Localizing 6 Obeying commands

Full Outline of Unresponsiveness Eye response 0 eyelids remain closed with pain 1 eyelids closed but open to pain 2 eyelids closed but open to loud voice 3 eyelids open but not tracing 4 eyelids open, tracking, or blinking to command Motor response 0 no response to pain or myoclonic status 1 extension response to pain 2 flexion response to pain 3 localizing to pain 4 thumbs-​up, fist, or peace sign Respiration 0 breathes at ventilator rate or apnea 1 breathes above ventilator rate 2 not intubated, irregular breathing 3 not intubated, Cheyne-​Stokes breathing 4 not intubated, regular breathing

Chapter 1

Glasgow Coma Scale Eye opening 1 None 2 To pressure 3 To speech 4 Spontaneous

9

Table 1.2 Coma Scales

Neurological Conditions

Coma Resuscitation, Focused history/exam, Stat labs

Section 1

Structural or Unclear

Nonstructural

CT

Diagnostic

Nondiagnostic

10

Vascular Imaging

MRI

EEG

Figure 1.1  Suggested algorithm for initial diagnosis of coma etiology.

Normalization of vital signs is crucial to ensure adequate perfusion of the brain. Hypoxia should be treated with supplemental oxygen. If airway protection is a concern and initial measures do not reverse coma, intubation should be performed without delay with in-​line cervical spine immobilization. Hypotension should be treated with Trendelenburg positioning (if elevated intracranial pressure is not suspected), fluids, and vasopressors. Extreme hypertension (systolic blood pressure > 250 mmHg or mean arterial pressure > 130 mmHg) should be treated with intravenous medications such as labetalol or hydralazine or use of antihypertensive drips such as nicardipine or clevidipine. In the setting of possible elevated intracranial pressure, care should be taken when treating blood pressure to avoid lowering of cerebral perfusion pressure below 60 mmHg. In general, a target mean arterial pressure of 85 mmHg or a decrease of approximately 15% is acceptable. Hyperthermia should be immediately corrected with cooling blankets or pads, cold saline bolus, or intravenous cooling catheters. For most patients, cervical spine precautions are appropriate in the immediate phase. If there is any possibility of traumatic injury, cervical immobilization should be part of the initial resuscitation effort.

Once the patient has been stabilized, assessment for structural or toxic/​metabolic etiology of coma is important. Gather as much information as possible regarding the onset, evolution, and associated symptoms as well as pertinent past medical history, drug abuse history, and medication list. A good general physical exam, including analysis of vital signs, can help narrow a differential diagnosis by suggesting a specific toxidrome, metabolic/​ endocrine derangement, or organ failure. The neurologic exam is focused on identifying a structural lesion versus diffuse neuronal dysfunction. This can usually be accomplished by assessing level of consciousness, orientation, cranial nerves, and motor responses. All assessments should be done off sedation when possible. Coma scales should be used to reliably communicate deficits and help identify changes on repeat exams.

Coma and Low Arousal States

General Physical and Neurologic Assessment

Chapter 1

An EKG early in assessment is helpful for evaluating a primary cardiopulmonary event and is almost always abnormal in a significant toxic exposure or electrolyte derangement.

Initial laboratory studies are aimed at discovering readily correctable metabolic and electrolyte derangements that could possibly reverse coma. A point-​of-​care glucose should be checked immediately. If a glucose meas­ urement is not available, consider empiric treatment with dextrose. In alcoholics or malnourished patients such as those with gastric bypass, empiric thiamine is warranted. Other initial laboratory tests should include a complete blood count and comprehensive metabolic panel (sodium, potassium, urea, creatinine). Depending on the history, additional studies such as calcium, magnesium, liver function panel, ammonia, urine and blood toxin screen (note: drug levels are more informative than a positive screen), serum osmolality, and arterial blood gases may be obtained. Derangements in these values should be relatively acute to cause a significant change in arousal. Chronic changes should prompt evaluation for another cause of coma. See Table 1.3 for laboratory values compatible with coma.

Table 1.3  Laboratory Values Compatible with Coma Hyponatremia Hypernatremia Hypercalcemia Hypermagnesemia Hypercapnia Hypoglycemia Hyperglycemia Note. Changes should be acute.

≤ 110 mmol/​L ≥160 mmol/​L ≥ 3.4 mmol/​L ≥ 5 µg/​L ≥ 70 mmHg ≤ 40 mg/​dL ≥ 800 mg/​dL

11

Laboratory Studies

Neurological Conditions Section 1

A history of panhypopituitarism, thyroid dysfunction, or chronic steroid use may alert examiners to the possibility of an endocrine derangement. Checking thyroid function evaluation for Hashimoto’s encephalitis may be warranted. In cases of suspected steroid deficiency, hypotension may not always be present, so assessing response to a stress dose of corticosteroids may be diagnostic. Autoimmune encephalopathies and central nervous system (CNS) malignancies (particularly CNS lymphoma) may also respond to steroids.

Imaging Cerebral imaging should be pursued unless there is rapid improvement in consciousness. To avoid additional injury, this should be obtained after stabilization of vital signs and correction of acute metabolic derangements. Computed tomography (CT) of the head is widely available and most useful for evaluating intracranial hemorrhage. CT angiography should be considered in all patients if there is any possibility that the patient’s exam is consistent with basilar occlusion. Nondiagnostic studies should then prompt consideration for vascular imaging or magnetic resonance imaging.

12

Electroencephalogram Patients with a history of epilepsy, seizure on presentation with treatment abolished motor symptoms, or coma otherwise unexplained after initial evaluation should be evaluated with EEG. Patients outside of the ICU should be initially evaluated with 20-​minute EEG to avoid delaying other evaluations and treatments. Any clinically apparent seizure or any patient with high pretest probability should be empirically treated if EEG is not readily available. Status epilepticus is common in critically ill patients and is often comorbid in the elderly with sepsis. Up to 20% of unresponsive patients in a general medical ICU may have an abnormal EEG that should be treated, and the majority of those patients have no clinical correlate to alert caregivers of seizure activity. Any patient who continues to be comatose despite treatment of presumed cause in the ICU should be monitored on continuous EEG for up to 48 hours.

Prognosis and Treatments for Coma and Low Arousal States Prognosis should not be attempted or commented on in the first 72 hours of coma. This timeline should be extended to 72 hours post-​rewarming for any patient undergoing therapeutic hypothermia. Aside from brain death and cardiac arrest (considered separately), no reliable metric is available for predicting if a patient will recover or how much recovery could be expected. The cause of coma clearly impacts the prognosis and natural history and can be broadly divided into traumatic and nontraumatic.

With increasing knowledge of pathways governing arousal, several pharmacologic treatments have been studied and shown to improve recovery in select patients. Generally, patients in persistent vegetative states are left with variable levels of disability despite treatment due to disruption of the arousal pathways. Patients in a minimally conscious state may respond better, although the recovery process can be prolonged. See Table 1.4 for commonly used pharmacological agents. Deep brain stimulation of thalamic nuclei and epidural spinal cord stimulation has limited data but in a minority of selected patients has been shown to improve outcomes. More study is required to elucidate pathways involved and identify patients who could benefit.

Table 1.4  Commonly used Pharmacologic Interventions for Coma and Low-​Arousal States Medication Amantadine Methylphenidate Modafinil Carbidopa/​levodopa

Mechanism of Action NMDA receptor antagonist, dopamine agonist Dopamine and norepinephrine receptor agonist Inhibits norepinephrine and dopamine transport; glutamate, serotonin, and histamine release Dopamine receptor saturation

Coma and Low Arousal States Chapter 1

Emerging Treatments

13

Drug-​induced coma generally has a good outcome if supportive care is instituted early and reversible derangements are addressed quickly. Mortality is relatively low for coma induced by epilepsy or poisoning (up to 7%) versus patients suffering from a neurovascular catastrophe or post-​anoxic injury (54%–​ 95%). The most common nontraumatic etiologies are stroke and post-​anoxic injury. Patients without recovery at one month are unlikely to demonstrate meaningful recovery and may be left with severe disability if unconsciousness improves. Traumatic coma is equally difficult to prognosticate early after injury. In contrast to nontraumatic causes, one month of coma does not suggest an inability to recover. Age, neurologic exam at one week, and initial postresuscitation GCS are the most prognostic factors. For severe traumatic brain injury that survives to the ICU, mortality still approaches 30%, with 22% achieving independence at six months.

Neurological Conditions Section 1

14

Further Reading Berger J. Stupor and Coma, 7th ed. Daroff R, Jankovic J, Mazziotta J, Pomeroy S, eds. Philadelphia: Elsevier; 2012. Bruno MA, Ledoux D, Lambermont B, et al. Comparison of the full outline of unresponsiveness and Glasgow Liege Scale/​Glasgow Coma Scale in an intensive care unit population. Neurocrit Care. 2011;15(3):447–​453. Edlow JA, Figaji A, Samuels O. Emergency neurological life support: subarachnoid hemorrhage. Neurocrit Care. 2017;27(1):116–​123. Edlow JA, Rabinstein A, Traub SJ, Wijdicks EFM. Diagnosis of reversible causes of coma. Lancet. 2014;384(9959):2064–​2076. Georgia M De, Raad B. Prognosis of coma after cardiac arrest in the era of hypothermia. Continuum. 2012;18(3):515–​531. Horsting MWB, Franken MD, Meulenbelt J, van Klei WA, de Lange DW. The etiology and outcome of non-​traumatic coma in critical care:  a systematic review. BMC Anesthesiol. 2015;15:65. Jennett B, Teasdale G, Braakman R, Minderhoud J, Heiden J, Kurze T. Prognosis of patients with severe head injury. Neurosurgery. 1979;4(4):283–​289. Lulé D, Zickler C, Häcker S, et al. Life can be worth living in locked-​in syndrome. Prog Brain Res. 2009;177:339–​351. Oddo M, Carrera E, Claassen J, Mayer SA, Hirsch LJ. Continuous electroencephalography in the medical intensive care unit. Crit Care Med. 2009;37(6):2051–​2056. Posner J, Saper C, Schiff N, Plum F. Plum and Posner’s Diagnosis of Stupor and Coma, 4th ed. Oxford: Oxford University Press; 2007. Rasmussen SA, Mazurek MF, Rosebush PI. Catatonia: our current understanding of its diagnosis, treatment and pathophysiology. World J Psychiatry. 2016;6(4):391–​398. Rousseau M-​C, Pietra S, Nadji M, Billette De Villemeur T. Evaluation of quality of life in complete locked-​in syndrome patients. Ann Phys Rehabil Med. 2012;55(Suppl. 1):e363. Shaibani A, Sabbagh MN. Pseudoneurologic syndromes: recognition and diagnosis. Am Fam Physician. 1998;57(10):2485–​2494. Teasdale G, Maas A, Lecky F, Manley G, Stocchetti N, Murray G. The Glasgow Coma Scale at 40 years: standing the test of time. Lancet Neurol. 2016;13(8):844–​854. Traub SJ, Wijdicks EF. Initial diagnosis and management of coma. Emerg Med Clin North Am. 2016;34(4):777–​793. Wijdicks EF. The Practice of Emergency and Critical Care Neurology. New York: Oxford University Press; 2010.

Chapter 2

Encephalopathy and Delirium Joshua Keegan and Colleen Moran

Although sometimes confused or used interchangeably, delirium and encephalopathy are distinct disorders. Delirium is defined as an acute, often reversible disturbance in attention (ability to direct, focus, sustain, and shift attention) that tends to fluctuate, is associated with additional changes in cognition, and occurs acutely over hours to days. This change must be a direct physiological consequence of another medical condition and not better explained as part of an evolving dementia. Encephalopathy, on the other hand, is a much broader term encompassing any brain damage or dysfunction and therefore does not necessitate changes in attention or significant acute fluctuations. Encephalopathy is extremely heterogeneous in nature and has numerous underlying causes, including a variety of metabolic causes, structural lesions, traumatic injuries, infection, hypoxic-​ ischemic injury, and medications. Consequently, risk factors, detection, and management vary with the underlying cause, and a comprehensive review is beyond the scope of this chapter. While delirious patients often have associated hallucinations, delusions, sleep disturbances, and abnormal psychomotor activity, none of these are necessary to make the diagnosis. Of note, delirium may be either hyperactive or hypoactive; hypoactive delirium in particular may be easily missed or misdiagnosed in intensive care unit (ICU) patients. Much of the knowledge base regarding delirium has been generated from medical and surgical ICUs, and thus extrapolation to neurological ICU (NICU) patients requires caution.

Prevalence and Relevance Delirium is quite common, in some studies affecting up to 80% of mechanically ventilated ICU patients and costing $4 billion to $16 billion annually. Delirium has been identified as an independent predictor of multiple negative outcomes, including increased mortality, cost, prolonged ICU and hospital length of stay, and long-​term cognitive impairment (although to some extent delirium may unmask or identify patients with pre-​existing limited cognitive reserve).

15

Definitions

Neurological Conditions Section 1

16

Risk Factors and Causes Although the pathophysiology of delirium is not well understood, multiple risk factors and causes have been identified, allowing practitioners to identify patients at high risk for development of delirium during their ICU stay. Significant risk factors identified include pre-​existing dementia, alcoholism, hypertension, coma, and high severity of medical illness at admission. Notably, although age is an independent delirium risk factor for non-​ICU patients, only two of six studies found it to be significant in ICU populations. Regardless of underlying risk factors, delirium may be caused or worsened by multiple contributors, including • Underlying or complicating disease o Sepsis o Organ dysfunction o Alcohol/​drug withdrawal o Withdrawal from analgesia and sedatives, including opiates and dexmedetomidine • Medication exposures o Opiates (most studies demonstrate no risk, but some do show an increase) o Benzodiazepines (several studies report strong effects while others show none) • Environmental factors o Physical restraints o Prolonged immobilization o Sleep disruption o Visual impairment o Hearing impairment Whenever possible, therapeutic interventions should be chosen so as to limit their delirium-​inducing potential.

Screening ICU personnel often underestimate the prevalence of delirium, particularly in its hypoactive form. Delirium detection is improved with the routine use of screening tools, and a variety of tools exist for this purpose. The Confusion Assessment Method for the ICU (CAM-​ICU) and Intensive Care Delirium Screening Checklist (ICDSC) have been found to be the most accurate (high sensitivity and specificity) and repeatable (high interrater reliability), and as such are the screening tools recommended by the American College of Critical Care Medicine. The CAM-​ICU is performed every shift, with the ICDSC performed every 24 hours; several studies exist demonstrating the

Treatment Often, treatment of ICU delirium with either typical or atypical antipsychotics occurs. Despite the frequency of this practice, data supporting it are limited, with no published evidence supporting treatment with haloperidol and very limited data suggesting that quetiapine may shorten duration of delirium, although at the expense of increased somnolence. Given the likelihood of polypharmacy and concurrent electrolyte imbalances, ruling out QTc prolongation via electrocardiogram prior to initiation of these medications should be undertaken. Statins may also have some effect on delirium, particularly in sepsis, via limitation of production of inflammatory mediators thought to play a role in delirium pathogenesis. One study found that statin use in the ICU on day one of sepsis was shown to decrease delirium; however, this study was not a randomized trial, and the criteria for initiation/​continuation of a statin were not reported.

Sedation and Delirium Sedation to minimize agitation and anxiety in the ICU setting is often desirable from a patient comfort perspective. However, sedatives may also cause or worsen delirium and result in multiple other complications. The type and amount of sedative used should be carefully considered to minimize these

Encephalopathy and Delirium

Given the significant morbidity and mortality associated with delirium, increasing interest in pharmacologic and nonpharmacologic methods of prevention has developed. Early mobilization has been found to decrease the prevalence and duration of delirium in the ICU by as much as 50%. Multicomponent protocols targeted toward reducing modifiable environmental risk factors for delirium have been shown to be helpful in non-​ICU settings, although they have not yet been studied in the ICU. Studies examining pharmacologic preventative strategies, including medications to maintain sleepwake cycles, use of haloperidol, and use of atypical antipsychotics have been fairly limited, and consequently no current recommendation regarding such approaches has been made. One large study in medical and surgical ICUs found that interruption of a previously prescribed statin also increased risk for delirium, and consequently continuing such medications may have preventative value.

Chapter 2

Prevention

17

feasibility of such screening. One important caveat specific to the neurologically impaired patient is that it can be difficult or impossible to perform the CAM-​ICU in aphasic patients.

Yes

Neurological Conditions 18

Section 1

negative effects. Of note, when a clear cause for agitation is identified (i.e., pain, urinary retention, hypoxia, ventilator dyssynchrony), correcting the underlying cause is often more effective and with fewer adverse effects. ICU patients frequently experience pain, and most sedatives have minimal analgesic effects. Consequently, a trial of analgesics, potentially including aceta­ minophen and nonsteroidal anti-​inflammatory agents, should be considered prior to administration of sedation. In a NICU-​specific population, using a protocolized analgesia-​first regimen did not change durations of ventilation, NICU, or hospital stay but improved patient alertness and decreased patient pain. A  sample of such a protocol can be found in Figure 2.1. Medications commonly used for sedation in the ICU include propofol, benzodiazepines (e.g., midazolam and lorazepam), dexmedetomidine, and, less frequently, ketamine and barbiturates. In recent years, there has been a greater shift toward avoiding benzodiazepines as they can exacerbate delirium. As previously mentioned, both sedative agent and amount should be chosen to minimize adverse effects. Ideally, the minimum dose necessary for the desired effect should be used, with frequent reassessment of this requirement

Tylenol 650 mg q4 PO/PR/IV PRN Fentanyl 25–50 mcg IV PRN

NeuroICU Protocol

>3 boluses/hr

Pain

Fentanyl infusion 25–50 mcg/hr Titrate up to 2 mcg/kg/hr (max 200 mcg/hr) No Monitor closely Hold sedation until Riker = 4 Restart sedation 50% lower

Riker < 4

Riker = 4

Sedation

Daily Sedation Interruption with SBT Restart Sedation 25% lower

Riker > 4 Propofol infusion 25 mcg/kg/hr Increase every 15 min by 20 mcg/kg/hr to Riker = 4 Triglycerides checked q72 hrs

Dexmedetomidine indications: Wean to extubate in agitated or delirious patient Wean to extubate with difficult airway

Figure 2.1  Sample neurologic ICU sedation protocol.

CAM-ICU qshift Minimize restraints Maximize daytime activity Consider Seroquel 25–100 mg q12 PRN or Haldol 1–2 mg IV if CAM-ICU+

Delirium

Specific Medications Benzodiazepines Benzodiazepines are centrally acting GABA agonists with anxiolytic, sedative, and amnestic effects; undesirable side effects include respiratory depression,

Encephalopathy and Delirium Chapter 2

19

as a patient’s underlying condition evolves. Two methods of achieving this goal are daily sedation interruptions and targeting light or minimal, rather than heavy, sedation. It should be noted that sedation interruptions may occur more often in the NICU, due to the paramount importance of reliable neurologic exams to guide patient care. However, particularly among patients with decreased cerebral compliance, sedation interruption may cause intracranial pressure (ICP) crises, significant swings in cerebral perfusion pressure, and critical decreases in brain tissue oxygenation, and therefore harm may outweigh benefit in certain patients. Maintaining light levels of sedation decreases the duration of mechanical ventilation and ICU stay. While this results in increased levels of physiological stress (i.e., elevated heart rate, blood pressure, increased catecholamines), no negative clinical outcomes (such as myocardial infarction) have been demonstrated. Studies of decreased sedation on psychological outcomes have varied, with some studies showing no or minimal negative psychological outcomes for sedation interruptions versus light sedation, respectively. One study demonstrated that light sedation was associated with greater recall and risk of perceiving the ICU experience negatively; however, another demonstrated more disturbing memories with deep sedation. Multiple studies comparing sedative agents exist, primarily comparing a benzodiazepine to either propofol or dexmedetomidine. A  review of two studies comparing propofol to benzodiazepines did not find a significant difference in delirium rates, and five studies comparing dexmedetomidine to benzodiazepines generally favored dexmedetomidine, although results were mixed. One multinational randomized controlled trial found a 22.6% absolute reduction in delirium rates with dexmedetomidine versus midazolam. In addition to their general effects on ICU patients, sedative medications have specific effects pertinent to neurological ICU patients. Sedatives often decrease the cerebral metabolic rate and may thereby limit ischemic damage in low-​flow regions as well as limiting ICP. Additionally, many sedatives including benzodiazepines, propofol, and ketamine have antiepileptic properties which may be desirable in patients who are seizure-​prone from a variety of neurological insults. Ultimately, many different options exist for the management of agitation. There is no ideal agent for all situations; specific agents are best chosen based on the underlying cause of agitation, with consideration of their pharmacology and side effect profiles. These effects particularly include the potential of these agents to cause or worsen delirium, a side effect which must be explicitly considered.

Neurological Conditions Section 1

20

hypotension, and increased delirium. They are primarily metabolized by the liver, and many have active metabolites prolonging their duration of action. When used for short-​term sedation, midazolam has a faster offset than lorazepam; however, studies regarding prolonged use have demonstrated a longer and more variable duration of action with midazolam, possibly from accumulation of these metabolites in peripheral tissues. Propylene glycol is a diluent for lorazepam and may result in toxicity with prolonged use at high doses.

Propofol Propofol acts on multiple central receptors including GABA, resulting in anx­ iolytic, sedative, amnestic, and hypnotic effects (the amnestic effects at light doses are less than with benzodiazepines). Propofol is very lipid-​soluble and rapidly redistributes to peripheral tissues, resulting in a rapid offset of effect with short-​term use, which may facilitate frequent neurologic exams in NICU patients. However, accumulation in these tissues may lead to prolonged duration with heavier use. Propofol is also associated with numerous adverse effects, including respiratory depression, vasodilation, negative inotropy, triglyceridemia, and pancreatitis. Triglyceride levels should be checked every 72 hours in patients treated with propofol infusions, and alternate treatments should be sought if levels become elevated. One of the most concerning adverse effects is propofol infusion syndrome, which has up to a 33% mortality rate. Risk of propofol infusion syndrome is elevated in younger patients on high rates of infusion (>60 mcg/​kg/​min). Earliest laboratory abnormalities include elevated CK and lactic acidosis.

Dexmedetomidine Dexmedetomidine is a hepatically metabolized centrally acting alpha-​2 agonist with primarily sedative effects; side effects include hypotension and bradycardia. As compared to other sedatives, it often results in a much more arousable patient and causes less respiratory depression; consequently, it is the only sedative infusion approved for use in nonintubated ICU patients. Additionally, dexmedetomidine may decrease opiate requirements.

Opioids Although not sedatives, opioid medications are very helpful for managing agitation secondary to pain. All opioids act via similar mechanisms, resulting in fairly similar benefits and side effects. However, patients may respond better to certain agents, particularly given incomplete cross-​tolerance with chronic use of other opioids. The majority of opioids cause hypotension through a histamine-​mediated pathway which is therefore not reversible with naloxone (which counteracts somnolence and respiratory depression from opioid toxicity). A specific opioid deserving additional discussion is fentanyl. Fentanyl is fast-​acting and generally fairly quick in offset, although tissue accumulation may occur with prolonged use due to its lipid-​soluble structure. As a completely synthetic opioid, fentanyl does not cause histamine release and therefore does

Further Reading American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Washington, DC: Author; 2013. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41:263–​306. Beretta L, De Vitis A, Grandi E. Sedation in neurocritical patients: is it useful? Minerva Anestesiol. 2011;77:828–​834. Devlin JW, Fong JJ, Fraser GL, Riker RR. Delirium assessment in the critically ill. Intensive Care Med. 2007;33:929–​940. Devlin JW, Roberts RJ, Fong JJ, et  al. Efficacy and safety of quetiapine in critically ill patients with delirium:  a prospective, multicenter, randomized, double-​ blind, placebo-​controlled pilot study. Crit Care Med. 2010;38:419–​427. Egerod I, Jensen MB, Herling SF, Welling KL. Effect of an analgo-​sedation protocol for neurointensive patients: a two-​phase interventional non-​randomized pilot study. Crit Care. 2010;14:R71. Helbok R, Kurtz P, Schmidt MJ, et al. Effects of the neurological wake-​up test on clinical examination, intracranial pressure, brain metabolism and brain tissue oxygenation in severely brain-​injured patients. Crit Care. 2012;16:R226. Inouye SK, Bogardus ST Jr, Charpentier PA, et  al. A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med. 1999;340:669–​676. Kress JP, Gehlbach B, Lacy M, Pliskin N, Pohlman AS, Hall JB. The long-​term psychological effects of daily sedative interruption on critically ill patients. Am J Respir Crit Care Med. 2003;168:1457–​1461.

Encephalopathy and Delirium

Delirium is common in the ICU, is often underrecognized, and is associated with significant morbidity and mortality. Providers should be aware of the variety of baseline and modifiable risk factors that have been elucidated, and, particularly in high-​risk populations, screening tools should be utilized to limit underdiagnosis. In accordance with available evidence , providers should attempt delirium prevention through environmental modifications such as sleep promotion, consideration of side effects when choosing medications, using the minimal levels of sedation necessary, and institution of early mobility. Limited data are currently available to guide effective pharmacologic treatments after delirium occurs, but quetiapine should be considered. Future research will hopefully further clarify safe and effective treatments for ICU delirium.

Chapter 2

Conclusion

21

not intrinsically generate in hypotension. However, hypotension after administration may still result in certain patients due to attenuation of a pain-​induced catecholamine response.

Neurological Conditions Section 1

22

Morandi A, Hughes CG, Thompson JL, et al. Statins and delirium during critical illness: a multicenter, prospective cohort study. Crit Care Med. 2014;42:1899–​1909. Needham DM, Korupolu R, Zanni JM, et al. Early physical medicine and rehabilitation for patients with acute respiratory failure: a quality improvement project. Arch Phys Med Rehabil. 2010;91:536–​542. Neto AS, Nassar AP Jr, Cardoso SO, et al. Delirium screening in critically ill patients: a systematic review and meta-​analysis. Crit Care Med. 2012;40:1946–​1951. Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA. 2009;301:489–​499. Samuelson KA, Lundberg D, Fridlund B. Stressful experiences in relation to depth of sedation in mechanically ventilated patients. Nurs Crit Care. 2007;12:93–​104. Schweickert WD, Pohlman MC, Pohlman AS, et  al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. Lancet. 2009;373:1874–​1882. Skoglund K, Enblad P, Marklund N. Effects of the neurological wake-​up test on intracranial pressure and cerebral perfusion pressure in brain-​injured patients. Neurocrit Care. 2009;11:135–​142. Spronk PE, Riekerk B, Hofhuis J, Rommes JH. Occurrence of delirium is severely underestimated in the ICU during daily care. Intensive Care Med. 2009;35:1276–​1280. Treggiari MM, Romand JA, Yanez ND, et al. Randomized trial of light versus deep sedation on mental health after critical illness. Crit Care Med. 2009;37:2527–​2534. Vasilevskis EE, Morandi A, Boehm L, et al. Delirium and sedation recognition using validated instruments: reliability of bedside intensive care unit nursing assessments from 2007 to 2010. J Am Geriatr Soc. 2011;59(Suppl. 2):S249–​255.

Chapter 3

Acute Ischemic Stroke Cynthia L. Kenmuir and Tudor G. Jovin

Early evaluation and treatment is critically important for obtaining good clinical outcomes in acute ischemic stroke (AIS). A brief history should include the patient’s last known well (LKW) time. Importantly, LKW must be distinguished from the time that symptoms were first noted. Level 1 evidence of benefit is available for intravenous (IV) thombolysis administered within four and a half hours from LKW and for endovascular therapy initiated within twenty-​four hours from LKW. For both treatment modalities a strong time dependency between treatment initiation relative to LKW and likelihood of obtaining a good outcome has been established. When evaluating the patient, vital signs including blood pressure (BP) and respiratory status should be monitored regularly. While BP management in AIS remains somewhat controversial, it is generally accepted that BP should not be acutely lowered during the initial assessment but should be maintained below systolic pressure of 220 mmHg and diastolic pressure of 120 mmHg. If a patient qualifies for IV thrombolysis, additional BP lowering may be necessary. The National Institutes of Health Stroke Scale (NIHSS) score (Table 3.1) is a universally used bedside tool that quantifies the severity of the neurological deficit in a quick and consistent manner. Once cardiopulmonary stability is confirmed, a noncontrasted computed tomography scan of the head (CTH) is essential in order to rule out intracerebral hemorrhage, determine extent of infarction, and rule out mass lesions or other potential conditions (e.g., subdural hematoma) that may render the patient ineligible for IV tissue plasminogen activator (tPA). The only laboratory study needed emergently for the purposes of IV tPA administration is serum glucose, with both hyper-​ and hypoglycemia addressed. In addition, if the patient has received heparin within 48 hours; has a known bleeding diathesis; or is taking warfarin, direct thrombin inhibitors, or other novel anticoagulant drugs, then prothrombin time (PT)/​international normalized ratio (INR), partial thromboplastin time (PTT), and platelet counts are needed. If eligibility for IV tPA has been confirmed, the drug should be mixed early to avoid treatment delays. In 2015 the Food and Drug Administration released an updated version of the prescribing information for IV tPA that eliminated many of the previously listed contraindications

23

Acute Management of Acute Ischemic Stroke

Table 3.1  National Institute of Health Stroke Scale Score Instructions 1a. Level of Consciousness: The investigator must choose a response if a full evaluation is prevented by such obstacles as an endotracheal tube, language barrier, orotracheal trauma/​bandages. A 3 is scored only if the patient makes no movement (other than reflexive posturing) in response to noxious stimulation.

1b. LOC Questions: The patient is asked the month and his/​her age. The answer must be correct—​there is no partial credit for being close. Aphasic and stuporous patients who do not comprehend the questions will score 2. Patients unable to speak because of endotracheal intubation, orotracheal trauma, severe dysarthria from any cause, language barrier, or any other problem not secondary to aphasia are given a 1. It is important that only the initial answer be graded and that the examiner not “help” the patient with verbal or nonverbal cues. 1c. LOC Commands: The patient is asked to open and close the eyes and then to grip and release the nonparetic hand. Substitute another one step command if the hands cannot be used. Credit is given if an unequivocal attempt is made but not completed due to weakness. If the patient does not respond to command, the task should be demonstrated to him or her (pantomime), and the result scored (i.e., follows none, one, or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-​step commands. Only the first attempt is scored. 2. Best Gaze: Only horizontal eye movements will be tested. Voluntary or reflexive (oculocephalic) eye movements will be scored, but caloric testing is not done. If the patient has a conjugate deviation of the eyes that can be overcome by voluntary or reflexive activity, the score will be 1. If a patient has an isolated peripheral nerve paresis (CN III, IV, or VI), score a 1. Gaze is testable in all aphasic patients. Patients with ocular trauma, bandages, pre-​existing blindness, or other disorder of visual acuity or fields should be tested with reflexive movements, and a choice made by the investigator.

Scale Definition 0 = Alert; keenly responsive. 1 = Not alert; but arousable by minor stimulation to obey, answer, or respond. 2 = Not alert; requires repeated stimulation to attend, or is obtunded and requires strong or painful stimulation to make movements (not stereotyped). 3 = Not alert; responds only with reflex motor or autonomic effects or totally unresponsive, flaccid, and areflexic. 0 = Answers both questions correctly. 1 = Answers one question correctly. 2 = Answers neither question correctly.

Score _​_​_​_​_​

0 = Performs both tasks correctly. 1 = Performs one tasks correctly. 2 = Performs neither tasks correctly.

_​_​_​_​_​

0 = Normal. 1 = Partial gaze palsy; gaze is abnormal in one or both eyes but forced deviation or total gaze paresis is not present. 2 = Forced deviation; or total gaze paresis not overcome by the oculocephalic maneuver.

_​_​_​_​_​

_​_​_​_​_​

Instructions Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a partial gaze palsy.

Scale Definition

Score

3. Visual: Visual fields (upper and lower quadrants) are tested by confrontation, using finger counting or visual threat, as appropriate. Patients may be encouraged, but if they look at the side of the moving fingers appropriately, this can be scored as normal. If there is unilateral blindness or enucleation, visual fields in the remaining eye are scored. Score 1 only if a clear-​cut asymmetry, including quadrantanopia, is found. If patient is blind from any cause, score 3. Double simultaneous stimulation is performed at this point. If there is extinction, patient receives a 1, and the results are used to respond to item 11. 4. Facial Palsy: Ask—​or use pantomime to encourage—​the patient to show teeth or raise eyebrows and close eyes. Score symmetry of grimace in response to noxious stimuli in the poorly responsive or noncomprehending patient. If facial trauma/​bandages, orotracheal tube, tape, or other physical barriers obscure the face, these should be removed to the extent possible.

0 = No visual loss. 1 = Partial hemianopia. 2 = Complete hemianopia. 3 = Bilateral hemianopia blind including cortical blindness).

_​_​_​_​_​

0 = Normal symmetrical movements. 1 = Minor paralysis (flattened nasolabial fold, asymmetry on smiling). 2 = Partial paralysis (total or near-​total paralysis of lower face). 3 = Complete paralysis of one or both sides (absence of facial movement in the upper and lower face). 0 = No drift; limb holds 90 (or 45) degrees for full 10 seconds. 1 = Drift; limb holds 90 (or 45) degrees, but drifts down before full 10 seconds; does not hit bed or other support. 2 = Some effort against gravity; limb cannot maintain (if cued) 90 (or 45) degrees, drifts down to bed, but has some effort against gravity. 3 = No effort against gravity; limb falls. 4 = No movement. UN = Amputation or joint fusion, explain: _​_​_​_​_​_​_​_​_​_​_​ 5a. Left Arm 5b. Right Arm

_​_​_​_​_​

5. Motor Arm: The limb is placed in the appropriate position: extend the arms (palms down) 90 degrees (if sitting) or 45 degrees (if supine). Drift is scored if the arm falls before 10 seconds. The aphasic patient is encouraged using urgency in the voice and pantomime, but not noxious stimulation. Each limb is tested in turn, beginning with the nonparetic arm. Only in the case of amputation or joint fusion at the shoulder, the examiner should record the score as untestable (UN), and clearly write the explanation for this choice.

_​_​_​_​_​​​

(continued )

Table 3.1 Continued Instructions 6. Motor Leg: The limb is placed in the appropriate position: hold the leg at 30 degrees (always tested supine). Drift is scored if the leg falls before 5 seconds. The aphasic patient is encouraged using urgency in the voice and pantomime, but not noxious stimulation. Each limb is tested in turn, beginning with the nonparetic leg. Only in the case of amputation or joint fusion at the hip, the examiner should record the score as untestable (UN), and clearly write the explanation for this choice.

7. Limb Ataxia: This item is aimed at finding evidence of a unilateral cerebellar lesion. Test with eyes open. In case of visual defect, ensure testing is done in intact visual field. The finger-​nose-​finger and heel-​shin tests are performed on both sides, and ataxia is scored only if present out of proportion to weakness. Ataxia is absent in the patient who cannot understand or is paralyzed. Only in the case of amputation or joint fusion, the examiner should record the score as untestable (UN), and clearly write the explanation for this choice. In case of blindness, test by having the patient touch nose from extended arm position. 8. Sensory: Sensation or grimace to pinprick when tested, or withdrawal from noxious stimulus in the obtunded or aphasic patient. Only sensory loss attributed to stroke is scored as abnormal and the examiner should test as many body areas (arms [not hands], legs, trunk, face) as needed to accurately check for hemisensory loss. A score of 2, “severe or total sensory loss,” should only be given when a severe or total loss of sensation can be clearly demonstrated. Stuporous and aphasic patients will, therefore, probably score 1 or 0. The patient with brainstem stroke who has bilateral loss of sensation is scored 2. If the patient does not respond and is quadriplegic, score 2. Patients in a coma (item 1a = 3) are automatically given a 2 on this item.

Scale Definition 0 = No drift; leg holds 30 degree position for full 5 seconds. 1 = Drift; leg falls by the end of the 5-​second period but does not hit bed. 2 = Some effort against gravity; leg falls to bed by 5 seconds, but has some effort against gravity. 3 = No effort against gravity; leg falls to bed immediately. 4 = No movement. UN = Amputation or joint fusion, explain: _​_​_​_​_​_​_​_​_​_​_​ 5a. Left Leg 5b. Right Leg 0 = Absent. 1 = Present in one limb. 2 = Present in two limbs. UN = Amputation or joint fusion, explain: _​_​_​_​_​_​_​_​_​_​_​_​

Score _​_​_​_​_​​​

0 = Normal; no sensory loss. 1 = Mild-​to-​moderate sensory loss; patient feels pinprick is less sharp or is dull on the affected side; or there is a loss of superficial pain with pinprick, but the patient is aware of being touched. 2 = Severe to total sensory loss; patient is not aware of being touched in the face, arm, and leg.

_​_​_​_​_​

_​_​_​_​_​

9. Best Language: A great deal of information about comprehension will be obtained during the preceding sections of the examination. For this scale item, the patient is asked to describe what is happening in the attached picture, to name the items on the attached naming sheet, and to read from the attached list of sentences. Comprehension is judged from responses here, as well as to all of the commands in the preceding general neurological exam. If visual loss interferes with the tests, ask the patient to identify objects placed in the hand, repeat, and produce speech. The intubated patient should be asked to write. The patient in a coma (item 1a = 3) will automatically score 3 on this item. The examiner must choose a score for the patient with stupor or limited cooperation, but a score of 3 should be used only if the patient is mute and follows no one-​step commands. 10. Dysarthria: If patient is thought to be normal, an adequate sample of speech must be obtained by asking patient to read or repeat words from the attached list. If the patient has severe aphasia, the clarity of articulation of spontaneous speech can be rated. Only if the patient is intubated or has other physical barriers to producing speech, the examiner should record the score as untestable (UN), and clearly write an explanation for this choice. Do not tell the patient why he or she is being tested. 11. Extinction and Inattention (formerly Neglect): Sufficient information to identify neglect may be obtained during the prior testing. If the patient has a severe visual loss preventing visual double simultaneous stimulation, and the cutaneous stimuli are normal, the score is normal. If the patient has aphasia but does appear to attend to both sides, the score is normal. The presence of visual spatial neglect or anosagnosia may also be taken as evidence of abnormality. Since the abnormality is scored only if present, the item is never untestable. https://​www.ninds.nih.gov/​sites/​default/​files/​NIH_​Stroke_​Scale.pdf

0 = No aphasia; normal. 1 = Mild-​to-​moderate aphasia; some obvious loss of fluency or facility of comprehension, without significant limitation on ideas expressed or form of expression. Reduction of speech and/​or comprehension, however, makes conversation about provided materials difficult or impossible. For example, in conversation about provided materials, examiner can identify picture or naming card content from patient’s response. 2 = Severe aphasia; all communication is through fragmentary expression; great need for inference, questioning, and guessing by the listener. Range of information that can be exchanged is limited; listener carries burden of communication. Examiner cannot identify materials provided from patient response. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 0 = Normal. 1 = Mild-​to-​moderate dysarthria; patient slurs at least some words and, at worst, can be understood with some difficulty. 2 = Severe dysarthria; patient’s speech is so slurred as to be unintelligible in the absence of or out of proportion to any dysphasia, or is mute/​ anarthric. UN = Intubated or other physical barrier, explain: _​_​_​_​_​_​_​_​_​_​_​_​

_​_​_​_​_​

0 = No abnormality. 1 = Visual, tactile, auditory, spatial, or personal inattention or extinction to bilateral simultaneous stimulation in one of the sensory modalities. 2 = Profound hemi-​attention or extinction to more than one modality; does not recognize own hand or orients to only one side of space.

_​_​_​_​_​

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Neurological Conditions SECTION 1

28

and warnings that were not considered to be grounded in evidence. In response to these changes, in 2016, the American Heart Association released new guidelines for IV thrombolysis with a thorough evidence-​based review of each potential inclusion and exclusion criterion. The new guidelines have eased many of the previous exclusion criteria as follows. IV tPA inclusion criteria:

• Diagnosis of ischemic stroke causing measurable disabling neurological deficit • Treatment can begin within four and a half hours of LKW • Age >18 years IV tPA exclusion criteria:

• Sustained elevated BP (systolic >185 mmHg or diastolic >110 mmHg). Eligible for tPA if BP can be stabilized below 185/​110. Goal for first 24 hours after tPA is below 180/​105. • Blood glucose concentration 15 sec, current use of direct thrombin or factor Xa inhibitor within the past 48 hours with elevated active PTT, INR, platelet count, ecarin clotting time, thrombin time, or factor Xa activity assay. IV tPA additional precautions (determination to be made by a physician with expertise in stroke care):

• Active internal bleeding or recent major surgery/​arterial puncture at a noncompressible site • Recent major trauma, stroke, or myocardial infarction • Previous intracranial hemorrhage not including microhemorrhages, severe head trauma within three months, or intracranial surgery within three months • Intracranial neoplasm or unruptured arteriovenous malformation (AVM) aneurysm • Pregnancy • Seizure at onset The risk of symptomatic intracranial hemorrhage associated with IV tPA treatment in stroke mimics like complicated migraine and seizure has been estimated as 94%. A bedside dysphagia screen should be performed prior to oral intake, and a temporary nasogastric tube may be required. Formal swallowing evaluation by a speech therapist should be performed prior to considering percutaneous gastric tube placement. Euvolemia should be maintained with isotonic crystalloids, and any arrhythmia suspected to lower cardiac output should be corrected. Dextrose-​containing fluids are not recommended due to the risk of hyperglycemia, which has been associated with poor outcomes. Hypoglycemia (glucose 38ºC should be treated with antipyretic medications and/​or surface cooling. Sources of hyperthermia should be investigated and suspected infections treated with appropriate antibiotics. Anemia should be avoided, as should transfusions unless hemoglobin is less than 7 mg/​100 ml3. While clinical seizures should be treated with appropriate medications, prophylactic antiseizure medications are not recommended. Pharmacologic prophylaxis for deep venous thrombosis of immobilized patients should be initiated on admission. Aspirin should be administered within 48 hours of symptom onset if not otherwise contraindicated. Hypertension should be cautiously managed in the patient with AIS. Systemic hypertension in AIS is a compensatory mechanism to preserve cerebral perfusion, and aggressive BP reduction has been shown to worsen outcomes. For patients who have not received IV or intra-​ arterial (IA) thrombolysis, the current guideline is to allow permissive hypertension if tolerated up to systolic BP 220 mmHg and diastolic BP 120 mmHg, and it may be reasonable to consider gradual reduction of BP by up to 15% over the first 24 hours. In the case of large vessel occlusive disease not amenable to endovascular therapy, BP augmentation may be considered beginning with conservative treatments like an IV fluid bolus and supine body position. Although there is limited evidence to support BP augmentation in AIS, in some centers more aggressive BP support with IV vasopressors is temporarily used to improve cerebral perfusion pressure and thus prevent progression of ischemia.

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Table 3.2  Radiographic Classification of the Spectrum of Hemorrhagic Transformation Hemorrhagic Classification Hemorrhagic infarction type 1 (HI1) Hemorrhagic infarction type 2 (HI2) Parenchymal hematoma type 1 (PH1) Parenchymal hematoma type 2 (PH2)

Radiographic Appearance Small hyperdense petechiae More confluent hyperdensity throughout the infarct zone; without mass effect Homogenous hyperdensity occupying 30% of the infarct zone; significant mass effect. Or, any homogenous hyperdensity located beyond the borders of the infarct zone

if needed (e.g., nicardipine or clevidipine). An emergent noncontrasted CTH should be obtained with any change in neurologic exam, new headache, acute increase in BP, or vomiting. Repeat head imaging is recommended 24 hours after IV tPA administration to assess for the presence of intracranial hemorrhage (Table 3.2) or large territorial infarction prior to initiating antiplatelet or anticoagulation therapy. Symptomatic intracranial hemorrhage (ICH; defined as NIHSS increase of 4 points or higher) is estimated to occur in up to 6% of patients treated with IV tPA and usually occurs within the first 24 hours. If ICH is suspected, emergent blood samples for complete blood count, PT/​ PTT/​INR, type and screen, and fibrinogen should be collected in addition to obtaining an emergent CTH. Although there is no current universal guideline for reversal of IV tPA in the setting of acute hemorrhage, a reasonable approach includes aggressive BP reduction below 140/​90 and the use of cryoprecipitate for fibrinogen 180 mmHg within the first 12 hours have been

Acute Ischemic Stroke Chapter 3

33

A reasonable systolic BP cap in the absence of evidence could be between 140 and 180 mmHg depending on the resulting angiographic reperfusion and/​or the presence of any untreated large vessel stenosis. In general, if reperfusion is complete, a lower BP cap is recommended. Additionally, the puncture site should be inspected for signs of developing hematoma or frank hemorrhage, and peripheral pulses distal to the puncture site should be assessed. BP and heart rate should be closely monitored for signs of instability. Relative hypotension, pallor, lightheadedness, chest pain, or shortness of breath can be early signs of blood loss from a retroperitoneal hemorrhage after a high femoral puncture. If a retroperitoneal hemorrhage is suspected, pressure should be held at the arterial site and the patient should be hemodynamically stabilized, including crystalloid and/​ or blood cell transfusion, before obtaining CT imaging of the abdomen/​pelvis with CT angiography of the femoral vessels. Occasionally, severe retroperitoneal hemorrhages and/​or pseudoaneurysm formation may require acute vascular surgery intervention. Similar to the care of AIS patients treated with IV thrombolytics, close neurological monitoring of the post–​endovascular treatment patient is required to allow early detection of post–​endovascular treatment complications such as parenchymal hematoma, vessel reocclusion, and in cases of large infarcts malignant edema with secondary deterioration due to brain swelling and herniation. Hemorrhagic complications may be managed with reversal of antithrombotic agents (if any were used), strict BP control, and neurosurgical evacuation. Reocclusion may at times require reintervention if the size of the infarct is acceptably small.

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In addition to avoiding hyperglycemia, hyperthermia, anemia, and hypoxemia as described here, avoiding hypercarbia and consequently cerebral vasodilation is critical for patients at increased risk of developing malignant edema. If intubation and mechanical ventilation are required, sedation should be minimized when possible to maintain the neurologic examination. Minimally sedating agents like dexmedetomidine are preferred if needed for patient comfort. The head of the bed can be elevated to 20º to 30º to encourage venous drainage. Pharmacologic deep venous thrombosis prophylaxis is encouraged, though anticoagulation should be discontinued with an INR goal of 320 mOsm/​kg and a persistent elevation in the osmolar gap. The use of mannitol is generally reserved as a temporary ICP-​lowering measure prior to surgical decompression. Hypertonic saline has also been shown to reduce ICP in patients with clinically suspected transtentorial herniatiation. Hypertonic saline is commonly administered for ICP reduction as a 30 cc IV bolus of 23.4% saline, a 250 cc bolus of 3% saline, or as a continuous infusion of 3% saline. A  goal sodium range should be established (typically 140–​150 mEq/​L), and treatment titrated to maintain that goal. Care should be taken to maintain euvolemia when administering osmotic agents as mannitol is a potent diurectic and can cause hypovolemia while hypertonic saline is a volume expander and can cause hypervolemia and exacerbated heart failure. Notably, no data exists comparing dosing regimens of these osmotic agents, so institutional protocols should be followed when available. Hyperventilation with a goal PaCO2 of 30 to 35 mmHg can also be used in the intubated patient as a temporizing measure to reduce ICP prior to decompressive surgery. Intravenous glyburide may improve outcomes and reduce mortality when administered to patients with large ischemic infarcts

34

associated with malignant edema. Although serial CTH scans are commonly used to monitor edema progression after large territorial infraction, currently there is no data to support this practice. Within the first six hours, an infarct volume of >82cc on MRI diffusion weighted imaging (DWI) and within 14 hours after stroke onset an infarct volume of >145cc on DWI are strongly predictive of malignant edema. Early CTH scan with large hypodensity or absence of perfusion in two-​thirds of the MCA territory have also been associated with increased risk of herniation.

Management of Edema

Further Reading Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-​PA versus t-​PA alone for stroke. N Engl J Med. 2013;368:893–​903. CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: randomised placebo-​ controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet. 1997;349:1641–​1649. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scientific rationale for the inclusion and exclusion criteria for intravenous Alteplase in acute ischemic stroke: a statement for healthcare professionals from the American Heart Association/​American Stroke Association. Stroke. 2016;47:581–​641.

Acute Ischemic Stroke

Decompressive craniectomy can be life saving for patients with malignant cerebral edema. A 2007 pooled analysis of three randomized controlled trials showed a significant mortality benefit (78% medical management, 29% surgical management—​absolute risk reduction 50%) of decompressive surgery for patients 60 years old or younger with large hemispheric infarction who developed a decrease in their level of arousal within 48 hours. The number needed to treat for survival irrespective of functional outcome was two (four for survival with modified Rankin Scale 1 mm in the subarachnoid space was predictive of vasospasm. However, Fisher grade 4, which denotes the presence of intraparenchymal or intraventricular hemorrhage without thick SAH, appears to have lower vasospasm risk. As a result, a modified Fisher scale was later developed and is now more commonly used (Table 5.2).

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Table 5.1  SAH Clinical Brading Scales Grade

I II

III IV V

Hunt and Hess

World Federation of Neurological Surgeons

Asymptomatic, mild headache, slight nuchal rigidity Moderate to severe headache, nuchal rigidity, no neurological deficit except cranial nerve palsy Drowsiness, confusion, mild focal deficit Stupor, moderate to severe hemiparesis Coma, decerebrate posturing

GCS

Motor Deficit

15

Absent

14–​13

Absent

14–​13 12–​7 6–​3

Present Present or absent Present or absent

GCS = Glasgow Coma Scale.

46

Acute SAH Management Immediate SAH management includes delivery of any emergent critical care necessary to ensure the patient has adequate airway, breathing, and circulation, and the prevention or treatment of any impending cardiopulmonary collapse. It is equally important to diagnose and treat any ongoing or impending hyperacute neurological deterioration due to acute hydrocephalus and/​or aneurysm rebleeding.

Hydrocephalus Acute hydrocephalus is a well-​known complication of SAH. Hydrocephalus is a clinical diagnosis and should be considered in any SAH patient with unexplained impaired consciousness. Treatment of acute symptomatic hydrocephalus with urgent insertion of external ventricular drain or CSF diversion is Table 5.2  SAH Radiographic Grading Scales Grade 0 1 2 3 4

Fisher n/​a No blood Diffuse deposition or vertical layer of SAH 1 mm thick IPH or IVH with diffuse or no subarachnoid blood

Modified Fisher No SAH or IVH Focal or diffuse SAH 1 mm, with IVH

SAH = subarachnoid hemorrhage; IVH = intraventricular hemorrhage; IPH = intraparenchymal hemorrhage.

Aneurysm Treatment Definitive treatment with complete obliteration of the bleeding aneurysm after SAH should be performed as early as possible. Typical treatments include open surgical clipping and endovascular coil embolization of the aneurysm. Choice of the optimal modality of aneurysm treatment depends on aneurysm factors such as size, morphology, location, as well as patient factors such as periprocedural risk and comorbidities. One large prospective randomized trial compared aneurysm clipping to coil embolization in patients clinically amendable to either modality and showed no significant difference in mortality rate at one year (8.1%–​10.1%) but greater disability with open surgical approach (21.6% vs. 15.6%). In contrast, the coil embolization group had higher rebleeding rate (2.9% vs. 0.9%) and a higher incidence of needing additional aneurysm treatments. At this time, aneurysm management is determined based on institutional preferences and feasibility with increasing use of endovascular techniques.

Early Brain Injury, Cerebral Vasospasm, and Delayed Cerebral Ischemia Angiographic vasospasm occurs in 30% to 70% of all SAH patients, typically starting three to five days post-​SAH ictus, achieving maximal narrowing at 5 to 14 days post-​SAH, and resolves over two to four weeks.

Subarachnoid Hemorrhage

Aneurysm rebleeding is associated with high mortality and morbidity. Risk for aneurysm rebleeding is greatest in the first 2 to 12 hours after SAH and may be as high as 13.6% within the first 24 hours. Following the first 24 hours, if the aneurysm is not obliterated, the SAH rebleeding risk goes up cumulatively over time, increasing by 1% to 2% per day up to 20% to 30% for the first month. Urgent treatment and obliteration of the bleeding cerebral aneurysm is the best way to decrease rebleeding risk following SAH. Prior to definitive treatment of the bleeding cerebral aneurysm, possible medical interventions to minimize the risk of rebleeding include strict blood pressure control, bed rest, and antifibrinolytic therapies such as aminocaproic acid or tranexamic acid infusion. Bed rest alone is not sufficient to prevent aneurysm rebleeding. While studies show conflicting results on blood pressure control and risk of rebleeding, it is generally recommended to maintain good control to avoid both hypertension and hypotension. There are conflicting data on the utility of antifibrinolytic therapy. While there is some evidence that short-​term use may reduce risk of early aneurysm rebleeding, prolonged use is not recommended due to increased risk of thrombotic events.

Chapter 5

Re-​bleeding Risk

47

generally associated with neurological improvement. Lumbar drainage of CSF in SAH-​related hydrocephalus is reported to be safe and may be associated with early improvement but does not improve long-​term SAH outcome.

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48

Approximately half of all patients develop delayed neurological ischemic deficit, which may resolve or progress to cerebral infarction. Despite maximal therapy, 15% to 20% of SAH patients will develop ischemic infarcts or die from vasospasm. The pathogenesis and potential therapy for cerebral vasospasm has been the focus of intense research for decades. For many years, clinicians and scientists focused on the hypothesis that narrowing of cerebral vessels, or cerebral vasospasm, leads to cerebral ischemia and that is the main pathophysiologic process in SAH-​associated brain injury. Recent data and clinical trial results now suggest that while severe vasospasm may lead to ischemic infarction in SAH, the pathogenesis of SAH-​associated brain injury is multifactorial. Cohort studies and clinical trials have not shown a consistent association between angiographic vasospasm and SAH outcome. In fact, only 50% of patients with vasospasm may show corresponding symptoms of cerebral ischemia, while some patients with severe angiographic vasospasm may not demonstrate any symptoms of ischemia. Diagnosis of delayed cerebral ischemia (DCI) can be problematic for several reasons. By definition, DCI is a decline in neurologic function attributable to ischemia from cerebral vasospasm with other etiologies excluded. There is inherent ambiguity in such a definition in a heterogeneous and critically ill patient population. Neurologic examinations are of limited sensitivity to detect DCI in poor clinical grade SAH patients due to their poor baseline neurologic function to begin with, and yet these patients are in fact the highest risk population for DCI and poor outcome after SAH. Current practice and treatment protocols for vasospasm and DCI surveillance vary between individuals and institutions; this lack of a standardized approach is partly due to limited sensitivity and specificity in detecting impending vasospasm related ischemic brain injury. More advanced monitoring and surveillance methods such as the use of biomarkers and multimodal monitoring are under investigation, but there is yet limited data on the efficacy and utility of these novel methods. While DCI is consistently shown to predict death and disability in SAH clinical trials, there is no clear evidence that treatment and resolution of angiographic vasospasm is associated with incidence of DCI or with SAH outcome. Prophylactic hypervolemia and cerebral angioplasty aimed to prevent vasospasm do not improve outcome and may cause increased morbidity. To date, oral nimodipine 60 mg administered every four hours for 21 days is the only therapy that has been shown to improve SAH functional outcome in a prospective randomized clinical trial. However, the same trial showed that nimodipine did not reduce the incidence of angiographic vasospasm, suggesting that the beneficial effects of nimodipine may be mediated mechanisms unrelated to vasospasm. Similarly, many drugs that are efficacious in reducing angiographic cerebral vasospasm did not improve SAH outcome in clinical trials. These include L-​type calcium channel blockers such as nicardipine and endothelin receptor 1A antagonists such as clozosentan.

Systemic Complications and Critical Care Management Considerations Seizures and Seizure Prevention The diagnosis of seizures in SAH can be complicated because patients may manifest seizure-​like motor movements or posturing at the time of the aneurysm rupture that may be secondary to a sudden increase in intracranial pressure and/​or direct brain compression from acute aneurysm rupture. In a patient with known SAH who has not yet had the bleeding cerebral aneurysm(s) secured, a clinical seizure event often represents aneurysm re-​ rupture and may require emergent management. Furthermore, up to 20% of comatose SAH patients may experience nonconvulsive seizures that have no or very subtle clinical manifestation and can only be reliably detected using continuous EEG monitoring. Clinical seizures are uncommon in SAH, affecting only 1% to 7% of patients. Risk factors for developing seizures in SAH include thick subarachnoid clot, open surgical aneurysm repair in patients >65 years of age, and presence of intraparenchymal hematoma or cerebral infarction. Whether anticonvulsants should be used for seizure prophylaxis in SAH remains controversial. Some studies found that anticonvulsant use in SAH patients with secure aneurysms is associated with worse outcome. It should be noted that most of the SAH patients in these studies were exposed to phenytoin and there is limited data on the use of other anticonvulsants and SAH outcome.

Subarachnoid Hemorrhage Chapter 5

49

Potentially neuroprotective agents such as statins and high dose magnesium started within 96 hours of SAH also did not improve SAH outcome in large phase III clinical trials. Oral nimodipine remains the only medication recommended in SAH for potential reduction of DCI. Historically, clinicians treated vasospasm and DCI with “triple-​ H” therapy—​h ypertension, hypervolemia, and hemodilution—​with or without endovascular rescue therapy (endovascular injection of vasodilators and/​or angioplasty). No large randomized trials have been conducted to evaluate the efficacy of triple-​H therapy. Two prospective randomized trials showed that prophylactic hypervolemic therapy did not improve cerebral blood flow or outcome of SAH, but it was associated with increased incidence of pulmonary edema. Most recent guidelines from the American Heart Association and the Neurocritical Care Society recommend that treatment of DCI includes maintenance of euvolemia, prevention hypovolemia, and hemodynamic augmentation by inducing hypertension. For patients who do not respond to hemodynamic augmentation or with sudden focal neu­ rological deficits attributable to the vascular territory with visible vasospasm, endovascular injection of vasodilators and/​or angioplasty may lead to clinical improvement.

Neurological Conditions SECTION 1

Fever is highly prevalent after SAH and may occur in up to 72% of patients. Risk factors for fevers include poor-​grade SAH, more blood in the subarachnoid space, and intraventricular blood. While several retrospective studies in SAH found that fever is independently associated with more cerebral infarction and poor outcome there is currently no clear data to suggest a beneficial effect of fever suppression on SAH outcome. Despite this, many centers do practice fever suppression in SAH given the connection between fever and poor outcome. Acetaminophen and ibuprofen alone are not very effective in SAH-​related fever suppression. Continuous infusions of nonsteroidal anti-​ inflammatory drugs (NSAIDS) may be more effective than oral agents, but there is a concern that the antiplatelet effects of NSAIDs may worsen intracranial bleeding in patients who undergo craniotomy. Surface and intravascular cooling devices are often used in temperature management in SAH patients, and they are more effective than oral antipyretics in fever suppression. There is no data on the effect of antipyretic use or cooling device use and clinical outcome in SAH. Systemic inflammatory response syndrome (SIRS), which includes fever/​h ypothermia, leukocytosis/​leukopenia, tachycardia, and tachypnea, is prevalent in SAH. In addition to fever, leukocytosis is common in SAH and is associated with increased mortality, vasospasm, and poor outcome. Spontaneous hyperventilation is also common in SAH, found in up to 55% of patients, and is associated with DCI and poor SAH outcome. One large prospective randomized trial found up to 63% of SAH patients met SIRS criteria within four days of presentation. Several studies showed that SIRS burden is associated with vasospasm and poor SAH outcome. SIRS in SAH is mostly of noninfectious etiology. There is limited data to determine whether SIRS is simply a symptom of more severe SAH or if it in fact worsens brain injury in SAH.

50

In patients with no history of seizure, 72 hours of anticonvulsant prophylaxis appears as effective in preventing seizures as a more prolonged course. While there is no data, expert consensus states that SAH patients who have had a clinical seizure should be treated with anticonvulsants and that anticonvulsants should be discontinued if patients remain seizure free for three to six months. The Neurocritical Care Society SAH treatment guideline recommends against the routine use of phenytoin for seizure prophylaxis in SAH.

Fever and Systemic Inflammatory Response

Neurogenic Cardiac and Pulmonary Injuries Commonly referred to as “neurogenic stress cardiomyopathy” or “neurogenic stunned myocardium,” cardiac dysfunction and injury is common following SAH. Approximately 35% SAH patients have troponin I elevation, 35% suffer arrhythmias, and 25% have cardiac wall motion abnormalities. Cardiac injury following SAH is generally not due to coronary ischemia but rather

Subarachnoid Hemorrhage Chapter 5

thought to result from catecholamine surge secondary to SAH. Clinically, neurogenic stunned myocardium demonstrates a wide spectrum of severity, from elevated cardiac biomarkers, dyspnea, hypoxemia, and pulmonary edema to cardiogenic shock and even sudden death. This syndrome may develop within hours of SAH onset and typically lasts one to three days, after which cardiac function generally returns to pre-​SAH baseline. Treatment of choice is supportive critical care to maintain adequate blood pressure, cerebral perfusion, and cerebral oxygen delivery. Symptomatic pulmonary dysfunction including pulmonary edema, acute lung injury, and acute respiratory distress syndrome occur in over 20% of SAH patients. Pulmonary edema can occur in the absence of cardiac dysfunction and is referred to as “neurogenic pulmonary edema.” The pathophysiology of neurogenic pulmonary edema remains controversial, and treatment is supportive critical care to maintain adequate oxygen delivery to the brain and other end organs while avoiding hypovolemia, which may worsen secondary brain injury following SAH.

Hyponatremia occurs in up to 50% of all SAH patients. The key to managing hyponatremia in SAH lies in the accurate determination of the patient’s intravascular volume and careful management to avoid hypovolemia. Both syndrome of inappropriate secretion of antidiuretic hormones (SIADH) and cerebral salt wasting may occur in SAH, and sometimes the two syndromes may coexist. Diagnosis of SIADH can only be made if the patient is intravascularly euvolemic or mildly hypervolemic. Cerebral salt wasting, on the other hand, requires hypovolemia in addition to excessive urine output. Hyponatremia treated with fluid restriction is associated with poor SAH outcome. This likely reflects the detrimental effect of hypovolemia on SAH outcome. With adequate fluid resuscitation, there is no evidence that hyponatremia alone confers poor SAH prognosis. Fludrocortisone and hydrocortisone may mitigate excessive natriuresis and hyponatremia and reduce the volume of fluids needed to maintain euvolemia in SAH. Clinicians should anticipate and treat potential side effects such as hypokalemia related to mineralocorticoid use and hyperglycemia related to corticosteroid use. Clinical studies did not suggest any increase in incidence of congestive heart failure associated with hydrocortisone or fludrocortisone use in SAH with hyponatremia and excessive natriuresis. Use of a 3% hypertonic sodium chloride solution in SAH-​associated hyponatremia may be safe, but there is not enough data to determine its efficacy. Vasopressin-​ receptor antagonists should be used with extreme caution in treating SAH-​ related hyponatremia. While they are effective in treating euvolemic and hypervolemic hyponatremia, their use can be associated with significant diuresis that may lead to intravascular hypovolemia and worsen SAH outcome, particularly in the presence of vasospasm and DCI.

51

Hyponatremia and Intravascular Volume

Neurological Conditions SECTION 1

Anemia and Transfusion SAH-​associated anemia occurs in over half of all SAH patients, and 80% of all anemic SAH patients have hemoglobin below 11 g/​dl. The pathophysiologic mechanism of SAH-​associated anemia is poorly understood. The transfusion threshold in SAH patients, particularly those with vasospasm and DCI, has been an issue of debate because cerebral oxygen delivery is determined by cerebral blood flow and arterial oxygen content, which is dependent on hemoglobin concentration. Retrospective studies have demonstrated that an increase in hemoglobin from 8 to 10 g/​dl increases cerebral oxygen delivery and that higher hemoglobin concentration is associated with good SAH outcome. However, transfusion in critically ill patients is associated with deleterious effects such as infection, and small studies in SAH showed red blood cell transfusion may be associated with infection, vasospasm, and poor outcome. Currently, the appropriate target hemoglobin for SAH patients is undetermined. A pilot randomized trial to test liberal versus conservative transfusion strategies is ongoing.

52

Further Reading Allen GS, Ahn HS, Preziosi TJ, et  al. Cerebral arterial spasm—​ a controlled trial of nimodipine in patients with subarachnoid hemorrhage. N Engl J Med. 1983;308(11):619–​624. Connolly ES, Rabinstein AA, Carhuapoma JR, et  al. Guidelines for the management of aneurysmal subarachnoid hemorrhage:  a guideline for healthcare professionals from the American Heart Association/​ American Stroke Association. Stroke. 2012;43(6):1711–​1737. Diringer MN, Bleck TP, Connolly ES, et  al. Critical care management of patients following aneurysmal subarachnoid hemorrhage:  recommendations from the Neurocritical Care Society’s Multidisciplinary Consensus Conference. Neurocrit Care. 2011;15(2):211–​240. Frontera JA, Claassen J, Schmidt JM, et al. Prediction of symptomatic vasospasm after subarachnoid hemorrhage: the modified Fisher scale. Neurosurgery. 2006;59(1):21–​ 27; discussion 21–​27. Hasan D, Lindsay KW, Wijdicks EF, et al. Effect of fludrocortisone acetate in patients with subarachnoid hemorrhage. Stroke. 1989;20(9):1156–​1161. Hunt WE, Hess RM. Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg. 1968;28(1):14–​20. Kassell NF, Torner JC, Haley EC Jr, Jane JA, Adams HP, Kongableet GL. The International Cooperative Study on the Timing of Aneurysm Surgery. Part 1: overall management results. J Neurosurg, 1990;73(1):18–​36. Lee VH, Oh JK, Mulvagh SL, Wijdicks EFM. Mechanisms in neurogenic stress cardiomyopathy after aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2006;5(3):243–​249. Molyneux AJ, Kerr RS, Yu LM, et al. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms:  a randomised comparison of effects on survival,

Subarachnoid Hemorrhage Chapter 5

53

dependency, seizures, rebleeding, subgroups, and aneurysm occlusion. Lancet, 2005;366(9488):809–​817. Muench E, Horn P, Bauhuf C, et al. Effects of hypervolemia and hypertension on regional cerebral blood flow, intracranial pressure, and brain tissue oxygenation after subarachnoid hemorrhage. Crit Care Med. 2007;35(8):1844–​1851; quiz 1852. Report of World Federation of Neurological Surgeons Committee on a Universal Subarachnoid Hemorrhage Grading Scale. J Neurosurg. 1988;68(6): 985–​986.

Chapter 6

Reversible Cerebral Vasoconstriction Syndrome Krystle Shafer and Bradley J. Molyneaux

54

Introduction Reversible cerebral vasoconstriction syndrome (RCVS) is a rare disorder that often presents with acute thunderclap headache and can result in infarcts as well as intraparenchymal and subarachnoid hemorrhage. Headache is a well-​ known common patient complaint with 90% of these complaints falling under benign diagnoses. However, this means that 1 out of 10 patients will have a dangerous diagnosis as the cause of their headache, and oftentimes the symptomatology of these dangerous headaches mimics benign conditions. It is important for providers to appropriately recognize and treat these critically ill patients. Arguably one of the great masqueraders is RCVS, a rare diagnosis that has the potential to result in permanent neurologic injury and death.

Definition and Pathophysiology RCVS refers to the reversible multifocal narrowing of cerebral arteries. The reversibility suggests an abnormality in control of cerebrovascular tone, but the pathophysiology of this vasculopathy is not well understood. This is not an inflammatory process but rather a disorder of the endothelial smooth muscle tone. Peak incidence for developing this order is reported as between the ages of 20 and 50 years old. This disorder is more common in women and has been associated with pregnancy (including the postpartum period). Other risk factors include exposure to vasoactive medications, pheochromocytoma, history of migraine headaches, and physical exertion, among many others.

Signs and Symptoms The overwhelming predominate symptom of RCVS is dramatic and severe headaches, which are often sudden-​onset thunderclap in nature. Associated symptoms also include nausea and vomiting, photophobia, and visual changes. Resolution of the headaches and vasoconstriction occurs over days to weeks. Complications from RCVS in one study occurred in 81% of patients and

RCVS Chapter 6

included ischemic infarcts, subarachnoid hemorrhage, lobar hemorrhage, and cerebral edema. As these complications develop, additional symptomatology such as focal neurologic deficits, seizures, coma, and even death (although rare) may occur. Seizures, subarachnoid hemorrhage, and intracerebral hemorrhage tend to occur within the first week of headache onset while ischemic events typically present within two weeks.

Diagnosis Despite having widespread cerebral artery vasoconstriction, up to 70% of patients will have no abnormalities on their initial brain computed tomography and/​or magnetic resonance imaging. Thus cerebral angiography is arguably the gold standard for diagnosis. The angiography in these patients typically displays segmental narrowing and dilation of multiple segmental arteries in a “string and beads” pattern (Figure 6.1).

Management of RCVS can be difficult as there is little data supporting the treatment options, the headaches can be severe despite attempts at treatment, and patients can experience continued clinical decline resulting in death. Oftentimes the first-​line treatment and prevention of the cerebral arterial vasoconstriction induced cerebral ischemia is with oral calcium channel antagonists such as nimodipine or verapamil. Use of calcium channel blockers

Figure 6.1  Segmental narrowing and dilation of multiple segmental arteries in a “string and beads” pattern.

55

Treatment

Neurological Conditions SECTION 1

56

is extrapolated from the data supporting nimodipine use in subarachnoid hemorrhage patients. Nimodipine is typically administered as 60 mg every four hours. Due to the need for frequent administration and high cost, nimodipine as not ideal for transition to hospital discharge. Alternatively, verapamil can be administered at 80 to 160 mg every 8 hours, dose can be titrated, and it can more easily be continued at hospital discharge. Calcium channel blockers can usually be tapered off after resolution of symptoms as an outpatient. These agents may not shorten the course of vasoconstriction, but they may lessen the intensity of the headaches. For patients with persistent headache and vasospasm despite use of calcium channel blockers, infusion of magnesium in dosing regimens used for pre-​eclampsia and eclampsia patients has highly effective in case reports with dramatic relief of symptomatology. Typical magnesium dosing would be a loading dose of 2 to 4 grams over 15 to 20 minutes, which may result in complete relief of headache. Continued treatment with oral magnesium oxide is an option. Opioid analgesics and acetaminophen may also be used as adjunctive therapy for headache management. If symptoms continue to progress despite these interventions, directed intra-​arterial therapies with medications such as milrinone or verapamil as well as cerebral balloon angioplasty have all been reported with successful results. Intra-​arterial intervention is not routinely recommended for all patients due to the risk of reperfusion injury and also because the majority of patients will have a self-​limited disease course with no long-​term focal deficits. Previously it was thought that treating these patients with permissive hypertension to overcome the flow limited by vasoconstriction would be effective, but studies have demonstrated that pharmacologically induced hypertension can induce further cerebral vasoconstriction and/​or result in brain hemorrhage. However, in patients with severe symptomatology requiring intra-​ arterial therapy, occasionally pharmacology-​induced hypertension is utilized as a temporary bridge to improve blood flow to the affected brain regions while awaiting this directed therapy. Finally, it is important to recognize that glucocorticoids were previously given to all RCVS patients more so to treat a suspected angiitis component of the disease. However, the literature has demonstrated steroid use in RCVS patients to be an independent predictor of clinical, imaging, and angiographic worsening as well as poor outcome. As such, steroids should never be given prophylactically in this particular patient population.

Risk of Recurrence Five percent of RCVS patients will develop recurrence. Sexual activity as the precluding trigger to the thunderclap headache is an independent predictor for recurrent RCVS. Patients who develop this condition during or

Bouchard M, Verreault S, Gariépy J, Dupré N. Intra-​arterial milrinone for reversible cerebral vasoconstriction syndrome. Headache. 2009;49(1):142–​145. Calabrese L, Dodick D, Schwedt T, Singhal A. Narrative review: reversible cerebral vas­ oconstriction syndromes. Ann Intern Med. 2007;146(1):34–​44. Chen S, Fuh J, Lirng J, Wang Y, Wang S. Recurrence of reversible cerebral vasoconstriction syndrome: a long-​term follow-​up study. Neurology. 2015;84(15):1552–​1558. Ducros A, Boukobza M, Porcher R, Sarov M, Valade D, Bousser M. The clinical and radiological spectrum of reversible cerebral vasoconstriction syndrome. a prospective series of 67 patients. Brain. 2007;130(Pt. 12):3091–​3101. Katz B, Fugate J, Ameriso S, et al. Clinical worsening in reversible cerebral vasoconstriction syndrome. JAMA Neurol. 2014;71(1):68–​73. Mijalski C, Dakay K, Miller-​Patterson C, Saad A, Silver B, Khan M. Magnesium for treatment of reversible cerebral vasoconstriction syndrome: case series. Neurohospitalist. 2016;6(3):111–​113. Rosenbloom M, Singhal A. CT angiography and diffusion-​perfusion MR imaging in a patient with ipsilateral reversible cerebral vasoconstriction after carotid endarterectomy. Am J Neuroradiol. 2007;28(5):920–​922. Sattar A, Manousakis G, Jensen M. Systematic review of reversible cerebral vasoconstriction syndrome. Expert Rev Cardiovasc Ther. 2011; 8(10);1417–​1421. Singhal A, Hajj-​ Ali R, Topcuoglu M, et al. Reversible cerebral vasoconstriction syndromes: analysis of 139 cases. Arch Neurol. 2011; 68(8):1005–​1012. Singhal A, Kimberly W, Schaefer P, Hedley-​Whtye E. Case 8-​2009:  a 36-​year old woman with headache, hypertension, and seizure 2 weeks postpartum. N Engl J Med. 2009;360:1126–​1137. Singhal A, Topcuoglu M. Glucocorticoid-​associated worsening in reversible cerebral vas­ oconstriction syndrome. Neurology. 2017;88(3):228–​236.

RCVS Chapter 6

Further Reading

57

immediately following pregnancy only rarely develop this syndrome with recurrent pregnancies, and thus it is not considered a contraindication for future pregnancies.

Chapter 7

Anoxic Brain Injury Jonathan Elmer and Jon C. Rittenberger

58

Incidence and Epidemiology Sudden cardiac arrest is the most common cause of death in North America. Each year, more than 120,000 patients in the United States are treated in the hospital after resuscitation from cardiac arrest. Recent advances in post-​arrest care including targeted temperature management, early coronary revascularization, and delayed neurological prognostication have improved the likelihood of favorable neurological outcome. Yet, a majority of patients hospitalized after cardiac arrest still die before discharge. Anoxic-​ischemic brain injury is the most common proximate cause of death in nonsurvivors (Table 7.1). Fortunately, for those discharged with a favorable neurological outcome, long-​ term survival is excellent.

Initial Patient Evaluation Etiology of Cardiac Arrest Cardiac arrest is the final common pathway for numerous disease processes. Accurately diagnosing or excluding specific etiologies of an individual patient’s arrest is critical for acute management (e.g., emergent cardiac catheterization Table 7.1  Patient Outcomes After Cardiac Arrest Patient Outcome Survive to discharge Favorable neurological outcome Unfavorable neurological outcome In-​hospital death Withdrawal of life-​sustaining therapy based on perceived neurological prognosis Brain death Pre-​existing advanced directives or surrogates’ representation of patient’s wishes Rearrest or medically unstable

Percentage of Patients 30–​50 10–​20 20–​30 50–​70 40–​60 5–​10 5–​15 10–​20

Precise neurological prognostication based on initial evaluation is impossible (see later discussion). However, there are several validated tools for early risk stratification after cardiac arrest that can inform discussions with families and surrogates and help them understand a patient’s anticipated clinical course. The simplest validated tool is the Pittsburgh Cardiac Arrest Category scale, which stratifies patients into four categories based on initial neurological examination and severity of cardiopulmonary dysfunction (Figure 7.1). In addition to a focused physical examination, brain imaging with computed tomography (CT) should be part of the initial evaluation of the comatose post-​arrest patient. Baseline CT imaging may alter early post-​arrest management and further inform risk stratification. Approximately 1 in 20 patients will have intracranial hemorrhage or other acute primary central nervous system etiologies of arrest identified on initial post-​arrest CT scan. More commonly, in roughly 20% of cases, the initial brain CT will demonstrate at least some degree of early cerebral edema, characterized by loss of gray-​white differentiation, as well as mass effect and effacement of the sulci and basal cisterns when severe. Studies demonstrate a significant increase in mortality when the ratio of Hounsfield units in gray matter compared to white matter falls below 1.2.

Emergent Cardiac Catheterization In patients who may have suffered cardiac arrest from acute coronary syndrome, emergent cardiac catheterization is strongly associated with favorable neurological outcomes for both patients with ST-​elevation myocardial infarction and those without ST elevation. However, in the face of severe brain injury with loss of brainstem reflexes (Pittsburgh Cardiac Arrest Category 4), risk of death from neurological deterioration far outweighs the risk of death from multiple system organ failure. In these patients, it may be reasonable to delay coronary angiography in favor of stabilization and aggressive neurocritical care in the intensive care unit.

Critical Care Management Anoxic-​ ischemic brain injury is the major driver of both morbidity and mortality for these patients, particularly after out-​of-​hospital cardiac arrest

Anoxic Brain Injury Chapter 7

Severity of Illness

59

in acute coronary syndromes, early antibiotics, and hemodynamic resuscitation for septic shock), secondary prevention (e.g., internal defibrillator placement) and risk stratification. Historically, consensus guidelines dichotomized arrest etiology as “presumed cardiac” and “noncardiac.” While potentially useful for clinical research, this definition has little clinical utility, and providers must generate a more comprehensive differential diagnosis. Fortunately, thoughtful consideration and targeted testing can identify or rule out the underlying etiology of cardiac arrest in most patients (Table 7.2).

Neurological Conditions SECTION 1

Table 7.2  Common Causes of Cardiac Arrest and Suggested Initial Diagnostic Evaluation Etiology Cardiovascular   Acute coronary syndrome   Congenital arrhythmia (long QT, Brugada, etc)   Congenital structural heart disease   Arrhythmia from (non-​)ischemic cardiomyopathy   Cardiogenic shock  Pulmonary hypertension/​right ventricular failure Pulmonary   Large airway obstruction  Respiratory failure (e.g., asthma, pneumonia, chronic obstructive pulmonary disease)

60

Catastrophic neurological event Exsanguination (traumatic or nontraumatic)

Obstructive shock Pulmonary embolism Pneumothorax Tamponade Distributive shock Sepsis Anaphylaxis Metabolic   Diabetic ketoacidosis   Hypokalemia or hyperkalemia  Hypomagnesemia Overdose   Sedative, hypnotic, opioid  Sympathomimetic  Other Environmental (electrocution, hypothermia, etc.)

Diagnostic Evaluation ECG—​ischemia, rhythm, intervals Troponin Echocardiogram

Chest x-​ray Arterial blood gas Physical exam Bronchoscopy CT head History Physical exam Hemoglobin CT scan chest/​abdomen/​pelvis Echocardiogram Chest x-​ray CT chest Chest x-​ray Urinalysis White blood cell count Cultures Arterial blood gas Serum chemistries

History ECG Drug screen History

ECG = electrocardiogram; CT = computed tomography.

(OHCA). Post-​arrest brain injury can be conceptualized as a primary ischemia-​ reperfusion injury occurring during pulselessness and the minutes after return of spontaneous circulation and secondary brain injury that may develop in the days after resuscitation when the acutely damaged brain is vulnerable to new

Category 2 Light coma without severe cardiopulmonary failure Does not follow commands or make purposeful movement, but brainstem reflexes are present. Modest vasopressor requirements (norepinephrine 80 mm Hg during active temperature management, then liberalize as conditions allow.

64

Post-​arrest Seizures Electroencephalographic (EEG) findings after resuscitation from cardiac arrest are prognostic. Seizures and other epileptiform EEG findings develop in approximately 25% of patients resuscitated from cardiac arrest and are associated with in-​hospital mortality. Early malignant EEG patterns in the first 48 hours after initial resuscitation are ominous. In this population, most authors consider periodic epileptiform discharges, seizures, and polyspike bursts to be malignant, although definitions vary in the literature. Observation of myoclonic jerks in lock-​step with polyspike bursts, variably termed status myo­ clonus or myoclonic status epilepticus, portends poor prognosis. By contrast, favorable neurological outcomes are not uncommon among patients who develop malignant EEG patterns later in their post-​arrest course. Other prognostic EEG features include the presence of reactivity and development of a continuous background by 48 hours post-​arrest, both of which are strongly associated with favorable outcome. Whether early malignant EEG patterns after cardiac arrest are injurious in and of themselves or simply a sign of severe brain injury is controversial. It is our practice to aggressively treat these patients with antiepileptic drugs. In other critically ill populations, early seizure control has been associated with improved outcomes (see ­chapter 8). However, data supporting this practice after cardiac arrest are lacking.

Neurological Prognostication Accurate neurological prognostication after cardiac arrest is challenging, and withdrawal of life-​sustaining therapy based on anticipated neurological prognosis is the most common proximate cause of death after cardiac arrest. Evidence-​ based guidelines advocate delaying neurological prognostication until at least 72 hours after cardiac arrest, and this timeline should be extended to 72 hours after rewarming to normothermia for patients treated with

Anoxic Brain Injury Chapter 7

hypothermia. Before this time, no clinical sign, test result, or combination of findings precludes a favorable neurological outcome. Importantly, awakening from coma may occur days to weeks after cardiac arrest, and patients who remain comatose at 72 hours may go on to have favorable recoveries. In the absence of awakening or progression to brain death, prognostication depends on integration of results from multiple diagnostic modalities (Table 7.4). It is important to note that many prognostic findings once thought to uniformly predict poor outcome are imprecise and observational studies of prognostic modalities have a high risk of bias. To date, no blinded studies of neurological prognostication after cardiac arrest have been conducted. Thus, clinicians caring for patients included in observational studies are at liberty to withdraw life-​sustaining therapy based on the results of prognostic tests. Since withdrawal of life-​sustaining therapy after cardiac arrest invariably results in death, self-​fulfilling prophecies are created that have biased the literature toward inappropriately pessimistic point estimates and narrow confidence intervals when reporting false positive rates for predicting poor outcome. Table 7.4  Prognostic Modalities after Cardiac Arrest Timing Daily

Brain CT

Baseline

EEG

Days 1–​3

Notes

• Initial exam findings can be summarized by

the Pittsburgh Cardiac Arrest Category classification system (Figure 7.1) • Persistent coma on Day 3 does not preclude a favorable outcome • Persistent absence of pupillary and corneal reflexes on Day 3 is ominous • Gray matter to white matter ratio of Hounsfield units 12 yr), 0.3 mg/kg for (6–11 yr), 0.5 mg/kg (2–5 yr), or • Midazolam IM 0.2 mg/kg (max 10 mg) or intranasal 0.2 mg/kg

Chapter 8

• Recognize prolonged seizure >5 min • Airway, Breathing, Circulation

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First-Line Management

Table 8.1  Overview of Therapeutic Options for SE Drug

Dosing

Mechanism

Metabolism/​ Elimination

Side Effects

Comments

GABAA agonist, increases frequency of Cl-​ channel opening

Hepatic/​renal

Respiratory depression, some hypotension (less than propofol or barbiturates)

Preferred first-​line treatment for in-​hospital SE

Emergent management Lorazepam

0.1 mg/​kg IV, up to 4 mg per dose (in 5-​to 10-​min intervals)

Low lipid solubility, stays in intravascular space

Midazolam

0.2 mg/​kg IM (max 10 mg)

GABAA agonist, increases frequency of Cl-​ channel opening

Hepatic/​renal

Respiratory depression, some hypotension (less than propofol or barbiturates)

Diazepam

0.15 mg/​kg IV (max 10 mg per dose), repeat in 5 min

GABAA agonist, increases frequency of Cl-​ channel opening

Hepatic/​renal

Respiratory depression, some hypotension (less than propofol or barbiturates)

0.2 mg/​kg PR (for age >12 years)

Highly lipid-​soluble, quickly absorbed and redistributed out of intravascular space (within 15–​30 mins)

Significant tachyphylaxis IV contains propylene glycol In prehospital setting, has been shown to be at least as effective as IV lorazepam in cessation of SE Significant tachyphylaxis Can accumulate in the body with repeated doses Significant tachyphylaxis IV contains propylene glycol

Phenytoin/​ Fosphenytoin

20 mg/​kg IV (can load an additional 10 mg/​kg IV if seizures persist)

Blocks voltage-​gated Na+ channels

Check level 2 hrs after loading:

Hepatic/​renal and biliary

Hypotension, bradycardia, arrhythmias with infusion

Cytochrome P450 inducer, multiple drug interactions

Therapeutic levels can cause or exacerbate pancytopenia, drug fevers, and rash (including SJS)

▸ If in desired range, start maintenance dose (typically 100 mg q8 hrs)

Toxic levels can cause sedation, nystagmus, diplopia, dysarthria, ataxia, tremor, and coma

▸ If supratherapeutic, hold dose until in therapeutic range ▸ If subtherapeutic, give another smaller loading dose and start maintenance Valproic acid

Levetiracetam

20-​40 mg/​kg IV (can load with another 20 mg/​kg IV if seizures persist)

Blocks voltage-​gated Na+ channels and T-​ type Ca2+ channels

Check level 2 hr after loading, but do not delay maintenance dose (typically starting at 15 mg/​kg divided over two doses); lab processing time longer than PHT levels Load with 1 g–​3 g IV bolus, then start maintenance dose (typically 500–​1500 mg q12 hrs)

May increase turnover of GABA (and therefore increase GABA levels)

Binds to synaptic vesicle glycoprotein SV2A, inhibits presynaptic Ca2+ channels

Hepatic/​renal Cytochrome P450 inhibitor; multiple drug interactions

Hyperammonemia, thrombocytopenia, sedation, pancreatitis, tremor, elevated transaminases Significant teratogenicity, avoid in pregnant patients unless absolutely necessary

Enzymatic hydrolysis/​ renal No major drug interactions

May cause mood disturbances

Fosphenytoin is water-​ soluble prodrug, less likely to cause local reactions, can be infused three times faster than phenytoin (150 mg PE/​min vs. 50 mg/​min) 90% protein bound, should check free level; if unavailable, check serum albumin and calculate corrected level Normal therapeutic range 1–​2 free, 10–​20 corrected; in SE, typically aim for 2–​ 2.5 free, 20–​25 corrected Noninferior to phenytoin in clinical studies, has advantage of multiple mechanisms Typical therapeutic range 50–​100 µg/​ml (total), but can be as high as 150 in SE

Also a preferred agent for seizure prophylaxis Levels not monitored

(continued)

Table 8.1 Continued Drug

Dosing

Mechanism

Metabolism/​ Elimination

Side Effects

Comments

see Emergent Management

see Emergent Management

see Emergent Management

Preferred first infusion for RSE

Acts on GABAA receptor (different site than BZDs or barbiturates), potentiating its activity

Hepatic glucuronidation/​ hepatic

Significant hypotension and respiratory depression

Less tachyphylaxis than BZDs

PRIS: cardiac arrhythmias, heart failure, hyperkalemia, lactic acidosis, ↑ creatinine kinase and transaminases, rhabdomyolysis, renal failure

PRIS associated with prolonged use and high doses, especially in pediatric and septic patients

Adjust dose for renal function: ▸ CrCl 90% A multimodal approach is necessary to prevent secondary brain injury related to cerebral ischemia. Establishing an early protected airway via endotracheal intubation improves outcomes in severe TBI. Arterial oxygen saturations

Traumatic Brain Injury Chapter 9

Surgical Intervention

91

decreased cerebral metabolism, cerebral vasoconstriction, and prevention of neurotoxic excitatory cascades. There is no benefit to prophylactic treatment with burst suppression in severe TBI; however, patients with intracranial hypertension refractory to all other interventions have decreased mortality if ICPs respond to barbiturate therapy. Complications of barbiturate-​induced burst suppression include systemic hypotension and increased infection rates. Pharmacologic burst suppression unfortunately obviates the ability to complete neurologic exams for long periods of time, often 24 to 48 hours after barbiturate infusions are stopped.

Neurological Conditions

3

Venous

Arterial blood

CSF

SECTION 1

2

Venous

CSF

92

1

Mass/ edema

Mass/ edema Arterial blood

ICP

50

30 Arterial blood 10

Brain

Brain

Brain

Normal

Compensated

Uncompensated

Figure 9.3  The rigid skull with fixed intracranial volume (represented by the rectangle) contains brain, cerebrospinal fluid (CSF), and blood. Intracranial pressure (ICP) is influenced by the dynamic interplay among the individual components (1). The addition of another component within the intracranial space, such as posttraumatic cerebral edema or mass lesion, will result in concomitant decrease in volume of another component in s compensated state where ICP does not rise (2). However, an uncompensated state with elevations in ICP will eventually ensue when compensatory measures are exhausted (3). Source: Exo J, Smith C, Bell MJ. Emergency treatment options for pediatric traumatic brain injury. Pediatric Health. 2009;3:533–​541.

should be treated to maintain above 90%. Given oxygen delivery to the brain is highly dependent on oxygen content of blood, anemia may also enhance secondary brain injury. There is no current consensus on appropriate transfusion thresholds in severe TBI; however, low hemoglobin is associated with increased morbidity and mortality. Transfusion of packed red blood cells may improve outcomes for the severely injured via multiple mechanisms including improving cerebral oxygenation and increasing blood pressure which thereby modulates CPP. However, transfusion is also associated with increased thromboembolic events, transfusion reactions, and increased rates of acute respiratory distress syndrome.

Hyperpyrexia: Goal Normothermia, Core Body Temperature 38.5°C is shown to increase cerebral metabolism and increases mortality in severe head injury. Cornerstones in effective fever management include antipyretics, cooling blankets, and intravascular cooling catheters. Our institutional protocol for severe TBI patients involves immediate placement of a femoral or subclavian intravascular cooling

Fluid Balance and Electrolytes Electrolyte abnormalities are common in the TBI population, with up to 60% demonstrating an electrolyte abnormality in the acute posttrauma period. Abnormal serum sodium concentrations are the most common alteration, and posttraumatic hyponatremia is associated with worse outcomes and increased hospital days. Underlying pathophysiology involved with posttraumatic hyponatremia most often involves cerebral salt wasting or syndrome of inappropriate antidiuretic hormone (SIADH). These two entities are distinguished based on volume status with SIADH resulting in eu-​or hypervolemia, whereas cerebral salt wasting results in hypovolemia. Distinguishing between the two is important, as management differs. In SIADH, fluid restriction is indicated, while sodium supplementation is the mainstay of therapy for cerebral salt wasting. Hypernatremia is not uncommon after TBI and is most often secondary to central diabetes insipidus related to pituitary stalk dysfunction. Incidence of posttraumatic central diabetes insipidus is directly related to severity of brain injury. Management may involve a combination of free-​water boluses or administration of hypotonic fluids, and rarely necessitates use of desmopressin (DDAVP). Following initial fluid resuscitation, the intravenous maintenance fluid of choice in TBI is normal saline (0.9% NaCl). Fluids with dextrose should be avoided given concern for inducing or worsening hyperglycemia.

Nutrition Severe TBI and other frequently associated polytraumas can cause a hypermetabolic state. Enteral feeding (unless there is some absolute contraindication) should commence as soon as possible with full caloric replacement by postinjury day 5. Patients with malnutrition during the first two weeks after injury have significantly increased mortality when compared to patients who have caloric needs met by postinjury day 7. Additionally, early initiation of enteral feeding is associated with decreased infection rates. In choosing between orogastric and nasogastric enteral feeding tubes, one must note the presence or absence of anterior skull base fractures. Placement of nasogastric tubes in the setting of severe skull base fractures can adversely result in intracranial penetration of the feeding tube. Other considerations

Traumatic Brain Injury

Hyperglycemia is common after TBI secondary to activation of the sympathetic nervous system and adrenergic catecholamine release. Both early and persistent hyperglycemia is associated with poor functional outcomes in severe TBI. Frequent glucose checks and tight glycemic control via sliding scale insulin administration are paramount.

Chapter 9

Glycemic Control: Goal Serum Glucose 20% listhesis, angulations exceeding 11o (cervical) or 20o (thoracolumbar), and/​or loss of >50% anterior compared with posterior vertebral body height.

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motor groups) compared to the lower extremities, with signs of myelopathy (usually urinary retention) and variable sensory disturbances (hyperpathia, hypesthesia, etc.). Fifty percent recover the ability to ambulate; most recover bladder control. The anterior cord syndrome involves dissociated sensory loss (no pain or temperature sensation, preserved proprioception, vibratory sense, and deep pressure) with either paraplegia or quadriplegia (if above C7). Prognosis for recovery is poor. The posterior cord syndrome, which is relatively rare, includes pain and paresthesias (burning sensations) of the neck, upper arms, and torso with mild paresis of upper extremities. Hemisection of the spinal cord (secondary to penetrating injury) results in the Brown-​Sequard syndrome with ipsilateral motor paralysis and loss of proprioception and vibratory sense with contralateral loss of pain and temperature sensation. The conus medullaris syndrome consists of bilateral sacral sensory deficit (“saddle anesthesia”), pronounced autonomic dysfunction (especially urinary retention), and symmetric paraparesis. The neurologic exam may be confounded by spinal shock in the first 24 to 72 hours following traumatic injury. Spinal shock presents as transient loss of all neurologic function below the level of injury demonstrated by flaccid paralysis and areflexia, the resolution of which is often heralded by return of anal-​cutaneous and/​or bulbocavernosus reflexes. This syndrome should not to be confused with neurogenic shock, which is characterized by bradycardia, hypotension, hypothermia, and priapism caused by loss of sympathetic tone.

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Cervical Spine Clearance Cervical collars must be removed as soon as it is safe to do so. They have been associated with skin breakdown, increased intensive care unit (ICU) stays, and elevated intracranial pressure. Cervical collars may be removed in patients who are awake, alert, and without neurologic deficit or distracting injury who have no neck pain/​tenderness and full range of motion of the cervical spine without the need for imaging. Meta-​analysis of the current literature demonstrates that multislice helical CT alone is sufficient to detect unstable cervical spine injuries in trauma patients unable to be clinically cleared, thus permitting the removal of the cervical collar from obtunded or intubated trauma patients if a modern CT is negative for acute injury.

Treatment

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Patients with acute traumatic SCI should be managed at a Level 1 trauma center to optimize outcomes. Patients suffering SCI, regardless of severity, frequently experience cardiovascular instability and pulmonary insufficiency necessitating vigilant monitoring. Management in an ICU has been shown to improve neurologic outcome and reduce cardiopulmonary-​related morbidity and mortality.

Respiratory Management Ventilatory dysfunction correlates with spinal level and completeness of injury. Cervical injuries (C2 through C6) may result in 80% to 95% reductions in vital capacity, with absent or impaired cough. Low cervical and high thoracic cord injuries (i.e., C7 through T4) may also lead to reduced vital capacity (30%–​50% of normal) and ineffective cough. Patients who may be able to initially compensate for reduced ventilation can rapidly fatigue and progress to respiratory arrest. Endotracheal intubation is frequently indicated in the setting of airway compromise, respiratory failure (PaO2 60 mm Hg), and/​or associated severe TBI (GCS ≤8), with up to 30% of patients with cervical SCI requiring intubation in the first 24 hours. Care should be taken to avoid spinal movement during intubation. Options include awake fiberoptic guidance or direct laryngoscopy with manual in-​line spine stabilization. Ventilation typically worsens between postinjury days two and five, followed by gradual improvement; the mean duration of mechanical ventilation is 22 days in cervical SCI and 12 days in thoracic SCI. Management of respiratory problems related to neuromuscular weakness after SCI should mirror res­ piratory management of other neuromuscular conditions (see Chapter 13). Establishing an ICU protocol to guide management of respiratory issues (e.g., gradual weaning, secretion clearance, cough assist, inspiratory force and vital capacity measurements) after SCI is strongly recommended. Pulmonary complications are the leading causes of death and morbidity in the SCI population; atelectasis, pneumonia, aspiration pneumonitis, pulmonary

Management should be tailored to the etiology of hemodynamic disturbance while optimizing spinal cord perfusion and avoiding injury to other organ systems. Potential causes of hypotension include neurogenic shock, occult hemorrhage, tension pneumothorax, myocardial injury or tamponade, and sepsis. Hypotension immediately following acute SCI is most commonly due to hemorrhage; however, neurogenic shock is an important etiology that must be diligently sought and treated. Neurogenic shock (classically characterized by hypotension, hypothermia, and bradycardia) occurs in up to 90% of patients suffering complete cervical SCI with lesions above the T6 neurological level (compared to 50% of those with incomplete SCI). Spinal cord injury with interruption of the anterior interomedial tract results in sympathetic denervation, thus leading to arteriolar dilation and hypotension (SBP ≤80  mm Hg) with relative hypovolemia (venous pooling), as well as unopposed parasympathetic drive (bradycardia and decreased contractility). Hemodynamic instability secondary to neurogenic shock may be corrected by judicious volume resuscitation, avoiding pulmonary edema, followed by norepinephrine infusion (increases systemic vascular resistance and has inotropic properties) as needed. Optimal blood pressure management in patients with SCI is largely inferred from data on cerebral autoregulation and perfusion pressure goals for treatment of severe TBI. Class II and III evidence suggests hemodynamic augmentation in SCI with a goal of maintaining mean arterial pressure >80–​85 mm Hg for at least seven days is safe and may be associated with improved neurologic outcome in SCI. Hypotension should be aggressively avoided.

Venous Thromboembolism Patients suffering SCI have the highest risk of venous thromboembolic disease of any hospitalized patient population, with the risk being greatest during the first three months. Untreated, 40% to 100% will develop deep venous thrombosis (DVT), while even with adequate prophylaxis (unfractionated heparin and pneumatic compression stockings vs. low molecular weight heparin alone) 12 to

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edema, and pulmonary embolism occur in >60% of patients with cervical and upper thoracic SCI. Additionally, SCI patients frequently suffer from comorbid traumatic injuries, further predisposing them to acute lung injury and acute respiratory distress syndrome. Management strategies advocate lung protective ventilation utilizing low tidal volumes (6–​8 mL/​kg predicted body weight) with steps to enhance alveolar recruitment (positive end-​expiratory pressure). Early conversion to tracheostomy should be considered in patients anticipated to require more than two weeks ventilatory support. Early tracheostomy has been associated with better subjective tolerance, improved ventilation, reduced airway resistance, shorter ventilator weaning, and shorter ICU stays.

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16% will develop major venous thromboemboli. Although the necessity of DVT/​ PE prophylaxis has been established, the optimal treatment strategy remains elusive. Systematic reviews and evidence-​based consensus conferences have recommended low molecular weight heparin alone, adjusted dose unfractionated heparin, or unfractionated heparin combined with a nonpharmacologic device; treatment should begin no later than 24 to 72 hours postinjury.

Other Critical Care Concerns Infectious complications most frequently involve the respiratory or urinary tract and are a leading cause of death and morbidity following SCI. Fever or leukocytosis not explained by an infectious source should prompt investigation of acute abdominal processes (e.g., pancreatitis, cholecystitis, bowel obstruction/​ischemia/​perforation) that may be occult with SCI. Gastrointestinal stress ulceration is a known complication in trauma, with SCI conferring independent risk. Either H2-​blockers or proton pump inhibitors are indicated and should be started at admission and continued for at least four weeks. Autonomic dysreflexia is characterized by symptoms of paroxysmal hypertension, cutaneous flushing, blurred vision, and nausea in response to a stimulus (hollow viscera distention or surgical procedures) below the level of the cord lesion. If untreated, this may result in encephalopathy, seizures, stroke, myocardial infarction, arrythmias, and death. Management priorities are removal of stimulus and correction of hypertension.

Surgical Management Surgical intervention plays a role in the management of spine trauma regardless of whether SCI exists. Surgery is performed with two goals in-​mind: (a) to decompress neural elements in those with neurologic deficit and (b)  to re-establish spinal alignment and stability in order to prevent further cord injury and facilitate early mobilization. Early surgical intervention is not associated with increased complication rates and may improve neurologic outcome. In the cervical spine, cord decompression may be performed through either closed or open means. Closed reduction of cervical spinal fracture-​dislocation injuries with craniocervical traction is utilized to restore of anatomic alignment of the cervical spine as a bridge to definitive surgical fixation.

Neuroprotective Strategies and Future Research Research in SCI over the past several decades has elucidated many of the mechanisms at play in secondary injury. Pharmacologic therapies investigated to date in large multicenter prospective randomized controlled trials have included methylprednisolone and the related compound tirilizad mesylate, GM-​1 ganglioside, thyroid releasing hormone, gacyclidine, naloxone, and nimodipine. None of these therapies has yet been shown in a randomized control trial to definitively improve neurologic outcome.

Traumatic Spinal Cord Injury Chapter 10

Prospective, multicenter trials of methylprednisolone for neuroprotection in SCI have demonstrated modest motor score benefits in secondary analyses. However, subsequent studies and analyses have found significantly higher rates of severe pneumonia, severe sepsis, and death. The American Association of Neurological Surgeons/​Congress of Neurological Surgeons systematic review of this literature in 2002 concluded that “treatment with methylprednisolone for either 24 or 48 hours is recommended as an option in the treatment of patients with acute spinal cord injuries that should be undertaken only with the knowledge that the evidence suggesting harmful side effects is more consistent than any suggestion of clinical benefit.” There is much ongoing clinical research in both pharmacologic as well nonpharmacologic interventions for SCI. These include trials on the optimal timing of surgical decompression, therapeutic hypothermia, cerebrospinal fluid drainage, cellular transplantation (e.g., Schwann cells, stem cells, etc.), as well as targeting specific cellular inhibitors of regeneration.

Berlly M, Shem K. Respiratory management during the first five days after spinal cord injury. J Spinal Cord Med. 2007;30(4):309–​318. Bracken MB, Shepard MJ, Collins WF Jr, et al. Methylprednisolone or naloxone treatment after acute spinal cord injury:  1-​year follow-​up data. Results of the second National Acute Spinal Cord Injury Study. J Neurosurg. 1992;76(1):23–​31. Bracken MB, Shepard MJ, Holford TR, et al. Methylprednisolone or tirilazad mesylate administration after acute spinal cord injury:  1-​ year follow up. Results of the third National Acute Spinal Cord Injury randomized controlled trial. J Neurosurg. 1998;89(5):699–​706. Casha S, Christie S. A systematic review of intensive cardiopulmonary management after spinal cord injury. J Neurotrauma. 2011;28(8):1479–​1495. PMCID: 3143388. Chappell ET. Pharmacological therapy after acute cervical spinal cord injury. Neurosurgery. 2002;50(3 Suppl.):S63–​72. Chiodo AE, Scelza WM, Kirshblum SC, Wuermser LA, Ho CH, Priebe MM. Spinal cord injury medicine. 5. Long-​term medical issues and health maintenance. Arch Phys Med Rehabil. 2007;88(3 Suppl. 1):S76–​83. Consortium for Spinal Cord Medicine. Respiratory management following spinal cord injury:  a clinical practice guideline for health-​care professionals. J Spinal Cord Med. 2005;28(3):259–​293. Dhall SS, Hadley MN, Aarabi B, et al. Deep venous thrombosis and thromboembolism in patients with cervical spinal cord injuries. Neurosurgery. 2002;50(3 Suppl.):S73–​80. Frankel HL, Coll JR, Charlifue SW, et al. Long-​term survival in spinal cord injury: a fifty year investigation. Spinal Cord. 1998;36(4):266–​274. Ganuza JR, Garcia Forcada A, Gambarrutta C, et al. Effect of technique and timing of tracheostomy in patients with acute traumatic spinal cord injury undergoing mechanical ventilation. J Spinal Cord Med. 2011;34(1):76–​84.

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Hadley MN, Walters BC, Grabb PA, et  al. Management of acute spinal cord injuries in an intensive care unit or other monitored setting. Neurosurgery. 2002;50(3 Suppl.):S51–​57. Hawryluk GW, Rowland J, Kwon BK, Fehlings MG. Protection and repair of the injured spinal cord: a review of completed, ongoing, and planned clinical trials for acute spinal cord injury. Neurosurg Focus. 2008;25(5):E14. Hoffman JR, Mower WR, Wolfson AB, Todd KH, Zucker MI. Validity of a set of clinical criteria to rule out injury to the cervical spine in patients with blunt trauma. National Emergency X-​Radiography Utilization Study Group. N Engl J Med. 2000;343(2):94–​99. Kirshblum SC, Priebe MM, Ho CH, Scelza WM, Chiodo AE, Wuermser LA. Spinal cord injury medicine. 3. Rehabilitation phase after acute spinal cord injury. Arch Phys Med Rehabil. 2007;88(3 Suppl. 1):S62–​70. Krassioukov A, Warburton DE, Teasell R, Eng JJ. A systematic review of the management of autonomic dysreflexia after spinal cord injury. Arch Phys Med Rehabil. 2009;90(4):682–​695. Marino RJ, Barros T, Biering-​Sorensen F, et al. International standards for neurological classification of spinal cord injury. J Spinal Cord Med. 2003;26(Suppl. 1):S50–​S56. Panczykowski DM, Tomycz ND, Okonkwo DO. Comparative effectiveness of using computed tomography alone to exclude cervical spine injuries in obtunded or intubated patients: meta-​analysis of 14,327 patients with blunt trauma. J Neurosurg. 2011;115(3):541–​549. Paralyzed Veterans of America, Consortium for Spinal Cord Medicine. Early Acute Management in Adults with Spinal Cord Injury: A Clinical Practice Guideline for Health-​ Care Providers. Washington, DC: Consortium for Spinal Cord Medicine; 2008. Spinal Cord Injury Thromboprophylaxis Investigators. Prevention of venous thromboembolism in the acute treatment phase after spinal cord injury: a randomized, multicenter trial comparing low-​dose heparin plus intermittent pneumatic compression with enoxaparin. J Trauma. 2003;54(6):1116–​1124; discussion 25–​26. Rogers FB, Cipolle MD, Velmahos G, Rozycki G, Luchette FA. Practice management guidelines for the prevention of venous thromboembolism in trauma patients: the EAST practice management guidelines work group. J Trauma. 2002;53(1):142–​164. Wilson JR, Fehlings MG. Emerging approaches to the surgical management of acute traumatic spinal cord injury. Neurotherapeutics. 2011;8(2):187–​194. Wuermser LA, Ho CH, Chiodo AE, Priebe MM, Kirshblum SC, Scelza WM. Spinal cord injury medicine. 2.  Acute care management of traumatic and nontraumatic injury. Arch Phys Med Rehabil. 2007;88(3 Suppl. 1):S55–​61.

Chapter 11

Meningitis and Encephalitis Ruchira Jha

Meningitis Meningitis can have multiple etiologies classified as either infectious (bacterial, viral, fungal, tick-​borne) or noninfectious (neoplastic, drug-​related). This chapter outlines key features in the epidemiology, diagnosis, and management of common causes of meningitides. Key points are summarized in Table 11.1. Epidemiology Acute bacterial meningitis (ABM) typically presents within hours and requires early recognition and aggressive management including antibiotics, steroids if indicated, isolation, and prophylaxis of contacts when necessary. Mortality in adults remains up to 20% depending on the organism and immune constitution of the patient. Fortunately, only 10% of diagnosed meningitis cases have a bacterial origin. Five pathogens are responsible for 80% of ABM cases: Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, Group B streptococcus, and Listeria monocytogenes. The H. influenzae type B, pneumococcal, and meningococcal vaccines have dramatically reduced the global incidence of meningitis. Several studies have indicated a potential genetic predisposition to ABM (particularly related to complement deficiencies) however these details are beyond the scope of this chapter. In immunocompromised intensive care unit patients, aerobic gram-​negative bacilli like the Enterobacteriaceae family are also important pathogens. Other risk factors such as sinusitis, endocarditis, penetrating trauma, neurosurgical procedures, or nosocomial infections further broaden the potential spectrum of causative microbes (Table 11.1). Diagnosis and Presentation The clinical presentation of ABM classically includes two of the four findings of headache, fever (77%), nuchal rigidity (83%), or altered mental status (69%) in about 95% of patients. Seizures occur in approximately 20% of patients. Lethargy is also common, most often in pneumococcal meningitis. The need for neuroimaging prior to lumbar puncture (LP) is controversial, as herniation related to ABM is rare. Practice guidelines recommend computed tomography (CT) prior to LP in patients with an immunocompromised state,

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Bacterial Meningitis

Table 11.1  Meningitis Evaluation and Treatment A: Bacterial Meningitis

• Typical CSF Profile: OP ↑↑ >20 cmH2O, WBC ↑↑ 250–​100,000/​mm3 (polymorphonuclear predominance), Protein ↑↑ 100–​500 mg/​dL, Glucose ↓↓ 20 cmH2O, WBC ↑↑ 100–​500/​mm3, Protein ↑ 100–​500 mg/​dL, Glucose ↓ 1180 cells/​uL. Importantly, these findings are not significantly changed by antibiotic pretreatment compared to the gram stain yield which is reduced by 16%. Given the reduction in diagnostic yield of CSF gram stain and culture after antimicrobial treatment, molecular methods are becoming increasingly important to diagnose ABM and other CNS infections including PCR (that can detect organisms for several days after antibiotics), multiplex PCR, 16S PCR, MALDI-​TOF, and whole genome sequencing. The details of these technologies are beyond the scope of this chapter since they are not currently standard of care, but are important to be aware of since they may soon revolutionalize clinical microbiology in this field. Management Prompt diagnosis and management of ABM is essential to decreasing the morbidity and mortality of ABM. Treatment should not be delayed to obtain imaging or LP. Empiric treatment should be initiated immediately upon suspicion for ABM based on the patient’s risk for specific organisms (Table 11.1). The classic regimen includes vancomycin and a third-​generation cephalosporin with good central nervous system (CNS) penetration such as ceftriaxone (see Table 11.1 for doses). In patients who are above 50 years old, pregnant, or immunocompromised, ampicillin should be added. Those with penetrating head trauma or neurosurgery are at risk for pseudomonal infections, and third-​ generation cephalosporins should be replaced by cefepime or ceftazidime. Unless there are contraindications to steroids, patients with suspected ABM should receive 10 mg dexamethasone every six hours for four days, with the first dose administered prior to antibiotics. Once culture data are available, antibiotics should be narrowed appropriately (Table 11.1).

Viral Meningitis Epidemiology Most cases of meningitis are viral. Enteroviruses are the most common offender, causing approximately 60% of all cases. Transmission is usually fecal-​ oral. Herpesviruses (such as herpes simplex virus [HSV-​2]), Varicella Zoster virus (VZV), and arboviruses (like West Nile virus [WNV]) are also neurotropic and can cause meningitis, though HSV-​1 typically causes an aggressive encephalitis. HSV-​2 can cause meningitis at the time of initial genital infection. Arboviruses such as WNV typically cause disease in the mid-​to late summer months. Most cases of WNV are asymptomatic or cause a mild febrile illness; only 1% develop neuroinvasive disease such as meningitis, encephalitis, or a flaccid paralysis. Acute HIV may cause meningitis in 5% to 10% of newly infected patients.

Fungal Meningitis Most fungal meningitides are subacute to chronic and present in immunocompromised hosts. The following section focuses on four relatively common fungal infections:  Cryptococcus neoformans, Coccidioides immitis, Histoplasma capsulatum, and Aspergillus fumigatus. Epidemiology Cryptococcus neoformans has four serotypes, with type A (C. neoformans grubbi) being the most common. Cryptococcal meningitis has a prevalence of approximately 10% in the United States and is as high as 30% in sub-​Saharan Africa and is most common in patients with cell-​mediated immunocompromise. Coccidioides immitis is endemic to southwestern United States and typically results in a self-​limited respiratory infection (valley fever). Patients at risk for disseminated infection including cavitary pneumonia, osteomyelitis, and meningitis include pregnant women, those on long-​term immunosuppressive therapy, and those with HIV. Histoplasma capsulatum is endemic to the Ohio and Mississippi river valleys. It has also been related to exposure to bird excrement and bat guano. Patients often have an acute pulmonary infection. Immunocompromised patients have disseminated disease including meningitis. Aspergillus fumigatus is an increasing cause of infection related to immunosuppression. Patients susceptible to invasive aspergillosis can be neutropenic,

 Meningitis and Encephalitis Chapter 11

Management Management of viral meningitis is predominantly supportive. Enteroviral infection is usually mild and self-​limited. HSV-​1 typically causes an encephalitis and is treated emergently with intravenous (IV) acyclovir (see section on encephalitis). HSV-​ 2 commonly causes acute meningitis and is the most common cause of recurrent viral meningitis. Like most viral meningitides, the course is generally self-​limited; however, severe recurrent episodes can be treated with IV acyclovir. If episodes are particularly frequent, then intermittent prophylaxis can be considered with oral valacyclovir. VZV-​related meningitis has become increasingly recognized; however, CSF VZV may be positive in the absence of clinical symptoms. Immunocompromised patients are treated with IV acyclovir (Table 11.1).

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Diagnosis and Presentation Viral meningitis commonly presents with fever, severe headache, photophobia, and nausea. Altered level of consciousness is rare. There may be evidence of a viral exanthema in enteroviruses and occasionally also with WNV. The CSF profile shows a normal opening pressure, mild leukocytosis (100–​ 1000/​mm3), lymphocytic predominance (although neutrophils may prevail early in the course in approximately 40% of patients), mildly elevated protein (50–​250 mg/​dL), and a normal glucose. CSF evaluations for specific viral etiologies are summarized in Table 11.1. HIV-​related acute meningitis can be diagnosed by CSF polymerase chain reaction (PCR) since patients may not have seroconverted at the time of meningitis presentation.

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have defects in phagocyte function, or have decreased cell-​mediated immunity. CNS infection is typically from direct extension (e.g., sinusitis) or hematogeneous spread. Diagnosis and Presentation In general, the CSF profile of fungal meningitides includes elevated opening pressure, moderate pleiocytosis (100–​500/​mm3) with a lymphocytic predominance, elevated protein (100–​500 mg/​dL), and decreased glucose (20–​40 mg/​dL with a CSF to blood glucose ratio of 1), and an elevated IgG index (>0.66). It is important to recognize that many pathologic antibodies may be present in CSF only and without significant evidence of CSF inflammation. Electroencephalography (EEG) is rarely specific but often very informative diagnostically in understanding encephalopathy or even localizing pathologic regions within the brain. Occasionally, certain findings may be suggestive of specific disease processes (see Table 12.3 for details).

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Constipation screen

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Table 12.3  Suggested Imaging and Diagnostic Studies for the Evaluation of Autoimmune Central Nervous System Disease Diagnostics CT/​CTA Head

CT Chest/​Abd/​ Pelvis MRI

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MRI spectroscopy FDG PET

EEG

Transvaginal US

Finding Vascular beading Venous engorgement Atrophy Mass

Potential Diagnosis Vasculitis AVM, fistula, VST Neurodegenerative process Malignancy screen

Leptomeningeal enhancement Mesotemporal T2/​DWI changes Focal cortical DWI changes Cortical DWI ribboning Dawson’s fingers Basal ganglia T2 changes Microhemorrhages Lactate peak Focal uptake Focal cerebellar uptake Mesotemporal uptake Spinal cord uptake Extreme delta brush PSWC Periodic temporal discharges Diffuse slowing with triphasics Ovarian mass

Meningitis Limbic encephalitis Focal seizures CJD, anoxia Multiple sclerosis Arbovirus, toxydromes CAA, TTP, DIC Metabolic abnormalities Malignancy Acute cerebellar degeneration Limbic encephalitis Transverse myelitis NMDA encephalitis CJD HSV Metabolic encephalopathy NMDA encephalitis

CT = computed tomography; CTA = computed tomography angiography; AVM = arteriovenous malformation; VST = venous sinus thrombosis; MRI = magnetic resonance imaging; FDG-​ PET = fluorodeoxyglucose-​positron emission tomography; EEG =electroencephalography; PSWC = periodic sharp wave complexes; CJD = Creutzfeldt-​Jakob disease; CAA = cerebral amyloid angiopathy; TTP = thrombotic thrombocytopenia purpura; DIC = disseminated intravascular coagulopathy; HSV = herpes simplex virus; US = ultrasound.

Often the workup of neurologic disease yields only nonspecific markers of inflammation without providing a specific diagnosis, in which case biopsy may be required to further narrow the pathologic process and guide treat­ ment. When considering CNS biopsy, the potential diagnostic benefit must be weighed against the very significant risk of potentially permanent neurologic injury. In general, targets for biopsy should be in regions of active disease in­ volvement on neuroimaging. When the area of active involvement is inacces­ sible, the potential diagnostic yield of biopsy drops considerably, and the utility of such an intervention should be further considered. When feasible, brain and/​or meningeal biopsy yields invaluable information regarding the nature of the inflammatory response, the underlying cellular/​immune process, and the

Result Normal elevated >0.66 >1

Paraneoplastic panel New generation sequencing WBCs Flow cytometry Cytology HSV1/​HSV2 PCR VZV PCR and Ab β2 microglobulin IgH gene rearrangement

positive negative 5–​100 normal normal negative negative normal absent

Inflammation and Demyelination

CSF Study Glucose Protein IgG index Oligoclonal bands

Chapter 12

Table 12.4  CSF Studies Consistent with Inflammation of the Central Nervous System

microstructural distribution of the inflammation, all of which can have signifi­ cant impact on the choice of therapy.

Treatment Options In the intensive care unit (ICU) setting, the clinical examination and diagnostic workup must be focused on identifying specific pathophysiologic processes that allow for early targeted treatment, rather than solely aimed at securing a specific diagnosis. The balance between the risks of treatments, diagnostic confidence, and the risk of disease progression will ultimately define individual patient care. Table 12.5 lists categories of autoimmune pathophysiology and associated disorders as well as potential acute interventions. The risk of these interventions is real and may significantly contribute to secondary se­ quelae such as opportunistic infections. This is true for other widely accepted indications for these medications including immune suppression in organ transplantation. The treatment of immunologic diseases of the brain is not limited to immunomodulation, and it is important to recognize that immunolog­ ical attacks on central nervous tissue may manifest as seizures, vascular events, cerebral edema, pain, or psychiatric symptoms. These clinically rel­ evant symptoms may have to be treated directly in the acute setting and may be even exacerbated by disease-​modifying therapies. Finally, many of

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CSF = cerebrospinal fluid; WBC = white blood count; PCR = polymerase chain reaction.

Table 12.5  Autoimmune Central Nervous System Diseases and Treatments Classified by Mechanism of Underlying Immune Dysfunction Predominant Pathophysiology Disorders

T-​Cell Mediated

B-​Cell Mediated

Multiple sclerosis ADEM

SLE NMO (anti-​AQP4)

PACNS (PCNSV)

Transverse myelitis NOS

Aβ-​related angiitis IgG4-​RD Sjögren’s syndrome Intracellular antigen antibodies: Hu, Ma2, GAD, CV2, Ri, Yo, Amphiphysin CLIPPERS

Miller-​Fisher syndrome Bickerstaff encephalitis Antiphospholipid syndrome SREAT Stiff-​Person syndrome Synaptic antibodies: NMDA, AMPA, GABA, mGluR5, D2 receptor Channel targeting antibodies: LGl1, CASPR2, DPPX, MOG

Granulomatous Disorders Sarcoidosis GCA Wegener’s granulomatosis

Autoinflammatory Disorders Behçet’s disease

NOS Susac disease Churg-​Strauss Syndrome Microscopic Polyangiitis

Treatments

Glucocorticoids Cyclophosphamide

Glucocorticoids Plasma exchange

Anti-​CD20 targeting therapies Natalizumab

IVIG Anti-​CD20 targeting therapies Anti-​C5 (eculizumab) Anti-​IL-​6R (tocilizumab)

Glucocorticoids TNF-​alpha inhibitors (GCA does not respond) Anti-​CD20 targeting therapies Cyclophosphamide

Glucocorticoids TNF-​alpha inhibitors

Glucorticoids Cyclophosphamide

Anti-​CD20 targeting therapies

ADEM = acute disseminated encephalomyelitis; PACNS = primary angiitis of the central nervous system; SLE = systemic lupus erythematosus; NMO = neuromyelitis optica; SREAT = steroid responsive encephalopathy associated with autoimmune thyroiditis; GCA = giant cell arteritis; CLIPPERS = chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. Compiled with assistance of Ivana Vodopivec, MD, PhD.

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these autoimmune disorders have been associated with neoplasia or benign tumors. These lesions are frequently small but need to be identified and treated rapidly.

Treatment Risks Treatment with immunomodulatory agents incurs a significant risk for infec­ tion and other systemic side effects, and patients should be properly screened and protected to minimize potential complications. Most complications re­ lated to chronic immune suppression are due to opportunistic infections; de­ spite these, treatment is generally necessary as the autoimmune disease may lead to loss of life or severe neurologic disability. Vaccinations play a significant role in prevention against opportunistic infections in patients who are chron­ ically immune suppressed. However, routine vaccinations against Influenza, Streptoccocus pneumoniae, and latent Zoster are frequently avoided during the period of acute illness as they may conceivably worsen immunologic disease. Table 12.6 lists standard laboratory tests that should be obtained prior to the initiation of immune suppression in order to better understand the risks of these interventions. Frequently, these labs are positive but the immuno­ logic treatment is still given; in these cases, additional antimicrobials, an infec­ tious disease consultation, or additional discussions with the family may be warranted. For example, JC virus serologies are often positive prior to initia­ tion of therapy, in which case the JC virus (JCV) antibody index may be useful to assess the relative risk of progressive multifocal leukoencephalopathy (PML) in the individual patient ( JCV antibody index >1.5 indicates an in­ creased risk for PML). Glucocorticoids and many immunomodulators increase the risk for Pneumocystis jiroveci pneumonia; this is more relevant in chronically Table 12.6  Suggested Pretreatment Screening Studies for Immunomodulatory Therapy Infection Screens Hepatitis B sAB Hepatitis B cAB Hepatitis C AB HIV AB/​CD4 HIV PCR Strongyloides T. cruzi JC virus AB index PPD/​IGRA

Other Labs BUN/​Cr LFTs hCG IgM, IgG, IgA Vitamin D TMPT

Anti-​CD20

Anti-​TNFalpha

IVIG

PLEX

Anti-​C5

1–​1.5 plasma volumes × 5 over 10 days Eculizumab 400–​1200 mg IV Q2 weeks

Major risks Psychosis, myopathy, hyperglycemia, osteonecrosis, hypertension

Prophylaxis Proton pump inhibitor Vitamin D/​calcium TMP/​SMX, Mepron, Dapsone

Hemorrhagic cystitis, lymphoma, sterility, hepatotoxicity

IVF Mesna antiemetics TMP/​SMX

Anaphylaxis, hypogamma­ globulinemia, PML, fever

Acetaminophen Diphenhydramine Methylprednisolone

Anaphylaxis, hepatotoxicity, optic neuritis, CNS demyelination

Treat latent Tb TMP/​SMX acetaminophen

Anaphylaxis, hypercoagulability, aseptic meningitis, anemia Hypotension, coagulopathy

Acetaminophen Diphenhydramine

Hypertension, anemia

Acetaminophen Diphenhydramine Acetaminophen Diphenhydramine Acetaminophen Diphenhydramine

Anti-​IL-​6R

Tocilizumab 8 mg/​kg IV Q4 weeks

Anaphylaxis, GI perforation

Natalizumab

300 mg IV Q4 weeks

PML, anaphylaxis

IVF

SLE = systemic lupus erythematosus; NIH = National Institutes of Health; GI = gastrointestinal; PML = progressive multifocal leukoencephalopathy; IV = intravenous.

Inflammation and Demyelination

Cyclophospha­ mide

Dosing Methylprednisolone 1000 mg IV QD × 3–​5 days Dexamethasone 4–​ 10 mg IV Q6H × 3–​5 days Partners MS protocol: 800 mg/​m2 IV Q4 weeks × 6 EULAR protocol: 15 mg/​kg IV Q2 weeks × 3 SLE NIH protocol: 0.5–​1 g/​m2 Q4 weeks × 6 EURO lupus protocol: 500 mg IV Q2 weeks × 6 Rituximab 1000 mg Q2 weeks × 2 Rituximab 375 mg/​ m2 Qweek × 4 Infliximab IV 3–​10 mg/​kg Q2 weeks Adalimumab SC 40 mg Q2 weeks 2 g/​kg over 3–​5 days

Chapter 12

Agents Glucocorticoids

127

Table 12.7  Doses and Appropriate Prophylaxis for Commonly Used Immunomodulatory Drugs

Neurological Conditions SECTION 1

immune-​ suppressed patients, but antibiotic prophylaxis is frequently considered. Table 12.7 lists available acute immunomodulatory regimens and associated prophylaxis. While there is limited data guiding the use of these medications, there is often little to lose in critically ill patients with rapidly progressive immunologic disorders, and the risk of withholding potentially efficacious treatment often outweighs those associated with these agents. Finally, immunologic interventions may affect the yield of future diagnostic studies; for this reason it is reasonable to collect extra serum and necessary tissue biopsies prior to the initiation of therapy. If a paraneoplastic disorder is being treated, the treatment should be focused against the primary ma­ lignancy in addition to immunologic modulation. This requires a multidisci­ plinary approach involving oncologists, surgeons, radiation oncologists, and neurologists.

128

Conclusion Immunologic disorders in the neurocritical care unit often cause significant morbidity and mortality and are associated with prolonged and expensive ICU stays. Fortunately, if treated rapidly these are potentially reversible disorders. Expanding our understanding of the basic pathophysiology of these diseases and focusing on currently available immunomodulatory tools will allow us to benefit more patients in the future.

Further Reading Agnihotri S, Singhal T, Stern B, Cho T. Neurosarcoidosis. Semin Neurol. 2014;34(4):386–​394. Antiphospholipid Antibodies in Stroke Study Group. Clinical and laboratory findings in patients with antiphospholipid antibodies and cerebral ischemia. Stroke. 1990;21(9):1268–​1273. Bhattacharyya S, Berkowitz AL. Primary angiitis of the central nervous system: avoiding misdiagnosis and missed diagnosis of a rare disease. Pract Neurol. 2016;16(3):195–​ 200. doi:10.1136/​practneurol-​2015-​001332 Bhattacharyya S, Helfgott SM. Neurologic complications of systemic lupus erythema­ tosus, Sjögren syndrome, and rheumatoid arthritis. Semin Neurol. 2014;34(4):425–​436. Biotti D, Deschamps R, Shotar E, et  al. CLIPPERS:  chronic lymphocytic inflamma­ tion with pontine perivascular enhancement responsive to steroids. Pract Neurol. 2011;11(6):349–​351. Castillo P, Woodruff B, Caselli R, et al. Steroid-​responsive encephalopathy associated with autoimmune thyroiditis. Arch Neurol. 2006;63(2):197–​202. Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol. 2008;7(4):327–​340.

McKeon A, Pittock SJ, Lennon VA. CSF complements serum for evaluating paraneoplastic antibodies and NMO-​IgG. Neurology. 2011;76(12):1108–​1110. Olmez I, Moses H, Sriram S, Kirshner H, Lagrange AH, Pawate S. Diagnostic and ther­ apeutic aspects of Hashimoto’s encephalopathy. J Neurol Sci. 2013;331(1–​2):67–​71. Plavina T, Subramanyam M, Bloomgren G, et al. Anti-​JC virus antibody levels in serum or plasma further define risk of natalizumab-​ associated progressive multifocal leukoencephalopathy. Ann Neurol. 2014;76(6):802–​812. Saip S, Akman-​ Demir G, Siva A. Neuro-​ Behçet syndrome. Handb Clin Neurol. 2014;121:1703–​1723. Scolding NJ, Joseph F, Kirby PA, et al. Abeta-​related angiitis: primary angiitis of the cen­ tral nervous system associated with cerebral amyloid angiopathy. Brain. 2005;128(Pt. 3):500–​515. Shahrizaila N, Yuki N. Bickerstaff brainstem encephalitis and Fisher syndrome:  anti-​ GQ1b antibody syndrome. J Neurol Neurosurg Psychiatry. 2013;84(5):576–​583. Shams’ili S, Grefkens J, de Leeuw B, et  al. Paraneoplastic cerebellar degeneration as­ sociated with antineuronal antibodies:  analysis of 50 patients. Brain. 2003;126(Pt. 6),1409–​1418. Tenembaum S, Chitnis T, Ness J, Hahn JS, International Pediatric MS Study Group. Acute disseminated encephalomyelitis. Neurology. 2007;68(Suppl. 2):S23–​S36.

Inflammation and Demyelination Chapter 12

129

Dalmau J, Tüzün E, Wu HY, et al. Paraneoplastic anti-​N-​methyl-​D-​aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol. 2007;61(1):25–​36. Eng JA, Frosch MP, Choi K, Rebeck GW, Greenberg SM. Clinical manifestations of ce­ rebral amyloid angiopathy-​related inflammation. Ann Neurol. 2004;55(2):250–​256. Graus F, Titulaer MJ, Balu R, et  al. A clinical approach to diagnosis of autoim­ mune encephalitis. Lancet Neurol. 2016;(15):S1474–​ S4422. doi:10.1016/​ S1474-​4422(15)00401-​9 Gwathmey K, Balogun RA, Burns T. J Neurologic indications for therapeutic plasma ex­ change: 2013 update. J Clin Apher. 2014;29(4):211–​219. Hajj-​Ali RA, Singhal AB, Benseler S, Molloy E, Calabrese LH. Primary angiitis of the CNS. Lancet Neurol. 2011;10(6):561–​572. Hardy TA, Chataway J. Tumefactive demyelination: an approach to diagnosis and man­ agement. J Neurol Neurosurg Psychiatry. 2013;84(9):1047–​1053. Hauser SL, Waubant E, Arnold DL, et al. B-​cell depletion with rituximab in relapsing-​ remitting multiple sclerosis. N Engl J Med. 2008;358(7):676–​688. Lafitte C, Amoura Z, Cacoub P, et al. Neurological complications of primary Sjögren’s syndrome. J Neurol. 2001;248(7):577–​584. Lancaster E, Dalmau J. Neuronal autoantigens—​pathogenesis, associated disorders and antibody testing. Nat Rev Neurol. 2012;8(7):380–​390. Linker RA, Gold R. Use of intravenous immunoglobulin and plasma exchange in neurol­ ogical disease. Curr Opin Neurol. 2008;21(3):358–​365. Lu LX, Della-​ Torre E, Stone JH, Clark SW. IgG4-​ related hypertrophic pachymeningitis:  clinical features, diagnostic criteria, and treatment. JAMA Neurol. 2014;71(6):785–​793. McDaneld LM, Fields JD, Bourdette DN, Bhardwaj A. Immunomodulatory therapies in neurologic critical care. Neurocrit Care. 2010;12(1):132–​143.

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Vodopivec I, Miloslavsky E, Kotton C, Cho T. a neurologist’s guide to safe use of immu­ nomodulatory therapies. Semin Neurol. 2014;34(4): 467–​478. von Geldern G, McPharlin T, Becker K. Immune mediated diseases and immune modu­ lation in the neurocritical care unit. Neurotherapeutics. 2011;9(1):99–​123. Yu Z, Kryzer TJ, Griesmann GE, Kim K, Benarroch EE, Lennon VA. CRMP-​5 neuronal autoantibody:  marker of lung cancer and thymoma-​ related autoimmunity. Ann Neurol. 2001;49(2):146–​154.

Chapter 13

Neuromuscular Conditions Deepa Malaiyandi and Saša A. Živković

The clinical manifestation of neuromuscular disorders in the intensive care unit (ICU) setting includes focal or diffuse weakness, dysphagia, sensory loss, and, when severe, respiratory failure. Physical signs of impending respi­ ratory failure include tachypnea, slow and deliberate speech, use of acces­ sory respiratory muscles at rest, and ineffective cough, which in combination with dysphagia may lead to aspiration and sudden worsening of respiratory function. Various other comorbidities can precipitate worsening of respiratory function, including infections and toxic/​metabolic disturbances. Pulmonary function testing and clinical alertness are essential to avoid unexpected res­ piratory failure as delayed intubation is directly related to worse outcomes and increased morbidity and mortality. In addition to severe weakness and respiratory failure, progressive cardiomyopathy associated with muscular dys­ trophies can precipitate cardiac failure and even necessitate cardiac transplan­ tation. Guillain-​Barré syndrome (GBS) is one of few neuromuscular disorders that can be associated with significant dysautonomia. Clinical manifestations of dysautonomia include orthostatic hypotension, cardiac arrhythmia, gas­ trointestinal dysmotility, and anhidrosis. Prolonged ICU stay in patients with severe medical illnesses may also lead to ICU-​acquired weakness or nerve entrapments. Based on pathophysiology and site of neuromuscular dysfunction we can divide neuromuscular disorders into (a) disorders of muscle; (b) disorders of neuromuscular junction; (c) disorders of peripheral nerve, and (d) disorders of motor neurons.

Myopathies Respiratory muscle weakness associated with myopathies typically manifests late in the course of disease as a result of severe diffuse muscle weakness. However, respiratory failure may also be the initial presentation in ambula­ tory patients with mild or minimal limb weakness. Weakness of respiratory muscles can directly result in respiratory failure, and contributing factors may

131

Introduction

Neurological Conditions SECTION 1

include kyphoscoliosis, weakness of pharyngeal and laryngeal muscles, and un­ derlying pulmonary disorders. Inflammatory myopathies may be associated with ventilatory dysfunction due to inflammation of respiratory muscles and also due to interstitial lung disease (especially with elevated Jo-​1 antibody titers). Nevertheless, respiratory failure is rare in patients with inflamma­ tory myopathies. Hereditary myopathies are typically associated with slowly progressive weakness but can manifest with sudden respiratory failure fol­ lowing unrecognized chronic respiratory insufficiency. Rhabdomyolysis in ICU patients often presents in the absence of muscle weakness and pain, and it has been estimated that 10% to 50% of patients with rhabdomyolysis may develop acute kidney injury. Risk factors for rhabdomyolysis in the ICU setting include trauma, recent surgery, and vascular occlusions. An underlying myopathy can also present with rhabdomyolysis following use of medications or strenuous exertion, and it is recommended to wait at least six weeks from resolution for muscle biopsy, as necrosis may mask the underlying primary disease of the muscle. Treatment of rhabdomyolysis is mostly focused on preserving renal function with fluid replacement and potentially dialysis.

132

Myasthenia Gravis Myasthenia gravis (MG) has a prevalence of 14 to 20 per 100,000 in the United States. The typical clinical course of MG is characterized by fatigable weakness and episodic exacerbations. It often begins with ocular symptoms such as ptosis or diplopia, but more than 80% of patients eventually develop generalized weakness. However, if symptoms remain isolated to the eyes for >3 years, the likelihood of generalization is  30% Arterial partial pressure of oxygen (PaO2)  45–​50

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140

Fletcher DD, Lawn ND, Wolter TD, Wijdicks EF. Long-​term outcome in patients with Guillain-​ Barre syndrome requiring mechanical ventilation. Neurology. 2000;54(12):2311–​2315. Ghasemi M, Norouzi R, Salari M, Asadi B. Iatrogenic botulism after the therapeutic use of botulinum toxin-​A: a case report and review of the literature. Clin Neuropharmacol. 2012;35(5):254–​257. Gilhus NE, Verschuuren JJ. Myasthenia gravis:  subgroup classification and therapeutic strategies. Lancet Neurol. 2015;14(10):1023–​1036. Henderson RD, Lawn ND, Fletcher DD, McClelland RL, Wijdicks EF. The mor­ bidity of Guillain-​Barre syndrome admitted to the intensive care unit. Neurology. 2003;60(1):17–​21. Hermans G, De Jonghe B, Bruyninckx F, Van den Berghe G. Interventions for preventing critical illness polyneuropathy and critical illness myopathy. Cochrane Database Syst Rev. 2014;1:CD006832. Hermans MC, Pinto YM, Merkies IS, de Die-​Smulders CE, Crijns HJ, Faber CG. Hereditary muscular dystrophies and the heart. Neuromuscul Disord. 2010;20(8): 479–​492. Hughes RA, Cornblath DR. Guillain-​ Barre syndrome. Lancet. 2005;366(9497): 1653–​1666. Hulse EJ, Davies JO, Simpson AJ, Sciuto AM, Eddleston M. Respiratory complications of organophosphorus nerve agent and insecticide poisoning. Implications for respira­ tory and critical care. Am J Respir Crit Care Med. 2014;190(12):1342–​1354. Kiernan MC, Vucic S, Cheah BC, et  al. Amyotrophic lateral sclerosis. Lancet. 2011;377(9769):942–​955. Kress JP, Hall JB. ICU-​acquired weakness and recovery from critical illness. N Engl J Med. 2014;370(17):1626–​1635. Lacomis D. Neuromuscular disorders in critically ill patients: review and update. J Clin Neuromuscul Dis. 2011;12(4):197–​218. Lawn ND, Wijdicks EF. Fatal Guillain-​Barre syndrome. Neurology. 1999;52(3):635–​638. Nance JR, Mammen AL. Diagnostic evaluation of rhabdomyolysis. Muscle Nerve. 2015;51(6):793–​810. Nitahara K, Sugi Y, Higa K, Shono S, Hamada T. Neuromuscular effects of sevoflurane in myasthenia gravis patients. Br J Anaesth. 2007;98(3):337–​341. Oosterhuis HJ. Observations of the natural history of myasthenia gravis and the effect of thymectomy. Ann N Y Acad Sci. 1981;377:678–​690. Pfeffer G, Povitz M, Gibson GJ, Chinnery PF. Diagnosis of muscle diseases presenting with early respiratory failure. J Neurol. 2015;262(5):1101–​1114. Phillips LH, 2nd. The epidemiology of myasthenia gravis. Ann N Y Acad Sci. 2003;998:407–​412. Shoesmith CL, Findlater K, Rowe A, Strong MJ. Prognosis of amyotrophic lateral scle­ rosis with respiratory onset. J Neurol Neurosurg Psychiatry. 2007;78(6):629–​631. Sorenson EJ, Crum B, Stevens JC. Incidence of aspiration pneumonia in ALS in Olmsted County, MN. Amyotroph Lateral Scler. 2007;8(2):87–​89. Wakerley BR, Uncini A, Yuki N, GBSC Group. Guillain-​ Barre and Miller Fisher syndromes—​new diagnostic classification. Nat Rev Neurol. 2014;10(9):537–​544. Winer JB, Hughes RA. Identification of patients at risk of arrhythmia in the Guillain-​ Barre syndrome. Q J Med. 1988;68(257):735–​739.

Chapter 14

Movement Disorder Emergencies and Movement Disorders in the ICU Mihai C. Sandulescu and Edward A. Burton

Movement disorders are characterized by slowness and paucity of voluntary movement (hypokinetic disorders) or involuntary movements (hyperkinetic disorders). Conventionally, motor weakness (paresis) and motor incoordination (ataxia) are not included, since their anatomy, diagnostic workup, and clinical management differ from hypokinetic and hyperkinetic disorders. The pathophysiology of many movement disorders involves diseases or drugs that impair neurotransmission in the basal ganglia, although there are exceptions. The most common hypokinetic disorders are caused by pathology affecting the dopaminergic projection from the substantia nigra of the midbrain to the putamen and caudate. In addition to degenerative diseases such as Parkinson’s disease (PD), drugs that are antagonists at dopamine receptors can cause a very similar clinical picture. In contrast, lesions in a variety of anatomical locations can provoke involuntary movements, and a syndromic approach based on recognizing the type of involuntary movement is usually most helpful. In this chapter, we summarize diagnosis and management of common movement disorders that require hospital admission or intensive care unit (ICU) management. These are grouped by the clinical appearance of the most prominent abnormalities (hypokinetic versus hyperkinetic), although it should be recognized that different types of movement abnormality can be seen concurrently.

Hypokinetic Movement Disorders Hypokinetic disorders are characterized by an increase in muscle tone that is equal in flexion and extension and throughout the range of movement (rigidity), reduced spontaneous movement (akinesia), and slowness of movement (bradykinesia). The most common hypokinetic disorders are PD and drug-​induced parkinsonism.

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Introduction

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142

Neuroleptic Malignant Syndrome Neuroleptic malignant syndrome (NMS) is caused by dopamine receptor antagonist drugs and has a very high mortality (20%–​30%). All dopamine receptor antagonists and drugs that disrupt other aspects of dopaminergic function have been reported to induce this syndrome, regardless of the presence of a psychiatric or neurological condition. The neuroleptics showing the weakest association with NMS are clozapine and quetiapine. Symptoms of NMS typically start within two weeks from initiating treatment or following a rapid dose escalation. Reported risk factors include abrupt dose increase, concurrent use of lithium or selective serotonin reuptake inhibitors (SSRIs), dehydration, high temperatures, exhaustion, and prior NMS episode. The classical clinical picture includes a change in mental status, fever, rigidity, dysautonomia, and an elevated serum creatinine kinase (CK) (Box 14.1). However, not all patients show all of these signs, and the diagnosis should be considered in any patient with a subset of these features following exposure to relevant drugs. Patients are usually transferred to the ICU for management of complications and airway protection. The offending drug(s) are discontinued immediately. CK should be monitored and appropriate measures taken to prevent renal injury from rhabdomyolysis. Dantrolene, bromocriptine, and benzodiazepines are the standard treatments in the ICU setting, although there may be a role for other dopaminergic agents. Neuroleptics can be restarted two weeks after the acute phase of an episode of NMS, if clinically indicated in patients with ongoing psychosis. Drugs should be reintroduced at low doses and slowly titrated with close monitoring of response and adverse effects. It is recommended that concurrent use of lithium is avoided in this situation.

Parkinsonism-​Hyperpyrexia Syndrome It is well recognized that patients with PD who stop taking dopaminergic medication abruptly can develop a syndrome that is clinically indistinguishable from NMS. Parkinsonism-​hyperpyrexia syndrome (HPS) has also been

Box 14.1  Diagnosis of Neuroleptic Malignant Syndrome • Exposure to a dopamine antagonist or dopamine-​agonist withdrawal • Hyperthermia • Rigidity • Mental status alteration • Elevated CK • Sympathetic nervous system lability (hypertension, fluctuating blood pressure, diaphoresis or urinary incontinence) • Tachycardia and tachypnea Patients may have only a subset of these features; there are currently no validated diagnostic criteria. Gurrera RJ, Caroff SN, Cohen A, et al. An international consensus study of neuroleptic malignant syndrome diagnostic criteria using the Delphi method. J Clin Psychiatry. 2011;72(9):1222–​1228.

Movement Disorder Emergencies

Patients in the ICU are frequently unable to tolerate oral medications for a variety of reasons including unconsciousness, failure of bulbar or respiratory function, loss of airway protection, and following some types of gastrointestinal surgery. Due to the danger of parkinsonism-​h yperpyrexia syndrome, it is rarely advisable to discontinue dopaminergic medications abruptly in these patients. Even though intravenous levodopa is considered generally safe, it is not available in the United States. Immediate release levodopa/​ carbidopa tablets can be crushed and dissolved and given by nasogastric tube. In this case, care should be taken to avoid giving the tablets at the same time as protein-​rich enteral nutrition sources that compete with levodopa for absorption. A  nasogastric tube is often the most straightforward way to administer PD medications to patients who cannot swallow tablets, and many different formulations can be given this way. In situations where enteral absorption of levodopa is not possible, there are several other options (Table 14.1). In addition, it is important to remember that some drugs used commonly in the ICU are harmful to PD patients. For example, several antiemetics (including metoclopramide and prochlorperazine) are potent dopamine receptor antagonists and are contraindicated in patients with PD. Alternatives, including 5HT3 receptor antagonist antiemetics such as ondansetron, can be used in this setting if necessary. Other dopamine receptor blocking drugs that are sometimes used in a hospital to manage agitation, such as haloperidol, are also contraindicated in patients with PD, whereas benzodiazepines can be used judiciously if necessary. For management of hallucinations and other psychotic symptoms in PD, see later discussion. Finally, it should be noted that monoamine oxidase B (MAO-​B) inhibitors, including rasagiline and selegiline, which are commonly used to treat symptoms of PD, have the potential for significant drug interactions. Of particular importance is the risk of uncontrolled hypertension or serotonin syndrome (see later discussion) with the analgesics meperidine and propoxyphene and the antitussive dextromethorphan, all of which should be avoided. A large number of drugs are known to interact with MAO-​B inhibitors, and it is safest to check

Chapter 14

Managing PD Drugs in the ICU

143

described in patients after decreasing the dose of dopaminergic medication, changing from immediate release to extended release levodopa, discontinuing nondopaminergic medications including anticholinergics, or even when deep brain stimulation is stopped. The reported time of onset of symptoms after changing dopaminergic therapy ranges from 18 hours to seven days. Treatment consists of prompt recognition, ICU admission for supportive treatment and management of complications as in NMS, and reinstituting dopaminergic therapy urgently. Options for treatment include non-​ergot dopamine agonists, such as ropinirole or pramipexole, levodopa preparations, or apomorphine (see Table 14.1 for medications, including formulations that can be used in patients who cannot swallow).

Neurological Conditions SECTION 1

Table 14.1  Dopaminergic Drugs: Formulations and Routes of Administration Drug Amantadine

Available Formulations Capsules, tablets, oral suspension (Symmetrel®)

Apomorphine Carbidopa

Injectable (Apokyn®) Tablets (Lodosyn®)

Entacapone

Tablets (Comtan®)

Levodopa Benserazide/​Levodopa

Not available commercially Available in Europe and Canada as tablets (Madopar®, Prolopa®) Tablets as IR (Sinemet®), ER (Sinemet CR®) or combination (RytaryTM); orally disintegrating tablets (Parcopa®); enteral suspension gel (DuodopaTM) Tablets (Stalevo®)

144

Carbidopa/​Levodopa

Levodopa/​Carbidopa/​ Entacapone Lisuride Pramipexole

Available in Europe and China as Dopergin® IR and ER tablets (Mirapex®, Mirapex ER®)

Ropinirole

IR and ER tablets (Requip®, Requip XL®)

Rotigotine Rasagiline

Patch (Neupro®) Tablets (Azilect®)

Selegiline

Capsules, tablets (Eldepryl®) Orally disintegrating tablet (Zelapar®) Patch (Emsam®)

Routes of Administration PO; crushed/​dissolved tablets or oral suspension can be given by NGT subcutaneous PO; crushed/​dissolved tablets can be given by NGT PO; crushed/​dissolved tablets can be given by NGT PO; intravenous PO; (tablets cannot be crushed) PO; crushed/​dissolved Sinemet® IR tablets can be given by NGT; Parcopa® can be given sublingually; DuopaTM can be given enterally PO; (tablets cannot be crushed) PO; intravenous; subcutaneous PO; crushed/​dissolved pramipexole IR tablets can be given by NGT PO; crushed/​dissolved ropinirole IR tablets can be given by NGT Transdermal PO; crushed/​dissolved rasagiline tablets can be given by NGT PO; crushed/​dissolved selegiline tablets can be given by NGT; Zelapar® is given sublingually; Emsam® is given transdermally

PO = by mouth; NGT = nasogastric tube; IR = immediate release; ER = extended release.

any individual drug before adding it to a regimen or to consider discontinuing or switching an MAO-​B inhibitor to another treatment.

Acute Parkinsonism Parkinsonism can occasionally develop rapidly over hours to days, resulting in admission to hospital and occasionally the ICU. This is a relatively infrequent

Infectious

Autoimmune Poisoning /​Toxins Metabolic Structural

clinical situation, and dopamine receptor antagonist drugs are by far the most common cause. In any patient that develops parkinsonism, especially acutely, the most important clinical investigation is the medication and toxin history; this should be elicited completely from patient, family, caregivers, and pharmacy records scrutinized carefully for possible causes (drugs known to provoke parkinsonism are listed in Table 14.2). There are several other causes of acute parkinsonism that should be considered once drugs have been excluded (Table 14.2). Treatment should be targeted at the underlying etiologic mechan­ism, but symptomatic management with dopaminergic medications can also be considered.

Psychosis in PD Up to half of PD patients develop psychosis at some point during the disease, and it is one of the most common triggers for hospital admission and nursing home placement. The clinical spectrum includes misidentification of visual stimuli, visual hallucinations, delusions, and confusion or agitation. As with many chronic neurological diseases, patients with PD are especially at risk for development of encephalopathy during intercurrent illness. The acute development of psychotic symptoms in a PD patient should always prompt a thorough search for infection, metabolic abnormalities, or superimposed neurological conditions such as seizure, stroke, or subdural hematoma resulting from a fall, and a review of recent medication changes that may have provoked symptoms. In the absence of an identifiable cause for psychotic symptoms, consideration should be given to whether the symptoms are caused by long-​term medications or attributable to PD itself. Although all medications used to treat PD can provoke hallucinations in susceptible

Movement Disorder Emergencies

Genetic

Etiology Amiodarone; carbamazepine; chemotherapeutic and cytotoxic agents (including cyclosporin); dopamine receptor antagonists (including all neuroleptics and many antiemetics); lamotrigine; lithium; melatonin; phenytoin; valproic acid; tricyclic antidepressants Rapid onset dystonia-​parkinsonism Acute decompensating Wilson’s disease Coxsackie; Epstein Barr Virus; Human immunodeficiency virus; influenza; Japanese B encephalitis; Murray Valley encephalitis; poliovirus; post measles; western equine encephalitis; lymphocytic choriomeningitis Antiphospholipid syndrome; systemic lupus erythematous Carbon monoxide; cadmium; cyanide; disulfiram; ethanol withdrawal; methanol; manganese; organophosphates; designer drugs Central pontine myelinosis; hepatic encephalopathy Ischemic stroke; obstructive hydrocephalus; subdural hematoma; tumor

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Mechanism Drug-​ induced

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Table 14.2  Acute Parkinsonism

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146

subjects, the worst offenders tend to be anticholinergics, followed by amantadine, MAO-​B inhibitors, dopamine agonists, COMT inhibitors, and levodopa. These medications should be slowly withdrawn in the order listed; it is often most effective to manage PD symptoms in patients with psychosis using levodopa/​carbidopa alone. Delusions and hallucinations without insight, and which do not respond to rationalization of the medication regimen as indicated previously, can be suppressed in some patients using small doses of antipsychotic medications under supervision. Most antipsychotic medications are contraindicated in this setting because of the high risk of worsening motor symptoms and the possibility of NMS. However, clozapine or quetiapine are moderately effective and relatively safe. Quetiapine is preferred since monitoring tests are unnecessary; the starting dose in this setting should be no more than 12.5 mg daily, but the medication can often be titrated slowly to 50 mg a day, given either at night or in divided doses. Clozapine can also be effective at 6.25 to 50 mg daily (this dose is much lower than the doses often used to treat schizophrenia) but requires regular blood monitoring to detect agranulocytosis, a well-​recognized adverse effect of clozapine therapy. More recently, pimavanserin has been approved by the Food and Drug Administration, specifically for treatment of psychosis in PD. It is given as a single dose of 34 mg daily and in clinical trials produced no worsening of motor function at doses that were efficacious for improving hallucinations and delusions. Like quetiapine and clozapine, pimavanserin has been associated with QT prolongation, and care should be taken when introducing these medications, particularly in patients with comorbidities or on the presence of polypharmacy.

Hyperkinetic Movement Disorders –​ Chorea Chorea is characterized by involuntary movements of short duration, irregular frequency, and pseudo-​random distribution. Movements are typically distal and often also involve the face, oral, and lingual muscles. Especially when mild, chorea is typically partially suppressible by the patient. Involuntary movements can be incorporated into more purposeful movements and patients with chorea often appear “fidgety” or “restless.”

Hemiballismus-​Hemichorea Hemiballismus-​hemichorea is characterized by unilateral involuntary choreiform movements; there is a spectrum of abnormalities ranging from typical chorea with predominately distal movements to ballismus, which describes forceful, high-​amplitude flailing movements caused by involvement of more proximal muscle groups. Although uncommon, this is a dramatic clinical pres­ entation that is not easily forgotten once seen; in severe cases, movements can be continuous and violent such that injury is a recognized complication. It was previously thought that hemiballismus-​hemichorea was pathognomonic of

Autoimmune Orobuccolingual Dyskinesia Although uncommon, encephalitis associated with antibodies directed against NMDA receptors can present as an emergency with a prominent movement disorder. The typical history involves a prodromal illness with headaches and flu-​like symptoms, followed by agitation, paranoia, psychosis, or seizures. Orobuccolingual dyskinesia is a characteristic feature of this condition. The movements may include bruxism, grimacing, tongue protrusion and rolling, nares flaring, palatal elevation, oculogyric crisis, smiling-​like movements, and forceful jaw opening and closing, severe enough to cause local injuries. In the later stages of the disease, typical chorea, ballismus, and opisthotonic postures have also been observed. Patients with advanced disease are frequently admitted to the ICU because of autonomic dysfunction, hypoventilation, or loss

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a lesion in the contralateral subthalamic nucleus (STN); however, STN lesions were responsible for less than half of cases in recent series, and it is now recognized that damage to other parts of the basal ganglia or contralateral cortex can provoke the same clinical presentation. Cerebral infarction is the most common recognized etiology of hemiballismus-​hemichorea, followed by non-​ketotic hyperosmolar hyperglycemia. Multiple sclerosis, toxoplasmosis and anticardiolipin syndrome can also cause a similar clinical presentation. Hemiballismus-​ hemichorea patients usually require hospitalization for investigation and symptom control to prevent exhaustion or injury. Routine biochemical studies and brain imaging often indicate the cause. In cases related to hyperglycemia, symptoms frequently resolve within a few days of the patient’s return to normoglycemia, although milder symptoms can persist beyond three months. The movements may take much longer to resolve when caused by other etiologies, although there is a good chance of remission by three months, and it may be possible to discontinue drugs without recurrence. There are no randomized treatment trials for management of acute hemiballismus, and case reports must be interpreted in light of the relatively high rate of spontaneous resolution. Where movements are uncomfortable or violent, treatment is usually initiated with a neuroleptic agent such as haloperidol, with a starting dose of 0.5 to 1 mg twice a day, titrating upwards as needed. In emergency situations, haloperidol may be given by intravenous injection at a dose of 1 to 4 mg every four hours. If ongoing treatment is required beyond a few days, dopamine depletion with tetrabenazine may be preferable for long-​term suppression of hemichorea, because of the lower risk for development of tardive dyskinesia. Tetrabenazine is started at 12.5 mg three times a day and titrated slowly. If there is no response at 50 mg a day, it is recommended that patients are genotyped for CYP2D6 to determine if they are a poor metabolizer prior to further dose increment. Doses up to 150 to 200 mg per day are sometimes required to suppress movements; adverse effects such as hypotension or depression can be limiting. In patients who do not respond to medication, stereotactic surgery can be considered, although experience with this approach for hemiballismus-​ hemichorea is currently limited.

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of consciousness. The syndrome is readily recognized in its characteristic form but should be considered in other patients with a subset of these symptoms. The presence of serum NMDA receptor antibodies is diagnostic. The importance of accurate diagnosis in this condition is twofold. In approximately 60% patients, this is a paraneoplastic autoimmune condition (often associated with ovarian teratoma in young women) and the neurological syndrome may improve with treatment of the malignancy. Consequently, a thorough search for malignancy, including appropriate imaging studies, should be carried out in patients with this condition. Second, even in cases not associated with malignancy, immunotherapy may be effective. Corticosteroids, intravenous immunoglobulin, and plasmapheresis are first-​line treatments; rituximab and cyclophosphamide have been employed in refractory cases (discussed in more detail in Chapter 11). There are two important caveats in the diagnosis and management of NMDA receptor antibody encephalitis. First, since patients usually present initially with neuropsychiatric disturbances, many are already taking neuroleptic medications at time of admission. The orobuccolingual dyskinesia in these patients can be misinterpreted as tardive dyskinesia, and the hyperthermia, elevated creatinine kinase, and rigidity can be ascribed incorrectly to neuroleptic malignant syndrome. Second, patients frequently have both dyskinesia and seizures causing involuntary movements; EEG monitoring is often necessary to distinguish these possibilities to ensure that antiepileptic medications are deployed appropriately.

Hyperkinetic Movement Disorders—​Myoclonus Myoclonus describes rapid, brief, shock-​ like involuntary movements that typically arise within the central nervous system. Myoclonus may be positive (caused by sudden muscle contraction) or negative (caused by sudden disruption of ongoing contraction of postural muscles, sometimes also called asterixis) and is usually not suppressible by the patient.

Serotonin Syndrome Serotonin syndrome (SS) describes a constellation of symptoms and signs caused by serotoninergic drugs. The diagnostic criteria include agitation, tremor, hyperthermia, dysautonomia, and hypertonia/​hyperreflexia/​clonus (Box 14.2). The characteristic clinical syndrome also includes prominent myoclonus, although this is not required for diagnosis. SS is an iatrogenic condition; there are multiple medications and combinations that can provoke this syndrome (Table 14.3). The greatest risk for SS appears to be the combination of SSRI antidepressants with MAO inhibitors. Diagnosis is clinical, but ancillary tests are frequently employed to exclude other diagnostic possibilities, for example EEG to exclude seizures in disoriented patients with myoclonus. The diagnosis should be considered in any patient with a history of exposure to relevant medications, presenting with confusion, autonomic findings, hyperreflexia, or increased tone. The majority of cases show substantial

improvement within 24 hours of discontinuing the offending drug(s), which is the most critical part of management. Supportive treatment is also necessary; in severe cases, sedation with benzodiazepines and even intubation might be required. There are some data suggesting that serotonin antagonists may be helpful. Cyproheptadine has been used as an initial 12 mg dose (oral or via nasogastric tube) followed by an additional 2 mg every hour if symptoms persist and a maintenance dose of 8 mg four times a day, once the patient is stabilized. Table 14.3  Drugs Implicated in Serotonin Syndrome Mechanism 5HT receptor agonist

Inhibit 5HT metabolism Stimulate 5HT release

Inhibit 5HT reuptake

Drugs Anticonvulsants: carbamazepine, valproic acid Antidepressants: mirtazapine, trazodone Opiates: fentanyl, meperidine Hallucinogen: LSD Mood stabilizer: lithium Anxiolytics: buspirone Herbal supplements: St. John’s wort, Syrian rue MAOIs: methylene blue, phenelzine, rasagilline, selegiline Amphetamine Antidepressants: mirtazapine Weight loss drugs: phentermine Certain opiates: meperidine, oxycodone Over-​the-​counter cold remedies: dextromethorphan Parkinson disease: Levodopa Amphetamine, cocaine, MDMA (Ecstasy) Antiemetics: granisetron, ondansetron Antihistamines: chlorpheniramine Atypical Antidepressants: bupropion, trazodone Opiates: levomethorphan, methadone, pethidine, tramadol SNRIs: venlafaxine, duloxetine, venlafaxine SSRIs: citalopram, escitalopram, fluoxetine, paroxetine, sertraline TCAs: amitriptyline, desipramine, doxepin, nortriptyline

MAOIs = monoamine oxidase inhibitors; SNRI = serotonin and norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant.

Movement Disorder Emergencies

Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM. 2003;96(9):635–​642.

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• History of exposure to a relevant drug or other chemical agent • Satisfies at least one of: • Spontaneous clonus • Inducible clonus + agitation or diaphoresis • Tremor + hyperreflexia • Hypertonia + temperature above 38oC + inducible clonus

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Box 14.2  Diagnosis of Serotonin Syndrome

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Chlorpromazine, 50 to 100 mg intramuscularly, can be considered if oral or nasogastric administration of medication is not possible.

Post-hypoxic Myoclonus Cerebral anoxia due to cardiac arrest can cause both acute myoclonic status epilepticus and chronic post-hypoxic myoclonus. Myoclonic status epilepticus manifests clinically as generalized myoclonus in deeply comatose patients, usually within 12 to 24 hours after return of spontaneous circulation and is generally considered indicative of a poor prognosis for survival (although some recent reports present more favorable outcomes with aggressive treatment). While phenytoin is seldom helpful, some benefits have been reported with valproic acid, levetiracetam, and continuous infusions of GABA-A agonists. Note to editor-the A after GABA should be subscript and no dash between GABA and the subscript A. Both the EEG findings (burst suppressions and continuous generalized epileptiform discharges) and myoclonic movements can be suppressed by the infusion of propofol and other anesthetics, although there is no strong evidence that this improves the poor prognosis for recovery (see Chapter 14). Chronic post-hypoxic myoclonus (aka Lance Adams Syndrome) can occur within a few days of return of spontaneous circulation but is typically a late complication following recovery from anoxic brain injury. The clinical picture characteristically includes action and stimulus-​sensitive myoclonus in an awake patient. Cognitive function may be preserved. The involuntary movements may resolve over several years but if persistent, they are often difficult to control medically.

Myoclonus in Other Conditions Prominent positive and negative myoclonus is commonly seen in hospital and ICU patients with a variety of systemic conditions, often in the setting of encephalopathy. The most common associations include renal failure, hepatic failure, hypercapnia, and sepsis. Some medications also characteristically provoke myoclonus, including SSRIs and gabapentin. EEG is frequently employed in this setting to ensure that the combination of altered conscious level and myoclonus are not caused by seizures. Usually, symptomatic treatment to suppress the movements is unnecessary and therapy is directed at the underlying cause, such as addressing uremia, or discontinuing offending medications, following which myoclonus usually resolves quickly. Oral clonazepam 0.5 mg can be considered if the movements are uncomfortable or otherwise bothering the patient.

Hyperkinetic Movement Disorders—​Dystonia Dystonia refers to involuntary sustained muscle contractions that produce abnormal postures and twisting movements. Primary dystonia refers to diseases in which dystonia is the sole or predominant manifestation and there is no focal pathology or other extrinsic cause (which define secondary dystonia). Many types of primary dystonia are genetically determined.

Drugs reactions are the most common cause of acute focal dystonia. If maintenance of the airway or respiratory function is compromised, this can be life-​threatening. Acute dystonia usually appears within 24 hours following drug exposure, and it often manifests with predominant orofacial dystonia. Common presentations include tongue protrusion, oculogyric crisis, blepharospasm, torticollis, trismus, and dysarthria. Neuroleptics and dopamine receptor antagonist antiemetics are the most commonly implicated drugs, but SSRIs, tricyclic antidepressants, carbamazepine, phenytoin, or cocaine have also been reported to provoke acute dystonia. Acute dystonic reactions are usually self-​limiting but when distressing they can frequently be reversed by 1 to 2 mg of benztropine given as an intravenous or intramuscular injection and repeated 20 minutes later if needed. A course of oral benztropine tapering over a week may be required to prevent the dystonia from returning.

Conclusions Movement disorder emergencies can be associated with dramatic clinical presentations that sometimes appear confusing or overwhelming. Diagnosis is nearly always based on careful appraisal of the history and examination findings, and is frequently relatively straightforward. Rapid clinical recognition of these conditions in the emergency room and ICU often results in effective treatment and a good prognosis for recovery, so that familiarity with diagnosis and management of common movement disorders emergencies is both important and useful.

Further Reading Artusi CA, Merola A, Espay AJ, et al. Parkinsonism-​hyperpyrexia syndrome and deep brain stimulation. J Neurol. 2015;262(12):2780–​2782. Boyer EW, Shannon M. The serotonin syndrome. New Engl J Med. 2005;352(11): 1112–​1120.

Movement Disorder Emergencies

Acute Dystonic Reactions Secondary to Drugs

Chapter 14

Dystonic storm refers to a state of unremitting severe dystonia. This can occur in patients with primary or secondary forms of dystonia, precipitated by infection, medication changes, trauma, or abrupt failure of deep brain stimulation (DBS) hardware. Patients are usually admitted to ICU for supportive treatment including fluid and electrolyte balance. Treatment may also include antimuscarinic medications, baclofen, or benzodiazepines, but these are often ineffective and so sedation, airway protection, and even paralysis are sometimes necessary to relieve the movements. Episodes may take days to weeks to respond to treatment. Bilateral DBS of the globus pallidus interna is now considered a treatment of choice for severe refractory forms of dystonia.

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Dalmau J, Lancaster E, Martinez-​Hernandez E, Rosenfeld MR, Balice-​Gordon R. Clinical experience and laboratory investigations in patients with anti-​NMDAR encephalitis. Lancet Neurol. 2011;10(1):63–​74. Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM. 2003;96(9):635–​642. English WA, Giffin NJ, Nolan JP. Myoclonus after cardiac arrest: pitfalls in diagnosis and prognosis. Anaesthesia. 2009;64(8):908–​911. Gurrera RJ, Caroff SN, Cohen A, et al. An international consensus study of neuroleptic malignant syndrome diagnostic criteria using the Delphi method. J Clin Psychiatry. 2011;72(9):1222–​1228. Huddleston DES. Parkinsonism-​ hyperpyrexia syndrome in Parkinson’s disease. In: Frucht SJ, ed. Movement Disorder Emergencies: Diagnosis and Treatment, 2nd ed. New York: Humana Press; 2013:29 -​ 42. Friedman JH, Factor SA. Atypical antipsychotics in the treatment of drug-​induced psychosis in Parkinson’s disease. Move Disord. 2000;15(2):201–​211. Krauss JK, Pohle T, Borremans JJ. Hemichorea and hemiballism associated with contralateral hemiparesis and ipsilateral basal ganglia lesions. Move Disord. 1999;14(3):497–​501. Munhoz RP, Teive HA, Eleftherohorinou H, Coin LJ, Lees AJ, Silveira-​Moriyama L. Demographic and motor features associated with the occurrence of neuropsychiatric and sleep complications of Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2013;84(8):883–​887. Postuma RB, Lang AE. Hemiballism:  revisiting a classic disorder. Lancet Neurol. 2003;2(11):661–​668. Ristic A, Marinkovic J, Dragasevic N, Stanisavljevic D, Kostic V. Long-​term prognosis of vascular hemiballismus. Stroke. 2002;33(8):2109–​2111.

Section 2

Interventions and Monitoring

Chapter 15

Multimodality Monitoring Maranatha Ayodele and Kristine O’Phelan

Introduction

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Advancements in in the critical care of patients with neurological conditions recognizes that in addition to the initial insult, there is a secondary cascade of physiological events that contribute to morbidity and mortality. Multimodality monitoring (MMM) in neurocritical care aims to help recognize this process, and then help tailor management to prevent or minimize any secondary injury. This chapter will discuss a variety of invasive and non-invasive MMM techniques aimed at monitoring brain physiologic parameters (Table 15.1), and offer a practical guide to their integration and use in the intensive care setting.

The Basics: Intracranial Pressure and Cerebral Perfusion Pressure Intracranial pressure (ICP) monitoring allows for determination of cerebral perfusion pressure (CPP). These parameters are intrinsically linked together with mean arterial pressure (MAP), and this relationship is detailed by the equation CPP  =  MAP  –​ICP. ICP and CPP are arguably the most commonly assessed physiologic parameters in brain-​injured patients. Per the equation, knowledge of ICP and MAP can allow for the calculation of CPP. Table 15.1  Multimodal Monitors Physiologic Parameter

Intracranial Brain Tissue and Cerebral Oxygenation Perfusion Pressures

Cerebral Blood Flow

Brain Metabolism

Electrical Activity

Invasive

EVD Micro­ transducers

Jugular bulb oximetry Brain tissue oxygen tension

Thermal dilution probe Laser-​Doppler Flowmetry

Cerebral microdialysis

EEG depth electrode eCOG

Noninvasive

Pupillometry ONSD

NIRS

TCD

cEEG qEEG

EVD = external ventricular drain; EEG = electroencephalography; eCOG = electocorticography; NIRS = near-​infrared spectroscopy; ONSD = optic nerve sheath diameter (via ultrasound); TCD = transcranial doppler ultrasonography; cEEG = continuous electroencephalography; qEEG = quantitative electroencephalography.

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Optimization of ICP and CPP remains an essential component in the critical care management of neurocritical care patients. Invasive and noninvasive methods of assessing ICP exist. The most commonly used invasive technique involves the use of either intraventricular fluid–​coupled transducers (considered by many to be the gold standard) or solid-​state microtranducers.

Invasive Techniques External Ventricular Drain An external ventricular drain (EVD) is a fluid-​coupled transducer that can be placed via burr hole into the lateral ventricle with the tip positioned at the level of the foramen of Monroe. The internal catheter is connected to an external pressure transducer. This pressure transducer must be zeroed to the level of the foramen of Monroe using the tragus of the ear as an external landmark. EVD use has advantages and disadvantages. Advantages:

• It allows for the continuous monitoring of ICP when not draining cerebrospinal fluid (CSF) • Analyses of ICP waveforms provide information about brain compliance • Elevations in ICP may be alleviated by draining CSF • Intrathecal medications may be administered through the catheter Disadvantages:

• Requires placement through the brain parenchyma, and this may lead to • Hemorrhage—​along the EVD tract or into the ventricle, especially in coagulopathic patients • Infection • There may be CSF over drainage leading to intracranial hypotension and development of subdural hematomas • The catheter may become occluded and prevent accurate measurements of ICP • The fluid-​filled system must be closed to accurately measure pressure • Malposition may prevent accurate readings Parenchymal Monitors An alternative invasive method of ICP monitoring involves the use of microtransducer devices. With these devices, the transducer is located at the distal tip of the catheter and is composed of a fiberoptic cable, strain gauge device, or pneumatic sensor that responds directly to pressure changes in the tissue in which it is placed. These microtransducers are most commonly placed intraparenchymally because this location yields the most accurate data. However, they may be placed anywhere in the intracranial vault including the epidural, subdural, subarachnoid, and intraventricular spaces. Advantages:

• May be placed through smaller burr hole, and the small size of the catheter allows for minimal trauma to brain tissue with fewer hemorrhagic and infectious complications

Noninvasive Techniques Noninvasive methods of monitoring of ICP are much desired in neurocritical care as they provide alternatives for patients in which invasive methods may be undesirable (i.e., ongoing coagulopathy) and are devoid of complications such as intracranial hemorrhage and infection seen with invasive methods. Pupillometry, the use of transcranial doppler ultrasonography (TCD) to determine pulsatility index (PI), and ultrasound duplex imaging of the optic nerve sheath diameter (ONSD) represent noninvasive methods of evaluating ICP, though each has significant limitations. Pupillometry Pupillometry involves the use of a portable computer-​based infrared digital video device to assess pupillary size and reactivity. Changes in the pupillary light reflex have long been observed to predict severity and prognosis in various forms of brain injury. The pupillometer device allows for a quantitative assessment of this important reflex. The pupillometer is placed over the patient’s eye and shines a fixed-​intensity, fixed-​duration light stimulus into the eye. Pupillary images are captured in rapid sequence. The device measures variables such as pupillary size at baseline and after constriction, latency in milliseconds, and constriction/​dilation velocity in millimeters per second. Using these parameters, some devices can calculate a score known as the Neurological Pupil Index (NPi). The NPi ranges from 0 to 5 with scores above 3 considered normal. Several studies have examined the use of such quantitative pupillometry in patients with brain injury and have found correlations predictive of elevations in ICP (Table 15.2). Pupillometry use has its limitations in that the parameters measured may be affected by medications, some of which are used routinely in the management of neurocritical care patients. The device also cannot measure consensual pupillary responses and cannot be used in patients with direct eye trauma, with prior surgery to the iris, or who resist the exam with forced eye closure. Ultrasound Modalities Determination of PI and ONSD are two distinct ways in which ultrasound may be used as a noninvasive determinant of ICP. PI is determined by using TCD to insonate the middle cerebral arteries (MCA) via thin temporal bone windows. PI is calculated as systolic flow velocity minus diastolic flow velocity divided by mean flow velocity. While Bellner et al. found a reasonably strong correlation between PI and invasively determined ICP, Behrens et  al. and Morgalla and

Multimodality Monitoring

• Elevations in ICP cannot be alleviated by draining CSF • Calibration drift may occur over time as the device cannot be re-​zeroed once inserted

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Disadvantages:

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• Allows for the continuous monitoring of ICP • Analysis of ICP waveform provides information about brain compliance

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Table 15.2  Pupillometry Parameters Constriction velocity

Neurological Pupil Index

CV 5 mm to be predictive of increased ICP. Additionally, in a recent large systematic review and meta-​analysis by Ohle et al. this value had a sensitivity of 95.6% and a specificity of 92.3% for predicting elevated ICP.

Cerebral Oxygenation Cerebral oxygenation may be monitored invasively and noninvasively. Invasive techniques currently involve measuring jugular venous oxygen saturation (SjVO2) and brain oxygen tissue tension (PbtO2). These two techniques allow for global and regional determination of cerebral oxygenation, respectively.

Invasive Techniques Jugular Bulb Oximetry SjVO2 involves retrograde cannulation of the internal jugular vein. A  small fiber-​optic catheter is inserted and positioned into the jugular bulb at the base of the skull. Appropriate positioning at the base of the skull around the level of the C1 vertebrae is verified on a lateral skull X-​ray. Once calibrated,

Brain Tissue Oxygen Monitoring PbtO2, or the partial pressure of oxygen in brain tissue, is determined via burr-​hole insertion of an intraparenchymal oxygen probe into the subcortical white matter of the brain. Current commercially available probes include Licox (Integra Neurosciences) and Neurovent-​PTO (Raumedic, Inc). Normal PbtO2 measurements are usually 25 to 30  mm Hg. Values less than 15 to 20 mm Hg are concerning for local tissue ischemia and are the typically used thresholds for initiating interventions. PbtO2 values are especially used in conjunction with ICP and CPP monitoring. Optimization of CPP to alleviate ischemia and treatment of elevated ICP are guided by PbtO2 values in this setting (see Table 15.3 for clinical algorithm). Observational studies have shown favorable outcomes for patients with subarachnoid hemorrhage (SAH) and severe traumatic brain injury (TBI) treated with a combination of PbtO2 and ICP/​CPP guided therapy over ICP/​CPP–​based therapy alone. PbtO2 values are greatly influenced by the location in which the probe is placed. The probe provides regional measurement of PbtO2 for an area reflecting only about 14 mm3 of tissue. If placed in contusional tissue or if a hematoma develops around the probe site, values may be greatly reduced and resistant to therapeutic interventions, giving a false sense of the degree of brain ischemia. Alternatively, if placed in normal-​appearing tissue remote from focal brain injury, values may not reflect the degree of regional ischemia present. These are the limitations of this technology at this stage.

Noninvasive Techniques Near-​Infrared Spectroscopy Noninvasive assessment of cerebral oxygenation is possible using near-​ infrared spectroscopy (NIRS). NIRS involves placement of probes emitting near-​infrared light (~700–​1000 nm) along the forehead. The emitted near-​ infrared light penetrates into the underlying brain tissue to an estimated depth of about 2 to 3  cm, and the amount of light absorbed is used to

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SjVO2 measurements reflect the oxygen saturation of blood returning from the brain. This represents the balance between oxygen delivery and utilization and allows for estimation of global oxygen consumption. Normal SjVO2 values are between 60% and 85%. SjVO2 desaturations (i.e., values less than 50%) are concerning for global cerebral ischemia and were found by Robertson et al. to be associated with poor outcomes in patients with severe brain injury. SjVO2 values greater than 85% are also problematic and may indicate an excess of oxygen delivery relative to consumption. Routine use of SjVO2 monitoring in the neurointensive care unit is challenged by the need for frequent recalibration of the catheter once inserted. Additionally, there are complications of catheter misplacement, infection, and risk of venous thrombosis around the catheter propagating intracranially or obstructing venous outflow. This technique is also criticized for its low accuracy to detect regional ischemia. Thus, it may be best when used in patients with widespread brain injury or in conjunction with a regional monitor such as PbtO2.

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Table 15.3  Brain Tissue Oxygen Monitoring Physiologic Parameter

PbtO2 20 mm Hg ICP >20 mm Hg Administer FiO2 Treat ICP 100% × 15 min Follow to test the probe PbtO2 for Drain CSF changes Optimize CPP Administer fluids to euvolemia goal Give blood products for anemia Administer mannitol 0.25–​ 0.5 gm/​kg Administer hypertonic saline Optimize sedation/​ analgesia Consider paralytics Cooling measures for brain temp >37 ºC

PbtO2 >20 mm Hg ICP 40 Glucose 20 mm Hg Treat ICP • Elevate head of bed • Drain CSF • Osmotic therapy • Consider paralysis Optimize: PaCO2, temperature, sedation, CPP, hemoglobin, systemic glucose

ICP = intracranial pressure; CPP = cerebral perfusion pressure; CSF = cerebrospinal fluid.

commonly used for preoperative assessment and seizure foci localization in epilepsy patients. EEG depth electrodes have been used in some centers for continuous EEG monitoring in high-​risk patients with acute brain injury and can detect epileptiform activity that is not well seen on surface EEG. EEG depth electrodes are placed through a standard twist drill burr hole. Electrocorticography grids are placed along the surface of the brain via craniotomy. Their use as a continuous bedside monitor is thus far limited to research studies such as COSBID, where they are used to detect spreading cortical depression.

Noninvasive Techniques Continuous and quantitative electroencephalography with surface electrodes are used to detect not only seizure activity but changes suggestive of underlying cellular injury in high-​risk patients with acute brain injury. Their use is discussed in detail in ­chapter 7.

Further Reading Behrens A, Lenfeldt N, Ambarki K, Malm J, Eklund A, Koskinen LO. Transcranial Doppler pulsatility index:  not an accurate method to assess intracranial pressure. Neurosurgery. 2010;66(6):1050–​1057. Bellner J, Romner B, Reinstrup P, Kristiansson KA, Ryding E, Brandt L. Transcranial Doppler sonography pulsatility index (PI) reflects intracranial pressure (ICP). Surg Neurol. 2004;62(1):45–​51. Bhatia A, Gupta AK. Neuromonitoring in the intensive care unit. I. Intracranial pressure and cerebral blood flow monitoring. Intensive Care Med. 2007;33(7):1263–​1271. Chen JW, Gombart ZJ, Rogers S, Gardiner SK, Cecil S, Bullock RM. Pupillary reactivity as an early indicator of increased intracranial pressure: the introduction of the Neurological Pupil Index. Surg Neurol Int. 2011;2:82. Dubourg J, Javouhey E, Geeraerts T, Messerer M, Kassai B. Ultrasonography of optic nerve sheath diameter for detection of raised intracranial pressure: a systematic review and meta-​analysis. Intensive Care Med. 2011;37(7):1059–​1068.

Multimodality Monitoring

Interventions

Lactate/​Pyruvate Ratio >40 Glucose 14 days

Chapter 17

Stage Hyperacute Acute Early subacute Late subacute Chronic

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Table 17.1  T1 and T2 Sequences to Determine the age of Blood Products at the Time of MRI

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as described further in the following neurointerventional procedures section. Transcranial Doppler (TCD) monitoring is recommended daily and can be used to monitor intravascular cerebral blood flow velocities and calculate Lindegaard ratio, both of which have been correlated to symptomatic and/​or angiographic vasospasm. SDH Hemorrhage into the subdural space is caused by damage to small bridging veins. Most commonly this damage is caused by head trauma, but it can also be seen in the elderly, infants, or neurodegenerative disorders where the subdural space is wider and therefore bridging veins are more prone to damage with changes in head velocity. CTH classically shows a crescent-​shaped hemorrhage that crosses suture lines. While a hyperacute SDH may appear isodense with brain tissue, the typical acute SDH will appear hyperdense on CTH, and chronic SDH are typically hypodense although anticoagulation may result in a fluid-​fluid level of varying densities. EDH The most common cause of EDH is head trauma resulting in damage to the middle meningeal artery, which courses near the pterion, the skull point where the frontal, temporal, parietal, and sphenoid bones merge, making it thin and more susceptible to injury. CTH shows a convex or lentiform-​shaped extra-​ axial hemorrhage due to restriction between suture lines. Due to the high velocity nature of arterial hemorrhage, EDH can cause increased mass effect, increased intracranial pressure, and herniation. Interval CTH can be a useful tool to monitor for midline shift and early signs of herniation if clinical examination cannot be reliably followed.

Ischemic Stroke Acute ischemic stroke (AIS) accounts for 85% of strokes in adults. Workup and treatment of AIS is largely dependent on etiology, which can be categorized as follows: • large vessel atherosclerotic disease resulting in hypoperfusion or

arteriogenic emboli

• penetrating artery disease due to lipohyalinosis • cardiogenic embolism including atrial fibrillation, valvular disease, and ventricular thrombus • cryptogenous stroke • other causes including dissection, drug abuse, prothombotic states, vasculopathy, and vasospasm Initial AIS workup starts with CTH, which may show frank hypodensity or early signs of infarction including cortical effacement, blurring of the grey-​ white junction, loss of the insular ribbon, or a hyperdense vessel sign. The ASPECT score is a standardized scoring system for quantifying the size of infarction and subtracts 1 point from 10 total for each of the following regions of hypodensity scored only on the affected side: at the ganglionic level

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caudate, lentiform nucleus, internal capsule, insular ribbon, anterior middle cerebral artery (MCA) cortex (M1), MCA cortex lateral to the insular ribbon (M2), posterior MCA cortex (M3), and then at the supraganglionic level an additional three cortical areas (M4–​6) immediately superior to M1–​3. Large strokes (APSECT 1–​4) are associated with high risk of reperfusion bleeding if revascularized. DSA is the gold standard for extracranial and intracranial vascular imaging for AIS, but generally noninvasive studies are first obtained. CTA of the head and neck can be used to identify and measure the degree of a flow-​limiting stenosis and is often helpful in determining the composition of the stenosis (soft plaque, thrombus, calcified plaque). In the case of arterial dissection, a true and false lumen can often be identified. Multiphase CTA is a technique where multiple additional CT images are collected following one bolus of intravenous (IV) dye and can be used to detect delayed vessel filling in a particular area. This technique can help discriminate occluded vessels from pseudo-​occlusions and help characterize collateral supply in the setting of acute intracranial occlusions. Although CTA can usually be obtained more quickly than MRI/​A, it does require the use of IV dye, which limits its application in patients with iodine-​based contrast allergy or renal impairment. CT perfusion (CTP) is a powerful tool for AIS imaging that can also be obtained quickly, though with additional IV dye and radiation exposure. CTP raw data can be reformatted into cerebral blood volume (CBV), cerebral blood flow (CBF), and mean transit time (MTT) or time to peak (TTP). The ischemic core is the area with low CBV (and therefore low CBF and high MTT and/​or TTP). The ischemic penumbra, or area at risk that may be salvaged if blood supply is restored quickly, is the area with preserved CBV but reduced CBF with increased MTT and/​or TTP. MRI may also be used for AIS imaging, though it is not as widely available, is more costly, and is not compatible in all patient populations (e.g., patients with retained metal products). DWI is exquisitely sensitive for identifying the ischemic core in AIS. The ischemic core is the area of DWI hyperintensity that correlates to apparent diffusion coefficient hypointensity. Early AIS changes can be detected as FLAIR hyperintensity after approximately six hours. GRE or susceptibility weighted imaging (SWAN, SWI, T2*) is highly sensitive for detecting early blood products. Magnetic resonance angiography (MRA) of the head time of flight (TOF) are images collected without gadolinium and can help to identify intracranial occlusions or flow-​limiting stenosis. MRA neck TOF is often limited by motion artifact and an inability to visualize the vertebral and/​or internal carotid origins, so MRA neck with gadolinium is preferred unless there is renal insufficiency. MR perfusion can be interpreted similarly to CTP described previously. CTA and MRA both tend to overestimate the degree of vessel stenosis versus DSA but provide additional information concerning the blood vessel wall and plaque composition not obtained by lumenogram (DSA). It is estimated that 1.9 million neurons die per minute, so there must be an urgency to the rapid evaluation of AIS. As such, there are certain situations

Interventions and Monitoring Section 2

where it may be warranted to skip directly to emergent DSA without first obtaining noninvasive vessel imaging, perfusion imaging, or MRI. DSA is useful for identifying the location of occlusion, measuring the degree of stenosis, identifying collateral vascular supplies, and providing endovascular revascularization via thrombectomy and/​or stenting. Dual energy CTH can be useful to separate hyperdensity from acute hemorrhage from that of iodinated contrast media. Carotid duplex ultrasound (CDUS) is a noninvasive technique useful for identifying and tracking carotid stenosis. B-​mode images can be obtained, which help to visualize the vessel wall. Doppler measurements are also obtained, and blood velocities can be correlated to degree of stenosis. While CDUS also typically overestimates the degree of stenosis versus DSA, it is a safe, cost-​ effective way to manage carotid disease over time without exposure to excess IV dye or radiation. Similarly, TCD can also be used to measure blood velocity, which can be correlated to degree of stenosis for intracranial vessels. Notably skull thickness may limit the operator’s ability to obtain good recording windows. TCD can also be useful for prolonged monitoring to detect high intensity transient signals (HITS) in patients with cardiac sources of embolism.

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Postanoxic Injury Anoxic brain injury occurs in the setting of widespread cardiopulmonary compromise including cardiac arrest, asphyxiation, near-​drowning, drug overdose, and carbon monoxide poisoning. Without oxygen, neurons begin to die after about four minutes, but increased neuronal survival has been demonstrated with use of aggressive resuscitation techniques and targeted temperature management. Grey matter is first affected by hypoxia due to its high metabolic rate, and damage is further exacerbated by excite-​toxic glutamate release. Areas most commonly affected include basal ganglia, thalami, cerebral cortices, cerebellum and hippocampi. CTH may initially show diffuse edema with sulcal effacement, loss of grey-​white differentiation, and basal ganglia hypodensities. In more severe cases, a reversal of the normal grey/​white differentiation can be seen due to venous engorgement from venous outflow obstruction due to increased ICP. Rarely a “white cerebellum sign” may be seen where the brainstem and cerebellum appear relatively hyperdense due to severe hypoattenuation of the cerebrum. A “pseudo-​subarachnoid hemorrhage sign” may also be seen due to engorgement and dilatation of the superficial venous structures appearing hyperdense relative to the ischemic parenchyma. Cortical laminar necrosis may be seen as linear hyperdensities outlining the cortex appearing several weeks after anoxic injury. MRI can detect signs of cytotoxic edema within the first few hours after postanoxic brain injury. DWI changes often pseudonormalize within the first week. During the first 24 hours, T1-​and T2-​weighted images often appear normal. T2 hyperintensities may be seen from 24 hours to two weeks. T1 hyperintensities corresponding to cortical laminar necrosis may be seen around two weeks after injury. Functional MRI and positron emission tomography (PET) may be helpful for prognostication, though larger studies are needed.

Meningitis CTH has a low sensitivity for detecting signs of uncomplicated meningitis but may be used to monitor for complications including edema and hydrocephalus. Nonobstructive hydrocephalus is typically caused by inflammation of the arachnoid villi and thus reduced CSF resorption. Obstructive hydrocephalus results from extension of the primary infection into the ventricles with deposition of purulent debris resulting in ventriculitis, which can cause focal obstruction of CSF outflow. Enhancement of the meninges may be seen on CT or MRI with contrast. Recently, contrast-​enhanced T2 sequences were reported to have a higher sensitivity for leptomeningeal enhancement than traditional contrast-​enhanced T1 sequences. MRI FLAIR may also reveal hyperintense sulci resulting from a failure of FLAIR suppression due to inflammatory proteinaceous material. Location of meningeal involvement may also help to identify the pathogen; for instance, CNS tuberculosis and neurosyphillis tend to affect the basal meninges. Encephalitis Vasogenic edema may be seen in early parenchymal infections, which appears hypodense on CTH and hyperintense on T2-​weighted MRI sequences. For bacterial infections, as cerebritis progresses to abscess formation, a thickened enhancing rim appears and the fluid-​filled cavity fills with purulent material that restricts diffusion and is therefore hyperintense on DWI. CNS toxoplasmosis may appear similar to abscess on CTH, though it is usually restricted to the grey-​white junction. MRI DWI may be helpful to differentiate since restricted diffusion is not typically seen with toxoplasmosis. HSV encephalitis typically causes edema and sometimes hemorrhage in the mesial temporal lobes that may be identified on CTH, though MRI FLAIR is more sensitive early in the disease. Arboviruses commonly affect deep grey nuclei. CTH with contrast may be helpful to identify enhancing parenchymal lesions but may not be as useful in the postoperative period where evolving hematoma, seroma, and early infection may all have similar enhancing appearances and MRI may be needed for further differentiation.

Neuroimaging & Neurointervention

Extra-​axial Infections Epidural and subdural collections suspicious for infection may be first identified on CTH, but additional imaging is often needed to distinguish epidural phlegmon and subdural empyema from EDH and SDH. MRI typically shows a fluid collection with irregular borders, interior restricted diffusion, and an enhancing rim. An abscess is formed once the collection becomes loculated with a fully enhancing rim.

Chapter 17

Prompt identification and treatment of CNS infection may significantly limit morbidity and mortality. Neuroimaging can be helpful for identifying a specific pathogen based on characteristic imaging findings, managing complications, and prognostication of CNS infectious diseases. MRI with and without contrast is the test of choice for identifying CNS infections, though CTH can be helpful in some situations.

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Interventions and Monitoring Section 2

Encephalopathy Some metabolic encephalopathies result in cytotoxic edema recognizable in distinct anatomical patterns. For instance, Wernicke’s encephalopathy may be associated with restricted diffusion on DWI but more commonly is associated with hypodensity on CTH that correlates to T2 hyperintensity on MRI. Wernicke’s encephalopathy classically involves bilateral thalami, mammillary bodies, tectum, and periaqueductal grey; however, changes have also been reported in dentate nuclei, cerebellar vermis, inferior olivary complex, caudate, abducens and vestibular nuclei, red nuclei, and splenium. Metronidazole-​ induced encephalopathy has been associated with bilateral T2 hyperintensity in some similar locations including the dentate nuclei, abducens and vestibular nuclei, red nuclei, and splenium. Hepatic encephalopathy is typically associated with T1 hyperintensity in the globus pallidum but has also been reported in the substantia nigra and cerebellar dentate nuclei.

Neurointerventional Procedures 180

Indications Catheter-​based neuroangiography can be performed for diagnostic or interventional purposes. Catheter-​based cerebral angiography can be used to identify, follow, and/​or treat vascular anomalies including cerebral aneurysms, arteriovenous malformations (AVM), arteriovenous fistulas (AVF), and vasospasm. Cerebral angiography is also essential in acute stroke treatment for thrombectomy, angioplasty, and/​or stenting. Other common uses for cerebral angiography include tumor embolization, venous imaging, thrombectomy and/​or stenting, and WADA testing. Catheter-​based cervical angiography is useful for evaluating the degree of extracranial stenosis of the great vessels, vertebral arteries, and carotid arteries, and has become the gold standard for the measurement of extracranial carotid stenosis. Additionally, cervical angiography may be useful for evaluation and treatment of cavernous-​carotid fistulas, epistaxis, tumor, and vascular abnormalities in the setting of neck trauma. Spinal angiography can be useful for identifying the spinal arteries prior to spinal surgery and spinal vascular malformations, including arteriovenous malformations and fistulas, and for vessel identification and/​or embolization for spinal tumors.

Treatments In addition to high resolution vascular imaging, catheter-​based neuroangiography can be utilized for acute thrombectomy in ischemic stroke; venous thrombectomy for refractory venous sinus thrombosis; embolization using coils, glue, or flow-​diverting stents (aneurysm, AVM/​AVF, tumor, epistaxis); angioplasty (intracranial and extracranial flow-​limiting stenosis or vasospasm); application of intra-​arterial medications (calcium channel blockers for acute vasospasm, lytics for central retinal artery occlusion); and for stent placement (most commonly

Table 17.2  Agents used in Endovascular Procedures Medication

Commercial Name

Indication

Dose

Mechanism

Half Life

Side Effect

Reversal

Long-​term prevention of postprocedure thromboembolism

Load: 325 mg; 81–​ 325 mg daily

Platelet inhibition for 11 d

Bleeding, gastritis

Platelets

Long-​term prevention of postprocedure thromboembolism Long-​term prevention of postprocedure thromboembolism Long-​term prevention of postprocedure thromboembolism Short-​term prevention of periprocedure thromboembolism Short-​term prevention of periprocedure thromboembolism

Load: 600 mg; 75 mg daily

Inhibits Cyclooxygenase and decrease thromboxane A2 production Inhibits ADP-​ induced platelet-​ fibrinogen interaction antiplatelets: blocks ADP receptors

Platelet inhibition for 11 d

Bleeding

Platelets

7 hr

Bleeding

Platelets

Inhibits phosphodiesterase III, increased cyclic AMP Inhibits GP Iib/​IIIa receptor

11–​13 hr

Bleeding, leukopenia

Platelets

90–​120 min

Bleeding

Platelets

Prevents factor X activation

90 min

Bleeding, thrombocytopenia

Protamine sulfate, 1 mg for 100 units (not to exceed 50 mg total)

Antithrombotic agents Aspirin

Clopidogrel

Plavix

Prasugrel

Effient

Cilostazol

Pletal

Eptifibatide

Integrilin

Heparin

Load: 60 mg; 10 mg daily

50–​100 mg BID

180 µg/​kg lV bolus followed by 2 µg/​kg per minute infusion for 20–​24 hr 70–​100 U/​kg IV bolus during procedures (typically 5000 U), postprocedure 18 U/​kg/​hr and titrated

(continued)

Table 17.2 Continued Medication

Indication

Dose

Mechanism

Half Life

Side Effect

Reversal

Bivalirudin

Commercial Name Angiomax

Short-​term prevention of periprocedure thromboembolism

Direct thrombin inhibitor

25 min

Bleeding

Recombinant activated factor VII

IA alteplase

Activase

Arterial occlusion

0.75mg/​kg bolus prior to procedure followed by 1.75 mg/​kg/​hr for duration of procedure and up to 4 hr post if needed 540 mg

Converts plasminogen to plasmin

37.5°C within the first 72 hours is independently associated with poor outcome, and patients with fever have a significantly higher risk of hematoma expansion. In patients with SAH and TBI, fever has been independ­ ently linked to adverse outcomes. This detrimental impact is partly explained by the pathophysiology outlined previously, with brain temperature far exceeding core temperature and heat trapping in injured areas. The generalized increase in metabolic rate with corresponding increases in minute ventilation and oxygen consumption could also be detrimental, depending on the patient’s condition. Not all of the processes triggered by an episode of brain ischemia are purely harmful. For example, it has been shown that some degree of neuroinflammation can contribute to cellular repair after an ischemic insult. Further, in some situations the proinflammatory state that may be associated

Clinical Evidence and Potential Indications for Temperature Control Though randomized controlled trials assessing benefits of fever control are still lacking, based on the pathophysiological data discussed here and dozens of observational studies showing a link between fever and adverse outcome, maintaining normothermia is a widely accepted goal in patients with all types of acute brain injury. Some observational and case-​control studies in patients with SAH, AIS, and TBI have reported that aggressive temperature control using a combination of antipyretic drugs and mechanical cooling devices can indeed improve outcomes. Whether hypothermia could further improve outcome compared to strict fever control remains a matter of debate. Evidence for use of fever control and/​or TH for some specific types of injury is briefly discussed next.

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with fever can help the body fight infections. Fever can inhibit the growth of certain species of bacteria while simultaneously stimulating immune cell function and enhancing antibody and cytokine synthesis. Several studies suggest that suppression of fever with antipyretics in patients with influenza can adversely affect outcome. However, when the processes are uncontrolled and overwhelming they are harmful and can lead to cell destruction and death. A  useful analogy might be the process of infection and inflammation, where an immune response is needed to combat the infection, but an extreme cascade of inflammation as may be seen in septic shock can overwhelm the organism and lead to death. In this situation mitigating these processes can improve outcome. Thus the potential benefits of fever should be weighed against the risks. This balance may shift even within the same patient, with protective effects of a febrile response outweighing harm in some phases of a disease, while harm outweighs benefits in other phases. The majority of patients with acute brain injury are likely to suffer harmful consequences of fever and will benefit from strict fever control or even therapeutic hypothermia (TH). As the destructive processes play out over periods of several days and can be restarted by new episodes of ischemia, maintaining an “appropriate” core temperature should be a key goal of care in critically ill patients, especially in those with acute neurological injuries. As with blood pressure and ventilation, there is an “optimal” temperature that suits the patient’s need. Usually this is normothermia; in some situations (such as following anoxic brain injury), a below-​normal temperature may provide additional benefits, while in other situations (such as early stage influenza and perhaps intracranial infections), a mild degree of hyperthermia could be beneficial.

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Neonatal Asphyxia Several randomized controlled trials (RCTs) in infants with perinatal asphyxia have reported significant improvements in neurological outcome when treated with TH (32o–​34oC for periods of 48-​72 hours). The benefits in neurocognitive function persist on multiyear follow-​up in middle childhood. The estimated number needed to treat for the therapy is 6, i.e. six newborns with post-​asphyxia injury need to be treated with hypothermia to achieve one additional case of good neurological outcome. Multiple nonrandomized trials have reported similar benefits. Use of TH in neonatal asphyxia should be considered a standard of care.

Cardiac Arrest Two RCT cooling patients to 32o to 34oC and more than forty nonrandomized before/​after studies have reported significantly improved outcomes in patients with witnessed cardiac arrest and an initial rhythm of ventricular fibrillation or pulseless ventricular tachycardia. In contrast, a large RCT published in 2013 found no difference between strict temperature control at 36oC compared to 33.0oC. The conclusions of this study have been criticized for problems such as delay (up to 4 hours) in randomizing patients, prolonged time (10 hours) to target temperature, temperature fluctuations during the maintenance phase, excessively rapid rewarming, potential selection bias limiting generalizability, and other issues. Thus although there is general agreement on the need for targeted temperature management after witnessed cardiac arrest, the precise optimal target temperature is still being debated. Current guidelines from the American Heart Association (AHA), the American Academy of Neurology (AAN) and the Neurocritical Care Society (NCS) recommend using TH in all patients who have return of spontaneous circulation following witnessed out-​of-​hospital cardiac arrest with an initial rhythm of ventricular fibrillation or pulseless ventricular tachycardia and considering TH for patients with witnessed asystole or pulseless electrical activity arrest. The AHA guidelines recommend strict temperature management with a relatively wide temperature range of 32o to 36oC, followed by strict fever control. The AAN and NCS guidelines recommend 32o to 34oC followed by strict fever control, with 36o as an alternative option in patients where hypothermia is deemed risky, for example because they are actively bleeding (hypothermia can cause mild coagulopathy).

Acute Ischemic Stroke As outlined previously, there is compelling evidence suggesting harmful effects of fever in AIS. Data suggests that mild hypothermia applied in the hours following injury could significantly improve neurological outcome. Three feasibility studies have used TH in combination with treatments aimed at achieving reperfusion through administration of clot-​dissolving drugs and/​or mechanical thrombectomy. Application of TH appeared feasible and safe, though one study reported a high rate of pneumonia in the intervention group. Several

Other Potential Indications Under the right circumstances, hypothermia can improve myocardial contractility (see Table 18.1) and has been used to treat cardiogenic shock. Several small case series have described the use of hypothermia to treat intracranial hypertension and hepatic encephalopathy in patients with acute liver failure. The appropriate target temperature and duration remain unclear, and, in most studies, TH was used as bridge to liver transplant. Some case series and case control studies have reported successful usage of hypothermia for adult respiratory distress syndrome, generalized seizures, and spinal cord injury. A larger study assessing TH for severe spinal cord injury is currently ongoing. The use of TH in all of these indications is still experimental, though fever control should be regarded as the standard of care.

Practical Aspects Temperature can be increased by conserving heat (mainly through vasoconstriction of arteries in the skin) and by generating heat (mainly through shivering). Under normal circumstances, vasoconstriction begins at a core temperature of around 36.5oC; the reduction in heat loss resulting from cutaneous vasoconstriction is ±25%. The effectiveness of heat conservation and heat generation decreases with age; this is due to a less effective vascular response, decreased ability to detect small temperature changes (leading to

Hypothermia and Fever Control

Hypothermia may help in control of intracranial pressure and with efforts to reduce brain edema in patients with TBI. Trials of hypothermia in this patient population have many significant limitations, including heterogeneous patient populations, variable triggers to initiate therapy, and differences in the duration of treatment. Several studies using TH in early management after TBI have reported improved outcomes, while one larger RCT found that there was no difference in outcomes between strict fever control compared to TH. A recent trial using TH to treat refractory ICP elevations in later stages of TBI reported significantly worse outcome in the TH group. Based on these conflicting results, strict fever control should be the goal in patients with severe TBI, while TH should be used only in the context of clinical trials.

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other trials with limited numbers of patients have studied TH as a treatment for brain edema after large middle cerebral artery (MCA) strokes. Outcomes were better compared to historical controls; however, use of TH for this indication has largely been replaced by surgical decompression for malignant MCA infarctions. The use of TH for a limited period of time in combination with reperfusion treatment appears to be a promising approach, but no large RCT addressing this issue has so far been performed. Strict fever management after AIS should be a goal of care, with the use of TH limited to clinical trials.

Interventions and Monitoring Section 2

Table 18.1  Effects of Mild Hypothermia (32o–​34oC) on Key Physiological Parameters Cardiovascular • Decreases heart rate (unless there is a stress-​mediated and hemodynamic

tachycardia related to shivering or discomfort). Hypothermia-​ induced bradycardia does not require treatment in most circumstances. • Decreases cardiac output • Increases central venous pressure • Increases myocardial contractility unless the patient develops tachycardia • Increases membrane stability; care should be taken to keep core temperature ≥30oC

Electrolytes & metabolism

• Electrolyte disorders can develop in the induction phase of cooling and require frequent monitoring

• Decreases insulin sensitivity and reduces insulin secretion;

of note, insulin requirements are likely to decrease during rewarming • Increased synthesis of glycerol, free fatty acids, ketonic acids, and lactate producing a mild metabolic acidosis • Decreases metabolic rate by 7–​10% per degree C Ventilation

• Decreases O2 consumption and CO2 production, thus requires

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ventilator adjustments and frequent monitoring of blood gases

• Blood gas values are temperature dependent; lab analysis of

PaO2, PaCO2, and mixed venous or venous saturation should be performed at the patients actual core temperature, or corrected for temperature • Temperature corrections:   • for PaO2, subtract 5 mmHg for every 1oC below 37oC   • for PaO2, subtract 2 mmHg for every 1oC below 37oC   • for pH, add 0.012 points for every 1oC below 37oC. Infections

• Impairs immune function and inhibits inflammatory responses   • Assessment for infection should include cooling system workload (i.e., the energy expenditure of the cooling device to maintain target temperature) • May increase risk of wound infections, delayed healing, and skin breakdown

Coagulation

• Induces a mild bleeding diathesis due to effects on platelet

count, platelet function, the kinetics of clotting enzymes, and plasminogen activator inhibitors   • Coagulation tests need to be performed at patients’ actual core temperature Drug clearance

• Significantly increases the half-​life of many drugs, particularly

those metabolized by the liver; this includes benzodiazepines, propofol, fentanyl and morphine. • Increases drug levels and/​or enhances effect of medications

Table 18.2  Examples of Antishivering Measures and Drug Regimens Potential antishivering measures Skin counterwarming is highly effective in most patients and can significantly reduce the dose of antishivering drugs (including sedation) required to manage shivering Commonly used antishivering drug regimens Magnesium bolus 4–​8 g over 10–​30 minutes, magnesium drip 0.5–​1 gram per hour; target serum levels up to 1.2–2 mmol/​l (3–5 mg/​dl) Buspirone 15–​30 mg Q8 hr by mouth Ondansetron 8 mg bolus (once) Meperidine bolus 12.5–​50 mg; some studies have used meperidine drips of 0.5–​1.0 mg/​kg Fentanyl bolus 12.5–​50 µg, drip 50–​200 µg/​hr Dexmedetomidine 0.5–​1 µg/​kg loading dose, 0.2–​1.0 µg/​kg/​hr maintenance dose Addition of acetaminophen (paracetamol) and/​or (in selected patients) NSAIDs can help reduce temperature (usually by around 0.3o in central fever and 0.7oC in infectious fever) NSAID = nonsteroidal anti-​inflammatory drugs.

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a slower counterregulatory response), and a lower basal metabolic rate. This means that, in general, fever control and induction of hypothermia are easier to achieve and maintain in older patients than in younger ones. Heat generation through shivering is usually much more active, and therefore more effective, at temperatures close to the normal range than at temperatures that are several degrees below normal. In patients with a normal hypothalamic setpoint, the shivering threshold is ±1oC below the vasoconstriction threshold, so ±35.5oC. The shivering response peaks at core temperatures around 35oC and decreases significantly at temperatures below 33.5o to 34oC; in most patients shivering ceases completely at core temperatures around 31oC, though there is a wide variability between patients and even within the same patient based on the hypothalamic setpoint (see later discussion). Shivering can cause multiple problems in patient management. Sustained shivering can double the metabolic rate, thereby preventing effective temperature management. In addition, it increases oxygen consumption (by 40%–​ 100%), the work of breathing, and heart rate; it induces a stress-​like response with tachycardia, hypertension, and elevated intracranial pressure; and it has been linked to increased risk of morbid cardiac events and adverse outcome in the perioperative setting. Therefore, shivering should be aggressively and pre-​emptively controlled, and shivering management should be an integral part of the temperature management strategy. Some common antishivering measures and drug regimens are listed in Table 18.2. As explained earlier, shivering will generally be most active at temperatures around 2oC below the hypothalamic setpoint (1oC below the skin vasoconstriction threshold). Febrile

Interventions and Monitoring Section 2

192

Table 18.3  Most Frequently Occurring Hypothermia-Induced Changes in Laboratory Measurements Increase in serum amylase levels Mild-​to-​moderate thrombocytopenia (platelet count 30–​100 × 1012) Increase in serum lactate levels (2.5–​5 mmol/​l) Hyperglycemia (risk of hypoglycemia during rewarming when insulin requirements decrease) Electrolyte disorders (low Mg, K, P, Ca) Increase in liver enzymes (SGOT and SGPT) Mild metabolic acidosis Mild coagulopathy Changes in blood gasses

patients with acute brain injury are likely to have an elevated hypothalamic setpoint, so shivering will occur at significantly higher temperatures. Another important parameter affecting the ease and speed of cooling is body mass; obese patients are more difficult to cool, especially with surface cooling, due to insulating properties of adipose tissue and because of the greater mass that needs to be cooled. Finally, an issue that often confounds studies dealing with temperature management is that severe brain injury can significantly diminish or even obviate the thermoregulatory response; it is therefore much easier to cool patients with very severe brain injury (and absent shivering response) than those with less severe injury. Thus “easy” temperature control is, paradoxically, often a poor prognostic sign, whereas increased workload of cooling devices predicts better neurologic outcome. The most important physiological changes associated with induction of hypothermia and some management strategies are listed in Table 18.1. Associated changes seen in laboratory values are listed in Table 18.3. Temperature elevations have the opposite effects.

Cooling Methods Cooling technologies can be broadly divided into invasive (core cooling) and noninvasive (surface cooling) methods. The theoretical advantages of invasive cooling over surface cooling are 1. Some studies suggest greater speed of hypothermia/​normothermia induction when core cooling is used; however, it is unclear whether more rapid induction improves outcome. 2. Possibly, invasive cooling has fewer and smaller temperature fluctuations in the maintenance phase. 3. Some types of endovascular catheter allow continuous central (blood) temperature measurement. 4. There is no risk of surface cooling-​induced skin lesions.

The available data on safety and efficacy of different cooling technologies is limited. Most published studies are small and evaluate only a single cooling device or method; comparative studies have often been retrospective or nonrandomized and/​or have enrolled only small numbers of patients. Some studies have suggested that invasive cooling may have more rapid and effective temperature control and may help reduce nursing workload; in addition, these studies all reported nonsignificant trends toward more favorable outcome with more accurate temperature control.

Summary In summary, temperature is a key physiological parameter in critically ill patients. It should be regarded in the same way (and controlling it granted the same importance) as blood pressure, heart rate, and ventilation parameters. As with these other parameters, usually normal values are good, particularly if the patient has acute brain injury, and as a general rule fever should be avoided, which is easier said than done as the vast majority of these patients will develop fever as a direct and indirect consequence of their neurologic injury. The availability of effective mechanical cooling devices has allowed improved and more accurate temperature control, and preliminary data suggests that this can lead to further improvements in outcome.

Further Reading Andrews PJ, Sinclair HL, Rodriguez A, Harris BA, Battison CG, Rhodes JK, Murray GD, Eurotherm3235 Trial Collaborators. Hypothermia for intracranial hypertension after traumatic brain injury. N Engl J Med. 2015;373:2403–​2412.

Hypothermia and Fever Control

1. It is easy to use and can be applied by nurses or nurse practitioners without intervention by a physician. 2. No invasive procedure is required. 3. There is no delay in the initiation of cooling. 4. Compared to endovascular cooling, there is no risk of catheter-​induced thrombus formation. 5. It can be easily applied outside the ICU setting.

Chapter 18

The theoretical advantages of surface cooling over invasive cooling are

193

5. The patient is easily accessible (i.e., no need to cover large areas of the skin to achieve cooling). 6. Less medication may be needed to control shivering because there is more effective shivering suppression with skin counterwarming (i.e., the entire surface area can be warmed using warm air, leading to a significantly diminished shivering response). In a related issue, there may be better tolerance/​less shivering with endovascular cooling when TH is used in awake, nonintubated patients.

Interventions and Monitoring Section 2

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Auer RN. Non-​pharmacologic (physiologic) neuroprotection in the treatment of brain ischemia. Ann N Y Acad Sci. 2001;939:271–​282. Azzopardi D, Strohm B, Marlow N, et al. TOBY Study Group. Effects of hypothermia for perinatal asphyxia on childhood outcomes. N Engl J Med. 2014;371:140–​149. Badjatia N, Fernandez L, Schmidt JM, et al. Impact of induced normothermia on outcome after subarachnoid hemorrhage:  a case-​ control study. Neurosurgery. 2010;66:696–​700 Bernard SA, Gray TW, Buist MD, et al.Treatment of comatose survivors of out-​of-​ hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346:557–​563. Crossley S, Reid J, McLatchie R, et al. A systematic review of therapeutic hypothermia for adult patients following traumatic brain injury. Crit Care. 2014;18:R75. Deye N, Cariou A, Girardie P, et al. Endovascular versus external targeted temperature management for out-​of-​hospital cardiac arrest patients: a randomized controlled study. Circulation. 2015;132:182–​193. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346:549–​556. Karvellas CJ, Todd Stravitz R, Battenhouse H, Lee WM, Schilsky ML, US Acute Liver Failure Study Group. Therapeutic hypothermia in acute liver failure:  a multicenter retrospective cohort analysis. Liver Transpl. 2015;21:4–​12. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013;369:2197–​2206. Piironen K, Tiainen M, Mustanoja S, et al. Mild hypothermia after intravenous thrombolysis in patients with acute stroke: a randomized controlled trial. Stroke. 2014;45:486–​491. Polderman KH. Induced hypothermia and fever control for prevention and treatment of neurological injuries. Lancet. 2008;371:1955–​1969. Polderman KH. Mechanisms of action, physiological effects, and complications of hypothermia. Crit Care Med. 2009;37:S186–​202. Polderman KH, Herold I. Therapeutic hypothermia and controlled normothermia in the intensive care unit: practical considerations, side effects, and cooling methods. Crit Care Med. 2009;37:1101–​1120.

Chapter 19

Neuropharmacotherapy Gretchen M. Brophy and Theresa Human

Medications used in the treatment of neurocritical care patients need to be monitored closely and adjusted based on individual patient characteristics. Pharmacokinetics (PK; the effects of the body on the drugs) and pharmacodynamics (PD; the effects of drugs on the body) are not always predictable due to changes in physiologic parameters in critically ill patients, age, and drug-​ drug interactions. This chapter includes information on the PK/​PD and drug interactions of select medications. Physiologic changes that can impact medication PK in critically ill patients as well as the older adult patient are listed in Table 19.1. These changes can alter medication concentrations, which will also impact the medication’s duration of action, efficacy, and toxicity.

Hyperosmolar Pharmacotherapy for Intracranial Pressure Management Mannitol and hypertonic saline (HS) are commonly used in neurologically injured patients in the acute setting to treat elevated intracranial pressure (ICP) and cerebral edema. HS is also used in the treatment of hyponatremia. Both agents theoretically work by producing osmotically driven fluid shifts and appear to be equally effective at equal osmolar doses. Patient characteristics to consider when choosing agent of choice: • Serum sodium concentrations • Serum osmolality • Osmolar gap • Fluid status • Renal function

Mannitol Dose: • 0.5–​1 gm/​kg over 5–​15 minutes • Can redose every 4–​6 hours • Duration of effect 90 minutes to 6 hours

195

Neuropharmacotherapy Considerations

PK Parameter

Changes in Older Adults

Changes in Critical Illness

Absorption

­ Gastric pH ↓ ↑ Gastric motility ↓ Absorptive surface ↓ Splanchnic blood flow

­ Gastric pH ↓ ↑ Gastric motility ↓ Perfusion Enteral nutrition Exocrine pancreatic dysfunction

Distribution

↓ CO ↓ Total body water ↓ Lean body mass ↓ Serum albumin ↑­ Alpha-​1 acid glycoprotein ↓Body fat, but ↑ % of total body weight

Metabolism

↓ Hepatic mass ↓ Enzyme activity (primarily phase I [oxidative pathways]) ↓ Hepatic blood flow

↓CO ↑ Total body weight and total body water (fluid accumulation/​ volume overload) ↓ Lean body mass ↓Serum albumin ­↑Alpha-​1acid glycoprotein ­↓↑ Plasma pH ↓ Enzyme activity(phase I reactions are more profound than phase II conjugative metabolism)­ ↑↓ Hepatic blood flow (early vs. late effects based on disease state, iatrogenic vaso­ constriction)

196

Section 2

Interventions and Monitoring

Table 19.1  Potential Physiologic Changes that can Impact PK Characteristics in Critically Ill and Older Adult Patients Potential Combined Effect in Critically Ill Older Patients ­↑↓ Drug absorption with GI changes (pKa of drug) ↓ Drug and nutrient absorption with decreased perfusion ↓ Bioavailability of oral drugs Third spacing and Vd alterations Significant changes in unbound fraction of drugs—​ changes in effect and rate of elimination

Medications Impacteda

Reduced first-​pass metabolism Reduced effect of CYP2D6 prodrug substrates Decreased clearance of high-​ extraction drugs

Codeine, oxycodone, hydrocodone, tramadol, clopidogrel, dabigatran, tamoxifen, lidocaine, verapamil, propranolol, midazolam, labetalol, promethazine

Itraconazole, ketoconazole, sulfonamides, dapsone, acetaminophen, dabigatran

Aminoglycosides, β-​lactams, daptomycin, phenytoin

Changes in Older Adults

Changes in Critical Illness

Excretion

↓ Renal blood flow ↓ GFR ↓ Tubular secretion ↓ Renal mass ↓ Ventilatory capacity

↓ GFR RRT ↓ Ventilatory capacity

Potential Combined Effect in Critically Ill Older Patients ↓ Drug elimination and increased risk of toxicity ↓ Elimination of inhaled anesthetic agents

Medications Impacteda

Isoflurane, desflurane, sevoflurane, H2RAs, enoxaparin, antibiotics, anticonvulsants, fluoroquinolones

Neuropharmacotherapy

PK Parameter

Chapter 19

Table 19.1 Continued

PK = pharmacokinetics; GI = gastrointestinal; GFR = glomerular filtration rate; RRT = renal replacement therapy. a

Not all-​inclusive.

Use with caution in these situations: • Renal failure (acute or chronic)—​may cause drug accumulation • Dehydration/​hypovolemia—​may worsen • Mannitol causes wide fluid shifts by causing rapid fluid expansion followed by diuresis. Use cautiously in volume-​sensitive patients and possibly consider a fluid bolus (500–​1000 ml 0.9% NaCl) postdose • Osmolar gaps >15–​20 mOsm/​kg or rapid increase or increasing trajectory between calculations Monitoring: • Osmotic gap = measured osmolality—​calculated osmolality • Calculated osmolality: [(2 × Na) + (BUN/​2.8) + (glucose/​18)] • Osmolar gap is the most accurate monitoring tool to detect presence of unmeasured osmoles, such as mannitol • It is useful in assessing the clearance of mannitol between doses • Osmolar gap of greater than 15–​20 mOsm/​kg indicates incomplete clearance between doses • High osmolar gaps correlate with increased risk of reverse osmotic shift and nephrotoxicity • Osmolality >320 mOsm/​kg is not a contraindication for continued mannitol administration

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Adapted from “Critical Illness and the Aging Population: Clinical Implications and Pharmacotherapy Challenges.”

Interventions and Monitoring Section 2

• Laboratories • Serum osmolality, BMP necessary to calculate osmolar gap (see previous calculation); drawn as a trough or prior to the mannitol dose • Na, K, Mg, Phosphorus—​monitored to prevent/​treat imbalances due to excessive diuresis • Urine output should be evaluated to prevent hypotension and dehydration due to excessive diuresis Adverse effects: • Rebound ICP elevation (with high, repeated dosing) • Acute kidney injury • Dehydration • Hypotension • Electrolyte imbalances Administration pearls: • Requires in-​line filter (precipitates causing crystal formation); may re-

quire warming to dissolve crystals prior to administration

198

• May be given via peripheral intravenous access

Hypertonic Saline Dose (concentrations listed are approximately equal osmolar to mannitol 1g/​kg): • • • • •

3% NaCl: 5 mL/​kg over 5–​20 minutes (range 2.5–​5 mL/​kg) 5% NaCl: 3 ml/​kg over 5–​20 minutes (range 2.5–​5 mL/​kg) 7.5% NaCl: 2 ml/​kg over 5–​20 minutes (range 1.5–​2.5 ml/​kg) 23.4% NaCl: 30 ml over 10–​20 minutes (range 0.3–​0.7 ml/​kg) Duration of effect 90 minutes to 4 hours Other dosing option:

• Continuous infusion titrated to a goal-​sodium range • Controversy exists regarding the benefit of a continuous infusion for ICP control Use with caution in these situations: • Serum sodium >160 mEq/​L or rapidly rising serum sodium • Serum sodium 160 meq/​L • Cl-​, CO2; HS can induce hyperchloremic acidosis when used repeatedly; consider decreasing chloride content and replacing with sodium acetate

Administration pearls: • Central access required for 23.4% NaCl bolus and should be consid-

ered for bolus doses of >2% NaCl in nonemergent situations

Treatment Strategies for Status Epilepticus and Refractory Status Epilepticus Treatment of status epilepticus (SE) should be initiated and escalated rapidly until seizure activity is controlled both clinically and electrographically. Anticonvulsants should be monitored closely for efficacy and toxicity, especially when administering first-​generation anticonvulsants that have narrow therapeutic concentration targets. Pharmacotherapy pearls for medications used for emergent, urgent, and refractory SE treatment can be found in Tables 19.2, 19.3 and 19.4. Table 19.2  Emergent Control Treatment Options Drug Name Diazepam (Valium®)

Lorazepam (Ativan®)

Midazolam (Versed®)

Dose/​Rate 0.15 mg/​kg IV (up to 10 mg per dose); may repeat in 5 min Rate: 5 mg/​min 0.1 mg/​kg IV (up to 4 mg per dose); repeat in 5–​10 min Rate: 2 mg/​min 0.2 mg/​kg IM up to 10 mg per dose

Adverse Effects Hypotension, respiratory depression

Clinical Pearls Rapid redistribution rate; can be given rectally; contains propylene glycol May be longer-​acting for seizure cessation than diazepam; contains propylene glycol Can also be given buccally or intranasally

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• If a continuous infusion is given, central access required for >2% NaCl

Interventions and Monitoring

Drug Name Phenytoin (Dilantin®)

Dose/​Rate Load: 20 mg/​kg Maintenance dose: 4–​6 mg/​kg/​ day divided in 2–​3 doses Max rate: 50 mg/​min

Fosphenytoin (Cerebryx®)

Load: 20 mg PE/​kg Maintenance dose: 4–​6 mg/​kg/​ day divided into 2–​3 doses Max rate: 150 mg PE/​min

Phenobarbital

Load: 20 mg/​kg Maintenance dose: 1–​3 mg/​kg/​ day divided into 1–​3 doses Rate: 50–​100 mg/​ min

Valproate sodium (Depacon®)

Load: 20–​40 mg/​ kg IV Maintenance dose: 10–​15 mg/​ kg/​day divided into 2–​4 doses Rate: 3–​6 mg/​kg/​ min

Levetiracetam (Keppra®)

1000–​3000 mg/​day in 2 divided doses Rate: over 15 min

Lacosamide (Vimpat®)

200–​400 mg IV every 12 hrs Rate: over 15 min

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Section 2

Table 19.3  Anticonvulsants for Urgent Control of SE Adverse Effects Arrhythmias, hypotension, bradycardia

Clinical Pearls Hypotension, esp in older adults; STRONG CYP inducer with many potential drug interactions; total serum level 10–​20 mcg/​ml; free level 1–​2 mcg/​ml; levels may be attained 1 hr after infusion Paresthesias, Prodrug—​converts hypotension, to phenytoin 7-​15 bradycardia min after infusion; less thrombophlebitis than phenytoin; same drug interactions, monitoring, and drug level goals as phenytoin Hypotension, Long-​acting; contains sedation, propylene glycol; respiratory STRONG CYP depression enzyme inducer with many potential drug interactions Serum level goal: 15–​40 mcg/​ml Hepatotoxicity, Fewer CV side effects pancreatitis, than phenytoin; CYP thrombocytopenia, enzyme inhibitor hyperammonemic with many potential encephalopathy drug interactions; meropenem will significantly reduce VPA levels and should not be used with VPA; caution use with pre-​ existing pancreatitis, mitochondrial, hepatic, or bleeding disorders Serum level goal: 50–​ 150 mcg/​ml Dizziness, behavior Reduce dose CrCl disturbances 500 ml, use of a prokinetic agent, such as metoclopramide or erythromycin, may help. If not, switching to postpyloric feeding would be the next step. If the patient is not going to be able to tolerate sufficient oral feeding for several weeks, there may be a role for placement of an endoscopic or operative feeding tube.

Patients who require mechanical ventilation for more than 48 hours or are coagulopathic are at high risk for developing stress ulcerations that can lead to clinically significant hemorrhage. Debate continues as to whether a histamine2 (H2) blocker or a proton pump inhibitor (PPI) is the better option for prophylaxis in terms of efficacy and/​or cost. With increased gastric pH by either agent, there is an increased risk for health care–​associated pneumonia or development of Clostridium difficile colitis. Either agent is currently appropriate. Also, gastric feeding alone may confer some level of benefit, but it is not clear that this benefit is equivalent to that provided by either an H2-​blocker or PPI.

Further Reading Dellinger RP, Levy MM, Rhodes A, et  al. Surviving sepsis campaign:  international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41580–​637. Holcomb JB, Tilley BC, Baraniuk S, et al. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma. The PROPPR randomized clinical trial. JAMA. 2015;313(5):471–​482. Kacmarek RM, Villar J, Sulemanji D, et  al. Open lung approach for the acute respiratory distress syndrome:  a pilot, randomized controlled trial. Crit Care Med. 2016;44:32–​42. Levitov A, Frankel HL, Blaivis M, et al. Guidelines for the appropriate use of bedside general and cardiac ultrasonography in the evaluation of critically ill patients—​part II: cardiac ultrasonography. Crit Care Med. 2016;44:1206–​1227. Rhodes A, Evans LE, Alhazzani W, et  al. Surviving Sepsis Campaign:  international guidelines for management of sepsis and septic shock:  2016. Crit Care Med. 2017;45:486–​552. Taylor BE, McClave SA, Martindale RG, et al: Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (ASPEN). Crit Care Med. 2016;44:390–​438.

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Stress Ulcer Prophylaxis

Chapter 21

Managing the Postoperative Neurosurgical Patient Daniel Ripepi and Colleen Moran

224

Introduction Managing the postoperative neurosurgical patient involves timely recognition and management of specific issues that arise in the immediate postoperative period. The likelihood that a specific complication will arise for a given patient is influenced by the nature of the procedure, the anesthetic techniques used, and the patient’s preoperative comorbidities. The risk of some complications can be reduced with appropriate preoperative assessment and medical optimization. The management and treatment of postoperative complications is equally important, and often management techniques used are unique among neurosurgical patients. Management strategies along with rationale for these postoperative concerns will all be discussed.

Postoperative Nausea and Vomiting Postoperative nausea and vomiting (PONV) is one of the most common complications of general anesthesia. Many studies have shown that there are certain groups of patients whom are particularly at risk for PONV. Studies comparing surgery types have shown patients undergoing thoracic, integumentary, musculoskeletal, and superficial surgeries have significantly less requirement for PONV treatment postoperatively when compared to patients undergoing neurological, head or neck, and abdominal surgeries. Breast, axilla, and endoscopic procedures had similar high rates of requiring PONV treatment. Other studies have shown that a 10-​year increase in age decreased the likelihood of PONV by 13%, the risk for men was one-​third that for women, a 30-​minute increase in the duration of anesthesia increased the likelihood of PONV by 59%, general anesthesia increased the likelihood of PONV 11 times compared with other types of anesthesia, and patients with plastic and orthopedic shoulder surgery had a six-​fold increase in the risk for PONV. In summary, the factors that increase likelihood of PONV include female, nonsmoker, history of PONV or motion sickness, anesthesia type, use of nitrous oxide, anesthesia duration, intraoperative and postoperative opioid

Table 21.1  Medications for Treating Postoperative Nausea and Vomiting Drug Class

Common Example

Mode of Action

Serotonin Receptor Antagonist Glucocorticoids

Ondansetron

5HT-​3 Antagonism

Preventive or Rescue Both

Comments

Contraindications

Dexamethasone

Unknown

Preventive

Anticholinergic

Scopolamine

Unknown

Preventive

Nonsedating, may cause QT QT prolongation prolongation May affect wound healing and glucose control Sedating Narrow angle glaucoma

Neurokinin Receptor Antagonist

Aprepitant

Preventive

Expensive

Phenothiazine

Prochlorperazine

Block neurokinin’s effect (proemetic agent) at receptor site Dopamine receptor antagonist

Rescue

Phenothiazine

Promethazine

Antihistamine

Rescue

Side effects: acute dystonic reactions, pseudoparkinsonism, neuroleptic malignant syndrome (at high doses) Sedating

Bone marrow depression, blood dyscrasias, Parkinson disease, severe liver or cardiovascular disease

General Management Section 3

administration, and certain surgeries including neurological, head or neck, abdominal, breast, axilla, and endoscopic procedures. PONV can be treated prophylactically preoperatively and intraoperatively as well as with rescue therapy postoperatively if the patient develops symptoms. Prophylactic PONV treatments including ondansetron, dexamethasone, and droperidol each reduce the risk of postoperative nausea and vomiting by about 26%. Propofol and nitrogen (total intravenous [IV] anesthetic) were similar to that observed with each of these antiemetics. All the interventions act one another and the patient’s baseline risk. New medications for the prevention of PONV include neurokinin receptor antagonists such as aprepitant, which is an oral medication taken preoperatively. See Table 21.1 for examples of PONV treatments.

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Airway Management in the Postoperative Neurosurgical Patient Airway and pulmonary management of the patient with neurological disease contain an array of challenges, whose composition varies with the pathology at hand. The managing physician should be familiar with the patient’s neu­rological and cerebrovascular pathophysiology and the implications for management of his or her airway and respiratory status. Extubation of the neurological patient also demands consideration of airway patency as well as respiratory mechanics. It is the goal of many neurosurgical procedures for the anesthesia team to reverse the anesthetic agents and extubate the patient at the end of the procedure. This is because the diagnosis of complications relies on rapid neurological examination after early awakening, and an awake patient is the easiest way to obtain a neurologic exam. An early diagnosis of postoperative neurological complications can limit potentially devastating consequences. Many neurosurgical patients have ventilation impairment. Elevated PaCO2 or reduced PaO2 will increase cerebral blood flow or cerebral blood volume, which can lead to a rise in intracranial pressure (ICP). ICP will also be a function of cranial vault compliance and any intracranial mass effect secondary to the neurologic disease. Managing the airway postoperatively is of utmost importance in neurosurgical patient. If the patient is not intubated, assessment of the airway and review of previous intubation notes will be the starting point for airway management. Particular attention should be paid to examination of the oropharynx, teeth, mouth opening, and tongue, and it should be noted that the airway exam postoperatively can be significantly different compared to the preoperative assessment secondary to swelling of tongue, lips, and pharyngeal soft tissue, as well as neuromuscular tone. Care should be taken to assess the patient for respiratory distress or airway obstruction in the postoperative period. All patients should have standard

Box 21.1  Indications for Intubation for the Neurological Patient

Immediate (life-​threatening hypoxia likely) Persistent apnea Persistent airway obstruction despite airway insertion Inability to bag/​mask ventilate

Urgent Glasgow Coma Scale 5th percentile for age. 9. Reliability of any one variable for prognostication in children after cardiac arrest has not been established. Practitioners should consider multiple factors when predicting outcomes in infants and children who achieve ROSC. Consider the following: 1. Use of ICP monitoring in infants and children with severe TBI (GCS ≤8). 2. CSF drainage through an EVD in management of elevated ICP. 3. Treatment of ICP at a threshold of 20 mm Hg. 4. A CPP threshold of 40–​50 mm Hg. There may be age-​specific thresholds with infants at the lower end and adolescents at the upper end of this range. 5. If PbtO2 monitoring is performed, maintenance of PbtO2 ≥25 mm Hg. 6. Hypertonic saline for severe TBI with elevated ICP. Effective bolus dose is 6.5–​10 mL/​kg. Used as an infusion, effective dose range between 0.1 and 1 mL/​kg/​hr. Minimum dose to maintain ICP 100,000, international normalized ratio (INR) 100 mm Hg; hypotension is common from both loss of peripheral vascular tone and hypovolemia secondary to diabetes insipidus. Vasopressors and/​ or volume replacement may be necessary. c. Absence of severe electrolyte, acid base, or endocrine disturbances. Evaluate for acidosis, hyperammonemia, or other markedly deviated laboratory values. Specific values have not been defined, and it is left to

1981

1995

2010

NIH-sponsored multicenter U.S. Collaborate Study of Cerebral Death seeks prospective neurologic factors to predict cardiac arrest The President’s Commission publishes guidelines to define death on the basis of expert medical, legal, religious testimony The American Association of Neurology (AAN) publishes evidence-based practice parameters

Led adoption of the national, Uniform Determination of Death Act (UDDA), which states “An individual who has sustained either (1) irreversible cessation of circulatory and respiratory functions, or (2) irreversible cessation of all functions of the entire brain, including the brain stem, is dead. A determination of death must be made in accordance with accepted medical standards”

The AAN updates brain death guidelines to separate evidence- and opinion-based data

Figure 26.1  A history of brain death determination.

the clinician’s judgment as to whether the abnormality could be sufficient to influence the clinical examination. d. Absence of drug intoxication, poisoning, sedatives, or neuromuscular blocking agents. If available, plasma drug levels should be in the therapeutic range or below; otherwise, use a combination of history, drug screen, and clearance calculation using 5 times the drug’s half-​life, assuming normal hepatic and renal function (see Table 26.1). Exercise caution, as up to 4-​fold differences in cerebral effects for a given blood concentration have been reported in critically ill patients. Also note that therapeutic hypothermia will delay drug metabolism.

Brain Death and Organ Donation

1977

• Unreceptivity and unresponsivity • No movements or breathing • No reflexes • Flat electroencephalogram (EEG) • All tests must be repeated in 24h with no change • Exclusion of hypothermia (200 mm Hg. • Establish normocapnea. • Reduce positive end expiratory pressure to 5 cm H2O (desaturation with this maneuver may signal difficulty performing the apnea test). • Uncover the chest and abdomen to aid in observation for respiratory movements. • Disconnect the patient from the ventilator—​modern ventilators are sensitive and can autocycle, confounding the test. • Preserve oxygenation by providing oxygen (flow rate of 4–​6 liters/​min) to the level of the carina via a flow catheter through the endotracheal tube. Higher flow rates may wash out CO2, making it more difficult to attain the requisite values, or may cause barotrauma. In patients who cannot tolerate being off of the ventilator, a trial using a T piece with 100% oxygen flow, or the continuous positive airway pressure setting may be used. • Observe for respiratory movements and hemodynamic stability for at least 10 minutes. • Abort if the SBP falls to